Tumor Pathology Atlas

Tumor
Diagnosis
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seCOnD edition
Tumor
Diagnosis
Practical approach
and pattern analysis
Awatif I Al-Nafussi MBChB DPhil(Oxford) FRCPath
Senior Lecturer/Honorary Consultant, Department of Pathology,
The Royal Infirmary of Edinburgh, Edinburgh, UK
Hodder Arnold
A member of the Hodder Headline Group
LONDON
First published in Great Britain in 1997
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I dedicate this book to the loving memory of my father, who devoted his life to the
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contents
List of contributors ix
Acknowledgments xi
General introduction xiii
PART I: HISTOLOGICAL PATTERNS 1
1 Common histological patterns and cell types of tumors 3
PART II: SYSTEM/ORGAN CHAPTERS IN ALPHABETICAL ORDER 63
2 Bone tumors Awatif I Al-Nafussi and David Hughes 65

3 Brain tumors Colin OC Smith 97
4 Breast tumors Awatif I Al-Nafussi, Lee B Jordan and Jeremy St J Thomas 131
5 Digestive system tumors 197
5.1 Gastrointestinal tract tumors David K Worrall and Hassan MH Kamel 197
Tumors of the esophagus 199
Tumors of the stomach 207
Tumors of the duodenum, jejunum, and ileum 219
Tumors of the appendix 226
Tumors of the colon and rectum 229
Tumors of the anal canal 238
5.2 Hepatobiliary tract tumors Christopher OC Bellamy 242

Intrahepatic tumors 243
Tumors of the gallbladder and extrahepatic bile duct 265
5.3 Pancreatic tumors David K Worrall and Hassan MH Kamel 267

Tumors of the endocrine pancreas 268
Tumors of the exocrine pancreas 273
6 Endocrine tumors Catriona Anderson and Kathryn M McLaren 333

Tumors of the adrenal glands 333
Tumors of the parathyroid glands 341
Tumors of the thyroid glands 344
7 Female genital tract tumors Awatif I Al-Nafussi 365

Tumors of the vulva 368
Tumors of the vagina 382
Tumors of the uterine cervix 388
Tumors of the uterine corpus 412
Tumors of the ovary 457
Tumors of the Fallopian tube 516
Tumors of the peritoneum 517
8 Head and neck tumors Kathryn M McLaren and Awatif I Al-Nafussi 569
Tumors of the ear 570
Tumors of the nasopharynx 572
viii Contents
Tumors of the oral cavity 576

Tumors of the jaw 579
Tumors of the salivary glands 592
9 Lung and pleural tumors William AH Wallace 629

Lung tumors 629
Pleural tumors 642
10 Lymphoreticular system tumors 651

10.1 Bone marrow tumors Jeremy St J Thomas 651
10.2 Lymph node and related lymphoid tissue tumors Lee B Jordan, Awatif I Al-Nafussi and 667
Kathryn M McLaren
Atypical lymphoid disorders 670
Histiocytic and dendritic cell tumors 675
Leukemia and related conditions 680
Hodgkin lymphoma 682
Non-Hodgkin lymphoma: B-cell neoplasia 692
Non-Hodgkin lymphoma: T-cell and NK-cell neoplasia 714
Mastocytosis 730
Mesenchymal tumors of lymph nodes 731
Miscellaneous tumors of lymph nodes 735
10.3 Tumors of the spleen Bridget S Wilkins 738

10.4 Tumors of the thymus Awatif I Al-Nafussi 743
11 Male genital tract tumors Awatif I Al-Nafussi, Catriona Anderson and Kenneth M Grigor 787
Tumors of the prostate 788
Tumors of the urethra 804
Tumors of the testis 805
Tumors of the paratesticular region 819
12 Skin tumors Awatif I Al-Nafussi and Kathryn M McLaren 835

13 Soft tissue tumors Awatif I Al-Nafussi 965
14 Urinary system tumors 1143
14.1 Tumors of the kidney Awatif I Al-Nafussi and Stewart Fleming 1143
Tumors of the ureter and renal pelvis 1165
14.2 Tumors of the urinary tract Awatif I Al-Nafussi, Catriona Anderson and Kenneth M Grigor 1166
15 Carcinomas Awatif I Al-Nafussi 1193
16 Techniques used in the diagnosis of tumors 1215
16.1 Immunochemistry in tumor pathology Saad Eissa 1215
16.2 Molecular techniques Saad Eissa and Sohair Shoman 1234
PART III: SYSTEM INDEX ACCORDING TO VARIOUS MICROSCOPIC PATTERNS AND

CELL TYPES OF TUMORS 1261
Index 1289
contributors
LEAD AUTHOR Hassan MH Kamel MBChB MSc PhD(Glasgow) FRCPath

Consultant Pathologist, Department of Pathology,
Awatif I Al-Nafussi MBChB DPhil(Oxford) FRCPath
The Royal Infirmary of Edinburgh, Edinburgh;
Senior Lecturer/Honorary Consultant,
Honorary Senior Lecturer,
Department of Pathology, The Royal Infirmary of
University of Edinburgh, UK
Edinburgh, Edinburgh, UK
CONTRIBUTORS Kathryn M McLaren BSc MBChB FRCPath FRCPE FRCSEd

Senior Lecturer/Honorary Consultant,
Cartiona Anderson BSc MBChB DRCOG Department of Pathology, The Royal Infirmary of
Specialist Registrar in Histopathology, Edinburgh, Edinburgh, UK
Department of Pathology, The Royal Infirmary
of Edinburgh, Edinburgh, UK Colin OC Smith MRCPath
Senior Lecturer in Pathology, Department of Pathology,
Christopher OC Bellamy MBBS PhD MRCPath University of Edinburgh, Western General Hospital,
Senior Lecturer in Histopathology, University Medical Edinburgh, UK
School, Edinburgh, UK
Jeremy St J Thomas MA MRCP(UK) FRCPath
Saad Eissa MD PhD
Consultant Pathologist, NHS Lothian,
Professor of Pathology, Department of Pathology,
Department of Pathology, Western General Hospital,
National Cancer Institute, Cairo University,
Edinburgh, UK
Cairo, Egypt
Stewart Fleming William AH Wallace BSc(Hons) MBChB(Hons) PhD MRCPath

Professor of Pathology, Department of Pathology, Consultant Pathologist, Department of Pathology,
Ninewells Hospital and Medical School, The Royal Infirmary of Edinburgh; and
Dundee, UK Honorary Senior Lecturer in Pathology,
Edinburgh University, Edinburgh, UK
Kenneth M Grigor
Department of Pathology, Bridget S Wilkins BSc MBBCh DM PhD FRCPath
Western General Hospital, Edinburgh, UK Consultant Histopathologist and
Honorary Senior Lecturer in Pathology,
David Hughes BMedSci PhD MBChB FRCPath Department of Cellular Pathology,
Department of Musculoskeletal Pathology, Royal Victoria Infirmary,
Robert Aitken Institute of Clinical Research, Medical Newcastle upon Tyne, UK
School, Birmingham University, Birmingham, UK
David K Worrall BMedSci PhD MBChB FRCPath
Lee B Jordan BSc(Hons) MBChB MRCPath Consultant Histopathologist, Sheffield Teaching
Consultant Pathologist, Department of Pathology, Hospitals NHS Foundation Trust, and
Ninewells Hospital and Medical School, Dundee, UK Honorary Senior Lecturer, University of Sheffield, UK
acknowledgments
I would like to thank all those who actively and willingly con- My great thanks and appreciation go especially to Mrs
tributed to chapter editing or authoring, some of whom were Helena Black for her endless secretarial support, her punctual-
invited at relatively late stages. My sincere appreciation also ity, and her light spirit on receiving any task given to her. My
goes to Dr T Anderson who read the chapter on breast tumors thanks also go to many of the trainees in our department who
and suggested some important changes. willingly read and proof-corrected some of the chapters.
Special gratitude to Dr T Gardner, our information technology I am also grateful to Dr D Salter for allowing me to choose
manager, whose expertise contributed enormously in handling from his bone collection when photographic evidence of bone
and enhancing the digital images that were taken on the Fieryfield tumors was required.
system. I would also like to thank Dr Ammar Ibraheem, for help The writing of this book would have not been successful
in taking many of the digital images, in particular for the chapters without the great facility that has been provided to me in the
relating to the head and neck, skin and gastrointestinal tract. I am Department of Pathology at the University of Edinburgh, and
also grateful to Dr Alistair Lessells and Dr Paul Fineron for the the constant encouragement of Professor D Harrison, Head of
use of some of their archived images. the Pathology Division.
general introduction
THE AIM OF THIS BOOK been expanded whenever possible to provide important points
The aim of this book is to aid pathologists in arriving at diag- when distinguishing one tumor from another. Special techniques
noses or differential diagnoses of tumors and tumor-like condi- are listed whenever appropriate. Within this Second edition, the
tions in day-to-day practice. Part II chapters relating to systems and organs have been
Traditionally, when confronted by a difficult or unfamiliar expanded considerably, and consequently many have been sub-
case, pathologists may have to search either general or special- divided into more than one section. For example, the chapter
ist reference texts for a ‘best-fit’ description. This problem may on the digestive system has been divided into three sections
be compounded in some cases by uncertainty of the precise tis- (gastrointestinal tract, hepatobiliary tract, and pancreas), that on
sue of origin (e.g. in mediastinal or retroperitoneal biopsies). the endocrine system into three (adrenal, parathyroid, and thy-
Although the majority of reference texts used by histopathologists roid), the female genital tract into seven (vulva, vagina, uterine
are organized according to anatomical location and underlying cervix, uterine corpus, ovary, Fallopian tube, and a new section
pathogenesis (i.e. inflammatory, neoplastic, etc.), histopatho- on the peritoneum), the head and neck into five (ear, nasophar-
logical diagnoses are made by interpretation of microscopic ynx, oral cavity, jaw, and salivary glands), the lymphoreticular
features that often can be categorized into particular patterns system into four (bone marrow, lymphomas, spleen, and thy-
or appearances. mus), the male genital tract into four (prostate, urethra, testis,
This book puts these fundamental issues into practice. The and paratesticular tissue), and the urinary system into two
approach is simple, and the book takes an appearance-orientated (kidney and urinary tract).
approach in addition to the usual system-orientated method. Chapter 13, on soft tissues, is by far the largest of the book
It thus attempts to mirror the diagnostic approach used by as it includes all soft tissue tumors that can be seen in the var-
the pathologist in practice – that is, an analysis of architectural ious systems. Each entity has therefore been covered exten-
and cytological features, special stains and other auxiliary tech- sively in this chapter but mentioned only briefly in text relating
niques in the context of knowledge of the clinical background to the specific anatomical site. Chapter 15, on carcinomas in
of the case. In this book, therefore, the microscopic patterns are general, has also been included.
the most important determinant factor in approaching the Finally, Chapter 16 has been added to include special tech-
correct diagnosis. niques in diagnostic tumor pathology, and is divided into two
Although disease exists as a spectrum, with many gray areas sections outlining immunohistochemical staining and molecular
of overlap, pathologists are required in practice to attempt to techniques, respectively.
place individual cases into diagnostic pigeon holes, particularly
in the case of tumors and tumor-like conditions, in order to HOW TO USE THIS BOOK
allow their clinical colleagues to make decisions about any sub-
The book is divided into three main parts:
sequent management of the patient. Here, for ease of practical
● Part I. Histological patterns. This section is aimed
use, diseases have been divided into diagnostic ‘entities’ as
principally at trainee pathologists who are not yet familiar
described in the histopathology literature.
with the various histological patterns and sub-patterns that
may be encountered in various tumors. It therefore lists
CHANGES IN THE SECOND EDITION 14 main broad histological patterns with their sub-patterns,
When compared with the First edition, this Second edition has each of which is defined and illustrated. Typical and
been changed in various aspects. Part I – histological patterns – common examples of tumors that exhibit these patterns
has been enhanced by increasing the number of colored illus- are also provided.
trations, and providing clearer descriptions of the histological ● Part II. System/organ chapters in alphabetical order.
patterns, with only typical examples of tumors that exhibit In this section, all tumors and tumor-like conditions of the
such appearances being given instead of all possible entities. various anatomical sites or systems are described.
The second part – system chapters – has benefited from the
contribution of several contributors who are specialized in their
fields. Moreover, it is also enhanced by categorizing tumors
The chapters are listed in alphabetical order, whilst the
under organ systems rather than listing them all together. Tumor
entities for each organ are grouped in histogenetic order
classification and staging whenever appropriate were included.
and also in alphabetical sequence.
The ‘differential diagnosis’ component within each entity has
xiv General introduction
Each entity is written in a standard format which often includes ● Part III. System index according to various microscopic
the following subsections: patterns and cell types of tumors. This section relates
1. The clinical features of the entity provide a brief summary principally to differential diagnosis, with all anatomical
of potentially relevant information on presentation and sites or systems being listed alphabetically. Under each
prognosis. system, further lists are provided of all possible
2. The pathological features describe all possible features that microscopic (and sometimes macroscopic) patterns of
can be seen in the tumor. tumors and tumor-like conditions. Within each pattern or
3. The secondary changes are included when relevant. sub-pattern, a list is provided of all possible tumors that
4. The cell morphology is detailed whenever necessary. are seen within that sub-pattern.
5. The differential diagnosis section provides a list of entities
This system is intended to provide a rapid tumor diagnosis when
with similar appearances with, on occasion, short com-
the only known factors are the histological pattern and the
ments on distinguishing features also being provided if
anatomical site. For example, if confronted with monomorphic
deemed necessary.
spindle cell tumor in the soft tissue, one would first look under
6. The special techniques section lists all relevant and practical
‘soft tissue’, then under ‘soft tissue tumors predominantly con-
methods used to confirm or rule out a diagnosis or possi-
sisting of spindle cells’, then glance at the various sub-patterns
ble differential diagnosis.
listed below this, and then choose ‘monomorphic sub-pattern’. In
7. A bibliography section, which includes a brief but
this way, a list of all monomorphic spindle cell tumors and tumor-
up-to-date bibliography for each entity has been compiled
like conditions that occur in the soft tissue would be identified.
at the end of each chapter.
PART I
histological patterns
1 COMMON HISTOLOGICAL
PATTERNS AND CELL TYPES
OF TUMORS
Glandular/pseudoglandular pattern 4 Diffuse monomorphic highly cellular spindle cell pattern

Ductal glandular pattern 4 (fibrosarcoma pattern) 30
Tubular pattern 5 Pleomorphic spindle cell pattern (malignant fibrous
Acinar/microacinar pattern 6 histiocytoma pattern) 31
Papillary and pseudopapillary pattern 6 Spindle and epithelioid cell pattern 32
Cribriform pattern 9 Spindle cell pattern with prominent sclerosis 32
Follicular pattern 9 Storiform and whorled pattern 32
Adenoid cystic pattern 10 Nodular fasciitis pattern 34
Canalicular pattern 11 Spindle cell pattern with significant inflammatory components 35
Endometrioid pattern 11 Spindle cell pattern with osteoclast-giant cells 37
Mucinous glandular pattern 11 Spindle cell populations with hemangiopericytomatous pattern 37
‘Signet ring’ glandular pattern 12
Spindle cell admixed with other mesenchymal components 38
Retiform pattern 12
Spindle cell lesions with signficiant fatty component 39
Adenomatoid pattern 13
Spindle cell lesions with significant myxoid component 39
Microcystic glandular pattern 13
Spindle cell lesions with significant osteoid component 42
Adenocarcinomas with ‘bull’s eye’-type cells 13
Spindle cell lesions with significant chondroid component 43
‘Hobnail’ pattern 15
Tumors with mixed mesenchymal components 43
Glandular structures with squamous change/metaplasia 15
Glandular structures with clear cell change 16 Biphasic pattern 43
‘Slit-like’ pattern 16
Pseudoglandular pattern 16 Vascular pattern 44
Anastomosing/intercommunicating/slit-like vascular channels 44
Non-glandular epithelial/epithelioid pattern 17 Granulation tissue-type vessels 44
Basaloid pattern 17 Hemangiopericytomatous-type vessels 45
Comedo pattern 18 Plexiform capillary pattern (‘chicken feet’) 45
Alveolar pattern 19 Ectatic vessels 46
Packeted pattern 19 Papillary vascular pattern 46
Palisading pattern 19 Capillary hemangioma pattern 46
Reticular, reticulated or lattice patterns 21 Cavernous hemangioma pattern 46
Squamoid pattern 21 Mixed vessels pattern 47
Trabecular pattern 21 Epithelioid hemangioma pattern 47
Scirrhous/desmoplastic pattern 23 Pseudovascular 47
Undifferentiated pattern 24
Pseudocystic patterns 25 Prominent non-cellular pattern 48
Amyloid/amyloid-like material 48
Round cell pattern 25 Calcification/microcalcification 48
Diffuse round cell pattern 25 Hyaline bands/strands/nodules/keloid-like hyalinization 49
Septate or lobulated round cell pattern 25 Hyaline globules 51
Alveolar/pseudoalveolar round cell pattern 25 Psammoma bodies 51
Round cell pattern with rosettes 25 Crystals 51
Round cell pattern with other component(s) 26
Round cell pattern with hemangiopericytomatous Distinctive cell types 52
vascular pattern 27 Anaplastic cells 52
Round cell pattern with desmoplastic stroma 27 Clear cells 52
Mixed round cell pattern 28 Granular cells 52
Large round cell pattern 28 Oxyphilic/oncocytic/oncocytoid cells 52
Hyalinized/plasmacytoid cells 54
Spindle cell pattern 28 Rhabdoid cells 55
Diffuse monomorphic bland spindle cell pattern Signet ring cells 56
(fibromatosis pattern) 28 Vacuolated cells 56
4 Common histological patterns and cell types of tumors
Xanthomatous/foam cells 56 Pseudoepitheliomatous hyperplastic 60

‘Ganglion-like cells’ 57 Acanthoma pattern 60
Giant cells 57 Pattern with ‘cup-shaped’ or inverted lobules of
‘Hobnail’ cells 58 squamous epithelium 60
Nesting or clonal proliferation ‘Borst–Jadassohn
Surface epithelial patterns associated with or affected by phenomenon’ 60
neoplastic process 58 Pagetoid pattern 61
Lichenoid reaction pattern 58 Elongated anastomosing strands 61
Psoriasiform reaction pattern 58 Broad anastomosing/interlacing epithelium 62
Clear cells within the epidermis 59 Verrucous pattern 62
Dysplastic changes of epidermis or squamous mucosa 59
This section is principally aimed at trainee pathologists who

are not yet familiar with the various histological patterns and
sub-patterns that may be encountered in the various tumors.
It therefore lists 10 main broad histological patterns with their
sub-patterns. Each of these patterns is defined and illustrated,
and typical and common examples of tumors that exhibit these
patterns are also provided.
GLANDULAR/PSEUDOGLANDULAR PATTERN
This category includes all tumors and tumor-like conditions in

which the tumor cells are epithelial or have the morphology
of epithelial cells (epithelioid) that form distinct glandular,
pseudoglandular, or papillary structures. The term glandular is
used in its broadest sense to describe structures that resemble
Figure 1.2 A breast duct lined by inner epithelial and outer
normal glands or ducts. myoepithelial cell layers.The latter is highlighted by actin immunostains.
The following patterns are commonly recognized.
DUCTAL GLANDULAR PATTERN (Figures 1.1–1.3)
Ducts are glandular structures that vary in size and shape

and in their lining epithelium according to their origin. Breast
Figure 1.3 Ductal structures exhibiting angulations, wall thinning

and malignant epithelial cell lining in a case of colonic carcinoma
metastasizing to the ovary.
ducts, for example, can be either small (as in the terminal duct-
lobular unit) or large (as in the collecting duct system), and are
Figure 1.1 Breast ducts lined by inner epithelial and outer lined by inner epithelial and outer myoepithelial cell layers.
myoepithelial cell layers.The latter is highlighted by cytokeratin 14. These two cell layers are maintained in benign lesions. Invasive
Glandular/pseudoglandular pattern 5
duct carcinoma of the breast of no special type typically consists

of irregularly shaped, angulated tightly or loosely cohesive
islands of medium sized, variably pleomorphic epithelial cells.
The other tumor that is prototypic of ductal pattern is pancre-
atic carcinoma.
TUBULAR PATTERN (Figures 1.4–1.9)
Like ducts, tubules are round or elongated glandular structures

lined by single or double layers of epithelial cells. This pattern
is commonly seen in breast lesions such as microglandular
adenosis, tubular adenoma and tubular carcinoma, and in
tubular adenoma or adenoid cystic carcinoma of salivary
glands. The tubular outlines in carcinomas are usually irregu-
lar and exhibit angulations.
Figure 1.6 Tubules lined by single and double layers of epithelial

cells. This is an ovarian metastasis from a primary breast carcinoma.
Figure 1.4 Small round tubules lined by cuboidal cells and

containing colloid-like material, from a case of tubular adenoma
of the breast. Figure 1.7 Tubules from a case of tubular carcinoma of the breast
lined by cells with hyperchromatic nuclei and exhibiting apical
cytoplasmic snouts.
Figure 1.5 Crowded round and elongated tubules lined by

cuboidal cells and containing colloid-like material, from a case of
tubular adenoma of the salivary gland. Note the similarity to that of Figure 1.8 Uniform, round and elongated tubules of a Sertoli
tubular adenoma of the breast (Figure 1.4). cell nodule, from a woman with testicular feminization syndrome.
Figure 1.9 Slightly distorted tubules of Sertoli cells from a Figure 1.10 Classic acinar pattern is seen in granulosa cell tumor.
case of ovarian Sertoli–Leydig cell tumor.
ACINAR/MICROACINAR PATTERN (Figures 1.10–1.13)
An acinus is a microgland or a small rounded space surrounded

by an epithelial layer. A typical example of the acinar pattern is
seen in acinic cell carcinoma of the pancreas, acinic cell carci-
noma of salivary gland and both parathyroid adenoma and
carcinoma. An acinar pattern is also a feature of endometrioid
carcinomas, granulosa cell tumor, prostatic carcinoma, and neuro-
endocrine tumors.
PAPILLARY AND PSEUDOPAPILLARY PATTERN

(Figures 1.14–1.24)
Papillae are finger-like structures of any size or shape. Large

polypoid papillae with densely hyalinized or edematous cores Figure 1.11 Acinar pattern is common in endometrioid
are characteristically seen in ovarian serous cystadenofibroma. carcinoma of the ovary.
Similar papillae, but with a prominently cellular stroma, are a fea-
ture of phyllodes tumor of the breast, mullerian adenofibroma
and mullerian adenosarcoma. Villous papillae are elongated with
vertical fibrovascular cores. When these are lined by glandular
epithelium, they are characteristic of villous adenoma of the
colon, papillary carcinoma of the thyroid and of villoglandular
adenocarcinoma of the cervix and endometrium. If the lining
is atypical transitional or squamous epithelium, they represent
transitional cell carcinoma and papillary squamous carcinoma,
respectively. Cellular papillae are thin, delicate structures with no
discernible central connective tissue cores, are seen in borderline
and malignant serous tumors of the ovary, in micropapillary car-
cinoma in situ of the breast, and in aggressive digital papillary
adenoma. Branching papillae in hierarchical pattern are seen in
serous borderline tumor or in non-hierarchical pattern in serous
carcinoma. Hyalinized papillae have avascular and distinctly
hyalinized stromal cores. This is typically seen in papillary
mesothelioma and in clear cell/mesonephroid carcinoma of the
Figure 1.12 Acinar pattern is seen in the epithelial component
ovary. Glomeruloid papillae are short papillae contained within of malignant mixed mullerian tumor. It may either represent an
glomerulus-like structures; this is mainly seen in endodermal sinus endometrioid epithelial component or a rare neuroendocrine
tumor and sometimes in clear cell carcinoma of the ovary. differentiation, as in this case.
Figure 1.13 Acinar pattern is common in prostatic carcinoma. Figure 1.16 Broad leaf-like papillae with cellular stroma showing small
rhabdomyoblasts, characteristically seen in mullerian adenosarcoma.
Figure 1.14 Branching papillae in hierarchical pattern are Figure 1.17 Papillary carcinoma of the thyroid showing villous
characteristically seen in ovarian serous cystadenofibroma. papillae with a vascular core.The lining epithelium shows nuclear
grooves and intranuclear inclusion.
Figure 1.15 Large, broad, leaf-like papillae with cellular stroma Figure 1.18 Villous papillae lined by stratified columnar
characteristic of phyllodes tumor of the breast. endometrioid type epithelium from a case of villoglandular carcinoma
of the cervix. A similar pattern is seen in villoglandular carcinoma of
the endometrium, and in some endometrioid carcinomas of the ovary.
Figure 1.19 Micropapillary serous carcinoma showing cellular Figure 1.22 Branching papillae in non-hierarchical pattern is seen
papillae with no discernible central connective tissue cores. in serous ovarian carcinoma.
Figure 1.20 Glomeruloid papilla to the right and cellular papillae Figure 1.23 Branching papillae in hierarchical and non-hierarchical
to the left in ovarian serous carcinoma. pattern is seen in uterine serous carcinoma.
Figure 1.21 Branching papillae in hierarchical pattern is seen in Figure 1.24 Hyalinized papillae, lined by malignant epithelial cells
serous borderline tumor of the ovary. with clear cytoplasm and some hobnail nuclei, are seen in clear cell
carcinoma of the ovary.
CRIBRIFORM PATTERN (Figures 1.25–1.28)
‘Cribriform’ means perforated by small holes, as in a sieve. In

tumor pathology, ‘cribriform’ is used to describe a neoplastic
epithelial proliferation in which such holes are present. In gen-
eral, the epithelial proliferation forms holes, which may vary in
size and are usually round or oval, rather than irregular, slit-like,
or some other shape. The background cells tend to be uniform,
giving the impression of a monomorphic round cell population
punched-out by holes. There is some orientation of the nuclei
around the holes; the latter represent true gland lumina that may
contain mucin. The term ‘cribriform’ usually implies carcinoma,
and it is commonly seen in breast, prostatic, endometrial, and
colonic carcinomas and adenocarcinoma of the nasal sinuses.
Cribriform pattern is sometimes seen in glandular yolk sac
tumor. The cribriform pattern should be distinguished from ade-
noid cystic pattern, though cribriform areas can occur in adenoid Figure 1.27 Cribriform pattern is seen in endometrioid
cyst carcinoma, and from closely packed glands and from Call– carcinoma of the ovary.
Exner bodies. The latter characterize adult granulosa cell tumor
Figure 1.28 Cribriform pattern is commonly seen in salivary duct

carcinoma.
Figure 1.25 Cribriform pattern is illustrated in the epithelial
component of this uterine malignant mixed mesodermal tumor.
and are defined as small cavities resembling the Call–Exner
bodies found in developing follicles. These cavities are often
spherical and contain eosinophilic fluid with degenerate nuclei
and occasionally hyaline material.
FOLLICULAR PATTERN (Figures 1.29–1.32)
Thyroid follicles are gland-like structures containing densely

eosinophilic colloid, which is positive immunohistochemically
for thyroglobulin. These are found in normal thyroid, follicu-
lar adenoma, and follicular carcinoma of the thyroid, follicular
variant of papillary carcinoma and in struma ovarii. Similar
structures (follicle-like), but lacking thyroglobulin, can be seen
in other tumors. Classic examples of such tumors are parathy-
roid adenoma and carcinoma, acinic cell carcinoma of salivary
glands, ovarian tumor of probable wolffian origin, secretory
carcinoma of the breast, endometrial/endometrioid carcinoma,
Figure 1.26 Cribriform pattern is seen in this metastatic colonic endocervical adenocarcinoma, clear cell/mesonephroid carci-
carcinoma involving both ovaries. noma, and Sertoli–Leydig cell tumor.
Figure 1.29 Thyroid follicles containing densely eosinophilic Figure 1.32 Colloid-like material in tubules of mesonephric duct
colloid, from a case of follicular adenoma. remnants.
ADENOID CYSTIC PATTERN (Figures 1.33 and 1.34)
This term was originally used to describe a salivary gland

tumor that resembles basal cell carcinoma of the skin of the
adenoid cystic type. This distinctive pattern is characterized by
the presence of well-defined nests of basaloid epithelial cells
within which there are round spaces. These represent invagina-
tions of stroma resulting in a glandular space-like appearance.
Such spaces are filled with basement membrane material. True
glands lined by epithelial cells are also present, but they are less
numerous, smaller, and may be hard to identify. The staining
reaction of the secretory material in the two types of spaces is
different. A classic example of this pattern is seen in adenoid
cystic carcinoma, a biphasic tumor consisting of epithelial and
myoepithelial cells. The myoepithelial cells tend to be larger
than the epithelial cells, have hyperchromatic nuclei, and clear
cytoplasm, whereas the epithelial cells are smaller, have a
Figure 1.30 Colloid-like material in tubules of salivary duct
adenoma.
Figure 1.33 Well-defined nests of basaloid epithelial cells

Figure 1.31 Proliferating endometrioid ovarian tumor showing surrounding and branching through thick basement membrane
endometrioid type glands with luminal colloid-like material.This material. Some nests completely encircle the hyaline material,
represents inspissated secretion. producing a pseudoglandular pattern.
Figure 1.34 True glands lined by epithelial cells are also present in Figure 1.35 Intestinal-type proliferating (borderline) mucinous
adenoid cystic carcinoma, but these are less numerous, smaller and ovarian tumor with goblet cells.
may be difficult to identify (see encircled spaces).
lighter nucleus, and may have a visible nucleolus. This pattern

should be distinguished from cribriform pattern. The cells
within the nests of the latter pattern are monomorphic epithe-
lial cells with no myoepithelial component.
CANALICULAR PATTERN
This is characterized by elongated and branching epithelial-

lined structures separated by fibrous tissue. These epithelial
structures simulate channels, hence the name ‘canalicular’. This
is typically seen in fibroadenoma of the breast and salivary
gland canalicular adenoma or carcinoma.
ENDOMETRIOID PATTERN
Figure 1.36 Transition between benign and proliferation
Glandular structures with endometrioid pattern usually recapit- (borderline) mucinous ovarian tumors.
ulate the microscopic appearances of proliferative endometrial
glands. These are tubular or round patent glands, lined by strat-
ified non-mucin-containing epithelium and having a smooth
luminal border. This pattern is seen in endometrial hyperplasia,
endometrial carcinoma, in endometrioid ovarian tumors, and in
endometrioid variant of endocervical carcinoma. A similar pat-
tern is also seen in prostatic duct carcinoma, in endometrioid
variant of yolk sac tumor, and in some colonic carcinomas.
Endometrial/endometrioid carcinomas often show immature
(squamous morules) or mature squamous metaplasia. According
to the degree of tumor differentiation, the endometrioid glan-
dular structures vary from back to back well-defined glands to
complex intercommunications.
MUCINOUS GLANDULAR PATTERN (Figures 1.35–1.37)
The glands are medium- to large-sized, round, oval or elon-

gated, often with papillary infoldings. Tall columnar cells that Figure 1.37 Mucinous glands lined by columnar cells with
have excessive cytoplasmic mucin and basal nuclei with varying excessive cytoplasmic mucin and basal nuclei in case of mucinous
numbers of goblet cells line these glands. Typical examples subtype of endometrial carcinoma.
include mucinous ovarian tumors, mucinous carcinomas of

gastrointestinal origin and endocervical adenocarcinoma. Other
carcinomas such as broncho-alveolar carcinoma, endometrial
adenocarcinoma, and adenocarcinoma of the nasal sinuses may
exhibit similar patterns. The glands of well-differentiated muci-
nous carcinoma may appear so bland that they may be mistaken
for benign mucinous cysts or normal structures such as endo-
cervical or colonic crypts. This appearance can also be found
in metastatic mucinous carcinoma. A typical example of this is
seen in ovarian metastasis from colonic or pancreatic mucinous
carcinoma. In these cases, the lesion simulates primary benign
or borderline mucinous ovarian tumor. Some mucinous tumors
are associated with lakes of extracellular mucin, resulting in
glands that either float in or open into pools of mucin.
This pattern is typically seen in some pseudomyxoma peri-
tonii, gastrointestinal adenocarcinoma and mucoid carcinoma of
the breast. Abundant eosinophilic cytoplasm of malignant glan- Figure 1.39 Signet ring cells in metastatic lobular carcinoma
dular cells is sometimes seen in adenocarcinomas, particularly at in the ovary.
the invasive front. This may be a helpful feature in identifying
early invasion in cases of adenocarcinoma in situ. Thinning of
the glandular wall with loss of nuclear polarity is another feature
suggestive of invasion.
‘SIGNET RING’ GLANDULAR PATTERN

(Figures 1.38–1.40)
‘Signet ring’ cells are very distinctive, characterized by the pres-

ence of one large intracytoplasmic vacuole which pushes the
nucleus to one side. These cells are the hallmark of signet ring
adenocarcinoma. Some non-glandular tumors may also have
signet ring morphology, and these include signet ring lym-
phoma, sclerosing stromal tumor of the ovary, chordoma,
epithelioid hemangioendothelioma, liposarcoma, and signet
ring melanoma. The large intracytoplasmic vacuole may repre-
sent a collection of mucin as in adenocarcinoma, intracytoplas- Figure 1.40 Signet ring lipoblasts in liposarcoma.
mic vascular lumina as in hemangioendothelioma, deposits of
fat as in liposarcomas and sclerosing stromal tumor of the RETIFORM PATTERN (Figure 1.41)
ovary, or may represent an artifact of fixation as in signet ring
lymphoma or melanoma. ‘Retiform’ means resembling the rete testis; that is, elongated,
intercommunicating glandular structures. This pattern is seen in
Figure 1.38 Signet ring in Kruckenberg tumor (ovarian metastasis

from gastric carcinoma). Figure 1.41 Retiform Sertoli–Leydig cell tumor.
retiform endometrioid carcinoma and retiform Sertoli–Leydig

cell tumor. A retiform pattern can also occur in mesenchymal
tumors such as retiform hemangioendothelioma and biphasic
synovial sarcoma. The arborizing vascular channels of the for-
mer and the glandular arrangement of the latter impart a reti-
form appearance to these lesions.
ADENOMATOID PATTERN
Adenomatoid tumor is an ill-defined lesion composed of

pseudoglandular and/or pseudovascular spaces lined by cuboidal
or flattened, often-vacuolated cells that occasionally contain a
basophilic secretion. A similar pattern can also be seen in epithe-
lial tumors such as clear cell carcinoma of the ovary and tumors
of probable wolffian origin.
MICROCYSTIC GLANDULAR PATTERN Figure 1.44 Microcystic pattern in endodermal sinus tumor.
(Figures 1.42–1.44)
endocervical glands following subinvolution. In the cervix, this
Some distended glands have the appearance of microcysts, and type of subinvolution is called ‘tunnel clusters’. Distension of
this is especially seen in breast ducts, prostatic glands, and fundic gastric glands results in a microscopic appearance of
microcysts and gross features of polyps called fundic gland
polyps. In the context of tumors, such microcysts are seen in
microcystic cystadenoma of the pancreas, endometrial hyperpla-
sia, mucinous ovarian tumors, and ovarian tumor of probable
wolffian origin.
ADENOCARCINOMAS WITH ‘BULL’S

EYE’-TYPE CELLS (Figures 1.45–1.51)
‘Bull’s eye’-type cells are mucin-secreting cells characterized by

the presence of central eosinophilic globule (inspissated mucin)
surrounded by a halo. Mucin stains such as Alcian blue/
periodic acid–Schiff (PAS) highlights the very dark blue color
of the central globule of the ‘bull’s eye’-type cell. These cells are
commonly seen in clear cell carcinoma of the ovary or other
part of the female genital tract, in lobular carcinoma of the
Figure 1.42 Cystic dilatation of fundic glands, resulting in fundic breast, and in transitional cell carcinoma of the bladder. They
gland polyp. can also be seen in endometrial carcinoma.
Figure 1.43 Microcysts lined by flattened epithelium in clear cell

carcinoma of the ovary. Figure 1.45 ‘Bull’s eye’-type cells in clear cell carcinoma of the ovary.
Figure 1.46 Mucin stain (Alcian blue/periodic acid–Schiff) Figure 1.49 ‘Bull’s eye’-type cells in microglandular type of
highlights the very dark blue color of the central globule of the endometrial carcinoma.
‘bull’s eye’-type cells.
Figure 1.47 ‘Bull’s eye’-type cells in endometrioid carcinoma of Figure 1.50 ‘Bull’s eye’-type cells in transitional cell carcinoma of
the ovary. the bladder.
Figure 1.48 ‘Bull’s eye’-type cells in lobular carcinoma of the breast. Figure 1.51 Mucin stain (Alcian blue/periodic acid–Schiff)
highlights the very dark blue color of the central globule of the
‘bull’s eye’-type cell.
‘HOBNAIL’ PATTERN (Figures 1.52–1.54) cytoplasmic limits of the cells. A typical example is seen in clear
cell carcinoma of the ovary. The ‘hobnail’ cells are also a feature
The ‘hobnail’ cells are characterized by abundant cytoplasm of the Arias–Stella reaction and lactating adenoma of the breast.
and nuclei that protrude into a lumen beyond the apparent ‘Hobnail’ cells are rarely seen in other tumors such as juvenile
granulosa cell tumor, Sertoli–Leydig cell tumor and in yolk sac
tumor. The malignant endothelial cells of angiosarcoma or some
hemangioendotheliomas may appear as ‘hobnail’ cells.
GLANDULAR STRUCTURES WITH SQUAMOUS

CHANGE/METAPLASIA (Figures 1.55 and 1.56)
This is characterized by the presence of squamous differentia-

tion that blends imperceptibly with the glandular component.
The degree of the squamous differentiation is usually similar to
that of the accompanying glandular element. Squamous meta-
plasia is frequently seen in endometrial carcinoma. It is also not
uncommon in endometrioid ovarian carcinoma and in lung
carcinoma. When the squamous epithelium is of the immature
type, the change is referred to as squamous morules, which is a
Figure 1.52 ‘Hobnail’ cells in Arias–Stella reaction.
Figure 1.55 Squamous differentiation in endometrioid

carcinoma of the ovary.
Figure 1.53 ‘Hobnail’ cells in clear cell carcinoma of the ovary.
Figure 1.54 ‘Hobnail’ cells line the vessels in retiform Figure 1.56 Atypical adenomyoma showing typical squamous
hemangioendothelioma. morules.
common finding in endometrial carcinoma and in some cases ‘SLIT-LIKE’ PATTERN (Figures 1.59 and 1.60)
of endometrial hyperplasia.
This is a self-explanatory term, whereby slit-like spaces with
GLANDULAR STRUCTURES WITH CLEAR CELL some irregularities of outline are present between the neoplas-
tic cells. ‘Slit-like’ pattern can be seen in both glandular and
CHANGE (Figures 1.57 and 1.58) non-glandular tumors. This pattern is frequently seen in serous
carcinoma of the ovary and in mesothelioma, but it is more
Clear cells are those with diffuse, water-clear cytoplasm, usu-
typical of angiosarcoma, in which abortive vessel formation
ally related to the presence of abundant glycogen. The typical
results in the ‘slit-like’ spaces.
example is clear cell carcinoma of the kidney and clear cell carci-
noma of the ovary. Subnuclear cytoplasmic clear cell change,
resembling early secretory endometrial glands, is seen in the
secretory variant of endometrial carcinoma, in the epithelial com-
ponent of pulmonary blastoma, and in the rare ‘endometrioid
variant’ of endodermal sinus tumor. Clear cells may predominate
in some struma ovarii and in Arias–Stella reaction. In the ovary,
the latter two conditions can mimic clear cell carcinoma.
Figure 1.59 Irregular slits are commonly seen in serous ovarian

carcinoma.
Figure 1.57 Endometrioid-type endodermal sinus tumor of the

ovary, showing subnuclear clear cell change reminiscent of early
secretory endometrial change.
Figure 1.60 Slit-like spaces in serous ovarian carcinoma.
PSEUDOGLANDULAR PATTERN (Figures 1.61–1.63)
False glands are sometimes formed in non-glandular tumors,

usually as a result of acantholysis of the cells (as in some
squamous carcinomas) or of accumulations of extracellular
Figure 1.58 Clear cell carcinoma of the ovary showing distinct connective tissue mucoid material with peripheral condensa-
cytoplasmic glycogen. tion of the neoplastic cells (as in adenoid basal cell carcinoma
Non-glandular epithelial/epithelioid pattern 17
NON-GLANDULAR EPITHELIAL/
EPITHELIOID PATTERN

which the tumor cell populations have the morphology of
epithelial or epithelioid cells but no distinct glandular forma-
tion, even though the tumor might be of glandular nature. The
following patterns can be recognized in this category.
BASALOID PATTERN (Figures 1.64–1.66)
This term refers to well-formed, round, oval, elongated or irreg-

ular nests of fairly uniform, cohesive, small cells with relatively
hyperchromatic nuclei and little cytoplasm. The peripheral
cell layers of these nests often exhibit palisading arrangement;
Figure 1.61 Pseudoglandular spaces in basal cell carcinoma. that is, the long axes of the nuclei are arranged at right-angles
to the basement membrane. Classic examples are basal cell car-
cinoma, trichoepithelioma, pilomatrixoma, cylindroma, basal
cell adenoma of salivary gland, basal cell hyperplasia and ade-
noid basal cell tumor of the prostate, and adamantinoma.
Figure 1.62 Pseudoglandular spaces in lymphangiosarcoma.
Figure 1.64 Basal cell carcinoma showing basaloid nests with

peripheral palisading.
Figure 1.63 Myxoid liposarcoma with pseudoglandular pattern.
and myxoid liposarcoma). A gland-like neoplastic epithelium

is very common in malignant mesothelioma; a gland-like
pattern may also be seen in angiosarcoma, lymphangiosarcoma Figure 1.65 Basaloid carcinoma of the cervix showing distinct
and epithelioid hemangioendothelioma. basaloid nests.
(a)
Figure 1.66 Basal cell adenoma of the salivary gland showing

basaloid nests separated by basement membrane-like material.
COMEDO PATTERN (Figures 1.67–1.70)
This pattern is characterized by the presence of well-

circumscribed epithelial nests containing central coagulative
(b)
Figure 1.69 (a) Comedo necrosis in serous ovarian carcinoma.

(b) CINIII involving endocervical gland with central dyskeratotic
necrosis.These features are suggestive of impending stromal
invasion.They are also seen in CINIII-like squamous carcinoma.
Figure 1.67 Metastatic colonic carcinoma in the ovary showing

extensive comedo necrosis.
Figure 1.70 Comedo necrosis in basosquamous carcinoma of

upper aerodigestive tract.
necrosis. Typical examples are seen in invasive and in-situ

comedo carcinoma of the breast, basaloid carcinoma of upper
Figure 1.68 Salivary duct carcinoma showing comedo necrosis aerodigestive tract, salivary duct carcinoma, and in some
similar to comedo carcinoma of the breast. CINIII that shows features of impending invasion.
ALVEOLAR PATTERN (Figures 1.71–1.74)
In this pattern, packets of neoplastic cells separated by fibrous

tissue or vessels become loosely cohesive especially in the centers,
Figure 1.74 Alveolar soft part sarcoma showing loss of cohesion

resulting in an alveolar pattern.
resulting in a lung-like (alveolar) appearance. Classic examples

are alveolar rhabdomyosarcoma, alveolar soft part sarcoma and
Figure 1.71 Alveolar rhabdomyosarcoma with classic alveolar pattern broncho-alveolar carcinoma. Malignant melanoma often shows
showing loosely cohesive cells separated by fibrous septae and vessels. alveolar pattern, as do some traumatized intradermal naevi.
Focal alveolar pattern is often seen in high-grade sarcomas and
in anaplastic tumors in which loss of cell cohesion results in such
a pattern.
PACKETED PATTERN (Figures 1.75–1.79)
Cells are grouped in small, usually round packets surrounded or

invested by delicate vascular network (as seen in renal cell carci-
noma), or surrounded by a separate supporting (‘sustentacular’)
population of cells (as seen in paragangliomas). Other tumors
that show this pattern are alveolar soft part sarcoma, malignant
melanoma, and pheochromocytoma.
Figure 1.72 Malignant melanoma showing alveolar pattern due

to loss of cell cohesion.
Figure 1.75 Alveolar soft part sarcoma exhibiting classic packets

of cells surrounded by delicate vascular network.
PALISADING PATTERN (Figures 1.80 and 1.81)
Figure 1.73 Acantholytic squamous cell carcinoma resulting in an This pattern is characterized by the presence of tumor cells that
alveolar pattern. show parallel alignment of nuclei. A peripheral layer of palisaded
Figure 1.76 Clear cell carcinoma of the kidney with packeting Figure 1.79 Some sclerosing B-cell lymphomas show distinct
pattern. nesting and packeting due to the presence of excessive sclerosis.
Figure 1.77 Seminoma showing packeted pattern of cells, Figure 1.80 Malignant peripheral nerve sheath tumor showing
separated by stroma containing dense lymphocytic infiltrate. palisading pattern.
Figure 1.78 Paraganglioma shows classic packeted pattern.The Figure 1.81 Uterine leiomyoma showing palisading pattern.
cells are surrounded by a belt of sustentacular cells.
cells is characteristic of nests of basal cell carcinoma. Palisaded

lines of cells are very common in schwannoma and in some
uterine leiomyomas. Similar palisading is seen rarely in syn-
ovial sarcoma.
RETICULAR, RETICULATED OR LATTICE

PATTERNS (Figures 1.82–1.84)
These terms imply a geometric regular meshwork or net-like

pattern which is due to the presence of spaces between neo-
plastic cells. The spaces may vary in size from small to those
that merge with microcysts. This is characteristic of endoder-
mal sinus tumor, acinic cell tumor of the salivary gland and of
microglandular hyperplasia of the cervix. Lattice or reticulated
pattern is frequently seen in vascular and hydropic leiomyoma
and sometimes in Sertoli–Leydig cell tumor. This pattern is
Figure 1.84 Myxoid leiomyosarcoma showing classic reticulated
rarely seen in synovial sarcoma. pattern.
SQUAMOID PATTERN (Figures 1.85–1.88)
This pattern is characterized by the presence of epithelial or epithe-

lioid cells that have abundant, solid or glassy-looking cytoplasm
reminiscent of squamous cells. Squamoid change is often seen in
the invasive front of many adenocarcinomas, and this feature is
very helpful for example in deciding whether a cervical lesion is a
high-grade cervical glandular intraepithelial neoplasia (CGIN) or
early invasive adenocarcinoma. This is also very useful in decid-
ing whether a mucinous ovarian tumor is borderline or invasive.
Some tumors show marked cytoplasmic eosinophilia which
imparts a squamous look to the lesion. Typical examples of such
tumors are mesothelioma, malignant melanoma, and Spitz nevus.
Figure 1.82 Meshwork, lattice or reticulated pattern is

characteristic of endodermal sinus tumor.
Figure 1.85 Adenosquamous carcinoma, showing cytoplasmic

eosinophilia of the squamous component.
TRABECULAR PATTERN (Figures 1.89–1.92)
Trabecula is a Latin word that means ‘little beam’ but, when

used to describe a neoplasm, it generally refers to strands of
Figure 1.83 Microglandular hyperplasia of cervix with reticulated neoplastic epithelium that are separated by connective tissue.
pattern. Usually, the epithelium is linear or elongated, while the breadth
Figure 1.86 Metastatic colonic carcinoma in the ovary, showing Figure 1.89 Neuroendocrine carcinoma, showing trabecular
nests of squamoid cells at the invasive front. pattern.
Figure 1.87 Pelvic recurrence of well-differentiated ovarian Figure 1.90 Endometrioid carcinoma with sex-cord
mucinous carcinoma. Note the focal increase in cytoplasmic volume differentiation, showing broad trabecular pattern.
and eosinophilia (squamoid change).
Figure 1.88 Metastatic malignant melanoma, showing squamoid Figure 1.91 Leiomyoma with sex-cord differentiation, showing
features. broad trabecular pattern.
Figure 1.92 Granulosa cell tumor, showing gyriform pattern. Figure 1.93 Metaplastic carcinoma of the breast with florid
desmoplastic stroma.
of the trabeculae varies from narrow to broad. Trabecular pat-
tern of growth is quite common in both benign and malignant
epithelial tumors, but it is particularly characteristic of carci-
noid tumors. Other tumors that show trabecular pattern are
hepatocellular carcinoma, Merkel cell tumor, granulosa cell
tumor and hyalinizing trabecular adenoma and Hurthle cell
carcinoma of thyroid. Non-epithelial tumors may also show
trabecular pattern; these include intra-abdominal desmoplastic
small round cell tumor, epithelioid smooth muscle tumors and
sclerosing lymphoma.
Variations of trabecular pattern include:
● ‘Insular’ pattern (insula means island in Latin) shows round
rather than elongated groups of epithelial cells; this is

commonly seen in carcinoid tumor and granulosa cell tumor.
● ‘Festoon’ is used to describe undulating curving cords of
cell; this pattern may be seen in carcinoid tumor, islet cell

tumor, epithelioid sarcoma, and endodermal sinus tumor.
● ‘Plexiform’ (network or tangle in Latin) shows freely
anastomosing and interconnecting cords; this is seen in Figure 1.94 Tubular carcinoma of the breast with desmoplastic
stroma.
some epithelioid smooth muscle tumors, and focally in
pleomorphic adenoma of salivary glands.
● ‘Indian-file’ or ‘cord-like’ pattern is characterized by the
presence of a single line of tumor cells, and is very

characteristic of lobular carcinoma of the breast. Small
cord-like myofibroblastic cells are seen in vulval
angiomyofibroblastoma. Rarely, myxoid liposarcoma
features cell rows separated by myxoid or hyalinized
stroma. A cord-like pattern is also seen in some hydropic
and vascular leiomyomas.
● ‘Gyriform’ pattern is characterized by the presence of
elongated and curved cords of tumor cells, as seen in

granulosa cell tumor.
SCIRRHOUS/DESMOPLASTIC PATTERN
(Figures 1.93–1.97)
This pattern reveals variably compressed and distorted epithelial

structures that are embedded in a loosely sclerosed, so-called Figure 1.95 Intra-abdominal small round cell desmoplastic
desmoplastic, stroma. Typical examples of this pattern are seen in tumor.
Figure 1.96 Basosquamous cell carcinoma of the skin with Figure 1.98 Malignant melanoma, showing undifferentiated cell
desmoplastic stroma. pattern.
Figure 1.97 Biphasic mesothelioma, showing glandular-like

structures of malignant mesothelial cells with florid desmoplastic-like
Figure 1.99 Metastatic leiomyosarcoma with anaplastic features.
malignant stroma.
invasive ductal carcinoma of the breast, cholangiocarcinoma,

malignant mesothelioma, and morphoeic type of basal cell car-
cinoma. A prominent desmoplastic stroma can also be seen in
non-epithelial tumors such as in intra-abdominal desmoplastic
tumor or sclerosing fibrosarcoma, producing a pseudoglandular
pattern.
UNDIFFERENTIATED PATTERN (Figures 1.98–1.101)
This shows extensive solid areas of tumor that lack any signif-
icant identifiable architectural pattern. The cells of undifferen-
tiated tumors tend to be large and pleomorphic, but can be
uniform. This pattern characterizes a large number of undif-
ferentiated carcinomas, sarcomas, and malignant melanoma.
Perivascular condensation of tumor cells in an undifferentiated
tumor should always raise the suspicion of a pigmented malig-
nant melanoma. Figure 1.100 Anaplastic seminoma.
Round cell pattern 25
Figure 1.101 Anaplastic endometrial carcinoma. Figure 1.102 Small cell undifferentiated carcinoma of the lung.
PSEUDOCYSTIC PATTERNS
These are cystic spaces of various sizes and shapes, which often
result from degenerative changes within the tumor. Microcysts
filled with granular eosinophilic material are common in myx-
oid liposarcoma, and serve as a useful marker of this tumor.
Pseudocyts can be seen in a large number of tumors including
synovial sarcoma, thymoma, desmoplastic small cell tumor, and
juvenile granulosa cell tumor.
ROUND CELL PATTERN
The term small round cells (or alternatively small blue cells) is
used to describe lesions in which the dominant population con-
sists of relatively small cells with basophilic nuclei and little or
no cytoplasm. Figure 1.103 Primitive neuroectodermal tumor, showing small
These cells may either be small lymphocyte-like (as in small cells interspersed by thin, short and irregular vascular septae.
lymphocytic lymphoma), embryonal-type (as in neuroblastoma)
or undifferentiated epithelial cells (as in small cell carcinoma).
sarcoma/primitive neuroectodermal tumor and alveolar
Within the small cell pattern there are several sub-patterns that
rhabdomyosarcoma.
can help in the differential diagnosis.
DIFFUSE ROUND CELL PATTERN (Figure 1.102)

ALVEOLAR/PSEUDOALVEOLAR ROUND CELL
PATTERN (Figure 1.104)
The cell population is arranged in diffuse sheets, without any
identifiable architectural arrangement. This pattern is typically In this category, there is at least focal poor cohesion of the round
seen in lymphoma, leukemic infiltrate, small cell undifferenti- cell population resulting in a pseudoalveolar appearance. This is
ated carcinoma, primitive neuroectodermal tumor (PNET) and seen in alveolar rhabdomyosarcoma and PNET.
Ewing’s sarcoma. It is also seen in Merkel cell tumor, embryonal
rhabdomyosarcoma, and in malignant melanoma. Pagetoid ROUND CELL PATTERN WITH ROSETTES
involvement of the overlying mucosa is sometimes seen in round
(Figures 1.105–1.107)
cell tumors involving mucosal organs.
A ‘rosette’ is like a flower; with the cells being arranged radially

SEPTATE OR LOBULATED ROUND CELL around a central area. According to the central area, four types
PATTERN (Figure 1.103) of rosette are recognized:
1. Flexner’s (also called Flexner–Wintersteiner, true or
In this category, sheets of small round cells are divided by retinoblastoma) rosette contains clearly delineated empty
fibrous/fibrovascular septae. This is typically seen in Ewing’s central lumen. This is seen in tumors of the central
Figure 1.104 Alveolar rhabdomyosarcoma consists of small Figure 1.107 Myoepithelioma of the salivary gland, showing
round cells separated by fibrous septae. pseudorosettes with central radiating amianthoid-like fibers.
nervous system and in particularly the neuroblastoma and

in PNET. Large rosettes that contain central cellular debris
can be confused with glands.
2. Ependymal rosette. Here, cells surrounding the central
lumen have cilia and blepharoplasts.
3. Homer Wright (or neuroblastoma) rosette. The center has no
lumen, but abundant fibrillary material representing tangled
neuropil. This is typically seen in olfactory neuroblastoma.
4. Perivascular (or glial-vascular) rosette. In this pattern there
is a central small blood vessel around which tapered cell
processes converge. The pattern is seen in astrocytic
tumors and ependymomas. Pseudorosettes are seen rarely
in poorly differentiated synovial sarcoma, carcinoid tumor,
and thymoma.
ROUND CELL PATTERN WITH OTHER

COMPONENT(S) (Figures 1.108 and 1.109)
Figure 1.105 Primitive neuroectodermal tumor, showing small
cells with rosettes. In this category, in addition to the small round cells, other
cellular or mesenchymal components can be identified. These
Figure 1.108 Mesenchymal chondrosarcoma, showing small

Figure 1.106 Granulosa cell tumor with pseudorosettes. round cells with islands of mature hyaline cartilage.
Round cell pattern 27
Figure 1.109 Mesenchymal chondrosarcoma, showing malignant

chondroid with round cell infiltrate. Figure 1.111 Mesenchymal chondrosarcoma, showing small
round cell tumor with hemangiopericytomatous pattern.
include ganglion cells as in ganglioneuroblastoma, glands or
pseudo-glands as in poorly differentiated synovial sarcoma,
desmoplastic small cell tumor, and Wilms’ tumor; or the pres-
ence of cartilage, as in mesenchymal chondrosarcoma.
ROUND CELL PATTERN WITH HEMANGIO-

PERICYTOMATOUS VASCULAR PATTERN
(Figures 1.110 and 1.111)
In this category, the small round cell tumors exhibit a distinct

hemangiopericytomatous vascular pattern. Typical examples
are poorly differentiated synovial sarcoma and mesenchymal
chondrosarcoma.
ROUND CELL PATTERN WITH DESMOPLASTIC

STROMA (Figures 1.112 and 1.113)
Figure 1.112 Intra-abdominal small cell desmoplastic tumor.
In this pattern, sharply outlined, large, solid, round or oval
and elongate nests and islands or clusters and cords of small cells
Figure 1.110 Poorly differentiated synovial sarcoma with Figure 1.113 Epithelioid leiomyosarcoma with desmoplastic
hemangiopericytomatous pattern. stroma.
are set within a highly desmoplastic stroma. This is classically

seen in desmoplastic small cell tumor and sometimes in epithe-
lioid leiomyosarcoma.
MIXED ROUND CELL PATTERN (Figure 1.114)
This term implies the presence of mixture of round cells of vari-

ous histogenesis such as lymphocytes and epithelial or epithelioid
cells. This is classically seen in benign lymphoepithelial lesion,
dysgerminoma, thymoma, and nasopharyngeal carcinoma.
Figure 1.116 High-grade epithelioid leiomyosarcoma.
particular epithelioid leiomyosarcoma, poorly differentiated

synovial sarcoma, and proximal variant of epithelioid sarcoma.
SPINDLE CELL PATTERN

which the predominant cell populations are spindle-shaped.
Some tumors are highly cellular, whilst others are moderately
Figure 1.114 Lymphoepithelial carcinoma, showing undifferentiated or hypocellular. Various patterns can be distinguished within
epithelial cells admixed with inflammatory round cells. the spindle cell tumors.
DIFFUSE MONOMORPHIC BLAND SPINDLE CELL

LARGE ROUND CELL PATTERN PATTERN (FIBROMATOSIS PATTERN)
(Figures 1.117–1.124)
This shows predominant round cell population, but has a

The spindle cells are uniform, cytologically bland and loosely
larger size than those seen in typical small round cell tumors.
arranged in a sweeping pattern. The cells are usually mature
This pattern can be seen in various undifferentiated carcinomas
fibroblasts with small, regular, dense nuclei that are set within a
and in some poorly differentiated or high-grade sarcomas, in
Figure 1.115 Proximal variant of epithelioid sarcoma, showing Figure 1.117 Fibromatosis with cytologically bland and loosely
large round cells. arranged spindle cells.
Spindle cell pattern 29
Figure 1.118 Fibromatosis. Figure 1.121 Desmoplastic fibroblastoma.
Figure 1.119 Solitary fibrous tumor showing fibromatosis Figure 1.122 Low-grade fibromyxoid sarcoma, showing
pattern. fibromatosis pattern. Note the presence of some nuclear
pleomorphism.
Figure 1.120 Gastrointestinal stromal tumor with fibromatosis Figure 1.123 Diffuse neurofibroma, showing fibromatosis
pattern. pattern.The lesion is usually superficially located and the cells
are S100-positive.
Figure 1.124 Sarcomatoid carcinoma of the breast, showing Figure 1.126 Fibrosarcoma, showing uniform malignant spindle cells.
fibromatosis pattern.
collagenous or sometimes myxoid stroma. In deep soft tissue or in

large skeletal muscle, the classic example is fibromatosis (desmoid
tumor), especially when associated with infiltrative margins. If a
similar lesion is seen in the breast, sarcomatoid carcinoma must
be considered. For a similar lesion in superficial soft tissue or
in the dermis and subcutaneous tissue with infiltrative edges,
consider diffuse neurofibroma, dermatofibrosarcoma protuberans
(DFSP) and low-grade fibromyxosarcoma. If the lesion has well-
circumscribed margins, consider desmoplastic fibroblastoma
(collagenous fibroma), benign neurofibroma, schwannoma, or
smooth muscle tumors and solitary fibrous tumor. Fibromatosis-
like areas can be seen focally in plexiform fibrohistiocytic tumor.
DIFFUSE MONOMORPHIC HIGHLY CELLULAR

Figure 1.127 Malignant peripheral nerve sheath tumor, showing
SPINDLE CELL PATTERN (FIBROSARCOMA fibrosarcoma pattern.
PATTERN) (Figures 1.125–1.130)
Lesions in this category are reminiscent of fibrosarcoma, usually

being highly cellular, with obvious features of malignancy such
Figure 1.128 Leiomyosarcoma, showing uniform spindle cells.
as mitoses, necrosis, and some pleomorphism. Fibrosarcoma

pattern is usually characterized by fascicles that intersect at acute
Figure 1.125 Fibrosarcoma, showing classic monomorphic spindle angles like ‘herring bone’. In soft tissue, the most common
cell pattern with fascicular pattern. tumors in this group are monophasic synovial sarcoma,
Figure 1.129 Metastatic osteosarcoma, showing fibrosarcoma Figure 1.131 High-grade uterine leiomyosarcoma with malignant
pattern. fibrous histiocytoma (MFH) pattern.
Figure 1.130 Osteosarcoma of frontal sinus, showing

fibrosarcoma pattern. Figure 1.132 Malignant melanoma, showing great nuclear
pleomorphism resulting in malignant fibrous histiocytoma (MFH)
pattern.
leiomyosarcoma, and malignant peripheral nerve sheath tumor
(MPNST). Occasionally, spindle cell non-lipogenic liposarcoma
and spindle cell rhabdomyosarcoma can have fibrosarcoma
pattern. When fibrosarcoma pattern is encountered in a tumor of
an epithelial or visceral organ (bowel, lung, bladder, uterus, etc.),
sarcomatoid carcinoma needs to be ruled out before entertaining
a diagnosis of any kind of sarcoma. Malignant melanoma – ‘the
mother of all mimics’ – should always be kept in mind when
dealing with a lesion that has fibrosarcoma pattern, especially if
it is found in lymph nodes or in the liver.
PLEOMORPHIC SPINDLE CELL PATTERN

(MALIGNANT FIBROUS HISTIOCYTOMA PATTERN)
(Figures 1.131–1.134)
The tumor cells in this category vary greatly in size and shape,
and they are clearly malignant. There are often mono- or multi-
nucleated bizarre giant cells, sometimes with osteoclast-type cells, Figure 1.133 Liposarcoma, showing malignant fibrous histiocytoma
typified by pleomorphic malignant fibrous histiocytoma (MFH). (MFH) pattern.
Figure 1.134 Metastatic osteogenic sarcoma with malignant Figure 1.136 Synovial sarcoma, showing monomorphic spindle cells
fibrous histiocytoma (MFH) pattern. with epithelioid cell morphology with attempted palisading pattern.
The most common soft tissue tumors with MFH pattern are
pleomorphic liposarcomas, pleomorphic leiomyosarcoma, and
MFH. Adult pleomorphic rhabdomyosarcoma is extremely rare.
If an identical lesion is found in an epithelial organ or in a lymph
node, then sarcomatoid carcinoma and malignant melanoma
should be considered first. In the skin, this pattern is seen in
atypical fibroxanthoma and in some melanomas and spindle
cell carcinomas. Benign pleomorphic spindle cell lesions include
pleomorphic fibroma of the skin, dermatofibroma with monster
cells, giant cell fibroblastoma, and desmoplastic Spitz nevus.
SPINDLE AND EPITHELIOID CELL PATTERN

(Figures 1.135–1.137)
Figure 1.137 Malignant peripheral nerve sheath tumor, showing

This category includes lesions in which the principal popula-
fascicles of spindle cells with aggregates of epithelioid areas.
tion shows a continuous spectrum of spindle through to ovoid
or epithelioid shaped cells. This is typically seen in synovial sar-
coma, melanoma, leiomyosarcoma, epithelioid sarcoma, and SPINDLE CELL PATTERN WITH PROMINENT
clear cell sarcoma of tendon sheath.
SCLEROSIS (Figures 1.138–1.142)
Some spindle cell tumors exhibit excessive sclerosis that imparts a

less aggressive appearance to the tumor. Typical examples of such
tumors are sclerosing liposarcoma, sclerosing mesothelioma, and
desmoplastic melanoma. In this setting, therefore, the anatomical
location is the determinant factor. Sclerosing liposarcoma is most
commonly seen in the retroperitoneum, sclerosing mesothelioma
is a disease of the pleura, and desmoplastic melanoma is almost
always encountered in the head and neck of elderly individuals.
Other tumors with sclerosing pattern include epithelioid sarcoma,
synovial sarcoma, and sclerosing fibrosarcoma.
STORIFORM AND WHORLED PATTERN

Storiform (storia ⫽ matting) pattern is characterized by groups

Figure 1.135 Synovial sarcoma, showing monomorphic spindle of cells that appear to radiate out from centers that may con-
cells with epithelioid cell morphology. tain a vessel, resembling ‘cartwheel’ or ‘wheel spokes’.
Figure 1.138 Sclerosing mesothelioma, showing pure spindle cell Figure 1.141 Desmoplastic melanoma, showing excessive
pattern. background sclerosis with scattered atypical cells.
Figure 1.139 Sclerosing mesothelioma, showing excessive Figure 1.142 Sclerosing lymphoma. In a small biopsy, the only
sclerosis. feature may be a sclerotic stroma.
Figure 1.140 Sclerosing mesothelioma, showing cytokeratin- Figure 1.143 Dermatofibrosarcoma protuberans, showing classic
positive cells. storiform pattern.The cells are strongly positive for CD34.
Figure 1.144 Perineuroma, showing storiform pattern.The cells Figure 1.146 Nodular fasciitis consisting of plump, active
are epithelial membrane antigen (EMA)-positive. fibroblasts and myofibroblasts arranged in short, loose bundles with
scattered lymphocytes.The background matrix shows collagen with
small myxoid pools, giving rise to what appears to be ‘holes’ or
‘tears’ in the fabric of the tumor.
Normal ovarian stroma has a distinct storiform pattern. This
pattern can be seen in diverse conditions, including reactive
fibrohistiocytic proliferations, sclerotic fibroma (circumscribed
storiform collagenoma), deep dermatofibroma, solitary fibrous
tumor, fibromatosis, dermatofibrosarcoma protuberans, low-
grade fibromyxosarcoma, and malignant fibrous histiocytoma.
Whorled appearance is more or less similar to storiform, and is
characterized by the radial arrangement of cells around an
imaginary stem. This is characteristically seen in low-grade
fibromyxoid sarcoma, meningioma, and dedifferentiated
liposarcoma.
NODULAR FASCIITIS PATTERN (Figures 1.145–1.150)
Nodular fasciitis is a reactive proliferative process, and presents

as a rapidly growing, small subcutaneous or soft tissue mass that
occurs mainly on the upper arms and trunk of young adults, and
Figure 1.147 Myofibrosarcoma of the nasal sinus, showing nodular
fasciitis-like pattern, though the lesion was large and destructive.
Figure 1.145 Nodular fasciitis shows loose cellular stroma

reminiscent of desmoplastic stroma that is seen in association Figure 1.148 Low-grade fibromyxoid sarcoma, showing nodular
with invasive carcinomas. fasciitis-like pattern.The lesion was large and infiltrative.
SPINDLE CELL PATTERN WITH SIGNIFICANT

INFLAMMATORY COMPONENTS (Figures 1.151–1.159)
This category includes spindle cell tumors which contain a

prominent infiltrate of normal inflammatory cells identifiable
at low-power magnification and which involves most of or the
entire tumor. Typical examples are MFH, acral myxoinflam-
matory fibroblastic sarcoma, nodular fasciitis, and atypical
fibroxanthoma. Rarely, other sarcomas may exhibit significant
inflammatory cells such as leiomyosarcoma and liposarcoma.
Sarcomatoid carcinomas and spindle cell melanomas usually
contain large number of inflammatory cells. In some tumors
(e.g. angiomatoid MFH), the chronic inflammatory cells are
great in number and are arranged in aggregates that impart a
granulomatous appearance to the lesion.
Figure 1.149 Nodular fasciitis-like sarcomatoid carcinoma of the

breast, showing infiltration of the breast substance.
Figure 1.151 Inflammatory fibrosarcoma (inflammatory

myofibroblastic tumor) in the abdomen, showing loosely arranged
Figure 1.150 Nodular fasciitis-like sarcomatoid carcinoma of the spindle cells with numerous inflammatory component. Note the
breast, almost indistinguishable from lesions of nodular fasciitis. focal keloidal hyalinization, a common finding in these lesions.
rarely on the head and neck of infants and children. Similar

lesions can occur in epithelial organs such as the bladder, breast,
or gastrointestinal tract, and are referred to as inflammatory
myofibroblastic (pseudotumor) tumor. Lesions of nodular fasci-
itis consist of plump, active fibroblasts and myofibroblasts
arranged in short, loose, irregular bundles, or small C- or
S-shaped fascicles; occasionally, they have a vague storiform
appearance. The nuclei are uniform and elongated, while the
background matrix consists of collagen, which may be myxoid
or hyalinized, depending on the age of the lesion. The myxoid
pools may give rise to what appear to be ‘holes’ or ‘tears’ in the
fabric of the tumor, an appearance which is usually referred to as
‘feathery’ or ‘tissue culture-like’. Granulation tissue-type vessels
and scattered inflammatory cells – particularly lymphocytes – are
distributed throughout the lesion. Some malignant mesenchymal
or epithelial tumors may have nodular fasciitis picture. Examples
of the former are MPNST and fibromyxosarcoma, while typical Figure 1.152 Rosia–Dorfman disease, showing background spindle
of the latter is sarcomatoid carcinoma. cells with numerous inflammatory cells.
Figure 1.153 Sarcomatoid carcinoma of the nasopharynx,
showing a prominent inflammatory component.This may obscure Figure 1.156 Inflammatory malignant fibrous histiocytoma (MFH)
the nature of the disease. showing numerous inflammatory components that may obscure the
malignant nature of the tumor.
Figure 1.157 Acral inflammatory myxohyaline sarcoma, showing

extensive inflammatory element.
Figure 1.154 Malignant fibrous histiocytoma (MFH): pleomorphic
and inflammatory spindle cell lesion.
Figure 1.155 Inflammatory malignant fibrous histiocytoma (MFH)

showing large malignant tumor cells with numerous inflammatory Figure 1.158 Sclerosing B-cell lymphoma may resemble a spindle
components. cell lesion with inflammatory element.
Figure 1.159 Inflammatory myofibroblastic tumor. Figure 1.161 Giant cell epulis.
SPINDLE CELL PATTERN WITH OSTEOCLAST-

GIANT CELLS (Figures 1.160–1.164)
Numerous osteoclast-giant cells are typically found in giant cell

tumor of bone and in giant cell tumor of tendon sheath. Soft tis-
sue tumor osteoclast-giant cells include: the giant cell variant of
MFH, plexiform fibrohistiocytic tumor, and leiomyosarcoma.
Osteoclast giant cells may also be seen in sarcomatoid carci-
noma and nodular fasciitis.
SPINDLE CELL POPULATIONS WITH

HEMANGIOPERICYTOMATOUS PATTERN
(Figures 1.165–1.168)
The hemangiopericytomatous pattern here refers to the vascu-

Figure 1.162 Sarcomatoid carcinoma of the breast with
lar spaces that are seen within the spindle cell lesion. These are osteosarcomatous element, showing osteoclast giant cells.
prominent, thin-walled, dilated, ramifying vessels ranging from
Figure 1.160 Giant cell tumor of bone. Figure 1.163 Leiomyosarcoma with osteoclast-giant cells.
Figure 1.164 Osteosarcoma, showing both malignant and Figure 1.167 Liposarcoma, showing focal hemangiopericyto-
osteoclast-type giant cells. matous vascular pattern.
Figure 1.168 Hemangiopericytoma, showing classic pattern of

Figure 1.165 Synovial sarcoma with hemangiopericytomatous vessels.
vascular pattern.
capillary-sized to large gaping sinusoidal spaces. These vessels

are usually angulated, forked, or have a ‘stag-horn’ appear-
ance. This pattern occurs in several tumors other than heman-
giopericytoma, including synovial sarcoma, mesenchymal
chondrosarcoma, solitary fibrous tumor, and deep dermatofi-
broma. This pattern can sometimes also be seen in dedifferen-
tiated liposarcoma.
SPINDLE CELL ADMIXED WITH OTHER

MESENCHYMAL COMPONENTS

which mesenchymal components other than pure spindle cells
Figure 1.166 Synovial sarcoma with hemangiopericytomatous predominate. The various tumors within this group can be dis-
vascular pattern (CD34 highlighting the vessels). tinguished according to the following patterns.
SPINDLE CELL LESIONS WITH

SIGNIFICANT FATTY COMPONENT
(Figures 1.169–1.176)
Some spindle cell lesions are characterized by the presence of

significant amounts of mature fatty tissue. This is either due to
the infiltrative nature of the lesion that incorporates the sur-
rounding fatty tissue, or to the fatty element being a compo-
nent of the tumor. Typical examples of the former include
fibromatosis and dermatofibrosarcoma protuberans, and of the
latter, spindle cell lipoma, myolipoma/lipoleiomyoma, leiomy-
oma with fatty degeneration, lipomatous hemangiopericytoma,
fibrous hamartoma of infancy, dedifferentiated, spindle cell and
sclerosing liposarcoma, mammary-type myofibroblastoma of
soft tissue, and lipofibromatosis.
Figure 1.170 Diffuse neurofibroma incorporates fat cells as it
infiltrates the tissue.
SPINDLE CELL LESIONS WITH
SIGNIFICANT MYXOID COMPONENT
(Figures 1.177–1.184)
Myxoid stroma is characterized by loose, very pale, hypocellular

tissue with scattered neoplastic cells. The myxoid component can
be either focal or extensive, and often gives the lesion a lobulated
appearance. The neoplastic cells can be small, uniform and bland
as in intramuscular myxoma, myxoid fetal rhabdomyoma,
aggressive angiomyxoma, superficial angiomyxoma, low-grade
fibromyxosarcoma and in some myxoid liposarcoma; alterna-
tively, they may be pleomorphic and malignant-looking, as in
myxoid MFH (myxofibrosarcoma), acral myxoinflammatory
fibroblastic sarcoma, embryonal rhabdomyosarcoma and in
some of the other sarcomas that exhibit focal or extensive myx-
oid changes. Some myxoid lesions have more rounded and
epithelioid cells arranged in cords. These include chordoma, Figure 1.171 Lipofibromatosis, showing almost equal amounts of
chondroid lipoma, extraskeletal myxoid chondrosarcoma, and fat and spindle cells throughout the lesion. In fibromatosis, such an
vulval angiomyofibroblastoma. appearance is only seen at the infiltrative edge.
Figure 1.172 Lipomatous hemangiopericytoma, showing

significant amounts of mature fat cells as a tumor component.
Figure 1.169 Fibrous hamartoma of infancy, showing spindle and The spindle cells exhibit a hemangiopericytomatous vascular
fatty elements as true components of the lesion. pattern.The spindle cells are CD34-positive.
Figure 1.173 Spindle cell lipoma consisting of bland spindle cells Figure 1.176 Spindle cell lipoma: admixture of spindle cells and
with mature fat cells. mature fat cells.
Figure 1.174 Myofibrosarcoma of the breast, showing low-grade Figure 1.177 Myxofibrosarcoma (myxoid MFH) shows
malignant tumor incorporating the underlying fat. multinodular growth of myxoid lesion with pleomorphic cells.
Figure 1.175 Dermatofibrosarcoma protuberans, showing a Figure 1.178 Myxofibrosarcoma (myxoid MFH) shows myxoid
mixture of fat cells and spindle cells.This pattern is seen at the background with numerous giant and pleomorphic malignant cells.
infiltrative edges due to incorporation of the underlying
subcutaneous fat.
Figure 1.179 Myxoid leiomyosarcoma showing pleomorphic and Figure 1.182 Low-grade fibromyxoid sarcoma.
bizarre giant cells.
Figure 1.180 Myxoid leiomyosarcoma, showing desmin-positive Figure 1.183 Myxoid leiomyosarcoma, showing rounded and
cells. epithelioid cells arranged in cords.
Figure 1.181 Cellular intramuscular myxoma. Figure 1.184 Myxoid liposarcoma, showing small uniform tumor
cells with plexiform vascular pattern.
SPINDLE CELL LESIONS WITH SIGNIFICANT

OSTEOID COMPONENT (Figures 1.185–1.189)
Osteoid is dense collagen which, if mineralized, becomes bone.

Bone or osteoid that is laid down by tumor cells is called neo-
plastic bone, while osteoid that is not produced by the cells is
called metaplastic bone. Neoplastic bone is densely eosinophilic,
rimmed by tumor cells, and most often laid down in long narrow
trabeculae with irregular margins and cross branches, likened to
lace. Less often, tumor osteoid is produced in sheets or broad
trabeculae with irregular margins. In benign osseous lesions, the
osteoid trabeculae tend to have a smoother contour and are
often broad and the osteoid-forming cells are uniform and have
bland nuclei. In malignant osseous lesions the trabeculae are typ-
ically narrower and the osteoid-forming cells are pleomorphic.
When tumor osteoid mineralizes, it often takes on a purplish
hue when stained with hematoxylin and eosin (H&E), and this Figure 1.187 Osteosarcoma, showing broad trabeculae of
neoplastic bone.
tinctorial quality – combined with its irregular thin trabecu-
lar arrangement – almost always allows easy recognition of
mineralized tumor bone. Benign osteoid-forming lesions are
Figure 1.188 Osteosarcoma, showing broad trabeculae of

neoplastic bone, lined by malignant osteoblasts.
Figure 1.185 Sarcomatoid carcinoma of the breast with
osteosarcomatous element showing neoplastic bone.
Figure 1.189 Carcinoid tumor of the lung, showing metaplastic

Figure 1.186 Osteosarcoma with lace-like neoplastic osteoid. bone formation.
osteomas and osteochondromas, and in soft tissue include myosi- Extraosseous chondromas most commonly occur on the
tis ossificans and related lesions such as fibro-osseous pseudotu- hands and feet. Synovial chondromatosis is histologically iden-
mor of the digits, ossifying fasciitis, ossifying panniculitis, and tical to soft tissue chondromas, but is localized to the synovium.
progressive fibrodysplasia ossificans. Osteosarcoma is the only Chondrosarcoma is a malignant, cartilage-producing tumor.
malignant tumor that lays down neoplastic bone. Metaplastic hyaline cartilage is seen in a number of benign soft
Metaplastic bone usually does not have the irregular, fine, lace- tissue tumors such as chondrolipoma, atypical lipoma, giant cell
like trabecular pattern of neoplastic bone, nor does it have its tumor of tendon sheath and calcifying apponeurotic fibroma and
lavender hue; rather, metaplastic bone is usually deposited as reg- mixed salivary tumor. Metaplastic cartilage is almost always focal.
ular fragments of well-formed, most often eosinophilic bone, Benign cartilage within a sarcoma is generally metaplastic and the
which has smooth outlines and sometimes a lamellar pattern. sarcoma is classified on the basis of the non-cartilaginous areas.
Characteristically, metaplastic bone is located at the periphery of Metaplastic bone and cartilage often coexist in the same lesions,
the tumor and is sparse in contrast to tumor bone, which is typ- but when both neoplastic cartilage and neoplastic bone are seen
ically more widely distributed throughout the lesion. Metaplastic in the same bone or soft tissue sarcoma, the neoplastic bone takes
bone can be seen in a wide variety of benign and malignant soft precedence and the tumor is classified as an osteosarcoma. Benign
tissue tumors, the most important being synovial sarcoma, giant tumors composed of bone and cartilage are very rare in soft tis-
cell variant of MFH, atypical lipomas, liposarcoma, epithelioid sue but, as in bone, they are classified as osteochondromas.
hemangioendothelioma, and epithelioid sarcoma. Benign tumors
that have metaplastic bone are calcifying aponeurotic fibroma, TUMORS WITH MIXED MESENCHYMAL
ossifying fibromyxoid tumor of soft tissue, and leiomyoma with
osseous metaplasia. Nodular fasciitis located near bone or COMPONENTS (Figure 1.191)
periosteum may show metaplastic ossification. It may be impos-
sible in some cases to determine whether bone is metaplastic or The term mesenchymoma has been used for benign and malig-
neoplastic. nant tumors, which demonstrate more than two lines of differ-
entiation. There are so many such tumors that the term
mesenchymoma has lost its specificity. For the purpose of sim-
plicity, we shall use mesenchymoma pattern to indicate tumor
SPINDLE CELL LESIONS WITH SIGNIFICANT with more than two mesenchymal components. Benign tumors
CHONDROID COMPONENT (Figure 1.190) with mesenchymoma pattern include angiomyolipoma, intra-
muscular hemangioma, and aneurysmal bone cyst. Malignant
These are tumors in which the constituent cells produce carti- tumors with mesenchymoma pattern include leiomyosarcoma
lage. While tumor osteoid is accepted as evidence of osseous dif- with chondroid or osteoid metaplasia, liposarcoma with osteoid
ferentiation, it is not generally accepted that ‘chondroid’ is metaplasia, and the rare true malignant mesenchymoma.
evidence of cartilaginous differentiation. Chondroid is essentially
acid mucopolysaccharide and is morphologically non-specific (as
seen in myxoid chondrosarcoma), while differentiated hyaline
cartilage is more specific and features cells in lacunae surrounded
by a uniform, dense, basophilic matrix. Benign tumors with
mature hyaline cartilage are called chondromas; these can be
seen in bone and soft tissue.
Figure 1.191 Angiomyolipoma, showing mature fat cells

intermixed with smooth muscle and thickened-wall vessels.
BIPHASIC PATTERN (Figures 1.192–1.195)
These spindle cell tumors contain either epithelial/epithelioid or

Figure 1.190 Chondroblastic osteosarcoma, showing both glandular components. Both the epithelial and the mesenchymal
chondroid and osteoid elements. elements can take any of the forms described in the preceding
Figure 1.192 Biphasic synovial sarcoma, showing nests of Figure 1.195 Malignant mixed mullerian tumor, showing an
epithelioid cells set in a myxoid background malignant stroma. endometrial gland with malignant round cell background stroma
containing scattered rhabdomyoblasts.
chapters, and may be either benign or malignant. In benign

biphasic lesions, both elements have a clearly bland appearance;
this pattern is classically seen in benign phyllodes tumor of the
breast, pleomorphic salivary gland adenoma, adenomyomas, bile
duct adenoma, and ameloblastoma. In malignant bi/triphasic
lesions, one or both elements are malignant; typical examples are
sarcomatoid carcinoma, synovial sarcoma, malignant peripheral
nerve sheath tumor, mesothelioma, Wilms’ tumor and in some
malignant melanomas.
VASCULAR PATTERN

which the predominant feature is an abundance of blood ves-
sels. The various tumors within this group can be distinguished
Figure 1.193 Biphasic synovial sarcoma, showing undifferentiated according to the patterns of the vessels.
spindle and epithelioid cells with isolated glandular structures.
ANASTOMOSING/INTERCOMMUNICATING/
SLIT-LIKE VASCULAR CHANNELS
These terms describe intercommunicating and freely anasto-

mosing vascular channels lined by endothelial cells. This is typ-
ically seen in truly vascular tumors such as angiosarcoma,
hemangioblastoma, littoral cell hemangioma, lymphangiomy-
oma, lymphangiomatosis, Masson’s hemangioma, and retiform
hemangioendothelioma.
GRANULATION TISSUE-TYPE VESSELS

These are small, straight or curved capillary-type vessels lined

by prominent and rather plump or epithelioid-looking endo-
Figure 1.194 Malignant peripheral nerve sheath tumor, showing thelial cells. Sometimes, the endothelial cells are lined in a
cords and nests of epithelioid cells with a neural-type mesenchymal ‘tombstone’ pattern which is commonly seen in nodular fasciitis
background. and in myofibrosarcoma.
Vascular pattern 45
Figure 1.196 Angiosarcoma, showing intercommunicating, Figure 1.199 Juvenile nasopharyngeal angiofibroma, showing
anastomosing vascular spaces lined by malignant endothelial cells. granulation tissue-like capillary vessels.
HEMANGIOPERICYTOMATOUS-TYPE VESSELS
This is represented by thin-walled, endothelial-lined vascular

channels ranging from capillary-sized vessels to large gaping
sinusoidal spaces. These are usually angulated, forked, or have a
‘stag-horn’ appearance, and are typically seen in hemangioperi-
cytoma. Other tumors showing hemangiopericytomatous vascu-
lar pattern are monophasic synovial sarcoma, subcutaneous/
deep fibrous histiocytoma, solitary fibrous tumor and low-grade
endometrial stromal sarcoma. Mesenchymal chondrosarcomas
also have hemangiopericytomatous vessels.
PLEXIFORM CAPILLARY PATTERN

(‘CHICKEN FEET’) (Figure 1.200)
Figure 1.197 Masson’s hemangioma, showing anastomosing Numerous thin-walled, elongated often straight capillary-sized
vascular spaces lined by bland endothelial cells.This process of vessels arranged in an arborizing fashion. This is typical of
intercommunication results in the formation of papillae with myxoid liposarcoma.
hyalinized cores.
Figure 1.198 Myofibrosarcoma, showing prominent granulation Figure 1.200 Myxoid liposarcoma, showing classic ‘chicken-feet’
tissue-like vessels. pattern.
ECTATIC VESSELS (Figures 1.201 and 1.202)
A selection of vascular abnormalities are characterized by dilata-

tion of pre-existing vessels. Among the cutaneous lesions, port-
wine stain and angioma serpiginosum are characterized by
dilatation of thin-walled vessels within the dermis while in nevus
araneus (spider nevus) the dilated dermal vessels are thick-walled
arterioles. Venous lake on the other hand consists of a single,
dilated and congested venous varicosity located in the superficial
dermis. Ectatic thin-walled vessels with a rim of eosinophilic
amorphous material around them are characteristically seen in
schwannomas, in gastrointestinal stromal tumors, and in pleo-
morphic hyalinizing angiectatic tumor of soft tissue. In hobnail
hemangioma, the superficial dermal vessels are ectatic and lined
by protuberant (hobnail) nuclei.
PAPILLARY VASCULAR PATTERN (Figure 1.203) Figure 1.203 Masson’s hemangioma, showing hyalinized papillae
lined by endothelial cells.
This is characterized by the presence of numerous small papil-
lae with hyaline core and covered by endothelial cells. This is typically seen in Masson’s hemangioma, which is often formed
in a background of vascular thrombus that may develop within
a normal vessel, a pre-existing vascular lesion or in a hematoma.
The organization and recanalization of the thrombus in such
cases result in papillae formation that is lined by the prominent
endothelial cells. Such papillary pattern is seen rarely in
angiosarcoma, but is often associated with endothelial cell with
malignant morphology.
CAPILLARY HEMANGIOMA PATTERN
The term ‘capillary hemangioma’ encompasses a group of his-

tologically similar but clinically distinct hemangiomas. Capillary
hemangioma is a benign vascular proliferation composed of
small, capillary-sized vessels and most often has a lobular archi-
tecture. Individual lobules are composed of closely packed,
small capillaries. These show little or no luminal canalization
(as is seen in juvenile hemangioma) or show progressive vascu-
Figure 1.201 Cellular schwannoma, showing ectatic vessels lar canalization and dilatation as in more mature or regressed
surrounded by hyaline material. hemangiomas. Endothelial cells are usually plump and may
show mitotic figures. A larger feeding vessel is often seen at the
base of the lesion, with its branches entering each lobule.
Capillary hemangioma pattern is seen in juvenile hemangioma,
pyogenic granuloma, tufted angioma and verrucous heman-
gioma. Reactive angioendotheliomatosis and glomeruloid
hemangioma are also characterized by capillary hemangioma-
type vessels. In the former, there is multifocal discontinuous pro-
liferation of small, close-packed capillaries in the dermis and
less often in the subcutis. In glomeruloid hemangioma, capillary
proliferation is seen within a dilated dermal vessel which results
in a renal glomeruli-like appearance.
CAVERNOUS HEMANGIOMA PATTERN

Cavernous hemangioma is a benign vascular proliferation

Figure 1.202 Schwannoma, showing ectatic vessels. composed of dilated, generally thin-walled blood vessels lined
Vascular pattern 47
EPITHELIOID HEMANGIOMA PATTERN

(Figure 1.206)
Well-formed vessels lined by endothelial cells with abundant

eosinophilic and sometimes vacuolated cytoplasm and plump
vesicular nuclei characterize this pattern. A variety of vascular
tumors or pseudotumors may show this pattern. These include
bacillary (epithelioid) angiomatosis, epithelioid hemangioma,
epithelioid hemangioendothelioma, and epithelioid angiosarcoma.
Figure 1.204 Cavernous hemangioma.
Figure 1.206 Angiolymphoid hyperplasia with eosinophilia,

showing vessels lined by plump vesicular nuclei.
PSEUDOVASCULAR (Figures 1.207–1.211)
This term refers to the presence of cleft-like, slit-like, cavernous-

type or intercommunicating spaces that closely mimic vascular
structures. These are usually lined by cells similar to those seen
in the rest of the tumor, rather than by endothelium. This pattern
Figure 1.205 Intramuscular cavernous hemangioma.
can be seen in a variety of tumors, for example angiomatoid
squamous cell carcinoma that exhibits extensive acantholytic
by flattened endothelium. These vessels are often congested change resulting in an angiosarcomatous or pseudoglandular
and may show thrombosis. Variation in vessel size is common,
and there may be areas with more capillary-type vessels as
well as larger, thick-walled vessels. This pattern is typically
seen in cavernous and sinusoidal hemangioma. Cherry heman-
gioma is a mature form of lobular capillary hemangioma,
forming a small number of lobules in the papillary dermis, but
is composed of thin-walled canalized capillary vessels, more
akin to cavernous hemangioma. Glomangioma shows cav-
ernous vessels cuffed by a round thick rim of glomus cells.
Spindle cell hemangioendothelioma consists of a mixture of
cavernous vessels and areas of solid spindle endothelial cell
proliferation.
MIXED VESSELS PATTERN

Some vascular lesions contain various types of vessels. This is
typically seen in arteriovenous hemangioma in which a mixture
of thick-walled veins, arterial vessels, and areas of capillary and Figure 1.207 Traumatized intradermal nevus often shows
cavernous vessels are seen. cleft-like spaces.
Figure 1.208 Traumatized intradermal nevus, showing cleft-like Figure 1.211 Renal cell carcinoma with the cavernous-like spaces
pseudovascular spaces lined by nevus cells. lined by carcinoma cells.
appearance. Angiomatoid malignant fibrous histiocytoma is

characterized by the presence of pools of blood lined by tumor
cells rather than by endothelial cells. Pools of connective tissue
mucin with peripheral condensation of neoplastic cells in myxoid
liposarcoma may result in lymphangioma pattern or in pseudo-
glandular arrangement. Giant cell fibroblastoma is characterized
by the presence of vascular-like spaces lined by stromal cells and
giant cells. Sometimes, the branching appearance of the neoplas-
tic ducts of pleomorphic salivary gland adenoma may result in a
pseudovascular pattern. Traumatized intradermal naevi fre-
quently exhibit cleft-like spaces.
PROMINENT NON-CELLULAR PATTERN
This category includes lesions which consist predominantly of,

Figure 1.209 Myxoid liposarcoma, showing pseudovascular or contain a significant proportion of, acellular material.
spaces resulting from pools of connective tissue mucin. The following sub-patterns are presented according to the
predominant non-cellular component.
AMYLOID/AMYLOID-LIKE MATERIAL (Figure 1.212)
This is characterized by the presence of pale, eosinophilic, glassy

material. This may be Congo red-positive and therefore a true
amyloid, or Congo red-negative and therefore amyloid-like
material. Examples of tumors that contain true amyloid are
amyloid tumor, medullary carcinoma of the thyroid, basal cell
carcinoma, and pheochromocytoma. Keloid usually shows
amyloid-like areas.
CALCIFICATION/MICROCALCIFICATION
This is characterized by the presence of calcium deposit within

the tissue. The calcification seems to arise out of dense, often
Figure 1.210 Renal cell carcinoma, showing interstitial paucicellular fibrous tissue. In calcifying aponeurotic fibroma, the
hemorrhage with cavernous-like spaces. calcific nodules are often associated with cartilage formation. In
Prominent non-cellular pattern 49
calcifying fibrous tumor/pseudotumor, the calcifications vary

from psammomatous to irregular, structureless, and dystrophic.
Calcification is commonly seen in pleomorphic salivary ade-
noma, synovial sarcoma and in leiomyomas.
HYALINE BANDS/STRANDS/NODULES/
KELOID-LIKE HYALINIZATION (Figures 1.215–1.221)
This is characterized by the presence of rounded, oval, elongated

or irregularly shaped eosinophilic hyaline material that can be
obviously seen at low power magnification. Amianthoid fibers
are acellular, dense, eosinophilic collagen, which appear to
radiate from the center. This is classically seen in intranodal
myofibroblastoma and endometrial stromal tumors. Ropey hya-
line bands are frequently seen in synovial sarcoma, in nodular
fasciitis, in thecoma and fibroma, in myoepithelioma and in
Figure 1.212 Amyloid tumor, showing deposit of amyloid
material. some lipomas and liposarcomas. Keloid-like hyalinization is
characterized by convoluted or undulated broad bands of glassy
Figure 1.213 Calcifying aponeurotic fibroma, showing early Figure 1.215 Endometrial stromal sarcoma, showing amianthoid
calcification associated with cartilage formation. fibers.
Figure 1.214 Scrotal calcinosis, showing extensive nodular Figure 1.216 Endometrial stromal sarcoma, showing amianthoid
calcification with foreign body giant cell reaction. fibers radiating from the center.
Figure 1.217 Fibromatosis, showing keloidal-like hyaline bands. Figure 1.220 Spindle cell lipoma, showing a short, thick hyaline
band.
Figure 1.218 Fibrous hamartoma of infancy, showing focal broad

bands of hyalinized material. Figure 1.221 Solitary fibrous tumor, showing elongated branching
hyaline bands.
acellular hyaline. This is classically seen in keloid, fibromatosis

and in nodular fasciitis. Thin bands of collagen are characteristi-
cally seen in solitary fibrous tumor. Some large hyaline nodules
are surrounded by peripheral palisades of cells resulting in what
resemble ‘giant rosettes’. These are seen mainly in hyalinizing
spindle cell tumor with giant cell rosettes and in endometrial
stromal tumors. Similar rosettes can be seen in calcifying
aponeurotic fibroma, and it has also been observed in calcifying
fibromyxoid tumor of soft tissue. Myoid nodules are roughly
rounded eosinophilic, very sparsely cellular structures reminis-
cent of hyaline nodules. The cells in these myoid nodules are
CD34 and desmin-negative, but actin-positive. They are some-
times seen in DFSP, especially in fibrosarcomatous areas. Fibrous
tissue bands of varying width may divide the tumor into nodules;
these are seen in a variety of tumors, but occur most characteris-
Figure 1.219 Pleomorphic lipoma, showing short fibrillary hyaline tically in clear cell sarcoma of tendon sheath and alveolar soft
bands. part sarcoma.
Prominent non-cellular pattern 51
HYALINE GLOBULES (Figures 1.222–1.225)
These are round, deeply eosinophilic bodies that are seen both
inside and outside the cells. They appear refractile, and are rem-
iniscent of red blood cells but are of various sizes. They are PAS/
diastase-positive, phosphotungstic acid hematoxylin (PTAH)-
positive, and are immunoreactant with alpha-1 antitrypsin. In
addition, they are immunoreactant with alpha-fetoprotein in
endodermal sinus tumor. The nature of these globules is contro-
versial, but they may represent phagocytosed dead red blood
cells coated by serum glycoprotein. They are seen in the major-
ity of gynecological tumors, but in particular in mixed muller-
ian tumors, clear cell carcinoma and endodermal sinus tumor. In
skin lesions they are mainly seen in Kaposi’s sarcoma and some-
times in atypical fibroxanthoma. In soft tissue tumors, they are
found in liposarcoma and malignant fibrous histiocytoma. They
are also seen in sarcomatoid carcinomas. Figure 1.224 Malignant mixed mesodermal tumor of the uterus,
showing numerous intracytoplasmic hyaline globules.
Figure 1.222 Ovarian serous carcinoma, showing cytoplasmic

hyaline globules in some of the luminal cells. Figure 1.225 Kaposi sarcoma with intracytoplasmic hyaline
globules stained dark blue with PTAH.
PSAMMOMA BODIES
Psammoma bodies are round, deeply basophilic, laminated cal-

cific material, that are clearly seen at low-power magnification.
They are seen in diverse tumors, including the various gynecol-
ogical tumors (the most common of which are the serous ovar-
ian tumors), as well as papillary carcinoma of the thyroid,
papillary mesothelioma, bronchoalveolar carcinoma, calcifying
epithelial odontogenic tumor, meningiomas, cutaneous hetero-
topic meningeal nodules, and psammomatous melanocytic
schwannoma.
CRYSTALS
These are either intra- or extracellular crystals. They are seen

Figure 1.223 Pleomorphic liposarcoma, showing various sizes of in alveolar soft part sarcoma, crystal-storing histiocytosis,
intracytoplasmic hyaline globules. pleomorphic salivary gland adenoma, and multiple myeloma.
DISTINCTIVE CELL TYPES
This category consists of lesions in which the dominant cell

type has a distinctive cytoplasmic appearance, usually apparent
at low-power magnification.
ANAPLASTIC CELLS (Figure 1.226, see also

Figures 1.98–1.101)
The term ‘anaplasia’ is defined as a reversion of cells to a more

primitive or less-differentiated form. In this sense, the term
implies dedifferentiation of the neoplasm and as such is used
almost exclusively for malignant tumors of any histogenesis. The
cells tend to be disorganized, poorly differentiated, pleomorphic,
with increased nuclear/cytoplasmic ratio and staining intensity.
Anaplastic cells can be seen in various high-grade malignant Figure 1.227 Clear cell carcinoma of the kidney.
tumors. Typical examples are anaplastic lymphoma, anaplastic
carcinoma, anaplastic seminoma, angiosarcoma, malignant
mesothelioma, and malignant melanoma.
Figure 1.228 Acinic cell carcinoma of the salivary gland, showing

cytoplasmic clearing.
Figure 1.226 Anaplastic endometrial carcinoma. Pleomorphic clear cell change is due to glycogen, mucin or lipid content within
malignant cells with no distinct differentiation. the cells.
CLEAR CELLS (Figures 1.227 and 1.228) GRANULAR CELLS (Figures 1.229–1.234)
These cells have distinctly water-clear or empty-looking cyto- These cells are characterized by the presence of numerous fine
plasm. They may form the predominant cell population in a or coarse intracytoplasmic granules. These are usually PAS-
tumor such as renal cell carcinoma, parathyroid and adrenal positive after diastase digestion. They may constitute the main
tumors and clear cell carcinoma of the ovary, benign clear cell population as in granular cell tumor, or represent a secondary
tumor of the lung, or they form part of the tumor as in a variety change as in variety of tumors such as dermatofibrosarcoma
of other tumors. Focal clear cell change may be seen in squamous protuberans, synovial sarcoma, and angiosarcoma.
carcinoma, adenocarcinoma, myoepithelioma, acinic cell tumor,
angiosarcoma, epithelioid leiomyosarcoma, mesothelioma, acinic
cell carcinoma, clear cell chondrosarcoma, paraganglioma, clear OXYPHILIC/ONCOCYTIC/ONCOCYTOID CELLS
cell sarcoma of tendon sheets, clear cell sarcoma of the kidney, (Figures 1.235–1.238)
nodular hidradenoma, tricholemmoma, germ cell tumors,
struma ovarii, steroid cell tumors, sex-cord stromal tumor, and Oncocytes are large, round or polygonal cells with abundant,
melanoma. Arias–Stella reaction may exhibit distinct clear cell deeply eosinophilic granular cytoplasm due to the presence
change. Clear cell change in the context of round cell tumors of numerous mitochondria. The nuclei are centrally located,
is seen in Ewing’s sarcoma and alveolar rhabdomyosarcoma. The often with prominent nucleoli. Typical examples include salivary
Figure 1.229 Ovarian hilar cells are usually granular and found Figure 1.232 Granular cell tumor showing CD68-positive
within a nerve bundle in the ovarian hilum. granular cells.
Figure 1.233 Oncocytoma of the kidney, showing round cells

with abundant, eosinophilic granular cytoplasm.
Figure 1.230 Granular cell tumor showing large cells with

cytoplasmic granules.
Figure 1.231 Granular cell tumor showing S-100-positive Figure 1.234 Hepatocellular carcinoma showing large cells with
granular cells. abundant eosinophilic cytoplasm.
Figure 1.237 Clear cell carcinoma of the ovary with focal

hepatoid pattern.
Figure 1.235 Hepatocellular carcinoma showing large cells with

abundant eosinophilic cytoplasm.
Figure 1.238 Steroid cell tumor of the ovary, showing cells with
abundant granular eosinophilic cytoplasm reminiscent of
hepatocytes.
gonads, paraganglioma, proximal-type epithelioid sarcoma, and

most apocrine neoplasms.
Figure 1.236 Hepatoid carcinoma of the ovary illustrating Oncocytoid cells with fibrillary cytoplasm are characteristic
collection of hepatoid cells, some of which show intracytoplasmic of myoid cells such as seen in rhabdomyoma and in renal
(␣-fetoprotein-positive) eosinophilic globules. angiomyolipoma.
Mesothelioma, epithelioid leiomyosarcoma and melanoma
and renal oncocytomas, Warthin’s tumor, Hurthle cell tumors of may also have an oxyphil cell pattern.
the thyroid, and oncocytic carcinoma of the salivary glands and
of the nasal cavity. Oncocytoid cells are morphologically similar
to oncocytes but lack mitochondrial abnormality and have HYALINIZED/PLASMACYTOID CELLS
either abundant lysosomes as in granular cell tumor, or neuro- (Figures 1.239–1.241)
secretory granules as in the Hurthle-cell form of medullary
carcinoma of the thyroid and some low-grade neuroendocrine These are medium-sized, round cells containing deeply acido-
carcinomas of the lung, and acidophilic pituitary adenoma. philic homogeneous or glassy cytoplasm with an eccentrically
In other instances, oncocytoid cells contain smooth endoplasmic placed nucleus resembling plasma cells. Tumors with hyalinized
reticulum with mitochondria. This is seen in Leydig cell or lipid cells include pleomorphic and monomorphic salivary gland
cell tumors of the gonads and adrenocortical neoplasm. Other adenomas, myoepithelioma, chondroid syringoma, pituitary
tumors with oncocytoid cells due to the presence of non- adenoma, multiple myeloma, medullary carcinoma of the thy-
mitochondrial inclusions include: chromophobe renal cell carci- roid, neuroendocrine tumors, hepatocellular carcinoma, and
noma, hepatocellular carcinoma, hepatoid neoplasms of the malignant melanoma.
Distinctive cell types 55
RHABDOID CELLS (Figures 1.242–1.244)
These are large, dyscohesive, round, polygonal or sometimes

spindled cells with round to kidney bean-shaped vesicular nuclei
that almost always contain a large, central eosinophilic nucleo-
lus and abundant amphophilic or eosinophilic cytoplasm. The
most distinctive feature is the paranuclear, cytoplasmic homo-
geneous acidophilic inclusion consisting of accumulations of
intermediate filaments. These inclusions have a globular config-
uration and displace the nucleus. They can be inconspicuous
and present in only a few cells, or may be present in many cells
and occasionally in every tumor cell. Rhabdoid cells are seen
in rhabdoid tumor of kidney, extra-renal rhabdoid tumors,
proximal epithelioid sarcoma, malignant mesothelioma, epithe-
lioid leiomyosarcoma, desmoplastic small cell tumor, neuro-
endocrine carcinoma, anaplastic carcinoma, malignant melanoma,
Figure 1.239 Salivary gland myoepithelioma, showing cells with and rare lymphomas.
plasmacytoid pattern.
Figure 1.242 Malignant mixed mullerian tumor of the uterus,

showing rhabdomyosarcomatous element.The rhabdomyoblasts are
Figure 1.240 Chondroid syringoma of the skin, showing large eosinophilic cells with a cytoplasmic pattern reminiscent of
plasmacytoid myoepithelial cells. ‘finger-printing’. Some rhabdomyoblasts exhibit cytoplasmic
vacuolation with spider-like pattern (see circled cells).
Figure 1.241 Malignant melanoma, showing plasmacytoid cells, Figure 1.243 Rhabdoid tumor of soft tissue showing classic
some of which are binucleated. rhabdoid cells (circled).
Figure 1.244 Malignant melanoma showing numerous rhabdoid Figure 1.246 Retroperitoneal liposarcoma, showing focal
cells. hibernoma-like areas.The cells are multivacuolated.
SIGNET RING CELLS
See ‘Signet ring’ glandular pattern, p. 12.
VACUOLATED CELLS (Figures 1.245–1.248)
These are characterized by the presence of usually numerous

intracytoplasmic vacuoles, and are typically seen in liposarcomas
and in acral myxoinflammatory fibroblastic sarcoma. Vacuoles
are also seen in rhabdomyoblasts.
XANTHOMATOUS/FOAM CELLS
These are macrophages that contain hundreds of fine lipid vac-

uoles. These cells may represent the main cell population as in
juvenile xanthogranuloma, xanthoma of tendon sheath and Figure 1.247 Rhabdomyosarcomatous element in malignant
xantholasma or a secondary infiltrate as in fibrous histiocytoma, phyllodes tumor. Some rhabdomyoblasts (encircled) are
endometrial carcinoma, and verruciform xanthoma. multivacuolated.
Figure 1.245 Acral inflammatory myxohyaline sarcoma, showing Figure 1.248 Liposarcoma, showing multivacuolated lipoblasts.The
multivacuolated, lipoblast-like cells (boxed). vacuoles (encircled) indent the nuclei.
Distinctive cell types 57
‘GANGLION-LIKE CELLS’ (Figures 1.249 and 1.250) GIANT CELLS (Figures 1.251–1.254)
A ‘ganglion cell’ is usually a large, ovoid, pyramidal, or polyg- There are numerous types of giant cells, and each type may be
onal bipolar or multipolar cell with basophilic cytoplasm seen in a particular tumor or in more than one tumor.
which varies in size and shape. Each contains a single large ● ‘Floret-like multinucleated giant cell’ is characterized by
vesicular nucleus (or sometimes two or three nuclei) that the presence of numerous, hyperchromatic nuclei arranged
contains a prominent, eosinophilic centrally or eccentrically at the periphery of the cytoplasm in a circular or
located nucleolus. The cytoplasm is usually granular or clear, semicircular pattern. This cell is characteristically seen in
and often contains peripheral condensation of brownish/ atypical lipomas.
golden pigment (Nissl granules). As well as in normal ganglia, ● ‘Foreign body giant cell’ is a multinucleated cell
these cells are seen in tumors such as ganglioneuroma and gan- characterized by the presence of numerous nuclei arranged
glioneuroblastoma. ‘Ganglion-like cells’ are myofibroblasts haphazardly in an eosinophilic, often-vacuolated,
that are somewhat reminiscent of ganglion cells but are devoid cytoplasm. This is typically seen in amyloid tumor.
of peripheral pigmentation. Occasionally, these cells mold to ● ‘Mono/multinucleated bizarre giant cell’ refers to a cell
one another and form clusters, mimicking epithelial cells. showing extreme pleomorphism and hyperchromasia with
These cells are characteristically seen in proliferative lesions lobulation of the nucleus. Such cells can be seen in diverse
such as proliferative fasciitis and proliferative myositis. Similar tumors, including symplastic leiomyoma of the uterus,
cells are characteristically seen in acral myxoinflammatory pleomorphic liposarcoma, pleomorphic leiomyosarcoma,
fibroblastic sarcoma. pleomorphic malignant fibrous histiocytoma, sarcomatoid
carcinoma, and melanoma.
Figure 1.249 Ganglioneuroma, showing classic ganglion cells. Figure 1.251 Pleomorphic lipoma, illustrating classic ‘floret-like’
giant cells.
Figure 1.250 Proliferative myositis, showing numerous ganglion cells. Figure 1.252 Liposarcoma with ‘floret-like’ giant cells.
conditions such as type A lymphomatoid papulosis,

anaplastic lymphomas of both T- and B-cell types, and
in acral myxoinflammatory fibroblastic sarcoma.
● ‘Touton giant cell’ is a large cell with many nuclei
arranged as a circle in the middle of the cell, leaving a
peripheral rim of cytoplasm that usually shows
xanthomatous change (dissolved lipid content) or
sometimes hemosiderin pigment. This cell type is
characteristically seen in juvenile xanthogranuloma and
in dermatofibroma.
‘HOBNAIL’ CELLS
See ‘Hobnail’ pattern, p. 15.
Figure 1.253 Dermatofibroma, showing ‘Touton giant cells’.

SURFACE EPITHELIAL PATTERNS ASSOCIATED
WITH OR AFFECTED BY NEOPLASTIC PROCESS
Certain tumors are associated with surface epithelial changes, and

this is seen particularly in the skin. Some of the common patterns,
seen notably in the skin, are described in the following sections.
LICHENOID REACTION PATTERN (Figure 1.255)
The term lichenoid refers to band-like inflammatory infiltrate

confined to the papillary dermis as seen in lichen planus,
associated with basal cell degeneration. A variety of epidermal
tumors may show lichenoid reaction pattern. These include irri-
tated seborrheic keratosis, solar keratosis, flat wart, intraepi-
dermal carcinoma, and the lichen-planus like keratosis.
Figure 1.254 Acral myxoinflammatory hyaline tumor, showing

scattered Reed–Sternberg-like myofibroblastic cells (boxed).
● ‘Osteoclast/osteoclast-like giant cell’ is a large rounded

or ovoid cell with eosinophilic cytoplasm containing
numerous, usually centrally located nuclei (up to 200) that
may contain small prominent nucleoli. The nuclei appear
crowded but separated one from another and the cytoplasm
may show some vacuolation. Osteoclast-type giant cells are
the hallmark of giant cell tumor of bone, and are found in
a variety of other bone and soft-tissue tumors. The most
common of these are giant cell tumor of tendon sheath,
giant cell carcinoma, plexiform fibrous histiocytoma, giant
cell angioblastoma, giant cell-type malignant fibrous
histiocytoma, osteogenic sarcoma, nodular fasciitis, alveolar
rhabdomyosarcoma, and leiomyosarcoma.
● ‘Reed –Sternberg/Reed–Sternberg-like cell’ classically has
two large kidney-shaped, mirror-image nuclei with Figure 1.255 Actinic lichenoid keratosis.
prominent eosinophilic nucleoli surrounded by clear halos,
and peripheral chromatin condensation. The cytoplasm is
usually eosinophilic and variable in amount. Mononuclear PSORIASIFORM REACTION PATTERN
and multinucleate variants also occur. Classical Reed–
Sternberg cells are the diagnostic hallmark of Hodgkin’s This is characterized by the presence of epidermal hyperplasia
disease, but Reed–Sternberg-like cells are also seen in with regular elongation of the rete ridges. Mycosis fungoides – a
Surface epithelial patterns associated with or affected by neoplastic process 59
variant of cutaneous T-cell lymphoma – is usually associated with to the presence of glycogen, or occasionally due to the presence
psoriasiform reaction, in conjunction with epidermotropism of of mucin or as a consistent artifact of fixation and processing;
atypical lymphocytes. Bowen’s disease is a variant of carcinoma examples include clear cell acanthoma (glycogen), and mam-
in situ showing full-thickness involvement of the epidermis. mary and extramammary Paget’s disease (mucin). Other lesions
In the psoriasiform variant of Bowen’s disease, there is regular that are associated with clear cells are: pagetoid dyskeratosis
acanthosis with thickening of the rete ridges and overlying which is an incidental histological finding characterized by the
parakeratosis. Psoriasiform pattern is also a feature of clear cell presence of pyknotic nuclei surrounded by halo and a rim of
acanthoma, which shows a well-demarcated area of epidermal pale cytoplasm; clear cell papulosis (this may be considered as
hyperplasia with clear cell changes of the cells. Inflammatory precursor of cutaneous Paget’s disease) and is characterized by
linear verrucous epidermal lesion is also characterized by psori- the presence of large clear cells scattered mainly among the
asiform hyperplasia associated with alternating zones of ortho- basal cells with a few cells in malpighian layer; and pagetoid
keratosis and parakeratosis in a horizontal direction. Bowen’s disease which shows nests of pale cells with thin
strands of intervening normal keratinocytes.
CLEAR CELLS WITHIN THE EPIDERMIS
(Figures 1.256 and 1.257) DYSPLASTIC CHANGES OF EPIDERMIS OR
SQUAMOUS MUCOSA (Figures 1.258 and 1.259)
This term is used to describe lesions in which a large proportion
of the constituent cells have pale or clear cytoplasm, usually due ‘Dysplasia’ is a term most frequently used to describe atypia
of surface epithelial cells, and as such is a precancerous condi-
tion. Dysplastic surface epithelium is characterized by lack of
Figure 1.256 Clear-cell acanthoma, showing clearing of the

involved epidermis, compared with the normal to the left.
Figure 1.258 Basaloid VIN3, showing loss of maturation, mitoses
and apoptosis throughout the full thickness of the epithelium.
Figure 1.257 Clear-cell acanthoma showing PAS-positive

cytoplasmic glycogen. Figure 1.259 Intraepidermal carcinoma.
maturation with proliferation of neoplastic cells showing pleo- pale-staining keratinocytes. Clear cell papulosis shows slight
morphic, hyperchromatic nuclei, increased mitotic activity and acanthosis with presence of clear cells, mainly among the basal
loss of normal polarity. Examples include actinic keratosis, squa- layers. In large cell acanthoma, epidermal thickening is due to
mous carcinoma in situ, and the various intraepithelial neoplasias. enlargement of the keratinocytes; this is usually associated with
mild papillomatosis, mild basal pigmentation, and some down-
PSEUDOEPITHELIOMATOUS HYPERPLASTIC ward budding of the rete ridges, together with orthokeratosis
and hypergranulosis. Acanthotic change with basal cell differen-
(Figure 1.260) tiation is a common feature of the epidermis that overlies
dermatofibroma.
This is characterized by pronounced hyperplasia of the epider-
mis, with irregular expansion and downgrowth of the rete ridges
in a manner simulating squamous cell carcinoma. This prolifer- PATTERN WITH ‘CUP-SHAPED’ OR INVERTED
ation occurs in response to a wide range of stimuli, including LOBULES OF SQUAMOUS EPITHELIUM
chronic irritation, such as around urostomy and colostomy sites,
trauma, cryotherapy, chronic lymphedema and various dermal A number of epidermal lesions take the form of one or several
inflammatory processes such chromomycosis, arthropod bite, irregular or cup-shaped invaginations of surface epithelium.
and amebiasis. Pseudoepitheliomatous hyperplasia may develop These may exhibit hyperplastic, dysplastic, or other features.
in association with prurigo nodularis, chondrodermatitis nodu- Examples are inverted follicular keratosis, keratoacanthoma,
laris helices, Spitz nevus, malignant melanoma, and overlying and warty dyskeratoma. Molluscum contagiosum also shows
granular cell tumor. Unlike squamous carcinoma, pseudoepithe- similar lobules with molluscum bodies maturing towards
liomatous hyperplasia shows minimal cytological atypia and the surface.
only a few mitoses.
NESTING OR CLONAL PROLIFERATION

‘BORST–JADASSOHN PHENOMENON’
(Figures 1.261–1.264)
This is characterized by the presence within the surface

epithelium or the epidermis of groups or nests of a uniform cell
population differing in appearance (but not necessarily in
histogenesis) from the surrounding cells. In intraepidermal
lesions, this is sometimes referred to as the Borst–Jadassohn
phenomenon. Typical examples are clonal Bowen’s disease,
clonal seborrheic keratosis, hidroacanthoma simplex (intraepi-
dermal eccrine poroma), intraepidermal basal cell carcinoma,
intraepidermal squamous cell carcinoma, and pagetoid malignant
melanoma.
Figure 1.260 Pseudoepitheliomatous hyperplasia overlying

granular cell tumor.
ACANTHOMA PATTERN
Acanthomas are benign tumors of the epidermal keratinocytes,

and are characterized by variable hyperkeratosis, papillomatosis,
and acanthosis. These may be associated with epidermolytic
changes as in epidermolytic acanthoma, or with suprabasal cleft-
ing and numerous acantholytic and dyskeratotic cells as in warty
dyskeratoma, or with prominent acantholysis as in acantholytic
acanthoma. The acanthotic-type seborrheic keratosis has a simi-
lar pattern but with intervening horn cysts, and the cells are
basaloid. Melanoacanthoma also has acanthoma pattern with
slightly verrucous epidermis and the presence of dendritic Figure 1.261 Clonal intraepidermal carcinoma, showing aggregates
melanocytes scattered throughout the lesion. Clear cell acan- of abnormal keratinocytes sharply delineated from the normal
thoma shows both acanthosis and psoriasiform pattern with epidermal cells.
Surface epithelial patterns associated with or affected by neoplastic process 61
PAGETOID PATTERN (Figures 1.265–1.267)
This term is used to describe lesions showing the growth pat-

tern typified by Paget’s disease of the nipple. It is characterized
by the presence of nests or isolated single cells at the dermo-
epidermal junction or throughout the epidermal layers. Classic
examples include mammary and extramammary Paget’s dis-
ease, superficial spreading malignant melanoma, and the page-
toid variant of Bowen’s disease.
ELONGATED ANASTOMOSING STRANDS

(Figure 1.268)
This pattern is characterized by the presence of usually thin,

elongated, and intercommunicated cords of basaloid epithelial
Figure 1.262 Clonal intraepidermal carcinoma (higher power cells connected to the under-surface of the epidermis. This is typ-
micrograph of Figure 1.261). ically seen fibroepithelial variant of basal cell carcinoma, eccrine
poroma, and acrosyringeal nevus and syringofibroadenoma.
Figure 1.263 Clonal intraepidermal carcinoma cells are highlighted Figure 1.265 Extramammary Paget’s disease, showing scattered
by MIB1 (Ki-67 Antigen; Dako M7240). intraepidermal malignant glandular cells with clear cytoplasm.
Figure 1.266 Pagetoid Bowen’s disease, showing pale

intraepidermal neoplastic squamous cells separated by
Figure 1.264 Clonal seborrheic keratosis. intervening normal keratinocytes.
VERRUCOUS PATTERN (Figures 1.269 and 1.270)
This is characterized by hyperkeratosis and marked acanthosis

with some papillomatosis. It is typically seen in seborrheic
keratosis, condyloma acuminatum, viral wart, verrucous carci-
noma, verrucous melanoma, verrucous hemangioma and verru-
ciform xanthoma.
Figure 1.267 Superficial spreading melanoma, showing nests of

abnormal melanocytes.
Figure 1.269 Viral wart showing verrucous pattern.
Figure 1.268 Fibroepithelial polyp of Pinkus (basal cell carcinoma).
Elongations of the rete ridges occur in a variety of lesions

including organoid nevus (nevus sebaceous of Jadassohn), reti-
culated seborrheic keratosis and Becker’s nevus. A similar pattern
with intervening heavy inflammatory infiltrate is seen in milker’s
nodule, which results from infection with the paravaccinia virus,
transmitted from the udders of infected cows.
Figure 1.270 Verrucous carcinoma of the vulva.
BROAD ANASTOMOSING/INTERLACING
EPITHELIUM
This pattern is characterized by the presence of broad, irregularly

shaped anastomosing and intercommunicating epithelial struc-
tures. These may appear to communicate with or be separated
from the overlying surface epithelium. Examples of such pattern
are seen in eccrine poroma, pillar tumor, and viral wart.
PART II
SYSTEM/ORGAN chapters in
alphabetical order
2 bone tumors
Awatif I Al-Nafussi and David Hughes
Cartilage tumors 65 Miscellaneous tumors 77

Chondroblastoma 65 Adamantinoma 77
Chondromas 66 Aneurysmal bone cyst 78
Chondromyxoid fibroma 66 Chest wall hamartoma 79
Chondrosarcoma, clear cell type 68 Intraosseous ganglion 79
Chondrosarcoma, conventional 68 Langerhans histiocytosis 79
Chondrosarcoma, mesenchymal 69 Lymphoreticular tumors 79
Synovial chondromatosis 71 Other mesenchymal tumors 80
Fibro-osseous tumors 71 Notochondral tumors 81

Bizarre paraosteal osteochondromatous proliferation Chordoma 81
of bone (Nora’s lesion) 71
Fibrocartilaginous mesenchymoma of bone 71 Osteogenic tumors 82
Fibrous dysplasia 72 Osteoblastoma 82
Florid reactive periostitis 73 Osteochondroma 82
Non-ossifying fibroma/metaphyseal fibrous defect 73 Osteoid osteoma 82
Ossifying fibroma/osteofibrous dysplasia 74 Osteoma/bone island 83
Osteosarcomas 83
Fibrous and fibrohistiocytic tumors 74
Benign fibrous histiocytoma 74 Tumors of uncertain histogenesis 85
Desmoplastic fibroma 75 Ewing’s sarcoma/primitive neuroectodermal tumor (PNET) 85
Fibrosarcoma 75
Malignant fibrous histiocytoma 76 WHO classification of bone tumors 85
Giant cell tumor 76

Giant cell tumor of bone 76
GENERAL COMMENTS CARTILAGE TUMORS

Primary bone tumors are relatively uncommon, occur at any age,
and can be either benign or malignant. Secondary involvement CHONDROBLASTOMA
by metastases is more common. In dealing with bone tumors,
pathologists need to be familiar not only with the common
CLINICAL FEATURES
tumors, but with the rare and unfamiliar tumors and tumor-like
conditions. The consequences of a pathological misdiagnosis Chondroblastoma represents less than 1% of all primary bone
can be quite drastic to the patient’s management. The key to tumors. It is generally regarded as a benign, solitary cartilage-
pathological diagnosis of bone tumors is the knowledge of clini- producing lesion, but tumors showing aggressive behavior or
cal information and the imaging and X-radiographic findings. even metastases have been documented. It most commonly affects
Many mesenchymal lesions found in soft tissue – both benign the epiphyses of long bones during the second and third decades
and malignant – can also occur in bone. of life. There is a male predominance. The tumor is located more
The diagnostic categories used here are the same as those used frequently at other sites such as the skull or temporal bone in
in the current World Health Organization (WHO) classifica- older patients. Chondroblastoma is characteristically painful and
tion of bone tumors. often associated with inflammatory responses such as marrow
In this chapter, all tumors and tumor-like conditions of bone and soft-tissue edema, and reactive synovitis. Radiologically, it is
are described and listed in alphabetical and histogenetic order. a well-demarcated lesion containing areas of rarefaction.
66 Bone tumors
The treatment of choice is complete curettage with bone graft- Focal necrosis and aneurysmal bone cyst-like change can
ing, providing local control in 82% of patients at 2 years’ follow- occur as secondary features.
up. Recurrent tumors can usually be treated in the same manner.
Differential diagnosis
PATHOLOGICAL FEATURES (Figures 2.1 and 2.2) ● Giant cell tumor of bone
Chondroblastoma is a solid and hypercellular lesion, consisting
● Aneurysmal bone cyst
of round, oval or polyhedral cells with varying amounts of
● Chondromyxoid fibroma
immature chondroid tissue and variable numbers of osteo-
clasts. Lace-like areas of calcification are often seen. Mitoses Special techniques
are commonly seen in small numbers. No morphological fea- ● The cells are S-100-positive
tures are of value in assessing the aggressive potential of any
particular tumor. CHONDROMAS
CLINICAL FEATURES
Chondromas are common benign cartilaginous tumors that are
most commonly located in the central portion of the diaphysis
(enchondromas), or may arise from the periosteal surface with
thinning of the adjacent cortex (periosteal chondromas). They
most commonly affect the tubular bones of the hands and feet.
Radiologically, they produce a well-defined rarefaction, often
with stippled or mottled calcification.
Chondromas can be multiple (Ollier’s disease). This condition
is usually sporadic, but can be familial, being inherited in a
autosomal dominant pattern with reduced penetrance. Multiple
chondromas associated with soft tissue hemangiomas constitute
Mafucci’s syndrome. There is an increased risk of malignant
transformation in the multiple chondroma syndromes.
PATHOLOGICAL FEATURES (Figures 2.3 and 2.4)

Chondromas are distinctly lobulated lesions consisting of variably
cellular hyaline cartilage. There may be foci of calcification,
ischemic necrosis, endochondral ossification and myxoid change.
The chondrocytes are variable in size and shape, but are usu-
ally small and have regular nuclei. Occasional binucleate cells
are present. Mitoses are very rarely seen. Lesions in peripheral
locations tend to have greater cellularity.
● Chondrosarcoma (the distinction between chondroma and
low-grade chondrosarcoma may not be possible on
histological grounds alone).
● Osteochondromas and bizarre parosteal osteo-
chondromatous proliferation may mimic periosteal
chondroma in a small biopsy specimen.
Special techniques
● The chondrocytes are S-100-positive.
CHONDROMYXOID FIBROMA
CLINICAL FEATURES
Figures 2.1 and 2.2 Chondroblastoma. A uniform population Chondromyxoid fibroma is a rare benign lesion constituting less
of ovoid/polygonal cells forming a cartilage-like matrix in areas. than 1% of bone tumors. It usually occurs in individuals under
Osteoclast-like giant cells are also present (encircled). the age of 30 years, and is typically located in the metaphysis
Cartilage tumors 67
Figures 2.3 and 2.4 Chondroma. A lobulated lesion consisting of

variably cellular hyaline cartilage.The chondrocytes are variable
in size and shape, but are usually small and have regular nuclei.
of long bones, but may occur in other locations such as the

small bones of hands and feet, pelvic girdle, and ribs.
It has a characteristic X-ray appearance of a sharply circum- Figures 2.5, 2.6 and 2.7 Chondromyxoid fibroma. A lobular
scribed, eccentric rarefaction. Chondromyxoid fibromas are lesion with fibrovascular septae separating the lobules. Each lobule
best treated by en-bloc excision, as local recurrence may follow consists of a hypocellular chondromyxoid central zone and a
curettage in about 25% of cases. hypercellular peripheral zone containing concentrated nuclei,
fibroblasts, and osteoclasts.
PATHOLOGICAL FEATURES (Figures 2.5–2.7)
osteoclasts. Varying degrees of collagenization may be seen in the
Chondromyxoid fibroma is characteristically lobular with fib- lobules. Foci of amorphous or sometimes lace-like calcification
rovascular septae separating the lobules. Each lobule consists of may be present.
a hypocellular chondromyxoid central zone and a hypercellular The constituent cells are a mixture of chondrocytes, stellate cells
peripheral zone containing concentrated nuclei, fibroblasts, and and spindle cells, the latter having long cytoplasmic processes
68 Bone tumors
in areas of myxoid matrix. The osteoclasts are of conventional

appearance.
● Chondrosarcoma
● Chondroblastoma
● Myxoma of bone
● Myxoid malignant fibrous histiocytoma of bone
CHONDROSARCOMA, CLEAR CELL TYPE
CLINICAL FEATURES
Clear cell chondrosarcoma of bone is a low-grade malignant
tumor that differs clinically and radiologically from conven-
tional chondrosarcoma. It is more common in males, affecting
patients in their third or fourth decades.
It has a predilection for the ends of long bones, most cases
occurring in the epiphyses of the femoral or humeral head. It is
a lytic expansile lesion on X-radiography. Clear cell chondro-
sarcoma is best treated by en-bloc resection with a margin
of normal bone and soft tissue. The mortality rate is 15%.
Dedifferentiation can occur in the same way as for conven-
tional chondrosarcomas.

Clear cell chondrosarcoma is composed of multiple microscopic
lobules separated by fibrovascular stroma. These lobules consist
of sheets of round clear cells with uniform central nuclei. The
intercellular stroma is scanty and may contain small bone tra-
beculae. Areas mimicking other benign or malignant primary
bone tumors (aneurysmal bone cyst, giant cell tumor, chon-
droblastoma, osteoblastoma, and osteosarcoma) are frequently
present. Foci of conventional chondrosarcoma may be seen.
The principal constituent cells are round with abundant clear
or ground glass cytoplasm and usually indistinct cell membrane
and centrally located nuclei with evenly distributed chromatin.
Mitoses are rarely seen.
● Conventional chondrosarcoma Figures 2.8 and 2.9 Clear cell chondrosarcoma.This consists
● Chondroblastoma of sheets of round clear cells with uniform central nuclei.The
● Metastatic carcinoma intercellular stroma is scanty.The cells are round with an abundant
clear or ground-glass cytoplasm, a usually indistinct cell membrane,
● Osteosarcoma and centrally located nuclei with evenly distributed chromatin.
Special techniques
● See Chondrosarcoma, conventional (below) commoner types of primary bone tumors, and can occasionally
arise in soft tissue. They may be derived from a precursor benign
cartilaginous lesion, most commonly in one of the multiple
CHONDROSARCOMA, CONVENTIONAL chondroma/osteochondroma syndromes. Chondrosarcomas can
also complicate Paget’s disease of bone.
Chondrosarcomas occur most commonly in adults between
CLINICAL FEATURES
the ages of 30 and 60 years.
Chondrosarcoma is defined as a malignant neoplasm consisting They may be located centrally (in the medulla) or peripher-
purely of hyaline cartilage. Chondrosarcomas are one of the ally (in the cortex or periosteum) of bone.
Cartilage tumors 69
Radiologically, they present as osteolytic lesions with a vari-

able degree of blotchy calcification.
Prognosis depends on grade, survival varying between 78 and
22% according to the grade of the tumor. Low-grade lesions
commonly recur after local excision, sometimes with multiple
recurrences over many years. A small proportion of these
tumors dedifferentiate, giving rise to high-grade undifferenti-
ated sarcomas or osteosarcomas with high metastatic potential.
Breast cancer and cartilaginous tumors (enchondroma and
chondrosarcoma) are found to occur rather frequently in the
same patient. This association may suggest a genetic trait.

Low-grade chondrosarcomas (grades 1, 2) resemble benign chon-
dromas. They are generally lobulated and consist of abundant,
hyaline cartilaginous matrix containing variable numbers of
chondrocytes. These are located in variably sized groups within
lacunae, and may exhibit mild pleomorphism. The nuclei are gen-
erally hyperchromatic and may be multiple. Mitoses may be pres-
ent. The distinction between grades 1 and 2 is subjective and
based on cellularity, frequency of binucleation, and multiple cells
per lacuna. The key criterion for the diagnosis of malignancy is
permeative growth between pre-existing bone trabeculae or with
Haversian canals.
Endochondral ossification of the neoplastic cartilage is com-
mon and can be extensive. There may be a variable degree of
myxoid change.
The constituent cells are clearly identifiable as chondrocytes,
residing within lacunae containing pericellular matrix. These
chondrocytes may be of variable size and shape, may be
binucleate or multinucleate, and more than one cell may be
present within a single lacuna. Mitoses may be present, but are
rarely numerous.
In some tumors the chondrocytes have a predominantly signet
ring morphology ‘signet ring chondrosarcoma’.
High-grade chondrosarcomas (grade 3) represent a minority
of chondrosarcomas (3% in one series). They exhibit islands of
atypical cartilage bordered by more primitive precartilaginous
mesenchyme. The latter is composed of a myxoid background
containing spindle and/or round cells displaying varying degrees
of hyperchromasia, cellular pleomorphism, and giant cell for-
mation. The volume of intercellular matrix is significantly less
than is seen in low-grade lesions. Figures 2.10 and 2.11 Chondrosarcoma.This grade 3 lesion
Dedifferentiated chondrosarcomas are chondrosarcomas of shows areas of high cellularity and areas where cells are arranged
any grade in which there is a distinct high-grade, non- singly or grouped in lacunae.The key criterion for the diagnosis of
chondrosarcomatous element. This may consist of undifferen- malignancy in any chondrosarcoma is permeative growth between
pre-existing bone trabeculae.
tiated spindle cell or pleomorphic sarcoma or high-grade
osteosarcoma. A rhabdomyosarcomatous component may also
be seen.
Special techniques
Differential diagnosis ● The tumor cells are immunoreactive for S-100 protein,
● Chondroma vimentin, and sometimes actin.
● Osteochondroma
● Synovial chondromatosis
● Osteosarcoma (particularly periosteal) CHONDROSARCOMA, MESENCHYMAL
● Chondroblastoma See also Extraskeletal mesenchymal chondrosarcoma (p. 1053).
70 Bone tumors
Figure 2.14 Dedifferentiated chondrosarcoma; this consists of

undifferentiated spindle cells resembling fibrosarcoma.
The behavior is aggressive, with frequent metastasis to regional

lymph nodes and distant sites, sometimes as long as 20 years
after initial presentation.
Dedifferentiation has been reported to occur. Oncogenic
osteomalacia has been reported in association with this tumor.

Mesenchymal chondrosarcoma consists of a combination of
undifferentiated small cells with areas of cartilaginous differen-
tiation. The small cells are fairly uniform, round, polygonal, or
spindle-shaped, are arranged in sheets, and show perivascular
condensation. In some tumors the vascular component is so
prominent that a hemangiopericytomatous growth pattern is pro-
duced. Isolated, sharply demarcated foci of well-differentiated
cartilage that may show ossification are usually present.
Figures 2.12 and 2.13 Low-grade chondrosarcoma (grade 2).

This is more cellular than grade I.The nuclei are hyperchromatic, ● Rhabdomyosarcoma
and some are multiple. ● Ewing’s sarcoma
● Small cell osteosarcoma
● Malignant hemangiopericytoma
CLINICAL FEATURES ● Monomorphic synovial sarcoma
● Dedifferentiated conventional chondrosarcoma
Mesenchymal chondrosarcoma is a rare type of chondrosar-
coma, constituting less than 10% of chondrosarcomas. It typi-
cally affects younger individuals, usually in their second or third Special techniques
decades. ● The small cell component expresses CD99 and
Mesenchymal chondrosarcomas usually present with pain vimentin and occasionally markers of neural
and swelling. Most parts of the skeleton can be affected, differentiation
notably flat bones (including the craniofacial bones) and verte- ● The cartilaginous areas is positive for S-100 protein
brae. This type of tumor can also present in soft tissue and the ● The cells are occasionally positive for smooth-muscle
meninges. actin
Fibro-osseous tumors 71
FIBRO-OSSEOUS TUMORS
BIZARRE PAROSTEAL OSTEOCHONDROMATOUS

PROLIFERATION OF BONE (NORA’S LESION)
CLINICAL FEATURES
Bizarre parosteal osteochondromatous proliferation of bone
(BPOP) is a form of heterotopic ossification that can occur at
any age, but typically occurs in the third or fourth decade, and
affects both sexes equally. It usually involves the small bones of
the hands and, less often, the feet. The lesion varies in size from
0.4 to 3 cm, and shows a typical X-radiographic appearance of
a heavily calcified, mushroom-shaped mass with broad base
attached to the underlying cortex. Although a benign lesion, it
may behave aggressively with rapid growth and high risk of
local recurrence after local resection. Local recurrences occur
in nearly 55% of cases. BPOP apparently arises from the
periosteal tissues through a process of cartilaginous metaplasia.
PATHOLOGICAL FEATURES
BPOP is characterized by a rather disordered mass of cartilage
and fibrous tissue undergoing endochondral ossification. There
is usually a cartilaginous cap, but this lacks the polarization and
organization seen in osteochondromas. The lesional tissue is in
continuity with the underlying periosteum. The constituent cells
(chondrocytes, fibroblasts, osteoblasts, osteoclasts) are morpho-
logically normal, although the chondrocytes may be binucleate.
The fibroblastic areas may be mitotically active, but atypical
forms are not seen.
● Osteochondroma
● Fracture callus
● Parosteal or periosteal osteosarcoma
● Subungual exostosis (histologically lacks the chondroid
component and is usually painful and has a characteristic
location)
● Heterotopic chondro-ossification
● Florid reactive periostitis (lacks the cartilaginous component)
Figures 2.15 and 2.16 Mesenchymal chondrosarcoma of the ● Myositis ossificans (lacks a cartilaginous cap)
mandible.These consist of small round cells with chondroid islands.
The latter may show early ossification. ● Fibro-osseous pseudotumor (this is considered to be a
superficial form of myositis ossificans, which only rarely
contains islands of cartilage)
● Desmin may highlight scattered small cells or may rarely

show diffuse expression FIBROCARTILAGINOUS MESENCHYMOMA
● Focal expression of myoD1 may occasionally be seen OF BONE
within the small cell component of the tumor
● The 11;22 translocation of Ewing’s family tumors is not
seen in mesenchymal chondrosarcoma CLINICAL FEATURES
Fibrocartilaginous mesenchymoma of bone is a very rare,
SYNOVIAL CHONDROMATOSIS locally aggressive primary bone tumor, presenting in patients
between the ages of 9 and 25 years. It occurs most commonly
See Chapter 13, Soft tissue tumors. in the metaphyses of long bone, with the fibula accounting for
72 Bone tumors
one-third of cases. The radiological appearance is of an expansile PATHOLOGICAL FEATURES (Figures 2.17 and 2.18)
radiolucent lesion expanding the involved bone with small
Fibrous dysplasia of bone is characterized by the presence of
areas of cortical destruction and focal lesional calcification. It
fibrous and bony components:
has a tendency for local recurrence, but does not metastasize.
1. The fibrous component is usually cellular and arranged in
whorls or fascicles, but may also be collagenous or
PATHOLOGICAL FEATURES arranged in an interlacing pattern.
Fibrocartilaginous mesenchymoma of bone consists of three 2. The bony component consists of rather slender trabeculae
components: spindle cells admixed with bone trabeculae and of immature woven bone (maturation into lamellar bone
islands of cartilage. can be seen in long standing lesions). These are of various
The spindle cells are elongated, somewhat hyperchromatic, sizes and shapes, often Y- or W-shaped, and sometimes
and are arranged in compact fascicles. They tend to invade
marrow spaces and sometimes extend into surrounding soft tis-
sue. Clusters of benign-looking giant cells are often seen.
The bone trabeculae vary from short to long or rounded
islands similar to those seen in fibrous dysplasia.
The cartilaginous component shows two distinct patterns: well-
circumscribed nodules of cellular hyaline cartilage interspersed
with proliferating fibroblasts and epiphyseal plate-like cartilage
reminiscent of the normal epiphyseal plate or the cartilaginous
cap of an osteochondroma. These epiphyseal plate-like cartilagi-
nous islands show characteristic arrangement of chondrocytes in
columns together with presence of endochondral ossification.
● Chest wall hamartoma or mesenchymoma (similarly shows
cartilage plates but loose arrangement of spindle cells and
occurs only in infants and has a limited growth potential)
● Fibrous dysplasia (the spindle cells are short and do not
show hyperchromasia and lacks epiphyseal plate-like
cartilage)
● Dedifferentiated chondrosarcoma (is a high-grade malignant
tumor with the spindle cells being obviously sarcomatous)
● Low-grade osteosarcoma
● Desmoplastic fibroma
FIBROUS DYSPLASIA
CLINICAL FEATURES
Fibrous dysplasia is a developmental defect that often presents
in infants and children, but may remain quiescent until adoles-
cence or adulthood. It may affect solitary (monostotic fibrous
dysplasia) or multiple sites (polyostotic fibrous dysplasia). The
latter can be associated with cutaneous pigmentation, endocrine
disorders, precocious puberty and premature skeletal maturation
(Albright’s syndrome).
Fibrous dysplasia tends to occur segmentally, with localization
to one limb or one side of the body. Any bone can be affected.
The radiological appearance is of translucent cystic areas
with a mottled, ground glass-like appearance.
Fibrous dysplasia tends to stabilize with completion of skele-
tal growth. The approach to surgical management is conserva-
tive, although regrowth may occur postoperatively. Malignant
Figures 2.17 and 2.18 Fibrous dysplasia of bone.The fibrous
transformation can occur, but appears to be rare. An association component is cellular and arranged in whorls or fascicles.The bony
between fibrous dysplasia and paranasal mucoceles has been component consists of rather slender trabeculae of immature
described. woven bone lacking a surrounding layer of osteoblasts.
Fibro-osseous tumors 73
showing a ‘Chinese letter’ pattern. Characteristically, these tubular bones (upper tibia, lower femur, lower tibia), typically
trabeculae lack a surrounding layer of osteoblasts, although in children and adolescents. They may cause pain or patholog-
this may occur focally. Cartilage formation may be seen in ical fractures, but are benign and self-limiting.
polyostotic lesions. Jaw lesions are more heavily ossified They appear as well-delineated lytic lesions in the metaphy-
than those of other bones, the trabeculae tend to be seal region on X-radiography, and are so distinctive radiologi-
thicker and blunter and may show spheroidal calcification. cally that they are rarely biopsied.
Metaphyseal fibrous defect is usually smaller and involves
Fibrous dysplasia can undergo aneurysmal bone cyst-like
only the cortex, while non-ossifying fibroma is larger and also
change.
involves the medullary cavity.
The constituent cells are a monomorphic population of spindle
These lesions can occasionally be multifocal, affecting a sin-
cells. Mitotic activity is absent; infiltrates of foamy macrophages
gle bone or several bones. Complication by osteosarcoma has
or small numbers of osteoclast-like giant cells can occur.
been described.
PATHOLOGICAL FEATURES (Figure 2.19)
● Osteofibrous dysplasia/ossifying fibroma. Although fibrous
dysplasia and ossifying fibroma of the facial bones may, These lesions are histologically reminiscent of the fibrohistio-
with some difficulty, be distinguishable pathologically, they cytic lesions seen in soft tissue and skin. They are characterized
are inseparable radiographically. Therefore, ‘benign by the presence of spindle cells arranged in storiform and
fibro-osseous lesion’ has been proposed for these entities whorled patterns admixed with multinucleated giant cells and
● Cementifying fibroma foamy xanthomatous histiocytes. The latter can be prominent
● Desmoplastic fibroma in certain lesions, giving the appearance of xanthoma. A net-
● Low-grade spindle cell sarcomas of bone (including central work of collagen fibers is present, but abundant production of
low-grade osteosarcoma and parosteal osteosarcoma in a collagen is rarely seen. Reactive bone spicules may be seen at
small biopsy specimen) the periphery of the lesion.
FLORID REACTIVE PERIOSTITIS
CLINICAL FEATURES
Florid reactive periostitis most commonly affects the tubular
bones of the hands and feet of women in their third and fourth
decades. The presenting symptoms are pain and swelling, and
there is often a history of minor trauma. Radiologically, there
is a variably calcified soft tissue mass arising from the perios-
teum. This is a self-limiting condition that can be treated by
local excision.
Florid reactive periostitis consists of a proliferation of
fibroblast-like spindle cells. There is a variable degree of ossifi-
Figure 2.19 Non-ossifying fibroma.These lesions are histologically
cation, particularly towards the surface of the lesion. Mitoses reminiscent of the fibrohistiocytic lesions seen in soft tissue and skin.
may be present.
● Myositis ossificans
● Bizarre parosteal osteochondromatous proliferation
● Giant cell tumor of bone
● Parosteal osteosarcoma
● Xanthoma
● Xanthogranuloma
● Healed eosinophilic granuloma
NON-OSSIFYING FIBROMA/METAPHYSEAL ● Benign fibrous histiocytoma of bone (histologically
FIBROUS DEFECT identical to non-ossifying fibroma and fibrous defect,
but affects other bones and occurs in older individuals)
CLINICAL FEATURES Special techniques

Non-ossifying fibroma/metaphyseal fibrous defects are proba- ● The cells have immunohistochemical features characteristic
bly developmental abnormalities that occur most often in long of those seen in fibrous histiocytoma of soft tissue
74 Bone tumors
OSSIFYING FIBROMA/OSTEOFIBROUS DYSPLASIA
CLINICAL FEATURES
Ossifying fibroma and osteofibrous dysplasia are histologically
similar lesions that are distinguished by the sites that they
affect. The term ‘ossifying fibroma’ is applied to jaw lesions,
while ‘osteofibrous dysplasia’ is applied to lesions arising in
long bones (usually the tibia).
These are slowly growing, expansile lesions. Ossifying fibroma
usually affects individuals between the ages of 20 and 30 years.
There is a juvenile variant that tends to be locally aggressive.
Osteofibrous dysplasia most commonly occurs in the first
decade of life and affects almost exclusively the tibia, but can
be seen in the fibula and other long bones. It causes anterolat-
eral bowing of the tibia and has a characteristic radiological
appearance (eccentric, intracortical, expansile osteolytic lesion
with a few blister-like areas). It can be complicated by the
development of adamantinoma.
PATHOLOGICAL FEATURES (Figures 2.20 and 2.21) Figure 2.21 Ossifying fibroma. Shown here at a higher
This lesion is well-circumscribed and encapsulated, and con- magnification than in Figure 2.20.
sists of trabeculae of bone and cellular fibrous stroma. The
fibrous stroma is made up of spindle cells arranged in whorls
or fascicles. The bone trabeculae are evenly placed, of lamellar rimmed by large numbers of osteoblasts. Focal transformation
type, usually rimmed by osteoblasts and, when illuminated of woven bone to lamellar bone may be seen.
with polarized light, exhibit widely spaced dark and light bire-
fringent parallel lines. Differential diagnosis
Extragnathic ossifying fibroma of bone consists of a well- ● Fibrous dysplasia (is non-encapsulated, has ill-defined
vascularized cellular fibrous tissue containing irregularly margins, and contains woven bone trabeculae. These almost
shaped, focally calcified or ossified woven bone trabeculae always lack a rim of osteoblastic cells, and when examined
under polarized light show random birefringence)
● Adamantinoma
FIBROUS AND FIBROHISTIOCYTIC TUMORS
BENIGN FIBROUS HISTIOCYTOMA
CLINICAL FEATURES
Benign fibrous histiocytoma of bone is a very rare, slowly grow-
ing tumor which may occur at any age, but mainly in adults. It
presents as bone pain with or without swelling, and rarely with
pathological fracture. Any bone can be affected, but more than
30% of cases are seen in the ilium, pubis, sacrum and femur.
This tumor exhibits local bone destruction, and the recom-
mended treatment is excision with clear margins.
Benign fibrous histiocytoma of bone is a cellular spindle cell
lesion showing storiform pattern. The cells are fibroblasts, his-
tiocytes with varying number of osteoclast giant cells. There is
Figure 2.20 Ossifying fibroma.The stromal spindle cells are usually no nuclear atypia of any significant mitotic figures. The
arranged in whorls or fascicles with evenly placed bone trabeculae. tumor may sometimes infiltrate into the medullary spaces.
Fibrous and fibrohistiocytic tumors 75
Secondary features
● Cholesterol clefts
● Hemosiderin deposits
● Reactive bone formation
● Non-ossifying fibroma (younger age group, no pain and
less aggressive bone destruction)
● Malignant fibrous histiocytoma (much more pleomorphic,
increased mitotic figures with atypical forms)
● Desmoplastic fibroma (less cellular, no storiform pattern,
with no giant cells, or histiocytes)
● Low-grade fibrosarcoma (lacks storiform pattern with
presence of mitoses)
● Late-stage eosinophilic granuloma (lacks storiform pattern
and shows presence of eosinophils)
● Giant cell tumor
Special techniques
Similar to fibrous histiocytoma of the skin.
DESMOPLASTIC FIBROMA
CLINICAL FEATURES
Desmoplastic fibroma of bone, also termed desmoid tumor of
bone, is a rare, locally aggressive fibroblastic tumor with a high
incidence of local recurrence after surgical resection. It is usu-
ally seen in young patients, and involves the mandible and long
bones. It may be discovered incidentally in association with
fibrous dysplasia, or rarely associated with swelling, tenderness
or pain.
Desmoplastic fibroma has occasionally been reported in asso-
ciation with osteosarcoma, and with enchondromatous nodule
formation. The occurrence of the latter may result in a mistaken
diagnosis of chondrosarcoma.
This tumor exhibits local bone destruction, and the recom-
mended treatment is excision with clear margins.

Figures 2.22 and 2.23 Desmoplastic fibroma of bone.These are
Desmoplastic fibroma of bone is histologically identical to soft histologically identical to soft-tissue fibromatosis.
tissue fibromatosis.
FIBROSARCOMA
● Fibrous histiocytoma of bone
CLINICAL FEATURES
● Malignant fibrous histiocytoma (much more pleomorphic,
increased mitotic figures with atypical forms) Fibrosarcoma of bone is a relatively rare tumor; it accounts
● Low-grade fibrosarcoma (lacks storiform pattern with for less than 5% of bone sarcomas. The anatomical sites most
presence of mitoses) commonly involved are the metaphyses of long tubular bones.
● Late-stage eosinophilic granuloma (lacks storiform pattern Local pain, swelling, limitation of motion, and pathological
and shows presence of eosinophils) fracture are the common clinical signs and symptoms. Typical
● Parosteal fibromatosis imaging findings include eccentrically located lytic lesions, with
● Solitary fibrous tumor of the periosteum a geographic, moth-eaten, or permeative pattern of bone
● Fibrous dysplasia destruction, and extension into adjacent soft tissues. Surgery is
76 Bone tumors
the treatment of choice. The type of surgical procedure depends the age of 20 years, being rare before skeletal maturity. It is
mainly on histological grade, local conditions, and tumor loca- most commonly located in the epiphyses and metaphyses of long
tion. With a high probability of metastases (⬎70%) after sur- bones, particularly around the knee, the spine and flat bones,
gical treatment, perioperative adjuvant treatment modalities and is extremely rare in the small bones of hands and feet.
should be considered for high-grade tumors. The most impor- Giant cell tumors have a typical X-radiographic appearance
tant prognostic factors affecting survival include tumor grade, of an expansile, lytic lesion with no peripheral sclerosis.
patient’s age, and tumor location. Treatment is usually by curettage, but local recurrence is not
Fibrosarcoma of bone can be multiple. uncommon.
Fibrosarcoma of bone secondary to a pre-existing lesion is Pulmonary metastasis occurs in 2% of cases, but these metas-
more common. The underlying conditions include radiation, tases often behave in an indolent fashion and may sponta-
osteomyelitis, infarction and Paget’s disease of bone, enchon- neously regress.
dromas, giant cell tumor, fibrous dysplasia.
Malignant giant cell tumor of bone
PATHOLOGICAL FEATURES True malignant transformation (development of a high-grade
sarcoma with a giant cell tumor) can occur, but appears to be
The histological appearances are similar to those seen in soft
very rare. This embraces primary malignant giant cell tumor
tissue.
and secondary malignant giant cell tumor.
● Primary malignant giant cell tumor is a high-grade sarcoma
that arises side-by-side with benign giant cell tumors.
● Fibrous histiocytoma of bone ● Secondary malignant giant cell tumor is a high-grade
● Malignant fibrous histiocytoma sarcoma that occurs at the sites of previously treated giant
● Desmoplastic fibroma cell tumors of bone. Approximately 50% of these are post-
radiation sarcomas, and the remainder are spontaneous.
MALIGNANT FIBROUS HISTIOCYTOMA The average latent period between diagnosis of giant cell
tumor and diagnosis of secondary malignant giant cell
tumor is 9 years (range: 3–15 years) for patients with post-
CLINICAL FEATURES radiation tumors and 19 years (range: 7–28 years) for
patients with tumors resulting from spontaneous
Malignant fibrous histiocytoma (MFH) of bone is rare, can be
transformation.
multiple, and has male predilection. It affects mainly the long
tubular bones. The outcomes associated with all malignancies in giant cell
Malignant fibrous histiocytoma of bone secondary to pre- tumors appear to be poor, with the worst outcome associated
existing lesion is more common. The underlying conditions with post-radiation sarcoma.
include radiation, osteomyelitis, infarction, and Paget’s disease
of bone. This variant of MFH tends to affect older patients, Extraskeletal giant cell tumors
and has a poor prognosis. Giant cell tumors histologically identical to those found in
bone can occur in extraskeletal sites, including breast, lung,
PATHOLOGICAL FEATURES thyroid, liver, ovary, uterus, salivary gland, pancreas, and skin.
Malignant fibrous histiocytoma of bone is a large tumor, usu-
ally showing cortical destruction and medullary extension. PATHOLOGICAL FEATURES (Figures 2.24–2.26)
The histological appearances are similar to those seen in soft Giant cell tumor of bone is a highly cellular lesion consisting of
tissue. a mixture of mono- and multinucleated cells. The mononuclear
cells are round, oval or spindle-shaped, arranged loosely or
Differential diagnosis compactly depending on the vascularity of the stroma. They
● Fibrous histiocytoma of bone consist of a population of stromal cells plus mononuclear
● Fibrosarcoma osteoclast precursors.
The mononuclear cells show no more nuclear pleomorphism
than the multinucleated component, except in lesions that have
GIANT CELL TUMOR undergone malignant transformation.
The multinucleated cells have the typical morphology of osteo-
clasts, and are evenly distributed among the other cell popula-
GIANT CELL TUMOR OF BONE tion although, in some areas, the mononuclear spindle cell
component may dominate. Formation of reactive-type osteoid
is common. Giant cell tumors are highly vascular lesions, and
CLINICAL FEATURES
there may be extensive hemorrhage and/or hemosiderin depo-
Giant cell tumor of bone is most commonly a benign lesion sition, commonly leading to aneurysmal bone cyst-like change.
that can be locally aggressive. It usually affects individuals over Accumulation of foamy macrophages is common. When this is
Miscellaneous tumors 77
● Metaphyseal fibrous defect and non-ossifying
fibroma
● Chondroblastoma
● Osteosarcoma
● Giant cell-rich spindle cell sarcomas of bone
● Osteitis fibrosa cystica/brown tumor of
hyperparathyroidism
● Osteoblastoma
● Eosinophilic granuloma
● Pigmented villonodular synovitis
● Giant cell reparative granuloma of the mandible
Special techniques
● The osteoclasts are CD45-positive and express some
macrophage markers
● The stromal mononuclear cells express vimentin
MISCELLANEOUS TUMORS
ADAMANTINOMA
CLINICAL FEATURES
Adamantinoma is a low-grade malignant tumor that character-
istically arises in the anterior diaphysis or metaphysis of the
tibia, but may occur in other long bones. It affects individuals
between the age of 13 and 63 years, usually presenting with
swelling and pain.
Adamantinoma appears on X-radiography as single/multiple
intramedullary or cortical lytic lesion(s) surrounded by a scle-
rotic margin.
It has a high rate of local recurrence when not widely excised,
and gives rise to lymph node or visceral metastases in 12–29%
of cases. The treatment of choice is wide excision.
Osteofibrous dysplasia has been suggested as a precursor
lesion to adamantinoma. Evidence for the relationship between
these two tumors is based on their similar histological features,
immunohistochemistry, shared clonal abnormalities, overlap-
ping skeletal distribution, and simultaneous occurrence in the
tibia and fibula.
Adamantinomas associated with osteofibrous dysplasia tend
to occur at a younger age. Histologically, adamantinomas can
be very difficult to distinguish from uncomplicated osteo-
Figures 2.24, 2.25 and 2.26 Giant cell tumor of bone. Figure 2.24
fibrous dysplasia. Cytokeratin staining may be necessary to
shows a highly cellular lesion consisting of a mixture of mono- and
multinucleated cells. Figures 2.25 and 2.26 show focal areas within unequivocally demonstrate the epithelial component.
the tumor, with no giant cells.
seen in lesions with few osteoclasts, the histological appearance
can be indistinguishable from benign fibrous histiocytoma. The lesion is composed of epithelial and mesenchymal compo-
The histological classification of high-grade sarcomas in nents. The epithelial component takes a variety of forms such as:
malignant giant cell tumors is osteosarcoma, malignant fibrous ● Ameloblastic pattern; i.e. inter-anastomosing, elongated
histiocytoma or fibrosarcoma. double-layered epithelial structures

78 Bone tumors
lesion, and may resemble fibrous dysplasia. Myxoid change

and focal osteoid formation may also be present. The epithelial
component may show focal squamous differentiation.
● Sweat gland tumors
● Epithelioid hemangioendothelioma of bone
● Osteofibrous dysplasia
● Metastatic carcinoma
Special techniques
● Adamantinoma is a tumor of true epithelial nature,
predominantly expressing cytokeratins 14 and 19
● The stromal component expresses vimentin
ANEURYSMAL BONE CYST
CLINICAL FEATURES
Aneurysmal bone cyst is a benign lesion of unknown histo-
genesis. It typically affects patients between the ages of 10 and
20 years, occurring in the metaphyses of long bones, the pos-
terior elements of the vertebrae, and less commonly in other sites.
It has occasionally been reported in soft tissues (extraosseous
aneurysmal cyst).
Aneurysmal bone cysts exhibit a characteristic X-radiographic
appearance: a zone of well-circumscribed eccentric rarefaction
of bone with erosion and destruction of the cortex with
periosteal new bone formation.
They are best treated by complete excision with bone grafting
if necessary; recurrences occur in nearly one-third of cases if
treated by curettage only.
Malignant transformation of aneurysmal bone cysts has been
reported.

Aneurysmal bone cyst essentially consists of blood-filled cav-
ernous or cystic spaces separated by mature vascular fibrous tis-
sue septa lined by and containing fibroblasts, myofibroblasts,
histiocytes, and osteoclast-like giant cells. Characteristically,
the septa contain areas of basophilic osteoid (‘blue bone’) that
Figures 2.27 and 2.28 Adamantinoma. Nests and clusters of
epithelial cells in a spindle cell background stroma. follows the contours of the septa. Sometimes, solid areas com-
posed of fibrous tissue, bone trabeculae and osteoclasts are
seen in the presence or absence of cyst formation.
● Basaloid nests with peripheral palisading reminiscent of Differential diagnosis

basal cell carcinoma Secondary aneurysmal bone cyst-like change can be seen in a
● Spindle cells arranged in a haphazard pattern, whorling, or wide variety of osseous lesions. This most commonly occurs in
showing nuclear palisading reminiscent of schwannoma giant cell tumors, but can develop in osteosarcomas and other
● Squamoid cells arranged in solid sheets malignant tumors. It is therefore important to exclude the
● Tubular, alveolar or pseudovascular (angioblastic) patterns possibility of secondary aneurysmal bone cyst-like change in
lined by flattened or low cuboidal cells another lesion before making this diagnosis. The principal dif-
● A combination of patterns may be seen ferential diagnoses are as follows:
The mesenchymal component is usually loose, but may be ● Solitary bone cyst
collagenous when it is the predominant component of the ● Giant cell tumor
CHEST WALL HAMARTOMA
CLINICAL FEATURES
Chest wall hamartoma is a rare congenital lesion that usually
presents in infancy as an extrapleural mass arising from the rib
cage. Because the lesion grows into the thoracic cavity, respira-
tory distress is a common presentation. Owing to its ominous
cytopathological features, this condition ought to be kept in
mind while dealing with infantile chest wall masses in order to
avoid an erroneous diagnosis of malignancy.
Resection is curative.
Histologically, hamartoma is composed of a mixture of bone
trabeculae with spindle-cell stroma, chondroblast-like cells,
and mature and immature hyaline cartilage. Blood-filled cystic
spaces with a histological appearance very similar to aneurys-
mal bone cyst are frequently seen. The chondrocytes resemble
those of growth plate cartilage; the chondroblastic component
resembles that of chondroblastoma.
● Teratoma
● Chondroma
● Chondroblastoma
Special techniques
The cells in the hyaline cartilage component and the
chondroblastoma-like component express S-100.
INTRAOSSEOUS GANGLION
See Chapter 13, Soft tissue tumors.
LANGERHANS HISTIOCYTOSIS
See Chapter 10, Lymphoreticular system tumors.
Figures 2.29 and 2.30 Aneurysmal bone cyst. Ectatic spaces LYMPHORETICULAR TUMORS
separated by cellular stroma containing numerous osteoclast-like
giant cells.The latter are particularly present adjacent to the lumina
of the ectatic spaces.
CLINICAL FEATURES
Lymphoma
Non-Hodgkin’s lymphomas occasionally arise in bone, either as
● Giant cell reparative granuloma a primary lymphoma or as part of widespread disease. The out-
● Hemangioma look and treatment are similar to that for other non-Hodgkin’s
● Telangiectatic osteosarcoma lymphomas of the same subtype and stage. Treatment is similar
● Chondroblastoma to that for lymphomas which arise in lymph nodes.
● Fibrous dysplasia
● Osteoblastoma Multiple myeloma (see section on Bone marrow, p. 661)
● Non-ossifying fibroma Although multiple myeloma almost always arises in bone, and
● Chondrosarcoma causes bone destruction, it is treated as a systemic disease.
80 Bone tumors
Figures 2.31 and 2.32 B-Cell-non-Hodgkin’s lymphoma of bone. Figures 2.33 and 2.34 Multiple myeloma of bone showing
deposits of mature and some immature plasma cells within dense
PATHOLOGICAL FEATURES (Figures 2.31–2.34) fibrous stroma.
The term plasmacytoma is applied to solitary lesions, some of

which are precursors of systemic disease. PRIMARY LEIOMYOSARCOMA OF BONE
Primary leiomyosarcoma of bone is a rare tumor, of which one
OTHER MESENCHYMAL TUMORS of the most characteristic locations is the proximal third of the
tibia.
Clinical follow-up suggests that primary osseous leiomyosar-
VASCULAR TUMORS
coma has an aggressive biological behavior. It is thought that
Primary vascular tumors of bone are very rare, and can be osseous leiomyosarcomas arise from the vascular smooth mus-
either benign or malignant. All known vascular entities have cle cells within the bone.
been described in bone. This includes hemangiomas, hemangio- The histological analysis showed that the osseous leiomyosar-
endotheliomas, angiosarcoma, glomus tumor, and hemangio- comas are most commonly of the classic type, followed by the
pericytoma, lymphangioma, and angiomatosis. epithelioid, myxoid, and pleomorphic variants.
Notochondral tumors 81
PRIMARY MALIGNANT MESENCHYMOMA OF BONE

Primary malignant mesenchymoma of bone is a rare neoplasm
consisting of two or more unrelated malignant mesenchymal
components other than fibrosarcoma or malignant fibrous histi-
ocytoma. The reported cases are composed of osteosarcoma and
liposarcoma, osteosarcoma and rhabdomyosarcoma (osteo-
liposarcoma and osteo-rhabdomyosarcoma respectively) or ded-
ifferentiated chondrosarcoma and conventional intramedullary
osteosarcoma, dedifferentiated chondrosarcoma with rhab-
domyosarcoma, angiosarcoma, chondrosarcoma, osteosarcoma,
and leiomyosarcoma, in addition to fibrosarcomatous areas.
PRIMARY RHABDOMYOSARCOMA OF BONE

Primary intraosseous rhabdomyosarcoma has very rarely been
reported.
NOTOCHONDRAL TUMORS
CHORDOMA
CLINICAL FEATURES
Chordoma is a rare tumor arising from notochordal remnants
occurring at both ends of a neuro-axis. About one-half of the
cases arise in the sacrococcygeal area, over one-third in the
spheno-occipital region, and the remaining cases in other parts
of the vertebral column.
The majority of cases follow an indolent course of multiple
local recurrences, ultimately leading to the patient’s death.
Rare examples have been associated with sarcomatous compo- Figures 2.35 and 2.36 Chordoma. Lobular myxoid lesion
nents, resulting in a more aggressive course, with poor response consisting of large, bubbly vacuolated physaliphorous cells.
to treatment and death following a relatively short time course.
Chordoma has been reported in peripheral bone (chordoma
periphericum). This lesion has the potential to metastasize.
and shape; they may be small, rounded, centrally located with
prominent nucleoli, or they may be pyknotic, reniform, flattened,
PATHOLOGICAL FEATURES (Figures 2.35 and 2.36) or spindle-shaped. Binucleation and multinucleation may be seen.
Chordoma is a lobulated, usually pseudoencapsulated myxoid Cystic changes, hemorrhage, necrosis, hemosiderin deposition
lesion with fibrous trabeculae of varying thickness. The lobules and lymphocytic infiltrate may be present as secondary features.
are variably cellular, and composed of epithelioid and vacuolated
cells (‘physaliphorous cells’) arranged singly, in cords, in small Differential diagnosis
aggregates, or sometimes in a concentric spherical pattern. Dedif- This tumor should be differentiated from myxoid chondrosar-
ferentiated components such as islands of malignant cartilage or coma, myxoid liposarcoma and myxopapillary ependymoma.
high-grade malignant spindle cells may rarely be seen admixed The midline location is an important factor in the differential
within areas of conventional chordoma in approximately 5% diagnosis. The presence of physaliphorous cells in the tumor and
of cases (‘sarcomatoid/dedifferentiated chordoma’). Some chor- expression of cytokeratin rule out other types of myxoid tumor.
domas are composed almost entirely of small round cells, but on Metastatic signet-ring carcinoma of gastrointestinal origin
close examination the classic physaliphorous cells may be may also simulate chordoma. The latter is S-100-negative.
identified. Delicate blood vessels are seen mainly in the interlob-
ular septa.
The oval or polygonal epithelioid cells have abundant Special techniques
eosinophilic, granular cytoplasm, while the physaliphorous cells Chordoma expresses cytokeratin (CK), epithelial membrane
show single or multiple small or large vacuoles or signet-ring antigen (EMA), vimentin, S-100 protein antigen and alpha-
morphology. Some physaliphorous cells have degenerate nuclei, 1-anti-chymotrypsin, and also occasionally expresses type IV
giving the appearance of ghost cells. The nuclei vary in number collagen, as is seen in parachordoma.
82 Bone tumors
OSTEOCHONDROMA
OSTEOGENIC TUMORS
OSTEOBLASTOMA CLINICAL FEATURES

Osteochondroma is the most common benign tumor of bone.
It is seen in adolescents and young adults. In a small propor-
CLINICAL FEATURES
tion of cases the lesion is multiple and familial with autosomal
Osteoblastoma (also called giant osteoid osteoma) is an dominant inheritance ‘multiple osteochondromatosis’. This
uncommon benign bone tumor. It is histologically similar to condition is also known as diaphyseal aclasia.
osteoid osteoma, being distinguished by larger (more than Osteochondromas can arise from any bone that develops
1.5 cm in diameter) and less well-defined central nidus. The by endochondral ossification, but are most commonly seen in
most common site is the spine. It affects young adults, and has the long bones of the lower extremities. They present as
a male predominance. The common presenting feature is pain, masses that can be painful and are often associated with a
and this is usually relieved with non-steroidal anti-inflammatory bursa in the overlying tissue. Malignant transformation
drugs. Treatment is by curettage. can occur, but is uncommon and is usually seen in multiple
Aggressive osteoblastoma is a rare, bone-forming neoplasm osteochondromatosis.
composed of prominent epithelioid cells that demonstrate
locally invasive growth with a high rate of recurrence, but no
metastatic potential.
Osteoblastomas may rarely undergo malignant transformation. This tumor has a characteristic architecture, consisting of a car-
tilaginous cap with underlying trabecular bone. Active endo-
PATHOLOGICAL FEATURES (Figure 2.37) chondral ossification may be seen at the interface between the
cartilage and bone. The cartilaginous cap is usually 2–3 mm in
Osteoblastoma resembles osteoid osteoma, consisting of anas- thickness, but can be absent in inactive lesions or may reach up
tomosing bone trabeculae rimmed by osteoblasts and separated to 1 cm in actively growing bone of adolescent patients. It con-
by very vascular stroma. The network of dilated capillary-sized sists of well-formed hyaline cartilage containing chondrocytes
vessels adjacent to seams of osteoblasts is a characteristic fea- arranged in larger and more variably-shaped clusters than
ture. The osteoblasts normally resemble their non-neoplastic those seen in normal articular hyaline cartilage. The underlying
counterparts, but can be large and epithelioid with nuclear bone consists of regular trabeculae showing prominent
atypia in some lesions. Mitoses may be present. osteoblastic and osteoclastic activity. Hematopoietic cells are
often present between the trabeculae. Occasionally, islands of
Differential diagnosis cartilage are present within the underlying cancellous bone,
● Osteoid osteoma which may show degenerative change and calcification.
● Osteosarcoma
● Periosteal chondroma or chondrosarcoma
● Bizarre parosteal osteochondromatous proliferation
Special techniques
● PAS-positive inclusions may be seen in the cytoplasm of
the chondrocytes
OSTEOID OSTEOMA
CLINICAL FEATURES
Osteoid osteoma is a distinctive benign osteoblastic tumor. It
usually occurs in patients between the age of 10 and 30 years,
and is more common in males. It can affect any bone, but is
more common in the lower extremities. It is characteristically
painful, the pain often being relieved by non-steroidal anti-
inflammatory drugs.
On X-radiography, osteoid osteoma is typically a round or oval
lesion of decreased density surrounded by a sclerotic peripheral
Figure 2.37 Osteoblastoma anastomosing bone trabeculae zone. Treatment is by curettage or thermal ablation, but there is
rimmed by osteoblasts and separated by highly vascular stroma. evidence that some lesions may regress spontaneously.
Osteogenic tumors 83
PATHOLOGICAL FEATURES (Figure 2.38) PATHOLOGICAL FEATURES

This lesion consists of a central nidus and a peripheral zone. These lesions consist of dense, mature, predominantly lamellar
The central nidus consists of an interlacing network of small, bone. The constituent cells are morphologically normal osteo-
thin, irregularly shaped bone trabeculae arranged haphazardly cytes within the lesion and bone lining cells on the surfaces of
and rimmed by plump osteoblastic cells. The intertrabecular the lesion.
spaces contain osteoclasts and prominent vessels. The network Occasionally, a compact osteoma undergoes spontaneous
of dilated capillary-sized vessels adjacent to seams of osteo- sequestration to produce a ‘dead osteoma’.
blasts is a characteristic feature. The peripheral zone consists of
densely sclerotic but essentially normal bone trabeculae, show- OSTEOSARCOMAS
ing less cellular activity than the central nidus. Mature osteoid
osteoma may contain more solid osseous trabeculae.
CLINICAL FEATURES
Osteosarcoma is the most common primary malignant tumor
● Osteoblastoma of bone. It is usually of unknown etiology, but may be associ-
● Osteosarcoma ated with irradiation, bone infarction, fibrous dysplasia,
Paget’s disease or familial retinoblastoma. It most commonly
occurs in the metaphyses of long bones, particularly the distal
femur, proximal tibia and proximal humerus. Peak incidence is
between the ages of 10 and 25 years.
‘Conventional’ osteosarcoma usually arises within the
medullary cavity and subsequently extends through the cortex.
It usually has a ‘sunburst’ appearance on X-radiography, but
may be completely lytic, sclerotic, or a combination of these.
Periosteal new bone and formation of Codman’s triangle may
be seen at the periosteal margins of the tumor.
Ideally, osteosarcomas are treated by chemotherapy, fol-
lowed by wide local excision. The response to the chemother-
apy and prognosis of an individual lesion can be assessed by
the amount of tissue necrosis seen in a resection specimen.
With optimal treatment, the 5-year survival rate is
around 50%.
Osteosarcoma variants
● Parosteal osteosarcoma affects slightly older individuals. It
arises on the surfaces of long bone, usually the femur or
tibia. It grows slowly and has a good prognosis, but can
occasionally undergo dedifferentiation to a high-grade
Figure 2.38 Osteoid osteoma. A central nidus consists of an
interlacing network of small, thin, irregularly shaped bone trabeculae. sarcoma.
A network of dilated capillary-sized vessels adjacent to seams of ● Periosteal osteosarcoma affects the surfaces of the mid- or
osteoblasts is a characteristic feature. upper shafts of the tibia or femur, and has a slightly better
prognosis than conventional osteosarcoma.
OSTEOMA/BONE ISLAND ● Telangiectatic osteosarcoma presents as a rapidly growing
lytic lesion and has an unfavorable prognosis.
● Small cell osteosarcoma presents in a similar way to con-
CLINICAL FEATURES
ventional osteosarcoma, but has a slightly worse prognosis.
Osteoma/bone island are terms applied to overgrowths of ● Low-grade central osteosarcoma is similar to parosteal
dense, well-formed lamellar bone. Osteomas are deforming, osteosarcoma in its histological appearance and clinical
tumorous lesions, whereas bone islands are non-deforming behavior, but arises within the metaphyses of long bones.
lesions within cancellous bone. Osteomas occur almost exclu- ● High-grade peripheral osteosarcoma is similar to
sively in the flat bones of the skull and face (particularly the conventional osteosarcoma in its histological appearance and
mandible or maxilla), being far more rarely reported on the clinical behavior, but arises on the surface of long bones.
surfaces of long bones and in soft tissue. ● Secondary osteosarcoma can present at any site as a
Osteomas can be associated with Gardner’s syndrome. They complication of Paget’s disease, radiation exposure and,
may cause facial deformity by extension into paranasal sinuses more rarely, a number of other conditions such as bone
and orbit, and may also cause neurological signs and symptoms infarct and fibrous dysplasia. The histological appearance
through local extension. They are, however, benign lesions is that of conventional osteosarcoma. The prognosis is
with indolent behavior. poor (5-year survival rate ⬍20%).
84 Bone tumors
PATHOLOGICAL FEATURES (Figures 2.39–2.43) The proportion and degree of differentiation of each element
varies in different tumors. Osteosarcoma may therefore have a
Osteosarcomas are malignant, bone-forming tumors. They
wide variety of histological appearances.
consist of varying combinations of three neoplastic elements:
The osteoid component consists of anastomosing or reticu-
osteoid; chondroid; and undifferentiated mesenchymal cells.
lated bone trabeculae, small sharply bordered fragments, or del-
icate lace-like osteoid surrounding individual cells, surrounded
by malignant osteoblast-like cells. Examination under polarized
light reveals a complex, disorganized pattern of collagen fibrils.
The chondroid component may be the predominant feature,
and exhibits cytological features indistinguishable from those
of chondrosarcoma. This cartilaginous component may calcify
or undergo endochondral ossification.
Figure 2.39 Osteosarcomas: predominantly giant cells.
Figures 2.42 and 2.43 Osteosarcoma, high-grade (fibroblastic

Figures 2.40 and 2.41 Osteosarcomas. Figure 2.40: predominantly differentiation).These show a fibrosarcoma-like pattern, but on
chondroblastic; Figure 2.41: delicate, lace-like malignant osteoid. closer examination (Figure 2.43) the neoplastic osteoid is apparent.
WHO classification of bone tumors 85
The cellular component may consist of spindle cells, epithe-

lioid or plasmacytoid cells or bizarre mono- or multinucleated TUMORS OF UNCERTAIN HISTOGENESIS
giant cells. Numerous osteoclasts may also be present. Spindle
cells, when monomorphic and arranged in fascicles, may form EWING’S SARCOMA/PRIMITIVE
areas reminiscent of fibrosarcoma and if pleomorphic may
resemble malignant fibrous histiocytoma.
NEUROECTODERMAL TUMOR (PNET)
At the periphery of the lesion there may be abundant reactive
See Chapter 13, Soft tissue tumors (p. 965).
non-neoplastic new bone formation. Osteosarcomas can undergo
aneurysmal bone cyst-like change.
Differential diagnosis WHO CLASSIFICATION OF BONE TUMORS

● Fracture callus
Cartilage tumors
● Aneurysmal bone cyst (particularly versus telangiectatic
Osteochondroma
osteosarcoma)
Chondroma
● Myositis ossificans ● Enchondroma
● Fibrous dysplasia/osteofibrous dysplasia ● Periosteal chondroma
● Osteoblastoma ● Multiple chondromatosis
● Chondrosarcoma
Chondroblastoma
● Malignant fibrous histiocytoma/other pleomorphic
Chondromyxoid fibroma
sarcomas
Chondrosarcoma
● Non-osteogenic spindle cell sarcomas, e.g. fibrosarcoma ● Central, primary and secondary
● Giant cell tumor ● Peripheral
● Malignant lymphoma ● Dedifferentiated
● Metastatic carcinoma ● Mesenchymal
● Angiosarcoma ● Clear cell
● Ewing’s sarcoma (versus small cell osteosarcoma)
Osteogenic tumors
Osteoid osteoma
Histological appearance of osteosarcoma variants
Osteoblastoma
● Parosteal osteosarcoma and low-grade central Osteosarcoma
osteosarcoma are characterized by a prominent, ● Conventional
bland fibroblast-like component with relatively – Chondroblastic
well-formed osteoid component. The chondroid – Fibroblastic
component is usually small, often forming a ‘cap’ in – Osteoblastic
parosteal osteosarcomas. ● Telangiectatic
● Periosteal osteosarcoma is characterized by a prominent, ● Small cell
histologically malignant cartilaginous component which ● Low-grade central
may undergo endochondral ossification. ● Secondary
● Telangiectatic osteosarcoma is characterized by the ● Parosteal
presence of large angiomatoid vascular spaces which may ● Periosteal
make up most of the volume of the lesion. The cellular ● High-grade surface
component is typically pleomorphic and poorly
Fibrogenic tumors
differentiated with poorly formed osteoid.
Desmoplastic fibroma
● Small cell osteosarcoma has a cellular component which
Fibrosarcoma
closely resembles Ewing’s sarcoma or other small blue cell
Fibrohistiocytic tumors
tumors, but can be identified by the presence of malignant
Benign fibrous histiocytoma
osteoid or chondroid. Like Ewing’s sarcoma, the cells may
Malignant fibrous histiocytoma
express CD99, but the 11;22 Ewing’s chromosomal
translocation is not present. Ewing sarcoma/Primitive neuroectodermal tumor
Ewing sarcoma
Special techniques Hematopoietic tumors
Plasma cell myeloma
● Alkaline phosphatase activity can be demonstrated
Malignant lymphoma NOS
histochemically in fresh tumor cells, but does not survive
formaldehyde fixation and routine processing. Giant cell tumor
● Osteosarcomas have been demonstrated to express Giant cell tumor
bone matrix proteins such as osteocalcin and Malignancy in giant cell tumor
osteonectin. Notochordal tumors
● Small cell osteosarcomas can express CD99. Chordoma
86 Bone tumors
Vascular tumors Miscellaneous lesions

Hemangioma Aneurysmal bone cyst
Angiosarcoma Simple cyst
Smooth muscle tumors Fibrous dysplasia
Leiomyoma Osteofibrous dysplasia
Leiomyosarcoma Langerhans cell histiocytosis
Erheim–Chester disease
Lipogenic tumors
Chest wall hamartoma
Lipoma
Liposarcoma Joint lesions
Neural tumors Synovial chondromatosis
Neurilemmoma
Miscellaneous tumors
Adamantinoma
Metastatic malignancy
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3 brain tumors
Colin OC Smith
Astrocytomas 98 High grade meningiomas (WHO grade III) 112

Diffuse astrocytomas 98 Papillary meningiomas 112
Anaplastic astrocytomas 98 Rhabdoid meningiomas 112
Glioblastoma 98 Anaplastic (malignant) meningiomas 112
Pilocytic astrocytoma 98
Pleomorphic xanthoastrocytoma 98 Mixed gliomas 112
Subependymal giant cell astrocytoma 98
Neuroepithelial tumors of uncertain origin 113
Choroid plexus tumors 102 Astroblastoma 113
Choroid plexus papilloma and choroid plexus carcinoma 102 Chordoid glioma of the third ventricle 113
Gliomatosis cerebri 113
Embryonal tumors 104
Atypical teratoid/rhabdoid tumor 104 Neuronal and mixed neuronal-glial tumors 114
Ependymoblastoma 104 Central neurocytoma 114
Medulloblastoma and its variants 105 Cerebellar liponeurocytoma 114
Medulloepithelioma 106 Desmoplastic infantile ganglioglioma 115
Supratentorial primitive neuroectodermal tumor (PNET) 106 Dysembryoplastic neuroepithelial tumor 116
Dysplastic gangliocytoma of the cerebellum 116
Ependymoma 107 Gangliocytoma 116
Ependymoma variants 107 Ganglioglioma 117
Cellular ependymoma 107 Paraganglioma of the filum terminale 117
Papillary ependymoma 107
Clear cell ependymoma 107 Oligodendroglial tumors 117
Tanycytic ependymoma 108 Oligodendroglioma 117
Anaplastic (malignant) ependymoma 108
Subependymoma 108
Pineal parenchymal tumors 119
Myxopapillary ependymoma 108
Pineocytoma/pineoblastoma 119
Meningeal tumors 109
Pituitary tumors 120
Benign meningiomas (WHO grade I) 110
Granular cell tumor of the neurohypophysis 120
Meningothelial meningioma 110
Pituicytoma 120
Fibrous meningioma 110
Pituitary adenoma and carcinoma 120
Transitional (mixed) meningioma 110
Psammomatous meningioma 111
Angiomatous meningioma 111 Tumors of sellar region 121
Microcystic meningioma 111 Craniopharyngioma 121
Secretory meningioma 111
Lymphoplasmocyte-rich meningioma 112 Tumors of uncertain histogenesis 122
Metaplastic meningioma 112 Hemangioblastoma 122
Intermediate grade meningiomas (WHO grade II) 112
Clear cell meningioma 112 WHO classification of tumors of the central nervous system 123
Chordoid meningioma 112
Atypical meningiomas 112 Grading of intrinsic brain tumors 123
GENERAL COMMENTS
a wide range of primary neoplasms arising within the CNS.
The most common group of tumors involving the central nerv- Primary tumors of the CNS include tumors arising within the
ous system (CNS) – and therefore the most commonly seen in parenchyma of the nervous system and those arising from the
diagnostic practice – are metastatic tumors. There is, however, coverings of the nervous system. Tumors should be classified
98 Brain tumors
according to the World Health Organization (WHO) scheme, PATHOLOGICAL FEATURES (Figures 3.1–3.17)
which was updated in 2000 by an international working group
of experts. Variants
As with all aspects of pathology, the interpretation of histo- ● Diffuse astrocytomas (WHO grade II)
logical features should not be undertaken in the absence of ● Anaplastic astrocytomas (WHO grade III)
appropriate clinical information and imaging results. Informa- ● Glioblastoma (WHO grade IV)
tion such as the age of the patient, the site of the lesion, clinical ● Pilocytic astrocytoma (WHO grade I)
presentation, and evidence of radiological enhancement are ● Pleomorphic xanthoastrocytoma (WHO grade II)
important. Indeed, in some cases – such as dysembryoplastic ● Subependymal giant cell astrocytoma (WHO grade I)
neuroepithelial tumor – the final diagnosis cannot be made in the
absence of the appropriate clinical and radiological history.
This chapter deals with a selected group of primary CNS neo-
plasms, and highlights the varied tumor patterns seen. They are
presented alphabetically, and include some entities only recently
included in the WHO classification. In addition, pituitary tumors
are covered as these are often considered to be part of the neuro-
pathologist’s remit.
ASTROCYTOMAS
CLINICAL FEATURES
Astrocytomas are tumors consisting of cells with astrocytic dif-
ferentiation. They may diffusely infiltrate the surrounding brain
tissue while others are more circumscribed.
These tumors typically occur in early adult life, with a peak
in the fourth and fifth decades. They vary widely in their clini-
cal behavior, this being influenced both by the histological
grade and the anatomical location. They generally present as
space-occupying lesions within the CNS, sometimes with focal
neurological signs appropriate to their anatomical location. Figure 3.1 Diffuse astrocytoma: pleomorphic cells with astrocytic
Astrocytomas most commonly occur in the cerebral hemi- morphology and diffusely infiltrate neuropil.The cytoplasm is poorly
spheres, though they may also be seen anywhere in the CNS, defined.
including the spinal cord. In children, they are often seen in
the pons.
Astrocytomas are treated, where anatomically possible, by
surgical resection, or by palliative irradiation. They recur fre-
quently due to incomplete local excision.
Astrocytic tumors (diffuse astrocytoma, anaplastic astrocytoma,
and glioblastoma) account for the majority of primary intra-
cerebral tumors in adults. Pilocytic astrocytoma, pleomorphic
xanthoastrocytoma, and subependymal giant cell astrocytoma
are uncommon and have restricted age distribution and anatom-
ical locations.
Pilocytic astrocytoma occurs predominantly in children,
involves mainly midline, basal and posterior fossa structures,
and is generally considered to be a benign tumor of childhood.
Pleomorphic xanthoastrocytoma occurs during the first two
decades of life, and is usually superficially located. These are
usually very slow-growing tumors, but they may recur rapidly
after partial excision and behave as high-grade tumors.
Subependymal giant cell astrocytoma is a rare tumor with a
favorable prognosis, and is characteristic of tuberous sclerosis.
Typically, it appears as a nodule on the ependymal surface of the
lateral ventricular wall, and occurs in children and young adults. Figure 3.2 Diffuse astrocytoma, gemistocytic type: the neoplastic
It is considered to be a grade I tumor and is usually cured by cells have small pleomorphic nuclei with abundant eosinophilic
surgical excision. cytoplasm.
Astrocytomas 99
Figure 3.3 Pilocytic astrocytoma: the classical biphasic architecture Figure 3.5 Pleomorphic xanthoastrocytoma: at low power
is demonstrated.There are compact and cystic areas. magnification, the superficial location is highlighted.
Figure 3.4 Pilocytic astrocytoma: several dense eosinophilic Figure 3.6 Pleomorphic xanthoastrocytoma: at higher power
Rosenthal fibers are shown here. magnification, the pleomorphic astrocytic cells are intermixed with
xanthomatized cells.
Astrocytomas are glial neoplasms that consist of cells showing ● Fibrillary astrocytoma shows cells with hyperchromatic,
the morphological characteristics of astrocytes. A number of oval to irregular nuclei and scant or barely discernible
distinct morphological subtypes exist. cytoplasm. In more cellular lesions, the numerous cell
processes produce a loose fibrillary matrix, sometimes with
Low-grade variants microcyst formation.
Diffuse astrocytomas can exist as fairly pure forms of, or as a ● Protoplasmic astrocytoma is characterized by the presence
mixture of three different histological types – fibrillary, gemis- of small cells with small numbers of flaccid cytoplasmic
tocytic, and protoplasmic. processes. Microcystic formation is commonly seen.
100 Brain tumors
Figure 3.7 Pleomorphic xanthoastrocytoma: silver staining Figure 3.9 Subependymal giant cell astrocytoma: the tumor cells
demonstrates the presence of a dense reticulin network within show moderate pleomorphism and have abundant rather hyaline
the tumor, a feature not seen in normal brain tissue. cytoplasm.These large cells can resemble neurons.
Figure 3.8 Pleomorphic xanthoastrocytoma: the glial nature of Figure 3.10 Subependymal giant cell astrocytoma: variable GFAP
the tumor is demonstrated using bifocal GFAP immunoreactivity. cytoplasmic immunoreactivity is seen in the tumor cells.
● Gemistocytic astrocytoma differs from the other types in ● Pilocytic astrocytoma is usually circumscribed and consists
that it consists of gemistocytic astrocytes. The tumor cells principally of compact elongated pilocytic (hair-like)
are large, with eosinophilic cytoplasm and angular astrocytes interspersed with microcystic spaces. Rosenthal
cytoplasmic processes; the nuclei are round to oval fibers (elongated eosinophilic, club-shaped structures) and
and eccentrically located. Perivascular lymphocytic intracytoplasmic eosinophilic droplets (granular bodies)
infiltration is often seen. Gemistocytic astrocytomas, by are the hallmarks of this tumor.
definition, show little evidence of anaplasia or mitotic ● Pleomorphic xanthoastrocytoma is somewhat reminiscent
activity. of malignant fibrous histiocytoma, and consists of a
Astrocytomas 101
Figure 3.11 Glioblastoma: tumor necrosis with pseudopalisading. Figure 3.13 Giant cell glioblastoma: marked cellular pleomorphism
including many multinucleated cells is a feature of this high-grade
neoplasm.
Figure 3.12 Glioblastoma: microvascular proliferation. Figure 3.14 Giant cell glioblastoma: variable GFAP
immunoreactivity is seen, although a proportion of the tumor
cells will stain.
mixture of pleomorphic cells, including ordinary fibrillary
astrocytes, giant cells, multinucleated and xanthomatized
cells. Mitoses may be seen. High-grade variants
● Subependymal giant cell astrocytoma is a circumscribed These correspond to grades III and IV in the WHO classification.
intraventricular tumor consisting of large plump cells ● Anaplastic astrocytoma can be distinguished from low-
that resemble neurons. These often show perivascular grade astrocytomas by greater cellular pleomorphism and
clustering and pseudopalisading. The nuclei are vesicular hyperchromasia, more frequent mitoses and prominent
and may contain prominent nucleoli. Calcification is small vessels lined by epithelioid endothelial cells. Any
usually seen. of the patterns of differentiation associated with the
102 Brain tumors
Figure 3.15 Gliosarcoma: a mixture of a glioblastoma, in this Figure 3.17 Gliosarcoma: focal GFAP immunoreactivity confirms
example with a rather epithelioid morphology, and a sarcomatous glial differentiation within the tumor.
component, usually malignant spindle cells.
glioblastoma is characterized by the presence of numerous
bizarre giant cells.
● Gliosarcoma is a glioblastoma admixed with a sarcomatous
component in the form of fibrosarcoma or malignant
fibrous histiocytoma.
Special techniques
● Astrocytes are glial fibrillary acidic protein (GFAP)-positive
● They may express glutamine synthetase
● Astrocytomas may also express S-100 protein
● Reactive gliosis, e.g. associated with infarction,
demyelination
● Oligodendroglioma
● Poorly differentiated metastatic carcinoma or melanoma
(from glioblastoma)
CHOROID PLEXUS TUMORS
CHOROID PLEXUS PAPILLOMA AND CHOROID

Figure 3.16 Gliosarcoma: the sarcomatous component shows
abundant reticulin fiber production, a feature not seen in PLEXUS CARCINOMA
glioblastomas.
CLINICAL FEATURES
low-grade tumors (fibrillary, gemistocytic, and
protoplasmic) may be seen in these tumors. Choroid plexus papilloma (WHO grade I) is a benign tumor
● Glioblastoma typically exhibits great cellularity and of ependymal lining cells which occurs most frequently in the
pleomorphism, frequent bizarre giant cells and abnormal fourth ventricle. It most commonly affects children, in whom
mitotic figures, and endothelial cell proliferation. Areas of it appears as an intraventricular papillary mass. These lesions
necrosis surrounded by nuclei aligned in pseudopalisading may cause intraventricular obstruction of cerebrospinal fluid
pattern is a defining histological feature. Giant cell (CSF) flow, and are usually cured by excision (when operable).
Choroid plexus tumors 103
Figure 3.18 Choroid plexus papilloma: the very obvious Figure 3.20 Choroid plexus carcinoma: these tumors can
papillary architecture is the striking low-power magnification retain a papillary architecture, as seen in this example, but can
feature of these tumors. also grow as solid sheets.
Figure 3.19 Choroid plexus papilloma: the cells show minimal Figure 3.21 Choroid plexus carcinoma: pseudo-stratification
pleomorphism and remain as a single layer. Mitotic figures are and cellular pleomorphism are seen. In addition, mitotic figures are
not a feature. easily identified.
Choroid plexus carcinoma (WHO grade III) is an extremely vessels and loose connective tissue, closely resembling normal
rare tumor that spreads through the ventricular system and sub- choroid plexus.
arachnoid spaces, and occurs most commonly in children. Choroid plexus carcinoma retains some papillary architecture,
thus indicating a choroid plexus origin, but exhibits cytological
pleomorphism and evidence of invasion of adjacent structures.
An anaplastic variant of choroid plexus carcinoma can be seen
Choroid plexus papilloma is characterized by the presence of that may be difficult to differentiate from medulloblastoma. The
numerous papillae, the cores of which consist of thin-walled lining cells are cuboidal or columnar, with a tendency towards
104 Brain tumors
pseudostratification of nuclei. Pleomorphism, mitotic activity and Differential diagnosis

necrosis are seen in choroid plexus carcinoma. ● Medulloblastoma
● Metastatic rhabdoid tumor
● Ependymoma Special techniques
● Metastatic adenocarcinoma (from choroid plexus carcinoma) ● Rhabdoid cells express EMA and vimentin
● Medulloblastoma (from anaplastic choroid plexus ● Pancytokeratin will demonstrate an epithelial component
carcinoma) within the tumor
● Smooth muscle actin (SMA) shows variable immuno-
Special techniques reactivity for rhabdoid cells
● Some cells are mucin-positive
● The cells are cytokeratin 7 and 8 (Cam.5.2)-, epithelial
membrane antigen (EMA)-, vimentin-, GFAP-, and EPENDYMOBLASTOMA
transthyretin-positive
● Some tumor cells are S-100-positive
CLINICAL FEATURES
Ependymoblastoma is a rare type of embryonal malignant CNS
EMBRYONAL TUMORS neoplasm (WHO grade IV) which affects young individuals and
is mostly seen in intra- or paraventricular locations. It is often
ATYPICAL TERATOID/RHABDOID TUMOR massive, but well-circumscribed, and occasionally shows cystic
changes.
CLINICAL FEATURES
Atypical teratoid/rhabdoid tumor is an uncommon high-grade PATHOLOGICAL FEATURES (Figure 3.23)
embryonal tumor of the nervous system (WHO grade IV)
which predominantly affects children. It is seen most commonly Ependymoblastoma is a highly cellular tumor that consists of
in the posterior fossa, but is not uncommon supratentorially. a uniform population of small undifferentiated round cells
The tumor metastasizes throughout the CSF pathways. resembling those of other neuroblastic tumors. The most
characteristic feature is the presence of ependymal rosettes and
tubules (ependymoblastic tubules) lined by columnar cells.
PATHOLOGICAL FEATURES (Figure 3.22) These structures are easily identified and are distributed through-
out almost every low-power field. Larger irregular spaces lined
Atypical teratoid/rhabdoid tumors show a varied growth pattern,
by ependymal cells may also be found. The cells are round,
depending upon the varied phenotypic expression of the neoplas-
oval, or spindle-shaped. The cytoplasm is ill-defined, while the
tic cells. Invasion of adjacent brain is common. Rhabdoid cells,
nuclei are round to oval in shape and contain coarse chromatin.
with eosinophilic ‘inclusion-like’ bodies and an eccentric nucleus,
The central lumen of the rosette is lined by an internal limiting
are seen in all cases. A poorly differentiated small cell component
membrane, and the rosette-lining cells demonstrate cilia and
is seen in a large number of cases. Epithelial differentiation, some-
juxtaluminal blepharoplasts. Mitotic figures are numerous.
times with keratin formation or glandular structures, may be
seen. Mesenchymal differentiation may also be seen.
Figure 3.22 Atypical teratoid/rhabdoid tumor: the cells have large Figure 3.23 Ependymoblastoma: small undifferentiated cells
nuclei and prominent nucleoli. forming characteristic ependymyoblastic tubules.
Embryonal tumors 105
MEDULLOBLASTOMA AND ITS VARIANTS spindle or ‘carrot’-shaped and have little cytoplasm. Astrocytic
and/or oligodendroglial differentiation may be seen. Striated
muscle cells may be seen and, when numerous, the term ‘medullo-
CLINICAL FEATURES myoblastoma’ might be used. Mitotic figures are numerous.
Medulloblastoma (WHO grade IV) is a malignant tumor of prim-
itive neuroectodermal cells that occurs most commonly in chil- Differential diagnosis
dren, but may also be seen in adolescents and adults. In the ● Metastatic neuroblastoma or extra-CNS primitive
majority of cases it affects the vermis of the cerebellum, but it neuroectodermal tumors
may occur in the cerebellar or cerebral hemispheres. The tumor
is rapidly growing, may expand, destroy and replace surround-
ing tissue; it may also block the CSF circulation, leading to raised
intracranial pressure. It commonly spreads within the CNS via
the CSF and may metastasize outside the CNS. Medulloblastoma
is radiosensitive.

Medulloblastoma is a very cellular, poorly differentiated tumor
consisting of small, primitive round or spindle cells. The tumor
cells may exhibit palisading, fascicular, rosetting, or pseudoroset-
ting patterns. In conventional medulloblastoma, the intervening
stroma is usually sparse and consists of glial or connective tissue.
Desmoplastic medulloblastoma is characterized by abundant
reticulin fibers, giving the lesion an appearance of a malignant
mesenchymal tumor.
Medullomyoblastoma is another variant of medulloblastoma
that shows distinct rhabdomyoblastic and sometimes smooth
muscle differentiation.
Melanotic medulloblastoma is another variant of medullo-
blastoma that consists of islands of melanin-containing
epithelioid cells arranged in glandular or papillary structures. Figure 3.25 Medulloblastoma: the tumor is composed of small
Histologically, this tumor resembles the pigmented neuroecto- undifferentiated cells. Mitotic figures and apoptotic bodies are
dermal tumor of infancy. The cells are hyperchromatic, round, abundant.
Figure 3.24 Medulloblastoma: the tumor grows as a dense sheet Figure 3.26 Medulloblastoma: the pale islands are less cellular and
of poorly differentiated cells with paler islands. may show neuronal differentiation.
106 Brain tumors
● Choroid plexus carcinoma

Special techniques
● Neurofilaments are expressed in neuronal and
neuroendocrine cells
● GFAP highlights glial cytoplasmic filaments of astrocytes
and ependymal cells
● S-100 protein stains cytoplasm and nuclei of glial and
Schwann cells
● Synaptophysin is a marker of neuronal and
neuroendocrine differentiation
● Leu-7 is expressed in tumors of neuroectodermal origin
and in peripheral nerve sheath tumors
SUPRATENTORIAL PRIMITIVE
NEUROECTODERMAL TUMOR (PNET)
CLINICAL FEATURES
Figure 3.27 Medulloblastoma: immunohistochemistry for the Supratentorial PNETs are aggressive tumors of childhood (WHO
neuronal marker synaptophysin demonstrates focal cellular grade IV). As indicated by the nomenclature, they are found in
immunoreactivity and focal neuropil differentiation.
the supratentorial region. Their presentation is dependent upon
site, but they often present with complications of raised intra-
● Metastatic melanoma, poorly differentiated carcinoma, cranial pressure.
sarcoma, or lymphoma
Special techniques
Highly cellular diffuse sheet of tumor cells, often with extensive
● The neuroblastic cells express varying combinations of necrosis. The cells resemble those of medulloblastoma, and are
neurofilaments, protein gene product 9.5, neuron-specific small with little distinctive morphology. There is a high mitotic
enolase, synaptophysin and Leu-7
● Astrocytes and ependymal cells express GFAP, when these
are components of the tumor
MEDULLOEPITHELIOMA
CLINICAL FEATURES
Medulloepithelioma (WHO grade IV) is an undifferentiated
tumor of primitive neuroepithelial cells which affects infants or
children, and occurs most commonly in the cerebral hemi-
spheres adjacent to ventricles. The lesion is highly malignant,
with a tendency to spread within the CNS via the CSF and to
metastasize outside the CNS.
The tumor is highly cellular, consisting of tubules and papillae
lined by pseudostratified columnar or cuboidal cells. The cells
are either cuboidal or columnar. Mitotic figures are frequent.
Striated muscle and cartilaginous cells may occasionally be seen.
Differential diagnosis Figure 3.28 Supratentorial primitive neuroectodermal tumor

(PNET): the tumor is composed of a dense sheet of poorly
● Malignant teratoma differentiated cells. Mitotic figures and apoptotic bodies are
● Malignant ependymoma numerous.
Ependymoma 107
Subependymoma (WHO grade I) is a distinct, slowly grow-

ing variant of ependymoma, and occurs as a well-demarcated
lesion, with multiple nodules occasionally protruding from the
wall of the cerebral ventricles. It is usually asymptomatic, and is
often discovered incidentally at post-mortem examination in
adults. It may sometimes cause symptoms as a result of obstruc-
tion of the CSF pathway.
Myxopapillary ependymoma (WHO grade I): for details, see
Chapter 13, Soft tissue tumors.

Ependymomas typically consist of sheets of uniform round cells
with widespread pseudorosette formation. Pseudopapillary or
true papillary structures with vascular or hyaline cores are often
seen. Areas of the tumor may show small, irregular, gland-
like, or thyroid follicle-like spaces containing a homogeneous
eosinophilic substance, or microcystic or cystic structures lined
by flattened, cuboidal, or columnar cells. Some ependymomas are
predominantly or completely patternless. The background sub-
stance is usually made up of glial tissue. Focal oligodendroglioma-
like or astrocytoma-like areas are sometimes seen.
Figure 3.29 Supratentorial primitive neuroectodermal tumor
(PNET): the tumor cells contain minimal cytoplasm.
rate, and apoptotic bodies are common. Neuronal differentia-

tion may be seen (cerebral neuroblastoma), or, rarely, ganglion
cells may be seen (cerebral ganglioneuroblastoma).
● Metastatic neuroblastoma
Special techniques
● The neuroblastic cells express varying combinations of
neurofilaments, protein gene product 9.5, neuron-specific
enolase, synaptophysin and Leu-7
● GFAP is expressed by astrocytes when they are
components of the tumor
EPENDYMOMA
EPENDYMOMA VARIANTS
Figure 3.30 Ependymoma: the tumor grows as a sheet

CLINICAL FEATURES composed of small cells.
Ependymomas (WHO grade II) are slow-growing tumors of
ependymal or subependymal cells surrounding the ventricles There are several histological variants:
and central canal of the spinal cord and also from ependymal ● Cellular ependymoma is characterized by diffuse small
clusters in the filum terminale. They may also arise in the soft round cells with subtle pseudorosette or rosette formation.
tissues of the sacrococcygeal region, or as a teratomatous ● Papillary ependymoma is characterized by the presence of
process in the ovaries, posterior mediastinum, or lung. They papillary structures lined by pseudostratified tumor cells
are usually solid and demarcated, and rarely infiltrate adjacent with pseudorosette formation. This type may resemble
brain tissue. They rarely metastasize to various sites, such as choroid plexus papilloma.
lung, pleura, peritoneum, lymph nodes, liver, and bone. In the ● Clear cell ependymoma is characterized by tumor cells
CNS, they occur predominantly in children and tend to fill the with clear cytoplasm and well-defined cell membranes.
ventricular lumen. Spinal ependymomas usually occur in adults This variant may resemble oligodendroglioma, neuro-
and located in the lumbosacral region. cytoma, or metastatic renal cell carcinoma.
108 Brain tumors
Figure 3.31 Ependymoma: the most characteristic feature of Figure 3.33 Ependymoma: ependymal canals can be useful
these tumors is the presence of perivascular pseudorosettes. diagnostic features.
Figure 3.34 Subependymoma: groups of ependymal cells with

small round nuclei are surrounded by a fibrillary stroma.
● Subependymoma is characterized by clusters of ependymal

cells with round nuclei, surrounded by fibrillary matrix.
Microcysts and calcification are commonly seen. Vascular
hyalinization and foci of hemosiderin deposition are often
Figure 3.32 Ependymoma: perivascular pseudorosettes are seen in large tumors. Occasional tumors exhibit features of
composed of fibrillary processes abutting onto vessels.
both subependymoma and ependymoma.
● Myxopapillary ependymoma (see Chapter 13, Soft tissue
tumors)
● Tanycytic ependymoma is characterized by fascicles of
spindle cells of variable cell density. The cells have The cells forming the rosettes or pseudorosettes appear elongated,
bipolar elements, and may cause confusion with having tapering cytoplasmic processes connecting the cells to thin
astrocytoma. Ependymal rosettes are absent and vascular septa. These processes are the diagnostic characteristic
pseudorosettes only poorly defined. of this group of tumors. The nuclei are uniform and round to oval
● Anaplastic (malignant) ependymoma (WHO grade III) is in shape, with finely dispersed chromatin and indistinct nucleoli.
a highly cellular tumor with anaplastic features, high The cells between the rosettes are similarly uniform, round and
mitotic activity and prominent vascular endothelial cell loosely cohesive, creating an artificial separation of the tumor
proliferation. There may be widespread necrosis. into pseudopapillary structures. Scattered ciliated cells are seen
● Metastatic renal cell carcinoma

● Astrocytoma
Special techniques
● GFAP is positive in 50% of cases
● The tumor cells are positive for, S-100 protein, NSE, and
vimentin
● Cells show distinctive EMA positivity (apical membrane
reactivity in a discontinuous fashion presumably staining
the ciliated cells)
● Cytokeratin may be positive, especially in the papillary
areas and in the cystic areas
● Phosphotungstic acid-hematoxylin (PTAH) highlights
the tumor cells and their processes, and also stains the
blepharoplasts (basal bodies of the cilia); if present,
these are diagnostic
● Electron microscopy is useful in identifying the ciliary
structures
MENINGEAL TUMORS
Figure 3.35 Myxopapillary ependymoma: long, tapering fibrillary
processes abut onto delicate vascular channels.
MENINGIOMAS
CLINICAL FEATURES
Meningiomas are tumors of meningothelial (arachnoid) cells that
occur most commonly in adults, predominantly in women. The
tumors are mostly attached to the dura, particularly in areas
where arachnoid villi are numerous, though they may occur any-
where within the cranial cavity. They may also occur in the orbit,
nasal cavity, paranasal sinuses, bones of the skull, and adjacent
soft tissues. Cutaneous meningioma may arise from embryologi-
cally displaced arachnoidal cells found in locations such as scalp,
face, paravertebral region and around sensory organs of the head,
and along the course of cranial or spinal nerves. The tumors are
typically round or oval and lobulated, with a whorled pattern on
cut section; occasionally, the tumors exhibit carpet-like growth
over the dural surface (‘meningioma en-plaque’). They are cur-
rently classified (according to the new WHO classification of
brain tumors) into benign, atypical, and malignant tumors:
● Benign meningiomas run a benign clinical course and
correspond to WHO grade I.

● Atypical meningiomas show an overall increased risk of
local recurrence after complete resection compared with

Figure 3.36 Myxopapillary ependymoma: a glial marker (GFAP) benign meningiomas, and correspond to WHO grade II.
highlights the tumor component. ● Papillary meningiomas are most commonly seen in
young patients, show aggressive behavior with frequent

recurrences, brain invasion and late metastasis, and
either singly or in clusters along the surface of the cysts or
correspond to WHO grade III.
papillae. Mitoses are scarce. Cellular pleomorphism is seen in
● Anaplastic (malignant) meningiomas correspond to
malignant tumors.
WHO grade III.
● Choroid plexus papilloma
● Oligodendroglioma Meningiomas are well-demarcated but unencapsulated lesions
● Neurocytoma with frequent finger-like projections that penetrate into the
110 Brain tumors
Figure 3.37 Meningioma: cellular whorls, sometimes with central Figure 3.39 Microcystic meningioma: numerous intracellular cysts
psammoma bodies, are a useful diagnostic feature. are present, and the cells have fine processes.
Figure 3.38 Meningioma: intranuclear pseudo-inclusions are Figure 3.40 Secretory meningioma: small eosinophilic globules
commonly seen in the arachnoidal cells comprising this neoplasm. are seen within the dense sheets of arachnoid cells.
surrounding tissues. They consist of round polygonal or spindle to round pale nuclei with intranuclear cytoplasmic inclusions.
cells arranged in whorls, syncytial spheres (poorly formed Giant cells with bizarre single or multiple nuclei may be seen.
whorls), palisades, epithelial-like sheets or cords, or fascicles. Whorls are not a prominent feature.
Usually one pattern predominates, and this results in a variety Fibrous meningioma shows parallel and interlacing bundles
of histological appearances. of fibroblast-like tumor cells with extensive collagen deposition.
Whorl formation and psammoma bodies are occasionally seen.
Transitional (mixed) meningioma shows extensive whorl for-
Benign meningiomas (WHO grade I) mation in a meningioma with meningothelial and fibrous fea-
Meningothelial meningioma consists of solid lobules of tures. The whorls often show a central capillary, and some contain
meningothelial cells showing ill-defined cell membranes, and oval hyaline, occasionally calcified cores, or psammoma bodies.
Figure 3.41 Secretory meningioma: the eosinophilic globules are Figure 3.43 Chordoid meningioma: the tumor cells are arranged
highlighted by periodic acid–Schiff (PAS) staining. in epithelioid cords.
Figure 3.42 Secretory meningioma: the cells surrounding the Figure 3.44 Chordoid meningioma: the cells show moderate
secretory globules immunoreact with cytokeratin. pleomorphism, and are separated by a mucinous matrix.
Psammomatous meningioma shows abundant, often-calcified Microcystic meningioma is a loosely textured lesion consisting
psammoma bodies. Sometimes only small nests of meningothe- of numerous large intercellular spaces containing pale eosinophilic
lial cells may be seen within mineralized areas. This type of mucin. The intervening cells have elongated cytoplasmic processes
meningioma is more often seen in the spine, or arises in the circumscribing the microcysts. Eosinophilic PAS-positive globules
olfactory groove. may be seen. Whorls or psammoma bodies are scanty or absent.
Angiomatous meningioma shows hypervascularized stroma Secretory meningioma is characterized by features of
with occasional nests of neoplastic meningothelial cells. This meningothelial or transitional meningioma, with focal epithelial
tumor may resemble hemangioblastoma. differentiation evidenced by the formation of lumina that
112 Brain tumors
High-grade meningiomas (WHO grade III)

Papillary meningiomas are highly cellular tumors that form
papillary structures around vessel cores, reminiscent of ependy-
momas. Foci of ordinary meningioma can be seen. Whorls and
psammoma bodies are usually absent in the papillary areas.
Mitotic figures are usually present, but vary in numbers.
Rhabdoid meningiomas contain patches or extensive sheets of
rhabdoid cells, which are rounded cells containing eosinophilic
inclusion-like cytoplasm. The nucleus is displaced and often
contains a prominent nucleolus. Mitotic figures are usually
prominent.
Anaplastic (malignant) meningiomas are highly cellular,
patternless or sometimes spindle cell sarcoma-like tumors with
numerous mitotic figures and extensive invasion of the adjacent
brain parenchyma. The cells are round, polygonal, or spindle-
shaped with pale eosinophilic cytoplasm and indistinct cell bor-
ders. The nuclei are round or oval with finely granular and
vesicular chromatin pattern.
Figure 3.45 Anaplastic meningioma: the tumor is composed of ● Metastatic carcinoma
poorly differentiated cells with abundant mitotic activity. ● Schwannoma
● Hemangioma
● Hemangiopericytoma
contain PAS-positive and carcinoembryonic antigen (CEA)-
● CNS lesion of sinus histiocytosis with massive
immunoreactive globules and lined by cells with marked lymphadenopathy (from lymphoplasmocytic meningioma)
immunoreactivity for cytokeratin.
Lymphoplasmocyte-rich meningioma is characterized by Special techniques
the presence of prominent lymphoplasmocytic infiltration that ● The cells are vimentin-, desmoplakin-, and EMA-positive
may obscure the underlying meningioma. The latter may be ● Some are S-100-positive
meningothelial, transitional or even fibrous-type meningioma. ● Cytokeratin expression can be demonstrated in frozen
This type of meningioma (or its recurrence) may be associated tissue
with polyclonal gammopathy and/or anemia.
Metaplastic meningioma is characterized by the presence of
metaplastic change such as xanthomatous, cartilaginous, osseous,
myxoid, or lipomatous in otherwise meningothelial, transitional MIXED GLIOMAS
or fibrous-type meningioma.
CLINICAL FEATURES
Intermediate-grade meningiomas (WHO grade II)
Mixed gliomas are neoplasms that exhibit two or more neo-
Clear cell meningioma is a patternless meningioma with poly-
plastic glial cell types, including:
gonal clear tumor cells that are rich in glycogen. Whorl formation
is vague or absent, and psammoma bodies are often lacking. ● Oligo-astrocytoma corresponding to WHO grade II
This type of meningioma is more often seen in the cerebellopon- ● Anaplastic oligo-astrocytoma corresponding to WHO
tine angle and the cauda equina region. grade III
Chordoid meningioma is usually lobulated and characterized ● Other gliomas
by the presence of chordoma-like chains of eosinophilic, vacuo-
lated tumor cells in a mucus-rich matrix. The interlobular stroma
may exhibit lymphoplasmocytic infiltrate. Focal meningothelial
or transitional features may be seen. Psammoma bodies are few Oligo-astrocytoma consists of a mixture of neoplastic oligo-
in number. Cytokeratin, S-100 protein and EMA are less strongly dendrocytes and astrocytes. These are either diffusely intermin-
expressed than in chordomas. This type of meningioma or its gled or separated into distinct areas.
recurrence may be associated with Castleman’s disease. Anaplastic oligo-astrocytoma shows marked anaplasia,
Atypical meningiomas show marked nuclear atypia, frequent increased cellularity, numerous mitotic figures and vascular
mitoses, increased cellularity, small cells with high nuclear: proliferation.
cytoplasmic ratios and/or prominent nucleoli and focal or geo- Other gliomas may contain additional cell components such
graphical necrosis. as neoplastic ependymal cells.
Neuroepithelial tumors of uncertain origin 113
NEUROEPITHELIAL TUMORS OF
UNCERTAIN ORIGIN
ASTROBLASTOMA
CLINICAL FEATURES
Astroblastoma is a rare type of glial tumor that is seen in the
cerebrum of young adults.
Astroblastoma usually occurs as a component of other types of
astrocytomas, and only rarely as a pure form. It is characterized
by uniform compact small cells arranged around blood vessels.
The cells strongly express GFAP. Similar cells may be seen focally
in low- and high-grade astrocytomas.
CHORDOID GLIOMA OF THE THIRD VENTRICLE

Figure 3.46 Chordoid glioma of the third ventricle: the tumor
consists of loosely arranged cords of fibrillary cells and groups of
CLINICAL FEATURES epithelioid cells.
Chordoid glioma of the third ventricle is a rare, low-grade glial

tumor (WHO grade II) that occurs in adults and occupies the
anterior portion of the third ventricle.

Chordoid gliomas are solid tumors with a mucinous stroma.
The cells form epithelioid cords, or can sometimes show more
obvious fibrillary architecture. The epithelioid cells are oval and
have abundant cytoplasm. Glial differentiation is identified in
the form of coarse cellular processes. The stroma is mucinous,
and a lymphoplasmacytic infiltrate – often with prominent
Russell bodies – can be a striking feature.
● Meningioma
Special techniques
● Strong, diffuse immunoreactivity with GFAP
● Focal EMA immunoreactivity, but pancytokeratin is
negative
Figure 3.47 Chordoid glioma of the third ventricle: the
epithelioid groups of cells have abundant cytoplasm.
GLIOMATOSIS CEREBRI
CLINICAL FEATURES PATHOLOGICAL FEATURES

Gliomatosis cerebri, corresponding to grade III to IV (WHO), Gliomatosis cerebri shows diffuse permeation of the brain
represents a diffuse cell infiltration of the brain involving sev- tissue by neoplastic astrocytes. These are widely distributed
eral cerebral lobes and, on occasion, infratentorial structures along myelinated pathways. The cells frequently lack GFAP
and the spinal cord. It is an ill-defined lesion that causes diffuse immunostaining. Focal transformation to glioblastoma may
enlargement of the involved structure. be seen.
114 Brain tumors
NEURONAL AND MIXED NEURONAL-GLIAL

TUMORS
CENTRAL NEUROCYTOMA
CLINICAL FEATURES
Central neurocytoma (WHO grade II) is an intraventricular
tumor that occurs in young adults, and is located in the lateral
ventricles in the region of the foramen of Monro and septum
pellucidum. It may obstruct the CSF flow and has a favorable
prognosis.

Central neurocytoma is characterized by the presence of a uni-
form population of round cells with little, but often clear cyto-
plasm and distinct cell membranes. Focal perivascular nuclei-free
zones reminiscent of ependymoma are often seen. There are also
foci of acellular areas consisting of finely fibrillary processes Figure 3.49 Central neurocytoma: tumor cells show perinuclear
clearing, and the stroma contains a fine capillary network.There is
resembling neuropil.
little cellular pleomorphism.
Special techniques
See Gangliocytoma (p. 116)
Figure 3.50 Central neurocytoma: the neuronal nature of the

tumor is revealed by immunoreactivity with a neuronal marker,
synaptophysin.
CEREBELLAR LIPONEUROCYTOMA
CLINICAL FEATURES
Cerebellar liponeurocytoma is a rare cerebellar neoplasm
Figure 3.48 Central neurocytoma: the tumor is composed of involving predominantly adults. It has a favorable postopera-
small round cells with areas of acellular stroma. tive prognosis (WHO grade I).
Neuronal and mixed neuronal-glial tumors 115

Cerebellar liponeurocytoma is a densely cellular tumor with a
diffuse growth pattern. Focal areas of lipomatous differentia-
tion are seen within the tumor. The cells have a uniform
appearance with small round nuclei. Mitotic figures are incon-
spicuous. Lipidized tumor cells are present within the tumor,
often forming small aggregates.
Figure 3.53 Cerebellar liponeurocytoma: the neuronal nature of

the tumor is revealed by immunoreactivity with a neuronal marker,
synaptophysin.
● Medulloblastoma
● Neuroblastoma
Figure 3.51 Cerebellar liponeurocytoma: areas of small round Special techniques

cells separated by a fibrillary stroma. Focal lipomatous differentiation ● Neuronal markers, such as synaptophysin, are consistently
is seen. expressed
● Focal glial differentiation, demonstrated by GFAP
immunoreactivity, may be present
DESMOPLASTIC INFANTILE GANGLIOGLIOMA
CLINICAL FEATURES
Desmoplastic infantile ganglioglioma (WHO grade I) is a slow-
growing tumor which usually affects infants and is often
located in the superficial cerebral hemispheres. It appears as a
large fibrous mass, and is often associated with favorable
outcome following surgical resection.
Desmoplastic infantile ganglioglioma is characterized by the
presence of marked desmoplastic stromal component contain-
ing neuroepithelial cells with astrocytic and neuronal differen-
tiation. The ganglion cells are usually small and lack Nissl
substance. Mitotic figures are occasionally seen.
Special techniques
Figure 3.52 Cerebellar liponeurocytoma: lipomatous
differentiation within groups of small round cells. See Gangliocytoma (p. 116)
116 Brain tumors
DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR
CLINICAL FEATURES
Dysembryoplastic neuroepithelial tumor (WHO grade I) is a
slow-growing, usually benign tumor that occurs in children
and young adults, mostly in the temporal lobe, and is associ-
ated with a history of partial complex seizures. It has rarely
been reported as multifocal lesions, and does not recur after
surgical excision.

Dysembryoplastic neuroepithelial tumor is a multinodular,
loosely textured cortical lesion consisting of a heterogeneous
population of cells, most commonly neoplastic oligodendro-
cytes, neurons, and a small number of astrocytes. The inter-
vening cerebral cortex often shows an increase in the number
of oligodendroglial cells and of neurons. Cystic change or cal-
cification may be seen. There is minimal atypia and mitotic fig-
ures are rarely seen.
Figure 3.55 Dysembryoplastic neuroepithelial tumor: the tumor
classically has microcysts lined by axons and oligodendroglial-like
cells. Neurons may be seen within the microcysts.
● Oligodendroglioma DYSPLASTIC GANGLIOCYTOMA OF THE
● Diffuse astrocytoma
CEREBELLUM
Special techniques CLINICAL FEATURES

● Neuronal markers such as synaptophysin or neurofilament
Dysplastic gangliocytoma of cerebellum (Lhermitte–Duclos)
protein highlight the neuronal component
(WHO grade I) is a very rare, slow-growing, benign tumor-like
● GFAP highlights the glial component
condition of the cerebellum that is commonly associated with
Cowden disease. It can be associated with some malformations
such as megalencephaly and leontiasis ossea.
This is an ill-defined lesion that consists of abnormally large,
dysplastic granular cells reminiscent of Purkinje neurons dif-
fusely present in the cerebellar cortex. It is often associated
with a reduction in the number of normal granular neurons.
Special techniques
See Gangliocytoma below.
GANGLIOCYTOMA
CLINICAL FEATURES
Gangliocytoma (WHO grade I) is a slow-growing tumor of
mature ganglion cells which affects children and young adults.
It occurs anywhere in the CNS, but is most commonly found in
the temporal lobe.
Figure 3.54 Dysembryoplastic neuroepithelial tumor: the
intracortical location of this tumor is highlighted at low-power Gangliocytoma is a well-demarcated, hypocellular lesion con-
magnification. sisting predominantly of neoplastic ganglion cells supported by
Oligodendroglial tumors 117
non-neoplastic glial cells. The ganglion cells are mature and

highly differentiated, and distinguished from normal ganglion
cells by their dysplastic and occasionally bizarre appearance.
Calcification is occasionally seen.
Special techniques
● Neuronal markers such as synaptophysin or neurofilament
protein highlight the neuronal component
● GFAP highlights the glial component
GANGLIOGLIOMA
CLINICAL FEATURES
Ganglioglioma (WHO grade I) is a benign, slow-growing
tumor of neoplastic astrocytes and ganglion cells, and affects
both children and young adults. It is often cystic and occurs
anywhere in the CNS.
Anaplastic (malignant) ganglioglioma (WHO grade III) is a
rare variant with an aggressive behavior.
Figure 3.56 Paraganglioma of the filum terminale: the tumor cells
are arranged in groups (zellballen).
Ganglioglioma is characterized by mixed glial and neuronal
cells. The glial cells are of astrocytic type, and oligodendrocytes
are rarely present. The neuronal cells are usually in the form of
binucleate ganglion cells. A prominent mesenchymal compo-
nent and perivascular lymphocytic infiltrate may be seen.
Anaplastic (malignant) ganglioglioma is similar to gangli-
oglioma, but the glial component exhibits distinct atypia,
increased mitotic figures, and necrosis.
Special techniques
See Gangliocytoma (p. 116)
PARAGANGLIOMA OF THE FILUM TERMINALE
CLINICAL FEATURES
Paraganglioma of the filum terminale (WHO grade I) is a
slowly growing, benign tumor which occurs in adults.

Paraganglioma of the filum terminale is identical to paragan- Figure 3.57 Paraganglioma of the filum terminale: chromogranin
gliomas seen elsewhere. immunoreactivity is seen within the tumor cells.
in the cerebellum and spinal cord. It may invade the brain sub-
OLIGODENDROGLIAL TUMORS
stance, recurs locally in about 50% of cases, and may metasta-
size via the CSF to the other ventricles or to arachnoid, but
OLIGODENDROGLIOMA rarely appears outside the CNS.
CLINICAL FEATURES PATHOLOGICAL FEATURES (Figures 3.58–3.61)

Oligodendroglioma (WHO grade II) is usually a slow-growing Oligodendroglioma is a richly cellular lesion that consists of a
tumor that is most commonly seen in adults, but also occurs in uniform population of round cells with clear cytoplasm and
children. It affects the cerebral hemispheres, but may also occur very distinct cell membranes. These cells are arranged in sheets,
118 Brain tumors
Figure 3.58 Oligodendroglioma: the tumor cells diffusely infiltrate Figure 3.60 Oligodendroglioma: focal mineralization can be a
and have a prominent, capillary-rich stroma. prominent feature in oligodendrogliomas.
Figure 3.59 Oligodendroglioma: the tumor cells show moderate Figure 3.61 Anaplastic oligodendroglioma: there is increased
pleomorphism and have prominent perinuclear clearing. cellularity and pleomorphism. Mitotic figures are easily identified,
and there is microvascular proliferation.
groups, or nests separated by a delicate, very vascular stroma. and eventually converts into calcareous channels) is frequently
Sometimes small groups of tumor cells are separated by seen in the stroma. The cells are round, with distinct perinuclear
connective tissue septa. Other types of gliomas (especially clear zones and clearly visible cell borders; this gives the cells a
astrocytoma) may be found in association with oligoden- ‘honeycomb’ pattern. The nuclei are typically spherical and
droglioma (mixed gliomas). Malignant cellular morphology may hyperchromatic. Elongated tumor cells may be seen in tumors of
be seen in some tumors (anaplastic oligodendroglioma WHO the optic nerve and chiasma. Cells with granular eosinophilic cyto-
grade III). Rarely, a sarcomatous component may be seen. plasm and signet-ring cells may be seen. Cells of other gliomas
Arborescent vessels are seen in the delicate stroma. Calcification (particularly astrocytes) may be seen. Mitotic figures and cyto-
(which frequently commences in the walls of the blood vessels logical atypia are seen in malignant tumors.
Pineal parenchymal tumors 119
● Central neurocytoma
Special techniques
● Some of the tumor cells are GFAP-positive
PINEAL PARENCHYMAL TUMORS
PINEOCYTOMA/PINEOBLASTOMA
CLINICAL FEATURES
Pineal parenchymal tumors include pineocytoma, pineal
parenchymal tumor of intermediate differentiation, and
pineoblastoma.
Pineocytoma is a rare, slow-growing tumor of pineal parenchy-
mal cells. It may cause symptoms by compressing adjacent brain
structures, including the aqueduct, resulting in hydrocephalus.
The tumor may occasionally spread via the CSF. It has a favor-
able prognosis, and corresponds to WHO grade II. Figure 3.63 Pineocytoma: neuronal differentiation may be seen
Pineoblastoma is a rare, highly malignant, embryonal tumor in some tumors.
of precursor cells of the pineal gland. It occurs in children and
young adults, and usually causes symptoms by obstructing CSF
pathways or infiltrating adjacent brain structures. It tends to
metastasize via the CSF, and corresponds to WHO grade IV.

Pineocytoma is a well-demarcated, moderately cellular tumor
consisting of round cells arranged in a sheet-like or lobulated pat-
tern with delicate vascular stroma. The cells often form large
rosettes. The cells are consistently positive for synaptophysin.
Figure 3.64 Pineocytoma: the tumor immunoreacts with a

neuronal marker, synaptophysin.
Occasionally, neural differentiation and mature ganglion cells are

seen. Retinal and astrocytic differentiation may sometimes be seen.
Pineoblastoma is a highly cellular tumor consisting of round
cells with Homer Wright rosettes, closely resembling medullo-
blastoma or neuroblastoma. Immunohistochemical evidence
of neuronal or glial differentiation is less often seen than in
pineocytoma.
Pineal parenchymal tumor of intermediate differentiation
consists of cells with features intermediate between those of
Figure 3.62 Pineocytoma: small round cells are separated by a pineocytoma and pineoblastoma or of an admixture of immature
fibrillary stroma, forming pineocytomatous rosettes. (pineoblastic) and differentiated (pineocytic) neoplastic cells.
120 Brain tumors

Pituicytomas are solid tumors composed of elongated spindle
cells with a fascicular architecture. Mitotic figures are not a
conspicuous feature, and there are few intercellular reticulin
fibers.
Figure 3.65 Pineoblastoma: the tumor is hypercellular and

shows moderate pleomorphism. Mitotic figures and apoptotic
bodies are seen.
PITUITARY TUMORS
GRANULAR CELL TUMOR OF Figure 3.66 Pituicytoma: spindle cells arranged in a fascicular
THE NEUROHYPOPHYSIS architecture.
CLINICAL FEATURES Differential diagnosis

Granular cell tumor of the neurohypophysis (WHO grade I) is ● Pilocytic astrocytoma
a slow-growing tumor which is usually diagnosed in adults. It ● Fibroblastic meningioma
arises from the neurohypophysis or infundibulum, and is com- ● Schwannoma
monly found at autopsy as asymptomatic nodules. Alternatively, ● Neurofibroma
it may present as hormonal and/or visual disturbances.
Special techniques
● S-100 strongly immunostains tumor cells
The tumors consist of densely packed cells with abundant gran- ● GFAP shows mild to moderate focal positivity
ular eosinophilic cytoplasm. The cytoplasm stains with PAS. ● The tumor cells do not immunoreact with EMA
Special techniques
● The cells immunoreact with S-100 protein PITUITARY ADENOMA AND CARCINOMA
● Electron microscopy shows abundant membrane-bound,
electron-dense material
CLINICAL FEATURES
Pituitary adenoma may occur with signs attributable to hormonal
PITUICYTOMA secretion, or due to pressure effects on adjacent structures, usually
the optic chiasma. When large and in suprasellar location, it may
compress the cerebrum without true invasion. It occasionally
CLINICAL FEATURES
involves the adjacent sinuses or nasal cavity.
Pituicytoma is a slow-growing glioma of the neurohypophysis. Pituitary carcinoma usually presents in a similar manner
It presents with hypopituitarism and/or visual disturbance, and to pituitary adenoma, and sometimes gives rise to distant
has a low incidence of recurrence after surgery. metastases.
Tumors of sellar region 121
Pituitary adenoma is characterized either by a diffuse pattern
with confluent sheets of cells separated by delicate vascular
stroma, or by a sinusoidal pattern of growth in which clusters
of cells form palisades around sinusoidal vascular spaces. The
latter pattern may impart a glandular appearance to the lesion.
The tumor usually shows infiltrative margins.
The classification of pituitary adenomas is based on cell type
identified by immunohistochemical reactions against the spe-
cific hormones and electron microscopy. According to this clas-
sification, the adenomas can be divided into somatotroph cell
adenoma, adrenocorticotroph cell adenoma, thyrotroph cell ade-
noma, and gonadotroph cell adenoma. Null cell adenoma and
multihormonal adenoma are also recognized.
Pituitary carcinoma shows similar histological appearances,
but with more cellular pleomorphism and increased numbers of
mitotic figures. Amyloid deposition is seen in some cases, especi-
ally in prolactin-producing tumors.
The cells are round with abundant eosinophilic cytoplasm.
Prominent nucleoli may be seen. Nuclear pleomorphism can be
seen in both adenoma and carcinoma. Mitotic figures are rare Figure 3.67 Adamantinomatous craniopharyngioma: epithelial
or sparse in adenoma, and abundant in carcinoma. structures are intermixed with fibroblastic and gliotic tissues.
● Adenocarcinoma
● Plasmacytoma
● Melanoma
● Olfactory neuroblastoma
Special techniques
● With the exception of null cell tumors, the cells are
positive for one or more pituitary hormones
● Cytokeratin is positive, but EMA negative
● Electron microscopy shows neurosecretory granules. The
various subtypes can be identified by the size and distribu-
tion of the granules, providing valuable information
TUMORS OF SELLAR REGION
CRANIOPHARYNGIOMA
Figure 3.68 Adamantinomatous craniopharyngioma: the
epithelial structures have a lining of basaloid cells with palisading
CLINICAL FEATURES nuclei.There is a nodule of compact ‘wet’ keratin.
Craniopharyngioma (WHO grade I) is a tumor of uncertain
and contain cells with a loose reticular pattern and a central squa-
histogenesis, typically presenting as a suprasellar or infundibu-
mous pearl. The papillary variant has broad papillary epithelial
lar mass causing visual disturbances or mass effects. It grows
structures. Glial response and giant cell reaction towards keratin
by expansion and insinuation into adjacent brain, and often
may be seen. Astrocytic response with Rosenthal fibers may also
forms a cyst that may fill the third ventricle.
be present.
PATHOLOGICAL FEATURES (Figures 3.67–3.70) Differential diagnosis

Craniopharyngioma is characterized by the presence of numerous ● Pilocytic astrocytoma (particularly when the tumor is
epithelial structures with a villiform pattern present in a fibro- inadequately biopsied due to the glial and fibroblastic
blastic stroma that imparts an adamantinomatous appearance. responses at the margins of the tumor)
The epithelial structures are outlined by a layer of basaloid cells, ● Epidermoid cysts
122 Brain tumors
been suggested). It occurs mainly in the cerebellar hemispheres,

but may also be seen in vermis, spinal cord, and medulla, and
rarely in the cerebral hemispheres and optic nerve. It affects
individuals between the ages of 20 and 30 years. The tumor
may be a component of von Hippel– Lindau disease; it may also
be associated with syringomyelia, pheochromocytoma and ery-
throcythemia (due to the secretion of erythropoietin-like sub-
stance by the tumor) and may be multicentric. This tumor has
a good prognosis, is treated surgically, but may recur locally.

Hemangioblastoma is a well-circumscribed lesion consisting of
numerous thin-walled vascular spaces separated by round cells.
These cells have abundant pale or clear cytoplasm and contain
small, rounded nuclei. Variously sized and shaped thin-walled
capillary vessels form the bulk of the tumor. These are uniformly
distributed in the lesion and only separated from each other by
the round stromal cells. The endothelial lining cells are bland. The
stromal cells are round or polygonal, and contain abundant clear
cytoplasm and small uniform nuclei. Nuclear pleomorphism and
hyperchromatic bizarre nuclei may be seen.
Figure 3.69 Papillary craniopharyngioma: the papillary architecture
is seen at low-power magnification.
Figure 3.71 Hemangioblastoma: numerous thin-walled vessels

Figure 3.70 Papillary craniopharyngioma: the papillae are lined surround cells with pale, well-defined cytoplasm.
by well-differentiated, stratified squamous epithelium.
TUMORS OF UNCERTAIN HISTOGENESIS
Special techniques
HEMANGIOBLASTOMA ● The stromal cells contain neutral fat
● The vessels are lined by factor VIII-related, antigen-
positive cells
CLINICAL FEATURES
● Entrapped astrocytes are GFAP-positive
Hemangioblastoma (WHO grade I) is a primary tumor of ● The majority of stromal cells are negative for the above
obscure histogenesis (vascular or neuroendocrine origin has markers
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Tumors of the sellar region

WHO CLASSIFICATION OF TUMORS Pituitary adenoma
OF THE CENTRAL NERVOUS SYSTEM Pituitary carcinoma
Pituicytoma
Tumors of neuroepithelial tissue Craniopharyngioma
Tumors of peripheral nerves Granular cell tumor
Tumors of the meninges Metastatic tumors
Lymphomas and hematopoietic neoplasms
Germ cell tumors
Tumors of the sellar region GRADING OF INTRINSIC BRAIN TUMORS
Metastatic tumors
In the grading of brain tumors, the following features are to be
Tumors of the intrinsic brain substance (neuroepithelial tissue)
considered: Invasiveness; cellularity; cellular heterogeneity; cellu-
Astrocytic tumors
lar pleomorphism; differentiation potential of neoplastic cells;
Oligodendroglial tumors
presence of primitive cells; anaplastic changes; mitotic index;
Mixed gliomas
endothelial hyperplasia; and the presence or absence of necro-
Ependymal tumors
sis and hemorrhage.
Choroid plexus tumors
Gradings may present several problems as the histology of
Neuroepithelial tumors of uncertain origin
many of the intrinsic – particularly glial – tumors may vary from
Neuronal and mixed neuronal-glial tumors
area to area. For this reason, the grading of small biopsies can be
Neuroblastic tumors
misleading.
Pineal parenchymal tumors
The WHO grading is more specific for gliomas, and is based
Embryonal tumors
on histological evidence of differentiation or anaplasia in a tumor.
Tumors of the meninges There are four histological grades (grade I ⫽ benign to grade
Tumors of meningothelial cells IV ⫽ malignant) based on the degree of cytological atypia,
Mesenchymal, non-meningothelial tumors mitotic activity, tumor necrosis and microvascular proliferation.
Primary melanocytic lesions In addition to grading, assessment of patients with brain
tumors should include the site of the tumor, and the age and
Tumors of uncertain histogenesis general health status of the patient. For example, in children
pilocytic astrocytomas, medulloblastomas and ependymomas
Lymphomas and hematopoietic neoplasms together account for around 90% of all tumors and this is of
importance in the differential diagnosis of posterior fossa
Germ cell tumors tumors in the appropriate age group.
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4 breast tumors
Awatif I Al-Nafussi, Lee B Jordan and Jeremy St J Thomas
Epithelial lesions, benign 132 Invasive carcinoma, variants 156

Adenoma, ductal (sclerosing papilloma) 132 Adenoid cystic carcinoma 156
Adenoma, nipple (florid papillomatosis of the nipple) 132 Apocrine carcinoma 157
Adenomas, general 132 Clear cell carcinoma 157
Tubular adenoma 133 Histiocytoid carcinoma 157
Lactating adenoma 134 Inflammatory carcinoma 157
Pleomorphic adenoma 134 Intracystic carcinoma 158
Apocrine adenoma 134 Irradiated carcinoma 158
Adenosis, microglandular (MGA) 134 Lipid-rich carcinoma 158
Adenosis, sclerosing 135 Metaplastic carcinoma (sarcomatoid carcinoma and
Adenosis, tubular 135 carcino sarcomas) 158
Columnar cell lesions 136 Microinvasive carcinoma of the breast (MICB) 162
Epithelial hyperplasia: atypical lobular hyperplasia (ALH) 136 Micropapillary carcinoma 163
Epithelial hyperplasia: ductal hyperplasia 136 Papillary carcinomas 163
Fibrocystic change and associated conditions 138 Secretory (juvenile) carcinoma 164
Mammary mucocele-like lesion 138 Signet ring cell carcinoma 164
Papilloma 139 Small cell carcinoma 165
Intraduct papilloma 139
Intracystic papilloma 139 Epithelial/stromal (biphasic) lesions 165
Breast papillomas with areas of atypical Adenomyoepithelioma (myoepithelioma) 165
proliferation 139 Fibroadenoma 168
Radial scar and complex sclerosing lesion 140 Myxoid fibroadenoma and allied conditions 171
Phyllodes tumor 171
Epithelial lesions, malignant 141
Carcinoma in situ 141 Secondary metastasis from extramammary malignancies 173
Carcinoma in situ, ductal (DCIS) 141 Metastatic hemangiopericytoma 173
Non-comedo small-cell type DCIS (cribriform and Metastatic malignant melanoma 174
micropapillary) 145 Renal cell carcinoma 174
Comedo-type DCIS 145
Neuroendocrine DCIS 145 Stromal lesions 174
Cystic hypersecretory DCIS 145 Collagenous spherulosis 174
Spindle cell DCIS 145 Hamartoma 174
Carcinoma in situ, indeterminate features (CIS-IF) 145 Lymphomas 176
Carcinoma in situ, lobular (LCIS) 146 Myofibroblastic lesions: inflammatory myofibroblastoma
Carcinoma in situ, Paget’s disease of the breast 147 tumor 176
Invasive carcinoma 147 Myofibroblastic lesions: myofibroblastoma 177
Invasive carcinoma of no special type (NST)/invasive Myxamatous lesions 177
carcinoma not otherwise specified (NOS)/ Periductal stromal sarcoma 177
ductal carcinoma 149 Pseudoangiomatous stromal hyperplasia of the breast 178
Lobular carcinoma 151 Sarcomas of the breast 179
Medullary carcinoma 153 Solitary fibrous tumor 180
Mucinous (mucoid, colloid) carcinoma 153 Sclerosing lymphocytic lobulitis (diabetic mastopathy) 180
Tubular and cribriform carcinoma 154 Spindle cell stromal tumors of the breast 180
Tubulo-lobular carcinoma 155 Vascular lesions of the breast 180
GENERAL COMMENTS their lifetime, and over 14 000 women die from the disease each
year. With the introduction of the breast screening program in
Breast cancer is the most common cancer affecting females. It the UK and the routine use of large-core needle biopsy utilizing
comprises 18% of all female cancers and is the leading cause of stereotactic mammography or ultrasound guidance as the initial
cancer-related death in women. Approximately 1 in 10 women diagnostic approach to non-palpable breast lesions, the pathol-
in the United Kingdom can expect to contract breast cancer in ogist has witnessed a significant increase in the number of
132 Breast tumors
non-malignant lesions which pose dilemmas with regard to the It can cause erosion of the nipple that may clinically be mis-
most appropriate clinical management. taken for Paget’s disease. This lesion is usually treated by local
Details of all tumors and tumor-like lesions of the breast and excision.
the non-tumorous proliferative process are included in this chap-
ter. The lesions are listed in alphabetical order, and also accord- PATHOLOGICAL FEATURES
ing to histogenesis.
Nipple adenoma is located superficially under the nipple, has
rather well-defined margins, and consists of complex glandular
EPITHELIAL LESIONS, BENIGN elements embedded in a densely sclerosed fibrous stroma. The
glandular elements are composed of a mixture of glandular or
ductular structures with a tendency for arrangement in parallel
ADENOMA, DUCTAL (SCLEROSING PAPILLOMA) arrays, papillomatous processes and epithelial hyperplasia. The
latter is in the form of solid proliferation of cells or pseudo-
papillary buds projecting into the elongated spaces. There may
CLINICAL FEATURES
also be features reminiscent of adenosis.
Ductal adenoma is a benign lesion of breast ducts which may
be single or is occasionally multiple. It occurs in women of Secondary features
all ages, but is more common over the age of 60 years. It ● Erosion of the overlying epidermis.
presents as a breast lump which may mimic carcinoma; less ● Central necrosis (does not indicate malignancy).
commonly, it is associated with nipple discharge. Most ductal
adenomas evolve by sclerosis of benign intraduct papillary Cell morphology
lesions, although processes similar to sclerosing adenosis and, ● The cells are similar to those of duct papilloma (two cell
possibly, duct ectasia may contribute to the pathogenesis of a
types), and have a uniform nuclear morphology.
proportion of cases. Circumstantial evidence suggests that ● They often show nuclear hyperchromasia and a relatively
ductal adenoma of the breast is a component of the complex
high nuclear:cytoplasmic ratio.
of myxomas, spotty pigmentation, endocrine overactivity, and ● Squamous change may be seen in the most superficial
schwannomas.
component of the lesion.
PATHOLOGICAL FEATURES Differential diagnosis

The lesion usually occupies medium- and large-sized breast ducts ● Invasive carcinoma
and appears to have a fibrous capsule. It consists of arrays of ● Intraduct papilloma
long, straight, narrow, roughly parallel tubules composed of
distinct uniform epithelial and myoepithelial cells. The tubules
are separated by a modest amount of fibrous tissue. These
ADENOMAS, GENERAL
lesions can be multifocal, but are closely clustered together.
CLINICAL FEATURES
Secondary changes
Tubular adenoma is a benign lesion occurring in young women
● Apocrine change is commonly seen.
in early reproductive life. The tumor may reach up to 4 cm in
diameter, and in young women they may resemble non-calcified
fibroadenomas on mammography and ultrasound. In older
● Complex sclerosing lesion women, tubular adenomas may resemble malignant masses with
● Invasive carcinoma microcalcifications.
Lactating adenoma is an uncommon, well-differentiated,
Special techniques benign tumor of secretory mammary epithelium that occurs in
● The myoepithelial cells exhibit immunoreactivity for S-100 pregnant and lactating women. Although most lactating adeno-
protein, alpha-SMA, GFAP, vimentin, CD10, CK14 and mas involute spontaneously, the diagnosis is not always straight-
CK5/6, and also express p63, maspin, and P-cadherin. forward and surgical resection may be required for definitive
diagnosis and exclusion of other neoplasms. Most lactating
adenomas show one or more typically benign features on ultra-
ADENOMA, NIPPLE (FLORID PAPILLOMATOSIS
sound, such as circumscribed borders, smooth lobulation, or an
OF THE NIPPLE) echogenic pseudocapsule. Some, however, have features typically
associated with malignancy, including irregular, angulated, or
ill-defined margins, or posterior acoustic shadowing.
CLINICAL FEATURES
Pleomorphic adenoma (mixed tumor of salivary gland type)
Florid papillomatosis of the nipple presents as a unilateral mass of the breast is a rare, benign tumor most commonly seen in
under the nipple. It is usually less than 1 cm in diameter, and is postmenopausal women. This may be misdiagnosed as invasive
accompanied by a serous or bloody discharge from the nipple. carcinoma.
Epithelial lesions, benign 133
Apocrine adenoma is a rare benign epithelial tumor of the hypocellular stroma. The tubules or ductules are similar to those
breast which may present radiologically as a well-defined opacity. seen in normal breast lobules. The cells lining the tubules are
round with moderate amount of cytoplasm and regular nuclei.
PATHOLOGICAL FEATURES (Figures 4.1 and 4.2) Mitoses may occasionally be seen.
Tubular adenoma is a sharply circumscribed lesion consisting

of uniform tubular structures separated by delicate, scant
(a) (b)
Figure 4.1 (a, b) Lactational adenoma of the breast, showing packed glandular units with striking lactational change. Note the
intracytoplasmic and luminal secretion.
(a) (c)
(b) (d)
Figure 4.2 (a–d) Tubular adenoma of the breast, showing a circumscribed mass of mature acinar units with intervening fibrovascular stroma.
134 Breast tumors
Lactating adenoma is a sharply circumscribed lesion that PATHOLOGICAL FEATURES

may contain fibrous septa. It consists of closely packed uniform
MGA is characterized by the presence of increased number of
tubular or acinar structures separated by very scant stroma.
uniform, rounded acinar structures with patent lumina that
The tubules or ductules are similar to those seen in normal lac-
may contain colloid-like material. These are haphazardly and
tating breast. They are lined by cells with vacuolated cytoplasm
randomly distributed within the breast substance (including
and large nuclei. Lactating adenoma should be distinguished
both fat and fibrous tissue), and not confined to lobules as in
from lactational change superimposed on a pre-existing fibro-
sclerosing adenosis. The structures lack a myoepithelial layer.
adenoma – a common cause of the clinical appearance of a
In atypical microglandular adenosis – in contrast to ordinary
breast lump in pregnancy/lactation.
MGA – the glands are more irregularly shaped, closely packed,
Pleomorphic adenoma is characterized by an admixture of
cytologically atypical, and tend to lack secretions. Transfor-
epithelial and myoepithelial cells embedded in abundant
mation of areas of microglandular hyperplasia into atypical
myxomatous stroma. It may rarely be mistaken for mucinous
microglandular hyperplasia and into peculiar invasive carci-
carcinoma.
noma may be seen.
Apocrine adenoma is characterized by a circumscribed pro-
liferation of metaplastic apocrine cells which may contain
calcifications. Cell morphology
● The cells are bland, with no evidence of pleomorphism
Cell morphology or atypia.
● A myoepithelial cell layer should be present in all types of ● They often show clear cell cytoplasmic change.
adenomas, although immunostaining with cytokeratin (CK) ● The myoepithelial cell layer is absent, but a similar lesion
5/6 or CK14 does not always show a complete layer with myoepithelial proliferation has been reported.
throughout the lesion. ● Mitotic figures are uncommon.
● Apical snouts may be seen.
Special techniques
● Cam 5.2 (CK8 and 18), AE1/AE3 (CK2, 4, 5, 6, 8, 9, 10, Differential diagnosis
15, 16 and 19) and epithelial membrane antigen (EMA) ● Sclerosing adenosis
highlight the epithelial component in these lesions. ● Tubular carcinoma (the glands are confined within a
● The myoepithelial cells exhibit immunoreactivity for S-100 stellate area, angulated and present within desmoplastic
protein, alpha-smooth muscle actin (SMA), glial fibrillary stroma, the cells are flatter and contain numerous apical
acidic protein (GFAP), vimentin, CD10, CK14 and CK5/6, snouts, and often associated with papillary or cribriform
and also express p63, maspin, and P-cadherin. carcinoma in situ)
● Tubulo-lobular carcinoma (has both small tubules and
ADENOSIS MICROGLANDULAR (MGA) invasive cords typical of lobular carcinoma)
● Lobules showing glands reminiscent of microglandular
Adenosis is defined as increased numbers of glands and lobular hyperplasia
units and occurs in reproductive life and in perimenopausal
women. There are several histological varieties of adenosis (see Special techniques
below). ● The luminal hyaline material is PAS-positive, and may
stain with Alcian blue and mucicarmine.
CLINICAL FEATURES ● The clear cells contain glycogen and are therefore
Microglandular adenosis (MGA) is a very uncommon benign PAS-positive.
proliferative disorder of the breast that may mimic tubular car- ● Circumferential type IV collagen deposition is observed
cinoma both radiologically and pathologically. In the majority around constituent glands.
of cases, the lesion presents as a palpable mass, affecting women ● The cells express CK7, while CK20 is negative.
between their late twenties and eighth decade of life. MGA may ● Immunohistochemistry for HMW-CK903
affect women with a family history of breast cancer. The lesions (MA903/34␤E12) shows no reactivity in invasive or in situ
vary in size from an incidental microscopic focus up to several carcinomas, or atypical MGA, but may be focally present
centimeters diameter, but the majority are 3–4 cm in diameter. in the associated MGA.
Grossly, it resembles normal breast or an ill-defined indurated ● Immunohistochemistry for MIB-1 and p53 are useful in
area of fibro-fatty tissue. Controversy persists as to whether the distinguishing between carcinoma and MGA or AMGA.
lesion is associated with an increased risk of subsequent cancer Carcinomas tend to show a more intense staining than
development, although it has been found recently that the in AMGA.
lesion may have a significant premalignant potential. When ● MGA and AMGA do not demonstrate myoepithelial cell
carcinomas arise in MGA, there is often a transition from ordi- marker positivity in the cell layer subjacent to luminal
nary MGA to atypical MGA (AMGA) to carcinoma. epithelial cells (S-100 protein, alpha-SMA, GFAP,
Atypical microglandular adenosis must be widely excised with vimentin, CD10, CK14, CK5/6, p63, maspin, and
follow-up, as in cases of atypical lobular or ductal hyperplasia. P-cadherin are negative).
ADENOSIS, SCLEROSING
CLINICAL FEATURES
Sclerosing adenosis mostly presents as a non-palpable lesion
with different mammographic and ultrasound appearances.
The most common finding is microcalcification on mammo-
grams. The radiological features may sometimes mimic malig-
nancy, so histopathological examination is mandatory for
definite diagnosis. The lesion carries no increased cancer risk,
and perhaps regresses after menopause. Sclerosing adenosis
often accompanies fibrocystic disease of the breast. Lobular
carcinoma has rarely been reported in a background of scle-
rosing adenosis.

Figure 4.3 Sclerosing adenosis. Note the preservation of
Sclerosing adenosis is an ill-defined lesion consisting of aggre- architectural organization in this lesion.
gates of enlarged, distorted lobular units associated with fibrosis
or sclerosis of the specialized lobular stroma. The individually
Special techniques
deformed acini often still show two cell layers (epithelial and ● The myoepithelial cells exhibit immunoreactivity for S-100
myoepithelial), and are typically less compressed towards the protein, alpha-SMA, GFAP, vimentin, CD10, CK14 and
periphery of the lobules. Adjacent glandular spaces often have CK5/6, and also express p63, maspin, and P-cadherin. The
similar shapes and tend to be arranged in parallel lines. Early finding of myoepithelial cells helps in distinguishing the
lesions are more cellular, and late ones sclerotic. Sclerosing lesion from invasive carcinoma.
adenosis may extend into fat, into vessels or around nerves,
mimicking perineural invasion. These features do not indicate ADENOSIS, TUBULAR
malignancy.
Tubular adenosis is an uncommon benign lesion of the breast
Secondary features that may mimic invasive carcinoma. It occurs in women over
● Microcalcification the age of 40 years. The lesion may present with breast mass,
● Apocrine change, sometimes with atypia or is found in specimens resected for carcinoma.
● Foci of atypical lobular hyperplasia or lobular carcinoma Tubular adenosis appears to be a benign lesion per se, but
in situ whether it has premalignant potential remains to be determined.
Cell morphology PATHOLOGICAL FEATURES

● The cells are bland, with no significant pleomorphism, and The histological hallmark of tubular adenosis is haphazard
rarely show mitotic activity. proliferation of elongated tubules that are non-crowded, nar-
● Two cell layers are seen at least focally. row, and sometimes branching. This shows no lobular arrange-
● Apocrine change may be present. ment or, at most, vague lobular grouping, with some tubules
often extending into the fat. The tubules contain either basophilic
Differential diagnosis or granular eosinophilic secretion, are lined by bland-looking
● Tubular carcinoma: the maintenance of normal lobular ductal cells, and surrounded by an intact myoepithelial layer.
architecture seen on panoramic view, the presence of two The stroma is sclerotic to edematous.
cell layers and of basement membrane surrounding the
glands and the frequent association with ductal carcinoma Differential diagnosis
in situ (DCIS) distinguishes sclerosing adenosis from ● Invasive carcinoma (especially at intraoperative frozen
carcinoma. section or when the lesion is cancerized by DCIS)
● Radial scar or complex sclerosing lesions: these show ● Microglandular adenosis (tubular adenosis shows an
characteristic floret-type growth pattern with ducto-lobular infiltrative growth similar to microglandular adenosis but
structures radiating out from a central zone of dense it differs by the interdigitating tubular configuration and
fibro-elastic tissue. by the presence of myoepithelium)
● Microglandular adenosis: this lacks a lobular organoid ● Sometimes the tubular adenosis is cancerized by non-
pattern and is made up of rounded, single-layered tubules. comedo DCIS, producing a pattern strongly mimicking
● Physiological change of lobules, in which acini may look infiltrating carcinoma
somewhat deformed due to atrophy of cells and fibrosis ● Adenomyoepithelial adenosis (a form of adenosis which
of stroma. is similar in several ways to microglandular adenosis,
136 Breast tumors
but one significant difference is the presence of cytological and architectural features to warrant a diagnosis of
myoepithelial cells) atypical ductal hyperplasia or DCIS.
● Sclerosing adenosis (tubular adenosis lacks an obvious On occasion, columnar cell lesions are classified into three cat-
lobular architecture or whorled arrangement and a wider egories based on the number of cell layers and complexity of pro-
separation of the tubules) liferation: mild columnar lesions shows one cell layer; moderate
lesions show two to four cell layers; and severe lesions have five
Special techniques layers and/or micropapillary tufts and/or cribriform spaces.
● The myoepithelial cells exhibit immunoreactivity for S-100
protein, alpha-SMA, GFAP, vimentin, CD10, CK14 and EPITHELIAL HYPERPLASIA: ATYPICAL LOBULAR
CK5/6, and also express p63, maspin, and P-cadherin. The
finding of myoepithelial cells helps in distinguishing the
HYPERPLASIA (ALH)
lesion from invasive carcinoma.
CLINICAL FEATURES
COLUMNAR CELL LESIONS Atypical lobular hyperplasia is found incidentally in 1%
of benign breast biopsies, usually in perimenopausal women.
CLINICAL FEATURES It carries a cancer risk four times that of the general population.
This risk is doubled if there is first-degree (mother, sister and
Columnar cell lesions are encountered with increasing fre- daughter) family history of breast cancer. The subsequent
quency in both excisional and core needle biopsies performed invasive carcinoma may develop in either breast and is often of
because of mammographic microcalcifications. These lesions, the tubular or lobular variant.
at the low grade end of the spectrum, are variously described The lesion is often multifocal and bilateral. It has been shown
as columnar alteration of lobules, blunt duct adenosis, colum- that about 18% of patients with lobular neoplasia (ALH and
nar alteration with prominent apical snouts and secretions lobulo-ductal carcinoma in situ, LDCIS) on core biopsy show
(CAPSS), and metaplasia cylindrique; and at the high end by carcinoma (invasive and/or DCIS) on subsequent excision.
DCIS lesions with columnar cell morphology. The optimal Currently, the recommended treatment involves excisional
management of such lesions is at present uncertain, particularly biopsy to rule out DCIS and/or invasive carcinoma.
when encountered in core needle biopsy specimens. However,
it would seem prudent at the present time to recommend exci-
sion when columnar cell lesions with atypia are encountered in
core needle biopsy specimens. ALH is similar to lobular carcinoma in situ, but differs in that
the affected lobules contain intercellular spaces and lack obvi-
PATHOLOGICAL FEATURES (Figure 4.4) ous distension of the involved lobules or ductules and contain
other cell types. Cells of ALH may extend into ductal units in
Columnar cell lesions represent a spectrum of lesions which a similar way to that of LCIS.
have in common the presence of columnar epithelial cells lining
variably dilated terminal duct lobular units. Cell morphology
These lesions range from those that show little or no cyto-
logical or architectural atypia to those that show sufficient
● The cells are uniform, round with pale nuclei and
sometimes contain a small nucleolus.
● Other cell types such as ductal cells may be seen.
● Lobular carcinoma in situ
● Atypical ductal hyperplasia
EPITHELIAL HYPERPLASIA: DUCTAL HYPERPLASIA
CLINICAL FEATURES
Usual type ductal hyperplasia is the most common type of
hyperplasia seen in the breast. This term is used only for cases
showing no atypia or atypia of only minor degree. It is found
in approximately 50% of breast biopsies from perimenopausal
women. The change may occur alone or in association with
cystic change or other benign lesions. Moderate and florid
Figure 4.4 Columnar cell lesion with calcification and mild hyperplasia carries a risk of subsequent carcinoma of one- to
cytological atypia. two-fold that of the general population.
Atypical ductal hyperplasia (ADH) represents a generalized of cells, spindle-cell tufting and bridging without trabecular
risk factor for the development of breast cancer, which is four- formation.
to five-fold that of the general population. This risk is approxi- ● Mild ductal hyperplasia: this shows focal or circumferential
mately equal in both breasts. The diagnosis of ADH at needle increase in the number of cell layers lining the ducts or
core breast biopsy is typically regarded as an indication for sur- lobular units (normally two cell layers). There may be
gical excision. Even an unequivocal diagnosis of ADH on a heaping up of cells, but these do not cross the luminal spaces.
core needle biopsy does not preclude the presence of DCIS in
the immediate vicinity. It seems that ADH on core biopsy rep-
resents an underdiagnosis in many cases, with carcinoma found
in 33–87% of patients. About two-thirds to three-quarters of
these are DCIS, and the remainder are invasive cancer. It is
therefore recommended that surgical excision be performed in
all cases following a diagnosis of ADH on core needle biopsy.

Usual type ductal hyperplasia may involve large ducts, termi-
nal ducts or lobules. Ductal hyperplasia may be mild, moder-
ate or florid. The principal architectural features are streaming
(a)
Figure 4.5 Simple epithelial hyperplasia. Note the admixture of

epithelial and myoepithelial cell types and apparent streaming of (b)
cells.There is no cytological atypia.
(c)
Figure 4.7 (a–c) Atypical ductal hyperplasia with moderate to

Figure 4.6 Apocrine metaplasia in a needle core biopsy. severe cytological atypia.
138 Breast tumors
● Moderate ductal hyperplasia: in this condition there is a blunt duct adenosis and various other adenosis and sometimes
tendency to distension of the involved spaces and crossing gynecomastia-like changes. The process occurs mainly during
of the luminal spaces by hyperplastic epithelium. reproductive life. The process may result in a clinical lump, cyst
● Florid ductal hyperplasia (epitheliosis): this shows both or microcalcification.
distension and filling of the ducts or lobular units
with intercellular ovoid, irregular or serpiginous
spaces. Some of the spaces represent true glandular
differentiation. Fibrocystic change is characterized by the presence of several to
numerous macroscopically visible cysts, the majority of which
Sometimes, the component cells are predominantly spindle-
are lined by apocrine epithelium.
shaped and represent myoepithelial cells.
Apocrine metaplasia. Apocrine proliferations most often are
ADH is similar to florid hyperplasia or solid epitheliosis, but
metaplasia as a component of fibrocystic change. However,
in addition it shows some nuclear pleomorphism and irregu-
apocrine metaplasia may be seen within various breast lesions,
larity and focal hyperchromasia of cells. More commonly, it
such as papillomas, ductal adenomas, fibroadenomas and
encompasses a collection of features that just falls short of the
sclerosing adenosis.
criteria required to diagnose low-grade DCIS (see below).
Distinguishing benign from malignant apocrine prolifer-
ations can sometimes be problematic owing to the nuclear
Secondary features
characteristics of apocrine cells.
● Calcification Gynecomastia-like change is characterized by ductal hyper-
● Foamy macrophages plasia with periductal stromal fibrosis or edema, often associ-
● Apocrine metaplasia ated with fibrocystic changes in the adjacent breast.
Fibroadenomatoid hyperplasia shows features of fibroadenoma
Cell morphology and fibrocystic change. It may be a cause of suspicious, granular,
● The cell borders are indistinct, so the nuclei appear to lie clustered microcalcification on screening mammography.
in a syncytial mass.
● The cytoplasm is pale, eosinophilic and may show clear
cell change. MAMMARY MUCOCELE-LIKE LESION
● The nuclear morphology is bland with some variation in
size and shape. The cells possess a delicate nuclear
CLINICAL FEATURES
membrane, and lack prominent chromatin markings or
prominent nucleoli. They have distinct streaming and Mucocele-like tumors of the breast encompass a spectrum of
often show focal crowding and overlapping. pathological lesions, including benign tumor, ADH, carcinoma
● Immunostaining for myoepithelial cells (e.g., CK5/6) in situ, and colloid carcinoma. They are rare lesions, the benign
will demonstrate clearly a dual cell population in the form of which has a non-specific mammographic appearance.
proliferation. The tumor can present as indeterminate microcalcifications or
● Apocrine cytoplasmic change may be seen. as a nodule, often containing calcifications. The ultrasound
● Apical snouts are commonly seen. findings are of multiple well-defined hypoechoic oval or tubu-
● Mitoses are only occasionally present. lar structures with low-level internal echoes resembling complex
cysts. Mucocele-like tumors of the breast can be associated with
Differential diagnosis atypical hyperplasia or carcinoma. If a mucocele-like tumor is
● Low-grade DCIS is diagnosed when all of the following diagnosed at core needle biopsy, complete surgical excision is
features are seen in at least two or more ducts: recommended, with careful evaluation of the entire specimen
1. A uniform population of cells. to exclude the presence of atypia or carcinoma. When malig-
2. Even cellular placement. nant mucocele-like tumor is histologically of low grade, exci-
3. Smooth geometrical spaces between rigid bars or sional biopsy is sufficient for a single lesion with intraductal
micropapillary formation. carcinoma, while it may be necessary to perform a subcuta-
4. Hyperchromatic nuclei. neous mastectomy for multiple lesions.
ADH has some – but not all – of these features (see above).
The lesions are composed of mucin-containing cysts that often
FIBROCYSTIC CHANGE AND ASSOCIATED
rupture, with resultant extravasations of mucin into surround-
CONDITIONS ing stroma.
The lining of the cysts in most areas are of flat or cuboidal
epithelium and devoid of cellular atypia. On occasion, the
CLINICAL FEATURES
epithelium shows proliferative change ranging from ADH to
The term fibrocystic change encompasses a combination of DCIS, micropapillary type. A microscopic focus of mucinous
benign processes including cyst formation, apocrine metaplasia, carcinoma within some lesions may also be seen.
● Mucinous carcinoma
● Nodular mucinosis of the breast (is a benign process
composed of a poorly circumscribed and unencapsulated
lesion, usually located in the nipple)
Special techniques
● Fewer of the benign lesions are estrogen receptor (ER)
and progesterone receptor (PR) positive.
● HER2/neu positivity is more common in malignant
mucocele-like tumor.
PAPILLOMA (a)
CLINICAL FEATURES
Breast papilloma occurs predominantly in middle-aged women,
but may also occur in a younger age group. Papillomas can be
solitary and often seen in the sub-areolar region, or multiple and
more likely to be peripheral. Multiple lesions accompanied by
epithelial hyperplasia are usually associated with an increased
risk of subsequent invasive carcinoma. The presence of atypia in
a papilloma implies an increased risk for subsequent breast
cancer.
The finding of benign papilloma on core needle biopsy of the
breast carries a small but definite chance of atypia or malig-
nancy on excision. As for other benign lesions, repeat core
biopsy, if not excision, should be undertaken if there is a dis-
crepancy between the findings on the imaging studies and the
pathological findings on the biopsy samples. It seems prudent to
recommend complete excision for papillary lesions diagnosed
on needle core biopsy, particularly when there are foci of atypia.

Intraduct papilloma appears as a nodular or multinodular intra-
cystic lesion. The fibrovascular cores of papillomas are usually
(b)
broad and extend throughout the lesion. The papillae are covered
by two cell layers; a basal myoepithelial layer, and single layer of
luminal cells. Some papillomas show more solid appearances with
proliferating epithelial cell elements reminiscent of adenosis.
Entrapped epithelium within surrounding fibrous tissue may
be seen (pseudo-infiltration).
‘Intracystic papilloma’ is a papilloma present within a widely
dilated duct.
Breast papillomas with areas of atypical proliferation

It is well recognized that otherwise benign papillary lesions
may harbor foci of atypical hyperplasia or DCIS, although this
appears to be more common in patients with multiple periph-
eral papillomas than in those with solitary central papillomas.
The ADH usually occupies a portion of the papilloma (25–50%).
ADH is also seen in the surrounding breast tissue in 63% of
(c)
cases in which there is ADH in the papilloma. The relative risk
for carcinoma among patients with papillomas containing Figure 4.8 (a–c) Intraduct papilloma of the breast. Note the well-
atypical hyperplasia is in the region of 7.5-fold that of those formed fibrovascular fronds and the presence of two cell types
with papillomas without atypia. (myoepithelial and epithelial) within the papillary structures.
140 Breast tumors
Secondary features high proportion of cells (⬎70%). In contrast, the majority

● Hemorrhage. of papillary carcinomas express this marker in ⬍10% of
● Focal necrosis. the cells.
● Hemorrhagic infarction (this may produce a worrying
appearance due to distortion and separation of isolated RADIAL SCAR AND COMPLEX
epithelial cells).
● Sclerosis. SCLEROSING LESION
● Apocrine, squamous or sebaceous metaplasia.
CLINICAL FEATURES
Cell morphology
● The main epithelial population comprises cuboidal or Radial scar and complex sclerosing lesions are essentially similar,
columnar cells with a low nuclear:cytoplasmic ratio that but differ in that the former is less than 10 mm in diameter and
may demonstrate an apocrine differentiation. found incidentally, while the latter is larger than 10 mm and
● The basal myoepithelial cells are more rounded and have can be detected clinically. These can mimic carcinoma both on
clear cytoplasm. mammography and on gross examination of the specimen. The
● Apocrine secretion may be seen. radial scar and complex sclerosing lesion are frequently associ-
● Intracytoplasmic secretory vacuoles are sometimes seen. ated with fibrocystic disease and/or duct ectasia, can be multi-
● Mitoses may be seen, but they are infrequent with no centric and, when associated with a carcinoma in situ, the
abnormal forms. prognosis would be guarded accordingly. In most cases, radial
scars are incidental microscopic findings (median size 4.0 mm).
Differential diagnosis It has been shown that women with a radial scar may have a
two-fold increase in breast cancer risk, independent of the his-
● Breast lesions with a papillary growth pattern include
tological category of benign breast disease, and the risk is
completely benign lesions such as intraductal papillomas,
related directly to scar size.
papillomas that exhibit foci of atypia or carcinoma in situ,
The risk of finding associated DCIS is greater in mammo-
DCIS with a papillary growth pattern (including encysted
graphically detected speculated lesions.
papillary carcinomas), and invasive papillary carcinomas.
Carcinomas associated with radial scars are often located at the
The fibrovascular cores of encysted papillary carcinoma are
periphery of the lesions. This is especially relevant in patients
usually fine and may be lacking in some part of the lesion.
undergoing core needle biopsy, whereby sampling the center of
The myoepithelial layer is either absent or discontinuous.
the lesion might miss an associated carcinoma. It is recom-
The luminal cells are tall and more monotonous, with oval
mended that all patients with radial scars diagnosed on core
nuclei that show hyperchromatic chromatin and more
biopsy should undergo surgical excision in order to exclude the
frequent mitotic figures including abnormal forms. DCIS
possibility of concomitant carcinoma.
may be seen adjacent to the carcinoma.
● Pathologists may encounter difficulty in reliably distinguishing
between benign, atypical, and malignant papillary lesions on PATHOLOGICAL FEATURES (Figure 4.9)
the limited, fragmented material obtained by core biopsy. Radial scar is essentially composed of a central hypocellular scar
A second consideration is the ability of pathologists to or sclerotic core surrounded radially by a more cellular prolifer-
distinguish benign papillary lesions with sclerosis and ative zone. The latter is composed of epithelial proliferation,
entrapment of epithelial elements from invasive carcinoma. papilloma formation, and cystic and apocrine change. Tubules,
The third consideration is whether the histological features usually showing double layers of epithelium and myoepithelium,
observed in the core biopsy specimen are representative of the are often randomly distributed within the central elastosis. The
most worrisome area of the papillary lesion. majority or the entire lesion may consist of hyaline elastosis.
Early lesions may show spindle cell myofibroblastic prolifer-
Special techniques ation and inflammatory infiltration with less distortion of
● The epithelial cells of papilloma are CEA-negative, while parenchymal component.
those of papillary carcinoma are CEA-positive in a large In mature lesions the hyperplastic and cystic changes become
number of cases. more evident, as does apical snouting.
● Myoepithelial cell markers are often positive. The Complex sclerosing lesions (sclerosing papillary prolifera-
myoepithelial cells exhibit immunoreactivity for S-100 tion) are usually larger than radial scars, and show greater
protein, alpha-SMA, GFAP, vimentin, CD10, CK14 and structural disturbance with more extensive papillomatosis,
CK5/6, and also express p63, maspin, and P-cadherin. apocrine change and sclerosing adenosis. They may also show
The finding of myoepithelial cells helps in distinguishing pseudoinfiltrative foci and entrapment of epithelial cells at the
the lesion from carcinoma. periphery of the lesion.
● CD44s detection by immunohistochemistry is useful in Other breast lesions may be seen in the surrounding tissue
distinguishing intraductal papillomas from papillary independent of the radial scar or sclerosing lesion. For example,
carcinomas of the breast. Normal breast epithelial cells foci of sclerosing adenosis are commonly seen either at the
and intraductal papillomas usually express CD44s in a periphery or within a large sclerosing lesion.
reticulin stain or basement membrane antibodies (against

specific collagen types and laminin).
● The myoepithelial cells exhibit immunoreactivity for S-100
protein, alpha-SMA, GFAP, vimentin, CD10, CK14 and
CK5/6, and also express p63, maspin, and P-cadherin. The
finding of myoepithelial cells helps in distinguishing the
lesion from invasive carcinoma.
EPITHELIAL LESIONS, MALIGNANT
CARCINOMA IN SITU (CIS)

(a)
CLINICAL FEATURES
Carcinoma in situ (CIS) of the breast are commonly detected in
the screened population. CIS is categorized as either DCIS or lob-
ular carcinoma in situ (LCIS). A third group of CIS has been
recently identified, showing histological features of both ductal
and lobular CIS. The latter is also called ‘ductolobular carcinoma
in situ’ (DLCIS), ‘carcinoma in situ of both lobular and ductal
type’ and ‘carcinoma in situ with indeterminate features’ (CIS-IF).
The distinction between LCIS and DCIS has important therapeu-
tic implications. Patients with LCIS are most often managed by
careful observation (and more recently with the addition of
tamoxifen), whereas treatment of DCIS is aimed at eradication of
the lesion (with wide local excision, excision and radiation ther-
apy, or mastectomy). Furthermore, assessment of margin status is
clinically important in DCIS but not in LCIS. CIS-IF should be
(b) managed as DCIS; however, it is not clear whether these cases are
actually indeterminate, whether they merely represent true com-
Figure 4.9 Radial scar/complex sclerosing lesion. Low- (a) and bined DCIS and LCIS, or whether they represent DCIS variants.
medium-power (b) views showing stellate structure and usual-type
hyperplasia within the lesion.
CARCINOMA IN SITU, DUCTAL (DCIS)
Secondary features
● Microcalcification. CLINICAL FEATURES (Figures 4.10–4.15)
● Elastosis.
DCIS is the most common type of in situ carcinoma of the breast.
Cell morphology
Classification of common variants of DCIS
● The epithelial cells may show minimal pleomorphism.
DCIS is classified according to three histological features:
Differential diagnosis 1. Nuclear grade (low, intermediate, or high).
2. Architectural pattern (cribriform, papillary, micropapillary,
● Invasive tubular carcinoma (usually lacks the zonal or solid).
character; the glands are present in a loosely cellular or 3. The presence and type of necrosis (comedo or non-comedo
desmoplastic stroma rather than hyalinized elastic-rich necrosis).
stroma, they are lined by a single rather than double
layers of epithelial cells, often infiltrate fat, and are often DCIS classification according to nuclear grading system
associated with cribriform or micropapillary type ● High nuclear grade DCIS shows large pleomorphic cells
carcinoma in situ). with a high nuclear:cytoplasmic ratio. The nuclei have
● Sclerosing adenosis (often found within or adjacent to coarse chromatin, often with large nucleoli. This condition
the lesion). is associated with frequent mitotic figures, including
atypical ones. High-grade nuclear DCIS is usually
Special techniques associated with necrosis, and in particular the comedo
● The basement membrane surrounding the tubules or type. The necrotic center may undergo dystrophic
groups of cells is intact and can be highlighted by PAS, calcification.
142 Breast tumors
(a) (b)
Figure 4.10 Comedo pattern high-grade ductal carcinoma in situ (DCIS). (a, low power; b, medium power.)
(a) (b)
Figure 4.11 Intermediate-grade DCIS with a ‘clinging’ pattern. (a, low power; b, high power.)
(a) (b)
Figure 4.12 (a, b) Low-grade DCIS with a partial papillary morphology.

● Low nuclear grade DCIS shows evenly spaced cells with Mitoses are infrequent and necrosis is uncommon.
small regular nuclei, usually with indistinct nucleoli. This Calcification may be seen within luminal secretion.
is usually associated with cribriform and papillary ● Intermediate nuclear grade DCIS shows less nuclear
architecture, and less commonly with a solid pattern. pleomorphism than in the high-grade nuclear DCIS,
but lacks the uniformity of the low-grade type.
Nucleoli may be present, but they are usually not
very prominent. Necrosis may be seen, but is not
extensive. Some cell polarization may be seen. The
architectural patterns include solid, cribriform or
micropapillary.
DCIS classification according to architectural patterns

● Cribriform DCIS: the distended ductal units show a
uniform population of cells punched out with rounded or
slightly elongated spaces reminiscent of nests of adenoid
cystic carcinoma. Cribriform DCIS may show calcification,
occasional minute foci of necrosis, and the presence of
foamy histiocytes may also be seen.
● Micropapillary DCIS: the cells are arranged in the form of
small pseudopapillae with bulbous ends, arches, bulges,
sprouts, bars, trabeculae or cartwheel-shaped structures.
Figure 4.13 Intermediate grade, solid pattern DCIS. These luminal bars and pseudopapillae may coalesce to
(a) (b)
Figure 4.14 Micropapillary pattern DCIS of low to intermediate nuclear grade. (a, medium power; b, high power.)
(a) (b)
Figure 4.15 Micropapillary DCIS, low nuclear grade. (a, low power; b, medium power.)
144 Breast tumors
form an early cribriform pattern. Micropapillary DCIS is solid sheets and festoons traversed by delicate fibrovascular
often multicentric but is rarely microinvasive, and clinically septa. Accumulation of basophilic mucin might be found
requires treatment of the entire breast, although axillary within the growth and the fibrovascular septa. There may be
node clearance is not indicated, as with other non-invasive variable degrees of stromal sclerosis. In some cases, the solid
carcinomas. intraductal cellular proliferations may focally be punctuated by
● Solid DCIS: the cells fill up the duct spaces, without any microglandular spaces and rosettes. Comedo necrosis is usually
particular architectural arrangement such as papillary or absent. Pagetoid spread into the adjacent ducts and ductules or
cribriform. into an intraductal papilloma that may be found in the imme-
diate vicinity of the tumors, is a common feature. The tumor
DCIS classification according to patterns of necrosis cells are polygonal, oval, or spindly, often with eccentrically
● Comedo-type DCIS: this consists of expanded ducts placed, bland-looking, ovoid nuclei and abundant eosinophilic
containing central necrotic material and a peripheral, granular cytoplasm. Intracellular mucin is commonly demon-
usually solid rim of malignant, large, pleomorphic strable. The invasive component, which comprises between 5
epithelial cells. Central calcification, hemorrhage and the and 95% of the tumor, may be colloid carcinoma, ‘carcinoid’
presence of foam cells may be seen. tumor, mixed ‘carcinoid’/colloid carcinoma, or small cell neu-
Grossly comedo necrosis is characterized by the presence of roendocrine carcinoma.
soft cheesy material protruding from visible ducts, reminiscent Signet ring cell DCIS
of the common comedone. Comedo-type DCIS is usually more
This is a unique form of intraductal carcinoma of the breast char-
extensive than the other types of CIS, and may be detected
acterized by varying numbers of intraductal neoplastic cells
clinically or on mammography (presence of linear or branched
with eccentric nuclei and either ground-glass or optically clear,
arrays of calcification).
mucin-containing cytoplasm. This lesion may be found in some
It may be associated with foci of microinvasion or invasive
of the ducts of otherwise benign fibrocystic disease and radial
foci in subsequent mastectomy specimens (in 5% of cases). It
scars, as well as breasts with other forms of intraductal carci-
is associated with axillary lymph node metastases in 1–2%
noma or invasive carcinoma.
of cases. The invasive potential relates to the extent of the
lesion. Comedo-type DCIS, when extensive (defined as an
Other unusual types of DCIS
area ⬎40 mm2), is usually treated by definitive surgery.
● Small-cell solid DCIS: in this variant, small uniform
Management of DCIS cells of low-grade nuclear morphology fill up the duct
spaces, without any papillary or cribriform pattern.
Local excision and radiation therapy is a standard treatment
When such a lesion involves terminal duct lobules, it
option for DCIS. The volume of DCIS in a specimen and the
becomes indistinguishable from LCIS. The latter, however,
volume of DCIS near the margin seem to be related to local
often shows dyscohesion of cells and illustrates loss of
recurrence. It has been shown that DCIS lesions containing a
E-cadherin.
comedo or cribriform element are more likely to have micro-
● Cystic hypersecretory DCIS: this is a rare histological
scopic spread and involvement of lobules. DCIS lesions con-
variant of ductal carcinoma of the breast. It is characterized
taining a papillary element are likely to be multicentric, and
by the formation of cystically dilated ducts containing a
therefore should be treated by multiquadrant mastectomy.
homogeneous eosinophilic secretion that resembles thyroid
colloid. In most cases of cystic hypersecretory carcinoma
Other variants of DCIS
the intraduct component features a micropapillary pattern.
Apocrine DCIS Cystic hypersecretory DCIS has the same low-grade
Any architectural type of DCIS may exhibit cytological features clinical course as other forms of intraductal carcinoma.
of apocrine differentiation. The cells show variable combina- However, the invasive carcinoma may be histologically
tions of granular, eosinophilic, vacuolated or clear cytoplasm. high-grade, it is therefore important to recognize and
Apocrine features may be seen in up to 50% of DCIS. Apocrine promptly treat the lesion while still in its in-situ phase.
DCIS should be distinguished from intraduct apocrine hyper- Foci with the appearance of cystic hypersecretory
plasia. The presence of clear cytological and some architectural hyperplasia may be found.
abnormalities is essential for the diagnosis. On occasion, the ● Clinging carcinoma: the existence of this variant is
apocrine differentiation shows predominantly clear cells. currently controversial, and some pathologists consider it
Apocrine DCIS must be distinguished from other subtypes of as atypical ductal hyperplasia and tend to avoid this
DCIS such as neuroendocrine, lipid- and glycogen-rich, mucin- terminology. It shows a scant population of tumor cells
producing and myoepithelial in situ carcinomas. attached to the lining of the ducts. The cells may be bland
(reminiscent of micropapillary DCIS) or may be
Neuroendocrine DCIS pleomorphic (reminiscent of the large cells seen in comedo
Endocrine DCIS is an uncommon entity, and is predominantly or cribriform DCIS).
a disease of older women. It is frequently accompanied by ● Spindle cell DCIS: a new variant of DCIS has recently
papillomas in the vicinity, and may present as nipple discharge. been recognized consisting either exclusively or
Histologically, it shows expansile intraductal growths forming predominantly of spindle cells arranged in fascicles,
whorls, and solid sheets. The lesion usually presents as Special techniques
a palpable mass, or is discovered at mammography. The ● The myoepithelial cells exhibit immunoreactivity for S-100
radiological appearances of the lesions may raise concern protein, alpha-SMA, GFAP, vimentin, CD10, CK14 and
for carcinoma. Cytological preparations usually yield CK5/6, and also express p63, maspin, and P-cadherin. The
suspicious or malignant results. The tumor typically finding of myoepithelial cells around the periphery of a
measures between 3 and 15 mm (mean 8.65 mm). Minute unit confirms the in-situ nature of the DCIS component.
foci of stromal invasion or frank invasion may be seen in ● DCIS is usually E-cadherin-positive.
association with the spindle cell DCIS. Recognition of this ● DCISs are usually negative with HMW-CK903
pattern of DCIS is important in order to avoid its frequent (MA903/34␤E12).
misclassification as a benign lesion. ● High-grade DCIS is often positive for HER2/c-erbB-2/neu
The fascicular arrangement of the spindle cells simulates the and p53, tends to be negative for ER, PR and bcl-2, and
‘streaming’ phenomenon associated with ordinary intraductal has a high proliferative rate.
epithelial hyperplasia. It also resembles the myoid, solid form ● Low-grade DCIS is often negative for HER2/c-erbB-2/neu
of intraductal myoepithelial proliferation. Spindle cell DCIS is and p53, tends to be positive for ER, PR and bcl-2, and
distinguished from the streaming pattern of ordinary intraduc- has a low proliferative rate.
tal epithelial hyperplasia by its solid growth pattern, lack of ● The majority of neuroendocrine DCISs show strong
secondary spaces or peripheral fenestrations, uniformity of staining with the neuroendocrine markers chromogranin,
appearance and distribution of nuclei, and cytological atypia in synaptophysin, and neuron-specific enolase (monoclonal).
the range of low- to intermediate-grade DCIS. An admixture Immunostaining also highlights the pagetoid spread into
with conventional cribriform DCIS may be observed. the papillomas and ductules by outlining the tumor cells
between the negatively stained residual ductal epithelium
Differential diagnosis and myoepithelium. The cells are immunoreactive for ER
and PR, but not p53 and HER2/c-erbB-2/neu. The Ki-67
Non-comedo small cell-type DCIS (cribriform and micro-
index is usually ⬍5%. Neuroendocrine markers are also
papillary):
consistently demonstrable in the invasive component.
● Florid ductal hyperplasia
● Cystic hypersecretory DCIS is positive for one or more
● Atypical ductal hyperplasia
of the following: mucin by mucicarmine stain; CEA;
● Mucocele-like tumor of the breast
alpha-lactalbumin; and mouse mammary tumor virus
● Cystic hypersecretory hyperplasia
GP52 antigen.
● Cystic hypersecretory duct carcinoma
● Gynecomastoid hyperplasia (the presence of benign
micropapillary change in female breast ducts as seen in

CARCINOMA IN SITU, INDETERMINATE
gynecomastia)
● Duct extension of LCIS forming a solid pattern FEATURES (CIS-IF)
● Irradiated non-neoplastic breast ducts may show scattered
atypical hyperchromatic cells protruding into the lumina

CLINICAL FEATURES
and exhibiting cytoplasmic vacuolation
This is a newly described variant of CIS, and is of uncertain
Comedo-type DCIS
clinical relevance. Various terminologies have been used for
● Solid variant of DCIS that contains central apoptotic cells
such lesions, including ‘ductolobular carcinoma in situ’
or foamy xanthomatous cells
(DLCIS), ‘carcinoma in situ of both lobular and ductal type’,
● Early invasive carcinoma (especially when it shows
and ‘carcinoma in situ with indeterminate features’ (CIS-IF).
cancerization of the lobules and in the presence of fibrosis
CIS-IF should be managed as DCIS; however, it is not clear
and inflammatory response)
whether these cases are actually indeterminate, whether they
Neuroendocrine DCIS merely represent true combined DCIS and LCIS, or whether
● This can mimic epitheliosis (florid ductal hyperplasia of they represent DCIS variants.
usual type) histologically, but the pagetoid spread is a
helpful clue to its neoplastic nature
Cystic hypersecretory DCIS
CIS-IF is divided into three groups based on the following his-
● This should be differentiated from juvenile (secretory)
tological criteria:
carcinoma, from mucinous (colloid) carcinoma, and from
● Group 1 shows all of the cytological and architectural
benign mucocele-like lesions
features typical of LCIS, but with areas of comedo-type
Spindle cell DCIS (central) necrosis.
● The fascicular arrangement of the spindle cells simulates ● Group 2 consists of CIS lesions with some features of
the ‘streaming’ phenomenon of intraductal epithelial DCIS and some features of LCIS, rendering categorization
hyperplasia (ductal hyperplasia of the usual type), and may difficult. All of these lesions comprise small, monomorphic
also mistaken as intraduct epitheliosis neoplastic cells. In some cases, the cells grow in a
146 Breast tumors
primarily solid pattern and show focal microacinar-like

structures – features which are suggestive of DCIS.
However, there is also evidence of cellular dyscohesion – a
feature more characteristic of LCIS. On occasion, Group 2
CIS-IF shows small uniform cells growing in a solid,
cohesive, mosaic pattern, suggesting DCIS. However, some
neoplastic cells show intracytoplasmic vacuoles, a feature
suggestive of LCIS.
● Group 3 shows growth patterns characteristic of LCIS, but
the individual cells show marked nuclear pleomorphism
(at least two-fold variation in nuclear size and irregularity),
with increased nuclear:cytoplasmic ratios and frequent
prominent nucleoli. The cytological features of Group 3
are similar to those found in the individual cells of
high-grade DCIS. Cases such as these have been previously
referred to as pleomorphic LCIS.
Figure 4.16 Lobular carcinoma in situ (LCIS): ductal involvement
by LCIS.
Special techniques
Immunohistochemistry for E-cadherin is valuable in character-
izing cases of CIS-IF. Those cases that differ from typical LCIS
only by the presence of comedo-type necrosis (Group 1) or
marked nuclear pleomorphism (Group 3) are all negative for
E-cadherin by immunohistochemistry, suggesting a closer kinship
to LCIS than to DCIS. In contrast, CIS-IF Group 2 cases are
heterogeneous, with some cases E-cadherin-positive (akin to
DCIS), some E-cadherin-negative (akin to LCIS), and some
with both E-cadherin-positive and E-cadherin-negative tumor
cells, suggesting a combined lobular and ductal phenotype.
CARCINOMA IN SITU, LOBULAR (LCIS)
CLINICAL FEATURES
LCIS is found in 1% of breast biopsies. It is usually a multi-
Figure 4.17 Lobular carcinoma in situ (LCIS) involving a terminal
focal process, affects both breasts, and is clinically or grossly duct lobular unit.
undetectable. It is considered to be a marker of increased cancer
risk. In about 20–30% of cases, invasive carcinoma will develop
in either breast in 15–20 years if not treated by mastectomy. It LCIS may also involve sclerosed lobular units and may rarely
occasionally arises in fibroadenoma. LCIS detected on core develop in a fibroadenoma. The expansion must involve
biopsy is potentially a significant marker for concurrent breast approximately 50% of the acini within a lobule. Pagetoid
pathology requiring complete intensive multidisciplinary clinical spread of abnormal cells into the adjacent ducts or ductules
follow-up with specific individualization of patient care. may be found.
More recently, a pleomorphic type of LCIS has been
described.
Classical-type LCIS, also sometimes called ‘type A’, shows lob- Differential diagnosis
ules distended by a uniform proliferation of non-cohesive small ● Atypical lobular hyperplasia: it shows apparent spaces
cells, with small, uniform, round-to-oval nuclei showing rela- between the cells, lacks obvious distension of the involved
tively homogeneous chromatin and absent or inconspicuous lobule or ductal, and contains other cell types
nucleoli. The nuclei are often eccentrically placed, and the cyto- ● Solid DCIS: the distinction between solid low-grade DCIS
plasm is pale to lightly eosinophilic. Some of the cells contain and ductal involvement by LCIS is difficult, and in many
cytoplasmic vacuoles, which occasionally are large enough to cases is subjective. The distinction is further complicated
produce signet ring cell forms. Rarely LCIS, sometimes called by the observation that LCIS and DCIS may coexist in the
‘type B’, shows cells with more abundant cytoplasm, more vari- same biopsy specimen in a significant number of cases,
ation in nuclear size and shape, and with nucleoli. The division and within the same terminal duct lobular unit in a smaller
into type A and B is of unknown clinical relevance. percentage of cases. E-cadherin-positivity favors DCIS
CARCINOMA IN SITU, PAGET’S DISEASE OF Special techniques

THE BREAST ● The neoplastic cells are HER2/c-erbB-2/neu, CAM 5.2,
CK7, CEA and EMA-positive.
● Mammary Paget’s disease is
CLINICAL FEATURES MUC1⫹, MUC2⫺, MUC5AC⫺.
Paget’s disease of the breast is secondary involvement of the ● The cells are PAS-positive/diastase-resistant, and
epidermis of the nipple, areola or adjacent skin by malignant occasionally are Alcian blue-positive.
cells extending from underlying invasive or intraduct breast ● Mammary Toker cells are also CK7-positive.
carcinoma, or sometimes from epidermal Toker cells. In nearly
50% of cases the lesion is associated with palpable breast mass,
and in these cases between 25% and 60% show axillary lymph
INVASIVE CARCINOMA
node metastases. The lesion is always unilateral, and rarely
affects the male breast. The disease presents as an erythema- CLINICAL FEATURES
tous, crusting lesion.
Carcinomas of the breast are the most common cancer in the
female population. In countries where a breast screening pro-
PATHOLOGICAL FEATURES (Figure 4.18) gram is operational, invasive carcinoma and its precursor lesions
Paget’s disease of the nipple consists of an intra-epidermal infil- are being detected at earlier stages. Breast carcinoma affects
trate of large malignant cells arranged singly and in groups, postmenopausal women as well as those in their reproductive
and found throughout the entire thickness of the epidermis. years. In the non-screened population, the tumor commonly
These cells are sharply demarcated from the surrounding presents as a lump in the breast, or it may be associated (at a
epidermal cells and from the flattened basal cells. later stage) with dimpling of the skin, nipple discharge and
fixation to the chest wall.
There are several types of breast carcinoma. Some are very
common, such as ductal carcinoma of no special type, lobular
and tubular carcinoma, whilst others are less commonly
encountered. All of these types of carcinoma are discussed
separately below.
The management of breast cancer

Following a diagnosis of breast cancer, women need to know
the probability of recurrence of – and death from – the disease,
as well as the magnitude of benefit they are likely to receive
from adjuvant endocrine therapy or cytotoxic chemotherapy. The
histopathology laboratory has a major role to play in both the
diagnosis and the prediction of prognosis of breast cancer
patients.
Histopathology is a central pillar of both screening and symp-
tomatic breast services. The support includes on-site diagnostic
Figure 4.18 Paget’s disease of the breast. Note the intraepidermal ‘one-stop’ fine needle aspiration clinics, in addition to a core
nests of Paget’s cells.The underlying breast showed high-grade
biopsy/mammotome service. Cytology and core biopsy should
comedo DCIS and invasive lobular carcinoma.
follow the usual categorization – that is, C1–5 and B1–5 respec-
tively. This encourages a clarity of communication between the
Secondary features histopathologist and surgeon, to the benefit of the patient.
● Ulceration of the skin. Those less familiar with this scenario should consult NHSBSP
● Inflammatory infiltrate. Publication No. 50, Guidelines for non-operative diagnostic
procedures and reporting in breast cancer screening (first edi-
Cell morphology tion, 2001). The criteria have been summarized as follows:
● Paget’s cells are vacuolated cells with large nuclei containing
C1 Inadequate/Unsatisfactory (⬍5 clusters of epithelial
an abnormal chromatin pattern and distinct nucleoli.
cells or artifacts making a firm diagnosis impossible)
● Melanin pigment may be seen in some Paget’s cells.
C2 Benign
● Mitotic figures may be seen.
C3 Atypia, probably benign
C4 Atypia, suspicious of malignancy
C5 Malignant
● Malignant melanoma (the cells border directly on, as well B1 Unsatisfactory/normal tissue only (e.g., may not
as invade, the dermis) represent mass lesion)
● Bowen’s disease B2 Benign (e.g., fibroadenoma)
148 Breast tumors
B3 Lesion of uncertain malignant potential (e.g., ADH, Tumors in which 75% or more, 10–75%, and less than
LCIS, radial scar/complex sclerosing lesion, intraduct 10% of the area is composed of such tubules would be
papilloma, unclassified epithelial proliferation with atypia) scored as 1, 2 and 3, respectively.
B4 Suspicious of malignancy (e.g., high-grade atypical ● Nuclear pleomorphism: Score 1 ⫽ small nuclei with little
epithelial proliferation not classifiable based on criteria, increase in size, uniform chromatin, regular outline with
artifactual impairment to diagnosis) little variation in size. Score 2 ⫽ cells larger than normal
B5a Malignant – in-situ (e.g., DCIS, non-invasive epithelial cells, have open vesicular nuclei, visible
papillary carcinoma) nucleoli and moderate variability in both size and shape.
B5b Invasive (e.g., any invasive malignancy) Score 3 ⫽ vesicular nuclei, often with prominent nucleoli,
B5 Malignant – invasion not assessable (e.g., artifactual marked variation in size and shape, occasionally with
impairment, unable to classify as B5a or B5b) bizarre forms.
● Number of mitotic figures per 10 high-power fields (HPF):
Further biopsy reporting should be based on local and national
the mitotic count should be standardized for the individual
guidelines, such as The Royal College of Pathologists minimum
microscope that is being used for the purpose of grading.
dataset for breast cancer. Facilities for frozen section and a
This is carried out by calculating the field diameter of the
knowledge of handling sentinel node biopsies and nodal sam-
microscope based on the objective to be used. This figure
ples and clearances is essential.
must then be compared with the published graph (originally
Patients who have extremely good prognostic indicators after
defined in NHSBSP Publication No. 3 Pathology reporting
tumor excision may not require adjuvant therapies, while those
in breast cancer screening (first edition, 1995; updated in
with poor prognostic factors may benefit from an aggressive
1997 (second edition), currently undergoing revision, 2003).
adjuvant approach.
This then provides the mitotic count by field diameter – that
Prognostic indicators is, the score boundaries to be used. These boundaries are
At the present time, the most valuable prognostic factors appear dynamic, and vary between microscopes, so a ‘generic’ approach
to be those that can be assessed on routinely fixed, processed is inadequate.
and stained material. These include histological grade, lymph For example:
node stage, tumor size, vascular invasion, and tumor type. The
Field diameter ⴝ 0.5 mm Field diameter ⴝ 0.62 mm
precise determination of these features demands well-prepared
Score 1: 0–6 mitoses/10 HPF Score 1: 0–10 mitoses/10 HPF
H&E sections. Using a combination of histological features, it
Score 2: 7–13 mitoses/10 HPF Score 2: 11–20 mitoses/10 HPF
is possible to predict an individual patient’s likelihood of sur-
Score 3: 14⫹ mitoses/10 HPF Score 3: 21⫹ mitoses/10 HPF
vival. Additional information predicting response to specific
therapies can be obtained from the ER status of the tumor. In addition, the count should be conducted at the infiltrative
margin in an area of active proliferation rather than the central
The Nottingham Prognostic Index (NPI)
aspect of a lesion.
The NPI is the most widely accepted criterion, and uses three
prognostic factors: lymph node status; tumor size; and histo- Steroid receptor status
logical grade. The index is calculated as follows: ER status is a specific test which is currently widely used to pre-
NPI ⫽ [Size (cm) ⫻ 0.2] ⫹ [lymph node stage (1–3)] dict response to a specific therapy in breast cancer manage-
⫹ [grade (1–3)] ment. Approximately 30% of unselected patients with breast
cancer respond to hormone therapy such as oophorectomy or
where node stage 1 ⫽ node-negative, stage 2 ⫽ one to three treatment with tamoxifen.
nodes involved; and stage 3 ⫽ more than four nodes involved. ER and PR are located in the nuclei of breast epithelial and
According to the NPI, three prognostic groups are identified: carcinoma cells. The proportion of tumor cells showing positive
● A good group, with scores ⬍3.4; these have an 80%
reactivity, their intensity of reactivity, combinations of both of
15-year survival. these, and a simple categorical system are used.
● A moderate group, with scores of 3.4–5.4; these have a
The following scoring system is a simple, additive system
42% 15-year survival. which gives a range from 0 to 8, and has proven to be highly
● A poor group, with scores ⬎5.4; these have a 13%
reproducible:
15-year survival.
Score for proportion Score for staining
Tumor size: smaller carcinomas are generally associated with a staining intensity
better prognosis. 0 ⫽ no nuclear staining 0 ⫽ no staining
Histological grading: this involves the assessment of three 1 ⫽ ⬍1% nuclei staining 1 ⫽ weak staining
components, each of which is scored from 1 to 3 as described 2 ⫽ 1–10% nuclei staining 2 ⫽ moderate staining
in the NHS breast screening publication Pathology reporting in 3 ⫽ 10–33% nuclei staining 3 ⫽ strong staining
breast cancer screening. Adding the scores provides the overall 4 ⫽ 33–66% nuclei staining
histological grade: 5 ⫽ 66–100% nuclei staining
● Tubule formation: only structures in which there is
clearly defined central lumen should be counted as tubules. Adding the two scores together gives a maximum score of 8.
Experience to date suggests that using such a simple scoring FISH detection (e.g., Pathvysion; Vysis Inc. and HER2 FISH
system allows appropriate cut-off values for treatment of pharmDx™; DakoCytomation Ltd.) will detect increased copy
advanced disease. These are as follows: numbers of the HER2/c-erbB-2/neu gene (gene amplification).
● A score of zero indicates that endocrine therapies will This can be used separately or as an adjunct to immunohisto-
definitely not work. chemistry. In the latter circumstance, a 2⫹ score on immunohis-
● A score of 2–3 indicates a small (20%) chance of response tochemistry will require correlation with FISH prior to treatment
to endocrine therapies. with trastuzumab (Herceptin®).
● A score of 4–6 indicates an even (50%) chance of response.
● A score of 7–8 indicates a good (75%) chance of response. Other prognostic factors
Other factors which may have a role in predicting outcome in
All laboratories routinely using such assessments must take
breast cancer are proliferation markers, p53 expression, DNA
part in an external quality assessment (EQA) scheme, for exam-
ploidy analysis, microvessel density, epidermal growth factor
ple, NEQAS in the United Kingdom.
receptor, transforming growth factor-alpha, bcl-2, pS2, and
HER2/c-erbB-2/neu oncoprotein cathepsin D.
The human epidermal growth factor receptor HER2, also

known as c-erbB-2/neu, is a type I tyrosine kinase membrane INVASIVE CARCINOMA OF NO SPECIAL TYPE
receptor which, when activated, induces a phosphorylation
(NST), INVASIVE CARCINOMA NOT OTHERWISE
cascade in cytoplasmic kinases leading to increased protein
transcription and cellular growth. HER1–3 overexpression is SPECIFIED (NOS), DUCTAL CARCINOMA
associated with reduced survival in breast cancer patients, but
most recent activity has focused on HER2/c-erbB-2/neu due to
CLINICAL FEATURES
recent advances in therapeutics, particularly the targeted agent
trastuzumab (Herceptin®). HER2/c-erbB-2/neu is overexpressed Invasive carcinoma NST/NOS or ductal carcinoma is a term
in a subset of breast carcinomas, and has been associated with a applied to invasive carcinomas of the breast which do not fall
more aggressive disease and a poor clinical prognosis in 20–30% into any of the ‘special types’ (lobular, tubular, tubulo-lobular,
of breast cancer patients. In most cases, this overexpression cribriform, papillary, medullary, mucinous, secretory), and there-
is secondary to amplification of the HER2/c-erbB-2/neu gene fore incorporates a spectrum of morphological appearances. It
(chromosome 17q12). is the most common type of breast carcinoma, and classically
Identification of HER2/c-erbB-2/neu overexpression is based has a stellate gross appearance, though circumscribed or multi-
on detection of protein or gene amplification. In the diagnostic nodular configuration may also be seen. The tumor often con-
setting, this is performed using immunohistochemistry and flu- tains yellowish chalky streaks (due to extensive elastosis) with
orescence in situ hybridization (FISH), respectively. a firm gritty texture (likened to an unripe pear). It has the poor-
Immunohistochemical detection of the HER2/c-erbB-2/neu est prognosis of any category of invasive carcinoma of the
gene product should utilize an officially licensed protocol that, breast; however, prognosis depends on the grade and stage of
based on a positive or negative results, provides a basis for treat- the tumor.
ment selection with trastuzumab (Herceptin®). In the UK, at Factors influencing prognosis are: histological features of the
the time of publication, this is restricted to the ‘Herceptest™’ primary tumor, axillary lymph node status and immunohisto-
(DakoCytomation Ltd.), though competitor products are chemical staining for ER and PR.
currently undergoing tests. The Herceptest™ utilizes an anti- A distinctive subtype of breast carcinoma, ‘centrally necro-
HER2/c-erbB-2/neu monoclonal antibody, with staining being tizing carcinoma’, has recently been described. This is charac-
graded on the basis of a four-point scoring system: terized by an unusual and aggressive natural history, and in the
majority of cases is negative for ER and PR.
0–1⫹ Negative No treatment
2⫹ Weakly staining Treatment based on FISH positivity PATHOLOGICAL FEATURES (Figures 4.19–4.22)
3⫹ Strongly staining Treatment
Invasive carcinoma NST typically has invasive margins and
The test should only be performed in a center where at least consists of irregularly shaped, angulated tightly or loosely
250 cases per annum are seen. Recent advice suggests the use cohesive islands of medium-sized, variably pleomorphic epithe-
of well-fixed material such as a core biopsy or lymph node lial cells. Diffuse sheets, nests, cords, alveoli, glandular struc-
metastasis. Controls should always be included for all scoring tures, single cells and interlacing aggregates of tumor cells may
categories and negatives. Only membrane staining should be also be seen.
reported, as cytoplasmic staining may be artifactual. No com- Any of the patterns associated with ‘special type’ cancers may
ment should be made on in situ disease positivity, and published be seen focally.
guidelines should be followed on pitfalls and interpretation. DCIS is frequently seen in association with invasive car-
Should a center not wish to use a commercial product such as cinoma NST.
Herceptest®, it is acceptable to use an alternative provided in Centrally necrotizing carcinomas are composed of well-
house methodology is rigorously standardized to national/ circumscribed nodules with extensive central necrosis that are
international guidelines. surrounded by a narrow rim of viable high-grade tumor cells.
150 Breast tumors
(a)
Figure 4.19 DCIS and invasive intermediate-grade carcinoma

which is focally cribriform. Note the prominent lymphatic invasion
in the bottom right-hand corner.
These tumor cells show minimal ductal differentiation (i.e.,

tubule formation), but are usually associated with focal DCIS.
Rarely, a breast carcinoma may exhibit a melanoma compo-
nent, and this probably arises from the same clone which gives
rise to both elements.
Irradiated breast carcinoma shows histological features such
as extensive fibrosis, hyalinization, entrapment of tumor cells,
prominent necrosis and marked nuclear atypia and cytoplasmic
vacuolation.
Apocrine carcinoma of the breast is a rare variant of duct
carcinoma, and consists predominantly of cells with abundant (b)
granular eosinophilic cytoplasm resembling apocrine meta-
plasia. Associated CIS with apocrine features may also be seen. Figure 4.20 Low-grade DCIS and invasive carcinoma NST. (a, low
Oncocytic carcinoma, in situ and invasive, of the breast has power; b, medium power.)
recently been described. The tumors are composed mostly of cells
with ‘low-grade’ nuclei and abundant granular eosinophilic cyto-
plasm. This variant may be confused with apocrine carcinoma.
Secondary features
● Necrosis; when extensive, this should be documented in
the report as it is associated with a poor prognosis.
● Squamous metaplasia.
● Apocrine metaplasia.
● Clear cell metaplasia.
● Calcification.
● Elastosis (of the ducts wall, blood vessels and stroma).
● Inflammatory infiltrate.
● Granulomatous reaction.
Cell morphology
● The cells of invasive carcinoma NST have moderate
Figure 4.21 Grade 2 invasive carcinoma NST.
amounts of usually eosinophilic cytoplasm which may
contain intracytoplasmic lumina. They have pleomorphic
nuclei with a coarse chromatin pattern, and often contain Differential diagnosis
prominent nucleoli. ● Sclerosing adenosis (especially when associated with
● Mitotic figures, including abnormal forms, are usually apocrine metaplasia)
easily identified. ● Nipple adenoma
The classical lobular carcinoma has by far the best prognosis of

the lobular carcinoma variants. It is frequently ER-positive.
Pleomorphic lobular carcinoma (PLC) is an aggressive variant
of infiltrating lobular carcinoma. PLC tends to appear in older
postmenopausal women who present with locally advanced dis-
ease. PLC in situ (PLCIS) is identified in approximately 45%,
and lobular carcinoma in situ (LCIS) in 21% of PLC. The
aggressive clinical course of patients with PLC is supported by
tumor immunoreactivity with unfavorable markers HER2/
c-erbB-2/neu and p53. Overexpression of HER2/c-erbB-2/neu in
PLC may be therapeutically relevant, enabling the use of novel
chemotherapeutic drugs such as Herceptin. Tumors that are
HER2/c-erbB-2/neu immunoreactive are also ER-positive.

Invasive lobular carcinoma is distinguished from NST invasive
Figure 4.22 Grade 3 invasive carcinoma NST.
carcinoma by its relatively uniform cytological appearance, and
● Complex sclerosing lesion or radial scar (dense sclerotic its tendency to invade in single files or in solid patterns. There
collagen seen side by side with loose connective tissue) are six histological subgroups of invasive lobular carcinoma:
● Special type carcinomas (the distinction of NST 1. Classical lobular carcinoma consists of single files of
carcinomas containing areas of special type differentiation uniform, relatively small, round tumor cells diffusely
from the special types of carcinoma depends upon the infiltrating the breast stroma and surrounding ducts and
proportion of the tumor exhibiting the special pattern) lobules (often containing lobular carcinoma in situ) in a
circumferential (targetoid) manner. The invasive component
Special techniques may be inconspicuous (paucicellular lobular carcinoma).
● The cells may be PAS-positive due to cytoplasmic glycogen, Lobular carcinoma in situ or atypical lobular hyperplasia is
show variable amounts of Alcian blue-positive intracyto- seen in 90% of the classic type, and in 40–60% of the other
plasmic mucin, and may contain focal argyrophilic granules. variants.
● The cells express epithelial markers, and may express 2. Alveolar variant is characterized by arrangement of the
S-100 protein. invasive component in small, rounded aggregates. The
● The myoepithelial cells exhibit immunoreactivity for S-100 constituent cells are similar in appearance to those of the
protein, alpha-SMA, GFAP, vimentin, CD10, CK14 and classical variant.
CK5/6, and also express p63, maspin, and P-cadherin. The 3. Solid variant consists of sheets, or irregularly shaped nests,
finding of myoepithelial cells helps in distinguishing the of uniform small tumor cells separated by thin strands of
invasive carcinoma from its benign mimics. stromal tissue. This variant may sometimes be confused
● Alpha-catenin, especially its cytoplasmic expression, with malignant lymphoma.
seems to be a sensitive prognostic marker in invasive
breast cancer. Survival analysis has demonstrated a
statistically significant association between abnormal
alpha-catenin expression and poor patient survival.
● Immunostaining for HER2/c-erbB-2/neu oncoprotein
occurs mainly in large cell DCIS and infiltrating ductal
carcinoma NST, especially those with an extra-tumoral
DCIS component.
● Most ductal carcinomas show diffuse membrane
expression of E-cadherin, and lobular carcinomas are
characterized by complete lack of membrane staining
of E-cadherin.
LOBULAR CARCINOMA
(a)
CLINICAL FEATURES
Figure 4.23 Invasive lobular carcinoma; classical pattern with
Invasive lobular carcinoma of the breast generally shows high streaming of single files and small groups of small to intermediate-
incidence of bilaterality (approximately 10%). In the absence sized regular tumor cells. (a, low power; b, medium power; c, high
of metastases, it has a better prognosis than the NST carcinoma. power.)
152 Breast tumors
(b) (c)
Figure 4.23 (Continued).
(a) (b)
Figure 4.24 (a, b) Invasive lobular carcinoma showing a classical pattern of infiltration.The tumor showed pleomorphic features cytologically.
(a) (b)
Figure 4.25 (a, b) Invasive lobular carcinoma, alveolar pattern. Note the discohesive islands of tumor cells.
4. Pleomorphic variant consists, histologically, of multifocal PATHOLOGICAL FEATURES

nodular aggregates of dyscohesive pleomorphic tumor cells
The hallmarks of diagnosis of typical medullary (medullary-
that are seen interspersed in dense and fibrotic breast
like) carcinoma include the tumor circumscription, syncytial
parenchyma. Some tumors show associated signet ring
architecture of greater than 75% of constituent cells with atyp-
cells or discohesive, globoid, plasmacytoid cells with
ical nuclei, a diffuse lymphocytic infiltrate, and no glandular
high-grade nuclear features.
architecture. The lesion somewhat resembles the undifferenti-
5. Mixed variant, which contains a mixture of the above
ated type of nasopharyngeal carcinoma.
variants.
Carcinoma in situ is usually absent, but its presence does not
6. Signet ring cell variant (see Signet ring cell carcinoma,
rule out this diagnosis. The presence of more than one focus of
p. 164).
irregular non-pushing invasion in the surrounding tissue rules
Secondary features out the diagnosis of classical medullary carcinoma.
Atypical medullary carcinoma shows similar features, except
● Calcification
for several microscopic foci of invasion, the presence of up to
Cell morphology 25% of carcinoma of no special type, the presence of dense
fibrous bands within the tumor, and slight or absent tumor lym-
● The cells are uniform (less so in the pleomorphic variant),
phoid infiltrate. The use of the atypical categorization in disputed.
are typically round with scant cytoplasm, and have round
nuclei lacking prominent nucleoli. Secondary features
● Intracytoplasmic lumina containing a central dot
● Focal stromal hyalinization.
(representing mucinous material) are frequently seen.
● Focal necrosis.
● On occasion, the intracytoplasmic mucin displaces the
nucleus, giving the cells a signet ring appearance. Cell morphology
● Mitotic figures are sparse.
● The cells have a pale, eosinophilic, occasionally granular,
● Nuclear pleomorphism is seen only in the pleomorphic
cytoplasm with indistinct cell borders.
variant of lobular carcinoma.
● The nuclei are large, rounded with chromatin clearing
Differential diagnosis and contain prominent nucleoli.
● Bizarre tumor giant cells may be seen (10% of cases).
● Lymphoma (those displaying a more solid architecture)
● Signet ring cell carcinoma (when there are significant Differential diagnosis
numbers of cells with signet ring morphology)
● Invasive carcinoma NST with lymphocytic infiltrate
● Periductal lymphocytic infiltrate (may sometimes simulate
(lymphocytes are present within the tumor islands)
the classic type of lobular carcinoma)
● Lymphoepithelioma-like carcinoma of the breast is a rare,
Special techniques newly recognized subtype of breast carcinoma, regarded as
an unusual form of lobular carcinoma. Breast carcinoma
● Alcian blue/PAS is useful in highlighting intracytoplasmic
with features showing both lymphoepithelioma-like and
mucin.
lobular infiltrating carcinoma has been described. Unlike
● The cells express epithelial markers as in NST carcinoma.
the lymphoepithelial carcinoma of the nasopharynx, it
● Lobular carcinomas show a complete lack of membrane
does not seem to be associated with Epstein–Barr virus
staining of E-cadherin.
(EBV) infection. Distinction from medullary carcinoma is
important because of the difference in biological behavior
MEDULLARY CARCINOMA of these two neoplasms. It lacks sharp circumscription, a
syncytial growth pattern, nuclear pleomorphism, and
a high mitotic rate.
CLINICAL FEATURES
Medullary carcinoma of the breast is a rare type of carcinoma. Special techniques
It is characteristically sharply circumscribed, and soft in con- ● Medullary carcinomas of the breast express all the
sistency. According to certain histological criteria (see below), glandular type cytokeratins (CK7, CK8–18 and CK19).
the tumor has been divided into two variants: In addition, a proportion of the tumors express some of
● Typical medullary carcinoma, which has a better prognosis the cytokeratins typical for myoepithelial cells (CK14).
than carcinoma NST (84% versus 63% 10-year survival). The tumors are CK20-negative.
● Atypical medullary carcinoma, which has a survival rate
intermediate between the classical medullary and NST MUCINOUS (MUCOID, COLLOID) CARCINOMA
carcinoma of the breast.
Both variants tend to be well-circumscribed masses on both mam-

CLINICAL FEATURES
mography and ultrasound. Both also demonstrate a similar, high
proclivity to be aneuploid, and to lack ER and PR and nodal Mucinous carcinoma of the breast is defined as carcinoma
metastases. exhibiting pure mucinous features throughout the lesion, with
154 Breast tumors
no other pattern of breast carcinoma. This tumor comprises

approximately 2% of invasive carcinomas of the breast, and is
more common in older women. The lesion varies in size from
1 to 4 cm in diameter, though rare example of massive size have
been reported. It is soft in consistency, and has smooth borders
with a glistening cut surface. In its pure form it has a signifi-
cantly better prognosis than conventional ductal carcinomas.
It has been shown that mucinous cancers of the breast do not
have the extensive genomic alterations that are typically found
in more common variants of breast cancer. Thus, mucinous
cancers most likely have less genetic instability than most other
forms of breast cancer, and the molecular pathogenesis of this
form of breast cancer is likely to be substantially different from
that of usual ductal breast cancer.
Primary mammary mucinous cystadenocarcinoma is a rare, (a)
clinicopathologically distinct type of primary breast carcinoma
that should be distinguished from typical mucinous (colloid) car-
cinomas of the breast and, more importantly, metastases from
other sites.

Invasive mucinous carcinoma of the breast is a well-
circumscribed lesion surrounded by connective tissue stroma
and consisting of pools of mucin-containing islands of tumor
cells. These islands of carcinoma cells are sharply demarcated,
have irregular outlines and contain rounded or elongated holes
reminiscent of cribriform or papillary pattern. On occasion, the
islands are interconnected, thereby producing a reticulated or
fenestrated appearance. Occasionally, the tumor islands are
concentrated at the periphery of the lesion and may extend into
the adjacent stroma, whereas sometimes the tumor is sparsely (b)
cellular, appearing to consist almost entirely of mucin. Adjacent
carcinoma in situ is uncommon. Figure 4.26 Invasive mucinous carcinoma. Islands of
Primary mammary mucinous cystadenocarcinoma is multi- well-differentiated tumor cells sitting in lakes of mucin. (a, low
power; b, medium power.)
cystic and appears virtually identical to mucinous cystadeno-
carcinoma of the ovary and pancreas, consisting predominantly
of tall columnar cells with abundant intracytoplasmic mucin.
Varying degrees of cytological atypia are focally evident, with TUBULAR AND CRIBRIFORM CARCINOMA
gradual loss of the intracytoplasmic mucin and transformation
to an eosinophilic squamoid cell population. Multifocal invasion
from these eosinophilic, squamoid areas is commonly seen. CLINICAL FEATURES
Tubular and cribriform carcinomas are both well-differentiated
types of breast carcinoma, and are considered to be the same
● Mucinous carcinoma should be distinguished from disease. They are defined as tubular or cribriform by the per-
carcinoma NST with loose edematous stroma, and from centage of invasive pattern. In tubular carcinoma at least 90%
benign interstitial mucin pools of the lesion is of tubular architecture, whereas in cribriform
carcinoma less than 50% is tubular and the remainder is of
Special techniques cribriform pattern. This tumor is usually smaller than the other
● Alcian blue/PAS highlights the interstitial mucin. types of breast carcinoma (0.5–1 cm, usually less than 2 cm), is
● A Grimelius stain reveals cytoplasmic argyrophilic poorly circumscribed, and hard in consistency. It has an excel-
granules in some of the mucinous carcinomas. lent prognosis, with lymph node metastases occurring in
● The mucin produced, MUC2 (also called gel-forming around 10% of cases. The lesion comprises about 2% of inva-
mucin), is highly specific for mucinous carcinoma. sive breast carcinomas, and it is more common among cancers
● Mucinous cystadenocarcinoma of the breast is detected by mammography (9%). Patients with pure tubular car-
CK7-positive, CK20-negative, and shows high MIB1 cinoma are appropriate candidates for breast-conserving therapy
nuclear staining. The tumor usually shows no based on the clinical/pathological features. When a multifocal
immunoreactivity for ER and PR. association is suspected preoperatively, either a wide local
excision or a quadrantectomy which includes other lesions is Invasive cribriform carcinoma consists of islands of cells with
recommended. features similar to those of cribriform carcinoma in situ. These
islands are of irregular size and shape, are haphazardly scattered
PATHOLOGICAL FEATURES (Figure 4.27) within the stroma, and may be associated with tubular structures
identical to those seen in invasive tubular carcinoma. Adjacent
Invasive tubular carcinoma of the breast consists of round or cribriform carcinoma in situ is frequently seen (75% of cases).
oval-shaped, partly angulated tubules distributed haphazardly
within and separated by a loosely cellular fibroblastic stroma. Secondary features
The lesions may also be found in adjacent fat. These neoplastic
● Microcalcification.
tubules have patent lumina that may be focally partitioned by
● Elastic tissue may be seen in the stroma or around ducts.
trabecular bars, or contain basophilic secretion and are lined
by a single layer of bland-looking cells. Associated intraduct Cell morphology
cribriform, micropapillary carcinoma or atypical ductal hyper-
plasia is often seen intermingled with the invasive component.
● The lining cells are small and cuboidal with rounded,
Ectatic ducts lined with small uniform, hyperchromatic cells usually centrally located nuclei with no distinct nucleoli.
showing apocrine-like snouts (probably represent a form of Their luminal borders often show apical snouts
low-grade DCIS) reminiscent of the cells seen in the adjacent (apocrine-type secretion).
invasive tubular carcinoma may be seen.
● A myoepithelial cell layer is absent.
Areas with tubular pattern may be found in many other types
● Cytologic atypia is absent.
of breast cancer. Similarly, areas of other carcinoma variants
● Mitoses are extremely sparse.
(usually less than 10%) may be seen in otherwise typical tubu-
lar carcinoma. Tubular carcinoma may show a significant inva-
sive cribriform component. ● Sclerosing adenosis (partly lobular or nodular configuration,
collapsed lumina and double cell layer lining)
● Radial scar
● Microglandular adenosis
● Invasive carcinoma NST/ductal carcinoma (when it
contains areas with tubular carcinoma pattern)
● Invasive tubulo-lobular carcinoma
TUBULO-LOBULAR CARCINOMA
CLINICAL FEATURES
Controversy persists as to whether tubulo-lobular carcinoma is
a variant of lobular or of tubular carcinoma. The tumor is usually
(a)
(b) (c)
Figure 4.27 Tubular carcinoma. Note the comma-shaped infiltrating tubules and prominent apical snouts. (a, low power; b, medium
power; and c, high power.)
156 Breast tumors
small (⬍1 cm in diameter), and therefore is often detected by Differential diagnosis

screening mammography. This lesion comprises about 1% of ● Invasive tubular carcinoma
invasive carcinomas of the breast, and has a prognosis some- ● Invasive lobular carcinoma
what worse than that for tubular carcinoma, but better than
that for invasive carcinoma NST/ductal carcinoma.
Special techniques
PATHOLOGICAL FEATURES (Figure 4.28) ● E-cadherin immunostaining has not yet proven useful.
Invasive tubulo-lobular carcinoma of the breast consists of sin-
gle strands or files of tumor cells identical to those of classical
lobular carcinoma intermixed with well-differentiated tubules INVASIVE CARCINOMA, VARIANTS
similar to those of tubular carcinoma. These may be distributed
in a targetoid pattern. ADENOID CYSTIC CARCINOMA
Secondary features
CLINICAL FEATURES
● Calcification
● Elastosis Adenoid cystic carcinoma (ACC) of the breast is an unusual
malignancy that represents less than 1% of breast carcinomas.
Cell morphology It has an excellent prognosis, despite the fact that it does not
express ER. The excellent prognosis may be related to the pecu-
● Uniform population of cells without nuclear pleomorphism, liar differentiation, and is maintained even with higher nuclear
resembling those of invasive lobular carcinoma. grades and mitotic counts.
The solid variant of mammary ACC is reported to have a more
aggressive clinical course than conventional mammary ACC.

See also Chapter 8, Head and neck tumors; Salivary gland
(p. 601).
Morphologically, this subset of breast carcinomas is histo-
logically indistinguishable from ACC arising from other sites.
A variety of microscopic growth patterns have been described
in ACC of the salivary gland, which also have been used to
subclassify these tumors in the breast. One subtype – the solid
variant – has been reported to be associated with a more
aggressive clinical course both in the salivary glands and
the breast. ACC with a basaloid appearance is a variant of
(a) solid ACC.
(b)
(a)
Figure 4.28 (a, b) Invasive tubulo-lobular carcinoma; area of
otherwise classical invasive lobular carcinoma showing tubulo-lobular Figure 4.29 (a, b) Adenoid cystic carcinoma of high grade.Tumor
differentiation. (a, medium power; b, high power.) islands showing basaloid and cylindromatous areas.
HISTIOCYTOID CARCINOMA
CLINICAL FEATURES
Histiocytoid carcinoma of the breast is an extremely rare vari-
ant of, possibly lobular, breast carcinoma. It has been shown
recently that histiocytoid carcinoma has an immunophenotyp-
ical profile consistent with both ductal and lobular differentia-
tion. It may first present with metastases, especially in the region
of the eyelid.
Invasive histiocytoid carcinoma of the breast has the low-
(b)
power microscopic appearance of a benign histiocytic lesion.
On close examination, however, the epithelial nature of the
Figure 4.29 (Continued). tumor is suggested by the presence of focal packeting or Indian-
file arrangement of tumor cells.
APOCRINE CARCINOMA Cell morphology

● The cells are rounded, with pale or clear cytoplasm and
See Invasive carcinoma of no special type (NST), invasive relatively small rounded nuclei.
carcinoma not otherwise specified (NOS), ductal carcinoma ● The tumor may also contain lipid-laden macrophages
(pp. 149–51). similar in appearance to the tumor cells themselves.
CLEAR CELL CARCINOMA Differential diagnosis

● Xanthelasma
● Fibrohistiocytic lesions
CLINICAL FEATURES ● Granular cell tumor
Primary clear cell carcinoma of the breast is a rare tumor. The ● Lipid-rich carcinoma
clear cell morphology of the neoplastic population in these ● Secretory carcinoma
tumors has been ascribed to the presence of intracellular lipid, ● Fat necrosis
mucin or glycogen (Glycogen-rich (clear cell) carcinoma of
the breast), or to myoepithelial, apocrine or neuroendocrine Special techniques
differentiation. Rarely, a clear cell neoplasm exhibits a range of ● The cells contain intracytoplasmic mucin.
differentiation. ● The cells express epithelial markers.
● There is no E-cadherin immunohistochemical staining in
PATHOLOGICAL FEATURES 72% of cases.
Histologically, clear cell carcinoma is reminiscent of renal cell
carcinoma. Cytologically, the presence of a delicate/foamy to INFLAMMATORY CARCINOMA
clear cytoplasm distinguishes these tumors from the more
common infiltrating duct carcinoma.
CLINICAL FEATURES
Differential diagnosis Inflammatory breast carcinoma is a rare but aggressive form
Clear cell ‘sugar’ tumor of the breast is an extremely rare of breast cancer. It is associated with redness, edema and
tumor, and a member of the PEComa (perivascular epithelioid inflammation of the overlying skin, with or without dermal
cell tumor) group composed of clear epithelioid cells with lymphatic involvement. The presence of isolated inflammatory
abundant glycogen and distinct cell borders. The tumor shows signs is sufficient to suggest inflammatory breast carcinoma
strong immunoreactivity with HMB45 antibody and Melan-A. clinically. Inflammatory breast carcinoma has a mammo-
It also shows diffuse and strong nuclear staining for PR, but ER graphic pattern of inflammatory changes, such as skin thicken-
is usually negative. ing and stromal coarsening and/or diffusely increased breast
Renal clear cell (RCC) (conventional) carcinoma may be differ- density, with or without associated mass and/or malignant-type
entiated by the new immunohistochemical RCC tumor marker. microcalcifications. Ultrasound is helpful not only in identify-
RCC carcinomas are typically EMA- and vimentin-positive. ing masses masked by the edema pattern but also in the
Renal tumor variants have differing immunohistochemical and demonstration of skin and pectoral muscle invasion and axil-
histochemical profiles (see Chapter 14). lary involvement.
158 Breast tumors
Occult inflammatory carcinoma shows dermal lymphatic inva- structures show apocrine features with ‘hobnail’ appearance.
sion, but without inflammatory clinical symptoms. The prog- They may be associated with ductal or lobular carcinoma in
nosis of this variant tends to be poorer than that of the usual situ, or with focal areas of invasive ductal-type carcinoma.
inflammatory carcinoma. Nodal involvement is sinusoidal in distribution.
Inflammatory carcinoma is frequently a poorly differentiated,

● Histiocytoid carcinoma
high-grade tumor. Lymphatic invasion is often seen.
● Secretory carcinoma
● Signet-ring carcinoma
INTRACYSTIC CARCINOMA Special techniques

● The cells contain intracytoplasmic lipid (demonstrable
CLINICAL FEATURES by oil red O).
● The cells express epithelial markers.
Intracystic carcinoma of the breast is a term applied to any
type of breast carcinoma which arises within a cyst wall. It is a
very rare type that shows a predilection for older women but METAPLASTIC CARCINOMA (SARCOMATOID
may also be seen in males. It has a relatively good prognosis, CARCINOMA AND CARCINOSARCOMA)
and is much more likely to be cured by local treatment. Cysts in
postmenopausal women should be viewed with suspicion.
Blood-stained aspirated cyst fluid should be sent for cytology, CLINICAL FEATURES
and breast imaging should be carried out in such cases. Residual
The terminology is rather confusing and contradictory in this
mass after cyst aspiration is also an indication for open biopsy.
area, as are the debates surrounding histogenesis. Sarcomatoid
carcinoma implies an epithelial neoplasm mimicking a sarcoma,
PATHOLOGICAL FEATURES and carcinosarcoma implies a collision-type of lesion or two
Cyst formation can be seen in association with intraduct carci- defined separate and extractable cell lineages within the neo-
noma, non-invasive papillary carcinoma, and rarely with inva- plasm. Consequently, we will restrict ourselves to the term
sive carcinomas. The cysts have a thick collagenous capsule, ‘metaplastic carcinoma of the breast’. This is a rare type of
and may contain blood-stained fluid. carcinoma which tends to have a poor prognosis. In the breast,
the most popular theory regarding the histogenesis of the sar-
Differential diagnosis comatous component is through transformation of myoepithe-
lial cells. Another theory is through myofibroblastic metaplasia
● Epidermal cysts
of the malignant epithelial cells.
● Benign breast cysts with pseudoinvasion
● DCIS of papillary type
● Invasive papillary carcinoma PATHOLOGICAL FEATURES (Figures 4.30–4.37)
Classic metaplastic carcinomas are biphasic characterized
IRRADIATED CARCINOMA by an admixture of glandular epithelial components, which
See Invasive carcinoma of no special type (NST), invasive

carcinoma not otherwise specified (NOS), ductal carcinoma
(pp. 149–51).
LIPID-RICH CARCINOMA
CLINICAL FEATURES
Lipid-rich carcinoma is a rare variant of breast carcinoma, and
has a relatively poor prognosis.
Invasive lipid-rich carcinoma of the breast shows tumor islands
separated by scant and loose stroma. The tumor cells have (a)
abundant foamy or vacuolated cytoplasm, sometimes in the
form of sebaceous differentiation, with malignant nuclear Figure 4.30 Metaplastic carcinoma with squamous areas. (a, medium
morphology. Occasionally, the tumor cells lining glandular power; b, high power.)
(c)
(b) Figure 4.31 (Continued).
(a)
(a)
(b) (b)
Figure 4.31 Fibromatosis. (a–c) Needle core biopsy. Infiltration Figure 4.32 Metaplastic carcinoma of the breast. (a) A single
of fat by a bland proliferative spindle cell lesion.There is no atypia, overview image of classic metaplastic carcinoma with epithelial
and mitoses are uncommon.This has to be distinguished from ‘squamoid’ nests merging with a variably hyalinized spindle cell
fibromatosis-like metaplastic carcinoma. stroma. (b) Same section, high-power view.
frequently exhibit features of squamous differentiation, and not uncommon. The sarcomatous element is either ‘homolo-
mesenchymal malignant components. The carcinoma is fre- gous’, resembling fibrosarcoma or malignant fibrous histio-
quently poorly differentiated, and cysts lined by squamous cytoma, or ‘heterologous’, showing differentiation towards
carcinoma and small foci of invasive or in situ carcinoma are cartilage, bone, smooth or striated muscle and adipose tissue.
160 Breast tumors
(a) (d)
(b) (e)
(c)
Figure 4.33 Metaplastic carcinoma of the breast. (a–e) Further

examples of the varied morphology to be expected.
A hemangiopericytoma-like, angiosarcoma-like or angiotropic Figure 4.34 Metaplastic carcinoma with a fibromatosis-type of

spindle cell stromal architecture.
growth pattern can also be seen. The boundaries between the
carcinoma and sarcoma are usually sharp, but a transition
between the two may be found. Additional components include bland, mimicking nodular fasciitis, fibromatosis or a granula-
inflammatory infiltrates and stromal osteoclast-like giant cells. tion tissue.
Monophasic metaplastic carcinoma contains little or no dis- Spindle or sarcomatoid squamous cell carcinoma is often
cernible epithelial component and may appear deceptively described as being a variant of metaplastic carcinoma.
(a) (d)
(b) (e)
(c) (f )
Figure 4.35 Nodular fasciitis-like sarcomatoid carcinoma. (a–f) From low- to high-power. A further variant of metaplastic carcinoma. Note
the plump spindle/cigar-shaped cell morphology associated with a scattered lymphocyte-rich inflammatory background, mimicking nodular
fasciitis.
Differential diagnosis Special techniques

● Primary sarcoma ● The epithelial component expresses cytokeratins, EMA
● Fibromatosis and vimentin.
● Nodular fasciitis ● The sarcomatous component exhibits mesenchymal and
● Phyllodes tumor occasionally also epithelial markers.
162 Breast tumors
● Classic myoepithelial markers (actin, S-100 protein,

CK14, CK5/6 and CD10) as well as the recently developed
‘putative myoepithelial markers’ (p63, maspin, and P-
cadherin) are usually positive, especially in the squamous
areas.
MICROINVASIVE CARCINOMA OF THE

BREAST (MICB)
CLINICAL FEATURES
The exact definition of microinvasive carcinoma of the breast
remains controversial. In the new TNM staging scheme, T1mic
is defined as microinvasion of 1 mm or less in the greatest
dimension.
Figure 4.36 Sarcomatoid carcinoma spindle-epithelioid pattern. The majority of patients are women aged over 45 years
In this example, the mixture of a spindle and epithelioid stromal (mean age is 61 years). These tumors are discovered on routine
cell morphologies can be seen.This reinforces the wide
mammograms showing abnormal calcifications. Because of
spectrum of changes that can be expected in ‘metaplastic’
carcinomas. the small size of MICBs, grading schemes cannot be applied.
However, the architecture, nuclear grade, and presence of
necrosis in the adjacent DCIS may be helpful in formulating a
treatment plan.
The potential of MICB to metastasize to the axillary lymph
nodes is reported to vary from 0% to 20%, which partly reflects
different criteria used to define microinvasion. Treatment of
the breast for both DCIS and MICB should be similar, and
based on the size of the DCIS component relative to the breast
size, margin status, the ability to follow the patient mammo-
graphically, and patient needs.
More than 85% of MICBs are ductal in type, and referred to
as ‘MICD’; the remainder are lobular, and only a very small pro-
portion occur as tubular MICB.
Ductal MICB (‘MICD’): about 72% of MICD are associated
with comedo-type DCIS. The incidence of invasion has been
reported to be related directly to the size and number of ducts
involved by comedo-DCIS. It has been found that 45% of
comedo-DCIS measuring more than 2.5 cm is associated with
(a) stromal invasion, as opposed to none among those measuring
less than 2.5 cm. The mean size of the associated DCIS is even
smaller (1.3 cm) in the screening population. It has been shown
that the DCIS component of MICB is more often aneuploid
and overexpresses HER-2/neu more frequently.
Lobular MICB (‘MICL’): this is a very unusual lesion, show-
ing classic lobular carcinoma, often in association with LCIS,
and sometimes with atypical lobular hyperplasia.
Tubular MICB: this has rarely been seen in association with
low-grade micropapillary and cribriform DCIS.
The dominant lesion in microinvasive carcinoma is DCIS,
usually of the comedo-type, large nuclear grade, but with one
or more clearly separate invasive foci (no more than 1 mm
(b) in size) into the non-specialized interlobular or interductal
fibrous or adipose tissues. The invasive foci are cytologically
Figure 4.37 (a, b) Metaplastic carcinoma with a malignant osteoid malignant, and demonstrate an absence of basement membrane
component. or myoepithelial layer.
● In-situ carcinoma distorted by inflammatory and
reparative changes
● Cancerization of the lobules in cases of comedo-type DCIS
may mimic microinvasive nests
Special techniques
● The detection of MICB may be greatly enhanced by the
double immunolabeling technique. The vivid-red CK-
positive epithelial cells stand out in the stroma beyond the
confines of the dark-brown SMA-positive myoepithelial
boundaries, even when present in small numbers. The
technique appears invaluable in the assessment of invasion
in the setting of sclerosing adenosis, radial scar, and
(a)
fibroadenoma complicated by in-situ carcinoma.
● The myoepithelial cells in the non-invasive component
exhibit immunoreactivity for S-100 protein, alpha-SMA,
GFAP, vimentin, CD10, CK14 and CK5/6, and also
express p63, maspin, and P-cadherin. The finding of
myoepithelial cells surrounding the lesion support the
diagnosis of DCIS.
MICROPAPILLARY CARCINOMA
CLINICAL FEATURES
Invasive micropapillary carcinoma of the breast is a recently rec-
ognized type of breast carcinoma with an aggressive behavior, as
shown by frequent skin invasion, specific pattern of local recur-
(b)
rence, and extensive nodal involvement.
Figure 4.38 Papillary carcinoma. (a) Low-power view showing
PATHOLOGICAL FEATURES circumscribed in situ lesion. (b) High-power view demonstrating poorly
formed fibrovascular fronds covered by a single cell type.
Invasive micropapillary carcinoma of the breast is character-
ized by growth of cohesive tumor cell clusters within promi-
nent clear spaces, resembling dilated angiolymphatic vessels. carcinoma of the ovary or/and mucinous carcinoma of the
breast. The cells may have apocrine-type cytoplasm, and may
exhibit apical snouts. The nuclei are round, contain small
PAPILLARY CARCINOMAS nucleoli, and may show pleomorphism.
Non-invasive papillary carcinoma of the breast is essentially
composed of intracystic papillary process reminiscent of
CLINICAL FEATURES intraduct papilloma. However, the lining epithelium may
exhibit a variety of appearances. These include: elongated, uni-
Invasive papillary carcinoma of the breast is a rare type, and is
form, spindle-shaped cells with hyperchromatic nuclei per-
seen more often in elderly women. It has a good prognosis
pendicularly oriented to the fibrovascular papillary stalks. A
which is similar to that of mucinous carcinoma of the breast.
cribriform carcinoma in situ pattern may be present between
Non-invasive papillary carcinoma of the breast is often seen
the fibrovascular cores, or micropapillary or atypical hyper-
in middle-aged and older women. The tumor is soft, and mea-
plasia pattern. There may be extension of tumor into the sur-
sures 1–3 cm in maximum dimension. It can be cured by wide
rounding thick fibrous wall. Carcinoma in situ is often seen in
local excision.
the surrounding tissue. The cells are often uniformly tall and
hyperchromatic, lack apocrine features, may have eosinophilic
PATHOLOGICAL FEATURES (Figure 4.38) cytoplasm, and may exhibit cytological atypia.
Invasive papillary carcinoma of the breast is a well-
circumscribed lesion which is soft in consistency and frequently Differential diagnosis
shows foci of elastosis. It consists of a complex invasive epithe- ● Invasive papillary carcinoma should be distinguished from
lial component with features reminiscent of serous papillary non-invasive papillary carcinoma, mucinous carcinoma
164 Breast tumors
which often shows papillary clusters floating within the

mucin, and invasive cribriform carcinoma
● Non-invasive papillary carcinoma needs to be
distinguished from complex sclerosing lesion and
intraduct papilloma
SECRETORY (JUVENILE) CARCINOMA
CLINICAL FEATURES
Secretory carcinoma of the breast is a very rare variant of breast
carcinoma. It occurs more often in children and young girls,
but it also occurs in adults. Good prognostic factors include
occurrence in children, less than 2 cm in size, and an absence of (c)
stroma invasion.
Invasive secretory carcinoma of breast carcinoma is a fairly islands containing numerous variably sized tubular, follicular or
well-circumscribed lesion, surrounded by a continuous or dis- cystic spaces. These spaces contain pale eosinophilic material and
continuous layer of connective tissue, and consisting of epithelial are lined by flattened epithelial cells; the intervening cells are uni-
form round/polygonal. The tumor stroma is often sclerotic.
Cell morphology
● The cells are bland-looking, with abundant pale granular
or vacuolated cytoplasm and round nuclei which may
contain prominent nucleoli.
● Mitotic figures are either sparse or absent.
● Lipid-rich carcinoma of the breast
● Cystic hypersecretory carcinoma
Special techniques
● The material seen within the spaces is mucin. It is
PAS-positive after diastase, and Alcian blue- and
(a)
mucicarmine-positive.
SIGNET RING CELL CARCINOMA
CLINICAL FEATURES
Primary signet ring cell carcinoma of the breast is usually con-
sidered as a variant of mucinous carcinoma or lobular carcinoma,
and usually originates from the lobular epithelium. It is also
recognized as a variant form of papillary carcinoma. It has a
poor prognosis, with an unusual metastatic pattern and a ten-
dency to involve serosal surfaces, gastrointestinal tract and sub-
mucosal surfaces of the stomach, bladder and endometrium. It
may also cause ureteric obstruction in a fashion similar to retro-
peritoneal fibrosis.
(b)
Figure 4.39 (a–c) Invasive secretory carcinoma.Trabecular growth
pattern with islands of tumor cells and abundant intracytoplasmic Invasive signet ring cell carcinoma of the breast is a poorly
and luminal secretions. defined, infiltrative tumor consisting predominantly of signet
Epithelial/stromal (biphasic) lesions 165
SMALL CELL CARCINOMA
CLINICAL FEATURES
Small cell carcinoma of the breast is an uncommon neoplasm
that has been reported rarely in the literature. These tumors
usually have poor prognosis.
Histologically, the tumors show characteristics of small cell
carcinoma with high mitotic activity and necrosis. A dimorphic
histological appearance may also be observed, consisting of
small cell carcinoma merging with invasive lobular carcinoma,
(a) or with invasive, poorly differentiated duct carcinoma; or with
‘lobular and gland-forming elements’; and focal squamous dif-
ferentiation. Lymphatic tumor emboli are a frequent finding.
An in-situ component is seen in a large number of cases; these
are either small cell-type in ducts or ductal-type with high
nuclear grade.
Special techniques
● Immunohistochemical analysis shows consistent staining
for cytokeratin markers, but with variable staining for
neuroendocrine markers.
● These tumors are usually positive for bcl-2 and negative
for HER2/c-erbB-2/neu.
(b) EPITHELIAL/STROMAL (BIPHASIC) LESIONS

Figure 4.40 Signet ring cell carcinoma, core biopsy specimen.
This lesion showed papillary features elsewhere. (a, medium ADENOMYOEPITHELIOMA (MYOEPITHELIOMA),
power; b, high power.) MYOEPITHELIOSIS AND MYOEPITHELIAL
ring cells. These are arranged either singly or in aggregates. In-situ CARCINOMA
carcinoma with signet ring morphology may be seen.
Secondary features CLINICAL FEATURES

● The main cell populations are signet ring cells: they have Myoepitheliosis is a multifocal microscopic lesion which is
a large cytoplasmic vacuole indenting and displacing the located in the terminal duct-lobular units, and appears grossly
nucleus to one side. as firm irregular areas. It is a benign lesion which is adequately
● Nuclear pleomorphism and hyperchromasia are often seen. treated by total excision.
Adenomyoepitheliomas (myoepitheliomas) of the breast are
Differential diagnosis currently classified as low-grade malignant tumors that may
● Metastatic signet ring carcinoma recur and rarely metastasize. Adenomyoepithelioma is a mixed
● Invasive lobular carcinoma with signet cell change epithelial and myoepithelial tumor. In rare cases, adenomyo-
● Breast carcinoma NST with focal signet ring differentiation epitheliomas give rise to carcinomas with epithelial, myoepi-
thelial, or mixed epithelial and myoepithelial differentiation.
Special techniques Carcinomas arising in adenomyoepithelioma range from low-
● The cytoplasmic mucinous vacuoles are positive with grade to high-grade, including sarcomatoid carcinoma.
mucicarmine, PAS after diastase, and Alcian blue.
● CK7, CK20 and ER are useful markers in distinguishing
between signet ring cell carcinoma of bowel or breast
origin. Breast carcinoma is CK20-negative/CK7-positive Myoepitheliosis is often well-demarcated, characterized by
and ER-positive, and bowel carcinoma is CK20-positive/ proliferation of spindled to cuboidal myoepithelial cells within
CK7-negative and ER-negative. and sometimes around multiple ducts.
166 Breast tumors
(a) (d)
(b) (e)
proliferating glandular and myoepithelial cells, the lesion can

assume a variety of histological appearances:
● Tubular-adenosis type consists predominantly of rounded
or elongated tubular structures reminiscent of tubular

adenoma lined by prominent or hyperplastic myoepithelial
cells. Some tubules are completely occluded by the
proliferating myoepithelial cells.
● Sclerosing-adenosis type is characterized by haphazard
distribution of small tubules with obliterated lumens.

These are lined by plump myoepithelial cells.
● Spindle cell type is composed predominantly of spindle
myoepithelial cells arranged in a solid pattern, occluding

(c)
ducts or admixed with a few epithelial-lined spaces. In solid
areas, the spindle cells may resemble smooth muscle tumor.
Figure 4.41 Adenomyoepithelioma. (a–e; from low- to high-
● Lobulated type is composed of multiple lobules separated
power) A typical, circumscribed adenomyoepithelioma with
a tubular adenoma-like morphology. by fibrous tissue, and contains solid nests of clear,
eosinophilic or hyaline (plasmacytoid) myoepithelial cells
Adenomyoepithelioma consists of a significant number of present around and compressing epithelial-lined spaces.
myoepithelial cells in conjunction with an epithelial component. A thick fibrous capsule is usually seen in this type of
Many of the adenomyoepitheliomas have areas of intraduct adenomyoepithelioma. Satellite nodules may be seen in the
hyperplasia, papillomatosis or cystic change. Myoid hyper- adjacent areas, and hyaline degeneration is usually
plasia of the myoepitheliomatous component may produce prominent. Massive central infarction and calcification are
leiomyomatous features. Depending on the relative amounts of sometimes seen.
(a) (a)
(b) (b)
Figure 4.42 Adenomyoepithelioma. (a, b) The intraduct Figure 4.43 Adenomyoepithelioma. (a–h; from low- to
component that is frequently seen. (a, low power; b, higher power.) high-power) Multiple views of a well-circumscribed
adenomyoepithelioma.This falls into the lobulated category, but
does show a variable architecture when viewing the multiple high-
Some adenomyoepitheliomas may show areas of cytologically power images. CK14 immunohistochemical staining highlights the
myoepithelial component (J2). Arrows in (h) indicate granular
malignant epithelial (adenocarcinoma) or myoepithelial com- myoepithelial cells.
ponent (myoepithelial carcinoma) or both.
Myoepithelial carcinoma is an infiltrative lesion that may show
variable appearances; interlacing bundles of plump spindle cells
with indistinct stroma or interconnecting epithelioid cords with ● The spindle cell myoepithelial cells are plump, with
easily identifiable mitotic figures. abundant eosinophilic cytoplasm.
Both benign and malignant areas may be seen in the same ● Cytological atypia and high mitotic figures should be
tumor. considered as signs of malignancy.
Secondary features Differential diagnosis

● Microcystic spaces. ● Metaplastic carcinoma
● Apocrine metaplasia. ● Smooth muscle tumor
● Mucinous metaplasia.
Cell morphology Special techniques

● The epithelial cells are low cuboidal or columnar without ● CAM 5.2, AE1/AE3 and EMA highlight the epithelial
cytological atypia, except in malignant cases. component.
● The myoepithelial cells that are basally located beneath ● The myoepithelial cells exhibit immunoreactivity for S-100
the epithelial cells lining the tubular structures usually protein, alpha-SMA, GFAP, vimentin, CK14, CK5/6 and
exhibit clear cell change. CD10. They also express p63, maspin, and P-cadherin.
168 Breast tumors
(c) (f )
(d) (g)
(e) (h)
FIBROADENOMA fibroadenoma). The tumors occur mainly in young women

(aged 20–30 years), but can also occur in adolescents (juvenile
fibroadenoma) and rarely in postmenopausal women. It is
CLINICAL FEATURES
painless, and can be multiple (10–20% of cases). The lesion is
Fibroadenoma is a common benign breast lesion, arising by grossly very well-circumscribed and firm, but may also be soft
proliferation of mammary stroma and epithelial elements. with a glistening, myxoid cut surface showing small clefts.
Fibroadenoma varies in size from a few to several centimeters Other pathologies can be seen in association with fibro-
in diameter (when larger than 8–10 cm it is referred to as ‘giant’ adenoma, such sclerosing adenosis, duct ectasia, apocrine
(a) (b)
Figure 4.44 Myoepithelial carcinoma. (a, b) Images showing the characteristic infiltration around pre-existing glandular structures. Note the
clear cell morphology of the myoepithelial cells.
(a) (b)
Figure 4.45 Myoepithelial carcinoma. (a, b) Images showing a more usual morphology of spindle cells with a weakly eosinophilic cytoplasm
in a notable, collagen-rich stroma.
(a) (b)
Figure 4.46 Myoepithelial hyperplasia. (a) Easily identifiable hyperplasia of myoepithelial cells with a clear cytoplasm. Further highlighted on
smooth muscle actin immunohistochemical staining (b).
170 Breast tumors
(a) (b)
Figure 4.47 Myoepithelial hyperplasia. (a) A similar myoepithelial expansion, but in this case the cells take on a more spindle/stromal type
of architecture. Further highlighted on smooth muscle actin immunohistochemical staining (b).
(a) (b)
Figure 4.48 Fibroadenoma showing substantial areas of lactational change.This is a common cause of enlargement of fibroadenomas in
pregnancy.The two sections were taken from the same patient. (a, low power; b, high power.)
metaplasia, florid fibrocystic disease, duct papillomatosis, infil- Secondary features

trating duct carcinoma, duct carcinoma in situ, and lobular carci- ● Fibrosis.
noma in situ. These are more commonly seen in older age groups. ● Infarction.
Juvenile fibroadenoma grows rapidly, usually achieves a large ● Calcification.
size (over 10 cm), stretches the overlying skin, and may distort ● Epithelial metaplasia (apocrine and squamous).
the nipple. ● Mesenchymal metaplasia (fatty change, osseous metaplasia
and rarely smooth muscle metaplasia).
PATHOLOGICAL FEATURES (Figures 4.48 and 4.49) ● Superimposed epithelial changes such as sclerosing
adenosis, in-situ or invasive carcinoma especially lobular
Fibroadenoma is a sharply circumscribed, non-encapsulated or any other change that may be seen outside a
lesion consisting of epithelial and stromal components. The fibroadenoma.
epithelial element most commonly forms slit-like canalicular ● An inflammatory reaction may sometimes be present.
(intracanalicular type) spaces, or less often forms rounded or ● Malignant transformation is a rare event. It is usually
irregularly shaped tubules (pericanalicular). These are surrounded sarcomatous (see Phyllodes tumor, below), but when
by large amounts of loose, myxoid moderately cellular stroma. carcinomatous a lobular type is usually seen.
Focal tubular adenoma-like areas may occasionally be seen.
Juvenile fibroadenoma usually shows epithelial and/or stro-
mal hypercellularity that can mimic phyllodes tumor. Cell morphology
Fibroadenomatosis or fibroadenomatoid hyperplasia shows ● The epithelial lining cells may show hyperplasia with
features of both fibroadenoma and fibrocystic disease. The lob- micropapillae reminiscent of those seen in gynecomastia.
ules exhibit increased stroma, and they may loosely coalesce. ● The stromal cells are stellate and fibroblastic.
The lesions themselves are innocuous; their discovery on patho-

logical examination should however raise suspicion of the com-
plex, and affected patients (and their primary relatives) should
be evaluated accordingly.
Nodular mucinosis of the breast is a benign process composed
of a poorly circumscribed and unencapsulated lesion, usually
located in the nipple region. Ultrasonography shows a clearly
circumscribed, lobulated, and homogeneous hypoechoic lesion.
Mammography shows a round to lobular-shaped radio-opaque
mass without microcalcifications or spicula formation. Nodular
mucinosis may be mistaken for mucinous carcinoma or phyl-
lodes tumor on clinical and imaging examinations, and should
be included in the differential diagnosis in cases of mucinous
lesions occurring near the nipple in a young woman.
Figure 4.49 Fibroadenoma. Low-power view of fibroadenoma
showing a predominantly intracanalicular pattern. Myxoid fibroadenoma and myxomatous lesion of the
breast are characterized by accumulations of large amounts of
● The stroma may be cellular and exhibit a modest number ground substance in breast lobules. The myxoid stroma may
of mitoses and pleomorphism (cellular fibroadenoma). compress the acinar structures, giving a pericanalicular or
● Atypical epithelial hyperplasia may be observed in intracanalicular fibroadenoma-like appearance. This process
juvenile fibroadenoma. may involve single lobules (lobular myxoid change), small
● Reactive stromal multinucleated giant cells may be seen. groups of lobules (nodular myxoid change), or large aggregates
of lobules (myxoid fibroadenoma). The interlobular stroma is
Differential diagnosis affected to a lesser degree. The lesions are often multicentric
● Phyllodes tumor (this is especially in cases of giant, and bilateral.
juvenile and cellular fibroadenoma. The number of mitoses Nodular mucinosis of the breast consists of an abundant
in fibroadenoma should not exceed 3 per 10 HPF) myxoid substance with scattered spindle cells without epithelial
● Sclerosing lobular hyperplasia (numerous lobules in a elements in the mucous lake. The mucinous substance stains
fibrous stroma) positively with Alcian blue.
● Fibromatosis (when it incorporates ducts and lobules;
however, it is an infiltrative lesion) Secondary features
● Virginal hypertrophy (should be distinguished from ● Cystic dilatation of the epithelial component.
juvenile fibroadenoma, it is however bilateral and diffusely ● Secretory and squamous metaplasia.
involves the breast)
Special techniques PHYLLODES TUMOR

● bcl-2 is frequently expressed in spindle cells in fibroadenomas.
CLINICAL FEATURES
MYXOID FIBROADENOMA AND Phyllodes tumor is a term preferable to cystosarcoma phyllodes
ALLIED CONDITIONS as it has no connotation of biological behavior. In the majority
of cases, this tumor is benign, though some are malignant and
may show distant metastases. Others have a biological behavior
CLINICAL FEATURES
which is intermediate between the two (borderline tumor). This
Myxoid fibroadenoma and myxomatous lesion of the breast is borderline group of tumors may recur, but rarely metastasize.
a component of a familial condition (Carney’s complex) char- Exceptionally, benign phyllodes tumor may undergo malignant
acterized by myxoma, spotty pigmentation (lentiginous pig- transformation. Phyllodes tumor is usually of a large size (aver-
mented lesions that typically occur on the face and the vermilion age 5 cm diameter), but smaller tumors may occur and the
border of the lips, and blue naevi at any site), endocrine over- lesion has rapid growth. It affects women between the ages of
activity (Cushing syndrome due to primary pigmented nodular 30 and 70 years. The lesion is sharply circumscribed, round or
adrenocortical disease), sexual precocity in boys in association bosselated, and contains slit-like or cystic spaces.
with one or more of three testicular tumors (large cell calcifying Pathologists should qualify whether the tumor is either ‘benign’,
Sertoli cell tumor, Leydig cell tumor, and adrenocortical rest ‘borderline’ or ‘malignant’ depending on the histological appear-
tumor), acromegaly or gigantism caused by a pituitary somato- ance of the lesion and the mitotic count. Several different criteria
tropin adenoma, and psammomatous melanotic schwannomas. may be applied; the following is based on Nottingham practice:
The tumor affects individuals between the ages of 6 and 64 ● benign tumor usually has less than 5 mitoses per 10 HPF,
years, and may be both multicentric and bilateral. and lacks sarcomatous foci;
172 Breast tumors
● borderline tumor shows 5–9 mitoses per 10 HPF, and

may show a fibrosarcomatous component; and
● malignant tumor usually shows more than 10 mitoses
per 10 HPF and often contains foci of other sarcomatous
elements.
Other authors such as Shousha (personal communication)

advocate the following:
● benign tumor usually has less than 2 mitoses per 10 HPF
and lacks sarcomatous foci;

● borderline tumor shows 2–5 mitoses per 10 HPF; and
● malignant tumor usually shows more than 5 mitoses per
10 HPF.
Furthermore, the presence of sarcomatous elements, pleomor-

phism, necrosis and stromal overgrowth must be taken into (a)
account. Suspicion should always be high, especially if the
specimen is not an excision biopsy and all the lesion is not
available for sampling.
Phyllodes tumors require complete excision with free mar-
gins, even when pathological features suggest benignity because
of a proclivity to local recurrence. The most important compo-
nent of therapy is wide surgical excision, and mastectomy is
necessary only when free margins cannot be achieved without
it. Involvement of axillary nodes is rare, and axillary dissection
is not indicated. The role of radiation therapy and chemother-
apy is not established, and has not been studied in randomized
trials due to the rarity of the tumor. At present, there is no con-
sensus that patients with high-grade phyllodes tumors of the
breast will benefit from either of these modalities.
After local excision, 21%, 46%, and 65% of patients with
benign, borderline, and malignant phyllodes tumors, respec-
tively, recur in the breast. Following wide local excision, 8%, (b)
29%, and 36% of patients with benign, borderline, and malig-
nant phyllodes tumors recur in the breast. Malignant phyllodes Figure 4.50 Phyllodes tumor, benign form. (a) Low-power view
tumors are much more likely than benign phyllodes tumors to showing the leaf-like architecture that typifies this lesion. (b) Higher
power view showing the biphasic nature of hyperplastic epithelium
recur in the breast after breast-conserving surgery. This high
with variable stromal cellularity.
rate of local recurrence of borderline and malignant phyllodes
tumors suggests that wide local excision is less than optimal
therapy.
Phyllodes tumor in aberrant breast tissue: aberrant breast tis- The epithelial lining of the clefts and the broad papillae
sue may occur anywhere along the embryonic milk line (from is usually hyperplastic, reminiscent of gynecomastia, but it
the base of the forelimb to the region of the hindlimb). Similar may also resemble that of normal ducts and it may show areas
to normal breast, aberrant breast tissue is subject to the same of adenosis, squamous metaplasia and lobular carcinoma
benign and malignant processes including fibroadenoma, phyl- in situ.
lodes tumor, fibrocystic disease, carcinomas and sarcomas. The A phyllodes tumor occasionally contains microcysts, and
vulva is a well-known site for diseases of aberrant breast. rarely shows a morphologically intracystic pattern.
Benign phyllodes tumor may resemble giant fibroadenoma,
but it has more cellular stroma with condensation of stromal
cells under the epithelium.
Phyllodes tumor is a well-circumscribed lesion consisting of Malignant phyllodes tumor may exhibit the following stro-
epithelial and stromal elements reminiscent of those seen in a mal features: overgrowth of the stroma in relation to the
fibroadenoma. The stroma, however, is far more cellular and epithelial component; cellular pleomorphism with significant
the epithelial clefts are more patent and may be cystically number of mitotic figures; and focal invasion of the surround-
dilated. Projecting into these spaces are broad, blunt-ended, ing breast tissue. Malignant phyllodes tumors usually show
epithelial-lined stromal papillae producing the characteristic a fibrosarcomatous or myxoliposarcomatous component. Less
leaf-like pattern of phyllodes tumor. A similar appearance often rhabdo-, chondro- or osteosarcomatous elements are
is seen in mullerian adenofibroma and also in mullerian seen; on occasion, the sarcomatous component overgrows the
adenosarcoma. epithelial element.
Secondary metastasis from extramammary malignancies 173
(a) (c)
(b) (d)
Figure 4.51 Phyllodes tumor, malignant form. (a–d) Various images showing the stromal overgrowth, pleomorphism and mitoses that
typify the malignant form. Note the collagen matrix seen in some areas.
Secondary features
SECONDARY METASTASIS FROM
● Cystic change.
● Hemorrhage. EXTRAMAMMARY MALIGNANCIES
● Necrosis.
Metastasis to the breast from extramammary malignancies
Cell morphology is rare, and usually presents as multiple or bilateral well-
● Depends on the degree of malignancy and the presence circumscribed nodules, suggesting a benign process on mam-
of heterologous sarcomatous components. mography. Accurate diagnosis by using a panel of antibodies is
● Cellular pleomorphism and increased mitotic figures are important to avoid unnecessary mastectomy and to ensure
seen in malignant tumors. appropriate therapy.
● Bizarre giant cells are sometimes seen.
METASTATIC HEMANGIOPERICYTOMA
● Giant fibroadenoma. Metastatic hemangiopericytoma of the breast has rarely been
● Juvenile fibroadenoma. reported. Hemangiopericytoma is usually a well-circumscribed,
● Fibromatosis. pseudoencapsulated spindle cell lesion with prominent vascular
component. The latter consists of numerous, dilated and com-
Special techniques pressed or slit-like, irregularly shaped vascular spaces, lined by
● Mesenchymal markers such as vimentin, actin, desmin flattened endothelial cells surrounded by predominantly oval
and myoglobin may help in identifying the sarcomatous or round cells. Some tumors – particularly the malignant ones –
component of malignant phyllodes tumor. may contain more primitive mesenchymal cells. Some metasta-
● CD34 and bcl-2 are expressed in the stromal cells. tic hemangiopericytomas have a prolonged survival.
174 Breast tumors
METASTATIC MALIGNANT MELANOMA lesion which typically presents as an incidental microscopic

finding, and very rarely as a breast mass. It can also coexist
Malignant melanoma is one of the most common neoplasms to with malignant breast processes.
metastasize to the breast parenchyma. Metastatic melanoma
may mimic almost any other poorly differentiated tumor. It PATHOLOGICAL FEATURES
may exhibit angiosarcomatous, rhabdoid, myxoid, chondroid,
osteoid or malignant biphasic patterns. It may even mimic Collagenous spherulosis of the breast is a distinctive breast his-
signet-ring cell adenocarcinoma. Immunohistochemistry may tological finding characterized by the accumulation of base-
resolve the dilemma, as S-100 protein is positive in almost all ment membrane material in the form of eosinophilic or rarely
melanocytic lesions. HMB-45 antigen and Melan-A, whilst basophilic spherules that exhibit concentric and radiating fib-
detected less frequently, is fairly specific for melanoma. Surgical rillary patterns. These are typically found within – and appear
excision is the appropriate treatment that provides local con- to originate from – the spaces of fenestrated epitheliosis (‘papil-
trol with or without adjunctive chemo- and immunotherapy. lomatosis’), and involve lobular acini and ductules. The lesion
Although mastectomy has not improved survival, it is some- is typically situated adjacent to, or is encompassed by, other
times required if the tumor is bulky, deep-seated, or painful. benign proliferative processes, including intraductal papilloma,
sclerosing adenosis, and ‘infiltrating epitheliosis’ (radial scars).
RENAL CELL CARCINOMA (Figure 4.52) Differential diagnosis

● Adenoid cystic carcinoma of the breast is an invasive
The breast is an unusual site for metastasis from renal cell car-
lesion that is almost always palpable, while collagenous
cinoma. The reported cases have been of the classic clear cell
spherulosis is almost always an incidental microscopic
type. However, sarcomatoid renal cell carcinoma can occur,
finding
and in theory could present as a metastatic breast lesion. The
● Intraductal signet ring cell carcinoma
mesenchymal component in sarcomatoid renal cell carcinoma
● Lobular carcinoma in situ with features of collagenous
may resemble malignant fibrous histiocytoma, fibrosarcoma,
spherulosis (lobular carcinoma in situ rarely forms round,
or unclassified sarcoma and thus could be indistinguishable
regular lumens similar to the cribriform spaces of ductal
from sarcomatoid carcinoma of the breast.
carcinoma in situ; these spaces seem to be due to the
presence of collagenous spherulosis)
Special techniques
● The presence of hyaline pink globules surrounded by
benign myoepithelial cells in Giemsa-stained smears is
a diagnostic feature of this entity.
● The spherules are collagen-rich, but also contain variable
amounts of acidic mucin, PAS-positive basement
membrane-like material, and elastin.
● Immunohistochemistry and electron microscopy
demonstrate the presence of two cell types: epithelial
cells and myoepithelial cells with associated basement
membrane-like material.
HAMARTOMA
Figure 4.52 Metastatic renal cell carcinoma in the breast.This
patient had widespread metastatic disease. CLINICAL FEATURES
Breast hamartoma is an under-recognized entity, best consid-
ered as representing a clinicopathological spectrum of stromal
STROMAL LESIONS proliferation in the breast, and encompassing lesions variously
termed adenolipoma, muscular hamartoma, and fibrous
hamartoma. It is probably related to pregnancy and lactation,
COLLAGENOUS SPHERULOSIS or may represent a normal physiological process. It occurs over
a broad age range (typically between 13 and 88 years), and
presents as a palpable mass or as a discrete lesion on mam-
CLINICAL FEATURES
mography. It has a disk-like or lentiform shape with a smooth,
Collagenous spherulosis is a rare benign lesion occurring in less glistening surface. The tumors varies in size from 0.6 to 9.0 cm in
than 1% of benign breast biopsies. It is either a uni- or multi-focal its greatest dimension, and may grow to a large size, producing
Stromal lesions 175
breast asymmetry. It has rarely been reported in ectopic breast

tissue present along the embryonic milk line.

Breast hamartoma is a well-circumscribed lesion, often encap-
sulated or surrounded by compressed normal breast tissue.
It is composed of two elements, epithelial and stromal. The
epithelial element consists of randomly dispersed lobular and
ductal structures that may show changes of benign cystic
disease. The stromal component consists of hyalinized fibrous
tissue exhibiting a concentric arrangement around the epithelial
structures and containing inter-anastomosing slit-like spaces
centered on lobules (pseudoangiomatous hyperplasia). There is
usually obliteration of the normal, loosely arranged interlobular
connective tissue.
Some hamartomas have other mesenchymal components, such
as mature fat cells (‘adenolipoma’) and smooth muscle cells
(‘muscular hamartoma’).
The histological appearance of some hamartomas is reminis-
cent of gynecomastia – that is, containing isolated mammary
ducts surrounded by loosely arranged collagen and separated
by fibro-fatty tissue.
Secondary features
● Cystic change and apocrine metaplasia of the glandular
structures.
● Chondroid metaplasia, hence the name ‘chondrolipoma’
or ‘choristoma’.
● Ductal hyperplasia, and malignant changes may rarely
develop within a hamartomatous tissue.
Cell morphology (a)
● The slit-like spaces are lined by flattened cells.

● Fat cells are variably present.
● Myofibroblasts may be seen.
(b)
Figure 4.54 (a, b) Adenolipoma of the breast, showing

Figure 4.53 Breast hamartoma, showing circumscribed mass of circumscribed mass of mature adipose tissue containing mature
normal breast tissue admixed with mature adipose tissue. glandular elements.
176 Breast tumors
● Foci of dense fibrosis sometimes seen in breast (usually
present as diffuse or irregular nodularity and do not
appear as a discrete mass on mammography)
● Fibroadenoma
● Pseudoangiomatous hyperplasia
● Low-grade angiosarcoma
Special techniques
● The pseudoangiomatous spaces are highlighted by strong
vimentin positivity.
● The epithelial component is strongly positivity for CK
and EMA, as well as for ER and PR.
● The stromal cells are positive for vimentin and
(a)
muscle-specific actin.
● The myoepithelial cells are highlighted by myoepithelial
markers.
LYMPHOMAS
CLINICAL FEATURES
Primary breast lymphoproliferative disorders are rare lesions,
and include both the malignant lymphomas and the benign
pseudolymphomas. Primary breast lymphoma is an aggressive
breast malignancy with a poor prognosis, despite different
treatment options. There are no laboratory or imaging signs of
early detection, and excisional biopsy or Tru-cut biopsy are the
only correct methods of diagnosis.
(b)

See Chapter 10, Lymphoreticular tumors (p. 651).
The majority of breast lymphomas are B-cell non-Hodgkin
lymphoma. Other reported variants include intravascular
lymphoma, Sezary syndrome and Burkitt’s lymphoma.
MYOFIBROBLASTIC LESIONS: INFLAMMATORY

MYOFIBROBLASTIC TUMOR
CLINICAL FEATURES
Inflammatory myofibroblastic tumor (IMT) is a distinctive
lesion of myofibroblastic origin, often admixed with inflam-
(c)
matory cells (including plasma cells and eosinophils). The
lesion has only very rarely been described in the breast.
Figure 4.55 Large B-cell non-Hodgkin lymphoma. Needle core
Before contemplating such a diagnosis, several blocks should biopsy. (a, low-power view; b, high-power view; c, CD20.)
be taken and an immunohistochemical study performed in
order to exclude the deceptively bland monomorphic sarcoma-
toid carcinoma.
● Sarcomatoid carcinoma
● Nodular fasciitis
See Chapter 13, Soft tissue tumors. ● Fibromatosis
Stromal lesions 177
MYOFIBROBLASTIC LESIONS: ● Multinucleated cells may be present.

● Mast cells are seen, especially in perivascular locations.
MYOFIBROBLASTOMA ● Cellular pleomorphism is minimal.
● Mitotic figures are uncommon (up to 2 mitoses per 10 HPF).
CLINICAL FEATURES
Myofibroblastoma of the breast is a distinctive benign lesion of
myofibroblastic origin, occurring more often in males over the age ● Spindle cell lipoma
of 40 years. The tumor presents as a firm, freely mobile, and pal- ● Neurofibroma
pable mass, seldom more than 3 cm in diameter. A rare example ● Schwannoma
of giant myofibroblastoma (10 cm) has been reported. The lesion ● Leiomyoma
is amenable to simple excision. It has been postulated that the ● Muscular (myoid) hamartoma of the breast is a rare
androgen receptor or its ligands may be pathologically related to tumor-like lesion originating from stromal cells via
the development of myofibroblastoma of the breast, and diagnos- leiomyomatous metaplastic changes. The cells express
tically useful in differentiating it from other spindle cell lesions. CD34 antigen in smooth muscle cells and focally, also
positive for smooth muscle markers (alpha-smooth muscle
PATHOLOGICAL FEATURES (Figure 4.56) actin and desmin)
● Solitary fibrous tumor
Myofibroblastoma is a well-circumscribed, pseudoencapsulated
lesion, located within the breast parenchyma or rarely under Special techniques
the nipple. It consists of a uniform population of spindle cells
● Trichrome stain highlights the collagenous bands
arranged in short fascicles interspersed with broad bands of
(blue-green) and myofibroblastic cells (eosinophilic).
hyalinized collagen (amianthoid-like) and scattered multinucle-
● The main cell population expresses myofibroblastic
ated giant cells. Breast ducts or acini are absent within the
features (vimentin, desmin and actin).
lesion, but fat lobules are frequently seen. Morphological vari-
● The cells are CD34-positive, bcl-2-positive, and
ations include atypical mono- or multi-nucleated cells, and a
CD99-positive.
varying amount of mature lipomatous tumor component.
● The cells are S-100 protein- and CK-negative.
Myofibrosarcoma is characterized by marked cellular pleo-
● The cells show strong nuclear antibody staining for the
morphism, infiltrating margins and a high mitotic rate.
androgen receptor, and often show an ER/PR immunoprofile.
MYXOMATOUS LESIONS
CLINICAL FEATURES
This is an unusual collection of lesions, often collectively referred
to a ‘myxoma’ if circumscribed, or a ‘myxomatosis’ if diffuse.
They may be associated with the Carney complex (myxomas,
spotty pigmentation, endocrine overactivity, and schwannomas).
Isolated breast lesions are rare, and have been described in
young females (aged less than 20 years) in the central breast/
subnipple region.
The tumors are dominated by a loose myxoid stroma, without
Figure 4.56 Breast myofibroblastoma. A uniform population of any secondary glandular or muscular component. They may
spindle cells arranged in short fascicles interspersed with broad resemble cardiac myxomas.
bands of hyalinized collagen (amianthoid-like) and scattered
multinucleated giant cells.
Secondary features ● Breast hamartomas
● Chondroid metaplasia (very rare).

● Lymphocytic and plasma cell infiltrates. PERIDUCTAL STROMAL SARCOMA
Cell morphology
CLINICAL FEATURES
● Myofibroblasts are slender, bipolar spindle cells with single
ovoid nuclei showing irregular nuclear contour and con- Periductal stromal sarcoma is a useful descriptive designation
taining one or two nucleoli. Nuclear grooving may be seen. for generally low-grade biphasic tumors with sarcomatous
178 Breast tumors
stroma that do not have features of a phyllodes tumor. It has

been suggested that some – and possibly all – periductal stro-
mal sarcoma may evolve into a phyllodes tumor with time.
Given the presence of infiltrative margins, excision with a rim
of uninvolved tissue is required.
Patients with periductal stromal sarcoma ranged in age from
37 to 89 years (mean 55.3 years). Typically, the tumors mea-
sured between 0.2 and 6.0 cm in diameter (mean 2.97 cm).
HISTOLOGICAL FEATURES
The histological features of periductal stromal sarcoma are:
1. A predominantly spindle cell stromal proliferation of
variable cellularity and atypia around open tubules and
ducts devoid of a phyllodes pattern.
2. One or more often multiple nodules separated by adipose
tissue.
3. Stromal mitotic activity ⬎3 per 10 HPF.
4. Stromal infiltration into surrounding breast tissue.
Criteria for periductal stromal hyperplasia are: (a)

1. Nodular, bland stroma growing as cuffs around normal
or altered ducts.
2. No to minimal atypia.
3. At most, 0–2 stromal mitotic figures per 10 HPF.
Special techniques
● The neoplastic cells of periductal stromal sarcoma are at
least focally immunoreactive for CD34.
● The cells may show CD117 positivity.
● The cells are less reactive for actin.
● The cells are negative for ER and PR.
PSEUDOANGIOMATOUS STROMAL HYPERPLASIA

OF THE BREAST
CLINICAL FEATURES
Pseudoangiomatous stromal hyperplasia (PASH) of the mam-
mary gland is a benign localized form of stromal overgrowth with
(b)
probable hormonal etiology, and consistent with myofibroblastic
histogenesis. The ‘pseudoangiomatous’ term describes a recogniz-
Figure 4.57 Pseudoangiomatous stromal hyperplasia.These images
able pattern, but does not describe the tumor’s histological show the characteristic slit-like spaces lined by non-endothelial
nature. Some authors propose the term ‘nodular myofibroblastic spindle cells.These are reminiscent of vascular channels. Note the
hyperplasia of the mammary stroma’ as being more accurate. It is dense hyalinized collagen background. (a, low power; b, high power.)
a relatively common lesion, seen in one study in 23% of 200 con-
secutive breast biopsy specimens. It is either discovered inciden-
tally in breast tissue removed for other conditions, or may present homogeneous cut surface. Histologically, the lesion shows a
as a painless, well-circumscribed mass. Rarely, the overlying skin proliferation of the collagenous stroma with varying degrees of
shows peau d’orange change reflecting verrucous epidermal density, and hyalinization with many pseudovascular slit-like
hyperplasia. The process is frequently multifocal and tends to anastomosing spaces lined by spindle cells with scant cyto-
occur in younger patients. plasm and bland chromatin.
PATHOLOGICAL FEATURES (Figure 4.57) Cell morphology

Grossly, pseudoangiomatous stromal hyperplasia consists of ● The slit-like spaces are lined by stromal fibroblasts, some
a well-circumscribed, rubbery tissue with a solid white-tan of which may show cytological atypia.
Stromal lesions 179
Differential diagnosis be distinguished from spindle cell myoepithelioma. Both tumors

● Low-grade angiosarcoma are actin-positive, but the presence of S-100 protein and focal
positivity for cytokeratin would favor a myoepithelioma.
Special techniques
Malignant fibrous histiocytoma (MFH)
● The spindle cells lining the spaces are strongly reactive for
Malignant fibrous histiocytoma of the breast often follows
vimentin, and weakly reactive for CD34, actin, and desmin.
radiotherapy. The tumor usually behaves aggressively, with a
● The cells are negative for factor VIII, S-100 protein, and
high rate of local recurrence. Thus, a radical or modified radi-
pancytokeratin.
cal mastectomy is sometimes advocated. Monophasic sarcoma-
● In more cellular fascicular lesions, the stromal cells
toid carcinoma should be ruled out before making a diagnosis
acquire desmin and actin positivity.
of primary MFH in the breast.
● Pseudoangiomatous hyperplasia shows patchy, intense
labeling of the stromal cells with PR antibodies – Fibrosarcoma
a pattern contrasting markedly with the absence of
Fibrosarcoma in general should only be diagnosed after exclud-
immunoreactivity in normal (non-gestational) mammary
ing other ‘look-alike’ benign or malignant lesions. These include
stroma or the stromal component of common juvenile
spindle cell myoepithelioma and monophasic sarcomatoid carci-
mammary hyperplasia.
noma. Fibrosarcoma may occur following radiotherapy for
breast cancer, or as a malignant transformation of phyllodes
SARCOMAS OF THE BREAST tumor. Compared to the high-grade lesions, low-grade fibrosar-
coma of the breast is a slow-growing tumor.
Primary sarcoma of the breast accounts for less than 1% of all
breast malignancies. It is essential to rule out sarcomatous
Liposarcoma
overgrowth of phyllodes tumors, sarcomatoid carcinoma, and Although liposarcoma is considered to be one of the most
secondary sarcoma before accepting a primary sarcoma of the common soft tissue sarcomas in adults, its occurrence in the
breast. breast is very rare. It may arise following radiation therapy for
breast carcinoma, or as a malignant component of phyllodes
Classification of breast sarcomas tumor. Pleomorphic liposarcoma may simulate MFH or sarco-
Periductal stromal sarcoma matoid carcinoma, and is usually associated with aggressive
behavior.
See above (p. 177).
Neurogenic sarcoma
Mammary osteogenic sarcoma
Neurogenic sarcoma is a highly malignant tumor, which rarely
Acceptance of this diagnosis requires exclusion of metastatic
occurs in the breast and may present as an isolated, painless
or primary skeletal osteosarcoma and osteosarcomatous meta-
clinically benign nodule. Histologically, it simulates fibrosar-
plasia in tumors such as sarcomatoid carcinoma, malignant
coma or may show a biphasic appearance with glandular or
adenomyoepithelioma, and phyllodes tumor. Unlike skeletal
epithelial differentiation, making the distinction between this
osteosarcoma, which occurs in children and young adults,
tumor and sarcomatoid carcinoma almost impossible on light
extraskeletal osteogenic sarcoma affects older individuals, and
microscopy alone.
in the breast has a female predominance. Most tumors arise
de novo, but may follow local irradiation and trauma. They Follicular dendritic cell tumor
present as large, circumscribed tumors and have an aggressive
Follicular dendritic cell tumor may rarely occur in the breast.
behavior with early recurrence and blood-borne metastases.
Recently, a myxoid variant which was indistinguishable from
Treatment includes mastectomy and adjuvant chemotherapy.
MFH or sarcomatoid carcinoma has been documented in the
Chondrosarcoma breast.
Primary chondrosarcoma of the breast is an extremely rare Rhabdomyosarcoma
tumor and should only be diagnosed after excluding sarcoma-
toid carcinoma. In the breast, rhabdomyoblasts are more commonly seen as a
component of sarcomatoid carcinoma rather than in primary
Angiosarcoma rhabdomyosarcoma. The latter is exceedingly rare in this site,
See Vascular lesions of the breast (p. 180). and often represents metastasis. Alveolar rhabdomyosarcoma
is the type most often reported in breast, and it is often mis-
Leiomyosarcoma interpreted as small blue cell tumor. Pleomorphic rhabdomyo-
Leiomyosarcoma of the breast is one of the rarest primary sar- sarcoma is the one that might be mistaken for sarcomatoid
comas. It is usually low grade, and should be distinguished carcinoma or MFH and, rarely, breast metastasis of this type has
from leiomyoma. Leiomyoma is particularly rare in the breast, been reported.
and usually occurs in the nipple or beneath the areola. The
presence of 2–3 mitoses per 10 HPF (⫻400) is usually indica- Dermatofibrosarcoma protuberans of breast
tive of malignancy. Smooth muscle tumors of the breast should This has rarely been reported in the breast.
180 Breast tumors
Solitary fibrous tumor of the breast VASCULAR LESIONS OF THE BREAST

See Spindle cell stromal tumors of the breast (below).
CLINICAL FEATURES
Special techniques
● In any suspected case of primary sarcoma of the breast,
Hemangiomas (perilobular hemangiomas)
sarcomatoid carcinoma must first be ruled out by A variety of hemangiomas have been described in the breast,
performing epithelial marker investigations. including cavernous, juvenile, venous, Mason’s (papillary endo-
● General and specific mesenchymal marker investigations thelial hyperplasia), epithelioid (angiolymphoid hyperplasia
should then be made to confirm the particular sarcoma. with eosinophilia) and sinusoidal. Clinical diagnosis is rather
difficult. Generally, they are coincidental microscopic findings,
SCLEROSING LYMPHOCYTIC LOBULITIS with an average size 1.8 cm (range 0.8 to 3.2 cm). Hemangiomas
usually have well-circumscribed borders, and tend to grow around
(DIABETIC MASTOPATHY) ducts and lobules – hence the term ‘perilobular hemangioma’.
The anastomosing vascular spaces in hemangioma are not as
CLINICAL FEATURES serpiginous as in angiosarcoma. Subcutaneous hemangiomas of
the breast do not differ appreciably in their clinical or patho-
Sclerosing lymphocytic lobulitis or ‘diabetic mastopathy’ is a logical features from comparable lesions at other anatomic
well-recognized breast disease, occurring in various autoimmune sites. They are benign, and are not prone to recurrence or pro-
disorders, particularly type 1 diabetes mellitus. It has also been gression to angiosarcoma; however, complete excision is usu-
reported occasionally in Hashimoto’s thyroiditis, and very rarely ally recommended to exclude the possibility of an underlying
in Graves’ disease. It may be associated with retinopathy and angiosarcoma.
neuropathy. Sclerosing lymphocytic lobulitis may be identified in
up to 70% of subjects with type 1 diabetes, and in 1.8% of those Atypical hemangioma
with autoimmune thyroid disease diagnosed with benign breast
‘Atypical’ hemangiomas are rare lesions characterized by small
disease at surgery. The pathogenesis is unknown, and the disor-
size (⬍2.0 cm), relative circumscription, broadly anastomosing
der does not seem to predispose to breast carcinoma or lym-
vascular channels, and endothelial hyperplasia. Destructive
phoma. The disease presents in young and middle-aged women
invasion, solid areas and hemorrhage or necrosis are absent.
as breast lump. It has rarely been reported in men.
The vascular patterns include cavernous, compact capillary, cap-
illary budding, and a combined cavernous and compact capillary
PATHOLOGICAL FEATURES type. The size of the lesion ranges from 0.4 to 2.0 cm (mean
On gross examination, the lesion may appear firm and fibrotic. 0.9 cm). These usually are not associated with local or systemic
Histologically, it shows dense, well-circumscribed collections of recurrences. These must be distinguished from hemangiomas
small lymphocytes distributed in and around ducts and lobules and from the atypical vascular lesions that follow radiotherapy.
and in perivascular locations. The stroma shows keloid-type The latter usually form circumscribed clusters of vascular chan-
fibrosis. Infiltrating cells are predominantly B lymphocytes. nels with endothelium that lacks mitotic activity or cytological
atypia, but may show nuclear hyperchromasia.
SPINDLE CELL STROMAL TUMORS OF Angiosarcoma

THE BREAST Angiosarcoma may rarely develop after radiotherapy for carci-
noma of the breast. The latent period between radiation expo-
Benign spindle cell stromal tumors of the breast encompass sure and the development of these tumors varies from 2 years
more than one tumor entity. The precursor cells are the to several decades.
vimentin⫹/CD34⫹ cells of the mammary stroma, which have Post-radiation angiosarcoma typically presents with unusual
the well-known inherent plasticity to differentiate toward skin changes in the form of reddish-blue discolored macules, or
several mesenchymal lines. occasionally as nodules or a mass. Rarely, the tumor is detected
Based on morphological and immunophenotypical features, at mammography. Angiosarcoma occurs almost exclusively in the
three main subtypes are recognized: female breast and often presents during the third or fourth decade
● Fibroblastic tumors include a typical solitary fibrous tumor of life. Pathologically, all angiosarcomas are evident on gross
(SFT) and a spindle-cell lipoma-like tumor. These are closely inspection with poorly defined margins and vary in size from 1.5
reminiscent of their soft tissue counterpart. Both tumors are to 12 cm. Microscopically, three grades can be identified:
immunoreactive for vimentin, CD34, bcl-2, and CD99. ● Grade I tumor consists entirely of anastomosing vascular
● Myofibroblastic tumors (myofibroblastoma): see also channels, invading the fat and glandular parenchyma, lined
Myofibroblastoma (p. 976). by hyperchromatic endothelial cells with a few mitotic
● Mixed benign spindle cell stromal tumors of the breast figures but no papillary endothelial proliferation.
show a diverse pattern, including myofibroblastoma, ● Grade II tumors are similar to those of grade I, but with
solitary fibrous tumor and pleomorphic/spindle cell microscopic foci of more solid or papillary endothelial
lipoma-like areas. proliferation.
Bibliography 181
● Grade III tumors show a predominance of solid epithelioid Post-mastectomy angiosarcoma (lymphangiosarcoma)
or sarcomatous pattern with numerous mitotic figures and Lymphangiosarcoma is an extremely rare, highly lethal compli-
necrosis or hemorrhage. This type may be mistaken for cation of chronic lymphedema. The condition usually develops
poorly differentiated carcinoma, melanoma or spindle cell after mastectomy for breast cancer followed by local irradiation.
sarcoma. It has been suggested that chronic lymphedema and lymphangi-
Immunohistochemical localization of factor VIII and the more ectasia may lead to lymphatic hyperplasia, dysplasia and
specific PECAM-1 (CD31) is useful in confirming the diagnosis. neoplasia. Histologically, the lesion is indistinguishable from
Angiosarcoma of the breast shares the general tendency of soft angiosarcoma. The majority of lesions develop about 10 years
tissue sarcomas to metastasize to the lungs and liver. Poorly or after mastectomy, but the time interval varies from a few years
moderately differentiated tumors usually have a poor prognosis. to several decades. Early recognition of the condition and early
Mastectomy without axillary dissection is the recommended biopsy and amputation influence prognosis; there may be a role
treatment. for adjuvant chemotherapy.
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5 digestive system tumors
5.1 GASTROINTESTINAL TRACT TUMORS 197

5.2 HEPATOBILIARY TRACT TUMORS 242
5.3 PANCREATIC TUMORS 267
5.1 GASTROINTESTINAL TRACT TUMORS

David K Worrall and Hassan MH Kamel
Tumors of the esophagus 199 WHO classification of esophageal tumors 206

Epithelial tumors, benign 199
Adenoma 199 Tumors of the stomach 207
Squamous cell papilloma and papillomatosis 199 Epithelial tumors, benign 207
Adenoma 207
Epithelial tumors, malignant 200 Adenomyoma 207
Adenocarcinoma 200
Adenoid cystic carcinoma 200 Epithelial tumors, malignant 207
Adenosquamous carcinoma 201 Adenocarcinoma, common variants 207
Basaloid squamous carcinoma of the upper Papillary adenocarcinoma 208
aerodigestive tract 201 Tubular adenocarcinoma 209
Choriocarcinoma 202 Mucinous adenocarcinoma 209
Melanoma 202 Signet ring cell adenocarcinoma 210
Mucoepidermoid carcinoma 202 Undifferentiated carcinoma 210
Salivary gland-type pleomorphic adenoma 202 Adenocarcinoma, rare variants: hepatoid 210
Spindle cell carcinoma 202 Adenocarcinoma, rare variants: medullary 211
Squamous cell carcinoma 203 Adenocarcinoma, rare variants: Paneth cell-rich 211
Verrucous carcinoma 204 Adenocarcinoma, rare variants: parietal cell 211
Adenosquamous carcinoma 211
Neuroendocrine tumors 204 Carcinosarcoma 212
Carcinoid tumors 204 Choriocarcinoma 212
Small cell carcinoma 204 Malignant rhabdoid tumor 212
Squamous cell carcinoma 212
Non-epithelial tumors 204 Neuroendocrine tumors 212
Gastrointestinal stromal tumor (GIST) 204 Carcinoid tumors 212
Granular cell tumor 204 Small cell carcinoma 214
Histiocytoma 205
Kaposi’s sarcoma 205 Non-epithelial tumors 214
Leiomyoma and leiomyosarcoma 205 Angiosarcoma 214
Lipoma and liposarcoma 205 Gastrointestinal autonomic nerve tumors (GANT) 214
Lymphangioma 205 Gastrointestinal stromal tumors (GIST) 214
Lymphoma 205 Glomus tumor (glomangioma) 214
Neurofibroma 205 Hemangioma/hemangioendothelioma/hemangiopericytoma 214
Rhabdomyosarcoma 205 Histiocytoma 214
Histiocytosis, Langerhans’ cell (histiocytosis X) 214
Tumor-like conditions 205 Inflammatory myofibroblastic tumor 214
AIDS-related neoplasia 205 Kaposi’s sarcoma 214
Cysts 205 Leiomyoblastoma/leiomyoma/leiomyosarcoma 215
Fibrovascular/fibrous polyps 206 Lipoma 215
Glycogenic acanthosis 206 Lymphangioma 215
Heterotopias 206 Lymphoma 215
Inflammatory fibroid polyps 206 Neurofibroma 216
198 Digestive system tumors
Paraganglioma 216 Hamartoma, Brunner’s gland 224

Rhabdomyosarcoma 216 Heterotopia: heterotopic and metaplastic gastric mucosa 224
Schwannoma 216 Heterotopia: pancreatic (myoepithelial hamartoma) 224
Smooth muscle tumors 216 Lipohyperplasia 224
Teratoma 216 Lymphoid hyperplasia 224
Myoepithelial hamartoma 225
Tumor-like conditions 216 Xanthomatosis 225
Amyloid tumor 216
Bezoars 217 Polyps and polyposis syndromes 225
Heterotopias 217 Inflammatory fibroid polyp 225
Ménétrier’s disease 217 Juvenile polyps and polyposis 225
Xanthelasma 217 Peutz–Jeghers polyps 225
Polyps 218 WHO classification of small intestine tumors 226

Cowden syndrome 218
Cronkhite–Canada syndrome 218 Tumors of the appendix 226
Familial adenomatous polyposis 218 Epithelial tumors, benign 226
Fundic gland polyps 218 Adenoma 226
Gastritis cystica polyposa 218
Hyperplastic polyps 218 Epithelial tumors, malignant 227
Inflammatory fibroid polyps 218 Adenocarcinoid tumors 227
Juvenile polyps 218 Adenocarcinoma 227
Peutz–Jeghers polyps 218
Neuroendocrine tumors 227
Carcinoid tumors 227
WHO classification of gastric tumors 218
Non-epithelial tumors 228
Tumors of the duodenum, jejunum, and ileum 219 Granular cell tumor 228
Epithelial tumors, benign 219 Kaposi’s sarcoma 228
Adenoma 219 Leiomyomas and leiomyosarcoma 228
Adenoma: Brunner’s gland 219 Lymphoma 228
Epithelial tumors, malignant 219 Tumor-like conditions 229
Adenocarcinoma 219 Heterotopias 229
Adenosquamous carcinoma 220 Mucocele 229
Choriocarcinoma 220
Melanoma 220 WHO classification of appendiceal tumors 229
Neuroendocrine tumors 220 Epithelial tumors, benign 229
Carcinoid tumors/endocrine tumors 220 Adenoma: serrated 229
Gastrinoma and gastrin cell tumors 221 Adenoma: tubular, tubulovillous and villous 229
Paraganglioma 221 Adenomatous polyposis coli 230
Small cell carcinoma 222
Epithelial tumors, malignant 230
Non-epithelial tumors 222 Carcinoma 230
Angiosarcoma 222 Hereditary non-polyposis colorectal carcinoma (HNPCC) 232
Ganglioneuroma and ganglioneuromatosis 222 Melanoma 233
Gastrointestinal stromal tumor (GIST) 222
Hemangioma 222 Neuroendocrine tumors 233
Hemangiopericytoma 222 Carcinoid tumors 233
Histiocytoma 222
Histiocytosis, Langerhans’ cell (histiocytosis X) 222 Non-epithelial tumors 234
Immunoproliferative small intestinal disease (IPSID) 222 Angiosarcoma 234
Inflammatory myofibroblastic tumor 222 Ganglioneuroma and ganglioneuromatosis 234
Kaposi’s sarcoma 223 Granular cell tumor 234
Leiomyoma and leiomyosarcoma 223 Hemangioma 234
Lipoma 223 Histiocytoma 234
Lymphangioma 223 Histiocytosis, Langerhans’ cell (histiocytosis X) 234
Lymphoma 223 Kaposi’s sarcoma 234
Neurofibroma and neurofibromatosis 223 Leiomyoma and leiomyosarcoma 234
Schwannoma (neurilemmoma) 224 Lipoma and liposarcoma 234
Lymphangioma 235
Tumor-like conditions 224 Lymphoma 235
Cysts 224 Teratoma 236
Tumor-like conditions 236 Basaloid carcinoma 239

Hamartomas 236 Buschke–Lowenstein tumor (giant condyloma) 239
Heterotopia: gastric 236 Melanoma 239
Lymphoid polyposis 236 Mucoepidermoid carcinoma 240
Malakoplakia 236 Paget’s disease, perianal 240
Mucosal prolapse 236 Squamous cell carcinoma 240
Xanthoma 236 Verrucous carcinoma 241
Polyps and polyposis syndromes 236

Cowden syndrome 236 Neuroendocrine tumors 241
Cronkhite–Canada syndrome 236 Small cell carcinoma 241
Familial adenomatous polyposis 237
Hyperplastic (metaplastic) polyps and polyposis 237
Non-epithelial tumors 241
Inflammatory fibroid polyps 237
Kaposi’s sarcoma 241
Juvenile polyps and polyposis 237
Teratoma 241
Lymphoid polyps 238
Peutz–Jeghers polyps 238
Tumor-like conditions 241
WHO classification of tumors of the colon and rectum 238 Abscess 241
Cyst hamartoma 241
Tumors of the anal canal 238 Hemorrhoids 241
Epithelial tumors 238 Malakoplakia 242
Adenocarcinoma 238
Anal intraepithelial neoplasia 239
Anal margin tumors 239 WHO classification of tumors of the anal canal 242
GENERAL COMMENTS these entities that are either unique or prevalent to the site. This
facilitates the job of the pathologist in suspecting or excluding the
Most of the spectrum of benign and malignant neoplasms that GI tract as a primary site for metastatic deposits in other organs
arise in the various parts of the gastrointestinal (GI) tract is shared of the body. On the other hand, metastatic deposits in the GI tract
with those arising in other organs. Squamous carcinomas, neuro- can be a diagnostic challenge dependent on the nature of the
endocrine carcinomas, carcinoids, lymphomas and mesenchymal primary neoplasms and the familiarity with its morphological
neoplasms are obvious examples that share the same morpholog- pattern.
ical patterns, regardless of where they arise. In a way, this makes Tumor-like conditions can also be a diagnostic challenge,
the majority of tumors arising in the GI tract easily recognizable particularly if not suspected or if they represent an entity that
and unlikely to represent a diagnostic challenge in the day-to-day is not frequently encountered or unfamiliar to the pathologist.
practice of surgical pathology. With regard to ‘polyps’ and ade- In this chapter, various entities have been described to various
nocarcinomas, the GI tract presents morphological patterns for lengths according to their frequency.
TUMORS OF THE ESOPHAGUS
EPITHELIAL TUMORS, BENIGN SQUAMOUS CELL PAPILLOMA AND

PAPILLOMATOSIS
ADENOMA
CLINICAL FEATURES
Adenomas of the esophagus are rare. The histological features
are identical to those of gastric adenomas. Most are polypoid Squamous cell papilloma is a benign, often asymptomatic lesion.
tumors arising in the setting of dysplasia within Barrett’s They are typically small (⬍1.5 cm diameter), sessile, and single.
esophagus. The distal third of the esophagus is most commonly affected,
although the lesions may occur at any level. Where multiple and an improved outlook. Spread of esophageal adeno-
papillomas are present, a proportion of cases will be associated carcinoma is usually via local invasion and metastasis to local
with Goltz syndrome (focal dermal hypoplasia). Giant papillomas lymph nodes. Distant metastatic spread generally occurs late in
have also been described. Some cases of squamous papilloma the natural history of these tumors.
appear to be related to prolonged irritation or human papillo-
mavirus (HPV) infection. TNM STAGING OF ESOPHAGEAL ADENOCARCINOMA
(The TNM classification includes adenocarcinomas of the gastro-
esophageal junction primarily located on the esophageal side.)
As the name of the lesion would suggest, squamous papillomas T Stage:
have obvious papillary architecture, with hyperplastic squamous Tis Carcinoma in situ
epithelium lining cores of fibrovascular connective tissue. T1 Invasion of the lamina propria or submucosa
T2 Invasion of muscularis propria
Cell morphology
T3 Invasion of adventitia
● The squamous epithelium shows normal maturation. T4 Invasion of adjacent structures
● Changes associated with HPV such as koilocytosis and
N Stage:
multinucleation may be seen.
N0 No regional lymph node involvement
Differential diagnosis N1 Regional lymph node involvement
● Well-differentiated (verrucous) squamous carcinoma. M Stage:
M0 No distant metastasis
Lower thoracic esophagus
EPITHELIAL TUMORS, MALIGNANT M1a Metastasis to celiac lymph nodes
M1b Other distant metastases
ADENOCARCINOMA Upper thoracic esophagus
M1a Metastasis to cervical lymph nodes
M1b Other distant metastases
CLINICAL FEATURES
Mid thoracic esophagus
Adenocarcinoma of the esophagus is an increasingly common M1a Not applicable
tumor. The incidence rate has risen sharply in the last few M1b Non regional lymph nodes or other distant metastasis
decades, and continues to do so by an estimated 5–10% per year.
In parts of Europe and the USA, the number of new cases of PATHOLOGICAL FEATURES (Figure 5.1)
esophageal adenocarcinoma now matches or even exceeds those
Well-differentiated adenocarcinomas usually show papillary or
of squamous cell carcinoma. In other parts of the world, where
tubular patterns, or a mixture of the two. Tumors comprising
the incidence of esophageal adenocarcinoma is much lower, the
more than 50% mucin are classified as mucinous adenocarcino-
trend is nevertheless upwards.
mas. Occasionally, esophageal adenocarcinomas may show a dif-
The most important risk factor for the development of ade-
fuse pattern similar to that seen in the stomach; signet ring cells
nocarcinoma is Barrett’s esophagus – intestinal metaplasia
may sometimes be seen in these tumors. In addition to the nor-
occurring in the distal esophagus. Barrett’s esophagus usually
mal glandular structures, some adenocarcinomas may show foci
occurs in the setting of chronic gastro-esophageal reflux disease.
of endocrine, Paneth cell or squamous differentiation. Glandular
Exposure to gastric and/or duodenal contents promotes cellular
structures are poorly formed or absent in less well-differentiated
proliferation, and may also directly cause DNA damage. Other
or undifferentiated tumors. Barrett’s mucosa (often showing high-
known risk factors include smoking and obesity, whilst alcohol
grade dysplasia) may be seen adjacent to the invasive tumor.
and Helicobacter pylori infection are not thought to play an
important role. A small number of cases occur in the mid or Differential diagnosis
proximal esophagus, in which case the tumor is thought to arise
from heterotopic columnar mucosa present from birth. Diagnostic problems usually occur only in the setting of small
The mean age at diagnosis of esophageal adenocarcinoma is biopsies.
● Reactive hyperplasia and atypia
65 years. There is a striking male predominance (by a ratio of
● Dysplasia in Barrett’s mucosa
7 to 1), and the incidence rates in whites are higher than those
in blacks (in contrast to squamous cell carcinoma). Genetic sus-
ceptibility factors may in part explain these disparities. The ADENOID CYSTIC CARCINOMA
presenting symptoms are usually dysphagia and weight loss,
but these are often late symptoms and the tumor is frequently Adenoid cystic carcinoma, which is similar in morphology to its
at an advanced stage when diagnosed. The prognosis is corre- counterpart in salivary glands, is a very rare tumor arising from
spondingly very poor in these cases. Endoscopic surveillance esophageal submucosal glands. The tumors are generally small,
of Barrett’s esophagus, including biopsies to assess dysplasia confined to the esophageal wall, and covered by normal squa-
within such segments, may result in earlier detection of tumors mous epithelium. The prognosis of ‘classical’ tumors is relatively
squamous cell carcinoma. The histogenesis of this tumor is

uncertain, but it may be the product of bidirectional differentia-
tion in a pre-existing carcinoma. Most reported cases have been
in the distal esophagus and associated with Barrett’s esophagus.
BASALOID SQUAMOUS CARCINOMA OF THE

UPPER AERODIGESTIVE TRACT
CLINICAL FEATURES
This is a rare but distinctive tumor with a grave prognosis.
Basaloid squamous carcinoma is much more aggressive than
adenoid cystic carcinoma – a tumor with which it shares some
architectural similarity. The tumor occurs most commonly in
elderly males and usually presents at an advanced stage. Basaloid
carcinoma of similar histology is also seen in the lung (basal cell
or basaloid carcinoma of the lung) and in the anal canal (some-
times referred to as cloacogenic carcinoma).
(a)
Basaloid carcinoma of the upper aerodigestive tract shows a
mixed epithelial pattern in which a basaloid component with
architectural features similar to adenoid cystic carcinoma is
intimately associated with a neoplastic squamous component,
which can be either invasive or in situ. The basaloid component
is in the form of invasive lobules with frequent comedo-necrosis,
solid sheets, trabeculae and festoons. The squamous component
may be keratinizing or non-keratinizing. Occasionally, true glan-
dular spaces and spindle cell areas are seen. There is often focal
continuity of the tumor with the overlying surface epithelium.
The background stroma exhibits prominent hyalinization, which
extends between and replaces tumor cells. The tumor lacks the
neurotropism of adenoid cystic carcinoma.
Secondary features
● Necrosis
● Hyalinization
● Focal inflammatory infiltrate
(b) Cell morphology

Figure 5.1 (a, b) Adenocarcinoma arising at the gastro-esophageal ● The basaloid cells possess round to oval nuclei with a
junction. dusty chromatin pattern and small, indistinct nucleoli.
The cytoplasm is scant, but may be abundant and clear.
good. Many cases of so-called ‘adenoid cystic’ carcinoma that
● Mitotic figures are frequent.
have been published in the literature are probably best regarded
● Nuclear pleomorphism may be seen.
as squamous or undifferentiated carcinoma with focal adenoid
cystic-like differentiation. There may be necrosis associated with Differential diagnosis
such foci. In contrast to the salivary gland-type tumors, these ● Adenoid cystic carcinoma
carcinomas are highly aggressive, widely metastatic, and have a ● Small cell undifferentiated carcinoma
prognosis similar to squamous cell carcinoma. ● Superficial esophageal carcinoma with basaloid features
ADENOSQUAMOUS CARCINOMA Special techniques

● Immunoreactivity for cytokeratin is remarkably absent in
Adenosquamous carcinoma is a rare and aggressive tumor the basaloid component, while it is strongly positive in the
composed of an admixture of invasive adenocarcinoma and squamous component.
● Carcinoembryonic antigen (CEA) highlights the glandular metastatic, and have a prognosis similar to that of squamous
spaces. cell carcinoma.
● Some tumors are vimentin-positive.
● S-100 protein is negative. SALIVARY GLAND-TYPE PLEOMORPHIC
ADENOMA
CHORIOCARCINOMA
Pleomorphic adenoma of the esophagus, similar to that seen in
Cases of pure esophageal choriocarcinoma and choriocarci- salivary glands, is extremely rare. The tumor arises from sub-
noma arising within an esophageal adenocarcinoma have been mucosal mucous glands.
documented. The pure form is exceedingly rare.
SPINDLE CELL CARCINOMA

MELANOMA
CLINICAL FEATURES
CLINICAL FEATURES
Spindle cell carcinoma is the name used by the current WHO
Primary malignant melanoma of the esophagus is well-recognized, classification for a tumor also known in the literature as
but uncommon. Affected individuals are usually middle-aged or carcinosarcoma, polypoid carcinoma or pseudosarcoma. This
elderly, and present with dysphagia. There is some geographical uncommon tumor comprises a mixture of typical in situ or
variation in incidence, with higher rates reported in Japan, parti- invasive carcinoma, usually squamous cell carcinoma, and a
cularly in women. The prognosis is poor. spindle-cell sarcomatous component. The histogenesis of the
tumor is uncertain; however, the spindle-cell component may
PATHOLOGICAL FEATURES show immunohistochemical or ultrastructural evidence of
epithelial differentiation – a finding which suggests focal
The mid or lower esophagus is the most common site for primary
mesenchymal metaplasia within an otherwise typical squamous
melanoma. Tumors are usually intraluminal, polypoidal, and
cell carcinoma.
non-pigmented; satellite lesions may also be seen. Histologically,
The tumor most commonly occurs in middle-aged or elderly
primary esophageal melanoma shows a very similar range of
males, and presents with dysphagia and weight loss. The prog-
growth patterns and cell types to those seen in cutaneous
nosis may be slightly better than that of typical squamous cell
melanoma. The adjacent mucosa may show atypical prolifera-
carcinoma, although this is not a universal finding in all pub-
tion of melanocytes; it is from these areas that the tumor is
lished studies.
thought to arise. Pagetoid infiltration of the epithelium by
melanocytes is sometimes seen. Unlike cutaneous melanoma,
where measurement of the Breslow thickness is an important PATHOLOGICAL FEATURES
prognostic indicator, the depth of esophageal melanoma does Most spindle cell carcinomas arise in the mid or distal esopha-
not seem to be related to prognosis. gus. They are typically large, polypoid tumors attached to the
esophageal wall via a narrow stalk. The epithelial component
Differential diagnosis is usually squamous in type, but may occasionally show focal
● Poorly differentiated carcinoma and sarcoma glandular features. Sarcomatous areas consist of collagenous or
myxoid stroma containing spindle cells arranged either in a
Special techniques haphazard fashion or in interlacing bundles. The spindle cell
component may be highly mitotic.
● The melanoma cells are immunoreactive for S-100 protein
and HMB-45.
Secondary features
● The spindle cells may show maturation, leading to the
MUCOEPIDERMOID CARCINOMA
formation of neoplastic bone, cartilage or striated muscle.
● Bizarre giant cells are often present within the sarcomatous
Mucoepidermoid carcinoma, similar in morphology to its
areas.
counterpart in salivary glands, is a very rare tumor arising from
esophageal submucosal glands. The tumors are generally small,
confined to the esophageal wall, and covered by normal squa-
mous epithelium. The prognosis of ‘classical’ tumors is rela- Diagnostic problems may arise in small biopsies or due to inad-
tively good. Many cases of so-called ‘mucoepidermoid’ equate sampling of resected tumors.
● Polypoid leiomyosarcoma
carcinoma reported in the literature are probably best regarded
● Granulation tissue adjacent to an esophageal ulcer
as squamous or undifferentiated carcinoma with focal
mucoepidermoid-like differentiation. Such foci may show ker-
atinization – a finding not usually observed in salivary gland Special techniques
mucoepidermoid carcinoma. In contrast to the salivary gland- ● Immunoreactivity for keratin supports the diagnosis of
type tumors, these carcinomas are highly aggressive, widely spindle cell carcinoma.
SQUAMOUS CELL CARCINOMA
CLINICAL FEATURES
Squamous cell carcinoma (SCC) is the most common malignancy
of the esophagus in most parts of the world. In some European
countries and the USA, the number of new cases of SCC per year
may now be fewer than those of adenocarcinoma, due to the
rapid rise in incidence of the latter. There is a striking geograph-
ical variation in the incidence of SCC, with very high rates in
Iran, China, South Africa, and South Brazil. The most important
risk factors in Western countries are smoking and heavy alcohol
consumption. In other countries, nutritional deficiencies, dietary
carcinogens (such as nitrosamines) and the consumption of very
hot beverages are thought to be more important. Most of these
risk factors lead to chronic esophagitis which may be asympto-
matic. The DNA of HPV can be detected in up to 40% of cases
in parts of China, although the relevance of this finding is
unclear. Other reported associations with esophageal squamous
carcinoma are Paterson–Kelly (Plummer–Vinson) syndrome, (a)
achalasia, celiac disease and tylosis.
The median age at presentation is around 65 years. There is
a male predominance, although the male to female ratio shows
significant geographical variation. Presenting symptoms are
most commonly dysphagia, weight loss and anemia. Most
squamous carcinomas are widely invasive at the time of diag-
nosis, and the prognosis is very poor. In some cases – parti-
cularly where screening is undertaken – the tumor may be
confined to the mucosa or submucosa (‘early’ or ‘superficial’
esophageal carcinoma) and prognosis is significantly better.
Verrucous carcinoma is an uncommon, very well-differentiated
variant of esophageal SCC which grows slowly and seldom
metastasizes. It may cause considerable diagnostic problems as
the degree of atypia may be minimal; patients not infrequently
die from the tumor because of failure to diagnose malignancy
before extensive local spread has occurred.
STAGING OF ESOPHAGEAL SCC

The TNM staging of esophageal squamous carcinoma is iden-
tical to that for adenocarcinoma (see Adenocarcinoma, p. 200).
(b)
PATHOLOGICAL FEATURES (Figure 5.2) Figure 5.2 (a, b) Squamous cell carcinoma of the esophagus.
The histological appearances of esophageal squamous carcinoma
are broadly similar to those of SCCs occurring elsewhere in the Verrucous carcinoma is characterized by broad papillae rem-
body. They show a range of appearances, from well-differentiated iniscent of a viral wart. The squamous epithelium is well dif-
tumors which show extensive keratinization and characteristic ferentiated and keratinizing, with minimal cytological atypia.
intercellular bridges, to poorly differentiated tumors in which The tumor has a broad, pushing margin composed of blunt
the squamous origin of the tumor is not immediately apparent. epithelial projections.
Some tumors may show a mixture of well-differentiated and
moderate to poorly differentiated areas. There may be small foci Secondary features
showing glandular differentiation or areas with small cell carci- ● Tumor necrosis and lymphovascular invasion indicate
noma morphology. aggressive behavior.
Local invasion takes the form of two distinct growth pat- ● Significant stromal desmoplasia is a favorable prognostic
terns: expansive or infiltrative. In tumors showing expansive indicator.
growth, the tumor margin is well demarcated and the cells at ● Extensive lymphocytic infiltration is also a favorable
the margin are arranged in cohesive groups. Infiltrative growth indicator, but may make assessment of invasive depth
implies an irregular margin with tumor cell dissociation. difficult.
Differential diagnosis vary from less than 1% to almost 8% of esophageal carcinomas.

Diagnostic problems usually occur only in the setting of small In addition to symptoms of dysphagia and weight loss, a minor-
biopsies. ity of tumors cause paraneoplastic phenomena due to secretion of
● Reactive/regenerative hyperplasia and atypia adjacent to hormones such as antidiuretic hormone (ADH), adrenocortico-
an esophageal ulcer. tropic hormone (ACTH), calcitonin or vasoactive intestinal poly-
● Radiation-induced atypia. peptide (VIP). The peak incidence occurs in the sixth to seventh
● The problems associated with verrucous carcinoma have decades of life, and there is a male predominance of 2 to 1. The
been discussed above. tumor is usually well advanced at presentation, and survival aver-
ages less than 6 months from the time of diagnosis.
VERRUCOUS CARCINOMA PATHOLOGICAL FEATURES

See Squamous cell carcinoma (p. 203). Small cell carcinoma of the esophagus is histologically identical
to its counterparts in the lung and elsewhere.
NEUROENDOCRINE TUMORS Special techniques

● Tumor cells are argyrophilic using the Grimelius technique.
CARCINOID TUMORS ● Immunohistochemistry reveals positivity for NSE,
synaptophysin, chromogranin and Leu-7.
● Occasionally, there may be positivity for hormonal
CLINICAL FEATURES products such as ACTH or calcitonin.
The esophagus is a very uncommon site for the development of ● Electron microscopy reveals small dense-core granules.
gastrointestinal endocrine tumors. These tumors range from
well-differentiated carcinoids to poorly differentiated small cell
carcinoma (see below, Small cell carcinoma). Esophageal carci- ● Primary small cell carcinoma of lung invading the esophagus
noids account for less than 0.1% of all gastrointestinal carci- ● Poorly differentiated SCC
noid tumors. Analysis of the small numbers of reported cases ● Basaloid squamous carcinoma
reveals an average age at presentation of around 60 years, with ● Lymphoma
a male predominance of 6 to 1. Presenting symptoms include
dysphagia, weight loss, and chest pain.
NON-EPITHELIAL TUMORS
Most reported esophageal carcinoids have been located in the
GASTROINTESTINAL STROMAL TUMOR (GIST)
submucosa of the distal esophagus. They are typically large
(1 to 12 cm), and show extensive infiltration of the esophageal
wall. Metastatic spread is not uncommon. The typical histo-
logical appearance is that of solid nests of cells. Cytological GRANULAR CELL TUMOR
atypia, high mitotic activity and focal necrosis have all been
reported in esophageal carcinoids.
CLINICAL FEATURES
Special techniques Granular cell tumors are uncommon in the gastrointestinal tract
● Tumor cells show positive staining with the Grimelius as a whole, but occur most frequently in the esophagus. They
technique. are usually asymptomatic but can occasionally, where large,
● The cells are immunoreactive for neuron-specific enolase produce a degree of stenosis and hence dysphagia. Macroscop-
(NSE) and chromogranin. ically, the tumor appears as a 1- to 2 cm-diameter, firm, circum-
● Electron microscopy reveals characteristic membrane- scribed, submucosal nodule with a pale yellow color. Granular
bound neurosecretory granules. cell tumors usually occur in the distal third of the esophagus, and
are only rarely multiple. The lesion is benign in nature.
The histological features are identical to those of granular cell
CLINICAL FEATURES
tumors found elsewhere in the body, consisting of circum-
Primary small cell carcinoma of the esophagus represents the scribed nodules of tumor cells.
most poorly differentiated end of the spectrum of esophageal neu-
roendocrine tumors. It is a highly aggressive tumor, identical both Secondary features
histologically and immunohistochemically to small cell carcinoma ● There may be pseudoepitheliomatous hyperplasia of the
of the lung. Small cell carcinoma is rare; estimates of its frequency overlying squamous mucosa.
Cell morphology obstruction. Microscopically, these tumors are identical to their

● The cells are large, with voluminous cytoplasm containing counterparts elsewhere in the body.
eosinophilic granules.
LYMPHANGIOMA
Special techniques
● The granular cytoplasm is periodic acid–Schiff (PAS) Lymphangiomas, identical to their counterparts elsewhere in
stain-positive, and immunoreactive for S-100 protein. the body, are very rare in the esophagus.
HISTIOCYTOMA LYMPHOMA
Primary malignant fibrous histiocytoma (MFH) of the esopha-

CLINICAL FEATURES
gus is a rare tumor. The pathological features are identical to
those occurring in other sites. Primary lymphoma of the esophagus is extremely rare. Less
than 1% of lymphomas affecting the gastrointestinal tract
involve the esophagus, and most of these cases represent sec-
KAPOSI’S SARCOMA
ondary spread from either the mediastinum or stomach. The
rare primary tumors arising in the esophagus are usually of
Primary Kaposi’s sarcoma of the esophagus is a rare tumor. It is
large B-cell-type or low-grade extranodal marginal zone lym-
particularly associated with immunodeficiency and HIV infection,
phomas (MALT lymphomas). Primary T-cell lymphoma and
although esophageal lesions have been documented in ‘Mediter-
Hodgkin’s lymphoma have also been described in the literature.
ranean’ Kaposi’s sarcoma (which is not HIV-related). The patho-
logical features are identical to those occurring in other sites.
LEIOMYOMA AND LEIOMYOSARCOMA See Chapter 10, Lymphoreticular tumors.
NEUROFIBROMA
CLINICAL FEATURES
Smooth muscle tumors of the esophagus are uncommon, and Benign neurofibromas, typical of those found at other sites, are
very few cases of leiomyosarcoma have been reported in the exceedingly rare in the esophagus.
literature. These tumors are most commonly asymptomatic, but
may present with dysphagia, heartburn or bleeding. The peak RHABDOMYOSARCOMA
incidence is in middle age, with an apparent male predominance.
Multiple tumors occur only rarely, and a proportion of these A small number of cases of primary esophageal rhabdomyo-
cases are associated with diffuse leiomyomatosis, a rare condi- sarcoma have been documented, generally occurring in older
tion of unknown etiology resulting in abnormalities in the entire patients and arising in the distal esophagus. The histology and
esophageal musculature. Prognosis is generally good, except in immunohistochemical findings are the same as those of rhab-
rare cases showing diffuse local spread at the time of diagnosis. domyosarcomas occurring at other sites.
TUMOR-LIKE CONDITIONS
The histological features are similar to those of smooth muscle
tumors found elsewhere in the body. Larger lesions (⬎5 cm)
with necrosis or hemorrhage and a raised mitotic rate (⬎5 per
AIDS-RELATED NEOPLASIA
10 HPF) are more likely to be malignant in nature.
HIV infection is associated with a range of pathologies within
Differential diagnosis the gastrointestinal tract, particularly infections – often by
organisms which would be unlikely to cause problems in
Leiomyoma immunocompetent individuals. Severe esophageal candidiasis
● Nerve sheath tumor
is relatively common in AIDS. Neoplastic complications arising
Leiomyosarcoma in the esophagus are uncommon, but the development of
● Spindle cell carcinoma Kaposi’s sarcoma is well documented.
● Amelanotic melanoma
● Gastrointestinal stromal tumor

CYSTS
LIPOMA AND LIPOSARCOMA

CLINICAL FEATURES
Lipomas and liposarcomas are decidedly rare in the esoph- Esophageal cysts may occasionally mimic neoplastic lesions,
agus. The most common presenting symptoms are related to both radiographically and endoscopically. There are a variety of
types encountered. Congenital cysts may be simple, unilocular INFLAMMATORY FIBROID POLYPS
inclusion cysts or more complex developmental cysts such as
duplication, bronchogenic or neurenteric cysts. Acquired cysts
(retention cysts) are caused by dilatation of the excretory ducts CLINICAL FEATURES
of submucosal glands following an inflammatory process. Inflammatory fibroid polyps are benign lesions arising
most commonly in the mid and distal esophagus. Their etiology –
PATHOLOGICAL FEATURES inflammatory or neoplastic – is the subject of some con-
troversy. Common presenting symptoms are dysphagia and
The lining of congenital and acquired cysts varies with the nature
hemorrhage.
of the cyst. Inclusion cysts are lined by columnar, ciliated or
squamous epithelium; the lining is usually smooth, but may
sometimes show papillary infoldings. Duplication, bronchogenic
and neurenteric cysts are lined by esophageal, bronchial and Inflammatory fibroid polyps consist of edematous granulation
gastric mucosa, respectively. These cysts usually possess an tissue containing a mixed inflammatory cell and fibroblastic
underlying muscularis propria. Acquired cysts have a cuboidal or infiltrate. Blood vessels are typically prominent. Unlike fibrovas-
squamous lining. cular polyps, these lesions may involve the full thickness of the
esophageal wall, occasionally mimicking an infiltrative growth
pattern.
FIBROVASCULAR/FIBROUS POLYPS
CLINICAL FEATURES WHO CLASSIFICATION OF ESOPHAGEAL

Fibrovascular polyps arising in the esophagus may represent a
TUMORS
response to chronic irritation; alternatively, some may be
hamartomatous in nature. They may occur at any level of the The WHO classification of tumors of the esophagus contains
esophagus, but the upper third appears to be most frequently the following entities:
affected. The presenting symptom is usually dysphagia, as these Epithelial tumors
polyps may reach a considerable size. Squamous cell papilloma
Intraepithelial neoplasia
● Squamous
PATHOLOGICAL FEATURES ● Glandular (adenoma)
Fibrovascular polyps are usually solitary lesions with a long Carcinoma

stalk. They are composed of acanthotic or ulcerated squamous ● Squamous cell carcinoma
epithelium surrounding a core of edematous fibrovascular tis- ● Verrucous (squamous) carcinoma
sue containing variable amounts of fat. ● Basaloid SCC
● Spindle cell (squamous) carcinoma
● Adenocarcinoma
GLYCOGENIC ACANTHOSIS
● Adenosquamous carcinoma
● Mucoepidermoid carcinoma
Glycogenic acanthosis is an asymptomatic lesion which is
● Adenoid cystic carcinoma
detected endoscopically but has no known malignant potential.
● Small cell carcinoma
Multiple small, raised, white plaques are seen on the esophageal
● Undifferentiated
mucosa, particularly in the distal third. Microscopically, these
● Others
plaques show thickening of the superficial epithelium by
enlarged vacuolated cells containing abundant glycogen. Basal Carcinoid tumor
cell hyperplasia is not usually seen, and atypia is absent. Patients Non-epithelial tumors
with Cowden syndrome (see p. 236) may show widespread Leiomyoma
glycogenic acanthosis. Lipoma
Granular cell tumor
HETEROTOPIAS GIST
● Benign
● Uncertain malignant potential

Heterotopic elements in the esophagus may occasionally mimic
● Malignant
tumors endoscopically. Patches of heterotopic gastric mucosa
measuring up to 4 cm in diameter are not uncommonly found Leiomyosarcoma
in the post-cricoid region of the esophagus. These are usually Rhabdomyosarcoma
asymptomatic; however, adenocarcinoma arising in the gastric Kaposi’s sarcoma
mucosa has been described. Other heterotopic elements in the Malignant melanoma
esophagus, such as pancreatic tissue and sebaceous glands, are Others
uncommon. Secondary tumors
TUMORS OF THE STOMACH
ADENOMYOMA
EPITHELIAL TUMORS, BENIGN
ADENOMA CLINICAL FEATURES

Adenomyomas are benign, non-neoplastic lesions occurring in the
uterus, gallbladder, stomach, duodenum, jejunum and ileum, or
CLINICAL FEATURES
within a Meckel’s diverticulum. They present as small tumor-like
Adenomas in the stomach, like those more typically found in the nodules or plaques on the wall of the affected organ. The lesions
large bowel, are benign neoplasms with the potential to become may occur at any age, including in infancy. Rare examples of
invasive. The risk of transformation to adenocarcinoma increases adenocarcinoma developing in a pyloric adenomyoma have been
with the size of the adenoma and the grade of dysplasia. Flat ade- reported. Upper GI tract lesions are thought to be hamartomatous,
nomas, as opposed to the more common pedunculated lesions, possibly representing a form of ectopic pancreatic tissue.
are also more prone to progression. Most adenomas occur in the
antrum, generally in the setting of chronic atrophic gastritis PATHOLOGICAL FEATURES
and intestinal metaplasia. They are usually large (3–4 cm) and
Adenomyomas consist of tubular, cystically dilated or irregularly
solitary.
shaped benign glandular structures situated within a background
The incidence of gastric adenomas increases with age. They
of fibrous and smooth muscle stroma. Adenomyomas of the
may sometimes occur in patients with familial polyposis (FAP).
stomach may contain Brunner’s glands or heterotopic pancreas.
Most are asymptomatic, although the larger tumors may ulcer-
ate and bleed. Gastric outflow obstruction may occasionally
occur. Cell morphology
The epithelial component of these lesions depends upon their
PATHOLOGICAL FEATURES anatomical site.
● The epithelial component may consist of mucin-secreting
Gastric adenomas arising from intestinally metaplastic epithe- columnar, cuboidal or flattened epithelium and Brunner’s
lium are almost identical to the adenomatous polyps seen in the glands.
large bowel. Like their colonic counterparts, such tumors can be ● The stromal component consists of fibroblasts and normal
subclassified on the basis of architecture into tubular, tubulovil- smooth muscle cells arranged in whorls or fascicles.
lous, and villous adenomas. The assessment of dysplasia is
based on the same criteria used in colonic polyps. Differential diagnosis
A smaller number of gastric adenomas comprise foveolar or
● Adenomyomatous hyperplasia of the papilla of Vater
pyloric gland epithelium; intestinal-type epithelium may also
● Other polyps, e.g. hyperplastic (regenerative) polyps,
be present within the same lesion.
adenomatous polyps
● Well-differentiated adenocarcinoma
Cell morphology
● Adenomas arising from an area of intestinal metaplasia
may contain a mixture of cells showing intestinal
EPITHELIAL TUMORS, MALIGNANT
absorptive cell, goblet cell, endocrine cell or Paneth cell
differentiation.
● Very occasionally, Paneth cells may predominate (‘Paneth ADENOCARCINOMA, COMMON VARIANTS
cell adenoma’).
CLINICAL FEATURES
Gastric carcinoma is a common malignancy worldwide, although
● Hyperplastic polyps
there is a striking geographical variation in incidence rates, with
● Fundic gland polyps
particularly high rates in East Asia and parts of South America.
● Hamartomatous polyps
Multiple etiological factors are implicated, including diet,
● Heterotopias
Helicobacter pylori gastritis, biliary gastritis, smoking, alcohol
● Ménétrier’s disease
consumption, Epstein–Barr virus (EBV) infection and genetic
● Invasive adenocarcinoma
susceptibility. Incidence rates rise progressively with age; children
and adolescents are very seldom affected. There is a male predomi-
Special techniques nance, and the male to female ratio tends to increase with age.
● Mucin histochemistry is useful to distinguish between The signs and symptoms of gastric carcinoma often only occur
intestinal and gastric epithelium. late in the course of the disease, contributing to a poor prognosis.
These can include dyspepsia, anorexia, weight loss, early satiety,

abdominal pain, hematemesis, and anemia. Depending on the
site and extent of the tumor, the esophageal inlet or pyloric out-
let may become obstructed. Where endoscopic surveillance is
performed – for example, in patients known to have Barrett’s
esophagus – early tumors can be detected whilst the patient is
still asymptomatic.
The Laurén classification divides gastric adenocarcinoma into
intestinal, diffuse, mixed, and indeterminate types. The etiology,
natural history and epidemiology of these types appear to differ.
Intestinal types occur more frequently in older patients, particu-
larly male patients. Environmental factors are commonly impli-
cated, and are likely to be the major reason for the worldwide
variation in incidence. Dissemination via blood-borne spread,
often to the liver, is typical of intestinal-type gastric adeno-
carcinoma. In contrast, diffuse types tend to occur in younger
patients, particularly females, and spread via peritoneal dissemi-
nation. The linitis plastica or ‘leather-bottle stomach’ appearance
is a result of diffuse infiltration by carcinoma cells. In diffuse
tumors, genetic factors seem to play a more important role.
(a)
The value of the Laurén classification as a prognostic indicator
is debated; some authors suggest that diffuse types have a poorer
prognosis, whereas other studies have shown no difference.
Gastric carcinoma arises from a pre-existing area of intra-
epithelial neoplasia. Dysplasia may arise in the native gastric
mucosa, or in the setting of chronic gastritis and intestinal meta-
plasia. About 10% of gastric polyps are adenomatous in nature
(see section above); dysplasia and carcinoma may arise in an
adenoma – analogous to the adenoma–carcinoma sequence in the
large bowel. Carcinomas arising from intestinally metaplastic
epithelium are usually of the intestinal type. Diffuse types often
arise in the absence of intestinal metaplasia.
TNM STAGING OF GASTRIC ADENOCARCINOMA

(The TNM classification includes adenocarcinomas of the gastro-
esophageal junction primarily located on the gastric side.)
T Stage:
Tis Carcinoma in situ
T1 Invasion of the lamina propria or submucosa (‘early gastric
cancer’)
T2 Invasion of muscularis propria or subserosa (b)
T3 Penetration of serosa without invasion of adjacent structures
T4 Invasion of adjacent structures Figure 5.3 Gastric adenocarcinomas. (a) Tubular architecture;
(b) Papillary architecture.
N Stage:
N0 No regional lymph node involvement
A variety of different stromal patterns may be observed in associa-
N1 Metastasis in 1–6 regional lymph nodes
tion with gastric adenocarcinoma. These include: (1) desmoplasia,
N2 Metastasis in 7–15 regional lymph nodes
often seen with tubular carcinomas; (2) lymphocytic infiltration,
N3 Metastasis in more than 15 regional lymph nodes
a feature which may be associated with an improved prognosis;
(3) stromal eosinophilia; and (4) sarcoid-like granulomas.
The WHO classification recognizes five principal patterns of gas- Papillary adenocarcinoma
tric adenocarcinoma: papillary; tubular; mucinous; signet ring cell; Papillary tumors are well-differentiated neoplasms in which the
and undifferentiated. There is frequently a mixture of different tumor cells are arranged in macropapillary processes containing
patterns within the same tumor – in which case the tumor is clas- a central fibrovascular core. These lesions are generally exo-
sified according to the predominant type. Hepatoid and medullary phytic in their growth pattern, with a well-defined invasive
adenocarcinoma, both rare tumors, are discussed separately. border. Very occasionally there may be a micro- rather than
(c) (e)
(d) (f)
Figure 5.3 (c) High-power view of an adenocarcinoma showing a largely papillary architecture. (d) Hepatoid variant of gastric
adenocarcinoma. (e) Diffuse-type adenocarcinoma composed of signet ring cells within large amounts of extracellular mucin. (f) Typical signet
ring cells.
macro-papillary architecture. A mixture of papillary and tubular acinar structures. The tubules vary in size and may show
elements is sometimes seen, in which case the term papillotubu- prominent cystic dilatation.
lar may be applied. The fibrovascular cores may contain a mixed
inflammatory cell infiltrate. Mucinous adenocarcinoma
As the name suggests, mucinous adenocarcinomas contain
Tubular adenocarcinoma prominent extracellular lakes of mucin (over 50% of the tumor
Tubular adenocarcinomas range from well to poorly differenti- by definition). The carcinoma cells may be arranged as clusters or
ated neoplasms. Poorly differentiated tumors may be com- chains floating within these mucin lakes, or as mucin-secreting
posed of solid sheets of tumor cells, in which case the term glands separate from the interstitial mucin. Signet ring cells
solid carcinoma may be used. More well-differentiated neo- may be observed, but should not constitute a major component
plasms comprise branching tubules sometimes admixed with of the tumor.
Signet ring cell adenocarcinoma ● Lymphoma showing signet-ring cell morphology

Signet ring cell carcinomas comprise single cells or small groups of
● GISTs showing signet-ring cell morphology
cells showing a diffusely infiltrative pattern. Occasionally, tumor
● Metastatic lobular breast carcinoma
cells may also form delicate trabecular or solid arrangements. N.B. Gastric carcinoma can also be estrogen receptor-positive.
Undifferentiated carcinoma
Special techniques
Undifferentiated carcinomas comprise pleomorphic cells show-
ing no discernible pattern to allow subclassification. As a result,
● Tumor cells usually produce mucin which stains with PAS,
they are included in the indeterminate group of the Laurén mucicarmine, or Alcian blue.
classification.
● The mucin in signet ring cells is acidic, staining with
Alcian blue at pH 2.5.
Cell morphology ● Immunohistochemistry for CEA and CA19-9
(carbohydrate antigen 19-9) is usually positive.
Papillary adenocarcinoma
● The tumor cells are cylindrical or cuboidal in shape with
basally located nuclei. ADENOCARCINOMA, RARE VARIANTS: HEPATOID

● In some cases there may be severe nuclear atypia and loss
of cell polarity.
● The mitotic rate is variable. CLINICAL FEATURES
Tubular adenocarcinoma This is a rare type of gastric carcinoma showing a varying
● The tumor cells are columnar or cuboidal in shape. degree of hepatocellular differentiation. It is associated with
● Mucin within the tubules and/or acini may compress the raised serum ␣-fetoprotein (AFP) levels. The tumor occurs pre-
surrounding tumor cells. dominantly in middle-aged or elderly people, and most com-
● In some cases the tumor cells may show clear cell change. monly arises in the gastric antrum. Metastasis to the liver is a
● Cytological atypia is highly variable, but may be severe. frequent occurrence, and the prognosis is poor.
● Oncocytic variants of tubular carcinoma have been
described. PATHOLOGICAL FEATURES

Mucinous adenocarcinoma Hepatoid carcinoma of the stomach is an adenocarcinoma in
● The tumor cells are of columnar, mucin-secreting type. which the tumor cells exhibit varying degrees of differentiation
● Signet ring cells (see below) may be observed.
toward hepatocytes. A well-differentiated tumor consists of
Signet ring cell adenocarcinoma polygonal cells with eosinophilic or clear cytoplasm arranged in
● Classical ‘signet ring’ cells contain large, clear trabeculae or large nests. Less well-differentiated tumors show
intracytoplasmic mucous vacuoles which push the nucleus cellular pleomorphism and bizarre giant cell formation. Focally,
up against the cell membrane. the tumor may show loss of cellular cohesion, with the con-
stituent cells exhibiting rhabdoid features (densely eosinophilic
A variety of other cell types may also be admixed with the
cytoplasm with eccentrically located nucleus). Occasionally, the
more classical signet ring cells:
cells show spindle cell morphology. Invasion of tumor cells into
● Histiocyte-like cells with centrally placed nuclei.
small or medium-sized veins is not uncommonly seen. Adjacent
● Strongly eosinophilic cells containing small cytoplasmic
gastric mucosa often shows intestinal metaplasia and intra-
granules of neutral mucin.
mucosal tubular or papillary adenocarcinoma.
● Small cells containing no mucin.
● Anaplastic cells with or without mucin.

SECONDARY FEATURES
Differential diagnosis ● Central coagulation necrosis of large tumor nests
Gastric intraepithelial neoplasia/carcinoma in situ ● Cystic change
● Reactive and regenerative atypia secondary to active
inflammation Vascular pattern

● Chemical gastritis secondary to bile reflux/drugs/other ● Numerous capillary vessels are seen within the tumor stroma
chemicals
● Radiotherapy or chemotherapy changes Cell morphology
Invasive adenocarcinoma ● Well-differentiated tumor cells are large and polygonal,
Problems of misinterpretation are largely confined to small with abundant eosinophilic cytoplasm reminiscent of
gastric biopsies. hepatocellular carcinoma cells. They have centrally located
● Severe reactive atypia in peptic ulceration hyperchromatic nuclei.
● Radiotherapy changes ● Bile secretion may be seen.
● Muciphages within the lamina propria ● Less well-differentiated tumors show cellular
● Xanthomas pleomorphism and bizarre giant cell formation.
● Clear cell change due to cytoplasmic glycogen may be seen. Special techniques
● The adenocarcinomatous foci are lined by intestinal cells ● Immunohistochemistry for cytokeratin may be required to
with eosinophilic or clear cytoplasm and hyperchromatic demonstrate the epithelial component.
eccentrically located nuclei. ● Lymphoid markers usually reveal a predominance of
● PAS-positive hyaline globules are constantly seen. T cells within the infiltrate.
ADENOCARCINOMA, RARE VARIANTS:
● Metastatic hepatocellular carcinoma
● Metastatic malignant melanoma
PANETH CELL-RICH
● Rhabdoid tumor
A small number of otherwise typical gastric adenocarcinomas
● Germ cell tumor
contain significant numbers of Paneth cells which may also be
seen in lymph node metastases. Immunohistochemistry for
Special techniques
lysozyme is positive in the Paneth cell component. Paneth cell
● The tumor cells in hepatoid foci are AFP, alpha-1 adenoma and dysplasia are also reported in the literature.
antitrypsin (AAT), ACT (alpha-1-antichymotrypsin), ALB
(albumin), PALB (prealbumin), and TF (transferrin)-
positive.
ADENOCARCINOMA, RARE VARIANTS:
● The cells in the adenocarcinomatous foci often PARIETAL CELL
demonstrate CEA positivity, and may contain some of the
above proteins.
CLINICAL FEATURES
● The hyaline globules are PAS-positive after diastase and
AFP-positive. Very few cases of parietal cell adenocarcinoma have been
described in the literature. Those reported have almost all been
in male patients, and have been associated with a generally good
ADENOCARCINOMA, RARE VARIANTS: prognosis, despite an invasive growth pattern. Long-term sur-
MEDULLARY vival even with lymph node metastasis is documented.
CLINICAL FEATURES
Parietal cell carcinomas tend to grow externally to the gastric
Gastric medullary adenocarcinoma, also known as gastric carci- mucosa.
noma with lymphoid stroma, is an uncommon variety of adeno-
carcinoma. The WHO classification incorporates medullary Cell morphology
adenocarcinoma into the category of tubular adenocarcinoma
● Tumor cells are round or polygonal with abundant
(see above), as the tumor cells show (albeit often inconspicuous)
granular, eosinophilic cytoplasm.
tubular differentiation. It is suggested by some authors that
medullary carcinoma has a better prognosis than the more
common varieties of gastric carcinoma. Interestingly, in a high
proportion of cases, Epstein–Barr Virus (EBV) can be demon- ● Leiomyoblastoma
strated within the tumor cells. ● Lymphoma
Special techniques
● Tumor cells are usually immunoreactive for vimentin.
Medullary carcinomas show an expansile growth pattern, with ● The cytoplasmic eosinophilia is due to the presence of
well-defined pushing margins. The tumor consists of cells
large numbers of mitochondria, detectable by electron
arranged in solid nests and tubules within a dense stromal infil-
microscopy, Luxol fast blue, and phosphotungstic acid-
trate of polyclonal lymphocytes and plasma cells. This infiltrate
hematoxylin (PTAH) preparations.
may almost completely obscure the carcinoma cells, thus pos-
ing a significant diagnostic problem. Germinal centers may be
present. Stromal desmoplasia, often seen in conventional tubu- ADENOSQUAMOUS CARCINOMA
lar adenocarcinomas, is absent.
Adenosquamous carcinoma describes an uncommon gastric
Cell morphology tumor comprising both adenocarcinoma and squamous cell car-
cinoma, thought to arise as a result of bidirectional differentia-
● Tumor cells are generally large, with eosinophilic cytoplasm. tion in a tumor of glandular origin. The antrum is the most
commonly reported site of origin. Where there is a clear delin-
Differential diagnosis eation between the two components, a collision tumor should
● Lymphoma be considered as an alternative to adenosquamous carcinoma.
In addition, some adenocarcinomas may contain foci of squa- MALIGNANT RHABDOID TUMOR
mous metaplasia – these are referred to as ‘adenocarcinoma
with squamous differentiation’ or adenoacanthomas.
CLINICAL FEATURES
Malignant rhabdoid tumor of the stomach, also known as
CARCINOSARCOMA
vimentin-positive gastric carcinoma with rhabdoid features, is
an extremely uncommon variant of gastric carcinoma with a
CLINICAL FEATURES very poor prognosis, even when apparently superficial.
Gastric carcinosarcoma is a rare tumor in which neoplastic

glandular elements are present together with sarcomatoid areas.
Cases reported in the literature, most of which originate from The poorly cohesive tumor cells are usually arranged in solid
Japan, indicate that the tumor tends to arise in younger patients sheets and/or an alveolar growth pattern. In some cases, this may
rather than conventional gastric adenocarcinoma. There is also be found in combination with conventional gastric carcinoma.
a male predominance. Carcinosarcomas generally behave in an
aggressive fashion, and the prognosis is usually poor. Cell morphology
● Tumor cells are polygonal in shape and exhibit significant
PATHOLOGICAL FEATURES pleomorphism.
● The cytoplasm is abundant, deeply eosinophilic, and
Gastric carcinosarcomas are usually polypoidal in appearance,
usually contains large paranuclear hyaline inclusions.
most commonly arising from the pylorus. The tumor is com-
posed of an admixture of adenocarcinoma cells, often arranged
Special techniques
as tubules and solid sheets similar to conventional tubular carci-
noma, and sarcomatoid areas. The spindle-cell component most ● The cytoplasmic inclusions are strongly positive for vimentin.
commonly shows leiomyosarcomatous, rhabdomyosarcomatous ● There may also be immunoreactivity for cytokeratin
or chondrosarcomatous differentiation. A neuroendocrine (small and NSE.
cell) component has also been described in some cases. It is sug- ● CEA immunoreactivity is absent.
gested that the sarcomatous areas arise from transformed carci-
noma cells, as epithelial cell markers may also be expressed by SQUAMOUS CELL CARCINOMA
the spindle-cell component.

● Spindle-cell areas show vimentin positivity. Primary squamous cell carcinoma is very uncommon in the
● Lineage-specific markers such as smooth muscle actin stomach. The pathogenesis of these tumors is uncertain, but they
(SMA) and desmin may be negative. may arise from a pre-existing area of squamous metaplasia.
Careful examination of the tumor is required to exclude the pres-
ence of foci of adenocarcinoma. Squamous carcinoma in the
CHORIOCARCINOMA proximal stomach usually represents spread from an esophageal
primary tumor.
CLINICAL FEATURES
Gastric choriocarcinoma is a rare, highly aggressive tumor
The features of gastric squamous cell carcinoma are similar
derived from a population of cells of the gastric gland neck
to those arising elsewhere. Keratinization and the presence of
which are immunoreactive for human chorionic gonadotropin
intracellular bridging are pre-requisites for confident diagnosis.
(hCG). The tumor is widely invasive, and has a correspond-
ingly poor prognosis. In some cases, the level of serum hCG is
elevated and this can be used as a marker to monitor response
to therapy.
NEUROENDOCRINE TUMORS
PATHOLOGICAL FEATURES CARCINOID TUMORS

Most gastric choriocarcinomas contain a mixture of typical
choriocarcinoma (see Chapter 7, Female genital tract) and adeno- CLINICAL FEATURES
carcinoma of variable differentiation. A few cases have also
Endocrine tumors of the stomach range from well-differentiated
shown embryonal carcinoma or yolk sac elements.
carcinoid tumors to the poorly differentiated and highly aggres-
sive small cell carcinoma (see Small cell carcinoma below).
Special techniques Gastric carcinoids usually arise from oxyntic mucosa in the body
● The trophoblastic cells are positive for hCG. or fundus of the stomach, and are generally well-differentiated
and non-functioning. Most carcinoids in the stomach are of may be marked crowding. Mitotic figures, with occasional
enterochromaffin-like (ECL) type. A small number of tumors atypical forms, are easily identified. In some tumors there may
(around 1%) are of the G-cell type and secrete gastrin, while also be small foci of necrosis.
EC-cell (serotonin-producing) carcinoids are very rare. The devel-
opment of ECL carcinoids appears to be closely related to hyper- EC-cell carcinoid
gastrinemia, resulting either from hypersecretion of gastrin by a The histological features of EC-cell carcinoids are discussed in
duodenal or pancreatic gastrinoma, or from the physiological the sections on ileal and appendiceal carcinoids, where they
response of antral G cells to achlorhydria. The ECL carcinoids comprise the majority of such tumors.
are split into three groups based on their postulated etiology.
Type I tumors (⬃75% of cases) arise in the setting of autoim- G-cell (gastrin cell) carcinoid
mune chronic atrophic gastritis; type II (⬃5% of cases) are asso- Gastrin cell carcinoids of the stomach most frequently com-
ciated with multiple endocrine neoplasia type 1 (MEN-1) and prise uniform cells arranged in thin, gyriform trabeculae or
Zollinger–Ellison syndrome; and type III (⬃15% of cases) are solid nests.
sporadic tumors not associated with hypergastrinemia or
autoimmune gastritis. Cell morphology
The stomach was previously said to be the location of less
ECL-cell carcinoid (types I and II):
than 5% of all gastrointestinal carcinoids, although more recent
● Most of these tumors comprise uniform, polygonal or
studies suggest that it is actually a relatively common location.
cuboidal cells with abundant, faintly eosinophilic or
Incidence rates are highest in areas such as Japan, where there
occasionally clear cytoplasm.
is a high incidence of chronic atrophic gastritis. The mean age
● The nuclei are regular, round or oval in shape, and have a
at presentation of type I ECL carcinoids is 63 years, although
stippled chromatin pattern. Nucleoli are usually
there is a wide age range. Females are affected more commonly
inconspicuous or absent.
than men (by a ratio of 2.5 to 1). Type II ECL carcinoids have
● Nuclear pleomorphism is minimal, and mitotic figures are
a younger mean age of presentation (around 50 years) and an
usually very infrequent.
equal sex distribution. Type III ECL carcinoids show a male pre-
dominance (by a ratio of 2–3 to 1) and a mean age at presenta- ECL-cell carcinoid (type III):
tion of 55 years. Type III tumors are usually solitary, unlike type ● Tumor cells may be round, polyhedral or spindle-shaped.
I and II tumors where over 50% of cases are multiple. ● The nuclei may be relatively large and vesicular with
Despite the well-differentiated nature of most ECL-cell carci- prominent eosinophilic nucleoli, or small and
noids, their clinical behavior remains variable and often diffi- hyperchromatic with a clumped chromatin pattern and
cult to predict. Some tumors behave in a benign fashion, whilst small nucleoli.
others are highly mitotic and metastasize widely. A greater pro-
G-cell carcinoid:
portion of the sporadic (type III) tumors behave in a malignant
● Typical gastrin cell carcinoids are composed of uniform
fashion. Other factors predicting aggressive behavior are inva-
cells with scant cytoplasm and regular nuclei.
sion of the muscularis propria, size ⬎1 cm, vascular invasion,
and a high mitotic rate. Functioning tumors are also more
likely to show a malignant phenotype than non-functioning Special techniques
tumors. ● ECL-cell tumors show immunoreactivity for chromogranin
A, NSE, synaptophysin, Leu-7 and protein gene peptide
PATHOLOGICAL FEATURES (PGP) 9.5.
● CEA positivity is also frequently demonstrated.
ECL-cell carcinoid (types I and II) ● ECL-cells are strongly argyrophilic using the Grimelius
The tumor cells in most type I and II ECL-cell carcinoids are or Sevier–Munger techniques. They should not normally
arranged in a mixture of small nests, trabeculae and microlob- show reactivity with argentaffin or diazonium tests for
ular patterns. The spacing of the cells is often highly uniform, serotonin.
and there may be a regular alignment of the cells. In some ● Most ECL-cells do not show immunoreactivity for
tumors the cells may also form tubules, rosettes or acinar struc- hormonal products, although a few tumors can contain
tures. Vascular invasion is seen infrequently and mitoses are small populations of cells secreting peptides such as
sparse. Perineural invasion can be seen occasionally; the signi- serotonin, gastrin and somatostatin. Rare tumors may
ficance of this finding is uncertain. The tumor stroma generally secrete histamine or serotonin, potentially resulting in the
comprises loose connective tissue. atypical carcinoid syndrome.
● Vesicular monoamine transporter type 2 (VMAT-2) is a
ECL-cell carcinoid (type III) specific marker for ECL-cell carcinoids.
The sporadic form of ECL-cell carcinoid tumor is usually more ● EC-cells are strongly argyrophilic and argentaffinic. They
aggressive than types I and II, and exhibits more pronounced are immunoreactive for chromogranin and serotonin.
architectural and cytological atypia. The tumor cells are ● G-cells are immunoreactive for gastrin.
arranged in solid aggregates and large trabeculae. Cell spacing ● Electron microscopy is useful for identifying ECL-cells,
is much less regular than in type I and II carcinoids, and there EC-cells and G-cells based on their cytoplasmic granules.
SMALL CELL CARCINOMA Cell morphology

● Glomus cells are round or polygonal with scant, lightly
eosinophilic or clear cytoplasm.
CLINICAL FEATURES
● The nuclei are regular, round or oval-shaped, with a
Primary small cell carcinoma of the stomach represents the most granular chromatin pattern and inconspicuous nucleoli.
poorly differentiated end of the spectrum of gastric endocrine
cell tumors. Like its counterpart in the lung, small cell carcinoma Differential diagnosis
arising in the stomach has a poor prognosis. It is an uncommon ● Epithelioid stromal tumors
tumor, accounting for less than 1% of gastric carcinomas over- ● Hemangiopericytoma
all, and 6% of gastric endocrine tumors. The tumor is most ● Carcinoid tumors
common in the 5th to 7th decades of life, with a mean age of 63 ● Lymphoma
and a male predominance.
Special techniques
PATHOLOGICAL FEATURES ● Tumor cells are immunoreactive for SMA, vimentin,
calponin, laminin, and type IV collagen.
The morphological features and immunohistochemical profile
● Desmin, CD34, CD117 (C-KIT), chromogranin,
of gastric small cell carcinomas are the same as those arising in
synaptophysin, S-100 protein and AE1/AE3 are usually
the lung and esophagus.
negative.
● Electron microscopy reveals features suggesting smooth
NON-EPITHELIAL TUMORS muscle differentiation.
HEMANGIOMA/HEMANGIOENDOTHELIOMA/
ANGIOSARCOMA
HEMANGIOPERICYTOMA
Primary angiosarcoma of the stomach is exceedingly rare. The
pathological features are similar to those found elsewhere in Vascular tumors of the stomach are rare, malignant varieties being
the body. exceedingly so (see Angiosarcoma above). Most hemangiomas of
the stomach are of the cavernous variety and appear identical to
those found at other sites. Hemangioendotheliomas and heman-
GASTROINTESTINAL AUTONOMIC NERVE giopericytomas have also been documented in the literature. The
TUMORS (GANT) behavior of hemangioendotheliomas is categorized as ‘border-
line’, whilst gastric hemangiopericytomas appear to behave some-
See Chapter 13, Soft tissue tumors (p. 1064). what less aggressively than their counterparts elsewhere.
GASTROINTESTINAL STROMAL TUMORS (GIST) HISTIOCYTOMA
See Chapter 13, Soft tissue tumors (p. 1064). A few cases of benign and malignant fibrous histiocytomas
arising in the stomach are documented in the literature. They
GLOMUS TUMOR (GLOMANGIOMA) are extremely rare tumors.
HISTIOCYTOSIS, LANGERHANS’ CELL

CLINICAL FEATURES
(HISTIOCYTOSIS X)
The stomach is the second most common site for the develop-
ment of glomangiomas (after peripheral soft tissue). Most glo- Langerhans’ cell histiocytosis (histiocytosis X) occasionally
mangiomas of the stomach arise in the antrum. Compared to affects the stomach, either in the form of a localized lesion or
those occurring in the skin, gastric glomangiomas tend to be in association with systemic disease.
slightly larger. The presenting feature may be that of hemor-
rhage as the tumors not uncommonly ulcerate and bleed. INFLAMMATORY MYOFIBROBLASTIC TUMOR
Glomangiomas in the stomach are usually solitary, although
multiple lesions have been described. All of the cases reported See Tumors of the duodenum; jejunum, and ileum (p. 222).
in the literature to date have been benign.
KAPOSI’S SARCOMA
The histology of gastric glomangioma is similar to that seen in Primary Kaposi’s sarcoma of the stomach is a relatively rare
the skin and other sites. The tumor is composed of a mixture tumor. It is particularly associated with immunodeficiency and
of solid areas and areas showing mucoid-hyalin differentiation, HIV infection, although gastric and esophageal lesions have been
associated with slightly dilated pericytoma-like vessels. documented in ‘Mediterranean’ Kaposi’s sarcoma (which is not
HIV-related). The pathological features are identical to those

occurring in other sites. Occasionally, gastric Kaposi’s sarcoma
may present radiographically with a ‘linitis plastica’ appearance
similar to that seen in diffuse-type adenocarcinomas.
LEIOMYOBLASTOMA/LEIOMYOMA/
LEIOMYOSARCOMA
See Smooth muscle tumors (p. 216).
LIPOMA
Lipomas are encountered much less frequently in the stomach

than in the colon. They are identical histologically to lipomas
occurring at other sites. The literature also contains a few case
reports of gastric angiolipomas and liposarcomas.
LYMPHANGIOMA
(a)
Gastric lymphangiomas are extremely uncommon, even more
so than hemangiomas. The features are identical to lymphan-
giomas occurring elsewhere.
LYMPHOMA
CLINICAL FEATURES (Figure 5.4)

Primary lymphoma of the stomach, defined as any lymphoma in
which the main bulk of the disease is located within the stom-
ach, is a relatively common tumor. The various subtypes of
lymphoma which involve the stomach make up approximately
10% of all malignant gastric tumors. In Western countries, the
stomach is the most common site of gastrointestinal lymphoma,
whereas in Middle Eastern countries the small intestine is more
frequently involved. Most gastric lymphomas are of B-cell type,
predominantly extranodal marginal zone lymphomas (MALT
lymphomas) and mantle cell lymphoma. Primary T-cell lym-
phomas and Hodgkin lymphomas are rare. In the context of
HIV-associated immunodeficiency, large B-cell and Burkitt or
Burkitt-like lymphoma are the most commonly encountered (b)
types. The pathological features of gastric lymphomas are simi-
lar to their counterparts occurring in nodal and extranodal sites Figure 5.4 (a, b) Extranodal marginal zone lymphoma of mucosa-
associated lymphoid tissue (MALT lymphoma) arising in the
elsewhere; these are discussed in detail in Chapter 10. stomach.These tumors are strongly associated with Helicobacter
pylori infection.The classical feature of such lymphomas is the
Extranodal marginal zone lymphoma (MALT lymphoma) presence of lymphocytes infiltrating and destroying the gastric
In Western countries, MALT lymphomas comprise the majority glands (lymphoepithelial lesions).
of gastric lymphomas. These lymphomas tend to occur in
middle-aged or elderly adults and present either with symptoms conditions in which a lymphoma may develop. The develop-
of peptic ulcer disease or a long history of vague, non-specific ment of low-grade MALT lymphoma appears to be indirectly
symptoms. There is no significant difference in the incidence driven by the bacteria via a T-cell-mediated proliferative
rates in men and women. response. The particular genotype of the H. pylori bacterium
The evidence linking gastric MALT lymphomas to Helicobacter involved may have some influence on the risk of progression to
pylori infection is very strong. Nearly all such tumors arise on a lymphoma. Approximately 65–85% of all low-grade MALT
background of H. pylori-associated chronic gastritis. H. pylori lymphomas regress with H. pylori eradication therapy, with the
infection greatly increases the population of lymphocytes and best responses occurring in superficial tumors. High-grade MALT
plasma cells present in the lamina propria, thus creating the initial lymphomas – identified by the appearance of a population of
transformed B-cell blasts amongst the more typical low-grade SCHWANNOMA

tumor – do not respond to eradication therapy. The prognosis
in cases unresponsive to H. pylori eradication is dependent pri- Gastric schwannomas, identical histologically to their counter-
marily on tumor stage and grade. parts arising elsewhere in the body, are benign neurogenic
Mantle cell lymphoma tumors. They usually arise from nerve sheaths in Auerbach’s
plexus or, less commonly, Meissner’s plexus. The tumors are
Most cases of gastric mantle cell lymphoma arise in the setting usually solitary, submucosal and encapsulated, and may be rel-
of lymphomatous polyposis, manifested as multiple polyps atively large in size. The overlying mucosa may show ulceration.
along the gastrointestinal tract. In the stomach, involvement of
the mucosa and submucosa by mantle cell lymphoma may cause Differential diagnosis
thickening of the rugae, producing a cerebriform pattern seen at ● Other benign stromal tumors, particularly leiomyomas
endoscopy. The prognosis of gastric mantle cell lymphoma is
poor. Very occasionally, lymphomas other than mantle cell lym- Special techniques
phoma may present with lymphomatous polyposis. ● The tumor cells are positive for S-100 protein, NSE and
Other low-grade B-cell lymphomas glial fibrillary acidic protein (GFAP).
Other low-grade B-cell lymphomas such as follicle center cell

lymphoma are extremely uncommon in the stomach.
SMOOTH MUSCLE TUMORS
Diffuse large B-cell lymphoma
CLINICAL FEATURES
Diffuse large B-cell lymphoma is uncommon in the stomach.
Histologically, there is extensive effacement of the gastric Changes in terminology now mean that most tumors previously
glands by large cells typical of those seen in large B-cell lym- described as leiomyoma, leiomyoblastoma or leiomyosarcoma
phomas occurring elsewhere in the body. should now be reclassified as gastrointestinal stromal tumors
(GIST; see section in Chapter 13, Soft tissue tumors, p. 1064).
Burkitt lymphoma
True gastric leiomyomas and leiomyosarcomas, as defined by
Primary gastric Burkitt lymphoma is rare, but may be seen in current criteria, are rare neoplasms; epidemiological and clini-
the setting of HIV-related immunodeficiency. cal data are somewhat lacking. Leiomyosarcomas tend to be
T-cell lymphomas high-grade malignant tumors.
Gastric T-cell lymphomas are rare, except in areas where

HTLV-1 infection is endemic, such as Japan and eastern Asia.
In these areas, around 5–7% of gastric lymphomas may be of Leiomyomas and leiomyosarcomas should show definite histo-
T-cell type, and most of these are likely to be associated with logical and immunohistochemical evidence of smooth muscle
adult T-cell lymphoma/leukemia (ATLL). differentiation to be classified as such.
Hodgkin lymphoma Special techniques

Primary Hodgkin lymphoma of the stomach is decidedly rare; sec- ● Tumor cells are positive for SMA and desmin.
ondary involvement by a nodal primary is a more likely scenario. ● Immunoreactivity for CD34 and CD117 (C-KIT) is, by
definition, absent.
NEUROFIBROMA
TERATOMA
Gastric neurofibromas, occurring either as solitary lesions or in
association with neurofibromatosis (Von Recklinghausen’s dis-
ease), are extremely uncommon tumors. The histological and CLINICAL FEATURES
immunohistochemical features are the same as neurofibromas Gastric teratomas are rare tumors, occurring in children under
occurring elsewhere in the body. 1 year of age. Nearly all reported cases have been in boys, and
have been benign in nature. The greater curvature is the most
PARAGANGLIOMA commonly reported site of occurrence. As with teratomas
occurring elsewhere, these lesions may contain a wide range of
Only a few cases of gastric non-chromaffin paragangliomas tissue types including epithelial, neural, connective tissue and
(chemodectomas) have been reported in the literature. bony elements. Prognosis following excision is excellent.
RHABDOMYOSARCOMA
Rhabdomyomas and rhabdomyosarcomas are extremely rare in
the stomach. Occasional cases of embryonal rhabdomyosarcoma AMYLOID TUMOR
have been reported. The features of gastric striated muscle
tumors do not differ from their counterparts arising elsewhere Gastric amyloid ‘tumor’ is an uncommon lesion which may
in the body. mimic carcinoma, both radiographically and endoscopically.
Amyloid deposition in the gastric wall may be primary or asso-

ciated with systemic amyloidosis. Several cases are reported in
combination with gastric lymphoma. The amyloid appears as
homogeneous, eosinophilic material on hematoxylin and eosin
(H&E)-stained sections, and shows characteristic red-green
birefringence with the Congo red stain.
BEZOARS
Bezoars are foreign bodies composed of ingested material which

arise as the result of impaired gastric motility or abnormal gas-
tric anatomy. Most bezoars are either phytobezoars (composed
of vegetable fibers) or trichobezoars (composed of hair). They
may simulate a mass lesion radiographically.
HETEROTOPIAS
A variety of heterotopic elements may be found in the stomach,

posing a diagnostic problem for the endoscopist. Heterotopic
pancreatic tissue is the most common congenital type, most fre-
quently presenting as a mass in the gastric antrum or pylorus. Figure 5.5 Ménétrier’s disease. A section of the gastric rugal fold
The pathological processes seen in the pancreas, such as pan- showing thickened mucosa with foveolar hyperplasia and cystic
dilatation of deep gastric glands.
creatitis, abscesses, cysts and exocrine or endocrine tumors,
may also occur in heterotopic pancreatic tissue. Brunner’s
gland heterotopia, sometimes forming polypoid adenoma-like
structures, is a less frequently encountered type. Differential diagnosis
● Hyperplastic polyp
MÉNÉTRIER’S DISEASE
XANTHELASMA (Figure 5.6)
CLINICAL FEATURES
Gastric xanthomas consist of aggregates of lipid-laden
Ménétrier’s disease, also known as hyperplastic, hypertrophic or macrophages within the lamina propria. The lesions are impor-
giant rugal gastropathy, is a rare condition resulting in hyper- tant only because the macrophages may be occasionally mistaken
trophy of the rugal folds in the body or fundus of the stomach.
This tends to produce a distinctive cerebriform or polypoidal
appearance which is visible at endoscopy – these features may
occasionally be mistaken for carcinoma or lymphoma. The etiol-
ogy of this condition is uncertain, but various reports have sug-
gested that H. pylori or cytomegalovirus (CMV) infection may
be involved. Most affected individuals are middle-aged,
although the condition has also been documented in children.
There is a definite male predominance. The risk of development
of gastric carcinoma may be increased in Ménétrier’s disease,
although this link remains to be demonstrated convincingly.

The most prominent feature of Ménétrier’s disease is that of
marked foveolar hyperplasia. The gastric mucosa is thickened,
elongated and shows complex folding of the foveolar surface.
Underlying glands frequently show cystic dilatation and a reduc-
tion in the normal proportion of parietal and chief cells. The foveo-
lar segments contain large numbers of mucus-secreting cells;
these cells may also be found in the underlying glands. There is
marked edema of the lamina propria, although inflammation is
not usually a significant feature. Smooth muscle spurring, sim-
ilar to that often seen in chemical gastritis, may also be seen in Figure 5.6 Gastric xanthoma. Lipid-laden histiocytes in the lamina
some cases. propria.
for carcinoma cells (similar to those seen in signet ring cell HYPERPLASTIC POLYPS
carcinomas) in small gastric biopsies.
CLINICAL FEATURES
POLYPS Gastric hyperplastic polyps

Hyperplastic polyps of the stomach are the most common
gastric polyps, accounting for approximately 50–90% of cases.
COWDEN SYNDROME They are usually less than 1 cm in diameter, may be sessile or
pedunculated, and are often multiple. Rare examples of giant
See Colon and rectum: Polyps and polyposis syndromes:
hyperplastic polyp of the stomach – up to 17 cm in maximum
Cowden syndrome (p. 236).
dimension – have been reported. Very occasionally, adenocar-
cinoma may arise in a hyperplastic polyp of the stomach.
CRONKHITE–CANADA SYNDROME Focal foveolar hyperplasia
This may represent the earliest stages of hyperplastic polyp for-
See Colon and rectum: Polyps and polyposis syndromes:
mation in the stomach.
Cronkhite–Canada syndrome (p. 236).
FAMILIAL ADENOMATOUS POLYPOSIS Histologically, gastric hyperplastic polyps consist of elongated,
tortuous, and often cystically dilated crypts lined by foveolar-
See Colon and rectum: Polyps and polyposis syndromes: Familial type epithelium. The deeper glandular component is of pyloric
adenomatous polyposis (p. 237). or, less commonly, fundic-type epithelium. The stroma is usually
prominent, and is characterized by edema, inflammation, focal
fibrosis and scattered smooth muscle bundles derived from the
FUNDIC GLAND POLYPS muscularis mucosa. Some polyps show characteristic ‘onion
skin’ infolding of the central papillary surface epithelium. The
CLINICAL FEATURES adjacent gastric mucosa often shows chronic atrophic gastritis.
Fundic gland polyps of the stomach may occur singly or, more
often, multiply. The term sporadic fundic gland polyposis (SFGP)
INFLAMMATORY FIBROID POLYPS
is used in cases where multiple fundic gland polyps arise in a
patient without a history of adenomatous polyposis coli (APC). CLINICAL FEATURES
Inflammatory fibrous polyps of the stomach are uncommon
lesions found mainly in the antral mucosa. They are small,
Fundic gland polyps show cystic dilatation of specialized gas- well-circumscribed and sessile or rarely pedunculated.
tric glands – that is, glands lined by attenuated chief or parietal
cells. PATHOLOGICAL FEATURES
Histologically, these consist of granulation tissue-type vessels,
GASTRITIS CYSTICA POLYPOSA thickened arterioles and inflamed fibroblastic stroma. Numerous
eosinophils are usually seen.
CLINICAL FEATURES JUVENILE POLYPS (Figure 5.7)

The term gastritis cystica polyposa refers to the development of
multiple flat or polypoid lesions around gastroenterostomy sites See Colon and rectum: Polyps and polyposis syndromes: Juvenile
or, less frequently, the margins of a peptic ulcer. Multiple case polyps and polyposis (p. 237).
reports have linked this condition to the development of gastric
stump carcinomas. PEUTZ–JEGHERS POLYPS
PATHOLOGICAL FEATURES See Tumors of the duodenum, jejunum, and ileum: Polyps and
polyposis syndromes: Peutz–Jeghers polyps (p. 225).
Microscopically, the lesions seen in gastritis cystica polyposa
resemble hyperplastic polyps. There is cystic dilatation of the
glands and thickening of the underlying muscularis mucosae. WHO CLASSIFICATION OF GASTRIC TUMORS
Typically, the glands often extend through the muscularis – a
feature not seen in hyperplastic polyps. Intestinal metaplasia The WHO classification of tumors of the stomach contains the
may also be seen. following entities:
● Papillary adenocarcinoma
● Tubular adenocarcinoma
● Mucinous adenocarcinoma
● Signet-ring cell adenocarcinoma
● Adenosquamous carcinoma
● Squamous cell carcinoma
● Undifferentiated carcinoma
● Others
● Carcinoid (well-differentiated endocrine neoplasm)
Non-epithelial tumors
Leiomyoma
Schwannoma
Granular cell tumor
Glomus tumor
Leiomyosarcoma
GIST
● Benign
● Uncertain malignant potential
● Malignant
Figure 5.7 Juvenile polyps typically comprise irregular, dilated glands
set in abundant, usually inflamed stroma.They are hamartomatous Kaposi’s sarcoma
in nature, and represent overgrowth of the lamina propria. Others
Epithelial tumors Malignant lymphomas

Intraepithelial neoplasia – adenoma ● Marginal zone B-cell lymphoma of MALT-type
● Carcinoma ● Mantle cell lymphoma
● Adenocarcinoma ● Diffuse large B-cell lymphoma
– Intestinal type ● Others
– Diffuse type Secondary tumors
TUMORS OF THE DUODENUM, JEJUNUM, AND ILEUM
EPITHELIAL TUMORS, BENIGN EPITHELIAL TUMORS, MALIGNANT
ADENOMA ADENOCARCINOMA
Small bowel adenomas are much less common than those Adenocarcinoma is rare in the small intestine, arising most com-
arising in the colon and rectum. The periampullary region is the monly in the ampullary and periampullary regions. The morpho-
most commonly affected site. Their macroscopic and microscopic logical pattern is similar to that of colonic adenocarcinoma and
features are similar to those seen in the large bowel, although a shows the same range of differentiation, although the relative pro-
greater proportion are of villous or tubulovillous type in the small portion of poorly differentiated tumors is higher in the small
bowel. The adenoma–carcinoma sequence seen in the colon also bowel than the colon. Cases showing signet ring cell morphology
appears to occur in the small intestine (see Adenocarcinoma, and colloid patterns have also been described. An adenoma–
below). Duodenal adenomas and true ampullary adenomas carcinoma sequence as seen in the colon also appears to occur
should be treated as separate entities as the latter are associated in the small intestine, with adenomatous mucosa found adjacent
with a high risk of malignancy. to the invasive adenocarcinoma in approximately 80% of cases.
Chronic inflammation is an important predisposing factor in
small bowel adenocarcinoma, and associations with Crohn’s
ADENOMA: BRUNNER’S GLAND disease and celiac disease are recognized. Associations with
polyposis syndromes such as familial adenomatous polyposis
See Hamartoma, Brunner’s gland (p. 224). (FAP) and Peutz–Jeghers syndrome have also been described.
ADENOSQUAMOUS CARCINOMA hemorrhage, abdominal pain or intestinal obstruction. Functional

tumors may cause signs and symptoms related to hormone secre-
This is an exceedingly rare tumor in the small intestine, with cases tion (such as Zollinger–Ellison syndrome with gastrinomas), but
reported mainly in the jejunum and ileum. The morphological pat- such presentations are less common. Duodenal somatostatin-cell
tern of the tumor, comprising malignant squamous and glandular tumors – in contrast to their pancreatic counterparts – do not
elements, is essentially the same as that described in other sites. present with the so-called ‘somatostatinoma syndrome’ (see
Tumors of the endocrine pancreas, p. 272). Ileal tumors may lead
CHORIOCARCINOMA to obstruction, volvulus and infarction because of their tendency
for deeply invasive growth and the fibroblastic or desmoplastic
Although extragenital or non-gestational choriocarcinoma in response secondary to this. Carcinoid syndrome associated with
the small intestine is rare, it should be included in the differen- ileal EC-cell tumors occurs in less than 10% of cases.
tial diagnosis of small intestinal malignant neoplasms.
Choriocarcinomas have been reported in the duodenum, ileum PATHOLOGICAL FEATURES (Figure 5.8)
and jejunum, and tend to present as irregular mucosal ulcera-
Macroscopically, small bowel carcinoids appear as a protrud-
tion. They are hypervascular tumors associated with an elevated
ing mass or an annular stenotic lesion. The surface mucosa may
serum human chorionic gonadotropin (hCG) level, and are
show focal ulceration in some cases. On sectioning, the tumor
composed of both syncytiotrophoblastic and cytotrophoblastic
is firm, pale yellow, and has a well-defined structure. Most are
cells. Immunohistochemical staining for hCG is positive.
solitary lesions, with multiple tumors occurring in only
10–15% of cases.
MELANOMA Histologically, the tumors may show a variety of common
patterns, with uniform cells arranged in trabeculae, cords, tubulo-
Metastatic malignant melanoma is known to occur in the small glandular structures, nests or more solid foci. Occasional
intestine. A rare primary melanoma has also been reported. mucin-secreting cells may also be present within the tumor.
Psammoma bodies are sometimes present in somatostatin-cell
SQUAMOUS CELL CARCINOMA tumors, and may be a prominent feature in some cases. Most
duodenal carcinoids form a small submucosal mass, though a
Only a few cases of primary squamous cell carcinoma arising smaller proportion display an aggressive behavior with invasion
in the small bowel have been reported in the literature. of other layers of the bowel wall.
EC-cell (enterochromaffin-cell) carcinoids

NEUROENDOCRINE TUMORS EC-cell carcinoids in the ileum are similar in appearance to
those in the appendix, although a combination of solid and
CARCINOID TUMORS/ENDOCRINE TUMORS glandular structures is commonly observed – a finding which
may be associated with a better prognosis compared to pure
solid tumors. As previously noted, ileal carcinoids frequently
CLINICAL FEATURES show deeply invasive growth with involvement of the peri-
toneum. In these areas, tumor cells may be arranged in ribbons
Endocrine tumors of the small intestine range from well-
or cords rather than in nested structures. Tumor nests lack the
differentiated tumors (carcinoid tumors) to the highly aggressive
S-100 protein-positive sustentacular cells seen in appendiceal
but very uncommon small cell carcinoma similar to that seen in
EC-cell carcinoids – a finding which may reflect a difference in
the lung. At least 45% of gastrointestinal carcinoids occur in the
tumor origin.
small intestine, with about half of these arising in the distal
jejunum or ileum. Gastrin cell tumors (these are dealt with in
more detail in a separate section below) are the most common Special techniques
type of duodenal carcinoid. Other duodenal and proximal jeju- ● The tumors show positive staining for common neuro-
nal types include somatostatin-cell tumors and PP-cell tumors. endocrine markers such as chromogranin and synaptophysin.
EC-cell carcinoids (serotonin-producing) occur very infrequently ● About 50% of somatostatin-cell tumors are negative for
in the duodenum and proximal jejunum, but are the most com- chromogranin A.
monly encountered type in the distal jejunum and ileum. ● Some tumors show positive staining for specific endocrine
Gangliocytic paraganglioma is also included under the heading markers reflecting the substances produced by the tumor
of endocrine tumors of the small intestine (this is described sep- cells such as gastrin, somatostatin, pancreatic polypeptide
arately below). Rare mixed adenocarcinoma-carcinoid tumors (PP) and calcitonin.
have been reported in the small intestine. ● The tumor cells in EC-cell carcinoids are argentaffinic
The clinical features of small bowel carcinoids are usually and argyrophilic, and show immunoreactivity for
the result of local infiltration. In the duodenum, this may lead chromogranins A and B. There may also be positivity for
to outflow obstruction around the ampulla of Vater and result substance P, and about 30% of cases show prostatic acid
in jaundice or pancreatitis. Other presentations may be with phosphatase immunoreactivity.
non-functioning, or produce only low levels of gastrin. This

compares to the situation in the pancreas, where most such
tumors are functional.
Functional tumors (gastrinomas) tend to occur in younger
patients (median age 40 years), and are more likely to show
invasive growth (about 60% of cases) and metastatic spread
(25–50%). The median age of patients with non-ZES tumors
(gastrin cell tumors) is 60–70 years; very few of these tumors
show invasion or metastasis. Gastrinomas spread to local
lymph nodes with a similar frequency to their pancreatic coun-
terparts (30–40%), but involve the liver much less commonly
(3% versus 30% of cases). A proportion of duodenal gastrino-
mas and gastrin cell tumors occur in patients with multiple
endocrine neoplasia type 1 (MEN-1), in which setting they may
be multiple.
Most duodenal gastrinomas and gastrin cell tumors are less
(a) than 1 cm in diameter and may be difficult to detect endo-
scopically. Metastatic spread to local lymph nodes may occur even
with very small tumors, when the metastasis may in fact be
larger than the primary tumor. Microscopically, the tumor is
composed of uniform cells arranged in nests and trabeculae
(for more details, see Endocrine tumors of the pancreas:
General aspects, p. 268).
Special techniques
● Gastrinomas and gastrin cell tumors show strong
immunoreactivity for gastrin.
● Serotonin is also positive in a proportion of cases.
PARAGANGLIOMA
CLINICAL FEATURES
Gangliocytic paraganglioma is rare in the small bowel. It is a
benign tumor which arises almost exclusively in the duodenum,
particularly the periampullary region and the ampulla of Vater.
(b)
As a result, the lesion may present clinically as a periampullary
carcinoma, and therefore it is important to recognize and diag-
Figure 5.8 (a, b) Small intestinal carcinoid tumor composed of
nests of cells with uniform nuclei and a coarse chromatin pattern. nose this rare (but benign) entity which is of uncertain histo-
Predicting the clinical behavior of these tumors is often difficult. genesis. There is a slight male predominance in the incidence of
gangliocytic paraganglioma. Adults over a wide age range are
affected, with a mean age of presentation of around 55 years.
GASTRINOMA AND GASTRIN CELL TUMORS
The endoscopic appearance is often that of a polypoid, ulcer-
CLINICAL FEATURES
ated mass. Microscopically, the tumors show similar features to
The duodenum is the second most common site for the devel- gangliomas arising elsewhere, and comprise epithelial cells
opment of gastrin cell tumors (the pancreas being the first). (constituting more than 50%), spindle cells and ganglion-like
Only about 40% of these tumors result in the full Zollinger– cells. The epithelial cells display clear cytoplasm and tend to
Ellison syndrome (ZES) in which elevated gastrin levels lead to form nests (‘zellballen’ or paraganglioma-like groups) and less
gastric acid hypersecretion and intractable peptic ulceration. frequently, cords (carcinoid-like) within the mucosa and sub-
These functional tumors are referred to as gastrinomas. mucosa. Ganglion cells are sparse and scattered, but are con-
The remaining 60% – referred to as gastrin cell tumors – are sistently associated with the spindle cells.
Special techniques HISTIOCYTOMA

Immunohistochemically, both epithelial and ganglion cells
show synaptophysin, chromogranin A, and anti-neurofilament Malignant fibrous histiocytomas (MFH) of the small intestine
positivity, while the spindle cells show S-100 protein positivity. are extremely rare. The histological features are identical to
those seen in more common sites such as the extremities.

HISTIOCYTOSIS, LANGERHANS’ CELL
Small cell carcinoma, representing the most poorly differentiated (HISTIOCYTOSIS X)
end of a spectrum of neuroendocrine tumors, is exceedingly rare
in the small bowel. Most cases have been reported in the peri- Involvement of the small intestine by Langerhans’ cell histio-
ampullary region of the duodenum. The histological features are cytosis – a rare systemic infiltrative disease of unknown etiology –
identical to those of small cell carcinoma of the lung. has been documented, but is extremely uncommon.
NON-EPITHELIAL TUMORS IMMUNOPROLIFERATIVE SMALL INTESTINAL

DISEASE (IPSID)
ANGIOSARCOMA
See Lymphoma (p. 223).
Primary angiosarcoma of the small intestine is exceedingly
rare, and metastatic spread from a primary site elsewhere needs INFLAMMATORY MYOFIBROBLASTIC TUMOR
to be excluded first. They can present as solitary or multifocal
masses involving a part or the full thickness of the bowel wall.
Their morphological pattern is similar to that in other sites. CLINICAL FEATURES
Angiosarcomas with an epithelioid cell morphology and cyto- Inflammatory myofibroblastic tumor (inflammatory pseudo-
keratin expression may be erroneously diagnosed as a carcinoma. tumor) of the gastrointestinal tract is extremely rare, and differs
They can be differentiated from the latter by their intense clinically, histologically and immunohistochemically from
immunoreactivity for CD31, CD34 and factor VIII-related inflammatory fibroid polyp. It occurs in adults (mean age
antigen. Radiation and long-term dialysis are recognized risk 41 years), who present with abdominal pain, fever and weight
factors. loss, and less frequently with bowel obstruction. The tumor
usually has an average size of 8 cm.
GANGLIONEUROMA AND GANGLIONEUROMATOSIS
Ganglioneuromas are rare in the small bowel. They may occur
Inflammatory myofibroblastic tumor is a poorly defined infil-
as solitary lesions or as a diffuse process (ganglioneuromatosis)
trative lesion arising in the lamina propria or the submucosa of
in association with Von Recklinghausen’s neurofibromatosis or
the bowel wall, and is composed of highly vascularized stroma
multiple endocrine neoplasia type IIb (comprising medullary
with a mixture of spindle cells and chronic inflammatory cells
thyroid carcinoma, pheochromocytoma and neuromas).
including numerous eosinophils, lymphocytes, plasma cells,
histiocytes, neutrophils, and multinucleated giant cells forming
GASTROINTESTINAL STROMAL TUMOR (GIST) small granuloma. The spindle cells are arranged loosely, in an
‘onion-skin’ or whorling pattern. The stroma often exhibit
See Chapter 13, Soft tissue tumors (p. 1064). myxoid change. The lesion may extend through the muscularis
propria into peri-intestinal adipose tissue and may, on rare
HEMANGIOMA occasions, involve regional lymph nodes.
Hemangiomas are uncommon in the small bowel, although Secondary features

they nevertheless account for most vascular tumors at this site. ● Ulceration of the overlying mucosa
They are benign tumors with a predilection for relatively ● Hemorrhage
young individuals, and can occasionally present with massive ● Necrosis
bleeding. ● Myxoid degeneration
HEMANGIOPERICYTOMA Cell morphology

● The main cell populations are fibroblasts and
There are few reports of hemangiopericytoma arising in the myofibroblasts.
small bowel. They are usually solitary masses, and can present ● Mixed inflammatory cells are variably present.
with massive intestinal bleeding. ● Cellular pleomorphism and mitoses may be present.
Differential diagnosis lineage. Most commonly, these are of mucosal-associated lym-

● Inflammatory fibroid polyp (a mucosal polyp, usually phoid tissue (MALT) type, either low grade or a more aggres-
smaller and shows more eosinophils and fibrosis and sive large cell variety, although any type of B-cell lymphoma can
fewer lymphoid cell infiltrates than inflammatory occur in the small intestine. Immunoproliferative small intes-
myofibroblastic tumor. Most (82%) inflammatory fibroid tinal disease (IPSID) is a subtype of MALT lymphoma charac-
polyps are positive for CD34) terized by a high production of alpha-heavy chains. It is found
● Polypoid carcinosarcoma most commonly in Middle Eastern and Mediterranean countries.
● Granulation tissue polyp Unlike gastric MALT lymphoma, the etiology of intestinal
● Lymphoma MALT lymphoma is poorly understood. It is thought that IPSID
● Myxoid liposarcoma is related to bacterial infection, though no particular organism
● Dendritic follicular cell sarcoma has been implicated.
Other primary small intestinal B-cell lymphomas include dif-
Special techniques fuse large B-cell lymphomas of centroblastic, immunoblastic or
plasmablastic type, Burkitt lymphoma and mantle cell lym-
See Inflammatory myofibroblastic tumor (p. 989).
phoma. Burkitt lymphomas occur predominantly in the terminal
ileum and affect children or young adults. Intestinal mantle cell
KAPOSI’S SARCOMA lymphoma is associated with an unfavorable prognosis, and
often presents as multiple polyps (lymphomatous polyposis).
Primary Kaposi’s sarcoma of the small intestine is uncommon. The gastrointestinal tract is a favored location for the develop-
Most cases occur in patients with the acquired immunodeficiency ment of extranodal lymphomas in patients with immunodefi-
syndrome (AIDS), though Mediterranean Kaposi’s sarcoma (non- ciency as a result of HIV infection or organ transplantation.
HIV-related) has also been documented. Primary intestinal T-cell lymphomas are rare, accounting for
only 5% of gastrointestinal lymphomas. Most are enteropathy-
LEIOMYOMA AND LEIOMYOSARCOMA type T-cell lymphomas associated with celiac disease. They are
high-grade lymphomas with a correspondingly poor prognosis.
These are very uncommon tumors in the small bowel. It is likely The presenting symptoms of small intestinal lymphomas
that some cases previously reported in the literature would include abdominal pain, bowel obstruction, weight loss, nausea
now be classified as gastrointestinal stromal tumors (GISTs). and vomiting. Aggressive tumors, including the enteropathy-type
Immunohistochemically, true smooth muscle tumors are posi- T-cell lymphomas, may present with an abdominal mass or
tive for SMA but negative for C-KIT (CD117). perforation. Weight loss, diarrhea and a protein-losing entero-
pathy may be seen in patients with IPSID.
LIPOMA
Lipomas are rare in the small bowel. They can occur in any The macroscopic appearances often provide a clue to the type
part of the small bowel, but show a predilection for the ileo- of lymphoma likely to be found microscopically. High-grade
cecal region where they can cause obstruction, intussusception B-cell lymphomas often present as a localized ulcerating lesion,
or volvulus. The macroscopic appearance is that of a polypoid whilst low-grade lymphomas (including IPSID) tend to show
or bulging mucosal mass. The histological pattern is that of diffuse thickening of the wall. A common presentation of
benign lipomas occurring elsewhere in the body. Burkitt lymphoma is an ileocecal mass causing intussusception
and small bowel obstruction. T-cell lymphoma often presents
LYMPHANGIOMA as multiple shallow ulcers.
The diagnosis of small bowel lymphoma is not straightfor-
Lymphangiomas are rarely seen in the small bowel. They arise ward and requires the assessment of multiple factors including
most frequently in the small bowel mesentery, while the the density of the lymphoid infiltrate, the extent of involvement
mucosa and submucosa are less commonly affected. Those of the bowel wall, uniformity of the cytological features (as
arising in the duodenum or in the ampullary region can cause to favoring high or low grade), and the presence of epithelio-
obstructive jaundice and may be confused clinically with a car- tropism. Immunophenotyping is essential for confirming the
cinoma. Their microscopic appearance is similar to lymphan- diagnosis and establishing the exact subtype. This follows the
giomas occurring elsewhere. same immunophenotyping pattern as for lymphomas elsewhere
(see Chapter 10, Lymphoreticular tumors).
LYMPHOMA
NEUROFIBROMA AND NEUROFIBROMATOSIS
CLINICAL FEATURES
Isolated neurofibroma of the small bowel in the absence of neu-
Malignant lymphoma of the small intestine accounts for rofibromatosis is a rare finding which has nevertheless been
approximately one-third of all malignant tumors at this site. reported in the literature. Involvement of the small intestine
The majority of primary intestinal lymphomas are of B-cell by neurofibromatosis is more common, with gastrointestinal
bleeding being the most frequently reported mode of presenta- HETEROTOPIA: PANCREATIC (MYOEPITHELIAL
tion. It is now well recognized and documented in the literature
HAMARTOMA) (Figure 5.9)
that the incidence of a variety of neoplastic conditions is increased
in neurofibromatosis. This spectrum includes gangliocytic para-
Pancreatic heterotopia can occur in any part of the small intes-
ganglioma, carcinoid tumors, gastrointestinal stromal tumors,
tine including Meckel’s diverticulum, though it is most com-
leiomyoma, leiomyoblastoma and leiomyomatosis, ampullary
monly encountered in the duodenum.
somatostatinoma, ganglioneuromas and malignant mixed tumor.
SCHWANNOMA (NEURILEMMOMA)
Like other neurogenic tumors, schwannomas are very uncom-

mon in the small intestine. The histological features are iden-
tical to those occurring elsewhere in the body.
TUMOUR-LIKE CONDITIONS
CYSTS
Congenital duplication or enterogenous cysts may produce

signs and symptoms which raise the suspicion of malignancy.
These include abdominal pain, vomiting, an abdominal mass,
intussusception, obstruction, or perforation. The cysts arise on
the mesenteric aspect and possess a wall containing all of the
normal layers present in the small bowel. Duplications may
communicate with the normal intestinal lumen.
HAMARTOMA, BRUNNER’S GLAND Figure 5.9 Heterotopic pancreatic tissue in the wall of the small
intestine.
CLINICAL FEATURES
This hamartomatous lesion (also known as Brunner’s gland
The macroscopic appearance is that of a mucosal nodule or ele-
adenoma) is usually seen as a nodular growth at the junction of
vation. The histological pattern comprises some or all of the nor-
the first and second parts of the duodenum.
mal pancreatic tissue elements in various proportions, often in
PATHOLOGICAL FEATURES combination with intervening smooth muscle elements – hence
the alternative label of myoepithelial hamartoma.
This lesion consists of diffuse or focal nodular proliferation of
histologically normal Brunner’s glands. These may show a lob-
ular configuration and may be accompanied by ducts and scat-
LIPOHYPERPLASIA
tered stromal cells.
This is an uncommon condition affecting the area of the ileoce-
cal valve which, when viewed colonoscopically, could potentially
HETEROTOPIA: HETEROTOPIC AND METAPLASTIC mimic malignancy. Abundant fat in the submucosa of the termi-
GASTRIC MUCOSA nal ileum causes distortion of the ileocecal valve. Protrusion of
the affected segment into the cecum may raise the suspicion of
Congenital heterotopic gastric mucosa or acquired metaplastic extrinsic compression by tumor.
gastric surface epithelium may be found in the duodenum.
LYMPHOID HYPERPLASIA
The gross appearance at endoscopy is that of a nodular or Lymphoid hyperplasia of the small intestine occurs in young
elevated lesion which raises the suspicion of neoplasia. patients, mainly infants and children. The lesions are often focal,
Histologically, the presence of inflammation, Helicobacter though a diffuse nodular form has also been described in patients
pylori infection and ulcer often indicates gastric metaplasia with primary hypogammaglobulinemia. The most common
which is of the pyloric type. Heterotopia occurs in the absence symptomatic site is the terminal ileum, where the hyperplastic
of inflammation or ulceration, and it can be formed of any gas- process may cause obstruction of the ileocecal region. The
tric mucosal elements. Dysplasia and malignancy can arise in benign nature of the lesion is demonstrable histologically by the
heterotopic gastric epithelium. reactive pattern of the lymphoid aggregate.
MYOEPITHELIAL HAMARTOMA
See Heterotopia: Pancreatic (p. 224).
XANTHOMATOSIS
Infiltration of the small bowel wall by lipid-laden histiocytes is

an uncommon non-neoplastic process which may cause bowel
obstruction and hence raise the suspicion of malignant disease.
POLYPS AND POLYPOSIS SYNDROMES
INFLAMMATORY FIBROID POLYP
CLINICAL FEATURES
The small intestine is the most common location for the
development of inflammatory fibrous polyps. These lesions are (a)
small, well-circumscribed and sessile or rarely pedunculated.
Presentation is usually with intussusception or obstruction.
Histologically, these consist of granulation tissue-type vessels,
thickened arterioles and inflamed fibroblastic stroma. Numerous
eosinophils are usually seen.
JUVENILE POLYPS AND POLYPOSIS
See Colon and rectum (p. 237).
PEUTZ–JEGHERS POLYPS
CLINICAL FEATURES
Peutz–Jeghers polyps are hamartomatous lesions comprising part
of the Peutz–Jeghers syndrome (the three salient features of which
are gastrointestinal polyp formation, mucocutaneous melanin
(b)
pigmentation and an autosomal dominant mode of inheritance).
These polyps are most commonly seen in the small intestine, but Figure 5.10 (a, b) Peutz–Jeghers polyps show characteristic tree-
also frequently arise in the stomach and colon. The polyps them- like branching with central cores composed largely of smooth
selves are not premalignant lesions; however, the Peutz–Jeghers muscle fibers which are enveloped by intestinal or gastric
syndrome does convey an increased risk of malignancy in other epithelium.
organs such as the breast and pancreas. The gene associated with
muscular layer, as one would see in normal mucosa. Pseudo-
Peutz–Jeghers syndrome (LKB1) is found on chromosome 19p13.
carcinomatous invasion may be seen in polyps larger than 3 cm.
The misplaced epithelium may be seen in the submucosa or mus-
PATHOLOGICAL FEATURES (Figure 5.10) cularis propria, as well as the serosa of the polyp, and consists of
Histologically, Peutz–Jeghers polyps show a very characteristic proliferating mature small intestinal epithelium, intermingled
tree-like branching of the muscularis mucosa with individual with arborizing smooth muscle bundles. Mucus-filled cysts with
branches ‘clothed’ by normally orientated mucosal epithelium. an associated inflammatory reaction and hemosiderin deposition
These branches of muscular tissue become thinner and eventually or calcification may also be seen.
disappear as they reach the periphery of the polyp. In small intes-
tinal lesions it is easy to find normally located Paneth cells at Differential diagnosis
the base of the crypts in close proximity to the branches of the ● Inflammatory myoglandular polyp
Mixed carcinoid-adenocarcinoma
WHO CLASSIFICATION OF SMALL INTESTINE Gangliocytic paraganglioma
TUMORS Others
The WHO classification of tumors of the small intestine con- Lipoma
tains the following entities: Leiomyoma
Epithelial tumors GIST
Adenoma Leiomyosarcoma
● Tubular Angiosarcoma
● Villous Kaposi’s sarcoma
● Tubulovillous Others
Intraepithelial neoplasia (dysplasia) associated with chronic Malignant lymphomas
inflammatory diseases Immunoproliferative small intestinal disease (includes ␣ heavy
● Low-grade glandular intraepithelial neoplasia chain disease)
● High-grade glandular intraepithelial neoplasia Western type B-cell lymphoma of MALT
Carcinoma Mantle cell lymphoma
● Adenocarcinoma Diffuse large B-cell lymphoma
● Mucinous adenocarcinoma Burkitt lymphoma
● Signet-ring cell carcinoma Burkitt-like/atypical Burkitt lymphoma
● Small cell carcinoma T-cell lymphoma
● Squamous cell carcinoma ● Enteropathy-associated
● Adenosquamous carcinoma ● Unspecified
● Medullary carcinoma Others

Carcinoid (well-differentiated endocrine neoplasm) Secondary tumors

● Gastrin-cell tumor, functioning (gastrinoma) or non- Polyps
● Hyperplastic (metaplastic)
functioning
● Somatostatin-cell tumor ● Peutz–Jeghers
● EC-cell, serotonin-producing neoplasm ● Juvenile
● L-cell, glucagon-like peptide and PP/PYY producing tumor
TUMORS OF THE APPENDIX
mucocele. Localized or polypoid morphology is often seen in

EPITHELIAL TUMORS, BENIGN tubular adenomas. Sessile, non-mucinous, localized or diffuse
patterns are often seen in serrated adenomas and in hyperplastic
ADENOMA polyps.
Histologically, the localized tubular adenomas and non-
The terminology of appendiceal adenomas is comparable to those mucinous serrated or hyperplastic polyps are similar to those seen
commonly seen in the large bowel, including serrated, tubular, in the large bowel. The mucinous cystic change often seen in the
tubulovillous and villous adenomas. Like their counterparts in the villous and tubulovillous types makes their accurate recognition
colon and rectum, appendiceal adenomas are considered to be and assessment of the degree of dysplasia rather difficult, par-
pre-malignant neoplasms. ticularly when one takes into account the fact they are not
commonly encountered in diagnostic practice. Nevertheless, a
thorough search will reveal a focus of adenomatous epithelium
showing either villous or tubulovillous architecture, and this
Appendiceal adenomas, with the exception of tubular adenomas, should permit accurate assessment of dysplasia. Lakes of mucin
involve the appendix in a circumferential or diffuse pattern. With and islands of adenomatous epithelium in the wall of the appen-
the entrapment of their mucinous secretion, the appendix con- dix are not uncommon and may be mistakenly interpreted as
verts into a distended mass of mucinous cystic adenomas or cyst- evidence of invasion. The presence of inflammatory changes
adenomas. Thinning of the wall, accumulation of mucin and and the absence of a desmoplastic reaction are clues to the
flattening of the lining epithelium heralds the formation of a absence of true invasion.
Tumors of the appendix 227
of other neuropeptide hormones such as somatostatin,

EPITHELIAL TUMORS, MALIGNANT enteroglucagon and pancreatic polypeptide (PP).
● Goblet cells are positive for CEA.
ADENOCARCINOID TUMORS ● The cells in tubular carcinoids are argentaffinic in 75%
of cases and argyrophilic in 90% of cases.
Immunohistochemistry may reveal positivity for
CLINICAL FEATURES chromogranin A, serotonin, glucagon and IgA.
Adenocarcinoid tumors are also known as goblet cell carci-
noids or mucus-secreting carcinoids. The term encompasses ADENOCARCINOMA
goblet cell carcinoids, tubular carcinoids and mixed carcinoid-
adenocarcinoma. Unlike ordinary carcinoids, they are rarely an
incidental finding, and these tumors often present as acute CLINICAL FEATURES
appendicitis or as an emergency abdominal obstruction if the Like their large-bowel counterparts, the majority of appendiceal
tumor already extends to the terminal ileum. Adenocarcinoids adenocarcinomas appear to arise in a pre-existing adenoma.
are associated with a more aggressive course than ordinary carci- They are uncommon tumors which nevertheless account for
noids and have a tendency to show direct spread to adjacent 50–60% of malignant tumors at this site – most of the remain-
structures. Metastatic spread is reported in approximately der being carcinoids. The mean age at presentation is around
20% of the tumors. 65 years, and there is a male predominance. An association with
longstanding ulcerative colitis (and possibly also Crohn’s disease)
is documented. The most common presentation is with signs and
symptoms suggestive of acute appendicitis.
Adenocarcinoid tumors may not be recognizable grossly because
of their infiltrative growth pattern. In some cases, there may be PATHOLOGICAL FEATURES
diffuse thickening of the appendiceal wall with features of sec-
ondary acute appendicitis. An ulcerating mass at the base of the The majority of appendiceal adenocarcinomas are of mucinous
appendix which may extend to and obstruct the distal ileum is type, and often present as a large, distended, cystic appendiceal
another presentation seen in advanced tumors. mass which is rich in mucinous material. Abdominal spread may
The tumor comprises a mixture of neuroendocrine cells and give rise to pseudomyxoma peritonei. Solid adenocarcinomas
mucin-secreting goblet cells in varying proportions. These form also occur but much less commonly. Cystadenocarcinomas
small acinar and nested structures that widely infiltrate the (sometimes called colloid carcinomas) may pose some diagnostic
appendix and spread to adjacent structures. difficulty as the cytological features can be rather bland.
● Goblet cell carcinoid: These tumors infiltrate widely, Demonstration of an invasive component involving other layers
particularly within the submucosa, and involve the of the appendix may be required for definite diagnosis of malig-
appendix in a circumferential manner. Mucosal nancy. Non-mucin-producing tumors are easily distinguished
involvement is relatively uncommon. Characteristically, and resemble those seen in the large bowel.
the tumor is composed of small solid nests of cells with a
signet-ring morphology. Pools of extracellular mucin are
often observed. Cells more typical of ordinary carcinoid NEUROENDOCRINE TUMORS
tumors may also be present, either scattered or in small nests.
● Tubular carcinoid: These tumors are composed of
CARCINOID TUMORS
uniform, cytologically bland endocrine cells arranged in
tubules, some of which may contain luminal mucin.
Trabecular structures and scattered endocrine cells may CLINICAL FEATURES
also be seen, however nests are uncommon. An origin
Despite its small size, the appendix is the most common site of
from a crypt base may be identifiable, but the tubular
gastrointestinal carcinoid tumors, accounting for approximately
architecture and lack of mucosal involvement may lead to
20% of cases. Carcinoids make up over 50% (and up to 75%
the erroneous diagnosis of metastatic adenocarcinoma.
● Mixed carcinoid-adenocarcinoma: This term is used for
in some series) of all appendiceal tumors. They occur over a
wide age range, with a mean age of presentation in the fourth
appendiceal carcinomas arising as the result of progres-
decade of life. There is an apparent female predominance.
sion of a goblet-cell carcinoid. The overlying mucosa does
Most appendiceal carcinoids are asymptomatic, particularly
not appear neoplastic.
when located in the tip, and these may be discovered incidentally
in appendicectomy specimens. Acute appendicitis can occur when
Special techniques more proximally located tumors cause obstruction of the lumen.
● Mucin stains are strongly positive in goblet cell carcinoids. The majority of appendiceal carcinoids are of EC-cell (serotonin-
● Argentaffinic and argyrophilic cells (the latter more common) producing) type; however, clinical carcinoid syndrome is rare and
are seen in over 50% of goblet cell carcinoids. These cells usually only seen in tumors which have metastasized widely.
are also positive for chromogranin A, serotonin and a variety Occasional carcinoids are of L-cell (glucagon-like peptide and
nodule, typically at the tip of the appendix. Most are less than
1 cm in diameter, but rare tumors can exceed 2 cm.
Most appendiceal EC-cell carcinoids are composed of solid
nests of uniform cells with peripheral pallisading present in some
nests. A ribboning growth pattern may also be seen where the
tumor invades into muscle. Acinar structures are seen less com-
monly in appendiceal EC-cell carcinoids than those occurring in
the terminal ileum. Muscular, lymphatic and perineural invasion
is common, and around two-thirds show invasion of the peri-
toneum at the time of resection. However, compared to ileal carci-
noids, those occurring in the appendix seldom metastasize to
lymph nodes or distant organs. The reasons for the difference in
clinical behavior between ileal and appendiceal EC-cell carci-
noids is unclear – the only histological clue being the presence of
sustentacular cells around tumor nests in the appendix; these
are absent in ileal carcinoids and may reflect a difference in
tumor origin.
Special techniques
(a) ● EC-cells are strongly argentaffinic.
● Substance P is positive in a proportion of cases.
● Electron microscopy reveals pleomorphic, strongly
osmiophilic granules.
● S-100 protein stains the sustentacular cells surrounding
tumor nests.
GRANULAR CELL TUMOR
These are exceedingly rare in the appendix. For a description

of the pathological features, see Esophagus: Granular cell tumor
(p. 204).
KAPOSI’S SARCOMA
The appendix is rarely involved by Kaposi’s sarcoma, with

most cases being seen as part of a generalized involvement of
(b)
the gastrointestinal tract, mainly in association with HIV infec-
Figure 5.11 Appendiceal carcinoid tumor. Despite its size in relation tion and in the immunocompromised.
to the remainder of the gastrointestinal tract, the appendix is the
most common site for such tumors.The biological and clinical
behavior of this tumor differs from that of those arising in the jejunum LEIOMYOMAS AND LEIOMYOSARCOMA
and ileum, for reasons which are currently unclear. (a) Uniform cells
arranged in solid nests. (b) Immunohistochemistry for S-100 protein
These are exceedingly rare tumors of the appendix. They
highlights the sustentacular cells not found in small bowel carcinoids.
resemble their counterparts in other parts of the large bowel.
Leiomyosarcomas are negative for C-KIT (CD117), in contrast
PP/PYY-producing) types – these are discussed in more detail in to gastrointestinal stromal tumors (GISTs) which are also
the section on Large bowel carcinoids (see p. 233). extremely rare in the appendix.
Goblet cell and tubular carcinoids are discussed in the section
on Adenocarcinoid tumors (see p. 227).
LYMPHOMA
Primary lymphoma of the appendix is extremely uncommon.
Macroscopically, EC-cell (enterochromaffin cell) carcinoids Most lymphomas at this site represent involvement by more
appear as a gray-white or yellow-colored, firm, circumscribed generalized gastrointestinal disease.
● Tubulovillous
TUMOR-LIKE CONDITIONS ● Serrated
Carcinoma
HETEROTOPIAS ● Adenocarcinoma
The most frequently encountered heterotopic element in the ● Signet-ring cell carcinoma
appendix is decidualized tissue arising during pregnancy. The ● Small cell carcinoma
serosal surface is most commonly involved. Endosalpingiosis of ● Undifferentiated carcinoma
the muscularis propria of the appendix has also been reported. Carcinoid (well-differentiated endocrine neoplasm)
● EC-cell, serotonin-producing neoplasm
MUCOCELE ● L-cell, glucagon-like peptide and PP/PYY-producing
tumor
Mucocele of the appendix indicates an obstructive dilatation of the ● Others
appendiceal lumen due to abnormal accumulation of mucus which

may be precipitated by a variety of pathological conditions includ- Tubular carcinoid
ing mucinous cystadenomas and cystadenocarcinomas. In the lat- ● Goblet cell carcinoid (mucinous carcinoid)
ter case, rupture of the mucocele, either spontaneously or during ● Mixed carcinoid-adenocarcinoma
surgery, may result in pseudomyxoma peritonei, with spread of ● Others
malignant cells throughout the entire peritoneal cavity in the form

of multiple mucinous deposits. Simple mucocele is seen following Non-epithelial tumors
healed episodes of acute appendicitis due to stenosis of the lumen Neuroma
at the proximal end with entrapment of the secreted mucin. Lipoma
Leiomyoma
GIST
WHO CLASSIFICATION OF APPENDICEAL TUMORS Leiomyosarcoma
Kaposi’s sarcoma
The WHO classification of tumors of the appendix contains Others
the following entities: Malignant lymphoma
Epithelial tumors Secondary tumors
Adenoma Hyperplastic (metaplastic) polyp
● Tubular
● Villous
TUMORS OF THE COLON AND RECTUM
neoplasia. Although considered as benign neoplasms, they never-

EPITHELIAL TUMORS, BENIGN theless harbor the potential for malignant transformation.
Mutational inactivation of the APC gene is the most commonly
ADENOMA: SERRATED identified genetic abnormality in colorectal adenomas, and is an
early event in the proposed adenoma–carcinoma sequence.
Serrated adenomas are relatively uncommon and are character- Adenomas are more common in males, but the risk of malignant
ized by low-level microsatellite instability (MSI-L) and altered transformation is higher in females. They are uncommon before
mucin. They possess the same serrated (‘saw-tooth’) architec- the fifth decade of life in the absence of an acquired or inherited
ture of hyperplastic/metaplastic polyps, but show dysplasia of polyposis syndrome (described in more detail later in this section).
the superficial luminal and crypt epithelium. Serrated adenomas There is no predeliction for a specific site in the large bowel,
are larger in size than hyperplastic polyps, and can be either though left-sided adenomas are often larger than those on the
solitary or multiple. Like other adenomas, these lesions are con- right side. The risk of malignancy increases with adenoma size,
sidered pre-malignant in nature. and tends to be greater in large villous adenomas compared to
tubulovillous and tubular adenomas.
ADENOMA: TUBULAR, TUBULOVILLOUS AND

VILLOUS PATHOLOGICAL FEATURES (Figure 5.12)
Small adenomas are often sessile while polypoidal adenomas are
of a larger size. Large sessile adenomas are often villous in type.
CLINICAL FEATURES
Other less common variants include flat or depressed lesions.
Adenomas of the colon and rectum – whether polypoid, flat or Adenomas are classified on architectural grounds into tubular,
depressed – share the same characteristic feature of intraepithelial tubulovillous and villous types. The dysplastic epithelial
adenocarcinoma) indicates associated invasion of the lamina

propria only.
ADENOMATOUS POLYPOSIS COLI
See Polyps and polyposis syndromes: Familial adenomatous

polyposis (p. 237).
CARCINOMA
CLINICAL FEATURES
Carcinoma of the large bowel represents one of the most com-
mon types of cancer in the Western world. Dietary and lifestyle
factors appear to play an important etiological role, with the
(a) consumption of high-calorie foods, meat and alcohol particularly
implicated. Smoking is also an important risk factor. Countries
which have tended to adopt a more Western lifestyle such as
Japan and Korea have seen a rapid increase in the number of
cases recently, in contrast to a general decrease in incidence
elsewhere. Vegetable consumption, estrogen replacement ther-
apy and non-steroidal anti-inflammatory drugs appear to exert
a protective effect.
Longstanding chronic inflammation of the colon and rectum
is also associated with an increased risk of colorectal carcinoma.
This is particularly true of ulcerative colitis, where the incidence
rate has been reported as up to 20-fold higher in patients with
longstanding disease. Patients with Crohn’s disease show an
approximately three-fold increase in incidence relative to the
general population. In both types of inflammatory bowel dis-
ease, the risk of colorectal carcinoma is related to the age of
onset, duration of disease and extent of disease; the highest risks
are in patients with longstanding disease from an early age with
involvement of the entire colon (pancolitis).
Colorectal carcinoma is rare in patients under the age of 40
years in the absence of a genetic predisposition or chronic inflam-
(b)
matory bowel disease. Incidence increases with age, with the
highest rates in the seventh decade of life. Younger patients seem
Figure 5.12 Colonic adenomas. (a) Tubulovillous adenoma. (b) Tip to develop particularly aggressive tumors more commonly, but
of a villous adenoma. their tolerance of major surgery relative to elderly patients results
in a similar prognosis for different age groups. There is a slight
component shows a variable degree of both cytological and male predominance overall, though the situation is complicated
architectural atypia. In tubular adenomas, the tubular elements by the interactions between age, gender and site. Carcinomas of
comprise at least 80% of the lesion. Villous adenomas are char- the right colon are more common in females of all age groups,
acterized by long finger-like or leaf-like projections, again com- whereas tumors of the left colon are more common in women in
prising at least 80% of the lesion. The distinction between the under-50 age group and more common in men in the over-70
elongated tubules and villous projections is somewhat blurred age group. Rectal carcinoma shows a distinct male predomi-
but for practical purposes glands longer than twice the thick- nance, and this difference in incidence between males and females
ness of normal colonic mucosa can be considered villous in increases with age.
architecture. Tubulovillous adenomas, as the name implies, are An increasing proportion of cases of colorectal carcinoma are
composed of a mixture of villous and tubular elements, neither now discovered by screening or surveillance in asymptomatic
of which exceed 80% of the lesion. The degree of dysplasia individuals. Classically, symptomatic patients present with signs
in adenomas is subclassified into mild, moderate and severe. and symptoms such as change in bowel habit, weight loss, lower
Intramucosal neoplasia (also referred to as intramucosal GI tract bleeding and/or iron-deficiency anemia, tenesmus and
abdominal pain. The likelihood of bowel obstruction (and with and squamous cells are not uncommon components of colorectal
it the possibility of perforation) is greatest in left-sided tumors adenocarcinomas. Whether such findings have prognostic signifi-
where the bowel lumen is narrowest. The concept of the cance is not clear. The grading of colorectal adenocarcinomas is
adenoma–carcinoma sequence in colorectal carcinoma is well based largely on the architectural features and the proportion of
established and remains the subject of extensive research. Most the tumor composed of well-formed glands (⬎75% in well-
adenocarcinomas arise in a pre-existing adenoma, the rem- differentiated tumors and ⬍25% in poorly differentiated cases).
nants of which may or may not be identifiable in resection Carcinomas showing variable differentiation are classified accord-
specimens. Microsatellite instability (MSI) is a prominent ing to the least well-differentiated area.
feature of some colorectal carcinomas, and this has some bear- A desmoplastic response to the invasive carcinoma is com-
ing on the site and histological subtype of the tumor. mon, and this represents a useful diagnostic feature – particularly
when assessing microinvasive tumors. Extensive stromal elasto-
TNM STAGING OF COLORECTAL CARCINOMA sis may be seen in some cases. The degree of inflammatory
response to the tumor varies. Some carcinomas are associated
T Stage:
with a dense lymphocytic infiltrate, while others contain promi-
T0 No evidence of primary tumor
nent lymphoid aggregates with germinal centers resembling the
Tis Carcinoma in situ (includes invasion of the lamina propria –
pattern seen in Crohn’s disease.
see below)
A variety of other less common histological types of colorec-
T1 Invasion of submucosa
tal carcinoma have been reported in the literature. These are
T2 Invasion of muscularis propria
discussed below.
T3 Invasion through musculara propria into subserosa or into
● Mucinous (or colloid) carcinoma: This is defined as an
non-peritonealized pericolic or perirectal tissue
adenocarcinoma in which pools of extracellular mucin
T4 Direct invasion of other organs or structures and/or
account for over 50% of the tumor. Malignant glandular
perforates visceral peritoneum
structures or individual carcinoma cells appear to float
N Stage: freely within the mucin pools. High levels of microsatellite
N0 No regional lymph node metastasis instability (MSI-H) are found in some mucinous
N1 Metastasis in 1–3 regional lymph nodes carcinomas. These tumors often affect younger patients,
N2 Metastasis in 4 or more regional lymph nodes and have a generally poor prognosis with high rates of
local recurrence.
Dukes staging:
● Signet ring cell carcinoma: This is similar to that seen in the
A Confined to bowel wall (submucosa or muscularis propria)
stomach, and is defined as an adenocarcinoma in which
B Extension beyond muscularis propria
more than 50% of the tumor cells contain prominent
C1 Regional lymph node metastasis
intracytoplasmic mucin vacuoles. Smaller numbers of signet
C2 Apical lymph node involvement
ring cells may be found in other histological subtypes such
as mucinous carcinoma. Some signet ring cell carcinomas
are associated with MSI-H. Recurrence rates in signet ring
Macroscopically, colorectal carcinomas show a variety of cell carcinoma are very high.
appearances. Ulcerating lesions are seen most frequently; other ● Adenosquamous carcinoma: This comprises areas of
carcinomas appear polypoidal or exophytic/fungating. Carcino- adenocarcinoma and squamous carcinoma which may be
mas which show diffuse infiltration of the wall microscopically closely admixed or separate within the tumor. The term
may appear as an area of stricturing with little evidence of should not be used to describe adenocarcinomas with
tumor on the surface. ‘Flat’ carcinomas, reported most com- small foci of squamous differentiation.
monly in Japan, may be difficult to appreciate macroscopically, ● Medullary carcinoma: This is strongly associated with
appearing as plaque-like flat or depressed lesions. Superficial MSI-H. These tumors are composed of solid sheets of
lesions are the subject of some controversy since invasive colo- cells with abundant eosinophilic cytoplasm and vesicular
rectal carcinoma is generally defined as invasion beyond the nuclei with prominent nucleoli. The epithelial cells are
muscularis mucosae. In the absence of submucosal invasion, associated with a striking lymphocytic infiltrate. The
the terms high-grade intraepithelial neoplasia and intramucosal prognosis of medullary carcinoma is good compared to
neoplasia are suggested by the recent WHO classification. other poorly differentiated tumors.
The majority of colorectal carcinomas are typical adeno- ● Undifferentiated carcinoma: Completely undifferentiated
carcinomas, mostly moderately differentiated or well-differentiated epithelial tumors of the colon are uncommon. Many are
gland-forming neoplasms. The neoplastic glands are lined by tall associated with MSI-H.
columnar cells showing a variable degree of dysplasia and mitotic ● Spindle cell carcinoma (sarcomatoid carcinoma): As the
activity. Particularly well-differentiated tumors may show little name suggests, these contain focal areas of spindle cell
cytological atypia and thus pose a significant diagnostic chal- morphology. These spindle cells show immunoreactivity
lenge. The presence of multipotent stem cells at the base of large for cytokeratin, although in some cases this may be focal.
bowel crypts can give rise to a variety of cell types within a ● Carcinosarcoma: These are rare tumors comprising both
tumor – a finding which does not alter the diagnosis of adeno- malignant epithelial components and heterologous
carcinoma. Thus goblet cells, Paneth cells, neuroendocrine cells mesenchymal tissue.
● Pleomorphic (giant cell) carcinoma: This is a rare tumor of the HEREDITARY NON-POLYPOSIS COLORECTAL
large bowel and is similar to that seen in the lung, comprising
CARCINOMA (HNPCC)
giant cells, spindle cells and polygonal cells arranged in sheets.
Focally, there are areas of glandular, squamous and sometimes
neuroendocrine differentiation. All three cell types seen show CLINICAL FEATURES
immunoreactivity for cytokeratin and vimentin.
HNPCC, also known as Lynch syndrome, is an autosomal
● Squamous cell carcinoma: Pure squamous cell carcinoma
dominant trait associated with germline mutations in five genes
of the large bowel is extremely rare. The diagnosis requires
involved (or likely to be involved) in the process of DNA mis-
exclusion of metastasis from elsewhere, direct spread from
match repair. These genes are as follows (numbers in parenthe-
a tumor of the anal squamous epithelium and origin from
ses indicate chromosomal location): MSH2 (2p21); MLH1
a squamous-lined fistula.
(3p31-p23); PMS1 (2q31-q33); PMS2 (7p22); and MSH6
● Basaloid (cloacogenic) carcinoma: These are similar to those
(2p21). Such mutations give rise to high levels of microsatellite
occurring in the anal canal, and are very rare tumors that
instability, a feature which may also be seen in some sporadic
arise mostly in the sigmoid colon. The secretion of hormones
colorectal carcinomas (see above).
such as parathyroid hormone (PTH) and adrenocorticotropic
Patients with HNPCC have a high lifetime risk of developing
hormone (ACTH) has been reported in some cases.
colorectal carcinoma and endometrial carcinoma with a lower,
● Choriocarcinoma: Pure primary choriocarcinoma,
but still increased risk of cancer in other organs such as the kid-
comprising a mixture of cytotrophoblastic and
ney, stomach, small bowel and ovary. The increased relative risk
syncytiotrophoblastic tissue, is extremely rare in the colon
of endometrial, ureteric, renal pelvis and small-bowel carcino-
and rectum. Mixed adenocarcinoma/choriocarcinoma is
mas compared to the general population make these tumors
more common, and scattered hCG-positive cells are not
particularly specific for HNPCC. The diagnosis of HNPCC uti-
uncommonly found in typical adenocarcinomas of the
lizes the Amsterdam criteria (listed below). Muir–Torre syndrome
large bowel. Mixed adenocarcinoma/choriocarcinoma
refers to the association of sebaceous gland tumors and
occurs more frequently in the left side of the colon and is
HNPCC-related internal cancers, while Turcot syndrome refers
capable of widespread metastasis. Metastatic deposits may
to the combination of a primary brain tumor with multiple colo-
or may not contain areas of choriocarcinoma.
rectal adenomas, either in the setting of HNPCC or familial
● Clear cell carcinoma: Occasional adenocarcinomas
adenomatous polyposis (FAP, see below).
showing a clear cell morphology have been described.
Immunohistochemistry is required to distinguish these
cases from other clear cell tumors, particularly metastatic Revised Amsterdam criteria for diagnosis of HNPCC (ACII)
renal cell carcinoma. 1. At least three relatives with HNPCC-associated cancer
● Stem cell carcinoma: Some authors have used the term (colorectal, endometrial, small bowel, ureteric or renal pelvis).
stem cell carcinoma to describe tumors showing multi- 2. One patient a first-degree relative of the other two.
directional differentiation, presumably derived from 3. At least two successive generations involved.
pluripotent stem cells at the base of large bowel crypts. 4. At least one tumor diagnosed before age 50 years.
● Paneth-cell rich carcinoma (crypt cell carcinoma): Paneth 5. Familial adenomatous polyposis excluded in any
cell metaplasia is not a uncommon feature of colorectal colorectal carcinomas.
adenocarcinomas, most commonly in more well- 6. Histological confirmation of tumors.
differentiated tumors. In a few cases this can be a
prominent feature.
● Glassy cell carcinoma: This is a rare form of poorly
differentiated adenosquamous carcinoma that is usually Large-bowel carcinomas associated with HNPCC arise most
seen in the uterine cervix. At least one case of glassy cell frequently in the proximal colon. Multiple adenomas may also
carcinoma arising in the large bowel has been reported. be seen, though not in large numbers and not always in the
● Pigmented carcinoma: A single case of an anorectal areas where carcinomas develop most commonly. The majority
adenocarcinoma in which the tumor cells had of carcinomas are relatively well circumscribed, and present as
phagocytosed melanin pigment produced by anal mass lesions rather than strictures associated with diffuse infil-
melanocytes has been reported. Not surprisingly, the tration of the bowel wall by tumor.
macroscopic appearance was suspicious of a melanoma. Adenomas in patients with HNPCC are more frequently of
villous type than those in non-HNPCC patients. The degree of
dysplasia tends to be greater, and hence these lesions have a
Differential diagnosis high risk of progression to invasive malignancy. The adeno-
Conditions associated with displacement or herniation of carcinomas most typically associated with HNPCC are similar
mucosal glandular elements into the lamina propria or sub- to the sporadic tumors which show high levels of microsatellite
mucosa may cause some diagnostic difficulty. instability (MSI-H), in particular mucinous adenocarcinoma,
● Mucosal prolapse syndromes/solitary rectal ulcer poorly differentiated or undifferentiated adenocarcinoma and
● Inflammatory bowel disease medullary carcinoma (all of these are described in the Carcinoma
● Adenoma section above).
MELANOMA uncommon with endocrine tumors at this site. Carcinoid tumors

found in patients with ulcerative colitis and Crohn’s disease
Primary melanoma originating in the gastrointestinal tract is may be incidental findings rather than directly linked.
very rare, and the majority of these tumors arise in the mucosa Colorectal carcinoids are of EC-cell (serotonin-producing) or
of the anus or rectum. L-cell (glucagon-like peptide and PP/PYY-producing) types.

Colonic carcinoids occur most commonly on the right side and
appear as a submucosal nodule or polypoid lesion. They tend
CARCINOID TUMORS to be larger than those seen in the rectum, ileum and appendix,
growing to around 5 cm in diameter on average. Rectal carcinoids
CLINICAL FEATURES
Large-bowel carcinoids account for approximately 30% of all
gastrointestinal carcinoid tumors. They occur most frequently
in the rectum, followed by the cecum, sigmoid colon and
ascending colon. The mean age of presentation is younger in
rectal carcinoids compared to colonic carcinoids (58 years and
66 years, respectively). Rectal carcinoids show a slight female
predominance. Colonic carcinoids are often malignant and
associated with a poor prognosis, though it has been suggested
that some cases reported as malignant carcinoid tumors may
in fact be poorly differentiated adenocarcinomas. Rectal carci-
noids are malignant in up to 15% of cases and have a generally
better prognosis. The incidence of non-carcinoid second malig-
nancies in patients with colorectal carcinoids appears to be
significantly increased.
Presenting signs and symptoms differ between colonic and
rectal carcinoids. Colonic lesions present most frequently with
abdominal pain and weight loss. Only a minority of cases are
associated with clinical carcinoid syndrome. Rectal carcinoids
may present with rectal bleeding, constipation and pain, although
about 50% are asymptomatic. Carcinoid syndrome is extremely (b)
(a) (c)
Figure 5.13 (a) Poorly differentiated neuroendocrine tumor of the rectum. (b) Same tumor, showing pleomorphic cells arranged in a
prominent trabecular pattern. (c) Magnification of (b), showing highly atypical mitosis.
are usually less than 1 cm in diameter and tend to arise on the a proliferative process similar to that seen in ganglioneuromas
anterior or lateral wall of the rectum. involving the myenteric plexus and surrounding bowel wall.
EC-cell carcinoids: The histological and immunohistochemical
features of colorectal EC-cell carcinoids are the same as those
arising in the ileum (see tumors of the duodenum, jejunum and ● Diffuse ganglioneuromatosis may resemble the neuronal
ileum). The sustentacular cells found in appendiceal EC-cell car- hyperplasia seen in Crohn’s disease
cinoids are absent.
L-cell carcinoids: These are typically composed of uniform GRANULAR CELL TUMOR
cells arranged in ribbons and cords. Tubuloacinar structures or
trabecular patterns with rosetting are also frequently seen. The See Esophagus: Granular cell tumor (p. 204).
solid, nested appearance seen commonly in EC-cell carcinoids
is infrequently observed in L-cell carcinoids. HEMANGIOMA
Special techniques Benign hemangiomas occur more frequently in the large bowel
For EC-cell carcinoids, see the section on ileal carcinoids for than malignant vascular tumors. They are nevertheless very
immunohistochemical and ultrastructural features. uncommon.
L-cell carcinoids:
● These are usually non-argentaffinic, but positive with the HISTIOCYTOMA
Grimelius stain. Immunopositivity with common endocrine
markers such as chromogranin, synaptophysin and NSE is Rare examples of primary malignant fibrous histiocytoma aris-
observed. ing in the large bowel have been documented. The features are
● Most (about 80%) are positive for glucagon-like peptide similar to those of histiocytoma occurring elsewhere.
or pancreatic polypeptide/peptide-YY (PP/PYY).
● Scattered cells may be positive for serotonin or somatostatin. HISTIOCYTOSIS, LANGERHANS’ CELL
● Positivity for prostatic acid phosphatase is common (the
(HISTIOCYTOSIS X)
rectum and prostate share a common embryological origin).
● Electron microscopy reveals round or angular secretory
Involvement of the large bowel by Langerhans’ cell histiocyto-
granules. sis, a rare systemic infiltrative disease of unknown etiology, has
Differential diagnosis been documented but is decidedly uncommon.
● Malignant carcinoids must be distinguished from poorly KAPOSI’S SARCOMA

differentiated adenocarcinomas showing a carcinoid-like
growth pattern (see Clinical features above). Primary Kaposi’s sarcoma of the large bowel is well reported
in association with HIV infection and AIDS. A few cases of
non-AIDS-related Kaposi’s sarcoma are also documented in
NON-EPITHELIAL TUMORS the literature. Primary colorectal angiosarcoma appears to be
exceedingly rare.
ANGIOSARCOMA
LEIOMYOMA AND LEIOMYOSARCOMA
See Kaposi’s sarcoma (p. 205).
Stromal tumors of the large bowel are relatively uncommon, and
most show a smooth muscle phenotype. Benign leiomyomas
present as small polyps which develop from the muscularis
mucosae of the colon and rectum. Diffuse leiomyomatosis, simi-
CLINICAL FEATURES lar to that seen in the esophagus, has also been reported. As with
smooth muscle tumors elsewhere in the gastrointestinal tract, the
Ganglioneuromas, similar to those occurring elsewhere in the
literature regarding leiomyosarcoma is confusing as an unknown
body, are rare in the colon and rectum. They present in adults of
proportion of previously reported cases would now be classified
all ages, and may be solitary or multiple (the latter more common
as gastrointestinal stromal tumors (GIST). True leiomyosarcoma
in males), typically appearing as small nodules or polyps up to
is negative for C-KIT (CD117) and positive for SMA.
2 cm in diameter. Diffuse ganglioneuromatosis, a distinct entity,
may be seen in children or adults. In adults, a proportion of cases
LIPOMA AND LIPOSARCOMA
are associated with MEN-IIb or von Recklinghausen’s disease.
Lipomas occur most commonly in the submucosa of the cecum or
sigmoid colon. They typically appear as a discrete collection of
Solitary or multiple ganglioneuromas arising in the colon and mature adipose tissue enclosed by a fibrous capsule. Ulceration of
rectum are identical to those occurring elsewhere. Diffuse ganglio- the overlying mucosa may produce a degree of reactive atypia in
neuromatosis typically presents either as a mass or a segment of the fat cells. Diffuse lipomatosis of the bowel and liposarcoma are
strictured bowel. The characteristic histological appearance is of both extremely rare.
LYMPHANGIOMA Immunoproliferative small intestinal disease (IPSID) is not seen

in the colon and rectum, but all other lymphomas occurring in
Lymphangioma of the large bowel is very rare, although the small bowel can also occur in this site.
involvement of the mesentery occurs more frequently. The Colorectal lymphomas tend to occur in older patients,
histological features are identical to those of lymphangiomas although those associated with immunodeficiency and AIDS
occurring elsewhere. usually occur earlier. The left colon, rectum and anus is involved
most frequently. In addition to immunosuppression, recognized
LYMPHOMA risk factors for the development of colorectal lymphoma are
ulcerative colitis and (to a lesser extent) Crohn’s disease.
Presenting signs and symptoms include rectal bleeding, diar-
CLINICAL FEATURES rhea, abdominal pain, change in bowel habit, weight loss and an
abdominal mass.
Compared to lymphoma of the stomach and small intestine,
large-bowel lymphoma is uncommon, accounting for less than
1% of malignant tumors at this site. As in the small bowel, the
most common colorectal lymphoma is extranodal marginal The macroscopic appearance of large-bowel lymphomas is
zone lymphoma of mucosal-associated lymphoid tissue (MALT variable. A well-circumscribed mass invading through the
lymphoma) type. Mantle cell lymphoma, most commonly pre- bowel wall and protruding into the lumen is commonly seen
senting as lymphomatous polyposis, accounts for a greater in low-grade lymphomas. Diffuse large B-cell lymphoma and
percentage of cases in the large bowel than the small bowel. Burkitt’s lymphoma may be associated with ulceration and
(a) (b)
(c) (d)
Figure 5.14 Mantle cell lymphoma presenting as lymphomatous polyposis. Colonoscopy revealed multiple small polypoid lesions in the
left colon. (a) Submucosal aggregate of lymphoid cells. (b) Closer examination reveals a monotonous population of small to medium-sized
lymphocytes. Immunohistochemistry confirmed mantle cell lymphoma with CD5 (c) and cyclin D1 (d).
stricturing. Multiple small polyps (lymphomatous polyposis)

are most commonly seen with mantle cell lymphomas. The his-
tological and immunohistochemical features are described in
Chapter 10 (Lymphoreticular tumors).
TERATOMA
Benign cystic teratomas arising in the large bowel have been

documented, but appear to be extremely rare.
HAMARTOMAS
See Polyps and polyposis syndromes: Cowden syndrome below.
HETEROTOPIA: GASTRIC
Heterotopic gastric mucosa is an uncommon finding in the
colon. It typically appears as an area of mucosal irregularity Figure 5.15 Intestinal xanthomatosis. Numerous lipid-laden
or as a polypoid lesion, and may cause some concern for the histiocytes occupy much of the lamina propria in this section.
colonoscopist. There is often an associated gut malformation.
POLYPS AND POLYPOSIS SYNDROMES
LYMPHOID POLYPOSIS
Lymphoid polyposis is a benign process occurring in a variety of

COWDEN SYNDROME
settings, most commonly following viral infection in children.
For obvious reasons, malignant lymphomatosis polyposis (most CLINICAL FEATURES
commonly a presentation of intestinal mantle cell lymphoma)
must be excluded. Cowden syndrome describes an autosomal dominant condition
resulting in the formation of multiple hamartomas in different
organs. The disease is caused by a mutation in the PTEN gene
MALAKOPLAKIA
on chromosome 10q23.3. The most classical lesions associated
with Cowden syndrome are trichilemmomas (particularly of
The sigmoid colon and rectum are the second most common
the face), but many other organ systems are affected. Sufferers
sites of involvement by malakoplakia, following the urinary
have a greatly increased risk of developing breast and thyroid
tract. The features are identical to those of malakoplakia
malignancies, and mutations in the PTEN gene have been
occurring elsewhere, with characteristic polypoid or plaque-
increasingly found in other cancers. In the gastrointestinal
like lesions composed of histiocytes with abundant eosinophilic
tract, Cowden syndrome causes the development of mostly
cytoplasm. Calcified Michaelis–Guttmann bodies are the hall-
asymptomatic hamartomatous polyps.
mark of this condition, though these may not be a prominent
feature in some cases.
MUCOSAL PROLAPSE The gastrointestinal polyps associated with Cowden syndrome

are usually small, most measuring less than 1 cm. They are
Mucosal prolapse in the colon, rectum and anal canal gives rise composed of variable proportions of connective tissue, particu-
to a variety of presentations including solitary rectal ulcer larly smooth muscle, and non-dysplastic mucosal glands con-
syndrome, complete rectal prolapse and diverticular disease. taining normal goblet cells and columnar cells. Occasional
These conditions may give rise to lesions such as ulcers and polyps may contain adipose tissue or autonomic nerves, the lat-
inflammatory polyps, which could be mistakenly interpreted as ter imparting a ganglioneuromatous appearance.
malignant in origin.
CRONKHITE–CANADA SYNDROME
XANTHOMA (Figure 5.15)
CLINICAL FEATURES
Colorectal xanthomas are rare asymptomatic lesions. The histo-
logical features are similar to those of xanthomas occurring Cronkhite–Canada syndrome is an extremely rare, non-
elsewhere. hereditary condition characterized by the presence of multiple
gastrointestinal polyps associated with ectodermal changes (alope- PATHOLOGICAL FEATURES

cia, nail atrophy and hyperpigmentation). Adenomatous change
The macroscopic features of FAP are striking, with hundreds to
and colorectal carcinoma may also develop in this syndrome.
thousands of polyps of various size present mainly in the large
bowel. The adenomas are most commonly tubular in nature,
with tubulovillous and villous types less commonly encoun-
The polyps are juvenile or hyperplastic (metaplastic) in type. tered. A small proportion of adenomas in FAP are sessile rather
than polypoidal. Tiny microadenomas can often be found on
histological examination of grossly unremarkable mucosa.
HYPERPLASTIC (METAPLASTIC) POLYPS AND

POLYPOSIS
CLINICAL FEATURES
Hyperplastic/metaplastic polyps occur mainly in the left colon
and rectum, and present as small, asymptomatic polypoid
lesions, rarely more than 1 cm in diameter. The incidence of
hyperplastic polyps increases with age. The traditional view of
these polyps as non-neoplastic has been challenged more recently
by the frequent finding of Ras mutations and the demonstration
of clonality. Hyperplastic polyps (or a subset of so-called hyper-
plastic polyps) may in fact be neoplastic but do not follow the
same adenoma–carcinoma sequence (with inactivation of the
APC pathway) normally associated with the colon and rectum.
The term hyperplastic polyposis has been used to describe rare
cases of multiple hyperplastic polyps associated with an increased
risk of carcinoma and possible familial clustering. The validity of
Figure 5.16 Gastric polyp in a patient with Cronkhite–Canada this term is unclear as some authors have suggested that the
syndrome. Such polyps are usually hyperplastic polyps or, as in this polyps seen were in fact of serrated adenoma type – a distinction
case, juvenile polyps. which is not entirely straightforward.
FAMILIAL ADENOMATOUS POLYPOSIS PATHOLOGICAL FEATURES

The characteristic feature of these polyps is a serrated pattern of
significantly elongated crypts. The cells are characterized by
CLINICAL FEATURES
basally located round, vesicular nuclei with prominent nucleoli,
Familial adenomatous polyposis (FAP) is an autosomal dominant and eosinophilic cytoplasm containing a large luminal mucin
condition arising from a germline mutation in the APC (adeno- vacuole. Smooth muscle cells protruding into the lamina propria
matous polyposis coli) gene on the long arm of chromosome 5. are also characteristically seen. An inflammatory cell component
Adenomas, which range in number from hundreds to thousands, comprising mainly mononuclear cells and eosinophils may be
manifest themselves early in the second decade of life. The large observed, but the number of lymphocytes and plasma cells may
bowel is most commonly affected, but adenomas are also encoun- actually be reduced compared to the normal colonic mucosa.
tered in the stomach and small intestine. If left untreated, invasive
carcinoma will inevitably occur, mostly around the fifth decade,
INFLAMMATORY FIBROID POLYPS
although the risk is increased relative to the general population
well before the patient reaches the age of 40 years. An attenuated
See under Duodenum, jejunum and ileum (p. 225).
form of FAP is recognized in which the number of polyps is less
than 100 and they are mainly found in the right side of the colon.
The risk of malignancy is also mainly on the right side and man- JUVENILE POLYPS AND POLYPOSIS
ifests itself at relatively later age than ordinary FAP.
FAP is also associated with a variety of extracolonic manifes-
CLINICAL FEATURES
tations such as epidermoid cysts and osteomas of the skull and
mandible (referred to as Gardner’s syndrome). Turcot syndrome These polyps are hamartomatous in nature, representing an
refers to the combination of a primary brain tumor and multiple overgrowth of the lamina propria. They are characteristically
colorectal polyps – some of these cases are associated with APC seen as solitary lesions in the rectum in children, but they may
mutations; most of the remainder are associated with hereditary be multiple and seen elsewhere along the gastrointestinal tract.
non-polyposis colorectal carcinoma (HNPCC). They may also be seen in adults. Juvenile polyposis is a term
applied to cases showing more than five juvenile polyps of the Intraepithelial neoplasia associated with chronic inflamma-
colorectum; and/or juvenile polyps throughout the gastro- tory diseases
intestinal tract; and/or any number of juvenile polyps with a ● Low-grade glandular intraepithelial neoplasia
family history of juvenile polyposis. These cases may have a ● High-grade glandular intraepithelial neoplasia
small risk of malignant transformation. Carcinoma

● Adenocarcinoma
PATHOLOGICAL FEATURES ● Mucinous adenocarcinoma
These polyps are characterized by dilated, irregularly shaped ● Signet-ring cell carcinoma
glands present in an abundant and usually inflamed stroma. ● Small cell carcinoma

Cell morphology ● Adenosquamous carcinoma
The constituent glands are lined either by a single layer of ● Medullary carcinoma
columnar mucin-secreting epithelium or flattened, attenuated ● Undifferentiated carcinoma
epithelium. There is no cytological atypia. Carcinoid (well-differentiated endocrine neoplasm)

● EC-cell, serotonin-producing neoplasm
Differential diagnosis ● L-cell, glucagon-like peptide and PP/PYY-producing tumor
● Inflammatory, regenerative polyps ● Others
Mixed carcinoid-adenocarcinoma
● Others
LYMPHOID POLYPS
Lymphoid polyps are simply surface projections caused by promi- ● Lipoma
nent mucosal or submucosal aggregates of reactive mucosa- ● Leiomyoma
associated lymphoid tissue. The differential diagnosis is with ● GIST
malignant lymphomatous polyposis, most commonly a presenta- ● Leiomyosarcoma
tion of gastrointestinal mantle cell lymphoma. ● Angiosarcoma
● Kaposi’s sarcoma
● Malignant melanoma
● Others
See under Duodenum, jejunum and ileum (p. 225). Malignant lymphomas
● Marginal zone B-cell lymphoma of MALT type
● Mantle cell lymphoma

WHO CLASSIFICATION OF TUMORS OF THE ● Diffuse large B-cell lymphoma
COLON AND RECTUM ● Burkitt lymphoma
● Burkitt-like/atypical Burkitt lymphoma
● Others
The WHO classification of tumors of the colon and rectum con-
tains the following entities: Secondary tumors
Epithelial tumors Polyps
Adenoma ● Hyperplastic (metaplastic)
● Tubular ● Peutz–Jeghers
● Villous ● Juvenile
● Tubulovillous
● Serrated
TUMORS OF THE ANAL CANAL
congenital anal fistulae. Adenocarcinomas of the anal canal

EPITHELIAL TUMORS often arise in association with other pathological conditions in
the region such as Crohn’s disease and duplication of the hind
ADENOCARCINOMA gut or, very uncommonly, as a result of implantation of viable
tumor cells in a pre-existing fistula.
CLINICAL FEATURES PATHOLOGICAL FEATURES (Figure 5.17)

Adenocarcinoma may arise from the mucosal lining of the Anal adenocarcinoma tends to present as an ulcerating or
upper part of the anal canal or rarely from the anal ducts and sometimes polypoid lesion. Histologically, adenocarcinomas
glands. Occasional tumors are associated with acquired or arising in the upper part of the anal canal are similar to those
(a)
Figure 5.17 Possible anal gland carcinoma.This tumor showed

extensive infiltration through the submucosa and muscularis
propria, but no apparent connection to the overlying mucosa.
Confident diagnosis of anal gland carcinoma is very difficult.
arising in the rectum. Tumors with an origin from the anal

ducts and glands are composed of haphazardly dispersed,
small glands with scant mucin production invading the wall of
the anorectal region. In these tumors an intraluminal com-
ponent is absent, and an origin from pre-existing anal gland
dysplasia confirms the diagnosis. Adenocarcinoma asso-
ciated with acquired or congenital anal fistulae can be mucin-
producing.
ANAL INTRAEPITHELIAL NEOPLASIA
Anal intraepithelial neoplasia and perianal Bowen’s disease

(see section below) are precursors to squamous carcinoma of
the anus. Histologically, they are similar to – and are associated
with – cervical and vulval intraepithelial neoplasia. They also (b)
share human papillomavirus infection as an underlying etio-
logical factor. Biopsy and histopathological examination are Figure 5.18 (a, b) Basaloid variant of squamous cell carcinoma
required for diagnosis and distinction from perianal der- arising in the anal canal.
matoses or other pathology.
ANAL MARGIN TUMORS BUSCHKE–LOWENSTEIN TUMOR (GIANT

CONDYLOMA)
The spectrum of tumors arising in the anal margin is the
same as those of the skin elsewhere. Common tumors at this These terms are applied to verrucous carcinoma of the anogenital
site include squamous carcinoma, condyloma accuminatum, area (see Squamous cell carcinoma, p. 240).
keratoacanthoma, basal cell carcinoma, and hidradenoma
papilliferum. Bowen’s disease and Bowenoid papulosis are also MELANOMA
seen at this site.
BASALOID CARCINOMA (Figure 5.18)

CLINICAL FEATURES
Malignant melanoma is not an uncommon primary tumor of
See Squamous cell carcinoma (p. 240). the anus originating from basal melanocytes at the transitional
zone above the dentate line. It is a highly aggressive tumor at SQUAMOUS CELL CARCINOMA
this site with early direct, lymphatic and metastatic spread.
PATHOLOGICAL FEATURES CLINICAL FEATURES
Macroscopically, anal melanoma usually appears as an ulcerat- Squamous cell carcinoma (SCC) of the anal canal remains a
ing or a polypoid lesion. Morphologically, the melanocytes may relatively uncommon disease, though the incidence has risen
be epitheloid or spindle-shaped. Melanin pigment is absent or sharply during the latter half of the twentieth century. Patients
scarce in approximately half of the cases. The main histological typically present in the sixth or seventh decades of life, although
challenge is that of identifying a junctional component which squamous carcinoma arising in immunosuppressed patients is
may be absent due to extensive ulceration. seen more commonly in young adults. There appears to be a
female predominance. The incidence rates of anal squamous
carcinoma in homosexual men is particularly high, especially in
MUCOEPIDERMOID CARCINOMA association with HIV infection. Recognized risk factors include
multiple sexual partners, anal intercourse, coexisting sexually
Mucoepidermoid carcinoma of the anus is exceedingly rare. transmitted diseases, smoking (at least in women) and immuno-
The immunohistochemical staining pattern is different from suppression due to HIV infection or transplantation.
that of anal squamous cell carcinoma. The tumor is positive Infection by human papillomavirus, particularly HPV type
for EMA, CEA and CAM5.2, but negative for cytokeratin 16 (one of the ‘high-risk’ types associated with cervical intraep-
(CK) 10. An origin from the anal transitional zone has been ithelial neoplasia and carcinoma), appears to be central to the
postulated. pathogenesis of most squamous carcinomas of the anal canal.
HPV DNA can also be detected in many SCCs arising in perianal
PAGET’S DISEASE, PERIANAL skin – albeit less frequently – suggesting that other pathogenetic
mechanisms may also be involved.
Anal carcinomas often present late, with non-specific symp-
CLINICAL FEATURES toms. Patients may complain of pruritus, pain, change in bowel
habit, fecal incontinence, bleeding and the sensation of a mass.
Extramammary perianal Paget’s disease is an uncommon but
Anal fissures and fistulae to the skin or adjacent structures may
distinctive intraepidermal neoplasm, presenting as a slowly
also be seen.
growing erythematous plaque. True Paget’s disease is an intra-
epithelial adenocarcinoma arising from dermal apocrine sweat
glands. The neoplasm has a high local recurrence rate and may TNM STAGING OF CARCINOMA OF THE ANAL CANAL
be accompanied by an invasive adenocarcinoma or in situ ade- N.B. Tumors of the anal margin are staged as for tumors of
nocarcinoma of apocrine or eccrine glands. ‘Paget’s disease’ in the skin.
the context of a coexisting malignancy (most commonly col-
orectal adenocarcinoma) represents pagetoid extension by the T Stage:
primary tumor. Immunohistochemistry is required to distinguish T0 No evidence of primary tumor
these cases from true Paget’s disease (see below). Tis Carcinoma in situ
T1 Tumor 2 cm or less in greatest dimension
PATHOLOGICAL FEATURES T2 Tumor more than 2 cm but not more than 5 cm in
greatest dimension
Paget’s disease is characterized by infiltration of the squamous T3 Tumor more than 5 cm in greatest dimension
epithelium by cells with large vesicular nuclei and abundant T4 Tumor of any size invading adjacent organ(s), e.g., vagina,
pale cytoplasm. Some of the cells may display a signet-ring mor- urethra, bladder (involvement of the sphincter muscle(s)
phology. Paget cells may occupy only the basal layer or spread alone is not classified T4)
to infiltrate the entire thickness of the epidermis.
N Stage:
Special techniques N0 No regional lymph node metastasis
N1 Metastasis in perirectal lymph node(s)
● Paget cells are positive with mucin stains.
N2 Metastasis in unilateral internal iliac and/or inguinal lymph
● Immunoreactivity for CK7 is present in most cases.
node(s)
● Gross cystic disease fluid protein-15 (an apocrine cell
N3 Metastasis in perirectal and inguinal lymph nodes
marker) is positive in true Paget’s disease, but usually
and/or bilateral internal iliac and/or inguinal lymph
negative in pagetoid spread by colorectal
nodes
adenocarcinoma.
Differential diagnosis PATHOLOGICAL FEATURES

● Bowen’s disease Squamous carcinomas arise mainly in the transitional zone
● Malignant melanoma with direct spread upwards to the lower rectum. The majority
● Pagetoid spread of colorectal primary of these tumors present as ulcerating lesions.
A variety of histological patterns are seen, with a mixture of

patterns observed in many tumors. Large cell keratinizing and NON-EPITHELIAL TUMORS
non-keratinizing subtypes are recognized, as is a ‘basaloid’ sub-
type composed of small cells showing peripheral pallisading. KAPOSI’S SARCOMA
The latter is commonly associated with HPV 16 infection. There
does not appear to be any prognostic significance in subclassi- These resemble those lesions seen in the large bowel, and share
fying tumors based on these histological subtypes, and in any with them their clinical, gross and histological features.
case reproducibility is generally poor. The following three sub-
types do however have prognostic implications:
1. Squamous cell carcinoma with mucinous microcysts. TERATOMA
This variant is characterized by the presence of distinct
glandular or cystic structures containing PAS-D and Benign cystic teratoma has been described in the anorectal and
Alcian blue-positive mucin. It is associated with a presacral regions. The latter are sometimes seen as a part of
poorer prognosis than conventional squamous cell the Currarino triad. This triad comprises an association of a
carcinoma. congenital anorectal stenosis, or another type of low anorectal
2. Small cell (anaplastic) carcinoma. The terminology used malformation, an anterior sacral defect, and presacral mass.
for this variant is somewhat unfortunate as these tumors They present in neonates and young children. Malignant trans-
are not related to conventional small cell carcinomas (i.e., formation is known to occur, and therefore adequate excision
poorly differentiated neuroendocrine carcinomas). They should be ensured.
nevertheless share some features with their more familiar
namesake, including nuclear molding, a high mitotic
rate and diffusely infiltrative growth pattern. Perhaps
unsurprisingly they are associated with a poorer
prognosis. ABSCESS
3. Verrucous carcinoma (Buschke–Lowenstein tumor/Giant
(malignant) condyloma). Verrucous carcinomas are The gross pattern and radiological appearance of an anal
associated with a good prognosis. Their behavior and abscess may be confused with neoplastic growth (and vice
clinical course lie somewhere between that of a typical versa). As such, histological evaluation is advised in longstand-
condyloma and a squamous cell carcinoma, with local ing or unresolving lesions. Abscess cavities are a recognized site
invasion but no metastatic spread. Malignant of origin of perianal mucinous adenocarcinomas, an uncom-
transformation is well recognized, as is regression mon tumor.
following interferon therapy. HPV may be found in these
lesions, particularly the ‘low-risk’ types 6 and 11. They
are typically large tumors (up to 12 cm in diameter).
CYST HAMARTOMA
Microscopically, verrucous carcinoma shows both
exophytic and endophytic growth with acanthosis, CLINICAL FEATURES
papillomatosis and keratin-containing cysts. Features of
viral infection such as koilocytosis may be observed. Cyst hamartomas are of retrorectal origin. They often occur in
Mitotic activity is limited to the basal layers only, and association with recurrent anal fistulae or abscesses.
dysplastic features should be absent or minimal.
VERRUCOUS CARCINOMA These lesions comprise multilocular cysts lined by a variety of
epithelial cell types – squamous, columnar and transitional.
See Squamous cell carcinoma above. This represents a morphological pattern not unlike that seen in
other cysts nearby such as Bartholin’s gland duct cysts.
NEUROENDOCRINE TUMORS Differential diagnosis

● Duplication cyst of the rectum
● Simple anal gland cysts
SMALL CELL CARCINOMA ● Benign cystic hamartoma
● Adenocarcinoma of anal glands
Anorectal neuroendocrine small cell carcinomas are rare. They
need to be distinguished from epidermoid anal canal tumors
due to their poor prognosis and their frequent presentation HEMORRHOIDS
with hepatic and pulmonary metastasis. An association with
HIV infection has been reported. The possibility of metastatic Histological examination of hemorrhoids should be mandatory
origin from more common sites such as the lungs needs to be as the literature demonstrates several examples where they con-
carefully excluded. tained metastatic deposits from elsewhere, or were primary
neoplasms disguised as hemorrhoids. There is no convincing Epithelial tumors

evidence that hemorrhoids are a predisposing factor for the Intraepithelial neoplasia (dysplasia)
development of anal squamous carcinoma. ● Squamous or transitional epithelium
● Glandular
● Paget’s disease
MALAKOPLAKIA
Carcinoma
Malakoplakia is rarely described in the anal region, and can be
● Adenocarcinoma
misdiagnosed clinically as a common perianal abscess. The his-
tology is similar to that described elsewhere, though it has been
reported that at this site the lesions are characterized by a
paucity of Michaelis–Guttman bodies.
● Others
Carcinoid tumors
WHO CLASSIFICATION OF TUMORS OF THE Malignant melanoma
ANAL CANAL Non-epithelial tumors
Secondary tumors
The WHO classification of tumors of the anal canal contains the
following entities:
5.2 HEPATOBILIARY TRACT TUMORS

Christopher OC Bellamy
Intrahepatic tumors 243 Hepatoblastoma 255

Bile duct epithelial tumors, benign 243 Hepatocellular carcinoma (HCC) 256
Bile duct cystadenoma 243 Undifferentiated liver carcinoma 259
Bile duct papillomatosis 244
Mesenchymal tumors of the liver, benign 259
Biliary adenofibroma 244
Angiomyolipoma 259
Biliary microhamartoma (Von Meyenberg complex) 245
Hemangioma, sclerosed hemangioma 259
Peribiliary gland hamartoma (bile duct adenoma) 245
Infantile hemangioendothelioma 259
Peribiliary gland hyperplasia 246
Inflammatory myofibroblastic tumor (inflammatory
Bile duct epithelial tumors, malignant 247 pseudotumor) 260
Cystadenocarcinoma 247 Mesenchymal hamartoma 260
Intrahepatic cholangiocarcinoma 247 Solitary fibrous tumor 260
Cystic lesions of the liver 248 Mesenchymal tumors of the liver, malignant 260
Choledochal cyst 248 Angiosarcoma 260
Ciliated hepatic foregut cyst 248 Embryonal rhabdomyosarcoma 261
Cystic peribiliary glands (hilar cysts, cystic periductal glands) 248 Embryonal sarcoma (undifferentiated sarcoma) 261
Endometriotic cyst 248 Epithelioid hemangioendothelioma 261
Hydatid cyst 249 Follicular dendritic cell tumor 261
Pancreatitic pseudocyst of liver 249 Lymphoma of liver 262
Polycystic liver disease 249 Ossifying malignant mixed epithelial and stromal tumor 262
Solitary intrahepatic biliary cyst 250 Miscellaneous tumors 262
Liver cell tumors, benign 250 Abscess 262
Dysplastic nodule (adenomatous hyperplasia) 250 Accessory liver lobes 262
Focal nodular hyperplasia (FNH) 251 Caroli’s disease (congenital intrahepatic bile
Hepatocellular adenoma 252 duct dilation) 263
Partial nodular transformation 253 Ecotopic tissues 263
Regenerative (post-necrotic) multiacinar nodules in Encysted fat necrosis (pseudolipoma) 263
submassive liver necrosis 254 Focal fatty change 263
Regenerative multiacinar ‘macro-nodules’ in cirrhosis 255 Infarction 263
Langerhans’ cell histiocytosis 264
Liver cell tumors, malignant 255 Necrotic nodule 264
Combined hepatocellular and cholangiocarcinoma 255 Secondary metastasis 264
Tumors of the gallbladder and extrahepatic bile duct 265 Miscellaneous tumors 266
Epithelial tumors, benign 265 Acquired diverticular disease of the gallbladder
Adenoma (tubular, papillary, tubulopapillary) 265 (localized adenomyomatous hyperplasia) 266
Bile duct cystadenoma 265 Rarities 267
Granular cell tumor 266 Xanthogranulomatous cholecystitis
(fibroxanthogranulomatous cholecystitis) 267
Epithelial tumors, malignant 266
Carcinoma of the gallbladder 266
Carcinoma of the extrahepatic bile duct 266
GENERAL COMMENTS ● What is the non-tumorous liver like, and has any been
included in the sample pot (perhaps not separately labeled
This subchapter details non-neoplastic and neoplastic diseases as such)?
that may present, at least apparently, as a discrete tumorous lesion ● How confident is the person who took the sample that
or lesions affecting the liver parenchyma or the extrahepatic bil- they removed the entire lesion?
iary tree. Perhaps the most common hepatic tumor samples sub- ● If there is more than one lesion, which one (or more) was
mitted to the general diagnostic pathologist are needle biopsies of sampled?
presumed metastatic disease. In that setting, the pathologist is
With regard to the clinical history, as in all cases, consider
hopefully able to confirm and type the malignancy, thereby
whether the diagnosis that the morphology is suggesting is likely
permitting the oncologist to formulate a management strategy
in that clinical setting, or whether there might be a more likely
with confidence in the diagnosis. More problematic are issues of
alternative. For example, before diagnosing a hepatic adenoma
identifying a clinically occult primary site for the malignancy,
on a needle biopsy, the information that the biopsy came from
and while this may be possible for some cases, based upon histo-
one of three lesions in the cirrhotic liver of an elderly man
logical pattern and/or immunohistochemistry, other cases are
would of course suggest hepatocellular carcinoma to be the
frustratingly ambiguous. There is much room for more refined
main consideration. Likewise, a diagnosis of cirrhosis is not
assessments, which most probably will come from immunohisto-
likely where the biopsy has been of a small focal lesion in the
chemistry, expression arrays, or proteomics.
radiologically otherwise normal liver of a young adult woman
Regularly, however, the pathologist will be faced with tissue
with a possible focal nodular hyperplasia. Hopefully, such infor-
from intrinsic hepatobiliary tumors for interpretation. There are
mation would be provided with the specimen, but this may not
a wide range of lesions that, individually, may be seen only infre-
always be the case!
quently, but collectively are not uncommon. Important principles
Finally, an important consideration to bear in mind is the
to bear in mind when evaluating hepatobiliary disease include
limitation of a small sample to formulating a confident diag-
correlating the morphological appearances with the radiology
nosis. It may simply be possible only to provide a weighted dif-
and clinical setting. Then, having evaluated the morphology, there
ferential diagnosis based on a needle biopsy or even a wedge
is a need to identify the clinical setting and radiology from the
biopsy. This is not a failure of the pathologist – it is just a fact
person who imaged/viewed the liver and carried out the biopsy.
of sampling.
Here, helpful questions to consider might include:
● Is the sample from a focal lesion?
● Is the lesion solitary?
INTRAHEPATIC TUMORS
with a mass, abdominal pain, and sometimes raised serum

BILE DUCT EPITHELIAL TUMORS, BENIGN CA19-9 levels.
A potential for recurrence and malignant transformation
BILE DUCT CYSTADENOMA mandates curative excision when technically possible.

CLINICAL FEATURES
Most of these tumors are intrahepatic, forming a characteristi-
These are rare lesions, and mucinous cystadenoma is much more cally multilocular cystic lesion which may be a few to several
frequent than serous cystadenoma. They almost always affect centimeters in diameter. Polypoid extension into the common
women, at any age (but typically over 40 years), and present hepatic duct has been described.
and some degree of nuclear hyperchromasia. Mitotic figures or

MIB1 immunopositivity are apparent. Epithelial dysplasia is
suspicious for progression towards hepatobiliary cystadeno-
carcinoma, and may merit further sampling.
Serous cystadenoma is uncommon, lined with cuboid,
glycogen-rich clear cells. There is no ‘ovarian-like’ stroma, as
with the mucinous cystadenoma.
● Bile duct cystadenocarcinoma may be missed if sampling
is not thorough and directed to exophytic tumor foci
● Simple cyst (unilocular by definition)
● Endometriosis
Special techniques
● The lining epithelial cells are cytokeratin-, epithelial
membrane antigen (EMA) and carcinoembryonic antigen
(CEA)-positive.
● The ovarian-like stroma shows smooth muscle actin
(a)
immunopositivity, and stromal cell positivity for estrogen
and progesterone receptors.
● Focal chromogranin or synaptophysin immunopositivity
indicates neuroendocrine change in some cases.
BILE DUCT PAPILLOMATOSIS
CLINICAL FEATURES
This is a benign but often multifocal papillary neoplasm which
may affect any part of the biliary tree, gallbladder and occasion-
ally also the pancreatic ducts. It usually affects middle-aged or
elderly adults, some with many years’ history. Presentation is with
effects of intermittent biliary obstruction. The multifocality
means that recurrence is common after local resection, and many
patients die within 2–3 years due to recurrent obstruction and
cholangitis. The condition may be complicated by the develop-
ment of focal invasive carcinoma.
(b)
There are dilated bile ducts with friable luminal papillary excres-
Figure 5.19 Bile duct mucinous cystadenoma, showing a compact cences, and variable mucus secretion. Secondary changes may be
subepithelial stroma (a), and cytologically bland epithelial lining (b). evident, such as local fibrosis, suppuration or abscess. Each
lesion is a papillary or villous adenoma. Focal progression to
invasive adenocarcinoma may be evident. Secondary parenchy-
On microscopy, the locules are lined by cytologically bland or mal changes in the proximal liver segments are related to
occasionally mildly atypical mucinous columnar or cuboidal obstruction (biliary fibrosis, suppurative cholangitis).
epithelium, with basal nuclei reminiscent of endocervical or
gastric foveolar cells. Mitotic figures are absent. Areas with bland
small papillary projections may occur. There may be focal intes- BILIARY ADENOFIBROMA
tinal metaplasia, and rarely squamous change is apparent. In
women, the immediately subepithelial stroma is often cellular and
CLINICAL FEATURES
compact with numerous myofibroblastic cells, resembling ovar-
ian stroma (also seen with pancreatic cystadenoma). Degenerative A rare, benign and probably neoplastic proliferation of the bil-
changes include hemorrhage and xanthogranulomatous reaction. iary epithelium. The lesion is reminiscent of ovarian adeno-
Dysplastic change is recognized by the usual criteria that fibroma and breast fibroadenoma. The natural history is
include loss of nuclear polarity accompanied by stratification unknown, but a presumed (rare) potential for malignant change
mandates complete excision of this lesion whenever possible. ● Bile duct adenoma: this shows more closely packed, regular,
The potential for recurrence is unknown. small ductular structures that lack cystic change or luminal
bile, and are more usually associated with an inflammatory
cell infiltrate.
PATHOLOGICAL FEATURES ● Biliary adenofibroma.
This is a solitary lesion which may attain a diameter of several
centimeters. It is a circumscribed, complex tubulocystic proli-
feration of cubocolumnar epithelium, with abundant desmo- PERIBILIARY GLAND HAMARTOMA (BILE DUCT
plastic stroma, and is negative for mucin. Mitoses, atypia and
focal epithelial tufting are evident, by contrast with a peribil-
ADENOMA)
iary gland hamartoma. There may be luminal bile or cell
debris, and associated inflammation. CLINICAL FEATURES
This is an uncommon condition, and is usually an incidental
Differential diagnosis finding that raises concern for metastasis at surgery/laparoscopy.
● Intrahepatic cholangiocarcinomas or metastatic The pathogenesis is obscure, but probably hamartomatous or a
adenocarcinomas show stromal and/or perineural reaction to a local injury, rather than neoplastic. The lesion may
invasion, lack luminal bile concretions, and lack the present at any age.
organized overall architecture of biliary adenofibroma
● Biliary microhamartoma (Von Meyenberg complex)
● Peribiliary gland hamartoma (bile duct adenoma) PATHOLOGICAL FEATURES (Figure 5.20)
The lesion is a circumscribed, pale, 1- to 20-mm-diameter lesion
Special techniques in the liver parenchyma. It shows an organoid appearance at
low-power magnification. It is composed of aggregated small,
● The epithelium is mucin-negative, and EMA- and
bland, regularly dispersed ductules in a stroma showing variable
CEA-immunopositive.
neutrophil infiltration and fibrosis. The ductules have either a
● The stromal cells are vimentin-positive.
simple tubular pattern or a more tortuous configuration; the
lumens are narrow or slightly dilated or compressed, without
cystic change or luminal bile. The lining epithelial cells are
BILIARY MICROHAMARTOMA (VON MEYENBERG cuboidal with basally located, round or oval nuclei. They lack
COMPLEX) hyperchromasia or mitotic figures. Neutrophils may enter the
ductular epithelium. The stroma is either cellular fibroblastic or
acellular and collagenous. The adjacent liver parenchyma is
CLINICAL FEATURES usually normal. Microcalcification or non-caseating peripher-
This is a common incidental finding that, at surgery or autopsy, ally sited granulomas are very occasionally encountered.
may raise concern for metastases. It is a developmental anomaly
that is believed to be part of the spectrum of polycystic liver dis-
ease, and is associated with autosomal dominant polycystic kid-
ney disease. ● Adenocarcinoma, either primary peripheral cholangio-
carcinoma, or metastatic (e.g., gastrointestinal or
pancreatic). Look for cytological atypia, single cell
PATHOLOGICAL FEATURES invasion, perineural invasion, atypical structures
This is a gray-white nodule(s) in the parenchyma, less than (cribriform or back-to-back pseudoglands with tumor
5 mm diameter. On microscopy, there are loose aggregates of necrosis), mitotic activity, and vascular invasion.
dilated ductular structures topographically related to portal Non-biliary cytokeratin staining may help
tracts, lying within a hyalinized stroma. The ductular struc- ● Biliary microhamartoma/von Meyenberg complex.
tures are lined by bland cuboid or attenuated epithelial cells Small nodules of ductular structures embedded in a
with oval/round nuclei, and lacking mitotic figures. Unlike bile hyalinized stroma, topographically related to portal tracts.
duct adenoma, the ductules typically show variable degrees of Unlike bile duct adenoma, the ductules in von Meyenberg
cystic dilatation and contain luminal bile. Acute inflammation complex exhibit variable degrees of cystic dilatation and
is uncommon. often contain luminal bile
● Biliary adenofibroma
● Adenocarcinoma, either metastatic or primary peripheral Special techniques
cholangiocarcinoma. Not usually a problematic distinction, ● Ductular cells stain with biliary cytokeratins (CK7, 19),
given the blandness and architecture of this lesion, and EMA and CEA.
obvious luminal bile. ● Ductules show luminal mucin.
(a) (b)
Figure 5.20 Peribiliary gland hamartoma, showing the organoid

low-power appearance (a), and regular gland structures that lack
(c)
luminal bile (b) and show mucin expression (c).
macroscopically or with imaging as an incidental finding.

PERIBILIARY GLAND HYPERPLASIA
There is an association with hepatolithiasis, and other inflam-
matory biliary diseases.
CLINICAL FEATURES
Extrahepatic and large intrahepatic bile ducts, and the neck of
the gallbladder normally contain groups of small seromucinous Local inflammation and scarring may distort the glands in such
glands (peribiliary glands) lying within the fibromuscular a manner as to superficially resemble adenocarcinoma (a
wall, and in periductal connective tissue. These glands drain frozen-section diagnosis pitfall). The glands may also show
into the bile duct lumen through small channels (sacculi of intestinal or gastric metaplasia. Dysplasia of the glands pres-
Beale in extrahepatic bile ducts). Hyperplasia of these glands ents a further diagnostic challenge for discrimination from
is common, but is only rarely severe enough to be visible invasive adenocarcinoma.
BILE DUCT EPITHELIAL TUMORS, MALIGNANT
CYSTADENOCARCINOMA
CLINICAL FEATURES
This is a rare condition, arising in a bile duct cystadenoma or,
uncommonly, within a unilocular intrahepatic biliary cyst (see
also Bile duct cystadenoma, p. 243). Men and women are
equally affected, in contrast to bile duct cystadenoma. The age
at presentation shows a wide range, but is often over 40 years.
The prognosis is probably better than for intrahepatic
cholangiocarcinoma, and depends on resectability.
The malignant change is often multifocal, manifesting as tubulo-
papillary adenocarcinoma. Spindle cell change or adenosqua-
mous carcinoma may occur. Non-malignant epithelium often
(a)
shows dysplasia, and stromal invasion can be evident. In women,
there may be ovarian-like stroma, as in bile duct mucinous
cystadenomas.
● Bile duct cystadenoma with dysplasia lacks stromal
invasion and the frankly malignant cytoarchitecture (e.g.,
back-to-back glands, solid sheets) of the tubulopapillary
carcinoma foci. Special techniques are not helpful in
the differential diagnosis
INTRAHEPATIC CHOLANGIOCARCINOMA
CLINICAL FEATURES
The distinction between intrahepatic and extrahepatic bile
ducts is defined to be the point where the first-order ducts
(right and left hepatic) give rise to the second-order bile ducts.
Most cases of intrahepatic cholangiocarcinoma arise in periph-
eral liver and present late.
Carcinoma arising in the region of the hepatic duct confluence (b)
has been termed hilar adenocarcinoma (Klatskin tumor). Such
tumors are slow-growing and present with progressive obstruc- Figure 5.21 Cholangiocarcinoma in a targeted needle biopsy of
tive jaundice. An uncommon malignancy with equal gender dis- liver. Sparse, angulated glands, lined by moderately atypical cells, are
tribution, it usually presents in the elderly. Predisposing factors irregularly distributed in a desmoplastic stroma (a).The cells show
abnormal accumulation of immunoreactive p53 (b).
include chronic liver fluke (Opisthorchis) infestation, primary
sclerosing cholangitis, ulcerative colitis, hepatolithiasis, biliary
Secondary changes related to local biliary obstruction may be evi-
malformations (e.g., Caroli’s disease, solitary cyst, congenital
dent (fibrosis, suppuration).
hepatic fibrosis) and Thorotrast administration.
Microscopically, this manifests as a tubular, papillary and/or
cord-like adenocarcinoma. There are usually well-differentiated
regular tubules, but focal, moderately differentiated structures
Three growth patterns are recognizable with imaging: mass- (cribriform elements, more distorted tubules) or nuclear pleo-
forming is the most common, producing white parenchymal nod- morphism and mitoses assist recognition as malignant. An often
ules; the periduct invasive pattern invades along and expands the abundant fibroblastic stroma separates carcinomatous struc-
portal tree, producing thickened duct walls; intraduct papillary tures, often showing concentric arrangement around the malig-
carcinoma occupies a dilated duct segment with often limited nant ducts or glands. Perineural invasion can be helpfully evident
mural invasion, and can develop from biliary papillomatosis. in large portal tracts.
Uncommon cytological variants include signet ring cell, clear PATHOLOGICAL FEATURES
cell and mucinous (abundant intra- and extracellular mucin).
Macroscopically, there is a focal dilation of the common bile
Occasionally, more poorly differentiated examples may manifest
duct, of up to several liters capacity. Microscopically, the wall
squamous differentiation (adenosquamous carcinoma), spindle
is fibrous and bile-stained, with only scant residual strips of lin-
cell change, or as undifferentiated lymphoepithelioma-like carci-
ing epithelium. Mucinous, goblet cell and Paneth cell changes
noma. Mucoepidermoid carcinoma is exceptionally rare.
are common.
A peripheral zone of bile duct epithelial dysplasia is typical,
Complications include rupture, secondary infection, stones, dys-
mandating a wide excision to achieve resection. Sclerosing
plasia and progression to carcinoma (usually adenocarcinoma,
cholangitis (primary or secondary) may coexist with cholangio-
but rarely undifferentiated or squamous carcinoma). The risk
carcinoma as a primary predisposing factor or a secondary
of malignancy accumulates with age.
complication.
CILIATED HEPATIC FOREGUT CYST
● Metastatic adenocarcinoma. Intrahepatic cholangio-
carcinoma is a diagnosis of exclusion because it cannot
be discriminated with certainty by histology alone from CLINICAL FEATURES
metastatic carcinoma from extrahepatic sites (biliary tree, Ciliated hepatic foregut cyst is a rare incidental intrahepatic
pancreas or elsewhere). Diffuse CK20 expression strongly cyst of a few centimeters in diameter. It is more common in the
favors – but does not prove – metastatic adenocarcinoma left lobe of males – unlike most other solitary cysts, which are
of non-biliary origin. Metastatic colonic adenocarcinoma more common in women and in the right lobe. Squamous cell
may enter and grow along intrahepatic bile ducts carcinoma has been described in such cysts.
● Hepatocellular carcinoma (HCC) shows capillarized
sinusoids between neoplastic cells, rather than desmoplastic
stroma. Bile production is diagnostic. Mucin is absent. Focal PATHOLOGICAL FEATURES
hepatocyte antigen positivity strongly favors HCC (or a
This is an intrahepatic cyst lined by respiratory-type (bronchi-
combined carcinoma)
olar) ciliated pseudostratified epithelium, with smooth muscle
● Peribiliary gland hyperplasia retains a regular organoid
and fibrous tissue surrounding. It is occasionally multilocular.
arrangement of glands on low-power microscopy, with
lack of both atypia and the usual indicators of invasion
(single cells, cords, perineural invasion) CYSTIC PERIBILIARY GLANDS (HILAR CYSTS,
● Biliary adenofibroma lacks definitive stromal invasion
CYSTIC PERIDUCTAL GLANDS)
Special techniques
● CK7, CK19, EMA, CEA are typically positive, and CK20 CLINICAL FEATURES
typically negative. However, differential CK staining is not
These represent aggregates of cystic peribiliary glands (up to
sufficiently predictive in individual cases to completely
3–4 cm cysts) around large bile ducts in the liver hilum, which
discriminate cholangiocarcinoma from other carcinomas
no longer communicate with the bile duct. The lesion is discov-
(CK20 is occasionally positive; CK7 and 19 are not biliary-
ered as an incidental finding on imaging or resection specimens.
specific). Hepatocyte antigen is very occasionally positive.
They most likely represent post-inflammatory retention cysts
with no clinical significance, but may compress the bile duct.
CYSTIC LESIONS OF THE LIVER
CHOLEDOCHAL CYST The lesions show organoid clusters of cysts lined with cuboidal
or attenuated epithelium, lying between or within relatively
normal peribiliary glands. Periglandular fibrosis usually sepa-
CLINICAL FEATURES
rates and invests these clusters.
This is a congenital dilation of the common bile duct which usu-
ally affects females. Antenatal diagnosis is sometimes possible.
Infants present with jaundice and a painful mass, while adults ENDOMETRIOTIC CYST
present with ascending biliary infection or with an incidental
lesion (e.g., at antenatal screening). The condition may be clini-
CLINICAL FEATURES
cally silent until old age. It can be associated with various
anatomical abnormalities of the biliary tree (including biliary Hepatic endometriotic cyst is a solitary uni- or multilocular
atresia, Caroli’s syndrome), and with anomalous junction of bil- cyst found within otherwise normal liver. It is often associ-
iary with pancreatic ducts, which permits reflux of pancreatic ated with pain and a history of previous pelvic surgery, or
juice up the bile duct. endometriosis.
PATHOLOGICAL FEATURES identical cyst histology manifesting from different diseases that
have not yet been fully characterized or separated from each
This is similar to endometriotic cyst of the ovary, but seen in
other in many published series.
otherwise normal liver parenchyma. It may be misdiagnosed as
Isolated polycystic liver disease is a dominantly inherited
metastatic adenocarcinoma. The endometrial stromal elements
condition characterized by multiple liver cysts of biliary epithe-
and lack of glandular atypia should provide the clue to the
lial origin, without cystic kidney disease. The number of cysts
diagnosis.
varies from just several to innumerable. Germline mutations in
the hepatocystin protein, encoded by the PRKCSH gene, have
HYDATID CYST been identified as the cause of many cases.
Many cases of polycystic liver disease are part of autosomal
dominant polycystic kidney disease. This is itself genetically
CLINICAL FEATURES
heterogeneous, with most cases caused by germline mutation in
Hydatid cyst is the most common manifestation of human the genes for polycystin 1 (PKD1) or polycystin 2 (PKD2) pro-
hydatid disease: approximately two-thirds of hydatid cysts man- teins. Many affected individuals show liver cysts, although the
ifest in liver. About one-quarter of pulmonary hydatid cysts are cysts are usually clinically silent. By contrast, macroscopic liver
also accompanied by hepatic cysts. Hepatic cysts enlarge by cysts are not a feature of autosomal recessive polycystic kidney
about 1 cm per year, and they are usually asymptomatic until a disease, which is more closely linked with ductal plate malfor-
complication occurs, such as rupture. Serology is sensitive in mations and congenital hepatic fibrosis, and is due to mutation
hepatic disease. The disease usually follows ingestion of ova in the gene encoding the fibrocystin protein (PKHD1).
of the canine parasite Echinococcus granulosus. Echinococcus The liver cysts enlarge slowly with age. Symptomatic pre-
multilocularis infection is less common. Other echinococcal sentation is usually during or after early middle age, with
infections are exceptional. hepatomegaly. Ultrasound is diagnostic.
Complications include rupture (with spread), secondary bac- Complications are uncommon, including cyst infection, rup-
terial infection, invasion of the biliary tree with obstruction ture and cholangiocarcinoma.
(therapeutic scolicidal agents may then leak into the biliary
tract and cause secondary sclerosing cholangitis). PATHOLOGICAL FEATURES (Figure 5.22)
Unilocular cysts of various size are distributed through the liver,
or are occasionally prevalent in one lobe. The cysts are lined with
Grossly, there are single or multiple circumscribed cystic lesions cubocolumnar epithelium that may be either attenuated or
with an outer white membrane; unilocular or multilocular due detached focally, and lies on a thin fibrous bed. Foci with second-
to thin-walled daughter cysts. E. multilocularis produces a ary changes related to rupture, hemorrhage and/or infection may
more infiltrative, tumor-like lesion. be evident. Scattered von Meyenberg complexes may be evident.
Microscopically, fibrous reaction surrounds the cyst’s char-
acteristic outer acellular laminated membrane. Cysts have an Differential diagnosis
inner germinative layer that generates thin-walled daughter ● Hepatic lymphangioma or lymphangiomatosis are
cysts with budding protoscolices with refractile hooklets. extremely rare, but the endothelial lined, lymph-filled
Inflammation (including granulomas) is most notable if there spaces may be mistaken for polycystic disease
has been rupture. Old cysts may degenerate and calcify.
Special techniques
● The hooklets are refractile, and acid-fast. The laminated
cyst membrane is PAS-positive.
PANCREATITIC PSEUDOCYST OF LIVER
As with pancreatic pseudocysts elsewhere (see next section of

this chapter), these have a fibrous, inflamed and granulation
tissue wall, with no epithelial lining, and arise in patients with
acute or chronic pancreatitis.
POLYCYSTIC LIVER DISEASE

(a)
CLINICAL FEATURES
Figure 5.22 Polycystic liver disease. Innumerable cysts occupy the
The liver contains multiple liver cysts of biliary epithelial ori- parenchyma (a), and are composed of attenuated epithelium on a
gin. Polycystic liver disease is genetically heterogeneous, with thin fibrous bed (b).
The morphological appearances span the spectrum between

multiacinar regenerative nodule and low-grade hepatocellular
carcinoma. Unambiguous discrimination at either end of this
spectrum is problematic, because clear objective phenotypic or
genetic diagnostic criteria are lacking. The morphological cri-
teria are likely to be superseded – or at least made more robust –
by ancillary molecular/genetic evaluations.
The diagnosis is best reserved for complete excision speci-
mens: confident diagnosis is impossible on a non-excisional
biopsy because of the limitations of sampling error for exclud-
ing carcinoma. In such incisional biopsies, terminology such as
‘hepatocellular nodule with dysplastic features, but indetermi-
nate for malignancy’ probably better conveys the frailty of the
assessment.
Grossly, there is a distinct parenchymal nodule over 1 mm
diameter, and seldom more than 20 mm diameter (lesions
smaller than 1 mm are called dysplastic foci). The surround-
(b) ing liver is not always cirrhotic, but dysplastic nodules are
often distinct from adjacent cirrhotic nodules in color/softer
texture/more bulging cut surface. Dysplastic nodules may
occur within cirrhotic nodules (‘nodule-in-nodule’).
On microscopy, there is a distinct expansile, nodular region
Special techniques of hepatocytes. Portal tracts are present, but often reduced in
● CD31 immunopositivity will confirm the endothelial density, with a corresponding increase in the prevalence of soli-
nature of the lymphangiomatous lesions. tary arterioles/arteries. More than five such unpaired arteries
per 1.1 mm2 was found to positively discriminate dysplastic
nodules from regenerative cirrhotic nodules, although fewer
SOLITARY INTRAHEPATIC BILIARY CYST was not discriminatory for either diagnosis.
Clustered, similar-appearing (clone-like) hepatocytes show-
ing any of fatty change, clear cell change, Mallory bodies,
CLINICAL FEATURES basophilic or densely eosinophilic cytoplasm, may draw atten-
This may be a congenital lesion, but usually presents in adult- tion to a dysplastic nodule. Likewise, dysplastic nodules may
hood, most often in women. be less fibrotic than regenerative neighboring nodules. Iron-free
foci within otherwise iron-rich nodules may highlight a dys-
plastic nodule-within-nodule.
PATHOLOGICAL FEATURES An arbitrary sub-categorization of dysplastic nodules as high
or low grade has been suggested, although the reproducibility
This is a unilocular intrahepatic cyst, having a fibrous wall lined
and robustness against differential diagnoses are insufficiently
with cubocolumnar epithelium. Complications include hemor-
proven in general usage. Essentially, high-grade dysplastic nod-
rhage, rupture and (rarely) malignant progression (cystadeno-
ule may be diagnosed where the changes fall just short of
carcinoma). Some cysts are pedunculated, and may tort.
unequivocal malignancy.
Features of high-grade dysplastic nodules include any of: foci
with cell/nuclear density more than 1.3-fold normal (termed
LIVER CELL TUMORS, BENIGN small cell change when the hepatocytes also show cytoplasmic
basophilia); nuclear hyperchromasia; moderate nuclear irregu-
larity; rare mitoses; rare plates three cells thick; and cytoplas-
DYSPLASTIC NODULE (ADENOMATOUS mic basophilia.
HYPERPLASIA)
● Multiacinar regenerative nodules show few solitary
CLINICAL FEATURES
arterioles (as identified with smooth muscle actin staining).
This is a presumptively neoplastic hepatocellular lesion, and is More than five such vessels per 1.1 mm2 was found only in
believed to have significant malignant potential if unresected dysplastic nodules or malignancy. Extensive sinusoidal
(i.e., the equivalent of intraepithelial neoplasia in surface capillarization (CD34-positive) correlates positively with
epithelia). dysplasia and carcinoma, but is not sufficiently clear-cut
to permit the distinction alone. Multiacinar nodules may subdivided by slender septa radiating from a central stellate
show large cell change (nuclear polyploidy) but lack any scar with large tortuous blood vessels. Calcification in the scar
features ascribed to high-grade dysplastic nodules. is uncommon, and ossification rare. Hemorrhage and necrosis
● Distinction of a high-grade dysplastic nodule from are also rare.
hepatocellular carcinoma is made easier with thorough On microscopy, there are no portal tracts or acinar architec-
sampling. Dysplastic nodules are seldom greater than 2 cm ture. The central hypertrophic artery/arteries pass smaller
in diameter. The presence of portal tracts does not exclude branches that ramify through the lesion. Each arterial branch is
malignancy. Foci of clear-cut carcinoma reveal themselves surrounded by a nodular (⬃1 mm) region of hyperplastic hepato-
through regions of complex architecture incompatible with cytes, having two- to three-cell-thick plates that are easily appre-
simple dysplasia (groups of plates greater than three cells ciable with reticulin stains. Fatty change may be evident. The
thick, ‘floating’ trabecular islands of hepatocytes, groups arteries lie in slender fibrous septa without an accompanying bile
of pseudoglands, loss of reticulin) or severe cytological duct, but with stretches of characteristically prominent marginal
atypia. Unambiguous parenchymal or portal tract invasion ductular reaction at the interface of septum with parenchyma.
indicates hepatocellular carcinoma. Distinct, small foci of The intermittent nature of the cholangiolar proliferation, particu-
unequivocal carcinoma may be usefully designated as larly toward the periphery of the FNH where the thick-walled
‘carcinoma in situ’ within a dysplastic nodule, although hypertrophic arteries may also not be evident, can cause parts of
others would simply designate the whole nodule as a the lesion to mimic adenoma. The interface parenchyma may
hepatocellular carcinoma. show evidence of chronic cholestasis (cholate stasis, neutrophils).
● The presence of hepatocytes showing large cell change Foci with large cell change or mild hepatocyte cytological atypia
(enlarged hepatocytes with proportionately enlarged and are acceptable. The arteries themselves typically show reactive
occasionally slightly irregular or hyperchromatic nuclei) eccentric intimal fibrosis. There are no obvious sizeable portal
does not discriminate a dysplastic from multiacinar veins in the septa, only small vascular channels.
regenerative nodule, although livers with large cell Telangiectatic FNH is a variant with blood-filled grossly dilated
change have an increased risk to develop hepatocellular sinusoidal spaces occupying at least 25% of the lesion, which may
carcinoma. Hepatocytes showing large cell change are lack a central scar.
very probably polypoid and senescent – reflecting Non-classical or incomplete forms of FNH may be present
sustained/chronic liver cell injury and turnover – but are and multiple in livers bearing other forms of FNH. These retain
not themselves neoplastic cells. the defining hypertrophied branching arteries, lack of portal
tracts, and (sometimes very) focal ductular proliferation, but
lack a central scar, are usually small (⬍1.5 cm), and show only
FOCAL NODULAR HYPERPLASIA (FNH) subtle/early and focal hyperplastic changes in the hepatocytes.
Distinction from adenoma can be problematic, requiring good
sampling and evaluation of levels.
CLINICAL FEATURES Osler–Weber–Rendu disease may manifest FNH-like lesions
This appears as a discrete region of hepatocyte hyperplasia, with large arteries in the lesions and adjacent non-lesional
usually in otherwise normal or nearly normal liver (although parenchyma.
identical lesions may occur in cirrhosis). This is probably a Cirrhosis and chronic Budd–Chiari disease may show FNH-
hyperplastic hepatocyte response related to exaggerated aber- like lesions in the abnormal parenchyma.
rant local arterial flow, itself due to arterial malformation or Discrete FNH lesions can also occur adjacent to hepatocellu-
acquired hypertrophy, with other acquired abnormalities such lar carcinoma or other neoplasm, perhaps reflecting a localized
as venous obstruction. It is usually an incidental finding with bystander effect of a particular amplified arterial supply to the
normal liver function. Improved radiological techniques are carcinoma on adjacent non-neoplastic liver parenchyma sup-
increasing the detection rate. The condition may be identified plied by the same vessel.
at any age, but occurs predominantly in adult women.
Multiple FNH syndrome describes the association of multiple Special techniques
FNH with other vascular malformations (liver hemangiomas, ● Reticulin highlights the nodular hyperplastic hepatocyte
dysplasia of muscular arteries) and intracranial lesions (menin- plates.
gioma, astrocytoma). ● Sinusoids are often capillarized (CD34-positive).
A rare progressive variant which recurred after excision, not ● Peripheral hepatocytes may express cytokeratin 19.
premalignant, has been described. Most are resected because of
uncertainty about the diagnosis, rather than about intrinsic
complications such as hemorrhage, which are rare.
● Liver cell adenoma: lacks ductular proliferation, lacks the
hierarchical arterial structure with septae and central scar
of classical FNH. However, the peripheral portions of
Some 80% of the lesions are solitary, and many are smaller than FNH may appear histologically identical to adenoma,
5 cm in diameter. A characteristic appearance is a circumscribed, requiring careful scrutiny of levels for the characteristic
lobulated parenchymal lesion with lobules separated and cholangiolar proliferation around small artery branches.
(a) (b)
Figure 5.23 Focal nodular hyperplasia. Lobules of hepatocytes are

separated by slender radiating septae (a, reticulin).The septae have
no interlobular bile ducts, but show focal inflammation, focal
cholangiole proliferation, and arterial structures (b).The arteries
(c)
characteristically show irregular mural hypertrophy (c).
The lack of a central scar in incomplete or non-classical HEPATOCELLULAR ADENOMA

forms of FNH can further mislead on initial histological
evaluation
CLINICAL FEATURES
● Multiacinar regenerative nodule (e.g., cirrhotic or post-
necrotic, Budd–Chiari): this retains an acinar structure This is a rare, benign hepatocyte neoplasm. Typical presentation
● Low-grade hepatocellular carcinoma (HCC) in non- is with a mass or pain (due to intratumoral hemorrhage). It usu-
cirrhotic liver: Aside from differences in typical clinical ally affects young adult females, and is very rare in males and
setting, HCC lacks the hierarchical structure of FNH, and children without an identifiable cause. Most cases are due to pro-
shows focal hepatocyte architectural complexity and longed liver stimulation with high levels of estrogenic oral con-
cytological atypia or invasion that is incompatible with traceptives or anabolic or exogenous/endogenous androgenic
FNH. Sampling error is the biggest limitation to achieving steroids. Some cases are associated with glycogen storage dis-
correct diagnosis ease, familial diabetes mellitus, and other drugs.
PATHOLOGICAL FEATURES (Figure 5.24) with bile plugs may be frequent. The sinusoids between plates
are often compressed and inconspicuous.
The lesion arises in non-cirrhotic liver, and is usually seen as a soli-
The neoplastic cells are mostly normal sized or slightly
tary, circumscribed, yellow-brown tumor with foci of hemorrhage,
enlarged hepatocytes, with at worst mild atypia, although there
up to 30 cm in diameter. Occasionally, multiple tumors are seen.
are often scattered foci of large cell change (polyploidy/senes-
On microscopy, the tumor consists of uniform one- to two-
cent cells: large cells with correspondingly large nuclei, normal
cell-wide liver cell plates (never more than three cells wide) with
nuclear:cytoplasmic ratio and occasionally slightly distorted
scattered solitary arteries and central veins. There are charac-
nuclei). The cytoplasm is typically pale or vacuolated (glycogen,
teristically no portal tracts, although some may be entrapped at
water or fatty change), and extensive fatty change may conceal
the periphery. Peripheral abnormal thick-walled arteries and
the diagnosis. Mitoses are exceptional.
veins may draw attention to the neoplastic tissue. Pseudoglands
Blood lakes (dilated sinusoids), foci of recent or old hemor-
rhage or myxoid degeneration, hematopoiesis and granulomas
may all be encountered. Kuppfer cells are present. The neo-
plastic cells may contain lipofuscin-like material.
Complications include rupture with intratumoral or serious
intraperitoneal hemorrhage (pregnancy is a particular risk fac-
tor). Amyloid is rare.
Non-neoplastic liver may show prominent peliosis, especially
in those patients receiving anabolic steroids.
Adenomatosis has been proposed for livers bearing more
than three (usually over 10) adenomas, which are typically
smaller than solitary tumors. Multiple adenomas may be due to
any of the causes of solitary adenoma.
● Well-differentiated hepatocellular carcinoma: loss of reticulin
staining or cell plates more than three cells thick are
diagnostic. Cirrhosis, more than rare mitoses or three-cell-
thick plates, and diffuse rather than peripheral CD34 staining
of sinusoid endothelium, are strongly supportive. Because of
the focality of diagnostic changes within well-differentiated
(a)
HCC, the distinction from adenoma may be impossible on
needle biopsy alone, although clearly the differences in clinical
settings are suggestive, independently of such difficulty.
● Focal nodular hyperplasia: foci of ductular proliferation
exclude adenoma, but may be very sparsely distributed.
FNH may occur independently of adenoma in the same
liver (see also Focal nodular hyperplasia, p. 251).
Special techniques
● Reticulin usefully delineates the slender neoplastic cell plates.
● PAS may highlight the reduced glycogen content of the
neoplastic cells.
● Alpha-fetoprotein (AFP) is negative.
PARTIAL NODULAR TRANSFORMATION
CLINICAL FEATURES
Thrombosis of large intrahepatic portal vein branches pro-
duces downstream regions of contiguous hepatocellular atro-
(b)
phy. Compensatory hypertrophy of adjacent segments around
the hilum gives an overall nodular appearance to the liver due
Figure 5.24 Liver cell adenoma, showing regular plates of
cytologically bland hepatocytes.There are small ramifying arteries to the juxtaposition of atrophic with normal or hypertrophic
(a), but no portal structures away from the margins. Blood lakes are regions. Patients may develop portal hypertension or compli-
sometimes encountered in the neoplastic parenchyma (b). cations thereof.
PATHOLOGICAL FEATURES (Figure 5.25) or biliary inflammation in small portal tracts which could
cause secondary thrombosis of the adjacent vein branches.
Parenchymal macronodules (up to 10 cm in diameter) lie deep in
Grossly, no tumor-like macronodules are appreciable, but
the liver, in the perihilar regions containing first- and second-order
the liver shows fine nodularity (1–2-mm nodules, with
portal vein branches. The intervening parenchyma is atrophic.
scattered 8–10-mm clusters of nodules). Histologically,
portal tracts show absent (scarring obliteration) portal
veins, or veins with intimal thickening. Depending
on cause, the artery or bile duct branches may also be
obliterated from small tracts. The lobules show
perivenular atrophy, with periportal compensatory
hyperplasia (monoacinar hyperplasia), together giving rise
to the characteristic nodularity that is best appreciable
with reticulin stains: nodular expansile periportal regions
‘bulge onto’ the intervening atrophic perivenular zones
that show closely spaced reticulin around the small
atrophic hepatocytes. There is no perinodular fibrosis to
suggest cirrhosis.
Special techniques
● Elastic and trichrome stains may help to show scarred
portal structures and obliterated vessels.
REGENERATIVE (POST-NECROTIC)
MULTIACINAR NODULES IN SUBMASSIVE
LIVER NECROSIS
Figure 5.25 Nodular ‘regenerative hyperplasia’ is a misnomer for
compensatory intra-acinar hypertrophy of part of the acinus after CLINICAL FEATURES
the remainder becomes atrophic. Reticulin readily shows the
thickened expansile liver cell plates of adjacent acini appearing to These ‘post-necrotic’ regenerative nodules occur in the livers of
bulge against the narrowed, atrophic plates that lie between. patients who survive some weeks with submassive necrosis due
to acute injury such as viral hepatitis or hepatotoxins.
On microscopy, large intrahepatic portal veins (⬎0.2 mm

diameter) show changes indicative of past thrombosis: eccentric PATHOLOGICAL FEATURES (Figure 5.26)
intimal thickening, medial smooth muscle hyperplasia (occa-
The lesions are recognizable as grossly evident pale masses of
sionally so marked as to cause the vein to resemble an artery:
regenerating parenchyma amidst the reddish brown necrotic
‘arterialization’), or total obliteration of the vascular profile to
liver tissue. Histologically, the regenerative parenchyma shows
leave a scarred remnant of elastic and smooth muscle fibers.
two-cell-thick liver plates, increased binuclear hepatocytes, and
The liver segments downstream of affected vessels show atro-
often bilirubin stasis. Residual necroinflammation and mitotic
phy and portal tracts having absent or obliterated small portal
figures in the regenerating hepatocytes may be appreciable.
veins. Paraportal, thin-walled shunt vessels develop adjacent to
the portal tract. These collaterals look rather like aberrantly
located hepatic veins. Unaffected liver segments may show
portal vein branch dilation (hyperperfusion).
● Diffuse nodular regenerative hyperplasia. This would be
better termed diffuse micronodular change, or more
informatively, intraacinar compensatory hyperplasia. It is
the consequence of diffusely distributed atrophic change in
non-cirrhotic liver, caused by obliteration of small
(⬍0.2-mm) portal vein branches, in the presence of a
normal portal vein and its large branches. Random needle
biopsy is likely to be informative because of the diffuse Figure 5.26 Multiacinar (post-necrotic) regenerative nodules in
liver involvement. The causes are protean, including sub-fulminant liver failure (hepatectomy).The pale nodules contrast
hematological disorders and any causes of diffuse arterial strongly with the remaining brownish necrotic liver tissue.
REGENERATIVE MULTIACINAR ‘MACRO-NODULES’ Some studies have suggested that the outcome may be worse
than conventional hepatocellular carcinoma, due to higher stage
IN CIRRHOSIS
(multifocality or nodal spread) at presentation.

These are ‘standout’ nodules in a cirrhotic liver, arbitrarily con- By definition, the carcinoma is sufficiently differentiated to
spicuously larger than the rest of the cirrhotic liver nodules, and allow unequivocal demonstration of the different phenotypes
generally at least 2–3 cm in diameter. Their recognition on imag- (e.g., bile secretion or hepatocyte antigen positivity, with mucin
ing or laparoscopy raises concern for malignancy. A simple macro- secretion).
regenerative nodule has no special clinical import, but establishing
this reassuring diagnosis requires sufficient pathological sampling
to exclude the differential diagnosis of a dysplastic nodule or car-
HEPATOBLASTOMA
cinoma. In particular, dysplastic nodules or carcinoma may occur
within regenerative macronodules as smaller ‘nodule-in-nodule’ CLINICAL FEATURES
lesions.
This is a malignant neoplasm of the liver which shows primitive
hepatocellular and often other differentiations that suggest it to
be a stem cell neoplasm retaining multipotential differentiation. It
The nodule encompasses multiple portal areas (i.e., multi- is the most common primary liver neoplasm of children; some
acinar), usually bounded by fibrous septa, or occasionally merg- 90% of hepatoblastomas present before the age of 5 years. The
ing more indistinctly with adjacent cirrhotic parenchyma. lesion presents as an abdominal mass, with anemia and often
The portal areas may be normal or scarred, some with marginal thrombocytosis. Rarely, ectopic ␤-human chorionic gonadotropin
cholangiolar proliferation, obliterated portal veins, and promi- (␤-HCG) causes precocious puberty. Some 5% of these tumors
nent lymphatics (that lack smooth muscle, unlike portal vein are associated with various congenital abnormalities; others are
branches). Rarely, the portal areas lack bile ducts. Hepatocyte associated with Beckwith–Wiedemann syndrome, trisomy 18 and
mitoses and dysplastic features are absent. familial adenomatous polyposis (APC gene mutation). The lesion
Large cell change (hepatocyte polyploidy) is acceptable in is associated with high serum AFP for age (except small cell undif-
regenerative macronodules, and does not indicate them to be ferentiated variant), and this is used to monitor response to treat-
neoplastic (see Dysplastic nodule, p. 250). However, large cell ment and recurrence after resection.
change itself indicates a cirrhotic liver to be at increased risk Treatment is with chemotherapy to render the lesion
for development of hepatocellular carcinoma. resectable. Spread may occur via the hepatic veins to the lungs,
brain and other organs.
● Dysplastic nodule (see p. 250). PATHOLOGICAL FEATURES
● Adenoma occurs in normal or near-normal liver, and lacks
The lesion presents as a solid or cystic lesion that can exceed 1 kg
portal tracts (although some may be entrapped at the
in weight. Focal calcification is apparent on imaging, and some
periphery).
20% of the tumors are multifocal at presentation. Hemorrhage
● FNH by convention occurs in normal or near-normal
and necrosis are common.
liver. However, a small proportion of multiacinar nodules
Microscopically, cell differentiations may be epithelial, epithe-
in cirrhosis have some or many features of focal nodular
lial and mesenchymal (mixed) without or with other differ-
hyperplasia. It seems unlikely that all were pre-existing
entiations (teratoid), or rarely, small cell undifferentiated. Pure
lesions that have only become apparent after development
fetal epithelial pattern and the mixed pattern without teratoid
of cirrhosis.
features account for about one-third of cases each.
Pure fetal epithelial: this demonstrates one- to three-cell-thick
trabeculae of cells reminiscent of fetal hepatocytes. Cells are
LIVER CELL TUMORS, MALIGNANT smaller than mature hepatocytes, with prominent cell borders
and have variably eosinophilic or pale cytoplasm depending on
the glycogen and lipid contents; this gives rise to pale and dark
COMBINED HEPATOCELLULAR AND
‘zones’ on low-power inspection. Bile is rare. Fibrous septae
CHOLANGIOCARCINOMA may be evident and reticulin is decreased. Hepatocyte antigen
and AFP are diffusely immunopositive.
Fetal and embryonal epithelial: as fetal, but with focal sheets
CLINICAL FEATURES
of poorly cohesive immature oval or tapered cells that have scant
This is a rare malignancy, characterized by intermingled ele- cytoplasm. These embryonic hepatocyte-like cells may show
ments of hepatocellular carcinoma with cholangiocarcinoma pseudogland formations, and stand out from fetal cells with PAS
(by contrast with two distinct carcinomas in collision, or or oil red stains by virtue of their much diminished cytoplasmic
separately located). glycogen and lipid.
Macrotrabecular epithelial: applicable with a prominent aflatoxin B1 ingestion, genetic hemochromatosis (in males) and
tumor component of numerous macrotrabeculae over 10 cells hereditary tyrosinemia (type I). Cirrhosis itself – or sufficient
thick, composed of fetal, embryonal and a larger cell type with liver injury to cause cirrhosis – is an important co-factor in
more cytoplasm. May raise concern for a hepatocellular carci- carcinogenesis.
noma, but the cells are smaller than mature hepatocytes and Patients with HCC present with weight loss, mass, or
classic fetal pattern histology is evident elsewhere. signs of liver decompensation (ascites, jaundice). With portal
Mixed epithelial and mesenchymal: primitive mesenchyme vein invasion, complete portal venous thrombosis may occur,
and/or osteoid-like matrix or cartilage are admixed with fetal precipitating presentation with complications of severe portal
and embryonal epithelial elements. Some cases also show ‘ter- hypertension or liver decompensation. Unexplained worsening
atoid’ elements: mature epithelial and mesenchymal cells, such of liver function in cirrhosis or increased serum AFP is
as striated muscle, bone, squamous or mucinous epithelium, suspicious.
or melanin. The tumor invades readily into the portal venous tree, spread-
Small cell undifferentiated: sheets of poorly cohesive ‘small ing in both directions along the vessels into other segments.
round blue cells’. Cytoplasmic cytokeratin staining, and foci Hepatic vein spread may extend into the atrium. Uncommonly,
with glycogen or bile may help identification. intrabiliary spread causes obstruction or hemobilia.
If the lesion is untreated, the median survival is only
Differential diagnosis 6 months from the time of diagnosis. Excision is the treatment
of choice for limited stage disease. Non-cirrhotic and selected
● Hepatocellular carcinoma
cirrhotic patients can tolerate partial hepatectomy. Selected cir-
● Hepatocellular adenoma is rare in this age group
rhotic patients with small HCC without node involvement or
● Mesenchymal hamartoma
macrovascular invasion benefit from liver transplantation.
● Infantile hemangioendothelioma
Chemotherapy (systemic/regional), arterial embolization and
● Metastatic Wilms’ tumor
percutaneous ablation are the main non-excisional methods of
● Teratoma: does not contain epithelial hepatoblastoma
tumor control.
components
● In adults (aged over 20 years) the diagnosis is exceptional,
and much more likely to be a hepatocellular carcinoma PATHOLOGICAL FEATURES (Figures 5.27–5.29)
with focal sarcomatous change, or a combined
Approximately 80% of HCC develop in cirrhotic liver. HCC in
hepatocellular and cholangiocarcinoma. A distinctive
non-cirrhotic liver is typically large (⬎10 cm). In cirrhosis, one
tumor of malignant spindle cells, adenocarcinoma and
or more tumor nodules distinct in terms of color/texture/size
extensive osteoid has been reported and termed ossifying
from adjacent regenerative nodules are usually readily appre-
malignant mixed epithelial and stromal tumor of
ciable. Occasionally, there are dispersed micronodules of tumor
the liver
that are difficult to discriminate from adjacent cirrhotic nod-
ules. Prior ablative treatment may produce extensive or total
Special techniques tumor necrosis. There may be tumor thrombi in major portal
● Immunoreactivity varies commensurately with vein branches with intrahepatic metastases arising, and meta-
differentiation. Fetal epithelial areas stain for AFP, stasis to regional lymph nodes. Transcapsular invasion and trans-
hepatocyte antigen and CK18. Embryonal and small peritoneal spread is rare. Spread along biopsy needle tracks
cell areas may stain with CK19. Osteoid-like areas stain may occur.
with EMA. Microscopically, the malignant cells resemble hepatocytes,
and may secrete bile, visible as intracytoplasmic pigment or
intercellular bile plugs.
HEPATOCELLULAR CARCINOMA (HCC) Various growth patterns may be seen together in a single
tumor, including trabecular (a parody of normal liver, but with
variably thickened plates), pseudoglandular (cell aggregates
CLINICAL FEATURES
with central spaces containing debris or thin colloid-like mate-
This is the most common primary liver malignancy, is more rial), compact (having slit-like vessels between close-packed
common in males, and accounts for 7.4% (males) and 3.2% tumor cells), and scirrhous (prominent perisinusoidal collagen
(females) of malignancies worldwide, excluding skin cancer. It fibrosis, typically with atrophic intervening malignant cells).
may occur at any age, with peak incidence in the third to fourth Very dilated sinusoidal spaces manifest as ‘blood lakes’
decades of life in high-prevalence areas, and the sixth to seventh (unhelpfully called ‘pelioid’). These patterns have no particular
decades in low-prevalence areas. significance, although scirrhous foci are associated with
The tumor shows geographic variation in its incidence due chemo- or radiotherapy.
to environmental factors. China, East Asia, Sub-Saharan and Cytological variations that may be seen in foci or scattered
South Africa and Alaskan arctic are high-prevalence zones. The cells include pleomorphic giant cells, clear cells (glycogen,
low incidence in Western countries is rising, perhaps in part water or fat), spindle cell change (‘sarcomatoid change’), fatty
due to spread of chronic viral hepatitis C. The tumor has change, oncocytic (mitochondria-rich) and rhabdoid cells.
strong risk factors that include chronic viral hepatitis B or C, Cytoplasmic inclusions may occur, including Mallory bodies,
PAS/diastase-positive globules (which include alpha-1-anti-

trypsin), lipofuscin-like material, and pale bodies (fibrinogen-rich
pale eosinophilic ovoid bodies). HCC may show neuroendocrine
differentiation by morphology and immunophenotyping, which
rarely is so marked as to resemble pulmonary small cell
carcinoma.
HCC with prominent lymphoid stroma is described, but appar-
ently not associated with Epstein–Barr virus. Extramedullary
hematopoiesis may occur, Kupffer cells may be present, and
sinusoids are typically capillarized. Dysplastic foci/nodules, or
large cell change may occur outwith the HCC.
HCC grading is of marginal prognostic value when other
parameters such as size are taken into account, and given the
Figure 5.27 Hepatocellular carcinoma of fibrolamellar pattern,

arising from non-cirrhotic liver (partial hepatectomy).
Figure 5.28 Hepatocellular carcinoma of conventional type,

arising in the cirrhotic liver of genetic hemochromatosis
(hepatectomy).
(b)
(a) (c)
Figure 5.29 Hepatocellular carcinoma, showing a variety of architectural patterns in a single tumor (a–c, at the same magnification).
dismal prognosis. After curative resection of HCC, microvascu- ● Contains cells that may form microtrabeculae or
lar invasion or high nuclear grade independently predicted poor pseudoglands, but remain cytologically distinctive. Mitoses
survival. The WHO discriminates well, moderate and poorly dif- are rare. The stroma may contain smooth muscle, arteries
ferentiated HCC. Uniformly well-differentiated HCC are usually and some inflammatory cells.
small (⬍2 cm). They show thin trabeculae (only few over two ● Shows metastasis, as with conventional HCC, to local
cells thick), frequent pseudoglands, and small but minimally nodes and the lung.
atypical cells with increased nuclear:cytoplasmic ratio, with fre-
quent fatty change. Small, early-stage HCC often have an indis- Differential diagnosis
tinct boundary macroscopically. Cells at the HCC margin merge
● Hepatocellular adenoma (see p. 253)
with the non-neoplastic liver plates (‘replacement growth’).
● Dysplastic nodule (see p. 250)
Portal tracts may remain in the carcinoma, and may be invaded,
● Focal nodular hyperplasia: lacks trabecular growth, atypia,
although vascular invasion is not seen, and such early-stage
and has positive defining features (see p. 251)
HCC are essentially curable with excision.
● Cholangiocarcinoma
Poor differentiation is rare in small HCC, but as carcinoma
● Metastatic carcinoma. Most carcinomas with abundant
size increases beyond 1 cm, the likelihood of having central
stroma are not HCC, excepting fibrolamellar carcinoma
moderate and poorly differentiated regions increases, until there
with its distinctive stroma, and foci of scirrhous change in
is normally little or no well-differentiated HCC in lesions
HCC. To accept a carcinoma with scirrhous change as
of ⬎3 cm. Poorer differentiation often manifests in the center of
HCC requires positive evidence of hepatocellular
a tumor, as an expansile ‘nodule-in-nodule’, until better differen-
differentiation. Clear cell renal carcinoma stains with
tiated carcinoma occupies just the margins or is overtaken.
EMA and CD15 (unlike HCC). Hepatoid adenocarcinoma
Features of moderate differentiation include prevalent thicker
metastatic to liver may show positive hepatocyte antigen
trabeculae (more than two cells thick) and prominent nucleoli
staining
with abundant eosinophilic cytoplasm. Poor differentiation man-
● Metastatic melanoma, especially amelanotic metastasis.
ifests with solid or compact architecture and pleomorphic nuclei
Melan A, or HMB45 are immunopositive
with an increased nuclear:cytoplasmic ratio.
● Neuroendocrine carcinoma
Multicentric HCC ● Hepatoblastoma
● Metastatic germ cell tumor
This condition has a high risk of HCC arising in remnant liver
● Angiomyolipoma with dominant myoid component:
after excision of the presenting carcinomas. Muliticentricity
shows HMB45 and smooth muscle actin positivity, but is
may be diagnosed if there are any of the following:
cytokeratin-negative
1. Supportive molecular-genetic clonality studies.
● Adrenal cell carcinoma
2. At least one HCC nodule that is small and uniformly well
● Adrenal rest tumor
differentiated.
3. Each HCC has peripheral well-differentiated areas.
4. Multiple HCC of very different histology. Special techniques
● Reticulin usefully shows the reduced or absent reticulin
Fibrolamellar HCC framework of HCC, and abnormally wide trabeculae
This is a clinicopathologically distinctive HCC with relatively (⬎2 cells thick) compared with regenerative or normal
better survival after treatment (5-year survival rate after resec- liver plates (1–2 cells thick).
tion of 40–65%) compared with conventional HCC. Survival ● Antibody to hepatocyte antigen (Hep Par1) stains normal
is heavily stage-dependent. The tumor: and a proportion of malignant hepatocytes in most HCC
● Typically arises in non-cirrhotic liver of young adults/ (including many fibrolamellar HCC). The focality of staining
adolescents. in HCC means that a negative result on needle biopsy has no
● Shows no male predominance, unlike conventional HCC. significance. False-positive staining occurs with metastatic
● Occurs most commonly in Western countries, but hepatoid or poorly differentiated adenocarcinomas of the GI
represents less than 5% of HCC cases. tract, and very occasional cholangiocarcinomas.
● Shows one (or occasionally more) demarcated, scalloped ● Liver export proteins (albumin, alpha-1-antitrypsin)
tumor mass, often with central scarring and calcification, may be helpful in discriminating HCC from metastatic
and an overall lobulated appearance. carcinoma.
● Has distinctive fibrous stroma and tumor cells. ● AFP antibody stains a minority of hepatocytes in about
● Contains stroma composed of parallel, variably thick one-third of HCC (by contrast with the diffuse strong
and (always) thin lamellae of hyalinized collagen; the staining in hepatoblastoma), and a negative result has no
lamellar stroma separates sheets and nests of distinctive discriminatory value.
large polygonal tumor cells. The cells have abundant ● Polyclonal CEA may show bile canaliculi in HCC.
coarse granular and deeply eosinophilic cytoplasm Monoclonal CEA is typically negative.
(mitochondria-rich), and distinct nucleoli within large ● Cytokeratin 8 and 18 are typical of normal hepatocytes,
pale nuclei. Cytoplasmic pale bodies are common, and bile but biliary cytokeratins (7, 19) may be expressed by both
may be evident. neoplastic and non-neoplastic hepatocytes.
UNDIFFERENTIATED LIVER CARCINOMA PATHOLOGICAL FEATURES (Figure 5.30)

The tumor is seen as solitary or multiple circumscribed lesions,
This is very rare, so it is better to consider metastatic carci-
dark red-brown in color and with a spongy texture; they become
noma as the presumptive diagnosis until that possibility has
grayish as areas of sclerosis accumulate. Completely sclerosed
been thoroughly excluded clinically and radiologically.
hemangiomas are less common, rarely with central debris
(resembling the ‘solitary necrotic nodule’).
MESENCHYMAL TUMORS OF THE LIVER,

BENIGN
ANGIOMYOLIPOMA
CLINICAL FEATURES
This tumor may possibly be derived from perivascular epithe-
lioid cells (see also Chapter 14, Urinary system tumors, p. 1160).
These are identical to those of such lesions occurring elsewhere
(see Chapter 14, Urinary system tumors, p. 1160). A malignant
example in liver, of monomorphic epithelioid pattern, has been
reported.
● A predominant myoid component may suggest leiomyoma
(HMB45-negative) Figure 5.30 Hemangioma, showing cavernous spaces lined with
● The occasionally rather wild appearance of the myoid endothelium.
component makes these tumors a pitfall for misdiagnosis
as a sarcoma or hepatocellular malignancy; melanin in the There is no normal liver parenchyma within the lesion, which
myoid cells may suggest metastatic melanoma is composed of thin-walled cavernous blood-filled spaces lined
● Predominance of the fatty component may mislead for with endothelium and lacking an organized elastica. Organized
hepatic lipoma (HMB45-negative), or focal fatty change thrombi may be evident. Areas of central sclerosis are common
(acinar architecture intact); additional extramedullary (sclerosing hemangioma), and degenerative calcification may
hematopoiesis may also suggest myelolipoma (extremely occur. Mast cells are evident in non-sclerosed areas.
rare, HMB45 and melan-A negative). Other examples are almost completely replaced with dense
hyaline collagen fibrosis (sclerosed hemangiomas, ‘solitary
Special techniques fibrous nodule’). In these, there is typically an appreciable resid-
● When diagnosing any hepatic fatty tumor, it is prudent ual architecture of small collapsed vascular channels containing
to exclude angiomyolipoma with HMB45 scant blood, and peripheral thick-walled vessels reflecting the
immunohistochemistry. origin as a hemangioma.
Special techniques
HEMANGIOMA, SCLEROSED HEMANGIOMA ● Vascular markers are helpful to highlight the endothelial
lining (CD31, CD34, factor VIII-related antigen) in
sclerosed examples.
CLINICAL FEATURES
Cavernous hemangioma is the most common benign liver tumor. INFANTILE HEMANGIOENDOTHELIOMA
It is probably congenital and hamartomatous, although most
often manifesting in adults. Small lesions are usually an inciden- See also Chapter 13, Soft tissue tumors (p. 1097).
tal finding during liver investigation for other reasons. Computed
tomography (CT) or magnetic resonance (MR) imaging is nor-
CLINICAL FEATURES
mally sufficient for accurate diagnosis. Complications are rare,
including enlargement and rupture during pregnancy or estrogen This is a congenital benign – but sometimes fatal – vascular
therapy, or consumption coagulopathy. tumor of the liver that usually presents in infancy. Presentation
with liver or congestive cardiac failure is an ominous sign. It is The rare presentations in adults usually affect women, who
associated with skin hemangiomas and various congenital present with abdominal pain.
abnormalities.
Grossly, the tumor is pink-brown, solid-cystic, and sometimes
The tumor is either solitary or multifocal in liver, forming hem- pedunculated.
orrhagic solid lesions that are composed of plump endothelial Microscopically, it is composed of admixed bile ducts (CK7-
cells lining small vascular channels with scant stroma. Focal positive) scattered within a loose vascularized mesenchyme that
tufting and multilayering of endothelium may be evident. characteristically stretches and distorts the ducts in a manner
Central areas may show thrombosis and hemorrhage with scar- reminiscent of breast fibroadenoma. Aggregates of hepatocytes
ring, cavernous change of the tumor vessels, and there may be and extramedullary hematopoiesis are appreciable. The cysts
extramedullary hematopoiesis. are degenerative fluid-filled spaces without a lining in the mes-
enchyme, although some microcysts can be appreciated to be
Special techniques dilated ducts with intact epithelial lining.
● The tumor endothelial cells are CD34-, CD31- and factor In adults, there may be extensive stromal hyalinization, with
VIII-related antigen-immunopositive. few areas of looser typical mesenchyme, and more sparsely dis-
tributed bile duct elements.
INFLAMMATORY MYOFIBROBLASTIC TUMOR Differential diagnosis

(INFLAMMATORY PSEUDOTUMOR) ● Embryonal sarcoma shows clear features of stromal
malignancy
See also Chapter 13, Soft tissue tumors (p. 988). ● Infantile hemangioendothelioma may show myxoid
change, but has a characteristic vascular pattern and lacks
CLINICAL FEATURES the distorted, prominent bile ducts and hepatocyte
aggregates
In liver, these tumors usually affect men, across a wide age
● Lymphangioma lacks the mesenchyme and epithelial
range. Presentation may be with systemic symptoms (fever,
elements of mesenchymal hamartoma, and shows an
weight loss) or related to local obstruction (jaundice, portal
endothelial lining to the cysts
hypertension). There may be prior or concurrent hepatobiliary
● Biliary adenofibroma
or pancreatic suppurative inflammatory disease. Excision is
usually necessary.
SOLITARY FIBROUS TUMOR
Solitary or multiple solid tumors are apparent, ranging from 1 to CLINICAL FEATURES
over 20 cm in diameter. The histology is similar to that of lesions
See also Chapter 13, Soft tissue tumors (p. 982).
at other sites: exuberant mixed inflammatory cell infiltrate dis-
This neoplasm normally has benign behavior, but malignant
persed through a vascularized and variably scarring myofibro-
examples occur, and the liver is a site of spread for malignant
blastic stroma. Xanthogranulomatous foci and phlebitis may
solitary fibrous tumors of other sites. Presentation is in adult-
occur.
hood and may be associated with hypoglycemia. Hepatic soli-
tary fibrous tumors are identical to those at other sites.
● Intrahepatic sclerosing cholangiocarcinoma with secondary Differential diagnosis
inflammation is excluded with careful searching for the
● Metastatic solitary fibrous tumor from another site
invasive carcinoma cells that can be rather inconspicuous
● Follicular dendritic cell tumor
● Solitary fibrous tumor (CD34-positive)
● Inflammatory myofibroblastic tumor
● Follicular dendritic cell tumor (CD21-positive)
● Sclerosed hemangioma
● Plasmacytoma (light chain restricted)
● Leiomyoma
● Confluent hepatic sarcoidosis (typical epithelioid
granulomas)
MESENCHYMAL TUMORS OF THE LIVER,

MESENCHYMAL HAMARTOMA
MALIGNANT
CLINICAL FEATURES
ANGIOSARCOMA
This is a benign developmental lesion that usually presents in early
childhood as an enlarging mass, and is cured with resection. See also Chapter 13, Soft tissue tumors (p. 1099).
CLINICAL FEATURES be present. Solid foci of angiosarcoma are rare, and always
accompanied with more typical vascular areas.
Angiosarcoma is rare, but is the most common sarcoma of liver,
typically presenting in the elderly. Some cases are linked with
exposure to Thorotrast, vinyl chloride, arsenic or androgenic EMBRYONAL RHABDOMYOSARCOMA
steroids. Most are idiopathic.
The sarcoma cells invade along sinusoids, disrupting liver cell CLINICAL FEATURES
plates to form irregularly dilated cavities lined with the atypi- This tumor arises in the extrahepatic biliary tree of young
cal, sometimes tufting cells. Extramedullary hematopoiesis may children, but may spread into large intrahepatic bile ducts.
EMBRYONAL SARCOMA (UNDIFFERENTIATED

SARCOMA)
CLINICAL FEATURES
This is a rare childhood liver malignancy which may occur over
an age range of 5 to 20 years. It forms a hemorrhagic and
necrotic solid-cystic mass that may invade up the inferior vena
cava into the heart.
The tumor is composed of neoplastic stromal cells that may be
either spindle or stellate, show abundant mitoses, and which
can be severely atypical. The cells are dispersed in a loose matrix
that shows foci of pseudocytic degeneration, but more com-
pactly arranged in areas. PAS/diastase-resistant cytoplasmic
eosinophilic globules are characteristic. Entrapped parenchymal
elements may be evident at the periphery.
(a)
EPITHELIOID HEMANGIOENDOTHELIOMA
CLINICAL FEATURES
This is a vascular neoplasm of unpredictable aggression, which
affects males and females over a wide age range.
Grossly, multiple pale tumor nodules are scattered through the
liver. Peripherally, the proliferating epithelioid tumor cells infil-
trate hepatic sinusoids and into portal and hepatic veins as
polypoid tongues or occlusive plugs. More deeply, there is atro-
phy and eventual loss of liver cell plates. The central areas can
show dense hyaline fibrosis, with only very inconspicuous
vacuolated or stellate tumor cells.
FOLLICULAR DENDRITIC CELL TUMOR

(b)
Figure 5.31 Angiosarcoma on needle biopsy of liver (a and b). CLINICAL FEATURES
Malignant cells replace and fill sinusoidal spaces, with disruption of
liver cell plates. See also Chapter 13, Soft tissue tumors (p. 1014).
In liver, this lesion may be mistaken for an inflammatory myofi-
broblastic tumor, but shows CD21 and CD23 immunopositivity.
ABSCESS
LYMPHOMA OF LIVER
CLINICAL FEATURES
In Western countries, blood-borne infection has been superseded
CLINICAL FEATURES
by ascending biliary infection as the most common cause of
For designation as a primary hepatic lymphoma, the presumed abscess, which is readily diagnosed with ultrasound. The patho-
origin, bulk of the lymphoma and the clinical presentation is in genesis of abscess is variable:
the liver, although there may be spread. (Immunophenotyping ● Biliary: this commonly occurs secondary to partial
is discussed in Chapter 10, Lymphoreticular tumors.) Patients biliary obstruction and ascending infection, especially
are typically middle-aged or elderly males (younger for hepato- if an interventional procedure has been performed
splenic ␥␦ T-cell lymphoma). (e.g., biliary stenting) or there is a predisposing anatomic
abnormality (Caroli’s syndrome or disease). Abscesses
PATHOLOGICAL FEATURES secondary to ascending cholangitis are often
multiple.
Features on needle biopsy meriting suspicion for lymphoma ● Direct infection: amebiasis, perinephric abscess, secondary
include any of: (i) a marked sinusoidal lymphoid infiltrate infection of cyst/hematoma.
without commensurate hepatocellular injury, but with rather ● Blood spread: portal pyemia due for example to
large and atypical cells on closer inspection; (ii) dramatically appendiceal abscess or Crohn’s colitis; systemic spread
dense lymphoid infiltration that does not seem to respect may occur from left-sided infective endocarditis.
anatomic compartments and obliterates the normal structures; Immunosuppression (leukemia, drug-induced, HIV)
and (iii) polymorphic inflammatory infiltrate with scattered is a common setting for more unusual pathogens
large atypical blasts. (e.g., Aspergillus, Candida), while Klebsiella may affect
Most primary hepatic lymphomas are diffuse large cell type, diabetics.
generally B-cell lymphomas, with fewer peripheral T-cell lym-
phomas. These usually form tumor masses, but may occasion-
ally show diffuse angiotropism without a discrete mass. PATHOLOGICAL FEATURES
Low-grade extranodal marginal zone lymphoma is rare in
One or more pus-filled cavities within the parenchyma, often
liver, and characterized by massively expansile portal infiltrates
with necrosis of adjacent parenchyma. The lesion may be bile-
of small to medium-sized cells, showing lymphoepithelial
stained or hemorrhagic.
lesions in bile ducts.
Microscopy reveals tissue necrosis with neutrophil suppura-
Hepatosplenic ␥␦ T-cell lymphoma is a clinicopathologically
tion. A predisposing condition may be apparent. Pathogenic
distinctive neoplasm (for a discussion, see Chapter 10,
organisms are occasionally appreciable with H&E staining, but
Lymphoreticular tumors) that is characterized in liver by a
infective organisms should be specifically sought with special-
marked sinusoidal infiltrate of medium-sized lymphoid cells,
ized stains.
sometimes with monocytoid cytology, on other occasions with
cleaved nuclei and scant cytoplasm.
Special techniques
OSSIFYING MALIGNANT MIXED ● Gram, PAS (fungi/yeasts/amebae) or equivalent are merited.
● Immunohistochemistry is possible for amebae (Entamoeba
EPITHELIAL AND STROMAL TUMOR histolytica).
CLINICAL FEATURES
This is a recently described hepatic tumor showing distinctive
ACCESSORY LIVER LOBES
combination of morphological features and prolonged survival.
It is much different from previously reported cases of mixed CLINICAL FEATURES
malignant hepatic tumors, which were typically rapidly fatal.
The tumor is treated by partial hepatectomy. Small additional liver lobes often lie on the inferior liver
surface, and are recognized only incidentally with imaging or
perioperatively, whereby they may masquerade as a disease
lesion. Accessory lobes may have their own mesentery. They
This tumor comprises three distinct neoplastic phenotypes: have no particular disease significance, unless there is torsion
malignant spindle cells, with adenocarcinomatous differentia- about a pedicle. (Riedel’s lobe is an extension of the right lobe,
tion, and extensive osteoid formation. and is readily recognized with imaging.)
CAROLI’S DISEASE (CONGENITAL INTRAHEPATIC ECTOPIC TISSUES

BILE DUCT DILATION)
CLINICAL FEATURES
CLINICAL FEATURES Pancreas, adrenal or splenic tissue may occur either in direct
Caroli’s disease is a congenital ectasia of the large intrahepatic topographic continuity with, or within, the liver.
bile ducts, possibly due to incomplete ductal plate remodeling
during biliary tree development. Associations include polycys- ENCYSTED FAT NECROSIS (PSEUDOLIPOMA)
tic kidney disease.
Caroli’s syndrome is the common co-occurrence of congenital
hepatic fibrosis with Caroli’s disease. Patients diagnosed with CLINICAL FEATURES
congenital hepatic fibrosis who develop cholangitis merit suspi- This is probably derived from omental or pericolic fat subject
cion of Caroli’s syndrome. to trauma or torsion. Previous surgery is a common etiological
The condition may first present at any age, but usually by factor.
age 30 years. Presentation is due to biliary infections/
stones, which become recurrent. Caroli’s syndrome patients PATHOLOGICAL FEATURES
present first with portal hypertension (variceal bleed, hepato-
splenomegaly). This lesion shows an encapsulated oval mass up to 2 cm diameter
of mature adipose tissue attached to the liver surface, resembling
a fatty lymph node. Histologically, fat necrosis is evident,
PATHOLOGICAL FEATURES (Figure 5.32) commonly with calcification or even metaplastic bone.
Macroscopic features include segmental, lobar or diffuse liver

involvement. Affected liver segments show aneurysmally dilated
FOCAL FATTY CHANGE
segments of bile ducts, often with luminal bile casts. Stretches of
normal bile duct may lie between the regions of dilation. CLINICAL FEATURES
Complicating luminal pus, abscesses and intraduct stones may
be evident. This is characterized by one or more discrete multiacinar regions
Histologically, affected ducts show periduct fibrosis with of parenchyma showing diffuse hepatocellular macrovesicular
chronic inflammation. The lining epithelium often shows fatty change, sharply contrasting with adjacent parenchyma.
hyperplasia and mucinous change. Stones and infection produce These are readily detected with imaging studies, and may ini-
ulceration and acute suppurative inflammation. tially raise concerns for malignancy. The lesion may be seen in
Complications include ascending bile infection, intrahepatic association with insulin-dependent diabetes mellitus and alco-
stones, bile duct dysplasia and cholangiocarcinoma (7% of hol liver injury. The pathogenesis of this condition is uncertain.
patients).
Unlike neoplasms with a fatty content, the basic hepatic acinar
architecture is retained in this lesion.
INFARCTION
CLINICAL FEATURES
Cirrhotic nodules may infarct following systemic hypotension,
as for example after a variceal hemorrhage.
Regional infarcts are usually due to obstruction of both hepatic
artery and portal vein, although occasionally there is only portal
vein thrombosis, or no appreciable residual occlusive vascular
lesion.
Predisposing factors include complex hepatobiliary surgery
in patients with underlying vascular disease, any prothrombotic
state such as anticardiolipin antibodies, and arteritis. Liver
infarction is a rare complication of transjugular intrahepatic
portosystemic shunt (TIPSS) placement. Vascular thrombosis is
Figure 5.32 Caroli’s syndrome. Hepatectomy showing a focally a relatively frequent complication after liver transplantation.
ectatic intrahepatic biliary tree in a fibrotic parenchyma (congenital Hepatocellular carcinoma may cause regional infarcts due to
hepatic fibrosis). vascular invasion. Carcinoma infarction is also the therapeutic
goal of transarterial embolization, whereby the lumen of a target Differential diagnosis

artery is occluded with gelatin, starch microspheres or metallic ● Visceral larva migrans manifests with palisading,
coils. Approximately 20% cases achieve complete tumor necro- eosinophil-rich granulomas that often show
sis on pathologically sampled material. Charcot–Leyden crystals and central necrosis. Serial
sections or immunohistochemistry for Toxocara canis on
PATHOLOGICAL FEATURES (Figure 5.33) paraffin sections may reveal the larva.
The dead tissue is bright yellow in color, with congested periph-
Special techniques
eral margins. In cirrhosis especially, sampling for microscopy is
merited to exclude an unsuspected necrotic malignancy. ● Paraffin section immunohistochemistry for CD1a or S-100
protein will decorate the Langerhans’ cells.
NECROTIC NODULE
CLINICAL FEATURES
This is a descriptive rather than diagnostic term. It usually rep-
resents a sclerosed hemangioma with degenerative change (see
Hemangioma, p. 259). This is usually an incidental finding at
surgery that may raise concern for metastasis. There is no
intrinsic significance in the finding.
This is usually a solitary pale lesion with a central soft area; it
is typically subcapsular, and up to 5 mm in diameter. Micro-
scopically, there is dense fibrosis and central degeneration;
often, an appreciable vascular architecture or immunostaining
with vascular endothelial markers (CD31) permits recognition
as a sclerosed hemangioma.
● Necrotic carcinoma. Look for fresh tumor necrosis,
Figure 5.33 Liver infarct. Note the organized thrombus in
the vein. residual viable tumor tissue.
● Infection. Tuberculosis or infestation with larva such as
Toxocara species (visceral larva migrans) merit consideration:
LANGERHANS’ CELL HISTIOCYTOSIS granulomatous caseous necrosis is characteristic for
mycobacterial infection, and acid-fast bacilli clinch the
diagnosis. With larval infestation, look for central necrosis
CLINICAL FEATURES with peripheral granulating inflammation, degranulating
This involves the infiltration of tissues with neoplastic eosinophils (‘eosinophilic granuloma’), and occasionally
Langerhans’ cells. Liver involvement is comparatively uncom- diagnostic larval forms (multiple levels may be required).
mon. The condition usually presents in young children/infants, A polyclonal antiserum is available to demonstrate Toxocara
and the diagnosis merits exclusion in any childhood presenta- canis in macrophages on paraffin sections.
tion with apparent primary sclerosing cholangitis.
SECONDARY METASTASIS (Figure 5.34)
Typical features include pale tumor mass or masses in the
CLINICAL FEATURES
parenchyma, or cystic dilation of infiltrated large bile ducts, or
biliary fibrosis. Characteristic features with microscopy include: In Western countries, secondary metastases are collectively
(i) Langerhans’ cell cholangitis (Langerhans’ cells between epithe- many-fold more common than primary liver tumors.
lial cells and the duct basement membrane) with biliary epithelial A majority of secondary metastases are metastatic carcinoma,
damage, periduct fibrosis, and secondary sclerosing cholangitis; most often from lung, colon, pancreas, breast and stomach.
and (ii) parenchymal or portal masses of Langerhans’ cells, from Colorectal metastases often have a characteristic sharply defined
microscopic to tumor-forming. Accompanying granulocytes, margin with cribriform complex gland formations having central
macrophages, and lymphoid cells are usual. Eosinophils are debris. Differential diagnosis from hepatocellular carcinoma and
sometimes prominent. cholangiocarcinoma is discussed in the specific sections.
(a) (b)
Figure 5.34 Metastatic adenocarcinoma, displacing and replacing liver cells in the hepatic plates on needle biopsy (a), and showing mucin
secretion (b, same biopsy).
Of other malignancies, melanoma, disseminated lymphoma may present with liver metastasis, although a spindle cell
or leukemia, carcinoids and neuroblastoma frequently spread malignancy in a liver biopsy is more likely to be a carcinoma
to the liver. Malignant GI stromal tumors (CD34, c-kit positive) (primary or metastatic) with spindle cell change.
TUMORS OF THE GALLBLADDER AND EXTRAHEPATIC BILE DUCT
● Extension of the dysplastic epithelium into the Rokitansky–
Aschoff sinuses may mimic invasive adenocarcinoma
ADENOMA (TUBULAR, PAPILLARY, ● Papillary hyperplasia of the gallbladder mucosa is common
TUBULOPAPILLARY) in cholecystitis, and may be misinterpreted as the rare
papillary adenoma with biliary-type cytology
CLINICAL FEATURES
BILE DUCT CYSTADENOMA
This condition affects adults more often than children, and it
is often found incidentally in gallbladders removed due to
cholecystitis. Examples in extrahepatic bile ducts present with CLINICAL FEATURES
obstruction or cholangitis. Associations include Gardner See Benign bile duct epithelial tumors (p. 243). Extrahepatic
syndrome and Peutz–Jehgers syndrome. examples usually cause obstructive jaundice or cholangitis,
typically in adult women.
These adenomas are more common in the gallbladder than ● Endoscopic biopsies of extrahepatic cystadenoma or
in extrahepatic ducts. They usually occur as a solitary cystadenoma extending down the distal common hepatic
polyp, but may be multiple. The architecture may be tubular, duct may sample the mesenchymal stroma, leading to
papillary or tubulopapillary, with gastric pyloric, intestinal potential confusion with biliary smooth muscle lesions.
or biliary-like cytology. Small squamoid morules may be The latter are not cystic on ultrasound, and do not show
appreciable. estrogen receptor positivity.
GRANULAR CELL TUMOR
CLINICAL FEATURES
This is the most common non-epithelial tumor of the extra-
hepatic biliary tract. It typically affects young adults, especially
black women. There may be multiple lesions, located usually
near the junction of cystic, hepatic and common bile ducts.
The pathological features are identical to those of granular cell
tumor that is seen elsewhere.
CARCINOMA OF THE GALLBLADDER
CLINICAL FEATURES
Figure 5.35 Gallbladder carcinoma, showing transmuscular
The gallbladder is the most common site of cancer in the bil- invasion by a well-differentiated adenocarcinoma that
iary tract. This tumor predominantly affects the elderly (and macroscopically and radiologically was evident only as a diffuse
especially women), whilst cholangiocarcinoma of extrahepatic mild thickening of the gallbladder wall.
bile ducts is more common in men. Predisposing factors include
porcelain gallbladder (diffusely calcified wall), gallstones, and primary sclerosing cholangitis, ulcerative colitis, and abnormal
anatomic factors promoting chronic pancreatic juice reflux. choledocho-pancreatic junction with chronic reflux, choledochal
The carcinoma is often detected incidentally after cholecystec- cysts, and infestation with liver flukes. Gallstones are not a risk
tomy for presumed cholecystitis. Some patients present with factor. It may arise anywhere between the origin of the common
acute cholecystitis or empyema. The 5-year survival rate is less hepatic duct and the ampulla of Vater, although most are proxi-
than 5%. mal. Local spread may affect the gallbladder or pancreas.

There is either diffuse or polypoid growth pattern, usually con- Well-differentiated tubular or papillary adenocarcinoma is com-
sisting of adenocarcinoma with varying degrees of differentia- monest. The microscopic features and differential diagnoses are
tion. Intestinal metaplasia, dysplasia and carcinoma in situ are described in Intrahepatic cholangiocarcinoma (p. 247).
often present in the adjacent mucosa.
Differentiation may be graded (WHO) into well, moderate
and poor categories, defined by over 95%, over 40%, and over
5% glandular structures, respectively. Less than 5% glands is MISCELLANEOUS TUMORS
designated as undifferentiated.
Histological variants of adenocarcinoma include papillary, ACQUIRED DIVERTICULAR DISEASE OF THE
mucinous, intestinal type, clear cell, signet ring and adeno-
squamous.
GALLBLADDER (LOCALIZED ADENOMYOMATOUS
Rare other types of carcinoma include carcinosarcoma, squa- HYPERPLASIA)
mous carcinoma, mixed carcinoid-adenocarcinoma, small cell
neuroendocrine carcinoma, and undifferentiated carcinoma
CLINICAL FEATURES
(including spindle and giant cell carcinoma, carcinoma with
osteoclast-like giant cells, small cell carcinoma). This condition is typically an incidental finding in a routine
cholecystectomy specimen.
CARCINOMA OF THE EXTRAHEPATIC BILE DUCT

Focal or diffuse mucosal herniations (pseudodiverticula) are
CLINICAL FEATURES
seen in the gallbladder wall, developing in association with
This condition predominantly affects men (unlike gallbladder gallstones. Hypertrophy of the muscularis between the diver-
carcinoma), who present with obstructive jaundice, and fre- ticula may give rise to a tumor-like thickening of the gall-
quently at a late stage (local metastases). Risk factors are bladder wall.
RARITIES also with an obstructing carcinoma of the extrahepatic biliary

tree or gallbladder.
Rare primary malignancies include carcinoid, melanoma, lym-
phoma and leiomyosarcoma. Embryonal rhabdomyosarcoma PATHOLOGICAL FEATURES
is the most common malignancy of the biliary tract in children.
A variety of other rare lesions are described in small num- Gross appearances are variable, from discrete to ill-defined
bers, including lipoma, lymphangioma, hemangioma, paragan- tumor-like masses, and yellow to brown in color. These tumors
glioma and ganglioneuromatosis. are composed of an intramural admixture of xanthogranulo-
matous reaction, chronic inflammation and fibrosis, in varying
proportions. The lesions may take origin in ruptured Rokitansky–
XANTHOGRANULOMATOUS CHOLECYSTITIS Aschoff sinuses.
(FIBROXANTHOGRANULOMATOUS
CHOLECYSTITIS) Differential diagnosis
● Granular cell tumor
● Malakoplakia shows diagnostic Michaelis–Gutman bodies
CLINICAL FEATURES with PAS staining
This is an uncommon form of chronic cholecystitis that may ● Cholesterolosis is a subepithelial, non-scarring
form a tumor-like mass. Most patients have gallstones, some accumulation of histiocytes
5.3 PANCREATIC TUMORS

David K Worrall and Hassan MH Kamel
Tumors of the endocrine pancreas 268 Parasitic cysts 278

Gastrinoma 270 Para-ampullary duodenal wall cysts 278
Glucagonoma 270 Enterogenous cysts 279
Insulinoma 271 Lymphoepithelial cysts 279
Nesidioblastosis 271 Endometrial cysts 279
Somatostatinoma 272 Pseudocysts 279
VIPoma 272
Cystic pancreatic tumors 279
WHO classification of pancreatic endocrine tumors 273 Mucinous cystic tumors 279
Benign mucinous cystic tumors 279
Tumors of the exocrine pancreas 273 Borderline mucinous cystic tumors 279
Carcinoma, common variants 273 Mucinous cystadenocarcinomas 279
Adenocarcinoma, ductal 273 Serous cystic tumors 280
Adenosquamous carcinoma 275 Benign serous microcystic adenoma 280
Ampullary carcinoma (carcinoma of the ampulla of Vater) 275 Benign serous oligocystic (macrocystic) adenoma 280
Colloid (mucinous non-cystic) carcinoma 276 Malignant serous cystadenocarcinoma 280
Microglandular adenocarcinoma 276 Solid and cystic tumor 280
Pancreatoblastoma (infantile pancreatic carcinoma) 276
Ductal lesions 281
Undifferentiated carcinoma 276
Ductal changes 281
Carcinoma, rare variants 277 Intraductal papillary mucinous tumors 281
Acinar cell carcinoma 277 Benign intraductal papillary mucinous adenoma 281
Mixed acinar-endocrine carcinoma 277 Intraductal papillary mucinous borderline tumor 281
Acinar cell cystadenocarcinoma 277 Intraductal papillary mucinous carcinoma and
Acinar cell cystadenoma 277 papillary mucinous carcinoma 281
Choriocarcinoma 277 Mucinous ductal ectasia 281
Clear cell carcinoma 277 Miscellaneous lesions 281
Oncocytic carcinoma 278 Chronic pancreatitis 281
Signet ring cell carcinoma 278 Inflammatory myofibroblastic tumor 282
Undifferentiated carcinoma with osteoclast-like giant cells 278 Lipomatous pseudohypertrophy 282
Mature teratoma 282
Cystic lesions 278
Pseudolymphoma (focal lymphoid hyperplasia) 282
Cysts 278
Splenic heterotopias 282
Retention cysts 278
Congenital pancreatic cysts 278 WHO classification of pancreatic exocrine tumors 282
GENERAL COMMENTS diverse spectrum of other organs, including those of the sali-
vary glands, ovaries, gastrointestinal tract and bone.
Tumors of the pancreas are divided into those arising from the The difficulty in categorizing the various entities of pancreatic
exocrine part and those from the endocrine component. The tumors do not stem from unusual morphological patterns, but
morphological pattern of the latter group shares similar fea- mainly from the infrequency with which many of these entities
tures of neuroendocrine tumors in general, though their wider are encountered in day-to-day practice. Their infrequency pre-
spectrum within the endocrine pancreas reflects their varied cipitates unfamiliarity, and the matter is complicated further
specialization, functionality and products. by the presence of tumor-like lesions, which can mimic true
The majority of neoplastic lesions of the exocrine pancreas neoplasms and vice versa. Recognition of those tumor-like lesions
share morphological patterns with similar counterparts in a is therefore essential if erroneous diagnosis is to be avoided.
TUMORS OF THE ENDOCRINE PANCREAS
GENERAL ASPECTS entity. Most resected non-functioning tumors are larger than
5 cm in diameter, and may show evidence of local invasion.
In general, the microscopic appearances of pancreatic endocrine
CLINICAL FEATURES tumors are non-specific, and similar architectural patterns may be
Endocrine tumors of the pancreas are uncommon entities, com- seen in both functioning and non-functioning tumors. On occa-
prising approximately 1–2% of all pancreatic neoplasms. The sion there may be features that suggest a particular tumor type;
term ‘islet cell tumor’ is often used synonymously to describe these include the presence of amyloid deposition in insulinomas or
these lesions. Strictly speaking, however, this term should be psammoma bodies associated within somatostatinomas. However,
reserved for those tumors derived from the normal cells of the immunohistochemistry is ultimately required to distinguish
pancreatic islets, as a proportion of tumors may secrete neuro- between non-functioning and functioning tumors and to identify
peptide hormones or neurotransmitters ectopic to the pancreas. the specific hormone or hormones produced by the latter. Four
The majority of clinically apparent tumors are functioning – that basic patterns are seen, as detailed below, though many tumors
is, they are tumors associated with a recognized hormonal syn- will show a mixture of more than one pattern.
drome. These tumors can be subcategorized according to the hor- 1. Trabecular pattern: In tumors with a trabecular
mone produced into insulinomas, glucagonomas, gastrinomas, architecture, the cells form cords arranged in a ribboning
somatostatinomas and VIPomas. The clinical features of func- or gyriform pattern. Some tumors – in particular
tioning endocrine tumors are discussed in more detail separately. glucagonomas – consist of cords one or two cell layers
Non-functioning tumors are classified as such because they thick which are separated by stroma containing large
produce no symptoms specifically attributable to an excess of a numbers of blood vessels. PP-cell tumors often show thin
particular hormone. These tumors may still produce active hor- trabeculae arranged as parallel lines, whilst large gyriform
mones, but the quantity may be insufficient to produce symp- trabeculae and lobular nests of cells are often seen in
toms. Alternatively, some hormones secreted in excess may insulinomas.
produce only non-specific symptoms, for example pancreatic 2. Tubuloacinar (glandular) pattern: Some pancreatic tumors –
polypeptide (PP) and neurotensin. Non-functioning tumors usu- most notably VIPomas – show arrangements of tumor cells
ally present with symptoms related to local pressure effects, inva- in tubular and acinar structures. These structures possess
sion of surrounding organs or distant metastasis. The majority of a lumen that may contain secretory material. The
these tumors are malignant in nature. tubuloacinar areas are often found in association with
About 15–25% of pancreatic endocrine tumors are thought more solid areas or poorly formed trabeculae.
to be associated with multiple endocrine neoplasia type 1 3. Solid (medullary) pattern: Tumors with a solid architecture
(Werner’s syndrome). The presence of multiple tumors should consist of cells arranged as large sheets with little
raise the possibility of this condition, which is the result of an intervening stroma. The growth pattern of these tumors
inherited mutation of the MEN-1 tumor suppressor gene on may be nodular, diffuse, or a mixture of the two.
chromosome 11q13. Of the syndromes associated with func- 4. Poorly differentiated: Poorly differentiated pancreatic
tioning endocrine tumors, Zollinger–Ellison syndrome is the endocrine tumors are rare, consist of highly pleomorphic,
most commonly encountered in patients with MEN-1 (see mitotically active cells, and may resemble small cell lung
Pancreatic endocrine tumors: Gastrinoma, p. 270). carcinoma. Immunohistochemistry is required to confirm
the neuroendocrine origin of the tumor cells.
PATHOLOGICAL FEATURES (Figure 5.36) Assessment of malignancy

The macroscopic appearances of functioning pancreatic Several criteria are used to determine the nature of well-
endocrine tumors are dealt with in the specific sections for each differentiated endocrine tumors of the pancreas. The presence
(a) (c)
Figure 5.36 Pancreatic endocrine tumors. (a) Insulinoma

composed of cells arranged in a trabecular pattern.
(b) Immunohistochemistry for insulin. (c) Gastrinoma composed of
cells arranged in a solid pattern. Individual endocrine tumors may
(b)
show more than one pattern.
of gross local invasion, with spread to adjacent organs, and/or Cell morphology
metastasis to lymph nodes and liver are unequivocal indicators The cells in well-differentiated endocrine tumors of the pancreas
of malignancy. Other features that may indicate malignancy are usually cuboidal in shape, with finely granular eosinophilic
include: cytoplasm. The nuclei are round to oval in shape, and may con-
● Lymphovascular or perineural invasion
tain a distinct nucleolus. In tumors showing a trabecular pattern
● Necrosis
there is usually polarization of the nucleus.
● More than two mitoses per 10 high-power fields (HPF)
● More than 2% of tumor cells positive for Ki-67 or MIB-1

Special techniques
● Size greater than 2–4 cm
● Functioning tumors (except insulinoma) ● The tumors are positive for neuroendocrine markers such
as neuron-specific enolase (NSE), PGP9.5, synaptophysin,
Several of these criteria are incorporated into the World Health chromogranins A, B and C, protein convertase 2 and 3
Organization (WHO) classification of endocrine pancreatic (PC2 and PC3) and Leu-7.
tumors (see p. 273). ● Cytokeratins 8, 18 and 19 are also positive.
● Functioning tumors are identified by staining for specific PATHOLOGICAL FEATURES

peptides or hormones particular to that tumor (see
Macroscopically, pancreatic gastrinomas appear as well-
separate sections).
circumscribed, non-encapsulated lesions with a pushing margin.
● Electron microscopy may allow categorization of the
The consistency may be firm or soft, depending on the cellular
tumor based on specific features of the cytoplasmic
architecture and amount of fibrous stroma. Any part of the
granules within the cell.
organ may be involved, but there is a predilection for the head
of pancreas.
The histological features are, in common with other pancreatic
● Lobular islet aggregation in chronic pancreatitis endocrine tumors, non-specific (see Pancreatic endocrine tumors:
● Solid and cystic tumor (solid pseudopapillary tumor) General aspects, p. 268). The most common architecture observed
● Acinar cell carcinoma in gastrinomas is the trabecular pattern. Immunohistochemistry
● Pancreatoblastoma is essential for diagnosis.
● Poorly differentiated ductal adenocarcinoma
● Clear cell carcinoma Special techniques
● Oncocytic carcinoma
● Staining for general endocrine markers such as
● Mixed acinar-endocrine carcinoma
chromogranin A and B is positive.
● Ductal-endocrine carcinoma
● Gastrin positivity is the most important diagnostic feature;
● Epithelioid gastrointestinal stromal tumor (GIST)
this is present in nearly all pancreatic gastrinomas. In the
● Peripheral neuroectodermal tumors (PNET)
rare cases where this is absent (presumably due to
defective hormone synthesis), in-situ hybridization for
GASTRINOMA gastrin mRNA may be required.
● Positivity for other peptides and hormones such as PP,
glucagon, insulin, somatostatin, ACTH and serotonin may
CLINICAL FEATURES also be observed.
Hypersecretion of the hormone gastrin by pancreatic endocrine ● Electron microscopy may be unreliable as the granules in
tumors results in the characteristic Zollinger–Ellison syndrome gastrinoma cells are often variable in size and shape.
(ZES). Patients with this syndrome present with intractable gas-
tric ulceration secondary to excess production of gastric acid. GLUCAGONOMA
These ulcers are frequently multiple, and can recur very rapidly
following cessation of medical therapy. Regions of the stomach
not normally prone to peptic ulceration may be involved in CLINICAL FEATURES
ZES. Hematemesis and perforation are potentially fatal compli- Functionally active tumors showing A-cell differentiation pro-
cations. Other presenting symptoms can include gastro- duce a characteristic glucagonoma syndrome. Manifestations of
esophageal reflux, severe esophagitis and diarrhea caused by this syndrome include skin rashes (necrolytic migratory ery-
acid overload to the small intestine. thema), stomatitis and angular cheilitis, glossitis, mild diabetes
Gastrinomas are the second most common pancreatic mellitus, anemia of normochromic normocytic type, depression,
endocrine tumor (behind insulinoma), accounting for 20% of weight loss and a predisposition towards venous thrombosis.
all endocrine tumors and 30% of functioning tumors. Adults The exact pathogenesis of these symptoms is not fully under-
within a wide age range may be affected, although the peak stood, but is related to increased catabolic activity in response to
incidence is in the fifth and sixth decades of life. Gastrinomas elevated glucagon levels. The majority of glucagonomas (more
presenting in children are uncommon. Males are more com- than 60%) are malignant in nature, and metastatic spread occurs
monly affected than females (ratio of approximately 3:2). most commonly to the liver and local lymph nodes.
Somewhere between 25% and 40% of gastrinomas arise in the Glucagonomas account for approximately 5% of pancreatic
context of MEN-1, the remainder are sporadic tumors. Most endocrine tumors, and usually occur in adults aged between
MEN-1-associated gastrinomas actually occur in the duodenum 40 and 70 years (mean age 55 years). A small number of cases
(around 90%) rather than the pancreas. Where the pancreas is occur in association with MEN-1. There appears to be a slight
involved, the tumors seldom produce significant amounts of female predominance.
gastrin.
At least 70% of pancreatic gastrinomas are malignant
(compared to 25–60% of those arising in the duodenum).
Gastrinomas are generally slow-growing, and long-term sur- Glucagonomas can arise in any part of the pancreas, although
vival has been reported not infrequently, even in patients with the tumor is most commonly found in the distal portion of the
metastatic disease. Metastasis, most commonly to the liver and gland. They are usually single, and may be of considerable size
regional lymph nodes, is usually a late feature in the natural (ranging from less than 1 cm to over 30 cm). An invasive growth
history of the tumor. Pancreatic gastrinomas spread to the liver pattern is seen in over 50% of cases.
more commonly than duodenal tumors, and this results in a Microscopically, the tumor cells are arranged in an admixture
generally poorer prognosis. of trabecular and solid growth patterns. Histology alone is
unreliable as these features may also be seen in other endocrine a useful diagnostic clue, though this is only present in approxi-
pancreatic tumors (see Pancreatic endocrine tumors: General mately 5% of insulinomas. This amyloid is composed of islet
aspects, p. 268). Mitoses are an infrequent finding, and signifi- amyloid polypeptide (IAPP), which is commonly expressed by
cant nuclear atypia is seldom seen. Vascular and perineural infil- insulinoma cells. Other endocrine tumors of the pancreas may
tration by tumor cells may be present in some cases. be associated with amyloid deposition, but less commonly. The
absence of a tumor capsule is common in microadenomas. Larger
Cell morphology tumors are usually encapsulated, although the capsule may be
The tumor cells are usually polygonal in shape and have faintly incomplete – a finding which does not, on its own, indicate
granular cytoplasm. malignancy.
Special techniques Cell morphology

● Tumor cells are argyrophilic and non-argentaffinic. Well-differentiated tumors are composed of uniform cuboidal
● Staining for glucagon is often weakly positive. cells with eosinophilic, finely granular cytoplasm. The nuclei
● Immunohistochemistry for proglucagon-derived peptides are round or oval with a finely stippled chromatin pattern and
such as glicentin and glucagon-like peptides 1 and 2 is an inconspicuous nucleolus.
also positive.
● Smaller numbers of PP cells, somatostatin cells and insulin Special techniques
cells may also be seen.
● Electron microscopy reveals A-granules. In symptomatic
● Tumor cells are positive for insulin (basal) and proinsulin
glucagon-secreting tumors, these granules are often atypical. (perinuclear). The degree of positivity may be weak or
variable, particularly in insulinomas with a solid growth
pattern.
INSULINOMA ● Other hormones may be secreted by both benign and
malignant tumors.
CLINICAL FEATURES ● Amyloid deposition within the tumor stroma may be seen
in a small proportion of cases.
The characteristic symptoms of an insulinoma arise as a direct ● Electron microscopy most commonly reveals crystalline-
result of fasting hypoglycemia caused by inappropriately ele- type beta granules. Occasionally, these granules may be
vated levels of plasma insulin and proinsulin. slightly pleomorphic or sparse in number. A few cells
Hypoglycemia severely impairs brain function, leading to containing A and PP granules may also be seen.
headaches, dizziness, weakness, fatigue, confusion, dysarthria,
convulsions and eventually coma. In the setting of a patient with
pre-existing type II diabetes mellitus, the signs and symptoms of NESIDIOBLASTOSIS
diabetes may resolve.
Unlike other pancreatic endocrine tumors, the majority of CLINICAL FEATURES
insulinomas (85–99%) are benign in nature. They occur most
commonly in adults aged between 40 and 60 years; children Nesidioblastosis is the pathological abnormality underlying the
are only rarely affected. Neonatal and infantile persistent rare condition of persistent neonatal hyperinsulinemic hypo-
hyperinsulinemic hypoglycemia most likely indicates nesidio- glycemia (PNHH). This condition is probably related to func-
blastosis (see section below). There is a small female predomi- tional and morphological dysmaturation of the endocrine
nance in the incidence of insulinoma. pancreas, and there appears to be a genetic predisposition.
Nesidioblastosis may be either localized (one or a few foci) or
PATHOLOGICAL FEATURES diffuse, involving the entire pancreas. In the localized type, the
lesion may be very small (only a few millimeters) and can easily
Macroscopically, insulinomas appear as a small (less than 2.5 cm be missed unless several sections are taken for histology.
diameter), well-circumscribed and partially or fully encapsulated Treatment is by partial pancreatectomy with excision of the dis-
lesion. Tumors greater than 3 cm in size are uncommon, and are eased segment. Recurrence of symptoms may occur following
likely to be malignant in nature. There is no apparent predilec- surgery in cases of diffuse and multifocal disease.
tion for any part of the pancreas. Insulinomas may be soft or
firm and can vary in color from gray to deep red. In less than
10% of cases, two or more synchronous or metachronous
tumors may be identified; this finding should raise the suspicion There are two forms of nesidioblastosis:
of MEN-1. Insulinomas arising in extrapancreatic sites are rare, ● The localized type is characterized by the presence of one
accounting for less than 1% of the total cases. or a few (unifocal or multifocal) adenoma-like nodules.
Insulinomas show the same range of architectural patterns seen These consist of an ill-defined accumulation of islet-like
in other pancreatic endocrine tumors (see Pancreatic endocrine and partly confluent cell clusters separated by, or
tumors: General aspects, p. 268). For this reason, histology alone haphazardly incorporating, acinar tissue. Lesions also
is insufficient for diagnosis. The finding of amyloid deposition contain ductulo-insular complexes (a common finding in
in the fibrovascular stroma surrounding the tumor cells provides the developing pancreas), which are composed of small
ducts containing both epithelial and endocrine cells. PATHOLOGICAL FEATURES

The latter appear to bud off and merge into the adjacent
Macroscopically, somatostatinomas appear as a single, relatively
endocrine cell clusters and may show nuclear enlargement
large (3.5–11 cm diameter), well-circumscribed but unencap-
or giant and bizarre nuclei.
sulated lesion with a soft consistency. They may arise anywhere in
● The diffuse type involves the entire pancreas, and no
the pancreas, but are most commonly seen in the head. Local
distinct abnormality can be identified macroscopically.
invasion is present in about 75% of cases, and metastatic spread
Histologically, the condition is characterized by the
is most commonly to the liver and lymph nodes. Occasionally,
presence of irregularly shaped and sized islets and poorly
there may be widespread distant metastatic spread.
defined clusters of endocrine cells distributed throughout
Microscopically, the architectural pattern is similar to that of
the pancreas. Ductulo-insular complexes containing
other pancreatic endocrine tumors (see Pancreatic endocrine
distinctly hypertrophied insulin giant cells are also
tumors: General aspects, p. 268). In a small number of cases,
commonly seen. Occasionally, the diffuse type fails to
psammomatous calcifications may be seen within glandular
show prominent B-cell hyperplasia, and the only indication
structures. Despite the malignant nature of the majority of
is the presence, on immunostaining, of diffusely dispersed
somatostatinomas, there is usually little evidence of nuclear
small endocrine cell clusters or single endocrine cells
pleomorphism, mitotic activity or necrosis.
throughout the acinar structures reminiscent of the
histology of the perinatal pancreas.
Special techniques
Cell morphology ● Many of the tumor cells show positive staining with
antibodies against somatostatin.
See Pathological features, above.
● Staining for other hormones such as calcitonin,
adrenocorticotropin and gastrin may also be present.
Special techniques ● Electron microscopy reveals large granules (250–450 nm
● Immunohistochemistry reveals a normal spatial diameter) which are similar to those of normal D-cells,
distribution of the endocrine cell types. and smaller granules (150–300 nm diameter) with a
● There may be a reduction of the number of A-cells or peripheral halo.
D-cells.
VIPOMA
● Islet cell hyperplasia
● Islet cell tumors CLINICAL FEATURES
The clinical symptoms of pancreatic VIPomas are related to
excess secretion of vasoactive intestinal polypeptide (VIP), pep-
SOMATOSTATINOMA tide histidine methionine (PHM) and a range of other molecules
with hormone-like properties. The characteristic features, which
CLINICAL FEATURES comprise the Verner–Morrison syndrome, are watery diarrhea,
hypokalemia and achlorhydria (hence the term WDHA syn-
Somatostatinomas are extremely rare neoplasms, accounting for drome). Severe dehydration and metabolic disturbances may be
less than 1% of pancreatic endocrine tumors. The clinical syn- fatal if untreated, and occasionally tumors have been first diag-
drome associated with hypersomatostatinemia is less well nosed at autopsy. Over 80% of VIPomas are malignant in
defined than those of other functioning tumors. Somatostatin nature, with the most common sites of metastatic spread being
has widespread inhibitory effects on multiple cell types, includ- the liver and local lymph nodes.
ing the cells responsible for the secretion of insulin, secretin, VIPomas comprise approximately 8% of pancreatic endocrine
cholecystokinin (CCK) and gastrin. Other cells such as gastric tumors. The tumor affects adults within a wide age range (20–80
parietal cells, pancreatic acinar cells, intestinal absorptive cells years), although a few cases have been reported in children.
and gallbladder smooth muscle cells are also targets of the hor- There appears to be a slight female predominance. Small num-
mone. Elevated somatostatin levels result in diabetes mellitus, bers of cases arising in association with MEN-1 have been
cholelithiasis and choledocolithiasis, steatorrhea, hypochlor- reported.
hydria, weight loss and anemia.
Epidemiological data regarding somatostatinomas are limited,
given the rarity of the tumor. Cases reported to date have been in
adults with a peak incidence in the fourth and sixth decades of VIPomas are most commonly located in the tail of the gland,
life. There is a slight female predominance. A small number with the head and body affected in decreasing order of fre-
of extrapancreatic somatostatinomas have been described, quency. The tumor is usually solitary and well-defined, and
mostly in the duodenum, where some cases have been associated ranges in size from 1 to 20 cm (median diameter 4.5 cm).
with type 1 neurofibromatosis and pheochromocytomas. Extra- Larger tumors are more likely to be malignant, but this may be
pancreatic tumors do not seem to be associated with the clinical an unreliable guide in some cases as tumors less than 2 cm in
features of hypersomatostatinemia described above. diameter have been known to metastasize.
The microscopic features are similar to those seen in other 140–190 nm. The smaller granules react with antibodies
pancreatic endocrine tumors (see Pancreatic endocrine tumors: to VIP.
General aspects, p. 268). The solid pattern is seen most fre-
quently; in some cases there may be irregular cystic areas con-
taining eosinophilic material interspersed between the solid WHO CLASSIFICATION OF PANCREATIC
sheets. Less commonly, the tumor cells are arranged in broad ENDOCRINE TUMORS
trabeculae or tubuloacinar patterns. The tumor stroma is vari-
able but may be abundant and highly vascularized. Amyloid
The WHO clinicopathological classification of pancreatic
deposition within the stroma has been reported, although this
endocrine tumors allocates lesions to the following categories:
feature is much more commonly associated with insulinomas.
1.1 Well-differentiated endocrine tumors
Lymphovascular invasion is present in about 50% of cases, and
Benign behavior
most of these tumors will have liver or lymph node metastasis
Confined to pancreas
at the time of presentation.
No evidence of lymphovascular invasion
Less than 2 cm in size
Cell morphology Two or fewer mitoses per 10 HPF
The tumor cells are generally polygonal in shape with fairly abun- Less than 2% Ki-67-positive cells per 10 HPF
dant, faintly granular, eosinophilic cytoplasm. Cells arranged in Functioning tumors: insulinoma
trabecular and tubuloacinar patterns may be more cylindrical or Non-functioning tumors
cuboidal in shape. Most tumors are composed of cells showing
Uncertain behavior
significant nuclear pleomorphism and hyperchromatism. In less
Confined to pancreas
than 15% of cases there may be frequent mitotic figures, some of
At least 2 cm in size
which may be atypical. About one-third of tumors comprise cells
More than two mitoses per 10 HPF
with less pronounced nuclear pleomorphism.
More than 2% Ki-67-positive cells per 10 HPF
OR
Special techniques Lymphovascular invasion
● Staining for VIP is positive, although poorly preserved Functioning tumors: gastrinoma, insulinoma, VIPoma,
specimens may lose this reactivity. glucagonoma, somatostatinoma or others
● Immunohistochemistry for PHM-27 (see above) is also Non-functioning tumors
positive in approximately 60% of cases.
1.2 Well-differentiated endocrine carcinomas
● Other markers that may be positive include PP,
Low-grade malignant tumors with gross local invasion
neurotensin and calcitonin. VIPomas may also secrete a
and/or metastasis
variety of other pancreatic and ectopic hormones such
Functioning tumors: gastrinoma, insulinoma, VIPoma,
as insulin, glucagon, somatostatin and growth
glucagonoma, somatostatinoma or others
hormone-releasing hormone.
Non-functioning tumors
● Electron microscopy usually reveals two types of secretory
granules – smaller granules measuring 120–160 nm with a 2.1 Poorly differentiated endocrine carcinomas
thin halo; and larger, more solid, granules measuring High-grade malignant (small to intermediate cell) carcinoma
TUMORS OF THE EXOCRINE PANCREAS
TNM STAGING OF PANCREATIC CARCINOMA

CARCINOMA, COMMON VARIANTS
T Stage:
T1 Tumor limited to the pancreas, 2 cm or less in greatest
ADENOCARCINOMA, DUCTAL dimension
T2 Tumor limited to the pancreas, more than 2 cm in greatest
CLINICAL FEATURES dimension
T3 Tumor extends beyond pancreas, without involvement of
This is the most frequently encountered malignant neoplasm celiac axis or superior mesenteric artery
of the pancreas, constituting more than 90% of cases. There T4 Tumor involves celiac axis or superior mesenteric
is a male predominance of approximately 2:1, with the majority artery
of those affected being in the 60- to 80-year-old age group. The
range of common symptoms and presentations include abdomi- N Stage:
nal pain, unexplained weight loss, jaundice, diabetes, pancreati- N0 No regional lymph node metastasis
tis and, in advanced tumors, liver metastasis and ascites. N1 Regional lymph node metastasis
(a) (b)
(c) (d)
Figure 5.37 (a) Large pancreatic duct showing pancreatic intraepithelial neoplasia (PanIN). (b) Ductal adenocarcinoma showing perineural
invasion, a common finding in such tumors. (c) Ductal adenocarcinoma showing signet ring cell morphology. (d) Mixed endocrine-ductal
adenocarcinoma. In this case, neuroendocrine cells arranged in cords and trabeculae were closely admixed with typical ductal
adenocarcinoma.

dilatation of the pancreatic and hepatic ducts is a not infre-
The tumor is most commonly encountered in the head of quent finding.
the pancreas, with the tail and body being less frequent sites Histologically, the tumor is often graded as well or moder-
of involvement. It has an ill-defined boundary, firm consistency ately differentiated, whilst poorly differentiated neoplasms are
and a yellowish-white fibrotic cut surface. Most tumors are less common. The neoplastic ductular and glandular elements
in the range of 2–3 cm in size, but they can measure from 1 up of well-differentiated ductal carcinoma may have a very banal
to 10 cm in diameter. Those arising in the body and tail appearance, both architecturally and cytologically. A sclerotic
are often larger than those in the head at the time of presenta- background stroma and disorganized distribution of glands
tion. Necrosis and hemorrhage are uncommon. In contrast, and ducts, together with the frequently encountered perineural
invasion and lymphatic permeation, provide diagnostic clues to squamous pearls and keratohyaline granules. The immunohisto-
its sinister nature. Mitotic figures are rare. chemical profile of the tumor is similar to that of ductal adeno-
Moderately differentiated tumors show significant histological carcinoma, at least within the glandular elements.
and cytological criteria of malignancy which facilitate their diag-
nosis. Neoplastic ductular and glandular elements are more pro-
nounced and abundant than in the well-differentiated tumors.
AMPULLARY CARCINOMA (CARCINOMA OF THE
There is still a significant component of sclerotic stroma, but AMPULLA OF VATER)
mitotic figures are easily seen. Poorly differentiated neoplasms
are less frequently seen. They consist of large numbers of poorly
differentiated glandular epithelial elements within a less obvious
CLINICAL FEATURES
sclerotic stroma. Mitotic activity is brisk. Adenocarcinomas of the ampulla of Vater arise from intestinal-
type epithelium of the ampulla or adjacent duodenal mucosa.
Cell morphology Invasive carcinoma may arise from a pre-existing villous or vil-
Well-differentiated tumors comprise a population of columnar loglandular adenoma. The tumor usually bulges into the duo-
cells with eosinophilic or clear cytoplasm, round or oval nuclei denal lumen as a polypoid mass, but may also appear as an
and conspicuous nucleoli. Less well-differentiated tumors show ulcerating tumor. Patients present with obstructive jaundice or
obvious and often considerable atypia. partial duodenal obstruction. Ampullary carcinoma has a high
mortality rate unless detected early; the 5-year survival rates
Special techniques vary from 6% to 85% depending on the stage. Surgical treat-
● There is positive staining for mucin, including diastase- ment is by Whipple’s procedure.
resistant periodic acid–Schiff (PAS). Ampullary villous adenoma or villoglandular polyp are con-
● Positive staining for carcinoembryonic antigen (CEA) helps sidered to be precursors of invasive carcinoma, and have been
to distinguish these neoplasms from other pancreatic found in 22–82% of ampullary carcinomas. Ampullary ade-
carcinomas and neuroendocrine tumors. nomas have an excellent prognosis in the absence of malignant
● There is positive staining for M1, CA19-9, and Du-Pan 2. transformation.
● There is negative staining for endocrine markers, though
scattered positive cells may be present. Positive staining is TNM STAGING OF AMPULLARY CARCINOMA
encountered in the mixed ductal-endocrine neoplasms.
● There is negative staining for pancreatic enzyme markers. T Stage:
T1 Tumor limited to ampulla of Vater or sphincter of Oddi
Differential diagnosis T2 Tumor invades duodenal wall
● Chronic pancreatitis, particularly the localized tumor-like T3 Tumor invades pancreas
variant T4 Tumor invades peripancreatic soft tissue or other
● Other pancreatic neoplasms including acinar cell adjacent organs or structures
carcinoma, intraductal papillary mucinous tumor, solid N Stage:
and cystic tumor, endocrine tumors and N0 No regional lymph node metastasis
pancreatoblastoma N1 Regional lymph node metastasis
● Ampullary carcinoma
ADENOSQUAMOUS CARCINOMA Ampullary carcinomas are almost always intestinal adenocar-
cinomas with varying degrees of differentiation. The superficial
CLINICAL FEATURES component commonly exhibits a papillary configuration remi-
niscent of villous adenoma of the colon. Residual tubular,
Adenosquamous carcinoma is also known as mucoepidermoid tubulovillous or villous adenoma can be seen especially in the
carcinoma or adenoacanthoma of the pancreas. The tumor is well-differentiated tumors. Dysplasia of the adjacent biliary or
considered a variant of ductal adenocarcinoma, sharing its pancreatic duct epithelium may be identifiable.
predilection for the head of the gland, similar age distribution, Rare cases of small cell undifferentiated carcinoma of the
and male to female ratio, and gross morphology. ampullary region have been reported.
Ampullary villous adenoma or villoglandular polyp usually
PATHOLOGICAL FEATURES show features similar to those of colonic origin. They usually
As the various names for this tumor imply, the lesion shares a contain goblet cells, and may also contain Paneth cells and
morphological pattern similar to that seen in adenosquamous argentaffinic and argyrophilic cells. Foci of severely dysplastic
carcinoma, mucoepidermoid carcinoma or adenoacanthoma in epithelium may be present.
other organs, with both glandular and squamous elements
closely intermingled. The glandular component resembles that of Differential diagnosis
the ductal adenocarcinoma, whilst the squamous component ● Carcinoma of the terminal third of the common bile duct
constitutes at least 30% of the tumor and may display typical ● Adenocarcinoma of the duodenum
COLLOID (MUCINOUS NON-CYSTIC) CARCINOMA an overall pattern reminiscent of carcinoid or neuroendocrine

tumor admixed with well-formed glands. The latter are often
arranged circumferentially around the tumor nests. Cystic degen-
CLINICAL FEATURES eration is not uncommon. The epithelial component shows brisk
Colloid (mucinous non-cystic) carcinoma shares similar clinical mitotic activity. Squamoid corpuscles with clear nuclei rich in
characteristics with ductal carcinoma, of which it is a variant. biotin are often seen. The intervening mesenchymal elements
The tumor is said to have a more favorable prognosis than clas- comprise fibrous tissue showing hyalinization, myxoid change
sical ductal adenocarcinoma, but a more aggressive behavior and vascularization. Cartilaginous tissue is not uncommon.
than that of mucinous cystadenocarcinoma.
Special techniques
PATHOLOGICAL FEATURES Unlike islet cell tumor, the pancreatoblastoma cells lack neuro-
secretory granules. However, they express acinar cell markers
The tumor shares the morphological pattern characteristic of col-
such as lipase, trypsin and chymotrypsin and may also express
loid carcinoma elsewhere. The macroscopic appearance is that of
alpha-fetoprotein and alpha-1-antitrypsin.
a well-defined large mass with a gelatinous soft consistency.
Histologically, the tumor is composed of copious mucin lakes that
are partially lined by well to moderately differentiated glandular
cells. These cells may also be seen scattered within the mucin. ● Acinar cell carcinoma
● Solid and cystic tumor
● Endocrine tumors
MICROGLANDULAR ADENOCARCINOMA
Microglandular adenocarcinoma is now regarded as an uncom-

UNDIFFERENTIATED CARCINOMA (Figure 5.38)
mon variant of ductal adenocarcinoma with a particularly
Other synonyms for this tumor include sarcomatoid carcinoma,
aggressive clinical course. The most striking feature of this
anaplastic carcinoma, giant cell carcinoma and pleomorphic
variant is its close resemblance to neuroendocrine tumors, and
large cell carcinoma. As these names imply, the tumor has an
this is an important differential diagnosis. The tumor is com-
exceedingly poor prognosis. The tumors are considered to be
posed of uniform small cells with round to oval nuclei, clumped
variants of ductal adenocarcinoma, as they often display at least
chromatin and a high nuclear to cytoplasm ratio, arranged
minor glandular elements that share a similar immunohisto-
in solid sheets admixed with microglandular and cribriform
chemical profile, in addition to vimentin positivity. Unlike usual
areas.
ductal adenocarcinoma, they are more common in the body and
Despite the appearances, immunohistochemical staining for
tail rather than the head of the pancreas. They form large
neuroendocrine and peptide hormone markers is negative,
masses with considerable hemorrhage and necrosis.
whilst CAM 5.2 staining is positive.
PANCREATOBLASTOMA (INFANTILE PANCREATIC

CARCINOMA)
CLINICAL FEATURES
Infantile pancreatic carcinoma/pancreatoblastoma is a primitive
type of pancreatic carcinoma, currently viewed as the pancreatic
counterpart to hepatoblastoma and nephroblastoma, and with
not a dissimilar morphology. It is one of the most common pan-
creatic tumors in children, though cases have also been reported
in adults.
At presentation, the tumor is usually of a large size (up to
20 cm), and may metastasize to the liver and elsewhere.
Encapsulated resectable tumors have a relatively favorable
prognosis, however.
Pancreatoblastomas arise in the head or body of the pancreas.
They are circumscribed masses with a hemorrhagic and necrotic (a)
cut surface, and can be either fully or partially encapsulated.
Histologically, the tumor is characterized by the presence of Figure 5.38 (a) Undifferentiated (anaplastic) carcinoma of the
solid nests and trabeculae of small uniform epithelial cells with pancreas.
as a deceptively circumscribed nodular growth ranging in size

from 2 to 6 cm, with an often rounded or lobulated soft struc-
ture. The yellowish-brown cut surface shows areas of hemor-
rhage and necrosis.
Histologically, this tumor often spreads beyond its naked-
eye boundaries to adjacent structures. The tumor consists of
epithelial cells displaying either a single pattern of solid, nested or
trabecular appearance, or a mixture of these appearances.
Occasionally, small clusters of cells may simulate normal acini.
Thin-walled capillaries are seen in between the tumor nests. More
frequently, the tumor is less well-differentiated and exhibits cellu-
lar pleomorphism, giant cell formation and spindle cell areas.
Mixed acinar-endocrine carcinoma has been described and
should be distinguished from acinar cell carcinoma with a
minor endocrine component. Mixed acinar-endocrine carci-
noma contains a substantial component of endocrine elements,
comprising at least 25% of the tumor population.
Acinar cell cystadenocarcinoma represents the cystic variant
of acinar cell carcinoma. It is a rare tumor that is characterized
by cystic spaces lined by neoplastic acinar cells resembling, on
(b)
histological, immunohistochemical and ultrastructural grounds,
Figure 5.38 (b) Undifferentiated carcinoma with osteoclast-like the cells of the classical acinar cell carcinoma.
giant cells. Acinar cell cystadenoma is a recently described entity pro-
posed to represent the benign variant of acinar cell cystadeno-
carcinoma. In well-differentiated neoplasms, the neoplastic cells
The morphological pattern of these tumors, as their names are large, rounded or polygonal in shape with sharply demar-
imply, ranges from that of sarcomatoid carcinoma to the giant cated borders, ample granular eosinophilic cytoplasm and uni-
cell carcinoma and pleomorphic large cell carcinoma seen in form nuclei. Poorly differentiated acinar cell cystadenomas
other organs, in particular the lungs. comprise a population of small undifferentiated cells.
Special techniques
CARCINOMA, RARE VARIANTS ● The cells are immunoreactive for pancreatic enzymes
including lipase, trypsin and chymotrypsinogen.
● Positive for alpha-1-antitrypsin.
ACINAR CELL CARCINOMA ● Positive CAM 5.2 for cytokeratin.
● Zymogen granules are identifiable by electron microscopy.
CLINICAL FEATURES ● Variable staining for endocrine markers.
Acinar cell carcinoma is a rare type of pancreatic carcinoma

accounting for approximately 1–2% of all pancreatic tumors.
It presents mainly in adults, although cases in children and ● Endocrine tumors
adolescents have been described. It is twice as common in males ● Poorly differentiated pancreatic duct carcinoma
as in females. The tumor rapidly replaces the normal architect- ● Solid cystic tumor
ure of the pancreas and infiltrates the surrounding tissue – a ● Ductal adenocarcinoma
behavior not dissimilar to that of pancreatic duct carcinoma. ● Acinar cell adenoma
Characteristically, it may be associated with widespread subcu-
taneous fat necrosis, eosinophilia and arthralgia due to the CHORIOCARCINOMA
lipase secreted by the tumor. Presentation is often the result of
local pressure effects, though weight loss, anemia and jaundice A rare case of pancreatic choriocarcinoma has been reported.
are also seen. Metastatic disease and elevated serum alpha-feto- The tumor has a similar morphological pattern to that described
protein (AFP) levels are not uncommon findings. The overall in other organs.
prognosis is similar to that of conventional ductal carcinomas of
the pancreas.
CLEAR CELL CARCINOMA
This is a rare tumor with a morphological pattern which resem-
Grossly, these tumors present in any part of the pancreas, with bles the corresponding tumor in the kidney. The cells may show
a slight predilection for the head. They appear macroscopically scattered mucin positivity.
ONCOCYTIC CARCINOMA
CYSTIC LESIONS
This is exceedingly rare in the pancreas. The morphological
pattern resembles its counterparts in other organs. Invasive CYSTS
carcinoma arising from an intraductal papillary oncocytic
tumor (see Intraductal papillary mucinous tumors, p. 281) may
be oncocytic in appearance. CLINICAL FEATURES
Non-neoplastic cystic lesions of the pancreas are common, and
can mimic malignancy both radiologically and macroscopically.
SIGNET RING CELL CARCINOMA Most such lesions are so-called ‘pseudocysts’, and these are dis-
cussed later in the chapter. True cysts (i.e., epithelial lined struc-
Signet ring cell carcinoma of the pancreas is very rare, and has tures) are less common and are detailed below. Many of these
the same pattern of morphology and poor prognosis as its lesions are asymptomatic. Para-ampullary duodenal wall cysts
counterparts in other organs. It is considered as a variant of often give rise to symptoms of pain, vomiting, weight loss and
ductal adenocarcinoma, and displays at least a minor compo- jaundice, and hence from a clinical stand-point may mimic pan-
nent of neoplastic glandular elements. They can sometimes creatic carcinoma.
diffusely replace the entire pancreas, and in these cases it may be
difficult to determine if they are of primary or secondary origin.
A pancreatic neuroendocrine variant of signet ring appearance PATHOLOGICAL FEATURES
has been described highlighting the importance of immunohis- Retention cysts
tochemistry in distinguishing between the two variants.
Obstruction of a pancreatic duct by tumor, fibrous scarring or
mucus plugging may cause dilatation of ducts distal to the
obstruction. Cystic dilatation of ducts produces a retention cyst
UNDIFFERENTIATED CARCINOMA WITH lined by normal pancreatic ductal epithelium. In the setting of
OSTEOCLAST-LIKE GIANT CELLS chronic pancreatitis, the wall may be inflamed, leading to dis-
ruption or necrosis of the cyst lining. Retention cysts are often
seen in patients with cystic fibrosis.
CLINICAL FEATURES
This is a rare neoplasm which was once thought to have a rela- Congenital pancreatic cysts
tively favorable outcome but it is now considered to have a poor These may be single or, more commonly, multiple. Large soli-
prognosis. Its histogenesis remains controversial, though recent tary cysts have been described in children, and a small number
reports favor an epithelial origin with a ductal phenotype. Whilst of cases have even been diagnosed on antenatal screening.
some reports suggest a common cell lineage for the tumor, Multiple congenital cysts are usually associated with an under-
others suggest that the giant cell component may represent a lying syndrome such as von Hippel–Lindau disease or a variety
paraneoplastic product of the tumor. of malformation syndromes associated with cystic dysplasia of
the pancreas. Congenital cysts are lined by a single layer of flat
or cuboidal epithelium with an underlying fibrous wall. The
PATHOLOGICAL FEATURES (Figure 5.38b) cysts contain serous fluid, and hence the differential diagnosis
Grossly, osteoclast-like giant cell tumors of the pancreas may is that of a serous cystadenoma.
present as cystic lesions, and should be included in the differ-
Parasitic cysts
ential diagnosis of pseudocysts.
Histologically, the tumor is characterized by atypical, poly- Cystic masses of the pancreas produced by parasitic infection
gonal or spindle-shaped, pleomorphic mononuclear cells asso- are rare. Most are echinococcal (hydatid) cysts.
ciated with benign-looking, osteoclast-like giant cells. The
pleomorphic cell component shows significant mitotic activity.
Para-ampullary duodenal wall cysts
Areas of osteoid metaplasia are often present, together with The origin of para-ampullary duodenal wall cysts is uncertain,
other areas showing nested and ductal glandular epithelial but it may be related to ductal elements of heterotopic pancre-
elements. atic tissue in the duodenum. Such cysts arise in the submucosa
or intramuscular layers of the duodenum close to the ampulla
of Vater, or around the intrapancreatic segment of the common
Special techniques bile duct. The cyst lining is of columnar mucin-secreting type,
● The pleomorphic tumor cells are positive for cytokeratin, and there may be eosinophilic hyaline material within the cyst.
epithelial membrane antigen (EMA) and vimentin. This material is associated with a mixed inflammatory cell pop-
● The osteoclast-like giant cells and histiocytes stain for ulation, often including foreign body giant cells. There may be
vimentin, leukocyte common antigen and the histiocytic necrosis of the cyst wall adjacent to the cyst contents, and this
marker CD68. may elicit inflammation and fibrosis of the surrounding tissue.
Fibrosis eventually leads to stenosis of the common bile duct

and symptoms which are clinically suggestive of carcinoma of CYSTIC PANCREATIC TUMORS
the pancreas head.
MUCINOUS CYSTIC TUMORS
Enterogenous cysts
Enterogenous cysts represent segmental duplication of part of
the intestinal tract. They are developmental in nature, and CLINICAL FEATURES
hence present in children, sometimes with symptoms of pan- Like their ovarian counterparts, mucinous cystic tumors are
creatitis. The majority occur in the duodenal wall, with very classified into:
rare examples in the body and tail of the pancreas. Duodenal ● Benign mucinous cystic tumors
cysts may communicate with the pancreatic duct system. The ● Borderline mucinous cystic tumors
cyst lining is of intestinal-type epithelium. ● Mucinous cystadenocarcinomas
Lymphoepithelial cysts As a general rule, these tumors resemble their ovarian counter-
parts, both grossly and histologically. They occur predominantly
These cysts closely resemble branchial cysts of the neck, with a
in middle-aged women and can be located in any part of the
lining composed of keratinizing squamous epithelium and
pancreas, though the body and tail are most commonly affected.
underlying lymphoid tissue, often containing small follicles and
They may be an incidental finding, particularly when small in
germinal centers. The main differential diagnosis is that of a
size. Larger tumors may cause pressure symptoms. Computed
cystic teratoma. It has been suggested that these cysts arise
tomography (CT) scanning reveals a well-circumscribed cystic
from protrusion of a pancreatic duct into an adjacent lymph
mass in benign cases. Invasion of adjacent structures may be vis-
node. Most reported cases of lymphoepithelial cysts have been
ible with malignant tumors.
in male patients.
Endometrial cysts PATHOLOGICAL FEATURES

Endometriosis of the pancreas is extremely uncommon. The The morphological pattern of these tumors is similar to that of
microscopic appearances are identical to those seen elsewhere, their ovarian counterparts, and therefore will be referred to
and diagnosis requires the recognition of both endometrial here only briefly.
glands and surrounding endometrial stroma. Grossly, these tumors form large cystic, encapsulated, uniloc-
ular or rarely multilocular masses containing mucoid material.
The cut-surface appearance is reminiscent of the corresponding
PSEUDOCYSTS ovarian tumor.
Histologically, they are characterized by the presence of large
branching cystic spaces lined by endocervical-type or intestinal-
CLINICAL FEATURES type mucinous epithelium, surrounded by desmoplastic or
Pancreatic pseudocysts comprise approximately three-quarters ovarian like stroma – a morphology which is largely indistin-
of all pancreatic cystic lesions. They arise in the setting of pan- guishable from that of mucinous ovarian tumors.
creatitis, usually due to alcohol, bile reflux or trauma. Males The classification of these tumors as benign, borderline or malig-
are affected more commonly than women. Pseudocysts may nant depends on the same criteria. A malignant sarcomatous stro-
mimic malignancy both radiologically and macroscopically. mal component has been well documented. Focal calcification is
The erosion of portal vessels can give rise to potentially serious sometimes observed. On occasion, endocrine-type cells may be
complications such as thrombosis, hemorrhage and disseminated found in the lining of the cystic structures; these are sometimes
fat necrosis. functional cells, secreting mainly gastrin (they may therefore be
associated with Zollinger–Ellison syndrome). Pancreatic acinar
atrophy and chronic inflammation due to large duct obstruction
PATHOLOGICAL FEATURES are not uncommon findings in the adjacent pancreatic tissue.
Pseudocysts arise as a result of tissue necrosis following the
Cell morphology
release of destructive pancreatic enzymes into the surrounding
gland. Most pseudocysts are located outwith the pancreas itself, The lining cells are tall columnar cells with basal nuclei and
but are connected by inflammatory tissue to the gland; some may abundant cytoplasmic mucin reminiscent of intestinal goblet
also communicate with the pancreatic ducts. As the name sug- cells or endocervical epithelial cells. Paneth cells and neuro-
gests, pseudocysts do not possess an epithelial lining. The wall endocrine cells may also be present focally.
consists of fibrin, granulation tissue and collagen, the amount of
which increases with the age of the lesion. Pseudocysts contain Differential diagnosis
variable amounts of necrotic and hemorrhagic material and ● Intraductal papillary mucinous tumor
enzyme-rich fluid. The surrounding pancreas shows evidence of ● Pseudocysts
acute or chronic pancreatitis. ● Colloid carcinoma
Special techniques Differential diagnosis

● AB-PAS can be used to demonstrate mucin in less well- The differential diagnosis is with other cystic tumors of the
differentiated tumors. pancreas and pseudocystic lesions or structures.
● The tumors show positive staining with epithelial markers,
CEA and CA19-9. Special techniques
● Focal positivity for endocrine markers can also be ● The cells of serous cystadenoma are derived from the
demonstrated if neuroendocrine cells are present. centroacinar cells of the pancreas.
● The cells are also glycogen-rich and hence PAS-positive,
SEROUS CYSTIC TUMOURS and exhibit minimal or no mucin positivity. They show
EMA and cytokeratin positivity (CK 7, 8, 18 and 19) but
negative staining for neuroendocrine markers, trypsin
CLINICAL FEATURES and CEA.
Serous cystic tumors encompass three main categories:
● Benign serous microcystic adenoma SOLID AND CYSTIC TUMOR
● Benign serous oligocystic (macrocystic) adenoma
● Malignant serous cystadenocarcinoma

CLINICAL FEATURES
Solid serous adenoma represents a less common variant of
serous tumor. Solid and cystic tumor of the pancreas is also known as solid
Serous cystic tumors arise in any part of the pancreas, pre- pseudopapillary, papillary and cystic tumor or solid and papillary
dominantly in middle-aged and elderly patients. Microcystic epithelial neoplasm. It is a relatively rare tumor, with distinctive
adenomas are more common in women than men, whilst oligo- clinical and histological features. The tumor is found almost exclu-
cystic adenoma and cystadenocarcinoma show almost equal sively in young women of reproductive age, usually in the second
sex distribution. They may be discovered incidentally, or pres- or third decade of life, although cases have been reported in men as
ent as an abdominal mass or with signs and symptoms related well as in postmenopausal women and in children. Patients often
to their pressure effect on adjacent organs and structures. They present with a gradually enlarging mass in the upper abdomen,
may result in gastrointestinal and biliary obstruction when sometimes combined with discomfort or pain and occasionally rup-
located in the head of the pancreas. Most serous cystic tumors ture. The characteristic CT appearances permit preoperative diag-
are benign; their malignant counterparts are relatively rare. nosis, and this has been reported in asymptomatic cases.
The tumor is often categorized as having a borderline malignant
potential. However, it has a very favorable prognosis when com-
pletely excised. Unresected or partly resected tumors progress very
Grossly, benign serous cystic tumors appear as a solitary mass slowly. It has been suggested that solid cystic tumors show small
located in any part of the pancreas. The tumors can attain a large ductal cell differentiation, perhaps being derived from a primi-
size, perhaps up to 25 cm diameter in the microcystic variant. tive epithelial cell capable of multi-directional differentiation.
Oligocystic adenoma is often associated with von Hippel–Lindau Malignant variants of solid cystic tumors are exceedingly rare.
disease. Serous microcystic adenoma and serous oligocystic
(macrocystic) adenoma are characterized by the presence of PATHOLOGICAL FEATURES
numerous, variably sized micro- and macrocystic spaces, respec-
tively. These spaces, which are filled with serous fluid, are sepa- Grossly, the tumor is usually rounded and well circumscribed
rated by a vascular stroma. The cysts are numerous but small with a peripheral fibrous capsule. It is most commonly encoun-
(generally less than 0.5 cm in diameter) in the microcystic vari- tered in the body and tail of the pancreas. Sectioning often reveals
ant, while they are fewer but larger (0.5–2 cm diameter) in the peripheral, pale, solid tissue encompassing brown, hemorrhagic
macrocystic subtype. cystic areas containing altered blood or necrotic material.
Histologically, these cystic spaces are lined by a single or dou- Histologically, solid and cystic tumor of the pancreas has a
ble layer of uniform cells with clear cytoplasm. The lining cells very distinctive appearance. The solid areas show monotonous
are small, flat or cuboidal, with centrally located nuclei and cuboidal or rounded cells with no cytological atypia, forming
clear cytoplasm. A basal layer of myoepithelial cells can be iden- solid masses of sheets and trabeculae or covering papillary hya-
tified. Focal calcification is a frequent finding in the microcystic line cores. The cystic areas contain degenerating cells with
variant, which also displays a dense central collagenized stroma, necrosis and hemorrhage.
radiating out in a stellate pattern. Solid serous adenoma com-
prises nests of similar clear or occasionally eosinophilic cells dis- Cellular morphology
persed in a fibrous stroma with no significant cystic component. The cells are small, cuboidal or rounded, with a small amount
Serous cystadenocarcinoma is a very rare neoplasm that pres- of pale eosinophilic cytoplasm. The nuclei are round and contain
ents as a mass invading the adjacent structures. Histologically, inconspicuous nucleoli. Mitotic figures are rarely seen, except
the pattern is not unlike that of their benign counterparts, but in the malignant variant which shows invasion of adjacent
there is cytological evidence of malignancy, and the tumor infil- structures and can metastasize to lymph nodes and other
trates stroma as well as adjacent structures. organs.
Special techniques reveals a dilated duct containing solitary or multiple polypoidal

● Tumor cells show very little mucin or glycogen, and are or nodular masses ranging in size from 2 to 4 cm. The sur-
neither argentaffinic nor argyrophilic. rounding pancreatic tissue appears fibrotic.
● The cells are positive for NSE and vimentin. In the benign variant, the dilated ducts may be lined by focally
Immunoreactivity for progesterone receptors (but not atypical cells. They contain papillary structures of varied mor-
estrogen receptors) has been found in these tumors. phology lined by mucin-secreting cells; these may also show
● There is variable reactivity for cytokeratin, alpha-1- focal atypia.
antitrypsin and alpha-1-antichymotrypsin. In the more recently described entity of intraductal papillary
● The cells are negative for PP and other islet cell markers, oncocytic tumor, the lining cells are of oncocytic type.
CEA and AFP. Intraductal papillary mucinous carcinoma shows invasion of
the underlying stroma by malignant elements. Papillary muci-
Differential diagnosis nous carcinoma shows invasion of the surrounding pancreatic
tissue, and can spread to adjacent organs.
● Acinar cell tumor
● Neuroendocrine tumors Special techniques
● The tumor cells show positive mucin staining.
DUCTAL LESIONS ● There is positive staining for the CEA marker.
DUCTAL CHANGES ● Ductal papillary hyperplasia
● Ductal adenocarcinoma
The assessment of metaplasia, hyperplasia and dysplasia in small ● Mucinous cystic tumors
pancreatic ducts is complicated by the use of multiple different ● Mucin-secreting bile duct adenoma
grading and classification systems. Recently, there has been a
move to introduce and refine a standardized system based on the MUCINOUS DUCTAL ECTASIA
concept of pancreatic intraepithelial neoplasia (PanIN). This sys-
tem incorporates many older terms such as mucinous cell hyper-
trophy, ductal papillary hyperplasia and atypical hyperplasia. It CLINICAL FEATURES
is suggested that the development of pancreatic carcinoma fol-
Mucinous ductal ectasia of the pancreas may not be a neoplas-
lows a stepwise progression sequence involving the accumulation
tic process, though malignant transformation has been docu-
of multiple genetic mutations. Standardization of nomenclature
mented. The lesion usually affects the accessory ductal system,
should aid the investigation of the earliest microscopic changes
and is rare or non-existent in the main pancreatic ducts. Patients
associated with this proposed sequence.
often present with symptoms of chronic pancreatitis.
INTRADUCTAL PAPILLARY MUCINOUS TUMORS PATHOLOGICAL FEATURES

Grossly, this lesion usually appears as a multiloculated, poorly
CLINICAL FEATURES defined cystic mass associated with fibrosis in the posterosuperior
part of the head of pancreas. Histologically, it shows a markedly
Intraductal papillary mucinous tumors are further subclas-
dilated ductal system containing inspissated and often laminated
sified into:
eosinophilic mucin. The lesion has an ill-defined border.
● Benign intraductal papillary mucinous adenoma
● Intraductal papillary mucinous borderline tumor Cellular morphology

● Intraductal papillary mucinous carcinoma and papillary
● The lining epithelium is a single layer.
mucinous carcinoma ● Atypical features are absent.
These are uncommon pancreatic tumors which often present
with pancreatitis-like symptoms attributed to early ductal Differential diagnosis
obstruction. Pancreatic atrophy and insufficiency secondary to ● Mucinous cystadenoma
this may also precipitate diabetes. Other presentations include
steatorrhea and an elevated serum amylase level. The tumors
are more common in men, and occur most often in the sixth MISCELLANEOUS LESIONS
decade of life. The CT scanning appearances of a polypoid
structure within a main pancreatic duct and associated duct CHRONIC PANCREATITIS
ectasia are strongly suggestive of the diagnosis.
PATHOLOGICAL FEATURES CLINICAL FEATURES

Macroscopically, the tumor appears as a thickened or nodular Chronic pancreatitis is an important differential diagnosis of
area, usually within the head of the pancreas. Sectioning pancreatic carcinoma, not only in the clinical setting but also in
certain histological settings such as in frozen section material. PATHOLOGICAL FEATURES

Recurrent acute pancreatitis due to chronic alcoholism is the
Macroscopically, the pancreas is enlarged but of normal shape.
most common cause of chronic pancreatitis in Western countries.
Histologically, the pancreatic parenchyma contains large amounts
Other recognized causes include ductal obstruction, malnutri-
of mature adipose tissue. Thin fibrous septae containing normal
tion, hereditary chronic pancreatitis and autoimmune condi-
pancreatic islets run through the fatty parenchyma.
tions. The most common presenting symptom is continuous or
recurrent abdominal pain which may be severe in nature.
Malabsorption and steatorrhea are late features of chronic pan- MATURE TERATOMA
creatitis, and only develop when damage to pancreatic acini is
extensive. Pancreatic islets are relatively resistant to the destruc- Benign mature teratoma can occur in the pancreas. Its mor-
tive and fibrotic process, but diabetes mellitus does develop late phological pattern is similar to that seen in other sites.
in a proportion of cases.
PSEUDOLYMPHOMA (FOCAL LYMPHOID
PATHOLOGICAL FEATURES HYPERPLASIA)
In cases of early chronic pancreatitis the gland is irregularly
Focal, non-neoplastic lymphoid proliferation (pseudolymphoma)
enlarged and firm or hard in consistency. With time, there is
is a very uncommon process in the pancreas (in contrast to the
involvement of the entire pancreas, and this results in a hard,
gastrointestinal tract). Microscopically, these lesions consist of
shrunken gland. The ducts are irregularly dilated and distorted,
dense fibrous stroma containing large pancreatic ducts and lym-
and often contain calculi. The intrapancreatic common bile
phoid follicles, many with germinal centers.
duct may be stenotic because of scarring in the head of the pan-
The differential diagnosis is with lymphoma (primary lym-
creas. Pseudocysts (see below) may be present adjacent to scle-
phoma of the pancreas has been reported, but is extremely rare).
rotic areas.
Microscopically, there is interlobular fibrosis in the early stages
of the condition. Chronic inflammatory cells are present within SPLENIC HETEROTOPIAS
the fibrous tissue. This process becomes increasingly widespread
and eventually extends into the lobules (intralobular fibrosis), Ectopic splenic tissue is well recognized in the pancreas, and
with replacement of the acinar cells. Pancreatic islets are gener- forms an uncommon differential diagnosis of a pancreatic mass
ally spared and may appear so prominent that a diagnosis of an lesion. The ectopic tissue appears as a small (up to 4 cm) red
endocrine tumor is considered. Remaining ductules are dilated mass, usually in the tail of the gland. Epidermoid cysts occur-
and distorted, while the duct epithelium may be focally atrophic ring in accessory splenic tissue have been described.
or replaced by fibrous tissue. The lobular pattern of the gland is
preserved even in advanced cases, and this allows distinction
from an invasive carcinoma. Other reassuring features are lack WHO CLASSIFICATION OF PANCREATIC
of cellular atypia, an absence of perineural invasion, and the EXOCRINE TUMORS
presence of calculi.
The WHO clinicopathological classification of pancreatic
exocrine tumors allocates lesions to the following categories:
INFLAMMATORY MYOFIBROBLASTIC TUMOR Epithelial tumors
Benign
Inflammatory myofibroblastic tumors, also known as inflamma- ● Serous cystadenoma
tory pseudotumors, are extremely uncommon in the pancreas. ● Mucinous cystadenoma
The microscopic features are similar to their more common ● Intraductal papillary-mucinous adenoma
counterparts in the respiratory tract. ● Mature teratoma
Borderline (uncertain malignant potential)

LIPOMATOUS PSEUDOHYPERTROPHY ● Mucinous cystic neoplasm with moderate dysplasia
● Intraductal papillary-mucinous neoplasm with moderate
dysplasia
CLINICAL FEATURES ● Solid pseudopapillary neoplasm
Lipomatous pseudohypertrophy is an uncommon process which Malignant

may cause diagnostic difficulties on ultrasound and CT scan- Ductal adenocarcinoma
ning. The pathogenesis is unclear, but recent reports have linked ● Mucinous non-cystic carcinoma
the process to advanced hepatic disease. Ductal obstruction may ● Signet ring cell carcinoma
also give rise to significant lipomatosis of the pancreas, whilst ● Adenosquamous carcinoma
lipomatosis may be extensive in cases of advanced cystic fibro- ● Undifferentiated (anaplastic) carcinoma
sis. Pancreatic exocrine and endocrine function is usually pre- ● Undifferentiated carcinoma with osteoclast-like giant cells
served in lipomatous pseudohypertrophy. ● Mixed ductal-endocrine carcinoma

Bibliography 283
Serous cystadenocarcinoma ● Acinar cell cystadenocarcinoma

Mucinous cystadenocarcinoma ● Mixed acinar-endocrine carcinoma
● Non-invasive
Pancreatoblastoma
● Invasive
Solid pseudopapillary carcinoma
Intraductal papillary-mucinous carcinoma Others
● Non-invasive
● Invasive (papillary-mucinous carcinoma)
Acinar cell carcinoma Secondary tumors
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6 endocrine tumors
Catriona Anderson and Kathryn M McLaren
Tumors of the adrenal glands 333 Common carcinomas 347

Adrenocortical adenoma 333 Follicular carcinoma 347
Adrenocortical carcinoma 335 Papillary carcinoma 349
Neuroblastic tumors 336 Columnar cell variant 351
Pheochromocytoma 339 Cystic variant 351
Diffuse sclerosing variant 351
Miscellaneous neoplasms 340 Follicular variant 351
Adrenal cysts 340 Oncocytic variant 351
Myelolipoma 341 Papillary carcinoma with exuberant nodular
Other mesenchymal neoplasms 341 fasciitis-like stroma 351
Papillary microcarcinoma 351
Tumors of the parathyroid glands 341 Tall-cell variant 352
Adenoma 341
Carcinoma 342 Less common carcinomas 352
Insular carcinoma 352
Hyperplasia 343 Medullary carcinoma 352
Primary parathyroid hyperplasia 343 Mucoepidermoid carcinoma 354
Secondary and tertiary parathyroid hyperplasia 343 Squamous carcinoma 355
Undifferentiated (anaplastic) carcinoma 355
Parathyroid cysts 343 Miscellaneous tumors 356
Parathyroid lipoadenoma (hamartoma) 344 Lymphoma 356
Mesenchymal neoplasms 357
Tumors of the thyroid glands 344 Solid cell nests 357
Adenomas 344 Spindle epithelial tumor with thymus-like
Follicular adenoma 344 elements (SETTLE) 357
Hyalinizing trabecular adenoma 345
Oncocytic lesions 346
GENERAL COMMENTS
Tumors of endocrine glands are, in comparison with tumors of with which they produce excess native hormones. The major-
other sites, uncommon. Overall, the majority are benign and ity of tumors are adenomas, but the carcinomas are import-
may present early due to functional effects, for example a ant since, according to the subtype, their prognosis is very
steroid-producing adrenocortical adenoma. different.
The thyroid gland is the most common site for an endocrine Herein, the methods of diagnosis of endocrine tumors are
tumor and differs from the other endocrine glands in the rarity alluded to.
TUMORS OF THE ADRENAL GLANDS
ADRENOCORTICAL ADENOMA syndrome or Conn’s syndrome – or virilizing or feminizing fea-

tures. However, with improvements in imaging, so-called cortical
‘incidentalomas’ are now being detected, many of which are
CLINICAL FEATURES
non-functional, though some of these appear to be associated
Adrenocortical adenomas are benign tumors arising in the with a sub-clinical Cushing’s syndrome. Adrenocortical adeno-
adrenal cortex. They usually present with a clinical syndrome mas may occur as part of multiple endocrine neoplasia type I
characteristic of the hormone produced – namely Cushing’s (MEN I), where they may be multiple.
334 Endocrine tumors

Macroscopically, these tumors are usually solitary, well-
circumscribed, and rarely exceed 5 cm in diameter or 50 g in
weight. They often have a tan- to brown-colored cut surface.
Figure 6.4 Spironolactone body within a zona glomerulosa cell.
Figure 6.1 Adrenocortical adenoma.
Figure 6.5 Immunohistochemistry for melan A, showing positivity

of adrenal adenoma cells.
Adenomas producing aldosterone are typically bright yellow

when visualized macroscopically.
Adrenocortical tumors are characterized by the presence of
clear, foamy, or eosinophilic cells arranged in fascicles, anasto-
Figure 6.2 Adrenocortical adenoma showing cystic change. mosing columns, or solid sheets. Myxoid and cystic change
may occur.
Secondary features
● In patients with a Cushing’s adenoma the background
adrenal and contralateral gland are usually atrophic.
This is not the case in non-functioning adenomas or
those producing other hormones. Indeed, in aldosterone-
producing adenomas, paradoxical hyperplasia of the
adjacent and contralateral adrenal cortex can be seen.
Cell morphology
● The main cell populations usually resemble those of the
zona fasiculata. Adenomas producing aldosterone may
contain glomerulosa-like cells.
● Large atypical and multinucleated giant cells may be seen.
Figure 6.3 High-power magnification of the component cells of an ● Adenomas composed entirely of oncocytic cells can occur,
adrenocortical adenoma. Note the similarity to zona fasiculata cells. and these are usually non-functional.
● Mitotic figures are rare in adenomas.

● In patients treated with spironolactone, spironolactone
bodies may be present in the background gland within the
cells of the outer fasiculata and glomerulosa. They may
also be seen within tumor cells, and are thought to be
derived from smooth endoplasmic reticulum.
● A testosterone-secreting adrenal adenoma may contain
crystalloids characteristic of Leydig cells.
● Adrenal hyperplasia: differentiation between nodular
hyperplasia of the adrenal cortex and an adrenal adenoma
can be difficult, particularly if the hyperplastic nodules are
very large. Usually, the presence of diffuse hyperplasia of
the surrounding cortex and in the contralateral gland is
helpful in diagnosing a hyperplastic nodule. However, this
could be misleading in the case of an aldosterone-secreting Figure 6.6 Adrenocortical carcinoma, low-power magnification.The
architectural arrangement of cells is similar to that seen in an adenoma.
adenoma showing hyperplasia of the background gland.
● Adrenal carcinoma (see below).
● Pheochromocytoma (see below).
Special techniques
● Cortical adenomas can express inhibin-␣, calretinin and
melan A (clone A103)
● They do not express chromogranin A (which aids
differentiation from pheochromocytoma)
● Neuron-specific enolase (NSE), PGP 9.5 and
synaptophysin can be expressed by cells in an adrenal
adenoma or carcinoma.
ADRENOCORTICAL CARCINOMA
(a)
CLINICAL FEATURES
This is an uncommon but highly malignant tumor with an inci-
dence of 2 per million population. Functional carcinomas are
more common and are detected earlier than non-functioning
tumors, but by the time of presentation many have already meta-
stasized primarily to the liver or lungs. Spread to adjacent struc-
tures also occurs, and surgical resection is the only effective
treatment.

Adrenocortical carcinomas usually weigh more than 100 g,
although metastases have been reported in cases weighing less.
Macroscopically, they are usually yellow to brown in color, and
may contain areas of hemorrhage or necrosis. (b)
The microscopic appearances of adrenocortical carcinoma are
often similar to adenomas with cells arranged in fascicles, anas- Figure 6.7 Adrenocortical carcinoma: (a) The cells resemble those
tomosing columns, or solid sheets. Myxoid change may occur. of the zona glomerulosa. (b) A larger cell with a prominent
intranuclear inclusion.
Cell morphology ● Large atypical and multinucleated giant cells may be seen
● The main cell populations may resemble those of the zona with granular chromatin and prominent, multiple nucleoli.
glomerulosa or zona fasiculata. ● Mitoses are rare in adenomas but frequent in carcinomas,
● Some cells may have intra-nuclear inclusions. often with atypical forms.
Weiss reported that lesions with two or fewer of these

features rarely metastasized, whereas those with three or
more almost all behaved in a malignant fashion.
More recently, these criteria of malignancy have been

re-examined (Aubert et al. 2002) and five of Weiss’ original cri-
teria have been identified as most useful (denoted by asterisks
in Table 6.1). The presence of three or more of these criteria is
strongly associated with aggressive behavior, showing good
interobserver agreement.
A Ki-67 (MIB-1) labeling index of higher than 4% appears
to be associated with malignancy.
● Pheochromocytoma: the most useful immunocytochemical
discriminator is chromogranin A, which is expressed by

pheochromocytomas but generally not by cortical neoplasms.
Some adrenocortical carcinomas contain foci of
neuroendocrine differentiation and express synaptophysin
Figure 6.8 Tripolar mitotic figure in an adrenocortical carcinoma.
and NSE, which would also be expressed in pheo-
chromocytomas.
● Metastatic carcinoma (e.g. renal cell or hepatocellular
carcinoma): differentiation from renal cell or hepatocellular

carcinoma can be difficult, as carcinoma arising in the
adrenal cortex may infiltrate the kidney or liver.
Adrenocortical carcinomas are variably positive for
cytokeratins, epithelial membrane antigen (EMA) and
vimentin depending on fixation and the technique used,
and therefore the most useful immunocytochemical
markers in this situation are ␣-inhibin and melan-A, which
are positive in most carcinomas of adrenal origin but not
expressed in renal cell or hepatocellular carcinoma.
Special techniques
The immunohistochemical profile of adrenocortical carcinoma
cells is similar to that of adenomas (see above).
Figure 6.9 An area of coagulative necrosis in an adrenocortical NEUROBLASTIC TUMORS

carcinoma.
Neuroblastic tumors, including neuroblastoma, ganglioneuro-
blastoma, and ganglioneuroma, are the most frequent extra-
cranial solid tumors of childhood, occurring primarily in infancy
● Adrenal adenomas: several criteria have been identified and childhood. Neuroblastic tumors are derived from embryonal
which, if present, are suggestive of malignancy in an neuroectodermal cells which originate in the neural crest and
adrenocortical neoplasm. These are listed in Table 6.1. migrate to the adrenal medulla and sympathetic ganglia. They
arise wherever sympathetic tissue exists, and may be seen in the
Table 6.1: Histological features suggestive of malignancy in neck, posterior mediastinum, adrenal gland, retroperitoneum,
adrenocortical tumors and pelvis. These tumors differ in their degree of cellular and
extracellular maturation, with immature tumors tending to be
● Mitotic rate ⬎5 per 50 high-power fields (HPF)*
aggressive whilst mature tumors usually behave in a benign
● Clear cell component 25% or less*
fashion.
● Abnormal mitoses*
The International Neuroblastoma Pathology Committee
● Necrosis* (see Figure 6.9)
(INPC) classifies neuroblastic tumors into four groups, based on
● Capsular invasion*
the degree of maturation of the neuroblasts and the amount of
● Nuclear pleomorphism
schwannian stroma present:
● Venous invasion
1. Neuroblastoma (schwannian stroma-poor)
● Diffuse growth pattern
2. Ganglioneuroblastoma, intermixed (schwannian stroma-rich)
● Sinusoidal invasion
3. Ganglioneuroma (schwannian stroma-dominant)
● Broad fibrous bands
4. Ganglioneuroblastoma, nodular (composite schwannian
* Features identified as being most useful by Aubert et al. (2002). stroma-rich/stroma-dominant and stroma poor).
CLINICAL FEATURES
Neuroblastoma and ganglioneuroblastoma occur predomi-
nantly in children, with a median age of 22 months, and with
95% of cases being diagnosed in those less than 10 years of age.
Some 75% of neuroblastomas arise within the abdomen or pelvis,
and half of these originate within the adrenal medulla; the
remainder arise in the mediastinum and head and neck.
Ganglioneuromas behave in a benign fashion and are thought
to represent the final stage of differentiation of neuroblastic
tumors – a view that is supported by the fact that most of these
tumors are diagnosed in later childhood and occasionally in
adults. Less than one-third of ganglioneuromas arise in the
adrenal. Most originate within the mediastinum, and rarely they
involve unusual sites such as the skin.
Most neuroblastic tumors occur sporadically, but a minority
are familial and may be associated with a variety of conditions
including Beckwith–Wiedemann syndrome, neurofibromatosis,
and Hirschsprung’s disease.
A small subset of neuroblastomas may undergo spontaneous
regression. However, the majority of these tumors behave aggres-
sively and present at an advanced stage, often with dissemi-
nated disease. Several features are associated with prognosis in Figure 6.11 Neuroblasts in a poorly differentiated neuroblastoma.
neuroblastoma. Earlier age at diagnosis is associated with a good
prognosis, as is lower stage (see below). Furthermore, prognosis
is related to the molecular and genetic features of these tumors.
In particular, amplification of N-myc, 1p deletion and a diploid
or near-diploid karyotype confer a worse prognosis.

Macroscopically, neuroblastomas and ganglioneuroblastomas
are lobulated and hemorrhagic. Necrosis, cystic change and
calcification may be present. In contrast, ganglioneuromas are
Figure 6.12 Ganglioneuroblastoma: mature ganglion cells adjacent

to more poorly differentiated neuroblasts.
well-circumscribed and have a homogeneous cut surface which

may be either gelatinous or fibrous.
Microscopically, neuroblastic tumors are composed of one or
more components, dependent upon the degree of differentia-
tion present. These components are undifferentiated neuro-
blasts, differentiating neuroblasts, ganglion cells, neuropil,
Schwann cells, and fibrous tissue.
In neuroblastomas, the tumor cells are commonly arranged
Figure 6.10 Homer Wright rosettes in neuroblastoma metastatic in sheets or lobules with intervening fibrillar, neuropil stroma and
to a lymph node. a delicate supporting vascular network. Groups of neuroblastoma
neuroblastomas have abundant neuropil, and more than 5% of

the tumor cells show ganglion cell differentiation.
Ganglioneuroblastomas are partly differentiated neuroblastic
tumors in which more than 50% of the tumor cells show gan-
glioneuromatous differentiation with abundant, Schwann cell-
rich stroma. In the intermixed type, groups of neuroblastic cells
are randomly distributed amongst the more mature components.
In the nodular variant, the neuroblastic nodules are sharply sep-
arated from the mature, stroma-rich areas, often with interven-
ing fibrous septa.
Ganglioneuromas have been sub-classified into two groups
by the INPC. The maturing subtype is composed of scattered
differentiating neuroblasts and mature ganglion cells set in an
abundant stroma which is the dominant component. The mature
subtype consists of mature ganglion cells and schwannian
stroma. No neuroblast component is present.
Cell morphology
Neuroblastoma
● Neuroblastomas are composed of varying numbers of
undifferentiated neuroblasts, which are small, round cells
Figure 6.13 Ganglioneuroma composed of ganglion cells set in
with basophilic, hyperchromatic nuclei and little
schwannian stroma.
discernible cytoplasm. This is the only cell present in the
undifferentiated subtype with no background neuropil.
● In poorly differentiated and differentiated neuroblastomas,
neuroblasts differentiating towards ganglion cells are
present. These have identifiable eosinophilic or
amphophilic cytoplasm and a nucleus with vesicular
chromatin and a prominent nucleolus. The background
neuropil is fibrillary and lightly eosinophilic.
● In neuroblastoma, estimation of the mitosis-karyorrhexis
index (MKI) is recommended. This is defined as the
number of tumor cells showing mitosis or karyorrhexis,
and the index is usually estimated per 5000 neuroblastic
cells. A high MKI is associated with a poor prognosis and
with other adverse biological features.
● The presence of calcification within a neuroblastoma
should be recorded, as this may be associated with an
improved response to treatment.
Ganglioneuroblastoma and ganglioneuroma

● Ganglioneuromas and the ganglioneuromatous areas in
ganglioneuroblastoma contain ganglion cells with
accompanying stoma composed of neuritic processes in a
fasicular arrangement with numerous Schwann cells.
Figure 6.14 High-power magnification of neuroblasts, showing ● Ganglion cells vary in size, but are generally large and are
hyperchromatic nuclei and little discernible cytoplasm.
round, oval, triangular in shape. They have abundant
bright eosinophilic cytoplasm and Nissl granules are often
cells often form Homer Wright pseudorosettes, where neuro- seen aggregated at the periphery of the cytoplasm. The
blasts encircle a core of neuropil but, unlike true rosettes, there nuclei are round, centrally or eccentrically located, vesicular
is no central blood vessel. Neuroblastomas are classified into and contain prominent nucleoli. More than one nucleus
undifferentiated, poorly differentiated, and differentiating sub- may be seen. Some cells may contain neuromelanin.
types. The undifferentiated subtype is composed entirely of
undifferentiated neuroblasts with no background neuropil. This Differential diagnosis
is associated with a poor prognosis. Poorly differentiated neuro- ● Peripheral primitive neuroectodermal tumor/Ewing’s sarcoma
blastomas contain neuropil and are composed predominantly ● Embryonal rhabdomyosarcoma
of undifferentiated neuroblasts, although 5% or less show ● Lymphoma
differentiation towards ganglion cells. Differentiating ● Wilms’ tumor
Special techniques
● Neuroblastic tumors variably express NSE, synaptophysin,
chromogranin A, and PGP 9.5
● CD99, CD45, smooth muscle actin, desmin and vimentin
are usually not expressed
● S-100 can be helpful in highlighting a Schwann cell
component
PHEOCHROMOCYTOMA
CLINICAL FEATURES
Pheochromocytoma is a tumor composed of chromaffin cells
derived from the adrenal medulla. It is generally benign, but a (a)
proportion of around 10% do metastasize. It characteristically
produces varying degrees of hypertension, hypermetabolism,
and hyperglycemia. It may also produce severe and alarming
clinical effects such as paroxysmal hypertension, renal failure,
arrhythmia, cardiovascular dysfunction mimicking cardio-
myopathy, pulmonary edema and cerebral hemorrhage. Mani-
pulation of the tumor during surgery may also an initiate an
attack. It is occasionally non-functional and discovered at
autopsy.
Pheochromocytoma can be familial and may occur in MEN
IIA and IIB. It is also associated with neurofibromatosis and
von Hippel–Lindau syndrome. Bilateral pheochromocytomas
are more common in the familial setting.
(b)
Figure 6.15 (a, b) Pheochromocytoma: the tumor cells are
These tumors are generally intensely vascular and macroscop- arranged in nests with a surrounding vascular stroma.
ically appear red or brown in color. Pheochromocytomas
showing malignant behavior are heavier than their benign
counterparts, with one study demonstrating a mean weight of
383 g in malignant tumors (Linnoila et al. 1990).
Histologically, they are composed of pleomorphic round or
polyhedral cells in a Zellballen arrangement of solid nests, small
acini, trabeculae, whorls, cords and sheets bounded by delicate
vascular stroma. A supporting network of sustentacular cells is
also present surrounding the nests of tumor cells.
Secondary features
● Hemorrhage
● Cystic degeneration
● Amyloid deposition occurs in a variable proportion of
pheochromocytomas
Figure 6.16 The component cells of a pheochromocytoma have

Cell morphology granular cytoplasm and indistinct cell borders. Note the vesicular
● The tumor cells are generally polyhedral with eosinophilic nuclei with prominent nucleoli in this case.
or basophilic, granular, vacuolated or foamy cytoplasm
often with indistinct cell borders. Occasionally, spindle
cells predominate. ● Dark brown, fine and coarse granules are found within
● The nuclei are round or oval, hyperchromatic, pleomorphic small groups of tumor cells, in macrophages or lying free
and often eccentrically located. They have a vesicular or within the stroma.
solid chromatin pattern and may contain prominent ● Occasionally ganglion cell, neuroblastic or Schwann cell
nucleoli or intranuclear inclusions. components are present. If these elements are prominent
● Multinucleated and bizarre cells may be seen. and make up a distinct area within the tumor, then the
Table 6.2: Histological features which lead to a suspicion of

malignancy in pheochromocytomas
● Absence of hyaline globules

● Small cell type
● Confluent tumor necrosis
● Presence of vascular invasion and/or extensive local invasion
● Absence of sustentacular cells (identified by S-100
immunocytochemistry)
● Proliferative index of ⬎2.5% (measured by MIB-1
immunocytochemistry)
Special techniques
● The chromaffin reaction: when fresh tissue is immersed in
dichromate solution (pH 5–6), the fluid turns dark brown
within 30 min. When frozen or paraffin sections of this
Figure 6.17 Ganglion cells within a pheochromocytoma. tissue are then examined, fine brown granules are seen
within the cells.
● Schmorl’s modified Giemsa method: the cells stain pink if
fixed in formalin, and olive green if fixed in dichromate
solution.
● Gomori’s azo-carmine staining reaction: when performed
on formalin-fixed tissue, cytoplasmic granules are stained
bluish-violet.
● The intracytoplasmic granules are agyrophilic.
● The cells are positive for catecholamines, chromogranin A,
PGP 9.5, and synaptophysin. They may express
neurofilaments, serotonin, somatostatin, calcitonin,
substance P, vasoactive intestinal peptide, and ACTH.
● The sustentacular cells express S-100 protein.
MISCELLANEOUS NEOPLASMS
Figure 6.18 Pheochromocytoma strongly expressing chromogranin A.
term ‘composite tumor’ may be applied, although this is ADRENAL CYSTS

thought to have no clinical significance. A case of
combined pheochromocytoma and neuroendocrine CLINICAL FEATURES
carcinoma has also been described (Juarez et al. 1999).
● Periodic acid–Schiff (PAS)-positive, diastase-resistant Adrenal cysts present either incidentally or with symptoms of
hyaline globules are often seen. an intra-abdominal mass.
● Mitotic figures are usually scarce.
Differential diagnosis Histologically, these cysts are classified according to the nature
● Benign versus malignant pheochromocytoma: of the cells lining them.
– The only definite feature of malignancy in ● Endothelial or vascular cysts: these are most common and
pheochromocytoma is the presence of metastasis. have a lining of flat endothelial cells which express
– Several features have been identified as occurring more vascular markers such as CD31 and CD34. They are
commonly in malignant pheochromocytomas, and these thought to have a lymphatic origin.
are listed in Table 6.2. ● Pseudocysts: the name given to cysts which apparently lack
– Recently, a scoring system was devised to evaluate lining cells, although on closer examination many of these
malignant potential based on several histological are in fact lined by endothelium. Some authors suggest
features (Thomson 2002). that all pseudocysts were originally vascular in nature but
– The diagnostic utility of other markers such as p53, have lost their endothelial lining.
bcl-2 and E-cadherin in differentiating between benign ● Epithelial cysts: this category has been used to encompass
and malignant pheochromocytomas is currently the cystic adrenal neoplasms as well as cysts lined by a single
subject of research. layer of cells expressing cytokeratins, which may be more
● Adrenocortical adenoma or carcinoma (see above). properly termed mesothelial cysts.
● Parasitic cysts: these rare cysts are usually associated with PATHOLOGICAL FEATURES
Echinococcus.
Macroscopically myelolipomas vary in size from small to very
Differential diagnosis large. They are usually yellow to brown in color and are
non-encapsulated.
● Cystic change in an adrenal neoplasm or adrenal meta-
static disease. Cell morphology
● Myelolipomas are composed of mature adipose tissue
MYELOLIPOMA admixed with aggregates of hematopoietic cells.
● Focal myelolipomatous change has been reported both in
adrenocortical tumors and pheochromocytomas.
CLINICAL FEATURES
These are uncommon, non-neoplastic lesions which occur pre- OTHER MESENCHYMAL NEOPLASMS
dominantly in middle-aged patients. They may present with
loin pain, but most are asymptomatic and detected incidentally. A variety of mesenchymal neoplasms have been described in
Occasionally, they may rupture resulting in retroperitoneal the adrenal gland, including hemangioma, angiosarcoma, leio-
hemorrhage. myoma, leiomyosarcoma and liposarcoma, all of which are rare.
TUMORS OF THE PARATHYROID GLANDS
ADENOMA
CLINICAL FEATURES
Parathyroid adenomas are the most common cause of primary
hyperparathyroidism, occurring more often in females with a
peak incidence in middle age. The lower parathyroid glands are
more frequently affected. Variation in the location of the parathy-
roid glands can cause surgical difficulties, as an adenoma may
lie within the mediastinum, the thymus, the thyroid gland
or the retro-esophageal tissue. There is an association with
MEN I and MEN IIA.

Macroscopically, parathyroid adenomas are ovoid or pyrami-
dal masses which are tan in color and surrounded by a thin Figure 6.20 Parathyroid adenoma, showing a prominent follicular
architectural pattern.
Figure 6.19 Low-power magnification of a parathyroid adenoma,

showing a compressed rim of normal gland. Figure 6.21 Parathyroid adenoma; chief cells.
possible to make a firm diagnosis of adenoma. However, if

only one gland is removed, the pathologist can only favor
one interpretation over another. Histological features such
as the presence of a rim of compressed normal parathyroid
tissue, a diffuse growth of chief cells, and a relative lack of
stromal fat may be suggestive of a diagnosis of adenoma.
Even so, inter-observer variability in differentiating
adenoma from hyperplasia is not inconsiderable.
Furthermore, the situation is complicated by the rare but
recognized occurrence of ‘double adenomas’.
● Parathyroid carcinoma (see below).
● Thyroid adenoma: this distinction is more of a problem
at frozen section, particularly with an intrathyroidal
parathyroid adenoma showing a follicular arrangement of
chief cells.
Figure 6.22 Parathyroid adenoma; oxyphil cells. Special techniques

● The chief cells in an adenoma react positively with a
Grimelius stain.
capsule. Occasionally, they are multilobulated. The average ● A PAS stain highlights intracytoplasmic glycogen within
weight of a normal parathyroid gland is 35–55 mg, whereas a chief cells in both normal parathyroid and adenomas.
parathyroid adenoma can weigh anything from 300 mg to sev- ● An oil red O fat stain shows a reduction in cytoplasmic fat
eral grams. In 50–60% of cases, a narrow rim of compressed in the chief cells of an adenoma as compared to those in
normal parathyroid tissue is found particularly at the hilar normal parathyroid tissue.
region, although this is more easily identified microscopically. ● Chief cells in normal parathyroid glands and adenomas
Stromal fat, which is seen in normal parathyroid tissue, is express parathyroid hormone (PTH) and chromogranin A.
usually lacking in an adenoma. The tumor cells may be
arranged in a variety of patterns including sheets, alveoli,
rosettes, trabeculae, and follicular structures around central CARCINOMA
eosinophilic, proteinaceous material. A mixture of architec-
tural patterns is commonly seen. Some adenomas contain areas
CLINICAL FEATURES
of hemorrhage, calcification or cystic degeneration; occasion-
ally, parathyroid adenomas undergo spontaneous infarction Parathyroid carcinoma is rare, being the underlying cause
with a resulting normalization of the serum calcium. in less than 0.02% of cases of primary hyperparathyroidism.
It occurs with equal frequency in men and women, and it is
usually associated with markedly elevated serum calcium and
Cell morphology
PTH, as well as the clinical manifestations of hypercalcemia
● Chief cells are rounded, polygonal or cuboidal in shape, such as abdominal pain and nephrolithiasis. In around 50% of
with a centrally located, dark nucleus. Usually, the cases, a palpable mass is present in the neck, and invasion of
cytoplasm is pale and granular, but chief cells with clear or surrounding structures may be seen at operation. Aggressive
vacuolated cytoplasm can also be found, as well as those surgical resection with removal of adjacent invaded structures
with a more peripherally located nucleus. is the treatment of choice, with a 10-year survival rate of 49%.
● Oxyphil cells are slightly larger than chief cells and have
intensely eosinophilic, granular cytoplasm. The frequency PATHOLOGICAL FEATURES
of these cells increases with age in the normal parathyroid,
and they are usually found clustered together in nodules Macroscopically, parathyroid carcinomas may be ill-defined
within adenomas. Occasionally, adenomas may be entirely and firm with invasion of adjacent structures, in which case the
composed of oxyphil cells and these have generally been diagnosis of malignancy is straightforward. However, some car-
regarded as non-functioning, although a subset may cinomas are encapsulated and indistinguishable from an ade-
present with hyperparathyroidism. noma macroscopically.
● Single or multi-lobated hyperchromatic nuclei may be seen, In cases which are not clearly malignant the microscopic
but these do not indicate malignancy. Mitotic figures are appearances are often similar to those seen in adenomas, with
infrequent. tumor cells arranged in sheets, or with a trabecular, acinar or
follicular pattern. Certain histological features are suggestive of
malignancy, including a thick fibrous capsule, fibrous septa, and
Differential diagnosis vascular or capsular invasion. The presence of mitoses in tumor
● Parathyroid hyperplasia: if all four glands have been cells is also thought to be significant, and one study suggested
sampled and only one is enlarged, then it should be that more than five mitotic figures per 50 HPF is associated
with aggressive behavior (Bondeson et al. 1993). Moreover, Differential diagnosis

local recurrence and distant metastasis are related to breach of ● Parathyroid adenoma or carcinoma
the capsule.
Special techniques
Cell morphology
● The cytoplasm of hyperplastic chief cells is usually devoid of
● The cells may resemble normal parathyroid cells showing lipid droplets, and therefore an oil red O stain is negative.
only mild pleomorphism, often less than that seen in
adenomas. However, bizarre nuclei and giant cells may be
seen. SECONDARY AND TERTIARY PARATHYROID
● Sometimes, a spindle cell component is present. HYPERPLASIA
● Mitotic figures may be identifiable, with atypical forms.
Differential diagnosis CLINICAL FEATURES

● Parathyroid adenoma Secondary hyperparathyroidism occurs as a result of long-
● Thyroid adenoma or carcinoma standing lowering of the serum calcium level, usually in the
context of chronic renal disease. This results in increased serum
Special techniques PTH levels with normal or low serum calcium. Tertiary hyper-
● Recent studies have suggested that immunocytochemistry parathyroidism describes the development of autonomous para-
for the proliferation marker Ki-67 may be useful in thyroid hyperfunction on a background of prolonged secondary
differentiating between adenomas and carcinomas, with hyperparathyroidism.
carcinomas showing a significantly higher proliferation index.
Parathyroid glands showing early secondary hyperparathy-
HYPERPLASIA roidism appear grossly and microscopically similar to those in
primary chief cell hyperplasia. In late secondary hyperparathy-
roidism and in tertiary hyperparathyroidism, there is a nodular
PRIMARY PARATHYROID HYPERPLASIA
pattern of hyperplasia, with fibrous bands transecting the
enlarged glands. The chief cells often have vacuolated cytoplasm
CLINICAL FEATURES and nodules of oxyphil cells may also be present. An oil red O
stain reveals little or no intracytoplasmic lipid within chief cells.
Parathyroid hyperplasia accounts for about 15% of the causes
of primary hyperparathyroidism, with about 20% of these being
associated with the MEN syndromes. The clinical features are
identical to those seen in parathyroid adenoma. MISCELLANEOUS TUMORS
PATHOLOGICAL FEATURES PARATHYROID CYSTS

Primary parathyroid hyperplasia is most commonly chief cell in
type. Usually, all four glands are affected, and in the majority of CLINICAL FEATURES
cases the total gland weights amount to less than 1 g. The glands
are usually tan in color and may appear nodular to the naked eye. Parathyroid cysts may present as a mass in the anterior neck,
Microscopically, the gland parenchyma is expanded. A rim of where they can be mistaken for thyroid nodules; others may arise
normal parathyroid gland is lacking and stromal fat is identifi- within the mediastinum. These cysts may be non-functional,
able, although it is usually reduced. The cells are arranged in but some present with symptoms of hyperparathyroidism.
an alveolar or compact pattern. Aspiration of the cysts characteristically yields crystal-clear
In very rare cases, usually involving the upper glands, clear fluid that contains a high level of PTH. Some parathyroid cysts
cell or ‘water clear’ hyperplasia occurs. These glands are often represent cystic change within a hyperplastic or adenomatous
grossly cystic and histologically are composed of diffuse sheets gland, but others arise from normal parathyroid tissue.
of clear cells.
Cell morphology Most parathyroid cysts are thin-walled macroscopically, and
● In chief cell hyperplasia, chief cells comprise the major cell collapse once incised. Many are found within the thyroid
component, but oxyphil cells are also usually present. gland, and mediastinal cysts may be associated with thymic
● The cells in clear cell hyperplasia are larger than chief tissue. Some parathyroid cysts weigh up to 10 g.
cells, with a clear cytoplasm and crisp cell membranes. Histologically, they have a fibrous wall which may contain
Nuclear pleomorphism is often found, and the cells may islands of chief cells. Usually, the cyst is lined by chief cells
have multiple nuclei. (albeit focally), but sometimes lining cells are absent.
Figure 6.23 Low-power magnification of a section from the lower

pole of the thyroid gland. A collapsed parathyroid cyst can be seen
in the top left of the section.
Figure 6.24 Parathyroid chief cells in the wall of a parathyroid cyst.

PARATHYROID LIPOADENOMA (HAMARTOMA)
CLINICAL FEATURES
Parathyroid lipoadenoma is a well-circumscribed, non-
This rare lesion usually arises in the mediastinum or in the encapsulated lesion consisting of nests of parathyroid cells
lower neck, and is functional in 75% of cases. There is dispute intimately associated with large areas of mature adipose tissue.
as to the nature of this entity, with some regarding it as hamar- Normal parathyroid tissue may be seen adjacent to the lesion.
tomatous but many, as a variant of parathyroid adenoma. Myxoid change and metaplastic bone formation may occur.
TUMORS OF THE THYROID GLANDS
ADENOMAS
FOLLICULAR ADENOMA
CLINICAL FEATURES
Follicular adenomas are benign neoplasms derived from thyroid
follicular cells, and represent the most common type of thyroid
neoplasm. The frequency of these lesions depends to some
extent on definition. Approximately 50% of apparently solitary
thyroid lesions are in fact dominant nodules within a multi-
nodular goiter. However, follicular adenomas may occur on a
multinodular background and the so-called dominant nodule of
a multinodular goiter (MNG) often shows a clonal population.
The majority of follicular adenomas are cool or cold on iso-
tope scanning, and only rarely cause hyperthyroidism (the Figure 6.25 Hyalinization within a follicular adenoma.
so-called hot adenoma). Most are treated by simple lobectomy.
is removed for adenoma. The adenoma may be of normal color.
The neuromelanin reflects treatment with Minocycline (e.g.
Macroscopically, follicular adenomas are circumscribed and used for acne vulgaris).
encapsulated. They may be large, but a lesion over 2.5 cm Microscopically, a cushion of smooth muscle in the walls of
should be treated with caution and the capsule examined care- vessels in the capsule is often seen, but transcapsular or vascu-
fully. Neuromelanin may accumulate in thyroid cells to pro- lar invasion are absent. Distinction from a nodule of MNG can
duce a black thyroid. This will be seen, for example, if one lobe be difficult particularly as MNG can initially show unilateral
HYALINIZING TRABECULAR ADENOMA
CLINICAL FEATURES
Hyalinizing trabecular adenoma is a rare but distinctive entity
that was first described in 1987 by Carney and colleagues.
Considerable debate persists about the nature of these lesions,
and some are found in association with papillary carcinoma.
Indeed, the nuclear appearances of hyalinizing trabecular
lesions, as well as the discovery that many show re-arrange-
ments of the RET proto-oncogene, have led some to suggest
that these lesions are all variants of papillary carcinoma. The
frequent association of hyalinizing trabecular lesions with
lymphocytic thyroiditis also favors this hypothesis, as this is a
feature of papillary carcinoma. However, some lesions with
this distinctive pattern have been described which show capsular
Figure 6.26 Follicular adenoma. and vascular invasion, suggesting similarity to a follicular
carcinoma.
Unfortunately, due to the rarity of these neoplasms, clinical
involvement. Some histological features may be helpful, for follow-up information is sparse, and therefore it is difficult to
example the relative paucity of calcium oxalate crystals in an predict their behavior. One author recommends that hyaliniz-
adenoma compared with the nodules of an MNG. Further- ing trabecular lesions be sampled in their entirety, and if any
more, the follicular pattern within a follicular adenoma tends areas with the features of papillary or follicular carcinoma are
to be more uniform than that seen in MNG. However, there are found then they should be classified accordingly (LiVolsi
no serious clinical implications of being unable to distinguish 2000).
an adenoma from a dominant nodule on the lobectomy
specimen.
The follicular architecture is generally quite uniform, for
example mostly micro- or mostly macro-follicular. The latter Macroscopically, hyalinizing trabecular adenoma is typically
pattern is uncommon in a follicular carcinoma. Papillary hyper- circumscribed and is often encapsulated. It is pale yellow in
plasia may also be seen, and some follicular adenomas have a color and may arise in any part of the gland. Histologically, it
predominantly solid architecture. Cystic change, hyalinization, shows a predominantly nested or trabecular growth pattern
fibrosis, calcification, chondroid metaplasia and bone forma- with islands of tumor cells set amongst a hyalinized stroma.
tion have all been described in follicular adenomas. Occasionally, Psammoma bodies are occasionally found.
the entire adenoma can undergo necrosis, particularly following
fine-needle aspiration (FNA), and this is most often seen in Cell morphology
oncocytic lesions. Cases of follicular adenoma where a propor- ● The cells are epithelioid or spindle in shape, and often
tion of the neoplastic cells have spindle cell morphology have have distinct outlines and finely granular eosinophilic or
also been described (Vergilio et al. 2002). amphophilic cytoplasm.
● The nuclei vary in appearance and may have a sharply
Cell morphology defined nuclear membrane, optical clarity, intranuclear
cytoplasmic protrusions, and even nuclear grooves.
● Constituent cells resemble normal thyroid follicle cells with ● Mitotic figures are seldom found.
evenly placed, round nuclei. A small nucleolus may be
present.
● There is minimal cellular pleomorphism, and very few
mitoses. ● Papillary carcinoma, solid variant: lesions with a
hyalinizing trabecular pattern should be carefully sampled
to allow identification of any areas showing the features
Differential diagnosis of a classical papillary carcinoma. One study recently
● Dominant nodule in multinodular goiter examined 15 hyalinizing trabecular lesions with
● Minimally invasive follicular carcinoma immunohistochemistry for MIB-1 and found strong cell
● Papillary carcinoma, follicular variant (see below) membrane and cytoplasmic staining in most cases. This
● Medullary carcinoma. unusual expression pattern was not present in any of
the papillary carcinomas studies (Hirokawa and Carney
2000).
Special techniques ● Medullary carcinoma: the nested arrangement of the
See below. constituent cells and the hyalinized stroma, which may be
● Paraganglioma: in this entity, the cells express

chromogranin A and do not express thyroglobulin.
Special techniques
● The cells express thyroglobulin and cytokeratins.
● The hyalinized material is Congo-red negative, and has
been demonstrated to be immunoreactive for basement
membrane components such as type IV collagen and
laminin.
● Isolated cells can express somatostatin and contain
argyrophilic cytoplasmic granules.
ONCOCYTIC LESIONS (Figure 6.29)

(a)
Oncocytic thyroid neoplasms in which over 75% of the cells
have oncocytic, granular cytoplasm were formerly regarded as
a distinct entity, but are now generally classified according to
the features of the component neoplastic cells. If the lesion has
papillary architecture and the nuclear features of papillary
carcinoma, then it is categorized as such. A small number
of medullary carcinomas can also show oncocytic change.
(b)
Figure 6.27 (a, b) Hyalinizing trabecular adenoma.
(a)
Figure 6.28 Hyalinizing trabecular adenoma; intranuclear inclusion.
mistaken for amyloid, can cause confusion with medullary

carcinoma. Immunohistochemistry for carcinoembryonic
antigen (CEA) and calcitonin (both found in medullary (b)
carcinoma), and thyroglobulin (found in thyroid adenoma)
will distinguish these entities. Figure 6.29 (a, b) Oncocytic follicular adenoma.
The remaining lesions are currently classified as a subtype of

follicular neoplasm, although the underlying molecular biology
of oncocytic neoplasms appears to be different, being associ-
ated with mutations in mitochondrial DNA.
There is dispute as to whether oncocytic follicular neoplasms
have an intrinsically greater growth and metastasizing potential
than a traditional follicular neoplasm, but it is capsular invasion
and vascular spread which determine prognosis. If the neoplasm
has been sampled adequately and these are absent, then it should
be classified as benign. Those neoplasms that show histological
evidence of malignancy usually behave in a clinically aggressive
fashion.
A subset of oncocytic tumors has papillary architecture but
lacks the classic nuclear features required to make a diagnosis
of papillary carcinoma, and are proposed to have a different
molecular basis. One large study regarded these lesions as a
variant of an oncocytic follicular neoplasm (Katoh et al. 1998). Figure 6.30 Metastasis of follicular carcinoma within bone marrow.
These tumors are generally encapsulated, and may show cap-
sular and vascular invasion similar to that seen in a follicular
neoplasm, whereas the oncocytic variant of papillary carcinoma
usually lacks a capsule and is diffusely infiltrative, similar to its
classic counterpart.
COMMON CARCINOMAS
FOLLICULAR CARCINOMA
CLINICAL FEATURES
Follicular carcinomas can be divided into two groups which are
presumed to correspond to two stages in the biological devel-
Figure 6.31 Minimally invasive follicular carcinoma with a tongue
opment of the neoplasm, namely minimally invasive or encap-
of tumor completely penetrating the capsule of the neoplasm.
sulated carcinoma, and widely invasive carcinoma. The
prognosis of these neoplasms is vastly different. The encapsulated
variety may attain the figures of survival usually equated with
a papillary carcinoma, with a 10-year survival of about 90%.
In contrast, widely invasive follicular carcinoma is associated
with a 10-year survival of about 30–40%, although more recent
studies have found a case-specific survival of 67% when treated
by total thyroidectomy and radioiodine (Chow et al. 2002).
Follicular carcinoma has female predilection and is most
common in patients aged over 50 years, presenting as a solitary
nodule. It usually does not involve lymph nodes, instead being
characterized by vascular spread and distant metastasis, often
many years after the original diagnosis.
At a molecular level, follicular carcinoma is associated with
activation of Ras and translocation of PAX8/PPAR-gamma1
instead of the RET proto-oncogene mutations found in papil-
lary carcinomas.
Figure 6.32 Minimally invasive thyroid carcinoma; invasion of
PATHOLOGICAL FEATURES (Figures 6.30–6.34) intra-capsular blood vessels.
Minimally invasive follicular carcinoma tongue of tumor, and should not be confused with entrapment
This differs from follicular adenoma principally by the pres- of follicles or pseudoinvasion due to previous FNA. The latter
ence of vascular and/or capsular invasion. Capsular invasion is is usually associated with inflammation and hemosiderin dep-
defined as complete penetration of the capsule by an invasive osition. Vascular invasion is defined as the presence of tumor
carcinoma, and this should not be misinterpreted as represent-

ing a minimally invasive lesion. Careful macroscopic inspection
and adequate sampling should help avoid this pitfall.
The neoplastic cells in both minimally and widely invasive
follicular carcinoma may be arranged in macrofollicular, micro-
follicular, acinar, cribriform, trabecular, solid, or alveolar pat-
terns. On occasion, the appearances may mimic other tumors
such as a medullary carcinoma and in these cases the immuno-
histochemical localization of thyroglobulin and absence of
calcitonin or CEA expression are useful techniques.
Follicular carcinoma should be staged using the TNM
classification:
TNM STAGING OF THYROID CARCINOMA (6th edition, 2002)

T0 No evidence of primary tumor
T1 ⭐20 mm, limited to thyroid
T2 ⬎20 to ⭐40 mm, limited to thyroid
T3 ⬎40 mm, limited to thyroid or any tumor with
minimal extrathyroidal extension (e.g. extension to
sternothyroid muscle or perithyroidal soft tissues)
Figure 6.33 Low-power magnification of widely invasive follicular T4a Tumor invades any of following: subcutaneous soft
carcinoma with large nodules of carcinoma infiltrating the thyroid
tissues, larynx, trachea, esophagus, recurrent
parenchyma.
laryngeal nerve
OR anaplastic carcinoma, any size, limited to thyroid
T4b Tumor invades prevertebral fascia, mediastinal vessels
or encases carotid artery
OR anaplastic carcinoma extending beyond thyroid
capsule
TX Primary tumor cannot be assessed
Multifocal tumor of all histological types should be designated

(m), the largest determining the classification, e.g. T2(m).
N0 No nodes involved
N1 Regional nodes involved (cervical or upper
mediastinal)
N1a Metastasis in level VI (pretracheal and paratracheal)
nodes
N1b Metastasis in other unilateral, bilateral or
contralateral cervical or upper/ superior mediastinal
nodes
NX Cannot assess nodal involvement
M0 No distant metastases
M1 Distant metastases
MX Cannot assess distant metastases
Figure 6.34 Widely invasive follicular carcinoma.
Cell morphology
cells adherent to the wall and protruding into the lumen of a
vessel within or adjacent to the capsule.
● Cytologically, the cells resemble those seen in a follicular
adenoma, with round nuclei and dense chromatin.
Widely invasive follicular carcinoma ● Nuclear atypia and mitotic activity may be present.
Invasion of the surrounding thyroid by tumor is obvious macro-

scopically. Microscopically, there is easily identified capsular Differential diagnosis
invasion, and tongues of tumor spread into the surrounding ● Papillary carcinoma, follicular variant (see under Papillary
gland. There may also be invasion of the thyroid capsule. In carcinoma for distinguishing features)
some cases the capsule may re-form around islands of invasive ● Medullary carcinoma
Special techniques
● Galectin-3 is a carbohydrate-binding lectin which is
expressed in papillary carcinomas and a high percentage
of follicular carcinomas. It is seldom expressed, other than
in scattered cells, in a follicular adenoma or a dominant
nodule of multinodular goiter. Therefore it may be of value
in distinguishing a minimally invasive carcinoma from a
cellular follicular adenoma, as galectin-3 positivity would
prompt further sampling of the lesion to identify foci of
capsular invasion.
● Galectin-3 appears to be most strongly expressed by cells
of the leading invasive tongue of tumor in minimally
invasive follicular carcinoma.
PAPILLARY CARCINOMA Figure 6.35 Papillary carcinoma, showing papillary fronds and
classic nuclear features.
CLINICAL FEATURES
Papillary carcinoma is the most common form of primary dif-
ferentiated thyroid carcinoma, occurring most often in young
and middle-aged women. It usually presents as a thyroid mass
or solitary nodule, with or without cervical lymphadenopathy.
In a proportion of cases it is associated with irradiation of the
head and neck, particularly if irradiation occurs in childhood.
Since the Chernobyl nuclear accident in the mid-1980s, the
incidence of papillary carcinoma has increased in young people
from the surrounding area. Around 35% of sporadic cases
have a translocation involving the RET proto-oncogene, and
this mutation is more common in cases related to radiation
exposure.
Papillary carcinoma limited to the thyroid gland, with or
without nodal metastasis, has an excellent prognosis. In contrast,
those with breach of the thyroid capsule or extra-thyroidal spread
are associated with a poorer prognosis. Total thyroidectomy is
the treatment of choice, as papillary carcinoma is often multi- Figure 6.36 Papillae, showing hydropic change within a papillary
focal within the thyroid gland. In addition, removal of macro- carcinoma.
scopically enlarged nodes is advised but radical neck dissection
is usually not performed routinely.

Macroscopically, papillary carcinoma is usually pale in con-
trast to the colloid-rich appearances of a follicular neoplasm,
and diffusely replaces the thyroid lobe. In some cases, pale
strands of tumor may radiate from a central scar. Occasionally,
papillary carcinomas are encapsulated. Areas of carcinoma in
the contralateral lobe may be visible as multiple pale foci.
In a classic case, the histological appearances are characteristic
with papillary fronds of aligned, columnar cells showing the
characteristic nuclear features (see below). Sometimes, the pap-
illary structures undergo hydropic change, and multinucleate
giant cells may invest the apex of the papillae. Psammoma bodies
of concentric, laminated calcium occupy the cores of the papillae
in about 50% of cases. The tumor is generally poorly delineated,
with peripheral, radiating tongues of carcinoma invading in a Figure 6.37 Classic nuclear features of papillary carcinoma:
rather angular fashion. optically clear nuclei and nuclear grooves (arrows).
(a)
Figure 6.38 Papillary carcinoma, follicular variant.
(b)
(a) Figure 6.40 (a, b) Papillary carcinoma, diffuse sclerosing variant.

Note the characteristic fibrotic stroma with scattered islands of
papillary carcinoma cells.
(b)
Figure 6.39 (a, b) Papillary carcinoma, tall-cell variant.
Cell morphology Figure 6.41 Papillary microcarcinoma.
Papillary carcinoma of the thyroid is characterized primarily by ● Optically clear nucleoplasm

its cytological and, in particular, its distinctive nuclear features: ● Sharply defined nuclear membranes
● Oval, elongated nuclei compared with round nuclei of ● Nuclear grooves – either longitudinal or horizontal
follicular neoplasms ● Intranuclear cytoplasmic protrusions.
Cystic variant
Approximately 10% of cases of papillary carcinoma are
encapsulated and often cystic. An FNA from this variant may
contain only cyst macrophages and be misdiagnosed as a col-
loid cyst.
Diffuse sclerosing variant

This variant is usually found in a younger age group, and
shows more aggressive behavior than classical papillary carci-
noma. The gland is usually diffusely affected and shows notable
macroscopic pallor, reflecting the diffuse fibroplasia. Inconspi-
cuous, small islands of papillary carcinoma lie scattered within
a hyalinized, fibrous stroma. The presence of bare psammoma
bodies and lymphatic invasion may be helpful in making the
diagnosis. Obliterative endarteritis may be present.
This tumor may be clinically mistaken for thyroiditis due to
Figure 6.42 Papillary hyperplasia within a multinodular goiter. Note the diffuse gland involvement and the frequent presence of
that the classic nuclear features of papillary carcinoma are lacking.
autoantibodies to thyroid antigens.
Follicular variant
This variant of papillary carcinoma has a follicular architecture.
The optical clarity of the nuclei may be evident even at low-power
magnification and the other classic cytological features are also
present. The follicles may have a rather elongated, ‘collapsing’
appearance; the colloid is generally intensely eosinophilic with
scalloping and large rhomboidal crystals may be present within it.
Other features helpful in recognizing this variant are intrafollicu-
lar multinucleate giant cells which are rarely found in a follicular
neoplasm, as well as alternating dark and light cell change.
Oncocytic variant
In this variant, the majority of the neoplastic cells have granular,
oncocytic cytoplasm. Usually, there is at least focal papillary
architecture, and the nuclear features of papillary carcinoma
Figure 6.43 Immunocytochemistry for cytokeratin 19 in the are apparent. This variant is commonly associated with auto-
follicular variant of papillary carcinoma. immune thyroiditis. A subtype of this variant with a prominent
lymphoid stroma has also been described, with appearances
similar to the Warthin’s tumor of the salivary glands. Both of
In a FNA specimen, the presence of straight-edged sheets of these subtypes of papillary carcinoma behave in a similar fashion
epithelial cells as well as psammoma bodies and multinucleate to the classical variant and should not be confused with the tall-
giant cells is also suggestive of this diagnosis. Histological diag- cell or columnar variants, which have a poorer prognosis.
nosis also relies heavily on these cytological features, as in
Papillary carcinoma with exuberant nodular
some variants of papillary carcinoma, the classic architecture is
fasciitis-like stroma
lacking.
In this unusual form of papillary carcinoma, the malignant cells
PAPILLARY CARCINOMA: VARIANTS have the classical nuclear features of papillary carcinoma and
are found in islands, solid sheets, or showing papillary architec-
Columnar cell variant
ture. They are surrounded by a prominent collagenous or mucoid
These carcinomas are composed of columnar cells with a papil- stroma which resembles nodular fasciitis and contains spindle
lary, cribriform, microfollicular, or solid growth pattern. The cells that express vimentin and desmin. This tumor should be dis-
cells usually lack the classical nuclear features of papillary carci- tinguished from an undifferentiated carcinoma in which the spin-
noma, although focal areas with these appearances may be pres- dle cell element is actually epithelial and may demonstrate
ent. Characteristically, the cells show prominent nuclear cytokeratin expression and, rarely, thyroglobulin production.
stratification and express cytokeratins. Expression of thyroglob-
ulin, CEA and EMA are variably reported. Whilst it is widely Papillary microcarcinoma
believed that this subtype of papillary carcinoma is associated This is defined as a focus of papillary carcinoma which meas-
with a poorer prognosis, other studies have suggested that this ures 10 mm or less, and which may be found incidentally. The
entity is not clinically distinct from the classical variant. management of these lesions is disputed, particularly with
regard to whether or not they necessitate total thyroidectomy.

Some studies suggest that a relatively high proportion is asso- LESS COMMON CARCINOMAS
ciated with nodal metastasis and that aggressive surgical treat-
ment is warranted. However, other series have found that these INSULAR CARCINOMA
carcinomas have an excellent prognosis, irrespective of how
they are managed.
CLINICAL FEATURES
Tall-cell variant
Some differentiated thyroid carcinomas of both follicular and pap-
In this variant, the cells are at least twice as tall as they are illary type may contain areas with a more poorly differentiated
broad. The nuclei may be pleomorphic and show greater appearance. This entity has been termed ‘insular carcinoma’
nuclear density often with large macronucleoli, although the due to the nested arrangement of the malignant cells histologi-
majority usually do show the classic nuclear features of papillary cally. Clinically, insular carcinomas are associated with a poorer
carcinoma. On FNA, these carcinomas are characterized by prognosis than well-differentiated thyroid carcinoma, and with a
groups of elongated cells with oncocytic cytoplasm and distinct higher risk of distant metastasis, nodal spread and extra-
cell membranes. Nuclear stratification is not a feature. The thyroidal extension. Indeed, in this regard, insular carcinoma
tumor may be CEA-positive, which is otherwise unusual in a shows biological behavior which overlaps between that of pap-
papillary or a follicular carcinoma. This variant is thought to be illary and follicular carcinoma. Undifferentiated foci within an
more aggressive than classical papillary carcinoma as a greater insular carcinoma predict poor survival.
percentage present with stage 3 or 4 disease.
The malignant cells are arranged in nests with surrounding tis-
● Papillary hyperplasia: in hyperplasia, the nuclear features sue retraction, and they adopt either a solid or microfollicular
of papillary carcinoma are lacking, and it is usually found pattern. The cells are usually small, and mitotic figures and
focally in the context of a hyperplastic nodule or thyroiditis. necrosis are often found. The histological appearances may intro-
The core of the papillary structure often contains duce a differential diagnosis that includes small cell medullary
microfollicles. In difficult cases immunocytochemistry may carcinoma – particularly if no better-differentiated areas are
be of help (see below). identified – but immunohistochemistry in the form of thy-
● Follicular adenoma versus follicular variant of papillary roglobulin, calcitonin and CEA should help in making this dis-
carcinoma: clearly, this is a clinically important distinction, tinction. There is probably a biological spectrum from a
and in cases where the nuclear features of papillary differentiated form of thyroid cancer through the insular pat-
carcinoma are obvious, it is straightforward. Difficulty tern to an undifferentiated (anaplastic) carcinoma, and in some
arises in follicular lesions with focal cells showing nuclear cases each pattern can be seen in different parts of the tumor.
optical clarity. This can be a fixation artifact and in this
situation, nuclear grooves and overlapping should not be
present and the nuclei should retain the round shape
characteristic of follicular epithelial cells. However, there is
disagreement about what exactly constitutes nuclear
optical clarity and about when this is diagnostically
significant (Hirokawa et al. 2002).
Special techniques
● Cytokeratin 19 is intensely expressed by almost all
examples of papillary carcinoma, including all its variants.
Its value lies in the distinction between papillary
carcinoma and papillary hyperplasia, and in the evaluation
of a follicular lesion which possesses some but not all of
the nuclear criteria required for a diagnosis of the
follicular variant of papillary carcinoma. In both cases,
over- and under-diagnosis of papillary carcinoma may be Figure 6.44 Insular carcinoma; other areas in this case showed the
prevented, although CK19 positivity should supplement features of papillary carcinoma.
and not supersede the histological impression.
● EMA and S-100 are typically expressed by papillary MEDULLARY CARCINOMA
carcinomas, and not by areas of papillary hyperplasia.
● Immunohistochemistry for the RET proto-oncogene
CLINICAL FEATURES
product can also be helpful in identifying papillary
carcinomas, although not all papillary carcinomas will be Medullary carcinoma accounts for about 10% of all thyroid
positive and findings vary between the histological types. carcinomas, and is derived from the parafollicular or C-cells.
The majority of medullary carcinomas are sporadic, but

10–20% are hereditary. The sporadic form presents as a soli-
tary thyroid mass in adults that is cold on radioisotope scan-
ning, and may be associated with intractable diarrhea or
Cushing’s syndrome. Hereditary medullary carcinoma is inher-
ited as an autosomal dominant trait and either occurs in isola-
tion where it is termed ‘familial medullary thyroid carcinoma’
or as part of MEN IIa or IIb. The inherited form presents in a
younger age group, is often bilateral and accompanied by
C-cell hyperplasia in both lobes of the residual gland. In MEN IIa
(Sipple’s syndrome), medullary carcinoma is associated with
bilateral pheochromocytoma and parathyroid chief cell hyper-
plasia. In MEN IIb, it is associated with pheochromocytoma
and mucosal neuromas, and the prognosis is less favorable than
in MEN IIa or in sporadic medullary carcinoma. The majority of
hereditary medullary carcinomas have an underlying mutation
involving the RET proto-oncogene located on chromosome 10. Figure 6.46 Medullary carcinoma with amyloid deposited within
Medullary carcinoma invades locally, and metastasizes to cer- the stroma.
vical and mediastinal lymph nodes as well as distant sites such as
bone, liver, and lung. It is usually treated by total thyroidectomy
and central node dissection. Ipsilateral modified neck dissec-
tion may be performed if the primary is greater than 2 cm in
size. Medullary microcarcinomas are defined as those less than
1 cm in maximum extent. These may be found incidentally and
have a better prognosis than larger medullary carcinomas, but
a significant number are associated with regional nodal metas-
tasis and therefore they should be treated aggressively.

Medullary carcinoma is usually located in the upper two-thirds of
the thyroid, where C-cells are most numerous. Macroscopically
it is typically pale and non-encapsulated.
The histological architecture may be variable. Often, there is a
nested or trabecular growth pattern, and the islands of tumor are
separated by hyalinized stroma which frequently contains
amyloid. A variety of other histological types are described,
including small cell, giant cell, squamoid, pigmented (the pig- Figure 6.47 Medullary carcinoma with follicular architecture.
ment being melanin), papillary and follicular. In the follicular
pattern, the follicles sometimes contain mucin which is otherwise
Figure 6.48 Medullary carcinoma component cells with granular

Figure 6.45 Medullary carcinoma, showing nested growth pattern. eosinophilic cytoplasm.
Diffuse or nodular intra- or inter-follicular C-cell hyperplasia

is often seen in familial cases, and also occurs in a larger number
of sporadic cases than previously thought. One study showed that
familial medullary microcarcinomas are commonly associated
with a desmoplastic stromal reaction, unlike their sporadic
counterparts. Furthermore, tumors with a desmoplastic stroma
appear to be more likely to develop lymph node metastasis
(Kaserer et al. 2001).
Cell morphology
● The cells are round, polygonal or plasmocytoid and have
granular, eosinophilic cytoplasm. Occasionally, they are
spindle-shaped.
● The nuclei usually have stippled chromatin characteristic
of other neuroendocrine tumors, and may have several
distinct nucleoli.
Figure 6.49 Prominent spindle cells in a medullary carcinoma.
● Hyalinizing trabecular adenoma
● Paraganglioma
● Poorly differentiated (insular) thyroid carcinoma
● Small cell variant may resemble small cell undifferentiated
carcinoma or lymphoma
Special techniques
● A Congo red stain highlights amyloid deposition. The
presence of amyloid should be recorded, as this is
associated with a better prognosis.
● The tumor cells usually express calcitonin, which is also
often found in the amyloid stroma. They are also
cytokeratin-, chromogranin A- and NSE-positive.
● The tumor is almost always CEA-positive.
● Thyroglobulin is not expressed, and there must be cautious
Figure 6.50 Medullary carcinoma; Congo red staining.
interpretation of apparent positivity as this usually reflects
small residual thyroid follicles which have been subsumed
by the tumor. In the rare mixed medullary and follicular
carcinomas, thyroglobulin is expressed in the component
showing follicular differentiation.
CLINICAL FEATURES
Mucoepidermoid carcinoma can occasionally arise in the thyroid
gland as a primary malignancy at this site. Fewer than 50 cases
have been described in the literature, but these appear to behave
in an indolent manner. Thyroid mucoepidermoid carcinoma
occurs over a wide age range but is more common in females.
Figure 6.51 Immunohistochemistry for carcinoembryonic antigen PATHOLOGICAL FEATURES

(CEA); strong expression by medullary carcinoma cells.
Grossly, these tend to be circumscribed tumors and appear
very rare in any primary thyroid cancer. Mixed medullary and solid or cystic. Histologically, they are similar to mucoepider-
follicular or medullary and papillary carcinomas have been moid carcinoma of the salivary glands with islands of kera-
described which show a mixture of two distinct cell populations. tinizing squamous epithelium interspersed with mucin-producing
The histogenesis of these lesions is not well understood. glandular structures. The stroma is variably fibrotic, and
psammoma bodies may be seen. The epithelial elements express

cytokeratin and thyroglobulin, but are negative for calcitonin.
A distinctive histological variant of mucoepidermoid carcinoma
has been described in association with chronic lymphocytic thy-
roiditis. The background stroma is markedly sclerotic and con-
tains an eosinophil-rich infiltrate; this entity has been termed
‘sclerosing mucoepidermoid carcinoma with eosinophilia’.
Interestingly, the epithelial cells in this variant are thyroglobulin-
negative, which has led some authors to suggest that the histo-
genesis differs from the standard mucoepidermoid carcinoma.
● Papillary carcinoma with squamous differentiation
● Medullary carcinoma with squamous differentiation
● Primary squamous carcinoma of thyroid. (a)
SQUAMOUS CARCINOMA
The thyroid may be involved secondarily by squamous carci-

noma, particularly from the head and neck region. Rarely, pri-
mary squamous carcinoma arises within the thyroid gland
usually in elderly females who present with neck swelling or
obstructive symptoms.
UNDIFFERENTIATED (ANAPLASTIC) CARCINOMA
CLINICAL FEATURES
Undifferentiated thyroid carcinoma occurs most often in the eld-
erly, with a slight female predominance. It usually presents with (b)
a hard, fixed mass, stridor, nerve entrapment and invasion of
local structures, such as the trachea or larynx. There are few Figure 6.52 (a, b) Undifferentiated carcinoma composed of rather
other conditions which produce these clinical features. The spindle-shaped cells with prominent nuclear pleomorphism.
very rare Riedel’s thyroiditis is a fibro-inflammatory disorder
akin to primary mediastinitis and retroperitoneal fibrosis which
may present as a hard fixed mass, but it often involves only one
lobe of the gland and seldom causes nerve entrapment.
Undifferentiated carcinoma has a poor prognosis with most
patients dying of the disease within one year of presentation.

Histologically, undifferentiated thyroid carcinoma is composed
of a mixture of undifferentiated cells showing spindle cell,
squamoid or giant cell morphology. The gland is diffusely infil-
trated with widespread extrathyroidal extension. Necrosis and
polymorph infiltration are frequently seen. In some cases,
well-differentiated areas may also be present and one study
found that these carcinomas have a slightly better prognosis
(Rodriguez et al. 2000). A paucicellular variant is recognized
which is composed predominantly of hyalinized stroma with
scattered malignant cells. Figure 6.53 Undifferentiated carcinoma with hyalinized stroma.
Differential diagnosis is myofibroblastic in nature, and is cytokeratin-negative.

● Fibroinflammatory processes (e.g. Riedel’s thyroiditis): here, There is usually an accompanying infiltrate of
fibrous tissue – often with extensive hyalinization – replaces lymphocytes, plasma cells, and eosinophils. The blood
large areas of the thyroid gland. The spindle cell component vessels may show obliterative endarteritis.
● Sarcoma: the presence of heterologous elements confirms a

diagnosis of sarcoma. A pure spindle cell sarcoma may be
indistinguishable from spindle cell carcinoma (with both
expressing vimentin), but the latter may retain focal
cytokeratin expression.
● Lymphoma: even if the lymphoma is high grade, the
immunoprofile should allow differentiation from
anaplastic carcinoma.
LYMPHOMA
CLINICAL FEATURES
Lymphoma may arise in the thyroid as a primary site, or the
thyroid may be involved by a systemic lymphoma. Primary
lymphoma of the thyroid is rare, constituting approximately 3%
of thyroid malignancies. It occurs most frequently in elderly
females, with a male:female ratio of 1:4. There is frequently a Figure 6.54 Follicular lymphoma of the thyroid gland; diffuse
involvement with expansile neoplastic follicles.
history of Hashimoto’s thyroiditis, and this condition is associ-
ated with a 70-fold increase in the incidence of lymphoma com-
pared with normal glands.
Thyroid lymphoma presents as a rapidly expanding thyroid
mass, often with dysphagia, hoarseness, and tracheal compres-
sion. It is important to establish a histological diagnosis as the
clinical differential diagnosis of this presentation is undifferen-
tiated carcinoma; this is treated differently and has a consider-
ably worse prognosis.
The role of surgery in the management of thyroid lymphoma
is debated, although in some cases the diagnosis is made on the
lobectomy specimen. The treatment of choice is a combination
of chemotherapy and radiotherapy, which results in a good
response in the majority of cases.
PATHOLOGICAL FEATURES (Figures 6.54 and 6.55) Figure 6.55 MALToma of the thyroid; strong CD20 expression by
the neoplastic B lymphocytes.
Macroscopically, the thyroid gland is generally pale and firm,
without any obvious macroscopic colloid. Primary follicular lymphoma may also occur in the thyroid
Most thyroid lymphomas – especially if occurring on a back- gland, and primary Burkitt lymphoma, Hodgkin lymphoma,
ground of lymphocytic thyroiditis – fall into the category of and T-cell lymphoma have also been described.
extra-nodal marginal B-cell lymphomas of mucosa-associated
lymphoid tissue (MALT lymphoma). Lymphoid follicles are Cell morphology
usually prominent, and lymphoma cells expand the marginal
zone around the germinal center and mantle zone. These areas
● The cells in a MALToma are usually small or medium
coalesce and overrun follicles, giving rise to the classic lym- sized and centrocyte-like. They have an inconspicuous
phoepithelial lesions, and in some cases a diffuse lymphomatous nucleolus and dispersed nuclear chromatin, with abundant
infiltrate subsumes the whole gland. In the context of cytoplasm.
Hashimoto’s thyroiditis, areas showing complete filling and
● Plasmacytoid cells may be seen.
expansion of follicles by lymphocytes or complete loss of the fol-
● Scattered cells resembling immunoblasts or centroblasts
licular epithelium raise the suspicion of lymphoma. Transformed are usually present.
blast-like cells may be found focally in MALT lymphoma, but
if solid sheets of blasts are present then the tumor should be Special techniques
classified as a diffuse large B-cell lymphoma, noting the associ- ● The typical immunoprofile of a MALToma shows
ated MALT component. expression of CD45 and CD20, without expression of
CD5, CD10 or cyclin D1. It is helpful to demonstrate cystic or tubular structures. The nuclei are usually oval in
light chain restriction. shape, and the cytoplasm basophilic. Some show rudimentary
● In cases where discrimination between lymphocytic follicular structures, and squamous differentiation may be pres-
thyroiditis and lymphoma is difficult, demonstration of ent. The cells express cytokeratins, but specific thyroid antigens
monoclonal gene rearrangements by polymerase chain are not expressed, although occasional cells showing thyro-
reaction (PCR) is essential. globulin or calcitonin positivity may be found. Calcitonin-
positive C cells may be prominent in the area around the solid
Differential diagnosis cell nest.
● Secondary involvement with systemic lymphoma
SPINDLE EPITHELIAL TUMOR WITH
● Hashimoto’s thyroiditis.
THYMUS-LIKE DIFFERENTIATION (SETTLE)
MESENCHYMAL NEOPLASMS
CLINICAL FEATURES
A number of mesenchymal neoplasms have been described in the The term spindle epithelial tumor with thymus-like differentia-
thyroid, occurring as both primary lesions and metastases tion (SETTLE) was first used by Chan and Rosai in 1991 to
including liposarcoma, leiomyosarcoma, chondrosarcoma, and describe a rare tumor thought to be derived from ectopic thy-
osteosarcoma. The head and neck is a recognized site for synovial mus or branchial pouch remnants. It occurs predominantly in
sarcoma, which may involve the thyroid gland. Angiosarcoma children and adolescents, and involves the thyroid gland or lat-
of the thyroid has also been described, most often occurring in eral neck. It is best regarded as a neoplasm of low-grade malig-
patients from Alpine regions. A proportion of neoplasms with nancy as it does have a propensity for vascular spread, often
the appearances of angiosarcoma express cytokeratins, prompt- many years after the original diagnosis. Overall, it is associated
ing some authors to designate these neoplasms ‘angiomatoid with long survival in most cases.
carcinomas’.
SOLID CELL NESTS (Figure 6.56) SETTLE usually has a biphasic pattern and is composed of
bland spindle cells arranged in fascicles interspersed with glan-
Solid cell nests are sometimes found incidentally in thyroid dular structures. A monophasic variant composed entirely of
resection specimens. They are thought to be derived from spindle cells has also been described.
remnants of the ultimobranchial bodies and may be mistaken
for micro-foci of carcinoma. They are composed of bland Cell morphology
epithelial cells showing either a solid architecture or with
The spindle cells have oval nuclei with a small, inconspicuous
nucleolus, and a moderate amount of cytoplasm. The glandu-
lar structures are lined by cuboidal or columnar cells. The spin-
dle cell and glandular components both express cytokeratins,
with strongest staining for high-molecular-weight cytokeratins,
but do not express S-100, thyroglobulin, calcitonin, or smooth
muscle actin.
● Anaplastic carcinoma: sarcomatoid anaplastic carcinoma
has high-grade nuclear features and a high mitotic rate,
neither of which are seen in SETTLE.
● Thymoma: SETTLE lacks the terminal deoxytransferase
(TdT)-positive lymphocytes and the characteristic
lobulation seen in thymoma.
● Synovial sarcoma: this distinction can be very difficult.
The spindle cells in synovial sarcoma show only patchy
cytokeratin expression, whereas in SETTLE a more diffuse
Figure 6.56 Solid cell nest of the thyroid. pattern of cytokeratin staining is expected.
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7 FEMALE GENITAL TRACT
TUMORS
Awatif I Al-Nafussi
Tumors of the vulva 368 Tumors of the uterine cervix 388

Epithelial tumors: malignant 368 Epithelial tumors: glandular lesions, benign 388
Basal cell carcinoma 368 Ectopic prostatic tissue 388
Sebaceous carcinoma 369 Endocervical tunnel clusters 388
Squamous carinoma and vulval intraepithelial neoplasia (VIN) 369 Glandular hyperplasia, diffuse laminar 389
Glandular hyperplasia, lobular endocervical 389
Skin appendage tumors 374 Mesonephric remnants and mesonephric hyperplasia
Bartholin gland adenomas 374 of the uterine cervix 390
Bartholin gland carcinoma 374 Microglandular hyperplasia of the cervix 391
Bartholin gland nodular hyperplasia 374 Prolapsed Fallopian tube 392
Extramammary Paget’s disease 375
Epithelial tumors: glandular lesions, malignant 393
Melanocytic tumors 377
Adenocarcinoma, common variants 393
Malignant melanoma 377
Microinvasive (early invasive) 393
Special site nevi 377
Mucinous endocervical adenocarcinoma 393
Mesenchymal tumors 377 Mucinous intestinal adenocarcinoma 393
Aggressive angiomyxoma 377 Colloid or signet ring cell carcinoma 393
Angiomyofibroblastoma 378 Endometrioid adenocarcinoma 394
Cellular angiofibroma 379 Adenocarcinoma, less common variants 394
Sarcomas 380 Clear cell mesonephroid 394
Smooth muscle neoplasms 380 Serous papillary adenocarcinoma 394
Villoglandular papillary adenocarcinoma 394
Miscellaneous tumors 381 Minimal deviation adenocarcinoma 395
Adenosis 381 Adenocarcinoma, rare variants 396
Ectopic breast tissue and neoplasms 381 Adenoid cystic carcinoma 396
Unusual vulval tumors 382 Adenosquamous carcinoma 396
Basaloid carcinoma of the uterine cervix
Tumors of the vagina 382 (adenoid basal carcinoma) 396
Epithelial lesions, benign 382 Glassy cell carcinoma 398
Vaginal adenosis 382 Malignant mixed mullerian tumor
(carcinosarcoma/sarcomatoid carcinoma) 398
Epithelial lesions, malignant 382 Mesonephric adenocarcinomas 398
Squamous cell carcinoma and vaginal intraepithelial Cervical intraepithelial glandular neoplasia (CGIN) 399
neoplasia (VAIN) 383
Epithelial tumors: squamous lesions, benign 402
Melanocytic lesions 383 Condyloma acuminatum 402
Melanosis 383
Epithelial tumors: squamous lesions, malignant 402
Mesenchymal tumors 383 Cervical intraepithelial neoplasia (CIN) 402
Fibroepithelial stromal polyps of the lower female Microinvasive squamous carcinoma (MICA) 405
genital tract 383 Squamous carcinoma 406
Sarcomas 385 Highly differentiated keratinizing squamous
cell cancer of the cervix 408
Mixed epithelial and mesenchymal tumors 386 Lymphoepithelial carcinoma 408
Mixed tumor of the vagina (spindle cell epithelioma) 386 Papillary squamotransitional cell carcinoma 408
Mullerian (mesonephric) papilloma 387 Rapidly prognesive carcinoma 409
Squamous carcinoma of the uterine cervix with
Secondary metastasis 387 CINIII-like growth pattern 409
Unusual vaginal tumors 387 Verrucous carcinoma 409
366 Female genital tract tumors
Mesenchymal tumors 409 Mesenchymal tumors 424

Sarcomas 409 Endometrial stromal tumors 424
Endometrial stromal nodule (ESN) 425
Miscellaneous tumors 410 Endometrial stromal sarcoma (ESS; previously termed
Malignant lymphoma/leukemia and lymphoma-like lesion 410 low-grade endometrial stromal sarcoma) 425
Melanocytic lesions 410 Mixed endometrial stromal and smooth muscle tumors 429
Mixed epithelial and mesenchymal tumors 410 Undifferentiated uterine sarcoma 431
Adenomyomas 410 Perivascular epithelioid cell tumor (‘PEComa’) 431
Mixed mullerian tumors, malignant (sarcomatoid Smooth muscle tumors, leiomyomas 431
carcinoma/carcinosarcoma) 410 Classic leiomyomas 432
Mixed mullerian tumors, mullerian adenofibroma 410 Cellular leiomyoma 432
Mixed mullerian tumors, mullerian adenosarcoma 410 Hemorrhagic cellular (apoplectic) leiomyoma 433
Neuroendocrine tumors 410 Epithelioid leiomyoma 433
Secondary tumors 411 Symplastic (bizarre) leiomyoma 436
Unusual primary tumors 411 Mitotically active leiomyoma 436
Extrarenal Wilms’ tumor 411 Myxoid leiomyomas 436
Primitive neuroectodermal tumor 411 Lipoleiomyoma 436
Teratoma 411 Vascular leiomyoma 436
Yolk sac tumor 411 Leiomyoma with haematopoietic elements 436
Leiomyoma with sex cord-like pattern 436
WHO classification of cervical tumors 411 Granular cell leiomyoma 436
Diffuse uterine leiomyomatosis 436
Tumors of the uterine corpus 412 Intravenous leiomyomatosis 436
Epithelial lesions, benign 412 Benign metastasizing leiomyoma 436
Endometrial hyperplasia 412 Disseminated peritoneal leiomyomatosis 437
Endometrial hyperplasia, papillary 413 Perinodular hydropic leiomyoma 437
Endometrial metaplasia 414 Multinodular hydropic leiomyoma 437
Endometrial polyp 415 Infiltrative uterine leiomyomas 437
Cotyledonoid dissecting leiomyoma 437
Epithelial lesions, malignant 416 Smooth muscle tumor of uncertain malignant
Endometrial carcinoma 416 potential (STUMP) 438
Endometrioid-type carcinoma 420 Smooth muscle tumors, leiomyosarcomas 438
Adenocarcinoma with squamous differentiation 421 ‘Classic’ leiomyosarcomas 438
Variants of endometrioid adenocarcinoma Uterine epithelioid leiomyosarcoma 439
Villoglandular adenocarcinoma 421 Dedifferentiated leiomyosarcoma 440
Secretory adenocarcinoma 421 Myxoid leiomyosarcoma 440
Ciliated cell carcinoma 421 Intravenous leiomyosarcomatosis 440
Endometrioid carcinoma with sertoliform Osteoclast-like giant cells in smooth muscle tumors 440
differentiation 421 Uterine leiomyosarcoma with a clear cell component 440
Other endometrial carcinoma variants Uterine sarcoma with liposarcomatous differentiation 440
Uterine serous papillary carcinoma 421
Clear cell carcinoma 421 Miscellaneous tumors 441
Mucinous carcinoma 421 Nodular histiocystic hyperplasia of the endometrium 441
Pure squamous cell carcinoma 421
Undifferentiated carcinoma 421 Mixed epithelial and mesenchymal tumors 441
Mixed type carcinoma 421 Adenomyomas 441
Rare types of endometrial carcinoma Adenomyosis 443
Endometrial small cell neuroendocrine carcinoma 421 Mixed mullerian tumors, malignant (sarcomatoid
Microglandular adenocarcinoma 421 carcinoma/carcinosarcoma) 443
Signet ring cell carcinoma 422 Mixed mullerian tumors, mullerian adenofibroma 445
Transitional cell carcinoma 422 Mixed mullerian tumors, mullerian adenosarcoma 445
Glassy cell carcinoma 422
Mucinous adenocarcinoma of intestinal type 422 Tamoxifen-related gynecological lesions 447
Lymphoepithelial-like carcinoma 422 Tamoxifen-related polyps 447
Giant cell carcinoma of the endometrium 422 Tamoxifen-related carcinomas 447
Endometrial adenocarcinoma with trophoblastic Tamoxifen-related sarcomas 448
differentiation 422 Other tamoxifen-related lesions 448
Verrucous carcinoma 422
Minimal deviation endometrioid adenocarcinoma 422 Trophoblastic tumors and tumor-like lesions 448
Adenocarcinomas arising from adenomyosis uteri 422 Choriocarcinoma 448
Metastatic tumors 422 Epithelioid trophoblastic tumor (ETT) 449
Endometrial intraepithelial carcinoma 423 Exaggerated placental site (EPS) 451
Mesonephric tumors 424 Hydatidiform mole 452
Female genital tract tumors 367
Placental site nodule (PSN) 454 Neuroectodermal tumors 485

Placental site trophoblastic tumor (PSTT) 455 Epidermoid cyst in the ovary 485
Yolk sac tumor (endodermal sinus tumor) 486
WHO classification of uterine corpus tumors 457
Mixed germ cell and sex cord–stromal tumors 488
Tumors of the ovary 457 Gonadoblastoma 488
Epithelial–stromal tumors 457 Unclassified (gonadal anlage tumor) 488
Clear cell tumors 457 Sex cord–stromal tumors 489
Benign and borderline clear cell tumors 457 Granulosa–stromal tumors, adult granulosa cell tumor 489
Clear cell carcinoma 457 Granulosa–stromal tumors, juvenile granulosa cell tumor 492
Endometrioid tumors 460 Gynandroblastoma 492
Benign endometrioid tumors 460 Hyperreactio luteinalis (multiple luteinized follicle cysts) 493
Proliferating (borderline) endometrioid tumors 460 Massive ovarian edema 493
Endometrioid carcinoma 460 Ovarian fibromatosis 494
Mucinous tumors, benign (mucinous cystadenoma) 464 Sclerosing stromal tumor 494
Mucinous tumors, malignant (mucinous carcinoma) 464 Sertoli–stromal cell tumors, Sertoli–Leydig cell tumors
Mucinous tumors, proliferating (borderline) 465 (androblastomas) 495
Seromucinous tumors 467 Sex cord tumor with annular tubules 498
Atypical proliferative tumor 467 Stromal hyperplasia and stromal hyperthecosis 499
Atypical proliferative seromucinous tumor with Thecoma–fibroma (fibrothecoma) group of ovarian
intraepithelial carcinoma 467 tumors 499
Atypical proliferative seromucinous tumor with Thecoma 500
microinvasion 467 Luteinized thecomas 500
Invasive seromucinous carcinoma 467 Stromal tumors with minor sex cord element 500
Serous epithelial ovarian tumors, benign 469 Fibroma 500
Benign serous cyst 469 Fibrothecoma 500
Benign serous adenofibroma 469 Classical malignant fibrothecomas 500
Benign papillary serous cystadenoma 469 Unclassified sex cord–stromal tumors 501
Serous cystadenofibroma 470
Serous epithelial ovarian tumors, malignant 470 Steroid (lipid) cell tumors 501
Serous epithelial ovarian tumors, proliferating (borderline) 471 Leydig cell hyperplasia 502
Proliferating (borderline) serous tumors with a Hilar Leydig cell hyperplasia 503
micropapillary pattern (so-called ‘micropapillary Stromal Leydig cell hyperplasia 503
carcinoma’) 472 Pregnancy luteoma 503
Proliferating (borderline) serous tumors with
microinvasion 472 Tumors of the rete ovarii 504
Extraovarian peritoneal lesions ‘implants’ associated Cysts of the rete ovarii 504
with proliferating (borderline) serous tumors 472 Adenomas of the rete ovarii 504
Primary peritoneal proliferating (borderline) serous Adenomatous hyperplasia 504
tumors 472 Rete adenocarcinoma 504
Proliferating (borderline) serous tumor arising in pelvic
Tumors of uncertain origin and miscellaneous tumors 504
lymph nodes 472
Endometriosis 504
Transitional cell tumors (Brenner tumors) 475
Deep endometriosis 505
Benign transitional cell (Brenner) tumor 475
Incisional endometriosis 505
Proliferating transitional cell (Brenner) tumor 475
Gastrointestinal endometriosis 505
Malignant transitional cell tumors (including malignant
Ovarian endometriotic cysts 505
Brenner tumor) 475
Malignant transformation of endometriosis 505
Endometriosis-associated stromal sarcomas 505
Germ cell tumors 477 Atypical endometriosis 505
Choriocarcinoma, carcinoma 478 Hepatoid ovarian carcinoma 506
Dysgerminoma 478 Mural nodules in ovarian epithelial cystic tumors 506
Embryonal carcinoma 478 Ovarian tumor of probable wolffian origin 507
Polyembryoma (polyembryonic carcinoma) 479 Small cell carcinoma (hypercalcemic type) 508
Teratoma, immature 479 Uterus-like ovarian mass 509
Teratoma, mature cystic teratoma (dermoid cyst) 481
Mature cystic teratoma 481 Secondary (metastatic) ovarian tumors 510
Mature cystic teratoma with secondary malignant Metastatic breast carcinoma 510
transformation 481 Metastatic gastrointestinal carcinomas 510
Teratoma, mature solid-type 483 Metastatic colonic adenocarcinoma 510
Teratoma, monodermal, and highly specialized teratomas 484 Krukenberg tumor 511
Struma ovarii 484 Metastatic carcinoma of the gallbladder, bile ducts
Carcinoid tumor 484 or pancreas 513
Strumal carcinoid 485 Metastatic carcinoma of the appendix 513
Metastasis from other parts of the female genital tract 513 Mesothelioma, deciduoid 519
Synchronous or metastatic endometrial or Mesothelioma, diffuse malignant 519
ovarian carcinoma 513 Mesothelioma, multicystic 520
Ovarian metastases from cervical carcinoma 513 Mesothelioma, well-differentiated papillary 520
Other metastatic tumors 514
Metastatic renal cell carcinoma 514 Metastatic tumors 520
Metastatic transitional cell carcinoma of the ovary 514 Gliomatosis 520
Pseudomyxoma peritonei 521
WHO revised classification of ovarian tumors 511 Strumosis peritonei 522
Miscellaneous lesions 522

Tumors of the Fallopian tube 516
Disseminated peritoneal leiomyomatosis 522
Epithelial tumors 516
Splenosis 522
Adnexal tumor of probable wolffian origin 516
Supernumerary ovary 522
Carcinomas of the Fallopian tube 516
Trophoblastic implants 522
Epithelial metaplasia, hyperplasia and pseudocarcinomatous
lesions 516 Mullerianosis (mullerian tumor-like conditions) 523
Deciduosis 523
Miscellaneous lesions 517 Endocervicosis 523
Adrenal rest 517 Endometrioid, clear cell and transitional cell changes 523
Salpingitis isthmica nodosa 517 Endosalpingosis 523
Mullerian inclusion cysts 524
Mesothelial tumors 517 Primary peritoneal epithelial tumors 525
Adenomatoid tumor 517 Mucinous tumors 525
Inclusions, cysts and hyperplasia 518 Serous tumors 525
GENERAL COMMENTS 2. The difficulty in deciding whether a malignant lesion

found in specific location is a primary or metastatic
Tumors of the female genital tract form a heterogeneous group tumor.
of epithelial, mesenchymal, sex-cord, germ cell, or mesothelial 3. The problem of misinterpreting unusual non-epithelial
origin. They are either benign or malignant tumors. Of the malignant tumors, as undifferentiated carcinomas or other
most commonly encountered benign lesions, leiomyoma ranks forms of sarcomas.
number one, followed by endocervical or endometrial polyps, 4. The concept of proliferating/borderline ovarian tumors.
dermoid cyst or benign ovarian cysts. Amongst the malignant
These problems often create diagnostic challenges in respect to
tumors of the female genital tract, endometrial carcinoma,
their extraovarian involvement, whether a stromal invasion is
squamous cell carcinoma of the cervix and its precursor lesions
found or not, and, in cases of mucinous tumor that is associ-
(CINI–III), and epithelial ovarian tumors are frequently seen in
ated with pseudomyxoma, if it is primary or secondary tumor.
gynecological practice. Of the sex cord-stromal tumors, adult
The role of immunohistochemistry is of paramount impor-
granulosa cell tumor and fibrothecoma are not uncommon,
tance in difficult cases.
while malignant germ cell tumors are very rare.
In this chapter, tumors and tumor-like conditions of the female
There are four major problems in the pathological interpre-
genital tract and peritoneum are described according to site, and
tation of gynecological tumors:
in alphabetical order.
1. The problem of underdiagnosing some malignant tumors,
as benign or of less aggressive nature.
TUMORS OF THE VULVA
significant morbidity and occasional mortality if they are neg-

EPITHELIAL TUMORS: MALIGNANT lected or improperly treated. Genital BCC occurred in an older
age group with no identifiable predisposing risk factors and
BASAL CELL CARCINOMA did not show evidence of human papillomavirus (HPV) infection.
Hematogeneous metastasis at presentation appears to result in
Basal cell carcinoma (BCC) of the vulva comprises 2–4% of rapidly progressive disease. The treatment of choice consists
all vulvar cancers. In general, vulvar BCCs tend to grow at of surgical excision with tumor-free margins. Because of local
slow rates. They can be aggressive and are capable of causing recurrence risk and possible association with other primary
cancers in this age group, long-term follow-up is necessary. complications and satisfactory cosmetic results. A significant
A giant basal cell carcinoma of the vulva has been reported. number of women with VINIII on a vulvar biopsy may harbor
occult vulvar cancer. Recurrences are almost three-fold higher
when margins are positive for residual VINIII. It seems that
SEBACEOUS CARCINOMA surgical resection is an appropriate method of treatment of
VINIII for both diagnostic and therapeutic purposes.
Vulvar sebaceous carcinoma is an uncommon neoplasm. It has
been reported in association with Bowen’s disease in the over-
lying epidermis. A significant increase in intranuclear p53 Differentiated VIN ‘simplex vulvar intraepithelial
staining has been demonstrated in several areas of neoplastic neoplasia’
aggregations of sebaceous carcinoma. This carcinoma may be This is a highly differentiated form of vulvar squamous cell
mistaken for metastatic renal cell carcinoma, as both have carcinoma in situ, and is the probable precursor of many, if not
cytoplasmic glycogen and lipid. Intraepidermal invasion of most, invasive squamous carcinomas of the vulva. In contrast
tumor cells has been reported in sebaceous carcinoma. to ‘classic VIN’, differentiated ‘simplex VIN’ occurs character-
istically in postmenopausal women (mean age 66.8 years). The
SQUAMOUS CARCINOMA AND VULVAL lesions are infrequently associated with multicentric lower geni-
tal tract squamous neoplasia, tend to be less discrete or bulky,
INTRAEPITHELIAL NEOPLASIA (VIN) and are more often associated with ‘dystrophic’ vulvar lesions,
such as lichen sclerosus (LS) and squamous hyperplasia.
CLINICAL FEATURES
Microinvasive squamous carcinoma of the vulva
Vulval intraepithelial neoplasia (VIN)
This condition is controversial, because 15% of tumors with
This is a common problem that is more frequent in young stromal invasion of ⭐5 mm, 12% of tumors of ⭐3 mm, and 3%
women. HPV nucleic acids are found in 53–90% of cases, and of tumors of ⬍1 mm metastasize to regional lymph nodes.
HPV 16 is the most common genotype. VIN rarely progresses
(2–10% of cases of VINIII) to invasive carcinoma, and a similar Invasive squamous carcinoma
proportion may regress. Patients of advanced age and those with
immunosuppression are at increased risk of invasion. ‘Classic’ Vulvar invasive squamous cell carcinomas can be subdivided
VIN produces obvious lesions, including macules, elevated into HPV-positive tumors and HPV-negative tumors. The for-
plaques and verruciform or polypoid areas that are white, red, or mer tend to occur in relatively young women, and have histo-
sometimes pigmented; it may also be asymptomatic, or may cause logical features resembling the warty and basaloid forms of
pruritus. VIN may also involve the anal skin and squamous ‘classic’ VIN that are often associated with the cancer. The more
mucosa of the anal canal. VIN is treated by wide local excision, common HPV-negative invasive squamous cell carcinomas tend
laser ablasion or shallow vulvectomy. VINIII may be persistent or to occur in older women, have ‘conventional’ keratinizing histo-
recur after local excision. logical features, and are associated infrequently with ‘classic’
One-fifth to one-third of invasive vulval squamous carci- and more often with differentiated ‘simplex’ VIN.
noma has adjacent foci of VINIII. Patients with VIN are at high Squamous hyperplasia and LS are found commonly adjacent
risk for the development of dysplasia or invasive squamous cell to invasive squamous cell carcinomas. Although histological
carcinoma of the cervix or vagina. changes of LS are often found in vulvectomy specimens per-
In young women under 45 years of age, VIN lesions tend to be formed for invasive squamous cell carcinomas, less than 5% of
multifocal (63.2%). HPV infections concomitant with VIN and patients with clinical LS subsequently develop vulvar carcinoma.
vulvar cancer stage I occurred in 61.5% of young women and in In a recent study of 60 patients with vulvar invasive
17.5% of older females. The risk factor for VIN and early vulvar squamous cell carcinomas, LS was present in 65% and VINIII
carcinoma occurrence in young women is different than in older (classic or simplex CIS) was present in 37%. Of the eight
patients. Long-term follow-up of VINI and VINII shows that in invasive squamous cell carcinomas with both VIN and LS, the
over one-third of cases the lesions may persistent or recur after VIN was of the simplex type in 75%. By contrast, none of the
a transient remission. Progression is dependent not only on dys- 14 VINIII lesions without LS were of the simplex type.
plasia stage, but also on histological pattern. Over the past two
decades, a subset of women aged younger than 50 years with PATHOLOGICAL FEATURES (Figures 7.1–7.6)
squamous cell carcinoma of the vulva has emerged. Most of these
carcinomas appear to arise in a field of warty or basaloid VIN. Vulval intraepithelial neoplasia (VIN)
Treatment should be tailored to each individual patient, and The most common form of VIN is the ‘classic type’, which
may include a period of expectant observation. Variations and includes the Bowenoid, basaloid or a mixture of both.
combinations are used whenever necessary to preserve normal Histologically, the ‘Bowenoid type’ has all the hallmarks
function and anatomy. Frequent surveillance is a must because of a high-grade dysplasia or carcinoma in situ (CIS) with
recurrence rates are high, especially with multifocal disease in marked architectural disorganization, marked nuclear atypia,
young women. Skinning vulvectomy seems to have a high suc- high nuclear-to-cytoplasm ratios, and numerous normal and
cess rate in treatment of VINII–III, with minimal postoperative abnormal mitotic figures at all levels of the epidermis or
Figure 7.1 VINIII: full-thickness epithelial dysplasia, hyperkeratosis Figure 7.4 VINIII: complex, elongated rete ridges often seen in VIN,
and focal parakeratosis. does not indicate invasion, but deeper levels are advisable to rule it out.
Figure 7.2 Basaloid VINIII: replacement of the epidermis by small Figure 7.5 Microinvasive squamous cell carcinoma of the vulva: a
undifferentiated cells. small nest of more eosinophilic squamous cells detached from VINIII.
Figure 7.3 VINIII: complex, elongated rete ridges often seen in Figure 7.6 Acantholytic differentiated VINIII.
VIN, does not indicate invasion.
Figure 7.7 Invasive squamous cell carcinoma: small nests of Figure 7.10 Invasive squamous cell carcinoma: the invasive
invasion with the overlying epithelium showing differentiated VIN. nests are more eosinophilic and keratinized than the in-situ
component.
Figures 7.8 and 7.9 Keratinizing squamous cell carcinoma of Figures 7.11 and 7.12 Basaloid squamous carcinoma of the
the vulva: irregularly shaped nests of keratinizing squamous cell vulva: irregular nests of basaloid cells with central keratinized areas.
carcinoma in a loose desmoplastic stroma.
Figure 7.13 Verrucous carcinoma of the vulva. A well-

differentiated squamous cell carcinoma showing papillary fronds
with irregularly shaped, swollen rete ridges growing along a broad
front.There is often florid inflammatory response in the dermis.
Figures 7.16 and 7.17 Warty squamous carcinoma of the vulva:

hyperkeratotic, papilliferous squamous lesion with parakeratosis and
full-thickness dysplasia.
mucosal epithelium. A papillomatous surface, striking nuclear

pleomorphism with multinucleation, dyskeratosis, corp ronds,
and superficial koilocytotic cells are particularly prominent in
the ‘warty type’, whereas a diffuse replacement of the epidermis
with small undifferentiated squamous cells predominates in the
so-called ‘basaloid type’. However, there is considerable over-
lap and mixtures of all these histological patterns.
Grades of ‘classic’ VIN:
Figures 7.14 and 7.15 Verrucous carcinoma of the vulva. A well- ● VINI lesions: the above cytological features are limited to
differentiated squamous cell carcinoma showing papillary fronds
with irregularly shaped, swollen rete ridges growing along a broad the lower one-third of the epithelium.
● VINII lesions: the above cytological features are limited to
front. There is often florid inflammatory response in the dermis.
The epithelium shows koilocytes with no evidence of atypia. the lower two-thirds of the epithelium.
Figures 7.18 and 7.19 Warty squamous carcinoma of the vulva (further examples).
● VINIII lesions: the above cytological features are seen carcinoma extending from overlying simplex VIN into the der-
throughout the full thickness of the epithelium. In addition, mis. Large keratinocytes with dense eosinophilic cytoplasm and
abnormal cells may extend into hair follicles. The rete enlarged nuclei with prominent nucleoli are seen typically in
ridges may be thickened and branched with squamous both differentiated VIN and microinvasive squamous carcinoma.
pearl formation.
Microinvasion in classic VIN (Figure 7.5): this is seen in up Invasive squamous cell carcinoma (Figures 7.8–7.10)
to 19% of cases if thorough pathological examination is per- The pathological features of classic squamous carcinoma of the
formed. It is characterized by small, irregular, angulated nests vulva are not different from those seen elsewhere. Well-
of usually more differentiated squamous cells, which appear to differentiated keratinizing squamous cell carcinoma shows
arise from the basal layers. The adjacent stroma is usually desmo- variably sized nests of squamous cells with abundant cyto-
plastic and exhibits inflammatory cells. Early invasion should plasm. Loose desmoplastic stroma is frequently seen around
be distinguished from extensive involvement of pilar structures, the invasive nests.
deep invagination or infoldings of the epidermis, or tangential Squamous carcinoma variants include:
cutting and thickened rete ridges. The presence of stromal and ● Basaloid carcinoma (Figures 7.11 and 7.12): basaloid
epithelial eosinophils is a feature that favors stromal invasion. carcinomas of the vulva have been reported to occur
Differentiated VIN ‘simplex vulvar intraepithelial neoplasia’ mostly in young women and are often associated with
(Figure 7.7): this is unlike the classic VINIII, in that it shows HPV infection. Microscopically, it is characterized by a
preservation of the architectural differentiation of the abnor- relatively uniform population of small, ovoid cells with a
mal cells in the superficial portions of the epidermis. The epi- high nuclear:cytoplasmic ratio resembling that of VINIII.
dermis is irregularly thickened by a proliferation of abnormal, It seems that women with basaloid carcinoma appear
enlarged keratinocytes with dense eosinophilic cytoplasm and to have a survival advantage compared with women with
enlarged nuclei with prominent nucleoli contrasted with smaller keratinizing squamous carcinoma.
hyperchromatic basal cell layers. Intercellular bridges are promi- ● Basosquamous carcinoma: for details, see Chapter 12,
nent, and occasional cells are binucleated. A parakeratotic sur- Skin tumors (p. 852).
face reaction is frequently seen. The dermis contains chronic ● Verrucous carcinoma (Figures 7.13–7.15): this variant of
inflammatory cells. Whorls of differentiated cells with or with- epidermoid carcinoma can easily be misdiagnosed if
out keratin pearls are sometimes present; this suggests incipient correlation is not made between the clinical and
microinvasion, and deeper sections may demonstrate unequivo- histopathological appearance. These tumors tend to invade
cal stromal invasion. These lesions are often multifocal with locally, and rarely metastasize. Anaplastic transformation
intervening non-neoplastic epidermis. has been reported after radiation therapy, making surgical
Microinvasion in differentiated ‘simplex’ vulvar intra- excision the treatment of choice.
epithelial neoplasia (VIN) (Figure 7.7): this is characterized by the Verrucous carcinoma of the vulva is of special interest
presence of a few microscopic nests of keratinizing squamous because of its rarity, its special morphology, and the
problems in differential diagnosis that are encountered.

There is also evidence that there is an association with
HPV infection, in particular HPV 6/11.
● Warty carcinoma (Figures 7.16–7.19): this is a rare variant
of squamous cell carcinoma primarily described in the
vulva in younger women, and is classically associated with
HPV infection. The gross findings are similar to those of
verrucous carcinoma, with large, exophytic tumors that
have a papillomatous surface.
Microscopically, the tumor is papillated and contains
fibrovascular cores covered by hyperkeratotic epithelium.
The keratinocytes demonstrate nuclear pleomorphism and
nuclear ‘halo’, resembling koilocytes. In addition, the
nuclei show an important degree of atypia, and high
mitotic activity. HPV-16 has been demonstrated both in
the warty carcinoma and in adjacent skin.
MIB-1 expression is usually noted in all the epithelial
layers of warty carcinoma.
SKIN APPENDAGE TUMORS
Various sweat gland-type tumors may arise in the vulva. These

include hidradenoma papilliferum (Figures 7.20 and 7.21),
syringoma, trichoepithelioma, trichofolliculoma, eccrine poro-
carcinoma, pigmented hidrocystoma of eccrine secretory coil,
and folliculosebaceous cystic hamartomas. Malignant myo-
epithelioma possibly derived from minor vestibular glands
or ectopic breast tissue has also been reported. Differential
diagnoses of the latter should include extrarenal rhabdoid
tumor and ‘proximal type’ epithelioid sarcoma.
For details see Chapter 12, Skin tumors.
Figures 7.20 and 7.21 Hidradenoma papilliferum: elongated,
intercommunicating glandular and papillary structures; they are lined
BARTHOLIN GLAND ADENOMAS by bland columnar epithelium showing apical snouts.
Inflammatory lesions and cysts are by far the most common

causes of swelling or enlargement of Bartholin’s glands, and adnexal sweat gland, clear cell and small cell neuroendocrine
carcinomas – though rare – are the most frequent solid lesions carcinomas.
that arise at this site. The management recommendations have been based on lim-
● Bartholin adenomas are solid or solid and cystic, small ited information. Radical vulvectomy with negative margins of
lesions 2–3 cm in size, and on clinical examination are resection is recommended. Groin dissection should be reserved
frequently thought to be Bartholin’s cysts. The lesions are for cases in which the inguinal lymph nodes are clinically sus-
well-circumscribed, and composed of a haphazard picious or in cases of tumor recurrence.
proliferation of acini and tubules. Conservative management of advanced carcinoma of the
● A salivary gland-type ‘hybrid carcinoma’ may arise within Bartholin gland with primary chemoradiation may be appropri-
a Bartholin’s gland adenoma. Both epithelial-myoepithelial ate whilst sparing patients the sequelae of exenterative surgery.
carcinoma and adenoid cystic carcinoma have been
reported in association with adenoma. p53 immunostaining
BARTHOLIN GLAND NODULAR HYPERPLASIA
may be helpful in such cases, as positivity is evident in up
to 40% of the carcinoma cells, while the cells in the
Nodular hyperplasia of Bartholin’s gland is very rare, and may
adjacent adenoma are usually negative.
present as painless bilateral vulvar masses in younger patients
and is often associated with inflammation or obstruction of
BARTHOLIN GLAND CARCINOMA Bartholin’s duct. Whether the hyperplastic gland forms in
response to a stimulus is unclear. However, it appears to share
Various histological variants of carcinoma may arise from the some features with Bartholin’s gland hamartoma or adenoma.
Bartholin glands. These include squamous, adenosquamous, Microscopically, nodular hyperplasia is a well-circumscribed,
basaloid squamous, adenoid cystic, mucinous, microcystic unencapsulated lesion with an irregular or lobulated contour
and is composed of cytologically bland mucinous acini with classifying them into distinct lesions in order to avoid potential
maintenance of the normal duct-to-acinar relationship. Varying confusion and unnecessary surgery.
degrees of inflammation and squamous metaplasia of the ducts
are commonly seen. PATHOLOGICAL FEATURES (Figures 7.22–7.28)
EMPD is characterized by the presence of isolated clusters of
EXTRAMAMMARY PAGET’S DISEASE large, pale intraepidermal cells. These appear clearly demarcated
CLINICAL FEATURES
Extramammary Paget’s disease (EMPD) is characterized by the
presence of intraepidermal adenocarcinoma cells, which contain
clear cytoplasm and abundant mucin. In contrast to mammary
Paget’s disease (MPD), only 15–33% of patients with EMPD have
associated malignancy of an adjacent organ such as the rectum,
anal glands, Bartholin’s glands (and also prostate in males). The
vulva is the most common site of EMPD, followed by the perianal
region, perineum, groin, pubic area, scrotum and penis (in males),
thigh, buttock, axillae, and eyelids. Paget’s disease presents as a
slowly enlarging, erythematous, eczematous, itchy reddish patch
with sharp borders. The histogenesis of MPD is clearer than that
of EMPD. MPD is caused by epidermotropic spread of known
underlying ductal carcinoma of the breast, and very rarely from
in-situ transformation of Toker cells (glandular cells found in
nearly 10% of normal nipples), without identifiable underlying
breast carcinoma. On the other hand, the histogenesis of EMPD
is not completely understood, though some theories are usually
considered:
1. EMPD represents the epidermotropic spread of tumor
cells from regional organs.
2. Paget cells originate from tumors of the skin adnexa,
such as eccrine or apocrine glands.
3. EMPD arises from ectopic mammary cells (i.e., Toker
cells of the nipple) or intraepidermal ectopic sweat
gland epithelial cells (i.e., clear cell papulosis).
4. EMPD is the result of in-situ transformation of
pluripotential stem cells within the epidermis.
5. A unifying common histogenesis of both mammary MPD
and EMPD, from accessory nipples along the milk line.
6. Ectopic epithelial cells originating from Bartholin’s glands or
other unidentified MUC5AC⫹ cells in the epidermis are the
possible origins of intraepidermal vulvar Paget’s disease.
For therapeutic purposes, it is most important to determine

whether Paget’s disease is either intraepidermal or extra-
epidermal in origin.
In a recent review, vulvar Paget’s disease has been classified
according to the origin of the neoplastic cells as either primary
(of cutaneous origin) or secondary (of non-cutaneous origin).
Each classification has three subtypes: primary, intraepithelial
cutaneous Paget’s disease of the usual type; intraepithelial cuta-
neous Paget’s disease with invasion, and intraepithelial cutaneous
Paget’s disease as a manifestation of underlying skin appendage
adenocarcinoma; secondary, Paget’s disease of anorectal origin,
Paget’s disease of urothelial origin, and Paget’s disease of other
origin. The distinction between these three types of Paget-like
lesions is essential in that the specific diagnosis has a signifi- Figures 7.22–7.24 Extramammary Paget’s disease: malignant
cant influence on current treatment. The difference in surgical glandular cells in nests, isolated cells and glandular pattern. Notice
approach to the subtypes of vulvar Paget’s disease justifies Paget’s cells within the keratinous layers in Figures 7.22 and 7.23.
Figure 7.27 Extramammary Paget’s disease: cytokeratin (CK7)

highlights the malignant epithelial cells.
Figures 7.25 and 7.26 Extramammary Paget’s disease: isolated

cells in a pagetoid spread within the epidermis.
Figure 7.28 Extramammary Paget’s disease: cytokeratin (CK20)

from the surrounding epidermal cells. Focal glandular differen- highlights the malignant epithelial cells.
tiation is often seen at the basal layers. Numerous abnormal
cells are seen migrating upward toward the keratinous layers of sweat gland lineage and could represent the cell origin
and seem to exude through the surface epithelium. Involvement of EMPD.
of the skin appendages is often seen. An intradermal invasive ● Genital junctional nevi.
component may rarely be seen. ● Pagetoid spread may occur in some tumors such as small
cell undifferentiated carcinoma, sebaceous carcinoma and
Cell morphology Merkle cell tumor (these lesions however occur in different
● Paget’s cells are large, pale cells, containing abundant locations).
clear or eosinophilic cytoplasm and round nuclei
with small prominent nucleoli. Special techniques
● Mitotic figures may be seen. ● Alcian blue highlights the intracytoplasmic mucin found
within the abnormal cells.
Differential diagnosis ● The cells are carcinoembryonic antigen (CEA)-, epithelial
● Malignant melanoma. membrane antigen (EMA)- and cytokeratin-positive.
● Clonal Bowen’s disease with clear cell change. ● Primary vulvar Paget’s disease is immunoreactive for CK7
● Clear cell papulosis: this entity shows multiple white and gross cystic disease fluid protein-15 (GCDFP-15), but
papules involving the lower abdomen, and is uncommonly for CK20. Vulvar Paget’s disease secondary
characterized histologically by the presence of benign- to anorectal carcinoma demonstrates CK20 immuno-
appearing clear cells in the epidermis which have the reactivity, but is usually non-reactive for CK7 and
immunohistochemical and ultrastructural features of sweat consistently non-immunoreactive for GCDFP-15. Vulvar
glands. They are considered to be aberrant embryonic cells Paget’s disease secondary to urothelial carcinoma is
immunoreactive for CK7 and CK20 but non-immuno-

reactive for GCDFP-15. In addition, uroplakin-III (UP-III) MESENCHYMAL TUMORS
is specific for urothelium and is immunoreactive in
secondary vulvar Paget’s disease of urothelial origin. AGGRESSIVE ANGIOMYXOMA
● Mucins are high-molecular-weight glycoproteins expressed
by epithelial glands such as mammary glands, intestinal
goblet cells, and skin adnexal structures. Several mucin CLINICAL FEATURES
genes (MUC1–MUC12) have been identified or cloned Aggressive angiomyxoma is an uncommon mesenchymal
recently, and monoclonal antibodies are available for tumor that exhibits fibroblastic and myofibroblastic features.
clinical research. Like different subtypes of cytokeratin, It preferentially involves the pelvic and perineal regions of
different mucin genes show relative specificity for tissue females, and rarely occurs in men. The tumor usually attains a
type. For example, MUC1 is expressed in the breast and large size and has a gelatinous consistency. It is characterized by
pancreas, whereas MUC2 is expressed in intestinal goblet high recurrence rate, but this is often attributed to incomplete
cells and MUC5AC is expressed in the stomach and surgical excision. Treatment should consist of wide surgical
endocervical glands. Toker cells (bland cells with clear excision – as complete as technically possible – ideally by
cytoplasm, round nuclei, and scant nuclear chromatin, obtaining negative resection margins without causing distur-
present either singly or in small clusters mainly in the bance to urinary or anorectal function.
lower half of the epidermis), and normal mammary glands
exhibit the same mucin immunophenotype (MUC1⫹
MUC5AC⫺), as do breast ductal carcinoma cells. MUC1 PATHOLOGICAL FEATURES (Figures 7.29–7.32)
is universally expressed by nearly all cases of Paget’s
Aggressive angiomyxoma is an ill-defined lesion which displays
disease, and can be used for screening for and confirming
an infiltrative growth pattern. It consists of variably sized,
the presence of Paget cells in the epidermis. MUC1 is
evenly distributed vessels present within a myxoid, poorly
comparable with CK7 as a universal cytokeratin marker
cellular stroma. Delicate, wavy collagen fibrils may be seen
for Paget cells. Both MUC1 and CK7 are present in simple
dispersed in the stroma. Occasionally, less vascular and more
ductal structures, such as eccrine ducts, apocrine glands,
cellular areas are present, particularly in recurrent tumors.
and Bartholin’s glands. This suggests that simple ducts or
Entrapped mucous glands may be found within the lesion.
their derivatives may represent the origins of various
Smooth muscle bundles are often highlighted when the section
subtypes of EMPD. MUC2 is expressed in perianal Paget’s
is stained with smooth muscle markers. Various types of vessels
disease associated with rectal adenocarcinoma, comparable
are seen, including thin-walled, congested vessels with a well-
with the positivity of CK20. However, MUC2 seemed to
developed smooth muscle coat, thick hyalinized blood vessels,
be more specific than CK20 in predicting a colorectal
and rarely plexiform capillaries.
origin of Paget’s disease because several of cases of vulvar
Paget’s disease without underlying malignancy may also be
positive for CK20 but negative for MUC2. The exclusive Secondary features
expression of MUC5AC in EMPD, but not in MPD or ● Extravasation of red blood cells
normal breast tissue, clearly indicates that these two ● Perivascular lymphocytic infiltrate.
groups of Paget’s disease have different origins.
MELANOCYTIC TUMORS
MALIGNANT MELANOMA
CLINICAL FEATURES
Vulvar melanoma is an unusual tumor with a poor prognosis.
Patients with lesion depths of 1.75 mm or less may be treated
with wide local excision. Patients with greater lesion depths are
at high risk for the development of distant metastases. The
patients with well-lateralized lesions may be equally well
served with a less morbid procedure deferring therapeutic node
dissection until there is a regional recurrence.
SPECIAL SITE NEVI

Figure 7.29 Aggressive angiomyxoma: loose myxoid background
See Chapter 12, Skin tumors (p. 887). and scattered capillary-sized vessels.
Cell morphology
● The stromal cells are evenly distributed, have oval, bland
nuclei and delicate, multipolar or bipolar cytoplasmic
processes.
● Mast cells are usually present within the lesion.
● Stromal multinucleated cells are rarely seen.
● Mitoses and cellular pleomorphism are lacking.
● Angiomyofibroblastoma of the vulva
● Cellular angiofibroma of the vulva
● Superficial cervicovaginal myofibroblastoma
● Intramuscular myxoma
● Myxoid liposarcoma
● Myxoid neurofibroma
● Myxoid leiomyoma
Figure 7.30 Aggressive angiomyxoma. Stellate stromal cells and ● Myxoid lipoma
isolated smooth muscle fibers (arrow).
● Embryonal rhabdomyosarcoma
● Superficial angiomyxoma
● Myxofibrosarcoma
● Prolapse of the Fallopian tube associated with an
exuberant angiomyofibroblastic stromal response (may
show richly vascularized stroma arranged in a retiform
pattern) and mildly atypical glandular inclusions, which
has the morphology of tubal epithelium. The stroma of the
lesion is composed of either thin bipolar cells with tapered
nuclei and stellate cells with minimal amount of cytoplasm
or small epithelioid-looking cells with eosinophilic
cytoplasm. If the tubal glandular component is overlooked,
these tumors might be erroneously diagnosed as
mesenchymal lesions of the vagina, such as vaginal
fibroepithelial polyp, angiomyofibroblastoma, aggressive
angiomyxoma, or superficial myofibroblastoma.
Special techniques
Figure 7.31 Aggressive angiomyxoma: vascular, hyalinized stroma,
and capillary-sized vessels infiltrating fat cells. ● The vascular endothelium stains for factor VIII-related
antigen and vimentin.
● The stromal cells are vimentin positive and a proportion
are muscle-specific actin- and desmin-positive.
● Estrogen and progesterone receptors are frequently
positive.
● The cells are CD44 positive.
ANGIOMYOFIBROBLASTOMA
CLINICAL FEATURES
Angiomyofibroblastoma is a distinctive neoplasm that has a
propensity to occur in the female genital tract, especially in the
superficial area of the vulva. It can also be seen in the vagina
and perineum, and has also been reported in the perineum of
male patients. It has rarely been reported in the Fallopian tube.
The tumor is presumably derived from primitive mesenchymal
cells which occur normally in this region and which show the
Figure 7.32 Aggressive angiomyxoma: hyalinized background potential for diverse lines of myoid differentiation. Angio-
stroma, various-sized vessels, and isolated smooth muscle fibers. myofibroblastoma predominantly occurs in middle-aged or
young women. Clinically, most of the tumors present as slowly Cell morphology
growing painless masses and are often diagnosed as Bartholin’s ● The plump, spindle- or oval-shaped cells have bland
gland cysts. The tumor should be distinguished from ‘aggressive nuclei.
angiomyxoma’, a locally aggressive, infiltrative lesion of the ● Some of the cells have abundant hyaline eosinophilic
vulva and perianal region. Angiomyofibroblastoma does not cytoplasm, and some may have enlarged hyperchromatic
recur following excision. nuclei.
● Mast cells are frequently seen.
PATHOLOGICAL FEATURES (Figures 7.33 and 7.34) ● Mitotic figures (MFs) are absent or very sparse. A
Histologically, the tumors are all well-circumscribed and char- mitotically active variant (maximum 3 MFs per 10 HPF)
acterized by alternating hypocellular and hypercellular areas has been described.
with abundant thin-walled blood vessels. The tumor cells are
bland and spindle-shaped or epithelioid and tend to concen- Differential diagnosis
trate around the vessels or cluster in small nests. Abundant ● Aggressive angiomyxoma (is less well circumscribed and
capillary-type vessels and thin wavy strands or thick bundles
exhibits a similar immunohistochemical profile except
of collagen are distributed throughout the lesion.
for CD44, which appears to be positive in aggressive
Secondary features angiomyxoma but not in angiomyofibroblastoma)
● Myxoid smooth muscle tumors
● Interstitial hemorrhage ● Glomus tumor
● Focal fibrosis ● Nerve sheath tumor
● Malignant transformation (angiomyofibrosarcoma) is ● Superficial cervicovaginal myofibroblastoma (a distinctive
extremely rare. mesenchymal tumor that arises in the superficial lamina
propria of the cervix and vagina and may show identical
immunohistochemical profile to angiomyofibroblastoma).
Special techniques
● Immunohistochemistry of the tumor cells show diffuse
immunoreactivity for estrogen receptors, progesterone
receptors, and vimentin
● CD34 is variably positive
● The stains for cytokeratin and epithelial membrane antigen
are negative
● Desmin and smooth muscle alpha-actin, muscle-specific
actin may be positive
● S-100 is usually negative.
CELLULAR ANGIOFIBROMA
CLINICAL FEATURES
Cellular angiofibroma is a recently described, rare soft tissue neo-
plasm of the vulva that typically occurs as a well-circumscribed,
small-sized (⬍3 cm), solid rubbery vulvar mass in middle-aged
women or rarely in postmenopausal women. They appear clini-
cally as labial or Bartholin’s gland cysts.
The characteristic features of a cellular angiofibroma are the
presence of an admixture of medium to small hyalinized blood
vessels and loose cellular stroma. A component of mature
adipocytes may be seen.
Cytological features
Figures 7.33 and 7.34 Angiomyofibroblastoma of the vulva: a

● The cells are uniform, bland, spindled stromal cells
well-circumscribed vascular hypocellular lesion; the stroma is loose ● Mitotic activity is usually brisk, with up to 11 mitoses per
fibrillary and the nuclei are small and spindle-shaped. 10 HPF.
Differential diagnosis these tumors may create diagnostic problems. For details, see
● Aggressive angiomyxoma Chapter 13, Soft tissue tumors (p. 965).
● Angiomyofibroblastoma
● Spindle cell lipoma SMOOTH MUSCLE NEOPLASMS (Figures 7.35–7.39)
● Perineuroma Smooth muscle tumors are uncommon lesions of the vulva and
● Leiomyoma represent a variety of histological types. These lesions are usu-
ally circumscribed, but may show focally infiltrative margins.
Special techniques
● The stromal cells are immunoreactive for vimentin and CD34,
and usually negative for desmin, actin, and S-100 protein.
● The nuclei of the stromal cells demonstrated strong
reactivity for estrogen and progesterone receptors.
SARCOMAS
Various sarcomas can present as primary vulval tumor. These

include leiomyosarcoma, proximal epithelioid sarcoma, malig-
nant peripheral nerve sheath tumor, peripheral primitive neuro-
ectodermal tumor (PNET), dermatofibrosarcoma protuberans,
and endometrial stromal sarcoma. Due to their rarity in this site,
Figures 7.37 and 7.38 Vulval epithelioid leiomyoma: a well-

circumscribed lesion consisting of pale epithelioid cells with
abundant cytoplasmic and round nuclei. Perinuclear clearing is
Figures 7.35 and 7.36 Vulval leiomyoma: interlacing epithelioid noticed in some cells. At first glance, the histological appearance may
smooth muscle cells in a loose background. not give the impression of a smooth muscle tumor.
ADENOSIS
CLINICAL FEATURES
Vulvar adenosis has rarely been reported after diathermy treat-
ment for condylomas, as a side effect of CO2 laser vaporization
and in associations with Stevens–Johnson syndrome.
See Vaginal adenosis, p. 382.
ECTOPIC BREAST TISSUE AND NEOPLASMS

Ectopic breast tissue has been described rarely in the vulva, and
is known to develop a variety of pathological changes. Lesions
which have been described in ectopic vulval breast tissue include
Figure 7.39 Vulval epithelioid leiomyoma (higher magnification of
fibroadenoma, lactating changes, phyllodes tumor, infiltrating
Figures 7.37 and 7.38).
Histologically, they are composed mainly of spindle cells; some

tumors show prominent myxoid stroma. Others are predomi-
nantly epithelioid, with a prominent hyalinized or myxoid
stroma and with cells arranged in a plexiform pattern. Some
tumors may exhibit mild, moderate, or severe cytological
atypia. Mitotic figures range from 0 to 10 (average 1.8) per
10 HPF.
Immunohistochemically, all the tumors stained for one or
more muscle markers. The majority of tumors are positive for
estrogen and progesterone receptors. These tumors may recur
locally, and rarely metastasize. Criteria distinguishing benign
from malignant tumors have been proposed, and tumors with
the presence of three or all of the four following features
should be considered as sarcomas: ⭓5 cm in the greatest
dimension; infiltrative margins; ⭓5 mitotic figures per 10 HPF;
and moderate to severe cytological atypia. Those that have
only one of these characteristics should be diagnosed as leiomy-
oma, while those that exhibit only two features should be con-
sidered benign but atypical leiomyomas. The sarcomas should
be excised with widely negative margins; the leiomyomas and
the atypical leiomyomas should be excised conservatively, with
long-term, careful follow-up.
Vulvar leiomyoma with extensive myxoid change may be
misinterpreted as an aggressive angiomyxoma. Myxoid vulvar
leiomyoma should also be differentiated from angiomyofibro-
blastoma. The key to the differential diagnosis is the presence
of interlacing smooth muscle cells and an awareness of ten-
dency toward myxoid change in vulvar leiomyomas. Almost all
cases of vulval smooth muscle tumors show immunohisto-
chemical evidence of muscle differentiation.
Vulval leiomyoma may rarely resemble a fibroma ‘fibroma-
like leiomyoma’. Figures 7.40 and 7.41 Ectopic breast tissue, vulva.
ductal or lobular adenocarcinoma, malignant myoepithelioma, UNUSUAL VULVAL TUMORS

and papillary apocrine fibroadenoma. Metastasis of breast
carcinoma to the vulva may also occur, and this should be dis- Some benign or malignant tumors, usually of extravulval sites,
tinguished from primary carcinoma of the vulva. Estrogen and may present as primary tumor in the vulva. These include sar-
progesterone receptor studies may be helpful in identifying comatoid squamous cell carcinoma, yolk sac tumor, primary
vulval adenocarcinoma of uncertain origin. The management adenocarcinoma of the vulva of the cloacogenic type, neuro-
of primary breast carcinoma of the vulva should be modeled endocrine tumors, primary non-Hodgkin lymphoma, malignant
after that for primary carcinoma of the breast, with primary rhabdoid tumor, primary choriocarcinoma, atypical fibrous
surgery followed by systemic chemotherapy and pelvic radio- histiocytoma, nodular fasciitis, and pleomorphic and spindle
therapy. Chemotherapy should be similar to that employed for cell lipoma. Because of their extreme rarity in this sites and
breast carcinoma. Tamoxifen should be prescribed for patients their unusual histological appearances, these tumors may
whose tumors contain estrogen receptors. create a major challenge to the pathologist.
TUMORS OF THE VAGINA
that of the cervix. The diagnosis of invasive adenocarcinoma

EPITHELIAL LESIONS, BENIGN should be made with caution unless there are both architectural
and cytological features of malignancy. These changes are often
VAGINAL ADENOSIS seen at the margins of clear cell adenocarcinoma, associated
with adenosis.
CLINICAL FEATURES Secondary features

Vaginal adenosis is rare, and is defined as the presence of ● Squamous metaplasia
mullerian-type epithelium within the vaginal wall. It is associated ● Chronic inflammation
with in-utero exposure to diethylstilbestrol (DES). Spontaneous ● Microglandular hyperplasia
vaginal adenosis can also be seen, but is mostly an insignificant ● Superimposed intraepithelial neoplasia
coincidental finding. Vaginal adenosis has rarely been reported ● Malignant transformation
in patients on tamoxifen and following treatment with 5-
fluorouracil cream for multiple vaginal condylomas or vaginal Differential diagnosis
intraepithelial neoplasia. The lesion occurs chiefly in the upper
third of the vagina as red granular spots or patches and pres-
● Endometriosis
ents as excessive mucous vaginal discharge, or it may be found
● Clear cell adenocarcinoma
incidentally. Cases of vaginal adenosis in young women should be
● Mesonephric remnants
investigated and screened appropriately, and preferably referred
to centers where colposcopic expertise is available. Although Special techniques
clear cell carcinoma is the most common type of malignancy seen ● The cells contain sparse intraluminal or intracytoplasmic
in association with adenosis, other primary vaginal adenocar- mucin.
cinomas such as intestinal-type adenocarcinoma and adenocar- ● Immunostaining of the glandular structures are similar to
cinoma in situ have also been reported. other mullerian epithelium.
The abnormal glands seen in vaginal adenosis are present at the EPITHELIAL LESIONS, MALIGNANT
mucosal surface or in the superficial lamina propria, or both.
They are either seen focally or they may involve a large area. Primary cancers of the vagina are rare. They comprise 1–2% of
The abnormal glands are most commonly endocervical in type, all gynecological malignancies, and occur predominantly in older
but endometrial and tubal-type glands may also be seen. Cystic women. The diagnosis of primary carcinoma of the vagina
dilatation of glands ‘Nabothian follicle-like’ and glands with requires that the cervix and vulva be intact, and that no clinical
papillary infolding may be seen. Rarely, other type of epithe- evidence of other primary tumors exist. Approximately 90% of
lium is noticed such as intestinal-type glands with presence of all vaginal tumors are squamous cell carcinoma. Adenocarci-
argentaffin cells. noma, which is much less common (2–4%), is seen primarily in
Atypical adenosis appears in the form of atypical tubo- younger women with in-utero exposure to DES. In addition to
endometrial glands is associated with intraglandular bridging. exposure to DES, other environmental factors have been associ-
The cells may show enlarged hyperchromatic, pleomorphic ated with the development of vaginal tumors, including chronic
nuclei, some with prominent nucleoli. The spectrum of atypical irritation from pessaries, previous hysterectomy for benign
glandular changes in vaginal adenosis may seem analogous to disease, immunosuppression therapy, cervical irradiation, and
endometriosis. Infectious causes seem to play an even more per- PATHOLOGICAL FEATURES
nicious role in vaginal cancer. The two agents most often impli-
● VAIN: The pathological features and the grading of VAIN
cated are herpes simplex virus and human papillomavirus (HPV).
are identical to those of CIN.
These viruses appear to serve as cofactors in the inducement of
● Squamous carcinoma of the vagina is similar to its
various genital cancers, working together or with environmental
counterpart in the vulva or cervix.
agents such as DES and host-related genetic abnormalities. The
● Other variants of squamous carcinoma such as verrucous,
prognosis of vaginal cancer depends on the stage of the disease,
warty, lympho-epithelial and papillary squamotransitional
with an overall 5-year survival rate of 80–90% for early stages.
carcinomas are rare.
Primary vaginal clear cell carcinoma occurs in young women
● Small cell carcinoma similar to that of cervical origin is rare.
exposed to DES in utero, and it may rarely occur without such
association. Vaginal adenocarcinoma has rarely been reported in
association with endocervicosis.
Other rare primary carcinomas of the vagina are small cell MELANOCYTIC LESIONS
undifferentiated carcinoma, which is associated with a very
poor prognosis, a polymorphous low-grade adenocarcinoma Malignant melanomas of the vagina are rare tumors. The most
similar to salivary type, and carcinosarcoma of the vagina. common presenting symptom is vaginal bleeding, followed by
vaginal mass. The clinical behavior of this lesion is notoriously
more aggressive than that of cutaneous and vulvar melanoma,
SQUAMOUS CELL CARCINOMA AND VAGINAL with a 5-year survival rate ranging from 5% to 25%. Tumor size
INTRAEPITHELIAL NEOPLASIA (VAIN) is the strongest predictor of survival, whereas tumor thickness
is a weak predictor of survival. Grossly, the tumor is usually
polypoid-nodular. The tumor exhibits epithelioid or spindled
CLINICAL FEATURES neoplastic cells or both cell types. They may exhibit cartilaginous
Vaginal intraepithelial neoplasia (VAIN) accounts for less than differentiation and such cases must be distinguished from pri-
0.5% of lower genital tract neoplasia, but the frequency of its mary malignant mixed mullerian tumor.
detection is increasing, especially in younger patients. These Immunohistochemistry using a panel of antibodies including
lesions are most commonly found in the upper third of the epithelial, melanoma and sarcoma markers are valuable in the
vagina, and are often multifocal in nature. The close proximity differential diagnosis.
of the upper vagina to the rectum, bladder, and ureters makes Melanosis is a term given to lesions in which melanin pig-
treatment difficult. VAIN is a premalignant lesion, often asso- ment is confined to the basal layer of squamous epithelium,
ciated with VIN or CIN or invasive squamous carcinoma of the and on visual inspection may have an appearance similar to
cervix or vulva. It is also frequently associated with HPV infec- that of malignant melanoma. Although relatively common in
tion. The occult invasion rate may be as high as 28%, and a the oral and gastrointestinal tract, melanosis is an uncommon
wide variety of therapies are available. finding in the female genital tract and is especially rare in the
Treatment modalities vary according to the severity and vagina; most reported cases have been in the vulva. Vaginal
extent of the lesions. In post-hysterectomy patients with melanosis may be difficult to distinguish clinically from malig-
VAIN(3) at the vaginal apex, in the region of vaginal cuff scar, nant melanoma, but it carries a much different prognosis.
upper vaginectomy is the treatment of choice, while multifocal A biopsy of any pigmented lesion is always indicated prior to
VAIN(2–3) or colposcopically well-defined lesions, involving determining the need for therapy versus observation.
large areas of vaginal mucosa, could be successfully managed by
CO2 laser ablation. Skinning vulvectomy also seems to have a
high success rate in treatment of VAIN(2–3) with minimal post- MESENCHYMAL TUMORS
operative complications and satisfactory cosmetic results.
Although most VAIN goes into remission after treatment,
FIBROEPITHELIAL STROMAL POLYPS OF THE
5% of cases may progress from occult foci to invasion, in spite
of close follow-up. LOWER FEMALE GENITAL TRACT
The sensitivity of the vaginal smear cytological examination
in detecting VAIN is 83%.
CLINICAL FEATURES
Vaginal squamous cell carcinoma is infrequent, often associ-
ated with HPV DNA type 16, and tends to have poor progno- Fibroepithelial stromal polyps of the female genital tract are
sis. Like VAIN, it is most commonly seen in the upper third of benign lesions that occur generally in young to middle-aged
the vagina. Tumor stage and tumor diameter are the important women in their reproductive years; however, they can present
prognostic factors. Stage I and II squamous vaginal cancer at any age. They occur most commonly in the vagina, but they
patients have good outcomes in terms of survival and local can also occur in the vulva and, less commonly, in the cervix.
tumor control if they are managed by initial surgery followed Fibroepithelial stromal polyps are usually asymptomatic, dis-
by selective radiotherapy. covered incidentally during vaginal examination, or may be a
Microinvasive squamous cell carcinoma is not well defined in cause of post-coital bleeding, or discovered as a vaginal or vul-
the vagina. val lump by the patient. They are more commonly seen on the
anterior vaginal wall and vary in size from 5 to 35 mm, with an ● Giant cells of myofibroblastic origin
average of 11 mm. ● Mast cells
When these lesions occur during pregnancy, they are more com- ● Lymphocytes
monly multiple and tend to exhibit greater cellular pleomorphism
and atypia. These lesions can occasionally recur, sometimes more
than once. Spontaneous regression can occur after delivery.
Although the pathogenesis of fibroepithelial stromal polyps is ● Leiomyosarcoma: cellular fibroepithelial stromal polyps
not well understood, these lesions are benign and seem likely to occasionally exhibit a fascicular architecture which, in
represent a reactive hyperplastic process involving the distinc- combination with an increased mitotic rate, atypical cells
tive subepithelial myxoid stroma of the lower female genital and/or atypical mitoses, can raise the possibility of
tract. The stromal cells of fibroepithelial stromal polyps can leiomyosarcoma (LMS). The lack of a clear boundary
express estrogen and progesterone receptors, which suggest that between the lesional cells and the overlying epithelium and
hormonal influences may play a role in the pathogenesis of these a polypoid or pedunculated appearance are features not
lesions. In addition, these polyps are sometimes associated with seen in LMS.
tamoxifen treatment and hormone replacement therapy. ● Botryoid rhabdomyosarcoma: these characteristically
A similar polyp has recently been reported in the endometrium. exhibit a submucosal hypercellular zone ‘cambium layer’
while in fibroepithelial stromal polyps, the increased
PATHOLOGICAL FEATURES (Figures 7.42–7.44) cellularity is toward the center of the lesion.
Vaginal polyps usually have a smooth surface, but some may

show a papilliform external surface. The overlying squamous
epithelium is slightly hyperplastic, and shows focal hyperkerato-
sis and parakeratosis. The stroma of the polyps varies from a
loose fibrillary to a more collagenous type, with varying numbers
of spindle-shaped and stellate cells. Scattered multinucleated
myofibroblastic cells are often seen. Numerous small capillaries
are always seen, and some appear to radiate from a central, rela-
tively thick-walled muscular vessel. Some polyps show conden-
sation of the fibroblastic cells in the subepithelial zone. Some
polyps are hypercellular, showing a mitotic rate of more than
10 mitoses per 10 HPF, atypical mitoses, and atypical stromal
cells. Ulceration of the overlying surface epithelium may rarely
be seen. Inflammatory infiltrates – especially perivascular lym-
phocytes and mast cells and elastic degeneration within the
stroma – may be seen.
Cell morphology Figure 7.43 Vaginal polyp: atypical and giant cell myofibroblasts are
the hallmark of vaginal polyp.
● Fibroblasts
● Myofibroblasts
Figure 7.42 Vaginal polyp: the covering epithelium is acanthotic, Figure 7.44 Vaginal polyp: the giant cell myofibroblasts are C-kit
and the stroma is hyalinized and vascular. positive.
● Endometrial stromal sarcoma: this can be polypoid, and is ● Both actin and vimentin also highlight the prominent
characteristically very vascular but the vessels typically vascular component of the polyps.
resemble spiral arterioles. ● The stromal cells of cellular fibroepithelial stromal
● Malignant mixed mullerian tumor: this shows clear polyp are commonly desmin-positive, and occasionally
epithelial malignancy. actin-positive.
● Malignant peripheral nerve sheath tumor: the spindle ● The stromal cells can be both estrogen- and progesterone-
cells of some cellular fibroepithelial polyps can be wavy receptor-positive.
and tapered, reminiscent of neural cells. This feature, in ● The myofibroblast can be C-kit positive (personal
combination with mitotic activity, raises the possibility of a experience).
malignant peripheral nerve sheath tumor (MPNST). The
characteristic perivascular accentuation seen commonly in
MPNST is also lacking in cellular fibroepithelial stromal SARCOMAS (Figures 7.45–7.48)
polyps. Immunoperoxidase stains may be helpful in that
approximately 50% of MPNST show focal staining for Rhabdomyosarcoma is a very rare tumor, but is the most
S-100 protein. common sarcoma of the vagina in young girls. The tumor usually
● Dermatofibrosarcoma protuberans: this is uncommon in presents as a polypoidal mass. Other sarcomas reported in this
the vulva, is generally storiform throughout, is more site are alveolar soft part sarcoma, granulocytic sarcoma and
uniform cytologically, typically has infiltrative margins, angiosarcoma, extraskeletal Ewing’s sarcoma, endometrial
and is consistently CD34-positive but negative for desmin stromal sarcoma, and leiomyosarcoma.
and smooth muscle actin.
● Aggressive angiomyxoma: this is more deeply located, is
less polypoid, and exhibits a prominent vascular pattern
that is distributed more diffusely throughout the lesion. It
tends also to have myoid bundles that cuff the vascular
component – a finding not seen in cellular fibroepithelial
stromal polyps. Immunoperoxidase staining is not useful
in discriminating between these two lesions since both are
often desmin-positive.
● Angiomyofibroblastoma: this is usually a well-circumscribed
submucosal nodule. Plump epithelioid cells and
multinucleate cells can be seen in either cellular
fibroepithelial stromal polyps or angiomyofibroblastoma;
however, the usual absence of nuclear atypia in
angiomyofibroblastoma, and the relationship of these cells
to the vasculature are the distinguishing features. The
stromal cells of angiomyofibroblastoma characteristically
cluster around the vasculature – a feature that is not
prominent in cellular fibroepithelial stromal polyps. In
addition, the vasculature of angiomyofibroblastoma tends
to be composed of vessels with more delicate walls as
opposed to the large thick-walled and often hyalinized
vessels present in cellular fibroepithelial stromal polyps.
Immunoperoxidase does not play a role in distinguishing
between these two entities since both are often
desmin-positive.
● Cellular angiofibroma: this is less polypoid, is usually
well circumscribed, and does not show the indistinct
boundaries of cellular fibroepithelial stromal polyp. It
is more diffusely vascular and the vessels are usually
of similar caliber, with hyalinized walls. Atypical
stromal cells are not a feature of cellular angiofibroma.
Immunohistochemistry may be of some use in
distinguishing between the two since the stromal cells
of cellular angiofibroma are desmin-negative.
Special techniques
Figures 7.45 and 7.46 Botryoid rhabdomyosarcoma of the
● Elastic van Gieson’s stain highlights delicate elastic fibers vagina. Polypoid lesion with cellular stroma showing cambium layer
running perpendicular to the surface epithelium. and condensation of cells around vessels.
possibility of an origin from embryonic remnant. One theory

stresses the mullerian origin, with possible association of these
tumors with endometriosis or vaginal adenosis. Other theories
highlight a derivative from urogenital sinus due to the fact that
the majority of the cases reported occurred in or near the
hymenal ring, a site of urogenital sinus epithelium. There has
also been a suggestion that estrogen plays a role in histogene-
sis, in keeping with the fact that most of these tumors have
been described in women in their reproductive years, or rarely
in older women using topical vaginal estrogen cream or on
tamoxifen. These tumors follow a benign course, and rarely
recur as a result of incomplete primary excision.

This lesion is typically well-circumscribed and located within a
few millimeters of the overlying epithelium. It consists of a
Figure 7.47 Botryoid rhabdomyosarcoma of the vagina
(a magnified view from Figure 7.45). major component of spindle cell population and a minor com-
ponent of epithelial structures. The spindle cells may appear in
cords, or nested due to the presence of intervening fibroblastic
stroma. The epithelial component includes tiny foci of either
glandular or squamous epithelium, or occasionally both.
Figure 7.48 Botryoid rhabdomyosarcoma of the vagina. Strap cells

are found among the round cell rhabdomyoblasts (encircled).
MIXED EPITHELIAL AND MESENCHYMAL

TUMORS
MIXED TUMOR OF THE VAGINA (SPINDLE CELL

EPITHELIOMA)
CLINICAL FEATURES
Spindle cell epithelioma of the vagina (SCEV) – also referred to
as benign mixed tumor of the vagina – is a well-recognized, but
unusual, vaginal tumor that consists of both epithelial and mes-
enchymal elements. The patient’s age varies between 20 and
69 years, with a mean of 30 years. The majority of tumors
are discovered incidentally, but some lesions may present Figures 7.49 and 7.50 Mixed tumor of the vagina: subepithelial
with vaginal bleeding. The histogenesis of benign mixed tumor lesion consisting of glandular structures (arrows), epithelial nests, and
of the vagina is controversial. Most reports emphasize the spindle cell stroma.
Secondary features ● It may also be confused with the extremely rare malignant
● Myxomatous change mixed tumor of the vagina, and metastatic carcinoma,
● Focal spherical stromal hyalinization especially of endometrial or endocervical origin.
Special techniques
Cell morphology
● Both the epithelial and mesenchymal components in
● The spindle cells are small, with sparse, faintly granular
the tumor stain with cytokeratin AE1/AE3, cytokeratin 7
cytoplasm and poorly defined cell borders. They
and CD10. The epithelium, in addition, is EMA-positive.
have ovoid, slightly vesicular nuclei with fine ● The mesenchymal element may stain for bcl-2, estrogen and
chromatin pattern and lack significant atypia or mitotic
progesterone receptors, desmin, smooth muscle actin and
figures.
CD34.
● The glands are lined by low cuboidal or columnar
epithelium, and contain luminal granular secretion. Some
glands contain squamous morules.
MULLERIAN (MESONEPHRIC) PAPILLOMA
● The squamous nests contain glycogenated epithelium.
CLINICAL FEATURES
Mullerian papilloma is a very rare lesion of mullerian rather
● Because of the predominant endometrial stromal-like cells than mesonephric origin. It occurs mainly in the vagina or
in some lesions, it can be misinterpreted as endometrial cervix of infants or young girls under the age of 6 years who
stromal tumor with benign glands. present with vaginal bleeding.
Mullerian papilloma is a grossly papillary or polypoid lesion
consisting of variably myxoid edematous or focally hyalinized
fibrovascular stroma and lined by cuboidal, columnar or squa-
mous epithelial cells. Occasionally, solid nests of cells are seen
which may contain hyaline eosinophilic globules. The cores of
the papillae contain prominent vessels. Polymorphs and lympho-
cytic infiltrate, cholesterol clefts, foam cells, osseous metaplasia
and psammoma body formation and edema may be seen.
● Botryoid rhabdomyosarcoma
● Papillary cervicitis
● Fibroepithelial stromal polyps
Figure 7.51 Mixed tumor of the vagina: glandular structure Special techniques
(arrow), and spindle cell stroma. ● The luminal borders of the glands are PAS-positive/
diastase-resistant.
● PAS-positive eosinophilic globules are sometimes seen.
SECONDARY METASTASIS
Secondary metastasis in the vagina is more common than pri-

mary tumors. Primary sites of origin are gynecological organs
(in particular those of endometrial origin), kidney, breast, blad-
der, and colon. True vaginal metastases from colonic cancer are
exceedingly rare. It often signals an ominous prognosis. More
frequently, the vagina is synchronously involved by direct
contiguous spread from the colonic lesion.
UNUSUAL VAGINAL TUMORS
Figure 7.52 Mixed tumor of the vagina: CK7 highlights the Some tumors of extravaginal sites may be seen as primary within
epithelial nature of the majority of the stromal cells. the vagina. These include yolk sac tumor, choriocarcinoma,
small cell carcinoma, carcinosarcoma, mucinous adenocarci- site and their unusual histological appearances, they may pose
noma, and Wilms’ tumor. Because of their extreme rarity at this a great challenge to the pathologist.
TUMORS OF THE UTERINE CERVIX

EPITHELIAL TUMORS: GLANDULAR LESIONS,
This lesion is characterized by the presence of one or multiple,
BENIGN well-circumscribed aggregates of thin-walled tubular structures.
These are closely packed, often cystically dilated, round, oval,
ECTOPIC PROSTATIC TISSUE or irregularly shaped, containing pale homogeneous eosinophilic
luminal secretion with small amounts of intervening stroma.
Large retention cysts are often seen in association with these
CLINICAL FEATURES tunnel clusters.
Ectopic prostatic tissue is a rare incidental finding that is seen
at any age, in loop excisions and cone biopsy of the cervix for
high-grade squamous dysplasia. It may also rarely present as a
cervical mass.
Ectopic prostatic tissue appears as small scattered foci of closely
packed ducts and acini with undulating borders present immedi-
ately beneath the cervical squamous epithelium. The ducts show
prominent intraluminal papillae and cribriform foci and are lined
by two cell layers. One is a discontinuous basal cell layer of small
cuboidal to flattened cells with little or no discernible clear cyto-
plasm and round bland nuclei, and the other is a columnar cell
with secretory features having more abundant vacuolated cyto-
plasm. There may be evidence of hyperplasia and sometime cystic
dilatation of the glands. Squamous metaplasia is focally prominent
within these glandular foci. No smooth muscle hyperplasia is pres-
ent in association with the glandular proliferation, but increased Figure 7.53 Tunnel clusters. Crowded, dilated, thin-walled
intervening fibrous tissue and focal chronic inflammation is appar- endocervical glands arranged in a ‘jigsaw-puzzle’ pattern.These are
ent when compared with non-involved cervical stroma. lined by attenuated epithelium and contain pale, homogeneous
mucin secretion.
● Lobular endocervical glandular hyperplasia (it shows
prominent lobulation and lacks the papillary infolding and
squamous metaplasia of ectopic prostate).
Special techniques
● The glandular epithelium is positive for prostatic acid
phosphatase and prostate-specific antigen. The basal cells
are highlighted in a manner similar to the normal prostate
by high-molecular-weight keratin.
ENDOCERVICAL TUNNEL CLUSTERS
CLINICAL FEATURES
Tunnel clusters (focal hyperplasia of endocervical glands) are
an incidental finding representing an involutionary change of
Figure 7.54 Tunnel clusters. Crowded, dilated, thin-walled endo-
normal or hyperplastic endocervical crypts in a manner similar cervical glands arranged in a ‘jigsaw-puzzle’ pattern.These are lined by
to that seen in glandular structures of prostate or breast. It has attenuated epithelium and contain pale, homogeneous mucin
no clinical significance. secretion.
Figure 7.55 Tunnel clusters. Crowded, dilated endocervical glands, Figure 7.56 Diffuse laminar hyperplasia of the endocervical glands.
still lined by columnar mucin-secreting cells and containing
eosinophilic mucinous material.
GLANDULAR HYPERPLASIA, LOBULAR
Cell morphology ENDOCERVICAL
● The lining cells are flat, low cuboidal or low columnar
with some nuclear reactive changes.
CLINICAL FEATURES
● Mitotic figures are absent.
Lobular endocervical glandular hyperplasia is a rare pseudoneo-
Differential diagnosis plastic lesion which is found incidentally in hysterectomy speci-
mens or associated with excessive mucoid cervical or vaginal
● Minimal deviation adenocarcinoma (adenoma malignum)
discharge, abdominal discomfort, or a cervical mass. The
● Microglandular hyperplasia
patients’ ages range from 37 to 71 years (mean 45 years; median
● Adenocarcinoma in situ
49 years). A history of hormone use is obtained in less than 30%
● Mesonephric duct remnants
of patients.
Special techniques
● The epithelial cells are usually CEA-negative; occasionally, PATHOLOGICAL FEATURES
they show very weak luminal staining. The lesion shows a distinctly lobular proliferation of densely
packed small to moderately sized rounded glands, often centered
GLANDULAR HYPERPLASIA, DIFFUSE LAMINAR on a larger dilated gland. The lobular proliferation is well to
poorly demarcated, and usually confined to the inner half of the
cervical wall. Glands within the lobules are usually separated
CLINICAL FEATURES from each other by unaltered or hypercellular cervical stroma,
Diffuse laminar endocervical glandular hyperplasia is a and are lined by columnar mucinous cells similar to the normal
pseudoneoplastic pathological process that is usually discov- endocervix with frequent pyloric gland metaplasia. Occasionally,
ered incidentally in hysterectomy specimens. The patients reactive atypia of the endocervical cells and mitoses are seen, but
range in age from 22 to 48 (mean 37) years. no significant cytological atypia is identified.
PATHOLOGICAL FEATURES (Figure 7.56) Cell morphology

The process is characterized by a proliferation of moderate-
● The columnar cells have a pale eosinophilic cytoplasm,
sized, evenly spaced, differentiated endocervical glands within and show a morphological resemblance to pyloric glands
the inner one-third of the cervical wall, sharply demarcated of the stomach.
from the underlying cervical stroma. Reactive atypia is seen
in some cases, but significant cytological atypia is absent. Special techniques
A marked inflammatory response is often present. ● The cells contain periodic acid–Schiff (PAS)-positive
neutral mucin
Differential diagnosis ● They show immunostaining for M-GGMC-1, a monoclonal
● The main consideration in differential diagnosis is minimal antibody which can recognize pyloric gland-type mucin
deviation adenocarcinoma ‘adenoma malignum’. ● The cells are CEA-negative
Differential diagnosis a few chromocenters. Nuclear crowding can occasionally be seen,

● Minimal deviation adenocarcinoma of the endocervical but mitotic activity is absent.
type ‘adenoma malignum’. Mesonephric hyperplasia forms larger collections (4–25 mm
in the greatest dimension) of tubules and ducts that are arranged
in a lobular or diffuse pattern. The lining cells are columnar or
MESONEPHRIC REMNANTS AND MESONEPHRIC cuboidal and occasionally pseudostratified, with coarse chro-
HYPERPLASIA OF THE UTERINE CERVIX matin pattern reminiscent of endometrial cells. Mitotic figures
can be seen, but less than 1 in 10 HPF. Psammoma bodies may
be seen.
CLINICAL FEATURES Lobular mesonephric hyperplasia is characterized by the pres-
Mesonephric (wolffian) duct remnants are identified in up to ence of a moderate or large number of clustered mesonephric
22% of adult uterine cervices; however, neoplasms derived from tubules, with or without a centrally placed duct. The lobules are
mesonephric remnants only rarely involve the female genital usually large, irregularly shaped, loosely organized and randomly
tract. There are two distinct areas of the wolffian system: (i) an scattered within the cervical stroma. The tubules are of variable
upper zone that includes the rete ovarii; and (ii) a lower zone size and shape; some are cystically dilated and may contain small
encompassing mesonephric derivatives of the cervix and vagina. papillary tufts or focal bridging by proliferating epithelial cells.
Tumors arising in these locations are generally distinct morpho- Diffuse mesonephric hyperplasia is characterized by non-
logically. Female adnexal tumors of probable wolffian origin typ- clustered diffuse distribution of mesonephric tubules, with or
ically arise along the upper zone of the wolffian duct, whereas without centrally placed ducts. The process may not only be
mesonephric adenocarcinomas and the recently described malig- restricted to the lateral wells of the cervix, it may be seen in
nant mesonephric mixed tumor arise from the lower zone. multiple sections, deep to the resection margins and up to a few
Mesonephric duct hyperplasia is a benign lesion which is millimeters from the endocervical surface epithelium.
almost always discovered incidentally in a cone biopsy or hys- Mesonephric ductal hyperplasia is characterized by the pres-
terectomy specimens. The lesion may rarely present with ence of papillary proliferations of the large ducts within a focus
abnormal glandular cells in cervical smears. Hyperplasia of of mesonephric remnants.
mesonephric duct remnants has been described in the prostate Additional features that can be seen include: focal tubular or
and periprostatic tissue. This should not be confused with pro- glandular crowding with or without cytological atypia; colloid
static carcinoma. depletion; cystic change; endometrioid metaplasia; retiform pat-
tern; and the presence of intracytoplasmic lipofuscin pigment.
Mesonephric remnants are characterized by the presence of one
Mesonephric duct hyperplasia
or more small collections (largest 6 mm) of benign-looking,
rounded or irregularly shaped tubules, some of which contain ● Clear cell adenocarcinoma: this is often associated with a
colloid-like eosinophilic secretion. These are often seen grouped history of intrauterine DES exposure, has a distinctive
around a large, branched central duct. The adjacent stroma is tubulopapillary structure, and solid patterns and clear and
either normal, or slightly hypercellular or sclerotic. The lining hobnailed cells
cells are cuboidal, with scant pale eosinophilic or clear cytoplasm, ● Minimal deviation adenocarcinomas
and the nuclei are round or ovoid with powdery chromatin and ● Mesonephric adenocarcinoma: the tubular pattern of
mesonephric adenocarcinoma may closely resemble the
diffuse form of florid mesonephric hyperplasia owing to
the often inconspicuous stromal response in the former
and the pseudoinfiltrative pattern of the latter. Helpful
features supporting a diagnosis of adenocarcinoma include
the presence of other morphological patterns of
mesonephric adenocarcinoma (e.g. solid or ductal),
lymph-vascular space invasion, nuclear atypia, mitotic
activity exceeding one mitosis per 10 HPFs, and necrotic
luminal debris. Moreover, mesonephric hyperplasia is nearly
always an incidental microscopic finding, whereas patients
with mesonephric adenocarcinoma are more likely to be
symptomatic and have a grossly apparent lesion
● Endocervical adenocarcinoma
● Endometrial adenocarcinoma
Special techniques
Figure 7.57 Mesonephric duct remnant: clusters of round or
oval-shaped glandular structures lined by cuboidal epithelium ● Mesonephric structures lack mucin content, and therefore
and containing colloid-like material. are negative when stained with Alcian blue.
● PAS highlights the basement membrane and the colloid-

like material.
● The cells are CK7-, EMA- and CD15-positive, but CK20-,
estrogen receptor-, progesterone receptor- and CEA-negative.
● CD10 is conspicuously expressed in mesonephric remnants
and tumors, and may be useful in defining specifically
tumors with mesonephric differentiation.
MICROGLANDULAR HYPERPLASIA OF THE

CERVIX
CLINICAL FEATURES
Microglandular hyperplasia is a benign proliferative lesion of
the cervix, which is often related to progesterone stimulation
(e.g. oral contraceptive pill) and, less commonly, pregnancy.
Occasionally, it is seen in patients receiving estrogens or even in
those receiving no hormonal medication. It is usually seen in
premenopausal women, but also occurs sometimes in post-
menopausal women. The lesion most often resembles a cervical
polyp, and patients may complain of postcoital bleeding or spot-
ting. In over 25% of cases the lesion is found as an incidental
microscopic feature in cone biopsies or hysterectomy specimens.

Microglandular hyperplasia may show a variety of histological
appearances:
● The tubular pattern: this is the most common type,
consisting of one or more foci of tightly packed tubules

or glands of variable size and shape, and containing
eosinophilic or basophilic secretion. They are separated
by inflamed, variably hyalinized, fibrosed or edematous
stroma. Cystic dilatation of intercellular spaces imparts a
vacuolated appearance.
● The reticular pattern: this is less common, consisting of a
more spindle-shaped population of cells in an edematous

stroma.
Figures 7.59–7.61 Reticulated microglandular hyperplasia of

the cervix. Numerous variably sized, thin-walled glandular spaces
separated by edematous, dissociated immature squamous cells.
Some of the rounded spaces contain eosinophilic mucinous droplets.
● The solid pattern: this consists of sheets of cells;

Figure 7.58 Microglandular hyperplasia of the cervix.There are some of which exhibit signet ring morphology,
small glandular structures separated by cellular stroma occupied by interspersed by occasional small tubules or
proliferating reserve cells and inflammatory cells. glands.
● The trabecular pattern: this is a rare type, the cells being

arranged in cords or trabeculae.
● Pseudoinfiltrative pattern: this is characterized by the
presence of small nests or large aggregates of cells
irregularly distributed in a myxoid stroma.
Combinations of the above patterns may also be seen.

● Atypical microglandular hyperplasia: this may consist of
any of the above patterns (most commonly the latter
three), and is defined by the presence of significant
cytological atypia and mitotic activity.
Immature squamous metaplasia and reserve cell hyperplasia

are often seen in association with microglandular hyperplasia.
Cell morphology
● The lining cells are uniform, flat or cuboidal with small
uniform nuclei and faintly basophilic granular
cytoplasm.
● Subnuclear vacuolation may be seen.
● Signet ring-type vacuolation is often present.
● Rarely, the cells have a hobnailed pattern with abundant
eosinophilic cytoplasm.
● They lack cellular atypia and mitotic figures, except in
cases of atypical microglandular hyperplasia.
● Well-differentiated endocervical adenocarcinoma
● Endometrial carcinoma implants, especially the
microglandular subtype
● Mesonephric duct remnants
● Clear cell adenocarcinoma
Figures 7.62 and 7.63 Prolapsed Fallopian tube: inflamed, loose
● Microglandular variant of endometrial carcinoma papillae lined by tubal epithelium with ciliated cells (indicated by the
(pathologists need to be cautious about diagnosing arrow in Figure 7.63).
microglandular hyperplasia when dealing with endometrial
biopsy of postmenopausal women)
Special techniques vaginal vault. The finger-like papillae can be mistaken for a
papillary tumor of cervical origin. The cells lining the papillae
● The cells contain a small amount of mucin
are those of normal Fallopian tube. Ciliated cells are often seen.
● They lack cytoplasmic glycogen
On rare occasions, prolapse of the Fallopian tube is associated
● They are CEA-negative, in contrast to most
with an exuberant angiomyofibroblastic stromal response with
endocervical adenocarcinomas which are
richly vascularized stroma arranged in a retiform pattern and
CEA-positive
mildly atypical glandular inclusions, which have the morphology
of tubal epithelium. The stroma of the lesion is composed of
PROLAPSED FALLOPIAN TUBE either thin bipolar cells with tapered nuclei and stellate cells with
minimal amount of cytoplasm or small epithelioid-looking cells
with eosinophilic cytoplasm. If the tubal glandular component
CLINICAL FEATURES is overlooked, these tumors might be erroneously diagnosed as
Prolapsed Fallopian tube occurs as a result of previous vaginal mesenchymal lesions of the vagina, such as vaginal fibroepithe-
or abdominal hysterectomy, and presents as vaginal vault gran- lial polyp, angiomyofibroblastoma, aggressive angiomyxoma,
ulation tissue that may be mistaken as a tumor. or superficial myofibroblastoma.
PATHOLOGICAL FEATURES (Figures 7.62 and 7.63) Differential diagnosis

Prolapsed Fallopian tube is characterized by the presence of ● Papillary cervicitis
Fallopian tube epithelium in the cervical biopsy or a biopsy of ● Villoglandular adenocarcinoma
changes (somewhat reminiscent of the early buds of micro-

EPITHELIAL TUMORS: GLANDULAR LESIONS, invasive squamous carcinoma) and thinning and attenuation or
MALIGNANT stretching of part of the gland wall in an ‘elastic band-like’
manner. These are often accompanied by florid inflammatory
response and loosening of the periglandular connective tissue.
ADENOCARCINOMA, COMMON VARIANTS
Mucinous endocervical adenocarcinoma (Figures 7.66–7.68)
CLINICAL FEATURES Mucinous endocervical adenocarcinoma is the most common

subtype and tends to be well differentiated. It shows epithelium
Adenocarcinomas constitute about 25% of all cervical which maintains some of the features of normal endocervical
carcinomas. crypts, with obvious mucin production and elongated, crowded
Invasive adenocarcinomas of the cervix detected by screening abnormal nuclei, but the glandular architecture is clearly abnor-
are found at an earlier stage, and are associated with lower mal, showing crowding, cribriform pattern, complex glands and
disease-specific mortality than those not detected by screening. papillary projections.
Microinvasive adenocarcinoma represents the earliest stage
of invasive adenocarcinoma, and is classified as the squamous Mucinous intestinal adenocarcinoma
counterpart. Unlike microinvasive squamous carcinoma, the Mucinous intestinal adenocarcinoma shows cells similar to those
treatment of this tumor is still controversial, due mainly to a of colorectal adenocarcinoma with numerous goblet cells with
lack of sufficient information on its natural history. Until more or without Paneth or argentaffin cells. The intestinal features may
information is obtained on the disease progress, each case needs be seen focally or diffusely within the lesion. Colloid or signet
to be handled individually. It has been shown recently that early ring cell carcinomas may also be seen in the cervix, often in
invasive cervical adenocarcinoma with a depth of invasion
⭐3 mm and a horizontal spread ⭐7 mm has little potential for
nodal metastasis or recurrence. It seems possible that the FIGO
definition (1994) of early cervical cancer may be applicable in
its present form to early cervical adenocarcinoma.
FIGO classification of endocervical adenocarcinomas:
● Microinvasive (early invasive)
● Mucinous (endocervical type)
● Mucinous (intestinal type)
Colloid or signet ring cell carcinoma
● Endometrioid
Microinvasive (early invasive) (Figures 7.64 and 7.65)

Features suggestive of an early invasion are the presence of back-
to-back arrangement of the involved glands, cribriform pat- Figure 7.65 A focus of microinvasive adenocarcinoma, with cells
tern, or solid nests with irregular borders. Other useful features at the invasive front (arrows) appearing more squamoid.
are the presence of localized areas of squamoid cytoplasmic
Figure 7.66 Endocervical-type adenocarcinoma: mucin secretion

Figure 7.64 A focus of microinvasive adenocarcinoma. towards the lumen with nuclear stratification.
● Villoglandular
● Adenoma malignum (minimal deviation)
Clear cell mesonephroid
Clear cell mesonephroid is similar to its ovarian, endometrial
and vaginal counterparts. It usually arises in young women and
even children.
Serous papillary adenocarcinoma
Serous papillary adenocarcinoma of the cervix is extremely
rare, and resembles microscopically its counterparts elsewhere
in the female genital tract and peritoneum. Because of its rarity
in the cervix, pathologists need to rule out the possibility of the
more commonly encountered carcinoma of uterine or ovarian
origin before making a definitive diagnosis of primary cervical
origin. Uterine and cervical serous papillary carcinoma have
been considered as aggressive tumors typically with a high
Figure 7.67 Well-differentiated endocervical subtype of
relapse rate, early and deep myometrial invasion and frequent
adenocarcinoma.
lympho-vascular space involvement.
Villoglandular papillary adenocarcinoma (Figures 7.69 and 7.70)
Villoglandular papillary adenocarcinoma of the uterine cervix
is a distinct subtype of cervical adenocarcinoma characterized
Figure 7.68 Well-differentiated endocervical subtype of

adenocarcinoma.To the left, there is thinning of the abnormal glands;
this feature is often seen in invasive adenocarcinoma.To the right,
one abnormal gland is seen in between thickened wall vessels,
usually indicative of deeper location.
association with intestinal and less often endocervical mucinous

carcinoma.
Endometrioid adenocarcinoma
Endometrioid adenocarcinoma is reminiscent of classic endo-
metrial carcinoma, and accounts for 30% of cervical adeno-
carcinoma. The malignant epithelium shows stratification of
oval nuclei, with little or no intracellular mucin. This type of car-
cinoma is usually well-differentiated and reveals a mixed glan-
dular and papillary pattern.
ADENOCARCINOMA, LESS COMMON VARIANTS
FIGO classification of endocervical adenocarcinomas,

less common variants:
Figures 7.69 and 7.70 Villoglandular adenocarcinoma of the
● Clear cell cervix: finger-like villous structures with inflamed and vascular cores,
● Serous lined by endometrial-type neoplastic epithelium.
by exophytic proliferation, papillary architecture, and mild to adenocarcinoma of the uterine cervix. It shows deceptively
moderate cellular atypia. It may have superficial stromal inva- benign histological features that cause problems in interpreta-
sion, or be associated with other lesions such as in-situ or inva- tion. These tumors occur in women aged between 34 and 42
sive adenocarcinoma or in-situ or invasive squamous cell years. The lesions are often discovered incidentally in hysterec-
carcinoma. Clinically, it affects a younger age group (25–45 tomy or cone-biopsy specimens, or discovered following detec-
years), and has an excellent prognosis. For selected cases, a con- tion of abnormal glandular cells on a cervical smear. HPV has
servative surgical approach (cervical conization) is considered been reported to be associated with MDA. MDA has been
possible. However on rare occasion, the tumor may spread divided into two histological subtypes.
beyond the cervix, suggesting caution in the management and The endocervical subtype (Figures 7.71–7.74) has been des-
follow-up of this clinicopathological entity. This tumor is often ignated ‘adenoma malignum’, and is sometimes associated with
underdiagnosed as villoglandular adenoma – an entity that does Peutz–Jeghers syndrome. In less than half of the cases the diag-
not exist in the cervix. It may also be incorrectly diagnosed when nosis is made on the basis of the examination of a cervical
villoglandular adenocarcinoma of endometrial origin presents in biopsy specimen, endocervical curettage specimen, or both.
cervical biopsy, and labeled as cervical villoglandular carcinoma. Sometimes up to four biopsies are performed before the diag-
nosis is established. In more than 50% of patients, the diagno-
Minimal deviation adenocarcinoma (Figures 7.71–7.76) sis is not made until the time of operation or pathological
Minimal deviation adenocarcinoma (adenoma malignum; MDA) examination of a hysterectomy specimen. This tumor has
is a rare pathological type of an extremely well-differentiated been reported in association with ovarian mucinous tumors.
Figures 7.71 and 7.72 Minimal deviation ‘endocervical-type’ adenocarcinoma of the cervix. Numerous bland endocervical glands, with
slight architectural abnormality, but no stromal reaction.
Figures 7.73 and 7.74 Minimal deviation ‘endocervical-type’ adenocarcinoma of the cervix. Bland endocervical glands with no stromal
reaction.Thinning and attenuation of some glands (Figure 7.74) is indicative of invasion. Note the horizontal arrangement of some of the
nuclei within the attenuated gland.
Figures 7.75 and 7.76 Minimal deviation ‘endometrioid-type’ adenocarcinoma of the cervix. Isolated bland-looking glands situated deep into
the cervical stroma with no inflammatory or desmoplastic response.The presence of a large, thickened-wall vessel is an indication of a deep
location. One mitotic figure is shown in Figure 7.76 (arrow).
The prognosis is considered poor despite radical therapy, proliferation include the number of glands and their distri-
although some reports suggest better prognosis than that for bution, the shapes of the glands, their presence deep in the
ordinary cervical adenocarcinoma. On gross examination, the cervical wall and adjacent to large muscular vessels, the focal
cervix usually appears firm or indurated. Histologically, the presence of a stromal reaction, and moderate cytological atyp-
glands are often irregular in size and shape, and lined predom- icality with occasional mitotic figures. Isolated glands with
inantly by mucin-containing columnar epithelial cells with squamoid features or thinning of their walls are often seen.
basal nuclei. The tumors typically exhibit deep invasion of the The latter features are usually indicative of actual invasion.
cervical wall, and a portion of the infiltrating tumor is often The presence of these features in a suspicious lesion should
associated with a stromal response. Minor foci of tumor with therefore raise the possibility of invasive carcinoma. An
a less well-differentiated appearance are present in over 50% of immunohistochemical study often shows only focal reactivity
tumors. Mixed components of minimal deviation and less well- of neoplastic glands for CEA, which would limit its diagnostic
differentiated endometrioid carcinoma have been documented. use in small biopsy specimens. This variant has a very good
The endocervical variant of MDA lacks expression of the char- prognosis.
acteristic mullerian-type substances such as estrogen receptor Microcystic endocervical adenocarcinoma has recently been
(ER), progesterone receptor (PR), and CA125, and a propor- reported which mimics benign process.
tion of its cells contain gastric epithelial substances, comprising
gastric mucin and carcinoembryonic antigen (CEA). It has been
shown that immunostaining for gastric mucin with a mono- ADENOCARCINOMA, RARE VARIANTS
clonal antibody HIK1083 and p53 may be useful in the diag-
nosis of this variant of MDA. Expression of gastric mucin is ADENOID CYSTIC CARCINOMA
especially seen in the well-differentiated areas, and p53 stains
some of the nuclei in the less well-differentiated glands. These See Chapter 15, Carcinomas (p. 1196).
two markers may be related to the histological differentiation Adenoid cystic carcinoma of the cervix is a very rare tumor
of MDA, and detection of p53 over-expression may help to which occurs in older women (mean age 70 years), but is not
identify critical steps in the local progression of MDA. of myoepithelial origin as are those of other locations.
Differential diagnosis of this tumor subtype of MDA includes
normal endocervical glands, endocervicosis, lobular endocervi- ADENOSQUAMOUS CARCINOMA (Figures 7.77–7.79)
cal glandular hyperplasia, hyperplasia of mesonephric duct rem-
See Chapter 15, Carcinomas (p. 1196).
nants, diffuse laminar endocervical glandular hyperplasia, and
deep Nabothian cysts.
The endometrioid subtype (Figures 7.75–7.76) of MDA BASALOID CARCINOMA OF THE UTERINE CERVIX
shows widely spaced glands that are distributed haphazardly (ADENOID BASAL CARCINOMA)
within the cervical stroma and are morphologically indistin-
guishable from normal proliferative phase endometrial glands Clinical features
exhibiting cilia and apical snouts in the majority of neoplasms. Adenoid basal carcinoma/epithelioma of the uterine cervix is a
Features that indicate the neoplastic nature of the glandular rare tumor of obscure but possible ‘reserve cell’ origin. The
tumor is usually asymptomatic, occurs in postmenopausal contains integrated HPV type 16 DNA. Due to the excellent
women, and may be associated with adenoid basal hyperplasia behaviors of this tumor, the term ‘adenoid basal epithelioma’
of the cervix. Adenoid basal carcinoma is usually associated with has been proposed to replace adenoid basal carcinoma and
high-grade squamous intraepithelial lesions (HSIL) or CIN and adenoid basal hyperplasia, because it better describes the clini-
copathological features of these distinctive lesions and their
excellent prognosis, and may also reduce the likelihood of
unnecessarily aggressive treatment.
Adenoid basal carcinoma of the uterine cervix, on rare occa-
sions, is seen coexisting with carcinosarcoma.
Pathological features (Figures 7.80 and 7.81)

This condition is characterized by the presence of nests or cords
of small basaloid cells with prominent peripheral palisading of
cells and no significant stromal reaction. An associated neoplas-
tic squamous lesion is present in 92% of patients, including high-
grade CIN and microinvasive squamous cell carcinoma. Foci of
squamous differentiation in some portions of the small nests
are sometimes seen. One case has recently been observed which
Figure 7.77 Adenosquamous carcinoma of the cervix: glandular

features admixed with squamous features.
Figure 7.80 Adenoid basal carcinoma of the cervix: basaloid nests

present deep into the cervical stroma with no stromal response.
Figure 7.81 Adenoid basal carcinoma of the cervix: sharply

Figures 7.78 and 7.79 An early invasive adenosquamous demarcated basaloid nests with some suggestion towards glandular
carcinoma associated with a superficial squamous component. differentiation. Mitotic figures are encircled.
consisted predominantly of squamous nests. Occasionally, the MALIGNANT MIXED MULLERIAN TUMOR
tumor cells are arranged in slender cords that penetrate deep into (CARCINOSARCOMA/SARCOMATOID CARCINOMA)
the stroma and are surrounded by myxoid matrix resembling
morphea-type basal cell carcinoma of the skin. Cervical carcinosarcoma/malignant mixed mullerian tumors
(MMMT) differ significantly from their counterparts in the uter-
Cell morphology ine corpus in terms of their histological features and the extent of
disease at presentation. The tumors are more commonly confined
● The tumor cells are usually small and uniform, with scanty
to the uterus at presentation, and may have a better prognosis
cytoplasm and dark, oval nuclei with no conspicuous
than MMMTs of the uterine corpus. An additional point of dis-
nucleoli.
tinction is that the neoplastic epithelial component is frequently
● The acini are lined by a single layer of cuboidal or
non-glandular in cervical MMMTs, whereas MMMTs of the
columnar basaloid, vacuolated, or mucin-producing
uterine corpus almost invariably contain an adenocarcinomatous
epithelial cells.
epithelial element. The epithelial component of cervical MMMTs
● The squamous cells seen within some of the nests are often
may be represented by squamous cell carcinoma, adenosquamous
uniform and cytologically bland, and only occasionally
carcinoma, basaloid carcinoma, adenocarcinoma, adenoid cystic
atypical.
carcinoma, or adenoid basal carcinoma or a combination of more
● Mitotic figures are usually sparse.
than one epithelial pattern.
Several reported cases have shown an overlying high-grade
squamous intraepithelial neoplasia, and some had documented
● Adenoid cystic carcinoma: this is usually associated with HPV implication in the histogenesis of certain tumors.
undifferentiated areas, shows necrosis and high mitotic
figures. It also shows type IV collagen and laminin
MESONEPHRIC ADENOCARCINOMAS
staining, in relation to the extracellular basement
membrane-like material. Clinical features
● Basaloid squamous cell carcinoma.
Mesonephric adenocarcinoma is very rare, usually originates
● Adenosquamous carcinoma.
deep in the wall of the cervix, and is often symptomatic. It is
● Undifferentiated small cell carcinoma.
sometimes present as a cervical mass or with postcoital or post-
● Carcinoid tumor.
menopausal bleeding, and has a predilection for pelvic recur-
rence. This lesion requires surgical treatment.
Special techniques
● The cells show focal or diffuse positivity for
Pathological features
cytokeratin, and usually negativity for S-100
protein. Mesonephric adenocarcinoma often shows intermixed, mor-
● The acini are highlighted by EMA and CEA phological patterns including tubular, ductal (resembling
positivity. endometrioid adenocarcinoma), solid, retiform, and sex cord-
● p53 gene alterations are common in this tumor. like. Focal papillary tufting is frequent. The glands are lined by
stratified columnar or cuboidal epithelial cells with varying
degrees of cytological atypia and may contain colloid-like
GLASSY CELL CARCINOMA eosinophilic secretions. The malignant tubules may blend with
Glassy cell carcinoma forms 1% of all cervical carcinomas, areas of diffuse mesonephric duct hyperplasia, or may entrap
and occurs in slightly younger women (mean age 30–35 years). mesonephric remnants. Adjacent stroma usually lacks desmo-
It usually has a poor response to radiotherapy, and a worse prog- plastic response. Perineural invasion can be seen. Malignant
nosis than the usual types of adenocarcinoma and squamous spindle cell component – even with foci of osteosarcomatous
cell carcinoma. This tumor is composed of cells with a large, differentiation – may be in association with mesonephric carci-
round to oval nucleus containing one or multiple prominent noma (malignant mesonephric mixed tumor). Another pattern
nucleoli, finely vacuolated eosinophilic to amphophilic cyto- is the papillary villoglandular pattern associated with exo-
plasm, and distinct cell borders. These cells occur in sheets and phytic growth into the endocervical canal. Papillary luminal
cords, with fibrovascular septae presenting a mixed inflamma- infoldings are observed, at least focally, in the ductal compo-
tory infiltrate. In addition to squamous differentiation, glassy nent of most neoplasms. Solid sheets of cells within which are
cell carcinoma sporadically produced intestinal-type mucin. gland-like arrangements are another pattern. These tumors
Glassy cell carcinoma may originate from multipotential stem may have an infiltrative or nodular growth pattern with a
or reserve cells that undergo early squamous differentiation. pushing margin.
The presence of HPV 18 might stimulate biphasic squamous
and glandular differentiation. Glassy cell carcinoma has a pro- Differential diagnosis
file of cytokeratin expression similar to that of reserve cells or ● Mesonephric hyperplasia: the tubular pattern of
immature squamous cells of the cervix. ER and PR positivity is mesonephric adenocarcinoma may closely resemble the
found in 22% and 11% of cases, respectively, suggesting that diffuse form of florid mesonephric hyperplasia, owing to
this tumor might be hormonally responsive. the often inconspicuous stromal response in the former
and the pseudoinfiltrative pattern of the latter. Helpful

features supporting a diagnosis of adenocarcinoma include
the presence of other morphological patterns of
mesonephric adenocarcinoma (e.g. solid or ductal),
lymph-vascular space invasion, nuclear atypia, mitotic
activity exceeding one mitosis per 10 HPFs, and necrotic
luminal debris. Moreover, mesonephric hyperplasia is
nearly always an incidental microscopic finding, whereas
patients with mesonephric adenocarcinoma are more likely
to be symptomatic and have a grossly apparent lesion.
● Endocervical adenocarcinoma.
● Endometrial adenocarcinoma.
Special techniques
● Mesonephric structures lack mucin content, and therefore
are negative when stained with Alcian blue.
● PAS highlights the basement membrane and the colloid- Figure 7.82 Mixed CINIII and CGIN: CGIN to the left, CINIII to
like material. the right, and mixed feature at the bottom.
● The cells are CK7-, EMA- and CD15-positive, and CK20-,
estrogen receptor-, progesterone receptor- and CEA-negative.
● CD10 is conspicuously expressed in mesonephric
remnants and tumors, and may be useful in specifically
defining tumors with mesonephric differentiation.
CERVICAL INTRAEPITHELIAL GLANDULAR

NEOPLASIA (CGIN)
CLINICAL FEATURES
Cervical intraepithelial glandular neoplasia (CGIN) is often dis-
covered in loop excisions from CIN. There are no firm
criteria for their colposcopic appearances, and cytological exam-
ination is still less sensitive in detecting early glandular neoplasia.
Mixed lesions (glandular neoplasia in association with CIN)
have been reported in up to 69% of cases.
The distribution of CGIN is most commonly unifocal, but
multifocal and circumferential distribution may also be seen. Figure 7.83 Mixed lesion: CGIN associated with nests of
neoplastic squamous epithelium.
Midline disease – either CGIN or squamous CIN, or both – is
very common. Therefore, examining the midline blocks from
hysterectomy specimens will result in the identification of
CGIN lesions in over 90% of patients, either because the CGIN
lesion is present in the midline or because an associated squa-
mous CIN lesion will be identified, which will result in the
examination of the entire cervix, with the consequent identifi-
cation of the CGIN lesion.
CGIN is treated by loop excision with follow-up cytology
and colposcopy.
For practical purposes, CGIN is classified as low- and high-
grade lesions. High-grade lesions are almost certainly precursors
of invasive adenocarcinoma, while the premalignant nature of
the low-grade lesions is questionable.

CGIN is characterized by varying degrees of architectural and
cytological abnormalities of the involved crypts. Architecturally,
the abnormal crypts tend to aggregate together in small clusters
or lobules. Cytologically, there is nuclear enlargement and Figure 7.84 Mixed lesion: CGIN in close association with CINIII.
Figure 7.85 High-grade CGIN. Abrupt transformation of Figure 7.88 High-grade CGIN. Endocervical crypt shows
normal endocervical epithelium into stratified and hyperchromatic cribriform pattern, nuclear stratification, mitoses, and apoptosis.
epithelium.
Figure 7.86 High-grade CGIN. Endocervical crypt shows nuclear Figure 7.89 Tuboendometrial metaplasia in the cervix: abrupt
enlargement, crowding and stratification, with mitotic figures towards transformation of endometrial-type epithelium (right lower arrow).
the lumen. Ciliated epithelium is clearly seen in the upper glands (upper left arrow).
Figure 7.87 Low-grade CGIN. Abrupt transformation of normal Figure 7.90 Viral wart changes in endocervical epithelium.
endocervical epithelium into epithelium showing nuclear Multinucleated, hyperchromatic nuclei involving part of the
enlargement and crowding and a few mitotic figures. endocervical gland, may be misinterpreted as CGIN.
● Mesonephric hyperplasia
● Tuboendometrial metaplasia (Figure 7.89)
● Endometriosis
● Arias–Stella reaction
● Various infectious and reactive atypia (Figure 7.90)
● Ectopic prostatic tissue
● Endocervical involvement in cases of endometrial
carcinomas (endometrial cancer cells usually spread to the
cervix by luminal surface contiguity or by implantation
more than by deep tissue plains or via lymphatic
channels. This may produce a lesion similar to in-situ
change. The other change that can be seen in cases of
endometrial carcinoma is the presence of atypical
reserve cell hyperplasia with micropapillary pattern,
features that can be misinterpreted as being
neoplastic)
Figure 7.91 Postmenopausal basaloid reserve change: this is common ● Postmenopausal basaloid change: this can be seen in a
in the postmenopausal cervix, and may be mistaken for CGIN. proportion of normal cervixes of postmenopausal women
(personal observation; Figure 7.91).
hyperchromasia, depletion of cytoplasmic mucin, stratification

or pseudostratification of cells, and presence of mitotic figures Special techniques
and apoptotic bodies. Mitotic figures, in the absence of any ● Dysplastic or neoplastic endocervical epithelium expresses
inflammation almost certainly mean CGIN. CGIN may affect CEA positivity.
both the surface epithelium and the underlying crypts and is ● CD44v5 has recently been shown to be a useful diagnostic
usually found adjacent to the squamocolumnar junction, or at marker of endocervical neoplasia. CGIN and cervical
the edge of CIN, invasive squamous carcinoma or invasive ade- adenocarcinoma show consistent immunostaining for
nocarcinoma. CGIN may be focal, multicentric or diffuse. CD44v5. Normal endocervical columnar cells exhibit no
The most common subtype of CGIN is the endocervical vari- reactivity, whereas the subcolumnar reserve cells are
ant, which retains some of the features of endocervical epithe- strongly positive.
lium, especially the cytoplasmic mucin. The endometrioid ● MIB-1 (a proliferative marker) shows numerous positive
subtype shows more pronounced nuclear stratification and loss of nuclei within each abnormal gland compared to the
cytoplasmic mucin, a pattern reminiscent of well-differentiated presence of only a few if any positive nuclei in normal
endometrioid carcinoma. The intestinal (enteric, colonic) form crypts.
shows mucin-rich goblet cells, with or without argyrophilic or ● Cdc6 expression is a marker for high-grade cervical
Paneth cells. squamous and glandular dysplasia and carcinoma, and is
Low-grade CGIN usually shows more cytological than archi- associated with HPV infection. The mechanistic basis of
tectural abnormality. The nuclei are elongated, ‘cigar-shaped’ the association between HPV infection and Cdc6
and hyperchromasic with abnormal chromatin pattern, but no immunopositivity remains to be determined, but may
significant loss of polarity. The abundant cytoplasmic mucin represent either up-regulation of Cdc6 expression or
often persists in low-grade lesions. The cytological abnormal- stabilization of the Cdc6 protein.
ity is usually limited to a few glands or only a small proportion ● p53 protein expression is frequent in endocervical
of the circumference of the gland. adenocarcinoma, and suggests that mutation of
High-grade CGIN usually exhibits pronounced architectural the p53 gene may be important in the evolution of
and cytological abnormalities. There is a loss of nuclear polar- some cases of endocervical adenocarcinoma. Scattered
ity, stratification, loss or great reduction of the cytoplasmic p53-positive cells may be seen in endocervical
mucin with frequent mitotic figures, some of which are abnor- adenocarcinoma in situ and in non-neoplastic
mal, together with numerous apoptotic bodies. The lobular or endocervical glandular lesions, the significance of
clustering arrangement of the abnormal glands is clearly seen which is uncertain.
in high-grade lesions. There may be papillary infoldings and ● Bcl-2 protein expression is seen in a proportion of
outpouchings. A cribriform pattern raises the suspicion of early endocervical adenocarcinomas, and may play a role
invasion. Argyrophilic cells may be seen in glandular dysplas- in the evolution of these tumors through inhibition of
tic lesions. apoptosis. Widespread positivity for bcl-2 protein is
seen in most cases of tuboendometrial metaplasia,
Differential diagnosis suggesting that this type of metaplastic epithelium
● Tunnel clusters may represent an unusually stable population
● Microglandular hyperplasia of cells.
EPITHELIAL TUMORS: SQUAMOUS LESIONS,

BENIGN
CONDYLOMA ACUMINATUM
See Chapter 12, Skin tumors (p. 845).
EPITHELIAL TUMORS: SQUAMOUS LESIONS,

MALIGNANT
CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN)
CLINICAL FEATURES
Cervical intraepithelial neoplasia (CIN) is a premalignant
lesion of cervical squamous cell carcinoma which may persist
unchanged, regress to normal or a lesser grade of CIN, or Figure 7.92 CIN1: this shows loss of polarity of the cells, with
progress to a higher grade of CIN or invasive carcinoma. nuclear enlargement.
Rates of progression correlate directly with the CIN grade.
HPV detection is a significant determinant of CIN, regardless
of grade. Accumulating evidence suggests that high-risk
HPV DNA (HPV 16 and 18) detection and persistence are
predictive of CINI progressing to CINII/III. Other possibilities
are persistence of a high-risk HPV variant, altered cell immu-
nity, and cigarette and oral contraceptive use. Factors that
accurately predicted residual dysplasia in post-loop conization
hysterectomy specimens were found in a large study to be
cytological reports, increasing age, severity of disease, gland
involvement, and endocervical curettage. The presence or
absence of dysplasia in the loop conization, ectocervical mar-
gin and endocervical margin was not predictive of residual
dysplasia.
CIN is traditionally divided into three grades: CINI, CINII,
and CINIII. The Bethesda system of classification has proposed
two grades: (i) The low-grade lesions, which include CINI
(mild dysplasia) and flat or exophytic condyloma; and (ii) the
high-grade intraepithelial lesions, which include CINII, CINIII, Figure 7.93 CIN1 in thin epithelium: relatively thin epithelium showing
and carcinoma in situ. CIN is currently treated by laser, cold loss of nuclear polarity limited to the lower part of the epithelium.
coagulation or loop excisions of cervix (LLETZ). LLETZ is
almost identical in terms of its therapeutic efficacy to hysterec-
tomy, and should be accepted as a standard treatment for PATHOLOGICAL FEATURES (Figures 7.92–7.102)
CINIII.
Cervical cytology is the most important tool in detecting the The histological diagnosis of CIN is a highly subjective and
preinvasive stages of cervical cancers, and is also extensively arbitrary exercise. Inter- and intra-observer variations among
used as a follow-up measure to detect recurrent abnormality in histopathologists are widely recognized, especially in deciding
patients who have undergone treatment for various stages of whether a lesion is CINI or another reactive non-neoplastic
epithelial neoplasia. There has been shown to be a lack of cor- condition.
relation between cytological and histological diagnosis of CIN,
and there is a tendency for cytology to underestimate the sever- CINI
ity of histological lesions. These show abnormal nuclei throughout the full thickness of the
CIN may rarely extend into and involve mesonephric duct epithelium with lack of cytoplasmic maturation and stratification
remnants, resulting in an erroneous diagnosis of invasive squa- limited to the lower third of the epithelium. Pleomorphic nuclei
mous cell carcinoma. may also be seen. Features of viral wart change may be present
Figure 7.96 CINIII. Full-thickness dysplasia including crowded

nuclei, mitotic figures and lack of any cytoplasmic maturation.
Figure 7.94 Immature metaplasia: this may be mistaken for CIN.
Figure 7.97 CINIII with features suggestive of impending invasion:

involvement of endocervical crypts; some of which are expanded,
with central dyskeratotic necrosis.
Figure 7.95 Immature metaplasia: MIB-1 illustrates the staining of

nuclei at the basal cell layers only.
(cytoplasmic clearing, nuclear irregularity, and multinucleation).

Mitotic figures – some of which are abnormal – are usually lim-
ited to the lower third of the epithelium.
CINII
These show abnormal nuclei throughout the full thickness of the
epithelium, with lack of cytoplasmic maturation and stratification Figure 7.98 CINIII expanding: endocervical crypt exhibits central
limited to the lower two-thirds of the epithelium. Pleomorphic dyskeratotic necrosis.
Figures 7.99 and 7.100 Viral wart change may be confused with CIN.
Figures 7.101 and 7.102 Immature metaplasia with inflammation may be mistaken as CIN1. MIB-1 is useful in showing MIB-1-positive
clustering of cells in the upper layers of the epithelium in CIN.
nuclei may also be seen. Features of viral wart change may be CINIII with features of impending invasion
present (cytoplasmic clearing, nuclear irregularity, and multi- This shows usually extensive CINIII involving both surface
nucleation). Mitotic figures – some of which are abnormal – are epithelium and deep endocervical crypts. The lesion also
commonly seen at the lower two-thirds of the epithelium. appears to expand the involved crypts often with evidence of
central comedo-type necrosis and focal squamous or
CINIII eosinophilic maturation. There is usually associated pericryptal
These show abnormal nuclei throughout the full thickness of inflammatory response and pericryptal fibroplasia. Deeper
the epithelium, with lack of cytoplasmic maturation and stra- levels should always be performed on such lesions to rule out
tification throughout the full thickness of the epithelium. foci of microinvasion.
Pleomorphic nuclei may also be seen. Features of viral wart CINIII lesions are usually associated with increased sub-
change may be present (cytoplasmic clearing, nuclear irregular- mucosal vasculature.
ity, and multinucleation). Mitotic figures – some of which
are abnormal – are commonly seen at all levels of the epithe- CIN in thin epithelium (upgradeable CIN)
lium. CINIII lesions often extend into superficial endocervical The epithelium is made up of a few cell layers only, but the cells
crypts. exhibit high nuclear abnormality.
CIN lesions often exhibit koilocytotic atypia (variation in detected at a very early stage in which 87% are ⬍2 mm in size
nuclear size and shape, wrinkling of nuclei, polychromasia, and (unpublished personal experience). This obviously reflects
binucleation with perinuclear halo). the successes of cytology screening programs in detecting and
curing earlier stages of squamous neoplasia. MICA far more
Differential diagnosis often originates from the base of the endocervical crypts than
● Epithelial changes of uncertain significance: nuclear from the surface epithelium. The definition of MICA has been
enlargement, a minor degree of nuclear pleomorphism, controversial. The criteria used for the diagnosis of MICA are
normal mitoses with koilocytosis-associated features. those defined by the Society of Gynaecological Oncologists
● Basal cell hyperplasia: replication of basal layers with nuclear (SGO) in 1985: ‘MICA is defined as a lesion that invades the
enlargement but no pleomorphism or hyperchromasia. stroma to a depth of 3 mm or less and in which there is no evi-
● Basal cell hyperplasia with remarkable nuclear dence of lymphatic space invasion’. We use SGO classification
abnormality but normal maturation of the upper cell rather than FIGO because a literature review shows a statisti-
layers (excessive differentiation). This may in fact represent cally different frequency of lymph node metastasis (0.7% ver-
true high-grade CIN. sus 4.3%) for tumors 0.1–3.0 mm and for tumors 3.1–5 mm in
● Immature squamous metaplasia: reserve cell hyperplasia, depth. Therefore, a small number of women with FIGO stage
early squamous differentiation, variable polarity and nuclear 1a2 (up to 5 mm in depth and 7 mm in width) will have tumor
enlargement often with persistence of endocervical cells on extension beyond the uterus.
the surface but no nuclear pleomorphism or hyperplasia. MICA is usually treated by loop excision with clear margins,
● Inflammatory change. or by simple hysterectomy.
● Repair: the epithelium shows poorly organized layers of
immature squamous epithelium, the nuclei lack PATHOLOGICAL FEATURES (Figures 7.103–7.108)
pleomorphism or hyperchromasia and contain prominent
nucleoli, and the underlying stroma is usually floridly The diagnosis of MICA should only be made on a loop or cone
inflamed. excisional biopsy of cervix. In the majority of cases, MICA arise
● Viral wart change: the hallmark is the presence of from CINIII with features of impending invasion (extensive
koilocytes – intermediate cells which have an atypical involvement of surface epithelium and deep endocervical crypts,
nucleus surrounded by a prominent space or halo with a luminal necrosis and intraepithelial squamous maturation).
sharp edge. The nuclei are enlarged, hyperchromatic with The invasive foci are represented by irregular tongues or buds
wrinkled borders. Other features include the presence of of epithelial cells. They usually show loss of the normal palisade-
bi- or multinucleation, and individual cell dyskeratosis. like arrangement of the basal layer. The cells are larger and
● Atrophic epithelium: usually thin epithelium consisting more differentiated, with intense cytoplasmic eosinophilia or
entirely of uniform, parabasal type cells often with mild actual keratinization. The majority of the nuclei show distinct
nuclear hyperchromasia but lacks pleomorphism. nucleoli and exhibited nuclear chromatin clearing. Inflammatory
● Postmenopausal squamous atypia: prominent perinuclear infiltrates and single dyskeratotic cells are frequently seen
halo, nuclear hyperplasia, some variation in nuclear size, among the epithelial nests.
multinucleation.
● Thermal artifact: the epithelium is smudged,
hyperchromatic, fragmented with loss of cellular and
nuclear details.
● Transitional cell metaplasia: the epithelium appears dark and
the nuclei seem crowded and positioned vertically to the
basement membrane, but there are no mitoses in abnormal
positions. ‘Umbrella’ cells are usually found on the surface.
Special techniques
● MIB-1 stain is useful in detecting ‘MIB-1 cell clusters’
(a cluster of at least two stained nearby nuclei in the upper
two-thirds of the epithelial thickness). Their presence
usually indicates CIN rather than normal, metaplastic,
or reactive cervical epithelia.
MICROINVASIVE SQUAMOUS CARCINOMA (MICA)
CLINICAL FEATURES Figure 7.103 Microinvasive squamous carcinoma. CINIII involving

and expanding endocervical glands (CINIII with concerning features)
Microinvasive squamous carcinoma (MICA) is on the increase associated with early tongues of invasion.The invasive nests tend to
(relative to the number of frankly invasive diseases), and is be more eosinophilic, and elicit a florid inflammatory response.
Figure 7.104 Microinvasive squamous carcinoma. CINIII involving and Figure 7.105 Microinvasive squamous carcinoma. Within a CINIII
expanding two endocervical glands (CINIII with concerning features) lesion, a localized area of more squamous differentiaton usually
associated with early tongues of invasion.The invasive nests tend to heralds an early invasion.
be more eosinophilic, and elicit a florid inflammatory response.
Figures 7.106 and 7.107 Viral wart in the cervix: hyperkeratosis, koilocytosis with dyskeratosis and irregular buddings.This should not be
confused with microinvasive carcinoma.
● Basal budding, especially those associated with viral wart
● CINIII involving glands with tangential cuttings
● CINIII-like invasive carcinoma is often mistaken as CINIII
● Cautary or crush artifact
● Previous biopsy site.
SQUAMOUS CARCINOMA
CLINICAL FEATURES
Invasive squamous carcinoma of the cervix is still the most com-
mon cervical cancer, and constitutes about 75% of all invasive
carcinomas. Due to the success of cervical cytology screening
programs, a large proportion of squamous cell carcinoma is of
Figure 7.108 Irregular budding of viral wart should not be the microinvasive subtype, and a curable disease. The most com-
misinterpreted as microinvasive carcinoma. mon presentations are abnormal cervical smear or postcoital or
postmenopausal bleeding. Advanced carcinoma is usually low-grade CINs, the majority of high-grade CINs and cervical
grossly apparent on speculum examination, while early stage dis- cancer contain either HPV 16 or 18. By using polymerase chain
ease may only be apparent on colposcopic examination. reaction (PCR) analysis, HPVs can be identified in all CINs and
Etiological association and possible risk factors for cervical in most cervical cancers.
carcinoma are: sexual and reproductive factors; socioeconomic
factors (education and income); viruses (e.g., herpes simplex
virus (HSV), HPV, human immunodeficiency virus (HIV) in
cervical carcinogenesis); and other factors such as smoking,
diet, oral contraceptives use and hormone use. The accumulated Frankly invasive squamous cell carcinomas of the cervix often
evidence suggests that cervical cancer is preventable, and is show extensive variation in the pattern of growth, cell type and
highly suited to primary prevention. Sexual hygiene, use of bar- degree of cellular differentiation.
rier contraceptives, and ritual circumcision can undoubtedly Large-cell, non-keratinizing carcinomas comprise two-thirds
reduce cervical cancer incidence. Education, cervical cancer of cases, and show well-defined broad, irregular masses of
screening and improvement in socioeconomic status can reduce tumor with no squamous pearls. The constituent cells are large,
cervical cancer morbidity and mortality significantly. polygonal and eosinophilic, with variable degrees of cellular
It is well documented that infection by HPV is a necessary pleomorphism and mitotic figures. Dyskeratotic cells may be
cofactor for the development of CIN and, thus, cervical cancer. seen. Clear cell change due to accumulation of glycogen may
Whereas ⬎20 different genotypes of HPV have been found in also be seen.
Figures 7.109 and 7.110 Invasive squamous carcinoma of the cervix: loose inflammatory stroma around the invasive nest with
lymphovascular space invasion.
Figure 7.111 Papillary squamotransitional cell carcinoma of the Figure 7.112 Papillary squamotransitional cell carcinoma of the
cervix: the vascular core is seen with a malignant squamous cervix: vascular cores with basaloid epithelium reminiscent of
epithelial covering. transitional cell carcinoma of the bladder.
Figures 7.113 and 7.114 CINIII-like invasive carcinoma. Expansion and crowding of what appear like endocervical crypts with central
necrosis.
association of carcinogenesis at this site with intraepithelial

neoplasia and HPV infection. The salient histological features
of this tumor, besides the lack of coexistent high-grade CIN,
includes extensive parakeratosis and hyperkeratosis without
atypia in the area of the cervix not involved with cancer, an
associated normal cervical smear test, marked hyperkeratosis
in the invasive cancer with keratin pearls often containing ⬎25
cells per nest, and extensive infiltration of adjacent tissues
without documented metastases or vascular invasion. These
HPV-negative, highly differentiated, keratinizing squamous cell
carcinomas do share some similarities with other rare, well-
differentiated cervical carcinomas such as verrucous carcinoma,
a tumor that has minimal atypia and surface hyperkeratosis.
However, the broad-based areas of invasion of verrucous
carcinoma do not typically show extensive keratin pearl for-
mation. Further, verrucous carcinoma of the cervix has been
Figure 7.115 Invasive squamous carcinoma of the cervix: this shows
associated with coexistent CIN, and there are several reports
focal CINIII-like areas, but with other irregular nests of invasion.
describing its association with HPV, typically HPV 6. Further,
the HPV-negative highly keratinizing squamous cell carcinoma
Keratinizing carcinomas comprise one-third of cases, and often shows a complex architecture of the invasive component
show clearly recognizable squamous epithelium with squamous compared with the broad-based invasive front of a verrucous
pearls. Mitotic figures are sparse in this type of carcinoma. carcinoma. The behavior of HPV-negative highly keratinizing
Small-cell, non-keratinizing carcinomas (one-sixth of cases) squamous cell carcinoma appears to be different from that of
usually show anastomosing broad trabeculae and nests or classic squamous cell carcinoma of the cervix, with a lack of
masses of basaloid tumor cells. The cells are small and oval- lymphovascular invasion with high-stage tumors. Rather, it
shaped, with scant cytoplasm. The morphology is somewhat appears to be more similar to verrucous carcinoma, spreading
reminiscent of CINIII lesions; indeed, in small superficial by direct local extension. Rare fatalities reported in some
biopsy this tumor is often misdiagnosed as strips of CINIII. patients with this subtype of carcinoma are usually due to
Foci of squamous differentiation and keratinization may be extensive local infiltration of the bladder, bowel and ureters,
seen, but no squamous pearls. Necrosis is frequent in this type. with no clinical evidence of metastases.
This tumor is somewhat reminiscent of the basaloid carcinoma Lymphoepithelial carcinoma – see Chapter 15, Carcinomas.
of the vulva and vagina. Small-cell non-keratinizing carcinoma Papillary squamotransitional cell carcinoma: non-glandular
should be distinguished from neuroendocrine carcinoma. papillary carcinoma of the cervix is an unusual tumor which has
appeared under a variety of names such as papillary squamous
Squamous carcinoma variants carcinoma, transitional cell carcinoma of the uterine cervix and –
Highly differentiated keratinizing squamous cell cancer of the most appropriately – as squamotransitional cell carcinoma.
cervix is a recently described subset of squamous cell carcinoma This tumor is frequently mistaken as squamous papilloma, a
of the cervix that appears not to follow the well-documented rare, presumably benign neoplastic lesion of the cervix, that
occurs in young women and histologically resembles squamous Differential diagnosis

papilloma seen in other parts of the body. ● Squamous cell carcinoma with clear cell change may be
The lining epithelium of the papillary component usually mistaken for clear cell carcinoma
resembles abnormal transitional epithelium. Nonetheless, the ● Small-cell non-keratinizing carcinoma may look like
majority of cases show, in addition to the superficial non-invasive neuroendocrine carcinoma or, in a small biopsy, like
papillary component, an in-situ and possibly superficial or rarely CINIII
deep invasive element of conventional carcinoma. In a small ● CINIII-like carcinoma is often mistaken as CINIII
biopsy therefore, one may see only the papillary non-invasive involving crypts or microinvasive carcinoma
component, and for those who are unaware of the existence of
such an entity a diagnosis of CINIII with some papillary con- Special techniques
figuration may be seriously considered. This would almost cer-
tainly result in under-treatment. From the clinical point of
● CK14 is a good marker of squamous carcinoma
view, this tumor appears to be a distinct clinicopathological
● CEA usually stains the most differentiated and keratinized
entity, occurring mainly in postmenopausal women and having cells.
a risk for local recurrence and distant metastasis of 27% and
death rate of 23% within a short period. Pathologists therefore
MESENCHYMAL TUMORS
need to recognize papillary squamotransitional cell carcinoma
of the cervix as a distinct lesion reminiscent of grade 1 or 2
papillary transitional cell carcinoma of urothelial origin, and to SARCOMAS
be cautious of diagnosing squamous papilloma in postmeno-
pausal women, especially if they exhibit dysplasia. Further- Primary sarcomas of the uterine cervix are extremely rare.
more, a diagnosis of papillary squamotransitional cell carcinoma Rhabdomyosarcoma and leiomyosarcoma are the two sarcomas
should alert the clinician to the possibility of a more advanced that can be seen at this site. Endometrial stromal sarcoma may
disease or deeper invasion in the remaining cervix. rarely present as cervical polyp or mass. Malignant peripheral
Rapidly progressive carcinoma (interval cancer) is defined as nerve sheath tumor has rarely been reported in the cervix.
a cancer that has been diagnosed within 3 years of a truly neg- Epithelioid leiomyosarcoma: within the female genital tract,
ative cervical smear test. This is still a controversial entity. epithelioid leiomyosarcoma occurs mainly in the uterus and has
Squamous carcinoma of the uterine cervix with CINIII-like rarely been described in the cervix. It is characterized by nests
growth pattern is a recently described rare variant of squamous and sheets of epithelioid round- or spindle-shaped cells, some
cell carcinoma of the cervix, highlighting the problem of squa- with clear cytoplasmic change, or with oncocytic features, and
mous neoplastic lesion occupying deep endocervical crypts sometimes exhibits osteoclast-like giant cells. Due to the epithe-
with some irregularities and back-to-back arrangement. CINIII lioid morphology of the cells, this tumor may be mistaken for
associated with or predictive of early invasion, is characterized carcinomas or other round cell sarcomas. Immunohistochemical
by CINIII lesion expanding endocervical crypts with evidence stains usually solve the problem; however, care must be exercised
of luminal dyskeratotic cell necrosis and focal intraepithelial as some tumors express epithelial markers.
squamous maturation. However, the borders of these crypts are Myxoid leiomyosarcoma is a rare variant of leiomyosarcoma
usually smooth and even. In squamous carcinoma of the uter- which occurs in both soft tissues and the uterus, and rarely in
ine cervix with CINIII-like growth pattern, the predominant the cervix. This tumor exhibits malignant biological behavior,
features are very prominent comedo necrosis, quite obvious despite the absence of cytological atypia and of significant
intralesional squamous maturation with extensive replacement, mitotic activity. Microscopically, these tumors show spindle or
expansion, unevenness in outline, and frequent peripheral epithelioid cells entrapped in an abundant myxoid material.
bulging of what appeared to be deep endocervical crypts. This Immunohistochemical stains are useful in recognizing the
pattern gives a false impression of CINIII involving complex smooth muscle nature of this type of leiomyosarcoma.
crypts that might have been tangentially cut. However, these Rhabdomyosarcoma rarely occurs in the female genital tract.
nests were often seen in association with small tongues of inva- The typical variant is sarcoma botryoides (a variant of embry-
sion surrounded by stromal loosening and various degrees of onal rhabdomyosarcoma) which occurs in the vagina or cervix,
inflammation. Similar appearances may be seen deep within in infancy and childhood. This variant has rarely been reported
endocervical stroma in the hysterectomy specimen. At present, in older women and in other locations such as the uterus. In
due to a lack of awareness of these histological criteria, the postmenopausal women, the tumor may be mistaken for small
majority of such lesions in a small biopsy or loop excision are cell carcinoma. Pathologists need to think of malignant mixed
being reported as equivocal or CINIII suspicious of invasion. mesodermal tumor with predominant rhabdomyosarcomatous
This would certainly necessitate further biopsies until a defini- component before diagnosing pure rhabdomyosarcoma. They
tive diagnosis of invasion is made. On the other hand, such a therefore need to take sufficient blocks and also to use immuno-
pattern might lead to a false assurance that we are dealing with histochemical stains for epithelial markers to search for epithe-
a very early stage disease. On receiving such equivocal reports, lial elements. Alveolar rhabdomyosarcoma on the other hand – a
some gynecologists might perform further LLETZ, while oth- tumor of the extremities of children and adolescents – has rarely
ers might just closely follow-up the patients. been reported in the female genital tract, either in children or
Verrucous carcinoma – see Chapter 15, Carcinomas. adults. The diagnostic clues for alveolar rhabdomyosarcoma are
the characteristic ‘alveolar’ pattern of growth, the evidence of with smaller lymphocytes, plasma cells, macrophages and neu-
cross-striations in strap or elongated cells with abundant trophils. Mitotic activity can be prominent. The infiltrate is pres-
eosinophilic cytoplasm, the presence of multinucleated cells ent in the superficial subepithelial layer, with no deep stromal
with peripherally placed ‘wreathlike’ nuclei, and the expression invasion and no zone separating the infiltrate from the epithe-
of muscle antigens by the tumor cells. The diagnostic problem lium. The infiltrate extends into the surface epithelium and may
with this variant is due to its round cell and epithelioid be associated with ulceration. Usually, there is no nodularity,
morphology; it may easily be mistaken for an undifferentiated sclerosis or perivascular infiltrate. Immunohistochemical stain-
carcinoma, epithelioid leiomyosarcoma, or even malignant ing is generally not helpful in distinguishing this lesion from
melanoma. The other problem is the occasional association of malignant lymphoma. No specific treatment is necessary for this
alveolar rhabdomyosarcoma with atypical clinical features sim- condition.
ulating lymphomas, leukemia and systemic metastatic disease
with an unknown primary neoplasm. The other variant of rhab-
domyosarcoma is the pleomorphic subtype, a rare and contro-
versial tumor of skeletal muscle phenotype which occurs in the
extremities of adult individuals, and has also been reported in
the female genital tract. All variants of rhabdomyosarcoma are
highly aggressive tumors, and therefore accurate diagnosis is of
paramount importance.
MALIGNANT LYMPHOMA/LEUKEMIA AND

LYMPHOMA-LIKE LESION
Malignant lymphomas rarely arise in the uterus, but are more

commonly seen in the cervix than the corpus. The majority are
Figure 7.116 Pseudolymphoma of the cervix: this is Chlamydia-
B-cell non-Hodgkin lymphoma (NHL). Involvement of the related, with diffuse infiltration of the lamina propria by small
cervix as part of a systemic lymphoma is more common than lymphocytes.
primary lymphoma. It is important to distinguish lymphoma-
like lesion from true lymphoma. The former is a benign,
self-limiting inflammatory process usually associated with
MELANOCYTIC LESIONS
infectious mononucleosis or Chlamydia infection. Distinction
Blue nevus may rarely be seen incidentally in the cervix as a
between benign and malignant lymphoid infiltrate can be
blue-blackish little lesion, located superficially in the submu-
facilitated by immunohistochemical staining and application
cosa of the endocervix.
of the histological criteria for the reactive nature of such
Malignant melanoma is very rare in the cervix. Both primary
lesions.
and metastatic melanomas may mimic almost any other tumor,
Leukemia of the female reproductive organs is rare.
epithelial, mesenchymal or lymphoreticular. Malignant
Granulocytic sarcoma is a rare, extramedullary solid tumor
melanoma rarely occurs in the cervix, and in such location the
composed of malignant immature cells of the granulocytic
possibility of metastatic melanoma should be excluded before
series. It may herald, accompany or signal acute myeloid
making a diagnosis of primary cervical melanoma. In such
leukemia or chronic granulocytic leukemia. Granulocytic sar-
locations it is easily mistaken as carcinoma. However, immuno-
coma may also occur in patients with myelodysplastic syn-
histochemical stains contribute to the diagnosis.
dromes, where it is a sign of imminent disease progression.
Granulocytic sarcoma can occur in the female genital tract
(particularly the ovary), and may be the first clinically signifi- MIXED EPITHELIAL AND MESENCHYMAL
cant manifestation of a hematological malignancy. It is often
histologically confused with other inflammatory or neoplastic
TUMORS
conditions, including large cell lymphoma and undifferentiated
These include: adenomyomas; mixed mullerian tumors: malig-
carcinoma or sarcoma.
nant (sarcomatoid carcinoma/carcinosarcoma), mullerian adeno-
Lymphoma-like lesion of the uterine cervix (Figure 7.116) is
fibroma and mullerian adenosarcoma.
a very rare benign reactive lymphoid hyperplasia which is asso-
See also pp. 441–7.
ciated with chronic cervicitis, and may pose a problem in dif-
ferential diagnosis from malignant lymphoma. The lesion is
often associated either with Epstein–Barr virus (EBV) or NEUROENDOCRINE TUMORS
Chlamydia infection. Histologically, this lesion shows dense
lymphocytic infiltrate of large lymphocytes, usually associated See Chapter 15, Carcinomas (p. 1202).
Neuroendocrine carcinoma of the cervix occurs in slightly – Papillary

younger women (median age 42 years) than squamous carcinoma, – Lymphoepithelioma-like carcinoma
and is usually associated with aggressive clinical behaviors.
Glandular lesions
SECONDARY TUMORS Cervical glandular intraepithelial neoplasia (CGIN)
(Glandular dysplasia and adenocarcinoma in situ)
Metastasis of distant malignancies to the cervix uteri is a rare – Low grade
occurrence, and the frequency is approximately 4% for all – High grade
tumors. The most common secondary tumor occurs by direct Adenocarcinoma
implantation from endometrial adenocarcinoma. Other pri- Mucinous adenocarcinoma
mary sites include the ovary, breast, colon, and stomach. – Endocervical type
Features suggestive of secondary metastasis are the presence of – Intestinal type
extensive lymphatic permeation, and tumor cells insinuating Endometrioid adenocarcinoma
among endocervical glands. Clear cell adenocarcinoma
One case has been seen (unpublished data) of recurrent pro- Serous adenocarcinoma
liferating (borderline) mucinous ovarian tumor presenting as a Villoglandular adenocarcinoma
pelvic mass with direct involvement of the cervix. An initial Adenoma malignum (minimal deviation adenocarcinoma)
cervical biopsy showed the presence of bland-looking muci-
nous glands deep in the cervical stroma, and this was initially Other epithelial tumors
thought to be a benign process. Adenosquamous carcinoma (mucoepidermoid carcinoma)
Glassy cell carcinoma
Adenoid cystic carcinoma
UNUSUAL PRIMARY TUMORS Adenoid basal carcinoma
Endocrine tumor
Extrarenal Wilms’ tumor is rare in any site, and few cases arising ● Carcinoid tumor (small cell/neuroendocrine carcinoma)
within the uterus have been reported. They may present as a poly- ● Atypical carcinoid tumor
poid lesion and show triphasic differentiation with mesenchymal ● Large cell neuroendocrine carcinoma
stroma, epithelial differentiation, and blastemal cells. The mes- ● Small (oat) cell carcinoma
enchymal component often contains a rhabdomyosarcomatous Mesonephric duct adenocarcinoma
element. This tumor should be distinguished from malignant Undifferentiated carcinoma
mixed mesodermal tumor and from rhabdomyosarcoma. Unlike
malignant mixed tumors, Wilms’ tumor affects young girls. Mesenchymal tumors
Primitive neuroectodermal tumor of the cervix has rarely been Leiomyoma
reported, and therefore it is important to keep it in mind in the Leiomyosarcoma
differential diagnosis of small cell neoplasms of the uterine cervix. Endocervical stromal sarcoma
Teratoma has rarely been described in the uterine cervix, but Embryonal rhabdomyosarcoma (sarcoma botryoides)
may present as a conventional cervical polyp. Endometrioid stromal sarcoma
Yolk sac tumor may rarely occur in the cervix, endometrium, Alveolar soft part sarcoma
or vagina.
Mixed epithelial and mesenchymal tumors
Adenomyoma
WHO CLASSIFICATION OF CERVICAL TUMORS Atypical polypoid adenomyoma (variant)
Adenosarcoma
Epithelial tumors and related lesions Carcinosarcoma (malignant mesodermal mixed tumor,
Squamous lesions malignant mullerian mixed tumor)
Condyloma acuminatum Wilms’ tumor
Squamous cell (cervical) intraepithelial neoplasia (CIN)
● CINI (Mild dysplasia) Miscellaneous tumors
● CINII (Moderate dysplasia) Melanocytic lesions
● CINIII (Severe dysplasia and carcinoma in situ) ● Melanocytic nevus
Microinvasive squamous cell carcinoma ● Blue nevus
Squamous cell carcinoma ● Malignant melanoma
● Non-keratinizing Mesonephric adenocarcinoma

● Keratinizing Lymphoma and leukemia
● Small cell (non-endocrine) Tumors of germ cell type
● Variants ● Yolk sac tumor (endodermal sinus tumor)
– Verrucous carcinoma ● Dermoid cyst (mature cystic teratoma)
– Warty Secondary tumors

TUMORS OF THE UTERINE CORPUS
associated with diffuse thickening of the endometrium, often with

EPITHELIAL LESIONS, BENIGN polypoid overgrowth, and may be associated with an increased
risk of development of endometrial carcinoma. This is espe-
ENDOMETRIAL HYPERPLASIA cially true in cases of atypical hyperplasia which progress in
20–30% of cases. Endometrial hyperplasia has been observed
in patients receiving long-term tamoxifen treatment. If the con-
CLINICAL FEATURES dition shows no or only minimal cytological atypia, then treat-
Endometrial hyperplasia is defined as morphologically abnormal ment is by hormonal manipulation. Atypical hyperplasia is
proliferative endometrium associated with increased endometrial ideally treated by hysterectomy unless fertility is desired, or there
volume. It usually indicates estrogenic stimulation unopposed is high surgical risk.
or weakly opposed by progestogen. Endometrial hyperplasia may
be found in pre- or perimenopausal women with anovulatory PATHOLOGICAL FEATURES (Figures 7.117–7.120)
cycles, on supplementary estrogens, or sometimes in post-
menopausal women without clinical evidence of hyperestrogenic WHO classification of endometrial hyperplasia
state. The lesion usually presents with abnormal uterine bleeding, Endometrial hyperplasia
often in perimenopausal or postmenopausal, obese women with – Simple
a history of menstrual irregularities. Endometrial hyperplasia is – Complex
Figures 7.117 and 7.118 Complex endometrial hyperplasia with mild cytological atypia.
Figures 7.119 and 7.120 Complex endometrial hyperplasia: complex glands with secretory change and morule formation.
Atypical endometrial hyperplasia ● Well-differentiated endometrial carcinoma (shows

– Simple complex, confluent and cribriform pattern of the glands,
– Complex stromal desmoplastic response and papillary pattern
with vascular cores)
Simple endometrial hyperplasia is characterized by the pres-
● Arias–Stella reaction
ence of glands of various sizes and shape that are separated by
● Artifact
moderate amounts of stroma and typically exhibit cystic dilata-
tion. The lining epithelium is either normal proliferative or
shows varying degrees of stratification. ENDOMETRIAL HYPERPLASIA, PAPILLARY
Complex endometrial hyperplasia is characterized by the pres-
ence of highly complex, crowded glands with little or no interven- CLINICAL FEATURES
ing stroma. The lining epithelium is proliferative and frequently
stratified. Intra-glandular papillary structures may be seen. Papillary proliferations devoid of malignant nuclear features are
Atypical simple endometrial hyperplasia is characterized by unusual endometrial alterations that are closely related to endo-
the presence of varying degrees of cytological atypia, in asso- metrial epithelial metaplasia. They are often found within endo-
ciation with architectural features of simple hyperplasia. This metrial polyps, and most often occur in postmenopausal women.
condition is extremely rare. Polypectomy and/or curettage may be sufficient treatment,
Atypical complex endometrial hyperplasia is characterized provided that unequivocal atypical glandular hyperplasia or car-
by the presence of varying degrees of cytological atypia such as cinoma is absent. Hysterectomy may be appropriate in post-
rounding of nuclei with the presence of nucleoli, in association menopausal patients with an extensive complex papillary
with architectural features of complex hyperplasia. Frequent hyperplasia, especially in view of those studies that regard such
glandular crowding and infolding are seen. architectural patterns as having a high risk of carcinoma in sub-
Adenomatous change is a term sometimes used to describe a sequent hysterectomy specimens. Repeat biopsy or curettage,
small microscopic focus of crowded budded hyperplastic glands however, should also be considered to assist evaluation of whether
present within otherwise non-hyperplastic endometrium. The the lesion was completely removed by the initial diagnostic pro-
term is also applied to endometrial tissue of small volume but cedure. Additional studies of complex papillary proliferations
which shows architectural features of hyperplasia. with fibrovascular stromal cores that are devoid of malignant
nuclear features are needed to further evaluate their behavior.
Secondary features
● Various forms of endometrial metaplasia.
● Presence of xanthomatous stromal cells; their presence Two histological architectural patterns are found:
indicates excessive estrogen and is more often seen in 1. A simple papillary pattern consisting of small foci or clus-
carcinoma. ters of papillae, often found within endometrial polyps in
● Secretory change (subnuclear vacuolation) and hysterectomy specimens; the papillae protrude into a cysti-
pseudodecidualization of the stromal cells may be seen cally dilated endometrial gland.
in association with exogenous progestogen treatment. 2. A complex papillary pattern showing florid papillary pro-
liferation and involving many endometrial glands and
resembling a complex hyperplasia.
Cell morphology
Some papillae are on the surface, but most are within glands.
● The normal proliferative endometrium is lined by
The papillae are usually branched, have well-defined fibrovascu-
pseudostratified, radially arranged cells with cigar-shaped
lar stromal core, and they may be either long and slender or
or oval nuclei with no prominent nucleoli. The chromatin
short and broad, and with a mixture of sizes and shapes. A few
pattern is coarse, with no evidence of clearing. Mitotic
inconspicuous polymorphonuclear leukocytes may be seen
figures are frequently seen. Proliferative endometrial cells
within the stromal cores. The epithelia covering the papillae vary
line normal glands, disordered proliferative glands and
from a single layer to multiple layers with prominent epithelial
glands of endometrial hyperplasia without atypia.
cellular tufts and detached clusters of epithelial cells. One or
● Atypical cytological features include rounded rather
more metaplastic epithelial cell types are usually found within
than elongated nuclei, chromatin clearing and clumping
the papillary proliferation. Endocervical-type mucinous cells are
with irregularity of nuclear membranes, and the
the most common, followed by eosinophilic cells, ciliated cells,
presence of nucleoli, together with cytoplasmic
focal squamous metaplasia, hobnail cells, and syncytial change.
eosinophilia.
Often, the proliferating cells show cytological features that
would be interpreted as serous cells (‘serous metaplasia’). Indeed,
Differential diagnosis the complex papillary lesions are very much reminiscent of ovar-
● Atrophic endometrium with cystic or adenomatous ian papillary proliferating/borderline tumors of serous or mixed-
architecture epithelial cell type. Mild nuclear atypia is probably acceptable,
● Disordered proliferative endometrium without warranting a diagnosis of atypical papillary hyperplasia.
● Endometrial polyp Mitotic figures may be seen.
● Mullerian adenofibroma The remaining endometrium is usually atrophic.
Differential diagnosis PATHOLOGICAL FEATURES (Figures 7.121–7.125)

● Uterine serous papillary carcinoma Endometrial epithelial metaplasia
● Endometrial hyperplasia
● Low-grade papillary adenocarcinoma Several widely differing varieties of endometrial epithelial meta-
● Benign endometrial surface syncytial change plasia have been identified.
Morules (a form of immature squamous metaplasia) are
sharply demarcated spherical, oval or elliptical epithelial struc-
ENDOMETRIAL METAPLASIA tures which appear in continuity with the lining epithelium of
the involved glands, may replace entire glands, or may leave
small luminal spaces. The constituent cells are round or some-
CLINICAL FEATURES
times spindle-shaped, bland, squamoid with moderate amounts
Endometrial epithelial metaplasia refers to focal or extensive of eosinophilic cytoplasm and poorly defined cell borders that
replacement of endometrial epithelium by different types of produce a syncytial pattern and resemble those of immature
mullerian epithelium. This is seen most commonly in the endo- squamous epithelium or reserve cell hyperplasia of the uterine
metrium of postmenopausal women who are receiving exogenous cervix. Morules may involve glands of any architectural con-
estrogens. Epithelial metaplasia has no clinical significance, apart figuration; they may also involve single glands or may be exten-
from the potential confusion with malignancy. sive and involve a large area of the endometrium. Morules
Endometrial mesenchymal metaplasia is rarely found in the often merge imperceptibly with foci of squamous metaplasia.
endometrium, and may pose a diagnostic confusion with the Central ‘necrosis’ may be present. Mitotic figures are
sarcomatous component of a malignant mixed mullerian tumor. sparse, and there may be minimal nuclear pleomorphism.
Figure 7.123 Syncytial endometrial metaplasia.
Figures 7.121 and 7.122 Papillary metaplasia of the Figure 7.124 Mucinous and papillary metaplasia of the
endometrium. endometrium.
Mucinous metaplasia is characterized by the presence of focal,

patchy or rarely extensive endocervical-type mucinous epithelium
replacing endometrial glands. The cells have bland basal nuclei
that may be either pyknotic or vesicular. Mitotic figures are rarely
seen. Mucinous metaplasia may involve complex budded hyper-
plastic glands imparting a picture reminiscent of borderline muci-
nous ovarian tumor. Mucinous metaplasia is most often seen in
hyperestrogenic settings. Rarely, goblet cell metaplasia is found.
Mucinous metaplasia should be distinguished from mucinous
adenocarcinoma of endometrium, mucinous adenocarcinoma of
cervix with extension to corpus, cervical microglandular hyper-
plasia, and metastatic mucinous carcinoma.
Eosinophilic metaplasia is characterized by the presence of
usually non-stratified endometrial glands lined by cytologically
bland, cuboidal cells, with densely eosinophilic, granular cyto-
plasm with centrally located, uniform, vesicular nuclei. Some-
Figure 7.125 Eosinophilic and ciliated metaplasia of the times, cilia are seen at the luminal borders; the condition is
endometrium: endometrial hyperplasia with metaplasia. then termed ‘ciliated metaplasia’. This should be distinguished
from endometrial adenocarcinoma.
Hobnail metaplasia is characterized by the presence of
The differential diagnosis of morules includes intra-endome- endometrial glands lined by non-stratified cytologically bland
trial leiomyoma, lymphoid nodules, granuloma and disinte- cells arranged in a hobnail pattern (pear-shaped cells with
grating endometrial stroma. When morules are in a sheet-like rounded apical bleb, eosinophilic or vacuolated cytoplasm and
form and associated with necrosis, they may be mistaken for nuclei pushed towards the luminal border). Mitotic figures and
poorly differentiated endometrioid adenocarcinoma, metastatic minimal nuclear pleomorphism may be seen. Hobnail metapla-
adenocarcinoma, and uterine sarcoma. When morules are sia should not be mistaken for clear cell carcinoma.
associated with squamous metaplasia, they may be confused Clear cell metaplasia shows cytologically bland cells with
with mixed adenosquamous carcinoma and adenocarcinoma strikingly clear cytoplasm (containing glycogen and scant
with bland squamous metaplasia. mucin). Mitotic figures are usually absent, and minimal nuclear
Squamous metaplasia is characterized by the presence of pleomorphism may be seen. This condition may occasionally
squamous differentiation that blends imperceptibly with the be mistaken for clear cell carcinoma or Arias–Stella change.
glandular component. The degree of squamous differentiation
is usually similar to that of the accompanying glandular ele- Endometrial mesenchymal metaplasia
ment. Squamous metaplasia should not be mistaken for primary Cartilaginous metaplasia is the presence of mature hyaline
squamous carcinoma of endometrium or extension of a cervi- cartilage in the endometrium. Sometimes, a transition of the
cal squamous carcinoma to corpus. endometrial stromal cells, present in a background with abun-
Papillary metaplasia is characterized by the presence of dant mucopolysaccharide, into chondrocysts can be seen.
branching papillary aggregates, usually encountered over the Osseous metaplasia is the presence of microscopic specules of
endometrial surface, but perhaps also involving portions of the viable or sometimes necrotic bone, usually in association with
glandular lining and often punctuated by collections of poly- acute or chronic endometritis. The surrounding endometrial
morphs and karyorrhectic fragments. The constituent cells form glands may exhibit morules or squamous metaplasia.
a syncytium-like mass with indistinct cytoplasmic borders, and Smooth muscle metaplasia is the presence of small micro-
have either shrunken pyknotic or degenerated or cytologically scopic nodules of smooth muscle within the endometrium.
bland nuclei. This must be distinguished from fragmented Mesenchymal metaplasia should be distinguished from malig-
endometrioid carcinoma and papillary adenocarcinoma. nant mixed mullerian tumor and from fetal tissue obtained from
Ciliated (tubal) metaplasia: ciliated epithelial cells are nor- products of conception.
mally present in proliferative endometrial glands, particularly
those of the lower uterine segment and of the fundus. When
these cells are numerous and prominent, the term ‘ciliated ENDOMETRIAL POLYP
metaplasia’ is applied. The ciliated cells are cytologically bland
with eosinophilic or clear halo-like cytoplasm. ‘Clear cells’
CLINICAL FEATURES
present either singly or in small, pear-shaped aggregates. The
involved epithelium is either stratified or non-stratified, and Endometrial polyp is a benign, non-neoplastic lesion which char-
may form bridge-like tufts or have a micropapillary appear- acteristically is asymptomatic and is found incidentally. Some of
ance. Cilia are easily found on the luminal borders of the these lesions cause uterine bleeding or spotting. Endometrial
involved glands, but mitotic figures are infrequent. This lesion polyp with focal severe atypia has been reported in association
may be mistaken for adenocarcinoma with cilia or adenocarci- with tamoxifen treatment. Endometrial polyp prevalence rises by
noma of endometrioid type. age and/or menopause. Malignant degeneration of endometrial
polyp is rare, and mainly seen in postmenopausal women. Cell morphology

Magnetic resonance imaging (MRI) can help to distinguish most ● The cells lining the glandular structures are usually
polyps from endometrial carcinomas on the basis of morpholog- atrophic, but they can assume any functional, hyperplastic
ical features. or neoplastic appearance.

Endometrial polyp is a polypoid lesion consisting of a fibrovas- ● Cystic hyperplasia
cular core containing large thick-walled vessels, cystically ● Polypoid fragment of endometrium (especially secretory-
dilated or sometimes crowded glands, and fibrous tissue. Any type endometrium may have polypoid areas)
type of endometrial gland can be seen in a polyp, including ● Adenofibroma
atrophic, proliferative, secretory, hyperplastic and rarely ● Polypoid adenomyoma (shows abundant smooth muscle in
adenocarcinomatous-type endometrium. The stromal cells of a the core of the polyp)
polyp can be active and show slight nuclear atypia, particularly ● Atypical polypoid adenomyomatous polyp (similar to
in patients receiving tamoxifen, or in those harboring a func- adenomyomatous polyp, but in addition shows
tional ovarian tumor. Stromal mitoses are relatively common, architecturally complex glands with cytological atypia).
ranging from 0 to 8 mitotic figures per 10 HPF.
Secondary features EPITHELIAL LESIONS, MALIGNANT

● Squamous metaplasia
ENDOMETRIAL CARCINOMA
CLINICAL FEATURES
Endometrial carcinoma is the most common malignant tumor
of the uterine corpus. There are two distinct forms:
1. ‘Estrogen-related tumors’ includes patients between the
ages of 40 and 60 years with a history of excessive
exogenous (HRT) or endogenous (functioning ovarian
tumors, polycystic ovaries and stromal hyperplasia and
hyperthecosis) estrogen. These often have a very well-
differentiated, ‘usual-type’ endometrial carcinoma, usually
limited to the endometrium and associated with
endometrial hyperplasia.
2. ‘Non-estrogen-related’ includes elderly women with no
history of exogenous or endogenous estrogen. These usually
have a high-grade tumor, often of special type, and of a
high-stage disease such as serous and clear cell carcinomas.
Endometrial carcinoma might rarely develop in younger

women who may have a functioning ovarian tumor. In such
patients, the tumor is again very well differentiated. Endometrial
carcinoma is often associated with some constitutional factors
such as obesity, hypertension, diabetes mellitus and nulliparity,
and may show a genetic predisposition. It has also been reported
in association with tamoxifen treatment. Endometrial carcinoma
is treated by hysterectomy, followed by radiotherapy for higher
grade and/or stage disease. The prognosis of endometrial carci-
noma depends on the stage, histological subtype, and grade of
the tumor. Vascular invasion, uterine serosal involvement, and
presence of diffuse uterine invasion worsen the prognosis.
Classification of endometrial carcinoma

Common variant
Figures 7.126 and 7.127 Endometrial polyp: this is a large polyp Endometrioid adenocarcinoma with squamous differentiation
occupying a large proportion of the endometrial cavity; a large (Adenoacanthoma and adenosquamous carcinoma)
feeding vessel is usually seen at the base of the polyp. Other less common or rare variants
Villoglandular adenocarcinoma Stage III: Pelvic extension

Secretory adenocarcinoma IIIA: Involves serosa and/or adnexa and/or positive peri-
Ciliated adenocarcinoma toneal cytology
Serous adenocarcinoma IIIB: Vaginal metastases
Clear cell adenocarcinoma IIIC: Pelvic and/or para-aortic lymph node involvement
Mucinous adenocarcinoma
Stage IV: Extraperitoneal extension
Squamous cell carcinoma
IVA: Bladder and/or bowel involvement
Mixed types carcinoma
IVB: Distant metastases including intra-abdominal and/or
inguinal lymph nodes
Staging of endometrial carcinoma

Stage I: Tumor confined to the uterus
IA: Limited to the endometrium Endometrial carcinoma may involve the entire endometrial cav-
IB: Invasion of less than half the myometrium ity, or may present as a polypoid lesion. The residual endometrial
IC: Invasion of more than half of the myometrium tissue may be normal, atrophic, or hyperplastic. The tumor may
have either pushing or ragged infiltrative margins. Myometrial
Stage II: Involves uterus and cervix invasion is often associated with granulation-type reaction.
IIA: Involves endocervical glandular epithelium only Involvement of foci of adenomyosis by endometrial carcinoma
IIB: Invades cervical stroma should be distinguished from true myometrial invasion.
Figures 7.128 and 7.129 Grade I endometrioid endometrial carcinoma.
Figures 7.130 and 7.131 Grade I endometrioid endometrial carcinoma. Back-to-back arrangement of glands with intraepithelial early
gland within gland formation.The squares indicate a gland within a gland.
Figure 7.132 Grade 1 endometrioid endometrial carcinoma with Figure 7.133 Grade 1 endometrioid endometrial carcinoma with
clear cell change. squamous change (arrows).
Figures 7.134 and 7.135 Villoglandular carcinoma of the uterus.The arrows (Figure 7.134) indicate myometrial invasion.
Figure 7.136 Uterine serous carcinoma: the tumor is Figure 7.137 Uterine serous carcinoma: varying degrees of
indistinguishable from its ovarian counterpart. endometrioid differentiation are frequently seen in uterine serous
carcinoma.
Figure 7.138 Uterine serous carcinoma: extensive lymphatic

invasion is a common feature of this type of endometrial carcinoma.
Figures 7.141 and 7.142 Uterine serous carcinoma: larger views

from Figure 7.140.
Figure 7.139 Uterine serous carcinoma: malignant cells implanting

on the tubal epithelium. Arrows indicate floating and implanted cells.
Figure 7.140 Uterine serous carcinoma: malignant cells implanting Figure 7.143 Mucinous endometrial carcinoma.
on the remaining atrophic endometrial epithelium.
Histological appearances interconnecting glands, cribriform, and microacinar patterns.

Endometrioid-type carcinoma (Figures 7.128–7.133) is the most These are lined by stratified epithelium with varying degrees
common variant. It varies from a very well-differentiated carci- of atypia. The luminal borders are characteristically smooth
noma mimicking atypical complex hyperplasia to a poorly dif- and often show apical blebs. The stroma may show marked
ferentiated tumor with little or no glandular differentiation. The
glandular architecture varies from back-to-back glands, complex
Figures 7.147 and 7.148 Endometrial carcinoma, microglandular

subtype: glandular cells with abundant eosinophilic cytoplasm and
glandular spaces, some containing polymorphs.
Figure 7.149 Endometrial carcinoma, microglandular subtype:

Figures 7.144–7.146 Mucinous endometrial carcinoma. AB/PAS staining highlights the mucin secretion.
desmoplastic response in the form of densely arranged fibro- can be misinterpreted as being of cervical origin. In 68% of cases
blasts with eosinophilic, wavy collagen. of USPC, the cervix is involved in various ways: confluent sur-
Adenocarcinoma with squamous differentiation: squamous face and stromal tumor invasion, a tumor floater within the
change is commonly seen in endometrial carcinoma of the usual endocervical canal, and by cancerization of the endocervical
type. This varies from highly keratinized epithelium to sheet-like epithelium. The frequent cervical involvement in USPC necessi-
or aggregates of cells with indistinct cytoplasmic borders, repre- tates adequate sampling of the cervix, preferably in the same
senting immature squamous epithelium (morules). The squamous manner as a cervical loop or cone biopsy. Due to the aggressive
component may show an abrupt central keratinization or a cen- nature of this disease, most authors advocate adjuvant therapy,
tral accumulation of necrotic material. The squamous epithelium even when the disease is apparently confined to the uterus.
often appears bland-looking, but it may be clearly malignant. Platinum-based chemotherapy has been used for the treatment of
USPC in protocols similar to that of ovarian carcinoma.
Variants of endometrioid adenocarcinoma Clear cell carcinoma is similar to the ovarian, cervical or vagi-
nal clear cell carcinoma, and is associated with a poor prognosis.
Villoglandular adenocarcinoma (Figures 7.134 and 7.135) has
Mucinous carcinoma (Figures 7.143–7.146) is diagnosed
been reported in the uterine corpus, mainly in postmenopausal
when at least 50% of the cells in the tumor contain prominent
women. At this site, the tumor has different biological behavior to
intracytoplasmic mucin, identical to cervical and ovarian muci-
those reported in the cervix, and tends to have a more aggressive
nous tumor. This subtype is usually a well-differentiated tumor,
outcome than the usual endometrioid carcinoma. It is therefore
and has a prognosis similar to that of the usual variant of
imperative that distinction is made regarding the site of origin.
endometrial carcinoma. A high incidence of mucinous carci-
Villoglandular carcinoma of the endometrium has a tendency for
noma has been reported in patients receiving tamoxifen and
trans-luminal spread to the cervix; as such it may be picked up by
synthetic progestagens.
cervical biopsy and misinterpreted as being of cervical origin. Since
Pure squamous cell carcinoma is only diagnosed after exclud-
villoglandular adenocarcinoma of cervix occurs mainly in young
ing an associated endometrial adenocarcinoma or primary
women and can be treated conservatively, pathologists should be
cervical squamous carcinoma. This tumor may be seen in post-
cautious in making such a diagnosis in a small biopsy specimen.
menopausal women who may have cervical stenosis and chronic
Secretory adenocarcinoma is an uncommon variant of well-
pyometra. It may be associated with benign endometrial squa-
differentiated endometrioid adenocarcinoma which consists of
mous metaplasia. Cervical squamous cell carcinoma may, on
glands resembling those of early or mid-secretory endometrium
rare occasions, extend into and replace the entire endometrial
with subnuclear or supranuclear vacuolation. It is associated
cavity. The prognosis of this variant is exceedingly poor, and
with a good prognosis, and when seen in younger women may
postoperative radiotherapy does not appear to improve survival.
be confused with secretory endometrium.
Undifferentiated carcinoma shows no evidence of glandular or
Ciliated cell carcinoma is a rare variant of very well-
squamous differentiation. Some are small cell carcinomas with
differentiated endometrioid endometrial carcinoma. The tumor
neuroendocrine differentiation. Osteoclast-type giant cells or syn-
shows extensive ciliated cell metaplasia involving at least 75%
cytiotrophoblasts may be seen in undifferentiated carcinomas.
of the tumor cells.
Mixed type carcinomas show at least 10% of a different his-
Endometrioid carcinoma with sertoliform differentiation
tological variant. The finding of small areas of one histological
shows closely packed tubules or trabeculae with basally ori-
variant of endometrial carcinoma among other subtypes is not
ented nuclei with clear to fibrillary cytoplasm. The lesions
uncommon, and does not alter the terminology.
resemble sex-cord stromal tumors.
Other endometrial carcinoma variants Rare types of endometrial carcinoma

Uterine serous papillary carcinoma (USPC) (Figures 7.136–7.142) Endometrial small cell neuroendocrine carcinoma is a rare, but
is an aggressive tumor which typically has a high relapse rate, aggressive neoplasm, with patient ages ranging from 30 to 75
early and deep myometrial invasion and frequent lympho-vas- years. Most of the tumors are bulky, intraluminal masses that
cular space involvement. It occurs in older women and is usu- have invaded at least half of the myometrial wall. Most
ally associated with endometrial atrophy. It has also been shown patients present with abnormal vaginal bleeding, with symp-
that patients without any myometrial invasion are just as likely toms related to those of metastatic tumor.
to have extra-uterine disease as those with deeply invasive The tumors are either composed of pure small cells or show
tumors. Histologically, the tumor is characterized by a complex small cells admixed with elements of adenocarcinoma, adeno-
papillary pattern, a high degree of cytological atypia, numerous squamous carcinoma, or heterologous mesodermal mixed
mitoses, extensive necrosis, and the presence of psammoma bod- tumor. Immunohistochemical evidence of neuroendocrine dif-
ies. Focal areas of other differentiation are frequently seen, espe- ferentiation is demonstrated by using the markers chromo-
cially endometrioid and clear cell pattern. To classify a tumor as granin, synaptophysin, leu-7, or neuron-specific enolase. These
serous, at least 25% of the tumor must demonstrate serous dif- tumors are often interpreted as mixed mesodermal tumors, with
ferentiation. The tumor also spreads throughout the abdominal a homologous, stromal-type sarcomatous component.
cavity in a fashion similar to that of ovarian serous carcinoma, Microglandular adenocarcinoma (Figures 7.147–7.149) is a
and trans-luminally along the endometrial cavity, Fallopian tube distinctive variant of endometrial carcinoma that is most likely
and into the endocervical canal. In the latter situation, the tumor a form of mucinous adenocarcinoma. This subtype often causes
diagnostic problems, especially in biopsy specimens, because of its Minimal deviation endometrioid adenocarcinoma is a rare
similarity to benign microglandular hyperplasia of the cervix. pathological variant of endometrioid adenocarcinoma. It shows
Pathologically, it usually consists of polypoid tissue fragments, a proliferation of mildly atypical endometrial-type glands
within which are microcystic spaces lined by flattened, cuboidal, sparsely distributed in the fibrovascular tissue, reminiscent of
or columnar cells. Solid nests or sheets of tumor cells surrounding minimal deviation endometrioid adenocarcinoma of the cervix.
glands may also be seen. The nuclei are uniform and bland, The tumor may invade extensively into the myometrium and
and mitotic figures, although readily identifiable, are infrequent may involve the entire cervix and focally the cervical resection
(1 per 10 HPF). A majority of tumor cells contain intracytoplasmic margins. Focal transitional areas between typical and minimal
mucin. Numerous neutrophils are present in the gland lumens and deviation endometrioid adenocarcinoma are common. Due to a
tissues. The tumor is focally positive for CEA and vimentin. When relatively normal gross appearance and the microscopic decep-
such a tumor spreads to the luminal surface of the endocervix, dif- tively benign-looking appearance, minimal deviation endometri-
ferentiation from microglandular hyperplasia becomes a real chal- oid adenocarcinoma may pose problems of obtaining adequate
lenge. In such cases, deeper levels and extra blocks from the cervix sampling and evaluating the thickness of invasion of the endo-
should be taken, and immunohistochemical stains for vimentin metrial carcinoma on gross, as well as microscopic, examination.
and CEA may be useful. Pathologists must be cautious about diag- Adenocarcinomas arising from adenomyosis uteri are rare
nosing microglandular hyperplasia (MGH) when dealing with tumors, and difficult to diagnose preoperatively. Their aggres-
endometrial biopsy of postmenopausal women and also be aware sive behavior in some cases seems to be related to the histolog-
of this type of endometrial cancer, as it may be misdiagnosed. ical subtype.
Signet ring cell carcinoma is an extremely rare primary endo-
metrial carcinoma. Metastatic ‘signet ring’ cell carcinoma from Metastatic tumors
breast or gastrointestinal tract must be ruled out before making Cervical and ovarian carcinomas are the most common tumors
such a diagnosis. Endometrial stroma occasionally may contain that metastasize to the endometrium. This is followed by lobu-
non-neoplastic signet ring cells that closely mimic adenocarci- lar carcinoma of the breast and signet ring carcinoma of the
noma. These are of decidual or histiocytic nature. stomach or colon.
Transitional cell carcinoma is a rare, distinct subtype of
endometrial carcinoma with morphological features of urothe- Grading of endometrial carcinoma
lial differentiation, but retention of a mullerian immunoprofile.
While the overall prognosis does not appear to be worse than
Figo system
what might be anticipated for the stage of tumor present, it The most widely used grading system for endometrial carci-
appears to be the more aggressive histological subtype among noma is the International Federation of Gynecology and
the patterns with which it is admixed. Obstetrics (FIGO) system. This is based primarily on the extent
Glassy cell carcinoma is a rare neoplasm, and is considered to of non-squamous solid growth, and secondarily on nuclear
be a poorly differentiated variant of adenosquamous carci- atypia. Specifically, tumors that are architecturally grade 1 or 2
noma. The microscopical features of glassy cell carcinoma are elevated to grade 2 or 3 respectively if ‘notable’ nuclear
appear to be highly characteristic and diagnostic. The cells show atypia is present.
a ground-glass cytoplasm with a distinct cell wall and large ● Grade 1: this consists of glands which are difficult to
nuclei containing prominent nucleoli. differentiate from atypical complex hyperplasia with ⬍5%
Mucinous adenocarcinoma of intestinal type has very rarely of the tumor showing solid growth pattern (excluding
been described in the endometrium. morules or sheets of squamous epithelium). The cells are
Lymphoepithelial-like carcinoma can occur in the endometrium slightly more abnormal than those of atypical hyperplasia.
and, in this location, may not be associated with EBV infection. ● Grade 2: glands are easily identified, with 6–50% of the
Giant cell carcinoma of the endometrium is an aggressive tumor showing solid growth pattern. Malignant
tumor that should be distinguished from other endometrial cytological features are easily appreciated.
tumors with a prominent giant cell component, including ● Grade 3: this shows over 50% solid pattern, and usually
trophoblastic tumors, certain primary sarcomas, and malig- causes concern whether it is an adenocarcinoma, sarcoma,
nant mixed mullerian tumors. or undifferentiated carcinoma. The tumor cells are clearly
Endometrial adenocarcinoma with trophoblastic differentiation: malignant, with hyperchromatic nuclei, prominent
foci of trophoblastic differentiation in the primary endometrial nucleoli, and numerous mitotic figures (including many
carcinoma are very rare. The trophoblastic component is usu- abnormal ones).
ally positive for human chorionic gonadotrophin (hCG) by
immunocytochemical staining. Binary grading system
Verrucous carcinoma is a rare variant of epidermoid carcinoma In the binary architectural grading system, tumors are graded as
with distinct clinical and histopathological features. They are typ- either low or high grade. A tumor is classified as high grade if
ically slow-growing, locally invasive tumors with low potential at least two of the following architectural features are present:
for lymphatic metastasis, and appear to be radio-resistant. Deep 1. More than 50% solid growth, without distinction between
myometrial invasion can be seen in these tumors. Before diagnos- squamous versus non-squamous differentiation.
ing primary endometrial verrucous carcinoma, one needs to rule 2. A diffusely infiltrative growth pattern characterized by
out an extension from primary cervical verrucous carcinoma. irregularly distributed glands, masses, cords, or nests of
tumor cells infiltrating the myometrium haphazardly, in ● Atypical adenomyomatous polyps

contrast to an expansile growth pattern in which the invasive ● Endocervical adenocarcinoma (the cells are CEA-positive and
tumor has a lobulated appearance with pushing borders. vimentin- and ER-negative, while endometrial carcinomas
3. Tumor cell necrosis. are vimentin- and ER-positive and CEA-negative)
● Metastatic adenocarcinoma
For tumors that are confined to the endometrium, only per-
● Malignant mixed mullerian tumor (if the epithelial
centage solid growth and necrosis are used for grading because
component is the predominant finding)
there is no infiltrative tumor in the myometrium to be assessed.
● Endometrial stromal sarcoma
Those with both solid growth of more than 50% and necrosis
● Epithelioid leiomyosarcoma.
are considered to be of high grade. Tumor cell necrosis is defined
as areas of necrotic tumor immediately adjacent to viable tumor.
Ghost outlines of the necrotic cells are often present within the Special techniques
necrotic areas. Single-cell necrosis and necrotic debris within ● Focal luminal and intracytoplasmic mucin is commonly
masses of squamous epithelium do not qualify as tumor cell seen in most endometrial carcinomas.
necrosis. ● Endometrial carcinomas often co-express cytokeratin, ER,
The binary grading system has several diagnostic advantages and vimentin.
over FIGO grading. First, an assessment of solid growth does not ● Endometrial carcinoma are usually CEA-negative.
depend on whether the solid masses of epithelium are squamous ● In endometrioid carcinoma, p53 overexpression is
or non-squamous – a distinction that is critical in the FIGO sys- associated with high-grade and advanced-stage tumors,
tem but is frequently difficult and often arbitrary. Second, a whereas ER and PR expression is associated with low-
tumor is regarded as exhibiting solid growth if ⬎50% of the grade and early-stage tumors. Bcl-2 immunopositivity is
tumor is solid. Determining whether the majority of the tumor is more common in low-grade, early-stage rather than in
solid is more straightforward than deciding whether a tumor has high-grade, advanced-stage adenocarcinomas.
more or less than 5% solid non-squamous growth (that is, a dis-
tinction between FIGO grades 1 and 2). Third, unlike the FIGO
grading system, there is no need to perform nuclear grading.
ENDOMETRIAL INTRAEPITHELIAL CARCINOMA
Secondary features CLINICAL FEATURES

● Necrotic cellular debris and polymorph infiltration within Endometrial intraepithelial carcinoma (EIC) is a recently described
the glandular lumina entity which means uterine serous carcinoma (USC) without
● Desmoplastic stromal response myometrial or endometrial stromal invasion. Its presence is highly
● Foamy xanthomatous cells in the stroma correlated with a coincident invasive USC. The average age of the
● Epithelial metaplasia (especially squamous metaplasia and patients is 73 years, and the tumor presents with abdominal dis-
morule formation and sometimes oncocytic metaplasia) tention or vaginal bleeding. Although controversy persists as to
● Necrosis whether these superficial carcinomas behave less aggressively than
● Hemorrhage deeply invasive carcinomas, it is commonly acknowledged that
● Rare findings include hyalinization, psammoma bodies, even superficial USCs can be associated with significant extrauter-
and foci of stromal metaplasia such as osteoid. ine disease. Moreover, it is suggested that EIC might be a precur-
sor of both uterine and extrauterine invasive serous carcinoma.
Cell morphology The finding of EIC in an endometrial curettage specimen should
● The tumor cells of the usual endometrial carcinoma vary prompt a thorough search for an invasive uterine and/or extrauter-
from a bland-looking appearance reminiscent of those seen ine serous carcinoma. Conversely, an endometrial origin should
in endometrial hyperplasia to one of clearly malignant cells. be excluded in patients with peritoneal carcinomatosis.
● They are larger than the cells of normal proliferative The mechanism of dissemination from EIC has not been
endometrium, have eosinophilic granular cytoplasm, and firmly established. The possibility of transtubal spread has been
have rounded rather than elongated nuclei showing considered, and this is substantiated by the infrequent finding
chromatin clearing and containing prominent nucleoli. of so-called in-transit deposits of serous carcinoma in the
● Mitotic figures are almost always seen. Fallopian tubes. Alterations in cell-surface adhesion molecule
expression, including CD44v6, E-cadherin, and beta-catenin,
might also be associated with the tendency of malignant serous
cells to dislodge and implant at distant sites.
● Endometrial hyperplasia (features favoring carcinoma
include complex papillary pattern, confluent glandular
arrangement, cribriform pattern, and prominent
desmoplastic stromal response) Hysterectomy often shows endometrial polyps with EIC,
● Endometrial epithelial metaplasia but without invasive USC, in a background of atrophic endo-
● Disintegrating endometrium metrium. Bilateral salpingo-oophorectomy and staging often
● Microglandular hyperplasia of cervix shows serous carcinoma involving the ovarian hilum, the
surfaces of the Fallopian tubes and ovaries, in addition to peri- PAS-positive, hyaline contents. The epithelial structures may
toneal carcinomatosis. merge with solid sheets of closely packed oval or spindle cells
The diagnosis of EIC can be difficult because it does not present with a sarcomatoid appearance. Bundles of myometrial smooth
as a mass lesion, and may be a focal finding in an otherwise muscle are observed between the tumor aggregates. Extensive
unremarkable endometrial polyp. The histological findings include areas of necrosis may be evident. Cytological atypia is moder-
strips of superficial epithelium composed of cells with markedly ate, and up to three mitoses per HPF are identified in the most
enlarged, irregularly shaped, and crowded nuclei that contain proliferative areas.
prominent nucleoli. Frequent and atypical mitotic figures are also
seen. The finding of an endometrial polyp in a patient in or beyond Differential diagnosis
the seventh decade of life should prompt a careful search for EIC. ● Endometrial adenocarcinoma.

● The most important differential diagnostic concern is the ● Immunohistochemically, neoplastic cells are diffusely
exclusion of a benign condition such as tubal or ciliary positive for cytokeratin 7, epithelial membrane antigen and
metaplasia. Endometria with tubal metaplasia can show CD15, and focally positive for BerEP4 and vimentin.
mild-to-moderate nuclear and nucleolar enlargement, but ● CD10 is conspicuously expressed in mesonephric remnants
extreme pleomorphism and anaplasia are not seen. p53 and tumors, and may be useful in specifically defining
and MIB-1 immunostains can prove helpful in the tumors with mesonephric differentiation.
distinction of EIC from benign metaplastic lesions.
Special techniques MESENCHYMAL TUMORS

● EICs are almost invariably proliferative lesions with high
(⬎50%) MIB-1 indices. The vast majority of EICs also
express p53 in a strong and diffuse manner, which is
ENDOMETRIAL STROMAL TUMORS
incompatible with a benign, metaplastic lesion. Diffuse and Endometrial stromal tumors (EST) are divided into two major
intense p53 expression in USC and EIC is strongly categories: endometrial stromal nodules and endometrial stro-
associated with the detection of p53 mutations. However, mal sarcomas. The distinction is made on the basis of the lack
because rare EICs contain p53 mutant proteins that are of significant infiltration at the periphery of the former. The
not detectable with routine anti-p53 antibodies, an entirely division of endometrial stromal sarcomas into low- and high-
negative p53 immunohistochemical result does not grade categories has been replaced by endometrial stromal sar-
guarantee the absence of malignancy. coma (ESS) and undifferentiated uterine sarcoma, respectively.
The latter is invariably high grade, and often resembles the
MESONEPHRIC TUMORS mesenchymal component of a malignant mullerian mixed
tumor.
Two features of ESTs may cause confusion: the first is in
CLINICAL FEATURES those tumors which contain smooth muscle differentiation
Mesonephric (wolffian) neoplasms of the female genital tract (mixed endometrial stromal and smooth muscle tumors) which
occur infrequently, but are found in sites where embryonic rem- often have a characteristic ‘starburst’ pattern of collagen for-
nants of wolffian origin are usually detected, such as the uterine mation; the second feature is in those tumors associated with
cervix, broad ligament, mesosalpinx, and ovary. In the uterine epithelial structures. The most common epithelial patterns
corpus, despite the presence of vestiges of the mesonephric duct, resemble those seen in ovarian sex-cord stromal tumors
only isolated examples of hyperplasia or squamous metaplasia (endometrial stromal tumors resembling ovarian sex cord
of the Gartner’s duct have been reported. Mesonephric tumors tumors). Much less common is the presence of endometrioid
have involved the lower uterine segment or have secondarily glandular differentiation (endometrial stromal neoplasms with
invaded the corpus. Malignant mesonephric carcinoma has endometrial glands); when these structures are prominent, the
rarely been reported in the uterine corpus. lesion may resemble endometriosis, hence some of the older
terminology (aggressive endometriosis).
Some ESTs have a prominent fibrous or myxoid appearance,
and this causes confusion and possible misdiagnosis as myxoid
Mesonephric carcinoma shows a variety of merging patterns. leiomyosarcoma. Endometrial stromal sarcomas at extrauter-
These include: retiform appearance, with elongated, slit-like ine sites may be primary or metastatic from a uterine tumor, the
branching tubules enclosing intraluminal papillae, lined by latter sometimes being occult and difficult to establish defini-
cuboidal to flattened atypical cells; a glandular pattern with tively, particularly if there is a history of a remote hysterectomy
elements of variable size, lined by tall, columnar cells, resulting for ‘leiomyomas’. Rarely, a striated muscle component may be
in an endometrioid-like appearance; and a small tubular (ductal) seen in ESTs.
pattern with back-to-back, small, round, uniform tubules lined ESTs are usually soft and yellow in their gross appear-
by cuboidal or flattened cells containing densely eosinophilic, ance, and may show gelatinous and cystic degeneration.
A hysterectomy is almost always necessary to evaluate the on low-power magnification, and therefore diligent high-
margin when an EST is diagnosed in a curettage specimen. power scrutiny is required to identify this important feature.
Occasionally stromal nodules contain epithelioid cells arranged
Secondary features in anastomosing cords, trabeculae, small clusters or aggregates,
● Bands and small nodules of glassy hyaline material solid or hollow tubules or gland-like structures. When this fea-
● Accumulation of foamy macrophages ture predominates, these lesions are called ‘uterine sex cord-
● Small areas of necrosis may be seen in some stromal like tumors’ or ‘uterine tumors resembling ovarian sex cord
nodules, but extensive necrosis is a feature of high-grade tumor’. Gland-like structures may sometimes be seen. A
sarcoma smooth muscle metaplasia is not uncommon and when present
● Calcification and bone formation may be seen in significant amount and in an organoid manner (mixed
● Myxoid and gelatinous changes. endometrial stromal and smooth muscle tumor), they may
either be misconstrued as residual normal myometrial elements
Cell morphology or may create a pitfall in diagnosis and the lesion is misinter-
preted as showing an infiltrative pattern.
● The constituent cells are uniform, and reminiscent of normal
endometrial stromal cells. They have scant cytoplasm with
poorly defined margins, and the nuclei are oval to fusiform.
● Abundant eosinophilic or vacuolated cytoplasm may be ● ESN in an endometrial location may be confused with
seen in some tumor cells. lymphoid aggregates or morule.
● Less than 10 mitoses per 10 HPF are seen in low-grade ● ESN in a myometrial location may be mistaken for cellular
stromal sarcoma. leiomyoma, hemangiopericytoma and endometrial stromal
sarcoma. ESN has well-delineated, expansible growth at its
Special techniques margin, which contrasts with the infiltrative pattern of
ESSs. Some ESNs may exhibit minimal infiltration or may
● All endometrial stromal cells are vimentin- and CD10-
show prominent smooth muscle metaplasia that result in
positive.
features somewhat reminiscent of ESS.
● The epithelioid cells which resemble ovarian sex cord
tumor are frequently immunoreactive for vimentin,
desmin, and muscle specific actin, less commonly Special techniques
immunoreactive for cytokeratin and inhibin, and not ● See Uterine endometrial stromal tumors (p. 424).
immunoreactive for epithelial membrane antigen.
● h-Caldesmon highlights the smooth muscle differentiation.
ENDOMETRIAL STROMAL SARCOMA (ESS;
PREVIOUSLY TERMED LOW-GRADE
ENDOMETRIAL STROMAL NODULE
ENDOMETRIAL STROMAL SARCOMA)
CLINICAL FEATURES
CLINICAL FEATURES
Endometrial stromal nodule (ESN) is a benign, always solitary,
lesion which is present at various locations including intra- Endometrial stromal sarcoma (ESS) is a malignant tumor which
cavitary, submucosal, or mural. It is well-circumscribed, yellow to is seen in middle-aged women and may arise at extrauterine
orange in color, and varies in size from microscopic to a few cen- locations such as the rectovaginal area, ovary, and peritoneal
timeters. It may be associated with abnormal uterine bleeding, serosa. It may also present as a metastatic lung lesion.
and is usually cured by simple removal. The presence of focal ESS is yellowish in color and has a variety of gross appear-
margin irregularities in some ESNs probably has no adverse prog- ances including globoid enlargement of the uterus, multiple
nostic significance. It is important adequately to excise ESN with polypoid masses, worm-like growth extending into uterine,
the rim of normal tissue surrounds so that the interface between and parametrial vessels and cystic change. The tumor recurs or
the tumor and the normal tissue is thoroughly sampled. metastasizes (sometimes after many years) in 50% of cases, and
20–25% of patients die as a result of their disease. Endometrial
PATHOLOGICAL FEATURES stromal sarcoma may respond to progestational agents.
Stromal nodule is a well-circumscribed lesion composed of uni-

form round, oval, or elongated cells arranged in sheets, and
with vague whorling of cells around blood vessels. It has a Endometrial stromal sarcoma is a solid, infiltrative myometrial
pushing margin, and no evidence of intravascular extension or or endometrial lesion that frequently extends into distended vas-
invasion. Some focal irregularity of the margin in the form of cular and lymphatic spaces. There are several different histolog-
one to three, often lobulated or finger-like projections into the ical patterns. The hyaline vascular type features bands of hyaline
adjacent myometrium is allowed, none of which exceeded connective tissue separating islands and clusters of bland neo-
2–3 mm in length. The typical arterioles of ESTs are a well-known plastic stromal cells. Cleft-like or rounded hyalinized vessels are
and helpful diagnostic feature, but they may not be conspicuous present in this type. The cellular type lacks the prominent vessels,
Figure 7.153 Endometrial stromal sarcoma: small spiral, arteriole-

like vessels are commonly seen in these tumors.
Figure 7.154 Endometrial stromal tumor, abdominal recurrence

after 16 years.The cells are still similar to the primary uterine
tumor; the lesion is strongly ER-positive.
Endometrial stromal tumor resembling ovarian

sex cord tumors
Figures 7.150–7.152 Endometrial stromal sarcoma: sharply
demarcated basophilic nodules of small round cells; interstitial bands There are two groups within this lesion:
of collagenous amianthoid fibers are common (Figure 7.152). ● Group I is similar to endometrial stromal tumors but
contains epithelioid cells arranged in anastomosing

cords, trabeculae, small clusters or aggregates, solid or
hollow tubules, or glands resembling sex cord ovarian
is more cellular, and more clearly infiltrative. Some tumors tumors.
exhibit a mixture of both patterns. Hemangiopericytomatous ● Group II shows lesions indistinguishable from ovarian sex
vascular pattern and small thickened spiral arteriole-like vessels cord tumors. The degree of malignancy depends on the
are frequently seen in stromal tumors. characteristic of the stromal element.
Figure 7.158 Endometrial stromal sarcoma: cytoplasmic

vacuolation is not uncommon in endometrial stromal tumors.
Figure 7.155 Endometrial stromal tumor.The cells are strongly

ER-positive.
Figure 7.159 Endometrial stromal sarcoma: stromal sclerosis with

residual stromal cells.
Figure 7.156 Endometrial stromal sarcoma: amianthoid fibers are
frequently seen in this tumor.
Figure 7.160 Endometrial stromal tumor with sex cord

Figure 7.157 Endometrial stromal sarcoma: lymphatic permeation differentiation. Notice the cord-like epithelioid arrangement of the
by the tumor with presence of amianthoid fibers. stromal cells.
Figures 7.161 and 7.162 Endometrial stromal tumor with sex cord differentiation (as in Figure 7.160).
Figure 7.163 Endometrial stromal sarcoma with slight spindling of Figure 7.164 Endometrial stromal sarcoma with predominant
the cells. glands in the vaginal wall.
Figures 7.165 and 7.166 Endometrial stromal sarcoma with predominant glands in the bowel wall.
as endometriosis; hence the older terminology ‘aggressive

endometriosis’. One case has been reported of stromal sarcoma
with numerous endometrial glands which has repeatedly been
misinterpreted as upper vaginal/cervical endometriosis over a
period of 5 years, culminating in eventual widespread intra-
abdominal malignancy with similar histological features of
endometriosis but together with areas of clearly malignant stro-
mal sarcoma. The clues to the diagnosis of malignancy in cases
that resemble endometriosis are: (i) the presence of abnormal
vascular pattern similar to that of stromal sarcoma; and (ii) an
increased number of mitotic figures and the presence of pleo-
morphism within the stromal cells.
● Intravenous leiomyomatosis.
● Stromal nodule (occasional ESS lack the typical permeative
Figure 7.167 Endometrial stromal sarcoma with predominant
glands in the bowel wall. infiltration).
● Cellular leiomyoma with adjacent microscopic intravascular
invasion.
● Endometrial stromal tumors resembling ovarian sex cord
tumors may have a striking resemblance to granulosa
cell tumors or Sertoli cell tumors, including those with a
retiform pattern, and have recently been shown to be
frequently inhibin-positive.
● Extragenital endometrial stromal sarcomas may be confused
with diverse lesions such as gastrointestinal stromal tumors,
hemangiopericytoma, lymphangiomyomatosis, or
mesenchymal cystic hamartoma of the lung.
Special techniques
See Uterine endometrial stromal tumors (p. 424).
MIXED ENDOMETRIAL STROMAL AND SMOOTH

MUSCLE TUMORS
CLINICAL FEATURES
Uterine tumors composed of a prominent component of smooth
muscle (SM) and endometrial stroma (ES) (so-called stromomy-
omas) are defined as those containing more than 30% of each
component. The patients’ ages range from 29 to 68 years (mean
46 years), and the tumor sizes range from 3 to 27 cm (average
9.6 cm) in diameter. Most lesions were grossly well circum-
scribed. Until knowledge of their clinicopathological features is
more complete, these tumors should be reported as endometrial
stromal nodules or as ESS with smooth muscle differentiation,
and any unusual features of either component should be
recorded. The presence of even focal endometrial stromal dif-
Figures 7.168 and 7.169 Endometrial stromal sarcoma with ferentiation in an invasive uterine mesenchymal lesion with a
predominant glands and sex cord differentiation. predominant low-grade smooth muscle, fibroblastic, and/or
myxoid phenotype should permit classification as low-grade
Endometrial stromal tumor with endometrioid glands sarcoma; such lesions should be considered as endometrial stro-
(Figures 7.164–7.169) mal sarcomas.
Stromal nodule or stromal sarcoma may contain either

endometrioid glands (which may be numerous) or glands lined by
clear cells. Within the uterus, such a lesion is often misinterpreted The cut surfaces of these tumors are often soft, with tan-yellow
as adenomyosis with sparse glands, or in extrauterine locations areas admixed with firm, whorled areas. Microscopically,
Figures 7.170 and 7.171 Mixed endometrial and smooth muscle Figures 7.173 and 7.174 Mixed endometrial and smooth
stromal tumor: the outline is that of endometrial stromal sarcoma, muscle stromal tumor: amianthoid fibers are seen amongst the
and the cells are round with some spindling. stromal cells.
the tumors are either well circumscribed, or show infiltrating

tongues typical of ESS. The endometrial stromal component may
predominate the picture, and is typically characterized by a diffuse
growth of closely packed, minimally atypical small cells accom-
panied by numerous vessels. The smooth muscle component,
when predominant, is composed of spindle cells in disorganized
short fascicles, longer fascicles, or nodules with prominent central
hyalinization. This component appears benign in the majority of
cases, and rarely shows moderate cytological atypia, focal tumor
cell necrosis, and less than 5 mitotic figures per 10 HPF. The
tumors usually show a highly vascular supportive stroma.
Hyalinized collagen with a starburst pattern and prominent
perivascular collagen deposition are frequently seen. Features sug-
gestive of an epithelial arrangement are present in some tumors,
including gland-like arrangements and trabeculae or ‘cell clusters’.
Figure 7.172 Mixed endometrial and smooth muscle stromal

● Highly cellular leiomyomas
tumor: desmin highlights the normal myometrial smooth muscle and ● Pure endometrial stromal tumors
focal staining of the tumor cells. ● ‘Uterine tumors’ resembling ovarian sex cord tumors.
and they may also present as lung metastases. The aggressiveness

of these tumors is directly related to level of mitotic activity.
Undifferentiated uterine sarcoma is a highly cellular tumor
consisting of stromal cells which may bear little resemblance to
normal endometrial stromal cells. The constituent cells are spin-
dle and polygonal in shape, arranged in sheets and cords, and
infiltrate extensively between muscle fibers. The cells exhibit
greater cellular pleomorphism and mitoses than endometrial
stromal tumors. This type of sarcoma lacks the usual vascular
pattern of endometrial stromal tumors.
Secondary features
● Necrosis
● Calcification
● Bone formation.
Cell morphology
● The constituent cells usually bear little resemblance to
normal endometrial stromal cells. They are typically
pleomorphic, polygonal or spindle-shaped, with vesicular
nuclei and small nucleoli.
● Rarely do they have abundant eosinophilic or vacuolated
cytoplasm.
● The cells are individually surrounded by reticulin fibers.
● A minor smooth muscle component may be present.
● The mitotic count exceeds 10 mitoses per 10 HPF.
● Undifferentiated or anaplastic carcinoma
Figures 7.175 and 7.176 Mixed smooth muscle stromal tumor: ● Lymphomatous or leukemic infiltrate
an admixture of spindle cells with eosinophilic cytoplasm of ‘smooth ● Malignant mixed mullerian tumor
muscle origin’, with round, basophilic cells of ‘endometrial stromal ● Mullerian adenosarcoma
origin’. ● Metastatic carcinoma
● Leiomyosarcoma
Special techniques
● The smooth muscle component is strongly desmin-positive,
and the endometrial stromal component desmin-negative,
PERIVASCULAR EPITHELIOID CELL TUMOR
except in occasional cases. (‘PECOMA’)
● h-Caldesmon marked smooth muscle exclusively. See Chapter 13, Soft tissue tumors (p. 1035).
● Endometrial stromal cells as well as some fibroblasts and
smooth muscle cells expressed CD10.
SMOOTH MUSCLE TUMORS, LEIOMYOMAS
UNDIFFERENTIATED UTERINE SARCOMA
CLINICAL FEATURES
The leiomyomas are the most frequent tumors found in the
CLINICAL FEATURES
female genital tract. They are present in about 40% of women
Undifferentiated uterine sarcoma (previously termed high-grade aged over 40 years, and in 56–69% of hysterectomies for non-
endometrial stromal sarcoma) is a highly aggressive tumor which cancerous conditions. The etiology of leiomyomas is not clear, but
occurs in older women and presents with abnormal uterine they are generally hormone-sensitive, with rates of growth semi-
bleeding and abdominal or pelvic pain. It has a high recurrence quantitatively related to estrogen and progesterone receptor lev-
and metastatic rate. The overall 5-year survival is 20–25%. els. They most commonly affect the uterus, but may also be found
Undifferentiated uterine sarcoma may arise in extrauterine loca- in the cervix, broad ligaments and, rarely, the ovary. Smooth mus-
tions such as the rectovaginal area, ovary and peritoneal serosa, cle tumors may be asymptomatic or present as a mass, or with
abnormal bleeding. They are often multiple, of different sizes ● a soft creamy surface is seen in cellular and epithelioid
and present in the myometrium, subserosa, or submucosa. leiomyomas. Hemorrhage and cystic changes are seen in
Submucosal lesions may appear polypoid and often protrude into cellular hemorrhagic (apoplectic) leiomyoma.
the uterine cavity, and may appear as cervical polyps. ● Plexiform leiomyomas usually show a nodular
Surgical excision is usually curative. Some leiomyomas become white-yellowish cut surface.
dislodged from the serosal surface and become attached to ● Diffuse leiomyomatosis typically shows symmetrically
other pelvic or abdominal locations (parasitic leiomyomas). enlarged uterus due to almost complete replacement of the
myometrium by innumerable, poorly defined, confluent
PATHOLOGICAL FEATURES (Figures 7.177–7.192) nodules.
● Cotyledonoid dissecting leiomyoma or ‘Sternberg tumor’
Gross appearance is characterized by bizarre, sarcoma-like gross appearances,
Leiomyomas are characteristically sharply circumscribed, with with large, exophytic, fungating, multinodular,
a line of cleavage in the surrounding myometrium that results pedunculated tumor extending into the broad ligament or
in easy shelling out of these lesions. The uncomplicated usual peritoneal cavity with an attachment to the uterus.
leiomyomas show whitish, whorled, cut surfaces.
Other gross appearances include: Microscopic appearance
● red or pinkish cut surface with loss of whorling pattern
Classic leiomyomas (Figure 7.177)
(red degeneration), calcifications, cystic change, and necrosis.
Classic leiomyomas are generally well-circumscribed lesions
consisting of monomorphic spindle cells arranged in interweav-
ing fascicles. These fascicles are separated by variable amounts
of hyalinized collagen which may divide the tumor into nod-
ules. Typical smooth muscle cells are elongated, with abundant
eosinophilic cytoplasm and uniform, cigar-shaped nuclei. The
cells appear round in transverse section. The usual common
leiomyomas lack cellular pleomorphism, significant mitotic
figures, or tumor necrosis. Sometimes the nuclei palisade in a
pattern similar to that seen in schwannoma ‘neurolemmoma-
like leiomyoma’.
Variants of leiomyomas
Cellular leiomyoma (Figures 7.178 and 7.179) is characterized by
an increased density of cells, less apparent fascicular arrangement,
and inconspicuous hyalinization and other degenerative changes.
The cells range from spindle-shaped to round, with scant cyto-
plasm. Blood vessels with large, thick muscular walls and cleft-
like spaces are conspicuous features in the majority of these
tumors. Irregular focal extensions into the adjacent myometrium
Figure 7.177 Classic leiomyoma: the cells are uniform, spindle cells
are also common. These features may result in a misinter-
with abundant eosinophilic cytoplasm.
pretation of cellular leiomyomas as endometrial stroma tumors.
Immunostaining for h-caldesmon, calponin, CD10, desmin,
Figures 7.178 and 7.179 Cellular leiomyoma: densely cellular basophilic spindle cells reminiscent of endometrial stromal tumor.
and smooth muscle actin (SMA) are helpful in the differential Epithelioid leiomyomas (Figures 7.180–7.182) are uncom-
diagnosis. Some tumors do exhibit features of both ‘mixed mon neoplasms which consist of round or polygonal cells with
smooth muscle-endometrial stromal neoplasms’. In such tumors, eosinophilic or clear cytoplasm separated by variably hyalin-
h-caldesmon expression is markedly decreased or absent in areas ized collagen. The cells may be arranged in sheets, cords, nests,
that morphologically resemble endometrial stromal tumors. columns, ‘Indian files’, or rows. Sometimes they appear cohesive
Cellular leiomyomas may also be mistaken as leiomyosarcomas. and may mold around each other. Rarely, they may be arranged
Hemorrhagic cellular (apoplectic) leiomyoma: this distinctive in a cartwheel fashion around blood vessels, giving the lesion
uterine smooth muscle tumor usually occurs in patients taking a a hemangiopericytomatous pattern. The stroma may show
combination-type oral contraceptive hormonal medication con- extensive hyalinization or abundant collagen fibers, resulting in
taining the progestin norethindrone for 2–4 years. Abdominal separation of the epithelioid smooth muscle cells into small,
pain is the most frequent presenting symptom. The tumors range irregularly shaped strands or cords. ‘Symplastic’ multinucle-
in size from about 1.1 to 4 cm, and show multiple gross hemor- ated giant cells similar to those seen in bizarre leiomyomas, as
rhages. Microscopically, they are characterized by stellate zones well as osteoclast-type giant cells, may rarely be seen in epithe-
of recent hemorrhage and edema within nodules of hypercellular lioid smooth muscle tumors. Epithelioid cells may be the pre-
smooth muscle. Coagulative necrosis, as seen in ‘red degenera- dominant cell in a variety of leiomyomas including intravenous
tion’, is usually inconspicuous. Mitotic figures are usually sparse, leiomyomatosis and lipoleiomyoma.
not exceeding 2 per 10 HPF, and are mostly located in the peri- Based on the nuclear grade of the epithelioid tumor cells, three
hemorrhagic areas. Abnormal blood vessels of various sizes are groups of ‘epithelioid smooth muscle tumors’ are recognized:
frequent. Recognition of their distinctive pathological features ● Nuclear grade 1 tumors: the cells have uniform, bland
will prevent misdiagnosis as leiomyosarcoma. nuclei with inconspicuous nucleoli and evenly distributed
Figure 7.180 Epithelioid leiomyoma: the cells are round Figure 7.182 Leiomyoma–sex cord differentiation: grouping of
epithelioid with clear cytoplasm. Hyaline bands separate the cells. epithelioid smooth muscle cells results in a sex-cord pattern.
Figure 7.181 Epithelioid leiomyoma: the cells are Figure 7.183 Symplastic leiomyoma: scattered, large, bizarre and
desmin-positive. hyperchromatic nuclei with no necrosis or significant number of
mitoses are the hallmark of symplastic leiomyoma.
Figures 7.184 and 7.185 Symplastic smooth muscle tumors of uncertain malignant potential. Diffuse pleomorphism, but no coagulative
tumor cell necrosis and less than 5 mitotic figures per 10 HPF.
It appears that benign uterine epithelioid smooth muscle

tumors fall into nuclear grade 1, and the malignant tumors
belong to nuclear grade 3. Although nuclear grade 2 tumors are
problematic, most of them behave in a benign fashion. They may
be called epithelioid smooth muscle tumor, probably benign.
Clinically malignant tumors (epithelioid leiomyosarcomas)
typically have the combination of significant nuclear atypia
(either grade 2 or grade 3 nuclei) and some mitotic activity (usu-
ally at least 3–4 mitotic figures per 10 HPF); they must also have
tumor cell necrosis. Epithelioid smooth muscle tumors of the
uterus should be classified as tumors of uncertain malignant
potential under the following conditions: if they are larger than
5 cm; if they show at least moderate cellular pleomorphism; if
their mitotic index is at least 1 per 10 HPF, or if they show cel-
lular necrosis.
Subtypes of epithelioid leiomyoma

Figure 7.186 Mitotically active leiomyoma: classic leiomyoma, not
cellular or of any other variants, but contains up to 19 mitotic Leiomyoblastoma ‘epithelioid leiomyoma, clear-cell type’: the
figures (boxed) per 10 HPF, and no tumor cell necrosis. term ‘leiomyoblastoma’ implies a primitive tumor and is inap-
propriate; ‘epithelioid leiomyoma, clear-cell type’ is preferred.
These tumors exhibit cytoplasmic vacuolation and clearing in a
chromatin. These tumors show up to 3 mitotic figures per large number of cells. Signet ring cells are also common. The
10 HPF, and no tumor cell necrosis. ultrastructural features of the uterine clear cell tumor suggest
● Nuclear grade 2 tumors: the cells have an intermediate that the lesions represent a leiomyoma that has undergone sub-
degree of nuclear atypia, often with small nucleoli. These lethal cell injury. Some uterine leiomyoblastomas have been
tumors show mitotic count of up to 5 mitotic figures shown to invade locally, metastasize, and recur, resulting in the
per 10 HPF, an absence of tumor cell necrosis, and they patient’s death. These tumors, if examined carefully, usually
may show an infiltrative border. reveal randomly distributed clusters of neoplastic cells with
● Nuclear grade 3 tumors: the cells have enlarged overt malignant features, such as cellular and nuclear atypia,
hyperchromatic nuclei with prominent macronucleoli and abnormal mitoses, local infiltrating tendencies, and vascular
unevenly distributed chromatin. These tumors show up to invasion. According to these findings, it has been suggested that
9 mitotic figures per 10 HPF, and may show tumor cell uterine leiomyoblastomas should be viewed as neoplasms of
necrosis or an infiltrative border. low-grade malignancy of a distinct clinicopathological entity.
Figure 7.187 Lipoleiomyoma: smooth muscle cells admixed with Figure 7.190 Intravenous leiomyomatosis: this shows hydropic
fat cells and fibrous tissue. changes resulting in isolated strands of residual smooth muscle.
Figure 7.188 Lipoleiomyoma (desmin-positive cells).
Figure 7.189 Intravenous leiomyomatosis: tongue-like protrusion Figures 7.191 and 7.192 Perinodular hyaline leiomyoma:
of vascular leiomyoma into a vein. excessive interstitial hyalinization resulting in a nodular aggregate of
the residual smooth muscle.
The plexiform tumor is a microscopic lesion which locates at nature. Intravascular leiomyomatosis (IVL) with histological
the endometrial-myometrial junction and consists of strands of features of a lipoleiomyoma has been rarely reported.
‘Indian-file’ and small nests of ‘epithelial-like’ epithelioid cells Vascular leiomyoma is characterized by the presence of
with inconspicuous eosinophilic cytoplasm and crumpled numerous muscular-walled blood vessels, separated by edema-
bland nuclei. These are embedded in a collagenous matrix. The tous, myxoid or hyalinized stroma, sometimes with cystic changes.
cells in this type of leiomyoma may be confused with metastatic The smooth muscle cells are arranged in fascicles or in poorly
breast carcinoma, in particular lobular breast carcinoma. defined strands or cords, and may show symplastic nuclear
Multiple plexiform tumorlets may have an infiltrative pattern change. It can be misinterpreted as a vascular tumor.
and mimic endometrial stromal sarcoma. Leiomyoma with hematopoietic elements: although leiomy-
Symplastic (bizarre) leiomyoma (Figures 7.183–7.185) contains omas of the uterus are common, hematopoietic components
a significant number of cells with dense eosinophilic cytoplasm within these tumors are exceedingly rare.
and enlarged, often bizarre, single or multiple hyperchromatic Leiomyoma with sex cord-like pattern is characterized by the
nuclei that are scattered singly or in small groups. These changes presence of epithelioid structures arranged in cords, trabeculae,
are more often seen in fibroids removed from pregnant women, nests, or tubules that merge into areas otherwise typical of
and from patients receiving progestogen therapy. smooth muscle tumor.
Symplastic leiomyomas have benign behavior, even for those Granular cell leiomyoma is an exceedingly rare variant which
tumors with high cellularity, numerous widely distributed exhibits a marked granular change
bizarre cells, and mitotic counts in the 2–7 mitotic figures per
10 HPF range by the highest count method. The bizarre giant Leiomyomas with unusal growth patterns
cells are distributed in a unifocal, multifocal or diffuse pattern. There are some uterine smooth muscle tumors which exhibit
Degenerative changes and fibrinoid changes in blood vessels unusual morphological features or growth patterns that cause
accompanied by chronic inflammation are not uncommon. Up difficulty in their distinction from malignant neoplasms and
to 7 mitotic figures per 10 HPF (mean 1.6) can be seen. Some those with endometrial stromal tumors.
pyknotic and karyorrhectic nuclei resembling abnormal mitotic Diffuse uterine leiomyomatosis is a rare condition which is
figures are seen. This type of leiomyoma should not be over- distinguished from the common uterine leiomyomas by involve-
diagnosed as leiomyosarcoma. On very rare occasions, leio- ment of the entire myometrium by innumerable, ill-defined,
myomas may harbor metastatic carcinoma cells. These may be often small and confluent, histologically benign smooth-muscle
confused as a bizarre or symplastic leiomyoma. nodules. The nodules blend with each other and merge imper-
Mitotically active leiomyoma (Figure 7.186): when up to 19 ceptibly with the surrounding less-cellular normal myometrium.
mitoses per 10 HPF are seen in otherwise classic leiomyoma This variant of leiomyomas should be distinguished from
(not cellular, bizarre or any other special variants of leiomy- intravenous leiomyomatosis and low-grade endometrial stromal
oma), with no evidence of cytological atypia or CTCN, a diag- sarcoma. Diffuse leiomyomatosis may exhibit concomitant para-
nosis of mitotically active leiomyoma can be made. metrial, pelvic, and bilateral ovarian involvement, and rarely
Myxoid leiomyomas are characterized by an extensive extension of the disease processes to the pelvic mesocolon.
myxoid degeneration of the connective tissue stroma. Myxoid Molecular analysis suggests that diffuse uterine leiomyomatosis
leiomyomas tend to be richly vascular and, therefore, prominent may be an exuberant example of diffuse and uniform involvement
blood vessels and sometimes a focal lymphangioma-like pattern of the entire myometrium by multiple leiomyomas.
are seen. Myxoid leiomyomas may be misinterpreted as myxoma Intravenous leiomyomatosis (Figures 7.189 and 7.190) is char-
or hemangioma. Since myxoid leiomyosarcoma exhibits no or acterized by the presence of leiomyomas growing within venous
very little mitotic activity, it may be under-diagnosed as myxoid and lymphatic vessels outside the confines of, or in the absence
leiomyoma. However, it usually shows an infiltrative pattern with of, an adjacent leiomyoma. This lesion may extend into vena
some degree of nuclear enlargement and pleomorphism. cava or even the heart. Histological examination reveals prolif-
Lipoleiomyoma (Figures 7.187 and 7.188) of the uterus is erations of benign-appearing smooth muscle within myometrial
extremely rare; these tumors show scattered islands of mature vessels, at least some of which are large veins. Most of the histo-
fat cells which may represent ‘lipomatous’ metaplasia of a pre- logical variants of benign uterine leiomyoma (epithelioid, myx-
existing leiomyoma. It has a prevalence in menopause, and a oid, bizarre or lipoleiomyomas) can exhibit the intravascular
preferential onset in the subserosal. These tumors consist of growth pattern of intravenous leiomyomatosis. Rarely, it may
smooth muscle tissue admixed with varying amounts of mature show an endometrial component. Other common features of
adipose tissue, which did not show cytological atypia. The intravenous leiomyomatosis are the presence of numerous small,
smooth muscle cells are most commonly of the usual spindle thickened-wall vessels, hyalinization, and edema. Intravenous
cell type, but rarely epithelioid cells are seen. The fat cells are leiomyomatosis should be distinguished from other tumors, par-
similarly of the mature adipocytes, and sometimes immature fat ticularly endometrial stromal sarcoma and leiomyosarcoma. In
cells and lipoblasts with marked nuclear atypia are seen. Rarely, rare instances, intravenous leiomyomatosis may be associated
cartilaginous differentiation or anomalous arterial blood vessels, with distant parenchymal (pulmonary) metastases.
resembling those seen in renal angiomyolipoma, are observed. Benign metastasizing leiomyoma is characterized by the pres-
Lipoleiomyoma with the latter features should be distinguished ence of multiple benign extrauterine leiomyomatous nodules
from ‘angiolipoleiomyoma’, a tumor that is seen in cases of (in locations such as the lungs, mediastinal and retroperitoneal
tuberous sclerosis and which is most likely of a choristomatous nodes, bone and soft tissue) in women with typical uterine
leiomyoma. There is controversy regarding the pathogenesis true vascular invasion and diffuse hydropic degeneration
and biology of these lesions. Although it is biologically pecu- within non-neoplastic myometrium are the other characteristic
liar, benign metastasizing leiomyoma should continue to be features of this variant of leiomyoma. These features may also
recognized as a distinct entity because current morphological occur in other unusual uterine leiomyoma variants, such as
criteria do not allow primary myometrial tumors to be reclas- intravascular leiomyomatosis, cotyledonoid dissecting leiomy-
sified as leiomyomas of uncertain malignant potential, even if oma and uncomplicated intramural dissecting leiomyoma.
they have metastasized to the lung. Recently, some studies have Infiltrative uterine leiomyomas are characterized by infiltrat-
suggested that benign metastasizing leiomyomas represent a ing margins and/or extension of the lesion outside the uterus,
multifocal process or a slow-growing variant of leiomyosarcoma most often into the broad ligament and sometimes other con-
of the uterus, which becomes clinically apparent at a young age tiguous structures.
and progresses with low velocity. Some cases of benign metas- Cotyledonoid dissecting leiomyoma: this is also known as
tasizing leiomyomas are associated with benign uterine leiomyo- ‘Sternberg tumor’ or ‘grapelike tumor’, and is a very rare vari-
mas with intravascular invasion. These nodules are treated ant of smooth muscle tumors with a distinctive gross appear-
surgically, if feasible, or by hormonal therapy. ance (see above). This is apparently the result of a combination
Disseminated peritoneal leiomyomatosis is characterized by of several uncommon growth patterns operating together,
the presence of numerous smooth muscle nodules distributed including subserosal growth, dissecting growth, and perinodu-
throughout the superficial subperitoneal tissue. The serosal lar hydropic degeneration. Histologically, this tumor shows
surfaces of the uterus, tubes and ovaries may also be involved. variably sized micronodules of benign smooth muscle fascicles,
This condition occurs mainly in women, is associated with which are separated by fibrous connective tissue with a marked
current or recent pregnancy, and regresses spontaneously. hydropic change and rich vascularity. Due to bizarre, sarcoma-
Decidual nodules may be seen in association with the smooth like gross appearances, this type of lesion should be subjected
muscle nodules. They are usually found incidentally, and may to frozen-section examination in order to avoid over-treatment
be confused with disseminated abdominal malignancy. and to preserve fertility in young women.
Perinodular hydropic leiomyoma (Figures 7.191 and 7.192): Significant nuclear atypia, mitotic activity, and coagulative
the gross and microscopic examination of this variant of leiomy- tumor necrosis are usually absent. Although ‘cotyledonoid dis-
oma is otherwise typical of cellular leiomyomas with focal accu- secting leiomyoma’ involves both mural and extramural com-
mulations of edema fluid (hydropic degeneration), typically ponents, rare cases of pure intramural or pure extramural
associated with variable amounts of collagen (‘hyaline degenera- dissecting leiomyomas are also seen.
tion’), and rarely significant accumulations of acid mucin (myx- Some leiomyomas may exhibit combinations of unusual growth
oid degeneration). These acellular changes show variable patterns such as cotyledonoid, intravenous leiomyomatosis,
distribution within the lesion. When it is seen around small nests and/or hydropic changes. Such leiomyoma ‘cotyledonoid hydropic
of smooth muscle cells, it results in characteristic perinodular intravenous leiomyomatosis’ may create a diagnostic challenge.
acellular zones (‘perinodular hydropic change’) that mimics intra-
venous leiomyomatosis on both gross and microscopic examina- Degenerative changes in smooth muscle tumors
tion. The hydropic changes may extend beyond the confines of
the leiomyomas, resulting in a picture that is suspiciously like Several forms of degenerative change can occur in the leiomyoma.
myxoid leiomyosarcoma; when the hydropic changes are exten- The most common is hyaline degeneration, which is important
sive, they may obliterate the usual architecture of the leiomyoma. in that it should not be mistaken for the coagulative tumor cell
These stromal changes are often accompanied by numerous necrosis seen in leiomyosarcoma. Hydropic degeneration is par-
thick-walled blood vessels that tend to obscure the stroma’s ticularly prominent in vascular leiomyomas and in intravenous
smooth-muscle nature. An awareness of these changes, combined leiomyomatosis. Extensive hydropic degeneration often leads to
with mucin stains and immunohistochemical stains for endothe- cystic degeneration (cyst formation). Red degeneration (necrobio-
lial antigens, should facilitate the diagnosis. Hydropic leiomyo- sis) is a form of degeneration that occurs characteristically – but
mas are clinically similar to typical leiomyomas; obviously it is not exclusively – in pregnancy, and the process is often the cause
important that they are not confused with intravenous leiomyo- of pain and fever and also, very rarely, spontaneous perforation.
matosis or myxoid leiomyosarcoma. Myxoid degeneration results from mucoid degeneration of the
Multinodular hydropic leiomyoma typically consists of two connective tissue of the leiomyoma. A combination of hydropic,
types of hydropic degeneration, including hydropic degeneration myxoid, and cystic degeneration is common in some leiomyomas,
within leiomyoma and leiomyoma with perinodular hydropic particularly intravenous leiomyomatosis.
degeneration. In the first group, hydropic changes are seen inside Calcification is commonly encountered in longstanding leiomy-
the leiomyoma resulting in the appearance of fibroblasts, strands, omas. Psammoma body formation may also sometimes be seen.
rounded collagen fibers and thick-walled vessels within a pale Palisading granuloma-like nodules with a necrobiotic or
background. These areas are also associated with neoplastic hyaline core ‘giant rosettes’ have rarely been described in deep-
smooth muscle cells appearing as thin cords in a plexiform pat- seated leiomyomas.
tern. In the second group, the tumor is subdivided into numerous,
well- to ill-defined smooth muscle nodules by edematous con- Changes in leiomyomas due to hormonal treatment
nective tissue. Intramural dissecting growth pattern, satellite ● Rapid growth of leiomyoma with intralesional hemorrhage
smooth muscle nodules simulating intravascular growth, minor is usually seen in women receiving an estrogenic agonist.
● Shrinkage of uterine leiomyomas occurs in patients treated pleomorphism, and a MI of at least 1 per 10 HPF, or if
with gonadotropin-releasing hormone (GnRH) agonist. they show cellular necrosis.
The pathology of such shrinkage is usually illustrated by ● Uterine leiomyoma with clear cell change ‘leiomyoblastoma’
confluent nodular hyaline degeneration representing a is often viewed as neoplasm of low-grade malignancy.
scar-like retraction, geographic hydropic degenerative ● Mitotically active leiomyoma.
necrosis, and obliteration of the interface between the
leiomyoma and myometrium – which may explain the SMOOTH MUSCLE TUMORS, LEIOMYOSARCOMAS
difficult enucleation of myomatous nodules in some
treated patients. GnRH analogue (GnRHa) therapy can
induce a reduction in fibroid volume by up to 50% over a CLINICAL FEATURES
period of 3 months’ treatment. This effect may be Leiomyosarcomas are relatively infrequent but aggressive tumors
beneficial in selected patients, prior to open or endoscopic that affect women after the menopause. Some leiomyosarcomas
myomectomy, to aid the surgical procedure. are progesterone- and estrogen-receptor positive, and may
increase in size during pregnancy. According to reports, neither
Changes in leiomyomas following uterine artery embolization radiotherapy nor chemotherapy have proven effective in the
● Bilateral uterine artery embolization has recently been treatment of these tumors. Hormonal therapy has rarely been
employed as an alternative to operational treatment of used, but may have some influence on the disease.
uterine leiomyoma. The pathological features induced by
uterine artery embolization include massive necrosis PATHOLOGICAL FEATURES (Figures 7.193–7.199)
(sometimes with dystrophic calcification), vascular
‘Classic’ leiomyosarcomas are cellular tumors, with infiltrative
thrombosis, and intravascular foreign material that elicits
or well-circumscribed margins, often larger than 5 cm. The clas-
a histiocytic and foreign-body giant cell reaction. In some
sic leiomyosarcoma consists of monomorphic or pleomorphic
cases, intravascular foreign material is present elsewhere
in the myometrium, the cervix, or paraovarian region.
In occasional cases, foci of myometrial necrosis and
microabscess formation beyond the confines of the
leiomyomas may be seen. Histopathologists should be
aware of these findings because the use of uterine artery
embolization will possibly become more widespread in the
future.
SMOOTH MUSCLE TUMOR OF UNCERTAIN

MALIGNANT POTENTIAL (STUMP)
The classification of uterine smooth muscle neoplasms into
clinically benign and clinically malignant groups has been
shifted from exclusive reliance upon mitotic index (MI) to an
approach that incorporates additional histopathological char-
acteristics such cytological atypia (CA) and the presence or
absence of coagulative tumor cell necrosis (CTCN). The latter
feature appears to be most significant when placing a tumor
into the malignant category.
Between leiomyoma and leiomyosarcoma there exists a series
of smooth muscle tumors of the uterus that are difficult to cat-
egorize. The terms ‘borderline smooth muscle tumors of the
uterus’ or ‘smooth muscle tumors of uncertain malignant poten-
tial’ have been used for such lesions (STUMP). Management of
these tumors seems to be the same as that for usual leiomyoma,
but follow-up may be necessary. There are few tumors within
the STUMP category:
● ‘Atypical leiomyomas with a low risk of recurrence’ show
no CTCN, diffuse moderate to severe atypia, and less than

10 MF per 10 HPF.
● Smooth muscle tumors with favorable outcome show
focal or multifocal significant atypia, with 1–20 MF per

10 HPF, but no CTCN.
● Epithelioid smooth muscle tumor with the following
Figures 7.193 and 7.194 Leiomyosarcoma: cellular spindle cell
features: ⬎5 cm in size, with at least moderate cellular tumor with coagulative tumor cell necrosis.
Figure 7.198 Myxoid leiomyosarcoma: this is often misdiagnosed

as one of the other myxoid tumors.
Figure 7.199 Pleomorphic leiomyosarcoma: this exhibits cellular

pleomorphism, abnormal mitosis (boxed) and occasional osteoclast-
type giant cells (circled).
whorling patterns may be seen focally. Leiomyosarcomas are

often vascular and sometimes may exhibit a prominent heman-
giopericytomatous pattern. Typical smooth muscle cells are
elongated, with abundant eosinophilic cytoplasm and uniform,
cigar-shaped nuclei. The malignant cells exhibit pleomorphism,
a coarse chromatin pattern, and nuclear membrane irregulari-
ties, often with multiple prominent nucleoli. Mitotic figures are
frequent, and the presence of coagulative tumor cell necrosis is
very common.
Figures 7.195–7.197 Epithelioid leiomyosarcoma: the malignant Uterine epithelioid leiomyosarcoma is an unusual smooth
cells are round and undifferentiated, reminiscent of carcinoma. muscle neoplasm which is distinguished on cytoarchitectural
Desmin shows focal staining (7.196). Coagulative tumor cell necrosis grounds from the majority of leiomyosarcomas that arise in
is a significant indicator of malignancy (7.197). the uterus. Epithelioid leiomyosarcoma typically consists of
epithelial-like round cells that show moderate amounts of cyto-
plasm and significant nuclear atypia with some mitotic activity
spindle cells arranged in bundles or fascicles arranged at right- (usually at least 3–4 MF per 10 HPF); and most also have
angles to each other (reminiscent of benign smooth muscle tumor cell necrosis. The majority of these tumors are initially
tumors), but they exhibit varying degrees of nuclear pleomor- misdiagnosed as undifferentiated carcinomas. Some epithelioid
phism and mitotic activity. Nuclear palisading, storiform, and leiomyosarcomas exhibit rhabdoid or oncocytic phenotype and
early rhabdomyoblastic differentiation ‘composite extrarenal Uterine sarcoma with liposarcomatous differentiation: a
rhabdoid tumor’. Hence, this lesion should be differentiated liposarcoma in combination with a leiomyosarcoma of the uterus
from malignant mixed mullerian tumors, rhabdomyosarcoma, is very rare.
endometrial stromal sarcoma, and pure rhabdoid tumors of the
uterus. The recognition of a rhabdoid phenotype is of clinical Differential diagnosis
importance since these tumors are prone to be aggressive.
● Benign smooth muscle tumors (see p. 431). A variety of
Occasionally, epithelioid leiomyosarcoma show round or
gross and microscopic features may be found in both
polygonal cells arranged in cords and nests, closely resembling
benign and malignant tumors, and great care must be
those of plexiform tumor. Rarely, epithelioid leiomyosarcoma
taken not to mistake leiomyomas with atypical or unusual
exhibits prominent myxoid changes, and this may lead to diffi-
features with leiomyosarcomas. Individual features, such
culty in histological diagnosis. Positive immunoreactivities for
as hypercellularity, necrosis, nuclear atypia, mitotic figures,
desmin and vimentin help in the diagnosis of such cases.
and intravascular growth, are ominous but must be
Dedifferentiated leiomyosarcoma is a very rare histological
interpreted with caution because variants of benign
variant which shows a variety of patterns, including epithe-
leiomyoma may contain such changes.
lioid, alveolar rhabdomyosarcoma-like, malignant fibrous his-
● Endometrial stromal tumors.
tiocytoma (MFH)-like or giant cell tumor-like areas.
● Pure rhabdomyosarcomas are extremely rare, and should
Myxoid leiomyosarcoma is a rare variant of uterine sarcoma,
only be diagnosed after ruling out rhabdomyosarcoma
exhibiting malignant biological behavior despite the absence
component of an adenosarcoma or carcinosarcoma
of cytological atypia and of significant mitotic activity.
(malignant mixed mullerian tumor) or rhabdoid
Microscopic examination shows well-differentiated smooth
differentiation in some leiomyosarcomas. Pure
muscle cells without atypia, and with a few mitotic figures in the
rhabdomyosarcoma is a very aggressive neoplasm with an
copious myxoid matrix. These tumors often show very low
extremely poor prognosis. Immunohistochemical
mitotic activity ranging from 0 to 2 MF per 10 HPF. Features in
demonstration of skeletal muscle differentiation is
favor of malignancy include the presence of infiltrative pattern
necessary for a definitive diagnosis.
of growth and a high MIB-1 index (60% of cells positive).
● Undifferentiated carcinoma often resembles epithelioid
Myxoid leiomyosarcoma may arise in leiomyoma. Some uterine
leiomyosarcoma.
myxoid leiomyosarcoma may present as a huge abdominal cys-
tic mass. Rarely, myxoid leiomyosarcoma shows highly atypical
pleomorphic cells and numerous mitoses. The best therapy for Special techniques
this tumor is unknown, as too few cases have been reported ● Desmin seems to be positive in almost all smooth muscle
from which conclusions may be drawn. Myxoid leiomyosar- tumors except those of the epithelioid type, which are
coma should be distinguished from myxoid malignant fibrous positive in only about half of the cases. Desmin also stains
histiocytoma, which is exceedingly rare in the uterus. areas of smooth muscle differentiation in endometrial
Intravenous leiomyosarcomatosis: on very rare occasions a stromal tumors and the majority of tumors resembling
leiomyosarcoma of the uterus may exhibit striking involvement ovarian sex cord tumors.
of large vessels of the myometrium and broad ligament on both ● h-Caldesmon appears to be positive in almost all non-
gross and microscopic examination – a pattern reminiscent of epithelioid smooth muscle tumors, and also in areas of
that seen in intravenous leiomyomatosis. smooth muscle differentiation in endometrial stromal
Osteoclast-like giant cells in smooth muscle tumors: osteo- tumors. It is positive in approximately half of the
clast-like giant cells (OGC) in leiomyomatous tumors of the epithelioid smooth muscle tumors, and tends to be
uterus are rarely seen, and their significance is unknown. negative in tumors resembling ovarian sex cord tumors.
Immunohistochemical studies show positive staining for mus- ● Calponin is positive in most tumor types.
cle actin, alpha-smooth muscle actin, and KP-1 (CD68) in both ● CD10 seems to be positive in 90% of endometrial stromal
the spindle cells and osteoclast giant cells. The latter also stains tumors, and focally in two-thirds of tumors resembling
for alpha-1-antitrypsin and alpha-1-antichymotrypsin. These ovarian sex cord tumors. It appears to be expressed,
findings suggest that OGC may be formed by the fusion of however, in almost all leiomyosarcomas, almost 50% of
spindle cells of leiomyosarcoma and also express histiocytic highly cellular leiomyomas, and rarely in the other smooth
markers. muscle tumors.
Uterine leiomyosarcoma with a clear cell component is a very ● CD34 is usually negative.
peculiar variant of a low-grade leiomyosarcoma, composed mainly ● CD99 and inhibin seem to be positive in some of the
of watery, clear large cells with round, fairly regular nuclei. tumors resembling ovarian sex cord tumors.
No appreciable pleomorphism or high mitotic activity is noted, ● Keratin may be positive in tumors resembling ovarian sex
nor evidence of necrosis. The presence of occasional areas of tran- cord tumors, and occasionally in smooth muscle tumors.
sition between these cells and typical spindle leiomyosarcoma ● C-kit is negative in all uterine stromal tumors.
cells, together with the immunohistochemical results, allows the ● CD44v3 immunostaining is useful in distinguishing
recognition of a smooth muscle origin of this clear cell tumor. between benign and malignant smooth muscle tumors.
Patients are treated by hysterectomy. Soft tissue metastasis of such Leiomyomas and normal myometrium express CD44v3,
variant may be misdiagnosed as hibernoma, or a liposarcoma. while leiomyosarcoma does not.
Some adenomyomas show atypical histological features

MISCELLANEOUS TUMORS ‘atypical polypoid adenomyoma/adenomyofibroma’, or ‘atypi-
cal polypoid adenomyofibromas of low malignant potential’.
NODULAR HISTIOCYTIC HYPERPLASIA OF This is based on their potential risk for myometrial invasion
and the markedly complex glands (high architectural index).
THE ENDOMETRIUM A treatment program includes local excision, despite the presence
of recurrent or persistent disease. Close follow-up, however
CLINICAL FEATURES may be warranted for cases of ‘atypical polypoid adenomyofi-
bromas of low malignant potential’.
Nodular histiocytic hyperplasia of the endometrium is a
recently described lesion of the endometrium, which may rep-
resent a reactive response to intra-cavity debris.
Adenomyomas are composed of an admixture of endometrioid
PATHOLOGICAL FEATURES glands, endometrioid stroma, and smooth muscle that lacked
the characteristic features of atypical polypoid adenomyoma.
The lesion is composed of aggregates of histiocytes with either Atypical adenomyomas show a biphasic proliferation of
lobulated or ovoid, vesicular nuclei, distinctive cytoplasmic architecturally complex and cytologically atypical endometrial
margins, and a moderate amount of amphophilic cytoplasm. glands within a myofibromatous stroma. The histological pat-
Mitoses may be frequent. terns range from widely separated and loosely clustered irregu-
lar but branched glands embedded in broad zones of cellular
Differential diagnosis myofibromatous stroma to those possessing crowded,
● Xanthogranulomatous endometritis markedly complex, branching glands separated by sparse,
● Malakoplakia
● Histiocytic granuloma
● Hormonal changes of the endometrial stroma
● Langerhans’ cell histiocytosis
● Morule formation
● Extravillous trophoblast
● Exaggerated placental site reaction
Special techniques
● CD68 and lysozyme are strongly expressed in the
cytoplasm. Neither estrogen receptor nor progesterone
receptor is expressed, in contrast to the background
endometrium.
● The cells are also negative for S-100 and cytokeratin.
MIXED EPITHELIAL AND MESENCHYMAL

TUMORS
ADENOMYOMAS
CLINICAL FEATURES
Adenomyomas are benign, non-neoplastic polypoid lesions
which occur in the endometrium and myometrium, and also in
the cervix. The patients’ ages range from 25 to 73 years (mean
39.9 years). Adenocarcinoma may rarely develop in adeno-
myoma. Multilocular cystic adenomyoma of the pelvic cavity
has been described. Adenomyoma can be seen in other parts of
the female genital tract such as in Bartholin’s gland.
Uterine adenomyomas can be either submucosal, mural, or
subserosal. The lesions vary in size from 0.3 to 17 cm in their
greatest dimension, and they are firm, often with cystic areas and
sometimes focal hemorrhage. Uterine adenomyomatous polyp Figures 7.200 and 7.201 Adenomyoma: benign endometrial
may rarely demonstrate a vesicle pattern on ultrasonography. glands with stroma containing desmin-positive smooth muscle cells.
Figures 7.205 and 7.206 Atypical adenomyoma: the glandular

crowding with morule formation may be mistaken for
adenocarcinoma.
endocervical-type epithelium, or squamous epithelium. The

smooth muscle component is usually cellular, and in some cases
Figures 7.202–7.204 Atypical adenomyoma: a polypoid shows occasional bizarre nuclei. Up to 5 MF per 10 HPF can
endometrial lesion showing smooth muscle stroma, and irregularly
occasionally be seen.
shaped glands with morule formation.
On rare occasions, uterine adenomyoma may resemble a
small uterus-like mass.
intersecting fascicles of fibromuscular tissue. Florid morular/
squamous metaplasia is present most cases. The architectural Differential diagnosis
complexity of the glands may be indistinguishable from ● Endometrial polyp
that of well-differentiated endometrial adenocarcinoma. The ● Well-differentiated adenocarcinoma
glands may also be lined by tubal-type epithelium, mucinous ● Mullerian adenosarcoma.
Special techniques the absence of desmoplasia or an inflammatory response, and

● The stroma is either actin- or desmin-positive, or both. the presence of adjacent uninvolved islands of adenomyosis.
Adenomyosis, endometrial hyperplasia, and endometrial car-
cinoma may coexist, thereby indicating a common denomina-
ADENOMYOSIS tor (possibly hormonal) that might exist in all three lesions. It
has been suggested that the hyperplastic and atypical changes
CLINICAL FEATURES in adenomyosis might be due to a carcinogenic ‘field effect’ in
the vicinity of the endometrial carcinoma rather than direct
Adenomyosis is a fairly frequent disorder in adult women. The invasion. Histopathological changes ranging from simple cystic
condition is characterized by the haphazard location of hyperplasia to carcinoma in situ may be observed in adenomy-
endometrial glands and stroma deep within the myometrium of otic foci in patients with endometrial carcinoma.
the uterus. Adenomyosis may be caused primarily by defects in
the formation of the myometrium. Adenocarcinomas arising
from adenomyosis are very rare, and often difficult to diagnose MIXED MULLERIAN TUMORS, MALIGNANT
preoperatively. The prognosis of such adenocarcinoma is not (SARCOMATOID CARCINOMA/CARCINOSARCOMA)
adversely affected when the myometrial involvement by the
carcinoma is confined to the adenomyosis.
CLINICAL FEATURES
PATHOLOGICAL FEATURES Malignant mixed mullerian tumors (MMMT) (sarcomatoid car-
Adenomyosis shows benign invasion of the endometrium into the cinoma/carcinosarcoma of the female genital tract) are highly
myometrium, associated with reactive hypertrophy of the sur- malignant neoplasms expressing mixed epithelial and mesenchy-
rounding musculature. The ectopic endometrium in adenomyosis mal differentiation. These tumors occur anywhere in the female
is of the basalis type, and menstrual bleeding is less common than genital tract, including the peritoneum, but most commonly
in endometriosis. Occasionally, a focus of adenomyosis may in the uterus. They affect mainly postmenopausal and elderly
assume a polypoid form and project into the endometrial cavity, women, and tend to disseminate early to the pelvic and peri-
or it may involve a submucosal uterine fibroid. Adenomyosis may toneal cavity. On very rare occasions, the tumor may arise in
show multiple, large, blood-filled cysts of 1–5 cm in maximum children or young adults. These tumors are characteristically
diameter, termed ‘adenomyotic cysts’. large, bulky, soft and polypoid, and often protrude through the
cervical os. Malignant mixed mesodermal tumor has been docu-
Adenocarcinoma arising in adenomyosis mented to arise in a benign cystic teratoma of the ovary.
The current concepts strongly support the theory of single
Various histological variants of adenocarcinomas may develop
cell origin in uterine MMMT, and suggest that the mesenchy-
in foci of adenomyosis; the most common one is the usual
mal elements originated from primitive mullerian epithelial
endometrioid adenocarcinoma.
cells capable of differentiating into epithelial, mesenchymal,
The criteria for the diagnosis of carcinoma arising from
or both elements. As endometrial MMMT often protrudes
adenomyosis are:
● The carcinoma must not be situated in the endometrium or
through the cervix, it is essential to distinguish between MMMT
of cervical or endometrial origin as the former is more com-
elsewhere in the pelvis.
● The carcinoma must be seen to arise from the epithelium
monly confined to the uterus at presentation, and has a better
prognosis.
of the adenomyosis and not to have invaded from another
source; this is usually indicated by the presence of either a
transition or continuity between the benign adenomyotic PATHOLOGICAL FEATURES (Figures 7.207–7.212)
endometrial glands and the carcinomatous glands.
The epithelial component may take the appearance of an undif-
● Endometrial (adenomyotic) stromal cells must be present
ferentiated carcinoma, poorly differentiated adenocarcinoma,
to support a diagnosis of adenomyosis.
papillary, serous, clear cell, and endometrioid carcinomas. Very
Adenocarcinomas arising within adenomyosis should be dis- rarely neuroendocrine differentiation can be seen. A non-
tinguished from the more common phenomenon in which other- glandular epithelial component such as squamous, basaloid or
wise typical endometrial adenocarcinomas arising from the rarely adenoid cystic element is more commonly seen in the
eutopic endometrium extend into foci of adenomyosis. When an rare MMMT of cervical origin. The mesenchymal component
endometrial carcinoma and adenomyosis coexist in the same may show a variety of homologous or heterologous differenti-
uterus, the latter process is involved by the carcinoma in approx- ation such as stromal sarcoma, leiomyosarcoma, rhabdomyosar-
imately 25% of the cases, with a range of 10% to 60%. The coma, chondrosarcoma, and osteosarcoma. The relative
pathologist should distinguish carefully between carcinomatous contributions of the epithelial and mesenchymal components
involvement of adenomyosis and true myometrial invasion. are variable, and that is why some lesions can be misinter-
Features useful in identifying involvement of adenomyotic foci by preted as carcinoma or sarcomas according to the predominant
carcinoma include the presence of a smooth rounded contour with component. The pathologist must be careful in diagnosing
the surrounding myometrium, the presence of non-neoplastic rhabdomyosarcoma or chondrosarcoma of the uterus before
glands or endometrial-type stroma within the foci in question, excluding MMMT.
Figure 7.207 Malignant mixed mullerian tumor: is a biphasic lesion Figure 7.208 Malignant mixed mullerian tumor: the mesenchymal
showing malignant glandular element (boxed) set in a malignant component is predominately rhabdomyoblastic.
mesenchymal background.
Figure 7.209 Malignant mixed mullerian tumor: the Figure 7.210 Malignant mixed mullerian tumor: the primitive cross
rhabdomyoblasts have abundant eosinophilic cytoplasm (boxed) and striations within the rhabdomyoblasts impart a ‘finger-print’ pattern
some have vacuolated ‘spider-shaped’ cytoplasm (circled). to the cells.
Figure 7.211 Malignant mixed mullerian tumor: the mesenchymal Figure 7.212 Malignant mixed mullerian tumor: the mesenchymal
component is predominantly rhabdomyoblastic. component is predominantly chondroblastic.
The stroma of these tumors is usually very vascular, and distends the uterine cavity. The lesion is best treated by hyster-
occasionally a localized angioproliferative pattern is found. ectomy to prevent local recurrence and to exclude underlying
adenosarcoma.
Secondary features
● Hemorrhage PATHOLOGICAL FEATURES
● Necrosis
Mullerian adenofibroma is a polypoid lesion composed of broad
● Psammoma body formation
papillae projecting into cystic spaces. There are also cleft-like
● Myxoid change.
spaces lined by cuboidal or columnar, often hyperplastic of mul-
lerian epithelium of any type. The stroma is usually uniformly
Cell morphology
cellular, consisting of fibroblastic spindle cells, with additional
● The morphology of the constituent cells corresponds to areas of endometrial stromal cells in the uterine adenofibroma.
that seen in the relevant carcinoma or sarcoma seen The stroma is often more cellular in the subepithelial zones.
elsewhere. A case of uterine malignant mixed mesodermal Uterine adenofibroma with a fatty component, ‘lipoadeno-
tumor harboring endocrine cells has been reported. fibroma’ has been described.
● Mitotic figures are numerous and frequently atypical.
● Intracellular as well as extracellular hyaline eosinophilic Secondary features
globules are seen in almost all cases.
● Edema
● Vacuolar degeneration of rhabdomyoblasts may impart a
● Focal hyalinization.
lipoblastic appearance.
Cell morphology
● The glandular component is made up of cuboidal or
● Mullerian adenosarcoma
columnar, often hyperplastic mullerian epithelial cells of
● Poorly differentiated or undifferentiated carcinomas
any type.
● Various sarcomas
● The stromal cells are uniform fibroblast-like spindle cells
● Immature teratoma.
which may rarely show mild atypia. Rarely, smooth muscle
component is identified.
Special techniques
● A few mitotic figures (⬍4 per 10 HPF) are seen in the
● PAS/diastase highlights the hyaline globules. cellular subepithelial zones.
● Alcian blue/PAS may demonstrate luminal and cytoplasmic
mucin. Differential diagnosis
● Phosphotungstic acid-hematoxylin (PTAH) highlights
● Benign endometrial or endocervical polyps
the dark blue color of the hyaline globules and the cross-
● Mullerian adenosarcoma
striation of rhabdomyoblasts, when present.
● Cervical mullerian papilloma
● Reticulin stains differentiate between the epithelial and
● Polypoid adenomyoma.
mesenchymal components.
● The epithelial component shows strong positivity for
epithelial markers such as cytokeratins and EMA and
Special techniques
focal, vimentin positivity. ● The stromal cells express vimentin, and the epithelial cells
● The mesenchymal component is strongly and diffusely express epithelial markers.
positive for vimentin and in a significant proportion of
cases for smooth muscle actin and desmin. MIXED MULLERIAN TUMORS, MULLERIAN
● Myoglobin positivity is seen only in areas of rhabdo-
myoblastic differentiation. ADENOSARCOMA
● Both epithelial and mesenchymal elements may show
positive staining with alpha-1-antitrypsin (A1AT), Leu-M1, CLINICAL FEATURES
S-100 protein, Leu-7, and neuron-specific enolase (NSE).
Mullerian adenosarcoma is an uncommon tumor arising from the
endometrium, and rarely in the myometrium, endocervix, ovary,
MIXED MULLERIAN TUMORS, MULLERIAN or peritoneum. Multifocal tumors within the uterus may some-
ADENOFIBROMA times be seen. This tumor may occur at any age, but often does
so after the menopause. It is generally considered to be of low-
grade malignancy, but when associated with sarcomatous over-
CLINICAL FEATURES
growth the outcome is poor. Pelvic recurrence occurs in 25% of
Mullerian adenofibroma is an extremely rare benign mixed cases and the condition is fatal in about 10%. This tumor may
mullerian tumor occurring mainly in the uterus and cervix, and occasionally be associated with tamoxifen therapy used as an
rarely in the Fallopian tube and other extrauterine pelvic loca- adjuvant drug for breast carcinoma. Mullerian adenosarcoma can
tions. The tumor appears as a broad-based polypoid mass that also be seen in association with endometriosis.
PATHOLOGICAL FEATURES (Figures 7.213–7.216) fibroadenoma-like clefts. The stroma outgrows the epithelial
component and exhibits dense or moderate cellularity with
Mullerian adenosarcoma is multilobulated polypoid lesion which
prominent condensation of cells under the glandular epithelium.
is reminiscent of the phyllodes tumor of the breast. Within the
It may have the appearance of a low-grade stromal sarcoma of
substance of the broad papillae there are variably sized, benign
or hyperplastic endometrial glandular structures, cystic spaces or
(a)
(b)
(c)
Figure 7.216 Extrauterine mullerian adenosarcoma, bowel wall.

Leaf-like papillae (a), the cores of which are made up of endometrial
Figures 7.213–7.215 Mullerian adenosarcoma. Leaf-like cellular stromal sarcoma (b, c). In places, there is periglandular condensation
papillae lined by bland endometrial epithelium (Figures 7.213 and (c) of malignant cells.The lining epithelium shows squamous
7.215).The stroma is made up of rhabdomyoblasts (Figure 7.215). metaplasia (b).
the uterus, or a poorly differentiated sarcoma with epithelioid or ● CD10 expression might be one of the characteristics of
spindle cell features. Angiosarcomatous component has been mullerian system-derived neoplastic mesenchymal cells.
reported in adenosarcoma. When at least 25% of the lesion con- ● The proliferative activity evaluated by Ki-67
tains pure sarcoma, the term ‘adenosarcoma with sarcomatous immunoexpression is usually higher in the stroma than
overgrowth’ is used. Areas of rhabdomyoblastic, chondroblastic, the epithelium.
osteoblastic and rarely angiosarcomatous differentiation may be
present. Sometimes, a prominent smooth muscle component con-
fers an adenomyomatous appearance to the tumor. Large areas of TAMOXIFEN-RELATED GYNECOLOGICAL LESIONS
the tumor may consist only of the sarcomatous element. Focal
fibrosis, hyalinization and storiform pattern can be seen.
Occasionally, uterine adenosarcomas contain sex cord-like CLINICAL FEATURES
elements similar to those described in endometrial stromal Tamoxifen is a non-steroidal anti-estrogen which has a partial
tumors and uterine tumors resembling ovarian sex cord tumors. estrogen-antagonist activity, and is widely used as a hormonal
The clinical and pathological features of these tumors are other- adjuvant therapy for breast cancer in women with positive
wise similar to those of typical uterine adenosarcomas. receptors for estrogens. It acts as an estrogen inhibitor on the
mammary gland, but stimulates the postmenopausal uterine
Secondary features mucosa in about 25% of cases while decreasing the risk of
● Hemorrhage osteoporosis. Prolonged administration of tamoxifen has been
● Necrosis associated with a variety of benign and malignant gynecologi-
● Cystic change cal tumors, as well as other proliferative changes. It has been
● Fibrosis and hyalinization shown that the proliferation index (as measured by MIB-1) in
● Psammoma body formation benign endometrial epithelium is higher in tamoxifen users
than in non-users, and this might play a role in the reported
Cell morphology higher incidence of endometrial cancer in postmenopausal
● The epithelium is usually of endometrial type and is often tamoxifen users.
hyperplastic, but lacks significant cytological atypia.
● The stromal cells are similar to those seen in low-grade PATHOLOGICAL FEATURES
stromal sarcoma (uniform, reminiscent of normal
Tamoxifen-related polyps: endometrial polyps are the most
endometrial stromal cells, with scant, poorly defined
common endometrial pathology described in association with
cytoplasm and oval to fusiform nuclei).
postmenopausal tamoxifen exposure. The polyps are character-
● Other sarcomatous mesenchymal cells, for example
istically multiple and fibrotic, and show a variety of changes
smooth muscle cells, rhabdomyoblasts, chondroblasts,
involving the glandular and stromal elements. The stroma often
and undifferentiated spindle cells.
shows periglandular cellular condensation or a cambium layer,
● Multinucleated giant cells are occasionally seen.
and sometimes myxoid degeneration. The glandular component
● Sometimes, a foamy histiocytic component is seen.
exhibits a variety of metaplasias, polarized glands along the
long axis of polyps, ‘staghorn’ glands, cystic dilatation, and
small glands. The latter are usually inactive and reminiscent of
● Adenomyosis the ‘pill effect’; they can be seen alternating with larger, variably
● Mullerian adenofibroma (criteria that are useful in shaped glands. Polyp infarction is seen more frequently in
separating mullerian adenosarcomas from mullerian tamoxifen-related lesions. Similar morphological features may
adenofibromas include, alone or in combination: two or be seen in polyps associated with hormone replacement therapy
more stromal MFs per 10 HPF, marked stromal cellularity, and also in control groups, though to a variable, lesser extent.
and significant stromal cell atypia) Some polyps are large, with special histological features interme-
● Endometrial stromal sarcoma diate between benign and malignancy, and these might represent
● Malignant mixed mesodermal tumor a step in the tumor formation. Atypical polypoid adenomyoma
● Cervical adenosarcoma may be mistaken for benign has also been reported in relation to tamoxifen treatment.
cervical polyp or embryonal rhabdomyosarcoma It is generally accepted that the occurrence of malignancy in
(sarcoma botryoides) endometrial polyps among healthy women is up to 0.5%.
● Peritoneal adenosarcoma may be mistaken for endometriosis However, up to 3.0% of endometrial polyps recovered from
postmenopausal breast cancer tamoxifen-treated patients may
Special techniques show malignant changes. Stromal decasualization is also seen in
● The stromal cells – whether fibroblasts, endometrial these cases.
stromal cells, smooth muscle cells or rhabdomyoblasts – Tamoxifen-related carcinomas: although the incidence of
express the appropriate lineage-specific markers. endometrial cancer associated with tamoxifen use is not high, the
● There is high expression of estrogen receptors in the risk is true (a two- to three-fold increased risk in postmenopausal
epithelial component of the lesion, and irregularly positive women). A variety of carcinomas have been described, but it
in the stroma. seems there is an increased risk of the development of some
high-grade endometrial carcinomas such as malignant mixed are hyperchromatic with irregular outlines. Mononucleate
mullerian tumor, uterine serous papillary carcinoma, and clear implantation site intermediate trophoblastic cells occasionally
cell carcinoma. fuse into multinucleated cells. Implantation site intermediate
Tamoxifen-related sarcomas: sarcomas that have been trophoblastic cells infiltrate the decidua, surround glands, and
reported in patients receiving tamoxifen therapy are endometrial invade the myometrium, dissecting between smooth muscle
stromal sarcomas, adenosarcomas, and leiomyosarcomas. Some fibers, but without destroying them. These cells characteristi-
of the leiomyosarcomas reported with tamoxifen treatment cally invade spiral arteries, replacing the smooth muscle of the
show unusual features, such as epithelioid, tubular, and myxoid. vessel wall but leaving the overall structure intact. Eosinophilic
Other tamoxifen-related lesions: other changes that are seen fibrinoid material is often deposited around the implantation
in association with tamoxifen therapy are endometrial hyper- site intermediate trophoblast. Implantation site intermediate
plasia, variety of metaplasia (ciliated, papillary syncytial, trophoblastic cells are the predominant cellular population of
eosinophilic, hobnail, mucinous, squamous, and clear cell), EPSs and PSTTs.
stromal decidualization, adenomyosis, proliferative and atypi- Chorionic-type intermediate trophoblast: this is composed for
cal changes in endometriosis, cellular pseudosarcomatous the most part of relatively uniform cells with either eosinophilic
fibroepithelial stromal polyps of the lower female genital. A or clear (glycogen-rich) cytoplasm arranged in a cohesive layer
high incidence of distinctive small blue cells in Papanicolaou in the chorion laeve. Most of the cells are smaller than implan-
tests of women who had received tamoxifen treatment for tation site intermediate trophoblasts, but larger than cytotro-
breast carcinoma may also be noticed. These distinctive small phoblasts. As with implantation site intermediate trophoblastic
blue cells are found more frequently in older patients, and most cells, some chorionic-type intermediate trophoblastic cells are
probably represent non-neoplastic, proliferative reserve cells of multinucleated. The chorionic-type intermediate trophoblast is
cervical/vaginal epithelium resulting from the estrogenic ago- the cellular population found in PSNs and ETTs.
nist effect of tamoxifen. Increased incidence of benign ovarian
cysts is also seen in postmenopausal tamoxifen-treated breast CHORIOCARCINOMA
cancer patients.
CLINICAL FEATURES
TROPHOBLASTIC TUMORS AND TUMOR-LIKE Choriocarcinoma is a malignant growth of trophoblastic cells
LESIONS characterized by secretion of human chorionic gonadotropin
(hCG). Choriocarcinoma usually arises from fetal trophoblasts
Four trophoblastic lesions are thought to arise from the inter- (gestational choriocarcinoma), and rarely arises from germ
mediate trophoblast: cells in the testis or ovary or derives from dedifferentiation of
● Exaggerated placental site (EPS) other carcinomas (non-gestational choriocarcinoma). Non-
● Placental site nodule (PSN) gestational choriocarcinoma has been reported at various sites
● Placental site trophoblastic tumor (PSTT) including the stomach, bladder, breast, and lungs. Gestational
● Epithelioid trophoblastic tumor (ETT). choriocarcinoma is a highly malignant tumor which affects
women at any age after puberty, but tends to be more common
EPSs and PSTTs are related to the differentiation of the inter-
around the age of 40 years and is seen more commonly in Asiatic
mediate trophoblast in the implantation site (implantation site
than European communities. Almost half of the cases follow a
intermediate trophoblast), whereas PSNs and ETTs are related
molar pregnancy, but the condition may also follow normal
to the intermediate trophoblast of the chorion laeve (chorionic-
pregnancy, abortion, or ectopic pregnancy. Choriocarcinoma can
type intermediate trophoblast).
arise at any implantation site, including the Fallopian tube,
ovary, or any location in the uterus. The tumors metastasize fre-
BACKGROUND ON THE DIFFERENTIATION OF quently by hematogenous dissemination, and this can be the first
INTERMEDIATE TROPHOBLAST presenting feature. It is treated by use of cytotoxic chemotherapy,
and followed by regular monitoring blood levels of hCG.
Villous intermediate trophoblast: the villous intermediate tropho-
Choriocarcinoma has an overall 5-year survival of 71–81%, but
blast in the trophoblastic columns is mononucleate and larger
poor prognostic factors include advanced disease at diagnosis,
than cytotrophoblast, but smaller than the implantation site inter-
cerebral or hepatic metastases, very high pre-treatment hCG
mediate trophoblast. The constituent cells are polygonal, with
levels, and disease following full-term gestation.
clear cytoplasm and highly cohesive cell–cell interaction.
Implantation site intermediate trophoblast: these cells have a
variable appearance. In the endometrium, they are polygonal,
closely resembling the decidualized stromal cells with which they Gestational choriocarcinoma is a hemorrhagic and necrotic infil-
are admixed. In the myometrium, they are frequently spindle- trative tumor consisting of a mixture of syncytiotrophoblast (ST),
shaped and resemble the smooth muscle cells of the myometrium. cytotrophoblast (CT), and intermediate trophoblast (IT). The CT
Generally, the cytoplasm of implantation site intermediate tro- and IT tend to grow in sheets, clusters, or islands separated by ST
phoblastic cells is abundant and is eosinophilic to amphophilic. that line large angular hemorrhagic spaces; this results in distinc-
The nuclei of implantation site intermediate trophoblastic cells tive festoons and plexiform patterns. The cells are devoid of a
● Placental site trophoblastic tumor (PSTT). In contrast to

the biphasic pattern of choriocarcinoma, PSTTs are
composed of a relatively monomorphic population of
trophoblasts, and the multinucleated intermediate
trophoblastic cells in PSTT should not be confused with
the STs of choriocarcinoma. In contrast to the interlacing
pattern of elongated STs in choriocarcinoma, the
multinucleated IT cells in PSTTs are usually polygonal
or round. Additionally, PSTTs are diffusely positive for
human placental lactogen (hPL) but only focally positive
for ␤-hCG, whereas the reverse staining pattern is seen in
choriocarcinomas. The Ki-67 labeling index in Mel-CAM
(CD146)-defined IT cells is also helpful in the differential
diagnosis of PSTT versus choriocarcinoma. The Ki-67
index in IT cells of PSTTs is 14 ⫾ 6.9%, and in
choriocarcinomas is 69 ⫾ 20% (p ⬍ 0.001)
Figure 7.217 Choriocarcinoma: there is an admixture of cyto- ● Epithelioid trophoblastic tumor (ETT) (the cells in an ETT
and syncytiotrophoblasts. form discrete nests and cords). In addition, an ETT is not
associated with marked hemorrhage as in a
supporting stroma. Chorionic villi are present only in exceptional choriocarcinoma. Immunostains for ␤-hCG can be helpful
cases where the tumor arises within a normal placenta. On rare in the differential diagnosis. ␤-hCG immunostains
occasions, the tumor acquires a sarcomatoid or anaplastic cell highlight the dimorphic trophoblastic population of
pattern. Vascular invasion is usually prominent. choriocarcinoma with ␤-hCG-negative cytotrophoblast
Non-gestational choriocarcinoma often shows features of the and IT alternating with ␤-hCG-positive SCT. In contrast,
associated tumor such as germ cell tumor of undifferentiated ␤-hCG-positive cells are randomly distributed as single
carcinoma. mononucleate cells or small clusters of cells in ETTs
● Exaggerated placental site (EPS) (The immunophenotypic
Secondary features profile of trophoblastic cells in the EPS is identical to the
● Extensive necrosis and hemorrhage implantation site IT cells found in the normal placental
● Inflammatory response. site. These cells are diffusely positive for Mel-CAM
(CD146) and hPL, and focally positive for hCG and
Cell morphology placental alkaline phosphates (PLAP). The Ki-67 indices
of implantation site IT are near 0, despite the profuse
● ST cells are large, multinucleate cells with dense infiltration the cells)
eosinophilic cytoplasm containing multiple vacuoles.
Bizarre forms can be seen. Special techniques
● CT cells are a uniform population of round, oval or
● Choriocarcinoma is diffusely positive for ␤-hCG, but only
polygonal cells with sharp cytoplasmic borders. They
focally positive for hPL.
have clear or granular cytoplasm and single nuclei
● The Ki-67 index in IT cells in choriocarcinomas is
containing prominent nucleoli.
69 ⫾ 20%. The cytotrophoblast and intermediate
● IT cells are larger than CT cells; they are round, polygonal
trophoblast are CAM 5.2-positive.
or spindle cells with abundant eosinophilic or vacuolated
cytoplasm. The nuclei are irregular and hyperchromatic with
a coarse chromatin pattern; the nucleoli are smaller and EPITHELIOID TROPHOBLASTIC TUMOR (ETT)
less prominent than those in CT. Cytoplasmic intranuclear
vacuolation may be found. IT cells are mononucleate, but
bi-, tri- and multinucleate forms can be seen. CLINICAL FEATURES
● There may be considerable cytological atypia, Epithelioid trophoblastic tumor is an unusual type of tro-
pleomorphism, and bizarre cellular configurations. phoblastic tumor which is composed of chorionic-type inter-
● Nuclear changes such as coarsening and irregularity of mediate trophoblastic cells and is distinct from placental site
chromatin and the presence of multiple nucleoli. trophoblastic tumor (PSTT) and choriocarcinoma, but has fea-
● Mitoses may be either sparse or numerous, and abnormal tures resembling a carcinoma. ETTs may represent the neo-
forms may be seen. plastic counterpart of placental site nodules (PSNs). Patients
are usually in their reproductive years, with antecedent (previ-
Differential diagnosis ous) gestation. The interval between the preceding gestation
● Normal trophoblast of early gestation and diagnosis of an ETT is variable, ranging from 1 to 18 years
● Molar pregnancy (average 6.2 years). Abnormal vaginal bleeding is the most
● Undifferentiated carcinoma common presenting symptom. Rarely, a vaginal metastasis is
the presenting manifestation of a uterine tumor. Extrauterine insinuating between muscle bundles and fibers. In
ETTs without an identifiable trophoblastic lesion in the uterus addition, the cells in an ETT are smaller than those of a
have also been described in the lungs or small bowel. These PSTT and tend to grow in nests and cords – a pattern
may represent metastases from a primary uterine ETT which usually not observed in the PSTT. Blood vessels in an ETT
has disappeared. As with PSTTs, serum ␤-hCG levels are nearly are often surrounded by tumor cells, but vascular invasion
always elevated at the time of diagnosis, but are generally low is not a striking feature. In contrast, vascular invasion in
(⬍2500 mIU/mL) compared with those in patients with chorio- PSTT – like that seen at an implantation site – results in
carcinoma. ETTs generally behave in a benign fashion, with replacement of the smooth muscle of the walls of the
metastasis and death occurring in about 25% and 10% of vessels by tumor cells and hyaline-like material. Finally,
patients, respectively. Because the number of tumors that have hPL and Mel-CAM (CD146) are diffusely positive in
behaved in an aggressive fashion is small, and follow-up for PSTT, whereas staining for both of these markers in ETTs
many cases has been short, features that predict outcome have is generally focal.
not been identified. ● Placental site nodule PSNs. These are almost always
The available data suggest that – like PSTTs – ETTs may not microscopic paucicellular lesions, without associated
be responsive to chemotherapeutic agents used in to treat other necrosis. In addition, the Ki-67 index in ETTs (⬎10%) is
types of gestational trophoblastic disease (GTD). Hysterectomy significantly higher than in PSNs (⬍10%).
and lung resection have been used successfully to treat localized ● Choriocarcinoma. The cells in an ETT form discrete nests
disease. and cords. In addition, an ETT is not associated with
marked hemorrhage as in a choriocarcinoma. Immunostains
PATHOLOGICAL FEATURES for ␤-hCG can be helpful in the differential diagnosis.
␤-hCG immunostains highlight the dimorphic trophoblastic
ETTs are nodular and generally well circumscribed, although population of choriocarcinoma with ␤-hCG-negative
foci of infiltrating tumor cells may be present in the periphery cytotrophoblast and intermediate trophoblast alternating
of the tumor. The tumors are composed of a relatively uniform with ␤-hCG-positive syncytiotrophoblast. In contrast,
population of mononucleate trophoblastic cells typically ␤-hCG-positive cells are randomly distributed as single
arranged in nests, cords, and masses intimately associated with mononucleate cells or small clusters of cells in ETTs.
eosinophilic, fibrillar, hyaline-like material and necrotic debris ● Keratinizing squamous cell carcinoma of the cervix. This
that can simulate keratin. The extensive areas of necrosis sur- can be very difficult, particularly because ETTs tend to
round islands of viable tumor cells, creating a ‘geographic’ pat- grow in the lower uterine segment and cervix and because
tern of necrosis. Typically, a small blood vessel is located within they replace and merge into the endocervical epithelium.
the center of the nests of tumor. Blood vessels within the tumor Immunostains for inhibin-␣ and CK18 are very helpful.
are preserved with occasional deposition of amorphous fibri- Almost all ETTs are positive for inhibin-␣ and CK18 in
noid material in their walls. Focal calcification can sometimes the majority of tumor cells, whereas squamous cell
be identified within the lesions. carcinomas of the cervix are negative for these two
markers. Furthermore, unlike ETTs, in which the Ki-67
Cell morphology
labeling index is relatively low (10–25%), cervical
The tumor cells resemble those in PSNs, which resemble in turn squamous cell carcinomas almost always have a very high
the trophoblastic cells in the chorion laeve (chorionic-type inter- Ki-67 labeling index (⬎50%).
mediate trophoblast). These cells contain round, uniform nuclei ● Epithelioid smooth muscle tumors. These usually display
and eosinophilic or clear (glycogen-rich) cytoplasm surrounded areas composed of typical smooth muscle cells in addition
by a well-defined cell membrane. For the most part, the cells are to epithelioid areas. In addition, epithelioid smooth muscle
larger than cytotrophoblastic cells but smaller than the implanta- tumors are often positive for muscle markers, including
tion site intermediate trophoblastic cells. The tumor cell nuclei desmin and smooth muscle actin, which are not expressed
have finely dispersed chromatin and occasional prominent by ETTs. Conversely, ETTs are positive for CK18 and
nucleoli. Occasionally, larger cells resembling implantation site inhibin-␣, which are not detected in smooth muscle tumors.
intermediate trophoblastic cells can be found among the smaller ● Pulmonary ETT may be mistaken for a primary squamous
tumor cells or embedded in the extracellular hyaline matrix. The cell carcinoma of the lung. Useful clues that support the
mitotic index varies from 0 to 9 MF per 10 HPF (⫻40), with an diagnosis of ETT include a lack of cytoplasmic
average of 2 MF per 10 HPF. Although most ETTs have a uni- eosinophilia and intercellular bridges, as well as
form architectural pattern, focal areas resembling PSNs, PSTTs, infiltration of alveolar spaces by highly atypical tumor
or choriocarcinomas can occasionally be identified within the cells with preservation of the alveolar septa – features
tumor. ETTs located in the cervix sometimes grow on the surface, which are not usually seen in squamous cell carcinoma.
replacing the surface endocervical epithelium. Squamous cell carcinoma of the lung fails to react with
antibodies to inhibin-␣ and CK18.
● Placental site trophoblastic tumor. The nodular growth Special techniques
pattern and expansile border of ETTs contrasts with the ● The immunohistochemical features of ETTs are similar to
PSTT, the cells of which infiltrate the myometrium by those of chorionic-type intermediate trophoblast. The
typical trophoblastic markers including hPL, hCG, and

Mel-CAM (CD146), are only focally expressed. Thus, the
immunophenotype of ETTs contrasts with that of PSTTs,
which is diffusely positive for Mel-CAM and hPL.
● The mean Ki-67 labeling index in ETTs is 10–25%.
● ETT is CK18-positive.
EXAGGERATED PLACENTAL SITE (EPS)
CLINICAL FEATURES
The exaggerated placental site (EPS) is characterized by an
exuberant infiltration of the myometrium by implantation site
intermediate trophoblasts, and represents the extreme end of a
physiological process rather than a true lesion. The distinction
between a normal placental site and an EPS is somewhat arbitrary
because there are no reliable data quantifying the amount and
extent of trophoblastic infiltration at different stages of normal
gestation. The EPS can occur in a normal pregnancy or an abor-
tion from the first trimester, and is found in approximately 1.6%
of spontaneous and elective abortions. An EPS is a physiological
process that resolves spontaneously after curettage; no specific
treatment or follow-up is required. An EPS that is associated with
a hydatidiform mole may carry an increased risk of persistent
GTD. Follow-up by monitoring serum ␤-hCG levels should be
performed in such cases. Persistently elevated levels indicate the
presence of residual trophoblast and require further evaluation.

The EPS is composed of an extensive infiltration of the
endometrium and myometrium by individual and small cell clus-
ters of implantation site intermediate trophoblastic cells.
Occasionally, aggregates of cells form small confluent sheets.
Despite the massive infiltration by trophoblastic cells, the overall
architecture of the placental site is not disturbed. Endometrial
glands and spiral arteries may be completely engulfed by tro-
phoblastic cells, but there is no necrosis. Similarly, the smooth
muscle cells of the myometrium are separated by cords, nests,
and individual trophoblastic cells that diffusely infiltrate the
myometrium without necrosis. The trophoblastic cells in an EPS
contain abundant eosinophilic cytoplasm with hyperchromatic
and irregularly shaped nuclei. Multinucleated intermediate tro-
phoblastic cells can be numerous, and mitotic activity is usually
absent. The associated placentas are unremarkable. Complete
hydatidiform moles are always accompanied by an EPS in which
the implantation site intermediate trophoblastic cells are often
more atypical. Figures 7.218–7.220 Exaggerated placental site of Fallopian tube.
Atypical chorionic epithelium and decidual cells within the muscular
wall and lining a blood vessel. CK7 highlights the chorionic
Differential diagnosis epithelium (Figure 7.220).
● Symplastic leiomyoma. The intermediate trophoblast at the
implantation site may resemble atypical smooth muscle
cells of symplastic leiomyoma. The presence of chorionic ● Placental site trophoblastic tumor (PSTT). An EPS
villi, the infiltrative growth pattern of the trophoblastic accompanying complete hydatidiform moles is often
cells, and positive cytokeratin and hPL stains support the atypical and associated with Ki-67 labeling index
diagnosis of an EPS. that is higher (⬎5%) than that associated with
Special techniques
● The immunophenotypic profile of trophoblastic cells in
the EPS is identical to the implantation site intermediate
trophoblastic cells found in the normal placental site.
These cells are diffusely positive for Mel-CAM (CD146)
and hPL, and focally positive for hCG and PLAP.
● The Ki-67 indices of implantation site intermediate
trophoblast are near 0, despite their profuse infiltration
in EPS.
HYDATIDIFORM MOLE
CLINICAL FEATURES
Hydatidiform mole is not a true neoplasm, but rather represents
a non-invasive abnormal placenta. It is characterized by grossly
swollen chorionic villi in association with trophoblastic prolifer-
ation. There are two distinct entities; complete and partial mole.
These differ in their histogenesis and morphological appear-
ances, but generally have similar clinical features and manage-
ment. Hydatidiform mole shows a marked variation in incidence
in different parts of the world. It occurs more frequently in part
of Asia, Latin America, and the Middle East than elsewhere. The
risk of molar pregnancy is higher for women over the age of 45
years and for those under the age of 20 years. Chromosomal
abnormalities seem to play a key role in the development of
molar pregnancy. Hydatidiform mole may be followed by per-
sistent trophoblastic disease. Close follow-up is therefore essen-
tial (monitoring of serum ␤-hCG levels).
Complete hydatidiform mole is a diploid with a 46,XX karyo-
type, and is rarely triploid or tetraploid; all their chromosome
complements are paternally derived – that is, the spermatozoon
has fertilized an empty ovum. Sometimes, two spermatozoa
(one with an X and the other with a Y chromosome) fertilize
the empty ovum, and this results in 46XY chromosome com-
plements. It has been hypothesized that the formation of a mole
is associated with an excess of paternal compared with mater-
nal haploid contributions. The higher the ratio of paternal to
maternal, the greater the molar change. Complete hydatidiform
mole is grossly characterized by voluminous curetting with grape-
like transparent vesicles of 1–2 cm in diameter and has no embryo
or fetus. If an embryo is found in association with a complete
mole, twin gestations – one of which is molar – is suggested.
Complete hydatidiform mole typically presents between the 11th
and 25th week of gestation with marked uterine enlargement,
often accompanied by severe vomiting and hypertension, or it
may present with spontaneous abortion. It is associated with
marked elevation of hCG level and a classic ‘snowstorm’ pattern
Figures 7.221–7.223 Exaggerated placental site trophoblastic on ultrasonography. Complete hydatidiform mole is followed by
reaction, uterus. Atypical chorionic epithelium and decidual cells
persistent trophoblastic disease in 10–30% of cases. Choriocar-
within the muscular wall and lining a blood vessel.
cinoma is the most serious of the persistent trophoblastic diseases.
It occurs in 2–3% of complete mole.
normal pregnancy. It should be noted that the Partial hydatidiform mole accounts for up to 43% of all
concurrent finding of a mole and a PSTT has never been molar pregnancies. It most frequently shows triploidy (69 chro-
reported, nor is it likely to occur because both lesions mosomes) with two paternal sets and one maternal set (result-
are distinct gestational events that are unrelated to one ing from the fertilization of an egg with a haploid set of
another. chromosomes either by two spermatozoa, each with a set of
haploid chromosomes, or by a single spermatozoon). It has two (especially vagina, vulva, or lung). It results from complete or
populations of villi, one of normal size and the other grossly partial mole, is detected on follow-up of patients with hydatidi-
hydropic, and many show evidence of embryo or fetus. Partial form mole (elevated or rising serum levels of hCG), and may
hydatidiform mole usually presents with abnormal uterine result in transmural invasion of the uterus and parametrial tis-
bleeding and, unlike the complete moles, the size of the uterus sue. Invasive mole may rarely regress spontaneously.
is typically normal in size or small for the gestation and the
hCG level is generally not markedly elevated. It is associated
with less risk of persistent trophoblastic disease, and chorio-
carcinoma is an extremely rare occurrence. Complete mole demonstrates large, distended edematous villi
Invasive mole should only be diagnosed when molar villi are with occasional small villi. The outline of the villi is smooth, with
identified in the myometrium and its vessels or at distant sites no evidence of scalloping or irregularity as is seen in partial mole.
Figures 7.224 and 7.225 Normal villous structure.There is no undue trophoblastic proliferation. Fetal blood cells are seen in 7.225.
(a) (b)
Figure 7.226 Trophoblastic diseases: molar pregnancy.Trophoblastic proliferation, hydropic degeneration and absence of fetal red blood cells.
Many villi have central, acellular, fluid-filled spaces devoid of Special techniques
cells (‘cisterns’). The latter are separated from the surrounding ● Syncytiotrophoblasts are hCG-, hPL-, and PLAP-positive.
trophoblasts by a small rim of mesenchyme. The villi are cir- ● Intermediate trophoblasts show diffuse cytokeratin and
cumferentially surrounded by variable degrees of trophoblastic hPL staining.
proliferation. The villous stroma often lacks blood vessels, and ● Cytotrophoblasts are negative for all of the above.
neither fetal parts nor amnion are found. ● Flow-cytometry of nuclear DNA to identify ploidy.
Partial mole demonstrates a mixture of large edematous villi ● The p57KIP2 protein is a cell cycle inhibitor and tumor
and normal-sized villi. The outline shows irregular scalloping and suppressor encoded by a strongly paternally imprinted gene.
sometimes infoldings resulting in stromal inclusions. Cisterns Using a monoclonal antibody on paraffin-embedded, formalin-
are occasionally seen, and some villi show stromal fibrosis. fixed tissue sections, p57KIP2 is strongly expressed in cyto-
Villous capillaries with fetal erythrocytes are usually present. trophoblasts and villous mesenchyme in normal placenta,
The trophoblasts are only focally and mildly hyperplastic. in partial hydatidiform moles, and in spontaneous losses
Invasive mole is rarely diagnosed histologically because the with hydropic changes. In contrast, p57KIP2 expression in
disease is managed medically. However, it means the presence cytotrophoblasts and villous mesenchyme is absent or
of molar villi in the myometrium, and its blood vessels or in markedly decreased in complete hydatidiform moles. In all
distal sites. gestations, p57KIP2 is strongly expressed in decidua and in
intervillous trophoblast islands, which serve as internal
Secondary features
positive controls for p57KIP2.
● Necrosis
● Patchy calcification of villous stroma PLACENTAL SITE NODULE (PSN)
Cell morphology
Complete mole CLINICAL FEATURES
● Syncytiotrophoblastic cells (ST) are large, multinucleate Placental site nodules (PSN) occur in the reproductive age group,
cells with dense eosinophilic cytoplasm containing and are typically incidental findings in uterine curettage or cervi-
multiple vacuoles. Bizarre forms can be seen. cal biopsy specimens, and also occasionally in hysterectomy
● Cytotrophoblastic cells (CT) are a uniform population of specimens. Many patients have a history of therapeutic abortion
round, oval, or polygonal cells with sharp cytoplasmic and Cesarean section, and a significant number have a history of
borders. They have clear or granular cytoplasm and single a tubal ligation. The antecedent pregnancy has been reported to
nuclei containing prominent nucleoli. have occurred as many as 108 months before the diagnosis. In
● Intermediate trophoblastic cells (IT) are larger than CT, patients with tubal ligations, it is not clear whether the PSN is
they are round, polygonal or spindle cells with abundant derived from persistent trophoblast from a pregnancy that pre-
eosinophilic or vacuolated cytoplasm. The nuclei are ceded the tubal ligation, or from a new gestation following an
irregular and hyperchromatic with a coarse chromatin unsuccessful tubal ligation. PSNs range in size from 1 to 14 mm
pattern. The nucleoli are smaller and less prominent than (average 2.1 mm). Occasionally, multiple nodules are found.
those in CT. Cytoplasmic intranuclear vacuolation may be When grossly visible, PSNs appear as a yellow or tan-colored
found. Intermediate trophoblastic cells are mononucleate, surface nodule or plaque in the endometrium (superficial
but there may be considerable cytological atypia, with myometrium), the lower uterine segment, or the endocervix.
nuclear enlargement and irregularity. Mitoses may be
sparse or numerous and abnormal forms may be seen. PATHOLOGICAL FEATURES (Figure 7.227)
Partial mole Microscopically, PSNs are nodular with rounded, well-

circumscribed borders surrounded by a thin rim of chronic
● The trophoblasts are mainly of the ST and CT types.
inflammatory cells and occasionally decidual cells. The lesions
are characterized by an abundant hyalinized or fibrinoid extra-
cellular matrix that separates trophoblastic cells resembling
Hydatidiform mole those found in the chorion laeve of the fetal membranes
● Early non-molar pregnancy, especially those with hydropic (chorionic-type intermediate trophoblast). The trophoblastic cells
change and blighted ovum. The edema is only a microscopic are arranged in a haphazard pattern – dispersed singly, in small
finding, the villi are surrounded by attenuated trophoblasts, clusters and cords, or occasionally as diffuse sheets. The cells
when trophoblastic proliferation is present, it is only polar vary in size, with many having relatively small uniform nuclei
and not circumferential and shows no evidence of atypia, and a few having large, irregular, and hyperchromatic nuclei.
and cisterns are occasionally encountered. Multinucleated cells are occasionally present. The cytoplasm of
the larger trophoblastic cells is abundant and eosinophilic to
Invasive mole amphophilic, whereas the smaller cells contain glycogen-rich,
● Non-invasive mole clear cytoplasm. Mitotic figures are rare or absent.
● Choriocarcinoma (lacks villi) Atypical PSNs are an intermediate stage of development
● Placenta increte or percreta (the villi lack hydropic change) between a PSN and an ETT. The few lesions for which we have
intermediate trophoblasts. They react with antibodies

against CK, EMA, PLAP, and inhibin-␣. Most PSNs also
express the ‘typical’ intermediate trophoblastic markers,
including hPL and Mel-CAM (CD146), although only in
a small number of cells. The trophoblastic cells in PSNs
exhibit mild proliferative activity with a Ki-67 labeling
index of about 5%, similar to that in the intermediate
trophoblastic cells in the chorion laeve (3–6%). These
findings contrast with the absence of Ki-67 labeling in
trophoblastic cells in the normal implantation site.
PLACENTAL SITE TROPHOBLASTIC TUMOR (PSTT)
CLINICAL FEATURES
Patients usually are in the reproductive age group and present
Figure 7.227 Pregnancy plaque: a nodule of hyalinized with either amenorrhea or abnormal bleeding. Some patients
amyloid-like stroma representing a completely scarred decidua
may have uterine enlargement, and frequently are thought to
or pregnancy products.
be pregnant. When uterine enlargement ceases, the diagnosis of
follow-up information have had a benign behavior. Atypical a missed abortion is usually made. Serum levels of ␤-hCG are
PSNs are intermediate in size between typical PSNs – which generally low. In contrast to choriocarcinoma, which is prefer-
rarely exceed 4 mm in diameter – and ETTs, which are usually entially associated with a complete mole, PSTTs occur most
at least a few centimeters in greatest dimension. These atypical commonly following a normal pregnancy or non-molar abor-
PSNs tend to have higher cellularity, and the trophoblastic cells tion; in only 5–8% of patients is there a clinical history of a
are arranged in more cohesive nests and cords compared with complete mole. Sex chromosome analysis suggests that the
typical PSNs. The Ki-67 labeling index in atypical PSNs is development of PSTTs involves the paternal X chromosome.
higher than in normal PSNs but lower than in ETTs. PSTTs often invade through the myometrium to the serosa
and, therefore, may lead to perforation. Despite deep myome-
Differential diagnosis trial invasion, most PSTTs are self limited, and some patients
have been cured by curettage alone. Approximately 10–15% of
● Placental site trophoblastic tumor PSTT: their microscopic
PSTTs are clinically malignant. The mortality rate in patients
size, circumscription, extensive hyalinization, and
with PSTTs is about 15–20%. The tumor may result in wide
paucicellularity are features that separate them from
disseminated metastases resembling the distribution of meta-
PSTTs. PSNs are positive for placental alkaline
static choriocarcinoma, with the lungs, liver, abdominal cavity,
phosphatase, but only focally positive or negative for
and brain being the most commonly involved sites.
Mel-CAM (CD146) and hPL. In contrast, PSTTs have
Despite the low levels of serum ␤-hCG in patients with PSTTs,
diffuse staining for Mel-CAM (CD146) and hPL, but
this is the best available marker to monitor the course of the
show only scattered and faint staining for PLAP.
disease, although the disease may still progress even if ␤-hCG
● Cervical squamous cell carcinoma: the circumscription of
levels are low. For those patients with undetectable or very low
the lesion, abundant eosinophilic extracellular hyalin, and
serum levels of ␤-hCG, the urinary ␤-core fragment of ␤-hCG
lack of mitotic activity favor a PSN. The majority of PSNs
may be a better method to monitor response to treatment.
express inhibin-␣ and CK18, but intraepithelial squamous
The most important prognostic factor is the FIGO stage.
lesions and squamous cell carcinomas do not. In contrast,
The outcome of patients with FIGO stage I–II disease after
PSNs are only focally positive or negative for high-
hysterectomy is excellent, whereas those patients with FIGO
molecular-weight cytokeratin, whereas cervical squamous
stage III–IV diseases have a 30% survival rate. Among the
cell carcinomas are diffusely positive. Additionally, the
histopathological features that influence prognosis is the pres-
Ki-67 labeling index is low (⬍10%) in PSNs in contrast
ence of extensive tumor necrosis. Other factors such as DNA
to the generally high Ki-67 labeling index in cervical
ploidy, immunohistochemical features, and S-phase fraction
carcinoma and intraepithelial squamous lesions (⬎50%).
seem to have little prognostic significance.
The immunoreactivity of ␤-hCG is not helpful in these
Extrauterine placental site trophoblastic tumor has rarely
cases because both PSNs and cervical carcinomas can be
been described in the pouch of Douglas as a complication of
focally reactive to ␤-hCG.
calcified abdominal pregnancy.
● Epithelioid trophoblastic tumor (ETT).
Special techniques PATHOLOGICAL FEATURES (Figures 7.228–7.230)

● The trophoblastic cells in the PSN exhibit an The predominant cell type in PSTTs is implantation site
immunophenotype similar to that of trophoblastic cells in intermediate trophoblast, monomorphic cells with occasional
the chorion laeve, but distinct from the implantation site multinucleated giant cells. The cells form confluent sheets, but
Figure 7.228 Placental site trophoblastic tumor: abnormal

trophoblasts with focal necrosis.The arrow indicates a mitotic figure.
Figure 7.230 Placental site trophoblastic tumor.The large epithelioid

cells exhibit mitotic figures, some of which are abnormal (circled).
● Exaggerated placental site (EPS): features that support
the diagnosis of PSTT include confluent masses of
trophoblastic cells, unequivocal mitotic figures, and
absence of chorionic villi. In contrast, the EPS is
microscopic, the cells are separated by masses of hyaline
material admixed with decidua and chorionic villi, has no
mitotic figures, and shows multinucleated trophoblastic
cells. The Ki-67 labeling index in a PSTT is significantly
elevated (14 ⫾ 6.9%), but it is near 0 in an exaggerated
implantation site. A diagnosis of a PSTT should be
strongly considered if the Ki-67 index in implantation
site intermediate trophoblastic cells exceeds 5%.
● Choriocarcinoma: in contrast to the biphasic pattern of
choriocarcinoma, PSTTs are composed of a relatively
Figure 7.229 Placental site trophoblastic tumor.The myometrium
is infiltrated by large epithelioid cells with nuclear pleomorphism. monomorphic population of trophoblasts, and the
multinucleated intermediate trophoblastic cells in PSTT
should not be confused with the syncytiotrophoblasts of
at the periphery of the tumor they invade singly or in cords and choriocarcinoma. In contrast to the interlacing pattern of
nests, characteristically separating individual muscle fibers and elongated syncytiotrophoblasts in choriocarcinoma, the
groups of fibers. The individual neoplastic cells extensively multinucleated intermediate trophoblastic cells in PSTTs
infiltrate the endomyometrium and may deeply penetrate the are usually polygonal or round. PSTTs are diffusely
uterine wall. Although some tumors appear to cause relatively positive for hPL but only focally positive for ␤-hCG,
little tissue destruction, others are associated with extensive whereas the reverse staining pattern is seen in
necrosis. As in the normal placental site, PSTTs are character- choriocarcinomas. The Ki-67 index in intermediate
ized by abundant extracellular eosinophilic fibrinoid material. trophoblastic cells of PSTTs is 14 ⫾ 6.9%, and in
The neoplasm displays a characteristic form of vascular inva- choriocarcinomas is 69 ⫾ 20%.
sion in which blood vessel walls are extensively replaced by ● Smooth muscle tumors: PSTT often has a highly infiltrative
trophoblastic cells and fibrinoid material, as observed in the pattern within the myometrium, dissecting among the
normal placental site. PSTTs are generally not associated with smooth muscle fibers and simulating origin from these cells.
the presence of chorionic villi. Helpful clues in the differential diagnosis include the
On rare occasions, PSTT shows histological features of both distinctive pattern of vascular invasion and the deposition
choriocarcinoma and PSTT (mixed choriocarcinoma-PSTTs). of fibrinoid material in PSTT, features not found in smooth
Similarly, a PSTT can also be associated with an ETT. muscle tumors or most other malignancies. Positive staining
for hPL, inhibin-␣ and CK18, and negative staining for Endometrial stromal sarcoma
smooth muscle markers, confirm the diagnosis of PSTT. ● Endometrial stromal tumors resembling ovarian sex cord
● Poorly differentiated carcinoma and metastatic melanoma: tumors

immunohistochemical stains for hPL, inhibin-␣ and ● Endometrial stromal neoplasms with endometrial glands
HMB-45 help to distinguish PSTTs from poorly Undifferentiated uterine sarcoma

differentiated carcinomas and melanomas. Smooth muscle tumors
● Epithelioid trophoblastic tumor (ETT). ● Leiomyoma
– Variants of leiomyoma
Special techniques Cellular leiomyoma
● PSTTs are immunoreactive for cytokeratin (AE1/AE3 cocktail Epithelioid (plexiform, leiomyoblastoma, clear cell)
and CK18), inhibin-␣, hPL, and Mel-CAM (CD146), but Hemorrhagic cellular leiomyoma
rarely positive for ␤-hCG or PLAP, an immunophenotype Lipoleiomyoma
characteristic of implantation site intermediate trophoblast. Symplastic (atypical or bizarre) leiomyoma
● Leiomyosarcoma
– Variants of leiomyoma
WHO CLASSIFICATION OF UTERINE CORPUS Epithelioid
TUMORS Myxoid
● Other smooth muscle neoplasms
– Benign metastasizing leiomyoma

Epithelial tumors and related lesions
– Diffuse leiomyomatosis
Endometrial hyperplasia (with cytological atypia)
– Disseminated peritoneal leiomyomatosis
Simple
– Intravenous leiomyomatosis
Complex (adenomatous)
Mixed endometrial stromal and smooth muscle tumors
Atypical endometrial hyperplasia
Adenomatoid tumor
Simple
Other mesenchymal tumors
Complex (adenomatous with atypia)
Homologous
Endometrial carcinoma
Heterologous
● Common variant Mixed epithelial and mesenchymal tumors
– Endometrioid adenocarcinoma with squamous differen- Benign
tiation (adenoacanthoma and adenosquamous carcinoma) Adenofibroma
● Rare variants Adenomyoma
– Villoglandular adenocarcinoma Malignant
– Secretory adenocarcinoma Adenosarcoma
● Homologous
– Ciliated adenocarcinoma
● Heterologous
Serous adenocarcinoma
Clear cell adenocarcinoma Carcinofibroma
Mucinous adenocarcinoma Carcinosarcoma (malignant mesodermal mixed tumor,
Squamous cell carcinoma malignant)
● Homologous
Mixed types carcinoma
● Heterologous
Tumors of germ cell type
Mesenchymal tumors and related lesions Neuroendocrine tumors
Endometrial stromal tumors Lymphoma and leukemia
Endometrial stromal nodule Secondary tumors
TUMORS OF THE OVARY
EPITHELIAL–STROMAL TUMORS always benign and show no extraovarian implants; more-

over, borderline tumors are somewhat larger than the benign
lesions.
CLEAR CELL TUMORS Clear cell carcinoma constitute up to 11% of all ovarian
carcinomas, and are bilateral in up to 10% of cases. Similar
tumors also arise in extraovarian locations such as the uterus,
CLINICAL FEATURES
cervix, vagina, and urinary tract, or from broad ligament, sig-
Benign and borderline clear cell tumors of the ovary are very moid mesocolon, pelvic and abdominal endometriosis. This
rare, and occur at about the age of 45 years. They are almost lesion has rarely been seen in association with other tumors
such as benign mucinous tumor and rhabdomyosarcoma. Clear ● Reticular pattern shows variably sized and shaped cystic
cell ovarian adenocarcinoma may often be associated with spaces lined by attenuated epithelium; these are often
endometriosis, more so than the endometrioid type of ovarian separated by hyalinized stroma.
carcinoma. Paraneoplastic hypercalcemia is an uncommon but
recognized change in this type of carcinoma. Similarly, para-
thyroid hormone-related protein (PTH-rP) has rarely been
detected in recurrent clear cell carcinoma. This type of ovarian
carcinoma is chemo-resistant to platinum-based chemotherapy,
and has a poor prognosis.
Clear cell adenofibroma consists of a fibrous cellular or hyalin-
ized stroma containing glandular and tubular structures of var-
ious sizes and shapes. The lining epithelial cells have clear
cytoplasm and are often arranged in a hobnail pattern.
Clear cell cystadenoma and cystadenofibroma consists of
broad papillae projecting from the surface or into cystic spaces.
They are lined mainly by hobnail and clear cells and have dense
fibrous or markedly edematous, or cellular fibrous cores. A solid
adenofibromatous component is occasionally seen in the wall
of the lesion.
Clear cell proliferating (borderline) tumors are similar to benign
clear cell tumor, but in addition show more glandular or tubu-
lar crowding, nuclear pleomorphism and up to 3 mitoses per
10 HPF, but with no evidence of stromal invasion. Small solid
nests of clear cells with smooth outlines are sometimes found.
Clear cell adenocarcinoma (Figures 7.231–7.237)

This lesion can show a variety of histological appearances:
● A common pattern is the presence of small or large
sheets of polyhedral clear cells separated by delicate
fibrous septa.
● The second major pattern, the tubulopapillary pattern,
shows numerous relatively uniform papillae lined by clear,

hobnail, eosinophilic or secretory cells. These papillae have
hyalinized or loose connective tissue cores. Complex cystic
and glandular tubular structure may also be seen.
Figures 7.232–7.234 Clear cell carcinoma of ovary. Branching

papillae with hyalinized cores and clear cell morphology. Hepatoid
Figure 7.231 Clear cell carcinoma. Branching papillae with morphology (Figure 7.233) and thin ectatic infiltrative glands are
hyalinized cores and clear cell morphology (Figure 7.233). sometimes seen (Figure 7.234).
● Solid and microcystic patterns are also commonly seen,

either focally or throughout the entire tumor. The
microcystic spaces represent coalescence of mucin droplets.
● A hepatoid pattern is characterized by solid proliferation
of eosinophilic malignant cells arranged in sheets,
trabeculae, cords or nests reminiscent of those seen in
hepatoid carcinoma of the ovary. In reticular pattern, some
tumors have loose, edematous stroma with their cells
arranged in a reticular pattern reminiscent of yolk sac
tumor.
● Tumors with heavy lymphoplasmacytic infiltrate may be
seen, causing a resemblance to dysgerminoma.
● Bizarre malignant cells may be dispersed or line most of
the glandular structures, giving the tumor a rather
different pattern.
● One rare pattern is the presence of small clusters of
epithelial cells within a loose fibrous stroma reminiscent of
Kruckenberg tumor.
● A mixture of the above patterns may be seen, and other
types of mullerian epithelial differentiation such as
endometrioid or serous carcinoma can also be present.
● Clear cell adenofibrocarcinoma/cystadenofibrocarcinoma is
a rare variant of malignant clear cell tumor. It shows
excessive stroma, with very little evidence of destructive
stromal invasion.
Cell morphology
● The three major cells seen in clear cell carcinoma are the
clear cells, the eosinophilic cells, and the hobnail cells.
● The clear cells are polyhedral, have distinct cell borders,
with abundant clear cytoplasm and eccentrically located
rounded or angular nuclei, often with prominent nucleoli.
Figures 7.235 and 7.236 Clear cell carcinoma. In this case, in They resemble those cells seen in Arias–Stella reaction of
addition to the clear cell morphology, there are cells with a
gestational endometrium.
prominent ‘bull’s-eye’ pattern and intracytoplasmic mucin, highlighted
by AB/PAS staining. ● Hobnail cells have little cytoplasm, but large bulbous
nuclei that protrude into the lumina of the glandular or
cystic spaces.
● Eosinophilic cells with granular cytoplasm.
● Flattened cells may line some of the cystically dilated spaces.
● Intra- and extracellular PAS-positive and diastase-resistant
globules are seen in 70% of clear cell carcinomas.
● Some cells contain intracytoplasmic mucin with a single
central eosinophilic droplet imparting a ‘bulls-eye’
appearance.
● Formation of basement membrane-like substance or
so-called collagen core ‘raspberry body’ is characteristic
of clear cell carcinoma of the ovary in ascites cytology.
Secondary features
● Microcalcification
● Hemorrhage and necrosis
● Lymphocytic infiltrate.
Figure 7.237 Clear cell carcinoma: prominent ‘hobnail’ pattern.
● Less common patterns include the presence of granular ● Adenomatoid tumor
eosinophilic (oxyphilic) cells scattered amongst the clear ● Metastatic renal cell carcinoma
cells or in small clusters. ● Endometrioid carcinoma
● Hepatoid carcinoma PATHOLOGICAL FEATURES

● Dysgerminoma
Benign endometrioid tumors (adenofibroma and
● Steroid cell tumors
cystadenofibroma)
● Yolk sac tumor
● Kruckenberg tumor These show simple tubular and cystic glands, similar to other
● Metastatic colonic carcinoma: although intestinal types of benign adenofibroma (serous, mucinous or clear cell),
adenocarcinomas metastatic in the ovary typically simulate but are lined by epithelium resembling that of proliferative
endometrioid adenocarcinoma of the usual type or endometrium. Squamous metaplasia or morules can be seen.
mucinous adenocarcinoma, they may mimic either primary Mitotic figures are rarely seen. Smooth muscle fibers and
clear cell adenocarcinoma or the secretory variant of luteinized cells may be prominent in the stroma.
endometrioid adenocarcinoma, particularly when the
Borderline endometrioid tumors (Figures 7.238–7.251)
primary tumor is, even focally, the clear cell variant of
intestinal adenocarcinoma These include low-grade adenofibromatous and cystadenofi-
● Malignant perivascular epithelioid cell neoplasms: in spite bromatous variants, atypical proliferative endometrioid tumors.
of the epithelial-like appearance, the tumor cells are They show crowded and complex endometrial glands reminiscent
negative for epithelial markers but are strongly positive of endometrial polyp or endometrial hyperplasia embedded in
with the melanogenesis-related marker HMB45. Other
markers including S-100 protein, vimentin, muscle-specific
actin, desmin and chromogranin A, are negative.
Special techniques
● The clear cell change is due to the presence of glycogen
and not mucin; sometimes stainable fat can also be
detected.
● PAS/diastase and PTAH highlight the eosinophilic globules.
● Alcian blue highlights the focal intracellular and
intraluminal mucin secretion.
● Aside from minor differences, clear cell carcinoma appears
to have the same immunophenotype regardless of whether
it originates in the endometrium, ovary, or genitourinary
tract. The characteristic immunoprofile is positivity for
CK7, CAM 5.2, CEA, Leu-M1 (CD15), vimentin, bcl-2,
p53, and CA-125; with variably positivity for ER; and
Figure 7.238 Proliferating endometrioid ovarian tumor.
negative for CK20 and progesterone receptor (PR).
ENDOMETRIOID TUMORS
CLINICAL FEATURES
Benign endometrioid tumors are very rare, mostly unilateral
cystadenofibromas that are seen in older women.
Proliferating (borderline) endometrioid tumors are extremely
rare, occurring in older women (aged 55–60 years), and may
be associated with synchronous endometrial hyperplasia or
carcinoma.
Endometrioid carcinoma is the second most common ovarian
carcinoma after serous adenocarcinoma (constituting up to 24%
of all primary ovarian carcinomas). It mainly affects women over
the age of 50 years, with very rare examples occurring in young
girls. Pre-existing endometriosis is seen up to 17% of cases, and
a synchronous primary endometrial carcinoma in 5–30%. This
tumor may rarely be associated with long-term tamoxifen use.
Ovarian endometrioid tumors with yolk sac tumor component
should be considered as a variant of endometrial carcinoma.
Its recognition is necessary in view of its unusually aggressive Figure 7.239 Proliferating endometrioid ovarian tumor: features
behavior and poor prognosis. reminiscent of complex endometrial hyperplasia.
Figure 7.242 Moderately differentiated endometrioid

carcinoma.
Figure 7.240 Proliferating endometrioid ovarian tumor: features

reminiscent of complex endometrial hyperplasia.
Figure 7.241 Well-differentiated endometrioid carcinoma with

morule formation.
ovarian hyalinized or collagenous stroma. In high-grade proli-

ferating endometrioid tumor, the architectural pattern is very
complex and similar to that of atypical endometrial hyperplasia,
with a villoglandular or papillary appearance. Nuclear strati-
fication and up to 4 mitoses per 10 HPF are seen. Squamous
metaplasia or morules, focal smooth muscle metaplasia and
stromal luteinization can also be seen.
A rare example of collagenous spherulosis mimicking
keratinizing squamous metaplasia has been reported in a bor-
Figures 7.243 and 7.244 Endometrioid carcinoma, sex cord
derline endometrioid tumor of the ovary. A well-differenti- differentiation. Malignant epithelial tumor with microacinar/
ated endometrioid adenocarcinoma may on rare occasions microfollicular pattern reminiscent of granulosa cell tumor. Alcian
coexist with benign and borderline endometrioid adenofibroma. blue highlights the intracytoplasmic mucin.
Figure 7.248 Endometrioid carcinoma, sex cord differentiation.

Alcian blue stain highlights the intracytoplasmic mucin.
Figure 7.249 Endometrioid carcinoma, sex cord differentiation.

CK7 shows strong staining of the epithelial cells.
Endometrioid carcinoma (Figures 7.241–7.251)

● The usual type endometrioid carcinoma shows all the
features of the classic endometrioid endometrial carcinoma
of the uterus with predominance of tubular glands,
complex glandular or microglandular patterns or cystically
dilated glands or papillary structures. These are lined by
pseudostratified epithelium with smooth luminal borders
(unlike serous tumors, which show irregular, micropapillary
luminal borders with cells shedding and falling out into the
luminal spaces). Endometrioid carcinoma may also show
Figures 7.245–7.247 Endometrioid carcinoma, sex cord evidence of secretory change or squamous metaplasia.
differentiation. Malignant epithelial tumor with small glandular
structures separated by plump stromal cells reminiscent of sex cord Poorly differentiated endometrioid carcinoma may be
tumor. difficult to differentiate from other poorly differentiated
ovarian carcinomas. Some tumors show other mullerian
The term ‘atypical proliferative tumor with intraepithelial elements such as serous or clear cell patterns.
carcinoma’ is used when there is high-grade cytology but ● Endometrioid carcinoma resembling sex cord stromal
no stromal invasion, and ‘atypical proliferative tumor with tumor may have insular, trabecular or microfollicular
microinvasion’ when there are foci of microinvasion of ⬍5 mm. patterns reminiscent of the various patterns seen in
Frankly invasive carcinoma shows invasion of at least 5 mm. granulosa cell tumor.
Figures 7.250 and 7.251 Endometrioid carcinoma: microacinar and trabecular patterns.
● Endometrioid carcinoma resembling Sertoli–Leydig cell eosinophilic debris with nuclear fragments. Although
tumor consists of tubules with intervening stroma containing intestinal adenocarcinomas metastatic in the ovary
luteinized stromal cells reminiscent of Leydig cells. typically simulate endometrioid adenocarcinoma of the
● Endometrioid carcinoma with retiform pattern shows usual type or mucinous adenocarcinoma, they may mimic
glandular structures reminiscent of hyperplastic or either primary clear cell adenocarcinoma or the secretory
neoplastic rete testis. variant of endometrioid adenocarcinoma, particularly
● Other rare variants include those with adenosquamous, when the primary tumor is, even focally, the clear cell
spindle cell or yolk sac differentiation, and those with variant of intestinal adenocarcinoma
pilometrixoma-like areas. ● Granulosa cell tumor
● Sertoli–Leydig cell tumor
Secondary features ● Poorly differentiated serous or mucinous carcinoma
● Hemorrhage ● Poorly differentiated clear cell carcinoma
● Necrosis
● Psammoma body formation Special techniques
● Squamous morules or squamous metaplasia ● Alcian blue/PAS highlights – at least focally – luminal and
● Keratin granulomas intracytoplasmic mucin. This is a very useful and easy
method to distinguish quickly between epithelial
Cell morphology malignancy and sex cord stromal tumors.
Endometrioid carcinoma ● PAS-positive and diastase-resistant hyaline eosinophilic
globules may be seen.
● The constituent cells vary according to the degree of
● Like other epithelial ovarian tumors, the cells are
differentiation. They are generally cytologically malignant
CK7-, EMA- and CA125-positive, and CK20- and
with large vesicular nuclei and often with prominent nucleoli.
CEA-negative. The foci of keratinization may show
● Sometimes ciliated cells are predominant.
CEA staining.
● Tall columnar secretory cells with subnuclear or
● Inhibin, CD99, CK7, and EMA are useful markers in
supranuclear vacuolation.
the differential diagnosis between sex cord–stromal
● Large (oxyphilic) eosinophilic cells may be prominent.
tumors and endometrioid carcinomas resembling
● Occasionally, histiocytic giant cells are seen within
sex cord–stromal tumors, as inhibin and CD99 usually
cellular debris within the lumina of some glands.
stain sex cord–stromal tumors, and CK7 and EMA stain
Differential diagnosis carcinoma.
● Endometrioid carcinoma is often strongly
Endometrioid carcinoma vimentin-positive and CEA-negative, which greatly
● Metastatic adenocarcinoma of bowel origin: this usually aids in distinguishing them from endometrioid or
shows more extensive tumor necrosis and contains luminal pseudoendometrioid tumors that arise in the endocervix
and colon and are rarely and very focally vimentin-positive, MUCINOUS TUMORS, MALIGNANT (MUCINOUS
and usually CEA-positive.
CARCINOMA)
MUCINOUS TUMORS, BENIGN (MUCINOUS
CLINICAL FEATURES
CYSTADENOMA)
Mucinous carcinoma constitutes 10% of all ovarian mucinous
tumors, and 6–10% of all primary malignant ovarian neo-
CLINICAL FEATURES plasms. It most commonly affects women between the ages of
Mucinous cystadenoma constitutes 80% of all ovarian mucin- 30 to 60 years, and is bilateral in about 25% of cases.
ous tumors, and 20% of all benign ovarian neoplasms. It most Mucinous carcinoma is cystic and multilocular, varies in size
commonly affects women between the ages of 20 to 40 years. from a few to several centimeters (up to 50 cm), and often con-
The tumor is bilateral in about 5% of cases, is cystic and multi- tains solid and papillary areas.
locular, and varies in size from a few to several centimeters
(15–50 cm). These lesions can be associated with benign cystic PATHOLOGICAL FEATURES (Figures 7.252–7.255)
teratoma in 5% of cases, and may be seen in association with Mucinous carcinoma of the ovary may show features of benign
other malignant or benign ovarian tumors or rarely in associa- and borderline mucinous tumor, but with evidence of stromal
tion with pancreatic mucinous tumors. invasion. Alternatively, the tumor consists of clearly malignant
glands with mucin secretion both within the cells and in the
PATHOLOGICAL FEATURES glandular lumina, and it may be of well, moderate or poor
Mucinous cystadenomas vary from a simple unilocular cyst to
complex multilocular pattern. These variably sized cystic spaces
are lined by a single layer of endocervical-type or sometimes
intestinal-type epithelium. Proliferation of smaller acini or crypt-
like areas at the base of the cyst may produce a pseudo-invasion
pattern. Simple fronding and complex papillary areas can be
seen. Dilatation of some of the locules or small cystic spaces may
result in thinning of the wall and eventual rupture, with extrava-
sations of mucinous material into the ovarian stroma resulting in
pseudomyxoma ovarii or florid foreign body giant cell reaction.
Secondary features
● Presence of foamy macrophages
● Polymorph infiltrate
● Stromal luteinization
● Bone formation.
Figure 7.252 Mucinous carcinoma: crowded glands lined by
Cell morphology
malignant epithelium.
● Tall columnar endocervical-type mucinous cells with
small basal nuclei
● Intestinal goblet cells
● Paneth cells (rare)
● Argentaffin cells (uncommon)
● Bile-secreting cells (rare)
● Occasional mitotic figures can be seen in the base of the
crypts
● Bizarre degenerative nuclear change may occasionally be
seen in benign mucinous cyst
● Focal squamous metaplasia may be seen.
● Mucinous tumor of borderline malignancy: this shows
heaping up of cells and the presence of mitoses and
cellular atypia.
Special techniques Figure 7.253 Mucinous carcinoma: luteinized ovarian stromal cells
are commonly found in mucinous ovarian tumors. Arrow indicates
See Mucinous carcinoma, which follows. early budding; the box indicates the presence of luteinized stromal cells.
Special techniques
● The cells contain mucinous material and therefore stain
with Alcian blue.
● Silver stains highlight the occasional argentaffin cells.
● Mucinous ovarian carcinomas are CK7-positive
(100%), CEA-positive (85%), CK20-positive (25%), and
CA125-negative (100%). CK20 usually indicates lower
intestinal origin, although some appendiceal tumors
express CK7.
● The cells are usually negative for estrogen receptors (ER).
MUCINOUS TUMORS, PROLIFERATING

(BORDERLINE)
CLINICAL FEATURES
Proliferating (borderline) mucinous tumor constitutes 10% of
all ovarian mucinous tumors affecting women between the ages
of 9 and 70 years (median age 35 years). It may be seen in asso-
ciation with pancreatic mucinous tumors, or in association with
extraovarian mucinous metaplasia. The lesion rarely progresses
into invasive disease. Nearly all mucinous borderline tumors
which display aggressive behavior have been associated with
pseudomyxoma peritonei, a condition now known to be of
appendiceal origin. The remaining mucinous borderline tumors
are always confined to the ovaries and have a benign behavior.
Figures 7.254 and 7.255 Mucinous carcinoma usually shows Traditionally there are two subtypes:
features of benign and borderline/proliferating tumor. ● Endocervical proliferating (borderline) mucinous tumor,
which constitutes 15% of MBTs, is bilateral in 40%, and

differentiation. Focal mural nodules of anaplastic carcinoma or is associated with endometriosis in 30%. This subtype is
undifferentiated small neuroendocrine carcinoma may be seen. biologically different, and has an apparently good
Malignant mucinous adenofibroma shows cytologically and prognosis even in the presence of stage II or III disease.
architecturally malignant glands, but these present in abundant When associated with peritoneal implants, it is in the form
dense ovarian stroma. A pseudomyxomatous pattern with of discrete nodules. This is currently considered as low-
small nests of carcinoma cells simulating pseudomyxoma peri- grade proliferating mucinous tumor.
tonei may occasionally be seen. Rarely, a poorly differentiated ● Intestinal proliferating (borderline) mucinous tumor is
mucinous carcinoma may mimic Krukenberg tumor in having bilateral in only 6% of cases and shows no association
small clusters or single cells infiltrating dense fibrous stroma. with endometriosis. Moreover, its peritoneal implants are
in the form of pseudomyxoma peritonii and have a poor
Secondary features prognosis. This lesion is therefore considered to be a high-
● Presence of foamy macrophages grade proliferating mucinous tumor.
● Polymorph infiltrate Mucinous proliferating (borderline) ovarian tumors with
● Necrosis microinvasion: microinvasion is an infrequent finding and is
● Hemorrhage. defined as the presence of very early buds or isolated cell nests
that are seen adjacent to the epithelium of the proliferating
Cell morphology
tumor. It appears that the presence of microinvasion has no
● Endocervical type mucinous cells clinical implication with respect to treatment or prognosis.
● Intestinal goblet cells Pseudomyxoma ovarii is the presence of mucin dissecting
● Paneth cells into the ovarian stroma. This occurs in about 50% of cases of
● Argentaffin cells MBTs, and usually precedes the development of the more sin-
● Mitotic figures are frequently seen. ister process of pseudomyxoma peritonei.
Pseudomyxoma peritonei is the presence of mucinous material
Differential diagnosis within the peritoneal cavity, usually associated with viable tumor
● Mucinous tumor of borderline malignancy cells. The mucin may also dissect into the peritoneal surfaces, and
● Intestinal carcinoma with ovarian metastases in the serosa and muscular layer of visceral organs. The great
● Endometrioid carcinoma. majority of the ovarian tumors associated with pseudomyxoma
peritonei also have ‘pseudomyxoma ovarii’, with atypical epithe-

lium. This condition is usually associated with a poor prognosis
due to local adhesion, intestinal obstruction, and infection.

Proliferating (borderline) mucinous ovarian tumors may show
areas that are indistinguishable from benign mucinous tumor
(various sized cystic spaces lined by a single layer of endocervi-
cal type or sometimes intestinal-type epithelium with focal
intestinal-type crypts). In addition, they exhibit multilayering of
cells, complex folding of the lining epithelium (‘glands within
glands’) and, occasionally, micropapillae or tufting and budding
reminiscent of those seen in proliferating (borderline) serous
tumors. Their defining feature is lack of stromal invasion. Some
tumors show a prominent back-to-back arrangement of glands
with cribriform pattern, but no evidence of destructive stromal
Figure 7.258 Proliferating (borderline) seromucinous tumor.
invasion. It remains controversial as to whether these features
represent true invasion, or not. Nevertheless, these features are
Figure 7.259 Proliferating (borderline) mucinous tumor. Malignant

nuclear morphology with slightly crowded glands; note luteinized
Figure 7.256 Proliferating (borderline) mucinous tumor: stromal cells to the left and in between glands (upper left).
stratification, hyperchromasia with enlargement of nuclei to the
right compared with benign epithelium to the left.
Figure 7.260 Proliferating (borderline) mucinous tumor. Malignant

Figure 7.257 Proliferating (borderline) seromucinous tumor. In nuclear morphology with very early cribriform formation (top
addition to features of mucinous tumor, there are micropapillae gland).These features should alert the pathologist to the possibility
that usually characterize serous tumors. of invasion.
Figure 7.261 Proliferating (borderline) mucinous tumor with Figure 7.262 Microinvasive mucinous carcinoma. Arrow indicates
microinvasion. Small nests and single cells detached from the main very early bud of invasion.
epithelium. Arrow indicates single cell invasion.
associated with 2–4% risk of recurrence or death from the dis- Based on the cytological features and presence or absence of
ease. The epithelial tufting and budding is more often seen in the invasion, these tumors may be classified as atypical prolifera-
endocervical subtype, while the glandular crowding with back- tive, intraepithelial carcinoma, microinvasive carcinoma, or
to-back arrangement and occasional cribriform pattern are seen invasive carcinoma.
more in the high-grade proliferating (borderline) mucinous Atypical proliferative tumors are the most common type
tumor of the intestinal subtype. and account for 64% of the seromucinous tumors; they are bilat-
Mucinous proliferating (borderline) ovarian tumors with eral in 26% of cases. The mean age of the patients is 39 years,
microinvasion: microinvasive buds appear to have abundant and the mean tumor size is 9 cm (median 8 cm; range 2.5–25 cm).
eosinophilic cytoplasm with squamoid features. Atypical proliferative seromucinous tumor with intraepithe-
lial carcinoma is uncommon, accounts for 9% of seromucinous
Secondary features tumors, and is bilateral in 40% of cases. The mean age of
● Presence of foamy macrophages patients is 35 years.
● Polymorph infiltrate Atypical proliferative seromucinous tumor with microinva-
sion accounts for 15% of the cases, and is bilateral in 25%.
Cell morphology The mean age of patients is 44 years.
● The cells show greater pleomorphism than their benign Invasive seromucinous carcinoma accounts for 13% of cases
counterparts. and occurs in patients with a mean age of 45 years.
Despite containing mucinous epithelium, the papillary architec-
Differential diagnosis ture, serous-type differentiation, association with endosalpingosis,
● Mucinous cystadenoma frequent bilaterality, size, and clinical behavior of endocervical-
● Mucinous carcinoma type mucinous tumors closely resemble those of serous tumors.
● Metastatic colonic or pancreatic carcinoma The non-invasive tumors, as well as those with invasion
⬍5 mm, usually behave in a benign fashion.
Special techniques
See Mucinous carcinoma of the ovary (p. 464). PATHOLOGICAL FEATURES (Figures 7.257, 7.258 and
7.263–7.267)
SEROMUCINOUS TUMORS All of these tumors are composed of a heterogeneous population
of cells, consisting mainly of serous (ciliated) and endocervical-
type mucinous cells. In addition, they contain endometrioid-
CLINICAL FEATURES
type cells, hobnail cells, and indifferent cells with abundant
Ovarian seromucinous tumors are poorly recognized and often eosinophilic cytoplasm to a varying degree.
misinterpreted as pure serous or pure mucinous tumors. They Atypical proliferative seromucinous tumor shows complex
are defined as tumors showing endocervical-type mucinous papillary architecture with an epithelial lining composed of
epithelium admixed with other type of mullerian epithelium endocervical-type mucinous epithelium displaying variable
such as serous, endometrioid, and indifferent cells with abun- cellular stratification and mild to moderate cytological atypia
dant eosinophilic cytoplasm. with no evidence of stromal invasion. The glands are lined by
Approximately 30% of these tumors are bilateral, and mucinous epithelium, with basal nuclei and abundant apical
endosalpingosis is identified in 41% of cases. cytoplasm resembling the epithelium of the endocervix. The
Figure 7.263 Seromucinous proliferating ovarian tumor: mucinous

tumor with surface papillae similar to serous tumor.
tips of the papillae are usually lined by indifferent round to

polygonal cells with eosinophilic cytoplasm showing stratifica-
tion and epithelial budding.
In some areas, the tips of papillae were lined by epithelium that
is tufted without supporting fibrovascular cores. Frequently, small
detached clusters of cells are observed directly over the papillary
tufts. The cells in these areas are round or polygonal with small,
bland nuclei and abundant eosinophilic cytoplasm.
Cellular necrosis may be prominent, and focal areas of
necrosis may also be seen.
These tumors may be associated with non-invasive implants
in the peritoneum.
Atypical proliferative seromucinous tumor with intraepithe-
lial carcinoma shows similar features to atypical proliferative
seromucinous tumor, but with either marked cytological atypia
or a cribriform growth pattern involving the surface of papillae
or lining cystic spaces. Cytological atypia is considered marked
if nuclei are enlarged (more than three times the size of stromal
nuclei), hyperchromatic, or vesicular with coarsely clumped
Figures 7.264 and 7.265 Microinvasive focus in seromucinous
chromatin and have prominent nucleoli.
tumor.
Atypical proliferative seromucinous tumor with microinva-
sion exhibits architecture and epithelial lining as those with measuring ⬎5 mm in diameter. It shows variations of the con-
intraepithelial carcinoma, but with stromal invasion measur- fluent growth pattern of stromal invasion, and may also show
ing ⬍5 mm in diameter in any focus. serpiginous, cribriform or a mixture of cribriform, serpiginous,
Two patterns of stromal invasion may be identified. The and more solid growth patterns. It may also show an infiltra-
most common is a confluent glandular pattern showing coa- tive pattern of invasion with small glands and nests of cells
lescing glands that merge without intervening stroma and show within desmoplastic stroma.
either a serpiginous or cribriform growth pattern. A second Prominent areas of cellular necrosis may be seen.
pattern of invasion is characterized by small clusters of cells
and individual cells with abundant eosinophilic cytoplasm Differential diagnosis
displaying moderate nuclear atypia infiltrating the stroma. The ● Mucinous tumors
clusters of cells are often surrounded by clear spaces. ● Serous tumors
Invasive seromucinous carcinoma is similar to the above, but ● Endometrioid tumors
with any focus of stromal invasion or micropapillary architecture ● Metastatic colonic carcinoma
Figures 7.268 and 7.269 Cystadenofibroma: large connective

tissue papillae giving rise to smaller ones in a hierarchical pattern.
These papillae are lined with inactive or slightly proliferative
tubal-type epithelium.
Serous adenofibroma is a solid tumor, ranging in size from 1 to

20 cm. Similar cystic tumors have been reported in the omen-
tum, Fallopian tube and epididymis. Occasionally, psammoma
bodies or ciliary tuft can be identified in cervical smears from
women harboring benign cystadenoma.
Figures 7.266 and 7.267 Seromucinous ovarian carcinoma of
the ovary. Well-differentiated mullerian-type carcinoma showing PATHOLOGICAL FEATURES (Figures 7.268 and 7.269)
serrated borders suggesting papillary formation. AB/PAS staining
illustrates the abundant luminal mucin secretion. ● Benign serous cyst is a unilocular smooth cyst lined by a
single layer of cuboidal or low columnar, ciliated
epithelium (similar to the cells lining the Fallopian tube).
SEROUS EPITHELIAL OVARIAN TUMORS, BENIGN Under pressure of the cyst content, the lining epithelium
may appear flattened. In simple cyst there is no significant
number of glands within the stroma.
CLINICAL FEATURES ● Benign serous adenofibroma consists of a fibrous cellular
Benign serous tumor constitutes 60% of all serous epithelial or hyalinized stroma containing glandular spaces of
tumors; it is bilateral in 15–20% of cases and occurs in the various sizes and shapes. The lining epithelial cells are
reproductive age group. The cysts are usually unilocular, but similar to the above.
can be multilocular, have smooth external surfaces and a ● Benign papillary serous cystadenoma shows a more
smooth inner lining which may bear soft papillary projections. complex pattern with multiple variably sized cysts with
The latter can be seen on the surface or on the inner lining. focal complex papillary projections, but no significant cell
dropping from the surface of the papillae, as is seen in as a form of well-differentiated carcinoma overridden by psam-
proliferating tumors. moma bodies (present in over 75% of the tissue or papillae).
● Serous cystadenofibroma has papillary projections that
are broad and consist of either dense fibrous, markedly PATHOLOGICAL FEATURES (Figure 7.270–7.273)
edematous, or cellular fibrous tissue. They are lined by
cuboidal, columnar, hobnail, ciliated, clear cells and a Malignant ovarian serous tumors vary from well, to poorly dif-
variety of other forms of mullerian epithelium. There is ferentiated. The well-differentiated tumors contain numerous
often a narrow acellular zone separating the epithelial well-formed papillae with desmoplastic or immature connec-
lining cells from the underlining fibrous stroma. A solid tive tissue cores. These project into cystic spaces, or grow on
adenofibromatous component is occasionally seen in the wall. the surface of the tumor or in the stroma. Some tumors contain
broader and larger papillae. Some other tumors show glandu-
Secondary features lar spaces with very shallow, blunted papillae, more akin to
endometrioid carcinoma. Another unusual pattern in the well-
● Old or recent hemorrhage in the stroma with
differentiated group is the adenofibromatous pattern; this
hemosiderin-laden macrophages.
shows malignant glands widely separated by dense fibrous
● Deposition of eosinophilic pseudoxanthomatous
stroma, thereby giving a wrong impression of a benign process.
‘lipofuchsin granulomas’ under the surface epithelium.
The moderately differentiated tumors are less well organized,
● Stromal luteinization.
and the papillae are more crowded, delicate, thin, and
● Epithelial metaplasia.
elongated.
Serous cyst
● Hydrosalpinx
● Simple paraovarian cyst.
Serous cystadenofibroma
● Mullerian adenofibroma.
Solid adenofibroma
● Inclusion cysts
● Endometriosis
● Brenner’s tumor.
SEROUS EPITHELIAL OVARIAN TUMORS,

MALIGNANT
CLINICAL FEATURES Figure 7.270 Serous ovarian carcinoma: malignant epithelium

with slit-like spaces and papillary structures.
Ovarian serous carcinoma: malignant serous tumors are the
most common malignant ovarian tumors, occurring between
the age of 40 and 65 years, and are bilateral in up to 65% of
cases. Like ovarian cancer, it may have a familial basis and can
metastasize distally. Serous carcinoma of the ovary can some-
times be diagnosed by cervical smear test.
Peritoneal serous carcinoma: primary peritoneal serous car-
cinoma is defined as extensive involvement of the peritoneal
surfaces with minimal or no ovarian paranchymal involve-
ment. The ovaries are usually normal in size or, if enlarged, the
tumor is due to a benign process.
The age and presentations are similar to advanced stage serous
ovarian carcinoma. There is a suggestion that these tumors are
polyclonal rather than monoclonal (as are the ovarian tumors).
As with primary ovarian serous carcinoma, debulking surgery
with minimal residual disease seems appropriate.
Serous carcinoma arising in pelvic lymph nodes may take
origin from benign glandular inclusions.
Psammocarcinoma is a rare variant of serous carcinoma Figure 7.271 Serous ovarian carcinoma: malignant epithelium
which can occur in the ovary or in the peritoneum. It is defined with slit-like spaces, papillary structures and central necrosis.
Secondary features
● Psammoma body formation
● Cholesterol granuloma
● Fibrin deposition
● Occasional intracytoplasmic hyaline globules
● Hemorrhage and necrosis.
● Mixed-epithelial carcinoma
● Mesothelioma.
Special techniques
● Malignant serous tumors contain at least focally,
intracytoplasmic mucin.
● Occasional tumors contain intracellular PAS-positive/
Figure 7.272 Serous ovarian carcinoma: small, solid, epithelial diastase-resistant and PTAH-positive hyaline globules.
papillae. ● Serous papillary ovarian tumors are all CK7-positive,
CA125-positive and CK20-negative.
● Lower intestinal tumors are CK7-negative and usually
CK20-positive, while upper gastrointestinal tumors –
including those of pancreatobiliary origin – are mostly
CK7-positive and CK20-negative.
● The p53 immunostaining may have diagnostic value in
discriminating between borderline and malignant serous
ovarian tumors. The p53 suppressor gene protein is seen in
about 53% of the malignant tumors, and is negative in all
benign and the majority of borderline tumors. Malignant
ovarian tumors with negative staining for p53 are usually
associated with a 67% 3-year crude survival rate as
compared with only an 18% 3-year survival rate if p53
staining is positive.
SEROUS EPITHELIAL OVARIAN TUMORS,

PROLIFERATING (BORDERLINE)
Figure 7.273 Serous ovarian carcinoma: malignant, pleomorphic
cells with intracytoplasmic eosinophilic globules.
CLINICAL FEATURES
The terms proliferating tumors, tumors of low malignant
The poorly differentiated tumors consist of solid sheets of potential and borderline tumors are synonyms. They are
malignant epithelial cells exhibiting marked pleomorphism, defined as neoplasms exhibiting an unusual degree of cellular
frequent mitotic figures and the presence of large bizarre cells proliferation, more than that encountered in the benign coun-
and hyperchromatic giant nuclei. In the poorly differentiated terpart, but showing no destructive invasion of the stroma.
tumor, the cells can be either small, intermediate, or large. Ovarian serous neoplasms of low malignant potential are asso-
A characteristic feature of all serous carcinomas is the presence ciated with a low recurrence rate, which has been documented
of cells dropping from the luminal borders of the papillae, due to to range from 10% to 17%. Such recurrences are generally
the loss of cell cohesion and the presence of slit-like, irregular found in the pelvis or abdomen. However, on very rare occa-
spaces often seen in the poorly differentiated serous tumors. sions, the involvement of an extra-abdominal/extra-pelvic site
Psammoma bodies are often seen in serous tumor. without the accompaniment of the usual sites of involvement
Malignant peritoneal serous tumors vary from well to poorly has been reported.
differentiated serous carcinoma; they are indistinguishable Proliferating (borderline) serous tumors affect younger women
from papillary serous carcinoma of the ovary, and frequently (aged 40–43 years) and are frequently bilateral (35–40%).
involve almost the entire peritoneum or rarely are discrete Papillary excrescences are more common and complex than
tumor nodules. The ovaries are either normal or contain a those seen in benign tumors. The survival for patients with
microscopic deposit of less than 5 ⫻ 5 mm which is present on serous borderline tumors confined to the ovaries is virtually
the surface with or without stromal invasion, or is seen in the 100%, and has good prognosis when associated with extra-
ovarian substance. ovarian spread.
Proliferating (borderline) serous tumors with a micropapil- The histogenesis of these peritoneal lesions is controversial.
lary pattern (so-called ‘micropapillary carcinoma’) is not a Because of the strongly positive correlation between exophytic
widely accepted category, and is not included in the new WHO tumor and peritoneal implants, the implantation theory remains
classification. However, the term is still being used in the liter- as a highly likely explanation for extraovarian spread of ovarian
ature and it might be useful to identify this lesion, as quite serous low malignant potential tumors. The multicentric ‘field
often less experienced pathologists wonder whether this repre- effect’ theory, however, cannot be entirely excluded and may be
sents a carcinoma of a borderline tumor. These tumors are operative in some cases.
more often bilateral, have a greater frequency of invasive Proliferating (borderline) serous tumor arising in pelvic
implants, and a large number of patients experience either pro- lymph nodes: these tumors may originate from benign glandu-
gression or recurrence of disease. However, it is controversial lar inclusions.
whether the overall long-term survival of patients within this
category is different from that of the usual type. PATHOLOGICAL FEATURES (Figures 7.274–7.288)
Proliferating (borderline) serous tumors with micro-
invasion is defined as the presence of very early buds or Proliferating (borderline) serous ovarian tumors: these are usu-
isolated cell nests that are seen adjacent to the epithelium of ally more cellular than benign serous tumors, with numerous
the proliferating tumor. It appears that the presence of micro- epithelial tufts and delicate micropapillae without connective tis-
invasion has no clinical implication in respect to treatment sue cores, lined by more than one cell layer. Numerous glandu-
or prognosis. lar inclusions are found in the stroma, especially in subepithelial
Proliferating (borderline) serous tumors with a micro- locations. Many of the cells detach from the papillary structures,
papillary pattern or with microinvasion are much closer in and are present within the luminal spaces. Solid morules of cells
their biological behavior to the usual proliferating (borderline) may also occur in these lesions. There is often moderate cellular
serous tumors than to serous carcinomas. The micropapillary atypia, and mitotic figures are easily seen.
pattern alone does not imply an unfavorable prognosis; only
micropapillary tumors associated with invasive implants may
behave aggressively.
Extraovarian peritoneal lesion ‘implants’ associated with
proliferating (borderline) serous tumors are epithelial neoplas-
tic lesions seen in association with ovarian proliferating serous
tumors. They are frequently located on or under the serosal
surface of pelvic viscera or the omentum. They are less com-
monly found in the retroperitoneal lymph nodes, and rarely
outside the abdominal cavity. Peritoneal implants are seen in
up to 40% of cases of proliferating (borderline) serous tumors,
and it is more often with those tumors that have an exophytic
surface component.
Peritoneal implants are classified as non-invasive and inva-
sive, and the non-invasive implants are further subdivided into
epithelial and desmoplastic types.
The prognosis and adequate clinical management of prolifer-
ating (borderline) serous tumors are highly dependent on the
morphological features of their peritoneal implants, which can
only be labeled as invasive or non-invasive after complete
surgical staging and careful histopathological examination.
Although invasive implants that actually invade the underlying
tissues are associated with poor prognosis, their diagnostic cri-
teria remain problematic.
Primary peritoneal serous tumors of borderline malignancy
(proliferating serous tumors of low malignant potential) are rel-
atively rare lesions that are histologically indistinguishable from
the peritoneal ‘implants’ associated with ovarian papillary serous
tumors of low malignant potential. They occur most commonly
in the pelvic peritoneum of younger women, who usually pres-
ent with abdominal pain or infertility. They commonly appear
as miliary granules, often clinically diagnosed as peritoneal
carcinomatosis. These lesions are associated with an excellent
prognosis similar to that for ovarian borderline or proliferating Figures 7.274 and 7.275 Serous borderline ovarian tumor:
tumors with non-invasive implants. These lesions are usually shallow and hyalinized, broad papillae with micropapillae showing
treated conservatively. cells falling into the spaces.
Figure 7.276 Serous borderline ovarian tumor: epithelial

invagination lined by micropapillae falling into spaces.
Figures 7.279 and 7.280 Serous borderline ovarian tumor: some

cribriform pattern at the tips of the papillae. Within the epithelial
invagination there are features suggestive of early invasion.
Figure 7.281 Serous borderline ovarian tumor. Epithelial

stratification with epithelial cells falling into the space. Note also the
Figures 7.277 and 7.278 Micropapillary serous carcinoma: small epithelial invagination with eosinophilic appearance – features
branching papillae lined by well-differentiated cells. suspicious of early invasion.
Figure 7.285 Non-invasive serous peritoneal implants. Sharply

demarcated proliferating serous epithelium, some with central
psammoma bodies.
Figures 7.282 and 7.283 The arrows in Figure 7.282 indicate

non-invasive implants associated with micropapillary serous
carcinoma.There are also small nests surrounded by heavy
lymphocytic infiltrate indicative of invasive implant (seen magnified
in Figure 7.283).
demarcated proliferating serous epithelium, seen implanted on the
serosal surface.
Proliferating (borderline) serous tumors with a micropapillary

pattern (so-called ‘micropapillary carcinoma’): these are char-
acterized by: (i) a filigree pattern of small, uniform, elongated,
stroma-poor or stroma-free papillae, at least five times as long
as wide, arising directly in a non-hierarchical fashion from large
fibrotic, edematous, or myxoid papillary stalks or from cyst walls
or a cribriform pattern of the epithelial cells lining the stalks or
cyst walls, or both; and (ii) the presence of either or both pat-
terns on a confluent area at least 5 mm in greatest dimension
on at least one slide. Tumors exhibiting one or more minor foci
of a micropapillary or cribriform pattern ⬍5 mm in greatest
dimension are still included in the typical SBT category.
Proliferating (borderline) serous ovarian tumors with
microinvasion: microinvasion is the presence of very early buds
demarcated proliferating serous epithelium, some with central or isolated cell nests that are seen adjacent to the epithelium of
psammoma bodies.These are seen within the peritoneal stroma and the proliferating tumor. These appear to have abundant
implanted on the serosal surface. eosinophilic cytoplasm with squamoid features.
atypical serous cells as well as psammoma bodies and

inflammatory cells. The presence of single cells or small
clusters of cells in an otherwise typical desmoplastic
implant is not considered evidence of invasion.
3. Invasive peritoneal implants (Figures 7.287 and 7.288):
this shows disorderly infiltration of the underlying normal
tissues by mild to moderately (rarely severe) atypical
epithelial cells usually resembling those of a low-grade
serous adenocarcinoma or destruction of omental adipose
tissue by an irregular infiltrate of such cells. Two
additional criteria apply for the diagnosis of invasive
implants: namely micropapillary architecture; and the
presence of solid nests of epithelial cells or papillae
separated from a densely fibrous stroma by clear spaces or
clefts. The glands and papillae appear disorderly
distributed within a desmoplastic (‘collagenized’) stroma,
and many of them are surrounded by clefts.
Some 89% of invasive implants had micropapillary architec-

ture, and 83% had solid epithelial nests surrounded by clefts.
Primary peritoneal proliferating (borderline) serous tumors
show all of the patterns seen in superficial (‘non-invasive’) peri-
toneal implants of ovarian serous borderline tumors. Psammoma
bodies tend to be a prominent feature.
Proliferating serous tumors
● Mullerian adenofibroma
● A benign, epithelial proliferation involving cystic
endosalpingosis
● A well-differentiated serous carcinoma
Figures 7.287 and 7.288 Invasive peritoneal implants.

Special techniques
Proliferating serous implants showing irregular tongues of invasion See Malignant serous tumors, p. 471.
with inflammatory response.
Rarely, ‘sarcoma-like mural nodules’ are seen in association

TRANSITIONAL CELL TUMORS (BRENNER
with proliferating serous tumors. TUMORS)
Extraovarian peritoneal lesions associated with proliferating
serous tumor ‘implants’ are of two types:
CLINICAL FEATURES
1. Endosalpingosis: these are glandular inclusions lined by
serous cells without significant cytological atypia. Benign transitional cell (Brenner) tumor is an uncommon ovar-
Psammoma bodies may be seen. ian epithelial tumor that can be seen at any age (mean age 50
2. Non-invasive peritoneal implants (Figures 7.282–7.286): years). It rarely arises in other locations such as the uterus and
these are characterized by the presence of sharply demarcated vagina, but may be seen in association with other ovarian
foci of epithelial (epithelial non-invasive implants) or tumors, particularly mucinous cystadenomas, cystic teratomas
epithelial and stromal elements (desmoplastic non-invasive and rarely with struma ovarii. It has rarely been reported in asso-
implants) on the peritoneal surface, in subperitoneal ciation with leiomyomatosis peritonealis disseminata in patients
invaginations and in-between lobules of omentum. The receiving tamoxifen. Brenner tumor has also been seen in associ-
‘epithelial subtype’ is composed predominantly of mild to ation with transitional cell carcinoma of the endometrium.
moderately atypical epithelial cells resembling those of the Proliferating transitional cell (Brenner) tumor is an entirely
ovarian tumor, present on the surface of the peritoneum or benign lesion, occurs at an older age than the benign Brenner
in smoothly contoured subperitoneal invaginations, and tumor (mean age 60 years) and, due to its larger size, presents
exhibiting little or no stromal reaction. The ‘desmoplastic as an ovarian mass. It has rarely been seen in association with
subtype’ shows ⬎75% loose stromal proliferation or synchronous or metachronous transitional cell carcinomas of
granulation tissue-like ‘plastered’ upon serosal surfaces or the urinary bladder.
invaginations between lobules of omental fat, containing Malignant transitional cell tumors (including malignant
small glands and papillae lined by mild to moderately Brenner tumor) are rare tumors, presenting in postmenopausal
women. The most common clinical symptoms are abdominal

pain and swelling, sometimes with postmenopausal bleeding due
to associated endometrial hyperplasia secondary to estrogen
production by the tumor. Malignant Brenner tumor is diagnosed
only when it is associated with foci of benign Brenner tumor,
while transitional cell carcinoma lacks foci of the benign com-
ponent. These tumors have rarely been reported in association
with low-grade urothelial carcinoma of the urinary bladder.
Malignant Brenner tumor seems to have a better prognosis
than transitional cell carcinoma, which most likely represents a
poorly differentiated adenocarcinoma of mullerian type with a
morphological transitional cell pattern.

Benign transitional cell (Brenner) tumor is grossly solid and
firm, and is usually fairly small in size. It consists of well-
Figure 7.291 Brenner tumor: some of the epithelial nests may
defined solid or partly cystic nests of epithelial cells present show glandular lumina, suggesting metaplastic Brenner.
within a dense fibroblastic stroma. The epithelial cells of
Figure 7.289 Brenner tumor: nests of epithelial cells within a Figure 7.292 Metaplastic Brenner tumor: the epithelial nests
densely fibroblastic ovarian stroma. clearly show glandular lumina with mucin secretion.
Figure 7.290 Brenner tumor: the nests are composed of epithelial Figure 7.293 Metaplastic Brenner tumor: the mucin secretion is
cells with grooved nuclei and sometimes clear cytoplasm. clearly demonstrated with AB/PAS staining.
the bladder with evidence of stromal invasion. On occasion, it

resembles squamous carcinoma or undifferentiated carcinoma.
Occasionally, glandular differentiation is seen. Comedo-type
necrosis may also be seen. The presence or absence of areas of
benign or proliferating Brenner tumor determines whether the
tumor is malignant Brenner or transitional cell carcinoma
(non-Brenner type), respectively.
Secondary features
● Stromal luteinization
● Stromal hyalinization and dystrophic calcification
● Edema or myxoid change
● Cyst formation
● Solid adenofibroma: when benign Brenner tumor
Figure 7.294 Proliferating Brenner tumor: papillary structures contains very few epithelial nests, it may look like solid
lined by benign transitional-type epithelium. adenofibroma.
● Metaplastic cystadenofibroma: cystadenofibroma
occasionally shows extensive squamous metaplasia
producing a condyloma-like lesion which could be
mistaken for proliferating Brenner tumor.
● Poorly differentiated carcinoma: may resemble malignant
Brenner tumor.
● Cervical squamous carcinoma: extension of malignant
Brenner tumor into the cervix might result in misdiagnosis
of cervical squamous carcinoma.
Special techniques
● Mucin stains highlight the mucin secretion seen in
mucinous metaplastic areas.
● As in normal and neoplastic bladder urothelium, urothelial
markers, including uroplakin III, thrombomodulin, CK13,
and CK20, may be detected in the epithelial nests of
Brenner tumors. Brenner tumor cells may also express
Figure 7.295 Proliferating Brenner tumor: transitional-type uroplakins Ia and II.
epithelium with nuclear grooving (encircled). ● Both Brenner tumor and transitional cell carcinoma of
urothelial origin are also positive for CK7 and may
benign Brenner tumors are polygonal and squamoid, with pale, express CEA. In contrast, transitional cell carcinoma of the
eosinophilic cytoplasm and oval nuclei showing ‘coffee bean’ ovary and Walthard nests lack uroplakins and are
grooving. Psammomatous-like calcification may rarely be seen essentially negative for CK20 and CK13 but quite strongly
in Brenner tumors. express CA125.
Some benign Brenner tumors exhibit marked mucinous ● CA125 is observed focally in some Brenner tumors.
metaplasia with cystic change (metaplastic Brenner tumor).
The cystic spaces are lined by benign endocervical-type muci-
nous epithelium. Other types of epithelium such as ciliated GERM CELL TUMORS
columnar epithelium may also line the cystic spaces.
Proliferating transitional cell (Brenner) tumor/Brenner In females aged less than 20 years, germ cell tumors represent
tumor of borderline malignancy: proliferating Brenner tumor is approximately two-thirds of malignant ovarian tumors.
usually larger than ordinary benign Brenner tumor, and con- Immature teratoma, endodermal sinus tumor, dysgerminoma
sists of bland transitional-like epithelium thrown into folds or and mixed-type account for the majority (⬎80%), while embry-
papillary structures reminiscent of a condyloma or low-grade onal carcinomas and polyembryomas are very few in number.
transitional cell carcinoma of the bladder with no evidence of The overall age of the patients ranges from 6 to 69 years, with
stromal invasion. Mitotic figures may be seen. Mucus-secreting a median range of 16–20 years. Clinically, these tumors are
cells, ciliated cells, and squamous metaplasia are sometimes characterized by rapid growth and extensive intra-abdominal
seen, as in benign Brenner tumor. spread. Patients usually present with abdominal pain, palpable
Malignant transitional cell tumors (including malignant mass, abdominal distention and vaginal bleeding, and a very
Brenner tumor) usually resemble transitional cell carcinoma of few with amenorrhea and precocious puberty. The size of the
tumors ranges from 7 cm to 40 cm (median 15–16 cm). Germ other germ cell components such as yolk sac tumor, embryonal
cell tumors are rarely bilateral (12–19%), and are never so in carcinoma and teratocarcinoma. After careful surgical staging
cases of endodermal sinus tumor. Diagnosis depends mainly on and confirmation of unilateral disease, conservative surgery –
age, abdominal symptoms, size and consistency of the tumor, followed if necessary by adjuvant chemotherapy – seems to be
and tumor markers such as ␣-fetoprotein and ␤-human chori- the ideal treatment in cases of pure ovarian dysgerminoma.
onic gonadotropin (␤-hCG). Surgery is the first step of man-
agement, followed by adjuvant therapy, according to the PATHOLOGICAL FEATURES
histological type. Dysgerminoma is very sensitive to radiation,
Dysgerminoma consists of variably sized and shaped nests of
whilst other germ cell tumors are not.
round or polygonal cells with clear or granular cytoplasm.
These are separated by fibrous septae infiltrated by numerous
CHORIOCARCINOMA, CARCINOMA small lymphocytes, sometimes with lymphoid follicle forma-
tion. Overall, the appearances are very similar to those of the
classical testicular seminoma. Anaplastic variants can be seen.
CLINICAL FEATURES There may be necrosis, hemorrhage, hyalinization, and granulo-
Ovarian choriocarcinomas may represent a metastasis or a matous reactions.
primary ‘gestational choriocarcinoma’ or a germ cell tumor
‘non-gestational choriocarcinoma’. Pure ‘non-gestational
Cell morphology
choriocarcinoma’ is an extremely rare and highly malignant ● The dominant population consists of neoplastic germ cells
tumor which occurs in young women and adolescents. The which are characterized by large nuclei containing
presence of other germ cell elements or its occurrence in children single or multiple elongated or rectangular nucleoli.
are features indicative of ‘non-gestational choriocarcinoma’. The cytoplasm may be clear or granular, and the cell
Ovarian choriocarcinoma may also represent a dedifferentiation membranes are prominent.
of surface carcinomas. Serum ␤-hCG levels assist in the diag- ● Giant cells, when present, are of trophoblastic type.
nosis of choriocarcinoma. The staging of the disease is more ● The mitotic rate is variable.
important clinically than whether the tumor is either gesta-
tional or non-gestational. Treatment includes cytoreductive Differential diagnosis
surgery (unilateral adnexectomy for stage IA), followed by ● Small cell carcinoma of the ovary
combination chemotherapy. ● Clear cell carcinoma
PATHOLOGICAL FEATURES ● Metastatic melanoma
● Epithelioid leiomyosarcoma
See p. 448. ● Malignant lymphoma

● Dysgerminoma ● The cells are immunoreactive for CAM 5.2, placental
● Embryonal carcinoma alkaline phosphatase (PLAP), lactase dehydrogenase, and
● Undifferentiated carcinoma frequently for neuron-specific enolase (75%) and
occasionally for cytokeratin AE1/AE3 (and ␤-hCG).
Special techniques ● c-kit stains germ cells.
See p. 449. ● Dysgerminoma cells are negative for vimentin, EMA, S-100
The identification of paternal human leukocyte antigen protein, leukocyte common antigen (LCA) and ␣-fetoprotein.
(HLA) patterns is sometimes required in deciding whether a
choriocarcinoma is gestational or non-gestational. EMBRYONAL CARCINOMA
DYSGERMINOMA CLINICAL FEATURES

Embryonal carcinoma is a highly malignant germ cell tumor
CLINICAL FEATURES which affects patients under the age of 30 years, and is always
unilateral. This tumor is the least differentiated of all germ cell
Dysgerminoma is a malignant germ cell tumor of the ovary that
tumors. It is often associated with hormonal manifestation such
occurs in young women and children. About 5% of these tumors
as abnormal uterine bleeding or precocious pseudo-puberty and
arise in abnormal gonads. Dysgerminoma can metastasize to
a high level of ␤-hCG.
the contralateral ovary, peritoneal cavity and paraaortic
nodes. The tumor has a 5-year survival rate of 95% when con-
fined to the ovary, 78% if there is ascites, adhesion or rupture
of the capsule, and 33% when associated with metastasis. The tumor is usually solid, with hemorrhagic and necrotic areas.
A less-favorable prognosis is seen in those associated with Histologically, it shows varying degrees of differentiation, with
the least differentiated areas revealing solid sheets of primitive embryonic tissue. A mixed germ cell tumor containing both
cells, reminiscent of the cytotrophoblastic cells of chorio- polyembryoma and choriocarcinoma is exceedingly rare. A
carcinoma or the cells seen in anaplastic dysgerminoma. In more rare example of retroperitoneal tumor formed by migrating
differentiated areas there are slit-like or alveolar spaces lined polyembryoma with numerous embryoid bodies from an ovar-
by primitive cells or even glandular or papillary structures. ian mixed germ cell tumor has been reported. Clinically, some
Rarely, there are abortive embryoid bodies. Interspersed amongst patients show pseudo-precocious puberty caused by eleva-
the primitive cells are scattered syncytiotrophoblasts. The stroma ted hCG which is synthesized by trophoblastic cells in poly-
may show a loose edematous pattern or fibrosarcoma-like embryomas. Patients with polyembryomas are usually followed
appearance. The contralateral ovary often shows changes of with serial ␣-fetoprotein and ␤-hCG assays, as well as with
hyperreactio luteinalis due to the high ␤-hCG levels. Vascular serial abdominal and pelvic computed tomography (CT) scans,
invasion is commonly seen. following surgical staging and a total abdominal hysterectomy
and bilateral salpingo-oophorectomy.
Cytological features
● The tumor cells are medium to large in size, polyhedral in PATHOLOGICAL FEATURES
shape, and have abundant pale granular cytoplasm with The characteristic feature of this tumor is the presence of
no obvious cell borders, hence forming syncytial cell masses. numerous embryoid bodies lying in loose myxoid stroma.
● The nuclei are centrally located, pleomorphic, with These bodies show embryonic disc, amniotic cavity, and yolk
vesicular chromatin pattern, and contain one or more sac surrounded by primitive mesenchyme.
large nucleoli.
● Giant multinucleated syncytiotrophoblastic cells are Differential daignosis
commonly found clustered around tumor nodules or
scattered randomly throughout the tumor.
● The appearances are so characteristic that
misinterpretation with other tumors is rather difficult.
● Mitotic figures, including abnormal forms, are frequent.
● Hyaline droplets are seen within and in between the tumor
cells. Special techniques
● The epithelium lining the yolk sac is strongly positive for
Differential diagnosis ␣-fetoprotein, while the endodermal epithelium of the
embryonic disc is weakly positive.
● Anaplastic dysgerminoma (lacks cytokeratin positivity, and
the cells are less pleomorphic than those of embryonal
carcinoma; likewise, syncytiotrophoblasts – if present – are TERATOMA, IMMATURE
much less in number than those seen in embryonal
carcinoma).
● Undifferentiated carcinoma (affects older women, often CLINICAL FEATURES
bilateral, and histologically lacks syncytiotrophoblasts, and Immature ovarian teratoma is an uncommon tumor of the
shows variably hyperchromatic and angular nuclei. The ovary that is seen during the first and second decades of life. In
cells are usually EMA-positive and negative for germ cell contrast to most immature teratomas of other localizations,
markers). immature ovarian teratomas rarely occur in children under 7
● Carcinosarcoma (affects older women and may show years of age. The lesion is unilateral in about 70% of cases, and
heterologous elements and lacks syncytiotrophoblasts). tends to grow rapidly. Immature teratoma may coexist with a
benign cystic teratoma in the opposite ovary. It is usually
Special techniques asymptomatic until it reaches a large size. Abdominal pain,
● The giant multinucleated syncytiotrophoblastic cells are abdominal mass, and vaginal bleeding are the major symp-
commonly ␤-hCG-positive. toms; these can occur either singly or in combination, with an
● The tumor cells and the hyaline droplets are ␣-fetoprotein- average duration of 3.2 months in some series. Immature ter-
positive. atoma tends to rupture through the capsule, invade locally, and
● The cells are also positive for placental alkaline cause adhesion, ascites or hemoperitoneum. Extension outside
phosphatase (PLAP) and cytokeratin, but negative for the ovary may lead to widespread peritoneal and lymph node
EMA. involvement. Retroperitoneal, para-aortic nodes and distant
lymph nodes are the first to be involved. Later, lung, liver and
other organs are involved. The tumor may rupture during sur-
POLYEMBRYOMA (POLYEMBRYONIC CARCINOMA) gery with spillage of tumor into the peritoneal cavity, and this
may be associated with a poor outcome. The lesion is predom-
inantly solid (occasionally predominantly cystic), but fre-
CLINICAL FEATURES
quently contains cystic structures. It is usually treated by
Polyembryomas are rare, immature germ cell malignancies radical surgery, and it shows good response to combination
characterized by numerous embryo-like bodies in association chemotherapy. In early childhood the biological behavior of
with mature and immature teratoma structures and primitive immature teratomas is evidently similar to that of mature
teratomas (provided that the tumor can be totally excised).

In older children, malignancy must be assumed when the tumor
is located in the ovary and/or showing grade 3 histology.
Immature teratoma exhibits frequent local recurrences which
occur within a few weeks or months following primary
treatment.
Gliomatosis peritonei
Peritoneal glial implants are found in childhood and adoles-
cence as well as in young women, and are the result of a rup-
tured capsule of mature or immature teratoma of the ovary. It
has been reported as a complication of ventriculoperitoneal
shunt. Nodal gliomatosis, in the absence of gliomatosis peri-
tonii is a very rare event in association with immature ter-
atoma. The implants of glia nodules have a distinct gross
feature and are localized mostly in the parietal and visceral
peritoneum, in the omentum and in the space of Douglas. A
combination of gliomatosis and endometriosis has rarely been
reported. The nature of the gliomatosis is confirmed by positive
immunoreactivity for glial fibrillary acidic protein and neu-
ronal antigens, as well as against determinants of hematopoi-
etic cells (HNK-1). In the teratoma, the neuroectodermal part
is strongly HNK-1-positive. Treatment depends on the histo-
logical grading of the gliomatous lesions. All grades, except
grade 0, qualify for adjuvant chemotherapy. Repeated laparo-
tomies for cytological sampling and the removal of tumor are
essential.

Immature teratoma consists of a variety of immature or embry-
onal and mature tissues derived from the three germ cell layers
(ectoderm, mesoderm and endoderm).
● Ectodermal derivatives are represented by neural tissue
and skin elements. The former includes glia, ganglion cells,

neuroblastic tissue, neuroepithelium, nerve trunks, and
ocular structures such as retinal anlage. The latter includes
pilosebaceous units, sweat glands and hair.
● Mesodermal derivatives are represented by fibrous tissue,
bone or cartilage, smooth muscle, striated muscle,

lymphoid tissue and undifferentiated embryonic
mesenchyme.
● Endodermal derivatives include gastrointestinal and
bronchial epithelium and tubules lined by columnar

sometimes ciliated epithelium.
These tissues are scattered haphazardly, and may be seen

in varying degrees of maturity. Neural tissue often predomi-
nates. Tightly grouped neuroepithelial tubules are the most Figures 7.296–7.298 Immature teratoma: immature neural tissue,
conspicuous structures in the neural elements, and they are neural tubules, and immature cartilage.
surrounded by dense cellular population of neural elements.
Astrocytomatous, glioblastomatous and medulloblastomatous Secondary features
areas of differentiation have been observed. Immature ter-
atoma may be combined with other neoplastic germ cell ele-
● Hemorrhage and necrosis are frequent findings.
ments such as endodermal sinus tumor, dysgerminoma,
embryonal carcinoma, choriocarcinoma, and polyembryoma. Cell morphology
Immature teratoma may rarely develop from the germ cells of Grading is based on:
gonadoblastoma. ● The relative amounts of immature and mature tissue
● Differentiation of the immature component examination a mobile abdominal or pelvic mass is often found.
● The mitotic rate Mature omental teratomas may be treated by simple resection.
The immature teratomas of the greater omentum, however, are
Grade 0: All tissues are mature with no mitotic activity.
potentially malignant tumors requiring postoperative chemo-
Grade 1: Mostly mature tissues with minor immature or
therapy and radiotherapy.
embryonic tissues and slight mitotic activity.
Mature cystic teratoma with secondary malignant transfor-
Grade 2: Moderate quantities of embryonal tissue with
mation: apart from the malignancy that is seen sometimes in
moderate mitotic activity.
monodermal teratomas such as thyroid carcinomas and car-
Grade 3: Large quantities of embryonal tissue with a high
cinoid tumors and also excluding malignant germ cell tumor
mitotic rate.
elements such as choriocarcinoma and others, mature cystic
teratomas may rarely undergo malignant transformation
(1–2% of cases). This is often associated with poor prognosis,
● Malignant transformation of mature teratoma especially when disseminated disease is present. A radical sur-
● Mature solid teratoma gical approach with en-bloc resection should be employed in
● Small cell undifferentiated carcinoma such cases. Adjuvant therapy with radiation or chemothera-
● Juvenile granulosa cell tumor peutic agents in general has not been shown to improve the
● Ependymoma outcome, especially in disseminated disease.
● Malignant mixed mullerian tumor
Special techniques
Mature cystic teratoma is principally a cyst that may show
● Immunohistochemistry for ␣-fetoprotein, ␣-1-antitrypsin, focal protrusion of the inner wall (dermoid protuberance). The
ferritin, CEA, and hCG to detect embryonal components.
● Immunohistochemical analysis of the neuroectodermal
components show that mature astrocytes contained glial
fibrillary acid protein, whereas mature nerve cells, nerve
fibers and a few groups of immature cells react with an
antibody to neuron-specific enolase.
TERATOMA, MATURE CYSTIC TERATOMA

(DERMOID CYST)
CLINICAL FEATURES
Mature cystic teratoma is the most common type of teratoma,
and the most common type of ovarian germ cell tumor. It
occurs usually during the reproductive years, but may also be
seen in other age groups. It is often discovered incidentally, but
may cause abdominal swelling and pain. Mature cystic ter-
atomas can be associated with autoimmune hemolytic anemia.
The cyst is usually unilocular, filled with fatty material and
hair, and has a smooth inner lining except for one or occasion-
ally several areas of solid or partly cystic protuberances con-
taining variety of tissues. Teeth and hair may be seen in these
areas. Other grossly recognizable tissues such as loops of intes-
tine, parts of ribs or any other bone, phalanxes and rarely a
fetus-like structure. Patients who have had a dermoid cyst
removed from an ovary appear to be at a slightly increased risk
for the subsequent development of an immature teratoma in
the same ovary. The risk is even higher if there are multiple der-
moid cysts or if there is rupture of the cyst.
Parasitic omental teratoma is an exceedingly rare event that
usually originates from an ovarian dermoid that underwent
torsion, autoamputation and omental reimplantation. In some
cases, the mature teratoma of the omentum shows histological
evidence of ovarian stroma, and is associated with a dermoid Figures 7.299 and 7.300 Dermoid cyst. Empty spaces separated
tumor of the remaining contralateral ovary. Abdominal pain is by connective tissue with foamy macrophages are common in
the main presenting symptom of these tumors, and on physical dermoid cyst.
Figure 7.301 Malignant teratoma (cystic teratoma with Figure 7.303 Malignant teratoma: the malignant nature of the
adenocarcinomatous transformation): benign squamous and glandular cells is clearly seen.
glandular epithelium.
● Mesodermal component is represented by bone and

cartilage, smooth muscle, fibrous and fatty tissue.
● Endodermal component is represented by bronchial and
gastrointestinal epithelium, salivary glands, and thyroid
tissue. Prostatic tissue in mature cystic teratomas of the
ovary has rarely been reported. Mature teratomas with
formation of complete segments of intestinal wall are
exceedingly rare.
The three germ cell layers of mature cystic teratoma – in con-

trast to those of immature teratoma – are usually arranged in an
organoid, orderly manner. ‘Pneumatosis cystoides-like’ appear-
ance represented by pseudovascular, spongiform or lattice or
sieve-like cystic spaces, often accompanied by foreign body-type
reaction or lipophagic granulomatous reaction, are frequently
seen in mature cystic teratomas. These probably represent dis-
solved sebaceous material. A prominent vascular proliferation
composed of long, thin-walled, curved vessels or a solid
glomeruloid arrangement may rarely be seen in mature or
immature teratoma, especially in areas of neural differentiation.
Mature cystic teratoma with secondary malignant transfor-
mation: a wide variety of malignant tumors may arise from
Figure 7.302 Malignant teratoma: abrupt transformation of benign mature cystic teratoma, the most common being squamous cell
glandular epithelium into dysplastic epithelium.
carcinoma. Other carcinomas reported in association with
mature cystic teratoma include: adenocarcinoma, undifferenti-
cyst is predominantly lined by skin and its appendages, occa- ated carcinoma, basal cell carcinoma, small cell carcinoma, seba-
sionally by bronchial or gastrointestinal type epithelium. Focal ceous carcinoma, sweat gland carcinoma, microcystic adnexal
loss of lining epithelium associated with foreign body reaction carcinoma, adenosquamous carcinoma, clear cell carcinoma,
may be seen. The area around the dermoid protuberance may carcinosarcoma, and extramammary Paget disease. Other malig-
contain tissues from three germ layers: nant tumors are melanomas, various sarcomas, neuroblastoma
● Ectodermal component represented by skin and its and glioblastoma. Malignant morphological changes, in the rare
appendages, brain and neural tissue, glial tissue, retina, cases of prostatic tissue that are seen in ovarian teratomas, have
choroid plexus, and ganglia. also been documented.
Secondary features TERATOMA, MATURE SOLID-TYPE

● Torsion
● Rupture with glial implants on the peritoneum
CLINICAL FEATURES
● Infection.
Mature solid teratoma is a very rare type of teratoma, com-
Cell morphology posed of entirely mature tissues derived from the three germ
cell layers. It occurs in children and young adults, and has an
● All cellular elements are mature and of normal
excellent prognosis. The tumor is usually unilateral, and it may
morphology.
be associated with peritoneal implants of mature glial tissue.
Unilateral oophorectomy is the treatment of choice. A rare
example of mature solid teratoma has been reported in the
● Fetus in ovo Fallopian tube. It is believed that tubal teratomas might result
● Immature cystic teratoma from the failure of germ cells (which normally migrate from the
● Metastatic hepatocellular carcinoma. yolk sac to the primitive gonadal bud) to reach the ovary.

Mature solid teratoma is composed of a variety of orderly
arranged tissues derived from the three germ layers. Mature
neural tissue usually predominates, and choroid plexus is often
seen. Immature tissues are entirely absent.
Cell morphology
● Squamous epithelium
● Glandular epithelium
● Adipose tissue
● Fibrous tissue
● Cartilage
● Glial tissue
● Choroid plexus.
● Immature teratoma
● Malignant mixed mullerian tumor.
Figures 7.304 and 7.305 Malignant teratoma: the invasive

component is that of an adenocarcinoma. Figure 7.306 Mature teratoma, showing cartilage and skin.
TERATOMA, MONODERMAL, AND HIGHLY of other types such as hepatoid yolk sac tumor. Rarely,
malignant struma shows features of papillary or follicular car-
SPECIALIZED TERATOMAS
cinomas.
On rare occasions, struma ovarii shows mucinous glands
CLINICAL FEATURES lined by goblet cells that are argyrophilic. Struma ovarii may
show secondary changes such as fibrosis, cystic changes, hem-
Monodermal teratomas consist predominantly or exclusively of
orrhage, stromal luteinization and Leydig cell hyperplasia.
one adult tissue that may result from teratomatous development
Carcinoid tumor shows insular, trabecular, strumal or muci-
of one germ cell layer or overgrowth of on tissue at the expense
nous patterns. The insular variant shows small acini with minor
of other teratomatous elements. Typical examples of mono-
trabecular component, usually less than 5%. The cells are
dermal teratoma are stuma ovarii, carcinoid, and neuroectodermal
argentaffinic (positive for NSE, serotonin, chromogranin, calci-
tumors. Other rare variants of monodermal teratomas include
tonin and prostatic acid phosphatase), and weakly argyrophilic
epidermoid cyst, pituitary adenoma, endodermal variant of
(Grimelius-positive). Associated teratomatous elements are usu-
mature cystic teratoma, sebaceous tumor, and salivary tumors.
ally of endodermal origin.
Struma ovarii is a rare form of mature teratoma of the ovary
The trabecular variant shows long or short wavy ribbons of
composed entirely or predominantly of thyroid tissue (at least
one or two cells thick, separated by loose or dense connective
50% of the tumor should consist of thyroid tissue, or the thyroid
tissue stroma, wide bands, trabecular and small nests. A minor
tissue is functionally active). This tumor is generally benign,
insular component may also be seen.
although malignant transformation may occur. The latter may
The tumor cells are predominantly argyrophilic. Small cystic
have clinical features highly suspicious of ovarian cancer. Struma
spaces lined by mucinous epithelium are often seen, and these
ovarii may show multiloculated cystic adnexal mass on imaging,
appear as an intrinsic part of the tumor.
features which are indistinguishable from benign multicystic
ovarian tumor. Patients with struma may present with non-
specific abdominal symptoms, or the lesion is discovered inci-
dentally. Sometimes symptoms related to hyperthyroidism or
signs indicating excessive estrogen due to activation of luteinized
stromal cells are seen in the vicinity of the tumor. Very rarely,
malignant struma ovarii presents with metastatic disease. Rarely,
struma ovarii is also associated with raised parathyroid hormone
levels.
Carcinoid tumor forms less than 5% of ovarian teratomas, and
the majority is associated with other teratomatous components
and often seen in postmenopausal women, apart from the
mucinous carcinoid which is seen in younger women. Ovarian
carcinoid tumors can be shown to contain a wide variety of
neurohormonal peptides, but clinical effects – apart from
the carcinoid syndrome – are very rare. Non-islet cell tumors with
hyperinsulinemic hypoglycemia may rarely occur. Raised serum
serotonin levels and raised urinary 5-hydroxyindoleacetic acid (5-
Figure 7.307 Struma ovarii: thyroid follicles, some with colloid
HIAA) levels are useful in the diagnosis of ovarian carcinoid. material. Arrows indicate the presence of colloid material.
Strumal carcinoid is the presence of carcinoid tumor in asso-
ciation with struma ovarii.
Ovarian neuroectodermal tumors are very rare. They have
been reported in females aged between 6 and 69 years (average
23 years), who present with symptoms of abdominal swelling
or pain. The tumors vary from cystic to solid, and range from
4 to 20 cm in diameter (average 14 cm).
Epidermoid cyst in the ovary: in the ovary, epidermoid cysts
are rare, representing monodermal and highly differentiated
teratomas.

Struma ovarii often resemble normal thyroid, but there may
be features of hyperactive thyroid, adenomatous hyperplasia,
adenoma-like lesion, Hashimoto’s thyroiditis and (rarely)
development of malignancy. Occasionally, struma ovarii may
not look like normal or hyperplastic thyroid tissue but may
show diffuse proliferation of cells, trabecular, tubular, clear Figure 7.308 Ovarian carcinoid tumor: nests of large eosinophilic
cell or oncocytic appearances that can simulate ovarian tumors cells.
a ribbon or trabecular pattern similar to that of hindgut carci-

noids, but an insular component may also be seen.
Mixed strumal and mucinous carcinoid tumor of the ovary has
rarely been reported. This shows carcinoid cells arranged in a
trabecular–insular configuration admixed with obvious thyroid
follicles. In addition, glands lined by mucin-producing cells are
seen in some areas. A transition from the strumal carcinoid com-
ponent to the mucinous glands is also seen. Immunohistochemical
studies indicate that the strumal and mucinous carcinoid compo-
nents are positive for chromogranin A, serotonin, and vasoactive
intestinal polypeptide, clearly demonstrating that both are neuro-
endocrine in nature.
Neuroectodermal tumors
There are three histological categories of neuroectodermal
tumor – differentiated, primitive, and anaplastic – with the
Figure 7.309 Mucinous-carcinoid tumor: nests of carcinoid were tumors in the first group having a better prognosis than those in
distributed in the stroma of a benign mucinous tumor. the other two groups. The differentiated gliomas are in the form
of pure ependymomas, or an ependymoma with an astrocytoma
component. The primitive tumors are reminiscent of medullo-
Mucinous variant can be divided into three groups on the epithelioma, ependymoblastoma, neuroblastoma, or medullo-
basis of their microscopic features. A ‘well-differentiated’ group blastoma. Some tumors have teratomatous foci of other types,
consists of small glands, many of which float in pools of mucin. including dermoid cysts. Anaplastic tumors are reminiscent of
The glands are lined by goblet cells and columnar cells, some of glioblastoma; these may contain foci of squamous epithelium.
which are of neuroendocrine type. An ‘atypical’ group is char- The differential diagnosis of neuroectodermal tumors of the
acterized by crowded glands (some of which are confluent), ovary includes many primary and metastatic ovarian neoplasms
small islands with a cribriform pattern, and scattered microcys- of diverse types, and distinction among them is important.
tic glands. The glands are lined by cuboidal to columnar cells Neuroectodermal tumors should be considered when examining
(some of them neuroendocrine), admixed with goblet cells. The unusual ovarian tumors, particularly if the patient is young.
third group is ‘carcinoma arising in mucinous carcinoid’, con-
taining islands and larger nodules of tumor cells, or closely Epidermoid cyst in the ovary
packed glands, as well as single cells, mainly of the signet ring
An epidermoid cyst in the ovary shows a smooth inner lining
cell type. Most of the cells are devoid of mucin and severely
composed of stratified squamous epithelium, but with no evi-
atypical, with marked mitotic activity. Necrosis is present in
dence of hair or skin appendages.
most tumors. The majority of tumors with a carcinomatous
component contain at least minor foci of well-differentiated
mucinous carcinoid; on occasion, they show foci of atypical Differential diagnosis
mucinous carcinoid. The neuroendocrine nature of a variable Struma ovarii
proportion of the cells in all three groups is demonstrated by ● Clear cell carcinoma
staining for neuroendocrine markers. The mucinous nature of ● Androblastoma
other cells is confirmed by mucicarmine or Alcian blue stains. ● Endometrioid carcinoma
The remaining ovarian tissue may contain an intrinsic compo- ● Granulosa cell tumor
nent of trabecular and insular carcinoid, strumal carcinoid, an ● Carcinoid tumor
adjacent mature cystic teratoma, mucinous cystadenocarci- ● Hepatoid yolk sac tumor
noma, borderline mucinous cystic tumor, borderline Brenner ● Sertoli cell tumor
tumor, or epidermoid cyst. Primary mucinous carcinoids must ● Metastatic renal cell carcinoma
be distinguished from metastatic mucinous carcinoid tumors ● Metastatic malignant melanoma
from the appendix or elsewhere. Features supporting an ovarian

Carcinoid tumor
origin are the additional presence in the specimen of teratoma
● Metastatic carcinoid (usually insular, bilateral and appear
or an ovarian surface epithelial tumor, an absence of blood ves-
multinodular)
sel or lymphatic space invasion, and confinement to a single
● Granulosa cell tumor
ovary. Mucinous carcinoids should also be distinguished from
● Poorly differentiated carcinoma
strumal carcinoids, which can contain mucinous glands, and
● Androblastoma
insular carcinoid tumors that arise rarely in the wall of a muci-
● Malignant struma
nous cystic neoplasm. The degree of differentiation, particularly
the presence of frank carcinoma, is an important prognostic fac-
tor in these tumors. Special techniques
Strumal carcinoid consists of thyroid parenchyma admixed ● Immunohistochemical stain for thyroglobulin to identify
with carcinoid elements. The latter component usually exhibits struma ovarii.
● The colloid is PAS-positive, and contains birefringent pleomorphic cells with hyperchromatic nuclei and frequent
oxalate crystals. mitoses.
● Argentaffin and argyrophil reaction and ● Alveolar-glandular pattern is characterized by the presence
immunohistochemical stains for neuroendocrine granules of alveoli and glandular structures lined by a single or more
to identify carcinoid tumor. than one layer of flat or low cuboidal epithelial-like cells
with large prominent nuclei or by papillary projections.
YOLK SAC TUMOR (ENDODERMAL SINUS TUMOR)
CLINICAL FEATURES
Endodermal sinus tumor (EST) is a rare but highly malignant
neoplasm of children and young adults, and very rarely also of
postmenopausal women. It usually arises in the testis or ovary,
and rarely in extragonadal sites such as the mediastinum,
vagina, vulva, brain, head and neck region and in the peri-
toneum. The most common presenting symptom of ovarian EST
is abdominal pain. An element of Leydig cells within the stroma
of EST may lead to virilization. The serum ␣-fetoprotein level is
a useful marker for diagnosis and monitoring the recurrence of
EST. The overall survival rate of patients with malignant germ
cell tumors in general is in the region of 60.6%, for dysgermi-
noma it is 78.5%, for immature teratoma 53.3%, for endo-
dermal sinus tumor 12.0%, and for mixed germ cell 33.3%.
Staging and tumor-reductive surgery strongly affects the
prognosis of this disease.
Rare examples of endometrioid carcinomas with a yolk sac
tumor (YST) component have been described. These unusually
have aggressive behavior and a poor prognosis.

The tumor can exhibit a variety of patterns:
● Microcystic/reticular and myxomatous pattern consists
of loose myxomatous or vacuolated network in which

various-sized microcystic spaces and numerous cavities and
channels are seen. These spaces are lined by either flat or
Figure 7.310 Yolk sac tumor, endometrioid subtype. Cellular

stroma with glandular structures lined by germ cell epithelium Figures 7.311–7.313 Yolk sac tumor. Pseudoglandular structures
exhibiting subnuclear vacuolation reminiscent of early secretory and cords of germ cells in a loose stroma; note the numerous hyaline
endometrium. globules within the epithelium lining some of the papillae (Figure 7.313).
● Papillary pattern demonstrates the presence of

papillary structures consisting of cores of connective
tissue lined by pleomorphic, mitotically active epithelial-
like cells.
● Macrocystic pattern exhibits larger cysts.
● Hepatoid pattern is characterized by large, polygonal,
eosinophilic cells arranged diffusely or in compact nests
reminiscent of hepatocellular carcinoma.
● Glandular pattern, where the cells are either arranged in
cribriform configuration or endometrioid-like glandular
pattern that often simulates that of an early secretory
endometrium.
● Minor teratomatous foci (squamous epithelium and
cartilage) may be present.
All of these patterns can be seen in one tumor, or one or two

patterns may predominate.
Figure 7.314 Yolk sac tumor. Pseudoglandular structures and ● Intestinal pattern is illustrated by the presence of glandular
cords of germ cells in a loose stroma.
structures interspersed amongst polygonal cells with
prominent cell borders.
Secondary features
● Necrosis
● Hemorrhage
● Cystic change
Cell morphology
● Cuboidal cells line the cystic areas
● Poorly differentiated or undifferentiated cells in the solid
areas
● Syncytiotrophoblastic
● Hepatoid cells
● Intestinal-type differentiation
● Various sizes of hyaline eosinophilic globules are seen both
Figure 7.315 Yolk sac tumor: Schiller-Duval bodies. intra- and extracellularly
● Solid pattern consists of loose aggregates of mitotically Differential diagnosis

active, usually pleomorphic, clear cells with vesicular or ● Juvenile granulosa cell tumor
pyknotic nuclei and prominent nucleoli. ● Anaplastic dysgerminoma
● Endodermal sinus pattern shows a complicated labyrinth ● Adenomatoid tumor
of intercommunicating spaces in which focal perivascular ● Lymphangioma
formations are seen as ‘Schiller-Duval bodies’ or ● Clear cell carcinoma
‘glomerulus-like structures’. These consist of a central ● Hepatoid carcinoma
capillary vessel surrounded by a cuff of connective tissue, ● Endometrioid carcinoma
followed by a layer of mitotically active, cuboidal or low ● Vascular tumors
columnar epithelial-like cells with large vesicular nuclei ● Malignant struma ovarii
and prominent nucleoli, and then a sinusoidal space
lined by a single layer of flat cells with hyperchromatic
nuclei. These structures, though not always seen, Special techniques
are considered diagnostic of endodermal sinus tumor. ● The hyaline globules are PAS-positive/diastase-resistant,
Similar structures, though lacking sinusoidal spaces, are PTAH positive, and immunoreact with ␣-fetoprotein and
also seen. ␣-1-antitrypsin.
● The polyvesicular vitelline pattern shows numerous ● The tumor cells are uniformly positive for cytokeratin and
different-sized, pear-shaped cysts or vesicles that are partly ␣-fetoprotein.
lined by flat mesothelial-like and partly by cuboidal or ● Inhibin alpha-subunit and calretinin could be used to
columnar epithelium. detect the Leydig cells.
● The germ cells are round with pale or slightly granular

MIXED GERM CELL AND SEX CORD–STROMAL cytoplasm and large round vesicular nuclei often with
TUMORS prominent nucleoli. They may show mitotic activity.
GONADOBLASTOMA
● Sex cord–stromal tumor with annular tubules
● Unclassified mixed germ cell and sex cord–stromal
CLINICAL FEATURES tumor
Gonadoblastoma is a rare, mixed germ cell and sex cord–stromal
tumor of the gonads. In 80% of cases it occurs in young pheno- Special techniques
typic females who may be virilized or non-virilized, and in 20% ● Germ cells express placental alkaline phosphatase
of cases in phenotypic males with cryptorchism, hypospadias and ● Inhibin stains the sex cord–stromal cells
female internal secondary sex organs. Primary amenorrhea is a
very common presenting symptom. A few phenotypic females
however may have episodes of spontaneous cyclical bleeding. The UNCLASSIFIED (GONADAL ANLAGE TUMOR)
tumor is bilateral in more than 38% of cases, and varies in size
from a microscopic focus to several centimeters in diameter. The
CLINICAL FEATURES
tumor is larger when associated with dysgerminoma or other
germ cell tumors. Gonadoblastoma has an excellent prognosis. Unclassified mixed germ cell and sex cord–stromal tumor is a
The outcome is still very good when associated with dysgermi- very rare tumor containing a mixture of germ cells and sex
noma, but poor if associated with other germ cell tumors. cord elements, but lacks the characteristic pattern of
gonadoblastoma. This tumor occurs in normal phenotypic
PATHOLOGICAL FEATURES females, typically children, and rarely in adult males. It may
present as abdominal mass or is rarely associated with preco-
Gonadoblastoma is composed of well-defined rounded or oval
cious puberty. The lesion is usually unilateral and is a large
solid nests (rarely cystic) of tumor cells separated by connective
solid with a lobulated surface. It generally has a good progno-
tissue stroma. These nests are surrounded by thick basement
sis, except when complicated by germ cell malignancies other
membrane-like hyaline material and consist predominantly of
than dysgerminoma.
small-sized epithelioid immature sex cord cells (immature gran-
ulosa or Sertoli cells) intermixed with larger pale germ cells
reminiscent of dysgerminoma or seminoma. The sex cord cells PATHOLOGICAL FEATURES
are arranged at the periphery of the nests, around groups of or
The tumor consists of a combination of germ cells and sex cord
single germ cells and around spaces reminiscent of Call–Exner
elements intimately mixed together. These may be arranged in
bodies (see Granulosa cell tumor, p. 489). The stroma is scant
the form of long narrow ramifying cords that may expand
or abundant, densely hyalinized or cellular, and occasionally
focally into wider columns or cellular aggregates separated by
edematous. It contains varying numbers of Leydig cells or
abundant, usually loose and edematous connective tissue
luteinized cells.
stroma; solid tubular structures that may focally become less
‘Burnt out’ gonadoblastoma shows almost complete hyalin-
obvious and form round or cellular masses separated by dense,
ization of the stroma and calcification of the lesion, with very
hyalinized fibrous septae; scattered collections of germ cells
few identifiable residual tumor cells.
surrounded by variable numbers of sex cord cells; or in the
Secondary features form of individually scattered or small groups of germ cells and
sex cord cells within connective tissue.
● Hyalinization of Call–Exner spaces, intercellular tissue,
A rare example of a mixed germ cell tumor (immature ter-
basement membrane surrounding the nests and the
atoma and dysgerminoma) with sarcomatous component and
connective tissue stroma.
areas resembling granulosa cell tumor has been reported.
● Calcification of the hyalinized areas in the form of
microcalcification, psammoma bodies, and larger calcific
nodules.
Cell morphology
● Lymphocytes or sometimes histiocytic giant cells are seen ● The germ cells are similar to those seen in gonadoblastoma
within the tumor nests. and dysgerminoma. Rarely, they are more mature,
● Malignant transformation (dysgerminoma occurs in 50% resembling primordial germ cells. They show mitotic
of cases, other germ cell tumors such as immature activity.
teratoma, endodermal sinus tumor, embryonal carcinoma, ● The sex cord cells are more frequently Sertoli than
and choriocarcinoma occur in 10%). granulosa cell-type. They are arranged in lines and at the
periphery of the cords, and may exhibit varying degrees of
Cell morphology mitotic activity.
● The immature sex cord cells are small-sized with dark, ● Leydig cells or luteinized cells are occasionally seen in the
round, oval or elongated nuclei. stroma.
● Sometimes clefts and cystic spaces containing papillary

projections reminiscent of retiform Sertoli–Leydig cell
tumor are seen.
● Gonadoblastoma
● Sertoli–Leydig cell tumor (in particular the retiform variant)
● Sex cord tumor with cystic degeneration
Special techniques
● Germ cells express placental alkaline phosphatase
● Inhibin stains the sex cord stromal cells
SEX CORD–STROMAL TUMORS

Figure 7.316 Microfollicular-type granulosa cell tumor.
GRANULOSA–STROMAL TUMORS, ADULT
GRANULOSA CELL TUMOR
CLINICAL FEATURES
Granulosa cell tumor is a slow-growing, potentially malignant,
sex cord–stromal tumor of the ovary accounting for only 5%
of ovarian malignancies. It has a favorable prognosis, but
relapse and extraovarian spread may occur as late as 20 years
after diagnosis. It can be seen at any age (5% before puberty,
55% during child-bearing age, and 40% in postmenopausal
women) and is rarely discovered after ovarian stimulation
treatment with clomiphene citrate and/or gonadotropins.
Granulosa cell tumor has the potential to produce large
amounts of estrogen (or rarely androgens), and thus may be
associated with endometrial hyperplasia or endometrial carci-
noma, and rarely with development of endometriosis and
leiomyomata. The tumor is usually encapsulated, with a smooth
lobulated outline and a predominantly solid cut surface. Cysts
may be seen that sometimes may be so prominent as to simulate
cystic ovarian tumors. The tumor may recur after several years,
has a 10-year survival rate of 85%, and is clinically malignant in
5–25% of cases. It spreads largely to the pelvis and lower
abdomen, and rarely distally. There is currently no standard
treatment, but a vigilant follow-up protocol is recommended for
all patients to detect early recurrences and achieve complete cure.
Tumor stage, size (over 5 cm), and nuclear atypia and mitoses
may all influence the outcome.

Due to the various arrangements of the sex cord cells within
the fibrothecomatous stroma, granulosa cell tumor has a vari-
Figures 7.317 and 7.318 Macrofollicular type granulosa cell
ety of histological patterns:
tumor. Small acini of microfollicular pattern are also seen; the nuclear
● Microfollicular pattern is characterized by well-demarcated
grooving is distinct.
islands of small, uniform polyhedral cells surrounded by a
peripheral layer of palisading cells. Within the cell nests ● Macrofollicular pattern is characterized by the presence
there are numerous, small, rounded, spaces or rosette-like of cysts of various sizes lined by well-differentiated
structures containing eosinophilic or sometimes basophilic granulosa cells.
acellular material, reminiscent of Call–Exner bodies in the ● Insular pattern and trabecular pattern are characterized by
developing follicle. bands or branching columns of granulosa cells.
Figure 7.319 Macrofollicular type granulosa cell tumor. Small acini

of microfollicular pattern are also seen; the nuclear grooving is
distinct.
Figure 7.320 Granulosa cell tumor: gyriform pattern.The circle

indicates nuclear (‘coffee-bean’) grooving.
Figures 7.322–7.324 Granulosa cell tumor with thecomatous

component. Desmin is sometimes positive in the thecomatous
component (Figure 7.324).
● Gyriform/watered-silk pattern is characterized by the

presence of undulating or zigzag-like single file rows
of cells.
Figure 7.321 Diffuse-type granulosa cell tumor from pelvic ● Diffuse pattern or solid pattern is characterized by a
recurrence. monotonous proliferation of round or elongated
Cell morphology
● Granulosa cells are rounded, oval or sometimes spindle-
shaped, with little cytoplasm and containing uniform,
angulated, pale and grooved ‘coffee-bean’ nuclei.
● Luteinized cells may be present.
● Multinucleated giant cells (sometimes of the ‘floret’ type)
may occasionally be seen.
● Bizarre nuclei may be present.
● Mitoses are often seen in the malignant tumors.
● Metastatic breast carcinoma has been reported within the
substance of granulosa cell tumor.
● Carcinoid tumor
● Endometrioid carcinoma with sex cord differentiation
(often contains AB/PAS-positive intracytoplasmic mucin
and usually CK7-positive and inhibin-negative)
● Gonadoblastoma (the hyaline bodies are often larger and
show frequent calcification)
● Gynadroblastoma
● Sex cord tumor with annular tubules (from the
microfollicular variant)
● Poorly differentiated carcinoma (from the diffuse or solid
form of carcinoid)
● Small cell undifferentiated carcinoma (from the diffuse or
solid form of carcinoid)
● Sertoli–Leydig cell tumor
● Follicular cysts (from cystic macrofollicular granulosa cell
tumor)
● Stromal sarcoma.
Figures 7.325 and 7.326 Cystic granulosa cell tumor. A cyst

Special techniques
wall lined by thickened epithelium exhibiting microacinar pattern.
The lining epithelium is indistinguishable from the solid granulosa ● Granulosa cell tumor is positive for alpha- and
cell tumor. beta-inhibin, Ewing’s sarcoma antigen 013 (CD99),
vimentin positivity, and smooth muscle actin.
● The cells are frequently positive for S-100 protein, and
cytokeratin AE1/AE3, and occasionally for CAM 5.2, and
cells arranged in sheets or masses containing ill-defined
desmin.
pseudorosettes (reminiscent of neuroendocrine
● Other markers that have been used to assist in the
tumors).
diagnosis of sex cord–stromal neoplasms include
● Sarcomatous pattern is characterized by the presence of a
relaxin-like factor, mullerian-inhibiting substance, and
monotonous population of small spindle cells.
melan-A (A103).
Luteinized granulosa cell tumor consists predominantly ● The tumor is negative for EMA, CEA, and CA125.
of cells containing abundant dense eosinophilic, or pale ● The cells are cytokeratin- and CD10-negative, except
vacuolated cytoplasm resembling cells of corpus luteum. The sometimes focally in areas of epithelial differentiation.
nuclear grooves tend to disappear in this variant. ● Calretinin, a 29-kDa calcium-binding protein, a marker for
Combined granulosa cells with benign mucinous tumor may mesothelial cells and mesothelioma, has recently been
rarely be seen. shown to be positive in ovarian sex cord–stromal
neoplasms. Calretinin is expressed in all types of granulosa
cell tumors, Sertoli–Leydig cell tumors, thecomas, and
Secondary features fibrothecomas. Calretinin is particularly useful in the
● Edema diagnosis of sex cord–stromal and fibrous neoplasms
● Focal luteinization which are inhibin-negative.
● Hemorrhage ● The cells may contain fine argyrophilic granules.
● Cystic change is occasionally seen ● Reticulin stain highlights fibers around aggregates of cells
● Pronounced sclerosis of the tumor islands. rather than around single cells (as in thecoma).
GRANULOSA–STROMAL TUMORS, JUVENILE Special techniques

GRANULOSA CELL TUMOR ● The eosinophilic material within the follicles is
mucicarmine-positive.
● The cells contain intracytoplasmic lipid.
CLINICAL FEATURES ● One-third of juvenile granulosa cell tumors are S-100
Juvenile granulosa cell tumor is an ovarian sex cord tumor that protein-positive.
occurs during the first three decades of life. It results in isosexual ● The majority of cases are NSE-positive.
pseudoprecocity or abdominal pain and swelling, and some- ● Tumor cells stained focally with low-molecular-weight
times also menorrhagia or amenorrhea, depending on the cytokeratins (8, 18, and 19), smooth-muscle-specific actin,
patient’s age. In 10% of cases it presents with acute abdominal desmin and, more noticeably, with vimentin.
symptoms due to rupture of the tumor, and 10% of cases pres- ● Calretinin is particularly useful in the diagnosis of
ent with ascites. The tumor rarely spreads beyond the ovary, or sex cord–stromal and fibrous neoplasms that are
runs a fatal course. The lesion is bilateral in 2% of cases. inhibin-negative.
Juvenile granulosa cell tumor may develop in testicular tissue.
Congenital juvenile granulosa cell tumor with sex chromo- GYNANDROBLASTOMA
somal abnormality and tumor arising from immature testicular
tissue has been rarely reported.
CLINICAL FEATURES
PATHOLOGICAL FEATURES Gynandroblastoma is an extremely rare tumor of the ovary.

The term should only be used when both granulosa cell and
Juvenile granulosa cell tumor is a predominantly solid cellular Sertoli–Leydig cell tumor elements are seen within the lesion.
lesion that typically shows distinct follicle formation, but may This tumor is derived from a common gonadal mesenchyme
also be uniformly solid or uniformly follicular. The follicles precursor or indifferent cell. The tumor occurs at any age
vary in size and shape, contain eosinophilic or basophilic mate- (15–65 years), and when functioning is often masculinizing;
rial, and are lined by a layer of granulosa cells of varying thick- however, it can also be feminizing and result in postmeno-
ness. These either blend into the surrounding stroma or into a pausal bleeding and endometrial cystic hyperplasia.
layer of theca cells. Sometimes the lining cells have a hobnail Preoperative serum hormonal assays may show elevated
appearance. In the solid areas, the cells are distributed diffusely levels of estrone, estradiol and testosterone, and low levels of
or as multiple nodules or small clusters. The constituent gonadotropins.
cells are mainly granulosa cells, but theca cells are also present
and may predominate in some areas. An example of Wilms’
tumor nodule within juvenile granulosa cell tumor has been
described. The tumor consists of substantial amounts of a granulosa cell
element and a Sertoli cell element with intermingled Leydig
cells. These are present in variable numbers, either as com-
Secondary features
pletely or partly separated discrete tumor nodules or inter-
● Occasional hemorrhage and necrosis mixed with each other. The epithelial component is usually well
● Areas of sclerosis with hyaline bands resembling those seen demarcated from the stroma. The latter may be spindly and
in thecoma fibroblastic, or may contain plump or polyhedral cells. The
● Calcification female type is similar to granulosa cell tumor, often containing
Call–Exner bodies, and similarly may be insular, micro- or
Cell morphology macrofollicular, trabecular, or sarcomatoid. The male compo-
nent is usually in the form of Sertoli–Leydig tumor consisting
● The granulosa cells have moderate or abundant
of epithelial nests, hollow tubules with a true lumen lined by
eosinophilic, solid or vacuolated cytoplasm and rounded
cuboidal or columnar epithelium, accompanied by round or
hyperchromatic nuclei which, in contrast to the cells of
polygonal cells with abundant eosinophilic cytoplasm and
adult granulosa cell tumors, usually lack grooves.
bland, uniform nuclei resembling Leydig cells of normal testis.
● The theca cells are usually luteinized.
Rarely, the predominant component (especially in children) is
● There may be severe nuclear atypia and very high mitotic
juvenile granulosa cell tumor. Stromal theca and luteinized cells
figures.
may be identified. An additional histological finding is the pres-
ence of heterologous intestinal type glands.
● Small cell carcinoma Differential diagnosis
● Tubulocystic variant of clear cell carcinoma ● Granulosa cell tumor with rare hollow tubules lined by
● Undifferentiated carcinoma typical Sertoli cells
● Metastatic malignant melanoma ● Sertoli–Leydig cell tumor (androblastoma) with occasional
● Large solitary luteinized follicle cyst small focal areas simulating granulosa cell tumor
Special techniques
Immunohistochemically, the tumor cells in both the granulosa
cell and Sertoli cell elements are positive for cytokeratin
CAM5.2.
● The granulosa cell element shows strong membrane
staining of Ewing’s sarcoma antigen 013 (CD99) and

inhibin, and the Sertoli cell element is focally positive.
● Vimentin is observed in both the Sertoli cell element and
the granulosa cells.

● Both elements and the Leydig cells are uniformly negative
for epithelial membrane antigen, muscle specific actin,

CD31, and CD34.
● The tumor is usually aneuploid as monitored by flow
cytometry.
HYPERREACTIO LUTEINALIS (MULTIPLE Figure 7.327 Hyperreactio luteinalis.The cysts are lined by
partially or completely luteinized granulosa cell layer and prominent,
LUTEINIZED FOLLICLE CYSTS) hyperplastic (also luteinized) theca interna layers.The intervening
stroma is edematous, congested, and contains varying numbers of
luteinized stromal cells.
CLINICAL FEATURES
Hyperreactio luteinalis is a non-neoplastic tumor-like ovarian
Cell morphology
lesion associated with pregnancy. Most patients are asymptom-
atic, with the ovarian enlargement being incidentally discov- ● The granulosa cells are mostly luteinized, and may show
ered at the time of Cesarean section. It can simulate a neoplasm degenerative features such as nuclear enlargement,
on clinical, gross and sometimes microscopic examination. pleomorphism and hyperchromasia.
Hyperreactio luteinalis is characterized by moderate to marked ● The luteinized cells, theca interna and stromal cells are round,
cystic enlargement of the ovaries related to multiple theca with abundant, finely granular eosinophilic cytoplasm. The
lutein cysts, and is associated with very high sex steroid con- nuclei are centrally or eccentrically placed and contain small
centrations. It is most often associated with hydatidiform mole central nucleoli. Occasional cells are vacuolated.
choriocarcinoma, multiple gestation, or fetal hydrops. Hyper-
reactio luteinalis rarely occurs in normal singleton pregnancy. The Differential diagnosis
cause of this condition is unknown, but is believed to be related ● Six non-neoplastic ovarian lesions are associated with
to elevated levels of, or abnormal ovarian response to, human pregnancy or the puerperium, each of which can simulate
chorionic and pituitary gonadotropins. It can develop in women a neoplasm on clinical, gross, or microscopic examination.
undergoing ovulation induction, particularly in those with These lesions are pregnancy luteoma, hyperreactio
polycystic ovaries. The cysts may attain a diameter ⬎20 cm, and luteinalis, large solitary luteinized follicle cyst of pregnancy
contain clear or hemorrhagic fluid. and puerperium, intrafollicular granulosa cell
The clinical presentation of hyperreactio luteinalis can mimic proliferations, hilus cell hyperplasia, and ectopic decidua.
ovarian hyperstimulation. Hemorrhage into the cysts or into
the peritoneal cavity may occur. Because these lesions involute
spontaneously after termination of pregnancy or are ade- MASSIVE OVARIAN EDEMA
quately treated by a conservative surgical approach, unneces-
sarily radical operations can be avoided if the correct diagnosis
is made. CLINICAL FEATURES
Massive ovarian edema refers to an accumulation of edema
fluid within the ovarian stroma. It is of unknown histogenesis,
but is probably caused by partial obstruction of vascular or
Findings that would suggest the correct diagnosis are the sym- lymphatic drainage due to intermittent torsion of the ovary on
metrical and bilateral pattern of the mass, as well as the rather its pedicle; alternatively, it may be due to secondary deposit of
uniform size of the loculi, which are 1 to 3 cm in diameter. The tumor within pelvic lymphatics. It usually occurs in younger
cysts are lined by partially or completely luteinized granulosa age groups, and presents with abdominal pain and distension
cell layer and prominent, hyperplastic also luteinized theca or menstrual irregularities. It can be associated with andro-
interna layers. The intervening stroma is edematous, congested, genic manifestations due to the presence of aggregates of
and contains varying numbers of luteinized stromal cells. luteinized cells in the stroma, or is occasionally associated with
Dilated, ectatic and elongated thin-walled and congested capil- estrogenic manifestations. The ovary appears enlarged and
lary vessels are usually seen. fluctuant, with a shiny white smooth cut surface.
Massive ovarian edema is characterized by striking edema of the
ovarian stroma except for a small subserosal rim of ovarian cor-
tex which appears rather fibrotic. The follicular structures appear
widely separated and sometimes involved by the edematous
stroma. Dilated blood vessels are frequently seen. Pseudocyst for-
mation and focal stromal luteinization may be seen.
Cell morphology
● The ovarian stromal cells appear spindle-shaped and
widely separated by the edema fluid.
● Sclerosing stromal tumor
● Fibroma
● Krukenberg tumor
● Ovarian myxoma
OVARIAN FIBROMATOSIS
CLINICAL FEATURES
Ovarian fibromatosis is a fibroblastic proliferative process
affecting young women, who may present with abdominal pain
and menstrual abnormalities, and less commonly with viriliza-
tion and hirsutism. The lesion may be discovered incidentally
at Cesarean section, and may be seen in association with mas-
sive ovarian edema. It is occasionally bilateral. Coexistence of
ovarian fibromatosis and intra-abdominal fibromatosis may
occur.
Ovarian fibromatosis is characterized by the presence of diffuse
fibroblastic proliferation of the ovarian stroma. Focal stori-
form pattern is often seen. Variable degrees of hyalinization
may be found. Microscopic foci of sex cord elements may occa-
sionally be seen. Small foci of stromal edema may be seen.
● Fibroma
● Thecoma
● Sclerosing stromal tumor
● Ovarian involvement by abdominal fibromatosis
Figures 7.328–7.330 Sclerosing stromal tumor. Pale sclerosed

SCLEROSING STROMAL TUMOR stroma with numerous large vessels; the sclerosed stroma contains
bland, vacuolated stromal cells.
CLINICAL FEATURES
Sclerosing stromal tumor is a benign stromal ovarian tumor
which presumably arises from perifollicular myoid stromal Sclerosing stroma tumor has a pseudolobular, vaguely nodular
cells that are seen in the theca externa. The tumor is usually pattern with an edematous, vascular or collagenized background.
seen in younger women. It is almost always unilateral, and may It consists of a disorganized admixture of fibroblasts, rounded
be associated with estrogenic manifestations. vacuolated cells, and areas of sclerosis. Prominent thin-walled
vessels are present throughout the lesion, some showing a

hemangiopericytomatous pattern. Edema, sclerosis, cyst for-
mation and calcification may be seen.
Cell morphology
● The cells are rounded or polyhedral with vacuolated or
eosinophilic cytoplasm, or spindle-shaped fibroblasts
● Some cells show a signet ring appearance
● Luteinized cells may also be seen
● Mast cells can be prominent
● Mitotic figures are rare
● Ovarian myxoma
Special techniques
● The cells contain intracellular lipid, demonstrable by fat
stains or electron microscopy.
● CD31 and CD34 show a surprisingly high number of
small vessels that are not apparent in hematoxylin and
eosin-stained sections. The tumor cells are positive for
alpha-inhibin, CD99, and actin; and negative for S-100
protein and epithelial markers.
● A few stromal cells may stain with desmin.
● A103 (an antibody to melan-A) is positive in sclerosing
stromal tumor.
SERTOLI–STROMAL CELL TUMORS, SERTOLI–

LEYDIG CELL TUMORS (ANDROBLASTOMAS)
Figures 7.331 and 7.332 Well-differentiated Sertoli–Leydig cell
CLINICAL FEATURES tumor: note well-differentiated tubules of Sertoli cells with diffuse
Leydig cells.
Sertoli–Leydig cell tumors (androblastomas) are rare ovarian
sex cord–stromal tumors which account for less than 0.5% of numbers of Leydig cells. Within the nodules there are
all ovarian neoplasms. They usually occur in women under the small round or elongated, hollow or solid glandular
age of 30 years, and rarely have been reported in children and structures lined by Sertoli cells and possibly containing an
infants. These tumors are associated with virilization in 30% of eosinophilic secretion. The Leydig cells are arranged in
cases, and may be associated with elevated ␣-fetoprotein levels. ribbons, nests, or solid sheets.
The tumors may also be estrogenic, probably due to peripheral ● Moderately differentiated variants are characterized by the
conversion of androgenic secretion into estrogen. They may presence of immature Sertoli cells that may be arranged in
also present with abdominal pain or swelling. These tumors are ill-defined masses, or solid and hollow tubules, branched
almost always unilateral. Sertoli–Leydig cell tumors generally angulated glands reminiscent of endometrioid neoplasm,
have good prognosis, but are prone to early recurrence, except nests, thin anastomosing cords, broad columns, sieve-like
for the poorly differentiated tumors and those with a retiform and rarely thyroid follicle-like structures. These are
component. The tumors are treated by surgery, with or without separated by stroma that may be fibromatous, edematous,
chemotherapy or radiotherapy, depending on the stage and myxomatous or immature and densely cellular, and
differentiation. contains clusters of well-differentiated Leydig cells.
● Poorly differentiated variants are characterized by the
PATHOLOGICAL FEATURES (Figures 7.331–7.345) presence of spindle-shaped sarcomatous areas containing
cord-like structures, or trabeculae of immature Sertoli
There are several histological patterns, all of which may contain
cells. The sarcoma-like areas may exhibit numerous
heterologous elements, except the well-differentiated variant.
mitotic figures. The Leydig cells are sparse, and may be
● Well-differentiated variants (tubular androblastomas) are difficult to identify in this variant. Sometimes the Sertoli
characterized by the presence of tumor nodules separated cells are arranged in gyriform, cribriform or ‘moiré-silk’
by dense fibrous connective tissue containing a variable areas, similar to granulosa cell tumor.
Figures 7.333 and 7.334 Sertoli–Leydig cell tumor, intermediate

differentiation. Dark cords of Sertoli cells intermixed with larger,
eosinophilic Leydig cells.
Figures 7.336–7.338 Poorly differentiated Sertoli–Leydig cell

tumor. Diffuse admixture of Sertoli and Leydig cells; spindle cell
morphology is sometimes confused with fibrosarcoma or spindle
cell carcinoma.
Figure 7.335 Sertoli–Leydig cell tumor, poorly differentiated:
diffuse admixture of Sertoli and Leydig cells.
● Retiform variants are characterized by the presence of name retiform. Projecting within some of these spaces are
elongated, branching angular, slit-like or tubular or cystic papillary structures which contain hyaline cores and are
spaces lined by cuboidal epithelium, some with a hobnail lined by Sertoli cells. The papillae may be very delicate, and
pattern, somewhat reminiscent of rete testis – hence the reminiscent of those seen in borderline or well-differentiated
Figures 7.339 and 7.340 Poorly differentiated Sertoli–Leydig cell tumor. Diffuse admixture of Sertoli and Leydig cells; spindle cell
morphology is sometimes confused with fibrosarcoma or spindle cell carcinoma.
Figures 7.341 and 7.344 Sertoli–Leydig cell tumor, poorly differentiated. Inhibin (Figure 7.341), melan-A (Figure 7.342), and calretinin
(Figure 7.343) highlight the Leydig cells. SMA (Figure 7.344) highlights some of the stromal cells.
serous tumors. The intervening stroma similarly may be represent a small or a large component of moderately or
hyalinized, edematous or immature and cellular. On rare poorly differentiated Sertoli–Leydig cell tumors. Tumors
occasions, the metastases show a pure sarcomatoid pattern with this pattern occur at a slightly younger age and are less
without any retiform areas. The retiform areas may likely to be virilizing.
● Malignant mixed mullerian tumor/carcinosarcoma

● Yolk sac tumor (may be confused with the retiform
variant)
● Immature teratoma
● Metastatic gallbladder and bile duct carcinomas may
simulate primary ovarian neoplasms, including
Sertoli–Leydig cell tumors
Special techniques
● The cells lining the tubules are cytokeratin-positive
(normal Sertoli cells are negative) and occasionally
vimentin-positive.
● Leydig cells are negative for keratins, positive for vimentin,
and intensely positive for inhibin (inhibin is a glycoprotein
hormone produced by normal ovarian granulosa cells and
testicular Sertoli cells).
Figure 7.345 Sertoli–Leydig cell tumor, retiform type.Tubular ● Rarely, the tumor shows tissue immunoreactivity for
structures of Sertoli cells intermixed with Leydig cells.
␣-fetoprotein.
● Hepatocytes are positive for cytokeratins (AE1/AE3
● Tumors with mixed pattern show a combination of all or and CAM 5.2), ␣-fetoprotein, and ferritin; negative for
some of the above patterns. vimentin; and show weak to moderate staining for
● Tumors with heterologous elements show intestinal-type inhibin.
epithelium, foci of carcinoid, cartilage, areas of embryonal
● A103 (an antibody to melan-A) is positive in
rhabdomyosarcoma, or rarely neuroblastomatous or Sertoli–Leydig cell tumors of the ovary.
retinal structures.
● Calretinin is particularly useful in the diagnosis of sex
● Calcifying Sertoli cell neoplasms have been described. cord–stromal tumors.
● A well-differentiated Sertoli–Leydig cell tumor has also
been described arising in a septum of serous cystadenoma,
as a circumscribed nodule. SEX CORD TUMOR WITH ANNULAR TUBULES
Cell morphology CLINICAL FEATURES

● The Sertoli cells are cuboidal or columnar, with Sex cord tumor with annular tubules occurs in two settings.
moderate amounts of dense cytoplasm and round or oval One is the bilateral, multicentric, small or microscopic lesions
nuclei without prominent nucleoli. The cytoplasm may be that are discovered incidentally in association with Peutz–Jeghers
vacuolated and sometimes contains large lipid vacuoles. syndrome and are usually benign. The other is sporadic,
● Leydig cells are round or polygonal with eosinophilic unilateral, clinically palpable and not associated with Peutz–
granular cytoplasm that may contain lipochrome pigment Jeghers syndrome. The sporadic type is malignant in about
or Reinke crystals. They may show cytoplasmic 22% of cases and associated with estrogenic manifestations in
vacuolations and large lipid droplets. 40% of cases.
● The intestinal epithelium seen in the heterologous element
consists of well- to moderately differentiated cells,
including goblet cells, argentaffin cells and, rarely, Paneth
cells. This distinctive tumor consists of multiple, sharply circum-
● Other types of heterologous cells such as hepatocyte, scribed, rounded or lobulated basaloid epithelial structures.
retinal, and neuroblastomatous cells are occasionally These are made up of a single central or multiple rounded inter-
seen. communicating spaces filled with glassy homogeneous, hyaline
material, sometimes containing calcified bodies. The periphery
Differential diagnosis of these acellular spaces is lined by a single row of nuclei, and
the intervening cells contain vacuolated or clear cytoplasm. The
hyaline material may be so extensive that it may obliterate the
● Endometrioid carcinoma with sertoliform features (the
tumor architecture.
cells are positive for keratin and EMA, and negative for
inhibin)
● Tubular Krukenberg tumor Differential diagnosis
● Borderline or malignant papillary serous tumors (may be ● Gonadoblastoma
confused with the retiform variant) ● Sertoli cell tumor
● Carcinoid tumor of the trabecular type ● Granulosa cell tumor.
Stromal hyperthecosis is characterized by the presence of

small collections or clusters or nodules of polygonal cells with
pale eosinophilic or vacuolated cytoplasm. These are most
commonly seen in the medulla.
Other ovarian lesions which can be seen in association with
stromal hyperthecosis include: nodules of metaplastic smooth
muscle, Leydig cell hyperplasia, Leydig cell tumors, stromal
luteomas, thecomas, and massive edema.
Cell morphology
● The stromal cells in stromal hyperplasia are plump in
shape, and contain vesicular nuclei and frequently also
cytoplasmic lipid.
● The luteinized cells in stromal hyperthecosis are polygonal,
with pale eosinophilic or vacuolated cytoplasm due to
their lipid contents. The nucleus is round and contains a
Figure 7.346 Sex cord–stromal tumor with annular tubules. small central nucleolus.
Multiple, sharply circumscribed, rounded basaloid epithelial structures
which are comprised of multiple rounded intercommunicating Differential diagnosis
spaces filled with glassy homogeneous, hyaline material.
● Luteinized stromal cells seen in the stroma adjacent to
various ovarian tumors (tumors with functioning stromal
Special techniques
cells).
● The cells are inhibin-positive. ● Solid non-neoplastic proliferation of luteinized cells (as
● Both cytokeratins and vimentin are detected in sex cord seen in pregnancy luteoma, Leydig cell hyperplasia).
tumor with annular tubules. ● Neoplastic proliferation of luteinized cells (luteinized
● A103 (an antibody to melan-A) is a moderately sensitive thecoma, steroid cell tumor).
and specific marker of sex cord–stromal differentiation
(Sertoli/Sertoli–Leydig cell tumors, steroid cell tumors,
thecomas/fibrothecomas, and sclerosing stromal tumors).
THECOMA–FIBROMA (FIBROTHECOMA) GROUP
Normal hilus cells and rete ovarii epithelium also OF OVARIAN TUMORS
expressed A103. Normal and neoplastic wolffian
elements may also express A103.
CLINICAL FEATURES
STROMAL HYPERPLASIA AND STROMAL Thecomas, fibromas and fibrothecomas are benign neoplasms
of ovarian cortical origin that usually occur after menopause.
HYPERTHECOSIS
They are commonly associated with – and appear to originate
from – pre-existing ovarian cortical hyperplasia. They may
CLINICAL FEATURES present with abdominal mass, cause menstrual abnormalities,
or appear as an incidental finding at laparotomy. Ascites
Stromal hyperplasia refers to non-specific proliferation of ovar-
or Meig’s syndrome may be associated with these tumors.
ian stromal cells, resulting in bilateral enlargement of the ovaries.
Thecoma and fibromas are mostly unilateral, and vary in size
This condition is most commonly seen in patients aged over
from microscopic to very large tumors. Thecomas are often
60 years, and is often associated with androgen secretion, and to
associated with endometrial hyperplasia. Fibrothecoma may
a lesser extent with obesity, hypertension, and glucose intolerance.
rarely be seen in association with massive ovarian edema.
Stromal hyperthecosis refers to the presence of focal
Malignant thecomas are very rare and tend to have a poor
luteinization of the stromal cells often in association with stro-
prognosis.
mal hyperplasia. Similar to stromal hyperplasia, it is seen after
Spindle cell proliferations of the ovary resembling luteinized
the age of 60 years, and may be associated with bilateral
thecomas in association with extensive sclerosing peritonitis is
enlargement of the ovary. It may be associated with estrogenic
a recently described condition that can be mistaken as malig-
manifestations such as endometrial hyperplasia or carcinoma.
nant thecoma. These lesions are found in patients aged from
The lesion is occasionally familial, and in some cases is associ-
13 to 76 years who present with abdominal swelling, pelvic
ated with HAIR-AN syndrome. This syndrome is characterized
masses, ascites, or small bowel obstruction. At laparotomy,
by the presence of hyperandrogenism (HA), insulin resistance
there is fibrotic thickening of the peritoneum, most promi-
(IR), and acanthosis nigricans (AN).
nently involving the omentum and small bowel, with unilateral
or bilateral, predominantly solid ovarian tumors. The ovarian
lesion is usually unilateral, may reach up to 31 cm in maximum
Stromal hyperplasia is characterized by varying degrees of dimension, and looks like a luteinized thecoma. It may exhibit
nodular or diffuse proliferation of ovarian stromal cells. a brisk mitotic activity and, on rare occasions, foci of sex cord
elements may be seen. The process may be confined to the ovar- Luteinized thecomas tend to have clusters of large eosinophilic
ian cortex. Residual ovarian follicles may be seen entrapped by lipid-containing cells with no evidence of stromal hyperplasia.
the proliferation. Additional features include brisk mitotic activ-
ity (predominantly in the spindle cells) and striking edema. The Stromal tumors with minor sex cord element
peritoneal process shows a variably cellular proliferation of These are characterized by the presence of two components: a
fibroblasts and myofibroblasts separated by collagen, fibrin, major component of stromal elements such as fibroma,
and occasional chronic inflammatory cells. thecoma or stromal–Leydig cell tumor, and a minor component
of sex cord elements such as granulosa cell, Sertoli cell, or indif-
PATHOLOGICAL FEATURES (Figures 7.347–7.349) ferent sex cord cell tumors. The latter can comprise up to 10%
Thecoma is a vaguely nodular mesenchymal lesion consisting of the volume of the tumor, is usually located peripherally, and
of plump spindle cells arranged in islands, diffuse sheets, inter- occurs in small groups. The clinical and biological behavior
lacing bands and bundles, in whorls, or in anastomosing tra- of this tumor is similar to that of the main stromal tumor.
beculae. The cells are separated by varying amounts of delicate Mucinous cystadenomas rarely coexist with stromal tumors
or coarse fibrillary matrix. Occasionally, the stroma is edema- with minor sex cord elements.
tous and the cells are stellate. More often, the intercellular Fibroma is similarly a monomorphic spindle cell tumor. It dif-
stroma is hyalinized and forms eosinophilic osteoid-like struc- fers from thecoma in the degree of maturation of cells, these being
tures. Some of the cellular areas show epithelioid cells with vac- more slender, fibroblastic, and arranged in fascicles and whorls.
uolation. Focal luteinization of stromal cells can be seen. The Fibrothecoma is usually more fibroblastic than thecoma, is
remaining ovarian stroma is often hyperplasic and nodular. often collagenous and edematous, and lacks luteinization.
Hyalinization, calcification, and chondroid or osteoid metaplasia Classical malignant fibrothecomas are said to show four or
may be seen. more mitotic figures per 10 high power fields (HPF). However,
formal mitotic counts are not an absolute indicator of malig-
nant behavior in this group of tumors.
Cell morphology
● Oval or plump spindle-shaped cells containing round
nuclei and vacuolated pale cytoplasm
● Stellate cells
● Luteinized cells
● Mitotic figures are rarely seen (cellular tumors with
over 4 mitoses per 10 HPF should be followed-up and
considered suspicious)
● Occasionally, bizarre nuclei are seen
● Hyalinized smooth muscle tumor
● Stromal luteomas (are seen as dominant nodules in
a background of nodular hyperplasia)
Figures 7.347 and 7.348 Fibrothecoma. Loose spindle cell lesion

with amianthoid-like collagen bundles.The nuclei are plump, and the
cytoplasm is eosinophilic and fibrillary. Calcification may be seen Figure 7.349 Thecoma: plump stromal cells in a loose stroma
within the amianthoid-like collagen bundles. with fibrillary collagen.
● Fibromatosis
● Brenner tumors and Krukenberg tumor (when the STEROID (LIPID) CELL TUMORS
epithelial component is not obviously seen)
● Massive edema of the ovary
CLINICAL FEATURES
● Sclerosing stromal tumor of the ovary
Steroid cell tumors of the ovary are classified into three major
Special techniques categories:
● Fat stains of frozen section material demonstrate ● Stromal luteoma accounts for 25% of cases, occurs in
intracellular fat droplets within the cells of thecomas. postmenopausal women, and results in uterine bleeding
● Desmin is demonstrated in some thecomas and fibromas. due to estrogen production by the tumor. The remaining
● Calretinin is expressed in all types of sex cord–stromal cases are either androgenic or non-functioning. Stromal
and fibrous neoplasms. luteoma is unilateral, and usually smaller than 3 cm in
● Thecomas show positive immunohistochemical staining diameter.
with anti-inhibin. ● Leydig cell tumor (hilar and non-hilar) accounts for 15%
● A103 is positive in thecomas/fibrothecomas. of cases, occurs in postmenopausal patients, and is
androgenic in a large number of cases. All clinical
symptoms and signs are the consequence of extremely
UNCLASSIFIED SEX CORD–STROMAL TUMORS
high testosterone levels. The diagnosis is confirmed using
hormone analysis.
CLINICAL FEATURES ● Steroid cell tumor not otherwise specified affects younger
women and sometimes children, is typically androgenic,

About 10% of ovarian sex cord–stromal tumors are difficult to
but may be estrogenic or progestagenic, or may produce
classify, mainly due to the presence, within these tumors, of fea-
cortisol and cause Cushing’s syndrome. The tumor tends
tures intermediate between granulosa and Sertoli cell tumors.
to be larger than the other types, and there is a 20%
The term ‘unclassified ovarian gonadal tumors’ is sometimes
chance of finding extraovarian spread during surgery. This
applied to these neoplasms. They occur at any age (range from
subtype is bilateral in 5% of cases, and malignant in up to
14 to 83 years).
40%. It may occasionally originate from adrenal rests in
Presenting symptoms and physical findings include abdomi-
the broad ligament.
nal pain, abnormal uterine bleeding, ascites, and abdominal and
pelvic masses. The tumors range from 4 to 27 cm in diameter,
and are usually described as partially encapsulated, solid, and PATHOLOGICAL FEATURES (Figures 7.350–7.352)
cystic. The biological behavior of unclassified sex cord–stromal
All three types (stromal luteoma, Leydig or hilar cell tumor,
tumors resembles that of Sertoli–Leydig cell tumors of interme-
and steroid tumor, not otherwise specified) generally show
diate differentiation rather than poorly differentiated tumors,
similar features with some minor variations. The tumors are
which might have been expected in view of the lack of specific
well-circumscribed and occasionally lobulated, and are com-
differentiation. This finding is important with regard to post-
posed of fairly uniform, medium-sized, rounded or polygonal
operative management.
tumor cells arranged diffusely or in nests, thin cords, irregular
PATHOLOGICAL FEATURES clusters, columns and loosely dispersed tumor cells. These are
The tumors show either predominance (⬎80%) of an undiffer-

entiated or immature spindle cell gonadal type stroma or com-
posed of cords, trabeculae or tubules of indifferent cells with
features intermediate between those of granulosa and Sertoli–
Leydig cell tumor.
Tumors in the first group are spindle-shaped, with scant
cytoplasm arranged in fascicular or storiform pattern. Minor
components with cords or trabecular pattern may also be seen.
Scattered bizarre nuclei may be seen in the stroma. Numbers of
mitotic figures range from 0 to 24 per 10 HPF.
Tumors in the second group may show varying proportions
of both granulosa and Sertoli–Leydig cell patterns with areas of
intermediate cords and trabeculae. A primitive spindle cell
component is also often seen. Scattered bizarre nuclei may also
be seen in the stroma, and numbers of mitotic figures range
from 0 to 12 per 10 HPF.
Additional features in both groups include fibrothecomatous
elements, follicle-like structures, edema, myxoid areas, hemor- Figure 7.350 Hilar cell tumor: medium-sized cells with round nuclei
rhage, and necrosis. and abundant eosinophilic cytoplasm containing lipofuscin pigment.
Cell morphology
● Rounded or polygonal tumor cells.
● Abundant eosinophilic and slightly granular and
occasionally pale and abundant, foamy cytoplasm.
● The nuclei are round or angular and often hyperchromatic,
with single distinct nucleoli. Intranuclear cytoplasmic
inclusions may be seen.
● Intracytoplasmic lipochrome pigment is present in
40–60% of tumors.
● Reinke crystals and their precursors (intracytoplasmic
spheres) are seen in Leydig cell tumor only.
● Nuclear atypia is absent or minimal, except in the
malignant tumors.
● Mitotic figures are rare except in the NOS category. Two
or more mitotic figures per 10 HPF is associated with
malignant behavior.
Figure 7.351 Steroid cell tumor. Diffuse or nodular infiltrate of the ● Occasional multinucleated cells may be present.
ovarian stroma by large cells with abundant eosinophilic cytoplasm, ● Lipid-laden cells and inflammatory cells may be seen.
round nuclei with prominent nucleoli; mitotic figures may also be
seen. Circles indicate mitotic figures.
● Luteinized adult granulosa cell tumor and thecomas
● Lipid-rich Sertoli cell tumors
● Clear cell carcinoma of the oxyphil type
● Hepatoid yolk sac tumors
● Hepatoid carcinomas
● Metastatic renal cell carcinomas
● Adrenocortical carcinomas
● Hepatocellular carcinomas
● Primary and metastatic melanomas
● Struma ovarii (that takes the form of Hurthle cell adenoma)
● ‘Lipid cell thecoma’, an ovarian tumor of mixed
thecomatous and lipid cell structure. Functionally, this
resembles lipid cell tumors in being mainly androgenic and
has a similar in size range and age incidence
● The extensive degenerative spaces in steroid cell tumors
may be confused with an adenocarcinoma or with vascular
Figure 7.352 Steroid cell tumor: the cells are large with clear tumors
cytoplasm. ● Pregnancy luteoma (hyperplastic nodules of lutein cells) is
bilateral in one-third of cases, multiple in about 50% of
cases, and can attain a diameter of 30 cm
usually set in an inconspicuous stroma, but sometimes the Special techniques

stroma is prominent and contains fibromatous, hyalinized, ede-
● Lipid staining is positive in 75% of cases.
matous, or myxoid areas. On occasion, degenerative pseudovas-
● Iron hematoxylin and trichrome stains highlight the
cular (slit-like) or pseudoacinar (round or oval) spaces are seen.
Reinke crystals.
Microscopic (stromal hyperthecosis) or/and macroscopic
● The tumor is positive for vimentin, and sometimes for
(nodular hyperthecosis) foci of luteinized stromal cells in the
cytokeratin, and smooth muscle actin.
same or contralateral ovary are seen in the majority of stromal
● A103 (an antibody to melan-A) is positive in steroid cell
luteomas and in some Leydig cell tumors. A rich vascular net-
tumors.
work is usually evident, and fibrinoid degeneration of blood
vessel walls may be prominent.
Features often associated with malignancy include: tumor size LEYDIG CELL HYPERPLASIA
⬎7 cm; presence of necrosis; hemorrhage; ⬎2 mitotic figures
per 10 HPF; and marked nuclear atypia. Stromal edema, myx-
CLINICAL FEATURES
oid change, hyalinization, hemorrhage and necrosis may be
seen – particularly in the ‘not otherwise specified’ malignant Leydig cell hyperplasia is defined by the presence of promi-
category. Rarely, calcification and psammoma body formation nent Leydig cells, most commonly in the hilum of the ovary
are seen. (hilar Leydig cell hyperplasia) or rarely within the ovarian
stroma or in the lamina propria or adventitia of the tube (stro- in diameter, and appears as multiple fleshy, red-brown nodules.
mal Leydig cell hyperplasia). This may be associated with It is usually asymptomatic, discovered incidentally during
endocrine disturbance, virilization and occasionally raised Cesarean section or postpartum tubal ligation, or may be asso-
serum testosterone levels. The lesion is more commonly seen ciated with hursutism or virilization due to raised plasma
in postmenopausal women as a result of elevated pituitary androgen levels. Rarely, a pelvic mass is palpable and may
gonadotropins. It may also be seen during pregnancy (as a cause obstruction of the birth canal. Pregnancy luteoma is a
result of hCG). self-limited lesion that regresses within days after delivery.
PATHOLOGICAL FEATURES PATHOLOGICAL FEATURES (Figures 7.353 and 7.354)
Hilar Leydig cell hyperplasia is characterized by the presence of Pregnancy luteoma is sharply circumscribed ovarian nodule/
an increased number of Leydig cells in the hilum of the ovary. nodules, consisting of round eosinophilic cells arranged in solid
These are arranged in a nodular or a diffuse pattern. Hilar cell
hyperplasia can be seen in association with other ovarian lesions
such as stromal hyperplasia, stromal hyperthecosis, stromal
Leydig cell hyperplasia, and hilar cell tumor.
Stromal Leydig cell hyperplasia is the presence of focal aggre-
gates of Leydig cells in the ovarian stroma. Associated stromal
hyperthecosis and hilar cell hyperplasia or neoplasia is often
seen. Leydig cell hyperplastic nodules may also be seen in
the stroma of a variety of ovarian tumors such as mucinous
and serous tumors, Brenner tumors, stuma ovarii, and strumal
carcinoid.
Cell morphology
● Leydig cells are large polygonal cells with eosinophilic
cytoplasm.
● Cellular pleomorphism, hyperchromasia, and
multinucleated cells may be seen.
● Mitotic figures may sometimes be present.
● Reinke crystals are rarely seen.
● Leydig cell tumor
● Stromal hyperthecosis
● Ovarian decidual reaction
Special techniques
● Inhibin alpha-subunit and calretinin could be used to
detect the Leydig cells.
● A103 (an antibody to melan-A) is a moderately sensitive
and specific marker of sex cord–stromal differentiation
(Sertoli/Sertoli–Leydig cell tumors, steroid cell tumors,
thecomas/fibrothecomas, and sclerosing stromal tumors).
Normal hilus cells and rete ovarii epithelium also
expressed A103. Normal and neoplastic wolffian elements
may also express A103.
PREGNANCY LUTEOMA
CLINICAL FEATURES
Pregnancy luteoma is the most common non-neoplastic, tumor-
like lesion of the ovary. It occurs predominantly in multiparous
women in the third or fourth decade of life, and is rarely seen Figures 7.353 and 7.354 Pregnancy luteoma: masses of large
in subsequent pregnancies. The lesion is bilateral in one-third eosinophilic cells with granular cytoplasm showing distinct
of cases, varies in size from microscopic to several centimeters eosinophilic globules.
sheets, trabeculae or in a follicular pattern. The follicles few mitoses, but does not invade the adjacent ovarian stroma.
contain clear or colloid-like fluid. It has a nodular and focal Rete adenomas may be confused with female adnexal tumors
pseudoalveolar growth pattern, and was associated with areas of probable wolffian origin, but usually lack the sieve-like and
of tubular sertoliform component, consistent with granulosa solid components of the latter.
cell proliferation. Adenomatous hyperplasia has poorly defined margins which
Regressed lesions show degenerating cells with abundant blend with the existing tubular architecture of the rete and
vacuolated cytoplasm and small pyknotic nuclei. Hemorrhage, extend diffusely into the adjacent stroma. Furthermore, within
infarction, fibrosis and pronounced cystic changes may be seen. the lesion there is a greater degree of proliferation of the fibro-
muscular stroma than is seen in rete adenomas and a lack of
Cell morphology uniformity in the epithelial tubular structure.
● The cells are round, with abundant eosinophilic cytoplasm The rete adenocarcinoma is usually partly localized to the
and intermediate in size between luteinized granulosa cells hilus, and reveals retiform spaces containing papillae and nests
and luteinized theca cells. They have central nuclei and of transitional-like epithelium. It should be distinguished from
prominent nucleoli. retiform Sertoli–Leydig cell tumor.
● Focal balloon cell change may be present.
● Intracellular hyaline droplets may also be seen. Special techniques
● Cells of the rete ovarii are diffusely positive for CAM 5.2,
Differential diagnosis vimentin, epithelial membrane antigen, calretinin, CA125,
● Luteinized thecoma and progesterone receptors.
● Steroid cell tumor ● A103 (an antibody to melan-A) is positive in normal
● Granulosa cell proliferation which may occur due to the hilus cells and rete ovarii epithelium.
follicular stimulating hormone (FSH)-like activity of
human chorionic gonadotropin (hCG).
TUMORS OF UNCERTAIN ORIGIN AND
Special techniques MISCELLANEOUS TUMORS
● Immunohistochemistry shows a diffuse positivity to
inhibin A, CD99, cytokeratin, and vimentin.
ENDOMETRIOSIS
TUMORS OF THE RETE OVARII CLINICAL FEATURES

Endometriosis is defined as the presence of functional
CLINICAL FEATURES endometrium located outside the uterus. It is a chronic, invasive
and metastasizing disease that shares features with malignant
The rete ovarii may give rise to a number of lesions including
tumors (invasion and metastasis), but is not neoplastic. Several
cysts, adenomas, hyperplasia and, very rarely, carcinoma. The
hypotheses have attempted to explain the development of such
benign lesions are usually discovered incidentally entirely or
tissue. The most often cited theory – that of implantation –
predominantly within hilar location and are of little clinical
proposes that the physiological phenomenon of endometrial
significance. On occasion, they have been associated with viril-
reflux in the Fallopian tubes during menstruation may, under
ization. The causes of such lesions remain speculative, although
certain conditions, overcome local defense mechanisms, implant,
the sparsity of estrogen and progesterone receptor proteins
and proliferate. The peritoneal fluid in unaffected women pos-
would tend to exclude these hormones in the development of
sesses the capacity to prevent endometriotic tissue from becoming
the condition.
established. Another theory involves metaplasia of the coelomic
tissue into endometrium. A more recent theory raises the
possibility that, like malignant diseases, the development of
Cysts of the rete ovarii are usually small in size, may reach up endometriosis may involve the acquisition of somatic genetic
to 8 cm diameter, and are usually lined by non-ciliated cuboidal alterations in genes that regulate cell growth and differentiation.
or ciliated columnar epithelium. This theory has been substantiated with the identification, in
Adenomas of the rete ovarii are usually well-circumscribed, endometriotic lesions, of a variety of genetic abnormalities
characterized by a proliferation of tubules and papillae lined by usually only associated with malignancies. Endometriosis may
a single layer of cuboidal or columnar epithelial cells, some vary from microscopic endometriotic implants to large cysts
with clear cytoplasm. The tubules may be dilated, sometimes (endometriomas). The physical manifestations are protean, with
significantly, giving rise to a cystadenoma. The stroma may some patients being asymptomatic and others having disabling
show extensive differentiation of polygonal, Leydig-like cells. pelvic pain, infertility, or adnexal masses. Symptoms do not
On occasion, an atypical lesion can be seen which shows necessarily correlate with the severity of the disease. Ultrasono-
a complex papillary proliferation different in pattern and cel- graphic (US) features are variable and can mimic those of other
lularity from a retiform Sertoli–Leydig cell tumor. It shows benign and malignant ovarian lesions. Laparoscopy remains
extensive areas of eosinophilic change, pleomorphism and a the standard of reference for diagnosis and staging. Both
medical and surgical treatment options are available, depend- women with breast cancer who are receiving tamoxifen treat-
ing on the patient’s specific case. ment. A recent study has shown that somatic mutations in the
The ovaries are the most common sites affected, but endo- PTEN (a tumor suppressor) gene were identified in 20% of
metriosis can also involve the gastrointestinal tract, urinary endometrioid carcinomas and 20.6% of solitary endometrial
tract, chest, liver, umbilical hernia, and soft tissues. cysts, suggesting that inactivation of the PTEN gene is an early
Deep endometriosis is defined as an endometriotic lesion that event in the development of ovarian endometrioid carcinoma. In
penetrates the retroperitoneal space for a distance of ⬎5 mm. addition to cancerous transformation at the site of endometrio-
Deep endometriosis is extremely active, occurs in phase with sis, there is recent evidence to indicate that having endometriosis
eutopic endometrium, evolves progressively with age, and is itself may increase a woman’s risk of developing non-Hodgkin
most often located in the pouch of Douglas, the rectovaginal lymphoma, malignant melanoma, and breast cancer.
septum, the uterosacral ligaments, and occasionally in the It is estimated that malignant change in ovarian endometrio-
uterovesical fold. These lesions are associated with pelvic pain, sis occurs in 0.7% of the disease.
the intensity of which is proportional to the depth of penetration. Atypical endometriosis is defined as cytological abnormality
Incisional endometriosis is found in women with a history of of the endometrial epithelial component of endometriosis. This
Cesarean section. may act as a precancerous lesion in the malignant transforma-
Gastrointestinal endometriosis: This can be seen in the tion of endometriosis. Atypical endometriosis may be observed
appendix, the small or the large intestine. It can produce cyclic in endometriotic foci adjacent to carcinoma.
pain or bleeding in the tract. It usually includes the muscle wall
and the serosa or rarely the mucosa. PATHOLOGICAL FEATURES (Figure 7.355)
Typical endometriosis usually shows a disordered glandular
Ovarian endometriotic cysts
pattern with some cystic changes. The stroma frequently shows
The currently available literature describes three different hemosiderin-laden macrophages and hemorrhage. The lining
pathogenetic types of ovarian endometriotic cyst: epithelial cells and the stromal cells are identical to normal
1. Cortical invagination cysts arise when surface ovarian endometrium.
endometriotic deposits adhere to another structure (such as Atypical endometriosis shows at least focal tufting and
the broad ligament), blocking the egress of menstrual fluid prominent stratification of the lining epithelium. Other fea-
produced by cycling endometriosis, which then collects tures include a prominent nucleolus and angulations of nuclear
and causes the ovarian cortex to invaginate. contour. In cases of endometriosis associated with a carcinoma,
2. Surface inclusion cyst-related endometriotic cysts develop a transition from typical endometriosis to atypical endometrio-
when endometriotic tissue colonizes pre-existing inclusion sis is frequent, and a transition from atypical endometriosis to
cysts. carcinoma is also common. It has been shown that the prolif-
3. Physiological cyst-related endometriotic cysts occur when eration activity of atypical endometriosis seems intermediate to
endometriosis gains access to a follicle, such as at the time those of typical endometriosis and ovarian carcinoma, suggest-
of ovulation. ing that it may be a precancerous lesion (the mean Ki-67 index
for ovarian carcinoma is 23.1; for atypical endometriosis is 9.9;
Malignant transformation of endometriosis and for typical endometriosis is 2.7).
Many case reports and occasional reviews concerning malig- Metaplasia in endometriosis, eosinophilic metaplasia and cil-
nant neoplasms arising in ovarian and extraovarian endo- iated metaplasia are the most common types.
metriosis have been published in the literature. Most of these
neoplasms are carcinomas, but sarcomas and mixed mullerian
tumors have also been reported. The anatomic distribution and
frequency of these cancers usually parallels the frequency with
which benign endometriosis occurs at various sites. Only
21.3% of cases of malignant transformation of endometriosis
occur at extragonadal pelvic sites. Carcinomas complicating
extragonadal endometriosis are almost always of endometrioid
or clear cell type, and only exceptionally are either serous, tran-
sitional, or mucinous in nature. The finding of mullerian-type
carcinoma in unusual locations without primary gynecological
tumors should raise the possibility of carcinoma arising from
endometriosis. Some rare examples of serous carcinoma are
found in the inguinal region.
Endometriosis-associated stromal sarcomas have been reported
in the rectovaginal septum and the gastrointestinal tract. The
association between exogenous hormonal therapy and the devel-
opment of malignancy in endometriosis is well known, particu- Figure 7.355 Endometriosis of the ovary: a focus of normal-
larly in patients receiving unopposed estrogen therapy, and in looking endometrial tissue within the ovarian stroma.
Complex hyperplasia and atypia in endometriosis can also be fibrosis reminiscent of fibrolammelar-type hepatocellular carci-
seen in cases of endometriosis associated with malignant trans- nomas. A transition from adenocarcinoma to a region resembling
formation. Their presence in a surgical specimen – particularly hepatocellular carcinoma may be observed. A combined pattern
in older patients – should indicate a careful examination of the of hepatoid and serous papillary carcinoma may also occur.
entire lining of the cyst and a strict follow-up of the patient. Psammoma bodies may be seen.
HEPATOID OVARIAN CARCINOMA Cell morphology

● Cells resembling hepatocellular carcinoma (uniform in size
and shape with moderate to abundant amount of
CLINICAL FEATURES cytoplasm and round to ovoid centrally located nuclei).
Hepatoid carcinoma is an aggressive ovarian epithelial tumor ● Occasional bizarre giant cells.
that occurs mainly in postmenopausal women. It is usually ● Cellular pleomorphism is common.
associated with high serum levels of ␣-fetoprotein and CA125. ● Mitotic figures are numerous.
This tumor is considered as an ovarian epithelial carcinoma. ● Intracellular and extracellular hyaline globules are often seen.
Histologically, the tumor resembles hepatocellular carcinoma

● Hepatoid yolk sac tumor
in terms of its architectural and cytological features, which
● Endometrioid carcinoma
consist of a fairly uniform population of cells with hepatoid
● Clear cell carcinoma
features. The tumor cells may be arranged in solid sheets,
pseudopapillary structures, glands, cords, trabeculae, and also
● Steroid cell tumor
rarely in a sarcomatoid pattern. Some cases show fibrolammelar
● Metastatic hepatocellular carcinoma
Special techniques
● The cells may contain PAS-positive cytoplasmic glycogen,
bile pigment, luminal or intracytoplasmic mucin and
PAS-positive/diastase-resistant hyaline globules.
● The cells are immunoreactive for ␣-fetoprotein, albumin
and alpha-1 chymotrypsin. Some tumors show
immunoreactivity for CEA, A1AT, CA125, and hCG.
● Electron microscopically, the rough-surfaced endoplasmic
reticulum had developed into a meshwork within which
mitochondria were present.
MURAL NODULES IN OVARIAN EPITHELIAL

CYSTIC TUMORS
CLINICAL FEATURES
The presence of mural nodules in common cystic epithelial
tumors of the ovary is a very rare occurrence. Various termino-
logies have been used to describe these nodules, including
sarcoma-like mural nodules, anaplastic giant cell tumor, mural
nodule of carcinomatous derivation, sarcomatous mural nodule,
sarcoma-appearing mural nodule of anaplastic carcinoma,
mural nodules of anaplastic carcinoma, and solid mural nod-
ules. From these terminologies, it is clear that mural nodules can
be either reactive or neoplastic. Neoplastic mural nodules are
either benign or malignant. The malignant nodules can be a car-
cinoma with or without reactive stromal elements, sarcoma, or
an admixture of carcinoma and sarcoma; the latter category has
some similarities to malignant mixed mesodermal tumors.
Sarcoma-like mural nodules (SLMNs) occur mainly in young
women, are of small size (range 0.6 to 6 cm), and have indolent
Figures 7.356 and 7.357 Hepatoid carcinoma ovary: Large cells clinicopathological features and a favorable outcome. The num-
with abundant eosinophilic cytoplasm with hyaline globules. ber of nodules varies from one to several; they may protrude into
the lumens of the locules, but are usually found within the con- Occasionally, a linear proliferation of pleomorphic and multi-
fine of the ovarian cyst. Their color varies from red to brown, and nucleated giant cells are seen just beneath the mucinous epithe-
their consistency from soft to firm; they may also exhibit areas of lium without forming a true nodule; this may represent the
hemorrhage and necrosis. The accompanying ovarian cyst is usu- earlier stage of the nodule formation. The epithelial component
ally large, multi- or unilocular, and often unilateral. The patho- of the mucinous cyst is usually of the intestinal type, and can
genesis of these sarcoma-like nodules is not known, but it has be benign, borderline, borderline with intraepithelial carci-
been suggested that: (i) they may possibly be true sarcomas or noma or microinvasion, and invasive carcinomas. The carci-
true carcinomas, but are too small to be biologically malignant; noma may exhibit a well-circumscribed area of anaplastic
(ii) they are neoplastic, but are discovered at an earlier stage; and component in the form of mural nodules. A striking inflamma-
(iii) they could represent an unusual reaction in response to intra- tory component consisting of lymphocytes, plasma cells,
mural hemorrhage or to the mucinous content of the cyst, which eosinophils, and polymorphonuclear leukocytes is usually seen,
eventually becomes a pseudotumor, such as inflammatory in variable proportions. Some nodules may contain scattered
(pseudotumor) myofibroblastic tumor. As to the histogenesis, it glandular structures or isolated nests of epithelial cells, repre-
has been postulated that they may represent fibrohistiocytic cell senting entrapment of the mucinous epithelial component.
reaction, or may result from proliferation of undifferentiated mes- Some SLMNs of the pleomorphic and epulis-like type may
enchymal cells, underlying the mucinous epithelium, by some rarely show nodules of anaplastic carcinoma. Some mural nod-
stimulus such as hemorrhage in the cyst wall, or most likely rep- ules exhibit morphological features of more than one lesion –
resent an abnormal but self-limited submesothelial proliferation that is, sarcoma, sarcoma-like, or anaplastic carcinoma.
of mesenchymal cells, which normally undergo transformation The mural nodules of poorly differentiated (anaplastic) car-
into epithelial cells. This neometaplasia would account for the cinoma tend to lack any prominent inflammatory reaction or
characteristically ambiguous phenotype of the SLMNs at light multinucleated giant cells, and often contain obvious carcino-
microscopic and immunohistochemical levels. matous differentiation, shown either morphologically or by
The prognosis of SLMNs is excellent as long as they appear immunohistochemistry. The cells can be spindle-shaped or
sharply circumscribed and lack invasion of the surrounding round and anaplastic.
tissues or vascular spaces. Their presence does not influence In appearance, the sarcomatous nodules may resemble
the prognosis of the cystic ovarian tumor, which should be leiomyosarcoma, fibrosarcoma or malignant fibrous histiocytoma-
based on the pathological features of the mucinous epithelial like sarcoma or even rhabdomyosarcoma.
component.
The mural nodules of poorly differentiated (anaplastic) car- Special techniques
cinoma tend to be larger in size (range 0.5–12 cm), poorly cir- ● Immunohistochemistry can be useful in distinguishing the
cumscribed, and can be associated with poor prognosis. different types of nodules; although the SLMNs may
The sarcomatous nodules usually develop in older patients contain a few scattered keratin-positive cells, a strong and
and are characterized by large size, poor circumscription with diffuse keratin immunoreaction favors the diagnosis of
frequent vascular invasion, and aggressive behavior. poorly differentiated carcinoma.
● Immunohistochemistry does not help in the differential
PATHOLOGICAL FEATURES diagnosis between SLMNs and true sarcomas because both
lesions are usually negative for keratins and positive for
Sarcoma-like mural nodules are small, sharply demarcated
vimentin.
from the adjacent cyst epithelium and exhibit one or combina-
● SLMNs show strong immunoreactivity for vimentin
tions of the following patterns:
● Pleomorphic and epulis-like, composed of a heterogeneous
and CD68.
● ALK and CD34 are usually negative in the SLMNs.
cell population, including numerous multinucleated giant
● Calretinin is often positive in the SLMNs.
cells of the epulis type, atypical spindle cells with
● Ki-67 immunostaining is usually weakly positive
prominent mitotic activity (0–14 per 10 HPF), including
(range ⬍ 10–50% positive nuclei).
atypical ones, and inflammatory cells.
● Pleomorphic and spindle cell, in which the predominant
● Immunostaining for muscle-specific actin and smooth
muscle actin may be focally positive.
elements are atypical spindle-shaped cells containing large,
● Staining for desmin is sometimes focal and weak.
hyperchromatic nuclei with prominent nucleoli and
frequent atypical mitoses admixed with typical histiocytes
and other inflammatory cells. OVARIAN TUMOR OF PROBABLE WOLFFIAN
● Giant cell-histiocytic, which is composed almost
ORIGIN
exclusively of mononucleated cells with ample cytoplasm
and vesicular nuclei, with only slight pleomorphism and
low mitotic activity. CLINICAL FEATURES
Some mural nodules have a zonation phenomenon character- Ovarian (adnexal) tumors of probable wolffian origin are rare
ized by central blood-filled spaces of hemorrhage and necrosis, tumors of unclear histogenesis, but of probable wollfian duct
surrounded by a cellular zone containing multinucleated giant origin, in particular from the rete ovarii. They vary in size
cells, in a manner reminiscent of an aneurysmal bone cyst. between 1 and 18 cm, and are usually seen in the leaves of the
broad ligament, ovary or rarely in the retroperitoneum of adult Cell morphology

patients (aged 15–81 years). The tumor is often discovered inci- ● The cells are uniform, round or polygonal with small
dentally, and is rarely present as a pelvic mass. Most female amounts of eosinophilic cytoplasm. The nuclei are oval,
adnexal tumors of wolffian origin behave in a benign fashion; vesicular and may contain a small nucleolus.
however, there is a potential risk of recurrence or metastasis. ● Mitotic figures are rare.
Surgical excision by total abdominal hysterectomy and bilat- ● Cellular atypia may be seen.
eral salpingo-oophorectomy at the time of diagnosis may be the
best recommended mode of therapy. The role of adjuvant radi-
ation therapy or chemotherapy is questionable.
● Sex cord–stromal tumors (Sertoli–Leydig and Sertoli cell
tumors)
PATHOLOGICAL FEATURES (Figures 7.358 and 7.359) ● Granulosa cell tumor
● Carcinoma
Ovarian tumor of probable wolffian origin is usually a well- ● Adenomatoid tumor.
circumscribed tumor consisting of uniform, round, or ovoid
cells. These are arranged in solid sheets, nests, poorly or well-
Special techniques
formed tubules, branching or cystic glands, anastomosing cords,
or in a sieve-like pattern with spaces containing eosinophilic ● PAS stain highlights the basement membrane-like material
droplets. These are surrounded by hyaline basement membrane- investing the tumor nests or tubules.
like material. Collapsed or ectatic vessels are frequently seen in ● Staining for mucin is negative.
the stroma. ● The tumor cells are immunoreactive for pan-cytokeratin
(AE1/AE3, CK1), CAM 5.2, androgen receptor, inhibin,
calretinin, and vimentin.
● They show only focal staining for cytokeratin 7 (CK7).
● They may show focal staining for EMA, estrogen, and
progesterone receptor.
● They are negative with monoclonal carcinoembryonic
antigen and CK20.
● Because of the immunoreactivity for inhibin and calretinin
in a significant number of ovarian (adnexal) tumors of
probable wolffian origin, immunostains alone do not allow
absolute distinction of these tumors from sex cord–stromal
tumors (inhibin-positive) and adenomatoid tumors
(calretinin-positive).
● Normal and neoplastic wolffian elements may express
A103 (an antibody to melan-A).
SMALL CELL CARCINOMA (HYPERCALCEMIC

TYPE)
CLINICAL FEATURES
Small cell carcinoma of the ovary is a distinctive type of undif-
ferentiated ovarian carcinoma of unknown histogenesis. It
occurs in patients between the ages of 7 and 43 years (average
24 years), is almost always unilateral (except in rare familial
cases), and is associated with hypercalcemia in two-thirds
of cases. Spread of the tumor occurs in approximately half of
the cases at the time of laparotomy.

Small cell carcinoma of the ovary consists of monotonous,
closely packed, small cells, arranged diffusely, in nests, in
cords or as irregular groups. Follicle-like structures lined by
Figures 7.358 and 7.359 Ovarian tumor of probable wolffian small cells and containing eosinophilic or basophilic material
origin. Round cells arranged diffusely and in tubular structures are often seen. On occasion, collections of larger cells with
separated by basement membrane-like material. eosinophilic cytoplasm and mucin-secreting or signet ring cells
Cell morphology
● The small cells have little cytoplasm and small nuclei
containing a small single nucleolus. It should be noted
that their appearance differs from the cells of small cell
carcinoma of the bronchus and other viscera, which does
occasionally occur in the ovary.
● The large cells show abundant eosinophilic cytoplasm and
large nuclei with prominent nucleoli.
● Mucin-secreting cells may be seen in approximately 10%
of cases.
● Mitoses are frequent.
● Poorly differentiated carcinoma
● Malignant lymphoma
● Intra-abdominal desmoplastic small cell tumor (may mimic
an ovarian primary tumor by presenting with involvement
of the ovary and an elevated CA125 level, and should be
included in the differential diagnosis of ovarian neoplasms
in young patients)
● Primitive neuroectodermal tumor [immunohistochemically,
the tumor cells show intense cell-membranous
immunoreactivity for MIC2 protein (CD99). A short-term
cell culture and karyotypic analysis reveals the tumor to
possess a balanced t(11;22)(q24;q12) chromosomal
translocation that is highly specific for tumors of the
PNET/Ewing’s sarcoma family]
● Metastatic melanoma
● Metastatic alveolar rhabdomyosarcoma.
● Primary ovarian small cell carcinoma of pulmonary type
[the neurosecretory granules are argyrophilic and positive
for neuroendocrine markers (chromogranin, leu7,
neuron-specific enolase, and synaptophysin)]
● Ovarian ependymoma [presence of typical ependymal
rosettes and positivity to glial fibrillary acidic protein
(GFAP) confirmed the diagnosis of ependymoma].
Special techniques
● Immunohistochemically, many tumor cells are diffusely
positive for epithelial membrane antigen and some cells
contained cytokeratin CAM 5.2, vimentin, neurofilament,
neuron-specific enolase, or alpha-1-antitrypsin.
● The tumor cells are also positive for vimentin.
● Ultrastructurally, they contain an abundance of dilated
rough endoplasmic reticulum and numerous free ribosomes.
● Around 80% of cases exhibit p53 protein accumulation
by immunohistochemistry, supporting the presence of
Figures 7.360–7.362 Small cell carcinoma: diffuse infiltration p53 gene mutations in these tumors.
of the ovary by small round cells with some spaces lined by the
tumor cells.
UTERUS-LIKE OVARIAN MASS
lining glandular or cyst-like spaces are seen. When the large
cells predominate, the term ‘large cell variant’ may be used.
CLINICAL FEATURES
Secondary features Uterus-like ovarian mass is an extremely rare entity that may
● Hemorrhage represent an unusual manifestation of endometriosis that is
● Necrosis complicated by smooth muscle metaplasia. The latter may
originate from metaplastic endometrial stromal cells in endo- at a gynecological oncology clinicopathological meeting and
metriotic foci or from metaplastic ovarian stromal cells in the histological review of any previous malignancy, is often of
rim of endometriosis. Similar lesions have also been reported in the value in drawing attention to the fact that this may not be a pri-
small intestine, mesentery, broad ligament, cervix and in asso- mary ovarian neoplasm.
ciation with endometrioid carcinoma of the ovary.
PATHOLOGICAL FEATURES METASTATIC GASTROINTESTINAL CARCINOMAS

As the name suggests, this lesion consists of a uterus-like struc- METASTATIC COLONIC ADENOCARCINOMA
ture with a central cavity lined by endometrial-type epithelium,
surrounded by a thick layer of smooth muscle fibers inter-
spersed by fibrous septa and thick-walled blood vessels. CLINICAL FEATURES
Residual ovarian structures may be seen at the periphery.
Gastrointestinal tumors may present as advanced ovarian can-
cer, which is equally frequent in pre- and postmenopausal
Differential diagnosis women. Primary sources are diverse, but the colon is the com-
● Endometriotic cysts. monest site of origin. Metastatic colonic adenocarcinoma can
be indistinguishable from a primary ovarian mucinous or
endometrioid adenocarcinoma. Primary ovarian serous and
SECONDARY (METASTATIC) OVARIAN TUMORS clear cell adenocarcinoma usually do not pose a problem. Most
patients with ovarian involvement tend to have the primary
Metastatic tumors account for 17–21% of malignant ovarian tumor at the recto-sigmoid region and to have nodal and peri-
tumors. Nearly two-thirds of these tumors are from non- toneal involvement. In addition to the lymphatic route, the
gynecologic organs, in particular the breast and colon. Gyneco- exposure of the tumor to the serosal surface and the subse-
logic primary sites include the uterine corpus, uterine cervix, quent peritoneal dissemination may be an important route by
and Fallopian tube. It is essential to distinguish between the which malignant tumor cells reach the ovaries. The metastatic
various metastatic ovarian tumors as they tend to have differ- nature of ovarian tumors is supported by bilaterality, extra-
ent outcomes. pelvic spread, high mitotic index, and immunohistochemical
stains.
METASTATIC BREAST CARCINOMA

Metastatic adenocarcinoma of bowel origin typically simulates
CLINICAL FEATURES endometrioid adenocarcinoma of the usual type but with the
Ovarian metastases from breast cancer generally reflect presence of extensive tumor cell necrosis, seen in the form of
advanced breast disease. They are usually clinically silent and luminal eosinophilic debris with nuclear fragments. It is there-
frequently discovered at autopsy or in therapeutic oophorec- fore essential for pathologists when dealing with what look like
tomy. Patients with a history of breast carcinoma who present endometrioid ovarian carcinoma but with these features to per-
with new findings of an adnexal or pelvic mass are more likely form immunohistochemical stains to confirm the diagnosis.
to have a new ovarian or tubal malignancy than metastatic breast Colonic carcinomas express CK20 and CEA but lack Ca125,
cancer, by a ratio of 3:1. Ovarian metastasis is particularly and CK7 immunoreactivity, whereas endometrioid carcinomas
frequent from invasive lobular breast cancer. Breast carcinoma express CK7 and Ca125 but not CK20 or CEA. Alcian blue/PAS
has rarely been reported to metastasize to another ovarian tumor does not distinguish between the two because endometrioid
such as granulosa cell tumor. carcinoma, at least focally, reveals luminal and intracytoplas-
mic mucin. PAS-positive/diastase-resistant hyaline eosinophilic
globules may be seen in some endometrioid carcinomas but not
in colonic carcinoma.
Histologically, ovarian metastatic breast cancer may exhibit Metastatic colonic adenocarcinoma may look identical to
diffuse infiltrate, Indian files, ductal patterns, cords, and tra- primary mucinous ovarian carcinoma including the presence of
beculae. Micropapillary appearances may also be seen. Meta- benign and borderline features. The presence of coagulative
static breast carcinoma may be mistaken as sex cord–stromal ‘dirty’ tumor necrosis is the essential clue to the diagnosis.
tumor, granulosa cell tumor, dysgerminoma, poorly differenti- In the case of mucinous ovarian neoplasms, caution should be
ated ovarian carcinoma and carcinoid tumor. It may also mimic exercised since primary ovarian lesions, especially those showing
tumor-like conditions such as stromal luteoma or hypertheco- intestinal differentiation, may exhibit CK20 positivity. However,
sis and it may have a Krukenberg-like pattern. Infiltration of the CK7 positivity is almost always maintained. With ovarian
follicular structures and lymphatic permeation is common. mucinous neoplasms exhibiting both CK7 and CK20 positivity,
Differential cytokeratin expression is generally of no value in the pattern is usually that of diffuse CK7 and patchy CK20
the distinction between primary ovarian and metastatic breast positivity. The converse is true for metastatic colonic adeno-
tumors. In such cases the full clinical picture, following discussion carcinomas exhibiting mucinous differentiation (diffuse CK20
and patchy CK7 positivity). Colonic adenocarcinomas are epithelial differentiation, such as tubular glands, nests, or cords
usually negative for ER and for vimentin while ovarian carci- of cells, could be found at least focally in all Krukenberg tumors.
nomas are usually vimentin and ER positive. Expression of The prominent stroma that accompanies Kruckenberg tumor
the mucin genes MUC5AC and MUC2 may also be useful in with the presence of stromal luteinization in the presence of
the distinction between colonic adenocarcinoma metastatic to the sparse glands or signet ring cells may sometimes lead to erro-
ovary and primary ovarian carcinoma. MUC5AC is expressed in neous diagnosis of thecoma/fibroma. The presence of mucin
ovarian mucinous tumors but is typically absent in colorectal within the epithelial cells helps in distinguishing Krukenberg
carcinomas. Another marker which has recently been recog- tumor from fibroma/thecoma and the sclerosing or signet ring
nized as useful in distinguishing between colonic adenocarcinoma cell stromal tumors. These are also usually unilateral. The very
and primary mucinous ovarian carcinoma is beta-catenin. rare mucinous ovarian fibrocarcinoma may closely mimic
Nuclear localization of this marker is found in around 83% of Krukenberg tumor (personal experience). The cells however
colonic carcinoma metastatic to the ovary, but in 9% of pri- usually show immunohistochemical features of primary ovarian
mary ovarian mucinous carcinoma. Nuclear staining of beta- carcinoma (CK20- and CEA-negative, but CK7- and Ca125-
catenin can also be detected in endometrioid carcinoma of the positive). Gastric signet ring cell adenocarcinomas may be
ovary, so it cannot be used to distinguish endometrioid ovarian immunoreactive for CK7 and/or CK20. Mucinous carcinoid
carcinoma from metastatic colonic carcinoma. Recent studies tumors of the ovary may also contain signet ring cells, which
have suggested that caudal-related homeobox transcription fac- are PAS-D positive, but they show other features such as acini,
tor CDX2 regulates the differentiation of intestinal epithelial glands, red cytoplasmic granules, and expression of neuro-
cells. CDX2 immunoreactivity is also detectable in the majority endocrine markers. Many mucinous carcinoids of the ovary
of benign, borderline and malignant ovarian mucinous tumors
and this, therefore, makes it unsuitable when distinguishing
primary from metastatic ovarian mucinous adenocarcinomas.
However, CDX2 immunoreactivity could be useful in the distinc-
tion between endocervical and intestinal-type mucinous tumors
of the ovary, which may have clinical relevance.
Very rarely clear cell variant of intestinal adenocarcinoma
may be indistinguishable from primary clear cell carcinoma.
The former is characterized microscopically by glands and
cysts lined by cells with abundant clear cytoplasm with or with-
out striking sub-nuclear or supra-nuclear vacuoles.
KRUKENBERG TUMOR
CLINICAL FEATURES
Krukenberg tumors are typically bilateral ovarian metastases
from a gastrointestinal malignancy. They are more common Figure 7.363 Kruckenberg tumor: collection of signet ring cells in
in premenopausal women than in postmenopausal women. The loose fibroblastic stroma.
tumor is most commonly of gastric origin, but may be from the
large bowel, appendix, gall bladder or breast. Exceptionally, no
primary tumor can be identified. Krukenberg tumors are solid,
bosselated tumors that tend to preserve the original ovarian
outline.

This is characterized by the presence of densely fibroblastic
ovarian stroma that is diffusely infiltrated by malignant signet
ring cells arranged singly, in cords or in nests. A tubular variant
of Krukenberg tumor may occur and this may mimic Sertoli–
Leydig cell tumor. Very rarely Krukenberg tumor may show a
predominant multicystic mucinous component which on gross
and microscopic examination resembles a mucinous cystade-
nocarcinoma. The presence of signet ring cells in Krukenberg
tumor may resemble lipid-containing vacuolated cells of scle-
rosing stromal tumor, in particular the signet ring cell stromal
tumor. Nevertheless, despite the histologic similarity of scleros- Figure 7.364 Kruckenberg tumor: architecturally abnormal malignant
ing stromal tumor to Krukenberg tumor, additional evidence of glands with some signet ring cells in loose fibroblastic stroma.
Figure 7.365 and 7.366 Mucinous fibrocarcinoma. Isolated

malignant mucinous glands within a densely fibroblastic stroma, easily
mistaken as Krukenberg tumor. CK7 highlights the malignant
mucinous glands.
can be microscopically indistinguishable from Krukenberg

tumors, and the immunohistochemical features overlap.
Mucinous carcinoids may account for at least some or even
most of the primary Krukenberg tumors described in the older
literature.
METASTATIC CARCINOMA OF THE GALLBLADDER,

BILE DUCTS OR PANCREAS
CLINICAL FEATURES Figures 7.367–7.369 Mucinous fibrocarcinoma. CA125 highlights

the malignant mucinous glands, and CK20 and CEA reveal no
The gallbladder and bile ducts are rare sources of metastatic staining of the malignant mucinous glands.
ovarian tumors. These are usually bilateral, uniformly or pre-
dominantly solid, have lobulated external surfaces, are often
multinodular on sectioning and may rarely be multiloculated available which definitively facilitates distinction between a
or cystic. Features pointing toward the metastatic nature of primary ovarian adenocarcinoma and a metastatic adenocarci-
the ovarian tumors include bilaterality, surface desmoplastic noma from the pancreas or biliary tree. In such cases, the full
implants, and extraovarian spread. As yet there is no antibody clinical picture is of paramount importance.
PATHOLOGICAL FEATURES excellent survival for patients with Grade 1 dual endometrioid
tumors treated with surgery alone suggests that adjuvant ther-
Histologically they may simulate primary ovarian neoplasms,
apy may not be necessary for this subgroup. To classify a tumor
especially an endometrioid carcinoma, a mucinous cystadeno-
as being an ovarian metastasis from uterine cancer it must ful-
carcinoma, or sometimes a Sertoli–Leydig cell tumor. Features
fill certain criteria. One major criterion is the presence of a
helpful in establishing the metastatic nature of the ovarian
multinodular ovarian pattern and two or more minor criteria
tumors are bilaterality, surface implants, multinodularity, and
including small ovaries (⬍5cm), bilateral ovarian involvement,
extraovarian spread.
deep myometrial invasion, vascular permeation and tubal lumi-
nal involvement. However, in many instances the tumors do
METASTATIC CARCINOMA OF THE APPENDIX not meet all the differential criteria and share features of both
categories. It is suggested that when each tumor is confined
within the limits of its tissue of origin the tumors may be
CLINICAL FEATURES considered as two separate primaries and surgery may be less
Metastatic appendiceal adenocarcinoma should be considered aggressive. When there is evidence that at least one tumor is
in the differential diagnosis of mucinous ovarian tumors with spreading to adjacent tissues and organs, the question of whether
signet ring cell, goblet cell, or intestinal type differentiation, they are two separate primaries or one metastatic tumor becomes
especially when these tumors are associated with extraovarian academic only and aggressive surgical treatment with adjuvant
disease and are bilateral. chemotherapy is indicated.
PATHOLOGICAL FEATURES PATHOLOGICAL FEATURES
Metastases of appendiceal adenocarcinomas of colorectal type The synchronous tumors are rarely of dissimilar histology.
usually simulate both metastatic colorectal carcinoma and pri- Immunostaining with ER, PR and bcl-2 have been found to be
mary ovarian endometrioid carcinomas. The appendiceal and useful in distinguishing between synchronous carcinomas by
ovarian tumors are usually immunophenotypically identical. demonstrating a different immunostaining pattern in the two
CK20 positivity of the ovarian tumors is consistent with gas- primaries. The application of molecular technology and DNA
trointestinal origin; CK7 positivity does not confirm ovarian flow cytometric study may also play an important role for the
origin, because appendiceal carcinomas are positive in 50% of differential diagnosis between synchronous primary carcino-
cases. Mucinous carcinoid tumor of the appendix, an uncom- mas and a single carcinoma with metastasis but differential
mon variant of appendiceal carcinoid, may present clinically diagnosis must presently rely largely upon conventional clinico-
with ovarian metastases. The primary and metastatic tumors pathologic criteria.
are composed of mucin-producing cells and small argyrophilic
cells arranged in cords and acini. Tumor cells in both primary
and metastatic sites exhibit identical patterns of immunoreac-
OVARIAN METASTASES FROM CERVICAL
tivity for epithelial antigens and neuroendocrine markers. CARCINOMA
METASTASIS FROM OTHER PARTS OF THE FEMALE CLINICAL FEATURES

GENITAL TRACT
Ovarian metastases of cervical carcinoma are uncommon with
Ovarian metastases from other gynecological organs originate adenocarcinoma more frequent than squamous cell carcinoma.
predominantly from the uterine corpus and less commonly Patients with ovarian metastases usually have other evidence of
from the cervix or Fallopian tube. extra-cervical disease. The ovarian and cervical tumors are
either synchronous or discovered after the detection of a cervi-
cal neoplasm and rarely before the discovery of cervical cancer.
SYNCHRONOUS OR METASTATIC ENDOMETRIAL
The cervical cancers are often grossly evident and usually
OR OVARIAN CARCINOMA deeply invasive, often with extra-cervical extension. Various
features, including bilaterality of the ovarian tumors, the find-
ing that the histologic features of the ovarian tumors are
CLINICAL FEATURES
unusual for a primary ovarian neoplasm, and the presence of
The synchronous occurrence of carcinoma confined to the extensive extra-cervical disease, suggest that the ovarian
ovary and endometrium presents a diagnostic and therapeutic tumors are metastatic from the cervix.
dilemma. These tumors have been variously staged as FIGO Ovarian metastasis is histologically one of the ominous signs
Stage IIA ovarian carcinoma, Stage III endometrial carcinoma, of cervical carcinomas regardless of stage. Lymphatic spread
or synchronous dual primary carcinomas. Accumulating evidence and trans-tubal implantation are possible pathways of cervical
suggests that patients with synchronous dual primary carcinomas cancer metastasizing to ovary, and involvement of the corpus
appear to have a more favorable prognosis than that expected may facilitate this mechanism. Metastatic endocervical adeno-
with Stage IIA ovarian or Stage III endometrial carcinoma carcinoma may rarely present as a virilizing ovarian mass and
(100% vs 63% or 42% survival at 3 years, respectively). The simulates a primary ovarian endometrioid tumor.
PATHOLOGICAL FEATURES cell carcinoma in the ovary is important and has therapeutic as
well as prognostic implications.
The ovarian metastatic lesions tend to be microscopic in size
and to be located in the ovarian hilum. As for the primary
lesion, it often shows deep myometrial invasion, corpus inva-
sion, and lymphatic permeation. Endometrioid adenocarcino- Metastatic transitional cell carcinoma of urothelial origin is
mas developing in endometrium and ovary are most often positive for uroplakin III, thrombomodulin, CK13, and CK20.
strongly vimentin-positive and CEA-negative, which greatly Transitional cell carcinoma of urothelial origin is also positive
aids in distinguishing them from endometrioid or pseudo- for CK7 and may express CEA. In contrast, transitional cell
endometrioid tumors arising in endocervix and colon, which carcinomas of the ovary lack uroplakins and are essentially
are only rarely, and very focally vimetin- and CEA-positive. negative for CK20 and CK13 but quite strongly express Ca125.
OTHER METASTATIC TUMORS WHO REVISED CLASSIFICATION OF

METASTATIC RENAL CELL CARCINOMA OVARIAN TUMORS
Surface epithelial–stromal tumors

CLINICAL FEATURES Tumor-like conditions
The diagnosis of a primary ovarian or renal clear cell carci- ● Serous inclusion cysts
noma is usually straightforward. However, problems may arise Serous tumors

in those rare instances when a renal clear cell carcinoma metas- ● Benign
tasizes to the ovary or vice versa, or when there is disseminated – Cystadenoma and papillary cystadenoma
clear cell carcinoma and the primary site is not certain. An – Surface papilloma
additional problem is that with renal carcinoma metastatic to – Adenofibroma and cystadenofibroma
the ovary (and to other sites) the primary lesion may not be ● Of borderline malignancy (of low malignant potential)
clinically evident. Radiologic imaging may be useful in identi- – Cystic tumor and papillary cystic tumor
fying a primary renal lesion, but on rare occasions the primary – Surface papillary tumor
renal neoplasm may remain occult for some time. – Adenofibroma and cystadenofibroma
● Malignant
PATHOLOGICAL FEATURES – Adenocarcinoma, papillary adenocarcinoma, and

papillary cystadenocarcinoma
There are some histologic differences between ovarian and – Surface papillary adenocarcinoma
renal carcinoma, such as tubulocystic and papillary patterns – Adenocarcinofibroma and cystadenocarcinofibroma
and hobnail cells being more common in the ovarian tumors. Mucinous tumors: endocervical-like and intestinal type
The presence of endometriosis adjacent to a clear cell carcinoma ● Tumor-like lesions
in the ovary suggests a primary ovarian lesion. On the other – Mucinous inclusion cysts
hand, a prominent sinusoidal vascular pattern favors renal ori- ● Benign
gin. However, none of these features are specific and there may – Cystadenoma
be morphologic overlap. There is considerable overlap in the – Adenofibroma and cystadenofibroma
immunoprofile patterns of primary renal and ovarian clear ● Of borderline malignancy (of low malignant potential)
cell carcinomas. Ovarian carcinomas usually demonstrate at – Cystic tumor
least focally intracellular mucin secretion; detected by alcian – Adenofibroma and cystadenofibroma
blue/PAS while clear cell is usually negative. Various immuno- ● Malignant
histochemical stains have been tried, however the most useful – Adenocarcinoma and cystadenocarcinoma
antibodies seem to be 34␤E12, Ca125, CK7, ER, and PR, which – Adenocarcinofibroma and cystadenocarcinofibroma
are positive more commonly in ovarian carcinomas, and vimentin
Endometrioid tumors
and CD10, which is more commonly positive in renal carcino-
● Tumor-like lesions
mas. It should be noted that chromophobe and papillary renal
– Endometriosis
carcinomas and are CK7-positive.
● Benign
– Cystadenoma
METASTATIC TRANSITIONAL CELL CARCINOMA
– Cystadenoma with squamous differentiation
OF THE OVARY – Adenofibroma and cystadenofibroma
– Adenofibroma and cystadenofibroma with squamous
differentiation
CLINICAL FEATURES
● Of borderline malignancy (of low malignant potential)
Metastatic transitional cell carcinoma to the ovary is rare, – Cystic tumor

and morphologically resembles a primary ovarian malignancy. – Cystic tumor with squamous differentiation
The differential diagnosis of a primary or metastatic transitional – Adenofibroma and cystadenofibroma
– Adenofibroma and cystadenofibroma with squamous Granulosa–stromal cell tumors

differentiation ● Granulosa cell tumors
● Malignant – Juvenile
– Adenocarcinoma and cystadenocarcinoma – Adult
– Adenocarcinoma and cystadenocarcinoma with ● Tumors of the thecoma-fibroma group
squamous differentiation – Thecoma

– Adenocarcinofibroma and cystadenocarcinofibroma Typical
– Adenocarcinofibroma and cystadenocarcinofibroma with Luteinized
squamous differentiation – Fibroma
Typical
Clear cell tumors Cellular fibroma
● Benign – Fibrosarcoma
– Cystadenoma – Stromal tumor with minor sex cord elements
– Adenofibroma and cystadenofibroma – Sclerosing stromal tumor
● Of borderline malignancy (of low malignant potential) – Stromal luteoma
– Cystic tumor – Unclassified (fibrothecoma)
– Adenofibroma and cystadenofibroma Sertoli–stromal cell tumors; androblastomas
● Malignant
● Well differentiated
– Adenocarcinoma – Sertoli cell tumor; tubular androblastoma
– Adenocarcinofibroma and cystadenocarcinofibroma – Sertoli–Leydig cell tumor
● Sertoli–Leydig cell tumor of intermediate differentiation
Transitional cell tumors
– Variant – with heterologous elements (specify types)
● Brenner tumor
● Sertoli–Leydig cell tumor, poorly differentiated
● Brenner tumor of borderline malignancy (proliferating)
(sarcomatoid)
● Malignant Brenner tumor
● Transitional cell carcinoma (non-Brenner type)
● Retiform
Squamous cell tumors
Sex cord tumor with annular tubules
Epithelial–stromal and stromal Gynandroblastoma
● Benign tumors and tumor-like conditions
– Disseminated peritoneal leiomyomatosis Steroid (lipid) cell tumor

– Leiomyoma and histological variants Tumor-like conditions
– Endometriosis, deciduosis ● Leydig cell hyperplasia
● Malignant tumors ● Nodular hyperthecosis
– Pure sarcomas ● Stromal luteoma
Homologous ● Luteoma of pregnancy
Leiomyosarcoma Tumors
Low-grade stromal ● Leydig cell tumor, hilus and stromal variants
Heterologous ● Adrenal rest tumor
– Mixed epithelial and stromal tumors ● Steroid cell tumor, unclassified (not otherwise specified)
Low-grade adenosarcoma
Homologous Germ cell tumors
Heterologous Dysgerminoma
High-grade (carcinosarcoma) ● Variant – with syncytiotrophoblastic cells
Yolk sac tumor (endodermal sinus tumor)

Mixed epithelial tumors (specify types)
Variants
● Benign
● Polyvesicular vitelline tumor
● Of borderline malignancy (of low malignant potential)
● Hepatoid
● Malignant
● Glandular (also called ‘endometrioid-like’)
Undifferentiated carcinoma Embryonal carcinoma

Polyembryoma
Sex cord-stromal cell tumors Choriocarcinoma
Tumor-like conditions Teratomas
● Massive ovarian edema and fibromatosis ● Immature
● Diffuse stromal hyperplasia and hypethecosis ● Mature
● Dysfunctional cysts and polycystic ovary syndrome – Solid

Hyperreactio luteinalis – Cystic (dermoid cyst)
With secondary tumor formation (specify type) Tumors of rete ovarii

– Fetiform (homunculus) Adenoma and cystadenoma
● Monodermal and highly specialized Adenocarcinoma
– Struma ovarii
Mesothelial tumors
Variant – with thyroid tumor (specify type)
Adenomatoid tumor
– Carcinoid
Mesothelioma
Insular
Trabecular Tumors of uncertain origin and miscellaneous
– Strumal carcinoid Small cell carcinoma
– Mucinous carcinoid Tumor of probable wolffian origin
– Neuroectodermal tumors Hepatoid carcinoma
– Sebaceous tumors Myxoma
Gestational trophoblastic diseases
Mixed germ cell and sex cord–stromal tumors
Soft tissue tumors not specific to ovary
Gonadoblastoma
● Variant – with dysgerminoma or other germ cell tumor
Malignant lymphomas
Secondary (metastatic) tumors
Germ cell–sex cord–stromal tumor of non-gonadoblastoma type
● Variant – with dysgerminoma or other germ cell tumor
TUMORS OF THE FALLOPIAN TUBE
and comprehensive surgical staging, also including a systematic

EPITHELIAL TUMORS pelvic and para-aortic lymphadenectomy, and aggressive
debulking in patients with advanced tumor.
ADNEXAL TUMOR OF PROBABLE WOLFFIAN
ORIGIN PATHOLOGICAL FEATURES
Serous papillary carcinoma is the most common histological
See Ovarian tumor (p. 507). type of Fallopian tube carcinomas. Other variants that have
been described include endometrioid carcinoma, transitional
CARCINOMAS OF THE FALLOPIAN TUBE cell carcinoma, clear cell carcinoma, squamous cell carcinoma,
and carcinosarcoma.
CLINICAL FEATURES
EPITHELIAL METAPLASIA, HYPERPLASIA AND
Primary carcinoma of the Fallopian tube is the rarest cancer of PSEUDOCARCINOMATOUS LESIONS
the female genital tract, with an incidence of 0.5% of all gyne-
cological tumors. Ovarian cancer and primary carcinoma of
the Fallopian tube are similar in many aspects. Both carcino- Fallopian tube mucosal metaplasia
mas have a similar age distribution, show an increase among Mucinous metaplasia is the presence of endocervical type
nulliparous women, are often of serous papillary histology, columnar mucin-producing epithelium within the lining epi-
have a poor prognosis with stage and residual tumor size as thelium of the Fallopian tube. This may be seen in association
important prognostic factors, and initially respond well to with endocervical or/and ovarian mucinous tumors in patients
platinum-based chemotherapy. Nevertheless, there appears to with Peutz–Jeghers syndrome.
be a difference between the two diseases: primary carcinoma of Endometrial metaplasia (endometrialization) may be found
the Fallopian tube is more often diagnosed in an earlier stage. in the isthmic or interstitial portion of the tube, and may
This may be due to lower-abdominal pain resulting from represent a shift in the junction between the endometrial and
tubal dilatation and to abnormal bloody–watery discharge. Fallopian tube mucosa. It may lead to tubal occlusion and sub-
Fallopian tube carcinomas may sometimes be detected by sequent infertility or ectopic pregnancy.
positive cervical cytology or by endometrial curetting. Staging Transitional metaplasia is extremely rare, and may act as pre-
of Fallopian tube carcinoma is by use of a system analogous to cursor for transitional cell carcinoma in such location.
the International Federation of Gynecology and Obstetrics Papillary metaplasia is the presence of papillary epithelium
(FIGO) classification of ovarian carcinoma. Primary Fallopian consisting of cells exhibiting abundant eosinophilic cytoplasm.
tube carcinomas are aggressive tumors, and their management This is mainly seen in pregnancy or postpartum.
is similar to that of ovarian carcinoma. Surgery should consist of Squamous metaplasia is extremely rare, and similar to that
bilateral salpingo-oophorectomy, total abdominal hysterectomy, seen in the endometrium.
Decidual reaction is rarely seen during pregnancy or as a

result of progestogen therapy. These foci are present within the
lamina propria and are characterized by large polygonal, round
or spindle cells with abundant eosinophilic cytoplasm.
Hyperplasia and pseudocarcinomatous lesions

These lesions may be seen in association with excessive estro-
gen production (e.g., functioning ovarian tumors), chronic
inflammation and upper genital tract malignancy. The changes
include the presence of papillae or pseudopapillae lined by cells
showing mild or moderate nuclear pleomorphism, hyper-
chromasia, and mitotic figures. These may resemble carcinoma
in situ of the Fallopian tube. It is important to distinguish these
changes from malignant cells in transit from uterine or ovarian
carcinoma. This is not infrequently seen if careful examination
of the tube is made, particularly in cases of uterine papillary
serous carcinoma and in ovarian tumors.
MISCELLANEOUS LESIONS
Figure 7.370 Salpingitis isthmica nodosum: diverticular-like
extension of Fallopian tube epithelium deep into the muscular wall.
ADRENAL REST
Adrenal rests are well known in the broad ligament, and may PATHOLOGICAL FEATURES (Figure 7.370)
rarely arise in the wall of the Fallopian tube. The histogenesis Salpingitis isthmica nodosum is characterized by the presence
is not known, but it may arise secondary to coelomic epithelial of benign-looking, irregularly shaped glands within the muscular
metaplasia. Benign tumors of the adrenal rest have also been layer of the Fallopian tube. These may also extend into the
reported. serosa.
Cell morphology
SALPINGITIS ISTHMICA NODOSA
● The glands are lined by tubal-type epithelium.

Salpingitis isthmica nodosa is a well-recognized pathological ● Endometriosis (surrounded by endometrial stromal cells)
condition which affects the proximal Fallopian tube and is ● Mesonephric duct remnants (small round glands
associated with infertility and ectopic pregnancy. It usually surrounded by concentric muscular layer, found only in
causes nodular thickening of the affected segment of the tube. the serosa)
TUMORS OF THE PERITONEUM
MESOTHELIAL TUMORS and the Fallopian tubes. In rare cases it is described in the ovar-
ian and paraovarian connective tissue. In the uterus, it is
usually located in the cornual region, and its size usually
ADENOMATOID TUMOR varies between 0.5 and 2.0 cm, although giant size has been
described. The histogenesis of adenomatoid tumor is unknown,
but it may be related to a reactive process. There is a frequent
CLINICAL FEATURES
association between adenomatoid tumor and leiomyomas in
Adenomatoid tumor is a rare benign neoplasm of presumed the uterus, with a variation between 56% and 80%. Talc
mesothelial origin, and is seen in both the male and female gen- crystals as well as repair and inflammatory processes should
ital tracts. In men, it is the most common neoplasm of the epi- be taken into account as initiating factors in the development
didymis, but also occurs in the spermatic cord and ejaculatory of ovarian adenomatoid tumors, in patients with susceptibil-
ducts. In women, it is seen with equal frequency in the uterus ity to such lesions. Composite multicystic mesothelioma
and adenomatoid tumor of the uterus has been described. The

treatment of this lesion is simple excision. Recurrences have not
been described, and ‘malignant degeneration’ is extremely rare.
Malignant mesothelioma (malignant adenomatoid tumor) of
the tunica vaginalis testis is a very rare neoplasm with highly
aggressive biological behavior. Treatment is difficult, and wide-
spread local invasion and/or metastatic disease at presentation
are associated with a poor prognosis.

Adenomatoid tumor is an ill-defined lesion composed of pseudo-
glandular and/or pseudovascular spaces and solid cords of
plump acidophilic cells irregularly distributed within fibrous
stroma containing areas of smooth muscle proliferation and
sometimes-abundant bundles of elastic fibers. The spaces may
be round, oval, elongated or sometimes cystically dilated, and
are lined by vacuolated, cuboidal or flattened epithelial cells
sometimes with signet-ring appearance.
The ovarian and juxta-ovarian tumors may contain intra-
cytoplasmic hyaline globules. Mitotic figures are rarely seen.
Lymphocytes, plasma cells and histiocytes may be identified
both in the tubular lumen and between the epithelial cells.
● Lymphangioma and histiocytoid hemangioma both are
extremely rare in the male or female genital tracts. Positive
staining for CD31 and CD34, and negative staining for
epithelial and mesothelial markers, can easily confirm the
diagnosis.
● The ovarian adenomatoid tumor can be mistaken for
well-differentiated tubular-type clear cell carcinoma; more
clearly malignant areas are usually seen in other sections
in cases of adenocarcinoma.
● Uterine adenomatoid can simulate smooth muscle tumors.
This is due to the associated smooth muscle hypertrophy
and the subtle changes of the cells lining the spaces.
Special techniques
● The tumor cells are positive for keratin and for the specific
mesothelial markers.
● A proportion of cases also express S-100 protein, neuron-
specific enolase, vimentin, and human milk fat globule
protein.
● They also show hyaluronidase-sensitive staining with
Alcian blue.
INCLUSIONS, CYSTS, AND HYPERPLASIA

Figures 7.371–7.373 Adenomatoid tumor.Variably sized and
Mesothelial hyperplasia of the pelvic and abdominal peritoneum shaped vacuolated spaces arranged in between smooth muscle
may be seen in patients with ovarian tumors. On occasion, the bundles.The spaces are focally lined by flattened or oval nuclei.
hyperplasia is so florid that it creates problems in diagnosis. The
hyperplasic mesothelial cells may be seen as small nests, cords, tumor, the presence of metastatic tumor elsewhere in the pelvis,
and gland-like structures, and when seen within the cyst wall of ascites, and coexistent endometriosis. Distinction of mesothelial
a serous or mullerian mucinous tumor of borderline malignancy, proliferation from invasive or metastatic ovarian tumor is obvi-
this may initially suggest a possibility of foci of stromal invasion, ously important in correct classification, staging, and management
lymphatic invasion, or both. Factors that may have predisposed of the tumor. Awareness of the occasional occurrence of florid
to the mesothelial hyperplasia include large size of the primary mesothelial hyperplasia in patients with ovarian neoplasms and
mesothelial hyperplasia. Deciduoid mesothelioma is a highly

malignant tumor which may also occur in older age, in men,
and in the pleura with or without any history of asbestos expo-
sure. The cause of this lesion is unknown, and considering
the young age of the patients and the failure to demonstrate
hormone receptors in the neoplastic cells, it is unlikely that
asbestos exposure or hormonal imbalance has played any role
in the development of the disease.
There are usually multiple small peritoneal nodules, histologi-
cally characterized by an unusual pattern with a superficial
resemblance to decidual reaction, but with significant mitotic
activity. The tumor may also be misinterpreted as epithelioid
smooth muscle tumor oxyphilic uterine and extrauterine
tumors and malignant melanoma.
Special techniques
● See Chapter 9, Mesotheliomas (p. 643).
MESOTHELIOMA, DIFFUSE MALIGNANT
CLINICAL FEATURES
Diffuse malignant mesothelioma of the peritoneum is a highly
malignant tumor affecting middle-aged patients of both sexes.
The most common initial clinical presenting features are ascites
and abdominal pain. The tumors typically appear as multiple
nodules measuring ⬍1.5 cm in their greatest dimension. In
women, this tumor is commonly mistaken as disseminated
ovarian malignancy. The tumor is usually found in the peri-
toneum, but may also be seen in the parietal and visceral
Figures 7.374 and 7.375 Adenomatoid tumor: CK7 highlights
the mesothelial cells. pleura, pericardium, and in the vaginal tunica. The vast major-
ity of cases are associated with asbestos exposure.
It is difficult to explain how inhaled asbestos induces peri-
attention to the histological, histochemical, and immunohisto- toneal neoplasms. The best option for treatment is always
chemical features of the mesothelial proliferation should facili- based on surgical resection, radiation, or chemotherapy (alone
tate the correct diagnosis. or combined). If radical surgery is not possible, these patients
Hyperplasic mesothelial cells within intra-abdominal lymph must be treated with either chemotherapy or radiotherapy,
nodes may also be encountered in staging procedures in women defined after complete staging of the disease.
with ovarian tumors. The intranodal mesothelial cells usually
occupy the sinusoids of the lymph, and should be distinguished PATHOLOGICAL FEATURES
from metastatic tumor – an error that could result in inaccurate
staging in a patient with a known tumor – or prompt a futile The pathology of diffuse malignant mesothelioma of the peri-
search for an occult primary tumor. toneum is similar to that of the pleura (see p. 643).
MESOTHELIOMA, DECIDUOID ● Peritoneal carcinomatosis
● Primary serous adenocarcinoma
● Primary epithelioid hemangioendothelioma of the peritoneum
CLINICAL FEATURES
Malignant mesothelioma with deciduoid features is a rare mor- Special techniques
phological variant of epithelioid malignant mesothelioma. The ● A panel of immunostains for undifferentiated tumors
name deciduoid is given due to the histological similarity should be employed; this includes stains for
between this lesion and exuberant ectopic decidual reaction. It adenocarcinoma, melanoma, lymphoma, and sarcoma.
occurs more often in the peritoneum of young women with no Leiomyosarcoma, malignant peripheral nerve sheath
history of asbestos exposure. In these situations, the lesion is tumor, gastrointestinal stromal tumor (GIST), and
frequently misdiagnosed as peritoneal deciduosis or florid angiosarcoma should always be considered.
● Alcian blue/PAS, a mucin stain is very useful as it is at Differential diagnosis

least focally positive in most adenocarcinomas. ● Lymphangioma (has smooth muscle fibers in the vessel walls)
● The immunohistochemical profile of the cells is that of ● Pseudocyst of the peritoneal cavity
mesothelioma (see Chapter 9, Mesotheliomas, p. 644). ● Lymphangiomyomatosis
● Emphysematous bullae
MESOTHELIOMA, MULTICYSTIC ● Endometriosis
● Adenocarcinoma
CLINICAL FEATURES
Special techniques
Benign multicystic mesothelioma (also known as multilocular ● The lining cells express the mesothelial cell phenotype
peritoneal inclusion cyst) is a rare mesothelial lesion of
(see Chapter 9, Mesotheliomas, malignant, p. 644).
unknown histogenesis, but may represent a reactive process. It
occurs mainly in the peritoneal cavity, but has also been
described in the pleural cavity. It predominantly affects young MESOTHELIOMA, WELL-DIFFERENTIATED
women, and is often associated with previous pelvic surgery,
endometriosis, or inflammation. The lesion is often multifocal
PAPILLARY
and frequently recurs, but is never fatal. Multicystic mesothe-
lioma may rarely occur in association with adenomatoid tumor CLINICAL FEATURES
of the ovary, leiomyomatosis peritonealis disseminata, or
endometriosis. Malignant transformation of ‘benign’ cystic Well-differentiated papillary mesothelioma is a rare neoplasm
mesothelioma of the peritoneum has very rarely been reported. of the peritoneum that is found mainly in women of reproduc-
tive age without any history of asbestos exposure. It is usually
PATHOLOGICAL FEATURES (Figure 7.376) characterized by an indolent course and good prognosis. This
lesion may also occur in the tunica vaginalis testis. Papillary
The lesion consists of irregular cystic spaces lined by a single mesotheliomas are mostly discovered incidentally or misdiag-
layer of flattened or cuboidal cells that are separated from each nosed as an ovarian mass.
other by loose fibrous tissue. Chronic inflammatory cell infil-
trate within the wall of the cysts, hemorrhage and fibrin depo-
sition may be seen. PATHOLOGICAL FEATURES (Figures 7.377 and 7.378)
Papillary mesothelioma consists of delicate tubulo-papillary
Cell morphology
structures covered by a single layer of regular cuboidal epithelial
● The lining cells are usually rounded, flattened or inactive cells. Hyalinization of the cores of these papillae can be promi-
looking, but occasionally are active and atypical. nent. Extensive areas of myxoid stroma may result in misinter-
● Mitotic figures are usually absent. pretation as pseudomyxoma peritonei. Psammoma bodies may
be seen within the papillae.
Cell morphology
● The cells have acidophilic or vacuolated cytoplasm and
vesicular, folded or convoluted nuclei containing
inconspicuous nucleoli.
● Papillary mesothelial hyperplasia
● Metastatic well-differentiated papillary carcinoma
Special techniques
● The cells express mesothelial markers (see Pleura,
mesothelioma, p. 644).
METASTATIC TUMORS
GLIOMATOSIS
Figure 7.376 Cystic mesothelioma: cystic spaces lined by bland
mesothelial cells. See Ovary, teratoma, immature (p. 479).
It has been suggested that the vast majority of mucinous

ovarian neoplasms occurring in this condition are secondary to
the appendiceal tumors resulting from incorporation of
implanted mucus and neoplastic mucinous epithelial cells of
the pseudomyxoma peritonei. This is supported by the follow-
ing facts: (i) the synchronous presentation and histological sim-
ilarity of both ovarian and appendiceal tumors; (ii) the high
frequency of bilaterality of the ovarian tumors and the pre-
dominance of right-sided ovarian involvement; and (iii) the
finding of mucin and mucinous epithelial cells on the ovarian
surfaces. Recent molecular genetic studies suggest the appendix
as being the organ of primary origin of this disease.

The intraperitoneal disease consists of mucinous material com-
partmentalized within fibrous septae and usually associated with
viable strips of neoplastic mucinous epithelium. This process is
seen within the peritoneal surfaces, and in the serosa and mus-
cular layer of visceral organs.
The appendix is usually grossly distended, ruptured, or may
appear normal and often shows luminal distension by mucous
material. The latter usually dissects through the wall into the
Figures 7.377 and 7.378 Benign papillary mesothelioma:

numerous papillae lined by bland mesothelial cells.
PSEUDOMYXOMA PERITONEI
See also Mucinous proliferating (borderline) ovarian tumors

(p. 465).
CLINICAL FEATURES
Pseudomyxoma peritonei is the presence of masses of gelatinous
mucinous material in the peritoneal cavity, usually resulting from
rupture, spillage, leakage or metastasis of a primary mucinous
tumor of an intraperitoneal organ, especially the appendix. A
large proportion of female patients have coexistent appendiceal
and ovarian mucinous tumors. This combination is almost
always associated with pseudomyxoma ovarii. It presents
with abdominal enlargement, pain or discomfort, or intestinal
obstruction, and is usually associated with poor prognosis due to
local adhesion, intestinal obstruction and infection. Pseudomyx-
oma is an uncommon condition that affects both males and
females. The etiology and treatment of this condition are currently
controversial. Most investigators agree that surgical debulking
and appendectomy are adequate initial therapeutic measures.
The role of intraperitoneal chemotherapy, radiotherapy, or appli- Figures 7.379 and 7.380 Pseudomyxoma peritonei: pools of
cation of mucolytic therapy remains uncertain. mucin and mucinous glandular epithelium.
ruptured mucinous cysts) should not be over-interpreted

as pseudomyxoma ovarii
● Pelvic mesothelioma with myxoid change may simulate
pseudomyxoma
Special techniques
● Alcian blue or mucicarmine can be very helpful in
identifying the mucinous material in a small biopsy
lacking the epithelial component.
● Tumors of mullerian origin are usually CK7-positive and
CK20-negative, while gastrointestinal mucinous
carcinomas are CK20-positive and CK7-negative.
STRUMOSIS PERITONEI
See p. 484.
Figure 7.381 Pseudomyxoma peritonei: AB/PAS staining highlights Strumatosis peritonei ‘metastatic ovarian strumosis’ or
the mucin secretion.
‘benign strumosis’ is the presence of peritoneal implants of
mature thyroid tissue occurring in cases of struma ovarii. The
underlying struma ovarii is rarely malignant. ‘Strumosis’
should not be confused with malignancy.
MISCELLANEOUS LESIONS
DISSEMINATED PERITONEAL LEIOMYOMATOSIS
See p. 437.
SPLENOSIS
Splenosis is heterotopic autotransplantation and seeding of

splenic tissue, usually caused by implantation of splenic tissue
following abdominal trauma. Splenosis may also be seen in the
Figure 7.382 Pseudomyxoma peritonei: the epithelial cells are
CEA-positive. pulmonary parenchyma following lacerating trauma to the
spleen, and as such may masquerade as a metastatic neoplasm.
Pelvic splenosis may clinically be mistaken for endometriosis.
serosa and exhibits similar compartmentalization within fibrous
tissue. The mucosal lining is replaced by mucin-producing neo-
plastic epithelium reminiscent of that seen in borderline muci- SUPERNUMERARY OVARY
nous ovarian tumor or that of intestinal adenomas. It rarely
shows frankly invasive mucinous adenocarcinoma. Supernumerary ovary is a rare gynecological anomaly, repre-
The ovary is usually a multicystic mucinous ovarian tumor senting ovarian tissue in an abnormal place such as the omen-
with frequent rupture of the capsule. It shows pools of mucin tum. These structures may rarely undergo cystic changes or
dissecting through the fibrous stroma (pseudomyxoma ovarii), result in the development of ovarian-type tumors.
accompanied by cystic structures lined by mucinous epithelium
resembling that of borderline mucinous tumors. Benign-looking TROPHOBLASTIC IMPLANTS
mucinous epithelium may also be seen. Mucinous implants are
often seen on the ovarian surfaces. Extratubal secondary trophoblastic implants are a rare compli-
cation of conservative laparoscopic procedures for tubal ectopic
Differential diagnosis pregnancy. These implants present with persistent ␤-hCG titers
● A small biopsy of the omentum or of any other serosal postoperatively, and are probably the result of disruption of the
or visceral muscular wall containing mucinous material ectopic pregnancy at tubal surgery. Disseminated trophoblastic
without epithelial component can be completely peritoneal implants may present as hemoperitoneum. The
overlooked, as it may resemble edema omental implants appear as tiny red-black nodules and, micro-
● Mucinous granulomas (discrete collections of macrophages scopically, consist of degenerating chorionic villi associated with
surrounding small deposits of mucin released from implantation changes in the surrounding tissue.
MULLERIANOSIS (MULLERIAN TUMOR-LIKE

CONDITIONS)
DECIDUOSIS
Ectopic decidua is a physiological phenomenon of pregnancy,

and arises from a progesterone-induced metaplasia of the
pluripotential cells of the ‘subcelomic’ mesenchymal. Deciduosis
is the presence of tiny nodules of decidual cells on the serosal
surfaces of the pelvic and lower abdominal peritoneum, beneath
the ovarian surface and on the Fallopian tube. It may also be
seen in lymph nodes. Gross deciduosis peritonei is a rare lesion
characterized by the presence of grossly visible peritoneal decid-
ual tissue in pregnant women. They appear as multiple, light tan
peritoneal masses which involve the cul-de-sac, ovaries, pelvic
wall, omentum, or both the large and small bowel. The intra-
operative appearance is usually suggestive of peritoneal carci-
nomatosis. Microscopic examination shows typical features of
deciduas. On occasion, decidual cells undergo myofibroblastic
transformation resulting in spindle cell morphology. A fibrosing
deciduosis of the omentum with development of a collagenous
connective tissue may also be seen. Deciduosis can also be seen
in extra-abdominal locations such as the skin, lung, and pleura,
based on a pre-existing extragenital endometriosis. Immunohis-
tochemically, the decidual cells are positive for vimentin, actin,
smooth muscle actin, desmin, ER, and PR.
ENDOCERVICOSIS (Figures 7.383 and 7.384)
Endocervicosis is a benign lesion in which endocervical mucosa

Figures 7.383 and 7.384 Endocervicosis: the presence of normal
develops in anatomic locations distant from the endocervical endocervical glands with pools of mucin within the outer wall of
canal. It is seen on serosal surfaces, in particular the serosal the cervix with no connection to the mucosal glands.
aspect of the bladder. They may also be seen deeply situated in
the urinary bladder wall, in the vagina, and in the outer cervi- ENDOMETRIOID, CLEAR CELL AND
cal wall and paracervical connective tissue. The glands are
mostly lined by tall columnar and bland-looking mucous cells TRANSITIONAL CELL CHANGES
with mucin secretion, rarely with ciliated cells. They may
undergo cystic changes. Awareness of the lesion and attention Endometrioid-, clear cell- and transitional cell-lined epithelial
to its typical histological features should facilitate its crucial inclusions may be seen as small granular structures on serosal
distinction from adenocarcinoma, in particular minimal devia- surfaces. Transitional cell-lined epithelium (Walthard rests) are
tion (adenoma malignum) type of cervical adenocarcinoma. a very common finding on the serosal aspect of the Fallopian
Awareness of the distinctive features of endocervicosis in this tube. They often show some degree of cystic changes.
site, including its dominant location in the outer portion of Florid mullerianosis may involve inguinal lymph nodes and
the cervix and paracervical connective tissue and the typical lead to a misdiagnosis of metastatic adenocarcinoma. Some
presence of an uninvolved zone of cervical wall between the of the glands of mullerianosis may be partially surrounded by
endocervicosis and the eutopic endocervical glands, facilitate a cellular ovarian-like stroma. Focal cytological atypia, oxyphil
the correct diagnosis. Endocervicosis glands displayed stronger cell metaplasia or atypical hobnail cells may be seen, but no
expression of HBME-1, ER, and PR than normal endocervices, mitotic figures. There may also be some cystically dilated
while the urothelium is negative. A primary vaginal adenocar- glands with rupture; this results in mucin being extravasated
cinoma may arise from endocervicosis. It has recently been into the stroma, but does not elicit any desmoplastic response.
appreciated that endosalpingosis is rarely seen in the bladder,
usually in association with endocervicosis or endometriosis, ENDOSALPANGOSIS (Figures 7.385–7.389)
leading to a suggested use of the designation ‘mullerianosis’. In
such locations they may be misinterpreted as nephrogenic ade- Endosalpingosis is the presence of glandular structures resem-
noma or a urethral diverticulum. bling Fallopian tube epithelium on the serosal surfaces of any
Figures 7.388 and 7.389 Endosalpingiosis, uterine serosa:

primitive (boxed) and mature (arrows) ciliated cells.
masses or cystic structures that resemble neoplasms. They are

described in women aged between 20 and 74 years.
Endosalpingosis can also be seen as lymph node inclusions,
and has been reported in the wall of a lymphangioma. Benign
epithelial proliferation involving cystic endosalpingosis with
features resembling a mullerian papilloma with fibrous and
fibrovascular cores or a microglandular growth pattern resem-
bling cervical microglandular hyperplasia, or a solid growth
pattern may occasionally lead to a mistaken diagnosis of neo-
plasia. Similarly, extensive endosalpingosis with cystic changes
involving the myometrial wall of the uterine cervix or corpus
may be interpreted as ‘suspicious for invasive minimal deviation
adenocarcinoma’. Endosalpingosis often contains psammoma
Figures 7.385–7.387 Endosalpingiosis, surface of the Fallopian bodies, and these can be detected sometimes on a Papanicolaou
tube.Tubal glandular structures with shallow papillae, lined by
partly ciliated epithelium. smear. Glandular structures from the surface of endosalpingosis
may be detected in peritoneal washings, leading to an erroneous
diagnosis of malignancy.
of the following organs: the uterus, adnexa, colon, recto-
sigmoid, pelvic sidewalls, and the cul-de-sac. They may also
be seen within the uterine wall. Endosalpingosis appears to be an MULLERIAN INCLUSION CYSTS
incidental finding, associated with additional pelvic pathology,
rather than being a frequent cause of pelvic pain. These lesions Mullerian cyst of the mesentery and retroperitoneum is an
usually appear as small whitish granules, or may present as extremely rare disease entity. Microscopically, the lining cells
Bibliography 525
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lining of smooth muscle bundles, adipose tissues, lymphovas- metaplasia of the lining cells to form a cystadenoma. Estrogen
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Mullerian lymph node inclusion is not an uncommon occur- the occurrence exclusively in women.
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borderline malignancy. The lymph nodes most often involved by and histologically resembles the ovarian counterpart. It may
mullerian inclusions are from para-aortic sites, which reflects the show a typical area of benign, low malignant potential and
primary drainage route from the ovary. Not uncommonly, neigh- malignant mucinous epithelium. Patients with retroperitoneal
boring areas in the same lymph node group with the inclusions cysts are more likely to have incomplete excision of the cyst
disclose separate foci of obvious metastatic borderline tumor. and therefore a higher incidence of recurrence.
PRIMARY PERITONEAL EPITHELIAL TUMORS SEROUS TUMORS
See Ovarian serous tumors (p. 471).

MUCINOUS TUMORS Benign, borderline and malignant serous cysts may rarely
develop primarily in the omentum. These are histologically
Primary retroperitoneal mucinous cystadenoma is an uncommon similar to the ovarian counterparts.
tumor found exclusively in women. These tumors may arise
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8 head and neck tumors
Kathryn M McLaren and Awatif I Al-Nafussi
Tumors of the ear 570 Lateral periodontal, botryoid, and glandular cyst 581
Epithelial tumors 570 Odontogenic keratocyst (primordial cyst) 582
Aggressive papillary middle-ear tumor 570
Ceruminoma 570 Odontogenic tumors 583
Middle-ear adenoma 571 Adenomatoid odontogenic tumor 583
Ameloblastic fibroma and related lesions 584
Miscellaneous tumors 571 Ameloblastoma 585
Inflammatory masses 571 Calcifying epithelial odontogenic tumor 587
Other rare tumors 571 Cementoma (cementoblastoma, gigantiform cementoma,
periapical cemental dysplasia and cementifying fibroma) 587
Clear cell odontogenic tumor 588
Neuroendocrine tumors 571
Malignant odontogenic tumors: odontogenic carcinomas
Glomus jugulare 571
and sarcomas 589
Odontogenic fibroma 590
Tumors of the nasopharynx 572 Odontogenic myxoma 590
Epithelial tumors 572 Odontomas 591
Inverted papilloma of nose 572 Squamous odontogenic tumor 591
Mucosal gland adenomas 572
Olfactory neuroblastoma 573
Mesenchymal tumors 574 Epithelial tumors, benign 593
Angiofibroma, juvenile nasopharyngeal 574 Basal, membranous, canalicular, trabecular, sebaceous
and tubular monomorphic adenomas 593
Miscellaneous tumors 575 Basal cell adenoma 593
Mucous membrane plasmacytosis of the upper Membranous adenomas (dermal anlage tumor) 594
aerodigestive tract 575 Hybrid basal cell adenoma 594
Other tumors 575 Canalicular adenoma 594
Sebaceous adenoma 594
Tubular adenoma 594
Tumors of the oral cavity 576 Myoepithelioma 594
Epithelial tumors, benign 576 Oncocytoma 596
Microcystic papillary adenomas 576 Pleomorphic salivary adenoma 597
Squamous papilloma 576 Warthin’s tumor 599
Epithelial tumors, malignant 576 Epithelial tumors, malignant 600

Squamous carcinoma 576 Acinic cell carcinoma 600
Adenoid cystic carcinoma 601
Mesenchymal tumors 577 Basaloid carcinoma 602
Ectomesenchymal chondromyxoid tumor of the tongue 577 Clear cell carcinoma 603
Epithelial–myoepithelial carcinoma 603
Mucoepidermoid carcinoma 603
Miscellaneous tumors 578 Polymorphous low-grade adenocarcinoma/terminal
Giant cell granuloma (epulis) 578 duct carcinoma 605
Salivary gland tumors 579 Salivary duct carcinoma 605
Wegener’s granulomatosis 579
Tumors of the jaw 579 Benign lymphoepithelial lesion 607
Odontogenic cysts and cystic lesions 579 Inverted ductal papilloma of minor salivary glands 609
Dentigerous (follicular) cyst 580 Necrotizing sialometaplasia 609
Gingival cysts 580 Salivary gland choristoma 609
Inflammatory odontogenic cysts 580 Sialadenoma papilliferum 609
570 Head and neck tumors
GENERAL COMMENTS prognosis. Salivary gland tumors are most often benign, but the
classification of the malignant tumors is important because of
Tumors and tumor-like conditions of the ear, nasopharynx, oral the management and prognostic implications. In all sites, tumor-
cavity and salivary glands form a protean group, with the ear like conditions may produce diagnostic difficulties, and means of
being an uncommon site of any tumors. Those in the other epithe- resolving these are alluded to in this chapter.
lial sites are most often squamous carcinomas. Rarer entities are The conditions are essentially listed in alphabetical order
important because of the different associations, management and according to the organ system involved.
TUMORS OF THE EAR
includes both benign and malignant tumors. The latter are

EPITHELIAL TUMORS more common, presenting as polypoid lesion in the external
auditory canal, and with symptoms such as otalgia and otor-
AGGRESSIVE PAPILLARY MIDDLE-EAR TUMOR rhea. As a group, they show varied clinical behavior, usually
dependent on the histological appearances of the tumor.
CLINICAL FEATURES
Aggressive papillary middle-ear tumor is a distinct entity with
Histology of the normal ceruminous glands
a propensity for local and intracranial invasion and bone
destruction, but the lesions do not metastasize. The tumor Normal ceruminous glands are similar to apocrine glands.
affects young and middle-aged adults (aged 26–55 years), and They are large, irregularly shaped, and lined by cuboidal or
is usually asymptomatic, though it may present with hearing columnar eosinophilic secretory cells.
loss, tinnitus, facial weakness, otitis or vertigo. There is an Ceruminomas are classified into four histological patterns:
● Ceruminous adenoma: this is characterized by
association with von Hippel–Lindau disease.
proliferation of benign-looking ceruminous glands with no
invasive features. There may be cystic change with
formation of papillary structures.
Aggressive papillary middle-ear tumor consists of complex, ● Ceruminous adenocarcinoma: this may show histological
interdigitating papillae reminiscent of papillary carcinoma of features identical to ceruminous adenoma, but with the
the thyroid or of low-grade papillary adenocarcinoma of minor addition of invasive features. The tumor may show
salivary glands. glandular, adenoid-tubular, or adenoid cystic patterns.
● Adenoid cystic carcinoma: this is similar to that of salivary
Cell morphology gland origin, consisting of nests of small dark cells with
cystic spaces or hyaline cylinders.
● The papillae are lined by uniform, cuboidal to low
● Pleomorphic adenoma (mixed tumor): this is again
columnar cells resembling the epithelium of the normal
identical to that of salivary gland origin, consisting of
middle ear or middle-ear adenoma.
strands and nests of epithelial cells present in a myxoid,
chondroid or hyalinized stroma.
Mixtures of the above histological patterns can be seen in the
● Low-grade polymorphous carcinoma of salivary gland origin
same tumor.
● Metastatic papillary carcinoma
Cell morphology
Special techniques
● The secretory cells of the normal ceruminous glands are
● The cells express cytokeratin (CK), epithelial membrane
cuboidal or columnar, with eosinophilic cytoplasm and
antigen (EMA), vimentin and sometimes neuron-specific
small dark ovoid nuclei. They show apical ‘snouts’, and
enolase (NSE).
may contain golden brown (iron and lipochrome)
● The cells are negative for other neuroendocrine markers.
cytoplasmic granules. Myoepithelial cells are located
between the secretory cells and the basement membrane.
CERUMINOMA (CERUMINOUS GLAND TUMORS) ● Cellular pleomorphism and mitoses can be seen in the
malignant tumors.

Ceruminoma is a generic term applied to tumors arising from ● Glomus tumor
ceruminous glands found in the external auditory canal. It ● Tumors of salivary gland origin
Tumors of the ear 571
Special techniques Special techniques

● The cytoplasmic granules are positive with iron stains ● Immunohistochemical and ultrastructural studies reveal
(Pearl’s Prussian blue reaction), and they are PAS-positive bidirectional mucinous and neuroendocrine character.
and diastase-resistant.
● Masson’s Trichrome highlights the cytoplasmic granules of
both epithelial and myoepithelial cells. MISCELLANEOUS TUMORS
INFLAMMATORY MASSES
MIDDLE-EAR ADENOMA
Fungal infection – in this regard mucormycosis – is particularly
CLINICAL FEATURES serious, and may occur in children. More often, there is an
underlying risk factor for opportunistic infection.
Middle-ear adenoma is unique to the middle ear, arising from Granulation tissue polyp is a richly vascular, usually acquired
its lining epithelium. It probably represents a carcinoid tumor lesion, which may bleed profusely.
of the middle ear. Middle-ear adenoma most correctly describes
the lesion’s morphological features and clinical behavior,
although ‘neuroendocrine adenoma of the middle ear’ may be OTHER RARE TUMORS
a more accurate designation. The tumor usually occurs in
adults, may present with tinnitus, decreased hearing, pain, Malignant melanoma, meningiomas, embryonic sarcoma,
fullness or vertigo, and has a benign clinical course. The lesion chordoma, chondroma and chondrosarcoma, osteoma, cavernous
is usually cured by simple surgery. Mastoidectomy or radio- angioma, eosinophilic granuloma, solitary plasmocytoma and
therapy may be required in recurrent cases. fibrous dysplasia of the petrous bone may rarely be seen in
the ear. Metastatic tumors are a rare occurrence. The present
authors have seen an example of metastatic squamous carci-
PATHOLOGICAL FEATURES noma of cervix invading the tympanic membrane. Obviously, a
primary squamous carcinoma in a middle-ear site would be
Middle-ear adenoma shows a variety of histological appear-
very rare, and even a squamous carcinoma of the external
ances. It essentially consists of round or ovoid cells arranged in
canal is most unusual.
irregular nests, anastomosing cords, sheets, well-formed glands,
or rarely in a cribriform pattern. The background stroma can
be loose, edematous, or densely collagenous.
Secondary features
GLOMUS JUGULARE
● Mixed inflammatory infiltrate.
● Granulation tissue reaction.
● Perforation of the tympanic membrane. CLINICAL FEATURES
● Bone invasion.
Glomus jugulare (extra-adrenal paraganglioma; chemodectoma)
is a neuroendocrine tumor akin to a carotid body tumor and to
Cell morphology a pheochromocytoma. It is found mostly in women, and usually
● The cells are round or ovoid with occasional irregular presents as bleeding from the ear. It may be seen as a polypoidal
contours. structure that may be visible in the external canal, although it
● The cytoplasm is finely granular, and occasionally originates from the middle ear. The term ‘glomus jugulare’ is
vacuolated. often used and is acceptable, but it is important not to confuse
● The nuclei are round or ovoid, usually eccentrically this with a glomus tumor – that is, a variant of hemangioperi-
located, contain finely dispersed chromatin and small cytoma. A similar tumor may also occur in the nasal cavity.
single nucleoli.
● Scattered binucleate cells may be seen. PATHOLOGICAL FEATURES
● Mitotic figures are usually absent.
The cells are nested with surrounding dendritic cells of susten-
tactular nature. The tumor cells express chromogranin A and
Differential diagnosis variable other neuroendocrine markers such as protein gene
● Ceruminous gland adenomas peptide 9.5 (PGP9.5), synaptophysin and NSE. The dendritic
● Paraganglioma cells express S-100. Often, because they are richly vascular and
● Plasmacytoma (cells have perinuclear hof, amphophilic easily squeezed by the forceps, the architectural pattern is less
rather than eosinophilic cytoplasm, and coarse evident due to compression of the cells and only the richly vas-
chromatin) cular stroma may be identifiable, though immunohistochem-
● Neuroendocrine tumors istry would demonstrate the nests of tumor cells.
TUMORS OF THE NASOPHARYNX
EPITHELIAL TUMORS
INVERTED PAPILLOMA OF NOSE (TRANSITIONAL

CELL, SCHNEIDERIAN PAPILLOMA)
CLINICAL FEATURES
Inverted papilloma is a benign tumor of the nose and nasal
sinuses that occurs over a wide age range, and predominantly in
men. It is usually unilateral, involves a considerable area, and is
a polypoid, firm lesion that bleeds easily on removal. It has a
tendency for local recurrence, and rarely undergoes malignant
transformation. The latter may be a small stretch of squamous
carcinoma in situ on the surface, this having a good prognosis,
or a more obvious focus of invasive squamous carcinoma.

Inverted papilloma of nose is characterized by the presence of (a)
a complex enfolded hyperplastic epithelium. The latter variably
consists of pseudostratified or stratified columnar, transitional
or metaplastic squamous epithelium. The underlying stroma is
edematous. The epithelial nests are separated by small amounts
of stroma. Microcystic degenerative spaces are often seen within
the epithelial nests; these are often infiltrated by polymorphs,
which are also seen throughout the epithelium. When the
epithelial cells are oncocytic, the term microcystic oncocytic
papilloma is used. Clear cell cytoplasmic change is commonly
seen, and goblet cells may also be present. The basal cell layers
may exhibit cellular atypia and mitotic figures.
● Squamous papilloma
● Microcystic papillary adenoma
MUCOSAL GLAND ADENOMAS (TUBULOCYSTIC

AND MICROCYSTIC PAPILLARY ADENOMAS)
CLINICAL FEATURES (b)
Tubulocystic adenoma is a benign mucosal gland tumor that

Figure 8.1 (a, b) Inverted papilloma of the nose. A complex
occurs in the larynx and the nasal cavity. architecture is typical of these lesions, and they have very little in
Microcystic papillary adenoma is a rare benign mucous the way of a differential diagnosis. However, the lesions must be
gland tumor that occurs predominantly in elderly individuals. studied carefully for the development of squamous metaplasia
It is usually seen in the nasal cavity and paranasal sinuses, and which may show focal dysplasia.
presents as a polypoid lesion causing nasal obstruction. It may
recur locally.
Microcystic papillary adenoma is characterized by the pres-

ence of broad, variably thickened epithelial lined papillary
Tubulocystic adenoma is characterized by the presence of structures projecting into the cystic spaces. The constituent cells
numerous, small tubules lined by columnar or cuboidal, usu- are mainly cylindrical, with abundant eosinophilic/oncocytic
ally, eosinophilic cells. cytoplasm. A very characteristic feature of this lesion is the
(a) (c)
● Tubulocystic adenoma should not be confused with a
well-differentiated adenocarcinoma and metastatic renal
cell carcinoma
Special techniques
● Mucin stains highlight the presence of the mucin-
containing microcysts in microcystic papillary adenoma.
OLFACTORY NEUROBLASTOMA
(AESTHESIONEUROBLASTOMA)
CLINICAL FEATURES
Olfactory neuroblastoma (esthesioneuroblastoma) is a rare
tumor of neuroectodermal origin, which arises usually in the
area of the olfactory epithelium and invades the paranasal
(b) sinuses, the orbit, and the brain. It occurs at any age (from 3 to
79 years), but most commonly in adults. The tumor presents as
Figure 8.2 (a–c) Microcystic papillary adenoma.Variably thickened a polypoid fleshy lesion in the nasal cavity. It has a high rate of
epithelial lined papillary structures with numerous rounded spaces local recurrence and late metastasis. It has a predilection for
containing inspissated eosinophilic (mucin) secretion.
cervical lymph node metastasis, and also has potential for dis-
tant metastasis to unusual sites such as the scalp, face, aorta,
spleen, liver, adrenal gland, breast and ovary. It rarely extends
presence, among the epithelial cells, of numerous rounded spaces intracranially. Olfactory neuroblastoma is best managed by
containing inspissated eosinophilic (mucin) secretion. Collections craniofacial surgery with complete tumor resection. Adjuvant
of polymorphs in small microabscess-like patterns are also seen therapy may be useful for palliation of advanced disease.
within the lining epithelium. The underlying stroma may show Olfactory neuroblastoma has occasionally been reported in
marked hyalinization. association with a carcinomatous component.
Secondary features PATHOLOGICAL FEATURES (Figure 8.3)

● Inflammation. Olfactory neuroblastoma is a very cellular tumor consisting of
● Stromal fibrosis. small round cells arranged in compact or loose clusters, in sheets,
(a) (b)
Figure 8.3 (a, b) Olfactory neuroblastoma. Small round cells arranged in compact clusters of round cells, with highly fibrovascular stroma.
The cells are chromogranin-positive.
and in lobules. These are present in a characteristically fibrillary ● The MIB-1 (Ki-67) index shows high values, of 20–40%.
background. Focal rosetting may be seen. The intervening stroma ● About 10% of the tumor cells reveal positivity for p53
is fibrovascular, and may separate the tumor cells into aggre- protein.
gates. Some tumors contain larger cells with more abundant cyto-
plasm reminiscent of undifferentiated carcinoma. The stroma is
highly vascular. MESENCHYMAL TUMORS
Secondary features ANGIOFIBROMA, JUVENILE NASOPHARYNGEAL

● Hemorrhage.
● Necrosis.
CLINICAL FEATURES
Cell morphology Angiofibromas are uncommon vascular tumors with a strong
predilection for the nasopharynx of adolescent males (juvenile
● The main cell population consists of small, uniform,
nasopharyngeal angiofibromas). Although they are slowly grow-
round cells with indistinct cytoplasm and round nuclei
ing and histologically benign, they have the potential to cause
containing coarse or finely granular chromatin.
significant morbidity with laryngeal involvement. They charac-
● The cells may show a suggestion of cytoplasmic processes
teristically originate in the posterior lateral wall of the nasophar-
or fibrils.
ynx, and may extend beyond the nasopharynx, but they rarely
● Melanin is occasionally present within the tumor cells.
originate outside the nasopharynx. The clinical characteristics
● Mitotic figures are infrequent.
of extranasopharyngeal angiofibromas do not conform to those
● Ganglioneuronal maturation may occur after
of nasopharyngeal angiofibromas. Therefore, they can present
chemoradiotherapy.
diagnostic challenges. The lesions are best treated by steroids,
radiotherapy, arterial embolization or surgery. They commonly
Differential diagnosis recur after surgery, yet may regress spontaneously. The mor-
● Malignant lymphoma bidity and mortality associated with this tumor are related to
● Plasmacytoma its prominent vascularity and its propensity for aggressive local
● Malignant melanoma growth.
● Alveolar rhabdomyosarcoma
● Undifferentiated carcinoma PATHOLOGICAL FEATURES (Figure 8.4)
Juvenile nasopharyngeal angiofibroma is a non-encapsulated,
Special techniques broad-based, hypocellular lesion consisting of a fascia-like col-
● Most of the tumor cells are shown to be positive for lagenous background containing irregularly shaped ectatic ves-
NSE and vimentin, and weakly positive for synaptophysin, sels. These vessels are especially prominent at the margins and
chromogranin and S-100 protein. S-100 highlights the in lesions of short duration. They are open, thin-walled erectile
sustentacular cells which surround the nests of small vessels, sometimes with a rim of smooth muscle and lined by a
cells. single layer of endothelial cells.
mucosa, and affects the larynx, pharynx, palate, lips, mouth,

tongue, and trachea with frequent multiple site involvement.
Clinically, the condition may be mistaken for cicatrical pem-
phigoid, sarcoidosis, fungal infection or carcinoma, and is
sometimes associated with other conditions such as diabetes,
polymyositis, psoriasis, or Raynaud’s phenomenon.
The correct treatment of this condition remains uncertain.
Local corticosteroid therapy may result in short-term improve-
ment, and surgical excisions have been attempted. The disease
may progress, but no evidence of malignancy has been
reported.
Mucous membrane plasmacytosis of the upper aerodigestive
Figure 8.4 Nasal angiofibroma. Blood vessels are of variable tract is characterized by dense, diffuse and expansive subepithelial
thickness, and the differential diagnosis would include a granulation plasma cell infiltrate. The overlying mucosal lining exhibits
tissue polyp or even a more worrying neoplastic angiomatous psoriasiform epithelial hyperplasia with dyskeratosis.
lesion.These tumors occur in pubertal males, and sometimes the
thick muscular-walled vessels can resemble corpus cavernosum.
Cell morphology
Secondary features ● The plasma cells are mature, and show no evidence of
atypia. They are polytypic.
● Ulceration. ● Dyskaryotic cells are often seen in the overlying squamous
● Squamous metaplasia of the surface epithelium.
epithelium.
● Hyalinization.
● Myxoid change.
● Inflammatory infiltrates. Differential diagnosis
● Plasmacytoma
Cell morphology ● Fungal infection
● The main cell populations are fibroblasts and myofibroblasts. ● Rhinoscleroma (results from Klebsiella rhinoscleromatis
● Mast cells may be seen. infection, occurs most commonly in younger individuals
from Russia, Central Europe, Egypt, Africa, and South
Differential diagnosis or Central America. Histologically, this condition is
● Inflammatory polyps characterized by foamy macrophages containing
● Granulation tissue reaction Gram-negative bacilli. These are referred to as
Mikulicz cells).
Special techniques ● Syphilis
● The stromal and endothelial cells of nasopharyngeal ● Rosai–Dorfman disease
angiofibroma often show androgen receptors, and
sometimes also progesterone receptors (PR).
Special techniques
● Immunohistochemistry shows polyclonal ␬ and ␭ light
chains.
MISCELLANEOUS TUMORS ● No specific micro-organisms have so far been isolated in
the cases reported.
MUCOUS MEMBRANE PLASMACYTOSIS OF THE
UPPER AERODIGESTIVE TRACT OTHER TUMORS
A variety of other tumors can be seen in the nasal cavity and

CLINICAL FEATURES
nasopharynx. These include any of the salivary gland tumors,
Mucous membrane plasmacytosis of the upper aerodigestive adenocarcinoma, ameloblastoma, malignant melanoma, lym-
tract is an unusual but distinctive plasma cell proliferative dis- phomas, granulocytic sarcoma, hemangioma, nerve sheath
order of the upper aerodigestive tract, and is of unknown etio- tumor, solitary fibrous tumor, hemangiopericytoma, nodular
logy and pathogenesis. It affects patients between the ages of 40 fasciitis, rhabdomyosarcoma, sinonasal undifferentiated carci-
and 67 years, with a male predilection, and may cause dysphonia, noma, chondroma, osteoma, psammomatoid ossifying fibromas,
dysphasia, breathing difficulty and oral pain. It produces a plasmacytoma, meningioma, nasal encephalocoele and glial tis-
cobblestone or warty appearance of the aerodigestive tract sue presenting as a polypoidal mass.
TUMORS OF THE ORAL CAVITY
In the tongue, the tumor is generally on the lateral border,

EPITHELIAL TUMORS, BENIGN and a warty lesion at this site always requires a biopsy for
diagnosis. An erythematous appearance and induration are
MICROCYSTIC PAPILLARY ADENOMAS (MUCOSAL suspicious features.
The prognosis for squamous carcinoma depends on the grade
GLAND ADENOMAS) and stage of tumor.
There may be a variably intense host reaction which may
See p. 572.
show an inverse correlation with local progression of disease.
Several reports attest to the apparent protective effect of an
SQUAMOUS PAPILLOMA intense eosinophilic infiltrate (with the paradoxical finding of a
peripheral eosinophilia being an adverse prognostic factor).
This is relatively common, and often has a viral (human papil- In surgery on the tongue, assessment as to whether the tumor
lomavirus, HPV) etiology. The typical warty architecture shows has crossed the midline is of importance in determining whether
inward pointing of ridges, delicate telangiectatic blood vessels hemiglossectomy or glossectomy will be required. The floor of the
in the cores of the papillae, and cell vacuolation. A comment mouth and internal cheek may also be approached surgically. For
should be made on the presence or absence of dysplasia. They all sites, contemplation may be given to delivering radiotherapy
may be highly proliferative and complex and, on occasion, so to the primary site combined with chemotherapy. Performing a
much so that there is mimicry of a carcinoma. Cytological neck dissection may precede the chemotherapy or may follow.
atypia and often suprabasal cell separation are to be sought prior Assessment of nodal involvement may include: (i) clinical exami-
to a diagnosis of carcinoma. nation; (ii) the result of fine needle aspiration cytology; and (iii)
However, a verrucous carcinoma typically lacks any significant the presence of ‘suspicious’ lymph nodes – that is, those greater
dysplasia. It merely shows broad fronts of invaginating epithe- than 1 cm in diameter – on computed tomography scanning.
lium, often exciting an intense host reaction. It is usually relatively
large with a broad base. Thus, in all ways it mimics a large viral
wart and there is much evidence to suggest a role for HPV. Often,
multiple repeat biopsies are required prior to this diagnosis See Chapter 15, Carcinomas (p. 1204).
being established. The patient is frequently older than is the usual
case for a viral wart, for example in the fifth decade of life and Differential diagnosis
upwards. ● Median rhomboid glossitis: This rather rare condition
The preferable management is of local excision, without the
causes a hyperplastic swelling, usually in the midline of the
requirement for a deep submucosal excision. Laser therapy has
tongue at the junction between the anterior two-thirds and
been attempted. The traditional teaching is that radiotherapy is
the posterior third. There was a prior thought that this
to be avoided because of the apparent risk of conversion to a
may be a congenital abnormality at the site of fusion of
more high grade and truly invasive carcinoma, but some studies
the tongue, but more recent evidence suggests that
suggest that – at least in the laryngeal sites – the apparent initial
Candida plays a significant role in stimulating the mucosal
increase in size may have been due to reactive edema after radio-
hyperplasia. Pathologically, it shows broad fronds of
therapy, and the long-term results as regards local recurrence
mucosa with very broad bases proliferating into the
are more favorable. Obviously, in the oral cavity – as opposed
submucosa. The appearance is often symmetrical. The
to the larynx – a surgical approach is more feasible.
lesion is not dysplastic. Thus, the midline location, broad
fronds and lack of dysplasia would all argue against a
EPITHELIAL TUMORS, MALIGNANT misinterpretation of a carcinoma. However, a small
superficial biopsy may be misleading.
The presence of Candida should be sought using special
SQUAMOUS CARCINOMA stains (e.g., PAS). Please note that Candida may play a role
in several conditions in the oral cavity producing mucosal
hyperplasia. The hyperplastic form is termed chronic hyper-
CLINICAL FEATURES
plastic candidiasis; the atrophic form, erythematous (atrophic)
This is the most common histogenetic subgroup of the oral car- candidiasis.
cinomas. The patient is usually over the age of 50 years, though It has been estimated that up to 30% of the general popu-
younger individuals have been described and there is an impres- lation harbor Candida in the oral cavity, but that sympto-
sion that the overall age incidence for all head and neck cancers matic disease is found in only 3%. In contrast, patients who
is falling. are HIV-positive may harbor Candida in 90% of cases, with
The etiological risk factors are cigarette smoking and alcohol symptomatic disease being found in 60%. Other forms of
ingestion, though in Eastern countries chewing of certain nuts immunocompromise, including diabetes mellitus, are associ-
(e.g., Betel nut) produces carcinogenic agents. ated with an increased incidence of oral candidiasis.
Tumors of the oral cavity 577
● Granular cell tumor: A granular cell tumor (previously median 32 years), but occurs more often in young individuals.
called granular cell myoblastoma) in the tongue may The tumor may recur after surgical treatment.
stimulate hyperplasia of the overlying mucosa, and a
superficial biopsy may suggest the presence of a well- PATHOLOGICAL FEATURES (Figures 8.5 and 8.6)
differentiated squamous carcinoma. It is important always
to examine the submucosal tissue in such biopsies or, if Ectomesenchymal chondromyxoid tumor of the tongue is a
there is any doubt, to request a deeper biopsy. well-circumscribed, lobulated myxoid/chondromyxoid lesion
The granular cell tumor has large cells with small central within the superficial musculature of the tongue. The tumor is
nuclei and decidedly granular, eosinophilic cytoplasm. They either separated from the overlying epithelium by vascularized
are essentially Schwann cells, and express S-100 protein. connective tissue, or extends and abuts on the basal layers, with
Often, the nerves in the vicinity show granular cell change or without ulceration. The lobules are separated and surrounded
in their Schwann cells. by fibrous septae, and consist of relatively uniform cells with
● Organ of Chevitz: These organs are normally occurring
neuroepithelial structures with an alleged neuroreceptor
function. They lie deep to the internal pterygoid muscle
and are associated with small branches of the buccal
nerve. Nodular hyperplasia of these structures may
occur.
MESENCHYMAL TUMORS
ECTOMESENCHYMAL CHONDROMYXOID TUMOR

OF THE TONGUE
CLINICAL FEATURES
Ectomesenchymal chondromyxoid tumor of the tongue is a
benign tumor of unclear histogenesis, but may arise from a cell of
undifferentiated ectomesenchyme. It presents as a slow-growing,
painless, firm, submucosal nodule of the anterior dorsum of the
tongue. It can be seen at any age (typically from 9 to 73 years,
(b)
(a) (c)
Figure 8.5 (a–c) Ectomesenchymal chondromyxoid tumor.The periphery is well demarcated from the surrounding tissue, without an
infiltrative edge.The cells are partly small and epithelioid, and partly spindle cell in morphology.They sit in a somewhat myxoid
or chondroid matrix.
● Ossifying fibromyxoid tumor of soft tissue (has been

reported in the tongue, and 80% have a shell of bone at
their periphery)
● Extraskeletal myxoid chondrosarcoma (is extremely rare in
the head and neck)
● Chondroid choristoma/extraskeletal chondroma (consists
of mature hyaline cartilage)
● Pleomorphic adenoma
● Myoepithelioma
● Neurofibroma
Special techniques
● The tumor is characterized immunophenotypically by a
mesenchymal and neurogenic profile with positivity for
vimentin, S-100 protein, and glial fibrillary acidic protein
(GFAP).
● The tumor is negative for epithelial markers.
Figure 8.6 Ectomesenchymal chondromyxoid tumor.The matrix is GIANT CELL GRANULOMA (EPULIS)
visible, and appears both myxoid and cartilaginous. Alcian blue
staining would be positive, as would S-100 protein.
CLINICAL FEATURES
small nuclei and basophilic cytoplasm mostly arranged in net-
Central giant cell epulis is a solitary benign reactive process
like sheets or in cords, strands and neural-like swirling. These are
affecting, most commonly, the tooth-bearing areas of the
set in a mucinous stroma that varies from densely basophilic
mandible and maxilla. It can also be seen in the temporal bone,
and vacuolated to loosely myxoid and clear. Features such as
paranasal sinuses and anywhere in the craniofacial bone. The
multilobulated nuclei, foci of cellular atypia, infiltration into
tumor often presents as a painful swelling, mainly in adolescents
adjacent muscle, fat or entrapment of nerve or muscle fibers or
and young adults, but it may occur at any age. It affects females
focal hyalinization may be seen.
twice as often as males, and is a well demarcated, radiolucent
Secondary features X-radiographic finding. It may be multiloculated and traversed
by slender bony trabeculations. The overlying cortex is usually
● Focal extravasation of red blood cells.
expanded, and may extend into the adjacent soft tissue.
● Hemosiderin deposition.
Peripheral giant cell granuloma is a reactive process occurring
● Minimal lymphocytic infiltrate, especially at the margins.
at any age, and more commonly in females. Affecting the gingiva
● Ulceration of the overlying mucosa may be seen.
of both the mandible and maxilla, the tumor presents as a well-
Cell morphology circumscribed lesion which pushes the teeth aside, and may also
erode the bone.
● The cells are round, fusiform or polygonal in shape.
● The nuclei are small and uniform, with frequent
perinuclear clearing. Some nuclei are cup-shaped, others
are binucleate and some show pseudo-inclusions. Central and peripheral giant cell (reparative) granuloma closely
Multilobated nuclei with occasional atypia can be seen. resembles giant cell tumor of bone consisting of a background
hemorrhagic, spindle cell stroma containing loosely arranged
Differential diagnosis cells with storiform or herringbone patterns. Osteoclast-type
● Mucocele (is a granulation tissue-lined pseudo-cyst giant cells are irregularly distributed within the stroma. These
resulting from spillage of salivary mucin due to trauma of tend to form clusters around areas of hemorrhage and necrosis.
minor salivary gland ducts. Unlike ectomesenchymal The stroma contains little interstitial collagen. Foci of ossifica-
myxoid tumor of the tongue, mucocele is usually seen in tion are present in most lesions.
the ventral rather than the dorsal surface)
● Oral mucinosis (is the oral equivalent of cutaneous focal Secondary features
mucinosis, characterized by focal separation of fibroblasts ● Hemorrhage.
by connective tissue mucin, and it does not have the ● Focal necrosis.
lobular pattern) ● Osteoid production and ossification.
● Myxoma (very rare in the mouth) ● Hemosiderin deposition.
● Nerve sheath myxoma (is rarely seen in the tongue) ● Inflammatory infiltrate.
● Aneurysmal bone cyst (when this affects craniofacial

bones, it is indistinguishable from giant cell epulis and may
complicate giant cell granuloma)
● Giant cell tumor of bone (the giant cells are usually evenly
distributed within the lesion)
● Eosinophilic granuloma (contains large number of
eosinophils and Langerhans’ cells in the background)
● Non-ossifying fibroma
Special techniques
● The giant cells and a large proportion of the stromal cells
are strongly positive for acid phosphatase and acid esterase.
SALIVARY GLAND TUMORS

Figure 8.7 Giant cell epulis. Classic multinucleate osteoclast-like Any of the salivary gland tumors described in the major glands
giant cells with a monotonous smaller epithelioid and spindle cell
background.These cells express CD68, a macrophage marker. may occur in the oral cavity and some – for example, the poly-
Distinction from other giant cell lesions of the jaw requires clinical morphous low-grade adenocarcinoma – are more often found
correlation (e.g., hyperparathyroidism can produce similar lesions), in minor than in major salivary glands.
but there is more often iron pigment deposited in the lesion.
WEGENER’S GRANULOMATOSIS
Cell morphology
● The stromal cells are spindle-shaped, or may be round or
polygonal. They have pale eosinophilic cytoplasm and
CLINICAL FEATURES
elongated or rounded nuclei. This may manifest itself in the mouth and presents an unusual
● Osteoclast-type giant cells are similar to those of giant cell clinical appearance of exuberant polypoidal vascular lesions,
tumor of bone (contain more than 100 nuclei, have often on the gum mucosa. The lesions have been termed ‘straw-
abundant eosinophilic cytoplasm, and contain berry gums of Wegener’s’.
phagocytosed cells or lipid material).
● Mitotic figures are sparse or absent; however, the presence PATHOLOGICAL FEATURES
of 4 or 5 mitoses per 10 high-power fields (HPF) identifies
lesions that are more likely to recur. The histology shows a polypoidal, ulcerated mucosa which is
● Iron deposition may be found both within stromal and intensely inflamed and with a notable eosinophil infiltrate.
giant cells. Multinucleate giant cells may be present, but they may not
● Other cells that may be seen in the stroma are adopt the usual rather ‘squashed’ nuclei of the giant cells in the
lymphocytes, plasma cells, polymorphs and mast cells. vasculitis. Instead, they may show a more non-specific multi-
nucleate foreign body giant cell appearance. There is not
Differential diagnosis necessarily any vasculitis at this site.
● Cherubism (is a non-neoplastic bone lesion related to the
jaws, occurring in children, predominantly females, has an Differential diagnosis
autosomal dominant inheritance pattern, and affecting the ● Pemphigus (true acantholysis should be seen, and of course
mandible, maxilla or both diffusely and symmetrically. direct immunofluorescence may be required on fresh tissue)
Histologically it may be indistinguishable from giant cell ● Pyostomatitis vegetans of Hallopeau (this is often an oral
tumor of bone or from central giant cell granuloma) manifestation of an underlying inflammatory bowel
● Brown tumor of hyperparathyroidism (clinical investigations disease, especially ulcerative colitis, but it may also be seen
are required to rule out undiagnosed hyperparathyroidism) in Crohn’s disease)
TUMORS OF THE JAW
gradually involute following the completion of tooth

ODONTOGENIC CYSTS AND CYSTIC LESIONS development and eruption. They are further divided into
two major groups:
These are divided into three major categories: A. Developmental cysts
1. Benign cysts of odontogenic origin. These are derived from Dentigerous cyst
residues of odontogenic epithelium which otherwise Eruption cyst
Odontogenic keratocyst
Lateral periodontal cyst
Botryoid odontogenic cyst
Glandular odontogenic cyst
Gingival cyst
B. Inflammatory cysts
Radicular cyst, lateral radicular cyst, residual cyst,
paradental cyst
2. Benign cysts of non-odontogenic origin
Nasopalatine duct cyst
‘Fissural’ cyst
3. Cystic neoplasms
Ameloblastoma
Unicystic ameloblastoma
Calcifying odontogenic cyst
Malignant transformation in jaw cysts is an extremely rare
event, and is most frequently seen in residual cysts, dentigerous
cysts and odontogenic keratocysts. These lesions tend to occur
in older age groups than do benign cysts, and they have a bet-
ter prognosis than other mucosal or intra-osseous carcinomas.
Figure 8.8 Dentigerous cyst.The cystic element is seen on the right.

DENTIGEROUS CYST The epithelium is thin without multilayering and is often columnar, as
opposed to the relatively thick and squamous lining of a radicular cyst.
CLINICAL FEATURES
Dentigerous (follicular) cyst is a developmental odontogenic GINGIVAL CYSTS
cyst that occurs at all ages, and is more common in males. It is
most commonly seen in relation to mandibular third molar, the CLINICAL FEATURES
maxillary canine and third molar, and the mandibular second
molar. It appears radiographically as a well-defined radiolucent Gingival cysts of infants (‘Epstein pearls’) are developmental
area associated with the crown of an unerupted tooth. odontogenic cysts that are usually present at birth and rarely
seen over the age of 3 months. They appear as white or yellow
PATHOLOGICAL FEATURES (Figure 8.8) nodules on the alveolar mucosa.
Gingival cysts of adults are developmental odontogenic cysts
Dentigerous (follicular) cyst is a thin-walled cyst lined by non- that occur in the gingiva or interdental papillae on the facial
keratinizing epithelium of four to ten cells thick, or with a aspect. They are most commonly seen in the canine premolar
cuboidal basal layer. Mucous metaplasia is a frequent occur- region of the mandible, and may be associated with radiologi-
rence, and ciliated cells may be seen. The epithelium becomes cal features of superficial bone erosion.
thicker and more squamous-looking in the presence of inflam-
mation. Keratinization is not a usual feature, but may some- PATHOLOGICAL FEATURES
times be seen. In young patients, the wall is myxoid and
contains islands of inactive odontogenic epithelium. The latter Gingival cysts of infants (‘Epstein pearls’) are small submucosal
may form squamous pearls. cysts lined by stratified squamous epithelium and containing
keratinous material. The basal cells of the cysts are flat.
Secondary features Gingival cysts of adults are lined by epithelium of variable
● Inflammatory changes including polymorphs in the epithelial thickness. In some areas, this is very thin with one to two lay-
lining and lymphoplasmocytic infiltrates in the wall. ers of flattened or cuboidal epithelium, whereas in other areas
● Accumulation of cholesterol clefts, foreign body giant cells it consists of a thick stratified squamous epithelium without
and hemosiderin-laden macrophages. rete ridges. Localized epithelial plaques are seen in the lateral
● Cementicle-like mineralization. region; periodontal cysts may also be seen.
Differential diagnosis INFLAMMATORY ODONTOGENIC CYSTS

● Radicular cyst
● Myxoma
CLINICAL FEATURES
● Odontogenic fibroma
● Odontoma Inflammatory (radicular) cyst is the most common odontogenic
● Ameloblastoma jaw cyst, and is formed from epithelial rests of Malassez.
Residual radicular cyst is the cyst that is retained following LATERAL PERIODONTAL, BOTRYOID, AND
removal of the offending tooth or root.
GLANDULAR CYSTS
Apical and lateral radicular cysts are those that form along-
side a non-vital tooth.
Paradental cyst is an inflammatory cyst lying on the disto- CLINICAL FEATURES
buccal aspect of fully or partially erupted third molar teeth,
Lateral periodontal cyst is a developmental odontogenic cyst
near the bifurcation of the roots, and occurs predominantly in
that is usually unilocular and seen either between the roots or
males. It is commonly associated with a history of pericoronitis,
on the lateral aspect of vital teeth. It is most commonly located
and is associated with vital tooth.
in the premolar area of the mandible and the anterior region of
The mandibular infected buccal cyst is related to paradental
the maxilla, and occurs at all ages.
cyst, but occurs in a younger age group.

All inflammatory odontogenic cysts show similar histological
appearances, namely, a thick-walled cyst lined by variably hyper-
plastic, non-keratinizing squamous epithelium. There may also
be ciliated and mucin-secreting cells. Focal ulceration is com-
mon. The epithelium and the underlying stroma are heavily infil-
trated by mixed inflammatory cells.
In about 10% of cases, elongated, eosinophilic bodies –
Rushton bodies – lie in the inflammatory reaction of the lining.
They may originate as foreign material related to infection or
to hyalinized vessels.
● Secondarily inflamed dentigerous cyst
● Keratocyst
● Ameloblastoma
(b)
(a) (c)
Figure 8.9 (a–e) Odontogenic cyst.The low-power view (a) demonstrates the cystic nature of the lesion.The epithelium surrounds a
central core of keratin.The cyst wall is multilayered, with a bland orthokeratotic surface and content. Odontogenic epithelial islands are set in
a myxoid stroma (d, e).
(one to five cell layers thick) layer of non-keratinizing squamous

or cuboidal epithelium interrupted by frequent presence of focal
thickening in the form of epithelial plaques. These plaques may
be either rounded or flattened, and consist of fusiform or clear
cells. The botryoid and the glandular odontogenic cysts are mul-
tilocular, and in addition the glandular odontogenic cysts show
extensive glandular and ductal structures. The botryoid type has
cushions of squamoid cells in its wall.
● Inflammatory cyst
● Dentigerous cyst
● Keratocyst
ODONTOGENIC KERATOCYST
(PRIMORDIAL CYST)
(d)
CLINICAL FEATURES
Odontogenic keratocyst (primordial cyst) is a developmental
odontogenic cyst that arises in the tooth-bearing areas of the
jaws, especially the mandible. It tends to grow at the expense
of the medullary bone, and extends between the roots of the
teeth. It occurs over a wide age range, and is more common
in males. The lesion appears as a unilocular or multilocular
cyst on radiography. It has a higher recurrence rate due either
to its physical fragility, which may lead to disruption during
surgery and the lining epithelium being left behind, or to the
presence of daughter cysts in the wall that remain after enucle-
ation. Multiple keratocysts can be seen in association with
nevoid basal cell carcinoma and jaw cyst syndrome (Gorlin’s
syndrome).
Odontogenic keratocyst (primordial cyst) is lined by slightly
corrugated keratinized squamous epithelium, and has a thin
fibrous capsule. The basal cells are either columnar or cuboidal.
Islands of epithelium or separate daughter cysts may be seen in
(e)
the fibrous wall. In the presence of inflammation, the capsule
may become thickened and the epithelium acquires rete ridges.
Dysplastic changes of the epithelial lining may sometimes be seen.
This cyst reveals a higher frequency of mitoses than other types
of odontogenic cyst, especially in the cysts seen in Gorlin’s
Botryoid odontogenic cyst is so-called because it resembles syndrome.
a bunch of grapes. It is a multilocular variant of lateral
periodontal cyst that is radiologically multilocular and located in Secondary features
the mandible. It may be associated with a high recurrence rate. ● Inflammation
Glandular (sialo- or mucoepidermoid-) odontogenic cyst has ● Loss of the keratinized cyst lining due to extensive
only recently been recognized as a separate entity. It is radio-
inflammation
graphically multilocular.
● Inflammatory cyst
Lateral periodontal, botryoid and glandular cysts share a simi- ● Dentigerous cyst
lar histological appearance. The cyst is lined by a uniform, thin ● Ameloblastoma
Neoplasms and other lesions related to bone

ODONTOGENIC TUMORS Osteogenic neoplasms
Cemento-ossifying fibroma (cementifying fibroma,
Odontogenic tumors are tooth-forming tumors of the jaw. The ossifying fibroma)
jaws contain many developing or embryonic structures up to the Non-neoplastic bone lesions
age of 25 years. These include odontogenic epithelial rests of Fibrous dysplasia of the jaws
Malassez, with or without their associated mesenchymal anlage, Cemento-osseous-dysplasias
and non-odontogenic structures. Tumors may arise from these Periapical cemental dysplasia (periapical fibrous
structures. Normally, the odontogenic epithelial structures dysplasia)
(enamel organ) have an inductive effect on the surrounding mes- Florid cemento-osseous dysplasia (gigantiform
enchyme – that is, as the epithelium becomes more differentiated cementoma, familial multiple cementomas)
it induces the adjacent mesenchyme to become more specialized Other cemento-osseous dysplasias
and able to produce a matrix which eventually becomes calcified Cherubism (familial multilocular cystic disease of the jaws)
(dentin). The calcified matrix (dentin) then influences the origi- Central giant cell granuloma
nal odontogenic epithelium to elaborate a matrix which becomes Aneurysmal bone cyst
mineralized enamel. According to this process of odontogenesis, Solitary bone cyst (traumatic, simple, hemorrhagic bone
there are three categories of odontogenic tumors: (i) epithelial cyst)
with little or no mesenchymal induction; (ii) epithelial with sig- Other tumors
nificant mesenchymal induction; and (iii) mesenchymal with or Melanotic neuroectodermal tumor of infancy (melanotic
without included odontogenic epithelium. This has been taken progonoma)
into consideration in the revised WHO (Second Edition 1992)
classification of odontogenic tumors:
ADENOMATOID ODONTOGENIC TUMOR
Benign tumors
(ADENOAMELOBLASTOMA)
Odontogenic epithelium without odontogenic ectomesenchyme
Ameloblastoma
Squamous odontogenic tumor CLINICAL FEATURES
Calcifying epithelial odontogenic tumor (Pindborg
Adenomatoid odontogenic tumor is classified under ameloblastic
tumor)
fibroma and related conditions – that is, lesions consisting of
Clear cell odontogenic tumor
odontogenic epithelium and ectomesenchyme showing varying
Odontogenic epithelium with odontogenic ectomesenchyme,
degrees of inductive changes. It is a slowly growing, expansile
with or without dental hard tissue formation
benign lesion that erodes – but does not invade – the surround-
Ameloblastic fibroma
ing bone. Arising from the pre-ameloblast or inner enamel
Ameloblastic fibrodentinoma (dentinoma) and ameloblas-
epithelium, this tumor is most commonly seen in females during
tic fibro-odontoma
the second decade of life. Occurring in both the upper and lower
Odontoameloblastoma
jaws, it is often associated with an absent canine tooth, and
Adenomatoid odontogenic tumor
appears radiographically as a cystic lesion. It does not usually
Calcifying odontogenic cyst
recur following enucleation.
Complex odontoma
Compound odontoma
Odontogenic ectomesenchyme with or without included PATHOLOGICAL FEATURES
odontogenic epithelium The lesion is characteristically cystic, with focal solid areas
Odontogenic fibroma surrounded by a loosely arranged fibrous tissue capsule. The
Myxoma (odontogenic myxoma, myxofibroma) odontogenic epithelium consists of tubules, duct-like elements
Benign cementoblastoma (cementoblastoma, true and islands that may have an invaginated or inverted appear-
cementoma) ance. The tubular structures are either empty or contain a layer
Malignant tumors of eosinophilic hyaline substance. There is also solid tissue con-
Odontogenic carcinomas taining glands, tubules, rosettes with tiny lumina, or sometimes
Malignant ameloblastoma cells arranged in a cribriform pattern. Areas of spindle cells
Primary intraosseous carcinoma arranged in whorls or streams may also be seen.
Malignant variants of other odontogenic epithelial The stroma shows varying amounts of acidophilic hyalinized
tumors tissue (dysplastic dentine) often containing entrapped epithelial
Malignant changes in odontogenic cysts tissue. Enamel matrix, amyloid-like material and calcification
Odontogenic sarcomas may be seen.
Ameloblastic fibrosarcoma (ameloblastic sarcoma)
Ameloblastic fibrodentinosarcoma and ameloblastic Secondary features
fibro-odontosarcoma ● Calcifying bodies
Odontogenic carcinosarcoma ● Cystic degeneration
Cell morphology PATHOLOGICAL FEATURES

● The cells lining the tubular or glandular structures are Ameloblastic fibroma is usually encapsulated and consists of
cuboidal or tall columnar, with their nuclei polarized away long, slender, branching strands, islands or cords of uniform
from the basement membrane. epithelial cells set in an abundant cellular fibroblastic mes-
enchymal background.
Ameloblastic fibrodentinoma (dentinoma) is similar to
ameloblastic fibroma, but in addition shows dentine forma-
● Odontogenic cyst tion. The latter is seen as islands of dysplastic and poorly
formed mineralized dentine. Entrapped epithelial or mesenchy-
Special techniques mal cells may be seen within the dentine.
Ameloblastic fibro-odontoma is similar to ameloblastic
● Odontogenic epithelium is CK14-positive. fibromodentinoma, but in addition shows enamel formation.
● CK13 and CK19 label squamous differentiation or Odontoameloblastoma is similar to ameloblastoma, but in
epithelial cells near the surface epithelium, and CK7 shows addition shows ectomesenchyme similar to that seen in
variable expression. ameloblastic fibroma, and dentine and enamel similar to those
seen in ameloblastic fibrodentinoma and ameloblastic
odontoma.
AMELOBLASTIC FIBROMA AND RELATED Adenomatoid odontogenic tumor (see Adenomatoid odonto-
LESIONS genic tumor, p. 583).
Calcifying odontogenic cyst is a cystic lesion lined by epithe-
lium showing columnar basal cells and upper layers resembling
CLINICAL FEATURES stellate reticulum, but including ghost cells (cells showing loss
of nuclear basophilia but retention of outline; shadow cells)
Ameloblastic fibroma and related lesions are uncommon lesions
lying individually and in small groups. The ghost cells (kera-
consisting of a disorderly mixture of odontogenic epithelium and
tinizing cells) may become calcified.
odontogenic ectomesenchyme. Some are developmental anom-
Dysplastic dentine may be laid adjacent to the basal layer of
alies (see Complex and compound odontomas, p. 591), while
the epithelium.
others are benign neoplasms. These lesions usually occur in the
Occasionally, extensive dental hard tissue is seen that resem-
younger age group.
bles complex or compound odontoma.
Amelobastic fibroma is often seen as a cyst on X-radiography
On occasion, areas indistinguishable from ameloblastoma
in the mandible, and can be associated with an unerupted tooth.
are seen in association with calcifying odontogenic cyst. Such
It rarely recurs, and is usually cured by simple curettage.
lesions are sometimes termed ‘odentinogenic ghost cell tumor’ or
Ameloblastic fibrodentinoma appears radiologically as a well-
‘odontogenic ghost cell tumor’.
defined radiolucency containing varying amounts of radio-
Complex odontoma (see Odontogenic tumors: Odontoma,
opaque material. It is mostly seen within bone, but a few are seen
p. 591).
outside bone.
Compound odontoma (see Odontogenic tumors: Odontoma,
Ameloblastic fibro-odontoma appears radiologically as a well-
p. 591).
defined radiolucency containing varying amounts of radio-
opaque material.
Odontoameloblastoma is a very rare tumor that produces Secondary features
radiolucency with mineralized tissue. ● Juxtaepithelial or occasionally more diffuse
Adenomatoid odontogenic tumor (see p. 583). hyalinization.
Calcifying odontogenic cyst is most commonly found
during the second decade of life. It affects both the mandible
and maxilla, and may occur in the soft tissues of the Cell morphology
tooth-bearing area. Radiologically, it appears as a well-defined ● The main epithelial cell populations are cuboidal
radiolucency containing a varying amount of radio-opaque cells of odontogenic origin, mostly arranged in double
material. layers.
‘Odentinogenic ghost cell tumor’ or ‘odontogenic ghost cell ● Granular epithelial cells may sometimes be seen
tumor’ occurs in older patients, and may have an infiltrative (Granular cell ameloblastic fibroma).
growth pattern. ● The mesenchymal cells may be spindle-shaped, stellate
Complex odontoma (see Odontogenic tumors: Odontomas, or polygonal.
p. 591). ● Rarely, the stromal cells show atypia and increased
Compound odontoma (see Odontogenic tumors: Odontomas, mitoses. Such tumors behave more aggressively.
p. 591).
Ameloblastic fibrosarcoma is usually painful, and is charac-
terized by frequent local recurrences. It may cause death due to Differential diagnosis
extensive local disease. ● Ameloblastoma
Special techniques ameloblastic columnar cells which show reverse polarity, with
● Odontogenic epithelium is CK14-positive. a subnuclear space or vacuole. They may be arranged in the
● CK13 and CK19 label squamous differentiation or form of elongated or rounded masses (follicular ameloblas-
epithelial cells near the surface epithelium, and CK7 toma), or in anastomosing cords, compact alveoli and in broad
shows variable expression. or narrow convoluted columns (plexiform ameloblastoma).
Although the stromal component is generally in excess of the
epithelial element, this varies considerably from tumor to
AMELOBLASTOMA tumor, and from area to area within the same tumor. The stro-
mal component may be cellular or may be hyalinized or it may
CLINICAL FEATURES be very vascular, thereby conferring a hemangiomatous appear-
ance to the lesion (vascular ameloblastoma). Ameloblastoma
Ameloblastoma is an uncommon, benign but locally invasive typically extends through cancellous bone.
tumor of proliferating odontogenic epithelial origin that usu-
ally occurs as intraosseous growth arising from remnants of
odontogenic epithelium. As the tumor enlarges, it may fuse
with the overlying oral epithelium. It may sometimes arise from
the surface epithelium or from residues of odontogenic epithe-
lium lying outside the bone (peripheral ameloblastoma), but
may also arises from the lining of a dentigerous cyst. Most
commonly affecting individuals in their thirties or forties, the
tumor occurs in the mandible in the majority of cases. Typically
producing a multilocular destruction of bone on X-radiography
(unilocular lesion can also be seen), the lesion has invasive
properties and a tendency for local recurrence. These tumors
rarely metastasize. Unicystic ameloblastoma, peripheral
ameloblastoma and possibly desmoplastic ameloblastoma have
lower recurrence rates than other types of ameloblastoma.

Ameloblastoma is characterized by the presence of an epithelial
element sharply demarcated from the surrounded connective
tissue stroma. The epithelial structures are composed of cen-
trally placed, stellate cells confined within a belt or a layer of
(b)
(a) (c)
Figure 8.10 (a–c) Ameloblastoma. Complex invaginations of epithelium with peripheral palisading. Reverse polarity wherein the nucleus
is located at the apex of the cell with a subnuclear space.
Keratoameloblastoma is characterized by the presence of exten-

sive keratinization, sometimes with cystic lumina containing
keratinous material. Occasionally, it shows micropapillary
luminal projections without distinct keratinization (papillifer-
ous keratoameloblastoma).
Secondary features
● Cystic or microcystic degeneration within the stellate cell
areas and in the foci of squamous metaplasia.
● Collections of osteoclast-like giant cells are often seen at
the infiltrating edge of the tumor.
● Hemorrhage.
● Eosinophilic or granular material may be seen within the
pseudoglandular and cystic spaces.
● Calcification may rarely be seen in the areas of squamous
metaplasia with keratinization.
● Osteoid metaplasia (dentine-like tissue) is occasionally seen
in direct contact with the columnar epithelial cells.
● Granular cell change.
(a)
Cell morphology
● The stellate cells are small fusiform or polyhedral with
long, anastomosing delicate cytoplasmic processes. They
are usually disposed as a loose network resembling the
stellate reticulum of the developing tooth buds. They may
exhibit squamous metaplasia, squamous pearl formation
(acanthomatous type) and pseudoglandular or cystic
spaces. Mucinous metaplasia may rarely be seen within the
squamous metaplastic element (mucoepidermoid pattern),
or within the cystic spaces. The stellate cells may also take
the form of spindle cell fascicles that commonly lack a
surrounding layer of columnar epithelium, or in the form
of small whorls and compact alveoli or may have a
plexiform pattern (long ramifying cords or branching
(b)
processes present in an abundant stroma).
Figure 8.11 (a, b) Plexiform ameloblastoma. Stellate and strand-
● The columnar ameloblastic cells are tall, with clear or
like epithelial cords lie in a myxoid stroma, but here the epithelium granular cytoplasm and hyperchromatic nuclei that are
is very pronounced. Both complex and reverse polarity are seen. polarized away from the basement membrane and may
A higher magnification view (b) demonstrates the plexiform exhibit mitotic figures.
architecture and the reverse polarity. ● Transitional flattened and polygonal cells are seen at the
junction between the stellate and the columnar cell areas.
Other histological variants of ameloblastoma ● Clear cell change. This may be seen, usually focally, but
Unicystic ameloblastoma consists predominantly of a cyst lined extensive clear cell change is associated with a more
by a thin, odontogenic epithelial layer. However on closer exam- infiltrative behavior.
ination one may see either focal transformation of the cyst-lining ● Granular cells reminiscent of those of granular cell tumors
epithelium into cuboidal or columnar basal cells with palisading, may sometimes be seen focally or extensively within the
subnuclear vacuolation and subepithelial hyalinization. Alterna- tumor (granular cell variant of ameloblastoma).
tively, there may be a localized nodule of plexiform ameloblas-
toma projecting within the lumen of the cyst (plexiform unicystic Differential diagnosis
ameloblastoma). The third type is the presence of a mural nod- ● Ameloblastic fibroma (plexiform variety of ameloblastoma)
ule of plexiform or follicular ameloblastoma. ● Basal cell carcinoma (especially in those arising from the
Desmoplastic ameloblastoma is a variant of ameloblastoma surface mucosa)
which exhibits dense stromal fibrosis. Small nests or strands of ● Ameloblastoid hyperplasia in odontogenic cyst (from
odontogenic epithelium are usually seen entrapped within the ameloblastoma arising within odontogenic cyst and from
stroma. cystic ameloblastoma)
Basal cell ameloblastoma is characterized by the presence ● Intraosseous squamous cell carcinoma (from ameloblastic
of basaloid nests. This type should be distinguished from carcinoma with extensive squamous metaplasia or from a
intraosseous adenoid cystic carcinoma. metastasis)
Special techniques Special techniques

● Odontogenic epithelium is CK14-positive. ● The amyloid-like material is Congo red-positive.
● CK13 and CK19 label squamous differentiation or ● Odontogenic epithelium is CK14-positive.
epithelial cells near the surface epithelium, and CK7 shows ● CK13 and CK19 label squamous differentiation or
variable expression. epithelial cells near the surface epithelium, and CK7 shows
variable expression.
CALCIFYING EPITHELIAL ODONTOGENIC TUMOR

(PINDBORG’S TUMOR) CEMENTOMA (CEMENTOBLASTOMA, GIGANTIFORM
CEMENTOMA, PERIAPICAL CEMENTAL DYSPLASIA
CLINICAL FEATURES AND CEMENTIFYING FIBROMA)
Calcifying odontogenic tumor is a benign but locally infiltrative
tumor, probably arising from residues of dental lamina or from CLINICAL FEATURES
the rests of Malassez. It is usually intraosseous, but peripheral
or extraosseous variants may also be seen. The tumor affects Cementoblastoma (true cementoma) is currently classified
patients in their fifth and sixth decade, and is usually situated under tumors of odontogenic ectomesenchyme with or without
within bone, in the premolar and molar areas, and also within included odontogenic epithelium, and is a relatively common
the mandible. It presents as a slowly enlarging painless mass lesion. It occurs in connection with premolar and molar teeth,
that is usually related to the crown of an unerupted tooth. and is more commonly seen in the mandible. It occurs more
However, it may also arise in extraosseous locations, for exam- frequently in males than in females, often under the age of
ple in the anterior region of the jaw. X-radiography often shows 20 years. The tumor is usually asymptomatic, but it may be
intralesional calcification. multiple and cause a well-defined radio-opacity involving the
root with a peripheral radiolucent zone. Treatment is by enu-
cleation or removal of the lesion with the involved tooth.
Florid cemento-osseous dysplasia (gigantiform cementoma;
This lesion consists of polyhedral epithelial cells arranged in familial multiple cementoma) is classified under cemento-
sheets and strands, or more rarely glandular or acinic patterns osseous dysplasias (a type of non-neoplastic bone lesion char-
and present within a fibrous stroma. Characteristic amyloid- acterized histologically by the presence of cementum-like
like material is usually present in the stroma, and occasionally dysplastic rather than neoplastic tissue). As the name suggests,
amongst the epithelial cells and within their cytoplasm. A dis- the lesion may grow to a large size, and is characteristically
tinct feature is the presence of various stages of psammomatous multiple. It occurs most commonly in adult females, and if
microcalcification which coalesce to form large calcific masses. untreated may cause considerable deformity.
Peripheral lesions may look less active than the intraosseous Periapical cemental dysplasia is classified under cemento-
tumors. osseous dysplasia (a type of non-neoplastic bone lesion), and is
Some tumors have a mixed pattern of calcifying odontogenic multiple in the majority of cases. The lesion occurs at the apices
tumor and adenomatoid odontogenic tumor. of the mandibular incisor teeth, and occasionally in those of the
maxilla. It most commonly affects middle-aged women, and is
Secondary features usually asymptomatic. It is detected radiologically as a localized
● Calcification radiolucent area in the bone at the apex of a tooth. This tumor
differs from fibrous dysplasia by being symptomless, and does
Cell morphology not enlarge sufficiently to cause enlargement of the jaw.
Cementifying fibroma is classified under osteogenic neo-
● Small epithelial cells.
plasms and is similar to periapical cemental dysplasia except
● Larger polyhedral myoepithelial cells with hyperchromatic,
for being solitary, lacking female predominance, and affecting
often eccentric nuclei.
premolar or molar regions.
● Intercellular bridges can be seen.
● Multinucleated cells are occasionally present.
● Moderate cellular pleomorphism. PATHOLOGICAL FEATURES (Figure 8.12)
● Clear cell change has been reported. Cementoblastoma is a lesion which is reminiscent of osteoma or
osteoblastoma, but arises in relation to a tooth. Continuity of the
Differential diagnosis lesion with the tooth root is often seen, both grossly and micro-
● Calcifying epithelial odontogenic tumor is so distinct that scopically. The lesion consists of a mass of calcified cementum/
differentiation from other odontogenic tumors is not a osteoid-like tissue containing numerous deeply stained reversal
problem lines and a vascular connective tissue component that may
● Other maxillary or mandibular lesions forming similar contain osteoclasts and osteoblast-like cells. Zones of actively
multiple foci of microcalcification are cementifying growing uncalcified tissue containing numerous osteoblast-like
fibroma and calcifying odontogenic cyst cells are often seen at the periphery of the lesion.
(a) (b)
Figure 8.12 (a, b) Cementoblastoma. Calcified cementum/osteoid-like tissue containing numerous deeply stained reversal lines and a
vascular connective tissue component that may contain osteoclasts and osteoblast-like cells.
Florid cemento-osseous dysplasia (gigantiform cementoma; intraosseous, and appears radiographically as a radiolucent
familial multiple cementomas) is characterized by the presence lesion with a poorly defined margin. It is usually more locally
of lobulated masses of dense, highly calcified acellular cemen- aggressive than ameloblastoma, and often recurs after many years.
tum. This may be seen in continuity with the normal cementum
seen at the root of the tooth. The spaces between the masses
of cementum often contain necrotic material, but may contain PATHOLOGICAL FEATURES (Figure 8.13)
fibrous tissue. In the lesion’s early stages, fibroblastic areas Clear cell odontogenic tumor consists of closely packed nests,
indistinguishable from cementifying fibroma may be present. strands or sheets of clear cells surrounded by mature collage-
Periapical cemental dysplasia and cementifying fibroma both nous stroma.
have similar histological appearances. There is vascular fibro-
blastic connective tissue containing spherical or irregularly
Cell morphology
shaped masses of calcified cementum. As the lesion ages, the
masses of cementum increase in size and tend to fuse. ● The cells are polygonal or round with clear to finely
stippled eosinophilic cytoplasm and distinct cell borders.
Cell morphology
● The nuclei are centrally located with minor variation
in size.
● Osteoblast-like cells.
● Osteoclast-like cells.
● A mild degree of cellular pleomorphism may be present.
● Mitotic figures are usually absent. ● Clear cell tumor of salivary gland origin (clear cell variant
of mucoepidermoid carcinoma, clear cell variant of
Differential diagnosis myoepithelioma, clear cell carcinoma, glycogen-rich
adenoma)
● Cementoblastoma is reminiscent of osteoblastoma ● Metastatic clear cell carcinoma
● Periapical cemental dysplasia and cementifying fibroma are
reminiscent of fibrous dysplasia
Special techniques
● The cells are PAS-positive (contain glycogen); this is
CLEAR CELL ODONTOGENIC TUMOR especially demonstrated in frozen-section material.
● Alcian blue shows no evidence of mucin secretion.
● Enzyme histochemical studies demonstrate
CLINICAL FEATURES
dehydrogenase, non-specific esterase, and acid phosphatase
Clear cell odontogenic tumor is a rare benign, but locally inva- activities.
sive, tumor of the jaw, probably arising from residues of dental ● Immunohistochemically, tumor cells react positively to
lamina or from the rests of Malassez. The lesion is usually CK19, EMA and S-100 protein.
(a)
(a)
(b)
Figure 8.14 (a–d) Carcinosarcoma.The predominantly spindle cell

area is clearly pleomorphic, with mitotic figures (encircled in b).
Some cohesive areas reflect the epithelial element (c, d).
Immunohistochemistry reveals cytokeratins not only in the epithelial
islands but also on occasion in the spindle cells. On other occasions
there may be a differentiated component in the spindle cells
(b) (e.g., toward rhabdomyosarcoma).
Figure 8.13 (a, b) Clear cell odontogenic tumor.Within a vascular

stroma there lie islands of epithelial cells which have a clear cytoplasm.
The peripheral cells appear to show subnuclear vacuolation, and the odontogenic epithelium (primary intraosseous carcinoma), or
differential diagnosis would include an ameloblastoma. from the epithelial lining of odontogenic cysts.

MALIGNANT ODONTOGENIC TUMORS: If there are recognizable areas of benign ameloblastoma, then
ODONTOGENIC CARCINOMAS AND SARCOMAS the term ‘malignant ameloblastoma’ may be used, whilst those
lesions exhibiting widespread atypia, pleomorphism, mitoses,
necrosis, etc. are termed ‘ameloblastic carcinoma’. This is an
CLINICAL FEATURES
arbitrary distinction, however.
Malignant odontogenic tumors are very rare tumors that are Ameloblastic carcinoma is an ameloblastoma which exhibits
locally invasive and destructive. They may metastasize distantly. malignant cytological features. Such a tumor may exhibit exten-
Odontogenic carcinomas may arise through malignant trans- sive squamous metaplasia that can be mistaken for intraosseous
formation of an ameloblastoma, directly from residues of squamous cell carcinoma.
atypia and increased cellularity of the mesenchymal cells and

diminution of the epithelial component.
Ameloblastic fibrodentinosarcoma and ameloblastic fibro-
odontosarcoma are similar to ameloblastic fibrosarcoma, but in
which a small amount of dysplastic dentin or enamel is present,
respectively.
Odontogenic carcinosarcoma (a very rare tumor) is similar to
ameloblastic fibrosarcoma, but with the epithelial component
also exhibiting malignant features.
● Intraosseous mucoepidermoid salivary gland carcinoma
● Carcinosarcoma
● Metastatic carcinomas
ODONTOGENIC FIBROMA
CLINICAL FEATURES
(c) Odontogenic fibroma is a rare tumor that is mostly seen within
bone, although peripheral lesions may also occur known as
‘peripheral odontogenic fibroma’.
Odontogenic fibroma consists predominantly of fibroblastic
stroma containing variable amounts of inactive odontogenic
epithelium. Islands of dysplastic cementum or bone may also
be seen.
Granular cell change may be seen in the fibrous component,
‘granular cell odontogenic tumor’.
● Ameloblastic fibroma
● Odontogenic gingival epithelial hamartoma (is a distinctive
gingival, non-neoplastic lesion consisting of mature fibrous
tissue containing strands and islands of epithelium that
may show squamous features)
ODONTOGENIC MYXOMA (MYXOFIBROMA)

(d)
CLINICAL FEATURES
Odontogenic myxoma is a locally invasive tumor that may grow
rapidly and often extends into the bone and soft tissue, with little
Primary intraosseous carcinoma is a squamous carcinoma aris-
evidence of encapsulation. It commonly shows multiple, variably
ing within the jaws. It may be indistinguishable from squamous
sized radiolucent areas with bony septa producing a ‘soap-bubble’
carcinoma of the oral cavity, or it may have a distinctly odonto-
appearance. It recurs frequently, and is difficult to remove.
genic pattern with basaloid cells arranged in an alveolar or plex-
iform pattern, together with palisading of the peripheral cells.
Squamous metaplasia or keratinization reminiscent of an acan-
thomatous ameloblastoma may be seen. Odontogenic myxoma is similar to myxoma seen elsewhere,
Malignant changes in odontogenic cysts (a rare event) show and shows stellate, rounded or angular cells scattered within
features of benign odontogenic cysts associated with frankly an abundant myxoid stroma. Islands or strands of inactive
malignant epithelium with or without adjacent epithelial odontogenic epithelium surrounded by a zone of hyalinization
dysplasia. may occasionally be seen within some myxomas.
Ameloblastic fibrosarcoma (ameloblastic sarcoma) is similar to Some myxomas contain varying amounts of hyaline bands,
ameloblastic fibroma, but with increasing degrees of cytological ‘odontogenic fibromyxoma’.
(a) (c)
Complex odontoma is a malformation in which all the den-

tal tissues are represented in a disorderly pattern. It is most
commonly seen in the premolar or molar areas of the mandible,
in female patients during the first two decades of life. Radio-
logically, the tumor appears as a well-defined radiolucency with
progressive deposition of radio-opaque material. It usually has
a self-limiting growth; however, the lesion may recur if incom-
pletely excised at its early stages of development.
Compound odontoma is a malformation in which all the
dental tissues are represented in a more orderly pattern than in
the complex odontoma. This tumor is seen more often in the
maxilla and the anterior region of jaw.
Complex odontoma shows no actual tooth formation, but a dis-
ordered picture of dental tissues. At an early stage the lesion may
resemble ameloblastic fibroma or fibro-odontoma. Entrapped
(b) residues of odontogenic epithelium may still be seen at later stages.
Compound odontoma consists of masses of misshapen teeth,
Figure 8.15 (a–c) Odontogenic myxoma.The myxoid areas can in each of which enamel, dentine, cementum and pulp may be
be very pronounced, with minimal epithelium.The differential seen, arranged as in a normal tooth.
diagnosis would then include a myxoma.
SQUAMOUS ODONTOGENIC TUMOR

● A thickened follicle surrounding an unerupted tooth CLINICAL FEATURES
Squamous odontogenic tumor is a tumor of the jaw that is
ODONTOMAS thought to originate from remnants of dental lamina, and is of
more uncertain biological behavior. Radiographically, the tumor
appears as a well-circumscribed radiolucent lesion with a scle-
CLINICAL FEATURES
rotic margin. It presents as a painless swelling, with loosening
Odontomas are odontogenic tumors that produce calcified parts of the teeth, and may also appear as multiple discrete lesions.
of teeth, occur in the alveolar ridge of mandible and maxilla and The lesion occurs in a wide age range, and is mostly located in
have, rarely, been reported in the middle ear. the anterior maxilla and posterior mandible. Although it may
behave favorably when seen in association with an odontogenic Cell morphology

cyst, it behaves aggressively when it extends into and destroys ● The cells forming the nests are mature squamous cells.
bone, and when it extends into soft tissue.
PATHOLOGICAL FEATURES ● A well-differentiated squamous cell carcinoma
The lesion consists of islands of mature squamous epithelium ● Acanthomatous ameloblastoma (this usually shows
present within a collagenous or cellular connective tissue. peripheral palisading of cells)
Squamous pearl formation may be seen within the nests. ● Verrucous carcinoma
● Keratoacanthoma
Secondary features
● Microcystic degeneration. Special techniques
● Calcification within the squamous nests. ● The cells express epithelial markers.
TUMORS OF THE SALIVARY GLANDS
GENERAL CONSIDERATIONS the myxoid stroma is best seen in Giemsa preparations. The
plasmacytoid or hyaline cell variant of the myoepithelial cell is
easily recognized, but is in fact less often seen as it is more com-
HISTOLOGICAL CLASSIFICATION OF SALIVARY GLAND mon in tumors of minor salivary glands which are less frequently
TUMORS subject to aspiration.
The present authors recommend that, where possible, the
Pleomorphic salivary adenoma (PSA) (syn. mixed parotid tumor)
aspirate is submitted in a medium (various commercial forms
Monomorphic adenoma
are available, for example Autocyte™), after which smears,
Warthin’s tumor (adenolymphoma) cytospins and cell blocks can be prepared. The latter may pro-
Basal cell adenoma vide the diagnostically helpful architecture, and both it and the
Canalicular adenoma cytospin may be subject to histochemistry and immunohisto-
Myoepithelioma chemistry examination.
Oncocytoma Most malignant neoplasms will lack the stromal component,
Mucoepidermoid carcinoma though an adenoid cystic carcinoma may have a hyaline matrix.
Acinic cell carcinoma However, if present, it is closely admixed with the epithelial cells,
Adenoid cystic carcinoma and in general the aspirate will be more cellular. The PSA more
Polymorphous low-grade adenocarcinoma often shows segregation of epithelium from stromal elements.
Epithelial-myoepithelial carcinoma of the salivary gland Oncocytic tumors have a characteristic epithelial appearance
Hyalinizing clear cell carcinoma of the salivary gland and, when of Warthin’s type, have a helpful lymphoid admix-
Basal cell adenocarcinoma ture. Inflammatory change in the wall and lumen can result
Malignant myoepithelioma in squamous metaplasia and inflammatory-associated atypia.
Carcinoma in a pleomorphic adenoma Failure to recognize clinically that the lesion is salivary and not
Small cell undifferentiated carcinoma nodal can supplement this cytological concern with a conse-
Undifferentiated carcinoma quential erroneous diagnosis of metastatic squamous carci-
Salivary duct carcinoma noma. The background oncocytic cells should be sought.
Squamous carcinoma Careful appraisal will usually reveal that the squamous com-
Malignant lymphoma ponent is highly degenerate, and that its atypia is insufficient
Capillary hemangioma for a diagnosis of metastatic carcinoma. A cautious report will
then result in local excision and prevent the inappropriate
alternative management decision of radiotherapy and/or radi-
THE ROLE OF THE FINE NEEDLE ASPIRATE
cal neck dissection.
Fine needle aspiration cytology is valuable in the management The lymphoid component consists of scattered, single mature
of a salivary gland swelling. Its main value lies in the relative lymphocytes. However, lymphoid tangles – crushed cell aggregates
ease of recognition of a pleomorphic salivary adenoma with its and foci showing variable nuclear size with blast forms – may
protean components. The admixture of epithelial cells, forming occur when material from the germinal centers is aspirated.
ductular units and a myoepithelial element usually recognized by If the epithelial cellularity is high and the lymphoid compo-
a relatively elongated morphology and oval nuclei with smooth nent low, then the differential diagnosis will include oncocytic
contours and a variable admixture of the myoepithelial stromal elements of a pleomorphic adenoma, solid oncocytoma or mul-
product, comprise diagnostic features. The metachromasia of tifocal oncocytosis. As these all fall into the spectrum of benign
salivary tumors, there will be no adverse influence on manage- adenoma is sometimes associated with cylindroma of the skin,
ment. Mucinous metaplasia and squamous metaplasia may and has an increased risk of malignant transformation. The
occur in Warthin’s tumors and, with their bland appearance, presence of myoepithelial cells in a basal cell adenoma sug-
may suggest mucoepidermoid carcinoma. If the epithelial pop- gests a close relationship between this tumor and pleomorphic
ulation is poor, then the granularity may be mistaken for the adenoma.
zymogen granules of an acinic cell carcinoma. Parotidectomy
would ensue in all cases but, for the two low-grade malignan-
cies mentioned, there might be a case for intraoperative frozen PATHOLOGICAL FEATURES (Figure 8.16 and 8.17)
section to confirm a benign tumor when superficial parotidec- Basal cell adenoma is most often located in the parotid gland.
tomy will suffice. Non-neoplastic lesions such as lympho- It is a well-circumscribed tumor that is characterized by the
epithelial cysts and intra- or para-parotid branchial cysts may presence of a monomorphic population of basaloid cells arranged
produce mimicry, but in these cases the squamous element pre- in ribbons, trabeculae, tubules, canaliculae, or in solid nests (as
dominates and the ‘dirty’ luminal content contains a greater seen in basal cell carcinoma). These epithelial structures often
acute inflammatory component. display palisading of the peripheral cell layer. Basosquamous
The diagnosis and classification of malignant salivary gland whorling may also be seen. The stroma is usually fibrotic
tumors presents a greater challenge. or hyalinized; occasionally, the stroma is focally loose, which
A poorly differentiated adenocarcinoma may be diagnosed imparts an ameloblastomatous appearance to the tumor. Mitotic
on the basis of its evidently malignant nature. This contrasts figures are rare or absent.
with the sub-types of special tumors and thus, from a practical
aspect, it may suffice to distinguish benign from malignant
and, in the malignant category, epithelial from lymphoid. The
identification of acinic cell carcinoma is dependent on recog-
nizing the zymogen-rich cytoplasm. If unstained material is
available, its diastase-resistant, PAS staining is demonstrable
and immunohistochemistry will allow localization of ␣-amy-
lase. The predominant cell population should show these fea-
tures; it is not enough to recognize an occasional acinic cell as
the aspirate may contain normal salivary acini.
It may be possible to demonstrate the three cell types of a
muco-epidermoid carcinoma – goblet, intermediate, and squa-
mous cells. The implications for prognosis relate to the squa-
mous element and progressive pleomorphism, and these two
features may be recognized on fine needle aspiration, again
emphasizing that management decisions and prognosis may be
furthered by cytology despite a lack of precise sub-classification.
An adenoid cystic carcinoma presents a challenge of recognition, (a)
but cohesive groups of uniform cells with a high nuclear:cyto-
plasm ratio without obvious duct formation, cell vacuolation or
keratinization may permit recognition. It is from PSA rather than
from another malignancy that the tumor is most difficult to dis-
tinguish, and in this regard immunohistochemistry plays little
role, with both tumors retaining a myoepithelial component
with S-100 protein expression. The polymorphism and myxoid
stroma of the PSA are the main distinguishing features.
BASAL, MEMBRANOUS, CANALICULAR,

TRABECULAR, SEBACEOUS AND TUBULAR (b)
MONOMORPHIC ADENOMAS
Figure 8.16 (a–c) Basal cell adenoma. A complex architecture
which may resemble an adenoid cystic lesion, but there is less
CLINICAL FEATURES stroma and less retraction.The cells are uniformly small in size,
with some hyalinized matrix around them.The nuclei appear
These tumors occur most often in the parotid or minor salivary larger and open, with small nucleoli, in contrast to adenoid cystic
glands of middle-aged or elderly individuals. Membranous carcinoma.
Hybrid basal cell adenoma is characterized by the presence

within basal cell adenomas of areas suggesting adenoid cystic
carcinoma or mixed salivary adenoma.
Canalicular adenoma (usually seen in the upper lip) has a
characteristic morphology of anastomosing bi-layered strands
of dark cells set in a loose vascular stroma containing small
capillaries and venules and occasionally microcystic areas.
Sebaceous adenoma is characterized by the presence of seba-
ceous glandular epithelium present in a background of fibrous
and lymphoid stroma. Small squamous cysts can be seen.
Tubular adenoma is reminiscent of tubular adenoma of the
breast, characterized by crowded tubules of basaloid cells.
(c) For Basal cell adenoma:
Figure 8.16 (Continued). ● Adenoid cystic carcinoma – infiltrative edges; perineural

invasion
● Pleomorphic salivary adenoma – this has an acinar
component (i.e., glandular differentiation), but it is, to
some extent, an arbitrary distinction
● Ameloblastoma – shows reverse polarity and stellate
reticulum
Special techniques
● Carcinoembryonic antigen (CEA) and EMA are expressed
in apical portions of luminal cells, in luminal secretions,
and in the duct lining cells.
● Cytokeratin is expressed in all epithelial cells.
● S-100 protein is strongly expressed in stromal cells and in
some of the basaloid cells.
● Vimentin stains the stromal cells and the outer layer of the
(a) epithelial cells.
● Canalicular adenomas stain in a similar fashion showing
positive staining with anti-keratin, anti-vimentin, and
anti-S-100 protein, and rarely focal staining with anti-
EMA and anti-GFAP is noted.
● It has been shown recently that basal and canalicular
adenomas have a distinct immunoprofile for both
neoplasms. Tubular areas of basal adenoma express CK7,
CK8, CK14 and CK19 in luminal cells, and vimentin
in non-luminal cells; the solid areas of basal cell
adenomas do not stain for any of these antibodies.
By contrast, canalicular adenomas strongly expressed CK7
and CK13.
MYOEPITHELIOMA
(b)
CLINICAL FEATURES
Figure 8.17 (a, b) Tubular adenoma. A tubular architecture is
evident.This tubular form occurs in minor salivary glands, and may Myoepithelioma is a rare tumor composed entirely of neoplas-
mimic a pleomorphic adenoma, though both are benign. tic myoepithelial cells that has recently been accepted as a sep-
arate entity (it is regarded by many as a monomorphic variant
Membranous adenomas (dermal analogue tumor) is a vari- of pleomorphic adenoma). This tumor is clinically indistin-
ant of basal cell adenoma, and exhibits excessive intercellular guishable from pleomorphic salivary adenoma, and may occur
hyaline and basement membrane-like material reminiscent of in the major salivary glands or in the palate or oral cavity of
skin appendage tumors (typically cylindromas). younger individuals.
PATHOLOGICAL FEATURES (Figures 8.18–8.21) Differential diagnosis

Myoepithelioma may have a variety of histological appear- ● Spindle cell carcinoma
ances. The tumor should be graded if mitoses and pleomor- ● Plasmacytoma
phism are seen. ● Synovial sarcoma
Spindle cell variant consists predominantly of spindle cells ● Hyalinizing clear cell carcinoma of minor salivary gland
arranged in solid sheets, fascicles, whorls, or a vague storiform Special techniques
pattern. The stroma often contains glassy hyalinized fibrous
tissue that may appear as small nodules or irregular masses, or
● The tumor cells (both the spindle and epithelial) are
as radially arranged clusters of needle-shaped fibers (collage- positive for muscle-specific actin, S-100 protein, CK,
nous crystalloids). CAM 5.2, and focally for GFAP.
Hyaline or plasmacytoid variant consists of a monomorphic
population of plasmacytoid or polygonal cells with a uniform
eosinophilic cytoplasm. These are arranged in loose aggregates,
anastomosing sheets, or solid or microcystic nests.
Biphasic variant composed of spindle and epithelial plasma-
cytoid cells.
Clear cell variant exhibiting extensive clear cell change.
This may show a more aggressive course, and may be confused
with mucoepidermoid carcinoma, acinic cell carcinoma and
metastatic renal cell carcinoma.
(a)
(a)
(b)
Figure 8.19 (a, b) Myoepithelioma.The epithelial cells frequently

have a plasmacytoid appearance, sometimes termed a ‘hyaline cell’.
The nucleus is eccentric, and the cytoplasm intensely eosinophilic
(b) (b, arrow). As opposed to plasma cells, which demonstrate CD38
positivity, the epithelial cells express cytokeratin markers. EMA will
Figure 8.18 (a, b) Myoepithelioma.This lesion resembles a stain both plasma cells and epithelial cells, and this does not further
pleomorphic adenoma, but lacks definite gland formation. this distinction.
(a) (b)
Figure 8.20 (a, b) Myoepithelioma.The central radiation in these rosetting areas is visible.These are pseudorosettes, not true rosettes (which
would demonstrate positivity for neural markers and would be found, for example, in a neuroblastoma).These foci should be polarized as tyrosine
crystals may radiate in such a fashion and would be found more often in either normal salivary gland or a pleomorphic adenoma.
(a) (b)
Figure 8.21 (a, b) Myoepithelioma.This is a variant composed mostly of plasmacytoid or hyaline cells; these exhibit epithelial markers and
myoepithelial markers (e.g., cytokeratin and S-100 protein).The eccentric nuclei do not have the chromatin pattern of plasma cells.The
stroma is myxoid and fibrocartilagnious.
ONCOCYTOMA (OXYPHILIC ADENOMA) These are arranged in broad parallel columns, solid rounded
acinar groups, or occasionally as tubules. The lumina of the lat-
ter are often empty. The nuclei are centrally located, vesicular
CLINICAL FEATURES and contain one or two nucleoli. Mitotic figures are rarely
Oncocytoma accounts for less than 1% of all salivary gland seen. Small dark compressed cells are seen in between the larger
neoplasms. This tumor most commonly occurs in the parotid cells. The stroma is delicate and scant, and may occasionally
gland, and rarely in the submandibular salivary glands. It can be contain lymphoid cells. Isolated collections of oncocytic cells
bilateral and multicentric, and can affect minor salivary glands (oncocytic hyperplasia) are frequently seen in glands harboring
of the oral cavity and oropharynx, as well as accessory ear glands an oncocytoma, and clear cell change can be a prominent
and the upper respiratory tract (extrasalivary gland oncocy- feature.
toma). These often represent hyperplasia rather than neoplasia,
which is often cystic and papillary in configuration. Differential diagnosis
Malignant oncocytoma may show aggressive local recur- ● Multifocal nodular oncocytic hyperplasia
rences or regional lymph node metastases. ● Diffuse oncocytosis
● Pleomorphic adenoma with oncocytic change
● Monomorphic adenoma with oncocytic change
● Carcinomas with oncocytic change
Oncocytoma/oxyphilic adenoma is characterized by the pres- ● Carcinoid tumor with oncocytic change
ence of large cells with granular, pale, eosinophilic cytoplasm. ● Myoepithelioma
(a) (b)
Figure 8.22 (a, b) Oncocytoma.These cells resemble those of a Warthin’s tumor, but in the latter there is a papillary and cystic
architecture with a notable lymphoid stroma. An oncocytoma may (as in Warthin’s tumor) show multifocality and bilaterality. Oncocytosis of
the salivary gland may be multifocal, and again affect more than one salivary gland. On occasion, acinic cells can show this cytoplasmic
appearance, with alpha-amylase being expressed. Electron microscopy would verify the high mitochondrial content of oncocytic cells.
Special techniques first few days of life. Its histological similarity to the developing
● Tyrosine-rich crystals have been seen in several oncocytic salivary gland suggests that this may represent a hamartoma of
salivary gland neoplasms. minor salivary gland tissue.

PLEOMORPHIC SALIVARY ADENOMA
Mixed salivary gland tumors are well-circumscribed, lobulated
(MIXED TUMOR) tumors. They are delineated, but have pushing – often
mesenchymal-rich – peripheral tongues. They are biphasic
with a mixture of epithelial and mesenchymal components. Both
CLINICAL FEATURES
components show enormous variation in appearance.
Pleomorphic salivary adenoma is a slowly growing benign sali- The mesenchymal element may be the predominant com-
vary gland tumor. It is most commonly seen in the parotid gland, ponent, or may be very scant. There is usually elastin deposition,
but can also be found in the minor salivary glands within the oral and the stroma may also consist of loose myxoid or hyalinized
cavity, nasopharynx, respiratory and upper digestive tract. This fibroblastic tissue often with fibrocartilaginous (or true cartilagi-
tumor has also been reported in the female breast. It can occur nous) differentiation. Groups of adipocytes may also be present.
at any age, but is most common in the fifth decade of life. It is The epithelial element includes epithelial and myoepithelial
usually a solitary, well-circumscribed, lobulated, encapsulated, cells. The epithelial cells are variably arranged in ducts, tubules
firm, smooth-surfaced lesion, and often shows minute ‘satellites’ or small nests. The myoepithelial cells are often seen loosely
outside the capsule. The presence of satellites is a source of local arranged in the background myxoid stroma, or as sheets or
recurrence. Adequate excision with a margin of normal salivary nests of rounded or spindle cells. They are also seen as a flat-
tissue is necessary to prevent recurrence. tened layer of cells at the periphery of duct-like structures.
Malignant mixed tumor/carcinoma ex pleomorphic adenoma Tumors consisting primarily of epithelial cells with no mes-
occurs in 3–4% of pleomorphic adenomas. The risk of malig- enchymal elements are considered to be monomorphic adeno-
nant transformation of pleomorphic adenomas increases with mas (see above).
time (1.5% with a 5-year history of benign tumor and 9.5% in Pleomorphic salivary adenomas may exhibit areas reminiscent
those present for over 15 years). The tumor characteristically of cylindroma (groups of cells surrounded by hyaline sheaths),
presents as recent enlargement of a long-standing mass. It may neurilemmoma (elongated myoepithelial cells arranged in parallel
be accompanied by pain or facial paralysis. The lesion pursues formations with accumulation of hyaline and fibrillary material
an aggressive course if extracapsular invasion is present. between the cells), oncocytoma, and areas of squamous epithe-
Congenital pleomorphic adenoma (salivary gland anlage lium. Within the latter there are small laminated keratin-filled
tumor) is a benign tumor occurring mainly in the nasopharynx, cysts that are lined by squamous epithelium including keratohya-
and presenting with respiratory distress at birth or within the line granules. Sebaceous glands and goblet cells may also be seen.
(c)
(a)
Features in pleomorphic adenoma that raise suspicion of

malignancy include: cytological pleomorphism; mitoses; extra-
capsular invasion; excessive hemorrhage; and necrosis.
When carcinoma occurs on a background of pleomorphic sali-
vary adenoma, the complication is sometimes termed carcinoma
ex-PSA. However, the strict original definition of the latter
required that both epithelial and mesenchymal elements were
malignant. The most common stromal malignancy in these cases
was chondrosarcoma. In fact, this development must be extremely
rare, whereas a carcinoma with an associated pleomorphic sali-
vary adenoma is, whilst rare, accepted at an incidence of about
2–5% of that of adenomas.
The most common malignancy is adenocarcinoma not other-
wise categorized, but all sub-types may occur, with adenoid
cystic being particularly unusual.
The prognosis relates to adequacy of excision and, of course,
evidence of spread prior to removal. An arbitrary figure of
invasion outwith the contour of the PSA of greater than 7 mm
(b) is predictive of adverse survival – perhaps 10% at 5 years – but
clearly this seems somewhat arbitrary.
Figure 8.23 (a–c) Pleomorphic salivary adenoma. A cord-like and In one study of submandibular gland malignancies, carcinoma
microacinar pattern with cells of variable nuclear size, the nuclei being ex-PSA accounted for 26% of cases, and pure adenoid cystic
larger and more vacuolated than would be seen in an adenoid cystic carcinoma for an additional 37%.
carcinoma.The stroma is somewhat hyalinized, and a psammoma
body is encircled (c).These bodies may be found rarely in several Valuable assistance in demonstrating the background PSA
salivary gland tumors, including a pleomorphic adenoma and an acinic derives from the identification of elastic tissue in the stroma.
cell carcinoma. Focal oncocytic metaplasia is seen (a, b). Congenital pleomorphic adenoma (salivary gland anlage
tumor) is a polypoid lesion of the nasopharynx which shows var-
ious features of pleomorphic salivary gland adenoma. In particu-
Carcinoma ex pleomorphic adenoma (malignant mixed tumor)
lar, these include solid and cystic squamous nests, solid cords and
can assume the histological appearances of any carcinoma (e.g.,
duct-like structures that are focally continuous with the surface
duct carcinoma, low-grade polymorphous carcinoma), but in
epithelium and also blending into the stromal spindle cells.
addition there are pre-existing areas of pleomorphic adenoma. It
may also present as a histologically benign pleomorphic adenoma
that has metastasized without significant alteration of the histo- Secondary features
logical appearances, as a carcinosarcoma with a chondrosarcoma- ● Hyalinization
tous mesenchymal component, or as a malignant myoepithelioma. ● Calcification
● Ossification
● Hemorrhage
● Cystic degeneration
● Elastic degeneration
● Necrosis is seen in malignant mixed tumors
Cell morphology
● Epithelial cells are the predominant cell population. They
vary from intercalated duct-like cells (i.e., large with
rounded nuclei) to epidermoid cells. The lining cells may
be flattened, or may show keratohyaline granules.
● Myoepithelial cells are predominantly seen in the myxoid
areas as loosely cohesive rounded, polygonal or spindle
cells with abundant glassy, eosinophilic cytoplasm.
Hydropic or clear cell degeneration may be seen and
confer a chondrocyte-like appearance to the cells.
● Tyrosine crystals are unique to this tumor and are found
predominantly in the extracellular matrix. They appear as
small, rounded, daisy-like clusters of needle-like crystals.
● Monomorphic adenomas Figure 8.24 Warthin’s tumor.The intensely eosinophilic, double-
● Polymorphous low-grade adenocarcinoma layered oncocytic cells (the cytoplasm is rich in mitochondria) and
the supporting lymphoid stroma are visible.
● Chondroma or other chondromyxoid tumors
● Oncocytoma
● Adenoid cystic carcinoma PATHOLOGICAL FEATURES (Figure 8.24)
● Synovial sarcoma Warthin’s tumor has a very distinctive low-power microscopy
appearance. It is a well-circumscribed, partly lobulated and
Special techniques encapsulated lesion which consists of epithelial glandular struc-
● PAS highlights intracytoplasmic glycogen granules within tures separated by heavy lymphoid infiltrate including lym-
the myoepithelial cells seen in the loose areas, while those phoid follicles. The epithelial component is in the form of
present in solid sheets are usually negative. tubular glands, or cystic and papillary structures lined by bland
● Alcian blue shows the presence of connective tissue and oncocytic epithelial cells. Focal goblet cell and sebaceous dif-
epithelial mucin. ferentiation may be seen. Occasionally, the latter can be exten-
● Verhoeff’s elastic stain highlights ring-like or beaded sive, hence the lesion’s name of sebaceous adenolymphoma.
tortuous lines of elastic tissue representing sites of Within the interstitial tissue there may be cholesterol clefts
‘burnt-out’ ducts. (these can be seen also within the cysts), sarcoid granulomas,
● The epithelial cells express CAM 5.2, the myoepithelial abscess formation and variable numbers of mononuclear
cells express S-100 protein and smooth muscle actin (SMA). cells and foamy macrophages. The cystic spaces often contain
● GFAP is usually expressed, compared with only rare eosinophilic debris, cholesterol crystal clefts and crystalloids.
expression in a polymorphous low-grade adenocarcinoma. Away from the main tumor there may be additional small
cysts lined by similar glandular epithelium and surrounded by
WARTHIN’S TUMOR lymphoid structures.
Secondary features
CLINICAL FEATURES
● Cystic changes
Warthin’s tumor is the second most common benign tumor of ● Hemorrhage
the salivary glands, and accounts for 2–6% of all parotid tumors. ● Infarction
The tumor occurs most commonly in the parotid gland, but ● Squamous metaplasia (see below, Differential diagnosis)
occasionally affects minor salivary glands of the mouth or
oropharynx. It can occur at any age, but is typically a tumor of
the elderly. It may be more common in males. The tumor is Cell morphology
multicentric and bilateral in over 10% of cases, and is often ● The lining glandular cells are arranged in two layers.
cystic. Malignant transformation into carcinoma or lymphoma ● A superficial layer of oncocytic, columnar cells, with
is extremely rare. A cutaneous counterpart of sweat gland origin abundant granular eosinophilic cytoplasm and parallel
has been described. uniform nuclei.
● A basal layer of smaller, polyhedral cells with more

irregularly disposed nuclei.
● Occasional ciliated cells, mucin-secreting cells and
sebaceous cells.
● The lymphocytes are predominantly B cells.
● Mast cells may be seen.
● The lesion is very distinct and rarely causes diagnostic
problems, unless it is predominantly cystic. Beware,
however, in cases showing squamous metaplasia, the
potential mimicry of cystic change in a lymph node of a
metastatic, well-differentiated squamous carcinoma.
The anatomy of a lymph node should be sought
(e.g., peripheral sinus, etc.), and the squamous epithelium (a)
carefully studied for atypia.
Special techniques
● Alcian blue highlights the luminal mucin and the focally
scattered mucin-secreting cells.
● The majority of the tumor cells are EMA- and CEA-positive.
● The lymphocytes are polyclonal, with a predominance of
IgA-producing cells. Occasional S-100 protein-positive
dendritic cells are seen.
ACINIC CELL CARCINOMA

(b)
CLINICAL FEATURES
Figure 8.25 (a, b) Acinic cell carcinoma. Partly clear cells, but
Acinic cell carcinoma is an uncommon salivary gland tumor definitive granularity of the cytoplasm is seen.The cytology is often
that usually occurs in the third decade of life, and is more com- bland, but they are classified as malignant tumors.They should all be
mon in males. These lesions have occasionally been reported studied for areas of high grade change, wherein the prognosis is
worse. An alpha-amylase stain will identify these cells as deriving
in children. The tumor is less aggressive than adenoid cystic
from the lobules of salivary glands.
carcinoma or intermediate and high-grade mucoepidermoid
carcinoma. The lesion is slow-growing, and recurs in 12% of
cases after apparently curative surgery, whilst it develops late Cell morphology
metastases in 7.8% and results in death in 6% of cases. Even The cells show a wide variety of appearances:
the most benign-looking acinic cell tumor must be considered
● The majority of cells are basophilic, with granular
as malignant, even though it may take many years to metastasize.
cytoplasm and distinct cell membranes reminiscent of
It is best managed by wide local excision.
normal acinar cells; the granularity reflects the presence of
Acinic cell carcinoma has been described in the breast.
zymogen granules.
● Other cells have clear, bubbly or vacuolated cytoplasm due
PATHOLOGICAL FEATURES (Figure 8.25) to the presence of glycogen or fixation artifact.
Acinic cell carcinoma is a well-circumscribed cellular tumor ● The nuclei are usually small, darkly stained and eccentrically
consisting of rounded or polygonal cells variously arranged in located, or sometimes vesicular and centrally placed.
solid sheets, abortive acini, microcystic, papillary-cystic, thy- ● Mitotic figures are sparse, but areas of high-grade nuclear
roid-like follicular or clear cell (hypernephroid) patterns. The atypia and/or mitoses should be recorded and related to
stroma is sparse. Lymphoid follicle formation can be seen at the metastatic potential.
tumor margins.
Secondary features ● Clear cell myoepithelioma – S-100 protein expression
● Cystic change ● Metastatic thyroid carcinoma – thyroglobulin and thyroid
● Necrosis transcription factor expression
● Metastatic renal cell carcinoma – glycogen, not zymogen

granules (i.e., PAS/diastase-resistant)
● Hyalinizing clear cell carcinoma – glycogen, not zymogen,
granules
Special techniques
● PAS/diastase shows cytoplasmic zymogen granules.
PAS highlights the cytoplasmic glycogen.
● Alcian blue may show focal mucin positivity in the
papillary-cystic and follicular areas.
● The cells express CKs, ␣-amylase, lactoferrin and secretory
component of IgA.
● Occasional neuroendocrine cells positive for vasoactive
intestinal peptide are present.
● Tumor cells sometimes show positivity for (a)
␣-1-antichymotrypsin.
● Ultrastructural study shows cytoplasmic, membrane-bound
zymogen granules characteristic of serous cells and
well-developed rough endoplasmic reticulum.
ADENOID CYSTIC CARCINOMA
CLINICAL FEATURES
Adenoid cystic carcinoma (ACC) is a rare neoplasm arising
from the epithelial cells of mucus-secreting exocrine glands
such as those seen in salivary glands, lacrymal glands, upper
respiratory tract, breast, uterine cervix or prostate. Intracranial
involvement is commonly from direct skull base involvement,
although metastasis may rarely be seen. The predisposition of
the ACC for perineural and perivascular invasion is the prime
reason for the locally invasive character of the tumor, often (b)
extending into the cranium via foramina at the skull base. ACC
usually affects patients in their mid-40s, but may also be seen
in children and adolescents. Patients treated for tumors of the
nose and paranasal sinuses experienced more morbidity than
those with tumors at other sites. Positive margins, perineural
invasion and solid histology of ACC are associated with increased
morbidity and treatment failure.
Hybrid adenoid cystic and other types of salivary gland car-
cinoma may occasionally be seen.

ACC is an infiltrative tumor consisting of small basaloid cells.
These are arranged in various patterns, the most characteristic
being cribriform in which well-circumscribed nests of tumor cells
contain round or elliptical ‘punched-out’ spaces containing
basophilic mucinous material. Other patterns seen are pseudo- (c)
glandular, tubular, small or large solid nests, anastomosing cords,
strands or columns of cells. The stroma is pale, hyalinized and Figure 8.26 (a–d) Adenoid cystic carcinoma. A cribriform
eosinophilic, extending around and into small tumor nests. Focal architecture is typical.There may be a cystic appearance at the
mucoid stromal change is often present. Perineural or intraneural center of the spaces, but sometimes there is a hyalinized matrix.
invasion is a characteristic finding at the tumor margins. Retraction around the nests is typical.The complex, both trabecular
Spindle- and dendritic-shaped cells containing excessive and plexiform, growth is seen, and the ‘product’ of the islands is
evident.The cells are bland with a low mitotic rate.There is little
amounts of melanin pigment resulting in a blue nevus-like cytoplasm and there tends to be little in the way of nucleolation;
appearance have been reported in the stroma of adenoid cystic this contrasts with some of the mimickers such as a polymorphous
carcinoma. low-grade adenocarcinoma.
The neoplastic clusters are formed by two cell populations:

the small dark cell type (that predominates); and a large
cell type. Necrosis, either of the comedo or the apoptotic
type, is a frequent finding. Perineural growth occurs in
50% of the cases and vascular permeation in 25%.
Immunohistochemistry identifies a dual differentiation
with a reactivity pattern indicative of ductal epithelial and
myoepithelial differentiation, which can be confirmed by
electron microscopy. The differential diagnosis of the
neoplasm includes its benign counterpart, the basal cell
adenoma, solid variant of adenoid cystic carcinoma,
undifferentiated carcinoma, and basaloid squamous
carcinoma. The tumors recur more frequently than lesions
originating in major salivary glands. Mortality is
(d) associated with the anatomic site of the lesion, advanced
stage, residual neoplasia at surgery, and tumor recurrence.
Figure 8.26 (Continued). The importance of recognizing basal cell adenocarcinoma
outside major salivary glands is related to the clinical
Secondary features behavior of the neoplasm that seems to be less indolent
● Necrosis occasionally seen. than that of tumors arising in major salivary glands)
● Adenoid basal cell carcinoma
Cell morphology
● Basaloid squamous carcinoma
● Adenoid cystic-like tumor of the prostate. This tumor has
● The cells are rounded, have little cytoplasm and a better outcome than the salivary counterpart, is usually
hyperchromatic nuclei with no conspicuous nucleoli. multinodular, and is associated with basal cell hyperplasia
● Two-cell populations (pale duct epithelial and dark
basaloid cells) are frequently seen. Special techniques
● Mitoses and nuclear pleomorphism are infrequent. ● The rounded spaces contain PAS/diastase-positive material,
and focally also Alcian blue-positive mucinous material.
Differential diagnosis ● The cells are CK- and CEA-positive.
● Monomorphic basaloid adenoma ● S-100 protein-positive myoepithelial cells can be seen,
● Mixed salivary gland tumors particularly in the salivary tumors.
● Polymorphous low-grade adenocarcinoma (PLGA) (PLGA
and ACC have several overlapping histological patterns, BASALOID CARCINOMA
including cribriform, tubular and solid patterns. PLGA is
uncommon in the major salivary glands. Histopathological
distinction is therefore mainly a problem in tumors of CLINICAL FEATURES
minor salivary gland origin where small biopsies often
Basaloid carcinomas most often affect the parotid. These tumors
contribute to diagnostic difficulties. The potential
include two groups:
discriminating value of immunohistochemistry between
1. Basal cell adenocarcinoma is a tumor of low-grade malig-
cases of PLGA and ACC remains controversial)
nancy, representing the malignant counterpart of basal cell
● Adenoid squamous cell carcinoma (is an uncommon
adenoma.
variant of squamous cell carcinoma, usually localized to
2. Solid variant of adenoid cystic carcinoma (undifferentiated
the skin of the head and neck region; it only rarely
basaloid carcinoma) is a highly aggressive tumor reminiscent
involves the mucosal sites. The biological behavior of this
of the basaloid carcinoma of the upper aerodigestive tract.
neoplasm is more aggressive when it involves mucosal
areas, and the prognosis seems worse than that of
conventional squamous cell carcinoma)
● Basal cell adenocarcinoma of salivary glands (is an Basaloid carcinomas, like basal cell adenomas, are subdivided
uncommon and recently described entity occurring most into solid, membranous, trabecular and tubular types. The basa-
often in the major salivary glands, but recently described loid nests in the membranous variant are usually enclosed by
in the minor salivary glands of the head and neck region). hyaline sheaths, reminiscent of cutaneous cylindroma. Immuno-
Basal cell adenocarcinoma predominates in the seventh histochemically, they exhibit epithelial and focal myoepithelial
decade, without sex preference. The tumors affecting the differentiation.
minor salivary glands occur most frequently in the oral Solid variant of adenoid cystic carcinoma (undifferentiated
cavity. The prevalent histological pattern is represented by basaloid carcinoma): this tumor consists of solid nests of malig-
solid neoplastic aggregates with peripheral cell palisading, nant-looking, pleomorphic basaloid cells with extensive central
frequently delineated by basement membrane-like material. necrosis and frequent mitotic figures.

The differential diagnosis of salivary glands with basaloid The histological hallmark is a biphasic cell arrangement formed
features: by an inner layer of duct-forming epithelial cells and an outer
● Basal cell adenoma
layer of myoepithelial cells. The latter often display striking clear
● Hybrid basal cell adenoma with adenoid cystic carcinoma
cell change reminiscent of clear cell carcinoma. Occasionally, the
● Adenoid cystic carcinoma
lesion shows an extensively hyalinized and sclerotic stroma with
● Basal cell adenocarcinoma
only occasional bi-layered ducts. Collagenous spherulosis has
● Undifferentiated basaloid carcinoma (solid variant of
been described in this variant of salivary gland carcinoma.
adenoid cystic carcinoma).
Note: A basaloid variant of squamous carcinoma is a separate
entity, affecting mucosal (e.g., laryngeal, tonsillar) sites. ● See Clear cell carcinoma of salivary gland (p. 603)
● Metastatic medullary carcinoma of the thyroid
Special techniques
● The epithelial cells are immunoreactive for low-molecular-
CLINICAL FEATURES
weight CK; the myoepithelial cells are immunoreactive
Clear cell carcinoma is a very rare, poorly recognized tumor of for S-100 protein, muscle-specific actin and vimentin.
low-grade malignancy which is found almost exclusively in minor
salivary glands. The term hyalinizing clear cell carcinoma of
salivary glands is sometimes applied to a similar tumor with a
distinctly hyalinized stroma.
CLINICAL FEATURES
PATHOLOGICAL FEATURES Mucoepidermoid carcinoma (MEC) accounts for 3–9% of the
Clear cell carcinoma consists predominantly of optically clear major and 19% of the minor salivary gland tumors. It occurs
cells, and occasionally granular cells, with well-defined borders at any age, and represents the most common malignant salivary
reminiscent of clear cell carcinoma of the kidney. The cells are gland tumor in children. The lesion may be found in other loca-
arranged in cords, trabeculae, islands or nests. The tumor has tions such as esophagus, lung, lacrimal glands, skin, pancreas,
infiltrative margins, and perineural invasion can be seen. The anal canal, intrahepatic bile duct, thyroid and thymus.
cells are positive for epithelial markers, negative for S-100 pro- Mucoepidermoid carcinoma has been reported in association
tein (a myoepithelial marker), and contain varying amounts of with Warthin’s tumor, and may rarely occur as a carcinoma ex
cytoplasmic glycogen, but no lipid or mucin. Hyalinizing clear pleomorphic adenoma. It has also been reported in adults as a
cell carcinoma of the salivary gland is similar to the above, but complication of low-dose irradiation received during child-
with a distinctly hyalinized stroma. hood. Mucoepidermoid carcinoma has a variety of clinical out-
comes, but prognosis seems to be related to the tumor grade.
Differential diagnosis (Table 8.1) Low-grade tumors have a good prognosis, but may recur locally;
distant metastases usually occur only in high-grade tumors. The
Several primary salivary gland tumors may exhibit clear cell
best treatment is by surgery, and postoperative radiotherapy is
features. In certain cases (e.g., the hyalinizing clear cell carci-
administered to high-grade tumors.
noma), the clear cell component characterizes and constitutes
one of the criteria of diagnosis. In others, the clear cell change
is literally a change – an alteration in cytological appearance that
may hamper the correct diagnosis by dominating the appearance Mucoepidermoid carcinomas are defined as carcinomas with
and obscuring the true nature of the tumor, as for example with mixed squamous and glandular differentiation. Low-grade
clear cell acinic carcinoma. Fortunately, the clear cell change tumors are relatively well-circumscribed and often cystic, with
in these cases is focal, and the diagnosis rests on the accepted a predominance of mucin-secreting cells. In contrast, high-grade
criteria, irrespective of the clear cell element. tumors tend to be infiltrative, more solid, and with a predomi-
nance of squamous, intermediate or clear cells. The following
patterns may be present: solid mosaic sheets of squamous or
EPITHELIAL–MYOEPITHELIAL CARCINOMA intermediate cells, ductular and cystic spaces lined by mucin-
secreting cells; expanded tubules or spaces lined by both squa-
mous and mucin-producing cells; solid clusters of squamous cells
CLINICAL FEATURES
within a fibrous stroma, and thyroid follicle-like closely packed
Epithelial–myoepithelial carcinoma is a low-grade malignant tubular structures. Some mucoepidermoid carcinomas show
tumor that usually occurs in the major salivary glands. A signet ring cells.
high-grade carcinomatous component can occur, and imparts A low-grade malignant mucoepidermoid carcinoma with stro-
an aggressive clinical behavior to the tumor. mal fibrosis and eosinophilic infiltration is a recently recognized
Table 8.1: Summary of the differential diagnosis of salivary gland tumors with a clear cell morphology
Histological type Useful pointers to diagnosis
Hyalinizing clear Minor salivary glands. N.B. Intra-oral.

cell carcinoma Cords of clear cells with minimal glycogen.
Epithelial marker expression but no myoepithelial component: S-100 protein- and SMA-negative.
Characteristic hyalinized stroma.
Epithelial–myoepithelial Definite luminal differentiation of double-layered cords and tubules.The outer layer is clear cell,
carcinoma contains small amounts of glycogen, and expresses S-100 protein and SMA.
Clear cell The growth pattern may be as lobules, nests or cords and the stroma may exhibit the expected range of
myoepithelioma fibrocartilaginous differentiation, originating as it does from the tumor cell.
The cells express CAM 5.2, S-100 protein and SMA.
If there is a duct component constituting over 10% of the tumor, it would be best classified as a PSA.
All myoepithelial tumors require assessment for malignant potential, and this relates to mitotic activity,
necrosis and infiltrative pattern rather than cytological atypia.
Clear cell change in The typical zymogen granule-rich cell must be sought.The growth pattern: solid, microcystic,
acinic cell carcinoma papillary-cystic or follicular is useful, such variable patterns being unusual in histological mimicries such
as hyalinizing clear cell carcinoma, clear cell myoepithelioma and metastatic renal carcinoma.
The cells express ␣-amylase (and ␣-anti-chymotrypsin and lactoferrin), and immunohistochemistry may
be useful.
Electron microscopy to visualize the zymogen granules offers similar diagnostic support.
Clear cell predominance The intermediate cell may have clear cytoplasm and lack the useful mucin. However, mucin-producing
in mucoepidermoid cells are usually present and squamous elements, not always keratinizing, but at least exhibiting
carcinoma desmosomes, should be sought.
Metastatic renal The characteristic nests and their sinusoidal-supporting vasculature are typical.The cells contain glycogen
carcinoma and lipid, both of which may be identified.
Duct differentiation is seldom found, though the papillary variant may show luminization.
There is no mucin production.
The cells express both low- and high-molecular-weight CKs, but immunoexpression may be weak.
They are usually EMA-positive, often express vimentin, and may express CD15.
Since S-100 protein expression may be found, it is evident that immunohistochemistry is seldom the final
arbiter in difficult cases. A constellation of features must be used.
Direct invasion from Mucosal tumors, for example malignant melanoma or squamous carcinoma, may directly invade the
an intra-oral tumor salivary gland. Both tumors may show clear cell change.
Attempts should be made to identify their more characteristic elements.
(a) (b)
Figure 8.27 (a–c) Mucoepidermoid carcinoma.The islands appear squamous, with minimal mucin production. Mucoepidermoid carcinoma
behaves according to the squamous and/or glandular element. When the latter predominates, the prognosis is better than when the
squamous component predominates.
carcinoma or squamous cell carcinoma because of its

histologically scant mucus-producing epithelial components
● Mucinous cystadenocarcinoma of the salivary glands
(a rare entity)
Special techniques
● The cells express both epithelial and myoepithelial markers.
● Alcian blue, PAS/diastase or mucicarmine all highlight the
intra- (and extra-) cellular mucin.
POLYMORPHOUS LOW-GRADE
ADENOCARCINOMA/TERMINAL DUCT CARCINOMA
(c) CLINICAL FEATURES
Figure 8.27 (Continued). Polymorphous low-grade adenocarcinoma (PLGA) or terminal

duct carcinoma arises almost exclusively from intra-oral minor
subtype of mucoepidermoid carcinoma. A similar tumor has been salivary glands, especially the palate. It may arise within a pre-
reported in the thyroid, and is considered as a differentiated existing pleomorphic adenoma and may recur locally, but
malignant neoplasm of the thyroid that can be confused with rarely metastasizes.
anaplastic carcinoma, medullary carcinoma, squamous cell carci- Papillary cystadenocarcinoma has a more aggressive behavior.
noma, or Hodgkin’s disease. A correct diagnosis of sclerosing
mucoepidermoid carcinoma with eosinophilia involves awareness PATHOLOGICAL FEATURES (Figure 8.28)
of this entity and appropriate immunohistochemical analysis.
PLGA consists of uniform cells arranged in a variety of patterns
including ducts, cribriform nesting, Indian files, solid structures
Secondary features
and sometimes papillary structures. It has infiltrative margins,
● Extravasation of mucinous or keratinous material into the and perineural invasion can be seen. When the tumor consists
interstitial tissue. almost entirely of papillary structures, the term papillary cysta-
● Secondary inflammatory response. denocarcinoma is sometimes applied. A large papillary compo-
● Abundant, dense fibrohyaline stromal reaction. nent is associated with a higher morbidity and mortality.
Cell morphology Differential diagnosis

● The majority of squamous cells have vacuolated or clear ● Adenoid cystic carcinoma
cytoplasm, and relatively few show keratinization ● Basal cell adenocarcinoma
(c.f. squamous foci in a pleomorphic adenoma or ● Mucoepidermoid carcinoma
keratinization in a squamous carcinoma). ● The possible role of immunohistochemistry in
● Intermediate cells reminiscent of normal salivary duct. distinguishing PLGA from adenoid cystic carcinoma
● Mucinous, columnar, cuboidal, and goblet-like or signet (ACC) is described under ACC (see p. 601).
ring cells, sebaceous cells, basal and oxyphilic cells may
also be present.
SALIVARY DUCT CARCINOMA
● Cellular pleomorphism and mitoses are infrequent.
● Oncocytic changes may be seen in some mucoepidermoid
carcinomas. CLINICAL FEATURES
Differential diagnosis Salivary duct carcinoma is a rare, but distinctive tumor most
often found in major salivary glands. It affects adults, more com-
● Poorly differentiated adenocarcinoma or squamous monly men, and is best treated by wide local to radical excision
carcinoma followed by radiotherapy. This tumor has very aggressive behav-
● Adenosquamous carcinoma ior, with few patients surviving beyond 3 years after diagnosis.
● Mucoceles (well-differentiated mucoepidermoid carcinoma
with mucin-filled cystic spaces may resemble mucocele)
● Mixed salivary gland tumor – pleomorphic adenoma
● Metastatic follicular carcinoma of thyroid – the latter does Salivary duct carcinoma has a striking similarity to duct carci-
not contain mucus noma of the breast, with evidence of invasive and in-situ comedo
● A low-grade malignant mucoepidermoid carcinoma with or cribriform component. The stroma is desmoplastic and the
stromal fibrosis and eosinophilic infiltration may be cells are large, polygonal with well-defined borders, and have
misdiagnosed as a highly malignant mucoepidermoid granular eosinophilic cytoplasm. Perineural invasion is often seen.
(a) (c)
(b) (d)
Figure 8.28 (a–h) Polymorphous low-grade adenocarcinoma. As suggested by the name, these tumors demonstrate a variety of
architectural patterns which may include papillary, tubular, cribriform and solid with hyaline stroma.The nuclei vary in shape, size and clarity,
but the cytoplasm is evidently clear and may, on occasion, mimic an acinic cell carcinoma. However, in the latter lesion the pattern is solid
with neither ducts nor cribriform areas. Polymorphous low-grade adenocarcinoma frequently shows perineural invasion, but the prognosis
remains favorable.The infiltrative pattern is seen.The edge is often irregular and evidently invasive, yet the prognosis remains more favorable
than, for example, an adenoid cystic carcinoma.
Pre-existing pleomorphic adenoma and transition from normal to Special techniques

neoplastic epithelium may sometimes be seen. Predominance of ● The tumor is immunoreactive for low- and high-molecular-
intraduct component (⬎90%), minimal invasion (⬍8 mm), origin weight CK antibodies, and expresses the conventional
within a pre-existing pleomorphic adenoma, and small size immunohistochemical profile of adenocarcinoma (i.e.
(2–3 cm) are all favorable prognostic features. CEA, Leu-M1 and EMA).
● The tumor may express prostate-specific antigen, and
Differential diagnosis anti-estrogen therapy has been suggested as a theoretical
● Metastatic breast carcinoma form of treatment.
(e) (g)
(f ) (h)
of cases, patients suffer only from chronic parotitis without any

MISCELLANEOUS TUMORS serious consequences. A small number, however, evolve into
Sjögren’s syndrome.
Sjögren’s syndrome consists of three clinical components:
BENIGN LYMPHOEPITHELIAL LESION keratoconjunctivitis sicca (lacrimal gland involvement); xeros-
(MIKULICZ’S DISEASE AND SJÖGREN’S SYNDROME) tomia (involvement of salivary and oral mucous glands); and
connective tissue disease (particularly rheumatoid arthritis).
Sjögren’s syndrome may also be associated with extrasalivary
CLINICAL FEATURES
manifestations. These include nodal or extranodal lymphoretic-
Lymphoepithelial lesion is a lymphoproliferative disorder of ular lesions such as lymphomatoid granulomatosis of the lung
salivary glands characterized by diffuse and bilateral enlarge- and/or lymphoid interstitial pneumonia and Waldenstrom’s
ment of salivary and lacrimal glands. Occasionally, there is macroglobulinemia. The skin, bone marrow, liver and kidneys
only unilateral involvement of the parotid gland. In the majority can also be affected.
(a)
(a)
(b)
Figure 8.29 (a–b) Salivary duct carcinoma.This is essentially an

adenocarcinoma that exhibits comedo necrosis and a cribriform
pattern. As compared with many of the other malignancies of
salivary glands, it is high grade with necrosis. It occurs most often in
elderly males.
Malignant lymphomas may complicate Sjögren’s disease (⫻45

increase compared with normal glands). These lymphomas are
of the MALT type, B-cell type, with the immunoprofile CD20⫹, (b)
CD5⫺, CD10⫺, bcl-2⫾ and CD30⫺. They are graded accord-
Figure 8.30 (a, b) Benign lymphoepithelial lesion in Sjögren’s
ing to cell size, presence of blasts and mitotic rate.
syndrome.The surviving epithelium is difficult to demonstrate, but will
be seen with ease on a stain for cytokeratin. Sometimes epithelial
islands are difficult to demonstrate, and when the lymphoid population
predominates – and indeed forms a sheet-like growth – the possibility
Benign lymphoepithelial lesion is characterized by a total or near- of a marginal zone lymphoma occurring on the background of
Sjögren’s syndrome must be considered. Fresh tissue for PCR for gene
total replacement of a salivary or lacrimal gland by lymphoid
rearrangement may be useful.The marginal zone lymphoma (MALT
tissue containing numerous germinal centers. Isolated islands of type) typically expresses CD20, but lacks CD10 or CD5.
epithelial cells infiltrated by lymphocytes (epimyoepithelial nests)
are present within the lymphoid background. Hyaline material is
present between the epithelial cells, representing collapsed acini Differential diagnosis
and consisting of basal and myoepithelial cells. ● HIV-associated lymphoepithelial lesion (cystic
lymphoepithelial lesions of salivary glands are nodular or
Secondary features diffuse salivary gland enlargements that are observed in
● Malignant transformation of the lymphomatous, or less HIV-positive patients)
often, of the epithelial components. ● Low-grade lymphoma
Special techniques extensive squamous metaplasia of the salivary acini. Dissolution

● There is a mixed population of B and T lymphocytes, and rupture of some acini may produce an inflammatory/
histiocytes and S-100 protein- and actin-positive granulation tissue reaction.
myoepithelial cells.
● The B lymphocytes are usually polyclonal, but may exhibit
light chain restriction. ● Squamous cell carcinoma
INVERTED DUCTAL PAPILLOMA OF MINOR

SALIVARY GLAND CHORISTOMA
SALIVARY GLANDS
CLINICAL FEATURES
CLINICAL FEATURES
Salivary gland choristoma is the presence of salivary gland tissue
Inverted ductal papilloma of minor salivary glands is a benign
in an abnormal location. It is a unique clinico-pathological entity
lesion arising from the reserve cells of the excretory ducts of
that usually presents at birth as a soft tissue mass, most com-
minor salivary glands. The tumor presents as a slow-growing,
monly in the gingiva, middle ear, neck or as a lymph node inclu-
smooth-surfaced, raised or exophytic swelling of less than 2 cm
sion. The tissue may give rise to any type of salivary gland tumor.
diameter in the oral cavity in adults.
PATHOLOGICAL FEATURES PATHOLOGICAL FEATURES
This lesion consists of complex invaginations of well- Salivary gland choristoma has the appearance of normal salivary
differentiated squamous and basaloid epithelium with cystic gland tissue within a fibrovascular stroma. This is often associ-
spaces. The luminal borders of these invaginations are lined ated with sebaceous glands when present in the gingiva.
by basaloid and columnar cells. The lesion is either covered by
Secondary features
intact mucosa or open to the surface. Lobules of minor salivary
glands may be seen adjacent to the lesion. ● Focal chronic inflammation
● Tumor formation
Secondary features
● Acute and chronic inflammatory cell infiltrate. SIALADENOMA PAPILLIFERUM
Cell morphology
● Well-differentiated stratified squamous cells. CLINICAL FEATURES
● Columnar cells. Sialadenoma papilliferum is a rare lesion that affects the oral
● Goblet cells are occasionally seen. cavity more often than the parotid, and occurs in late childhood.
Special techniques
● The tumor cells display strongly positive reactions with
CK13 and CK14, and less strong reactions with CK7, CK8 Sialadenoma papilliferum is a peculiar tumor which is reminis-
and CK18. cent of the cutaneous syringocystadenoma papilliferum. It is char-
● Alcian blue can be used to demonstrate intracytoplasmic acterized by the presence of numerous papillary folds lined by
mucin in goblet cells. oxyphil, mucus or squamous epithelium similar to those seen in
Warthin’s tumor. The cores of the papillae are vascular. Tortuous,
widely dilated salivary ducts are also seen. If associated with
NECROTIZING SIALOMETAPLASIA marked lymphoid infiltrate, the resemblance to Warthin’s tumor
becomes remarkable or indistinguishable; however, a Warthin’s
CLINICAL FEATURES tumor is usually located in the parotid and almost never in the
oral cavity and it occurs in adults, often in the elderly.
Necrotizing sialometaplasia is a benign lesion of salivary tissue
that can present either as a spontaneous ulcer in the palate, or Differential diagnosis
as a reactive lesion secondary to injury of minor (or rarely ● Warthin’s tumor
major) salivary tissue. It may, in part be due to ischemia. The ● Papillary adenocarcinoma
lesion usually heals completely with or without surgery.
Special techniques
● One cell subset expresses CK14, S-100 protein, GFAP,
Necrotizing sialometaplasia is characterized by the presence of vimentin and SMA, consistent with myoepithelial
mucosal ulceration, pseudoepitheliomatous hyperplasia of the differentiation. The second subset of basal cells expresses
adjacent lining epithelium, lobular infarct-like necrosis and CK13 and CK14.
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9 lung and pleural tumors
William AH Wallace
Lung tumors 629 Intravascular bronchoalveolar tumor (IVBAT) or

Epithelial tumors, benign 629 epithelioid hemangioendothelioma 637
Adenomyoepithelioma 629 Localized organizing pneumonia 638
Pulmonary adenomatosis (bronchoalveolar cell Minute pulmonary meningothelial-like nodules 638
adenoma or atypical adenomatous hyperplasia) 629 Pleuropulmonary blastoma 638
Pulmonary blastoma 639
Epithelial tumors, malignant 630 Sclerosing hemangioma/pneumocytoma 639
Adenocarcinoma 630
Adenosquamous carcinoma 631 Neuroendocrine tumors 640
Carcinomas of salivary gland type 632 Carcinoid tumors 640
Carcinomas with pleomorphic, sarcomatoid or Tumorlets of the lung and neuroendocrine cell hyperplasia 641
sarcomatous elements 632
Large cell carcinoma 633 WHO classification of lung tumors 641
Non-small cell carcinoma 633
Small cell carcinoma 633 Pleural tumors 642
Squamous carcinoma 634 Mesothelial tumors, benign 642
Adenomatoid tumor of the pleura 642
Lymphoproliferative lesions 635
Lymphocytic interstitial pneumonia (LIP) 635 Mesothelial tumors, malignant 643
Lymphoma 635 Mesotheliomas 643
Lymphomatoid granulomatosis (LYG) 636
Nodular lymphoid hyperplasia 636 Miscellaneous tumors 644
Chest wall/pleural sarcomas 644
Miscellaneous tumors 636 Solitary fibrous tumor of the pleura 644
Clear cell tumor of the lung (sugar tumor) 636
Hamartoma/benign mesenchymoma 637 WHO classification of mesothelial tumors 644
GENERAL COMMENTS
Tumors of the lung are commonly seen in clinical practice, and this site are classified according to the WHO guidelines, and
can present problems in their diagnosis – especially as they are staged using the TNM system and the International Staging
also common sites for metastatic disease. Primary tumors at System for Lung Cancer.
LUNG TUMORS
EPITHELIAL TUMORS, BENIGN PULMONARY ADENOMATOSIS

(BRONCHOALVEOLAR CELL ADENOMA OR
ADENOMYOEPITHELIOMA ATYPICAL ADENOMATOUS HYPERPLASIA)
Adenomyoepithelioma of the lung is an extremely rare tumor

CLINICAL FEATURES
of myoepithelial cell origin. The tumor is histologically iden-
tical to those seen in the breast (see Chapter 4, Breast tumors: These tend to be identified incidentally in lungs harboring
Adenomyoepithelioma, p. 165). adenocarcinoma, and may represent an early, premalignant
630 Lung and pleural tumors
phase of glandular neoplasia with a potential for evolution to

carcinoma. This phenomenon may help explain the relatively
high incidence of multicentric synchronous and metachronous
lung cancer cited in the literature. The majority are detectable
only at the microscopic level, but some of the larger ones may
be visible or palpable in well-inflated resection specimens. The
majority measure less than 5 mm, but lesions up to 10 mm may
occur. The lesions may be bilateral.
Pulmonary adenomatosis is characterized by the presence of
collection of alveoli lined by cuboidal or columnar epithelial
cells resembling type II pneumocytes which show variable mild
to severe cytological atypia. In the more severely atypical
examples, differentiation from bronchoalveolar carcinoma (BAC)
is difficult, but in general BACs are larger and would normally
Figure 9.1 Non-mucinous bronchoalveolar carcinoma.The residual
be regarded as greater than 10 mm in size. These lesions are alveolar walls of the lung are thickened and fibrotic, with a population
focally distributed, and are often seen adjacent to areas of of columnar and cuboidal peg-like cells present on the alveolar
primary adenocarcinoma. surface.The cells show a variable degree of pleomorphism, but
no evidence of vascular, stromal, or pleural invasion is seen.
● Reaction to injury
● Metastatic nodule
● Bronchoalveolar carcinoma
ADENOCARCINOMA
CLINICAL FEATURES
Primary bronchogenic adenocarcinoma is rising in incidence,
and in Japan and North America is now the most common pri-
mary lung malignancy. While the majority occur in smokers, a
disproportionate number occur in non-smokers and women
under the age of 55 years, although the reasons for this change Figure 9.2 Mucinous bronchoalveolar carcinoma showing focal
in incidence are unclear. lining of the alveolar walls by tall columnar epithelial cells with
goblet cell morphology.The alveolar walls remain thin and
attenuated.There is no evidence of vascular, stromal, or
PATHOLOGICAL FEATURES (Figures 9.1–9.3) pleural invasion.
See Chapter 15, Carcinomas: Adenocarcinomas (p. 1193).
Bronchogenic adenocarcinomas may be central or peripheral at other sites. Most resected tumors, however – if appropriately
in the lung and, in contrast to squamous carcinoma, rarely show sampled – will show a mixture of patterns.
cavitation. The tumors may be associated with a central scar, In addition, there are two patterns of adenocarcinoma which
leading to previous descriptions of these as ‘scar cancers’, are more specific to the lung.
although lung carcinomas of all types may be seen with an
increased incidence in patients with diffuse lung fibrosis. The Bronchoalveolar carcinoma
peripheral placed lesions are often associated with marked This has been defined by the WHO as a tumor in the lung with
indrawing and puckering of the pleura. Small peripheral lesions a surface growth pattern showing no evidence of stromal, vas-
may also extensively involve the visceral pleura, giving rise to a cular, or pleural invasion. Tumors showing focal areas of inva-
pseudo-mesotheliomatous pattern. These tumors are also most sion are designated as mixed adenocarcinoma, bronchoalveolar,
closely associated with pulmonary lymphangitis carcinomatosis. and acinar/papillary/clear cell, etc. subtype.
Histologically, these tumors show a wide variety of architec- Histologically, bronchoalveolar carcinoma is divided into two
tural variants which are described in the WHO classification subtypes:
(acinar, papillary, solid with mucin, mucinous/colloid, signet ● Mucinous type: this tends to be diffuse or ill-defined
ring, and clear cell), and are essentially similar to that occurring (occasionally well-circumscribed), and grows along an
Lung tumors 631
contain abundant glycogen. A small amount of mucin may also

be present.
● The conventional bronchial adenocarcinoma may be
mistaken for metastatic adenocarcinoma, malignant
epithelioid mesothelioma, mucinous cystadenoma/
pulmonary mucinous cystadenoma of borderline malignant
potential, and pulmonary adenomas.
● Bronchoalveolar carcinoma must be distinguished from
mixed pattern primary bronchogenic carcinoma, metastatic
adenocarcinoma, bronchoalveolar adenoma, and atypical
adenomatous hyperplasia.
● Well-differentiated fetal adenocarcinoma must be
distinguished from metastatic adenocarcinoma, conventional
bronchial adenocarcinoma, and pulmonary blastoma.
Figure 9.3 Fetal type adenocarcinoma of the lung, showing a
pronounced cribriform (endometrioid) growth pattern.The tumor
Special techniques
cells are moderately pleomorphic and arranged in a bland fibrous
stroma showing no atypical features. ● Immunohistochemistry; 80% of primary lung
adenocarcinomas express TTF1 and CK7, 60–70% express
CEA, and over 90% express BerEp4.
unaltered pulmonary alveolar framework with some ● Mucinous-type BAC is TTF1-negative, shows Alcian blue
tendency for papillary formation. The lining cells are cytoplasmic mucin, and exhibits linear staining for laminin
bland-looking, columnar and mucin-secreting, with and type IV collagen.
abundant cytoplasm and basally placed nuclei. The lesion ● Non-mucinous-type BAC is TTF1-positive, and is also
may elicit a B-lymphocytic response. Extracellular mucin positive for anti-human surfactant apoprotein (SAP). It
can be seen. may also show absent or interrupted staining for laminin
● Non-mucinous type: this form of adenocarcinoma is and type IV collagen.
characterized by a poorly circumscribed area of air spaces ● Well-differentiated fetal adenocarcinoma shows
lined by one or more layers of cuboidal, or polygonal PAS-positive intracytoplasmic glycogen, occasional
epithelial cells. These cells have abundant faintly Grimelius-positive argyrophilic cytoplasmic granules,
eosinophilic cytoplasm, are often exfoliated into or fill and and the cells are cytokeratin (CK)-, carcinoembryonic
distend the alveolar spaces, have apical snouts, and form antigen (CEA)-, and EMA-positive. They may also express
papillary structures with fibrovascular cores. There is often neuroendocrine markers (calcitonin, somatostatin,
central fibrosis due to collapse of the alveolar framework, chromogranin and serotonin).
which may make exclusion of an invasive component
difficult. The presence of invasion is suggested by finding
tumor cells with an acinic, papillary or solid architecture ADENOSQUAMOUS CARCINOMA
within the fibrous tissue.
See Chapter 15, Carcinomas.
Well-differentiated fetal adenocarcinoma
Despite the name, this is not a pediatric tumor but has a peak CLINICAL FEATURES
incidence in middle age. This lesion is generally regarded as These tumors are similar in presentation to adenocarcinoma,
an epithelial monophasic variant of pulmonary blastoma (see but are most commonly peripheral and may be associated with
Lung: Carcinomas with pleomorphic, sarcomatoid or sarcoma- central scarring or pleural indentation.
tous elements, p. 632). This lesion has an association with
smoking, and it is believed to have a pathogenesis similar to
other bronchial carcinomas, although the prognosis is signifi-
cantly better. Histologically, these tumors show both squamous and glandu-
These lesions usually present as a solitary, well-demarcated lar differentiation. Since lung tumors are often mixed in their
mass in the mid or peripheral lung, with focal hemorrhage pattern, small areas of squamous differentiation in an other-
and cystic degeneration. Histologically, the tumor has a pro- wise typical adenocarcinoma should be ignored. In general,
nounced ‘endometrioid’ appearance with tubular and cribri- both components should be obviously identifiable by routine
form structures with scant stroma resembling fetal lung. Other histology as the diagnosis is a purely morphological one. The
areas may show a more solid architecture with nests and cords recent WHO classification suggested that each component
and, in many cases, squamous morules. The tumor cells should comprise at least 10% of the tumor, although the
are pseudostratified columnar cells with no cilia, and often authors accepted that this was arbitrary.
● Squamous carcinoma
● Adenocarcinoma
CARCINOMAS OF SALIVARY GLAND TYPE
CLINICAL FEATURES
These are rare tumors which occur predominantly in the cen-
tral major airways and present as polypoid or obstructing
lesions. The most common type is adeoidcystic carcinoma, but
mixed tumors, mucoepidermoid carcinomas and acinic cell
tumors (Fechner tumor) also occur.
PATHOLOGICAL FEATURES Figure 9.4 Giant cell carcinoma: this tumor is composed of large,
atypical, poorly cohesive cells with a high mitotic rate.Tumor cells
These tumors are believed to arise from the tracheal or bronchial are extremely pleomorphic, with multinucleate forms.
submucosal seromucinous glands, and are identical to those
seen in the salivary glands (see Tumors of the salivary glands,
p. 605). ● Carcinosarcoma/sarcomatoid carcinoma (see also Chapter
15, Carcinomas: Carcinosarcoma, p. 1199) is a high-grade,
aggressive tumor composed of a mixture of carcinoma of
CARCINOMAS WITH PLEOMORPHIC, any type and sarcomatous areas showing morphological or
SARCOMATOID OR SARCOMATOUS ELEMENTS immunohistochemical evidence of heterologous
differentiation (e.g. nerve, muscle, bone, cartilage).
(Carcinomas with spindle and/or giant cells)
See also Chapter 15, Carcinomas. Differential diagnosis
● Pleomorphic carcinoma should be distinguished from
CLINICAL FEATURES
carcinosarcoma, choriocarcinoma, and malignant
These represent a group of tumors that are of non-small cell melanoma.
type that contain spindle cells, giant cells, or a mixture of both. ● Spindle cell carcinoma should be distinguished from
The tumors may be composed entirely of these, or they may various sarcomas and from melanoma.
represent only a component of an otherwise typical squamous ● Giant cell carcinoma can be mistaken for osteoclast-like
carcinoma, adenocarcinoma, or large cell carcinoma. The giant cell inflammatory responses, malignant fibrous
tumors are often large at presentation, and tend to be high histiocytoma and choriocarcinoma.
grade with a poor prognosis. The presence of a small cell com- ● Carcinosarcoma must be distinguished from pleomorphic
ponent within such tumors would indicate that the tumor be carcinoma and the various sarcomas.
classified as a combined small cell carcinoma. Adequate sam-
pling of these tumors is essential for accurate classification. Special techniques
● The spindle cells of pleomorphic carcinoma may, or may
not, express epithelial markers. Tumor giant cells may
These tumors have been subdivided by the WHO as shown show focal positivity with human chorionic gonadotropin
below: (hCG) in pleomorphic carcinoma.
● Pleomorphic carcinoma is a poorly differentiated, non-small ● The spindle cell population often, at least focally, shows
cell carcinoma with areas of spindle cell and/or giant cells, positivity with epithelial markers, and should be negative
or solely a mixture of spindle cells and giant cells. These for specific mesenchymal markers such as smooth muscle
components should constitute at least 10% of the tumor. actin, desmin, CD34, and S-100. If no staining with any
● Spindle cell carcinoma is a very rare carcinoma composed markers is obtained, then differentiation of this entity from
solely of spindle cells, and has a poor prognosis. sarcoma is difficult.
● Giant cell carcinoma is a rare form of high-grade, non-small ● The giant cells may express epithelial markers, although
cell carcinoma composed entirely of large pleomorphic and this may be focal; they should be negative for macrophage
often multinucleate tumor giant cells. The tumor cells are markers such as CD68 and may be focally positive
often poorly cohesive with variably granular eosinophilic for hCG.
cytoplasm and hyperchromatic nuclei with prominent ● The sarcomatous and carcinomatous elements of carcino-
nucleoli. Focal infiltration by neutrophils is common. sarcoma can be confirmed by immunohistochemistry.
Lung tumors 633
LARGE CELL CARCINOMA growth pattern with insular, solid, trabecular, and rosetted
areas. The tumor cells are often moderately pleomorphic, with
extensive necrosis and a mitotic rate of greater than 10 per
CLINICAL FEATURES 2 mm2. These tumors may be combined with other patterns of
These tumors present clinically with a similar pattern to squa- large cell carcinoma, squamous carcinoma, or adenocarcinoma
mous carcinoma and adenocarcinoma as lung masses in a (combined tumors). It has also been noted that around
similar age group with similar risk factors. 10–20% of non-small cell carcinomas which morphologically
show no obvious neuroendocrine features may show focal
immunohistochemical or ultrastructural evidence of neuro-
endocrine differentiation. The significance of this is unclear,
These tumors are large cell carcinomas that lack evidence of and the WHO classification has coined the term ‘non-small cell
squamous or glandular differentiation on routine histology or carcinoma with neuroendocrine differentiation’ to cover these
by simple histochemistry. In general, the cells are large and tumors. There is no evidence however that routine immuno-
pleomorphic with prominent nucleoli and prominent cyto- histochemical staining for neuroendocrine differentiation is of
plasm. According to this definition, the classification of these any clinical value.
tumors is by exclusion, as focal areas of squamous or glandu- Large cell carcinoma with rhabdoid phenotype: these are
lar differentiation will remove these tumors from this category. poorly differentiated tumors with pleomorphic epithelial cells
As such in most instances these tumors can only be classified showing scattered larger ‘rhabdoid’ cells with abundant
within this category following resection and adequate sampling eosinophilic cytoplasm, sometimes with a rather globular
of the tumor for histology. appearance. The rhabdoid cells contain aggregates of inter-
mediate filaments, and can express cytokeratins, vimentin, and
desmin. Rhabdoid cells may also be seen in conjunction with
other types of carcinoma, most commonly adenocarcinoma.
● Basaloid variant of large cell carcinoma should be
distinguished from basaloid variant of squamous
carcinoma.
● Clear cell variant of large cell carcinoma may be mistaken
for clear cell variant of squamous carcinoma, clear cell
variant of adenocarcinoma, clear cell tumor, and
metastatic renal cell carcinoma.
● Large cell neuroendocrine carcinoma should be distinguished
from atypical carcinoid tumor and small cell carcinoma.
NON-SMALL CELL CARCINOMA

Figure 9.5 Large cell neuroendocrine carcinoma: this tumor has a
solid and rosetted architecture composed of pleomorphic cells, This term is not a recognized entity within the WHO classifica-
some of which have rather punctate nucleoli and a high mitotic tion but absolute classification of many lung tumors is not pos-
rate (⬎10 mitoses per 2 mm2).
sible on small biopsies or cytological specimens. Thus, when a
carcinoma is identified in a diagnostic specimen which is mor-
Variants phologically not small cell carcinoma, and there is no absolute
Basaloid carcinoma (see also Chapter 15, Carcinomas): this evidence of glandular or squamous differentiation, this term is
is a tumor showing a pure basaloid pattern but without any advisable due to the recognized poor correlation between cell
evidence of squamous differentiation (keratin formation, inter- typing in such specimens and subsequent resection specimens.
cellular bridges).
Clear cell carcinoma: this is a tumor composed of large
polygonal cells showing a clear cell pattern without evidence of
squamous (keratin formation, intercellular bridges) or glandu-
See also Chapter 15, Carcinomas (p. 1193).
lar differentiation (mucin positivity).
Lymphoepithelioma-like carcinoma (see also Chapter 15,
CLINICAL FEATURES
Carcinomas): this is a rare tumor which is similar to the
nasopharyngeal carcinoma of the same name. The association Small cell carcinoma accounts for around 20% of primary
with Epstein–Barr virus is however less well defined, especially bronchogenic carcinomas. This tumor is characterized by rapid
in cases occurring in the Western hemisphere. growth with early and widespread metastatic spread to regional
Large cell neuroendocrine carcinoma and combined large cell lymph nodes and beyond. The prognosis is generally poor,
neuroendocrine carcinoma: these tumors show a neuroendocrine although in limited disease with chemotherapy and radiotherapy
there may be an initial response; however, this is usually cytoplasm, and often show marked smear artifact making assess-
followed by subsequent relapse. ment difficult. Encrustation of vessels by DNA material is com-
mon. There is often prominent vascular and lymphatic invasion.
PATHOLOGICAL FEATURES (Figures 9.6 and 9.7) Combined small cell carcinomas are defined as mixed tumors
with invasive small cell carcinoma admixed with any other sub-
Small cell carcinoma is a densely cellular tumor, composed of type of carcinoma. This may be seen in up to 20% of small cell
a monotonous population of round hyperchromatic cells carcinomas, but as most are only diagnosed on small biopsies
arranged in solid sheets, nests, trabeculae, ribbons, rosettes and the proportion of cases where this is detected is much less.
pseudorosettes, tubules and ductules and as individually disposed Small cell carcinoma with associated overlying mucosal squa-
cells separated by a sparse stroma. Nuclear molding is a variable mous carcinoma in situ is usually excluded from this group.
feature. Foci of either in-situ or invasive squamous or adenocar-
cinoma may occasionally be seen. These may be discrete or inti- Differential diagnosis
mately admixed with the neoplastic cells (see Combined small cell
● The classic small cell carcinoma may be mistaken for
carcinomas in next column). There is usually a high mitotic and
lymphoma and leukemia, small cell and basaloid variants
apoptotic rate and often widespread necrosis. The cells have little
of squamous carcinoma, carcinoid tumors, primitive
neuroendocrine tumor, and malignant melanoma.
● Combined small cell carcinoma should be distinguished
from small cell variant of squamous carcinoma and large
cell neuroendocrine carcinoma.
Special techniques
● The tumor cells of classic small cell carcinoma express one
or more epithelial cell markers (cytokeratin, epithelial
membrane antigen, CEA, human milk fat globule protein-2).
Cytokeratin staining may be focal, but shows a
characteristic para-nuclear accentuation which is helpful
even in crushed biopsies. CD56 and TTF1 are often
positive, and the lesion may also stain for one or more
neuroendocrine marker (neuron-specific enolase,
chromogranin, Leu-7, vasoactive intestinal polypeptide,
serotonin, and synaptophysin). Electron microscopy may
demonstrate dense-core granules.
Figure 9.6 Combined small cell and non-small cell carcinoma of ● Combined small cell carcinoma shows CD56- and
the lung, showing mixed differentiation with areas of small cell para-nuclear dot-positive staining with cytokeratin in the
undifferentiated carcinoma adjacent to other areas of the tumor small cell component, and appropriate separate staining of
showing features consistent with an adenocarcinoma.
‘non-small cell’ component.
SQUAMOUS CARCINOMA
See also Chapter 15, Carcinomas (p. 1203).
CLINICAL FEATURES
Traditionally, this has been the most common form of primary
bronchial carcinoma in most countries, although recently the
incidence of adenocarcinoma has been rising and has become
more common, especially in the Far East and more recently in
North America. The majority of these tumors arise in current or
ex-smokers over the age of 60 years. The majority arise in asso-
ciation with a major bronchus, but some may arise at the peri-
phery of the lung.
Figure 9.7 Small cell carcinoma of the lung.The cells are of See also Chapter 15, Carcinomas.
intermediate size with scant cytoplasm showing evidence of nuclear
molding.The chromatin pattern is finely granular, and the nucleoli are Macroscopically, squamous carcinomas in the lung have a
indistinct.There is usually widespread mitotic activity, apoptotic pale, lobulated appearance and often show areas of central
debris, and necrosis. necrosis giving rise to an apparently cystic lesion. They may
Lung tumors 635
present as very large lesions in the lung, with infiltration into carcinoma, p. 633), metastatic renal carcinoma, and clear
adjacent structures (chest wall, mediastinum, pericardium, etc.) cell tumor (sugar cell tumor).
and extension into regional hilar and mediastinal lymph nodes, ● The small cell variant must be distinguished from small
yet not show evidence of distant metastatic spread. The prog- cell carcinoma and from the combined small cell carcinoma.
nosis is related largely to stage. Due to the tendency of these ● Basaloid squamous carcinoma can be mistaken for
lesions to arise in larger airways, distal obstructive changes with basaloid carcinoma or for transitional cell carcinoma.
lipoid pneumonia, bronchiectasis and fibrosis is frequently seen.
Histologically, the majority of squamous carcinomas in the Special techniques
lung have a typical appearance with identifiable keratinization ● The cells of squamous cell carcinoma show diffuse
and intercellular prickles. In the more poorly differentiated forms staining with cytokeratins and they show no staining with
however these may be more sparse. In addition, in some tumors CD56 or neuroendocrine markers.
areas of spindle cell differentiation may also be encountered. ● Clear cell variant shows intracytoplasmic glycogen
(PAS-diastase), lack intracytoplasmic mucin (AB-PAS),
Variants and are positive for CK14 and negative for HMB45.
In addition to the typical pattern of squamous carcinoma, sev-
eral variants are recognized. It is important to realize that these
patterns are commonly seen focally within otherwise typical LYMPHOPROLIFERATIVE LESIONS
squamous carcinomas. Consequently, the specific labeling of a
tumor as one of these variants requires a pure pattern and is
therefore relatively rare and can only be achieved reliably on LYMPHOCYTIC INTERSTITIAL PNEUMONIA (LIP)
resection specimens.
Papillary squamous carcinoma: this is essentially a tumor of CLINICAL FEATURES
the proximal bronchi which shows an exophytic endobronchial
growth pattern. This may be associated with minimal evidence Patients usually present with breathlessness and cough. Most
of invasion into the underlying submucosal tissue. The lesion cases occur in adults. There is a clinical association with HIV
differs from squamous papilloma by the presence of significant infection, and cases occurring in children are usually in this set-
cytological atypia. Differentiation of these two lesions may be ting. The clinical picture is usually suggestive of interstitial lung
extremely difficult on small biopsy samples. disease with bilateral shadowing and a restrictive lung defect.
Clear cell squamous carcinoma: clear cell change within a The clinical course is variable, with most patients remaining
squamous carcinoma is common, and the diagnosis is usually stable, though some may deteriorate and cases of subsequent
obvious when more typical areas of coexisting tumor are iden- lymphoma are described.
tified. In its pure form, the identification of intercellular bridges
confirming squamous differentiation is required. PATHOLOGICAL FEATURES
Small cell variant squamous carcinoma: this is a poorly dif-
The lung parenchyma is diffusely infiltrated by a mixed popu-
ferentiated squamous carcinoma which nonetheless retains fea-
lation of small mature lymphocytes, plasma cells, and histio-
tures of a non-small cell carcinoma with focal squamous
cytes that surround vessels and airways and expand alveolar
differentiation and intercellular bridges. The nuclear features
walls. Germinal centers may be seen, and occasional loose
of the cells lack the characteristics of small cell carcinoma.
granulomas may be identified. In some cases there may be a
Basaloid squamous carcinoma: these are poorly differenti-
variable degree of interstitial fibrosis.
ated squamous carcinomas with a prominent basaloid pattern,
often showing larger cells with more cytoplasm within tumor
islands and relatively abrupt keratinization. If keratinization
and intercellular bridges are not identified, then designation as ● Low-grade non-Hodgkin lymphoma of MALT type.
a basaloid carcinoma is appropriate (see Large cell carcinoma, ● Chronic lymphatic leukemia/lymphocytic lymphoma.
p. 633). Differentiation of these possibilities on small biopsy
samples is often impossible. The possibility of metastatic tran- Special techniques
sitional cell carcinoma may also be considered in the differen- ● In LIP, the lymphoid infiltrate are predominantly
tial diagnosis. CD3-positive T cells.
Differential diagnosis LYMPHOMA

● Classic squamous carcinoma can be mistaken for
adenocarcinoma, large cell carcinoma, pleomorphic The lung may be involved by a wide range of lymphomas, most
carcinoma and metastatic transitional cell carcinoma. commonly in addition to nodal disease elsewhere. The com-
● Papillary variant may be misdiagnosed as squamous monest primary lymphoma of the lung is the extranodal
papilloma. marginal B-cell lymphoma (maltoma).
● Clear cell variant may be mistaken as an adenocarcinoma The features of these lesions are identical to those seen at
with clear cell change, clear cell carcinoma (see Large cell other sites (see Chapter 10).
LYMPHOMATOID GRANULOMATOSIS (LYG)

CLINICAL FEATURES The lung may be the primary site, or be involved by metastatic
spread from a wide variety of tumors, including lymphoma,
Patients present with chest symptoms such as cough, pain and
sarcomas, melanoma, germ cell tumors, thymoma, and granular
hemoptysis, often with associated systemic features of fever,
cell tumors.
weight loss, and malaise. Chest X-radiography shows rounded
The appearances of these tumors are similar to those seen at
lung masses with usually no significant lympadenopathy. Central
other sites, and detailed descriptions of each of these in the
airway involvement is rare, but extra-pulmonary lesions may
lung is beyond the scope of this chapter. Reference to the
be seen. The prognosis is generally poor.
appropriate sections elsewhere is recommended.
CLEAR CELL TUMOR OF THE LUNG
Macroscopically, the lesions are well circumscribed and firm,
often with areas of necrosis. Histologically, the lesions are com-
(SUGAR TUMOR)
posed of an angiocentric polymorphous infiltrate with scat-
See also Chapter 13, Soft tissue tumors: Perivascular epithe-
tered large atypical blast-like cells admixed with lymphocytes,
lioid cell tumor (‘PEComa’) (p. 1035).
plasma cells, and histiocytes. There is prominent infiltration of
vessel walls within the lesion, but there is no true necrotizing
CLINICAL FEATURES
vasculitis.
This a is a rare neoplasm which occurs in middle-aged or elderly
Differential diagnosis patients. It is usually asymptomatic and presents as an incidental
lesion often measuring ⬍2 cm in diameter. Traditionally, these
● Hodgkin’s disease
tumors have been considered benign, but some cases – especially
● Pulmonary involvement by nodal non-Hodgkin lymphoma
those larger than 4 cm – may be capable of metastatic spread. The
● Pulmonary vasculitis
lesion therefore should be regarded as a potentially malignant
neoplasm. The tumor is of uncertain histogenesis, but has recently
Special techniques been shown to be derived from perivascular epithelioid cells.
● LYG is now known to be a B-cell lymphoma, and the large
blast cells stain with B-cell markers. PATHOLOGICAL FEATURES (Figure 9.8)
● Latent membrane protein (LMP) is frequently positive in
Clear cell tumor of the lung is a well-circumscribed lesion con-
the larger cells.
sisting of uniform, round cells or polygonal cells with clear and
eosinophilic granular cytoplasm. These are randomly arranged
NODULAR LYMPHOID HYPERPLASIA around thin-walled vascular spaces, some of which contain
thrombi. Focal necrosis may be seen. Tubules of entrapped
alveolar epithelium may be seen at the periphery of the tumor.
CLINICAL FEATURES
This represents hyperplasia of the bronchial-associated lym-
phoid tissue in the lung, and may be seen in association with
congenital and acquired immunodeficiency states, as well as in
patients with connective tissue disorders. It may overlap with
follicular bronchiolitis.
This may represent a localized or multifocal prominence
of reactive-appearing lymphoid tissue with plasma cells and
histiocytes in the lung, usually with prominent germinal center
formation.
● Low-grade non-Hodgkin lymphoma
Figure 9.8 Clear cell tumor of the lung (sugar tumor).This
Special techniques presented as an incidental well-circumscribed lesion in the lung and
was asymptomatic.The tumor cells are relatively uniform, with clear
● In nodular lymphoid hyperplasia the lymphoid component and eosinophilic granular cytoplasm.The cells show positivity with
is polyclonal. HMB45 and focal positivity to S-100 protein.
Lung tumors 637
● Squamous, adeno- or large cell carcinoma with clear cell
change
● Acininc cell carcinoma of the lung (Fechner tumor)
Special techniques
● The cytoplasm is PAS-positive and diastase-sensitive.
● Immunohistochemistry shows strong reactivity for the
melanocytic markers HMB45 and HMB50, and focal
positivity for S-100, neuron-specific enolase,
synaptophysin, and Leu-7.
● Staining for vimentin, CK, EMA, chromogranin, and
glial fibrillary acid protein is uniformly negative.
● Electron microscopy shows an abundance of
intracytoplasmic glycogen, particularly within
Figure 9.9 Pulmonary chondroma/epithelial mesenchymoma
membrane-bound vacuoles. showing lobules of mature cartilage with adjacent fat and fibrous
tissue.
HAMARTOMA/BENIGN MESENCHYMOMA
CLINICAL FEATURES
This lesion – although still commonly referred to as a hamar-
toma – is in fact neoplastic, and the term ‘benign mesenchymoma’
may be preferable. These are usually discovered incidentally
on radiography or at autopsy as solitary or rarely multiple
well-circumscribed lesion(s) in adult individuals. They are
most commonly located in the lung parenchyma, beneath the
pleura, and less commonly as a polypoid tumor within a large
bronchus.
They may sometimes be seen as a component of Carney’s
syndrome (a familial syndrome characterized by pulmonary
chondromas, epithelioid leiomyosarcoma in the stomach and
functioning extra-adrenal paragangliomas).
Figure 9.10 Leiomyomatous hamartoma: this lung lesion is
composed of fascicles of smooth muscle cells admixed with
PATHOLOGICAL FEATURES (Figures 9.9 and 9.10) epithelial lined clefts and fat. No atypical features are seen within
Pulmonary hamartomas are well-circumscribed, lobulated lesions either the epithelial or spindle cell components.
consisting of a mixture of benign mesenchymal and epithelial
elements. The mesenchymal elements commonly include hyaline Special techniques
cartilage, mature fat, smooth muscle, and fibrous tissue. The
● The epithelial cells are CK- and EMA-positive.
hyaline cartilage predominates in the lesions in the majority of
● The mesenchymal cells are positive for their corresponding
cases (pulmonary chondroma). Less frequently, the core of the
normal counterparts.
lesion may be composed of non-cartilaginous elements such
as fat (lipochondroadenoma), smooth muscle (fibroleiomyo-
matous hamartoma), or loose fibromyxoid tissue or fibroblastic
INTRAVASCULAR BRONCHOALVEOLAR
tissue (pulmonary fibroadenoma). Rarely, the excessive fibro-
blastic stroma assumes club-shaped papillary structures lined by TUMOR (IVBAT) OR EPITHELIOID
cuboidal epithelium, thereby imparting an adenofibromatous HEMANGIOENDOTHELIOMA
appearance reminiscent of mullerian adenofibroma of the
female genital tract (pulmonary adenofibroma). Calcification
and ossification are frequently seen. CLINICAL FEATURES
This is a neoplastic process of endothelial origin that is thought
Differential diagnosis to represent a pulmonary form of epithelioid hemangio-
● Metastatic mesenchymal tumors endothelioma. It is typically multinodular, and can involve both
● Pulmonary blastoma the lung parenchyma and the pleura.
This tumor occurs predominantly in young females, and has or mesothelial origin, but more recently meningothelial deriva-
a slow but progressive growth pattern which may ultimately tion has been suggested. They present as an incidental finding
cause death. There may occasionally be associated tumors else- of small, tan-yellow (often multiple) pleural or parenchymal
where, particularly in the liver. nodules, often involving the upper lobe in resection cases, or at
autopsy. They may occur at any age (from 12 to 91 years, median
PATHOLOGICAL FEATURES (Figure 9.11) age 57 years), but are more common in females. Malignant
primary pulmonary meningioma has also been reported.
This tumor is characterized by the presence of intra-alveolar,
polypoid, hyalinized and sometimes calcified masses surrounded
by rims of epithelioid/histiocytoid/decidual-like eosinophilic cells.
Tumor cells may fill the lumina of arteries or veins. The nodules are recognized as small nests or whorls of cells
present within or expanding the interstitium, in association
with small veins or venules. Bands of collagen are sometimes
seen interspersed between longitudinally arranged fascicles of
cells. The cells are moderate in size, elongated or spindle-
shaped with eosinophilic cytoplasm and indistinct cell borders.
Mitotic figures are absent.
● Tumorlets
● Metastatic tumors
Special techniques
● The cells are positive for vimentin and EMA, but negative
for CK, S-100 and neuron-specific enolase.
PLEUROPULMONARY BLASTOMA
Figure 9.11 Epithelioid hemangioendothelioma: this lobulated
tumor is composed of rather indistinct epithelioid cells within an
eosinophilic stroma. Some of the cells show evidence of CLINICAL FEATURES
intracytoplasmic lumina containing red blood cells.
Two patterns of tumor occur which are regarded as following
Special techniques within this classification, and are differentiated by the degree of
cystic change.
See Epithelioid hemangioendothelioma (p. 1095). Predominantly cystic lesions occur in children up to the age
of 9 years, and these may be asymptomatic. Radiologically,
LOCALIZED ORGANIZING PNEUMONIA these lesions are either single or multiloculated peripheral cysts
which may have an associated solid component and are pre-
dominantly intra-pulmonary in location. Predominantly solid
CLINICAL FEATURES pleuropulmonary blastomas are tumors which may arise in
A non-specific pattern of localized organizing pneumonia may, the lung, mediastinum or pleura of children up to the age of
on occasion, mimic a tumor in the lung. This may be isolated 12 years. Symptoms relate to the presence of a large mass
focus of acute pneumonia or represent cryptogenic organizing within the chest, and there may be associated pleural effusion.
pneumonia (COP)/idiopathic bronchiolitis obliterans organiz- Both patterns have a favorable prognosis, but this relates to the
ing pneumonia (iBOOP). degree of cystic change present. There may be a family history
of solid childhood malignancies in up to 30% of cases.
The alveolar spaces and terminal ducts contain plugs of orga-
nizing exudate with a variable interstitial inflammatory infiltrate. The cystic lesions are composed of thin-walled cysts lined by
benign alveolar or respiratory-type epithelium which may be
ciliated. Beneath this are aggregates of immature epithelioid
MINUTE PULMONARY MENINGOTHELIAL-LIKE
and spindle cells with a rhabdomyoblastic morphology within
NODULES loose myxoid stroma. More solid areas composed of primitive-
type epithelioid and stellate cells may also be seen. The solid
tumors are composed of immature blastematous cells arranged
CLINICAL FEATURES
in areas of varying cellularity within a myxoid stroma and
These are probably hamartomatous proliferations rather than possible areas of more differentiated sarcomatous elements
neoplasms. Originally, they were thought to be of chemoreceptor (e.g. chondrosarcoma). Variable cystic glandular spaces may be
Lung tumors 639
identified which have benign epithelial lining cells analogous to branching glands or tubules lined either by stratified epithelium
the cystic lesions described above. or by a single layer of epithelial cells with cytoplasmic sub-
nuclear or supranuclear vacuolation reminiscent of glands seen
Differential diagnosis in endometrioid carcinoma (endometrioid pattern). Solid balls
● Bronchogenic cyst of epithelial cells (morules) may be seen in some glands. The
● Congenital cystic adenomatoid malformation mesenchymal component is in the form of adult spindle cell sar-
● Rhabdomyosarcoma coma or embryonal type in which the spindle cells are smaller
● Metastatic Wilms’ tumor and set in a myxoid background. Foci of immature striated
● Germ cell tumors muscle, cartilage, and immature bone may also be present.
● Malignant mesenchymoma There may be evidence of extensive necrosis, and there is usu-
ally widespread mitotic activity in both components. Purely
Special techniques mesenchymal variants occur and are still regarded as blastomas,
although differentiation from sarcomas is difficult. Pure epithe-
● The primitive cells are vimentin-positive; further lial lesions are classified as fetal-type adenocarcinoma.
immunohistochemical staining reflects the pattern of
differentiation observed. Differential diagnosis
● Conventional adenocarcinoma
PULMONARY BLASTOMA ● Malignant mesothelioma
● Carcinosarcoma
CLINICAL FEATURES
● Malignant mesenchymoma
This is a rare lung tumor which, despite its name, occurs pre- Special techniques
dominantly in adults (mean age 43 years) but can also occur in
● PAS staining highlights the intracytoplasmic glycogen.
children. The lesions are usually solitary, large, and well-
● Grimelius staining may show occasional argyrophilic
demarcated, but occasionally multiple tumor nodules are seen.
granules in scattered glandular cells.
The prognosis is generally poor, with similar survival to other
● The epithelial component of the tumors is CK-, CEA-, and
types of high-grade, non-small cell carcinoma.
EMA-positive. They may also express neuroendocrine
markers (calcitonin, somatostatin, chromogranin, and
PATHOLOGICAL FEATURES (Figure 9.12) serotonin).
Pulmonary blastoma is a biphasic tumor consisting of a mixture ● The mesenchymal component expresses vimentin, actin
of immature neoplastic epithelial and mesenchymal elements and (less frequently) desmin and myoglobin positivity.
(biphasic blastoma). The epithelial component is identical to
that seen in well-differentiated fetal adenocarcinoma, and may SCLEROSING HEMANGIOMA/PNEUMOCYTOMA
show various patterns. The most common is in the form of
CLINICAL FEATURES
This is a rare lesion of the lung which most often affects young
or middle-aged women, with a predilection for those women
from South-East Asia. The lesions present either as an inciden-
tal radiographic finding in asymptomatic individuals, or they
may present with hemoptysis and chest pain. The lesions are
well-circumscribed, and most commonly arise in the lower or
middle lobes, often in a subpleural location. The tumors are of
controversial origin. Originally, they were thought to be a
hamartomatous lesion or tumor of vascular or mesothelial ori-
gin, but current evidence favors a neoplasm of respiratory
epithelial cells with the potential for pneumocytic, Clara cell,
or bronchial differentiation. The tumor has an excellent prog-
nosis after surgical removal. Rare cases of multifocality and
metastasis of sclerosing hemangioma of the lung have been
reported. This further supports the neoplastic rather than the
hamatomatous theory.
Figure 9.12 Pulmonary blastoma: biphasic pattern of the tumor.
The epithelial component has an ‘endometrioid’ pattern with
pronounced cribriform structure.The epithelial cells are PATHOLOGICAL FEATURES (Figure 9.13)
pleomorphic and clearly malignant.The stromal component shows
variable cellularity, with the spindle cells being pleomorphic and Sclerosing hemangioma of the lung is a well-circumscribed lesion
showing the presence of numerous mitotic figures. with an interstitial pattern of infiltration seen at the periphery
● S-100 protein may highlight clusters of reactive

Langerhans’ cells.
CARCINOID TUMORS
CLINICAL FEATURES
These are relatively rare lung tumors, accounting for 1–2% of
all primary lung neoplasms. They may occur either centrally
or peripherally. The central lesions are more common and
often present with hemoptysis or persisting pneumonia due to
bronchial obstruction. The tumors are highly vascular and often
Figure 9.13 Sclerosing pneumocytoma. Lung lesion with a described as having a cherry-red appearance. The vascularity
papillary architecture: the lesion is composed of two cell and risk of severe hemorrhage may be seen as a contraindication
populations, the outer rim of cells having the appearances of type
to biopsy outwith thoracic surgical centers. There may in some
2 alveolar epithelial cells.The more central cells have more indistinct
outlines and eosinophilic cytoplasm. cases be an association with ectopic hormone production, par-
ticularly adrenocorticotropic hormone (ACTH). All carcinoid
tumors should be regarded as malignant. Classical carcinoids
with reactive appearing alveolar epithelial cells on the surface. have been described as having hilar nodal metastases in up to
They show a heterogeneous appearance consisting of one, or 5% of cases.
more commonly a combination, of the following patterns:
● Solid variant: this is characterized by the presence of sheets
and clusters of polygonal tumor cells with a background of PATHOLOGICAL FEATURES (Figures 9.14 and 9.15)
collagenous matrix. Entrapped within the solid areas are
This group of tumors shows a typical neuroendocrine growth
distorted alveoli lined by hyperplastic pneumocytes and
pattern with rosetting, insular, and trabecular patterns. The
containing foamy macrophages, mononulcear
tumor cells are relatively uniform with eosinophilic cytoplasm
inflammatory cells, and proteinaceous debris.
and in some tumors may have a spindle morphology. The
● Hemorrhagic variant: this is characterized by the presence of
tumors are richly vascular, and the background stroma may be
cavernous hemangioma-like blood-filled spaces separated by
fibrotic or contain amyloid. Occasionally, chondroid or osseous
septae which are irregularly expanded by the tumor cells.
metaplasia may be seen. Very occasionally, the tumor cells may
● Papillary variant: this is characterized by the presence of
contain mucin or melanin.
papillary structures, the cores of which are filled by the
tumor cells, and lined by cuboidal cells, some of which
show a tombstone-like configuration.
● Sclerotic variant: this is characterized by a dense eosinophilic
sclerotic matrix containing cords of neoplastic cells

admixed with hemosiderin, foamy macrophages and
entrapped alveolar epithelial cells. This variant often contains
numerous small hyalinized vessels with obliterated lumina.
● Adenocarcinoma
● Angiosarcoma or epithelioid hemangioendothelioma
● Inflammatory pseudotumor
● Benign clear cell tumor (sugar tumor) of the lung
Special techniques
● The tumor cells are positive for vimentin and EMA, but
negative for CK, although this will stain the overlying Figure 9.14 Atypical carcinoid, showing a focal rosette-like
residual alveolar epithelial component. architecture.The tumor is composed of intermediate-size cells with
eosinophilic, in places granular, cytoplasm showing mild pleomorphism.
● The tumor cells are negative for endothelial markers; the The classification of an atypical carcinoid is based on the
latter highlight the fine arborizing vascular network. demonstration of a mitotic count of between 2 and 10 mitotic
● The cells also express estrogen and progesterone receptors. figures per 2 mm2. Focal necrosis may also be evident.
Lung tumors 641
with bronchiectasis or other lung pathology with chronic

inflammation or scarring. They are more common in females,
and probably represent a hyperplastic process rather than a neo-
plasm. By definition, these must be less than 5 mm, and anything
larger than this would be regarded as a carcinoid tumor (see
Lung: Carcinoid tumor, p. 640). If there is widespread evidence
of neuroendocrine hyperplasia – particularly in association with
carcinoid tumors – the term ‘diffuse idiopathic pulmonary neu-
roendocrine cell hyperplasia’ (DIPNECH) has been suggested.

These lesions consist of small, discrete nests of round hyper-
chromatic epithelial cells, reminiscent of a mini carcinoid. They
are seen in proximity to bronchioles, but may be separated
from the bronchial epithelium by a connective tissue zone, or
Figure 9.15 Classical carcinoid tumor.These tumors show variable they may replace the epithelial lining. The underlying lung
rosetted, insular and trabecular pattern.The tumor cells are relatively parenchyma is often affected by inflammation or fibrosis.
uniform showing minimal pleomorphism with eosinophilic granular
cytoplasm.There is no evidence of necrosis and mitotic figures are
rare (⬍2 per 2 mm2).
Primary lung carcinoids are subclassified into classical and atyp-

ical on the basis of mitotic activity or the presence of necrosis:
● Classical carcinoids have fewer than 2 mitoses per 2 mm2,
and no necrosis.
● Atypical carcinoids have a mitotic rate of between 2 and
10 per 2 mm2, and often show small focal areas of

necrosis, although this is not always seen.
Tumors with a neuroendocrine pattern and a mitotic count of

greater than 10 per 2 mm2 are classified as large cell neuroendo-
crine carcinoma (see Lung: Large cell carcinoma, p. 632).
Differentiation between classical and atypical carcinoid on small
biopsies is often not possible, but the presence of any necrosis or
mitotic activity in a small biopsy should be regarded as evidence
that the lesion is not a classical carcinoid tumor.
Figure 9.16 A small subpleural tumorlet.These are composed of
small epithelioid cells with monomorphic nuclei and finely granular
Differential diagnosis cytoplasm showing no significant cytological atypia.
● Large cell neuroendocrine carcinoma Differential diagnosis
● Small cell variant of squamous carcinoma ● Carcinoid tumors of the lungs
● Melanoma ● Minute chemodectomas
Special techniques
Special techniques
● Carcinoid tumors variably express neuroendocrine markers ● The cells show identical histochemical and
such as synaptophysin, chromogranion, and PGP9.5.
immunohistochemical features to those of carcinoid tumor
● The tumors may be negative for cytokeratin.
(Grimelius-, neuron-specific enolase-, PGP9.5- and
● Electron microscopy may demonstrate neurosecretory
chromogranin-positive; electron microscopy reveals
granules.
electron-dense granules). These markers may reveal many
more smaller clusters than are seen on hematoxylin and
TUMORLETS OF THE LUNG AND eosin sections.
NEUROENDOCRINE CELL HYPERPLASIA
WHO CLASSIFICATION OF LUNG TUMORS

CLINICAL FEATURES
These are minute incidental microscopic, tumor-like cell aggre- It is important to realize that the WHO classification of lung
gates of neuroendocrine cells that are most frequently associated tumors is based on the appearance of the tumors in resection
specimens. Since primary lung carcinomas are notoriously Diffuse pulmonary lymphangiomatosis
variable in their histological pattern, and may show mixed Desmoplastic round cell tumor
differentiation, it is often impossible to fully classify these Others
tumors on small bronchoscopic biopsies, needle biopsies or
Mesothelial tumors (see Pleural tumors)
cytological specimens. Indeed, attempts to do so may result in
a poor correlation between diagnostic specimens and subse- Miscellaneous tumors
quent resections (see Lung: Non-small cell carcinoma). Hamartoma
Sclerosing hemangioma
Epithelial tumors
Clear cell tumor
Benign
Germ cell tumors
Papillomas
Thymoma
Adenomas
Malignant melanoma
Preinvasive lesions Others
Squamous dysplasia and carcinoma in situ
Lymphoproliferative diseases
Atypical adenomatous hyperplasia
Lymphoid interstitial pneumonia
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
Nodular lymphoid hyperplasia
(DIPNECH)
Low-grade marginal zone B-cell lymphoma of the mucosal
Malignant associated lymphoid tissue (MALT)
Squamous cell carcinoma and variants Lymphomatoid granulomatosis
Small cell carcinoma
Secondary tumors
Adenocarcinoma and variants including bronchoalveolar
carcinoma Unclassified tumors
Large cell carcinoma and variants Tumor-like lesions
Adenosquamous carcinoma Tumorlets
Carcinomas with pleomorphic, sarcomatoid and sarcoma- Minute meningothelioid nodules
tous elements Langerhans’ cell histiocytosis
Carcinoid tumors Inflammatory pseudotumor (inflammatory myofibroblastic
Carcinomas of salivary gland type tumor)
Unclassified Localized organizing pneumonia
Soft tissue tumors Amyloid tumor
Localized fibrous tumor Hyalinizing granuloma
Epithelioid hemangioendothelioma Lymphangioleiomyomatosis
Pleuropulmonary blastoma Micronodular pneumocyte hyperplasia
Chondroma Endometriosis
Calcifying fibrous pseudotumor of the pleura Bronchial inflammatory polyp
Congenital peribronchial myofibroblastic tumor Others
PLEURAL TUMORS
Tumors of the pleura can present problems in their diagnosis, PATHOLOGICAL FEATURES
especially as they are also common sites for metastatic disease
The lesion is usually well circumscribed and composed of slit-
and may mimic inflammatory/fibrotic processes. Primary
like glandular spaces arranged within fibrous tissue with a pat-
mesothelial tumors at this site are classified according to the
tern similar to that seen with adenomatoid tumors at other sites.
WHO guidelines and staged using the TNM system.
MESOTHELIAL TUMORS, BENIGN ● Malignant mesothelioma
ADENOMATOID TUMOR OF THE PLEURA

Special techniques
● The mesothelial cells lining the gland-like clefts express
CLINICAL FEATURES
mesothelial markers such as CK5/6, calretinin, HBME1,
This is a rare, benign mesothelial tumor, usually encountered as and are negative for epithelial markers such as BerEp4,
an incidental finding during surgery for other reasons. CEA, and TTF1.
Pleural tumors 643
MESOTHELIAL TUMORS, MALIGNANT
MESOTHELIOMAS
CLINICAL FEATURES
Malignant pleural mesothelioma is, in the majority of cases,
associated with asbestos exposure. In some cases the exposure
may be difficult to identify as it may appear relatively light or for
a short period of time. The time from exposure to development
of mesothelioma is typically in excess of 20 years, but may be
longer. Patients often present with pleural effusion or chest wall
pain. Radiologically, there may be evidence of pleural thickening
and often calcified pleural plaques. The tumor usually encases (a)
the lung, extends along fissures, and buds into underlying lung
parenchyma. Infiltration of chest wall tissue and metastatic
spread to local lymph nodes is common. In extensive disease the
tumor can extend to involve the mediastinum, contralateral pleu-
ral space, and peritoneal cavity. In autopsy cases, distant metas-
tases are frequently encountered. The prognosis is poor.

Mesotheliomas can present very diverse histological patterns,
which makes their differentiation from reactive pleural processes
and other tumors difficult. Four common patterns are, however,
recognized to occur:
● Epithelioid mesothelioma: this pattern is characterized by
an infiltrative tumor composed of epithelioid cells showing
(b)
a variable papillary, acinar, trabecular, and solid growth
patterns, often within fibrous stroma. A similar population
Figure 9.17 Epithelioid mesothelioma. Photomicrographs showing
of cells may frequently be seen growing on the pleural an infiltrative pleural tumor showing a rather variable microglandular
surface. The tumor cells are uniformly round or polygonal (a) and solid (b) architecture.The tumor cells are relatively bland in
with acidophilic or vacuolated cytoplasm and vesicular appearance. Mitotic figures are variable, and there may be evidence
hyperchromatic nuclei and prominent nucleoli. Focal areas of necrosis.
of necrosis may be evident. The mitotic rate is variable,
but in many cases mitotic figures are indistinct.
● Sarcomatous mesothelioma: this is a variably cellular
lesion consisting of spindle cells arranged in fascicles or a
storiform pattern reminiscent of soft tissue sarcomas with
predominantly fibrous but, on occasion, myxoid stroma.
There are often areas of necrosis, although this may be
focal. The spindle cells show variable pleomorphism and
mitotic activity. Infiltration into chest wall fat is common.
● Biphasic (mixed epithelial and sarcomatous)
mesothelioma: this consists of an intimate admixture of
glandular, tubular, or solid epithelioid structures, with a
malignant stromal component, each of which is similar in
appearance to those described above.
● Desmoplastic mesothelioma: this is either a sarcomatoid
or biphasic mesothelioma associated with excessive
amounts of dense hyalinized fibrous stroma such that the
malignant cell population may be inconspicuous. Diagnosis
Figure 9.18 Biphasic mesothelioma. Sections from a pleural tumor,
is often very difficult, and is often only achieved with good showing this to be composed of both malignant epithelioid cells
deep thoracoscopic biopsies, thereby demonstrating that showing a glandular pattern of differentiation admixed with
the process is extending into underlying chest wall tissues. malignant stromal elements.
Differential diagnosis for sarcomatoid mesothelioma

● Reactive inflammatory processes with fibrosis
● Chest wall/pleural sarcomas
● Synovial sarcoma and metastatic carcinosarcoma or
melanoma
● Pleural fibrosis; this relies on confirmation that the sparse
cells within the fibrous tissue – particularly around chest
wall fat – are mesothelial rather than fibroblastic/
myofibroblastic in nature.
Special techniques
● The spindle cells in most sarcomatoid mesotheliomas
express cytokeratin, but this may be focal.
● Focal staining with other mesothelial markers such as
CK5/6 and calretinin may be seen.
● Focal staining with smooth muscle actin may also be seen
Figure 9.19 Sclerotic mesothelioma.The tumor is composed
predominantly of mature bundles of dense collagenous tissue with in sarcomatoid mesotheliomas, and should not be regarded
only occasional scattered atypical mesothelial cells admixed. as excluding this diagnosis.
Extensive sampling of these tumors may reveal more typical areas
of tumor for assessment.
● Other rare variants of mesothelioma include:
– Sarcomatoid mesothelioma with heterologous elements
(cartilage, bone, neural, etc.) CHEST WALL/PLEURAL SARCOMAS
– Adenomatoid tumor-like mesothelioma
– Malignant mesothelioma with squamous differentiation A wide range of sarcomas may present as pleural or chest wall
– Lymphohistiocytoid or lymphomatoid mesothelioma masses. The appearances of these tumors at this site are iden-
– Deciduoid mesothelioma tical to those described elsewhere (see Chapter 13, Soft tissue
– Clear cell mesothelioma tumors).
– Small cell mesothelioma
– Mesothelioma with osteoclast-like giant cells
– Myxoid mesothelioma SOLITARY FIBROUS TUMOR OF THE PLEURA
Differential diagnosis for epithelioid mesothelium Although in the WHO classification these tumors are regarded
as soft tissue tumors rather than mesothelial tumors, they
● Reactive mesothelial proliferation (shows no evidence of
are included here with other pleural tumors. These present as
stromal invasion although care needs to be taken in
pleural-based masses, although more rarely they may be intra-
assessing this as mesothelial ‘trapping’ may occur in
pulmonary and are histologically similar to those occurring at
inflammatory processes)
other sites (see Solitary fibrous tumor, p. 982). Previous terms
used for this tumor include localized fibrous mesothelioma or
● Epithelioid haemangioendothelioma
‘pleural fibroma’. The majority are benign, but malignant trans-
Special techniques formation is recognized when the lesion has the appearance of
a sarcoma.
● Epithelioid mesotheliomas may show focal extracellular
Alcian blue positivity and some apical staining of cells in
glandular spaces. True intracytoplasmic mucin is described
but is rare.
WHO CLASSIFICATION OF MESOTHLIAL
● There is no single immunohistochemical marker to TUMORS
differentiate epithelioid mesothelioma from
adenocarcinoma and a panel of antibodies is usually Benign
recommended as staining is variable and focal Adenomatoid tumor
– Mesothelial – CK5/6, calretinin, HBME1, Malignant
thrombomodulin and membrane staining with EMA Epithelioid mesothelioma
– Epithelial – CEA, BerEp4, B72.3, CD15, TTF1 Sarcomatoid mesothelioma
● Mesothelial cells are negative for endothelial markers Desmoplastic mesothelioma
● Electron microscopy typically shows long micro-villi in Biphasic mesothelioma
epithelioid mesothelioma Others
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10 lymphoreticular system
tumors
10.1 BONE MARROW TUMORS 651

10.2 LYMPH NODE AND RELATED LYMPHOID TISSUE TUMORS 667
10.3 TUMORS OF THE SPLEEN 738
10.4 TUMORS OF THE THYMUS 743
10.1 BONE MARROW TUMORS

Jeremy St J Thomas
Assessment of bone marrow trephines 651 Hodgkin’s disease 658

Reactive lymphoid aggregates 652 Lymphoplasmacytic NHL/Waldenström’s
macroglobulinemia 659
Lymphoproliferative disorders and leukemias 653 Mantle cell lymphoma 660
Acute myeloid leukemia 653 Marginal zone lymphoma 660
Anaplastic large-cell lymphoma 654 Multiple myeloma 661
Angioimmunoblastic T-cell lymphoma 654 Peripheral T-cell lymphoma, unspecified 662
Burkitt lymphoma 654 Precursor lymphoblastic leukemia/lymphoblastic
Chronic lymphocytic leukemia (CLL)/Small lymphoma (B- and T-cell acute lymphoblastic leukemia) 664
lymphocytic lymphoma (SLL) 655 Refining the diagnosis of low grade B-cell NHL in
Diffuse large B-cell NHL 656 bone marrow infiltrates 665
Follicular lymphoma 656
Hairy cell leukemia 657 Metastatic disease 665
GENERAL COMMENTS the cellularity of those spaces expressed as a percentage of the

area of the whole space. Adequacy is difficult to define, because
This chapter describes briefly those tumors that are commonly if a single space is available and it contains a diagnostic lesion
encountered in trephine biopsies in routine surgical pathology then the specimen is, by necessity, adequate. Often however, the
practice. For lesions more usually seen in hematological prac- trephine is carried out for staging purposes or the assessment of
tice, readers are referred to standard hematology texts. tumor load, and in these circumstances a core containing 10 to 20
The most common lesions seen in trephine biopsies are reactive spaces is desirable. Marrow cellularity peaks in early infancy and
lymphoid aggregates, lymphoproliferative disorders, myeloma, then declines steadily throughout life. As a rule of thumb, the
metastatic carcinoma and acute leukemia. This text will not cover average cellularity for a particular age can be calculated by sub-
myeloproliferative disorders and the myelodysplasias. tracting the patient’s age from 100 – for example, a patient aged
In the sections on lymphoma, the World Health Organization 60 years would normally have a marrow with a cellularity of
(WHO) classification is used throughout, and the reader is 40%. However, there is a wide normal range around these crude
referred also to the section on lymph node and related lym- ‘average’ figures.
phoid tissue tumors (p. 667). A useful approach to the assessment of marrow trephines is
to try and see if one of four basic patterns is present. Although
ASSESSMENT OF BONE MARROW TREPHINES there is a lot of overlap between the various pathologies seen in
the different patterns, it is a helpful framework to tackle biop-
The report on a bone marrow trephine should include a comment sies that frequently present difficulties in routine surgical
on the number of marrow spaces available for examination and pathology practice (Table 10.1).
652 Lymphoreticular system tumors
Table 10.1: Common patterns of marrow pathology
Mixed: hypercellular Mixed: hypocellular Diffuse: uniform population Focal lesions
Reactive hyperplasia Low normal Diffuse lymphoma or myeloma Granulomas and reactive
lymphoid aggregates
Myeloproliferative Hypoplastic/aplastic Acute leukemias Metastatic carcinoma
disorders conditions
Myelodysplasias Hypoplastic myelodysplasias – Lymphomas
Interstitial infiltrates, – – –
e.g. some myelomas
A number of simple practice guidelines will also help to avoid A number of studies have explored this problem to investi-
some of the common pitfalls in marrow diagnosis: gate the immunohistochemical profiles of the two types of
● Wherever possible, try to correlate the trephine findings lesion, and these have proved helpful in some cases. One of the
with the clinical and hematological (peripheral blood and most important factors to consider however is the nature of the
marrow aspirate) findings – this will save time frequently, underlying pathology in the patient. Clearly, if the patient is
and embarrassment on occasions. undergoing a marrow trephine to stage a known low-grade,
● If the marrow appears to be normal and the reticulin is B-cell non-Hodgkin lymphoma (NHL), then knowledge of the
increased, then re-examine the marrow. A focal increase morphology and immunoprofile of the primary pathology is
of reticulin may point to a previously unrecognized focal
lesion, while a diffuse increase may indicate a primary
marrow abnormality such as myelodysplasia or a
myeloproliferative disorder.
● In a hypercellular marrow where the cause of the
hypercellularity cannot be explained by the cell types

identified, it is worthwhile carrying out some simple
immunohistochemistry to exclude a subtle but significant
interstitial infiltrate – usually of lymphoma or myeloma.
● Myeloproliferative disorders are associated usually with
raised peripheral blood indices (e.g., thrombocytosis),

while myelodysplasias are associated usually with
cytopenias. The distinction between the two groups of
disorder may be difficult on a trephine alone, and the
morphology of the two groups of disorders does overlap.
● In staging marrow for low-grade lymphoma, always perform
CD3 and CD20 immunostaining. It is amazing what can be (a)

missed on a hematoxylin and eosin (H&E) staining.
● Always think about myeloma – it is very easy to miss.
REACTIVE LYMPHOID AGGREGATES
The distinction between reactive and neoplastic lymphoid infil-

trates in a marrow trephine can be difficult. The main features
of reactive aggregates are listed in Table 10.2.
Table 10.2: Main features of reactive aggregates (after Foucar 2001)
Feature Comment
Distribution Perivascular; non-paratrabecular

Number/size Few in number and usually small in size
Circumscription Usually good except in some patients
with immuno-deficiency (b)
Germinal centers Present occasionally
Immuno profile Usually rich in small T-cells Figure 10.1 Low-power (a) and high-power (b) views of a
Genotypic studies Lack clonality by polymerase chain reactive lymphoid aggregate in a marrow trephine. Note the non-
reaction (PCR) paratrabecular location, mixture of lymphoid cells including plasma
cells and central vessel.
Bone marrow tumors 653
crucial to the interpretation of any lymphoid aggregates in the based on cytogenetics, then on immunophenotype, and only
marrow. Notwithstanding the issue of discordance between finally on morphology (see below). AML is usually characterized
concurrent lymph node and marrow lymphomas in some indi- by diffuse sheets of blasts, with little remaining background mar-
viduals (see below), the morphology and phenotype of any row. It may be difficult to determine precisely the cut-off point
putative marrow deposits will usually be consistent with the between a transforming myelodysplasia (blasts ⬍20% of nucle-
histology of the primary (usually nodal) lesion. Thus, in follic- ated cells) and AML (blasts ⬎20%) in a trephine – for practical
ular lymphomas, marrow lesions are invariably paratrabecular purposes, this is not an issue as therapy would usually be given in
and of the appropriate morphological and phenotypical pat- a borderline case anyway. The morphological distinction between
tern. Likewise, in chronic lymphocytic leukemia (CLL)/small AML and ALL is not always straightforward (see Table 10.3).
lymphocytic lymphoma, a neoplastic marrow infiltrate will
usually be composed of small lymphocytes positive for the CD5 Classification (WHO 1997)
and CD23 markers. It should also be remembered that patients ● AML with recurrent cytogenetic translocations.
with lymphoma – particularly after treatment – can have reac- ● AML with multilineage dysplasia.
tive aggregates in their marrow. ● AML, myelodysplasia-related.
It should be remembered that, on occasion, it will be impossi- ● AML not otherwise categorized.
ble to be certain whether an aggregate is reactive or neoplastic
and if so, then this doubt should be conveyed in the biopsy report.
Usually in these circumstances, follow-up of the patient and fur-
ther investigation over a period of time will yield the true nature ● Acute lymphoblastic leukemia
of the process. ● Diffuse large-cell NHLs
Immunohistochemistry
LYMPHOPROLIFERATIVE DISORDERS AND ● More helpful in ALL than AML.
LEUKEMIAS ● Should be used to exclude other possible diagnoses, but is
relatively unhelpful for primary diagnosis.
● A proportion of blasts (often low) may be
ACUTE MYELOID LEUKEMIA myeloperoxidase-positive.
● Primitive blasts will stain with CD34, but so will they
CLINICAL FEATURES in ALL.
● M4 and M5 subtypes show dot positivity with CD68
Acute myeloid leukemia (AML) is primarily an adult disease. The (monocytoid differentiation).
prognosis is poor, particularly in the elderly. Primary and sec-
ondary (progressing from myelodysplasia) forms are recognized. Special techniques: cytogenetics
The diagnosis is usually made on peripheral blood/marrow aspi-
rate, while the trephine is used to estimate tumor load and also (AML with recurrent cytogenetic translocations.)
● AML with t(8:21)(q22;q22), AML1(core binding factor;
to provide a semi-quantitative measure of response to treatment
(follow-up biopsies) and relapse. CBF␣)/eight twenty-one (ETO).
● Acute promyelocytic leukemia [AML with
t(15:17)(q22;q11-12)] and variants, PML/RAR␣.

PATHOLOGICAL FEATURES ● AML with abnormal bone marrow eosinophils
Most subtypes of AML are remarkably similar in morphologi- [inv(16)(p13q22) or t(16;16)(p13;q11)], CBF␤/MYH11.
cal terms on trephine biopsies. Subclassification is now primarily ● AML with 11q23 (MLL) abnormalities.
Table 10.3: Morphological characteristics of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)
ALL AML
Marrow cellularity; Very high Variable

numbers of blasts
Cell size Small to medium Medium to large
Amount of cytoplasm Minimal – moderate Moderate
Cytoplasmic vacuoles ⫹ or ⫹⫹⫹ (Burkitt) ⫾
Auer rods (smears only) – 60–70% of cases
Cytoplasmic granules – Variable
Nuclear irregularities ⫹⫹ or ⫺ (Burkitt) ⫾
Chromatin Fine Coarse
Nucleoli Absent or few in number, 1–4, prominent
and small and indistinct
ANAPLASTIC LARGE-CELL LYMPHOMA Differential diagnosis

● Florid reactive condition (e.g., viral infection)
● High-grade NHL
CLINICAL FEATURES
This condition is characterized by two peaks of incidence, in
older children, and in the elderly. It accounts for 20–30% of Immunohistochemistry
childhood lymphomas and for 2–3% of adult NHLs. A t(2:5)
chromosome translocation is responsible for the expression of
● CD2⫹ CD3⫹; CD4⫾; CD5⫹; CD7⫹; CD8⫺.
a new fusion protein p80 from the genes nucleophosmin
● Admixed EBV-positive B-cells may be numerous.
(NPM) and anaplastic lymphoma kinase (ALK). ALK-positive
cases account for 90% of young people’s cases and for 70% of Special techniques: cytogenetics
older patients’ cases. ALK positivity associated with a favor- ● TCR genes rearranged in 75% of cases.
able prognosis (5-year survival rate of 80%). The primary sys- ● Ig gene rearrangement in 10% of cases.
temic form may be either nodal or extranodal. Extranodal sites ● Trisomy 3, trisomy 5 and an additional X chromosome
are commonly involved (less so in ALK-negative cases). also seen in some cases.
PATHOLOGICAL FEATURES BURKITT LYMPHOMA

The tumor is typified by large pleomorphic lymphoid cells in
sheets which may resemble metastatic carcinoma. The lesion
CLINICAL FEATURES
shows a cohesive growth pattern. Nuclei are irregular, with a
single prominent nucleolus. Two forms of Burkitt lymphoma are recognized:
Lymphohistiocytic and small cell variants are recognized. 1. The African endemic form (usually of childhood) which
presents with jaw involvement or other extranodal sites.
Differential diagnosis Epstein–Barr virus (EBV) associated with a t(8:14) translo-
cation.
● Other large-cell NHLs 2. The non-endemic form, which usually affects adults, and
● Metastatic carcinoma and melanoma may affect the gastrointestinal tract and other extranodal
● Lymphohistiocytic and small-cell variants recognized sites, although nodal disease also occurs. This condition is
usually non-EBV-related
Burkitt lymphoma accounts for 2.5% of all NHLs.
● CD30⫹ (membrane and Golgi); CD3⫾; CD80⫾;
embryonic membrane antigen (EMA)⫾; CD45⫾;
CD25⫾; p80⫾.
Marrow involvement is seen in 20% of non-endemic cases. The
Special techniques: cytogenetics morphology of the endemic and non-endemic types is identical,
and is usually characterized by diffuse sheets of intermediate-
● Clonal rearrangement of TCR gene in 90% of cases.
size regular cells with little cytoplasm. The nuclei are rounded,
● t(2;5)(p23;35) is frequent.
with up to five or so tiny nucleoli. Mitotic figures are a fre-
quent occurrence. The ‘starry sky’ pattern is not usually seen in
ANGIOIMMUNOBLASTIC T-CELL the marrow.
LYMPHOMA
● Other large B-cell NHLs, particularly lymphoblastic
CLINICAL FEATURES
lymphoma
This condition accounts for 15–20% of T-cell neoplasms and ● Anaplastic carcinoma
1–2% of all NHLs. It usually affects the middle-aged and eld-
erly, and presents with fever, generalized lymphadenopathy, Immunohistochemistry
skin rashes and polyclonal gammopathy. Bone marrow is com- ● sIgM⫹; CD19⫹; CD20⫹; CD22⫹; CD79a⫹; CD10⫹;
monly involved at presentation.
CD5⫺; CD23⫺; TdT⫺.
● Ki-67 positivity in approaching 100% of cells.
The diagnosis is invariably made on lymph node biopsy. In the Special techniques: cytogenetics
marrow there may be foci of pleomorphic immunoblasts with ● Clonal rearrangements of Ig heavy and light chain genes.
a rich admixture of reactive lymphoid cells and a complex ● t(8;14) in all cases (MYC translocation usually at
network of vessels. There is associated fibrosis. band q32).
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)/

SMALL LYMPHOCYTIC LYMPHOMA (SLL)
CLINICAL FEATURES
Distinction between SLL and CLL depends on the tissue
involved; SLL applies unless there is peripheral blood lympho-
cytosis present. The mean age at diagnosis is 60 years, and
males are affected more commonly than females. Some 99% of
cases are B-cell subtypes, and 1% are T-cell subtypes. SLL
accounts for 6–7% of all lymphomas.
Patients are asymptomatic or show constitutional symptoms
in the early stages, typically tiredness and malaise. Presentation
may also occur as an incidental finding, for example with lym-
phocytosis, lymphadenopathy or hepatosplenomegaly. Skin (a)
involvement occurs in T-cell CLL, whilst splenomegaly is char-
acteristic in chronic prolymphocytic leukemia (PLL). Liaison
with the hematologist is important to determine the clinical
picture, the level of lymphocytosis, and flow cytometry data on
peripheral blood/marrow aspirate if available. A marrow
trephine often is not performed when the patient is at an early
stage of the disease, and therapy is not proposed.

Three patterns of CLL are recognized: nodular; interstitial; and
diffuse (with progressively worse prognosis), and the patterns
may be mixed. In nodular CLL the nodules are usually non-
paratrabecular. The small lymphocyte cell type is evident at
scanning power, and at higher power the cell size approximates
to that of a late normoblast. Lymphocytes are very small, (b)
round, and have very little cytoplasm. The nucleus is small and
rounded, with clumped chromatin and inconspicuous nucleoli.
Recognition of proliferation centers is helpful in diagnosis, but
is less common than in nodal involvement and is not seen in
T-cell CLL. Prolymphocytes are up to 50% larger in size than
small lymphocytes.
This can be a difficult area of practice, with many pitfalls:
● Reactive lymphoid aggregates
● All other low-grade NHLs in the marrow
● Acute lymphoblastic leukemia (sometimes)
B-cell: (c)
● CD3⫺; CD5⫹; CD10⫺; CD20⫹; CD23⫹; CD43⫹.
Figure 10.2 Chronic lymphocytic leukemia (CLL) in bone marrow.
T-cell: (a) Nodular pattern; (b) diffuse pattern with proliferation center;
● CD3⫹. (c) diffuse pattern.
Special techniques: cytogenetics

● Normal karyotype in ⬍50% of cases. ● Karyotypic evolution linked to disease progression.
● All clonal cytogenetic abnormalities (except for 13q ● Trisomy 12; 14q⫹; 11q deletion/translocation; 17q13
deletions/translocations) are associated with a worse deletion/translocation; Ig gene rearrangement; p53
prognosis. mutations.
DIFFUSE LARGE B-CELL NHL may be diffuse. It is always worthwhile carrying out basic
immunohistochemistry on a staging marrow for low-grade NHL
to identify subtle deposits initially overlooked on the H&E stain-
CLINICAL FEATURES ing. Grading is not usually performed on marrow samples, but
Diffuse large B-cell NHL constitutes about 30% of adult any grade discordance or progression compared with the orig-
NHLs. Patients are usually aged over 40 years and present with inal nodal grade should be reported.
rapidly enlarging lymphadenopathy. The disease may be extra-
nodal, and is potentially curable.

Marrow involvement is less common than in low-grade NHL,
but is usually more obvious. Typically, the infiltrate shows sheets
of large lymphoid cells. Interstitial infiltration may be less easy
to identify – it is always good practice to screen a hypercellular
marrow with some routine immunohistochemical markers
(e.g., CD3 and CD20) if the cause of the hypercellularity can-
not be explained on the H&E staining. Marrow involvement
by a T-cell-rich large B-cell lymphoma may at first glance
appear to be over-run by T-cells – it is very helpful to know the
details of the primary nodal pathology.
(a)
● Metastatic anaplastic carcinoma
● sIg⫾; CD19⫹; CD20⫹; CD22⫹; CD79a⫹; CD10⫾;
CD5⫾; CD45⫾.

● Ig gene rearrangements common.
● t(14;18) in 20–30% of cases (indicating follicle center
cell origin).
● Many cases have complex abnormalities.
FOLLICULAR LYMPHOMA
(b)
CLINICAL FEATURES
Follicular lymphoma affects adults, usually those aged more
than 40 years. Patients are generally well at presentation, which
is usually with lymphadenopathy that is often widespread. The
condition is slowly progressive and usually incurable, although
some success has been achieved with grade 3 tumors. The
marrow is involved in 40% of cases on staging. Follicular lym-
phoma accounts for 22% all NHLs.

Marrow involvement is usually seen as paratrabecular aggre-
gates of follicle center cells admixed with a variable number of
‘background’ small T lymphocytes. The foci appear to wrap
themselves around the trabeculum, and unless this strict crite- (c)
rion is adhered to diagnostic errors will occur. Focal involve-
ment is associated with a deposit of reticulin; this may help in Figure 10.3 Interstitial infiltrate of large B-cell NHL. (a, b) H&E
locating a subtle deposit. Much less commonly the involvement staining. (c) Immunoperoxidase staining for CD20.
(a)
(b)
(d)
Figure 10.4 (a, b) Follicular lymphoma in marrow, showing

paratrabecular foci of infiltration. (c) High-power view of focus.
(c) (d) Positive staining with CD10.
Differential diagnosis there being a male:female incidence ratio of 5:1. The condition
● Reactive lymphoid aggregates; these are rarely presents with tiredness, recurrent infections and abdominal dis-
paratrabecular comfort. Splenic involvement is common. It may be detected by
● Other low-grade NHLs may be seen in a paratrabecular finding characteristic ‘hairy’ cells in the peripheral blood film.
location
Marrow involvement is usually in the form of sheets of clear cells
● sIg⫹; CD19⫹; CD20⫹; CD22⫹; CD79a⫹; CD10⫾;
with centrally placed round/ovoid nuclei and moderate amounts
CD5⫺; CD23⫾; CD43⫺.
of clear cytoplasm. It may be either focal, diffuse or interstitial.
Focal areas of hemorrhage may be seen. Cell boundaries are usu-
ally very distinct. A fine ‘chicken-wire’ reticulin mesh is charac-
● t(14:18)(q32;q21) in 70–95% of cases (involves teristic, and is often responsible for a dry tap on bone marrow
rearrangement of the BCL2 gene). aspiration.
HAIRY CELL LEUKEMIA Differential diagnosis

● It is relatively easy to overlook a subtle infiltrate of
hairy cells
CLINICAL FEATURES ● Background marrow may give an impression of
This is an uncommon lymphoproliferative disorder which is myelodysplasia, and the interstitial hairy cells may be missed
most likely related to CLL. It usually affects middle-aged males, ● Systemic mast-cell disease
● Assessing low-level residual disease after treatment can be Special techniques: cytogenetics
difficult ● No specific abnormality described.
HODGKIN’S DISEASE
● CD79a⫹; CD20⫹; CD68⫹; DBA44⫹.
CLINICAL FEATURES
Hodgkin’s disease uncommonly involves the bone marrow, and
almost never at presentation. Marrow involvement is sometimes
seen on relapse. Staging bone marrow examination (at diagnosis)
has been discontinued in many centers because of an almost nil
yield. In view of the relatively uncommon finding of Hodgkin’s
disease in the marrow, it is advisable to review the primary nodal
pathology to ensure that the original diagnosis is correct.

Marrow involvement is usually focal or as confluent sheets. The
histological appearances tend to parallel the nodal picture with
a mixed reactive-like lymphoid, histiocytic and eosinophil infil-
(a) trate often with substantial fibrosis. Hodgkin’s or Reed–Sternberg
(b) (a)
(c) (b)
Figure 10.5 (a–c) Diffuse/interstitial marrow infiltration by hairy Figure 10.6 Marrow infiltration by Hodgkin’s disease.
cell leukemia. Note the scattered late normoblasts with small inky Note the large Reed–Sternberg/Hodgkin’s cells, and a dense
black nuclei in among the infiltrate and diffuse ‘chicken-wire’ reticulin lymphoid background. [(a, b) H&E staining; (c) Immunoperoxidase
deposition. [(a, b) H&E staining; (c) Reticulin staining.] for CD30.]
that an IgM paraproteinemia may complicate a number of

B-cell NHLs, and that Waldenström’s macroglobulinemia and
lymphoplasmacytic lymphoma are not absolutely synonymous.

This lymphoma is characterized by nodular or diffuse infiltra-
tion by small lymphoid cells that are typically lymphoplasma-
cytoid. The majority of cells are usually small lymphocytes with
some plasmacytoid small lymphocytes and true plasma cells.
Plasmacytoid cells may contain Dutcher (apparently intra-
nuclear) or Russell (cytoplasmic) eosinophilic (PAS-positive)
inclusions. Early involvement may be subtle.
(c) ● As before, all other low-grade NHLs
● Multiple myeloma (however, only very rarely secretes IgM)
● CD3⫺; CD5⫺; CD10⫺; CD19⫹; CD20⫹; CD23⫺;
cells may be difficult to identify amongst this background, but sIg (M)⫹.
identification is usually assisted by immuno studies.
● High-grade NHL, especially T-cell-rich large B-cell NHL
● Ensure ‘Hodgkin’s cells’ are not megakaryocytes (use CD34)
● Cellular phase of some myeloproliferative disorders
● Metastatic carcinoma (sometimes)
● Classical Reed–Sternberg cells/Hodgkin’s cells: CD30⫹;
CD15⫹; CD45⫺; EMA⫺; CD34⫺.
● Lymphocyte-predominant (LP) Hodgkin’s cells: B-cell
antigens⫹; CD15⫺; CD30⫺; CD45⫹; EMA⫾.
Special techniques: cytogenetics (a)
The cytogenetics of Hodgkin’s disease is complex, and the

reader is referred to the section on Nodal lymphomas (p. 684).
LYMPHOPLASMACYTIC NHL/WALDENSTRÖM’S
MACROGLOBULINEMIA
CLINICAL FEATURES
This is a low-grade B-cell NHL which affects bone marrow
(invariably), spleen and lymph nodes (20–40%). The majority
of patients have an IgM paraprotein, and 30% have blood
hyperviscosity syndromes.
The condition presents with increasing tiredness, visual dis-
turbances (hyperviscosity), neuropathies (IgM deposition),
(b)
cryoglobulinemia and coagulopathies. A leukocytosis occurs in
30% of cases, with a relative or absolute lymphocytosis. This
Figure 10.7 (a) Low- and (b) medium-power views of
condition accounts for 1% of all lymphomas. lymphoplasmacytic non-Hodgkin lymphoma in a case of
The diagnosis depends on the integration of clinical, mor- Waldenström’s macroglobulinemia. Note the intranuclear
phological and immunological features. It should also be noted Dutcher bodies.
Note: in day-to-day practice, this is one of two low-grade B-cell

NHLs in the marrow that is only CD20-positive. All the others,
except for marginal zone lymphoma (e.g., MALToma) have a
second positive B-cell marker (other than CD20).

● t(9;14)(p13;q32): linked to the PAX-5 gene rearrangement.
MANTLE CELL LYMPHOMA
CLINICAL FEATURES
It is important to recognize this lymphoma because it has a
worse prognosis than the other low-grade B-cell NHLs. It has
(a)
a median survival of 3–5 years, and is usually incurable. It
commonly affects males aged over 50 years, and presents with
constitutional symptoms. Lymph nodes are the most com-
monly involved site, though marrow and spleen involvement is
also common. Gastrointestinal tract involvement occurs in up
to 30% of cases (polyps). Mantle cell lymphoma accounts for
6% of all lymphomas.

Marrow involvement is seen in 50–80% of cases on staging.
There is a very variable pattern of marrow infiltration, namely
nodular (paratrabecular or non-paratrabecular), interstitial
or diffuse. The infiltrate is composed of a uniform population
of small/intermediate-sized lymphoid cells (centrocyte-like).
A blastoid subtype is also recognized which has an even worse (b)
prognosis.
Figure 10.8 (a) Mantle cell lymphoma in bone marrow.
(b) Positive nuclear staining using immunoperoxidase for cyclin D1.
● Other large-cell NHLs 3. Splenic marginal zone lymphoma (with circulating villous
● Metastatic carcinoma and melanoma lymphocytes).
● Lymphohistiocytic and small cell variants recognized
The three neoplasms share almost identical immunophenotypic
Immunohistochemistry profiles. There are however differences at genetic and chromo-
somal levels. Marrow involvement is very uncommon except in
● CD3⫺; CD5⫹ (negative in 5%); CD10⫺; CD20⫹;
splenic marginal zone lymphoma. Taken together, the marginal
CD23⫺; cyclin D1⫹.
zone lymphomas account for 10% of NHLs.

● t(11:14) translocation characteristic of condition (activates
cyclin D1). Marrow involvement may be either nodular (non-paratrabecu-
● Ig heavy and light chain gene rearrangements. lar) or diffuse. It is characterized by a monotonous population
of small to intermediate-sized lymphoid cells, sometimes with
plasmacytoid differentiation. The morphology may vary from
MARGINAL ZONE LYMPHOMA case to case.
Marginal zone lymphoma comprises three distinct clinico-

● Reactive lymphoid aggregates
pathological entities, each of which is classified separately under
● Other low-grade B-cell NHLs
the WHO system. These comprise:
1. Extra-nodal marginal zone lymphoma (e.g., MALToma of Immunohistochemistry
the gastrointestinal tract). ● CD19⫹; CD20⫹; CD22⫹; CD79a⫹; IgM variable; IgD
2. Nodal marginal zone lymphoma. variable; CD5⫺; CD10⫺; CD23⫺; BCL2⫾.
(a) (c)
(b) (d)
Figure 10.9 (a–d) Medium- and high-power views of marrow infiltration by splenic marginal zone lymphoma. Note the admixture of small
lymphoid cells, plasma cells, and occasional large lymphoid cells.
MULTIPLE MYELOMA
The following applies primarily to MALTomas. Splenic mar-
CLINICAL FEATURES
ginal zone lymphomas are much more variable, except for
complete or partial trisomy 3. This condition may present as malaise, bone pain, together
● Ig heavy and light chain gene rearrangements common. with symptoms related to either anemia or hypercalcemia. The
● Trisomy 3 in 60% of cases. diagnosis depends on a combination of features including mar-
● t(11;18)(q21;q21) in 25–50% of cases. row plasma cell load (⬎10% monotypic plasma cells), para-
● t(1:14)(p22;q32) (fusion of BCL10 gene to Ig heavy chain proteinemia with immune pariesis and lytic bone lesions (two
gene on chromosome 14q32). out of three required).
Marrow involvement may be either interstitial or diffuse. Plasma

cells may be atypical and difficult to recognize as such – the
paranuclear clear halo (hof) is helpful – but erythroblasts also
have this feature. A marrow containing ⬍10% monotypic
plasma cells is classified as monoclonal gammopathy of uncer-
tain significance (MGUS).
● Reactive plasmacytosis
● B-cell NHL (low-grade or high-grade) especially
Waldenström’s macroglobulinemia
● Promyelocytes and erythroblasts resemble plasma cells
(a)
● Light chain immunohistochemistry requires a very high
standard of technical quality to be interpreted with
confidence.
● Reactive plasmacytosis – usually maintains the normal
kappa:lambda ratio of 2:1.
● Usually a ratio of ⬎10:1 kappa:lambda or ⬎5:1
lambda:kappa required.
● A light chain restriction ratio of ⬎16:1 is diagnostic of a
neoplastic process.
● A subset of the plasma cells may be CD20⫹ (more are
CD79a⫹). CD38 and 138 are relatively specific plasma
cell markers but need to be correlated with the
morphology of the cells concerned.
● Plasma cells may be EMA⫹, but experience suggests that
this is not very helpful.
(b) ● Positive staining with cyclin D1 has been reported to
confer a worse prognosis.

● Ig gene rearrangements.
● Wide range of cytogenetic abnormalities reported.
PERIPHERAL T-CELL LYMPHOMA, UNSPECIFIED
CLINICAL FEATURES
It should be noted that T-cell lymphomas have been extensively
subclassified in the WHO classification. Overall, mature T-cell
lymphomas account for 7–8% of all NHLs. This brief account
addresses the most common subgroup, peripheral T-cell lym-
(c)
phoma unspecified. This is a group of predominantly nodal
T-cell lymphomas that constitute a significant proportion of the
Figure 10.10 (a, b) Marrow infiltration by multiple myeloma.
T-cell lymphomas seen in Western countries. The majority of
(c) Immuno preparation showing predominant kappa-positive
plasma cell population with a negative lambda-stained insert. patients are adults with nodal, sometimes skin and variable
visceral involvement. The male:female ratio is 1:1. Marrow
involvement is common.
Detection of myeloma in the marrow may be either straight-
forward or may be one of the more challenging aspects of bone
marrow pathology. In general, plasma cells are more easily rec- The marrow infiltrate is usually similar to the primary pathology.
ognized as such in the marrow aspirate than in the trephine. There may be an attendant eosinophil infiltrate.
(a) (b) (c)
(d) (e)
Figure 10.11 Marrow infiltration by diffuse sheets of high-grade peripheral T-cell lymphoma (unspecified). [(a–c) H&E staining; (d) CD-3-positive; (e) CD30-positive.]
● The biggest problem is deciding whether the infiltrate
is neoplastic, particularly if the marrow is the primary
tissue for diagnosis. This is particularly the case with small
T-cell infiltrates
● May require gene rearrangement studies to confirm
neoplastic nature
● CD2⫾; CD3⫾; CD4 ⬎ CD8; CD4⫾; CD8⫾;
CD5⫾.

(a)
● T-cell receptor (TCR) genes rearranged in the majority
of cases.
● No single consistent abnormality recognized.
● Trisomy 3 common in lymphoepithelioid (Lennert) variant.
PRECURSOR LYMPHOBLASTIC LEUKEMIA/

LYMPHOBLASTIC LYMPHOMA (B- AND
T-CELL ACUTE LYMPHOBLASTIC
LEUKEMIA)
CLINICAL FEATURES
These are precursor cell lymphoid neoplasms. The age range
of patients is as follows: 75% of precursor B-lymphoblastic
leukemia (B-ALL) occurs in children aged under 6 years, while (b)
75% of precursor B-lymphoblastic lymphoma (B-LBL) occurs
in young people aged under 18 years. Precursor T-lymphoblastic Figure 10.12 (a) Precursor lymphoblastic leukemia/lymphoblastic
leukemia (T-ALL) accounts for 15% of childhood leukemias, lymphoma (B-cell); (b) Acute myeloblastic leukemia.
while precursor T-lymphoblastic lymphoma (T-LBL) accounts
for 80–90% of lymphoblastic lymphomas. Overall, 80% of all
precursor cases are B-cell and 20% T-cell. The overwhelming
majority presenting in bone marrow are B-cell, while T-cell Immunohistochemistry
lesions are often organ-based (e.g., the testis or mediastinum). B-cell:
● TdT⫹; CD10⫾; CD19⫹; CD20⫺ or weak; CD79a⫹;
sIg⫺; myeloperoxidase⫾
T-cell:
The B- and T-cell subtypes are morphologically identical.
● TdT⫹; CD2 variable; CD3⫹; CD4⫾; CD5 variable;
Marrow spaces are infiltrated diffusely in sheets with elimina-
CD7⫹; CD8⫾
tion of background precursors. There is a uniform population
of lymphoid cells with a high nuclear:cytoplasmic ratio. There
is a narrow rim of eosinophilic/faintly basophilic cytoplasm, Special techniques: cytogenetics
while the nuclei are round/ovoid with very small and often mul- B-cell:
tiple nucleoli [in contrast with the situation in acute myelo- ● Range of cytogenetic abnormalities recognized.
blastic leukemia (AML)]. The chromatin pattern is fine, and ● t(9:22)(q34;q11.2) (50% of cases); BCR/ABL and
mitotic figures are numerous. others.
● Specific cytogenetic profile prognostically important and
modifies treatment protocols.

● Acute myeloid leukemia T-cell:
● Diffuse infiltration by CLL, particularly if of intermediate ● One-third of cases show translocations involving the ␣
cell size and ␦ T-cell receptors.
Table 10.4: Key immunophenotypic profiles of low-grade between the marrow and nodal histology. This is usually char-
non-Hodgkin lymphomas acterized by high-grade nodal histology with concurrent low-
grade histology in the marrow. On a more subtle level, the
Low-grade lymphoma Key positive markers
nodal and marrow histology may appear the same but show
Chronic lymphocytic leukemia CD5; CD20; CD23 minor differences between their immunophenotypes.
Waldenström’s macroglobulinemia CD20
Mantle cell lymphoma CD5; CD20; Cyclin D1
Follicular lymphoma (FL) CD20: see note below;
METASTATIC DISEASE
BCL2 and 6 (not specific)
Marginal zone lymphoma CD20
CLINICAL FEATURES
Staging trephines for patients with a primary diagnosis of car-
REFINING THE DIAGNOSIS OF LOW-GRADE cinoma are now rarely performed, and although marrow
B-CELL NHL IN BONE MARROW INFILTRATES involvement is common in advanced malignant disease, mar-
row examination is rarely justified. In the present author’s hos-
Having decided that a bone marrow lymphoid infiltrate is neo- pital (which has a large oncology practice), marrow trephine
plastic, the pathologist will be asked for an opinion on whether biopsy showing metastatic carcinoma has usually been carried
it is either low or high grade and, if it is low grade, what sort out to investigate anemia where the differential diagnosis
of lymphoma it is. The majority of low-grade B-cell NHLs are includes marrow failure (e.g., post chemotherapy or marrow
characterized by positive staining with more than one B-cell infiltration by tumor). Common primary carcinomas include
marker. Only two are not: lymphoplasmacytic NHL (usually breast, bronchus (especially small cell) and prostate. Sarcomas
Waldenström’s macroglobulinemia) and marginal zone lym- rarely metastasize to the marrow. Marrow trephines are com-
phoma. The key immunophenotypic profiles of the low grade monly part of the work-up in pediatric oncology practice.
B-cell NHLs, CD20 and/or CD79a which would be expected to
be positive in all these lesions are listed in Table 10.4.
In the present authors’ laboratory, the CD10 marker has been
found to be less useful in separating the subtypes of low-grade Two basic patterns are seen: (i) marrow involvement by tumor
B-cell NHLs in marrow samples. There is frequently extensive aggregates; and (ii) extensive fibrosis obscuring carcinoma
background staining from polymorphs, and it is negative suffi- cells. Immunohistochemistry is usually helpful to confirm diag-
ciently often in the follicular lymphomas to render it an unreliable nosis and to point to the primary origin.
marker in the bone marrow trephine. In diagnosing marrow
involvement in FLs, heavy reliance is placed on the location
and morphology of the lesions, and only secondary attention is
paid to the immunophenotype (as long as this situation is not ● High-grade NHL, especially T-cell-rich large B-cell NHL
contradictory to the diagnosis). In the diagnosis of Waldenström’s ● Ensure ‘Hodgkin’s cells’ are not megakaryocytes (use CD34)
macroglobulinemia, information about the aspirate and any ● Cellular phase of some myeloproliferative disorders
paraproteinemia is also very important, as is the cytomorphol- ● Metastatic carcinoma (sometimes)
ogy of the infiltrate (see below). In a proportion of staging
trephines for patients with nodal or extranodal low-grade B-cell Immunohistochemistry
NHLs, having identified evidence of marrow involvement it may ● Should be tailored to the suspected primary tumor.
not be possible to allocate a grading of more than ‘low-grade ● Pan cytokeratin (and CD45) examination is a useful
B-cell NHL’ to the marrow specimen because the defining fea-
precaution when presented with a marrow with extensive
tures required to diagnose a specific subtype may not be evident.
fibrosis.
● Cytokeratin subsets, prostate-specific antigen (PSA),
DISCORDANCE thyroglobulin, thyroid transcription factor 1 (TTF1; lung)
and estrogen receptor (ER; breast) may also be helpful.
As indicated above, it is not always straightforward to classify a
non-Hodgkin lymphoma – particularly low-grade lymphomas –
on a bone marrow trephine. The task is made more compli- Special techniques: cytogenetics
cated still by the relatively frequent occurrence of discordance ● As for the primary disease.
(a) (b)
Figure 10.13 Marrow infiltration by metastatic carcinoma of breast with pronounced desmoplastic reaction. [(a) H&E staining; (b) reticulin.]
(a) (b)
Figure 10.14 Metastatic alveolar rhabdomyosarcoma. [(a) H&E staining; (b) immunohistochemistry for desmin.]
Lymph node and related lymphoid tissue tumors 667
10.2 LYMPH NODE AND RELATED LYMPHOID

TISSUE TUMORS
Lee B Jordan, Awatif I Al-Nafussi and Kathryn M McLaren
Overview:The WHO (2001) classification of tumors of Primary effusion lymphoma (PEL) 711
hematopoietic and lymphoid tissues 668 Splenic marginal zone lymphoma (S-MZL) 712
Atypical lymphoid disorders 670 Plasma cell neoplasms 712

Acquired immune deficiency syndrome (AIDS) 670 Monoclonal immunoglobulin deposition diseases 712
Autoimmune lymphoproliferative syndrome 670 Plasma cell myeloma 713
Castleman’s disease 671 Plasmacytoma 713
Hemophagocytic lymphohistiocytosis 673 Precursor lesion: monoclonal gammopathy of
Histiocytic necrotizing lymphadenitis uncertain significance (MGUS) 713
(Kikuchi–Fujimoto disease) 673
Post-transplant lymphoproliferative disorders (PTLD) 674 B-cell, proliferations of uncertain malignant potential 713
Lymphomatoid granulomatosis 713
Histiocytic and dendritic cell tumors 675 Post-transplant lymphoproliferative disorder,
Crystal-storing histiocytosis 675 polymorphic (PTLD) 713
Follicular dendritic cell sarcoma 675
Interdigitating cell dendritic sarcoma/tumor 676 Non-Hodgkin lymphoma:T-cell and NK-cell neoplasia 714
Langerhans’ cell histiocytosis 677
Malignant histiocytosis 678
Rosai–Dorfman disease 679 Precursor T-cell neoplasia 714
Precursor T-lymphoblastic leukemia (T-ALL)/
lymphoblastic lymphoma (T-LBL) 714
Myeloid sarcoma 680
Plasma cell neoplasia: multiple myeloma and Mature T-cell and NK-cell neoplasia: general/systemic 715
solitary plasmacytoma 680 Adult T-cell leukemia/lymphoma (ATLL) 715
Richter’s syndrome 682 Aggressive NK-cell leukemia (AgNKL) 716
Anaplastic large cell lymphoma (ALCL) 716
Angioimmunoblastic T-cell lymphoma (AITL) 719
Enteropathy-type T-cell lymphoma (ETTL) 720
Extranodal NK-/T-cell lymphoma, nasal type (EN-NKTL) 722
Classical Hodgkin lymphoma 683 Hepatosplenic T-cell lymphoma (HSTL) 723
Hodgkin lymphoma (HL) 683 Peripheral T-cell lymphoma, unspecified (PTL-U) 724
Lymphocyte-depleted Hodgkin lymphoma (LD-HL) 684 T-cell large granular lymphocyte (lymphocytic)
Lymphocyte-rich Hodgkin lymphoma (LR-HL) 685 leukemia (T-LGL) 726
Mixed cellularity Hodgkin lymphoma (MC-HL) 687 T-cell prolymphocytic leukemia (T-PLL) 727
Nodular sclerosis Hodgkin lymphoma (NS-HL) 688
Mature T-cell and NK-cell neoplasia: predominantly skin-related 728
Non-classical Hodgkin lymphoma 690
Blastic NK-cell lymphoma (BNKL) 728
Nodular lymphocyte-predominant Hodgkin
Mycosis fungoides and Sézary syndrome (MF, SS) 728
lymphoma (NLP-HL) 690
Primary cutaneous CD30-positive T-cell
lymphoproliferative disorders 728
Non-Hodgkin lymphoma: B-cell neoplasia 692 Subcutaneous panniculitis-like T-cell lymphoma (SPL-TL) 728
Precursor B-cell neoplasia 692
T-cell proliferations of uncertain malignant potential 729
Precursor B-lymphoblastic leukemia (B-All)/lymphoblastic
Lymphomatoid papulosis (LP) 729
lymphoma (Precursor B-cell acute lymphoblastic
leukemia, B-LBL) 692
Mastocytosis 730
Mature B-cell neoplasia 693
B-cell prolymphocytic leukemia 693 Mesenchymal tumors of lymph nodes 731
Burkitt lymphoma (BL) 693 Inflammatory (pseudotumor) myofibroblastic tumor 731
Chronic lymphocytic leukemia/small lymphocytic Intranodal myofibroblastoma 732
lymphoma (CLL/SLL) 695 Kaposi’s sarcoma of the lymph node 733
Diffuse large B-cell lymphoma (DL-BCL) 696 Polymorphous hemangioendothelioma of the
Follicular lymphoma (FL) 699 lymph node 734
Follicular lymphoma variant: diffuse follicle center Primary vascular tumors of lymph nodes 734
lymphoma (DFCL) 702 Smooth muscle proliferation in lymph nodes 734
Hairy cell leukemia (HCL) 703 Vascular transformation of sinuses in lymph nodes 734
Intravascular large B-cell lymphoma (IVL-BCL) 703
Lymphoplasmacytic lymphoma/Waldenström Miscellaneous tumors of lymph nodes 735
macroglobulinemia (LPL) 704 Bacillary angiomatosis 735
Mantle cell lymphoma (MCL) 706 Lymph node inclusions 735
Marginal zone B-cell lymphoma, extranodal (EN-MZL) 707 Mycobacterium avium-intracellulare-induced spindle
Marginal zone B-cell lymphoma, nodal (N-MZL) 709 cell pseudotumor 736
Mediastinal (thymic) large B-cell lymphoma (ML-BCL) 710 Secondary tumors in lymph nodes 737
GENERAL COMMENTS and, for the first time, combined aspects beyond pure morphol-
ogy into a classification, it fell short. The REAL classification
In this part of the chapter we will be covering various disorders was simply a stepping stone in our understanding of lymphoid
of the lymphoid tissue that arise within lymph nodes and neoplasia, and progress during the late 1990s was rapid.
within other lymphoid tissues (excluding spleen and thymus). Moreover, as our knowledge expanded, the inadequacies of the
Although the pattern of changes seen within lymphoid tissues REAL classification became apparent. An attempt to unify the
are quite extensive, from the non-infectious reactive to the pathological world behind one robust classification was made
infectious reactive to the neoplastic, we shall restrict ourselves by the World Health Organization (WHO). The effort began in
to those that are true neoplasms and those that may be con- 1994/5 by various steering committees utilizing the advances
fused as such. made in the REAL classification, and was extended to cover
myeloid, lymphoid, histiocytic/dendritic cell and mast cell neo-
plasia, whilst bringing clinicians, oncologists and pathologists
OVERVIEW: THE WHO (2001) together, and incorporating recent scientific advances in the field.
CLASSIFICATION OF TUMORS OF The result is the ‘World Health Organization [2001]
Classification of Tumours of Haematopoietic and Lymphoid
HEMATOPOIETIC AND LYMPHOID TISSUES Tissues’, as described excellently in the recent WHO publication
(Jaffe et al., 2001). Some drawbacks still remain – most notably
Various classifications of lymphoid neoplasia have evolved over the classification of cutaneous lymphomas – and some may still
the years. Those commonly used in the past have included clas- feel the need to use the 1997 classification proposed by the
sifications for non-Hodgkin lymphomas such as the Working Cutaneous Lymphoma Study Group of the European Organi-
Formulation, the Lukes and Collins, the Kiel and others related zation for Research and Treatment of Cancer (EORTC) (Willemze
to leukemias and Hodgkin’s disease. These were based on the et al., 1997). Other areas that need addressing include the amor-
morphological aspects of lymphoid neoplasia. During the 1980s phous diffuse large B-cell lymphoma category that is in danger of
and 1990s, these classifications were rendered increasingly obso- being used as a dumping ground. However, these aspects are triv-
lete by developments in immunophenotyping, cytogenetics and ial considering what went before, and future revisions will – no
molecular genetic analysis. For this reason, the Revised European- doubt – add to the current classification. Classification, itself,
American Lymphoma (REAL) classification was proposed dur- must be seen as a dynamic process that will change in light of
ing the mid 1990s. Although the REAL incorporated all nodal advances and with the need to provide information that is clini-
and extranodal lymphoid tumors (including Hodgkin’s disease), cally relevant. Unsurprisingly, the contents of this section will
recognized new categories (such as the mantle cell lymphoma) constantly refer to the WHO (2001) classification.
Table 10.5: Modified World Health Organization (2001) Classification of Tumours of Haematopoietic and Lymphoid Tissues. Reproduced
(in part) from Jaffe ES, Harris NL, Stein H, and Vardiman JW (eds) World Health Organization Classification of Tumours. Pathology and genetics:
tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer (IARC) Press, Lyon, 2001.
HISTIOCYTE/DENDRITIC CELL LINEAGE

HISTIOCYTIC AND Macrophage/histiocytic Histiocytic sarcoma
DENDRITIC-CELL Dendritic cell Langerhans’ cell histiocytosis
NEOPLASIA Langerhans’ cell sarcoma
Interdigitating dendritic cell sarcoma/tumor
Follicular dendritic cell sarcoma/tumor
Dendritic cell sarcoma, not otherwise specified
LYMPHOID LINEAGE
HODGKIN LYMPHOMA Classical Lymphocyte-depleted Hodgkin lymphoma
Lymphocyte-rich Hodgkin lymphoma
Mixed cellularity Hodgkin lymphoma
Nodular sclerosis Hodgkin lymphoma
Non-classical Nodular lymphocyte predominant Hodgkin lymphoma
B-CELL NEOPLASIA Precursor Precursor B lymphoblastic leukemia/lymphoma
(NON-HODGKIN Mature B-cell prolymphocytic leukemia
LYMPHOMA) Burkitt lymphoma/leukemia
Chronic lymphocytic leukemia/small lymphocytic lymphoma
Diffuse large B-cell lymphoma
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid
tissue
Nodal marginal zone B-cell lymphoma
Follicular lymphoma (and variant)
(continued)
Lymph node and related lymphoid tissue tumors 669
Hairy cell leukemia

Intravascular large B-cell lymphoma
Lymphoplasmacytic lymphoma
Mantle cell lymphoma
Mediastinal (thymic) large B-cell lymphoma
Plasma cell myeloma
Plasmacytoma
(Monoclonal gammopathy of uncertain significance)
(Monoclonal immunoglobulin deposition diseases)
Primary effusion lymphoma
Splenic marginal zone lymphoma
Uncertain malignant potential Lymphomatoid granulomatosis
Post-transplant lymphoproliferative disorder
T-CELL AND NK-CELL Precursor Precursor T lymphoblastic leukemia/lymphoma

NEOPLASIA (NON- Blastic NK cell lymphoma (uncertain stage of differentiation)
HODGKIN LYMPHOMA) Mature [General/systemic] Adult T-cell leukemia/lymphoma
Anaplastic large cell lymphoma
Angioimmunoblastic T-cell lymphoma
Enteropathy type T-cell lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Hepatosplenic T-cell lymphoma
Peripheral T-cell, lymphoma, unspecified
T-cell large granular lymphocytic leukemia
Aggressive NK-cell leukemia
T-cell prolymphocytic leukemia
Mature [Skin related] Subcutaneous panniculitis-like T-cell lymphoma
Blastic NK cell lymphoma (uncertain stage of differentiation)
Mycosis fungoides/Sézary syndrome
Primary cutaneous anaplastic large cell lymphoma
Uncertain malignant potential Lymphomatoid papulosis (including ‘Borderline’ lesions)
MAST CELL LINEAGE
MASTOCYTOSIS Cutaneous mastocytosis

Indolent systemic mastocytosis
Systemic mastocytosis with associated clonal, hematological
non-mast cell lineage disease
Aggressive systemic mastocytosis
Mast cell leukemia
Mast cell sarcoma
Extracutaneous mastocytoma
MYELOID LINEAGE
ACUTE MYELOID With recurrent AML with t(8;21)(q22;q22), (AML1/ETO)

LEUKEMIA cytogenetic abnormalities AML with inv(16)(p13;q22) or t(16;16(p13;q22),
(CBF␤/MYH11)
Acute promyelocytic leukemia (AML with t(15;17)(q22;q12),
(PML/RAR␣) and variants)
AML with 11q23 (MLL) abnormalities
With multilineage With prior myelodysplastic syndrome
dysplasia Without prior myelodysplastic syndrome
With myelodysplastic Alkylating agent-related
syndrome, therapy related Topoisomerase II inhibitor-related
Not otherwise categorized Acute myeloid leukemia, minimally differentiated
Acute myeloid leukemia without maturation
Acute myeloid leukemia with maturation
Acute myelomonocytic leukemia
Acute erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma
(continued)
CHRONIC MYELO- Chronic myelogenous leukemia

PROLIFERATIVE DISEASE Chronic neutrophilic leukemia
Chronic eosinophilic/leukemia/hypereosinophilic syndrome
Polycythemia vera
Chronic idiopathic myelofibrosis
Essential thrombocythemia
Chronic myeloproliferative disease, unclassifiable
MYELODYSPLASTIC/ Chronic myelomonocytic leukemia
MYELOPROLIFERATIVE Atypical chronic myeloid leukemia
DISEASE Juvenile myelomonocytic leukemia
Myelodysplastic/myeloproliferative diseases, unclassifiable
MYELODYSPLASTIC Refractory anemia
SYNDROME Refractory anemia with ringed sideroblasts
Refractory cytopenias with multilineage dysplasia
Refractory anemia with excess blasts
Myelodysplastic syndrome associated with
isolated del(5q) chromosome abnormality
Myelodysplastic syndrome, unclassifiable
Ambiguous lineage [No further subtype]
ATYPICAL LYMPHOID DISORDERS
ACQUIRED IMMUNE DEFICIENCY SYNDROME predilection for extranodal sites, such as the central nervous
system, gastrointestinal tract, bone marrow, and liver. The cen-
(AIDS)
tral nervous system lymphomas are consistently associated
with Epstein–Barr virus (EBV), but overall only around 40% of
CLINICAL FEATURES all AIDS-associated NHLs are associated with EBV.
The acquired immune deficiency syndrome (AIDS) results from

a lymphotropic retrovirus (HIV, human immunodeficiency virus) AUTOIMMUNE LYMPHOPROLIFERATIVE
infection, and is characterized by specific opportunistic infec- SYNDROME
tions and malignancies. The virus is transmitted primarily by
semen and blood. Infection was limited principally to defined
risk groups – that is, homosexual men and intravenous drug CLINICAL FEATURES
users – but is becoming more frequent within the wider het- Autoimmune lymphoproliferative syndrome is a multicentric
erosexual population, particularly in Asia, China and Africa. lymphadenopathy in association with clinical and laboratory
Patients infected with HIV are prone to a wide variety of lym- findings suggestive of an ‘autoimmune disease’. This condition
phoproliferative disorders. In these patients, the clinical presen- is associated with a genetic defect in programmed cell death, or
tation of malignant lymphoma often overlaps with that of benign apoptosis, leading to breakdown of lymphocyte homeostasis
lymphoid proliferations. Both may include lymphadenopathy, and normal immunological tolerance. Some authors have referred
splenomegaly, blood and bone marrow dyscrasias, and to this condition as Canale–Smith syndrome or lymphoprolif-
lymphocyte-rich effusions. Head and neck manifestations erative syndrome with autoimmunity.
include cervical lymphadenopathy and Kaposi’s sarcoma as well Patients frequently have lymphadenopathy, splenomegaly and
as parotid gland enlargement due to hyperplastic changes of the hepatomegaly, especially at young ages. Elevated numbers and
intra-parotid lymph nodes or due to benign lymphoepithelial percentages (⬎1%) of double-negative (CD4–CD8–) T cells,
lesions. Oral manifestations include Kaposi’s sarcoma, candidiasis, and characteristic pathological findings in lymph nodes or
hairy leukoplakia, precocious periodontal disease, xerostomia, spleen are other important diagnostic features.
herpes simplex, recurrent aphthae, erythema multiforme, and
venereal warts. Recently a ‘multicentric’ Castleman’s disease has
been noted in these patients.
The most common forms of lymphomas that occur in The lesions are characterized by paracortical hyperplasia with
patients with AIDS are diffuse large B-cell lymphomas. Other prominent vascular proliferation and many lymphoid folli-
peculiar forms of lymphoma occurring in AIDS are primary cles with germinal centers. The paracortical area usually
effusion lymphoma and plasmablastic lymphoma. The lym- contains numerous small T lymphocytes without cytological
phoma is often widespread at presentation (stage III/IV) with a atypia, accompanied by a variable number of plasma cells,
B immunoblasts, and histiocytes. These features are similar to The hyaline vascular type of Castleman’s disease (HVCD) is
those seen in T-zone dysplasia with hyperplastic follicles. characterized by the presence of single, unifocal masses with no
evidence of systemic manifestations, most commonly located in
Differential diagnosis the mediastinum. Other sites include the cervical and axillary
● T-zone lymphoma with follicles lymph nodes, root of mesentery, pelvis, retroperitoneal and rarely
● Angioimmunoblastic lymphoma with hyperplastic within muscle. Isolated case reports have been documented in the
germinal centers skin, uterus, pancreas and nasopharynx. Surgical excision is cur-
ative. Malignant lymphoma has rarely been described in associa-
Special techniques tion with localized hyaline vascular type. The pathogenesis of the
hyaline vascular variant of Castleman’s disease is currently
● Polymerase chain reaction (PCR) analysis demonstrates
unknown; however, vascular and dendritic cell proliferations are
no clonal rearrangement of the T-cell-receptor chain gene.
common in this disorder. Localized clonal proliferations of stro-
● Immunoglobulin heavy chain rearrangement may rarely
mal elements – particularly follicular dendritic cells – occur in
be detected.
typical HVCD, and this is a likely explanation for the increased
incidence of follicular dendritic cell sarcomas in these patients.
CASTLEMAN’S DISEASE The plasma cell variant of Castleman’s disease (PCD) may
occur in a variety of clinical settings. One recently delineated
type of PCD is caused by human herpesvirus 8 (HHV8) infec-
CLINICAL FEATURES
tion. The disease is characterized by a dominant mass, usually
Castleman’s disease is considered as an atypical lymphoprolifera- associated with systemic manifestations such as fatigue, fever
tive disorder with heterogeneous morphological and clinical fea- and night sweats, hepatosplenomegaly, nephrotic syndrome,
tures. It is characterized by giant lymph node hyperplasia with hypergammaglobulinemia, hyperfibrinogenemia, and raised
plasma cell infiltration, fever, anemia, hypergammaglobulinemia, erythrocyte sedimentation rate (ESR) and alkaline phosphatase
and an increase in the plasma level of acute-phase proteins. levels. This variant can be seen in lymph nodes from patients
Castleman’s disease is associated with a risk of developing malig- with POEMS syndrome. The latter is a rare, multisystem afflic-
nant lymphoma. It can be classified into two types: hyaline-vas- tion known for its signs, from which it also takes its acronym
cular and plasma cell types, according to the histological features name ‘peripheral neuropathy, organomegaly, endocrinopathy,
of the affected lymph nodes. The latter type can be multicentric, monoclonal (M) protein, and skin lesions’.
is frequently associated with systemic manifestations, and is often Multicentric Castleman’s disease (MCD) is a rare subvariant
refractory to systemic therapy including corticosteroids and of the plasma cell type of Castleman’s disease. It is character-
chemotherapy, particularly when in its multicentric form. ized by diffuse or multicentric involvement of peripheral lymph
Castleman’s disease is essentially of unknown histogenesis, nodes, with frequent splenomegaly. This type is associated with
though some cases are attributable to rheumatoid arthritis. An inflammatory symptoms and IL-6 dysregulation. In the context
increasingly large number are also due to acquired immuno- of HIV infection, MCD is associated with Kaposi’s sarcoma-
deficiency syndrome (AIDS), and therefore are currently associated herpesvirus, also called human herpesvirus type 8
regarded as a peculiar form of immune reaction. (KSHV/HHV8). Patients with multicentric Castleman’s disease
Interleukin-6 (IL-6) – a cytokine which induces B-cell differ- have an increased risk of developing non-Hodgkin lymphoma.
entiation to immunoglobulin-producing cells and regulates the
biosynthesis of acute-phase proteins – is produced in large
quantities in the germinal centers of hyperplastic lymph nodes
of patients with Castleman’s disease, and hence is thought to be Castleman’s disease is characterized by lymph node enlarge-
responsible for the systemic manifestations of this condition. ment due to hyperplasia of abnormal lymphoid follicles and
There seems to be a correlation between serum IL-6 level, paracortical lymphocytic hyaline vascular (HV) stroma or
lymph node hyperplasia, hypergammaglobulinemia, increased plasmacytosis (PC).
level of acute-phase proteins, and clinical abnormalities. In a The lymphoid follicles in Castleman’s disease show involuted
patient with a solitary hyperplastic lymph node, clinical germinal centers and prominent mantle zone lymphocytes – the
improvement and a decrease in serum IL-6 level are observed ‘onion-skin pattern’.
following surgical removal of the involved lymph node. The interfollicular regions are rich in vessels that are lined by
Therefore, interference with IL-6 signal transduction, by using plump endothelial cells, and contain lymphocytes, plasma cells,
humanized anti-IL-6 receptor antibody (rhPM-1) may consti- immunoblasts and macrophages.
tute a new therapeutic strategy for this disease. The vascular component is present both within and around
The clinical evolution of the disease includes persistent or the abnormal follicles and consists of thick-walled, hyalinized,
stable disease, and aggressive or relapsing disease (recurrences or rarely calcified vessels.
and remissions). Peripheral neuropathy has infrequently been Depending on the relative amounts of these microscopic
reported. Tumors reported in association with Castleman’s components, there are three main histological variants: hyaline-
disease include: Hodgkin lymphoma, malignant vascular tumors vascular; plasma cell; and mixed types.
such as Kaposi’s sarcoma or other types of vascular tumors and ● The plasma cell variant shows reactive follicular
dendritic follicular cell tumor. hyperplasia, without significant regressive transformation

of germinal centers. The interfollicular areas contain a

prominent plasma cell infiltrate and varying degrees of
vascularity and sclerosis. In the spleen, there is prominent
plasmacytosis and white pulp hyperplasia with a spectrum
of germinal centers ranging from large, hyperplastic
centers to typical hyaline-vascular centers.
● The hyaline vascular variant is characterized by
obliteration of the lymph node architecture (except at the
periphery of the lesion) and regressive transformation of
the germinal centers – that is, progressive loss of germinal
center cells with prominence of hyalinized blood vessels
and dendritic reticulum cells. This variant has similar
histological features when present in the spleen.
(a)
Vasoproliferative lesions complicating

hyaline-vascular Castleman’s disease
This condition is the stroma-rich variant of Castleman’s disease
of hyaline-vascular type. It may rarely be associated with a con-
fusing variety of stromal cell overgrowths and neoplasms,
which include:
● Focal proliferations of angiomyoid non-neoplastic growths:
This shows hyperplastic proliferation of vasculature and

actin-positive myoid cells in the expanded interfollicular area.
Microscopically, the degree of widening of this area varies
from slight overgrowth to vague nodularity and finally to the
formation of prominent nodules. Patients with angiomyoid
proliferations tend to be young women, who present with an
abdominal mass and are usually cured by surgery.
● Follicular dendritic cell proliferation is characterized by
neoplastic growths of oval to spindle cells intermixed with

lymphocytes; these grow in long, intersecting bundles,
feature various degree of atypia, and express the markers
of follicular dendritic cells (CD21, CD35, KiM4p). The
(b)
follicular dendritic cell proliferations tend to occur in older
patients of either gender, and present with masses at
various sites, recapitulating the profile of follicular
dendritic cell tumors arising independently from HVCD.
Recurrences or metastases may develop at various intervals
following the initial diagnosis.
Secondary features
● Eosinophilic proteinaceous material is seen in lymph node
sinuses in the plasma cell variant.
● Marked white pulp fibrosis with severe lymphocyte
depletion and marginal zone fibrosis with prominent
plasmacytosis may be present in some plasma cell cases.
● Secondary amyloidosis has been reported.
● Rarely, the development of calcifying fibrous pseudotumor.
Cell morphology
The lymphoid follicles consist of:
● Mature lymphocytes.
● Plasma cells.
● Immunoblasts.
(c) ● The presence of bizarre giant cells resembling mummified
cells seen in Hodgkin lymphoma has been seen (personal

Figure 10.15 (a–c) Castleman’s disease hyaline vascular type. experience); these may represent a virally induced change.
Differential diagnosis is unknown, and the condition is self-limiting, but some type of
● Reactive non-specific hyperplasia of lymph nodes viral or post-viral etiology has been implicated. The involvement
● Hodgkin and non-Hodgkin lymphoma of bacterial and protozoal organisms, as well as various other
● Multiple myeloma involving lymph node antigens (chemical, physical and neoplastic) has also been postu-
● Lymph node changes in rheumatoid arthritis lated. An association with systemic lupus erythematosus has also
● POEMS syndrome been shown. Lymphadenitis, hepatomegaly and splenomegaly –
● AIDS-related lymphadenopathy as well as leukopenia, elevated ESR and hepatic abnormalities –
● Inflammatory pseudotumor are common findings. Fever, malaise, fatigue, headache, night
sweats, nausea, vomiting, weight loss, cutaneous manifestations,
and even neurological symptoms are other complaints.
Special techniques
● The mantle zone cell populations are immunophenotypically
aberrant, showing Ki-B3-negative B lymphocytes.
● The follicular dendritic cells are CD21-, CD35-, and In its early proliferative phase, Kikuchi–Fujimoto disease is
KiM4p-positive. characterized by focal or complete involvement of lymph node
● The myoid cells stain by smooth muscle alpha-actin, and architecture by proliferation of macrophages, plasmacytoid
are usually negative for desmin, CD34, factor VIII-related cells and immunoblasts. The macrophages are variable in size
antigen, S-100 protein, CD21, and CD68. and shape, and the plasmacytoid cells are present either singly
or in clusters at the periphery of the affected areas. In the
necrotic phase of the disease, there is overt necrosis with abun-
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
dant karyorrhexis and eosinophilic fibrinoid necrosis.
CLINICAL FEATURES Cell morphology

Hemophagocytic syndrome is a condition in which there is
● The histiocytes vary in size and shape; they have highly
uncontrolled activation of the cellular immune system. irregular nuclei with karyorrhexis and pyknosis of
Diagnostic criteria include idiopathic fever, splenomegaly, individual cells, and little evidence of phagocytosis.
cytopenias, hypertriglyceridemia, hypofibrinogenemia and the
● The plasmacytoid cells are probably of histiocytic origin
presence of hemophagocytosis. (plasmocytoid monocytes); these cells have round nuclei
Hemophagocytic lymphohistiocytosis is the prototype of with open chromatin and absent or very small indistinct
hemophagocytic syndrome, which may be either familial or nucleoli.
sporadic, with or without an associated viral infection.
● Epithelioid histiocytes, neutrophils, eosinophils and
Current concepts of pathophysiology focus on the role of plasma cells are rare or absent.
cytokines, particularly interleukin (IL)-1, IL-2, soluble IL-2
● Mitotic figures may be present.
receptor, plasminogen activator, and prostaglandins. The clinico-
pathological features of the syndrome can be accounted for by
the uncontrolled and unopposed production and release of
these mediators.
Hemophagocytic lymphohistiocytosis is one of the most
important of the ‘benign’ histiocytosis syndromes that involve
ordinary histiocytes of the mononuclear phagocytic system;
this is in contrast to Langerhans’ cell histiocytosis (histiocyto-
sis X), in which pathological dendritic histiocytes are operative.
PATHOLOGICAL FINDINGS
The surgical and autopsy pathology features infiltrates com-
posed of lymphocytes and ordinary, but activated, histiocytes
and hemophagocytosis.
HISTIOCYTIC NECROTIZING LYMPHADENITIS

(KIKUCHI–FUJIMOTO DISEASE)
CLINICAL FEATURES
Kikuchi–Fujimoto disease is a rare condition which presents with Figure 10.16 Histiocytic necrotizing lymphadenitis.There is focal
lymphadenitis, usually in the cervical region. Most reported cases paracortical histiocytic infiltrate with nuclear debris.The cells lack
of Kikuchi–Fujimoto disease have been of Asian origin. The cause B- or T-cell markers.
● High-grade lymphoma
● Cutaneous Kikuchi’s disease may be mistaken for
cutaneous lymphoma
Special techniques
● Ki-M1P is a marker for cells of monocyte/macrophage
system, including the plasmacytoid monocyte seen in this
disease.
POST-TRANSPLANT LYMPHOPROLIFERATIVE
DISORDERS (PTLD)
CLINICAL FEATURES
Post-transplant lymphoproliferative disorder (PTLD) is a syn-
drome of uncontrolled lymphoid growth in the immunosup-
pressed transplant patient. Clinical presentation is heterogeneous
and dependent upon the location and extent of disease. There (a)
are distinct categories to PTLD based on the type of cell involved
and whether it is either a monoclonal or polyclonal prolifera-
tion (see below). Most lesions are of B-lymphocyte origin. The
disorder complicates between 1 and 10% of all transplantations,
and usually develops at any time, though the majority of cases
arise within the first two years post-transplant.
Known risk factors include EBV seronegativity at the time of
transplant, pediatric age, and allograft type. Results from
recent studies have suggested that constitutional factors such as
cytokine gene polymorphisms may also predispose to the dis-
ease. Other risk factors include human lymphocyte antigen
(HLA)-mismatching, T-cell depletion, and the use of anti-
lymphocyte antibodies as conditioning or treatment of graft-
versus-host disease (GVHD).
Excellent long-term outcomes are achievable with early recog-
nition and institution of appropriate treatment. Surveillance tech-
niques with EBV antibody titers and/or PCR may have a role in
some high-risk settings.
Immune-based therapies such as monoclonal anti-B-cell anti-
bodies, interferon-alpha, and EBV-specific donor T cells, either
as treatment or as prophylaxis in high-risk patients, represent (b)
promising new directions in the treatment of this disease.
Figure 10.17 (a, b) Post-transplant lymphoproliferative disorder.
PATHOLOGICAL FEATURES (Figure 10.17) Most lesions show a cytologically polymorphous proliferation of
lymphoid cells with large areas of geographic necrosis.The cells
Post-transplant lymphoproliferative disorder represents a spec- range from small to large, with centroblast-like cells, immunoblasts,
trum of EBV-related diseases, from a benign mononucleosis- plasmacytoid cells, and plasma cells.Variable numbers of
like illness to a fulminant non-Hodgkin lymphoma. Lesions Reed–Sternberg (RS)-like cells are seen.
with various histopathological characteristics can be identified,
including variety of lymphomas. Abnormal proliferation of
lymphoid cells in the ear, nose, or throat (ENT) area, related to Categories of PTLD (WHO 2001 classification)
EBV infection, may be the first manifestation of the disease. Category 1 Early lesion: Reactive plasmacytic hyperplasia
Most lesions show a cytologically polymorphous proliferation Early lesion: Infectious mononucleosis-like
of lymphoid cells with large areas of geographic necrosis. The Category 2 Polymorphic PTLD
cells range from small to large, with centroblast-like cells, Category 3 Monomorphic PTLD (classify according to WHO
immunoblasts, plasmacytoid cells, and plasma cells. Variable 2001 classification):
numbers of Reed–Sternberg (RS)-like cells are seen. In general, the B-cell – Diffuse large B-cell lymphoma
RS-like cells are most conspicuous adjacent to areas of necrosis. (immunoblastic, centroblastic, anaplastic);
Burkitt/Burkitt-like lymphoma; Plasma cell Special techniques

myeloma; Plasmacytoma-like lesions ● The tumor cells show variable expression of CD20.
T-cell – Peripheral T-cell lymphoma, unspecified; ● Staining with antibodies specific for CD3 and CD5
Others accentuated admixed small reactive T cells.
Category 4 Hodgkin lymphoma and Hodgkin lymphoma- ● The RS-like cells are usually negative for CD15.
like PTLD
HISTIOCYTIC AND DENDRITIC CELL TUMORS
CRYSTAL-STORING HISTIOCYTOSIS ● The cells containing the crystals are either histiocytes or
plasma cells, and therefore express the corresponding
markers.
CLINICAL FEATURES
Crystal-storing histiocytosis is a rare event in disorders associ-
FOLLICULAR DENDRITIC CELL SARCOMA
ated with monoclonal gammopathy. The intracellular crystal
formation is almost always accompanied by the expression of
kappa light chains. The exact mechanism for storage is not CLINICAL FEATURES
clear, but molecular identification of the stored kappa sub-
group and detection of unusual amino acid substitutions sug- Follicular dendritic cell tumor – also known as dendritic
gest that conformational alterations induced by amino acid reticulum cell tumor – is an uncommon neoplasm arising from
exchanges represent a crucial pathogenic factor in crystal- antigen-presenting cells found in lymph node B-cell follicles.
storing histiocytosis. The deposits of Ig crystalline inclusions are The condition affects mainly lymph nodes, but it can also occur
accumulated in lymphoplasmocytic cells, in hematopoietic tis- in extranodal sites. It can occur at any age. It is considered as
sues, or in epithelial cells or connective tissue stroma of organs an intermediate-grade malignancy as it has significant recur-
and tissue such as the kidney, thyroid, parotid, gastrointestinal rent and metastatic potential. Marked cellular atypia, numer-
tract, cornea, conjunctiva and otolaryngeal mucosal-associated ous mitotic figures (including abnormal ones) and necrosis
lymphoid structures. This condition has also been described in correlate with an aggressive clinical behavior. Surgery is the
association with multiple myeloma, lymphoplasmocytic lym- treatment of choice. A small proportion of cases may arise
phoma, and amyloidosis. against a background of Castleman’s disease of the hyaline-
vascular type and others in association with EBV infection.
Adjuvant radiotherapy or chemotherapy is indicated in cases
with adverse pathological features and in recurrent or incom-
Crystal-storing histiocytosis is characterized by extensive pletely excised lesions.
replacement of the lymphoid architecture by cellular infiltrate
consisting of lymphoplasmocytic cells admixed with large
numbers of eosinophilic crystal-containing histiocytes.
The lymph node architecture is almost completely effaced by
Cell morphology spindle cells arranged in interwoven fascicles with focal stori-
● Plasma cells. form pattern and nests of polygonal cells. On occasion, the
● Lymphocytes. tumor is divided or lobulated by bands of fibrous tissue, or con-
● Crystal-containing cells are large, spindle-shaped or tains large vascular spaces which impart an angiomatoid
polygonal, or strap-shaped with abundant eosinophilic appearance. The two most characteristic histological features of
cytoplasm packed with sheaves of long crystals. this tumor are the intimate admixture of tumor cells and small
● Giant cells of foreign body type are occasionally seen. lymphocytes and the presence of perivascular cuffs of mature
lymphocytes. The tumor cells are spindle-shaped, arranged in
Differential diagnosis interwoven fascicles, storiform pattern or concentric whorls,
have large, oval or fusiform nuclei showing a lace-like chro-
● Adult rhabdomyoma matin pattern and containing one or two indistinct nucleoli. The
● Gaucher’s disease cytoplasm is pale with indistinct borders. Nuclear pleomor-
● Gout phism is usually minimal, scattered multinucleated giant cells
are frequent and mitotic activity ranges from 1 to 35 per 10
Special techniques high-power fields (HPF).
● The crystals are periodic acid-Schiff (PAS)-positive after Distinctive variants have been described. The myxoid variant
diastase, and stain blue with phosphotungstic appears indistinguishable from malignant fibrous histiocytoma
acid-hematoxylin (PTAH). (MFH), while the inflammatory pseudotumor-like variant is
described in intra-abdominal locations, is predominantly seen

in females, and is consistently associated with EBV.
● Metastatic carcinoma of unknown origin
● Inflammatory myofibroblastic tumor
● Ectopic thymoma
● Low-grade malignant fibrous histiocytoma
● Angiomatoid malignant fibrous histiocytoma
(c)
Figure 10.18 (c) The nuclei are vesicular, with a crisp nuclear
membrane and small, distinct nucleoli.
● Lymphoma
Special techniques
● Follicular dendritic cells ultrastructurally show numerous
thin cytoplasmic extensions and desmosomes.
● The tumor cells express CD21 and CD35 antigens.
● The cells may express S-100 protein, muscle-specific actin,
(a)
epithelial membrane antigen (EMA), and CD68 and
cytokeratins.
● The residual lymphoid tissue shows positive staining for
both T- and B-cell antigens.
● The lymphocytes closely intermingled with the tumor cells
are predominantly CD3-, UCHL1- or MT1-positve, and
occasional lymphocytes are CD30-positive.
INTERDIGITATING DENDRITIC CELL

SARCOMA/TUMOR
CLINICAL FEATURES
Dendritic cells are immune accessory cells which are widely dis-
tributed in many tissues. Those which are present within lym-
phoid follicle centers are classified as follicular dendritic cells.
Those which are found outside germinal centers may be referred
to as interdigitating reticulum cells. Interdigitating dendritic
cell sarcoma is an extremely rare, aggressive neoplasm that
mainly occurs in the lymph nodes and rarely in other organs.
(b)
Figure 10.18 (a, b) Follicular dendritic cell sarcoma. Sheets of oval to
spindle-shaped cells with eosinophilic granular cytoplasm and This lesion shows a diffuse proliferation of histiocyte-like cells
ill-defined cell borders admixed with small lymphocytes. with nuclear pleomorphism and occasionally multinucleation,
in paracortical distribution sparing the B-cell regions. Irradiation is used to treat inaccessible or incompletely
Erythrophagocytosis is commonly observed. The lesion often resected lesions. The prognosis of unifocal eosinophilic granu-
exhibits whorls and fascicles of spindle cells intermingled with loma is very good, with successful disease control being achieved
small lymphocytes. Other features include fibrosis, sinus infil- in 95% of cases. The treatment of patients who suffer from a
tration, and a prominent eosinophil/plasma cell infiltrates. disseminated form of LCH remains controversial. Interferon
(INF)-alpha may prevent recurrences in high-risk patients.
Differential diagnosis Langerhans’ cell histiocytosis of bone causes bone destruc-
● Sarcoma tion and frequent bone reactions that mimic benign and malig-
● Spindle cell carcinoma nant neoplasms as well as osteomyelitis. The most common
● Follicular dendritic cell tumor symptoms of eosinophilic granuloma of bone are local tender-
● Inflammatory myofibroblastic tumor ness and enlargement.
Pulmonary Langerhans’ cell histiocytosis (PLCH) is a rare
Special techniques disease which affects both sexes, with a greater incidence in the
second and third decades of life. Smoking appears to be the
● The tumor cells are positive for S-100 protein, vimentin,
most important risk factor. In contrast to systemic LCH, pul-
and CD68, but uniformly negative for CD45, B- and
monary LCH appears primarily to be a reactive process in
T-cell markers, CD1a, CD30, complement receptors,
which non-lethal, non-malignant clonal evolution of LCH cells
CD34, Factor VIII, HMB-45, and lysozyme.
may arise in the setting of non-clonal LCH cell hyperplasia.
● Ultrastructurally, the tumor cells possess complex
Cigarette smoking may be the stimulus for pulmonary LCH, in
interdigitating cytoplasmic dendritic processes, with
contrast to other forms of LCH. PLCH tends to cause a rela-
abundant rough endoplasmic reticulum and mitochondria
tively isolated pulmonary involvement as compared to other
in their cytoplasm.
forms of Langerhans’ cell disorders.
In its evolution, the granuloma is characterized by the pro-
LANGERHANS’ CELL HISTIOCYTOSIS gressive reduction in the number of Langerhans’ cells, with an
increase in fibrosis. As the fibrous tissue surrounds and
destroys part of the bronchiolar wall, the result is cystic dilata-
CLINICAL FEATURES
tion of the remaining bronchiolar lumen. Cyst formation also
Langerhans’ cells are bone marrow-derived dendritic cells, which results from traction exerted by fibrous tissue on the adjacent
can develop from CD34(⫹) hematopoietic progenitor cells, as alveolar. Vascular involvement occurs frequently, and may
well as from monocytes. Langerhans’ cell histiocytosis (LCH) – explain the onset of pulmonary hypertension in advanced cases
previously known as histiocytosis X and eosinophilic granu- of the disease. The disease may be asymptomatic, or it may
loma – is a rare disease that is characterized by clonal prolifer- present with specific respiratory signs and symptoms. It also
ation of Langerhans’ cells of unknown etiology; this results in has characteristic radiological findings, being included in the
a range of clinical manifestations. The etiology of the condition group of cystic parenchymal alterations. The diagnosis rests on
is unknown, although data exist indicating an uncontrolled a combination of clinical and radiological data; in particular,
immune response as a possible cause, sustained by the high-resolution computed tomography (CT) shows a typical
Langerhans’ cells, antigen-presenting cells for T lymphocytes, association of nodular and cystic changes, predominantly in
and their tissue accumulation. the upper and middle lobes. Further evaluation with surgical
Langerhans’ cell histiocytosis has a clear preference for infancy, lung biopsy is indicated in less typical situations. The diagnosis
and an incidence of 0.2–1.0 per 100 000 children worldwide. In could be suggested by finding the proportion of Langerhans’
60–70% of the cases the first manifestation is before the second cells among the total cell population of the bronchoalveolar
year of age, and up to 10% of cases are congenital. Occurrence lavage to be greater than 5%. Different therapies have been
in adults is very rare. The disease shows a male:female ratio of proposed, but the most important measure seems to be cessa-
2:1. LCH involves single organs or systems, or may present as a tion of smoking.
multisystem disease. The clinical presentation may vary widely, Pulmonary LCH has an unpredictable course, and may be
ranging from benign self-limiting types with spontaneous regres- associated with an increased susceptibility to the development
sion to slowly progressive malignant disease. LCH affects vari- of malignant neoplasms. The life expectancy of adults with pul-
ous organs, including the skin, bones, lungs, lymphatic ganglia, monary LCH is reduced, and respiratory failure accounts for a
and liver; rarely, it affects other organs such as the thyroid, thy- substantial proportion of deaths among such patients.
mus and oropharyngeal mucosa. LCH has been known to be Skin lesions in Langerhans’ cell histiocytosis are often painful
associated with a variety of malignant diseases. and difficult to treat. Topical application of nitrogen mustard
Because the prognosis depends particularly on the number of (0.02% mechlorethamine hydrochloride, mustine), an alkylat-
tissues involved, an accurate identification of the organs ing cytostatic agent, has been shown to be effective.
involved by granulomatous lesions is of critical importance.
Although current therapies are very effective at inducing remis-
sion, multiple recurrences and long-term sequelae are common
for patients with low-risk disease, and a significant proportion Overall, the histopathological picture of LCH is heterogeneous,
of young patients die from this condition. and involves the formation of granulomatous infiltrations
● The cells are positive for S-100 protein.

● CD31 is also positive in neoplastic Langerhans’ cells.
● Fascin, a 55-kDa actin-bundling protein, represents a
highly selective marker for dendritic cells of lymphoid
tissues and peripheral blood, and is involved in the
formation of dendritic processes in maturing epidermal
Langerhans’ cells. The immunoreactivity of lesional cells of
LCH for fascin supports their derivation from cells of the
dendritic system, and represents another alteration in the
phenotype of Langerhans’ cells that is associated with
maturation, migration, culture, or clonal expansion.
● Birbeck granules are seen by electron microscopy.
MALIGNANT HISTIOCYTOSIS
(a)
CLINICAL FEATURES
Until recently, malignant histiocytosis was a clearly defined clini-
cal entity marked by fever, progressive wasting, localized then gen-
eralized lymphadenopathy, hepatosplenomegaly, pancytopenia,
skin or soft tissue nodules and bone involvement. Now, it seems
clear that most cases of malignant histiocytosis represent anaplas-
tic large cell lymphoma (ALCL) with Ki-1 (CD30) expression, and
they are not related to the monocyte/macrophage system. This
conclusion is based on histopathological and immunohistochemi-
cal findings and, more recently, on results from genotypic studies.
Thus, malignant histiocytosis is a ‘vanishing’ disease. The diag-
nosis of malignant histiocytosis requires a high index of clinical
suspicion, awareness of its atypical features, and availability of
various tissue samples for morphological and special studies.
(b) Complete and definitive recovery may occur in some cases.
Figure 10.19 (a, b) Langerhans’ cell histiocytosis. Note the atypical

histiocytes with cleaved, ‘coffee bean nuclei’ (circled) on an
eosinophil-rich background. Hence the historic term; ‘eosinophilic Diagnosis is made on the basis of infiltration by a mixture of
granuloma’.
anaplastic and well-differentiated phagocytic histiocyte-like
cells in skin, lymph node, bone marrow and spleen.
consisting of Langerhans’ cells, histiocytes, lymphocytes and In lymph nodes, early stage disease is characterized by the pres-
eosinophilic granulocytes. The degree of eosinophilia and presence of non-cohesive proliferation of atypical cells within lymph
ence of necrosis is significantly higher in localized infiltrates node sinuses with sparing of follicles (a histiocytic medullary retic-
compared to disseminated infiltrates. Mitotic figures are detected ulosis). Rarely – and usually later in the course of the disease –
in more than half of the infiltrates. the neoplastic process appears to be diffuse, replacing the normal
Adult pulmonary Langerhans’ cell histiocytosis is character- architecture of the node and extending into perinodal tissue.
ized by granulomatous lesions which progressively invade and In the skin, the tumoral infiltrate involves the deep dermis
destroy the distal airways, leading to the formation of charac- with a perivascular and peri-appendageal distribution.
teristic cicatricial cystic lesions. Visceral involvement (liver, spleen, kidney, intestine, or heart)
is usually patchy in distribution.
● Sinus histiocytosis with massive lymphadenopathy Secondary features
● Interstitial lung disease ● Necrosis.
● Cutaneous mastocytosis ● Focal accumulation of granulocytes.
● Osteomyelitis ● Localized plasma cell reaction.
Special techniques Cell morphology

● Langerhans’ cells express on their surface the CD1a and ● The cells are large with clear or finely vacuolated
CD1c antigens, and the B7 molecule, essential for cytoplasm, irregularly shaped, or grooved nucleus and
activating quiescent T lymphocytes. several large, irregular, dense nucleoli.
● Atypical cells containing prominent nucleoli, and some

Reed–Sternberg-like cells are seen.
● Normal lymphocytes are often dispersed among the
neoplastic cells.
● Mitotic figures (including atypical ones) are numerous.
● Large multinucleated cells may be seen.
● Erythrophagocytosis may be seen.
● Hemophagocytic syndromes
● The sinusoidal distribution may resemble secondary
metastasis in lymph node
● Acute myeloblastic leukemia
● Langerhans histiocytosis
● Sinus histiocytosis with massive lymphadenopathy (a)
● Hodgkin lymphoma
● Regressing atypical histiocytosis
● (CD30-positive) Anaplastic large cell lymphoma
Special techniques
● S-100 protein is absent.
● The cells appear to react positively with EMA, CD30
(Ki-1; BerH2), CD25, HLA-DR, OKT9, and Ki-67
monoclonal antibodies.
● The cells may show CD68 (Kp-1, KiM6, KiM7)
immunoreactivity.
● The neoplastic cells show EBER1/2 positivity, suggesting
that the condition is an EBV-associated aggressive
NK/T-cell lymphoma rather than histiocytosis.
ROSAI–DORFMAN DISEASE (b)
Figure 10.20 (a, b) Rosai–Dorfman disease. Eosinophilic, polygonal

CLINICAL FEATURES or spindle-shaped histiocytes associated with collagen deposition.
Encircled are pale histiocytic cells that contain within their cellular
Rosai–Dorfman disease – also known as sinus histiocytosis
borders apparently engulfed lymphocytes (‘emperipolesis’).
with massive lymphadenopathy – is an uncommon benign pro-
liferation of hematopoietic and fibrous tissue. It is of unknown
Secondary features
origin, and often presents in lymph nodes in the head and neck
region. It may rarely involve extranodal tissues such as bones, ● Hemosiderin deposition is frequently present.
breast, skin, soft tissue, central nervous system, eye, orbit, upper ● Occasionally there is focal necrosis resembling microabscess.
respiratory tract, and salivary glands. The disease generally
peruses a benign course, but occasionally behaves aggressively, Cell morphology
especially when associated with immunological abnormalities. ● The polygonal and spindle-shaped histiocytes have
An underlying immune dysfunction may be central to the abundant, granular, eosinophilic or sometimes clear
pathogenesis of this disease. cytoplasm, giving the cell a moth-eaten appearance.
● The nuclei are round to oval with vesicular chromatin
PATHOLOGICAL FEATURES (Figure 10.20) and small prominent nucleoli.
Rosai–Dorfman disease is a sharply circumscribed or occasionally
● Multinucleated giant cells may be seen.
ill-defined lesion consisting of sheets of eosinophilic, polygonal
● Mature small lymphocytes and plasma cells are uniformly
or spindle-shaped histiocytes associated with collagen deposi- scattered throughout the lesion, or gather in small
tion and arranged in a vague storiform pattern punctuated by aggregates.
lymphoid aggregates with germinal centers. These features are
● Mitoses and cellular pleomorphism are rare.
less well-defined in extranodal disease. The key histological
feature of this disease is the presence of various numbers of Differential diagnosis
large, pale histiocytic cells that contain within their cellular Nodal disease may be mistaken for:
borders apparently engulfed lymphocytes (‘emperipolesis’). ● Langerhans’ cell histiocytosis
Emperipolesis tends to be less prominent in extranodal disease. ● Hodgkin lymphoma

● Non-Hodgkin lymphoma Special techniques

● Metastatic carcinoma ● The histiocytes are immunohistochemically positive for
● Metastatic malignant melanoma S-100 protein and CD68, but negative for CD1a.
Extranodal disease may simulate: ● Reticulin and trichrome stains highlight the nodularity of
● Benign fibrous histiocytoma the lesions and the numerous delicate and coarse strands
● Dermatofibrosarcoma protuberans of collagen fibrils.
● Lymphoma
● Malignant fibrous histiocytoma
● Dendritic follicular cell sarcoma
LEUKEMIA AND RELATED CONDITIONS
MYELOID SARCOMA [WHO, 2001] immunoglobulin in the serum and/or urine. The disease occurs
mainly in elderly patients, and is rare below the age of 40 years.
It may occur in patients with the adult Fanconi’s syndrome.
CLINICAL FEATURES (Figure 10.21) Multiple myeloma is clinically diagnosed by the presence of
Previous classification/synonyms of myeloid sarcoma include: multiple osteolytic lesions on X-radiography, and demonstra-
(i) Extramedullary myeloid tumor; (ii) Granulocytic sarcoma; tion of monoclonal gammopathy.
and (iii) Chloroma. The lesion commonly presents with bone pain and patho-
See also Chapter 13, Soft tissue tumors (p. 1014). logical fractures, and is often associated with normochromic
normocytic anemia, neutropenia, and thrombocytopenia (due
to marrow replacement by tumor and marrow suppression by
PLASMA CELL NEOPLASIA [WHO, 2001]: MULTIPLE tumor-derived cytokines). It often causes renal impairment.
MYELOMA AND SOLITARY PLASMACYTOMA Monoclonal IgG is found in 50% of multiple myeloma,
IgA in 25%, and light chain paraprotein in 20%. The para-
protein in multiple myeloma may lead to hyperviscosity syn-
CLINICAL FEATURES dromes.
See also Mature B-cell neoplasia (p. 693). Hypercalcemia (which may be seen in 30% of cases and is
Multiple myeloma is a malignant B-cell disorder character- due to bone resorption) may result in clinical manifestation
ized by the uncontrolled proliferation of monoclonal plasma such as abdominal pain, constipation, mental confusion,
cells in the bone marrow, and the presence of monoclonal polyuria, hypercalciuria, nephrocalcinosis and renal failure.
(a) (b)
Figure 10.21 (a) Myeloid sarcoma/granulocytic sarcoma. (b) Leukemic deposits within lymph node.
More extensive marrow involvement with immature plasma Solitary plasmacytoma consists of sheets of diffuse infiltrate
cells is associated with an unfavorable prognosis. Death may of plasma cells showing varying degrees of differentiation.
occur within 2–3 months, though some patients may have indo- These are usually seen in a very vascular background stroma.
lent disease and live for many years. The most common causes Amyloid deposition may be seen in 25% of lesions.
of death in multiple myeloma are infection and renal failure.
Plasma cell leukemia is the presence of large numbers of plasma Secondary features
cells in the peripheral blood (usually exceeding 20% of blood ● Amyloid deposition.
leukocytes) early in the disease. It is often associated with an unfa- ● Immunoglobulin crystal deposition.
vorable diagnosis and a higher incidence of organomegaly.
Solitary plasmacytomas are tumors composed almost entirely Cell morphology
of mature or immature plasma cells. This lesion should be ● The morphology of the constituent plasma cells varies
diagnosed only after thorough investigations have ruled out from mature-looking plasma cells to cells with blast-like
disseminated myeloma. It may be associated with serum or appearance (showing prominent nucleoli).
urine monoclonal protein, may recur locally, and progresses to
multiple myeloma in almost 35% of cases.
Solitary plasmacytomas are divided into two main groups
according to their locations:
1. Extramedullary or soft tissue plasmacytoma occurs any-
where in the body, but most commonly in the mucosa or
submucosa of the nasopharynx, oral cavity and upper res-
piratory tract. It may extend into the bone, it may be mul-
tiple, and is often associated with IgA.
2. Plasmacytoma of bone affects any bone, but most
commonly the vertebrae, ilium and skull. It may extend into
the soft tissue, may have a greater predilection to progress
to multiple myeloma, and is often associated with IgG.

Multiple myeloma is characterized by the presence of patchy or
diffuse tumorous infiltrate of bone marrow by plasma cells
exhibiting varying degrees of differentiation. Anaplastic trans-
formation may occasionally occur.
(b)
(a) (c)
Figure 10.22 (a–c) Solitary plasmacytoma of the testis.There are sheets or diffuse infiltrate of plasma cells showing varying degrees of
differentiation.
● Binucleate Reed–Sternberg-like cells may be seen. RICHTER’S SYNDROME

● Occasional multinucleated giant cells can be seen.
● Intracytoplasmic protein aggregates (Russell bodies) are
often seen. CLINICAL FEATURES
● Crystalline inclusions within the plasma cells may be seen Patients with chronic lymphocytic leukemia (CLL) may
(this is particularly prominent in patients with multiple develop a large-cell transformation known as Richter’s syn-
myeloma occurring in association with adult Fanconi’s drome (RS). This usually shows a diffuse large B-cell lym-
syndrome). phoma (DL-BCL) or its immunoblastic variant, and it can be
recognized simultaneously with CLL or even many years later.
Differential diagnosis Richter’s syndrome occurs mostly in lymph nodes, and may
represent a second neoplasm or a transformation from the
Multiple myeloma
● ‘Benign’ monoclonal gammopathy (the bone marrow may
same clonal population. Other low-grade B-cell neoplasms also
can undergo histological progression to a higher-grade lym-
be normal or show a slight increase in the number of
phoma during the course of the disease. Clinically, Richter’s
mature-appearing plasma cells; a proportion of these
transformation is characterized by worsening systemic symp-
patients develop plasma cell dyscrasias). This includes the
toms, progressive lymphadenopathy, elevated serum lactate
mononclonal gammopathy of uncertain significance
dehydrogenase, extranodal involvement, and elevated serum
(typified by monoclonal plasma cells occupying less than
paraproteins.
10% of involved bone marrow with detectable serum
Richter’s syndrome is found to be more frequent in patients
monoclonal immunoglobulin)
● Chronic inflammation
with CLL displaying either multiple chromosomal aberrations
● Plasmacytoid lymphoma
or monoclonal gammopathies. During the past two decades,
● Large-cell immunoblastic lymphoma
reports have evidenced the existence of two types of Richter’s
syndrome: (i) a ‘classical’ type, as a terminal event in a long-
Solitary plasmacytoma evolving CLL; and (ii) a ‘variant’ as the first clinical manifesta-
● Plasma cell granuloma tion of a previously unrecognized subclinical CLL. Aggressive
● Plasmacytoid lymphoma chemotherapy of CLL plays a role in transformation of CLL to
● Large cell immunoblastic lymphoma Richter’s syndrome.
● Olfactory neuroblastoma
● Spermatocytic seminoma
● Rhabdoid tumor These higher-grade neoplasms are usually diffuse large B-cell
lymphomas with a centroblastic morphology, but other histo-
logical subtypes occur, including diffuse large B-cell lymphoma
Special techniques with immunoblastic morphology, much less commonly peri-
● Immunohistochemical demonstration of light chain pheral T-cell lymphoma, and Hodgkin lymphoma. EBV-positive
restriction can be used to confirm the diagnosis. Such a B-cell lymphoproliferative disorders (BLPDs) have recently
finding would exclude the non-hematopoietic lesions. been reported as a complication of the treatment for low-grade
Reactive plasma cell proliferation should be polyclonal. B-cell neoplasm.
HODGKIN LYMPHOMA
Hodgkin’s disease was originally named after the description of In overview, Hodgkin lymphomas comprise 30% of all lym-
the first lymphoma, as documented by Thomas Hodgkin and phomas, and have an apparently static incidence, whereas non-
Samuel Wilks. They are a specific grouping of true lymphomas; Hodgkin lymphomas are continuing to increase in number.
the term ‘disease’ has been dropped in the new WHO (2001) There is a bimodal age distribution, with peaks of incidence in
classification. Consequently, these are now referred to as the third and seventh decades of life. Hodgkin lymphoma is
Hodgkin lymphomas. more common in males, except for the nodular sclerosis sub-
Hodgkin lymphoma contains two discrete entities – classical type which affects both sexes equally or may even show a
Hodgkin lymphoma and the nodular lymphocyte predominant female predominance. Presentation may be in many different
Hodgkin lymphoma. Despite the differences listed below, these ways, but the most common is that of a painless enlargement
conditions share many characteristics including an origin of superficial (usually cervical) lymph nodes. Neck and medi-
within a lymph node, demographically both affect the young astinal nodes are the most common sites of presentation, and
adult, and both show the presence of large mono/multinucleate less commonly axillary, inguinal and intra-abdominal nodes.
cells (Reed–Sternberg/Hodgkin/Popcorn) cells and an intimate Extranodal presentation is extremely rare. Furthermore,
association with small T-cells. Hodgkin lymphoma is also one of the classic causes of pyrexia
of unknown origin. EBV infection is associated with the classi-

cal form, and viral transformation of an immature lymphoid CLASSICAL HODGKIN LYMPHOMA
cell plays a major role in the induction of the aberrant lym-
phoid cell phenotype of the Reed–Sternberg cell. EBV does not HODGKIN LYMPHOMA (HL) [WHO, 2001]
appear related to the non-classical form.
The prognosis of Hodgkin lymphoma depends on stage, his- Previous classification/synonyms include:
tological type, the overall bulk of the disease, and the number ● Hodgkin’s disease.
of lymph node regions involved. In general, about 75% of
patients are cured of their disease. Treatment is based on stag- OVERVIEW
ing (clinical or rarely pathological) as defined by the Cotswolds
revision of the Ann Arbor staging system (Carbone et al., 1971; The classical forms have numerous features in common, includ-
Lister et al., 1989; WHO, 2001): ing the bimodal demographic distribution and an association
with EBV, often with a history of prior infectious mononucleo-
sis (glandular fever).
Stage I Involvement of a single lymph node region or The diagnosis of Hodgkin lymphoma (HL) is primarily
lymphoid structure (spleen, thymus,Waldeyer’s dependent on the identification of classical Reed–Sternberg cells,
ring [a rather rare site of involvement], etc). or variants (mononuclear Hodgkin cells), in an appropriate cel-
Associated with ⬎90% 5-year survival. lular background. When lymph nodes are involved, their archi-
Stage II Involvement of two or more lymph node tecture is variably disrupted. There may be total effacement of
regions on the same side of the diaphragm; architecture or only partial involvement of the lymph node.
mediastinum counts as one site, hilar nodes Interfollicular HL may not disturb the lymph node architecture.
are lateralized. (The number of sites is The nature of the cellular background in which Reed–
provided by a suffix, e.g. II3 for three sites). Sternberg cells are found forms the basis of the original Rye
Associated with ⬎70% 5-year survival. classification of Hodgkin’s disease which divided HL into four
Stage III Involvement of two or more lymph node main subgroups:
regions on both sides of the diaphragm. 1. Lymphocyte-depleted (LD).
Associated with 50% 5-year survival. 2. Lymphocyte-predominant (LP) – now called nodular lym-
Stage III1 With or without splenic, hilar, celiac or portal phocyte predominant, a separate non-classical variant
nodes. under the WHO (2001) classification.
Stage III2 With para-aortic, iliac or mesenteric nodes. 3. Mixed cellularity (MC).
Stage IV Involvement of extranodal site(s) beyond 4. Nodular sclerosis (NS).
those designated E. Associated with 20–50%
5-year survival. The provisional subtype lymphocyte-rich (LR), HL added in the
REAL (Revised European-American Lymphoma) classification
Annotations include: is now fully accepted as part of the WHO (2001) classification.
● A: No clinical symptoms. Consequently, the four classical HL variants are LD-HL,
● B: Fever, sweats or weight loss (constitutional symptoms). LR-HL, MC-HL and NS-HL.
● X: Bulky disease: ⬎one-third widening of mediastinum at
T5/6, or nodal mass ⬎10 cm. Secondary features

● E: Involvement of single extranodal site, or contiguous or ● Classical forms often have a notable inflammatory
proximal to known site of disease. background (eosinophils, neutrophils and plasma cells).
● CS: Clinical stage. ● Epithelioid granuloma formation. Epithelioid granulomas
● PS: Pathological stage. can be seen in spleen, liver or bone marrow in patients
with HL.
Adverse prognostic factors include: high stage of the disease,
● Necrosis.
constitutional symptoms, the mixed cellularity and lymphocyte-
● Deposition of amyloid or para-amyloid material
deplete histological subtypes, older age group, male sex (male
(hyalinosis). The node is partially or extensively replaced
patients with stage III and IV are worse than females with sim-
by a meshwork of amorphous, hyaline material. This is
ilar stage), and those with relapse. The presence of epithelioid
especially seen in HL of long standing. Residual neoplastic
granulomas in spleen, liver or bone marrow has no adverse
cells may be seen within the hyaline material.
effect on prognosis. Radiotherapy is the treatment of choice for
early-stage disease, and combination chemotherapy for advanced
disease. Hodgkin lymphoma can be complicated by opportunis- Cell morphology
tic infection, especially viral and fungal infection. Development The classical Reed–Sternberg cell is a large cell with abundant,
of secondary neoplasms due to impaired immunosurveillance weakly eosinophilic, homogenous, granular or vacuolated cyto-
and the mutagenic effects of cytotoxic therapy are possible; plasm. The nucleus is large, and often bilobed (so-called ‘owl’s
typically, these include other malignant lymphomas, leukemias eye’ or ‘mirror-image’ nuclei) or multilobed. It contains a dis-
and non-lymphomatous neoplasms such a fibrosarcoma, tinct, very large, round, triangular or sausage-shaped, acidophilic
Kaposi’s sarcoma, and Langerhans’ cell histiocytosis. nucleolus that is surrounded by a halo.
Reed–Sternberg variants include: Special techniques

● Mononuclear cells (Hodgkin cells) with nuclear These are with regard to neoplastic cells, unless otherwise
characteristic similar to the classic Reed–Sternberg cell. specified.
Aggregates of these cells in solid clusters may give a ● CD30 is positive in virtually 100% of cases.
syncytial arrangement reminiscent of malignant melanoma ● CD15 is positive in 75–85% of cases; beware of positive
or secondary carcinoma. This is typically seen in NS-HL. granulocytes.
● Multinucleated forms with bizarre or horseshoe-shaped ● Cell membranes are CD45-negative. Look for gaps of
arrangement of nuclei (megakaryocyte-like cells). absent staining as surrounding populations will be
● Lacunar cells are so-called because of the presence of uniformly positive; this often leads to misdiagnosis for the
empty lacuna around the cell. This represents a fixation unwary.
artifact, and is characteristic of NS-HL. Lacunar cells ● Usually, T- or B-cell markers are absent.
show abundant clear cytoplasm within which there is an ● CD20 may be weakly positive in occasional neoplastic
ovoid or polylobated nucleus showing fine chromatin and cells (up to 40% of cases); CD79a is present less
smaller nucleoli than in classical Reed–Sternberg cells. frequently.
Lacunar cells are classically seen in NS-HL, but they may ● T-cell markers can rarely be seen, but are often weak.
also be seen in a smaller number in MC-HL. ● CD75 and the PGM-1 clone of CD68 are negative.
● L&H ‘popcorn’ cell is characteristic of nodular ● B-cell activator protein is weakly positive (weaker than
lymphocyte-predominant HL (non-classical variant), reactive B-cells).
although it may occasionally be noted in the classical ● LMP1 (latent membrane protein 1) of EBV is variable (see
forms, leading to confusion on morphology alone. This HL subtype).
cell is characterized by the presence of a large multilobated ● EMA is positive in ⬍5%.
nucleus with finely dispersed chromatin pattern, and ● Ki-67 is positive.
contains one or more basophilic nucleoli. ● BOB.1 and Oct2 are negative.
● ‘Mummified’ cells have much denser chromatin
obscuring the nuclei, and an intensely stained eosinophilic See also individual subtypes of Hodgkin lymphoma.
cytoplasm.
Molecular diagnostics
See Genetic profile.
Genetic profile
● T-cell-receptor (TCR) gene rearrangements are absent (rare Differential diagnosis
cases are recorded, but they may be examples of peripheral
See individual subtypes of Hodgkin lymphoma.
T-cell lymphoma, unspecified that can mimic HL).
● Over 98% have monoclonal immunoglobulin gene
rearrangements. LYMPHOCYTE-DEPLETED HODGKIN LYMPHOMA
● Ongoing somatic mutations of the variable region have (LD-HL) [WHO, 2001]
been noted, indicating neoplastic derivation from a
germinal center B-cell or post germinal center B-cell. Previous classification/synonyms include:
● Lack of immunoglobulin mRNA production by ● Lymphocyte depletion Hodgkin’s disease (REAL)
promoter silencing explains the phenotypic lack of ● Lymphocytic depletion Hodgkin’s disease (Rye)
immunoglobulin expression; this relates to the lack of ● Lymphocytic depletion Hodgkin’s disease; Diffuse fibrosis
BOB.1 and Oct2. and reticular types (Lukes and Butler)
● Blockade of immunoglobulin production should initiate ● Hodgkin’s sarcoma (Jackson and Parker)
apoptosis. Consequently, this pathway must be
non-functional, perhaps relating to NF␬B cascade
CLINICAL FEATURES
abnormalities. These include over-expression of tumor
necrosis factor (TNF) receptor-associated factor-1 LD-HL is the least common type of HL, and accounts for less
(TRAF1). than 5% of cases. The median age of presentation is 37 years,
● EBV LMP1 plays a role, and is anti-apoptotic. and 75% of cases are male. It is typically a diffuse form of clas-
● EBNA1 is also expressed. sical HL with numerous Hodgkin/Reed–Sternberg cells and/or
● EBNA2 is absent. depletion of the non-neoplastic lymphocytic background. Sites
● Over-expression of p53 (mutations of TP53 have not of involvement include lymph nodes (particularly central over
been documented). peripheral nodes), bone marrow and abdominal organs. Many
● Aneuploidy and hypertetraploidy are present cases originally classified as this disorder are now recognized to
(unsurprising, given the nuclear size and multinuclearity). be non-Hodgkin lymphoma. An association with HIV infection
● Chromosomal gains are seen in 2p, 9p, 12q, 4p16, has been documented, and is seen more frequently in develop-
4q23-q24, and 9p23-p24. ing countries. With regards to prognosis, LD-HL was histori-
● t(2;5), anaplastic lymphoma kinase (ALK) is absent. cally seen as significantly more aggressive than other types
● t(14;18) is absent. of HL, with 70% presenting at high stage and 80% with
constitutional symptoms. However, modern chemotherapy has LD-HL and lymphocyte-depleted areas in NS-HL. The
brought this condition in line with other HL on a stage-for-stage differentiation of reticular LD-HL from anaplastic large-
basis. Those associated with HIV have a considerably worse cell lymphoma can be extremely difficult, and depends on
prognosis. careful assessment of both cytological and architectural
features of the tumor cell infiltrate and
PATHOLOGICAL FEATURES immunophenotypical investigation. Cytologically,
anaplastic large-cell lymphomas show marked
The appearances are highly variable, but the main identifiable pleomorphism, and include both mononuclear
feature is a predominance of diagnostic cells compared with the immunoblast-like cells and multinucleated tumor giant
background lymphocytic population. Two histological sub- cells with large vesicular nuclei containing large nucleoli
types of LD-HL are recognized: which may resemble Reed–Sternberg cells. In most cases,
● Diffuse fibrosis subtype: this is characterized by total loss
tumor cells have abundant eosinophilic cytoplasm. There
of the node architecture and the presence of disorganized is a high mitotic and apoptotic rate, and necrosis may be
sclerosis with a hypocellular background containing few seen. Architecturally, tumor cells tend to show cohesive
classical Reed–Sternberg cells and numerous abnormal growth, with preferential sinusoidal and paracortical node
large mononuclear Hodgkin’s cells. The latter may have infiltration. Some cases may show capsular and intranodal
spindle morphology reminiscent of soft tissue sarcomas. sclerosis. It is perhaps not justifiable to make a diagnosis
The identification of lymph node structure may be of LD-HL unless clear evidence of Hodgkin lymphoma is
difficult. The lymphocytes are few in number and along seen elsewhere in the biopsy, or an earlier biopsy has
with eosinophils and plasma cells appear to be scattered shown unequivocal evidence of Hodgkin lymphoma.
among the spindle cells. Should a nodular sclerosis EBV positivity is a good discriminator of being positive
dominate, a diagnosis of NS-HL should be given. in LD-HL.
● Reticular subtype: this is characterized by total loss of the ● The fibrohistiocytic variants of NS-HL may resemble the
node architecture and replacement by dense cellular diffuse fibrosis subtype of LD-HL and cases of reticular,
infiltrate of pleomorphic Reed–Sternberg cells, with pleomorphic or syncytial lymphocyte-depleted variants of
bizarre multilobated nuclei and large nucleoli, as well as NS-HL may resemble reticular LD-HL. Organized
large mononuclear cells together with small numbers of birefringent collagen band formation favors NS-HL.
lymphocytes, neutrophils and eosinophils. ● The reticular variant of LD-HL may resemble MC-HL.
Features of both subtypes commonly coexist within the same ● Hodgkin lymphoma treated by radiotherapy or
biopsy, and both subtypes often show foci of necrosis. This chemotherapy may result in cellular depletion reminiscent
may be confused with MC-HL. of LD-HL. The former however often shows acellular
eosinophilic hyaline material (representing the treated
Secondary features neoplastic tissue) with focal residual uninvolved lymph
node structure.
● Foci of necrosis. ● Soft tissue sarcomas – in particular inflammatory
● Inflammatory cells infiltration (neutrophils, eosinophils malignant fibrous histiocytoma and inflammatory
and macrophages). fibrosarcoma – may resemble the diffuse-type LD-HL.
Cell morphology
● Many of the tumor giant cells are very atypical, and LYMPHOCYTE-RICH HODGKIN LYMPHOMA
spindle-shaped forms may be seen. (LR-HL) [WHO, 2001]
● Classic Reed–Sternberg cells may be difficult to find.
Previous classification/synonyms include:
Genetic profile ● Lymphocyte-rich (provisional) Hodgkin’s disease (REAL)
● Not stated (Rye)
Similar profiles are seen as described in the generic classical HL
● Not stated (Lukes and Butler)
section (see p. 684).
● Not stated (Jackson and Parker)
Special techniques
● Similar immunohistochemical profiles are seen to that CLINICAL FEATURES
described in the generic classical HL section (p. 684). LR-HL was a provisional diagnostic entity proposed under
● HIV-related cases are EBV-associated, and LMP1 the REAL lymphoma classification, now formally accepted
expression can be demonstrated. under the WHO (2001) classification. It represents a subgroup
● Molecular diagnostics (see Genetic profile, p. 684). of classical HL previously classified with nodular lymphocyte-
predominant Hodgkin lymphoma (NLP-HL), before the classi-
Differential diagnosis cal and non-classical HL patterns were discerned. It has clinical
● Anaplastic large cell lymphomas may show considerable features in common with NS-HL or MC-HL, rather than
morphological and immunophenotypical overlap with NLP-HL.
LR-HL comprises 5% of all HL, equal to that of NLP-HL.

Some 70% of cases occur in male patients, and the median age
of presentation tends to be older than for other groups. Typically,
peripheral lymph nodes are involved; 15% of cases have medi-
astinal involvement. Bulky disease is rare. Most cases present
with stage I or II disease, and constitutional symptoms are rare.
Relapse is less frequent than with NLP-HL, and the prognosis
tends to be better than for other classical forms, and equivalent
to NLP-HL. However, the outcome is worse than for NLP-HL
following relapse.

LR-HL differs from NLP-HL in that the neoplastic population
consists of classical Reed–Sternberg cells rather than lymphocytic
(c)
(CD20-positive, CD45-positive) and histiocytic Reed–Sternberg
cells. The background population consists predominantly of
T lymphocytes.
Architecturally, two growth patterns are described; nodular
(common) and diffuse (rare). In the former, nodules replace vir-
tually the entire node, compressing the intervening T-zone that may not be readily identifiable. Most of these nodules appear
to be small lymphocytes; germinal centers may still exist in a
regressed state. Hodgkin and Reed–Sternberg cells are restricted
to the mantle zone. The diffuse form lacks the zonal definition
seen in the nodular pattern.
Cell morphology
● Hodgkin and Reed–Sternberg cell morphology may cause
confusion with NLP-HL, and therefore careful scrutiny of
the immunophenotype is essential.
● Eosinophils and/or neutrophils are absent.
● Background small lymphocytes and histiocytes
predominate.
Genetic profile
● Similar profiles are seen as described in the generic
classical HL section (p. 684).
(a)
Special techniques
● Similar immunohistochemical profiles are seen to that
described in the generic classical HL section (p. 684).
● Small lymphocytes express IgD indicating a mantle cell
phenotype. Nodules in the nodular form are expanded
mantle zones.
● CD21 and CD23 will highlight residual follicular dendritic
cells in the regressed germinal centers. These are rare in
NLP-HL.
● In the diffuse form, the lymphocytes are almost all T-cells;
this may cause confusion with T-cell-rich DL-BCL.
● Molecular diagnostics (see Genetic profile, p. 684).
(b)
● NLP-HL
● Other classical HL
Figure 10.23 Lymphocyte-rich Hodgkin lymphoma. Scattered
● T-cell/histiocyte-rich diffuse large B-cell lymphoma
Reed–Sternberg/Hodgkin cells within a lymphocyte-rich background ● Thymoma
(a).These are CD15 (b) and CD30 (c) positive. ● T-cell lymphoma
MIXED CELLULARITY HODGKIN LYMPHOMA Histiocytic and epithelioid or sarcoidal granulomas may be
numerous. Areas of lymphocyte depletion may also be identi-
(MC-HL) [WHO, 2001]
fied, but these cases show clinical behavior similar to typical
MC-HL and should therefore be retained in the MC-HL group.
● Mixed cellularity Hodgkin’s disease (REAL)
● Mixed cellularity Hodgkin’s disease (not true subtype,

Secondary features
diagnosis of exclusion) (Rye) ● Small foci of necrosis
● Not stated (Lukes and Butler)
● Not stated (Jackson and Parker) Cell morphology

● Classic Reed–Sternberg and mononuclear Hodgkin cells
CLINICAL FEATURES (scattered indiscriminately among the other cellular
elements without clustering, as seen in NS-HL).
This is the second most common type of classical HL and
● Both lacunar cells and pleomorphic variants of
accounts for 20–25% of cases. It is more common in individu-
Reed–Sternberg cells may be present.
als infected with HIV. This subtype lacks the typical bimodal
● Histiocytes.
age distribution; it occurs mainly in young adults (median age
● Epithelioid cells.
37 years), but it is more common than NLP-HL and NS-HL in
● Histiocyte-like cells of indeterminate type.
older patients. Males are more frequently affected than females.
● Plasma cells tend to congregate towards the periphery of
At presentation, MC-HL tends to be at a high stage (III or
the lesion.
IV) and associated with constitutional symptoms. It most com-
● Eosinophils are scattered throughout the lesion.
monly affects cervical glands, with mediastinal involvement
● Polymorphs (especially seen in relation to foci of
being less common than in NS-HL. Other organs may be
necrosis).
involved; these include the spleen (30%), bone marrow (10%)
and liver (3%). Historically, MC-HL had a worse prognosis
compared with NS-HL, but this has largely disappeared with
Genetic profile
the currently used chemotherapeutic regimens. ● Similar profiles are seen as described in the generic
classical HL section (p. 684).
Special techniques
The diagnosis of MC-HL requires identification of classical
Reed–Sternberg cells. The number and morphology of these
● Similar immunohistochemical profiles are seen to that
cells and the composition of the cellular background are described in the generic classical HL section (p. 684).
widely variable. The background population ranges from
● EBV LMP1 expression is more frequent than in other
lymphocyte-predominant to areas of lymphocyte depletion, but classical HL (up to 75% of cases are positive).
usually includes eosinophils, plasma cells and histiocytes, and
may also show irregular sclerosis. Typically, the lymph node Differential diagnosis
architecture is effaced, although an interfollicular pattern is ● Peripheral T-cell lymphoma, unspecified (Lennert
possible. Interstitial fibrosis is seen, but capsular thickening is lymphoma, T-zone lymphoma, AIL-like lymphoma) may
absent and fibrosis should not be seen in broad bands. show a similar polymorphous infiltrate including
(a) (b)
Figure 10.24 Mixed cellularity Hodgkin lymphoma. Note the typical Hodgkin/Reed–Sternberg cells within a mixed, eosinophil rich
background (a).These larger cells are CD30 positive (b).
eosinophils, plasma cells and histiocytes. However, marrow involvement in 3%. At clinical presentation NS-HL is
classical Reed–Sternberg cells are absent or present in only typically at stage II, with 60% of patients being free of consti-
very small numbers, sarcoidal granulomas are absent, tutional symptoms. Prognosis is said to be better than for either
pleomorphism of lymphocytes and higher mitotic figures MC-HL or LD-HL, mainly due to a tendency for patients to
and presence of clear cells are more indicative of present at a lower stage II, although massive mediastinal dis-
peripheral T-cell lymphoma. Large numbers of plasma ease is a poor prognostic sign.
cells and their precursors and large number of vessels are NS-HL has been subdivided into two prognostic categories
more in keeping with angioimmunoblastic-type of T-cell (British National Lymphomas Institute, BNLI, classification)
lymphoma. There is usually clear expression of T-cell based on the cellular composition of the lesion:
markers by neoplastic blast cells as well as small and ● The unfavorable group, NS2 (30% of cases) is defined as
intermediate lymphocytes. In T-cell lymphoma, although lesions in which ⬎25% of nodules show a sheet-like
CD30 expression by large blasts is common, CD15 presence (the sheet must fill a ⫻40 HPF) of bizarre and
expression – particularly strong membrane and/or Golgi highly anaplastic Hodgkin/Reed–Sternberg cells with or
area staining – is rare and, when present, favors a without lymphocyte depletion, or ⬎25% of nodules
diagnosis of HL. show lymphocyte depletion resembling reticular
● T-cell-rich and histiocyte-rich DL-BCL may show lymphocyte-depleted HL, or ⬎80% show fibrohistiocytic
considerable morphological overlap with MC-HL. In lymphocyte depletion. This lesion is associated with a
T-cell-rich DL-BCL only rare Reed–Sternberg-like cells can 66% five-year survival.
be identified, together with more numerous large blast ● The favorable group, NS1 (70% of cases) contains other
cells in a background of small lymphocytes, which may cases of NS-HL; typically, they have a lymphocyte-rich,
show nuclear irregularity. Although histiocytes may mixed cellularity or fibrohistiocytic background. They are
occasionally be numerous, other accompanying cells such associated with an approximately 83% five-year survival.
as eosinophils and plasma cells are not present.
The BNLI classification is mainly a research tool, and is not
Immunophenotyping shows that the large cells express
practiced routinely in diagnostic pathology.
B-cell antigens such as CD20, and also express EMA but
do not express the Reed–Sternberg-associated antigens
CD15 and CD30. The B-cells show monotypic PATHOLOGICAL FEATURES (Figure 10.25)
Ig expression in some cases, and most cases show clonal The diagnosis of NS-HL requires identification of classical
immunoglobulin gene rearrangements. Reed–Sternberg cells together with nodule formation, lacunar
● Cellular phase NS-HL. Identification of at least minimal cells and at least some evidence of intranodal fibrosis with
organized sclerosis with birefringent collagen within the organized birefringent collagen bands or strands.
lymph node and the presence of lacunar cells and Lacunar (‘lacunar’ is an artifactual retraction of cytoplasm
nodularity should be seen before cellular phase NS-HL is following fixation, giving the impression that cells are sitting in
diagnosed. lacunae) cells may be found singly or in aggregates, sometimes
● Other subtypes of HL. The distinction of MC-HL from forming large ‘syncytial’ sheets within which there are areas of
other subtypes of HL is not always clear, as MC-HL necrosis. The number and morphology of Reed–Sternberg and
represents a dumping ground where cases are placed if lacunar cells, and the composition of the cellular background
they do not fulfil all the criteria for other subtypes. in NS-HL are widely variable, ranging from lymphocyte-
predominant to lymphocyte-depleted with variable numbers of
eosinophils, plasma cells and histiocytes as well as intranodu-
NODULAR SCLEROSIS HODGKIN LYMPHOMA lar sclerosis. The degree of sclerosis varies widely. Dense col-
(NS-HL) [WHO, 2001] lagenous fibrosis may replace the greater part of the node and
split the node into cellular compartments, or the fibrosis may
Previous classification/synonyms include: be confined to collagenous thickening of the capsule with a few
● Nodular sclerosing/sclerosis Hodgkin’s disease (REAL)
slender bands of fibrous tissue passing from the capsule into
● Nodular sclerosis Hodgkin’s disease (Rye)
the node. Distinction of cellular-phase NS-HL with minimal
● Not stated (Lukes and Butler) sclerosis from other subtypes may only be possible after care-
● Not stated (Jackson and Parker) ful examination of sections from several areas.
CLINICAL FEATURES Vascular pattern

Concentric ‘onion-peel’ rings of collagen are commonly seen
NS-HL is the most common type of classical HL, accounting
around small arteries.
for around 70% of cases. It occurs mainly in young adults
(median age 28 years at presentation) and, in contrast to other
histological subtypes, does not show any male predominance Secondary features
(1:1 sex ratio). NS-HL predominantly involves the mediastinum ● Necrosis, which can be massive.
(80% of cases) and neck nodes. Bulky disease is frequent ● Polymorph infiltration.
(54%), splenic or pulmonary involvement occurs in 10%, and ● Perinodal inflammatory response.
(a) (c)
(b) (d)
Figure 10.25 Nodular sclerosis Hodgkin lymphoma.The typical nodularity caused by the dissecting bands of collagen is shown in the
low-power view (a). At higher power (b), the classical Reed–Sternberg cells become apparent. In this example, these cells are strikingly
CD15 (c) and CD30 (d) positive.
Cell morphology Special techniques

● Lacunar cells (see above): in classic NS-HL these cells are ● Similar immunohistochemical profiles are seen as
numerous, and often tend to congregate together in the described in the generic classical HL section (p. 684).
center of the tumor nodules. ● EBV LMP1 expression is less frequent than in
● Classic Reed–Sternberg cells. other classical HL (10–40% of cases are
● Bizarre giant cells. positive).
● Mononuclear Hodgkin cells can be numerous and
arranged in solid clusters (syncytial variant of NS-HL). Differential diagnosis
● Histiocytes. ● NLP-HL (may be confused with the cellular phase of
● Epithelioid cells. NS-HL).
● Histiocyte-like cells of indeterminate type. ● LD-HL (lymphocyte-depleted and fibrohistiocytic
● Plasma cells: when numerous, they are concentrated at the variants of NS-HL, including the syncytial variant of
margins of the node and in adjacent uninvolved nodes. NS-HL may be confused with LD-HL).
● Eosinophils may be sparse or abundant. Heavy ● High-grade non-Hodgkin lymphoma, especially
eosinophilia may be associated with necrosis. mediastinal (thymic) large B-cell lymphoma
(ML-BCL).
Genetic profile ● Metastatic carcinoma.
● Similar profiles are seen as described in the generic ● Malignant melanoma.
classical HL section (p. 684). ● Suppurative lymphadenitis.
axillary or inguinal nodes, and extranodal spread is rare.

NON-CLASSICAL HODGKIN LYMPHOMA Most patients are early/stage I or II at presentation, although
up to one-fifth may present with late/advanced disease.
NODULAR LYMPHOCYTE-PREDOMINANT The clinical course is one of relapse and remission; however,
each relapse is often treatable so that the prognosis is good.
HODGKIN LYMPHOMA (NLP-HL) [WHO, 2001] The overall 10-year survival rate is in excess of 80%.
Progression to diffuse large B-cell lymphoma (DL-BCL) has
been recorded in 3–5% of cases; in mixed lesions clonality has
● Nodular lymphocyte-predominant Hodgkin’s disease (REAL)
been proven.
● Lymphocyte predominance Hodgkin’s disease (Rye)
● Lymphocytic and/or histiocytic (L&H) predominance
Hodgkin’s disease (Lukes and Butler) PATHOLOGICAL FEATURES (Figure 10.26)

● Hodgkin’s paragranuloma (Jackson and Parker)
NLP-HL is a B-cell neoplasm characterized by a nodular, dif-
fuse or mixed pattern of lymph node effacement by a polymor-
CLINICAL FEATURES
phous cell population containing large (L&H/Popcorn) cells.
NLP-HL is a B-cell neoplasm, and represents 5% of all These are Reed–Sternberg variants that are scattered in associ-
Hodgkin lymphoma. Most cases are males, with an age ation with spherical follicular dendritic cell networks contain-
range of 30 to 50 years. Typically, NLP-HL affects cervical, ing bystander lymphocytes.
(a) (c)
(d)
Figure 10.26 Nodular lymphocyte-predominant Hodgkin lymphoma.

The typical nodularity is seen here in the low-power image (a). At higher
power (b) the potential differential diagnosis expands, consequently
immunohistochemistry is essential.The typical profile of the larger L&H
cells/popcorn cells is CD20 (c) and CD45 (d) positive, and they are
(b)
often ringed by a halo of CD3 (e) and CD57 (f) positive T-cells.
● Chromatin is vesicular, nucleoli are small but multiple, and

usually basophilic.
● Occasionally, Reed–Sternberg forms are present.
● Background cells include small lymphocytes,
histiocytes (including epithelioid forms) and polyclonal
plasma cells.
● Neutrophils and eosinophils are ABSENT.
● L&H cells are often surrounded by a halo of CD3-positive
T cells.
Genetic profile
● L&H cells have clonal immunoglobulin gene
rearrangements.
● Latent EBV is consistently absent; bystander cell infection
(e) may be seen.
Special techniques
● Reticulin stain highlights the large nodules.
● L&H cells are CD20-, CD45-, CD79a- and
Bcl-6-positive.
● EMA is positive in 50% of L&H cells.
● Immunoglobulins are strongly positive.
● CD15 is negative.
● CD30 may rarely be positive; these instances happen to be
lymphoblasts in most situations.
● Most L&H cells are MIB1/Ki67-positive, indicating cell
cycle activity.
● CD3 and occasionally CD57 highlight the T-cell halo
around L&H cells.
● Oct2 (a transcription factor that activates immunoglobulin
(f) genes, in conjunction with BOB.1) is consistently positive
in L&H cells.
Figure 10.26 (Continued). ● BOB.1 is positive in L&H cells.
● BOB.1 and Oct2 co-expression appears unique to
NLP-HL and differentiates it from classic forms but not
The surrounding lymph node shows reactive follicular hyper- from T-cell/histiocyte-rich DL-BCL.
plasia; sometimes progressive transformation of germinal cen- ● CD10 germinal center cells are depleted.
ters is observed. ● CD21 and CD23 highlight the follicular dendritic
Progressive transformation of germinal centers is a morpho- network.
logical change that can be seen in reactive hyperplasia of lymph
nodes, but also has an association with NLP-HL. The enlarged Differential diagnosis
germinal center appears to break up into fragments by the impo- ● Reactive follicular hyperplasia
sition of small lymphocytes. Gradually, these fragments are ● Classical Hodgkin lymphoma
reduced to isolated centrocytes or centroblasts, and the germi- ● T-cell/histiocyte-rich DL-BCL
nal center is no longer recognizable. Collections of small epithe- ● Follicular lymphoma
lioid cells may then appear around the transformed germinal ● Nodular variants of CLL/SLL with proliferation centers
center. The precise significance of this is uncertain, and some ● Peripheral T-cell lymphomas, especially lymphoepithelioid
debate exists as to whether these are true precursor lesions; how- (Lennert) lymphoma
ever, most patients with solely hyperplasia and transformation ● Toxoplasmosis, sarcoidosis and tuberculosis
do not develop NLP-HL.
Cell morphology
● L&H cells are large, with a central prominent nucleus and
scant cytoplasm. The nucleus is folded and multilobated,
giving rise to the ‘popcorn’ idiom.
NON-HODGKIN LYMPHOMA: B-CELL NEOPLASIA
In western countries, B-cell lymphomas are much more com- The prognosis of B-ALL depends on the demographic profile
mon than T-cell lymphomas, accounting for over 90% of all of the population; 95% remission (pediatric), 60–85% remis-
lymphoid neoplasms. The majority arise from follicular center sion (adult) and risk groups are based on genetic disposition,
cells and fall into the diagnostic categories ‘follicular lym- age, gender, blood count and response to therapy. B-LBL has a
phoma’ or ‘diffuse large B-cell lymphoma’. Low-grade B-cell median survival of 60 months with a high remission rate, but
lymphomas tend to have an indolent course, but are incurable relapse may occur in the central nervous system and other sites
by means other than surgical excision of localized (generally such as testis.
extranodal) disease, whereas high-grade B-cell lymphomas are
far more aggressive, but are potentially curable by combination PATHOLOGICAL FEATURES
chemotherapy.
This section will divide B-cell lymphomas into precursor The disorder is characterized by the complete replacement of
forms, mature forms, and those with uncertain malignant lymph node architecture with a diffuse infiltrate of non-
potential. Within each category the disorders will be listed in cohesive but closely packed, uniform, medium-sized lymphocytes.
alphabetical order unless they are otherwise interrelated. In cases where acute lymphoblastic leukemia supervenes on
chronic myeloid leukemia (CML) ‘lymphoid blast crisis’, the
lymph nodes may show residual myeloid or megakaryocytic
cells. These are particularly seen at the periphery of the node.
PRECURSOR B-CELL NEOPLASIA In extranodal sites, the lymphoblastic/leukemic infiltration may
acquire a gyriform pattern. In bone marrow, the lymphoblasts
PRECURSOR B-LYMPHOBLASTIC LEUKEMIA of B-ALL are uniform and sheet-like.
(B-ALL)/LYMPHOBLASTIC LYMPHOMA
Cell morphology
(PRECURSOR B-CELL ACUTE LYMPHOBLASTIC ● The neoplastic cells are of medium size, with large nuclei
LEUKEMIA, B-LBL) [WHO, 2001] and scant cytoplasm.
● The nuclei are round or oval, with a slightly irregular
Previous classification/synonyms include: outline. They contain fine chromatin and one or more
● Precursor B-lymphoblastic leukemia/lymphoma (REAL)
inconspicuous nucleoli.
● Lymphoblastic (convoluted cell, non-convoluted cell) ● Mitotic figures are numerous.
(Working Formulation)
● Lymphoblastic B-cell type (Kiel)
Genetic profile
● FAB: L1 and L2 (French-American-British)
● Acute lymphoblastic leukemias Grouped classification:

● Hypodiploid (5%, unfavorable prognosis)
Precursor B-lymphoblastic leukemia (B-ALL)/lymphoblastic ● Hyperdiploid ⬍50.
lymphoma (B-LBL) is a neoplasm of B-cell-committed lympho- ● Hyperdiploid ⬎50 (20–25%, favorable prognosis).
blasts. It often presents within the bone marrow and blood ● Translocations (see below).
(B-ALL), and rarely within nodal or extranodal sites (B-LBL). ● Pseudodiploid.
The terms are overlapping and distinction is arbitrary. The

Translocations:
term B-LBL is preferred if ⬍25% of the blasts are present in
● t(9:22)(q34;q11.2); BCR/ABL; 3–4% of B-ALL;
the marrow.
unfavorable prognosis.
● t(4:11)(q21;q23); AF4/MLL; 2–3% of B-ALL; unfavorable
CLINICAL FEATURES prognosis.

● t(1:19)(q23;q13.3); PBX/E2A; 6% of B-ALL (25% of
B-ALL is usually seen in young individuals, typically children.
pre-B-ALL); unfavorable prognosis.
Over 75% of patients are aged less than 6 years, and approxi- ● t(12:21)(p13;q22); TEL/AML1; 16–29% of B-ALL;
mately 2000–2400 new cases occur per annum in the USA. This
favorable prognosis.
condition presents with arthralgia, bone pain, bone marrow
failure and thrombocytopenia/anemia/neutropenia with a var-
ied leukocyte count. Lymphadenopathy and hepatosplenomegaly Special techniques
are also frequent occurrences. ● The cells express B-cell markers (CD19, CD79A), but
B-LBL accounts for 10% of cases, with most patients being CD20, CD22, CD45 may be negative. CD24 and CD10 are
aged less than 35 years, and there being a male predominance. often positive, except for cells with the t(4:11)(q21;q23)
Presentation includes skin nodules, bone and lymph node translocation. Terminal deoxynucleotidyl transferase (TdT)
involvement. and HLA-DR are positive. Myeloid antigens (CD13 and
Both conditions are treated with aggressive chemotherapy. CD33) can be positive, but do not indicate myeloid origin
in this case. Surface immunoglobulin may be negative. PATHOLOGICAL FEATURES

Cytoplasmic mu chains are expressed in the most mature
Most circulating cells (up to 90%) are prolymphocytes,
form of B-ALL (pre-B-ALL).
and these may be present in the bone marrow, spleen and
● There may be immunoglobulin or TCR gene
lymph nodes. Splenic involvement is typified by red pulp
rearrangements, plus specific genetic lesions as
prolymphocytes and an expanded white pulp displaying
mentioned above.
central compaction with larger peripheral cells. Lymph nodes
● PAS may highlight cytoplasmic glycogen in imprint
show diffuse and nodular infiltrates. No pseudofollicles are
preparations.
present.
● A negative chloroacetate esterase reaction helps to exclude
myeloblastic leukemia.
● Molecular diagnostics (see Genetic profile). Cell morphology
● Medium-sized cells (double that of a lymphocyte) are
Differential diagnosis present, each with a prominent central nucleolus
● Precursor T-lymphoblastic lymphoma/leukemia (the cells surrounded by a rim of condensed chromatin within an
are less uniform, the nuclei show convolutions, and the ovoid nucleus.
chromatin is finer, but the distinction is best made
● Occasionally, an angularity to the nuclear membrane is
immunohistochemically) noted.
● Acute myeloid leukemia (AML)
● The cells have a small rim of basophilic cytoplasm.
● Myeloblastic sarcoma/leukemia (some cells show
chloroacetate esterase activity, and may show a Genetic profile
positive reaction with MT1, KP1 and CD11c). ● There is clonal rearrangement of the immunoglobulin
Scattered eosinophils (particularly immature forms) may genes.
be seen ● The most common translocation is t(11;14)(q13;q32); this
● Infectious mononucleosis (widespread blast transformation is present in up to 20% of cases.
of lymphoid cells with numerous mitotic figures may ● Other break points around chromosome 14q32 have been
sometimes be seen in infectious mononucleosis; however, described.
the cell population is not homogeneous and many cells ● Over half of the patients have p53 abnormalities.
show plasmacytoid differentiation) ● Deletions of 11q32 and 13q14 are possible.
● Small round cell tumors of childhood (small-cell
rhabdomyosarcoma, Ewing’s sarcoma and Special techniques
neuroblastoma)
● Small-cell undifferentiated carcinoma
● Immunohistochemistry: surface positivity is seen for CD5
(one-third), CD19, CD20, CD22, CD79a, IgD and/or IgM.
CD23, CD10 and cyclin D1 are all negative.
● Immunoglobulin heavy and light chain gene
MATURE B-CELL NEOPLASIA
rearrangements can be detected.
● Fluorescence in-situ hybridization (FISH) for
B-CELL PROLYMPHOCYTIC LEUKEMIA translocational/deletional analysis.
[WHO, 2001] ● Molecular diagnostics (see Genetic profile).
Previous classification/synonyms include: Differential diagnosis

● B-cell prolymphocytic leukemia (REAL) ● Leukemic blastoid variant of mantle cell lymphoma
● Not classified (Working Formulation)
(MCL)
● B-cell prolymphocytic leukemia (Kiel) ● Transformed chronic lymphocytic leukemia/small
● B-cell prolymphocytic leukemia (French–American–British)
lymphocytic lymphoma (CLL/SLL)
CLINICAL FEATURES
BURKITT LYMPHOMA (BL) [WHO, 2001]
This extremely rare condition is responsible for less than 1% of
all lymphocytic leukemias. The majority of patients are male Previous classification/synonyms include:
(male:female ratio, 1.6:1), and the median age is 70 years. The ● Burkitt lymphoma (REAL)
condition involves the blood, bone marrow and spleen; conse- ● Small, non-cleaved cell, Burkitt type (Working
quently patients present with splenomegaly and peripheral Formulation)

lymphadenopathy with a rising leukocyte count. ● Small, non-cleaved follicular center cell (Lukes-Collins)
The response to CLL treatments is poor, but some response ● Burkitt and Burkitt lymphoma with intracytoplasmic
to CHOP (cytoxan, adriamycin, vincristine and prednisolone) immunoglobulin (Kiel)

has been documented. Splenectomy may be of assistance in ● Undifferentiated lymphoma, Burkitt type (Rappaport)
treatment. ● L3 ALL (French–American–British)

CLINICAL FEATURES by large macrophages containing nuclear debris, producing a

‘starry-sky’ appearance. The number of macrophages is vari-
Burkitt lymphoma (BL) is a highly aggressive lymphoma of the
able, and may be absent in occasional cases. Occasionally, a
germinal center B-cell that occurs endemically in Africa and
follicular arrangement of cells is seen. Staging is based on the
part of New Guinea, and is seen sporadically elsewhere in the
Murphy and Hustu criteria, later modified by McGrath
world. It usually affects children, but can also be seen in adults.
(WHO, 2001; Weitzman et al., 1991).
The endemic form is strongly associated with EBV infection,
the sporadic form less so. EBV is not essential for the develop-
ment of Burkitt lymphoma.
Cell morphology
The endemic form presents as tumors in the jaws of children, ● The neoplastic cells are of medium size, with large nuclei
or less frequently in the ovaries, retroperitoneum, bones, sali- and scant cytoplasm, often with angulated or truncated
vary glands, thyroid and breast. They show a dramatic borders.
response to chemotherapy. Rare cases of spontaneous remis- ● The nuclei are round or oval, with a slightly irregular
sion can also be seen. outline. The chromatin is dense, coarse and partially
The sporadic form usually presents as intra-abdominal tumors obscuring the small randomly distributed single or multiple
arising from the Peyer’s patches in the ileocecal region or mesen- nucleoli.
teric lymph nodes. It also occurs in other nodal and extranodal ● Mitotic and apoptotic figures may be numerous.
sites, including a leukemic form (L3/ALL). Breast involvement ● In the classical form, the cells are monotonous (see
during pregnancy/puberty is also possible. Central nervous sys- Variants, below).
tem involvement is typically spinal, causing paraplegia.
The immunodeficiency-associated form can occur in patients Genetic profile
with AIDS or other causes of immunosuppression. EBV is ● Immunoglobulin heavy and light chain gene
associated with 20–25% of cases, and nodal or bone marrow rearrangements.
localization is frequent. ● Somatic mutations of the variable region are present,
The clinical course is highly aggressive, but cures can be indicating a post-germinal center origin.
achieved with combination chemotherapy. However, the bulk ● MYC translocation (8q24), either t(8;14) or t(2;8) or
of the disease often present may cause tumor lysis syndrome t(8;22) in all cases. It is not specific for BL.
(hyperkalemia, renal failure, etc.) on initiation of treatment. ● TP53 mutations are present in 30% of cases.
Relapses can occur in the central nervous system. ● Variable EBV association.
PATHOLOGICAL FEATURES (Figure 10.27) Special techniques

The lymph node architecture is completely replaced by a uniform ● There is expression of membrane IgM.
population of cohesive, medium-sized lymphocytes interrupted ● There is light chain restriction.
(a) (b)
Figure 10.27 (a, b) Burkitt lymphoma. Diffuse infiltrate of medium-sized lymphoid cells with prominent apoptosis and ‘starry sky’
macrophages engulfing apoptotic debris.
● There is expression of pan B-cell markers (CD19, CD20, lymphadenopathy and hepatosplenomegaly. Furthermore, it
and CD22). may be associated with dysproteinemias (e.g., Waldenström’s
● BCL6 and CD10 are positive. macroglobulinemia) and with Coomb’s-positive hemolytic ane-
● CD5, CD23, CD34, TdT and bcl-2 are negative. mia. The diagnosis of CLL requires bone marrow or blood
● EBV antigens are commonly expressed in the endemic involvement; otherwise, the diagnosis should be restricted to
form. SLL. Transformation into a higher-grade disease with rapid clin-
● CD21 (C3d receptor) can be expressed in the endemic ical deterioration (Richter’s syndrome) occurs in 3.5% of cases.
form. Morphologically, this transformation resembles diffuse large
● Ki-67/MIB1 (proliferation marker) shows almost 100% B-cell lymphoma, but Hodgkin lymphoma is also possible. Non-
nuclear positivity. transformed cases have a median survival of about eight years
● Molecular diagnostics (see Genetic profile). (see Genetic profile below for further information), depending
on the data used. Radiotherapy and aggressive chemotherapy are
Differential diagnosis ineffective in this condition. Symptomatic disease can be con-
● Other types of high-grade lymphoma: B- and trolled for long periods with mild chemotherapy.
T-lymphoblastic lymphoma
● Other types of high-grade lymphoma: small-cell variants of PATHOLOGICAL FEATURES (Figure 10.28)
diffuse large B-cell lymphoma These lymphomas are characterized by diffuse effacement of
● Infectious mononucleosis (especially in cases in which the lymph nodes or extranodal tissues by a fairly uniform popula-
infiltrate is monomorphic) tion of small round cells. There is no follicular structure, but small
proliferation centers containing larger cells are often present,
Variants giving a nodular and pseudofollicular appearance. When lymph
● ‘BL with plasmacytoid differentiation’: the tumor cells
have an eccentric basophilic cytoplasm, and
immunoglobulin can be demonstrated. A degree of
pleomorphism not seen in the classical form is present.
This variant is associated with children and/or
immunodeficiency states.
● ‘Atypical Burkitt/Burkitt-like’: this shows almost identical
features to classic BL, but has much greater pleomorphism,
and the monotony is absent. Cells must have proven or
presumptive evidence of a MYC translocation for this
diagnosis.
CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL

LYMPHOCYTIC LYMPHOMA (CLL/SLL) [WHO, 2001]

(a)
● B-cell chronic lymphocytic leukemia/prolymphocytic
leukemia (REAL)
● Small lymphocytic (consistent with CLL) (Working
Formulation)
● Chronic lymphocytic leukemia of B-cell type;
Immunocytoma, lymphoplasmacytoid type (Kiel)

● Small lymphocytic B, chronic lymphocytic leukemia
(Lukes–Collins)
● Well-differentiated lymphocytic, diffuse (Rappaport)
● B-cell chronic lymphocytic leukemia
(French–American–British)
CLINICAL FEATURES
This type of lymphoma is a low-grade lymphoma, and comprises
6.7% of all NHL and 90% of chronic lymphoid leukemias in
Europe and the USA. It most commonly affects older individuals (b)
(median age 65 years) and is generally nodal at presentation, but
is often associated with the leukemic component. Clinical symp- Figure 10.28 (a, b) B-cell chronic lymphocytic leukemia (B-CLL).
toms include fatigue, autoimmune hemolytic anemia, infection, Note the monotonous, small-sized, CD20-positive lymphoid cells.
node involvement is partial, the paracortical/interfollicular areas Differential diagnosis

are most affected. ● T-cell small lymphocytic lymphoma/leukemia
The white pulp is prominent in splenic involvement, and ● Lymphocyte-predominant/-rich Hodgkin lymphoma
pseudofollicles may be present. Bone marrow involvement may ● Follicular lymphoma
be diffuse, nodular, interstitial, or any combination of these. ● Paracortical lymphoid hyperplasia
● Variant: mu heavy chain disease. (Resembles CLL; it is due
Cell morphology to a defective mu heavy chain lacking the variable region.
● The constituent cells usually resemble mature lymphocytes, Clinically, lacks the lymphadenopathy of CLL
having round or oval nuclei containing clumped chromatin and is slowly progressive. Morphology: CLL-like cells
and indistinct nucleoli and scant cytoplasm. admixed with vacuolated plasma cells – see Plasma cell
● Occasionally, prolymphocytes (see below) may neoplasms, p. 712).
predominate.
● Occasional plasmacytoid cells with more abundant
DIFFUSE LARGE B-CELL LYMPHOMA (DL-BCL)
cytoplasm and eccentrically placed nuclei may be present.
● Mitoses are rarely seen. [WHO, 2001]
● Prolymphocytes may be present within the proliferation
centers. These cells are slightly larger than mature Previous classification/synonyms include:
● Diffuse large B-cell lymphoma (REAL)
lymphocytes, and have more open chromatin with a
● Diffuse large cell, large cell immunoblastic, diffuse mixed
central nucleolus.
● The larger cells of the proliferation centers resemble small and large cell (Working Formulation)
● Large cleaved follicular center cell; Large non-cleaved
centroblasts, having larger vesicular nuclei with prominent
single or multiple nucleoli. follicular center cell; B-immunoblastic (Lukes-Collins)
● Centroblastic; B-immunoblastic; B-large cell anaplastic (Kiel)
● Diffuse histiocytic; Diffuse mixed lymphocytic and

Genetic profile
histiocytic (Rappaport)
● There are two distinct types, as defined by the mutational
status of the immunoglobulin VH genes; 40–50% show
no somatic mutations of their variable region genes like CLINICAL FEATURES
naïve B-cells, while 50–60% have somatic mutations, This category includes all high-grade B-cell lymphomas, other
suggesting derivation from post-germinal center B-cells. than the distinct clinicopathological entities of primary medi-
● Mutations in the Ig-variable region have a better prognosis astinal large B-cell lymphoma, Burkitt’s lymphoma and
(median survival 7 years) than those with germ-line VH Burkitt-like lymphoma. This subset accounts for a high pro-
mutations (median survival 3 years). portion (30–40%) of all non-Hodgkin’s lymphomas, the cyto-
● Some 80% have abnormal karyotypes. logical features of which vary depending on the variant in
Some cases show cytogenetic abnormalities including: question. The mean age of presentation is in the seventh decade
● Trisomy 12, which is associated with an aggressive of life, but covers all age ranges; males are affected more fre-
clinical course. quently than females.
● 13q abnormalities (13q14 deletions occur in up to 50%
DL-BCL can occur in lymph nodes (⬃60%) and a wide vari-
and are associated with a long survival). ety of extranodal locations (⬃40%). On occasion, DL-BCL
● Deletions of 11q22-23 (20% of cases), these are associated
derives from mucosa-associated lymphoid tissue, and on others
with extensive lymphadenopathy and poor survival. it apparently arises de novo. Presentation usually occurs after
● Deletions at 6q21 (5% of cases) and 17p13, the p53 locus
the development of a rapidly growing nodal or extranodal
(10% of cases). mass; often, the disease is disseminated on staging investiga-
● t(11;14) has been reported in some cases of
tion. Long-term remissions may be achieved with combination
prolymphocytic leukemia, as has the BCL1 gene, but these chemotherapy.
may be examples of leukemic MCL. Most lymphomas associated with immunodeficiency states
are of this type. Further, a proportion of diffuse large B-cell
lymphomas represent transformation of pre-existing low-grade
Special techniques
B-cell lymphomas (or more rarely nodular lymphocyte pre-
● Immunohistochemistry: surface positivity is seen for CD5, dominant HL).
CD19, CD20 (weak), CD22 (weak), CD79a, CD23,
CD43, CD11c (weak), IgD (weak) and/or IgM (weak).
CD10 and cyclin D1 are both negative. Prolymphocytes
lack the CD5 marker. The unifying characteristic of this histologically diverse cate-
● CD38 positivity has a worse prognosis. gory is a diffuse pattern of growth effacing the architecture of
● Immunoglobulin heavy and light chain gene the lymph node (or other tissue of origin). Blood vessel wall
rearrangements can be detected. invasion is seen more commonly than in other types of poorly
● Molecular diagnostics (see Genetic profile). differentiated lymphoma, and involvement of epithelium may
(a) (d)
(b) (e)
(c) (f)
Figure 10.29 Diffuse large B-cell lymphoma. A typical nodal diffuse large B-cell lymphoma (a) often contains a mixed small lymphocytic
background. In extranodal site, e.g. the subcutaneous tissues of the thigh, as in this example, the larger cells predominate (b).These cells are
always CD20 positive (c), with a high Ki-67 index (d).There are several variants and these include the anaplastic variant (e), which in this
example shows both CD20 (f) and CD30 (g) positivity.The T-cell rich variant (h) is also commonly seen in practice. Note how the large cells
are difficult to identify in the rich CD3 positive background (i) but are easily detected by CD20 (j).
(g) (i)
(h) ( j)
be seen in lesions originating in mucosa-associated lymphoid open chromatin and a large central nucleolus, and varying
tissue. There may be varying degrees of fibrosis. amounts of cytoplasm, often asymmetrically distributed.
A true follicular pattern is not seen. Plasmacytoid cells may be present; these have round
eccentrically placed nuclei, with prominent central
Cell morphology nucleoli, peripherally condensed nuclear chromatin and
The neoplastic B cells show a variety of appearances; in some strongly staining amphophilic cytoplasm with a paler
lesions the population is fairly uniform and of one type, while perinuclear ‘hof’.
in others there may be a mixture of appearances. The morpho-
● T-cell-/histiocyte-rich: In this variant most cells are T-cells,
logical patterns have been used to subdivide this entity, but plus or minus histiocyte-like cells. Less than 10% are true
these have poor inter- and intra-observer reproducibility and neoplastic B cells. Some may resemble immunoblasts,
special techniques are of little help in delineating variants. centroblasts, Reed–Sternberg and L&H cells. Small B cells
Although a subset with links to follicular lymphoma (FL) does are rare. Confusion with Hodgkin lymphoma, particularly
exist – demonstrable by immunohistochemistry/molecular NLP-HL is possible.
diagnostics – these are not necessarily identifiable on morpho-
● Unusual variants may have the following: myxoid stroma,
logical grounds alone. Variants include: fibrillary matrix, pseudorosettes, spindle cell, signet ring
● Centroblastic: see Follicular lymphoma. These cells may cell, cytoplasmic granules, microvillous projections, and
have a monomorphic or polymorphic appearance with intercellular junctions.
cerebriform/polylobated nuclei. Admixture with In all variants:
immunoblasts is possible. ● Mitoses are usually frequent, and apoptotic figures may be
● Immunoblastic: This is typified by large cells with large particularly prominent (in comparison to other poorly
nuclei characterized by a prominent nuclear membrane, differentiated lymphomas).
A variety of non-neoplastic cells may also be present: occasional Reed–Sternberg-like cells apparent. Lymph node
● Reactive plasma cells are often seen in small numbers, and replacement and sinus infiltration is characteristic. Cells
are especially numerous in extranodal tumors occurring in express ALK (granular cytoplasmic with dot Golgi positivity
association with autoimmune disorders. due to t(2;5) NPM-ALK fusion), EMA, CD4, CD57, CD20
● Small lymphocytes (B- or T-cells) or macrophages may be and weak CD45. IgA with light chain restriction can be
seen, and in some cases may outnumber the neoplastic demonstrated. All other markers are negative.
population.
● Inflammatory cells such as neutrophils may be seen,
especially in association with areas of necrosis.

FOLLICULAR LYMPHOMA (FL) [WHO, 2001]
Genetic profile Previous classification/synonyms include:

● Follicle center lymphoma, follicular (REAL)
● Immunoglobulin heavy and light gene rearrangements can ● Follicular, predominantly small cleaved cell; Follicular,
be demonstrated.
mixed small cleaved and large cell; Follicular,
● Somatic mutation of the variable regions occurs.
predominantly large cell (Working Formulation)
● BCL2 translocation, t(14;18), (see FL) occurs in 20–30% ● Small cleaved; Large cleaved; Small non-cleaved follicular
of cases (associated with a poorer prognosis).
center cell (follicular); Large non-cleaved follicular center
● 30% have abnormalities of 3p27, involving BCL6
cell (follicular) (Lukes–Collins)
(associated with a better prognosis). ● Centroblastic/centrocytic, follicular; Centroblastic,
● MYC rearrangement is uncommon.
follicular; Follicular and diffuse (Kiel)
● TP53 mutation occurs in a minority of cases (associated ● Nodular poorly differentiated lymphocytic; Nodular mixed
with a poorer prognosis).
lymphocytic-histiocytic; Nodular histiocytic; Nodular
● EBV infection may be detectable, particularly in
undifferentiated (Rappaport)
immunosuppression-related illness.
● Gene expression patterns suggest two distinct groups giving
rise to DL-BCL; either resembling a derivation from a CLINICAL FEATURES
germinal center B-cell or an activated peripheral blood B-cell. Follicular lymphoma (FL) is a lymphoma of follicular center cells
(defined as centrocytes or cleaved cells and centroblasts or non-
Special techniques
cleaved cells). FL comprises approximately 30% of NHL, and
● The neoplastic cells express pan B-cell markers (CD19, affects mostly older individuals (median age 59 years). It is very
CD20, CD22, CD79a), although all may not be expressed. rare in those aged below 20 years and in childhood, but when it
● They show immunoglobulin light chain restriction, and does occur in these patients it tends to be localized to the head and
surface/cytoplasmic immunoglobulin (IgM ⬎ IgG ⬎ IgA), neck with a grade 3 phenotype. The male:female ratio is 1:1.7.
particularly in cases with plasmacytic differentiation. Typically, FL is nodal in origin, but may occasionally origi-
● Anaplastic cases stain with CD30, others may not. nate in extranodal tissues (e.g., spleen, bone marrow, peripheral
● A minority of cases also express CD5 (10%) or CD10 blood and Waldeyer’s ring). Involvement of the gastrointestinal
(25–50%). tract or skin and other sites is usually secondary to nodal
● Cyclin D1 is negative, so blastoid MCL is not DL-BCL. spread. However, primary skin FL (cutaneous follicle center
● Plasma cell markers (CD138/syndecan) can be expressed. lymphoma; see EORTC) is one of the most common cutaneous
● MIB1/Ki-67 (proliferation marker) is high – usually over B-cell neoplasms.
90% of neoplastic cells stain. At presentation, most cases have widespread disease (rarely
● Bcl-2 expression occurs in 30–50%, bcl-6 nuclear staining stage I or II), but patients tend to be asymptomatic despite this.
is ubiquitous. FL transforms/progresses into a DL-BCL in 25–35% of patients.
● Molecular diagnostics (see Genetic profile). Perhaps one of the most common features of DL-BCL is the rela-
tionship of many with follicular lymphomas, as demonstrated by
Differential diagnosis cluster differentiation expression and translocation presence.
● Peripheral T-cell lymphoma, unspecified (PTL-U) Clinical management is similar to that for other low-grade B-cell
● Hodgkin lymphoma (HL, classic and non-classic) lymphomas. Generally, these lymphomas are incurable; however,
● Poorly differentiated carcinoma long-term remission can be achieved in some higher-grade lesions
● Anaplastic myeloma with combination chemotherapy. Prognostic data are confused
● Burkitt’s and Burkitt-like lymphomas (BL) by the new grading system and the mistaken inclusion of other
● Anaplastic large cell lymphoma (ALCL) low-grade lymphomas into this category prior to the advent of
● Melanoma immunohistochemistry (see below for further information).
● Lymphoepithelial carcinoma
● Merkel cell tumor PATHOLOGICAL FEATURES (Figure 10.30)
Variants This type of lymphoma is characterized by the presence of
● ‘DL-BCL with expression of full-length ALK’, is an evenly sized follicular structures; these are distinguishable from
aggressive lymphoma composed of immunoblastic cells with germinal centers by their fairly uniform population of small to
(a) (d)
(b) (e)
(c) (f )
Figure 10.30 Follicular lymphoma. Follicular lymphoma is a spectrum from low-grade disease typified by a centrocytes-predominant grade
1 pattern (a, b). Note the numerous follicles with absent mantle zones. Immunostaining with Bcl-2 (c) is exceedingly helpful in deciding
between neoplastic and non-neoplastic follicles (arrowed). Follicle centers with an increased blast component fall into the grade 2 category
(d). Once centroblasts predominate, the lymphoma is grade 3 (e, f). If there is still a centrocyte presence (e), this is referred to as grade 3A.
If there are sheets of blasts (f), this is grade 3B.The line between grade 3B and diffuse large B-cell lymphoma may be difficult to delineate.
Bone marrow involvement by follicular lymphoma is typically paratrabecular (g).There is a primary cutaneous variant of follicular lymphoma,
not recognized as an individual entity under the WHO 2001 classification but referred to under the EORTC 1997 classification as a primary
follicle center cell lymphoma (h, i).
polarization or ‘starry sky’ appearance characteristic of reactive

germinal centers. Some follicles may contain eosinophilic, PAS-
positive proteinaceous material. As a consequence, the mantle
zone is lost, as are tingible (stainable) macrophages.
The pattern of nodal involvement should be reported – that
is, the architecture described:
Follicular ⬎75% follicles

Follicular and diffuse 25–75% follicles
Minimally follicular ⬍25% follicles
Interfollicular involvement does not constitute a diffuse pattern.
Cell morphology
These lymphomas consist of cells resembling those of normal
(g)
germinal centers:
● Centrocytes: these are slightly larger than normal
lymphocytes and characterized by irregularly shaped

cleaved and indented nuclei with slightly clumped
chromatin and inconspicuous nucleoli, and scant
cytoplasm.
● Centroblasts: these are up to four times larger than normal
lymphocytes, have vesicular nuclei with prominent single

or multiple nucleoli, which are often peripherally sited,
and may have a thin rim of pale cytoplasm.
● Forms intermediate between centrocytes and centroblasts
may also be present (large cleaved cells). These are similar

to centrocytes in shape, but up to four times larger than
normal lymphocytes.
● Smaller numbers of small lymphocytes (T or B), plasma
cells and macrophages and follicular dendritic cells may

(h)
also be present. In some cases, T-cells (non-neoplastic) can
be so numerous that they are the dominant population
(‘T-cell-rich B-cell lymphoma’).
● Neoplastic B-cells with cytoplasmic clearing or signet ring
morphology are sometimes present.

● Tingible (stainable) body macrophages and apoptotic
figures are rare in neoplastic follicles, in contrast to

reactive germinal centers.
Grading
FL should be graded using the WHO (2001) approved scheme.
Grading is based on the proportion of centroblasts, and this
assists in predicting clinical outcome. It is a three-grade system
based on the counting of the absolute number of centroblasts
in ten neoplastic follicles and expressed per 40 ⫻ HPF. Ten
HPF are counted in ten separate follicles that are representative
and do not represent the most poorly differentiated areas of
(i)
disease. Should there be discrete areas of grade 3 disease, then
Figure 10.30 (Continued). a subdivided grade 3 can be used:
Grade 1 0–5 centroblasts/HPF

Grade 2 6–15 centroblasts/HPF
medium-sized cells. In early disease these follicles may be sur- Grade 3 ⬎15 centroblasts/HPF
rounded, and sometimes partially permeated by normal lym- Grade 3a ⬎15 centroblasts/HPF, but centrocytes are
phoid tissue. However, as the disease progresses a diffuse still present
background of neoplastic lymphoid cells becomes more predom- Grade 3b ⬎15 centroblasts/HPF with solid sheets of
inant. Neoplastic follicles are typically symmetrical, without the centroblasts
These counts are based on a HPF of 0.159 mm2 (one ocular with ● Bcl-6 expression in over half of cases.
an 18-mm field of view at 1⫻ magnification and 40⫻ objec- ● Reticulin, CD23, CD21 stain highlights the follicular
tive). Consequently, if the field of view is increased, the num- pattern and follicular dendritic meshwork.
ber of blasts counted will increase, thereby rendering the ● Molecular diagnostics (see Genetic profile).
grading inaccurate. One should calculate the area of HPF in
mm2, and compare it as a fraction to the reference 0.159 mm2. Differential diagnosis
This then provides the correction factor for the above scheme; ● Reactive lymphoid hyperplasia
for example, a 20-mm field of view provides an HPF of ● Nodular lymphocyte-predominant HL
0.196 mm2 – 1.2⫻ greater than the reference. Therefore, all ● Castleman’s disease
counts should be inflated by 1.2⫻ the original value. (See ● SLL with prominent proliferation centers
WHO classification for further information.)
Further, care must be taken not to misidentify large centro- Variants
cytes as centroblasts. Also areas of DL-BCL transformation ● Cutaneous follicle center lymphoma (see Cutaneous
should be reported separately to the FL and therefore do not lymphomas, p. 911).
add to this grading system. ● Diffuse follicle center lymphoma (see below).
Grades 1 and 2 are indolent and not usually curable. Grade 3
lymphomas are possibly curable with aggressive chemotherapy.
FOLLICULAR LYMPHOMA VARIANT: DIFFUSE
Genetic profile FOLLICLE CENTER LYMPHOMA (DFCL)
Bcl-2 translocation is an early phenomenon, and bcl-2 is not [WHO, 2001]
usually expressed within the follicle center. This enables resist-
ance to apoptosis, conferring survival advantage. It is theorized Previous classification/synonyms include:
● Follicle center lymphoma, diffuse, predominantly small cell
that arresting B-cells exposed to antigen enter blast transfor-
mation, and at this point the risk of developing lymphoma (REAL)
● Diffuse small cleaved cell; Mixed (Working Formulation)
begins. Typical translocations include:
● Centrocytic (Kiel)
● t(14;18)(q32;q21) is the most common, and is synonymous
● Mixed (Rappaport)
with FL. It involves a BCL2 gene rearrangement present in
70–95% of cases. It has no prognostic value.
● t(2;18)(p12;q21) is rare, and associates BCL2 with a light- CLINICAL FEATURES
chain gene. These are rare tumors, and are composed of a diffuse array of
Other genetic anomalies include: centrocytes and centroblasts. Grading is as for FL; grade 1 and
● BCL6 abnormality (5⬘ mutation of gene rearrangements, 2 only. Grade 3 is absent, becoming DL-BCL if centroblasts
affecting 55% of cases). predominate. DFCL has a poorer prognosis than true FL and
● Trisomies of X, 7 (20% of cases), 12 or 18 (20% of cases). has a significantly more aggressive clinical course.
● Chromosomal breaks on 1, 2, 4, 5, 13, and 17.
● Chromosome 17 abnormality affects TP53 (p53 gene, PATHOLOGICAL FEATURES

15% of cases).
This lesion consists of diffuse sheets of a fairly uniform popu-
● Deletions of 3q27-28 (15% of cases), 6q21, 6q23, 6q25-
lation of small cells, which tend to spread directly across
27 (all associated with a worse prognosis, 15% of cases),
anatomical boundaries, particularly blood vessel walls. No fol-
9p15 and 9p16 (both associated with DL-BCL
licular structures are present.
transformation).
● Immunoglobulin heavy- and light-chain gene rearrangements.
Cell morphology
● Numerous somatic mutations of variable region genes,
leading to intraclonal heterogeneity, typical of follicle ● These lymphomas consist almost entirely of centrocytes,
center cells. and are similar to FL.
Genetic profile
Special techniques
● Not defined.
● The neoplastic population expresses B-cell markers (CD45,
CD19, CD22, and CD20). Special techniques
● Secretory Ig production (IgM ⫾ IgD, IgG, and rarely IgA).
● CD10 positivity.
● As for FL.
● Immunoglobulin light-chain restriction.
● CD5 and CD43 are not expressed, but CD43 can be Differential diagnosis
positive in some grade 3 lesions. ● FL
● Bcl-2 is expressed in the majority of cases (in contrast to ● CLL/SLL
normal follicle center cells). ● EN/N-MZL
● Peripheral T-cell lymphoma, unspecified coagulation. Characteristic sites of involvement are the skin
● Small cell carcinoma and central nervous system. The disease is associated with a high
mortality, and diagnosis is often established at post-mortem
HAIRY CELL LEUKEMIA (HCL) [WHO, 2001] examination.
Previous classification/synonyms include: PATHOLOGICAL FEATURES (Figures 10.31 and 10.32)

● Leukemic reticuloendotheliosis. (See also Spleen
The hallmark of the disease is lymphoid proliferation confined
section, p. 740.)
to the intravascular compartment, without local tissue or ves-
sel wall infiltration. This feature is so striking that the disease
INTRAVASCULAR LARGE B-CELL LYMPHOMA was originally thought to arise from endothelial tissue – hence
(IVL-BCL) [WHO, 2001] (ANGIOTROPIC LARGE the term ‘malignant angioendotheliomatosis’. At first glance,
CELL LYMPHOMA)
CLINICAL FEATURES
Intravascular lymphoma – also called malignant angioendo-
theliomatosis and angiotropic large cell lymphoma – is a rare
disease characterized by the proliferation of neoplastic
mononuclear cells within the lumens of small blood vessels.
The neoplastic cells are usually of B-cell origin, and rarely of
T-cell or histiocytic origin. Although this clinicopathological
entity of lymphoma has not been listed in general pathological
classifications such as the REAL classification or the Working
Formulation, it has recently been included in the WHO classi-
fication scheme (which is essentially an updated REAL scheme)
and the EORTC classification scheme.
The clinical manifestations of the disease are protean, and are
due to multifocal medium and small vessel occlusion by tumor
cells, in various organs. These include nephrotic syndrome,
pyrexia and hypertension, breathlessness and hemolytic ane-
mia, leukopenia, pancytopenia and disseminated intravascular
(b)
(a) (c)
Figure 10.31 (a–c) Angiotropic lymphoma of the prostate gland. Dilated capillary vessels filled with medium-sized lymphocytes. At first
glance, this may be confused with metastatic carcinoma or carcinoid tumor.
● Depending on the cell of origin, they exhibit B, T or

histiocytic cell makers, but they are predominantly of
B-cell origin.
LYMPHOPLASMACYTIC LYMPHOMA/
WALDENSTRÖM MACROGLOBULINEMIA (LPL)
[WHO, 2001]

● Plasmacytoid lymphoma (REAL)
● Small lymphocytic (consistent with CLL) (Working
Formulation)
● Plasmacytic-lymphocytic (Lukes–Collins)
(a) ● Lymphocytic, chronic lymphocytic leukemia of B-cell type;
Immunocytoma, lymphoplasmacytic type (Kiel)

● Well-differentiated lymphocytic, plasmacytoid
(Rappaport)
● Waldenström macroglobulinemia
CLINICAL FEATURES
This is a group of generally low-grade B-cell neoplasms show-
ing varying degrees of plasmacytic differentiation, from small
lymphocytes to true plasma cells.
Plasmacytoid/plasmacytic variants of other disorders must be
excluded. LPL is rare (1.5% of nodal NHL), with a median age
of onset of 63 years, and a slight male predominance.
LPL may arise in a background of immunodeficiency,
immunosuppression or autoimmune disease. It may present as
(b) a nodal or extranodal tumor (e.g., in the lung, bone, blood, or
skin) and also as lymphoma of mucosa-associated lymphoid
tissue (MALT). Alternatively, it may be seen in association with
chronic lymphocytic leukemia, with a hyperviscosity syndrome
and paraproteinemia (generally IgM). LPL also shows a wide
range of behavior; in general, the prognosis is worse than that
of the B-lymphocytic lymphomas. The polymorphic subtype
shows a much shorter survival, while some of the extranodal
tumors such as those arising in the orbit, stomach or lung may
behave in a very indolent fashion with a median survival of five
years. As with lower-grade lesions, they may transform into a
high-grade lymphoma (DL-BCL).
Marrow-based LPL has been associated with the type II cryo-
globulinemia that arises in hepatitis C viral (HCV) infection. It
is unclear whether the HCV is driving the process, or whether
a reactive phenomenon has gone wrong, as with Helicobacter-
(c) driven MALTomas.
Figure 10.32 (a–c) Angiotropic lymphoma of the skin. Dilated

dermal capillary vessels filled with medium-sized lymphocytes. PATHOLOGICAL FEATURES (Figure 10.33)
The cellular infiltrate consists of a mixture of lympho-
and at a low-power magnification, one may consider vascular
cytes, plasma cells and cells intermediate between the two
permeation by metastatic tumor.
(lymphoplasmacytoid). These are either intermingled together or
segregated into groups. Epithelioid cells may be numerous and
Special techniques arranged in clusters, giving an appearance reminiscent of lympho-
● These cells are leukocyte common antigen (CD45)- and epithelioid/Lennert lymphoma. Solid sheets of immunoblasts
cytokeratin-negative. may indicate transformation into a high-grade lymphoma. LPL
is essentially a diagnosis of exclusion: in many cases, careful

examination and extensive sampling of neoplastic tissue will
reveal underlying small lymphocytic, marginal zone or follicular
lymphoma. Nodal infiltrates lack pseudofollicles and efface the
node; alternatively, interfollicular colonization may occur.
Vascular pattern
● The blood vessels may show endothelial proliferation or
hyaline thickening of their walls.
Secondary features
● Deposition of proteinaceous substance.
● Amyloid.
● Para-amyloid deposition: this is more widely dispersed
(a) eosinophilic material that fails to stain or stains only
weakly with amyloid stains. The material may outline
the blood vessels and the reticulin framework of the node.
● Hyalinization.
Cell morphology
● Lymphocytes.
● Plasma cells (round eccentric nuclei, a perinuclear ‘hof’,
and abundant strongly staining PAS-positive cytoplasm
and Russell bodies. The latter is an intracellular
immunoglobulin).
● Lymphoplasmacytoid cells; these are intermediate cells
between the above two. They have nuclear chromatin
similar to that of plasma cells and little cytoplasm, similar
to lymphocytes. Intranuclear inclusions of immunoglobulin
(Dutcher bodies) are often seen in these cells.
● Immunoblasts.
● Mast cells.
(b) ● Macrophages.
● Epithelioid cells.
Genetic profile
● Immunoglobulin heavy- and light-chain gene
rearrangements can be detected.
● Somatic mutation of the variable region indicates prior
antigen selection.
● t(9;14)(p12;q32) and PAX-5 gene rearrangement occurs in
50%. PAX-5 is important in early B-cell development.
Special techniques
● Methyl green-pyronin and Giemsa stains highlight the
cytoplasm of the plasmacytoid cells.
● PAS highlights the Russell and Dutcher bodies and the
proteinaceous substance.
● Demonstration of monoclonal Ig.
● The neoplastic cells are CD45, CD19, CD20, CD22,
(c) CD79a and HLA DR-positive, and show immunoglobulin
light-chain restriction. A proportion of cells fail to express
Figure 10.33 Lymphoplasmacytic lymphoma (LPL) is often one or more of these antigens (antigen loss).
diagnosed by bone marrow combined with the ● CD5 is negative in ‘true’ plasmacytoid lymphomas. Its
clinical/hematological picture. Immunohistochemistry is
indispensable.This example shows the hidden CD20-positive expression suggests the presence of underlying B-cell small
population (a), which is lambda light chain restricted (c). Kappa is lymphocytic lymphoma/leukemia.
essentially negative (b). ● CD10 and CD23 are negative.
● CD43 is variable.
● CD38 is positive (plasma cell marker).
● CLL/SLL
● FL
● EN/N-MZL
● Reactive plasmacytosis
● Plasma cell variant of Castleman’s disease
● Plasmacytoma/myeloma
● Immunoblastic types of high-grade lymphoma
● Angioimmunoblastic T-cell lymphoma (AITL)
LPL with amyloid and para-amyloid deposition:
● Primary amyloidosis of lymph nodes (a)
● Simple scarring
● Lymphocyte-depleted HL
MANTLE CELL LYMPHOMA (MCL) [WHO 2001]

● Mantle cell lymphoma (REAL)
● Malignant lymphoma, diffuse, small cleaved cell type;
Follicular, small cleaved cell; Follicular, diffuse mixed small

and large cell; Follicular, diffuse
● Large cleaved cell (Working Formulation)
● Centrocytic (mantle cell) lymphoma (Kiel)
● Intermediately of poorly differentiated lymphocytic
lymphoma, diffuse or nodular (Rappaport)

(b)
CLINICAL FEATURES
Mantle cell lymphoma (MCL) is a B-cell neoplasm that affects
predominantly elderly males (male:female ratio 2:1) and
accounts for 3–10% of all NHL. It usually presents with an
advanced stage (stage III or IV) of disease, associated with lymph-
adenopathy, splenomegaly and marrow involvement (⬎50%),
while 25% have peripheral blood involvement, occasionally
mimicking prolymphocytic leukemia. Extranodal sites include
the gastrointestinal tract and Waldeyer’s ring, and most exam-
ples of multiple lymphomatous polyposis are in fact MCL. The
condition is associated with a poor prognosis, being more
aggressive than other low-grade B-cell lymphomas. The median
survival is three to five years, and most cannot be cured.
Although the quoted mitotic count rates have varied reference
ranges, this remains the single most consistent adverse prog-
nostic parameter. The blastoid variant is also deemed to be of (c)
worse prognosis than the typical mantle zone lesion.
Figure 10.34 Mantle cell lymphoma.This is a low grade B-cell
lymphoma with a monotonous architecture (a).The differential
PATHOLOGICAL FEATURES (Figure 10.34) diagnosis is wide and the lesion is CD5 positive (b), which may be
This lymphoma consists largely of a monomorphic lymphoid confused with CLL/SLL. Consequently, cyclin D1 (c) staining is
essential; this shows nuclear positivity.
population arranged in ill-defined nodules, diffuse or mantle zone
patterns. Occasionally, larger cells may be arranged in residual
germinal center-like aggregates, giving a true follicular pattern. Cell morphology
Hyalinized vessels may be frequently seen. Transformation does ● The main population consists of small mature lymphocyte-
not occur in the same way as other lymphomas (e.g., FL), but a like cells (as seen in small lymphocytic lymphoma), small
‘blastoid variant’ does occur. cleaved follicle center cells (centrocytes; see Lymphoma,
follicular predominantly small cleaved cell, p. 701) and MARGINAL ZONE B-CELL LYMPHOMA,
cells intermediate between these two types.
EXTRANODAL (EN-MZL) OF MUCOSA-ASSOCIATED
● The nuclei have a moderately disperse chromatin with
inconspicuous nucleoli. LYMPHOID TISSUE (MALT LYMPHOMA) [WHO, 2001]
● Non-neoplastic plasma cells may be seen.
● Vague nodularity may be present, but proliferation centers Previous classification/synonyms include:
as seen in B-cell small lymphocytic lymphoma are not seen. ● Marginal zone B-cell lymphoma (extranodal low-grade
● A variable number of epithelioid histiocytes may be seen, maltoma) (REAL)
● Small lymphocytic; Lymphoplasmacytoid; Diffuse small
and a ‘starry-sky’ pattern may result.
● A ‘blastoid’ variant exists in which the cells resemble cleaved cell (Working Formulation)
● Lymphocytic; Plasmacytic-lymphocytic; Small cleaved cell
lymphoblasts; these should be mentioned, but not formally
graded (unlike FL). (Lukes–Collins)
● Immunocytoma (Kiel)
● Well-differentiated lymphocytic; Plasmacytoid

Genetic profile
lymphocytic; Poorly differentiated lymphocytic
● t(11;14)(q13;q32) is the most common translocation, and
(Rappaport)
is synonymous with MCL. It involves a CYCLIN D1 gene
rearrangement and fusion with a heavy-chain gene
promoter site. This is present in 70–75% of cases. CLINICAL FEATURES
● Point mutations and/or deletions of the ATM (ataxia-
telangectasia mutated) gene. This most commonly occurs in mucosa-associated lymphoid
● Other abnormalities including those affecting TP53, p16, tissue associated with the gastrointestinal tract, typically the
p18 are more frequent in the blastoid form, as are stomach or small intestine, but can also occur in the lung, sali-
deletions of 13q14 and 17p, and partial or total vary and thyroid glands. The lesions typically arise in a back-
Trisomy 12. ground of chronic inflammation with a persistent antigenic
● The pleomorphic blastoid variant has a high incidence of stimulus (Helicobacter pylori-associated gastritis, Borrelia
tetraploidy. burgdorferi-associated dermatosis, Sjögren’s syndrome,
● Immunoglobulin heavy- and light-chain gene Hashimoto’s disease).
rearrangements. The lesions comprise 7–8% of all B-cell lymphomas, and
● Variable region genes are not mutated in most scenarios, 50% of primary gastric lymphomas, but include only 2% of all
equating to a pre-germinal center lymphocyte. gastrointestinal neoplasms. They affect 1–2 people per 100 000
● BCL2 and C-MYC mutations are absent. population in the United Kingdom and North America.
The tumors can occur at any age, but appear predominantly
Special techniques in the middle-aged and elderly, with a median age of 61 years.
Intestinal lesions show geographical differences in their inci-
● These lymphomas show the typical B-cell phenotype dence, being most common in the Mediterranean region (also
(CD45, CD19, CD 20 and immunoglobulin light-chain known as immunoproliferative small intestinal disease
restriction), but also express CD5 and CD43. CD23 can [IPSID]/(Mediterranean lymphoma/␣ heavy chain disease).
be weakly positive. Rarely CD5 can be negative. The lesions present with symptoms reflecting their anatom-
● All cases are bcl-2- and cyclin D1-positive. ical location, and have a tendency to ‘home’ to mucosa-
● CD10 and bcl-6 are negative. associated lymphoid tissue in preference to nodal, splenic tissue
● Ig production (IgM ⫾ IgD). or bone marrow. About 20% do have bone marrow involve-
● CD21 and CD35 highlight the follicular dendritic meshwork. ment, but this varies depending on the primary site; gastric,
● Molecular diagnostics (see Genetic profile). ocular and pulmonary sites have the lowest rate of bone mar-
row involvement.
Differential diagnosis Plasmacytic differentiation is possible, but a clonal M-band/
● Low-grade B-cell lymphomas, including CLL/SLL, MZL, serum paraprotein is rare in MALT lymphomas, unless it is IPSID.
and FL EN-MZL displays an indolent course, is slow to disseminate,
● Benign mantle zone hyperplasia and has a good prognosis (83% 10-year survival). The stage
● Castleman’s disease of the disease and site of origin appear to be of prognostic
significance. Mesenteric and serosal involvements are poor prog-
Variants nostic features, and gastric lymphoma has a better outlook
● Blastoid, classic: the cells are lymphoblast-like with ⬎10 than intestinal lymphoma.
mitoses per 10 HPF. Treatment depends on the site, and includes antibiotic therapy
● Blastoid, pleomorphic: highly variable large cells with for H. pylori-related disease (see Genetic profile), local surgery/
large cleaved to oval nuclei and pale cytoplasm with radiotherapy and in cases where there is evidence of progression
prominent nucleoli. to higher grade disease, adjuvant chemotherapy following sur-
● Small lymphocytic lymphoma-like. gical resection can be beneficial in inducing long-term remission.
● EN/N-MZL-like. Transformation to a diffuse large B-cell lymphoma is possible.
PATHOLOGICAL FEATURES (Figures 10.35 and 10.36) In gastric biopsies, features which support the diagnosis of
lymphoma rather than reactive process include dense infil-
EN-MZL is characterized by diffuse infiltration of the affected
trates, prominent lymphoepithelial lesions, Dutcher bodies,
organ by pleomorphic, small to medium-sized, centrocyte-like
involvement of the muscularis mucosa, ulceration and cyto-
cells with plasmacytoid features together with a varying num-
logical atypia. EN-MZL shows similar histological features to
ber of small lymphocytes, cells with plasmacytoid or monocy-
that of PBCL with extreme plasmacytoid differentiation. It
toid differentiation, mature plasma cells, immunoblasts and
occurs in the proximal small intestinal mucosa of young adults
centroblasts.
of both sexes, often in Mediterranean areas.
Reactive follicles that are colonized or overrun by neoplastic
cells and lymphoepithelial lesions are often seen. Lympho- Cell morphology
epithelial lesions consisting of centrocyte-like cells infiltrating
the epithelium can often be identified. There may be a significant
● Characteristic marginal zone B cells have slightly
neoplastic plasma cell component. Lymph nodes draining the irregular nuclei with dispersed chromatin, inconspicuous
lesion show interfollicular and perifollicular patterns of infil-
tration similar to the distribution of nodal marginal zone lym-
phoma (see N-MZL).
(a) (c)
(b) (d)
Figure 10.35 Extranodal marginal zone lymphoma. (a–c) EN-MZL of gastric origin. (d) Nodules and sheets of blast cells indicating
transformation are seen in salivary gland harboring low-grade EN-MZL.Transformation typically results in a diffuse large B-cell lymphoma.
(IgM ⬎ IgA ⬎ IgG). CD5, CD10, CD23 and cyclin D1 are

negative. CD43 and CD11c are variable.
● CD21 and CD35 are positive. These are marginal
zone-associated antigens, and reflect the expanded
meshwork of follicular dendritic cells within colonized
follicles.
● There are no specific markers.
● Molecular diagnostics (see Genetic profile).
● Reactive processes (H. pylori gastritis, lymphoepithelial
sialadenitis, and Hashimoto’s thyroiditis)
● ‘Pseudolymphoma’. It is likely that lesions given this
diagnosis represent a spectrum of disease ranging from
intense chronic inflammation to marginal zone B-cell
lymphoma. If there is evidence of light-chain restriction or
invasive spread, the lesion should be regarded as a
lymphoma
● Reactive hyperplasia of the Peyer’s patches
(particularly near the ileocecal valve) can produce
localized tumefaction and should be distinguished from
Figure 10.36 Marginal-zone lymphoma, high-grade-transformation.
Nodules and sheets of blast cells are seen in salivary gland low-grade B-cell tumors by the absence of the above
harboring low-grade marginal-zone lymphoma. criteria
● Small intestinal lymphoid polyposis (is associated
with hypogammaglobulinemia and has no neoplastic
potential)
nucleoli and resemble centrocytes, being small to medium
in size.
● Accumulation of pale cytoplasm provides the MARGINAL ZONE B-CELL LYMPHOMA, NODAL
monocytoid appearance; otherwise they appear like small (N-MZL) [WHO, 2001]
lymphocytes.
● Plasmacytic differentiation occurs in one-third of Previous classification/synonyms include:
gastric cases, almost all thyroid cases, and all IPSID ● Marginal zone B-cell lymphoma (REAL)
cases. ● Small lymphocytic; Plasmacytoid; Follicular or diffuse
● Centroblasts and immunoblasts may be present. small cleaved cell; Follicular or diffuse mixed small and
● There is no high-grade variant; this should be referred to large cell (Working Formulation)
as a diffuse large B-cell lymphoma. ● Parafollicular B-cell (Lukes–Collins)
● Monocytoid B-cell (Kiel)
Genetic profile ● Well-differentiated lymphocytic; Poorly differentiated
● Ig heavy- and light-chain genes are rearranged with lymphocytic; Mixed lymphocytic-histiocytic
somatic mutation of the variable regions, typical of a post- (Rappaport)
germinal center memory B-cell.
● Trisomy 3 is found in 60%. CLINICAL FEATURES
● t(11;18)(q21;q21) translocations have been observed in
25–50% of cases. This is not found in primary large N-MZL is a lymphoma that resembles EN-MZL and splenic
B-cell lymphoma of the stomach. The translocation fuses MZL, but is a primary nodal B-cell lymphoma. It is a rare
API2 (apoptosis inhibitor) with MLT. This translocation lesion, and comprises only 1.8% of lymphomas. Over one-third
provides resistance to antibiotic therapy in the case of are combined with extranodal disease on further investigation.
H. pylori-induced EN-MZL. Presentation is often by means of lymphadenopathy, but
● No t(14;18) or t(11;14) translocations have been occasionally bone marrow and blood involvement is noted first.
described. The prognosis is consistent with an indolent low-grade lym-
phoma, and response to chemotherapy is reported.
Special techniques
● The neoplastic B-cells express pan B-cell markers
(CD19, CD20, and CD79a) and show light-chain This lymphoma is characterized by nodal marginal zone, parafol-
restriction. Heavy-chain expression is also a feature licular, interfollicular, sinusoidal or persinusoidal infiltration
by a uniform population of centrocyte-like B-cells, small lympho- MEDIASTINAL (THYMIC) LARGE B-CELL
cytes, monocytoid B-cells and rare centroblast/immunoblast-like
LYMPHOMA (ML-BCL) [WHO, 2001]
cells. In some cases there is diffuse involvement with no follicular
sparing. Two separate phenotypes exist: one mimics EN-MZL,
and the other splenic MZL (see relevant sections). Follicular ● Primary mediastinal (thymic) large B-cell lymphoma
colonization and plasma cell differentiation may be present.
(REAL)
Venules may stand out against the pale background of the tumor. ● Large cell lymphoma of the mediastinum
As with other low-grade lymphomas, a high-grade transforma- ● Primary mediastinal clear-cell lymphoma of B-cell type
tion may occur. ● Mediastinal diffuse large-cell lymphoma with sclerosis
Cell morphology
CLINICAL FEATURES
● Characteristic marginal zone B-cells have slightly
irregular nuclei with dispersed chromatin, inconspicuous This is a subtype of DL-BCL, and is now recognized as an
nucleoli and resemble centrocytes, being small to medium entity in its own right. It is possibly derived from thymic B
in size. cells. ML-BCL is a high-grade lymphoma that occurs primarily
● Accumulation of pale cytoplasm provides the in the anterior mediastinum and presents, as with other
monocytoid appearance; otherwise they appear like small mediastinal masses, with symptoms and signs such as superior
lymphocytes. venal caval syndrome. It spreads frequently to contiguous
● In less well-differentiated tumors, the cells are larger, structures, and commonly metastasizes distally. This type of
containing rounded nuclei and more prominent lymphoma rarely involves lymph nodes. It occurs in young
nucleoli. patients (third to fifth decades), more often in females. It may
● Plasmacytic differentiation may occur. relapse in unusual sites such as the gastrointestinal tract,
● Polymorphs may also be present. kidneys, ovaries and brain. Response to chemotherapy with/
● Centroblasts and immunoblasts may be present. without local radiotherapy tends to be good; spread outwith
● Mitotic figures are scant, but numerous if transformation the mediastinal has a poor prognosis, despite the therapeutic
is seen. response.
● There is no high-grade variant, this should be referred to
as a diffuse large B-cell lymphoma.
The lesion consists of diffuse infiltration of fibrous tissue
Genetic profile
stroma by clear or vacuolated cells. The cells may show some
● Trisomy 3 and t(11;18)(q21;q21) are infrequent, unlike packeting or grouping, separated by sclerosed or vascular
EN-MZL. fibrous tissue stroma, or may arrange loosely in the back-
● No t(14;18) or t(11;14) have been described. ground. At first glance, the histological appearance may not
give the impression of a lymphomatous process.
Special techniques
● Most are like EN-MZL; expression of pan B-cell Vascular pattern
markers (CD19, CD20, CD79a) and show light-chain ● Thin-walled blood vessels may be seen.
restriction. Heavy-chain expression is also a feature
(IgM>IgA>IgG). CD5, CD10, CD23 and cyclin D1 Secondary features
are negative. CD43 and CD11c are variable. CD21
● Sclerosis
and CD35 are positive. These are marginal zone-
associated antigens, and reflect the expanded
meshwork of follicular dendritic cells within colonized Cell morphology
follicles. ● The cells are large, with usually abundant clear or
● IgD-positive and CD43-negative phenotypes tend to mimic vacuolated cytoplasm, and may show some
splenic MZL. pleomorphism.
● Molecular diagnostics (see Genetic profile). ● The nuclei are medium-sized or large with small
● There are no specific markers. nucleoli.
● Some cells may resemble centroblasts or immunoblasts.
Differential diagnosis ● The frequency of mitotic figures is variable.
● Scattered normal lymphocytes are often present.
● Other low-grade lymphomas
● Particularly S-MZL and EN-MZL involving nodes
● T-zone lymphomas Genetic profile
● Hodgkin lymphoma ● Immunoglobulin gene rearrangements are present, despite
● Sinus B-cell reaction (as seen in toxoplasmosis) the lack of expression.
● Gains in 9p and amplification of REL are characteristic

and distinct from other DL-BCL.
● Overexpression of MAL is typical.
● Hyperdiploid karotypes are the norm.
● Abnormalities/rearrangements of BCL2, BCL6 and MYC
are absent.
● EBV is absent.
Special techniques
● The neoplastic cells express pan B-cell markers and show
immunoglobulin light-chain restriction.
● CD45 is positive.
● CD30 may be expressed in a minority of cases.
● CD10 and CD5 are negative.
(a) ● Molecular diagnostics (see Genetic profile).
● Secondary DL-BCL
● Clear cell change in T-cell lymphoma
● Nodular sclerosing HL
● Sclerosing liposarcoma
● Carcinoid tumor
● Paraganglioma
● Sclerosing mediastinitis
● Thymoma
● Carcinoma
PRIMARY EFFUSION LYMPHOMA (PEL)

[WHO 2001]
(b)
● Body cavity-based lymphoma
CLINICAL FEATURES
This is a high-grade, B-cell lymphoma arising from the post-
germinal center B cell. It presents as a serous effusion, often in
patients with immunodeficiency, and is typically HIV-related.
The lesion itself is associated with human herpesvirus 8
(HHV8), interleukin (IL)-6 and IL-10. Most patients are young
and without lymphadenopathy, but the condition may also
occur in the elderly. It may affect the pericardial, peritoneal and
pleural cavities, and can affect more than one such cavity at
presentation. The response to treatment is poor, and the prog-
nosis is bleak; median survival is generally less than 6 months.
This condition may be associated with multicentric Castleman’s
(c) disease.
Figure 10.37 (a–c) Sclerosing B-cell lymphoma.The lesion consists PATHOLOGICAL FEATURES (Figure 10.38)
of diffuse infiltration of fibrous tissue stroma by clear or vacuolated
cells.The cells are arranged loosely in the background. At first Typically the sampled effusion contains a variety of cellular
glance, the histological appearance may not give the impression of a appearances depending on preparation method.
lymphomatous process, and due to the excess fibrous tissue may
suggest a mesenchymal process. Pleomorphic B lymphocytes are Cell morphology
seen within the box.
● Cells may be immunoblastic to plasmablastic with
anaplastic morphology (cytology).
● Histology reveals more uniformity.
● Some aberrant T-cell-receptor gene rearrangements may be

found.
● No characteristic chromosomal aberrations are present.
● Gains in chromosome 12 and X (as with other HIV-related
lymphoma) may be detected.
● HHV8 is found in all cases.
● EBV infection is nearly always detectable, particularly in
immunosuppression-related illness, but tends to be absent
in the elderly (HIV-negative) group.
Special techniques
● Most cases are CD45-positive.
● The neoplastic cells are often negative for pan B-cell
markers (CD19, CD20, CD22, CD79a), although all may
not be expressed.
● Surface/cytoplasmic immunoglobulin is typically
absent.
● Activation/plasma cell markers are often detected (CD30,
CD38, and CD138).
(a) ● CD3 positivity has been reported.
● HHV8 staining is very useful for diagnosis.
● Molecular diagnostics (see, Genetic profile).
● Pyothorax associated with DL-BCL
● Reactive effusions
SPLENIC MARGINAL ZONE LYMPHOMA (S-MZL)

[WHO, 2001]

● Splenic marginal zone lymphoma (REAL).
● Small lymphocytic (Working Formulation/Lukes–Collins).
● Not classified (Kiel).
● Well-differentiated lymphocytic (Rappaport).
● Splenic lymphoma with circulating villous lymphocytes
(French–American–British).
See also Tumors of the spleen (p. 742).
(b)
Figure 10.38 (a, b) Primary effusion lymphoma. Large blastoid

PLASMA CELL NEOPLASMS
cells are scattered amongst smaller lymphocytes. Immunoblastic and
plasmablastic forms are common. (a) Low-power magnification; These are included under the WHO (2001) classification, and are
(b) high-power magnification. mentioned here for completeness. (See also Chapter 12, Skin
tumors, p. 835, and Leukemia and related conditions, p. 680.)
● All cells tend to have a prominent nucleolus, with a

perinuclear hof.
MONOCLONAL IMMUNOGLOBULIN DEPOSITION
● All cells tend to have a basophilic rim of cytoplasm. DISEASES [WHO 2001]
● Occasionally, Reed–Sternberg-like forms are present.
● Pleural biopsies may show chest wall infiltration. Variants include:
● Primary amyloidosis.
● Monoclonal light- and heavy-chain deposition diseases.
Genetic profile ● Osteosclerotic myeloma (POEMS [polyneuropathy,
● Immunoglobulin gene rearrangements can be organomegaly, endocrinopathy, monoclonal gammopathy,
demonstrated. skin lesions] syndrome).
● Pure heavy-chain diseases (gamma heavy-chain and mu Prognosis is variable depending on the clinical course and grad-
heavy-chain diseases). ing. Grade III lesions are EBV⫹ DL-BCL.
PLASMA CELL MYELOMA [WHO, 2001] PATHOLOGICAL FEATURES

Macroscopically, pulmonary nodules are seen; these are bilat-
Previous classification/synonyms include: eral and may cavitate following central necrosis. Similar lesions
● Multiple myeloma
can be seen elsewhere. Skin involvement may lead to extensive
● Myelomatosis
ulceration. Microscopically, LG is typified by an angiocentric
● Medullary plasmacytoma
destructive infiltration of polymorphous lymphoid cells within
● Kahler’s disease
the tissue affected. Lymphocytes predominate, but plasma cells,
Clinical variants include: immunoblasts and histiocytes are prominent, whilst neutrophils
● Non-secretory myeloma and eosinophils are inconspicuous. Background lymphocytes
● Smoldering myeloma show some unusual morphology but are not overtly neoplastic.
● Indolent myeloma
● Plasma cell leukemia Cell morphology

● A small number of EBV-positive cells in an inflammatory
PLASMACYTOMA [WHO 2001] background.
● EBV-positive cells show atypia, resembling immunoblasts
Variants include: or Hodgkin cells.
● Solitary plasmacytoma of bone. ● Reed–Sternberg-like forms may be seen.
● Extraosseous plasmacytoma (including cutaneous). ● Vascular changes include lymphocytic vasculitis, fibrinoid
necrosis of vessels and distal infarction.
PRECURSOR LESION: MONOCLONAL Grading (Lipford system)

GAMMOPATHY OF UNCERTAIN SIGNIFICANCE ● Grade I: Polymorphous lymphoid infiltrate without
(MGUS) [WHO 2001] cytological atypia (⬍5 cells per HPF are EBV-positive).
● Grade II: Occasional large lymphoid cells or immunoblasts
See Plasma cell neoplasms (p. 680). are present (5–20 cells per HPF are EBV-positive).
● Grade III: Easily identified as malignant lymphoma. Many
large cells are seen, but the inflammatory background is
B-CELL PROLIFERATIONS OF UNCERTAIN still present. Hodgkin and Reed–Sternberg-like cells are
present. Extensive necrosis is a feature. EBV positivity is
MALIGNANT POTENTIAL high. This is a subtype of DL-BCL.
LYMPHOMATOID GRANULOMATOSIS [WHO 2001] Genetic profile

● Immunoglobulin heavy- and light-chain gene
Previous classification/synonyms include: rearrangements are clonal in Lipford grades II and III.
● Angiocentric immunoproliferative lesion (not to be confused
● EBV infection.
with extranodal NK/T-cell lymphoma, nasal type). ● No further consistent anomalies.
CLINICAL FEATURES Special techniques

Lymphomatoid granulomatosis (LG) is an angiocentric, ● EBV-positive cells often express CD20.
angiodestructive lymphoproliferative disease, driven by EBV and ● CD79a and CD30 are variable.
involving extranodal sites. It is a lesion of B- and T-cells, with the ● LMP1 shows more intense staining in larger cells.
latter form predominating. Progression to DL-BCL may occur. ● Immunoglobulin stains are of little use.
This condition is rare, and affects males twice as frequently ● Numerous CD3-positive cells will be present
as females. Childhood cases are unusual, and are normally (CD4 ⬎ CD8).
immunodeficiency-related. The most common site of involve-
ment is the lung, but brain, skin, kidney and liver involvements Differential diagnosis
are common. Nodal and spleen involvement is infrequent. ● Hodgkin lymphoma.
Clinical presentation is often with respiratory symptoms
(e.g., cough and hemoptysis), often combined with systemic
illness. Predisposing conditions include HIV infection, alloge- POST-TRANSPLANT LYMPHOPROLIFERATIVE
nic transplantation, Wiskott–Aldrich syndrome and X-linked DISORDER, POLYMORPHIC (PTLD) [WHO 2001]
lymphoproliferative syndrome. The resulting immunodefi-
ciency state leads to ineffectual immunosurveillance for EBV. See also Atypical lymphoid disorders (p. 670).
NON-HODGKIN LYMPHOMA: T-CELL AND NK-CELL NEOPLASIA
T-cell lymphomas are much less common than B-cell lym- common, but where it does occur T-ALL accounts for 25% of
phomas, and account for up to 12% of non-Hodgkin lym- adult cases of ALL. T-LBL accounts for up to 90% of all
phomas in western countries. There is a major geographical lymphoblastic lymphomas. These lesions affect males more
variation in incidence, with the conditions being far more fre- frequently than females.
quent in Asians than other races; this is particularly related to Classically, the lesion presents as a rapidly growing mediasti-
human T-cell leukemia virus-1 (HTLV-1) infection. nal mass, with or without pleural effusion, and enlarged super-
T-cell lymphomas are histologically heterogeneous, but histo- ficial lymph nodes. It is frequently associated with the central
logical classification of the majority of cases into meaningful clin- nervous system (CNS), gonads, liver, spleen and Waldeyer’s ring
icopathological entities has proven difficult, as reflected in involvement. Treatment is possible with aggressive regimes of
previous classifications such as the REAL. The recent WHO combination chemotherapy. Prognosis is comparable with the
(2001) classification uses a multiparametric approach integrating precursor B-cell equivalents with current treatments.
morphological, immunophenotypical, genetic and clinical fea-
tures into the classification. The clinical features are essential for PATHOLOGICAL FEATURES
subclassification and the other parameters lack specificity.
T-cell lymphomas are most likely over-diagnosed, and some T-LBL is characterized by complete or partial replacement of
may represent cases of Hodgkin’s disease or T-cell-rich B-cell lymph node architecture by a diffuse cellular infiltrate of
lymphomas. Unlike B-cell lymphoma, there are no specific non-cohesive but closely packed, uniform, medium-sized lym-
immunohistochemical methods for detecting clonality. phocytes. The trabeculae are characteristically infiltrated by
Consequently, the most certain way of diagnosing T-cell lym- parallel columns of neoplastic cells. The capsule is usually
phomas is by the demonstration of a clonal T-cell-receptor gene involved. A ‘starry-sky’ pattern may be present. Partial cortical
rearrangement by molecular diagnostics (PCR, etc.). Therefore, involvement with sparing of germinal centers may occur.
access to such facilities is essential in order to provide a good- T-ALL variably effaces the marrow architecture, and will be
quality diagnostic service. seen on blood investigation.
In this section, the text will allocate T-cell lymphomas into
precursor forms, mature forms (general/systemic or predomi- Cell morphology
nantly skin-related) and those with uncertain malignant ● The neoplastic cells are of medium size, with large nuclei
potential. Within each category the disorders are listed in and scant cytoplasm.
alphabetical order unless they are otherwise inter-related. ● The nuclei are round or oval with convoluted outlines;
they contain fine dispersed chromatin and inconspicuous
(or absent) nucleoli.
PRECURSOR T-CELL NEOPLASIA ● Cytoplasmic vacuoles may be present in marrow
lymphoblasts; this tends to be associated with a stippled
PRECURSOR T-LYMPHOBLASTIC LEUKEMIA chromatin.
(T-ALL)/LYMPHOBLASTIC LYMPHOMA (T-LBL) ● Mitotic and apoptotic figures are numerous.
● Cellular pleomorphism is discernible at higher
(PRECURSOR T-CELL ACUTE LYMPHOBLASTIC magnification.
LEUKEMIA) [WHO, 2001] ● Eosinophils may be seen.
● Myeloid hyperplasia may be combined with eosinophil
Previous classification/synonyms include: presence in the marrow of certain subtypes, especially
● Precursor T-lymphoblastic leukemia/lymphoma (REAL). those associated with t(8;13)(p11.2;q11–22). The
● Lymphoblastic (working formulation). development of acute myeloid leukemia (AML) and
● T lymphoblastic (Kiel). myelodysplastic syndrome(s) (MDS) is possible.
● Convoluted T-cell lymphoma (Luke–Collins).
● Fab: L1 and L2 (French–American–British).

Genetic profile
● Acute lymphoblastic leukemia.
● Translocations between the alpha/delta T-receptor locus
(14q11.2) and the beta (7q35) or gamma locus (7p14–15)
CLINICAL FEATURES
and various genes are found in 30% of cases. Partners
This is a neoplasm of T-cell-committed lymphoblasts. Those include MYC (8q24.1), TAL1 (1q32), RBTN1 (11p15),
cases involving the bone marrow and blood are referred to as RBTN2 (11p13), HOX11 (10q24), and LCK (1p34.3–35).
T-ALL, while those presenting within lymph nodes or other ● A minor 5⬘ deletion of TAL1 is present in 25%, instead of
sites are named T-LBL. However, such use is essentially arbi- translocation.
trary as there is extensive clinical overlap and biological unity. ● del(9p), which equates to loss of CDKN2A (tumor
T-ALL usually occurs in children (15% of childhood ALL), suppressor gene and inhibitor of CDK4), affects at least
and more commonly in adolescents. Adult involvement is less 30% of cases.
Non-Hodgkin lymphoma:T-cell and NK-cell neoplasia 715
● Clonality may be demonstrated by the detection of ● Diffuse small cleaved cell, diffuse mixed small and large
T-cell-receptor gene rearrangement, though this is not cell, diffuse large cell, immunoblastic (Working
lineage-specific. Formulation)
● T-cell lymphoma, small/pleomorphic medium/pleomorphic
Special techniques large type (HTLV1⫹) (Kiel)
● The cells express an immature T-cell phenotype (positive
● T-immunoblastic sarcoma (Lukes–Collins)
for terminal deoxynucleotidyl transferase, TdT).
● CD7 and cytoplasmic CD3 are often positive; other T-cell CLINICAL FEATURES
markers (CD1a, CD2, CD4, CD5, and CD8) are variably
expressed. ATLL is a peripheral T-cell disorder associated with highly
● CD10 and CD79a may be positive. pleomorphic lymphoid cells. It is endemic principally in Japan,
● CD13 and CD33 (myeloid markers) may be positive. the Caribbean basin and areas of central Africa. It is the most
● CD117 (c-kit) is rarely positive. common type of peripheral T-cell lymphoma in Japan. The dis-
● Lesions can be differentiated based on stages of intrathymic tribution of ATLL mirrors that of the associated HTLV1 retro-
development. This is based on CD expression. Cytoplasmic viral infection, which is usually contracted in early life via
CD3, CD2 and CD7 are expressed early, followed by CD5 breast milk and other body fluids. There is a long latency
and CD1a, and then membrane CD3 being last. This may period prior to the development of ATLL, which occurs in
be related to the prognosis, but as yet is ill-defined. 2.5% of those infected and with a median onset at 55 years.
● Stains for acid phosphatase highlight the activity of this There is a slight male preponderance.
enzyme, which is found in the Golgi zone. This is best Typically, the condition presents with generalized lym-
demonstrated in smear/imprint preparations or phadenopathy, often accompanied by hepatosplenomegaly and
cytocentrifuge preparations from pleural effusions. skin involvement. The lung, gastrointestinal tract, bone mar-
● Molecular diagnostics (see Genetic profile). row and CNS may also be involved.
Several discrete clinical variants are known:
● Acute variant: this is systemic, and characterized by a
leukemic phase, raised leukocyte count, skin rash,
● B-cell acute lymphoblastic leukemia (B-ALL)/B-cell
constitutional symptoms, hepatosplenomegaly and
lymphoplasmacytoid lymphoma (B-LPL) (the cells are
lymphadenopathy. Hypercalcemia is common (30% of
more uniform, the nuclei show no or less convolution and
total ATLL), and this may be associated with lytic bone
the chromatin is more coarse)
lesions. Raised lactate dehydrogenase (LDH) activity
● AML: myeloperoxidase, lysosomal and chloroacetate
and peripheral eosinophilia are common. T-cell
esterase will assist in differentiation
immunocompetence is lost, leading to opportunistic
● Hematogones (benign lymphoid precursors that resemble
infections such as Pneumocystis carinii and
ALL blasts) seen in various disorders may confuse bone
strongyloidiasis.
marrow or blood investigations (disorders include iron-
● Lymphomatous variant: this is typified by prominent
deficiency anemia, neuroblastoma, idiopathic
lymphadenopathy, no leukemic phase, and hypercalcemia
thrombocytopenia, post-chemotherapy AML). These can
is less common. Survival tends to be less than one year,
be differentiated from lymphoblasts by flow cytometry.
despite intervention.
Hematogones may express TdT and CD10 (like
● Chronic variant: this is characterized by prolonged skin
lymphoblasts), but reliably express various B-cell markers
involvement appearing as an exfoliative eruption.
that are used in combination on flow cytometry
Hypercalcemia is not present, and the blood picture is
● Nodal T-LPL may be confused with Burkitt lymphoma
variable.
(children) or blastoid variant of mantle cell lymphoma (but
● Smoldering variant: this is associated with skin and lung
the T-LPL is distinguished by TdT expression)
involvement, but little else.
● Diffuse follicular center lymphoma (the mitotic rate is
much higher in T-cell lymphoblastic lymphoma; B-cell Approximately 25% of the chronic and smoldering variants
markers are expressed) will progress to the acute form.
MATURE T-CELL AND NK-CELL NEOPLASIA: PATHOLOGICAL FEATURES
GENERAL/SYSTEMIC Lymph nodes are dominated by a pleomorphic population of

neoplastic cells diffusely involving affected nodes. Remnants of
inactive follicles may sometimes be seen. Patent sinuses filled
ADULT T-CELL LEUKEMIA/LYMPHOMA (ATLL) with pleomorphic cells may also be present.
[WHO, 2001] Bone marrow involvement is one of patchy infiltration with
prominent osteoclastic giant cells.
Previous classification/synonyms include: Skin involvement includes dermal infiltration with Pautrier-
● Adult T-cell lymphoma/leukemia (HTLV1⫹) (REAL) like microabscesses.
Cell morphology affects Asian populations, notably the younger demographic frac-
● Medium to large lymphoid cells are seen, and the nuclei tion, and with a slight male predominance. Typically, AgNKL
exhibit prominent lobation, deep indentation and a coarse involves the blood, marrow, spleen and liver, but any organ
chromatin pattern (acute and lymphomatous variants). involvement is possible. There may be some overlap with the
● The peripheral blood contains distinctive, multilobed NK/T-cell lymphoma of nasal type; indeed, this condition may be
‘flower’ or ‘cloverleaf’ cells. the systemic/leukemic version of this disease. Presentation is often
● Bizarre giant cells with multiple basophilic nucleoli are with pyrexia and constitutional symptoms. Hepatosplenomegaly
usually present. is not infrequent, and lymphadenopathy may also be encoun-
● Smaller less atypical cells typify the chronic/smoldering tered. Peripheral blood counts are extremely variable with respect
variant. to the leukemic cell population. Complications include hemo-
● Hodgkin lymphoma-like histology, including phagocytic syndrome, multiorgan failure and coagulopathy.
Reed–Sternberg-like cells may be seen in early ATLL and Serum Fas levels may be helpful in monitoring. The prognosis
some smoldering variants; this often progresses to the is bleak, with all patients dying within 2 years of a positive
acute variant within months. diagnosis, and most within a few weeks.
● EBV-positive, CD30- and CD15-positive B-cells can be
seen in involved nodes. This is probably secondary to PATHOLOGICAL FEATURES
opportunistic infection of B-cells by EBV; the T-cells These diseases are diagnosed by examination of blood smears,
remain EBV-negative. rather than of tissue sections.
Bone marrow trephines show subtle to massive involvement
Genetic profile with a histiocytic background, often with hemophagocytosis.
● Clonal T-cell-receptor gene rearrangements are present.
Cell morphology
● Clonal and integrated HTLV1 is present.
● Copious amounts of pale basophilic cytoplasm with coarse
Special techniques or fine azurophilic granules (on electron microscopy these
appear as parallel tubular arrays).
● The neoplastic cells express variable combinations of T-cell ● Nuclei are variable, but may be hyperchromatic and
markers, including CD2, CD3 and CD5. irregular with variable nucleoli.
● CD7 and CD8 are not expressed, and CD4 is typically
positive. Rarely CD4, is negative and CD8 positive. Genetic profile
● CD30 is positive, ALK, T-cell intracellular antigen-1
● Clonal T-cell-receptor gene rearrangements are not present.
(TIA-1) and granzyme-B are negative.
● Clonality is established by X-chromosome inactivation
● The cells are CD25 (IL-2 receptor)-positive.
studies.
● Clonal and episomal EBV is present.
● del(6)(q21q25) has been reported.
● High-grade B-cell lymphoma Special techniques
● Peripheral T-cell lymphoma ● The neoplastic population expresses CD2 and CD56.
● CD3 and CD57 are negative.
AGGRESSIVE NK-CELL LEUKEMIA (AgNKL) ● CD11b and CD16 are variable.
● The overall pattern is similar to NK/T-cell lymphoma of
[WHO, 2001] nasal type.
● Large granular lymphocyte leukemia (natural killer cell-
type) (REAL)
● Indolent NK-cell lymphoproliferative disorders
● Not listed (Working Formulation)
● T-LGL
● Not listed (Kiel)
● Aggressive NK-cell leukemia/lymphoma
ANAPLASTIC LARGE CELL LYMPHOMA (ALCL)

See also T-cell large granular lymphocyte leukemia, p. 726.
[WHO, 2001]
CLINICAL FEATURES
AgNKL is a systemic proliferation of NK cells with an aggres- ● Anaplastic large cell lymphoma, T-cell and null-cell types
sive clinical course, and may arise de novo or evolve from more (REAL)
indolent NK disorders including the NK/T-cell lymphoma of ● Various categories have been used including: diffuse large
nasal type. There is a strong EBV association, and an unusual cell, immunoblastic (Working Formulation)
link with mosquito-bite hypersensitivity. This condition mostly ● Large cell anaplastic (Kiel)
● Not listed (but may have been described as

T-immunoblastic sarcoma) (Lukes–Collins)
CLINICAL FEATURES
ALCL is a T-cell lymphoma which is typified by the presence of
numerous pleomorphic lymphoid cells. The primary systemic
form must be distinguished from other anaplastic lymphomas
and the cutaneous type (see Chapter 12, Skin tumors). This
condition is responsible for 3% of adult and 10–30% of child-
hood non-Hodgkin lymphoma. The most common ALK-
positive form (the ALKoma) occurs during the first three decades
of life, with a male predominance (up to 6.5:1). The rarer ALK-
negative form tends to be restricted to the elderly age groups.
ALK-positive ALCL frequently involves lymph nodes and
extranodal sites (skin, bone, soft tissue, lung, liver). Central (a)
nervous system, gastrointestinal tract and mediastinal involve-
ment may also occur, but this is rare.
Most patients present with advanced disease with lym-
phadenopathy and extranodal infiltrates, and constitutional
symptoms are the norm. ALK expression is associated with a
good prognosis; 5-year survival is 80%, compared with 40%
in ALK-negative cases. Fewer than 30% of cases relapse, but
these are often chemosensitive.
ALCL apparently arising from transformed T-cell lym-
phomas often have a worse outcome.

ALCL morphology is variable, but the cells often efface the tissue
in which they are present. However, bone marrow involvement is
often subtle, and staining with CD30 or ALK is advised. The
low-power appearance in many tissues often gives the impression (b)
of an undifferentiated tumor such as carcinoma or melanoma
rather than lymphoma. In lymph nodes, the neoplastic cells often
infiltrate sinuses and form tumor nodules in a manner similar to
that of metastatic carcinoma. The remnants of pre-existing low-
grade lymphoma are seen, if the case is one of transformation.
Cell morphology
All cases contain a variable proportion of the following:
● The cells are large and pleomorphic, often with abundant
cytoplasm and often with an eosinophilic region near the

nucleus. Eccentric nuclei are rounded, kidney-shaped or
horseshoe-shaped, and contain prominent nucleoli; these
are referred to as ‘hallmark’ cells.
● False intra-nuclear inclusions of cytoplasm may be seen;
these are called ‘doughnut’ cells.

● Mitotic figures, including atypical ones, are often numerous.
● There may be numerous reactive histiocytes.

(c)
Variants
Figure 10.39 Anaplastic large cell lymphoma (ALCL) is often
ALCL, classical/common (70% of cases): typified by a large cell population permeated by a small lymphocytic
● The above cells plus a more monomorphic population background (a). However, one must look for the ‘Hallmark’ cells to
with rounded nuclei. provide the morphological diagnosis (arrows, b and c). ALCL is
● More cytoplasm than most other lymphomas; this may be CD30 positive (d) and often EMA positive (e).The key
immunohistochemical marker is ALK (f, g). Note the diffuse nuclear,
clear, basophilic or eosinophilic. nucleolar and cytoplasmic staining typically seen in the ALK-NPM
● Multiple nuclei in a ‘wreath’ pattern may be seen, giving
translocation (f), as compared with the pure cytoplasmic staining as
rise to misdiagnosis as Reed–Sternberg cells. seen with other ALK translocations (g) (see Genetic profile).
(d) (f )
(e) (g)
● Nuclear chromatin is fine and dispersed or occasionally ● Signet-ring

clumped with basophilic nuclei. ● Edematous/mxyoid
● Larger cells have more eosinophilic nuclei.
● Erythrophagocytosis may be seen. ALCL, ALK-negative:
● Morphologically and phenotypically ALCL, but ALK-
ALCL, lymphohistiocytic (10%): negative.
● The above cells, but admixed with large numbers of ● Is it a different entity?
histiocytes. ● Cells tend to be larger and more pleomorphic. Similar cells
● Histiocytes may mask the malignant population, leading to
(typically CD30-positive) are seen in transformed T-cell
misdiagnosis. neoplasms. Is this ALK-negative ALCL the end result of
● The key is to look for neoplastic cells residing around
transformation, thereby explaining the differing prognostic
blood vessels and perform the salient implications?
immunohistochemistry.
● Erythrophagocytosis may be seen in histiocytes.
Genetic profile
ALCL, small cell variant (5–10%):
● Clonal T-cell receptor gene rearrangement (80%),
● Most of the cell population of small to medium-sized
irrespective of T-cell marker expression.
neoplastic cells with irregular nuclei.
● EBV-negative (EBV-positive B-cell lymphomas may be
● Hallmark cells concentrate around vessels.
misdiagnosed as ALCL).
● Often misdiagnosed as peripheral T-cell lymphoma,
● ALK positivity. ALK codes for a tyrosine kinase that
unspecified.
belongs to the insulin receptor superfamily.
ALCL, others (not currently recognized): ● t(2;5)(p23;p35) translocates ALK to be in apposition with
● Giant cell-rich NPM (nucleophosmin). This leads to specific cytoplasmic,
● Sarcomatoid nuclear and nucleolar staining due to the formation of
ALK-NPM homodimers. These can translocate to the ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA

nucleus without a nuclear-localizing signal, the benefit of
(AITL) [WHO, 2001]
the translocation.
● Variant ALK translocations include chromosomes 1 (with
tropomyosin, diffuse staining is restricted to the ● Angioimmunoblastic T-cell lymphoma (REAL)
cytoplasm), 2 (with TFG or AITC, yielding cytoplasmic ● Various categories have been used including: diffuse mixed
staining only), 3 and 17 (with CLTC yielding granular
small and large cell, diffuse large cell, immunoblastic,
cytoplasmic staining). All these variants ultimately lead to
atypical hyperplasia (Working Formulation)
the autophosphorylation of the ALK product rather than ● AILD-type (lymphogranulomatosis X) T-cell lymphoma (Kiel)
to nuclear translocation. ● Immunoblastic lymphadenopathy (Lukes–Collins)
● Expression of clusterin is limited to the systemic form
of ALCL, and is negative in the primary cutaneous CLINICAL FEATURES
form.
AITL is a peripheral T-cell lymphoma with systemic involvement,
typically affecting elderly people. It is one of the most common
Special techniques
T-cell lymphoma subtypes, accounting for 15–20% of cases
● The large neoplastic cells express CD30, membrane and and 1–2% of all non-Hodgkin’s lymphomas. Presenting fea-
Golgi only. Diffuse staining should be regarded as a tures include tender generalized lymphadenopathy, a pruritic
false-positive result. Smaller cells tend to be only weakly skin rash, malaise, and fever. This lesion commonly involves
CD30-positive. the spleen, bone marrow, liver, lung, skin and gastrointestinal
● ALK expression is seen in up to 85% of cases; the tract. The peripheral blood picture includes hemolytic anemia,
staining pattern depends on translocation (see Genetic leukocytosis, polyclonal hypergammaglobulinemia, circulating
profile). immune complexes, cold agglutinins, rheumatoid factor, anti-
● ALK is almost unique, and is only seen in the IgA-secreting smooth muscle antibodies and, occasionally, eosinophilia. As
variant of diffuse large B-cell lymphoma (DL-BCL), suggested by the blood picture, AITL may arise in association
rhabdomyosarcoma and inflammatory myofibroblastic with autoimmune diseases and sometimes with the administra-
tumors. tion of drugs (antibiotics and antimalarials). Patients often exhibit
● The cells variably express T-cell markers (usually one or immunodeficiency, secondary to AITL, and consequently most
two), but a null phenotype is possible. cases (⬎75%) are EBV-positive; however, this often only relates
● CD3 is positive in 75% of cases; CD43 is positive in over to the B cells present. This immunodeficiency makes the use of
65%. CD2 and CD4 are useful. CD5, CD7 and CD8 are aggressive chemotherapy very difficult.
often negative. Originally, AITL was thought to be an atypical reactive process
● CD45 and CD45RO are variable. referred to as angioimmunoblastic lymphadenopathy, and this
● TIA-1, granzyme-B and perforin may be positive. was thought to progress to lymphoma. Currently, it is believed
● EMA is usually positive, and of an identical pattern to that that AITL arises de novo, though this point is still being disputed.
of CD30. AITL has a poor prognosis given the typical aggressive course;
● CD15 is negative in the majority of cases. the median survival is less than 3 years.
● CD25 is strongly positive.
● EBV is negative. PATHOLOGICAL FEATURES (Figure 10.40)
● Up to 20% of lymphomas with large cell anaplastic
morphology are proven by immunohistochemistry to be This lesion is characterized by a partial effacement of the lymph
of B-cell origin. Such tumors should be classified as node architecture. There is a presence of numerous ‘arborizing’
DL-BCL. blood vessels (high endothelial venules) and a mixed infiltrate,
● CD68 may be granular-positive with the KP-1 clone, but including many plasma cells and immunoblasts. The capsule is
negative with the PGM-1 clone. usually thickened and infiltrated by similar cells. The majority of
● Molecular diagnostics (see Genetic profile). native follicles are lost, except for the occasional ‘regressively
transformed’ follicles consisting of small collections of histiocytes/
dendritic cells arranged in a concentric fashion. Deposition of
amorphous eosinophilic material is often seen amongst the cells,
● Peripheral T-cell lymphoma, unspecified (PTL-U) around vessels, or within ‘regressively transformed’ follicles.
● DL-BCL
● Lymphocyte-depleted Hodgkin lymphoma (LD-HL) Cell morphology
● Lymphocyte-rich Hodgkin lymphoma (LR-HL) (versus ● Small lymphocytes are grossly reduced in number, but
small cell variant) those that remain show minimal atypia; this may be
● Anaplastic carcinoma confused with atypical T-zone hyperplasia.
● Melanoma ● Background-reactive lymphocytes, eosinophils, histiocytes
● Malignant fibrous histiocytoma and plasma cells.
● Rhabdomyosarcoma ● Large basophilic B-cell blasts are often present;
● Inflammatory myofibroblastic tumor immunoblasts vary from scattered cells to solid clusters.
● Polyclonal B cells or plasma cells rarely comprise more

than one-third of the total cell populations.
● EBV-positivity is seen in B cells; some T-cell positivity has
been reported.
● Hodgkin lymphoma (classic Reed–Sternberg cells are
absent in AILT, and the presence of intact germinal
follicles are against AILT)
● Lennert (lymphoepithelioid variant of PTL-U) lymphoma
● Lymphoplasmacytoid lymphoma (may share similar
polymorphous infiltrate, epithelioid cells and marked
vascularity. Eosinophils are however absent and the B-cells
(a) are monoclonal)
● Certain reactive lymphadenopathies such as post-vaccinial
and drug-induced lymphadenitis
● Lymphadenopathy associated with HIV infection
(particularly lymphocyte-depleted nodes)
● Atypical T-zone hyperplasia
ENTEROPATHY-TYPE T-CELL LYMPHOMA (ETTL)

[WHO, 2001]

● Intestinal T-cell lymphoma (with/without enteropathy)
(REAL)
● Not listed (but may have been described under diffuse
large cell, immunoblastic) (Working Formulation)

(b) ● Not listed (but may have been described under various
categories including: pleomorphic T-cell lymphoma;

Figure 10.40 (a, b) Angioimmunoblastic T-cell lymphoma is medium and large cell) (Kiel)
typified by a paracortical expansion effacing the lymph node
● Not listed (but may have been described under
architecture.This neoplastic T-cell population is associated with
arborizing blood vessels and a mixed cellular infiltrate. T-immunoblastic) (Lukes–Collins)
See also Chapter 5, Digestive system tumors.
● Mitotic figures are numerous, and some abnormal forms
can be seen.
CLINICAL FEATURES
● Reed–Sternberg-like cells may be present.
● Grading is not performed, but the numbers of T-cell ETTL is a neoplasm of intraepithelial T-lymphocytes with vary-
immunoblasts may increase over time. ing degrees of transformation, typically involving large cells.
These lesions most commonly affect adults, presenting with
Genetic profile
non-specific intestinal symptoms such as abdominal pain,
● 75% of cases show clonal T-cell receptor gene obstruction, perforation, and malabsorption. They frequently
rearrangements. arise on the basis of other diseases, most commonly celiac dis-
● 10% of cases show clonal immunoglobulin gene ease (typically present for 10 or more years before the onset of
rearrangements (these are probably the EBV-driven group). lymphoma), or occasionally Crohn’s disease. The prognosis is
● Trisomy 3, trisomy 5 and an extra X chromosome may be poor as the lesions pursue an aggressive course. Uncontrolled
found. malabsorption is often the most significant factor.
Special techniques
● PAS and reticulin stains highlight the vascular pattern.
● Amyloid may be seen. Macroscopically, the intestine contains multiple ulcerating
● The main proliferating population expresses a mature T-cell raised mucosal masses, but isolated single exophytic lesions
phenotype; CD4-positive ⬎ CD8-positive and CD3-positive. may cause obstruction. The condition diffusely infiltrates the
● CD21 highlights the follicular dendritic cells (or mucosa and submucosa of the affected bowel. The adjacent
fibroblastic reticulum cells, cell type is disputed) that mucosa frequently shows villous atrophy due to the accompa-
surround the high endothelial venules. nying/underlying celiac disease.
Cell morphology
● Most cells are monomorphic, medium to large size with
round to angular nuclei, prominent nucleoli, and pale
cytoplasm.
● Multinucleated cells may be present within an anaplastic-
type picture.
● Background inflammation is often present (histiocytes,
eosinophils).
● Some variants are associated with small cells with dark
nuclei and a small cytoplasmic rim.
● Adjacent mucosa may show features of celiac disease.
Genetic profile
● The celiac disease genotype is often present
(HLA DQA1*0501, DQB1*0201).
(c )
(a)
(d)
(b) (e )
Figure 10.41 Intestinal T-cell lymphoma. Small bowel ulceration (a–c) with infiltration by admixture of small, CD3-positive (d) neoplastic T-
cells, small B-cells, plasma cells, eosinophils and highly atypical CD30-positive T-cells (e).
● TCR ␣ and ␤ are clonally rearranged within the tumor. ‘lethal midline granuloma’ that prompts presentation. Often
Similar rearrangements are often seen in the adjacent there is extension to adjacent areas such as the orbit or oral
enteropathic mucosa; these are also found in the cavity. Dissemination is rapid to multiple sites (as mentioned),
premalignant ‘refractory’ celiac disease. and secondary nodal and blood/bone marrow involvement can
occur. Constitutional symptoms are common.
Special techniques The prognosis is highly variable, but the presence of systemic
● The neoplastic cells express CD3, CD7, CD103 and disease is a poor sign. Some studies have suggested that the
often CD8. cytological grade may be an important prognostic indicator.
● CD4 and CD5 are not expressed.
● CD30 expression is variable. PATHOLOGICAL FEATURES (Figure 10.42)
● The small cell variant is often CD8- and CD56-positive.
These lesions are characterized by an angiocentric or angio-
● Identical (abnormal) immunophenotypes may be seen in
invasive pattern of growth. The infiltrate is similar, regardless
adjacent and ‘refractory’ celiac disease.
of the site of involvement. Superficial or mucosal lesions are
accompanied by ulceration. There is often extensive coagula-
Differential diagnosis tive necrosis and apoptotic bodies present, secondary to the
chemo/cytokine-rich environment rather than to any direct
● Intestinal B-cell lymphoma
ischemic effect of vessel destruction.
● Hepatosplenic T-cell lymphoma (HSTL), variant
The cell of origin is purported to be an activated NK cell or
a cytotoxic T cell.
EXTRANODAL NK-/T-CELL LYMPHOMA, NASAL
Vascular pattern
TYPE (EN-NKTL) [WHO 2001]
● There is moderate to severe vascular injury in the form of
Previous classification/synonyms include: endothelial swelling, luminal obliteration and extravasation
● Angiocentric T-cell lymphoma (REAL). of fibrin (fibrinoid necrosis) and red blood cells.
● Not listed (but may have been described under various
Cell morphology
categories including: small lymphocytic diffuse small
cleaved cell, diffuse mixed small and large cell, diffuse
● Cells may be small through to anaplastic. The most
large cell, immunoblastic) (Working Formulation). common scenario is composed of mostly medium-sized
cells with scattered small and large cells.
categories including: pleomorphic T-cell lymphoma;
● Irregular nuclei with a coarse granular chromatin are
small/medium-sized/large cell types) (Kiel). common. Larger cells tend to have a vesicular chromatin.
● Not listed (Lukes–Collins).
● Nucleoli are inconspicuous.
● Malignant midline reticulosis.
● Cytoplasm is pale, and of variable volume.
● Polymorphic reticulosis.
● Lethal midline granuloma.
● Angiocentric immunoproliferative lesion.
CLINICAL FEATURES
EN-NKTL has a broad polyphenotypic appearance, accompanied
by clinical heterogeneity as it affects a wide range of ages and
a variety of sites (respiratory tract, gastrointestinal tract, skin,
soft tissue, testis and central nervous system). It is an angio-
centric, angiodestructive lesion that may consist of both NK
cells and T cells (rare). The upper respiratory tree – particularly
the nasal cavity – is the most common site of occurrence, hence
the ‘nasal type’ label. Historically, the synonyms for this lesion
have arisen because of the pleomorphic/polymorphic appear-
ances of the tumor or from its clinical nature. Confusion with
lymphomatoid granulomatosis (LG) has been longstanding.
The latter (LG) is now regarded to be an EBV-driven, T-cell-
rich, B-cell proliferation.
Epidemiologically, EN-NKTL is most prevalent in Asia,
Mexico and Central/South America’ It affects males more than
(a)
females, and adults more than children. It may arise following
immunosuppression (for whatever reason). Figure 10.42 (a–c) Extranodal-natural killer (NK)-T-cell lymphoma.
Classical presentation is following epistaxis or nasal obstruc- Diffuse infiltrate by medium-sized lymphocytes which have irregular
tion; occasionally, it is the distressing cosmetic effect of the nuclei.The infiltrate has a prominent angiocentric pattern.
● EBV in clonal episomal form is usually present in tumor

cells.
● No specific abnormality has been detected but like
AgNK-L, del (6)(q21q25) has been reported. This or
i(6)(p10) is the commonest.
Special techniques
● The typical immunophenotype is CD2- and
CD56-positive, but surface CD3-negative.
● CD3⑀ shows cytoplasmic positivity.
● Granzyme-B, TIA-1 and perforin are often positive.
● CD7 and CD30 are occasionally expressed.
● Other NK- and T-cell markers are negative (CD4, CD5,
CD8, CD16, CD43, CD45RO, CD57, TCR␤, TCR␦).
● IL-2, HLA-DR, CD95 (Fas) and Fas ligand are commonly
expressed.
● EBV-positive.
● Cases with CD56 negativity can be allowed as EN-NKTL,
provided that there is cytotoxic molecule expression or
(b) EBV positivity. Should these be absent, then this lesion
should be regarded as peripheral T-cell lymphoma,
unspecified (PTL-U).
● Note that CD56 is not specific and can be expressed in
other T-cell lymphomas, particularly those expressing the
␥␦-T-cell receptor.
● Other types of lymphoma, e.g., PTL-U, aggressive NK-cell
leukemia (AgNKL), T-cell rich DL-BCL, etc.
● HSTL, variant
● Lymphomatoid granulomatosis
● Reactive lymphoid hyperplasia
● Histiocytoid hemangioma
HEPATOSPLENIC T-CELL LYMPHOMA (HSTL)

[WHO, 2001]

● Hepatosplenic ␥␦ T-cell lymphoma (REAL)
(c)
● Not listed (but may have been described under diffuse
Figure 10.42 (Continued). small cleaved cell) (Working Formulation)

categories including: pleomorphic T-cell lymphoma; small

● Mitoses are frequent in all morphological types. cell, medium-sized cell) (Kiel)
● Not listed (Lukes–Collins)
● A notable inflammatory background will be present
(including histiocytes, plasma cells, lymphocytes and
eosinophils). Hence the previous term ‘polymorphic CLINICAL FEATURES
reticulosis’. HSTL was a provisional entity described under the REAL clas-
● In areas of skin involvement, pseudoepitheliomatous sification; it has now become a defined entity under the WHO
hyperplasia is associated, giving rise to concern over 2001 classification. It is a extranodal and systemic disorder of
squamous cell carcinoma, both clinically and histologically. cytotoxic T cells, the vast majority of which harbor the TCR␥␦.
This rare lesion occurs in adolescents and young adults, and
Genetic profile has a male predominance. A separate group associated with
● T cell receptor and immunoglobulin genes lack any clonal the TCR␣␤ is more common in females, but otherwise it is
rearrangement. identical. The main presenting feature is hepatosplenomegaly
with systemic symptoms. Bone marrow involvement is nearly pleomorphic T-cell lymphoma small/medium/large cell
always present, but lymphadenopathy is almost never encoun- types, T-immunoblastic lymphoma (Kiel)
tered. This leads to thrombocytopenia, anemia and leukocyto- ● T-immunoblastic lymphoma (Lukes–Collins)
sis. HSTL is an aggressive disease, frequently relapsing after
therapy. The median survival is 2 years. CLINICAL FEATURES
This is a group of various T-cell lymphomas that remain after
PATHOLOGICAL FEATURES the distinctive entities, such as those already referred to in this
HSTL is characterized by sinusoidal infiltration of the liver, section, are removed. Most are nodal, but some are extranodal
spleen and bone marrow by a monotonous population of lymphomas, and together they are referred to as peripheral
medium-sized neoplastic T cells. T-cell lymphoma (⫹/⫺unspecified). Attempts at separating
them on morphological grounds have failed due to poor
Cell morphology intra/inter-observer reproducibility.
PTL-U represent up to 50% of all T-cell lymphomas in west-
● The neoplastic cells are medium-sized with round nuclei, ern countries; they usually occur in adults, and have an equal
condensed chromatin, inconspicuous nucleoli, and a sex incidence. The sites of involvement include lymph nodes,
moderate amount of pale cytoplasm. bone marrow, spleen and skin, and occasionally there is a
● Rare cases show increased cytological atypia. leukemic blood picture. Consequently, most patients present
Variants with lymphadenopathy, and many have advanced disease with
constitutional (‘B’) symptoms and poor performance status.
● Involvement beyond the liver and spleen, including skin, Paraneoplastic eosinophilia, pruritus or hemophagocytic syn-
subcutaneous tissues, intestine or nasal lesions. They drome may be present. PTL-U are highly aggressive neoplasms –
resemble lesions of those sites including EN-NKTL, perhaps the worst of the non-Hodgkin lymphomas – and
mycosis fungoides, pagetoid reticulosis, subcutaneous respond poorly to combination chemotherapy. Relapses are
panniculitis-like T-cell lymphoma and ETTL. frequent, with a 5-year survival of less than 30%. EBV positiv-
ity may be related to a poor prognosis, and no significant
Genetic profile differences between the proposed variants have been noted.
● TCR␥ are rearranged in a clonal manner.
● TCR␤ rearrangement may be present. PATHOLOGICAL FEATURES (Figure 10.43)
● Isochromosome 7q is seen in all cases.
This is a histologically heterogeneous disease category. The pat-
● Trisomy 8 is common.
tern is diffuse rather than nodular, with effacement of the lymph
● EBV is negative.
node architecture. In extranodal sites, the cells lack cohesion
and invade surrounding tissues in a diffuse manner. There is a
Special techniques
great cytological diversity with an inflammatory background.
● The neoplastic cells express some peripheral T-cell markers In some cases, residual hyperplastic follicles are present with
(CD2, CD3), and are characterized by expression of ␥ and expansion of the interfollicular areas by neoplastic T cells and
␦ T-cell-receptor chains, rather than the more usual ␣ and accompanying reactive cell types (‘T zone’ lymphoma). Occasion-
␤ chains (unless the lesion is the rarer TCR␣␤ variant). ally, diffuse involvement may be present, when typically the cells
● CD4, CD5 and CD8 are negative. appear less pleomorphic than the standard PTL-U. In other
● TIA-1 is positive, and perforin is negative. cases, small granuloma-like clusters of epithelioid histiocytes are
● Molecular diagnostics (see Genetic profile). a dominant feature (Lennert/lymphoepithelioid lymphoma).
Differential diagnosis Vascular pattern

● Hepatic/splenic involvement by other lymphomas ● Arborizing capillary-sized blood vessels or high endothelial
● Hepatic/splenic involvement by myeloid leukemias venule-like vessels are often a conspicuous feature.
Cell morphology
PERIPHERAL T-CELL LYMPHOMA, UNSPECIFIED The neoplastic cells can show a wide variety of appearances,
(PTL-U) [WHO, 2001] and similar patterns are seen in the variants, albeit in a differ-
ent architectural distribution:
Previous classification/synonyms include: ● Irregularly shaped small lymphocytic cells with indented or
● Peripheral T-cell lymphoma, unspecified (provisional cerebriform nuclei, sometimes similar to centrocytes.
cytological categories include large/medium-sized/mixed ● Medium-sized cells resembling centroblasts, but with a
cell) (REAL) coarse chromatin pattern and irregular nuclear outline.

● Various categories may have been used including: diffuse ● Plasmacytoid cells.
small cleaved cell, diffuse mixed small and large cell, ● Immunoblast-like cells.
diffuse large cell, immunoblastic (Working Formulation) ● Reed–Sternberg-like cells.
● Various categories may have been used including: T-zone ● Bizarre anaplastic cells, often with abundant clear cytoplasm.
lymphoma, lymphoepithelioid (Lennert) lymphoma, ● Mitotic and apoptotic figures are often numerous.
(a) (d)
(b) (e)
(c) (f )
Figure 10.43 Peripheral T-cell lymphoma unspecified.These are three separate cases of peripheral T-cell lymphoma, unspecified (PTL-U) to
demonstrate the morphological diversity seen in this group. (a) A case in which there is a small lymphocyte predominance within the
paracortical expansion. (b) A more typical blast rich paracortical infiltrate with a mixed cellular background; (c) CD3 and (d) CD30 highlight
lesional cells. (e, f ) A further PTL-U.This appears to be a higher grade lesion as the majority of cells are blasts.This case expressed CD4 (g)
and CD30 (h). Other T-cell markers and CD45 were variable.This is typical of this entity and a warning to those who would use CD45
negativity as reassurance for the absence of lymphoma.
● Extranodal types can express CD56 and have a cytotoxic

immunophenotype.
● Other T-cell lymphomas, particularly anaplastic large cell
lymphomas
● B-cell lymphomas
● Paracortical lymphoid hyperplasia
● T-cell-rich DL-BCL
● Plasmacytoma
● Thymoma
● Metastatic undifferentiated carcinoma
(g) ● Melanoma
T-CELL LARGE GRANULAR LYMPHOCYTE

(LYMPHOCYTIC) LEUKEMIA (T-LGL) [WHO, 2001]

● Large granular lymphocyte leukemia (T-cell type) (REAL).
● Small lymphocytic lymphoma (Working Formulation).
● T-lymphocytic, chronic lymphocytic leukemia/lymphoma-
type lymphoma (Kiel).

● T-cell chronic lymphocytic leukemia.
● T␥-lymphoproliferative disorder.
● Proliferation of large granular lymphocytes.
● LGL leukemia.
(h) CLINICAL FEATURES
Figure 10.43 (Continued). The REAL classification described the T-cell and NK-cell vari-
eties of this disorder as one entity: large granular lymphocyte
leukemia. The WHO (2001) classification has subdivided this
into T-LGL and aggressive NK-cell leukemia (AgNKL).
Reactive populations of the following cell types are common: T-LGL is heterogeneous, and is characterized by a persistent
● Eosinophils.
(⬎6 month) increase in peripheral large granular lymphocytes
● Macrophages (often epithelioid).
without an identified cause. It is similar to T-cell chronic
● Plasma cells.
lymphocytic leukemia, with the exception of an Asian variant
of the natural killer cell type that occurs in young adults and is
Genetic profile highly aggressive. It represents 2–3% of small lymphocytic
● TCR genes are clonally rearranged. lymphoma (SLL), and typically involves blood, marrow, liver
● Complex karyotypes are frequent. and spleen. Lymph nodes tend to be spared.
● Trisomy 3 is common in lymphoepithelioid (Lennert) variants. Most cases are indolent, but neutropenia and anemia are com-
● No specific reliable abnormality has yet been found. mon, giving rise to symptoms in 60% of patients. Splenomegaly
is the main clinical finding. Associations with rheumatoid arthri-
Special techniques tis, autoantibodies, circulating immune complexes and hyper-
gammaglobulinemia are possible.
● The neoplastic population expresses a peripheral T-cell Transformation to a peripheral T-cell lymphoma, unspecified,
phenotype (combinations of CD45, CD43, CD2, CD3, is possible.
CD5, CD7, and CD4/8). Aberrant types are frequent.
● Nodal types are commonly CD4-positive/CD8-negative.
● CD30 can be expressed in the large cell variants; this may
lead to confusion with the anaplastic large cell lymphomas. These diseases are diagnosed by examination of blood smears,
● EBV is not present within tumor cells, but may infect rather than of tissue sections.
bystander B- and even T-cells. EBV may give rise to the Bone marrow trephines show lymphoid aggregates, myeloid
Reed–Sternberg morphology seen in some cases. maturation arrest and erythroid hypoplasia.
Cell morphology multi-chemotherapeutic use (pentostatin and CHOP) and mono-

● Copious amounts of cytoplasm with coarse or fine clonal antibody therapy.
azurophilic granules (on electron microscopy, these
appear as parallel tubular arrays). PATHOLOGICAL FEATURES
This is a diffuse lymphoma which is characterized by a uniform
Variant
population of small to medium sized prolymphocytes similar to
● Cases with an NK-cell immunophenotype (CD3-, those seen in the B-cell equivalent, and express a post-thymic
TCR␣␤-positive) are classified separately. T-cell phenotype. Cells of similar morphology involve the blood
and bone marrow. Skin involvement is by means of dense dermal
Genetic profile infiltrates surrounding appendages. Splenic involvement shows
● Clonal T-cell-receptor gene rearrangements are present dense red and white pulp infiltration. This lymphoma differs
(␤ chains); rarely, ␥ chain rearrangement is noted histologically from its B-cell counterpart in that it lacks prolif-
instead. eration centers and contains prominent high endothelial venules.
● Constitutive expression of CD95 (Fas) and Fas-ligand,
resistance to apoptosis comes from a disruption in the
Cell morphology
downstream pathway. ● Medium-sized cells double that of a lymphocyte, each with
● No specific anomaly noted. a prominent central nucleolus surrounded by a rim of
condensed chromatin within an ovoid nucleus. In 25% of
Special techniques these the nucleolus may not be apparent. Occasionally, an
angularity to the nuclear membrane is noted.
● The neoplastic population expresses a mature T-cell ● The cells have a small rim of non-granular, basophilic
phenotype, i.e., CD3-positive, CD4-negative, CD8-positive,
cytoplasm.
TCR␣␤-positive (common variant, 80%). ● The small cell variant accounts for 20%.
● Rare variants may differ (CD3-positive, CD4-positive, ● The cerebriform (Sézary cell-like) variant accounts for 5%.
CD8-negative, TCR␣␤-positive or CD3-positive,
CD4-positive, CD8-positive, TCR␣␤-positive or
Genetic profile
CD3-positive, TCR␥␦-positive).
● CD11b, CD56 and CD57 are variably expressed. ● Clonal T-cell-receptor gene rearrangements are present
● TIA-1 is commonly positive. (␥ and ␤ chains).
● Molecular diagnostics (see Genetic profile). ● Inversion of chromosome 14 (breakpoints are q11 and
q32), present in 80% of cases, t(14;14)(q11;q32),
reciprocal translocation is seen in 10%. These juxtapose
oncogenes (TCL1, TCL1b) with the TCR␣/␤.
● AgNKL. ● Trisomy 8, idic(8p11), and t(8;8)(p11–12;q12) are present
in 70–80% of cases.
● del 12p13 and/or del 11q23 (Ataxia Telangectasia Mutated
T-CELL PROLYMPHOCYTIC LEUKEMIA (T-PLL)
gene) may also be noted. The ATM gene is also associated
[WHO, 2001] with missense mutation in some cases.
● t(X;14)(q28;q11) is unusual, it relocates the oncogene
Previous classification/synonyms include: MTCP1, and is associated with the D4⫺/CD8⫹ variant.
● T-cell chronic lymphocytic leukemia/prolymphocytic
leukemia (REAL) Special techniques

● Small lymphocytic lymphoma (Working Formulation)
● T-prolymphocytic leukemia/T-cell lymphocytic leukemia

● The neoplastic population expresses a peripheral T-cell
phenotype; that is, they are TdT- and CD1a-negative.
(Kiel)
● ‘Knobby’ type of T-cell leukemia (Lukes–Collins)
● CD45, CD43, CD2, CD5 and CD7 are typically positive.
● CD3 may show weak membrane staining, indicating
immaturity as compared to a true peripheral mature
CLINICAL FEATURES T-cell.
T-PLL is a rare but aggressive disorder, which usually affects
● Among cells, 15% are CD8-positive/CD4-negative, 25%
older individuals. It represents 2% of SLL, and the presenta- are CD8-positive/CD4-positive, and 60% are CD8-
tion and clinical course is similar to that of B-cell chronic negative/CD4-positive.
lymphocytic/prolymphocytic leukemia. Sites of involvement
● Ultrastructural analysis to detect variants.
include blood, bone marrow, lymph nodes, spleen and skin.
Consequently, hepatosplenomegaly, lymphadenopathy and skin
masses are common features. Anemia and thrombocytopenia Differential diagnosis
also occur. The median survival is less than one year, although ● B-cell chronic lymphocytic/prolymphocytic leukemia
improved responses have been noted by stem cell transplantation, ● T-cell-rich, B-cell lymphomas
● TdT and CD34 may be positive.

MATURE T-CELL AND NK-CELL NEOPLASIA: ● Myeloperoxidase and CD33 are both negative.
PREDOMINANTLY SKIN-RELATED ● Molecular diagnostics (see Genetic profile).
BLASTIC NK-CELL LYMPHOMA (BNKL)
● Other NK cell neoplasms
[WHO 2001] ● Other T-cell neoplasms
● Myeloid lineage disorders
● Not recognized (REAL).
● Not recognized (Working Formulation). MYCOSIS FUNGOIDES AND SÉZARY SYNDROME

● Not recognized (Kiel).
(MF, SS) [WHO 2001]
● Not recognized (Lukes–Collins).
● Lymphoblastoid variant of NK-cell lymphoma.

● Monomorphic NK-cell lymphoma.
● Mycosis fungoides (REAL).
● Primary cutaneous CD4-positive/CD56-positive
● Mycosis fungoides (Working Formulation).
hematolymphoid neoplasm. ● Small cell, cerebriform (Kiel).
● Cerebriform T (Lukes–Collins).
CLINICAL FEATURES
See also Chapter 12, Skin tumors.
BNKL is a disorder of lymphoblast-like cells with definitive NK
lineage commitment, and consequently some represent a pre-
cursor NK-cell lymphoblastic lymphoma/leukemia. This lesion PRIMARY CUTANEOUS CD30-POSITIVE T-CELL
overlaps with primary cutaneous CD4-positive/CD56-positive LYMPHOPROLIFERATIVE DISORDERS [WHO 2001]
hematolymphoid neoplasm and CD56-positive AML. There is
no EBV association.
BNKL is very rare, with most patients being either middle- PRIMARY CUTANEOUS ANAPLASTIC LARGE CELL
aged or elderly, though the condition may occur at any age. It LYMPHOMA (C-ALCL) (Figure 10.44)
has a predilection for the skin, although involvement of lymph
nodes, soft tissue, blood and marrow also occurs. Occasionally, Previous classification/synonyms include:
● Primary cutaneous anaplastic large cell (CD30⫹)
nasal involvement can cause confusion with EN-NKL. Presen-
tation with a skin mass or lymphadenopathy is the most com- lymphoma (REAL).
● Various categories (diffuse large cell; immunoblastic)
mon situation.
This lesion has a very poor prognosis, but does show some (Working Formulation).
● Anaplastic large cell (Kiel).
response to acute leukemia-type chemotherapy. Skin restriction
● Not listed (T-immunoblastic) (Lukes–Collins).
equates to a better prognosis.
● Regressing atypical histiocytosis.
● Ki-1 (positive anaplastic) lymphoma.

BNKL is characterized by a diffuse, monotonous medium-sized LYMPHOMATOID PAPULOSIS
cell infiltrate effacing the tissue in which it resides. Single-file
infiltration can be noted. Homer–Wright rosettes may be seen. Previous classification/synonyms include:
● Not listed (REAL).
Coagulative necrosis and angiodestruction or angiocentricity is
● Not listed (Working Formulation).
rare (unlike EN-NKL). BNKL should only be diagnosed in the
● Not listed (Kiel).
absence of T-cell or myeloid lineage markers.
Cell morphology
BORDERLINE LESIONS
● Medium-sized lymphoblast-like or myeloblast-like cells.
● Fine nuclear chromatin. Previous classification/synonyms include:
● Lymphomatoid papulosis, diffuse large cell type (type C).
Genetic profile ● Anaplastic large cell lymphoma, lymphomatoid papulosis-
● Clonal TCR gene rearrangements are absent. like histology.

● There is no EBV association. See also Chapter 12, Skin tumors.
● No specific abnormality has yet been found.
Special techniques SUBCUTANEOUS PANNICULITIS-LIKE T-CELL

● CD3 is negative. LYMPHOMA (SPL-TL) [WHO, 2001]
● CD56 is positive.
● CD2, CD4, CD7 and CD43 are variable. Previous classification/synonyms include:
● CD68 is focal or negative. ● Subcutaneous panniculitic T-cell lymphoma (REAL).
(a) (c)
(b) (d)
Figure 10.44 (a–d) CD30-positive primary cutaneous T-cell lymphoma. A dermal infiltrate of lymphocytes seen in a diagnostic biopsy.
Note the larger CD30-positive (d) cells admixed with the small lymphocytic background.
● Various categories may have been used, including: T-CELL PROLIFERATIONS OF UNCERTAIN
diffuse small cleaved cell, diffuse mixed small and large MALIGNANT POTENTIAL
cell, diffuse large cell, immunoblastic (Working
Formulation).
● Not listed (but may have been described under LYMPHOMATOID PAPULOSIS (LP) [WHO, 2001]
various categories including: pleomorphic
T-cell lymphoma; small, medium-sized, mixed Previous classification/synonyms include:
or large cell, immunoblastic T-cell lymphoma)
● Not listed (REAL).
● Not listed (Working Formulation).
(Kiel).
● Not listed (Kiel).
See also Chapter 12, Skin tumors. See also Chapter 12, Skin tumors.
MASTOCYTOSIS
CLINICAL FEATURES 2. SM with an associated clonal hematological non-mast cell

lineage disease. Solid tumors or second hematopoietic disor-
Mastocytosis comprises a heterogeneous group of hematologi-
ders are found in almost one-third of systemic mast
cal disorders which are morphologically defined by prolifera-
cell disease cases, including myelodysplasia, myelo-
tion and accumulation of tissue mast cells in one or more
proliferative disorder, acute myeloid leukemia, and malig-
organs. Recently, it has been shown that systemic mastocytosis
nant lymphoma.
(SM) is a clonal disorder often exhibiting mutations of c-kit, a
3. Aggressive systemic mastocytosis (ASM) is a clonal mast
protooncogene encoding the tyrosine kinase receptor for stem
cell disease characterized by progressive growth of neo-
cell factor (SCF). Mutations of c-kit are considered to play a
plastic cells in diverse organs, and leads to organopathy.
key role in the pathogenesis of mastocytosis.
The organ systems most frequently affected are the bone
According to the WHO classification of tumors of
marrow, skeletal system, liver, spleen, and gastrointestinal
hematopoietic and lymphoid tissues, mast cell disease is
tract. Respective clinical findings (so called C-findings)
classified into:
include cytopenias, osteolysis (or osteoporosis) with patho-
● Cutaneous mastocytosis (CM). This disease group is
logical fractures, hepatosplenomegaly with impaired liver
defined by the triad of: (i) typical clinical aspects of skin
function and ascites, and malabsorption.
lesions; (ii) histological demonstration of typical focal
4. Mast cell leukemia is an aggressive leukemic disease with
infiltrates of mast cells into the dermis; and (iii) the
short survival.
absence of SM criteria that would allow the establishment
5. Mast cell sarcoma is defined by a local destructive
of a diagnosis of SM.
sarcoma-like growth of a tumor that consists of highly
● Urticaria pigmentosa (UP), also referred to as
atypical mast cells. This is an extremely rare entity among
maculopapular cutaneous mastocytosis (MPCM). The
mast cell proliferative disorders. By definition, systemic
condition of UP/MPCM appears to be the most frequent
involvement is not found in patients with mast cell
form of CM. Most patients are children, with the skin
sarcoma at diagnosis. However, secondary generalization
showing a maculopapular rash with a positive Darier’s
with involvement of visceral organs and hematopoietic
sign. Mediator-related symptoms may be present. The
tissues may occur. The terminal phase of mast cell sarcoma
prognosis of UP/MPCM is good, and most cases which
may be indistinguishable from mast cell leukemia.
develop in early childhood resolve at the end of (or shortly
after) puberty. Mast cell disease has a low prevalence, and is difficult to
● Telangiectasia macularis eruptive perstans (TMEP)
diagnose in the absence of the characteristic skin lesions that
UP variant; this occurs in adults, and the prognosis usually accompany the condition. Extracutaneous involvement
is good. is not easy to assess.
● Diffuse cutaneous mastocytosis (DCM). This is less
Patients with systemic mastocytosis present symptoms
frequently diagnosed than UP. Most patients are children, related to the tissue response to the release of mediators from
and the cutaneous lesions show a more diffuse mast cells and to the local mast cell burden. Such patients often
erythrodermic rash. In some patients there may be have a history of chronic and acute mediator-related symp-
extensive mast cell infiltrates, leading to diffusely toms. Symptoms can include pruritus, flushing, syncope, gas-
thickened skin or (additional) nodular lesions (a high tric distress, nausea and vomiting, diarrhea, bone pain and
burden of mast cells). The prognosis is good. neuropsychiatric symptoms, most of which are controlled by
● Mastocytoma of skin. Solitary mastocytomas in humans
medication. Because there is no current cure for mastocytosis,
are found almost exclusively in the skin (other organ sites successful therapeutic interventions rely on the recognition of
are very rare). Most patients are young infants, and these mediator-related symptoms and their treatment, and estab-
present with a yellow- or reddish-colored nodular lesion lished intervention approaches for the relatively uncommon
not exceeding 1 cm in diameter. Histologically, the lesion leukemic concomitants.
consists of densely packed, mature-appearing mast cells ● Extracutaneous mastocytoma is a localized benign
without cellular atypia. tumor with unifocal growth of tissue mast cells, without
● Systemic mastocytosis (SM) is defined by multifocal
systemic involvement (SM criteria not fulfilled). In contrast
histological lesions in the bone marrow or other to mastocytoma of skin, mastocytomas in extracutaneous
extracutaneous organs, together with cytological and organs are very rare. To date, extracutaneous
biochemical signs of systemic disease. Systemic mastocytomas have been detected primarily in the lungs. In
mastocytosis is further divided into the following contrast to mast cell sarcoma, mastocytomas do not show
categories: an aggressive (destructive) growth pattern. The prognosis
for patients with mastocytoma is good – no progression to
1. Indolent SM: patients with indolent SM usually have mac- aggressive disease or mast cell leukemia occurs. Therefore,
ulopapular skin lesions and a good prognosis, and may it is of great importance to differentiate between
spontaneously regress. mastocytoma and mast cell sarcoma at first presentation.
PATHOLOGICAL FINDINGS Differential diagnosis

Cutaneous mastocytosis (CM) shows typical focal infiltrates of ● Extramedullary myeloid cell tumors may be difficult
mast cells in the dermis. to distinguish from mast cell disease because they
In urticaria pigmentosa (UP) (maculopapular cutaneous frequently express CD43, CD68, and CD117 without
mastocytosis; MPCM), the mast cells exhibit a rather mature expression of lymphoid-associated antigens, similar to
morphology. mast cell tumors. Strong myeloperoxidase (MPX)
In telangiectasia macularis eruptive perstans (TMEP) the expression in the majority of cells is helpful in
mast cell infiltration is sparse and usually perivascular. Here, diagnosing myeloid tumors.
careful study of metachromatic cells is required, perhaps using ● The rare cases of marrow involvement by a diffuse mast
Giemsa or toluidine blue staining. cell infiltrate indicate a significant adverse prognostic
Diffuse cutaneous mastocytosis (DCM) may appear similar factor in urticaria pigmentosa.
to UP/MPCM or solitary mastocytoma of skin. ● Mast cell hyperplasia is commonly present in bone
In mastocytoma of skin, the lesion consists, histologically, of marrow specimens of patients with chronic
densely packed, mature-appearing mast cells without cellular lymphoproliferative disorders and in association with
atypia. other tumors. The cells demonstrate a similar
Indolent mastocytosis exhibits normal-appearing mast cells immunophenotype as mast cell disease. Mast cell
with predominant spindle-shaped morphology. The cells have a hyperplasia does not form the distinct lesions with
hypogranulated cytoplasm with focal accumulations of gran- fibrosis that are common for mast cell disease, and this
ules, and exhibit an oval (decentralized) nucleus (atypical mast differential diagnosis is only resolved by morphological
cells type I). The bone marrow biopsy in mastocytosis often features.
reveals characteristic mast cell collections associated with lym-
phoid cell aggregates. Special techniques
‘High-grade’ mast cell disorders (mast cell leukemia, aggres- ● The basophilic granules of mast cells are demonstrated by
sive mastocytosis) often show immature mast cells with a blast- Giemsa and toluidine blue staining.
like morphology (metachromatic blasts) or with bilobed or ● Mast cells are immunoreactive for tryptase, SCF receptor
multilobed nuclei (atypical mast cells type II ⫽ promastocytes). KIT (CD117), the common leukocyte antigen (CD45), and
For example: macrosialin (CD68R).
● Mast cell leukemia is characterized by a significant number ● Mast cells are also strongly and diffusely positive for
of leukemic mast cells in peripheral blood and/or bone CD43.
marrow smears. ● Mast cells are usually negative for CD1a, CD2, CD3,
● Mast cell sarcoma reveals a pleomorphic population of
CD5, CD14, CD15, CD19, CD20, or CD34.
mostly medium-sized cells with oval or lobated nuclei ● MPX is usually positive for cutaneous mast cells, whereas
containing moderately coarse or fine chromatin, and extracutaneous MCD may be negative.
occasionally small nucleoli. The nuclei are surrounded by ● Recent data indicate that mast cells in patients with SM or
moderately wide eosinophilic cytoplasm. mast cell leukemia exhibit characteristic phenotypic
Mononucleated or multinucleated giant cells were sometimes properties when compared with normal mast cells. Most
encountered, as were mitotic cells. The multinucleated giant significantly, these cells frequently express LFA-2 (CD2) on
cells often contained wreath-like nuclei attached to the cell their surface, whereas normal mast cells do not express
membrane. The inflammatory background is mostly composed this antigen.
of eosinophils.
● Depending on the type of disease and other factors, the
In extracutaneous mastocytoma the cells show a low-grade CD88 (C5a receptor) is differentially expressed on various
cytology, unlike mast cell sarcoma. subtypes of mast cell.
MESENCHYMAL TUMORS OF LYMPH NODES
INFLAMMATORY (PSEUDOTUMOR) considered in the differential diagnosis of malignant hematolog-

ical processes and of fever of unknown origin. There may be syn-
MYOFIBROBLASTIC TUMOR
chronous involvement of separate lymph node groups or
involvement of the spleen and para-aortic lymph nodes.
CLINICAL FEATURES
Inflammatory pseudotumor of the lymph nodes is a little-known
condition characterized mainly by cervical or multiple lymph
node enlargement, hematological manifestations, and major con- Histologically, the lesions are characterized by a fibrosing/
stitutional symptoms in most patients. This condition should be inflammatory process that shows marked heterogeneity and
striking variation from case to case. The lesions could be clas- INTRANODAL MYOFIBROBLASTOMA
sified into three different groups:
● Stage I is characterized by the appearance of single or
multiple small foci containing a spindle cell proliferation CLINICAL FEATURES

admixed with a prominent inflammatory background, Intranodal myofibroblastoma is a benign tumor of myofibro-
with complete preservation of the remainder of the nodal blastic origin. The lesion presents as a slowly growing mass,
architecture. mostly in the groin, but it may also be seen in other locations.
● Stage II is characterized by more diffuse involvement of the
It shows no tendency for local recurrence.
lymph node with a marked inflammatory response admixed
with a prominent myofibroblastic proliferation leading to
subtotal effacement of the nodal architecture, often with
extension of the process beyond the capsule into perinodal fat. The lymph node architecture is almost completely replaced by
● Stage III is characterized by almost complete replacement a monomorphic spindle cell lesion separated from the thin resid-
of the lymph node by diffuse sclerosis with scant residual ual lymph node cortex by a dense fibrous capsule. The spindle
inflammatory elements and total loss of the normal nodal cells are arranged in short, interlacing bundles with focal nuclear
architecture.
Recognition of the various stages of this process may be impor-
tant for differential diagnosis with other fibrosing/inflammatory
conditions of lymph nodes.
Secondary features
● Lymph node parenchymal infarction.
● Fibrinoid vascular necrosis.
Cell morphology
● Histiocytes with spindle cell morphology without atypia.
● Myofibroblasts.
● Lymphocytes.
● Plasma cells.
● Various reactive lymphadenopathy such as viral, post-
vaccinial, and drug-induced lymphadenopathy
● Kikuchi’s disease (a)
● Lymphadenopathy in autoimmune disease
● Syphilitic lymphadenitis
● Sinus histiocytosis with massive lymphadenopathy
(Rosai–Dorfman disease)
● Histiocytosis-X
● Intranodal myofibroblastoma
● Castleman’s disease
● Some types of T-cell lymphoma with prominent vascular
proliferation
● Spindle cell neoplasms of lymph nodes of probable
reticulum cell lineage
Special techniques
● In stage I lesions there is striking number of vimentin- and
actin-positive myofibroblastic cells with moderate increase
in CD20/CD45-positive small lymphocytes and polyclonal
plasma cells.
● In stage II there is an emergence of numerous
(b)
CD68⫹ histiocytes admixed with lymphocytes, plasma
cells, and abundant fibromyofibroblastic cells. Figure 10.45 (a–f) Intranodal myofibroblastoma. Spindle cell lesion
● In the stage III lesions, there are few remaining scattered with interstitial hemorrhage, hemosiderin pigment, and amianthoid
CD68⫹ histiocytes and fibroblasts. collagen fibers. (Illustrations courtesy Prof. C. Fisher.)
(c) (e)
(d) (f )
palisading; this gives a low-power impression of schwannoma or ● Leiomyoma

leiomyoma. Widespread interstitial hemorrhage and amianthoid ● Metastatic sarcomatoid carcinoma
or nodular hyalinization of collagen are distinctive features. ● Kaposi’s sarcoma
Secondary features
● Myxoid change. Special techniques
● Metaplastic bone formation.
● The tumor cells are positive for vimentin, smooth
Cell morphology muscle alpha-actin and common muscle actin
(HHF35).
● The cells are spindle-shaped, with eosinophilic cytoplasm ● Desmin and S-100 protein are negative.
and plump and thin tapering nuclei, some of which have
prominent nucleoli.
KAPOSI’S SARCOMA OF THE LYMPH NODE
● Schwannoma See Chapter 13, Soft tissue tumors.
POLYMORPHOUS HEMANGIOENDOTHELIOMA OF
THE LYMPH NODE
PRIMARY VASCULAR TUMORS OF LYMPH NODES
For details, see these entities in Chapter 13, Soft tissue tumors.
Primary vascular tumors of the lymph nodes – other than
Kaposi’s sarcoma – are very rare, but they include the following:
● Hemangiomas of capillary/cavernous, lobular capillary
cellular and epithelioid types may all be seen primarily

within lymph node structures. These lesions vary in size,
and may partly or almost completely replace the nodal
architecture; they appear to develop in the hilum or
medulla. These hemangiomas either represent incidental
Figure 10.46 Angiomyolipoma. Admixture of mature fat cells,
findings in lymph nodes, or are seen with solitary lymph
bundles of smooth muscle cells and thickened-wall vessels.
node enlargement. The evolution of these lesions is benign,
with no evidence of recurrence. Bacillary angiomatosis
may also occur in lymph nodes. node shows irregularly distributed thick-walled vessels in the
● Hemangioendothelioma of epithelioid or spindle cell hilum, extending into the medulla and focally into the cortex
variant may be seen in addition to the polymorphous of the node, eventually becoming more dispersed and
variant which occurs mainly as primary nodal tumor. associated with smooth muscle cells splaying into sclerotic
● Lymphangiomas of lymph nodes usually show stroma. On occasion, it shows the presence of a mixture of
simultaneous multifocal and extranodal involvement, and smooth muscle cells, blood vessels and adipose tissue,
are characterized by cystic endothelium-lined spaces filled haphazardly arranged within a fibrous background, extending
predominantly with lymph fluid. from the hilar region to the lymph node cortex. Such a lesion
may also be termed ‘angiomyolipomatous hamartoma’.
Differential diagnosis ● Leiomyomatosis of the lymph nodes may rise through
● Benign vasoproliferative lesions metaplasia of intranodal decidua or endometriosis by
● Kaposi’s sarcoma myofibroblasts or smooth muscle cells, reflecting the
● Angiosarcoma multipotentiality of the pelvic subcoelomic mesenchyme
● Metastatic cancer that can be found in the peripheral sinus of lymph nodes.
● Leiomyoma may rarely be discovered in lymph nodes. They
SMOOTH MUSCLE PROLIFERATION IN LYMPH show interlacing fascicles of spindle cells with blunt-ended
nuclei that seem to arise from the walls of blood vessels.
NODES (Figure 10.46) ● Angiomyoid proliferation that is seen in the hyaline
vascular variant of Castleman’s disease (see Castleman’s
Various smooth muscle proliferations can be seen in lymph nodes. disease, p. 671).
These include hilar smooth muscle proliferation, lymphan-
giomyomatosis, angiomyolipoma, angiomyomatous hamartoma, Differential diagnosis
leiomyomatosis, leiomyoma and angiomyoid proliferation that
are seen in the hyaline vascular variant of Castleman’s disease.
● Hilar smooth muscle proliferation is an incidental finding
● Metastatic sarcoma
in the hilum of the lymph node, often accompanied by
● Metastatic sarcomatoid carcinoma or melanoma
fibrosis and vascular proliferation.
● Lymphangiomyomatosis is an extremely rare benign Special techniques
disease which affects almost exclusively young women. ● The spindle smooth muscle cells show a positive reaction
It is characterized by extensive proliferation of smooth for smooth muscle actin and sometimes for desmin.
muscle cells within lymphatic vessels and lymph nodes in
mediastinal, retroperitoneal and often pulmonary
locations. Lymphangioleiomyomatosis may be associated
VASCULAR TRANSFORMATION OF SINUSES IN
with the tuberous sclerosis complex, which includes renal LYMPH NODES
angiolipoma, chylothorax and lymph node myomatosis.
● Angiomyolipoma may rarely involve extrarenal structures
CLINICAL FEATURES
such as lymph nodes.
● Angiomyomatous hamartoma is a rare disease with a Vascular transformation of lymph node sinuses, also called
predisposition for the inguinal lymph nodes. The affected ‘stasis lymphadenopathy’ or ‘nodal angiomatosis’ is a rare
Miscellaneous tumors of the lymph nodes 735
disorder which is characterized by transformation of lymph Nodular spindle-cell vascular transformation of lymph node
node sinuses into endothelium-lined, capillary-like channels. is characterized by the presence of either a single spindle cell
Venous or lymphatic obstruction is thought to be the underly- nodule or nodules admixed by sinusoidal growth reminiscent
ing mechanism, and in most cases factors that may contribute of the classic vascular transformation of lymph node sinuses.
to lymphovascular obstruction can be identified, such as tumor The nodule(s) has pushing margins, and consists of interlacing
in the vicinity, vascular thrombosis, heart failure, previous sur- fascicles interspersed by vascular spaces.
gery or radiotherapy. Intra-abdominal lymph nodes are the
most commonly involved group. The process involves either Cell morphology
single or multiple lymph nodes. ● The endothelial cells lining these vascular spaces are either
Nodular spindle-cell vascular transformation of lymph node flat or plump in shape.
is a newly recognized form of vascular transformation of ● The cells seen in nodular spindle-cell vascular
lymph nodes, most frequently seen in the retroperitoneal lymph transformation of lymph node are plump, showing
nodes excised in association with renal cell carcinoma or other elongated nuclei with granular chromatin and one to
malignant tumors. It is occasionally seen in superficial lymph two small nucleoli. Up to three mitotic figures per HPF
nodes in patients with no history of malignant disease. This may be seen.
lesion usually affects one lymph node, but two or more nodes
can be involved. Differential diagnosis
PATHOLOGICAL FEATURES ● Nodal hemangioma or hemangioendothelioma
Vascular transformation of lymph node sinuses is characterized
● Bacillary angiomatosis
by a diffuse or segmental expansion of the subcapsular, inter-
● Inflammatory pseudotumor of lymph node
mediate, and medullary sinuses by vasoproliferative processes.
● Intranodal myofibroblastoma
The intervening lymph node parenchyma usually shows vary-
ing degrees of lymphocyte depletion. The proliferated vessels
● Polymorphous hemangioendothelioma of lymph node
may exhibit various patterns such as ‘cleft-like spaces’ or
● Angiomyomatous hamartoma of lymph node
anastomosing narrow clefts, ‘plexiform channels’, or ‘solid’
spindled to plump cellular foci reminiscent of Kaposi’s sarcoma. Special techniques
These vessels are often associated with variable degrees of ● The spindle cells stain for vimentin and smooth-muscle
fibrosis or sclerosis. The vascular spaces are either empty, filled actin and for CD34.
with lymph-like fluid, congested with blood, or occasionally ● The endothelial cells lining the vascular spaces show
thrombosed. Extravasation of red cells is commonly seen. The Factor VIII, CD31, and CD34 positivity.
perinodal blood vessels are often thickened. ● The cells are negative for desmin, keratin and S-100 protein.
MISCELLANEOUS TUMORS OF THE LYMPH NODES
BACILLARY ANGIOMATOSIS
LYMPH NODE INCLUSIONS (Figure 10.47)
Various types of benign, non-lymphoreticular tissue can be seen

within lymph regional lymph nodes. These are usually found in
the capsule or cortical areas, and rarely involve whole lymph
nodes.
Breast epithelial inclusions: these develop from epithelial
entrapment during embryonal development, and occur exclu-
sively in axillary nodes in females. These lesions may resemble
normal breast lobules, or they may show pathological changes (a)
in the form of hyperplastic epithelium, cystic change with
papillary, squamous or apocrine lining epithelium and rarely Figure 10.47 Examples of lymph node inclusions. (a, b) Inclusions
carcinomatous change. of nevus cells. (c) Inclusions of mullerian glands.
Mullerian inclusions: these are a relatively common type of

glandular inclusion which is present in 1–40% of pelvic or para-
aortic glands. The lesion occurs almost exclusively in women,
and very rarely in men. It represents metaplastic proliferation
of peritoneal mesothelium derived from embryonal coelomic
epithelium. This is often associated with endosalpingiosis, salp-
ingitis, salpingitis isthmica nodosum and cervical or ovarian
malignancy. The glandular inclusions resemble normal endome-
trial or tubal epithelium, or they may look like endosalpangiosis
seen in the peritoneum or serosal surface of the tubes and ovaries.
They may show papillary structures and psammoma bodies,
and rarely undergo neoplastic transformation. Endometrial
stroma may sometimes be seen surrounding these inclusions
(nodal endometriosis).
(b) Nevocytic inclusions: these arise either as a result of arrest of
melanocytic migration from the neural crest or from nevocytic
differentiation of neural crest tissue within lymph nodes. They
are most commonly seen in the capsule or marginal sinuses of
lymph nodes, and very rarely within the lymph node parenchyma.
The most commonly affected nodes are the axillary group, but
they may also be seen in inguinal and cervical lymph nodes.
Blue nevus is the most common type of nevocytic inclusion.
Salivary gland inclusions are seen most commonly within
intra- or extra-parotid lymph nodes, and rarely within sub-
maxillary nodes. They develop from epithelial entrapment dur-
ing embryonal development. Benign or malignant salivary
tumors may originate in these inclusions, with Warthin’s tumor
being the most common type.
Thyroid follicle inclusions are seen in cervical lymph nodes.
The majority of these inclusions represent metastasis from
occult carcinoma of the thyroid, though some represent benign
(c) inclusions.
Other rare types of epithelial inclusion include pancreatic tis-
sue in celiac nodes, colonic glands in mesenteric glands, and
renal tubular epithelium within regional lymph nodes.
Decidual inclusions: these may develop from decidual change
of endometrial stroma within lymph nodes during pregnancy, Differential diagnosis
or from hormonally receptive mullerian-type cells. Decidual ● Metastatic tumors
inclusions may undergo transformation into smooth muscle
fibers. The presence of ectopic decidua in pelvic lymph nodes
from patients with squamous carcinoma of the cervix makes MYCOBACTERIUM AVIUM-INTRACELLULARE-
evaluation for metastatic disease difficult due to the light- INDUCED SPINDLE CELL PSEUDOTUMOR
microscopic similarity between decidua and sheets of squamous
epithelial cells. In the absence of obvious squamous differenti-
ation (i.e., intercellular bridges, dyskeratosis, and keratin CLINICAL FEATURES
‘pearl’ formation) – as is frequently the case with squamous Spindle cell pseudotumor caused by Mycobacterium avium-
carcinoma of the cervix – the light-microscopy features that are intracellulare is a rare, infectious disease that mimics a mes-
most useful in distinguishing squamous carcinoma from decidua enchymal tumor. It occurs in the skin, lymph nodes or bone
include the presence of well-defined nests of cohesive cells, marrow of patients with AIDS, or in immunosuppressed trans-
nuclear hyperchromasia, and cellular pleomorphism. plant patients. The formation of a pseudotumor in this lesion
Mesothelial inclusions: these are an extremely rare type of may represent a complex host–microbe interaction.
inclusion, seen only in mediastinal nodes. They may represent
benign metastasis from mesothelial cells found in pleural cav-
ity, especially in association with inflammation which results in
distension of lymphatic allowing free-floating mesothelial cells The lymph node architecture is completely, or almost com-
to enter and drain into the mediastinal nodes. They are present pletely, replaced by spindle cells arranged in a storiform pattern
either as single cells or as clusters of mesothelial cells within the intermixed with sparse inflammatory cells. A significant vaso-
subcapsular sinuses. proliferative component may be seen.
Miscellaneous tumors of the lymph nodes 737
Cell morphology history with the aid of tumor markers and tissue immunohis-
● The constituent cells are predominantly histiocytic. tochemistry may help in the identification of the primary
● Most of the spindle cells are phagocytic cells that origin.
contained large amounts of mycobacteria. Malignant melanoma: Metastatic malignant melanoma
within lymph node may be the first manifestation of the dis-
Differential diagnosis ease. In such cases – and especially when the histological features
are not the usual pigmented-type melanoma – the pathologist
● Metastatic or primary smooth-muscle neoplasm
may misinterpret the lesion as a carcinoma or sarcoma. The use
● Myofibroblastoma
of one or two of the melanoma markers with other immuno-
staining is essential in such cases.
● Idiopathic inflammatory pseudotumor
Axillary lymph node metastasis from an occult breast carci-
● Spindle and epithelioid hemangioendothelioma
noma: Occult primary breast carcinoma is uncommon. Most
● Metastatic MFH
reported series encompass large periods of time with great vari-
ability in diagnostic and treatment approaches. In the presence of
axillary metastasis from an unknown breast primary, an exten-
● Histiocytoid leprosy
sive work-up evaluation is not necessary. An axillary dissection
● Dendritic cell sarcoma
is recommended to provide prognostic indicators as well as
Special techniques local control. A breast-conservation approach seems to be fea-
sible, without affecting the local control and survival.
● Modified Ziel–Neelsen stains demonstrate intracellular
Metastatic cancer in thoracic lymph nodes without a primary
acid-fast bacilli.
site: This is a rare occurrence, and its origin is often difficult to
● The organisms are also PAS-positive, and stain dark brown
assess, but can be either of pulmonary, endogenous, or from
with methanamine silver.
extrathoracic sites. Survival can be increased by surgery.
● Occasional PAS-positive hyaline globules are seen.
Metastatic cancer in cervical lymph nodes: Metastatic cancer
● The spindle cells are positive for S-100 protein and CD68,
of unknown primary site occupies between 0.5 and 10% of all
and occasionally also for desmin.
diagnosed cancer patients, and includes various tumors with
diverse responses to systemic chemotherapy. Adenocarcinoma
SECONDARY TUMORS IN LYMPH NODES is the most common subtype. Almost 3% of all malignant
(Figure 10.48) ENT-tumors are cervical lymph node metastases of unknown
primary.
A variety of tumors can metastasize to lymph nodes, the most The management of such cases should be adapted according
common being the various carcinomas, followed by melanoma. to the site of nodal disease and the histopathological types.
Some sarcomas such as epithelioid sarcoma, synovial sarcoma Poorly differentiated carcinoma is best treated with radiother-
and leiomyosarcoma may disseminate via the lymphatic system apy, squamous cell carcinoma with radiotherapy and excision,
in addition to blood vessels. Alveolar rhabdomyosarcoma may and non-papillary adenocarcinoma by radical thyroidectomy
sometimes present as generalized lymphadenopathy. and neck dissection.
The problems of lymph node metastasis occur when the pri- Adenocarcinoma has no standard treatment, rarely responds
mary lesion is not identified. In these cases, a careful clinical to conventional treatment, and has a poor survival rate.
(a) (b)
Figure 10.48 (a, b) Secondary-metastatic melanoma.The primary tumor was of unknown origin, but immunohistochemical markers were
in keeping with melanoma (S-100 protein-, HMB45- and melan-A positive).
Depending on the patient and tumor characteristics, reported error. The tumor type that most frequently causes cystic change
5-year actuarial survival rates for patients with cervical nodal is thyroid papillary carcinoma, followed by squamous cell car-
metastasis from an unknown primary carcinoma range from cinoma, tumors of unknown origin, serous papillary carcinoma
18% to 63%. Prognostic factors for survival include N-stage, of the ovary or endometrium, and malignant melanoma.
number of nodes, grading, extracapsular extension, and per- Cystic change is observed most commonly in the head and neck
formance status. Current knowledge suggests that lymph node region lymph nodes, and is an important cause of diagnostic
metastases in the lower neck (supraclavicular fossa and poste- error on fine-needle aspiration counts (FNAC) as it may
rior triangle) are associated with a poor survival. yield negative, hypocellular or suspicious cystic aspirations.
Cystic change in metastatic lymph nodes: This occurs in cer- FNAC should therefore be repeated in patients with known
tain types of tumors, and is an important cause of diagnostic malignancy.
10.3 TUMORS OF THE SPLEEN

Bridget S Wilkins
Approach to the diagnosis of splenic tumors 738 Littoral cell angioma 741
Splenic tumors 740 Micronodular T-cell/histiocyte-rich large B-cell lymphoma 741
Hairy cell leukemia 740 Splenic marginal zone lymphoma 742
GENERAL COMMENTS may be associated with hypo- rather than hypersplenism if there
is significant infiltration of red pulp cords (e.g., by neoplastic
Tumors of the spleen are rarely encountered by the general sur- cells or amyloid) or if cordal macrophages become crippled by
gical pathologist; rather, they are more often seen in autopsy their content of abnormal storage products (e.g., Gaucher’s and
material or in larger regional centers. In this subchapter, an Neimann–Pick diseases).
approach to the diagnosis of tumors of the spleen is presented
as an algorithm, and the less rare entities that are seen prima- MACROSCOPIC PATTERN ANALYSIS
rily or mainly in this organ are described.
Solid pattern
Uniform parenchyma
APPROACH TO THE DIAGNOSIS OF ● Red and congested [myeloproliferative diseases; hairy cell
SPLENIC TUMORS leukemia (HCL); diffuse splenic marginal zone B-cell

lymphoma (SMZBL)].
● Pale (amyloidosis; macrophage storage disorders;
CLINICAL FEATURES Langerhans’ cell histiocytosis).
Splenomegaly, hypersplenism, hyposplenism, splenic rupture, Micronodular parenchyma [small B-cell lymphomas other than
and localized lesion may be detected using various imaging HCL; micronodular T-cell-rich diffuse large B-cell lymphoma;
techniques. miliary tuberculosis (TB)].
Hypersplenism describes a spectrum of peripheral blood Irregular single or multiple large nodules in parenchyma
● Pale/white (diffuse large B-cell lymphoma; large T-cell
cytopenias occurring due to increased red pulp sequestration
and destruction of cells from the circulation. It is usually accom- lymphomas; classical Hodgkin’s disease; nodular
panied by splenomegaly. lymphocyte and histiocyte-predominant Hodgkin’s disease;
Hyposplenism is reflected in a failure of red cell pitting by inflammatory pseudotumor; nodular lymphoid
splenic macrophages, leaving Howell–Jolly bodies and other hyperplasia; metastatic carcinoma).
● Dark red (splenic hamartoma; hemopoietic nodule in
inclusions in circulating red cells. The lifespan of the red cells
is prolonged. More crucially, hyposplenism predisposes to chronic myeloproliferative disease; metastatic carcinoma).
potentially life-threatening infections, particularly with encap-
sulated bacteria such as Streptococcus pneumoniae, Neisseria Cystic pattern
meningitidis and Haemophilus influenzae. This susceptibility ● Single, unilocular cysts (mesothelial inclusion cyst;
reflects impairment of both cordal macrophage and marginal epidermoid cyst; hydatid cyst).
zone functions. Hyposplenism is typically an accompaniment ● Localized multilocular cystic change (mesothelial inclusion
of asplenia or hyposplenia (congenital or surgical) or splenic cyst; hemangioma; lymphangioma; littoral cell angioma;
atrophy (e.g., in celiac disease and HIV infection). Splenomegaly angiosarcoma).
Tumors of the spleen 739
● Diffuse multilocular cystic change (hemangiomatosis; Step 5

lymphangiomatosis; peliosis; angiosarcoma). If lymphoid cells are normal, are immature myeloid cells pres-
ent? If so, which tissue compartments are involved?
MICROSCOPIC PATTERN ANALYSIS ● Recognizable erythropoiesis and/or megakaryocytes in red
pulp (may just be incidental or reflect significant

Diffuse pathology
extramedullary hematopoiesis; consider extent, cytological
Step 1 detail and hematological context).
● Recognizable or immunohistologically proven immature
Which compartments of the spleen are preferentially affected?
● Predominantly red pulp involvement (myeloid, macrophage and mature granulocytes in red pulp and/or peri-arteriolar
and vascular pathologies; hairy cell lymphoma; large lymphoid sheath (PALS) (significant extramedullary
granular T/NK lymphocyte proliferations). hematopoiesis, implying underlying myeloproliferative
● Predominantly white pulp involvement (lymphoid disorder or, rarely, underlying myelodysplastic syndrome).
● Immunohistochemically proven non-maturing primitive
pathologies).
● Both compartments equally involved (lymphomas with hematopoietic cells in red pulp (acute myeloid leukemias).
● Correlate with clinical, hematological and cytogenetic
tendency for leukemic spread; miliary granulomatous
inflammation). findings to confirm diagnosis and categorize according to
WHO classification.
Step 2
Step 6
Is the process solid or multicystic? (see macroscopic differential
diagnosis above): Are macrophages present? If so, which tissue compartments are
● If multicystic, proceed to Step 7 below.
involved?
● Red pulp and/or PALS and/or white pulp follicles
● If solid, is there excess or abnormal distribution of
lymphoid cells? If yes, follow Steps 3 and 4 below. (granulomatous inflammation; primary or secondary
● If no, proceed to Step 5.
storage disorders; Langerhans’ histiocytosis; systemic
mastocytosis mimicking macrophage infiltration).
● Mainly red pulp (storage disorders).
Step 3
● Peri-arteriolar lymphoid sheaths (mastocytosis, which is
If lymphoid cells appear abnormal, are they predominantly
usually accompanied by fibrosis; Langerhans’ cell
small or large?
histiocytosis).
● If predominantly small (differential diagnosis of small
● Active germinal centers in white pulp follicles (tingible
B-cell lymphomas as at other sites; also see Step 4 below).
body macrophages involved by primary storage disorders).
● If predominantly large (differential diagnosis of large-cell
● Confirm diagnosis using cytological criteria, stains for
lymphomas as at other sites; also see Step 4 below).
mycobacteria and fungi, immunohistochemistry (CD68,
● Mixed, with definite blast cells present (acute Epstein–Barr
tryptase, c-kit). Always ensure that TB has been excluded.
(EBV) infection; variants of B-cell chronic lymphocytic
Biochemical analyses (glucocerebroside, sphingomyelinase,
leukemia (B-CLL), follicular lymphoma (FL) and SMZBL
etc.) performed using blood cells or cultured tissue cells are
with higher blast cell content than typical; multinodular
required for confirmation of primary storage disorders.
T-cell-rich diffuse large B-cell lymphoma, Hodgkin’s disease).
Correlate histology with clinical history (particularly
Step 4 evidence of idiopathic thrombocytopenic purpura (ITP),
hematological neoplasia elsewhere or therapeutic drug use)
If lymphoid cells are abnormal, which tissue compartments are to exclude secondary storage disorders.
involved (particularly, germinal centers, marginal zones, peri-
arteriolar lymphoid sheaths, red pulp)? Step 7
● Germinal centers expanded (FL; SMZBL with follicular
If no abnormal lymphoid, myeloid cells or and spleen is multi-
colonization). cystic, confirm whether cyst lining cells are endothelial (lym-
● Germinal centers atrophic with or without expanded
phatic, sinusoidal, capillary), epithelial or mesothelial using
marginal zones (SMZBL; LPL; B-CLL or MCL with histological and immunohistochemical criteria as for such cell
marginal zone differentiation). types elsewhere.
● Peri-arteriolar lymphoid sheaths (T-PLL: other CD4-
● Use standard histological criteria to determine whether
positive T-cell lymphomas). benign or malignant.
● Red pulp [B-CLL; B-cell prolymphocytic leukemia (B-PLL);
● If no lining to cysts, consider post-infarction/embolization
SMZBL; lymphoplasmacytic lymphoma (LPL); mantle cell or peliosis.
lymphoma (MCL); T-cell prolymphocytic leukemia
(T-PLL); other CD8-positive T-cell lymphomas; NK cell Localized pathology
proliferations)].
● Confirm immunophenotype as for lymphomas at other
Unilocular cyst
sites; correlate with clinical history, cytological and ● Thick, trabeculated wall – epidermoid cyst.
hematological findings; categorize according to World ● Thin wall – parasitic, post-infarction or mesothelial
Health Organization (WHO) classification. inclusion cyst.
Solitary nodule or localized group of solid nodules

● Lymphoid cells predominate: diagnose as for
lymphoproliferative disease elsewhere.
(N.B. May be hyperplastic, not neoplastic).
● Epithelioid cells predominate: diagnose as for
carcinoma/melanoma/germ cell tumor elsewhere.
● Spindle cells predominate: consider inflammatory
pseudotumor, TB, bacillary angiomatosis, metastatic
sarcomatoid carcinoma or sarcoma.
● Small vessels predominate: consider splenic hamartoma,
hemangioma, bacillary angiomatosis.
SPLENIC TUMORS
HAIRY CELL LEUKEMIA Figure 10.49 Hairy cell leukemia. Note the absence of organized
white pulp around this penicillar arteriole.The infiltrating cells have
oval nuclei and abundant cytoplasm. Red cell leakage is evident in
CLINICAL FEATURES the background stroma.
Patients are usually middle-aged or older adults, predominantly
males, and present with splenomegaly in the absence of signif- Secondary changes
icant lymphadenopathy. Neutropenia or monocytopenia may Peliosis-like stromal changes and more widespread endothelial
be noted, but occasionally automated blood cell counting indi- damage occur in association with the increased reticulin depo-
cates a monocytosis due to mis-identification of hairy cells as sition stimulated by the presence of infiltrating hairy cells.
monocytes. Circulating lymphocytosis is usually mild, but the Incidental extramedullary erythropoiesis may be found ran-
cells have distinctive appearances with oval or bean-shaped nuclei domly distributed throughout the abnormal splenic tissue.
and moderately abundant pale cytoplasm with peripheral pro- Bone marrow is almost always involved, either packed with
jections. There may be a small paraprotein (usually IgM). Auto- a similar (although often more widely spaced) lymphoid infil-
immune cytopenias are relatively uncommon; hypersplenism or trate replacing hematopoietic tissue or appearing hypoplastic.
hyposplenism may be present, and splenic rupture following Involvement is usually diffuse but may be patchy, with normal
minor trauma occurs occasionally. Despite the sometimes very intervening hematopoietic tissue. In all cases, stromal reticulin
large spleen size, patients may be hyposplenic, with consequent is increased in infiltrated areas. Extravasated non-nucleated red
circulating red cell abnormalities and susceptibility to infection cells are usually abundant in the stroma.
by encapsulated bacteria. Hairy cell leukemia usually responds
well to interferon-alpha treatment, chemotherapy (deoxyco- Cell morphology
formycin or 2-chlorodeoxyadenosine) and/or splenectomy.
The cells form a monotonous population with bland, oval or
bean-shaped nuclei. They may have pale or empty-appearing
cytoplasm. Mitotic figures are rare.
Macroscopic
The spleen is enlarged from twice normal size to a weight of
several kilograms. Its capsule is normal, and the parenchyma is ● B-cell chronic lymphocytic leukemia
diffusely congested, appearing pink to dark red with loss of ● Lymphoplasmacytic lymphoma
normal pinhead white pulp nodules. Focal infarction is uncom- ● Mantle cell lymphoma
mon, but small hemorrhagic cysts may be formed due to sec- ● Splenic marginal zone B-cell lymphoma (diffuse
ondary peliosis-like stromal damage caused by tumor cell variants)
infiltration. Hilar lymph nodes are usually inapparent. ● Hairy cell leukemia variant [this resembles B-cell
prolymphocytic leukemia, and the cells are tartrate-
Microscopic resistant acid phosphatase (TRAP)-negative]
Parenchymal white pulp nodules are completely or nearly com-
pletely absent. The tissue is diffusely infiltrated by relatively Special techniques
well-spaced small lymphoid cells with pale or empty-appearing ● Immunohistochemistry, as for small B-cell lymphomas
cytoplasm. The ‘spaced out’ nature of this infiltrate is less at other sites. The typical immunophenotype of hairy
marked than in hairy cell leukemia infiltrates in bone marrow. cell leukemia in paraffin sections is: CD20⫹, CD79a⫹,
The structure of red pulp cords and sinusoids is severely dam- CD5⫺, CD10⫺, CD23⫺, BCL2⫹, BCL6⫺, cyclin
aged by the infiltrate; reticulin staining highlights loss of the D1⫹ or ⫺, TRAP⫹, antibody clone DBA44⫹. Ki-67
normal alternating pattern of cords and sinusoidal lumens. staining usually shows fewer than 10% proliferating cells.
Tumors of the spleen 741
● Flow cytometry using blood or aspirated bone marrow Secondary changes

cells also shows moderate to strong membrane IgM Longstanding littoral cell angiomas may show evidence of sec-
expression CD79b⫹, CD103⫹, CD11c⫹ and antibody ondary changes due to hemorrhage, thrombosis and organiza-
clone FMC7⫹. tion. Incidental extramedullary erythropoiesis and sequestered
● Hairy cells are post-germinal center B cells with megakaryocytes may be found throughout the background
hypermutated immunoglobulin heavy-chain genes. No splenic red pulp.
consistent cytogenetic or molecular genetic abnormalities
have been found in hairy cell leukemia. Cell morphology
The endothelial cells have bland, round or oval, pale nuclei and
LITTORAL CELL ANGIOMA abundant cytoplasm. The latter is variably eosinophilic and
may appear granular. Mitotic figures are rare.
CLINICAL FEATURES
Most patients are adults, although occasional examples pre-
senting in childhood have been reported. Splenomegaly may be
● Lymphangioma
present. Rarely, as with other sizeable vascular proliferations in
● Cavernous hemangioma
the spleen (e.g., lymphangiomas and usual types of hemangioma),
● Hemangioendothelioma
patients may present with thrombocytopenia due to platelet
● Angiosarcoma
sequestration within the tumor. However, most commonly this
lesion is detected incidentally during abdominal imaging or
● Post-infarction necrotic cyst
laparotomy performed for investigation of unrelated disease.
Splenectomy is curative. Special techniques
Immunohistochemistry. The endothelium of littoral cell angiomas
PATHOLOGICAL FEATURES (Figure 10.50) has immunophenotypic characteristics similar to those of normal
splenic sinusoidal endothelium. The cells express CD31 and von
Macroscopic Willebrand factor, but are negative or only weakly positive for
The spleen may be enlarged, or of overall normal size. Littoral CD34. Unusually for endothelium, they express CD8 and bcl-2.
cell angiomas vary from a few millimeters to many centimeters They show variable expression of CD68, which has been inter-
in diameter. They are usually solitary, but sometimes multiple, preted by some as evidence of hybrid endothelial/macrophage
forming well-defined cystic and solid, hemorrhagic masses. differentiation by sinusoidal lining cells. However, it should be
remembered that CD68 is a lysosome-associated antigen pres-
ent in a variety of cell types and is not entirely macrophage-
specific. Nonetheless, it is true that this antigen is not expressed
by endothelial cells elsewhere in the body.
MICRONODULAR T-CELL/HISTIOCYTE-RICH
LARGE B-CELL LYMPHOMA
CLINICAL FEATURES
Presentation is usually in adulthood, with a wide age range
and slight male predominance. Most patients present with
splenomegaly, anemia and constitutional ‘B’ symptoms. Low-
volume lymphadenopathy is also present in some cases. This is
a newly described variant of spleen-based lymphoma, and
follow-up data are, at present, limited. However, the tumor
Figure 10.50 Littoral cell angioma.Typical organization of vascular appears to behave aggressively, despite treatment with
channels resembling normal splenic sinusoidal pattern. Note the chemotherapy regimes that have a good success rate in node-
prominent ‘hobnail’ endothelial cells lining the vascular lumens.
based diffuse large B-cell lymphoma.
Microscopic PATHOLOGICAL FEATURES (Figure 10.51)

Littoral cell angioma is typically unencapsulated but sharply
demarcated from the background spleen parenchyma. It con- Macroscopic
sists of clustered vascular spaces lined by large, plump endothe- T-cell/histiocyte-rich large B-cell lymphoma mimics low-grade
lial cells. Papillary structures covered by such cells may be non-Hodgkin lymphoma in the spleen by forming miliary nod-
prominent, particularly in larger, more complex lesions. ules throughout the parenchyma. These nodules replace white
● Classical Hodgkin’s disease (particularly lymphocyte-rich

subtype)
● Nodular lymphocyte- and histiocyte-predominant
Hodgkin’s disease
● Diffuse granulomatous inflammatory processes
Special techniques
● Immunohistochemistry, as applied in other tissues for
investigation of the lymphoma types listed above. A typical
immunophenotype of the large lymphoid cells in this entity
is: CD20⫹, CD79a⫹, CD5⫺, CD10⫺, CD23⫺,
CD30⫺ (occasionally positive), CD15⫺, epithelial
membrane antigen (EMA) variably ⫹, bcl-2 variably ⫹,
BCL6⫹, EBV-LMP1⫺ (also EBV-EBER ⫺ by in-situ
hybridization), OCT-2⫹.
Figure 10.51 Micronodular T-cell-rich large B-cell lymphoma. Poorly

cellular nodules with occasional large atypical cells. SPLENIC MARGINAL ZONE LYMPHOMA
pulp structures, and usually also involve the red pulp. They CLINICAL FEATURES
vary in size and may coalesce to form larger, more irregular
This lymphoma occurs in middle-aged and older adults, with
masses of several millimeters diameter. This growth pattern is
no overall male or female predominance in its incidence.
notably different from that seen in typical diffuse large B-cell
Patients present with splenomegaly in the absence of significant
lymphomas in the spleen, which form one or more solid, white
lymphadenopathy. In a proportion of patients, the presenting
tumor masses against a background of normal or more dif-
features include peripheral blood lymphocytosis, with or with-
fusely infiltrated splenic parenchyma.
out a paraprotein (usually IgM and of low or modest concen-
tration). Auto-immune cytopenias are relatively uncommon,
Microscopic
although hypersplenism may be present. Treatment with
Individual nodules are pale, fibrotic and lymphocyte-depleted, single-agent chemotherapy usually controls the disease well for
some showing hemorrhage and necrosis. They contain long periods, while similar long-term complete or partial remis-
macrophages plus lymphoid cells of small, medium and large sion can be achieved by splenectomy.
sizes. The latter are distinctly in the minority and may be diffi-
cult to identify without immunostaining. Splenic hilar lymph PATHOLOGICAL FEATURES (Figure 10.52)
nodes, in cases where these have been available for study,
have shown a similar pattern of micronodular, mixed cell Macroscopic
infiltration. The spleen is enlarged from twice normal size to several kilo-
grams in weight. Its capsule is normal, and the parenchyma
Secondary changes
Incidental extramedullary erythropoiesis may be found, plus
Gamna Gandy bodies associated with areas of hemorrhage/
necrosis.
Bone marrow involvement has been present in most patients
reported to date, with small lymphocyte-rich nodular or para-
trabecular deposits containing scant large blast cells.
Cell morphology
● The large cells variably resemble centroblasts,
Reed–Sternberg cells and the ‘popcorn’ cells of lymphocyte
and histiocyte-predominant Hodgkin’s disease.
● Splenic marginal zone B-cell lymphoma
● B-cell chronic lymphocytic leukemia
● Follicular lymphoma Figure 10.52 Splenic marginal zone lymphoma. Note the typical
● Mantle cell lymphoma marginal zone cell mix of lymphocytes, lymphoplasmacytoid cells
● Lymphoplasmacytic lymphoma and occasional larger blast cells.
Tumors of the thymus 743
usually shows diffuse miliary white nodularity. Individual nod- Cell morphology
ules are generally of uniform size, from 2 mm to 10 mm diame- A typical marginal zone cell mixture consists of small lympho-
ter in different patients. Focal infarction is uncommon, forming cytes, lymphoplasmacytoid cells, scattered blast cells resem-
typical subcapsular wedge-shaped abnormalities if present. bling small centroblasts, and occasional mature plasma cells.
Circulating blood lymphocytes may be unremarkable in cytol-
Microscopic ogy or have a villous appearance, with coarser cytoplasmic pro-
Parenchymal white pulp nodules are uniformly expanded and jections than those seen in hairy cell leukemia.
typically have small, atrophic germinal centers surrounded by
expanded marginal zones. Red pulp cords may contain abun- Differential diagnosis
dant small satellite nodules of marginal zone cells centered on ● B-cell chronic lymphocytic leukemia
capillaries or small epithelioid granulomas. In patients with ● Lymphoplasmacytic lymphoma
peripheral blood lymphocytosis, red pulp involvement is more ● Mantle cell lymphoma
diffuse and extensive, with monotonous small lymphocytes ● Hairy cell leukemia
occupying cords and sinusoidal lumens. Splenic hilar lymph ● Follicular lymphoma
nodes are frequently enlarged and show nodular infiltration by
small lymphocytes. Marginal zone distribution and cytological Special techniques
features are not evident at these sites, but the immunopheno-
● Immunohistochemistry, as for small B-cell lymphomas at
type (see below) is identical to that of the neoplastic lymphoid
other sites. The typical immunophenotype of splenic
cells within the spleen.
marginal zone B-cell lymphoma in paraffin sections is:
CD20⫹, CD79a⫹, CD5⫺, CD10⫺, CD23⫺, BCL2⫹,
Secondary changes BCL6⫺, cyclin D1⫺, TRAP⫺, DBA44⫺. Ki-67 staining
Hypersplenism may cause increased sequestration of red cells, usually shows fewer than 10% proliferating cells.
neutrophils and platelets (in any combination) within red pulp ● Flow cytometry using blood or aspirated bone marrow
cords. Endothelium-lining sinusoids may appear activated, cells also shows moderate to strong membrane IgM
with cuboidal enlargement of individual cells. Sequestered expression (sometimes with co-expression of IgD),
megakaryocytes in cords may also be increased and incidental CD79b⫹ and FMC7⫹.
extramedullary erythropoiesis may be seen within sinusoids. ● Cells of splenic marginal zone B-cell lymphoma
Bone marrow staging is almost always positive, with nodu- demonstrate both non-mutated and hypermutated
lar, paratrabecular and interstitial infiltration by small B cells. immunoglobulin heavy-chain genes, sometimes with
The neoplastic lymphoid cells in aspirated bone marrow may evidence of ongoing mutation. Trisomy 3 occurs in a small
appear villous, sometimes with distinctive bipolar cytoplasmic proportion of cases (probably a late genetic event, not
processes. Marginal zone cell cytology is usually not apparent causal). Translocations found in extranodal marginal zone
in bone marrow trephine biopsy sections. Intrasinusoidal infil- lymphomas of MALT type are absent, but loss of material
tration is common and distinctive, although not completely from 7q21–35 has been described in up to 40% of splenic
specific. marginal zone B-cell lymphomas.
10.4 TUMORS OF THE THYMUS

Awatif I Al-Nafussi
Ectopic thymic and related branchial tumors 744 Thymic hyperplasia 755
Carcinoma showing thymus-like element (CASTLE) 744 Thymic Hodgkin and non-Hodgkin lymphoma of the thymus 755
Ectopic hamartomatous thymoma 744 Thymolipoma 755
Spindle epithelial tumor with thymus-like element Rare thymus tumors 756
(SETTLE) 745 Germ cell tumor 756
Neuroendocrine tumors 745 Sarcoma 756
Thymic cysts 747 Secondary tumors 756
Acquired multilocular thymic cysts 747 Solitary fibrous tumor 756
Congenital thymic cysts 747
Thymic epithelial tumors 747

Thymic carcinoma 747
Thymoma 749
GENERAL COMMENTS ECTOPIC HAMARTOMATOUS THYMOMA
The thymus is a complex lymphoid and epithelial organ, with het-

erogeneous cell types giving rise to various related histological CLINICAL FEATURES
types of thymoma and other tumors and tumor-like conditions. Ectopic hamartomatous thymoma is a rare benign tumor that
These tumors are a common cause of an anterior mediastinal is most likely derived from thymic anlage. Possible sources of
mass, and may be either benign or malignant. Thymoma and the ectopic thymic tissue include the third pharyngeal pouch,
thymic carcinoma are epithelial malignancies with distinct clini- the fourth pharyngeal pouch, and the cervical sinus of His.
copathological features. Thymic carcinoid is a rare aggressive Ectopic hamartomatous thymoma occurs mainly in men, and is
neuroendocrine malignancy. Thymolipoma is a benign neoplasm, usually seen in the subcutaneous tissue or deep soft tissue of the
and ectopic hamartomatous thymoma is seen in the subcutaneous lower neck in the vicinity of the sternoclavicular joint or
tissue or deep soft tissue of the lower neck in the vicinity of the suprasternal area. The lesions may reach up to 19 cm in diam-
sternoclavicular joint or suprasternal area. Thymic cysts are either eter, but are generally less than 8 cm.
congenital or acquired, and may be associated with a thymic
malignancy. True thymic hyperplasia and thymic lymphoid hyper-
plasia may enlarge the thymus and simulate a neoplasm. Hodgkin PATHOLOGICAL FEATURES (Figure 10.53)
and non-Hodgkin lymphoma may primarily or secondarily Ectopic hamartomatous thymoma demonstrates biphasic com-
involve the thymus. Primary mediastinal germ cell tumors may ponents; monomorphic spindle cells arranged in broad fascicles
arise primarily within the thymus and include mature teratoma, admixed with fat cells and epithelial components of variable
seminoma, and non-seminomatous malignant germ cell tumors. appearance. The latter varies from small tubular structures
lined by squamous epithelium or sometimes by glandular
epithelium (cuboidal cells with occasional goblet cells), irregu-
ECTOPIC THYMIC AND RELATED lar solid nests of squamous epithelium with focal keratinization
BRANCHIAL TUMORS or irregularly anastomosing strands or cords of primitive cells
with squamoid features. In places, the epithelial structures
CARCINOMA SHOWING THYMUS-LIKE ELEMENT
(CASTLE)
CLINICAL FEATURES
Carcinoma showing thymus-like differentiation (CASTLE) is a
rare malignancy that occurs in the soft tissues of the neck or in
the thyroid gland. When it occurs in the thyroid, it is difficult to
differentiate from thyroid tumor. CASTLE of the thyroid has a
much better prognosis than that of the primary squamous car-
cinoma of the thyroid, with a median survival time of 10.5 years.
(a)
Tumors of the CASTLE type are histologically similar to
thymic carcinoma of the lymphoepithelioma or squamous cell
variety. It has been postulated that this family of tumors arises
either from ectopic thymus or remnants of branchial pouches
which retain the potential to differentiate along the thymic line.
The tumor is often separated into lobules by fibrous tissues
infiltrated with small lymphocytes, and is composed of poorly
differentiated squamoid cells. Thymus-like tissue with Hassall’s
corpuscles is often seen adjacent to the tumor cells.
● Anaplastic thyroid carcinoma
● Follicular dendritic cell sarcoma
● Primary squamous carcinoma of the thyroid
(b)
Special techniques
Figure 10.53 (a, b) Ectopic hamartomatous thymoma, biphasic
● The tumor cells are positive for cytokeratin and CD5, but components; monomorphic spindle cells arranged in broad fascicles
negative for thyroglobulin. admixed with fat cells and epithelial component of variable
● The tumor cells are also positive for bcl-2 and mcl-1. appearance.
appear to blend with the spindle cell background component. PATHOLOGICAL FEATURES
Scattered throughout the lesion, especially in the spindle cell
This tumor is characterized by a spindle cell proliferation
areas, are small lymphocytes and adipocytes. Rarely, bundles of
showing varying degrees of atypia and mitotic activity.
spindle-shaped striated muscle fibers are seen encircling the
Transitions could be seen with areas that show the features of
epithelial structures. The myoid cell can be a predominant fea-
conventional spindle cell thymoma. Rarely, areas showing fea-
ture, and transition from spindle epithelial cell to myoid cell
tures of poorly differentiated (lymphoepithelioma-like) carci-
may occur. Rare examples have been reported which shows a
noma and anaplastic carcinoma can also be observed. Focal
dysplastic glandular component, some with cribriform pattern,
ductular component may be seen in association with the spin-
while others show adenocarcinomatous foci.
dle cell element. The presence of prominent mitotic activity and
necrosis may represent an aggressive variant.
Secondary features
● Psammoma bodies. Differential diagnosis
● Synovial sarcoma
Cell morphology
● The spindle cells are bland-looking, and have pale Secondary features
eosinophilic cytoplasm and narrow pointed vesicular
nuclei with a single inconspicuous nucleolus.
● Focal necrosis (rare).
● Mitotic figures are usually absent.
● Calcification (rare).

● Glandular nerve sheath tumor ● Strong positivity of the spindle tumor cells for CAM5.2
● Biphasic synovial sarcoma cytokeratin.
● Adnexal tumors ● The cells are usually negative for epithelial membrane
● Soft tissue adamantinoma antigen (EMA), carcinoembryonic antigen (CEA), actin,
● Ectopic salivary gland tissue desmin, vimentin, S-100 protein, HMB45, CD34, CD5,
● Teratoma and CD99.
Special techniques
● The spindle cells are strongly and diffusely positive for NEUROENDOCRINE TUMORS
cytokeratins, and some of them are positive for BRST2,
alpha-smooth muscle actin, and CD10.
CLINICAL FEATURES
● The tumor is negative for S-100 protein, glial fibrillary
acidic protein, and CD34. Neuroendocrine tumors of the thymus include carcinoid, atyp-
● Ultrastructurally, the spindle cells show tonofilaments and ical carcinoid and small and large neuroendocrine carcinomas.
desmosomes. These tumors may be discovered during routine examination,
● The lymphocytes express MT1 and UCHL1 (T-cell or patients may present with Cushing syndrome, chest pain,
marker) positivity, and are negative for B-cell markers. superior vena cava syndrome, or with hypercalcemia and
● The skeletal muscle cells are phosphotungstic acid- hypophosphatemia. The lesions can be associated with carci-
hematoxylin (PTAH)-, myoglobin-, and muscle-specific noid tumor elsewhere, and may also be associated with multi-
actin-positive. ple endocrine adenomatosis (MEN type I or IIa). These tumors
tend to have an aggressive biological behavior compared with
those located elsewhere.
SPINDLE EPITHELIAL TUMOR WITH
THYMUS-LIKE ELEMENT (SETTLE)
Thymic carcinoid is a well-circumscribed lesion showing no
CLINICAL FEATURES
distinct lobulation as in thymoma. A variety of histological
Spindle epithelial tumor with thymus-like element (SETTLE) is variants of thymic carcinoid tumor have been described,
a rare, apparently low-grade spindle cell tumor of the thyroid including an extremely rare variant pigmented spindle cell car-
gland with metastases that develop some years after diagnosis. cinoid. It consists of uniform round cells arranged in ribbons,
It occurs in young individuals, and is thought to be derived festoons, and pseudorosettes. Lymphatic and vascular invasion
from thymic or branchial pouch remnants. is frequently seen. The tumor shows no lymphocytic compo-
The close association of these cases with areas showing nent or perivascular spaces as are seen in thymoma. Rarely,
the features of spindle cell thymoma within the same tumor thymic carcinoid has spindle cell morphology, contains mela-
mass suggests that some of these lesions may arise as a result nin, shows prominent mucinous stroma, or produces amyloid
of malignant transformation in a pre-existing spindle cell and calcitonin.
thymoma. Atypical carcinoma is similar to its lung counterpart.
(a) (a)
(b) (b)
Figure 10.54 (a, b) Thymic carcinoid 1 consists of uniform round Figure 10.55 (a, b) Large cell neuroendocrine carcinoma is
cells arranged in ribbons, festoons, and pseudorosettes.The tumor composed of large cells with large nuclei and prominent nucleoli. It has
shows no lymphocytic component or perivascular spaces as are infiltrative margins.
seen in thymoma.
Small neuroendocrine (small cell undifferentiated) carcinoma Cell morphology

is similar to small undifferentiated carcinomas seen in the lung ● Thymic neuroendocrine cells are similar to those seen in
and in other sites. other carcinoid tumors (cells with granular cytoplasm and
Large cell neuroendocrine carcinoma is composed of large stippled nuclear chromatin).
pleomorphic cells with large nuclei and prominent nucleoli with ● Mitotic figures are a frequent occurrence.
high mitotic rate and large tracks of coagulative tumor necrosis.
Secondary features Differential diagnosis

● Calcification. ● Metastatic carcinoid from other sites (e.g., bronchus)
● Necrosis. ● Medullary carcinoma of thyroid
● Hemorrhage. ● Thymoma (epithelial areas)
they may be asymptomatic. Investigations including chest radi-

ography, ultrasonography and computed tomography (CT)
may show displacement of vital mediastinal or neck structures.
Successful and complete excision of the cysts can be achieved.
The cysts range in size from 2 to 22 cm in diameter.
The main histological features of multilocular thymic cyst
included the following: multiple cystic cavities partially lined
by squamous, columnar, or cuboidal epithelium (some having
features of Hassall’s corpuscles); scattered nests and islands of
non-neoplastic thymic tissue within the cyst walls, often con-
tinuous with the cyst lining; severe acute and chronic inflam-
mation accompanied by fibrovascular proliferation, necrosis,
hemorrhage, and cholesterol granuloma formation; and reac-
tive lymphoid hyperplasia with prominent germinal centers.
Secondary features
(c)
● Hemorrhagic.
● Necrotic areas.
Figure 10.55 (c) Chromogranin highlights the neoplastic cells.
● Fibrous adhesion.
Special techniques
● Thymoma with extensive cystic change (multilocular thymic
● Positive immunohistochemical reaction is observed using
cysts are distinguished from thymoma by the absence of
antibodies for CAM5.2 low-molecular-weight cytokeratins,
solid areas displaying the distinctive features of thymoma).
broad-spectrum keratin, chromogranin, synaptophysin,
● Thymic carcinoma with prominent cystic changes such as
and Leu-7.
basaloid carcinoma and mucoepidermoid carcinoma. The
basaloid cell islands are often found in continuity with
cystic structures that are lined by round cuboidal to
THYMIC CYSTS
squamoid cells. The cysts may occasionally show foci of
tumor necrosis in their lumens. Mucoepidermoid
CLINICAL FEATURES carcinoma of the thymus can also be associated with
prominent cystic changes. A periodic acid–Schiff (PAS) or
Acquired multinodular thymic cysts mucicarmine stain serves to highlight the cytoplasmic
Multilocular thymic cyst presents as an asymptomatic lesion dis- mucin content of the cells in mucoepidermoid carcinoma.
covered incidentally on routine chest X-radiography; alternatively,
● Germ cell tumors – including seminoma and yolk sac tumor –
it may present with acute symptoms of chest pain or discomfort, may be accompanied by prominent cystic changes.
sometimes associated with dyspnea. The cyst may contain an inci- Identification of the typical areas of seminoma or the
dental thymoma, or an incidental thymic carcinoma. reticular pattern of yolk sac tumor within the solid areas in
Multilocular thymic cyst most likely results from the cystic the walls of the cyst will serve to establish a definitive
transformation of medullary duct epithelium-derived structures diagnosis. In equivocal cases the use of immunohistochemical
(including Hassall’s corpuscles) induced by an acquired inflam- stains for placental-like alkaline phosphatase and
matory process. The changes are similar to those sometimes seen alpha-fetoprotein will serve to facilitate the distinction.
in association with thymic Hodgkin’s disease and thymic semi-
● Congenital cysts may be mistaken for cystic
noma, which are also probably due to the inflammation that lymphangiomas.
accompanies these tumors rather than to the tumors themselves.
Multilocular cystic lesion of the thymus can be seen as part
of HIV-related disease. THYMIC EPITHELIAL TUMORS
Congenital thymic cysts THYMIC CARCINOMA

Congenital thymic cysts are rare benign lesions of the neck and
mediastinum that are difficult to diagnose. They occur in
CLINICAL FEATURES
patients ranging in age from 2 weeks to 16 years, and present
either with wheezing and upper respiratory infection, with Thymic carcinomas are aggressive tumors that are mainly seen
cough and fever, or as cervical masses, mediastinal masses, or in adults, there being a male predominance. The tumors are
usually associated with high incidence of local recurrence and carcinoma have been identified:
distant metastasis. Thymic carcinoma can arise in any histo- ● Squamous cell carcinoma: the lobular pattern is maintained
logical type of thymoma, including spindle cell thymoma, and the appearances are indistinguishable from those of other
which is generally regarded as a benign neoplasm. Tumor types of squamous carcinoma. Squamous cell carcinoma may
necrosis in a thymoma should alert the pathologist to search rarely originate in the epithelial cells of a thymoma.
for malignant change. ● Lymphoepithelioma-like carcinoma: this is essentially
similar to lymphoepithelial carcinoma of the nasopharynx.

● Sarcomatoid carcinoma: this type is a highly malignant
tumor, and usually shows a diffuse spindle cell pattern
Thymic carcinoma often shows extensive infiltration of the with focal epithelial differentiation. This variant exhibits
surrounding tissue. A variety of histological types of thymic various sarcomatoid components such as cartilage and
rhabdomyoblastic differentiation. The sarcomatous cells
are derived from carcinomatous cells by tumoral
metaplasia, or from thymic primitive cells with
multidirectional differentiation potential.
● Primary thymic adenocarcinoma: this is a very uncommon
variant which usually arises from thymic cyst or types

A thymoma. Transition of carcinomatous epithelium to the
attenuated epithelium of a thymic cyst may sometimes be
seen. This tumor occurs mainly in men (age between 15
and 39 years), and has a variable clinical outcome.
Primary thymic adenocarcinoma may show a
predominantly mucinous pattern (mucinous carcinoma),
comprised of islands and strips of mucin-rich tumor cells
floating in large pools of extracellular mucin.
● Papillary carcinoma: this may be of low grade and
associated with spindle cell-type thymoma, or show high

grade with no evidence of an associated thymoma. The
histological similarities and the intimate association with
spindle cell thymoma indicate that papillary thymic
carcinoma may arise from the papillo-tubular formations
(a) sometimes seen in the former tumor.
● Thymic carcinoma with clear-cell features behaves as a
high-grade thymic carcinoma. The importance of this

entity is recognition of its aggressive clinical behavior and
its distinction from other primary and metastatic clear-cell
neoplasms of the mediastinum.
● Other patterns such as basaloid, mucoepidermoid, and
small cell carcinoma with neuroblastoma-like features of

the thymus have also been reported. The mucoepidermoid
and the basaloid carcinomas, however, have a better
prognosis. These two types of thymic carcinoma are
frequently associated with prominent cystic changes.
Basaloid carcinoma is characterized by a proliferation of
small, round hyperchromatic cells displaying prominent
peripheral palisading of nuclei. The basaloid cell islands
are often found in continuity with cystic structures that are
lined by round cuboidal to squamoid cells.
Atypical thymoma
This term is sometimes used for thymic epithelial tumors that
exhibit histological features intermediate between thymoma
(b) and thymic carcinoma.
Figure 10.56 (a, b) Lymphoepithelioma-like thymic carcinoma; this Cell morphology

is essentially similar to lymphoepithelial carcinoma of the
nasopharynx.The arrows indicate prominent nucleoli within the ● Neuroendocrine differentiation is commonly observed in
thymic epithelial cells. thymic carcinomas. Their presence could be useful for the
differentiation of thymic carcinomas from thymomas and closely related to the pathogenesis of thymic carcinoma,
carcinomas of other sites. but is unrelated to EBV infection in the thymus.
● Primary thymic adenocarcinoma is CK7- and CK20-
Differential diagnosis positive in 30% and 25%, respectively, of the tumor cells.
● A PAS or mucicarmine stain serves to highlight the
● Squamous cell carcinoma of the thymus should be
cytoplasmic mucin content of the cells in mucoepidermoid
differentiated from metastatic squamous carcinoma
carcinoma.
● Sarcomatoid carcinoma should be differentiated from
metastatic sarcomatoid carcinoma/carcinosarcoma, from
the biphasic malignant peripheral nerve sheath tumor, in THYMOMA
particular those with rhabdomyoblastic differentiation
‘malignant triton tumor’ and from other sarcomas
● Carcinoma of the thymus with clear-cell features should be CLINICAL FEATURES
distinguished from mediastinal seminoma, parathyroid Thymoma – a neoplasm of thymic epithelial cells – is one of the
carcinoma, and metastatic clear-cell carcinoma most common neoplasms in the anterior mediastinum.
● Papillary thymic carcinoma should be considered in the Thymomas are benign in 70–80% of cases, and have a strong
differential diagnosis of some metastatic papillary association with myasthenia gravis. Some 10% of myasthenia
carcinomas with or without psammoma bodies in cervical patients have a thymoma, and 30–45% of patients with thy-
lymph nodes, in which no tumor is found in the thyroid moma develop myasthenia gravis, though the condition may
gland also be seen in non-myasthenic patients. Thymoma can also
● Mucoepidermoid carcinoma of the thymus should be arise from ectopic thymic tissue seen in extra-mediastinal loca-
included in the differential diagnosis of cystic neoplasms tions such as the neck, thyroid, trachea and pleura, and also
of the thymus rarely within the lung.
● Because primary thymic adenocarcinoma is so rare, it is Thymoma in the pediatric age group is characterized by
important to consider other possibilities, such as metastatic fairly uniform clinicopathological features, with a low rate of
adenocarcinoma, mesothelioma, and germ cell tumor, association with myasthenia gravis and a favorable prognosis.
before accepting the diagnosis Organoid thymoma is a distinctive form of non-invasive or
minimally invasive thymoma arising in young or middle-aged
Special techniques female patients. It represents a well-differentiated variant of
● Thymic carcinomas are positive for CEA, Leu-M1, thymoma, with low-grade aggressiveness and a distinct clinico-
Ber-EP4, cytokeratins, and EMA. pathological profile.
● CD5 is detected in thymic carcinoma but not in thymoma
or other malignant tumors. Atypical thymoma may also Classification of thymoma
show focal positivity. Various classification systems for thymoma have been used:
● The lymphocytes express markers of the immature ● Lattes–Bernats classification is a morphological classification
thymocyte phenotype. based on the proportion between thymic epithelial cells and
● P53 gene mutation is an early event in thymic reactive lymphocytes or the predominance of spindle cells.
tumorigenesis, and the p53 protein-positive cells increase This classification divides thymomas into predominantly
with the progression of the tumor. Immunostaining epithelial, predominantly mixed, predominantly lymphocytic,
reactivity of p53 may be a useful adjunct to differentiate and predominantly spindle.
thymic carcinoma from thymoma. ● Muller–Hermelink classification is a histogenetic
● Antibodies for myoglobin and desmin strongly stain the classification dividing thymomas into cortical, medullary,
myoid component when present. and mixed types. This classification has predictive utility,
● The malignant change in thymoma is commonly associated and represents a major step towards the understanding of
with increased expression of EMA, CK subtypes (CK7, 8, the biology of thymic epithelial tumors. Thymoma with
18, and 19), or p53 protein, and loss of CD99⫹ immature cortical differentiation is a histologically and histogenetically
T lymphocytes, and is occasionally associated with a related neoplasm, associated with a more aggressive clinical
change in the expression of CD5 or vimentin. behavior and a significant risk of recurrence.
● The neuroendocrine small cells present in thymic ● Levine and Rosai classify thymomas into benign and
carcinomas displaying immunohistochemical malignant according to the presence of capsular

neuroendocrine markers. penetration and overt malignant features; hence, invasive
● CD70, a type II transmembrane glycoprotein, is a member thymoma and thymic carcinoma are called malignant
of the tumor necrosis factor (TNF) family that mediates thymoma, category I and II, respectively.
the interaction between B and T lymphocytes. CD70 has ● Modified Muller–Hermelink classification (Kirchner),
been shown to be expressed by malignant lymphoma separates thymomas into five categories: medullary, mixed,
(especially Hodgkin’s disease) and by nasopharyngeal predominantly cortical (organoid), cortical thymomas, and
carcinoma, both of which are frequently associated with well-differentiated thymic carcinoma, depending on the
Epstein–Barr virus (EBV). The expression of CD70 is degree of the neoplastic epithelial cells recapitulating the
normal counterparts of thymic epithelium. Statistically different from that of follicular neoplasm of thyroid. The
significant relationships exist between histological features encapsulated thymoma consequently is regarded as an
and age, surgical stage, and prognosis. in-situ malignancy. Spindle cell thymomas are well-known
● Suster and Moran proposed a novel conceptual approach as slow-growing tumors, and the majority of them are
to classify thymic epithelial tumors into thymoma, atypical either encapsulated or microinvasive.
thymoma, and thymic carcinoma based on the cytological 2. That aside from stage, the histology can also predict the
degree of atypia and the organotypical features of thymic outcome. Specifically, pure spindle cell (medullary) and
differentiation. mixed thymoma are thought to be ‘clinically benign’
tumors, whereas other types are thought to be of low-
The new WHO classification grade malignancy.
The new WHO classification does not directly adopt any exist- 3. That all thymic epithelial neoplasm are seen as being
ing classification, but provides a means to incorporate the ter- ‘potentially malignant’, with a histological spectrum rang-
minology used by various systems, including the Lattes–Bernats, ing from typical thymoma at one end, ‘atypical thymoma’
Müller–Hermelink–Kirchner, and Suster–Moran classifications, in the intermediate, and thymic carcinoma at the opposite.
and to determine the equivalence between them by assigning to It has been shown that spindle cell and mixed spindle/lym-
the presumed equivalent categories a combination of letters phocytic thymomas are not necessarily innocuous.
and numbers, thus facilitating comparison among many terms Recurrences and mortalities resulting from the predomi-
and classifications available to date. This classification states: nantly spindle cell thymomas have been reported in some
● Type A (medullary) thymomas: these show spindle/oval series.
neoplastic epithelial cells. This is equivalent to the spindle
cell or medullary thymoma of the other classification. PATHOLOGICAL FEATURES (Figures 10.57–10.62)
● Type B thymomas: these show dendritic or plump
Thymoma is a distinctly lobulated, cellular lesion which is sur-
(epithelioid) epithelial cells. This type is further subdivided
rounded and divided by thick fibrous connective tissue. The
into B1, B2, and B3 on the basis of the proportional
constituent cells are lymphocytes admixed with rounded, ovoid
increase and emergence of atypia of neoplastic epithelial
or spindle-shaped epithelial cells. The proportion of epithelial
cells. Some of these are equivalent to the cortical variants
cells to lymphocytes varies from case to case and from lobule
(cortical types and well-differentiated thymic carcinoma),
to lobule within the same lesion. When the epithelial compo-
and have more aggressive biological behavior.
nent predominates, it tends to grow in sheets, loose syncytial
Type B1 (predominantly cortical thymoma) tumor resembles cords, whorls or fascicular bundles. Other features of thymoma
the normal thymus, and is predominantly cortical in that there are abortive Hassall’s corpuscles, formation of pseudoglandu-
is a predominance of areas resembling cortex over those resem- lar structures or pseudorosettes.
bling medulla.
Type B2 (cortical thymoma) tumor resembles type B1 tumor,
but the epithelial cells are more numerous and have a more
neoplastic appearance.
Type B3 (well-differentiated thymic carcinoma, also corre-
sponds to Levine and Rosai type I malignant thymoma) tumor
has a predominance of the epithelial cells, with a less prominent
lymphoid component. These are the most common thymic malig-
nancy; they tend to spread locally, either by direct extracapsular
spread or pleural or pericardial implants. Distant metastases are
uncommon. They are essentially identical to those of benign thy-
moma, except for evidence of extracapsular spread or metastasis.
Perivascular spaces are common in type B2 or B3 tumors,
and perivascular arrangement of tumor cells can also be
encountered in type B3 tumors. Foci of squamous metaplasia
are common in type B3 tumors.
● Type AB (mixed) thymomas: these show both spindle/oval
and plump epithelial morphologies. This is equivalent to

the mixed spindle/lymphocytic thymomas, which are
alleged to be clinically benign.
Prognostic features (a)
There are three theories in regard to the biological behavior of

Figure 10.57 (a–c) Cystic change in thymoma. Microcystic spaces,
thymoma: lined by epithelial cells and containing pale proteinaceous fluid are
1. That the prognosis of thymoma is determined only by the not uncommonly seen in thymoma.These are found within the
status of capsular integrity – a situation not substantially lobules and in the fibrous septa.
(b) (a)
(c) (b)
Figure 10.57 (Continued). Figure 10.58 (a, b) Thymoma with abortive Hassall’s corpuscles.
Foci of hemangiopericytomatous vascular pattern, and ectatic

vessels surrounded by pale hyaline, pertinacious material are of the cysts may show hyperplastic changes with elongation
often seen in thymomas. and branching of the cells in a fibroepitheliomatous fashion. In
some instances the cyst wall could be traced to dilated Hassall’s
Cystic change in thymoma corpuscles. The walls of the cysts often show severe acute and
Microcystic spaces, lined by epithelial cells and containing pale chronic inflammation with granulation tissue and fresh hemor-
pertinacious fluid, are not uncommonly seen in thymoma. rhage, and they also show confluence and accumulation of
These are found within the lobules and in the fibrous septa. necrotic luminal debris admixed with dense inflammatory infil-
Thymoma may also contain cystic structures reminiscent of trate. Cystic changes in thymoma may be the result of two
acquired multilocular thymic cysts. The cysts in these areas are pathogenetic mechanisms:
lined by low cuboidal to squamous epithelium that may be 1. Confluence and dilatation of perivascular spaces with the
found in continuity with strands of thymic epithelium within creation of large cystic cavities devoid of an epithelial
the cyst wall. The residual epithelial remnants within the walls lining or inflammation.
(a) (c)
(b)
Figure 10.59 Spindle cell thymoma (WHO type A). (a, b)

Consists of oval to short cytokeratin-positive spindle cells variably (a)
intermixed with CD3-positive lymphocytes (c).
Figure 10.60 (a–c) Mixed spindle/lymphocytic thymoma (WHO
2. Cystic dilatation of thymic epithelium and/or Hassall’s type AB). A distinctly lobulated, cellular lesion, surrounded and
corpuscles secondary to underlying inflammatory and divided by thick fibrous connective tissue. It shows tightly
hyperplastic changes of residual non-neoplastic thymic intermingled spindle cells and lymphocytes with some cells having
more polygonal, plump, or dendritic cytoplasm resembling thymic
epithelium.
cortex.The neoplastic epithelial cells are CAM5.2-positive.
Spindle cell thymoma (WHO type A)
Two major patterns are recognized: short-spindled and long- The long-spindled variant is composed of fibroblast-like long
spindled variants. spindle cells arranged in interlacing fascicles or in a storiform pat-
The short-spindled variant consists of oval to short spindle tern mimicking fibrous histiocytoma. Rosette-like structures could
cells frequently arranged in a hemangiopericytomatous pattern. be observed. The numbers of lymphocytes in this variant range
Microcysts, glands, and rosette-like structures may be seen. from scant to moderate amounts. The neoplastic epithelial cells
The lymphocytes are usually sparse. are usually bland, but they may reveal a moderate nuclear atypia.
(b) (a)
(c) (b)
Figure 10.60 (Continued). Figure 10.61 (a, b) Malignant thymoma.This lesion has the low-
power nodularity of thymoma, but is histologically malignant.
A distinct micronodular pattern is also seen in spindle

cell thymoma. This is characterized by proliferation of small
aggregates of bland-looking spindle cells dispersed in a lym- In some cases the different elements are well-demarcated, and
phoid stroma containing frequent germinal centers. Occasionally, may be separated by fibrous bands. The spindle cells might be of
the germinal centers display focal central hyalinization. long-spindled or short-spindled type or a composite tumor made
Prominent cystic change reminiscent of multilocular thymic up of sharply segregated regions of short-spindled and micron-
cysts may be seen. This variant usually lacks lobulation or odular patterns and lymphocyte-rich ‘cortex’-like areas.
fibrous bands. ‘Organoid thymoma’ is characterized by a prominent and dif-
fuse ‘organoid’ pattern, defined by the presence of several areas
Mixed spindle/lymphocytic thymoma (WHO type AB) of medullary differentiation. These areas, which are strictly rem-
These are composed of tightly intermingled long spindle cells and iniscent of the medullary area of the normal thymus, are scat-
lymphocyte-rich areas containing epithelial cells with more polyg- tered within a neoplastic tissue resembling the thymus cortex, the
onal, plump, or dendritic cytoplasm resembling thymic cortex. overall appearance mimicking that of normal thymus.
Cell morphology
● The epithelial cells are cuboidal, oval, fusiform or spindle-
shaped with large, pale-staining nuclei. Nucleoli are
indistinct or absent in benign thymoma, but may be
prominent in their malignant counterparts.
● The cytoplasm is pale or vacuolated with no distinct borders,
and therefore tends to produce a syncytial arrangement.
● The lymphocytes may appear mature or may show varying
degrees of activation, including mitotic activity.
● Cells showing striated muscle differentiation may
occasionally be present.
● Neuroendocrine differentiation is commonly observed in
thymic carcinomas. Their presence could be useful for the
differentiation of thymic carcinomas from thymomas and
carcinomas of other sites.
● Lymphocytic predominant thymoma may be mistaken for
lymphoma
(a)
● Spindle cell thymoma may be mistaken for
hemangiopericytoma and peripheral nerve tumors
● Extra-mediastinal thymomas should be distinguished from
primary or metastatic carcinomas, sarcomas
Special techniques
Normal thymic tissue
● Normal thymic cortical cells are Leu-7-(CD57)-positive
and keratin-positive, while normal medullary epithelial
cells are Leu-7-(CD57)-negative and keratin-positive. The
thymoma cells may retain these characteristics to some
extent – that is, have the same phenotype of epithelial cells
of the cortex, especially the outer cortex of the thymus in
some instances (Leu-7-positive, keratin-positive) and of
both cortex and medulla (mixture of Leu-7-positive and
-negative cells) with organoid arrangement in other
instances, and thymic squamous cell carcinoma had the
same phenotype as epithelial cells in the thymic medulla
(Leu-7-negative, keratin-positive).
● The normal thymic epithelium (including cyst lining)
(b) shows weak to moderate staining for cytokeratin (CK) 7,
and is totally negative for CK20.
Figure 10.62 (a, b) Thymoma, predominantly lymphocytes.The
lymphocytes that accompany thymomas express an immature T-cell Thymomas
phenotype, as usually demonstrated by CD1 (b).
● All spindle cell and mixed spindle/lymphocytic thymomas
are positive for pan-cytokeratin AE1/3, KL-1, low-
Secondary features molecular-weight cytokeratin CAM5.2, and high-
● Calcification in the fibrous capsule. molecular-weight CK34␤E12. The epithelial cells are
● Cystic degeneration (can be extensive and most or the negative for CD5.
entire lesion becomes cystic). ● CD20, pan-B-cell marker, is found aberrantly expressed by
● Extensive areas of necrosis and hemorrhage as well as the neoplastic epithelial cells in some spindle cell and most
infarcted areas and cystic structures may be associated mixed spindle/lymphocytic thymomas. The epithelial cells
with more aggressive behavior. in cortical thymomas and thymic carcinomas do not
● Vessels displaying prominent vaso-occlusive express CD20.
phenomena are often located in the vicinity of the areas of ● Leu-7 (CD57) could be detected in up to 80% of spindle
infarction. cell and mixed spindle/lymphocytic thymomas, but has not
● Marked sclerosis may occasionally be seen. been demonstrated very often in thymic carcinomas.
● CD5 is negative in the epithelial cells of all spindle cell and follicles, an increased number of Hassall’s corpuscles, and cysts
mixed spindle/lymphocytic thymomas, but is often positive of varying sizes.
in thymic carcinomas. Both forms of thymic hyperplasia can occur in healthy
● The lymphocytes that accompany thymomas express an children as idiopathic thymic hyperplasia, or as a rebound
immature T-cell phenotype, as usually demonstrated by effect after administration of chemotherapy in patients with
CD1 or TdT immunoreactivity. Even when thymomas malignancies.
metastasize or occur in ectopic sites, the infiltrating
T lymphocytes show this unique immature phenotype,
contrasting with thymic and non-thymic carcinomas, in THYMIC HODGKIN AND NON-HODGKIN
which the infiltrating T lymphocytes typically show a
mature phenotype (CD1- and TdT-negative). Therefore,
LYMPHOMA OF THE THYMUS
the presence of an immature T-cell population in an
epithelial tumor strongly supports a diagnosis of Hodgkin and non-Hodgkin lymphomas may primarily or sec-
thymoma. ondarily involve the thymus.
● CD4⫹CD8⫹ double-positive T-cells are seen in thymomas, The majority of thymic lymphomas are lymphoblastic lym-
and also are shown to be present in the metastatic sites of phoma, large B-cell lymphoma or nodular sclerosing Hodgkin’s
thymomas. disease. On rare occasions, primary low-grade B-cell marginal
● Small polygonal cell of thymoma express CK14 and CK19. zone lymphoma is reported, especially in patients with autoim-
mune disorders. As observed with marginal zone lymphoma
Spindle cell thymoma (WHO type A) arising at other anatomic sites, these tumors may undergo
● The epithelial cells in 38% of short-spindled variants and transformation to a higher-grade lymphoma. The neoplastic
70% of long-spindled variants are positive for CD20, at cells are immunoreactive for the B-cell marker CD20, and are
least focally. The lymphocytes reveal mostly a CD1a/CD3- positive for bcl-2.
positive T-phenotype. The staining for CD57 is positive,
with a varied extent in 76% short-spindled and 80% long-
spindled variants. THYMOLIPOMA
● The immunohistochemical profile of the micronodular
variant differs from those of the two spindle-cell variants.
The epithelial cells do not express CD20, but express CLINICAL FEATURES
CD57 either focally or diffusely. The lymphocytes exhibit a Thymolipoma is a benign fat tumor and is usually asympto-
mixed immunophenotype of CD20-positive B-cells and matic, though it may be associated with myasthenia gravis,
CD1a-negative/CD3-positive T cells. A population of aplastic anemia or Graves’ disease. The tumors vary in size
CD5-positive lymphocytes is present, especially around the from 4.5 to 36 cm in their greatest dimension. Thymolipoma
mantle zone of lymphoid follicles. span the age ranges from the very young to adult individuals.
Thymoma may rarely arise within thymolipoma.
Mixed spindle/lymphocytic thymoma (WHO type AB)
● The epithelial cells of the mixed spindle/lymphocytic PATHOLOGICAL FEATURES
thymomas are immunoreactive for CD20. The intensity is
generally stronger than in spindle cell thymoma. The This is an encapsulated lesion consisting of mature fat cells,
epithelial cells also express Leu-7 (CD57) in 79% of cases. devoid of atypia, admixed with normal-looking thymic tissue.
The lymphocytes are predominantly CD1a/CD3-positive The thymic tissue component varies from strands of atrophic
T-phenotype. thymic epithelium to large areas containing thymic
parenchyma showing the typical mixed epithelial/lymphocytic
architecture with numerous Hassall’s corpuscles. Areas of cal-
THYMIC HYPERPLASIA cification and cystic degeneration of Hassall’s corpuscles may
be prominent.
True thymic hyperplasia means thymic tissue weights greater Thymofibrolipoma is a variant of thymolipoma, showing
than two standard deviations above the mean weight for age, abundant fibrous tissue.
together with histological evidence of expanded cortical and
medullary parenchyma with retention of a normal proportion Cell morphology
of connective tissue expected for age. ● Mature fat cells.
Lymphoid hyperplasia means an increase in the number and ● Normal thymic epithelial and lymphoid populations.
size of medullary lymphoid follicles, and this is usually seen in ● Myoid cells may rarely be found in thymolipoma.
the clinical setting of autoimmunity. The presence of an enlarged
thymus or a focal mass in patients with myasthenia gravis often
indicates lymphoid hyperplasia or thymoma. Thymic lymphoid Differential diagnosis
hyperplasia can also be seen as part of HIV-related disease. The ● Lipoma
resected thymus usually exhibits prominent medullary lymphoid ● Thymic liposarcoma
Special techniques neoplasms have the same morphological features, approximate

● Normal thymic cortical cells are Leu-7-(CD57)-positive distribution, and prognosis as the gonadal counterparts.
and keratin-positive, while normal medullary epithelial Germinoma-seminoma is the most frequent non-teratomatous
cells are Leu-7-negative and keratin-positive. malignant germ cell tumor. It should be remembered that medi-
astinal lymph nodes are metastatic sites for primary gonadal
germ cell tumors, so that a thorough clinical evaluation is nec-
essary to exclude the latter possibility.
RARE THYMUS TUMORS
A variety of tumors that are usually of extra-thymic or extra- MALIGNANT MELANOMA

mediastinal origin may arise within the parenchyma of the thy-
mus or in the anterior mediastinum. These include both benign Malignant melanoma has rarely been reported in the thymus.
and malignant tumors. Below are some of the commonly It is thought to originate from the nevocellular nevus in the
reported lesions. thymus. One needs to rule out secondary metastasis before
diagnosing primary thymic melanoma.
GERM CELL TUMOR
The anterior mediastinum is the most common primary extra-

SARCOMA
gonadal site for germinal neoplasms in adults, and is second to
In theory, any type of sarcoma can arise in the anterior medi-
the sacrococcygeal region for pathologically comparable
astinum and thymus. The most commonly reported ones are
tumors in children. These neoplasms are often associated with
leiomyosarcoma, liposarcoma, rhabdomyosarcoma and synovial
the thymus, and in many cases appear to have originated in the
sarcomas.
thymus; residual thymic tissue is not identifiable in the highly
invasive and malignant germ cell tumor. Regardless of the
pathological subtype, the mediastinal germ cell tumors have a SECONDARY TUMORS
predilection for patients during the first three decades of life.
The majority of neoplasms are mature cystic teratomas that are Secondary tumors may invade the thymus from adjacent
incidentally discovered on imaging studies of the thorax. organs, or they may spread from other sites such as the thyroid,
Respiratory difficulties and/or chest pain are the most frequent prostate, lung, or from primary melanoma elsewhere.
symptoms. Among the malignant germ cell tumors, males are
affected far more commonly than females, but the male to female
ratio is approximately equal among mature cystic teratomas. SOLITARY FIBROUS TUMOR
Histological grading of pure teratomas has prognostic signifi-
cance in those neoplasms that are diagnosed in adolescents and Solitary fibrous tumor with features identical to those
young adults; immature teratomas in the latter patients pursue reported elsewhere may rarely be seen in the thymus or in the
an aggressive clinical course. The non-teratomatous germinal mediastinum.
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LITTORAL CELL ANGIOMA

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11 male genital tract tumors
Awatif I Al-Nafussi, Catriona Anderson and Kenneth M Grigor
Tumors of the prostate 788 Malignant phyllodes tumor 804

Epithelial lesions, benign 788 Other sarcomas 804
Adenoid basal cell tumor (adenoid cystic-like tumor) 788
Adenosis/adenomatous hyperplasia 789 Secondary metastasis 804
Atypical adenosis 789
Basal cell hyperplasia 790 Tumors of the urethra 804
Atypical basal cell hyperplasia 790 Benign urethral lesions 804
Sclerosing basal cell hyperplasia 790 Collagen polyp of the urinary tract 804
Benign cribriform lesions (clear cell cribriform hyperplasia) 790 Fibroepithelial polyp 805
Benign prostatic hyperplasia (BPH) 790
Verumontanum mucosal gland hyperplasia 790 Malignant urethral lesions 805
‘Melanosis’ of the prostate 790 Primary adenocarcinoma 805
Epithelial polyps of the prostatic urethra 791 Primary malignant melanoma 805
Prostatic-type epithelial polyps 791 Primary mucosa-associated lymphoid tissue
Adenomatoid or nephrogenic-type polyps 791 (MALT) lymphoma 805
Post-atrophic hyperplasia 792 Primary neuroendocrine carcinoma 805
Sclerosing adenosis 793

Prostatic carcinomas 793
Germ cell tumors 805
Ductal adenocarcinoma 798
Carcinoma in situ (CIS)/intratubular germ cell
Mixed ductal-acinar carcinoma 798
neoplasia (ITGN) 807
Signet ring cell carcinoma 799
Polyembryoma 809
Carcinosarcoma/sarcomatoid carcinoma 799
Seminoma 809
Adenocarcinoma with neuroendocrine cells 799
Spermatocytic seminoma 811
Neuroendocrine/small undifferentiated cell
Teratomas 812
carcinoma 799
Yolk sac tumor (infantile embryonal carcinoma/
endodermal sinus tumor) 814
Adenosquamous carcinoma 799
Adenocarcinoma with oncocytic features 799
Rete testis tumors 814
Lymphoepithelial-like carcinoma 800
Adenomatous hyperplasia 814
Adenoid cystic carcinoma/basal cell carcinoma 800
Carcinoma 814
Prostatic carcinoma with treatment effect
(androgen-deprivation therapy) 800
Sertoli cell tumors 815
Prostatic adenocarcinoma resembling benign
Hamartomatous nodules and adenoma in testicular
hyperplastic glands 800
feminization (androgen insensitivity) syndrome 815
Transitional cell carcinoma 800
Sertoli cell tumor 816
Sertoli cell tumor, large calcifying 816
Prostatic intraepithelial neoplasia (PIN) 801 Sertoli cell tumor, sclerosing 817
Low-grade PIN 801
High-grade PIN 801 Sex cord–stromal tumors 817
Leydig cell tumor 817
Rare primary tumors 803
Malignant lymphoma 803 Tumors of the paratesticular region 819
Malignant melanoma 803 Neoplastic and non-neoplastic proliferations of the
testicular collecting system 819
Sarcomas and related proliferative lesions of the specialized Cysts and epithelial proliferations 819
prostatic stroma 803 Epididymal lesions 819
Prostatic stromal proliferation of uncertain Epididymal cysts 819
malignant potential 804 Epididymal papillary cystadenoma 819
Prostatic stromal sarcoma 804 Epididymal carcinoma 819
Leiomyosarcoma 804 Epididymal metastatic tumors 819
788 Male genital tract tumors
Paratesticular lymphoreticular tumors 819 Leydig cells outside the testicular parenchyma 821
Plasmacytoma 819 Malakoplakia 821
Granulocytic sarcoma 819 Vasitis nodosa 821
Malignant lymphoma 819 Paratesticular benign fibrous proliferations 822
Paratesticular mesothelial tumors 819 Inflammatory myofibroblastic (pseudotumor)
Mesothelial hyperplasia 820 tumor 822
Mesothelial cysts 820 Tumor of the adrenogenital syndrome and
Adenomatoid tumor 820 related lesions 822
Benign cystic mesothelioma 820 Sclerosing lipogranuloma 822
Mesothelioma 820 Splenic–gonadal fusion 822
Paratesticular ovarian-type epithelial tumors 820 Smooth muscle hyperplasia 822
Serous borderline tumor 820 Miscellaneous lesions 823
Serous papillary carcinoma 820 Tumors and pseudotumors of the seminal vesicles 823
Paratesticular soft tissue tumors 820 Cystic epithelial–stromal tumor 823
Paratesticular tumor-like lesions 821 Seminal vesicle involvement by in situ and invasive
Cribriform ‘hyperplasia’ of epididymis 821 transitional cell carcinoma of the bladder 823
Monstrous epithelial cells in human epididymis Seminal vesicle involvement by prostate cancer 823
and seminal vesicles 821
GENERAL COMMENTS with new tumor classifications having been developed and new
immunohistochemical techniques introduced.
Tumors and tumor-like conditions of the male genital tract are In this chapter, all clearly recognized tumors and tumor-like
frequently encountered in general practice. Tremendous advances conditions encountered in the prostate, testis, and paratesti-
have been made in this field during the past ten years or so, cular tissue are described.
TUMORS OF THE PROSTATE
GENERAL COMMENTS PATHOLOGICAL FEATURES

Adenoid basal cell tumor of the prostate is characterized by
Prostatic carcinomas and benign prostatic hyperplasia are the
the presence of a fibromyxoid stroma containing numerous
main prostatic lesions that are encountered in general practice.
basaloid glandular structures, irregular solid nests or intercon-
There are many other benign and proliferative lesions of the
nected cords with peripheral palisading. It may resemble cuta-
prostate, some of which may be confused with malignancy,
neous basal cell carcinoma or salivary gland basaloid adenoma.
especially in needle biopsies.
Tumor cells may form rosettes around spaces containing faintly
In this chapter, all prostatic tumors and proliferative lesions
acidophilic or hyaline matrix, and the nests may be surrounded
are described – and illustrated when possible – with the empha-
by hyaline membrane reminiscent of adenoid cystic carcinoma.
sis placed on differential diagnosis.
On occasion, the glandular or pseudoglandular spaces contain
pale acidophilic or colloid-like secretion.
Basal cell hyperplasia with or without atypia may be seen in
areas adjacent to the tumor.
EPITHELIAL LESIONS, BENIGN
Cell morphology
ADENOID BASAL CELL TUMOR (ADENOID ● The cells have scanty basophilic cytoplasm, plump or
CYSTIC-LIKE TUMOR) oval nuclei, multiple small nucleoli, and show a high
nuclear:cytoplasmic ratio.
● The chromatin pattern is delicate and evenly distributed.
CLINICAL FEATURES ● Mitoses are rare.
● The cells may show clear cell or squamous change.
Adenoid basal cell tumor of the prostate is a benign process,
probably arising from the prostatic urethra rather than the pros-
tatic ducts. It has an expansile growth pattern, and is often Differential diagnosis
multicentric. ● Basal cell hyperplasia
Special techniques may show fairly prominent nucleoli. Other features include
● The cells may show focal positivity for prostatic acid the presence of crystalloids in 40% of cases, mitotic figures in
phosphatase (PSAP) and prostate-specific antigen (PSA). 11%, and blue-tinged luminal mucinous secretions in 2%.
● High-molecular-weight cytokeratin (CK) monoclonal
antibody 34␤E12 is a marker for basal cells, and as such is Special techniques
very useful in the differential diagnosis of prostatic cancer High-molecular-weight CK monoclonal antibody 34␤E12 is a
from other benign neoplastic proliferation. The basal cell marker for basal cells, and as such is very useful in the differ-
layer is lost in prostate adenocarcinomas, but exists in ential diagnosis of adenosis from prostatic cancer. The basal
most of the proliferative lesions. cell layer is lost in prostate adenocarcinomas, but exists in most
of the proliferative lesions.
ADENOSIS/ADENOMATOUS HYPERPLASIA
CLINICAL FEATURES
Adenosis is a specific histological entity which is most fre-
quently seen in transurethral resection of the prostate, although
increasingly identified on needle biopsy. Its clinical signifi-
cance lies in its possible misdiagnosis as a low-grade prostatic
carcinoma.

The diagnosis of adenosis is based on a constellation of histolog-
ical features, and may be confirmed with the use of antibodies to
high-molecular-weight cytokeratin. The lesion is characterized by
a relatively well-circumscribed proliferation of benign glands
that frequently mimics low-grade adenocarcinoma.
Atypical adenosis may show minimal infiltration away from
the main nodule of adenosis, it may show a minor component
of poorly formed glands or even single cells, and some cells
(b)
(a) (c)
Figure 11.1 (a–c) Prostatic adenosis.The lesion is characterized by a relatively well-circumscribed proliferation of benign glands that
frequently mimics low-grade adenocarcinoma. High-molecular-weight cytokeratin monoclonal antibody 34␤E12, a marker for basal cells,
exists in this lesion (c).
BASAL CELL HYPERPLASIA BENIGN CRIBRIFORM LESIONS (CLEAR CELL

CRIBRIFORM HYPERPLASIA)
CLINICAL FEATURES
See Prostatic carcinoma, differential diagnosis (p. 800).
Basal cell hyperplasia of the prostate is a common lesion,
mostly seen in the periurethral ducts, and often in association
with benign prostatic hyperplasia. It is also commonly seen fol-
lowing androgen deprivation therapy, and may be a precursor BENIGN PROSTATIC HYPERPLASIA (BPH)
of the so-called adenoid basal cell tumor.
CLINICAL FEATURES
PATHOLOGICAL FEATURES Benign prostatic hyperplasia is a manifestation of the aging
Basal cell hyperplasia consists of a proliferation of basal cells process, being seen most commonly in adults aged over 60
(two or more cells in thickness) at the periphery of prostatic years. It presents with symptoms of urethral or bladder neck
acini. It sometimes appears as small nests of cells surrounded obstruction. Acute retention is more often seen in association
by a few concentric layers of compressed stroma, often asso- with prostatic infarction.
ciated with chronic inflammation. The nests may be either solid
or cystically dilated, and occasionally punctuated by irregular
round luminal spaces, creating a cribriform pattern. PATHOLOGICAL FEATURES (Figure 11.2)
Basal cell hyperplasia frequently involves part of an acinus, Benign prostatic hyperplasia is characteristically nodular, with
and sometimes protrudes into the lumen, retaining the over- participation of both epithelial and stromal components. Early
lying secretory cell layer. Less commonly there is symmetrical nodules are small and predominantly stromal, consisting of
duplication of the basal cell layer at the periphery of the acinus. fibrous tissue admixed with smooth muscle. On occasion, a
Atypical basal cell hyperplasia is identical to basal cell hyper- larger solitary stromal nodule, situated near the bladder neck,
plasia except for the presence of large prominent nucleoli in may protrude into the bladder as a midline mass.
more than 10% of the cells. Chronic inflammation is often seen Larger nodules are predominantly glandular, are more later-
in the background. ally situated, and consist of small and large acini with papillary
infolding and projections. A basal cell layer is usually seen, and
Secondary features basal cell hyperplasia is not uncommonly found in association
● Squamous metaplasia is infrequent and usually associated with nodular hyperplasia.
with infarction. Verumontanum mucosal gland hyperplasia is characterized
● Occasional nuclear grooves and ‘bubble’ artifacts are by a relatively well-circumscribed collection of closely packed
observed. glands, and is typically observed immediately subjacent to the
● Focal calcification is evident in some cases. urothelium. A basal cell layer is readily identifiable in routine
hematoxylin and eosin-stained sections. The luminal contents
Cell morphology of the verumontanum mucosal glands are distinctive and con-
sist of lamellated eosinophilic concretions typical of corpora
● The basal cells are enlarged, ovoid or round, and plump
amylacea, as well as unique orange-red concretions that are
with large pale nuclei, finely reticular chromatin, and a
commonly fragmented.
moderate amount of cytoplasm. Nucleoli are usually
inconspicuous except in atypical basal cell hyperplasia.
● Mucin-secreting cells may be seen intermingled with the Secondary features
basal cells.
● Clear cell change is common and often seen in the
● Diffuse lymphocytic and plasma cell infiltrate.
cribriform pattern type.
● Infections.
● Granulomatous prostatitis.
● Infarction (is usually found in 20–25% of specimens
removed for BPH).
● Adenoid basal cell tumor ● Scar formation (often following previous infarction).
● Well-differentiated adenocarcinoma ● Squamous metaplasia (is usually secondary to
● Sclerosing basal cell hyperplasia is identical to typical basal infarction).
cell hyperplasia, but is associated with delicate lace-like ● Basal cell hyperplasia.
fibrosis or dense irregular sclerotic fibrosis and hyperplasia ● Cystic atrophy reminiscent of the tunnel clusters seen in
of smooth muscle, resulting in distortion of the basal cell cervix or the involutionary changes seen in the breast.
aggregates ● Lipofuscin pigmentation, so-called ‘melanosis’ of the
prostate is commonly present in epithelial cells of BPH,
Special techniques and less frequently in those of prostatic intraepithelial
● The cells express high-molecular-weight cytokeratins. neoplasia and adenocarcinoma.
(a) (b)
Figure 11.2 (a, b) Benign prostatic hyperplasia. A glandular nodule consisting of small and large acini with papillary infolding and
projections. Corpora amylacia is seen in some of the acini.
Cell morphology PATHOLOGICAL FEATURES (Figure 11.3)

● The glandular structures are lined by tall columnar These polyps form a heterogeneous group of lesions.
epithelium with pale-staining granular cytoplasm. Prostatic-type epithelial polyps are characterized by the pres-
● The basal cell layer contains cells with scant cytoplasm ence of villous polypoid or papillary urethral lesions. The
and small oval nuclei oriented horizontally parallel to papillae contain fibrovascular stroma and are lined by epithe-
the basement membrane. lial cells similar to those normally seen in the prostate.
Glandular acini may also be seen in the underlying stroma.
Differential diagnosis Some lesions consist entirely of acini. On occasion, pseudo-
● Prostatic carcinoma stratification of the epithelial lining results in an endometrioid
● Prostatic adenosis appearance. Adenomatous transformation may be suggested in
● The histological features of verumontanum mucosal gland the presence of mitotically active cells.
hyperplasia are characteristic, and allow distinction to be Adenomatoid or nephrogenic-type polyps are characterized
made from other small glandular proliferations of the by the presence of complex papillary and tubular glandular
prostate, including nephrogenic adenoma, adenosis structures lined by flattened or low cuboidal epithelial cells
(atypical adenomatous hyperplasia), and low-grade reminiscent of adenomatoid tumor. The cells may show a ‘hob-
adenocarcinoma nail’ appearance. The stroma is edematous and contains dilated
capillaries, and is usually infiltrated by numerous plasma cells.
Some of the glandular spaces contain colloid-like eosinophilic
EPITHELIAL POLYPS OF THE PROSTATIC URETHRA material. Continuity of the lesion with normal transitional
epithelium may be seen.
CLINICAL FEATURES
Secondary features
Epithelial polyps of the prostatic urethra are not uncommon ● Eosinophilic concretions as seen in normal prostate may
benign lesions, that may arise from an ectopic prostatic tissue be seen.
(the latter can also be seen in urachal remnants, trigone of the
bladder, root of penis and pericolic fat) or from prolapsed pro-
static ducts into the prostatic urethra. They affect young adults, Cell morphology
may cause hematuria, recur locally, or may be the site of carci- The cells in the prostatic-type polyps are identical to those seen
noma or adenomatous transformation. in normal prostate:
Adenomatoid or nephrogenic-type polyps are often asso- ● There is an outer columnar cell layer with basally located
ciated with a history of trauma, previous surgery, or chronic uri- nuclei and an underlying flattened to cuboidal basal cell
nary tract infection. layer. The columnar cells have clear to pale eosinophilic
(a) (b)
Figure 11.3 (a, b) Prostatic-type epithelial polyps are characterized by the presence of villous polypoid or papillary urethral lesions.These
are lined by epithelial cells similar to those normally seen in the prostate. Glandular acini may also be seen in the underlying stroma.
cytoplasm and discrete cell borders and round to oval PATHOLOGICAL FEATURES
nuclei without prominent nucleoli.
There is a distinctive lobular pattern with a centrally located
● The nuclei of the basal cell layer are identical to those
large dilated acinus surrounded circumferentially by clusters of
of the columnar cells.
small acini. The acini show irregular luminal contours. Stromal
● The epithelial cells show no evidence of pleomorphism
fibrosis and sclerosis with smooth muscle atrophy is a promi-
or mitotic activity.
nent feature resulting in distortion of the acini. Foci of typical
The cells of the adenomatoid-type polyps: acinar atrophy can also be seen. This consists of thin-walled,
● Have eosinophilic, granular and finely vacuolated dilated, distorted, crowded glandular spaces reminiscent of
cytoplasm. tunnel clusters seen in the cervix and subinvoluting breast acini.
● The nuclei are centrally located, darkly stained and
usually lack nucleoli. Secondary features

● Corpora amylacea.
Differential diagnosis ● Patchy chronic inflammation.
● Papillary urethritis Cell morphology
● The small acini are lined by cuboidal cells with small
Special techniques nuclei and nucleoli.
● The epithelial cells lining the prostatic-type polyps are ● The cytoplasm is basophilic, but can be granular or clear.
positive for PSAP and PSA. The flattened cells lining the ● The larger dilated central acinus is lined by flattened
adenomatoid type polyps often do not express these markers. epithelium.
● The basal cell layer is usually identified.
POST-ATROPHIC HYPERPLASIA Differential diagnosis

● Low-grade adenocarcinoma
CLINICAL FEATURES
Post-atrophic hyperplasia of the prostate is a descriptive term Special techniques
applied to a distinctive pathological change seen in atrophic ● The basal cell layer can be demonstrated by antibodies
prostates. This is found exclusively in the peripheral zone in against high-molecular-weight cytokeratin, such as clone
18% of radical prostatectomy specimens. 34␤E12.
SCLEROSING ADENOSIS Special techniques

● Periodic acid–Schiff (PAS) with diastase staining highlights
the luminal secretions and the basement membrane
CLINICAL FEATURES
surrounding the glands and the clusters of cells.
Sclerosing adenosis of the prostate is a pseudoneoplastic lesion ● Alcian blue staining at pH 2.5 shows focal but strong
that can mimic prostate cancer. It is an uncommon benign positivity of the luminal secretions and the myxoid stroma.
lesion, and is usually found incidentally. It is present in about ● Reticulin staining highlights the thin stromal fibers
2% of elderly men who undergo transurethral resection, open in-between the proliferating glands.
prostatic adenectomy, radical prostatectomy, or total cysto- ● High-molecular-weight cytokeratin monoclonal antibody
prostatectomy. Because the lesion is more common in the tran- 34␤E12 is a marker for basal cells, and as such is very
sition zone, it is only rarely sampled in needle biopsy. useful in the differential diagnosis of prostatic cancer from
other benign neoplastic proliferation. The basal cell layer
is lost in prostate adenocarcinomas, but exists in most of
PATHOLOGICAL FEATURES the proliferative lesions.
Histologically, sclerosing adenosis of the prostate resembles

sclerosing adenosis of the breast, consisting of a well-demarcated
cellular nodule containing numerous glandular or epithelial struc- PROSTATIC CARCINOMAS
tures. These are of various sizes and shapes, and are haphazardly
arranged or crowded, some with compressed lumina. There CLINICAL FEATURES
may also be small solid nests and individual cells embedded in
a cellular, sclerotic, focally myxoid stroma, mimicking a small Prostatic carcinoma is a very common malignant tumor, the
acinar prostatic adenocarcinoma. A thickened basement mem- incidence of which increases with patient age. When the disease
brane is sometimes seen around the glands and cell clusters. occurs in men under the age of 50 years, it is usually clinically
Occasional foci of basal cell hyperplasia may be seen in the undetectable, a higher proportion of patients present with
glands of adjacent tissue. disseminated disease (stage D), and the condition is therefore
associated with a low survival rate (average 23 months). The
tumor is very rare in children and adolescents and is usually of
Secondary features
the poorly differentiated type that does not respond to therapy
● Occasionally foci of squamous metaplasia of adjacent glands. and is associated with very poor prognosis (average survival
● Inflammatory infiltrate. 3–10 months). Prostatic carcinoma tends to metastasize to the
left supraclavicular and supradiaphragmatic lymph nodes.
Cellular morphology
● The proliferating glands are lined by a single layer of Presentation of prostatic carcinoma
cuboidal or flattened secretory cells.
Clinically detected carcinoma usually has signs and symptoms
● These have an eosinophilic granular or vacuolated
attributed to prostatic carcinoma, including mass on rectal
cytoplasm, some with signet ring appearance.
examination, bladder outlet obstruction, irritation of the pro-
● Occasional basal cells are seen at the basal layers of
static urethra, and occasional hematuria.
some of the glands.
Incidental or subclinical carcinoma is detected on micro-
● The cells exhibit mild to moderate atypia.
scopic examination of surgically removed prostatic tissue, usually
● Mitotic figures can be seen.
for BPH.
● The cellular stroma contains fibroblasts, collagen fibers,
Occult carcinoma is the detection of metastases before the
myxoid substance and rounded, polygonal or spindle-
primary disease.
shaped cells representing myoepithelial differentiation
Prostatic carcinoma can be detected at autopsy in patients with
of the basal cells.
no clinical evidence of prostatic carcinoma ‘latent carcinoma’.
● The stroma however characteristically lacks a smooth
Androgen-deprivation therapy for prostatic cancer is used
muscle component; the latter is often seen in carcinoma.
for preoperative tumor shrinkage and treatment for prostatic
hyperplasia, and may be effective for cancer prophylaxis. It
Differential diagnosis may act by causing an acceleration of programmed cell death
● Small acinar prostatic adenocarcinoma of single cells (apoptosis), fragmentation of DNA, and inhibi-
● Basal cell adenomatosis (multiple clusters of basal cell tion of cell growth.
proliferation with some circumscription)
● Basal cell adenoma (consists of one or more large round, The Gleason system of grading
usually solitary circumscribed nodules of acini with basal The Gleason system is the most widely used grading system. It
cell hyperplasia in a setting of nodular hyperplasia) is based mainly on the architectural pattern of tumor growth
● Adenomatoid tumor seen at low-power magnification, and does not take into
● Atypical adenomatous hyperplasia account the cytological features of the tumor. There are five
grades, with grade 1 being the well-differentiated tumors and M ⫽ Distant metastasis
grade 5 the least differentiated. The main pattern and any sig- MX Distant metastasis cannot be assessed
nificant minor pattern of each tumor are graded, and the two M0 No distant metastasis
figures are added together to give the Gleason score (2–10). (For M1 Distant metastasis
a more detailed description of this grading system, see below.) M1a Non-regional lymph node(s)
Gleason grade 1 adenocarcinoma is very uncommon and dif- M1b Bone(s)
ficult to diagnose, especially in needle biopsy. M1c Other site(s)
Clinical significance of grading

● Correlation of grading and PSA: adenocarcinoma with an PATHOLOGICAL FEATURES (Figures 11.4–11.12)
elevated PSA is more likely to be of a higher grade, larger Prostatic carcinomas are classified into the following histolog-
volume and more advanced pathological stage than that ical categories:
associated with normal PSA level. ● Acinar adenocarcinomas constitute the majority of prostatic
● Correlation of grading and pathological stage: carcinomas; they tend to arise from the tubuloalveolar
adenocarcinoma with Gleason grade 8 or higher on glands in the outer peripheral zone of the prostate.
biopsy is strongly predictive of lymph node metastasis.
● Correlation of grading and tumor location: The Gleason grading system
adenocarcinoma arising in the transitional zone of the The Gleason grading system is based on degree of architectural
prostate appears to be of a lower grade and less aggressive of differentiation. Because most carcinomas are heterogeneous
clinically than the more common adenocarcinoma arising in their architectural patterns, the dominant pattern is
in the peripheral zone. assigned.
● Correlation of grading with recurrence and survival: the ● Gleason 1: this shows a circumscribed mass of well-formed,
Gleason score is the strongest predictor of time to evenly spaced, simple, rounded, monotonously replicated
recurrence after radical prostatectomy. medium-sized acinar structures closely packed together
with pushing, or expansile borders. The epithelial cells
TNM Staging of prostatic carcinoma have pale or clear cytoplasm with moderate nuclear and
T ⫽ Primary tumor nucleolar enlargement. The circumscription is the most
TX Primary tumor cannot be assessed important feature in distinguishing this from Gleason 2.
T0 No evidence of primary tumor Because of that, it is difficult to diagnose Gleason 1
T1 Clinically inapparent tumor not palpable or visible by carcinoma in a biopsy where the borders cannot be seen.
imaging In such cases, it is best to consider it as Gleason 2. Acidic
T1a Tumor incidental histological finding in 5% or less
of tissue resected
T1b Tumor incidental histological finding in more than
5% of tissue resected
T1c Tumor identified by needle biopsy (e.g., because of
elevated PSA)
T2 Tumor confined within prostate1
T2a Tumor involves one half of one lobe, or less
T2b Tumor involves more than half of one lobe, but
not both lobes
T2c Tumor involves both lobes
T3 Tumor extends through the prostatic capsule2
T3a Extracapsular extension (unilateral or bilateral)
T3b Tumor invades seminal vesicle(s)
T4 Tumor is fixed, or invades adjacent structures other than
seminal vesicles: bladder neck, external sphincter, rectum,
levator muscles, or pelvic wall
Notes:
1. Tumor found in one or both lobes by needle biopsy, but not palpable
or visible by imaging, is classified as T1c.
2. Invasion into the prostatic apex or into (but not beyond) the prostatic
(a)
capsule is not classified as T3, but as T2.
N ⫽ Regional lymph nodes Figure 11.4 (a–c) Gleason 1 prostatic carcinoma.This shows a
circumscribed mass of well-formed, evenly spaced, simple, rounded,
NX Regional lymph nodes cannot be assessed
monotonously replicated medium-sized acinar structures closely
N0 No regional lymph nodes metastasis packed together with pushing, or expansile borders.The epithelial
N1 Regional lymph node metastasis cells have pale or clear cytoplasm with moderate nuclear and
Note: Metastasis no larger than 0.2 cm can be designated pN1mi. nucleolar enlargement.
(b) (a)
(c) (b)
Figure 11.4 (Continued). Figure 11.5 (a, b) Gleason 2 prostatic carcinoma.This is

very similar to Gleason 1 except for lack of circumscription
of the focus, greater variation in acinar size and shape with more
luminal mucin is usually scant and wispy in Gleason 1 and acinar packing.The cytological pattern is identical to that of
2. Crystalloids are seen in more than half of the cases. Gleason 1.
● Gleason 2: this is very similar to Gleason 1 except for lack
of circumscription of the focus, greater variation in acinar
size and shape with more acinar packing. The cytological angular glands with variation in shape. These have
pattern is identical to that of Gleason 1. infiltrative borders. The epithelium appears
● Gleason 3: this is the most common pattern of prostatic more basophilic than that in Gleason grades
adenocarcinoma, and is characterized by variation in size, 1 and 2.
shape, and spacing of the acini. However, the glands – Gleason 3B (small gland variant): this is similar to
remain discrete and separate, with no fusion. The edges Gleason 3A, but with small-sized glands.
show a ragged appearance. This grade encompasses three – Gleason 3C (cribriform variant): this shows marked
main variants: infiltrative pattern of irregularly shaped sized glands
– Gleason 3A (large gland variant): this shows variably exhibiting papillary or cribriform pattern and with
packed, irregular masses of medium- to large-sized, smooth or rounded peripheral borders.
(a) (a)
(b) (b)
Figure 11.6 (a, b) Gleason 3 prostatic carcinoma.This is Figure 11.7 (a, b) Gleason 4 ⫹ 5 prostatic carcinoma. Acinar
characterized by variation in size, shape and spacing of the acini fusion, and haphazardly arranged acini.
and infiltrative margins.
The separation of Gleason 3B and 3C might not be necessary – Gleason 4B (clear or pale cytoplasm): this is almost
as both are more aggressive than 3A and have similar cancer- exactly as Gleason 4A, but with a clear, hypernephroid
specific death rates. cytoplasmic epithelial pattern.
● Gleason 4: the characteristic finding of this grade is acinar ● Gleason 5: the characteristic finding of this grade is fused
fusion, with ragged infiltrating cords and anastomosing sheets and masses of haphazardly arranged acini in the
network of epithelium. Grade 4 prostatic carcinoma is stroma, often displacing or overrunning adjacent
poorly differentiated and is much more malignant than epithelium. In a biopsy, the appearance may suggest an
grade 3. This pattern encompasses two variants: anaplastic carcinoma or sarcoma. Grade 5 pattern
– Gleason 4A (basophilic cytoplasm): this shows ragged encompasses two variants:
infiltration of irregularly sized fused glands with chains and – Gleason 5A: this shows irregularly sized, rounded to
cords. They exhibit microacinar, papillary and cribriform elongated glands with marked infiltrative features and
pattern, with cells showing darkly stained cytoplasm. smooth, rounded borders. However, the glands show
(a)
Figure 11.9 Metastatic prostatic carcinoma.The acinar pattern is

still identified, with cells showing prominent nucleoli.
(b)
Figure 11.8 (a, b) Gleason 5 prostatic carcinoma.This shows

irregularly sized rounded to elongated glands with marked
infiltrative features.
(a)
a comedocarcinoma pattern. The cytoplasmic staining Figure 11.10 (a–c) Papillary prostatic duct carcinoma/ductal
is variable. adenocarcinoma with endometrioid features.These consist of
invasive glands reminiscent of carcinoma of the endometrium – that
– Gleason 5B: this shows ragged infiltration of fused
is, lined by tall or stratified columnar epithelium, sometimes with a
sheets and masses with difficulty in identifying gland ciliated surface and apical blebs.
lumens. The cytoplasmic staining is variable.
Variants of prostatic carcinoma histological variants of prostate carcinoma is important, because

Most cases of carcinoma involving the prostate gland show some types are associated with a different clinical outcome and
characteristic acinar histological features. The term ‘variant’ is might have a different therapeutic approach. Recognition is also
used to describe a distinctly different histomorphological important because awareness of the unusual pattern might be
phenotype of a certain type of neoplasm. The recognition of critical in avoiding diagnostic misinterpretations.
(b) (a)
(c) (b)
Figure 11.10 (Continued). Figure 11.11 (a, b) Prostatic carcinoma with treatment effect
(androgen-deprivation therapy).This shows stromal fibrosis and
prominent epithelial clear cell change, nuclear shrinkage, nuclear
hyperchromasia and nucleolar shrinkage.These changes can result
Ductal adenocarcinoma in the carcinoma cells resembling lymphocytes or macrophages,
This is an adenocarcinoma with endometrioid features (syn. pap- particularly at low-power magnification.
illary carcinoma, endometrioid carcinoma). This lesion accounts
for 0.8% of prostatic carcinoma, and histologically resembles
endometrioid carcinoma of the uterus. This tumor typically carcinoma’. Ductal adenocarcinoma with endometrioid features
arises as a polypoid or papillary mass within the prostatic ure- usually consists of invasive glands reminiscent of carcinoma of
thra and large periurethral prostatic ducts, or it involves the the endometrium – that is, lined by tall or stratified columnar
verumontanum. As in endometrioid adenocarcinoma of the epithelium, sometimes with a ciliated surface and apical blebs.
uterus, this tumor may exhibit ductal pattern ‘classic endometri- Those showing a papillary pattern usually exhibit papillary
oid’ or papillary pattern ‘papillary adenocarcinoma of the fronds with a cribriform pattern composed of tall columnar or
prostate’ with some cribriform features. Some carcinomas show cuboidal epithelium, show small papillary projections lined by
significant histological and clinical features of ductal adeno- single or multilayered columnar cells, or appear as solid islands
carcinoma and typical acinar carcinoma ‘mixed ductal-acinar of clear cells with apocrine features.
Adenocarcinoma with neuroendocrine cells

A rich variety of neuroendocrine cells is present in the normal
prostate gland. Prostatic carcinoma may show divergent differen-
tiation towards a neuroendocrine phenotype in the form of neu-
roendocrine small cell carcinoma or carcinoid-like tumors. Much
more common is focal neuroendocrine differentiation in prostatic
adenocarcinoma, which may be pronounced in approximately
10% of adenocarcinomas. Neuroendocrine differentiation in car-
cinoma of the prostate appears to be associated with a poor prog-
nosis, tumor progression, and the androgen-independent state.
However, there seems to be no significant correlation between
neuroendocrine differentiation and prognostic markers such as
Gleason score and pathological stage in adenocarcinoma of the
prostate. Chromogranin A appears to be the best overall tissue
(a) and serum marker of neuroendocrine differentiation. Chromo-
granin A serum levels may be useful in the assessment of the emer-
gence of and/or progression of hormone-resistant cancer.
Neuroendocrine/small undifferentiated cell carcinoma

Neuroendocrine/small undifferentiated carcinoma of the
prostate is a rare, aggressive tumor. It should be distinguished
from the less aggressive prostatic carcinoma with small cell
features, but with no neuroendocrine differentiation. The fol-
lowing immunohistochemical stains may help to identify the
true nature of the small cell carcinoma: MIB-1; chromogranin
A (Chr A); synaptophysin (SNP); cytokeratin (CK) 34␤E12;
CK20; androgen receptor (AR); and PSA. Small cell neuroen-
docrine carcinomas demonstrate extremely high proliferation
activity (⬎80%) and express Chr A and SNP. CK34␤E12,
CK20, PSA and AR are negative.
(b)
Squamous cell carcinoma of the prostate
Figure 11.12 (a, b) Cowper’s gland.These consist of a collection of This is a rare tumor, and accounts for 0.5–1% of all prostatic
back-to-back small mucinous acini lined by cells showing clear cytoplasm
cancers. It is highly aggressive, and responds poorly to any
with small basal nuclei.This can be mistaken for prostatic carcinoma.
mode of therapy. It may develop in patients with prostatic ade-
Mucinous carcinoma nocarcinoma following radiation therapy.
Mucinous carcinoma is similar to mucinous carcinomas seen else- Adenosquamous carcinoma of the prostate
where. This diagnosis is made when at least 25% of the tumor
This is a rare tumor, with irradiation playing a pathogenetic
shows lakes of extracellular mucin. The cribriform pattern tends
role. The squamous component is represented by cells that con-
to predominate in mucinous carcinoma. Some carcinomas are
tain vesicular or hyperchromatic nuclei and large acidophilic
composed of signet ring cells but have no extracellular mucin.
cytoplasm. Adenosquamous cell carcinoma of the prostate
Signet ring cell carcinoma should be considered in the differential diagnosis when a
This is a distinct, aggressive, uncommon variant of primary patient with prostate cancer develops a rectal mass or rectal
prostatic carcinoma. The cytoplasmic change should be distin- bleeding following radiation therapy, and the rectal biopsy
guished from artifactual vacuolation of tumor, inflammatory reveals squamous cell carcinoma.
and stromal cells, and metastatic disease. Immunostaining con- The difficulty is when the subsequent squamous metastasis
firms the prostatic origin of the signet ring tumor which stains or recurrence shows only the malignant squamous component
for PSAP and PSA. Cytokeratin immunostaining shows the in some sites, with the adenocarcinoma present in other sites.
vacuoles to be true lamina, with clear and distinct outlines. Immunohistochemically, the glandular tumor cells are positive
This tumor should be distinguished from secondary signet ring for PSA.
cell carcinoma from the gastrointestinal tract.
Adenocarcinoma with oncocytic features
Carcinosarcoma/sarcomatoid carcinoma Primary carcinoma of the prostate may rarely express diffuse
Carcinosarcoma of the prostate is an uncommon and aggressive oncocytic changes. This may create diagnostic difficulty, espe-
tumor composed of an intimate admixture of adenocarcinoma cially if it presents primarily as a metastatic tumor. The bio-
and sarcomatous elements. The carcinomatous component is logical behavior of this tumor does not differ from the
usually positive for both cytokeratin and PSAP. conventional-type prostatic adenocarcinoma.
Lymphoepithelial-like carcinoma ● The cells of well-differentiated tumors closely resemble

This is an extremely rare – but distinctive – variant of prostatic normal acinar epithelium, but the abnormal basal layer
adenocarcinoma. is absent.
● The cells of moderately differentiated carcinomas are
Adenoid cystic carcinoma/basal cell carcinoma similar to normal acinar cells, but have larger nuclei with
easily identifiable nucleoli.
Adenoid cystic carcinoma of the prostate is an extremely rare ● The cells of poorly differentiated carcinomas show obvious
variant. This should be distinguished from other basaloid
pleomorphism, mitoses and prominent nucleoli.
tumors of the prostate such as adenoid cystic-like carcinoma, ● Sometimes the glands are lined by cells with voluminous
adenoid basal cell tumor and basal cell carcinoma.
xanthomatous cytoplasm and contain small nuclei with
little or no atypia.
Prostatic carcinoma with treatment effect (androgen-
● Cytoplasmic vacuolation with pyknotic nuclei may be seen
deprivation therapy) (see Figure 11.11)
in prostatic carcinoma following anti-androgen therapy.
This shows marked lobular and acinar atrophy, a decreased ratio ● Large vacuoles reminiscent of lipoblasts are sometimes seen.
of acini to stroma, basal cell hyperplasia in benign epithelium, foci ● Some carcinomas contain signet ring cells.
of epithelial hyperplasia, stromal edema in the early stages and ● Luminal blue-tinged mucinous secretions may be seen in
fibrosis in late stages, squamous and/or transitional metaplasia, about two-thirds of well- to moderately differentiated
and acinar rupture with extravasations of secretions. Androgen- prostatic adenocarcinomas. Mucin may also be seen in
deprivation therapy also causes a marked reduction in the pres- adenosis, but not in the form of blue-tinged secretions.
ence of high-grade prostatic intraepithelial neoplasia (PIN), and ● Dense eosinophilic crystalline-like structures that appear to
an apparent increase in the Gleason grade of the tumor. The cells have various geometrical shapes are seen in nearly 60% of
show prominent clear cell change, nuclear shrinkage, nuclear prostatic carcinomas (especially the well-differentiated
hyperchromasia and nucleolar shrinkage. These changes can result type). These may also be seen in benign glands adjacent
in the carcinoma cells resembling lymphocytes or macrophages, to carcinoma, or sometimes in adenosis.
particularly at low-power magnification.
Prostatic adenocarcinoma resembling benign hyperplastic
glands In a needle biopsy, classic prostatic carcinoma should be
distinguished from:
Also known as pseudohyperplastic prostatic adenocarcinoma,
● Atrophic glands, especially when associated with
this is a recently recognized entity. The lesion shows benign fea-
inflammation (they usually have open lumina and are lined by
tures, including papillary infoldings, large atypical glands, branch-
basophilic cells with an increased nuclear:cytoplasmic ratio).
ing, and corpora amylacea. The extent of pseudohyperplastic
● Seminal vesicle glands when included in the biopsy may be
cancer ranges from 1.0 to 10.0 mm (average 3.7 mm). Within the
mistaken for carcinoma (multiple small glands arranged
pseudohyperplastic foci, features helpful in establishing a malig-
around a central lumen, often showing scattered atypical
nant diagnosis are nuclear enlargement, pink amorphous secre-
but degenerate-looking nuclei and the presence of
tions, occasional to frequent nucleoli, and crystalloids. Other
lipofuscin pigment).
features associated with malignancy (mitoses, blue-tinged mucin,
● Cowper’s gland consisting of a collection of back-to-back
adjacent high-grade PIN, and perineural invasion) are infrequent.
small mucinous acini lined by cells showing clear
Immunohistochemical stains for high-molecular-weight keratin
cytoplasm with small basal nuclei.
shows an absence of basal cells in the pseudohyperplastic areas.
● Crushed cellular foci of benign hyperplasia.
It is critical to recognize pseudohyperplastic prostatic adenocar-
cinoma and the features needed to establish a malignant diagno- In a transurethral resection specimen (TUR).
sis so that these carcinomas are not misdiagnosed as benign. ● Adenosis/adenomatous hyperplasia consists of numerous,
crowded, small, pale-staining glands resembling a nodule of
Transitional cell carcinoma (TCC) of the prostate low-grade prostatic carcinoma. Benign glands with papillary
This is considered as urethral carcinoma, is usually high-grade infolding are often seen admixed with those of adenosis,
TCC, and may show evidence of invasion. Prostatic adenocar- and a basal cell layer can be identified at least focally.
● Atypical adenosis may show minimal infiltration away
cinoma and urothelial carcinoma (transitional cell carcinoma)
may coexist in the prostate. However, a carcinoma with mixed from the main nodule of adenosis, and may show a minor
features has rarely been reported. component of poorly formed glands or even single cells.
Some cells may also show fairly prominent nucleoli.
● Sclerosing adenosis (see Sclerosing adenosis of the prostate,
Secondary features
p. 793) usually shows a periglandular hyaline sheath;
● Necrosis is especially seen in estrogen-treated cases. occasional basal cells can be identified.
● Intraluminal rod-shaped crystalline-like structures. ● Benign cribriform lesions (clear cell cribriform hyperplasia)
show numerous glands with cribriform and Roman bridge

Cell morphology formation with clear cell change. The nuclei are benign-
● The cells become cytologically more obviously malignant looking and may contain small nucleoli. These glands
with increasing Gleason score. usually have striking basal cell layer.
● Prostatic cancer treated with androgen-deprivation therapy but not prominent. The basal cell layer and the basement mem-
can be confused with various benign conditions such as brane are intact.
clear cell cribriform hyperplasia, sclerosing adenosis,
acinar atrophy, atypical adenomatous hyperplasia and High-grade PIN
atypical basal cell hyperplasia. Furthermore, small clusters This is similar to low-grade PIN, but there are clear-cut cyto-
of tumor cells may be very inconspicuous and can be logical features of malignancy. There is a more pronounced
misinterpreted as lymphocytes or stromal cells. stratification and crowding of nuclei, numerous enlarged
● Verumontanum mucosal gland hyperplasia (see Benign nuclei, and prominent single or multiple nucleoli in most of the
prostatic hyperplasia, p. 786). cells. The basal layer shows some disruption, and the basement
membrane is intact. There are four main architectural patterns
Special techniques of high-grade PIN: tufting; micropapillary; cribriform; and flat.
● Immunostaining for PSAP and PSA is highly specific for
prostatic carcinomas when compared to carcinomas from
other sites. Weak focal staining for PSAP has been reported
in some other carcinomas. Some poorly differentiated
prostatic carcinomas (25–50%) show focal staining only
or (in 5–10%) fail to stain with one or either of these
markers.
● High-molecular-weight cytokeratin (34␤E12) stains the basal
cells of benign glands uniformly and intensely, is focally
expressed in adenosis, and is absent from carcinomas.
● Acidic mucin is seen in some carcinomas.
PROSTATIC INTRAEPITHELIAL NEOPLASIA (PIN)
CLINICAL FEATURES
Prostatic intraepithelial neoplasia (PIN) is a currently used ter-
minology applied to presumed premalignant lesions in the
prostate. The lesion is graded into low- and high-grade PIN to
replace the previous three grades system (PIN1 is considered
(a)
low grade and PIN2 and 3 are the high grade).
There is a strong association between PIN and prostatic carci-
noma, and PIN is more often seen in the peripheral zone of the
prostate, where most prostatic adenocarcinomas are thought to
arise. PIN and cancer are almost always multifocal in the prostate.
High-grade PIN has a high predictive value as a marker for ade-
nocarcinoma, and its identification in a biopsy specimen warrants
further search for concurrent invasive carcinoma. In particular,
patients with increased serum PSA levels appear to be at greater
risk of harboring prostatic adenocarcinoma. However, a signifi-
cant number of patients with high-grade PIN on initial biopsy
may not have evidence of carcinoma on repeat biopsy. Thus, rad-
ical prostatectomy or radiotherapy for PIN is not warranted.

PIN is characterized by both architectural and cytological abnor-
malities of the involved prostatic glands, without evidence of stro-
mal invasion. The glands are separated by a modest amount of
stroma and are generally large with papillary infolding resem-
bling normal glands, but are lined by abnormal cells.
(b)
Low-grade PIN
Figure 11.13 (a–e) Low-grade prostatic intraepithelial neoplasia
The epithelium lining the ducts and acini are heaped up, crowded, (PIN).The epithelium lining the ducts and acini are heaped up,
and irregularly spaced, with marked variation in nuclear size. crowded, and irregularly spaced with marked variation in nuclear
Elongated hyperchromatic nuclei and small nucleoli are present, size.The basal cell layer and the basement membrane are intact.
(c) (e)
(d)

(a)
These patterns often merge with each other. A rare pattern

Figure 11.14 (a–c) High-grade prostatic intraepithelial neoplasia
(solid PIN) with or without comedo-type necrosis may be seen (PIN).The epithelium lining is heaped up and forms small papillae.
in untreated patients.
Other features include microcalcifications, pertinacious lumi-
nal secretions, corpora amylacea, exfoliated cells of PIN, lumi- 2. Direct invasion through the ductal or acinar wall, with
nal crystalloids, and mucinous metaplasia. disruption of the basal cell layer.
PIN spreads into the prostatic ducts in three different pat- 3. Neoplastic cells invaginate between the basal cell layer
terns, similar to prostatic carcinoma: and the columnar secretory cell layer – this is termed
1. Neoplastic cells replace the normal luminal secretory ‘pagetoid spread’.
epithelium, with preservation of the basal cell layer and
basement membrane. Foci of high-grade PIN with this Pin after therapy
pattern are indistinguishable from ductal spread of The cells of PIN appear to be hormone-dependent, this being
carcinoma. illustrated by the marked decrease in the prevalence and extent
Hyperplasia:
● Benign epithelial hyperplasia
● Cribriform hyperplasia
● Atypical basal cell hyperplasia
● Post-atrophic hyperplasia
● Simple lobular atrophy
● Sclerosing adenosis
Metaplasia and reactive changes:

● Urothelial metaplasia
● Infarction-induced atypia
● Inflammation-induced atypia
● Radiation-induced atypia
● Nephrogenic metaplasia of the prostatic urethra
Carcinoma:
● Acinar adenocarcinoma
● Urothelial dysplasia and carcinoma
● Cribriform pattern of prostatic adenocarcinoma
● Ductal (endometrioid) prostatic adenocarcinoma
(b)
Special techniques
● High-molecular-weight cytokeratin monoclonal antibody
34␤E12 is a marker for basal cells, and as such is very
useful in the differential diagnosis of PIN.
RARE PRIMARY TUMORS
MALIGNANT LYMPHOMA
Lymphoma involving the prostate is rare, whether presenting

as primary extranodal lymphoma or as a secondary spread to
the prostate from other sites. It should be considered in the dif-
ferential diagnosis of lower urinary tract obstruction, particu-
larly in patients with a previous history of lymphoma.
MALIGNANT MELANOMA
Primary malignant melanoma of the prostate has rarely been

described.
(c)

SARCOMAS AND RELATED PROLIFERATIVE
of high-grade PIN in the prostate gland after androgen-depri- LESIONS OF THE SPECIALIZED PROSTATIC
vation therapy. This decrease is accompanied by epithelial STROMA
hyperplasia, cytoplasmic clearing and prominent acinar atro-
phy, with a decreased ratio of acini to stroma. Sarcomas and related proliferative lesions of the specialized pro-
PIN is difficult to recognize after radiotherapy. static stroma encompass a spectrum of histological features and
may be grouped into two clinicopathological categories: prosta-
Differential diagnosis tic stromal proliferation of uncertain malignant potential; and
Normal anatomic structures and embryonic rests: prostatic stromal sarcoma.
● Seminal vesicle and ejaculatory ducts The distinction is based on their degree of stromal cellularity
● Cowper’s glands and the presence of mitotic figures, necrosis, and stromal over-
● Paraganglionic tissue growth, and also on immunohistochemical profile. Patient age
● Mesonephric remnants ranges from 25 to 86 years; mean age is 54 years, and peak
● Ectopic prostatic tissue of the urethra incidence is in the sixth and seventh decades of life. The most
common clinical presentation is urinary retention, followed by leiomyosarcoma has a poor prognosis, although survival time
abnormal results of digital rectal examination, hematuria or can vary. A number of treatment approaches have been adopted,
hematospermia, and a palpable rectal mass. including radical surgery, radiotherapy and chemotherapy, but
these are often unsuccessful. Prostate leiomyosarcoma has a
Prostatic stromal proliferation of uncertain malignant varied histological appearance ranging from spindled cell neo-
potential plasm reminiscent of smooth muscle to pleomorphic sarcoma.
Epithelioid features may be present. Most tumors are immuno-
The entity called ‘prostatic stromal proliferation of uncertain
reactive with antibodies to vimentin and actin, and reactivity
malignant potential’ apparently has a benign behavior. Tumor
with antikeratin antibodies does not exclude the diagnosis of
recurrence may be seen in 46% of cases.
leiomyosarcoma. Prostate leiomyosarcoma has a poor progno-
Four histological patterns have been identified:
sis, although the duration of survival is variable.
1. Hypercellular stroma with scattered cytologically atypical
cells associated with benign glands.
Malignant phyllodes tumor
2. Hypercellular stroma with minimal cytological atypia
associated with benign glands. Malignant phyllodes tumor of the prostate is characterized by
3. Hypercellular stroma with or without cytologically a fibrosarcoma-like pattern with adjacent changes of fibroade-
atypical cells, associated with benign glands in a ‘leaf-like’ noma and phyllodes-type of prostatic atypical hyperplasia.
growth pattern that resembled phyllodes tumors of the
mammary gland. Other sarcomas
4. Hypercellular stroma without cytologically atypical Other very rare sarcomas that may be seen in the prostate
stromal cells and without glands. include malignant fibrous histiocytoma and synovial sarcoma.
Prostatic stromal sarcoma

The entity ‘prostatic stromal sarcoma’ might have a malignant
potential, but its line of differentiation is still unclear. Prostatic SECONDARY METASTASIS
stromal sarcoma shows greater cellularity, mitoses, necrosis,
and stromal overgrowth than prostatic stromal proliferation Secondary neoplasms represent 2.1% of all neoplasms in sur-
of uncertain malignant potential, and consists either of stro- gical specimens – a similar proportion of the total number of
mal elements with benign glands in a pattern that resembled malignant solid neoplasms as secondary tumors at other sites
malignant phyllodes tumors of the mammary gland or of in the genitourinary tract. The patients are usually sympto-
purely stromal elements. matic, presenting with prostatism, hematuria or pelvic pain,
and the condition occurs almost always in those patients with
Leiomyosarcoma widely disseminated disease. Primary sites include the bladder,
Leiomyosarcoma of the prostate is a rare neoplasm which rectum, skin (malignant melanoma), breast, eye (malignant
accounts for less than 0.1% of prostate malignancies. Prostate melanoma), adrenal cortex, and gallbladder.
TUMORS OF THE URETHRA
Overall, epithelial growths in the urethra are rare and present incontinence. The same technique has recently been used to
as either benign or malignant lesions at different periods of life. improve the function of urinary pouches surgically created
The incidence of these lesions varies between the sexes. Among from intestinal segments. This has been shown to result some-
the benign urethral growths, condyloma in younger men, and times in the development of a polypoid lesion consisting of
urethral caruncles in elderly women, are relatively common. In injected collagen with pathognomonic features (i.e., eosinophilic,
contrast, cancer of the urethra is relatively rare and shows a homogeneous, and poorly cellular material that is faintly pos-
clear predilection for the female sex. itive by PAS staining and strongly positive by trichrome
staining).
Hemangioma is an exceedingly rare, benign tumor which
commonly presents as urethral bleeding. The lesions usually
involve the entire urethra, or they may be localized to the ante-
BENIGN URETHRAL LESIONS
rior urethra.
Leiomyoma of the female urethra is a rare condition that
COLLAGEN POLYP OF THE URINARY TRACT commonly presents with recurrent urinary tract infections and
various lower urinary tract symptoms.
Injection of collagen into the urethral or bladder wall has Nephrogenic adenoma of the prostatic urethra is similar to
proven to be an effective way to control urinary stress those seen in the bladder.
Villous polyps of the urethra are rare, and generally localized prognosis, despite the wide variety of surgical treatment
in or around the verumontanum. available.
PRIMARY MALIGNANT MELANOMA

FIBROEPITHELIAL POLYP
Primary malignant melanomas of the urethra are extremely rare.
The fibrous polyp of the urethra (fibroepithelial polyp, simple
Clinically, they are usually mistaken for other malignant dis-
polyp, pedunculated polyp) is a rare benign epithelial tumor
eases, or even benign lesions. The histopathology does not usu-
which is encountered more frequently in males, and in the pos-
ally differ from that of melanoma at other body sites. Malignant
terior urethra. When it appears in females it is usually located in
mucosal melanoma appears to have an aggressive biological
the external meatus and is normally asymptomatic, though it can
behavior with a high incidence of local failure and metastasis. An
also present with terminal hematuria or urethral hemorrhage.
early diagnosis may benefit from radical surgery and adjuvant
Mechanical irritation by repeated transurethral procedures
immunotherapy with curative effect.
might be responsible for the development of fibroepithelial polyp
of the urethra as they may be seen during the postoperative
follow-up period of urothelial cancer. The differential diagnosis PRIMARY MUCOSA-ASSOCIATED LYMPHOID
includes other benign epithelial tumors of the urethra, such as TISSUE (MALT) LYMPHOMA
the caruncles, squamous papilloma, and condyloma.
Primary non-Hodgkin lymphomas rarely arise from the lower
urinary tract, the urethra being the most uncommon site of
origin.
MALIGNANT URETHRAL LESIONS
PRIMARY NEUROENDOCRINE CARCINOMA
PRIMARY ADENOCARCINOMA
Primary neuroendocrine carcinoma of the urethra has rarely
A variety of primary adenocarcinomas can occur in the been reported, and it is indistinguishable from neuroendocrine
urethra of both sexes. They are very uncommon with poor carcinoma seen elsewhere.
TUMORS OF THE TESTIS
GENERAL COMMENTS In addition to the stage of the disease and the presence of serum
markers, there are important pathological changes that have
Testicular neoplasms are mostly malignant and of germ cell ori- clinical significance. These include: (i) the cell type; (ii) the
gin. Other tumors of diverse origin are mostly rare, but may amount of the component; and (iii) the presence or absence of
create diagnostic difficulties. vascular invasion. Pure embryonal carcinoma (malignant ter-
In this section, all testicular tumors are described and illus- atoma undifferentiated) or embryonal carcinoma in excess of
trated whenever possible, with emphasis placed on their differ- 80% in a mixed tumor and vascular/lymphatic invasion are
ential diagnosis. high-risk factors as they are predictors of relapse. These factors
should be recognized by the pathologist, and should also be
taken into account by the oncologist when selecting the
GERM CELL TUMORS management of a patient with a germ cell tumor of the testis.
The etiology of germ cell tumors is unknown. Crypt-
orchidism, a prior testicular germ cell tumor, a family history of
GENERAL CONSIDERATIONS testicular germ cell tumors, and somatosexual ambiguity syn-
dromes remain well-established risk factors. Carcinoma in situ
(CIS)/intratubular germ cell neoplasia (ITGN) represents the
CLINICAL FEATURES
common precursor to the great majority of testicular germ cell
Germ cell tumors form the majority of malignant testicular tumors, and its identification in testicular biopsies reliably
tumors, arising from precursor malignant germ cells which have identifies those patients who will progress to an invasive lesion.
the potential to various differentiations. They occur mainly in Seminoma appears to represent the invasive derivative of intra-
young men, and are usually unilateral; however, the incidence of tubular germ cell neoplasia of the unclassified type; problematic
bilateral germ cell tumors has increased due to the improved sur- variants include seminomas with tubular, granulomatous, and
vival of patients with unilateral germ cell tumors. With advances edematous patterns. Spermatocytic seminoma is an essentially
in diagnosis and therapeutic approaches, germ cell tumors are non-metastasizing neoplasm unless complicated by the rare
now highly sensitive to treatment, providing long-term survival. development of a sarcomatous component. The combination
of positivity for placental alkaline phosphatase and negativity Germ cell tumors may occur outside the testis, for example
for epithelial membrane antigen (EMA) can assist in the dis- in the retroperitoneum, mediastinum, and central nervous system.
tinction of embryonal carcinomas from somatic carcinomas.
The treatment of clinical stage I patients with non-seminomatous TERMINOLOGY AND CLASSIFICATION
germ cell tumor with ‘surveillance only’ may be contraindicated
depending on features that include the proportion of embry- The British classification of testicular germ cell tumors has
onal carcinoma and the presence of lymphovascular invasion in many advantages over the World Health Organization (WHO)
the orchidectomy specimen. It is important to be aware that classification, but it is the latter system which is used most
pure teratoma differentiated in post-pubertal patients may be commonly worldwide. The new revised WHO classification is
associated with metastases of teratomatous or undifferentiated particularly confusing as it concentrates on individual patterns
non-seminomatous type. Yolk sac tumor is characterized by rather than on tumors as entities. It is advisable to use the
numerous patterns including glandular, myxomatous, sarcoma- British terminology and to give the WHO equivalent classifica-
toid, hepatoid, and parietal variants. Choriocarcinomas (malig- tion in the final diagnosis in a pathology report. Equivalent
nant teratoma trophoblastic) have a biphasic pattern of terminology is listed in Table 11.1.
syncytiotrophoblast and cytotrophoblast; trophoblastic prolif-
erations lacking a biphasic pattern also occur but are difficult CLINICAL MANAGEMENT OF TESTICULAR TUMOR
to classify unless this category is broadened. Mixed germ cell PATIENTS
tumors, consisting of two or more different elements, are more
common than a tumor of a single histological type. The poly- Orchidectomy for suspected testicular tumor is best performed
embryoma is a distinctive, well-organized form of germ cell by a urologist, or by a surgeon with a special interest in urology.
tumor consisting of numerous embryoid bodies. A preoperative blood sample should always be taken for mea-
Germ cell tumors of the testis are classified clinically into surement of tumor markers, especially alpha-fetoprotein (AFP)
seminomatous and non-seminomatous (NSGCT) categories. and the beta subunit of human chorionic gonadotropin (␤hCG).
‘Teratomas’ is the generic term for all NSGCTs in the British The role of a frozen section is debatable; some surgeons believe
classification. These show different clinical features and differ- that this should be routine, while others suggest that it is not
ent therapy and prognosis. Seminoma tends to remain localized required because the testis should always be excised if there
to the testis for a long period, spreads more often via the lym- is any suspicion of tumor, and an incision for frozen section
phatic system and is radiosensitive, while NSGCTs present with carries the risk of iatrogenic tumor dissemination.
advanced disease in about 60% of cases, are spread by blood When the diagnosis of germ cell tumor is confirmed patho-
in addition to the lymphatics, and are more radioresistant. The logically, the patient should be referred to an oncologist for fur-
tumors generally present as a painless enlargement of the testis. ther management. If the tumor is a pure seminoma confined to
They have a characteristic mode of spread, firstly via the lym- the testis (Stage I), the patient will receive prophylactic radio-
phatic system to retroperitoneal and para-aortic nodes, and therapy to the regional (pelvic and para-aortic) lymph nodes.
then to mediastinal and supraclavicular nodes; and secondly by Patients with Stage I teratoma will receive postoperative adju-
hematogenous spread to the lung, liver, brain, and bone. vant chemotherapy if the tumor invades the blood or lymphatic
There are four stages of the disease: vessels: however, if vascular invasion is not identified, the
● Stage I: the tumor is confined to the testis patient can be followed by an intensive surveillance program
● Stage II: a tumor with metastasis to the retroperitoneum without active postoperative treatment (radiotherapy or
● Stage III: tumor with supradiaphragmatic involvement of chemotherapy) unless or until evidence of metastatic spread or
the lymph nodes recurrence becomes evident.
● Stage IV: tumor with extranodal metastasis. In practical clinical management terms, the pathologist must:
(i) assess the extent of local invasion; (ii) differentiate between
Most NSGCTs may be treated effectively with surgery and/or teratoma and seminoma; and (iii) determine if vascular (blood
chemotherapy. or lymphatic) invasion can be identified.
Table 11.1: Comparison of British Testicular Tumors Panel and Registry (TTP & R) and WHO classifications of germ
cell tumors
British WHO
Seminoma Seminoma
Spermatocytic seminoma Spermatocytic seminoma
Teratoma Non-seminomatous germ cell tumor
– teratoma differentiated (TD) – mature teratoma
– malignant teratoma intermediate (MTI) – embryonal carcinoma with teratoma (teratocarcinoma)
– malignant teratoma undifferentiated (MTU) – embryonal carcinoma
– yolk sac tumor – yolk sac tumor
– malignant teratoma trophoblastic – choriocarcinoma
Handling the orchidectomy specimen An adequate number of blocks of tumor should be taken to
A testicular tumor should be removed with surrounding cover- ensure that all different components are likely to be repre-
ings (tunica vaginalis), epididymis and cord, and by using an sented. Empirically, one block of tumor should be taken for
inguinal approach rather than by a trans-scrotal incision. The each centimeter of maximum tumor dimension; for example, at
testis may be incised by the surgeon if a frozen section has been least seven blocks should be taken for a 7-cm tumor.
taken, or if his/her curiosity drives him/her to cut into the spec-
imen so that the tumor can be seen first hand. The surgical inci- Histological examination of the testis
sion causes gross distortion of the specimen; this makes It is important to differentiate between seminoma and teratoma
orientation difficult, but it does have the benefit of enabling because of their different clinical management. Combined tumors
better fixation of the tumor tissue. (seminoma plus teratoma) should be identified, although – in
Histological assessment of poorly fixed testicular tumors can practical terms – combined tumors tend to behave as teratomas
be difficult. The tunica vaginalis and tunica albuginea are potent and are managed clinically as such. The presence or absence of
barriers to the diffusion of fixative, and intact specimens should vascular invasion (blood or lymphatic) must be stated, as this
be opened on arrival in the pathology laboratory by a judicious has direct relevance to postoperative treatment.
longitudinal (sagittal) incision through the rete testis and epi- There are numerous histological variants of testicular germ
didymis using a sharp knife. The specimen should then be cell tumors. These occur either as a pure form (discussed sepa-
allowed to fix in an adequate amount of formalin fixative. rately) or as mixed germ cell tumors.
Cutting through a testicular tumor often results in smearing of In the WHO classification, mixed germ cell tumors contain
tumor cells by the knife to other parts of the specimen. This can different tumor components, whereas in the British classification
give an erroneous conclusion that the tumor has spread to extra- combined tumors contain seminomatous and non-seminomatous
neous sites such as beyond the tunica albuginea or into vascular (teratomatous) components.
spaces. For this reason, it is important to sample the cord, rete Metastasis of mixed germ cell tumor may show one or more
and epididymis with a clean knife before taking the tumor blocks. of the various neoplastic components, or may show a new line
of differentiation.
PATHOLOGICAL FEATURES Choriocarcinoma in the testis – in its pure form – is a rare
tumor, but foci of choriocarcinoma are much more common in
Macroscopic description
mixed germ cell tumors. On occasion, the primary testicular
The dimensions of the testis and length of cord are measured, choriocarcinoma is replaced by fibrous tissue or by a hemor-
and the specimen weighed. The tumor dimensions are recorded rhagic mass with tiny fragments of tumor tissue.
and whether single or multiple; well demarcated or irregular in
outline; and confined to the testis or invading adjacent struc-
tures. The relative position in the testis (upper or lower pole, or CARCINOMA IN SITU (CIS)/INTRATUBULAR
central) and its relation to the rete testis and epididymis are
noted. Involvement of the tunica albuginea or tunica vaginalis GERM CELL NEOPLASIA (ITGN)
should be assessed. The cut surface of the tumor should be
described. Seminomas are usually pale, homogeneous and well- CLINICAL FEATURES
demarcated, but may contain large geographical areas of yel-
low necrosis. Teratomas are more often variegated, irregular, All testicular germ cell tumors – with the exception of sperma-
multiple and hemorrhagic with focal areas of necrosis: cystic tocytic seminomas – arise from carcinoma in situ (CIS), which is
areas are common, and cartilaginous foci may be evident. The also called intratubular germ cell neoplasia (ITGN) or testicular
tumor may replace the whole testis: if not, the appearance of intraepithelial neoplasia (TIN). The presence or absence of CIS/
the residual testicular parenchyma is noted. ITGN should be recorded in the pathology report, although this
The periphery of the tumor is the most important region to does not affect clinical management. However, the contralateral
sample for histology because the tissue is more likely to be testis may also contain CIS, and this will progress to invasive
viable, whereas the center may be necrotic. Peripheral blocks germ cell tumor in the remaining testis. Some surgeons biopsy
will show invasion of surrounding tissue, and will be the most the contralateral testis to look for CIS, which can be eradicated
likely to demonstrate vascular invasion. by low-dose radiotherapy.
At 5 years after the initial diagnosis, about 50% of patients
Standard blocks Blocks for histology should be taken from: with a testicular biopsy positive for CIS/ITGN will develop
● Proximal (cut end) cord invasive germ cell tumors, and only a small fraction remain free
● Mid cord of invasive disease by 7 years. Orchidectomy is the treatment
● Distal cord of choice in patients with unilateral CIS/ITGN, and low-dose
● Block including upper pole of testis with adjacent rete radiation is efficacious in patients with bilateral CIS/ITGN
testis and head of epididymis (though sterility is certain). A recent study showed the esti-
● Tumor with surrounding testis mated risk of recurrent CIS/ITGN following chemotherapy to
● Tumor with adjacent tunica albuginea be 21% and 42% at 5 and 10 years, respectively.
● Hemorrhagic areas of tumor (more likely to contain CIS/ITGN is usually identified in the adjacent seminiferous
trophoblastic elements) tubules of almost all post-pubertal cases of testicular germ cell
(a) (b)
Figure 11.15 (a, b) Intratubular germ cell neoplasia, unclassified type (IGCNU).This is characterized by the presence of patchy involvement of
seminiferous tubules by seminoma-like cells occupying the basal layers.The involved tubules are atrophic and exhibit basement membrane
thickening and absent spermatogenesis.The abnormal cells have clear cytoplasm and enlarged hyperchromatic nuclei with prominent nucleoli.
tumors (the exception is spermatocytic seminoma). The lesion

is detected with increasing frequency in patients known to be
at increased risk of testicular germ cell tumors (cryptorchidism,
residual testis with prior germ cell tumor, infertile patients, in
patient with Y-chromosome ⫹ gonadal dysgenesis and andro-
gen insensitivity syndrome).

Intratubular germ cell neoplasia, unclassified type (IGCNU), is
characterized by the presence of patchy involvement of semi-
niferous tubules by seminoma-like cells occupying the basal
layers. The involved tubules are usually atrophic, and exhibit
basement membrane thickening and decreased or absent sper-
matogenesis. The lesion may be seen throughout the testis, but Figure 11.16 Pagetoid spread into the rete testis by testicular
more often in the region close to the epididymis. Intratubular tumors.The figure shows an intratubular germ cell tumor
germ cell tumor can spread into the rete testis in a pagetoid spreading into the rete testis in a pagetoid manner.The germ cells
manner; this occurs in 30% of cases, and can be associated have a clear or lightly eosinophilic cytoplasm, a distinct cell
with hyperplasia of the rete testis. membrane, a round or oval shape, and (usually) a large vesicular,
centrally located nucleus.
Intratubular embryonal carcinoma has rarely been reported
as an isolated finding.
Cell morphology carcinoma, and rarely by yolk sac tumor and teratoma.
These usually fill and distend the involved tubules, and
Germ cells have a clear or lightly eosinophilic cytoplasm, a dis-
adjacent invasive tumor is often seen.
tinct cell membrane, and a round or oval and large hyperchro-
matic, vesicular, centrally located nucleus, usually with a
prominent nucleolus. Special techniques
● Germ cells contain glycogen (PAS-positive).
Differential diagnosis ● The cells express placental-like alkaline phosphatase
● Tubular involvement by differentiated germ cell tumors (PLAP) and c-kit.
such as seminoma, spermatocytic seminoma, embryonal ● The cells are mostly cytokeratin-negative.
POLYEMBRYOMA
CLINICAL FEATURES
Polyembryoma is an extremely rare germ cell tumor.
The most distinctive feature of polyembryoma is the presence
of ‘embryoid bodies’. These are seen in the form of a disk com-
prising large undifferentiated cells reminiscent of the embry-
onic disk, or a space or tubular structures lined by flattened
epithelium reminiscent of the amniotic cavity. The embryoid
bodies are seen within a loose mesenchymal background in
which trophoblastic elements may be seen.
(a)
SEMINOMA
CLINICAL FEATURES
The terminology of seminoma is similar in the British and
WHO classifications.
Seminoma is the most common testicular germ cell tumor,
and occurs in men with a mean age of 40 years. It usually pres-
ents with a testicular mass and occasionally with lumbar back
pain (due to retroperitoneal metastases). Patients with classical
(or anaplastic) seminoma receive postoperative radiotherapy
whether or not vascular invasion has been identified.
It has been shown that the size of the primary tumor (⬎4 cm)
and rete testis invasion are important prognostic factors for relapse
in patients with Stage I seminoma managed with surveillance. (b)
Stage for stage, the anaplastic variant of seminoma has the
same prognosis as classical seminoma.

Seminoma is characterized by the presence of sheets of a uni-
form population of round or epithelioid cells with clear cyto-
plasm, separated by fibrous trabecula containing lymphocytes.
The cells may occasionally be arranged in cords reminiscent of
breast carcinoma, in diffuse inflammatory or lymphoma-like
pattern, or may exhibit marked edema resulting in micro-
cyst formation similar to those seen in yolk sac tumor and in
granulomatous-like patterns. A rare variant is the ‘tubular
seminoma’, which shows an architecture that closely resembles
that of a Sertoli cell tumor. Solid tubular structures may also be
seen. Intratubular involvement by seminoma cells is often seen
(c)
adjacent to the invasive component. Similarly, intratubular
germ cell neoplasm of undifferentiated type (see above) is com-
Figure 11.17 (a–c) Seminoma is characterized by the presence of
monly seen in testis harboring seminoma. Pagetoid spread to
sheets of a uniform population of round or epithelioid cells with
the rete testis via intratubular spread may also occur. clear cytoplasm, separated by fibrous trabecula containing
Focal non-seminomatous germ cell tumors may be identified lymphocytes.
in the primary seminomas, or sometimes in their metastases.
This raises the possibility that seminoma acts as a precursor for tumor giant cells, and the infrequent presence of lymphocytic
these tumors. and/or granulomatous reaction.
The anaplastic variant of seminoma is characterized by Although seminoma and teratoma are generally regarded as
greater cellular pleomorphism, a very high mitotic rate (more being different tumors, it is now recognized that there is a
than three mitotic figures per high power field, HPF), frequent continuum of differentiation ranging from classical seminoma
(a) (d)
(b) (e)
(c)
Figure 11.18 (a–e) Seminoma may exhibit marked edema,

resulting in microcyst formation.The cells shown are c-kit-positive
(c), placental-like alkaline phosphatase (PLAP)-positive (d) and
cytokeratin-negative (e). Figure 11.19 The anaplastic variant of seminoma lacks
lymphocytic infiltrates and shows anaplastic nuclei.
to undifferentiated teratoma. Highly anaplastic seminomas are

difficult to differentiate from teratomas. Some tumors are at Secondary features
the borderline between seminoma and teratomas, and should ● Necrosis; on rare occasions the entire lesion is necrotic.
be classified as anaplastic germ cell tumors. Masson trichrome plus selected immunostains offer a
promising approach to the diagnosis of certain necrotic Spermatocytic seminoma tends to occur in an older age group,
neoplasms. and the tumor usually has a gray gelatinous appearance and
● Lymphocytic infiltrate (sometimes with florid germinal does not stain for PLAP, AFP, hCG or cytokeratin. It is not
centers) occurs in over 80% of cases. associated with CIS or with teratomatous elements. It does not
● Granulomatous reaction occurs in 20–50% of seminomas. usually metastasize, and orchidectomy is normally curative.
● Syncytiotrophoblastic giant cells are seen in 10–20% of Very occasionally, spermatocytic seminoma can give rise to
seminomas. Their presence is associated with mildly sarcomatous elements, and these are much more aggressive.
elevated serum levels of hCG, and it is doubtful whether
this has an adverse effect on prognosis. PATHOLOGICAL FEATURES (Figure 11.20)
Cell morphology Spermatocytic seminoma is characterized by the presence of

diffuse infiltrate of polymorphous, somewhat plasmacytoid cell
● Seminoma cells have a clear or lightly eosinophilic
population, usually with no interstitial lymphocytic compo-
cytoplasm, and a distinct cell membrane. The nucleus is
nent. Occasional pseudoglandular or nesting patterns occur
round or oval, large, vesicular and centrally located, with
within an edematous background. Extension of tumor cells
a prominent nucleolus.
into the seminiferous tubules is often seen, but intratubular
Differential diagnosis germ cell neoplasm/in situ lesion has not been visualized.
Rarely, sarcomatous change in the form of undifferentiated
● Sertoli cell tumor: the nested growth pattern, prominence spindle cell sarcoma or embryonal rhabdomyosarcoma can
of clear cells, lymphoid infiltrate, inconspicuous tubular occur in spermatocytic seminoma.
differentiation, cytoplasmic glycogen, and prominent
nucleoli cause these tumors to be mistaken for seminomas.
The smaller, less pleomorphic nuclei of Sertoli cell tumors,
their lower mitotic rate, and the absence of intratubular
germ cell neoplasia are helpful differential features.
Immunohistochemistry is a useful adjunct in confirming
the diagnosis of Sertoli cell tumor: the tumor cells are
positive for inhibin-alpha, EMA and cytokeratin
(AE1/AE3), and negative for PLAP
● Lymphoma
● Undifferentiated teratoma
● Yolk sac tumor (the microcysts of seminoma are irregular,
lined by seminoma cells and contain proteinaceous fluid
and exfoliated malignant cells)
● Granulomatous orchitis (florid granulomatous reaction in
seminoma may obscure the underlying malignant cells.
(a)
Intratubular granulomatous reaction can be seen in both
seminoma and idiopathic orchitis)
● Metastatic seminoma may be mistaken for carcinoma
Special techniques
● Seminoma cells contain glycogen (PAS-positive).
● The cells express PLAP.
● The cells are characteristically cytokeratin-negative.
● The majority of seminomas are CD117/c-kit⫹/CD30⫺.
Conversely, the majority of embryonal carcinomas are
CD30⫹/CD117⫺. Cells of embryonal carcinoma in
addition express cytokeratins and EMA.
SPERMATOCYTIC SEMINOMA
(b)
CLINICAL FEATURES
Spermatocytic seminoma is a distinct pathological entity, rep- Figure 11.20 (a–c) Spermatocytic seminoma.This is characterized
resenting 1–2% of all testicular germ cell tumors, and occurs by the presence of a diffuse infiltrate of a polymorphous somewhat
plasmacytoid cell population, usually with no interstitial lymphocytic
only in testicular locations. Spermatocytic seminoma should be component.The cells are variable in size; some have hyperchromatic
regarded as a misnomer. Although these tumors resemble clas- smudged nuclei, while others are multinucleated giant cells.
sical seminomas, they are unrelated and behave differently. Placental-like alkaline phosphatase (PLAP) staining is negative (c).
postoperative serum tumor marker levels return to normal. Such

tumors may be completely cured by orchidectomy. However,
regional node recurrences may become evident, especially if
vascular invasion is evident microscopically in the orchidectomy
specimen. Patients with histopathologically detectable vascular
invasion are therefore treated with postoperative chemotherapy
in order to reduce the incidence of recurrence.
Malignant teratoma undifferentiated (MTU)/embryonal
carcinoma in its pure form accounts for 2–3% of testicular
tumors, but frequently occurs (45%) as a component of mixed
germ cell tumor. This lesion affects patients between the ages of
25 and 30 years, and is more aggressive and lethal than seminoma
in untreated patients.
(c)
Figure 11.20 (Continued). Mature teratoma consists of differentiated somatic tissues that
may exhibit cytological atypia in teratomas of adults.
Immaturity in a teratoma is expressed as a cellular stroma
Cell morphology
around the epithelial tissue. High-grade immaturity is mani-
● Spermatocytic seminoma cells are variable in size, and fested in the form of neuroepithelial tissues, blastomatous
polymorphous with hyperchromatic smudged nuclei. (Wilms’ tumor-like) tissues, and embryonic rhabdomyoblastic
● Intermediate-size cells also seen. tissue. Overgrowth of any of these high-grade immature ele-
● Giant and multinucleated cells may be seen. ments may place the tumor into a teratoma with secondary
malignant component of primitive neuroendocrine tumor,
Differential diagnosis a blastomatous Wilms’ tumor, and embryonal rhabdomyo-
● Malignant lymphoma sarcoma, respectively. Other sarcomas may complicate imma-
● Anaplastic seminoma ture teratoma, the most common type being chondrosarcoma.
● Undifferentiated carcinoma Carcinomas may also complicate teratomas; these are usually
EMA-positive (in comparison to the EMA-negative embryonal
Special techniques carcinoma cells or yolk sac element).
● Spermatocytic seminoma cells are PLAP-negative and Intratubular germ cell neoplasm can be seen in association
PAS-negative. with teratomas, except in childhood mature teratoma.
● CD117 (c-kit) positivity is seen in about 40% of cases. MTU/embryonal carcinoma is characterized by the presence
of pleomorphic malignant cells arranged in solid, glandular,
papillary and ‘double-layered’ patterns. The latter may repre-
TERATOMAS sent thick rows of embryonal carcinoma cells alternating with
thin rows of flattened (AFP-positive) yolk sac tumor cells. A
focal yolk sac component is often present, and undifferentiated
CLINICAL FEATURES
stromal element and choriocarcinoma-like areas may be seen.
Teratomas may be entirely undifferentiated (MTU: malignant Intratubular extension of tumor cells with comedo-type necro-
teratoma undifferentiated), entirely mature (TD: teratoma dif- sis is often seen adjacent to invasive areas of the tumor.
ferentiated), or a mixture of undifferentiated and mature tera-
tomatous elements (MTI: malignant teratoma intermediate).
Cell morphology
Undifferentiated teratoma may have areas of extraembryonic
differentiation in the form of yolk sac tumor (YST) or tropho- ● Embryonal carcinoma consists of pleomorphic cells with
blastic (choriocarcinomatous) elements. Raised serum levels of poorly defined cell borders, vesicular nuclei and large,
AFP and/or hCG do not necessarily indicate the presence of an often multiple, nucleoli.
extraembryonic tumor. ● Smudged small dark cells are frequently seen.
All teratomas (MTU, MTI, TD, YST, trophoblastic tumors)
are capable of metastasizing, and must be regarded as being Secondary features
malignant. Pelvic and para-aortic nodes are usually the primary ● Hemorrhage
sites of lymphatic spread, but not the inguinal nodes unless ● Necrosis
direct extension to the scrotum has occurred. Hematogenous
spread to lung, liver and brain may occur with all teratomas,
although trophoblastic tumors have a greater propensity for Differential diagnosis
blood-borne metastases. Stage I teratomas are confined to Mature teratoma must be distinguished from:
the testis, with no clinical evidence of metastasis after staging ● Epidermoid cyst (pure squamous-lined cyst)
which includes computed tomography (CT) scanning, and ● Dermoid cyst (squamous and skin appendages-lined cyst)
Figure 11.22 Mature teratoma, showing islands of mature

cartilage.
(a)
(a)
(b)
Figure 11.23 (a–c) Malignant teratoma intermediate. A cellular
stroma around primitive epithelial tissue with malignant cartilage and
Figure 11.21 (a, b) Malignant teratoma undifferentiated (MTU)/ keratinous cystic structure.
embryonal carcinoma is characterized by the presence of
pleomorphic malignant cells arranged in solid, glandular, papillary
and ‘double-layered’ patterns. A focal yolk sac component is
present, and undifferentiated stromal element and
choriocarcinoma-like areas may be seen. ● Areas of YST usually show strong staining for AFP, and
syncytiotrophoblast stains for hCG. However, AFP
and hCG can also be detected in other teratomatous
Embryonal carcinoma must be distinguished from: elements.
● Poorly differentiated adenocarcinoma
● Embryonal carcinoma cells are PLAP-positive and
● Undifferentiated carcinomas
EMA-negative.
● Angiosarcoma may masquerade as embryonal
● CD30 is strongly expressed in embryonal carcinomas. Loss
carcinoma of CD30 expression occurs frequently in metastatic
embryonal carcinomas after chemotherapy.
Special techniques ● The presence of hCG-positive syncytial cells and/or
● MTU normally stains for cytokeratin, and may also stain AFP-positive cells in the background indicates a mixed
for PLAP, AFP and hCG. germ cell tumor.
RETE TESTIS TUMORS
ADENOMATOUS HYPERPLASIA
CLINICAL FEATURES
Adenomatous hyperplasia of rete is a localized hyperplasia of
the collecting ducts of the rete testis, presenting either as an
incidental finding or as a testicular mass. It is often seen in
association with germ cell tumors and in undescended testes.
A poorly circumscribed lesion variably composed of irregularly
outlined, elongated tubuloglandular structures, papillae, and
small uniform glands. These are separated by dense fibrous tis-
sue or arranged in back-to-back pattern or in a pseudoinfiltra-
tive pattern. Focal epithelial proliferation forming bridges to
a pronounced intratubular cribriform pattern of the epithelium
(b)
of the epididymal tubules may be seen in association with
adenomatous hyperplasia of the rete testis.
Secondary features
● Intracytoplasmic hyaline globules are occasionally seen.
Cell morphology
● The lining epithelium is columnar and sometimes
vacuolated.
● There is little or no cytological atypia.
● Metastatic prostatic carcinoma
● Rete testis carcinoma (shows evidence of transformation of
normal rete into malignant glandular epithelium)
Special techniques
● Mucin staining is negative.
● PAS/diastase staining may highlight the intracytoplasmic
hyaline globules.
(c)

CARCINOMA
CLINICAL FEATURES
Carcinoma of the rete testis is a very rare tumor, occurring in
YOLK SAC TUMOR (INFANTILE EMBRYONAL men over the age of 50 years. It is usually unilateral, and often
CARCINOMA/ENDODERMAL SINUS TUMOR) solid, but may be cystic.
CLINICAL FEATURES
A poorly circumscribed lesion composed of irregularly out-
Pure yolk sac tumor of the testis is very rare in adults, but it is lined, elongated, compressed tubuloglandular structures, papil-
the most frequent germ cell tumor of the testis in children. lae, and solid sheets. These are separated by fibrous tissue or
arranged back-to-back in an infiltrative pattern. The lesion is
usually located in the vicinity of the rete testis, and sometimes
transition between the tumor and the uninvolved rete is seen.
See Chapter 7, Tumors of the ovary, Yolk sac tumor (p. 486). Cystic glandular spaces may be present.
Secondary features
● Dense hyaline fibrosis of the stroma.
Cell morphology
● The lining cells are cuboidal and arranged in either single
or multiple layers.
● Cellular pleomorphism and mitoses are present.
● Secondary adenocarcinoma
● Serous cystadencarcinoma or cystadenoma of the testis
● Mesothelioma
● Adenomatoid tumor (a)
● Adenomatous hyperplasia of the rete testis
● Prominent or hyperplastic rete in an atrophic testis
SERTOLI CELL TUMORS
HAMARTOMATOUS NODULES AND ADENOMA IN

TESTICULAR FEMINIZATION (ANDROGEN
INSENSITIVITY) SYNDROME
CLINICAL FEATURES
Testicular feminization (androgen insensitivity) syndrome is (b)
genetically male (46,XY) within intra-abdominal undescended
testis, but phenotypically female with well-developed breasts
and female external genitalia and a blind-ending vagina but
absent uterus and Fallopian tubes and absent or scant axillary
or pubic hair. It is a familial condition, with either X-linked
recessive or a male-limited autosomal recessive inheritance. It
results from failure of target organs to respond to masculiniz-
ing hormones. The lesion gives a characteristic gross appear-
ance of the testis: a smaller than normal testis, thickened tunica
albuginea, presence of fibromuscular thickening at one pole
and cyst formation at the other, and the presence of one or
multiple cream-colored nodules. This lesion may be complicated
by malignancy such as seminoma.

(c)
The background testicular tissue is usually made up of varying
numbers of immature seminiferous tubules lined by Sertoli or Figure 11.24 (a–c) Testicular feminization (androgen insensitivity)
undifferentiated cells. These are intermixed with a prominent syndrome.The Sertoli cell nodules are composed of uniform tubular
structures, with little intervening stroma.These are intermixed
Leydig cell population, and are present in a scant or moder-
with a prominent Leydig cell population. A Rankie crystal in the
ately abundant, hyalinized or loose edematous matrix some- Leydig cells is encircled (c).
what reminiscent of ovarian stroma. The Sertoli cell nodules
vary in size and shape and are well-defined, but not encapsu-
lated. They are composed of uniform tubular structures with Secondary features
little intervening stroma. Varying numbers of thickened-wall ● Perivascular lymphocytic infiltrate.
blood vessels are seen, particularly within the tunica albuginea ● Vascular congestion.
and the connective tissue stroma. ● Hyaline bodies are found in some of the tubules.
Cell morphology
● Mature or immature Sertoli cells: these are elongated cells
with granular or vacuolated cytoplasm and rounded nuclei
with a coarse chromatin pattern.
● Spermatogonia and spermatocytes may sometimes be seen
in the incomplete form of the disease.
● Leydig cells containing Reinke’s crystals or lipofuscin
pigment.
● Tubular testicular adenoma
Special techniques
● As for the normal cellular counterpart Figure 11.25 Sertoli cell tumor consists predominantly of solid
tubules lined by Sertoli cells, which often exhibit clear
vacuolated cytoplasm.
SERTOLI CELL TUMOR

● Hyperplastic Sertoli cell nodule
● Hamartomatous Sertoli cell nodule and Sertoli cell
CLINICAL FEATURES
adenoma of testicular feminization (androgen insensitivity)
Sertoli cell tumor comprises about 1% of all testicular neoplasms syndrome
affecting middle-aged men, and may be seen in association with
Peutz–Jeghers syndrome (especially the large calcifying Sertoli cell Special techniques
tumor and the sex cord tumor with annular tubules). The lesion
presents as a testicular mass, and may cause gynecomastia in the
● The cytoplasmic vacuolation is due to a high lipid
absence of virilism. The lesion is well-circumscribed, and usually content.
less than 3 cm in diameter. In 10% of cases the lesions may have
● The cells are inhibin-, cytokeratin- and vimentin-positive.
malignant behavior (especially in large, poorly circumscribed
tumors, those with a high mitotic rate and cellular pleomorphism
and in the presence of vascular/lymphatic invasion). SERTOLI CELL TUMOR, LARGE CALCIFYING
Intratubular Sertoli cell proliferation has rarely been observed
as multiple foci of seminiferous tubules with large and prolifer-
ated Sertoli cells replacing germ cells and limited by the base- CLINICAL FEATURES
ment membrane. The bilateral and multicentric character of
Large calcifying Sertoli cell tumor shows high incidence of bilat-
these lesions and their association with Sertoli cell tumors and
erality and multifocality. It is often associated with Carney’s syn-
Peutz–Jeghers syndrome suggest that they represent either pro-
drome, and may be seen in patients with Peutz–Jeghers syndrome.
liferative lesions with tumorigenic potential or the intraepithe-
It affects young age groups (under the age of 20 years), and pres-
lial stage in the evolution of some testicular Sertoli cell tumors.
ents with a testicular mass, gynecomastia or isosexual pseudo-
precocity due to hormone production by the tumor cells or
PATHOLOGICAL FEATURES (Figure 11.25) associated Leydig cell nodule. The tumor is usually less than
Sertoli cell tumor consists predominantly of solid tubules lined 4 cm in diameter.
by Sertoli cells which often exhibit clear vacuolated cytoplasm.
Tubules with open lumina nests and cords may also be seen.
Coalescence of cytoplasmic vacuolation may produce a micro- PATHOLOGICAL FEATURES (Figure 11.26)
cystic pattern. Large calcifying Sertoli cell tumor consists of nodules, nests, or
cords of large polygonal cells with abundant eosinophilic cyto-
Cell morphology plasm. The surrounding or underlying stroma often shows
● The Sertoli cells are cuboidal or columnar with moderate myxoid change or fibrosis. Intratubular growth is commonly
amount of dense cytoplasm and round or oval nuclei seen. Calcification is seen in about 50% of the cases, both in
without prominent nucleoli. The cytoplasm may be the intratubular as well as in the extratubular tumor foci.
vacuolated and sometimes contains large lipid vacuoles.
Cell morphology
Differential diagnosis ● The cells are polygonal, with eosinophilic cytoplasm and
● Metastatic prostatic carcinoma in the testis round or oval nuclei containing prominent nucleoli.
● Seminomas with tubular pattern ● Mitoses are rarely seen, except in malignant tumors.
● Adenomatoid tumor
● Metastatic carcinoma, especially of prostatic origin
Special techniques
● The cells may express both cytokeratin and vimentin.
SEX CORD–STROMAL TUMORS
LEYDIG CELL TUMOR
Figure 11.26 Large calcifying Sertoli cell tumor. Calcification is

seen in the intratubular as well as extratubular regions. CLINICAL FEATURES
Leydig cell tumor is a common type of sex cord–stromal tumor,
and comprises 2–3% of all testicular neoplasms. The lesion
Differential diagnosis is bilateral in 3% of cases, and occurs at any age, though it
● Leydig cell tumor with calcification is seen more often in the third or fourth decades of life, and
in children between the ages of 5 and 10 years. In the latter age
group the tumor produces isosexual pseudoprecocity (due
Special techniques
to androgen secretion). In adults, it presents as a testicular mass
See Sertoli cell tumor (p. 816). or gynecomastia. The tumor is grossly well-circumscribed, solid
and lobulated, and varies in size from 0.5 to 10 cm in diameter.
It is malignant in 10% of cases (larger tumors with infiltrative
SERTOLI CELL TUMOR, SCLEROSING TYPE margins, showing necrosis, cellular atypia and 1–10 mitotic fig-
ures per 10 HPF and with vascular invasion).
CLINICAL FEATURES
Sclerosing Sertoli cell tumor is a distinctive subtype of this PATHOLOGICAL FEATURES (Figure 11.27)
tumor which exhibits extensive sclerosis. The lesion usually
The tumor is usually well-circumscribed and consists of
occurs in adults, and there are no associated hormonal or other
polygonal cells with an abundant eosinophilic cytoplasm
unusual features. The tumor is usually less than 1.5 cm in
arranged in solid sheets, small nests, ribbons or cords and
diameter. It is almost always benign, and orchidectomy is the
surrounded by fibrous tissue. Some tumors show spindle cell
treatment of choice. The lesion may have the potential to
morphology, and rarely the presence of fat-like cells. It may
pursue a malignant course if histologically malignant.
also rarely show a microcystic pattern that mimics that of yolk
sac tumor.
PATHOLOGICAL FEATURES The presence of cytological atypia, necrosis, angiolymphatic
invasion, increased mitotic activity, atypical mitotic figures,
This well-demarcated lesion consists of epithelial structures set in and infiltrative margins, extension beyond the testicular
a diffusely sclerotic, prominent collagenous stroma. The epithelial parenchyma, DNA aneuploidy, and increased MIB-1 (Ki-67; a
component is arranged in solid and hollow, simple or anastamos- marker of nuclear proliferation) activity are significantly asso-
ing tubules, large irregular aggregates, and thin cords. Entrapped ciated with metastatic behavior in Leydig cell tumors.
non-neoplastic tubules are often seen within the tumor.
Cell morphology Secondary features

● The tumor cells are of medium size, with pale cytoplasm
● Calcification.
which sometimes contains large lipid vacuoles.
● The nuclei are round and vary from small and dark to Cell morphology
large and vesicular.
● The cells are polygonal with eosinophilic, sometimes
● Mitotic figures are rare.
vacuolated, cytoplasm.
● The nuclei are round with centrally located nucleoli and
Differential diagnoses may show moderate pleomorphism.
● Leydig cell tumor ● Mitoses are infrequent, except in malignant tumors.
● Carcinoid tumor ● Lipofuscin can be identified in a minority of cases.
(a) (b)
Figure 11.27 (a–c) Leydig cell tumor. A well-circumscribed tumor

consisting of round cells with abundant, granular cytoplasm and
(c)
uniform nuclei, some of which contain prominent nucleoli.
● Reinke crystals are seen in up to 40% of cases in the Special techniques

cytoplasm, and are pathognomonic. ● The cells are vimentin-positive.
● Leydig cells are identified using an antibody against the
Differential diagnosis steroidogenic enzyme 3␤-hydroxysteroid dehydrogenase
● Leydig cell hyperplasia (is characteristically multinodular) (3␤-HSD), which is characteristic of Leydig cells in
● Large cell calcifying Sertoli cell tumor testes.
● Testicular nodules of the androgenic insensitivity ● Lipofuscin pigment can be seen in the cytoplasm.
syndrome ● Phosphotungstic acid-hematoxylin (PTAH) highlights the
● Malakoplakia Reinke crystals.
● Lymphoma ● Leydig cell markers are inhibin-alpha, calretinin, and
● Plasmacytoma melan-A.
● Metastatic prostatic carcinoma ● The tumor cells may express S-100 protein.
TUMORS OF THE PARATESTICULAR REGION
GENERAL COMMENTS Microscopically, the lesion is a tubular, tubulocystic, or tubulo-

papillary adenocarcinoma lined by glycogen-containing clear
The paratesticular region includes the testicular collecting cells. The cells are usually mildly or moderately atypical, with
system, the testicular tunics, and spermatic cord. A wide variety visible nucleoli. Sheets of anaplastic cells may rarely be seen.
of cysts, hyperplasias, neoplasms, and tumor-like conditions may Other patterns include closely packed tubular structures lined
affect the region, and this may sometimes result in diagnostic by columnar epithelium with basally located nuclei, and cystic
problems. structures with complex papillary structures. The cells are CK-
and EMA-positive. Epididymal carcinoma may be mistaken for
some benign tumors such as clear cell papillary cystadenoma of
NEOPLASTIC AND NON-NEOPLASTIC the epididymis, adenomatoid tumor and adenoma and cystade-
PROLIFERATION OF THE noma of the rete testis. It may also be confused with some
paratesticular malignant tumors such as mesothelioma of the
TESTICULAR COLLECTING SYSTEM
tunica vaginalis, serous papillary carcinoma and adenocarci-
noma of the rete testis.
CYSTS AND EPITHELIAL PROLIFERATIONS
EPIDIDYMAL METASTATIC TUMORS
For neoplasms of the rete testis, see Testicular tumors (pp. 810–11).
The testicular collecting system extends from the rete testis to Metastatic prostatic carcinoma may sometimes be found inci-
the vas deferens. Benign cysts of the collecting duct system are dentally from a patient treated with surgical castration. Other
a very common clinical finding, but are of little pathological metastatic carcinomas are more likely to be clinically apparent.
interest. On the other hand, neoplasms of this system are very The most frequent tumors that metastasize to the spermatic
rare, but pathologically interesting. cord and epididymis are gastric carcinoma and prostatic carci-
noma. Other tumor primary sites include the kidney, urinary
EPIDIDYMAL LESIONS tract, lung, gastrointestinal tract, and skin.
Tumors of the epididymis are very rare, and are benign in 75%
of cases. PARATESTICULAR LYMPHORETICULAR TUMORS
EPIDIDYMAL CYSTS Plasmacytoma may rarely be seen in the testis or epididymis.

The majority of cases are seen in patients who also have plasma
Cysts of the epididymis are relatively common, usually small-
cell neoplasia distant from the testis. The tumor mass shows
sized, and of no clinical significance. Some cysts are large and
atypical plasma cells, including binucleated and multinucleated
undergo torsion. Multiple cysts may be seen in association with
cells and, occasionally, anaplastic cells that obliterate the underly-
polycystic kidney and in von Hippel–Lindau disease. These
ing parenchyma or invade between seminiferous or epididymal
cysts have fibromuscular walls and are lined by single layer of
tubules. The tumor may be misinterpreted as spermatocytic
cuboidal to flattened bland epithelial cells which may be ciliated.
seminoma, anaplastic seminoma or lymphoma.
Granulocytic sarcoma of the paratestis is very rare, and is
EPIDIDYMAL PAPILLARY CYSTADENOMA often susceptible to misinterpretation.
This condition represents 4–9% of epididymal benign tumors, Malignant lymphoma: there appears to be a tendency for
occurs at any age, is most commonly found in the head of the young men to have low-grade lymphomas with an indolent
epididymis, and is frequently associated with von Hippel–Lindau course, and older patients to develop higher-grade tumors. Most
syndrome. Microscopically, this is a multicystic lesion lined by testicular lymphomas are B-lineage, large-cell lymphomas, which
tubulopapillary structures lined by bland epithelial cells, exhibit- frequently involve other extranodal sites at presentation and at
ing clear cell change. The lesion should be distinguished from relapse, and which often have an aggressive clinical course.
epididymal adenocarcinoma/cystadenocarcinoma and from the
rare metastatic renal cell carcinoma.
PARATESTICULAR MESOTHELIAL TUMORS
EPIDIDYMAL CARCINOMA
Mesothelial lesions involving the paratesticular region include
Epididymal adenocarcinoma/cystadenocarcinoma is a very rare mesothelial cysts, reactive mesothelial hyperplasia, adenoma-
tumor, and typically presents in adults as a scrotal mass. It is toid tumors, benign cystic mesothelioma, well-differentiated
usually multicystic with partial or complete involvement of the papillary mesothelioma, and malignant mesothelioma. Meso-
epididymis, and may reach up to 14 cm in size. The tumor may thelial lesions are relatively uncommon, and most benign and
extend to the spermatic cord or adjacent tunica vaginalis, but malignant tumors present as testicular tumors with no specific
with no or limited involvement of the testis. findings. A preoperative diagnosis of malignancy is rarely made,
and there is no established effective therapy for malignant Serous borderline tumor of the paratestis is histologically iden-
mesothelioma. tical to its ovarian counterpart. The tumors are cystic, with
numerous intracystic blunt papillae lined by stratified epithelial
MESOTHELIAL HYPERPLASIA cells with minimal to mild cytological atypia. Psammoma bodies
may also be seen. The neoplastic cells stain strongly and diffusely
This is an incidental finding, usually associated with fibrosis,
for CK7, estrogen receptor and CD15, and some may be positive
probably secondary to irritation or inflammatory process. It is
for progesterone receptor. The cells are usually negative for
often seen in association with hydrocele, hematocele, inguinal
CK20, carcinoembryonic antigen (CEA), and calretinin.
hernial sacs, and paratesticular fibrous pseudotumor. The
Serous papillary carcinoma is characterized by invasive, well-
hyperplastic mesothelial cells arrange in individual cells, cell
formed papillae lined by serous cuboidal or columnar cells with
clusters, tubules, small papillae, or nests within an inflamma-
eosinophilic cytoplasm and malignant nuclear features.
tory fibroblastic background, and occasionally as luminal solid
Psammoma bodies are usually abundant. Areas of borderline
nodules. The clues to their benign nature are: orderly arrange-
serous tumor may be seen. These tumors may be misinterpreted
ment, usually in streaks; lack of significant cytological atypia;
as carcinoma of the rete testis or mesothelioma.
an absence of complex architectural pattern; the presence of
inflammatory infiltrate; and the absence of invasion of the
underlying tissue. PARATESTICULAR SOFT TISSUE TUMORS
MESOTHELIAL CYSTS Paratesticular soft tissue tumors are uncommon neoplasms that
may present significant challenges for both the pathologist and
These most commonly involve the tunica, and less commonly
clinician. In theory, any soft tissue tumor can occur in this region;
the epididymis and spermatic cord. (See also Chapter 7, Tumors
however, there are some neoplasms which appear to occur only
of the peritoneum, p. 517.)
in the paratesticular area and in the female counterpart, the
vulva. This includes aggressive angiomyxoma and angiomyo-
ADENOMATOID TUMOR fibroblastoma (see Chapter 7, Female genital tract, pp. 377–8).
This is the most common mesothelial lesion of the paratesti-
cular region. (See also Chapter 7, Tumors of the peritoneum, TUMORS IN ADULTS
p. 517.)
Benign
BENIGN CYSTIC MESOTHELIOMA Lipoma is the most common soft tissue tumor in this area, and
constitutes about 90% of all mesenchymal tumors of the
This is a very rare lesion which has been reported in the tunica inguinal and paratesticular regions. Other benign tumors include
vaginalis and spermatic cord. (See also Chapter 7, Tumors of leiomyoma, rhabdomyoma, hemangioma, neurofibroma and
the peritoneum, p. 517.) granular cell tumor.
MESOTHELIOMA Sarcomas
Mesothelioma typically presents as multiple nodules studding a Leiomyosarcoma, liposarcoma, and malignant fibrous histio-
hydrocele sac, and is frequently associated with a mass infil- cytoma are the most commonly reported sarcomas in adults in
trating the spermatic cord or adjacent testis. Microscopically, the paratesticular region. Other subtypes of sarcoma are rare. In
these lesions are either pure epithelial or biphasic mesothe- adults, paratesticular sarcomas are usually treated with complete
lioma. Mixtures of papillary, tubular, and solid patterns usually resection, including high ligation of the spermatic cord. Adverse
predominate in the epithelial areas; interlacing fascicles of pathological features include larger tumor size, inguinal location,
spindle cells with scant stroma characterizes the sarcomatous narrow or positive margins and prior intralesional surgery.
components. Adjuvant radiotherapy seems to reduce local recurrence.
Testicular mesothelioma has a wide age range, with occasional
occurrence at a young age, a wide morphological spectrum TUMORS IN CHILDHOOD AND ADOLESCENCE
with regard to the degree of differentiation, and an aggressive
Benign
natural history with a potential for late recurrence or metasta-
sis of even well-differentiated tumors, suggesting the need for Rare examples include fibroma, lipoma, and hemangioma.
initial aggressive surgical treatment. Paratesticular melanotic neuroectodermal tumor of infancy
is a low-grade neoplasm that is occasionally encountered in the
epididymis. Recognition of its features is essential to avoid mis-
PARATESTICULAR OVARIAN-TYPE EPITHELIAL diagnosis as a more aggressive ‘small blue cell’ neoplasm and
TUMORS consequent therapeutic mismanagement.
Various ovarian-type tumors can be seen in the paratesticular Sarcomas

region. These include serous and rarely mucinous tumors, Rhabdomyosarcoma is the most common tumor, followed by
Brenner tumor, and Walthard-like nests. undifferentiated sarcoma.
Paratesticular desmoplastic small round cell tumor is MALAKOPLAKIA

extremely rare, and histologically similar to the intra-abdomi-
The epididymis is the most commonly affected site of the male
nal counterpart.
genital tract. (See also Chapter 14, Urinary system tumors,
p. 1180.)
PARATESTICULAR TUMOR-LIKE LESIONS VASITIS NODOSA (Figure 11.28)
Diverse non-neoplastic lesions may occur in the paratesticular This is a benign proliferation and invagination of the epithelium
region, and may potentially mimic neoplasms. Some of these may of the vas deferens, and often follows previous vasectomy or
produce a mass that is clinically mistaken as a tumor. This includes herniorrhaphy. It is thought that the raised pressure leads
lesions such as fibrosis related to hydrocele, spermatocele, granu-
lomatous and non-granulomatous epididymitis, changes associ-
ated with vasculitis, and sperm granuloma. Other lesions may
produce histological concern, resulting in misinterpretation as
tumors. The latter group includes the following lesions.
CRIBRIFORM ‘HYPERPLASIA’ OF EPIDIDYMIS

Cribriform hyperplasia of the epididymis is a rarely recognized
variant of normal epididymal histological appearance that may
be present in up to half of surgically removed epididymes. The
tumor occurs over a broad age range, with a mean of 40 years.
It has no association (that could be documented) with either
testicular germ cell neoplasia, adenomatous hyperplasia of the
rete testis, or parenchymal atrophy. Cribriform hyperplasia of
the epididymis is very closely similar to patterns of cribriform
ductal CIS of the female breast, and is characterized by com-
plex arcades and cellular bridges spanning dilated epididymal
lumina. The cells lining these interconnecting arches have
hyperchromatic nuclei, but lack significant atypia or mitotic
activity. This finding may be misinterpreted as intraepididymal (a)
spread of testicular germ cell tumor, or could be misdiagnosed
as epididymal CIS.
MONSTROUS EPITHELIAL CELLS IN HUMAN EPIDIDYMIS

AND SEMINAL VESICLES
Peculiar monstrous epithelial cells simulating anaplastic malig-
nant transformation may rarely be observed in human epi-
didymis and seminal vesicles. These peculiar epithelial changes
are observed in both cancer and non-cancer patients. The
changes are not seen in persons under the age of 20 years, and
have no correlation to any particular systemic disease. The his-
togenesis remains speculative, but hormonal effects or degener-
ation due to aging seems to be contributory. The changes
should not be mistaken for cancer.
LEYDIG CELLS OUTSIDE THE TESTICULAR PARENCHYMA

Leydig cells may rarely be seen outside the testicular
parenchyma, particularly in the tunica albuginea. They may also
be seen in the rete testis, in the adventitia between the tunica (b)
albuginea and the epididymis, in the epididymis, and in the
cord. The cells are seen in groups of up to 50 cells, or less often Figure 11.28 (a, b) Vasitis nodosa. Multiple, haphazardly arranged,
irregularly shaped, small-sized, glandular structures extending from
larger nodules, frequently arranged in linear fashion in relation the lumen into the muscular layer of the vas deferens.The lining
to nerve bundles or even surrounding vessels. They are more cells are cuboidal or low columnar, and exhibit little or no atypia.
commonly seen in elderly men. Note the early perineural invasion (b).
to extravasation of sperm, followed by inflammation and cells. Most occur in the hilar region of the testis, but they may
epithelial proliferation. Restoration of fertility is not affected. also occur in the epididymis and spermatic cord. The nodules
Antisperm antibody may be a problem. Vasitis nodosa has show steroid-type cells with abundant eosinophilic cytoplasm
rarely been reported in the epididymis. At this site, the lesion and fibrous bands.
probably represents a regenerative effort following rupture of a
duct resulting from long-standing obstruction, either locally or SCLEROSING LIPOGRANULOMA
at some point distally in the ductal system. Recognition is
important in order to prevent misdiagnosis as a neoplasm. Sclerosing lipogranuloma is a peculiar granulomatous fatty
Microscopically, vasitis nodosa shows multiple, haphazardly tissue reaction. The majority of the cases occur in the genital
arranged, irregularly shaped, small-sized, glandular structures and urinary tracts. The condition is usually caused by self-injec-
extending from the lumen into the muscular layer of the vas def- tion with a foreign substance, and a T-cell-mediated immune
erens. The lining cells are cuboidal or low columnar and exhibit response might play a part in the formation of lipogranuloma.
little or no atypia. Intravascular and perineural invasion may be Treatment is often conservative after establishing the diagnosis.
seen. Sperm granuloma is found in one-third of cases. Vasitis Histologically, the lesion is composed of adipose tissue with
nodosa may be mistaken as prostatic adenocarcinoma, adeno- fibrosis together with many epithelioid granulomas with multi-
carcinoma of the rete testis or adenomatoid tumor. nucleated giant cells of foreign body and Langerhans’ types and
Immunohistochemically, most proliferating glandular cells heavy infiltrates of lymphocytes and eosinophils. Charac-
are strongly positive for CK7, CK19, 34␤E12, and vimentin. teristically, the lesion shows broad coagulative and lytic necro-
EMA and Leu-M1 stains the luminal surface of the cells. sis. Congestion and edema suggestive of ischemia may be seen
Focally, glandular cells may also be positive for CA125. CK20, in some areas.
CEA and PSA are usually negative. Sclerosing lipogranuloma of the male genitalia without a
history of injection of exogenous material is extremely rare.
PARATESTICULAR BENIGN FIBROUS PROLIFERATIONS SPLENIC–GONADAL FUSION

These are uncommon tumors, and fall into the category of so- Splenogonadal fusion is an extremely rare congenital anomaly
called fibrous pseudotumor, fibroma, and solitary fibrous tumor. that results from fusion between the splenic and gonadal anlage
during embryonic development. It occurs more often in the
Fibrous pseudotumor (fibromatous periorchitis/nodular male, where the abnormality may be associated with skeletal
abnormalities or cryptorchidism. The condition has been
periorchitis)
divided into two major groups: (i) continuous splenic–gonadal
These are rare, benign, solid masses originating from the tunica fusion, in which a continuous cord-like structure connects the
vaginalis, epididymis, and the tunica albuginea of the testes. spleen and the gonadal–mesonephric structure; and (ii) discon-
These lesions present as testicular mass and have two forms: tinuous splenic–gonadal fusion, in which no such connection
● Localized form shows single or disseminated nodules, or
exists. This anomaly is included in the differential diagnosis of
plaques, which may be confluent or may encase the testis. testicular masses.
They may involve the tunica vaginalis, epididymis or The condition presents early in infants and childhood as an
spermatic cord. inguinal mass or inguinal hernia. It has rarely been reported in
● Diffuse form shows dense fibrous tissue involving the
adult female as a duct, approximately 10 cm long, extending
tunica vaginalis. from the inferior pole of the spleen to a junction in the left
Microscopically, these lesions show hyalinized collagen in paral- ovarian suspensory ligament. The lesions are usually removed
lel arrays and occasionally with variable number of plasma cells without complications.
and lymphocytes, sometimes with germinal centers. Myxoid Histologically, the lesion shows splenic tissue, fat and fibrous
change, focal calcification and ossification may be found. tissue. Splenic–gonadal fusion should be considered in the
differential diagnosis of scrotal swellings.
INFLAMMATORY MYOFIBROBLASTIC (PSEUDOTUMOR) SMOOTH MUSCLE HYPERPLASIA

TUMOR This is a largely unrecognized benign cause for an intra-scrotal
The spermatic cord is the most common site in the male genital mass, representing a non-neoplastic excess of native smooth
tract for this lesion. (See also Chapter 13, Soft tissue tumors, muscle in the paratestis or spermatic cord growing between or
p. 988.) around vessels or efferent ducts. Typically, patients range in age
from 46 to 81 years, with a mean age of 63 years. The mean
lesion size is 2.5 cm (range from 0.6 to 7 cm). The cause of this
TUMOR OF THE ADRENOGENITAL SYNDROME AND lesion is not apparent, although microscopic epididymal or vas
deferens duct ectasia in some cases suggests a possible obstructive
RELATED LESIONS
etiology. Microscopically, the lesions consists of fascicles of
Patients with untreated or under-treated adrenogenital syn- smooth muscle, growing in a periductal, perivascular, interstitial,
drome may develop scrotal masses consisting of steroid-type or mixed pattern. The cohesive, interlacing growth pattern of a
Bibliography 823
leiomyoma is usually missing. This is a benign process, and has invasion (type A); or by direct extension from muscle-invading
no clinical significance after excision and correct diagnosis. carcinomas of the bladder (type B). Type A involvement of the
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MISCELLANEOUS LESIONS prostatic ducts, acini, and ejaculatory ducts. Extensive page-
Endometriosis, prostatic-type glands and Rosai–Dorfman toid spread of transitional cell carcinoma to the urethral mea-
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TUMORS AND PSEUDOTUMORS OF THE SEMINAL be aware of these phenomena.
VESICLES
SEMINAL VESICLE INVOLVEMENT BY PROSTATE CANCER
CYSTIC EPITHELIAL–STROMAL TUMOR
Prostatic carcinoma spreads to the seminal vesicle either by
This tumor resembles the rare cystadenoma of the seminal vesi- direct spread along the ejaculatory duct complex (type I),
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vesicle with no contiguous primary cancer in the prostate
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seen. Type III is usually associated with significantly smaller
INVASIVE TRANSITIONAL CELL CARCINOMA OF THE cancers and fewer positive margins than in other types. Type II
BLADDER is associated with a significantly higher risk of lymph node
metastasis.
Transitional cell carcinoma of the bladder may extend to
the seminal vesicles either by mucosal spread without stromal
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erature. Scand. J. Urol. Nephrol. 33: 197–199, 1999. 649–652, 1989.
Young RH, Koelliker DD, and Scully RE. Sertoli cell tumors of Peters MA, Teerds KJ, van der Gaag I, de Rooij DG, and van
the testis, not otherwise specified: a clinicopathologic analy- Sluijs FJ. Use of antibodies against LH receptor, 3beta-
sis of 60 cases. Am. J. Surg. Pathol. 22: 709–721, 1998. hydroxysteroid dehydrogenase and vimentin to characterize
Zukerberg LR, Young RH, and Scully RE. Sclerosing Sertoli different types of testicular tumour in dogs. Reproduction
cell tumor of the testis. A report of 10 cases. Am. J. Surg. 121: 287–296, 2001.
Pathol. 15: 829–834, 1991. Richmond I, Banerjee SS, Eyden BP, and Sissons MC.
Sarcomatoid Leydig cell tumour of testis. Histopathology
27: 578–580, 1995.
SEX CORD–STROMAL TUMORS Taniyama H, Hirayama K, Nakada K, et al. Immunohisto-
chemical detection of inhibin-alpha, -betaB, and -betaA chains
LEYDIG CELL TUMOR and 3beta-hydroxysteroid dehydrogenase in canine testicular
tumors and normal testes. Vet. Pathol. 38: 661–666, 2001.
Balsitis M and Sokal M. Ossifying malignant Leydig (interstitial) Ulbright TM, Srigley JR, Hatzianastassiou DK, and Young RH.
cell tumour of the testis. Histopathology 16: 599–601, 1990. Leydig cell tumors of the testis with unusual features:
Billings SD, Roth LM, and Ulbright TM. Microcystic Leydig adipose differentiation, calcification with ossification, and
cell tumors mimicking yolk sac tumor: a report of four cases. spindle-shaped tumor cells. Am. J. Surg. Pathol. 26:
Am. J. Surg. Pathol. 23: 546–551, 1999. 1424–1433, 2002.
TUMORS OF THE PARATESTICULAR REGION
Ferry JA, Young RH, and Scully RE. Testicular and epididymal
NEOPLASTIC AND NON-NEOPLASTIC plasmacytoma: a report of 7 cases, including three that were
PROLIFERATION OF THE TESTICULAR the initial manifestation of plasma cell myeloma. Am. J.
COLLECTING SYSTEM Surg. Pathol. 21: 590–598, 1997.
CYSTS AND EPITHELIAL PROLIFERATIONS

PARATESTICULAR MESOTHELIAL TUMORS
Jones MA, Young RH, and Scully RE. Adenocarcinoma of the
epididymis: a report of four cases and review of the litera- Butnor KJ, Sporn TA, Hammar SP, and Roggli VL. Well-
ture. Am. J. Surg. Pathol. 21: 1474–1480, 1997. differentiated papillary mesothelioma. Am. J. Surg. Pathol.
Jones EC, Murray SK, and Young RH. Cysts and epithelial 25: 1304–1309, 2001.
proliferations of the testicular collecting system (including Jayaram N, Ramaprasad AV, Chethan M, and Sujay RP.
rete testis). Semin. Diagn. Pathol. 17: 270–293, 2000. Tumours and tumour-like conditions of the para-testicular
region – a study of morphological features. Indian J. Pathol.
Microbiol. 41: 287–295, 1998.
PARATESTICULAR LYMPHORETICULAR TUMORS Jones MA, Young RH, and Scully RE. Malignant mesothe-
lioma of the tunica vaginalis. A clinicopathologic analysis of
Ferry JA, Harris NL, Young RH, Coen J, Zietman A, and 11 cases with review of the literature. Am. J. Surg. Pathol.
Scully RE. Malignant lymphoma of the testis, epididymis, 19: 815–825, 1995.
and spermatic cord. A clinicopathologic study of 69 cases Lane TM, Wilde M, Schofield J, and Trotter GA. Benign cystic
with immunophenotypic analysis. Am. J. Surg. Pathol. 18: mesothelioma of the tunica vaginalis. Br. J. Urol. Int. 84:
376–390, 1994. 533–534, 1999.
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borderline tumor of the paratestis: a report of seven cases. Sclerosing lipogranuloma of the testis. Urology 60: 515, 2002.
Am. J. Surg. Pathol. 25: 373–378, 2001. Sakaki M, Hirokawa M, Horiguchi H, Wakatsuki S, and
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12 skin tumors
Awatif I Al-Nafussi and Kathryn M McLaren
Cutaneous cysts 837 Skin appendage tumors, benign: sweat gland-derived tumors 865
Bronchogenic cyst 837 Chondroid syringoma 865
Cutaneous ciliated cyst 837 Cylindroma 867
Cutaneous follicular cysts 837 Eccrine spiradenoma 868
Dermoid cysts of the skin 838 Hidradenoma (clear cell hidradenoma; acrospiroma) 869
Digital mucous/myxoid cyst 838 Hidradenoma papilliferum 870
Epidermal cysts 839 Poromas 870
Epidermoid cysts 839 Syringocystadenoma papilliferum 871
Eruptive villus hair cysts 839 Syringoma 872
Hidrocystomas 839 Skin appendage tumors, malignant: hair follicle-derived tumors 873
Median raphe cyst of the penis 840 Pilomatrix carcinoma 873
Steatocystoma multiplex 840 Tricholemmal carcinoma 873
Tricholemmal cyst 840 Skin appendage tumors, malignant 874
Neuroendocrine carcinoma (Merkel cell carcinoma) 874
Skin appendage tumors, malignant: sebaceous
Epithelial tumors 841 gland-derived tumors 874
Epidermal tumors, benign 841 Sebaceous carcinoma 874
Clear cell acanthoma 841 Skin appendage tumors, malignant: sweat
Linear epidermal nevus 841 gland-derived tumors 875
Seborrheic keratosis 842 Adenoid cystic carcinoma 875
Solar lentigo 844 Aggressive digital papillary adenoma/carcinoma 875
Squamous papilloma 845 Hidroadenocarcinoma/malignant transformation of
Verrucae 845 cylindroma/spiradenocarcinoma 876
Epidermal tumors, in-situ malignancy 847 Microcystic adnexal carcinoma 876
Actinic keratosis 847 Mucinous carcinoma 877
Bowen’s disease 848 Porocarcinoma 878
Epidermal tumors, malignant 849 Primary extramammary Paget’s disease 879
Basal cell carcinoma 849
Squamous cell carcinoma, common variant 853
Melanocytic lesions, benign 879
Squamous cell carcinoma, other variants 853
Common nevi 879
Epidermal tumors, uncertain malignant potential 854
Junctional, intradermal and compound nevi 879
Keratoacanthoma 854
Lentigo 881
Skin appendage tumors, benign: hair follicle-derived tumors 854
Spitz nevi and variants 881
Dilated pore of Winer 854
Variant nevi 883
Fibrofolliculoma 855
Ancient nevus 883
Follicular nevi 856
Balloon cell nevus 883
Pilar sheath acanthoma 856
Blue nevus 883
Pilomatrixoma 856
Combined nevus 884
Proliferating pilar tumor 857
Congenital nevi 885
Trichoadenoma 857
Deep penetrating nevus (plexiform spindle cell nevus) 885
Trichoepithelioma 858
Halo nevus 886
Trichofolliculoma 859
Nevus after UV irradiation 886
Trichogenic tumors 860
Pigmented spindle cell nevus 886
Tricholemmoma 862
Pseudo-melanoma (persistent nevus) 887
Warty dyskeratoma 862
Special-site nevi and variants 887
Skin appendage tumors, benign: sebaceous gland-derived tumors 862
Hamartoma/hyperplasia: folliculosebaceous cystic
hamartoma 862 Melanocytic lesions, malignant 888
Nevus sebaceous (sebaceous nevi) 863 Common types of melanoma 888
Sebaceoma 864 Acral lentigenous melanoma in situ 888
Sebaceous adenoma 864 Lentigo maligna 889
Sebaceous hyperplasia 864 Nodular melanoma 889
836 Skin tumors
Variant melanomas 892 Pagetoid reticulosis 917

Animal type melanoma 892 Pleomorphic small-/medium-sized CTCL 918
Balloon cell melanoma 892 Primary cutaneous CD30-positive large
Desmoplastic melanoma 893 T-cell lymphoma 918
Merkel-like small cell melanoma 893 Primary cutaneous CD30-negative large
Myxoid melanoma 894 T-cell lymphoma 918
Nevoid melanoma variants 896 Cutaneous pseudolymphomas 919
Regressed melanoma 896 Cutaneous pseudo-B-cell lymphoma
Signet ring cell melanoma 897 (lymphocytoma cutis) 919
Spitzoid melanoma 898 Cutaneous pseudo-T-cell lymphoma 921
Varicose melanoma 898 Leukemia cutis 921
Mastocytoma 922
Melanocytic lesions, premalignant 898 Plasmacytoma 922
Atypical nevi: dysplastic nevus (nevus with Regressing atypical histiocytosis 922
architectural and cytological atypia) 898
Pigmented lentiginous nevus with atypia 899 Neural tumors 923
Neurofibromas 923
Mesenchymal tumors 900 Neurothekeoma 923
Fibroblastic/myofibroblastic 900
Acquired digital fibrokeratoma 900 Vascular tumors 923
Fibrous papule of nose and face 900 Endothelial tumors, benign 923
Inflammatory (pseudotumor) myofibroblastic tumor Acroangiodermatitis 923
of the skin 901 Glomus tumor 923
Keloids and hypertrophic scar 901 Hemangioma 925
Fibrohistiocytic tumors 902 Hemangioma, acquired tufted 925
Atypical fibroxanthoma (AFX) 902 Hemangioma, glomeruloid 925
Fibrous histiocytoma/dermatofibroma 903 Pyogenic granuloma 926
Histiocytic tumors 907 Endothelial tumors, intermediate 926
Juvenile xanthogranuloma (JXG) 907 Hemangioendotheliomas 926
Plexiform xanthoma 908 Endothelial tumors, malignant 926
Reticulohistiocytic granuloma and multicentric Angiosarcoma 926
reticulohistiocytosis 909 Lymphatic tumors 926
Verruciform xanthoma 909
Xanthelasma 910
Cutaneous heterotopic meningeal nodules 926
Lymphoreticular tumors 910 Fibroepithelial polyp of the skin (skin tag)
Actinic reticuloid 910 (achrocordon) 927
Granular cell tumor 927
Onychomatricoma 927
Cutaneous lymphomas 911
Acellular deposits 927
Primary cutaneous B-cell lymphoma (PCBCL) 911
Calcinosis cutis 927
Primary cutaneous T-cell lymphoma (PCTCL) 913
Gout tophi 929
Cutaneous/subcutaneous panniculitic
Osteoma cutis 929
T-cell lymphoma 913
Granulomatous slack skin 913
Lymphomatoid papulosis 914 Secondary malignant tumors 929
Mycosis fungoides/Sezary syndrome 914
GENERAL COMMENTS overdiagnosed or completely misinterpreted on hematoxylin and

eosin (H&E) sections, with possible dire clinical consequences.
Skin biopsies comprise a large proportion of the workload in any However, with the current availability of immunohistochemistry
surgical pathology department. Amongst the malignant tumors, in most pathology departments, this problem may be lessened.
basal cell carcinomas (BCCs) and squamous cell carcinomas Other malignant skin tumors, such as sarcomas, skin appendage
(SCCs) rank number one in their frequency. These tumors usu- tumors and lymphomas are rare.
ally create no or very little diagnostic difficulties. Malignant Of the benign skin tumors, the most commonly encountered
melanoma (MM) is much less frequent, but creates great lesion is nevus. Due to its frequency, pathologists tend to mis-
challenges. Malignant melanoma may be underdiagnosed, interpret some malignant tumors (especially in a small biopsy)
Cutaneous cysts 837
such as dermatofibrosarcoma protuberans, malignant periph- CUTANEOUS CILIATED CYST

eral nerve sheath tumor, desmoplastic melanoma, and desmo-
plastic leiomyosarcoma as being dermatofibromas.
Other benign skin tumors such as skin appendage tumors are CLINICAL FEATURES
much less common, but may generate diagnostic problems. These are rare benign cystic lesions occurring in the lower
Many entities within this group share some or many histologi- limbs of young women, although other locations have been
cal features, which makes accurate diagnosis of the lesion rather described. Their exact histogenesis is unclear, but has been
daunting. However, the fact that the majority are benign – and widely regarded as mullerian heterotopias.
when malignant, cytological features are obvious – lessens the
impact. Other very common skin lesions that may present as a
lump or tumor mass are skin cysts.
Cutaneous metastasis from internal malignancy is another Typically, the cyst wall is composed of cuboidal to columnar
problem that may face dermatopathologists. epithelium with partial stratification. An admixture of apo-
In this chapter, all tumor and tumor-like conditions of the crine and ciliated cells may rarely be seen.
skin are listed according to their histogenesis, and in an alpha-
betical order.
CUTANEOUS CYSTS
BRONCHOGENIC CYST
CLINICAL FEATURES
Bronchogenic cyst – an uncommon developmental anomaly
that originates from the primitive tracheobronchial tree and is
most commonly seen in the mediastinum – is rare in the skin.
Bronchogenic cyst is noted shortly after birth or in early child-
hood, and usually presents as a swelling or draining sinus. This
lesion is four times more common in males than in females.
The most common location is the suprasternal notch, followed
by the presternal area, neck, and scapula. Its origin and patho-
genesis can be explained as a developmental anomaly of the
tracheobronchial buds from the primitive foregut. Figure 12.1 Cutaneous ciliated cyst.The lining cells are cuboidal
Bronchogenic cyst should be included in the differential with focal ciliated epithelium.
diagnosis of congenital cystic and nodular skin lesions on the
upper chest, upper back, and neck. These cysts have also been
reported in other locations such as the abdominal wall and
Special techniques
shoulder region.
● The lining epithelial cells are epithelial membrane antigen
(EMA) and cytokeratin (CK)-positive, with less than 10%
PATHOLOGICAL FEATURES being positive for S-100 protein and estrogen receptor.
Bronchogenic cyst shows unilocular or multilocular small cys- ● The cells have been reported to be positive for estrogen
tic structures surrounded by fibro-adipose tissue. The lining and progesterone receptors.
epithelium consists of either pseudostratified ciliated columnar
epithelium with goblet cells or a single layer of ciliated or non-
ciliated cuboidal to columnar cells. The cystic walls contain
CUTANEOUS FOLLICULAR CYSTS
well-developed smooth muscle bundles, mucous glands and
hyaline cartilage plate. Malignant melanoma has rarely been CLINICAL FEATURES
reported to arise from cutaneous bronchogenic cyst.
Follicular cysts are cysts derived from the entire length or of
a particular segment of hair follicle. These include:
Differential diagnosis ● Epidermal/infundibular (epidermoid) cyst is a small
● Branchial cleft cyst: located laterally in the neck retention cyst which most probably results from occlusion
● Thyroglossal duct cyst: located in the midline of neck of the follicular orifice due to scarring or inflammation. It
● Cutaneous ciliated cyst occurs mainly on the head and neck and trunk, and
● Mature cystic teratoma presents as a skin-colored nodule that may become
838 Skin tumors
inflamed and painful as a result of result and release of squamous eddies), that simulate keratin pearls of well-
its content. Some palmoplantar epidermoid cysts have been differentiated squamous cell carcinoma.
reported to be caused by human papillomavirus (HPV) Steatocytoma multiplex is a cyst of the entire pilosebaceous
infection, or to be derived from eccrine ducts. Scrotal complex. It consists of a collapsed mid-dermal, squamous-lined
calcinosis may represent dystrophic calcification of cyst with a corrugated luminal border, a basaloid outer cell
epidermoid cysts. layer, and the presence of sebaceous lobules that are either com-
● Milia is the formation of multiple minute infundibular pressed against or partially incorporated within the cyst wall.
cysts involving vellus hair of the face (primary milia), or as The cyst may contain pale eosinophilic material. The inner cell
a result of superficial dermal scarring (secondary milia). layer is limited by a thin eosinophilic mantle of keratin.
● Trichilemmal cyst arises from the isthmus of the hair follicle Dermoid cyst is a subcutaneous cyst which is reminiscent of
(that part of the hair shaft located between the insertion of epidermal/infundibular cyst, but in addition it contains a vari-
the erector pili muscle and the attachment of the sebaceous ety of appendigeal structures (hair follicles, sebaceous lobules,
duct orifice). It is most commonly seen in the scalp. eccrine glands, and occasionally apocrine glands).
● Steatocytoma multiplex presents as multiple (rarely Eruptive vellus hair cyst is reminiscent of epidermal/infundibu-
solitary ‘steatocytoma simplex’) dermal nodules in lar cyst, but contains small vellus hair shafts and laminated kera-
presternal locations, upper arms, axillae and scrotum. tin. In addition, cords of glycogenated follicular epithelium that
It has an autosomal-dominant pattern of inheritance, may contain hair are present in close proximity to the cyst.
except for the solitary lesion or those restricted to the
scrotum.
Secondary features
● Dermoid cyst is a congenital subcutaneous cyst, seen
most commonly in the head and neck, particularly around ● Calcification: sometimes the whole trichilemmal cyst
the eyes. calcifies, resulting in a dermal calcified nodule.
● Eruptive vellus hair cyst presents in children or young ● Rupture of the cyst with a foreign body reaction.
adults in the chest or extremities as multiple, crusted or
umbilicated papules.
DERMOID CYSTS OF THE SKIN
PATHOLOGICAL FEATURES See Cutaneous follicular cysts (p. 837).
Epidermal/infundibular cyst/epidermoid/epidermal inclusion
cyst (Figure 12.2) is a superficially located dermal cyst lined by
infundibular type epithelium. (The normal hair infundibulum DIGITAL MUCOUS/MYXOID CYST
is the segment of the hair shaft located between the attachment
of the sebaceous duct orifice and the epidermal surface and
normally consists of epidermal-type epithelium with keratiniza-
CLINICAL FEATURES
tion via granular cell layers.) Neoplastic transformation of their Digital mucous/myxoid cysts are a relatively common pathol-
epithelium is extremely rare. ogy in the skin, representing a ganglion of the adjacent distal
Tricholemmal cyst (Figure 12.5) is again a superficially located interphalangeal joint. They present as solitary, clear, or flesh-
dermal cyst which arises from the isthmus of the hair follicle and colored nodules that develop on the dorsal digits between the
is therefore lined by isthmic-type squamous epithelium. (The distal interphalangeal joint and the proximal nail fold. There
isthmus is the part of the hair follicle located between the inser- are two types of digital mucous cysts: one type is associated
tion of the erector pili muscle and the attachment of the seba- with degenerative changes in the distal interphalangeal joint;
ceous duct orifice; it is normally composed of stratified and the second type is independent of the joint and arises from
squamous epithelium showing glycogenation and abrupt kera- metabolic derangement of fibroblasts that produce large quan-
tinization without the presence of granular cell layers – that is, tities of hyaluronic acid. The two types are clinically indistin-
tricholemmal keratinization.) The cyst contains homogeneous, guishable. The cysts can be asymptomatic, or they can cause
eosinophilic keratinous material, often with cholesterol clefts pain, tenderness, or deformity of the nail.
and dystrophic calcification. The lining squamous cells are large,
pale, glycogenated and glassy, and the luminal cells exhibit
rounded apical contours. The outer cell layer consists of palisad- PATHOLOGICAL FEATURES
ing basaloid cells. Similar to ganglion, in the early stage, the dermis shows loose
The cyst wall may exhibit variable degrees of hyperplasia that myxoid stroma, but later on cleft-like spaces are formed,
are indistinguishable from those seen in proliferating tricholem- followed by one cystic space containing mucin.
mal (pilar) tumor of the scalp.
Mixed tricholemmal/infundibular cyst shows mixed tricho-
lemmal and hair matrix differentiation. Differential diagnosis
Proliferating tricholemmal cysts may show a cytological ● Superficial angiomyxoma
resemblance to squamous cell carcinoma, with a predominance ● Cutaneous mucinosis
of squamoid cells, which form concentric structures (so-called ● Superficial digital fibromyxoma
Cutaneous cysts 839
ERUPTIVE VILLUS HAIR CYSTS
See Cutaneous follicular cysts (p. 837).
HIDROCYSTOMAS
CLINICAL FEATURES
Hidrocystomas are cystic skin appendage structures of sweat
gland origin, occurring preferentially on the head and neck.

Histologically, these lesions are composed of either a unilocular
or multilocular cystic structure with either a flattened basaloid
epithelium resembling eccrine epithelium (eccrine hidrocys-
toma) or apocrine cells. When the lining is of apocrine nature
with apical blebbing, then the term ‘apocrine cystadenoma’ is
used because, unless the lesion is in the vulva or nipple, then the
(a) apocrine cells are not normal for the site; hence it is assumed to
represent a (benign) tumor, not merely a dilated normal duct.
(a)
(b)
Figure 12.2 Epidermal cyst. (a) The lining epithelium shows

prominent granular cell layer, and the content is loose parallel layers
of keratin. (b) Ruptured cyst lined by foreign body giant cells.
EPIDERMAL CYSTS (Figure 12.2)
EPIDERMOID CYSTS
Special techniques
(b)
Epidermoid cysts express CK10, and eruptive vellus hair cysts
express CK17, whereas trichilemmal cysts and steatocystoma Figure 12.3 (a–c) Apocrine hidrocystoma. Dermal cystic spaces
multiplex show expression of both CK10 and CK17. lined by apocrine epithelium.
840 Skin tumors
proximal extremities. Steatocystoma multiplex is included in

the differential diagnoses of lipoma, fat necrosis, galactocele
and epidermoid cyst. Steatocystoma multiplex shares many
clinical features, and may show overlapping histopathological
features with eruptive vellus hair cyst. This supports the
hypothesis that these two lesions are hamartomatous condi-
tions and are variants of one disorder which originates in the
pilosebaceous duct.
The lesions are treated by simple surgical techniques.

These lesions are cysts of the entire pilosebaceous structure,
and consist of collapsed mid-dermal cysts with a corrugated
(c) luminal border. There is a basaloid outer cell layer with seba-
ceous lobules incorporated within the wall. The inner cell layer
Figure 12.3 (Continued). is limited by a thin eosinophilic mantle of keratin.
MEDIAN RAPHE CYST OF THE PENIS TRICHOLEMMAL CYST (Figure 12.5)

CLINICAL FEATURES
Penile median raphe cysts are uncommon benign lesions that
occur predominantly in the ventral aspect of the glans penis of
young men.
The tumors are usually lined by pseudostratified columnar or
stratified squamous epithelium. A ciliated variant has been
described. Melanocytes may be observed in the lining of the
cysts.
Special techniques
● The cyst lining cells are CK7(⫹⫹⫹), CK13(⫹⫹⫹),
CK20(⫺), CAM5.2(⫹), supporting the interpretation of a (a)
columnar mucinous epithelium undergoing immature
urothelial metaplasia.
● Carcinoembryonic antigen (CEA) immunostaining
positivity of the columnar cells is probably related to the
dysembryogenetic cloacal nature of the cysts.
● Neuroendocrine differentiation of sparse cells interspersed
in the cyst lining may occur.
STEATOCYSTOMA MULTIPLEX
CLINICAL FEATURES
(b)
Steatocystoma multiplex is a rare, autosomal-dominant condi-
tion characterized by multiple, widespread cutaneous cystic
lesions. These lesions can appear virtually anywhere on the Figure 12.4 (a–c) Steatocytoma multiplex. A collapsed mid-dermal
squamous-lined cyst with corrugated luminal border limited by a
body, but are more common in areas where the pilosebaceous thin eosinophilic mantle of keratin. Sebaceous lobules are
apparatus is well-developed, such as the trunk (especially the compressed against, or partially incorporated within, the cyst wall.
presternal area), neck, axilla, inguinal region, scalp, and The cyst contains pale eosinophilic material.
(c) (a)
EPITHELIAL TUMORS
EPIDERMAL TUMORS, BENIGN

CLEAR CELL ACANTHOMA
CLINICAL FEATURES
Clear cell acanthoma of Degos is a rare benign tumor of epi-
dermal origin which, clinically, is characterized by a ‘stuck-on’
appearance of a nodule or dome-shaped plaque. This tumor
usually occurs on the legs of middle-aged or elderly persons.
Multiple, pigmented, giant, and polypoid forms have been
described. Clear cell acanthoma may rarely develop in a pre-
existing epidermal nevus.
The nature of clear cell acanthoma has not been clarified,
though many hypotheses have been proposed, including a (b)
benign neoplasm derived from epidermis or the acrosyringium,
or a non-specific dermatosis. Recently, clear cell acanthoma has Figure 12.5 (a, b) Tricholemmal cyst.The lining epithelium lacks
been shown to exhibit a similar staining pattern to inflamma- granular layers, and the content is thick, solid keratinous material.
tory dermatoses such as psoriasis, lichen planus and discoid Parakeratosis is seen in the immediate vicinity of the cyst lining.
A prominent basement membrane material is common.
lupus erythematosus. Therefore, it is speculated that this con-
dition is a localized form of inflammatory dermatosis rather
Special techniques
than a neoplasm.
● The clear cells show periodic acid–Schiff (PAS)-positive
PATHOLOGICAL FEATURES (Figure 12.6) staining for glycogen.
Clear cell acanthoma has characteristic histological features

including acanthosis, marked sharply demarcated epidermal LINEAR EPIDERMAL NEVUS
clear cell change, and uniform elongation and psoriasiform
pattern of the rete pegs. The clear appearance is due to the
CLINICAL FEATURES
presence of cytoplasmic glycogen. The epidermis is characteris-
tically infiltrated by polymorphs. Squamous cell carcinoma in Linear epidermal nevus is a congenital neoplastic proliferation
situ may rarely arise within clear cell acanthoma. of epidermal cells which is usually present at birth, though
842 Skin tumors
lines of Blaschko. Both clinically and histologically, the lesions

resemble psoriasis.
In general, epidermal nevus is characterized by a verrucous,
papillary architecture with downward elongation of the rete
ridges. The lesion is often associated with subtle alterations of
the connective tissue of the superficial dermis and abnormali-
ties of hair follicles or adnexal structures.
The constituent keratinocytes are of normal appearance, and
sometimes basaloid cells predominate.
Secondary features
● Epidermolytic hyperkeratosis (retraction and clearing of
the cytoplasm of the upper epidermal keratinocytes with
coarse keratohyaline granules).
(a) ● Focal acantholytic dyskeratosis (loss of intercellular
attachments in suprabasal locations resulting in rounded
dyskeratotic cells).
● Cornoid lamella formation (the presence of tilting spires of
parakeratotic scale surmounting discrete invaginated zones
of epidermis which exhibit hypogranulosis). The change
mimics that seen in parakeratosis.
● Hyperkeratotic seborrheic keratosis (affects older
individuals, lacks upper dermal or adnexal abnormalities
and the cells are basaloid)
● Condyloma acuminatum (affects genital and perianal skin,
associated with koilocytosis)
● Acrokeratosis verruciformis (occurring predominantly on
the dorsal surfaces of hands, feet elbows and knees, it
(b) shows ‘church spire-like’ fibroepithelial papillae and lacks
parakeratosis)
Figure 12.6 (a, b) Clear cell acanthoma. A localized epidermal ● Acanthosis nigricans (affects intertriginous areas, often
thickening due to the presence of cytoplasmic PAS-positive associated with endocrine abnormalities or internal
glycogen (b).
malignancy)
● Nevus sebaceous (occurs as a plaque on the scalp or face,
some become apparent later in life. It presents either as a local- may be associated with alopecia. Sebaceous, apocrine and
ized or a generalized form. The localized form appears as lin- mesenchymal abnormalities are seen histologically)
ear streaks or keratotic plaques anywhere in the body, and are ● Squamous papillomas of HPV etiology (viral warts) often
often intensely itchy. The generalized form consists of multiple, show the nuclear inclusions of HPV and typically have
unilateral or bilateral parallel streaks that involve a large ectatic blood vessels in the papillary cores with consequent
portion of the body. The latter can be associated with mental bleeding into the overlying parakeratin and the formation
retardation, seizures and neural deafness. Inflammatory linear of blood lakes
verrucous epidermal nevus has been reported coexisting with
an autoimmune lymphocytic thyroiditis. SEBORRHEIC KERATOSIS
Many epidermal nevi with the histology of Darier’s disease
have been reported. It has been suggested that they are better
classified as acantholytic dyskeratotic epidermal nevi rather CLINICAL FEATURES
than nevoid Darier’s disease. Seborrheic keratosis is a very common benign localized prolif-
eration of basaloid keratinocytes. It affects middle-aged and
elderly individuals, and occurs anywhere on the body (except
the palms and soles), but is most commonly seen on the trunk,
Histologically, there are at least 10 different forms, many of extremities and head and neck. The lesion appears as multiple
which resemble seborrheic keratosis. The clue is in the age of or solitary round to oval, coin-like, ‘stuck-on’ plaques that are
the patient and the clinical history. Inflammatory linear verru- variably keratotic and pigmented with a velvety to granular
cous epidermal nevus (ILVEN) is a specific clinicopathological surface. Seborrheic keratosis is easily treated by curettage or
entity. It usually presents as a pruritic linear eruption along the locally destructive measures.
Actinic dysplastic change may rarely develop in seborrheic ● Adenoid/reticulated seborrheic keratosis is characterized
keratosis located on sun-exposed skin. by the presence of multiple narrow trabeculae that contain
Multiple seborrheic keratoses with explosive onset have been focal squamous differentiation or horn cysts.
reported in association with internal malignancy (Leser–Trélat ● ‘Irritated’ seborrheic keratosis is characterized by the
sign). This has been linked to an overproduction of transform- presence of prominent squamous differentiation, squamous
ing growth factor-alpha by the primary malignant tumor.

Seborrheic keratosis is a symmetrical epidermal lesion, the
lower border of which is often sharply defined and level with
adjacent normal epidermis. The lesion is characterized by a
proliferation of basaloid cells with variable degrees of squamous
differentiation, and almost always with horn cysts (containing
laminated orthokeratin).
There are several histological variants of seborrheic kerato-
sis, all of which have the above features:
● Hyperkeratotic seborrheic keratosis is characterized by the
presence of papillomatosis, marked hyperkeratosis, focal

superficial parakeratosis and multiple horn cysts.
● Acanthotic seborrheic keratosis is characterized by a
(a)
smooth surface with marked epidermal thickening
interrupted by numerous horn cysts.
(b)
(a)
(c)
(b) Figure 12.8 (a–c) Seborrheic keratosis, clonal type.The small

dermal cells of this variant of seborrheic keratosis are clearly
Figure 12.7 (a, b) Hypertrophic and pigmented seborrheic demarcated from the remaining epidermal cells.This can be
keratosis, classic type, showing uniform small basaloid epidermal cells misinterpreted as intraepithelial carcinoma, melanocytic lesion, or
with horn cysts. Note the melanin in the basal layer of the lesion. hidroacanthoma simplex.
844 Skin tumors
‘clonal’, as there is no evidence that irritation or trauma

produce these features.
● Inverted follicular keratosis somewhat resembles clonal
(irritated) seborrheic keratosis in its squamous
differentiation and inflammatory component, but the
proliferating epithelium seems to involve hair follicles and
grows in an ‘inverted’ manner.
● ‘Borst–Jadassohn phenomenon’ refers to a histological
appearance rather than to a clinicopathological entity.
It is characterized by the presence of discrete nests of
neoplastic cells within the epidermis that are surrounded
by normal keratinocytes. Several lesions can produce this
phenomenon – for example, seborrheic keratosis,
intraepidermal eccrine poroma, actinic keratosis,
(a) squamous cell carcinoma in situ/Bowen’s disease, and
occasionally basal cell carcinoma or clear cell acanthoma.
● Pigmented seborrheic keratosis is identical to the
acanthotic variant, but in addition contains melanin
pigment within the keratinocytes. The pigment may rarely
be seen in dendritic melanocytes, and the lesion is termed
melanoacanthoma.
● Acantholytic variant has recently been identified,
characterized by prominent acantholysis.
● Linear epidermal nevus (affects children and present at
birth, and has a linear distribution)
● Inactive verrucae (small often multiple lesions, shows
crown-like spires capped by parakeratotic scale and with
ectatic tortuous vessels in dermal papillae)
(b) ● Condyloma acuminatum (affects genital and perianal skin,
associated with koilocytosis)
Figure 12.9 (a, b) Seborrheic keratosis, irritated type.This variant ● Acrokeratosis verruciformis (occurring predominantly on
shows parakeratosis, squamous eddies, and increased mitotic figures.
the dorsal surfaces of hands, feet, elbows and knees, it
shows ‘church spire-like’ fibroepithelial papillae, and no
parakeratosis)
● Acanthosis nigricans (affects intertriginous areas, often
associated with endocrine abnormalities or internal
malignancy)
● Nevus sebaceous (occurs as plaque on the scalp or face,
may be associated with alopecia, and histologically shows
sebaceous, apocrine and mesenchymal abnormalities)
● Eccrine poroma (may resemble acanthotic seborrheic
keratosis)
● Squamous cell carcinoma (may resemble irritated
seborrheic keratosis which exhibit prominent squamous
eddies, foci of acantholysis and nuclear pleomorphism
with mitotic figures). The two should be distinguished by
the nuclear features which are reflecting moderate or
severe dysplasia
Figure 12.10 Seborrheic keratosis, reticulated type.This shows thin

elongated strands of basaloid cells, sometimes with pigmentation. SOLAR LENTIGO
eddies, parakeratosis and heavy lichenoid inflammatory

CLINICAL FEATURES
infiltrate. Some lesions may show focal acantholysis with
nuclear enlargement and frequent mitoses reminiscent of Solar lentigines are acquired pigmented lesions on sun-damaged
squamous cell carcinoma. These are probably best termed skin that, in general, have both keratinocytic and melanocytic
hyperplasia, but no melanocytic atypia and no nests of without treatment (erythema and pruritus may herald regres-
melanocytes. sion). They are seen in the skin and mucosal membranes.
The reticulated black solar lentigo (‘ink spot’ lentigo) usually Warts are common in renal allograft recipients, with a
has an irregular outline and is often considered suspicious for reported incidence ranging from 24% to 100%. These patients
melanoma. also demonstrate an increased risk of progression from wart to
carcinoma.
PATHOLOGICAL FEATURES There are various clinical types:
● Verruca vulgaris and filiform warts are the most common
Solar lentigo demonstrates lentiginous hyperplasia of the epi-
type associated with HPV types 2, 4, and 7, and present as
dermis, marked hyperpigmentation of the basal layer with
papillomatous hyperkeratotic papules and nodules most
‘skip’ areas that involve the rete ridges, and a minimal increase
commonly on the dorsum of hands and fingers.
in the number of melanocytes. The underlying dermis shows
● Plantar warts are either solitary or multiple, and occur on
solar elastosis, telangiectasia and slight chronic inflammation.
the soles of the feet. They are often painful, and covered
Facial solar lentigines frequently lack the rete ridge hyperplasia
by a thick callus. This is associated with HPV 1 and 2.
classically associated with lentigines from other anatomic sites.
● Flat wart/verruca plana is associated with HPV types 3
Cell morphology and 10, occurs on the hands and feet, and presents as
multiple flesh-colored papules that often show linear
● Transepidermal elimination of melanin pigment into the
distribution.
overlying stratum corneum is commonly seen. ● Condyloma acuminatum is associated with HPV types 6
Differential diagnosis and 11, and presents as a verrucous cauliflower-like

excrescence on the anogenital region, upper thigh and
● Pigmented actinic keratosis lower abdomen.
● Lentigo maligna ● Bowenoid papulosis affects the penis and vulva. It has a
benign behavior, and is associated with HPV 16, 18, 33

SQUAMOUS PAPILLOMA and 34.
● Epidermodysplasia verruciformis affects any part of the
skin, and is associated with HPV 3, 5, 8, 10, 12, 14, 15,

CLINICAL FEATURES 17, and 19. It may progress to malignancy.
Squamous papillomas are one of the most common types of ● Verrucae occurring in the setting of immunosuppression
benign epithelial tumor. They are seen mainly in the skin, but are usually multiple, locally aggressive, and may undergo
also in the mucosal lining such as in the nose (occurs mainly in malignant transformation.
the vestibule of middle-aged individuals as a cauliflower-like
lesion that obstructs or projects through the nasal cavity),
bronchus and esophagus. Squamous papillomas are usually soli-
tary, but can be bilateral (nose) or multiple, and are frequently Verruca vulgaris is a symmetrical, crown-like lesion that is
caused by HPV infection. characterized by multiple radiating verrucous spires surmounted
by parakeratotic zones and supported by fibrovascular cores
PATHOLOGICAL FEATURES containing dilated tortuous vessels which bleed into the over-
lying keratin, producing blood lakes. There is a hyperkeratotic
Squamous papillomas are exophytic squamous lesions showing
scale, and a prominent granular cell layer containing coarse
hyperkeratosis, papillomatosis and normal epidermal-type cell
granules and exhibiting cytoplasmic pallor and clearing (koilo-
layers. The basal cells may show dysplastic change. The stroma
cytic change). The cells in the upper layers also show cytoplas-
is usually inflamed and vascular. Mucosal squamous papillomas
mic clearing, nuclear pallor and dispersion of chromatin and
may exhibit HPV wart changes (koilocytosis).
presence of pale pink granular intranuclear inclusions.
Differential diagnosis Filiform verruca is similar to verruca vulgaris, but the ‘spires’
are more vertically oriented.
● Seborrheic keratosis Plantar wart is characterized by a crater-like lesion with
● Transitional cell papilloma (nose) numerous endophytic down-growths. The surface is often cov-
● Verrucous carcinoma ered by dense hyperkeratotic and parakeratotic scale. The cells in
● Pseudoepitheliomatous hyperplasia the uppermost epidermal layers contain characteristic large
● Hypertrophic actinic keratosis (skin) eosinophilic bodies which have irregular borders (representing
condensed cytokeratin) reminiscent of molluscum bodies, except
VERRUCAE that the latter are more rounded and variably eosinophilic.
Flat wart is similar to verruca vulgaris, but lacks prominent
papillomatosis and hyperkeratosis.
CLINICAL FEATURES
Condyloma acuminatum is characterized by both exophytic
Verrucae are benign squamoproliferative lesions caused by and endophytic squamous epithelium covered by hyperkera-
HPV. Most have a benign clinical course, and many regress totic and parakeratotic scale. The epithelium is separated by
846 Skin tumors
(a) (c)
(b) (d)
Figure 12.11 (a–d) Classic viral wart, showing inward growth pattern of the elongated acanthotic epidermis, hyperkeratosis,
hypergranulosis, and clear cell changes.
vascular connective tissue. The cytopathic effects are more

prominent in this type of viral wart. The nuclei have irregular Differential diagnosis
contours and a ‘salt-and-pepper’ chromatin pattern; there are Verrucae should be distinguished from other verrucous epider-
multinucleated cells as well as individual cell necrosis. Mitotic mal hyperplasias such as:
figures can be seen, and these may increase in number after ● Hyperkeratotic seborrheic keratosis
treatment with podophyllin. ● Nevus sebaceous
● Epidermal linear nevus
● Acanthosis nigricans
Secondary features ● Acrokeratosis verruciformis
● Thrombosis of the vessels within the dermal papillae.

● Brisk lichenoid lymphohistiocytic inflammatory response Plantar wart
indicating regression. ● Molluscum contagiosum
Condyloma acuminatum middle-aged and elderly people, and it may result in cutaneous
● Verrucous squamous cell carcinoma horn formation. It may affect the vermilion border of the lower
lip (actinic cheilitis). The large cell acanthoma variant is a rare
Special techniques subtype, more often seen on the legs as small tan-colored, vel-
● Identification of HPV type by immunohistochemistry, vety patches. If untreated, actinic keratosis may progress to
in-situ hybridization and polymerase chain reaction invasive squamous cell carcinoma, or sometimes to basal cell
(PCR) technique. carcinoma. The clinical, histological, and molecular parameters
of actinic keratosis are those of squamous cell carcinoma. It is
now accepted that actinic keratosis does not transform, convert,
EPIDERMAL TUMORS, IN-SITU MALIGNANCY or progress into cutaneous squamous cell carcinoma, but is the
earliest clinically recognizable manifestation of this malignancy.
ACTINIC KERATOSIS The tumor suppressor p16, encoded by the CDKN2/INK4a
locus, has been reported to be mutated in ⭓24% of squamous
cell carcinomas. Mutations of the p16 gene have also been
CLINICAL FEATURES found in actinic keratoses, the first identifiable lesion in the
continuum from normal skin to squamous cell carcinoma.
Actinic keratosis is a common skin disorder caused by expo-
sure to ultraviolet (UV) light. Similar lesions may be induced by
ionizing radiation, immunosuppression, arsenicals and carcino-
gens such as hydrocarbons. Actinic keratosis usually presents Actinic keratosis is characterized by abnormal maturation of
as multiple, erythematous scaly lesions on sun-exposed skin in epidermal keratinocytes with dysplasia of the basal cell layers,
(a)
(c)
(b) (d)
Figure 12.12 Intraepidermal carcinoma.The malignant intraepidermal cells may coalesce to form large nests (a), or may be arranged in an
isolated pagetoid pattern (b), or may show a mixture of nesting and pagetoid pattern (c). MIB-1 is a good marker of proliferating cells, and
shows the positive nuclei of the intraepidermal carcinoma (d).
848 Skin tumors
associated with alternating zones of hyperkeratosis and para- ● Lichenoid dermatitis (lichen planus) (lacks parakeratosis
keratosis. Dysplasia should be graded as mild, moderate or and keratinocytic atypia)
severe, and the latter should be treated as carcinoma in situ. ● Resolving nevi (presence of melanin incontinence, lack
The upper dermis almost always contains amorphous pale parakeratosis and keratinocytic atypia)
blue-gray elastic material (solar elastosis).
Large cell acanthoma-like actinic keratosis
Variants ● Clear cell acanthoma
● Atrophic actinic keratosis shows thin epidermis in Pagetoid variant
association with other changes of actinic keratosis. ● Extramammary Paget’s disease
● Hypertrophic/proliferative actinic keratosis is associated ● Clonal (irritated) seborrheic keratosis
with prominent epidermal hyperplasia with basaloid

budding.
● Lichenoid actinic keratosis shows striking superficial Special techniques
dermal lymphocytic infiltrates. ● Elastic stains highlight the elastic tissue seen in the
● Pigmented actinic keratosis is associated with marked superficial dermis.
melanin pigment in the basal layer of the epidermis or the ● Actinic keratosis shows a statistically increased
superficial dermis. proliferation rate, as identified by proliferating cell nuclear
● Acantholytic actinic keratosis is associated with suprabasal antigen (PCNA) staining.
clefting due to acantholysis of the dysplastic basal cells; ● Actinic keratoses show weak to moderate p16
this is usually a sign of severe dysplasia. staining in the lower third to lower half of the epidermis
● Large cell acanthoma-like actinic keratosis is a well- (especially the basal keratinocytes). This staining
demarcated lesion composed of large, pale keratinocytes is significant when compared with the lack of staining
showing minimal cytological atypia. seen in normal skin. Some 20% of in-situ squamous
● Bowenoid actinic keratosis represents squamous cell cell carcinomas show moderate to strong staining in
carcinoma in situ with nesting or intraepidermal only the lower half to lower two-thirds of the
epithelioma pattern. Bowenoid actinic keratosis is closely epidermis, whereas 70% of the in-situ squamous
related to a hypertrophic variant, as both show cell carcinomas exhibit full-thickness p16 staining,
significantly thickened squamous epithelium with full with no staining in the dermis. Some 30% of invasive
thickness dysplasia, occasionally thrown into folds. squamous cell carcinomas show full-thickness
When these latter variants are heavily inflamed, it can be staining of the in-situ component of the lesion, and
difficult to exclude early dermal invasion, and 100% of invasive squamous cell carcinomas exhibit
anticytokeratin antibody clone MNF116 is of value in moderate to strong staining of the invasive component
detecting these foci. of the lesion.
● Pagetoid actinic keratosis displays atypical keratinocytes
disposed in intraepithelial cell nests, and may simulate
extramammary Paget’s disease. The atypical keratinocytes BOWEN’S DISEASE
tend to form well- to poorly defined cell groups extending
from the basal cell layer to the corneal layer.
CLINICAL FEATURES
Cell morphology This is a common condition which affects the lower limbs
● The dysplastic keratinocytes have enlarged, irregularly of older individuals. Lesions with identical histology elsewhere
shaped nuclei that exhibit hyperchromasia and an in the body are frequently referred to as bowenoid actinic
abnormal chromatin pattern. keratosis. Clinically, the condition presents as an erythematous
● The retained nuclei seen in the parakeratotic layers exhibit scaly plaque. Pigmented variants occur which, clinically, may
more crowding and hyperchromasia than those seen in mimic malignant melanoma.
inflammatory conditions.
● Impetigo-like collections of polymorphs are often seen in
the parakeratotic scale. PATHOLOGICAL FEATURES (Figures 12.13–12.14)
Histologically, there is usually hyperkeratosis, mild epidermal
Differential diagnosis thickening and full-thickness dysplasia. Clear cell and pagetoid
variants have been described. HPV has been associated with
Hypertrophic actinic keratosis
the disease.
● Irritated seborrheic keratosis
Lichenoid actinic keratosis

● Benign lichenoid keratosis (a solitary scaling plaque, Differential diagnosis
affects trunk or upper extremities, shows basal cell ● Clear cell acanthoma
vacuolation and reactive nuclear change) ● Superficial spreading melanoma
(a) (c)
(b) (d)
Figure 12.13 (a–d) Bowen’s disease (intraepidermal carcinoma). Lack of epidermal cell maturation, acantholytic change with cellular atypia.
EPIDERMAL TUMORS, MALIGNANT

BASAL CELL CARCINOMA
CLINICAL FEATURES
Basal cell carcinoma (BCC) is the most common skin malig-
nancy in pale-skinned races, accounting for approximately half
of all cutaneous malignancies. BCC is a UV light-associated
malignancy, and is therefore most commonly found on the
face, head and neck. One variant – the superficial type – may
also occur on the trunk or limbs. The incidence of BCC is asso-
ciated with advancing age, but it may occur in younger patients
in association with xeroderma pigmentosum and nevus seba- Figure 12.14 Bowen’s disease (clonal type).The abnormal
ceous. It may also occur in association with certain syndromes, keratinocytes are distinct from the remaining epidermal cells,
which include nevoid basal cell carcinoma syndrome, Rombo producing a nesting-like effect.
syndrome, Bazex syndrome and the unilateral basal cell nevus
syndrome. BCC is a low-grade malignancy with a capacity for The incidence of total regression in BCC is unknown, but in
local recurrence; this is related to tumor type and distance to 50% of cases there is evidence of partial regression on histological
the closest margin. The micronodular, infiltrative and superfi- examination. Regression of skin tumors is likely to be mediated by
cial types have the higher incidences of recurrence. activated CD4⫹ T lymphocytes, possibly via cytokine secretion.
850 Skin tumors
Transformation from a trichoepithelioma to a BCC is a rare gives a degree of credence to the growth classification of BCC.
event. Several reports have documented the coexistence of BCC It is possible that beta-catenin may have a pathogenic role in
with other lesions, including melanoma. the invasive behavior of BCC.
Knowledge of the BCC molecular pathway has been helped
by the discovery of the fact that deregulation of the Hedgehog
(Hh) signaling pathway appears to be fundamental to tumor
growth. Many BCCs have mutations in the Patched1 (PTCH1) There are various classifications of BCCs based on histological
gene that plays a crucial role in the embryonic patterning and appearances and clinical behavior:
is a member of the Hh signaling pathway. Recent investigations ● The nodular (including micronodular) is the most
have suggested that the cellular localization of beta-catenin common, accounting for 50% of BCC. They are composed
(a) (c)
(b) (d)
Figure 12.15 Basal cell carcinoma. (a, b) Classic nest of basaloid cells with peripheral palisading, nuclear crowding, and presence of mitotic
and apoptotic bodies.The cellular edematous stroma is prominent. Focal melanin pigment is seen (pigmented basal cell carcinoma). (c) Cystic
change; (d) tricholemmal differentiation.
Figure 12.16 Basal cell carcinoma: clear cell changes.

Figure 12.19 Basal cell carcinoma. Classic nests showing basaloid
cell with peripheral palisading.
Figure 12.17 Basal cell carcinoma. Pseudoglandular change is Figure 12.20 Basal cell carcinoma. Cystic change is common in
common in basal cell carcinoma. basal cell carcinoma.
of large dermal clumps of basaloid cells with peripheral

palisading of cells and mitotic and apoptotic bodies. There
is usually artifactual clefting between the nests and the
surrounding stroma.
● The micronodular variant, where the nests are ⬍0.15 mm,
accounts for 15% of this group, and are said to be more
likely to recur.
● The infiltrative BCC includes the morphoeic type, and
accounts for 10–20% of the total. In this variant, the
dermal nests are irregular in size, with poor peripheral
palisading, and an irregular outline. The larger nests are
usually central, with the smaller groups at the periphery. In
the morphoeic type of BCC the islands are small, and there
is a prominent desmoplastic stroma.
● The superficial, multifocal BCC accounts for
Figure 12.18 Basosquamous carcinoma/basal cell carcinoma with approximately 15%. In this variant, small clumps of
squamous differentiation.This shows features of both basal cell basaloid cells arise in several distinct foci from and are
carcinoma and squamous cell carcinoma. still attached to the epidermis. There is usually artifactual
852 Skin tumors
(a) (b)
Figure 12.21 (a, b) Basal cell carcinoma; tricholemmal differentiation.The basaloid nests acquire a primitive hair follicle appearance.This
variant may be mistaken for trichoepithelioma.
(a) (c)
(b) (d)
Figure 12.22 (a–d) Basal cell carcinoma; fibroepithelial type. Elongated and intercommunicating strands of basaloid cells incorporating a
cellular stroma are characteristic features of this variant.
clefting and a distinctive stromal and lymphohistiocytic Other variants of BCC include fibroepithelioma (of Pinkus)
response. where, histologically, there are thin interconnecting basaloid
● Mixtures of the above growth patterns also exist, and cords in the dermis which remain attached to the epidermis.
account for approximately 10–15% of the cases. Metatypical (basosquamous) carcinoma is the term given to a
dermal tumor which has the architecture of BCC, but the com- presents as a shallow non-healing ulcer with an erythematous
ponent cells are larger and there are also features of squamous border.
cell carcinoma. It has been suggested that this tumor is more
likely to recur and to metastasize.
Basal cell carcinomas can also show areas of follicular and
sebaceous differentiation. See also Chapter 15, Carcinomas.
Pleomorphic basal cell carcinoma is a peculiar variant of Microscopically, there is usually an ulcerated skin tumor with
BCC showing giant cells within the epithelial nests and in the infiltration of the dermis, and poor circumscription. There are
surrounding stromal components. infiltrative cords of squamous cells with irregular outlines, and
nuclear pleomorphism with mitotic figures. Intercellular bridges
Differential diagnosis should also be seen as evidence of a positive diagnosis. The
degree of keratinization varies with the degree of differentiation
● Trichoepithelioma
of the tumor. Metastases are usually associated with thick or
● Sebaceoma
widely invasive lesions and poorly differentiated forms.
● Solar keratosis may simulate BCCs in small-punch or
superficial shave biopsies in which the overall global Differential diagnosis
architectural pattern of the lesion is not represented. bcl-2 ● Keratoacanthoma
is a reliable method for distinguishing between these two ● Pseudoepitheliomatous hyperplasia
lesions (BCCs are bcl-2-positive, while lesions of solar
keratosis are negative)
● Perianal BCC is a very rare tumor which accounts for only SQUAMOUS CELL CARCINOMA,
0.2% of anorectal tumors. It must be distinguished from OTHER VARIANTS
basaloid carcinoma of the anus (BCCs are Ber-EP4-
positive, while basaloid carcinoma is Ber-EP4-negative).
CLINICAL AND PATHOLOGICAL FEATURES (Figure 12.23)
Special techniques Carcinoma cuniculatum is an uncommon variant of well-
● Infiltrative types of BCC are more likely to express differentiated squamous cell carcinoma (and related to verrucous
the tumor suppressor gene p53, and staining with carcinoma) that has classically been described on the sole of the
bcl-2 and p53 can help to discriminate BCC from foot or palms of the hand (where it has been reported on the
trichoepithelioma. hands of barbers), though it has also been described in the oral
● BCCs are keratin-, smooth muscle actin (SMA)-, and cavity. Macroscopically, it can present as a large, warty lesion.
bcl-2-positive. Histologically, there is an endophytic burrowing pattern
● BCCs are diffusely and intensely labeled with Ber-EP4, composed of well-differentiated strands of squamous carci-
whereas squamous cell carcinomas are negative. noma, with only mild cytological atypia. HPV DNA has not
● BCCs are regularly populated by benign melanocytes been found in these lesions.
(melan-A- and S-100 protein-positive) and Langerhans’ Lymphoepitheliomatous carcinoma is a malignant tumor that
cells (CD1a-positive). has been described in the nasopharynx, where it is associated
● The giant cells of the epithelial component in pleomorphic with Epstein–Barr virus (EBV). It is a rare cutaneous malignancy,
BCC share the immunophenotype of the more typical cells and histologically the tumors consist of multiple circumscribed
of the BCC (keratin-, SMA-, and bcl-2-positive), whereas nodules composed of aggregates of undifferentiated malignant
the stromal giant cells are positive only for bcl-2. cells. The cells have moderate amounts of eosinophilic cytoplasm
and vesicular nuclei with prominent nucleoli. These islands are
surrounded by a dense lymphocytic infiltrate. The epithelial cells
stain positively for the cytokeratins. EBV studies have been neg-
SQUAMOUS CELL CARCINOMA, ative in these cutaneous lesions.
COMMON VARIANT Verrucous carcinoma is a clinicopathological variant of squa-
mous cell carcinoma that occurs in the perineum which, clini-
cally, appears banal and warty. They are locally invasive
CLINICAL FEATURES
tumors that do not metastasize. Histologically, they are com-
Cutaneous squamous cell carcinoma is the second most composed of a bland exophytic squamous proliferation with only
mon skin malignancy, and is typically associated with UV minimal atypia. They frequently have a broad invasive base
exposure. Hence, it tends to occur in the head and neck region, deeply, and can be easily dismissed as a benign viral lesion. One
and also the back of the hands and forearms. It may occur in component is squamoid, and the other is epithelioid and S-100
sites of longstanding ulceration or where there has been previ- protein-positive. Other variants of squamous cell carcinoma
ous exposure to a carcinogen. It is more common in transplant include acantholytic, bowenoid, clear cell, desmoplastic,
recipients, in whom there is a short clinical history. It may arise keratoacanthoma-like, neurotropic and spindle cell squamous
from previous actinic keratosis or Bowen’s disease. Clinically, it cell carcinoma.
854 Skin tumors
EPIDERMAL TUMORS, UNCERTAIN MALIGNANT

POTENTIAL
KERATOACANTHOMA
CLINICAL FEATURES
Keratoacanthomas represent epithelial tumors which are charac-
terized by a keratin-filled crater, rapid growth in the proliferation
stage, and the potential for spontaneous regression. Keratoa-
canthomas occur on the sun-damaged skin of elderly individuals.
They develop over 2–3 months, and then subsequently undergo
spontaneous regression. However, for cosmesis as well as for
(a)
diagnosis, they are frequently removed by double curettage.

Histologically, there are three recognized histological stages:
1. The fully evolved keratoacanthoma is a symmetrical
cratiform squamoproliferative lesion, with a keratin center.
The squamous proliferative element is composed of large
glassy cells with a pinkish cytoplasm, but no significant
cytological atypia, nor infiltrative margin. Perineural
invasion has been documented in these lesions, but it
seems that this does not necessarily imply a poor
prognosis. This stage mimics squamous cell carcinoma,
and there is a belief among some pathologists that
keratoacanthomas are squamous cell carcinomas. Others
(b)
have stated that it is occasionally impossible to make the
distinction on histological criteria alone.
2. The regressing keratoacanthoma shows the same overall
architecture as the fully evolved lesion, but there is a dense
subjacent lymphohistiocytic infiltrate and there is a
decrease in the squamous proliferative component.
3. The fully regressed keratoacanthoma shows a symmetrical
cratiform lesion, with the base being formed by a thinned
atrophic squamous epithelium. There is subjacent fibrosis,
inflammation and giant cells.
A subungual variant has been described.
● Well-differentiated squamous cell carcinoma
● Self-healing epithelioma of Smith–Ferguson
(c)
Figure 12.23 (a–c) Melanoma-like squamous cell carcinoma. SKIN APPENDAGE TUMORS, BENIGN: HAIR
Poorly differentiated cutaneous cell carcinoma may be mistaken for
melanoma. CK14 staining clearly highlights the malignant cells (c). FOLLICLE-DERIVED TUMORS
DILATED PORE OF WINER
● Atypical fibroxanthoma (with spindle cell carcinoma)
CLINICAL FEATURES
● Verruca vulgaris (verrucous carcinoma and carcinoma Winer’s dilated pore is a not uncommon hair follicle tumor
cuniculatum) arising from the pilosebaceous apparatus. Clinically, the lesion
● Keratoacanthoma (KA-like carcinoma) resembles a giant comedo, and is usually located on the facial
● Lymphoma (lymphoepithelial-like carcinoma) area of the elderly. Due to annular elevation of the borders,
differential diagnosis needs to be made with basal cell carci- commonly, projections of horn-like material. Surgical excision
noma and sebaceous adenoma. is curative.
Clinically, the lesion is a hairless nodule or visible cutaneous
defect containing either soft keratinaceous material or, more PATHOLOGICAL FEATURES
Histologically, this lesion appears as a flask-like cystic structure
with a wide external opening and laminated keratinaceous
content. The cyst has a thickened wall with numerous, closely
apposed rete ridges, either at its base or throughout most of the
circumference, with a thinner atrophic wall approaching the os.
● Epidermoid cyst
● Pilar sheath acanthoma
● Trichofolliculoma
FIBROFOLLICULOMA
CLINICAL FEATURES
Fibrofolliculoma is a rare tumor of the perifollicular mes-
enchyma. The lesion is usually solitary but, when multiple, the
(a)
(d)
(b)
(c) (e)
Figure 12.24 (a–e) Keratoacanthoma. A partly regressed lesion showing a cup-shaped structure with central hyperkeratotic layer and two
shoulders (a). A fully developed keratoacanthoma showing florid squamous cell proliferation (e).The cell nests may resemble squamous cell
carcinoma, but tend to be more glassy and eosinophilic.
856 Skin tumors
lesions are frequently associated with an autosomal-dominant cells located within a fibrotic stroma. Small keratin-filled cysts
condition in which there are other cutaneous and internal may be seen.
lesions. Multiple fibrofolliculomas, trichodiscomas, and acro-
chordons compose the triad of cutaneous lesions characterizing
the Birt–Hogg–Dube syndrome, which is inherited in an auto- PILAR SHEATH ACANTHOMA
somal-dominant fashion. Clinically, fibrofolliculomas are small
white firm papules with a centrally dilated follicle containing
CLINICAL FEATURES
horny (keratinous) material. They occur in the head and neck,
or upper trunk region. Some authors believe that trichodisco- Pilar sheath acanthoma is a tumor of the follicular infundi-
mas and fibrofolliculomas are different stages of a single entity. bulum, and usually presents as a nodule on the upper lip of
individuals between the ages of 40 and 70 years.
Histologically, the lesion is dermal and is composed of hyper- PATHOLOGICAL FEATURES
plastic follicular infundibulum with a central keratinous plug
Histologically, the tumor consists of a central keratin-filled cys-
and anastomosing strands of basaloid cells branching into an
tic space that often communicates with the surface epithelium,
angiofibromatous stroma.
surrounded by an irregularly acanthotic epithelium with elaborate
anastomosing projections at its periphery. The lesion has been
FOLLICULAR NEVI described in the mid dermis, or may extend into fat. The inner
wall of the cyst wall is lined by flattened keratinocytes and a
granular cell layer. The outer portions of the wall are composed
CLINICAL FEATURES of clear cells, reminiscent of outer root sheath.
Follicular nevi constitute several clinical variants of congenital
disorders of hair follicles that are usually present at birth, but
may become apparent in childhood, adolescence, or adulthood.
Baker nevus is a large plaque-like, evenly pigmented lesion ● Dilated pore of Winer
that later on becomes more pigmented, hairy and roughened. ● Trichofolliculoma
It is usually seen on the shoulder or chest of adolescents.
Nevus comedonicus is an uncommon developmental defect
of the pilosebaceous apparatus. The individual lesions are large
PILOMATRIXOMA
comedones, often arranged in groups or in a linear pattern.
Nevus comedonicus syndrome is a well-defined disorder within CLINICAL FEATURES (Figure 12.25)
the large group of epidermal nevus syndromes. In patients
suffering from this syndrome, the nevus is associated with Pilomatrixoma (calcifying epithelioma of Malherbe) is an
non-cutaneous abnormalities including skeletal defects, cere- uncommon skin tumor derived from the hair germ matrix. It
bral anomalies, and cataracts. occurs predominantly in young people and children, and it has
Hair follicle nevus presents as dome-shaped or pedunculated a predilection for the head and neck region. The lesion has
lesion. been rarely reported in other locations such as the breast and
Basaloid follicular hamartoma presents as solitary multiple paratesticular region. In the vast majority of cases the lesions
or generalized hyper- or hypopigmented plaques that may be are benign, but an aggressive variant and pilomatrical carci-
associated with hair loss and may be seen in association with noma have been reported. Multiple lesions have been described
myasthenia gravis. in trisomy 9. Most have been shown to be associated with a
mutation of the beta-catenin gene.
Pilomatrix carcinoma shows a predilection for elderly indi-
viduals (mean age 61 years) with a male:female ratio of 5:1.
All follicular nevi show an abnormal number of hair follicles. The lesions present as dermal or subcutaneous tumors, mainly
Baker nevus is characterized by the presence of increased on the head and neck, and vary in size from 0.6 to 2.5 cm
numbers of large deep hair follicles associated with hypertro- (mean 1.78 cm). Pilomatrix carcinoma is a neoplasm of low-
phied arrector pili muscles. grade malignancy, but with a potential for distant metastases.
Nevus comedonicus is characterized by the presence of The lesions are usually cured with wide local excision.
numerous cystically dilated, keratin-filled, pore-like epidermal
invaginations (infundibula) that may communicate in their
deeper aspects with one or more hair follicles.
Hair follicle nevus is characterized by the presence of numer- Pilomatrixoma is a well-circumscribed, often encapsulated
ous small vellus hair follicles surrounded by fibrovascular dermal and/or subcutaneous lesion, consisting of irregularly
stroma and located within the superficial and mid-dermis. shaped, variably sized epithelial islands embedded in a cellular
Basaloid follicular hamartoma is characterized by the pres- stroma often containing numerous foreign body giant cells.
ence of numerous anastomosing cords and buds of basaloid Each island is composed of a mixture of basaloid cells and
● Basal cell carcinoma
● Proliferating trichilemmal cyst
PROLIFERATING PILAR TUMOR
CLINICAL FEATURES
Proliferating tricholemmal cyst (proliferating pilar tumor) is
a benign lesion derived from the outer root sheath of the hair
follicle. It is usually located on the scalp of elderly individuals
(particularly women), though it may also occur on the back.
The lesions can grow to a large size, and may cause ulceration
of the overlying epidermis. They may be seen in association
(a)
with one or several tricholemmal cysts of the scalp. Although
these tumors are generally regarded as benign, local recurrence
and metastasis have been reported, which suggests that these
lesions fall into the same category as keratoacanthoma, in that
a percentage may have been malignant from the outset.
A malignant spindle cell component arising within a prolif-
erating pilar tumor is a rare neoplasm which has been associ-
ated with death from widespread metastasis.

Histologically, the tumors are well-circumscribed dermal lesions
composed of irregularly shaped squamous lobules which
undergo abrupt change into eosinophilic amorphous keratin,
similar to that seen in tricholemmal cysts.
Features suggesting malignancy are high mitotic rate, atypi-
(b) cal mitoses, invasion into adjacent tissues, and severe nuclear
pleomorphism.
Figure 12.25 (a, b) Pilomatrixoma. Basaloid and ghost cells.
shadow cells wherein there is a loss of nuclear staining, or one
Special techniques
component may predominate. Mitoses may be quite numerous
in the basaloid areas. Foci of abrupt keratinization are often ● The tumor cells show patchy positivity for CD34.
seen in the epithelial islands. Calcification and bone formation
may also be seen. TRICHOADENOMA
Aggressive pilomatrixoma has an infiltrative growth pattern
and mitotic activity, but lacks the other cytologically atypical
features. CLINICAL FEATURES
Perforating pilomatrixoma shows transepithelial elimination
This is a rare, well-differentiated, slow-growing tumor which
of the basophilic and shadow cells. In many cases, this is
occurs mainly on the face of adults, and is usually small in size.
accompanied by ulceration and epithelial damage. It may also
Clinically, it may be mistaken for basal cell carcinoma and
show relatively little or no damage to the epithelial structures.
epidermoid cyst.
Pilomatrix carcinoma shows the architectural features of a
malignant neoplasm (asymmetry and poor circumscription,
presence of several markedly sized and variably shaped basa-
loid aggregations, and ulceration). It is composed of pleomor- Trichoadenoma (trichogenic adenoma) is a dermal lesion
phic basaloid cells with prominent nucleoli and frequent consisting of numerous horn cysts containing keratinous debris
atypical mitoses accompanied by central areas with keratotic and surrounded by a proliferation of eosinophilic epidermoid
material, shadow cells, and foci of necrosis. The tumor nests cells. Foreign body reaction to rupture of the small cysts may
are surrounded by a desmoplastic stroma and infiltrate the occur. Sometimes, these cysts may expel their horn material
adjacent tissues. Abundant melanin pigment may be seen in the into the surface keratin layer. The term ‘verrucous trichoade-
cytoplasm of the basaloid cells. noma’ has been proposed for such lesions.
858 Skin tumors
Differential diagnosis It usually presents as a solitary small firm flesh-colored nodule

● Microcystic adnexal carcinoma on the face, particularly the nasolabial fold. Other sites on the
● Syringoma head and neck may be affected. Multiple lesions may arise in
● Trichoepithelioma the context of an autosomal dominant-inherited syndrome,
which has been mapped to chromosome 9p21, and may also
be associated with multiple cylindromas (Brooke–Spiegler
TRICHOEPITHELIOMA syndrome).
CLINICAL FEATURES
Trichepithelioma is regarded as a hair follicle hamartomatous
lesion, although it is included under the heading of tumor here. This is an upper and mid dermal lesion consisting of two com-
ponents: horn cysts and basaloid nests reminiscent of basal cell
carcinoma. The horn cysts show abrupt keratinization, and are
either present separately or located in the centers of some of the
basaloid nests. The basaloid epithelial nests vary in size and
shape, are rarely rounded, and they often show peripheral
branching and lace-like or adenoid configuration with palisad-
ing peripheral layer of cells. Some of the basaloid nests are
Y-shaped and reminiscent of abortive hair follicle with distinct
papilla formation. This is due to an indentation by the sur-
rounding stroma.
Desmoplastic trichoepithelioma is characterized by the pres-
ence of dense dermal fibrosis containing small compressed
basaloid nests with horn cysts.
Giant trichoepithelioma may involve the subcutaneous tissue.
Secondary features
● Foreign-body granuloma may occur when a horn cyst
ruptures.
● Calcification.
● Ossification.
(a)
(b) (c)
Figure 12.26 (a–c) Proliferating pilar tumor.This is composed of irregularly shaped squamous lobules which undergo abrupt change into
eosinophilic amorphous keratin, similar to that seen in tricholemmal cysts.
(a) (b)
Figure 12.27 (a, b) Trichoepithelioma. Upper dermal basaloid nests with bland cellular morphology.The borders of the nests tend to show
irregular branching.
Cell morphology TRICHOEPITHELIOMA, DESMOPLASTIC

● The basaloid cells are similar to cells of basal cell
carcinoma, except that they are less ‘juicy-looking’ and These often present in the face or upper limbs. Clinically they
lack mitotic figures. may mimic granuloma annulare. Histopathologically they
● There is less evidence of a cleft between the tumor islands comprise small basaloid nests in a notably sclerotic dermis and
and the stroma than in a basal cell carcinoma. there is typically a giant cell reaction to keratin.
TRICHOFOLLICULOMA
● Keratotic basal cell carcinoma CLINICAL FEATURES
● Desmoplastic basal cell carcinoma
● Syringoma Trichofolliculoma presents as a small solitary skin-covered nod-
● Cylindroma ule with a central crater or pore containing a tuft of woolly hairs.
● Microcystic adnexal carcinoma It commonly occurs on the face, scalp and neck, but has also
rarely been reported in the vulva. Complete primary excision of
trichofolliculoma is important, as it may show local recurrence.
Special techniques
● Ki-67 and PCNA staining intensity and characteristics
may help in differentiating between BCC and The morphological features of trichofolliculoma are variable,
trichoepithelioma. BCC shows intense and generalized reminiscent of the anagen, catagen, and telogen phases of a
expression of Ki-67 and PCNA, while Ki-67- and normal hair follicle in its cycle.
PCNA-labeled cells are much fewer in number in Trichofolliculoma is a well-defined dermal lesion consisting
trichoepithelioma. Additionally, Ki-67- and PCNA- of a central cystically dilated follicle lined by squamous epithe-
positive cells are usually limited to the peripheral layers of lium, which often communicates with the epidermis, and also
the neoplastic islands of trichoepithelioma. contains laminated keratin and small hair shafts. Radiating
● It has been suggested that CD34 staining may allow from this central follicle are numerous small distorted hair
distinction between trichoepithelioma and BCC. follicles and basaloid buds (secondary follicles) that are sur-
The spindle-shaped cells surrounding the islands of rounded by perifollicular fibroblastic sheath.
trichoepithelioma cells are focally strongly positive A sebaceous trichofolliculoma has been described in which
for CD34; the spindle-shaped cells surrounding the dilated follicle is in the form of a crater and the secondary
the nests of tumor cells in BCC are supposedly follicles contain well-formed sebaceous lobules. Folliculo-
negative. sebaceous cystic hamartoma is a recently described entity,
860 Skin tumors
● Pilar sheath acanthoma
● Dilated pore of Winer
TRICHOGENIC TUMORS
CLINICAL FEATURES
These benign trichogenic tumors are epithelial–mesenchymal neo-
plasms of hair germ origin, and are classified into two groups.
The first group comprises tumors with a predominant epithelial
component; the second group comprises tumors with a predomi-
nant mesenchymal component. Tumors of the former group are
subdivided according to the degree of normal hair follicle differ-
entiation into: (i) a trichoblastoma, which is characterized by the
presence of pure epithelial elements without germ cell develop-
ment; (ii) trichoblastic fibroma, which shows in addition early
germ cell development; and (iii) trichogenic fibroblastoma, which
(a) shows more advanced hair follicle development.
These tumors are mostly seen on the scalp, back and but-
tocks, and very rarely in other locations such as the breast.
Trichoblastomas are the most frequent benign tumor that
may occur in nevus sebaceous.
‘Melanotrichoblastoma’ is a recently described variant of
trichoblastoma that exhibits excessive melanin pigmentation.
Cutaneous lymphadenoma is an uncommon basaloid tumor
of uncertain histogenesis, but it has recently been classified as
a variant of trichoblastoma on the basis of similar immunohis-
tochemical profiles. Clinically, it occurs predominantly on the
scalp and face as a dome-shaped, skin-colored papule of long
duration.
Trichoblastic carcinoma has also been described.

Benign trichogenic tumors are usually well-circumscribed,
dermal tumors that characteristically show a biphasic pattern
consisting of basaloid epithelial cells arranged in nests, cords or
elongated epithelial strands intimately associated with a cellu-
lar fibroblastic stroma. The basaloid cells are bland-looking.
(b)
The basaloid epithelial nests or islands vary in size, shape and
Figure 12.28 (a, b) Trichofolliculoma. A central hair follicle with complexity, exhibit peripheral palisading, and may recapitulate
basaloid buds originating from its periphery. the various stages of hair follicle differentiation. Squamous
eddies and keratinous cysts containing keratohyaline granules
defined as an adnexal hamartoma, showing an infundibular may be seen. Hair follicles at a more advanced stage of devel-
cystic structure linked to many sebaceous lobules. Differentia- opment or abortive hair follicles containing keratohyaline
tion toward the inferior segment of the hair follicle also occurs, masses (sometimes with focal calcification) may be seen in con-
although to a markedly lesser degree. Signs of regression and tinuity with the basaloid cords. The anastomosing strands of
rest corresponding to the normal follicular cycle are often epithelial cells may produce a cribriform pattern.
apparent in these follicular proliferations. This lesion has More divergent differentiation in the form of sebaceous ele-
much in common with the late stage of trichofolliculoma, ments or apocrine features in trichoblastoma has infrequently
which also exhibits an infundibular cyst and sebaceous and been reported in the literature.
follicular differentiation with various signs of catagen and A unique case of a trichoblastoma arising within a poroma
telogen. This entity probably represents a very late stage of with apocrine and sebaceous differentiation has been reported.
trichofolliculoma. Cutaneous lymphadenoma is characterized by the presence
Hyperplasia of Merkel cells has been reported in all three of multiple, variably sized and shaped, well-defined epithelial
stages of trichofolliculoma. islands or lobules surrounded by sclerotic stroma. Numerous
(a) (b)
Figure 12.29 (a, b) Cutaneous lymphadenoma. Dermal basaloid nests infiltrated by lymphocytes.
(a) (b)
Figure 12.30 (a, b) Benign trichogenic tumors. A biphasic pattern consisting of basaloid epithelial cells arranged in elongated epithelial
strands intimately associated with a cellular fibroblastic stroma.
lymphocytes – predominantly of T-cell nature – infiltrate the ● Trichoepithelioma

lobules and also focally within the stroma. Each lobule consists ● Cylindroma
of cuboidal cells showing peripheral palisading and central
round, less cohesive epithelial cells intermixed with (or some- Special techniques
times obscured by) lymphocytes. The lobules are surrounded ● CK20-positive Merkel cells are often seen in
by a desmoplastic stroma with a prominent hyaline band. Focal lymphadenomas and trichoblastomas, but not in BCCs.
squamous eddies and cystic spaces may be seen within some of ● Trichoblastoma(s) and BCC show consistent expression of
the lobules. Unequivocal follicular differentiation may be seen CK6hf, CK14 and CK17; variable expression of CK15 and
at the periphery of the tumor. Plasma cells and eosinophils may CK19; and absence of hair keratins. This indicates a
be seen within the stroma. differentiation toward the outer root sheath epithelium or
‘Melanotrichoblastoma’ exhibits excessive melanin pigmen- the companion layer and not toward the inner root sheath,
tation. matrix, or cortex.
● Staining for bcl-2 accentuates the peripheral epithelial
Differential diagnosis layer in almost all lymphadenomas and in some of the
● Adenoid cystic carcinoma trichoblastomas, while the majority of trichoblastomas and
● Basal cell carcinoma BCCs stain diffusely.
862 Skin tumors
● Trichoblastomas, and BCCs may all contain Langerhans’ with a follicular adnexal neoplasm. On this basis, the alternative
cells (S-100 protein-positive cells which are also positive term ‘follicular dyskeratoma’ has been proposed in order to bet-
for CD1a). ter reflect the distinctive features of this peculiar lesion.
● CD30-positive cells in lymphadenomas appear to represent
histiocytes rather than activated lymphocytes. PATHOLOGICAL FEATURES
On scanning magnification, the lesions show mainly three
TRICHOLEMMOMA architectural patterns – namely, cup-shaped, cystic, and nodu-
lar, or a combination of two of these morphological patterns.
Characteristically, the epithelial component displays foci of
CLINICAL FEATURES acantholytic dyskeratosis with suprabasal clefts.
Tricholemmoma is a benign tumor arising from the follicular Variable features suggestive of follicular differentiation
infundibulum, and presents usually as a solitary warty or toward the infundibular portion of a normal hair follicle are
smooth papule on the upper lip, nose or cheek. The lesions may also observed, including a focal contiguity to pilosebaceous
be multiple in Cowden’s syndrome – a syndrome associated units in most cases, and the presence of small infundibular cys-
with breast carcinoma, thyroid tumors and tumors of the gas- tic structures in a subset of lesions. The majority of lesions also
trointestinal tract, reproductive system and soft tissue. reveal a hyalinized or fibrous stroma with intra-stromal clefts.
Corp ronds and grains may be present, and rarely multi-
nucleate giant cells may be seen.
Early lesions may show a hyperkeratotic follicular infundibulum Differential diagnosis
surrounded by a mantle of hyalinized connective tissue. More ● Acantholytic actinic keratosis
advanced lesions consist of plate-like lobular downgrowths of ● Darier’s disease – the lack of family history and of
glycogenated epithelium representing involvement of several appropriate clinical features should be sought
adjacent follicles. The peripheral zone of the lobules consists of ● Grover’s disease – is characterized by pruritic keratotic
more basaloid cells, and often shows palisading. The surface is papules and papulovesicles predominantly on the trunk,
variably verrucous and may exhibit hyperkeratosis and paraker- disappearing spontaneously after a few weeks or months
atosis. The stroma surrounding the lesion is fibrovascular. and demonstrating the histological features of epidermal
A desmoplastic tricholemmoma variant exists, in which there acantholysis. The etiology remains unknown; sweating,
is a desmoplastic reaction in the central portions of the tumor, heat and sunlight are suspected trigger factors.
which may mimic morphoeic basal cell carcinoma or squamous ● Syringocystadenoma papilliferum
cell carcinoma.
Special techniques
● Positive immunohistochemical staining of a lesion with
● Basal cell carcinoma (desmoplastic variant) antikeratin antibodies HKN-6 and -7, specific for human
● Squamous cell carcinoma (desmoplastic variant) hair keratin, supports a follicular origin for warty
● Verruca vulgaris dyskeratoma.
Special techniques
● The cells stain positively with PAS. SKIN APPENDAGE TUMORS, BENIGN: SEBACEOUS
GLAND-DERIVED TUMORS
WARTY DYSKERATOMA
HAMARTOMA/HYPERPLASIA:
FOLLICULOSEBACEOUS CYSTIC HAMARTOMA
CLINICAL FEATURES
This benign tumor has recently been reclassified as a follicular
CLINICAL FEATURES
adnexal neoplasm. It occurs at any age (range 3 to 88 years;
mean 59.8 years), and presents as solitary papules or small Folliculosebaceous cystic hamartoma is a distinctive cutaneous
nodules on the head and neck or trunk region. Less commonly, malformation characterized by marked overgrowth of folliculo-
it appears on the extremities. While warty dyskeratoma of the sebaceous units accompanied by appreciable mesenchymal
oral mucosa is rare, it appears to exhibit a variability of clinical alterations, including fibroplasia, increased vascular compo-
appearance and to have a special predilection for keratinized nents, and numerous adipocytes. Clinically, folliculosebaceous
mucosa exposed to friction and mechanical stress. Multiple cystic hamartomas present as skin-colored papulonodules of
warty dyskeratomas are rare. Despite some histopathological the face, especially the nose. The lesion may rarely occur in
similarities to viral warts, warty dyskeratoma is not a manifes- other locations such as the external genitalia. This is in contrast
tation of HPV infection. On the other hand, the majority of to sebaceous trichofolliculomas, which often present as
these lesions display overall histopathological features consistent depressed ostia containing terminal or vellus hairs.
PATHOLOGICAL FEATURES tumors. Sebaceous nevi may be associated with neurological

abnormalities, and it is strongly recommended that all patients
Folliculosebaceous cystic hamartoma comprises prominent
with sebaceous nevi undergo a detailed neurological assess-
epithelial and mesenchymal components. The epithelial com-
ment and that imaging be performed on all those in whom
ponent is characterized by folliculosebaceous proliferation
clinical abnormalities are demonstrated, as well as on those
with cyst-like infundibular dilatation, and the mesenchymal
patients with large nevi involving the centrofacial area.
component exhibits variable fibroplasia, vascular and neural
proliferation and adipocyte metaplasia. On occasion, aggrega-
tion of thick nerve bundles is seen in the deep portion of the PATHOLOGICAL FEATURES (Figure 12.31)
neoplasm. Rarely, the surrounding stroma is fibrillary, contain- Prepubertal nevus sebaceous is characterized by a well-
ing large quantities of mucin mimicking perifollicular muci- demarcated, subtle verrucous epidermal hyperplasia reminis-
nosis that is seen in Carney’s syndrome. cent of linear epidermal nevi. The associated hair follicles and
● Sebaceous hyperplasia
● Sebaceous adenoma
● Perifollicular mucinosis
NEVUS SEBACEOUS (SEBACEOUS NEVI)
CLINICAL FEATURES
Sebaceous nevi are uncommon congenital skin lesions with a
well-recognized potential for neoplastic change. They should
be considered as premalignant lesions as malignant degenera-
tion – most commonly BCC and squamous cell carcinoma –
occurs with a lifetime risk of between 5% and 22%. Nevus
sebaceous often becomes clinically apparent as a result of the
development of the sebaceous component. Nevus sebaceous
passes through a series of clinical stages: at birth, it presents
as a hairless, linear or slightly verrucous patch or plaque; at
puberty, it becomes more raised and verrucous; and during
adulthood it may be secondarily complicated by other skin
(b)
(a) (c)
Figure 12.31 (a–c) Nevus sebaceous.The dermis shows irregular thickening and elongation. Basal cell carcinoma (b) is a known
complication.The underlying sebaceous glands show variable degrees of maturation (c).
864 Skin tumors
sebaceous lobules may be either absent, diminished, or only ● Sebaceous carcinoma

rudimentary at this stage. ● Apocrine poroma with sebaceous differentiation
Pubertal nevus sebaceous is characterized by more prominent
verrucous epidermal hyperplasia associated with some degree Special techniques
of sebaceous hyperplasia, dilated apocrine glands in the deep
See Sebaceous hyperplasia below.
dermis, changes in hair follicle development in the form of
abortive or malformed hair buds, and localized changes in the
surrounding mesenchymal tissue. These include abnormally SEBACEOUS ADENOMA
cellular fibroblastic dermal collagen, proliferating vessels and
malformed smooth muscle bundles.
Tumors arising in nevus sebaceous include basal cell carci- CLINICAL FEATURES
noma (5–7% of cases), trichoblastoma, syringocystadenoma
Sebaceous adenoma is a relatively uncommon tumor which
papilliferum, apocrine gland cysts, warts, sebaceous adenomas,
usually occurs as a solitary lesion on the head and neck area.
apocrine nevi and adenomas, trichilemmomas, squamous cell
Multiple lesions can occur, however. Muir–Torre’s syndrome
carcinoma, and sebaceous carcinoma.
should be considered, even when the lesion is solitary.
Merkel cell hyperplasia is common in nevus sebaceous.
Differential diagnosis PATHOLOGICAL FEATURES (Figure 12.32)

● Linear epidermal nevus Histologically, this tumor is a sharply demarcated dermal
● Seborrheic keratosis lesion consisting of various sized and shaped lobules, separated
● Lichen simplex chronicus by compressed connective tissue septa. Each lobule is made up
of a mixture of undifferentiated basaloid cells at the periphery,
Special techniques with mature sebaceous cells centrally and transitional forms in
See Sebaceous hyperplasia in the next column. between. On occasion, there is a predominance of the basaloid
and germinative components with mitotic activity. Focal areas
SEBACEOMA of squamous differentiation may be seen. Cystic degeneration
may be seen in the center of some lobules.

Sebaceoma – previously called sebaceous epithelioma – is a dis- ● Sebaceous carcinoma
tinctive benign neoplasm of adnexal epithelium with differentia- ● Sebaceoma
tion toward sebaceous cells. Clinically, this lesion is similar to
BCC, and occurs frequently on the head and neck, where it can
Special techniques
be either solitary or multiple. As with all sebaceous tumors, these
lesions can be associated with Muir–Torre’s syndrome. This syn- See Sebaceous hyperplasia below.
drome should be considered even with the occurrence of a single
sebaceous tumor. The syndrome is autosomal dominant, in which
sebaceous neoplasms – particularly the deep-seated or cystic SEBACEOUS HYPERPLASIA
tumors – precede or are synchronous with a visceral malignancy.
Screening has been advocated, using immunohistochemistry to CLINICAL FEATURES
screen for mismatch repair genes within individual lesions.
Sebaceous hyperplasia is a localized increase in the density or
PATHOLOGICAL FEATURES cellularity and lobulation of sebaceous glands, and presents as
a small, skin-colored or yellow papule with central umblica-
Histologically, there is considerable overlap between sebaceous tion. It is common on the face of older individuals, and may be
tumors, and sometimes it is difficult to classify them accurately. mistaken clinically for BCC. It may also occur on the vermilion
Sebaceoma is an ill-defined lesion consisting of multiple irregu- borders of the lips (Fordyce’s spots).
larly shaped tumor masses reminiscent of BCC. However, in Diffuse sebaceous gland hyperplasia is a rare variant of
addition to the basaloid cells, there are sebocytes in various seboglandular proliferative disorders that is distinct from the
stages of sebaceous differentiation, randomly admixed amongst well-known circumscribed type.
the basal cells. Cells with transitional features between the basal
cells and mature sebaceous cell, showing early fatty vacuolation
are numerous. PATHOLOGICAL FEATURES
Histologically, there is an increased number of enlarged seba-
Differential diagnosis ceous lobules attached to a dilated follicle containing a keratin
● BCC with sebaceous differentiation plug. There is usually no associated increase in the basal cell
● Sebaceous adenoma layers, as is seen in sebaceous adenoma.
● CK17 is expressed in the keratinocytes of the

sebaceous duct
● CK1 is expressed in the keratinocytes of the infundibulum
● An enhanced expression of the proliferation cell antigen
Ki-67 (MIB-1) in the immature sebocytes
● CK18 and CK19 usually show no staining
● Androgen receptor is a sensitive marker of sebaceous
differentiation
● EMA stains well-differentiated sebaceous cells
SKIN APPENDAGE TUMORS, BENIGN: SWEAT

CHONDROID SYRINGOMA
CLINICAL FEATURES
Chondroid syringoma is a benign skin tumor which is charac-
terized by several histological aspects similar to those of sali-
(a) vary gland adenoma. The neoplasm is usually an asymptomatic
subcutaneous nodule that affects the head and neck, but it can
also occur in other locations such as the extremities, mainly the
hands or feet. The lesion occurs in the sixth and seventh
decades of life, and its incidence in males is twice that in
females. Rare examples of intraosseous chondroid syringoma
have been reported.
A few cases of malignant chondroid syringoma, however,
have been reported, most commonly in the extremities. The
neoplasm tends to produce metastases to both the regional and
distant lymph nodes, causing the death of the patient. In these
cases, radiation therapy follows the surgical excision.

Histologically, chondroid syringoma is a fairly well-
circumscribed dermal or subcutaneous lesion consisting of
epithelial elements set in a predominantly myxoid or chondroid
stroma with focal hyalinization. The epithelial component
either shows pure ductal differentiation, pure myoepithelial
(b)
Figure 12.32 (a, b) Sebaceous adenoma. A lobulated dermal lesion

showing peripheral basaloid cells with central sebaceous differentiation.
Diffuse sebaceous gland hyperplasia shows enlargement of

sebaceous acini, an increased number of immature sebocytes in
foci, and a dilated follicular infundibulum.
● Sebaceous adenoma
Special techniques
Figure 12.33 Chondroid syringoma (mixed tumor of the skin).
● CK14 is expressed in the keratinocytes of the This is similar to mixed salivary gland tumor, and often shows
infundibulum, the isthmus, and sebaceous duct, and tubular structures and myoepithelial cells set in a myxoid or
in the mature and immature sebocytes chondroid background.
866 Skin tumors
(a)
(a)
(b)
(b)
Figure 12.35 (a, b) Chondroid syringoma, mainly myoepithelial.

This consists purely of myoepithelial cells, set in a myxoid stroma.
by the presence of isolated cells, sheets or nests of compactly or

(c) loosely arranged polygonal or plasmacytoid hyaline cells.
Hyaline cell-rich chondroid syringoma is a rare benign cuta-
Figure 12.34 (a–c) Chondroid syringoma, predominantly tubular. neous neoplasm composed of cells with eosinophilic hyaline
This is a well-circumscribed lesion showing mainly tubular structure
with only focal areas of myoepithelial cells (c). cytoplasm and plasmacytoid features – that is, in the eccentric
nuclei and eosinophilic cytoplasm. The nuclei are ovoid nuclei,
with occasional invaginations, finely granular chromatin, and
differentiation, or a mixture of the two. The ductal differentia- discrete nucleoli.
tion is demonstrated by the presence of branching tubuloglan- Cutaneous myoepithelioma is considered to be a variant of
dular structures which are lined by two layers of epithelial cells, chondroid syringoma, showing only myoepithelioma differen-
and cystic or small ductular structures lined by a single layer of tiation. These tumors are well-circumscribed, dermal lesions,
epithelial cells. The myoepithelial differentiation is demonstrated composed of a solid cellular tumor, with monomorphous cells
with pale eosinophilic cytoplasmic cytoplasm and ovoid vesic-

ular nuclei and no atypia, and with a hyalinized or myxoid
stroma and occasional fatty metaplasia. To date, the cutaneous
tumors – unlike their counterparts in soft tissues – have not
shown any metastatic potential.
● Epithelioid hemangioendothelioma
● Glomus tumor
● Myxoid chondrosarcoma
● Soft tissue chondroma
Special techniques
● The inner cells of the tubuloglandular components express
cytokeratins, CEA and EMA.
● The outer cell layers, the stromal cells and the solid nests
are myoepithelial cells and express vimentin, S-100 protein
and cytokeratin. Sometimes myogenic differentiation
markers such as desmin, SMA and muscle-specific actin Figure 12.36 Cylindroma. Basaloid nests arranged as a ‘jigsaw
(MSA) are present. puzzle’, surrounded by a thickened basement membrane and, in
part, pierced by similar basement membrane material in the form of
round structures reminiscent of a cribriform pattern.
CYLINDROMA
CLINICAL FEATURES themselves contain a mixture of small dark and larger pale
cells, hyaline droplets, and occasional tubular lumina lined by
Dermal eccrine cylindroma is a benign adnexal tumor that
two cell layers. Peripheral palisading of the small dark cells is
commonly affects the scalp, neck, and face of older individuals.
often seen. Occasionally, areas of spiradenoma are seen as part
Occasionally, the lesions involve the face, trunk and extremi-
of the lesion.
ties. They may be associated with multiple trichoepitheliomas.
Malignant transformation is rare, but has resulted in several
cases of intracranial invasion. Differential diagnosis
Although cylindromas of the skin resemble basal cell adeno- ● Basal cell carcinoma
mas of the salivary gland, there is usually no salivary gland ● Spiradenoma
involvement. On the other hand, patients with basal cell ade- ● Trichoepithelioma
nomas of a salivary gland usually do not show dermal lesions. ● Adenoid cystic carcinoma
Familial autosomal dominant cylindromatosis (turban tumor
syndrome) is a rare hereditary disease usually presenting in the
second or third decade of life. With a female preponderance, Special techniques
dermal cylindromas predominantly arise in hairy areas of the ● Dermal cylindroma shares EMA, CEA, mucin-like
body, with approximately 90% on the head and neck. carcinoma-associated antigen (B12), laminin, collagen IV,
Molecular studies of familial and sporadic cylindromas have fibronectin, and CD34(QBEND/10) expression with both
shown frequent alterations at chromosome 16q12–13 that eccrine and apocrine glands.
have recently been found to house the cylindromatosis gene ● As with the various regions of eccrine and apocrine units,
(CYLD). Defective laminin 5 processing is felt to contribute to the expression by cylindromas of CK7, 8 and 18 indicates
the aberrations of the basement membrane. differentiation toward the secretory tissue, whereas the
expression of CK14 in some of the neoplastic cells points
toward ductal differentiation.
PATHOLOGICAL FEATURES (Figure 12.36) ● S-100 protein ascribed to eccrine differentiation and
Cylindromas are poorly circumscribed dermal or subcutaneous human milk fat globulin (HMFG) and lysozyme – two
lesions consisting of numerous rounded ovoid or cord-shaped markers associated with apocrine differentiation – are
basaloid dermal islands that fit together like a jigsaw puzzle. expressed by tubular cells in cylindromas. Lysozyme is also
Each lobule is surrounded by a distinct basement membrane- expressed in cylindromas by large, pale-staining cells.
like hyaline sheath, which stains PAS-positive and may pro- ● Antibodies to smooth muscle alpha-actin strongly
trude focally into the cellular islands. The tumor islands characterizes the small basaloid cells.
868 Skin tumors
ECCRINE SPIRADENOMA PATHOLOGICAL FEATURES (Figures 12.37–12.39)

Histologically, the tumor comprises one or several sharply
CLINICAL FEATURES demarcated lobules composed of basaloid cells. The vascular
content is variable, but may be the major component with large
Eccrine spiradenoma is a benign tumor of adnexal origin. It is blood-filled spaces. Within the lobules there are three cell types.
often seen in the head and neck region of young adults, and may The first two include lymphocytes (T cells predominantly) and
be present for years. It is usually small in size (a few millimeters), small, darkly staining epithelial cells encircling rounded or
though giant (a few centimeters) forms may occur. Although irregular spaces resulting in pseudotubular, pseudoglandular or
usually solitary, multiple lesions have been described. If the vas- rosette-like pattern, or arranged in intertwining cords; these
cular component is significant, these lesions may be mistaken for cells have little or no cytoplasm. The third cell type is larger and
a vascular neoplasm. They are frequently painful. Malignant paler, and the nuclei may contain nucleoli; these cells are dis-
transformation in a benign eccrine spiradenoma is rare. tributed in between the small cells.
Malignant degeneration has been mostly carcinomatous
dedifferentiation, and rarely sarcomatous.
Some cases may reveal features of both spiradenoma and cylin-
droma in the same tumor mass, termed ‘spiradenocylindromas’.
● Cylindroma
● Cutaneous lymphadenoma
Special techniques
● As with the various regions of eccrine and apocrine units,
the expression by spiradenoma of CK7, CK8 and CK18
indicates differentiation toward the secretory tissue,
whereas the expression of CK14 in some of the neoplastic
cells points toward ductal differentiation.
● S-100 protein ascribed to eccrine differentiation and
human milk fat globulin (HMFG) and lysozyme – two
markers associated with apocrine differentiation – are
expressed by tubular cells in spiradenoma.
● Antibodies to smooth muscle alpha-actin strongly
(a) characterize the small basaloid cells.
(b) (c)
Figure 12.37 (a–c) Eccrine spiradenoma.This is a sharply demarcated dermal lesion consisting of small basaloid cells with
duct formation.The cells are infiltrated by numerous CD3⫹ T-lymphocytes (c).
(a)
Figure 12.38 Eccrine spiradenoma. Dilated lymphatic-like vascular

spaces are common in this condition.
(b)
Figure 12.39 Eccrine spiradenoma. Basement membrane-like

eosinophilic material similar to those seen in cylindroma may be seen.
HIDRADENOMA (CLEAR CELL HIDRADENOMA;

ACROSPIROMA)
CLINICAL FEATURES
Hidradenoma (clear cell hidradenoma; acrospiroma) is a
benign tumor that can occur anywhere in the skin and usually
presents as a solitary nodule usually of ⬍2 cm diameter, and (c)
may be cystic.
It should be borne in mind that nodular hidradenoma may Figure 12.40 (a–c) Nodular (clear cell) hidradenoma. A dermal
lesion consisting of eosinophilic and clear cells separated by
occur in mammary ducts, and it should be included when dif-
hyalinized and vascular stroma. Ductal structure is seen (b).
ferential diagnoses are made of subareolar breast tumors.
Malignant hidradenoma is a very rare tumor. It comprises a
heterogeneous group of lesions that may range from locally
recurring, low-grade, well-differentiated tumors to highly aggres-
sive, high-grade tumors with a definite potential for uncontrol- Histologically, the lesion is a well-circumscribed, lobulated der-
lable local recurrence and metastasis. Wide surgical excision is mal tumor that may extend into the underlying subcutis and
recommended as the primary treatment for such neoplasms. may communicate with the overlying epidermis. Cystic and solid
870 Skin tumors
components are variable. The lobules are separated by hylanized POROMAS

connective tissue and consist of uniform, round epithelial cells
arranged in sheets with foci of abortive squamous eddies. Within
the lobules there are irregularly shaped tubuloglandular struc- CLINICAL FEATURES
tures and cystic spaces lined by an eosinophilic cuticle reminis- The ‘eccrine’ poroma is a benign eccrine sweat gland tumor
cent of the intraepidermal portion of the eccrine duct. The which primarily arises in hairless acral surfaces. The majority
predominant cells are round or polyhedral uniform, with pale of acral poromas occur in male patients. Poromas may also
eosinophilic cytoplasm and round nuclei containing small nucle- arise in the head and neck region, and at these sites they tend
oli. The cells may have a marked clear cell change, and there to be asymptomatic, show no gender predilection, and are of
may be mucinous metaplasia. There is no significant pleomor- apocrine origin.
phism or mitoses. Rarely there may be predominant oncocytic Poromas have been classified as eccrine neoplasms, but sev-
change. eral recent reports of poroid tumors with sebaceous, follicular,
and apocrine differentiation have challenged this concept.
Malignant eccrine poroma is a rare skin tumor which com-
monly presents as verrucous plaques or polypoid growths.
● Balloon cell melanocytic lesions (clear cell variant) Though the prognosis for this tumor is better than previously
● Glomus tumor thought, it still must be considered potentially fatal, or with the
● Metastatic renal cell carcinoma (clear cell variant) potential to metastasize.
● Poroma
Special techniques Four histopathological variants of poromas are accepted,
● The cells are cytokeratins CAM5.2 and 19, EMA-, CEA-, according to the architectural features of the neoplasm: (i)
S-100 protein- and p53-positive. hidroacanthoma simplex or intraepidermal poroma; (ii) eccrine
poroma, which is a poroma connected to the epidermis that
extends to superficial dermis; (iii) dermal duct tumor, which
HIDRADENOMA PAPILLIFERUM develops when the neoplasm is composed of small, solid aggre-
gations of poroid and cuticular cells confined to the dermis
with little or no connection with the epidermis; and (iv) poroid
CLINICAL FEATURES hidradenoma, which is a solid-cystic, dermal poroma. The
Hidradenoma papilliferum is a benign sweat gland tumor that malignant counterpart of hidroacanthoma simplex is named
occurs around the vulva and perineal areas in postpubertal malignant hidroacanthoma simplex or porocarcinoma in situ.
females, and presents as a single, circumscribed nodule that It may show an endophytic dermo-epidermal growth that
may either ulcerate or bleed. Non-anogenital (ectopic) hidrade- resembles psoriasiform epidermal changes. It may also show
noma papilliferum is rare. dermal lobules of small squamoid cells with small ductular
structures (dermal duct tumor). The cellular component is that
of uniform, small to medium-sized basaloid cells with little or
PATHOLOGICAL FEATURES moderate amounts of cytoplasm and distinct intercellular bridges.
They have rounded or deeply basophilic nuclei. Ductular struc-
Histologically, the lesion is frequently removed piecemeal, and
tures within the lesion are lined by cuboidal cells. Pleomorphism
therefore low-power architecture is difficult to assess. The tumor
and mitotic figures are uncommon unless the lesion has been
is composed of a complex glandular lesion with tubular, cystic
traumatized.
and papillary structures. The epithelial structures have a promi-
Apocrine poroma has recently been proposed as a new term to
nent fibrovascular core, and are lined by a double cell layer (inner
designate a distinctive benign skin neoplasm with differentiation
epithelial and outer myoepithelial). There may be apical bleb-
toward the folliculosebaceous-apocrine unit. Histologically, this
bing. Mild cytological atypia and very occasional mitotic figures
neoplasm consists of poroma-like, sebaceous and follicular
may be present if the lesion has been traumatized.
epithelial components.
Malignant eccrine poroma shows cytological features of
Differential diagnosis malignancy. Dendritic melanocytes containing melanin may be
● Adenocarcinoma seen intermingled with the tumor cells.
● Ectopic breast tissue
● Basal cell carcinoma
Special techniques ● Clear cell acanthoma
● The inner cell layers express epithelial markers. ● Seborrheic keratosis
● The outer cell layer expresses myoepithelial markers. ● Squamous cell carcinoma (if traumatized)
● The cells are estrogen receptor-positive (personal ● Hidracanthoma simplex should be distinguished from
experience). other lesions showing the Borst–Jadassohn phenomenon
(a) (a)
(b) (b)
Figure 12.41 (a, b) Eccrine poroma. Broad anastomosing bands Figure 12.42 (a, b) Hidroacanthoma simplex. An acanthotic
of small cells reminiscent of seborrheic keratosis but containing epidermis, thickened by the presence of proliferating intraepidermal
ductal structures and small holes (encircled) representing the eccrine sweat gland structure (b).
eccrine duct opening.
such as clonal Bowen’s disease, clonal actinic keratosis, SYRINGOCYSTADENOMA PAPILLIFERUM

clonal seborrheic keratosis, pagetoid melanoma in situ,
Paget’s disease (depending on site) and very early
superficial basal cell carcinoma CLINICAL FEATURES
Syringocystadenoma papilliferum is an unusual benign tumor
Special techniques which is most commonly located on the scalp or face, and fre-
● The cuboidal cells lining the ductular structures within the quently arises from a nevus sebaceous. Transition of this lesion
lesion stain with PAS and are CEA-positive. to basal cell carcinoma and, rarely, to metastatic adenocarci-
● Both eccrine poromas and porocarcinomas show noma may occur.
significant p53 expression; therefore, p53 positivity cannot The lesion often presents as a warty plaque, and tends to
be accepted as a valuable parameter for malignancy. occur in younger individuals around puberty.
872 Skin tumors
Figure 12.43 Eccrine poroma. At low magnification, this

resembles seborrheic keratosis.
Figure 12.45 Eccrine poroma.The bulk of the lesion is formed

by irregular proliferation of small epidermal cells, reminiscent of
seborrheic keratosis.The intervening stroma is usually vascular.
columnar cells and by squamous epithelium in the superficial

parts. The stroma around the cystic invagination usually con-
tains abundant plasma cells.
● Hidradenoma papilliferum
● Warty dyskeratoma
SYRINGOMA
CLINICAL FEATURES
Syringoma is a benign eccrine tumor that generally forms asymp-
tomatic papules on facial skin. Syringomas occur at puberty or
later in life, and are more common in females. Usually, the pres-
entation is of multiple (occasionally solitary) small skin-covered,
soft papules mainly limited to the lower eyelids or the scalp.
Figure 12.44 Eccrine poroma. At close examination there is Other less common sites of involvement include the cheeks,
ductal formation, within what appears to be thickened epidermal
abdomen and vulva. Similar lesions are seen within the nipple,
layers.
and are called syringomatous adenoma of the nipple. They are
reported to be more common in Down’s syndrome. Generalized
Other less common lesions reported with syringocystade- eruptive syringoma is the term used to describe the phenomenon
noma papilliferum include apocrine adenoma, condyloma where successive crops of syringomas occur on the anterior
acuminatum, hidradenoma papilliferum associated with hidro- aspects of the body surface of children, whereas linear syringoma
cystoma, poroma folliculare, and rarely verrucous carcinoma. is where the distribution is similar to that of an epidermal nevus
or giant congenital melanocytic nevus.
Eruptive syringoma is an eruptive form of the tumor. Based
on recent studies, some of the so-called ‘eruptive syringoma’
Histologically, these tumors are composed of one or several may represent a hyperplastic response of the eccrine duct to an
cystic invaginations extending downwards from the epidermis. inflammatory reaction rather than a true adnexal neoplasm.
The deeper cystic spaces are filled with numerous papillary A proposal for the term ‘syringomatous dermatitis’ for such
infoldings lined in their lower portions by two layers of cases is suggested.
other adnexal carcinomas, and cutaneous metastasis of an

adenocarcinoma.
Histologically, the lesions are small and located in the superfi-
cial parts of the dermis. They are composed of small nests,
cords and rounded, comma- or tadpole-shaped ducts, lined by
two layers of cells, which are usually flattened. These epithelial
elements are embedded in a fibrous stroma. The ducts may
contain a PAS-positive secretion. A clear cell syringoma variant
exists in which the ductular structures may be lined by clear
cells. This clear cell change may also be seen in lesions from
patients with diabetes mellitus.
(a)
● Desmoplastic trichoepithelioma
● Microcystic adnexal carcinoma
● Morpheic basal cell carcinoma
● Trichoadenoma
Special techniques
● Eruptive syringoma has been found to express
progesterone receptors, suggesting possible hormonal
control of the tumor.
SKIN APPENDAGE TUMORS, MALIGNANT:

(b)
HAIR FOLLICLE-DERIVED TUMORS
PILOMATRIX CARCINOMA
See Pilomatrixoma (p. 856).
TRICHOLEMMAL CARCINOMA
CLINICAL FEATURES
Tricholemmal carcinoma is a rarely recognized cutaneous
adnexal neoplasm. In general, the tumor presents as slow-
growing epidermal papule, indurated plaque, or nodule show-
ing predilection for sun-exposed, hair-bearing skin. The lesions
are most frequently misdiagnosed clinically as BCC. Despite
the seemingly malignant cytological appearance of these
lesions, clinical follow-up shows no evidence of either recur-
(c)
rence or metastasis. Thus, conservative surgical excision is the
recommended treatment.
Figure 12.46 (a–c) Syringocystadenoma papilliferum. Epidermal
invagination with papillary structures lined by double cell layers
and containing abundant plasma cells.
Syringoid carcinoma (syringoid ‘eccrine’ carcinoma or Histologically, these tumors show a variety of growth patterns
eccrine epithelioma) is a rare cutaneous tumor, with some including solid, lobular and trabecular. They are characterized
controversy regarding its correct definition. It may also be dif- by a proliferation of epithelial cells with features of outer root
ficult to differentiate from its benign counterpart (syringoma), sheath differentiation, including abundant glycogen-rich, clear
874 Skin tumors
cytoplasm, foci of pilar-type keratinization, and peripheral

palisading of cells with subnuclear vacuolation. Because of SKIN APPENDAGE TUMORS, MALIGNANT: SEBACEOUS
their variable growth pattern, overt cytological atypia, abundant GLAND-DERIVED TUMORS
clear cytoplasm, occasional pagetoid intraepidermal spread
and brisk mitotic activity, these tumors may pose difficulties of SEBACEOUS CARCINOMA
diagnosis and be confused with other malignant skin tumors
with clear cell changes.
CLINICAL FEATURES
Differential diagnosis Sebaceous carcinoma is a malignant neoplasm with the capac-

ity for metastasis. It may be either ocular or extraocular, with
● Tricholemmoma
the former type exhibiting a more aggressive clinical behavior.
● Other malignant skin tumors with clear cell changes
These lesions may be associated with Muir–Torre’s syndrome.
SKIN APPENDAGE TUMORS, MALIGNANT

NEUROENDOCRINE CARCINOMA Histologically, this tumor is reminiscent of squamous cell carci-
(MERKEL CELL CARCINOMA) noma, and is composed of irregularly shaped lobules of varying
sizes. Each lobule is composed of cells exhibiting cytoplasmic
vacuolation and eosinophilia with pleomorphic nuclei. Cells
CLINICAL FEATURES
with cytoplasmic vacuolation are especially seen at the center of
This is an aggressive cutaneous neoplasm which occurs mainly the lobule. Mitotic figures are easily identified. Atypical kera-
in elderly people. It is felt to be derived from precursor cells tinizing cells may also be present. The overlying epithelium may
which give rise to both squamous and Merkel cells; this is
supported by the finding of coexistent squamous lesions.
Approximately one-third of Merkel cell tumors recur, and
two-thirds metastasize to regional lymph nodes.
The lesion is usually a tumor of the dermis with spread to the
subcutis, although a purely intraepidermal variant has been
described.

Histologically, the tumor is composed of sheets and trabeculae
of cells with hyperchromatic cytoplasm and a high mitotic rate.
Pagetoid spread of cells in the epidermis has been described.
There is frequently an associated Bowen’s disease or associated
squamous carcinoma. Both rhabdomyosarcomatous and leiomyo-
sarcomatous differentiation have been described.
(a)
● Small cell melanoma (Merkel-like)
● Metastatic small cell carcinoma
Special techniques
● The immunohistochemical profile is positivity for
neurofilaments, cytokeratins, neuron-specific enolase
(NSE) and EMA. Tumor cells show positivity for
CAM5.2 (dot-like) and CK20 (dot-like). (Small cell
lung cancer expresses CK7 and is usually negative
for CK20.)
● Positivity for thyroid transcription factor 1 (TTF-1) and
CD 117 (KIT receptor tyrosine kinase). CK7 is usually – (b)
but not always – negative in these lesions.
● Trisomy for chromosome 6 has been identified in a Figure 12.47 (a, b) Merkel cell tumor. A dermal lesion consisting
percentage of these lesions. of small uniform cells with characteristic nuclei.

● Basal cell carcinoma with sebaceous differentiation
Special techniques
See also Sebaceous hyperplasia (p. 864).
● The fat within the tumor cells can be highlighted by fat
stain. The sebaceous cells are positive for EMA, CAM5.2,

BRST-1 and androgen receptors.
SKIN APPENDAGE TUMORS, MALIGNANT: SWEAT

(a)
ADENOID CYSTIC CARCINOMA
CLINICAL FEATURES
Primary cutaneous adenoid cystic carcinoma is a rare variant of
sweat gland carcinoma with characteristics of an indolent and
progressive course and high incidences of perineural invasion
and local recurrence. However, regional lymph node metastasis
is exceedingly rare. Cutaneous involvement can also result
from direct extension from a salivary gland neoplasm. The
tumor presents as a painful skin lesion on the scalp, trunk or
extremities of middle-aged or elderly individuals. It may also
occur in the vulva.
(b) PATHOLOGICAL FEATURES

Histologically, this is a dermal tumor consisting of nests of
basaloid cells showing cribriform, adenoid or solid patterns.
The cells have round hyperchromatic nuclei. Mitoses and cel-
lular atypia may be seen. The spaces or the ductular lumina are
partially filled with pale blue mucinous secretion. Occasionally,
larger cystic spaces are seen. The stroma is fibrotic and may
show mucoid degeneration. Mantles of PAS-positive hyalinized
connective tissue stroma may surround some of the basaloid
nests, and similar material may also be present as droplets
within the epithelial spaces. The mucin is hyaluronic acid, and
the cells express CEA.
● Adenoid cystic carcinoma of salivary gland
(c) ● Basal cell carcinoma
Figure 12.48 (a–c) Sebaceous carcinoma of the vulva. Extra- Special techniques
ocular sebaceous carcinoma shows basaloid nests with central
necrosis and sebaceous differentiation. See Adenoid cystic carcinoma (p. 602).
show pagetoid spread. Ulceration of the overlying epidermis

may occur, with secondary inflammatory changes. AGGRESSIVE DIGITAL PAPILLARY
ADENOMA/CARCINOMA
● Sebaceoma
CLINICAL FEATURES
● Eccrine porocarcinoma
● Malignant clear cell hidradenoma Papillary eccrine adenoma is a rare benign sweat gland neoplasm
● Extramammary Paget’s disease that typically behaves in a benign fashion, but which on the volar
● Malignant trichilemmoma surfaces may demonstrate more aggressive biological behavior.
876 Skin tumors
Aggressive digital papillary adenomas may histologically histological features do not allow the prediction of clinical
simulate papillary eccrine adenoma but behave in a more behavior. For that reason it is felt that all these aggressive pap-
malignant fashion. It is a rare tumor, and involves a clinical and illary tumors be designated carcinoma.
histological spectrum ranging from a locally destructive neo- A pattern of fused back-to-back glands lined by cuboidal to
plasm to a more aggressive metastasizing lesion. It usually low columnar epithelial cells with little evidence of papillary
involves the hands, feet and digits of young to middle-aged formations may also be observed. Continuity of the tumor to
adults, and presents as a cystic swelling. the epidermis is usually evident.
This tumor should be considered in the differential diagnosis
of non-healing wounds of the finger that have not responded to Differential diagnosis
other forms of treatment. Wide local excision with clear mar- ● Basal cell carcinoma
gins and close surveillance for signs of recurrence or metastasis
are indicated for this rare sweat gland neoplasm. Special techniques
● The neoplastic cells are immunohistochemically positive
PATHOLOGICAL FEATURES (Figures 12.49 and 12.50) for cytokeratins and sometimes for CEA, but negative for
EMA, and gross cystic disease fluid protein (GCDFP). The
Histologically, this is a dermal lesion and is an asymmetric cys-
intraluminal content shows positive reactivity with both
tic structure with the cyst lining composed of basaloid cuboidal
CEA and EMA.
cells. The inner aspect of the cyst is thrown into papillary
infolding or villi, also lined by similar cells. There may be more
cellular areas with poorly formed glands. The degree of nuclear HIDROADENOCARCINOMA/MALIGNANT
atypia and mitotic activity is variable. Local recurrence is TRANSFORMATION OF CYLINDROMA/
common, and metastasis occurs in 10–20% of individuals. The
SPIRADENOCARCINOMA
See text relating to the benign counterparts of these tumors

(p. 865).
MICROCYSTIC ADNEXAL CARCINOMA
CLINICAL FEATURES
Microcystic adnexal carcinoma, or sclerosing sweat duct tumor,
is an uncommon, cutaneous adnexal malignant neoplasm,
associated with significant morbidity as a consequence of its
propensity for perineural invasion. Although considered a malig-
nant tumor of sweat duct origin, it has been shown to exhibit
both pilar and sweat duct differentiation. Cases with sebaceous
differentiation have also been documented. This tumor is closely
related to low-grade carcinoma (eccrine epithelioma). Clinically,
Figure 12.49 Papillary adenoma of the sweat gland. Ductal it often masquerades as a firm, subcutaneous nodule on the
structures lined by bland cuboidal cells with shallow papillae. upper lip, nasolabial fold, periorbital region or axilla. It has also
been documented in other sites such as the vulva and breast.
This tumor is frequently misdiagnosed because of its bland
and asymptomatic clinical presentation. In addition, its defin-
ing histological features may be missed with a superficial
biopsy. Aggressive initial treatment by microscopically con-
trolled excision (Mohs’ micrographic surgery) appears to offer
the greatest likelihood of cure for this neoplasm, while provid-
ing conservation of normal tissue.

The tumor is composed of multiple cellular nests and strands
within a moderately sclerotic stroma involving the full thickness
of the dermis. Clusters of basaloid cells with extensive seba-
ceous differentiation may be present. Small keratin-filled,
squamous-lined cysts and foci of sebaceous ductal differentia-
Figure 12.50 Eccrine papillary adenoma. Ductal structures containing tion are usually observed in the more superficial areas. Neither
eosinophilic secretion and focally lined by papillary structures. strikingly atypical cells nor mitotic figures are features of this
tumor. Perineural invasion in the deeper aspect is common. ● Unlike basal cell carcinomas, these tumors have a low p53
In some cases, particularly when recurrent, there is some cyto- and Ki-67 staining pattern.
logical atypia with mitotic figures.
MUCINOUS CARCINOMA
● Desmoplastic trichoepithelioma
● Sclerosing basal cell carcinoma CLINICAL FEATURES
● Syringoma Primary cutaneous mucinous carcinoma is a rare epithelial neo-
● Trichoadenoma plasm derived from the sweat glands. It occurs mostly on the face,
more commonly in males, and affects a wide age range. There is
Special techniques
a high (30%) local recurrence rate, but nodal spread in uncom-
● The tumor cells stain with CK7, EMA and (patchily) with mon and distant metastases are rare. Cutaneous mucinous car-
S-100 protein. cinoma shows strong similarities to its mammary counterpart,
including expression of estrogen receptor, TFF1, and TFF3
mRNA. These observations suggest that some mucinous carcino-
mas of the skin might respond to anti-estrogenic therapies.
The neoplasm extends from the reticular dermis into the sub-
cutaneous fat, and exhibits features similar to its mammary
counterpart. The tumor cell aggregates show cribriform and
solid lobules and are embedded in lakes of mucin, separated by
thin, fibrous septa. Focally single neoplastic cells are arranged in
an Indian-file pattern. The tumor cells display an eosinophilic
cytoplasm, large basophilic nuclei and some nuclear atypia.
● Breast mucinous carcinoma
Special techniques
● The tumor cells stain with CEA, low-molecular-weight CK,
human milk factor globulins (HMFG1 and 11), gross
(a)
(b) (c)
Figure 12.51 (a–c) Microcystic adnexal carcinoma. Numerous small glandular structures present haphazardly deep within the dermis.
878 Skin tumors
(a) (c)
(b) (d)
Figure 12.52 (a–d) Microcystic adnexal carcinoma, or sclerosing sweat duct tumor.This is composed of cellular nests and strands within a
sclerotic stroma involving the full thickness of the dermis. Occasional microcysts are seen (d).
cystic disease protein (GCDP15) and with estrogen preferentially on the lower extremities, followed by the trunk.
receptor and variable staining for progesterone receptor. They present as verrucous plaques and nodules.
● The tumor exhibits endocrine differentiation by
immunohistochemistry and ultrastructural analysis. PATHOLOGICAL FEATURES
Histologically, the epidermis is thickened and composed of an
POROCARCINOMA intraepidermal proliferation of basaloid cells with ductal differ-
entiation and cytological atypia. An infiltrative dermal compo-
nent composed of similar cells is invariably present. Varieties of
CLINICAL FEATURES
histological patterns have been described, and include clear,
This is thought to be the most common sweat gland carci- squamous and spindle cell differentiation, mucus cell metaplasia
noma. These tumors are more common in women, and occur and colonization by melanocytes. In-situ disease, which can be
composed of clear cells, is also documented. The mitotic count, PATHOLOGICAL FEATURES (Figures 12.53 and 12.57)
presence of lymphovascular invasion and tumor depth predict
Junctional nevi show variably pigmented nests of melanocytes
a more aggressive clinical course, with local recurrence and
clustering at the tips and sides of rete ridges. Increased numbers
metastasis.
of single melanocytes are seen in the basal layer. These
melanocytes may be enlarged, but they lack pleomorphism or
Differential diagnosis hyperchromasia. There may be slight hyperplasia of the rete
● Bowen’s disease ridges. In acral locations these nevi may produce abundant
● Squamous cell carcinoma melanin pigmentation. Pagetoid spread, fibrosis and inflamma-
tion are usually absent. Junctional melanocytic nevi may rarely
Special techniques exhibit a massive production of melanin accumulated in, and
stored in, dermal macrophages.
● p53 expression does not differentiate between eccrine Compound nevi show some (or all) of the features of junc-
poromas and porocarcinomas. However, expression of the tional nevi, with an additional intradermal melanocytic compo-
p16 protein appears to be positive in porocarcinomas and nent. The lateral extent of the latter usually corresponds to that
negative in the benign counterpart. of the junctional component. Substantial extension of the junc-
tional component beyond that of the intradermal component
PRIMARY EXTRAMAMMARY PAGET’S DISEASE
See Chapter 7, Female genital tract tumors: Vulva (p. 375).
MELANOCYTIC LESIONS, BENIGN
COMMON NEVI
JUNCTIONAL, INTRADERMAL, AND
COMPOUND NEVI
CLINICAL FEATURES
Common nevi are collections of melanocytic cells at the dermo-
epidermal junction, in the dermis, or in both sites. They are
considered by some as hamartomas and by others as neoplasms. Figure 12.53 Compound nevus.The junctional component is
They are mostly of no clinical concern, and are removed for fear arranged in round, regular nests which present mainly at the tip of
of malignant change or for cosmetic reasons. They may be pres- the rete ridges.The dermal cells are more loosely arranged, and are
ent at birth (congenital nevi) or develop at or after puberty uniform in size and shape. Elongation of the rete ridges is common
(acquired nevi). They are usually acquired before the age of in benign nevi.
25 years in men and 30 years in women. Development of a new
pigmented skin lesion beyond this age requires the exclusion of
melanoma (except in the case of dysplastic nevus syndrome).
Acquired nevi are usually less than 5 mm in diameter. The
majority of nevi undergo progressive maturation and atrophy.
Junctional nevi present as a flat macules in which skin creases
are preserved. Compound nevi present as macules or papules
that may be verruciform and often bear hair. Intradermal nevi
often present as skin-colored, dome-shaped nodules.
It has been said that nevi evolve through several stages. The ear-
liest stage is lentigo simplex; this is a dark, uniform macule which
measures ⬍2 mm in maximum dimensions and is characterized
by a proliferation of single melanocytes at the basal layer of elon-
gated rete ridges. Lentigenous junctional nevi combine both the
features of lentigo simplex and the nesting of melanocytes seen in
junctional nevus. The nevus cells then descend into the dermis,
producing a compound nevus. When the nevus cells disappear
from the epidermis, the lesion loses its pigment and becomes an Figure 12.54 Compound nevus.This shows early balloon cell
intradermal nevus (flesh-colored papule). change.
880 Skin tumors
(a)
Figure 12.55 Compound nevus.The upper part of a compound

nevus illustrates few junctional nests in association with large and
multinucleated nevus cells in the upper papillary dermis.
(b)
Figure 12.57 (a, b) Benign pigmented lentigenous nevus.

(a) A junctional pigmented nevus showing nests and single cells at the
dermo-epidermal junction.
maturation process is an important sign of benignity. Advanced

maturation with spindle cell formation confers a neural look to
the intradermal nevus cells (neurotization). Features of periph-
eral nerve sheath differentiation such as neuroid cords, nerve
corpuscles, fascicle-like structures and, exceptionally, palisading
have been reported in melanocytic nevi. Multinucleated nevus
cells are mostly seen in the junction or the superficial zone.
Pigmentation is almost always limited to the larger, superficially
located cells. On rare occasions large pigmented nests similar to
those seen superficially are present in deeper locations (this may
be due to tangential cutting of hair follicle-associated nests).
Mitotic figures are very rare in ordinary benign nevi.
In congenital nevi the cells often extend deeply into the retic-
(b) ular dermis, ensheath erector pili muscles and sweat glands,
and may extend into subcutaneous fat.
Figure 12.56 (a, b) Intradermal nevus; pseudovascular pattern. In intradermal nevi the nevus cells are usually uniform in shape
Some intradermal nevi show marked pseudovascular changes. and size, often show deeper maturation, exhibit pigmentation only
in the superficial aspect and lack mitotic figures, an inflammatory
should raise the suspicion of melanoma in situ. As they descend response and pleomorphism. The overlying epidermis may show
deep into the dermis, the intradermal nevus cells progressively occasional residual small melanocytic nests or increased single
decrease in size, become round or oval, and are separated by basal melanocytes. Fat cells are often seen admixed with intrader-
more abundant dermal collagen (melanocytic maturation). This mal nevus cells (this indicates longstanding lesions).
Groups of nevus cells may be seen in the deep dermis, sepa- measure few millimeters in diameter. Simple lentigo has an over-
rated from the epidermis by a zone of scar tissue. This often lap with the simple freckle or ephilus.
represents a previous incompletely removed nevus, which has The senile or solar lentigo occurs on UV-associated areas of
usually been managed by a shave biopsy. the body in older individuals.
Occasionally, an otherwise benign-looking nevus will have a Patients with numerous, small, darkly pigmented melanocytic
mitotic figure in the dermal component. It is important to lesions may have a range of histologic diagnoses from simple
embed all the tissue, to perform levels of histological section- lentigo to junctional lentiginous nevus to thin melanoma.
ing, and then to scrutinize the sections. If after close examina-
tion there are no other cytologically or architecturally worrying PATHOLOGICAL FEATURES
features, it should be reported as a nevus with mitotic figures
with a guarded comment added to the report. Lentigo simplex shows slight to moderate elongation of the rete
Neoplastic transformation of the intradermal nevus without ridges with an increase in the number of basal melanocytes and
junctional activity is a rare occurrence. It is important to melanin pigment. Occasionally the melanin pigment is seen in
distinguish this neoplasm from other diagnostic possibilities, the upper layers of the epidermis including the corneal layer.
including a metastatic lesion originating from another site. Sometimes nests of junctional nevus are seen in association
Nevi of the palms and soles may show pagetoid melanosis – with the lesion.
that is, an upward discontinuous extension of melanocytes into Senile or solar lentigo shows significant elongation of the
the superficial epidermis. Unlike those seen in malignant reti ridges, sometimes reminiscent of reticulated seborrheic
melanoma, the cells lack cytological atypia and do not extend keratosis. This is associated with an increase in pigmentation
beyond the dermal component. of the basal cell layer with minimal increase in basal layer
melanocytes.
Secondary features
● Squamous cysts. Differential diagnosis
● Folliculitis often complicating the follicle enlargement with ● Lentigo maligna
multiple hair shafts of a congenital nevus. ● Pigmented lentiginous nevus with atypia
● Bone or cartilage formation.
● Deposition of mature fat cells.
SPITZ NEVI AND VARIANTS
Cell morphology
● Nevus cells are usually round or polyhedral, but can be CLINICAL FEATURES
spindle-shaped. They have uniform rounded nuclei,
Spitz nevus (large epithelioid and/or spindle cells nevus) is a
occasionally with small nucleoli.
benign melanocytic lesion that shares many histological fea-
● The cells often lack mitotic figures. tures with melanoma. While Spitz nevi characteristically occur
in children and young adults and melanomas in the middle-
Differential diagnosis aged and elderly, either tumor can occur in patients of any age.
● Common nevi are rarely a cause of diagnostic difficulty They frequently occur on the head and neck and extremities.
● Active junctional nevus may be confused with early stage The compound Spitz nevus is the most common variant, typi-
malignant melanoma cally appears as a pink papule, and is frequently mistaken
● Nevoid melanoma as pyogenic granuloma. Intradermal (desmoplastic, dermato-
● Mastocytoma fibroma-like) Spitz nevus occurs in both sexes, with the preferred
● Metastatic lobular carcinoma sites of trunk and extremities. The clinical appearance may
suggest a reddish-brown firm lesion or keloid.
Special techniques
● Common benign nevi are S-100 protein-and melan-A- PATHOLOGICAL FEATURES (Figure 12.58)
positive. HMB45 negative is usually in the intradermal
cells (except in a Spitz nevus). There are five variants of Spitz nevi:
● Pagetoid Spitz nevus: this is the name for the intraepidermal
● MIB-1/Ki-67 immunoreactivity closely correlates with the
variant of Spitz nevus and is rarely seen. It is characterized
benignancy or malignancy of melanocytic lesions, and may
by an intraepidermal pagetoid proliferation of cytologically
assist in the differentiation of benign nevi from melanomas.
similar large epithelioid cells. The term should be restricted
to small lesions in children and young adults.
LENTIGO ● Junctional Spitz nevus: these are lesions that are also
uncommonly biopsied. They are predominantly junctional

proliferations of large epithelioid and or spindle cells along
CLINICAL FEATURES
the basal layer. Like pagetoid Spitz nevi, the term should
Lentigo simplex is characterized by few scattered evenly pig- be restricted to small lesions in children and young adults,
mented lesions without predilection to sun exposed areas. They and with all the cells being cytologically similar to each other.
882 Skin tumors
(a) (c)
(b) (d)
Figure 12.58 (a–d) Spitz nevus. A compound-type nevus consisting of large epithelioid eosinophilic cells, infiltrated by lymphocytes.
● Compound Spitz nevus: histologically, these are typically There is a group of spitzoid lesions for which the biological
symmetrical and composed of large epithelioid and/or behavior is difficult to determine. Sentinel lymph node exami-
spindle cells. There might be pronounced cytological nation of such a lesion has been provisionally evaluated, and
atypia, with nuclear atypia and intranuclear inclusions. revealed that approximately half of them had positive sentinel
The cells should mature in the depth and have an lymph nodes.
infiltrative base. The overlying epidermis usually shows ● Intradermal (desmoplastic, dermatofibroma-like) Spitz
pseudoepitheliomatous hyperplasia, with edema and nevus: histologically, the lesion is dermal, poorly
prominent vascularity of the papillary dermal components. circumscribed, and composed of single epithelioid cells
Kamino bodies (eosinophilic globules) are typical and within a desmoplastic stroma. The cells may have a bizarre
occur at the dermo-epidermal junction and in the nuclear appearance and/or intranuclear inclusions. Some
superficial dermis. It has been emphasized that there are cells may resemble ganglion cells. However, no mitoses or
no single discriminating features between melanoma as abnormal mitoses are seen.
virtually all features described in Spitz nevi have been ● Plexiform Spitz nevus is characterized by a plexiform
described in melanoma. Features that cause concern are arrangement of bundles and lobules of enlarged spindle to
lack of maturation at the base, the presence of epithelioid melanocytes throughout the superficial and
numerous/deep or atypical mitoses, deep bulbous deep dermis. Intraepidermal melanocytic proliferation may
extension into the fat, an asymmetrical lateral lentiginous not be seen. Some lobules are circumscribed by a thin rim
growth pattern, thinning of the overlying epidermis, of compressed fibrous tissue. Myxoid stroma may be
intralesional variation and variable pigment distribution. present. The cells have abundant eosinophilic cytoplasm
Spitz lesions that show some atypical features yet lack the with well-defined borders. The nuclei are enlarged,
full criteria for melanoma have been termed atypical Spitz consistently ovoid and vesicular, with small nucleoli.
tumors. Some have advocated gradation of these atypical Scattered multinucleate giant cells similar to those
Spitz lesions into low-, intermediate- and high-risk lesions. observed in classical form of Spitz nevi may be seen.

● Spitz nevus commonly mistaken for malignant melanoma Histologically, these tumors are composed of variable numbers
● Junctional Spitz nevus should be distinguished from of small nevus cells and balloon cells, though the latter com-
atypical nevus ponent may account for the entire lesion. The balloon cells
● Desmoplastic Spitz nevus can be misinterpreted as contain abundant clear or pale foamy cytoplasm. There is usu-
dermatofibroma, or hyopigmented blue nevus ally a minimal junctional component, and the cells lack cyto-
● Plexiform Spitz nevus should be distinguished from logical atypia and mitoses.
desmoplastic/neurotropic melanoma, plexiform spindle cell
nevus, cellular blue nevus, plexiform neurofibroma and Differential diagnosis
cellular neurothekeoma
● Balloon cell melanoma
● Clear cell hidradenoma
Special techniques ● Clear cell dermatofibroma
● Tumor cells are strongly immunoreactive for S-100 protein ● Metastatic renal cell carcinoma
and melan-A and may express HMB-45.
BLUE NEVUS
VARIANT NEVI
CLINICAL FEATURES
ANCIENT NEVUS
Blue nevi are unique types of intradermal nevi derived from pre-
cursor cells, and have some features of both melanocytes and
CLINICAL FEATURES Schwann cells. They are usually present at birth or in early life
Ancient melanocytic nevus is an example of a simulator of in the head and neck region, extremities or the buttocks (in the
malignant melanoma, designated ancient because it shares case of cellular blue nevi). They may occur in mucosal surfaces
numerous features with ancient schwannoma. This variant has (e.g., oral and cervical mucosa), in lymph nodes, and rarely in
been described in lesions from the face of older (aged ⬎50 organs such as the prostate. Cellular blue nevi may occasionally
years) individuals. The neoplasm is usually a dome-shaped, recur locally or undergo malignant transformation.
skin-colored or reddish-brown papule.
The lesions are typically unencapsulated and grow in fascicles
These lesions are described as exoendophytic, intradermal pro- or in an alveolar pattern. They appear to be closely related to
liferations composed of two cell types. One population has large deep penetrating nevi. Variants have been described, including
Spitz cells, and the other is a population of small monomor- amelanotic, sclerosing, epithelioid, atypical cellular blue nevus
phous cells. Secondary degenerative changes may occur, and and large-plaque type with subcutaneous cellular nodules.
these include thrombi, zones of hemorrhage, pseudoangioma- Common blue nevus is an ill-defined hypocellular dermal
tous pattern, thick rims of sclerosis around dilated venules, and spindle cell lesion. The cells have long cytoplasmic dendrites,
mucin. A few mitotic figures may be present. However, caution and are heavily pigmented. Numerous melanophages are also
must be exerted in accepting mitotic figures in a melanocytic seen. The overlying epidermis is usually normal.
lesion from an older individual, especially if near the base of the Cellular blue nevus is a fairly well-circumscribed, markedly
lesion, numerous and/or atypical. cellular mid or deep dermal lesion, consisting of round or oval-
shaped cells, some of which contain heavy melanin pigmentation.
Differential diagnosis The overlying epidermis is spared.
Combined blue nevus shows features of common blue nevus
● Malignant melanoma arising in intradermal nevus
together with epidermal involvement by dendritic melanocytes.
True and blue nevus is a term used for a lesion consisting of
BALLOON CELL NEVUS a blue nevus in conjunction with an ordinary intradermal or
junctional nevus.
Epithelioid blue nevus is an unusual cytological variant of
CLINICAL FEATURES
blue nevus that has been recently described mostly in patients
Balloon cells are altered melanocytes with clear vacuolated cyto- with the Carney complex, although it may also occur in isola-
plasm caused by a defect in the process of melanogenesis. tion. This variant of blue nevus is composed of melanin-laden
Balloon cell change may rarely be observed in a variety of polygonal epithelioid melanocytes situated within the dermis.
melanocytic proliferations, particularly intradermal melanocytic The neoplastic cells show no maturation with progressive
nevi and melanoma. When such cells are predominant, the term depth of dermal infiltration and, in contrast to the usual stro-
‘balloon cell nevus’ is used. These frequently occur on the head mal changes in blue nevi, epithelioid blue nevi exhibit no der-
and neck area of young individuals. mal fibrosis. Immunohistochemically, epithelioid melanocytes
884 Skin tumors
mitotic rate, necrosis, nuclear atypia, pleomorphism, hyper-

chromasia and prominent nucleoli.
Secondary features
● Focal lymphocytic infiltrate may be seen in cellular
blue nevi.
● Myxoid and cystic changes – which can be extensive –
may rarely be seen in the center of cellular blue nevi. This
usually occurs in longstanding nevi, of larger size, and
those located on pressure areas such as the buttocks or feet.
This is probably due to repeated trauma with compression
of vessels and subsequent thrombosis and tissue hypoxia.
(a) Cell morphology

● Mitotic figures (one or two typical mitoses) may be seen in
cellular blue nevus. The presence of higher mitotic counts
and necrosis indicates malignancy.
● The presence of very prominent eosinophilic nucleoli with
a junctional component should raise the possibility of
deep-penetrating nevus.
● Cellular pleomorphism, nuclear hyperchromasia and
multinucleated cells are sometimes seen in cellular blue
nevi, especially in those showing myxoid degeneration.
● Deep-penetrating nevus
● Dermatofibroma
● Desmoplastic melanoma
(b) ● Regressed melanoma
● Bednar tumor
Special techniques
● The cells are S-100 protein-positive, and may also be
HMB-45-positive.
COMBINED NEVUS
CLINICAL FEATURES
Combined nevus is defined as a nevus with more than one his-
tological type of benign nevus. They may occur anywhere in the
skin, but can also be found in the conjunctiva and oral mucosa.
(c)
Figure 12.59 (a–c) Blue nevus. A dermal spindle cell lesion
Combined nevi show ordinary nevus cells in conjunction with
with pigmentation throughout the lesion.The pigment is seen both
within macrophages and dendritic melanocytes. other types of nevus variants such as Spitz, blue nevus or deep-
penetrating nevus. The most common type seen is the ‘true and
blue nevus’, where the blue nevus component is the deep com-
ponent, extending into the fat and around appendages.
expressed immunoreactivity for S-100 protein, HMB-45,
melan-A and MiTF antibodies.
Malignant transformation within a blue nevus has been Differential diagnosis
described, and the features to be concerned about are increased ● Malignant melanoma
CONGENITAL NEVI usually rare, and include: foci of increased cellularity, a prolifer-
ation simulating superficial spreading melanoma in situ, a
proliferation simulating nodular melanoma, and proliferating
CLINICAL FEATURES neurocristic hamartoma.
These are present at birth or early infancy, and vary in size Although some of these closely resemble melanoma both
from small to the giant forms covering major anatomical clinically and histologically, metastasis is rare.
regions of the body. Malignant transformation in congenital nevi: a variety of
Giant congenital melanocytic nevi are rare, and occur in malignancies have been reported to arise within congenital
about one out of every 200 000–500 000 births. Their impor- melanocytic nevi, most commonly malignant melanoma, but
tance resides in the esthetic alteration they produce and in the rarely rhabdomyosarcoma, liposarcoma, and malignant periph-
possibility of malignant transformation, or in their association eral nerve sheath tumor.
with nevi in the central nervous system as a distinctive syn-
drome: neurocutaneous melanoblastosis or nevomatosis, due
to the fact that nervous system lesions are produced by the ● Malignant melanoma
infiltration of nevus cells. These nevi often require a multi-
disciplinary approach involving pediatricians, family physicians, DEEP-PENETRATING NEVUS
internists, dermatologists, pathologists, psychologists, plastic (PLEXIFORM SPINDLE CELL NEVUS)
surgeons, neurologists, and radiologists. The cosmetic and psy-
chosocial issues – combined with the knowledge of the
increased risk of developing melanoma – are a huge burden CLINICAL FEATURES
that many of these patients and their families have to carry.
Deep-penetrating nevus is a variant of benign pigmented nevus
For the most part, moderately large congenital nevi are treated
with deep dermal and subcutaneous involvement. It occurs
with primary excisions and closures, assisted by tissue-expansion
techniques and skin grafting. Until the associated risks are better
defined, therapy of small congenital nevi should be individual-
ized, with consideration given to additional melanoma risk fac-
tors. However, very large lesions – for example, ‘bathing trunk
nevi’ or whole-limb involvement – may merely be observed.

Congenital nevi show periadnexal distribution of nevus cells with
nevus cells showing extensive involvement of the subcutis, and
show lymphatic and vascular invasion. Other diagnostic problems
include the marked junctional activity in infancy that can mimic
melanoma; proliferative dermal nodules can also occur which can
mimic intralesional transformation, as described below.
Secondary proliferations in congenital nevi: Several forms of
secondary proliferations can arise in congenital nevi. These are (b)
(a) (c)
Figure 12.60 (a–c) Congenital-type intradermal nevus.This shows sharp demarcation at the lower border, and clear maturation
of nevocytes.
886 Skin tumors
primarily during the first four decades of life, is somewhat Special techniques
more common in females, and has a predilection for the face, ● Melan-A staining is helpful in detecting the residual
trunk, and proximal extremities. The lesion is usually less than melanocytic cells and highlighting the architecture.
1 cm in diameter, and often shows variegation in color, includ-
ing shades of brown, blue and black that creates clinical con-
cern regarding malignant melanoma. Some believe that these NEVUS AFTER ULTRA-VIOLET IRRADIATION
lesions are related to, or are variants of, blue nevi.
CLINICAL FEATURES
These nevi occur after exposure to UV irradiation, as occurs on
Histologically, the lesion is usually compound but with only a
a typical holiday. This is mainly seen in nevi from chronically
minor junctional component. It is often wedge-shaped, with
UV-damaged areas (on the head and neck). This is thought to
the apex extending to the deep dermis or subcutis. Involvement
be a reversible phenomenon.
of neurovascular structures and adnexae and spread between
fibers of the reticular dermis create a fascicular-plexiform
architecture. The melanocytes are either fusiform or epithe- PATHOLOGICAL FEATURES
lioid, lightly to moderately pigmented, and exhibit mild to
Single UV irradiation induces histological changes that are sim-
focally prominent nuclear atypia. Sparse to abundant
ilar to those of atypical nevi and, in part, of melanoma in situ.
melanophages are characteristic. Mitotic figures are few in
UV causes alteration in the distribution and cytology of basal
number, and present in only a small minority of lesions. Deep-
layer melanocytes, with an increase in their numbers and sizes.
penetrating nevus is a frequent participant in combined nevus,
as it is associated with ordinary nevus in two-thirds of cases.
Differential diagnosis ● Melanoma in situ
● Blue nevus
● Malignant melanoma (features favoring deep-penetrating PIGMENTED SPINDLE CELL NEVUS
nevi are symmetry, inconspicuous junctional component,
few mitotic figures, bland chromatin pattern, and no
stromal reaction and little inflammation) CLINICAL FEATURES
This is a specific histopathological entity with some features
HALO NEVUS similar to Spitz nevus, and indeed it is thought by some that
they are related, because there is sometimes histological over-
lap. The importance of the entity is that it can mimic melanoma
CLINICAL FEATURES both clinically and histologically. Clinically, the lesions occur
Halo reactions to melanocytic nevi are a well-recognized phe- typically in young adults on the thigh, upper arm and shoulder,
nomenon. Halo nevi occur predominantly in childhood and and there is a female predominance. They are usually small
adolescence, and clinically the nevus has a ring of depigmenta- (⬍6 mm), darkly pigmented papules or macules, and occasion-
tion. A halo reaction has infrequently been reported in Spitz ally have a history of recent rapid growth.
nevi and in congenital nevi.
PATHOLOGICAL FEATURES Histologically, the tumors are symmetric, predominantly junc-
Histologically, there is a band-like infiltrate of lymphocytes at tional melanocytic lesions, composed of vertically orientated
the dermo-epidermal junction, obscuring the remaining theques of spindle cells that fill and expand the upper dermis.
melanocytes at this site. Halo reactions may cause misdiagno- Mitotic figures may be present in the junctional component.
sis of an otherwise benign nevus as melanoma because inflam- Atypical variants have been described in which the lesions
matory cells sometimes obscure the architectural features of the show upward migration, prominent lateral extension of lentig-
underlying nevus and may induce cytological atypia. Caution inous melanocytic hyperplasia, and cytological atypia of the
should be used if an involuting lesion is from an adult, is large, spindle cells.
from the trunk and particularly if the lymphocytic attack is Pigmented spindle cell nevus is often misdiagnosed as malig-
asymmetrical. Early and late stages of attack are not usually nant melanoma, despite reliable clinical and histopathological
seen within the same lesion of halo nevus. Lymphocytes are the diagnostic features. Numerous eosinophilic globules (Kamino’s
predominant cell type, and the presence of plasma cells should eosinophilic globules) are found in up to 80% of the cases.
raise the possibility of a melanoma.
Differential diagnosis ● Malignant melanoma
● Regressing malignant melanoma ● Atypical nevus
(a) (b)
Figure 12.61 (a, b) Pigmented spindle cell nevus. A junctional nevus with crowded spindle or ovoid cells with excessive pigmentation.
PSEUDO-MELANOMA (PERSISTENT NEVUS) Nevi from other anatomical sites such as flexural sites (axilla,
umbilicus, inguinal creases, popliteal fossa, pubis, scrotum,
infra-mammary zone and perianal area) are now also consid-
CLINICAL FEATURES ered as special-site nevi. It is likely that this list will grow, with
Benign nevi that have been incompletely excised (usually by possible additional sites being the scalp, conjunctiva, and nail
shave biopsy) or have been traumatized, may regrow in the scar matrix.
in a pattern that mimics melanoma in situ. The regrowth usu- The atypia of special-site nevi is even more exaggerated in
ally occurs within weeks of the original surgery, and intradermal children or in cases of Spitz nevus.
nests of the original nevus may be present deep to the scar. The
lesion may be clinically alarming, with asymmetry and variable PATHOLOGICAL FEATURES
pigmentation.
Pseudo-melanoma has also been documented as a complica- The atypia is predominantly architectural, and takes the form
tion of laser therapy of congenital nevi. This must be recognized of large nest size and a patchy lentiginous growth pattern. The
in order to avoid unnecessary surgical procedures. cytological atypia is mild, and there should be minimal or
absent inflammatory response.
Acral-lentiginous nevi differ from other acral non-lentiginous
nevi by the presence of elongation of rete ridges, continuous
Histologically, there is a lentiginous proliferation of melanocytes proliferation of melanocytes at the dermo-epidermal junction,
along a rather atrophic epidermis, with possible upward spread presence of single scattered melanocytes (or less commonly
and mitotic figures. The melanocytes are often highly pigmented. small clusters) within the upper epidermis, poor or absent lat-
Deep to this there is the scarring from previous surgery. The eral circumscription, melanocytes with abundant pale cyto-
intraepidermal component should not grow beyond the edge of plasm and round to oval, sometimes hyperchromatic, nuclei and
the scarring. prominent nucleoli present at the dermo-epidermal junction.
Flexural nevi have a ‘nested and discohesive pattern’ similar
Differential diagnosis to the melanocytic nevi of genital skin. This pattern is charac-
● Melanoma in situ terized by the confluence of enlarged nests with variation in
size, shape and position at the dermo-epidermal junction, and
by the diminished cohesion of melanocytes.
SPECIAL-SITE NEVI
CLINICAL FEATURES ● Some histological features of acral-lentiginous nevi are
Melanocytic nevi in certain locations such as the genital and acral similar to those of dysplastic nevi: however, anastomosing
sites may have atypical histological features simulating mela- rete ridges, cytological atypia and well-formed lamellar
noma. Genital nevi with atypical features are more common on fibroplasia are absent
the labia minora or the mucosa of the clitoral region than they ● The histopathological criteria to distinguish these nevi from
are on the labia majora. The other common atypical melanocytic melanoma are: the lack of pagetoid lateral spread; the
proliferation of this area is a dysplastic nevus, which is much absence of mitotic activity in the deep dermal component;
more common on the labia majora than on the labia minora. and the evidence of dermal nevocytic differentiation
888 Skin tumors
There are problems however, as the criteria for the diagnosis

MELANOCYTIC LESIONS, MALIGNANT of radial versus vertical growth are variable from study to study,
and are also difficult to apply unless multiple levels are exam-
COMMON TYPES OF MELANOMA ined. The most commonly used criteria are that a melanoma
will be in radial growth phase if there are no dermal mitoses and
the dermal melanocytic nests are smaller than the junctional
CLINICAL FEATURES
nests. In general, the intradermal cells are confined to the papil-
Malignant melanoma is the third most common cutaneous lary dermis. The criteria are also difficult to apply where there
malignancy, and is capable of causing metastasis and death. is significant regression, pseudoepithelial hyperplasia of the
The incidence has increased over the past two decades across epidermis, or when there is a nevoid dermal component as in a
the world, and this is thought to be related to changes in pre-existing intradermal nevus.
lifestyle and increased exposure to UVB radiation. Mutations Treatment of malignant melanoma
in the BRAF (v-raf murine sarcoma viral oncogene homolog
B1) have been described in malignant melanoma, and this was In-situ melanomas are treated by surgical excision with 5mm
initially thought to be a crucial step in melanocytic neoplasia; margins.
however, recently these mutations have also been described in Management of vertical-phase melanoma includes wide exci-
benign nevi. The highest incidence is in Australia, and the UK sion, with margins (in centimeters) equivalent to the depth in
has an intermediate risk with an incidence of 10.6 cases per millimeters of the lesion, up to 2 cm. Lesions deeper than 2 mm
100 000 population for men and 13.1 cases per 100 000 popu- are still managed by a 2-cm further excision.
lation for women. This represents increases of 303% and Sentinel lymph node biopsy is an increasingly established pro-
187%, respectively, over the past 25 years. The most common cedure in the management of melanoma. The technique detects
tumor site for men is the trunk, whereas for women the leg is the sentinel lymph node by lymphoscintigraphy and/or blue dye.
the preferential site. Although the approach is in its early stages, it has been stated
Melanoma can occur in childhood and adolescence, but is that the status of the node has important prognostic implica-
exceptionally rare in these age groups. Adults are most com- tions. Examination of the nodes within each individual labora-
monly affected, and are usually post-pubertal, though no age tory is still controversial and requires standardization. However,
group is exempt. it usually involves examination of four or more H&E-stained
The risk factors include a family history of melanoma sections at different levels, together with S-100 protein and
(including the atypical mole syndrome), presence of multiple either (or both) melan-A or HMB-45 staining. Examination of
nevi, and excessive exposure to UV light – especially as a child. further levels with additional immunohistochemistry reveals
The incidence of total regression in melanoma is unknown, but more positivity, and this is a worthwhile exercise in those cases
many lesions do show evidence of partial regression on histo- with thick primary melanomas that one would suspect to have
logical examination. Regression of skin tumors is likely to be micrometastasis. Dendritic cells are also positive with S-100
mediated by activated CD4⫹ T-lymphocytes, possibly via protein, but are usually uniformly distributed within the node
cytokine secretion. and have different immunostaining characteristics compared
Clinically worrying features are any change in a pigmented with melanocytic cells. Nerve bundles and nodal nevi need to
lesion, including increasing size, irregular shape and outline, be excluded, as the former are S-100 protein-positive and the
bleeding, and variable coloration within the lesion. The lesion latter are both S-100 protein- and melan-A-positive. The areas
may also be amelanotic. The clinical features should be in the node should be compared to the H&E sections and the
regarded with increasing suspicion with increasing age. primary lesion if available. Nerve bundles are usually easy to
The prognosis of melanoma is based on clinical and histo- recognize, but nodal nevi cells are more problematic. Features
logical parameters: suggesting nevi are the H&E appearance, whilst on immuno-
histochemistry the cells appear to be in a straight line. Although
● Clinical parameters: women have a better prognosis than the nevi are said to occur within the capsule, they can be seen
men, even after all other factors have been taken into within the node as there is cross-cutting and the capsule is a
account. Lesions from the trunk and head and neck have a three-dimensional structure. The PCR examination of sentinel
poorer prognosis than those from the limbs, with the lymph nodes may prove to be a better diagnostic tool for the
exception of the acral and subungual regions. Lesions from detection of micrometastasis.
the lower-leg regions of women have a relatively good Sentinel node sampling is recommended for lesions where
prognosis, for example in comparison with the male trunk. thickness is ⭓1 mm.
Prognosis deteriorates with increasing age.
● Pathological parameters: these include Breslow depth In-situ melanomas
(in millimeters), Clark levels of invasion (I–V), ulceration, Acral lentigenous melanoma in situ: this is the in-situ phase of
regression, vascular invasion, mitotic activity and adequacy acral lentiginous melanoma. The lesions occur on the palm,
of excision. Another prognostic factor is the differentiation sole and subungual sites, and are quite unusual in Caucasians.
of radial and vertical growth phase. The former results in a Clinically, there may be a delay in the diagnosis of the subun-
very low incidence of metastases, whilst the latter has a gual types as they are frequently misdiagnosed, usually as a fun-
considerable potential for metastatic disease. gal infection or subungual hemorrhage. These acral melanomas
Melanocytic lesions, malignant 889
usually affect older adults as they are not associated with expo-
sure to UV radiation.
In-situ melanoma arising in a pigmented lentigenous nevus
with atypia is a specific clinicopathological entity, with the clin-
ical picture of a pigmented lesion on the trunks of men and the
legs of women.
Lentigo maligna occurs on the head and neck of elderly or
middle-aged individuals who have had significant sun exposure.
Clinically, there is an irregular and variably pigmented lesion.
Mucosal melanoma in situ: melanomas at mucosal sites are
relatively uncommon, and UV light is not thought to play a
part in their pathogenesis. The most common sites are vulvo-
vaginal and oral mucosa.
Superficial spreading melanoma in situ is the most common
type of in-situ melanoma, and occurs in adults of all ages,
usually on the trunk and limbs.
In-situ melanomas (a)

Acral lentigenous melanoma in situ: histologically, there is a very
subtle lentiginous proliferation of initially cytologically banal
melanocytes along the basal layer. The epidermis shows epider-
mal psoriasiform hyperplasia. The diagnosis may well be missed
histologically, particularly in the subungual site as the prolifera-
tion is subtle and there is frequently mild cytological atypia.
In-situ melanoma arising in a pigmented lentigenous nevus
with atypia: histologically, there is elongation of the rete ridges,
increased basal layer pigmentation and a junctional melanocytic
component with variable features, which with severe architec-
tural and cytological atypia can evolve into melanoma in situ.
The transformation into melanoma in situ is usually associated
with patchy flattening of the epidermis.
Lentigo maligna: histologically, the epidermis is usually
atrophic, with sun damage to the dermal collagen. There is in
addition a lentiginous proliferation of melanocytes along the (b)
basal layer of the epidermis, and this extends down the hair fol-
licle structures. Since the epidermis is atrophic, the melanocytes Figure 12.62 (a, b) Lentigo maligna. A thin atrophic epidermis
may virtually replace the entire epidermal thickness and mimic with abnormal melanocytes arranged singly and sometimes in small
nests, at the basal layer. An upper dermal inflammatory response is
melanoma in situ. common.
Mucosal melanoma in situ: histologically, the squamous
epithelium is unremarkable, and there is a frequently multi-
focal subtle proliferation of melanocytes within the basal layer. The typical cytology of a common type of melanoma is that
An immediate subjacent lymphocytic infiltrate is characteristic. of plump epithelioid cells and/or spindle cells with abundant
Superficial spreading melanoma in situ: the skin is non- pinkish cytoplasm and cytological atypia. Other cell types can
atrophic, and there is a pagetoid growth both singly and in be present, and when the other cell type predominates, they are
groups of atypical melanocytes at all levels of the epidermis. In called ‘variant melanoma’.
the elderly atrophic skin, forearm and lower limb, the epider- One problem is distinguishing pre-existing nevus from
mis is devoid of its rete pegs, and the melanoma initially grows pseudonevoid maturation within melanomas, which occurs
in a lentiginous pattern that can be easily missed. at the base of the lesion. Features favoring pseudonevoid mat-
uration include the continuity and gradation from the surface
to the deep islands, the low-power nesting pattern, the presence
Invasive melanomas of cytological atypia, mitoses and apoptosis (single cell death)
Acral lentigenous melanoma, lentigo maligna melanoma, and the presence of a host reaction including the presence of
mucosal melanoma, melanoma in pigmented lentigenous nevus plasma cells.
and superficial spreading melanoma: these have an invasive Nodular melanoma: this tumor is frequently polypoidal, and
dermal component in addition to the in-situ disease. has no recognizable in-situ or radial phase.
890 Skin tumors
(a)
Figure 12.63 Clear cell melanoma. Clear cell changes in

melanoma may result in misinterpretation as other tumors with
clear cell features.
In-situ melanoma
● Atypical nevi
● Bowen’s disease variants
● Extramammary Paget’s disease
● Mycosis fungoides
● Pagetoid and junctional Spitz nevi

(b)
● Pigmented spindle cell nevi
● Senile lentigo
Figure 12.64 (a, b) Superficial melanoma in situ. Upward spread
● Simple lentigo of singly arranged or collections of abnormal melanocytes, some of
● Special-site nevi which show mitotic figures (arrows).
● UV-irradiated nevi
● Melanocytic hyperplasia in sun-damaged skin. The most
valuable criteria for the diagnosis of melanoma in situ, as

opposed to melanocytic hyperplasia, are presence of nests of
melanocytes, irregular distribution of melanocytes, descent of
melanocytes far down adnexal epithelial structures, irregular
distribution of pigment, presence of melanocytes above the
junction, a high number of melanocytes, pleomorphism of
melanocytes, and atypical nuclei of melanocytes
Invasive melanoma
● Atypical fibroxanthoma
● Bednar tumor
● Benign nevi
● Mastocytoma
● Poorly differentiated squamous cell carcinoma
● Epithelioid sarcoma
● Cutaneous leiomyosarcoma
● Lymphoma
Special techniques
Figure 12.65 Lentigo maligna melanoma. A very thin epidermis
Immunohistochemistry is a very valuable tool in melanocytic with abnormal basal melanocytes and very early invasive cells in the
pathology as melanomas can mimic other malignant neoplasms upper dermis.
(a)
Figure 12.66 Inflammatory nevus-like malignant melanoma.The
malignant cells are incorporated between heavy lymphocytic cells.
(a)
(b)
Figure 12.68 (a, b) Melanoma, superficial spreading-type.This

clearly demonstrates upward epidermal invasion by epithelioid
melanoma cells, with dermal invasion.
and other skin tumors can mimic melanocytic lesions. It is use-

ful to employ a panel of immunostains when dealing with a
poorly differentiated malignant tumor:
● S-100 protein is the most sensitive marker, staining benign
and malignant melanocytic lesions strongly and diffusely,

including desmoplastic melanoma.
● Melan-A is very specific for benign and malignant lesions,
(b)
but does not usually stain desmoplastic melanomas. It is
Figure 12.67 (a, b) Melanoma commonly shows pseudoalveolar very useful in heavily inflamed lesions (for example, halo
pattern and cellular pleomorphism, including the presence of nevi) and in diagnosis of in-situ lesions. In the latter,
multinucleated cells. melan-A reveals the architecture to help in making the
892 Skin tumors
lesions are blue-black nodules and can be very large, they occur
over a wide range of ages, and have no specific anatomic loca-
tion. They can result in metastasis and death, but their exact
biological behavior is as yet unknown.
Animal-type melanoma is a predominantly dermal lesion,
although some have an epidermal component. The tumor is
composed of confluent sheets of heavily melanized cells with
large nuclei and irregularly thickened nuclear membranes, coarse
chromatin, with prominent nucleoli. Mitoses are infrequent.
● Blue nevus
● Deep-penetrating nevus
BALLOON CELL MELANOMA
Figure 12.69 Malignant melanoma. Nesting is an important CLINICAL FEATURES

feature of melanocytic lesion. Notice also the intranuclear inclusion
(circled). Balloon cell melanoma is an uncommon variant of malignant
melanoma. Although it is generally believed that balloon
melanoma cells represent a degenerative change, the immuno-
diagnosis, and also clearly delineates the lesion so as to histochemical and electron microscopic findings suggest that
determine excision margins. the balloon tumor cells are most likely metabolically active
● HMB-45 is a marker of melanocyte activation. Its staining melanocytic cells.
pattern is variable, but may be of some help as with Ki-67 The prognosis of this variant of melanoma usually correlates
in trying to discriminate between pre-existing nevus and with the tumor thickness, similar to that in other histological
pseudonevoid maturation at the base of a melanoma. types. Recognition of this type of melanoma is important
Junctional melanocytes are positive, but the benign because of its malignant biological behavior.
intradermal component does not usually stain (compare
with melanomas). There are, however, numerous
exceptions – including Spitz nevi – where both junctional
and intradermal elements express HMB-45. Balloon cell melanoma shows variable numbers of large, round
● Some melanomas may exhibit an aberrant to polygonal cells with abundant, clear, often vacuolated
immunophenotype and may express cytokeratins, desmin, cytoplasm containing fine melanin granules and variable
and SMA, KP1 (CD68), CEA, EMA and VS38. amounts of lipid. Although mitoses may be found, sometimes
● Very rarely, neurofilament protein and glial fibrillary acidic the nuclear atypia is minimal. Finding areas of conventional
protein (GFAP) positivity may be seen. melanoma within the lesion aids diagnosis.
● Immunostaining for p53 and Ki-67 antigen may be helpful
to identify individuals with thick nodular melanomas who Differential diagnosis
are at risk of metastatic disease.
● Balloon cell nevus
● Clear cell hidradenoma
VARIANT MELANOMAS ● Clear cell dermatofibroma
● Clear cell sarcoma of soft parts
Melanomas exhibit a wide range of histological appearances,
● Hibernoma
and can mimic benign neoplasms including benign nevi and
● Xanthoma
other malignant neoplasms of variable histogenesis.
● Xanthogranuloma
● Sebaceous neoplasms
ANIMAL-TYPE MELANOMA ● Metastatic renal cell carcinoma
● Malignant clear cell acrospiroma
● Malignant granular cell tumor
CLINICAL FEATURES
● Granular (clear) cell basal cell carcinoma
This is a rare variant of melanoma, which mimics melanomas ● Clear cell syringoma
that occur in horses and laboratory animals. Clinically, the ● Atypical fibroxanthoma
(a) (b)
Figure 12.70 (a, b) Balloon cell melanoma. Superficial spreading malignant melanoma with balloon cell change.
DESMOPLASTIC MELANOMA ● Fibrosarcoma

● Desmoplastic leiomyosarcoma
● Desmoplastic squamous cell carcinoma
CLINICAL FEATURES ● Neurothekeoma
Desmoplastic neurotropic melanoma is an uncommon cuta- ● Scar
neous melanoma variant with pronounced neurotropism. The ● Sclerosing blue nevus
lesions arise commonly on the sun-exposed areas of the head ● Desmoplastic Spitz nevus
and neck region, usually of elderly individuals, and frequently
are associated with an overlying lentigo maligna. Clinically, the Special techniques
lesion has been described as having an innocuous appearance, ● Unlike other melanomas, the dermal component is only
frequently described as an indurated discoid papule, plaque or S-100 protein-positive, and is usually negative for melan-A
nodule. and HMB-45.
Desmoplastic neurotropic melanoma is a locally aggressive ● Some melanomas may express CD34.
type of melanoma with a high risk of local recurrence that can
be radioresponsive. The incidence of distant metastasis is low,
so aggressive treatment to control local disease is warranted.
MERKEL-LIKE SMALL CELL MELANOMA
This may include surgery plus adjuvant radiation therapy or
definitive radiotherapy for unresectable recurrences. CLINICAL FEATURES
Malignant melanomas with the cellular morphology similar to
PATHOLOGICAL FEATURES (Figures 12.71 and 12.72) Merkel cell carcinoma have been described, both in children
and in adults. They have also been reported in the sinonasal
Desmoplastic melanoma shows primarily spindle-shaped
tract. They appear to have a poor prognosis.
melanoma cells embedded in a fibrous stroma. The lesion is
poorly circumscribed, predominantly dermal, and deeply infil-
trating (usually ⬎4 mm) into the fat. The component cells are PATHOLOGICAL FEATURES (Figures 12.73 and 12.74)
spindle, usually showing enlarged atypical nuclei. Mitotic fig- The tumors are composed of sheets of undifferentiated hyper-
ures are usually present. Perineural invasion by tumor cells is chromatic cells with a high mitotic rate.
a frequent method of spread. The presence of deep lymphoid
follicles is a clue to the diagnosis at low-power magnification.
Differential diagnosis ● Merkel cell carcinoma – which would show ‘dot’ positivity
● Fibromatosis with CK20 (cf. small cell carcinoma)
● Dermatofibrosarcoma protuberans ● Metastatic small cell carcinoma
894 Skin tumors
(a)
(a)
(b)
(b)
Figure 12.72 (a, b) Desmoplastic melanoma.This may be

pigmented and show a neurotropic pattern.
MYXOID MELANOMA
CLINICAL FEATURES
Malignant myxoid melanoma is a rarely reported variant of
malignant melanoma which can often be confused with other
mucin-containing neoplasms. The prognosis appears to be equiv-
(c) alent to that of other primary melanomas. Diagnosis of this
entity requires a high index of suspicion. It has been postulated
Figure 12.71 (a–c) Desmoplastic melanoma.The lesion may be
missed as keloid or other benign fibroblastic lesion; close that mast cells and secretion of transforming growth factor-beta
examination discloses the junctional component. stimulate the fibroblast secretion of mucin, which contributes to
(a) (b)
Figure 12.73 (a, b) Melanoma; angiomatoid features. Cell dissociation results in pseudovascular spaces.
(a) (b)
Figure 12.74 (a, b) Melanoma; small cell-type. Small cell melanoma consists of cells reminiscent of nevus cells, but they lack maturation
and exhibit mitotic figures.
the tumor’s invasive potential. Myxoid melanoma shows no spe- composed of small stellate cells in cords, nests or acini. Only
cific age or sex preference, and most lesions appear to occur on tumors with more than 50% of the lesion being replaced by a
the trunk, although all other areas also appear to be represented. myxoid stroma appear to offer a diagnostic problem. S-100
protein is positive in all cases.
In the primary lesion, myxoid melanoma has been defined as a Differential diagnosis
melanoma that shows abundant basophilic acidic mucin in the ● Other myxoid tumors of skin
stroma in more than 15% cross-sectional area. Areas of con- ● Metastatic mucoid carcinoma
ventional melanoma are also present. The myxoid areas are ● Soft tissue sarcoma
896 Skin tumors
(a) (b)
Figure 12.75 (a, b) Myxoid melanoma.This is a recurrent melanoma which can be mistaken as myxoid soft tissue tumor, in particular
malignant peripheral nerve sheath tumor (MPNST).
Special techniques is frequently dysplastic nevus or melanoma. Histologically,

● The tumor cells are S-100 protein- and vimentin-positive, the junctional component is usually typical of superficial
but HMB-45-negative. spreading melanoma or lentigo maligna. The dermal
component is composed of expansile nests of small
hyperchromatic cells with a high nuclear to cytoplasmic
NEVOID MELANOMA VARIANTS ratio. Mitotic figures may only be sparse.
CLINICAL AND PATHOLOGICAL Differential diagnosis

FEATURES (Figures 12.76 and 12.77) ● Benign nevi
● Atypical nevi
Pseudonevoid melanomas are a heterogeneous group of
melanomas which resemble nevi at scanning power, and as
such are a potential cause for serious diagnostic error. The term REGRESSED MELANOMA
‘minimal deviation melanoma’ has in the past been used for
this group of lesions, but because of the vagueness of the diag-
nostic criteria, its use has in general declined. CLINICAL FEATURES
There are three groups of nevoid melanoma: Some melanomas undergo regression – either partial or
1. Verrucous or verrucous keratosis melanoma: these are complete – noted clinically by the area of depigmentation within
frequently submitted as a viral wart or seborrheic the melanoma. The incidence of partial regression varies between
keratosis, and are sent as shave biopsies or curettings. series, but it appears to be more common in thin lesions, and in
These lesions appear to behave as conventional melanoma. males, particularly from the back. When examining leg lesions,
At scanning power, they have a warty architecture and care must be taken to distinguish the vascular changes of vari-
resemble warty intradermal nevi. At higher power, they cose skin from the vascular changes of regression.
have the cytological features of typical melanoma and
usually have a radial growth phase, with or without
dermal invasion.
2. Dome-shaped nevoid melanoma: this frequently has a solid Histologically, there are two stages of regression with overlap.
growth pattern with smaller cells and little in the way of a The active stage is characterized by an intense lichenoid lym-
junctional component. There is a lack of maturation, and phohistiocytic attack on the melanocytes with apoptosis. There
mitotic figures are usually present in the dermal component. may be secondary epidermal changes with acanthosis and pallor.
Metastasis in this group has also been described. Late regression is characterized by epidermal atrophy, patchy
3. Small cell melanoma (non-Merkel like): this occurs in residual junctional component, horizontal dermal fibroplasia,
adults, is usually dome-shaped, and the clinical impression melanin deposition and increased vertically orientated dermal
(a) (b)
Figure 12.76 (a, b) Cellular blue nevus-like melanoma. Heavily pigmented melanoma may be misinterpreted as cellular blue nevus.
(a) (b)
Figure 12.77 (a, b) Pseudonevoid melanoma.The cells are small and uniform, but mitotic figures are clearly seen on close examination.
blood vessels. The diagnosis of completely regressed melanomas SIGNET RING MELANOMA
can usually only be made when there has been a metastatic
deposit and no obvious primary and the biopsied lesion only
shows heavy melanin pigment deposition and scarring. CLINICAL FEATURES
The prognosis of melanomas with regression remains Signet ring cell melanoma is a rare morphological variant of
unclear, but several studies have indicated that regression in melanoma. It thus has histological mimicry with other tumors
thin melanomas indicates a poorer prognosis. featuring signet ring cells.

● Blue nevus (late regression) This variant of melanoma shows numerous pleomorphic tumor
● Halo nevus (actively regressing lesion) cells with large, intracellular vacuoles and oval to spindle-shaped
898 Skin tumors
nuclei at their periphery. Mitotic figures and multinucleated VARICOSE MELANOMA

melanocytes are common.
Differential diagnosis CLINICAL FEATURES

● Signet ring cells are found in a variety of cutaneous Melanomas that arise on the background of stasis dermatitis
neoplasms, including primary cutaneous squamous and can be overlooked both clinically and histologically. Clinically,
basal cell carcinoma and melanoma, as well as in the skin is thin, pigmented and prone to ulceration.
metastatic adenocarcinoma.
● Signet ring lymphoma PATHOLOGICAL FEATURES
Special techniques Histologically, there are background varicose changes of epider-

mal atrophy, sloughing of the epidermis, intense proliferation of
● Some of the signet ring cells exhibit cytoplasmic PAS-
small thick-walled blood vessels, lymphocytic infiltrate, iron
positivity, but they do not contain Alcian blue-positive
deposition and dermal fibrosis. In the superficial aspects of the
mucin.
biopsies there is usually a clue to the diagnosis of melanoma.
● Immunohistochemistry shows a positive reaction of the
In the deeper aspects, in the reticular dermis, there may be groups
tumor cells for S-100 protein, HMB-45 and vimentin.
of melanocytes which mimic benign nevus cells.
● The tumor cells are negative for CKs, EMA and CEA.
● Electron microscopy showed only empty spaces in all cases.
● Stasis dermatitis
SPITZOID MELANOMA
Special techniques
CLINICAL FEATURES ● S-100 protein staining usually confirms the melanocytic
Spitzoid melanoma includes, first a lesion that has the clinical and nature of these lesions.
histological patterns of a Spitz nevus but with many atypical
features, hence ‘spitzoid melanoma’ or where a Spitz nevus has
resulted in a metastasis. Spitzoid melanoma in teenagers can be MELANOCYTIC LESIONS, PREMALIGNANT
distinguished from Spitz nevus if strict criteria are followed. Spitz
nevus is a benign melanocytic lesion that shares many histologi- ATYPICAL NEVI: DYSPLASTIC NEVUS
cal features with melanoma. While Spitz nevi characteristically
occur in children and young adults and melanomas in the middle-
(NEVUS WITH ARCHITECTURAL AND
aged and elderly, either tumor can occur in patients of any age. CYTOLOGICAL ATYPIA)
Spitzoid melanoma does not show a better prognosis than other
types of melanoma if the follow-up is sufficiently prolonged.
CLINICAL FEATURES
PATHOLOGICAL FEATURES Dysplastic nevus is a very controversial entity, with major
divergent opinions among melanoma experts as to its existence
In many cases, the histopathological diagnosis of Spitz nevus is
and, if it does exist, to the diagnostic criteria, prevalence and
straightforward, particularly in small lesions displaying many
clinical significance. While there is general acceptance of the
or all of the typical histological features and occurring in young
concept of dysplastic nevi in the context of the familial
patients. Tumors that deviate from the classic description, how-
melanoma syndromes, the problem is the acceptance, as an
ever, cause difficulties in diagnosis.
entity, of similar lesions occurring sporadically in members of
Features favoring Spitz nevus are: presence of symmetry;
the general population. Some studies have stated that 50% of
Kamino bodies; and uniformity of cell nests or sheets from side-
the caucasian population have sporadic dysplastic nevi. There
to-side. Features in favor of melanoma are: the presence of abnor-
is also controversy – even among the believers – as to whether
mal mitoses; a dermal mitotic rate of more than two per mm2, and
these individual lesions are markers of risk of subsequent devel-
mitotic figures within 0.25 mm of the deep border of the lesion.
opment of melanoma or a precursor, or both. Furthermore,
Despite this, in some cases it may not be possible to give an
there is poor clinicopathological correlation.
unequivocal diagnosis.
The family members of dysplastic nevus syndrome or atypi-
cal mole syndrome not only have a risk of development of
melanoma but also have numerous pigmented skin lesions
● Spitz nevus which have specific clinical and histological features of atypical
or dysplastic nevi. A percentage of these families have been
Special techniques shown to have a genetic abnormality. This is present on the
● Immunohistochemical stains for HMB-45 and Ki-67 short arm of chromosome 9, where the causation gene
sometimes help in distinguishing Spitz nevus from spitzoid CDKN2, which encodes a protein (p16) that is important in
melanoma. cell cycle control, lies.
Melanocytic lesions, premalignant 899
The clinical criteria for the diagnosis of these lesions are: A related lesion called lentiginous dysplastic nevus of the eld-
● Size ⬎5 mm and at least two of three other erly – also termed pigmented lentiginous nevus with atypia – is
characteristics: a related lesion that has been probably in the past (and still is)
● Variable pigmentation confused histologically with dysplastic nevus in practice.
● Irregular asymmetric outline
● Indistinct borders Differential diagnosis
● Early pigmented spindle cell nevus (PSCN)
PATHOLOGICAL FEATURES (Figure 12.78) ● Pagetoid and junctional Spitz nevi
● Pigmented lentiginous nevus with atypia
Dysplastic nevi show the following histological features: lentig-
● Recurrent nevi (pseudomelanoma)
inous and nesting proliferation; random cytological atypia;
● Special-site nevi
host lymphocytic response; proliferation of dermal capillaries;
● Superficial spreading melanoma in situ
delicate elongation of rete ridges and fusion of adjacent rete;
● UV-irradiated nevi
narrow elongated spindle-shaped melanocytes orientated hori-
zontally; and lamellar fibroplasia around rete pegs.
The problem with the histological criteria is that they are PIGMENTED LENTIGINOUS NEVUS WITH ATYPIA
subjective and open to individual interpretation, and that some
of the criteria for the diagnosis are found in ordinary nevi. CLINICAL FEATURES
Also, over time the criteria have drifted – particularly the
requirement for cytological atypia. Some authors have stressed These lesions are thought to be a specific clinicopathological
that it is not one single histological feature but rather the com- entity occurring on the trunk of males and lower limbs
bination of features that is crucial for the diagnosis and corre- of females in older individuals. These lesions are felt to be true
lates well with the clinical features. precursors of melanoma, and are frequently over 10 mm in
size. The provisional diagnosis is usually atypical nevus versus
superficial spreading melanoma. Such lesions have been pre-
viously classified as dysplastic nevi, atypical melanocytic
hyperplasia, atypical melanocytic proliferation, atypical lentig-
inous melanocytic proliferation or premalignant melanosis.

Histologically, there is elongation of rete pegs, intense basal pig-
mentation, and a variable lentiginous melanocytic component
ranging from mild, moderate and severe architectural atypia to
(a)
(a)
(b)
Figure 12.79 (a, b) Pigmented lentigenous nevus. A pigmented
Figure 12.78 (a, b) Dysplastic nevus. A junctional nevus junctional nevus with some architectural irregularity characterizes this
showing mild architectural disorder and fibrolamellar fibrosis. type of nevus.
900 Skin tumors
Figure 12.80 Acquired digital fibrokeratoma. A dome-shaped

lesion with a collagenous core covered by thick keratotic layers.
(b) closely packed collagen bundles; (ii) a variant with an increased

number of fibroblasts in the cutis; and (iii) a type with an ede-
Figure 12.79 (Continued). matous and poorly cellular structure. The core of the lesion is
devoid of adnexal structures. The overlying epidermis shows
in-situ melanoma. The cytological atypia is usually mild to secondary hyperplasia and hyperkeratosis.
moderate. There is usually a mild to moderate lymphocytic
response. A pre-existing intradermal nevus may be present. Differential diagnosis
● Extranumerary digit (which frequently contains a portion
Differential diagnosis of bone in the deep aspect)
● Spindle cell nevus of Reed ● Digital fibromas of tuberous sclerosis
● Dysplastic nevus ● Solitary periungual angiofibroma
● Thin melanoma ● Onychomatricoma
● Melanoma in situ
FIBROUS PAPULE OF THE NOSE AND FACE
MESENCHYMAL TUMORS
CLINICAL FEATURES
FIBROBLASTIC/MYOFIBROBLASTIC Fibrous papules of the nose and face are a distinctive clinico-
pathological entity that most probably represents an inflam-
ACQUIRED DIGITAL FIBROKERATOMA matory rather than a neoplastic process, sharing some
histological features of angiofibromas (angiofibrosis) and peri-
follicular fibromas (perifollicular fibrosis). The lesion presents
CLINICAL FEATURES as a dome-shaped nodule on the nose, around the nasolabial
Acquired digital fibrokeratoma is an uncommon benign soli- folds, and on the cheeks that may be mistaken clinically for
tary fibrous lesion that characteristically involves the digits of intradermal nevus or sometimes for basal cell carcinoma.
the hands and feet, and rarely other locations such as the heel
and nail beds. It may be confused clinically with supernumer- PATHOLOGICAL FEATURES (Figure 12.81)
ary digits, fibroma, neuroma or neurofibroma. Fibrous papule of the nose or face is a slightly raised hypo-
Garlic-clove fibroma is perhaps the same entity as acquired cellular upper dermal lesion. It consists of a loose edematous or
digital fibrokeratoma. Treatment involves shave excision under slightly myxoid stroma containing scattered stellate cells
local anesthesia. The lesion may rarely recur after excision. located superficially – sometimes with giant cells – together
Acquired digital fibrokeratoma may result from a neoforma- with small numbers of telangiectatic vessels. There may be
tion of collagen by the fibroblasts. occasional perivascular dermal lymphocytic infiltrate.
PATHOLOGICAL FEATURES (Figure 12.80) Differential diagnosis

This is an elevated, dome-shaped lesion that discloses three ● Angiofibroma
histological variants: (i) a tumor composed of thick dense and ● Regressed intradermal nevus
Mesenchymal tumors 901
lesion shows diffuse, fascicular or storiform patterns similar to

inflammatory pseudotumors of lung and other tissues. High
endothelial venules are seen adjacent to germinal centers and
areas of mononuclear cell infiltration. The centers are bcl-2
negative (compare with follicular lymphoma on p. 656).
Secondary features
● Variable degrees of central fibrosis may be present, giving
these lesions the low-power appearance of lymph nodes.
Cell morphology
● Mixed cellular infiltrate including plasma cells,
lymphocytes, eosinophils, and neutrophils.
● Background population of immature fibroblasts and
(a)
myofibroblasts.
● Xanthomatous cells may be seen.
● Dermatofibroma
● Cutaneous malignant lymphoma
● Cutaneous lymphoid hyperplasia
● Dermatofibrosarcoma protuberans
● Adult myofibromatosis
● Angiolymphoid hyperplasia with eosinophilia
● Foreign-body reaction
● Insect bite
● Superficial soft-tissue lymph node
(b) KELOIDS AND HYPERTROPHIC SCAR

Figure 12.81 (a, b) Fibrous papule of the nose. A polypoid skin
lesion, the core of which shows prominent vessels with CLINICAL FEATURES
myofibroblasts (within the box).
Keloids are a common lesion arising from sites of previous
● Non-specific dermal reaction trauma, and are a considerable source of morbidity because of
● Collagenoma continued growth of lesions, pruritus, and physical appear-
ance. Clinically, keloids are distinguished from scars in that
Special techniques they demonstrate continued growth over the borders of the
original injury. Keloids appear with increased frequency in
● The stromal cells are vimentin- and actin-positive.
patients of African and Asian descent. Currently, no entirely
satisfactory method of treatment exists for these lesions. The
INFLAMMATORY (PSEUDOTUMOR) mechanisms underlying the pathogenesis of keloids have not
MYOFIBROBLASTIC TUMOR OF THE SKIN been fully characterized. A few studies have shown that the
immune system is actively involved in the development of these
lesions. Other studies have suggested that hypertrophic scars
CLINICAL FEATURES and keloids are hypoxic, undoubtedly due to the microvascular
Cutaneous inflammatory pseudotumor is an extremely rare, occlusion. Hypoxia may stimulate excessive production of col-
idiopathic benign lesion which occurs on the extremities or the lagen, which forms the bulk of these lesions, from fibroblasts
neck of adult individuals. It presents as a solitary skin lesion. and myofibroblasts.
Available methods of treatment include external superficial
radiotherapy, interstitial irradiation, intralesional steroid injec-
tions, cryotherapy, ultrasound, systemic chemotherapy, zinc
These are well-circumscribed spindle cell lesions located in the tape strapping, pressure, and silicone gel. Any of these could be
superficial subcutis or in the reticular dermis, and surrounded used alone or in combination with other forms of treatment.
by a dense peripheral rim of lymphocytes and plasma cells. Surgical excision is not usually recommended since it results in
Peripheral germinal centers are present in some cases. The further collagen deposition.
902 Skin tumors
PATHOLOGICAL FEATURES (Figure 12.82) damaged skin of the face and scalp of the elderly, and has rarely
been reported on the extremities of younger people. It usually
Keloids are fairly well-circumscribed hypocellular, hyalinized
presents as a rapidly growing, solitary, ulcerated polypoid
collagenous dermal nodules, the margins of which merge into
lesion. AFX has an excellent prognosis following complete
the adjacent dermal collagen. The collagen of the lesion has a
excision. However, should the lesion exceed more than 2 cm,
homogeneous and glassy appearance, and its superficial com-
recur in deeper locations and show histological necrosis, it
ponent runs parallel to the surface epithelium. The overlying
should be considered to be a malignant fibrous histiocytoma.
epidermis is usually thin and atrophic, but is sometimes normal
or hypertrophic. Spindle-shaped or stellate and sometimes
multinucleated myofibroblasts are scattered between the fasci- PATHOLOGICAL FEATURES (Figures 12.83 and 12.84)
cles of collagen, more noticeably in early lesions. Atypical fibroxanthoma is an exophytic or slightly raised,
expansile, fairly well-defined intradermal nodule with an
Differential diagnosis epidermal collaret. It consists of a pleomorphic population of
● Longstanding dermatofibroma
● Fibroma durum
● Hypertrophic scar (more cellular, with collagen, which is
less glassy)
● Pleomorphic fibroma
● Collagenoma
● Circumscribed storiform collagenoma (sclerotic fibroma)
Special techniques
● Negative staining with CD34, Factor XIIIa and S-100
protein can help to differentiate scars from
dermatofibrosarcoma protuberans, dermatofibroma and
desmoplastic malignant melanoma, respectively.
● Smooth muscle alpha-actin staining is variable in scar tissue.
FIBROHISTIOCYTIC TUMORS
ATYPICAL FIBROXANTHOMA (AFX) (a)
CLINICAL FEATURES
Atypical fibroxanthoma (AFX) is a fibrohistiocytic and myofi-
broblastic tumor of intermediate malignancy, and is generally
considered to be a superficial non-metastasizing variant of
malignant fibrous histiocytoma. It occurs mainly in actinically
(b)
Figure 12.83 (a, b) Atypical fibroxanthoma. A subepidermal

Figure 12.82 Keloid.Thick bundles of glassy collagenous fibers is pleomorphic spindle cell tumor with numerous mitotic figures,
the hallmark of keloid. including atypical ones (encircled).
spindle and epithelioid cells arranged in fascicles together with ● Numerous typical and atypical mitotic figures are a
a variable number of mono and multinucleated bizarre giant characteristic feature.
cells. The overlying epithelium often shows focal ulceration or ● An inflammatory cell infiltrate and foamy macrophages
sometimes pseudoepitheliomatous hyperplasia. Pilosebaceous are often present.
units and eccrine glands are usually seen compressed at the ● Some AFX may show numerous multinucleated osteoclast-
base of the lesion. The presence of intravascular or perineural like giant cells scattered uniformly through a pleomorphic
invasion, extensive necrosis, and infiltrative margins should cellular proliferation.
rule out the diagnosis of atypical fibroxanthoma. Numerous ● Intracytoplasmic PAS-positive eosinophilic hyaline globules
telangiectatic vessels are usually present near the surface. It is may be seen in the cells located in the superficial
not uncommon to see dysplastic actinic keratosis and/or inva- subepidermal part of the lesion.
sive squamous carcinoma located towards one edge in the
superficial dermis. Differential diagnosis
Several variants of AFX have been recognized: ● Typical examples of AFX, both the pleomorphic and
● Monomorphic spindle cell variant consists predominantly
monomorphic variants, may be mistaken for spindle cell
of monomorphic spindle cells. cancers of the skin (most often spindle cell melanoma,
● Pigmented variant represents a poorly recognized variant
spindle cell squamous cell carcinoma, and
of the neoplasm that may be easily misinterpreted as leiomyosarcoma)
malignant melanoma. The neoplastic cells show ● The clear cell variant may be mistaken as balloon cell
erythrophagocytosis and accumulation of hemosiderin melanoma, sebaceous carcinoma, pleomorphic
pigment in the cytoplasm. liposarcoma, chordoma, parachordoma, tricholemmal
● Clear cell variant consists of sheets of large cells with
carcinoma and clear cell squamous cell carcinoma
foamy cytoplasm and hyperchromatic, polypoid nuclei ● The pigmented variant may be mistaken for malignant
manifesting frequent and atypical mitoses. melanoma
Secondary features Special techniques

● Hemorrhage. ● The cells show immunoreactivity for vimentin, MSA and
● Edema, especially of the superficial component. SMA, CD68, alpha-1-antitrypsin, and sometimes for EMA.
● Focal myxoid change. ● A small number of S-100 protein-positive dendritic cells
● Actinic change of the overlying epidermis. may be seen in some cases.
● Lymphatic stromal infiltrate. ● The neoplastic cells are negative for squamous epithelial
markers including CK5/6. The latter is a good marker for
Cell morphology spindle cell carcinoma if the other epithelial markers fail to
● The spindle cells form 10–90% of the cell populations. show positivity.
They have plump ovoid or elongated nuclei, with very ● The neoplastic cells are negative for melanocytic markers
prominent nucleoli. (S-100 protein, HMB-45, and melan-A).
● Epithelioid cells are numerous.
FIBROUS HISTIOCYTOMA/DERMATOFIBROMA
CLINICAL FEATURES
Dermatofibroma/benign fibrous histiocytoma is one of the
most common cutaneous soft tissue tumors. It represents a
benign fibrohistiocytic proliferation which may be either single
or multiple. Dermatofibroma is most commonly seen on the
extremities as a slowly growing nodule or induration which
may show a mild degree of pigmentation. It is rarely found in
the soft tissue and parenchymal organs as a slowly growing
mass. The lesion is cured by conservative excision.
Atypical fibrous histiocytoma represents potential pitfalls for
overinterpretation as pleomorphic sarcoma, which would
appear to be inappropriate in most cases. Provided that atypical
fibrous histiocytoma is treated by complete excision, a benign
outcome is to be expected in most cases. However, similar to the
cellular and aneurysmal variants of fibrous histiocytoma, atypi-
Figure 12.84 Monomorphic atypical fibroxanthoma (AFX).
Unlike classic AFX, which is clearly pleomorphic and indistinguishable cal fibrous histiocytoma shows a higher tendency to recur locally
from malignant fibrous histiocytoma (MFH), this variant shows little than ordinary fibrous histiocytoma, and may rarely metastasize.
or no pleomorphism.
904 Skin tumors
Deep fibrous histiocytoma is a rare and usually painless neo- PATHOLOGICAL FEATURES (Figures 12.85–12.88)
plasm found in adults; it may affect either soft tissue or bone,
Dermatofibroma may present with a wide variety of architec-
and is typically noted during the fifth decade of life.
tural, cellular or stromal peculiarities. Architectural features
The palisading cutaneous fibrous histiocytoma often occurs
include: deep penetration, atrophy, collarette formation, fasci-
in an acral location.
cular to plexiform architecture, massive hemorrhage, promi-
Combined dermatofibroma is a tumor comprising two or
nent hemangiopericytoma-like vascularity and palisading;
more variant patterns of dermatofibroma in a single lesion.
cellular peculiarities such as the presence of epithelioid cells,
Recognition of this variant allows the histopathologist to apply
clear cells, granular cells, prominent myofibroblastic differenti-
a confident benign label to unusual lesions which might other-
ation and atypical giant cells (‘monster cells’); or stromal pecu-
wise elude diagnosis, or tempt the description of ‘new’ entities
liarities such as prominent sclerosis, mucin, hemosiderin and
and to avoid a misdiagnosis of malignancy.
cholesterol deposits.
(a) (c)
(b) (d)
Figure 12.85 (a–d) Dermatofibroma (fibrous histiocytoma), classic type.There is marked elongation of the rete ridges, with basaloid
induction.The lesion itself is dermal, consisting of collagen and variable cellularity.
(a) (b)
Figure 12.86 (a, b) Dermatofibroma. Classic type, consisting of fibrohistiocytic cells with Touton giant cells.The mitotic figure is encircled in (b).
(a) (b)
Figure 12.87 (a, b) Dermatofibroma; hemosideritic/telangiectatic variant. Hemorrhagic spaces with deposition of excessive hemosiderin
pigment (shown by iron staining in (b)) are formed within an ordinary dermatofibroma, resulting in a pseudovascular pattern.
(a) (b)
Figure 12.88 (a, b) Epithelioid dermatofibroma.The cells are plump and epithelioid.This may be mistaken as Spitz nevus.
906 Skin tumors
Dermatofibroma in general is an ill-defined dermal lesion that cells evenly distributed within the dermal collagen and
blends imperceptibly into adjacent dermal collagen. It consists of tending to cluster around blood vessels and interdigitate
spindle cells arranged in vague storiform or short intersecting with one another in a jig saw puzzle arrangement. The
fascicles with a loose, criss-cross pattern. The stroma consists of nuclei are typically eccentrically located, with vesicular
a delicate network and small curved and thick bundles of colla- chromatin and small nucleoli. Spindle cells with similar
gen fibers. Foamy histiocytic cells, Touton or foreign-body giant features may be seen. Occasional binucleate cells are seen,
cells, xanthomatous cells and lymphocytes are scattered through- and mitotic figures are sparse. The overlying epidermis is
out the lesion, and vary greatly in number. Iron deposition is usually thin with focal hyperkeratosis and parakeratosis.
common in the macrophages and giant cells. Longstanding Ulceration of the epidermis is occasionally seen.
lesions are usually purely fibroblastic. The overlying epidermis ● Dermatofibroma with prominent myofibroblastic
often exhibits basal pigmentation and can be normal or atrophic, differentiation (dermatomyofibroma) (see Chapter 13, Soft
but is usually acanthotic and may show features indistinguish- tissue tumors).
able from those of early superficial basal cell carcinoma. The ● Lipidized-type fibrous histiocytoma is composed mainly of
cells include fibroblasts and fibrocytes, foamy histiocytes con- foamy cells distributed among keloidal collagen bundles. This
taining lipid and hemosiderin pigment, Touton giant cells, and type usually presents as a yellowish nodule around the ankle.
sometimes osteoclast-like giant cells. Atypical, hyperchromatic ● Palisading fibrous histiocytoma, as the name suggests,
monster cells may sometimes be seen. Up to 10 mitoses per exhibits nuclear palisading with the formation of Verocay-
10 HPF can be seen in cellular fibrous histiocytoma. like bodies in addition to the more typical features of the
According to the above-mentioned architectural and cytolog- ‘fibrous’ variant of cutaneous fibrous histiocytoma.
ical criteria, several distinctive variants of benign fibrous histio- ● Combined dermatofibroma exhibits two or more variant
cytoma have been described: patterns in complex or in homogeneous combination such
● Angiomatoid or aneurysmal fibrous histiocytoma is as the silhouette of a deep-penetrating dermatofibroma
characterized by the presence of slit-like or hemorrhagic with an ‘ordinary’ storiform pattern in the upper and
spaces, usually in the center or superficial part of the lesion, granular cell differentiation in the lower part of the
and is associated with extensive hemosiderin deposition. lesion; or a dermatofibroma with ordinary features in the
● Atypical fibrous histiocytoma/dermatofibroma with upper, prominent sclerosis in the middle and clear cells in
‘monster’ cells shows a proliferation of pleomorphic, the lower portion of the lesion; or the characteristic
plump, spindle, and/or polyhedral cells with mainly large, epidermal collarette and cells of epitheliod cell histiocytoma
hyperchromatic, irregular, or bizarre nuclei, set in a with a plexiform (‘neurothekeoma-like’) architecture
background of classic features of fibrous histiocytoma, surrounded by a myxoid stroma with spindle-shaped to
including spindle cell areas showing a storiform pattern stellate cells.
and entrapped thickened, hyaline collagen bundles,
especially at the periphery. Multinucleated giant cells, Differential diagnosis
often with bizarre nuclei and foamy, sometimes
The wide variety of architectural and cytological appearances
hemosiderin-rich, cytoplasm are also variably present.
of dermatofibromas may cause great difficulties in delineation
The degree of pleomorphism varies from only focal and
from a variety of benign and malignant tumors.
minimal or moderate to marked. Mitotic figures range
from 1 to 15 per 10 HPF. Atypical mitoses may be seen in Classic dermatofibroma may be mistaken for:
some lesions. Furthermore, some cases of atypical fibrous ● Dermal scar tissue
histiocytoma display other worrisome features less often ● Sclerosing (dermatofibroma-like) Spitz nevus
observed in ordinary fibrous histiocytoma, including ● Dermal neurofibroma
unusually large size (diameter ⬎2 cm) involvement of the ● Juvenile xanthogranuloma
superficial subcutis, and geographic necrosis. ● Hemangioma
● The cellular variant shows a well-demarcated, slightly ● Pseudoxanthoma elasticum
multinodular lesion centered in the reticular dermis, with ● Dermal leiomyoma
the constituent cells being more densely packed. This ● Dermatofibrosarcoma protuberans (unlike fibrous
lesion usually lacks prominent vascularity and epidermal histiocytoma, it shows a regular, lace-like/honeycomb or
changes. multilayered pattern of extension into subcutaneous
● Deep-penetrating fibrous histiocytoma differs from tissue). It has a classic storiform architecture and generally
cutaneous fibrous histiocytoma by being fairly well- lacks macrophages, lipid or iron. There is no overlying
circumscribed, and showing storiform architecture and spared papillary dermis or overlying epidermal
a hemangiopericytomatous vascular pattern. hyperplasia. The cells express CD34
● Epithelioid histiocytoma perhaps represents a benign ● Common blue nevus
tumor of dermal dendrocytes, hence a suggested name of ● Plexiform fibrohistiocytic tumor
‘dermal dendrocytoma’. Epithelioid fibrous histiocytoma ● Dermal extension of fibromatosis
is a symmetrically well-demarcated, raised dermal nodule ● Intradermal nodular fascitis
with epidermal collarette bordering most of the lesion. It ● Connective tissue nevus
consists of uniform large polygonal or spindle epithelioid ● Desmoplastic melanoma

Angiomatoid dermatofibroma: affect deep soft tissue, muscles and internal organs. It usually
● Angiomatoid fibrous histiocytoma presents as a red or yellowish-brown papule or papules in the
● Kaposi’s sarcoma skin of the head and neck or extremities. Multiple lesions are
more commonly seen in early childhood.
Atypical and cellular dermatofibroma: It is widely held that JXG is a proliferative disorder of den-
● Dermatofibrosarcoma protuberans drocytes, possibly dermal dendrocytes; thus, its clinical and
● Malignant fibrous histiocytoma pathological similarities to Langerhans’ cell histiocytosis are
● Superficial malignant peripheral nerve sheath tumor not entirely unexpected in light of the most recently proposed
● Smooth muscle tumor international classification of histiocytic disorders, which includes
JXG and Langerhans’ cell histiocytosis together as ‘dendritic cell-
Deep fibrous histiocytoma may mimic: related’ histiocytoses (non-Langerhans’ histiocytoses).
● Smooth muscle or stromal tumors (in cases of intra- PATHOLOGICAL FEATURES

abdominal variant of deep fibrous histiocytoma) Juvenile xanthogranuloma can be situated in either the skin or
● Solitary myofibroblastoma in adults
subcutaneous tissue. The cutaneous lesion is characterized by
an ill-defined, dermal infiltrate, consisting of sheets of benign-
Epithelioid fibrous histiocytoma can be mistaken for: looking epithelioid histiocytes, varying numbers of Touton
● Spitz nevus giant cells, focal aggregates of xanthomatous cells, oncocytic-
● Reticulohistiocytoma
looking mono and multinucleated cells, varying degrees of
● Epithelioid hemangioma
interstitial fibrosis, and a mixed inflammatory infiltrate. The
● Typical dermatofibroma
deeper lesion is more circumscribed, tends to blend with and
● Atypical fibroxanthoma
infiltrate the surrounding muscle, and may have fewer Touton
● Juvenile xanthogranuloma
giant cells and abundant eosinophils. Occasionally, the lesion
● Cellular neurothekeoma
has a storiform pattern.
● Histiocytosis X
Early-stage lesions are generally highly cellular and
● Epithelioid sarcoma
monomorphous with sheet-like appearance of vacuolated cells.
This variant is sometimes labeled as the mononuclear variant
● Metastatic or primary rhabdoid tumor
of JXG.
Interstitial fibrosis and microcalcification may rarely be seen.
Palisading fibrous histiocytoma:
● Schwannoma
Cell morphology
Special techniques ● In early lesions the histiocytes have eosinophilic cytoplasm,
● Iron pigment is particularly prominent in the aneurysmal but they gradually acquire vacuolated xanthomatous
variant. cytoplasm. The nuclei are bland and vesicular, and may
● Dermatofibromas are consistently positive with KiM1p, show grooves or folds, or they are kidney-shaped.
variably positive for Factor XIIIa, smooth muscle-specific ● Touton giant cells are typical of this lesion.
actin and with KP1 (CD68), NK1C3 and E9. ● Bi-, tri-, or multinucleated cells with irregularly distributed
● The spindle cells are negative for S-100 protein, desmin, nuclei are also seen.
and CD34 (QBEnd 10). ● Spindle cells intermingled among the mononuclear cells or
● Anti-metallothionein (MT) antibody has recently been forming short fascicles may be seen in both cutaneous and
recognized as a marker in a variety of tumors, and is extracutaneous lesions.
found to be positive in fibrous histiocytoma in comparison ● Mixed inflammatory cells, predominantly lymphocytes but
with dermatofibrosarcoma protuberans. also eosinophils, polymorphs and plasma cells, are
frequently seen.
● Mitotic figures are rare or absent.
HISTIOCYTIC TUMORS
JUVENILE XANTHOGRANULOMA (JXG) ● Histiocytosis-X (the xanthomatous reaction seen rarely in
this condition)
● Xanthoma
CLINICAL FEATURES ● Fibrous histiocytoma
Juvenile xanthogranuloma (JXG) is a benign, self-limiting and ● Epithelioid histiocytoma
regressing histiocytic disorder that is seen primarily – though ● Reticulohistiocytic granuloma
not exclusively – throughout the first two decades of life. The ● Neurofibroma and schwannoma (from deep juvenile
tumor occurs principally as a solitary cutaneous lesion, and can xanthogranuloma)
908 Skin tumors
Special techniques presents as skin nodules, especially on the elbow, and is not
The cells are: associated with hyperlipidemia.
● uniformly positive for vimentin, CD68, fascin, and Factor
XIIIa; PATHOLOGICAL FEATURES (Figure 12.89)

● negative for CD1a, CD3, CD21, CD34, or CD35; and
● often, but not always, S-100 protein-negative.

Plexiform xanthoma is an exophytic, multinodular, dermal or
subcutaneous lesion with a distinct plexiform arrangement. It is
composed of various admixtures of uniform epithelioid and xan-
PLEXIFORM XANTHOMA thomatous cells with inconspicuous nuclei. Most of the plexiform
nodules measure 0.5–2 mm. On rare occasions, cholesterol clefts,
necrosis, sparse inflammation and multinucleated Touton giant
CLINICAL FEATURES cells are present. Rarely, the lesion completely lacks xanthoma
cells and thus resembles an epithelioid tumor.
Plexiform xanthoma is a type of xanthoma characterized by a
plexiform growth pattern imparting a neoplastic appearance. It
Secondary features
● A sparse lymphocytic infiltrate.
● Focal stromal fibrosis.
Cell morphology
● The cells are round with prominent foamy cytoplasm and
inconspicuous nuclei.
● Occasional multinucleated giant cells may be seen.
● Schwannoma
● Neurofibroma
Special techniques
● The lesions are KP1- (CD68) and vimentin-positive.
● Lysozyme, S-100 protein, HMB-45, EMA, cytokeratins, Factor
VIIIrag, CD34, MSA, smooth muscle alpha-actin, desmin
(D33), desmin (Der-11), chromogranin, synaptophysin,
(a) neurofilament protein, and GFAP are negative.
(b) (c)
Figure 12.89 (a–c) Plexiform xanthoma. Nodular dermal lesion consisting of xanthomatized cells.
RETICULOHISTIOCYTIC GRANULOMA AND

MULTICENTRIC RETICULOHISTIOCYTOSIS
CLINICAL FEATURES
Reticulohistiocytosis is a benign proliferative process of histio-
cytic origin. It occurs in adults, and is found in two forms:
1. Reticulohistiocytic granuloma, presenting as one or more
nodules in the head and neck region.
2. Multicentric reticulohistiocytosis is a rare disorder which
presents with a rapidly destructive, sometimes permanently
debilitating, polyarthritis and a papulonodular eruption,
generally of the face and hands. The active disease
typically resolves spontaneously after 5–8 years, but the
(a)
articular destruction can lead to permanent joint
deformities.
Congenital self-healing reticulohistiocytosis is a variant of

Langerhans’ cell histiocytosis. It is present at birth, or appears
during the neonatal period and involutes spontaneously within
3–4 months. Although the skin eruptions in most cases consist
of papulonodules, several patients with vesicular or bullous
lesions have been reported.

Reticulohistiocytic granuloma is an ill-defined dermal lesion con-
sisting of a collection of large mononuclear and multinuclear
histiocytic cells intermixed with other inflammatory cells such
as lymphocytes, eosinophils and neutrophils. More mature
(b)
lesions contain numerous giant cells and fewer inflammatory
cells. The histiocytic cells are often separated by thin bands of
basement membrane-like material.
Cell morphology
● Mononuclear histiocytes have abundant, eosinophilic
granular ‘ground-glass’ cytoplasm.
● Multinucleated giant cells with pale finely granular,
‘ground-glass’ cytoplasm and two or more irregularly
arranged nuclei.
● Lymphocytes.
● Eosinophils.
● Neutrophils.
Differential diagnosis (c)

● Juvenile xanthogranuloma
● Fibrous histiocytoma Figure 12.90 (a–c) Reticulohistiocytic granuloma. A dermal lesion
consisting of mono and multinucleated epithelioid histiocytes with
● Atypical fibroxanthoma abundant glassy cytoplasm separated by prominent collagen.
● Sclerosing Spitz nevus
VERRUCIFORM XANTHOMA
Special techniques
● The histiocytic cells are best characterized on
CLINICAL FEATURES
immunohistochemistry by their immunoreactivity for
vimentin, CD68 and CD45, and their non-reactivity for Verruciform xanthoma is a rare lesion of unknown etiology
S-100 protein, CD34, and Factor XIIIa. that is typically solitary and predominantly located within the
910 Skin tumors
oral cavity. Less commonly, these lesions arise on the skin, with propria. The xanthomatous cells have a distinct cell membrane, a
the majority of cases occurring in anogenital sites. They can be round or oval nucleus, and no conspicuous nucleolus.
confused clinically with verruca vulgaris, condyloma, leuko-
plakia, verrucous carcinoma, and squamous cell carcinoma. Differential diagnosis
HPV 6 has recently been reported in association with this con- ● Balloon cell nevus
dition. Verruciform xanthoma affects a wide age range, and
may occur in association with a variety of cutaneous or Special techniques
mucosal disorders including epidermolysis bullosa, pemphigus ● Sudan black highlights the fat present within the cells.
vulgaris, lichen planus, squamous cell carcinoma, sun-damaged
skin and lymphedema.
LYMPHORETICULAR TUMORS
Verruciform xanthoma has a striking papillary or verruciform ACTINIC RETICULOID
exophytic growth pattern, with thickening of the involved non-
dysplastic mucosal or skin squamous epithelium. Within the
CLINICAL FEATURES
submucosa or the papillary dermis there is an accumulation of
foamy xanthomatous cells. The overlying epithelium is intensely Actinic reticuloid is considered as the most severe variant of
eosinophilic. Secondary inflammation and parakeratosis are chronic actinic dermatitis. It is probably of multifactorial ori-
commonly seen. On occasion, the lesion has a flat surface. gin, and involves contact allergic, photoallergic, phototoxic,
Telangiectatic vessels may be seen in the dermal papillae or the immunologic and metabolic processes. The lesions most com-
submucosa. Although epidermal atypia is not a characteristic monly affect the dorsum of the hands and the head and neck
finding, squamous cell carcinoma has rarely been reported in region (mainly the face) of middle-aged and elderly patients,
association with verruciform xanthoma. predominantly men. It presents as persistent infiltrated papules
and plaques on light-exposed skin, often with extension
Differential diagnosis to non-exposed areas. It may also present with generalized
● Viral wart erythroderma, and can be associated with generalized lym-
● Squamous papilloma phadenopathy. Actinic reticuloid usually runs a chronic course,
● Verrucous carcinoma rarely undergoes spontaneous resolution, can be improved rap-
● Granular cell tumor idly by strict avoidance of light, and is currently treated with
● Other variants of xanthoma oral psoralens and long-wave UV radiation in the A range
(PUVA), UV-B, azathioprine, and also cyclosporine.
Special techniques
● The cells contain abundant lipid material (positive with oil PATHOLOGICAL FEATURES
red O staining on frozen-section material), and are also ● Skin: the histological appearance depends on the severity
weakly positive with PAS after diastase. and age of the reactions. A mild reaction shows non-
● A mucin stain is negative. specific acute or chronic dermatitis. Fully established
lesions show dense and extensive band-like, perivascular
XANTHELASMA and periadnexal dermal and sometimes subcutaneous
lymphocytic infiltrates. The overlying epidermis is often
acanthotic and diffusely infiltrated by lymphocytes which
CLINICAL FEATURES in places may simulate Pautrier microabscesses, and may
Xanthelasma (xanthoma) are small, non-neoplastic nodules rarely exhibit spongiosis and parakeratosis. Some cases
resulting from an accumulation of fat-laden histiocytes. They show numerous multinucleated giant cells, thereby
are thought to be idiopathic, and only rarely may be a mani- imparting a granulomatous appearance to the lesion.
festation of hypercholesterolemia. Scattered multinucleated stellate myofibroblasts are also
Xanthomas occur mainly in the skin and tendons; however commonly seen.
they may occur in other locations such as around the eyes, the
● Blood: lymphocytes with increased nuclear indentation
stomach, aryepiglottic fold and the bladder. Mucosal xantho- reminiscent of Sezary cells may be present in the blood.
mas may be related to previous surgery or trauma.
● Lymph nodes: the histological changes in lymph nodes are,
in the majority of cases, in the form of dermatopathic
lymphadenitis. Occasionally, cerebriform cells are seen in
the paracortical areas.
Xantholasma consists of an ill-defined accumulation of closely
packed, large, polygonal, foamy or reticulated cells in the upper Cell morphology
dermis. Xanthomas are usually larger, and the foamy cells lie in ● The main cell population consists of lymphocytes with
the papillary and reticular dermis. In cases of mucosal xanthomas nuclei slightly larger than normal, and with marked
the foamy cells are also seen in the upper part of the lamina nuclear indentation.
● Blast cells are regularly seen. Intermediate

● Plasma cells and eosinophils can be present. Large B-cell lymphoma of the leg (EORTC)/diffuse large B-cell
● Mitotic figures may be seen. lymphoma (REAL/WHO)
● Multinucleated stellate myofibroblasts are usually seen in
Provisional
the chronic active phase of the disease (these may be
Intravascular large B-cell lymphoma
involved in elastolysis as elastic fibers seem to disappear in
Plasmacytoma
the areas adjacent to giant cells).
● Multinucleated giant cells may also be seen. Primary cutaneous T-cell lymphoma (PCTCL)
Indolent
Mycosis fungoides
● Non-specific dermatitis Mycosis fungoides-follicular mucinosis
● Mycosis fungoides Pagetoid reticulosis
● Sezary syndrome Large cell CTCL, CD30-positive
● Granulomatous reaction Anaplastic
● Cutaneous peripheral T-cell lymphoma Immunoblastic
Pleomorphic
Special techniques Lymphomatoid papulosis
● There may be excess CD8⫹ cells; this is especially seen in Aggressive
patients with generalized erythroderma. Sezary’s syndrome
● Occasional B lymphocytes may be seen. Large cell CTCL, CD30-negative
● Numerous macrophages are usually detected in the upper Immunoblastic
dermis. Pleomorphic
● IgE⫹ dendritic dermal Langerhans’ cells are often seen
among the infiltrates. Provisional
● Gene rearrangement analysis, in combination with Granulomatous slack skin
immunohistochemistry, may be an important adjunct in CTCL, pleomorphic small; medium-sized
differentiating between actinic reticuloid and cutaneous T-cell Subcutaneous panniculitic T-cell lymphoma
lymphoma. In patients suspected of having actinic reticuloid,
the application of both techniques is recommended. PRIMARY CUTANEOUS B-CELL LYMPHOMA (PCBCL)
CLINICAL FEATURES
CUTANEOUS LYMPHOMAS
Primary B-cell lymphomas of the skin are defined as malignant
Primary cutaneous T- and B-cell lymphomas are a heteroge- B-cell proliferations presenting with cutaneous involvement
neous group of diseases with varied clinical presentations and alone, with no evidence of extracutaneous manifestations over
prognosis. The use of new molecular, histological, and clinical a period of at least six months when complete staging has been
criteria has enhanced the recognition of primary cutaneous performed. The major subtypes are follicle center-cell lym-
T- and B-cell lymphomas. Compared to their nodal counterpart, phoma, marginal zone lymphoma, and large B-cell lymphoma
they have a different clinical behavior, and therefore require a of the leg (EORTC classification, 1997). Primary B-cell lym-
different approach to treatment. Independent predictive factors phomas of the skin differ significantly from nodal lymphomas,
identified clinically, histologically, and by immunopheno- and especially with respect to their clinical behavior.
immunogenotyping are essential to assess the appropriate
treatment for each subtype. The European Organization for
Indolent PCBCL
Research and Treatment of Cancer (EORTC) Cutaneous Follicle center cell lymphoma (EORTC)/follicular lymphoma
Lymphoma Study Group has provided a classification of cuta- (REAL/WHO): this is usually found in the head and neck region
neous lymphomas, taking into account both histological and or the trunk, and presents as non-scaling, solitary or grouped
molecular features. (For the WHO classification, see Chapter papules, plaques, and/or tumors. The lesions gradually increase
10, Lymphoreticular tumors, p. 668.) in size over years. Dissemination to extracutaneous sites is
uncommon.
EORTC CLASSIFICATION OF CUTANEOUS LYMPHOMAS Immunocytoma (EORTC) marginal zone lymphoma (REAL/
WHO): this type of PCBCL presents as solitary or multiple
Primary cutaneous B-cell lymphoma (PCBCL) cutaneous or subcutaneous lesions, usually on the extremities.
Indolent
Follicle center cell lymphoma (EORTC)/follicular lymphoma
Intermediate PCBCL
(REAL/WHO) Large B-cell lymphoma of the leg (EORTC)/diffuse large B-cell
Immunocytoma (EORTC) marginal zone lymphoma (REAL/ lymphoma (REAL/WHO): B-cell lymphomas of the lower limbs
WHO) appear as a special subgroup with a prognosis that is possibly
912 Skin tumors
worse than that of primary cutaneous B-cell lymphomas located of variable numbers of large B-cell lymphocytes, centroblasts,
on the trunk, arms or head, with more frequent relapses. large centrocytes, and immunoblasts.
● Intravascular large B-cell lymphoma (see Chapter 10,
Provisional Lymphoreticular tumors, p. 703).

● Intravascular large B-cell lymphoma (see Chapter 10, ● Plasmacytoma (see below).
Lymphoreticular tumors, p. 703).

● Plasmacytoma (see below).
● Cutaneous lymphoid hyperplasia (lymphocytoma cutis)
PATHOLOGICAL FEATURES (Figure 12.91) ● Lupus erythematosus profundus
● Gyrate erythemas
Follicle center cell lymphoma (EORTC)/follicular lymphoma
(REAL/WHO): this is composed of follicle center cells includ-
ing a mixture of centrocytes (small and large cleaved cells) and
centroblasts (large cells with prominent nucleoli). These are
distributed in nodular or diffuse pattern with sparing of the
epidermis. The proportion of the constituent cells varies
according to the age and size of the lesion. Early and small
lesions show a mixture of small centrocytes, few centroblasts
and many reactive T cells. Neoplastic follicles are rare, but
remnants of reactive follicles may be seen. Rapidly growing
lesions usually shows monotonous population of large follicle
center cells with numerous centroblasts, large centrocytes,
multilobated cells and immunoblasts.
Immunocytoma (EORTC)/marginal zone lymphoma (REAL/
WHO): this shows nodular or diffuse infiltrates of small lym-
phocytes, plasmacytoid lymphocytes and plasma cells.
Centrocytes, centroblasts and immunoblasts may be seen in
variable numbers.
Large B-cell lymphoma of the leg (EORTC)/diffuse large
B-cell lymphoma (REAL/WHO): these show diffuse infiltrates
(b)
(a) (c)
Figure 12.91 (a–c) Primary cutaneous B-cell lymphoma (PCBCL). Follicle center cell lymphoma ‘EORTC’/follicular lymphoma
(REAL/WHO).This shows dense lymphoid infiltrate throughout the dermis, with sparing of the epidermis.The infiltrate shows significant
numbers of small lymphocytes admixed with numerous large lymphocytes with cleaved or centroblast-like nuclei.The large cells are CD20-,
CD10-, bcl-6- and bcl-2-positive.The small lymphocytes are mostly of T-cell lineage.
● Reactive polyclonal plasma cell hyperplasia PATHOLOGICAL FEATURES

● Non-epidermotropic cutaneous T-cell lymphoma
The lymphomatous infiltrate occurs predominantly in the sub-
● Leukemic infiltrate of the skin
cutaneous fat, and consists of variably sized (usually small to
● The inflammatory reaction around the inclusions of
medium-sized) atypical lymphocytic cells.
molluscum contagiosum may be notably atypical.
Multiple levels may be needed before the virally infected
Cell morphology
cells are seen
● The neoplastic lymphoid cells may consist of either a
monomorphous population or a variable mixture of small,
Special techniques medium-sized, and large cells.
Follicle center cell lymphoma ‘EORTC’/follicular lymphoma ● Apoptosis is a prominent feature.
‘REAL/WHO’:
● CD20- and CD79a-positive. Differential diagnosis
● CD10- and/or bcl-6-positive.
● Other cutaneous lymphomas
● CD23-positive/-negative.
● Panniculitis (e.g., erythema nodosum)
● CD5-, cyclineD1-negative.
● Bcl-2 variable (positive in ⬎70%).

Special techniques
● t(14;18) variable but low (⬍10–40%).
● The cells are positive with pan T-cell markers, and also for
Immunocytoma ‘EORTC’/extranodal marginal zone lym- the cytotoxic granule protein T-cell intracellular antigen-1
phoma ‘REAL/WHO’: and granzyme B.
● CD20- and bcl-2 positive. ● The cells are EBV-negative, both by immunostaining
● CD23 variable.
(latent membrane protein-1) and by in-situ hybridization
● CD5-, CD10-, cycline-D1- and bcl-6-negative.
(EBV-encoded mRNA).
● Trisomy 3 in some, t(11;18). ● PCR gene analysis reveals a T-cell clone.
Large B-cell lymphoma of the leg ‘EORTC’/diffuse large B-cell
lymphoma ‘REAL/WHO’: GRANULOMATOUS SLACK SKIN
● CD20-positive.
● CD10, bcl-6 more common in upper-body lesions.
● CD23-positive/-negative. CLINICAL FEATURES

● CD5- and cycline-D1-negative.
Granulomatous slack skin is an extremely uncommon form of
● Bcl-2 significantly more frequent on the leg.
cutaneous T-cell lymphoma, currently regarded as a variant of
● t(14;18) rarely reported.
mycosis fungoides. It affects younger individuals than conven-
tional mycosis fungoides, and shows a striking male predomi-
nance. It classically affects the flexural areas of axilla and
PRIMARY CUTANEOUS T-CELL LYMPHOMA (PCTCL) groin, but may also affect the back, hands and eyelids, pre-
senting as ‘boggy’ plaques which gradually become pendulous
The majority of primary cutaneous lymphomas come under the wrinkled folds with erythematous scaly surface. The lesion may
mycosis fungoides/Sezary syndrome category, but a number of slowly evolve into systemic T-cell lymphoma.
clinicopathological entities have been described. These are
listed below in alphabetical order.
The striking feature of this lesion is the presence of numerous
CUTANEOUS/SUBCUTANEOUS non-caseating granulomas involving the dermis and subcuta-
PANNICULITIC T-CELL LYMPHOMA neous or sometimes the underlying muscular tissue. These
granulomas consist of histiocytes, multinucleated giant cells
and small numbers of lymphocytes. The multinucleated giant
CLINICAL FEATURES cells contain a remarkable number of nuclei (up to 90 nuclei
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an per cross-section) that are present in the center of the cell or
uncommon type of cytotoxic T-cell lymphoma of the skin with form a circular ring. The mononuclear histiocytes may form a
an aggressive natural history. In the World Health wreath around the giant cells. The epidermal changes resemble
Organization classification of T-cell and natural killer cell lym- those seen in conventional mycosis fungoides. Focal calcifica-
phoma, SPTCL is listed as an example of extranodal lym- tion of residual elastic fibers may sometimes be seen.
phoma. It generally carries a poor prognosis, despite standard
anthracycline-based chemotherapy. Cell morphology
The tumor affects adults, and presents with deep skin nod- ● The multinucleated giant cells have an ample amount of
ules. The disease is often localized, but a potentially fatal cytoplasm which may contain phagocytosed lymphocytes
hemophagocytic syndrome may supervene. or histiocytes.
914 Skin tumors
● The mononuclear histiocytes have oval or deeply grooved atypical lymphoid cells, ulceration and necrosis.
nuclei. Endothelial swelling of small vessels and extravasation of
● The lymphocytes have irregularly folded or cerebriform, red blood cells are often seen.
hyperchromatic nuclei. ● Early lesions usually lack atypical lymphoid cells and show
minimal epidermal change.
Differential diagnosis ● Resolving lesions are usually devoid of atypical cells, and
show a moderate superficial perivascular infiltrate and
● Granuloma annulare
fibrosis in the papillary dermis.
● Xanthogranuloma
● Sarcoidosis The cellular infiltrate is variable in character, but characteristi-
● Other infectious granulomatous disease cally contains large blast-like cells.
Special techniques Secondary features

● Elastic tissue staining reveals almost complete loss of the ● There is mild degree of vascular injury in the form of
elastic fibers. endothelial swelling, luminal obliteration and
● Both the mononuclear histiocytes and the multinucleated extravasation of fibrin and red blood cells.
giant cells stain for CD68 and Mac 387.
● The multinucleated giant cells shows striking thick cell Cell morphology
membrane staining for CD45, CD43 and CD45RO. The cellular infiltrate contains a variable mixture of the fol-
● The small lymphoid cells have the same phenotype as lowing cell types:
those of conventional mycosis fungoides. ● Normal lymphocytes.
● A few B-cells may be present. ● Small- to medium-sized atypical cells (similar to those
typically seen in mycosis fungoides) with hyperchromatic

nuclei often with cerebriform nuclear contour.
LYMPHOMATOID PAPULOSIS ● Large, blast-like cells with abundant eosinophilic cytoplasm,
round, oval or irregularly shaped nuclei containing one or

CLINICAL FEATURES several prominent, often eosinophilic nucleoli.
● Histiocytes.
Lymphomatoid papulosis is currently regarded as a type of ● Neutrophils.
CD30-positive, low-grade cutaneous T-cell lymphoma. However, ● Eosinophils.
because of its benign clinical course (in the majority of cases) ● Atypical mitotic figures are frequently seen in some
and the clinical similarities to pityriasis lichenoides, some lesions.
investigators consider it to be a pseudo-T-cell lymphoma. The
disease occurs at any age, but commonly between the ages of Differential diagnosis
20 and 40 years. It may arise in any cutaneous location, the
● Pityriasis lichenoides
most common being the trunk and limbs, though the face,
● Eczematous dermatitis
palms and soles may also be affected. It has occasionally been
● Large cell CD30-positive cutaneous lymphoma
seen in the oral or genital mucosa.
Lymphomatoid papulosis may be either localized or widespread,
● Atypical regressing histiocytosis (with which it may be
and is characterized by papular lesions, though eczematous
synonymous)
plaques and nodules or even tumors may be seen. These lesions
usually regress, but may persist for several months.
Some 20% of cases are associated with synchronous or
metachronous lymphoma (in the form of mycosis fungoides, Special techniques
Hodgkin’s disease or CD30-positive large cell lymphoma). ● The large cells strongly express CD30 and other activation
The estimated 5 year survival is 100%. The disease is treated antigen, but do not express CD15 (Leu-M1) and EMA.
using topical chemotherapy. ● The small cells express T-associated antigens.
● Many of the blast-like cells show strong expression of
PATHOLOGICAL FEATURES interleukin 2 receptors (CD25).
● T-cell-receptor gene rearrangements can be demonstrated.
The histological features of lymphomatoid papulosis vary con-
siderably, depending on the age of the lesion:
● Fully developed lesions (2–3 weeks old) show a MYCOSIS FUNGOIDES/SEZARY SYNDROME
diffuse/perivascular, superficial/deep, sometimes wedge-
shaped dermal infiltrate that may invade the subcutaneous
CLINICAL FEATURES
tissue. In the superficial dermis a lichenoid pattern with
epidermotropism may be seen. The epidermis may show Mycosis fungoides is a peripheral non-Hodgkin’s T-cell neo-
spongiosis, parakeratosis, and infiltration by typical or plastic process, representing the most common type of primary
cutaneous malignant lymphoma. Neoplastic lesions classically non-specific chronic inflammatory process. The epidermis is
show skin predilection and characteristic clinical and histolog- usually minimally hyperplastic, exhibits focal hyperkeratosis
ical features in patch, plaque, and tumor stages. In addition, and parakeratosis, and lacks the intercellular edema (spongiosis)
several clinicopathological variants of mycosis fungoides have that is often associated with inflammatory dermatoses. Papillary
been delineated, including poikiloderma atrophicans vasculare dermal fibrosis is frequently seen.
(parapsoriasis variegata), Sezary syndrome, granulomatous The plaque stage (mycotic stage) is characterized by a heavy,
mycosis fungoides, hypopigmented mycosis fungoides, follicu- polymorphous, band-like (lichenoid) lymphocytic infiltrate
locentric mycosis fungoides, syringotropic mycosis fungoides, involving the papillary and upper reticular dermis and the epi-
and Woringer–Kolopp disease. dermis. It may also involve skin appendages. The epidermal
The evolution of mycosis fungoides is typically quite slow, infiltrate may be in the form of single cells or clusters (Pautrier
with years between the first manifestations and development of micro-abscesses). The involved epidermis may show marked
advanced stages of the disease. Dissemination to extracuta- pseudoepitheliomatous hyperplasia that may be mistaken for
neous sites occurs at advanced stages of the disease. squamous cell carcinoma. In some cases, the epidermal com-
The etiology of this condition is still unknown. Patients may ponent can be very inconspicuous, or involvement of follicles
live for months to years with skin abnormalities before being may predominate (folliculocentric variant).
diagnosed. Mycosis fungoides/Sezary syndrome is an indolent The tumor stage has two forms:
disease, and patients with T1 disease have a normal life 1. The non-epidermotropic form, which comprises sheets and
expectancy. Patients who undergo transformation to large cell nodules of lymphocytic cells within the dermis, generally
lymphoma (between 8 and 23% of cases) have a poor progno- sparing the epidermis and the papillary dermis, but
sis, with mean survival ranging from 2 to 19 months. destructively involving skin appendages and blood vessels.
The goals of treatment in mycosis fungoides are the relief of 2. The epidermotropic form, which involves both the dermis
symptoms and improvement in cosmetic appearance. Despite and epidermis, and in which the constituent cells are more
some uncontrolled clinical trial results that have been reported polymorphic.
to suggest ‘cures’ for this disease, the general perception
Secondary pustule formation is common, and in some cases
remains that the condition is not curable with currently avail-
can be so florid that the underlying disease is obscured.
able standard therapies. Treatment is divided into topical (skin-
directed) and systemic therapies. The most active systemic
agent for the treatment of mycosis fungoides remains interferon- Lymph node changes
alpha, though many new modalities have recently been approved In the early stages, in addition to dermatopathic lymphadenitis,
to treat CTCL. there may be scattered atypical lymphocytes (resembling the typ-
Mycosis fungoides usually affects adults, is most commonly ical cells of mycosis fungoides – see below) in paracortical areas.
seen on the face or the scalp, and may predominantly involve During the passage of time, these cells increase in numbers to
hair follicles, resulting in alopecia (alopecia mucinosa). displace the other cell populations. Mitotic figures are usually
The patch stage (sometimes termed parapsoriasis en plaques) seen at this stage.
often involves the trunk and extremities, and presents as ery- Late stages may be indistinguishable from peripheral T-cell
thematous, eczema-like lesions that wax and wane and are lymphoma (T-zone pattern).
often refractory to topical treatment. This stage of the disease
is a relatively indolent lesion that may progress slowly over Secondary features
many years, without systemic involvement.
● Papillary dermal fibrosis.
The plaque stage may arise de novo or from pre-existing
● Epidermal hyperplasia.
patches, is characterized by the presence of raised indurated
● Parakeratosis.
and scaly pruritic pink, red or brown lesions, is relatively indo-
● Allergic contact dermatitis may result from topical
lent, and may progress slowly over many years.
treatment with nitrogen mustard.
The tumor stage may develop from untreated patch or
plaque stage or arise de novo. It presents as firm, dome-shaped Unusual secondary histological features include:
nodules on the face, scalp and body folds, and is associated ● Spongiotic vesiculation
with visceral involvement and a poor prognosis. ● Dermal mucin (some cases present as follicular mucinosis
Sezary syndrome is a leukemic variant of mycosis fungoides. with alopecia).

● Granulomas (can be present at any stage of the disease and
can be so extensive that the lesions mimic sarcoidosis).

PATHOLOGICAL FEATURES (Figures 12.92 and 12.93) ● Lichen simplex chronicus (this may result from frequent
rubbing of pruritic lesions of mycosis fungoides, and may

Skin lesions obscure the histological appearance of the lesion).
The patch stage (pre-mycotic stage) is characterized by the ● Formation of bullae.
presence of a sparse but diffuse lymphocytic infiltrate involving ● Vitiligo-like hyperpigmentation.
the papillary dermis, perivascular areas and the epidermis ● Extravasation of erythrocytes and siderophage
(epidermotropism), resembling chronic dermatitis, with occa- accumulation (clinically, this can cause lesions resembling
sional atypical cells and mitoses. The picture may resemble a pigmented purpura).
916 Skin tumors

● The majority of neoplastic lymphocytes are small to Skin lesions
medium-sized, hyperchromatic, and characterized by nuclei During the patch stage, low-grade inflammatory dermatoses
with irregular contours, often deeply indented or such as:
cerebriform.
● Larger immunoblast-like or Reed–Sternberg-like cells may ● Lichenoid dermatitis
be present in the plaque or tumor stages. ● Contact dermatitis
● Variable numbers of eosinophils may be present. ● Chronic lichen planus
● Pityriasis lichinoides chronica
● Dermatitis with superimposed lichen simplex chronicus
During the plaque stage:

● Actinic reticuloid (chronic form of photosensitivity reaction)
● Cutaneous lupus erythematosus
● Pseudoepitheliomatous folliculitis
During the tumor stage:

● Other cutaneous lymphomas
Mycosis fungoides involving lymph nodes:

● Dermatopathic lymphadenitis of other causes
● Systemic peripheral T-cell lymphoma
Special techniques
● Thin sections (1 ␮m) may show better nuclear
morphology.
● The neoplastic T cells express a peripheral T-cell
phenotype, usually CD4⫹/CD8⫺ and often CD7⫺.
● T-cell receptor gene rearrangements can be demonstrated.
● Serial biopsies may prove useful in confirming the
diagnosis in difficult cases of early-stage disease.
(a)
(b) (c)
Figure 12.92 (a–c) Mycosis fungoides, patch stage (pre-mycotic stage).This is characterized by the presence of a sparse but diffuse
lymphocytic infiltrate involving the papillary dermis, resembling chronic dermatitis, with occasional atypical cells and mitoses.The epidermis is
usually minimally hyperplastic, exhibits focal hyperkeratosis and parakeratosis, and lacks the intercellular edema (spongiosis) that is often
associated with inflammatory dermatoses. Papillary dermal fibrosis is frequently seen.
(a) (c)
(b) (d)
Figure 12.93 (a–d) Mycosis fungoides, tumor stage.This is characterized by sheets and nodules of polymorphic lymphocytic cells within the
dermis.The epidermal infiltrate may be in the form of single cells or clusters (Pautrier micro-abscesses).The involved epidermis may show
marked pseudoepitheliomatous hyperplasia.The majority of neoplastic lymphocytes are small to medium-sized, hyperchromatic, and
characterized by nuclei with irregular contours, often deeply indented or cerebriform.
PAGETOID RETICULOSIS lymphoma, leading to severe morbidity and death. Longstanding

lesions may have verrucous surfaces.
CLINICAL FEATURES
Pagetoid reticulosis is an extremely rare form of mycosis fun-
goides that may present clinically as a solitary, indolent plaque- The distinctive features of this lesion are the presence of
like lesion (Woringer–Kolopp), or it may manifest as a more medium- to large-sized, atypical cells infiltrating into the
generalized clinically aggressive condition (Ketron–Goodman lower epidermis. Small lymphocytes are seen in the papillary
disease). The generalized form may develop into systemic dermis.
918 Skin tumors
Secondary features abundant cytoplasm and prominent nucleoli. Reactive lympho-

● Papillary dermal fibrosis. cytes are commonly seen at the periphery of the lesions. On occa-
sion, numerous T lymphocytes, eosinophils and polymorphs are
Differential diagnosis seen. Epidermal hyperplasia can be prominent in such cases.
Special techniques
● Eczematous dermatitis
● Over 75% of the neoplastic cells are CD30-positive.
Special techniques ● EMA and CD15 are negative.
● The cells are CD3⫹, CD4⫺, CD8⫺, CD45RO⫺,
CD45RA⫹, and ultrastructural findings suggest that these
cells are immature T-cells.
PLEOMORPHIC SMALL-/MEDIUM-SIZED CTCL
CLINICAL FEATURES
This variant shows one or multiple red to purplish papules. It
has a favorable prognosis.
The lesion shows a dense infiltrate of small and medium-sized
pleomorphic cells within the dermis, with a tendency to involve
the subcutaneous tissue and epidermotropism.
● Large cell pleomorphic CTCL (⬎30% large cells)
(a)
● Pseudo T-cell lymphoma (the presence of many
CD8⫹ cells, CD20⫹ B cells and histiocytes favors
pseudolymphoma)
Special techniques
● The cells express helper T-cell markers with frequent loss
of pan T-cell markers.
PRIMARY CUTANEOUS CD30-POSITIVE

LARGE T-CELL LYMPHOMA
CLINICAL FEATURES
CD30-positive cutaneous large T-cell lymphoma occurs in
adults, and shows a male predominance. It presents as solitary
(usually ulcerating) nodules or tumors, and has a favorable
prognosis, with complete or partial regression in up to 25% of
cases. Approximately 90% of patients show a 5-year survival.
Radiotherapy is the treatment of choice for localized disease.
Multi-agent chemotherapy is considered for generalized disease.
CD30-positive cutaneous large T-cell lymphoma may (b)
develop from pre-existing mycosis fungoides. Such cases often
have a poor prognosis. Figure 12.94 (a–c) Cutaneous CD30-positive lymphoma.This is
an ulcerated lesion with heavy lymphoid deposit in the dermis with
associated pseudoepitheliomatous epidermal hyperplasia.The cells
PATHOLOGICAL FEATURES (Figure 12.94) are predominantly large, pleomorphic with vesicular nuclei and
prominent nucleoli.The large cells are positive for CD30, CD2, CD4
This shows a diffuse non-epidermotropic infiltration of large, and EMA.They are CD3-, CD5-, CD7-, CD8- and anaplastic
often anaplastic cohesive CD30-positive cells. These have lymphoma kinase (ALK)-negative.
Special techniques
● CD30 is negative or restricted to only a few scattered cells.
● The cells show an aberrant CD4⫹ T-cell phenotype with
variable loss of pan T-cell antigens.
● Most cases show clonally rearranged T-cell receptor genes.
CUTANEOUS PSEUDOLYMPHOMAS
Pseudolymphomas of the skin are inflammatory diseases that
simulate malignant lymphomas either clinically, histopatholog-
ically, or both.
Depending on the predominant cell type in the infiltrate,
cutaneous pseudolymphomas are divided into T- and B-cell
pseudolymphomas.
● Cutaneous T-cell pseudolymphomas include idiopathic
cutaneous T-cell pseudolymphoma, lymphomatoid drug

reactions, lymphomatoid contact dermatitis, persistent
nodular arthropod-bite reactions, nodular scabies, actinic
(c)
reticuloid, and lymphomatoid papulosis.
● Cutaneous B-cell pseudolymphomas include idiopathic
lymphocytoma cutis, borrelial lymphocytoma cutis, tattoo-
induced lymphocytoma cutis, post-zoster scar
● The cells show CD4⫹ T-cell phenotype with variable loss lymphocytoma cutis, and some persistent nodular
of pan T-cell antigens (CD2, CD3, CD5). arthropod-bite reactions.
● Some cases have CD8⫹ cells. The inflammatory infiltrate is band-like, nodular or diffuse,
● Most cases show clonally rearranged T-cell receptor genes. and is composed predominantly of lymphocytes with or with-
out other inflammatory cells.
PRIMARY CUTANEOUS CD30-NEGATIVE

LARGE T-CELL LYMPHOMA CUTANEOUS PSEUDO-B-CELL LYMPHOMA
(LYMPHOCYTOMA CUTIS)
CLINICAL FEATURES
CD30-negative cutaneous large T-cell lymphoma presents as CLINICAL FEATURES
solitary, localized or generalized plaques, nodules, or tumors. Pseudo-B-cell lymphoma (also termed lymphocytoma cutis,
Rapid development of generalized skin lesions is more common cutaneous lymphoid hyperplasia and pseudolymphoma of
than in CD30-positive large T-cell lymphoma. This type of lym- Spiegler–Fendt), in about two-thirds of cases, presents as a soli-
phoma tends to have a more aggressive behavior. Radiotherapy tary nodule, mostly on the face. In other cases it presents as
is considered as initial treatment for localized disease, and several grouped lesions or widespread lesions.
multi-agent chemotherapy is usually recommended. The pres- The lesions vary in size from a few millimeters to several cen-
ence of ⬎80% large pleomorphic cells or immunoblasts is timeters, are usually asymptomatic, have a firm consistency,
associated with a poor prognosis. and may be skin-colored, red or violaceous.
The lesions heal spontaneously, even though they may persist
for months or a few years. Sometimes there may be local recur-
rence. If lesions persist after many years or appear in lymph
This shows diffuse infiltration of large, often pleomorphic cells, nodes or the viscera, then the diagnosis of lymphoma should
with or without epidermotropism, or any angiotropic pattern. be made.
The large cells, which comprise at least 30% of the cell popu- The potential for certain cutaneous pseudolymphomas to
lation, have abundant cytoplasm and prominent nucleoli. progress to CBCL is real. The combination of histological and
immunophenotypic criteria – along with the clinical picture –
remains the best way to judge the aggressiveness of the lesion.
Differential diagnosis Gene rearrangement studies, whether performed by Southern
● Mycosis fungoides with transformation to diffuse large cell blot or PCR, are of limited value and should be used to support
lymphoma (the presence of prior or concurrent patches or the overall clinicopathological picture. Radiation therapy of
plaques is useful in the differential diagnosis) these patients should be considered early in the management
920 Skin tumors
plan, and is a very successful form of treatment when combined clusters of small lymphocytes. This variant is sometimes called
with close follow-up. large cell lymphocytoma. Mitotic figures may be frequent espe-
Pseudo-B-cell lymphoma may sometimes be induced by cially in large cell lymphocytoma.
insect bites.
PATHOLOGICAL FEATURES (Figure 12.95) ● Small lymphocytic lymphoma/chronic lymphocytic
leukemia
Pseudo-B-cell lymphoma consists of a heavy lymphocytic infil- ● Follicular lymphoma
trate in the dermis which sometimes extends into the subcuta- ● Jessner’s lymphocytic infiltration (is regarded by some as
neous tissue, but with a tendency to spare the papillary dermis
pseudo-T- rather than pseudo-B-cell lymphoma because of
and to surround skin appendages and blood vessels. The infiltrate
the immunohistological identification of T lymphocytes.
includes two cell populations: small lymphocytes, and large
These are usually normal-looking lymphocytes)
histiocyte-like cells. These vary in numbers and arrangement, but ● Papulonodular secondary syphilis
may appear intermingled together or arranged in a follicular
pattern with the histiocyte-like cells being at the center and the
lymphocytes at the periphery. If germinal centers are present this
favours a benign diagnosis and the centers are bcl-2 negative. Special techniques
There may be only a few histiocytes, and the picture is dominated ● Both the small lymphocytic and large histiocytic cells
by small lymphocytes, or there may be nodular infiltrates of large express B-cell markers and polyclonal immunoglobulin.
cells with pleomorphic, pale-staining nuclei and frequent mitoses ● Borrelia infection may be confirmed by PCR studies on the
reminiscent of histiocytic lymphoma accompanied by dense skin biopsy.
(a) (c)
(b) (d)
Figure 12.95 (a–d) Lymphocytoma cutis. Pseudo-B-cell lymphoma consists of a heavy lymphocytic infiltrate in the dermis with sparing of
the papillary dermis and arrangement around skin appendages and blood vessels.The infiltrate includes two cell populations: small
lymphocytes, and large histiocyte-like cells.
CUTANEOUS PSEUDO-T-CELL LYMPHOMA reaction, lymphomatoid drug reaction, and in idiopathic

pseudo-T-cell lymphoma. A marked histiocytic component
(often with prominent eosinophils) is seen in insect bite
CLINICAL FEATURES pseudo-T-cell lymphoma.
Cutaneous pseudo-T-cell lymphoma is a reactive lymphocytic Jessner’s lymphocytic infiltration of the skin is characterized
infiltrate of the skin that clinically or histologically simulates by patchy lymphocytic infiltrate. The cells lack cytological
cutaneous-T-cell lymphoma. It may be of unknown etiology atypia and blast formation.
(idiopathic pseudo-T-cell lymphoma), which usually presents
as a solitary lesion, or sometimes as widespread plaques or
papules. This category includes Jessner’s lymphocytic infiltrate. Differential diagnosis
On the other hand, it may have an identifiable etiology such as: ● Mycosis fungoides (mycosis fungoides-like pattern should
● Drug-induced pseudolymphoma (generalized skin eruption, be distinguished from patch-stage mycosis fungoides)
sometimes with fever and generalized lymphadenopathy, ● Peripheral T-cell lymphoma (should be distinguished from
most often due to anticonvulsants or angiotensin- the nodular pattern of pseudo-T-cell lymphoma)
converting enzyme inhibitors). ● Pseudo-B-cell lymphoma
● Insect bite reaction.
● Lymphomatoid contact dermatitis.

Special techniques
● Actinic reticuloid (a photosensitivity-type dermatosis
characterized by papules and plaques on light-exposed ● The T lymphocytes of pseudo-T-cell lymphoma express a
skin which secondarily extend into covered areas). complete peripheral T-cell phenotype, whereas some
markers are usually lost in true lymphomas.
Atypical cutaneous T-cell lymphoid hyperplasia in the setting ● T-cell receptor gene rearrangements cannot be
of drug therapy has recently been described. The skin biopsy demonstrated in pseudo-T-cell lymphoma.
usually shows atypical lymphoid infiltrates, which assume one or
more of the following patterns: mycosis fungoides (MF)-like; a
lymphomatoid vascular reaction; lymphocytoma cutis; and fol-
licular mucinosis. Based on the histopathology of the biopsied
LEUKEMIA CUTIS
lesions and the clinical course being one of lesional resolution
after cessation of drug therapy or excision of a solitary lesion CLINICAL FEATURES
without subsequent recurrence, a diagnosis of drug-associated
Leukemia cutis is characterized by the presence within the der-
lymphomatoid hypersensitivity can be established in all cases. A
mis of malignant cells of hematopoietic origin in the setting of
diagnosis of drug-associated pseudolymphoma should be con-
acute or chronic myelogenous, myelomonocytic or lymphocytic
sidered if the patient is receiving a drug which is known to alter
leukemia. This generally signifies a poor prognosis, and is very
lymphocyte function, particularly in the setting of systemic
rarely the first manifestation of an underlying leukemia. The
immune dysregulation or multidrug therapy where agents may
lesions present as red-pink purpuric papules, nodules or
act synergistically or cumulatively to alter lymphoid function.
indurated patches, plaques or ulcers. In the setting of lympho-
cytic leukemia, erythroderma may be seen. The condition
PATHOLOGICAL FEATURES affects any body sites, including the oral mucosa.
There are two histological subtypes:

1. Band-like or mycosis fungoides-like pattern: this is PATHOLOGICAL FEATURES
characterized by a subepidermal band-like infiltrate of Leukemia cutis may show a variety of histological appearances.
atypical lymphocytes with cerebriform nuclei. These are The cells may be present in a perivascular location reminiscent
mixed with moderate numbers of histiocytes and of benign dermatoses, or as a diffuse or nodular dermal infil-
occasional blast-like cells. Eosinophils and plasma cells are trate resembling B-cell lymphoma.
few in number, or absent. Epidermotropism is sparse, and
Pautrier’s abscesses are generally not found. This pattern
can be seen in actinic reticuloid, idiopathic pseudo-T-cell Cell morphology
lymphoma and in lymphomatoid drug reaction. In the ● The cells of chronic lymphocytic leukemia are generally
latter situation there may also be epidermal changes in the indistinguishable from those of low-grade
form of acanthosis, spongiotic foci, and infiltration by lymphoproliferative disease. CLL cells exhibit
atypical lymphocytes. CD20 and CD5.
2. Nodular pattern: this is characterized by the presence of ● The cells of chronic granulocytic leukemia vary between
superficial, deep dermal or sometimes a subcutaneous mature and immature myeloid forms, together with
nodular infiltrate. This consists of atypical lymphocytes occasional eosinophilic myeloblasts.
with cerebriform nuclei, intermixed with many small ● The cells of acute granulocytic leukemia may show large
reactive lymphocytes, histiocytes and occasional giant cells. blasts cells that may resemble large cell lymphoma or
This pattern can be seen in persistent arthropod bite histiocytic infiltrate.
922 Skin tumors
Differential diagnosis POEMS syndrome, normolipemic plane xanthoma, and

● Benign dermatoses plasmacytoma.
● B-cell lymphoma Patients with multiple myeloma show a short survival once
● Large cell lymphoma cutaneous metastases have appeared independently of the
therapy.
Primary cutaneous plasmacytoma is a rare type of cutaneous
Special techniques B-cell lymphoma which arises primarily in the skin and is
● A panel of immunostains to define the cell types. derived from clonally expanded plasma cells with various
● Full blood count and bone marrow aspirate for the degrees of maturation and atypia. The lesion presents as soli-
assessment of leukemia. tary or multiple reddish plaques or nodules.
MASTOCYTOMA Cutaneous plasmacytoma is characterized by the presence of
diffuse or nodular dermal cellular infiltrate with sparing of the
CLINICAL FEATURES papillary dermis and the epidermis. The cells have the charac-
See also Chapter 10, Lymphoreticular tumors; Masto- teristic appearance of plasma or plasmacytoid cells.
cytosis (p. 730).
The diagnosis cutaneous mastocytosis (CM) is based on Cell morphology
typical clinical and histological skin lesions and an absence ● The cell morphology varies from normal plasma cells to
of definitive signs of systemic involvement. Most patients with cells showing nuclear enlargement, hyperchromasia and
CM are children, and they present with maculopapular cuta- angulated nuclear contours.
neous mastocytosis (urticaria pigmentosa). In adults, telangiec- ● Mitotic figures are often seen.
tasia macularis eruptiva perstans (TMEP) is the most common ● Binucleate plasma cells may be seen.
form, with a rather subtle, dispersed infiltrate of mast cells in
the papillary and upper reticular dermis and some concentra-
tion of cells around blood vessels. Less frequent – and usually Differential diagnosis
found in children – is a mastocytoma of the skin. This has a ● Cutaneous lymphoid hyperplasia with plasmacytoid
benign biological behavior, and spontaneous regression is a features
well-recognized phenomenon. ● Benign cutaneous plasmacytoma
● Poorly differentiated carcinomas
Histologically, there is a dermal infiltrate which very closely Special techniques
mimics intradermal nevus. The cells are monotonous, and com-
● Methyl green pyronin (MGP) highlights the cytoplasmic
posed of round cells with abundant pink granular cytoplasm
RNA that characterizes plasmacytoid differentiation.
and centrally placed, rounded nuclei. No mitoses or atypical
● Immunoglobulin and light chain detection to illustrate
features are seen. The granules are metachromatic, and are best
light chain restriction.
seen with toluidine blue or Giemsa stains.
● The neoplastic plasma cells are strongly positive for
CD79a, CD138, and EMA, and variably positive for
Differential diagnosis VS38c and CD43.
● Benign nevus ● Deletion of the rb-1 gene may provide prognostically
● Nevoid melanoma relevant information to identify a high-risk subset of
patients with multiple myeloma.
Special techniques
● The cells stain with toluidine blue or Giemsa. REGRESSING ATYPICAL HISTIOCYTOSIS
CLINICAL FEATURES
PLASMACYTOMA
Regressing atypical histiocytosis is a dermal infiltrative process
of probable T-cell lineage, and is often considered as a subset
CLINICAL FEATURES
of anaplastic large cell lymphoma. It presents as recurrent
Multiple myeloma is a plasma cell dyscrasia characterized by a nodulo-ulcerative skin lesions in young or middle-aged adults,
clonal proliferation of plasma cells that produces a monoclonal and shows no sex predilection. It follows a typical regressing/
protein. Several dermatological disorders have been associated relapsing course for several years before progressing to high-
with this disease, including amyloidosis, cryoglobulinemia, grade neoplasia.
Vascular tumors 923
PATHOLOGICAL FEATURES patients with acquired iatrogenic arteriovenous fistula from

hemodialysis, and in an above-knee amputation stump.
The lesion consists of a dense dermal infiltrate of mononuclear,
The condition typically affects the lower extremities of
binuclear and multinucleated Reed–Sternberg-like cells associ-
elderly individuals, but it has also been reported in younger
ated with marked epidermal hyperplasia and, in the majority of
people. It presents as purple-colored, circumscribed violaceous,
cases, ulceration. A prominent granulation tissue reaction is
brown or dusky macules, papules, or plaques. The patients
often seen in the superficial areas of the lesion.
may complain of painful, swollen crusted vesicles and purple or
erythematous patches or plaques on their hands and fingers.
Cell morphology The condition may improve after oral erythromycin treat-
● The main population consists of large atypical ment, which seemed to be safe and effective for pseudo-
mononuclear Reed–Sternberg-like cells. They have Kaposi’s sarcoma.
eosinophilic cytoplasm and highly pleomorphic nuclei with
irregular contours, vesicular chromatin pattern and PATHOLOGICAL FEATURES
prominent nucleoli.
Histologically, the condition closely resembles Kaposi’s sarcoma,
● Eosinophils may be seen.
and had thus been named ‘pseudo-Kaposi’s sarcoma’. It is char-
acterized by the presence of numerous thick-walled, small, round
Differential diagnosis blood vessels lined by plump endothelial cells within the upper
● Anaplastic carcinoma dermis. These are arranged in small clusters or congeries.
● Malignant lymphoma There is usually an associated perivascular inflammation of
● Malignant melanoma superficial and mid-dermis, consisting of lymphocytes, histio-
● Type A lymphomatoid papulosis cytes, eosinophils, occasional plasma cells, extravasation of red
blood cells, and hemosiderin pigment deposition.
The intervening stroma is fibroblastic.
Special techniques Significant epidermal changes of spongiosis and mild acan-
● The cells express Ki-1 antigen (CD30). thosis are rarely observed.
● The majority of cells express aberrant T-cell antigenic
profiles, and rearrangement of T-cell receptor beta- and Differential diagnosis
alpha-chain genes can be detected by Southern blotting. ● Stasis dermatitis (unlike stasis dermatitis,
acroangiodermatitis is usually associated with minimal
epidermal changes and eosinophils in the inflammatory
NEURAL TUMORS infiltrate in the dermis)
● Kaposi’s sarcoma (Kaposi’s sarcoma shows CD34 labeling
both on endothelial cells and on the characteristic spindle-
NEUROFIBROMAS shaped, perivascular cells. In pseudo-Kaposi’s sarcoma
there is a complete absence of perivascular CD34
See Chapter 13, Soft tissue tumors (p. 1016). expression)
● Pigmented purpura
● Vasculitis
NEUROTHEKEOMA ● Lichen planus
GLOMUS TUMOR
VASCULAR TUMORS CLINICAL FEATURES

Glomus tumor is an uncommon, benign tumor of glomus cells. It
ENDOTHELIAL TUMORS, BENIGN usually presents as a painful single (or sometimes multiple) nod-
ule in the deep dermis or subcutaneous tissue of the extremities in
ACROANGIODERMATITIS adults. Glomus tumor can occur in locations other than the skin,
such as in the bone, eyelid, nose, stomach, rectum, cervix, vagina,
labia and mesentery. The multiple form may be genetic.
CLINICAL FEATURES
Glomangioma and glomangiomyoma are variants of glomus
Acroangiodermatitis (pseudo-Kaposi’s sarcoma) is an unusual with predominant vascular channels or vascular spaces with
cutaneous sequel to chronic venous insufficiency, increased smooth muscle, respectively.
venous pressure or circulatory abnormality and congenital vas- Glomangiosarcoma or malignant glomus tumor is an excep-
cular malformations of the lower extremities. It may also tionally rare tumor that occurs in the subcutaneous or muscu-
develop in patients with Klippel–Trenaunay syndrome, in lar tissue, particularly of the lower extremities. None of the
924 Skin tumors
reported cases metastasized. Complete excision seems to be the bundles and small vessels surrounded by glomus cells are often
treatment of choice. seen at the periphery of the tumor.
Glomus tumor may rarely originate from the wall of a vein
or protrude into the lumen of a blood vessel. This should be
recognized by surgeons, dermatologists and pathologists.
The classical glomus tumor is a well-circumscribed, pseudo- Glomangioma is less well-circumscribed and consists of
encapsulated, dermal lesion consisting of various-sized capillary cavernous-type vascular spaces containing glomus cells in their
vessels surrounded by collars of rounded epithelioid ‘glomus’ walls and separated by hyalinized stroma.
cells set in a hyalinized or myxoid stroma. On occasion, the Glomangiomyoma is basically identical to glomangioma
tumor is highly cellular and consists of solid sheets of epithe- or less often to classic glomus tumor, but in addition it exhibits
lioid cells focally interrupted by the presence of blood vessels. gradual transition of the glomus cells to smooth muscle
Such lesions may resemble sweat gland tumors. Less often, the cells. This is especially seen in the region of large vessels, where
lesion may have an intricate vascular pattern, giving the their smooth muscle fibers seem to blend with those of the
appearances of paraganglioma or hemangiopericytoma. Nerve tumor.
(a) (c)
(d)
Figure 12.96 (a–d) Glomus tumor. A sharply circumscribed

dermal nodule consisting of small uniform, bland, round cells.
The cells are actin-positive, and concentrate around vascular
(b)
spaces.
Vascular tumors 925
Glomangiosarcoma is the malignant counterpart of glomus HEMANGIOMA, ACQUIRED TUFTED

tumor, and is characterized by the presence of a only focal sarco-
matous spindle cell component reminiscent of fibrosarcoma or
leiomyosarcoma, in addition to the features of benign glomus CLINICAL FEATURES
tumor. Tufted angioma or angioblastoma of Nakagawa is a benign,
Glomangiomatosis is exceedingly rare, and is defined as the acquired, slowly progressive cutaneous tumor, which most com-
presence of glomus cells within an angiomatosis. monly arises in the neck and upper trunk in children and young
adults. It is frequently seen as an erythematous to red-brown,
frequently indurated plaque. Tufted angiomas typically enlarge
Secondary features
for a few years, and then cease growing and remain stable.
● Myxoid change
● Hyalinization
● Vascular thrombosis PATHOLOGICAL FEATURES
Acquired tufted hemangioma consists of numerous lobules of
Cell morphology closely packed capillaries scattered throughout the dermis.
● Glomus cells are round epithelioid cells with pale These show proliferating endothelial cells and pericyte-like
eosinophilic cytoplasm and punched-out, rounded nuclei. cells, and their vascular lumina are difficult to define. The cells
● Occasionally, the cells are vacuolated. tend to bulge into semilunar vascular spaces.
● Mast cells are often seen.
● The sarcomatous cells of glomangiosarcoma are spindle-
shaped, with elongated nuclei and prominent nucleoli.
Mitotic figures are common. ● Early-stage Kaposi’s sarcoma
● Acroangiodermatitis
● Bacillary angiomatosis
● Chondroid syringoma
● Nodular hidradenoma HEMANGIOMA, GLOMERULOID
● Paraganglioma
● Metastatic malignant melanoma CLINICAL FEATURES
Glomeruloid hemangioma probably represents a reactive
Special techniques endothelial cell proliferation resulting from stimulation of the
endothelial cells by deposition of immunoglobulin. It appears as
● Reticulin stain highlights the delicate interstitial reticulin multiple, small, dome-shaped, red or purple papules which pres-
fibers. ent predominantly over the trunk and proximal extremities.
● PAS and toluidine blue reveal a chicken-wire network of This disease is closely associated with POEMS (polyneuropathy,
matrix material between the cells. organomegaly, endocrinopathy, monoclonal gammopathy, skin
● Alcian blue staining often shows mucinous material within disorders) syndrome (a rare multisystemic disease associated
and outside some of the cells. with plasma cell dyscrasia), and occasionally appears before the
● Glomus cells are actin-, myosin-, and vimentin-positive. full-blown syndrome develops. It is therefore important to
● S-100 protein-positive Schwann cells are often seen. follow-up patients with glomeruloid or cherry-type capillary
● Neoplastic cells in glomus tumor may show a hemangioma with focal glomeruloid features.
co-expression of smooth muscle alpha-actin and CD34 –
an important finding regarding the differential diagnosis
of these lesions and the relationship to perivascular PATHOLOGICAL FEATURES
neoplasms.
● The cells do not express keratin markers (compare with Glomeruloid hemangioma is characterized by the presence of
nodular hiadredenoma). many ectatic dermal vascular spaces lined by flat endothelial
● Glomangiosarcoma cells react more strongly with vimentin cells and containing blood-filled capillary loops resulting in
than the ordinary glomus tumors. They lack the S-100 structures reminiscent of renal glomeruli. Aggregates or iso-
protein-positive Schwann cells seen in glomus tumors. lated plump stromal cells are seen in between the capillary
Actin expression is reduced in glomangiosarcoma. loops. Early lesions may resemble cherry-type capillary heman-
gioma with miniature glomeruloid structures.
HEMANGIOMA
Secondary features
See Chapter 13, Soft tissue tumors (pp. 1085–92). ● A few inflammatory cells are seen.
926 Skin tumors
Cell morphology
● The endothelial cells lining the capillaries are mostly flat,
with scant cytoplasm. Some, however, are plump with
abundant pale cytoplasm, clear vacuoles, or eosinophilic CUTANEOUS HETEROTOPIC MENINGEAL
globules. NODULES
● The stromal cells seen between the capillary loops are
plump, vacuolated cells and contain eosinophilic globules.
They have nuclei similar to endothelial cells, except for the CLINICAL FEATURES
presence in some of multiple indentations caused by the Cutaneous meningioma is a rare lesion that occurs in the scalp
cytoplasmic vacuoles or globules. and back (paravertebral areas) or on the upper limbs, and may
● Mitotic figures can be seen. arise from misplaced arachnoid cells. It is generally present at
birth or in childhood. It appears as small subcutaneous fibrous
nodules, with no specific clinical features, though these may be
associated with abnormalities of spinal closure.
● Histiocytoid hemangioma
● Intravascular pyogenic granuloma
● Acquired tufted angioma Cutaneous heterotopic meningeal nodule occurs in a variety of
● Masson’s hemangioma forms. These include fairly well-circumscribed dermal or sub-
● Metastatic adrenocarcinoma – the vacuolated cells cutaneous fibrocellular masses with focal strands extending
apparently lying in vascular channels. The cells are mucin between sweat glands and into subcutaneous fat, fibrocellular
negative and do not express cytokeratins. bands arranged perpendicular to the skin and a discrete col-
lagenous nodule with peripheral streak-like extensions. The
cellular component is made from nests of uniform oval or spin-
Special techniques dle cells arranged in a whorled or streaming pattern. Prominent
● The hyaline globules are PAS-positive and diagnostic features include psammoma bodies and small col-
diastase-resistant. lagenous bodies. An intimate relationship to nerves is seen in
● Both the endothelial lining cells and the stromal cells seen some cases.
in between the capillary loops stain for Factor VIII-related
antigen, CD31, and CD34. Cellular morphology
● Actin highlights the outer layer of pericytes that surround
● The cells have spindle- or oval-shaped nuclei, some of
some of the capillaries.
which show vacuolation.
● The cytoplasm is homogeneous eosinophilic, and shows no
distinct borders.
PYOGENIC GRANULOMA ● There is usually no significant cellular pleomorphism or
mitotic activity.
● Melanocytic lesions
ENDOTHELIAL TUMORS, INTERMEDIATE ● Metastatic carcinoma may be considered if the existence of
cutaneous meningioma is not realized
HEMANGIOENDOTHELIOMAS ● Meningioma-like tumor of the skin. This is a rare skin
lesion that presents as an asymptomatic, red-brown papule
See Chapter 13, Soft tissue tumors (p. 1090). or nodule. Histologically, it shows a poorly circumscribed
dermal nodule or nodules consisting of clusters or whorls
of spindle cells, arranged mainly around blood vessels, or
ENDOTHELIAL TUMORS, MALIGNANT sometimes around nerve trunks. Some cells are more
epithelioid and arranged in sheets. The intervening
ANGIOSARCOMA stroma is loose and myxoid, and often exhibits clefting.
Mitotic figures are rarely seen. The cells are positive for
See Chapter 13, Soft tissue tumors (p. 1099). vimentin only
Special techniques
LYMPHATIC TUMORS ● As with intracranial meningiomas, there is widespread

vimentin expression, and most cases show EMA
See Chapter 13, Soft tissue tumors (p. 1012). expression.
FIBROEPITHELIAL POLYP OF THE SKIN GRANULAR CELL TUMOR (Figure 12.98)

(SKIN TAG) (ACHROCORDON)
CLINICAL FEATURES
ONYCHOMATRICOMA
Fibroepithelial polyps are very common skin lesions, and usu-
ally present as small, benign dermal growths known as ‘skin
tags’. They are usually of unknown etiology; however, some CLINCIAL FEATURES
polyps develop secondary to a focal loss of elastic tissue. A pro- Onychomatricoma is an uncommon benign tumor of the nail
portion of these polyps represent dermal neurofibromas or matrix, and is clinically characterized by a thickened yellowish
intradermal nevi. Very rarely, basal cell carcinoma can develop nail with transverse over-curvature. A pigmented variant has
in fibroepithelial polyps. recently been described.

Fibroepithelial polyp usually shows an irregularly acanthotic The histological diagnosis requires three prerequisites: (i) a
epidermis. The connective tissue core consists of collagen, with fibroepithelial tumor consisting of two portions – the proximal
or without fat cells. Rarely, atypical degenerative nuclear zone (under the proximal nailfold, characterized by deep
change is observed, known as an ‘ancient’ skin tag. epithelial invaginations and a fibrillary and fibrocytic stroma),
and the distal zone (corresponding to the lunula), which pres-
ents with multiple digitations along its connective tissue axes;
(ii) a matricial tumor typified by a thick keratogenous zone;
and (iii) a thick nail plate, perforated by cavities.
● Fibrokeratoma
ACELLULAR DEPOSITS
CALCINOSIS CUTIS
CLINICAL FEATURES
Calcinosis cutis – the cutaneous deposition of calcium salts in
the dermis or subcutaneous tissues – can occur through a vari-
Figure 12.97 Fibroepithelial polyp of the skin. A polypoid lesion
lined by irregularly thickened epidermal layer.The core is variably ety of pathogenetic mechanisms, and can be associated with
collagenous and may contain fat cells. both normal and elevated calcium levels.
(a) (b)
Figure 12.98 (a–d) Granular cell tumor. The cells are large, pale eosinophilic with granular cytoplasm.They are S-100 protein-positive
(c) and CD68-positive (d).
928 Skin tumors
(c) (a)
(d) (b)
According to the underlying etiology, calcinosis cutis is clas-

sified into four forms:
● Metastatic calcinosis cutis results from a hypercalcemic or
hyperphosphatemic state, as occurs in patients with

hyperparathyroidism and end-stage renal disease.
● Dystrophic calcinosis cutis occurs in previously damaged
skin, such as in various connective tissue disorders. It can

also be due to iatrogenic causes such as extravasation of
intravenously administered calcium chloride or calcium
gluconate, and traumatic deposition of calcium in the skin.
It has also been reported following electroencephalographic
and electromyographic studies at sites of electrode (c)
placement following application of an electrode paste
containing calcium chloride. Figure 12.99 (a–c) Scrotal calcinosis. Dermal calcium deposits
with secondary foreign body giant cell reaction and fibrosis.
● Idiopathic calcinosis cutis shows no underlying disease.
Typical examples of idiopathic calcinosis cutis are tumoral

calcinosis and idiopathic calcinosis of the scrotum.
● Subepidermal calcified nodules (cutaneous calculi) occur
mostly in children, and present as single or multiple raised The dermal or subcutaneous calcium deposits appear as small
hard skin nodules, usually with an overlying verrucous or large masses of dark blue calcium granules. These are often
surface. Very occasionally, small groups of intradermal associated with an inflammatory reaction, foreign body giant
nevus cells lie superficially. cells and fibrosis.
Secondary malignant tumors 929
GOUT TOPHI adequate therapy which reduces or reverses the growth of

osteomas. Those tumors which are cosmetically disturbing may
be excised via a small surface incision.
CLINICAL FEATURES Progressive osseous heteroplasia is a recently described
Gout tophi are produced by deposition of monosodium urate genetic disorder of mesenchymal differentiation characterized
crystals resulting from hyperuricemia associated with either by dermal ossification during infancy and progressive hetero-
primary or secondary forms of gout. These are seen around topic ossification of cutaneous, subcutaneous, and deep con-
joints, often erode bone and articular cartilage, and may also nective tissues during childhood.
be seen in visceral organs. Gout tophi may produce a periartic-
ular radiological defect. They may be mistaken clinically as
squamous cell carcinoma.
There are usually variably sized spicules of lamellar bone
within the dermis or subcutaneous tissue; these often enclose
PATHOLOGICAL FEATURES areas of fat cells. Haversian canals containing blood vessels and
Gout tophi consist of large deposits of acellular crystalline connective tissue are often present, and marrow may also be
material surrounded by a rim of fibrous tissue containing giant found. The bone shows more osteoblasts than osteoclasts.
cells, macrophages and chronic inflammatory cells. On closer
examination of the acellular deposit, a ‘hair-like’ or ‘rays-like’ Differential diagnosis
shadowy appearance of the dissolved crystals is usually seen.
● Calcinosis cutis
Secondary features
● Calcification. SECONDARY MALIGNANT TUMORS
Cutaneous metastases may be the first sign of a previously

undiagnosed visceral malignancy, or the initial presentation of
● Tumoral calcinosis a recurrent neoplasm, and are usually associated with a poor
● Amyloid tumor survival. The overall incidence of cutaneous metastasis is
● Para-gout (deposition of rhomboid pyrophosphate 5.3%. The most common tumor to metastasize to the skin is
crystals) breast cancer; however, any internal malignancy can be the
source of primary origin for cutaneous metastasis. The chest,
followed by the head and neck region, is the most common site
Special techniques
of skin metastasis.
● The needle-shaped crystals can be demonstrated using Skin metastases usually present as a rapidly developing nod-
polarized light microscopy of an unstained section. The ule which can resemble a pyogenic granuloma.
crystals exhibit a strong, positive birefringence. Sister Mary Joseph’s nodule is a rare form of cutaneous
umbilical metastasis, and may present as the first sign of intra-
abdominal malignancy (gastrointestinal) or pelvic (ovarian). It
OSTEOMA CUTIS carries a very poor prognosis, and generally is inoperable.

Osteoma cutis – also called cutaneous ossification – is a rare The clue to diagnosis is the history and the site, and also the
disorder characterized by compact bone formation in the der- fact that these lesions simply do not quite ‘fit’ for a primary
mis and subcutaneous tissue. Primary osteoma cutis may be skin tumor. The lack of epidermal involvement, the history, and
considered as true bone formation rather than dermal mineral- immunohistochemistry usually allow their distinction.
ization. It is classified as primary and secondary forms accord-
ing to the presence or absence of previous cutaneous lesions.
Secondary cutaneous osteomas are correlated with inflamma- Differential diagnosis
tory processes, scars, or neoplasms. The latter include basal cell ● Metastatic renal cell carcinoma may simulate clear cell
carcinoma, pilomatrixoma, and intradermal nevi. hidradenoma and balloon cell melanoma
Miliary osteoma of the face is a form of primary osteoma ● Metastatic breast carcinoma may be mistaken for granular
cutis that occur on the face and upper trunk of young, healthy cell tumor, melanoma, or sweat gland carcinoma
women. This rare disorder was initially classified as a conse- ● Metastatic adenocarcinoma may be misdiagnosed as
quence of severe, longstanding acne vulgaris. However, several primary sweat gland carcinoma
cases have now been described in patients with no preceding ● Metastatic sarcomatoid carcinoma may simulate a primary
history of acne or other inflammatory conditions. There is no soft tissue tumor
930 Skin tumors
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13 soft tissue tumors
Awatif I Al-Nafussi
Fibroblastic/myofibroblastic tumors, benign 969 Reticulohistiocytic granuloma 995

Atypical decubital fibroplasia 969 Xanthoma 995
Calcifying fibrous tumor (pseudotumor) 969
Dermatomyofibroma 970 Fibrohistiocytic tumors, intermediate 995
Desmoplastic fibroblastoma (collagenous fibroma) 970 Dermatofibrosarcoma protuberans (DFSP) 995
Elastofibroma 971 Bednar tumor (pigmented dermatofibrosarcoma
Fibroma of tendon sheath 972 protuberans) 995
Fibroma, nuchal 972 Giant cell fibroblastoma 996
Fibromatosis colli (congenital torticollis, Plexiform fibrohistiocytic tumor 997
sternocleidomastoid tumor) 973
Fibromatosis, infantile digital 973 Fibrohistiocytic tumors, malignant 997
Fibromatosis, juvenile hyaline (fibromatosis hyalinica Malignant fibrous histiocytoma, angiomatoid 998
multiplex; systemic hyalinosis) 973 Malignant fibrous histiocytoma, giant cell type
Fibromatosis ‘knuckle pads’/pachydermodactyly 973 (malignant giant cell tumor of soft parts) 999
Fibrous hamartoma of infancy 974 Malignant fibrous histiocytoma, inflammatory type 1000
Giant cell angiofibroma 974 Malignant fibrous histiocytoma, pleomorphic
Infantile myofibromatosis and solitary myofibroma in adults 975 (storiform-pleomorphic MFH) 1000
Myofibroblastoma, intranodal 976
Myofibroblastoma, mammary-type 976 Lipocytic tumors, benign 1001
Myositis ossificans 976 Angiolipoma 1001
Nodular fasciitis 977 Chondroid lipoma 1002
Proliferative fasciitis 979 Dendritic fibromyxolipoma 1003
Proliferative myositis 979 Hibernoma 1003
Pyogenic granuloma 980 Intramuscular lipoma 1004
Retroperitoneal fibrosis 980 Lipoblastomatosis and benign lipoblastoma 1004
Sclerosing encapsulating peritonitis 981 Pleomorphic lipoma 1005
Sclerosing mesenteritis (idiopathic retractile mesenteritis) 981 Sclerotic lipoma 1005
Solitary fibrous tumor (SFT) 982 Spindle cell lipoma 1006
Fibroblastic/myofibroblastic tumors, intermediate 983 Lipocytic tumors, malignant 1008

Acral myxoinflammatory fibroblastic sarcoma Liposarcomas 1008
(inflammatory myxohyaline tumor) 983
Angiofibroma, juvenile nasopharyngeal 985 Lymphatic tumors 1012
Fibromatosis 985 Benign lymphangioendothelioma (acquired progressive
Fibromatosis, juvenile/infantile 987 lymphangioma) 1012
Fibromatosis, palmar (Dupuytren’s disease/contracture) 987 Lymphangioleiomyomatosis (lymphangiomyomatosis) 1012
Fibromatosis, penile (Peyronie’s disease) 987 Lymphangiomas 1013
Fibromatosis, plantar (Ledderhose disease) 987 Lymphangiomyoma 1013
Inflammatory myofibroblastic tumor (inflammatory
Lymphoreticular tumors 1013
pseudotumor) 988
Extramedullary hematopoiesis/hemopoietic tumor 1013
Lipofibromatosis 989
Follicular dendritic cell sarcoma 1014
Fibroblastic/myofibroblastic tumors, malignant 990 Granulocytic sarcoma 1014
Fibrosarcoma 990 Interdigitating cell sarcoma 1015
Inflammatory fibrosarcoma of the mesentery and Rosai–Dorfman disease 1015
retroperitoneum 990
Hyalinizing spindle cell tumor with giant rosettes (HSTGR) 991 Peripheral nerve sheath tumors, benign 1015
Low-grade fibromyxoid sarcoma 991 Fibrolipomatous hamartoma of nerve 1015
Myofibrosarcoma 993 Morton’s neuroma 1016
Myxofibrosarcoma (myxoid malignant fibrous histiocytoma) 994 Neurofibroma, solitary 1016
Neurofibromatosis (von Recklinghausen’s disease) 1016
Fibrohistiocytic tumors, benign 995 Neuroma, Pacinian 1018
Fibrous histiocytoma 995 Neuroma, solitary circumscribed 1018
Juvenile xanthogranuloma 995 Neuroma, traumatic 1019
Plexiform xanthoma 995 Neurothekeoma, nerve sheath myxoma 1019
966 Soft tissue tumors
Perineuroma (storiform perineurial fibroma) 1020 Gout tophi 1059

Schwannoma (neurilemmoma) 1021 Polyvinyl pyrrolidone granuloma 1060
Triton tumor, benign (neuromuscular Tumoral calcinosis 1060
hamartoma/choriostoma) 1024 Extragonadal germ cell tumors (GCTs) 1061
Extrarenal rhabdoid tumors 1061
Peripheral nerve sheath tumors, malignant 1025 Ganglion cyst 1062
Malignant peripheral nerve sheath tumor (MPNST) 1025 Ganglioneuroblastoma 1063
Triton tumor, malignant 1028 Ganglioneuroma 1063
Gastrointestinal stromal tumor (GIST) 1064
Peripheral neuroectodermal tumors 1029 Myoepithelioma of soft tissue 1066
Malignant ectomesenchymoma 1029 Radiation-associated sarcomas 1067
Myxopapillary, extraspinal or soft tissue ependymoma 1029
Neuroblastoma, olfactory (esthesioneuroblastoma) 1031
Neuroblastomas 1031
Soft tissue tumors, uncertain differentiation 1067
Paragangliomas 1031
Aggressive angiomyxoma 1067
Gangliocytic paraganglioma 1031
Alveolar soft part sarcoma 1067
Pigmented neuroectodermal tumor of infancy
Clear cell sarcoma of tendon sheath 1068
(melanotic progonoma, retinal anlage tumor) 1033
Desmoplastic small round cell tumor 1069
Perivascular tumors 1034 Epithelioid sarcoma 1070
Hemangiopericytoma 1034 Ewing’s sarcoma/primitive neuroectodermal tumor
Lipomatous hemangiopericytoma 1034 (PNET)/small cell tumor of thoracopulmonary
Perivascular epithelioid cell tumor (‘PEComa’) 1035 origin (Askin’s tumor) 1072
Perivascular myoid tumors 1036 Granular cell tumor 1073
Malignant mesenchymoma 1074
Skeletal muscle tumors, benign 1037 Myxomas 1075
Rhabdomyomas 1037 Low-grade myxoid neoplasm with recurrent potential
Rhabdomyoma, fetal 1037 (cellular myxoma) 1075
Rhabdomyoma, genital 1038 Myxoma, cardiac 1075
Rhabdomyoma, adult type 1038 Myxoma, intramuscular 1076
Rhabdomyoma, cardiac type 1038 Myxoma, juxta-articular 1077
Ossifying fibromyxoid tumor of soft parts 1077
Skeletal muscle tumors, malignant 1039 Parachordoma 1078
Rhabdomyosarcomas 1039 Pleomorphic hyalinizing angiectatic tumor 1079
Rhabdomyosarcoma, alveolar 1039 Superficial acral fibromyxoma 1079
Rhabdomyosarcoma, embryonal 1040 Superficial angiomyxoma 1080
Rhabdomyosarcoma, embryonal ‘botryoid variant’ 1042 Synovial sarcoma 1081
Rhabdomyosarcoma, embryonal ‘spindle cell variant’ 1042
Rhabdomyosarcoma, pleomorphic 1043
Rhabdomyosarcoma, sclerosing, pseudovascular 1043 Vascular tumors, benign 1084
Angioendotheliomatosis, benign, reactive 1084
Smooth muscle tumors, benign 1044 Benign vascular proliferation in irradiated skin 1084
Leiomyoma, extrauterine 1044 Epithelioid angiomatosis (bacillary angiomatosis) 1085
Myolipoma (lipoleiomyoma) of soft tissue 1046 Hemangioma, capillary 1085
Hemangioma, cavernous 1087
Smooth muscle tumors, malignant 1046
Hemangioma, epithelioid (angiolymphoid hyperplasia
Leiomyosarcomas, extrauterine 1046
with eosinophilia) and Kimura’s disease 1087
Soft tissue tumors, cartilage- and bone-forming, benign 1050 Hemangioma, intramuscular 1089
Calcifying aponeurotic fibroma 1050 Hemangioma, intravascular papillary endothelial
Extraskeletal chondromas 1051 hyperplasia/Masson’s vegetant
Myositis ossificans 1052 hemangioendothelioma/Masson’s hemangioma 1090
Synovial chondromatosis 1052 Hemangioma, microvenular 1091
Hemangioma, sinusoidal 1091
Soft tissue tumors, cartilage- and bone-forming, malignant 1053 Hemangioma, synovial 1091
Ectomesenchymal chondromyxoid tumor of the tongue 1053 Hemangioma: spindle cell hemangioma/
Extraskeletal mesenchymal chondrosarcoma 1053 hemangioendothelioma 1091
Extraskeletal myxoid chondrosarcoma 1054 Hemangioma: targetoid hemosiderotic hemangioma/
Phosphaturic mesenchymal tumor 1055 hobnail hemangioma 1092
Tenosynovial giant cell tumors (TGCTs) 1057 Littoral cell angioma, spleen 1092
Vascular malformations 1092
Soft tissue tumors, miscellaneous 1059 Vascular malformations, venous hemangioma
Acellular deposits 1059 (venous malformation) 1093
Amyloid tumor 1059 Vascular malformations, verrucous hemangioma/
Crystal-storing histiocytosis 1059 vascular malformation 1093
Classification of soft tissue tumors 967
Vascular tumors, intermediate 1093 Vascular tumors, malignant 1099

Composite hemangioendothelioma 1093 Angioendotheliomatosis, malignant, reactive
Epithelioid hemangioendothelioma 1094 (intravascular malignant lymphoma/angiotropic
Epithelioid sarcoma-like hemangioendothelioma 1095 large cell lymphoma) 1099
Giant cell angioblastoma 1097 Angiosarcoma and lymphangiosarcoma 1099
Kaposi-like infantile hemangioendothelioma 1097 Intimal sarcoma 1102
Polymorphous hemangioendothelioma of Kaposi’s sarcoma 1104
lymph nodes 1098 Malignant intravascular papillary angioendothelioma
Retiform hemangioendothelioma 1098 (Dabska’s tumor) 1104
GENERAL COMMENTS treated by local excisions with attention to margins with

no need for adjuvant therapy. Examples are atypical
There is a wide variety of soft tissue tumors, the majority of lipomatous tumors (well-differentiated liposarcomas) and
which are benign. Malignant soft tissue tumors are relatively dermatofibrosarcoma protuberans.
uncommon and are seen mainly in the extremities, trunk and ● Group IIc – Clinically of intermediate malignancy,
within the abdomen, especially in retroperitoneal space. Soft associated with frequent local recurrence and very rare
tissue tumors also occur within the mesenchyme of visceral metastasis (without dedifferentiation into sarcomas).
organs. Among the commonly encountered soft tissue tumors, These are treated by local excision, with attention to
there are limited numbers of morphological patterns and sub- margins and no need for adjuvant therapy. Examples
patterns that are identified (for details, see Chapter 1, Histo- are ossifying fibromyxoid tumor and plexiform
logical patterns). Some patterns are shared by both benign and fibrohistiocytic tumor.
malignant tumors. Recognizing these histological prototypes ● Group III – Clinically malignant, associated with local
would limit the number of lesions within the differential diag- recurrence and metastasize. These are treated by local
nostic list. Knowledge of the anatomical location would further excisions with compulsive attention to margins with
reduce the diagnostic possibilities. consideration for adjuvant therapy. This group include the
vast majority of soft tissue sarcomas.
● Group IV – Clinically malignant, associated with frequent
CLASSIFICATION OF SOFT TISSUE TUMORS
systemic disease. These are treated by local excision, with
adjuvant therapy. This group includes the embryonal
The classification of soft tissue tumors traditionally depends on
rhabdomyosarcomas and primitive neuroectodermal
histogenesis, but a more important aspect is the managerial
tumors/Ewing’s sarcoma.
classification, as listed below.
MANAGERIAL CLASSIFICATION OF SOFT TISSUE TUMORS GRADING OF SARCOMAS

This emphasizes the clinical outcome and management tech- Grading traditionally relies on the degree of cellular pleomor-
niques of tumors. It broadly classifies tumors into four major phism, mitotic activity, cellularity, extent of tumor necrosis,
clinical outcome groups, I to IV: and degree of differentiation. It seems that there is no single
● Group Ia – Clinically benign, with no evidence of local agreed-upon useful grading system that can be applied to the
recurrence. This group is treated by local excision only, various sarcomas. For practical purposes, certain sarcomas are
and includes a large numbers of soft tissue tumors. always classified as high-grade, low-grade or ungradable tumors.
Common examples are lipomas and fibrous histiocytomas. Other sarcomas have varying clinical outcome, for which grad-
● Group Ib – Clinically benign, associated with non- ing may be useful. Some soft tissue tumors have varying clini-
destructive local recurrence, but never metastasize. These cal behavior for which grading parameters are not yet established.
need local excisions with treatment of recurrence if they Below are examples of some sarcomas and their grades:
occur. This group includes a significant numbers of soft ● High-grade sarcomas
tissue tumors. Examples are atypical fibrous histiocytomas Ewing’s/PNET

and superficial angiomyxoma. Rhabdomyosarcoma
● Group IIa – Clinically of intermediate malignancy, Pleomorphic liposarcoma
associated with destructive local recurrence but never Soft tissue osteosarcoma
metastasize. These are treated by local excision, with Mesenchymal chondrosarcoma
attention to margins. Examples include desmoid Desmoplastic small cell tumor
fibromatosis and lipofibromatosis. Extrarenal rhabdoid tumor
● Group IIb – Clinically of intermediate malignancy, ● Low-grade sarcomas
associated with frequent local recurrence and extremely Well-differentiated liposarcoma

rare metastasis (if dedifferentiate into sarcomas). These are Dermatofibrosarcoma protuberans (DFSP)
Infantile fibrosarcoma Malignant peripheral nerve sheath tumor

Angiomatoid malignant fibrous histiocytoma Fibrosarcoma
● Non-gradable sarcomas (often metastasize within Myxofibrosarcoma
10–20 years) ● Tumors of varying behavior for which grading parameters
Alveolar soft part sarcoma are not yet established:
Clear cell sarcoma of tendon sheath Hemangiopericytoma
Epithelioid sarcoma Myxoid chondrosarcoma
Synovial sarcoma Malignant granular cell tumor
Low-grade fibromyxosarcoma Malignant mesenchymoma
● Tumors of varying behavior for which grading may be
useful: The National Cancer Institute and French Federation of
Myxoid liposarcoma Cancer Centers Sarcoma Group grading systems are shown in
Leiomyosarcoma Table 13.1.
Table 13.1: Tumor differentiation score according to histological type in the updated version of the French Federation of Cancer
Centre’s sarcoma group system*
Histological type Tumor differentiation score
Well-differentiated liposarcoma 1
Myxoid liposarcoma 2
Round cell liposarcoma 3
Pleomorphic liposarcoma 3
Dedifferentiated liposarcoma 3
Well-differentiated fibrosarcoma 1
Conventional fibrosarcoma 2
Poorly differentiated fibrosarcoma 3
Low-grade malignant peripheral nerve sheath tumor 1
Conventional malignant schwannoma 2
Poorly differentiated malignant schwannoma 3
Epithelioid malignant schwannoma 3
Malignant triton tumor 3
Well-differentiated malignant hemangiopericytoma 2
Conventional malignant hemangiopericytoma 3
Myxoid malignant fibrous histiocytoma (MFH) 2
Typical storiform/pleomorphic MFH 2
Giant cell and inflammatory MFH 3
Well-differentiated leiomyosarcoma 1
Conventional leiomyosarcoma 2
Poorly differentiated/pleomorphic/epithelioid leiomyosarcoma 3
Biphasic/monophasic synovial sarcoma 3
Embryonal/alveolar/pleomorphic rhabdomyosarcoma 3
Well-differentiated chondrosarcoma 1
Myxoid chondrosarcoma 2
Mesenchymal chondrosarcoma 3
Conventional angiosarcoma 2
Poorly differentiated/epithelioid angiosarcoma 3
Extraskeletal osteosarcoma 3
Primitive peripheral neuroectodermal tumor (PPNET)/Ewing’s sarcoma 3
Alveolar soft tissue sarcoma 3
Epithelioid sarcoma 3
Malignant rhabdoid tumor 3
Clear cell sarcoma 3
Undifferentiated sarcoma 3
* Reproduced from Guillou L, Coindre JM, Bonichon F, et al. Comparative study of the National Cancer Institute and French Federation of
Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J. Clin. Oncol. 15: 350–362, 1997.
Fibroblastic/myofibroblastic tumors, benign 969
FIBROBLASTIC/MYOFIBROBLASTIC TUMORS,
● Myxoid liposarcoma
BENIGN ● Myxoid malignant fibrous histiocytoma (MFH)
● Proliferative fasciitis
ATYPICAL DECUBITAL FIBROPLASIA ● Myxoid chondrosarcoma
Special techniques
CLINICAL FEATURES
● The proliferating stromal cells are positive for vimentin
Atypical decubital fibroplasia (ischemic fasciitis) is a pseudo- and collagen type IV, but negative for CAM5.2, epithelial
sarcomatous, fibroblastic proliferative lesion which affects membrane antigen (EMA), desmin, smooth muscle alpha-
mainly debilitated or immobilized elderly individuals. It pres- actin, muscle actin, HHF35, S-100 protein and CD34.
ents as a painless mass of a few months’ duration, and occurs
in the soft tissue overlying bony prominences subjected to
intermittent pressure such as the shoulder, posterior chest wall, CALCIFYING FIBROUS TUMOR (PSEUDOTUMOR)
sacrum, greater trochanter, and also in the thighs and arms.
The lesion may recur locally. The pathogenesis is chronically
repeated pressure with associated intermittent ischemia. Atypical CLINICAL FEATURES
decubital fibroplasia may occur in association with bizarre Calcifying fibrous (pseudotumor) tumor is a distinctive benign
paraosteal osteochondromatous proliferation (Nora’s reaction). mesenchymal neoplasm (previously thought to be fibroin-
flammatory reactive process) with a low risk for recurrence. It
PATHOLOGICAL FEATURES affects children and young adults, and occurs in the subcuta-
neous and deep soft tissue of the extremities, trunk, axilla,
Atypical decubital fibroplasia is an ill-defined, lobulated, vari-
pleura, mediastinum, neck, mesentery/omentum, and gastro-
ably cellular lesion. It primarily involves subcutaneous tissue,
intestinal tract, adrenal, groin, and scrotum. The lesion varies
but sometimes shows extension into the underlying muscle or
in size from 0.6 to 25 cm, and is usually cured by local excision
the overlying dermis. Involvement of the fat lobules confers a
with a rim of normal tissue. Local recurrence can be seen after
vaguely multinodular appearance on the lesion. Within these
many years. It has been reported in lesion of Castleman’s dis-
lobules there are zones of fibrinoid necrosis, fibrosis, and myx-
ease of the hyaline-vascular subtype. There is no convincing
oid change. These are surrounded by peripheral rim of vascu-
evidence to support an association between this lesion and
lar granulation tissue intermixed with numerous fibroblasts
inflammatory myofibroblastic tumor.
and myofibroblasts similar to those seen in proliferative fasci-
itis. Perivascular clustering of enlarged fibroblasts may be seen.
Other findings include hyalinization of vessel walls, fibrin PATHOLOGICAL FEATURES
thrombi, red blood cell extravasation, hemosiderin deposition,
Calcifying fibrous (pseudotumor) tumor is a well-circumscribed,
and acute and chronic inflammation.
non-encapsulated lesion, consisting of collagenized acellular
tissue interspersed by psammoma bodies, aggregates of lympho-
Secondary features plasmacytic infiltrate and focal calcification. Entrapped neuro-
● Fibrin thrombi within the vessels of the granulation vascular bundles may be seen at the periphery of the lesion.
tissue.
● Acute inflammation. Secondary features
● Hyalinization of vessel walls.
● Calcification.
● Infarction or inflammation of the underlying involved
● Psammoma body formation.
muscle.
● Occasionally minor hemorrhage and hemosiderin
Cell morphology
deposition.
● Pseudocyst formation. ● Myofibroblasts.
● Fat necrosis at the periphery of the lesion. ● Lymphocytes, plasma cells (some with Russell bodies)
occasional eosinophils, xanthoma cells, mast cells
Cell morphology occasional multinucleated giant cell bordering the
calcific areas.
● Fibroblasts and myofibroblasts reminiscent of those seen
in proliferative fasciitis.
● Residual subcutaneous fat cells are usually present. Differential diagnosis
● Plump and atypical endothelial cells are seen in the areas ● Nodular fasciitis (usually far more cellular and exhibits
of the granulation tissue. mitotic figures)
● Lipophages are present in areas of fat necrosis. ● Fibroma of tendon sheath (restricted to tendons in
● Mitotic figures are usually inconspicuous, but may acral locations and histologically shows clefted vasculature
sometimes be numerous. at the periphery of the lesion)
● Fibromatosis (characteristically infiltrative and

infrequently calcified)
● Localized amyloid tumor (foreign body giant cell reactions
are frequently seen)
Special techniques
● The cells are CD34-positive in most cases.
● Rarely the cells are positive for smooth muscle actin
(SMA) and desmin.
● The cells are negative for ALK-1 and S-100 protein.
DERMATOMYOFIBROMA
CLINICAL FEATURES
Dermatomyofibroma – also called plaque-like dermal fibro- Figure 13.2 Dermatomyofibroma.The cells are actin-positive.
matosis – is a recently described, benign myofibroblastic tumor.
It usually presents as 1- to 2-cm, firm, dermal plaque, often Differential diagnosis
with brown-red discoloration reminiscent of keloid. The lesion ● Dermatofibrosarcoma protuberans
is usually found around the shoulder, axilla and posterior neck, ● Diffuse neurofibroma
often in young adult females. It has also been reported in chil- ● Dermatofibroma
dren. Excision is usually curative. ● Piloleiomyoma
● Hypertrophic scar
Special techniques
This is a non-encapsulated but well-circumscribed, mid-dermal
lesion that often extends into the upper subcutaneous fatty tis- ● Immunohistochemically, most of the tumor cells express
sue. The tumor is composed of faintly eosinophilic, thin, wavy muscle actin and smooth muscle alpha-actin.
collagen fibers arranged as intersecting fascicles with an arrange- ● The tumor cells are usually negative for desmin,
ment predominantly parallel to the skin surface. Embedded h-caldesmon, Factor XIIIa, S-100 protein, and CD34.
among the wavy fibers are a fair number of uniform, elongated,
or vesicular nuclei. Cytological atypia is usually absent, and DESMOPLASTIC FIBROBLASTOMA
mitotic figures are minimal or absent. Collagen is often present
(COLLAGENOUS FIBROMA)
as thin fibers separating individual cells and as thicker bundles
between the fascicles. Elastic fibers are mostly preserved and
appear thicker or even increased in number. The adnexal struc- CLINICAL FEATURES
tures are usually spared.
Desmoplastic fibroblastoma is an extremely rare benign soft
tissue tumor of fibroblastic origin. The majority of reported
cases have been located in the deep subcutis, fascia, aponeurosis,
or skeletal muscle of the extremities, limb girdles, or head and
neck regions. It affects adults between the ages of 25 and
83 years. The lesion varies in size, from 1 to 9 cm, and is usually
cured by simple excision; there is no evidence of recurrence.

Desmoplastic fibroblastoma is usually a well-circumscribed,
sparsely cellular fibromyxoid or sclerotic lesion. It may show
focal interdigitation with the surrounding muscle or fat.
Secondary features
● Focal intralesional hemorrhage.
Cellular morphology
Figure 13.1 Dermatomyofibroma.This is similar to
dermatofibroma, but the cells appear more uniform and with ● Medium-sized to large stellate myofibroblasts.
myoid features. ● Mitotic figures are rare or absent.

Elastofibroma is a poorly circumscribed, hypocellular, mesen-
chymal lesion, consisting of a mixture of collagen bundles,
coarse acidophilic refractile elastic fibers, occasional fibro-
blastic spindle cells and mature fat cells.
Papillary elastofibroma of the heart is characterized by a
papillary configuration with fronds composed of a collagenous
and elastic tissue core lined by hyperplastic endothelial cells.
Secondary features
● Hyalinization.
Figure 13.3 Desmoplastic fibroblastoma. Sclerotic stroma with

sparse, slightly enlarged nuclei.
● Desmoid tumor
● Low-grade fibromyxosarcoma
● Fibroma of tendon sheath
● Calcifying fibrous tumor
Special techniques
● The tumor cells are diffusely positive for vimentin.
● Some tumors may show focal staining for smooth muscle
alpha-actin, muscle-specific actin (MSA), and desmin.
● The cells are usually negative for cytokeratin, S-100
(a)
protein or CD34.
ELASTOFIBROMA
CLINICAL FEATURES
Elastofibroma is a rare, benign tumor-like condition of fibro-
blastic, myofibroblastic or possibly periosteal origin. It pres-
ents as slowly growing, solid, ill-defined mass in the connective
tissue between the lower end of the scapula and the chest wall
in people over the age of 50 years. Other rare locations include
the connective tissue around the greater femoral trochanter, the
ischium, the upper humerus, or the lateral chest wall. Morpho-
logically similar lesions have been reported in the conjunctiva,
stomach and in the mediastinum.
The lesion is usually excised in order to exclude more sinis-
ter pathology. Elastofibromas may result from the friction of
the scapula against the thorax, thus generating tumor growth.
Papillary elastofibroma of the heart is an extremely rare
lesion which is usually discovered incidentally at autopsy.
These lesions occur more commonly on the surfaces of (b)
the valves than on the mural endothelium. Echocardiography
and cardiac catheterization may demonstrate the lesion Figure 13.4 Elastofibroma. (a, b) Fibro-collagenous background
preoperatively. with classic bead-like elastic fibers.

● Fibroblasts and myofibroblasts. ● Palmar and plantar fibromatosis
Differential diagnosis ● Desmoplastic fibroblastoma
● Angiofibroma of tendon sheath must be distinguished from
● Pseudoxanthoma elasticum a variety of benign lesions, including nodular fasciitis,
angiomyoma and giant-cell tumor of tendon sheath
Special techniques
Special techniques
● Elastic stains highlight coarse, branched and
unbranched elastic fibers and globules arranged in linear
● The constituent cells show diffuse and intense reactivity
patterns. to vimentin, muscle actin and sometimes S-100 protein.
● Polarization reveals birefringent collagen.
● The lesion shows rearrangement of 11q12.
FIBROMA OF TENDON SHEATH

FIBROMA, NUCHAL
CLINICAL FEATURES
Fibroma of the tendon sheath is a benign soft-tissue tumor that CLINICAL FEATURES
usually arises in association with tendons or ligamentous struc- Nuchal fibroma, or collagenosis nuchae, is a benign soft tissue
tures. It is considered to be an end stage of a previous benign tumor that arises from the posterior cervical subcutaneous
proliferative fibroblastic process, but the clonally occurring tissue, with a predilection for the interscapular and paraspinal
chromosome abnormality found in this fibroma of tendon sheath regions. It occurs mainly in men between the ages of 19 and 53
suggests that this proliferation is neoplastic and not a reactive years. The lesion is cured by local excision.
fibrosing process. It usually presents as a slowly growing nod- Nuchal fibrocartilaginous pseudotumor is a distinctive soft-
ule of less than 2 cm in the hands and feet, or near large joints, tissue fibrocartilaginous pseudotumor which is seen in the pos-
usually in adults. terior aspect of the base of the neck, at the junction of the
Angiofibroma of tendon sheath is a distinctive clinicopatho- nuchal ligament and the deep cervical fascia, usually with a his-
logical entity occurring mainly in young and middle-aged men tory of previous neck injuries. It probably develops as a reaction
and affecting dominantly the distal extremities. The trunk and to soft-tissue injury, in an analogous manner to fibrocartilage
neck are seldom affected. The lesions are generally small, firm, metaplasia seen in degenerated tendoligamentous structures.
and sometimes painful; they are attached to the tendon sheath The lesions vary in size from 1.0 to 1.5 cm.
and/or tendon.
PATHOLOGICAL FEATURES Nuchal fibroma is an ill-defined, hypocellular superficial sub-
Fibroma of tendon sheath is a well-circumscribed and lobu- cutaneous lesion consisting of dense collagen fibers replacing
lated collagenous lesion that consists of a dense collagenous the underlying fatty tissue. Entrapped nerve fibers and fat cells
stroma containing scattered small spindle-shaped and stellate are often present.
fibroblasts. Cleft-like spaces are present between the lobules. Nuchal fibrocartilaginous pseudotumor consists of a poorly
The lesion is generally hypocellular, though more densely defined, moderately cellular fibrocartilaginous nodule located
cellular areas may be present. within the nuchal ligament at its junction with the deep cervi-
‘Sclerotic fibroma of tendon sheath’ consists of hypocellular, cal fascia. Atypia or mitotic activity is not a feature.
homogeneous collagen bundles that are closely related to
the subjacent tendon sheath. It is possible that the sclerotic Differential diagnosis
fibroma may arise from fibroma of tendon sheath, and that ● Elastofibroma
common pathomechanisms exist between these two types of ● Fibrolipoma
fibroma. ● Nodular fasciitis
Angiofibroma of tendon sheath is similar to fibroma of ● Sclerosing fibrosarcoma
tendon sheath, but shows characteristic slit-like vascular ● Sclerosing liposarcoma
spaces. ● Scar tissue
● Fibrous hamartoma of infancy
Secondary features ● Fibromatosis
● Hyalinization.
Special techniques
Cell morphology ● The constituent fibroblasts are vimentin-positive.
● Small spindle-shaped and stellate fibroblasts. ● S-100 protein highlights the entrapped nerve bundles.
FIBROMATOSIS COLLI (CONGENITAL Differential diagnosis

TORTICOLLIS, STERNOCLEIODOMASTOID TUMOR) ● Acquired digital fibrokeratoma
● Fibrous hamartoma of infancy
CLINICAL FEATURES
Special techniques
Fibromatosis colli – which is also known as sternocleidomastoid
tumor of infancy or muscular torticollis – is a type of juvenile ● The eosinophilic globules are phosphotungstic
fibromatosis occurring in the lower third of the sternomastoid acid-hematoxylin (PTAH)-positive.
muscle. It is the most common cause of congenital torticollis, and
presents in approximately 0.4% of live births. The lesion usually FIBROMATOSIS, JUVENILE HYALINE
appears at birth, may be bilateral, and is frequently associated
(FIBROMATOSIS HYALINICA MULTIPLEX;
with various congenital anomalies. The lesion is usually associ-
ated with a good prognosis if physiotherapy is initiated and con- SYSTEMIC HYALINOSIS)
tinued for the appropriate period of time. The lesion may rarely
regress spontaneously, and is best treated by surgical excision.
CLINICAL FEATURES
Juvenile hyaline fibromatosis is a rare, autosomal recessive
hereditary condition with onset in infancy or early childhood,
Fibromatosis colli show skeletal muscle fibers uniformly split and which probably results from an inborn error of metabol-
by hypo- or moderately cellular fibroblastic proliferation. ism. It is characterized by multiple papulonodular skin lesions,
Degeneration of skeletal muscle fibers may produce strange subcutaneous nodular tumors, gingival fibromatosis, flexion
giant cells. Focal fibrosis may also be seen. contractures of the joints, and an accumulation of hyaline in the
dermis. The disease does not regress, and affected individuals
Differential diagnosis may continue to develop new lesions during adult life.
● Neurofibromatosis
Special techniques Juvenile hyaline fibromatosis is a poorly circumscribed,
● See Fibromatosis (p. 985). hypocellular dermal and subcutaneous fibrohyaline lesion con-
sisting of fibroblasts arranged in lines or cords within a homo-
geneous, eosinophilic, keloid-like collagenous background. On
FIBROMATOSIS, INFANTILE DIGITAL occasion, a characteristic chondroid appearance is imparted by
large peripheral vesicles in the stromal cell cytoplasm. Rarely,
giant cells may be seen.
CLINICAL FEATURES
Infantile digital fibromatosis is a form of fibromatosis that is
usually restricted to childhood. It typically occurs on the fingers ● Infantile myofibromatosis
and toes of children, and rarely in the oral cavity and in adults. ● Neurofibromatosis
It is a benign proliferative process of fibroblastic/myofibroblastic ● Amyloid deposition
origin presenting as multiple dome-shaped, skin-colored or pale ● Keloidal scar
red nodules on the fingers and toes. These lesions have a high
recurrence rate, but spontaneous regression can occur.
Special techniques
● The fibroblastic cells are vimentin-positive.
● Ultrastructurally, the fibroblasts show evidence of defective
synthesis of collagen, which is then deposited as
Infantile digital fibromatosis is a poorly circumscribed, hypo- fibrillogranular material in the matrix.
cellular fibrocollagenous spindle cell dermal lesion. The spindle ● CD68 highlights the macrophages and multinucleated
cells are arranged in fascicles or in a diffuse pattern. The over- histiocytic giant cells.
lying epidermis is either hyperkeratotic or acanthotic.
FIBROMATOSIS ‘KNUCKLE PADS’/
Secondary features
PACHYDERMODACTYLY
● Hyalinization.
Cell morphology CLINICAL FEATURES

● Fibroblasts. Pachydermodactyly is a rare superficial benign digital fibro-
● Myofibroblasts. matosis, usually involving the proximal portions of the fingers
● Some contain intracytoplasmic eosinophilic globules. in young male adults, and rarely in females. The condition is
characterized clinically by fibrous tumefaction of the dorsal and

ventral areas and the lateral edges of the proximal phalanges of
the hands, giving the fingers a sausage-like appearance. There
are usually no other subjective signs and no association with
other systemic diseases, although cases have been described in
association with carpal tunnel syndrome, Dupuytren’s disease,
gynecomastia, tuberous sclerosis, varioliform atrophy of the
skin and with Ehlers–Danlos syndrome.
The lesion shows epidermal hyperplasia with ortho- and
parahyperkeratosis, together with an increase of dermal colla-
gen bundles and a slightly increased number of fibroblasts. The
fibromatous thickening of the skin affects not only the finger
joints but also perhaps the dorsum of the hands. Sweat glands (a)
are surrounded by clear spaces containing mucin, which may
be stained with Alcian blue.
FIBROUS HAMARTOMA OF INFANCY
CLINICAL FEATURES
Fibrous hamartoma of infancy is an uncommon, self-limiting
benign myofibroblastic soft tissue lesion that usually presents
during the first 2 years of life; the condition is sometimes con-
genital. The lesion presents as a subcutaneous mass in the axilla,
inguinal region, or proximal portion of an extremity, and there
is a predilection for boys. The treatment of choice is local exci-
sion. Recurrence is very low, even with incomplete excision.
PATHOLOGICAL FEATURES (Figure 13.5) (b)
Fibrous hamartoma of infancy consists of fascicles of myofibro-

blasts, disorganized mature adipocytes, small nodular aggregates
of immature, stellate- or spindled-shaped cells, and variable
amounts of collagen. The stellate cells often show a whorled
arrangement with a myxoid stroma. The background collagen
is often hyalinized, with a ‘wire-like’ appearance. Eccrine gland
hyperplasia has rarely been reported in association with this lesion.
● Infantile fibromatosis
● Calcifying aponeurotic fibroma
● Rhabdomyosarcoma
Special techniques
● Immunohistochemically, the myofibroblastic component
(c)
expressed MSA and vimentin, and the primitive
component expressed vimentin only. Figure 13.5 Fibrous hamartoma of infancy. (a) Admixture of
● Desmin positivity has been reported in the fascicular- fibrous and fatty tissue; the former is made up of myofibroblasts
fibroblastic regions. with ‘wire-like’ hyalinization. (b) Myofibroblasts arranged in fascicles
in whorls. (c) Myofibroblasts with ‘wire-like’ hyalinization.
GIANT CELL ANGIOFIBROMA
and rarely in extraorbital locations such as the oral cavity,

CLINICAL FEATURES
mediastinum and inguinal region. The tumor presents as a soft
Giant cell angiofibroma is a rare, benign, mesenchymal tumor tissue nodule that may reach up to 10 cm in greatest diameter.
which most commonly arises in the soft tissues near the orbit, It is treated by local excision, and recurrence is very rare. It has
recently been suggested that this tumor may represent a giant second subtype visceral involvement is present. The prognosis
cell-rich solitary fibrous tumor. of the disease depends on whether visceral involvement is pres-
ent. Solitary and multicentric nodules without visceral involve-
ment usually have an excellent prognosis, with spontaneous
regression of lesions within 1 to 2 years of diagnosis. On the
This is a well-circumscribed, usually non-encapsulated lesion other hand, visceral lesions are associated with a significant
composed of a mixture of well-formed, thick-walled, often morbidity and mortality, resulting from vital organ obstruction,
branching blood vessels of varying size with an intervening failure to thrive, or infection. Death in these cases often occurs
stroma consisting of spindle-shaped to round cells. Some at birth, or soon after, and is usually due to either cardiopul-
lesions are very cellular and richly vascular; others may show monary or gastrointestinal complications.
alternating hypercellular and hypocellular/sclerotic areas.
Keloidal collagen deposition and myxoid stromal changes are
not uncommon. Fat cells may be seen incorporated within the PATHOLOGICAL FEATURES
lesion. The spindle cells show pale eosinophilic cytoplasm with
The lesion of infantile myofibromatosis is an ill-defined partly
plump nuclei with clumped chromatin. Large bizarre cells with
lobulated or multinodular, moderately cellular monomorphic
lobulated hyperchromatic nuclei and multinucleated floret-like
spindle cell lesion. It shows distinct zonation; at the periphery,
giant cells are commonly seen, and may border the vascular
the lesion appears more nodular and consists of fascicles and
spaces. The blood vessels are regularly distributed, small-sized,
whorls of plump, spindles cells with bland tapering nuclei, some
and may show hyalinized walls. Areas with a sieve-like pattern,
of which are reminiscent of smooth muscle fibers. The central
small slit-like spaces or larger pseudocystic spaces or hemangio-
areas of the lesion usually have prominent hemangiopericytoma-
pericytomatous vascular spaces may also be seen. Mitotic figures
like vascular component and are composed of rounded immature
rarely exceed 2 per 10 HPF.
mesenchymal cells with vesicular nuclei, eosinophilic cytoplasm
and indistinct cell margins. These components constitute a
Differential diagnosis variable percentage of individual tumors, and haphazard or
● Giant cell fibroblastoma reversed zonation may be seen, resulting in variations in the
● Solitary fibrous tumor morphology and overall architecture. Areas of necrosis and
● Pleomorphic lipoma intravascular growth are often present. Hypocellular areas and
● Synovial sarcoma stromal hyalinization are commonly seen at the periphery of
● Fibrosarcoma the lesion.
● Malignant fibrous histiocytoma Solitary myofibroma in adults shows identical histological
● Deep fibrous histiocytoma appearances, though necrosis is rarely seen.
● Schwannoma Secondary features
● Necrosis.
Special techniques ● Calcification.
● Both the mononuclear and bizarre stromal cells
are strongly and diffusely vimentin-, CD99- and CD34- Cell morphology
positive.
● Myofibroblasts are the dominant cell type of this
● The cells are strongly and diffusely positive
lesion.
for bcl-2.
● Fully differentiated smooth muscle cells may also be
● Immunostains for S-100 protein, desmin, SMA, and MSA
present.
are usually negative.
INFANTILE MYOFIBROMATOSIS AND SOLITARY ● Smooth muscle tumors
● Infantile hyaline fibromatosis
MYOFIBROMA IN ADULTS ● Hemangiopericytoma
CLINICAL FEATURES ● Neurofibroma
● Fibrous histiocytoma
Infantile myofibromatosis is a rare tumor of infancy and early
childhood, with a wide spectrum of disease activity ranging
from a solitary cutaneous nodule through to a multicentric form Special techniques
with widespread visceral involvement. The solitary type is ● The majority of cells show the immunophenotypic
defined as one nodule in the skin, muscle, bone or subcutaneous and electron microscopical features of myofibroblasts
tissue, and can occur in adults. The multicentric type can be (SMA and muscle actin (HHF-35) positive).
divided into two subtypes; in the first subtype the lesions are ● Desmin-positive cells have been reported in some infantile
multicentric but without visceral involvement, while in the myofibromatosis.
MYOFIBROBLASTOMA, INTRANODAL Cell morphology

● The spindle cells have cigar-shaped to slightly pointed
See Chapter 10, Lymphoreticular system tumors (p. 732). nuclei, inconspicuous nucleoli, and rare intranuclear
cytoplasmic inclusions. The cytoplasm is poorly defined,
and palely eosinophilic to amphophilic.
MYOFIBROBLASTOMA, MAMMARY-TYPE ● Some variation in adipocyte size is often seen.
● Up to 6 mitotic figures (range 0–6) per 10 HPF can be seen.
Mammary-type myofibroblastoma of soft tissue is a rare tumor

● Spindle cell lipoma
arising most commonly in male patients, and has a typical age
● Cellular angiofibroma
range of 35–67 years (median 53 years). The lesion usually
● Angiomyofibroblastoma
presents as either a slowly growing painless mass, or is discov-
ered incidentally. The site distribution includes the inguinal/
● Soft tissue perineurioma
groin area, posterior vaginal wall, buttock, anterior abdominal
wall, and mid-back. The tumor size varies from 2 to 13 cm
● Lipomatous hemangiopericytoma
(median 6 cm). The age distribution and apparent male sex
● Spindle cell liposarcoma
predilection is suggestive of some hormonal influence in the
● Low-grade malignant peripheral nerve sheath tumor
pathogenesis of myofibroblastomas. These lesions do not recur
after marginal excision.
Special techniques
● Tumor cells are positive for desmin and CD34, and
PATHOLOGICAL FEATURES (Figure 13.6) occasionally positive for SMA.
The lesion is well-circumscribed but unencapsulated, and
is composed of spindle to oval cells that are arranged MYOSITIS OSSIFICANS
haphazardly in variably sized fascicles, embedded in a
collagenous stroma. This is admixed with adipose tissue
CLINICAL FEATURES
(ranging from 10% to 60%). Interspersed thick hyalinized col-
lagen bundles, often with a zigzag-like pattern, separate the Myositis ossificans is a benign, reactive fibroblastic process rem-
fascicles. iniscent of nodular fasciitis, proliferative myositis and periostitis
Focal myxoid stromal change, epithelioid morphology of ossificans. The lesion develops rapidly (4–6 weeks), often fol-
some of the cells and atypical or multinucleated cells can lowing trauma, and typically presents as a well-circumscribed,
be seen. Numerous stromal mast cells are a common feature. usually painful and tender mass in the muscles of the extremities
Occasionally prominent pseudoangiomatous change, reminis- in young male patients. It shows a fairly characteristic pattern of
cent of that described in some cases of spindle cell lipoma, calcification on X-radiography. Many theories can be found con-
can be seen. cerning the etiology of myositis ossificans, but minor or major
traumas are considered to be the most common cause.
Myositis ossificans circumscripta refers to post-traumatic
calcification of soft tissue, including various ligaments.
Fibrodysplasia ossificans progressiva is an extremely rare
and disabling genetic disorder of connective tissue. The condi-
tion is characterized by congenital malformation of the great
toes, and by progressive heterotopic ossification of the tendons,
ligaments, fasciae, and striated muscles. Fibrodysplasia ossifi-
cans progressiva occurs sporadically and is transmitted as a dom-
inant trait with variable expression and complete penetrance.
Progressive osseous heteroplasia is a recently described genetic
disorder of mesenchymal differentiation characterized by dermal
ossification during infancy and progressive heterotopic ossification
of cutaneous, subcutaneous, and deep connective tissues during
childhood. The disorder can be distinguished from fibrodysplasia
ossificans progressiva by the presence of cutaneous ossification,
the absence of congenital malformations of the skeleton, the
absence of inflammatory tumor-like swellings, the asymmetric
mosaic distribution of lesions, the absence of predictable regional
Figure 13.6 Myofibroblastoma. Note bundles of bland patterns of heterotopic ossification, and the predominance of
myofibroblastic cells with focal stromal collagenization. intramembranous rather than endochondral ossification.
PATHOLOGICAL FEATURES (Figure 13.7) therefore bone will be seen at the periphery (zonation
phenomenon). The bone becomes clearly trabecular, with
The lesion of myositis ossificans passes through various stages
prominent osteoblastic rimming. The inter-trabecular tissue
of development including:
becomes less cellular, and at this phase osteoid appear to
● Incipient prebone forming phase (First week). Initially,
appear in the center of the lesion. At this phase the
there is hemorrhage and fibrin deposition, followed by
zonation phenomenon is classical.
proliferation of ‘tissue culture-like’ myofibroblastic cells
● Late osseous phase (6–7 weeks). Primitive lamellar bone
with granulation tissue-like vascularity reminiscent of
begins to appear, osteoblastic rimming becomes less
nodular fasciitis.
prominent, zonation is still seen, and primitive lipoblasts
● Early osseous phase (7–10 days). In this phase, in addition
and mature fat cells begin to appear in the inter-trabecular
to the mesenchymal myofibroblastic background, there is
spaces. Eventually, the primitive lamellar-woven bone
primitive osteoid formation in the form of small masses
scaffolding is converted into mature pure lamellar bone
starting at the periphery of the lesion. The stromal cells
with the appearance of fully mature marrow fat. Small,
start to round up and rim the periphery of the new bone,
elongated, endothelial-lined vessels are seen at later stages.
producing an osteoblast-like arrangement. The osteoid
then begins to calcify and form identifiable woven bone. Cell morphology
At this stage primitive cartilage may also be seen.
● Mid osseous phase (1–3 weeks). The lesion begins to
● The predominant population are myofibroblasts. They
mature from the periphery towards the center, and may be either stellate or spindle-shaped, and have
basophilic cytoplasm and prominent basophilic nucleoli.
● The osteoblasts rimming the bone are monolayered and
uniform in size and shape (unlike osteosarcoma in which
the cells are seen multilayered and pleomorphic).
● In early phase, the center of the lesion or the tissue culture-
like area can demonstrate more mitoses than most
sarcomas (up to 12 mitoses per HPF), but atypical forms
are not present.
● Osteosarcoma
● Proliferative myositis
● Ossifying synovial sarcoma
● Periostitis ossificans
Special techniques
(a)
● CD31, CD34 and Factor VIII highlight the vasculature.
● Ki-67, a proliferation marker, shows positive staining of
the stromal cells, being strongest in the immature spindled
areas.
NODULAR FASCIITIS
CLINICAL FEATURES
Nodular fasciitis is a benign proliferation of fibroblasts and
myofibroblasts arising in the superficial fascia and subcuta-
neous tissue, commonly in the upper extremities of adults and
in the head and neck region of infants and children. It can also
occur in a variety of other locations such as the parotid gland,
oral cavity, retroperitoneum, the hand, skin, within vessels,
(b) external auditory canal, forehead, vulva, the breast, and blad-
der. In the periosteum it is termed ‘paraosteal fasciitis’, in the
Figure 13.7 (a, b) Myositis ossificans. Skeletal muscle fibers cranium ‘cranial fasciitis’, and in the spermatic cord ‘prolifera-
separated by mesenchymal myofibroblastic cells with primitive tive funiculitis’. The lesions are generally small and solitary,
osteoid formation at the periphery of the lesion.The stromal cells and develop suddenly and rapidly. A history of trauma may
begin to round up and rim the periphery of the new bone,
producing an osteoblast-like arrangement.The osteoid then begins precede these reactive lesions, but their cause is unknown. An
to calcify and form identifiable woven bone. At this stage, primitive aberrant or exaggerated response to tissue injury without an
cartilage may also be seen. established cause has generally been favored as the pathogenesis
of nodular fasciitis. Excisional biopsy is curative, and the

nodules often resolve spontaneously.
Intravascular fasciitis is a very unusual variant of nodular
fasciitis involving arteries and/or veins. It may be confused with
other intravascular lesions, such as intravascular leiomyoma,
intravenous pyogenic granuloma, organized thrombus and,
even fibromuscular dysplasia if it arises in the arteries. A simple
excision is considered curable.
Ossifying fasciitis is an uncommon variant of nodular
fasciitis, usually post-traumatic with an unclear etiology of
ossification. It occurs in the subcutaneous tissue. Histologically,
it shows fibroblastic proliferation within a myxoid stroma,
with trabeculae of woven bone rimmed by plump osteoblasts.
Paraosteal fasciitis is similar to nodular fasciitis but is pres-
ent adjacent to the bone surface. (a)
Organ-associated fasciitis represents nodular fasciitis within
visceral organs. These lesions are known by a variety of names,
including organ-associated pseudosarcomatous myofibroblastic
proliferation, or pseudosarcomatous fibromyxoid tumors. The
most common location is the urinary bladder. Despite their
benign behavior, these lesions are frequently misinterpreted as
leiomyosarcomas and rhabdomyosarcomas in preoperative
biopsies and even in resected specimens because of their atypi-
cal spindle-cell features. A precise diagnosis of these lesions is
important to avoid unnecessary radical therapy.

The subcutaneous and intramuscular types of nodular fasciitis
are fairly well circumscribed, although they may appear to
infiltrate surrounding tissues. The fascial type is less well-
circumscribed and the intravascular variant is multinodular (b)
and present within dilated vessels. The morphological spec-
trum of nodular fasciitis is broad, including the classic pattern
of delicate fibroblasts suspended in a myxoid matrix, granula-
tion tissue-like areas, solid and whorled myofibroblastic prolif-
erations with multinucleated cells, mucoid cysts, and so-called
‘ancient’ forms with dense, refractile strands of keloid-like col-
lagen. This histological appearance is roughly correlated with
the duration of the nodule. The mitotically active myxoid form
tended to have the shortest history, the fibrous the longest,
while that of the cellular group is of intermediate duration.
Nodular fasciitis is correctly diagnosed in 43% of cases. The
rapid growth, abundant cellularity, and mitotic activity fre-
quently (21% of cases) cause these lesions to be misdiagnosed
as sarcomas, especially a myogenic sarcoma because of the
presence of actin.
There is often an impression of maturation towards the (c)
periphery of individual nodules. Scattered inflammatory cells –
particularly lymphocytes – are distributed throughout the Figure 13.8 Nodular fasciitis. (a) Myofibroblasts in a loose hyaline
lesion. Focal osteoid metaplasia may be seen. stroma with fluid-filled spaces. (b) Myofibroblasts in a loose feathery
background; note the scattered lymphocytes. (c) Myofibroblasts in a
myxoid background.
Secondary features
● Microhemorrhages.
● Mucoid pools. Cell morphology
● Fluid-filled spaces. ● Fibroblasts and myofibroblasts are the hallmark of this
● Keloidal-like hyaline fibrosis. lesion. They resemble cells in tissue culture; they are typically
● Focal osteoid metaplasia. rounded, rhomboid, triangular or stellate, with basophilic,
finely vacuolated cytoplasm and microvesicular nuclei Cell morphology

containing prominent nucleoli with a perinuclear halo. ● The cells of this lesion are active fibroblasts and
● Cellular pleomorphism is common. myofibroblasts, similar to those seen in nodular fasciitis.
● Mitotic figures may be seen, and can be numerous. ● A prominent feature of proliferative fasciitis is the presence
Atypical mitoses, however, are not present. of numerous ganglion-like cells. These are mono- or
● Lipid-containing macrophages may be present. binucleated myofibroblasts with finely vacuolated
● Multinucleated giant cells are not uncommon. basophilic cytoplasm, central or eccentric nuclei, and very
● Lymphocytes are constantly present and often evenly prominent nucleoli with perinucleolar halos.
distributed throughout the lesion. ● Mitoses may be numerous, but atypical forms are not seen.
Differential diagnosis Differential diagnosis

● Fibromatosis (is usually large, shows clearly infiltrative ● Ganglioneuroblastoma
margins and lacks any cellular pleomorphism) ● Rhabdomyosarcoma
● Low-grade fibromyxosarcoma (is usually larger with
infiltrative margins) Special techniques
● Myofibrosarcoma (larger infiltrative tumor with numerous ● The majority of cells exhibit myofibroblastic
mitotic figures) differentiation.
● Fibrosarcoma (often more densely cellular with high
mitotic rates and infiltrative margins)
● Malignant fibrous histiocytoma (much more pleomorphic
PROLIFERATIVE MYOSITIS
tumor with numerous typical and atypical mitosis)
● Dermatofibrosarcoma protuberans (is a dermal lesion that CLINICAL FEATURES
infiltrates and incorporates mature subcutaneous fat cells)
● Myxoma (usually intramuscular or juxta-articular in Proliferative myositis is a rare, reactive, tumor-like lesion (the
location) intramuscular counterpart of proliferative fasciitis) that is often
● Nodular fasciitis pattern can be seen in some spindle cell misdiagnosed as sarcoma. Typically, the lesion presents as a
carcinoma, especially metaplastic carcinoma of the breast rapidly growing nodule of 1–6 cm, mainly in the extremities,
the head and neck regions and flat muscles of the trunk and
Special techniques shoulder of people aged over 45 years. The clinical course of
proliferative myositis is benign, and local recurrence after
● A characteristic immunohistochemical profile includes
simple excision is uncommon.
SMA and MSA, vimentin, and KP1 (a histiocytic marker),
indicating dual myofibroblastic and histiocytic
differentiation. PATHOLOGICAL FEATURES (Figure 13.9)
Proliferative myositis shows a poorly demarcated, scar-like,
PROLIFERATIVE FASCIITIS intramuscular proliferative lesion involving muscle and over-
lying fascia creating a vague ‘checkerboard’ pattern. The com-
ponent cells are a mixture of plump stellate or spindle cells,
CLINICAL FEATURES numerous ganglion-like or rhabdomyoblast-like cells, and
Proliferative fasciitis is a reactive proliferative process, present- some inflammatory cells. The underlying skeletal muscle usu-
ing as a rapidly growing nodule of 1–5 cm. It occurs mainly in ally exhibits atrophy, but complete muscle replacement does
the extremities of adults, and rarely in children. Local excision not occur. Compressed vessels with circumferential fibrosis and
is usually curative. prominent endothelial cells may be seen.
Secondary features
● Occasional osteoid formation.
Proliferative fasciitis is a poorly circumscribed subcutaneous or
fascial lesion with infiltrative margins consisting of a mixture of Differential diagnosis
plump, spindle cells together with numerous ganglion-like cells ● Nodular fasciitis
set in a loose, myxoid or occasionally hyalinized collagenous ● Fibromatosis
matrix. In children, the lesion is well-circumscribed and more cel- ● Rhabdomyosarcoma
lular and less collagenous. Compressed vessels with circumferen- ● Myositis ossificans (when secondary osteoid formation is
tial fibrosis and prominent endothelial cells are usually seen. present)
● Atypical decubital fibroplasia
Secondary features
● Inflammatory infiltrate. Special techniques
● Extravasation of red blood cells. ● The cells have the immunohistochemical profile of
● Edema. myofibroblasts.
may be part of a systemic fibrosing disease. The disease prima-

rily affects men in their fifth and sixth decades of life, and often
presents with a colicky flank and back pain prior to abdominal
pain. It often causes renal failure due to ureteric obstruction.
Prompt diagnosis of idiopathic retroperitoneal fibrosis improves
the chances of preserving renal function, preventing involvement
of other organs, and relieving symptoms. Medical treatment –
that is, with corticosteroid or, more recently, with tamoxifen – has
been used successfully. Ureterolysis using conventional surgery or
laparoscopy remains the treatment of choice.

The lesion is ill-defined, and consists of a background fibro-
collagenous tissue containing variable numbers of inflammatory
(a)
cells, including germinal centers. Areas of fat necrosis may also
be seen. Hyalinization is frequently seen.
Cell morphology
● Plasma cells.
● Lymphocytes.
● Eosinophils.
● Fibroblasts and myofibroblasts.
(b)
Figure 13.9 (a, b) Proliferative myositis. Skeletal muscle fibers

separated by loose granulation tissue-type stroma containing
numerous ganglion-like cells and inflammatory cells.
PYOGENIC GRANULOMA
(a)
See Capillary hemangioma, lobular (p. 1085).
RETROPERITONEAL FIBROSIS
CLINICAL FEATURES
Retroperitoneal fibrosis is characterized by the development of
fibrotic mass surrounding the abdominal aorta and its branches.
In one-third of cases, the causes of this disease are known. These
include ergot-derivative drugs, retoperitoneal hemorrhage or
urine extravasation and desmoplastic response to a variety of
tumors. In the other two-thirds of cases, the retroperitoneal
fibrosis is idiopathic and is found most commonly as an isolated
fibrotic plaque centered over the lumbar spine and entrapping
one or both ureters. In these cases, it has been suggested that the
fibrosis is caused by a chronic inflammatory or autoimmune (b)
response to antigens leaking into the retroperitoneum from
atheromatous plaques in the aorta or common iliac arteries. Figure 13.10 (a, b) Retroperitoneal fibrosis. Inflammatory spindle
Evidence also suggests that idiopathic retroperitoneal fibrosis cell lesion with infiltrative margin.
Differential diagnosis Cell morphology

● Malignant lymphoma ● The main cell populations are fibroblasts and
● Fibromatosis myofibroblasts.
● Inflammatory fibrosarcoma of the retroperitoneum ● Inflammatory cells including lymphocytes and plasma cells.
● Sclerosing liposarcoma ● Foreign body giant cells may be seen.
● Inflammatory malignant fibrous histiocytoma (MFH) ● Occasional mitotic figures may be seen.
● Castleman’s disease
● Signet ring cell carcinoma of the stomach Differential diagnosis
● Sclerosing mesenteritis
Special techniques ● Mesenteric lipodystrophy
● Immunophenotypes correspond to the normal cell types ● Mesenteric panniculitis
listed above; however, many of the spindle-shaped cells are ● Inflammatory pseudotumor
macrophages, and therefore express macrophage- ● Peritoneal encapsulation (is a rare congenital malformation
associated antigens such as CD45, CD68, CD13, CD4 and in which an accessory peritoneal membrane encases loops
Mac387. of small bowel in a sac-like structure. This is usually found
● The plasma cells express polyclonal Ig. incidentally at laparotomy or autopsy)
● A significant proportion are IgA-producing cells. ● Mesenteric fibromatosis
● Idiopathic retroperitoneal fibrosis
● Sclerosing malignant lymphoma
SCLEROSING ENCAPSULATING PERITONITIS ● Desmoplastic response to a metastatic tumor
CLINICAL FEATURES SCLEROSING MESENTERITIS

Sclerosing encapsulating peritonitis is a reactive fibroblastic (IDIOPATHIC RETRACTILE MESENTERITIS)
process characterized by very thick sclerotic tissue involving
the whole peritoneal wall. The process can occur at any age, CLINICAL FEATURES
including children, with a median age at 44 years. Sclerosing
encapsulating peritonitis can be idiopathic, but most com- Sclerosing mesenteritis is a rare benign fibroproliferative dis-
monly follows chronic ambulatory peritoneal dialysis and treat- order of unknown etiology that often resembles a neoplasm.
ment with beta-blockers. Other rare causes include indwelling It has a variable clinical presentation, and is characterized by
peritoneovenous or ventriculoperitoneal shunts, mycobacterial thickening of the small-bowel mesentery, the mesenteric fat
infection, sarcoidosis, familial mediterranean fever, the carci- and, less commonly, the mesentery of the large bowel. This
noid syndrome, fibrogenic foreign material (drug users), liver condition rarely involves the pancreas. It appears grossly as
transplant, and abdominal trauma. This condition has been nodular hard tumor-like masses which cause shortening and
reported in association with ovarian tumors such as thecomas thickening of the mesentery. It affects middle-aged or elderly
and related lesions. It usually presents with small-bowel people, more often in males, and presents as abdominal mass
obstruction or abdominal mass, and most frequently affects the with small-bowel obstruction. The lesion is usually treated
serosa of the small bowel, and less commonly the peritoneum with surgery, often followed by corticosteroids and azathio-
of the large bowel and the visceral peritoneum of the pelvis prine. Tamoxifen has been shown to be useful in the treating
and upper abdomen. Sclerosing peritonitis is treated by opera- some cases of sclerosing mesenteritis.
tive removal of the thickened peritoneum and lysis of adhe-
sions, and in some cases by partial small-bowel resection. PATHOLOGICAL FEATURES
Corticosteroids have no effect. The lesion may be complicated
by postoperative intestinal obstruction and fistulae, and is Sclerosing mesenteritis is characterized by the presence of dense
occasionally fatal. lobular fibrosis of the peritoneal or mesenteric fat. The cells may
be arranged in a fascicular or storiform pattern, and may exhibit
excessive hyalinization. Elastic tissue is often found throughout
PATHOLOGICAL FEATURES the fibrous tissue. The lesion usually extends into the base of the
Sclerosing peritonitis is characterized by the presence of involved small bowel and entraps normal structures such as
fibrotic thickening and accentuation of the lobular pattern of lymph nodes and nerves. The mesenteric veins show muscular
the peritoneal fat. The fibrous tissue may be arranged in a hypertrophy and elastosis, with narrowing of the lumen.
fascicular or storiform pattern, or it may be hyalinized. Focal
collections of chronic inflammatory cells, surface fibrin deposi- Secondary features
tion, and focal hyperplasia of the surface mesothelial cells may ● Dystrophic calcification.
be present, often with inflammatory infiltrates, microabscesses, ● Submucosal edema and telangiectasia of the involved
giant cells of macrophagic origin, calcifications and severe small bowel with accumulation of lipophages within the
vascular alterations. lamina propria.
Cell morphology special pattern of growth, but may show fascicular and storiform
● The main cell populations are fibroblasts and arrangements. Some lesions show keloid-like hyalinized bands,
myofibroblasts. while others show cellular areas of plump epithelioid cells
● Lymphocytes, plasma cells and sometimes lymphoid arranged disorderly or in vague trabeculae or anastomosing
follicle formation are seen.
● Xanthomatous cells.
● Mesenteric lipodystrophy
● Mesenteric panniculitis
● Inflammatory pseudotumor
● Mesenteric fibromatosis
● Idiopathic retroperitoneal fibrosis
● Sclerosing malignant lymphoma
● Desmoplastic response to a metastatic tumor
● Sclerosing encapsulating peritonitis
Special techniques
● Elastic stains highlight the elastic fibers seen throughout
(a)
the fibrous tissue.
● The cells show fibroblastic and myofibroblastic
immunohistochemical features.
SOLITARY FIBROUS TUMOR (SFT)
CLINICAL FEATURES
The solitary fibrous tumor (SFT) is traditionally associated
with mesothelial-lined surfaces. As any organ with mesenchy-
mal tissue has the potential for developing this tumor, it has
been described in almost every organ in the body, but is not
associated with serosal surfaces and somatic soft tissue and
skin. These tumors usually present in adults during the fourth
to seventh decades of life, and rarely occur in children. They
either present as incidental findings or are associated with
(b)
symptoms related to the site of the tumor or with systemic
manifestations such as hypoglycemia, finger clubbing, arthral-
gia and osteoarthropathy. They range in size from 0.8 to 26 cm
in maximum diameter.
The behavior of these tumors is often unpredictable, and
does not always correlate with histological findings. Benign
tumors may remain unproblematic for several years before
changing into a malignant form. Most extrapleural SFTs behave
in a benign fashion, even in a higher histological grade group.
Orbital SFTs, however can behave aggressively and mimic
other orbital tumors. Malignant behavior, including distant
metastases, has been documented in as many as 20% of
pleural cases, with mortality rates as high as 50%. Complete
surgical excision with clear margins and long-term follow-up
may be advisable.
PATHOLOGICAL FEATURES (Figure 13.11) (c)
Solitary fibrous tumors are generally well-circumscribed, occa-

Figure 13.11 (a–d) Solitary fibrous tumor. A well-circumscribed
sionally multinodular, unencapsulated, or focally encapsulated spindle cell lesion with some thick- and thin-walled vessels.The
lesions consisting of varying numbers of elongated or plump spindle cells have oval nuclei and are separated by keloid-like fibers.
spindle cells set in a collagenous stroma. The cells have no Some tumors are indistinguishable from hemangiopericytoma.
Fibroblastic/myofibroblastic tumors, intermediate 983
FIBROBLASTIC/MYOFIBROBLASTIC TUMORS,
INTERMEDIATE
ACRAL MYXOINFLAMMATORY FIBROBLASTIC

SARCOMA (INFLAMMATORY MYXOHYALINE
TUMOR)
CLINICAL FEATURES
Acral myxoinflammatory fibroblastic sarcoma is a unique,
low-grade tumor of modified fibroblasts. The lesion develops
within the subcutaneous tissues of the distal extremities, with a
(d) predilection for the fingers and toes, in patients of all ages.
Clinically, this tumor is often suspected to be a ganglion cyst,
Figure 13.11 (Continued). tenosynovitis, or giant cell tumor of the tendon sheath. Clonal
chromosomal changes have been reported in this condition,
cords and strands alternating with hypocellular collagenized supporting its neoplastic nature. The tumor pursues a pro-
areas. Epithelioid tubules (representing mesothelial or epithelial tracted clinical course, a high rate of local recurrence, and a
inclusions from the surrounding tissue) may be seen entrapped low rate of metastasis.
within the tumor substance at the periphery.
Collapsed branching hemangiopericytoma-like vessels and
dilated thick-walled vessels surrounded by a hyaline cuff remi-
niscent of those seen in schwannomas may also be seen. PATHOLOGICAL FEATURES (Figures 13.12–13.17)
The tumor is poorly circumscribed, multinodular and infiltra-
Secondary features tive, and involves the subcutaneous fat, the dermis, and the
● Hyalinization. musculature. It is characterized by a dense chronic inflamma-
● Calcification. tory infiltrate that merges with the stroma, and which varies
● Psammoma body formation. from densely hyaline to focally myxoid and contains sheets of
● Occasionally, focal areas of myxoid change are seen. short spindled to rounded epithelioid cells. Focally, the epithe-
● Foci of necrosis are occasionally found. lioid cells are extremely large with bizarre, vesicular nuclei with
macronucleoli resembling Reed–Sternberg cells or virocytes.
Cell morphology Mitotic activity is usually low. In the myxoid areas vacuolated
● The spindle cells have poorly defined, pale eosinophilic lipoblast-like cells are seen; some of these contain inflamma-
cytoplasm, and either an elongated hyperchromatic, or tory cells within their cytoplasm (‘emperipolesis’) forming
plump, vesicular nucleus with a small nucleolus. so-called ‘cell microabscesses’.
● The epithelioid cells are polygonal or round, with
hyperchromatic nuclei.
● Mitotic figures vary from case to case, but are generally
low in number.
● Fibrosarcoma
● Benign and malignant fibrous histiocytoma
● Leiomyoma and leiomyosarcoma
● Fibrosing hamartoma
● Malignant mesothelioma
● Benign and malignant nerve sheath tumors
● Fibromatosis
Special techniques
● The cells show positive staining for CD34, vimentin and
bcl-2. Figure 13.12 Acral inflammatory myxohyaline tumor. A dermal
● Weak positivity for desmin has been reported. and subcutaneous inflammatory and myxoid lesion.
Figure 13.13 Acral inflammatory myxohyaline tumor. Figure 13.16 Acral inflammatory myxohyaline tumor. Multi-
Inflammatory picture with scattered bizarre tumor giant cells. vacuolated and signet ring lipoblast-like cells within the myxoid areas.
Figure 13.17 Acral inflammatory myxohyaline tumor. C-Kit

Figure 13.14 Acral inflammatory myxohyaline tumor. highlights the tumor cells.
Multinucleated giant cells within myxoid stroma.
● Inflammatory pseudotumors and various reactive fibro-
inflammatory processes
● Myxofibrosarcoma
● Pigmented villonodular tenosynovitis
● Liposarcoma
Special techniques
● The neoplastic cells are strongly positive for vimentin, and
focally positive for CD68 antigen and CD34.
● The Ki-67 labeling index with MIB1 is usually low.
● P53 immunoreactivity may be seen in both the primary
and recurrent tumor.
Figure 13.15 Acral inflammatory myxohyaline tumor.
● Keratin may be focally and weakly positive in some cases.
Reed–Sternberg-like cells scattered amongst other tumor and ● C-Kit strongly stains the atypical cells (personal
inflammatory cells. experience).
ANGIOFIBROMA, JUVENILE NASOPHARYNGEAL ● Infantile/Juvenile fibromatosis is a term often applied to

fibromatosis occurring in children and adolescents. It
See Chapter 8, Head and neck tumors, Tumors of the naso- resembles its adult counterpart, but has greater tendency
pharynx (p. 574). for local recurrence.

FIBROMATOSIS On gross examination, fibromatosis reveals a large, firm, ill-
defined whitish mass with a whorled cut surface. Histological
examination reveals an ill-defined moderately cellular or hypocel-
CLINICAL FEATURES
lular monomorphic spindle cell lesion. The constituent cells are
Fibromatosis (also known as desmoid tumor) is a generic term arranged in a diffuse sweeping pattern (or sometimes in loose
applied to a fibroblastic/myofibroblastic neoplastic process. fascicles), and infiltrate and incorporate the surrounding fatty
There are two main groups of fibromatosis: or muscular tissue. Thick bundles of keloidal collagen fibers
1. Superficial fibromatosis, including palmar, plantar and may be present. Recurrent fibromatosis may be more cellular,
infantile digital fibromatosis, which are typically small and and the cells may appear more epithelioid and exhibit some
less likely to recur. pleomorphism. Patent, round or oval-shaped, often empty cap-
2. Deep fibromatoses, such as abdominal, extra-abdominal, illaries are found throughout the lesion. These are usually
and mesenteric fibromatosis, which have an infiltrative rimmed by less cellular or edematous stroma. Muscular hyper-
growth pattern, are associated with aggressive clinical plasia of the small arteries is often seen, particularly in mesen-
behavior, and often arise in a muscular fascia (hence the teric fibromatosis.
name musculoaponeurotic fibromatosis).
Secondary features
Fibromatosis is usually a rapidly growing lesion, and is best
treated by radical local excision with a wide margin of unin- ● Perivascular lymphocytic infiltrate.
volved tissue. Endocrine treatment (tamoxifen, zoladex and ● Dystrophic calcification.
medroxyprogesterone) is sometimes used in treating inoperable ● Psammoma body formation.
tumors, or where there has been post-surgical recurrence. ● Metaplastic ossification.
Somatic beta-catenin or APC gene mutations have been ● Interstitial hemorrhage.
reported in ⱕ74% of sporadic deep fibromatoses, and in vir- ● Myxoid change.
tually 100% of Gardner syndrome-associated fibromatoses,
whereas genetic events in superficial fibromatoses remain less Cell morphology
well characterized. ● The fibroblastic/myofibroblastic cells are spindle-shaped
There are several recognized clinical variants of deep
with elongated tapering nuclei; these show numerous wavy
fibromatosis:
undulations or a zig-zag pattern resembling nerve sheath
● Intra-abdominal fibromatosis may be associated with
cells. (The undulation of neural cells is much less
Gardner’s syndrome, intra-abdominal surgery, or
pronounced, and they tend to have comma-shaped twists
estrogenic stimulation. Grossly, it is a well-circumscribed
rather than repeated undulations.)
lesion that most commonly involves the mesentery of the ● Mitotic figures are usually sparse.
small bowel. It may be multiple and be associated with
abdominal wall fibromatosis.
● Extra-abdominal fibromatosis: These aggressive, non- Differential diagnosis
metastasizing tumor-like lesions have a strong tendency ● Fibromatosis pattern can be seen in a variety of soft tissue
towards local infiltration, with a high recurrence rate. tumors. These lesions need to be remembered when
Trauma, hormones and heredity have been implicated as dealing with such patterns
etiological factors. The trunk and the extremities (shoulder, ● Hypertrophic scar/keloid
chest wall, back and thigh) are favored sites, but the ● Nodular fasciitis
lesions are also seen in locations such as the mediastinum ● Fibrosarcoma
and breast. ● Neurogenic sarcoma
● Head and neck fibromatosis is especially seen in ● Dermatofibrosarcoma protuberans
children and young adults, most frequently in the ● Smooth muscle tumors
supraclavicular region of the neck. It may also involve ● Liposarcoma
the oral and paraoral region. Erosion of bone is a ● Sclerosing mesenteritis
frequent finding in lesions arising in soft tissue around ● Gastrointestinal stromal tumors (GISTs)
the jaws. Head and neck fibromatosis may also be ● Desmoplastic fibroblastoma
seen within bone as ‘intraosseous fibromatosis’, also ● In epithelial organs such as the breast, spindle cell
called desmoplastic fibroma (see Chapter 2, Bone carcinoma and melanoma need to be ruled out before
tumors). making a diagnosis of fibromatosis
(a) (d)
(b) (e)
(c) (f)
Figure 13.18 Fibromatosis. (a) Hypocellular spindle cell lesions arranged in loose fascicles. (b) The lesion splits the skeletal muscle
fibers. (c) The spindle cells appear somewhat reminiscent of neural lesions.The opened vessels are surrounded by edematous areas.
(d) Keloidal fibrosis intermixed with the spindle cells. (e) Zigzag-like loose collagenous fibers; these are often mistaken as a neural tumor.
(f) Giant cells representing regenerative muscle fibers may be seen at the periphery of the lesion.
Special techniques ● Some tumors show estrogen receptor (ER)-positive

● The cells are vimentin positive and focally actin positive, cells.
and some show desmin positivity. ● Beta-catenin has been shown to be positive in some
● CD34 is negative. fibromatoses.
FIBROMATOSIS, JUVENILE/INFANTILE northwestern European origin. It affects mainly people over the
age of 60 years, and presents as a firm nodule or nodules in the
palmar surface of the hands. The nodules later become cord-like
CLINICAL FEATURES indurations, causing puckering and dimpling of the overlying skin
Juvenile (infantile) fibromatosis is a designation applied to a with subsequent contracture.
fibromatosis group that are seen in children and adolescents. The condition is usually treated by fasciectomy when there is
The infantile type usually affects children under the age of dysfunctional deformity.
5 years. The disease usually presents as a rapidly growing, deep-
seated, ill-defined mass in the region of the head and neck, PATHOLOGICAL FEATURES
shoulder, upper arm, and thigh. Similar to adult fibromatosis,
The disease is characterized by the presence of the two types of
these lesions tend to recur locally if inadequately excised.
structure: (i) nodules, consisting of proliferating fibro/myo-
fibroblastic cells; and (ii) thick bundles of collagen fibers. The
PATHOLOGICAL FEATURES clinically palpable nodules are sometimes histologically clas-
sified into those of the following three phases, according to
Infantile fibromatosis is an ill-defined, infiltrative, fibroblastic
Luck’s classification: proliferative phase; involutional phase;
lesion. It is usually intramuscular, but may extend into the
and residual phase. Lesions of the proliferative phase may exhibit
subcutaneous fat. The lesion shows variable patterns. The ‘diffuse
vascular features surrounded by one or more layers of cells.
immature form’ consists of small, haphazardly arranged ovoid
cells set in a myxoid and collagenized matrix. Intermingled
fat cells and lymphocytic infiltrate are often seen. The ‘mature
form’ consists of spindle cells and fibroblasts arranged in bun- ● Fibrosarcoma
dles and fascicles associated with varying amounts of collagen. ● Hypertrophic scar
More cellular or less cellular examples may resemble fibro- ● Calcifying aponeurotic fibroma
sarcoma and adult fibromatosis, respectively. ● Epithelioid sarcoma (can present as Dupuytren’s
contracture)
Secondary features
Special techniques
● Inflammatory infiltrate.
● Fat atrophy of the muscle fibers. ● The cells are vimentin-positive and focally actin-positive.
● Osseous metaplasia.
FIBROMATOSIS, PENILE (PEYRONIE’S DISEASE)
Cell morphology
● The cells of the immature form are small and ovoid with
little cytoplasm, whilst those of the mature form are CLINICAL FEATURES
spindle-shaped, with their cytoplasm blending into the Peyronie’s disease is a fibromatosis of the tunica albuginea, and
background matrix. is mainly seen in men between the ages of 20 and 40 years. The
disease presents with a palpable induration or mass in the dor-
Differential diagnosis sal aspect of the shaft of the penis, and this may cause abnor-
● Myxoma mal curvature of the organ. It has been suggested that trauma
● Myxoid liposarcoma to the erect penis is the inciting event, though more recently a
● Botryoid rhabdomyosarcoma role for perturbation of the p53 pathway has been implicated.
● Lipoblastomatosis Wide local excision is advocated as the treatment of choice for
● Non-ossifying stage of fibrodysplasia ossificans desmoid tumor of the penis.
progressiva
● Infantile fibrosarcoma PATHOLOGICAL FEATURES
● Lipofibromatosis
These are similar to those for other types of fibromatosis.
Special techniques
● The cells are vimentin-positive and focally actin-positive.
FIBROMATOSIS, PALMAR (DUPUYTREN’S FIBROMATOSIS, PLANTAR (LEDDERHOSE

DISEASE/CONTRACTURE) DISEASE)
CLINICAL FEATURES CLINICAL FEATURES

Palmar fibromatosis or Dupuytren’s disease is a common Plantar fibromatosis is a benign fibroproliferative process which
disabling hand disorder, mainly confined to caucasians of occurs in young adults and in children. It presents as a firm
nodule in the sole of the foot, rarely with any contraction INFLAMMATORY MYOFIBROBLASTIC TUMOR
deformity. Recurrence is rare.
(INFLAMMATORY PSEUDOTUMOR)
PATHOLOGICAL FEATURES (Figure 13.19) CLINICAL FEATURES

Plantar fibromatosis is a fairly well-circumscribed nodule Inflammatory myofibroblastic tumor (inflammatory pseudo-
consisting of alternating uniform collagenous and fibroblastic tumor) – previously termed plasma cell granuloma – is a distinctive
tissue arranged in parallel fascicles. Younger lesions are more lesion of myofibroblastic origin, often admixed with inflamma-
cellular, containing plump fibroblasts and myofibroblasts with tory cells, including plasma cells and eosinophils. The lesion has
occasional mitoses, while those of longer duration are less cel- been described in virtually all major organs. The lesion is grossly
lular, containing increasing amounts of dense birefringent col- circumscribed, ranges in size from 1 to 17 cm, and may be asso-
lagen and more slender cells which run in parallel waves typical ciated with constitutional symptoms such as fever, growth fail-
of mature fibrous tissue. ure, weight loss, raised erythrocyte sedimentation rate (ESR),
anemia, thrombocytosis, and polyclonal hyperglobulinemia.
Inflammatory myofibroblastic tumors have a benign course in
the majority of cases, despite multifocal lesions or recurrences.
They are currently considered as neoplasms due to their clonal
origin. In this connection, DNA analysis by flow cytometry is a
valuable diagnostic tool, because it allows identification of the
ploidy status – a procedure that is often useful for predicting the
nature and biological behavior of the lesion. Anaplastic lymphoma
kinase (ALK) – a hallmark of anaplastic large cell lymphoma –
has recently been implicated in the genesis of some inflammatory
myofibroblastic tumors in children and young adults. The human
herpesvirus-8 (HHV-8) gene expression has recently been
detected in both pulmonary and extrapulmonary inflammatory
myofibroblastic tumor, suggesting a possible role for this virus
in the pathogenesis of some of these tumors. Surgical resection is
the treatment of choice. The tumor recurs in up to 25% of cases,
this being related to the site, resectability, and multi-focality.
Malignant behavior may occur, and recurrence is possible.
Figure 13.19 Plantar fibromatosis. Alternating cellular and
hypercellular fibroblastic zones.
Secondary features Inflammatory myofibroblastic tumor shows a heterogeneous
● Chronic inflammatory cell infiltrates. pattern, but in principle it shows a mixture or predominance of
● Cartilaginous and osseous metaplasia.
Cell morphology
● The myofibroblasts present in younger lesions are plump,
spindle-shaped and stellate cells with a fairly abundant,
moderately basophilic cytoplasm.
● The nuclei may appear pale-staining or even clear, with
one or two prominent nucleoli.
● The older lesions contain mature fibroblasts.
● Multinucleated giant cells may sometimes be seen.
● Fibrosarcoma
● Deep fibrous histiocytoma
Special techniques
Figure 13.20 Inflammatory myofibroblastic tumor of the
● The cells are vimentin-positive and focally larynx. Submucosal spindle and myxoid lesion with scattered
actin-positive. inflammatory cells.
one or more of the following components: a myofibroblastic

element which is arranged in fascicles or whorls and can be
mistaken for sarcomas; a myxoid spindle cell component mim-
icking myxoid tumor; a mature fibroblastic component remi-
niscent of scar tissue; and mixed inflammatory infiltrates with
or without germinal centers. According to these constituents, in
histological terms, inflammatory myofibroblastic tumor shows
three basic patterns:
1. Granulation tissue or nodular fasciitis-like pattern: this
displays loosely arranged, plump, spindled myofibroblasts in
an edematous myxoid matrix with abundant blood vessels
and infiltrates of plasma cells, lymphocytes, and variable
number of eosinophils.
2. Fibromatosis or a myogenic or fibrohistiocytic neoplasm-
like pattern: this shows compact spindle cells with interlacing
bundles associated with a variable inflammatory cell infiltrate.
3. Scar-like or desmoid fibromatosis-like pattern: this exhibits Figure 13.21 Lipofibromatosis. Admixture of mature fat cells and
low cellularity, sparse inflammation and keloidal-like collagen monomorphic fibromatosis-like spindle cell components.
with occasional calcification or osseous metaplasia.
structures, including vessels, nerves, skin adnexa, and skeletal
Differential diagnosis muscle. The lesion is characterized by abundant adipose tissue,
● Leiomyosarcoma typically comprising more than 50% of the specimen admixed
● Inflammatory fibrosarcoma with fascicles of fibroblastic cells. In contrast with conven-
● Various spindle cell sarcomas tional fibromatoses, there is a striking association with fat
● Fibrous histiocytoma septa. The fibroblastic component generally contains a small or
● Well-differentiated inflammatory liposarcoma moderate amount of collagen, but in a few instances more
heavily collagenized foci have been noted. Myxoid change may
Special techniques be present, especially in specimens from the youngest patients.
● The myofibroblastic cells are SMA-positive, are Most tumors contain occasional small collections of univacuo-
occasionally desmin-positive, and may also be cytokeratin lated cells juxtaposed between the spindled fibroblastic com-
(CK)-positive. ponent and the mature adipocytes. These cells may represent
● ALK is sometimes positive. degenerate adipocytes, or lipid-rich fibroblasts or a transitional
● p53 is usually negative. stage between fibroblast and adipocyte. Cytological atypia is
● Flow cytometry identifies aneuploidy (hyperdiploidy) in invariably mild, and there is little or no nuclear pleomorphism.
approximately half of the cases of inflammatory Mitotic figures rarely exceed 5 per 50 HPF. In the occasional
myofibroblastic tumors. This feature appears to provide tumor there may be a small number of scattered pigmented,
the clinician with both diagnostic and prognostic spindled, or dendritic cells, similar to those found in Bednar
information. tumor (pigmented dermatofibrosarcoma protuberans), pig-
mented (melanotic) neurofibroma, and certain melanocytic
nevi. These may represent bystander cells that have become
LIPOFIBROMATOSIS passively incorporated within the mass, because their normal
migration pathway has been disturbed by the lipofibromatous
process.
CLINICAL FEATURES
Lipofibromatosis is a distinctive pediatric soft tissue tumor, Differential diagnosis
which appears to have a predilection for the hands and feet
but also occurs at a wide variety of other sites. In the past, this
● Lipomatous tumors (‘juvenile lipoma’, fibrolipoma,
lesion was classified primarily as a variant of fibromatosis lipoblastoma, spindle cell lipoma, or liposarcoma)
(especially congenital and infantile/juvenile types) or as fibrous
● Fibrous hamartoma of infancy (often shows ‘wire-like’
hamartoma of infancy; or as an early stage of calcifying aponeur- fibrocollagenous connective tissue or primitive myxoid
otic fibroma or a variant of lipoblastoma. Congenital lipofi- mesenchymal nodules with a concentric or whorled
bromatosis may also occur. Regrowth of the tumor or persistent architecture)
disease occurs in 72% of cases.
● Infantile or juvenile fibromatosis
● Mesenchymoma or mesenchymal hamartoma
● Calcifying aponeurotic fibroma
PATHOLOGICAL FEATURES (Figure 13.21) ● Diffuse neurofibroma
Lipofibromatosis shows an infiltrative edge, with both the ● Nodular fasciitis
fat and fibrous elements infiltrating and entrapping regional ● Lipomatous hemangiopericytoma
Special techniques On occasion, myxoid change and osseous metaplasia are found.
● Some tumors are immunoreactive for CD99, CD34, Fibrosarcoma is a diagnosis of exclusion, and it is therefore
smooth muscle alpha-actin and bcl-2, and less frequently important to rule out other lesions with a fibrosarcoma pattern.
for S-100 protein, SMA and EMA. The sclerosing epithelioid variant of fibrosarcoma is a relatively
● No reactivity is detected for desmin, keratins, or CD57. well-circumscribed lesion with pushing margins, sometimes with
focal infiltration. It has a hypocellular sclerotic background
stroma infiltrated by a uniform population of small round or oval
epithelioid cells arranged in nests, strands and cords, resulting in
FIBROBLASTIC/MYOFIBROBLASTIC TUMOURS, an acinar or alveolar pattern. The cells are usually surrounded by
MALIGNANT retraction artifacts which, in combination with the prominent
hyaline sclerosis, may give the lesion a chondro-osseous appear-
ance. Some fibrosarcomas may consist predominantly of uniform
FIBROSARCOMA
round cells with a striking plasmacytoid appearance.

Fibrosarcoma is a malignant soft-tissue tumor which is only ● Fibrosarcoma pattern can be seen in a wide range of tumors
diagnosed after excluding tumors with similar histological ● In soft tissues, the most common tumors in this group are
features. It occurs both in pediatric patients (infantile fibro- monophasic synovial sarcoma, leiomyosarcoma, and
sarcoma) and in adults (‘adult-type’ fibrosarcoma). The tumor malignant peripheral nerve sheath tumor (MPNST)
affects a wide variety of sites, including the bones and meninges. ● When fibrosarcoma pattern is encountered in a tumor of an
In adults, it presents as a solitary, slowly growing mass which epithelial or visceral organ (e.g., bowel, lung, bladder, uterus,
frequently metastasizes, whereas in childhood the lesion tends skin, breast), sarcomatoid carcinoma must be considered
to grow more rapidly but metastasize less often. Treatment is before entertaining a diagnosis of any kind of sarcoma
by wide local excision or excision of the whole compartment ● Malignant melanoma – the ‘mother of all mimics’ – should
containing the tumor. Adjuvant chemotherapy may be beneficial. always be borne in mind when dealing with a lesion that
Sclerosing epithelioid fibrosarcoma is an uncommon variant of has a fibrosarcoma pattern, especially if it is found in the
fibrosarcoma that occurs in deep soft tissues, often adjacent to lymph nodes or in the liver
the fascia or periosteum. This lesion affects the extremities, trunk ● Other sarcomas that can exhibit a focal monomorphic
or head and neck region of adults. The tumor is relatively low- spindle cell pattern are dermatofibrosarcoma protuberans
grade, and is characterized by protracted clinical evolutions. (DFSP), dedifferentiated liposarcoma, osteosarcoma,
There is a tendency for frequent local recurrence, followed by spindle cell variant rhabdomyosarcoma, extraskeletal
late metastasis. mesenchymal chondrosarcoma, and rarely chordoma
● Sclerosing epithelioid fibrosarcoma can be confused with a
variety of tumors such as infiltrating lobular carcinoma,
sclerosing lymphoma, granulocytic sarcoma, desmoid tumor,
Fibrosarcoma is a densely cellular, infiltrative and occasionally nodular fasciitis, myositis ossificans, fibroma, ossifying
well-circumscribed lesion consisting of monomorphic spindle fibromyxoid tumor of soft part, extraskeletal myxoid
cells arranged in fascicles with a distinct ‘herring-bone’ pattern. chondrosarcoma and clear cell sarcoma of tendon sheath
Varying degrees of collagenization and hyalinization can be seen.
Special techniques
● The cells are vimentin-positive.
● Reticulin staining reveals fibers surrounding each cell.
● CAM5.2 may be focally positive in childhood
fibrosarcomas.
● The epithelioid variant may show positivity for EMA
and CD34.
INFLAMMATORY FIBROSARCOMA OF THE

MESENTERY AND RETROPERITONEUM
CLINICAL FEATURES
Inflammatory fibrosarcoma of the retroperitoneum, mesentery,
mediastinum, and peritoneal surfaces is not a very well-
Figure 13.22 Fibrosarcoma consists of uniform malignant spindle characterized tumor. The use of the term has been proposed
cells arranged in fascicles. because of the difficulty in distinguishing reactive inflammatory
Fibroblastic/myofibroblastic tumors, malignant 991
myofibroblastic tumors from sarcomas with an inflammatory HYALINIZING SPINDLE CELL TUMOR WITH
component arising in these sites. This diagnostic category, there-
GIANT ROSETTES (HSTGR)
fore probably includes both low-grade fibrosarcomas, and
myofibroblastic inflammatory tumors. The lesion occurs mainly
in children and adolescents, is locally aggressive, and has CLINICAL FEATURES
metastatic potential.
Hyalinizing spindle cell tumor with giant rosettes (HSCT) is a
rare lesion that is considered to be a variant of low-grade
fibromyxoid sarcoma. It has an indolent clinical behavior with
Inflammatory fibrosarcoma of the mesentery and peritoneum metastatic potential. It most commonly occurs in the peripheral
is an infiltrative spindle cell lesion consisting of a mixture of deep soft tissues, and rarely in central deep soft tissues. It affects
fibroblasts, myofibroblasts, plump histiocytoid cells and inflam- young or middle-aged adults and also occurs in children.
matory cells, particularly plasma cells. The fibroblasts and
myofibroblasts are arranged in sweeping fascicles or whorled
structures. The background stroma may show edema, myxoid PATHOLOGICAL FEATURES (Figure 13.24)
change, or hyalinization with keloid-like areas and/or calcifica- This tumor is similar to low-grade fibromyxosarcoma (a hypo-
tion. Delicate and prominent blood vessels may be seen in the cellular, myxoid spindle cell tumor), and in addition it contains
myxoid areas. numerous giant collagen-containing rosettes.
The tumor cells show nuclear irregularity and hyperchro-
Secondary features
masia. The lesion usually shows areas of transition from the
● Fibrosis. typical spindle cells into more epithelioid forms. As these
● Calcification. epithelioid cells coalesce, there is an accumulation of collagen
at the center of the cell nests.
Differential diagnosis In the fully developed giant collagen rosette, the epithelioid
● Retroperitoneal fibrosis fibroblastic cells palisade around a central core of hyalinized
● Inflammatory pseudotumor collagen.
● Xanthogranuloma
● Leiomyosarcoma
● Sarcomatoid mesothelioma ● Low-grade fibromyxosarcoma
● Localized fibrous tumor of the pleura and peritoneum ● Dermatofibrosarcoma protuberans (the presence of giant
● Sclerosing lymphoma rosettes in fibrosarcomatous areas of dermatofibrosarcoma
protuberans suggests a possible histogenetic relationship
Special techniques between fibrosarcomatous areas of DFSP and hyalinizing
spindle cell tumor with giant rosettes)
● The majority of cells are myofibroblasts, and therefore
● Sclerosing fibrosarcoma
positive for SMA, MSA, and vimentin.
● The fibroblasts present in the submesothelial areas may
show cytokeratin positivity. Special techniques
● The cells around the collagen rosettes display positive
immunoreactivity for neuroendocrine markers (S-100
protein, synaptophysin, CD57, protein gene product 9.5,
and neuron-specific enolase, NSE).
● The spindle cell portions of the tumor are positive for
Factor XIIIa, vimentin, collagen IV, and CD68.
● Ultrastructurally, the rosette-forming cells contained
neurosecretory granules, However, recent
ultrastructural analysis of these cells indicates that
they have attributes of fibroblasts rather than of
neuroendocrine cells.
LOW-GRADE FIBROMYXOID SARCOMA
CLINICAL FEATURES
Figure 13.23 Inflammatory fibrosarcoma (inflammatory
myofibroblastic tumor) within the abdomen. Loosely arranged Low-grade fibromyxoid sarcoma is a rare, indolent but meta-
myofibroblastic cells, inflammatory cells and keloid-like hyalinization. stasizing soft tissue tumor which affects young adults. The
(a) (a)
(b) (b)
Figure 13.25 Fibromyxoid sarcoma (a) showing loose hypocellular

spindle and slightly myxoid lesions reminiscent of fibromatosis but
with hyperchromatic, slightly pleomorphic nuclei; (b) showing zigzag-
like, loose collagenous fibers, often mistaken as neural tumor or
fibromatosis.
low-grade fibromyxoid sarcoma, as both tumors show a pro-

longed preclinical period, deep extremity location, and overall
innocuous or ‘low-grade’ histological features. The suggestion
has been made that these two tumors be referred to as
‘fibrosarcoma, low-grade fibromyxoid type’, noting either the
presence or absence of rosettes.

(c)
The tumor is usually deceptively bland, with moderate or poor
Figure 13.24 (a–c) Hyalinizing spindle cell tumor with giant cellularity, the spindle cells of which are arranged in inter-
rosettes.This is a hypocellular, myxoid spindle cell tumor showing weaving fascicles, whorls, or in a storiform pattern. Scattered
transition from the typical spindle cells into more epithelioid and lymphocytic and plasma cell infiltration is often seen. The
classic giant collagen rosette. tumor may show epithelioid areas reminiscent of cells seen in
hyalinizing spindle cell tumor with giant rosettes; on occasion,
lesion occurs in various locations such as the extremities, trunk, miniature rosettes are seen. Recurrent tumors may demonstrate
neck, axilla, perineum, or small-bowel mesentery. Hyalinizing increased cellularity, focal pleomorphism, increased mitotic fig-
spindle cell tumor with giant rosettes is presently considered, ures, or rarely dedifferentiation into anaplastic round cell tumor.
by some, as being closely related to or even a variant of Occasionally, a rich capillary network is seen.
Fibroblastic/myofibroblastic tumors, malignant 993
Secondary features
● Hyalinization.
Cell morphology
● The cells are ovoid or spindle-shaped, with tapered
nuclei.
● The cells have moderate, eosinophilic cytoplasm.
● Nuclear pleomorphism is minimal.
● Mitoses are uncommon, or only few in number.
● Desmoid fibromatosis
● Spindle cell liposarcoma (a)
● Diffuse neurofibroma
● Low-grade myxofibrosarcoma
● Low-grade MPNST
Special techniques
● Most tumor cells show strong staining with antibodies to
vimentin, while occasional cells stain positively for actin,
desmin and cytokeratin, in keeping with focal
myofibroblastic differentiation.
● Staining for CD34 varies from focal to diffuse.
MYOFIBROSARCOMA (b)
Figure 13.26 Myofibrosarcoma. (a) This lesion resembles nodular

CLINICAL FEATURES fasciitis, but it has clear infiltrative margins. (b) Slightly pleomorphic
myofibroblasts with interstitial pale hyalinization.
Malignant mesenchymal tumors of myofibroblasts are uncom-
mon, and are variously reported under terms such as myofibro-
blastic sarcoma, myofibrosarcoma, low-grade myofibroblastic
encountered in recurrent lesions. Focal coagulation necrosis
sarcoma, myofibroblastic-rich fibrosarcoma, or spindle-cell
may be present.
sarcoma showing myofibroblastic differentiation. Myofibro-
sarcoma may be indolent, but can relapse and metastasize, even
after a long period. The clinical importance of these lesions lies Differential diagnosis
in the resemblance – particularly of low-grade examples – to ● Nodular fasciitis
reactive or pseudosarcomatous conditions. Most reported ● Leiomyosarcoma
cases have occurred in the head and neck region and rarely ● Fibrosarcoma
in the soft tissue of the trunk and breast. The age range is ● Sarcomatoid carcinoma
broad, and there is an approximately equal gender-related inci-
dence. These tumors may recur, or they may metastasize to the Special techniques
lungs.
● The tumor cells are positive for SMA, MSA, and
sometimes for desmin.
PATHOLOGICAL FEATURES (Figure 13.26) ● The main ultrastructural features of the myofibroblast are
Myofibrosarcoma may show a spectrum of myofibroblastic abundant rough endoplasmic reticulum (RER); modestly
differentiation from fasciitis-like to sarcomatous with focal developed peripheral myofilaments with focal densities
hemangiopericytomatous or myxoid pattern. Hypocellular (stress fibers); and fibronexus junctions. Other features
areas with various features, including collagenous, scar-like include a Golgi apparatus and collagen-secreting granules,
and rarely keloid-like areas, may be seen. Mitotic figures and gap junctions, and actin-associated non-desmosomal
focal necrosis are frequent, and cellular pleomorphism may be junctions.
MYXOFIBROSARCOMA (MYXOID MALIGNANT

FIBROUS HISTIOCYTOMA)
CLINICAL FEATURES
Myxofibrosarcoma – also known as a myxoid variant of malig-
nant fibrous histiocytoma (MFH) – is one of the most common
sarcomas. It affects adults between the ages of 22 and 91 years
(median age 66 years), and has an equal incidence in men and
women. This lesion occurs most commonly in the extremities,
but it can also be seen in various other locations, such as trunk,
head and neck, axilla, perineum, or small-bowel mesentery and
visceral organs. The lesions vary in size from 0.8 to 27 cm in
maximum diameter. It is classified into low-, intermediate- and
(a)
high-grade tumor according to histological criteria. Myxo-
fibrosarcoma tends to become progressively high grade in
recurrences, and the lesions may then metastasize. Local recur-
rence occurs in 54% of cases. Patients who develop local recur-
rence within 12 months have a higher risk of dying from their
disease. A rare example of dermatofibrosarcoma protuberans
with areas showing low-grade myxofibrosarcoma has been
reported.

Myxofibrosarcomas are either seen superficially within dermis
or subcutaneous tissue and appear as tumor nodules separated
by fibrous septa or deeply seated in intramuscular locations
and tend to form a discrete mass. According to histological
grade the tumors vary from hypocellular, predominantly myx-
oid and spindle-cell in appearance (low-grade myxofibro- (b)
sarcoma) to high-grade, very cellular, pleomorphic lesions with
multinucleated giant cells, high mitotic activity, and areas of Figure 13.27 (a, b) High-grade myxofibrosarcoma.Vaguely nodular
necrosis reminiscent of MFH. myxoid spindle cell tumor with pleomorphic and malignant giant cells.
Secondary features
● Hyalinization is frequently seen.
● Necrosis and hemorrhage is mostly seen in high-grade
tumors.
● Heavy inflammatory infiltrates composed of lymphocytes
and plasma cells are especially seen.
Vascular pattern
● Thin-walled, curvilinear vessels are often seen in low-grade
tumors.
● Occasionally, a plexiform pattern reminiscent of those seen
in myxoid liposarcoma is noted.
● A hemangiopericytomatous vascular pattern may also
be seen.
Cell morphology
● The cells are ovoid or spindle-shaped, with tapered nuclei. Figure 13.28 Low-grade myxofibrosarcoma. Myxoid background
● Nuclear pleomorphism and hyperchromasia is noted, with numerous, uniform malignant spindle cells.
even in low-grade tumors.
● Bizarre multinucleated giant cells with eosinophilic Differential diagnosis
cytoplasm are often seen in high-grade tumors. ● Myxoid neurofibroma
● Mitoses are often seen. ● Myxoma
Fibrohistiocytic tumors, intermediate 995
● Superficial angiomyxoma (is a slowly growing dermal or Dermatofibrosarcoma protuberans and giant cell fibroblas-
subcutaneous lesion that lacks atypia or nuclear toma are considered to be closely related tumors. Giant cell
hyperchromasia and pleomorphism and only infrequent fibroblastoma can sometimes recur as DFSP.
mitotic figures, and contains prominent dilated vessels) Fibrohistiocytic tumor with features of both DFSP and dermato-
● Low-grade fibromyxosarcoma (occurs in younger age fibroma: on rare occasions, some cutaneous fibrohistiocytic
group, frequently metastasizes and histologically shows lesions may exhibit clinical, histological, and immunohisto-
more bland-looking, uniform spindle cells, with prominent chemical features of both dermatofibroma and DFSP. These
hyalinized stroma) lesions have the potential for local recurrence, and are best
● Acral myxoinflammatory fibroblastic sarcoma treated by complete excision.
● Nodular fasciitis Dermatofibrosarcoma protuberans with malignant transfor-
● Dermatofibrosarcoma protuberans with myxoid change mation: Dermatofibrosarcoma protuberans may contain more
● Low-grade MPNST cellular areas with features of fibrosarcoma, malignant fibrous
● Cutaneous mucinosis histiocytoma, or myxofibrosarcoma. These areas are considered
● Dermatofibrosarcoma protuberans with myxoid as a tumor dedifferentiation, and are associated with a higher
changes rate of recurrence. A gain of chromosome 17 has been reported
● On rare occasions, an extension of mucinous material into in some recurrent or large-sized DFSPs; this occurs in high-risk
the dermis in cases of myxofibrosarcoma results in an groups, with the possibility of a progression to sarcoma.
erroneous diagnosis of papular mucinosis Bednar tumor is a pigmented variant of DFSP.
Special techniques
● Tumor cells show intense reactivity to vimentin and CD34.
● The cells show variable staining for smooth muscle DFSP has a characteristic histological appearance that is of uni-
alpha-actin and MSA (HHF35). form, moderately cellular spindle cells with a storiform pattern.
● Some tumor cells express p53 protein. The lesion involves the dermis, and also extends into the sub-
● The MIB-1 labeling index is variable, depending on the cutaneous fat in an infiltrative pattern. Giant rosettes in the
grade of the tumor. fibrosarcomatous areas of DFSP – similar to those observed in
hyalinizing spindle cell tumor with giant rosettes (HSCTGR) –
have been reported. DFSP may rarely show extensive myxoid
degeneration, sclerosis or a schwannoid histological appear-
FIBROHISTIOCYTIC TUMORS, BENIGN ance such as nuclear palisading and even Verocay body forma-
tion. Mitotic activity in DFSP ranges from 0 to 3 per 10 HPF,
and from 2 to 6 per 10 HPF in the sarcomatous component.
FIBROUS HISTIOCYTOMA, JUVENILE
Bednar tumor shows a similar histological appearance, but
XANTHOGRANULOMA, PLEXIFORM XANTHOMA, with the presence of dendritic pigmented cells.
RETICULOHISTIOCYTIC GRANULOMA AND
Cell morphology
XANTHOMA
● The main cell populations are the fibroblastic cells
See Chapter 12, Skin tumors (pp. 903–9). showing plump oval and spindle-shaped nuclei and pale or
FIBROHISTIOCYTIC TUMORS, INTERMEDIATE
DERMATOFIBROSARCOMA PROTUBERANS (DFSP)
CLINICAL FEATURES
Dermatofibrosarcoma protuberans (DFSP) is a locally aggres-
sive tumor with a limited risk of distant metastasis. Its histo-
genesis is controversial; fibroblasts and nerve sheath cells are
possible cells of origin, but the consistent expression of CD34
positivity indicates an origin from undifferentiated mesenchy-
mal precursor cells. This lesion occurs in the trunk and proxi-
mal extremities of young adults, and usually presents either as
a nodule, plaque or multinodular lesion, with or without ulcer-
ation. Radical excision is required, as local recurrence occurs in Figure 13.29 Dermatofibrosarcoma protuberans. Note the classic
50% of cases following simple excision. storiform pattern.
GIANT CELL FIBROBLASTOMA
CLINICAL FEATURES
Giant cell fibroblastoma is a rare, subcutaneous tumor of chil-
dren which is classified as a fibrohistiocytic tumor of inter-
mediate malignancy. The lesion occurs in the soft tissue and
subcutaneous tissue, most commonly in the region of the back
and thigh, but it can also occur at other sites such as the scro-
tum and orbit. It may rarely develop in adults. This neoplasm
has been considered by some authors to be a juvenile variant of
DFSP. Local recurrences are frequent after surgical excision,
and may occasionally take the form of DFSP.

Figure 13.30 Bednar tumor (pigmented dermatofibrosarcoma). This neoplasm is characterized by a proliferation of cytologi-
Note the spindle cells arranged in a storiform pattern with cally bland, spindle-shaped and ovoid cells of varying cellular-
scattered dendritic melanocytes. ity, intermixed with pseudovascular sinusoidal, angiomatoid
or cystic structures called ‘angiectoid spaces’. These spaces are
lined by large cells with pleomorphic nuclei intermixed with
eosinophilic cytoplasm that blends into the collagenous
multinucleated cells. The stroma is variably collagenous and
background.
myxoid. The tumor usually shows prominent, various-sized
● Other cells that may be seen are xanthomatous cells,
blood vessels, often with perivascular hyalinization. In addi-
osteoclast-like giant cells, and granular cells.
tion, scattered pseudovascular spaces filled with an amorphous
● Myofibroblastic/myoid differentiation may rarely be seen.
eosinophilic material are present and lined by spindle-shaped
● In Bednar tumor, dendritic pigmented cells containing
and ovoid cells similar to those found throughout the neo-
premelanosomes and mature melanosomes are dispersed
plasm. Rare multinucleated floret-like giant cells are seen.
among neoplastic cells.
Giant cell fibroblastoma may show features of DFSP, and a
unique case referring to a pigmented DFSP has been reported.
● Deep cellular dermatofibroma Differential diagnosis
● Pleomorphic fibroma of tendon sheath
● Fibromatosis
● DFSP
● Smooth muscle tumors
● Giant cell angioblastoma
● Giant cell angiofibroma
● Spindle cell liposarcoma
● Myxoma
● Low-grade myxofibrosarcoma (low-grade MFH)
● Low-grade MPNST
● Low-grade fibromyxoid sarcoma
Special techniques
● DFSP shows diffuse immunoreactivity for CD34. CD34 is
expressed in 50% of the sarcomatous component.
● Expression of EMA occurs in some DFSP, especially in
moderately cellular and collagen-rich areas, and in
perivascular areas. This may reflect true perineural cell
differentiation in DFSP.
● CD10 has recently also been shown in some spindle cell
tumors of skin, such as dermatofibroma, DFSP and
neurofibromas.
● Cells of DFSP show a negative reaction for NSE, HMB-45
or S-100 protein. In Bednar tumor, the main cell population
exhibits positive reactions for vimentin and CD34, while Figure 13.31 Giant cell fibroblastoma. Note cleft-like spaces
the pigmented cells show S-100 protein positivity. within a collagenous background, lined by giant cells.
Fibrohistiocytic tumors, malignant 997
● Liposarcoma Differential diagnosis

● Fibromyxoma ● Angiomatoid malignant fibrous histiocytoma
● Giant cell tumor of tendon sheath
Special techniques ● Tuberculoid leprosy
● The tumor cells stain strongly and diffusely for both
CD34 and bcl-2. Special techniques
● S-100 protein, desmin, SMA, and MSA are usually ● The cells express alpha-1-antitrypsin, alpha-1-
negative.
antichymotrypsin, vimentin, SMA, and CD68.
PLEXIFORM FIBROHISTIOCYTIC TUMOR

FIBROHISTIOCYTIC TUMORS, MALIGNANT
CLINICAL FEATURES Malignant fibrous histiocytoma is one of the most commonly

diagnosed soft tissue sarcoma, though this may represent an
Plexiform fibrohistiocytic tumor presents as slowly growing
over-diagnosis rather than a genuine increased incidence of the
dermal or subcutaneous nodule, most commonly in the upper
disease. MFH is also more often diagnosed amongst radiation-
arm of children and young adults. It is considered to be a
induced malignancies. This tumor occurs in the deep soft tissue
tumor of low-grade malignancy, mainly because of the reported
of middle-aged and elderly patients, most commonly in the
local recurrence and lymphatic and pulmonary metastases.
extremities, but it may also rarely occur in visceral locations.
This tumor requires a wide excision.
Most of the so-called MFH can be subclassified, by using
defined criteria, into other sarcomas, in particular pleomorphic
Plexiform fibrohistiocytic tumor is an ill-defined, infiltrative,
multinodular dermal or subcutaneous lesion, consisting of two
components: (i) numerous ramifying fibroblastic trabeculae inter-
mingled with ill-defined aggregates; or (ii) nodules of plump
epithelioid histiocytic cells. Osteoclast-like giant cells may be
seen within these nodules. Marked peripheral or total hyalin-
ization of the nodules may occur. Extravasation of red blood
cells and hemosiderin deposition is common.
Cell morphology
● The fibroblastic component shows bland, elongated nuclei.
● The histiocytic component consists of plump, eosinophilic
epithelioid cells with vesicular nuclei.
● Osteoclast-like giant cells.
● Inflammatory cells.
(b)
(a) (c)
Figure 13.32 (a–c) Plexiform fibrohistiocytic tumor. Numerous ramifying fibroblastic trabeculae intermingled with aggregates or nodules of
plump epithelioid histiocytic cells. Scattered osteoclast giant cells are frequently seen.
liposarcoma, myxofibrosarcoma or leiomyosarcoma. Pleomor- and proliferation of spindled, ovoid or round cells arranged in
phic sarcomas showing myogenic differentiation are signifi- whorls, fascicles or a diffuse pattern. Lymphoid follicle forma-
cantly more aggressive tumors. tion is not uncommon. Due to the amount of lymphoid infil-
MFH is further classified into: trate with follicle formation, the lesion may give the impression
of an intranodal process.
MALIGNANT FIBROUS HISTIOCYTOMA,
Secondary features
ANGIOMATOID
● Hemorrhage
● Hemosiderin deposition
CLINICAL FEATURES
Angiomatoid ‘malignant’ fibrous histiocytoma has been consid-
ered as a low-grade fibrohistiocytic sarcoma with a potentially
fatal outcome. It has been shown that the rates of recurrence,
metastasis, and mortality for this tumor are 23.2%, 8.7%, and
4.3%, respectively. The tumor presents as a deep dermal or sub-
cutaneous lesion in children and young adults, typically on the
extremities. The resemblance of these lesions to lymph nodes
(both clinically and morphologically), the finding of desmin-
positive cells in the tumor and in the adjacent lymphoid infil-
trate, and the fact that 66% of cases are found at sites of normal
lymphoid tissue, raise the possibility that some of these lesions
may arise from – or be related to – myoid cells of lymphoid tissue.

Angiomatoid ‘malignant’ fibrous histiocytoma is a fairly well-
circumscribed, moderately cellular lesion showing ill-defined
nodularity. It has a dense, fibrous pseudocapsule which extends
irregularly between the tumor nodules. The tumor shows three
main components: angiomatoid; lymphoplasmacytic infiltrate;
(b)
(a) (c)
Figure 13.33 (a–d) Angiomatoid ‘malignant’ fibrous histiocytoma.The tumor is a fairly well-circumscribed, moderately cellular lesion
showing ill-defined nodularity and has a dense fibrous pseudocapsule which extends irregularly between the tumor nodules. Note the tumor
lymphoplasmacytic infiltrate, and proliferation of the spindled, ovoid or round cells arranged in whorls, fascicles or diffuse pattern. Due to the
amount of lymphoid infiltrate with follicle formation, the lesion may give the impression of an intranodal process.The cells are ovoid or
spindle-shaped, with vesicular nuclei and small nucleoli (e).
Fibrohistiocytic tumors, malignant 999
Special techniques
● The tumor cells exhibit immunoreactivity for vimentin.
● Some tumors show CD68 and CD57 (Leu-7) positivity.
● The tumor cells may express CD34, desmin,
synaptophysin, and reactivity for smooth muscle alpha-
actin, EMA, NSE, and CD99 (O-13).
● Electron microscopy shows a mixture of fibrohistiocytic,
myofibroblastic and undifferentiated cells containing
cytoplasmic processes and dense-core granules.
● Heavy-caldesmon may be strongly positive, and calponin
may be focally or extensively positive.
● The lymphoplasmacytoid component is a mixture of B and
T lymphocytes.
MALIGNANT FIBROUS HISTIOCYTOMA, GIANT

CELL TYPE (MALIGNANT GIANT CELL TUMOR
OF SOFT PARTS)
(d)
CLINICAL FEATURES
Malignant giant cell tumor of soft parts – also known as ‘malig-
nant fibrous histiocytoma, giant cell type’ – is a rare tumor that
occurs mainly in the extremities, and rarely in the head and neck
region and visceral organs of adults and elderly people.
The prognosis is dependent upon the location of the tumor,
with superficial lesions having a much better prognosis.
This tumor is typically a multinodular soft tissue lesion, com-
prised of a mixture of mononuclear histiocyte-like cells, osteo-
clast-type and bizarre tumor giant cells, and a varying number
of spindle cells. These are separated by vascular fibrous tissue
bands. Towards the periphery, the nodules exhibit more spindle
cell areas reminiscent of the conventional malignant fibrous his-
tiocytoma; these cells may show areas of storiform architecture.
Secondary features
● Hemorrhage.
(e) ● Necrosis.
● Metaplastic bone formation is occasionally found at the
Figure 13.33 (Continued). periphery of the lesion.
Cell morphology Cell morphology

● The cells are ovoid or spindle-shaped, with vesicular nuclei ● The osteoclast-type giant cells are the predominant cell
and small nucleoli. population. They have abundant eosinophilic cytoplasm
● Mitoses are scarce. and numerous uniform nuclei containing prominent
● There are occasional multinucleated cells and foamy nucleoli. They occasionally contain phagocytic vacuoles
macrophages. and asteroid bodies.
● The remaining background cells are similar to those seen
Differential diagnosis in the other types of malignant fibrous histiocytomas.
● Inflammatory granulomatous processes These include plump, pale-eosinophilic spindle cells
● Nodular fasciitis arranged in short fascicles or storiform pattern with round
● Kaposi’s sarcoma histiocyte-like cells.
● Angiomatoid fibrous histiocytoma ● Scattered bizarre mono- and multinucleated tumor
● Epithelioid sarcoma giant cells may be present, some of which contain
eosinophilic or vacuolated intranuclear cytoplasmic infiltrate. Delicate granulation tissue-type vessels are seen
inclusions. throughout the lesion.
● Xanthomatous cells, lymphocytes, plasma cells, eosinophils
and polymorphs are often seen. Cell morphology
● Mitotic figures, both typical and atypical, are frequent ● The cells of the background population are essentially
occurrences. similar to those of typical (storiform-pleomorphic) MFH,
in that they consist of variably pleomorphic
Differential diagnosis undifferentiated spindle cells with hyperchromatic or
● Giant cell tumor of bone extending into soft tissue prominently nucleolated nuclei, some containing
● Giant cell tumor of tendon sheath phagocytosed neutrophils.
● Plexiform fibrohistiocytic tumor ● As well as the dense, neutrophil-rich inflammatory cell
● Giant cell carcinoma infiltrate, xanthomatous cells and multinucleated giant
cells may also be present.
Special techniques ● The mitotic rate is variable.
● Immunohistochemically, the tumor cells are positive for Differential diagnosis
vimentin, CD68 and alpha-1-antichymotrypsin.
● The cells express myofibroblastic markers.
● Xanthogranulomatous inflammatory processes
● Lymphomas (lymphocyte-depleted Hodgkin’s lymphoma,
T-cell lymphomas, Ki-1 anaplastic and high-grade B-cell
MALIGNANT FIBROUS HISTIOCYTOMA, lymphomas)
INFLAMMATORY TYPE ● Myxoid liposarcomas (a similar neutrophil-rich
inflammatory infiltrate can occur)
● Inflammatory fibrosarcoma
CLINICAL FEATURES ● Inflammatory myofibroblastic tumor
Inflammatory malignant fibrous histiocytoma (MFH) is an

aggressive tumor with high incidence of local recurrence and MALIGNANT FIBROUS HISTIOCYTOMA,
distant metastasis. It occurs in the deep soft tissues, and also in
PLEOMORPHIC (STORIFORM-PLEOMORPHIC MFH)
visceral organs. It may be seen in association with a leukemoid
reaction and eosinophilia.
CLINICAL FEATURES
PATHOLOGICAL FEATURES (Figure 13.34) This is the commonest subtype of MFH. It occurs in adults,
This lesion consists of a background population of variably especially elderly patients, and affects any site including
pleomorphic undifferentiated spindle cells showing areas of retroperitoneum and viscera.
storiform arrangement, necrosis, myxoid change and sometimes
giant cells. This background population is accompanied – and PATHOLOGICAL FEATURES (Figure 13.35)
sometimes obscured by – a dense, neutrophil-rich inflammatory
This is a highly cellular, pleomorphic spindle cell lesion. The
classical architectural pattern is storiform, though fascicular or
diffuse patterns may dominate. The background collagen either
encircles or may widely separate individual cells. Inflammatory
cells are usually numerous, especially at the periphery of the
lesion and in perivascular locations. Myxoid areas may occur in
which the lesion appears hypocellular. Slit-like vessels in the cen-
ters of storiform areas are often seen, whilst sometimes the vessels
are dilated and angulated, giving the lesion a hemangioperi-
cytomatous appearance.
Secondary features
● Inflammatory infiltrate
● Myxoid change
● Hyalinization
● Osseous or cartilaginous metaplasia
Cell morphology
Figure 13.34 Inflammatory malignant fibrous histiocytoma (MFH).
Spindle cell lesion containing numerous inflammatory cells and some
● The main cell population comprises plump, pale,
xanthomatous cells.The malignant cells are often obscured by the eosinophilic spindle cells arranged in short fascicles or a
inflammatory process. storiform pattern, and round histiocyte-like cells.
Lipocytic tumors, benign 1001
leiomyosarcoma. Adult pleomorphic rhabdomyosarcoma

is extremely rare
● Tumors with MFH pattern in epithelial organs or in lymph
nodes are sarcomatoid carcinomas and malignant
melanomas, and rarely anaplastic lymphoma
Special techniques
● Immunohistochemically, the tumor cells are positive for
vimentin, CD68 and alpha-1-antichymotrypsin.
● The cells express myofibroblastic markers.
LIPOCYTIC TUMORS, BENIGN
ANGIOLIPOMA
(a) CLINICAL FEATURES

Non-infiltrating angiolipoma is a variant of lipoma, and
classically presents as a painful, tender, subcutaneous nodule
or nodules on the extremities and trunk of healthy young
individuals. It may rarely arise in internal organs. Angiolipoma
is one of nine painful skin nodules: leiomyoma, eccrine
spiradenoma, neuroma, dermatofibroma, angiolipoma, neuri-
lemmoma, endometrioma, glomus tumor, and granular cell
tumor.
Infiltrating angiolipoma is a rare variant showing infiltrative
margins with a tendency to infiltrate bony, neural, muscular,
and fibrocollagenous tissue. This variant requires a wide exci-
sion, with radiotherapy to treat any recurrence.

Non-infiltrating angiolipoma is a sharply circumscribed lesion
consisting of mature fat cells containing a branching network of
small vessels (ranging from lesions with a few small angio-
matous foci to lesions with a predominance of dense vascular
and stromal elements, ‘cellular angiolipoma’). The angiomatous
(b)
foci are predominantly found in a subcapsular location.
Perivascular and interstitial fibrosis is often seen, especially in
Figure 13.35 (a, b) Malignant fibrous histiocytoma.This lesion
classically shows a storiform pattern with nuclear pleomorphism late lesions. The vessels appear as small, well-formed, empty or
and inflammatory component. engorged, or poorly formed, tortuous and complex branching
capillaries.
● Scattered bizarre mono- and multinucleated giant cells are Infiltrating angiolipoma is similar to the non-infiltrating
frequently present. These are characterized by the marked variant, but is usually unencapsulated or rarely partially
pleomorphism and irregular coarse chromatin pattern of encapsulated.
their nuclei, some of which contain eosinophilic or Cellular angiolipoma shows dense cellular angiomatous
vacuolated intranuclear cytoplasmic inclusions. tissue comprising more than 95% of the lesions, with only a
● Xanthomatous cells, lymphocytes, plasma cells, minimal amount of adipose tissue. Some of the numerous
eosinophils and polymorphs are often seen. small, well-formed blood vessels are filled with fibrin
● Mitotic figures, both typical and atypical, are frequently seen. thrombi.

● The most common soft tissue tumors with MFH pattern ● Spindle cell lipoma
are pleomorphic liposarcoma and pleomorphic ● Kaposi’s sarcoma
(a) (a)
(b) (b)
Figure 13.36 (a, b) Cellular angiolipoma.Vascular cellular spindle Figure 13.37 Chondrolipoma. (a, b) Mature fat cells admixed with
areas intermixed with mature fat cells. Intravascular hyaline thrombi fibrous tissue and containing mature hyaline cartilage.
are commonly seen.
CHONDROID LIPOMA ● Myxoid/round cell liposarcoma (shows plexiform vascular
pattern, myxoid rather than chondroid stroma, more
CLINICAL FEATURES uniform lipoblasts but both are vimentin- and S-100
protein-positive)
Chondroid lipoma is an uncommon benign fatty neoplasm ● Extraskeletal myxoid chondrosarcoma (usually shows
which affects middle-aged adults, especially women. It occurs distinct lobulation, peripheral tumor cell accumulation,
mainly in the subcutis, superficial fascia or skeletal muscle of more uniform chondroblasts, abundant myxoid matrix
the proximal extremities, and less frequently in the trunk, head with no lipoblasts or adipocytic. It is vimentin- and (less
and neck and distal extremities. consistently) S-100 protein-positive, and bears the
translocation t(9;22)(q11-12) or t(9;17)
● Myoepithelioma of soft tissue/mixed tumor (may show
hyalinized to chondroid matrix with occasional
Chondroid lipoma is a well-circumscribed lesion, often with a cartilaginous or adipocytic foci, but lacks lipoblasts.
lobular growth pattern. It consists of various admixtures of It is cytokeratin (CK)- and EMA-positive, and sometimes
uni- or multivacuolated cells resembling lipoblasts, hibernoma glial fibrillary acidic protein (GFAP)-, SMA-, and
cells or chondroblasts set within a myxohyaline extracellular desmin-positive)
matrix. The cells may arrange in cords or strands. Cellular ● Parachordoma (has no lipoblasts, and the cells are S-100
pleomorphism and mitotic figures are absent. protein-, CK8-, CK18-, and EMA-positive)
Secondary changes include microcystic stromal degeneration, ● Chondroma of soft tissues (occurs predominantly in the
stromal hyalinization, and calcification. hands and feet, and consists of variably cellular hyaline
cartilage with calcification or ossification with occasional Special techniques

giant cells and no lipoblasts) ● The spindle and stellate cells are strongly positive for
● Hibernoma CD34 and bcl-2, but negative for S-100 protein and for
● Lipoblastoma epithelial and muscle markers.
● Ultrastructurally, the cells show fibroblastic features.
Special techniques
● The cells contain glycogen (PAS-positive) and fat HIBERNOMA
(red-oil-O positive).
● The myxohyaline stroma shows strong staining with
toluidine blue at pH 4.0, and is also Alcian blue- CLINICAL FEATURES
positive before and after hyaluronidase treatment, in Hibernoma is an uncommon, benign neoplasm derived from the
keeping with the presence of chondroitin sulfate. remnants of fetal brown adipose tissue. It is typically asympto-
● The tumor cells are consistently S-100 protein- matic and slow-growing, and ranges in size from a few to several
positive, in less than 50% CD68-positive, and less centimeters. The lesion occurs principally in adults, and affects the
frequently CK-positive. They are SMA and EMA intercapsular region, axilla, thigh, head and neck mediastinum
antigen-negative. and retroperitoneum. It is usually treated by simple excision.
● A balanced translocation of t(11;16) (q13;p12-13) has
been reported. PATHOLOGICAL FEATURES (Figure 13.38)
Hibernoma is a well-circumscribed, lobulated lesion character-
ized by the presence of multivacuolated fat cells with small,
DENDRITIC FIBROMYXOLIPOMA central nuclei. According to a recent study of a large series of
hibernomas, several histological variants are recognized based
on the tinctorial quality of hibernoma cells, the nature of the
CLINICAL FEATURES stroma, and the presence of a spindle cell component:
● The typical variant shows a range of pale-staining and
This is a peculiar variant of spindle cell lipoma, and develops
mainly in the subcutaneous tissue of the shoulder region, upper eosinophilic hibernoma cells. The pale-cell subtype is
back, and posterior neck of middle-aged and elderly men. The composed of pale, multivacuolated cells seen in various
lesion may be large in size (median 6 cm; range 2–11 cm). numbers mixed with univacuolated white fat. The eosino-
philic cell subtype shows at least 50% of the hibernoma
cells to have deeply eosinophilic granular cytoplasm.
PATHOLOGICAL FEATURES A mixed-cell subtype has been identified which contains
This lesion shows various combinations of mature adipose tis- approximately equal numbers of pale and eosinophilic
sue, myxoid areas, thick-walled vessels, and proliferation of multivacuolated cells.
● The myxoid variant shows multivacuolated brown cells
cells ranging from spindle to stellate shape with dendritic cyto-
plasmic processes. Strands of keloidal collagen among more with a slightly eosinophilic cytoplasm separated by
collagenized stroma are characteristic. There is no evidence of acellular myxoid stroma.
● Spindle cell (lipoma-like) variants show some features like
cytological atypia, lipoblasts, or mitotic figures. Mast cells are
scattered in the lesion. There is usually a well-formed vascular spindle cell lipoma, and are composed of an admixture of
network consisting of small to medium vessels or plexiform hibernoma cells and bland spindle cells, thick bundles of
small capillary-sized vessels resembling those of myxoid collagen, mast cells, myxoid stroma, and mature adipocytes.
liposarcoma. Differential diagnosis
● Adult rhabdomyoma
Differential diagnosis ● Granular cell tumor
● Myxolipoma (lacks prominent collagenization and a ● Round cell liposarcoma
spindle cell component) ● Myxoid liposarcoma
● Myxoid solitary fibrous tumor (lacks an adipocytic ● Spindle cell lipoma
element and has a prominent hemangiopericytomatous ● Angiolipomyoma may rarely show hibernated fat
vascular pattern and large bundles of sclerotic
collagen) Special techniques
● Myxoid liposarcoma (negative for CD34 and positive ● Most hibernomas show positivity for S-100 protein,
for S-100 protein) ranging from focal to diffuse, with the multivacuolated
● Low-grade myofibrosarcoma (has multinodular growth hibernoma cells displaying stronger positivity than the
pattern, alternating hypercellular and hypocellular/ univacuolated white fat cells.
myxoid areas, curvilinear vessels, a perivascular ● CD34-positive spindle cells are seen in the spindle cell
accumulation of tumor cells, cytological atypia and variant. All other morphological variants are usually
mitotic figures) negative for CD34.
cured by complete excision; however, recurrence occurs in 15%

of cases.

Intramuscular lipoma is characterized by the presence of an area
of mature fat cells infiltrating in-between and entrapping striated
muscle fibers. Lipoma variants can also be seen within the muscle
such as spindle cell lipoma, pleomorphic lipoma, or angiolipoma.
(a)
Figure 13.39 Intramuscular lipoma.
● Well-differentiated liposarcoma
● Diffuse lipomatosis
● Diffuse lipoblastomatosis
● Intramuscular hemangioma
LIPOBLASTOMATOSIS AND BENIGN

LIPOBLASTOMA
CLINICAL FEATURES
Lipoblastoma(tosis) is a soft tissue tumor of infancy and early
(b) childhood. It has a wide anatomic distribution, but it chiefly
affects the extremities. The tumor may grow rapidly to a large
Figure 13.38 (a, b) Hibernoma. Multinodular pattern with size and have a myxoid, gelatinous appearance. These tumors
multivacuolated pale and eosinophilic fat cells. usually have an excellent prognosis. There are two clinical
forms of the disease:
● Characteristic cytogenetic abnormalities have been 1. The diffuse form (lipoblastomatosis) involves the subcuta-
described in hibernoma, including structural neous tissue and the underlying muscle.
rearrangements of 11q13 and 11q21. 2. The localized form (benign lipoblastoma) involves only the
subcutaneous tissue.
INTRAMUSCULAR LIPOMA Recurrence may occur in the diffuse form, and therefore wide
local excision is recommended for this lesion.
CLINICAL FEATURES PATHOLOGICAL FEATURES (Figure 13.40)

Intramuscular lipoma is a relatively common type of lipoma, Lipoblastomatosis and benign lipoblastoma are distinctly multi-
and occurs especially in the large muscles of the extremities in lobular, and consist of fetal fat cells at different stages of their
adult patients. It is characterized by its frequent large size, deep development, set in a myxoid stroma. The lobules are variably
location, and infiltrative growth pattern. The lesion is usually sized and are separated by fibrous tissue septa. The localized
Figure 13.40 Lipoblastomatosis. Admixture of pre-lipoblasts Figure 13.41 Pleomorphic lipoma. Note the mature fat cells,
(stellate or spindle-shaped mesenchymal cells), immature lipoblasts fibrillary collagenous fibers and ‘floret’ giant cells.
(small irregular-shaped fat cells containing small numbers of
intracytoplasmic vacuoles) and mature adipocytes.
middle-aged men, and rarely in other locations such as in the
form of the disease is usually well-circumscribed and may be dermis, palm, scalp, skeletal muscle or oral cavity and pharynx.
partially encapsulated, while the diffuse from infiltrates the Dermal pleomorphic lipomas are distinctive in their apparent
surrounding fibromuscular tissue. Prominent thin-walled com- female predilection, wider anatomical distribution than sub-
pressed vessels, some with a plexiform pattern, are often seen. cutaneous lesions, and lack of circumscription. Despite its
pleomorphic appearance, this tumor follows a benign course
Secondary features
and does not recur or metastasize if completely excised.
● Myxoid change.
● Hyaline collagen fibers.
Cell morphology Pleomorphic lipoma is usually circumscribed and characterized
● Pre-lipoblasts are primitive stellate or spindle-shaped by an intricate mixture of mature fibrous, adipose and myxoid
mesenchymal cells. tissues interspersed with cellular foci. Most characteristic of the
● Immature lipoblasts are small, irregularly shaped fat cells latter are a variety of giant cells and especially the ‘floret’ giant-
containing small numbers of intracytoplasmic vacuoles. cells, so named because of the arrangement of their nuclei
● Mature adipocytes are similar to those seen in normal which is reminiscent of the petals of a flower. The pleomorphic
subcutaneous tissue. cells are typically localized within the fibrous septae and within
● Brown fat cells are round, finely vacuolated cells, and areas of loose fibrous stroma. Focal transition to areas similar
resemble hibernoma cells. to spindle cell lipoma can be seen. Pseudopapillary structures
● Mitotic figures are usually absent. may rarely be seen in pleomorphic lipomas.
● Myxoid liposarcoma (usually lacks distinct lobulations)
● Intramuscular lipoma (when diffuse lipomatosis involves
● Pleomorphic liposarcoma
underlying muscle fibers)
● Infantile fibromatosis (in lesions containing broad fibrous
septae) SCLEROTIC LIPOMA
● Lipofibromatosis

● Ultrastructurally, the brown fat cells contain numerous
Sclerotic lipoma is a distinctive variant of lipoma, presenting as
mitochondria.
a subcutaneous nodule (1.5–5 cm diameter) in the scalp or
hands of young men.
PLEOMORPHIC LIPOMA
CLINICAL FEATURES
This is a well-differentiated paucicellular lesion composed of
Pleomorphic lipoma is included in the ‘atypical’ lipoma classi- sclerotic collagen bundles that exhibit a whorled, storiform
fication. It mainly occurs in the neck and shoulder regions of or ‘onion-like’ appearance, with few interspersed mature
adipocytes. Some lesions are more cellular, while others contain eosinophilic deposits, similar to the abnormal elastic fibers
floret-like giant cells. Cholesterol clefts and calcification may seen in elastofibroma dorsi)
occasionally be seen.
Special techniques
Differential diagnosis ● The stromal cells are reactive for vimentin and
occasionally for S-100 protein, whereas the mature fat
● Sclerotic fibroma/circumscribed storiform collagenoma
cells are strongly positive for S-100 protein.
(usually related to previous trauma, associated with
Cowden disease or multiple hamartoma syndrome, and is
S-100 protein-negative)
SPINDLE CELL LIPOMA
● Fibrolipoma
● Nuchal fibroma CLINICAL FEATURES
● Collagenous fibroma
● Hypertrophic scar Spindle cell lipoma is a distinct variant of lipoma, and presents
● Dermatofibroma as a solitary, circumscribed, painless mass in middle-aged men
● The nodular variant of dermal spindle cell lipoma in the regions of the posterior neck and shoulder. However, it
● Dermatofibrosarcoma protuberans may also arise at a variety of other locations.
● Elastofibrolipoma of the mediastinum (a recently described PATHOLOGICAL FEATURES (Figures 13.42–13.44)
entity composed of mature fat alternating with sclerotic Spindle cell lipoma shows an admixture of mature fat cells and
connective tissue, which also contained extensive monomorphic spindle cells. The latter constitute 20–80% of
(a) (c)
(b) (d)
Figure 13.42 (a–d) Spindle cell lipoma. Admixture of spindle cell mesenchyme and mature fat cells.The spindle cells have oval nuclei,
and the background shows short fibrillary collagen.The spindle cell mesenchymal component may be vascular and shows intraluminal
thrombi as in angiolipoma (d).
(a) (b)
Figure 13.43 (a, b) Spindle cell lipoma.The spindle cell mesenchymal component may show nuclear palisading.
(a) (b)
Figure 13.44 (a, b) Myxoid spindle cell lipoma. Palisading of the spindle cells and myxoid stroma with fibrillary background.The latter
feature may lead to an erroneous diagnosis of neural tumor.
the lesion, and are arranged either in short interlacing fascicles, with no evidence of cellular pleomorphism or
in circumscribed micronodules, or they may show nuclear mitoses.
palisading. Short, refractile, wavy eosinophilic collagen fibers ● Mast cells are often seen.
are frequently seen. Rarely, spindle cell lipoma shows cleft-like
dilated spaces containing villiform projections, thereby impart-
ing a pseudoangiomatous pattern to the lesion.
Pseudoangiomatous spindle cell lipoma: here, a few thick- ● Fibrolipoma
walled vessels of small or intermediate size and occasionally ● Neural tumor such as neurofibroma or schwannoma.
extensive vascularization with hemangiopericytomatous pat- ● Dermatofibrosarcoma protuberans (when its margins
tern may occasionally be seen. In extremely myxoid lesions the invade subcutaneous tissue)
vessels may resemble those seen in liposarcoma. ● Fibromatosis
● A well-differentiated liposarcoma
Secondary features ● Pseudoangiomatous spindle cell lipoma should be
distinguished from hemangioma, lymphangioma,
● Myxoid change.
lipomatous hemangiopericytoma, and well-differentiated
● Rarely cartilaginous and/or osseous metaplasia.
liposarcoma
Cell morphology
● Mature fat cells. Special techniques
● Small undifferentiated spindle cells with fusiform ● The spindle cells are S-100 protein-negative and
nuclei, and scant, pale-staining ill-defined cytoplasm CD34-positive.
LIPOCYTIC TUMORS, MALIGNANT
LIPOSARCOMAS
CLINICAL FEATURES
Liposarcoma is one of the most common soft tissue sarcomas.
This tumor may occur at any age, but the vast majority are in
middle-aged or elderly individuals. Liposarcoma affects the deep
soft tissue of the lower extremities and retroperitoneum, is
usually large, and although apparently circumscribed, it may be
surrounded by small tumor satellites. When arising in somatic
soft tissue, it has a better prognosis than in the retroperitoneum.
There are several clinicopathological variants of liposarcoma:
● Well-differentiated liposarcomas have a good prognosis,
and rarely metastasize, but may recur and cause Figure 13.45 Well-differentiated liposarcoma. Signet ring
lipoblasts.
complications through compression of neighboring
structures.
● Well-differentiated lipoma-like liposarcoma has a risk of
local recurrence, but no potential for metastasis.

● Myxoid liposarcoma is the most common type of
liposarcoma. Typically it is a low-grade sarcoma, and is

usually seen in older individuals, commonly in the extremities
and retroperitoneum. It has a tendency to local recurrence
and infrequent metastases. It may co-exist with a poorly
differentiated sarcoma ‘dedifferentiation’.
● Round cell liposarcoma has an aggressive clinical course
and a greater tendency for metastasis. Today, it is widely

accepted that round cell liposarcoma is considered as the
high-grade counterpart of myxoid liposarcoma. A round
cell component of ⬎5% portends a higher risk of
metastasis or death from the disease.
● Pleomorphic liposarcoma has an aggressive clinical
course and a greater tendency for metastasis than

well-differentiated or myxoid liposarcomas.
● Spindle cell liposarcoma is characterized by a prominent Figure 13.46 Well-differentiated liposarcoma. A multinucleated
spindle cell component. It usually arises in the lipoblast.
subcutaneous tissue of adults in the region around the
shoulder girdle or upper limbs. It often recurs locally over
a period of between 4 and 20 years, and may metastasize
to distant sites.

Well-differentiated liposarcomas show predominantly mature
fat cells of various sizes, typical multivacuolated lipoblasts
(containing numerous vacuoles causing scalloping of the cen-
trally located hyperchromatic nuclei); signet ring lipoblasts
contain large fat droplets which push the abnormal nuclei to
the periphery of the cells. Mitoses are usually sparse.
Well-differentiated lipoma-like liposarcoma is a lobulated
tumor with variably sized connective tissue septa. The compo-
nent of each lobule is similar to that of a lipoma (mature fat
cells), with the exception of finding variation in the size and
shape of the fat cells, presence of multivacuolar lipoblasts, and
the presence of hyperchromatic nuclei in the broad, connective Figure 13.47 Well-differentiated liposarcoma. Hibernoma-like
tissue septa present within these tumors. lipoblasts.
Lipocytic tumors, malignant 1009
Figure 13.48 Sclerosing liposarcoma. At first glance, the bland Figure 13.51 Dedifferentiated liposarcoma.The
sclerotic stroma intermixed with mature adipocytes impart a benign hemangiopericytomatous pattern is rarely seen in liposarcoma.
appearance to the tumor.
Figure 13.49 Spindle cell liposarcoma. Note the loose collagenous Figure 13.52 Myxoid liposarcoma. Numerous thin, forked
background with mostly bland-looking cells, reminiscent of spindle capillaries with straight branches (‘chicken feet’ vessels) in a myxoid
cell lipoma. stroma.
Figure 13.50 Dedifferentiated liposarcoma. Lipoblasts showing Figure 13.53 Myxoid liposarcoma.Thin, forked capillaries with
indentation of the nuclei by the fat vacuoles (encircled). straight branches (‘chicken feet’ vessels).
Figure 13.54 Myxoid liposarcoma. A column of red blood cells Figure 13.57 Round cell liposarcoma. Round to spindle cells with
often seen within the ‘chicken feet’ vessels. some bubbly myxoid pattern.
Figure 13.55 Myxoid liposarcoma. Pseudolymphangiomatous Figure 13.58 Pleomorphic liposarcoma. Signet ring and
pattern. multivacuolated lipoblasts.
Figure 13.56 Round cell liposarcoma. Sheets of round cells with Figure 13.59 Pleomorphic liposarcoma. Intracellular hyaline
only isolated differentiated adipocytes. globules are common in this type of liposarcoma.
Lipocytic tumors, malignant 1011
Well-differentiated liposarcoma with prominent inflamma- cords, or a pseudoglandular pattern. Transition to areas of
tory component is similar to the above, but in addition it con- myxoid liposarcoma is common, but to well-differentiated
tains considerable numbers of lymphocytes and plasma cells. liposarcoma is rare. Plexiform vessels are present, but these are
This sometimes is mistaken for an inflammatory process. usually obscured by the tumor cells, and a hemangiopericy-
Well-differentiated sclerosing liposarcoma is characterized by tomatous pattern is not uncommon. The tumor cells are round,
the presence of a loose or dense fibrous background which largely epithelioid lipoblasts with vesicular nuclei and a small amount
obscures the fatty nature of the lesion. However, within this of cytoplasm. Granular cells resembling brown fat and vacuo-
fibrous tissue there are atypical hyperchromatic nuclei, bizarre lated lipoblasts may also be seen. Mitoses are usually sparse.
giant cells in mitosis, mature and immature fat cells, and some- Pleomorphic liposarcoma is a multilobular tumor consisting of
times typical multivacuolated lipoblasts. Some tumors show pleomorphic cells including many tumor giant cells, spindle cells,
features of both lipoma-like and sclerosing-type liposarcomas. round cells and occasional lipoblasts. The cells may show a fasci-
Spindle cell liposarcoma shows a relatively bland spindle cell cular pattern, with areas resembling other types of liposarcoma
proliferation arranged in fascicles and whorls or a storiform pat- such as myxoid or round cell liposarcoma. Plexiform vessels are
tern, and set in a variably myxoid or hyalinized stroma. The spin- present, but are often obscured by the tumor cells, and a heman-
dle cell areas are accompanied by adipose tissue. Recurrences may giopericytomatous pattern may also be seen. Necrosis is more
show purely lipoma-like areas, or may show tumor dedifferentia- prominent in this variant, and intracytoplasmic hyaline globules
tion. The cells are monomorphic, spindle-shaped, and have are frequently seen. There are frequent malignant giant cells with
hyperchromatic nuclei and poorly defined, pale eosinophilic cyto- abundant, deeply eosinophilic cytoplasm resembling rhabdomyo-
plasm. The adipocytic component often exhibits the morpholog- blasts, and containing intranuclear cytoplasmic inclusions.
ical features of the well-differentiated liposarcoma–atypical Other cell types include bizarre lipoblasts with numerous intra-
lipoma group, including definite lipoblasts. Nuclear pleomor- cytoplasmic lipid droplets, round, epithelial-like lipoblasts with
phism is mild to moderate, and mitotic figures are scant vesicular nuclei and small amounts of cytoplasm, granular cells
(1–2 mitoses per 10 HPF). resembling brown fat, and vacuolated lipoblasts. Mitoses,
Dedifferentiated liposarcoma is a distinct type of liposar- including atypical forms, are usually numerous. An epithelioid
coma in which transition from low-grade to high-grade non- variant of pleomorphic liposarcoma has been described.
lipogenic morphology within a well-differentiated liposarcoma Liposarcoma with heterologous components shows various
is observed. The transition usually occurs in an abrupt fashion; other differentiation such as leiomyosarcoma, rhabdomyo-
however, in rare cases it can be more gradual. It has also been sarcoma, chondrosarcoma, osteosarcoma, and angiosarcoma.
proposed that dedifferentiated liposarcoma should be further These elements have been described mainly in dedifferentiated
subclassified into low and high grade. Dedifferentiated lipo- liposarcomas situated in the retroperitoneum.
sarcoma may rarely exhibit heterologous (most often myoid)
differentiation. A peculiar ‘neural-like whorling pattern’ of Secondary features
dedifferentiation has also been described recently. Surprisingly,
● Hemorrhage.
the clinical outcome of dedifferentiated liposarcoma is less
● Necrosis.
aggressive than that in other high-grade pleomorphic sarcomas.
● Cystic formation.
Myxoid liposarcoma is well-circumscribed, lobulated,
● Chondroid metaplasia.
hypocellular or myxoid, and exhibits a distinct vascular pat-
● Osseous metaplasia.
tern. The tumor lobules are separated by thin, fibrous septae.
● Smooth muscle metaplasia.
Although the mucoid material in the majority of cases is evenly
distributed between the cells, focal pooling with condensation
of tumor cells at the margins can produce pseudoacinar, cystic, Differential diagnosis
or lymphangiomatous growth patterns. Some condensation of ● Well-differentiated liposarcomas should be distinguished
tumor cells around blood vessels and under the fibrous septae from atypical lipomas, fat necrosis, atrophic or myxoid
can also be seen. The vascular pattern is one of the diagnostic degeneration of fat, panniculitis, lipogranulomas, silicone
hallmarks of this lesion, consisting of numerous thin, forked granuloma, atypical decubital fibroplasias, retroperitoneal
capillaries with straight branches (‘chicken feet’ vessels). Focal fibrosis and aggressive angiomyxoma of the vulva and
cartilaginous or rarely osseous metaplasia may be seen. The perineal region
primitive mesenchymal cells seen in this variant are small ● Myxoid liposarcoma should be distinguished from
undifferentiated spindle cells, with or without typical lipoblasts intramuscular cellular myxoma, cystic lymphangioma or
or signet ring lipoblasts. Small granular cells similar to brown lymphangiosarcoma, lipoblastomatosis, myofibrosarcoma,
fat and mature fat cells may be seen. Giant cells are rarely seen, low-grade fibromyxoid sarcoma, extraskeletal myxoid
and mitoses are scarce. Many myxoid liposarcomas may have chondrosarcoma and myxoid leiomyosarcoma
round cell areas, and both subtypes share similar cytogenetic ● Round cell liposarcoma should be distinguished from the
translocation (12;16)(q13;p11). The round cell differentiation various small cell undifferentiated tumors, including
ranges from 5% to 100% of the tumor volume. Ewing’s sarcoma and the primitive neuroectodermal tumor
Round cell liposarcoma is a multilobular tumor consisting (PNET) group, malignant lymphoma (signet ring type),
of a uniform population of round, epithelioid cells. These are epithelioid angiosarcoma, epithelioid leiomyosarcoma,
diffusely arranged or may show thin, branching trabeculae, undifferentiated carcinomas, balloon cell melanoma and
vacuolar degeneration in a variety of epithelial or Special techniques

mesenchymal tumors, e.g. prostatic carcinoma and ● D2-40 is a novel monoclonal antibody to a 40 000-Da
embryonal rhabdomyosarcoma O-linked sialoglycoprotein that reacts with a fixation-
● Pleomorphic liposarcoma shows a classic pleomorphic resistant epitope on lymphatic endothelium.
MFH-like picture. It should be considered in the ● The lining cells are immunoreactive for Factor VIII-related
differential diagnosis of tumors with this pattern. These antigen, CD34, and CD31.
include pleomorphic leiomyosarcoma, pleomorphic ● A smooth muscle cell layer may be observed focally
rhabdomyosarcoma, MPNST sarcomatoid carcinoma and around the vascular spaces.
malignant melanoma
● Spindle cell liposarcoma should be distinguished from
spindle cell lipoma, diffuse neurofibroma, LYMPHANGIOLEIOMYOMATOSIS
dermatofibrosarcoma protuberans, sclerosing liposarcoma,
(LYMPHANGIOMYOMATOSIS)
low-grade myxofibrosarcoma, low-grade MPNST, and
low-grade fibromyxoid sarcoma
CLINICAL FEATURES
Special techniques Lymphangiomyomatosis is an extremely rare benign disease
● The spindle cells are vimentin-positive, but negative for which is characterized by extensive proliferation of smooth mus-
S-100 protein and for SMA antibody. cle cells within lymphatic vessels and lymph nodes in media-
● The adipocytes and lipoblasts are S-100 protein-positive. stinal, retroperitoneal and often pulmonary lymphatics and
● Focal desmin and CD34 positivity of the spindle cells may lymph nodes. Between 10% and 15% of all patients show con-
be seen in some cases. comitant renal angiomyolipomas. This condition affects almost
● Fat stains such as Oil Red O confirm the cells’ lipoblastic exclusively young women. Lymphangioleiomyomatosis may be
identity. associated with the tuberous sclerosis complex, which includes
renal angiolipoma, chylothorax and lymph node myomatosis. Its
clinical pulmonary manifestations vary from simple cough to the
development of recurrent pneumothorax, hemoptysis or pleural
LYMPHATIC TUMORS effusions. Progressive dyspnea develops as the disease evolves,
and eventually most patients require lung transplantation. This
BENIGN LYMPHANGIOENDOTHELIOMA wide array of symptoms and signs makes the differential diag-
nosis extensive, and the clinician must be familiar with this
(ACQUIRED PROGRESSIVE LYMPHANGIOMA) disorder in order to arrive promptly at the correct diagnosis.
The involvement of lymph nodes often results in enlargement of
CLINICAL FEATURES retroperitoneal, inguinal, para-aortal or supraclavicular lymph
nodes. Lymphangioleiomyomatosis is rarely seen in the uterus.
Benign lymphangioendothelioma (acquired progressive lym-
phangioma) is a rare benign tumor of lymph vessels that occurs
both in children and adults. It presents as a slowly enlarging
pink or reddish plaque or macule on the extremities or trunk, In the lung, the lesion is characterized by the presence of exces-
usually of long duration. The lesion usually measures a few sive smooth muscle cells involving the alveolar and bronchiolar
centimeters, but may reach up to 30 cm in diameter. wall with consequent thickening and narrowing of the lumen
of bronchioles. Randomly proliferating smooth muscle cells are
also characteristically present around arterioles, venules, and
PATHOLOGICAL FEATURES lymphatics.
Benign lymphangioendothelioma is characterized by the pres- In the lymph nodes and extra-pulmonary lymphatics, smooth
ence of anastomosing, often widely dilated, vascular structures muscle cells are arranged in short fascicles around endothelial-
which develop in the superficial dermis. As the lesion grows ized empty spaces (see Lymphangiomyoma, p. 1013).
within the deeper dermis, the vascular spaces collapse and dis-
sect the dermal collagen in an angiosarcoma-like pattern. The Cell morphology
lining endothelium is flat and monolayered, with little or no ● Plump smooth muscle cells with abundant eosinophilic
cytological atypia and no evident mitoses. Some vascular struc- cytoplasm and blunt-ended or plump nuclei.
tures contain stromal papillary projections resembling papil- ● There is no pleomorphism and mitotic activity.
lary endothelial hyperplasia, and intravascular red blood cells ● Small foci of lymphocytes may be seen between the muscle
are also occasionally present. cells.

● Patch-stage Kaposi’s sarcoma ● Idiopathic pulmonary fibrosis
● Low-grade angiosarcoma ● Benign metastasizing leiomyoma (well-differentiated
● Hemosideritic targetoid hemangioma leiomyosarcoma)
Lymphoreticular tumors 1013
Special techniques Secondary features

● The smooth muscle cells of lymphangiomyomatosis are ● Masson’s hemangioma-like papillary proliferation may
positive for SMA, desmin, and HMB-45. be seen.
● Estrogen receptors may be weakly positive.
Cell morphology
LYMPHANGIOMAS ● The lymphatic vessels are lined by bland endothelial cells.
CLINICAL FEATURES ● Cavernous hemangioma
Lymphangiomas probably represent vascular malformations ● Cystic mesothelioma
rather than tumors. They may occur in skin, subcutaneous
Special techniques
tissue and deep soft tissues, or in visceral organs. These lesions
exist in three forms: capillary, cavernous, and cystic (cystic ● D2-40 is a novel monoclonal antibody to a 40 000-Da
hygroma) variants. O-linked sialoglycoprotein that reacts with a fixation-
Cutaneous lymphangiomas are seen in the neck, axilla, chest, resistant epitope on lymphatic endothelium.
breast, buttocks or thigh, and mainly in infancy. They can be ● The lining cells are immunoreactive for Factor VIII-related
seen in the upper dermis (lymphangioma circumscriptum) or in antigen, CD34, and CD31.
deep locations (lymphangioma cavernosum and cystic hygroma).
They may recur in 25% of cases. LYMPHANGIOMYOMA
Benign lymphangioendothelioma (acquired progressive lym-
phangioma) – see Acquired progressive lymphangioma (p. 1012).
Lymphangiomatosis is a diffuse and multicentric form of CLINICAL FEATURES
lymphangiomas which is most commonly seen in the thoracic Lymphangiomyoma occurs exclusively in females, and is mostly
cavity and is often associated with chylous pleural effusion or restricted to the mediastinum and retroperitoneum. Because of
chylopericardium. the hormone receptors present in the tumor cells, good thera-
peutic results have been obtained with progesterone therapy or
PATHOLOGICAL FEATURES (Figure 13.60) oophorectomy.
Lymphangiomas consist of large lymphatic vessels that usually
contain pale, proteinaceous fluid (lymph) and show focal collec- PATHOLOGICAL FEATURES
tion of lymphocytes in the interstitial tissue. Smooth muscle bun-
Lymphangiomyoma is a localized lesion which is composed of
dles may be seen in the walls of some of the lymphatic vessels.
short fascicles of smooth muscle cells arranged around inter-
Cystic lymphangiomas may be mistaken for cysts of cystic
communicating network of endothelialized lymphatic spaces.
mesotheliomas.
Cell morphology
● The smooth muscle cells are plump, with moderate to
abundant eosinophilic cytoplasm, and lack cellular or
nuclear pleomorphism.
● Mitotic activity is absent.
● Metastatic leiomyosarcoma
Special techniques
● The spindle cells exhibit smooth muscle markers.
● The lining cells show endothelial markers.
LYMPHORETICULAR TUMORS
EXTRAMEDULLARY HEMATOPOIESIS/
HEMOPOIETIC TUMOR
CLINICAL FEATURES
Figure 13.60 Lymphangioma. Dilated spaces lined by flat
endothelium and containing pale lymph fluid with scattered Extramedullary hematopoiesis (EH) is the ectopic production of
lymphocytes. Denser lymphocytic infiltrate is seen in the wall. myeloid, erythroid and megakaryocytic elements often associated
with chronic myeloproliferative disorders. This lesion usually FOLLICULAR DENDRITIC CELL SARCOMA
occurs in the spleen, liver, or lymph nodes, and often results in
splenomegaly, hepatomegaly, or adenopathy. Incidental micro- See Chapter 10, Lymphoreticular system tumors; Lymph nodes
scopic foci of EH are rarely discovered in non-lymphoreticular (p. 675).
organs. Similarly, symptomatic EH are very rare. Even rarer is the
presence of tumor mass(es) related to the presence of EH. The
latter finding is often referred to as extramedullary hematopoietic GRANULOCYTIC SARCOMA
tumor (EHT). Such tumor has been reported to occur in various
anatomical locations including the lung, trachea, mediastinum, CLINICAL FEATURES
nasal sinuses, kidney, mesentery, omentum, gut, skin, uterus,
cervix, genitourinary tract, thyroid, adrenal glands, spinal cord, Granulocytic sarcoma – also known as ‘chloroma’ – is a local-
breast, and subcutaneous tissue. ized malignant tumor which is composed of immature myeloid
cells. It is usually secondary to acute leukemia, which may not
be apparent at the time of diagnosis. The tumor affects children
PATHOLOGICAL FEATURES (Figure 13.61) more often than adults, but may occur at any age and is most
Morphologically, EHT may show atypical megakaryocytes, commonly seen in the periosteum and ligamentous structures
maturing granulocytic and erythroid precursors, and few to no related to the bones of the skull, paranasal sinuses, ribs, and
blasts. Some EHT are associated with a predominant fibrous vertebrae. It may also be seen in lymph nodes, skin, soft tissues,
stroma, mimicking myelofibrosis or the fibrosis seen in associa- or internal organs. On gross examination, this tumor often
tion with extramedullary hematopoiesis in the spleen or liver. shows a green coloration when freshly cut (hence the alterna-
These masses have been referred to as – fibrous hematopoietic tive name, chloroma). Despite the localized nature of the
tumors or sclerosing extramedullary hematopoietic tumors to tumor, intensive acute myelocytic leukemia-type chemotherapy
emphasize the extramedullary trilineage hematopoiesis and the is necessary. The disease may respond to local radiation in the
predominant sclerotic background. Occasionally the stroma absence of bone marrow involvement.
shows myxoid changes.
Differential diagnosis Granulocytic sarcoma consists of an infiltrate of uniform
● Morphologically, these tumors may be mistaken for round cells similar to lymphoma, but tends to infiltrate tissue
carcinoma, sarcoma, myelolipoma, or Hodgkin’s disease, planes without extensive destruction and necrosis of the tissue
especially if the clinical picture is not known architecture. The morphology of the tumors varies from well-
differentiated (which includes all stages of myeloid differentia-
Special techniques tion) to poorly differentiated or blastic, with little or no evidence
of myeloid differentiation. In the well-differentiated tumors
● The megakaryocytes, granulocytic precursors, and immature eosinophils are clearly identified. In the blastic type,
erythroid precursors are strongly positive with antibodies there is significant variation in the cellular morphology. A ‘starry
to Factor VIII, myeloperoxidase, and hemoglobin, sky’ pattern reminiscent of Burkitt’s lymphoma may be seen.
respectively.
Cell morphology
● The constituent cells are myeloblasts, promyelocytes and
immature and mature eosinophils and neutrophils.
● The nuclei in the majority of cases are round or oval with
an open chromatin pattern and prominent nucleoli. In
some cases, they may show nuclear infolding and grooving
similar to that seen in follicular center cell lymphoma,
or they may be bean-shaped/reniform reminiscent of
monocytes and may have fine chromatin and
inconspicuous nucleoli resembling lymphoblasts.
● The cytoplasm is usually pale, eosinophilic and abundant,
and may be plasmacytoid, exhibiting faint granularity.
● Mitotic activity is extremely variable.
● Apoptosis is frequent.
● Large cell lymphoma
Figure 13.61 Extramedullary hematopoiesis in the breast.
● Histiocytic lymphoma
Pleomorphic cell population of hematological precursor cells, ● Malignant melanoma
including many megakaryocytes. ● Anaplastic carcinoma
Peripheral nerve sheath tumors, benign 1015
ROSAI–DORFMAN DISEASE
See Chapter 10, Lymphoreticular system tumors (p. 679).
PERIPHERAL NERVE SHEATH TUMORS, BENIGN
FIBROLIPOMATOUS HAMARTOMA OF NERVE
CLINICAL FEATURES
Fibrolipomatous hamartoma of nerve is a rare, benign tumor-
like condition, affecting children and young adults. It usually
(a)
involves the upper limbs, and has a predilection for the median
nerve; it may also affect the ulnar nerve and toes. This lesion
has also been described in a peripheral branch of a cranial
nerve. It is associated with macrodactyly in about one-third
of cases.

The basic lesion is an overgrowth of fibrofatty tissue within a
neural trunk; this results in a histological appearance of several
nerve bundles entrapped and separated by mature fibrofatty
tissue together with the perineurium. Rarely, ossification may
be seen in some tumors.
● Lipoma of nerve
(b)
● Intraneural perineuroma
Figure 13.62 (a, b) Granulocytic sarcoma of nasaopharynx.

Subepithelial deposition of small- to medium-sized uniform cells Special techniques
with isolated immature eosinophils. ● S-100 protein highlights the nerve bundles and Schwann cells
● Basic myelin protein highlights the myelin.
● Small round cell tumors (alveolar rhabdomyosarcoma,
Ewing’s sarcoma, etc.)
● Monomorphic synovial sarcoma
Special techniques
● The tumor cells show leukocyte common antigen (LCA),
bcl-2, CD43, CD34 and myeloperoxidase positivity.
● Thin tissue sections may help in identifying the immature
eosinophils, the presence of which is helpful in making the
diagnosis.
● Granulocytic sarcoma shows bcl-2 gene rearrangement.
● c-Kit reactivity can be demonstrated in a high percentage
of granulocytic sarcoma; its presence may be useful not
only in diagnosis, but also in the treatment of the disease.
● Expression of CD56 is frequent in granulocytic sarcoma.
● A chloroacetate esterase immunoperoxidase stain will
confirm the granulocytic nature of the tumor cells.
INTERDIGITATING CELL SARCOMA Figure 13.63 Fibrolipomatous hamartoma of nerve, showing

several nerve tracks separated and embedded with mature
See Chapter 10, Lymphoreticular system tumors (p. 676). fibrofatty tissue.
MORTON’S NEUROMA is multinodular arrangement with two types of cells: Type I

cells are small, dark and lymphocyte-like, with a slightly
irregular nucleus and inconspicuous cytoplasm; type II cells
CLINICAL FEATURES are larger, with pale-staining vesicular nuclei and frequent
Morton’s neuroma is a variant of traumatic neuroma that may invaginations and intranuclear inclusions, and show abundant
be caused by multiple repeated mild trauma, for example by ill- clear eosinophilic cytoplasm that forms a stellate growth
fitting shoes. This lesion typically occurs in the interdigital plan- pattern. Type I cells are grouped concentrically around type II
tar nerve between the third and fourth toes, and is more common cells, and form pseudorosettes. Most of the type I and type II
in females. cells are S-100 protein- and CD57-positive, and various
proportions of both cell types are CD56- and PGP9.5-
positive. CD34 stains intralesional fibroblasts. Antibody to
EMA stains only the perineurium around the tumor masses,
Morton’s neuroma is characterized by the presence of peri- and suggesting that the lesions arise inside the nerve sheath.
endoneural hyaline fibrosis associated with vascular thickening
and interstitial fibrosis. Differential diagnosis
Secondary features
● Fibromatosis
● Leiomyoma
● Vascular thrombosis. ● Dermatofibroma
● Fibrinoid necrosis of vessel walls. ● Neurotized intradermal nevus
● Neurothekeoma
NEUROFIBROMA, SOLITARY ● Schwannoma
CLINICAL FEATURES
Solitary neurofibroma is a benign lesion, the majority of Special techniques
which show no association with neurofibromatosis (Von ● The majority of cells express S-100 protein and vimentin.
Recklinghausen’s disease). This tumor affects individuals between ● Some cells (perineural cells) are EMA-positive.
the ages of 20 and 30 years, and occurs anywhere in the body, ● CD34-positive cells with delicate dendritic processes could be
most commonly in the dermis and subcutaneous tissues. identified within normal nerves, neuromas, neurofibromas,
and Antoni B areas of neurilemmomas. (Malignant peripheral
PATHOLOGICAL FEATURES nerve sheath tumors are uniformly negative for CD34.)
Unlike schwannomas, neurofibromas are not encapsulated and

lack the two distinct patterns of Antoni A and B areas. The NEUROFIBROMATOSIS
lesions are moderately cellular or hypocellular depending on (VON RECKLINGHAUSEN’S DISEASE)
the amount of mucosubstance present in the background, and
consist of spindle cells arranged in loose elongated fascicles, in
whorls, or sometimes in a storiform pattern. The background CLINICAL FEATURES
stroma is usually loose and fibrillary, but often contains vari- Von Recklinghausen’s disease is an autosomal-dominant inher-
able amounts of wiry collagen bundles. Occasionally, the ited disease which occurs in all races. The condition is divided
tumor is very cellular and devoid of mucosubstances. Fatty into two forms: neurofibromatosis 1 (NF1) (peripheral); and
changes in a neurofibroma are rarely observed. neurofibromatosis 2 (NF2) (central). The genes responsible for
Neurofibroma variants include: NF1 and NF2 have been mapped to the long arm of chromo-
● Epithelioid neurofibroma exhibits epithelioid cells
somes 17 (17q11.2) and 22 (22q11.2) respectively, and their
arranged in nests or cords and single cells blending into protein product (neurofibromin and merlin or schwannomin,
conventional neurofibroma. Rarely, neurofibromas contain respectively) has been identified.
well-formed mature mucus-secreting glandular structures
or epithelial rosettes. Neurofibromatosis 1 (NF1)
● Granular cell neurofibroma shows an overall appearance Individuals with NF1 are predisposed to the development of
of neurofibroma, but the cells show marked granular cell peripheral nerve sheath tumors (neurofibromas and MPNSTs),
change reminiscent of that seen in granular cell tumor. astrocytomas (optic pathway gliomas), learning disabilities,
● Pigmented neurofibroma is similar to ordinary seizures, strokes, macrocephaly, and vascular abnormalities.
neurofibroma, but contains intracellular melanin pigment. The formation of dermal neurofibromas is a hallmark of the
● Dendritic cell neurofibroma: this is a recently described neurofibromatosis type 1 (NF1). NF1 is evident during the first
variant of neurofibroma which presents as a solitary, well- few years of life, and is characterized by the presence of pig-
circumscribed, superficial lesion located in the dermis, and mented, macular, freckle-like lesions (café au lait spots). These
measuring from 3 to 17 mm in diameter (mean 6.2 mm). are usually present on unexposed surfaces of the body. Their
The tumors form oval-shaped masses that run perpendi- number is proportional to the duration and severity of the dis-
cularly to the epidermis. In the deep part of the tumor there ease. This type of neurofibromatosis is associated with the
development of neurofibromas in any location and during child-

hood and adolescence, and is associated with skeletal abnor-
malities in 40% of cases.
Segmental neurofibromatosis is characterized by a limited,
segmental distribution of cutaneous NF1 lesions.
Variants of neurofibroma found in NF1 include:
● Localized neurofibroma: this is principally similar to
solitary neurofibroma, but is larger in size and can be seen

in deep soft tissue. It may undergo malignant change.
● Plexiform neurofibroma: about 30% of NF1 patients
develop plexiform neurofibromas, which are one of the

most common and disabling features of NF1. Plexiform
neurofibromas may involve a small or large nerve, or even an
entire limb (elephantiasis neuromatosa), and is considered
as diagnostic of the disease if it involves a major nerve. The (a)
lesion usually involves the subcutaneous tissues, which
may in turn affect the underlying bone and produce
deformities, but it may also develop in visceral locations.
● Diffuse neurofibroma: this occurs mainly in children and
young adults, mostly in the head and neck region. It

presents as a plaque-like lesion in the skin. At least 10% of
patients with diffuse neurofibroma have neurofibromatosis.
Neurofibromatosis 2 (NF2)
Neurofibromatosis type 2 (NF2) predisposes to the develop-
ment of bilateral vestibular schwannomas, sometimes associ-
ated with schwannomas at other locations, meningiomas,
ependymomas and juvenile posterior subcapsular lenticular
opacities. Bilateral acoustic neuromas are characteristic of this
form of the disease, and usually have none or only a few of the
peripheral manifestations.
(b)
Localized neurofibroma is identical to solitary neurofibroma. Figure 13.65 Diffuse neurofibroma. (a) Loose spindle cell
Plexiform neurofibroma is characterized by the presence of lesion separating skin appendages and incorporating fat cells.
(b) The neural nature of the lesion is highlighted by loose
irregularly expanded, tortuous nerve bundles cut in various
eosinophilic fibrillary background with scattered small,
planes of section. These nodules are composed of ‘neoplastic’ comma-shaped nuclei.
Schwann cells accompanied by other participating cellular and
non-cellular components. Nuclear pleomorphism may be seen,
and mitotic figures usually indicate malignant change.
Figure 13.66 Diffuse neurofibroma. Clusters of Wagner–

Figure 13.64 Plexiform neurofibroma. Irregularly expanded, Meissner bodies are seen to the right, and diffuse pattern to
tortuous nerve bundles cut in various planes of the section. the left.
Diffuse neurofibroma differs from ordinary neurofibroma

by having infiltrative margins, extending along connective
tissue septa into fat and enveloping normal structures, and by
the presence (in most lesions) of clusters of Wagner–Meissner
bodies. It has a uniform, fine fibrillary collagenous background.
A pigmented neurofibroma consists of bland, short spindle
cells and multiple foci of scattered melanin-laden cells. The
spindle cells may be arranged in a storiform pattern, resem-
bling features of dermatofibrosarcoma protuberans.
Secondary features
● Malignant transformation.
● Solitary neurofibroma may resemble leiomyoma,
dermatofibroma, neurotized intradermal nevus,
Figure 13.67 Pacinian neuroma. A well-demarcated, non-
neurothekeoma, and schwannoma encapsulated lesion consisting of abnormal aggregates of
● Plexiform neurofibroma may be mistaken for plexiform morphologically mature or hyperplastic pacinian corpuscles.
schwannoma
● Diffuse neurofibroma may be mistaken for fibromatosis,
Secondary features
dermatofibrosarcoma protuberans, spindle cell lipoma,
spindle cell liposarcoma and low-grade fibromyxosarcoma ● Mucinous change.
● A pigmented neurofibroma can be confused with a
pigmented dermatofibrosarcoma protuberans (Bednar Special techniques
tumor) because the melanin-laden cells of both processes ● The cells are perineural and therefore EMA-positive and
are similar. However, the latter entity exhibits a more S-100 protein-negative.
extensive storiform growth, has greater immunoreactivity
for CD34, and lacks a diffuse proliferation of S-100
protein-positive Schwann cells NEUROMA, SOLITARY CIRCUMSCRIBED
Special techniques
CLINICAL FEATURES
See Solitary neurofibroma (p. 1016).
● The spindle cells of pigmented neurofibroma are positive
Solitary circumscribed neuroma (palisaded encapsulated neur-
oma of the skin) is a benign, superficially located neural lesion
for S-100 protein and CD34. The melanin-laden cells
which accounts for approximately 25% of all nerve sheath
stained positively for HMB-45.
tumors of the dermis (true schwannomas rarely occur in the
dermis). It usually presents as solitary, asymptomatic, skin-
NEUROMA, PACINIAN colored papules on the face of middle-aged individuals, and is
not associated with von Recklinghausen’s disease.

Pacinian neuromas are extremely rare benign lesions represent- Solitary circumscribed neuroma is a well-circumscribed, round
ing an unusual hyperplasia of perineural cells, perhaps in or ovoid, completely or incompletely encapsulated dermal lesion,
response to trauma. They present mainly in adolescents and composed of spindle cells arranged in interlacing fascicles. The
adults as painful masses on the volar aspect of the digits. This lesion may also extend into the subcutaneous tissue, showing a
lesion has rarely been reported in other locations, such as inside club-shaped appearance. Small nerves may be seen at the periph-
the abdomen. ery of the lesion. An epithelioid variant has rarely been reported.
PATHOLOGICAL FEATURES (Figure 13.67) Secondary features

Pacinian neuroma is a well-demarcated, non-encapsulated lesion
● Epidermal acanthosis and occasionally
consisting of abnormal aggregates of morphologically mature pseudoepitheliomatous hyperplasia.
or hyperplastic pacinian corpuscles (a central homogeneous,
● Dermal elastosis.
acellular, eosinophilic core surrounded by many pale-staining
concentric collagenous lamellae). These are set in a background Cell morphology
stroma containing mature fat cells and small nerves or poorly ● The tumor cells have a typical neural morphology – that
formed nerve bundles. is, poorly delineated, eosinophilic cytoplasm and wavy,
pointed, deeply basophilic nuclei. Vague nuclear palisading Special techniques

is often seen. ● The cells are S-100 protein-positive.
● Occasional mitotic figures may be seen.
NEUROTHEKEOMA, NERVE SHEATH MYXOMA
● Schwannoma
● Neurofibroma
● Leiomyoma CLINICAL FEATURES
● Neurotized intradermal nevus Plexiform or myxomatous neurothekeoma is a benign nerve
sheath tumor which presents as skin-colored papules or nod-
Special techniques
ules. It primarily involves the head and neck and upper extrem-
● The tumor cells are positive for S-100 protein. ities of young adults. The lesion pursues a benign clinical course.
● The capsule is composed of flattened, elongated cells that Cellular neurothekeoma is a rare benign cutaneous neo-
are EMA-positive. plasm, and there are conflicting opinions regarding its histo-
genetic origin. It has been suggested that cellular neurothekeoma
NEUROMA, TRAUMATIC has a divergent cell origin, predominantly composed of undif-
ferentiated cells that can exhibit features of neuroendocrine
cells in addition to fibroblastic or myofibroblastic ones. Another
CLINICAL FEATURES theory suggests that cellular neurothekeoma is a plexiform
epithelioid variant of dermatofibroma. The lesion preferen-
Traumatic neuroma represents a non-specific proliferation of
tially occurs in adolescents to young adults on the upper half of
nerve axons and Schwann cells. It usually develops following
the body.
trauma or a surgical procedure (most commonly amputation of
a limb or digit). It presents as slowly growing, tender mass or
nodule which develops after a variable period of time. Post- PATHOLOGICAL FEATURES (Figure 13.69)
surgical visceral neuromas are often asymptomatic. There are two histological variants:
● Plexiform or myxomatous neurothekeoma consists of
PATHOLOGICAL FEATURES (Figure 13.68) multiple, variably-sized myxoid, intradermal or
Traumatic neuroma is characterized by the presence of numer- subcutaneous lobules separated by fibrous tissue septa
ous uniform or of different-sized nerve bundles. These are pres- reminiscent of perineurium. Each lobule contains plump,
ent in a fibrocollagenous background. Adjacent foreign-body spindle-shaped or round cells, some of which are
reaction, suture material and non-specific inflammatory cells histiocytic or epithelioid in appearance. These cells are
can also be seen. On occasion, traumatic neuroma exhibits gran- distributed singly or as small aggregates. Sometimes the
ular cell changes ‘granular traumatic neuroma’. This should not cells appear to line small degenerative cystic spaces.
be confused with granular cell tumor. Occasional giant cells may be seen.
● Cellular neurothekeoma differs from myxomatous
Differential diagnosis neurothekeoma in showing greater cellularity, less

myxomatous change, and less-pronounced plexiform
● Plexiform neuroma
compartmentalization by fibrous septa. Besides
● Intraneural perineuroma
characteristic whorled nests to fascicles of palely
eosinophilic epithelioid cells, the lesion shows variable
clues pointing to dermatofibroma: acanthosis, ill-defined
storiform periphery, peripherally accentuated prominent
sclerosis, and lymphocytic demarcation/infiltration.
Secondary features
● Perivascular lymphocytic infiltrate.
● Myxoid change.
● Cystic degeneration.
Cell morphology
● The cells are spindle-shaped or epithelioid, and have
abundant eosinophilic or pale-staining cytoplasm with
well-defined cell borders and neural characteristics (see
Neurofibroma, p. 1016).
Figure 13.68 Traumatic neuroma. Numerous uniform nerve ● The nuclei are vesicular, with a dispersed chromatin pattern.
bundles, present in a fibrocollagenous background. Some nuclei are indented and reminiscent of histiocytes.
● Low-grade cytological atypia and mitotic figures are

occasionally seen.
● Multinucleated giant cells are common.
● Spindle and epithelioid cell (Spitz) nevus
● Malignant melanoma (particularly desmoplastic-
neurotropic melanoma)
● Cellular blue nevus
● Fibrohistiocytic proliferations (fibrous histiocytoma and
juvenile xanthogranuloma)
Special techniques
● The tumor cells of plexiform or myxomatous
(a) neurothekeoma are strongly positive for S-100 protein,
NSE, and EMA.
● The neoplastic cells of cellular neurothekeoma strongly
express NK1C3 (CD57), synaptophysin, NSE and
vimentin, some express SMA and PGP9.5, but are negative
for S-100 protein, Factor XIIIa, CD34, CD56, CD57,
CD68, chromogranin A, desmin, EMA and von
Willebrand factor.
PERINEUROMA (STORIFORM PERINEURIAL

FIBROMA)
CLINICAL FEATURES
The perineurial cells that make up the perineurium of periph-
(b)
eral nerve fascicles are immunoreactive for vimentin and EMA,
but not for the Schwann cell markers, S-100 protein, and Leu-
7. These cells are seen in a number of pseudoneoplastic lesions
and true neoplasms, notably localized hypertrophic neuro-
pathy, neurofibromas of various types, and perineuromas. The
term perineurioma should be reserved for the neoplasm com-
posed only of perineurial cells and presenting as a soft tissue
tumor.
Two variants of perineuromas are recognized: intraneural
perineuromas; and soft tissue perineuroma, which includes
sclerosing and plexiform subsets.
Intraneural perineuroma usually involves large nerves in the
extremities, with some motor or sensory neurological symptoms.
The most characteristic feature is the presence of fusiform, seg-
mental nerve enlargement with a lesion length ranging from 3.5
to 30 cm. Most examples of intraneural perineuromas reported
in the literature may merely represent ‘localized hypertrophic
neuropathy’, which is also characterized by fusiform swelling of
(c)
a nerve, usually in the extremities.
Soft tissue perineuroma is a rare lesion which usually pres-
Figure 13.69 (a–c) Plexiform or myxomatous neurothekeoma.
Multiple, variably sized myxoid, intradermal lobules separated by ents as discrete mass in the subcutaneous or deep soft tissue of
fibrous tissue septa reminiscent of perineurium. Each lobule contains the extremities or trunk of middle-aged individuals. It has also
plump, spindle-shaped or round cells, distributed singly or as small been reported in deep soft tissue such as the capsule of the kid-
aggregates. Sometimes the cells appear to line small degenerative ney and the retroperitoneum.
cystic spaces. Sclerosing perineurial tumor is a distinctive subset of peri-
neurial tumor, most commonly seen in the hands. The process
typically presents as a painless mass of variable duration.
PATHOLOGICAL FEATURES (Figure 13.70) hypertrophic neuropathy contains distended fascicles

composed of whorls of perineurial cells and fibrous tissue
Intraneural perineuroma shows what appear to be hyper-
entrapping residual axons, probably representing a
trophic nerve bundles of varying sizes. Each bundle is made up
hyperplastic reaction to nerve damage
of uniform small pseudo-onion bulbs of EMA⫹ perineurial
● Soft tissue perineuroma may resemble dermatofibroma,
cells, surrounding S-100 protein⫹ and a central axon of
fibroma of tendon sheath, neurofibroma, schwannoma,
Schwann cells. Mitosis may rarely be seen. The process, when
nevus, pacinian neurofibroma, perineurial myxoma, nerve
seen at low-power magnification, is reminiscent of traumatic
sheath myxoma/neurothekeoma, cutaneous meningioma
neuroma or a reactive process.
and schwannoma
● Sclerosing perineuroma can be mistaken as a fibroma of
tendon sheath, the sclerotic fibroma associated with
Cowden’s disease, an epithelioid neurofibroma, a late stage
of tenosynovial giant cell tumor, and sclerosing adnexal
tumors
● Reticular perineurioma should be distinguished from
myoepithelial tumors, extraskeletal myxoid
chondrosarcoma, and myxoid synovial sarcoma
Special techniques
● Intraneural perineuroma shows a characteristic
immunohistochemical profile. The perineurial cells forming
the pseudo-onion bulbs are EMA-positive and S-100
protein-negative. The Schwann cells that are seen in the
centers of the bulbs are S-100 protein positive. The MIB-1
antigen labeling index may range from 4% to 17%.
● The spindle cells in soft tissue perineuroma are EMA-
Figure 13.70 Perineuroma. Note the storiform pattern of bland positive but negative for S-100 protein.
spindle cells.
SCHWANNOMA (NEURILEMMOMA)
Soft tissue perineuroma is a well-circumscribed, non-encap-
sulated, dermal to subcutaneous lesion consisting of slender
epithelioid to spindle-shaped cells arranged in fascicles or CLINICAL FEATURES
whorls reminiscent of DFSP. The main cell population is
Schwannoma is a benign nerve sheath tumor which usually
spindle-shaped, with slender bipolar cellular processes and
presents as a slowly growing, solitary, well-circumscribed lesion.
elongated nuclei, sometimes with nucleoli. The cells may be
It occurs most often on the head, neck and flexor surfaces of
either wavy or comma-shaped. Mast cells may be present.
the extremities. It is rarely multiple, and is associated with von
Subtypes of perineuroma have been described:
Recklinghausen’s disease. Deeply located schwannomas are
● Sclerosing perineuroma is generally well-circumscribed but
usually larger than the superficial lesions, and are found in the
non-encapsulated, and consists of abundant dense collagen
posterior mediastinum, retroperitoneum, and rarely in visceral
and variable numbers of small, epithelioid and spindled
locations. Schwannomas very rarely undergo malignant change,
cells exhibiting corded, trabecular, and whorled (onion
most often in the form of MPNST or – exceptionally rarely –
bulb-like) growth patterns.
into angiosarcoma. Patients with malignant change in schwan-
● Retic

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© 2005 Awatif I Al-Nafussi

All rights reserved. No part of this publication may be reproduced or

British Library Cataloguing in Publication Data

Library of Congress Cataloging-in-Publication Data

ISBN 0 340 80944 2

Commissioning Editor: Serena Bureau

Typeset in 9/12 Sabon by Charon Tec Pvt. Ltd, Chennai, India

PART I: HISTOLOGICAL PATTERNS 1

1 Common histological patterns and cell types of tumors 3

PART II: SYSTEM/ORGAN CHAPTERS IN ALPHABETICAL ORDER 63

2 Bone tumors Awatif I Al-Nafussi and David Hughes 65

5.2 Hepatobiliary tract tumors Christopher OC Bellamy 242

5.3 Pancreatic tumors David K Worrall and Hassan MH Kamel 267

6 Endocrine tumors Catriona Anderson and Kathryn M McLaren 333

7 Female genital tract tumors Awatif I Al-Nafussi 365

Tumors of the oral cavity 576

9 Lung and pleural tumors William AH Wallace 629

10 Lymphoreticular system tumors 651

10.3 Tumors of the spleen Bridget S Wilkins 738

12 Skin tumors Awatif I Al-Nafussi and Kathryn M McLaren 835

PART III: SYSTEM INDEX ACCORDING TO VARIOUS MICROSCOPIC PATTERNS AND

LEAD AUTHOR Hassan MH Kamel MBChB MSc PhD(Glasgow) FRCPath

CONTRIBUTORS Kathryn M McLaren BSc MBChB FRCPath FRCPE FRCSEd

Stewart Fleming William AH Wallace BSc(Hons) MBChB(Hons) PhD MRCPath

Glandular/pseudoglandular pattern 4 Diffuse monomorphic highly cellular spindle cell pattern

Xanthomatous/foam cells 56 Pseudoepitheliomatous hyperplastic 60

This section is principally aimed at trainee pathologists who

This category includes all tumors and tumor-like conditions in

DUCTAL GLANDULAR PATTERN (Figures 1.1–1.3)

Ducts are glandular structures that vary in size and shape

Figure 1.3 Ductal structures exhibiting angulations, wall thinning

duct carcinoma of the breast of no special type typically consists

TUBULAR PATTERN (Figures 1.4–1.9)

Like ducts, tubules are round or elongated glandular structures

Figure 1.6 Tubules lined by single and double layers of epithelial

Figure 1.4 Small round tubules lined by cuboidal cells and

Figure 1.5 Crowded round and elongated tubules lined by

ACINAR/MICROACINAR PATTERN (Figures 1.10–1.13)

An acinus is a microgland or a small rounded space surrounded

PAPILLARY AND PSEUDOPAPILLARY PATTERN

Papillae are finger-like structures of any size or shape. Large

CRIBRIFORM PATTERN (Figures 1.25–1.28)

‘Cribriform’ means perforated by small holes, as in a sieve. In

Figure 1.28 Cribriform pattern is commonly seen in salivary duct

FOLLICULAR PATTERN (Figures 1.29–1.32)

Thyroid follicles are gland-like structures containing densely

ADENOID CYSTIC PATTERN (Figures 1.33 and 1.34)

This term was originally used to describe a salivary gland

Figure 1.33 Well-defined nests of basaloid epithelial cells

lighter nucleus, and may have a visible nucleolus. This pattern

This is characterized by elongated and branching epithelial-

MUCINOUS GLANDULAR PATTERN (Figures 1.35–1.37)

The glands are medium- to large-sized, round, oval or elon-

include mucinous ovarian tumors, mucinous carcinomas of

‘SIGNET RING’ GLANDULAR PATTERN

‘Signet ring’ cells are very distinctive, characterized by the pres-

Figure 1.38 Signet ring in Kruckenberg tumor (ovarian metastasis

retiform endometrioid carcinoma and retiform Sertoli–Leydig