Surgical Pathology of Head & Neck - 1

Volu m e 1
Surgical
Pathology
of the
Head and Neck
Third Edition
EDITED BY LEON BAR NES
Surgical
Pathology
of the
Head and Neck
Volu m e 1
Surgical
Pathology
of the
Head and Neck
Third Edition
EDITED BY
LEON BARNES
University of Pittsburgh Medical Center
Presbyterian-University Hospital
Pittsburgh, Pennsylvania, USA
Printed in India by Replika Press Pvt. Ltd.
Preface to Third Edition
Seven years have elapsed since the second edition of Surgical Pathology of the Head
and Neck was published. During this interval there has been an enormous amount
of new information that impacts on the daily practice of surgical pathology.
Nowhere is this more evident than in the area of molecular biology and genetics.
Data derived from this new discipline, once considered to be of research interest
only, have revolutionized the evaluation of hematolymphoid neoplasms and are
now being applied, to a lesser extent, to the assessment of mesenchymal and
epithelial tumors. While immunohistochemistry has been available for almost
30 years, it has not remained static. New antibodies are constantly being
developed that expand our diagnostic and prognostic capabilities.
Although these new technologies are exciting, they only supplement and do
not replace the ‘‘H&E slide,’’ which is, and will continue to be, the foundation of
surgical pathology and this book particularly. This edition has been revised to
incorporate some of these new technologies that further our understanding of the
pathobiology of disease and improve our diagnostic acumen, while at the same
time retaining clinical and pathological features that are not new but remain
useful and important.
Due to constraints of time and the expanse of new knowledge, it is almost
impossible for a single individual to produce a book that adequately covers the
pathology of the head and neck. I have been fortunate, however, to secure the aid
of several new outstanding collaborators to assist in this endeavor and wish to
extend to them my sincere thanks and appreciation for lending their time and
expertise. In addition to new contributors, the illustrations have also been
changed from black and white to color to enhance clarity and emphasize
important features.
This edition has also witnessed changes in the publishing industry. The two
previous editions were published by Marcel Dekker, Inc., which was subse-
quently acquired by Informa Healthcare, the current publisher. At Informa
Healthcare, I have had the pleasure of working with many talented individuals,
including Geoffrey Greenwood, Sandra Beberman, Alyssa Fried, Vanessa San-
chez, Mary Araneo, Daniel Falatko, and Joseph Stubenrauch. I am especially
indebted to them for their guidance and patience.
I also wish to acknowledge the contributions of my secretary, Mrs. Donna
Bowen, and my summer student, Ms. Shayna Cornell, for secretarial support and
Ms. Linda Shab and Mr. Thomas Bauer for my illustrations. Lastly, this book
would not have been possible without the continued unwavering support of my
family, Carol, Christy, and Lori, who have endured yet another edition!
Leon Barnes
Contents
Preface to Third Edition . . . . iii

Contributors . . . . vii
Volume 1
1. Fine Needle Aspiration of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Tarik M. Elsheikh, Harsharan K. Singh, Reda S. Saad, and Jan F. Silverman
2. Uses, Abuses, and Pitfalls of Frozen-Section Diagnoses of Diseases

of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Mario A. Luna
3. Diseases of the Larynx, Hypopharynx, and Trachea . . . . . . . . . . . . . . . . . . . . . . 109

Leon Barnes
4. Benign and Nonneoplastic Diseases of the Oral Cavity
and Oropharynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
Robert A. Robinson and Steven D. Vincent
5. Noninfectious Vesiculoerosive and Ulcerative
Lesions of the Oral Mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
Susan M€uller
6. Premalignant Lesions of the Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

Pieter J. Slootweg and Thijs A.W. Merkx
7. Cancer of the Oral Cavity and Oropharynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

Samir K. El-Mofty and James S. Lewis, Jr.
8. Diseases of the Nasal Cavity, Paranasal Sinuses,
and Nasopharynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
Leon Barnes
9. Diseases of the External Ear, Middle Ear, and Temporal Bone . . . . . . . . . . 423
Bruce M. Wenig
10. Diseases of the Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475

John Wallace Eveson and Toshitaka Nagao
Volume 2
11. Midfacial Destructive Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
Leon Barnes
12. Tumors of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
Beverly Y. Wang, David Zagzag, and Daisuke Nonaka
13. Tumors and Tumor-Like Lesions of the Soft Tissues . . . . . . . . . . . . . . . . . . . . 773
Julie C. Fanburg-Smith, Jerzy Lasota, Aaron Auerbach, Robert D. Foss,
William B. Laskin, and Mark D. Murphey
14. Diseases of the Bones and Joints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951

Kristen A. Atkins and Stacey E. Mills
vi Contents
15. Hematolymphoid Lesions of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . 997

Alexander C. L. Chan and John K. C. Chan
16. Pathology of Neck Dissections ........................................... 1135
Mario A. Luna
17. The Occult Primary and Metastases to and

from the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147
Mario A. Luna
18. Cysts and Cyst-like Lesions of the Oral Cavity,

Jaws, and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163
Steven D. Budnick and Leon Barnes
Volume 3
19. Odontogenic Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201
Finn Prætorius
20. Maldevelopmental, Inflammatory, and Neoplastic
Pathology in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1339
Louis P. Dehner and Samir K. El-Mofty
21. Pathology of the Thyroid Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1385
Lori A. Erickson and Ricardo V. Lloyd
22. Pathology of the Parathyroid Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429

Raja R. Seethala, Mohamed A. Virji, and Jennifer B. Ogilvie
23. Pathology of Selected Skin Lesions of the Head and Neck . . . . . . . . . . . . 1475
Kim M. Hiatt, Shayestah Pashaei, and Bruce R. Smoller
24. Diseases of the Eye and Ocular Adnexa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1551
Harry H. Brown
25. Infectious Diseases of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1609

Panna Mahadevia and Margaret Brandwein-Gensler
26. Miscellaneous Disorders of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . 1717
Leon Barnes
Index . . . . I-1
Contributors
Kristen A. Atkins Department of Pathology, University of Virginia Health

System, Charlottesville, Virginia, U.S.A.
Aaron Auerbach Department of Hematopathology, Armed Forces Institute of

Pathology, Washington D.C., U.S.A.
Leon Barnes Department of Pathology, University of Pittsburgh Medical

Center, Presbyterian-University Hospital, Pittsburgh, Pennsylvania, U.S.A.
Margaret Brandwein-Gensler Department of Pathology, Albert Einstein

College of Medicine, Montefiore Medical Center—Moses Division, Bronx,
New York, U.S.A.
Harry H. Brown Departments of Pathology and Ophthalmology, Harvey and

Bernice Jones Eye Institute, University of Arkansas for Medical Sciences, Little
Rock, Arkansas, U.S.A.
Steven D. Budnick Emory University School of Medicine Atlanta, Georgia, U.S.A.
Alexander C. L. Chan Department of Pathology, Queen Elizabeth Hospital,

Hong Kong
John K. C. Chan Department of Pathology, Queen Elizabeth Hospital,

Hong Kong
Louis P. Dehner Lauren V. Ackerman Laboratory of Surgical Pathology,

Barnes-Jewish and St. Louis Children’s Hospitals, Washington University
Medical Center, Department of Pathology and Immunology, St. Louis, Missouri,
U.S.A.
Samir K. El-Mofty Department of Pathology and Immunology, Washington

University, St. Louis, Missouri, U.S.A.
Samir K. El-Mofty Lauren V. Ackerman Laboratory of Surgical Pathology,

Barnes-Jewish and St. Louis Children’s Hospitals, Washington University
Medical Center, Department of Pathology and Immunology, St. Louis, Missouri,
U.S.A.
Tarik M. Elsheikh PA Labs, Ball Memorial Hospital, Muncie, Indiana, U.S.A.
Lori A. Erickson Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A.
John Wallace Eveson Department of Oral and Dental Science, Bristol Dental
Hospital and School, Bristol, U.K.
Julie C. Fanburg-Smith Department of Orthopaedic and Soft Tissue Pathology,

Armed Forces Institute of Pathology, Washington D.C., U.S.A.
Robert D. Foss Department of Oral and Maxillofacial Pathology, Armed Forces

Institute of Pathology, Washington D.C., U.S.A.
Kim M. Hiatt Department of Pathology, University of Arkansas for Medical

Sciences, Little Rock, Arkansas, U.S.A.
William B. Laskin Surgical Pathology, Northwestern Memorial Hospital,

Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A.
viii Contributors
Jerzy Lasota Department of Orthopaedic and Soft Tissue Pathology, Armed

Forces Institute of Pathology, Washington D.C., U.S.A.
James S. Lewis, Jr. Department of Pathology and Immunology, Washington

University, St. Louis, Missouri, U.S.A.
Ricardo V. Lloyd Mayo Clinic College of Medicine, Rochester, Minnesota,

U.S.A.
Mario A. Luna Department of Pathology, The University of Texas,

M.D. Anderson Cancer Center, Houston, Texas, U.S.A.
Susan Müller Department of Pathology and Laboratory Medicine and

Department of Otolaryngology-Head & Neck Surgery, Emory University School
of Medicine, Atlanta, Georgia, U.S.A.
Panna Mahadevia Department of Pathology, Albert Einstein College of

Medicine, Montefiore Medical Center—Moses Division, Bronx, New York, U.S.A.
Thijs A.W. Merkx Department of Oral and Maxillofacial Surgery, Radboud

University Nijmegen Medical Center, Nijmegen, The Netherlands
Stacey E. Mills Department of Pathology, University of Virginia Health System,

Charlottesville, Virginia, U.S.A.
Mark D. Murphey Department of Radiologic Pathology, Armed Forces

Institute of Pathology, Washington D.C., U.S.A.
Toshitaka Nagao Department of Diagnostic Pathology, Tokyo Medical

University, Tokyo, Japan
Daisuke Nonaka Department of Pathology, New York University School of

Medicine, New York University Langone Medical Center, New York, New York,
U.S.A.
Jennifer B. Ogilvie University of Pittsburgh Medical Center, Pittsburgh,

Pennsylvania, U.S.A.
Shayesteh Pashaei Department of Pathology, University of Arkansas for

Medical Sciences, Little Rock, Arkansas, U.S.A.
Finn Prætorius Department of Oral Pathology, University of Copenhagen,

Copenhagen, Denmark
Robert A. Robinson Department of Pathology, The University of Iowa, Roy

J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, U.S.A.
Reda S. Saad Sunnybrook Hospital, University of Toronto, Toronto, Ontario,

Canada
Raja R. Seethala University of Pittsburgh Medical Center, Pittsburgh,

Jan F. Silverman Department of Pathology and Laboratory Medicine,

Allegheny General Hospital, and Drexel University College of Medicine,
Pittsburgh, Pennsylvania, U.S.A.
Harsharan K. Singh University of North Carolina-Chapel Hill School of

Medicine, Chapel Hill, North Carolina, U.S.A.
Pieter J. Slootweg Department of Pathology, Radboud University Nijmegen

Medical Center, Nijmegen, The Netherlands
Bruce R. Smoller Department of Pathology, University of Arkansas for Medical

Sciences, Little Rock, Arkansas, U.S.A.
Contributors ix
Steven D. Vincent Department of Oral Pathology, Oral Radiology and Oral

Medicine, The University of Iowa College of Dentistry, Iowa City, Iowa, U.S.A.
Mohamed A. Virji University of Pittsburgh Medical Center, Pittsburgh,

Beverly Y. Wang Departments of Pathology and Otolaryngology, New York

University School of Medicine, New York University Langone Medical Center,
New York, New York, U.S.A.
Bruce M. Wenig Department of Pathology and Laboratory Medicine,

Beth Israel Medical Center, St. Luke’s and Roosevelt Hospitals, New York,
New York, U.S.A.
David Zagzag Department of Neuropathology, New York University School of

Medicine, Bellevue Hospital, New York, New York, U.S.A.
1
Fine Needle Aspiration of the Head and Neck
Tarik M. Elsheikh
PA Labs, Ball Memorial Hospital, Muncie, Indiana, U.S.A.
Harsharan K. Singh
University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, North Carolina, U.S.A.
Reda S. Saad
Sunnybrook Hospital, University of Toronto, Toronto, Ontario, Canada
Jan F. Silverman
Department of Pathology and Laboratory Medicine, Allegheny General Hospital, and
Drexel University College of Medicine, Pittsburgh, Pennsylvania, U.S.A.
I. THYROID GLAND provide a relative risk of malignancy from which they

can base upon their management decisions, i.e., sur-
A. Introduction gery versus clinical follow-up (3). FNA has achieved a
Although clinically palpable thyroid nodules are only 35 to 75% reduction in the number of patients requiring
present in 4% to 7% of the adult population in the surgery, while doubling or tripling the incidence of
United States, the increasing use of diagnostic imag- malignancy detected at thyroidectomy (4). Therefore,
ing has greatly increased the frequency of incidentally the main priority of FNA is not to miss a cancer.
discovered thyroid nodules with a prevalence as high Accordingly, high sensitivity coupled with a low
as 50% in many studies (1,2). These incidental thyroid false-negative rate is what most pathologists and
nodules are usually detected with head and neck clinicians stride towards achieving.
ultrasound (US) studies for carotid or parathyroid All patients with a palpable thyroid nodule
disease, and on computed tomography (CT), magnet should undergo US examination. Solitary palpable
resonance imaging (MRI), or positron emission nodules may be sampled by freehand or US-guided
tomography (PET) scans for the work-up of metastatic FNA (US-FNA). In multinodular glands, sampling
disease unrelated to the thyroid. However, the preva- should be focused on lesions characterized by suspi-
lence of cancer appears to be similar in palpable and cious US features, rather than the larger or clinically
nonpalpable thyroid nodules, ranging from 5% to 8 %, dominant nodule (1). US-FNA is recommended for
with microinvasive papillary carcinomas being nonpalpable nodules larger than 1 cm (1). FNA is not
increasingly diagnosed at earlier stages because of recommended for nodules smaller than 1 cm, unless
widespread use of high-resolution US (1). they demonstrate suspicious US features or the patient
Fine needle aspiration (FNA) cytology has has a high-risk history.
become the standard of care for the initial diagnostic Diagnostic Categories
workup of thyroid nodules. FNA of the thyroid gland
is primarily a ‘‘screening test,’’ but can be diagnostic In general, FNA results fall into one of four major
in many conditions. Most clinicians use FNA results in diagnostic categories, with the relative frequency of
conjunction with clinical findings to guide patient diagnoses noted in parenthesis: benign (70%), indeter-
management. Clinical factors reported to be associat- minate or suspicious (10–15%), malignant (5%), and
ed with increased risk of malignancy include head nondiagnostic/unsatisfactory (10–15%) (5). The cyto-
and neck irradiation, family history of medullary logic findings can be grouped into four to six catego-
carcinoma or MEN2, extremes of age, male sex, a ries, depending on whether or not the indeterminate
growing or fixed nodule, firm/hard consistency, cer- category is further subdivided. We prefer to further
vical lymphadenopathy, and persistent hoarseness, subclassify the indeterminate category into three sub-
dysphonia, dysphagia, or dyspnea (1). However, groups, as was recommended by the Papanicolaou
most patients with thyroid nodules have few or no Society of Cytopathology (PSC) in 2006 and National
symptoms, and usually no clear relationship exists Cancer Institute (NCI) thyroid FNA state of the sci-
between nodule histologic features or size and the ence conference in 2007 (Table 1) (6,7). The use of this
reported symptoms. Clinicians generally use FNA to terminology is presented later in the discussion of
2 Elsheikh et al.
Table 1 Thyroid Diagnostic Categories, as proposed by PSC As many as one-third of the cases initially diagnosed
and NCI State of the Science Conference as ‘‘adequate and benign’’ were thought to be ‘‘non-
diagnostic’’ on second review by other pathologists
Category Thyroid diagnosis (9). Currently, there are no standardized criteria for
1 Benign, nonneoplastic judging aspirate sufficiency or cellularity. The most
2 Follicular lesion of undetermined commonly cited adequacy criteria in the published
significance literature are the presence of 5 to 6 groups of well
3 Follicular neoplasm/Hurthle cell preserved follicular cells with 10 or more cells per
neoplasm
4 Suspicious for malignancy
group (10); 10 or more clusters of follicular cells with
5 Malignant more than 20 cells per cluster (11); 6 groups of
6 Unsatisfactory follicular cells on at least 2 of 6 passes (12); and 8 to
10 clusters of follicular cells on each of two slides (13).
Abbreviations: NCI, National Cancer Institute; PSC, Papanicolaou
Society of Cytopathology With the application of these criteria, approximately
Source: Modified from Refs. 6, 7. 10% to 20% of thyroid aspirates fall in the nondiag-
nostic category. Repeat FNA, especially under US
guidance, will result in an adequate specimen in
‘‘follicular lesions.’’ The rendered cytologic diagnosis about half of these cases (14). Despite repeat FNAs,
should be specific enough to help the clinician appro- however, 5% to 10% of patients will continue to have
priately manage the thyroid condition. Increased com- persistently nondiagnostic FNAs. Studies evaluating
munication between the clinician and the pathologist, this subset of patients, with persistent nondiagnostic
and standardization of terminology within the pathol- FNAs, have found an incidence of 2% to 37% of
ogy department will greatly improve patient care. malignancy (14–16). Therefore, repeatedly nondiag-
Although the utilization of diagnostic categories is nostic FNAs should be surgically excised (1).
encouraged, they should not be used alone. These The main purpose of establishing the adequacy
diagnostic categories need to be qualified with a criteria is to minimize the number of false-negative
specific diagnosis when possible, or with a differential diagnoses. In our view, at least two passes are needed,
diagnosis, in order to give the clinician the clearest as a single pass may not be representative. In our
idea possible of the likely risk of malignancy, i.e., a practice, we obtain at least three to four passes from
diagnosis of follicular lesion alone is not encouraged, each nodule to insure sampling of different areas.
but rather should be further qualified as hyperplastic Exceptions include cystic lesions that collapse
nodule versus follicular neoplasm (FN) (8). completely following aspiration (1). We employ a
combined Kini-Hamburger criterion in our practice—
Diagnostic Accuracy at least six to eight groups of well-preserved follicular
Sensitivity of thyroid FNA ranges from 65% to 98%, cells (10 or more cells per group) on at least each of two
and specificity ranges from 72% to 100%. The false- slides, preferably from two separate passes. We do not,
positive rate varies from 0% to 7%, but is usually however, restrict ourselves to these numbers when
reported as below 1% if unsatisfactory, suspicious, aspirates are predominately cystic or contain abundant
and indeterminate diagnoses are excluded (3). The colloid, as the presence of few benign follicular cells
majority of false-positive diagnoses are due to overin- (3–4 groups) is sufficient to issue a diagnosis of benign/
terpretation of repair, hyperplastic papillae, and reac- colloid nodule in these situations. However, in cystic
tive nuclear changes as features of papillary carcinoma change alone, i.e., macrophages without follicular cells,
(3). False-negative rates range from 1% to 11%, and are we generate a nondiagnostic interpretation, as up to
predominately due to unsatisfactory/nondiagnostic 20% of cystic papillary carcinomas show only cystic
specimens, sampling error, misinterpretation, and change. Although abundant colloid alone represents a
cystic neoplasms (especially cystic papillary thyroid cytologically unsatisfactory specimen, we usually add a
carcinoma) (5,8). qualifier that colloid nodule is suggested if clinically
benign, and recommend repeat US-FNA in six months.
Adequacy Criteria Using our criteria, follow-up thyroidectomy showed a
12% cancer rate in nondiagnostic specimens (17). This
The goal of FNA is to provide a specimen from which rate, however, may be slightly overestimated because
the pathologist can render an accurate and meaningful of a selection bias, reflected by the fact that patients
interpretation, which the clinicians can then use in with clinically suspicious lesions are more likely to be
their management of the patient. This implies a speci- referred for surgical excision. Individual centers should
men with sufficient cellularity to yield a specific monitor their own diagnostic accuracy for guidance to
diagnosis that falls within one of the major diagnostic their clinicians, and make it unambiguous when the
categories listed above (Table 1), i.e., benign/nonneo- specimen is unsatisfactory. Nondiagnostic FNAs
plastic, FN, malignancy. A diagnosis of ‘‘rare or few should neither be considered benign nor be interpreted
benign follicular cells’’ without qualification is, in our as ‘‘negative for malignancy.’’ Repeat FNA is encour-
opinion, not considered an appropriate interpretation. aged, or excision may be indicated, especially in per-
An adequate sample should be representative of the sistently nondiagnostic cases and high-risk patients
lesion (appropriate cellularity) and technically well (14). A specimen should not be interpreted as ‘‘unsat-
prepared, i.e., good fixation, thin smear, adequate isfactory’’ in the presence of any degree of significant
staining. Unfortunately, judging specimen adequacy cytologic atypia, and should warrant an interpretation
tends to be subjective and differs among pathologists. of ‘‘atypical’’ or ‘‘suspicious’’.
Chapter 1: Fine Needle Aspiration of the Head and Neck 3
Role of Repeat FNA in Thyroid

Indications for repeat FNA of thyroid nodules include
follow-up of benign nodules, enlarging nodules, nod-
ules larger than 4 cm, recurrent cyst, nonshrinkage of
the nodule after levothyroxine therapy, and an initial
unsatisfactory/nondiagnostic FNA (1). Repeat con-
ventional (freehand) FNA in patients with initial
unsatisfactory specimens results in an adequate sam-
ple in approximately 50% of cases (14). Conversely,
repeat US-FNA of previously nondiagnostic biopsies
can lead to a definitive diagnosis in up to 90% of cases
and have resulted in a reduction in the unsatisfactory
rate from 15% to 3% in some studies (18,19). This is
especially helpful in small nodules less than 1.5 cm
and complex cystic lesions, where needles can target
the more solid component (4). Baloch et al. evaluated
the role of repeat FNA in 50 unsatisfactory and
‘‘indeterminate for follicular neoplasm’’ cases, with
surgical follow-up (20). Repeat US-FNA has led to a
more definitive diagnosis in 80% of cases. Unsatisfac-
tory diagnoses were associated with a 51% cancer rate,
while ‘‘indeterminate’’ diagnoses were associated with
a 48% cancer rate. Repeat FNA, however, is not rec-
ommended for ‘‘follicular neoplasm’’ diagnoses, as it Figure 1 Normal thyroid follicular cells arranged in a honey-
creates confusion and does not provide additional comb configuration. The nuclei have finely granular chromatin
useful management information (1). Repeat FNA and small or inconspicuous nucleoli and show slight anisonu-
should be performed at least three months following cleosis (Papanicolaou stain; magnification, 600).
the initial FNA, to prevent post-FNA reparative
changes (21). Flanagan et al. evaluated the role of
repeat FNA in 267 patients with initial benign cytologic
diagnoses, excluding unsatisfactory specimens, who
had follow-up surgery (22). The use of one repeat
FNA significantly increased the sensitivity for detecting
malignancy from 82% to 90%, and decreased the false-
negative rate from 17% to 11%. There was, however, no
significant improvement in sensitivity or specificity
when more than one repeat FNA were performed.
Normal Cytology and General Cytologic Features

to Assess in Thyroid FNA
Generally, the presence of abundant colloid is associ-
ated with benign conditions, whereas scant to absent
colloid is seen in neoplasms. Architecturally, a pre-
dominant honeycomb configuration of the thyroid
cells and minimal microfollicle formation is associated
with benign nonneoplastic conditions. Conversely, a
predominant syncytial and/or microfollicular pattern
is correlated with neoplasia. The normal thyroid cell
nucleus is about the size of a red blood cell (RBC) (7–9 m), Figure 2 Hashimoto’s thyroiditis. There is intimate admixture of
and has finely granular chromatin, and small or incon- oncocytes and lymphocytes (DQ stain; magnification, 400).
spicuous nucleoli (Fig. 1). In nonneoplastic conditions,
slight uniform enlargement and anisonucleosis can be
observed. On the other hand, neoplasms may show of admixed lymphocytes and follicular cells (Fig. 2).
considerable nuclear enlargement (3–4 times size of Oncocytes may predominate in an aspirate, raising the
RBC), and variable pleomorphism. differential diagnosis of oncocytic neoplasm. There is
usually limited colloid, and the lymphoid population is
polymorphic, showing admixture of small mature lym-
B. Nonneoplastic Disease phocytes, larger reactive lymphoid cells, and occasional
Thyroiditis
plasma cells. The inflammatory cells are often intimately
admixed with the follicular cells. The differential diagno-
Lymphocytic (Hashimoto’s) thyroiditis. Lymphocytic sis includes lymphoma, which is characterized by a
thyroiditis is the most common type of thyroiditis monomorphic population of lymphoid cells. The follicu-
encountered, and is characterized by variable numbers lar cells occasionally demonstrate reactive changes and
4 Elsheikh et al.
prominent nucleoli and may be arranged in single

cells and loosely cohesive groups (24,26). FNA of
benign lymphoepithelial lesion is characterized by
scant cellularity of the epithelial component and pre-
dominance of the lymphoid component. The squa-
mous and mucinous epithelial component may show
degenerative changes, but is devoid of significant
atypia. PTC variants, such as Warthin-like, tall cell,
and oncocytic types, arising in a background of lym-
phocytic thyroiditis should also be considered in the
differential diagnosis (27). These tumors show onco-
cytic features including prominent nucleoli, granular
cytoplasm, and admixed lymphocytes (20). The
absence of nuclear features of PTC, however, excludes
these entities from the differential diagnosis.
Subacute granulomatous (Dequervain’s) thyroiditis.
Subacute thyroiditis rarely presents for FNA, but with
the presence of epithelioid granulomas, the cytologic
features can be diagnostic. Nonspecific findings such
as mixed inflammatory cells, proteinaceous debris,
multinucleated giant cells, and scant degenerated
follicular cells might be seen. The biopsy procedure,
however, may be quite painful for the patient, pre-
Figure 3 Hashimoto’s thyroiditis associated with reactive venting adequate sampling. In the late fibrotic stages
changes, including nuclear enlargement and occasional nuclear of the disease, FNA is often nondiagnostic.
grooves (Papanicolaou stain; magnification, 600).
Acute thyroiditis. Acute thyroiditis is another
cause of painful thyroid aspiration, and it is rarely
sampled by FNA. The aspirates are rich in neutrophils,
atypia, including nuclear grooves and nuclear enlarge- and are associated with scant reactive follicular cells,
ment (Fig. 3). Therefore, the diagnostic threshold for fibrin, macrophages, and blood. Bacteria or fungal
papillary thyroid carcinoma (PTC) should be raised in organisms are occasionally seen in the background.
the presence of lymphocytic thyroiditis, and only consid-
ered when nuclear features of papillary carcinoma are Nodular Goiter/Colloid Nodule
diffusely present in a population of cells devoid of Nodular goiter or colloid nodule is the lesion most
infiltrating lymphocytes (23). Nonspecific chronic commonly sampled by FNA. Characteristically, there
inflammation may also be associated with nodular is abundant colloid and variable number of follicular
goiter. cells (Fig. 4). Romanowsky/Diff-Quik1 (DQ) stain best
The differential diagnosis of lymphocytic thy- demonstrates the presence of colloid (especially watery
roiditis also includes thyroid lesions that may demon-
strate lymphoepithelial features (Table 2). Thyroid
tumors with thymus-like features are extremely rare
and include a spectrum of tumors ranging from
benign to malignant, such as ectopic thyroid thymoma
and carcinoma showing thymus-like differentiation
(CASTLE) (24). These tumors are identical in mor-
phology to their mediastinal counterparts (25). CAS-
TLE may demonstrate variable atypia ranging from
bland morphology resembling thymoma, to highly
atypical features resembling nasopharyngeal carcino-
ma, anaplastic carcinoma, or squamous carcinoma.
The epithelial cells usually possess abundant eosino-
philic/pale cytoplasm and large vesicular nuclei with
Table 2 Thyroid Lesions with Lympho-Epithelial Features

Lymphocytic thyroiditis
Lymphoma
Papillary thyroid carcinoma, i.e., Warthin-like and tall cell variants
Ectopic thymoma
Benign lymphoepithelial lesion Figure 4 Colloid nodule showing abundant colloid and admixed
Carcinoma with thymus-like features benign thyroid follicular cells (Papanicolaou stain; magnification,
Metastatic carcinoma to intra or perithyroid lymph node 200).
Neoplasm arising in a background of lymphocytic thyroiditis
Figure 6 Thin watery colloid showing crazy pavement appear-

ance (A) and cellophane-like coating with folds (B) (DQ stain,
magnification, 200).
Figure 5 Dense colloid has a hyaline quality and stains blue-
violet on air-dried smears (A) and dark orange on fixed prepa-
rations (B). Note prominent cracks [(A)DQ stain; magnification,
200 (B) Papanicolaou stain; magnification, 200].
be seen. The cytoplasm is delicate, scant, and may have
small blue-black granules that are of no diagnostic
significance, as they can be observed in benign and
colloid). Colloid, when dense, is easy to recognize, has a
malignant conditions (29). Flat sheets of oncocytic cells
hyaline quality, and often shows cracks. It has a dark
with mild anisonucleosis may be observed in some
blue-violet-magenta appearance on DQ stain, while
aspirates, but no significant atypia is demonstrated.
stains dark green-orange with Papanicolaou (Fig. 5)
The number of macrophages present in the background
(8). Thin watery colloid has a blue-violet appearance
usually coincides with the extent of cystic degenera-
on DQ, and pale green-orange look on Papanicolaou
tion. Many of the macrophages may contain hemosid-
stain (Figs. 4 and 6). It often forms a ‘‘thin membrane/
erin pigment granules. Focal reparative changes might
cellophane’’ coating or film, frequently with folds
also be observed in cystic lesions, including the pres-
imparting a ‘‘crazy pavement’’ appearance and/or
ence of spindle cells and cells with tissue culture
cracks (Fig. 6) (8). Thin colloid, however, maybe diffi-
medium appearance (30). Hyperplastic/adenomatoid
cult to recognize in Papanicolaou-stained specimens
nodules show increased cellularity compared to colloid
and may also disappear completely in thin-layer prep-
nodules and may be confused with FNs. Detailed
arations (28). Thin colloid can also be confused with
cytologic features of hyperplastic nodules are later
serum in bloody specimens. Helpful clues are the
discussed with follicular lesions.
recognition of cracking and folding in colloid, as well
as its tendency to surround follicular cells, whereas
Diffuse Goiter/Hyperthyroidism (Graves’ Disease)
serum accumulates at the edges of the slide and around
platelets, fibrin, and blood clots (3). Most patients with Graves’ disease have diffuse
The individual thyroid follicular cells are small in enlargement of the thyroid gland, and do not require
size, arranged in monolayered sheets (Fig. 7) and/or biopsy. Occasionally, however, prominent nodules
large balls (Fig. 8), and show no significant nuclear develop, that prompt FNA. The cytologic features of
overlapping or crowding. Occasional microfollicles can Graves’ disease are nonspecific, and clinical correlation
6 Elsheikh et al.
Figure 7 Colloid nodule. Flat sheets of benign thyroid cells with

delicate cytoplasm and no significant nuclear overlapping (DQ
stain; magnification, 400).
Figure 9 Hyperthyroidism (Graves’ disease). The follicular cells

are commonly arranged in flat sheets and have foamy delicate
cytoplasm with distinctive flame cells. These flame cells, however,
represent a nonspecific finding (DQ stain; magnification, 400).
overdiagnose these changes as malignancy or neopla-

sia, and inquiry should be sought regarding prior
radioactive iodine therapy (32). Sometimes the follicu-
lar cells display focal nuclear chromatin clearing, but
other diagnostic nuclear features of papillary carcino-
ma such as grooves and inclusions are commonly
absent (33).
C. Follicular Lesions
Follicular lesions of the thyroid represent the most
Figure 8 Colloid nodule. The follicular cells are arranged in problematic area in thyroid FNA cytology. The major
large balls (microtissue fragments), but show no significant entities included in the differential diagnosis comprise
overlapping or atypia (Papanicolaou stain; magnification, 200). hyperplastic/adenomatoid nodule, FN (adenoma and
carcinoma), and follicular variant of PTC (Table 3).
Below is a discussion of the differential diagnosis of
follicular lesions, cytologic criteria, terminology com-
is needed for a definitive diagnosis. Specimens are monly used as well as terminology recently suggested
often cellular, containing numerous follicular cells by the PSC and NCI thyroid FNA state of the science
and thin colloid. Oncocytes and lymphocytes may be conference, and the clinical implications of various
found in the background (3). The follicular cells are diagnoses rendered (6,7). In general, smears contain-
commonly arranged in flat sheets and have foamy ing abundant colloid are more likely to be benign,
delicate cytoplasm with distinctive flame cells. Flame whereas markedly cellular aspirates are more likely to
cells are best appreciated on DQ stain and represent be neoplastic.
marginal cytoplasmic vacuoles with red to pink frayed
edges (Fig. 9) (31). Flame cells, however, are not specific
Table 3 Differential Diagnosis of Thyroid Follicular Lesions
to Graves’ disease as they may be encountered in other
nonneoplastic thyroid conditions, FN, and papillary Hyperplastic/adenomatoid nodule
carcinoma. Occasionally, treated Graves’ disease Follicular Neoplasm
shows prominent microfollicular architecture, signifi- Follicular adenoma
cant nuclear overlapping and crowding, and consider- Follicular carcinoma
Follicular variant of papillary carcinoma
able atypia. Therefore, care must be taken to not
Hyperplastic/Adenomatoid Nodule
Hyperplastic/adenomatoid nodule is characterized by
the presence of abundant colloid and variable number
of follicular cells. Often there is evidence of oncocytic
metaplasia and degenerative changes including mac-
rophages and old blood. Hyperplastic nodule is con-
sidered in the differential diagnosis of FN when
aspirates are cellular and contain scant colloid. Similar
to colloid nodules, the follicular cells are arranged
mainly in flat sheets with a honeycomb configuration
(Fig. 7). A few microfollicular structures can be seen.
Occasionally, balls and microtissue fragments are
present (Fig. 8), especially when larger gauge needles
are used. The nuclei are uniform in appearance and
approximate the size of RBCs. They show finely
granular chromatin with rare small nucleoli (Fig. 1).
There is minimal nuclear overlapping and crowding.
Figure 10 Follicular neoplasm showing prominent microfollicu-
FN (Adenoma and Carcinoma) lar architecture (DQ stain; magnification, 200).
Using specific cytologic criteria, Kini et al. reported a

75% accuracy rate in the diagnosis of follicular carci-
noma (34). Most other studies, however, could not
reproduce such accuracy (35). In our opinion, and
those of most expert cytopathologists, FNA cannot
distinguish follicular adenoma from follicular carcino-
ma, since histologic confirmation is needed to demon-
strate the presence of capsular and/or vascular space
invasion. There are, however, several cytologic fea-
tures reported to be associated with an increased
cancer risk (40–60% cancer risk) (36). These features
include an enlarged nuclei (at least twice the size of
RBC), marked nuclear atypia including significant
nuclear pleomorphism and irregularity, significant
nuclear overlapping, and predominance of microfol-
licular structures (involving >75% of thyroid clusters)
(36–40). Most follicular carcinomas (>90%) have
prominent microfollicular architecture, while 10% to
15% of cases show significant cytologic atypia (41). It
is important to emphasize, however, that the mere
presence of microfollicles is not equated with neopla-
sia. In fact, studies have shown that microfollicles Figure 11 Follicular neoplasm showing syncytial groups of
associated with no atypia had a low cancer risk follicular cells. The cells have a uniform appearance and display
comparable to that of benign FNA diagnoses (6% prominent nuclear overlapping and crowding (Papanicolaou
cancer risk) (36), and that microfollicles lacking nucle- stain; magnification, 400).
ar overlap and mixed with abundant colloid had a 0%
chance of harboring cancer (37). However, microfol-
licles with atypia were associated with a 44% cancer
risk, while atypia with or without microfollicles was finely to coarsely granular, and nucleoli are infre-
associated with malignancy in 60% of the cases, most quent (Fig. 11) (41). Significant nuclear atypia (which
of which represented follicular variant of papillary may or may not be present) is characterized by
carcinoma (FVPC) (36). nuclear enlargement that is greater than twice the
FNAs of FN are typically highly cellular with size of RBCs, coarse and clumped chromatin, and
scant colloid. There is prominent microfollicular prominent enlarged nucleoli (Fig. 12). FVPC and
and/or syncytial arrangement, involving greater medullary carcinoma should also be considered in
than 50% to 75% of the cellular groups. Microfollicles the differential diagnosis.
are defined as groups of cells (6–12 cells) arranged in
a ring or rosette-like configuration, and often display Challenges in the Diagnosis of Hyperplastic/
a repetitive pattern (Fig. 10) (41). The syncytial Adenomatoid Nodule and FN
groups exhibit a three-dimensional appearance with
loss of cell borders (Fig. 11). The nuclei are uniform Clearly, one of the most difficult problems in thyroid
and slightly enlarged, but usually demonstrate prom- cytology is distinguishing hyperplastic nodule with
inent overlapping and crowding. The chromatin is little colloid from FN with some colloid (41). As
8 Elsheikh et al.
FN diagnosis has ranged in the literature from none to

predominant. There was no clear definition of how
cellular an aspirate needed to be in order to be classi-
fied as ‘‘hypercellular.’’ There were also major dis-
agreements in recognizing colloid, especially when it
had a watery-thin appearance or was associated with
considerable blood in the background (46). A wide
range of interobserver variability (fair to substantial)
has been reported, even among pathologists from the
same institution, when cases diagnosed as follicular
lesion and FN were examined (45). Clary et al. reported
a higher accuracy in predicting neoplastic (84% sensi-
tivity) over nonneoplastic (66% specificity), which sup-
ported the utility of FNA as more of a screening test in
these conditions (45). Other studies analyzed clinical
factors that may complement FNA in predicting malig-
nancy, including size more than 4 cm, fixed lesions,
younger patients, male sex, solitary nodule, etc. Clinical
history, however, is provided to the pathologist in only
up to one-third of the cases (45).
Follicular Lesions, Grey Zone, and Terminology

Although the terms ‘‘follicular lesion’’ and ‘‘follicular
neoplasm’’ are used interchangeably by some authors,
we do not consider them synonymous. According to
Figure 12 Follicular neoplasm with significant atypia, including literature review, lesions categorized as indeterminate
nuclear enlargement, coarse and clumped chromatin, and prom-
account for 5% to 42% of FNA diagnoses. We do not
inent nucleoli (Papanicolaou stain; magnification, 600).
recommend the use of ‘‘indeterminate’’ as a stand-alone
diagnosis, as its meaning has not been standardized
and may be interpreted in different ways. Indetermi-
previously mentioned, the mere presence of micro- nate has been used by different authors and institutions
follicles is not diagnostic of FN, as microfollicles may to refer to a variety of diagnoses, including FN, follicu-
be focally seen in 5% to 10% of hyperplastic nodules. lar lesion, suspicious for malignancy, and atypia not
Up to 30% of hyperplastic nodules are highly cellular, otherwise specified. Redman et al. surveyed 133 clini-
and 15% to 20% show scant colloid (42,43). Although cians (endocrinologists, surgeons, and thyroid special-
degenerative changes are often associated with hyper- ists) in order to determine the implications of FNA
plastic nodule, they may be found in up to 30% of FN. diagnoses on management options (47). In this study,
A definitive diagnosis of hyperplastic nodule should clinicians appropriately opted for repeat FNA in 98% of
not be made in the absence of colloid (3,41–43). Low the nondiagnostic cytologic terminology, and elicited a
cellularity may be encountered in aspirates of FN 96% surgical excision response to ‘‘suspicious’’ diagno-
because of poor biopsy techniques or because of a ses. However, clinicians chose repeat FNA (58%) or
macrofollicular architecture yielding abundant colloid surgery (32%) for indeterminate diagnoses, and selected
and scant follicular cells. Some FNs are highly vascu- repeat FNA (37%) or surgery (52%) for ‘‘atypical’’
lar, yielding abundant blood, and rare follicular designations (47). The study clearly demonstrated that
groups with prominent nuclear overlapping and/or confusion arose with the atypical and indeterminate
microfollicular architecture (44). Oncocytic change diagnoses. Indeterminate was confused with nondiag-
and flame cells may also be found in FN (benign and nostic in some cases, while atypical was too ambiguous
malignant), in addition to hyperplastic nodule and and treated as suspicious in many other cases. The
colloid nodule. majority of clinicians, on the other hand, correctly
Several studies have evaluated the variability in interpreted the nondiagnostic and suspicious diagno-
reporting and diagnosing FN and cellular hyperplastic ses. The indeterminate category, in reality, includes two
nodules (40,45,46). The areas of greatest debate and types of lesions with different clinical implications:
confusion included terminology and criteria employed (i) truly indeterminate, showing features intermediate
in diagnosing FN. Differences in terminology involved between hyperplastic/colloid nodule and FN which
mainly the use of two diagnostic categories (i.e., follic- may be best managed by repeat FNA, clinical follow-
ular lesion and FN) versus one category. Some pathol- up, and correlation with US and ancillary studies; and
ogists apply the terms follicular lesion and FN (ii) follicular patterned lesion consistent with FN, in
interchangeably, while others require more stringent which repeat biopsy is unlikely to clarify the situation,
criteria for the diagnosis of FN. Other than increased and surgery would be indicated (8).
cellularity, the criteria used by cytopathologists in the Two European studies found no malignancy on
diagnosis of FN vary from strict to none. For example, follow-up of FNAs diagnosed as follicular lesion and
the proportion of microfollicles needed to establish a FN (48,49). The authors advocated a less aggressive
approach to management, i.e., clinical follow-up. The

authors, however, did not apply strict criteria, and FN
was loosely defined as hypercellular smears associated
with scant colloid and microfollicles, with no mention
of the percentage of microfollicle formation, nuclear
atypia, or other architectural patterns. Architectural
features and nuclear atypia, in addition to colloid and
cellularity, should be evaluated in these hypercellular
specimens, so pathologists can better define and classi-
fy those gray-zone lesions and lessen the number of
cases classified as indeterminate. We recommend sub-
dividing the indeterminate category, as was recom-
mended by the PSC and NCI, into (i) Follicular lesion
of undetermined significance (FLUS) and (ii) FN (6,7).
Follicular Lesion of Undetermined Significance

In 2006, the PSC introduced the terminology ‘‘cellular
lesion cannot rule out FN,’’ addressing lesions falling in
the gray zone (6). In 2007, The NCI thyroid state-of-the-
science conference suggested similar terminologies,
including ‘‘FLUS’’, ‘‘a typical follicular lesion’’, and
‘‘atypia of undetermined significance’’ (7). These ter-
minologies were chosen in order to avoid the confusing
terms of ‘‘follicular lesion,’’ ‘‘indeterminate,’’ ‘‘atypi-
cal,’’ etc. as stand alone diagnoses. This designation of
‘‘FLUS’’ is employed when the major differential diag-
nosis is between hyperplastic nodule and FN. These
aspirates are often highly cellular and have scant
colloid. There is admixture of flat sheets and micro-
follicles/syncytial fragments, with minimal nuclear
overlapping and crowding (Fig. 13A). This diagnosis
is also rendered when smears from different passes
show mixed cytologic findings ranging from ‘‘benign’’
to ‘‘possible FN.’’ Bloody specimens of low cellularity,
but containing microfollicles and prominent nuclear
overlap (highly vascular lesions) would also be includ-
ed in this category (Fig. 13 B). This latter cytologic clue, Figure 13 Follicular lesion of undetermined significance
although important in recognizing some FN, has rarely (A) This specimen showed admixture of flat sheets and micro-
been emphasized in the literature (40). follicles, with no significant atypia, and scant to absent colloid.
(B) This bloody aspirate had rare clusters of follicular cells with
prominent nuclear overlapping, and occasional microfollicles [(A)
DQ stain; magnification, 400 (B) DQ stain; magnification,
D. Oncocytic (Hurthle Cell) Neoplasms 200].
Similar to FN, the separation of oncocytic adenoma

from carcinoma requires histologic evaluation for evi- lymphoid cell component favors lymphocytic thyroid-
dence of capsular and/or vascular space invasion. itis. Endocrine neoplasms such as medullary carcino-
Oncocytic neoplasms usually render highly cellular ma, paraganglioma, and parathyroid adenoma may
aspirates with scant colloid and rare to absent lympho- show considerable variability in cell size and shape,
cytes. The oncocytes are arranged mainly in large and including polygonal to spindle cells with ill-defined
small clusters and isolated single cells (Fig. 14). Occa- granular cytoplasm and frayed borders. In medullary
sional microfollicles may be seen. The cells show carcinoma, the nuclei typically have a ‘‘salt and pep-
uniform appearance, and have abundant granular cyto- per’’ chromatin, but may show pleomorphism with
plasm with well-defined borders, round to oval nuclei, prominent nucleoli, and scattered stripped atypical
granular chromatin, and prominent nucleoli. Cytologic nuclei. The cytologic features of metastatic renal cell
atypia may be observed in oncocytic lesions, including carcinoma (RCC) are discussed later in the chapter.
scattered nuclear enlargement and pleomorphism (50).
A variety of other neoplastic and nonneoplastic lesions
may show oncocytic/granular features (Table 4). The E. Malignant Neoplasms
main differential diagnosis includes oncocytic nodule Papillary Thyroid Carcinoma
in association with a nodular goiter or lymphocytic
thyroiditis. Admixture of benign thyroid follicular cells PTC is the most commonly encountered thyroid
and colloid favors nodular goiter, while a prominent malignancy. It can be partially cystic, or entirely cystic
10 Elsheikh et al.
Figure 14 Oncocytic (Hurthle cell) neoplasm showing sheets of Figure 15 Papillary carcinoma, classic type. Tightly cohesive
oncocytic cells and minimal to absent colloid (DQ stain; magnifi- clusters with papillary architecture are seen (Papanicolaou stain;
cation, 200). magnification, 400).
Table 4 Thyroid Lesions with Oncocytic (Hurthle)/Granular Cell

Features
Oncocytic neoplasm
Nodular goiter
Medullary carcinoma
Papillary carcinoma: oncocytic, tall cell, and Warthin-like variants
Parathyroid adenoma
Paraganglioma
Metastatic renal cell carcinoma
in up to 10% of cases. Classic PTC shows distinctive

architectural and cytologic features. Architectural fea-
tures include the presence of papillary and tightly
cohesive three-dimensional clusters of neoplastic cells
(Fig. 15). Many of the neoplastic groups demonstrate
prominent nuclear crowding and overlapping. Thick
colloid with a ‘‘bubble-gum’’ appearance may be Figure 16 Papillary carcinoma showing thick colloid with a
present in the background in up to one quarter of ‘‘bubble-gum’’ appearance in the background (DQ stain; magni-
the cases (Fig. 16) (42). In most cases, the cytoplasm fication, 200).
has a thick ‘‘metaplastic’’ consistency, with well-
defined borders (51). Occasionally, especially in cystic
PTC, the neoplastic cells show prominent cytoplasmic
microvacuolization resembling macrophages (52). The all cases. These inclusions usually have sharp mar-
hallmark for diagnosing PTC, however, is based on its gins, and should reflect the color of the cytoplasm of
distinctive nuclear features. The diffuse presence of that cell (not just a clear hole in the nucleus) (53).
nuclear grooves, nuclear enlargement, and finely Nucleoli are often small and peripherally situated
granular (powdery) chromatin must be present, before against a thickened nuclear membrane. The presence
a definitive diagnosis is rendered (Fig. 17). The of psammoma bodies, although not diagnostic by
ground glass appearance of the nuclei seen in histo- itself, should raise a red flag for PTC, and may be
logic sections is an artifact of formalin fixation and is seen in up to 40% of cases (13). A proportion of cases
not recognized in cytologic preparations. Nuclear show multinucleated giant cells, the presence of which
grooves may traverse the entire longitudinal axis of should increase awareness about the possibility of
the nucleus, or may appear as invaginations of the PTC, and invoke a more thorough search for diagnos-
nuclear membrane. Intranuclear pseudoinclusions, tic nuclear features (Fig. 18). It is important to note
which are also distinctive of PTC, are not present in that there is no single feature that is diagnostic of PTC,
of entirely cystic PTC (56). This is mainly due to scant

cellularity and prominent degenerative changes. The
aspirate may consist predominately of foamy macro-
phages, blood, and reparative changes. Other neoplas-
tic and nonneoplastic lesions may also be associated
with prominent cystic change (discussed later in the
section on cystic lesions). When nuclear features of
PTC are diffusely present in the neoplastic cells, a
specific diagnosis can be rendered, but, occasionally,
PTC nuclear features are only found focally. However,
the presence of nuclear grooves and nuclear inclu-
sions in association with fine powdery chromatin,
even focally, should always raise a warning flag,
and elicit a ‘‘suspicious for PTC’’ diagnosis.
Variants of Papillary Thyroid Carcinoma

There are several described variants of PTC, including
follicular, tall cell, oncocytic, and columnar cell.
Follicular variant of PTC (FVPC) is by far the most
common of these subtypes. By definition, no papillary
Figure 17 Papillary carcinoma demonstrating characteristic structures are identified, and the neoplasm consists
nuclear features, including powdery chromatin, grooves, and
predominately of follicular structures. The aspirates
intranuclear pseudoinclusions (Papanicolaou stain; magnifica-
tion, 600). mainly display branching monolayered sheets, which
are considered to be a significant low-power discrimi-
nating feature from other follicular-patterned neo-
plasms (Fig. 19) (57). The combination of flat
syncytial sheets, nuclear enlargement, and fine pow-
dery chromatin, were found to be the most sensitive
criteria, whereas the combination of nuclear enlarge-
ment, fine chromatin, and nuclear grooves were the
most specific, in establishing the diagnosis of FVPC
(Fig. 20) (58). Intranuclear pseudoinclusions are seen
in less than half the cases. Fulciniti et al. also empha-
sized the presence of nuclear grooves and nucleoli
over intranuclear inclusions in the diagnosis of FVPC
(57). The importance of both architectural and nuclear
features in establishing the diagnosis of FVPC cannot
Figure 18 Multinucleated giant cells associated with papillary

carcinoma (Papanicolaou stain; magnification, 400).
and that a definitive diagnosis should be based on a

constellation of cytologic features. Several studies
have attempted to determine the most sensitive cyto-
logic criteria for diagnosing classic PTC, and found
nuclear inclusions, nuclear grooves, papillary struc-
tures, and metaplastic cytoplasm, when present in
combination, to be the most reliable cytologic features
(13,42,51,54). PTC may show prominent cystic change, Figure 19 Follicular variant of papillary carcinoma showing a
and this accounts for PTC being the most common distinctive low power appearance of branching monolayered
cystic neoplasm of the thyroid (55). FNA is unable to sheets (DQ stain; magnification, 200).
establish a diagnosis of malignancy, however, in 50%
12 Elsheikh et al.
Figure 21 Oncocytic (Hurthle cell) variant of papillary carcino-

ma. The neoplastic cells show cytoplasmic oncocytic features,
but demonstrate nuclear features of papillary carcinoma, includ-
ing a rare intranuclear inclusion (at 4:00) (DQ stain; magnifica-
Figure 20 Follicular variant of papillary carcinoma. The combi- tion, 400).
nation of nuclear enlargement, fine chromatin, and nuclear
grooves were found to be most specific in establishing the
diagnosis. Softer criteria include nuclear membrane thickening
and eccentric placement of nucleoli against the nuclear mem-
brane (Papanicolaou stain; magnification, 600).
be overstressed. The predominance of microfollicles in

some cases can lead to misclassification as FN, and a
predominant monolayered sheet pattern may be mis-
interpreted as honeycomb sheets associated with nod-
ular goiter. However, careful high-power examination
of the nuclei and recognition of the nuclear features of
PTC in these cases will usually establish the diagnosis
of FVPC, and prevent those potential pitfalls. Not
infrequently, FVPC may show abundant colloid or
paucity of nuclear features of PTC, leading to a misdi-
agnosis of benign thyroid disease or FN. In fact, FVPC
is only second to sampling error as the most common
cause of false-negative diagnoses in thyroid FNA. Wu
et al. reported 11 false-negative cases of FVPC, where 6
cases were attributed to sampling error (micropapillary
carcinoma), and 5 cases showed focal atypia in a
background of abundant colloid and cystic change (17).
The oncocytic (Hurthle cell) variant of PTC is char-
acterized by large tumor cells with abundant dense
cytoplasm, well-defined cytoplasmic borders, eccen-
tric nuclei, and nuclear features of PTC (Fig. 21). The Figure 22 Tall cell variant of papillary carcinoma. Elongated
tall cell variant of PTC shows elongated tumor cells tumor cells with abundant cytoplasm, enlarged overlapping
with enlarged nuclei, overlapping and stratification of nuclei, and characteristic nuclear features of papillary carcinoma
(Papanicolaou stain; magnification, 600).
nuclei, and dense eosinophilic cytoplasm (Fig. 22). The
nuclear features of PTC, in tall cell variant, are often
diffuse and extensive, compared with classic PTC. The
columnar cell variant of PTC demonstrates elongated to colonic adenocarcinoma. Cytologic classification of
columnar cells with ill-defined cell borders, delicate PTC is accurate in over 90% of classic PTC, and in
cytoplasm with focal vacuolization/clearing, nuclear most FVPC, but is much less reproducible in other
pseudostratification, and oval to elongated hyperchro- PTC variants (59). Tall cell and oncocytic variants of
matic nuclei (59). Architecturally, it may resemble PTC, in particular, show significant overlap in their
cytologic appearance. It is more important, in our

opinion, to be familiar with the spectrum of cytologic
appearances of PTC than it is to render a specific PTC-
variant diagnosis.
Suspicious for PTC

We issue a diagnosis of suspicious for PTC when
nuclear features of PTC are only focally present.
These nuclear features, however, must be present in
combination (Fig. 23), and include rare nuclear
grooves, nuclear enlargement, and powdery chroma-
tin. Focal nuclear grooves and/or intranuclear inclu-
sions (by themselves) can be found in a variety of
other neoplastic and nonneoplastic conditions,
including nodular hyperplasia, lymphocytic thyroid-
itis, FN, and medullary carcinoma (3). It is important
to recognize ‘‘suspicious for PTC’’ as a distinct cate-
gory, and not to lump it with other indeterminate or
FN diagnoses, because of its substantially greater
Figure 24 Medullary carcinoma. There are many single cells,
association with malignancy on surgical follow-up.
as well as clusters with a microacinar configuration (carcinoid-
Logani et al. and Wu et al. reported cancer follow-up like appearance). Amyloid is present in the background (DQ
rates of 77% and 75%, respectively, when rendering stain; magnification, 200).
such diagnoses (60). This is in contrast to the cancer
follow-up rate of 10% to 30% typically associated
with indeterminate or FN diagnoses. With such an
increased risk of malignancy, clinicians and patients Medullary Carcinoma
may consider total thyroidectomy as an alternative Medullary carcinoma is notorious for its variable cyto-
option to lobectomy. Another management choice logic appearances, ranging from a monomorphic to a
includes lobectomy with intraoperative consultation, pleomorphic cell population. Typically, medullary
which has been shown to be helpful in an additional carcinoma presents mostly as isolated cells with occa-
30% of cases (23). sional clusters (Fig. 24). The neoplastic cells may have a
plasmacytoid, spindle, epithelioid, or carcinoid-like
appearance, but often a mixture of different cell types
is encountered in the same specimen (Figs. 24–26). The
cytoplasm has a delicate lacy quality, and may show
Figure 25 Medullary carcinoma showing variable appearance,

Figure 23 Suspicious for papillary carcinoma. This case including loosely cohesive groups of uniform cells with delicate
showed nuclear enlargement, powdery chromatin, rare nuclear cytoplasm, round to oval nuclei, and occasional spindling. The
grooves, and no nuclear pseudoinclusions (Papanicolaou stain; nuclei have a salt and pepper chromatin pattern (Papanicolaou
magnification, 600). stain; magnification, 400).
14 Elsheikh et al.
background (Fig. 24). Amyloid has an appearance

similar to thick colloid, but is confirmed with Congo
red stain. Immunocytochemical stains for calcitonin
and neuroendocrine markers such as chromogranin
and synaptophysin are extremely helpful in establish-
ing the diagnosis. The tumor cells are usually positive
for carcinoembroyonic antigen (CEA), but negative for
thyroglobulin. Serum calcitonin levels are elevated in
most patients, and help establish the diagnosis. The
differential diagnosis includes oncocytic neoplasm,
papillary carcinoma, plasmacytoma, and mesenchymal
tumors. Oncocytic tumors show prominent nucleoli
and lack the neuroendocrine chromatin pattern.
Although medullary carcinoma may display intranu-
clear holes, it will not show other diagnostic nuclear
features of PTC such as nuclear grooves and powdery
chromatin (62). In addition, PTC is negative for calcito-
nin and chromogranin, and is positive for thyroglobu-
lin. Mesenchymal tumors and spindle cell melanoma
Figure 26 Medullary carcinoma consisting predominately of are included in the differential diagnosis of predomi-
single cells with abundant cytoplasm and eccentric nuclei nately spindle medullary carcinoma, while plasma-
(plasmacytoid appearance). There is also significant nuclear cytoma and melanoma may be confused with
pleomorphism and prominent nucleoli (Papanicolaou stain; plasmacytoid medullary carcinoma. Immunohis-
magnification, 600). tochemistry (IHC) can play a pivotal role in establish-
ing a definitive diagnosis in those cases.
Insular Carcinoma/Poorly Differentiated Carcinoma

pink cytoplasmic granules. Sometimes, the neoplastic
Insular carcinoma is a rare aggressive malignancy
cells show a predominately oncocytic appearance,
characterized histologically by the presence of focal
mimicking oncocytic neoplasms (Fig. 27). However,
or diffuse insular pattern. FNA smears are usually
oncocytic neoplasm usually has cells with well-defined
highly cellular and composed of monomorphic
borders, in contrast to ill-defined wispy borders of
appearing small follicular cells, occurring singly and
medullary carcinoma. Clear cell change may be
in clusters (63). Occasionally, intact insulae of follicu-
observed, but is often only focally present. The nuclei
lar cells surrounded by hyaline stroma are seen. The
are round to oval, with finely to coarsely granular
neoplastic cells show scant delicate cytoplasm with
chromatin (salt and pepper), and have small or incon-
round hyperchromatic nuclei, coarsely granular chro-
spicuous nucleoli (Fig. 25). Binucleation and multinu-
matin, and mild-to-moderate nuclear irregularities.
cleation are common. Occasional intranuclear
Many naked nuclei are often present in the back-
inclusions are appreciated in some cases (Fig. 27) (61).
ground. Microfollicles as well as infrequent grooves
Variable amount of amyloid may be present in the
and inclusions can be seen, mimicking FN and PTC. In
our experience, and those of others, a definitive diag-
nosis of insular carcinoma cannot be established by
FNA (63). Most cases are diagnosed as FN or suspi-
cious for malignancy. A helpful clue as to the aggres-
sive nature of this tumor is the presence of increased
mitotic activity and individual cell necrosis.
Anaplastic Carcinoma
Anaplastic carcinoma is the most aggressive of all
primary thyroid cancers and is usually unresectable
or present with metastatic disease. Therefore, an accu-
rate FNA diagnosis may spare the patient unnecessary
surgery, in favor of radiation therapy (3). Cytological-
ly, anaplastic carcinoma presents as isolated cells and
loose groups. The malignant cells show extreme
nuclear pleomorphism and atypia, and may have a
spindle, giant cell, or small cell appearance (Fig. 28).
Occasional multinucleated forms are seen. Typically,
Figure 27 Medullary carcinoma with a predominant oncocytic the nuclei have coarsely irregular chromatin and
appearance. Notice scattered intranuclear inclusions (DQ stain; prominent macronucleoli. Differential diagnosis
includes poorly differentiated components of papil-
lary, follicular, and medullary carcinoma. Anaplastic
Table 5 Differential Diagnosis of Lymphoid Lesions of Thyroid

Lymphoid hyperplasia in peri- or intrathyroid lymph node
Lymphoma
Medullary carcinoma
Small cell carcinoma
Suspicious for Malignancy

We use this diagnostic category when the cytologic
features are suggestive of a specific malignancy, but a
definitive diagnosis cannot be rendered. A definitive
diagnosis of malignancy may not be rendered due to
quantitative reasons (i.e., malignant appearing cells,
but limited cellularity) or qualitative reasons (i.e.,
focal or less than well developed features of malig-
nancy). The most commonly encountered example of
Figure 28 Anaplastic carcinoma. There are loosely cohesive this diagnostic category is ‘‘suspicious for PTC’’
groups of extremely pleomorphic cells with spindle cell appear- (Fig. 23). It is imperative to establish ‘‘suspicious for
ance (DQ stain; magnification, 600). malignancy’’ as a distinct and separate diagnostic
category and not to combine it with indeterminate or
FN diagnoses because of its significantly increased
association with malignancy on follow-up surgery.
carcinoma, therefore, can only be considered in the ‘‘Suspicious for PTC’’ has a reported cancer follow-
absence of well-differentiated components. Cytokera- up rate of approximately 75% (58,60). With such a
tin stain may be employed to exclude sarcoma, lym- high risk of malignancy, clinicians and patients may
phoma, and melanoma. In contrast to FNs, PTC, and consider total thyroidectomy as an alternative man-
medullary carcinoma, anaplastic carcinoma is infre- agement option to lobectomy. Intraoperative consul-
quently positive for thyroid transcription factor-1 tation may also be suggested. Careful attention to
(TTF-1). The differential diagnosis also includes gran- cytologic details is especially needed when examining
ulation tissue, repair, I131 therapy effect, and metastat- cystic lesions, as atypical reparative changes in benign
ic carcinoma. Abundant necrosis may be present in cysts may be confused with malignancy (41).
the background, rendering an unsatisfactory diagno-
sis. Therefore, the presence of rare pleomorphic cells F. Cystic Lesions
associated with necrosis in an elderly patient should
raise the possibility of anaplastic carcinoma and trig- Thyroid cysts account for approximately 15% to 25 %
ger additional studies. of all thyroid nodules, and are most commonly due to
cystic degeneration in nodular goiter. Thyroid cyst
fluid may be clear yellow, hemorrhagic, or dark
Lymphoma
brown. It usually contains macrophages (Fig. 29),
FNA cytology of thyroid lymphoma is similar to its inflammatory cells, colloid, and degenerated follicular
lymph node counterpart. Most patients have an cells. Features associated with benign cysts include
already established history of lymphoma. Non- complete drainage of the cyst with no residual mass,
Hodgkin’s lymphoma (NHL) is by far the most com- no recurrence, and absence of cytologic atypia. Lining
mon type, with Hodgkin’s disease representing a cells from benign cysts often show reparative features,
rarity in the thyroid. Diffuse large B-cell lymphoma including flat sheets of evenly spaced cells with elon-
(DLBCL) and extranodal marginal zone B-cell lym- gated shape, dense cytoplasm, distinct cell borders,
phoma are the most common types. The smears have and prominent nucleoli. The major differential diag-
a monomorphic lymphoid appearance and show nostic consideration in these cases is cystic PTC vs.
many lymphoglandular bodies in the background. benign cyst. Studies have shown that 7% to 29% of
Flow cytometry and/or immunocytochemistry are thyroid cysts are malignant (64). Cystic PTC often
necessary for establishing a definitive diagnosis, par- lacks the repair-like spindle morphology and shows
ticularly in patients with no previous history. Differ- atypia characterized by papillary architecture, nuclear
ential diagnosis includes lymphoid hyperplasia and enlargement and crowding, nuclear grooves, and rare
lymphocytic thyroiditis (Table 5), both of which are intranuclear inclusions (64). Atypical features may
characterized by a polymorphic population of also be focally encountered in benign cysts and
lymphoid cells. Flow cytometry is often required to include rare cells with nuclear grooves and fine pale
separate low-grade lymphoma from lymphoid hyper- chromatin, which could raise the suspicion for PTC
plasia. CD45, CD20, CD3, calcitonin, chromogranin, (Fig. 30). Other atypical features associated with cystic
CEA, and cytokeratin may be needed in difficult cases, change such as fibroblastic proliferation and atypical
to distinguish lymphoma from medullary carcinoma repair, including atypical elongated round or bizarre
and small cell carcinoma. cells, can be confused with malignancy (41). Some
16 Elsheikh et al.
Figure 31 Atypical histiocytoid cells showing abundant vacuo-

lated cytoplasm, enlarged nuclei, granular chromatin, and promi-
nent nucleoli. These cells have been strongly associated with
papillary carcinoma (Papanicolaou stain; magnification, 400).
Figure 29 Macrophages associated with cyst, showing vacuo-
lated cytoplasm, small uniform nuclei and small nucleoli (Papa-
nicolaou stain; magnification, 600).
Table 6 Differential Diagnosis of Thyroid Cysts

Nodular goiter/colloid nodule
Simple cyst
Thyroglossal duct and Branchial cleft cyst
Parathyroid cyst
Follicular and oncocytic neoplasm
Malignant neoplasms, especially papillary carcinoma
remaining after aspiration of a cyst should be sampled.

FNA, however, remains unable to establish a definitive
diagnosis in approximately 50% of cystic malignancies.
Therefore, patients should undergo careful follow-up,
with possible repeat FNA under US guidance in three
to six months. Other entities included in the differential
diagnosis of cystic lesions are listed in Table 6. General-
ly, the gross appearance of the aspirated cyst fluid is a
poor indicator of the nature of the cyst. Clear-colorless
fluid, however, should suggest a parathyroid cyst, and
trigger submitting cyst fluid for parathyroid hormone
measurements (66). Thyroglossal duct cyst is congenital
and is located in the midline of the neck, superior to the
Figure 30 Reparative and reactive cellular changes associated
with benign cyst. Note fine pale chromatin, occasional nuclear
thyroid gland. It occasionally, however, lies inferior to
groove, spindling, and prominent nucleoli (Papanicolaou stain; the hyoid bone and gets confused with the thyroid
magnification, 600). gland. Cytologic specimens are of low cellularity and
contain degenerated squamous and/or columnar epithe-
lial cells admixed with macrophages and proteinaceous
material. Thyroid tissue is found in approximately 50%
aspirates show rare atypical cells with a hobnail or of cases.
histiocytoid appearance, enlarged nuclei, granular chro-
matin, and abundant vacuolated cytoplasm, but lack G. Clear Cell Lesions
nuclear grooves and intranuclear inclusions (Fig. 31).
Although seldom encountered in aspirates, these atypi- Cellular proliferations with clear cell features raise the
cal histiocytoid cells have been strongly associated with possibility of primary and secondary thyroid neo-
PTC, and should provoke an atypical diagnosis when plasms (Table 7). Metastatic Renal Cell Carcinoma
observed (65). It is important to be aware of these (RCC) should first be excluded, when a neoplasm
atypical cells as they can be easily dismissed and displays prominent clear cell change. Detailed clinical
misclassified as macrophages. Any residual mass history is crucial. FNA of RCC shows single cells and
Table 7 Thyroid Tumors with Clear Cell Features and neck, breast and liver, as well as germ cell tumors,
may show prominent clear cell features and should be
Metastatic renal cell carcinoma
Follicular adenoma
considered in the differential diagnosis.
Follicular carcinoma
Papillary carcinoma, i.e., columnar cell variant H. Metastatic Malignancies to the Thyroid
Medullary carcinoma
Paraganglioma The thyroid gland is a rare site for involvement by
Parathyroid adenoma metastatic malignancy, with a reported incidence of
Histiocytes and cyst lining cells 1.3 to 25 % (68). Metastasis to the thyroid can present
Salivary gland type cancers, i.e., mucoepidermoid carcinoma
as multiple small nodules, or as a solitary tumor mass
Other metastatic cancers, i.e., lung, head and neck, breast, liver,
germ cell tumor
mimicking a primary neoplasm (Table 8) (69). In some
cases, metastasis to the thyroid can become manifest
long after the detection of primary cancer; this scenar-
sheets with moderate to abundant finely vacuolated/ io is especially encountered with RCC (68). Breast and
clear cytoplasm and frayed cytoplasmic borders lung cancers are the most common primary tumors
(Fig. 32). Nuclear to cytoplasmic ratios may range seen in autopsy studies, while the kidney is the most
from low to high, and nucleoli may or may not be common site reported in surgical series (70). Melano-
prominent. Occasionally, vascularized epithelial frag- ma and colon cancers not infrequently metastasize to
ments are seen. FN (adenoma or carcinoma) may show the thyroid (Fig. 33). The thyroid may also be involved
clear cell features; however, these changes are usually by direct extension from carcinomas of the upper
focal, and there is often an associated prominent micro- aerodigestive tract, such as squamous carcinoma
follicular architecture and/or syncytial arrangement, and adenoid cystic carcinoma (ACC). Metastasis
and pronounced nuclear overlap and crowding. should be suspected when the microscopic features
Columnar cell variant of PTC shows clear cytoplasm, appear alien to those neoplasms more commonly
but architecturally resembles colonic carcinoma, i.e., encountered in the thyroid such as PTC, FN, and
pseudostratification and elongated cells with hyper- medullary carcinoma. Michelow and Leiman reported
chromatic nuclei (63). Primary mucoepidermoid carci-
noma (MEC) is rarely reported in the thyroid, but
shows focal clear cell change and cytologic features Table 8 Malignancies Metastatic to the Thyroid Gland
similar to those described in the salivary glands, Kidney
including an admixture of metaplastic type squamous Lung
cells, mucin producing cells and intermediate cells (67). Breast
Clustering of histiocytes and cyst lining cells may at Colon
times raise the possibility of neoplasia (Figs. 29 and 30); Melanoma
however, these aspirates are of scant cellularity and Direct extension from upper aerodigestive tract, i.e., squamous
show spindling and degenerative changes. Finally, carcinoma, adenoid cystic carcinoma (ACC)
other metastatic cancers from such sites as lung, head
Figure 32 Metastatic renal cell carcinoma. FNA shows clusters Figure 33 Metastatic colon adenocarcinoma. There are cohe-
and single cells with abundant finely vacuolated cytoplasm and sive clusters of elongated cells with hyperchromatic nuclei and
frayed cytoplasmic borders. There is mild nuclear atypia (DQ palisading. Dirty necrosis was present elsewhere on the smears
stain; magnification, 400). (Papanicolaou stain; magnification, 600).
18 Elsheikh et al.
21 cases of metastases to the thyroid gland in which Table 10 Assessment of Probability of Cancer Risk on Follow-
only five patients had a known history of malignancy up Thyroidectomies
(71). Metastatic clear cell carcinoma of the kidney is
FNA diagnosis Cancer rate Cancer risk(a)
especially difficult to distinguish from primary
thyroid carcinoma with clear cell features (72). Immu- Benign nonneoplastic 3% —
nohistochemistry, including demonstration of thyro- Follicular lesion of undetermined 14% 5X
globulin and TTF-1 staining can help in establishing significance
Follicular neoplasm 33% 11 X
the diagnosis of a primary tumor. Granular RCC can Suspicious for malignancy 56% 20 X
cytologically mimic oncocytic neoplasm; while plas- Malignant 100%
macytoma associated with amyloid may be misinter- Nondiagnostic/unsatisfactory 12%
preted as medullary carcinoma (73). Again, the a
Cancer risk is compared with benign nonneoplastic diagnosis.
utilization of immunohistochemical stains such as Source: Modified from Ref. 17.
calcitonin, chromogranin, kappa, lambda, cytokeratin,
and TTF-1 may be helpful in separating medullary
carcinoma from plasmacytoma; while renal cell Table 11 Thyroid FNA Diagnoses and Suggested Manage-
antigen, TTF-1 and thyroglobulin are helpful in the ment Options
work-up of RCC. Recognition of metastatic malignancy FNA diagnosis Management options
can prevent unnecessary thyroidectomy, and appro-
priately direct the search for an unsuspected primary Benign/nonneoplastic
malignancy. Asymptomatic, <4 cm Repeat US in 6 mo
Symptomatic or >4 cm Consider lobectomy
Cyst, >2 recurrences Consider lobectomy
I. Ancillary Studies Follicular lesion of Repeat US in 6 mo or repeat
undetermined significance FNA, if <4 cm. Consider
Ancillary studies, especially immunohistochemistry, lobectomy if larger.
may prove valuable in the differential diagnosis of Follicular neoplasm Lobectomy
thyroid tumors, provided a cell block, thinly prepared Suspicious for malignancy Lobectomy or total
smear, cytospins, liquid-based preparation, or tissue thyroidectomy
Malignant Total thyroidectomy
biopsy is available for evaluation (Table 9) (74). Only a
Nondiagnostic/unsatisfactory Repeat FNA under US
few studies describing the utilization of molecular guidance
tests on thyroid FNA specimens have been reported. Multiple nondiagnostic Consider lobectomy
RET/PTC rearrangements and BRAF mutations have samples
been reported to be useful as ancillary tests to cytolo-
Abbreviations: FNA, fine needle aspiration; US, ultrasonography;
gy in selected cases, where they helped confirm the Source: Modified from Ogilvie Ref. 2
diagnosis of malignancy (75). However, we believe
that currently, the diagnosis of malignancy should be
established on the basis of cytomorphologic features.
criteria, diagnoses of FN and ‘‘FLUS’’ show cancer on
histologic follow-up in 30% and 10% of cases, respec-
J. Clinical Implications of an FNA Diagnosis tively. Cancer is found in 20% or less of these cases
when using lax criteria and/or when FN is combined
The majority (70–80%) of FNAs classified as FN are with other indeterminate diagnoses. It is important,
neoplastic on histologic follow-up. Using strict cytologic therefore, to designate FN as a diagnostic category
that is distinct from ‘‘cellular hyperplastic nodule’’ or
other indeterminate follicular lesions, in our opinion.
Table 9 Selective Immunohistochemical Stains in the Differ-
Most clinicians will recommend excision for FN and
ential Diagnosis of Thyroid Tumors
accept the fact that the cytologic diagnosis is probabilis-
Papillary carcinoma, follicular neoplasm tic and that it may be benign on follow-up (23,76–78).
Thyroglobulin þ , TTF-1 þ Clinical follow-up or repeat FNA is recommended for
Renal cell carcinoma those cases classified as ‘‘FLUS.’’
CD10þ, EMAþ, RCAþ, TTF-1–, thyroglobulin– Wu et al. examined 401 FNAs with follow-up
Histiocytes and cyst lining cells:
surgical excision and calculated the cancer rates and
CD68þ, cytokeratin–
Endocrine tumors risks associated with various cytologic diagnoses (17).
Chromograninþ, synaptophysinþ, thyroglobulin–; calcitoninþ Providing this data to clinicians and patients may be
(medullary carcinoma); PTHþ (parathyroid adenoma); S-100þ extremely helpful in deciding on management options
(sustentacular cells in paraganglioma) (Tables 10 and 11). The estimated incidence of malig-
Metastatic carcinoma nancy in patients who have thyroid nodules and no
TTF-1þ and thyroglobulin– (lung); GCFPþ (breast); ER/PRþ other associated risk factors is 9% to 13% (79).
(breast, ovary); PLAPþ (germ cell tumor); HepPar1þ (liver);
PSAþ (prostate); S100þ and HMB 45þ (melanoma)
Abbreviations: EMA, epithelial membrane antigen; ER/PR, estrogen/
K. Summary of Thyroid FNA
progesterone receptor; GCFP, gross cystic fluid protein; PLAP, placental
like alkaline phosphatase; PSA, prostate-specific antigen; PTH, para-
Thyroid FNA is primarily a screening tool; therefore, a
thyroid hormone; RCA, renal cell antigen; TTF-1, thyroid transcription conclusive diagnosis is not always required. The
factor-1; Source: Modified from Ref. 74. pathologist’s role is to minimize the number of
indeterminate diagnoses without yielding unaccept-

ably high rates of false-negative and false-positive
diagnoses. FNA can assign diagnostic probabilities
that would help guide patient management in many
cases. Although the use of these ‘‘diagnostic catego-
ries’’ is encouraged, they should not be used alone.
Diagnoses should be qualified, when applicable, with
an appropriate differential diagnosis. Individual cen-
ters should monitor their own diagnostic accuracy
and cancer risks and provide these data to their
clinicians in order to help guide the management of
their patients. Recommendations for follow-up may
be included in the report, if acceptable to clinicians in
your institution. The use of the terms ‘‘atypical’’ and
‘‘indeterminate’’ as stand-alone diagnoses is not rec-
ommended as their meanings are not standardized
and may be interpreted in different ways. Close
cooperation between pathologists and clinicians is
essential so that the accuracy of the technique, termi-
nology used in the report, and clinical implications of Figure 34 Parathyroid adenoma. The cells are uniform in
FNA are clearly defined. appearance, have delicate cytoplasm, and show a suggestion
of microfollicular architecture. Many stripped nuclei are found in
the background. Occasional anisonucleosis is observed (DQ
II. PARATHYROID GLANDS
Parathyroid glands are seldom sampled by FNA,
unless clinically presenting as a ‘‘thyroid nodule.’’
absence of nuclear features of papillary carcinoma
Parathyroid cysts and adenomas are the most com-
should prevent a false-positive diagnosis of malignan-
monly encountered lesions. Normal parathyroid
cy. Distinguishing parathyroid adenoma from thyroid
glands show cytologic features similar to normal
FN, however, is more problematic (84). FNA cannot
thyroid, i.e., monolayered sheets and loosely cohesive
discriminate between parathyroid adenoma and para-
groups of intermediate-sized cells with honeycomb
thyroid hyperplasia since clinical correlation is needed
configuration and occasional microfollicle formation.
for such a distinction. Parathyroid carcinoma may show
In addition, many naked nuclei are usually present.
uniform cytologic appearance similar to adenoma or
The cells have delicate cytoplasm and round nuclei
may display severe cytologic atypia and pleomor-
with inconspicuous nucleoli. In contrast to that of the
phism (Fig. 35) (41). Histologic confirmation is needed
thyroid gland, colloid is absent and lipid may be very
to confirm the diagnosis of malignancy.
noticeable in the background, especially in DQ
smears.
Parathyroid cysts, when aspirated, have a very
characteristic watery, clear consistency that is almost
always diagnostic. This gross appearance should ini-
tiate hormonal analysis of the cyst fluid for parathy-
roid hormone assay (C-terminal specific) to confirm
the diagnosis (66). Differential diagnosis includes cys-
tic lesions of the thyroid (Table 6). These parathyroid
cysts often represent cystic adenomas that are hor-
monally inactive; therefore, easily mistaken clinically
for thyroid nodules (80). Cytologically, the cyst fluid
may be acellular or show rare, degenerated groups of
cells (81). A specific diagnosis of parathyroid cyst will
enable appropriate treatment by complete fluid aspi-
ration, which thereby eliminates the need for hormon-
al treatment or surgery in most cases (66).
Solid parathyroid adenomas yield highly cellular
aspirates composed of clusters of uniform cells with
round nuclei, finely to coarsely granular chromatin,
and small distinct nucleoli (Fig. 34) (3). Occasional
chief cells with an oncocytic appearance are encoun- Figure 35 Parathyroid carcinoma. The aspirate is composed
tered. Anisonucleosis and many stripped nuclei in the mostly of single cells with occasional loose clusters. There is
background are commonly seen (82). Papillary clus- severe cytologic atypia and extreme pleomorphism (H&E stain;
ters or microfollicles may be present, which can lead
to a misdiagnosis of PTC or FN (83). Attention to the
20 Elsheikh et al.
III. MAJOR SALIVARY GLANDS

A. Introduction
Although FNA has an established role in guiding
patient management in many organ systems, the
significance of its value in salivary gland tumors is
surrounded by some controversy. Some investigators
believe that FNA biopsy should not be used in the
routine evaluation of salivary gland tumors (85). In
their opinions, preoperative FNA cytologic diagnosis
will not alter the management of patients or extent of
surgery in most instances since it is the anatomic
relation of the facial nerve to the parotid neoplasm
that determines the extent of surgery, not the histo-
logic classification. In addition, FNA may rarely
induce marked necrosis and epimyoepithelial prolif-
eration, possibly causing diagnostic problems on his-
tology (86,87). Many institutions, however, use FNA
in the initial work up of salivary gland enlargement
(88–91). FNA has a documented role in distinguishing Figure 36 Benign acinar cells arranged in ‘‘rosette’’ formation.
inflammatory from neoplastic disease, a differential The cells have abundant foamy vacuolated cytoplasm with
that may not be resolved solely by clinical investiga- indistinct cell borders, and eccentric nuclei (Papanicolaou stain;
tion. FNA has also an established role in distinguish- magnification, 600).
ing between benign and malignant neoplasms,
metastatic versus primary malignancies, and confirm-
ing the recurrence of cancer. In addition, FNA is fat may be admixed with the epithelial cell clusters. The
valuable in distinguishing neoplasms involving the acinar cells have a characteristic ‘‘rosette’’ or ‘‘clustered
submandibular gland or tail of parotid from enlarged ball’’ configuration (Fig. 36). The cells are large with
lymph nodes. abundant foamy vacuolated cytoplasm, indistinct cell
Most studies report a diagnostic accuracy of 81% borders, and eccentric nuclei. The nuclei are round
to 98% in the detection of malignant disease, with a with finely granular chromatin, and small or indistinct
specificity of 71% to 99% (92–94). Diagnostic accuracy, nucleoli. The ductal cells are arranged in monolayered
however, appears to increase with experience. Heller et sheets with a honeycomb configuration. They have
al. evaluated 101 patients, assessing the impact of FNA scant delicate cytoplasm and round, uniform nuclei.
on changing the clinical management; 35% of their Naked acinar cell nuclei may be seen in the back-
patients had a change in the clinical approach as a ground and should not be confused with lymphocytes
result of preoperative FNA diagnoses (95). Surgery was (100). Cellular aspirates should not be confused with
entirely avoided in 27% of the patients, and a lesser acinic cell carcinoma; the latter presents as flat and
surgical procedure was performed in another 8% of the cohesive sheets of cells that lack the characteristic
patients. In seven patients, FNA indicated a need for lobular or rosette configuration of benign acinar tissue.
surgery where clinically no surgery was planned.
Cohen et al. reported that FNA was as accurate as B. Nonneoplastic Salivary Gland Lesions
frozen sections in rendering a correct diagnosis (96).
Furthermore, FNA allowed for preoperative patient A variety of nonneoplastic conditions may cause dif-
management and therapy planning and had an overall fuse salivary gland enlargement or present as a mass
accuracy rate of 88%. Cystic salivary gland lesions were lesion. Some patients have prominent salivary glands
the most challenging on FNAs and frozens (97). Non- (sialosis), which present as diffuse enlargement, and
diagnostic FNA rates are approximately 10%, and false- show benign salivary gland elements on FNA (100).
negative and false-positive rates are reported to be on
the order of 4.0% and 3.5%, respectively (98). O’Dwyer Fatty Infiltration
et al., however, reported a 25% false-negative rate in Fatty infiltration of the salivary glands also presents as
their series (99). The majority of false-negative diagno- a diffuse enlargement. Cytologically, in addition to
ses are either because of sampling error or misinterpre- normal salivary gland elements, there is significant
tation. Interpretation errors are mostly associated with increase in the amount of adipose tissue situated
limited cellularity or neoplasms demonstrating bland between ductal and acinar cells (101). Sialosis and
cytology (98). Preoperative FNA diagnosis should fatty infiltration have been associated with diabetes,
probably be best interpreted in the context of the cirrhosis, alcoholism, medications, nutritional defi-
patient’s clinical picture. ciencies, and hormonal disturbances (102).
Cytology of Normal Salivary Glands Sialadenitis
The specimens are usually of low cellularity and are Acute sialadenitis. Acute sialadenitis is seldom
composed of acinar and ductal cells. A slight amount of sampled, and these patients are typically tender to
palpation and aspiration. Many neutrophils are Atypia, if present, is reactive and degenerative in
admixed with benign salivary gland elements. Reac- nature. Differential diagnosis of chronic sialadenitis
tive and reparative changes may be seen, as well as includes benign lymphoepithelial lesion (lymphoepi-
fragments of stone (98). thelial sialadenitis), Warthin tumor, and mucoepider-
Chronic sialadenitis. Chronic sialadenitis com- moid carcinoma (see lymphoid-rich lesions) (104).
monly results from stones or postsurgical scarring
and is more frequently seen in the submandibular C. Cystic Lesions
gland. The aspirates are usually of low cellularity and
show predominance of ductal cells (secondary to Nonneoplastic cysts present as mass lesions and may
acinar atrophy and ductular proliferation). The back- be congenital or a result of duct obstruction (retention
ground has variable number of lymphocytes, occa- cyst) (105).
sional plasma cells and neutrophils, and spindle Retention cyst. Retention cyst is the most com-
fibroblasts (Fig. 37). Squamous and mucinous meta- mon cause of benign cysts in the salivary glands and is
plasia may be focally encountered (Fig. 38) (103). a true cyst, i.e., lined by ductal epithelium. Grossly,
the aspirates have a watery, mucoid consistency. The
aspirates are of low cellularity and consist mostly of
proteinaceous mucoid material mixed with histiocytes
and few inflammatory cells. The ductal cells typically
show degenerative features (smudgy nuclei) and may
have a cuboidal or metaplastic squamous appearance.
Complete disappearance of the mass following aspi-
ration is supportive but not diagnostic of retention
cyst, as a number of neoplasms (especially low-grade
mucoepidermoid carcinoma) may present with a
prominent cystic component (Table 12). Therefore, a
descriptive diagnosis is warranted in these conditions,
with recommendations for clinical correlation and
follow-up. Re-aspiration of any residual mass follow-
ing evacuation of the cystic component is necessary, in
order to avoid a potential false-negative diagnosis.
Branchial cleft cyst. Branchial cleft cyst is the
most common cystic lesion of the lateral neck and is
usually located on the anterior border of sternoclei-
domastoid muscle. It has also been encountered in
Figure 37 Chronic sialadenitis characterized by low cellularity and around the parotid glands and in the floor of
and admixture of ductal and acinar cells. Inflammatory cells and mouth. Cytologically, it is indistinguishable from epi-
fibroblasts are present in the background (DQ stain; magnifica- dermoid cyst. The smears consist predominately of
tion, 200). anucleated and nucleated squamous cells, and vari-
able number of neutrophils (Fig. 39). Lymphocytes are
not commonly seen. Significant atypia may be appre-
ciated, especially if the cyst is secondarily infected
(Fig. 40). The atypia, however, is degenerative in
nature and is characterized by smudgy nuclei, low
nuclear-to-cytoplasmic ratios, and variably faint to
dense cytoplasm (106). However, extreme caution
must be exercised in these cases in order to avoid
overdiagnosing or underdiagnosing metastatic squa-
mous carcinoma.
Squamous carcinoma. Squamous carcinoma may
occasionally show minimal atypia, and can be indis-
tinguishable from an inflamed branchial cleft cyst. A
definitive diagnosis of malignancy, therefore, should
Table 12 Differential Diagnosis of Salivary Gland Cystic Lesions

Retention cyst
Branchial cleft cyst
Epidermoid cyst
Lymphoepithelial (HIV-associated) cyst
Pleomorphic adenoma
Figure 38 Chronic sialadenitis associated with squamous and Warthin tumor
mucinous metaplasia. There is mild atypia, which is reactive and Mucoepidermoid carcinoma, low grade
degenerative in nature (DQ stain; magnification, 400). Papillary cystic acinic cell carcinoma
Metastatic keratinizing squamous cell carcinoma
22 Elsheikh et al.
Figure 39 Branchial cleft cyst. There are many anucleated and Figure 41 Squamous carcinoma demonstrating clusters and
nucleated squamous cells and few neutrophils (DQ stain; mag- sheets of atypical epithelial cells (Papanicolaou stain, 400).
nification, 400).
Figure 42 Metastatic squamous carcinoma showing singly

Figure 40 Branchial cleft cyst showing inflammatory atypia, scattered markedly atypical keratinized cells (Papanicolaou
characterized by degenerated keratinized squamous cells. stain, 600).
Many neutrophils are present in the background. Metastatic
squamous carcinoma may have an identical appearance (Papa-
nicolaou stain, 400).
Warthin tumor. Warthin tumor may be associ-
ated with squamous metaplasia and extensive cystic
change, including atypical metaplasia, which can be
only be established in the presence of clusters and confused with metastatic squamous carcinoma; there-
sheets of atypical squamous epithelium (Fig. 41), or fore, search and recognition of the dual population of
singly scattered markedly atypical keratinized cells oncocytes and lymphoid cells in the smears should
(Fig. 42). Cytologic features found to be more support- establish the correct diagnosis. Lymphoepithelial cysts
ive of squamous carcinoma, compared with branchial are further discussed with lymphoid-rich lesions.
cleft cyst, are the presence of necrotic debris and fewer
neutrophils. We usually do not issue a diagnosis D. Salivary Gland Neoplasms, Interpretation
favoring branchial cleft cyst in patients older than Challenges, and a Morphologic Approach
25 years, but rather provide a descriptive diagnosis to the Diagnosis
of ‘‘cystic squamous lesion without significant aty-
pia,’’ and provide an appropriate differential diagno- Salivary gland FNA is probably one of the most
sis including cystic squamous carcinoma (106,107). challenging area in cytology, as it can be difficult to
render a specific diagnosis. This is due to the wide Table 14 Differential Diagnosis of Basaloid Neoplasms in
assortment of neoplasms arising in these organs, their Salivary Glands
relative rarity, and variability in their cytologic appear-
Basaloid neoplasms with Basaloid neoplasms without
ances (98). Histologic diversity may even occur within
significant cytologic atypiaa significant cytologic atypia
the same neoplasm. Diagnostic difficulties are encoun-
tered mostly with cystic lesions, as previously dis- ACC, cribriformb, and solid ACC, cribriformb, and solid
cussed, and with low-grade malignancies, cellular Basal cell adenocarcinoma Basal cell adenoma
benign neoplasms, atypical inflammatory and lym- Basaloid squamous cell Basal cell adenocarcinoma
carcinoma, metastatic
phoid lesions, and rarely encountered lesions (92,108). Poorly differentiated Cellular pleomorphic
Occasionally, an unusual cytologic presentation of a carcinoma, not otherwise adenoma
common tumor also presents a challenge. While FNA specified
diagnosis of high-grade malignancy is usually straight Neuroendocrine carcinoma Epithelial-myoepithelial
forward, distinguishing low-grade malignancies from carcinoma
benign neoplasms and some inflammatory processes Pilomatrixoma Polymorphous low-grade
may at times be problematic (109). adenocarcinoma
The more commonly encountered benign neo- Metastatic carcinoma, Pilomatrixoma
plasms include pleomorphic adenoma, basal cell ade- including cutaneous basal
noma, and Warthin tumor (110). Primary malignant cell carcinoma, thyroid,
breast, and lung
salivary gland neoplasms are subdivided into low Metastatic carcinoma
grade and high grade. Common low-grade malignan- a
cies include mucoepidermoid carcinoma (MEC) and Significant cytologic atypia is characterized by the presence of moderate
to marked nuclear pleomorphism and/or large prominent nucleoli. Small
acinic cell carcinoma. High-grade malignancies nucleoli may be seen in basal cell adenoma.
include adenoid cystic carcinoma (ACC), high-grade b
Cribriform ACC may or may not show significant cytologic atypia, but the
MEC, squamous cell carcinoma, salivary duct carci- combined architectural features of microcyst formation and hyaline
noma, and poorly differentiated carcinoma, not other- globules are usually diagnostic.
wise specified. Metastatic malignancies involving the
salivary glands include malignant melanoma and glands and its tendency for cytologic diversity and
squamous cell carcinoma. The salivary glands may mimicry of other neoplasms. This simplified approach
also be involved primarily or secondarily by malig- will emphasize differential diagnoses of tumors that
nant lymphoma. share similar cytomorphologic features and help iden-
The cytologic features of salivary gland tumors, as tify limitations associated with FNA.
well as some of the more commonly encountered
problems and pitfalls associated with FNA interpreta-
tions are presented in this chapter. Strict and well- E. Salivary Gland Neoplasms with
defined cytologic and architectural criteria that help Basaloid Cell Features
facilitate arriving at the proper diagnosis are discussed Salivary gland neoplasms with basaloid cell features are
in depth. The clinical significance of a precise cytologic a relatively uncommon and heterogeneous group of
diagnosis is highlighted. The role of ancillary studies tumors characterized by small cells, presenting mostly
such as immunocytochemistry and flow cytometry is in cohesive clusters. Most notable of these neoplasms
presented where appropriate. The traditional approach are ACC and basal cell adenoma. FNA cytology of these
of describing nonneoplastic and inflammatory salivary tumors is seldom described in the literature. The rare
gland lesions followed by benign and malignant neo- reports available emphasize the difficulty in making a
plasms, as presented in most textbooks, is not followed precise diagnosis. Appreciation of the architectural
in this discussion. Rather, we believe that subdividing features and nuclear atypia are most important for
salivary gland tumors into defined cytomorphologic evaluating basaloid tumors (Table 14).
groups is a more practical approach (Table 13) (111).
Four of these categories are based on cell size, amount Basal Cell Adenoma
of cytoplasm, degree of cytologic atypia, and the nature
of background. These categories include tumors with Basal cell adenoma is an uncommon benign neoplasm
small cell size (basaloid), intermediate-sized cells with accounting for approximately 2% of salivary gland
low-grade cytologic features, large cells with abundant tumors. Four architectural patterns are histologically
cytoplasm, and lymphoid-rich lesions (Table 13). A fifth described, including solid, trabecular, tubular, and
category is dedicated to pleomorphic adenoma, the membranous (110). These patterns, for the most part,
most commonly encountered neoplasm in salivary are not reproducible on FNA. Cytologic features
include the presence of tightly cohesive clusters of
basaloid cells with numerous naked nuclei in the back-
Table 13 Differential Diagnostic Categories in Salivary Gland
FNA
ground (Fig. 43) (112). The clusters may have sharp
smooth community borders, show a trabecular or jig-
Neoplasms with basaloid cell features saw puzzle configuration, or display branching and
Tumors with intermediate-sized cells and bland cytology budding (113). The basaloid cells have scant cytoplasm,
Tumors characterized by large cells and abundant cytoplasm round to oval nuclei, and finely to coarsely granular
Lesions rich in lymphocytes chromatin (Fig. 44) (114,115). The membranous variant
Variable cytologic appearances of pleomorphic adenoma
of basal cell adenoma often displays prominent dense
24 Elsheikh et al.
Figure 43 Basal cell adenoma. Tightly cohesive clusters of Figure 45 Membranous variant of basal cell adenoma. There is
basaloid cells and many background stripped nuclei (DQ stain, dense hyaline extracellular material surrounding the basaloid cell
200). clusters. Note the sharp interface between the stromal material
and cells (Papanicolaou stain, 400).
the third most common malignancy in salivary glands

(following MEC and acinic cell carcinoma) (110). The
cribriform (well differentiated) variant of ACC is the
most frequently encountered type, and is the easiest to
distinguish from basal cell adenoma (111). Solid variant
of ACC, on the other hand, is rarely encountered, and
may not be possible to separate from basal cell
adenoma. Cribriform ACC consists of broad cohesive
sheets of basaloid cells with prominent microcystic
spaces containing globules of homogenous acellular
hyaline material. These hyaline globules are numerous,
large, variable in size, shaped as spheres and bands,
and have smooth contours (Fig. 46). The globules may
Figure 44 Basal cell adenoma. The basaloid cells have scant

cytoplasm, round to oval nuclei, and finely to coarsely granular
chromatin (Papanicolaou stain, 600).
extracellular material (stains hyaline pink with DQ,

and green with Papanicolaou), corresponding to redu-
plicated basal lamina, surrounding the cell clusters
(Fig. 45) (116). The solid variant of basal cell adenoma
consists mostly of large flat and cohesive sheets of
basaloid cells. Canalicular adenoma is reported to
show clinical as well as cytologic features similar to
basal cell adenoma (117).
Adenoid Cystic Carcinoma

Figure 46 Adenoid cystic carcinoma, cribriform type. Broad
ACC is the most common of these basaloid tumors and cohesive sheets of basaloid cells associated with numerous
is the main entity to be considered in the differential hyaline globules. The globules are large, variable in size, and
diagnosis of basal cell adenoma. It accounts for approx- shaped as spheres and bands (DQ stain, 200).
imately 3% to 5% of major salivary gland tumors and is
be associated with the basaloid cells or lie freely in the

background, and stain purple red with DQ, or pale
gray with Papanicolaou (Figs. 47 and 48). The basaloid
cells may show nuclear and cytoplasmic features simi-
lar to basal cell adenoma, including oval hyperchro-
matic nuclei with finely to coarsely granular chromatin
and scant cytoplasm; but may illustrate more pro-
nounced atypia and prominent nucleoli (Fig. 48).
Solid ACC is characterized by paucity or absence of
Figure 49 Metastatic basaloid squamous carcinoma. The

smears showed many tightly cohesive clusters of basaloid cells
with significant cytologic atypia. This appearance may be indis-
tinguishable from solid variant of adenoid cystic carcinoma and
other malignant basaloid tumors (Papanicolaou stain, 400).
microcystic spaces and hyaline globules and moderate

to severe cytologic atypia, which should prompt a
malignant diagnosis. However, we have encountered
several cases of solid ACC that lacked significant
Figure 47 Adenoid cystic carcinoma, cribriform type. The hya- cytologic atypia and showed features identical to the
line globules are acellular, have a smooth outer border, and
solid variant of basal cell adenoma. Therefore, in our
show a sharp interface with surrounding basaloid cells (DQ stain,
400).
experience, in the absence of atypia, FNA cannot sepa-
rate between solid basal cell adenoma and solid ACC
(113). A malignant diagnosis can be rendered in the
presence of significant atypia, but it may be extremely
difficult to distinguish solid ACC from metastatic
basaloid squamous cell carcinoma (Fig. 49) (118).
Basal Cell Adenocarcinoma

Basal cell adenocarcinoma shows low power architec-
tural features highly reminiscent of basal cell ade-
noma, including tightly cohesive clusters of basaloid
cells with papillary and filiform architecture (119).
Although, often there is associated significant cyto-
logic atypia and mitotic activity, some cases lack
atypia. The diagnosis of basal cell adenocarcinoma
is confirmed histologically by demonstration of
parenchymal and soft tissue invasion; therefore, it
should be considered in the FNA differential diagno-
sis of all basaloid tumors.
Primary Small Cell Carcinoma/Neuroendocrine Carcinoma

Primary small cell carcinoma/neuroendocrine carci-
Figure 48 Adenoid cystic carcinoma, cribriform type. The neo- noma is cytologically identical to its pulmonary coun-
plastic cells have oval to round hyperchromatic nuclei with finely terpart; therefore, a metastatic lung carcinoma should
to coarsely granular chromatin and scant cytoplasm. They are first be excluded (120). FNA shows a predominately
associated with hyaline globules, which stain pale gray-green in dissociative cell pattern and few cohesive clusters. The
this preparation. Naked nuclei are observed in the background neoplastic cells have hyperchromatic nuclei and mini-
(Papanicolaou stain, 400). mal amount of cytoplasm, and may show cigar-
shaped nuclei and prominent nuclear molding.
26 Elsheikh et al.
Metastatic Carcinoma adenoma, basal cell adenocarcinoma, epithelial myoe-

pithelial carcinoma, and polymorphous low-grade
Metastatic carcinoma from various sites, such as breast, adenocarcinoma (PLGA) (Table 15). Hyaline globules
thyroid and head and neck, may also masquerade as a in these latter tumors are usually focal, small, uniform
primary basaloid neoplasm, especially if prepared in size, and have irregular contours (111). Careful
with a thin layer methodology (prominent shrinkage attention to the tinctorial quality and shape of the
of the neoplastic cells gives them a basaloid appear- stromal material and related neoplastic cells are help-
ance) (113). It is important, therefore, to consider the ful clues to establishing the appropriate diagnosis (98).
possibility of metastasis and inquire about previous
history of malignancy.
F. Salivary Gland Tumors with Intermediate-
Pilomatrixoma Sized Cells and Bland Cytology
Pilomatrixoma may be misdiagnosed as a basal cell This group of lesions is characterized by intermediate-
tumor or small blue-cell tumor of childhood if the sized cells with moderate amount of cytoplasm and
basaloid cells predominate in the aspirate. It is a minimal cytologic atypia (Table 16). Because of their
benign neoplasm that mostly arises in the head and bland cytology, they may be misinterpreted as benign
neck region of children. The finding of sheets of ghost neoplasms. In most instances, distinguishing cellular
squamous cells combined with basaloid cells is diag- benign neoplasm from low-grade malignancy does not
nostic of this lesion (121,122). Attention to the young alter patient management as conservative surgery is
age of the patient and careful search for the diagnostic indicated in both instances. However, it is appropriate
ghost cells should prevent a potential false-positive to render a relevant differential diagnosis when the
diagnosis (111). cytologic features are not diagnostic of a specific entity.
Cellular Pleomorphic Adenoma Low-grade MEC

Cellular pleomorphic adenoma is also included in the MEC is the most common malignancy involving the
differential diagnosis of basal cell tumors and shows salivary glands, and represents approximately 30% of
broad loosely cohesive clusters of intermediate-sized salivary gland cancers. It occurs among all age groups
cells with haphazard nuclear arrangement and indis- with a peak incidence in individuals aged 20 to 40 years
tinct community borders (123). This is in contrast to old (110). It is important to cytologically distinguish
basal cell tumors, which show tightly cohesive clus- low-grade MEC from high-grade MEC because of the
ters of small basaloid cells with sharp community difference in their prognosis (90% and 40% 5-year
borders. Pleomorphic adenoma, in addition, demon- survival, respectively). Low-grade MEC may be easily
strates background plasmacytoid appearing cells in misinterpreted on FNA as a benign neoplasm because
contrast to the naked nuclei associated with basal cell of its bland cytology. Diagnostic accuracy of MEC
adenoma and ACC. ranges from 33% to 75%, which is much lower than
In summary, neoplasms with basaloid cell fea- the overall accuracy of salivary gland FNA (73–90%).
tures represent one of the most challenging problems Low-grade MEC is commonly cystic and is cyto-
in salivary gland cytology. Depending on the presence logically characterized by an admixture of glandular
or absence of significant cytologic atypia, several and metaplastic squamous cells (124–126). The back-
entities should be considered in the differential diag- ground demonstrates mucinous material and debris
nosis (Table 14). In the absence of atypia, it is not (Fig. 50). The glandular cells may have a ductal appear-
possible to cytologically distinguish between solid ance (intermediate cells) or may resemble macrophages
ACC, basal cell adenoma, and basal cell adenocarci- (mucin-producing cells) (Figs. 51 and 52). Metaplastic
noma. In the presence of significant atypia, it may not cells are polygonal in shape and resemble immature
be possible to distinguish between solid ACC, basal metaplastic squamous cells and oncocytes (Fig. 51).
cell adenocarcinoma, and basaloid squamous carci- They have dense cytoplasm, round nuclei, and promi-
noma. FNA, however, can be reliable in diagnosing nent nucleoli. Variable cytoplasmic vacuolization may
cribriform ACC only if it shows prominent microcyst be observed. However, keratinized epidermoid cells are
formation in association with numerous hyaline glob- not usually seen in low-grade MEC. The predominance
ules that are large, variable in size, have smooth of mucin-producing cells in an aspirate may lead to a
contours, and shaped as spheres and bands. The
mere presence of extracellular matrix in conjunction Table 16 Salivary Gland Tumors with Intermediate-Sized Cells
with basaloid cells does not establish a diagnosis of and Bland Cytology (Includes Squamous and Cystic Lesions)
ACC, as extracellular matrix may be associated with
other tumors such as basal cell adenoma, pleomorphic Low-grade mucoepidermoid carcinoma
Polymorphous low-grade adenocarcinoma
Pleomorphic adenoma
Table 15 Stroma-Rich Salivary Gland Tumors Low-grade salivary duct carcinoma
Epithelial-myoepithelial carcinoma
Pleomorphic adenoma Branchial cleft cyst and retention cyst
Basal cell adenoma Neoplasms with a cystic component
Adenoid cystic carcinoma Metastatic keratinizing squamous cell carcinoma
Polymorphous low-grade adenocarcinoma Squamous metaplasia in chronic sialadenitis, Warthin tumor and
Epithelial myoepithelial carcinoma pleomorphic adenoma
Figure 50 Low-grade MEC with prominent mucinous back- Figure 52 Low-grade mucoepidermoid carcinoma. Mucin pro-
ground and admixed neoplastic cells. The mucin has a stringy ducing cells and intermediate cells. The mucin producing cells
appearance (Papanicolaou stain, 200). resemble macrophages (Papanicolaou stain, 400).
Polymorphous Low-Grade Adenocarcinoma

PLGA (terminal-duct carcinoma) may be difficult to
cytologically differentiate from low-grade MEC (111).
This is a low-grade adenocarcinoma, arising almost
exclusively in the minor salivary glands (especially
the palate) (129). Aspirates consist of sheets and three-
dimensional clusters of intermediate-sized cells with
moderate amount of delicate cytoplasm, uniform
round to oval nuclei and finely granular chromatin
(130–132). Nucleoli are inconspicuous. Acinar forma-
tion with overlapping of nuclei may be appreciated. A
DQ stain may show purple extracellular material
formed as dense stromal spheres, which can lead to
confusion with the hyaline globules of ACC (133–135).
Lesions Containing Squamous Cells

Other lesions containing squamous cells should be
considered in the differential diagnosis also (Table 17)
Figure 51 Low-grade MEC showing admixture of intermediate (103). Squamous and mucus metaplasia in chronic
cells and metaplastic appearing cells. Intermediate cells have
sialadenitis can raise concerns for a low-grade MEC
moderate delicate cytoplasm, round nuclei, and small nucleoli.
The metaplastic cells have more abundant and denser cyto-
(Fig. 38). These specimens, however, are usually
plasm, and prominent nucleoli. There is focal cytoplasmic vacuo- sparsely cellular and show admixture of benign ductal
lization (Papanicolaou stain, 400). and acinar cells, in addition to background inflamma-
tion and fibroblasts. The occasional presence of degen-
erated epithelial cells of ductal origin (cuboidal cells
or squamous metaplasia) in retention cyst may also
false-negative diagnosis of macrophages associated raise the suspicion of low-grade MEC, but the sparse
with benign cyst contents (124,127). The predominance cellularity of the specimen and disappearance of mass
of the glandular cells with their bland cytology can be after aspiration are features that favor a benign cyst.
easily mistaken for the epithelial component of pleo-
morphic adenoma (98). Also, the mucinous material in
Table 17 Salivary Gland Lesions Containing Squamous Cells
the background may be misinterpreted as the myxoid
stromal component of pleomorphic adenoma (128). The Mucoepidermoid carcinoma
presence of small nucleoli and the stringy nature of Squamous cell carcinoma
mucin admixed with macrophages favor MEC (Fig. 50). Squamous metaplasia associated with Warthin tumor,
The general absence of nucleoli and the fibrillary myx- pleomorphic adenoma, chronic sialadenitis
oid nature of stroma admixed with spindle cells favor Lymphoepithelial cyst
Branchial cleft cyst
pleomorphic adenoma (111).
28 Elsheikh et al.
Other cystic lesions that enter into the differential

diagnosis include branchial cleft cyst and epidermoid
cyst (Table 12).
G. Salivary Gland Neoplasms Characterized by

Large Cells and Abundant Cytoplasm
These neoplasms may have bland cytology or show
severe cytologic atypia and are subdivided according
to the degree of atypia (Table 18). Tumors with
oncocytic and/or clear cell features are also included
in this group. Some of these neoplasms may show
papillary, cystic, or cribriform architecture. Generally,
the greatest challenge is encountered with tumors
showing no significant atypia, as it may be extremely
difficult to distinguish low-grade malignancies from
benign neoplasms or discriminate among the various
types of low-grade malignancies. The presence of
severe atypia readily establishes the diagnosis of
malignancy, but it may not be able to establish the
specific type of malignancy.
High-Grade MEC Figure 53 High-grade mucoepidermoid carcinoma. The cells

are large, pleomorphic and show severe cytologic atypia. The
High-grade MEC has a less prominent cystic compo- cytoplasm has a dense quality with squamoid features (Papani-
nent and greater degree of atypia, compared with colaou stain, 600).
low-grade MEC. High-grade MEC is cytologically char-
acterized by large pleomorphic cells with predominant-
ly epidermoid or undifferentiated cell features (Fig. 53)
(104). Glandular cells are rarely seen in high-grade ACC, mucoepidermoid carcinoma, and squamous car-
MEC, but their presence in association with squamous cinoma (137–140). In the latter cases, aspirates will
cells establishes the diagnosis. The presence of marked demonstrate admixed but distinctive cytologic features
keratinization is seldom observed in MEC; therefore, its of those neoplasms.
presence favors metastatic squamous cell carcinoma
from the oral cavity or upper respiratory tract Salivary Duct Carcinoma
(Fig. 42) (124,126,136). Primary squamous carcinoma
of the salivary glands is very rare, accounting for less Salivary duct carcinoma (SDC) is a rare primary
than 1% of salivary gland tumors and is indistinguish- salivary gland malignancy characterized by its histo-
able cytologically from metastatic squamous carcinoma. logic resemblance to in situ and invasive ductal carci-
Primary malignancies may also present as a malignant noma of the breast. High-grade SDC is the most
component of carcinoma ex pleomorphic adenoma or common subtype (>90% of cases) and considered
as a hybrid carcinoma with other malignancies such as one of the most aggressive salivary gland malignan-
cies; while low-grade SDC is believed to carry a
Table 18 Salivary Gland Tumors with Large Cells and Abundant favorable prognosis (141–143). Architecturally, SDC
Cytoplasm (includes oncocytic and clear cell lesions) shows a spectrum of cytologic findings, including
broad flat sheets and three-dimensional tightly cohe-
With significant atypiaa Without significant atypia sive clusters of large monomorphic polygonal cells
High-grade mucoepidermoid Acinic cell carcinoma with abundant eosinophilic cytoplasm, round to oval
carcinoma hypochromatic nuclei, and prominent nucleoli. Medi-
High-grade salivary duct Oncocytic neoplasms, um-sized low columnar cells with central or eccentric
carcinoma including Warthin tumor and hyperchromatic nuclei may be found. Occasional cri-
oncocytoma briforming and papillary configurations are seen. In
Radiation-induced sialadenitis Low-grade salivary duct
low-grade SDC, the neoplastic cells have a uniform
carcinoma
High-grade adenocarcinoma, Epithelial-myoepithelial
appearance and show minimal atypia. High-grade
NOS carcinoma SDC shows moderate to severe nuclear atypia and
Metastatic carcinoma, pleomorphism (Fig. 54); however, the atypia can be
including breast, prostate, random or focal in distribution (144–146). The pres-
lung ence of associated necrosis in the background consti-
Hyalinizing clear cell tutes an important clue to the diagnosis of high-grade
adenocarcinoma SDC (Fig. 55). Occasionally, FNA may sample a more
a
Significant atypia is defined as focal or diffuse moderate-severe nuclear undifferentiated component of SDC in which case
atypia and pleomorphism. differentiating it from other high-grade carcinomas
Figure 54 High-grade salivary duct carcinoma. There are flat Figure 55 Salivary duct carcinoma, high-grade. Abundant
sheets of epithelial cells with abundant delicate cytoplasm and necrosis is associated with the malignant cells (DQ stain, 400).
moderate nuclear atypia. The nuclei are round to oval in shape
and show finely granular chromatin and prominent nucleoli.
(Papanicolaou stain, 600).
focal in nature (144). Papillary cystadenocarcinoma
(PCA) and PLGA show architectural similarities to
SDC, including cystic and papillary formation (147).
may not be possible. High-grade MEC is the most
Because of the absence of significant atypia, these
difficult neoplasm to cytologically distinguish from
neoplasms are difficult to distinguish from low-
high-grade SDC, since the latter is composed of large
grade SDC, but should not be confused with high-
epithelial cells that resemble the nonkeratinizing
grade SDC (145,148).
component of MEC (145). The presence of undifferen-
tiated intermediate squamous cells, poorly differenti-
Acinic Cell Carcinoma
ated squamous cells, and mucus producing cells in
addition to lack of papillary and cribriform configura- Acinic cell carcinoma is a low-grade malignancy char-
tion favors MEC (Table 19) (144). Furthermore, the acterized by sheets of large cells with abundant cyto-
atypia in MEC tends to be more pleomorphic and plasm. The neoplastic cells have foamy/vacuolated
diffuse in nature, whereas the atypia in high-grade cytoplasm with ill-defined borders, eccentrically
SDC tends to be uniform and sometimes random or placed nuclei, small inconspicuous nucleoli, and lack
Table 19 Differential Cytomorphologic Features of Salivary Gland Neoplasms with Large Cells and Abundant Cytoplasm
High-grade
High-grade mucoepidermoid
Salivary duct carcinoma carcinoma Acinic cell carcinoma Oncocytic lesions
Architecture Flat branching sheets and Tightly and loosely Large flat sheets Large flat sheets
tightly cohesive clusters cohesive clusters
Occasional cribriforming No cribriform or papillary
and papillary formation configuration
Cellular Large monomorphic Large atypical Monomorphic acinic cells Large monomorphic
Features polygonal cells showing keratinized and with abundant foamy epithelial cells with
abundant eosinophilic nonkeratinized vacuolated cytoplasm abundant dense
cytoplasm with squamous cells. eosinophilic cytoplasm
indistinct cell borders Rare mucus-producing and well-defined
cells cytoplasmic borders
Nuclear Focal/random moderate Diffuse marked nuclear Small eccentrically Centrally placed nuclei
Features nuclear atypia, round pleomorphism and placed nuclei and with prominent nucleoli
to oval enlarged atypia with nuclear inconspicuous nucleoli Nuclear/cytoplasmic ratio
hypochromatic nuclei hyperchromasia in the is low
with prominent nucleoli squamous epithelial
cells
Background Necrosis often present Necrosis and mucin may Naked nuclei Necrosis is absent
be present
Source: Modified from Elsheikh Ref. 144.
30 Elsheikh et al.
arrangement (Fig. 36), in contrast to the flat sheets

and syncytial architecture of acinic cell carcinoma.
Oncocytoma and High-Grade Oncocytic Carcinoma

Oncocytoma is characterized by large flat sheets of
epithelial cells with abundant dense eosinophilic cyto-
plasm, well-defined cytoplasmic border, enlarged cen-
trally placed nuclei, and prominent nucleoli.
Anisonucleosis and mild atypia are not uncommon,
but marked cytologic atypia, cribriforming, and necro-
sis are often absent.
High-grade oncocytic carcinoma may be sus-
pected based on the presence of severe cytologic
atypia, but histologic confirmation is warranted in
such cases (152,153).
Warthin Tumor
Warthin tumor is almost always seen in the parotid
Figure 56 Acinic cell carcinoma. Flat sheets of epithelial cells, gland, comprising approximately 5% to 10% of all
with abundant vacuolated basophilic cytoplasm and indistinct parotid tumors. The aspirate has a thin watery mucoid
cytoplasmic borders. The nuclei are peripherally located. This
appearance, and consists of a mixed population of
cell group is traversed by thin capillaries (DQ stain, 200).
lymphocytes, occasional plasma cells, and variable
number of oncocytes (Fig. 58). Acinic cell carcinoma,
especially if associated with a prominent lymphocytic
infiltrate, may be confused with Warthin tumor. In
contrast to oncocytes, acinar cells have delicate vacuo-
lated cytoplasm and show peripherally located nuclei
(Table 19); this distinction, however, can be difficult in
certain situations and may require histologic confirma-
tion. If the lymphoid component predominates in an
aspirate and oncocytes are not appreciated, Warthin
tumor can be misinterpreted as reactive lymphoid
hyperplasia. In oncocytic-rich aspirates, it is impossible
to distinguish epithelial-rich Warthin tumor from
oncocytoma. Warthin tumor can also present as a
Figure 57 Acinic cell carcinoma. The neoplastic cells show no

significant atypia, and round eccentrically placed nuclei with
small inconspicuous nucleoli. There is suggestion of acinar
configuration (Papanicolaou stain, 400).
significant nuclear atypia or pleomorphism (Figs. 56

and 57) (149). Some cellular groups may be traversed
by thin capillaries (Fig. 56). Stripped nuclei are often
present in the background. Occasionally there is pap-
illary configuration or prominent cystic component
(150). A number of cases show a dense lymphocytic
component, which may lead to confusion with Figure 58 Warthin tumor. There is admixed population of large
Warthin tumor (Table 19) or other lymphoepithelial flat sheets of oncocytes and lymphoid cells. The epithelial cells
lesions (151). Because of its bland cytology, acinic cell have abundant dense eosinophilic cytoplasm, well defined cyto-
carcinoma may be misdiagnosed as nonneoplastic plasmic border, enlarged centrally placed nuclei, and prominent
nucleoli (Papanicolaou stain, 600).
acinar tissue. However, benign acinar cells have a
characteristic low power rosette or clustered ball
predominately cystic mass with nonspecific cyst content vacuolization, nuclear smudging, and low nuclear to
findings, in which case it must be included in the cytoplasmic ratios are features suggestive for therapy
differential diagnosis of other cystic lesions. MEC and effect (92,136).
SDC may show oncocytic features, but these changes
are usually focal (142). Clear Cell Change
Clear cell change is not uncommonly encountered in
Metastatic Malignancies salivary gland FNAs. Neoplasms presenting with clear
Squamous cell carcinoma and melanoma from the head cell morphology are listed in Table 20. Epithelial-
and neck make up the majority of metastases to myoepithelial carcinoma (EMC) is regarded as a low-
salivary glands (154,155). Primary sites originating to intermediate-grade malignancy with propensity for
below the clavicle are extremely rare, but when pres- local recurrence. FNA is usually of high cellularity and
ent are usually due to metastases from lung, kidney, shows two distinct cell populations, ductal and myoe-
and breast (156). Rarely metastasis presents as the pithelial (Fig. 59). The ductal cells present as tightly
initial manifestation of disease, mimicking a primary cohesive and three-dimensional clusters and sometimes
salivary gland neoplasm. Metastatic breast ductal form tubular structures. They have a basaloid appear-
carcinoma and prostatic large duct carcinoma may ance, i.e., small cells with scant cytoplasm, uniform
show cytologic features identical to SDC; therefore, round nuclei, small nucleoli and well-defined cyto-
the possibility of metastases need to be clinically plasmic borders (169–171). The myoepithelial cells are
excluded before making a diagnosis of primary SDC characterized by sheets and loosely cohesive groups of
(157). Immunocytochemical studies including estro- large cells with pale vacuolated (clear) cytoplasm, elon-
gen receptor (ER), progesterone receptor (PR), and gated nuclei, and small distinct nucleoli. Single cells and
androgen receptor (AR) maybe helpful in this differ- numerous naked nuclei are seen in the background.
ential diagnosis. AR is positive in most SDC and a
subset of other primary salivary gland neoplasms, but Table 20 Salivary Gland Lesions Characterized by Clear Cells
negative in breast ductal carcinoma. ER is typically Epithelial-myoepithelial carcinoma
negative in SDC and positive in breast carcinoma Metastatic renal cell carcinoma
(158,159). SDC rarely expresses PR (<3% of cases) Hyalinizing clear cell adenocarcinoma
and, when positive, is seen in less than 25% of cells. Acinic cell carcinoma
Therefore, PR positivity in more than 25% of neoplas- Mucoepidermoid carcinoma
tic cells favors metastatic breast carcinoma (142). Polymorphous low-grade adenocarcinoma
Gross cystic disease fluid protein-15 (GCDFP-15), Clear cell myoepithelioma/myoepithelial carcinoma
Sebaceous adenoma/carcinoma
prostate-specific antigen (PSA) and prostate acid
Clear cell oncocytoma
phosphatase (PAP) are not helpful markers since
they are also expressed by SDC (160–163). Metastatic
large cell carcinoma of the lung can mimic other
primary high-grade carcinomas of the salivary gland
and, if associated with cytoplasmic vacuolization and
clearing, may raise the differential diagnosis of clear
cell carcinoma (164). Assessment of the cytokeratin
(CK) 7 and 20 immunohistochemical profiles is of
limited usefulness in the distinction between primary
salivary gland malignancies and metastases since
most are CK7-positive/CK20-negative (165). Nonethe-
less, the relatively common CK20 positivity among
SDC may help in distinguishing it from morphologi-
cally similar carcinomas of breast or lung. In addition,
the prevalent CK7-negative/CK20-negative profile of
cancers as adrenal cortical, prostatic, and RCCs can
further aid in their discrimination from SDC (165).
TTF-1 has been shown to be a highly specific marker
for primary and metastatic lung adenocarcinoma and
would be helpful in the differential diagnosis of
primary high-grade carcinoma (166,167).
Radiation therapy Figure 59 Epithelial-myoepithelial carcinoma. Dual populations

of ductal and myoepithelial cells. The ductal cells are more
Radiation therapy may cause significant atypia in the cohesive, three-dimensional, and show less amount of cyto-
lining epithelium of the salivary ducts (postirradiation plasm. The myoepithelial cells are arranged as loosely cohesive
atrophy and fibrosis), potentially resulting in a false- groups of large cells with pale vacuolated (clear) cytoplasm and
positive diagnosis of recurrent carcinoma (168). The have round-elongated nuclei and small nucleoli (Papanicolaou
sparsely cellular nature of the aspirate and radiation stain, 400).
therapy changes including cytomegaly, cytoplasmic
32 Elsheikh et al.
clear cytoplasm and no ductal differentiation (173).

Variable degree of atypia is observed in myoepithelial
carcinoma. Sebaceous adenoma and carcinoma are
characterized by foamy vacuolated cytoplasm, no
ductal cells, and negative myoepithelial markers.
In summary, it is important to recognize the
broad spectrum of cytomorphologic features associated
with neoplasms characterized by large cells and abun-
dant cytoplasm; and is especially important to sepa-
rate the high-grade cancers from the less aggressive
neoplasms. Some aspirates are obviously malignant
and show diffuse marked cytologic atypia, while
others may only show focal atypia. The distinction
between the various types of high-grade malignancies
such as high-grade MEC, high-grade SDC, and high-
grade carcinoma not otherwise specified is not critical
since these patients will receive appropriate aggres-
sive treatment. It is, however, crucial not to mistake a
high-grade carcinoma for a low-grade malignancy or a
Figure 60 Epithelial-myoepithelial carcinoma. Dense acellular benign neoplasm (144). The finding of cribriforming
mesenchymal component is associated with the cell clusters (DQ and necrosis with significant cytologic atypia, even if
stain, 200). the atypia is random or focal, should raise the diag-
nostic possibility of high-grade SDC (144,176).
Occasionally, there is predominance of the clear cells H. Salivary Gland Tumors

without appreciation of a basaloid cell component. Rich in Lymphocytes
Variable amount of acellular mesenchymal component, Lymphoid cells may be associated with a variety of
including pale blue material resembling mucin or dense salivary gland lesions including benign lymphoepi-
stroma surrounding cell clusters, is usually present thelial lesion, lymphoepithelial cysts associated with
(Fig. 60) (170,171). Hyaline globules are rarely encoun- AIDS, chronic sialadenitis, Warthin tumor, intra-
tered and may raise the possibility of ACC. However, parotid lymph node hyperplasia, and malignant lym-
there is typically no significant large clear cell compo- phoma (Table 21). The admixture of lymphoid cells
nent in ACC. Since EMC is composed of variable and oncocytes is diagnostic of Warthin tumor (Fig. 58).
mixtures of clear myoepithelial cells, basaloid cells, However, careful evaluation of the lymphocytes is
and hyaline stromal material, predominance of any of needed to ensure that they are reactive in nature.
those components can lead to diagnostic difficulties, The presence of a monomorphic population of lym-
with many of those lesions misinterpreted as pleomor- phoid cells should raise the possibility of malignant
phic adenoma, ACC or low-grade malignancy (169,172). lymphoma.
Other primary low-grade malignancies such as acinic
cell carcinoma, low-grade MEC, and PLGA may have Malignant Lymphoma
focal clear cell change, but other areas in the smears
should demonstrate cytologic features characteristic of Primary lymphoma in salivary glands is most com-
these neoplasms (111). monly associated with benign lymphoepithelial lesion
In clear cell-predominant aspirates, metastatic and Sjögren’s syndrome, or occasionally Warthin
RCC must first be excluded. RCC is characterized by tumor. Malignant lymphoma can arise in intraparotid
large cells with clear bubbly cytoplasm, distinct to or periparotid lymph nodes. Lymphoma may also
wispy borders, fine vasculature, and prominent nucle- secondarily involve the salivary glands as part of a
oli (Fig. 32). No basaloid cells or significant number of generalized disease or leukemia. Most lymphomas are
naked nuclei are seen. Immunocytochemistry may be B-cell NHL, and the majority of them are extranodal
helpful, as RCC demonstrates positive staining for marginal zone lymphoma (MALT type), follicular
CD10 and renal cell antigen, and shows negative
staining for myoepithelial markers (173,174). Also, Table 21 Lymphoid-Rich Salivary Gland Lesions
greater nuclear atypia is usually appreciated in RCC Chronic sialadenitis
compared with EMC. Primary (hyalinizing) clear cell Benign lymphoepithelial lesion
adenocarcinoma of the salivary gland may show Lymphoepithelial cyst
identical cytologic features to metastatic RCC. It is a Intraparotid lymph node hyperplasia
low-grade malignancy with predilection for minor Warthin tumor
salivary glands. No ductal differentiation is demon- Acinic cell carcinoma
strated, and IHC is negative for myoepithelial markers Mucoepidermoid carcinoma
(175). Myoepithelioma and myoepithelial carcinoma, Malignant lymphoma
clear cell types, are extremely rare and are composed Lymphoepithelial carcinoma
Metastatic carcinoma
of a uniform population of cells with less amount of
lymphoma, or DLBCL (177). Establishing a diagnosis

of malignancy in large cell lymphoma is not difficult,
but high-grade carcinoma, small cell carcinoma, and
melanoma must be excluded. The cytologic diagnosis
of low-grade lymphoma, including small lymphocytic
lymphoma (SLL)/chronic lymphocytic leukemia and
MALT lymphoma is most challenging as it is difficult
to distinguish them from reactive lymphoid hyperpla-
sia. Immunocytochemistry and/or flow cytometry play
a pivotal role in establishing a definitive diagnosis in
these cases (178). Hodgkin’s lymphoma (HL) rarely
involves the salivary glands, but shows a background
of mixed inflammatory cells including plasma cells and
eosinophils and variable number of Reed Sternberg cells
and their mononuclear variants. Atypical naked single
and multilobated nuclei are often present in the back-
ground. Immunocytochemical stains including CD15
(Leu-M1) and CD30 highlight the neoplastic cells.
Lymphoepithelial Carcinoma Figure 61 Benign lymphoepithelial lesion (lymphoepithelial sia-

ladenitis). Lymphoepithelial islands, when present, are charac-
Lymphoepithelial carcinoma is an aggressive undif- teristic. They consist of tightly cohesive clusters of ductal
ferentiated malignancy characterized by mixture of epithelial cells intermingled with reactive lymphoid cells (H&E
lymphocytes, plasma cells, and syncytial sheets of stain, 200).
large- to spindle-shaped cells (104). The malignant
cells show marked pleomorphism and have scant to
moderate amount of cytoplasm, vesicular nuclei, and
prominent nucleoli (179,180). Differential diagnosis examine lymphoid-rich specimens for evidence of
includes other high-grade malignancies such as large low-grade malignancy hiding in the background.
cell lymphoma, melanoma, and metastatic carcinoma,
including nasopharyngeal carcinoma. I. Pleomorphic Adenoma and its Variable
Cytologic Appearances
Lymphoid Hyperplasia and Lymphoepithelial Lesions
Pleomorphic adenoma (PA) is the most common
Lymphoid hyperplasia may be encountered in aspirates neoplasm of the salivary glands, accounting for
of intraparotid, periparotid, or submandibular lymph approximately 75% of neoplasms, with a peak age of
nodes that are mistaken clinically for salivary gland 30 to 40 years (183,184). It is characterized by admix-
neoplasms. These aspirates are composed of a mixed ture of cellular (ductal and myoepithelial cells) and
population of lymphoid cells, including small lympho- mesenchymal components (Fig. 62). The mesenchymal
cytes, large follicular center cells, plasma cells, and component may be myxoid or chondroid and is
tingible body macrophages. Benign lymphoepithelial usually admixed with spindle myoepithelial cells.
lesion (lymphoepithelial sialadenitis) shows a similar reac- The myxoid mesenchymal component stains poorly
tive lymphoid component, but scattered tightly cohe- with Papanicolaou stain, appearing gray or pale
sive clusters of ductal epithelial cells (lymphoepithelial green; but is better highlighted by DQ stain as dark
islands) will be invariably found (Fig. 61) (177). Admit- purple material with a fibrillary appearance (Fig. 63)
tingly, however, in the absence of the epithelial ele- (123). The stromal material is usually the most char-
ments, distinction from lymph node hyperplasia is not acteristic feature of PA, but other neoplasms may also
possible. Lymphoepithelial cysts and HIV-associated cys- be rich in extracellular stroma (Table 14) (185,186).
tic lymphoepithelial lesions have prominent cystic compo- Recognizing the intimate admixture of the cellular and
nents and show reactive lymphoid cells admixed with mesenchymal elements, on FNA, is what establishes
mucoid debris and macrophages (181,182). Metaplastic the diagnosis of PA (183,184).
squamous and glandular cells may be found, which can PA is notorious for mimicking the cytologic
raise the possibility of cystic low-grade MEC. appearance of other tumors, especially low-grade
Chronic sialadenitis may show a prominent malignancies. Therefore, PA should be considered in
reactive–lymphoid cell population admixed with duc- the differential diagnosis in the lesions listed in
tal cells. The sparse cellularity of the specimen, in Table 22. Although most cases of PA show classic
addition to the presence of occasional fibroblasts, cytologic features of admixed mesenchymal, ductal,
neutrophils and benign acinar cells favor a diagnosis and myoepithelial elements, problems in the diagno-
of chronic sialadenitis (103,105). Finally, low-grade sis may be encountered if there is a predominance of
malignancies such as acinic cell carcinoma and MEC any one of these elements (136,187). If the mesenchy-
may be associated with a rich lymphoid infiltrate, mal myxoid stroma, for instance, predominates in an
resulting in a false-negative diagnosis of reactive aspirate it can be misinterpreted as mucin, causing PA
lymphoid hyperplasia. Hence, it is crucial to carefully to be mistaken for cyst fluid or low-grade MEC. In
34 Elsheikh et al.
Table 22 Neoplasms That Have Overlapping Cytologic Fea-

tures with Pleomorphic Adenoma
Basal cell adenoma
Adenoid cystic carcinoma
Spindle cell tumors
Oncocytoma, Warthin tumor
Acinic cell carcinoma
Low-grade mucoepidermoid carcinoma
Myoepithelioma
Epithelial-myoepithelial carcinoma
Polymorphous low-grade adenocarcinoma
Low-grade salivary duct carcinoma
Carcinoma ex pleomorphic adenoma
Figure 62 Pleomorphic adenoma is characterized by admixture

of cellular (ductal and myoepithelial cells) and mesenchymal
components. The ductal cells present as cohesive groups.
Myoepithelial cells, present in the background, have a plasma-
cytoid appearance. The mesenchymal component stains dark
purple and has cells embedded in it (DQ stain, 200).
Figure 64 Pleomorphic adenoma. The neoplastic cells have

moderate amount of cytoplasm, round to oval nuclei, finely
granular chromatin, and lack distinct nucleoli. Focal atypia is
seen (at 10:00), which is acceptable in pleomorphic adenoma
(Papanicolaou stain, 400).
Cellular PA
Cellular PA is characterized by the presence of loosely
cohesive branching and arborizing sheets of interme-
diate-sized cells with indistinct (fuzzy) community
borders (Fig. 64). There is a haphazard cellular
arrangement with occasional spindling (123). The
Figure 63 Pleomorphic adenoma. This myxoid mesenchymal
component has a fibrillary appearance, and shows intimately
neoplastic cells have moderate amount of cytoplasm,
admixed spindle myoepithelial cells (Papanicolaou stain, x 400). oval to round nuclei, finely granular chromatin, and
lack distinct nucleoli. Typically, the background
shows singly scattered cells with plasmacytoid
appearance (myoepithelial cells) (188). Mesenchymal
elements may be scant or absent. Basaloid neoplasms
cellular PA, where the epithelial/myoepithelial cells are the most difficult lesions to distinguish cytolog-
predominate, other salivary gland neoplasms such as ically from cellular PA, an experience shared by
basal cell adenoma, ACC, and low-grade malignancies several authors (123,187). Basal cell adenoma is charac-
may be suspected (123,136,187). Because of the terized by tightly cohesive clusters of small basaloid
increased rate of false-positive and false-negative cells, and many naked nuclei in the background.
diagnoses associated with these cellular lesions, Cellular PA, in contrast, has intermediate-sized cells
some authors have recommended for highly cellular with moderate amount of cytoplasm, and plasmacy-
lesions lacking stroma to be classified as ‘‘salivary toid cells in the background (Table 23). ACC is also
gland neoplasm, not otherwise specified’’ (108). considered in the differential diagnosis, as PA may
Table 23 Major Differential Diagnostic Considerations of Cellular Pleomorphic Adenoma

Low-grade
Cellular pleomorphic mucoepidermoid
adenoma Basal cell adenoma Adenoid cystic carcinoma carcinoma
Architecture Broad, loosely cohesive Tightly cohesive clusters Broad sheets Loosely cohesive sheets
sheets Smooth community Microcysts contain large and few 3-D clusters
Indistinct community borders hyaline globules
borders
May have empty
pseudocysts
Cellular features Intermediate-sized cells Small-sized cells Small cells Intermediate-sized cells
Moderate cytoplasm Scant cytoplasm Scant cytoplasm Monomorphic population
Haphazard arrangement
Nuclear features Round to oval nuclei Round to oval nuclei Round to oval nuclei Round to oval nuclei
Finely granular Finely granular chromatin Coarse chromatin Finely granular chromatin
chromatin No nucleoli Occasional nucleoli Small nucleoli
No nucleoli
Background Plasmacytoid cells Naked nuclei Naked nuclei Single cells
Extracellular Fibrillary myxoid or Amorphous, homogenous, Dense hyaline globules Stringy mucin, admixed
matrix chondroid substance stromal material surrounded by with macrophages
admixed with spindle surrounding neoplastic neoplastic cells
cells cells
Source: Modified from Ref. 123.
focally show pseudocystic spaces or contain small

hyaline globules. This is a potential diagnostic pit-
fall that has been described in several reports
(123,187,189,190). Careful examination, however,
reveals that these spaces are empty and do not contain
the large hyaline globules characteristic of ACC. In
addition, the globules associated with PA are often
small and focal in nature (Fig. 65), in contrast to the
numerous large and variably sized globules associ-
ated with ACC (Figs. 46 and 47) (111,113,191).
Furthermore, the neoplastic cells of PA have more
abundant cytoplasm, compared to the basaloid cell
appearance of ACC (Table 23). It is important to
distinguish cellular PA from basaloid neoplasms espe-
cially ACC, since the latter is an aggressive malignan-
cy characterized by recurrences and late metastasis to
lungs and bone. Rarely, ACC may arise in PA, in
which case the cytologic features of both neoplasms
are present (192).
Figure 65 Pleomorphic adenoma. Rare hyaline globules may
be encountered. These globules are small, uniform in size, and
Spindle Cell Lesions have irregular outer contours (DQ stain, 200).
Cellular PA may have a predominant spindle cell
appearance, which could lead to confusion with soft
tissue spindle cell neoplasms (123). Cytologically, the also been reported (193). Histologic confirmation is
specimen is composed of cohesive clusters of spindle warranted in newly diagnosed spindle lesions.
cells with overlapping nuclei and crowding (Fig. 66).
Careful search of the background for mesenchymal Hyaline PA
elements is needed in such cases as this may be the
only clue to the diagnosis of PA. Otherwise, it is Plasmacytoid variant of PA (hyaline PA) is character-
difficult to differentiate spindle PA from other spindle ized by sheets, clusters, and singly scattered plasma-
cell tumors such as nerve sheath tumor, leiomyoma, cytoid appearing cells. The cells have abundant
myoepithelioma, and low-grade sarcoma (Table 24). dense/glassy cytoplasm with well-defined border,
Occasionally inflammatory conditions, such as round to oval eccentrically placed nuclei, and incon-
granulomatous sialadenitis, show a spindle cell appear- spicuous nucleoli (Fig. 67). These cells most likely
ance, but recognition of epithelioid histiocytes and represent modified myoepithelial cells (194,195).
mixed inflammatory background should secure the Differential diagnosis includes other neoplasms with
diagnosis. Malignant neoplasms such as metastatic abundant cytoplasm and no significant atypia, such as
spindle cell melanoma and high-grade sarcoma have acinic cell carcinoma and oncocytic tumors (Table 22).
36 Elsheikh et al.
Acinic cell carcinoma has eccentrically placed nuclei

similar to hyaline PA, but the cytoplasm has a foamy
granular quality with indistinct borders. Oncocytic
tumors, such as Warthin tumor and oncocytoma,
have dense eosinophilic cytoplasm similar to PA, but
the nuclei are centrally placed and show prominent
nucleoli (123). Differential diagnosis also includes
plasmacytoma, which is distinguished by nuclei
showing characteristic clumpy cartwheel chromatin,
perinuclear hoff, and plasma cell markers (CD79a,
CD138, kappa/lambda light chain).
Myoepithelioma and Myoepithelial Carcinoma

Myoepithelioma is a rare benign neoplasm that is
regarded as a monomorphic variant of PA. It is histo-
logically characterized by proliferation of myoepithelial
cells and scant-to-absent ductal elements (110). Spindle,
plasmacytoid, epithelioid, and clear cell variants are
Figure 66 Spindle pleomorphic adenoma/myoepithelioma, recognized (Figs. 66 and 67). Myoepithelial carcinoma
showing cohesive clusters of spindle cells with overlapping nuclei (malignant myoepithelioma) is characterized by an infil-
and crowding and no significant atypia (Papanicolaou stain, trative destructive growth, increased mitotic activity
400). and pleomorphism (196,197). However, the diagnostic
finding that distinguishes myoepithelial carcinoma
from benign myoepithelioma is the unequivocal infil-
Table 24 Differential Diagnosis of Spindle Cell Neoplasms trative destructive growth of malignancy (110). There-
fore, in the absence of cytologic atypia, FNA cannot
Cellular pleomorphic adenoma distinguish cellular PA and myoepithelioma from
Myoepithelioma myoepithelial carcinoma (123).
Nerve sheath tumor
Leiomyoma
Sarcoma, low grade and high grade PA vs. Low Grade Malignancies
Nodular fasciitis
Granulomatous sialadenitis Separating cellular PA from low-grade malignancies,
Malignant melanoma such as low-grade MEC, EMC, and PLGA, can be quite
challenging. In low-grade MEC, the predominance of
intermediate cells with bland cytology can be easily
mistaken for the epithelial component of PA (108).
Also, the mucinous material in the background may
be misinterpreted as the myxoid stromal component of
PA (128). Helpful distinguishing features are the
stringy nature of mucin admixed with macrophages
in MEC versus the fibrillary myxoid stroma admixed
with spindle cells in PA. Additional differentiating
features are listed in Table 23. Low-grade SDC has
been misdiagnosed as PA in one study and PLGA
may be difficult to tell apart from cellular PA, but this
latter diagnosis should not be considered in aspirations
of the parotid or submandibular glands, since PLGA is
seen almost exclusively in minor salivary glands (par-
ticularly the palate) (145,148). The bland nuclear fea-
tures of low-grade malignancies combined with
prominent metachromatic desmoplastic stroma have
resulted in these few reported cases of false-negative
diagnoses. The presence of prominent nucleoli, lack of
background plasmacytoid myoepithelial cells, and
Figure 67 Hyaline (plasmacytoid) pleomorphic adenoma/ absence of intimate admixture of myoepithelial cells
myoepithelioma. The specimen consisted predominately of and fibrillary extracellular stroma, however, should
plasmacytoid appearing cells having abundant dense/glassy prevent a misclassification of PA in most cases (123).
cytoplasm, with well-defined border, round to oval eccentri- Squamous and mucinous metaplasia have been
cally placed nuclei, and inconspicuous nucleoli (Papanicolaou described in PA, but this finding is often focal and
stain, 600).
should not raise the possibility of MEC. EMC is charac-
terized by dual populations of basaloid (ductal) and
low-grade cancers. Because of the challenging nature

of salivary gland FNAs, there is a potential significant
false-positive and false-negative rate, which should
improve with experience. In our discussion, we have
stressed the major difficulties and limitations associat-
ed with FNA cytology and provided a morphologic
diagnostic approach to the interpretation of such
specimens. This approach emphasized the differential
diagnostic possibilities and stressed the importance of
well-defined cytologic criteria. If established diagnos-
tic criteria are present and strictly observed, the great
majority of nonneoplastic lesions and common var-
iants of benign and malignant neoplasms can be
diagnosed with a high level of accuracy (89). How-
ever, there will remain a subset of problematic cases
where a specific diagnosis is not possible. Under these
circumstances, the clinician is best served with an
appropriate differential diagnosis, relating the uncer-
tainty of the interpretation and the recommendation
Figure 68 Carcinoma ex pleomorphic adenoma. There is for surgical pathology examination to help establish a
severe cytologic atypia and nuclear pleomorphism present more definitive diagnosis.
throughout the smears. Focally, there were cytologic features
of pleomorphic adenoma. This degree of atypia, however, is
beyond what is accepted for pleomorphic adenoma (Papanico- IV. LYMPH NODES
laou stain, 600).
A. Introduction
Fine needle aspiration biopsy (FNAB) is a well-accepted
clear (myoepithelial) cells admixed with extracellular diagnostic test of choice for the assessment of cervical
hyaline material. The prominence of clear cell compo- and supraclavicular lymphadenopathy in both adult
nent, numerous naked nuclei, and acellular quality of and pediatric patients. In the majority of cases, FNAB
the extracellular stroma help in separating it from can reliably distinguish between benign/reactive and
cellular PA. malignant processes. In most cases, results of FNAB
Finally, cytologic atypia may be seen in up to can provide adequate information to accurately guide
20% of PA and accounts for many of the problems patient management with either simple observation,
leading to false-positive diagnoses (191). Focal mild antimicrobial therapy for infectious processes, chemo-
atypia is acceptable in PA and should not raise con- therapy and radiation therapy for malignancies, or the
cerns for malignancy. This atypia may manifest as need for additional tissue in the form of core biopsies
scattered large cells with round to oval nuclei and or excisional biopsy of the lymph node. The technique
prominent nucleoli in an otherwise classic presenta- is well accepted among both oncologists and pathol-
tion of PA (Fig. 64) (104). Severe cytologic atypia, ogists for the diagnosis of metastatic malignancies
however, should raise the possibility of carcinoma ex and the documentation of lymphoma recurrences.
pleomorphic adenoma (Fig. 68). Typically, the malig- Workup of metastatic neoplasms has shown both
nancy associated with carcinoma ex pleomorphic ade- high sensitivity (91–98%) and high specificity
noma is poorly differentiated, and aspirates almost (95–99%) with an overall accuracy rate of 94% to
invariably contain numerous anaplastic malignant 97% (199–203). However, its role for the primary
cells without cytologic evidence of PA (187). A defini- diagnosis of lymphomas has remained controversial
tive diagnosis of carcinoma, therefore, should not be (204). The recent changes in the WHO classification of
rendered in the absence of overt malignant cytologic lymphomas has placed more emphasis on cytomor-
features, as most cases of PA-associated atypia are phologic rather than on architectural features allow-
benign on follow-up. Low-grade malignancies arising ing for a more expanded role of FNAB in the primary
in PA have been rarely reported (198). workup of NHLs (205). The evaluation of HL still
remains problematic; and while FNAB may suggest
J. Summary of Salivary Gland FNA the diagnosis based on cytomorphologic features, it is
often still necessary to obtain a tissue biopsy for a
Preoperative FNA of salivary gland tumors is clini- definitive diagnosis (178,206). In the workup of
cally useful and is especially helpful in distinguishing lymphadenopathy, a combined approach correlating
neoplastic from nonneoplastic lesions. In most cases, it the cytomorphologic features with results from ancil-
is not critical to distinguish between benign neo- lary tests such as immunohistochemistry, flow cytom-
plasms and low-grade malignancies, since patients etry, and molecular diagnostics [fluorescent in situ
with either type of neoplasm will be managed conser- hybridization (FISH) and polymerase chain reaction
vatively. It is very important, however, to separate (PCR)] yield more accurate results than any single
high-grade malignancies from benign neoplasms and modality alone (207–210).
38 Elsheikh et al.
B. Clinical Considerations dedicated needle passes can be performed for cell block
preparation to perform immunohistochemistry or
The workup of lymphadenopathy in the head and neck placed in transport media for flow cytometry, electron
region requires close clinicopathologic correlation to microscopy, and molecular diagnostic studies.
arrive at an appropriate differential diagnosis, includ- As with the evaluation of FNAB smears from
ing patient age, prior medical history, clinical symp- other organs, the use of both low- and high-power
toms including anatomic location, and chronicity. The magnification is recommended. Evaluation of the pre-
age of the patient is especially useful as the etiology of dominant pattern of cell dispersion, cell size, and
lympadenopathy is vastly different in children com- background elements provides important diagnostic
pared with adults. clues as to the etiology (Tables 25–30). The presence of
In the pediatric age group, FNAB is especially cohesive cell clusters raises the possibility of metast-
advantageous since tissue biopsy requires general atic carcinoma, certain HLs, NHLs, and granulomatous
anesthesia and the risk of potential morbidity, includ- inflammation, and even nonneoplastic lymphohistio-
ing scarring and cranial nerve injury. In this age cytic aggregates. Singly dispersed cells raise the dif-
group, the vast majority of cervical lymphadenopathy ferential diagnostic consideration of malignant
is due to reactive lymphoid proliferations, most of melanoma, primary lymphoid lesions, and poorly
which are associated with infectious etiologies. differentiated metastatic carcinomas. Monomorphic
Although much less likely, the possibility of a meta- singly dispersed cells are most often seen in malignant
static neoplasm must always be ruled out. The most
commonly metastasizing pediatric neoplasms include
small, round blue-cell neoplasms (neuroblastoma, Table 25 Lymph Node Aspirates with a Large-Cell Pattern
rhabdomyosarcoma, Ewing’s sarcoma, Wilms’ tumor) Metastatic carcinoma
and osteosarcoma that can be diagnosed by FNAB Malignant melanoma
(211). Malignant lymphomas of childhood include Germ cell tumors
high-grade lymphoblastic lymphoma, small non- Anaplastic large cell lymphoma
cleaved cell (Burkitt’s and non-Burkitt’s) lymphoma,
and intermediate-grade large cell lymphoma. In the
adolescents and young adults, metastases from germ Table 26 Lymph Node Aspirates with a Small-Cell Pattern
cell tumors, nasopharyngeal carcinomas, as well as
Reactive hyperplasias
Hodgkin lymphoma (HL) and NHL are most commonly Small lymphocytic lymphoma/chronic lymphocytic leukemia
seen (212). Mantle cell lymphoma
In adults, especially after the age of 40 years, Marginal-zone lymphoma
lymphadenopathy in the head and neck region due to Follicular lymphoma
a malignancy becomes the primary diagnostic consid- Burkitt’s lymphoma
eration. A clinical history of alcohol and tobacco usage Small cell carinoma
increases the likelihood of metastatic disease. FNAB is Sarcoma (rhabdomyosarcoma, Ewing’s/PNET, neuroblastoma)
highly accurate in the workup of patients with a Malignant melanoma
potential of metastatic squamous cell carcinoma and Lymphocyte-rich classical Hodgkin’s lymphoma
is, therefore, a widely used first-line diagnostic tech-
nique accepted by head and neck surgeons and oncol-
ogists (213). In patients with a past history of Table 27 Lymph Node Aspirates with a Squamous Pattern
malignancy, FNAB is especially useful for accurately
Metastatic squamous cell carcinoma
establishing metastatic disease. A history of an HIV Benign inclusion cysts
infection raises the differential diagnosis of reactive Branchial cleft cysts
lympadenopathies as well as malignant lymphoma. Germ cell tumors
Immunosuppression increases the possibility of Mucoepidermoid carcinoma
opportunistic infections, including mycobacterium Malignant melanoma, spindle variant
avium-intracellulare (MAI) and fungal infections such
as cryptococcus and histoplasma. Infectious processes
can be easily recognized by FNAB and additional Table 28 Lymph Node Aspirates with Biphasic Pattern (Small
material can be obtained for culture. and Large Cells)
Reactive hyperplasias
C. Diagnostic Approach Follicular lymphomas
Partial involvement of a lymph node by lymphoma
An on-site cytopathologist for immediate interpretation Lymphocyte-rich classical Hodgkin’s lymphoma
and appropriate triage of the aspirated specimen great- Classical Hodgkin’s lymphoma
ly increases the diagnostic accuracy of FNAB. Appro- T-cell-rich diffuse large B-cell lymphoma
priate triage also allows for a cost-effective workup of Malignant melanoma
lymphadenopathy of unknown origin. Immediate eval- Metastatic carcinoma (malignant mixed mullerian tumors)
uation of the aspirate can help categorize lesions as Germ cell tumors
inflammatory lesions or as an epithelial, primary lym- Sarcomas (malignant fibrous histiocytoma, synovial sarcoma)
Cat-scratch disease
phoid, or nonlymphoid nonepithelial neoplasm. On the
Toxoplasmosis
basis of this broad initial subcategorization, additional
Table 29 Lymph Node Aspirates with a Neutrophil Rich Pattern large numbers of lymphoglandular bodies arising from
the residual lymphoid cells.
Abscess
Inflammed inclusion cyst
Cat-scratch disease D. FNA of Non-Hodgkin Lymphomas
Metastatic carcinoma (squamous cell carcinoma)
Anaplastic large cell lymphoma Because of the extensive clinical overlap between non-
neoplastic reactions such as reactive lymphoid hyper-
plasia, lymphoma, and carcinoma, the use of FNA
Table 30 Lymph Node Aspirates with a Histiocyte-Rich Pattern
remains a controversial topic, especially for a primary
lymphoma diagnosis (204 ). Lymph node FNA has a
Infectious granulomas modest to high sensitivity (66–100%, average >80%),
Sarcoidosis high specificity (58–100%, average >90%), and high
Toxoplasmosis diagnostic accuracy (50–100%, average >85%) for
Cat-scratch disease
NHLs (199,204,207,208,214–219). In comparison, FNA
Kikuchi syndrome
Rosai-Dorfmann disease
of HL has a lower sensitivity (48–86%), but a similar
Langerhans’ cell histiocytosis high specificity rate (98–100%) (201,220–222). The use of
Germ cell tumors ancillary testing with flow cytometry, immunohis-
tochemistry, and molecular techniques has led to a
higher sensitivity and specificity and higher accuracy
for the diagnosis of lymphoid neoplasms by FNAB.
lymphomas compared with reactive lymphoid lesions, Additionally, the recent acceptance of the WHO classi-
which are polymorphic in appearance. The background fication scheme has allowed a more widespread use of
should be evaluated for necrosis, pigment, and lym- FNAB, since it places less importance on architecture
phoglandular bodies. The latter are an important clue and more emphasis on cytomorphology in combination
indicative of a lymphoid cell population and are char- with immunophenotype, genotype, and clinical char-
acterized as pale, basophilic rounded structures acteristics (204,205). Up to 85% of lymphomas may be
between 2 and 7 mm in size and representing fragments accurately classified by morphology alone, but total
of lymphocyte cytoplasm (Fig. 69) Lymphoglandular reliance on morphology can lead to misdiagnoses, such
bodies are seen in both reactive and neoplastic lym- as a large cell lymphoma misdiagnosed as a poorly
phoid proliferations, but their presence is a helpful clue differentiated carcinoma, HL mistaken for granuloma-
to differentiate lymphoid proliferations from other tous inflammation or a viral infection and finally, or an
small round-cell malignancies such as rhabdomyosar- overdiagnosis of a monomorphic lymphoid population
coma, Ewing’s sarcoma, and undifferentiated carcino- in a reactive hyperplasia as a small cell lymphoma (223).
mas. It must be kept in mind that partial involvement
of a lymph node by metastatic carcinoma may yield
E. Ancillary Studies
Cell Block and Core Needle Biopsy
Cell block and core needle biopsy (CNB) are important
diagnostic adjuncts in lymph node FNAB. The applica-
tion of IHC in paraffin embedded cell block prepara-
tions and/or CNBs is essential for an accurate
lymphoma diagnosis (219). The use of CD20 and CD3
immunostains can group most processes into broad
categories of B-cell dominance, T-cell dominance, or a
mixed B-cell and T-cell infiltrate. Additional more spe-
cific antibody panels can then be applied to B-cell and
T-cell processes for more specific classification. In situ
hybridization techniques for lambda and kappa light
chains have been successful in establishing clonality,
and show less nonspecific background staining com-
pared with conventional immunohistochemistry (224).
In patients at high surgical risk, CNB or a cell block is
particularly useful for evaluating lymphadenopathy. In
these cases, the tissue preparation can provide architec-
tural features important in the diagnosis of lymphoma.
The failure rate of core biopsy ranges from 14% to 58%
Figure 69 Lymphoglandular bodies (arrowheads) are pale, according to various studies (225–228).
basophilic rounded structures sized between 2 and 7 mm
and representing fragments of lymphocyte cytoplasm. They are
seen in both reactive and neoplastic lymphoid proliferations (DQ Flow Cytometry
stain, 400). Flow cytometry is critically important in lymph node
FNAB and has the distinct advantage of evaluating a
40 Elsheikh et al.
large population of cells. Flow cytometry allows Table 31 Key Diagnostic Features—Lymphoblastic Lymphoma
detection of small subpopulations of monoclonal
Cellular smears with dissociative cell pattern
cells and detection of low intensity expression of
Monotonous lymphoblasts with minimal cell variation (2 times
some markers that can be missed by IHC alone size of mature lymphocytes)
(210,229). Several studies have shown that the addi- Regular nuclei with minimal membrane convolutions; indistinct
tion of flow cytometry increases the sensitivity and nucleoli
accuracy of lymph node FNAB, especially in demon- Scant cytoplasm with or without minute vacuoles
strating B-cell clonality by kappa and lambda light
chain expression, a information that is vital for estab-
lishing a B-cell malignant lymphoma (178,207,208,
210,230,231). Nearly all small cell lymphomas show
clonality in FNAB specimens, especially in small
lymphocytic lymphoma (SLL) follicular lymphoma,
and mantle cell lymphoma (MCL). The combination
of CD19 with other antigens such as CD5, CD10,
CD23, and FMC7 allows phenotypic definition of
more specific lymphoma subtypes of B-cell origin
(231). In comparison, less than 50% of large B-cell
lymphomas show a monoclonal population by flow
cytometry (217,230). This may be due to a high fragil-
ity and lower viability of large lymphoma cells, a lack
of surface immunoglobulin light chain expression,
extensive necrosis, and fibrosis.
Flow cytometry can also be limited by low
cellularity of the sample, as well as occasional prob- Figure 70 Aspirates from lymphoblastic lymphoma are cellular
lems with nonspecific staining (217). Therefore, it and composed of a dispersed monomorphic population of small
must be interpreted in the context of the cytomorpho- to intermediate-sized lymphoblasts (DQ stain, 400).
logic findings from FNAB to avoid pitfalls such as
coexisting neoplastic and reactive cells in the speci-
men. It is important to recognize that the lack of adolescent males. The anterior mediastinum is the
identification of a monoclonal population does not most common location (50–80%) although, many
rule out a malignant lymphoma. In clinically suspi- patients have supraclavicular or cervical lymphade-
cious cases, additional sampling or tissue biopsy nopathy with most showing involvement of multiple
should be recommended. HL cannot be reliably diag- lymph nodes. FNAB had a high diagnostic accuracy
nosed by flow cytometry. for this entity. Smears are highly cellular, with a
monotonous lymphoid cell population composed of
FISH and PCR medium-sized cells with a blast morphology, round
FISH and PCR studies have shown that sufficient nuclei, finely granular chromatin, inconspicuous
material can be obtained with FNAB for analysis nucleoli, and scant cytoplasm (Fig. 70). Individual
(232). FISH analysis can be performed on air-dried cell necrosis may be seen and tingible body macro-
cytologic smears, cytospins prepared from cell sus- phages may be numerous, imparting a ‘‘starry sky’’
pensions, or destained archival cytologic smears. appearance typical of an aggressive lymphoma.
More consistent results are obtained from cytospin Mitotic activity is brisk. Phenotypically, the majority
preparations as the cell suspension is concentrated are of T-cell lineage, characterized by surface and/or
and evenly distributed on the slide. FISH studies for cytoplasmic expression of CD3, other T-cell lineage
cyclin-D1 and Bcl-2 can be useful for confirming markers, and TdT. There is often co-expression of CD4
mantle cell lymphoma (MCL) and follicular lympho- and CD8, with some cases expressing CD10. Myeloid
ma, respectively (232,233). PCR can reliably detect antigens such as CD13 and CD33 are often present
immunoglobulin gene rearrangement, Bcl-2 gene rear- and CD45 may be absent. Molecular testing demon-
rangement, and T-cell receptor gene rearrangement strates T-cell receptor gene rearrangements in approx-
from material obtained via FNAB. Other new technol- imately one-third of lymphoblastic lymphomas. Other
ogies recently applied to FNA include real-time PCR, differential considerations include Burkitt’s lymphoma,
automated DNA sequencing that aids in detecting any the blastoid variant of MCL, acute myeloid leukemia/
false-positives, and gene expression profiling to aid in chloroma, and other high-grade malignancies, includ-
subtyping lymphomas (234–236). ing metastatic carcinomas and sarcomas. Differ-
entiating lymphoblastic lymphoma from small cell
carcinoma often requires immunostaining for cytoker-
F. FNAB of Selected Non-Hodgkin Lymphomas atins and neuroendocrine markers.
Lymphoblastic Lymphoma
Burkitt’s Lymphoma
Lymphoblastic lymphoma (Table 31) is an aggressive,
rapidly growing neoplasm that comprises up to 50% Burkitt’s lymphoma (Table 32) is a highly aggressive
of lymphomas of childhood, most often affecting undifferentiated lymphoma closely associated with
Table 32 Key Diagnostic Features—Burkitt’s Lymphoma

Highly cellular smears with dispersed cell pattern
Monomorphic cell population; cells 2–3 times size of mature
lymphocyte
Basophilic cytoplasm with many lipid filled vacuoles
Nuclei with coarse granular chromatin and 1–4 nucleoli
Cell necrosis imparting a ‘‘dirty’’ background
Scattered tingle-body macrophages mimicking ‘‘starry sky’’
pattern
the Epstein-Barr virus (EBV) that is a potentially

curable neoplasm with a distinct chemotherapeutic
regimen. Cervical lymph node presentation is seen
in only a small percentage of patients. FNAB smears
from Burkitt’s lymphoma are highly cellular with a
uniform population of intermediate-sized cells with
round nuclei, coarse chromatin, and prominent nucle-
Figure 72 A core needle biopsy from Burkitt’s lymphoma con-
oli that are usually multiple. Characteristic peripheral
tains numerous background tingible body macrophages impart-
cytoplasmic vacuoles are an important diagnostic clue ing a ‘‘starry sky’’ appearance (H&E stain; magnification, 200).
for Burkitt’s lymphoma and are almost always present
on Romanowsky-type stains (Fig. 71). The background
contains numerous tingible body macrophages
imparting a starry-sky appearance, mitoses, and apo-
Diffuse Large B-Cell Lymphoma
ptotic cells, indicating a high proliferation rate
(Fig. 72) (178). Immunophenotypically, Burkitt’s lym- DLBCL comprises 30% to 40% of adult NHL, can
phoma shows a B-cell phenotype with monoclonal occur at any age, and is an aggressive but potentially
surface immunoglobulin light chain and CD10 expres- curable neoplasm. FNAB smears from DLBCL contain
sion. This phenotype is indistinguishable from a fol- a monomorphic population of large cells with vesicular-
licular lymphoma and, therefore, differentiation cleaved or noncleaved nuclei that are two to three
between the two lymphomas is based on the cytomor- times the size of a reactive lymphocyte (Figs. 73 and
phologic features. Burkitt’s lymphoma demonstrates a 74, Table 33). Cells typically contain multiple nucleoli
mature B-cell phenotype without expression of TdT and a moderate amount cytoplasm. Variable numbers
and CD34, which separates it from lymphoblastic of background tingible body macrophages are seen.
lymphoma. Genetically, all Burkitt’s lymphoma har- The most common cytomorphologic appearance of
bors a rearrangement of the c-myc proto-oncogene on DLBCL is the centroblastic type (205). Rare variants
chromosome 8. The most common translocation is of DLBCL include immunoblastic, plasmablastic, and
t(8;14), which occurs in 80% and involves the immu-
noglobulin heavy chain gene on chromosome 14. The
less common types include t(2;8) and t(8;22). These
translocations are demonstrable by FISH (237). The
c-myc rearrangement can also be seen in other lym-
phomas such as diffuse large B-cell lymphoma
(DLBCL), lymphoblastic lymphoma, and multiple
myeloma. Therefore, diagnosis of Burkitt’s lymphoma
requires correlation of the clinical, morphologic,
immunophenotypic, and cytogenetic findings.
Figure 73 An aspirate from a diffuse large B-cell lymphoma

Figure 71 In Burkitt’s lymphoma, uniform intermediate-sized with proliferation of numerous large, noncleaved lymphocytes
malignant lymphoid cells are seen with numerous small, round with a few smaller mature lymphocytes in the background (DQ
cytoplasmic vacuoles (DQ stain; oil magnification, 600). stain; oil magnification, 600).
42 Elsheikh et al.
diffuse pattern is essential since a nodular process may

indicate a high-grade follicular lymphoma. A B-cell
phenotype is generally established by CD20 immuno-
histochemical studies but patients who previously
received rituximab (anti-CD20 antibody) treatment
may completely lose CD20 expression in the lympho-
ma cells. However, other B-cell markers such CD79a or
Pax5 can be used for immunophenotyping.
Immunoblastic Lymphomas
Immunoblastic lymphomas are more often seen in
adults than in children. The aspirates yield highly
cellular smears containing numerous immunoblasts
with extreme pleomorphism and scattered multinucle-
ated giant cells. Nuclei often exhibit a plasmacytoid
appearance with eccentric vesicular nuclei with a
prominent central macronucleolus, and abundant cyto-
plasm (Fig. 74). Mitotic activity is brisk and the back-
ground contains mixed inflammatory cells including
Figure 74 The nuclei from diffuse large cleaved B-cell lympho- eosinophils, plasma cells, lymphocytes, and histiocytes.
mas show nuclear clefting and indentations and smaller mature
lymphocytes are present in the background (DQ stain; oil mag-
nification, 600).
Anaplastic Large Cell Lymphoma
Anaplastic large cell lymphoma (ALCL) (Table 34)
accounts for 3% of adult NHL and 10% to 30% of
childhood lymphomas. Aspirates may be polymor-
Table 33 Key Diagnostic Features—Diffuse Large B-Cell phic due to partial involvement of lymph nodes
Lymphoma where the neoplastic cells may be confined to the
Monomorphic large cells with a minority of small lymphocytes sinusoids thus leading to potential sampling errors.
Cells 3 or more times the size of mature lymphocytes Generally, FNAB smears are characterized by large,
Large pleomorphic nuclei; round to irregular to multilobated and pleomorphic cells, often with a horseshoe-shaped
bizarre shaped nucleus (so-called ‘‘hallmark’’ cells) (Fig. 75)
Conspicuous nucleoli; single or multiple (178,239–242). Necrosis may be prominent (241). Var-
Moderate to abundant cytoplasm iants include the small cell type, the lymphohistiocytic
Necrosis and tangible body macrophages common variant, in which a large number of histiocytes may
Morphologic variants: centroblastic, anaplastic, immunoblastic,
mask the large tumor cells, the rare signet cell variant,
T-cell rich
the neutrophil-rich variant, and the sarcomatoid vari-
ant. Binucleate, Reed-Sternberg-like cells may be seen,
and have been mistaken for lymphocyte-depleted HL
anaplastic types (205). In cases with a mixture of small (Fig. 76) (243).
and large cells, caution should be taken, and ancillary Immunophenotyping of ALCL shows that cells
tests such as flow cytometry and IHC should be care- are usually of T-cell lineage. It is somewhat unique in
fully evaluated to rule out any small cell lymphomas. that CD3, CD5, and CD7 expression are usually lost
Nearly all DLBCL expresses pan B-cell markers such as and usually the only indication of T-cell differentia-
CD19, CD20, CD22, CD79a, and Pax5. Demonstration tion is expression of CD2 and CD4. Occasional cases
of a large cell predominant lymphoma with expression are immunophenotypically null cell type, but show
of one or more of these markers is sufficient for a rearrangement of the T-cell receptor genes. ALCL
diagnosis. Other than pan B-cell antigens, DLBCL also expresses CD30 in either a membranous or
usually lacks specific antigen expression (238). An Golgi pattern, in addition to epithelial membrane
MCL can be ruled out by a predominance of large
cells with centroblast morphology and lack of cyclin D1
expression or rearrangement. A definitive diagnosis of Table 34 Key Diagnostic Features–Anaplastic Large Cell
DLBCL by FNA usually requires the demonstration of Lymphoma
clonality, which can be achieved by flow cytometry or Moderate to high cellularity smears
PCR. Since flow cytometry has become a routine pro- Predominant large malignant cells with marked pleomorphism
cedure in lymph node FNA in many institutions, Multinucleation common with mirror image Reed-Sternberg-like
establishment of clonality should be first attempted cells
by this method. Detection of a clonal B-cell population ‘‘Hallmark’’ cells: large cells with eccentric indented nuclei, small
by flow cytometry also rules out HL. A concurrent core nucleoli, prominent golgi zone and abundant cytoplasm
needle biopsy (CNB) is a useful adjunct to FNA in the Intranuclear inclusions, nuclear membrane convolutions,
diagnosis of DLBCL because sufficient material to conspicuous nucleoli
Abundant cytoplasm with fine to coarse vacuoles
render a definitive diagnosis can usually be obtained
Lack or absence of other lymphoid cells on smears
when FNAB is nondiagnostic (212). Observation of a
antigen (EMA) and T-cell intracellular antigen (TIA)-1.

This staining pattern can lead to a confusion with
metastatic carcinoma or HL. Genetically, 60% to 85%
of ALCL are associated with the translocation t(2;5)
(p23;q35), which results in expression of the anaplastic
lymphoma kinase (ALK) protein which can be dem-
onstrated either by flow cytometry or by IHC on cell
block preparations (178,239) ALK-positive ALCL is
most common in children and young adults with a
marked male predilection and is associated with a
better prognosis (239). By contrast, ALK-negative neo-
plasms are seen in older patients and with no gender
predilection (239).
The presence of large neoplastic cells in a lymph
node aspirate raises the differential diagnosis of
ALCL, large cell lymphoma, HL, metastatic carcino-
ma, embryonal carcinoma, lymphoblastic lymphoma,
sarcoma, and some peripheral T-cell lymphomas.
Embryonal carcinoma, HL, and many metastatic car-
Figure 75 A core needle biopsy from anaplastic large cell cinomas commonly express CD30. Rare examples of
lymphoma illustrating large pleomorphic cells, some with a each of the other entities in this differential may also
horseshoe shape (‘‘hallmark cells’’, center of field) (H&E stain; express CD30. A polymorphous lymphoid back-
magnification, 400). ground is seen in both HL and ALCL and can lead
to a misdiagnosis (244). Both HL and ALCL show
CD30 reactivity, but the higher proportion of larger
atypical cells may be helpful in identifying ALCL. In
cases where the atypical cells are confined to subcap-
sular sinuses, the findings on FNAB and excision of
the lymph node will simulate metastatic carcinoma or
primary HL (240).
G. B-Cell Non-Hodgkin Lymphoma

of Small Cell Type
In the WHO classification, this category includes SLL,
MCL, follicular center cell lymphoma, marginal zone
lymphoma (MZL), and lymphoplasmacytic lympho-
ma (LPL) (205). All demonstrate smears with small,
mature-appearing lymphocytes and all may contain
larger cells, such as immunoblasts (SLL and MZL),
plasma cells (LPL), histiocytes (in MCL), centroblasts,
and dendritic cells (in follicular lymphoma). The
entities are distinguished by a combination of mor-
phology, immunophenotype, and cytogenetics
Figure 76 The presence of binucleate, Reed-Sternberg-like (Table 35) (212). In general, FNAB has a high sensitiv-
cells in cases of anaplastic large cell lymphoma can raise the ity for diagnosis and classification of SLL, low-grade
possibility of lymphocyte-depleted Hodgkin lymphoma (DQ stain; follicular lymphoma , MCL, and LPL. FNAB, however,
oil magnification, 600). has been less reliable for the diagnosis of MZL
(207,216,217,231).
Table 35 Immunophenotyping of Small B-Cell Lymphomas (WHO Classification)

Small lymphocytic Mantle cell Follicular Marginal-zone
Immunophenotype lymphoma lymphoma lymphoma lymphoma
CD5 þ þ – –
CD10 – –/þ þ/– –
CD23 þ – –/þ –
Cyclin D1 – þ – –
CD43 þ þ – –/þ
Cytogenetics trisomy 12 t(11;14) t(14;18)
Source: Modified from Ref. 212.
44 Elsheikh et al.
Small Lymphocytic Lymphoma Mantle Cell Lymphoma

SLL is most often seen in older adults, with a male MCL is seen in adults over 50, with men affected twice
predominance. Patients usually have diffuse lymph- more often than women, and it is more aggressive than
adenopathy at the time of diagnosis and with involve- other small cell lymphomas. Unlike other small cell
ment of both peripheral blood and bone marrow. The lymphomas, it tends to present at a higher stage and
clinical disease course is often indolent but progres- commonly found in extranodal sites such as spleen and
sive. Aspirates are generally highly cellular and are bone marrow. FNAB from MCL is characterized by a
characterized by a monomorphous population of monomorphous small cell population with scant cyto-
small, mature-appearing lymphocytes with smooth plasm, resembling centrocytes (212,248,249). Nuclear
nuclear borders, clumped chromatin, and scant cyto- chromatin is fine and evenly dispersed, and slightly
plasm (Fig. 77) (245). Mitotic figures and nucleoli are irregular nuclear outlines than those in SLL are seen.
generally absent. A small component of larger cells, Large transformed cells such as centroblasts and immu-
including prolymphocytes with a distinct nucleolus noblasts are usually no seen as in other small cell
and more cytoplasm as well as paraimmunoblasts lymphomas. Histiocytes are commonly seen in MCL,
with a more prominent nucleolus and more basophilic but tingible body macrophages are rarely found.
cytoplasm, can be seen and may be confused with Several morphologic variants have been described in
Reed-Sternberg cells of HL. Tingible body macro- MCL. The blastoid variant is most common and is
phages and lymphohistiocytic aggregates are usually characterized by neoplastic cells that are intermediate
absent. Because of the predominance of small, mature- to large in size, resemble lymphoblasts and demonstrate
appearing lymphocytes, SLL can be an important nuclei with slightly irregular contours, fine evenly
cause of a false-negative FNA. Transformation to distributed chromatin, and several small distinct nucle-
large cell lymphoma (Richter’s syndrome) can occur oli. It is important to differentiate blastic MCL from
in 10% to 20% of cases. Features suggestive of trans- lymphoblastic lymphoma (250).
formation include increased numbers of prolympho- Flow cytometry is an essential component in the
cytes and paraimmunoblasts, increased mitotic figures, FNA diagnosis of MCL, which expresses a monoclo-
and the presence of apoptosis and necrosis (246). nal B-cell phenotype with a high intensity of surface
Immunophenotyping of SLL shows low-intensity B-cell antigens and immunoglobulin light chain (212).
CD20 and immunoglobulin light chain expression, MCL shows a characteristic CD5-positive/CD23-
and coexpression of CD5 and CD23, the latter combi- negative immunophenotype. Almost all cases of
nation being highly specific for SLL. Caution should be MCL are associated with a translocation involving
given when CD23 expression is low or heterogeneous, cyclin D1 and immunoglobulin heavy chain genes, t
which can be seen in MCL. The presence of trisomy 12 (11;14)(q13;32), leading to upregulation of the cyclin
or deletion of 13q14 (RB1) favors SLL. These chromo- D1 protein. The nuclear expression of cyclin D1 can be
some abnormalities can be demonstrated by FISH on detected on cell block preparations or on air-dried
FNAB smears (216,247). smears by immunohistochemistry (178). FISH is the
method of choice in detecting cyclin D1 rearrange-
ment at the genomic level and has been successfully
performed on FNAB material (251).
A definitive diagnosis of MCL by FNAB requires
a combination of typical cytomorphologic findings, a
monoclonal B-cell population, CD5-positive/CD23-
negative phenotype, and demonstration of cyclin D1
overexpression or rearrangement (232,251). The mor-
phologic and phenotypic overlap between MCL and
SLL can be a challenge for distinguishing between
these entities by FNAB findings alone.
Follicular Lymphoma
Follicular lymphoma is also generally seen in patients
over 50 with a slight female predominance. As with
MCL, follicular lymphoma tends to be widely dissem-
inated at the time of diagnosis. FNAB smears are
characterized by small, irregular lymphocytes with
notched and convoluted nuclei (centrocytes), few
associated tingible body macrophages, and lymphoid
Figure 77 Aspirates from small lymphocytic lymphomas are cell aggregates (212). Larger-cleaved and noncleaved
characterized by a monomorphous population of small, mature- lymphocytes are also seen and appear in proportion to
appearing lymphocytes with smooth nuclear borders, clumped the grade. Often there is enough material on a cell
chromatin, and scant cytoplasm (DQ stain; oil magnification, block preparation to appreciate a follicular architec-
600). ture. Immunohistochemical stains are useful to dem-
onstrate CD21-positive dendritic cells within follicles
and CD3-positive T cells at the periphery of follicles.

A definitive diagnosis of follicular lymphoma requires
the presence of centrocytes, centroblasts, and B-cell
monoclonality. Centrocytes (also known as small-
cleaved cells) are characterized by small, irregular
lymphocytes with notched and folded nuclei, indis-
tinct nucleoli, and scant cytoplasm. Centroblasts (also
known as large noncleaved cells) have large round or
oval nuclei with open chromatin and several small,
membrane-bound nucleoli and amphophilic cyto-
plasm (212).
The diagnosis of follicular lymphoma requires
either expression of CD10 by flow cytometry on the
neoplastic cells or evidence of Bcl-2 rearrangement, a
result of the translocation t(14;18)(q32;q21) that is seen
in 70% to 95% of cases of follicular lymphoma and can
be demonstrated at the genomic level by either FISH
or PCR (252). It must be remembered that the Bcl-2
rearrangement is not unique to follicular lymphoma ,
as a subset of DLBCL also shows this translocation. Figure 78 A binucleated Reed-Sternberg cell in a mixed inflam-
Therefore, a combination of cytomorphology and flow matory background from a case of Hodgkin lymphoma (DQ stain;
cytometry more accurately separates low-grade lym- oil magnification, 600).
phomas from DLBCL. Transformation of follicular
lymphoma to LBCL occurs in 25% to 35% of patients
and is associated with treatment failure and rapid
progression. Since follicular lymphoma is often wide- fifth category is nodular lymphocyte predominant
spread at the time of diagnosis and transformation HL, comprising approximately 5% of cases.
may only occur in some nodes and not others, FNAB Classical HL. Classical HL accounts for 95% of
has the advantage of allowing for multiple site sam- cases. There is an association with prior infectious
pling whereas obtaining multiple open biopsies mononucleosis. The majority of patients present with
would not be feasible (253). mediastinal and cervical lymphadenopathy, which is
typically painless. The key to an FNAB diagnosis of
HL is the identification of Reed-Sternberg cells in a
H. FNAB of Hodgkin Lymphoma mixed background of non-neoplastic cells (Fig. 78).
Hodgkin Lymphoma The classic Reed-Sternberg cell is binucleate, with
prominent nucleoli, often the size of an RBC. These
HL accounts for approximately 30% of all lymphomas cells are very large measuring between 40 and 100 mm.
and generally affects young adults, with a second However, Reed-Sternberg cells are generally the
peak in middle-aged patients. Supraclavicular, cervi- minority population in a polymorphous background
cal, and mediastinal lymph nodes are most often composed of non-neoplastic lymphocytes, eosino-
affected and generally, a small number of neoplastic phils, neutrophils, histiocytes, plasma cells, and fibro-
cells (Hodgkin and Reed-Sternberg cells) are seen in a blasts. This admixture of background cells is common
predominant heterogeneous background of nonneo- to all HL subtypes and granulomas may also be seen.
plastic cells (Table 36). There are four subtypes of In general, tingible body macrophages or lymphohis-
classical HL: nodular sclerosis, lymphocyte-rich, tiocytic aggregates are not seen, but exceptions
mixed cellularity, and lymphocyte-depleted. The include partial node involvement by HL and the
nodular lymphocyte predominant form (212). Immu-
nophenotypically, the Reed-Sternberg cells of classical
Table 36 Key Diagnostic Features—Hodgkin Lymphoma HL are CD15-positive, CD30-positive, CD20-negative,
CD45-negative, and EMA-negative. Because of the
Smear celluarity variable from highly cellular to hypocellular
Presence of enlarged mononuclear Reed-Sternberg variants in a paucity of neoplastic cells, flow cytometry has not
lymphoid background proven useful in the diagnosis of HL. Flow cytometry
Mononuclear Reed-Sternberg variants: enlarged four times or usually detects the background polyclonal lympho-
more size of mature lymphocytes, bosselated nuclear cytes because the diagnostic Reed-Sternberg cells are
contours, prominent enlarged nucleoli too few to be analyzed.
Classic binucleate Reed-Sternberg cells represent 0.1–1% of all Compared with NHLs, the FNA diagnosis of HL
cells in classic Hodgkin lymphoma remains highly controversial. In general, for patients
Differential diagnosis of Reed-Sternberg cells: without a previous history of HL, a definitive diagno-
Immunoblasts sis of HL by FNAB requires identification of multinu-
Anaplastic large cell lymphoma cleated, classic Reed-Sternberg cells or Reed-Sternberg
Malignant melanoma cell variants in an appropriate inflammatory back-
Pleomorphic sarcoma ground, and demonstration of appropriate antigen
Large cell carcinoma
expression by IHC on cell block preparations using
46 Elsheikh et al.
demonstration of T-cell antigen or ALK expression

virtually rules out HL. LBCL may express CD30 in as
many as 70% of cases and the tumor cells typically
lack surface immunoglobulin expression. In contrast
to HL, LBCL is more monomorphous and lacks an
inflammatory background. Strong, uniform expres-
sion of one or more B-cell antigens favors LBCL.
A small portion of nodular sclerosis HL contains
confluent sheets of large cells known as the syncytial
variant of HL. In such cases, FNAB smears are domi-
nated by flat sheets of large Reed-Sternberg variant
cells in a pleomorphic background leading to a mis-
diagnosis of metastatic carcinoma in some cases.
I. FNAB of Metastatic Neoplasms

to Cervical Lymph Nodes
Most cervical lymph nodes with metastases are four
times larger in size than normal lymph nodes. FNAB
Figure 79 Mononuclear Reed-Sternberg cell variants with is the preferred method for the initial evaluation of
prominent nucleoli are commonly seen. Their presence in a adult patients with enlarged lymph nodes with an
mixed inflammatory cell background should strongly suggest overall diagnostic accuracy of 96% for carcinomas and
Hodgkin lymphoma (DQ stain; oil magnification, 600).
100% for malignant melanomas (200,213). Metastatic
disease is by far a more common cause of cervical
lymphadenopathy than malignant lymphomas, espe-
cially in patients older than 50 years. Use of ancillary
CD20, CD30, CD15 and CD45 (254). For patients with
techniques (i.e., immunostains on cell block prepara-
recurrent disease, the identification of RS cells or its
tions) permits histologic subtyping and can determine
variants in a proper inflammatory background is
the primary site.
sufficient for diagnosis (Fig. 79). A concomitant CNB
can be a very useful addition to FNA. An adequate
Squamous Cell Carcinoma
CNB can provide valuable architectural information
such as nodularity and fibrosis in the nodular sclerosis Squamous cell carcinoma is the most common malig-
subtype of classical HL. A full panel of IHC can then nancy to metastasize to head and neck lymph nodes
be performed on the CNB to confirm the diagnosis. accounting for 90% of malignancies arising at this site.
The cytologic differential diagnosis of HL Most are found in patients older than 40 years age and
includes reactive hyperplasia, T-cell-rich large B-cell those with a history of alcohol and tobacco use. These
lymphoma, anaplastic large cell lymphoma, metastatic lesions can be cystic in nature presenting some unique
carcinoma, and metastatic melanoma (222). A false- diagnostic difficulties. Aspirates from cystic squa-
negative FNAB diagnosis may result from the aspira- mous cell carcinomas are often of low cellularity
tion of inadequate numbers of diagnostic Reed-Stern- containing anucleated cells or cells with only mild
berg cells because of partial involvement of the node cytologic atypia, with background abundant proteina-
or sampling of a fibrotic process such as a case of ceous or necrotic debris. The background often con-
nodular sclerosis HL. In a clinically suspicious case, a tains neutrophils and/or lymphocytes. Identification
careful search for Reed-Sternberg cells is necessary. of neoplastic squamous cells is critical in distinguish-
The relative paucity of Reed-Sternberg cells in most ing metastases from soft tissue abscesses or an
forms of HL (even with adequate sampling) can still inflamed branchial cleft cyst. The presence of necrotic
lead to the misdiagnosis of a reactive hyperplasia. debris with associated acute inflammation should
Conversely, certain reactive and neoplastic conditions, suggest a malignancy.
such as Epstein-Barr infection, NHLs (i.e., ALCL), and Smears obtained for metastatic squamous cell
certain immunosuppression states may contain large carcinomas show high cellularity arranged in cohesive
atypical cells resembling Reed-Sternberg cells leading flat sheets, nests of cells and/or single cells occasion-
to a false-positive diagnosis. It is therefore recom- ally with spindle to irregular shaped cells (Figs. 80
mended that any FNAB smear containing granuloma- and 81). Variable keratinization can be identified best
tous inflammation be evaluated carefully for Reed- on Papanicolaou-stained smears. Individual kerati-
Sternberg cells. CD15 can stain some carcinomas, and nized malignant cells can be found in most smears
some cases of HL can express EMA leading to a with bizarre shapes such as tadpole and spindle
misdiagnosis of metastatic disease. Among lymphoid shapes. The degree of cellular atypia varies with
neoplasms, the important differential diagnoses of HL well-differentiated carcinomas demonstrating only
include ALCL and LBCL (Table 36). Cytologically, slight nuclear enlargement and atypia, whereas poorly
ALCL cells are indistinguishable from Reed-Sternberg differentiated carcinomas demonstrated marked pleo-
cells (Fig. 76). Phenotypically, ALCL expresses strong morphism, nuclear enlargement, and nuclear irregu-
CD30 and may express weak CD15. In these cases, larities. Distinct nuclear membranes, moderate to
Figure 80 Aspirate from a metastatic keratininzing squamous

cell carcinoma. The cytoplasm is deep blue in DQ-stained
sections. Note the ‘‘dirty’’ background which is often see with Figure 82 Aspirate from a case of metastatic nasopharyngeal
metastases from squamous cell carcinomas (DQ stain; magnifi- carcinoma with cohesive clusters of malignant epithelial cells and
cation, 400). a few scattered lymphocytes in the background (DQ stain;
cells within a background of reactive lymphoid cells

(Fig. 82). Individual malignant cells with marked
nuclear pleomorphism can also be seen dispersed
among the non-neoplastic lymphoid cells (255). A
small percentage can show squamous cell differentia-
tion with a basaloid appearance. Differential diagnostic
considerations include malignant lymphoma and in
young patients, embryonal carcinoma. Positive immu-
nostains for cytokeratin and negative stains for CD45 can
confirm the epithelial nature of a nasopharyngeal carci-
noma. Most cases of embryonal carcinoma will show
positive staining with a fetoprotein, and CD30 and
scattered b-human chorionic gonadotrophin (b-HCG)
positive syncytiotrophoblasts.
Thyroid Carcinoma
Thyroid carcinoma metastases are a significant cause of
Figure 81 Large cohesive clusters of malignant cells, some
with a spindled pattern, from a lymph node aspirate containing
cervical lymphoadenopathy, and papillary carcinoma of
metastatic squamous cell carcinoma (DQ stain; magnification, the thyroid can initially present with cervical adenop-
400). athy in more than 10% of patients (256). Cytologically,
the smears demonstrate small clusters of neoplastic cells
with characteristic cytomorphologic features of papil-
lary carcinoma (nuclear grooves and intranuclear inclu-
abundant cytoplasm and retention of some cohesive sions best identified on Papanicolaou-stained smears)
clusters are seen even in nonkeratizing squamous cell (Fig. 83) (256). Occasionally, colloid may be seen in the
carcinomas. background. Medullary carcinoma can also be a source
of metastases to cervical lymph nodes.
Nasopharyngeal Carcinoma
Malignant Melanoma
Nasopharyngeal carcinoma exhibits a bimodal age
distribution with peaks during the second and sixth Malignant melanoma often metastasizes to cervical and
decades of life, with males being affected 2.5 times more supraclavicular lymph nodes even when the primary
often than females, and is associated with EBV infection site is unknown. FNAB smears are highly cellular with
(255). Asians are more often affected than Caucasians. loosely cohesive and singly dispersed cells with a wide
Patients often present with nasal symptoms in combi- range of cytologic features including spindle cell, epi-
nation with cervical lymphadenopathy. FNAB smears thelioid, plasmacytoid, small cell like, and giant cell
demonstrate high cellularity with clusters and sheets of morphologies (Figs. 84–86). Metastatic melanoma often
48 Elsheikh et al.
Figure 83 Fine needle aspirate from a metastatic papillary Figure 85 Lymph node aspirate from metastatic malignant
carcinoma demonstrating a papillary cluster of malignant cells melanoma with a discohesive population of large malignant
with slight nuclear enlargement and nuclear grooving (arrow) cells mimicking a lymphoma (DQ stain; magnification, 400).
(Papanicolaou stain; magnification, 400).
Figure 84 Aspirate from metastatic malignant melanoma with Figure 86 Loosely cohesive clusters of malignant plump plas-
large cohesive sheets and clusters of spindle-shaped cells (DQ macytoid cells from an aspirate of metastatic malignant melanoma
stain; magnification, 200). (DQ stain; magnification, 600).
shows a singly dispersed cell pattern similar to NHLs phragm. Primary sites of origin are from malignancies
(Fig. 85). Macronucleoli and nuclear pseudoinclusions above and below the diaphragm including the lung,
are often seen. Melanin pigment is only seen in a breast, stomach, prostate, ovary, colon, biliary tract,
minority of cases. In cases where a primary melanoma pancreas, and uterus. FNAB is valuable for document-
diagnosis has not been established, confirmation with ing metastases from inoperable lung carcinomas to
immunostains (HMB-45, MART-1, S-100) on cell block this site. In women with cervical carcinoma, supra-
material will be necessary. clavicular lymph node metastases most often show
squamous cell carcinoma and may be the only site of
Supraclavicular Lymph Node Metastases
extension outside the pelvis and abdomen, portending
a poor prognosis. Metastatic breast carcinoma must be
Left supraclavicular lymph node metastases often considered when evaluating aspirates from women, as
originate from malignancies arising below the (often lymph node status is a critical predictor of clinical
referred to as Virchow’s node) clavicle or the dia- outcome. Immunocytochemical staining for estrogen
and progesterone receptors in FNA samples from

metastatic breast carcinoma have been successfully
performed on formalin-fixed cell block preparations
and on Papanicolaou-stained slides. In men, dissemi-
nated disease from prostate carcinoma may first pres-
ent with supraclavicular lymphadenopathy. The
appearance is most often that of an adenocarcinoma.
Virchow’s node is often also the site of gastrointestinal
metastases. Demonstration of intracytoplasmic mucin
by immunostaining on cell block material can exclude
adenocarcinomas of liver, renal, adrenal, and thyroid
origin as well as lymphoma, sarcoma (except chor-
doma), and melanoma. The use of cytokeratins 7 and
20 and staining for tumor specific antigens and tran-
scription factors can aid in determining the origin of a
metastatic adenocarcinoma.
J. FNAB of Selected Nonneoplastic

Lymphadenopathies Figure 87 A mixed lymphoid cell population characteristic of
Reactive Lymphoid Hyperplasia reactive lymphoid hyperplasia is seen in this aspirate (DQ stain;
Reactive lymphoid hyperplasia is commonly found in
aspirates from enlarged cervical lymph nodes and the
most important differential diagnostic entity with
malignant lymphoma. FNAB smears of reactive hyper- recognize that the lack of a monoclonal population does
plasia demonstrate high cellularity with a heteroge- not rule out malignant lymphoma, especially HL. Thus,
neous population of lymphoid cells, including small when presented with a heterogeneous lymphoid popu-
mature-appearing lymphocytes, larger immunoblasts, lation on FNAB smears, it is crucial to search carefully
dendritic cells, follicular center cell fragments (lympho- for Reed-Sternberg cells and in clinically suspicious
histiocytic aggregates), and tingible body macrophages cases, additional sampling or tissue biopsy should be
(Table 37) (Fig. 87) (219,257). Small mature appearing performed for a definitive diagnosis (217).
lymphocytes are the dominant cell population. The When small, mature-appearing lymphocytes
presence of a polymorphic lymphoid population predominate in aspirates from reactive hyperplasia,
including the presence of follicular center cell fragments confusion with an SLL can occur (Fig. 88). However,
and tingible body macrophages are important diagnos- SLLs do not show the full spectrum of small to large
tic clues to the reactive nature of the proliferation. lymphocytes that is characteristic of a reactive process.
However, this heterogeneous population of cells can
also be misleading and found in highly proliferative
malignant lymphomas raising a wide differential diag-
nosis that includes HL, SLL, follicular lymphoma, T-cell
rich B-cell lymphoma, T-cell lymphoma, and partial
involvement of a lymph node by metastatic neoplasms.
Ancillary studies, including immunohistochemical
stains and flow cytometry, are crucial for ruling out a
malignant lymphoma (178,229). Material obtained for
flow cytometry offers the advantage of evaluating a
large population of cells, thereby allowing the detection
of small subpopulations of monoclonal cells and/or low
intensity expression of some markers that may be
missed by immunohistochemistry. A reactive process
is characterized by a polyclonal lymphocyte population
and an admixture of B and T cells. It is important to
Table 37 Key Diagnostic Features–Reactive Lymphoid

Hyperplasias
Moderate to highly cellular smears
Polymorphic lymphoid population Figure 88 Some cases of reactive lymphoid hyperplasia are
Single cell dispersed pattern dominant dominated by small lymphocytes raising the differential diagnosis
Follicular center cell fragments common of a small lymphocytic lymphoma. Note the numerous back-
Tingle body macrophages common ground lymphoglandular bodies indicative of a lymphoid process.
Lymphoglandular bodies in background
50 Elsheikh et al.
Figure 89 Aspirate from a case of suppurative lymphadenitis Figure 90 Well formed noncaseating granuloma from a case of
containing numerous polymorphonuclear leukocytes in a back- sarcoidosis that is composed of cohesive ‘‘boomerang-’’shaped
ground containing a mixed lymphoid population. histiocytes (DQ stain; magnification, 400).
Cellular crush artifact can cause difficulty in distinguish- histiocytes possess moderate cytoplasm and a single
ing small lymphocytes from a small cell carcinoma, or elongated, bent (‘‘boomerang’’)-shaped nucleus with
from lymphoblasts. finely granular chromatin and an inconspicuous nucle-
olus. A background of fluffy, granular debris is often
seen, along with multinucleated giant cells in varying
Suppurative Lymphadenitis
numbers. The presence of granulomatous inflamma-
Suppurative lymphadenitis is most commonly seen in tion alone has a poor sensitivity for tuberculosis (25%)
children and is most often caused by a bacterial (260). In a significant number of cases, the only finding
infection from Staphylococcus aureus. Patients often is either acute inflammation or necrosis, especially in
present with tender, enlarged nodes with overlying cases of atypical mycobacterial infections in the AIDS
erythema in the head and neck region, which may be population. On Romanowsky-type-stained FNAB
associated with fevers. FNAB smears are generally smears, mycobacterial organisms may appear as ‘‘neg-
highly cellular and characterized by many neutrophils ative’’ images, both extracellularly and within histio-
admixed with smaller numbers of histiocytes and cyte cytoplasm (Fig. 91) (261). Ancillary studies,
lymphocytes (Fig. 89). The differential diagnosis for including cell block preparation for special stains,
a neutrophil-predominant FNA biopsy includes other cultures, and special studies such as PCR, are crucial
infectious processes such as mycobacteria in AIDS and for establishing a diagnosis. On Papanicolaou-stained
other suppurative infections such as cat-scratch dis- smears, the organisms may exhibit autofluoresence,
ease. Neoplasms that may mimic an acute suppurative providing a quick, inexpensive means for identifica-
lymphadenitis include necrotic metastases (especially tion. Occasional examples of HL may mimic a granu-
squamous cell carcinoma) and rare presentations of lomatous lymphadenitis.
HL and anaplastic large cell lymphoma (206,258,259).
Additional aspirated material should be obtained for
Toxoplasmosis
cultures. Flow cytometric studies are not generally
indicated for a neutrophil predominant FNAB smear. Toxoplasmosis is often asymptomatic and is caused by
infection with the protozoan, Toxoplasma gondii. In
immune-competent patients, the most common presen-
Granulomatous Lymphadenitis
tation is of posterior cervical lymphadenopathy. FNA
Granulomatous lymphadenitis can be seen in sarcoid- smears show characteristic clusters of small histiocytic
osis, foreign body reactions, and some infections such cells with abundant cytoplasm and eccentric oval
as mycobacterial and fungal infections. Sarcoidosis is nuclei, forming ‘‘microgranulomas’’ (262–265). The
a diagnosis of exclusion, but the findings of non- background is composed of a mixed lymphoid popula-
caseating granulomatous inflammation in the appro- tion, reactive follicular center cell fragments, and tin-
priate clinical and radiographic setting may be gible body macrophages reflecting the histologic
sufficient for establishing a diagnosis (Fig. 90). The findings of small epithelioid clusters opposed to germi-
typical FNAB smear from a patient with tuberculosis nal centers. The causative organisms, both bradyzoites
reveals varying proportions of necrosis, epithelioid and tachyzoites, can be seen in a minority of FNAB
histiocytes, and epithelioid granulomas. The epithelioid smear preparations (262,266). The combination of these
Starry and modified Steiner stains but, in our experi-

ence, is usually negative (270). Therefore, serologic
studies may be helpful. The cytomorphologic findings
in cat-scratch disease present in three stages, each of
which may be confused with other processes. The early
phase is characterized by a dense reactive lymphoid
smear pattern with only few granulomas and no sup-
puration or necrosis. This stage raises a differential
diagnosis of reactive hyperplasia, infectious mononu-
cleosis, follicular lymphoma, and HL. The suppurative
phase (second or third week) is characterized by a
marked neutrophilic infiltrate and stellate granulomas
along with a minor component of necrosis. Differential
diagnostic considerations include a suppurative lymph-
adenitis and lymph node infarction (267,271). By the
third or fourth week, a necrotizing stage is seen charac-
terized by extensive necrosis and fibrin deposition that
may obscure the granulomas present. The differential
diagnosis at this stage includes Kikuchi lymphadenitis,
Figure 91 Characteristic and diagnostic ‘‘negative images’’ can granulomatous lymphadenitis, lymphoma, and meta-
be seen in DQ-stained smears in cases of mycobacterial infec- static carcinoma.
tions, especially from immunocompromised patients with infec-
tions from mycobacterium avium intracellulare (DQ stain; oil Infectious Mononucleosis
Infectious mononucleosis is the most common of the
benign lymphoproliferative disorders, is caused by the
EBV, and is most often seen in adolescents. Patients
present with fever, pharyngitis, splenomegaly, and
cytologic findings along with the subsequent confirma- atypical lymphocytosis in the peripheral blood. Lymph-
tion by serology can avoid a surgical procedure for this adenopathy is most often seen in the cervical region. In
self-limited process (267). An ELISA method for IgM the era of serologic testing and the monospot test, a
and IgG antibodies against T. gondii detects up to 90% biopsy is rarely necessary. However, FNAB has been
of cases (268). The differential diagnosis for toxoplas- useful in cases with a protracted clinical course or an
mosis includes other causes of a granulomatous lymph- unusual presentation where malignant lymphoma
adenitis. There are no multinucleate giant cells, necrosis, enters into the differential diagnosis. FNAB smears
or acute inflammation as seen in cases of tuberculosis are highly cellular and resemble reactive lymphoid
and fungal infections (267). hyperplasia, with a mixed population of small and
large lymphocytes, lymphohistiocytic aggregates (follic-
Cat-Scratch Disease ular center cell fragments), lymphoblasts, and plasma-
Cat-scratch disease is one of the more common causes cytoid lymphocytes (272,273). In some cases,
of lymphadenopathy in both children and adults; and immunoblasts are numerous and appear as large mono-
90% of patients have had contact with cats, and the nuclear cells with a smooth nuclear outline, evenly
lymphadenopathy occurs one to three weeks after the dispersed chromatin, a large central nucleolus, and
initial scratch. Cervical lymph nodes can be involved, abundant basophilic cytoplasm (Fig. 92). Binucleated
often unilaterally (posterior triangle nodes), and there is immunoblasts can be confused with Reed-Sternberg
often an associated rash and fever. FNAB smears gen- cells of Hodgkin’s disease. Immunostains for CD15
erally shows the appearance of a reactive lymph node and CD30 are helpful as they are negative in immuno-
with a mixed population of lymphocytes, neutrophils, blasts. The large number of immunoblasts should raise
tingible body macrophages, and follicular center cell the possibility of mononucleosis or other viral infections
fragments (Table 38) (269). Although seen in a minority but it also creates confusion with a neoplastic process
of cases, the most distinctive finding in cat-scratch (267). However, the pleomorphism of the immunoblasts
disease is the presence of microabscesses and suppura- should lead one to suggest mononucleosis rather than a
tive granulomas composed of aggregates of epithelioid lymphoma. Immunostains show a mixture of B cells
histiocytes arranged in a peripheral palisade with and T cells with a CD8 phenotype (274). The differential
central neutrophils. The causative organism, Bartonella diagnosis also includes reactive hyperplasias, follicular
henselae, may occasionally be demonstrated by Warthin- lymphoma, and large cell lymphoma. An abundance of
large immunoblasts may also lead to confusion with
metastatic carcinomas or malignant melanoma (267).
Table 38 Key Diagnostic Features—Cat-Scratch Disease
Moderate to highly cellular smears Rosai-Dorfman Disease
Neutrophils with variable background necrosis, karyorrhectic Rosai-Dorfman disease (sinus histiocytosis with mas-
debris
sive lymphadenopathy) is a rare idiopathic prolifer-
Granulomas (few to many)
ative disorder that typically affects male children or
52 Elsheikh et al.
or complex, indented nuclei of Langerhans’ histio-

cytes. In addition, the histiocytes of Langerhans’ cell
histiocytosis co-express S-100 and CD1a (279).
Kikuchi Lymphadenitis
Kikuchi lymphadenitis is a relatively rare, self-limited
disease seen in young adult women of Asian descent.
The cervical lymph nodes are most often involved.
FNAB smears show phagocytic histiocytes with a
crescent shaped nucleus with an irregular nuclear
outline, twisted contours, and inconspicuous nucleoli.
The cytoplasm contains phagocytosed debris. Also
seen are plasmacytoid monocytes that have eccentri-
cally placed round nuclei with basophilic cytoplasm.
Immunoblasts are seen and may be numerous. The
background contains karyorrhectic and granular
Figure 92 Aspirate from a case of infectious mononucleosis debris admixed with histiocytes and immunoblasts.
containing numerous immunoblasts with increased pleomor- There is an almost complete absence of neutrophils.
phism in a mixed lymphoid background (DQ stain; oil magnifica- There is significant overlap in the FNAB features of
tion, 600). Kikuchi lymphadenitis, reactive hyperplasias, and
tuberculosis (280,281). Additional differential diag-
nostic considerations include lymph node infarction,
metastatic carcinoma (particularly squamous cell car-
adolescents and most often leads to bilateral persistent cinoma), and high-grade lymphomas. The plasmacy-
and painless cervical lymphadenopathy. FNAB toid cells may also be confused with a plasmacytoid
smears are highly cellular with a pattern of reactive lymphoma. The atypical cells with crescent nuclei
lymphoid hyperplasia and a large number of histio- may be confused with signet ring carcinoma (280,281).
cytes containing phagocytosed lymphocytes and RBCs
termed ‘‘emperipolesis’’ (Fig. 93) (275–278). In the
proper clinical setting, the cytologic findings may be V. SARCOMAS
conclusive. A cell block preparation can allow for
immunohistochemical stains that show reactivity in A. General Considerations
the large histiocytoid cells for S-100 and CD68, but not
CD1a (279). The differential diagnosis includes reac- As a group, soft tissue sarcomas represent less than
tive hyperplasia, HL, and rare cases of nodal Langer- 1% of all malignant neoplasms diagnosed in the US
hans cell histiocytosis. The histiocytes of Rosai- each year (282). Furthermore, as an overall percentage
Dorfman disease do not exhibit the nuclear grooves of neoplasms, the incidence is higher in children than
in adults. Because of their absolute rarity and the
inexperience of many practicing pathologists in deal-
ing with the morphologic diversity of soft tissue
sarcomas, most institutions have traditionally
obtained diagnostic tissue from either open biopsies
or closed CNBs (211,283). Therefore, most pathologists
are uncomfortable making a definitive diagnosis of a
sarcoma, knowing that a misdiagnosis can potentially
lead to debilitating treatment such as an amputation
(282,284). FNAB has been further underutilized
because of the requirement of accurate histologic
subtyping for enrollment of pediatric patients into
histogenetic-specific therapeutic protocols (211,284).
However, a number of studies have systematically
evaluated the accuracy of FNAB and shown that on
adequate specimens and with the judicious use of
ancillary studies, there is an overall accuracy rate
comparable to CNB that approaches 95% for establish-
ing a benign versus malignant diagnosis and reported
false-positive and false-negative rates of less than 1%
to 4% (204,285–287). Studies evaluating the rate of
Figure 93 Aspirate from a case of Rosai-Dorfman disease accurate subtyping of soft tissue sarcomas by FNAB
showing a histiocyte containing phagocytized lymphocytes and have shown variable results with an average of 50% to
RBCs in a background of reactive lymphoid hyperplasia (DQ 70% (285–288). One of the largest series reported by
stain; oil magnification, 600). Kilpatrick and colleagues found the accuracy rate for
sarcoma subtyping of 92% in pediatric sarcomas (with
use of ancillary studies), a rate higher than that Table 39 Sarcomas That Metastasize to Lymph Nodes
achieved in adult sarcomas (52%) (289). For pediatric
Rhabdomyosarcoma
small round cell tumors, histological subtyping is Synovial sarcoma
critical as most of these patients are eligible for enroll- Ewing sarcoma
ment in histogenetic-specific treatment protocols. In a Kaposi sarcoma
series of 18 pediatric patients eligible for such treat- Angiosarcoma
ment protocols, Kilpatrick and colleagues showed an Epithelioid sarcoma
accurate diagnosis by FNAB in 17 of 18 patients (94%)
(285). Similar results have also been shown by Jones
and colleagues supporting the opinion that FNAB can predominate in the pediatric age group whereas
accurately subtype and grade soft tissue sarcomas in myxoid and pleomorphic cell sarcomas are common
most cases (290). Grading of soft tissue sarcomas is in older adults (>50 years) and are virtually nonexistent
important in both management and prognosis, but in children. The epithelioid/polygonal and spindle cell
requires accurate evaluation of the percentage of groups are generally seen in young to middle-aged
tissue necrosis and mitotic rates, parameters that adults.
cannot be adequately assessed by FNAB alone. Thus, An interpretative approach used by most cytopa-
for FNAB specimens, most studies recommend a thologists involves morphologic pattern recognition
classification system dividing soft tissue sarcomas and categorization by the dominant cytomorphologic
into five major subgroups on the basis of the predom- phenotype identified. Once a lesion has been catego-
inant cytomorphologic phenotype seen on the aspira- rized as malignant, subtyping should be attempted
tion smears (291). These are the small round cell, especially for the small round cell category (211). Ancil-
spindle cell, epithelioid/polygonal cell, myxoid, and lary studies can be extremely useful in establishing a
pleomorphic sarcoma subgroups. Once a cytomorpho- specific diagnosis when the clinical and morphologic
logic phenotype has been determined, the corresponding findings are equivocal. IHC, molecular, and genetic
histological grade, in most cases, becomes definitional analysis of FNAB material play a critical role in render-
and a two tiered grading system works best (low ing histogenetic-specific diagnoses of pediatric soft tis-
grade and high grade; i.e., round cell, pleomorphic, sue sarcomas, including the small round cell sarcomas,
and epithelioid/polygonal subgroups are, by defini- a requirement for enrollment of patients on specific
tion, high-grade sarcomas) (291,292). For most soft treatment protocols (i.e., Pediatric Oncology Group)
tissue sarcomas, the stage (incorporating grade) and (Table 40) (284,285,292,293). A panel of immunohisto-
anatomic location are used to determine therapy and chemical stains plays an important role in the workup
in adults with high-grade sarcomas (i.e., pleomorphic of small round cell, spindle cell, and the epithelioid/
and epithelioid/polygonal subgroups), the therapy is polygonal cell sarcomas. IHC screening panels are also
similar. As with any classification system, there are important to separate primary soft tissue sarcomas from
certain limitations related to the morphologic spec- metastatic carcinoma, malignant melanoma, and malig-
trum that can be seen with various soft tissue sarco- nant lymphoma. Although helpful, some cytogenetic
mas. For example, rhabdomyosarcomas can display a and molecular studies initially thought to be highly
variety of cytomorphologic features ranging from specific for certain soft tissue sarcomas have now been
small round cell to spindle cell morphology. Likewise, shown to actually be more nonspecific. The best exam-
synovial sarcoma may demonstrate a predominant ple is the Ewing’s sarcoma translocation, t(11;22)
epithelioid/polygonal pattern rather than the classic (q24;q12) with the WES-FLI1 fusion product, which has
spindle cell pattern (211). Especially in adults, it is also been reported in embryonal and alveolar rhabdo-
important to remember and rule out metastatic carci- myosarcomas, neuroblastoma, and mesenchymal
noma, malignant lymphoma, and malignant melano-
ma as these lesions vastly outnumber primary soft Table 40 Immunohistochemical Screening Panels for Small
tissue sarcomas in this age group (284). Round Sarcomas
Rhabdomyosarcoma MyoD1/myogeninþ
Diagnostic Approach Including Ancillary Studies Desminþ
Cytokeratin
FNAB requires a multidisciplinary approach for diag- S-100
nostic success. Clinical and radiographic correlation is Ewing sarcoma/PNET Desmin–
crucial as radiographic studies can provide information CD56–
relating to location (superficial vs. deep), presence/ CD99þ
absence of osseous involvement, size, relationship to FLI-1þ
other structures (nerves, vessels) and degree of hetero- Cytokeratin
geneity (fat content, cyst formation). Correlation of S-100–
these features with the cytomorphologic findings can Synovial sarcoma Cytokeratinþ
help narrow down the differential diagnosis (284). CD99þ
Certain soft tissue sarcomas have a predilection for EMAþ
metastasizing to lymph nodes (Table 39). Patient age Desmin–
is a critical factor to consider, as there is little overlap in CD34–
S-100þ (30%)
the lesions that predominate in each general age group
(282,291). For example, small round cell tumors Abbreviations: EMA, epithelial membrane antigen.
54 Elsheikh et al.
chondrosarcoma (285). The cytomorphology and histo- Table 43 Key Diagnostic Features—Rhabdomyoma
pathology findings (285) should always ‘‘trump’’ the
ancillary studies. Therefore, we believe that ancillary Smear with single large polygonal cells with abundant granular
cytoplasm
studies should be used to supplement, not replace, the Multiple eccentrically located nuclei with indistinct nucleoli
cytomorphologic findings and data obtained from such Intracytoplasmic cross striations seen in a minority of cells
tests should be interpreted only within the context of No mitotic activity
the full clinical and cytologic findings.
Rhabdomyoma
B. FNAB of Benign Soft Tissue Lesions Rhabdomyoma is a benign tumor with adult forms
occurring almost exclusively in the head and neck
Proliferative Myositis and Nodular Fasciitis
region of older adults (295). Up to 20% can be multifo-
These pseudosarcomatous lesions can occasionally cal. Cytologic smears demonstrate sparsely cellular
affect the head and neck region. Proliferative myositis specimens composed of large oval to round cell with
frequently arises in he sternomastoid muscle in abundant granular cytoplasm (Table 43). Occasionally,
patients aged between 45 and 65 years. Rapid growth cross-striations may be seen. The differential diagnosis
leads to confusion with a sarcoma. Proliferative myo- includes other neoplasms with granular cytoplasm
sitis can be considered the intramuscular homolog of including rhabdomyosarcomas, acinic cell carcinomas,
nodular faciitis (284). Aspiration smears contain a paragangliomas, and granular cell tumors. Smears of
mixture of skeletal muscle, reactive fibroblasts, and acinic cell carcinomas are highly cellular with cohesive
multinucleated cells (Table 41–42). Scattered large clusters of cells and contain many stripped nuclei in the
polygonal cells with prominent nucleoli and abundant background. FNAB smears from rhabdomyosarcoma
cytoplasm may be seen. The differential diagnosis demonstrate nuclear atypia and mitotic figures not
mainly includes sarcomas including rhabdomyo- seen in rhabdomyoma. IHC can help distinguish rhab-
sarcoma and malignant fibrous histiocytoma (MFH). domyomas from granular cell tumors, as only the latter
Nodular fasciitis also represents a pseudosarcomatous are S-100 positive (295).
response to injury that manifests as a rapidly enlarg-
ing mass (294). Peak incidence occurs in the third and Granular Cell Tumor
fourth decades with approximately 13% occurring in
the head and neck region (294). Smears are generally Granular cell tumor is a benign tumor of probable
cellular with an admixture of single and small clusters neural origin with a predilection for the head and
of spindle shaped cells along with variable numbers of neck region, with almost 50% occurring at this site, in
myxoid stromal fragments. Cells demonstrate vesicu- particular, the larynx and tongue. FNAB smears are
lar nuclei with small multiple nucleoli and wispy usually cellular with cells arranged in syncytial
cytoplasm. Mitoses are frequently seen and admixed groups and lying singly (296). Cells demonstrate
inflammatory cells are seen admixed with stromal abundant granular cytoplasm and small bland round
fragments. The cytologic smears display a ‘‘tissue- to oval nuclei. The differential diagnosis includes
culture’’ appearance on low power examination. Dis- rhabdomyoma and rhabdomyosarcoma (discussed
tinction from true sarcomas of soft tissue is based on a above), and alveolar soft part sarcoma (296). The latter
clinical history of rapid enlargement and presence of a demonstrates grated nuclear atypia and may show
mobile superficial nodule. intracytoplasmic crystalloids.
C. FNAB of Selected Soft Tissue Sarcomas

Table 41 Key Diagnostic Features—Nodular Faciitis Encountered in the Head and Neck Region
Cellular smears Round Cell Sarcomas
Cell clusters and single cell pattern
Spindled cells with long cytoplasmic processes Round cell sarcomas predominate in the pediatric age
Bland spindled nuclei with indistinct nucleoli population with rhabdomyosarcoma being the most
myxoid or fibrillar material may be present in background common extracranial soft tissue sarcoma occurring in
Mixed inflammatory cell infiltrate with neutrophils, lymphocytes, the head and neck (Tables 40 and 44) (211,293,297).
histiocytes The International Classification of Rhabdomyosarco-
Giant cells and pigment laden histiocytes often present ma (ICR) recognizes five prognostically significant
subtypes: spindle cell and botryoid embryonal (supe-
rior prognosis); embryonal (intermediate prognosis);
and alveolar and undifferentiated (poor prognosis)
Table 42 Key Diagnostic Features—Proliferative Myositis
(282,285,291). The various subtypes tend to predomi-
Cellular smears with single cells and tissue fragments nate in different age groups and anatomic sites; there-
Two cell population: ganglion like giant cells and spindled cells fore, clinical and radiographic correlation is essential.
resembling nodular faciitis Most rhabdomyosarcomas occur in children younger
Bland nuclear features, uniform chromatin, smooth nuclear than 10 years ; however, they can occasionally occur in
membranes
adolescents and young adults. In general, when
Hemorrhagic background containing fat, metachromatic stroma
compared with the other round cell sarcomas,
Table 44 Key Diagnostic Features—Rhabdomyosarcoma

Alveolar Highly cellular smears
rhabdomyosarcoma Single cells and sheets of cells with
fragile cytoplasm
Majority cell population is a small
early rhabdomyoblast with scant
cytoplasm
Variably sized nuclei with nuclear
irregularities, coarse chromatin,
and one or more nucleoli
Multinucleated giant cells and strap
cells characteristic
Embryonal Moderate to highly cellular smears
rhabdomyosarcoma Three cell types: early, intermediate,
and late rhabdomyoblasts
Predominant cell type is small with
scant cytoplasm; secondary popu-
lation of cells with more abundant
cytoplasm
Cytoplasmic vacuolization present
Mitoses readily seen in most smears Figure 95 Compared with embryonal subtypes, the alveolar
Round to oval eccentric nuclei with rhabdomyosarcoma has larger, more uniform rounded cells with
fine chromatin, nuclear irregulari- hyperchromatic nuclei, one or more nucleoli, and a thin rim of
ties, and variably sized nucleoli cytoplasm. Vacuoles in the cytoplasm are seen in the majority of
Background may be myxoid, tigroid, rhabdomyosarcomas (DQ stain; oil magnification, 600).
or contain necrosis
rhabdomyosarcoma tends to display more cytologic vacuolization is noted in the majority of rhabdomyo-
variability, especially in the embryonal subtype sarcomas; however, it is also commonly seen in
(Fig. 94 and 95). FNAB smears demonstrate cellular Ewing’s sarcoma and malignant lymphoma, which
smears with predominantly discohesive cells of small enter into the differential diagnosis (Fig. 95). A useful
to intermediate size and with round to ovoid hyper- cytologic finding is the presence of binucleated and
chromatic nuclei, and one or more prominent nucleoli. multinucleated cells, more often seen in the embryo-
A fragile scant rim of cytoplasm, which can be easily nal subtype (Fig. 94). IHC for myo-D1/myogenin,
stripped, is noted with many stripped nuclei present desmin, and actin are helpful in rendering a diagnosis
in the background. Occasional loosely cohesive of rhabdomyosarcoma. Cytogenetic studies demon-
groups of malignant cells can be seen. Cytoplasmic strate an 11q deletion and a 2;13 translocation in
alveolar rhabdomyosarcomas (285).
Ewing’s Sarcoma/PNET
Among round cell sarcomas, Ewing sarcoma/PNET is
the most difficult to diagnose based solely on cytomor-
phology; however, ancillary studies can help to estab-
lish a diagnosis by FNAB. Aspirated specimens
demonstrate highly cellular smears with strikingly uni-
form round cells with a very high nuclear/cytoplasmic
ratio and cytoplasmic vacuoles and most cases also
demonstrate pseudo-rosette formation (Fig. 96). Immu-
nohistochemical staining for CD99 and FLI-1 can aid in
the diagnosis and cytogenetic analysis for the t(11;22)
reciprocal translocation has been successfully per-
formed on aspirated material (285).
Polygonal/Epithelioid Cell Sarcomas

Polygonal/epithelioid cell sarcomas by definition rep-
resent high-grade sarcomas and include a diverse
group of entities including epithelioid sarcoma, alveolar
Figure 94 Embryonal rhabdomyosarcoma demonstrating a soft part sarcoma, clear cell sarcoma (melanoma of soft
range of small to large tumor cells, some with binucleation, a parts), and synovial sarcoma. Also included in the
feature helpful in differentiating from Ewing’s sarcoma (Papani- differential diagnosis of this subgroup is metastatic
colaou stain; magnification, 600). carcinoma and malignant melanoma as they commonly
display an epithelioid morphology. The sarcomas
56 Elsheikh et al.
Figure 97 An aspirate from an epithelioid sarcoma with loose

clustering of rounded to polygonal cells with eccentric nuclei,
prominent nucleoli, and abundant cytoplasm (Papanicolaou
Figure 96 Aspirates from Ewing’s sarcoma are highly cellular

and contain a strikingly uniform population of cells with a very Table 45 Key Diagnostic Features—Synovial Sarcoma
high nuclear-to-cytoplasmic ratio (Papanicolaou stain; oil magni- Cellular smears with cohesive clusters and single cells
fication, 600). Monomorphic population of round, ovoid, to occasionally spindled
cells
Nuclei with fine granular chromatin and inconspicuous nucleoli
Few mitoses present
included in this group tend to affect adolescent and
young adults and most often arise in the extremities,
however, also tend to present with a high frequency of smears with predominantly discohesive cells and occa-
regional lymph node metastases that are highly uncom- sional loose cell aggregates (Table 45). Cells are generally
mon in other soft tissue sarcomas. In such cases, exclu- uniform with round to ovoid to spindle cells, high
sion of metastases from carcinoma and melanoma is nuclear to cytoplasmic ratios, small nucleoli, and scant
necessary. Rendering a diagnosis of a polygonal/epi- to tapering cytoplasm (Fig. 98) (299). IHC plays a pivotal
thelioid sarcoma by FNAB without further subtyping
can be adequate to initiate therapy as treatment for all
sarcomas in this category is similar and includes both
chemotherapy and adjuvant radiation therapy (298).
FNAB smears demonstrate cellular smears domi-
nated by singly dispersed cells with a round/polygonal
shape and moderate to abundant cytoplasm (Fig. 97).
Nuclei tend to be eccentric and contain one or more
prominent nucleoli. Bi- and multinucleated tumor cells
can be identified in the smears. The cytomorphologic
features among entities in this group show considerable
overlap; therefore, ancillary studies are generally need-
ed to distinguish amongst them, but more importantly,
to rule out a nonsarcomatous malignancy.
Synovial Sarcomas
Approximately 3% of synovial sarcomas occur in the
head and neck region and have been reported in the
larynx, hypopharynx, and retropharyngeal areas. They
are of unknown histogenesis (299). Synovial sarcoma, Figure 98 Monophasic synovial sarcoma showing uniform,
with its biphasic morphology and immunohistochemical round- to oval-shaped cells in a loose cluster. The cells have a
staining profile may be considered a ‘‘carcinosarcoma’’ high nuclear to cytoplasmic ratio, tapering cytoplasm, and incon-
of soft parts. FNAB smears from synovial sarcomas spicuous nucleoli (DQ stain; magnification, 400).
(monophasic and biphasic) demonstrate highly cellular
Figure 99 Immunostaining for pancytokeratin shows positivity Figure 100 Aspirate from a malignant fibrous histiocytoma
within synovial sarcomas (immunohistochemical incubation for demonstrating a pleomorphic, multinucleated giant cell (DQ
AE1/AE3 pancytokeratin marker; magnification, 400). stain; oil magnification, 600).
role in the diagnosis of synovial sarcoma, which shows

positive staining for cytokeratin, epithelial membrane
antigen, and CD99 (Fig. 99). In addition, greater than 90%
have the characteristic t(x; 18) translocation by cytogenet-
ic analysis, which has been successfully performed on
FNAB material (285).
Pleomorphic Sarcomas
Pleomorphic sarcomas are easily recognized as malig-
nant and high-grade malignancies with moderate to
highly cellular smears and predominantly dyscohesive
cells and tumor giant cells. They tend to affect older
adults (>50 years) Currently, all pleomorphic sarcomas
(by definition, high-grade sarcomas) are treated simi-
larly with surgical excision in most cases along with
chemotherapy and/or radiation therapy. Therefore,
histologic subtyping is not usually necessary and an
FNAB diagnosis of ‘‘pleomorphic sarcoma, not other-
wise specified’’ is generally sufficient to initiate appro-
priate therapy. Malignant fibrous histiocytoma (MFH) Figure 101 Aspirate from a pleomorphic liposarcoma with a
classic lipoblast that shows an atypical and bizarre nucleus and
occurs in the sinonasal cavity and neck on rare occa-
abundant multivacuolated, lipid-laden cytoplasm (DQ stain; oil
sions. MFH is best considered a generic high-grade magnification, 600).
sarcoma demonstrating a pleomorphic phenotype that
can be more definitively classified with IHC and more
reproducible diagnostic criteria as other more specific
sarcomas, carcinoma, or melanoma (300). FNAB smears
are generally highly cellular with marked nuclear pleo-
MFH as both contain large numbers of anaplastic giant
morphism, tumor giant cell formation, and variable cell
cells. Demonstration of lipoblasts, which may be rare or
morphology ranging from spindle to epithelioid shapes
absent in an FNAB sample, is necessary for a definitive
(Fig. 100). Differentiation from sarcomatoid carcinomas
diagnosis of liposarcoma (Fig. 101) (301).
can be problematic. The presence of marked nuclear
anaplasia and prominent numbers of anaplastic giant
Osteosarcomas
cells favors a diagnosis of MFH. However, most cases
are best resolved by IHC for cytokeratins. Similarly, Most osteosarcomas in the head and neck region occur
immunostaining for S-100, HMB-45, and Melan-A can in the jaw. Smears generally contain osteoid along
confirm a diagnosis of malignant melanoma. Pleomor- with markedly pleomorphic ovoid to spindled cells
phic liposarcomas can be difficult to differentiate from with prominent nucleoli.
58 Elsheikh et al.
Spindle Cell Sarcomas

Spindle cell sarcomas include a broad group of tumors
including synovial sarcoma (discussed under the epi-
thelioid/polygonal sarcomas), malignant peripheral
nerve sheath tumor (MPNST), leiomyosarcoma, fibro-
sarcoma, angiosarcoma, and some forms of MFH. In
our experience and that of others, this group of lesions
is the most diagnostically challenging by FNAB
because of difficulties in accurately separating benign
lesions from low-grade sarcomas and definitively
classifying the sarcoma (302,303) Therefore, it is
doubtful that spindle cell sarcomas can be accurately
diagnosed by FNAB. Therefore, in this group of
lesions, a CNB may be the preferred diagnostic
modality (211).
Leiomyosarcomas
Leiomyosarcomas occur in the superficial soft tissues
of the head and neck and the low-grade leiomyosar- Figure 103 Singly dispersed and loosely clustered malignant
comas are aspirated most often. FNAB smears cells from a malignant peripheral nerve sheath tumor with
demonstrate low to moderate cellularity with a pre- characteristic comma- to serpentine-shaped cells with hyper-
dominance of cohesive cell clusters arranged in paral- chromatic nuclei and variable tapering cytoplasm (DQ stain;
lel bundles and containing characteristic cigar-shaped magnification, 600).
nuclei (Fig. 102). High-grade lesions demonstrate
increasing nuclear pleomorphism, prominent nucleoli,
and background necrotic debris. The high-grade pleo- actin, caldesmin) can help to separate leiomyosarco-
morphic leiomyosarcomas may be difficult to separate mas from other spindle cell sarcomas.
from other adult pleomorphic sarcomas; however, FNAB smears from MPNST demonstrate obvi-
treatment is essentially similar and an FNAB diagno- ous malignant features with moderate to highly cellu-
sis of ‘‘pleomorphic sarcoma, not otherwise specified’’ lar smears containing a predominance of single cells
would be enough to initiate appropriate therapy. and some loosely cohesive clusters of malignant cells.
Low-grade leiomyosarcomas may be impossible to The characteristic wavy, bent-shaped nuclei with
separate from leiomyomas, however, the presence of hyperchromasia, irregular nuclear membranes, and
atypia and mitoses would support a leiomyosarcoma high nuclear/cytoplasmic ratios are evident and mito-
diagnosis (291,303). Immunohistochemical staining ses can be seen with higher-grade lesions (Fig. 103)
with muscle markers (i.e., desmin, muscle specific (302). IHC can be useful in separating MPNST from
leiomyosarcoma (muscle markers), synovial sarcoma
(cytokeratin and epithelial membrane antigen), and
MFH. The most useful finding for making a correct
diagnosis is the clinical scenario for diagnosing a high-
grade MPNST with a history of preexisting neurofi-
broma, neurofibromatosis, and origin from a major
nerve trunk (211,291).
Myxoid Soft Tissue Sarcomas

Myxoid soft tissue sarcomas are lesions that, by defi-
nition, display myxoid morphology as a dominant
feature. In our experience, the most commonly sam-
pled myxoid sarcomas by FNAB are myxoid liposar-
coma, myxofibrosarcoma (myxoid MFH), and
extraskeletal myxoid chondrosarcoma. The FNAB
findings of these lesions have been previously well
described (291,303–306).
Myxoid liposarcomas. Myxoid liposarcomas are
low-grade sarcomas and are the most common malig-
nant lipomatous tumor in adults, affecting patients
Figure 102 Cellular aspirate from a leiomyosarcoma composed aged between 40 and 70 years. These lesions can occur
of cohesive clusters of tumor cells with variable pleomorphism, at almost any site but are most common in the deep
cigar-shaped nuclei, and tapering cytoplasm (DQ stain; magnifi- soft tissues. FNAB smears demonstrate variable num-
cation, 600).
bers of myxoid stromal fragments, plexiform or
‘‘chicken wire’’ vascular pattern (best seen on cell
lesions are initially examined with cytologic scrapings

in an attempt to differentiate them from malignant
lesions. Smears from buccal mucosa may show
enlarged nuclei in patients with pernicious or iron
deficiency anemias (317). Similar cytologic changes
can also be seen in patients who are receiving certain
drugs, irradiation treatment, or chemotherapy.
Ulcerations and Inflammatory Conditions

Regenerative and/or degenerative cellular changes
associated with acute and/or chronic inflammation
can be seen in a wide range of infectious diseases.
Scrapings from these lesions may reveal parabasal-
like cells with enlarged nuclei and scanty surrounding
cytoplasm. Infrequently, prominent and multiple
nucleoli, abnormal chromatin patterns, and multinuclea-
tion are seen. These findings can simulate malignant-
appearing cells; however, false-positive results are
Figure 104 Aspirate from a myxoid liposarcoma composed of a infrequent when examination is performed by experi-
vascular network in a myxoid stroma. The vascular channels are enced cytopathologist.
surrounded by atypical spindled cells (DQ stain; magnification, Oral radiation for cancer induces numerous
600). cytologic changes that may persist for long periods
after completion of the therapy. These changes include
nuclear and cytoplasmic enlargement, vacuolation,
block material), and uniform mononuclear cell popu- binucleation, and nuclear aberrations (318).
lation of oval to spindle cells as well as with variable Candida albicans pseudohyphae and spores are best
numbers of univacuolated lipoblasts (Fig. 104). The seen in scrape smears from whitish areas on the oral
presence of lipoblasts is the only significant feature for mucosa. The infection and organism load is commonly
rendering a diagnosis of myxoid liposarcoma (304). very intense in patients with immunosuppression, such
Lipoblasts must be searched for carefully as they are as HIV-positive patients (318).
not a dominant feature seen on most FNAB smears. Primary herpetic stomatitis. Primary herpetic sto-
matitis is an acute oral herpesvirus infection character-
ized by crusting of the lips, painful single or multiple
VI. ORAL CAVITY mucosal ulcers, associated with lymphadenopathy and
fever. Scraping cytology shows bizarre multinucleated
A. Introduction syncytial giant cells with molded nuclei, beaded nuclear
Annually, there are approximately 19,000 new cases of membranes and intranuclear inclusions or clear
oral cavity cancers in the United States, accounting for ‘‘ground glass’’ nuclei in Papanicolaou-stained smears
4% of all new malignancies. Most of these cases (318) (Fig. 105). The common recurrent aphthous ulcer
present in a late stage (307,308). Open surgical biopsy (canker sores) is not due to the herpesvirus and usually
is the standard procedure for the diagnosis of suspi- demonstrates slightly enlarged nuclei with surrounding
cious lesions of the oral cavity, although cytologic acidophilic cytoplasm (318,319).
examination of surface scrapings has been used for Pemphigus vulgaris. The mucosa of the mouth is
the diagnosis of dysplastic or neoplastic changes. usually involved in pemphigus vulgaris and may be the
However, a high false-negative rate was reported in initial finding. The type and appearance of the oral
several studies (309–311). In addition, exfoliative lesions are similar to those of the skin. Acantholytic
cytology has been found not to be practical for non- changes are characterized by numerous uniform basal
epithelial or submucosal lesions. In contrast, FNA has and parabasal cells with increased nuclear to cyto-
been shown to be a reliable and safe technique for the plasmic ratios and large single or multiple irregular
diagnosis of malignancy in oral and pharyngeal nucleoli (320). Perinuclear cytoplasmic halo formation
lesions (312,313) and provides an alternative to open may be seen. The cells may be mistakenly interpreted
biopsy with few false-negative cases (314,315). FNA is as suspicious for malignancy.
especially useful in deep-seated extranodal or glandu- Mucous retention cysts. Mucous retention cysts
lar masses covered with intact mucosa. In these or ranulas represent dilated ducts or collections of
instances, the needle usually has to be directed with extravasated mucous arising in association with minor
imaging techniques (316). salivary glands and most often occur in the lower lip
(321). Aspiration of these lesions will yield a small
amount of gray to white clear mucoid material. In
B. Benign Oral Lesions general, the aspirate is extremely hypocellular with
only scattered histiocytes.
Benign oral lesions have variable clinical appearances Leukoplakia. Leukoplakia may be defined as any
that often make diagnoses difficult. Many of these white plaque that cannot be scraped from the oral
60 Elsheikh et al.
Table 46 Key Diagnostic Features—Granular Cell Tumor

Cellular smears with dissociative cell pattern
Abundant granular cytoplasm with low nuclear to cytoplasmic
ratio, stains deep blue in Diff-Quik stain
Small, round and bland nuclei
Mitosis and necrosis can be seen in malignant tumors
in oral cavity. Adult rhabdomyoma is the most com-

mon type. The cytologic features have been infrequently
reported in the literature (324–326). The aspiration
smears and cytospin preparations contain clusters of
large polygonal cells with abundant granular cytoplasm
with indistinct borders and uniform, peripherally
located nuclei that are rarely multiple. Occasionally,
cross-striations are identified in the cytoplasm on Papa-
nicolaou and DQ stains, but are more prominently seen
in the cell block hematoxylin and eosin preparations.
Nuclear atypia and mitotic figures are absent (324–326).
Granular cell tumor. Granular cell tumor is a
benign neoplasm of probable neural origin, especially
Figure 105 Oral herpetic ulcers. Scraping cytology shows giant involving the larynx and tongue in the head and neck
cells with multinucleation, molded nuclei, beaded nuclear mem- region. As the name implies, these neoplasm are
branes, and clear ‘‘ground glass’’ nuclei. (H&E stain; magnifica- composed of large cells with abundant granular cyto-
tion, 600). plasm. The smears are generally highly cellular with
single cells or syncytial groups (327) (Table 46). The
nuclei are usually small, round, and bland, but can
show considerable pleomorphism. Nucleoli are indis-
mucosa. An erythematous component increases the tinct. The cytoplasm is abundant, granular, and stains
risk of dysplasia or carcinoma (322). Cytopathology deep blue in DQ preparation (Fig. 107). The granules
smears from the surface may yield dysplastic cells. within the cytoplasm stain positively with the periodic
Presence of any cytologic atypia requires a biopsy acid-Schiff (PAS) stain. The cells are fragile and nuclei
specimen (318,323) (Fig. 106). EBV appears to be a are frequently stripped from the cytoplasm, imparting
cofactor in the oral hairy leukoplakia associated with a granular background with a ‘‘dirty’’ appearance
HIV infection. Oral hairy leukoplakia presents primar- (328,329). Hyperchromasia, increased nuclear to cyto-
ily on the lateral tongue as a corrugated or hair-like plasmic ratios, coarse chromatin, numerous mitosis,
white lesion. The definitive diagnosis is established by vesicular nuclei with enlarged nucleoli, spindle cell
biopsy specimens, in which koilocytes and hyperkera- morphology, and increased proliferative activity eval-
tosis are seen (323). uated by IHC are associated with malignancy (328).
Rhabdomyoma. Rhabdomyoma is a rare benign Some authors caution that identification of mitosis
tumor of skeletal muscle origin, found most frequently
Figure 107 Granular cell tumor. FNAB shows dyscohesive

Figure 106 Leukoplakia. Scrape cytology smear from the leu- single cells, with small, round, bland nuclei, and indistinct nucle-
koplakia surface yields dysplastic cells. Tissue biopsy shows oli. The cytoplasm is abundant, granular and stains deep blue in
carcinoma in situ (Papanicolaou stain; magnification, 400). DQ preparation (DQ stain; magnification, 400).
and necrosis is needed before rendering a malignant from all three germ layers such as respiratory, intesti-
diagnosis (330). nal, and nervous system (339). The lumen of all three
Epithelioid hemangioendothelioma. Epithelioid types of dermoid cyst displays a greasy, cheese-like,
hemangioendothelioma is a rare vascular neoplasm white gray or yellow tan content, formed by shed
with a biological behavior intermediate between hem- keratin and sebaceous material (340–342). When lined
angioma and angiosarcoma (331). Only a few cases by squamous cells, differentiation between a thyro-
have been reported in the oral cavity, with a wide glossal duct cyst, branchial cleft cyst, and teratoid cyst
distribution of patient ages and female predominance can be difficult (342).
(332). The sites of the tumor include the tongue, lip, jaw,
buccal mucosa, and the floor of the mouth. A painless
solitary mass is the most common presentation (332). C. Malignant Oral Lesions
The smears are usually sparsely cellular consist- Squamous Cell Carcinoma
ing of predominantly single, large polygonal cells in a
bloody background. A few atypical cells embedded in Oral squamous cell carcinoma is the most common
a dense metachromatic stroma can be seen. These oral lesion to be sampled by swab and/or scrape
atypical cells have abundant dense or fine granular smears (318). Prior scrape or aspiration cytology of
cytoplasm with ill-defined cell borders. The nuclei are an indurated, raised, or ulcerated intraoral lesion,
enlarged, oval, and eccentrically located, with fine combined with aspiration of any associated cervical
chromatin and indistinct nucleoli. Some binucleated lymphadenopathy will establish the diagnosis in the
and multinucleated cells can be present. Characteris- majority of cases. In the absence of metastatic disease,
tically, some cells show large cytoplasmic vacuoles scrape cytology cannot reliably separate in situ from
compressing the nuclei, some of which contained invasive squamous tumor. In this instance, biopsy
degenerated RBCs. Intranuclear inclusions are seen may be recommended.
and considered to be the most reliable diagnostic Squamous cell carcinoma is divided into kerati-
feature in FNAB (333–335). Distinction between epi- nizing and nonkeratinizing types (318,343). Cytologic
thelioid hemangioendothelioma and epithelioid features of keratinizing squamous cell carcinoma is
angiosarcoma may be difficult. However, significant characterized by cellular smears in which numerous
cytologic atypia, nuclear pleomorphism, brisk mitotic dispersed anucleated keratinized squames and kerati-
activity, and necrosis favor a diagnosis of epithelioid nized nucleated cells (Fig. 108). The smears contain
angiosarcoma (336). Epithelioid sarcoma usually many single cells and clusters of neoplastic cells are
occurs in the distal upper extremities of young adults present. The individual cells have abundant pink to
(332). Aspirates are hypercellular and composed of orange dense cytoplasm. Squamous pearls are often
both cellular aggregates and isolated tumor cells. seen. When keratin debris is abundant, foreign body
Epithelioid sarcoma is positive for vimentin and cyto- giant cells may be present. Moderately and poorly
keratin and is negative for vascular markers such as differentiated squamous cell carcinomas demonstrate
factor VIII, CD31 and CD34, in contrast to epithelioid little evidence of keratinization consisting of individual
hemangioendothelioma (330–332).
Epithelioid hemangioma. Epithelioid hemangio-
ma is a benign vascular tumor rarely seen in the oral
cavity (337). It usually presents as a small (< 3cm), red
or brown, circumscribed mass, and composed of
lobular proliferation of vascular like channels lined
with plump endothelial cells (337). The vascular pro-
liferation is associated with infiltration of lympho-
cytes, plasma cells, and abundant eosinophils. On
FNA, the neoplastic cells may be spindle or polygonal
(338). The nuclei are bland and usually oval with
smooth nuclear contours and vesicular chromatin.
The cytoplasm is granular and eosinophilic, but
lacks the dense texture of hemangioendothelioma
cells. In addition, most of the neoplastic cells form
cohesive and vascular-like cell aggregates with only a
few single neoplastic cells in the background. Inflam-
matory components, particularly eosinophils are pres-
ent in aspirates of epithelioid hemangioma, but are Figure 108 Well differentiated kertinizing squamous cell carci-
not seen in epithelioid hemangioendothelioma (338). noma. Smears are characterized by high cellularity with abun-
Teratoid cysts. Teratoid cysts consist of three dant anucleated and nucleated keratinized squamous cells.
distinct histological types: epidermoid (simple), lined Differentiating reactive atypia in branchial cleft cyst from well-
by stratified squamous epithelium without dermal differentiated squamous cell carcinoma can be challenging.
appendages; dermoid (compound), consisting of typi- Features supporting the branchial cleft cyst include numerous
cal squamous epithelium and dermal appendages anucleated squames and prominent acute inflammation (not
such as hair, hair follicles, and sebaceous and sweat seen in this smear) (DQ stain; magnification, 200).
glands; and teratoid (complex), consisting of tissues
62 Elsheikh et al.
Figure 109 Poorly differentiated squamous cell carcinoma.

Smears show cohesive and dyscohesive group of cells with
vesicular nuclei, coarsely granular chromatin, and large promi-
nent nucleoli. No evidence of squamous keratinization is seen in
the specimen (Papanicolaou stain; magnification, 400).
cells or clusters with indistinct cytoplasmic margins and

large nuclei with irregular nuclear membranes. Squa-
mous cell carcinomas usually have hyperchromatic,
clumping to dense or opaque nuclei. In poorly differen-
tiated squamous cell carcinoma, vesicular nuclei with
coarsely granular chromatin and large prominent nucle- Figure 110 Basaloid squamous cell carcinoma. (A) Smears are
oli are seen (Fig. 109). Mitotic figures are numerous characterized by dyscohesive neoplastic cells with high nuclear
(344). to cytoplasmic ratio, hyperchromatic nuclei, mimicking small cell
Basaloid squamous cell carcinoma. The basaloid carcinoma. (B) In contrast to small cell carcinoma, large nucleoli
variant of squamous cell carcinoma is a highly malig- are evident [(A) DQ stain; magnification, 400 (B) Papanicolaou
nant neoplasm, frequently presenting with metastatic stain; magnification, 400].
disease at the time of diagnosis. Metastatic deposits
may consist of basaloid and/or squamous carcinoma
cells. Basaloid squamous cell carcinoma has a distinc-
tive cytological pattern characterized by occasional Table 47 Key Diagnostic Features–Basaloid Squamous Cell
sheets of cohesive neoplastic cells with high nuclear Carcinoma
to cytoplasmic ratios and hyperchromatic nuclei that Dyscohesive cells with high nuclear to cytoplasmic ratio
can occasionally mimic small cell carcinoma (345) Hyperchromatic nuclei with occasional molding
(Fig. 110A, Table 47). Smears of the aspirate show a Prominent nucleoli (in contrast to small cell carcinoma)
mixed lymphoid background with interspersed cohe- Magenta stained extracellular dense material within or adherent
sive clusters of small cells. The cells are generally to the malignant cell clusters.
hyperchromatic with evenly staining dense chromatin
or irregularly distributed coarse chromatin. In contrast
to small cell carcinoma, nucleoli are usually evident giant cells reaction, keratin plaques, and ghost cells.
(Fig. 110B). On DQ staining, irregular globules of Recognition of these patterns along with clinical corre-
magenta-stained extracellular dense material within lation enables the pathologist to prevent a false-negative
or adherent to the periphery of some clusters can be diagnosis (347).
seen. Abundant mitotic figures and necrosis are often Metastatic squamous cell carcinoma. Metastatic
present. IHC is useful since basaloid squamous carci- squamous cell carcinoma should be differentiated
noma is positive for high–molecular weight cytoker- from branchial cleft cyst (Fig. 108). Branchial cleft
atin, p63, and CK5/6, but negative for TTF-1, CK7, cyst occurs in the lateral neck along the anterior
and neuroendocrine markers (345,346). border of the sternomastoid muscle forming a soft to
There are several diagnostic problems and pit- firm nodule. Smear preparations show large number
falls in the interpretation of FNA of squamous cell of anucleated keratinizing squamous cells, with some
carcinoma, including cystic changes, well-differentiated squamous cells showing varying degrees of matura-
and spindle squamous cell carcinomas, foreign-body tion (348,349). The background is granular with
amorphous debris and frequently contains neutro- membrane–like material should exclude ACC. PLGA
phils. Squamous cell nuclei can show reactive atypia should not be confused with SDC, which is a high-
and can be a pitfall for squamous cell carcinoma. grade and clinically aggressive tumor showing con-
Increased nuclear to cytoplasmic ratios, irregularity siderable cellular pleomorphism, anisonucleosis, and
of nuclear outline, and nuclear hyperchromatism are tissue fragments with a cribriform pattern (355).
characteristics for squamous cell carcinoma. In addi-
tion, the background of squamous cell carcinoma Nonepithelial Tumors
contains more necrotic debris and fewer polymorpho-
nuclear cells than aspirates of benign cysts. However, Nodal and extranodal lymphoma. Primary intraoral
well-differentiated squamous cell carcinoma can have and perioral, localized nodal, and extranodal lymphoma
minimal atypia while branchial cleft cysts can show forms a considerable proportion of all lymphomatous
significant inflammatory atypia, making the distinc- presentations. We recommend that the initial investiga-
tion more challenging (Fig. 5). In such situations, tive biopsy should be FNAB. The diagnosis of lympho-
excision biopsy is highly recommended, especially in ma requires recognition of cell type with appropriate
older patients. application of immunostaining/or flow cytometry to
Aspirates from midline thyroglossal duct cysts define the immunophenotype (318,322).
may be indistinguishable from branchial cleft cysts. Kaposi’s sarcoma. In AIDS patients, Kaposi’s sar-
Cytomorphologic features are not unique; therefore, coma commonly presents with nodular orofacial masses
clinico-radiologic correlation should lead to the cor- without ulceration and is especially seen involving the
rect diagnosis. Abundant colloid, most often with palate (356). There may or may not be accompanying
ciliated columnar epithelium, is the predominant lymphadenopathy (318,356). Aspiration cytology usu-
cytopathologic finding (349). ally produces a hypocellular specimen. However, the
diagnosis may be more readily made when lymph
Salivary Gland Lesions
nodes are involved (357,358). If cellular, the aspirate
shows tangles and individually dispersed cells. The cells
Tumors of the minor (accessory) salivary glands most are spindle or polygonal cells with bland, plump nuclei
commonly occur as nodular or ulcerative lesions in the without hyperchromatism, and occasionally reveal
tongue, hard palate, or buccal mucosa. Minor salivary characteristic longitudinal nuclear grooves (356). Hemo-
tumors are commonly malignant such as mucoepider- siderin granules may be found in accompanying macro-
moid, adenoid cystic, and PLGA (Table 48). FNA of phages. The most characteristic cytologic features are
salivary gland neoplasms are discussed in detail intact tissue fragments composed of overlapping spin-
elsewhere in this chapter. dle cells with nuclear distortion and ill-defined cyto-
PLGA. PLGA is a rare neoplasm that occurs plasmic borders. Smaller groups of loosely cohesive
almost exclusively in the minor salivary glands, par- spindle-shaped cells and individual spindle cells with
ticularly in the palate (350). This tumor is a low-grade cytoplasm can also be helpful features (356). Radial
malignancy that infrequently metastasizes to regional arrangement and nuclear crush artifacts have not been
lymph node and rarely metastasizes to lung (350). described in other spindle-cell intranodal lesions that
FNA shows hypercellular smears with numerous epi- could be considered in differential diagnoses (51). Spin-
thelial cells in a blood-stained background. The cells dle cells are usually positively immunostained for factor
are mostly arranged in branching papillae, sheets, and VIII, CD34, CD31, and vimentin and negative for S-100,
clusters composed of bland, relatively uniform cells. alpha-smooth muscle actin (a-SMA), and desmin.
The cells are cuboidal in shape, with mild atypia. The Neurofibroma. Occasionally, neurofibroma
nuclei are enlarged, round to oval, moderately hyper- occurs in the tongue and may be diagnosed by FNA
chromatic in shape, with coarsely granular, dispersed biopsy. The appreciation of microtissue fragments of
chromatin, and absent or inconspicuous nucleoli. The thin spindle cells with wavy spindle nuclei along with
cytoplasm is moderate, dense, basophilic, with indis- loosely cohesive and individual scattered spindle cells
tinct borders (351–354). Bare nuclei also frequently are seen (321). Often intermingled mast cells are
appear in the background. Myxoid matrix, either present in the background.
dispersed in the background or interspersed with Sarcomas. Chondrosarcoma, osteosarcoma, rhab-
the cellular elements, is also seen often. domyosarcoma, fibrosarcoma, leiomyosarcoma, liposar-
The differential diagnosis includes ACC, mucoe- coma, and angiosarcoma may all present as primary
pidermoid, monomorphic adenoma, and pleomorphic tumors in the soft tissues and bone of the oral cavity.
adenoma. However, absence of squamous cells and The cytologic findings are variable depending on the
extracellular or intracellular mucin should exclude type of sarcoma with features comparable to soft tissue
mucoepidermoid. The absence of three-dimensional malignancies at other sites. Complete discussion of the
cell clusters with a central core of hyaline basement FNA cytology features of sarcoma has been previously
presented in this chapter.
Table 48 Differential Diagnosis of Minor Salivary Gland Tumors
Arising in Oral Cavity
Pleomorphic adenoma
VII. NASAL CAVITY AND PARANASAL SINUSES
Mucoepidermoid carcinoma A variety of benign and malignant lesions affect the
Adenoid cystic carcinoma
nose, paranasal sinuses, and facial bones. The para-
Polymorphous low-grade adenocarcinoma (PLGA)
pharyngeal space is a well-defined anatomic zone of
64 Elsheikh et al.
loose connective tissue lying deep to the tonsil and but smears are usually very bloody (323,343). Plump
lateral to the pharynx. Rare neoplasms arising within spindle-shaped cells with pale indistinct cytoplasm
the parapharyngeal space are salivary gland tumors, are admixed with blood cells. The nuclei are bacillary
squamous-cell carcinomas, adenocarcinoma, lipoma, shape with blunt ends and a few nuclei may have
neurofibroma, paraganglioma, schwannoma, chor- folds or bends in their nuclear membranes. The chro-
doma, and NHL (359). matin is finely granular and small, but distinct nucle-
oli may be present.
Angiofibromas can be distinguished from nerve
A. Benign Lesions sheath tumors and malignant vascular neoplasms by
Paranasal Sinus Mucoceles their location and clinical features. Vascular malignan-
cies generally have a population of plumper cells with
Paranasal sinus mucoceles are cystic expansions of the more nuclear atypia (367).
paranasal sinuses due to obstruction of the draining
ostia. Aspiration of these masses will yield thick clear Sinonasal Hemangiopericytoma (Solitary Fibrous Tumor)
white mucus, which contains foamy or vacuolated
Approximately 20% of hemangiopericytomas are
mucus-filled hisiocytes (321). In long-standing cases,
found in the head and neck, especially the nasal cavity
the surrounding bone may show radiologic evidence
and paranasal sinuses. Histologically, the tumor is
of resorption.
circumscribed and composed of tightly packed prolif-
eration of short spindle or oval cells that form arcades
Rhinoscleroma around vascular slits and spaces lined by endothelial
Rhinoscleroma is a chronic granulomatous disease cells (368). Reticulin stains demonstrate reticulin fibers
caused by the Gram-negative bacteria, Klebsiella around each pericyte.
pneumoniae rhinoscleromatis, occurs most frequently The cytologic smears are modestly cellular with
in the middle East, Africa, and South America, and bloody background (368). The cells usually form tight
primarily involves the nasal cavity and nasopharynx aggregates and run in bundles, often with an arching
(343). Cytologic examination shows granulomatous appearance. Individual cells are oval or short spindle-
inflammation in which foamy macrophages (Mikulicz shaped and radiate along the long axis of the bundles.
cells) are admixed with plasma cells and granular The nuclei are bland, uniform, and oval, with finely
histiocytes (360). These macrophages contain short granular chromatin and inconspicuous nucleoli. No
rod-shaped organisms with thick capsules and bipolar mitotic figures or necrosis are identified. The presence
cytoplasmic enlargements, best identified with of branched capillaries and abundant basement mem-
Warthin-Starry stain (361). brane material supports a diagnosis of hemangioper-
icytoma (368). Malignant hemangiopericytoma
Myospherulosis
demonstrates uninuclear tumor cells with high nuclear
to cytoplasmic ratios, evenly distributed chromatin and
Myospherulosis usually follows nasal surgery and one or two small but distinct nucleoli (369).
packing of the area with petroleum-impregnated
gauze (362–364). A chronic inflammatory infiltrate B. Malignant Lesions
surrounds spaces within a fibrotic stroma. Lying free
within the spaces are saclike structures called ‘‘parent Nasopharyngeal Carcinoma
bodies,’’ which contain many spherules.
Smears contain large numbers of spherules mea- Nasopharyngeal carcinoma is a relatively uncommon
suring between 4 and 7 mm in diameter, best seen in malignancy in western counties, but frequently seen
Papanicolaou stain (362). They have smooth distinct in China. It can be classified into keratinizing, non-
borders and contain discrete internal bodies that may keratinizing, and undifferentiated types. The neo-
be single and central with a halo or multiple attached plasms may present as a neck mass, with hearing
to the periphery of the large spheres (362,363). The loss, nasal obstruction, nasal discharge, headache, or
spherules are orange to green. Myospherulosis must bleeding (343).
be distinguished from fungal infections. However, Metastasis to neck lymph nodes often is the
fungal culture and stains are negative. initial presenting sign of occult head and neck carci-
nomas, including undifferentiated nasopharyngeal
Angiofibromas
carcinoma (370). Cytologic findings from metastatic
deposits have been reported (370–373). Cytologic find-
Angiofibromas occur almost exclusively in young ings in FNA obtained from the keratinizing and non-
adult men. It may be hormonally-induced, secondary keratinizing subtypes of nasopharyngeal carcinoma
to imbalance between estrogen and testosterone levels resemble squamous cell carcinoma arising at other
(365). Most angiofibromas arise along the lateral or sites. The aspirates of undifferentiated nasopharyn-
superior nasopharyngeal wall and associated with geal carcinoma are more unique. These smears are
local destruction. Angiofibromas manifest with unilat- highly cellular and show clusters of cohesive neoplas-
eral nasal obstruction, epistaxis, facial swelling, tic cells with sharp or irregular edges, along with
exophthalmos, diplopia, or headache (366). Clinically, numerous single neoplastic cells (Fig. 111). The nuclei
the tumor is lobulated, sessile, red to tan, filling the of the neoplastic epithelial cells are oval or spindle-
nasopharynx (366). Cytologic findings are variable, shaped, with hyperchromatic nuclei and prominent
Table 49 Key Diagnostic Features—Olfactory Neuroblastoma

Cellular smears with dispersed cell pattern and small clusters of
round cells
Rosettes formation with open central lumen or core containing
blood vessels (infrequently seen)
Distinct fibrillary appearance in cytoplasm and fibrillary material in
the background
Paranuclear ‘‘blue bodies,’’ minimally indent the nuclei or seen in
the cytoplasm of macrophages.
Nuclei with coarse granular chromatin and single or multiple
nucleoli
Tumor necrosis with dirty background
of intact viable cell nuclei and pyknotic nuclei are

seen. The clusters show marked nuclear overlapping.
Rosette structures are found with open central lumens
or cores containing blood vessels. Fibrillary back-
ground material is seen. The nuclei are uniform,
Figure 111 Undifferentiated nasopharyngeal carcinoma. FNAB round or oval, with dark condensed chromatin and
smears are cellular and show clusters of cohesive neoplastic one to two nucleoli (Figs. 112 and 113). Nuclear
cells with sharp or irregular edges, along with numerous single
neoplastic cells. The nuclei of the neoplastic epithelial cells are
oval or spindle-shaped, with hyperchromatic nuclei and promi-
nent nucleoli. (Papanicolaou stain; magnification, 400).
nucleoli. Mitotic figures are frequent. The cytoplasm

is generally pale, with ill-defined borders. Mature
lymphocytes are intermingled with tumor cells in all
cases (370).
It is frequently difficult to separate undifferenti-
ated nasopharyngeal carcinoma from lymphoma. Rec-
ognition of cohesive cell clusters supports the
epithelial nature of the tumor cells, along with posi-
tive staining for cytokeratins. In addition, the nuclei of
nasopharyngeal carcinoma are more vesicular and
have a more oval or spindle shape than nuclei seen
in lymphoma (371).
EBV infection is consistently associated with
undifferentiated nasopharyngeal carcinoma and can
be detected using a nonradioisotopic in situ hybrid-
ization assay in FNA specimens. Therefore, detection
of EBV may be successfully used to identify the
nasopharyngeal origin of metastatic undifferentiated
carcinoma (374,375).
Olfactory Neuroblastoma (Esthesioneuroblastoma)

Olfactory neuroblastoma (esthesioneuroblastoma) is a
rare tumor of neuroectodermal origin that was first
described by Berger and Richard in 1924 (376). Olfac-
tory neuroblastoma constitutes approximately 0.3% of
upper aerodigestive tract malignancies and 6% of
nasal cavity and paranasal sinus tumors (377). The
majority of patients are young adults, presenting with
unilateral nasal obstruction or epistaxis.
FNA of olfactory neuroblastoma is infrequently Figure 112 Olfactory neuroblastoma. (A) Smears are cellular
encountered and is limited to case reports or small with isolated and small clusters of round cells. Suggestions of
series in the literature (378–383) (Table 49). Aspirates rosette structures with central fibrillary material are seen. (B)
from olfactory neuroblastoma are generally cellular Immunostaining for chromogranin is positive [(A) Papanicolaou
and bloody with many isolated round cells and small stain; magnification, 200 (B) IHC; magnification, 400].
clusters of round cells (381–383). Two cell-population
66 Elsheikh et al.
Figure 114 Olfactory neuroblastoma. Paranuclear ‘‘blue bodies’’

which minimally indent the tumor cell’s nuclei can be seen within
the cytoplasm of the tumor cells. These blue bodies are better
identified in air-dried preparation. However, they can also be seen
in small cell carcinoma (DQ stain; magnification, 400).
Table 50 Differential Diagnosis of Small Blue Round Cell

Tumors of Nasal Cavity
Sinonasal undifferentiated carcinoma
Small cell neuroendocrine carcinoma (primary)
Olfactory neuroblastoma
Rabdomyosarcoma
Melanoma
Lymphoma
Figure 113 Olfactory neuroblastoma. FNAB shows loose clus-

ters cells with marked nuclear overlapping. The nuclei are cases (380), other investigators did not see any rosettes
uniform, round to oval, with dark, condensed chromatin. Recog- in their specimens (384). The cells of olfactory neuro-
nition of a distinct fibrillary appearance in the cytoplasm and blastoma can show nuclear molding, significant
fibrillary material in the background are helpful in separating crushed artifact, and smudging of the nuclear material
neuroblastoma from metastatic small cell carcinoma [(A) Papa- in the smears. Recognition of a distinct fibrillary
nicolaou stain; magnification, 400 (B) DQ stain; magnification, appearance in the cytoplasm as well as fragments of
400]. fibrillary material in the background are helpful in
separating neuroblastoma from metastatic small cell
carcinoma of the lung (Fig. 113). Immunohistochemi-
cal studies may be helpful since small cell carcinoma
streaking artifact is common, but not universal, and is cytokeratins and TTF-1 positive and lymphoma is
tingible body macrophages are commonly found. usually positive for leukocyte common antigen (LCA)
Infrequently, markedly enlarged nuclei are present. and negative for epithelial markers (384).
Paranuclear ‘‘blue bodies’’ that minimally indent the
tumor cell’s nuclei or are seen within the cytoplasm of Sinonasal Undifferentiated Carcinoma
tingible body macrophages are found in the majority
of cases in one series (384). They are especially recog- Sinonasal undifferentiated carcinoma (SNUC) can be
nized in air-dried, cytologic material stained with DQ cytologically similar to olfactory neuroblastoma. How-
stain (Fig. 114). ever, in contrast to olfactory neuroblastoma, SNUC cells
Because of its histological similarities, primary display greater pleomorphism and may contain
olfactory neuroblastoma can be confused with other enlarged nucleoli (385). The tumor cells are cytokeratin,
malignant ‘‘small’’ blue round cell tumors (Table 50). CEA, EMA positive, while synaptophysin, S-100 and
The presence of true rosettes and fibrillary neuropil- chromogranin are usually negative. Paraganglioma has
like background are critical in recognizing neuroblas- an immunophenotype identical to neuroblastoma
toma (376,377). Although some studies demonstrated (negative for keratin and positive for chromogranin,
the presence of rosettes in more than 70% of their synaptophysin, and NSE, with surrounding S-100
positive sustentacular cells. However, the cytomorphol- tive in SNUC and when positive are weak and patchy
ogy of paraganglioma is completely distinct from olfac- (388).
tory neuroblastoma (384).
SNUC is a rare tumor that occurs in the nasal Sinonasal Neuroendocrine Carcinoma
passages and paranasal sinuses. The malignancy usu-
ally presents with nasal obstruction and septal devia- The differential diagnosis of poorly differentiated
tion. Oral examination may reveal a large ulcerative malignant tumors of sinonasal tract includes SNUC,
lesion involving the maxilla, frequently extending olfactory neuroblastoma, rhabdomyosarcoma, mela-
across the midline (385,386). SNUC is highly aggressive noma, and small cell neuroendocrine carcinoma
tumor with a poor prognosis and is often inoperable. (389). FNA of sinonasal neuroendocrine carcinoma
FNA smears are highly cellular and contain are cellular and show a monotonous population of
poorly differentiated small- to medium-sized cells small to medium-sized cells, which can be singly
with high nuclear to cytoplasmic ratios (385–388). dispersed, form loose aggregates and/or arranged in
The cells are arranged in nests, trabeculae, and sheets. irregularly shaped sheets (389,390). Features of neuro-
The nuclei are mildly to moderately pleomorphic. endocrine differentiation can be found including
Nucleoli vary from prominent and large to inconspic- rosette-like structures, and round or oval-shaped
uous and small (Fig. 115). Chromatin is usually nuclei with stippled chromatin and indistinct nucleoli.
homogenous and diffuse. Numerous mitotic figures, There is little variation in nuclear size and shape and
apoptotic nuclei, and necrosis are seen. Immunoreac- the cytoplasm can be poorly preserved. A fibrillary
tion to cytokeratin, and EMA is identified (385,388). background is not seen (389,390). A high-grade neu-
Chromogranin and synaptophysin are usually nega- roendocrine carcinoma with extensive necrosis, high
nuclear to cytoplasm ratio, nuclear molding, pleomor-
phism, crush artifact, lack of nucleoli, and numerous
mitoses has been described (391,392). IHC shows
positive staining for chromogranin, and synaptophy-
sin with strong diffuse cytoplasmic staining with
cytokeratins (AE1/3 and CAM 5.2). Olfactory neuro-
blastoma usually shows abundant fibrillary material
between the tumor cells, rosette-like structures and
sometimes Homer-Wright or olfactory rosettes, unlike
sinonasal neuroendocrine carcinoma (380,385,392).
Olfactory neuroblastoma is usually negative for cyto-
keratin, but up to one third can show focal positivity.
Sinonasal Adenocarcinoma
Sinonasal adenocarcinoma is uncommon and may be
related to exposure to wood dust and leather process-
ing. It arises from the surface epithelium and seromu-
cous glands. They frequently have an intestinal
appearance (393). The aspirate is moderately cellular,
with cohesive clusters of atypical columnar cells lying
in a background of cellular debris and mucin. Indi-
vidual cells are columnar and contained granular or
mucin-rich cytoplasm surrounding hyperchromatic-
elongated nuclei. The chromatin is coarsely granular
and prominent nucleoli are frequently present (343).
Sinonasal adenocarcinoma must be distin-
guished from metastatic colonic adenocarcinoma. A
clinical history is most helpful in this distinction.
Evidence of mucin production, and glandular differ-
entiation, separate these lesions from squamous cell
carcinoma.
Paraganglioma
Figure 115 Sinonasal undifferentiated carcinoma. (A and B) Carotid body tumors (paraganglioma) are benign neo-
FNAB is cellular with dyscohesive undifferentiated small- to plasms that arise from the autonomic nervous system.
medium-sized cells and high nuclear to cytoplasmic ratios. Nuclei They can occur at any age but are more frequent seen
are mildly pleomorphic with prominent nucleoli and frequent in the fifth decade, manifesting as a slowly growing
mitosis. Immunostaining for cytokeratin, CEA, and EMA will painless neck mass that is usually asymptomatic.
confirm the diagnosis [(A) Papanicolaou stain; magnification, FNA cytologic findings of a carotid body tumor
200 (B) DQ stain; magnification, 400]. are characterized by low to moderate cellularity
with bloody background (Table 51). Smears show
68 Elsheikh et al.
Table 51 Key Diagnostic Features—Carotid Body Tumor

Low-moderate cellularity with blood background
Basophilic cytoplasm with ill-defined margins
Round to spindle nuclei and prominent nucleoli
Mild to moderate pleomorphism
Fine reddish intracytoplasmic granules seen with Diff-Quik stain
Occasional intranuclear cytoplasmic inclusions
Figure 117 Carotid body tumor. The cells show moderate to

abundant basophilic cytoplasm with ill-defined margins and
round to oval nuclei with nuclear pleomorphism. While many
cells are polygonal, some can have a spindle shape (DQ stain;
positivity for chromogranin, synaptophysin, calcitonin,

and TTF-1 can confirm the diagnosis of medullary
carcinoma, rather than a paraganglioma.
Figure 116 Carotid body tumor. Smears are characterized by
moderate cellularity with bloody background. Cells are individu-
ally scattered or/arranged in clusters demonstrating an acinar/ Heterotopic Central Nervous System Tissue (Nasal Glioma)
microfollicular pattern (DQ stain; magnification, 400). This congenital nonneoplastic heterotopia of neuroglial
tissue usually occurs in the nasal cavity. Cytologic
smears usually show hypocellularity with neural tissue
individually scattered cells or clusters, demonstrating containing scattered moderate-sized cells with eccentric
an occasional acinar/microfollicular pattern (394–398) nuclei and multiple wispy cytoplasmic processes.
(Fig. 116). The cells showed moderate to abundant
slightly basophilic cytoplasm with ill-defined margins VIII. THE JAW AND FACIAL BONES
and round to oval nuclei with mild to marked nuclear
pleomorphism. Fine reddish intracytoplasmic gran- A wide variety of neoplasms and cysts occur within
ules can be seen with DQ stain. While many cells the jaw and facial bones, including some having
are polygonal, some can have a spindle shape. Intra- sufficient size to cause thinning or destruction of the
nuclear inclusions are occasionally present (298–401). overlying bone, which enables FNA biopsy.
FNA smears can show pleomorphic nuclei, prominent
nucleoli, clumped chromatin with finely granular A. Benign Fibro-osseous Lesions
cytoplasm and occasional intranuclear cytoplasmic
inclusions that can lead to a false-positive diagnosis Fibrous dysplasia, ossifying fibroma, and juvenile
of carcinoma (398–400) (Fig. 117). Distinguishing active ossifying fibroma are the currently accepted
benign from malignant paraganglioma is difficult, designations for these clinicopathologic processes.
but malignant lesions tend to have a tumor diathesis, Aspirates of these lesions usually yield smears of low
mitotic figures, and more prominent nucleoli that are to moderate cellularity. Individual spindle-shaped cells
not seen in benign lesions. are oval or short, with bland spindle-shaped nuclei and
Follicular-like arrangement and intranuclear inclu- a fine granular chromatin pattern (402). Occasionally,
sions in paraganglioma may lead to the diagnosis of three-dimensional fragments of bone or osteoid are
PTC or a FN. Medullary carcinoma could also be in the found. These processes are cytologically indistinguish-
differential diagnosis because of the presence of spindle able; therefore, clinical and radiographic findings are
cells and intranuclear inclusions. The anatomic location helpful in differentiating these three entities.
of the lateral neck mass with its prolonged history,
along with a hemorrhagic FNA specimen exhibiting B. Odontogenic Myxoma
cytologic features of an endocrine neoplasm should
help to make the correct diagnosis of paraganglioma Odontogenic myxoma is an uncommon tumor that
(400,401). In challenging cases, immunohistochemical has the potential for extensive destruction of the jaws
(403). Although, odontogenic myxoma is a benign aggregates. The mononuclear cells have dense, well-
neoplasm, it may have an infiltrative pattern, involv- defined cytoplasm and round nuclei with thin, delicate
ing the facial skeleton such as the mandible or soft membranes and fine chromatin. Additionally, some of
tissue (318). the cells have reniform nuclei with nuclear grooves or
FNA cytologic features of myxomas will reveal folds. The majority of smears have chondroid matrix.
abundant myxoid material in which slender ‘‘spindle- The appreciation of the chondroblasts is the most
shaped’’ or stellate mesenchymal cells are trapped useful feature in establishing the cytologic diagnosis
(404–407). These cells have elongated nuclei with (409,410).
bland chromatin. The tissue fragments obtained on
aspiration has a three-dimensional appearance and E. Ameloblastoma
often have entrapped delicately branching capillaries.
While the cells may appear slightly atypical, there is Ameloblastoma is the most common odontogenic
no evidence of nuclear anaplasia. Low cellularity and tumor, representing 1% of all jaw lesions. This is a
absence of cellular atypia, combined with the abun- locally aggressive tumor, arising from odontogenic
dant myxoid material in the background are impor- epithelial nests within the mandibule (411). It usually
tant features to differentiate this lesion from myxoid presents as a painless swelling with nasal obstruction.
sarcomas (404,405). Ameloblastoma is characterized by an unencapsu-
lated growth of epithelial nests and sheets, arranged
C. Giant Cell Lesions around a central zone of loosely spaced cells resem-
bling the stellate reticulum of the enamel organ. The
Giant cell lesions of the jaw and facial bones consist of epithelial cells are columnar or cuboidal cells with
four major entities represented by true giant cell small bland nuclei polarized away from the basement
tumor, giant cell reparative granuloma, aneurysmal membrane (412).
bone cyst, and the giant cell lesions of hyperparathy- FNA smears are usually cellular and contain a
roidism. All these lesions contain a mixture of small variable mixture of squamous, basaloid, spindle-
spindle-shaped to oval mononuclear stromal cells shaped and stellate cells (413). Sheets and clusters of
with a prominent number of multinucleated osteo- basaloid epithelial cells have poorly defined cyto-
clast-like giant cells (343). plasmic borders, and peripheral palisading is a prom-
Aspirates obtained from these giant cell lesions inent feature (413,414). The nuclear to cytoplasmic
have a similar appearance, providing few clues to ratios are high, with nuclei having coarse chromatin
distinguish them (405–407). The aspirate is often highly and indistinct nucleoli. The squamous cells demon-
cellular with a bloody background. The cellular com- strate individual cell keratinization with a glassy hya-
ponent is composed of osteoclast-like giant cells and line dense cytoplasm and open chromatin. A few
small mononucleated spindle- to oval-shaped cells fragments of loosely aggregated spindle cells repre-
(406). The nuclei of the spindle, oval and giant cells senting the stellate reticulum are often seen. The
are identical in giant cell tumors, but the nuclei of the background contains granular debris, fragments of
spindle-shaped cells in other lesions tend to be more pink stroma, and inflammatory cells. Malignant
elongated. Giant cells are also more numerous in the cases that metastasized have demonstrated prominent
giant cell tumors, but this is often difficult to estimate cytologic pleomorphism, cellular crowding with
on FNA. The giant cells found in true giant cell tumors molding and a high mitotic/karyorrhectic index
have more nuclei (more than 20) than do those seen in (415,416).
other giant cell proliferations (343). In all these lesions, Separation of ameloblastoma from metastatic
the giant cells frequently palisade around the periphery squamous cell carcinoma may be difficult, but recog-
of the stromal cell clusters. Aspirates from aneurysmal nition of the basaloid cell component and prominent
bone cyst are highly bloody with a few giant cells and palisading are helpful features for the diagnosis of
stromal cells scattered throughout the smears, making ameloblastoma.
the diagnosis difficult. Hemosiderin is abundant in
giant cell reparative granuloma, but is rarely seen in F. Odontogenic Cysts and Inflammatory Cysts
giant cell tumor (408). Open biopsy may be necessary
to properly classify these lesions (408). Several types of cysts develop from the dental epithe-
lium and may produce radiolucent lesions within the
D. Chondroblastoma mandible or maxilla. FNA is rarely performed for
these cysts since they are often covered by intact
Chondroblastoma usually presents as a lytic lesion in bone (406,407). They are subclassified on the basis of
the epiphyseal region of long bones, but can rarely origin, histologic and radiographic findings into pri-
affect temporomandibular region. They tend to occur mordial cysts, odontogenic keratocysts, calcifying
in older patients and have a high rate of local odontogenic cysts, and dentigerous cysts.
recurrence. The characteristic radiologic image is a On histologic examination, all cysts show a strati-
growth-plate related, sharply defined radiolucency, fied squamous epithelium lining. Cytologic examina-
containing areas of calcification with sclerotic margin. tion will show small numbers of benign-appearing
Smears are moderately to markedly cellular, composed squamous, columnar, or cuboidal cells admixed with
of osteoclast-type giant cells and mononucleated inflammatory cells in a watery background. An abun-
round to polygonal cells occurring singly or in loose dance of keratinizing cells and anucleate squamous
70 Elsheikh et al.
cells characterizes odontogenic keratocytes. The impor- Orbital Cytology

tance of recognizing these cysts is in establishing their
benign nature and its separation from metastatic squa- The major indications for biopsy of an intraocular
mous cell carcinoma. In the benign cystic lesions, the tumor are (i) the failure to establish a diagnosis with
squamous component will appear bland with small noninvasive imaging techniques; (ii) a confusing clini-
uniform nuclei, while squamous cell carcinomas will cal presentation, such as an amelanotic uveal tumor
show significant nuclear atypia. In calcifying epithelial with a history of a prior carcinoma; (iii) presence of
odontogenic tumor, sheets, and large clusters of poly- media opacities, such as a dense cataract or vitreous
hedral cells with abundant calcific material and depos- hemorrhage with ultrasound demonstration of a cho-
its of an amorphous material are seen (417,418). roidal mass; and (iv) patients/or oncologist unwilling
Because of the lack of frank malignant cells and the to undergo definitive treatment without pathologic
presence of numerous calcific spherules and amor- confirmation of the clinical impression (428–430).
phous, eosinophilic material, squamous cell carcinoma
and MEC can be excluded (419). Sampling Techinques
Lesions involving the skin, conjunctiva, and to the
G. Intraosseous Salivary Gland Tumors lesser extent, the cornea can be scraped. The lesions
should be scraped gently, removing small fragments
Intraosseous salivary gland tumors primarily arising of tissue with a small spatula or blunt side of scalpel
in the jaw and mandible are quite uncommon. A blade. Local anesthesia may be needed for conjuncti-
variety of benign and malignant salivary gland neo- val and corneal lesions (425).
plasms can occur, with MEC being the most frequent The pars plana (closed) vitrectomy is the most
malignancy, which can have an aggressive course common intraocular biopsy technique to analyze cells
(420). The histogenesis of central intragnathic salivary in the vitreous (425,427). This technique was first
gland tumors has been a subject of debate with two described by Machemer et al. in early 1970s (431,432).
pathogenesis proposed: (i) sialogic tissue metaplasia It has been performed as a therapeutic procedure to
of odontogenic cysts or odontogenic tissue remnants, remove vitreous opacities due to hemorrhage and
and (ii) enclaves of salivary tissue retained during membranes and lens debris from the vitreous seen
embryogenesis (421). mainly in proliferative diabetic retinopathy (433).
Although most of intragnathic salivary gland In addition to therapeutic indications, vitrectomy
tumors have been diagnosed by histological methods is also performed for diagnostic purposes (433–437).
(422–424), there are reports of FNA diagnosis of these Engels et al. (435) divided diagnostic vitrectomies into
lesions (421,424). Most intraosseous gnathic mucoepi- three categories: (i) Those performed to make specific
dermoid carcinomas are of low grade with frequent diagnoses, (ii) those performed to confirm a presumed,
mucinous-cell components. The presence of squamous but clinically unproven diagnosis, and (iii) those per-
cells, especially if atypical, associated with mucinous formed to diagnose a previously unsuspected condi-
material is strongly suggestive of mucoepidermoid tion. Vitrectomy is usually performed to rule out
tumor (421). lymphoma, or metastatic tumors to the vitreous
(436,437).
IX. TUMORS OF THE EYE Specimens for cytologic examination can be pro-
AND OCULAR ADNEXA cessed using standard concentrating methods such as
Millipore filtration, liquid-based procedure such as
A. Introduction ThinPrep (Cytyc Corp., Marlborough, Massachusetts,
U.S.), and AutoCyte Prep (TriPath Imaging, Burling-
Primary tumors of the orbit can arise from the adnexal ton, North Carolina, U.S.), with results superior to
glands, connective tissue (i.e., fat, vascular fibrous direct smears. Cytospin preparations have also been
tissue, cartilage and bone), extraocular muscles, successfully used (429). Occasionally, samples may
peripheral nervous system, and the optic nerve and contain sufficient material for a cell block (435).
its sheath. In addition, tumors of adjacent structures We routinely perform microbiological and
can invade the orbit. Lymphoid tissue is not a normal cytological examination of the washings collected.
component of the orbit; however, lymphoid aggre- Immediate fixation of the specimen is preferred to
gates in the lacrimal gland become increasingly prevent overgrowth of the exogenous bacteria or
frequent with age. There are no lymphatics or lymph fungi, which can thrive in the highly nutritive vitreous
nodes behind the orbital septum (425). fluid and, thereby, elicit a false-positive diagnosis of
Biopsy of the eye and its adnexa is rarely per- bacterial infection (425).
formed, even in specialized centers. The eye anatomy is
complex and many cytopathologists are unfamiliar Fine Needle Aspiration Biopsy
with the cytology of various ocular lesions. Early
attempts with large core needle were associated with The role of FNA in the diagnosis of intraocular tumors
tumor extension in some cases (426,427). However, has been reported in a number of studies (427,438–443).
with the development of recent noninvasive imaging Despite initial concerns that FNAB could result in
techniques, there is increasing confidence of ophthal- tumor seeding along the needle tract (444) or produce
mologists in obtaining samples by FNA and vitreous major vision-threatening complications, it has proven
washing. to be a generally safe and reliable diagnostic technique
(445–447). FNAB has become an established diagnostic histologic concordance, with less than 2% false-
method for the evaluation of a variety of neoplastic and negative/false-positive rates and 6.3% insufficient
nonneoplastic intraocular lesions (448–452). FNA is a specimens (458). However, in Krohel’s series, a low
minimally invasive procedure without the morbidity cytopathologic concordance was reported with 24%
and expense of an orbitotomy. nondiagnostic or insufficient specimens (461). IHC
The diagnosis of orbital lesion is usually based could be helpful in assessment of specimens and
on clinical and radiologic findings. However, in some appropriate classification of the tumors (457). Eide et
occasions, the clinical and radiologic diagnoses are not al. (443), performed IHC on over half of their patients
conclusive, requiring a tissue diagnosis. FNAB has and they were able to increase the positive predictive
been used for the initial tissue diagnosis of orbital value of the cytologic diagnois from 93% to 96% and
mass lesions. There are two significant advantages of increased the specificity from 67 to 83%.
orbital FNA for the primary diagnosis of lacrimal and There are many advantages to orbital FNAB,
adnexal gland lesions. First, a definitive FNA diagno- including high accuracy (95%) in distinguishing
sis saves the patient from unnecessary surgical inter- benign from malignant lesions and allowing an imme-
vention. Second, preoperative FNA diagnoses may diate diagnosis reducing patient anxiety. FNAB also
help to better plan the surgical approach. FNAB is obviates the need for open biopsies in 40% to 50% of
generally reserved for the following situations: cases (458). However, FNAB does not allow assess-
(i) patients with nonresectable deep orbital lesions ment of tissue architecture, may produce a scanty
that require extensive surgery for diagnosis, (ii) the specimen and interpretation requires a trained cyto-
failure to establish a diagnosis with noninvasive imag- patholgist. Fibrotic or desmoplastic lesions of the orbit
ing techniques, (iii) patients with orbital lesions who may result in low cellular smears, with lack of diag-
cannot tolerate a more extensive procedure, and (iv) nostic material in 10% to 18% of specimens. False-
patients unwilling undergo definitive treatment negative biopsy may occur if the needle does not enter
before pathologic confirmation of the diagnosis the orbital lesion in question. Cohen et al. (462) found
(445,447,449,450). that tumors less than 2 mm had a higher incidence of
Orbital examination, visual acuity, and fundus false-negative diagnoses than those greater than
examination should be performed by the ophthalmol- 4 mm. Similarly, Augsburger et al. reported a diag-
ogist. Informed consent is obtained, with an explana- nostic accuracy of 68% in small choroidal lesions (463).
tion of the possible complications. Patients should be Although orbital FNA is a relatively safe proce-
informed that a negative biopsy is not definitive, and dure, there are certain limitations (459). Cystic orbital
even a diagnostic FNAB does not eliminate the possi- lesions should not be subjected to FNAB. Patients with
bility of subsequent surgical exploration. Local anes- a bleeding diathesis, those on anticoagulation, or
thesia is not used because there is generally minimal patients with highly vascular lesions, such as a sus-
pain from the FNA procedure and anesthetic injection pected arteriovenous malformation, cavernous hem-
could distort the tissue. angioma, or hemangiopericytoma, should not
For orbital FNAB, we usually use 23- to 25-gauge undergo FNAB (459). Individuals with high myopia,
needle, attached to a 10-mm syringe to generate especially those with intraocular lesions are at greater
negative suction. Orbital ultrasonography or computed risk for globe perforation, and should be approached
tomography (CT) guidance, may improve the accuracy with care. Uncooperative patients, such as the mentally
of deep orbital aspirates (453,454). The needle is intro- challenged or children, are poor candidates for orbital
duced by the ophthalmogist through the upper or FNAB (459).
lower lid in the lateral or medial quadrants, rather The risk of needle tract recurrence with the use
than in the superior or inferior quadrants. Once the of FNA (21–25 gauge) biopsy is exceedingly low.
needle is in the lesion, small forward and backward Henderson suggested that solid masses of lacrimal
movements through the lesion are made, while suction gland should not undergo FNA because of the risk of
is maintained. The suction should be released prior to disseminated disease (464). However, no case of
exit of the needle. For routine studies both alcohol tumor seeding due to the aspiration has been
fixed, Papanicolaou-stained, as well as air-dried, DQ- reported. In cases of suspected retinoblastoma, aspi-
stained smears are prepared. Zajdela et al. described a ration is contraindicated because of the risk of spread
successful series of orbital FNA without suction (455). along the needle track of this notoriously ‘‘sticky’’
The on-site cytopathologist may assess sample adeq- tumor (465). Some authors have reported experimen-
uacy to decrease false-negative results at the time of the tal data, suggesting that there is a risk of needle tract
procedure (456). In addition, tissue culture, immunos- seeding of melanoma cells (447,466). Shields et al.
taining, and even molecular studies can be performed have recommended enucleation within 24 hours of
on these samples (427,430,448,457). biopsy of a proven malignant neoplasm (466).
Complications of orbital FNA are not common,
Diagnostic Accuracy but can be serious. The more common complications
are retrobulbar hemorrhage and retinal detachment.
Combining the clinical and radiologic features of The most serious uncommon complication is eye
orbital lesions, with the aspiration biopsy results, the perforation, which may require cryoretinopexy
diagnostic yield of orbital FNAB can be greater than (467,468). Retrobulbar hemorrhage following FNAB
80% (458–460). In a review of 292 FNAB of palp- usually resolves without ocular sequelae. Other com-
able orbital and eyelid tumors, 87%, had a precise plications of FNAB include transient visual loss,
72 Elsheikh et al.
ocular motility disturbance, and ptosis (468). Lesions

directly over the vertical aspects of the globe are
associated with a greater risk of scleral perforation.
B. Benign Lesions
Infections
Viral diseases. Viral diseases include molluscum
contagiosum, verruca vulgaris, herpes zoster, and
herpes types 1 and 2, which can infect the lids and
conjunctiva. Some of these diseases are frequently
sexually transmitted and can be sight threatening.
Viral disease is not usually diagnosed by cytology
alone, but it is possible to diagnose poxvirus induced
molluscum contagiosum by identifying eosinophilic,
rounded cytoplasmic inclusions. Similarly, virus
induced veruca vulgaris and the effects of the herpes
simplex viruses 1 and 2 can be diagnosed by cytologi-
cal techniques (425,428). Cytomegalovirus (CMV)
infection can also be seen in immunocompromised
patients (469). Corneal scrapings showed many
enlarged cells with characteristic CMV nuclear inclu-
sions. The diagnosis can be confirmed by in situ
hybridization, and viral culture.
Bacterial and fungal conjunctivitis. Bacterial and
fungal conjunctivitis are best diagnosed by culture
(470,471). Cytology may be helpful in detecting
unusual infections such as actinomysis, acanthamoe-
bic keratitis (472), or blastomycosis, especially when
the organisms are superficial. In HIV and immuno-
suppressed patients, intraocular infections are more
common. FNA has been used to diagnose intraocular
aspergilosis, mucormycosis (Fig. 118) and coccidiodo-
mycosis (473,474). Cytologic examination of aqueous
Figure 118 Orbital fungal infection: FNA technique can be used
humor can reveal inflammatory cells (i.e., polymor- to diagnose orbital fungal infection. Smears usually show necrot-
phonuclear leukocytes, histiocytes-macrophages, and ic background with mixed chronic inflammatory cells. (A) Asper-
lymphocytes), cocci or other microorganisms gillus species with abtuse branching septate hyphae, better seen
(475,476). The collected sample in the syringe should with special fungal stain. (B) Mucormycosis infection in diabetic
be immediately sent to the laboratory: half mixed with patient demonstrates ribbon-like, pale-staining, pauciseptate,
an equal amount of 50% ethanol solution and fresh branching hyphae [(A) Silver fungal stain; magnification, 200
specimens for microbiologic examination. (B) DQ stain; magnification, 600).
Vernal conjunctivitis. Vernal conjunctivitis is a
recurrent hypersensitivity reaction of the conjunctiva,
occurring in atypic-allergic patients. Patients have
increased levels of IgE in the serum and tears (477). A number of entities can mimic ocular infection
This condition may mimic other causes of ‘‘red eye’’ including ghost cell glaucoma, phacolytic glaucoma,
and may be subjected to microscopic evaluation. The phacoanaphylactic endophthalmitis, and iridocyclitis
resulting smears contain inflammatory cells, including (475). In general, a more dense infiltration by neuro-
eosinophils, mast cells, basophils, and lymphocytes. If phils and lymphocytes supports the diagnosis of
the condition is chronic, goblet cells may be abundant. infectious endophthalmitis, even in the absence of
Careful search for signs of Chlamydia is important, micro-organisms in the cytologic specimens of the
because the treatment of the two diseases is different. aqueous humor.
Chlamydial conjunctivitis (trachoma). Chlamydial Ghost cell glaucoma. In ghost cell glaucoma,
conjunctivitis (trachoma) has characteristic inclusions, RBCs are present in the vitreous for an extended
which can be appreciated in conjunctival smears in 8% period losing their hemoglobin. They become ghost
of patients (478,479). Naib correlated perinatal ocular erythrocytes leading to mechanical obstruction and
and maternal genital infections concluding that 61% glaucoma. The cytological findings are pathognomo-
of 54 mothers of a set of infected newborns had nic, when numerous ghost erythrocytes in the absence
diagnosable Chlamydia in recent cervical smears of inflammatory cells are identified.
(480). PCR shows comparable results to standard Phacolytic glaucoma. Phacolytic glaucoma may
McCoy cell culture, with equal specificity and more occur exogenously after lens damage by traumatic
senitivity (479). disruption or endogenously with hypermature cataract.
Phacolytic cells are swollen histiocytes with lightly

eosinophilic granular cytoplasm and lens material.
These cells can be seen in anterior chamber aspirate
specimens causing mechanical obstruction of the ante-
rior chamber angle (481). Cytologically, the presence of
lens material and phacolytic large macropohages with
the synchronous absence of an inflammatory reaction
are characteristic.
Phacoanaphylactic endophthalmitis. Phacoana-
phylactic endophthalmitis develop infrequently after
hypermature cataracts, or cataract surgery (481,482).
The cytologic findings may demonstrate granuloma-
tous or a nongranulomatous inflammation (481). The
negative microbiological culture and the clinical out-
come (response to the removal of the lens or lens
remnants and corticosteroids) support the diagnosis.
Idiopathic orbital inflammation (Sclerosing Orbititis).
Also referred to as inflammatory pseudotumor, idio-
pathic orbital inflammation (sclerosing orbititis) in the
acute form has an abrupt onset of pain, injection,
chemosis, and decreased ocular motility. The inflam-
mation involves orbital soft tissues including fat, extra-
ocular muscle, tendon, lacrimal gland, and blood
vessels (483,484). In the chronic form, there is marked
fibrosis that may envelop the structures of the orbit and
mimic a malignant neoplasm. Occasionally FNAB may
be performed and revealed scant aspirates with a few
fibroblasts and lymphocytes.
Granulomatous Lesions
Foreign body granuloma. Foreign body granuloma
may present with a subconjunctival or orbital lesion.
Usually patients are not aware of a previous injury or
Figure 119 Ruptured dermoid cyst. Smears show anucleate
implanted foreign material. Patients present with a red squamous cells, keratin debris, and granulomatous inflammation
eye and reduced eye movements. FNA demonstrates with multinucleated giant cells [Papanicolaou stain; (A) magnifi-
granulomas with foreign-body type giant cells. Infec- cation, 200 (B) magnification, 400].
tions should be excluded with culture and special stains
(Table 52).
Chalazions. Chalazions are lipogranulomatous
reactions of the eyelid, occurring when Meibomian However, deep dermoids and those with extension
gland obstruction occurs secondary to inspissated through bone sutures are frequently difficult to diag-
secretions (485). These painful swellings are caused nose clinically and may be subjected to FNA (458).
by retained secretions of the Meibomian glands and FNA contains anucleate squamous cells, keratin debris,
are characterized by a mixture of lipogranulomatous and occasionally hair shafts. A ruptured dermoid cyst
and suppurative inflammation. Occasionally the cha- will also contain granulomatous inflammation with
lazion may present as a discrete nodular mass, mim- multinucleated giant cells (Fig. 119).
icking a sebaceous carcinoma (447,485). Smears of the Wegener’s granulomatosis. Wegener’s granulo-
aspirate show numerous hisiocytes with foamy cyto- matosis is characterized by necrotizing vasculitis and
plasm and occasional granulation tissue. granulomatous inflammation in the upper respiratory
Dermoid cyst. Dermoid cyst is the most common tract, lung, and kidneys. Orbital involvement occurs in
orbial tumor in children. It is preferable not to aspirate about 20% of the cases and is usually bilateral. These
a dermoid cyst to avoid spillage of its contents (485). lesions frequently have extensive fibrosis with scanty,
non-diagnostic FNA specimen.
Sarcoidosis. Sarcoidosis occurs more frequently
Table 52 Differential Diagnosis of Orbital Granulomatous
Lesions
in black women, involving lacrimal glands in 7% of
patients. Ocular sarcoidosis can clinically simulate a
Chalazions neoplasm. FNA demonstrates granulomatous inflam-
Dermoid cyst, ruptured mation without necrosis (Fig. 120). Multinucleated
Infections giant cells are usually evident. Culture and special
Wegener’s granulomatosis
stains are needed to rule out an infectious etiology.
Sarcoidosis
Whipple disease
Whipple disease. Selsky et al. (486) reported ocular
involvement in a patient with Whipple’s disease.
74 Elsheikh et al.
of the rectus muscles and composed of large vascular

channels. The vessel walls contain smooth muscle and
there is fibrous tissue in the trabeculae that separates
the vessels. Radiologic studies show a rounded mass
with smooth contours. Although it would preferable to
not aspirate this lesion because of the risk of orbital
hemorrhage, FNA of few cases have been performed
without complications. FNA specimen reveals only
bloody smears (447,459).
Hemangiopericytoma
Hemangiopericytoma is a vascularized tumor with
characteristic staghorn appearance of vessels, and
interspersed spindle cells. The clinical findings
include proptosis, palpable mass, pain, and diplopia.
FNA reveals spindle and oval cells with occasional
branched vessels.
Mucoceles
Mucoceles are tumors composed of extracellular
mucous debris, caused by obstruction of the ostia of
the sinuses. The frontal sinus is the most common
origin for orbital mucoceles (487). FNA reveals a large
amount of mucoid material with occasional vacuolated
macrophages (mucophages).
Pilomatrixoma
Pilomatrixoma is a benign neoplasm that appears as
subepidermal nodule in the head and neck region,
most commonly in children and young adults. Cyto-
logically, pilomatrixomas are characterized by cellular
Figure 120 Granulomatous inflammation. (A) Granulomatous smears with three cell populations (488,489) (Fig. 121).
reaction with chronic inflammation and extensive necrosis usual- The first is of the small basaloid type, with scanty
ly results from infectious agents. (B) Sarcoidosis aspirates cytoplasm and round regular nuclei. The nuclear
demonstrate granulomatous inflammation with clean background chromatin of these cells is finely granular and evenly
and occasional multinucleated giant cells. Sarcoidosis is the
distributed. The second is of the squamous cells type,
diagnosis of exclusion after negative special fungal stains with
clinical and serological correlation. [(A). Papanicolaou stain;
with bland nuclei and evidence of keratinization. The
magnification, 400 (B) DQ stain; magnification, 400]. third, which is the epithelial cell type, is the shadow or
ghost cell, showing a high degree of keratinization
and lacks demonstrable nuclei. The ghost cells are
most easily seen on air-dried material, but are also
Characteristic vitreous opacities and retinitis, with con- recognized on Papanicolaou-stained smears. They fre-
sequent compromised visual acuity, are a result of quently have a pale, poorly discernible cytoplasm and
infiltration of the tissue with foamy macrophages. often appear only as outlines of cells. In addition to
These benign histiocytes contain intracytoplasmic PAS the epithelial component, scattered multinucleated
positive material. Electron microscopy discloses baciliary foreign body giant cell reaction to the keratinous
bodies. Many patients respond favorably to antibiotics. material is often present. A pitfall for a false-positive
diagnosis is not recognizing the presence of ghost cells
and misinterpreting the basaloid cells as a high-grade
C. Benign Neoplasms malignancy (489).
Ectopic lacrimal glands may be aspirated and are
composed of clusters of acinar cells, having small Pleomorphic Adenoma
bland nuclei. These glandular groups should not be
confused with adenocarcinomas, in which the nuclei Pleomorphic adenoma of the lacrimal gland usually
have malignant features. present as slow growing, painless mass, accounting
for 50% of epithelial lacrimal gland tumors (490–492).
Cavernous Hemangiomas It has been suggested that open biopsy of lacrimal
pleomorphic adenoma may lead to needle-tract seed-
Cavernous hemangiomas are well-encapsulated ing (464). However, no documented case of seeding
tumors located behind the eyeball within the boundaries following FNA has been reported. Smears show
Figure 122 Orbital meningioma. Smears show bland round-

oval cells with smooth nuclear membranes and fine chromatin.
The meningiothelial cells tend to aggregate in whorls arrange-
ment. (Inset) Psammoma bodies can be occasionally seen
(Papanicolaou stain; magnification, 400 (Inset) magnification,
600).
inconspicuous nucleoli, and occasional nuclear pseu-

doinclusions. The classic three-dimensional concentric
whorls of these cells (noncalcified psammoma bodies)
provide for the conclusive diagnosis (496) (Fig. 122).
Psammoma bodies are not present as frequently in
primary central nervous system (CNS) meningiomas.
Figure 121 Pilomatrixoma. Smears are cellular with distinctive Reactive meningeal hyperplasia can be seen with optic
two cell populations. (A) Small basaloid cells with high nuclear nerve gliomas and metastatic carcinomatous meningitis.
to cytoplasmic ratio, high mitotic activity, and apoptosis.
(B) Clusters of benign anucleated squamous (shadow or
ghost) cells. The ghost cells are most easily seen on air-dried Schwannoma (Neurilemmoma)
material [(A and B) DQ stain; magnification, 400].
Schwannoma (neurilemmoma) occurs in patients aged
between 20 and 50 years and can be separated or
associated with neurofibromatosis. Clinically, patients
frequently exhibit proptosis, lid swelling, diplopia,
similar cytologic features of pleomorphic adenomas and indentation of the posterior sclera (485). FNA of
seen in the major salivary glands. schwannoma is usually not diagnostic because scant
material is obtained as a result of the cohesive archi-
Meningioma tecture of the neoplasm (459). However, when a
Although meningioma can involve the orbit by exten- myxoid background is associated with spindle cells
sion from the intracranial space, the lesion may also and wavy nuclei are seen in the smears, the possibility
arise from the meninges covering the optic nerve and of neural lesion can be suggested. Positivity for S-100
present as a retrobulbar mass within the orbit. Menin- will support the neural origin of these tumors.
giomas may compress the optic nerve and lead to
hearing and visual deficits (493,494). The optic nerve
may show fusiform swelling, diffuse thickening, or D. Malignant Tumors
globular enlargement (485). FNA can effectively diag-
Basal Cell Carcinomas
nose orbital meningiomas. The aspirate is composed of
small ovoid nuclei with scant cytoplasm (446,447, Basal cell carcinomas are the commonest malignant
494–496). Nuclei demonstrated fine chromatin, lesion of the eyelid and the cytodiagnostic method of
76 Elsheikh et al.
choice is scraping the lesion. Basal cell carcinomas

usually occur in elderly patients who have had a long
exposure to sunlight and are commoner in the lower
lids. They are usually single lesions, but can be
multiple in patients with xeroderma pigmentosum.
Because of their proximity to the eye, exenteration of
the orbit and loss of the globe may be necessary to
control the disease in neglected cases. These lesions
are often easily recognized clinically and are readily
amenable to undergo shave or excisional biopsy.
However, occasionally, recurrent basal cell carcino-
mas will undergo FNA (425).
The material produced by scraping appears
white or translucent and spreads easily on the slide
and/or separates into small fragments. This appear-
ance is characteristic for basal cell carcinoma. Smears
demonstrate clusters of small dark basaloid cells with
scant cytoplasm, and distinct cell border. Cytologic Figure 123 Kertinizing squamous cell carcinoma. FNAB may
examination reveals nuclear palisading along the show large numbers of neutrophils in the background, leading to
edges of the cell clusters (497). The individual cells false-negative diagnosis. Looking for the atypical keratinizing
show monomorphic nuclei with finely granular cells may give a clue for the appropriate diagnosis (Papanicolaou
hyperchromatic chromatin and occasional nucleoli. stain; magnification, 400).
Mitoses are rare except in rapidly growing tumors.
In cases with marked pleomorphism, squamous carci-
noma should be excluded.
Adenoid Cystic Carcinoma (ACC)
Squamous Cell Carcinoma ACC accounts for about 25% to 30% of all epithelial
lacrimal gland tumors (490,499). In addition, ACC can
Squamous cell carcinoma of the eyelid is less common be metastatic from lung (500). Clinically, the patients
than basal cell carcinomas. Squamous carcinomas can usually have symptoms of pain and develop a mass in
also occur at the limbus and conjunctiva, in contrast to the lacrimal fossa. With CT scan, ACCs are globular
basal cell carcinoma. Squamous cell carcinoma is also tumors, but frequently have irregular destructive mar-
the most common paranasal sinus tumor to invade the gins around orbital bone (501). FNA cytologic features
orbit (498). The clinical appearance is that of an have been previously discussed in this chapter.
indurated ulcer with a raised irregular border. Scrap-
ing is frequently painless, although the lesions usually
Sebaceous Carcinoma
easily bleed. Patients with squamous carcinoma of a
sinus involving the orbit have a poor prognosis (498). Sebaceous carcinoma of the eye is a rare tumor,
Scraping usually produces numerous single cells representing 5% of malignant epithelial tumors and
due to the lack of cellular cohesion. The cytologic frequently involves the lower eyelid (502). Sebaceous
appearances vary according to the degree of differen- carcinoma arises from either the Meibomian glands or
tiation. Poorly differentiated squamous cell carcinoma the glands of Zeiss. The clinical diagnosis of sebaceous
has cells with large vesicular nuclei, prominent nucle- carcinoma is difficult since it can simulate other eyelid
oli, pleomorphism and lack of polarity, and most lesions (503,504). Sebaceous carcinoma may present as
importantly, the presence of intercellular bridges. In a small yellow nodule (mimicking chalazion), a dif-
well-differentiated squamous carcinoma, the diagno- fuse thickening of the eyelid (mimicking blepharitis),
sis is readily made, especially in the Papanicolaou- or a mass in lacrimal fossa (504). Sebaceous carcinoma
stained smears. Typically, some of the cells may be are aggressive tumors, especially when they arise
highly keratinized with dense organeophilic cyto- around the ocular adnexae, requiring wide excision
plasm. Nuclei with malignant features are present, and careful follow-up is needed to detect metastases
but there are often degenerative forms having dark (504).
hyperchromatic and/or opaque pyknotic nuclei. Anu- FNA of sebaceous carcinoma has been reported
cleate necrotic ‘‘ghost’’ cells are almost always present in case reports and series of eyelid tumors (487,505–
(493). Smears often contain large numbers of neutro- 507). Aspirate smears are usually cellular consisting of
phils in the background and a granulomatous reaction large cell aggregates and individually scattered cells
can be present as a reaction to the keratinizing debris (487,507). Many of the cells within the aggregates are
(Fig. 123). A pitfall for a false-positive diagnosis of necrotic or degenerated, with densely clumped, frag-
malignancy is a scraping from benign skin ulcers, mented chromatin. The smear background generally
where the smears from the healing edges may contain contains abundant necrotic debris and fragments of
reparative atypical squamous cells, and occasional degenerating cells. Individual cells have moderate to
mitotic figures. However, these benign ulcers are abundant cytoplasm, which frequently has a foamy, or
nearly always painful and difficult to scrape unlike finely reticular or bubbly, sebaceous appearance. The
squamous carcinoma. nuclei are enlarged with coarse chromatin and
prominent nucleoli. Generally, mitotic figures are

easily identified. Oil red O stains will demonstrate
intracellular fat. A second population of basaloid cells
with small dark nuclei and scant cytoplasm is seen in
the smears. Multiple biopsies to determine the extent
of the tumor is recommended, since sebaceous carci-
noma in the eyelid can be multifocal in up to 10% of
cases (485).
Merkel Cell Tumor

Merkel cell tumor is a primary carcinoma of the skin
with neuroendocrine features, occurring most fre-
quently in elderly individuals. The face and upper
extremities are common sites of origin. Aspirates from
Merkel cell tumor are cellular, with the majority of
cells individually scattered with occasional rosette-
like clusters or three-dimensional groups (508–510)
(Fig. 124, Table 53). Nuclei are enlarged, with a finely
granular evenly dispersed chromatin pattern. The
nuclear membranes are delicate, and nuclear molding Figure 125 Merkel cell carcinoma. Formalin-fixed, paraffin-
is generally absent, a feature helpful in distinguishing embedded cell block section shows the characteristic nuclear
Merkel cell tumor from metastatic small cell carcino- features of Merkel cell carcinoma, imparting a ‘‘salt,’’ rather than
ma of the lung (Fig. 125). The nuclear distribution is the coarse and fine ‘‘salt and pepper’’ chromatin of small cell
uniform and fine imparting a ‘‘salt,’’ rather than the carcinoma. Immunostaining for CK20 and negative staining for
coarse and fine ‘‘salt and pepper’’ chromatin of small TTF-1 and CK7 support the diagnosis of Merkel cell carcinoma
cell carcinoma. Mitotic figures are plentiful. A feature and exclude metastatic small cell carcinoma (H&E stain; magni-
of diagnostic aid is the presence of perinuclear depos- fication, 400).
its best seen on Papanicolaou staining (508). IHC
staining demonstrates the presence of neuron specific

enolase (NSE), neurofilament, and a characteristic
pattern of CK-20 perinuclear, dot-like positivity, and
negativity for TTF-1 and CK7.
Orbital Teratomas
Orbital teratomas are rare, but they form an important
differential diagnosis in neonatal orbital masses. Only a
few FNA cases of orbital teratomas with malignant
changes have been reported (511–513). The eye may
show proptosis, lid edema, conjunctival chemosis, and
a keratinized cornea. Orbital teratoma is usually multi-
loculated, cystic masses with solid areas, compared
with the unilocular cystic lesions such as dermoid
and epidermoid inclusion cysts (513). Malignant tera-
tomas are of three types: teratomas with germ cell
tumors, teratomas with nongerminal malignant tumors
Figure 124 Merkel cell carcinoma. Smears are cellular with
(carcinoma and sarcoma), and immature teratomas that
small round blue dyscohesive malignant cells. The cells demon- metastasize. FNA cytologic features are dependent on
strate large nuclei and a finely granular evenly dispersed chro- the components sampled and the type of teratoma
matin. The nuclear membranes are delicate, and nuclear molding (513).
is generally absent (Papanicolaou stain; magnification, 400).
Retinoblastoma
Retinoblastoma is the most common intraocular neo-
plasm occurring in infants and children (514). It is
Table 53 Key Diagnostic Features—Merkel Cell Carcinoma
derived histogenetically from primitive neuroepithe-
Cellular smears with individually scattered cells lial cells that have the potential to differentiate into the
Large nuclei with finely granular, evenly distributed chromatin three layers of sensory retina, i.e., neurons, astrocytes,
Delicate nuclear membranes and photoreceptors (rods and cones) (515). Histologi-
Nuclear molding is usually absent (in contrast to small cell cally, the tumor is characterized by the presence of
carcinoma) undifferentiated small round cells with a variable
Tumor cells are positive for CK20 and negative for CK7 and TTF-1 tendency to form Flexner-Wintersteiner rosettes.
78 Elsheikh et al.
Table 54 Key Diagnostic Features—Retinal Neuroblastoma well-differentiated retinoblastomas (Fig. 126). The
presence of Flexner-Wintersteiner rosettes is consid-
Cellular smears with necrotic debris and inflammatory
background
ered to be an important morphologic feature for the
Two types of dyscohesive cells: undifferentiated cells (small diagnosis of retinoblastoma (449,515,520); although, in
round cells) and cells with early photoreceptor differentiation a significant number of cases, they may not be seen
(abundant, pale staining cytoplasm with cytoplasmic process) (521,522).
Flexner-Wintersteiner rosettes formed by peripheral arrangement As many as 16% of eyes removed with the
of nuclei with fine central fibrillary cytoplasmic process. clinical diagnosis of retinoblastoma contain a simulat-
However, a significant number of cases may not show this ing lesion (517). The main differential diagnoses are
feature. vitreous hemorrhage, Coat’s disease, and ocular tox-
ocariasis (517). Coats’s disease is suspected cytolog-
ically when a subretinal aspirate reveals foamy
macrophages, which frequently contain coarse, oval
Cytological smears are hypercellular with single melanin pigment. Inflammatory cells (especially lym-
cells and cohesive clusters in which nuclear molding phocytes) are also noted (450). In toxocariasis, cytolog-
can be present (515–519) (Table 54). Smears show ical aspiration reveals a predominance of eosinophils.
necrotic debris and inflammatory cell in the back- In vitreous hemorrhage, the FNA consists erythro-
ground. The single cells can be divided into two cytes without any tumor cells (450). Metastatic neuro-
types with several transitional forms. The first cell blastoma can occur within the eye including the orbit,
type includes undifferentiated cells with high nuclear which may lead to diagnostic confusion with retino-
to cytoplasmic ratios, and markedly basophilic cyto- blastomas (518). Flexner-Wintersteiner rosettes are
plasm (449,520). These cells are indistinguishable from more usually associated with retinoblastoma than
the undifferentiated cells present in other small round- neuroblastoma. History is crucial in this differential
cell malignant tumors of childhood (515) (Fig. 126). The diagnosis.
second cell type shows abundant, pale staining The diagnosis of the great majority of retinoblas-
cytoplasm with peculiar cytoplasmic processes. These toma can be achieved with noninvasive techniques,
processes are usually short and ‘‘hump-like,’’ although including indirect ophthalmoscopy, ultrasonography,
occasionally they can be long and slender. The and imaging procedure (CT and MRI). Shields and
presence of these cytoplasmic processes is probably Shields (517) reported only 2 FNA out of 500 referred
an indication of early photoreceptor differentiation. patients with a questionable retinoblastoma diagnosis.
The nuclei usually reveal deep indentations (451). The utilization of FNAB for the diagnosis of retino-
Flexner-Wintersteiner rosettes are formed by blastoma is controversial among ophthalmologists
peripheral arrangement of nuclei with fine central and ocular oncologists. Some authors have reported
fibrillary cytoplasmic processes. Florets with the usefulness of this procedure in cases with diag-
photoreceptor cell differentiation are found only in nostic clinical uncertainty (449). Other investigators
have argued against FNAB because of the possibility
of tumor seeding and spread outside the globe
(518,519). There is no question that tumor seeding of
the needle tract takes place, but the long-term viability
of the spilled tumor cells causing extraocular spread is
questionable (518). Tumor growth outside of the globe
is a rare but a serious occurrence. Therefore, FNAB
should be limited to the extraordinarily unusual clini-
cal circumstance such as parents requesting histopath-
ologic verification of retinoblastoma before definitive
treatment, (especially enucleation), and recurrent or
metastasis of retinoblastoma in extraocular tissues
(516,518,519,523).
Metastatic Carcinoma
The frequency of ocular metastases has been reported
to be about 1% from grossly detectable orbital lesions
and 12.6% for microscopic metastases (425,524). Most
metastatic cancers occur in the uveal tract, while
metastases to the retina and optic disc are rare
(524–526).
Figure 126 Retinal neuroblastoma. Smears are cellular with Although metastases to the orbit usually reflect
Flexner-Wintersteiner rosettes, formed by peripheral arrange- disseminated disease, the occurrence of a metastatic
ment of nuclei with fine central fibrillary cytoplasmic processes. deposit in this region may rarely be the initial presen-
The cells are elongated with early photoreceptor differentiation tation of a patient’s malignancy (527). When metastases
(DQ stain; magnification, 400). do occur in the region of the eye, they are commonly
from the breast in women, from the lung in men, and
from neuroblastomas in children (527,528). Small cell E. Melanocytic Lesions

carcinoma is the most common type of lung cancer that
metastasizes to the orbit. It is important to recognize Melanotic Neuroectodermal Tumor of Infancy
the possibility of metastases since the orbital findings Melanotic neuroectodermal tumor of infancy is a rare,
are sometimes the initial manifestations of the malig- usually benign neoplasm, involving the anterior alve-
nancy. The cytologic findings of small cell carcinoma olar ridge of the maxilla (539), but it has also been
can mimic another small cell neoplasms such as lym- described in other sites. CT and MRI are used to
phoma. The differentiating cytologic features include determine the amount of bony invasion and involve-
diffuse salt and pepper chromatin, lack of prominent ment of important structures (540,541). Increased lev-
nucleoli, nuclear molding, cell necrosis (apoptosis), and els of vanyl-manidelic acid in the urine occurs in a
nuclear crush artifact. small minority of cases (542,543).
A variety of orbital metastases from other differ- Grossly, the tumor is rapidly growing pig-
ent organs have been reported such as mucinous mented (blue-black) soft tissue mass that displaces
ovarian carcinoma (528,529), ovarian carcinoma the upper lip. It may invade bone and orbit. Histolog-
(530), chordoma (531) (Fig. 127), ACC from salivary ically, the tumor is not encapsulated and composed of
glands and bronchial epithelium (532,533), hepatocel- dual population of small neuroblastic cells and larger
lular carcinoma (534,535), and carcinoids (536). Con- melanin-containing epithelial cells in a dense fibrous
trary to the pattern of eye metastases in general, stroma. The small neuroblastic cells are tightly
metastases from the thyroid gland tend to involve arranged into small nests, surrounded by pigmented
the orbit more commonly than the globe (537,538). cells in an alveolar or tubular formation. FNA smears
Orbital invasion by tumors from adjacent structures is reveal a cellular aspirate with two different cell pop-
also common. ulations. The predominant cells consist of small, uni-
form neuroblastic cells with round nuclei and scanty
to absent cytoplasm. The second population is oval to
cuboidal large melanin-containing cells with eccentri-
cally placed nuclei and moderate amount of cyto-
plasm. The granules of melanin pigment had a
round to rod shape and stained brown with a Papa-
nicolaou, bluish with DQ and black with the Masson-
Fontana stain. The tumor is positive for HMB-45 and
cytokeratin in the large pigmented cells and synapto-
physin positive in the small round cells.
Melanocytoma (Magnocellular Nevus)

Melanocytoma (magnocellular nevus) is a rare,
benign, heavily pigmented tumor that classically
arises from the optic nerve; however, it might arise
anywhere in the uveal tract (544,545). Melanocytomas
occur primarily in heavily pigmented Caucasians and
African-American adults. Melanocytomas can cause
glaucoma either by direct spread into the anterior
chamber angle (546), or massive dispersion of pigment
into the angle from extensive necrosis of the tumor
(547).
Only 15% of melanocyomas of optic disc enlarge
over time (545), infiltrating the juxtapapillary choroids
and optic nerve mimicking uveal melanomas (544).
FNA examination reveals heavily pigmented polygo-
nal cells with small vesicular nuclei and abundant
cytoplasm totally packed with melanin granules
(Fig. 128). Other cells appeared as branching dendritic
cells with stubby cytoplasmic processs. Bleached
preparation revealed the bland cytologic features of
the melanocytic cells. Melanocytoma should be differ-
entiated from uveal melanoma. The pigment granules
Figure 127 Metastatic chordoma to the orbit. (A) FNAB shows in melanocytoma are much larger than those observed
tumor cells with low nuclear to cytoplasmic ratio, bubbly vacuo- in uveal melanomas, and the cellular features of the
lated cytoplasm, and relative bland nuclei (physaliferous cells). bleached cytologic preparations are benign (548).
(B) Chondromyxoid metachromatic stroma is wrapping around Benign melanocytic lesions (nevi) of the iris may
physaliferous cells, better seen in DQ [(A) Papanicolaou stain; grow to occlude the angle, leading to intractable
magnification, 400 (B) DQ stain; magnification, 400]. glaucoma. The presence of large numbers of mucin
containing goblet cells, sometimes aggregated into
80 Elsheikh et al.
Figure 129 Malignant melanomas, Optic disc, plasmacytoid

type. FNAB shows loosely cohesive malignant cells. Cells are
epithelioid with high nuclear to cytoplasmic ratio and prominent
nucleoli. Finely granular gray-black cytoplasmic pigment can be
seen (Papanicolaou stain; magnification, 400).
premalignant state known as primary acquired mela-

nosis with atypia (550).
Melanocytic primary tumors of the conjunctiva
can be diagnosed by scrape cytology and touch
preparation cytology. Primary malignant melanomas
should not be investigated by FNA cytology. How-
ever, metastatic deposits and occasional nodular
melanomas will undergo FNAB. Smears from these
lesions are usually highly cellular and often have a
bloody background. Melanomas have a wide range
Figure 128 Melanocytoma (magnocellular nevus). FNAB reveals of histologic and cytologic appearances, varying
hypocellular smears with heavily pigmented polygonal cells, small from spindle-shaped to plasmacytoid cells (Fig. 129).
vesicular nuclei, and abundant cytoplasm totally packed with Woyke et al. (550) reported the following cytologic
melanin granules. Bleached preparation revealed the bland cyto- features that frequently occur in melanoma: (i) lack of
logic features of the melanocytic cells. [(A) DQ stain; magnification, cellular cohesion; (ii) binucleation or multinucleation of
200 (B) Papanicolaou stain; magnification, 600].
tumor giant cells; (iii) prominent nucleoli, intranuclear
vacuoles, or pseudoinclusions. A subtype of melanoma
is the predominantly spindle cell melanoma, in which
the cells have long cytoplasmic processes and fusifom
cysts may suggest a mucoepidermoid tumor to the nuclei (Fig. 130). Occasionally lipoidal degeneration will
unwary. In addition, they may have an apparent rapid lead to balloon cells (551) Positivity for S-100, Melan-A,
increase in size, leading to the clinical suspicious of and HMB-45 are helpful in establishing the diagnosis of
melanoma. They may also involve the iris stroma malignant melanoma (552).
extensively as well as having plaque-like extensions Aspirates of the anterior chamber in cases of
across the face of the iris (425). Unlike true melanoma malignant melanoma may contain pigment-laden
cells, the nevus cells from these lesions do not have macrophages or even melanoma cells. Melanophages
prominent nucleoli. should be differentiated from hyperplastic pigmented
epithelial cells, derived from either the ciliary or iris-
pigmented epithelial cells or from retinal-pigmented
Malignant Melanoma
epithelium. Pigmented epithelial cells are typically
Malignant melanoma can occur in various ocular cuboidal, with large individual melanin granules,
structures such as the eyelid, conjunctiva, uveal whereas macrophages tend to have aggregates of
tract, and orbit. The great majority ocular melanomas melanin pigment present as clumps within lyosomes.
occur in the uveal tract (iris, ciliary body, and choroid) Pigmented macrophages containing iron are seen in
(548,549). However, choroid melanomas may rapidly the anterior chamber and angle following intraocular
enlarge, destroying visual function (549). Most con- hemorrhage and are often accompanied by ‘‘ghost’’
junctival melanomas either arise de novo or within the erythrocytes.
thyroid lesions. Available at: http://www.papsociety.

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535. Srinivasan R, Krishnanand G. Cytologic diagnosis of Ophthalmology 1999; 190:1516–1520.
metastatic hepatocellular carcinoma presenting as an
orbital mass: a case report. Acta Cytol 2007; 51(1):83–85.
2
Uses, Abuses, and Pitfalls of Frozen-Section Diagnoses

of Diseases of the Head and Neck
Mario A. Luna
Department of Pathology, The University of Texas, M.D. Anderson Cancer Center,
Houston, Texas, U.S.A.
I. INTRODUCTION within a short time. The use of the cold chamber cry-
ostat, introduced into surgical pathology in the late
The frozen-section tissue examination, performed 1950s by Ibanez et al. (3), has eliminated most of the
during surgery while the patient is still under anes- technical shortcomings of the procedure. In most
thesia, was introduced 100 years ago, and the tech- instances, the quality of the preparations is equal to
nique is accepted as an integral part of the proper or only slightly less perfect than that of permanent
surgical treatment of a patient (1,2). Entire generations sections subjected to paraffin embedding.
of pathologists and surgeons have become familiar Several methods and a variety of microtomes
with the method and its benefits to them and their are currently available for the preparation of frozen
patients. Although frozen sections may be requested sections. Within 15 minutes, the newer cryostats can
by surgeons for several specific reasons, all are based provide a satisfactory section stained with hemato-
on their desire to obtain accurate diagnostic informa- xylin and eosin (H&E). At the M. D. Anderson Hospi-
tion, from which they will decide on the immediate tal the procedure is as follows: The biopsy specimen
surgical procedure. removed at time of surgery is transported to the
Frozen-section diagnosis should be considered a pathology laboratory by surgical personnel; because
cooperative effort between physicians, because the the frozen-section laboratory is adjacent to the operat-
surgical pathologist’s report carries the same weight ing rooms, the transportation takes little time. The
as that of any other consulting physician. It is impera- gross specimen is examined by a staff pathologist and
tive that a sound dialogue be established between the a pathology resident, and a representative portion is
surgeon and pathologist over the need for, limitations selected for cryostat sectioning. All tissue sections are
of, and consequences of the frozen-section diagnosis; prepared by a technologist. The tissue is embedded on
however, the actual decision of whether or not to a metal chuck with the use of a commercial prepara-
prepare a frozen section is up to the pathologist, rather tion (OCT, optimal cutting temperature compound,
than the surgeon. manufactured by Laboratory Technical Instruments
Company, Westmont, Illinois, U.S.). The compound
II. HANDLING OF THE TISSUE SAMPLE is sectioned with the tissue, but disappears in the
staining process.
Fragments of tissue obtained for frozen sections For freezing, the metal chuck is placed in an
should be sent to the pathologist in the unfixed insulated stainless steel box containing aluminum
state. Immersion in formalin, even for a brief time, racks, around which dry ice is packed into the box.
interferes with adherence of the sections to the glass The temperature of the box is –668C or less. Into the
slide, makes the technique more difficult, and may top of the racks, cylindrical cavities have been drilled
inhibit the performance of special studies, such as for the tissue holders; these cavities are filled with
cultures and immunofluorescence. To avoid desicca- 95% ethyl alcohol. The metal chuck containing the
tion, the specimen may be sent to the pathology specimen of tissue is inserted into one of the cylindri-
laboratory, wrapped in a piece of gauze moistened cal cavities of the rack. From 15 to 20 seconds are
with saline solution. required for freezing a block of tissue 15 15 3 mm
in diameter. When frozen, the tissue, with the holder
III. TECHNIQUE FOR PREPARING attached, is placed on the microtome inside the cold
A FROZEN SECTION chamber and sections are cut at 6 to 8/mm for fixation.
The slides, with the tissue attached, are next immersed
The technique of frozen-section preparation is not for a few seconds in a solution composed of equal
difficult, although the sections must be thin and parts of ether and absolute methyl alcohol and then
clearly stained, and the study should be completed stained with H&E. Stained sections are mounted and
96 Luna
retained for permanent reference. The time required differences. Remsen et al. (11) found an accuracy rate
for preparation and microscopic interpretation aver- of 100% on the submandibular gland, nose, and para-
ages 10 minutes. The pathologic diagnosis is relayed nasal sinuses, followed by the thyroid gland (99.2%),
directly to the surgeon by an intercommunicating neck (97%), parotid gland (95.4%), skin (94.3%), and
system. The exact verbal report is recorded by the larynx (93.2%). Areas in which frozen-section diagno-
pathologist on a specially designed ‘‘Frozen Section sis was least accurate included the nasopharynx
Diagnosis Form,’’ which becomes a permanent part of (87.5%) and the oropharynx (91.3%).
the pathology record of the patient. A duplicate of the Factors involved in improving the reliability of
diagnosis form is retained in the laboratory. frozen sections are (i) preparations of high quality
A much faster technique has been used at the with the use of the cryostat, (ii) experience of the
Mayo Clinic for many years, with excellent results (4). pathologist in performing frozen-section diagnoses,
The difference is that the tissue slides are stained with (iii) familiarity of the pathologist with the clinical
toluidine blue instead of using the conventional H&E history of the patient, (iv) direct communication with
stain (5). The only inconvenience is that tissue stained the surgeon, (v) availability of a qualified histology
with toluidine blue will fade with time and cannot be technologist, (vi) readily available consultation with
retained as permanent reference. staff pathologists, (vii) close cooperation between an
Dehner and Rosai (6) have emphasized the experienced surgeon interested in pathology and a
importance of keeping a written record of the pathologist dedicated to patient care, (viii) continual
frozen-section diagnosis exactly as it was verbally retrospective critical analysis of performance, and
rendered. They have given the following reasons for (ix) examination of selected cases and periodic discus-
this precaution: (i) It provides a permanent record for sion of frozen sections with the surgical team.
medical and legal purposes, (ii) it protects the pathol-
ogist and surgeon from possible misunderstanding
at the time of verbal communication, and (iii) it V. ERRORS
provides a retrievable format for periodic evaluation
of the procedure. Four types of errors are possible in frozen-section
diagnosis: sampling, interpretive, communicative,
and technical (16). Although improper surgical or
IV. ACCURACY pathologic sampling errors are unavoidable, the num-
ber may be reduced by an even more cautious gross
In reviewing publications evaluating the accuracy of examination or by cutting additional sections of tissue
frozen-section diagnosis in head and neck surgery, from different levels of the block submitted for frozen-
one is impressed by the generally high degree of section diagnosis. In my experience, the latter practice
accuracy obtained. The figures quoted have often is especially useful in studies of cervical lymph nodes
included deferred diagnoses. When these are exclud- in metastatic melanoma and thyroid carcinoma.
ed, the number of accurate diagnoses has varied from Gross-sampling errors by pathologists are not unusual
97% to 99%. This figure compares favorably with the in neoplasms of the salivary and thyroid glands.
0.7% to 2.5% rate of error reported previously in Interpretive errors are those made when the
general surgery (4,6–16). Dehner and Rosai (6) quoted pathologist fails to recognize a lesion that is actually
an accuracy rate of 96% on 1187 individual nonde- present in the frozen sections. In tissues from the head
ferred frozen sections. This is identical with the data and neck, this error is not uncommon in the interpre-
of Remsen et al. (11) and Bauer (12), which dealt tation of sites of a previous laryngeal biopsy (13), in
exclusively with frozen tissues from the head and irradiated tissues (16), and in unsuspected, unusual
neck. Also, of interest is the pronounced difference lesions. In the first and second cases, it is helpful if the
between the incidence of false-positive and false- pathologist has knowledge of the clinical history of the
negative diagnoses. The percentage of false-negatives patient and has reviewed the previously removed
is quite low, although still three times that of false- histologic material. In the last instance, given clinical
positives. There is no doubt that the attitude of the information and adequate tissue, the pathologist may
pathologist is, as a rule, one of extreme conservatism still have difficulty in arriving at a correct diagnosis.
in handling frozen-section material. As a consequence, Only the experience of the surgical pathologist can
confronted with the situation in which the problem of reduce interpretive errors.
neoplasia must be resolved, we are three times as Lack of identification of the exact source of the
likely to err on the side of conservatism. tissue specimen submitted for frozen-section diagno-
Gandour-Edwards et al. (13) analyzed the accu- sis is the communicative error most often committed
racy of frozen-section diagnosis in head and neck by the clinician. This neglect is especially frustrating
surgery in relation to the reason for the intraoperative in the histopathologic evaluation of lymph nodes of
request. Their accuracy rate in 1947 specimens for the neck if the typical surgical pathology request form
evaluation of adequacy of surgical margins was contains nothing more than the information ‘‘cervical
98.3%. The accuracy rate for diagnosis of an unknown node.’’ Such a problem can be solved only through the
process in 258 specimens was 96.6%, and no discrep- exchange of information between the surgeon and the
ancies occurred in the five requests for tissue identifi- pathologist.
cation. Analysis of accuracy of consultation by Technical factors, for example, slides of poor
anatomic region of the head and neck revealed certain quality, lead to interpretive errors by the pathologist.
Chapter 2: Uses, Abuses, and Pitfalls of Frozen-Section Diagnoses 97
This, however, should not be accepted as the sole of adequacy of surgical margins, 11.7% (25) for diag-
cause of error. The pathologist is the ‘‘captain of the nosis, and only 0.2% (5) for tissue identification.
ship’’ in the frozen-section laboratory. We agree with
Saltzstein and Nahum that ‘‘the surgical pathologist
should be aware that he is having problems and either B. Contraindications
correct them if at all possible or, if he is unable to The contraindications for and misuses of frozen sec-
correct them, report the situation to the surgeon’’ (16). tion are as follows:
1. When the frozen-section diagnosis carries no
VI. INDICATIONS AND CONTRAINDICATIONS immediate decision, for example, academic curi-
A. Indications osity, drama, or gamesmanship.
2. If tissue is heavily calcified or ossified.
The indications for the frozen-section examination, 3. If the tissue specimen is unique and small.
which have been discussed at length by many authors 4. For lesions that, even under optimum conditions,
(4,6–16) are, briefly, as follows: require extensive study because of their complex-
ity. These include the lymphoreticular disorders,
1. As an initial study, to obtain a histologic diagnosis small superficial melanocytic lesions, and some
when a definitive therapeutic procedure is to be granulomatous diseases.
carried out immediately. If, however, the treat-
ment would be the same, regardless of the nature
of the lesion or of other information gained, there VII. INTRAOPERATIVE CYTOLOGY
is no justification for a frozen section.
2. To assess the adequacy of the surgical excision by The use of imprint and smear cytology is a useful
a check of the margins of resection. Frozen-section adjunct to the frozen section, with proved acceptable
examination of the margins of neoplasms of the accuracy rate (17–20). The reports that have compared
head and neck is a common practice. intraoperative cytologic techniques with frozen sec-
3. To preliminarily assess the nature of the planned tions have noted similar accuracy rates. However,
procedure, as determined by the extent and dis- when both techniques are combined, this figure
tribution of the tissue involved by tumor. This increases to almost 100% (20). Cytologic techniques
is especially common in laryngeal surgery in are particularly useful when sampling lymph nodes
which the decision is between partial and total that are suggestive of either lymphoma or metastatic
laryngectomy. disease, parathyroid tumors, salivary gland tumors, or
4. To identify or diagnose any abnormality of tissue thyroid lesions (21–23).
observed during surgery that gives rise to a ques- The greatest advantage of cytologic examination
tion in the surgeon’s mind. is that minimal tissue is needed for examination;
5. To ascertain whether a biopsy is satisfactory for therefore, diagnosis of very small lesions is facilitated,
diagnostic purposes, thus eliminating the need and tissue is saved for permanent sections and special
for additional multiple biopsies, even though studies. Certain tissues that often cannot be adequate-
further surgery is not contemplated at the time. ly assessed by frozen section for technical reasons
This point is not infrequently presented when (e.g., bone, fat, or necrotic tissue) may be also appro-
lymphoma is suspected clinically and a cervical priate for intraoperative cytologic diagnosis.
lymph node or tonsillar biopsy is performed. In There are several situations in which an intra-
such cases, one-half of the specimen should be operative cytologic study is generally not as useful as
used for frozen section, while the other half is frozen-section examination. These include the evalua-
fixed for paraffin sectioning to eliminate the devel- tion of resection margins, the presence or absence of
opment of artifacts incident to freezing. stromal invasion, or the depth of invasion of a malig-
6. To determine if a lesion requires immediate or nant neoplasm (17–23).
special handling. For example, tissue for electron
microscopy and immunofluorescence requires VIII. REGIONAL APPLICATIONS OF
special treatment for optimal results. By knowing FROZEN-SECTION DIAGNOSIS
that a lesion is inflammatory, one will be able to
obtain adequate bacteriologic or viral cultures. A. Surgical Margins
7. To use the frozen-section technique when neces-
sary on biopsies taken from outpatients. This pro- Successful local control of a malignant tumor depends
cedure allows triage of a large number of patients on eradication not only of the gross disease but also
with lesions of the upper respiratory and digestive of its microscopic or subclinical extension (24–27).
tracts and rapid scheduling and treatment when Usually an experienced surgeon is able to resect the
necessary. palpable or visible tumor with a fringe of normal
tissue and feel confident of its complete removal in
The reasons for requesting an intraoperative 67% of the cases (24). Occasionally, however, to the
consultation in head and neck surgery have been chagrin of the surgeon, the pathology report, complet-
analyzed by Gandour-Edwards et al. (13). In their ed several days postoperatively, indicates the pres-
material of 2210 frozen sections from 258 patients, ence of microscopic cancer at the resected margins. To
88.1% (1947) of sections were requested for evaluation avoid this dilemma, the experienced surgeon, with the
98 Luna
aid of a pathologist competent in frozen-section eval-

uations, can determine the extent of the resected
tumor, pinpoint areas of any microscopic cut-through,
and usually tailor the surgical procedure to comp-
letely eradicate the local disease. The reliability and
usefulness of frozen sections to assess surgical mar-
gins is well documented with an accuracy rate of 99%
(28). However, frozen sections do have limitations and
frozen sections are not always helpful in preventing
final positive margins (28). To be assured of adequate
margins when assessing a resected malignant tumor,
the pathologist must be familiar with the patient’s
anatomy in the area of the operation, must possess an
intimate knowledge of the clinical behavior of the
various types of tumor with which the surgeon
deals, and must develop a close working relation
with the surgeon during frozen-sections examina-
tion (29). Measurements of margins on formalin- Figure 1 Preparation of circumferential margins taken by the
fixed specimens are inferior to in situ, frozen-section pathologist for frozen-section examination.
samples because of postremoval and postfixation
shrinkage. Formalin-fixation, according to some stud-
ies, produces an overall mean shrinkage of 2.7%, and
dehydration, clearing, and paraffin embedding margin). From the pathologist’s point of view, in situ
account for 12.5%. Other studies, however, indicate carcinoma, severe dysplasia, and microinvasive carci-
that tissue processing may result in a reduction or noma have equal biologic significance (29).
shrinkage as high as 46% from the planned surgical The surgical margins for frozen section may be
margin before resection to the assessed measurement removed by two methods (24–26). In the first, depend-
of microscopic clearance in the pathology laboratory ing on the size of the tissue and the nature of the
(29). tumor, the pathologist may take full-thickness
The concept of adequate margins varies from samples or, alternatively, circumferential margins in
surgeon to surgeon and there is no uniform criteria addition to the base of the specimen (Fig. 1). In the
accepted to define a clear surgical margin among second method, the surgeon removes the surgical
practicing head and neck surgeons (30,31). The con- margins directly from the patient and submits them
cept of adequate surgical margins is influenced by the for frozen-section examination (Fig. 2). If positive,
size and type of the neoplasm, its anatomic site, and provides sequential margins until the new margin is
the type of operation (conservative, palliative, or free of neoplasm on frozen-section examination. This
radical) required. A surgical margin that is considered is the method used by most of the head and neck
to be adequate for a well-differentiated squamous surgeons at our institution since 2005.
carcinoma is of a different order from that indicated The usual practice at the M. D. Anderson Hospi-
for an adenoid cystic carcinoma or melanoma (29,32). tal, when the pathologists take the sections for frozen
The finding of a significant relationship between
involved margins and pT stage grouping is not sur-
prising (32). It is logical that large tumors are more
difficult to resect, given the anatomical restrains that
operate in many sites of the head and neck. The
surgical margins vary according to the anatomical
region; margins from carcinoma of the glottis cannot
be compared with those carcinomas of the oral cavity
and oropharynx. In a study by Bauer et al. (33), 39 of
111 patients treated by hemilaryngectomy had posi-
tive margins, none of the patients received any further
therapy, and in 5 to 12 years follow-up local recur-
rences developed in only 7 of 39 (18%). In contrast, the
reported local recurrence rate in patients with carci-
noma of the oral cavity, oropharynx, and hypophar-
ynx whose pathologic specimens exhibited positive
margins is 71% (25,26). Also, the presence of dyspla-
sia, carcinoma in situ, and invasive carcinoma at the
surgical margins cannot be placed in the same catego-
ry. In the study of Loree and Strong (26), the five-year Figure 2 Surgical resection of cancer. Margins of resection
survival rate was drastically different (94% of patients taken by the surgeon directly from the patient and submitted for
with dysplasia, 71% of those with in situ carcinoma, frozen-section examination.
and 43% of those with invasive carcinoma at the
Figure 3 Processing of surgical specimen. Sections are taken Figure 4 Ideal preparation for study of surgical margins for
from the different margins of resection as well as from the closest frozen section.
margins.
section, is as follows: the surgeon personally delivers

the resected tumor to the pathologist, orients the
specimen for him, and observes while the margins
are excised and examined microscopically (22,27). If
the margin is inadequate at any point, or if the tumor
is grossly very close, further marginal tissue is excised
and submitted for additional frozen-section evalua-
tion until a clear margin is confirmed or the surgical
procedure is terminated. However, it has to be recog-
nized that in those cases when the margin was initially
positive on frozen section, the assumption that the
final margins are negative may not be an accurate
assumption, because the well-known problems of
relocating the site from which the frozen section was
positive (27,34).
The frozen-section technique used to evaluate
the margins of the resected lesion consists of the
following: (i) The closest border of the resected lesion Figure 5 Histologic frozen-section slide of surgical margin.
is stained with india ink to determine its position as Sections should include full thickness from surface to base of
medial-lateral, superior-inferior, or anterior-posterior excision without tissue defects (cryostat-prepared section, H&E
(Fig. 3). (ii) Serial full-thickness sections are made, the stained). Abbreviation: H&E, hematoxylin and eosin.
lesion being sliced like a loaf of bread when possible
(Fig. 4); if this is not feasible, sections are taken of all of
the edges of the lesion, as well as of the base. As the specimens included 15 squamous cell carcinomas,
histologic frozen sections for microscopic evaluation 3 mucoepidermoid carcinomas, and 3 sarcomas (36).
exhibit the full thickness, these should include the For ‘‘adequate’’ surgical margins, the following
mucosal surface as well as base of excision and not observations are pertinent:
have tissue defects (Fig. 5).
For the mandibular margin of resection, a touch 1. No standard guidelines on evaluating surgical
imprint cytologic preparation or cryostat sections of margins intraoperatively have been established.
curetted samples of the cancellous bone have served 2. No uniform criteria to define a clear surgical margin
as specimens with varying degrees of success and exist among practicing head and neck surgeons.
acceptance. Forest et al. (35), with a 1-cm curettage 3. Frozen-section examination is the ideal method
specimen and frozen section, were able to correctly to assess distance between tumor and surgical
predict adequacy of mandibular resection in 32 of 33 margins because of postremoval and postfixation
margins. Oxford and Ducic (36) have developed a shrinkage.
simple technique that allowed frozen-section exami- 4. In spite of the lack of universally defined clear
nation of cortical bony margins in 38 patients; the margins, there is little doubt that gross residual
method has a sensitivity of 89% and a specificity of tumor will yield local persistence and nearly
100%. Malignancies diagnosed on frozen cortical bone always an increased mortality.
100 Luna
5. A significantly lower incidence of local recurrence

is reported in patients with primary cancers of the
glottic larynx who had positive surgical margins
than in patients who had primary tumors of the
oral cavity, oropharynx, or hypopharynx with posi-
tive surgical margins.
6. For Tl, T2, and T3 carcinomas of the oral cavity,
oropharynx, and hypopharynx, a 1-cm margin is
advisable. The margin of safety is reduced to 0.5 cm
for laryngeal carcinoma, which is amenable to con-
servative surgery. Laryngeal specimens with mar-
gins of 2 mm or less carry a five-year survival rate,
equal to that of patients with neoplasms at the
resected margins. Patients whose resected larynges
have a margin of clearance greater than 2 mm do
almost as well as those with a widely clear margin.
7. These issues could be addressed in a multicentric
prospective trial. Figure 6 Gross specimen showing mental nerve invaded by
squamous carcinoma of the lip.
B. Peripheral Nerves
The frozen-section technique has been invaluable for
studying the spread of tumor through the peripheral is made for mounting the nerve on the tissue holder
nerves, especially those in the head and neck. In these and the section is made in the longitudinal axis. The
locations the invasion and extension along the proximal end of the nerve should be cut transversely
branches of the cranial nerves is of particular signifi- for study of the entire circumference (Fig. 7).
cance (37–39). Once a branch is invaded, the disease is
certain to extend to the dura mater and brain (37,40).
C. Lymph Nodes
To prevent this, the involved segment of nerve must
be removed as a principal part of the surgical proce- Frozen sections of enlarged cervical lymph nodes
dure and studied by frozen section. The nerves most permit a full range of pathologic interpretation,
frequently involved are the greater palatine nerve, by among other things, primary lymphoma, metastatic
tumors of the palate; the maxillary nerve, by tumors of carcinoma, granuloma, or nonspecific reactive hyper-
the maxilla; the lingual nerve, by tumors of the plasia. A tumor diagnosed preoperatively as an
tongue, floor of mouth, and submaxillary gland; the enlarged cervical lymph node may prove, on frozen
mental nerve by cancer of the lip (Fig. 6); and the facial section, to be an unsuspected neoplasm or cyst. Para-
nerve, and branches of the auriculotemporal nerve by gangliomas, schwannoma, Warthin’s tumor, or cyst of
tumors of the parotid gland (37–39). Any malignant the branchial cleft, all have been responsible, on occa-
tumor of the head and neck can invade the cranial sion, for a preoperative diagnosis of ‘‘indeterminate
nerves, but the more common are adenoid cystic cervical adenopathy’’ (see chaps. 16 and 17).
carcinoma (39), skin carcinoma of the face (40), facial Usually, the diagnosis of carcinoma within a
melanoma (41), and squamous cell carcinoma of the lymph node is easy; lymph nodes from patients with
lip, sinuses, and tongue (37,38). known cancer are often submitted. Keratinizing squa-
For frozen-section examination of a nerve, the mous carcinoma, papillary carcinoma, and mucinous
procedure is as follows: A platform of OCT compound carcinoma are recognized without any problem. If
Figure 7 Routine preparation of peripheral nerve.

Note the transverse section of the proximal margin
(P). Distal margin (D) (cryostat-prepared section,
H&E stained). Abbreviation: H&E, hematoxylin and
eosin.
the initial section is negative, step sections of the

block should be studied to detect any small foci of
carcinoma in the capsular lymphatics and subcapsular
sinusoids.
Lymph nodes are the specimens most frequently
subjected to a deferred diagnosis (6), especially when
the possibility of lymphoma is entertained. The prob-
lems associated with the diagnosis of lymphoma and
in the classification of lymphomatous involvement of
lymph nodes are well recognized; we are often reluc-
tant to attempt such evaluation on frozen section. The
distinction between lymphoma and diffuse or follicu-
lar hyperplasia may be extremely difficult, and for
this, half of the lymph node should be used for frozen
section, the other half being fixed for paraffin section-
ing to eliminate the formation of artifacts incident to
freezing. In these circumstances, the frozen-section
examination is made to confirm the presence or
absence of disease and to ascertain if the tissue is
adequate for diagnosis. Figure 8 Fungal organisms clearly apparent in frozen section
Frozen-section analysis of the sentinel lymph (arrow), permitting to perform special procedures for identifica-
node (SLN) in patients with clinically N0 squamous tion (cryostat-prepared section, H&E stained).
cell carcinoma of the oral cavity and oropharynx have
proved to be of great help in their management to
decide if a neck dissection was necessary. Tschopp
et al. (42) analyzed 82 SLN by frozen section, micro- False-positive diagnoses are not uncommon in
metastases were found in 16 out of the 82 SLNs, previously irradiated mucosal tissues (44). Postirradi-
upstaging 14 out of 31 patients (45%), from cN0 to ation epithelial changes are misinterpreted as either
pN+. Furthermore, a total of 1295 lymph nodes from carcinoma in situ or superficially invasive carcinoma.
the neck dissection specimens were analyzed, con- Immediate preoperative irradiation leads to no such
firming only one more metastatic disease. Sensitivity problems, although days to years later, a range of
and negative predictive value of SLN’s biopsy were changes appear, some of which are a source of confu-
93% and 94%, respectively, for frozen-section analysis. sion if unrecognized. Irradiation fibroblasts are large
A study by Terada et al. (43) has shown frozen- cells with hyperchromatic atypical nuclei, usually
sections analysis of the SLN to be superior to imprint recognizable by being scattered in scar or inflamma-
cytology for detecting micrometastasis to SLN in tory tissue and not forming a coherent cellular group-
clinically negative neck oral cancer. ing after the manner of a sarcoma (45). Telangiectasia,
bizarre striated muscle degeneration, and pseudoepi-
theliomatous proliferation of mucosal glands or their
D. Mucosal Surfaces of the Head and Neck ducts are other changes observed after irradiation (45).
Familiarity with these unusual cytologic and histo-
Frozen sections are especially useful for the distinction logic features would preclude misinterpretation by
between an inflammatory and neoplastic lesion of the the pathologist. In view of their importance, it should
mucosa of the head and neck. In addition to infections be a rule that the pathologist is to be informed when
by acid-fast organisms, fungal disease, such as histo- the specimen submitted for examination has been
plasmosis, blastomycosis, or actinomycosis, may be previously irradiated (44,45).
responsible for chronic ulcerative lesions of the
mouth, oropharynx, and larynx. The demonstration
of a granulomatous process, rather than a neoplastic E. Salivary Gland
one, in a given biopsy specimen requires a special
procedure for identification of the pathogen (Fig. 8). Frozen-section diagnoses of tumors of the parotid and
Immediate microscopic determination by frozen submandibular salivary glands present no more seri-
section of the depth of invasion of a carcinoma of the ous problems than do frozen-section diagnoses of
mucous membrane at any site is easy and useful; it is tumors elsewhere in the body (46–51). The false-
particularly necessary in deciding whether or not a positive rate for frozen-section malignancy has been
neck dissection is necessary in a patient with a clini- reported in the range of 0% to 12% and the false-
cally N0 neck. Conversely, histologic grading of a negative rate 11% to 0% (46–48). With the advent of
squamous carcinoma should not be attempted in fine-needle aspiration (FNA), the need for frozen
frozen sections; classification of the carcinoma as section has shifted from diagnosis to assessment of
high, low, or intermediate grade is unlikely to be margins of resection, checking suspicious lymph
successful because of sampling limitations at the nodes and nerve invasion (46,48). Also, frozen section
time of primary surgery and artifacts introduced by is requested for diagnostic confirmation of an FNA
the procedure. that is called nondiagnostic or benign but still believed
102 Luna
to be clinically suspicious for malignancy (48). The removal of the tumor. To seek guidance on the basis of
plan for surgical treatment for malignant tumors of a frozen section of salivary gland tumor so that a neck
the parotid and submandibnular glands is based dissection might be performed in a patient with a neck
primarily on clinical staging, rather than on the histo- clinically negative for disease is to lack an apprecia-
logic type (52–54). tion and knowledge of the frequency of nodal metas-
Generally, one should not have trouble identify- tasis in the more commonly encountered salivary
ing the common tumors. The most difficult differential gland malignancies: adenoid cystic carcinoma, acinic
diagnoses, regardless of the salivary site, are (i) dis- cell carcinoma, and low-grade mucoepidermoid carci-
tinguishing mucoepidermoid carcinoma from noma. None of this trio exhibits a high incidence of
chronic sialadenitis and from necrotizing sialometa- metastases to regional lymph nodes. High-grade
plasia (Fig. 9), (ii) distinguishing some monomorphic carcinoma, such as the far less common primary
adenomas from adenoid cystic carcinoma, and squamous cell carcinoma, ductal carcinoma, and
(iii) distinguishing some low-grade adenoid cystic high-grade mucoepidermoid carcinoma, may warrant
carcinomas from pleomorphic adenomas. elective dissections of the neck; but this decision is
Resection of the facial nerve is not dependent on principally surgical, not pathologic (52–54).
the histologic subtype of a parotid neoplasm. It is Margins in salivary gland tumors are relative to
based on the gross anatomic intimacy of a parotid the glands involved. For the parotid gland, margin
neoplasm to the nerve (55). The extent of parotidec- selection is facilitated by nearly 80% of the tumors
tomy is also less guided by histologic type than by size occurring in the superficial lobe (lateral to the facial
and extensions, especially when a definitive biopsy nerve) and the appropriate ‘‘biopsy’’ being a lateral
specimen is obtained by subtotal parotidectomy with lobectomy. The deep surface must be examined, and
Figure 9 Frozen-section slides. (A) Chronic sialoadenitis (B) Low grade mucoepidermoid carcinoma (C) Necrotizing sialometaplasia
(cryostat-prepared sections, H&E stained).
any suspicious extension beyond the capsule of the F. Thyroid Gland

gland proper is required to be sectioned. Because the
facial nerve is preserved in nearly all instances, except The routine use of preoperative FNA biopsy has
when it is grossly nondissectable from the tumor, the restricted the use of frozen-section examination for
surgeon usually provides a specimen from near the only the cases in which the needle biopsy was not
nerve to discern any microscopic residual disease that diagnostic, when a previously unidentified nodule is
could be treated by postoperative irradiation (53,55). detected during surgery, to evaluate surgical margins
The appropriate operation for a submandibular or for detecting cervical lymph node metastasis (57).
salivary gland neoplasm is at least total removal of the Also, lesions suggestive of medullary carcinoma
gland. Sections from the superior (nearest the floor of should be confirmed prior to completion of thyrodec-
mouth), lateral, and medial aspects, with deep and tomy and possible bilateral anterior compartment
inferior margins, are necessary for the evaluation of lymph node dissection (57).
extraglandular extension into adjacent soft tissues (54). An acceptable risk taken by the pathologist
Margins for minor salivary gland tumors are includes the possibility of missing a minute papillary
similar to those for other mucosal lesions: depth and carcinoma on frozen section. It is not unusual that
circumferential excision lines (56). after a frozen-section diagnosis of benign tumor estab-
The often-variable microscopic appearance of sal- lished on a lobectomy specimen, the following day
ivary gland tumors in different areas gives rise to the when the sections of the remaining tissue are exam-
possibility of erroneous sampling (46–48). To keep ined, a microscopic focus of papillary carcinoma is
sampling error at a minimum, a careful gross examina- found elsewhere in the lobe (58). The same situation
tion of the specimen by the pathologist is imperative. happens when in a multinodular goiter only the
Three important features of the gross specimen should dominant nodule is sampled for frozen-section exam-
be studied: First, what is the relation between the lesion ination, a separate area taken for permanent study
and the adjacent normal salivary gland tissue? Sections demonstrates a simultaneous malignancy (59).
submitted for frozen section should demonstrate this Identification of the various types of thyroiditis,
relation. A frozen section should be taken at the including Riedel’s struma, is accomplished readily
junction of tumor and apparently normal tissue rather with frozen section (60). Because both Riedel’s struma
than from the center of the neoplasm. Second, how far and granulomatous thyroiditis may be mistaken for
is the tumor from the surgical resection margins? A cancers on gross examination, the use of the frozen-
frozen section should be taken between the neoplasm section technique is mandatory. Hashimoto’s thyroid-
and the closest line of excision. Third, are any lymph itis is less likely to resemble carcinoma, although it is
nodes involved by tumor? In parotid and submandib- sometimes confused grossly with lymphoma.
ular gland tumors, lymph nodes are often included Papillary lesions of the thyroid gland seldom
with the specimen. Any enlarged lymph node should present difficulty in histopathologic diagnosis on fro-
be examined by frozen section. zen section. Papillary hyperplasia in adenomatous
In examining frozen sections of lymph nodes goiter and diffuse toxic goiter are easily distinguished
related to salivary glands, the pathologist must not from papillary carcinoma. Papillary carcinoma shows
mistake benign glandular inclusions for malignant infiltrative growth into the capsule or surrounding
tumors; heterotopic islands of salivary gland tissue thyroid gland and frequently contains psammoma
may be found in paraparotid lymph nodes and, less bodies. On occasions, papillary carcinomas may not
frequently, in the upper cervical lymph nodes (see demonstrate obvious papillary formations and instead
chap. 16). The pathologist, unaware of this phenome- appear as broad, flat sheets of cells or a follicular
non, may incorrectly interpret these as metastatic pattern is observed. In those cases in which the
carcinomas in a frozen section. Lymphoid infiltrate possibility of papillary carcinoma exists and the mor-
is not unusual in some acinic cell carcinomas, mucoe- phologic characteristic of the tumor are distorted in
pidermoid carcinomas, and monomorphic adenomas the frozen sections, intraoperative touch imprints or
(see chap. 17). scrape preparations are of great help (Fig. 10). Papil-
Request for frozen-section diagnoses of lesions lary structures, oval nuclei, nuclear enlargement, nucle-
of the minor salivary glands requires especial interac- ar groves, and inclusions are more easily recognizable
tion between the pathologist and surgeon. The sur- on intraoperative cytology than on histologic frozen
geon must consider the possibility of resecting the sections (60–62).
lesion with a modest margin; further surgical treat- The distinction between follicular adenoma and
ment can easily be accomplished immediately if exam- well-differentiated, encapsulated follicular carcinoma
ination of the frozen section indicates the need. If the may present more difficulty to the surgical patholo-
extent or location of the lesion precludes an excisional gist. This distinction is possible only if one finds
biopsy, an incisional biopsy and frozen-section diag- capsular or vascular invasion (60). If no invasion is
nosis should be attempted. Under these circumstan- recognized, the lesion is considered benign. If atypical
ces, the pathologist should embed in toto and section features are present, the lesion is then classified as of
at different levels all the material submitted for study. ‘‘uncertain malignant potential’’ (63). To provide rele-
In biopsies of minor salivary gland tumors, sometimes vant information to the surgeon in this situation, the
only one of the levels will contain the characteristic entire capsule must be submitted for microscopic
microscopic areas that allow the pathologist to make a examination at the time of frozen section, a tedious
correct interpretation (56). and too often nonproductive endeavor. When the
104 Luna
follicular thyroid lesions.’’ The diagnosis of Hurthle

cell carcinoma by frozen-section examination involves
the same type of questions as the encapsulated,
well-differentiated follicular carcinoma (63). Here
again, adequate evaluation of the capsule-thyroid
interface is mandatory; this may necessitate histologic
examination of the entire border of the neoplasm (60).
The pathologist must remember that invasion of
muscle by nonneoplastic thyroid follicles can take
place in extreme degrees of toxic hyperplasia and
that, sometimes, apparently benign thyroid tissue
can be implanted within the lateral neck during thy-
roid surgery or blunt trauma (65). In the former case,
the clinical history and the absence of abnormal nuclei
distinguish Graves’ disease from follicular carcinoma.
In the latter the previous history, the microscopic
pattern of the tissue, and the presence of suture
material are helpful in ruling out cancer.
We must remind ourselves that, during the
development of the thyroid gland, small nodules of
the gland may become detached from the thyroid
proper. These nodules may show the same pathologic
changes that take place in the gland proper (thyroid-
itis, hyperplasia, and nodular goiter) (60). At surgery,
the discovery of such a nodule in the immediate
vicinity of the gland may lead the surgeon to believe
that he or she is dealing with metastatic tumor. If one
of the nodules is submitted for frozen-section exami-
nation, the pathologist may mistake this nodule of
chronic thyroiditis for metastatic thyroid carcinoma in
a lymph node.
An uncommon problem is the distinction between
thyroid and parathyroid tissue. This may require per-
manent sections for immunocytochemical techniques
for demonstration of parathyroid hormone or thyro-
globulin. Here again the preparation of intraoperative
touch imprints are of great help (21,23).
Figure 10 H&E-stained preparations. (A) Cryostat-prepared
section of papillary carcinoma with trabecular pattern note the
lack of nuclear characteristics. (B) Intraoperative cytologic
imprint showing nuclear features diagnostic of papillary carcino- G. Parathyroid Gland
ma. Abbreviation: H&E, hematoxylin and eosin.
With the advent of preoperative radionucleotide scan-
ning using technetium-99m sestamibi scanning (MIBI)
and intraoperative quick parathyroid hormone
(QPTH) monitoring to identify abnormal hyperfunc-
pathologist is faced with this dilemma at the time of tioning parathyroid glands, the role of the frozen
surgery, some authors recommend that only three section in the intraoperative diagnosis of abnormal
blocks from the capsule-thyroid interface should be parathyroid glands once again has been called into
examined by frozen section (64). Often this is inade- question. Some authors have espoused the superiority
quate and the diagnosis is deferred, because invasion of intraoperative hormone assays over frozen section,
is not often identified on frozen sections (63,64). In a as the results of these tests inform the operating
review by Callcut et al. (64), 152 patients underwent surgeon when the hyperfunctioning parathyroid tis-
surgical resection for follicular lesions, 32% (41) were sue has been removed (57,66–68). Furthermore, an
reported as benign, 4% (5) as malignant, and 2% (3) as experienced parathyroid surgeon doing a classic
indeterminate, and in 62% (80), the diagnosis was exploration on an unexplored neck can usually make
deferred to permanent histology. On paraffin section, the distinction between parathyroid tissue and other
all patients with malignant frozen section had had tissues (lymph nodes and thyroid) without a pathol-
thyroid carcinoma, and all 41 patients with benign ogist’s assistance (67).
frozen section had benign lesions. The authors con- Dewan et al. (67) analyzed 50 parathyroidecto-
cluded that ‘‘frozen sections analysis for follicular mies performed by a single surgeon. Diagnoses on
lesions seems to be highly specific and accurate. gross examination of both the surgeon and pathologist
However, because of the low sensitivity, routine use were recorded, cytologic smears made, and frozen
of frozen section is not cost effective in patients with sections performed. Of the 50 cases (35 adenomas
and 15 hyperplasias), both the surgeon’s and pathol- the accuracy of this methodology. The studies of Yao
ogist’s opinions on gross examination were concor- et al. (73) revealed that cytology does not provide the
dant. Incorrect gross identification occurred by both in accuracy needed in the operating room, where very
6% (3) of the cases. They concluded that experienced near 100% is required. A misinterpretation rate of 31%
parathyroid surgeons need not routinely request in identifying parathyroid and 44% in identifying
frozen-section examination for tissue confirmation, thyroid is not acceptable. This study provides addi-
especially with the use of MIBI and QPTH assays. tional support for the use of the standard frozen-
According to these authors, the situations that warrant section technique adjunct of cytology imprints and
the judicious use of frozen section would include the smears in the intraoperative pathologic evaluation of
following: (i) the infrequent parathyroid carcinoma, tissue during cervical exploration for primary hyper-
(ii) cases of multiple gland disease (primary, second- parathyroidism (57,66).
ary, or tertiary hyperparathyroidism), (iii) ectopic Although the combination of size and color
gland location, (iv) reoperant necks, (v) otherwise usually identifies a parathyroid gland as such, some-
technically difficult primary surgeries, and (vi) atypi- times a parathyroid gland may be inadvertently
cal parathyroid appearance (small, firm, or ectopic devascularized during thyroid surgery. In these
location). instances, biopsies of possible parathyroid tissue
The rarely encountered parathyroid carcinoma is may be submitted to the pathologist for proper iden-
identified largely by its invasion of adjacent structures tification by the frozen-section technique before auto-
(69–71). Questions are more likely to arise in the transplantation (57,69) (Figs. 11,12).
distinction between nonmalignant pathologic processes
in the gland (69,70). Parathyroid histopathologic inter-
pretation of an adenoma versus hyperplasia is consid-
ered by many pathologists to be a persistent challenge
(67).
The size of the parathyroid tumor is a factor in
its identification. A large tumor requires only a
section for its recognition as a parathyroid adenoma.
To determine whether a slightly enlarged parathy-
roid is an adenoma or not depends on its weight,
usually combined with examination of a histologic
section to establish the presence or absence of (i) fatty
stroma, (ii) an encapsulated nodule or mass with a
small rim of compressed normal tissue, and (iii) the
presence of cells with giant nuclei (70). These are not
absolute criteria. Furthermore, on frozen section, the
criteria for adenoma are seldom identified; hence, the
differentiation between adenoma and hyperplasia is
not based on pathologic criteria, but on operative
findings; optimally, all parathyroid adenomas should
be identified (57,69). Successful operations have been
shown to be strongly associated with experience of
the surgeon, with cure rates of 95% to 98% after neck
exploration and identification of all parathyroid
glands (57). Biopsy of each parathyroid is not neces-
sary and may lead to postoperative hypoparathy-
roidism.
Intracytoplasmic cytologic examination is of
great help during intraoperative consultation to
improve the diagnostic accuracy of parathyroid ade-
noma. Sasano et al. used air-dried Wright-Giemsa-
stained imprints and smears to demonstrate the pres-
ence of intraparenchymal and intracellular fat (72).
The cells of the parathyroid adenomas do not contain
extra or intracellular lipid, whereas the cytologic
material from normal or atrophic parathyroid glands
has large amounts of intracellular lipids and variable
amounts of extracellular lipid. They advocated that
this procedure is much more rapid, much easier, and Figure 11 Cryostat-prepared section and intraoperative cyto-
less labor intensive than using conventional frozen logy (A,B) of lymphoid tissue submitted as possible parathyroid.
sections with special stain procedures for fat staining. (A) Frozen section artifacts may simulate solid pattern of para-
Although there have been numerous studies thyroid gland. (B) Imprint showing cells with diagnostic features
(17–20,23) on the use of cytology in evaluating of of lymphoid cells.
parathyroid tissue, little attention has been paid to
106 Luna
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ative frozen section in a teaching hospital: an analysis of
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pathologic consultation: an audit of 1000 recent consecu-
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9. Novis DA, Gephart GN, Zarbo RJ. Interinstitutional com-
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college of American Pathologists Q-Probes Study of 18532
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Pathol 1988; 19(9):1019–1023.
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19. Shidham VB, Gupta D, Galindo LM, et al. Intraoperative
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logic imprint of parathyroid adenoma (A,B). (A) Frozen section specimen evaluation: frozen sections analysis, cytologic
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are comparable for intraoperative examination of sentinel
lymph nodes: a study in 133 breast cancer patients. Ann
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3
Diseases of the Larynx, Hypopharynx, and Trachea
Leon Barnes
Department of Pathology, University of Pittsburgh Medical Center,
Presbyterian-University Hospital, Pittsburgh, Pennsylvania, U.S.A.
I. VOCAL CORD NODULES AND POLYPS C. Clinical Features

A. Introduction VCNPs affect both sexes and all age groups, with a peak
incidence between 20 and 50 years of age. Presenting
A vocal cord nodule or polyp (VCNP) represents a symptoms range from ‘‘breaking’’ of the voice to hoarse-
nonneoplastic, vascular-stromal reaction to vocal ness. Patients often report that their voice fatigues easily,
abuse. Some otolaryngologists distinguish nodules and that it is typically best first thing in the morning and
from polyps; those that do, define a nodule as a deteriorates with prolonged speaking or singing (2).
small sessile lesion, usually less than 3 mm, which Some describe a constant desire to cough or clear the
occurs between the anterior and middle third of the throat. Airway compromise is not a significant issue.
true vocal cord. It is typically bilateral, symmetrical, The size of the lesion does not always correlate with the
and immobile during phonation (1–4). A polyp, in extent of the vocal disability. At laryngoscopy, VCNPs
contrast, may be sessile or pedunculated, usually appear as white, pearly gray, tan, or red growths that
larger than 3 mm, and it occurs on the free edge of rarely exceed 15 mm in greatest dimension (Fig. 1). As
the anterior third of the true vocal cord. It is generally the name implies, they occur only on the true vocal
unilateral and, if pedunculated, mobile on phonation. cords and nowhere else in the larynx. While they may
Data, however, indicate that vocal cord nodules appear anywhere on the true vocal cord, most occur on
and polyps are etiologically related and histologically the free edge at the junction of the anterior and middle
identical, differing only in size. If left untreated, any thirds. This site corresponds to the middle of the
nodule has the capacity to develop into a polyp. membranous cord and represents the maximum point
Distinguishing between the two lesions on the basis of vibratory impact during speaking and singing.
of the above criteria, therefore, has no merit or clinical They are equally distributed between the right
significance. The two terms can be used interchange- and left vocal cords and are sometimes multiple and/
ably or according to one’s bias. or bilateral. Although otolaryngologists are highly
In addition to focal lesions, the true vocal cord adept in recognizing VCNPs, other conditions such
can also be involved diffusely, a rare condition as ‘‘keratosis,’’ squamous papilloma, or even amyloid
referred to as diffuse polyposis or Reinke’s edema. may be mistaken for these lesions.
Synonyms VCNPs include laryngeal nodule,
screamer’s nodule, singer’s nodule, preacher’s nodule,
and corditis nodosa. D. Pathology
The pathology takes place in the free edge of the true
B. Etiology vocal cord in the space of Reinke (7–9). This space is
roughly triangular and is bounded superiorly by the
Phonotrauma in the form of vocal overuse (excessive superior arcuate line (which represents the junction of
quantity of voice), abuse (yelling), and misuse (vocal the squamous epithelium of the true vocal cord with
hyperfunction with excessive muscular tension) is the the respiratory epithelium of the ventricle) and inferi-
chief factor in the pathogenesis of VCNPs (5; see orly by the inferior arcuate line (which represents the
‘‘Pathology’’ below). Smoking, gastroesophageal junction of the squamous epithelium of the true vocal
reflux, atmospheric pollutants, and hypothyroidism cord with the respiratory epithelium of the subglottis).
may be additional contributing or aggravating factors The medial border is the vocalis muscle. The space of
(6). There is also some evidence to suggest that psy- Reinke, therefore, corresponds basically to the lamina
chological factors may play a role. For instance, some propria of the true vocal cord and, as such, contains
investigators have observed that VCNPs are more loose fibrous tissue and blood vessels.
common in individuals with vociferous and aggressive Five histologic types of VCNPs are recognized:
personalities and less frequent in those who are soft (i) edematous-myxoid, (ii) fibrous, (iii) hyaline (‘‘amyloid-
spoken, gentle, and more self controlled (2). like’’), (iv) vascular, and (v) mixed. It is speculated that
110 Barnes
vocal abuse leads to mechanical trauma of the cords as which, if not removed, eventually undergoes fibrosis
a result of vibration with excessive friction and force- creating the fibrous variant of a VCNP (Figs. 3 and 4).
ful opposition on adduction (10,11). This, in turn, If the vascular injury is more severe, fibrin escapes
leads to increased vascular permeability with leakage creating the hyaline variant of a VCNP (Fig. 5). In an
of contents into the stroma (Fig. 2). If only fluid attempt to organize the extravasated fibrin, as in any
escapes, an edematous-myxoid VCNP is formed, blood clot, there is an ingrowth of new blood vessels
transforming the hyaline stage into a vascular VCNP
(Fig. 6). VCNPs with two or more of the above
patterns (mixed type) are not uncommon (Fig. 7).
The epithelium overlying a VCNP may be nor-
mal, hyperplastic, atrophic, ulcerated, keratotic, para-
keratotic, or even mildly dysplastic. These changes,
however, have no clinical significance. Thickening
and hyalinization of the basement membrane is also
common but inflammatory cells are absent, unless the
VCNP is ulcerated. Hemosiderin may also be seen.
Figure 1. Typical appearance of a vocal cord nodule-polyp

(arrow) (H&E, whole mount).
Figure 3. Vocal cord nodule-polyp, edematous-myoid stage

H&E, 200). Note the loose, edematous stroma.
Figure 4. Vocal cord nodule-polyp, fibrous stage (H&E, 200).

The stroma is now more fibrous and is often mistaken for a
Figure 2. Pathogenesis of vocal cord nodules-polyps. fibroma.
Chapter 3: Diseases of the Larynx, Hypopharynx, and Trachea 111
Figure 7. Vocal cord nodule-polyp, mixed stage (H&E, 40).

Figure 5. Vocal cord nodule-polyp, hyaline stage (H&E, 200). Note the edematous, hyaline and vascular components.
Note the stromal exudation of fibrin.
the fact that it is positive for S-100 protein, while the

fibrous VCNP is negative. Mast cells can be seen in
both lesions but tend to be more prominent in the
neurofibroma. Amyloid can be distinguished from the
hyaline VCNP by the fact that amyloid will show
apple green birefringence with the Congo red stain
when viewed under polarized light and will be nega-
tive with stains for fibrin. Vascular VCNPs are sepa-
rated from hemangiomas by the large amount of
extravascular fibrin. Fibrin, if seen in hemangiomas,
is always intravascular. In addition, hemangiomas of
the larynx occur almost always in the supraglottic or
subglottic larynx; they are distinctly uncommon on
the true vocal cords.
F. Treatment and Prognosis

Although some VCNPs may resolve spontaneously
with voice counseling, others require surgical excision
(2,5,6,13). New lesions may develop if vocal abuse is
Figure 6. Vocal cord nodule-polyp, vascular stage (H&E, not curtailed, hence the need for counseling.
400). There is an ingrowth of blood vessels (open spaces) in
an attempt to organize the extravasated fibrin.
II. CONTACT ULCER, CONTACT GRANULOMA,
INTUBATION GRANULOMA
A. Introduction
E. Differential Diagnosis
Contact ulcers, contact granulomas, and intubation
The edematous-myxoid, fibrous, hyaline, and vascular
granulomas are essentially synonyms for a spectrum
VCNPs are often mistaken, respectively, for myxomas,
of nonspecific pathologic changes that are etiologically
fibromas-neurofibromas, amyloid, and hemangiomas.
related to vocal abuse, gastroesophageal reflux, and
Myxomas of the larynx are extremely rare, arise in the
intubation (1–16). Smoking, excessive alcoholic intake,
supraglottic larynx, are usually over 3 cm in size, are
and repeated episodes of coughing and throat clearing
histologically relatively avascular, and are not covered
may be additional or aggravating factors (11).
by surface epithelium (12). In contrast, myxoid
VCNPs always arise on the true cord, are less than
15 mm in size, are well vascularized, and are covered B. Clinical Features
by a mucous membrane. Fibromas of the true vocal
cord are also rare and more densely collagenized than They characteristically occur on the posterior third of
the fibrous VCNP. Neurofibroma can be excluded by the true vocal cord, usually in the area of the vocal
112 Barnes
Figure 8. Contact ulcer (H&E, 100). The ulcer is nonspecific,

Figure 9. Intubation granuloma (polypoid granulation tissue).
but when correlated with the site (posterior true vocal cord) and
Gross and cut surface.
clinical history, the correct diagnosis can usually be made.
process of the arytenoid cartilage. The predilection for to the development of the ‘‘granuloma’’ varied from 2
this site probably stems from the fact that the muco- to 28 weeks, with the majority appearing by the eighth
perichondrium in this region is very thin and tightly week (1).
bound with minimal subepithelial connective tissue.
This anatomic arrangement allows for little mobility of
the epithelium so that abrasion from intubation or C. Pathology
repeated forceful abuse of the voice may result in
ulceration. The histologic changes are nonspecific and range from
Hoarseness, as might be expected, is the most mucosal ulceration with marginal epithelial or pseu-
common presenting symptom. Others include dys- doepitheliomatous hyperplasia to a polypoid accumu-
phagia, sore throat, sensation of a foreign body in lation of granulation tissue. At times, the mucosa may
the throat, dysphonia, choking, and pain. even be intact but hyperplastic. Bacterial and fungal
The lesions may be unilateral or bilateral and contamination of the ulcers is not uncommon and may
present on laryngoscopic examination as a surface be responsible for progressive ‘‘activity’’ of the lesion.
irregularity, an ulcer, or as a tan, yellow, or red Although the histologic findings are nonspecific, the
polypoid or pedunculated mass from 1 to 30 mm characteristic location (posterior true vocal cord) cou-
(Figs. 8 and 9). Some are visible on computerized pled with the clinical history should suggest the
tomography and may be associated with sclerosis of correct diagnosis.
the underlying arytenoid cartilage (11). The mass of granulation tissue is often errone-
They occur in all age groups, but tend to be ously referred to as a ‘‘granuloma’’ or mistaken for a
uncommon in children. In general, those lesions that ‘‘pyogenic granuloma’’ (Fig. 9). Aside from the possi-
are related to vocal abuse and reflux are more com- ble occurrence of a few scattered multinucleated giant
mon in males, while those associated with intubation cells, granulomas are not seen. Accordingly the term
are more often seen in females. The smaller size of the ‘‘granuloma’’ is not only inappropriate but misleading
female larynx and the fact that the mucoperichon- since it suggests the possibility of an infectious lesion.
drium overlying the arytenoid cartilage is also thinner Pyogenic granuloma is now recognized to be a specific
in the female than the male (59 vs. 97 mm in thickness) hemangioma, namely a lobular capillary hemangioma
probably accounts for the predominance of intubation (17). The lobular arrangement of the capillaries in this
granulomas (4). lesion distinguishes it from the radial arrangement of
Considering the extent to which endotracheal capillaries in granulation tissue (Fig. 10).
intubation is practiced, intubation granulomas are
rare. The incidence in all surgical patients has varied
from 1 in 800 to 1 in 20,000 patients (4). The incidence D. Treatment and Prognosis
is higher, however, in patients confined to intensive
care. This is not unexpected since these patients are Once the diagnosis is established, therapy is directed
sicker and often have prolonged intubation. The at the underlying cause: voice counseling for vocal
‘‘granuloma’’ may develop weeks to months after abuse, medical therapy for acid reflux, and endoscopic-
intubation. In a review of 35 cases, Howland and laser excision for unresponsive lesions. Local recur-
Lewis noted the interval from operation (intubation) rences, however, are not uncommon.
Figure 10. Intubation granuloma (H&E, 40). The lesion con-

sists of polypoid granulation tissue and is often referred to as a
‘‘pyogenic granuloma.’’ Note the radial arrangement of the
capillaries. In ‘‘pyogenic granuloma (lobular capillary hemangio-
ma),’’ the capillaries are arranged in lobules.
Figure 11. Vertical section through the laryngeal glottis. Teflon

has been injected into the true vocal cord (H&E, 4).
III. TEFLON GRANULOMA (TEFLONOMA)
A. Introduction
Patients with unilateral vocal cord paralysis experience
difficulties in speaking and controlling their secretions.
To restore glottic competence and correct these deficien-
cies, Teflon (polytef, tetrafluoroethylene) is often
injected into the atrophic, paralyzed vocal cord in
order to expand the cord toward the midline to approx-
imate the contralateral functioning cord (1–3) (Fig. 11).
The injected Teflon is in the form of a paste
consisting of 50% Teflon and 50% glycerin, and is
administered through a syringe and needle (4,5).
Normally about 0.20 to 0.75 cc is injected (4).
B. Pathology
In tissue, Teflon appears as roughly round to ovoid, 50
to 100 mm particles with clear centers and prominent
dark borders that are birefringent under polarized light
(Fig. 12). For the first three to five days after injection,
there is a marked edematous and neutrophilic response Figure 12. Teflon particles associated with a prominent multi-
to the particles, followed over the next several days by a nucleated foreign body giant cell reaction. Insert shows charac-
decrease in neutrophils and a progressive increase in teristic round to ovoid Teflon particles with thick border and clear
chronic inflammatory cells and multinucleated foreign centers (H&E, 200).
body giant cells (6). Over the ensuing three to six
months, fibrosis and foreign body giant cells become
more prominent and chronic inflammation gradually
ceases to exist (4). By six months of age, the lesion has ovoid Teflon particles with clear centers and dark
normally reached histologic maturity. A few, however, borders however contrast with the thin, elongated
may continue to enlarge beyond this date (5). sodium urate crystals of gout. In addition, urate
crystals stain positive (black) with the de Galantha
C. Differential Diagnosis stain, but only if the specimen has been prefixed in
absolute alcohol. Urate crystals are water-soluble and
To the unwary, Teflon granulomas are sometimes will dissolve in most formalin-based fixatives. Patients
mistaken for gouty tophi. The basically round to with gout will also have elevated serum uric acid
114 Barnes
levels. Particles of Teflon can also be identified, some- granulomatosis will present as isolated subglottic ste-
times unexpectedly, on fine needle aspirates of neck nosis and, in this instance, testing of the serum for the
masses (6). presence of antineutrophil cytoplasmic autoantibodies
may be helpful in establishing the diagnosis (6).
The idiopathic form of subglottic stenosis is
D. Treatment and Prognosis characterized histologically by dense fibrosis of the
Although Teflon is not carcinogenic, at least in the keloidal type separated by sparse fibroblasts (5).
larynx, therapeutic misadventures have been docu- Chronic inflammatory cells are modest or even lack-
mented in about 2% to 10% of injections (6,8–13). ing and mucoserous glands and ducts are dilated.
Most complications are due to overinjection of the Calcification is absent. The surface epithelium gener-
vocal cord or from inadvertent injection in sites other ally shows squamous metaplasia or even ulceration
than the true vocal cords. These complications often with replacement by granulation tissue. The underly-
result in exacerbation of previous symptoms, airway ing cartilage typically shows little, if any, changes.
obstruction, or the formation of a laryngeal or neck
mass (Teflon granuloma, Teflonoma) that can be mis- D. Treatment and Prognosis
taken for a neoplasm (10,14,7). Teflon can also migrate
from the larynx to the region of the thyroid gland and Effective treatment depends on identifying and elimi-
masquerade as a thyroid tumor. Experimental evidence nating the cause and establishing an adequate airway.
in dogs also indicates that Teflon particles can even The latter may be achieved by endoscopic or laser
migrate or embolize to cervical lymph nodes (15). excision of the stenotic airway, temporary tracheotomy,
Surgical removal of Teflon granulomas often or segmental resection. Local recurrences, however, are
results in improvement or disappearance of all related not uncommon in the idiopathic variety.
symptoms. Attempts, however, to remove these gran-
ulomas endoscopically from the vocal cords may at
times prove difficult and require several procedures V. TRACHEOPATHIA
(5). In these instances, the quality of the voice may OSTEOCHONDROPLASTICA
deteriorate and be even worse than that before Teflon
injection (16). A. Introduction
Tracheopathia osteochondroplastica (TPO) is an idio-
pathic disorder in which multiple ossified and/or car-
IV. SUBGLOTTIC STENOSIS tilaginous nodules appear submucosally in the trachea,
A. Introduction infrequently in the major bronchi, and exceptionally in
the larynx (1–11). Fortunately, it is a rare condition.
Subglottic stenosis (laryngotracheal stenosis) may be Jepsen and Sorensen observed 5 cases in 3500 bronchos-
congenital or acquired (1–4). Causes of the acquired copies, while Prakash et al. identified only 1 in 2000
type include trauma (intubation), infections (rhinoscler- bronchoscopies (6,12). Eimind, on the other hand found
oma), neoplasms (chondrosarcoma), and local and sys- no examples among 25,000 bronchoscopies (13).
temic diseases (gastrointestinal reflux, amyloidosis,
Wegener’s granulomatosis). If no etiology is found,
the term ‘‘idiopathic subglottic stenosis’’ is used. B. Clinical Features
Although TPO has been observed in an 11-year-old
B. Clinical Features girl, the vast majority of patients are over 50 years of
age at diagnosis. The gender distribution depends on
Subglottic stenosis occurs in all age groups and the study, some indicating either a male or female
presents as progressive airway obstruction, often predominance (1,3). When viewed collectively, the
with associated voice changes. For reasons unknown, gender distribution is probably about equal (7).
the idiopathic form is decidedly more frequent in TPO typically involves the cartilaginous frame-
women (80–94% of all cases) (4,5). work (anterior and lateral walls) of the lower two-thirds
The typical lesion is circumferential and varies in of the trachea. The posterior noncartilaginous membra-
length from a few millimeters to about 5 cm. The nous wall is not affected. The osteocartilaginous nod-
narrowing begins just beneath the true vocal cords ules are usually confined to the trachea but, on occasion,
and dramatically increases in severity as the cricoid may involve the main stem bronchi. The segmented
cartilage is approached. The point of maximum steno- bronchi as well as the larynx are seldom affected.
sis is usually found at the level of the cricoid cartilage Symptoms, which are often confused with asthma
and upper trachea (5). or bronchitis, vary with the degree of airway com-
promise. Some patients are asymptomatic while
C. Pathology others experience chronic cough, hoarseness, wheez-
ing, dyspnea, or repeated episodes of infections.
The pathology depends, to a large extent, on the Hemoptysis is not common.
etiology—intubation, infections, amyloid, and neo- A single case of familial TPO (mother and
plasms (see ‘‘Contact Ulcer, Contact Granuloma, Intu- daughter) has been described (6). Serum calcium
bation Granuloma’’ above). Infrequently, Wegener’s and phosphorous levels are normal (1).
C. Imaging
Imaging studies show multiple broad-based, symmetric,
or asymmetric protrusions, often calcified with a
beaded-scalloped appearance involving the anterior
and lateral walls (3,5). The posterior (membranous)
wall is spared. The nodules are covered with mucosa
and centered in the submucosa attached to the carti-
laginous framework.
D. Pathology
The nodules are composed of cartilage and/or bone,
often with focal calcification, resembling small chon-
dromas, exostoses, or osteochrondomas. Some may Figure 13. Diagram of a coronal section through the larynx at
even contain marrow spaces with hematopoietic ele- the level of the saccule demonstrating (A) normal anatomy and
ments (2). The nodules are centered in the submucosa (B) a mixed laryngocele herniating through the thyrohyoid mem-
and often maintain a continuity with the inner surface brane.
of the tracheal cartilage. The overlying mucosa is
usually intact and may appear normal or metaplastic.
10 millimeters or more and in 7%, the saccule extended
E. Treatment and Prognosis 15 mm or more. Since the superior margin of the
thyroid cartilage is approximately 16 mm above the
There is no medical therapy for TPO. Asymptomatic superior surface of the vocal cords; this means that a
patients require no treatment other than instructions small number of adults have saccules that extend
to avoid respiratory irritants. Symptomatic patients, in above the cartilage (3). In the fetus and newborn,
turn, will usually have to have one or more of the 25% of the saccules routinely extend beyond this
nodules removed with meticulous attention to the border (4). These extended saccules are referred to
long-term tracheobronchial hygiene to thwart off clinically as ‘‘elongated saccules.’’ Apparently in some
superimposed infections. ‘‘normal’’ larynges, the saccule may be entirely absent
(4). Although it may be a vestigial remnant of the
ventricular air sacs of anthropoid apes, the saccule in
VI. CYSTS AND LARYNGOCELES humans appears to function as a source of lubricant
A. Introduction for the vocal cords.
If the saccule becomes obstructed, secretions
Large saccules, some laryngeal cysts, and laryngoceles accumulate and a cyst is formed—the so-called saccu-
represent a spectrum of congenital and acquired dis- lar cyst (Fig. 14). If the saccule becomes distended
orders that occur within the saccular appendage of the with air and maintains an open communication
laryngeal ventricle. To appreciate the clinical and with the laryngeal lumen, it is termed a laryngocele
pathologic features of these lesions, one must first (Fig. 15).
consider the anatomy of this structure.
C. Cysts
B. Anatomy and Terminology
Cysts of the larynx can be classified as congenital or
The saccule, also known as the appendix of the laryn- acquired; ductal or saccular; or as ‘‘tonsillar,’’ epithe-
geal ventricle, is a blind respiratory epithelial-lined lial, or oncocytic (5–7). Most are acquired and of the
sac, which ascends vertically from the anterior one- ductal-epithelial type. They occur in all age groups
third of the ventricle between the false cord and inner but are most frequent in individuals over the age of
surface of the thyroid cartilage (Fig. 13). In infants, it is 50 years (3,5–15). Although some studies have shown
relatively large and lined by a papillary mucous a male or female predominence, there is no gender
membrane associated with subepithelial lymphoid preference when these studies are viewed collectively
aggregates (1). In adults, the mucosa is less complex (3,6,7,12,14). Hoarseness, respiratory compromise,
and usually devoid of a lymphoid component. dysphagia, coughing, feeding problems, foreign
Approximately 60 to 70 mucous glands empty their body sensation in the throat, neck mass, and pain
secretions into the saccule, which in turn drains into are common complaints. In many instances, the cysts
the larynx. The saccular orifice at the ventricle mea- are asymptomatic and represent only an incidental
sures only 0.5 to 1.0 mm and can therefore be easily finding.
compromised by atresia, tumors, infections, fibrosis, Cysts, which may be either solitary or multiple,
and trauma. The saccule is of variable depth but tends occur primarily in the supraglottic larynx, less fre-
to be larger in males than females. Broyles observed quently in the glottis, and infrequently in the sub-
that in 75% of the cases the saccule extended to a glottis. They arise from obstruction of the ducts of
depth of 6 to 8 mm (2). In 25%, the depth extended mucous glands or the orifice of the laryngeal saccule.
116 Barnes
In some studies, 20% to 30% of laryngeal cysts in

infants and children, especially those of the saccular
type, have been associated with a variety of congenital
or developmental abnormalities (3,12,14). Among
these are included Down’s syndrome, cystic fibrosis,
cerebral palsy, cardiac anomalies, prematurity, hydro-
cephalus, microcephalus, high arched palate, micro-
gnathia, conductive hearing loss, laryngomalacia, and
vocal cord paralysis.
One of the more popular classifications of laryn-
geal cysts has been that proposed by DeSanto et al. (5).
These authors divide laryngeal cysts into two catego-
ries: (i) ductal, which represent about 75% of all cysts
of the larynx and (ii) saccular, which comprise the
remaining 25%.
Ductal Cyst
Ductal cysts arise when the ducts of mucous glands are
occluded; hence, they can occur at any site where these
glands are found. They are almost invariably less than
1 cm in diameter and are quite superficial, often
appearing to arise within the mucosa. Forty percent
occur in the vicinity of the true cords (excluding the
free margin which is essentially devoid of glands), 37%
Figure 14. Incidental saccular cyst (arrow) discovered in a
larynx removed for squamous cell carcinoma. The cyst was
in the epiglottis, 7% in the false vocal cords, 6% in the
lined by oncocytic epithelium and exhibited papillary infoldings. ventricles, 5% in the aryepiglottic folds, 3% in the
Such cysts are occasionally referred to as oncocytic papillary arytenoids, and the remainder in the anterior commis-
cystadenomas. sure, pyriform sinus, and subglottis (5).
Saccular Cyst
Saccular cysts are mucous filled cysts that develop
following obstruction of the laryngeal saccule. They
are always of supraglottic origin, distinctly submuco-
sal, covered by a normal mucous membrane, and vary
from 1 to 7.5 cm in diameter (Fig. 14). They most often
present in the region of the ventricles (58%), aryepi-
glottic folds (14%), lateral larynx (12%), or involve a
combination of adjacent sites (5).
There are two types of saccular cysts—anterior
and lateral. Approximately 60% of saccular cysts are
anterior (3,5). They arise near the orifice of the ventri-
cle and overhang the anterior glottis. Lateral saccular
cysts, on the other hand, tend to bulge the aryepiglot-
tic folds, false vocal cords, or epiglottis and, in a few
instances, may extend through the thyrohyoid mem-
brane to present in the neck. Whether a given cyst is
classified as anterior or lateral depends on the length
of the saccule and the level of obstruction.
Histologically, ductal and saccular cysts are both
lined by respiratory or squamous epithelium and,
therefore, have no distinguishing characteristics. A
few may even be lined, either focally or entirely, by
Figure 15. Gross picture of a resected external (air-filled) oncocytic epithelium. Accordingly, the DeSanto clas-
laryngocele that presented as a cyst of the neck. sification of laryngeal cysts into ductal or saccular is
largely clinical based on location, depth, and size and
is difficult for pathologists to use, and especially so,
since some of these cysts are removed in pieces
Some cysts, particularly those of the subglottis, are destroying the relation of the cyst to the surface
clearly related to postintubation while at least some mucosa. This has caused pathologists to search for a
vocal cord cysts may be related to vocal abuse trauma more useful but clinically relevant classification. That
(9,11,13). proposed by Newman et al. seems to fill this void (6)
Table 1 Classification of Laryngeal Cysts

I. Tonsillar cysts
II. Epithelial cyst
A. Ductal
B. Saccular
i. Anterior
ii. Lateral
III. Oncocytic cyst (oncocytic papillary cystadenoma
(Table 1). They propose three categories of laryngeal

cysts: tonsillar, epithelial, and oncocytic. In a collective
review of 92 patients with laryngeal cysts classified
according to the scheme of Neuman et al., 61% had
epithelial cysts, 25% tonsillar cysts, and 14% oncocytic
cysts (6,7).
Tonsillar Cyst
Tonsillar cysts resemble a palatine tonsillar crypt
distended with keratin, hence the name. They occur
almost exclusively in the epiglottis, vallecula, or pyri- Figure 17. Epithelial cyst filled with mucin and lined by attenu-
form sinus and may be single or multiple. They are ated respiratory epithelium (H&E, 20; insert, 300).
usually small and are lined by stratified squamous
epithelium, filled with keratin, and surrounded by
lymphoid tissue with prominent germinal centers
(Fig. 16). or may not have papillary infoldings and are lined
entirely by respiratory epithelium, squamous epitheli-
Epithelial Cyst um, or both or by a nonspecific attenuated epithelium.
They may therefore contain either keratin or mucin
These cysts are also found primarily in the supra- (Figs. 16 and 17). Some are focally associated with small
glottic larynx, pyriform sinus, or vallecula. They may aggregates of lymphoid tissue. With additional clinical
information, these cysts can be further subdivided into
ductal and saccular (anterior or lateral). See previous
discussion on ductal and saccular cysts.
Oncocytic Cyst
These cysts occur primarily in the area of the false
cords and ventricles in patients over the age of
50 years. They may be either unilocular or exhibit
papillary infoldings. Those exhibiting the latter fea-
ture are also referred to as oncocytic papillary cysta-
denomas. The cardinal features of these cysts are their
oncocytic epithelium and their tendency, on occasion,
for multifocality and local recurrence (Fig. 18).
Treatment
In order to avoid laryngeal stenosis, cysts in infants
and children should be managed conservatively.
Some advocate needle aspiration initially. Recurrence
may necessitate repeat aspiration, or, in some instan-
ces, the cyst may have to be deroofed, removed with
cup forceps, or marsupialized with lasers (16). Small
cysts in adults can be treated similarly. Larger cysts
Figure 16. A 42-year-old man presented with a sensation of a often require excision externally.
‘‘foreign body in his throat.’’ Endoscopic examination revealed a
cyst of the left pyriform sinus. Microscopically, the specimen Laryngocele
consisted of two adjacent cysts: (i) a tonsillar cyst (TC) filled with
keratin, lined by stratified squamous epithelium and surrounded Laryngoceles are abnormal dilatations of the saccule.
by lymphoid tissue; and (ii) an epithelial cyst (EC) also filled with They differ from saccular cysts in that they contain air
keratin and lined by stratified squamous epithelium, but without a rather than mucus and maintain an open communica-
mantle of lymphoid tissue (H&E, 20). tion with the lumen of the larynx (Figs. 13B, 15, and 19).
The distinction between a long saccule and a
118 Barnes
Figure 18. Oncocytic cyst. Note the focal intracystic papillary

projection and oncocytic character of the epithelium (insert).
Such cysts are often referred to as oncocytic papillary cystade-
nomas (H&E, 40; insert, 200) Figure 19. Computer tomography scan showing a mixed lar-
yngocele with large external (E) and small internal (I) compo-
nents. Abbreviations: SM, strap muscles; P, petiole; H,
hypopharynx; PEF, pre-epiglottic fat; SCM, sternocleidomastoid
muscle. Source: Image Courtesy of Dr. Jane Weissman, formerly
of Pittsburgh, PA.
laryngocele is somewhat subjective. According to
Holinger et al., a long, ectatic saccule becomes a
laryngocele when it is (i) symptomatic, (ii) palpable,
(iii) observed internally by indirect or direct laryngos-
copy, and (iv) observed radiologically or by dissection
to extend above the superior margin of the thyroid
cartilage (3). About 2% of ‘‘normal’’ larynges harbor
laryngoceles (17).
Laryngoceles are more common in the 40- to 70-
year age group and are seven times more frequent in
men than women (18). They are subclassified into
three categories—internal, external, and mixed. They
are termed ‘‘internal’’ when confined to the intrinsic
larynx, ‘‘external’’ when present in the neck commu-
nicating with an undistended saccule through the
thyrohyoid membrane, and ‘‘mixed’’ when both are
present (Fig. 19). The reported incidence of each is
variable. Canalis reviewed 131 cases and observed
44% to be mixed, 30% internal, and 26% external
(18). Macfie evaluated 52 patients, classifying 69% as
mixed and 31% internal (19). About 20% to 35% of
laryngoceles are bilateral.
Patients with symptomatic internal laryngoceles
usually present with hoarseness or change in quality
of the voice, dyspnea, cough, or sensation of a mass in Figure 20. Computed tomography scan showing an infected
their throat. External laryngoceles manifest as a soft mixed laryngocele (laryngopyocele). Both external (E) and internal
(I) components are filled with dense secretions (compare with air-
reducible neck mass accentuated by an increase in filled laryngocele in Fig. 15). Abbreviation: SG, submandibular
intralaryngeal pressure or as subcutaneous emphysema gland. Source: Image courtesy of Dr. Hugh Curtin, Boston, MA.
(20,21). Laryngoceles can become infected (laryngo-
pyocele) following upper respiratory infections or the
use of diagnostic procedures (Fig. 20).
Laryngoceles may be congenital or acquired (22).
They are usually associated with increased intralar- Carcinoma of the larynx is sometimes associated
yngeal pressure and, consequently, are common occu- with a laryngocele (Fig. 21). The frequency of this
pational hazards among glass blowers, musicians who association varies according to the stringency of
play wind instruments, and weight lifters (19). criteria used for diagnosing a laryngocele (elongated
histologically into nonkeratinized and keratinized

types (2–9).
In general, nonkeratinized papillomas occur pri-
marily in children and young to middle-aged adults,
may be solitary or multiple, are etiologically related to
the human papillomavirus (HPV) types 6 and 11,
often stubbornly recur following excision, and have
little malignant potential. In contrast, keratinized pap-
illomas occur primarily in adults, are usually solitary
lesions, generally are not related to a virus, may or
may not recur, and occasionally have a malignant
potential.
B. Recurrent Respiratory Papillomatosis—

Nonkeratinized Papilloma
Terminology
Figure 21. (A) Squamous cell carcinoma of the supraglottic Recurrent respiratory papillomatosis (RRP, papillo-
larynx associated with a laryngocele. The larynx was sectioned
matosis, juvenile papillomatosis, laryngeal papilloma-
vertically (hash marks) to show their relation. (B) Cross section of
tumor shown in A. Probe passes through the laryngocele. Note
tosis) is the term currently preferred to describe a
tumor (arrow) compressing the orifice of the saccule. ‘‘benign’’ disease of the aerodigestive tract character-
ized by the appearance of one or more, viral-related
squamous papillomas that have a persistent tendency
for recurrence and a relative resistance to treatment.
Terms such as juvenile papillomatosis are inappropri-
ate, since the disease may persist into adulthood or
saccule vs. laryngocele) and whether or not the find-
may not even manifest until late in life. Laryngeal
ings are based on anatomic or radiographic studies.
papillomatosis is also inaccurate since the disease may
The literature indicates that somewhere between 0%
involve other sites in the aerodigestive tract, including
and 29% of all laryngeal carcinomas are associated
the oral cavity, trachea, and lungs.
with laryngoceles (17,23–26). Conversely, of all lar-
yngoceles, 15% to 49% are associated with carcinoma
Etiology
(21,24). Generally, the carcinoma is clinically obvious,
but in a few instances (4%), the lesion will present The long-presumed viral etiology of RRP has now
initially as a laryngocele with an occult carcinoma been conclusively established. The disease is caused
(24). The carcinoma may be etiologically related to by the HPV, especially types 6 and 11, a DNA virus
the laryngocele by acting as a ball-valve mechanism that belongs to the family Papovariradae. This was first
entrapping air in the saccule. In some cases, however, suggested in 1923 when Ullman successfully trans-
the carcinoma is on the side opposite the laryngocele. planted a homogenate of a laryngeal papilloma
In this instance, it has been speculated that the tumor removed from one of his patients to his own arm (10).
activates the cough reflex causing an increase in intra- More recently viral antigens or genomes have been
laryngeal pressure with dilatation of the saccule. Most demonstrated in laryngeal papillomas by immunohis-
(74%) cancer-associated laryngoceles are of the inter- tochemistry, in situ hybridization, and the polymerase
nal type (24). chain reaction (11–17). Viral particles consistent with
Asymptomatic laryngoceles require no treatment HPV have also allegedly been identified by electron
but in the adult, direct laryngoscopy and biopsy are microscopy, although the frequency of finding these
mandatory in order to rule out concomitant carcinoma. particles ultrastructurally has varied from 0% to 20%
When symptomatic and large, they may have to be (18–22).
excised through an external approach (Fig. 15). The female genital tract is the predominant viral
Laryngopyoceles are best treated by incision and reservoir from which the respiratory infection is
drainage, antibiotics, and removal after the infection acquired. Retrospective studies have shown that
has subsided. approximately 30% to 70% of patients with RRP are
born to mothers with condylomata acuminata (genital
warts which are also etiologically related to HPV 6
VII. PAPILLOMAS and 11) (20,21,23,24,25). Although condylomata acu-
A. Introduction minata are easily recognized, cervical flat warts (also
related to HPV) are frequently overlooked or subclin-
Papillomas are the most common benign tumor of the ical. It is therefore possible that women with cervical
larynx (1). They can be divided clinically into three flat warts could transmit the virus to their newborns
categories according to age of onset (juvenile vs. without knowledge of their infection (24). This could
adult), severity of disease (aggressive vs. nonaggres- explain why the mothers of many individuals with
sive), and number of lesions (solitary vs. multiple) and RRP have no history of genital warts.
120 Barnes
Kashima et al. indicate that patients with juvenile- AO-RRP. The age limit that defines these categories,
onset RRP (JO-RRP) are frequently characterized however, is arbitrary and highly variable. For
by a clinical triad: (i) first born child, (ii) vaginal instance, JO-RRP has been defined in various studies
delivery, and (iii) a teen-aged mother (26). It is as patients who present before the age of 12, 16, 18, or
known that teen-aged mothers at the time of first 20 years and AO-RRP as those who present over these
delivery have prolonged labors, with subsequent ages (5,13,26,30). In a review of 110 cases of RRP,
increased exposure to the virus. In their study, 32% Strong et al. noted that 66% of patients experienced
of patients with JO-RRP and none of those with adult- onset of the disease between birth and 15 years of age
onset RRP (AO-RRP) manifested the complete triad. while 34% developed their disease at 16 years of age
This compared with a 10% and 3% incidence, respec- or later (21). The majority of patients with JO-RRP
tively, in a control population of normal juveniles and become symptomatic between two and five years of
adults (26). age. Abnormal crying, hoarseness, dyspnea, cough,
The risk of acquiring RRP in children born dysphagia, and stridor are the usual symptoms.
vaginally to an HPV-infected mother ranges from 1 The clinical course is, to some extent, correlated
in 143 deliveries for those with a history of condyloma with the age of onset. In JO-RRP, the distribution
during pregnancy to 1 in 400 deliveries for those between the two sexes is about equal and the papillo-
women with an active or latent HPV infection as mas are more often multiple (80–98% of all cases) and
demonstrated by cervicovaginal swabs for the preva- frequently exhibit extensive growth and occasionally
lence of HPV DNA (27–29). The low rate of RRP in rapid recurrence after excision (5,21,31). JO-RRP may
exposed children suggests that additional factors remit spontaneously or persist into adulthood. AO-
(? immune) may be necessary before acquiring the RRP, in contrast, is three to four times more common
disease. Nevertheless, there is an on-going debate in males and the papillomas are multiple in only 25%
with medicolegal overtones on whether a pregnant to 35% of cases and recur less often (5,39).
woman with known condylomas should be permitted The disease almost invariably involves the lar-
to deliver vaginally or by elective cesarean section ynx, especially the true and false vocal cords and
(30,31). Although cesarean sections do diminish the ventricles. In more advanced cases, the lesions may
odds for acquiring RRP, the protection is not absolute, also involve other laryngeal sites, nasal cavity, lips,
as illustrated in the study of Wiatrak et al. (32). These gingiva, palate, nasopharynx, esophagus, trachea,
authors evaluated 73 patients with JO-RRP. The mode bronchi and/or lungs. Data derived from the National
of delivery was known in 69, and of these, 64 (93%) registry for JO-RRP (N = 603 children) indicate that in
were delivered vaginally and 5 (7%) by cesarean 87.4% of cases only one anatomic sites is involved,
section. while in 9.8%, 2.6%, and 0.2%, two, three, and four
In AO-RRP, risk factors are less conclusive. sites, respectively, are involved (35).
Conceivably such individuals may acquire the virus Extension of papillomas into the trachea or bron-
at the time of delivery. The virus may then remain chi occurs in 2% to 15% of patients, an event that is
dormant, only to express itself in adulthood. Orogen- usually associated with subglottic disease and prior
ital contact with an infected partner is also receiving tracheotomy (21,35,37,40–43). Some individuals (1–
increasing attention (21,26). 5%) may even have pulmonary parenchymal involve-
There is no known instance of RRP occurring ment (32,43–48). This is a potentially ominous finding
among siblings or transmission of the disease attributed as these individuals often die of their disease (43).
to therapeutic interventions in the newborn Atelectasis, bronchiectasis, and thin-wall cavities with
nursery (26). There is an interesting case report, smooth borders are the most common roentgeno-
however, of a surgeon who contacted the disease graphic signs of lung disease. Patients with bronchoal-
following laser therapy of some of his patients who veolar involvement tend to follow a common pattern:
had anogenital condylomas (33). It was speculated that (i) the majority have had laryngeal papillomas discov-
he acquired the disease by inhaling viral particles ered before the age of five years, (ii) the interval
present in the laser plume. between the onset of laryngeal disease and the dis-
RRP is an uncommon disease. In the United covery of bronchoalveolar papillomatosis averages
States, it is estimated that approximately 2400 new 12 years (range 1–36), (iii) all have tracheostomies,
cases among children and 3600 new cases among and (iv) all have worn tracheal cannulas for extended
adults are diagnosed each year, with an incidence of periods of time (43).
about 1.7 to 4.3 per 100,000 children and 1.8 per The distribution or recurrence of papillomas in
100,000 adults (28,29,32,34–38). Despite it rarity, the the aerodigestive tract, however, is not random,
impact of the disease on patients, their families, and according to Kashima et al., but instead follows a
the health care system is immense. It is not unusual predictable pattern with lesions occurring at sites in
for some individuals to require more than 100 surgical which ciliated respiratory and squamous epithelia are
procedures with an average lifetime cost of thousands juxtaposed (squamociliary junction) (49). Injury to a
of dollars. ciliated mucosa such as from a biopsy or surgical
procedure often results in squamous metaplasia, cre-
Clinical Features ating an iatrogenic squamociliary junction and predis-
posing the patient for additional lesions. This might
According to the age at initial diagnosis, RRP is explain the tendency for papillomas to occur at tra-
commonly divided into two categories: JO-RRP and cheostomy sites.
Pathology ing (11) (Fig. 25). In a review of 58 cases of JO-RRP in

which the virus was genotyped at the time of initial
Grossly the papillomas present as one or more, pink, therapy, Wiatrak et al. observed that in 53.5% of cases
soft, warty growths that are often confluent and bleed the virus was HPV 6, in 39.7% HPV 11, and in 6.9%
with minor trauma (Fig. 22). By light microscopy, they both HPV 6 and 11 were found (32). Similarly, in a
are composed of papillary fronds of squamous cells study of 24 AO-RRP in which the papilloma was
containing fibrovascular cores (Fig. 23). Although genotyped, Pou et al. observed 87.5% were HPV 6,
typically nonkeratinized, an occasional case may 8.3% HPV 11, and 0.04% HPV 16 (50). Interestingly,
show a very thin scale of surface orthokeratin or they also found coinfection with other viruses. In 12
parakeratin (Fig. 24). The stroma is well vascularized cases (50%), Herpes simplex was found and in 3 cases
and may or may not contain inflammatory cells. Intra- (12.5%) Epstein-Barr was observed. None were asso-
nuclear or intracytoplasmic viral inclusions are not ciated with cytomegalovirus. They raised the possibil-
seen but koilocytic changes may be observed in some ity that viral coinfection might be predictive of an
instances. According to Lack et al., 48% of unselected aggressive clinical course.
papillomas will be positive for HPV on immunostain- The histologic appearance of the papillomas
tends to reflect the clinical activity of the disease
(51,52). Papillomas that recur within one month of
Figure 22. Recurrent respiratory papillomatosis. (A) Laryngo-

gram demonstrating multiple filling defects of the larynx. Note the
tracheal canula. (B) Laryngoscopic view showing multiple, fria-
ble, occasionally confluent papillary growths. Source: Images
courtesy of Dr. Mark May, (retd.) Shadyside Hospital, Pittsburgh, Figure 24. The typical squamous papilloma of recurrent respi-
PA. ratory papillomatosis demonstrates orderly growth and matura-
tion of the epithelial cells. There is little, if any, tendency to
keratinize.
Figure 25. Squamous papilloma of recurrent respiratory papil-

Figure 23. Low-power view of a squamous papilloma associat- lomatosis positive for human papillomavirus (immunoperoxidase,
ed with recurrent respiratory papillomatosis (H&E, 20). 40).
122 Barnes
excision frequently display varying degrees of atypia important in pathogenesis of the disease. If so, anti-
manifested by basal cell hyperplasia, increased mitotic vascular therapy may be of therapeutic value.
rate, prominent nucleoli, and focal variation in nuclear
size and shape. As the activity of the disease lessens, Treatment and Prognosis
the papillomas tend to revert back to normal epithelial
maturation. The natural history of RRP is highly variable and
unpredictable with remissions and exacerbations
occurring for no apparent reason. Some patients
Immunohistochemistry have only one or two papillomas with local recurrence
every two or three years and eventual spontaneous
Basal and occasionally suprabasal cells of papillomas
remission while others have extensive life-threatening
associated with RRP often stain positive by immuno-
histochemistry for Ki-67 and p53 (53–57). The signifi- disease. Benjamin and Parsons describe a patient who
had 20 operative procedures for JO-RRP and then
cance of these findings is controversial. Some indicate
remained disease-free for 25 years, only to experience
that these markers, especially if found throughout the
epithelium, correlate with more frequent recurrence another nine operations for recurrent disease later in
life (4). During periods of active growth, papillomas
and possible malignant transformation while others
may appear every two to four weeks, and it is not
contend that they have no predictive value.
uncommon for some patients to have undergone 50 to
Lele et al. examined four cases of HPV-11
100 operations or more for removal.
JO-RRP progressing to carcinomas utilizing immunos-
Majoros et al. followed 65 children and observed
tains for p53, pRb, p21, and p16 (58). They observed a
that the disease lasted five years or more in 80% (42).
marked increase expression of p53 and pRb and a
Ruparelia et al. identified 165 cases of JO-RRP with a
simultaneous decrease in p21 as the lesion progressed
median follow-up of 1.7 years (range 0.01–4.61 years).
from benign to dysplastic to malignant. p16 was
Disease remission, defined as the absence of surgical
expressed in all lesions and was, therefore nondis-
criminatory. On the basis of this combination of stains, intervention for at least one year, was seen in 36
(21.8%) of the children (64). It would appear, however,
the authors suggested that lesions with a malignant
from the case of Benjamin and Parsons noted above,
potential could be recognized. In contrast, Xu et al.
studied a single case of HPV-11 AO-RRP that pro- that patients with RRP may be at risk for possible local
recurrence throughout their life span (4).
gressed to carcinoma in which these stains (p53, Rb,
The effect of puberty on the course of the disease
and p16) were applied (59). They found these stains to
is controversial. Some are of the opinion that papillo-
be unaltered during tumor progression.
mas become less aggressive or even disappear during
puberty while others contend that puberty has no
Molecular-Genetic Data
relationship to the outcome of disease (4,21,42,65–
Patients with RRP may be unable to resist or control 67). The effect of pregnancy is also controversial; in
their disease because of an ineffective HPV-specific T- some pregnant women, the disease may resolve while
cell response. Bonagura et al. have observed that these in others it may become more aggressive (25,39,65).
individuals have an elevated percentage of CD8-posi- Although there are no parameters that allow one
tive, CD28-negative T-cells, and that the T-cells often to predict the course RRP, it is generally agreed that
express an increase in TH2-like cytokine mRNA in individuals who experience the onset of disease prior
response to autologous papilloma tissue (60). These to three years of age, have more than one anatomic
patients, otherwise, are not prone to other nonviral site of involvement, and are infected with HPV-11
infectious agents. tend to have a more aggressive disease.
Human leukocytes antigens (HLA) may also be Since RRP is often characterized by periods of
important in the etiopathogenesis of the disease. active growth and remission, it is difficult to evaluate
Gelder et al. studied a cohort of 60 RRP patients in the efficacy of various therapeutic modalities. Accord-
the United Kingdom for HLAs and compared the ing to Strong et al., there are three goals of manage-
results to 554 controls (61). Of these 60 patients, 36 ment: (i) to maintain the airway and voice and to
had JO-RRP and 24 AO-RRP. They noted that HLA avoid tracheotomy whenever possible, (ii) to reduce
DRB1*0301 was disproportionately present in the RRP the tumor burden to minimal proportions in hopes of
patients (55%) compared with the control population achieving remission via host responses, and (iii) in the
(25%). The possibility of a genetic association between presence of tracheotomy maintain the patency of the
this HLA and susceptibility was raised. Bonagura has airway by bronchoscopy and to use the shortest
also observed a potential relationship between HLA possible tracheotomy tube (21). Tracheotomy, howev-
DQ3 and DR11 and RRP (62). er, is ultimately required in a 1.8% to 64% of all
More recently, Rahbar, et al. found that vascular patients with RRP, with an average incidence of 30%
endothelial growth factor—A (VEGF-A) was strongly in combined studies (68,69).
expressed in the squamous epithelium of the papillo- The current standard treatment is microlaryng-
mas and that VEGF receptors 1 and 2 were strongly eal surgery using forceps, the microdebrider, or CO2
expressed in the endothelial cells of the underlying laser. Complications of treatment include webs, fibro-
blood vessel (63). Neither strong labeling of VEGF-A sis, arytenoid fixation, and laryngeal stenosis (70). In
nor labeling of its receptors was noted in the control general, the more vigorous the therapy, the greater the
population, suggesting that these factors may be complications.
Surgical excision of the papillomas, however, is from a papilloma. Some authors have also observed
only a palliative procedure. It has been shown for that the transformation of RRP to squamous cell
instance, that HPV can be found by DNA hybridiza- carcinoma does not always progress through the
tion or the polymerase chain reaction in the adjacent usual dysplasia sequence (60).
or nearby nondiseased mucosa in approximately 40% Crissman et al. studied by image analysis the
to 75% of patients. The persistence of the virus DNA content of papillomas obtained from seven
explains the tendency for recurrence (17,71–73). As a patients with RRP (5 JO-RRP and 2 AO-RRP) (93).
result, search for effective adjuvant medical therapy is All of the papillomas microscopically exhibited areas
ongoing (37,74,75). of atypia/dysplasia and, when these foci were specif-
The overall mortality rate in patients with RRP ically examined, six of the seven were found to have
has varied from 4% to 14% (42,65,76). Causes of death abnormal (aneuploid) DNA. The significance of this
have included asphyxia, infections, pulmonary com- finding, however, is uncertain since none of the six
plications, and superimposed carcinoma. individuals developed carcinoma after an average
Carcinoma complicating RRP, so-called carcinoma follow-up of 30 years.
ex papilloma, is an infrequent occurrence (77–92). In
some instances, the carcinoma occurs ‘‘spontaneously’’
while in others, it seems to be related to prior radiation C. Keratinized Papilloma—Papillary Keratosis
exposure. Some patients with RRP are also heavy
smokers or consumers of alcohol, which may act as Keratinized papillomas, as previously indicated, occur
additional co-carcinogens or promoters in the develop- primarily in adults; are usually solitary lesions; gener-
ment of carcinoma. ally are not related to a virus; may be etiologically
The incidence of carcinoma developing in the linked, in some instances, to smoking; may or may not
nonirradiated patient is stated to be 2% and for the recur; and occasionally exhibit malignant potential
irradiated patient, 14% (3,4,85). According to Linden- (8,9,12,94–96). The majority arises from the true vocal
berg and Elbrond, there is a 16-fold increased risk of a cord and manifest clinically as hoarseness.
subsequent carcinoma in patients who have received It has been our experience over the years that
irradiation for their RRP (84). Even a small dose of many clinicians and pathologists do not appreciate the
irradiation may be carcinogenic in these patients. differences between keratinized and nonkeratinized
Carcinoma complicating RRP develops in either papillomas and equate the term ‘‘papilloma,’’ regard-
the larynx or lung, and prognosis depends, to a large less of histologic appearance, as being of viral origin
extent, on whether the tumor arises spontaneously or and akin to recurrent respiratory papillomatosis. To
follows radiation exposure. Kashima et al. reviewed avoid this misunderstanding, we advocate the use of
17 patients with RRP who developed laryngeal carci- the term ‘‘papillary keratosis’’ in place of ‘‘keratinized
noma (81). Of the seven patients who developed papilloma.’’
spontaneous laryngeal carcinoma, all had JO-RRP. Papillary keratoses rarely exceed two cm. and
The average interval from onset of RRP to the devel- are composed, histologically, of fronds of squamous
opment of carcinoma was about 30 years, but only one cells with fibrovascular cores covered by a thick scale
of six patients available for follow-up died of disease. of orthokeratin or parakeratin (Figs. 26 and 27). In
In contrast, of the 10 patients that developed laryngeal some cases, the papillary fronds are small but yet
carcinoma following irradiation, 9 had JO-RRP with there is a definite papillary configuration to the sur-
the average interval from onset of RRP to the occur- face epithelium. Keratohyalin granules are usually,
rence of the carcinoma of about 10 years. Eight of the but not invariably, present, and the stroma contains
10 patients with follow-up died of disease. sparse to absent inflammatory cells. Not infrequently,
Guillou et al. reviewed 14 cases of spontaneous the squamous component will exhibit varying degrees
squamous cell carcinoma of the lung that occurred in of dysplasia which, if observed, should be quantitated
nonsmoking, nonirradiated patients with RRP and as mild, moderate, or severe, e.g. papillary keratosis
observed the following characteristic profile: (i) all with moderate dysplasia (Figs. 28 and 29). Likewise, if
patients developed laryngeal papillomatosis around no epithelial disturbances are see, it too should be
2.5 years of age (range 1–6 years), (ii) lung carcinoma noted, e.g., papillary keratosis without dysplasia.
was diagnosed at about 15 years after the onset of Clinically, the papillary keratoses appear to have
laryngeal papillomatosis (range 4–26 years), (iii) all the same significance as the flat keratoses. See
patients presented with pulmonary extension of their ‘‘Section X’’ below.
papillomatosis, (iv) the tumor was usually a well to Papillary keratosis may be confused, both clini-
moderately differentiated squamous cell carcinoma cally and microscopically, with verrucous carcinoma
often with regional lymph nodes and distant metasta- (VC) of the larynx (97,98). Verrucous carcinoma, how-
ses, and (v) most patients died soon after diagnosis of ever, contains expanded, club-shaped rete pegs, often
the carcinoma (82). distended with keratin, and a markedly inflamed
In most cases in which the papilloma and carci- stroma. Papillary keratosis, in contrast, has thin, pointy
noma have been examined for HPV, each has con- rete pegs and, at most, only a mildly inflamed stroma.
tained HPV-11. Rarely, HPV-6, 16, or 18 have been In addition, papillary keratosis usually, but not invari-
identified. able, has rather uniform keratohyalin granules in the
The squamous carcinomas are generally well epithelial cells just beneath the keratin layer (stratum
differentiated and, at times, difficult to distinguish granulosum). These granules are characteristically
124 Barnes
Figure 28. Papillary keratosis with mild to moderate epithelial

dysplasia. Note the papillary and heavily keratinized surface.
Keratohyaline granules are, however, absent (H&E, 100) (see
Fig. 25).
Figure 26. Papillary keratosis without dysplasia of right true

vocal cord (arrow; H&E, whole mount).
Figure 29. Higher magnification of the boxed area shown in

Figure 28. Note the dysplasia (H&E, 400).
Figure 27. Papillary keratosis (keratinized papilloma shown in VIII. VERRUCA VULGARIS
Fig. 26). Note the papillary, heavily keratinized surface, promi- A. Introduction
nent keratohyaline granules, and absence of dysplasia (H&E,
140). Verruca vulgaris occurs primarily on the skin and is
etiologically related to the HPV. On occasions, it can
also arise on mucous membranes, particularly the lips,
infrequently in the oral cavity, and exceptionally in
sparse to absent in verrucous carcinoma. The presence the larynx (1–6). In the latter location, it may be
of more than just ‘‘inflammatory atypia/dysplasia’’ confused with papillary keratosis, condyloma acumi-
supports the diagnosis of papillary keratosis rather natum, and verrucous carcinoma.
than verrucous carcinoma. Verrucous carcinoma of
the larynx is also uncommon below the age of B. Clinical Features
50 years and often exceeds 2 cm in size, whereas
papillary keratosis is not infrequent below the age of Barnes et al. described one case and reviewed seven
50 and rarely exceeds 2 cm. additional cases of verruca vulgaris of the larynx
(VVL) reported in the English language literature

(2,6). These eight patients, seven men and one
woman, were aged between 37 and 70 years (average
58 years). Although not always indicated, the true
vocal cord appeared to be the most common site of
origin and hoarseness the predominant symptom.
Most presented as unilateral, sometimes bilater-
al, exophytic sharply demarcated white growths, usu-
ally between 0.3 and 0.7 cm In one case, however, the
lesion involved almost the entire length of the vocal
cord (2).
C. Pathology
Histologically, VVL resembles its cutaneous counter-
part in all respects (Figs. 30 and 31). Most will also be
positive, on immunostaining, for HPV. Virologically,
however, there does appear to be a difference. Using
in situ hybridization, Barnes et al. studied a single case
of VVL and found it to contain HPV 6 or 11 which was
unexpected because verruca vulgaris of the skin, lips,
and oral cavity is associated with HPV 2 and 4 (3,5,6). Figure 31. Electron microscopy of verruca vulgaris of the true
This implies that verruca vulgaris can be caused by vocal cord in Figure 30 showing intranuclear viral particles
HPV types other than 2 and 4. In addition, since HPV consistent with the human papillomavirus.
6 and 11 are the same genotypes associated with
recurrent respiratory papillomatosis (laryngeal papil-
lomatosis), it further indicated that VVL is at least
virologically more related to recurrent respiratory
papillomatosis of the larynx than to its counterpart contain prominent keratohyalin granules. However, in
on the skin, lips, and oral cavity. contrast to VVL, papillary keratosis lacks clear cells in
the epithelial layer (koilocytes) and is almost invari-
ably negative on immunostaining for HPV. Moreover,
D. Differential Diagnosis papillary keratosis often exhibits varying degrees of
dysplasia, which is not seen in VVL.
VVL should be distinguished from ‘‘ordinary’’ papil- Condyloma acuminatum and VVL share many
lary keratosis (keratinized papilloma), condyloma histologic features and the differences between the
acuminatum, and verrucous carcinoma. Both VVL two are more quantitative than qualitative (7–9). In
and papillary keratosis occur in adults and involve general, VVL is more heavily keratinized than condy-
the true vocal cords. Both are heavily keratinized and loma acuminatum and contains larger and more vari-
ably sized keratohyalin granules. The rete pegs in
VVL also tend to be more pointed and elongated.
Like VVL, VC of the larynx occurs in adults
(median age 58 years) exhibits a male predominance,
arises primarily from the true vocal cords, and is
heavily keratinized (10). VVL can be separated from
VC by the presence of numerous large keratohyalin
granules and prominent koilocytosis. Keratohylain
granules are sparse to absent in VC and, while koilo-
cytotic cells may be found in VC, they are decidedly
less common than in VVL. In VVL, the rete pegs (if
apparent at all on some biopsies) are elongated, thin,
pointed, radially oriented, and sometimes branched,
whereas in VC they are bulbous, rounded, or club-
shaped and exhibit less branching. VVL is also usually
positive on immunostaining for HPV, whereas verru-
ca carcinoma is uniformly negative.
E. Treatment and Prognosis

Figure 30. Verruca vulgaris of the true vocal cord showing
marked acanthosis, papillomatosis, keratosis, prominent kerato- Simple endoscopic excision is usually curative,
hyaline granules, and koilocytes (H&E, 200). Source: From although one patient did experience two local recur-
Sec. VIII, Ref. 6) rences five and seven years, respectively, after initial
excision (2).
126 Barnes
IX. BENIGN NONEPITHELIAL TUMORS varying degrees of respiratory embarrassment, often

OF THE LARYNX confused with the ‘‘croup’’ (6,7). Cough, cyanosis, and
dysphagia may also be apparent, but hemoptysis is
A. Introduction distinctly uncommon. The symptoms are episodic and
The most comprehensive reviews of benign conditions vary from hour to hour or from day to day, depending
of the larynx have been by New and Erich and on the degree of vascular engorgement. Forty-five to
Holinger and Johnston (1,2). A critical analysis of fifty percent of patients also have additional heman-
these studies as well as our own experience at the giomas in locations other than the subglottis. Most of
University of Pittsburgh (3) (Table 2) indicates that these are cutaneous, rarely visceral (6,7).
mesenchymal tumors comprise 8% to 17% of all At laryngoscopy, one sees a pink to blue, sessile,
benign laryngeal neoplasms. Hyperkeratosis, leuko- compressible submucosal mass of the subglottis, usu-
plakia, cysts, myxomas (which probably represent ally on the left side. In a review of 116 patients, Bitar
vocal cord nodules), and various inflammatory et al. noticed the lesion to be bilateral in 22% of cases,
lesions, which were included in the former two stud- left-sided and posterior in 21%, circumferential in
ies, but not in the above calculations, are not consid- 21%, left-sided and unilateral in 16%, right-sided
ered by us to be neoplasms. A review of some of the and unilateral in 6%, posterior in 5%, right-sided
more common benign nonepithelial tumors of the and posterior in 2% and unknown in 7% (7). The
larynx follows. degree of airway narrowing ranged from 10% to
99% (mean 65%). Some hemangiomas are even appar-
ent on imaging examination. Others are inconspicu-
B. Hemangioma ous and difficult to identify even at autopsy, because
of postmortem emptying of blood vessels.
Hemangiomas of the larynx can be divided into two
Although it is commonly stated that biopsies
groups: those occurring in infants and those occurring
should be avoided because of the risk of excessive
in adults.
bleeding and aspiration, Shikhani et al. refer to 82
patients with subglottic hemangiomas who under-
Hemangiomas in Infants
went biopsies and, of these, only 2 experienced signif-
Hemangiomas of the larynx in infants arise primarily icant bleeding (6). The diagnosis in most instances can
in the subglottis and, as such, are ominous, potentially be established without biopsy if one pays close atten-
life-threatening lesions because of airway compro- tion to the age of onset, symptomatology, and lar-
mise. Fortunately, they are uncommon, as evidenced yngoscopic findings in conjunction with cutaneous
by only 17 cases being diagnosed over a 10-year hemangiomas.
interval at the Children’s Hospital in Boston (4) and, The tumors are most often solitary and limited to
in a review of 866 congenital lesions of the larynx, the subglottis, but on occasion, may involve the true
Holinger and Brown identified only 13 (1.5%) that vocal cords or trachea, or both. Multifocal hemangio-
were hemangiomas (5). mas of the upper aerodigestive tract are rare, but have
They are more common in females by a 2:1 ratio been described (8).
and almost invariably present during the first six Pathologically, subglottic hemangiomas are usu-
months of life. The infant is typically asymptomatic ally of the capillary type (92%) (6) (Fig. 32). Cavernous
at birth, but during the ensuing weeks to months (4%) and mixed capillary-cavernous types (4%) are
(average age at diagnosis 3.6 months), develops uncommon. Some may even be cellular enough to
Table 2 Benign Neoplasms of the Larynx at the Eye and Ear

Institute Pavilion of Pittsburgh and Presbyterian University
Hospital (1955–1993)
Type Number % of total
Squamous papilloma 326 80.7
Oncocytic papillary cystadenoma 35 8.7
Granular cell tumor 12 3.0
Hemangioma 9 2.2
Neurofibroma 3 0.7
Lipoma 3 0.7
Chondroma 3 0.7
Lymphangioma 2 0.5
Paraganglioma 2 0.5
Neurilemoma 2 0.5
Fibrous histiocytoma 2 0.5
Rhabdomyoma 2 0.5
Pleomorphic adenoma 1 0.2
Nodular fasciitis 1 0.2 Figure 32. Subglottic capillary hemangioma with entrapped
Fibromatosis 1 0.2 mucous gland (H&E, 200).
Total 404 100 %
qualify as benign hemangioendotheliomas. They are laser therapy is largely ineffective. Surgical excisions
typically confined to the lamina propria, but may are usually required.
extend to involve the perichondrium of the underling The vascular stage of a vocal cord nodule-polyp
cartilage or invade between the tracheal rings to lie is often confused with a hemangioma of the true vocal
external to the trachea (9). cord. See ‘‘Differential Diagnosis’’ in the discussion of
Because of the constant threat of asphyxiation, vocal cord nodules-polyps above.
some form of therapy is usually necessary. Tracheoto-
my with a ‘‘watch and wait’’ approach for spontane-
ous involution, as is commonly used and seen in C. Neurofibroma and Neurilemoma
cutaneous hemangiomas, is associated with 4% to Neurofibromas and neurilemomas are uncommon
46% mortality in subglottic hemangiomas (6,7). tumors in the larynx, representing in our experience
Other forms of therapy have been used with varying only 1.2% of all benign larynx neoplasms (Table 2). In
degrees of success and complications. Among these 1993, only about 130 cases were reported in the litera-
are included intralesional and systemic steroids, inter- ture (13–15).
feron, sclerosing agents, electrocautery, radioactive They typically occur in the 30- to 60-year-old age
gold implants, cryosurgery, laser ablation, surgical group but have been found in patients from birth to
excision, or a combination of these procedures old age (13–27). Although some studies indicate a
(6,7,10). Variables that have an impact on the form slight male predominance (61%), others suggest that
of therapy and outcome depend on age (younger they are more common in females by a ratio of 3:2
patients have more proliferative lesions), size of the (16,19).
lesion, location, and degree of airway compromise (7). Most arise submucosally in the supraglottic lar-
ynx in the vicinity of the aryepiglottic folds, false vocal
Hemangiomas in Adults cords, or arytenoids, presumable from branches of the
In contrast with laryngeal hemangiomas of infancy, superior laryngeal nerve (14) (Fig. 34). Symptoms are
which are primarily subglottic in origin and often life- slow to evolve and consist of a fullness or sensation of
threatening, hemangiomas in the adult larynx arise a foreign body in the throat, cough, hoarseness, and
primarily in the supraglottis and rarely compromise occasionally respiratory distress.
the airway. They also differ from the infantile type in The incidence of neurofibromas versus neurile-
that they are more common in men (67% of all cases) momas of the larynx is unknown, for studies often
and are usually of the cavernous type (11) (Fig. 33). lump the two lesions together under the generic term
Hoarseness, cough, dysphagia, and occasionally, of ‘‘neurogenic tumors.’’ In our series of five cases,
hemoptysis are the predominant symptoms. Pregnan- three were classified as neurofibromas and two as
cy, as in the case reported by Mugliston and Sangwan, neurilemomas (Table 2).
may have an adverse effect on preexistent laryngeal The distinction between these two neoplasms
hemangiomas, causing an increase in growth and can be difficult or even impossible or small diagnosis.
exacerbations of symptoms (12). In this instance, a diagnosis of ‘‘benign nerve sheath
Because adult hemangiomas tend to be of the tumor’’ would be appropriate.
cavernous type and composed of large blood vessels, Although neurilemomas are usually single
tumors, neurofibromas may be either solitary or
occur in association with neurofibromatosis
(16,20,22,24,26). Neurofibromatosis, however, rarely
Figure 33. Supraglottic cavernous hemangioma in a 46-year-

old man (H&E, 200). Figure 34. Neurofibroma of epiglottis (H&E, 200).
128 Barnes
involves the larynx. In a review of 257 cases of diagnosis (35). Fat is the only soft tissue with a density
neurofibromatosis, White et al. identified only one lower than water.
patient with a neurofibroma of the larynx (18). None- Because laryngeal lipomas are often deep-seated,
theless, examples of laryngeal neurofibroma associat- biopsies must also be deep or the lesion will be
ed with neurofibromatosis have been clearly missed. Treatment depends on the size and location
documented (20,22,26). of the lesion. Small tumors can usually be removed
Conservative excision is the treatment of choice. effectively through an endoscope, whereas larger ones
For small tumors, this can be accomplished endoscop- will require an external approach.
ically, whereas larger ones may require an open Although most lipomas of the larynx are of the
surgical procedure. If incompletely excised, local ‘‘usual’’ type, unusual variants have been described.
recurrence may develop. The plexiform neurofibroma Among these are included myxoid lipoma (36), spin-
is more problematic. These lesions are often more dle cell lipoma (37), intramuscular lipoma (38), and
extensive and ‘‘invasive’’ and to completely excise hibernoma (39).
might require loss of some laryngeal function. In this Lipomas may recur if incompletely excised (31).
instance, a subtotal excision might be appropriate in Such recurrences, however, must be meticulously eval-
order to preserve the integrity of the larynx (27,28). uated because some liposarcomas of the larynx are
often low-grade and initially mistaken for lipomas (40).
D. Lipoma
Approximately 112 lipomas of the larynx and hypo- E. Leiomyoma
pharynx have been described as of 2002 (29). At the Leiomyomas are benign tumors of smooth muscle that
University of Pittsburgh, it represents only 0.7% of all primarily occur in the uterus, gastrointestinal tract,
benign laryngeal neoplasms (Table 2). and skin. They are exceptionally rare in the larynx. In
It is more common in individuals in the seventh a review of 7684 leiomyomas at the University of
decade of life (range 8–83 years), and the majority are Witwatersrand, in which the location was known,
men (68%) (30–33). It typically presents in the supra- Farman observed only 1 that occurred in the larynx
glottic larynx in the area of the aryepiglottic fold, false (41). None was found in a review of 404 benign
vocal cord, or ventricle, areas that normally contain fat laryngeal tumors on file at the University of Pitts-
(Fig. 35). In come instances it may arise in adjacent burgh (Table 2).
anatomical sites and project into the larynx. Pathologically, leiomyomas can be divided into
Most are solitary lesions, but on occasion, may three types: conventional, vascular, and epithelioid.
coexist with lipomas in other body sites. At least one All of these have been described in the larynx.
case has been described in association with benign
symmetric lipomatosis (Madelung’s disease) (34). Conventional Leiomyoma
The tumors are sessile to polypoid and manifest
with dyspnea, change in quality of voice, snoring, or a These tumors in the larynx have been described in all
sensation of foreign body in the throat. Polypoid age groups, but primarily in adults, and are somewhat
lesions may even result in acute airway obstruction more common in males (42–46). The supraglottis is the
through a ball-valve effect. preferred site, especially in the region of the ventricle,
A CT scan can be extremely helpful, not only in false vocal cord, and aryepiglottic fold. Glottic and
localizing the lesion, but also in establishing the subglottic leiomyomas are uncommon.
Most are smaller than 3 cm and vary from sessile
to polypoid. Obstructive airway symptoms and
hoarseness are the usual presenting complaints. Exci-
sion, either through an endoscope or an open tech-
nique, is the treatment of choice. Subtotal removal will
almost assuredly result in recurrence.
Vascular Leiomyoma (Angiomyoma)

Vascular leiomyomas of the larynx are more unusual
than the conventional type, with fewer than 10 cases
reported in the literature as of 1994 (47–49). They are
more common in men, usually older than 50 years.
About half have occurred in the supraglottic larynx,
particularly in the region of the ventricle and aryepi-
glottic fold, and about half in the subglottis.
Dyspnea, hoarseness, and the sensation of a
foreign body in the throat are the usual symptoms.
A few patients may even present with acute airway
obstruction.
Figure 35. Lipoma of false vocal cord (gross). Clinicians should be aware that biopsies or
attempts to remove vascular leiomyomas endoscopically
may be accompanied by profuse bleeding that is diffi- Table 3 Classification of Premalignant Lesions of the Larynx
cult to control. Consequently, some advocate that these
2005 WHO Ljubljana
tumors in the larynx should always be excised through
Classification SIN Classification SIL
an external approach for better hemostatic control.
Squamous cell Squamous cell (simple)
Epithelioid Leiomyoma (Bizarre Leiomyoma, Leiomyoblastoma) hyperplasia hyperplasia
Mild dysplasia SIN 1 Basal/parabasal cell
There have been at least two documented cases of hyperplasiaa
epithelioid leiomyoma of the larynx (50,51). One Moderate dysplasia SIN 2 Atypical hyperplasiab
occurred in a 53-year-old man, who presented with Severe dysplasia SIN 3c Atypical hyperplasiab
a one-year history of hoarseness and was found to Carcinoma in situ SIN 3c Carcinoma in situ
a
have a 5-cm tumor of the left true vocal cord that was Basal/parabasal cell hyperplasia may histologically resemble mild
removed under general anesthesia using a suspension dysplasia, but the former is conceptually benign lesion and the latter
the lower grade of precursor lesions.
microlaryngoscope (50). He was reported free of the b
‘‘Risky epithelium.’’ The analogy to moderate and severe dysplasia is
disease 28 months later. approximate.
c
The other case occurred in a 49-year-old woman The advocates of SIN combine severe dysplasia and carcinoma in situ.
who presented with a one-year history of hoarseness Abbreviations: SIN, Squamous intraepithelial neoplasia; SIL, squamous
intraepithelial lesions.
(51). A 1-cm mass was demonstrated submucosally in Source: World Health Organization. Classification of Tumors. Pathology
the left true vocal cord, which was removed by and Genetics. Head and Neck Tumors, Barnes L, Eveson JW, Reichart P,
multiple microlaryngoscopic procedures. No addi- Sidransky D, eds., Lyon, IARC Press, 2005. Used with permission.
tional follow-up was provided.
F. Other Tumors
Rhabdomyomas, granular cell tumors, chondromas,
and other nonepithelial tumors are discussed else-
where in this book.
X. KERATOSIS WITH AND WITHOUT

DYSPLASIA
A. Introduction
The clinical significance of such terms as leukoplakia,
hyperplasia, atypia, dysplasia, and keratosis as
applied to isolated lesions of the larynx continues to
be a confusing and controversial topic for both otolar-
yngologists and pathologists. This is largely due to the
use of ambiguous and inconsistent terminology, the Figure 36. The vast majority of reactive and dysplastic lesions
lack of unanimous agreement on the definition of of the larynx present as white patches or leukoplakia (area
these terms, failure of the clinician to obtain a repre- outlined by black dots) Direct laryngoscopic exam of the larynx.
sentative biopsy, and the subjectivity of the patholo-
gist interpreting the biopsy. It is also particularly
frustrating when pathologists continue to invent new (CIS), preceded by the term ‘‘keratosis,’’ e.g. keratosis
terms for the same lesion. For instance, it is now with moderate dysplasia. The use of ‘‘keratosis’’ as
fashionable in some medical circles to speak of laryn- part of the diagnosis is arbitrary, especially since it has
geal intraepithelial neoplasia (LIN), laryngeal intra- no prognostic significance. However, considering that
epithelial lesion (LIL), squamous intraepithelial the vast majority of reactive—preneoplastic lesions of
neoplasia (SIN) and squamous intraepithelial lesion the larynx manifest as keratosis or white patches
(SIL and then grade the abnormality as I, II, or III. (leukoplakia), it does serve as a confirmatory marker
Such terms, as far as we are concerned, are only indicating that the clinician has indeed biopsied and/
additional new synonyms for dysplasia. They do not or removed the intended lesion (Fig. 36).
enhance our understanding of the lesion and serve Because of possible confusion, it is appropriate
only to introduce additional confusing terms for the that a discussion of this subject begin with a series of
clinician to deal with. Furthermore, the terms ‘‘LIN’’ definitions.
and ‘‘SIN’’ are misleading. They indicate a neoplasm
when in reality many of these lesions are reversible. B. Normal Histology
Nevertheless, there are strong proponents of each
of these classifications. Table 3 shows the three most At birth, the larynx is lined entirely by ciliated
popular schemes and the approximate equivalent respiratory epithelium. As the individual ages, the
terms of each. Preference depends on one’s training, respiratory epithelium is gradually replaced by non-
bias, and local custom. Our bias is in favor of the more keratinizing, stratified squamous epithelium to the
traditional system of dysplasia—carcinoma in situ point that, in the normal adult, the larynx is lined
130 Barnes
pseudoepitheliomatous hyperplasia. In the case of the

true vocal cords, anything more than 10 cells in thick-
ness can be considered as abnormal or hyperplastic.
D. Keratosis
This denotes the presence of keratin (orthokeratin) on
an epithelial surface and is often, but not always,
associated with a prominent granular cell layer.
Since the laryngeal mucosa is not normally kerati-
nized, the term ‘‘hyperkeratosis’’ is redundant.
E. Parakeratosis
Retention of nuclei within the keratin layer is referred
to as parakeratosis. It usually represents faulty matu-
ration or a more rapid turnover of epithelial cells than
Figure 37. Right true vocal cord biopsy showing normal matu- seen in keratosis. Otherwise, in the larynx, it has no
ration. Note the basal cells with their long axes perpendicular to clinical significance.
the basement membrane. As the cells approach the surface,
they become round, acquire intercellular bridges and ultimately
lie with their long axes parallel to the basement membrane. F. Dyskeratosis
There is no surface keratinization (H&E, 100).
Dyskeratosis represents faulty or premature keratini-
zation of individual squamous cells.
entirely by squamous epithelium, with the exception

of two areas—the ventricles and subglottis—which G. Atypia-Dysplasia
continue to be lined by respiratory epithelium. Infre-
quently, one may see small patches of persistent respi- The use of these terms varies according to pathologist.
ratory epithelium in an otherwise typical squamous Strictly speaking, atypia refer to cellular aberrations,
mucosa of the adult supraglottic larynx. such as pleomorphism, variation in nuclear size and
The normal nonkeratinized squamous mucosa of shape, presence or absence of nuclei, increased nucle-
the true vocal cords is about 5 to 10 cells thick. The ar—cytoplasmic ratios and thickness and irregulari-
cuboidal to columnar cells immediately adjacent to the ties of the nuclear and cell membranes. Dysplasia, in
basement membrane, so-called basal, reserve or germi- turn, is concerned with disturbances of growth and
nal cells, have ovoid nuclei and lie with their long axes maturation, such as loss of polarity and crowding of
perpendicular to the membrane (Fig. 37). Mitoses, if seen cells, dyskeratosis, keratin pearl formation, and the
at all, are normally limited to these or immediately presence of normal and abnormal mitoses in the
adjacent cells. With increasing maturation, the nuclei superficial epithelial layers.
become round and vesicular to hyperchromatic, the Some pathologists, however, equate atypia and
cytoplasm increases in volume, intercellular attachments dysplasia as being synonymous and apply the terms
(desmosomes) become apparent, and cells assume a interchangeably. Others use ‘‘atypia’’ when the
polygonal shape. As the squamous cells approach the cellular changes are thought to be benign or reactive
surface, they become flattened and lie parallel to the as occurs in various inflammatory, degenerative-
basement membrane. The epithelial cells that lie above regenerative, and traumatic conditions and ‘‘dysplasia’’
the basal cells are, at times, referred to as prickle cells, when the findings raise concern about a premalignant
the squamous cell layer, or the stratum spinosum. condition. In this chapter, we use the term dysplasia
Mucoserous glands are rather abundant in when we are concerned about premalignant changes.
the larynx, particularly in the epiglottis, ventricles, Dysplasia is graded as mild (Grade I) if the
false vocal cords, and subglottis. They are, however, abnormal changes are confined to the inner one-
sparse to absent in the true vocal cords, which has third of the epithelium, moderate (Grade II) if the
therapeutic implications when managing CIS. aberration involve from one-third to two-thirds of
the thickness of the epithelium, and severe (Grade III)
if the changes extend from two-thirds to just short of
C. Hyperplasia full-thickness involvement.
The term ‘‘hyperplasia’’ refers to a thickening of the
epithelium due to an absolute increase in number of H. Carcinoma In Situ
cells. It may be limited to the basal cells (basal cell
hyperplasia) or the prickle cells (acanthosis), or it may CIS is classically defined as full-thickness epithelial
involve both groups of cells. If extensive, irregular disarray and atypia without violation of the basement
tongues of basement membrane—enclosed epithelium membrane. Severe dysplasia, SIN-III, and LIN-III are
may extend into the underlying stroma, so-called regarded by some as synonyms.
I. Leukoplakia
This is a clinical term, not a pathologic diagnosis, used
to describe any white lesion on a mucous membrane
that cannot be rubbed off with the hand. Histological-
ly, such lesions range from being totally innocuous to
invasive carcinoma.
J. Erythroplakia
This is another clinical term used to describe any red
area on a mucous membrane. In contrast to leukopla-
kia, erythroplakia is a more ominous lesion often
associated with high-grade dysplasia or in situ or
superficially invasive carcinoma. It is uncommon in
the larynx.
K. Keratosis with and without Dysplasia

The above-defined abnormalities may exist individual-
ly or in combination. There is, however, a tendency in
some medical centers, which we endorse, to combine
these, as well as other closely related terms, into two
broad categories: keratosis without dysplasia (KWOD) Figure 38. Keratosis without dysplasia. Note the surface layer
and keratosis with dysplasia (KWD) (Table 4) (1–3). of keratin and prominent keratohyaline granules. There is no
KWOD refers to either a normal, hyperplastic, or atypia or dysplasia (H&E 200).
atrophic squamous epithelium covered by a scale of
orthokeratin or parakeratin (Fig. 38). Whether the scale
is orthokeratin or parakeratin has no clinical relevance;
therefore, it does not warrant a separate category and
can be safely included under the generic term ‘‘kerato-
sis.’’ KWD is similar in all respects to KWOD except for
the presence of abnormal epithelial cells and growth
(Figs. 39–41).
Although most keratoses are flat, occasionally
they are papillary. When papillary, the term ‘‘papillary
keratosis’’ can be used, followed by whether or not
there is dysplasia and, if so, how severe, e.g., papillary
keratosis with moderate dysplasia (see discussion on
‘‘keratinized papillomas’’ above) (Figs. 26–29).
The frequency of each of the categories of kera-
toses with and without dysplasia is shown in Table 5.
L. Clinical Features
KWOD and KWD are clinically indistinguishable and
typically present as a localized thick, white patch that
may be flat or papillary. On rare occasions, it may be Figure 39. Keratosis with mild dysplasia (H&E, 200).
diffuse, obstruct the glottis, and even necessitate a
tracheotomy (1).
KWOD and KWD average about 1 cm in greatest
dimension and can occur anywhere in the larynx. Most,
Table 4 Synonyms for Keratosis with and without Dysplasia however, arise from the true vocal cords with no
Keratosis without dysplasia Keratosis with dysplasia significant lateralization to either side. Bilateral
involvement of the true vocal cords occurs in about
Hyperplasia Atypia
25% to 30% of cases (3,6,7). As might be expected,
Acanthosis Dysplasia
Squamous hyperplasia Atypical hyperplasia
hoarseness or a change in quality of the voice are the
Keratosis SIN or SIL, I, II, III most common symptoms. Most patients (75–85%) are
Parakeratosis LIN or LIL, I, II, III male (3,8). The mean age at diagnosis, according to
Sllamniku et al. is 52 years for patients with KWOD
Abbreviations: SIN, squamous intraepithelial neoplasia; SIL, squamous
intraepithelial lesion; LIN, laryngeal intraepithelial neoplasia; LIN, and 59, 58, and 62 years, respectively, for those with
laryngeal intraepithelial lesion. keratosis with mild, moderate and severe dysplasia (3).
132 Barnes
follow-up. Whether patients whose biopsies show

severe KWD need additional therapy depends on
the extent of the lesion, local definition of ‘‘severe
dysplasia’’ (some equate severe dysphasia and CIS as
synonyms), and the experience of the clinician. If the
etiology can be identified, it should be eliminated.
Most often this means giving up smoking, which is the
single most common cause. In most studies, only 5%
to 20% of patients are nonsmokers (6,8–10). Other
responsible factors include alcohol, chronic infections,
voice abuse, vitamin A deficiency, and exposure to
various industrial or atmospheric irritants.
Both KWOD and KWD are potentially reversible,
the former more so than the latter; however, as the
severity of dysplasia increases, so does the likelihood of
persistence or progression of disease. Taken together,
the incidence of recurrence or (persistence?) following
initial therapy varies from 15% to 30% (8). In approxi-
mately 7% of cases, KWOD will progress to KWD (6,9).
Figure 40. Keratosis with moderate dysplasia (H&E, 200). In a collective review of 1502 cases of KWOD and
1188 cases of KWD, the risk of subsequent development
of invasive squamous carcinoma is approximately 3%
to 5% and 16% to 19%, respectively (Tables 6 and 7)
(1–6,9,11–18). For keratosis with mild, moderate, and
severe dysplasia, the risks are, respectively, 5.7%, 20%,
and 23.8% (Table 8) (2–5,15,17). Of those patients with
laryngeal keratosis who eventually develop invasive
carcinoma, the average latency period from the time
of diagnosis of keratosis to carcinoma is 3.8 years (3).
According to Blackwell et al., laryngeal biopsies
of patients that progress to invasive carcinoma com-
pared with those in whom the disease remains stable
or regresses more often demonstrate (i) abnormal
mitoses, (ii) prominent mitotic activity within the
middle or upper third of the mucosa, (4) (iii) prolifer-
ation of small uncommitted cells above the lower one-
third of the mucosa, (iv) moderate to severe nuclear
pleomorphism, and (v) moderate to severe stromal
inflammation (17).
Studies for DNA ploidy may also have prognostic
significance. Although not absolute, there is increasing
Figure 41. Keratosis with severe dysplasia (H&E, 200).
Table 6 Incidence of Invasive Carcinoma Developing in
Patients with Keratosis Without Dysplasia
Table 5 Frequency of KWOD and KWD Total Number of

number invasive % of all
Sllamnika (3) Gallo (4) Ricci (5) Author (yr) (Ref.) of cases carcinomas cases
Category (N = 921) (N = 259) (N = 207) McGavran (1960) (1) 66 1 1.5
KWOD 66% 55% 46% Norris (1963) (9) 30 1 3.3
KWD, mild 22% 22% 22% Gabriel (1973) (11) 50 3 6
KWD, moderate 3% 11% 20% Henry (1979) (6) 29 1 3.4
KWD, severe 10% 12% 11% Crissman (1979) (12) 50 0 0
Abbreviation: KWOD, keratosis without dysplasia; KWD, keratosis with
Hellquist (1982) (2) 98a 2 2
dysplasia. Gillis (1983) (13) 7 2 28.6
Kalter (1987) (14) 38 2 5.3
Sllamniku (1989) (3) 604 18 3
M. Treatment and Prognosis Hojslet (1989) (15) 128a 6 4.7
Cuchi (1994) (16) 167 14 8.7
Treatment consists of excisional biopsy, using either Blackwell (1995) (17) 6 0 0
forceps or vocal cord stripping, with thorough micro- Gallo (2001) (4) 143 6 4.1
scopic evaluation to rule our malignancy. If the biopsy Ricci (2003) (5) 86 2 2.3
shows only KWOD or mild to moderate KWD, no Total 1502 58 (3.9%) 5.2 (average)
further treatment is necessary except for periodic a
Includes some patients with mild atypia.
Table 7 Incidence of Invasive Carcinoma Developing in anterior one-third. Sometimes, it may involve the
Patients with Keratosis with Dysplasia entire cord, the anterior commissure, or both vocal
Total Number of
cords. Multifocal areas are not uncommon. The rarity
number of invasive % of all of CIS in the supraglottic and subglottic larynx is
Author (yr) (Ref.) cases carcinomas cases probably because these are clinically ‘‘silent’’ areas,
which allows a prolonged asymptomatic interval for
McGavran (1960) (1) 18 2 11.1
Norris (1963) (9) 86 5 5.8
the lesion to become invasive.
Gabriel (1973) (11) 55 4 7.3 CIS has the same propensity for men as invasive
Henry (1979) (6) 14 3 21.4 laryngeal carcinoma, with most studies indicating a
Crissman (1979) (12) 42 3 7.1 male/female ratio between 3:1 and 8:1 (8,11,12). It
Hellquist (1982) (2) 63a 12 19 occurs over a broad age range, with a mean/median
Gillis (1983) (13) 17 5 29.4 age of 60 to 65 years (12–18). Hoarseness is the usual
Kalter (1987) (14) 92 20 21.7 presenting symptom.
Sllamniku (1989) (3) 317 44 13.9
Hojslet (1989) (15) 19 8 42.1
Cuchi (1994) (16) 74 23 31 C. Pathology
Blackwell (1995) (17) 50 12 24
Gallo (2001) (4) 116 13 11.2 CIS (also referred to as squamous intraepithelial neo-
Ricci (2003) (5) 111 10 9 plasia or lesion, type III) is defined histologically as a
Jeannon (2004) (18) 114 28 24 neoplastic process in which the normal epithelium is
Total 1188 192 (16.2%) 18.5 (average) completely replaced by cells with malignant charac-
a
Includes only grade II and III dysplasia. teristics that do not extend beyond the basement
membrane. As such, the cells demonstrate loss of
polarity and maturation, normal and abnormal mito-
ses, occasional dyskeratosis, increased nuclear/cyto-
Table 8 Incidence of Invasive Carcinoma in Patients with
Keratosis with Mild, Moderate and Severe Dysplasia
plasmic ratios, and anisonucleosis. Infrequently, the
abnormal cells may extend down into ducts of subja-
Mild Moderate Severe cent mucoserous glands, but such an involvement is
(Carcinomas: (Carcinomas: (Carcinomas: still within the realm of CIS (Fig. 42).
Author (yr) (Ref.) total cases) total cases) total cases) CIS that consists of a rather uniform population
of small basaloid cells, with no surface maturation or
Hellquist (1982) (2) 2:98a 3:24 9:39b
keratinization, as seen in classic CIS of the uterine
Sllamniku (1989) (3) 15:204 4:23 25:90
Hojslet (1989) (15) 6:128a 4:9 4:10
cervix, is uncommon in the larynx (Fig. 43). More
Blackwell (1995) (17) 3:26 5:15 4:9 often, CIS of the larynx, and especially of the true
Gallo (2001) (4) 4:56 6:28 3:32 vocal cords, presents as a white patch (leukoplakia)
Ricci (2003) (5) 2:42 5:36 3:21 with a full-thickness disarray and admixture of basa-
Total 32:554 27:135 48:201 loid and dyskeratotic squamous cells, covered by a
(5.7%) (20%) (23.8%) scale of orthokeratin or parakeratin (Fig. 44).
a
Includes some cases of keratosis without dysplasia.
b
Includes some cases of carcinoma in situ.
evidence that laryngeal biopsies that demonstrate aneu-

ploidy correlate with genomic instability that is likely to
persist or eventuate in carcinoma (19–22).
XI. CARCINOMA IN SITU

A. Introduction
In the past, squamous cell CIS of the larynx, hereafter
referred to as CIS, was found most often adjacent to
and rarely remote from invasive squamous cell carci-
noma. However, since 1968 with the introduction of
microlaryngeal techniques developed by Kleinsasser,
surgeons and pathologists have become increasingly
aware that it can exist as an isolated lesion, without an
invasive component (1). Currently, it represents 1% to Figure 42. Carcinoma in situ with involvement of duct of
13% of all laryngeal carcinomas (2–10). mucoserous gland. The basement membrane around the duct
is intact. This should not be mistaken for invasive carcinoma. In
the overlying surface component, note that the cells in the lower
B. Clinical Features
half are more basaloid (‘‘uncommitted’’), whereas those in the
Although CIS can occur anywhere within the larynx, upper half appear more ‘‘squamoid’’ (H&E, 100).
most arise from the true vocal cords, especially the
134 Barnes

Effective treatment of laryngeal CIS consists of under-
standing the natural history of the disease. Unfortu-
nately, this is largely unknown for several reasons.
First, although the pathology is relatively straightfor-
ward, there is an inordinate amount of subjectivity
involved in the interpretation of biopsies. The incon-
sistencies in diagnosis of CIS among various patholo-
gists and even the same pathologist studying the same
case at different times is well known and accounts for
wide differences in the reported incidence of CIS
either progressing or regressing. Second, the natural
history of CIS is probably altered by the procedure
used to establish the diagnosis; that is, the biopsy,
which may contain the entire lesion. Third, a variety
of therapeutic modalities, ranging from watch-and-
Figure 43. Higher magnification of the surface mucosa shown wait to irradiation and surgery have been employed in
in Figure 42. With the absence of keratin on the surface, this the management of these patients. Fourth, the biopsy
carcinoma-in situ would present clinically as a red patch or
erythroplakia (H&E, 200).
may not be representative. Fifth, CIS at times may be
multifocal and not unrecognized. Sixth, follow-up has
often been inconsistent, inadequate, or nonexistent.
And, seventh, in contrast with uterine cervical cytolo-
gy, which is a reliable means of detecting and follow-
ing patients with abnormal conditions of the cervix,
laryngeal cytology is inconvenient and cumbersome
and, consequently, has not been widely accepted.
With the foregoing limitations in mind, it is
understandable why the incidence of CIS progressing
to invasive carcinoma reported in the literature has
varied from 1.5% to 90% (Table 9). When viewed
collectively, these studies indicate the incidence to be
in the range of 20% to 25% with an average latent
period from diagnosis of CIS to invasion of 3 to 5 years
(2,7,8,10–12,14,27–38).
Treatment of CIS of the vocal cords is not stan-
dardized. Options include vocal cord stripping, laser
surgery, cordectomy, hemilaryngectomy, radiation,
and/or a combination of these procedures. The choice
of initial therapy should be tailored to the patient and
depends on the extent of tumor, age, and reliability of
Figure 44. More typical carcinoma in situ of the true vocal cord the patient for follow-up, and the experience of the
composed of abnormal cells with more ‘‘squamoid’’ features, physician. Small lesions can usually be treated conser-
covered by a scale of parakeratin. Atypical nuclei are also vatively with stripping. The advantages of stripping
apparent in the parakeratin (H&E, 200). are that it can be accomplished in one session, as
opposed to six to seven weeks for radiation, and all
the specimens can be sent to pathology for thorough
examination to rule out carcinoma, whereas this
D. Molecular-Genetic Data opportunity is lost with radiation. When stripping
fails, the salvage rate with radiation is good (16).
Studies indicate that those dysplastic laryngeal lesions The paucity and/or absence of mucoserous (sal-
that show loss of heterozygosity at 3p21, 5q21, 9p21 and ivary) glands in the true vocal cords allows one to use
17p13 are more likely to progress to carcinoma (19). the mucosal stripping procedure with relative impu-
Much interest has also been expended toward nity. However, there is an extensive tubuloalveolar
developing reliable immunomarkers that could be system of glands in the region of the anterior commis-
used to identify lesions destined for malignant pro- sure (40–42). These glands at times may be located at
gression. Although data indicate that alteration in p53 some distance from the mucosal opening of their
plays a role in the early stage of malignant transfor- ducts and, therefore, if involved by CIS, may not be
mation of some (?most) squamous cell carcinomas of removed by simple mucosal stripping. Consequently,
the larynx, there is ongoing debate on whether its when CIS involves the anterior commissure (an
continued immunoexpression, either alone or in com- adverse sign associated with poor local control), addi-
bination with other biomarkers (p16, p21, Bc1-2), has tional therapy, such as laser ablation or even irradia-
any predictive value (20–26). tion, may be warranted.
Table 9 Incidence of Carcinoma In Situ of Larynx Progressing epithelial basement membrane, with no evidence of
to Invasive Carcinoma lymphatic or vascular invasion (Figs. 45–47).
At times, either because of tangential embedding
Total Number of % of
cases invasive invasive
or inflammatory cells obscuring the epithelial-stromal
Author (yr) (Ref.) of CIS carcinomasc carcinomas interface, one cannot determine, with confidence,
whether or not the lesion has violated the basement
Altmann (1952) (2) 29 1 3.4
membrane (Fig. 48). In these instances, a diagnosis of
Kleinsasser (1968) (27) 20 18 90
Miller (1971) (28) 203 32 15.7
‘‘squamous cell carcinoma in situ, with questionable
Holinger (1974) (29) 8 2 25 microinvasion’’ is appropriate.
Som (1976) (30) 24 4 16.7 Not all carcinomas evolve through a dysplasia-
Pene (1976) (31) 26 1 3.8 CIS sequence. Some are invasive without a significant
Elman (1976) (7) 81a 13 16
Hintz (1981) (11) 45 22 48.9
Hellquist (1982) (32) 39a 9 23.1
Gillis (1983) (33) 8 3 37.5
Maran (1984) (8) 28 2 7.1
Kalter (1987) (34) 8 4 50
Shvero (1988) (35) 21 1 4.8
Crissman (1988) (36) 25 12 48
Rothfield (1991) (10) 13 2 15.4
Stenersen (1991) (37) 41a,b 19 46.3
Small (1993) (38) 21 1 4.8
Murty (1993) (14) 37 8 21.6
Brooks (1993) (13) 12 2 16.7
Myssiorek (1994) (12) 41 16 39
Blackwell (1995) (39) 9 1 11.1
Le (2000) (16) 82 15 18.3
Spayne (2001) (17) 67 1 1.5
Garcia-Serra 30 3 10
(2001) (18)
Total 918 192 (20.9%) 23.9%
(average)
a
Includes some patients with severe dysplasia.
b
Includes only patients who were treated with repeat biopsies. (Their
group C).
c
Includes microinvasive and ‘‘ordinary’’ invasive carcinomas.
Abbreviation: CIS, carcinoma in situ.
Figure 45. Microinvasive squamous cell carcinoma of the true
According to Rothfield et al., the ultimate suc- vocal cord. The tumor extends 0.38 mm into the lamina propria,
cess of therapy may depend more on compulsive as measured from the adjacent intact basement membrane
(H&E, 100).
follow-up than the specific form of treatment (10).
XII. MICROINVASIVE (SUPERFICIAL)

CARCINOMA OF THE LARYNX
A. Introduction
The use of the term microinvasive carcinoma (MIC), also
known as superficially invasive carcinoma, as applied
to lesions of the larynx, is very subjective, with no
unanimous definition among pathologists. Fisher
describes it as ‘‘a very small number of cells, perhaps
a dozen or even just 50 that are in the entire lesion,
and only just below the basement membrane’’ (1).
Friedmann defines it as ‘‘scattered tongues or some
discrete foci of invasion through the basement mem-
brane’’ (2). Padovan uses the term for lesions limited
to 2 mm of invasion (3). Crissman et al. use it for any
‘‘squamous carcinoma violating the preexisting epi-
thelial basement membrane and limited to 1 to 2 mm
of invasion from the site of origin without vascular Figure 46. Incidental squamous cell carcinoma of the true vocal
invasion’’ (4). Our definition, which admittedly is cord (TVC, arrow) found at autopsy. Note the ventricle (V) above.
arbitrary and lies between these extremes, is that of This carcinoma measured 0.8 mm and exceeded our definition of a
an invasive squamous cell carcinoma that extends into microinvasive carcinoma (0.5 mm or less) (H&E, 20).
the stroma no more than 0.5 mm, as measure from the
136 Barnes
Figure 47. Higher magnification of the lesion shown in Figure 46. Figure 49. An invasive squamous cell carcinoma of the larynx
that appears to arise from the basal layer of the mucosa. Note
the absence of dysplasia or carcinoma in situ. These are
sometimes referred to as ‘‘drop-off’’ carcinomas (H&E, 100).
C. Treatment and Prognosis

Although the treatment of MIC is not standardized,
there is a movement toward more conservative pro-
cedures, such as stripping the vocal cord mucosa with
or without laser ablation (5–8). Stutsman and McGav-
ran were among the first to recommend an ultracon-
servative approach; namely, endoscopic removal of
the lesion, with periodic follow-up (9). This was based
on their study of 60 patients with T1 glottic carcino-
mas who underwent hemilaryngectomy; in 20% (13 of
60 patients) of these no residual tumor was found, the
lesion having been totally excised with the original
biopsy. Therefore, if surgery or radiation were admin-
istered to all patients with biopsy-proven MIC, one in
five would be receiving unnecessary therapy. The
paucity or absence of mucoserous (minor salivary)
glands in the true vocal cords, relative lack of lym-
Figure 48. Is this microinvasive carcinoma or a tangential phatics in the laryngeal glottis, and that recurrent
embedding issue (arrows)? If the dilemma cannot be resolved lesions manifest early with hoarseness, are all condu-
by deeper sectioning, then a diagnosis of ‘‘carcinoma in situ with cive to such a nonaggressive approach.
questionable microinvasion’’ is appropriate (H&E, 100). However, the success of this form of therapy
depends on compulsive follow-up, especially because
these patients are at risk not only for local recurrence,
but also for the development of new lesions. If the
mucosal component and appear to arise from the patient is not dependable for routine follow-up or is
basal layer of epithelium. These are sometimes medically unable to undergo anesthesia for periodic
referred to as ‘‘drop-off’’ carcinomas (Fig. 49). laryngoscopic examination, then other alternatives,
such as radiotherapy, should be considered (8). With
a compliant patient and meticulous surveillance, the
B. Clinical Features long-term prognosis is excellent.
MIC typically involves the true vocal cords, especially
the anterior and middle thirds and presents as hoarse- XIII. SUPERFICIAL EXTENDING CARCINOMA
ness (5). It is more common in men by a ratio of 3:1
and occurs over a broad age range, with a median of Superficial extending carcinoma (SEC) of the larynx
65 years (6). In a review of 15 cases, Nguyen et al. and hypopharynx is the morphological counterpart of
observed the right true vocal cord to be involved in the ‘‘early’’ or ‘‘superficial’’ carcinoma of the esopha-
nine (60%), the left in four (27%) and both cords in two gus and stomach (1–7). As such, it is defined in
(13%) (6). the larynx and hypopharynx as an early invasive
or seventh decades of life at the time of diagnosis,

with an average of about 60 years. Less than 1% of
laryngeal cancers occur in patients younger than
30 years of age.
Smoking and alcohol abuse are by far the princi-
pal risk factors and, of these, smoking is the more
important. In fact, only 3% to 4% of all laryngeal
carcinomas occur in nonsmokers (2,3). Other risk fac-
tors that have been proved, suggested, or debated
include prior radiation exposure, HPV infection,
genetic factors, air pollution, dietary deficiencies
(vitamins A and C, and iron), chronic gastrointestinal
reflux, and occupational exposure to wood dust,
Figure 50. Diagram showing conceptual differences between asbestos, nickel, mustard gas, hair dyes, gasoline
carcinoma in situ (CIS), microinvasive carcinoma (MIC), superfi- fumes, paint, sulfuric acid, and rubber products (4–10).
cial extending carcinoma (SEC), and deeply invasive carcinoma Marked geographic variations exist in the fre-
(DIC). quency of laryngeal carcinoma, not only between
countries, but also in different parts of the same
country. Regions in India, Spain, Brazil, Italy, and
squamous cell carcinoma that does not extend beyond France have the highest incidence, whereas areas in
the lamina propria, regardless of the presence or Japan, Sweden, and Norway have among the lowest
absence of cervical lymph node metastasis (8,9). (11). In general, urban environments tend to have
Whether SEC associated with positive cervical lymph higher cancer rates than rural (12).
nodes should still qualify as an early carcinoma is, In addition to variations in incidence, there are
however, open to debate. also geographic differences in the topographic distribu-
The SECs vary considerably in size. Some are tion of tumors within the larynx. In parts of the former
small, whereas others are quite large, with a promi- Yugoslavia, France, Italy, Spain, The Netherlands, and
nent surface (mucosal) component and extensive Finland, supraglottic tumors predominate, whereas in
involvement of the lamina propria, yet, by definition, the United States, Canada, England, and Sweden, glot-
they do not invade the adjacent muscle or cartilages. A tic lesions are more common (13) (Fig. 51). In Japan, the
component of CIS and chronic inflammation are addi- distribution of tumors between these two sites is about
tional frequently observed findings. A few may even equal.
be multifocal. A noticeable increase in laryngeal carcinoma in
Conceptually, SEC is more than an MIC, but less women has also been observed over the last two
than a deeply invasive carcinoma (one that invades decades, presumably owing to their increase in smok-
muscle or cartilage) (Fig. 50). It differs from MIC in ing (3,14). This is unfortunate because carcinoma of
that MIC is predominantly a CIS with only focal the larynx is a preventable disease. If only individuals
superficial invasion of the lamina propria, whereas would alter their lifestyles (stop smoking and drink-
in SEC the lamina propria is often extensively ing), over 90% of laryngeal carcinomas could be
involved. eliminated.
Although SEC may be treated by a variety of
conservative modalities, if recognized as such, the
diagnosis, however, can be established with confi-
dence only after the lesion has been totally excised
and thoroughly examined histologically (10–15). The
prognostic significance of this entity is unknown and
must await the accrual of more patients with long-
term follow-up.
XIV. SQUAMOUS CELL CARCINOMA

OF THE LARYNX
A. Introduction
According to the American Cancer Society, cancer of
the larynx accounts for 0.7% of all cancers and 1.1% of
all malignant tumors in men and 0.3% in women (1).
During 2006 there were 9510 new cases diagnosed in
the United States, of which 7700 (81%) occurred in
men and 1810 (19%) in women (1). For this same time Figure 51. Diagram showing the subdivisions of the larynx and
period, there were 3740 deaths from the disease. the relative frequency of squamous cell carcinoma involving each
Squamous cell carcinoma accounts for 95% of of these sites in the United States.
these neoplasms. Most patients are in the fifth, sixth,
138 Barnes
Anatomy and Embryology The paraglottic space is also not a space, but an
area deep to the true and false vocal cords that
The larynx anatomically extends from the tip of the contains adipose and loose areolar tissue (Fig. 53). It
epiglottis to the lower border of the cricoid cartilage is bounded by the cricovocal membrane (conus elas-
(Fig. 51). The posterior boundary includes the posterior ticus) inferiorly, the thyroid cartilage laterally, the
commissure mucosa, the mucous membrane covering quadrangular membrane medially, and the pyriform
the cricoid cartilage, the arytenoid region, and the inter- sinus posteriorly (24,29). Superiorly, the paraglottic
arytenoid space. The anterior limit is composed of the space is in continuity with the pre-epiglottic space.
lingual surface of the epiglottis, thyrohyoid membrane, Although both spaces contain lymphatics and blood
anterior commissure, thyroid cartilage, cricothyroid vessels, neither contains lymph nodes.
membrane, and the anterior arch of the cricoid cartilage.
The blood supply is by the superior laryngeal
branch of the superior thyroid artery and the inferior
branch of the inferior thyroid artery. The nerve supply
is derived from two branches of the vagus nerve, the
superior and inferior laryngeal.
The larynx can be subdivided into three regions:
supraglottic, glottic, and subglottic (Fig. 51). The
boundaries of each of these are described in the
following sections. The term ‘‘transglottic’’ does not
correspond to a specific anatomical site, but rather, is
used to describe any tumor that crosses the ventricle.
The supraglottic larynx is derived embryologi-
cally from the third and fourth branchial arches (buc-
copharyngeal anlage); therefore, it is closely related to
the oral cavity and oropharynx and, accordingly, more
susceptible to ingested carcinogens (alcohol). The
glottis and subglottis, on the other hand, arise from
the sixth branchial arch (pulmonary anlage); therefore,
they are more intimately related to the lungs and more
susceptible to inhaled carcinogens (smoking) (15).
The growth and spread of laryngeal carcinoma is Figure 52. Diagram showing the pre-epiglottic space and its
determined by the site of origin of the tumor and the boundaries.
anatomical barriers produced by the different laryngeal
structures and compartments (16–19). Pathologists
should be aware of at least three of these anatomical
components, which are often not covered in standard
textbooks of pathology: the anterior commissure tendon
(Broyles’ ligament), the pre-epiglottic space, and the
paraglottic space. These structures represent the
‘‘weak points’’ of the larynx, whereby tumors may
escape from the larynx into the soft tissue of the neck.
The anterior commissure tendon is especially
important in glottic carcinomas that approach or
involve the anterior commissure. It consists of a
band of fibrous tissue 10 mm in length and 1 mm in
width and contains both blood vessels and lymphatics
(20). It serves to anchor the true vocal cords to the
upper inner midline of the thyroid cartilage. It is
important because at its attachment to the thyroid
cartilage there is no perichondrium, thereby eliminat-
ing an important tumor barrier (21). This allows a
more direct opportunity for tumor to invade the
thyroid cartilage, the anterior soft tissue of the neck,
or to involve the immediate subjacent subglottis.
The pre-epiglottic space is not a space, but
rather, a roughly triangular area anterior to the epi-
glottic cartilage that is filled with adipose and loose
areolar tissue (Fig. 52). It is bounded anteriorly by the
hyoid bone, thyroid cartilage, and thyrohyoid mem-
brane; posteriorly by the epiglottic cartilage and thy- Figure 53. Diagram showing the paraglottic space and sur-
roepiglottic ligament; and superiorly by the rounding landmarks.
hyoepiglottic ligament, which forms its base (22–28).
The pre-epiglottic and paraglottic spaces are metastasis, which averages 30% to 40% (range
important in understanding the growth and behavior 23–60%) (33,36,37,42,44–53). If the tumor crosses the
of supraglottic and transglottic carcinomas, respec- midline of the larynx, some have observed the inci-
tively. Once tumors bridge these spaces, they can dence of contralateral or bilateral nodal involvement,
spread with little resistance in the loose areolar tissue either at or during the course of the disease, to range
and eventually escape from the endolarynx into the from 7% to 50% (49,55–59). Lutz et al., in a study of 202
soft tissue of the neck. supraglottic carcinomas, found the incidence of con-
tralateral nodal metastases to be 18% and noted the
Staging risk of contralateral cervical metastases in patients
with midline (epiglottic) lesions to be similar to that
The TNM staging (T, tumor; N, nodes; M, metastasis) observed in patients who had lateral (aryepiglottic
of carcinoma of the larynx is shown in Table 10 (30). fold) lesions (37). The upper and midjugular lymph
nodes are most often involved.
B. Supraglottic Carcinoma At the time of diagnosis, most supraglottic
tumors are relatively large and, as such, are often
The tip of the epiglottis and the aryepiglottic folds treated by surgery and radiation. Because the neck,
form the superior margin of the supraglottis. The especially the contralateral neck, is the most common
inferior border is an imaginary horizontal plane pass- site of relapse, laryngectomy (either supraglottic or
ing through the apex of the ventricle (Fig. 51). The total) and bilateral selective neck dissections is emerg-
supraglottic larynx is composed of the epiglottis (both ing as the most preferred treatment (37,42,48,60–62).
its lingual and laryngeal surfaces), aryepiglottic folds, Additional forms of therapy have also been used.
arytenoids, false vocal cords, and ventricles (30). The For selected small volume tumors, an endoscopic-laser
epiglottis is divided into suprahyoid and infrahyoid approach has been successfully used. In more
components by a plane at the level of the hyoid bone. advanced tumors (stage III and IV) there is evidence
Supraglottic carcinomas account for 30% to 35% indicating that a treatment strategy involving induc-
of all laryngeal carcinomas in the United States. Most tion chemotherapy and definitive radiation therapy
patients with these tumors complain of dysphagia, may be effective in preserving the larynx in a high
change in quality of voice, sensation of a foreign body percentage of patients without comprising overall
within the throat, or a neck mass. With more extensive survival (64).
disease, odynophagia, hemoptysis, and dyspnea may The overall five-year survival for all stages is
be noted. about 65% to 75% (33,37,42,47,49,52–54,58,65). Only
The tumors tend to be large and moderately to 5% to 15% of patients with supraglottic carcinoma
poorly differentiated squamous cell carcinomas with develop clinical evidence of metastases below the
pushing margins (Figs. 54 and 55). Most arise from the clavicles (37,49,50,52,54,66,67).
base of the epiglottis or from the false vocal cords. The Tumors that arise from the suprahyoid epiglottis
epiglottis is involved alone in 45% to 55% of all cases or and aryepiglottic folds are often referred to as mar-
in combination with other sites in 70% to 90% of cases. ginal or epilaryngeal lesions. As a group, they consti-
The next most frequent site of origin is the false vocal tute 18% of all supraglottic carcinomas and behave
cords (12–33%) followed by the aryepiglottic folds more like hypopharyngeal carcinomas in that they
(8–21%). The remaining cases are equally divided often spread to the base of the tongue and are less
between the ventricles (4–7%) and arytenoids (5–6%) prone to invade the pre-epiglottic space (13,68). There
(31–33). is controversy, however, about the prognosis of this
From the base of the epiglottis—false vocal cord group of lesions. Some authors indicate that marginal
region, the tumors tend to spread upward toward the (suprahyoid) tumors have a greater propensity for
free margins of the epiglottis and aryepiglottic folds, cervical lymph node metastasis and a poorer progno-
or into the pyriform sinus or vallecula—base of sis than infrahyoid tumors (13,69–72), whereas others
tongue. On rare occasions, they may extend posterior- have found the converse; that is, infrahyoid epiglottic
ly to the arytenoids. Because of fenestrations in the tumors have a worse prognosis and a greater tendency
epiglottic cartilage, invasion of the pre-epiglottic space for cervical lymph node metastasis than marginal
occurs in 50% to 85% of cases (26,34–37), and when (suprahyoid) tumors (68).
this occurs, there is a high incidence of lymph node
metastasis (27,34,38,39) (Fig. 56). Although supraglottic
carcinomas usually do not invade the glottis or thy- C. Glottic Carcinoma
roid cartilage, there are exceptions (40–43). Weinstein
et al. indicate that when supraglottic carcinomas are The American Joint Commission on Cancer defines
associated with impaired vocal cord mobility and the superior border of the glottis as a horizontal plane
involve the paraglottic space, there is a high probabil- passing through the apex of the ventricle and the
ity that the tumors have invaded the glottis or carti- inferior border as a horizontal plane 1 cm below the
laginous framework of the larynx (43). If so, then the apex of the ventricle (30) (Fig. 51). The components of
patient is a candidate for a total rather than supra- the glottis include the true vocal cords and the anterior
glottic laryngectomy. and posterior commissures. The true vocal cords
The most important factor in determining average 14 to 16 mm in length in the adult male and
prognosis is the presence of regional lymph node 10 to 12 mm in the adult female (73). At their midpoint,
140 Barnes
Table 10 Staging of Carcinoma of the Larynx

Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
Supraglottis
T1 Tumor limited to one subsite of supraglottis with normal vocal cord mobility
T2 Tumor invades mucosa of more than one adjacent subsite of supraglottis (e.g., mucosa of base of tongue,
vallecula, medial wall of pyriform sinus) without fixation of the larynx
T3 Tumor limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid area,
pre-epiglottic tissues, paraglottic space, and/or minor thyroid cartilage erosion (e.g., inner cortex)
T4a Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft
tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus)
T4b Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures
Glottis
T1 Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with normal mobility
T1a Tumor limited to one vocal cord
T1b Tumor involves both vocal cords
T2 Tumor extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility
T3 Tumor limited to the larynx with vocal cord fixation and/or invades paraglottic space, and/or minor thyroid
cartilage erosion (e.g., inner cortex)
T4a Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft
tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus)
Subglottis
T1 Tumor limited to the subglottis
T2 Tumor extends to vocal cord(s) with normal or impaired mobility
T3 Tumor limited to larynx with vocal cord fixation
T4a Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea,
soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or
esophagus)
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph node, 3 cm in greatest dimension
N2 Metastasis in a single ipsilateral lymph node, >3 cm but not >6 cm in greatest dimension, or in multiple
ipsilateral lymph nodes, none >6 cm in greatest dimension, or in bilateral or contralateral lymph nodes,
none >6 cm in greatest dimension
N2a Metastasis in a single ipsilateral lymph node, >3 cm but not >6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension
N3 Metastasis in a lymph node, >6 cm in greatest dimension
Distant Metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
STAGE GROUPING
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
T1 N1 M0
T2 N1 M0
T3 N1 M0
Stage IVA T4a N0 M0
T4a N1 M0
T1 N2 M0
T2 N2 M0
T3 N2 M0
T4a N2 M0
Stage IVB T4b Any N M0
Any T N3 M0
Stage IVC Any T Any N M1
Figure 54. Gross appearance of a supraglottic carcinoma. The

tumor is confined to the epiglottis.
Figure 56. Squamous cell carcinoma of the epiglottis invading

through fenestrations (arrow) of the epiglottic cartilage (c). Such
defects allow easy access of tumor into the pre-epiglottic space
(see Fig. 52).
Figure 55. Vertical section through a supraglottic tumor. The

tumor has a pushing margin and involves the pre-epiglottic space
(arrow). Figure 57. Typical gross appearance of a glottic carcinoma
arising primarily from the left true vocal cord (arrow), but also
crossing the anterior commisure to involve the anterior portion of
the right true vocal cord. The lesion was discovered incidentally
the vocal cords are approximately 5 mm in height, at autopsy in a 60-year-ol man who died of other causes.
whereas anteriorly they are only 1 to 3 mm (74).
Glottic carcinomas account for 60% to 65% of all
laryngeal carcinomas in the United States. Most arise
from the anterior half of the cord and, as a conse- (75–78). Carcinomas originating at the posterior com-
quence, produce hoarseness as a common early symp- missure are exceptionally rare.
tom (Figs. 57–59). They are equally distributed The tumor initially presents as an irregular area
between the right and left true cords. Although only of mucosal thickening or ulceration and, eventually,
1% to 9% of all cancers originate at the anterior as an exophytic or endophytic mass. Most are well to
commissure, depending on the series, it is involved moderately differentiated squamous cell carcinomas,
secondarily in 10% to 46% of all glottic carcinomas with either pushing or infiltrating borders.
142 Barnes
tendon (Broyles’ ligament) to extend over or through

the thyroid cartilage in the midline, with subsequent
growth into the soft tissue of the neck; (iii) posteriorly
to involve the arytenoids; (iv) subglottically, with the
potential to pierce the cricothyroid membrane and
grow into the soft tissue of the neck, or to gain access
to the lymphatic channels that drain to the paratra-
cheal and mediastinal lymph nodes; and (v) supra-
glottically, to involve the ventricle, false vocal cord,
and epiglottis.
Before the carcinoma extends beyond the vocal
cords, it often replaces or ‘‘fixes’’ the vocalis muscle,
an ominous clinical sign (81). If the cord is not fixed
and the carcinoma is superficial to the conus elasticus,
the incidence of lymph node metastasis is less than
2%. A fixed vocal cord is associated with cervical node
Figure 58. Hemilaryngectomy specimen. This is a voice- metastasis in about 25% of cases. Twenty to twenty-
conserving procedure done for small carcinomas of the true five percent of glottic carcinomas will demonstrate
vocal cord (arrow). It is important to orient the specimen for anterior either supraglottic or subglottic extension (75,76,82).
(A), posterior (P), superior (S), and interior (I) aspects. Sections
They do not invade the thyroid cartilage until there is
should always be taken vertically through the true and false vocal
cords and ventricle (line with hashmarks; see also Fig. 59).
more than 1 cm of subglottic extension (83).
The overall incidence of lymph node metastasis
during the course of the disease varies from 0% to 6%
for T1 lesions, 4% to 11% for T2 lesions, 14% to 22% for
T3 lesions, and 25% to 41% for T4 lesions (84–86). The
overall five-year survival rate for all glottic carcino-
mas is about 80% to 85% (75). The five-year survival
rates range from 82 to 96% for T1 lesions, 51% to 85%
for T2 lesions, 48% to 59% for T3 lesions, and 0% to
30% for T4 lesions (13). Risk factors associated with an
increased incidence of locoregional failures include (i)
prior tracheotomy, (ii) poor histological differentia-
tion, (iii) subglottic extension of tumor of more than
1 cm, and (iv) histologically positive cervical lymph
nodes (84,87,88).
Only about 3% to 6% of patients with glottic
carcinomas develop clinical evidence of metastases
below the clavicles (67,83,84). Those individuals
with positive cervical lymph nodes that show extrac-
apsular (extranodal) invasion into the surrounding
perinodal soft tissue are more likely to develop distant
metastases (84).
D. Subglottic Carcinoma
The American Joint Commission on Cancer defines
Figure 59. Histological section should always be taken verti-
cally through the laryngeal glottis to preserve anatomical rela-
the superior border of the subglottis as an imaginary
tions (see Fig. 58). Note the tumor arising from the true vocal horizontal plane 1 cm below the apex of the ventricle
cord encroaching on the underlying vocalis muscle (H&E, whole (30). The lower border is the inferior rim of the cricoid
mount). cartilage (Fig. 51). Tumors in this site account for 1%
to 5% of all squamous carcinomas of the larynx seen in
the United States (Fig. 60). They tend to be moderately
to poorly differentiated, with infiltrating borders.
Dyspnea and stridor are the most common symptoms.
Because of the limited lymphatic supply and Almost one-third of the patients with these symptoms
scant number of mucoserous glands in the true vocal will require emergency tracheotomy to maintain an
cords, glottic carcinomas tend to remain localized for airway (89). The tumor usually spreads circumferen-
an extended time; therefore, they are amenable to cure tially and anteriorly through the cricothyroid mem-
if detected early (79,80). As the disease progresses, the brane to involve the thyroid gland and paratracheal
tumor may extend along several pathways: (i) across and prelaryngeal lymph nodes. It can also spread
the anterior commissure to the opposite true vocal posteriorly below the thyroid cartilage and involve
cord; (ii) anteriorly through the anterior commissure the cervical esophagus, medially into the cricoarytenoid
E. Transglottic Carcinoma
The term ‘‘transglottic carcinoma’’ was coined by
McGavran et al. in 1961 to designate those tumors
that cross the ventricles to involve the supraglottis and
glottis (and often the subglottis) (55) (Fig. 61). Unlike
the latter terms, transglottic does not correspond to a
specific anatomical site within the larynx.
Mendonca and Bryce are of the opinion that
most transglottic carcinomas represent supraglottic
extension of primary glottic carcinomas (82). In their
experience, 25% of all glottic carcinomas extend across
the ventricles. It is generally accepted that primary
carcinomas of the ventricle are rare.
Not all transglottic carcinomas are large. Of 152
cases reviewed by Mittal et al., 31% were classified as
T2, 39% T3, and 30% T4 (100). Twenty-six percent of
their patients had cervical lymph node metastasis at
presentation and another 19% subsequently devel-
oped positive lymph nodes during the course of
their disease.
Most of these tumors are moderately differentiat-
ed squamous cell carcinomas, with infiltrating margins.
The tumors characteristically spread within the para-
Figure 60. Rare example of primary subglottic carcinoma of the
glottic space and escape from the endolarynx by grow-
larynx (arrows). Note the attached right lobe of the thyroid gland. ing through the cricothyroid or thyrohyoid membranes,
or by spreading submucosally into the pyriform sinus
(Fig. 62).
In the series of Mittal et al., 70% of the tumors
joint to reach the hypopharynx, or inferiorly to involve were confined to the larynx, and 30% demonstrated
the trachea. extralaryngeal growth (100). If the tumor is larger
About 15% to 25% (range 4–40%) of patients than 3.0 cm, there is a 75% chance that it has invaded
have cervical lymph node metastases, usually to the the cricoid or thyroid cartilages, or both, especially
lower jugular chain (89–96). Lymphatic drainage of the lower one-third of the latter (101). Extralaryngeal
the subglottis consists of three main tributaries: one spread, invasion of the laryngeal cartilages, or
anterior and two posterolateral (97). The anterior both should be suspected in any patient whose trans-
group pierces the cricothyroid membrane to terminate glottic carcinoma is accompanied by referred otalgia
in the prelaryngeal (Delphian) lymph node, which, in (102). The five-year survival rate is approximately
turn, drains to the pretracheal and supraclavicular 50% (100).
nodes (91). The two posterolateral groups pierce the
cricotracheal membrane and terminate in the para-
tracheal nodes, which are continuous with those in the
superior mediastinum. Although only 15% to 25%
(range 4–40%) of patients have positive cervical
lymph nodes, about 50% have positive, but clinically
undetectable, paratracheal lymph nodes (91). For this
reason, Harrison advocates total laryngectomy with
clearance of the paratracheal and superior mediastinal
lymph nodes (91). Furthermore, one or both lobes of
the thyroid should also be removed, for they may be
involved in 10% to 20% of cases (98).
About half of patients with subglottic carcinoma
die of local or stomal recurrences (91) and 15% to 20%
will develop distant metastases, most often to the
lungs and bones (89,98,99). The five-year survival
rate most frequently quoted for subglottic carcinoma
is about 40% (range 36–70%) (89–91,94,95).
Occasionally, glottic carcinomas with subglottic
extension will exhibit a clinical course indistinguish-
able from a de novo subglottic carcinoma. In general,
the greater degree of subglottic extension, the worse Figure 61. Total laryngectomy and right radical neck dissec-
the prognosis and the more the tumor behaves as a tion. Note the large, ulcerated, transglottic carcinoma.
subglottic primary.
144 Barnes
Selected Prognostic Factors

Margins of Resection In the larynx, a margin of
resection of only 2 mm is considered adequate. This is
based on the work of Futrell et al., who found that
patients whose tumors were 5 mm or more from the
laryngeal resection margin had a 52% five-year sur-
vival, whereas those with positive margins had a 28%
five-year survival (113). Individuals whose tumors
were technically free, but within a 2 mm of the
margin, had a five-year survival of 30%. They con-
cluded that, in the larynx, margins of 2 mm or greater
behaved similarly to widely clear margins, whereas
those within 2 mm constituted positive margins.
Bauer et al., in a study of hemilaryngectomy speci-
mens, observed that 18% of patients with positive
margins had local recurrences, as opposed to 6% of
patients who had free margins, but yet developed
local recurrences (114).
Cervical Lymph Nodes The status of the cervical
lymph nodes is one of the most important factors that
determine prognosis in laryngeal carcinoma. It is
commonly stated that the presence of even one histo-
logically positive lymph node decreases the five-year
survival almost by half (113). Some investigators have
Figure 62. Coronal section of a transglottic squamous cell observed that when cervical metastases are confined
carcinoma of the larynx. Compare with the uninvolved (normal) to lymph nodes, the survival rate is almost identical to
right side. Note that the tumor fills the paraglottic space and is that of those patients with histologically negative
beginning to escape from the endolarynx by growing through the nodes (115–118). Only when the tumor extends
cricothyroid interspace (arrow). beyond the lymph node into adjacent perinodal soft
tissue—so-called extracapsular spread (ECS)—is
prognosis significantly affected. According to these
investigators, ECS is an ominous finding associated
F. Laryngeal Carcinoma in Children with a 50% or more reduction in patient survival,
and Young Adults compared with individuals with positive lymph
nodes without ECS, and when found, warrants addi-
Squamous cell carcinoma of the larynx is distinctly tional therapy (radiation or chemotherapy) (115–118).
uncommon in individuals younger than 20 years of Invasion of Laryngeal Cartilages Invasion of the
age (103–112). Zalzal et al. identified only one case in a cartilaginous framework of the larynx, according to
9-year-old girl among 1000 pediatric cancer patients some, is an adverse prognostic indicator associated
treated over a 25-year time interval, for an incidence of with an increased incidence of cervical node metastases
only 0.1% (109). In 1984, 54 cases were recorded in the and death from disease (38,102,119). It occurs primarily
literature in individuals 15 years old or younger and, in transglottic, infrequently in glottic, and rarely in
by 1987, only 21 cases had been documented in supraglottic carcinomas. In a study of 185 laryngecto-
patients 10 years old or younger (105,107,109). my specimens removed for cancer and studied by
Most of these tumors have occurred in the region serial histological sections, Kirchner observed that
of the true vocal cords and have manifested clinically 50% of transglottic (28 of 65 cases), 20% of glottic (13
as hoarseness. In contrast with adults, however, the of 64 cases), and 0% of supraglottic tumors (0 of 65
incidence of laryngeal cancer in children is significant- cases) invaded the laryngeal cartilages (120).
ly greater in girls (40% of all cases; 105). When tumor invades cartilages, it typically does
For a long time, previous irradiation exposure, so in the area that has undergone ossification. As such,
usually for recurrent respiratory papillomatosis, was the lower one-third of the thyroid cartilage and the
the only known risk factor for patients in this age upper portion of the cricoid cartilage are the most
group. This is no longer true. The role of HPV and vulnerable sites (120).
passive smoking are gaining more attention, and Stomal Recurrence Stomal recurrence, defined as a
individuals who actively smoke and abuse alcohol diffuse infiltration of tumor at the junction of the
are becoming increasingly younger (111,112). amputated trachea and skin, occurs in 1.7% to 14.7%
Although some have indicated that cancer of (average 6%) of all patients who have undergone
the larynx is more aggressive in children than in laryngectomies (121–123). It is one of the most feared
adults, this remains to be proved (109). Delays in complications of this procedure, because it is relative-
diagnosis and undertreatment of these young ly resistant to further therapy and, once diagnosed,
patients may partly account for this alleged differ- the average survival is only 9 months (101). Seventy
ence in behavior. percent of patients who experience stomal recurrence
do so within the first year after laryngectomy and 98% 17% to 90% of all tumors are aneuploid (133–138). The
within 2 years (121). clinical significance of ploidy patterns in the larynx,
The precise pathogenesis of stomal recurrence is however, is both confusing and controversial. Some
unknown. Factors that have been suggested include investigators indicate that there is no correlation
(a) unrecognized tumor at the margin of initial resec- between tumor ploidy and survival, whereas others
tion, (b) development of a second primary malignant indicate that patients with aneuploid tumors have a
neoplasm, (c) tumor implantation at the time of tra- more favorable outcome (129,130). Still others, con-
cheotomy or at the time of primary surgery, and (d) versely, have found that diploid tumors are associated
recurrence secondary to metastases in the paratracheal with a better prognosis (139). Although Rua et al. have
or pretracheal lymph nodes. noted that the overall survival rates of patients with
It is generally agreed, however, that individuals diploid and aneuploid tumors are comparable, they
with tumors that involve the subglottis, either primar- did observe that aneuploid tumors with a well-
ily or secondarily, are especially at risk for develop- differentiated pattern are associated with a poor
ing this complication. Whether preoperative or prognosis (136).
emergency tracheotomy enhances the risk is highly Laryngeal ploidy patterns have also been used to
controversial. predict response to irradiation and chemotherapy.
Invasion of the Thyroid Gland Invasion of the Again, the results are confusing. Some investigators
thyroid gland occurs in 3% to 14% of all laryngeal have observed that nondiploid tumors respond
carcinomas and is characteristically associated with better to both irradiation and chemotherapy, whereas
advanced tumors (124,125). Of 23 cases of laryngeal others have found no relation between tumor
carcinoma in which the thyroid was involved, Gilbert ploidy and subsequent response to either of these
et al. noted that (a) all 23 cases tumors had invaded therapeutic modalities (135,139–142). Walter et al., on
one or more of the laryngeal cartilages, (b) 16 of 23 the other hand, indicate that T1N0M0 glottic tumors
(70%) tumors demonstrated perineural or vascular that are aneuploid are more radioresistant than are
invasion, and (c) 21 of 23 tumors (91%) extended 10 diploid lesions and should be treated primarily with
mm or more subglottically (124). surgery (137).
Involvement of the thyroid may be by direct Part of the foregoing controversy may be related
extension of tumor from the larynx (65%) or by to tumor (DNA) heterogeneity. El-Naggar et al. stud-
metastatic spread to one or both lobes of the thyroid ied 21 squamous cell carcinomas of the larynx by flow
(35%). Either mechanism is associated with a poor cytometry and observed that 76% were heterogeneous
prognosis, for 78% patients with involvement of the in DNA content (138). According to these investiga-
thyroid will die of their disease within 3 years of tors, the calculated probability of missing aneuploidy
diagnosis and often within 1 year (117). if only one, two, three, or four tissue samples were
The work of Gilbert et al. further underscores the analyzed was 33%, 17%, 8%, and 3%, respectively.
need to remove one or both lobes of the thyroid gland
when dealing with all primary subglottic carcinoma or
any laryngeal tumor that has 10 mm or more of G. Molecular Genetic Data
subglottic extension (124).
Multiple Primary Malignancies Patients with There is much interest in identifying biomarkers that
laryngeal carcinomas will develop a second primary could be used to stratify patients with laryngeal
malignant tumor in 10% to 24% of cases (85,126–128). carcinomas into those who could be managed conser-
Seventy percent of these additional primaries will vatively (radiation therapy) versus those who are in
occur in the respiratory and upper aerodigestive tracts need of more aggressive therapy (surgery). The two
and most will appear within 2 years of treatment of most widely studied markers have been p53 and Ki-67
the index tumor (126,128). (143–146).
The lung is, by far, the most common site of It is generally agreed that p53 when used alone,
occurrence of the second primary, which is unfortu- has no predictive value for local recurrence, survival
nate because pulmonary carcinomas are generally or response to radiation (143–145). Studies reporting
more life-threatening than laryngeal tumors. The asso- the role of Ki-67 index in predicting response to
ciation of laryngeal with pulmonary carcinoma is radiation have produced, on the other hand, conflict-
strongest for those tumors that arise in the supra- ing results (144,145,147–149). Part of this Ki-67 contro-
glottic larynx. Patients with supraglottic tumors have versy may be related to whether the radiation is
a 14 times greater chance of developing lung cancer administered by routine or accelerated fractionated
than the normal population and are 3 times more schedules. Rapidly growing tumors not only exhibit a
likely to develop a second primary tumor in the greater initial response to radiation but also a greater
lung than those with glottic primaries (127,129–131). likelihood of tumor repopulation with the use of a
Whether patients who present with lung cancer routine six-week course of radiotherapy as compared
are at increased risk for subsequent laryngeal carcinoma with slowly growing tumors. By keeping the total
is unknown (132). Most patients with lung cancer, dose of radiation the same but giving it over a five
however, do not live long enough to assess this rather than a six-week interval (accelerated fractionated
possibility. therapy), slowly growing tumors are less likely to
Tumor (DNA) Ploidy Flow cytometric studies on repopulate the tumor site and tend to have a better
squamous cell carcinoma of the larynx indicate that prognosis.
146 Barnes
XV. SPINDLE CELL CARCINOMA, SARCOMATOID There are those who seemingly use the term
CARCINOMA, CARCINOSARCOMA ‘‘spindle cell carcinoma,’’ rather loosely and are will-
ing to apply to it any carcinoma associated with a
A. Introduction spindle cell component, even in the presence of heter-
ologous elements. With this generic approach, one
This malignant biphasic tumor has been referred to by could rightfully argue that synovial sarcoma is also
a variety of names, including spindle cell carcinoma an example of a spindle cell carcinoma. After all, it is
(SPCC), pseudosarcoma, pleomorphic carcinoma, biphasic, and the spindle cells characteristically stain
metaplastic carcinoma, sarcomatoid carcinoma, and for cytokeratin.
collision tumor. Pathologically, it is composed of a The term spindle cell carcinoma does not address
squamous cell carcinoma, either in situ or invasive the sarcomatous component present in some, but not
(rarely an adenocarcinoma or neuroendocrine car- all, of these tumors. One simply cannot choose to
cinoma) and a spindle cell component that may vary overlook the sarcomatous elements, because they may
from bland to pleomorphic. The former component is also metastasize, albeit rarely, and may, therefore,
often small and elusive, requiring numerous sections warrant additional therapy. The use of the popular
for demonstration, whereas the latter tends to form the term metaplastic carcinoma is also equally disconcerting
bulk of the tumor. As the plethora of names might because it too does not convey to the clinician the
indicate, its histogenesis, especially the spindle portion, potential dual composition of this group of neoplasms.
is disputed. Is it a squamous cell carcinoma, with a The literature on SPCC has mostly focused on
benign reactive stroma, or is the entire lesion just a the concept of carcinomas undergoing ‘‘metaplasia’’
peculiar squamous cell carcinoma in which the squa- into various types of sarcomas. Is the converse also
mous cells have assumed a spindled (pseudosarcoma- true? Can sarcomas undergo metaplasia into carcino-
tous) appearance (1,2)? Or does it represent a collision mas? For instance, a significant number of alleged
tumor (squamous cell carcinoma growing next to a leiomyosarcomas can express cytokeratin on immu-
sarcoma), or a carcinosarcoma (a mixed epithelial- nostaining (30). Are these examples of metaplastic
mesenchymal neoplasm arising from a single stem sarcomas and, therefore, the mesenchymal counter-
cell in which both elements are intermingled) (3,4)? part of metaplastic carcinomas?
Contrary to initial belief, it is now apparent that As a corollary to the foregoing discussion, there
the spindle component is capable, in some instances, is a growing school of thought that tumors should be
or metastasizing either independently or in conjunc- classified according to their degree of differentiation,
tion with the squamous cell carcinoma (5–7). This rather than their presumed histogenesis or cell of
would seem to dispel the notion that the spindle origin (31,32). If one carries the cell of origin concept
portion is always reactive. By light microscopy, one to its logical conclusion, there would be only two
often finds zones in which malignant squamous cells categories of tumors in the entire field of pathology:
appear to transform into spindle cells. Tissue cultures a benign zygotoma and a malignant zygotoma.
have also confirmed that squamous cells can grow in a Data have accumulated indicating that neoplasms
spindled pattern (8). On the other hand, enzyme are not static, but are evolutionary in composition,
histochemistry on fresh-frozen tissue suggests that responding to inherent genetic changes, the microenvi-
the spindle cells are more compatible with fibroblasts ronment, or therapeutic manipulation. Presumably,
or histiocytes than with epithelial cells (9). each tumor carries a partial or complete genetic compo-
Immunohistochemical studies have shown vari- sition of its host and, as such, may exhibit a uniform or
able results. In some instance, the spindle cells have variable phenotypic expression during its life span. We
exhibited only epithelial (cytokeratin, epithelial mem- agree entirely with Gould that ‘‘it may prove useful to
brane antigen) or mesenchymal markers (vimentin, classify certain groups of neoplasms on the basis of
actin, desmin, myoglobin), whereas others have what they in fact are, as defined by a series of appro-
expressed both epithelial and mesenchymal differentia- priate phenotypic-differentiation marker expressions,
tion (10–18). Ultrastructurally, some investigators have rather than on the basis of questionable assumptions
found evidence supporting a mesenchymal origin of the about their origin’’ (31). In other words, if a malignant
spindle cells (6,9,19), whereas others contend that they biphasic spindle cell tumor stains only for epithelial
are epithelially derived (2,20). To further confuse the markers, it should be designated as a spindle cell
issue, a few tumors, usually those occurring in areas of squamous carcinoma. If a similar tumor expresses
previous irradiation may contain metaplastic bone or both epithelial and mesenchymal markers or contains
even malignant osteoid and cartilage (4,12). A few may heterologous mesenchymal elements, it should be
even exhibit skeletal muscle differentiation (17,20). The called a carcinosarcoma.
source of these heterologous elements—whether epithe- It should be emphasized that the term ‘‘carcino-
lial, mesenchymal, or even myoepithelial—is the subject sarcoma’’ used in this context indicates tumor differen-
of ongoing controversy and heated debates, for it strikes tiation and not presumed histogenesis; that is, it does
at the very heart of our traditional histogenetic classifi- not imply that the tumor arises from two separate
cation of tumors. clones of cells, one being epithelial and the other
Molecular data now indicate, rather definitively, mesenchymal. It is generally accepted that most, if not
that these tumors have a monoclonal origin from a all, tumors originate from a single clone. If a clone
noncommitted stem cell, which gives rise to both should develop along divergent lines into epithelial
components (22–39). and mesenchymal elements, the term carcinosarcoma
Table 11 Classification of Spindle Cell Carcinomas age group (9,12,13,35,40–45). Occurrence in young
patients is unusual. The case of SPCC of the tongue
1. Squamous cell carcinoma Spindle cells are bland and
occurring in a four-year-old boy reported by Kessler
with reactive stroma negative for epithelial
markers; cells may stain for
and Bartley may be the youngest patient with this
histiocytic markers tumor reported thus far (46).
2. Spindle cell squamous Spindle cells stain positive for Although SPCC can arise from any cutaneous or
carcinoma epithelial markers (keratin, mucosal site in the head and neck, the larynx, especially
EMA) or EM shows epithelial the true vocal cords and anterior commissure, and
features esophagus—usually the middle and lower thirds—are
3. Carcinosarcoma Epithelial and spindle cells among the most common sites. In the oral cavity, the
intermingled; spindle cells are predominant sites, in descending order of frequency,
negative for epithelial are the lips (particularly the lower lip), tongue, and
markers but may stain for
alveolar ridge-buccal mucosa (40). Most individuals
desmin, myoglobin, etc.; or
presence of malignant
present with hoarseness, a change in quality of the
osteoid or cartilage voice, dysphagia, or airway obstruction. Few may even
4. Collision tumor Carcinoma growing adjacent to cough up bits of their tumor. Oral cavity tumors, in
a sarcoma without significant turn, usually manifest as a swelling with or without
intermingling; sarcoma pain or a nonhealing ulcer.
should be negative for
epithelial markers and EM
shows no epithelial features D. Pathology
Abbreviation: EM, electron microscopy. Depending on the series, 70% to 100% of SPCCs of the
larynx are polypoid, firm, pink, white, or gray, with a
would seem to be appropriate, calling attention, both mucosal attachment that varies from a broad base to a
clinically and pathologically, to both components of the thin string-like stalk (27,44,45) (Fig. 63). Sessile or
tumor. ulceroinfiltrative lesions are less common. In the oral
We believe that SPCC, as is currently used, is a cavity, the distribution between polypoid and ulcera-
generic term that encompasses four different catego- tive tumors is about equal. Most are 1 to 6 cm, but in
ries of tumors that are potentially separable only by the esophagus, they may reach 12 to 15 cm (47). The
the use of immunohistochemistry or electron micros- surface of the tumor is frequently ulcerated and
copy. These include squamous cell carcinoma with a covered by a shaggy exudate (Fig. 64). As such,
reactive or demoplastic stroma, spindle cell squamous biopsies from these areas are often returned by the
carcinoma (note addition of the word squamous), car- pathologist as ‘‘granulation tissue,’’ ‘‘tissue consistent
cinosarcoma, and collision tumor. (Table 11). with pyogenic granuloma,’’ or as ‘‘inflammation with
It has been suggested, however, that spindle cell stromal atypia.’’ The squamous carcinoma tends to be
squamous carcinoma and carcinosarcoma may repre- concentrated at the base or stalk of the tumor; there-
sent a spectrum of a single entity and that the two share fore, when clinically suspected, all biopsies should
a similar prognosis (11,33–35). The finding of individual include this region (Fig. 64).
tumor cells that coexpress both epithelial and mesen- Immunohistochemical assays for epithelial
chymal immunomarkers does add credence to this markers (cytokeratin, epithelial membrane antigen)
hypothesis (12). However, to suggest that they have a and electron microscopy have shown epithelial
similar prognosis is undoubtedly premature and based
on a very limited sample. Until the clinicopathological
features of this group of tumors are better defined, we
strongly recommend that they be classified according
to the scheme listed in Table 11. Only then, will we be
able to determine the most beneficial course of therapy.
B. Etiology
Smoking, alcohol abuse, prior irradiation exposure
and, possibly, poor oral hygiene, all have been impli-
cated as important risk factors for the development of
these tumors (36–39). Studies thus far indicate that the
HPV has little, if any, etiological significance (39).
C. Clinical Features
Most patients with SPCC (used here in a generic sense
to encompass all of the subtypes in Table 11 because Figure 63. Spindle cell carcinoma of the larynx. Note the
most investigators have not attempted to subclassify characteristic polyploidy configuration.
these entities) are men (68–99%) in the 50 to 80 year
148 Barnes
differentiation of the spindle cells in only 40% to 75% stroma may contain inflammatory cells and increased
of cases (12,13,18,44,45). Approximately 7% to 15% of blood vessels, but the spindle cells (more appropriate-
tumors will also contain heterologous elements, such ly fibroblasts or myofibroblasts) show a uniformly
as malignant osteoid, cartilage, and muscle (12,44,45). negative result for cytokeratin. In addition, the carci-
This suggests, as noted earlier, that SPCC is not a noma is always well demarcated from the stroma.
uniform tumor, but rather, a heterogeneous group of Spindle cell squamous carcinomas, on the other
lesions that can be segregated, by routine histology, hand, contain areas of squamous cell carcinoma, either
immunohistochemistry, or electron microscopy, into in situ or invasive, and an obviously malignant spindle
the four categories shown in Table 11. cell component (Fig. 66). The carcinoma varies from
Squamous cell carcinomas with a reactive or well to poorly differentiated and may be either sharply
desmoplastic stroma contain islands of malignant demarcated from the spindle element, or poorly
squamous cells associated with a fibrocollagenous defined, often appearing to give rise to the spindle
stroma that is readily recognized by the pathologist cells. The spindle cells usually assume a pattern remi-
as being benign or, at most, atypical (Fig. 65). The niscent of a fibrosarcoma or a malignant fibrous histio-
cytoma, yet the cells test positive, either focally or
diffusely, for cytokeratin (Fig. 67). At times, especially
Figure 64. Ulcerated, polyploidy spindle cell carcinoma of the

true vocal cord. If suspected, biopsies should always be taken
from the base of the lesion (arrow), rather than the inflammatory
surface. This is usually where the most diagnostic portion of the Figure 66. Spindle cell squamous carcinoma. Both epithelial
tumor is found (H&E, 20). and spindle components appear histologically malignant. Also
note that the epithelial cells appear to merge or give rise to some
of the spindle cells (H&E, 200). See Figure 67.
Figure 65. Low-power view of a squamous cell carcinoma with

a reactive (desmoplastic) stroma (H&E, 100). The spindle
(stromal) cells are negative on immunostaining for epithelial Figure 67. The spindle cells of the tumor shown in Figure 66
markers such as cytokeratin and do not show epithelial differen- resembled a fibrosarcoma on H&E, but were positive for cyto-
tiation by electron microscopy. keratin (IHC, AE1/3, 400).
on small biopsies, only the spindle component is pres-

ent, and pathologists may be tempted to diagnose the
lesion as a sarcoma. However, because sarcomas are
rare in the head and neck, the temptation should be
resisted until a spindle cell squamous carcinoma has
been excluded by obtaining multiple, deeper histologi-
cal sections; examining immunostains for cytokeratin;
performing electron microscopy; or requesting another
biopsy (Fig. 67). Such lesions are often referred to as
‘‘monophasic spindle cell carcinomas.’’ As a general
rule, any sarcomatous-appearing lesions adjacent to a
mucous membrane in the head and neck, should
suggest a SPCC until proved otherwise.
Carcinosarcomas are those tumors composed of
a squamous cell carcinoma (rarely other types of
carcinomas) intimately associated with a malignant
spindle cell component. Foci of osteosarcoma, chon-
drosarcoma, or rhabdomyosarcoma are not uncom-
mon (Fig. 68). Although the spindle cells are Figure 69. Gross appearance of a collision tumor of the pyri-
form sinus area. This patient had a squamous cell carcinoma of
characteristically negative for cytokeratin and fail to
the pyriform sinus treated with surgery and radiation and approx-
show epithelial differentiation on electron microscopy, imately 12 years later, developed this multinodular tumor com-
a few tumors will be encountered in which the spindle posed of squamous cell carcinoma and malignant fibrous
cells are focally positive for cytokeratin. In these instan- histiocytoma. See Figures 70 and 71.
ces, to qualify as a carcinosarcoma, one must find
heterologous elements or demonstrate additional spin-
dle cells that stain positively for nonepithelial markers,
such as desmin, myoglobin, or other.
Collision tumors are extremely rare and presum-
ably arise from two simultaneous clones of malignant
cells, one epithelial and one mesenchymal that by
shear coincidence arise in adjacent sites, but yet do
not intermingle (Figs. 69–71).
When SPCCs disseminate, the metastases most
often will show a prominent epithelial pattern, but
occasionally both epithelial and spindle cell compo-
nents will appear and, in a few instances, only the
spindle cell element will metastasize (Fig. 72).
Figure 70. Collision tumor shown in Figure 69. Note the

squamous cell carcinoma at top and malignant fibrous histio-
cytoma at bottom. The two components do not intermingle (H&E,
100).
E. Immunohistochemistry
In a review of 187 SPCCs of the larynx, Thompson et
al. observed that the spindle cell component was
positive for at least one epithelial marker in 68% of
cases and suggested the use of a screening panel
consisting of AE1/3, epithelial membrane antigen
Figure 68. Carcinosarcoma. Focus of osteosarcoma found in a (EMA), K1 and K18 (45). More specifically, they
tumor histologically similar to that shown in Figure 67 (H&E, observed that 41% of the tumors were positive for
200). This combination of findings supports a diagnosis of K1, 26% for AE1/3, 24% for K18, 15% for K14, 9% for
carcinosarcoma. K6, and 7% for K5/6, and 18% for EMA. In contrast to
our experience, none was positive for CAM5.2. The
150 Barnes
cell with disparate phenotypic expression or divergent

differentiation (22–29).
Ploidy analyses of SPCCs have shown that the
majority (78% of cases) are aneuploid and or tetra-
ploid and that both epithelial and spindle components
usually exhibit concordant patterns (44).
G. Differential Diagnosis
Posttraumatic spindle cell nodules, inflammatory
myofibroblastic tumors (inflammatory pseudotu-
mors), and radiation fibrosis, must be considered in
the differential diagnosis (49–51). A history of trauma;
presence of a significant inflammatory component;
and lack of atypical mitoses, dysplasia and significant
cellular pleomorphism are features of pseudotumors
rather than SPCCs. It should be noted that inflamma-
Figure 71. Collision tumor shown in Figures 69 and 70. A tory myofibroblastic tumors may contain a few
cytokeratin stain shows the carcinoma to be positive and the keratin-positive cells (myofibroblasts), and should
sarcoma negative. Again, note that the tumor components are not be misconstrued as evidence to support a diagno-
separate and do not intermingle (IHC, prekeratin, 40). sis of SPCC. The fibroblasts associated with radiation
are negative for p53 while SPCCs are often positive
(52,53).
Attention has already been called to the fact that
some SPCCs are monophasic and may masquerade as
soft tissue sarcomas, especially since some SPCCs and
sarcomas share similar mesenchymal markers (vimen-
tin, smooth muscle actin, etc.) and even keratin
expression (especially leiomyosarcomas and synovial
sarcomas) (see ‘‘Pathology and Immunohistochemis-
try’’ above). A p63 stain may be very helpful. SPCCs
are often positive (63% of cases) for p63, while sarco-
mas are almost invariably negative (especially leio-
myosarcomas) (48). Amelanotic spindle cell
melanoma and spindle cell myoepithelioma may
also be included in the differential diagnosis but can
usually be excluded by appropriate immunomarkers.
In some small biopsies, a definitive diagnosis
cannot be rendered. In this instance, a diagnosis of
‘‘malignant spindle cell lesion’’ is appropriate with a
comment that an SPCC, as well as other lesions,
should be considered in the differential diagnosis.
Figure 72. Lymph node in which only the spindle cell compo-
nent has metastasized (H&E, 100).
H. Treatment and Prognosis
Surgery is the treatment of choice with the extent
based on the stage of the disease. Irradiation is gener-
tumors were also positive for a variety of mesenchy- ally unrewarding as a primary procedure but may
mal markers, including vimentin (100% positive), have merit as an adjunct. Whether additional therapy
smooth muscle actin (33%), S-100 protein (5%), and is warranted or prognosis is related to the four sub-
desmin (2%). types of SPCC listed in Table 11 is unknown since
More recently, p63 has been found to be a useful large series of tumors classified accordingly with
alternative marker. Lewis et al. observed it to positive adequate follow-up are not available. As a result, we
in the spindle cells in 63% of the cases tested (48). are forced to analyze the clinical data pertaining to
these tumors collectively. It is of interest, however, to
F. Molecular-Genetic Data note that there is data indicating that ‘‘metaplastic
carcinomas’’ of the breast with absent or minimal
Microdissection-based genotypic analysis of the epi- invasive carcinomatous component behave more like
thelial and mesenchymal components have shown sarcomas and therefore should probably be treated
that each exhibits an equivalent pattern of loss of with sarcoma rather than the usual breast cancer
heterozygosity implying that both elements most protocols (54). The incidence of cervical lymph node
likely originate from a single (monoclonal) totipotential involvement, distant metastasis, and mortality,
Table 12 Spindle Cell Carcinoma: Incidence of Metastasis and Mortality

Cervical lymph Distant
Author No. of cases Site mode metastasis (%) metastasis (%) Mortality (%)
Hyams 39 Larynx and 26 – 40 (mean 1 yr.)
hypopharynx
Lambert 116 Larynx and 15 Glottic tumors 5 32 at 3 yr
hypopharynx
30 Supraglottic
tumors
66 Hypopharyngeal
tumors
Ellis 59 Oral cavity 24 20 55 (mean 1.9 yr.)
Batsakis 111 All sites in head 24 – 35 (usually within 2.5 yr)
and neck
Leventon 20 All sites in head 45 – 45
and neck
Zarbo 25 All sites in head 32 20 28 (mean 10 mo.)
and neck
Berthelet 17 All sites in head – – 28 at 2 yr
and neck
Thompson 187 Larynx 7 10 32% (mean 3.1 yr.)
Lewis 26 Larynx 9 14 18% (median 6.4 yr.)
without regard to the site or stage of disease, are listed area and that the amount and degree of differentiation
in Table 12. Cervical lymph nodes and lungs are the of the carcinomatous component are not related to
most frequent sites of dissemination. Following treat- survival or tumor behavior (41). Positive cervical
ment, 20% to 45% of laryngeal SPCCs have developed lymph nodes are an ominous finding.
local recurrences.
Prognosis is related to location, tumor size,
depth of invasion, stage of disease, and, to some XVI. VERRUCOUS CARCINOMA
extent, with gross configuration of the tumor. Small
A. Introduction
tumors in strategic sites, such as the true vocal cords,
are more likely to have a favorable prognosis because Verrucous carcinoma was first described by Acker-
of early symptomatology. Tumors of the oral cavity man in 1948 and is often referred to as ‘‘Ackerman’s
and sinonasal tract tend to be more aggressive. Some tumor’’ in his honor (1–3). It is defined by the World
reports have indicated that polypoid tumors either do Health Organization as ‘‘a nonmetastisizing variant of
not metastasize or have a more favorable outcome well-differentiated squamous cell carcinoma charac-
than the flat ulcerative type. While polypoid lesions terized by an exophytic, warty, slowly growing neo-
do, in general, have a better prognosis, they are plasm with pushing margins (4).’’
certainly capable of metastasizing and causing death. Although the oral cavity is the most frequent site
Leventon and Evans indicate that the degree of inva- of origin, 10% to 15% of all VCs occur in the larynx
sion may be the most important factor rather than the and, in the larynx, 1% to 3% of all carcinomas are of
gross appearance of the tumor (41). According to the verrucous type (5–12).
them, tumors which invade muscle, minor salivary
glands or bone are associated with a poor survival
whereas those tumors which are superficial and do B. Clinical Features
not involve these structures have a good survival.
Some polypoid tumors, therefore, may exhibit rather Most arise from the true vocal cords, although in the
deep invasion. series of 44 cases reported by Lundgren et al., 27%
In the extensive review of SPCCs of the larynx by occurred in the supraglottic larynx (8,13) (Fig. 73). Most
Lambert et al., the three year survival rate was 90% for individuals have been men (85–95%), averaging 58 to 62
glottic tumors that were polypoid but only 44% for years of age (range 29–83 years) (6,8,14). Hoarseness is
sessile glottic lesions (35). Prognosis was poor for the usual presenting symptom. Dysphagia, airway
supraglottic and hypopharyngeal tumors, regardless obstruction, and hemoptysis are uncommon.
of pattern of growth. In Ellis and Corio’s review of
oral cavity tumors, 40% of patients with polypoid C. Etiology
tumors and 40% with endophytic lesions succumbed
to their disease (40). The use of tobacco appears to be an important risk
Leventon and Evans also indicate that tumors factor. Most of the patients described thus far have
that arise in a site of previous irradiation tend to be been smokers. HPV, particularly types 16 and 18 and
more aggressive than those that arise in a nonirradiated rarely 6 and 11, have been found in some, but not all,
152 Barnes
Figure 73. Direct laryngoscopic view of a verrucous carcinoma in Figure 75. Verrucous carcinoma. Note the papillary surface,
region of anterior commmisure. Note the exophytic appearance. prominent keratin layer and absence of keratohyaline granules
(H&E, 100).
VCs (15–19). Whether or not the virus is etiologically

linked to VC, however, is uncertain.
D. Pathology
The gross and histological features are identical with
those seen in the oral cavity (Figs. 74–76). Hybrid
(mixed) tumors composed of areas of both VC and
conventional squamous cell carcinoma have also been
described in the larynx; however, the frequency of
such tumors in the larynx (11% in one study) is
Figure 76. Verrucous carcinoma. The tumor invades as large

islands of well-differentiated squamous cells preceded by an
inflammatory stromal reaction (H&E, 100).
significantly less than the 20% incidence observed in

the oral cavity (12,20) (Fig. 77). Nevertheless, it
emphasizes the need for thorough microscopic exam-
ination of all VCs, because the presence of foci of
conventional squamous cell carcinoma in an other-
wise typical VC indicates a potential for metastasis.
E. Molecular-Genetic Data
p53 over expression as determined by immunohis-
tochemistry can be found in 40% of VCs, which is
similar to other head and neck neoplasms (21).
Sakurai et al. studied C-erbB-3 protein, a growth
Figure 74. Verrucous carcinoma shown in Figure 73. Note the factor, in a series of verrucous hyperplasia, verrucous
exophytic, warty growth and the extensive surface keratinization. carcinoma, and well-differentiated squamous cell car-
cinoma arising in verrucous carcinoma and observed
and neck sites treated with radiation, Ferlito et al.

observed 43.2% were cured and 56.8% failed therapy
(26). Other studies have also shown a 46 to 57% rate of
failure for primary radiation therapy (8,10,28). If a
tumor responds at all to radiation, it usually takes one
to two months before it disappears (8).
In the past, radiation was rarely used as a
therapeutic modality for VC for fear of anaplastic
transformation. A critical review of these cases of
alleged anaplastic transformation, however, has
shown that most were actually conventional squa-
mous carcinomas that were incorrectly labeled as
VCs. Current estimates indicate that no more than
5% to 10% of all irradiated VCs will become more
aggressive following treatment (8,28,29). Some of
these may be examples of unrecognized hybrid carci-
nomas. Selected patients with VC of the larynx may
Figure 77. Hybrid verrucous carcinoma. This tumor is com- also be managed with endoscopic resection, with or
posed of both verrucous carcinoma (left) and conventional without laser ablation (7,10,30). However, with this
squamous cell carcinoma (right). Note the degree of pleomor- approach, repeated endoscopic resections are often
phism between the tumor components (H&E, 400). necessary.
Although patients with VCs may have palpable
cervical lymph nodes, this is almost invariably due to
reactive hyperplasia secondary to an inflammatory
response associated with the primary tumor site. A
a progressive increase in expression. They suggested neck dissection is therefore not warranted. VC of the
that this protein might contribute to tumor growth larynx is rarely fatal; death due to disease is 4% (28,29).
and malignant transformation (22).
Choi et al. indicate that genetic alterations at the
short arm of chromosome 9 are early events in carci-
XVII. PAPILLARY SQUAMOUS CELL
nogenesis and are commonly shared by the majority
CARCINOMA
of squamous carcinomas of the head and neck, includ-
ing VC (23). They also observed that less aggressive A. Introduction
variants of squamous carcinomas (verrucous, papil-
lary and well-differentiated conventional) had signifi- Papillary squamous cell carcinoma (PSCC), strictly
cantly lower loss of heterogeneity (LOH) than the defined, is a nonkeratinizing variant of squamous
more aggressive types (basaloid, spindle cell, and cell carcinoma composed of mitotically-active, basa-
high grade conventional). loid cells arranged in a papillary configuration with
Although some investigators have observed dif- delicate fibroblastic cores. It has a favorable prognosis
ferences in LOH at 4q and 17q between VC and and should be distinguished from a conventional
conventional squamous cell carcinoma, these differ- (keratinizing) squamous cell carcinoma with a papil-
ences were not confirmed in a study that compared lary or exophytic growth (1–14).
VC with only well-differentiated, conventional squa-
mous cell carcinoma (23,24).
B. Etiology
F. Differential Diagnosis The tumors usually arise de novo but in some instan-
ces may arise in papillomas associated with recurrent
The differential diagnosis includes papillary keratosis, respiratory papillomatosis. HPV types 6,11,16 and 18
verruca vulgaris, and well-differentiated papillary have been detected in a few cases (2,3,5,6,). Whether
squamous cell carcinoma. Features that are useful in this virus has a role in the etiology of PSCC remains
separating these lesions are discussed in sections VIIC, unsettled. Smoking and alcohol are also possible risk
VIII and XVII. factors (2).
G. Treatment and Prognosis C. Clinical Features

Although VC may be treated with either surgery or PSCC may arise from any mucosal site of the upper
radiation, surgery is more effective (6,8,10,25–28). In a aerodigestive tract (3). The larynx, however, is one of
review of 144 VCs of the larynx treated by surgery the most frequent sites. In this location, they are more
(vocal cord stripping for T1 lesions, cordectomy or common in men by a 3:1 ratio and typically occur in
hemilaryngectomy for T2 lesions, and total laryngec- patients over the age of 50 years (range 30–74 years)
tomy for T3 and T4 lesions), Hagen et al. noted that (2). The supraglottic and glottic regions are the pre-
92.4% were cured, 7.6% failed therapy, and 3.5% died ferred sites and, as such, hoarseness and airway
of disease (28). In a review of 148 VCs from all head compromise are the usual manifestations.
154 Barnes
D. Pathology transitional cell carcinoma of the genitourinary tract.

Despite their large size, the tumors often remain in situ
PSCCs may be localized or diffuse, solitary or multi- or exhibit only superficial invasion. Not infrequently,
focal, and in situ or invasive. They have a characteris- more than one biopsy may be necessary to establish the
tic papillary surface and contain fibrovascular cores diagnosis.
covered by multiple layers of squamous cells with a Some PSCCs are positive immunohistochemi-
basaloid appearance (Figs. 78 and 79). Mitoses are cally for p53 and/or show evidence of HPV by in
frequent, but surface keratinization is characteristical- situ hybridization or polymerase chain reaction (3,4).
ly sparse to absent. Some tumors may also contain a
few interspersed mucous cells, especially when they
involve the laryngeal ventricle. E. Differential Diagnosis
The tumors often extend over a broad surface area
with a ‘‘stuck on’’ appearance, much like papillary The two lesions that are most often confused with
PSCC are the nonkeratinized papilloma (NKP) associ-
ated with HPV-recurrent respiratory papillomatosis
and the exophytic squamous cell carcinoma (ESCC)
(Figs. 23, 24, and 80). NKPs, especially those that
rapidly recur following excision, may show atypia/
dysplasia (7). Most often the atypia/dysplasia is in the
form of basal cell hyperplasia. Mitoses may be seen
but they are normal and limited to the lower half
of the epithelium, whereas in PSCC there is full-
thickness epithelial disarray and normal and abnor-
mal mitoses are often observed throughout all layers
of the epithelium. The clinical history may also be
helpful. NKP occurs primarily in children and young
adults and is often associated with a prolonged histo-
ry of recurrent lesions while PSCC frequently occurs
ab initio in individuals older than 50 years.
ESCC is a conventional (keratinizing) squamous
cell carcinoma but with an exophytic growth. In
contrast to the basaloid cells of PSCC, the cells in
ESCC are more pleomorphic and often exhibit dysker-
atosis (Figs. 79 and 80). The surface of an ESCC also
Figure 78. Papillary squamous carcinoma. Note the papillary tends to be somewhat keratinized. Mixed lesions with
surface, fibrovascular cores, and lack of surface keratinization features of both PSCC and ESCC should be classified
(H&E, 20). as an ESCC.
The literature often states that PSCC must also be
distinguished from a VC. This should never be an
issue. The two lesions do not even remotely resemble
Figure 79. Papillary squamous cell carcinoma. Observe the Figure 80. Exophytic squamous cell carcinoma. Note the cells
basaloid cells and frequent mitoses (arrows) throughout all are more keratinized (or squamoid) rather than basaloid (H&E,
layers. Compare with Figure 80 (H&E, 400). 400).
each other. VC has a heavily keratinized surface and fact, because of the submucosal growth, many are
the cells are exceedingly well differentiated with a clinically thought to be of nonepidermoid origin and
pink, nonbasaloid appearance free of mitoses. In addi- are often confused with a minor salivary gland neo-
tion, the rete ridges are bulbous. plasm or a soft tissue tumor (Fig. 82).
As the name implies, BSCC is composed micro-
scopically of two components: basaloid and squamous
F. Treatment and Prognosis cells. The basaloid cells are arranged in smooth-
PSCCs, as defined above, are uncommon and therefore contoured lobules, small clusters, and cords with fre-
no large series are available to evaluate the effectiveness quent mitoses and often prominent peripheral palisading
of various therapeutic strategies, which have ranged
from biopsy followed by radiation to surgical excision
(2). In the larynx, the prognosis is favorable and no
doubt relates to the fact that the majority of tumors are
either in situ or show only superficial invasion. Involve-
ment of regional lymph nodes is uncommon and dis-
tant metastasis is exceptional. PSCCs in other sites,
especially the sinonasal tract, may be more aggressive.
XVIII. BASALOID SQUAMOUS CELL

CARCINOMA
A. Introduction
Basaloid squamous cell carcinoma (BSCC) is an
aggressive variant of squamous cell carcinoma that
was first described in the head and neck by Wain et al.
in 1986 (1). In the upper aerodigestive tract, it occurs
primarily at the base of the tongue, hypopharynx and
supraglottic larynx but has also been found in the
palate, buccal mucosal, floor of mouth, nasopharynx,
nasal cavity, and trachea (1–13). It has also been
observed in sites below the clavicles, including the
lung, esophagus, glans penis, anus, and uterine cervix
(14–21).
Figure 81. Basaloid squamous cell carcinoma of the postcri-
B. Etiology coid area. Note the central ulceration and prominent submucosal
induration.
As with conventional squamous cell carcinoma, tobacco
and alcohol abuse are strong risk factors (2). The
Epstein-Barr virus (EBV) has been identified in three
patients from Hong Kong with BSCC of the nasophar-
ynx, but has not thus far been found in BSCC in other
sites (22). HPV, usually types 16 and 18, has also been
detected in some BSCCs, especially those of the glans
penis and anus (20,23–26). Whether EBV and HPV are
etiologically related to BSCC remains to be determined.
In the head and neck, BSCC occurs primarily in men
(82% of all cases) and patients between 27 and 88
years of age (average 63 years) (2). Symptoms vary
according to site of origin, but usually include a neck
mass, dysphagia, hoarseness, pain in the throat,
weight loss, otalgia, and/or hemoptysis.
D. Pathology
The tumors vary between 1 and 6 cm in greatest Figure 82. Basaloid squamous cell carcinoma. Smooth con-
dimension and are firm, white, or yellow-white with toured lobules with central comedonecrosis are undermining the
a characteristic gross appearance of central ulceration normal mucosa (H&E, 100).
with prominent submucosal infiltration (Fig. 81). In
156 Barnes
of nuclei (Fig. 83). The cells have scant cytoplasm and In about 5% of cases, the epithelial component will
round to ovoid nuclei that vary from vesicular to hyper- assume a spindle cell configuration, similar to that
chromatic. Nucleoli may or may not be present (Fig. 84). seen in SPCC (27,28). A case of BSCC associated with a
Small cyst-like spaces are occasionally encountered and, squamous cell carcinoma and rhabdomyosarcoma
rarely, even ductal differentiation is seen (Fig. 83). The (carcinosarcoma) has also been described (29).
spaces may be empty or contain material that resembles Although basaloid cells predominate, a definable
mucin, but stains, if at all, only weakly with periodic element of squamous cell carcinoma should be present
acid-–Schiff (PAS), Alcian blue, or mucicarmine. By to make the diagnosis with confidence. The squamous
electron microscopy, the cyst-like spaces are lined by component may be in situ or invasive and is typically
basal membranes and filled with either loose stellate well to moderately differentiated (Fig. 86). If there is
granules or replicated basal lamina (1). Central ischemic
necrosis (comedonecrosis) of the basaloid lobules is
characteristic, as well as the deposition of amorphous,
eosinophilic material between tumor cells, referred to as
hyalinosis (Fig. 85).
At times, the stroma has a myxoid appearance,
with basophilic, extracellular connective tissue mucin.
Figure 85. Basaloid squamous cell carcinoma. Cords of basa-

loid cells separated by eosinophilic hyaline material referred to as
hyalinosis (H&E, 100).
Figure 83. Basaloid squamous cell carcinoma. Smooth, con-

toured lobules of basaloid cells. Note the central necrosis,
peripheral palisading of nuclei and small cyst-like spaces
(H&E, 200).
Figure 86. Basaloid squamous cell carcinoma showing a sur-

Figure 84. Basaloid squamous cell carcinoma. Note the basa- face component of invasive squamous cell carcinoma (H&E,
loid cells with round nuclei and frequent mitoses (H&E, 400). 100).
Table 13 Immunoprofile of Basaloid Squamous Cell Carcinoma

Stain % positive
AE1/3 79–100
CK7 71
CK20 7
CAM5.2 55–86
34BE12 86–100
Epithelial membrane antigen 83–100
P63 82–100
Calretinin 45
Carcinoembryonic antigen 29–53
C-Kit 50
Thyroid transcription factor 0
S-100 protein 39–100
Vimentin 0–57
Desmin 0
Muscle specific actin 0–50
Smooth muscle actin 9
Synaptophysin 0–4
Figure 87. Low magnification of basaloid squamous cell carci-
Chromogranin 0
noma showing separate areas of basaloid (right) and squamous
Neuron specific enolase 13–75
cells (left) in the same area (H&E, 200).
p53 67–82
Source: Based on Refs. 6, 10, 18, 25, 30–37.
extensive surface ulceration, only dysplastic changes

Table 14 Basaloid Squamous Cell Carcinoma Vs. Adenoid
may be seen in the marginal, intact epithelium. Some
Cystic Carcinoma
of the basaloid islands may also exhibit squamous
differentiation and, when this occurs, the transition Features BSCC ACC
between the two components may be abrupt or show Lymph nodes + –
a zone of transition (Fig. 87). Cribriform pattern focal Often prominent
Some have observed that BSCC often exhibits a Nuclei Hyperchromatic to dark, angulated
multifocal origin from the overlying mucosa and a vesicular, round
marked tendency for perineural invasion (7,8); others Nucleoli +/– –
have not (2,15). Mitoses + +/–
Metastases to regional lymph nodes may be com- Squamous carcinoma + –
Perineural invasion Rare Frequent
posed of basaloid, squamous, or both components. In
Comedonecrosis Prominent Rare
general, the basaloid component predominates (2). Myoepithelial cellsa – +
p53 + –
E. Immunohistochemistry Ki-67 High Low
S-100 focal Diffuse
The immunoprofile and range of positivity of each C-kit +/– +
stain is given in Table 13 (6,10,18,25,30–36). P63 Diffuse, basaloid, Myoepithelial
and squamous cells only
cells
F. Electron Microscopy a
Although in our experience myoepithelial cells are usually not seen in
BSCC, a recent abstract indicates that myoepithelial cells may be seen in
Ultrastructurally, the basaloid cells contain desmosome BSCCs (37).
somes, rare tonofilaments, and free ribosomes, but Abbreviation: BSCC, basaloid squamous cell carcinoma; ACC, adenoid
few other organelles. Neurosecretory granules, myo- cystic carcinoma.
filaments, and secretory granules are absent (1).
common finding in BSCC. In addition, the larynx and
hypopharynx are relatively uncommon sites of origin
for ACC.
Because of its dual composition, it may be difficult, or
even impossible, to establish the diagnosis of BSCC on H. Treatment and Prognosis
small biopsies. For the most part, the differential
diagnosis revolves around adenoid cystic carcinoma BSCC is an aggressive tumor. Raslan et al. reviewed 90
(ACC), small cell neuroendocrine carcinoma patients and observed that 64% had positive cervical
(SCNEC) and adenosquamous carcinoma (ASC). Fea- lymph nodes and 44% distant metastases (lungs, liver,
tures that are helpful in distinguishing ACC and bones, brain, and skin) sometime during the course of
SCNEC from BSCC are shown in Tables 14 and 15. their disease (2). Thirty-eight percent of the patients
Clinical features are also potentially helpful in sepa- died of disease at a median follow-up of 17 months.
rating BSCC from ACC. ACCs are rarely associated Whether BSCC is more aggressive than conven-
with positive cervical lymph nodes, whereas this is a tional squamous cell carcinoma is controversial
158 Barnes
Table 15 Basaloid Squamous Cell Carcinoma Vs. Small Cell Gerughty et al. in 1968 (1). Originally thought to be
Neuroendocrine Carcinoma a type of salivary tumor, it is now established that this
is a distinct variant of squamous carcinoma character-
Feature BSCC SCNEC
ized by a dual composition of both squamous and
Growth lobular diffuse glandular components (2–7).
Spindle cells – +
Nuclear molding – +
Nucleoli +/– –
B. Etiology
Hyalinosis + – As in conventional squamous cell carcinomas, alcohol
Stromal mucin + –
and tobacco abuse appear to be important risk factors
Cyst-like areas + –
Peripheral palisading + –
for ASC. Siar and Ng have also described a case that
In situ or invasive squamous cell + – may have been related to prior radiation exposure (8).
carcinoma
Synaptophysin, chromogranin, or Leu-7 – +/– C. Clinical Features
34BE12 (keratin) + –
Thyroid transcription factor – +/– ASC is more common in males by a ratio of 4:1 and
Inclusion body-cytokeratin positivity – +/– occurs over a broad age (34–81 years) with an average of
Neurosecretory granules on EM – +/– 61 years (6). The larynx is the most common site,
Abbreviations: EM, electron microscopy; BSCC, basaloid squamous cell accounting for 45% of all cases in the upper aerodigestive
carcinoma; SCNEC, small cell neuroendocrine carcinoma. tract. In a review of 26 tumors of the larynx, Keelawat et
al. noted that 46% were supraglottic, 19% transglottic,
(8,9,11–13). The general consensus, however, is that 15% glottic, 4% subglottic and in 15% the site was
when the two tumors are matched for anatomic site, unknown (6). Symptoms vary according to site, but
stage, and treatment the prognosis is similar. usually include airway compromise, hoarseness, sensa-
Surgery with regional lymphadenectomy and tion of a foreign body in the throat, and/or dysphagia.
postoperative radiation is the treatment of choice.
Because of the high incidence of distant metastases, D. Pathology
adjuvant chemotherapy may also be warranted. The tumors are grossly indistinguishable from ordi-
Whether or not determination of the DNA con- nary squamous cell carcinoma and range from 1 to
tent of the tumor offers prognostic significance is 6.5 cm. Each is composed of squamous and glandular
controversial. Luna et al. studied nine BSCCs and foci in varying proportions, with the former usually
found that five were aneuploid and four were diploid. predominating. The squamous carcinoma is seen most
Three of the four patients with diploid carcinomas often in the central part of the tumor originating from
died with distant metastases from 11 to 20 months a dysplastic mucosa that may be either intact or
after diagnosis whereas two of the five with aneuploid ulcerated. The adenocarcinoma, in turn, is most
tumors died of their disease at 36 and 43 months (8). often observed in the deeper part of the tumor.
They concluded that patients with aneuploid BSCC The two carcinomas range from well to poorly
had a better mean survival time (39.5 months) than differentiated and are typically separate and distinct but
those with diploid tumors (16.3 months). Raslan et al. occasionally intermingled (Fig. 88). A mucicarmine
studied 10 BSCC and found 6 to be diploid and
4 aneuploid (2). They concluded that tumor ploidy,
as determined by flow cytometry, provided no addi-
tional prognostic information beyond that supplied by
routing histological evaluation.
Seidman et al. indicate that BSCC may be associ-
ated with a high incidence of second primary tumors,
particularly in the upper gastrointestinal tract and
larynx (38). Of six patients with BSCC that had addi-
tional primary tumors reviewed by Raslan et al., the
second tumor was found in the distal esophagus
(small cell carcinoma), soft palate (squamous cell
carcinoma), left arytenoid (squamous cell carcinoma),
nasopharynx (nasopharyngeal carcinoma), and pros-
tate and colon (one patient had adenocarcinoma in
both of these sites (2,3,6,39). The sixth patient had
chronic lymphocytic leukemia (6).
XIX. ADENOSQUAMOUS CARCINOMA

A. Introduction Figure 88. Adenosquamous carcinoma. Note the squamous
ASC is an uncommon, aggressive malignant tumor component in the upper right corner (H&E, 100).
that was first described in the head and neck by
stain shows, in most cases, luminal and intracellular seen at all, are an integral component of the basaloid
mucus in the glandular component while keratin pearls component.
and dyskeratotic cells may be seen in the squamous Conventional squamous cell carcinoma invading
areas. Perineural invasion is also quite common. and/or entrapping nontumorous mucoserous glands
Metastases are frequent and, while either compo- may also be confused with ASC, especially on small
nent may disseminate either alone or in combination, biopsies. Retention of the normal lobular architecture
the squamous carcinoma is usually dominant (6). of the mucoserous glands and the lack of any signifi-
cant cytologic atypia of the glands should always
suggest this possibility. Moreover, in true ASC one
E. Immunohistochemistry should see, if the specimen is large enough, one or
The adenocarcinoma is positive for CEA (92% of cases), more separate foci of unequivocal adenocarcinoma.
CK7 (75%), and CAM 5.2 (58%) while the squamous
carcinoma is either negative or focally reactive for these
markers (7). The high molecular weight cytokeratin G. Treatment and Prognosis
34BE12 is positive in both and CK20 negative. Most Treatment varies according to site and stage of dis-
are also aneuploid and positive for p53 (7). ease, but usually necessitates some form of laryngec-
tomy and neck dissection and possible supplemental
F. Differential Diagnosis radiation (6,10). In a review of 58 ASCs from all sites
in the head and neck, Keelawat et al. observed that
Because of its biphasic character the diagnosis of ASC 47% of patients experienced local recurrences, 65%
may not be apparent on small biopsies. Often the developed lymph node metastases and 23% had dis-
diagnosis can only be established after the entire tant dissemination (especially to the lung), with a
lesion has been resected and thoroughly evaluated 5-year determinant survival rate of 13% (6). If only
microscopically. The differential diagnosis includes ASCs of the larynx are considered, Fujino et al. in a
mucoepidermoid carcinoma, acantholytic (pseudo- review of 20 cases, observed that at presentation 25%
glandular) squamous cell carcinoma, basaloid squa- of patients had cervical lymph node involvement and
mous cell carcinoma, and conventional squamous cell 5% distant metastases. Following treatment, 55% of
carcinoma infiltrating nontumorous salivary and/or the patients experiences local recurrences and another
mucoserous glands. 15% developed systematic metastases. The 5-year
The distinction between ASC and mucoepider- survival rate was only 22% (4).
moid carcinoma (MEC) is more than academic. The
5-year survival rate for ASC is 13% to 20% compared
with 92%, 63%, and 27%, respectively, for low-, inter-
XX. ACANTHOLYTIC SQUAMOUS
mediate-, and high-grade MEC (9). ASC, as previously
CELL CARCINOMA
described, contains separate areas of adenocarcinoma
and squamous cell carcinoma as well as foci were the A. Introduction
two components commingle and also exhibits dys-
plastic-carcinomatous changes in the overlying sur- Acantholytic squamous cell carcinoma (ALSCC) is the
face (mucosal) epithelium. In contrast, the glandular term sanctioned by the World Health Organization to
and squamous elements in MEC are typically insepa- described an uncommon variant of squamous cell
rable, and there are no abnormalities of the surface carcinoma characterized by acantholysis of tumor
epithelium. Nuclear pleomorphism, high mitotic cells creating a false appearance of glandular differen-
activity, necrosis, dyskeratotic cells, and keratin pearls tiation (1). Adenoid squamous cell carcinoma is a
are common in ASC but rarely seen in MEC. MEC, in popular synonym but its usage often results in confu-
turn, often contains multiple cell types, including sion with adenosquamous carcinoma. Other terms
mucous, intermediate, clear, and epidermoid cells. that have been used to described this tumor include
As a result of acantholysis, spaces are created in pseudoglandular squamous cell carcinoma, squamous
acantholytic squamous cell carcinoma that be mistak- cell carcinoma with gland-like features, adenoacan-
en for true glands and thus cause confusion with ASC. thoma, and pseudovascular squamous cell carcinoma.
In contrast to ASC, the gland-like spaces in acantho- The tumor most often occurs on the sun-exposed
lytic squamous cell carcinoma are negative for mucin skin of the head and neck, including the vermilion
and carcinoembryonic antigen. border of the lips. Other than the lips, mucosal sites of
Basaloid squamous cell carcinoma (BSCC) may origin are exceptional and have included the tongue,
also be confused with ASC. Both neoplasms exhibit gingiva, floor of mouth, nasopharynx, hypopharynx
areas of squamous differentiation and duct formation and larynx (2–12).
and contain small cysts filled with material staining
positive with PAS and/or Alcian blue. However, in B. Etiology
BSCC the tumor is composed of large, round, solid
clusters of basaloid cells often with central comedo- Prolonged sun exposure appears to be an important
necrosis. Such areas are not seen in ASC. Also unlike etiologic factor for those tumors involving the skin
ASC, which contains separate foci of adenocarcinoma and lips, while prior radiation exposure might have a
and squamous cell carcinoma, the ducts in BSCC, if role in the origin of some mucosal lesions (4,5). As in
160 Barnes
conventional mucosal squamous carcinoma, smoking ‘‘Differential Diagnosis’’ under Adenosquamous Car-
and alcohol abuse are also likely contributors. cinoma above). The pseudovascular ALSCC can be
distinguished from an angiosarcoma by immunohis-
tochemistry. Pseudovascular ALSCC is positive for
C. Clinical Features cytokeratin and negative for vascular markers (3).
ALSCCs are more common in males and typically
occur in patients 40 to 70 years of age.
D. Pathology There are no large series of ALSCCs of the larynx for

evaluation. In fact, the largest series of mucosal
The tumors may be nodular, exophytic or indurated, ALSCCs deal primarily with those of the lip (8,12).
often with an ulcerative or ‘‘keratotic’’ surface. They In a review of 26 cases (21 lip, 2 tongue, 1 maxillary
rarely exceed four centimeters. gingiva, 1 floor of mouth and 1 unnamed site), Jones et
The acantholysis is commonly seen as a focal al. observed that 11.5% of patients had died of disease,
change in a background of conventional squamous 77% were free of disease at follow-up ranging from 2
cell carcinoma but in a few instances, the entire tumor to 72 months and 11.5% had no follow-up. All three of
may show this feature. The acantholysis results in the patients who died of disease had tumors involving
tumor nests with a gland-like appearance lined by the tongue and gingiva. Until proven otherwise, we
one or more layers of squamous cells (Fig. 89). The recommend that all patients with mucosal ALSCCs be
spaces may appear empty, contain acantholytic or treated according to guidelines used in the manage-
dyskeratosis cells, or cellular debris. Clear or spindle ment of similarly staged conventional squamous cell
cells may also be observed. The stroma is often carcinomas.
desmoplastic and inflamed. At times, the acantholysis
may create anastomosing spaces and channels mim-
icking an angiosarcoma (3). XXI. LYMPHOEPITHELIAL CARCINOMA
The gland-like areas are devoid of both luminal
and intracellular mucin and by electron microscopy
A. Introduction
exhibit hemidesmosomes and tonofilaments but no Tumors morphologically similar to the undifferen-
glandular features thus supporting the squamous tiated type of nasopharyngeal carcinoma can, in rare
derivation (5,10) instances, occur in the larynx and hypopharynx. Such
tumors have been referred to as lymphoepithelial
E. Differential Diagnosis carcinoma, lymphoepithelial-like carcinoma, lym-
phoepithelioma, undifferentiated carcinoma with
The differential diagnosis includes adenosquamous lymphoid stroma, and undifferentiated carcinoma of
carcinoma, mucoepidermoid carcinoma and, possibly, nasopharyngeal type. Of these various terms, lym-
angiosarcoma. Features important is separating the phoepithelial carcinoma (LEC) has emerged as the
first two tumors have already been covered (see most preferred (1).
Lymphoepithelial carcinoma of the larynx and
hypopharynx is an extremely rare neoplasm. Ferlito
identified only 1 case (0.05%) among 2052 malignant
neoplasms of the larynx and hypopharynx on file at
the University of Padua, and Micheau et al. observed
only 3 LECs (0.2%) among 1350 laryngeal carcinomas
at the Institut Gustave-Roussy (2,3).
B. Etiology
Although the undifferentiated type of nasopharyngeal
carcinoma is characteristically associated with the
Epstein-Barr virus (EBV), LEC of the larynx and
hypopharynx is only infrequently associated with
this virus. In a review of 16 cases that were specifically
evaluated for the presence of EBV, only 4 (25%) were
positive (4).
Some patients have also been heavy smokers
and/or consumers of alcoholic beverages. These may
be additional risk factors.
Figure 89. Acantholytic squamous cell carcinoma. Acantholy-

sis of tumor cells creates a pseudoglandular appearance (H&E,
200). LEC of the larynx and hypopharynx occurs in patients
averaging 62 years of age (range 40–82) and is 3 to 6
times more common in men (4,5). In a review of 23 disease after a mean interval of 32 months (range 9–75
cases, MacMillan et al. noted that 52% arose in the months) (4,5).
larynx, 43% in the pyriform sinus, and 4% in the The frequent occurrence of distant metastases
trachea (5). Of those occurring in the larynx, two- would seem to warrant consideration of adjuvant
thirds were of supraglottic origin. chemotherapy.
The most common presenting manifestations are
hoarseness, followed by a neck mass, sore throat,
dysphagia and episodic hemoptysis. XXII. GIANT CELL CARCINOMA
A. Introduction
D. Pathology
Giant cell carcinoma (GCC) of the larynx has been
The tumors have ranged in size from 0.8 to 4.5 cm defined by World Health Organization (WHO) as ‘‘an
(mean 2.5 cm) and are histologically identical with the undifferentiated carcinoma containing many bizarre
undifferentiated type of nasopharyngeal carcinoma. multinucleated cells. The tumor cells have abundant
As such, they are composed of single, small aggre- eosinophilic cytoplasm that may contain neutrophil
gates, or large syncytial masses of cells associated with leukocytes or cell debris. There is no evidence of
a prominent component of lymphocytes. The tumor squamous or glandular differentiation by light micros-
cells have large, round, vesicular nuclei and promi- copy’’ (1). Therefore, it is, morphologically identical
nent nucleoli and, on immunostaining, are positive for with the giant cell carcinoma of the lung (2–5).
cytokeratin (Fig. 90). In some instances, the tumor cells
may show focal, rather abrupt, squamous differentia-
tion or keratinization. In about half the cases, there is a B. Clinical Features
component of squamous cell carcinoma that accounts Giant cell carcinomas of the larynx are exceptionally
for 10% to 75% of the entire tumor. The overlying rare neoplasms. Ferlito et al. identified only four cases
epithelium may show carcinoma-in situ (5). among a very large series of laryngeal carcinomas on
file at the University of Padua (6). These tumors
E. Treatment and Prognosis occurred in four men, aged 56 to 64 years. All were
smokers, predominantly of cigarettes, and three con-
Treatment has ranged from biopsy and subsequent sumed alcoholic beverages in moderation. Dyspnea
radiation to some form of laryngectomy or pharyng- and dysphagia were the most common presenting
ectomy and neck dissection. Approximately 75% of symptoms.
patients either have or will develop positive cervical The tumors occurred in all areas of the larynx,
lymph nodes and 25% to 30% will experience distant with no specific preferential site. One was subglottic,
metastases (lung, liver, bone, skin and mediastinal one involved the right vocal cord and ventricle, one
and retroperitoneal lymph nodes (4,5). Local recur- encompassed the vocal cords and subglottis, and one
rence following initial therapy has been recorded in originated in the area of the epiglottis and aryepiglottic
10% of patients, and at least 25% to 30% have died of fold.
C. Pathology
The tumors are grossly indistinguishable from ordinary
squamous cell carcinoma. They have ranged in size
from a ‘‘small plum’’ to 2.0 cm and, on cross section, are
usually white, hemorrhagic, and necrotic (6).
The histological hallmark of the tumor is the
presence of numerous, noncohesive, bizarre giant
cells that contain prominent, frequently multiple,
nuclei. The cytoplasm is abundant, eosinophilic,
sometimes vacuolated, and often contains neutrophils,
or cellular debris. The vacuoles may or may not stain
for mucin. The tumor, in addition, contains a back-
ground population of smaller anaplastic tumor cells,
red blood cells, neutrophils, and frequent abnormal
mitotic figures. The cells are positive for cytokeratin
and, occasionally, carcinoembryonic antigen (5).
The GCC may exist in a pure (as just described) or
mixed form, the latter in association with a squamous
Figure 90. Lymphoepithelial carcinoma of the larynx. Syncytial cell carcinoma, adenocarcinoma, or SPCC. Because of
arrangement of tumor cells composed of round, clear nuclei, these mixed forms, some have questioned whether
prominent nucleoli, and sparse cytoplasm. Lymphocytes perme- GCC is indeed a specific entity and have proposed, at
ate the tumor (H&E, 400). least in the lung, that such mixed tumors should be
designated as ‘‘pleomorphic carcinomas’’ (4).
162 Barnes
D. Electron Microscopy Table 16 Classification of Neuroendocrine Tumors of the

Larynx
Ultrastructurally, GCC are characterized by abundant
mitochondria, concentric whirls of tonofilament-like Terminology Synonyms
fibrils, aggregates of centrioles, occasional basement 1. Typical carcinoid Carcinoid, well-differentiated
membranes, and cellular junctions (2). Ultrastructural (Grade I) neuroendocrine
studies further indicate that the neutrophils seen in carcinoma
the cytoplasm of the giant cells enter the cells by 2. Atypical carcinoid Malignant carcinoid, moderately
emperipolesis, rather than by phagocytosis (2). differentiated (Grade II)
neuroendocrine carcinoma
E. Differential Diagnosis 3. Small cell neuroendocrine Small cell carcinoma

carcinoma neuroendocrine type, poorly
The differential diagnosis includes squamous cell differentiated (Grade III)
carcinoma and adenocarcinoma with foci of giant neuroendocrine carcinoma,
cells, SPCC, rhabdomyosarcoma, giant cell tumor, oat cell carcinoma, small cell
and malignant fibrous histiocytoma. carcinoma, anaplastic small
If one rigorously applies the WHO definition for cell carcinoma, small cell
GCC, the presence of any squamous or glandular undifferentiated carcinoma
differentiation is sufficient to exclude its diagnosis. 4. Large cell neuroendocrine Poorly differentiated (Grade III)
Others, however, indicate that the quantity of giant carcinoma neuroendocrine carcinoma
cells in the tumor is important. To qualify as a GCC, 5. Combined neuroendocrine Composite small cell
carcinoma (small cell carcinoma, composite
various authors state that the giant cells must compose
neuroendocrine neuroendocrine carcinoma
10,30,40, or even 55% of the total volume of the tumor carcinoma with
(4,5,7). Normally, if giant cells are seen at all in squa- squamous cell
mous cell carcinoma or adenocarcinoma, they are only carcinoma of
focally prominent and not spread diffusely throughout adenocarcinoma)
the tumor. The presence of neutrophils in the cytoplasm 6. Paraganglioma Non-chromaffin paraganglioma,
of the giant cells should also suggest a GCC. A. Benign glomus tumor
SPCC of the larynx may occasionally contain giant B. Malignant
cells and express cytokeratin positivity. It can, however,
be distinguished from GCC by the lack of extensive
giant cells throughout the lesion, and the absence of
confusing, have been applied to these tumors. For
neutrophils within the cytoplasm of the giant cells.
consistency, we have basically adopted the nomencla-
GCC can be differentiated from rhabdomyosar-
ture proposed by the World Health Organization for
coma by the lack of cross-striations and the use of
those of the lung and larynx (Table 16) (1,2). The more
immunostains for myoglobin or desmin. Giant cell
common synonyms are also listed.
tumors, similar to those of bone, can also occur in
As a group, they are uncommon in the larynx
the larynx (8). They are, however, easily separated
with only about 500 cases recorded in the literature as
from GCC by their lack of pleomorphism and that, in
of 1998 (3). The atypical carcinoid is the most frequent,
contrast to GCC, they are negative for cytokeratin.
constituting 54% of neuroendocrine tumors of the
Malignant fibrous histiocytoma, likewise, is also neg-
larynx, followed by small cell neuroendocrine carci-
ative for cytokeratin.
noma (34%), paraganglioma (9%) and typical carci-
noid (3%) (3–7).
F. Treatment and Prognosis Cells histochemically similar to, if not identical
with, Kultschitzky cells of the bronchi have been iden-
Of the four patients with GCC of the larynx reported tified in the larynx (8,9). These, as well as pleuripoten-
by Ferlito et al., three developed metastases to cervical tial, endodermal stem cells, are the putative cells of
lymph nodes and three died of their disease 4, 6, and origin for the carcinoid, atypical carcinoid, and small
13 months post therapy (6). The fourth patient was cell neuroendocrine carcinoma (6,10). Paragangliomas
reported to be alive and well six years later. of the larynx, in turn, are thought to arise from para-
The propensity for cervical lymph nodes metas- ganglionic tissue normally found in the larynx (7).
tases suggests the need for either a partial or total
laryngectomy and some form of neck dissection. The
role of irradiation and chemotherapy remains largely B. Typical Carcinoid
untested.
Clinical Features
The typical carcinoid (TC) is the least common of the
XXIII. NEUROENDOCRINE TUMORS neuroendocrine tumors of the larynx with only 42 cases
A. Introduction recorded as of 2004 (11). They are three to nine times
more common in men and occur in patients averaging
Neuroendocrine tumors of the larynx are a heteroge- about 58 to 64 years of age (range 45–80) (4–11). Most
neous group of neoplasms that range from rather (83%) occur in the supraglottic larynx in the vicinity of
bland to highly malignant. Numerous terms, some the aryepiglottic fold, arytenoids or false vocal cord.
Figure 91. Supraglottic laryngectomy specimen opened posteri-

orly revealing a submucosal, hemorrhagic, typical carcinoid of the Figure 93. Typical carcinoid composed of small cells with
left aryepiglottic fold (arrow). Source: From Sec. XXIII, Ref. 12. uniform, round nuclei. Note the absence of nucleoli, mitoses,
and necrosis. Compare with Figure 97. (H&E, 400).
Symptoms, ranging from three weeks to four years in

duration, include dysphagia, hoarseness, and sore are not seen (1,2,10,12). The stroma is highly vascular
throat. Smoking appears to be a risk factor. and, often, focally fibrotic or hyalinized.
In a few instances, carcinoids, either typical or
Pathology atypical, may appear either oncocytic or oncocytoid
The TCs range from 0.5 to 3 cm (average 1.6 cm) in (13,14). Such tumors have abundant eosinophilic cyto-
greatest dimension and present as submucosal nod- plasm and neurosecretory granules. The distinction
ules or polypoid masses (4) (Fig. 91). Microscopically, between these two lesions depends on the presence
they are composed of small uniform cells that grow in (oncocytic) or absence (oncocytoid) of mitochondrial
cords, small nests, large sheets, glands, or pseudoro- hyperplasia on ultrastructural examination. A few may
settes (Fig. 92). The cells have cytoplasm that varies even contain mucin and, exceptionally, even amyloid.
from clear to eosinophilic. The nuclei are usually
round, occasionally spindled, and have finely stippled Immunohistochemistry
or dense chromatin (Figs. 93 and 94). Nucleoli and TCs are positive for cytokeratin, epithelial membrane
mitoses are sparse to absent (less than 2 mitoses per 10 antigen, carcinoembryonic antigen, synaptophysin,
high power fields), and necrosis and pleomorphism chromogranin, neuron specific enolase, and protein
Figure 94. Typical carcinoid with focus of spindle cells. There is

Figure 92. Figure 92 Typical carcinoid composed of small no nuclear molding or mitotic activity. Compare with Figure 99.
cords and clusters of cells (H&E, 100). (H&E, 400).
164 Barnes
gene product 9.5. They are also variably positive for a

variety of peptides, including serotonin, calcitonin,
bombesin, and somatostatin.
Electron Microscopy
TCs contain abundant membrane-bound, electron-
dense neurosecretory granules varying in size from
90 to 230 nm (10). Cell junctional complexes are
observed as well as numerous mitochondria if the
TC is of the oncocytic type.
Differential Diagnosis
See under ‘‘Atypical Carcinoid’’
Treatment and Prognosis

Because radiation and chemotherapy are largely inef-
Figure 95. Polypoid atypical carcinoid arising from the epiglottis.
fective, surgery is the treatment of choice (15). The
extent of resection should be as conservative as possi-
ble as long as complete removal is achieved. A neck
dissection is not warranted. simultaneous neuroendocrine carcinoma of the pan-
In a review of 12 patients with TCs of the larynx, creas (21).
El-Naggar and Batsakis observed that 4 subsequently
developed distant metastasis (liver, bones). At least Pathology
one patient developed the carcinoid syndrome and
another died of disease five years after treatment (4). ACs are infiltrative tumors that grow in a variety of
Although this data suggest that TCs of the larynx are patterns, including small nests, sheets, cords or tra-
more aggressive than those of the lung, the sample beculae, glands, rosettes, or a combination of these
size is very small and may not be statistically signifi- (Fig. 96). Cysts with intracystic papillary projections of
cant. It is also possible that some of these tumors on tumor cells are also not uncommon. The ACs are
critical review utilizing current criteria might best be distinguished from typical carcinomas by the presence
classified as atypical carcinoids. of larger cells, prominence of nucleoli, occasional
mitoses (up to 10/10 high power fields), necrosis,
pleomorphism, and/or vascular and perineural inva-
C. Atypical Carcinoid sion (Fig. 97).
Wenig et al. observed that 91% of their tumors
Clinical Features displayed intracytoplasmic or intraluminal PAS-
The atypical carcinoid (AC) was first described in the positive, diastase-resistant granules, and that 17%
larynx by Goldman et al. in 1969 (16). It is the most were mucicarmine-positive (22). Amyloid, although
frequent neuroendocrine tumor of the larynx, being 5 to described, is uncommon in our experience.
15 times more common that the typical carcinoid (5,11).
At the time of diagnosis, patients with ACs have
ranged from 20 to 83 years of age (average 61 years),
and the majority (74%) have been men (5,17).
As with typical carcinoids, ACs arise primarily
in the supraglottic larynx (96% of all cases), usually in
the region of the aryepiglottic fold, arytenoid, or false
vocal cord (5). They present as tan, gray, or hemor-
rhagic, 0.2- to 4.0-cm (average 1.6-cm) submucosal or
polypoid growths, with or without surface ulceration
(Fig. 95). Hoarseness and dysphagia are the usual
presenting symptoms. Approximately one-fifth of
patients also experience pain in the throat, and most
have a history of smoking.
An associated paraneoplastic syndrome is excep-
tional (15,18). A rare case has also been associated
with elevated levels of serum calcitonin (19,20).
The occurrence of multiple synchronous neuro-
endocrine tumors in the same patient is distinctly
uncommon. Laccourreye et al. document such a case Figure 96. Atypical carcinoid composed of clusters of cells.
in a 48-year-old man who had an AC of the left false Note the rosettes in the upper left hand corner (H&E, 200).
vocal cord—arytenoid cartilage area associated with a
carcinoma of thyroid (MCT). For many years AC has

been mistaken, especially on small biopsies, for LPG,
which has accounted for the erroneous impression that
up to 25% of all LPGs are malignant (7,10,23). The
distinction is important for obvious reasons: ACs are
often aggressive tumors, whereas LPGs are almost
always benign. These two can easily be separated on
the basis of any one of three immunostains: ACs are
positive for keratin, carcinoembryonic antigen (CEA),
and calcitonin, whereas LPGs are negative for these
stains (see Table 17) (7,24).
In some instances, ACs may be difficult to sepa-
rate from MCT, especially when dealing with meta-
static lesions (19,23,25,26). This is not unexpected
because both tumors are usually positive on immu-
nostaining for synaptophysin, calcitonin, CEA, and
occasionally, even for serotonin. Clinical and radio-
logic studies to detect the presence or absence of a
mass in the larynx or thyroid can be very helpful in
Figure 97. Atypical carcinoid. Note that the cells are larger than resolving this dilemma. Although the serum calcito-
those seen in a typical carcinoid (compare with Fig. 93). Mitoses nin level is almost invariably elevated in metastatic
are frequent (arrow) and some cells contain nucleoli (H&E, 400). MCT and usually negative in AC, Sweeney et al. and
Smets et al. have reported two cases of laryngeal AC
associated with elevated levels of serum calcitonin
Immunohistochemistry (19,20). Reliance on this test to distinguish between
these two tumors is, therefore, not absolute. Knowl-
According to Woodruff and Senie, 100% of ACs are edge of the serum CEA, however, may be helpful.
positive for synaptophysin, 96% for cytokeratin, 94% This test is almost universally elevated in metastatic
for chromogranin, 80% for calcitonin, 75% for carci- MCT, but thus far, has not been reported in associa-
noembryonic antigen, and 21% for serotonin (5). tion with AC (24,25). Staining for amyloid may offer
some supportive evidence for MCT. Although amy-
Electron Microscopy loid has been described in AC, it is uncommon in our
Neurosecretory granules ranging from 70 to 420 nm experience, but found in 75% to 80% of MCT. It has
are common, but they are less abundant than in been suggested that thyroid transcription factor (TTF)
typical carcinoids (10). may be used to separate the AC from MCT, it being
diffusely and strongly positive in medullary carcinoma
and negative or, at most, only focally weakly positive in
AC. Subsequent experience, however, has shown sig-
As previously indicated, ACs are distinguished from nificant variation in the expression of TTF in AC and,
typical carcinoids by the presence of larger cells, prom- accordingly, TTF may not be as important a discrimi-
inence of nucleoli, occasional mitoses (up to 10 per 10 nator as initially thought.
high power fields), necrosis, pleomorphism, and vascu-
lar and perineural invasion. Other tumors that are often Treatment and Prognosis
confused with AC and the immunohistochemical stains
that can be used to separate them are shown in In a review of 127 ACs of the larynx, Woodruff and
Table 17. Two that deserve special attention are Senie found metastases to cervical lymph nodes in
the laryngeal paraganglioma (LPG) and medullary 43%, to skin and subcutaneous tissue in 22%, and to
Table 17 Differential Diagnosis of Laryngeal Tumorsa

Medullary
carcinoma of Renal cell
Stain Carcinoid tumorb Paraganglioma thyroid Hemangiopericytoma Melanoma carcinoma
Keratin þ – þ – – þ
CEA þ – þ – – –
Synaptophysin þ þ þ – – –
Calcitonin +/– – þ – – –
Thyroid transcription factor +/– – þ – – –
Tyrosinase – – – – þ –
Renal cell carcinoma antigen – – – – – þ
Congo red –c – þ – – –
a
Typical staining pattern; variations may occur.
b
Includes typical and atypical carcinoids.
c
Although amyloid may be found in carcinoids, most are negative.
166 Barnes
other distant sites in 44% (particularly lungs, liver,

and bones) (5). The 5- and 10-year cumulative survival
rates were, respectively, 48% and 33%. Survival was
particularly worse among patients who developed
cutaneous-subcutaneous metastases. Because most
ACs of the larynx are aneuploid, determination of
DNA ploidy does not offer any additional prognostic
information (29).
Similar to typical carcinoids, ACs are also rela-
tively resistant to irradiation and chemotherapy (15).
Surgery, therefore, is the mainstay of treatment. The
extent of surgical excision depends on the size and
location of the tumor, but usually requires a partial or
total laryngectomy. Because of the high incidence of
cervical lymph node involvement, a neck dissection,
even when the lymph nodes are clinically negative, is
warranted.
D. Small Cell Neuroendocrine Carcinoma

Clinical Features
Small cell neuroendocrine carcinoma (SCNEC) of the
larynx was first described by Olofsson and van Nos-
trand in 1971 (30). Although it is the second most
common neuroendocrine tumor of the larynx, it is still Figure 98. Ulcerated small cell neuroendocrine carcinoma.
an infrequent neoplasm representing only 0.5% of all
laryngeal carcinomas (6).
SCNEC of the lung, on the other hand, is a
common tumor. Because the larynx is, in part,
embryologically related to the lungs, it is not surpris-
ing that the tumor could also arise de novo in the
larynx. The apparent rarity of SCNEC in this site and
the length of time it has taken to recognize it as such is
remarkable. In all likelihood, the tumor has gone
unrecognized and probably has been mislabeled as a
poorly differentiated squamous cell carcinoma or as
an anaplastic carcinoma.
In the larynx, the tumor is more common in men
by a ratio of 3:1, with an age range of 23 to 91 years (6).
Only 3% occur in patients younger than 40 years of
age. Hoarseness and dysphagia, often associated with
painless cervical lymph node metastases, are the most
common symptoms. Most are heavy smokers.
Pathology
Figure 99. Small cell neuroendocrine carcinoma composed of
Although SCNEC can occur anywhere in the larynx, cells with poorly defined cytoplasm and spindled hyperchromatic
the majority are of supraglottic origin. The tumors are nuclei. Note the nuclear molding and mitoses (arrow).Compare
often ulcerated and, as a consequence, there are no with Fig. 94.
gross characteristics that distinguish it from ordinary
squamous cell carcinoma (Fig. 98).
In the past, SCNECs were often divided micro-
scopically into three types—oat cell (composed of
spindle cells), intermediate (composed of round common, as well as nuclear molding and DNA coat-
cells) and combined (composed of both spindle and ing (‘‘hematoxyphilia’’) of the walls of blood vessels.
round cells). This classification has no prognostic Rare rosette formation may also be seen. The mucosa
significance and is now largely abandoned. is often ulcerated, but the marginal epithelium is free
The tumor grows in the submucosa as sheets or of significant dysplasia or in situ carcinoma.
ribbons of closely packed cells, with indistinct cyto- In a few instances, SCNEC may also contain foci
plasm and round, oval, or spindled, hyperchromatic of squamous cell carcinoma, adenosquamous, or even
nuclei without nucleoli (Fig. 99). Mitoses, necrosis, rhabdomyosarcoma (see ‘‘combined SCNEC’’ below)
and lymphatic, vascular, and perineural invasion are (2,31).
Immunohistochemistry and have usually been included under the category of

ACs (1,2,38–40). Microscopically these tumors are
SCNEC is usually positive for AE1/3, synaptophysin, characterized by large cells (generally 3 times the
CD56, and TTF and negative for p63. size of the nucleus of a resting lymphocyte) with
Electron Microscopy moderate amounts of cytoplasm, prominent nucleoli,
more than 10 mitoses per 10 high power fields,
Membrane-bound, electron-dense neurosecretory frequent necrosis, and positive staining with neuroen-
granules ranging from 50 to 200 nm are scant com- docrine markers.
pared with the typical and atypical carcinoid (10). To date, no large series of LCNECs of the larynx,
as defined above, have been described and therefore the
Differential Diagnosis clinicopathologic features and prognosis in this site are
The differential diagnosis includes TC, AC, BSCC, unknown. Although in the lung it has been stated that
malignant lymphoma, and a metastasis from a primary there is no difference in prognosis between SCNECs
SCNEC of the lungs. Compared with TC and AC, and LCNECs when stratified by stage, the overall five-
SCNEC is composed primarily of short spindle cells year survival rates for LCNECs has ranged from 13% to
without nucleoli and exhibits more nuclear molding, 47% (1,41). Therapy for LCNEC is not standardized and
necrosis, and mitoses. In addition, SCNEC is variably has varied from the use of protocols used to treat
positive for TTF and negative for CEA and calcitonin SCNEC to surgical excision (42).
while the AC is positive for CEA and calcitonin and
variably positive for TTF (28). F. Combined Small Cell Neuroendocrine
BSCC is a biphasic tumor composed of basaloid Carcinoma
and squamous cell components that characteristically
grow in a lobular pattern with central comedonecro- SCNEC associated with a squamous or adenocarcino-
sis. In addition BSCC often exhibits prominent vesic- matous component are referred to as combined or
ular to hyperchromatic nuclei, nucleoli, cyst-like areas composite carcinomas. They are unusual representing
and hyalinosis (Table 15). BSCC is also negative for less than 10% of all SCNECs of the larynx. Only 14
neuroendocrine markers and TTF. Malignant lympho- cases have been described as of 2004 (43). Most, if not
mas are positive for leukocytic common antigen and all, were associated with a squamous cell carcinoma,
negative for neuroendocrine markers. A metastasis either in situ or invasive. The patients were all men
from a primary SCNEC of the lung is based on with an age range of 41 to 83 years (median 55 years),
negative imaging studies of the lung. and all had a significant smoking history. The over-
whelming majority had supraglottic tumors and none
Treatment and Prognosis was associated with a paraneoplastic syndrome. The
tumors are aggressive with a behavior similar to
The clinical course of SCNEC of the larynx is aggres- ‘‘pure’’ SCNEC and death from disease usually within
sive, with early regional and distant metastases. two years of diagnosis (43).
Almost half of patients present with positive cervical
lymph nodes and about 60% to 90% will develop
distant dissemination, especially to the lungs, liver, G. Paraganglioma
and bones (30,33). In contrast to SCNEC of the lung,
only 8% of SCNECs of the larynx metastasize to the Paragangliomas of the larynx are discussed in chapter 12.
central nervous system and then only as a preterminal
event (33). The two- and five-year survival rates are,
respectively, 16 and 5% (6). XXIV. SALIVARY GLAND-TYPE NEOPLASMS
Because most patients have disseminated dis- OF THE LARYNX
ease at diagnosis, radical surgery (laryngectomy
with neck dissection) is rarely indicated. Instead, a
A. Introduction
therapeutic protocol using a combination of local Although mucoserous glands are sparse to absent in
irradiation and chemotherapy, similar to that in pul- the glottis, they are rather prominent in the supra-
monary SCNEC, is advocated (15). Because of early glottis and subglottis. Yet, paradoxically, salivary-type
intralesional angiolymphatic invasion, survival does neoplasms are uncommon, constituting no more than
not necessarily correlate with the size of the tumor. 1% of all laryngeal neoplasms (1,2). Because of their
A few laryngeal SCNECs have been associated rarity, no single institution has accumulated a large
with hormonally active paraneoplastic syndromes. series; therefore, details of their clinical and patholog-
Among these are included the Schwartz–Bartter syn- ical behavior come only through composite analysis of
drome (hypersecretion of antidiuretic hormone), Eaton– single case reports or small series. Alleged cases
Lambert syndrome (myasthesia gravis–like syndrome), contained in the older literature are particularly frus-
and Cushing’s syndrome (ACTH production) (18,34–37). trating; they are often poorly documented and do not
conform to modern-day classification.
E. Large Cell Neuroendocrine Carcinoma Although these tumors can occur in all ages,
most present in the 50- to 70-year age group and
Large cell neuroendocrine carcinomas (LCNEC) of the about 60% to 80% of the patients are men. Most of
larynx, similar to those described in the lung, are rare the neoplasms are malignant and, among these,
168 Barnes
adenoid cystic carcinoma and mucoepidermoid carci- 1 or 2 cm (Fig. 14). Histologically, the cysts often contain
noma are the most frequent types. Because these intraluminal papillary projections (Fig. 18). The cysts as
tumors are rare, the differential diagnosis must well as the papillae are lined or covered by multiple
always include the possibility of a metastasis from a layers of large, uniform, deeply eosinophilic columnar
distant site. The location, symptomatology, and cells that, by electron microscopy, contain numerous
behavior of these neoplasms are correlated, to some mitochondria. The nuclei are small and dark and situ-
extent, with the specific histological type and, there- ated near the center of the cells. The contents of the
fore, they will be considered separately. See chapter 10, cysts vary from watery to mucoid.
‘‘Diseases of the Salivary Glands’’ for gross and The treatment of choice depends on the extent and
histologic description of each of the following tumors. location of the lesion, but usually entails microlaryngo-
scopy and excision. Inadequate removal may result in
recurrence. Because some OPCs may be multicentric, it
B. Pleomorphic Adenoma is important for the surgeon to thoroughly examine the
laryngeal mucosa to determine the extent of the disease.
Although pleomorphic adenoma is the most frequent
The OPCs have no malignant potential; however, a
tumor of the major salivary glands, it is unusual in the
few have been found incidentally in association with
larynx. Of 391 pleomorphic adenomas tabulated at the
squamous cell carcinoma of the larynx (10).
University of Pittsburgh through 1976, only one
(0.25%) occurred in the larynx (3).
In 1997, Dubey et al. reported a pleomorphic
adenoma and identified 20 additional cases in a D. Adenoid Cystic Carcinoma
review of the world literature (4). These occurred in
Adenoid cystic carcinoma (ACC) of the larynx is a
12 males and 9 females, ranging in age from 15 to 82
distinctly uncommon tumor (11–19). In a review of 264
years (average 51 years). The tumors were generally
ACC from all sites in the head and neck on file at the
well demarcated and varied in size from 1 to 6 cm.
Memorial Hospital in New York, Spiro et al. identified
Fourteen arose in the supraglottic larynx (usually the
only three (1.1%) that originated in the larynx (20). As
epiglottis), three in the glottis and four in the sub-
of 1993, only about 120 cases have been reported in the
glottis. Most were treated by surgery and at the last
larynx in a review of the world literature (21).
follow-up, none was known to recur.
The tumor affects both sexes about equally and
Pleomorphic adenomas may contain areas of
occurs over a broad age range, with a peak incidence
squamous epithelium, which may represent a poten-
between 50 and 70 years. Approximately 50% to 60%
tial pitfall. MacMillan and Fechner, for instance, have
arise in the subglottic and 25% to 35% in the supra-
reported a pleomorphic adenoma of the larynx that
glottic larynx (11,14) (Figs. 100–102). Only 5% to 10%
had ulcerated and undergone peripheral squamous
involve the glottis. Airway obstruction, dysphagia,
metaplasia. A biopsy from this area was subsequently
misinterpreted as a squamous carcinoma and the
patient underwent unnecessary irradiation (5).
A few cases of carcinoma ex pleomorphic ade-
noma of the larynx have been reported (6–8). Some of
these, especially the case of Sabri and Hajjar are
questionable (6).
C. Oncocytic Lesions
Virtually all oncocytic lesions of the larynx are exam-
ples of what have been referred to as oncocytic cysts
or oncocytic papillary cystadenomas. Whether they
are true neoplasms or a cystic metaplastic-hyperplastic
response to various stimuli is the subject of ongoing
debate.
Such lesions, hereafter referred to as oncocytic
papillary cystadenomas (OPC), arise from the ducts of
laryngeal mucoserous glands and, as such, occur
primarily in region of the false vocal cords and
ventricles. They affect both sexes about equally and
are uncommon in individuals younger than 50 years
of age. Of 35 cases on file at the University of Pitts-
burgh, the average age is 69 years (range 55–82) (9).
Hoarseness is, by far, the most frequent com-
plaint. Dyspnea, stridor, pain, foreign body sensation,
and dysphagia have also been reported. Figure 100. Adenoid cystic carcinoma of subglottic larynx
When viewed endoscopically, OPCs appear as (arrows).
smooth, cystic, submucosal masses that rarely exceed
carcinoma (Table 14). A carcinoid can be excluded on

the basis of its immunopositivity for neuroendocrine
markers, such as synaptophysin.
Surgery is the treatment of choice for ACC of the
larynx, with the extent of the procedure being depen-
dent on tumor site. Because most are of subglottic
origin, a total laryngectomy is usually required,
whereas partial procedures may be sufficient for
those involving the supraglottic larynx. A neck dis-
section is not warranted unless the nodes are enlarged
or have been shown to contain tumor. Radiation
therapy may produce temporary regression, but rarely
permanent control.
Because of their rarity and lack of significant
follow-up, the long-term prognosis is largely unknown.
A few patients, however, have been reported to be
alive and disease-free as long as 15 years or more (16).
Figure 101. Adenoid cystic carcinoma. Cross section of tumor The absence of lymph node metastasis cannot be
shown in Figure 100. The tumor has invaded into the adjacent considered a favorable prognostic sign, for most ACC
soft tissue. metastasize systematically through the blood stream,
usually to lung, bone, or liver. Patients may, however,
live several years after developing metastases.
E. Mucoepidermoid Carcinoma
Mucoepidermoid carcinoma (MEC) and adenosqua-
mous carcinoma are often erroneously assumed to be
synonyms. The former, however, is a type of salivary-
mucoserous carcinoma while the latter is a variant of
squamous cell carcinoma. These limitations, must be
considered when viewing reports of MECs in uncom-
mon sites, such as the larynx (22).
According to Prgomet, 80 cases of MECs of the
larynx have been reported as of 2003, of which some
degree of information was available on 63 (23). Of
these, 70% occurred in males and 30% in females with
an average age of 57 years. Fifty-seven percent were of
supraglottic origin, 30% glottic, 8% subglottic, and 5%
transglottic. At least 30% developed metastases, pri-
marily to cervical lymph nodes.
It is not uncommon in small biopsies for MEC to
be mistaken for squamous cell carcinoma. Because
Figure 102. Microscopic view of adenoid cystic carcinoma MECs are only moderately responsive to radiotherapy,
shown in Figures 100 and 101 (H&E, 100).
surgery offers the best opportunity for cure. The histo-
logical grade as well as anatomical site of the tumor
influence the extent of the surgical procedure. Patients
with high-grade supraglottic tumors (and possibly
hoarseness, cough, sore throat, and occasionally, pain intermediate-grade tumors) may be treated by supra-
are the usual presenting symptoms. glottic laryngectomy and neck dissection, even if the
Although some studies have indicated a rather lymph nodes are clinically negative. A neck dissection
significant incidence of cervical lymph node metasta- is not warranted for low-grade tumors.
ses, especially for those arising in the supraglottic The overall five-year survival rate for all grades
larynx, we suspect that in most of these cases the of laryngeal MEC is 75% to 80% (22). For low-grade
lymph nodes were involved by direct tumor extension tumors, the five-year survival is 90% to 100% and, for
or that the tumor was some other neoplasm incorrectly high-grade tumors, 50% to 55% (22). Distant metasta-
labeled as an ACC. In our experience, embolic nodal ses have occurred in about 10% of cases, primarily to
metastasis by ACC is infrequent. lung, brain, bone, and kidney.
Two recently recognized tumors of the larynx
that may be confused with ACC are the BSCC and F. Other Tumors
carcinoid tumor (typical and atypical). In contrast
with ACC, BSCC often exhibits pleomorphism, necro- A limited number of other salivary-type neoplasms
sis, and frequent mitoses and, in addition, contains have also been described in the larynx. Because of
either in situ or invasive component of squamous cell their scarcity, no generalizations concerning prognosis
170 Barnes
can be made. Among these are included acinic cell (3). The significance of melanocytes in the larynx is
carcinoma (24), clear cell carcinoma (25,26), benign that they may rarely give rise to nevi and malignant
and malignant myoepitheliomas (27,28), epithelial- melanoma.
myoepithelial carcinoma (29), salivary duct carcinoma In 1997, Gonzalez-Vela et al. reported four cases
(30,31), oncocytoma and oncocytoid adenocarcinoma of melanosis of the larynx and found only 13 addi-
(32,33), papillary adenocarcinoma (34) and mucoid tional cases in an extensive review of the literature (4).
adenocarcinoma (35). These 17 patients were aged between 53 and 86 years
(median 59 years), and of the 16 in which the gender
was known 15 were males and one female. Nine cases
XXV. MELANOTIC LESIONS OF THE LARYNX involved the true vocal cords, five the supraglottic
larynx, two the false vocal cords, and in one, the site
A. Melanosis
was unknown. At least half, and maybe more, of the
‘‘Melanosis’’ is a clinical term, much like leukoplakia, cases occurred in individuals with a history of smok-
which can be loosely applied to any melanin-containing ing. Only 25% of the cases, however, were associated
lesion, be it congenital or acquired, benign or malignant, with gross pigmentation.
or simply the result of physiological stimulation. In the Nine of the 17 cases of melanosis were associated
case of mucous membranes, it is most often used to with laryngeal neoplasms—seven squamous cell car-
describe a flat or slightly elevated solitary or multifocal cinomas and two malignant melanomas (4).
area of benign melanin pigmentation with associated Whether melanosis might be related to malignant
melanocytes, the border of which varies from well to melanomas is unknown. In a review of 22 malignant
poorly defined (1). melanomas of the larynx only 2 (9%) were associated
Melanosis has been observed in both white and with melanosis (5). None of the four laryngeal melano-
black populations. It is relatively common in the oral mas reported by Wenig showed this associated (6). The
cavity, less frequent in the nasal cavity, and rare in the link, therefore, between mucosal malignant melanomas
larynx. The melanocytes and pigment are usually and melanosis is apparently weak. Likewise, since
confined to the basal layer of the mucosa, but on squamous cell carcinoma and possibly even melanosis
occasion, can be found in the stroma or in the walls are related to smoking, the two events occurring con-
of mucoserous glands (Fig. 103). Their presence in the currently is most likely a coincidental finding. Never-
endodermally derived larynx is probably best theless, the presence of melanosis in the larynx may
explained by erratic migration of melanocytic precur- warrant the need for thorough evaluation and surveil-
sors from the neural crest during embryogenesis (2). lance to exclude carcinoma or melanoma.
Other theories have postulated a metaplasia of squa-
mous or glandular epithelium into melanocytes, or the B. Nevus
transformation of various neural elements into mela-
nocytes (2). Nevi of the larynx are extremely rare, with only a
With the exception of the oral cavity, these cells, handful of cases contained in the world literature.
when present, rarely produce enough pigment to be Seals et al. describe a junctional nevus of the left
grossly detectable unless stimulated by local irritation, true vocal cord in a 10-year-old black girl and Schimpf
inflammation, or radiotherapy; the latter is analogous et al. report a compound nevus of the plica ventricu-
to the effect of sunlight on epidermal melanogenesis laris (false vocal cord) (7,8). Wenig also illustrates
what appears to be a compound nevus of the larynx,
but provides no additional information (9). Travis et
al. report a 65-year-old black man who had a malig-
nant melanoma of the oral cavity associated with an
alleged lentigo of the right pyriform sinus (10). A
photomicrograph of the ‘‘lentigo,’’ however, is more
consistent with melanosis, as described above, rather
than a lentigo.
Nevi of the larynx, especially in older patients,
should be excised to rule out malignant melanoma.
Whether they have any malignant potential is unknown.
C. Malignant Melanoma
Clinical Features
Primary malignant melanoma of the larynx (PMML) is
an exceptionally rare neoplasm, with only 22 cases
recorded in the world literature in 1986 and 54 cases in
Figure 103. Melanosis of the epiglottis. Note the melanin (dark- 2001 (5,6,11). The Otolaryngic Tumor Registry at the
staining areas) in the basal region of the squamous mucosa and in Armed Forces Institute of Pathology contains only
the duct of a mucoserous gland (Warthin–Starry melanin, 40). nine cases (0.09%) among 10,270 primary laryngeal
neoplasms accumulated over a 75-year interval (9).
The tumor is more common in men (85% of all Amelanotic PMMLs that grow in a spindle or
cases) and has been described in individuals from 35 storiform pattern must also be distinguished from
to 86 years of age (average about 58 years) (5,6). monophasic spindle cell squamous carcinoma and
Almost all of the tumors reported thus far have malignant fibrous histiocytoma. This can usually be
occurred in whites. accomplished by the use of immunostains for cytoker-
Most (60–80% of all cases) arise in the supra- atin, S-100 protein, and HMB-45. PMML is negative
glottic larynx and present as an exophytic polypoid or for cytokeratin and positive for S-100 protein and
sessile, occasionally ulcerated, black, brown, gray, HMB-45. All three of these stains are negative in
pink, or white mass, ranging anywhere from 3 mm malignant fibrous histiocytoma.
to 8.0 cm (5,9). A few have been associated with Other tumors, particularly typical and atypical
laryngeal melanosis (4,5). carcinoids, paraganglioma, and renal cell carcinoma,
Dysphagia, sore throat, hoarseness, pain, inter- may also enter into the differential diagnosis. Stains
mittent hemoptysis, and a cervical (metastatic) mass that are helpful in distinguishing these neoplasms are
are the usual presenting manifestations Although shown in Table 17.
most tumors have occurred in individuals who are
smokers and consumers of alcohol, it remains uncer- Treatment and Prognosis
tain whether these factors are etiologically significant.
Primary malignant melanoma of the larynx is associ-
Pathology ated with a poor prognosis, with an average survival
of about three years (5). Although PMMLs exhibit a
Similar to melanomas elsewhere, PMMLs are com- lower incidence of local recurrence compared with
posed predominantly of epithelioid or spindle cells other mucosal melanomas of the head and neck, about
that grow, respectively, in an alveolar or fascicular- 80% are associated with positive cervical lymph nodes
storiform pattern. The cells typically have eosinophilic sometime during the course of the disease, and 80%
cytoplasm and nuclei that range from vesicular to will eventually develop distant metastases (5).
hyperchromatic, with or without prominent nucleoli. Complete surgical resection is the treatment of
Nuclear pleomorphism, multinucleated tumor giant choice. Depending on the site of origin and stage
cells, intranuclear inclusions of cytoplasm, mitoses, of disease, this will usually involve a partial or total
and necrosis are not uncommon. Because of surface laryngectomy and probable cervical lymph node
ulceration, junctional activity may or may not be seen. dissection.
About one-third of PMML are amelanotic,
requiring a high index of suspicion when dealing
with this tumor. Special stains for melanin, such as XXVI. GIANT CELL TUMOR
the Warthin-Starry stain, and immunohistochemical
procedures for S100 protein, HMB-45 and tyrosinase, A. Introduction
are important in confirming the diagnosis. In instan- The giant cell tumor of the larynx is identical to the
ces for which these procedures are negative or equiv- giant cell tumor seen elsewhere in the skeleton and, as
ocable, electron microscopy for the presence of such, is defined as a benign but locally destructive
premelanosomes and melanosomes is helpful. neoplasm composed of sheets of ovoid to spindle-
shaped mononuclear cells with uniformly dispersed
osteoclast-like giant cells (1–6).
Before the diagnosis of PMML can be accepted, meta- They are very rare in the larynx, representing
static malignant melanoma (MMM) from another site only 0.09% of 8995 benign and malignant primary
must be excluded. MMM is considerably more com- laryngeal neoplasms accessioned at the Armed Forces
mon than PMML and accounts for 30% to 40% of all Institute of Pathology during the years 1966–2000 (1).
metastatic tumors of the larynx (12–16). In general,
PMML presents as an exophytic mucosal lesion, often B. Clinical Features
associated with junctional activity and positive cervi-
cal lymph nodes. MMM of the larynx, on the other Of 28 reported cases, 25 were in men and 3 in women,
hand, is usually submucosal and not associated with aged 23 to 62 years (mean about 40–45 years) (1). Most
junctional activity or enlarged cervical lymph nodes. originate from the thyroid cartilage, followed by the
Furthermore, MMM of the larynx is usually a preter- cricoid cartilage and epiglottis. The tumors enlarge
minal event, associated with a known primary and slowly and manifest as palpable neck masses, hoarse-
multiorgan dissemination. It should be emphasized ness, airway compromise, dysphagia, or sore throat.
again that because of surface ulceration, junctional On imaging, it often appears as a tumor exploding
activity may not always be apparent in PMML. from within the cartilage, destroying it, and extending
Wenig also indicates that since melanocytes can be into the soft tissue of the neck or endolarynx.
identified in mucoserous glands or stroma that it is
possible that a PMML may take origin from these C. Pathology
melanocytes and not arise from the surface epithelium.
Hence, the presence of an in situ or junctional compo- Most tumors have ranged from 2.4 to 7 cm (mean
nent is not always required to postulate a primary about 4–4.5 cm) and have been centered in the thyroid
origin in the larynx (6). or cricoid cartilages, especially in the normally
172 Barnes
ossified portions of these cartilages (1). On cut section, B. Etiology

they are soft, red to grey-pink and frequently extend
beyond the cartilage into the adjacent soft tissue. Traditionally, it has been regarded as a nonneoplastic
Hemorrhage and cystic degeneration are common. condition, possibly related to trauma or an infectious-
The tumors are similar histologically to giant cell immunologic process, which generally responds to
tumor of bone and, as such, consist of a dual popula- systemic corticosteroids, conservative excision, or
tion of cells: mononuclear cells and osteoclast-like even radiotherapy. The recent finding of human Her-
giant cells. The mononuclear cells appear as broad pes virus-8 DNA sequences and overexpression of
sheets of cells reminiscent of histiocytes. They are interleukin-6 and cyclin D1 in some IMTs does add
round, ovoid or spindled and have pink to ampho- credence to an infectious etiology (2). Those alleged
philic cytoplasm and round, vesicular nuclei with cases involving lymph nodes, liver and spleen associ-
occasional prominent nucleoli. The giant cells are ated with the EBV are, however, probably unrecog-
evenly distributed throughout the tumor and contain nized follicular dendritic cell tumors (3).
up to 20 or more nuclei per cell. The nuclei of the giant Not all IMTs, however, exhibit a bland behavior.
cells are identical to those of the mononuclear cells. Some are locally destructive, especially in the sino-
The stroma is vascular and contains many thin- nasal tract, while others have recurred following
walled vessels with small areas of hemorrhage and excision, and a few allegedly have even metastasized,
hemosiderin-laden macrophages. Mitoses are usually behaving in this regard, more like a true neoplasm.
seen, averaging 4 per 10 high power fields (range 1–12 The observation that some lesions are aneuploid or
per 10 high power fields) (1). Atypical mitoses are not clonal on cytogenetic evaluation supports this conten-
seen. tion, and raises the issue of whether some IMTs
should be considered as a borderline or low-grade
malignant tumor, especially those composed predom-
D. Differential Diagnosis inantly of myofibroblasts (4–8). From the above obser-
This includes giant cell (reparative) granuloma, brown vations, it would appear that IMTs may represent a
tumor of hyperparathyroidism, fibrous histiocytoma, diverse group of lesions of multiple etiologies that
and a pleomorphic carcinoma. Giant cell granuloma only share a common histologic bond—a tumoral mass
of the cricoid cartilage is exceptionally rare (7). The of inflammatory cells with a variable myofibroblastic-
giant cells in this tumor are not evenly distributed, but fibrous tissue response.
rather concentrate around areas of recent and/or old
hemorrhage. A giant cell granuloma also exhibits more C. Clinical Features
stromal fibrosis. A brown tumor is identical histologi-
cally to the giant cell granuloma, but is associated with IMT has been described in a variety of sites in the
an elevated serum calcium. A benign fibrous histiocy- head and neck, including the orbit, sinonasal tract,
toma contains a more uniform storiform arrangement of middle ear-mastoid, oral cavity, larynx, neck, and
fibroblasts and does not show a symmetrical distribu- major salivary glands (9–16).
tion of giant cells. A malignant fibrous histiocytoma The larynx, which is the focus of the remaining
(giant cell type) exhibits significant nuclear pleomor- discussion, is an uncommon site (3,17–22). In a review
phism and abnormal mitoses, none of which are seen in of 14 cases of IMTs in the larynx, 10 recurred in males
giant cell tumor. A pleomorphic carcinoma will not and four in females aged 2 to 74 years (average 46
only show abnormal mitoses and pleomorphism, but years) (17–21). Ten tumors arose from the true vocal
will also be positive for cytokeratin. cords, two were of supraglottic and two subglottic
origin. Most presented with hoarseness or, infrequently,
E. Treatment and Prognosis with a sensation of a foreign body in the throat or as
airway compromise.
Complete, but conservative surgical excision is the Some IMTs (15–30%) may also be associated
treatment of choice. Large tumors may require a partial with constitutional symptoms (fever, impaired
or total laryngectomy. Adjuvant therapy is unnecessary. growth, weight loss, malaise) or laboratory abnor-
There have been no convincing records of local malities (anemia, thrombocytosis, leukocytosis, poly-
recurrence or malignant behavior secondary to giant clonal hyperglobulinemia, elevated erythrocyte
cell tumor of the laryngeal framework. sedimentation rate). Production of cytokines, espe-
cially interleukin-6, are thought to be responsible for
the systemic effects. Most of the IMTs associated with
XXVII. INFLAMMATORY MYOFIBROBLASTIC systemic symptoms are found in the abdominal
TUMOR cavity. Guilemany et al., however have reported
A. Introduction such a tumor in the larynx (21). The patient, a
62-year-old man, had a 3 cm IMT of the right true
Inflammatory myofibroblastic tumor (IMT), also known vocal cord associated with a 20 kg weight loss, fever,
as inflammatory pseudotumor and plasma cell granu- and an elevated erythrocyte sedimentation rate over
loma, is an enigmatic lesion composed of myofibroblas- a six-month period. Following excision, the patient
tic spindle cells with an inflammatory infiltrate of regained his normal body weight with disappearance
plasma cells, lymphocytes, and eosinophils (1). It may of his fever and normalization of the erythrocyte
occur in any anatomic site, especially the lungs. sedimentation rate four months later.
D. Pathology
IMTs are typically smooth, polypoid or nodular with a
fleshy to firm consistency. They have ranged in size
from 0.4 to 3.5 cm (13,21).
Histologically, they consist, in varying propor-
tions, of inflammatory and spindle-fibrous compo-
nents. The inflammatory element is typically
polymorphous and composed of lymphocytes, plasma
cells, histiocytes, eosinophils and, infrequently, neu-
trophils. The lymphocytes are mature, and, on immu-
nostaining, are composed of both T and B cells. They
may be randomly distributed or aggregate in small
nodules with or without germinal centers. The plasma
cells are also mature and polyclonal. Large sheets of
plasma cells are unusual. Eosinophils vary from rare
to numerous, and neutrophils, if seen at all, are
usually near areas of necrosis or surface ulceration.
The histiocytes are bland and may process small,
barely visible nucleoli.
Figure 104. Inflammatory myofibroblastic tumor composed of
The fibrous component consists of cytologically
both compact and myxoid areas with admixed inflammatory cells
bland spindle to stellate cells with characteristics of (H&E, 100).
fibroblasts and/or myofibroblasts. The nuclei vary
from round to elongated and vesicular to mildly
hyperchromatic with moderate amounts of basophilic
to eosinophilic cytoplasm.
Some lesions contain very little stroma while observed that 60% of the cases were positive for ana-
others are composed almost entirely of densely, scle- plastic lymphoma kinase (ALK) especially in younger
rotic, hypocellular collagen with a laminated or keloi- patients (7). Those tumors occurring in patients over 40
dal appearance. Mitoses are infrequent and necrosis, if years of age are usually ALK-negative.
seen at all, tends to be spotty, unless the lesion has
ulcerated the mucosal surface.
The fibroinflammatory process may encase F. Differential Diagnosis
nerves and blood vessels, forming concentric rings
The differential diagnosis can be exhaustive and has
of collagen (‘‘onion skinning’’) around them.
been covered in detail by others (23). In the larynx,
Although blood vessels may show obliterative
SPCC (spindle cell carcinoma) should be excluded.
changes, inflammatory cells in the walls of blood
This may be difficult, if not impossible, on small
vessels are rare to absent.
biopsies coupled with the fact that some IMTs are
On the basis of the proportion of inflammatory
also focally positive for cytokeratin. In this instance,
and fibrous components, four histologic patterns are
look for cells with atypical mitoses and dyskeratosis
recognized: (i) myxoid-granulation tissue which con-
as well as mucosal changes of dysplasia or CIS. These
tains plump spindle to stellate cells lying in an edem-
findings should suggest SPCC. In addition, unless
atous, highly vascular, inflammatory background, (ii)
ulcerated, SPCC usually does not have a large compo-
compact comprised of a more prominent element of
nent of inflammatory cells. SPCC is also often positive
closely approximated spindle cells with admixed
for p63 while the IMT is negative.
inflammatory cells, (iii) sclerotic made up of dense,
eosinophilic, relatively acellular collagen with scat-
tered inflammatory cells, and (iv) mixed composed G. Treatment and Prognosis
of two or more of the preceeding patterns (Fig. 104).
According to Hussong et al., IMTs that contain Treatment has ranged from corticosteroids, conserva-
ganglion-like cells and exhibit cellular atypia, atypical tive excision, laser therapy, and irradiation with vary-
mitoses, p53 expression, and DNA aneuploidy are ing degrees of success. Of 14 cases involving the
aggressive and might warrant the diagnosis of a larynx, at least three (21%) recurred following initial
malignant IMT (6). therapy (13,19,21). This compares with a recurrence
rate of 25% for all other IMTs. In one case, the tumor
recurred twice over a two-year period and ultimately
E. Immunohistochemistry required a total laryngectomy (13).
Data collected from several series (including all sites,
not just the larynx) indicate that almost all IMTs are XXVIII. SARCOMAS OF THE LARYNX
positive for vimentin, 87% for muscle specific actin,
and 82% for smooth muscle actin (22). About half are Primary sarcomas of the larynx comprise a rare het-
focally or diffusely positive for desmin and about a erogeneous group of neoplasms that, collectively,
third may focally express cytokeratin (22). Cook et al. compose only 0.3% to 1% of all laryngeal malignancies
174 Barnes
(1–3). Any attempt to statistically analyze these XXIX. SQUAMOUS CELL CARCINOMA OF
tumors is met with frustration, not only because of THE HYPOPHARYNX
their rarity, but because many of the cases lack suffi-
cient clinical information, follow-up is incomplete, A. Introduction
pathological documentation is often poor, and confu- The hypopharynx, which lies behind the larynx and
sion with spindle cell carcinoma is rampant. partially surrounds it on either side, extends from the
Etiologically, they do not appear to be related plane of the hyoid bone superiorly to the lower border
to smoking or alcohol intake. Most occur spontane- of the cricoid cartilage inferiorly (Fig. 105). It consists
ously, but some are radiation-induced (4). In the of three regions: the pyriform sinuses, postcricoid
study of radiation-induced sarcomas by Kim et al., area, and the posterior pharyngeal wall. Although
the median latent periods from radiation exposure to useful for descriptive purposes and classification,
diagnosis of bone and soft tissue sarcomas were, these divisions are in continuity with one another
respectively, 11 and 12 years (range 3–20 years) (5). and merge with the oropharynx, larynx, and cervical
No irradiation tumors were seen in doses below 1100 esophagus. The lumen of the hypopharynx is cone-
rets. Exposure to thorium dioxide (Thorotrast) and shaped, with a wide opening superiorly and a nar-
polyvinyl chloride has also been incriminated in the rower lumen in the postcricoid and cervical esophageal
development of angiosarcomas, especially of the region.
liver. Although patients with neurofibromatosis are The hypopharynx is richly endowed with lym-
at risk for developing malignant schwannomas, phatics that drain primarily to the upper and mid-
these tumors are more commonly located in the jugular lymph nodes (1). The lymphatics of the
deep soft tissues or retroperitoneum and rarely, if posterior wall also have a significant communication
ever, in the larynx. Viruses may also be etiologically with the retropharyngeal lymph nodes and the node
related to some sarcomas (e.g., kaposi’s sarcoma and of Rouviere at the base of the skull (2).
the HIV). The incidence of hypopharyngeal carcinomas
Grossly, sarcomas, regardless of the putative cell more closely parallels the incidence of malignant
of origin, tend to present as polypoid or multilobu- tumors of the upper gastrointestinal tract, especially
lated, firm, submucosal masses that are usually pink, the oral cavity rather than the respiratory tract (3).
gray, or white. Flat ulcerative or fungating lesions are They are only about one-third as common as cancer of
rare. Multiple biopsies are sometimes necessary to the larynx (4).
establish the diagnosis. In fact, in the series of Setzen The distribution of malignant tumors within the
et al., 13% of the patients required more than one hypopharynx varies according to geographic location.
biopsy before the diagnosis was established (6). Cau- In the United States and Canada, approximately 65%
tion must be particularly exercised in evaluating to 85% arise in the pyriform sinus, 10% to 20% occur
laryngeal biopsies in patients who have received on the posterior wall, and 5% to 15% involve the
prior radiation therapy. The distinction between radi- postcricoid area (4–10) (Fig. 106).
ation-induced stromal atypia and de novo or radia-
tion-induced sarcomas can be difficult, requiring close
correlation with the clinical findings and, often, mul-
tiple biopsies over a time span to access the true
potential or autonomy of the lesion.
SPCCs of the larynx are also often confused with
sarcomas on small biopsies, usually a fibrosarcoma or
malignant fibrous histiocytoma. Accordingly, SPCC
must always be considered in the differential of all
alleged sarcomas of the larynx and excluded by exam-
ining multiple histological sections (for the biphasic
components), immunohistochemical stains for
cytokeratin, or electron microscopy.
Laryngectomy, either partial or total, is the
most successful form of therapy (7). Radiation ther-
apy may have merit as an adjunct, but not for
primary therapy. The role of chemotherapy is still
evolving, but has certainly proved useful in the
management of patients with embryonal rhabdo-
myosarcomas. Metastases are predominantly vascu-
lar, usually to the lungs. Involvement of regional
lymph nodes is uncommon.
Chondrosarcoma is, by far, the most common
sarcoma of the larynx, accounting for almost half of
all cases (8). For a more detailed discussion of the
clinical and pathological features of the various
sarcomas refer to the chapters on bone and soft Figure 105. Diagram showing boundaries of the hypopharynx.
tissue tumors.
Table 18 Ta Classification of Hypopharyngeal Carcinoma

T1 Tumor limited to one subsite of hypopharynx and
2 cm in greatest dimension
T2 Tumor involves more than 1 subsite of hypopharynx
or an adjacent site, or measures >2 cm but not
>4 cm in greatest diameter without fixation of
hemilarynx
T3 Tumor measures >4 cm in greatest dimension or with
fixation of hemilarynx
T4 Tumor invades adjacent structures (e.g., thyroid/
cricoid cartilage, carotid artery, soft tissues of
neck prevertebral fascia/muscles, thyroid and/or
esophagus)
a
The NM classification is similar to that previously given for laryngeal
carcinoma; see Table 10.
Source: From Ref. 23.
The medial wall is formed by the posterior surface

of the aryepiglottic fold and the arytenoid and cricoid
cartilages. The lateral wall consists of the inner surface
of the thyroid cartilage and thyrohyoid membrane.
There is no significant lateralization of neo-
Figure 106. Posterior view of the pharynx showing the distribu- plasms to either the right or left pyriform sinus (24).
tion and relative frequency of hypopharyngeal carcinomas Because the tumors are often large when discovered,
Source: From Ref. 11. their exact site of origin within the sinus is often
difficult to determine (Fig. 107). The tumor may
spread medially to invade the lateral wall of the
supraglottic larynx (Fig. 108). In this instance, Kirch-
ner indicates that it differs from the usual supraglottic
laryngeal carcinoma by growing downward within
the paraglottic space to extend beyond the level of the
B. Etiology ventricle, thereby behaving more like a transglottic
carcinoma (7). It can extend laterally, erode the thy-
The tumors are etiologically related to smoking, alcohol roid cartilage, and directly invade the superior lobe of
abuse, and the Plummer–Vinson syndrome (PVS) the thyroid gland. In some instances, the thyroid may
(4,11–15). There is also evidence that some of the tumors be free of contiguous growth, yet contain tumor
in patients from Japan may be related to the EBV (16). emboli within lymphatics or blood vessels. Kirchner
has noted that when the lateral wall of the sinus is
C. Clinical Features clinically involved, the thyroid cartilage is invaded in
55% of the cases, and when the tumor extends to the
The peak incidence is in individuals 55 to 65 years of apex of the sinus, the cartilage is almost invariably
age. Collectively, 80% to 85% of all patients are men, invaded (7). Some tumors may grow superiorly into
but when specific sites are considered, 50% to 90% of the base of the tongue or extend across the postcricoid
patients with postcricoid carcinomas are women
(8,15,17–20). Because the hypopharynx is a clinically
‘‘silent’’ area, patients usually present with advanced
tumors. Most are classified as T3 or T4, and 65% to
75% are associated with clinically positive cervical
lymph nodes (6,7,10,22,23) (Table 18).
The most common presenting symptoms are
dysphagia, sore throat, referred otalgia, hoarseness,
sensation of a foreign body in the throat, weight loss,
and hemoptysis. Some 20% to 25% of patients com-
plain of only a neck mass (15,17,22).
Pyriform Sinus Carcinoma

The pyriform sinus is shaped like an inverted pyra-
mid or pear. It consists of three walls—anterior,
medial, and lateral—that converge inferiorly toward Figure 107. Gross appearance of a squamous cell carcinoma
an apex at about the level of the inferior border of the of the right pyriform sinus that also involves the aryepiglottic fold
cricoid cartilage. The superior border of the sinus (specimen opened posteriorly).
begins at the level of the pharyngoepiglottic fold.
176 Barnes
15% of patients will develop bilateral cervical lymph

node metastases sometime during the course of their
disease (18,28). The lymphatic drainage is primarily to
the upper and middle jugular, as well as the retro-
pharyngeal lymph nodes. The retropharyngeal lymph
nodes are involved in 42% to 62% of cases and, in 10%
of patients, they are the only lymph nodes involved
(2,29). In general, however, the incidence of cervical
lymph node metastasis from posterior pharyngeal
wall cancers is less than that observed in patients
with pyriform sinus tumors. The tumors may spread
circumferentially to involve the larynx or, in advanced
disease, extend into the tonsillar pillars, soft palate,
nasopharynx, pyriform sinuses, or cervical esophagus.
Ballantyne indicates that the principal reasons for
local recurrence following surgery are (i) failure to
remove unrecognized local extension of tumor along
muscle or fascial planes or nerves, (ii) failure to eradi-
cate areas of in situ or early invasive cancer, and (iii)
implantation of tumor cells in the operative site (29).
Postcricoid Carcinoma
The postcricoid area (the posterior surface of the
larynx) extends from the posterior surface of the
Figure 108. Pyriform sinus cancers may grow medially to arytenoid cartilage to the inferior surface of the cricoid
involve the supraglottic larynx (1); erode the thyroid cartilage cartilage and is bounded laterally by the pyriform
laterally and invade the thyroid gland (2); extend into the para-
glottic space (3); and escape through the cricothyroid interspace
sinuses (3). There is marked geographic variation in
into the soft tissue of the neck (4); or they may grow superiorly the incidence of postcricoid carcinomas (PCC). They
toward the base of the tongue (5). Source: From Ref. 11. are especially common in Scandinavian countries
where PVS was at one time prevalent; the syndrome
is now being recognized earlier and treated accord-
ingly (20). PVS, also known as Paterson–Kelly syn-
drome and sideropenic dysphagia, is characterized
predominantly by dysphagia, iron-deficiency anemia,
glossitis, chelitis, and achlorhydria. The dysphagia is
area to involve the opposite pyriform sinus or the due to webs, stenosis, or mucosal atrophy. The webs
contiguous posterior pharyngeal wall. Invasion of the most often arise from the anterior esophageal wall just
cervical esophagus is unusual. distal to the cricoid cartilage. When carcinoma devel-
At the time of diagnosis, about 65% to 75% of ops, it arises immediately proximal to the webs and
patients will have positive cervical lymph nodes. not within them (14). In the past, of those patients
However, no more than 10% of patients will present with PCC, 30% to 70% have also had PVS (13,19,30,31).
initially with bilateral positive lymph nodes (15,18, Conversely, of those patients with PVS, only 1% to
24,25). 10% have developed carcinoma (13,30). Richards et al.
have observed that the peak incidence of PCC occurs
15 years later than the peak incidence of PVS (31).
Posterior Hypopharyngeal Wall Carcinoma
Food stasis secondary to webs or stricture may
Tumors of the posterior hypopharyngeal wall are partly explain the increased incidence of carcinoma in
three times more common than those of the posterior this site (14). Because the webs have been noted to
oropharyngeal wall (26,27). Most studies pertaining to decrease or even disappear with dietary supplements,
carcinomas of the posterior pharyngeal wall include particularly iron, early recognition, and therapy are
all levels of the pharynx. This is not unreasonable, for mandatory to lessen the incidence of this lethal tumor.
there are no natural anatomical barriers among the In addition to the postcricoid area, patients with PVS
three levels of the pharynx (nasopharynx, oropharynx, may develop tumors in other mucosal sites, especially
and hypopharynx) and, at the time of diagnosis, the oral cavity and esophagus (13).
tumors often encroach on or invade more than one Postcricoid carcinomas commonly invade the
level. Furthermore, when posterior pharyngeal wall cricoid cartilage and cricoarytenoid muscle. They fre-
tumors are divided according to level of occurrence, quently become circumferential, and may extend
there are no significant differences in prognosis through the muscular lateral walls to directly invade
(26,27). the thyroid gland. Such behavior may warrant the
Almost 80% of these tumors are larger than 5 cm need for partial or total thyroidectomy (32). In
when diagnosed (17). Because these tumors almost the surgical treatment of PCC, Harrison indicates
invariably cross the midline, a minimum of 10% to that the superior extent of the disease is technically
not difficult to excise, but extension inferiorly can be, warrants consideration of adjuvant chemotherapy (15).
for the disease has tendency to involve the party wall Eighty percent of recurrences manifest within two years
between the esophagus and trachea, necessitating of treatment (25,40). Of those patients dying of disease,
removal of a considerable length of trachea (21). The almost half do so within the year following diagnosis
lymphatic drainage is mainly to the middle and lower (6,25,33). When all three sites of the hypopharynx are
jugular chain and to the paratracheal nodes (18,33). considered collectively, the overall five-year survival
Eighteen percent of patients have or will develop rate is between 20% and 40% (4,5,8,15,17–20,22,
bilateral cervical lymph node metastasis (18). Howev- 24,41,43,50,51,54). If only pyriform sinus tumors are
er, it is unrecognized involvement of the paratracheal considered, some recent studies indicate a better sur-
nodes that is responsible for most local recurrences vival. Spector et al. reviewed 408 squamous carcinoma
(33). Metastasis to these nodes may also secondarily of the pyriform sinus and observed the 5-, 10-,
involve the thyroid. 15-, and 20-year cumulative survival rates to be, respec-
tively, 56, 35, 31, and 20% (55). If the tumor involved
only one wall of the pyriform sinus, the five-year
D. Treatment and Prognosis survival was 53%, compared with 63% for tumors that
involved the medial wall, aryepiglottic fold, or supra-
Treatment of hypopharyngeal carcinoma depends on glottic larynx, and 49% for tumors that involved two or
the patient’s general state of health, location and three walls of the sinus with extension to the pyriform
extent of the tumor, and the technical ability of the apex or postcricoid region.
surgeon. Any therapeutic regimen, however, that fails
to consider the following is doomed to failure:
1. Tumors in this region are notorious for growing XXX. TUMORS OF THE TRACHEA
beneath an intact mucosa, extending far beyond A. Introduction
their clinically apparent margins. The average
extent of submucosal spread is 10 mm (34). Primary tumors of the trachea are rare, with a
2. A total of 65% to 75% of patients have positive reported frequency of less than 0.2 per 100,000 persons
ipsilateral cervical lymph nodes at the time of per year and a prevalence of 1 per 15,000 autopsies (1).
diagnosis, and 10% to 20% will either have The ratio of benign to malignant tumors varies
or develop contralateral nodal metastases according to age. In children, 60% to 90% of all
(3,5,7,15,18,21,24,25,28,35–37). Furthermore, 10% tracheal tumors are benign and the most frequent
to 60% of patients with clinically negative cervical are squamous papillomas, hemangiomas, and granu-
lymph nodes can be expected to harbor occult lar cell tumors (2,3). Of the remaining 10% to 40% that
metastases (5,7,15). are malignant, malignant fibrous histiocytoma and
3. The retropharyngeal and paratracheal lymph mucoepidermoid carcinoma predominate (3). In con-
nodes must be considered, respectively, when trast, in adults almost 90% of primary tracheal neo-
dealing with posterior pharyngeal wall and post- plasms are malignant and the two most common, by
cricoid carcinomas. far, are squamous cell carcinoma and adenoid cystic
4. Because as many as 17% of all hypopharyngeal carcinoma (4). These two tumors together comprise
carcinomas may involve the thyroid, some form of about 70% of all primary tracheal neoplasms in adults.
thyroidectomy may be required (3,32). Whether squamous cell carcinoma or adenoid cystic
5. Clinically, 20% to 40% of patients either have or carcinoma is the more common depends on the series.
will develop systemic metastases (6,15,22,38,39). In a collective review of 766 adult tracheal tumors, we
The median time from diagnosis to detection of observed 51% to be squamous cell carcinomas and
metastasis is nine months (6). The most common 21% adenoid cystic carcinomas (4–7).
sites are the lungs, mediastinum, brain, bones, Currently, there is no TMN staging system for
and liver. tracheal tumors.
6. Approximately 15% (range 7–31%) of these indi-
viduals have multiple primary malignancies
(6,15,18,24,26,29). Thirty-five percent of the second B. Anatomy
primaries are diagnosed before, 25% synchronous
The trachea extends from the lower border of the
with, and 40% subsequent to the discovery of the
cricoid cartilage to the carina and averages 11 cm in
hypopharyngeal carcinoma (6,18). They are most
length in the adult, varying roughly in proportion to
often found in the head and neck, lung, esopha-
the height of the individual (8,9) (Fig. 109). It is 2.0 to
gus, colon, or rectum.
2.7 cm in transverse dimension and 1.6 to 2.0 in
Details of therapy have been adequately covered saggital diameter (10). There are approximately two
by others (4,5,7,8,15,17–19,22,25,28,29,32,33,38–54). In tracheal cartilaginous rings per centimeter of trachea,
general, TIS, T1, some T2, and advanced inoperable with a total number of about 18 to 22. The tracheal
lesions can be treated with irradiation, either curatively cartilages are connected one to another by fibroelastic
or palliatively. Other tumors are approached surgically annular ligaments. In a few instances, the first tracheal
in conjunction with pre- or postoperative radiotherapy. ring may be fused to the cricoid cartilage.
Although most deaths are due to uncontrolled local The trachea is continuous with the larynx supe-
disease, the relative high incidence of distant metastases riorly and the bronchi inferiorly. Anteriorly it is
178 Barnes
Figure 110. Cross section of a squamous cell carcinoma of the

trachea with a predominant intraluminal growth.
commonly observed at diagnosis and about 35% are

associated with positive cervical lymph nodes (11).
According to Gelder and Hetzel, 45% of all
squamous cell carcinomas are found in the lower
Figure 109. Anatomic boundaries of the trachea. one-third of the trachea, 32% in the upper one-third,
and 15% in the middle third; in the remaining 8%,
the tumors were extensive and involved multiple
sites (6).
Surgical excision followed by radiation and/or
intimately associated with the thyroid gland and chemotherapy offers the best chance for cure
posteriorly with the esophagus. (4,6,7,11–16). Distant metastases to lungs, cervical
The trachea is lined entirely by ciliated respira- lymph nodes, liver, and bones are common. Gelder
tory epithelium and contains abundant mucoserous and Hetzel observed an overall 25% five-year survival
glands in the lamina propria. Although usually rate in their review of 174 squamous cell carcinoma of
referred to as rings, the cartilages are incomplete the trachea (6). Tumors associated with negative
posteriorly and form only about two-third of a circle. lymph nodes and tumor-free margins that originate
The posterior noncartilaginous area, referred to as the in the upper trachea and are less than 2 cm in size
membranous portion, contains prominent smooth have the best prognosis.
muscle. The submucosal lymphatics drain toward
the posterior part of the trachea and connect with
the paratracheal lymph nodes. They also anastomose D. Adenoid Cystic Carcinoma
with subcarinal, peribronchial, and esophageal lymph Adenoid cystic carcinoma of the trachea, in contrast to
nodes (10). squamous cell carcinoma, occurs in a younger age
group (mean 45–50 years, range 15–80 years), exhibits
C. Squamous Cell Carcinoma an equal gender distribution and is not as strongly
associated with smoking (1,4,6). Symptoms are similar
Squamous cell carcinoma of the trachea occurs pri- but of much longer duration, averaging 15 months
marily in older individuals, usually in the sixth or before diagnosis.
seventh decade of life (mean age 65, range 25–83 In a review of 29 cases, Gelder and Hetzel
years) (4,6,) (Fig. 110). The gender distribution ranges observed an equal distribution between the upper,
from equal to 3:1 in favor of males. Most are heavy mid and lower thirds of the trachea (6). Extension
smokers. beyond the wall of the trachea is almost universal (1).
Signs and symptoms include airway compro- Surgical resection, often augmented with adju-
mise, cough, hemoptysis, hoarseness, fever, weight vant radiation, offers the best chance for cure. Sur-
loss, wheezing, and, infrequently, superior vena cava vival rates at 5 years range from 65% to 80% and, at
syndrome. A delay in diagnosis of months to even a 10 years 50% to 60% (1,6). In a follow-up of 38 cases,
year or more is not uncommon. This is due, in part, to Maziak et al. observed a local recurrence of 21%,
the fact that the symptoms are often mistaken for regional lymph node involvement in 19% and hema-
asthma and that 50% occlusion of the airway is togenous (distant) metastases in 44%, especially to
necessary to produce dyspnea on exertion and 75% the lungs (1). Patients with positive resection mar-
occlusion to produce dyspnea at rest (11). As a result, gins and even distant metastasis may still experience
tumors greater than 2 cm in greatest dimension are long-term palliation.
XXXI. METASTASES TO THE LARYNX,

HYPOPHARYNX AND TRACHEA
A. Introduction
Metastases to the larynx are uncommon. Batsakis et al.
observed only 11 cases over a 20-year interval at the
M.D. Anderson Hospital in Houston, Texas (1). Ferlito
identified eight additional cases in a series of more than
4000 malignant neoplasms of the larynx at the Univer-
sity of Padua, Italy (2). In 1993, only 134 cases were
recorded in the world literature (2). Metastases to the
hypopharynx and trachea are even more unusual.
Laryngeal metastases increase with age (median
58 years, range 24 to 83 years) and are more common
in males by a ratio of 2:1 (1). The overwhelming
majority of tumors that metastasize to the larynx are
either malignant melanomas or carcinomas (Table 19).
Only 5% or less are from mesenchymal tumors (bone
and soft tissue sarcomas). Figure 111. Adenocarcinoma of the colon metastatic to the
The sites of origin of 12 tumors metastatic to the larynx. Source: Courtesy of Mona Melhem, M.D, VA Hospital,
trachea are shown in Table 20. Pittsburgh, PA.
Metastases to the larynx may be submucosal,
cartilaginous, or both. If cartilage is involved, it is
usually only in the portion that has undergone ossifi-
cation (Fig. 111).
The most frequently affected site is the supra- plexus or thoracic lymphatic duct. The infrequent occur-
glottis (35–40% of all cases) followed by the subglottis rence of metastases to the larynx may therefore be related
(10–20%) and glottis (5–10%). Synchronous involve- to the terminal location of the larynx in the lymphatic-
ment of multiple laryngeal sites, however, is common vascular circulation. Known differences in regional lym-
and observed in about 35% of all cases (1,3,). phatic and vascular supply of the larynx determine the
The pyriform sinus is the most frequent site of distribution of metastases within the larynx.
metastasis in the hypopharynx.
The majority of metastases to the larynx are B. Clinical Features
through the systemic circulation, often following the
route of the inferior vena cava, right heart, lungs, left The signs and symptoms of metastatic tumors are
heart, aorta, external carotid artery, superior thyroid similar to those exhibited by primary tumors of the
artery and laryngeal artery. Spread may also take place larynx and vary according to location. Supraglottic
via the retrograde circulation of the paravertebral venous lesions present with a sensation of a foreign body in
the throat, dysphagia, or a change in quality of the
voice, while glottic deposits manifest as hoarseness,
Table 19 Site of Origin of 120 Tumors Metastatic to Larynx and subglottic lesions as compromise of the airway.
Site Frequency (%) Richly vascular tumors, such as renal cell carcinomas
and thyroid carcinomas, often result in hemoptysis.
Skin (melanoma) 39.1
Kidney 13.3 On rare occasions, the metastasis is the only evidence
Breast 9.2 of an otherwise occult primary tumor.
Lung 7.5 Tracheal metastases result in cough, stridor,
Prostate 6.7 wheezing, dyspnea, and/or hemoptysis.
Colon 3.3
Stomach 2.5
Miscellaneous 18.4 C. Prognosis
Source: Based on Ref. 3. Metastases to the larynx, trachea, or hypopharynx are
usually associated with terminal, widespread dissem-
inated disease. In some instances, the metastasis may
Table 20 Site of Origin of 12 Tumors Metastatic to Trachea be isolated or localized and, with appropriate therapy,
a prolonged survival can be achieved.
Site Frequency (%)
Breast 33
Colon 25 REFERENCES
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4
Benign and Nonneoplastic Diseases of the Oral Cavity

and Oropharynx
Robert A. Robinson
Department of Pathology, The University of Iowa, Roy J. and Lucille A. Carver
College of Medicine, Iowa City, Iowa, U.S.A.
Steven D. Vincent
Department of Oral Pathology, Oral Radiology and Oral Medicine, The University of Iowa
College of Dentistry, Iowa City, Iowa, U.S.A.
I. FORDYCE GRANULES B. Pathology

Fordyce granules are developmental anomalies of the Histologically, normal-appearing sebaceous glands
oral mucosa. They are thought to arise from ectoderm are seen directly beneath the epithelium and may
inclusions formed during the fusion of the mandibular have a central duct (Fig. 2). Generally these ducts do
and maxillary processes. Fordyce granules, also not open to the surface. The only difference between
known as Fordyce spots, are extremely common. Fordyce granules and sebaceous units of the skin is
There is an increasing frequency of Fordyce granules that they lack associated hair follicles. Rarely Fordyce
with age up to the second and third decades, with granules have been reported to actively secrete (7).
males exhibiting the process earlier and more fre- Very rarely Fordyce granules have been associated
quently than females in childhood. While unusual in with sebaceous adenomas, keratin-filled cysts, and
infants, Fordyce granules is found to be present in steatocystoma simplex (8). Sebaceous carcinoma of
approximately 60% of children 10 years and younger, the oral mucosa has been reported, but its direct
and close to 90% of adults are reported to show these association with Fordyce granules is difficult to con-
lesions (1–3). Although proposed by Fordyce origin- firm (9).
ally to be the result of the degeneration of the prickle
cells of the oral epithelium, these lesions are ectopic
sebaceous glands. The most common sites include the C. Treatment and Prognosis
buccal mucosa and vermilion borders of the lips. Fordyce granules do not require treatment (10). Some
Other extra head and neck mucosal sites include the lesions have been treated with isoretinoin (11).
esophagus, uterine cervix, and thyroglossal duct (4).
They are not found in the conjunctiva, but have been
reported in patients that have undergone oral mucous II. WHITE SPONGE NEVUS
membrane grafts to correct inflammatory processes
(5,6). White sponge nevus is a rare benign autosomal domi-
nant disorder of the mucus membranes that results in
disordered epithelial differentiation. It is not a melano-
A. Clinical Features cytic lesion but considered a hereditary leukokeratosis.
Fordyce granules are asymptomatic and appear as Its first description is generally attributed to Cannon in
groups of small yellowish, submucosal globoid lesions 1935 (1–4). Synonyms include pachyderma oralis,
forming large plaques or small, separate foci. They are hereditary leukokeratosis, familial white folded dyspla-
often bilateral and symmetric on the buccal mucosa sia of the mucous membrane, congenital leukokeratosis
opposite the mandibular first molars and are also mucosa oris, and oral epithelial nevus. White sponge
common in the retromolar mucosa lateral to the nevus has been reported in the mucosa of the nose,
anterior pillars of the fauces (Fig. 1). They may also esophagus, rectum, anus, vagina, as well as the mucosa
be seen on the hard and soft palate, tongue, floor of of the oral cavity (5–8).
the mouth, alveolar ridge, and frenulum. The granules
are sometimes slightly elevated and range from 1 to A. Clinical Features
2 mm in diameter. They may be widely separated or
clustered and may coalesce into plaque-like lesions White sponge nevus is asymptomatic. As it is inher-
measuring 1 cm or more. ited, the appearance of white sponge nevus in
202 Robinson and Vincent
Figure 3 White sponge nevus. Diffuse, white, wrinkled areas

involve widespread areas of oral mucosa, including buccal,
labial, glossal, gingival, and palatal mucosa.
Figure 1 Fordyce granule. Fordyce granules (ectopic seba- areas. The process appears as spongy and white
ceous glands) of oral mucosa appear clinically as 1 to 2 mm plaques with a folded appearance; hence the synonym
diameter, yellow submucosal nodules. They can be single or in familial white folded dysplasia of the mucus mem-
groups. They are most often identified in the mucosa of the lips brane (6) (Fig. 3). The lesions may be single or
and buccal mucosa. multiple.
B. Pathology
The histologic features of the white sponge nevus are
typified by acanthotic epithelium with parakeratosis
(Fig. 4). Keratin aggregates, characteristic of the lesion,
are present in the suprabasal cells. Intracellular edema
is seen by light and electron microscopy, with hyper-
keratotic plugs extending deep into the acanthotic
layers. These hyperkeratotic plugs are useful for the
histologic diagnosis and are considered pathogno-
monic (9).
Figure 2 Fordyce granule. Clusters of acini and ducts charac-

teristic of typical sebaceous glands. Cytoplasm of secretory cells
is usually clear or foamy with centrally placed nuclei.
childhood is not unexpected, and it may be identified Figure 4 White sponge nevus. The epithelium shows relatively
at birth. Bilateral involvement of the buccal mucosa is uniform acanthosis, spongiosis, and hyperparakeratosis. There
most common but other sites include the lips, palate, should be no evidence of dysplasia.
ventral tongue, peritonsillar, and hypopharyngeal
Chapter 4: Benign and Nonneoplastic Diseases 203
C. Molecular and Genetic Data A. Clinical Features

White sponge nevus is an autosomal dominant pro- Most intraoral nevi are less than 1 cm and the majority
cess with high penetrance. Many genetic conditions are 0.1 to 0.3 cm (2). Congenital oral melanocytic nevi
affecting squamous epithelium, either skin or mucosa, are extremely rare (3). The highest incidence appears
are due to mutations in keratin genes. Keratins have a to be in the third and fourth decades. In contrast to
common structure of a central helical rod domain nevi occurring in the skin, where there is no gender
flanked by nonhelical head and tail domains (4,12). predominance, oral mucosal nevi are more common in
Helix boundary peptides begin and end the central females. The most common site of oral melanocytic
rod domain and are common sites for keratin muta- nevi is the palate. Interestingly, the palate is also the
tions. Recent studies have found mutations in keratins most common site for the very rare occurrence of
K4 and K13 genes, which encode mucosa-specific intraoral melanoma. Other sites of involvement by
keratins (10–13). Mutations in these regions, such as oral melanocytic nevi include the buccal mucosa, the
seen in white sponge nevus, are associated with con- gingiva, vermillion border of the lip, soft palate, and
ditions in which there is keratin filament aggregation. retromolar trigone. Unusual sites include the tongue
Mutations in the helix initiation peptide of K4 and K13 and floor of the mouth. Oral melanocytic nevi usually
in affected members from two families have been have distinct borders but may be flat, elevated, or
reported (11,12). exophytic.
As in the skin, melanocytic nevi occur in the oral
mucosa as intraepithelial (junctional), compound, or
D. Differential diagnosis intramucosal lesions. Intramucosal lesions are by far
the most common variety; however, all the types of
The clinical differential can include chronic cheek melanocytic nevi of the skin may be seen as counter-
biting, although these lesions should be localized to parts in the oral mucosa, including balloon cell nevus,
the buccal and glossal mucosa directly adjacent to the common blue nevus, and cellular blue nevus (2,4–6).
teeth. Other genodermatoses may mimic white sponge In descending order of frequency the types are intra-
nevus, including keratosis follicularis, pachonychia mucosal, compound, and common blue nevus, with
congenita, hereditary benign intraepithelial dyske- junctional nevus being the least common of this
ratosis, and ichythosiform dermatoses. Atypical group. Combined nevi, defined as having evidence
squamous diseases such as proliferative verrucous of associated of one or more of either common blue,
leukoplakia can also mimic white sponge nevus, cellular blue, intramucosal, compound, and spindle
although the clinical features and historical data of cell, similar to the nomenclature for skin lesions, have
time of onset of the lesions are usually helpful in also been rarely reported (7).
determining if a biopsy is indicated.
B. Pathology
The developmental features of oral melanocytic nevi
The lesions require no treatment. White sponge nevus are thought to mirror those developing in cutaneous
has not been shown to be premalignant. locations. The melanocytic cells begin with growth in
the epithelium at the junction of subepithelial-
epithelial tissue and then develop in the subepithelial
III. ORAL MELANOCYTIC NEVI tissue as separate nests. These nevi are termed com-
pound intraoral melanocytic nevi. Over time, the
Oral melanocytic nevi are known by a variety of other intraepithelial (junctional) component vanishes, with
names, including mole, pigmented nevus, and nevo- only the nevus cells present in the subepithelial tissue
cellular nevus. Oral melanocytic nevi are uncommon remaining, resulting in the common type, intramu-
in the oral mucosa, but solitary oral pigmented cosal melanocytic nevus.
lesions of melanocytic origin as a whole are uncom- The histologic features of oral nevi also mirror
mon. In a study of 89,430 biopsies accessioned in an those of the skin. The nevus cells are usually round to
oral and maxillofacial pathology laboratory during a oval in shape, although there may be some variation
19-year period, 773 (0.83%) were solitary pigmented in some of the cells size. Junctional nevi reveal nevo-
melanocytic lesions (1). Oral melanotic macules melanocytes at the junction of the mucosal epithelium
comprised 86.1% of the melanocytic group (0.7% of and submucosal connective tissue arranged in small
the entire accessioned biopsy series), and oral mela- nests. Compound nevi are composed of nevomelano-
nocytic nevi comprised 11.8% (0.1% of the entire cytes at the junction but also with nests of nevus cells
accessioned biopsy series). For comparison, melano- in the subepithelial connective tissue. Intramucosal
mas and atypical melanocytic proliferations com- nevi, the counterparts to intradermal nevi in the skin
prised just 0.6% of the melanocytic group and with the entire nevomelanocytic proliferation con-
0.006% of the total accessioned biopsies in the series. fined to the subepithelial submucosal connective tis-
The very infrequent development of intraoral muco- sue, show nonencapsulated nevus cells in small
sal nevi contrasts sharply with the ubiquitous nature clusters and aggregates (Fig 5). Common blue nevi
of cutaneous melanocytic nevi seen in individuals show elongated dendritic-like processes associated
with light skin. with melanin pigmentation (Fig. 6). Cellular blue
(8–11). Foreign bodies may include diverse material

such as graphite (pencil lead), ink, and medicaments,
beside the most common, amalgam, used in dental
procedures.
Oral melanotic macules should be considered in
the differential diagnosis of oral nevi, as they are the
most common pigmented melanocytic lesions in the
oral cavity. These lesions may be blue, brown, or
black. They are usually less than 1 cm in diameter
and have a predilection for the lower lip and gingiva,
as opposed to oral nevi. They are usually solitary and
seen in patients over 40 (12). Histologically, they show
melanin production in the basal cell layer, lamina
propria, or both. They do not show increased melano-
cyte proliferation and they are not associated with
elongated rete ridges.
Melanomas do occur in the oral cavity but are
relatively rare (1). Common blue nevi are not consid-
Figure 5 Oral intramucosal nevus. Clusters and theques of ered by most authorities to be associated with devel-
nevus cells with substantial melanin pigmentation is seen in this opment of melanoma, but whether other types of oral
typical intramucosal nevus.
melanocytic nevi are precursors to melanoma is diffi-
cult to determine. As noted, the palate is the most
common site of intraoral melanocytic nevi as well as
the most common site for intraoral melanomas. Some
reports of intraoral melanoma have described pre-
existing clinical pigmentation of the mucosa in the
affected area.
D. Treatment and Prognosis

Evaluation by epiluminescence microscopy (dermo-
scopy) has been advocated for evaluation of pig-
mented lesions of the oral cavity (13). Excision of
suspected oral nevi is highly recommended since it
may not be possible to clinically differentiate them
from oral melanoma (8).
IV. AMALGAM TATTOO

Amalgam tattoos result from the unintentional inser-
tion of amalgam restorative material into the soft
tissues during dental procedures (1). Amalgam tattoos
are commonly seen in the buccal, gingival, and alveo-
Figure 6 Oral common blue nevus. Spindling of the melano- lar mucosa, but the mandibular arch may be the most
cytes and diffuse melanin pigmentation is noted in this oral common site (2). The reported incidence of amalgam
mucosal blue nevus. tattoo has been reported to be 1.0% to 1.3% in two
patient-based series of biopsied oral lesions in oral
pathology practices (2,3). Likely, the incidence is
much higher, as lesions identified clinically as amal-
nevi are characterized by a clump of rounded to oval gam tattoo are usually not biopsied.
melanocytes containing melanin pigment. In a study of 20,731 surgical specimens described
clinically as pigmented lesions from an oral biopsy
C. Differential Diagnosis service, 268 cases were of amalgam tattoos, 105 were of
melanotic macules, and 32 were melanocytic nevi (3).
Besides melanocytic lesions, focal pigmented lesions Amalgam contains mercury, silver, and tin.
in the oral cavity include foreign bodies, ecchymosis, Mercury and tin may be absorbed into the blood
hemangiomas, and neoplasms. Systemic disorders stream, leaving primarily silver to corrode, although
and drugs also result in intraoral pigmentation. energy-dispersive studies reveal that all these ele-
Drugs such as amiodarone, chlorpromazine, minocy- ments are to be found in an amalgam tattoo.
cline, and antimalarials may cause pigmentation, as Numerous reports in older literature suggest that the
can systemic conditions, including Peutz-Jeghers elements in amalgam have been responsible for a
syndrome, Addison disease, and neurofibromatosis wide variety of systemic symptoms. The presence of
these materials within the oral submucosa has never

been reliably associated with any local or systemic
symptoms (4).
A. Clinical Features
Clinically, amalgam tattoos may be solitary or multi-
ple but are asymptomatic. Their coloration is gray or
dark blue-black in appearance (Fig. 7). The blue-black
coloration seen clinically is due to the electrolytic
corrosion of the amalgam. Most amalgam tattoos
measure less than 0.5 cm in greatest dimension (2).
They appear generally as macules and may have
either defined or irregular borders. The pigmentations
observed are seldom palpable, although in some cases
formation of submucosal fibrosis during the formation
of the tattoo may remain palpable for years. Over
time, amalgam tattoos may clinically enlarge. This
may be due to spreading of amalgam particles by
engulfing macrophages (5).
The clinical differential diagnosis includes other Figure 8 Amalgam tattoo. Black, foreign material is distributed
pigmented intraoral lesions, including melanocytic throughout the submucosa. Some tattoos will show microscopic
nevus, oral melanoma, and oral melanotic macule. evidence of a reactive infiltrate of lymphocytes, plasma cells, and
Varicosities with and without thrombi formation macrophages. Other tattoos show remarkably little inflammation.
may also be clinically similar to tattoos. Various
chemicals and drugs may cause pigmentation, includ-
ing cisplatin, arsenic, and bismuth. Occupational
exposures to mercury and lead may also lead to oral
B. Pathology
pigment deposition.
Unintentional oral mucosal tattoos may also be Microscopically the amalgam material is usually seen
found in patients with no history of amalgam place- just in the superficial submucosa but may be seen
ment. In these patients, the source of the accidental deeper (Fig. 8). The black to dark brown material
foreign material placement is often a graphite pencil can be seen in macrophages and giant cells but also
point. in fibroblasts, collagen, elastic fibers, blood vessel
walls, and endothelial cells (3). The pigmentation
can also occur in the minor salivary glands, nerves,
skeletal muscle, and the basement membranes of the
mucosa (1,3). In nearly half of all cases, there is no
inflammatory reaction, but one study reported 17% of
cases to have a macrophage response and 38% to
show a chronic response with foreign body granu-
loma formation with multinucleated giant cells (3).
Asteroid bodies may also be seen (3). Energy-
dispersive microanalysis reveals silver, tin, mercury,
and copper in the pigment (1,6,7).

Amalgam tattoos do not need to be treated since they do
not cause any local or systemic disease. The only reason
for biopsy is if other lesions of concern such as melano-
mas cannot be excluded on the basis of the clinical
appearance. Amalgam tattoos may also be excised if
they involve the lips and are a cosmetic concern.
Figure 7 Amalgam tattoo. Commonly identified intraorally, V. BENIGN MIGRATORY GLOSSITIS

amalgam tattoos are typically grey to black depending in part (GEOGRAPHIC TONGUE)
on the amount and type of foreign material introduced into the
submucosa. Other sources of ‘‘accidental’’ oral tattoos include Benign migratory glossitis (geographic tongue) is usu-
graphite from pencils. If enough foreign material is present, it can ally an asymptomatic inflammatory disorder of the
often be seen on a dental radiograph. tongue mucosa. The condition has a large number of
synonyms, including erythema migrans, superficial
migratory glossitis, pityriasis linguea, glossitis areata

migrans, exfolatio areata linguae, and lingual dystro-
phy. The term ‘‘migratory glossitis’’ is a good descrip-
tor, as the lesions appear to change location or
migrate, in pattern and size, sometimes within hours
or days. The descriptor geographic (geographic
tongue) is applied to the patterned lesions because
of the similarity to the viewing of an aerial map of
land masses (1,2).
The prevalence of the lesion varies by report but
is generally thought to be between 1.0% and 2.5% of
the population (3–8). It is more common in children in
some series (9).
Some studies show a female predominance but
others show the lesion affecting males equally.
The process is poorly understood but has been
associated with nutritional deficiencies, anxiety, pso-
riasis, and lichen planus. Reiter syndrome has also
Figure 9 Benign migratory glossitis. Multiple foci of filiform
been associated. However, a genetic predisposition is
papillae atrophy leaving smooth, red macules, bordered on
often present and the process often occurs with fis- some sides by thin hyperparakeratotic rims is clinically diagnostic
sured tongue. Histocompatibility antigens DR5 and for benign migratory glossitis (geographic tongue, erythema
DRW6 have been seen to be increased in patients with migrans).
geographic tongue (10). Interestingly, both psoriasis
and benign migratory glossitis are associated with
HLA-Cw6 (11,12). Further, the histologic appearances
may mimic that of psoriasis. Conflicting views exist
about the association with diabetes. Patients with atopy,
including asthma, hay fever, or eczema are more likely
to have geographic tongue (13). Hormonal associations
also have been noted, including timing with oral con-
traceptive cycles.
Benign migratory glossitis is most often asymptomatic,
although some patients complain of irritation when
eating spicy foods. If patients complain of symptoms
such as burning, there can be a secondary condition
such as oral candidosis. The lesions appear as multi-
focal, rounded, or irregular flat, red patches usually
with an elevated white border composed of aggregat-
ed papillae (Fig. 9). Only a single lesion may be seen
in some patients. Most commonly affected areas are on
the dorsum of the tongue, followed by the lateral
margins, or the tip of the tongue (14,15).
B. Pathology Figure 10 Benign migratory glossitis. The surface epithelium

shows loss of the normal overlying filiform papillae, replaced by
Histologically, there may be an acute and chronic areas of irregular acanthosis or areas of atrophy. The epithelium
inflammatory infiltrate in the submucosa from the shows no evidence of cellular atypia. A chronic infiltrate of
center of the lesion with epithelial edema and neutro- lymphocytes, plasma cells and neutrophils is seen in the
phils. Epithelial regeneration is present. Neutrophilic submucosa.
microabscess formation, similar to Munro microab-
cesses, is typical. The epithelium of the hypertrophic
margin of the lesions is parakeratotic (1). These features
often bear a striking resemblance to epidermal psoria-
sis (Figs. 10,11). incisional biopsy is performed, the differential diag-
nosis would include other noninfectious inflammatory
C. Differential Diagnosis diseases such as lichen planus. However, neutrophils
and microabscess formation should not be found in
Benign migratory glossitis is most often diagnosed lichen planus. In symptomatic cases, evidence of a
entirely on the basis of its clinical features. If an secondary candidosis can be found.
Synonyms include central papillary atrophy, posterior

midline atrophic candidiasis, and posterior lingual
papillary atrophy. The prevalence in the general
population is approximately 0.2%. It is more common
in elderly patients and relatively rare in healthy
children (1,2).
Median rhomboid glossitis has been considered
under a wide variety of etiologies, including inflamma-
tory processes, developmental origins, or local alter-
ations in blood supply. The area affected is the
posterior dorsal aspect of the tongue. Some have sug-
gested that there is a defect in the fusion at the posterior
aspect of the paired lingual (lateral) tubercles that form
the tongue during embryogenesis, which results in a
depapillated surface. Others indicate that this area is
also prone to an impaired blood supply. The majority
opinion, however, is that median rhomboid glossitis is
a chronic atrophic epithelial reaction to Candida. (3,4)
Candida organisms, however, are not found in all
Figure 11 Benign migratory glossitis. Areas of alternating cases.
acanthosis and atrophy are seen in the stratified squamous Experimental work in rats does indeed reveal
epithelium. Psorisaform pockets of neutrophils are often seen that long-term Candida infection may result in histo-
in the superficial stratum spinosum. logic changes similar to those seen in median rhom-
boid glossitis (5). A few cases have been associated
with Actinomyces (6). A decrease in Langerhan’s cells
has been noted, which suggests a localized defect in
D. Treatment and Prognosis immune surveillance (7).
The lesions require no specific treatment, but the Smoking and denture wearing may also con-
patient may require explanation that the lesion is not tribute to the abnormality by favoring an environ-
malignant or premalignant (16). Some authorities ment for Candida proliferation. (8) It is also not
believe that cases in which the patient can clearly uncommon in patients with acquired immunodefi-
identify a precipitating cause, removal of the stimulus ciency syndrome (9,10). Diabetes, highly associated
may help, but this is not universally accepted. with oral candidiasis, is also linked with median
rhomboid glossitis. The lesion may be an indicator
of severity or extent of disease, as diabetic patients
VI. MEDIAN RHOMBOID GLOSSITIS with median rhomboid glossitis have been reported
to be more likely to have a longer duration of insulin-
Median rhomboid glossitis is a depapillated round or dependent diabetes mellitus and complications of
rhomboid, smooth, pink or erythematous, nodular nephropathy and retinopathy (11,12). Median rhom-
area found on the mid-dorsal surface of the tongue boid glossitis has also been associated with amyloid
just anterior to the circumvallate papillae (Fig. 12). production, presumably because of chronic inflam-
mation (13).
Median rhomboid glossitis presents as a red lesion in
the midline of the tongue, anterior to the circumvallate
papillae, and most lesions are less than 2 cm (14).
There is depapillation that is oval, rhomboid, or dia-
mond shaped. This area may be flat or slightly raised
and nodular. Because it is red with surface changes, it
can be occasionally confused clinically with erythro-
plakia. An adjacent palatal mucosal focus of inflam-
mation often termed a ‘‘kissing lesion’’ has been noted
in patients with median rhomboid glossitis (15).
B. Pathology
Figure 12 Median rhomboid glossitis. A focus of papillary Histologically, median rhomboid glossitis shows fili-
atrophy on the dorsal tongue midline, just anterior to the circum- form papillae atrophy, parakeratosis, and irregular
vallate papillae. The shape is often, but not always rhomboid. acanthosis. Both the fungiform and filiform papillae
are diminished or absent (Fig. 13). The rete can

Therapy for median rhomboid glossitis is controversial.
Some authors recommend treatment of patients with
antimycotic agents, but others suggest that antifungal
treatment is unwarranted and does little to affect the
course of the condition unless the cause of the oppor-
tunistic infection is identified and eliminated. Cessation
of smoking and correcting denture problems or limit-
ing denture wearing may help in some patients in
whom these issues are noted.
VII. NICOTINIC STOMATITIS

Nicotinic stomatitis (also known as smoker’s palate)
presents clinically with the appearance of hyperkera-
tosis of the hard and/or soft palatal mucosa with
multiple small red dots corresponding to the orifices
of minor salivary gland ducts (1–6). Nicotinic stomati-
Figure 13 Median rhomboid glossitis. The overlying papillae tis is seen almost exclusively in pipe smokers with
architecture is replaced by irregular areas of epithelial acanthosis intense usage, but cigar and cigarette smokers are not
or atrophy. Candidal hyphae and spores are often noted in the immune (7). Some believe that the response is primar-
superficial stratum spinosum. The underlying fibrovascular con- ily due to a response to heat rather than tobacco
nective tissue will show a moderate to dense infiltrate of lym- smoke by-products, although these two causes are
phocytes, plasma cells, macrophages, and neutrophils.
difficult to separate. Some patients that do not
smoke but consume very hot liquids may develop a
similar process. Men are more frequently afflicted
than women.
become elongated and lead to the forming of
‘‘test-tube’’ rete ridges. Pseudoepitheliomatous hyper-
plasia may be quite marked. Candida pseudohyphae A. Clinical Features
and spores are seen in the upper layers of the epithe-
Nicotinic stomatitis is asymptomatic. It characteristi-
lium in many cases. A chronic inflammatory cell
cally occurs posterior to the palatal rugae. The small
infiltrate primarily made up of lymphocytes, plasma
erythematous areas seen clinically represent dilated
cells, and macrophages as well as some fibrosis and
and inflamed openings of the minor salivary glands
hyalinized changes may be seen in the submucosal
surrounded and made more clinically prominent by
tissues (1,16–19).
surrounding hyperkeratotic palatal mucosa (Fig. 14).
Splitting or fissuring of the mucosa is seen in cases
C. Differential Diagnosis
This site-specific lesion is most often diagnosed on
the basis of its clinical presentation alone. In some
rare instances, Kaposi’s sarcoma of the dorsal tongue
in patients with acquired immunodeficiency syn-
drome may have resemblance to median rhomboid
glossitis (10). The histologies differ, as the atypical
vascular proliferation and spindle cell proliferation
is not seen in median rhomboid glossitis. Since
median rhomboid glossitis is a red mucosal area of
the oral mucosa, erythroplakia might be considered
clinically and result in a biopsy to rule out a pre-
invasive squamous lesion. Rarely, invasive squa-
mous carcinoma may mimic median rhomboid
glossitis (20). Histologically, the pronounced pseu-
doepitheliomatous hyperplasia may be so marked
that a diagnosis of well-differentiated squamous
carcinoma may be entertained. Clinical information
pertaining to the site and appearance of the tongue Figure 14 Nicotinic stomatitis. There is widespread, relatively
lesion would be useful in the evaluation of such uniform hyperkeratosis of the posterior hard and anterior soft
lesions. However, the epithelial hyperplasia in median palatal mucosa in this chronic pipe smoker. Multiple small ery-
rhomboid glossitis does not show a desmoplastic thematous nodules representing inflamed minor salivary gland
response nor are there other architectural changes of ducts are seen.
invasion carcinoma.
Usually the area affected is the dorsum of the

tongue immediately anterior to the circumvallate
papillae, but lateral and anterior distribution has
been described (6,7). Often this hyperkeratosis is
darkened and maybe known as black hairy tongue.
Other colors include dark green, yellow, or brown.
It is thought that the coloration most often arises
from tobacco or food products such as coffee or tea.
Hairy tongue is more common in elderly patients and
those with chronic illness with limited food intake. In
these instances, it is attributed to the lack of friction
food produces during mastication, but poor hygiene
practices are likely contributory as well (8–12).
Figure 15 Nicotinic stomatitis. The overlying stratified squamous Vitamin deficiency and use of mouth washes have
epithelium shows extensive hyperparakeratosis, hyperorthokera-
also been implicated. The pH of the tongue surface
tosis, and mild acanthosis with no evidence of cellular atypia. The
submucosa contains a mild to moderate infiltrate of lymphocytes, has been noted to be below 6 in many patients (13).
plasma cells, and neutrophils. Some sections can show inflamed Hairy tongue is often reported in patients who have
minor salivary gland ducts, often with squamous metaplasia. taken a wide variety of antibiotics and phenothiazines
(14–16). It has also been linked to smoking, but the
amount of tar and nicotine consumed daily does not
necessarily correlate with its presence (17).
where the hyperkeratosis is prominent giving a nodu-
lar appearance in advanced stages. The mucosa can A. Clinical Features
assume a grayish white or brown coloration because
of extrinsic staining, similar to that seen in hairy Patients frequently are asymptomatic but may com-
tongue. plain of bad breath. Hairy tongue presents as an
irregular, often dark brown to black plaque that can
be removed partially by vigorous scraping. The
B. Pathology
enlarged and the elongated papillae give the surface
Histologically, there is hyperortho- or parakeratosis of the tongue a hair-like appearance, sometimes
and acanthosis of the palatal epithelium and lympho- described as furry (Fig. 16). The medial aspect of the
cytic inflammation of the subepithelial tissues (Fig. 15). dorsal surface of the tongue is most often affected, but
There should be no evidence of epithelial dysplasia. the process may be localized unilaterally (18).
Squamous metaplasia of the minor salivary gland ducts In the clinical differential diagnosis, hairy
can be seen in some cases but is not necessary for the tongue should be separated from oral hairy leukopla-
diagnosis (8,9). kia, with which it has significantly different histologic
and clinical appearances as well as etiologic origins
(19).
Nicotinic stomatitis is not a premalignant lesion, but
tobacco exposure places the entire upper airway at
risk for dysplasia and carcinoma. Therapy is cessation
of smoking and the tissue may return to normal
appearance in as little as one to two weeks.
VIII. HAIRY TONGUE

Hairy tongue is a benign condition characterized by
hyperkeratosis and enlargement of the filiform papil-
lae. Whether there is an overproduction of keratin or a
loss of the ability to desquamate keratin is not known
and both processes may be at work. The elongated
filiform papillae also characteristically trap desqua-
mated cells and bacteria (1,2). Synonyms include black
hairy tongue, lingua villosa nigra, melanotrichia
linguae, and hyperkeratosis of the tongue (3). The Figure 16 Hairy tongue. There is profound hyperkeratosis of
prevalence of hairy tongue varies. In a study in the filiform papillae on the dorsal tongue. The increased kerato-
Jordan of over 1000 patients of all ages, 3.4% had sis is usually most prominent near the midline, just anterior to the
hairy tongue (4). Most of these patients were males circumvallate papillae. The keratin will retain a variety of extrinsic
and were smokers. In contrast, in a study of over products and is further colored by numerous bacteria and fungal
3600 school children from Minnesota, only two had colonies.
hairy tongue (5).
Oral hairy leukoplakia often does not occur

alone. Other oral pathologies are evident, and
Candida hyphae are reported to be present in as
many as 50% of oral hairy leukoplakia lesions (6,10).
It is most often identified in males with male-to-male
HIV risk behaviors. It is rare in children (3,11). Reports
appear mixed as to whether treatment of patients with
AIDS using multidrug therapy (highly active antire-
troviral therapy, HAART) has successfully decreased
the incidence of oral hairy leukoplakia (7,12–14).
Oral hairy leukoplakia is caused by Epstein-Barr
virus (EBV) infection, and experimental work suggests
that a recombinant variant of the EBNA-2 gene may
play a role in the pathogenesis (15). Evidence suggests
that CD4-positive T cells are involved in primary host
defense and that low CD4 counts are responsible for
oral hairy leukoplakia in HIV-positive patients (16,17).
Where the EBV initiates the lesion is incompletely
resolved. EBV is a ubiquitous herpes virus, and infection
results in persistence of the virus for life, and a reservoir
is thought to be B lymphocytes. Tongue epithelial cells
in nonimmunosuppressed patients are usually not able
to support EBV replication (18). However, even normal-
appearing tongue epithelial cells in patients with a
history of immune suppression have impairment of
Figure 17 Hairy tongue. There is profound hyperparakeratosis
the immune system allowing EBV replication (15,19).
of the filiform papillae. Numerous bacterial and fungal organisms
are seen among the hyperkeratotic layers. The stratified squa-
The mechanism of action of EBV in oral hairy leukopla-
mous epithelium should show no evidence of cellular atypia. kia is complex, and some data suggest an interaction of
blood and epithelial reservoirs of EBV in the pathogen-
esis of oral hairy leukoplakia (20). The presence of EBV
DNA in basal and parabasal epithelial cells of the
B. Pathology tongue supports the theory that hairy leukoplakia rep-
Hairy tongue is not always biopsied because the resents a reactivation of latent lingual infection (21). It is
clinical appearance is characteristic. Histologically, thought that the EBV evades mucosal immune response
the elongated papillae show marked surface hyper- in oral epithelial infection possibly because of a relative
keratosis and trapped microorganisms (Fig. 17). The decrease in Langerhan’s cells (22).
lamina propria may show a mild lymphocytic infil-
trate. Immunohistochemical studies have shown that A. Clinical Features
there is retention of cells expressing the hair-type
keratins (20). Electron micrographic studies have Oral hairy leukoplakia usually is asymptomatic. It is
shown abnormally long secondary papillae with seen as a white and poorly demarcated, usually cor-
the surface squamous cells arranged in a fish scale rugated or furrowed and ‘‘hairy’’ lesion, although
or roof tile pattern. These orthokeratinized cells are some lesions may be relatively flat. Most frequently,
often coated with microorganisms (21,22). it involves the tongue bilaterally but may be unilateral,
and other intraoral sites such the buccal mucosa have
C. Treatment also been reported (23). The lesion does not regress
after topical or systemic antifungal therapy.
A variety of treatments have been proposed with Oral hairy leukoplakia may be mimicked by other
brushing or light scraping of the tongue, the most diseases (10). The clinical differential diagnosis
effective and most recommended (11). Treatment includes papillomas and oral warts. Chronic abrasion
with isoretinoins has been attempted as well as podo- of glossal mucosa by the adjacent teeth can produce a
phyllin (23–26). hyperkeratosis of the lateral filiform papillae similar to
that seen in oral hairy leukoplakia. Plaque-forming oral
IX. ORAL HAIRY LEUKOPLAKIA candidosis, also a common finding in immunosup-
pressed patients, can form rough white lesions virtually
Oral hairy leukoplakia is observed mainly in individuals identical to oral hairy leukoplakia. Syphilis has also
with HIV infection (1–8). Most HIV-positive patients do been reported to give a similar appearance (24).
not have AIDS at the time of diagnosis of oral hairy Importantly, patients who are HIV-negative but
leukoplakia, but AIDS develops later in a high percent- are otherwise immunosuppressed may have oral
age (1). Oral hairy leukoplakia is only second in frequen- hairy leukoplakia. Uremic stomatitis and ulcerative
cy to oral Candidiasis in HIV-positive persons with colitis have also been reported to be associated with
frequencies ranging from 20% to nearly 50%, and patients lesions that appear histologically similar to oral hairy
with overt AIDS often have a higher incidence (9). leukoplakia (25,26). While oral hairy leukoplakia is
often an oral manifestation of sexually transmitted Many, but not all, authors believe that EBV
disease, this is not always the case. Oral hairy leuko- should be demonstrated in tissue biopsies before a
plakia has been described as an early indicator of diagnosis of oral hairy leukoplakia is rendered. A
EBV-associated posttransplant proliferative disorder variety of detection methodologies exist, including
and has occurred in HIV-negative patients with acute polymerase chain reaction (PCR) and in situ hybrid-
lymphocytic leukemia, multiple myeloma, bone mar- ization as well as immunohistochemistry (10,38–40).
row transplants, and other neoplastic diseases treated
with immunosuppressive oncologic therapies
C. Electron Microscopy
(8,27–32). ‘‘Pseudo-oral hairy leukoplakia’’ has also
been described in rare patients that have oral lesions By electron microscopy herpes virus nucleocapsids
with both clinical and histologic features of oral hairy can be demonstrated in the ballooned keratinocytes
leukoplakia but are HIV-negative, have no immuno- (35,41–44).
suppression, and whose lesions do not demonstrate
EBV (10,33). Because of these mimics, numerous
authors recommend that diagnostic criteria for oral D. Treatment and Prognosis
hairy leukoplakia include clinical, histopathologic, Oral hairy leukoplakia is usually asymptomatic and
and immunohistochemical or molecular analysis (10). often does not require therapy. If the lesions are
symptomatic, then usually culprit is a secondary
B. Pathology candidosis, and treatment with systemic or topical
antifungals will be of value. Acyclovir and valacy-
Although there are a number of histologic features clovir may be used for therapy, but some investigators
that have been associated with oral hairy leukoplakia, have reported drug resistance, which may limit their
these features are not always specific (23). The epithe- usefulness.
lium is characterized by hyperparakeratosis of vari-
able thickness, acanthosis, and minimal-to-absent
submucosal inflammation (Fig. 18). The tongue fre- X. FOCAL EPITHELIAL HYPERPLASIA
quently shows hair-like projections of keratin (34). (HECK’S DISEASE)
Often a band of parakeratin, sometimes with corruga-
tion, can be seen sharply demarcated from the spinous Focal epithelial hyperplasia is a benign hyperplastic
layer. In the upper part of the spinous layer the EBV- lesion of the oral cavity that is caused by human
infected cells often have the appearance of koilocytes. papilloma virus (HPV) infection (1,2). It is commonly
The cells show cytoplasmic ballooning or ground- known as Heck’s disease after publication of a study of
glass change and intranuclear inclusions (35). primarily Native American Navajo children in 1965 (3).
Candida hyphae and spores are seen in many cases. However, the literature indicates that the lesion had
Cytologic preparations have also been described for been described earlier in numerous reports (4–6).
detection of oral hairy leukoplakia and to show con- Focal epithelial hyperplasia is much more com-
densation and margination of nuclear chromatin mon in certain ethnic groups such as Native
forming a bead-like appearance as well as intranuclear Americans, Eskimos, and native people in Central
inclusions (36,37). and South America. It is relatively rare in Caucasians
(4). In Native Americans, it is most commonly seen in
children and teenagers. In Eskimos, the lesions have
been found in all age groups with the highest preva-
lence in people older than 30 years. The lesions in
Native Americans are most frequent in the mucosa of
the upper lip followed by the buccal mucosa, commis-
sures, and labial mucosa of the upper lip (7). In
Eskimos, more than half the lesions are on the tongue
(7). Focal epithelial hyperplasia has also been reported
in an adult HIV-positive individual (8).
The lesions present as circumscribed, sessile, soft, and
elevated nodules of the oral mucosa (Fig. 19).
Although beginning as separate nodules, the lesions
often become confluent and cover large areas of the
Figure 18 Oral hairy leukoplakia. The stratified squamous
oral mucosa of the lips and buccal surfaces as well as
epithelium shows evidence of irregular hyperparakeratosis and
acanthosis. The parakeratin often shows focal infiltration of
the tongue.
fungal hyphae and spores. Koilocytes are found nested in the
superficial stratum spinosum. The submucosa can show a B. Pathology
chronic inflammatory cell infiltrate or be free of inflammatory
cells presumably due to the patient’s immunosuppressed state. Histologically, the lesions show epithelial hyperplasia
with acanthosis and elongation and anastomosing of
D. Electron Microscopic Studies

Electron microscopic examination reveals viral particles
(4).

No treatment is generally required as the lesions
frequently spontaneously resolve. The period of time
for resolution is variable, usually months but some
patients require up to a year or more for resolution.
Focal epithelial hyperplasia is not considered prema-
lignant (1,2).
XI. CONDYLOMA ACUMINATUM

A. Definitions and Synonyms
Figure 19 Focal epithelial hyperplasia (Heck). Multiple, sessile,
smooth nodules involving any and all mucosal surfaces. The Condyloma acuminatum, also known as oral wart,
number and distribution of the nodules varies greatly form patient venereal wart, verruca acuminatum, and moist wart,
to patient. is caused by HPV and appears one to three months
after exposure (1–3). Condyloma acuminatum most
commonly involves anogenital sites. Lesions involv-
ing the oral mucosa were rarely reported until rela-
tively recently (4,5). Condyloma acuminatum is most
often associated with HPV subtypes 6 and 11 and is
frequently seen in HIV-positive patients. Similar to
anogenital condylomas, oral condylomas occur pre-
dominantly in young sexually active men in the third
and fourth decades (6,7). Immunocompromised indi-
viduals, including those infected with HIV or organ
transplant patients, are at an increased risk for oral
condylomas. Some suggest that there is an increase in
oral condylomas following use of HIV antiviral thera-
py, but this is controversial (6–10).
Oral condyloma is most commonly due to oral
sexual contact. The occurrence of oral condylomas in
young children and in patients with no sexual contacts
provides support for transmission by other means,
including autoinoculation, hematogenous spread, and
maternal transmission (1).
Figure 20 Focal epithelial hyperplasia (Heck). Focal areas of Oral condylomas may occur in conjunction with con-
stratum spinosum show acanthosis and mild hyperparakeratosis. dylomas at other sites, but may occur in the absence of
The lesions are well demarcated from the adjacent uninvolved condylomas elsewhere. Most are asymptomatic but
surface mucosa. may be tender if secondarily inflamed. They may be
multiple, and the most common sites are the upper
and lower lips, lingual frenulum, and dorsum of the
tongue. Other sites include the palate, buccal mucosa,
and floor of the mouth.
the rete ridges (Fig. 20). There is some resemblance to Condylomas appear as soft verrucous nodules or
condyloma acuminatum. Koilocytes are often found. multiple adjacent papillary clusters that tend to coa-
The lesions in focal epithelial hyperplasia do not form lesce into soft, pink cauliflower-like masses, although
fibrovascular cores as seen in papillomas (1,2). isolated lesions may occur (11) (Fig. 21). They may
also appear clinically as a diffuse verrucoid hyperpla-
C. Molecular and Genetic Data sia, an irregular exophytic mass with a granular
surface or multiple sessile fibroma-like lesions (12).
Multiple subtypes of HPV may be found in focal Clinically, condyloma may mimic other localized
epithelial hyperplasia, but HPV types 13 and 32 are epithelial proliferative conditions, including Heck’s
the most common (9). Other subtypes include HPV 6, disease, verruca vulgaris, squamous papilloma, or
HPV 16, and HPV 11. verrucous carcinoma (7).
Figure 21 Condyloma acuminatum. Rough, exophytic, sessile, Figure 23 Condyloma acuminatum. The epithelium shows evi-
papillary projections, occurring singularly or in groups. They may dence of profound stratum spinosum acanthosis-forming broad,
involve any oral mucosal surface but are most often noted to bulging rete ridges. There is often mild hyperparakeratosis.
involve soft palatal or floor-of-mouth mucosa. Koilocytes can often be noted but are not numerous. There
should be no evidence of dysplasia.
C. Pathology
acuminatum occurring in the anogenital regions.
Usually condyloma acuminatum has a pronounced However, dysplastic change may be detected, partic-
spinous layer hyperplasia and cellular ballooning, and ularly in those occurring in the presence of HIV
mitoses are seen extending into the spinous layer infection (13).
(Figs. 22,23). The base of the rete ridges are often
bulbous. The lesions show parakeratosis, acanthosis,
and papillomatosis. Frequently a mild lymphoplasma- D. Differential Diagnosis
cytic infiltrate is seen. Usually the base is sessile, and The microscopic differential diagnosis includes verruca
there is parakeratin crypt formation (1,7). These para- vulgaris, papilloma, and verrucous carcinoma (12).
keratin crypts invaginate into the spinous layers. Verrucae are typically sessile, circumscribed, exophytic
Condylomas often show koilocytes or paranuclear growths with elongated rete ridges often forming a
clearing, but frequency of these findings is variable in radial pattern pointing toward the center of the lesions.
the literature (1,7,11). The squamous proliferation seen Additionally, verruca vulgaris has epithelial projec-
in Condyloma acuminatum has also been reported to tions with more pointed ends (11). They exhibit hyper-
involve excretory ducts of minor salivary glands. parakeratosis at the tips and sometimes show
Malignant transformation of oral cavity condy- hyperorthokeratosis on the sides (11). Condylomas
loma appears to be rare as opposed to condyloma have a papillomatous surface, and the stratum cor-
neum is usually only slightly thickened.
Histologically, condyloma can be difficult to
separate from squamous papillomas at times, and
koilocytes are not always present. Squamous papillo-
mas are usually pedunculated and exophytic and tend
to exhibit epithelial tissue projecting outward from a
central vascular core of fibrovascular tissue (1).
E. Electron Microscopy
Electron microscopy reveals intranuclear viral particles,
and the particles are most numerous in the superficial
layers of the parakeratinized epithelium (3).
F. Molecular Genetic Data

Figure 22 Condyloma acuminatum. Marked stratum spinosum
acanthosis is present. HPV DNA may be found by immunohistochemistry
or molecular techniques such as in situ hybridization.
These techniques usually reveal that the oral condylo- B. Pathology

mas are caused by HPV types 6 and 11, but other
types are sometimes found (14,15). Histologically, verruca vulgaris in most cases reveals
long vascular cores coated in thick layers of epithelial
cells that form pointed projections (Fig. 25). Koilocytes
G. Treatment and Prognosis are seen in the majority of lesions, and an inflammatory
infiltrate may be present in the connective tissue cores.
The recommended therapy for single, localized lesions A granular layer is seen. There are variations in the
is excision. For widespread lesions, often noted in histologic appearance of verruca vulgaris giving rise to
immunocompromised patients, biopsy for diagnostic a number of low-power patterns. These have been
purposes followed by ablation is recommended. categorized as acropapilliform, acroform, and crypto-
Ablation can include, laser and topical applications form (5). The acropapilliform has an abrupt cupped
of podophyllin, 5 fluorouracil (5-FU) or tricholoracetic margin with papillomatous projections having both
acid (14). Intralesional antivirals have also been used angulated and rounded, bulbous patterns. The acro-
(6). As expected, oral lesions may recur after form has abrupt margins showing acutely angulated
treatment. verrucous projections. The cryptoform pattern has dis-
crete margins but with minimal exophytic projections.
XII. VERRUCA VULGARIS
Verruca vulgaris is a warty exophytic lesion that
C. Molecular and Genetic Data
resembles verrucae in other sites, including the skin. Many HPV types are seen in oral verruca vulgaris.
It is caused by the HPV (1,2). HPV type 2 is relatively common, but types 1, 4, 7, and
57 have also been reported (2,6,7).
Young adults and children are most often affected. It
D. Differential Diagnosis
is thought that autoinoculation of virus, possible from The histologic differential diagnosis includes benign
the hands, may be a factor in their intraoral develop- and malignant lesions, including squamous papillo-
ment. Usually verruca vulgaris is solitary but may be ma, condyloma acuminatum, verruciform xanthoma,
multiple. Common sites include the lips, palate, proliferative verrucous leukoplakia, verrucous carci-
alveolar ridge, and gingiva (3,4). Their appearance is noma, and papillary squamous carcinoma (8–10).
similar to verrucae elsewhere with a wart-like surface Squamous papillomas may be difficult to distin-
thatcan have irregular white spires protruding from guish from some verruca, but the former usually do
the surface of the mucosa (Fig. 24). Alternatively, they not show a broad or as sessile base as seen in the
can be nodular plaque-like lesions. Verruca have an latter. Papillomas also do not demonstrate a center-
entirely exophytic growth pattern, a feature which can ward curve of the outermost squamous proliferation
be of value in clinically distinguishing it from early
verrucous carcinoma and papillary squamous cell
carcinoma.
Figure 25 Verruca vulgaris. An exophytic, epithelial architec-

ture with acanthosis, and hyperparakeratosis. The base can be
sessile or pedunculated. Rete ridges often seem to radiate
Figure 24 Verruca vulgaris. A rough, multi-spiked, exophytic, outward from a central point. The epithelial proliferation does
well-demarcated lesion that can involve any mucosal surface but not invade into the submucosa. Koilocytes are often noted. There
is most often noted on labial or glossal sites. should be no evidence of dysplasia.
papillae. Further, papillomas do not show a distinct

granular layer or as distinct koilocytes as verrucae.
Condyloma acuminatum does not have prominent
verrucous projections and lacks a prominent granular
layer. Verrucous carcinomas may resemble verruca
vulgaris, but verrucous carcinoma extends deeply into
the underlying stroma and most are larger than
verruca vulgaris. Verruciform xanthoma has foamy
cells just beneath the epithelial layer. Proliferative
verrucous leukoplakia is not as localized as verruca
vulgaris.

Surgical excision is the treatment of choice, although
some lesions may spontaneously regress. Recurrences,
although unusual, are possible.
Figure 26 Papilloma. A rough, often pedunculated, exophytic,
well-demarcated lesion that can involve any oral mucosal
XIII. PAPILLOMA surface.
Papillomas are among the most common of benign
epithelial tumors of the oral cavity in both children
and adults but are most commonly seen in persons of
30 to 50 years (1–3). Papillomas accounted for 1.5% of
oral pathologies in a study of 2057 patient reports in a
study from Singapore (4). Studies appear to be split as to
whether females or males are more commonly affected
(4,5). Most papillomas are less than 1 cm, and fewer than
10% are over 2 cm in size.
Most investigators regard papillomas as neoplas-
tic, but some suggest that they are nonneoplastic,
possibly a tissue reaction to injury (6). A high percent-
age of squamous papillomas are shown to have HPV
sequences, and it seems likely that many papillomas
are caused by HPV. While not all studies of papillo-
mas reveal HPV sequences, it is likely that this may be
due to the technique used for detection (1,7–11). Using
the PCR, HPV can be found in a high percentage of
oral scrapings or swabs from adults and children with
no oral lesions (12–14).
Figure 27 Papilloma. An exophytic, often pedunculated, tree-like
Papillomas are exophytic proliferations arranged in a proliferation of stratified squamous epithelium. Each epithelial
finger-like configuration, giving a cauliflower-like branch has a core of fibrovascular connective tissue. There is
clinical appearance (Fig. 26). Papillomas are usually no extension into the underlying connective tissue. There can be
varying amounts of parakeratosis but without evidence of
solitary and reach their maximum size within a few
dysplasia.
weeks (2). Most are less than 1 cm in size. While the
majority are pedunculated, some are sessile (7).
Usually papillomas are white due to keratinization of
the surface, but those without abundant keratin pro-
duction may be pink. The tongue and palate are cells. Papillomas can rarely show dysplastic changes,
common sites of involvement (3). but this is uncommon in solitary papillomas (5).
B. Pathology C. Differential Diagnosis

Squamous papillomas are small exophytic lesions with Papillomas occurring singly must be differentiated
a central fibrovascular core covered by stratified, para- from other conditions resulting in multiple papillomas
keratinized epithelium (3) (Fig. 27). A chronic inflam- of the oral mucosa, including Heck’s disease, denture-
matory cell infiltrate can often be found in the otherwise related inflammatory papillary hyperplasia, and hairy
bland fibrovascular connective tissue. Viral changes tongue (2). Other papillomatous lesions include ver-
may be seen in the uppermost layers of the epithelial ruca vulgaris and condyloma (15).
Verruca vulgaris frequently mimics verrucae of

the epidermis with a more sessile base than squamous
papilloma and also show a more marked hyperkerato-
sis. Condylomas differ from papillomas in that condy-
lomas are usually multiple, confluent, and larger than
squamous papillomas. Condylomas histologically are
also more likely to show parakeratin crypt formation
and often show many more koilocytes (7,15).

Treatment is conservative, complete surgical excision.
Recurrence is unusual.
XIV. VERRUCIFORM XANTHOMA

Verruciform xanthoma was first reported in 1971 and is
a rare lesion of the oral cavity that usually involves the
buccal mucosa, gingiva, alveolar ridge, and, more Figure 28 Verruciform xanthoma. A well-demarcated, rough,
rarely, the lip (1–3). The reported age range has been hyperkeratotis, slightly exophytic soft tissue that can be found to
from 2 to 89 with a roughly equal female to male involve any area of oral mucosa.
occurrence. Most lesions are less than 2 cm in diameter.
The cause is unknown but some authors favor an
inflammatory origin. The inflammation has been pro-
posed to be an aberrant response leading to foam cell
accumulation, a viral or bacterial infection as an initia-
tor of the inflammatory response, or a genetic predis-
position leading to the accumulation of intracellular
lipids. The foam cells represent histiocytes (4,5).
Some cases of verruciform xanthoma have been
associated with other oral lesions or systemic condi-
tions, including pemphigus, lipid storage disease,
carcinoma in situ, warty dyskeratosis, graft versus
host disease, lichen planus, discoid lupus erythema-
tosus, and tobacco use (6–9).
Rare cases have been positive for HPV6/11 by in
situ hybridization, but other authors have not been
able to demonstrate HPV in these lesions (5,10,11).
Clinically, verruciform xanthoma is well circum-
scribed and may be flat, papillary, or sessile. Many
have a cauliflower-like roughened surface (12,13)
(Fig. 28). They generally are slow growing. The lesions Figure 29 Verruciform xanthoma. At low microscopic power, a
may be pink, red, yellow, or white, depending on the verrucous surface is evident.
degree of keratinization (14). The margins are often
sharply demarcated. The center of the lesion has been
described as depressed, cup-shaped, or crateriform
and may be ulcerated. Most lesions are asymptomatic minimally raised to flat. The verrucous pattern reveals
and are detected incidentally. a warty surface with marked hyperparakeratosis.
Clinically, the differential diagnosis includes The papillary pattern shows a less church-spire archi-
papillomas, verruca vulgaris, leukoplakia, carcinoma tecture than the verrucous patterns, and overall it is
in situ, and verrucous carcinoma (6). Of these, most more exophytic. In the flat pattern the rete proliferates
cases are clinically misdiagnosed as papillomas. below the surface of the overlying epithelium. The
rete shows relatively uniform hyperplasia. As the rete
B. Pathology dips into the submucosa, the intervening spaces
are filled with parakeratinized squamous plugs. In
Histologically, the lesions have a verrucoid surface addition, the parakeratininzed surface layer has a
with surface parakeratosis (2) (Fig. 29). The surface of distinctive keratinization, which is more brightly
the lesions can include a variety of different architec- eosinophilic on routine hematoxylin and eosin stained
tural appearances, including verrucous, papillary, or sections.
A. Phenytoin
Phenytoin is an anticonvulsant drug used in a wide
range of therapeutic modalities but particularly in
seizure control. Gingival hyperplasia affects up to
50% of patients taking phenytoin, although some
authors report much higher and lower percentages
(3). Phenytoin-induced hyperplasia is usually evident
within the first three months of starting the drug and
is most rapid in the first year of administration (1).
Studies have shown that phenytoin-associated gingi-
val hyperplasia is exacerbated by chronic inflamma-
tion, including those caused by accumulations of
bacterial plaque. Patients of a young age and those
with higher serum phenytoin levels are also more
likely to develop gingival hyperplasia (4).
Keratinocyte growth factor (KGF) levels have
been noted to be elevated in drug-induced gingival
hyperplasias (5). Both transforming growth factor
(TGF)-b-1 and platelet-derived growth factor-BB
levels have been shown to be increased in the tissues
Figure 30 Verruciform xanthoma. The epithelium shows hyper-
parakeratosis with the formation of keratin plugs between acan-
of gingival hyperplasia in patients receiving pheny-
thotic rete ridges. The papillary submucosa contains foamy toin (3). Extracellular matrix–degrading ability may be
histiocytes in varying numbers. There should be no cellular impaired by phenytoin as well as cyclosporine (6).
dysplasia. There is also evidence that mast cell–mediated andro-
gen action in the gingiva in response to phenytoin
could cause gingival hyperplasia.
While phenytoin is the most common cause of
In all the subtypes, there are varying numbers of drug-induced gingival hyperplasia, other anticonvul-
xanthoma cells, which abut the basal layer of the sants, such as phenobarbital, sodium valproate, and
squamous epithelium (Fig. 30). These xanthoma cells primidone have also been implicated (7). Other drugs
can be plentiful, occupying much of the papillary reported to cause gingival hyperplasia include sertra-
submucosa, or few in number and difficult to notice line, vigabatrin, topirimate, lithium ethosuximide,
at low power. The cytoplasm of the foam cells may ketoconazole, lamotrigine, cotrimoxazole, erythromy-
contain PAS-positive, diastase-resistant granules. cin, and oral contraceptives (2). Phenytoin-induced
Some cases have described occasional xanthoma hyperplasias is halted but is not reversed by cessation
cells infiltrating into the overlying epithelium (15). of the medication.
C. Immunohistochemistry B. Cyclosporine
The xanthoma cells stain with CD68 and other Cyclosporine is a common drug for treating patients
markers of histiocytic lineage but are frequently nega- with renal transplant, and it is estimated that 20% to
tive for S-100 (4,10,16–18). 35% of renal transplant patients have gingival hyper-
plasia as a result (8). Whether or not gingival hyperpla-
sia secondary to cyclosporine A use is dose dependent
D. Electron Microscopy is not clear (9). Concomitant use of ketoconazole,
amphotericin B, and cimetidine increase the activity
Ultrastructurally the xanthoma cells contain lipid and
of cyclosporine A by decreasing its hepatic metabolism
have characteristics of macrophages (13).
(9). Cyclosporine A has been shown to increase the
production of collagen by fibroblasts. Cyclosporine
E. Treatment and Prognosis increases the levels of interleukin-6, TGF-b-1, and
FGF-2 and decreases gamma interferon, all of which
The lesions are treated with conservative excision and are thought to increase collagen production (10). There
are not considered premalignant. Recurrence is rare is also a concomitant reduction in collagenase activity.
(14). KGF is upregulated by cyclosporine, and studies
have shown that the KGF receptor and the receptor
mRNA are higher in epithelial cells in gingival hyper-
XV. DRUG-INDUCED GINGIVAL HYPERPLASIA plasia compared with normal controls (5).
Drug-induced gingival hyperplasia may be caused by
a variety of drugs, but several categories are particu- C. Calcium Channel Blocking Agents
larly common and deserve mention, including phe-
nytoin, cyclosporine, and calcium channel blockers, Approximately 20% of patients taking nifedipine
such as nifedipine (1,2). experience gingival hyperplasia. Other calcium
channel blockers such as verapimil, nitrendipine, felo-

dipine, diltiazem, and amlodipine also cause gingival
hyperplasia (11). Similar to cyclosporine and phenyto-
in, KGF levels are increased (5). Experimentally, nifed-
ipine has been shown to increase p53-positive gingival
epithelial cells (12). Conversely, others have found
nifedipine to induce gingival hyperplasia in rats by
inhibiting apoptosis rather than by stimulating kerati-
nocyte production (13). Nifedipine may inhibit adher-
ence and lipopolysaccharide-stimulated macrophage-
induced death of fibroblasts (2).
D. Clinical Features
The gingiva in drug-induced hyperplasia is nodular
and centered on the interdental papillae (14). While
the gingival proliferation usually begins in the inter-
dental papilla, it gradually moves to involve the
gingival margins (Fig. 31).
Figure 32 Drug-induced gingival hyperplasia. Reactive acan-

E. Pathology thosis with elongated rete ridge formation is noted in the other-
wise normal overlying stratified squamous epithelium. The bulk
The histopathologic findings of these gingival hyper-
of the clinically evident nodules are the result of hyperplasia of
plasias are similar, regardless of the drug responsible the underlying fibroblasts and accumulation of dense collage-
(15). The epithelium shows irregular acanthosis with nous connective tissue. Chronic inflammation is often noted in
downward sharp rete ridge growth, sometimes in an the superficial submucosa.
interlacing reticular pattern (Fig. 32). The stroma shows
spindling of fibroblasts and collagen deposition. These
spindle cells may be arranged in a fascicular pattern.
Scattered calcifications may be seen. A lymphoplasma- metronidazole and other drugs derived from erythro-
cytic inflammatory infiltrate is often present. mycin (8). Optimum therapy is discontinuation of
cyclosporine, but that is often not possible.
Surgical therapy, including gingivectomy and
periodontal flap techniques have been used for treat-
For phenytoin, treatment consists of stopping the drug ment of gingival hyperplasia in patients receiving
if possible, but if regression does not occur, surgical calcium channel blockers as well as cyclosporine A.
remodeling of the gingiva may be necessary. These procedures reduce the tissue size for variable
Cyclosporine A–induced gingival hyperplasia time periods but usually do not attain permanent
has been treated with azithromycin, as well as results as long as the patient continues the drug.
Discontinuation of calcium channel blockers in a
series of peritoneal dialysis patients resulted in dis-
appearance of the gingival hyperplasia within one
month (11).
For all drug-induced hyperplasias, maintenance
of optimal oral hygiene, which reduces gingival
inflammation, is the best way to slow progression or
recurrence of the hyperplastic tissue.
XVI. DENTURE-INDUCED FIBROUS

HYPERPLASIA
Denture-induced fibrous hyperplasia is known by a
variety of names, depending on the location or the
cause. Synonyms include epulis fissuratum, denture
injury tumor, denture epulis, denture hyperplasia,
and denture-induced inflammatory hyperplasia.
Epulis is a general clinical term for lesions of the
Figure 31 Drug-induced gingival hyperplasia. Multinodular, firm oral mucosa having a direct contact with the peri-
proliferations of gingiva surrounding the teeth. Areas of inflam- odontal membrane or periosteum of the jaw. Denture-
mation, secondary to dental plaque and calculus accumulation induced fibrous hyperplasia (epulis fissuratum) is a
will accelerate the formation and size of the proliferations. term usually reserved for hyperplastic, reactive tissues
occurring along the flanges of upper or lower
Figure 33 Denture-induced fibrous hyperplasia (epulis fissur-

atum). Ridges and folds of linear soft tissue are characteristically
adjacent to the acrylic flange of a full or partial removable denture
appliance. The depth of the vestibule is often ulcerated due to Figure 34 Denture-induced fibrous hyperplasia (epulis fissur-
chronic trauma from the denture flange. atum). Marked acanthosis is present.
dentures (1) (Fig. 33). The term ‘‘fissuratum’’ derives

from the fissuring of the hyperplastic epithelium. The
fissures can form multiple folds or flaps, with some
folds overlying the ones adjacent, similar to pages in a
book (1). In a study of 23, 616 Caucasian-Americans
older than 35 years, denture-induced fibrous hyper-
plasia was seen at a prevalence of 0.4% (2). Generally,
denture-induced fibrous hyperplasia is the result of
chronic injury caused by ill-fitting dentures with
repeated cycles of injury and repair building up a
hyperplastic tissue response (3).
A. Clinical Findings
The clinical findings vary according to the degree and
length of trauma, inflammation, and subsequent fibro-
sis caused by the denture. The lesion may be sessile or
pedunculated and appears red and ulcerated or dense
and fibrous (3). Those that are ulcerated can have some
similarities to pyogenic granuloma. Lesions may be Figure 35 Denture-induced fibrous hyperplasia (epulis fissur-
present for a few months to many years. Most cases atum). A chronic inflammatory cell infiltrate is noted in the
occur in persons between 40 and 60 years, an age superficial submucosa. The bulk of the enlargement is due to a
associated with denture use. Denture-induced fibrous reactive buildup of dense, fibrocollagenous connective tissue.
hyperplasia is more commonly seen in women. The
anterior portions of both jaws appear affected more
than posterior locations, and more lesions are found
on the buccal aspect than the lingual aspect (3). epithelial changes may show acanthosis and hyper-
Occasionally, inflammatory papillary hyperplasia parakeratosis focally. Many have pseudoepithelioma-
may coexist. tous hyperplastic changes. It is thought that the
pseudoepitheliomatous response is a more severe
B. Pathology response to chronic trauma. In some cases, the epithe-
lium splits in the center of the rete pegs, and this
The histologic differential diagnosis is usually not splitting or clefting can extend into the underlying
difficult, given the appropriate clinical history and connective tissue (3). The stromal component may
findings (3). Histologically, the tissue shows dense, resemble that of a dermal hypertrophic scar (4).
fibrous tissue hyperplasia with varying amounts of Osseous and chondromatous metaplasia may be seen
mixed chronic inflammatory cells (Figs. 34,35). The and should not be mistaken for sarcomatous changes.

Treatment usually involves surgical removal. Denture
adjustments or fabrication of new dentures may be
necessary to prevent recurrence (4).
XVII. INFLAMMATORY PAPILLARY

HYPERPLASIA
Inflammatory papillary hyperplasia is a reactive pro-
cess that most often is caused by ill-fitting dentures or
by dentures that are worn 24 hours daily. It is also
known as denture stomatitis and denture papilloma-
tosis, although this term can be reserved for denture-
related inflammatory lesions that show no evidence of
hyperplasia (1–3). Its prevalence may be 20% of all
denture wearers. Thus, in some respects, its cause is
similar to fibrous hyperplasia (epulis fissuratum), but Figure 36 Inflammatory papillary hyperplasia. Multiple, ery-
its appearance and location differs. While denture- thematous papillary projections of soft tissue involving hard
induced fibrous hyperplasia shows large ridges of palatal mucosa. This is most often noted under a maxillary
redundant tissue predominantly at the margins of removable partial or full denture appliance, although the condi-
tion can also be seen as a result of nonspecific, chronic inflam-
the denture, inflammatory papillary hyperplasia is
mation in patients with high palatal vaults.
marked by multiple small, wart-like or papillomatous
projections most often under an upper denture involv-
ing palatal mucosa. It is most prevalent in patients
who keep their dentures retained while sleeping or
have poor oral hygiene. Candida has also been impli-
cated in the etiology of inflammatory papillary hyper-
plasia, but its true role is not completely known (4).
Inflammatory papillary hyperplasia may occur in
patients without dentures. These patients often have
a high palatal vault and are often predisposed to the
development of oral candidosis by chronic xerostomia
or use of steroidal inhalers. The process has also been
reported in patients who are preferential mouth-
breathers (5).
Most cases are associated with a complete denture but
partial dentures may also be at fault. While the palate
is the most common anatomic site of involvement,
inflammatory papillary hyperplasia may be seen
under any part of any denture. The clinical findings
are multiple small papillary growths separated
by clefts (Fig. 36). The surface is often red, but
pain is not a common complaint, and, in fact, most
patients with inflammatory papillary hyperplasia are Figure 37 Inflammatory papillary hyperplasia. The overlying
asymptomatic. stratified squamous epithelium shows acanthosis, hyperparaker-
atosis, and papillomatosis. There is an infiltrate of lymphocytes,
plasma cells, macrophages, and neutrophils in the underlying
B. Pathology hyperplastic, fibrovascular connective tissue.
The histologic appearance of inflammatory papillary

hyperplasia are multiple, superficial squamous cov-
ered papillary projections (6). In many lesions, the C. Differential Diagnosis
appearances are those of pseudoepitheliomatous
hyperplasia (Fig. 37). No epithelial atypia is present. The pseudoepitheliomatous hyperplasia may be so
The submucosal stromal tissue reveals a mixed, striking that invasive well-differentiated squamous
chronic inflammatory cell infiltrate. Involvement of carcinoma is entertained in the differential diagnosis
submucosal salivary glands may result in a ductal by the pathologist. The clinical information is critical,
squamous metaplasia, duct obstruction, and other but the lesion is well recognized by dentists and
features seen in sialadenitis or sialometaplasia. oral surgeons. No epithelial atypia is present in
inflammatory papillary hyperplasia, a very helpful The overlying mucosa is smooth and nonulcerated.
finding. Nevertheless, before rendering a diagnosis They are typically light pink but in patients with dark
of invasive well-differentiated squamous carcinoma skin, may be gray to blue-black in color. Irritation
from a palatal biopsy in a situation where there is fibromas may range in size from several millimeters
limited clinical history, it may be of value to ascertain to as much as 2 cm or more but the majority are less than
if the patient has a denture in place. 1 to 1.5 cm.
D. Treatment and Prognosis B. Pathology

Initial treatment usually involves directing the patient The low-power microscopic appearance of irritation
to remove the dentures when they sleep at night, in fibromas mimics the clinical appearance, as they show
combination with topical antifungal therapy. If the a bosselated, pedunculated, or sessile appearance
papillae fail to resolve, surgical removal may be (Fig. 39). The surface is covered by a stratified
necessary (1,3,7). squamous epithelium and the stroma is composed of
collagen, fibroblasts, and varying amounts of chronic
inflammatory cells. The stromal proliferation is unen-
XVIII. IRRITATION FIBROMA capsulated and merges with the surrounding stroma.
Irritation fibroma is also known as focal fibrous hyper- Usually the collagen is dense and tightly woven
plasia, fibroma, fibrous nodule, and traumatic fibroma. but may be loose. Dayan et al. have shown that the
Its etiology is the result of a chronic repair process that collagen fibers in irritation fibromas of long standing
occurs in response to injury. Irritation fibromas are are arranged in a more organized, packed manner,
among the most common benign, reactive oral lesions whereas lesions of lesser duration are more disorga-
with a reported occurrence rate from 0.2% to 0.7% of nized (3).
the population (1).
A. Clinical Features Giant cell fibroma has been described as a separate
The second decade of life is the most common age of entity, although it has some similarities to irritation
presentation, but some authorities suggest that in their fibroma. Some authors feel there is no need to separate
experience the lesions are more common in the fourth these lesions from irritation fibroma, as the treatment
to sixth decade. Females are more commonly affected is the same (4,5). Nevertheless, giant cell fibromas can
than males. The most common sites include buccal also occur in areas of oral mucosa where chronic
mucosa adjacent to the crowns of the teeth (the trauma is unlikely and irritation fibromas lack the
so-called bite line), the upper and lower labial mucosa, giant, stellate cells seen in the former.
and the lateral borders of the tongue (2). These are the
areas of oral mucosa which are most likely to be
traumatized repeatedly by the adjacent dentition.
These fibrous lesions can present as a pedunculated
nodule, but most frequently they are sessile (Fig. 38).
Figure 39 Irritation fibroma. The overlying stratified squamous

Figure 38 Irritation fibroma. A smooth-surfaced, ovoid, pedun- epithelium can appear normal, focally hyperkeratotic, acanthotic,
culated or sessile, exophytic soft tissue nodule is noted in an or ulcerated, depending on the clinical setting. The enlargement
area of chronic trauma, often involving buccal, glossal, or labial is the result of dense, reactive fibrocollagenous connective tissue
mucosa directly adjacent to the edges of the teeth. in the superficial submucosa.

Conservative surgical excision is the treatment of
choice. Recurrence only occurs if repeated injury to
the site continues.
XIX. GIANT CELL FIBROMA

Giant cell fibroma is a lesion that can clinically resem-
ble irritation fibroma (focal fibrous hyperplasia) (1,2).
Some authors do not separate the two entities, based
partly on the overlapping clinical appearance and the
similarities of treatment (3,4). However, there are
some differences in the frequency of site involvement,
in the average patient age at time of onset, and differ-
ences in histologic features (5). Importantly, giant cell
fibroma does not appear to be convincingly associated
Figure 41 Giant cell fibroma. The surface of parakeratinized or
with trauma. nonkeratinized stratified squamous epithelium often shows reac-
tive, pointed rete ridges extending down into a dense fibrocol-
A. Clinical Features lagenous connective tissue core. Of note are numerous stellate
and/or multinucleated fibroblasts, seen most often in the papillary
Giant cell fibroma is more common on the gingiva, submucosa (inset).
with nearly half of patients having involvement of this
site. The mandibular gingival is much more commonly
affected than the maxillary gingiva at a 2:1 ratio. There
is an equal sex distribution, and the process occurs dense. The most striking finding histologically is the
predominantly in the first three decades. These fea- presence of stellate fibroblasts in the stroma. Many of
tures differ from those seen in irritation fibroma. these fibroblasts have multiple nuclei (Fig. 41). The
The clinical appearance is that of a bosselated or collagen is characteristically dense and essentially
pedunculated lesion with a smooth mucosal surface identical to that found in an irritation fibroma (6–9).
(Fig. 40). Some lesions have a slightly papillary surface
and may be confused clinically with papilloma in
some cases. The size range is usually between 0.5 C. Treatment
and 1.0 cm. Giant cell fibromas are cured by local conservative
excision and recurrences are rare.
B. Pathology
The epithelium may show elongation of the rete, and XX. TONSILLITIS AND TONSILLAR
the underlying connective tissue may be myxoid or HYPERPLASIA
A. Introduction
The tonsils are part of the lymphoid tissue making up
Waldeyer’s ring, which consists of the adenoids (pha-
ryngeal tonsils), the palatine tonsils, and the lingual
tonsils at the base of the tongue. The palatine tonsils
are located in the tonsillar fossa between the palato-
glossal and palatopharyngeal arches of the oropharynx
(1). The palatoglossal muscle, the palatopharyngeal
muscle, and the superior constrictor muscle form the
ventral, dorsal, and lateral margins of the palatine
tonsil. The pharyngobasilar fascia serves as the tonsil’s
capsule. Anomalies of tonsil development are rare, but
occasionally foci of bone or cartilage can be found in
fibrous tissue adjacent to or in the tonsil (2). The
exposed surface of the tonsil has a cerebriform
appearance due to the presence of crypts. The forma-
tion of deep tubular crypts is a characteristic of human
palatine tonsils and pigs, but in some mammals crypts
Figure 40 Giant cell fibroma. A smooth-surfaced, sessile or are lacking (1). In the human, each tonsil has 10 to
pedunculated, exophytic, soft tissue nodule. These nodules enlarge 30 crypts, which increases the surface area. In the
very slowly and are often identified only during oral health checkups. crypts, luminal antigens are taken up for specialized
cells. The tonsils are located at the entryway of the
aerodigestive tract. They are exposed to many air- tube dysfunction, voice changes, obstructive sleep
borne and food antigens and have been considered as apnea, and changes in facial growth (16). Children
the first line of defense against pathogens (1,3). The with large obstructing tonsils have a smaller oropha-
epithelium lining the crypts is a specialized type of ryngeal diameter compared with children with small
squamous epithelium and has a variable infiltration of tonsils (16).
lymphocytes. Investigators have found unique expres- Recurrent streptococcal tonsillitis has also been
sion of tight junctions in the palatine tonsils and also associated with pediatric autoimmune neuropsychiat-
suggest that the crypt epithelium may possess an ric disorders (PANDAS) (18).
epithelial barrier different from that of the surface
epithelium (4). C. Pathology
The lymph nodes draining the tonsils are first
the submandibular and then deep cervical, which Tonsillar tissue is at its largest size and immunologi-
explains the enlargement of these nodes during cally most active during childhood, especially
bouts of acute tonsillitis. between 4 and 10 years but then decreases in size
Tonsillitis may be caused by viruses or bacterial with age (16). Tonsillar size is said to be proportional
infection, but viral infections are likely more common. to aerobic bacterial load and the absolute numbers of
Bacterial infection may develop in the tonsil initially lymphoid cells (16). How chronic inflammation of the
infected by virus. tonsil affects tonsillar size or histologic features is not
The most common viral pathogens associated entirely clear. Some studies suggest that H. influenza is
with tonsillitis include respiratory synctial virus, echo- highly associated with tonsillar hyperplasia (8).
virus, rhinovirus, adenovirus, influenza virus, and Controversy exists as to whether there are histopatho-
parainfluenza virus. EBV has also been implicated in logic differences in tonsils removed from children
recurrent episodes of tonsillitis (5–7). with either a history of recurrent tonsillitis or solely
Chronic tonsillitis and tonsillar hyperplasia tonsillar hyperplasia without a clinical history of
appear related to bacterial infection and there is evi- recurrent infections (19,20).
dence that the presence of bacterial biofilms may Because the tonsils are hematopoietic tissue, it
explain the recurrent and chronic nature of tonsillitis may be difficult to define inflammation or ‘‘-itis’’
(8–10). Immunologic alterations in the tonsil are also histologically. Tonsils are infrequently removed dur-
related to chronic tonsillitis. Investigators have found ing ‘‘acute’’ tonsillitis unless there is concomitant
changes in the distribution of the antigen presenting peritonsillar abscess (see peritonsillar abscess).
dendritic cells within tonsils of children with and Tonsils removed for chronic or recurrent tonsillitis
without chronic tonsillar disease (11). This may be show lymphoid hyperplasia with large germinal cen-
due to pathogenic bacteria in the crypts of chronically ters (Fig. 42). Lymphocytes are seen normally in the
inflamed tonsil (11). epithelium but neutophils are not and indicate, if
Bacterial etiologies include group A beta-hemolytic prominent, ‘‘acute mucositis’’ (Fig. 43). The continu-
streptococcus, Haemophilus influenza, and Staphylococcus ous antigenic stimulation of the tonsils has been
aureus (12,13). However, other bacteria, including aer- termed a ‘‘physiologic inflammation,’’ and tonsillitis
obe and anerobes, are important contributors to tonsil-
litis, and culture of tonsils removed for recurrent
tonsillitis often show multiple organisms (14). Some
investigators have suggested that while acute tonsillitis
may be associated with group A beta-hemolytic strepto-
coccus, Hemophilus groups are more likely to be
involved in the pathogenesis of recurrent tonsillitis
and tonsillar hyperplasia (14–16).
Separating viral and bacterial etiology by symptom-
atology may be difficult, as sore throat is the most
common symptom of tonsillitis in both viral and
bacterial etiologies (13). Clinical features suggestive
of viral etiology include cough, conjunctivitis, coryza,
and diarrhea. Clinical features suggestive of bacterial
tonsillitis include sore throat, fever, inflammation,
exudates, and enlarged and tender anterior cervical
lymph nodes. On physical examination, there is ton-
sillar and pharyngeal erythema. Palatal petechiae may
be seen. Because branches of the glossopharyngeal Figure 42 Tonsillar hyperplasia. Numerous hyperplastic lym-
and vagus nerves also innervate the ear, patients phoid germinal centers of varying sizes are present. Tonsillar
with tonsillitis may complain of ear pain (17). crypts with a minimal amount of desquamated surface epithelium
Changes associated with enlarged tonsils from are present.
chronic tonsillitis may cause otitis media, Eustachian
Figure 43 Tonsillar hyperplasia. The surface cryptal epithelium Figure 45 Tonsillar hyperplasia with skeletal muscle. This
is infiltrated by lymphocytes, a normal finding. tonsillectomy specimen reveals abundant skeletal muscle.
Skeletal muscle is not an unusual finding in tonsillectomy speci-
mens when an extratonsillar capsular surgical procedure is
performed.
complications include acute rheumatic fever, scarlet

fever, and poststreptococcal glomerulonephritis.
Suppurative complications include peritonsillar
abscess, which may spread and result in paraphar-
yngeal or retropharyngeal abscess (13). Lemierre’s
syndrome is characterized by septic thrombophlebi-
tis of the internal jugular vein secondary to dissemi-
nation by contiguous spread of acute tonsillitis or
pharyngitis (23). Spontaneous tonsillar hemorrhage
of noniatrogenic causes has been reported in
inflamed tonsil (24).

Separating viral from bacterial causes of tonsillitis can
Figure 44 Giant cells in a tonsil from a patient with HIV
be difficult. If the clinical findings suggest viral etiol-
infection. Multinucleated giant cells may be seen in tonsils in
patients with HIV infection. The giant cells are often near the
ogy, a number of authors suggest that additional
surface of the tonsil or near the cryptal epithelium. Source: diagnostic tests are not indicated (13,25). Most inves-
Photograph courtesy of Dr. Leon Barnes, Pittsburgh, PA. tigators emphasize the necessity of diagnostic testing
for bacterial causes before treating with antibiotics,
with rapid antigen detection testing the preferred
laboratory test (25–30). Some guidelines support
occurs if the pathogenic bacteria in the tonsillar tissue throat culture if the rapid antigen testing is negative,
go beyond the functional limits of the resident lym- but that in adults, cultures are not suggested if the
phoid population. Actinomyces are normal inhabi- rapid antigen detection testing is negative (13). One
tants and can frequently be seen to form large main objective of antibiotic therapy is eradication of
colonies in the crypts. These should not be mistaken the organism from the pharynx, which is necessary for
for disease. Giant cells may be seen in the epithelium the prevention of acute rheumatic fever (31). Penicillin
of patients with HIV infection (Fig. 44) (21). Skeletal has been the standard treatment of streptococcal ton-
muscle is not uncommonly found in tonsil specimens sillopharyngitis. However, in some studies, group A
surgically excised and is the result of extending the beta-hemolytic streptococcal resistance to penicillin
surgical excision to encompass the tonsillar capsule occurs in up to 30% of patients and other antibiotics
(22) (Fig. 45). are required (13). Other agents have been suggested to
Complications of tonsillitis may be classified as be used for shorter courses, possibly with better
nonsuppurative or suppurative. Nonsuppurative compliance (31,32).
Studies using bacterial interference have also XXI. PERITONSILLAR ABSCESS

been carried out to prevent group A beta-hemolytic
streptococcal-induced recurrent tonsillitis. In this The space between the tonsillar pillars and the supe-
method, patients are given alpha-hemolytic strept- rior constrictor muscle on the one side and the tonsil
ococcus to introduce bacteria that are not pathogenic on the other side is the peritonsillar space. This is the
but inhibit the growth of beta-hemolytic streptococcus location of peritonsillar abscess. Importantly, the lat-
(33). eral pharyngeal space may be involved by direct
The treatment of recurrent tonsillitis and ton- extension of the abscess through the constrictor
sillar hyperplasia with tonsillectomy is controver- muscles (1). Peritonsillar abscess usually occurs in
sial. Tonsillectomy is a procedure with a long history patients with recurrent tonsillitis or in those with
(34,35). Historically, the prevalence of tonsillectomy chronic tonsillitis with inadequate treatment (2).
and adenoidectomy is cyclical (36). The rates of Cervical necrotizing fasciitis has been reported follow-
tonsillectomy and adenoidectomy vary markedly in ing tonsillar infection (3). Clinically, there is unilateral
various countries, with the pediatric rate of 19 per swelling of the palate and anterior pillar with dis-
10,000 children in Canada to 118 per 10,000 children placement of the tonsil downward (2). Examination of
in Northern Ireland in 1998 (37). Tonsillectomy is the pharynx is difficult because of trismus (1). Also,
usually a procedure for children, but adults also there is inability to control salivation because of the
have tonsils removed for a variety of reasons, in- inability to swallow. Lateral plain radiographs may
cluding infections but also peritonsillar abscess, reveal thickening of soft tissues between the cervical
obstructive sleep apnea, as well as evaluation for vertebrae and the air column of the pharynx. Culture
suspected malignancy (38). Questions remain as to of the abscess often shows both anaerobic and aerobic
the efficacy of tonsillectomy for treating children bacteria (4). Because of the mixed flora, some inves-
with recurrent tonsillitis with proponents and oppo- tigators have suggested that antibiotics to cover
nents (12,39–43). anaerobic bacteria be used initially (4). If the abscess
A long-standing concern by some is that removal spreads into the parapharyngeal space, the process
of immunologically active organs in children may could also extend down the carotid sheath and into
have a deleterious effect on the children’s over- the mediastinum. Retropharyngeal abscesses likely
all health. In a review of long-term studies by arise because of the abscess forming in lymph nodes
Paulussen et al., the authors could not find clinically in the retropharyngeal space (2). Peritonsillar cellulitis
significant alterations in cellular or humoral immunity is treated medically with antibiotics. Needle aspira-
in patients who had undergone tonsillectomy and tion and incision and drainage are required for treat-
adenoidectomy (3). ment of peritonsillar abscess usually followed by
Some studies have suggested that tonsillectomy tonsillectomy later, although there may be indications
does little to decrease tonsillitis-related complications for immediate tonsillectomy (5).
(44). Others have advocated against tonsillectomy if
there is only mild symptoms of throat infections or XXII. ADENOID HYPERPLASIA
adenotonsillar hypertrophy (43). Relative indications
for tonsillectomy with adenoidectomy include upper Similar to the tonsil, the adenoids, also known as the
airway obstruction, dysphagia or speech impairment, pharyngeal tonsils, are part of Waldeyer’s ring. The
and halitosis, while recurrent or chronic pharyngoton- adenoids are also situated at the entrance of the naso-
sillitis, peritonsillar abscess, and streptococcal carrier pharynx, and their afflictions are similar to those of the
state are indications for tonsillectomy but not adenoi- tonsil. Anatomic differences exist, however, in that the
dectomy (45). adenoids do not have a peripheral capsule (fascia), as
Whether tonsils should be examined microscop- does the tonsil. The adenoids are covered by respiratory-
ically by the pathologist is controversial. Some litera- type epithelium in children, although the adenoids of
ture questions the value of histologic examination of adults may have a partial covering by squamous epithe-
all tonsils removed. Some suggest that tonsils lium. The adenoids likely have active immune function.
removed in which there is no suspicion of malignan- Immunologic functional studies have revealed a variety
cy, particularly tonsils removed for recurrent tonsilli- of immune processing in the adenoids such as toll-like
tis, or obstructive sleep apnea need not have histologic receptor expression (1).
examination if the specimens are carefully examined The adenoids cause problems because of inflam-
grossly and the clinical findings are appropriate mation and lymphoid hyperplasia. Numerous adverse
(38,46–51). Many pathology departments have set effects of enlarged adenoids have been described in
age-dependent criteria for omitting histologic exami- the literature and rationales for surgical removal have
nation of tonsils that show asymmetric enlargement or been given. The conclusions are controversial. Chronic
other abnormality (‘‘gross only’’). The most common nasal obstruction due to increased adenoidal size is
patient ages chosen for which no histologic examina- thought by some to be associated with obstructive
tion of tonsils is performed include 12, 16, and sleep apnea, eustachian tube dysfunction and otitis
21 years. In many instances, however, there is no media, and abnormal facial growth (2,3). Adenoidal
individual pathology department–derived validation hyperplasia may lead to nasal obstruction, with inves-
data that sets these age criteria for each institution. tigations showing that nasal obstruction is likely sec-
The safest policy is to examine all tonsils from all ondary to an absolute increase in adenoid size rather
patients, regardless of age. than a relatively smaller nasopharynx (4).
While some have suggested that abnormal facial increased and because the adenoids normally tend
and dental development have a relation to enlarged to decrease in size as puberty is reached, removal in
adenoids (adenoidal facies), not all investigators have older children is controversial (12). While some clini-
found this to be true (4). cians believe that symptoms due to enlarged adenoids
Increased stratified squamous epithelium and recur because of regrowth of the adenoid tissue,
decreased ciliated epithelium is seen in adenoids others suggest that adenoidal tissue rarely, if ever,
from patients with otitis media, and the investing proliferate sufficiently after resection to cause symp-
epithelial cell layer extends more deeply into the toms of nasal obstruction (13).
lymphoid crypts in patients with otitis media (5). Adenoidectomy has been suggested to be of
This epithelium appears to lack antigen-transporting benefit in patients with otitis media and chronic
cells and would support an abnormality of the antigen- nasal obstruction and is a common indication for
trapping systems that is seen in adenoidal hyperplasia adenoidectomy for some surgeons (8). Some authors
(6). suggest that there are specific indications for tonsil-
The role of enlarged adenoids in otitis media lectomy alone, tonsillectomy combined with adenoi-
with effusion is not completely clear. Besides potential dectomy, and adenoidectomy alone. Otitis media
obstruction of the Eustachian tube by enlarged ade- and recurrent or chronic rhinosinusitis or adenoiditis
noidal tissue, the inflammatory-induced metaplasia of are indications for adenoidectomy but not tonsillecto-
the nonciliated surface may impair mucociliary drain- my (3,14). Children with sleep apnea may benefit
age (7). Many authors, however, suggest that adenoid from tonsillectomy and adenoidectomy (14). Adeno-
enlargement is unrelated to otitis media and that there tonsillectomy in children with mild symptoms of
is no difference in adenoid size between children with throat infections or adenotonsillar hyperplasia may
or without otitis media with effusion (2,5,8). Most not have a benefit from surgical removal (15).
authors agree that the adenoids may have an impor-
tant role in the cause of otitis media with effusion by
serving as a reservoir for bacteria (5). H. influenza is XXIII. OBSTRUCTIVE SLEEP APNEA
often cultured more frequently in adenoid specimens
from patients who have otitis media with effusion. Obstructive sleep apnea is defined as obstruction,
This is a reason that some authors recommend that either complete or partial, of the upper airway during
children who have bacterial otitis media and nasal sleep, and when combined with daytime sleep symp-
obstruction should undergo adenoidectomy to remove toms, this condition is termed ‘‘obstructive sleep
the chronically infected tissue (9). apnea syndrome’’ (1,2). Obstructive sleep apnea is
Studies have reported adenoidal hypertrophy more common in males until patients reach their
occurring in adults with HIV infection (10). Adeno- fourth and fifth decade, when the male-to-female
tonsillar hyperplasia may be a precursor to EBV-related ratio drops from 3:1 to 1:1. Its prevalence is reported
lymphoid hyperplasia and posttransplant lymphopro- to be up to 5% in the Western world, and sleep apnea
liferative disease (11). is thought to affect 20 million Americans. The peak
age for obstructive sleep apnea in children due to
tonsil and adenoid hyperplasia is three to six years,
A. Pathology although it may occur in younger children, including
infants (3). Children with Down syndrome are also
The adenoids are prominent in children but begin to
thought to be at increased risk of obstructive sleep
shrink in size at puberty and are often small and
apnea from tonsillar and adenoid hyperplasia (4).
fibrotic in adults. The prominence is due to lymphoid
Besides hyperplasia due to bacterial and common
proliferation, which decreases with age (7). Mucosal
viral causes, obstructive sleep apnea has also occurred
and submucosal lymphocytic infiltration are normally
secondary to EBV-induced lymphoid hyperplasia of
present in the adenoid and should not be construed as
the tonsil and adenoid following transplantation (5).
chronic inflammation. The adenoids usually show
Obstructive sleep apnea is considered to be
follicular lymphoid hyperplasia with enlarged germi-
multifactorial and may even have a genetic basis
nal centers. Tingible body macrophages are commonly
with complex interactions of neural, hormonal, and
seen. Interestingly, neutrophils are not usually seen. In
structural abnormalities (2,6). Although there is vari-
children, the epithelial surface may be transformed
ability in the dimensions of airways in normal adults,
from a ciliated-type to a stratified squamous epithelium
most investigators believe patients with obstructive
extending into the adenoidal lymphoid tissue (6). In
sleep apnea have narrower airways than normal.
adults, the adenoids may show significant fibrosis.
In adults, obesity is probably the greatest risk
Epstein-Barr infection may cause the adenoids, like
factor. Regional fat distribution has also been shown
the tonsils, to show marked immunoblastic reactions
to have a genetic component and may be more impor-
with Reed-Sternberg-like cells.
tant than overall obesity. However, not all patients
with obstructive sleep apnea are overweight (2).
B. Treatment Obstructive sleep-disordered breathing occurs be-
cause of numerous other factors, including increased
Adenoidectomy is often an added procedure to ton- adipose tissue (parapharyngeal fat pad) alterations in
sillectomy but may add complications. Besides craniofacial structures, reduction in mandibular size,
increasing operative time, operative blood loss is disease of the paranasal sinuses, tonsil and adenoid
hyperplasia, hypertrophy of the soft palate and uvula,

low-set soft palate, micrognathia, macroglossia, and
tongue root depression (6–8). Narrowing or obstruc-
tion of the middle pharynx and hypopharynx is more
marked in patients with obstructive sleep apnea than
in normal patients and is particularly marked during
sleep (7).
Obvious genetic abnormalities such as Pierre-
Robin syndrome, Down syndrome, Apert syndrome,
Treacher-Collins syndrome, and achondroplasia are
associated with patients who have sleep-disordered
breathing (6). Obstructive sleep apnea is also reported
clustered in families, and some case reports suggest
autosomal dominant inheritance.
The cardinal symptom of obstructive sleep apnea is
excessive daytime sleepiness (9). Other symptoms
include unrefreshing sleep or chronic fatigue (1). Figure 46 Uvula and palatal tissue from uvulopalatoplasty. The
Snoring is often a common complaint, as is awakening overlying epithelium and submucosal glands and skeletal muscle
with a smothering sensation or gasping, awakening are normal in histologic appearance.
with a headache or dry throat, and restless sleep.
Other medical problems are associated with obstruc-
tive sleep apnea and include both systemic and pul-
monary hypertension, coronary artery disease, cardiac during sleep. Surgical therapy (uvulopalatoplasty) is
arrhythmias, diabetes, and decreased neurocognitive aimed at enlarging the posterior airway space and
functions. Gastroesophageal reflux, impotence, and reducing the ability of the airway to collapse (2).
depression are also associated with obstructive sleep
apnea, as are motor vehicle accidents, poor work
performance, and occupational accidents associated XXIV. LOBULAR CAPILLARY HEMANGIOMA
with obstructive sleep apnea (1,2,10). (PYOGENIC GRANULOMA)
Infants may have disturbed sleep with repetitive
crying and snoring. Children aged between one and Lobular capillary hemangioma is a common lesion of
three years may have snoring but also aggressive the oral cavity that has now been considered by some
daytime behavior. An overnight sleep study (polysom- to be synonymous with pyogenic granuloma, although
nography) is considered to be of great value in diag- some authors believe the two processes are distinct
nosing obstructive sleep apnea. Polysomnography can entities (1–3). Epulis granulomatosa is a designation
help determine the apnea-hypoxia index, determined used to describe lesions that appear as pyogenic gran-
by the average number of apneic and hypopneic epi- ulomas that arise in healing extraction tooth sockets.
sodes per hour of sleep. Lobular capillary hemangioma is a smooth or
lobulated mass that may be either sessile or peduncu-
lated. The tissue may histologically resemble granula-
B. Pathology tion tissue or, if there is minimal inflammation, a
hemangioma. Etiologies include lip biting, trauma,
Tonsil and adenoid hyperplasia is said to be to leading tissue edges of restorations, and tooth extraction sites.
cause of obstructive sleep apnea in children. The Rapid growth is not uncommon. Tie2, a human endo-
tonsils and adenoids do not have specific features thelial receptor tyrosine kinase, has been implicated in
that set them apart from the hyperplastic tissue seen the development of lobular capillary hemangioma (4).
in patients without obstructive sleep apnea. Both Pyogenic granuloma usually affects children and
children and adults may undergo uvulopalatoplasty young adults, but they may occur at any age, including
to enlarge the airway and help prevent it from col- infancy (5). In a study of patients 65 years and older,
lapsing. Uvulopalatoplasty specimens do not general- pyogenic granuloma was seen in 0.7% (6).
ly show any striking histologic changes (Fig. 46).
Lobular capillary hemangioma or pyogenic granulo-
Sometimes simple therapies may help alleviate milder ma varies from pink to red to purple and may range
symptoms of obstructive sleep apnea. Encouraging from several millimeters to several centimeters. These
the patient to sleep on their side, lose weight if tumors often arise on the gingiva, particularly the
obese, and to refrain from alcohol before bedtime anterior maxillary gingiva but may occur anywhere
may help. Other therapies include continuous positive in the oral cavity, including the lips, tongue, and
airway pressure (CPAP) and oral appliances used buccal mucosa (Fig. 47). They often have a rapid
Figure 47 Lobular capillary hemangioma or pyogenic granuloma.

An erythematous, sessile or pedunculated, easily bleeding soft Figure 48 Lobular capillary hemangioma or pyogenic granuloma.
tissue enlargement. They can occur anywhere, but when they The overlying epithelium is often normal but can be focally
involve the oral cavity, they are most often noted in areas of chronic ulcerated. The underlying fibrovascular connective tissue shows
inflammation adjacent to teeth. They can grow rapidly, often numerous thin-walled vascular channels, often arranged in
alarming the patient and clinician. lobules just subjacent to the surface epithelium. Most oral lesions
show a mixed infiltrate of lymphocytes, plasma cells, and neu-
trophils. The multifocal lesions of so-called pregnancy gingivitis
are often microscopically identical to oral lobular capillary heman-
growth rate mimicking aggressive malignant vascular gioma or pyogenic granuloma.
neoplasms. The majority of patients are female and
thus the role of estrogens and progesterone may well
have at least a partial etiologic role. The development
of these lesions during pregnancy has given rise to the inception, decreases with shrinkage of the endothelial
term ‘‘pregnancy tumor’’ or ‘‘granuloma gravidarum’’ cell nuclei. The end stages of the lesion result in a
(7). In this specialized clinical setting, the tumors are collection of small vessels in a lobular pattern with
initially seen in the first trimester and increase in minimal inflammation in a more prominent fibrous
frequency as the pregnancy continues up to around stroma (Fig. 48).
the sixth or seventh month of gestation, suggesting a
correlation with hormone levels. Interestingly, after
delivery, these lesions may regress on their own, with
only a fibrous process remaining. The lobular growth pattern is a key feature and helps
The clinical differential diagnosis includes other differentiate it from other vascular neoplasms.
vascular lesions, including angiosarcoma or vascular Mitoses are frequent in early lesions and may even
metastatic lesions (8,9). Bacillary angiomatosis mimick- exhibit more mitoses than low-grade angiosarcomas.
ing pyogenic granuloma has also been reported (10,11). Atypical mitoses, however, are not seen in lobular
capillary hemangiomas. Importantly, lobular capillary
B. Pathology hemangiomas do not show a diffuse or widely infil-
trative growth pattern.
Histologically, lobular capillary hemangiomas show a
spectrum or evolution of changes as they mature.
Initially the appearance is that of primarily vascular D. Treatment and Prognosis
proliferation and inflammation, which resembles Conservative surgical therapy is adequate for these
granulation tissue. The vessels are arranged in a benign lesions. Some authors suggest that pyogenic
lobular pattern often with central radiation to a more granulomas that arise during pregnancy should not be
central point at the base of the lesion. In early lesions, excised until some time after delivery, as they may
the surface may be ulcerated, and some authors use spontaneously involute.
the term ‘‘pyogenic granuloma’’ in this setting. There
is a variable amount of inflammatory infiltrate and,
when present, may be neutrophilic, lymphoplasma- XXV. CROHN DISEASE
cytic, or mixed. The inflammatory component is usu-
ally more pronounced near the surface. Over time, the Crohn disease is a chronic inflammatory process that
inflammatory component diminishes and the endo- most frequently involves the terminal ileum and colon
thelial cell proliferation, once marked at the lesions but may also affect the small bowel and upper
digestive tract, including the oral cavity. Involvement

of numerous extragastrointestinal sites has also been
reported, including the eye, skin, and joints. Multiple
oral mucosal sites of involvement have been reported,
including the tonsillar region (1,2). The prevalence of
Crohn disease has been increasing over the last sever-
al decades (3). Intraoral lesions may be seen in 4% to
16% of patients with Crohn disease and, interestingly,
lesions have been reported to frequently precede the
development of intestinal inflammation (4). No cause
has yet been proven for Crohn disease (5).
Oral Crohn is marked by a male predominance
and a young age at onset. There is a 3:1 male predom-
inance in the 16- to 30-year-old group. In young
patients who have recurrent painful intraoral ulcera-
tive lesions with no other signs, Crohn disease should
be excluded. The course of oral Crohn disease may be
very protracted (6). Oral findings appear to be more
common in patients with colonic disease than ileoco-
lonic or ileal disease (7). Figure 49 Crohn disease. The overlying epithelium shows focal
areas of atrophy, often to the point of ulceration. As with lower
gastrointestinal lesions, the submucosa will show foci of chronic
A. Clinical Features nonnecrotizing, granulomatous inflammation.
The clinical appearances are varied and include thick-
ening and redness of the gingiva, cobblestone appear-
ance of the buccal mucosa, diffuse labial swelling, and
epithelial tags (8–11). Apthous ulcerations are present the diagnosis of orofacial granulomatosis will develop
in 20% of patients, but this is not significantly higher signs of Crohn disease (20).
than in the general population (9). Linear ulcers,
similar to those seen in the gastrointestinal tract, D. Treatment
may be present. Midline lip fissuring, gingivitis, and
angular chelitis are also reported (12). Patients with Immunosuppressive therapy with steroids and other
oral Crohn disease also have a higher prevalence of drugs have been reported to be of value in the treat-
anal and esophageal involvement, suggesting that ment of oral lesions of Crohn disease. Exacerbations of
these patients have disease that is more likely to target oral lesions usually coincide with exacerbations of
squamous epithelium (6). Buccal space infection with colonic inflammation.
salivary duct fistula has been reported with Crohn
disease (13). Crohn disease is also associated with
poor dental health, including a higher risk of dental XXVI. ECTOPIC THYROID
caries, particularly in patients with active disease (14). Ectopic thyroid is thyroid tissue usually found along
the course of the thyroglossal duct, in the tongue, and
B. Pathology in lymph nodes of the neck. Other sites include the
parapharyngeal space, parotid gland, submandibular
Histologically, the inflammatory reaction shows gland, oropharynx, mediastinum, porta hepatis,
intense, frequently perivascular, lymphocytic infiltra- breast, uterus, duodenum, gallbladder, vagina, adre-
tion with follicle formation in addition to noncaseating nal, pancreas, axilla, heart, and dermis (1–7).
granulomas (7) (Fig. 49). The granulomas may or The following discussion concerns only lingual
may not be present in the superficial submucosa. thyroid, thyroid inclusions in cervical lymph nodes,
Granulomatous inflammation of minor salivary gland and thyroid tissue in nonlymphoid tissue of the head
ducts has also been reported (15). Some studies suggest and neck.
that granulomas are more commonly found in the oral
biopsies than in the intestinal biopsies of patients with
Crohn disease. A. Lingual Thyroid
Thyroid tissue located in the tongue is a congenital
C. Differential Diagnosis abnormality and is due to the failure of the thyroid
gland to descend from its embryologic site of origin at
Clinically, the differential for oral Crohn disease the foramen cecum to its usual pretracheal position
includes chelitis glandularis, infectious agents (includ- (8–10). The pathogenesis is unclear, but some have
ing fungal, bacterial, and mycobacterial), sarcoid, speculated that maternal antithyroid immunoglobulin
nonspecific aphthous ulcers, allergies, foreign body may stop thyroid gland descent.
reaction, and orofacial granulomatosis (5,8,9,12,16–19). Clinical manifestations of lingual thyroid are
If followed for a sufficient time, some patients with rare, but in an autopsy study of 184 cadaver tongues,
9.8% had thyroid inclusions (8). Hypothyroidism is Pathology

commonly seen in patients with lingual thyroid, and
some have speculated that lingual thyroid is a physi- Histologically, the thyroid tissue appears normal. The
ologic response by small thyroid remnants in the thyroid tissue may be circumscribed but is usually
tongue to low thyroid levels. Some have suggested interdigitating with skeletal muscle and minor sali-
that lingual thyroid becomes more prominent or is vary gland tissues.
brought to clinical attention under times of stress,
when the thyroid hormone normally produced is Treatment and Prognosis
insufficient and the resulting hypertrophy causes
symptomatic enlargement because of increases in Small lesions without symptoms usually require no
thyroid-stimulating hormone. Hyperthyroidism has therapy. Treatment may include the administration of
been reported in patients with lingual thyroid (11). It thyroid hormone with possible regression in the size
is important to realize that 70% of patients with of the tissue (17). Ablation with radioactive materials
lingual thyroid sufficiently prominent to be clinically is another potential method of treatment (14).
recognized have no other thyroid tissue and thus Indications for surgery include airway obstruction,
become hypothyroid after excision (12). dysphagia, obstructive sleep apnea, or repeated signifi-
cant hemorrhage (18). Rarely, thyroid carcinoma may
Clinical Features arise in lingual thyroid (19). Angiography may play an
important role in the preoperative assessment of
Lingual thyroid is reported to have a bimodal age patients who are candidates for surgical therapy, as
distribution, with peaks at ages 12 and 50 (12). there may be anatomic variations in the blood supply
Although lingual thyroid is congenital, most patients to lingual thyroid (10,17).
present with symptoms in the third decade with ages
ranging from infancy to the eighth decade. Lingual
thyroid is much more frequent in females than males
(13). Airway intubation failure due to obstruction in B. Benign Thyroid Inclusions in a Lymph Node
patients with lingual thyroid is well recognized (14). ‘‘Lateral aberrant thyroid tissue’’ is a term that has
In those cases where there are symptoms, the been employed to imply a number of situations in
patients complain of sensations of a foreign body in which thyroid tissue is found outside its normal
the throat, dysphonia, dysphagia, or hemoptysis location. Most commonly, this term has implied thy-
(9,15). Lingual thyroid may vary in size from several roid follicles in a cervical lymph node. To some, this
millimeters to several centimeters and is located in the finding has always meant that the tissue was meta-
midline of the base of the tongue, usually between the static from a thyroid primary. However, benign thy-
circumvallate papillae and the epiglottis (Fig. 50). A roid follicles may exist in a lymph node with no
radioactive thyroid scan is a good method to diagnose coexistent thyroid malignancy.
the process but fine needle aspiration has also been The unexpected presence of thyroid epithelial
used (2,15,16). Usually more anatomically refined cells in lymph nodes has caused significant controver-
imaging studies such as computed tomography or sy over the implication and therapeutic management
magnetic resonance are required to define the size of of the patient (1). The clinical situation most frequent-
the tissue. ly arises when thyroid epithelium is found in lymph
nodes that are removed in therapy for a nonthyroid
malignancy, such as squamous cell carcinomas. In
the opinion of some authors, almost all these ‘‘inclu-
sions’’ represent metastatic thyroid carcinoma (2,3).
However, other authors do not embrace this opinion
(4–6).
In an autopsy study, microscopically normal
thyroid follicles were found in cervical lymph nodes
in 5 of 106 autopsies, but no thyroid carcinomas were
found in the ipsilateral thyroid gland (7). In another
study, to determine the prevalence of occult metastatic
thyroid carcinoma or other unexpected malignancy
Ansari-Lari et al. studied 1337 patients who under-
went cervical lymphadenectomy during a 17-year
period (8). In 10 patients (0.7%), the lymph nodes
contained cells that were histologically diagnosed as
papillary thyroid carcinoma. In 11 patients (0.8%),
there were lymph nodes with what were histologically
considered to be benign thyroid inclusions (9 of the 11
Figure 50 Lingual thyroid. A smooth, sessile, vascular nodule, patients) or psammoma bodies (2 of the 11 patients).
usually noted on the dorsal tongue just anterior to the circumval- Four of these eleven patients underwent thyroid-
late papillae. ectomy, but no thyroid cancer was found on the
ipsilateral side.
Leon et al. reported that the incidence of unsus-

pected thyroid tissue in lymph nodes of patients with
head and neck carcinomas treated with neck dissec-
tion was 1.5%. Lymph node metastases from a papil-
lary carcinoma as well as benign thyroid inclusion
were found (9). These authors suggested that thyroid
tissue found incidentally in cervical lymph nodes
removed for other head and neck cancers did not
necessarily indicate the need for additional therapy.
A clonality study of benign-appearing thyroid follicles
in lymph nodes was reported to show that the tissue
was polyclonal (10).
Pathology
Benign inclusions should be represented by only a few
small follicles located in or immediately beneath the
lymph node capsule (11) (Fig. 51). These should not
have cleared nuclei or contain grooves, folds, or
inclusions nor show papillary formation (Fig. 52).
Figure 52 Benign thyroid inclusions in lymph node. Thyroid
Rosai et al. suggested that a diagnosis of meta-
follicles show no nuclear inclusions, clearing, grooves, or nuclear
static carcinoma be made in any case in which the overlap.
thyroid tissue has replaced one-third or more of the
node or in which several nodes are affected (11).
Treatment
unsuspected presentation in cervical lymph nodes,
No generic all-encompassing therapeutic approach is the thyroid carcinoma is often indolent (3,8,12).
possible. From a number of studies, it appears that Careful tailoring of diagnostic and therapeutic options
patients with small inclusions of thyroid tissue with- is required.
out features of papillary carcinoma do not always
require thyroidectomy. Most authorities do suggest
clinical examination of the thyroid and radiographic C. Ectopic Benign Thyroid Tissue in
or ultrasonic imaging to determine if thyroid masses Nonlymphoid Tissues of the Head
are present (1). Some studies suggest that even in and Neck
patients with histologic features of papillary thyroid Besides being found in the tongue or cervical lymph
carcinoma, thyroidectomy does not always ‘‘find’’ a nodes, benign thyroid tissue may be found in other
neoplasm in the gland. Further, in those patients with locales of the head and neck. The thyroid tissue may
primary thyroid carcinomas found after initial be incidentally found or may present as a mass.
Thyroid may be seen that is in the midline, outside
of the tissues of the tongue, along the track of the
normal descent of the thyroid. In the midline this
tissue is most commonly seen in the region of the
thyroglossal duct (1). The trachea and laryngo-
tracheal area are also known to harbor thyroid tissue,
and in this location the tissue may grow to such a size
as to obstruct the airway (2–4). Patients with ectopic
thyroid in the neck may also present with thryotox-
icosis, in a manner similar to those patients with
lingual thyroid that becomes hyperfunctional (5,6).
Nonmidline sites may also contain thyroid tissue,
including the submandibular gland, parotid, skin,
carotid sheath, and retropharyngeal and lateral oropha-
ryngeal spaces (7–13).
In some cases, thyroid may be found in patients
that have had prior surgery in the neck and thus may
represent unintentionally implanted thyroid tissue
(14).
Figure 51 Benign thyroid inclusions in lymph node. A small

Clinical Features
cluster of thyroid follicles is present in the subcapsular region of It is important to realize that in some patients, the
the lymph node. No papillary structures are evident. ectopic thyroid tissue may be the only functioning
thyroid tissue. This may suggest that use of
preoperative techniques, such as fine needle aspira- 4. McLean WHI, Lane EB. Intermediate filaments in disease.
tion, be performed prior to total surgical excision of a Curr Opin Cell Biol 1995; 7(1):118–125.
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66:481–493.
Pathology
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7. Nichols GE, Cooper PH, Underwood PB Jr., et al. White
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9. Whitten JB. The electron microscopic examination of con-
Treatment and Prognosis genital keratosis of the oral mucous membranes. Oral Surg
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mutations in keratin 13 as the cause of white sponge
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12. Rugg EL, McLean WHI, Allison WE. A mutation in the
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5
Noninfectious Vesiculoerosive and Ulcerative

Lesions of the Oral Mucosa
Susan Müller
Department of Pathology and Laboratory Medicine and Department of Otolaryngology-
Head & Neck Surgery, Emory University School of Medicine, Atlanta, Georgia, U.S.A.
I. INTRODUCTION equally affected by the disease. PV has a worldwide

case incidence between 0.1 and 3.2 cases per 100,000
Many conditions that affect the oral mucosa along individuals per year in the general population and
with other mucosal sites are either autoimmune or occurs in all ethnic and racial groups, with an
immunologically mediated. They include pemphigus, increased incidence among persons of Mediterranean
mucous membrane pemphigoid (MMP), lichen pla- descent and Ashkenazi Jews (1).
nus, aphthous stomatitis, linear IgA, bullous dermato- Studies of patients with PV indicate a histocom-
sis, dermatitis herpetiformis, and epidermolysis patibility antigen (HLA) link to disease susceptibility.
bullosa acquisita (EBA). The clinical manifestations There is a strong HLA concordance, and reports show
include vesicles, bullae, erosions, and ulcers. Often- that alleles of HLA-DR4, HLA-DR14, and HLA-B15
times, both the clinical and histopathological features confer susceptibility to PV in different ethnic groups (2).
of some of these conditions overlap, thereby making
even more sophisticated methods necessary for accu- Clinical Presentation
rate diagnosis (Table 1). Because both the clinical
presentation and the immunology of the disease can PV originates in the oral mucosa membranes in 50% to
be critical in making the correct diagnosis, both areas 70% of patients, and more than 90% of patients will
are addressed, along with the pathology of vesiculoer- have oral involvement at some time during the course
osive and ulcerative lesions of the oral mucosa. of their disease (3). Mucosal PV may precede cutaneous
PV by an average of five months or may be the sole
manifestation of the disease. Only 10% to 50% of
II. PEMPHIGUS patients demonstrate skin lesions initially. Although
the oral mucosa is most commonly affected, all mucosae
A. Introduction
may be involved, including the pharynx, larynx, esoph-
The condition known as pemphigus refers to a group of agus, cervix, urethra, anal mucosa, and conjunctiva.
related diseases that are characterized clinically by The primary lesion is a flaccid blister, and these
blistering, microscopically by acantholysis, and lesions coalesce to form bullae in the mouth. Red,
immunologically by autoantibodies directed against painful erosions, most commonly on the buccal, pala-
specific proteins in the epidermal (epithelial) cell tine, and gingival mucosa, are seen (Fig. 1). In severe
membrane resulting in the loss of cell-cell adhesion. cases, the entire mucosal surface can be involved.
There are three major subtypes of pemphigus— When the oropharynx is involved, swallowing can
pemphigus vulgaris (PV), pemphigus foliaceus, and become difficult and extension to the pharynx and
paraneoplastic pemphigus. This section will be limit- larynx may present as hoarseness. Esophageal
ed to discussing pemphigus subtypes that routinely involvement is uncommon with presenting symptoms
have an oral mucosal component. of odynophagia and dysphagia.
PV may remain limited to the oral cavity for
several weeks to more than one year before skin
B. Pemphigus Vulgaris involvement. Interestingly, oral lesions may also be
Introduction the last to clear. There are other vesiculoerosive
lesions that may have a presentation in the oral cavity
PV is an autoimmune intraepithelial blistering disor- similar to PV, including bullous pemphigoid, erosive
der affecting both skin and mucous membranes that lichen planus, lupus erythematosus (LE), erythema
usually occurs in patients aged between 40 and 60 multiforme (EM), Behçet’s disease, necrotizing gingi-
years. However, the age range is broad and PV has vostomatitis, idiopathic forms of desquamative gingi-
been described in children. Men and women are vitis, and ulcerative stomatitis. In view of the diverse
244 Müller
Table 1 Comparative Features of Oral Vesiculoerosive and Ulcerative Diseases

Histopathological Direct Indirect
Disease Clinical features features immunofluorescence immunofluorescence
Pemphigus 3rd to 4th decade, oral Suprabasal acantholysis Positive intercellular Circulating autoantibodies
vulgaris lesions in >50% of of keratinocytes with for IgG or IgM often correlate with
patients, may be ‘‘tombstone’’ and C3 disease activity
presenting symptom. appearance of basal
Flaccid blisters on cells
normal or erythematous
skin
Pemphigus Pustules or bullae followed Similar to pemphigus Similar to pemphigus Serum autoantibodies can
vegetans by formation of vulgaris with additional vulgaris sometimes be detected
verrucous vegetations. features of
Oral vegetations intraepidermal
unusual eosinophilic abscesses,
hyperkeratosis, and
papillomatosis
Paraneoplastic Mucous membrane Supra- or subbasal Positive intercellular Serum autoantibodies
pemphigus involvement universal, acantholysis, necrosis IgG with or without (use transitional type
erosive conjunctivitis, of individual complement epithelium as substrate)
associated malignancy keratinocytes and
vacuolar interface
change
Bullous 6th–7th decade with tense Subepithelial blister with IgG, C3 bound at BMZ Circulating IgG BMZ
pemphigoid blisters on normal or a mild inflammatory antibodies found in
erythematous skin. Oral infiltrate in dermis 70% of patients. Titer
lesions rarely presenting does not correlate
symptom with disease
activity
Mucous 6th–7th decade, blistering Similar to bullous IgG and C3, may also The incidence of
membrane disease of mucosal pemphigoid identify IgA and IgM, circulating antibodies
pemphigoid surfaces, oral bound at BMZ reported in 5–90% of
involvement nearly patients, no correlation
universal. Ocular lesions with disease activity
can lead to
symblepharon formation
Lupus Presents in 4th decade, Basal vacuolization, IgG, IgA, IgM, C3 Not specific
erythematosus mainly affects females, dyskeratosis with along basement
(oral findings) Erythematous, discoid superficial and deep membrane
or ulcerative oral lesions perivascular infiltrate
Oral lichen Presents in 5th–6th Basal cell liquefaction, Not specific, shaggy Not specific
planus decade, lace-like Civatte bodies, band- band of fibrinogen
reticular pattern. Erosive like inflammation of present at BMZ
form shows central lymphocytes at the
ulcerations epithelium-connective
tissue interface
Erythema 3rd–4th decade, target Interface dermatitis with Not specific Not specific
multiforme lesions on trunk and basal vacuolization
extremities, ulcerated and dyskeratotic cells
oral mucosa, scattered throughout
hemorrhagic crusting of the epidermis and
erosions on lips mucosa
Abbreviation: BMZ, basement membrane zone.
number of oral diseases that can mimic PV, obtaining layer (Fig. 2). The single row of basal cells, many of
tissue for microscopic examination and immunofluo- which are separated from each other, have a cuboidal
rescence is required for definitive diagnosis. shape giving the characteristic ‘‘tombstone’’ appear-
ance (Fig.2). Irregular upward growth of papillae,
Pathology which are lined by a single row of basal cells and
downward proliferation of strands of epithelial cells, in
Suprabasal bullae formation occurs in PV. The earliest the spaces between the papillae are observed (Fig. 3).
change is intercellular edema within the epithelium. During the early bullous phase of PV, there is
The subsequent acantholysis leads to the formation of little or no inflammation. At times, eosinophils invade
clefts and then of bullae immediately above the basal the epidermis before acantholysis, and this has been
Chapter 5: Noninfectious Vesiculoerosive, Ulcerative Lesions 245
Figure 1 Pemphigus vulgaris involving the soft palate present-

ing as an irregular ulceration. The upper portion of the lesion
represents the roof of the collapsed bulla. Figure 3 Pemphigus vulgaris demonstrating the irregular papil-
lary projections of the submucosa. The overlying epithelium is
absent, with the exception of the basal cells. Round and swollen
acantholytic cells, also called Tzanck cells, can be seen (arrows).
Figure 2 Pemphigus vulgaris. A suprabasal separation is pres-

ent. A mild amount of inflammation is present in the underlying
lamina propria. Figure 4 Direct immunofluorescence of perilesional skin in
pemphigus vulgaris. Note the IgG deposits in the intercellular
desmosomal areas. Abbreviation: IgG, immunoglobulin G.
referred to as eosinophilic spongiosis (1). Because of

the loss of cohesion, acantholytic cells, called ‘‘Tzanck
staining pattern is seen in all pemphigus variants
cells,’’ become round, swollen, and hyperchromatic
(Fig. 3). This feature is useful in identifying PV in except in some cases of pemphigus foliaceus, in
exfoliative cytological preparations. which the fluorescence may be limited to the site of
the blister. In addition to IgG deposits, complement
component C3 may have deposits in a similar pattern
Immunopathology
to IgG. Intercellular space staining with IgA is char-
The use of direct immunofluorescence can confirm the acteristic of IgA pemphigus, which shares clinical and
diagnosis of PV. Patients with active disease will have microscopic findings of pemphigus foliaceus and sub-
immunoglobulin G (IgG) deposits in the intercellular corneal pustular dermatosis.
space of lesional and clinically normal perilesional Indirect immunofluorescence studies of serum
skin (4). The best results for direct immunofluores- from patients with PV can be helpful in confirming the
cence are obtained by biopsy of fresh perilesional disease as well as in differentiating PV from other
tissue or tissue submitted in Michel’s solution. A related bullous diseases. Eighty to ninety percent of
homogeneous staining of the intercellular space at patients demonstrate circulating IgG antibodies
all levels of the epidermis is seen (Fig. 4). This distinct against keratinocyte cell surface. Monkey esophagus
246 Müller
is the best substrate to use for assay of indirect

immunofluorescence. Generally, antibody titers corre-
late with disease activity; however, false-positive
results have been reported (1,4).
Immunology
Autoantibodies in the serum of patients with PV react
against desmosomes, specifically the antigens, desmo-
glein 3 (DG3) and desmoglein 1 (DG1) in the basement
membrane zone (BMZ). DG3 is a 130-kD desmosomal
cadherin involved in cell-cell adhesion of keratino-
cytes. DG1 is a 160-kD antigen that reacts to pemphi-
gus foliaceous. Studies have demonstrated that
binding of PV antibodies to DG3 antigen causes loss
of intercellular adhesion mechanisms, thereby induc-
ing acantholysis and blister formation (2). Enzyme-
linked immunosorbent assays (ELISA) have shown Figure 5 Pemphigus vegetans. Prominent acanthosis with
that PV can be further divided into a mucosal domi- intraepidermal abscesses consisting of eosinophils can be seen.
nant type reactive with only DG3 and a mucocutane-
ous type reactive to both DG3 and DG1 (5).
Treatment and Prognosis has been reported to be a characteristic feature of

pemphigus vegetans (7). Fujimoto et al. reported a
Prior to the advent of systemic corticosteroids, PV was patient with the Hallopeau type who complained of
associated with a high morbidity and mortality rate. deafness, otalgia, and facial nerve paralysis though was
Treatment of PV consists of local and systemic therapy, due to pressure of the facial nerve from vegetations in
depending on the disease location and severity. the middle ear and external auditory canal (8).
Adjuvant immunosuppressants are used for their
steroid-sparing effect, including methotrexate, azathi- Pathology
oprine, cyclophosphamide, and cyclosporine. Drugs
with an anti-inflammatory effect such as minocin, The early lesions of the Neumann type, consisting of
dapsone, or tetracycline have been successfully used bullae and denuded areas, show the same histological
in the treatment of PV. Patients resistant to other picture as that seen in PV. Eosinophilic spongiosis is a
therapies have been treated with plasmapheresis or more prominent feature in pemphigus vegetans. The
high-dose intravenous Igs. The duration of treatment is pustules seen in the early vegetations are filled with
variable. The average time to achieve complete remis- eosinophils. These intraepithelial abscesses filled with
sion is reported from 2 to 10 years with complete eosinophils are highly diagnostic of pemphigus vege-
remission highest in patients who initially present tans. Older vegetations demonstrating papillomatosis
with mild disease and have a rapid response to treat- and hyperkeratosis are not diagnostic.
ment. Mortality from PV is about 6%, mainly due to In the Hallopeau type, the pustules show acan-
complications from the long-term immunosuppressive tholysis and the formation of clefts in a suprabasal
therapy. Systemic infections are the most common location. Within these clefts are numerous eosinophils
cause of death of patients with PV who are receiving and acantholytic epidermal cells (Fig. 5). Early vege-
steroid therapy. tating lesions show intraepidermal eosinophilic
abscesses that are more numerous and larger than
those seen in the Neumann type. Late vegetations of
C. Pemphigus Vegetans the Hallopeau type are histologically similar to the
Neumann type.
Pemphigus vegetans is an uncommon form of PV
occurring in 1% to 2% of pemphigus cases (6). Two Immunopathology
types of pemphigus vegetans are seen: the Neumann
type and the Hallopeau type (6). The Neumann type is Pemphigus vegetans, being a subtype of PV, shows
similar to PV, differing by having the denuded skin similar immunopathology on direct immunofluores-
heal with verrucous vegetations that can be studded cence of perilesional tissue. Autoantibodies in patients
initially with small pustules. In the Hallopeau type with pemphigus vegetans target both DG1 and DG3 (5).
(pyodermatitis vegetans), pustules rather than bullae
are the primary lesion. The pustules are followed by D. Paraneoplastic Pemphigus
verrucous vegetations that gradually extend peripher-
ally, particularly in the intertriginous area. Oral lesions Sporadic cases of patients with neoplasms who also
are present in almost all patients with pemphigus presented with blistering and erosive mucocutaneous
vegetans, although oral vegetations are unusual. Veg- lesions have been reported (9). Additionally, these
etations can be seen along the lip vermillion, and nasal patients have had high titers of ‘‘pemphigus-like’’
involvement is frequent. Cerebriform (scrotal) tongue anti-cell-surface autoantibodies (9). These antibodies
Figure 6 Paraneoplastic pemphigus presenting with extensive

ulcerations of the tongue. The lips also show multiple ulcerations
with hemorrhagic crusting similar to erythema multiforme.
Source: Courtesy of Dr. Carl M. Allen.
Figure 7 Paraneoplastic pemphigus, oral mucosa. A subbasal

separation with hydropic degeneration of the basal cells overly-
ing a mild chronic inflammatory cell infiltrate is seen.
are distinct from those present in patients with PV and
pemphigus foliaceus. In 1990, Anhalt et al. defined
paraneoplastic pemphigus (PNP) as a distinct entity
and developed specific diagnostic criteria (10). separation can be observed (Fig. 7) (14). Su et al.
Mucous membrane involvement, particularly reported a case of PNP in a patient with chronic
the oral mucosa, is a consistent finding in PNP. All lymphocytic leukemia in whom one biopsy specimen
reported cases of PNP have painful blisters and ero- revealed features of both PV and bullous pemphigoid,
sive mucosa involving labial, gingival, buccal, and along with necrotic keratinocytes and hydropic degen-
lingual mucosa and in 45% of reported cases was the eration of the basal cells (14).
initial manifestation (Fig. 6) (9). Mucosae of the oro-
pharynx, nasopharynx, and hypopharynx have also
Immunopathology
been involved in some cases. Erosive conjunctivitis
with subsequent scarring and symblepharon forma- With direct immunofluorescence, testing of perile-
tion has occurred in many patients (11). sional skin or mucosa show intercellular epidermal
Cutaneous manifestations of PNP include poly- IgG deposits and complement, with or without gran-
morphous skin eruptions, with papular lesions pro- ular linear complement deposition along the BMZ (4).
gressing to blisters and erosions (10). Other lesions Indirect immunofluorescence using sera of PNP
appear as erythematous areas with central vesicles, patient against human epidermis or monkey esopha-
similar to target lesions of EM. Typically, the lesions gus are indistinguishable from the cell surface binding
affect the trunk, extremities, and palms and soles. seen in PV or foliaceus. However, PNP does differ
Both malignant and benign neoplasms have been from other types of pemphigus in that the autoanti-
associated with PNP. Hematological malignancies or bodies also bind to simple, columnar, and transitional
disorders account for 84% of all reported cases of PNP epithelium. Rodent bladder epithelium substrate,
(9–12). Epithelial malignancies account for 8.6% of human respiratory tract, colon, and small bowel epi-
cases, and sarcomas account for 6.4%. A known malig- thelia, all have given consistent cell surface binding in
nancy prior to the eruption of PNP is noted in about patients with PNP (10). In all cases of PNP, the
two-thirds of cases. PNP associated with malignancy is antibody class responsible for cell surface binding on
refractory to treatment, and the patients usually have a indirect immunofluorescence is IgG.
rapidly fatal course. Mucosal ulcerations do not
respond to treatment with high-dose corticosteroids Immunology
and immunosuppressive medications, although some
patients have had clearing of cutaneous lesions (12). Five polypeptides can be consistently immunoprecipi-
tated from the sera of patients with PNP (5). The
Pathology
polypeptides identified are 250-kD (desmoplakin I),
230-kD (bullous pemphigoid antigen), 210-kD (desmo-
Light microscopy of biopsy specimens from patients plakin II), 190-kD (periplakin), and 170-kD (envopla-
with PNP can show a histological picture similar to PV. kin). This polypeptide complex is not seen in other
Individual cell necrosis of keratinocytes, acantholysis, pemphigus types. Desmoplakins are structural proteins
and a vacuolar interface change, similar to EM, has found in all epithelia associated with the cytoplasmic
been reported to be a predominant microscopic feature plaque at the desmosome cellular junction. This may
(13). At times, a subbasal, rather than a suprabasal, account for the ability of PNP sera to react with
248 Müller
numerous types of epithelia. This immunoprecipitation III. PEMPHIGOID

profile is the most consistent laboratory finding in PNP.
A. Bullous Pemphigoid
Diagnosis Bullous pemphigoid is a subepidermal blistering dis-
Anhalt et al. suggested five specific criteria to define ease characterized by the deposition of autoantibodies
PNP (10). Camisa and Helms proposed a revision at the BMZ. Bullous pemphigoid affects mostly the
dividing criteria into major and minor signs. Major elderly population, with most patients older than
signs include painful mucosal erosions and a poly- 60 years. No definitive sex, racial, or ethnic tendency
morphous skin eruption, with papular lesions is seen.
progressing to blisters and erosive lesions; immuno-
precipitation of a complex of four proteins from Clinical Presentation
keratinocytes by these antibodies; and concurrent The development of tense blisters on either normal-
internal neoplasia. Minor signs include histological appearing skin or, at times, on an erythematous base
evidence of epidermal acantholysis and interface is the characteristic lesion. After the blisters rupture,
changes; epidermal and BMZ deposition of IgG, as they become flaccid and result in an eroded area.
seen by direct immunofluorescence; and serum auto- These blisters can range in size from small vesicles
antibodies that bind to rat bladder epithelium on to large bullae many centimeters in diameter. Unless
indirect immunofluorescence (15). Three major or complicated by infection, most blisters will heal with-
two major and two minor signs are required for the out scarring. Pruritus without skin findings may be an
diagnosis of PNP. early symptom for some patients. Patients experienc-
Clinical differential diagnosis of PNP can ing pruritus with absence of skin lesions may develop
include PV, bullous pemphigoid, EM, and MMP. blistering lesions of bullous pemphigoid from one
Drug-induced pemphigus, a rare disease, must also month to four years later (1).
be considered. Evaluation of biopsies by light micros- Bullous pemphigoid can affect the oral mucous
copy and direct immunofluorescence of serum and, in membranes in up to 40% of patients, but it is rarely the
some cases, immunoprecipitation of a complex of four presenting symptom (2). In addition, these mucosal
proteins, are required to confirm the diagnosis of lesions are limited to the oropharynx. This presenta-
PNP. Repeat testing, including additional biopsies, tion is very different from MMP, in which oral muco-
and direct and indirect immunofluorescence are sal lesions are the primary location.
often needed to arrive at a final diagnosis.
Pathology
E. Drug-Induced Pemphigus The typical microscopic feature of tissue obtained
Many drugs have been reported to induce pemphigus from the perilesional margin of a bulla reveals a
on rare occasions (16,17). The clinical and histological subepidermal blister (Fig. 8). A modest number of
features reported are quite variable, with the only inflammatory cells, composed chiefly of eosinophils,
consistent finding being epidermal acantholytic but also containing lymphocytes, histiocytes, and neu-
lesions related to the intake of a certain drug. Oral trophils, may be present in the dermis or lamina
ulcerations are a common feature of drug-induced
pemphigus. Penicillamine, used in the therapy of
rheumatoid arthritis, progressive systemic sclerosis,
and Wilson’s disease, has reportedly been the causa-
tive agent of drug-induced pemphigus in 7% of
patients taking this drug for longer than six months
(16). Other drugs reported to cause pemphigus
include captopril, rifampin, pyrazolone derivatives,
thiopronin, pyritinol, and penicillin (16).
Most patients with drug-induced pemphigus
experience disease regression when the medication
is discontinued. In this group of patients, the disease
is thought to be directly induced by the drug, usually
one containing sulfhydryl groups and the prognosis is
quite good. In another group of patients, the disease
was believed to have been triggered by a nonsulf-
hydryl medication, which persists even after the med-
ication was discontinued (16). This group of patients
has a more protracted disease course, similar to
patients with idiopathic pemphigus. In this group of
patients, it has been postulated that genetic factors are
also responsible. Studies have shown that patients Figure 8 Bullous pemphigoid. A bulla is seen from the sub-
with drug-induced pemphigus and idiopathic pem- epithelial detachment of the epidermis from the dermis.
phigus share the same HLA alleles.
in bullous pemphigoid. The autoantibodies bind to the

BP-antigen and activate the complement cascade.
Inflammatory mediators are produced in the lamina
lucida, including the anaphylatoxins C3a and C4a (4).
Subsequent mast-cell activation and degranulation
occurs, with release of numerous inflammatory
mediators. Neutrophils and eosinophils migrate to
the region of the basement membrane and then
release their own inflammatory mediators, including
enzymes responsible for the destruction of the dermal-
epidermal junction. The final result is subepidermal
blister formation.

Unlike PV, bullous pemphigoid is rarely life threatening,
Figure 9 Bullous pemphigoid. Within the blister, eosinophils are
even without treatment. Most patients with generalized
prominent along with fibrin. disease are treated with systemic immunosuppressive
therapy including corticosteroids, dapsone, and azathio-
prine (5). Many patients with bullous pemphigoid expe-
rience spontaneous remission of their disease two to
propria (Fig. 9). Blisters that arise on an erythematous three years after initial presentation.
base show more extensive accumulations of inflam-
matory cells. Within the bullae, eosinophils tend to B. Mucous Membrane MMP
predominate. (Cicatricial Pemphigoid)
Immunopathology MMP is a chronic blistering disease affecting mainly
the mucous membranes and occasionally the skin.
Linear deposits of IgG, with IgG4 subclass predomi- Cicatricial refers to the scarring that can result partic-
nance, and C3 at the BMZ are observed by direct ularly when the conjunctival mucosa is involved.
immunofluorescence in most patients with bullous The exact incidence and prevalence of MMP is
pemphigoid (3). Linear deposits of IgM, IgA, and unknown, but it is less frequently diagnosed than
IgE may also be present in some patients. This immu- bullous pemphigoid. MMP usually affects the mid-
nofluorescence pattern is not specific for bullous pem- dle-aged or elderly, with the average age of onset of 66
phigoid and is seen in MMP, EBA, herpes gestationis, years (6). Women are affected more frequently than
and bullous systemic LE. men by a ratio of 1.5 to 2:1.
Unlike MMP, circulating IgG anti-BMZ antibod-
ies are detectable in about 70% of bullous pemphigoid
Clinical Presentation
patients by indirect immunofluorescence (3). There is
no correlation between antibody titer and severity of Oral mucosal involvement is the most consistent
disease. Because circulating IgG antibodies directed feature of MMP and occurs in almost all patients.
against the basement membrane may also be seen in Gingival involvement is seen in 64% of oral cases
EBA, herpes gestationis, and MMP, special studies and presents as a desquamative gingivitis (Fig. 10) (2).
are, at times, needed to diagnose bullous pemphigoid.
When using routine direct immunofluorescence,
the use of patient skin, split in vitro with 1-M NaCl,
can help delineate these disease processes. Incubation
of skin in 1.0 mol/L NaCl separates the BMZ through
the lamina lucida separating the skin. The IgG depos-
its in bullous pemphigoid bind only on the epidermal
side of the separation or both the epidermal and
dermal sides, whereas the same antibodies bind to
the dermal side in skin from patients with EBA.
Immunology
Patients with bullous pemphigoid have a circulating
antigen, BP-antigen (BPAG1), a 230-kD polypeptide
that is located intracellularly, associated with the
hemidesmosome (1,4). Another BP-antigen, a 180-kD Figure 10 Mucous membrane pemphigoid presenting as des-
(BPAG2) protein is a transmembrane protein of the quamative gingivitis. The gingiva is erythematous, and the surface
basal keratinocyte and upper lamina lucida (1,4). mucosa can be removed with ease. A similar clinical picture can
Some of the BP antibodies are complement activating sometimes be seen with pemphigus vulgaris or lichen planus.
and appear to play a very important pathogenic role
250 Müller
Figure 11 Mucous membrane pemphigoid occurring on the

ventral surface of the tongue. The white, necrotic area repre-
sents the collapsed, but not yet detached, bulla.
Figure 12 Mucous membrane pemphigoid. A patient with ocu-
lar involvement showing conjunctival inflammation and symble-
pharon formation.
Mild cases show erythema and edema of the
gingiva, whereas more severe cases show blister for-
mation and desquamation of the gingiva, resulting in
erosions and ulcerations. The facial gingiva is
involved more often than the lingual or palatal gingiva. formation. Involvement of the vocal cords may lead
A positive Nikolsky sign, where induced trauma can to dysphonia or hoarseness. If untreated, severe laryn-
elicit a blister or bullae in clinically normal mucosa, is geal lesions may lead to scarring with stenosis.
often seen in MMP. Although up to half of the patients Both the nasopharynx and the esophagus can be
who present clinically with desquamative gingivitis involved in MMP. Patients with esophageal involve-
have or will eventually develop MMP, other cases ment may complain of dyspepsia or dysphagia. A
may represent erosive lichen planus, or less likely, PV. complication of untreated esophageal lesions, which
Some cases of desquamative gingivitis without a ulcerate and scar, is esophageal stenosis.
specific diagnosis may represent a mucosal reaction Other mucosal sites affected by MMP involve the
to irritation (2). anus, rectum, and vagina. Skin involvement is vari-
MMP also involves in order of frequency, the able (10–43%) and clinically differs in presentation
buccal mucosa, palate, alveolar ridge, tongue, and from patients with bullous pemphigoid (6). One type
lower lip (Fig. 11). In these areas, lesions appear as of eruption seen is a generalized bullous eruption
vesicles that rupture to leave erosions. The ulcerated similar to bullous pemphigoid, but of short duration,
lesions can be painful and may persist for weeks if not which allows differentiation from patients with bul-
treated. Most erosions heal without scarring, however lous pemphigoid with oral lesions. Another type of
some scarring can result, appearing as a white, reticu- skin lesions seen in MMP is recurrent blisters confined
lated pattern resembling lichen planus. In severe to a limited area, usually the head and neck, or skin
cases, adhesions may form. adjacent to affected mucosa. These tense vesicles
Ocular involvement is a serious complication of rupture, leading to erosions that may heal with scar-
MMP and may occur in up to 37% of patients who ring in one-third of cases (6).
have oral involvement (7). The earliest change is
chronic conjunctival irritation, which may be unilater- Pathology
al or bilateral. Patients report a burning or a foreign Examination of perilesional tissue reveals a subepi-
body sensation and complain of dryness. As the thelial split, with a mild, chronic inflammatory cell
disease progresses, ulcerations can be seen and further infiltrate that consists of lymphocytes, plasma cells,
scarring occurs. Attempts at healing lead to fibrous eosinophils, and neutrophils (Fig. 13). Mucosal lesions
adhesions that fuse the bulbar (scleral) and palpebral often consist predominately of lymphocytes and plasma
conjunctiva (Fig. 12) (8). These adhesions are called cells.
symblepharons. If the disease progresses, the conjunc-
tiva can contract, inverting the eyelid margins (entro-
Immunopathology
pion). This causes the eyelashes to rub against the
cornea (trichiasis). Further corneal injury may result in Direct immunofluorescence of lesional and perile-
eventual blindness. Numerous other conditions can sional tissue from affected patients show a continuous
mimic ocular cicatricial pemphigoid, including linear linear band at the BMZ of fixed IgG or complement
IgA disease, dermatitis herpetiformis, Sjogrens’s syn- (Fig. 14). Primarily, both IgG and C3 are present,
drome, infection, and drug-induced conditions (9). occasionally in association with IgM and IgA (3).
Although uncommon, when MMP involves the Unlike bullous pemphigoid, the presence of cir-
larynx, airway obstruction may result from bullae culating anti-BMZ antibodies in the sera of patients
disease-specific circulating antibodies in all patients.

Studies of patients with circulating antibodies show
antibodies specific for the hemidesmosomal proteins
BPAG1 or BPAG2, similar to bullous pemphigoid.
Other studies showed that some patients with MMP
have autoantibodies against an anchoring filament
protein, laminin 5, called epiligrin (5).
When a patient presents with mucosal ulcers, a biopsy
of the blister or perilesional tissue should be per-
formed for microscopic examination. Other diseases
that present histologically as a subepithelial separa-
tion include linear IgA disease and EBA. Direct immu-
nofluorescence is useful to distinguish between these
conditions. If the deposition along the BMZ is pre-
dominately IgA, then the diagnosis of linear IgA
should be suspected.
EBA presents as an acquired subepidermal blis-
Figure 13 Mucous membrane pemphigoid. Characteristic sub- tering disease characterized by a combination of blis-
epithelial clefting is evident. The lamina propria contains a
ters, erosions, scars, milia, and dyspigmentation of the
moderate chronic inflammatory cell infiltrate.
skin (10). Involvement of the mucous membranes,
including oral, pharyngeal, laryngeal, nasal, conjuncti-
val, esophageal, and genital, are clinically similar to
MMP. In EBA, the production of autoantibodies to the
epithelial basement membrane protein type VII colla-
gen is distinct and permits differentiation from other
subepidermal blistering diseases (5). When EBA is
suspected, using 1.0-mol NaCl-split perilesional tissue,
which induces bullae formation, is helpful. The IgG
autoantibodies will be seen on the floor of the induced
bullae in EBA (corresponding to lamina densa), where-
as in MMP, the IgG deposits are seen on the roof of the
bullae (corresponding to lamina lucida) (3).
The reader is referred to specialty texts in der-
matology for an in-depth discussion of linear IgA
disease and EBA.

Therapy for MMP depends on disease severity.
Patients should be screened by an ophthalmologist,
even in the absence of ocular lesions, to obtain a
baseline examination of the conjunctivae. In limited
Figure 14 Direct immunofluorescence of perilesional tissue
from a patient with mucous membrane pemphigoid. A continuous
oral disease, the application of corticosteroids as either
linear band of IgG is seen at the basement membrane zone. a rinse or a topical form several times a day will
Abbreviation: IgG, immunoglobulin G. control the lesions. Once the lesions regress, the cor-
ticosteroids can be discontinued, although recurrences
are common. When extensive oral lesions are present
or ocular involvement is seen, systemic therapy is
with MMP are difficult to confirm. Various studies required. Dapsone, a sulfanilamide drug derivative,
have reported circulating antibodies from 5% to 90% has reportedly been effective in treating MMP. Sys-
of affected patients (3,9). Use of salt-split human skin temic corticosteroids, often in conjunction with immu-
and mucosa as a substrate increases the sensitivity of nosuppressive drugs, such as cyclophosphamide,
indirect immunofluorescence, although the binding have also been used.
patterns are not disease specific (6). No correlation Patients with ocular scarring who are in com-
between circulating antibody titers and severity of plete remission may benefit from cryotherapy abla-
disease is present in MMP. tion. It is important to ascertain that the disease is in
complete remission, for surgery can cause an exacer-
Immunology
bation of the disease, with consequent corneal ulcera-
tion and blindness (7). Surgical correction of laryngeal
The precise pathogenic mechanisms of MMP are not or esophageal stenosis is also contraindicated in a
completely understood. This is due to the lack of patient with active disease.
252 Müller
IV. LUPUS ERYTHEMATOSUS SLE have photosensitivity, and ultraviolet light (UV)
may precipitate or exacerbate the disease; however, the
A. Introduction exact mechanism is unclear. Bacterial or latent viral
LE is an autoimmune disease of unknown etiology infections have also been proposed as initiating events,
affecting connective tissues and multiple organs. although no clear evidence exists (1,4). Hormonal fac-
There are three major clinicopathological forms recog- tors have long been considered in view of the high
nized. Systemic lupus erythematosus (SLE) is a chronic female incidence. Antiphospholipid antibodies associ-
inflammatory disease involving multiple organs and a ated with venous and arterial thrombosis are also seen.
variety of cutaneous and oral manifestations. The clini- The clinical features of SLE are varied, and
cal features vary tremendously, but the most common because of this, a definitive diagnosis of SLE is often
features are skin rashes, joint pain, fever, nephritis, and not made until a few years after the initial symptoms.
pleurisy. Chronic cutaneous lupus erythematosus Initial complaints include extreme fatigue, joint pain,
(CCLE), or discoid lupus erythematosus, consists pri- and myalgia. Up to 85% of patients have mucocutane-
marily of cutaneous and oral lesions. Although some ous symptoms, including the classic butterfly rash
patients with CCLE (<5%) may develop SLE, CCLE over the malar region and bridge of nose in approxi-
generally represents an independent entity with a good mately 50% of patients (5). Oral mucosal lesions occur
prognosis. A third form of LE, subacute cutaneous primarily on the palate, buccal mucosa, and gingivae.
lupus erythematosus (SCLE) has clinical features of The clinical appearance can range from lichenoid to
both SLE and CCLE, although systemic disease is granulomatous, at times with ulceration. Alopecia,
usually mild. An overview of the clinicopathological either diffuse or patchy may be encountered in SLE.
features of these three forms of LE is presented. Renal involvement, referred to as lupus nephri-
tis, can be seen in up to 50% of patients, although renal
changes can be demonstrated in almost all cases of
B. Systemic Lupus Erythematosus SLE when immunofluorescence and electron micros-
copy are used (6). The development of nephrotic
SLE is a disease that is five to ten times more likely to syndrome and subsequent uremia is a serous compli-
affect women than men and also more common in cation of SLE and the most common cause of death.
blacks (1:250) than whites (1:1000). The onset of Cardiac involvement in the form of pericarditis
symptoms most frequently occurs between the ages is common. Nonbacterial verrucous endocarditis
of 15 and 40 years, with the average age of 30 years; (Libman–Sacks endocarditis) can also be seen in 50%
however, the disease can affect both the pediatric and of the patients at autopsy, but is usually not clinically
older patient (1). recognized. Central nervous systems symptoms can
In the United States, the reported prevalence of be noted with seizures and psychosis among the more
SLE ranges from 14.6 to 50.8 cases per 100,000. The serious neurological abnormalities.
basic etiological event of SLE is unknown, although
several factors have been proposed. Genetic factors
include an increased incidence of clinical SLE or sero- C. Chronic Cutaneous Lupus Erythematosus
logical positivity in family members. In 40% of cases of
Patients with CCLE have limited disease, generally
neonatal SLE, the mothers will either demonstrate
confined to mucocutaneous areas, and systemic
evidence of SLE, or will have developed SLE within a
involvement is rare. CCLE is also called discoid
year after childbirth (2). The reported concordance rate
lupus erythematosus because the cutaneous lesions
of SLE in monozygotic twins is 25%. In 6% of SLE
are characterized by well-defined, scaly, erythematous
cases, patients have inherited deficiencies of early
discoid patches. With time, many of the older lesions
complement components, including C2 and C4 (2).
heal, with atrophic scarring. The cutaneous lesions
Circulating autoantibodies directed against
most commonly affect the face, particularly the malar
nuclear material, also known as antinuclear antibodies
area and bridge of nose, although the scalp, ears, oral
(ANA), are the serological hallmark of SLE. From 95%
cavity, and the vermillion border of the lips can be
to 100% of patients with SLE have positive ANA (3).
affected. The oral lesions of CCLE may clinically
Other autoantibodies to cytoplasmic material, blood
resemble lichen planus (7). White, radiating striae
proteins, and cell membranes are also present. These
surrounding an erythematous or ulcerated central
antibodies can have direct effect, with manifestations
zone typify the oral mucosal lesions (Fig. 15). At
such as hemolytic anemia, thrombocytopenia, or leu-
times, a more diffused nondescript erythematous
kopenia. Another major effect of these formed
patch can be seen, particularly on the palate (Fig. 16).
immune complexes, especially by nuclear antigens
The exact pathogenesis of CCLE is unknown, but
and ANA, is their deposition in blood vessel walls,
most likely involves genetic factors in the develop-
glomerular basement membranes, and other sites. The
ment of the disease. Exposure to UV light can trigger
complexes activate the complement system, with sub-
as well as exacerbate CCLE.
sequent damage to the tissue sites.
Exogenous factors are also involved in the patho-
genesis of SLE. Drugs, including procainamide, hydral- D. Subacute Cutaneous Lupus Erythematosus
azine, isoniazid, and quinidine, may cause drug-
induced lupus, but this is limited to the duration of In SCLE, widespread nonscarring cutaneous lesions
drug usage (4). One-third to two-thirds of patients with arise mainly on the upper trunk and extensor part of
Figure 17 Chronic cutaneous lupus erythematosus. Epithelial

atrophy, edema, and interface change is seen. A deep perivas-
Figure 15 Chronic cutaneous lupus erythematosus presenting cular lymphocytic infiltrate is present (arrow).
on the buccal mucosa as white radiating striae (arrows).
Figure 16 Nondescript erythematous patch on the palate from

a patient with chronic cutaneous lupus erythematous.
Figure 18 Higher magnification of Figure 17 showing hydropic
degeneration of the basal cells and upward migration of lympho-
cytes.
the arms. Although photosensitivity is present, the
face is generally spared. Mild systemic disease, usually
arthralgia, is present and renal disease is unusual.
in LE of continuous or patchy periodic acid-Schiff
E. Histopathology (PAS)-positive deposits juxtaepithelially (8,9).
The cutaneous lesions of LE are diagnosed by the
The histopathological features of the oral lesions of the presence of hyperkeratosis with keratotic plugging in
different forms of LE share similar characteristics (8,9). the openings of hair follicles. Basal cell liquefaction
The epithelium can show either hyperorthokeratosis or and a patchy, predominately lymphocytic, infiltrate
hyperparakeratosis, with keratotic plugging (Fig. 17). both around vessels and skin appendages are seen.
Alternating areas of epithelial atrophy and acanthosis
can be seen. At times, a lichenoid appearance is pres-
ent, with sawtooth rete ridges. Basal cell liquefaction, F. Diagnosis
colloid bodies or Civatte bodies, intraepithelial vesicles,
The diagnosis of SLE includes both clinical and labo-
and upward migration of lymphocytes can also be seen
ratory findings. The criteria for SLE proposed by the
(Fig. 18). Subepithelial infiltration of lymphocytes can
American College of Rheumatology (11) include the
be seen both superficially and, more often, perivascu-
following:
larly, deep in the lamina propria. Many of these
features are also present in oral lichen planus, with 1. Malar rash
the exception of the deep perivascular infiltrate. One 2. Discoid rash
way to distinguish these two entities is by the presence 3. Photosensitivity
254 Müller
4. Oral ulcers to the skin and will eventually resolve in 50% of

5. Nonerosive polyarthritis involving two or more patients. However, development of SLE occurs in
peripheral joints about 5% of patients with CCLE.
6. Serositis: pleuritis or pericarditis
7. Renal disorder: cellular casts, proteinuria greater
than 500 mg/24 hr nephritic syndrome
V. LICHEN PLANUS
8. Neurological symptoms: psychosis or seizures A. Introduction
9. Hematological abnormalities: hemolytic anemia,
leukopenia, lymphopenia, or thrombocytopenia Lichen planus is a common, usually self-limiting
10. ANA eruption that affects mainly middle-aged adults and
11. Immunological disorder: anti-DNA or anti-SM involves the skin, mucous membranes, hair, and nails.
antibodies. Approximately one-third of patients with oral lichen
planus (OLP) and between 55% and 65% of patients
The presence of any two abnormal immunologi- with cutaneous lichen planus are women (1). Pediatric
cal findings in addition to two clinical findings pres- cases of lichen planus are most unusual, constituting
ent serially or simultaneously constitutes a diagnosis only 2% to 3% of all patients (1).
of SLE. These autoantibodies are generally not present
in CCLE, with less than 20% patients with a positive
ANA. Most patients with SCLE will have a positive B. Clinical Presentation
ANA. The cutaneous lesions of lichen planus consists of
Direct immunofluorescence of lesional tissue in violaceous polygonal papules that tend to preferen-
patients with both SLE and CCLE shows a granular tially involve the flexural areas. A network of fine
deposition of one or more immunoreactants (IgG, lace-like white lines, called Wickham’s striae, can be
IgM, or C3) at the BMZ. The lupus band test uses observed in many of the papules. The skin lesions of
direct immunofluorescence of normal uninvolved lichen planus are pruritic, although 20% of affected
skin. The lupus band test is usually positive in patients are asymptomatic (2).
patients with SLE, but not in patients with CCLE (12). Next to cutaneous lesions, OLP is the most com-
monly reported form. In fact, 15% to 35% of patients
have only oral manifestations of lichen planus (1).
G. Treatment and Prognosis Three different forms or presentations of OLP have
been described: reticular (papular, lacy, or plaque-like);
The primary treatment of patients with SLE is preven- erythematous (atrophic) and erosive (ulcerative or bul-
tive care with regular monitoring. Avoidance of sun- lous) (3). The reticular form is most common; however,
light is necessary to prevent exacerbation of disease. the erosive form is more commonly reported. This
Nonsteroidal anti-inflammatory drugs can be used to most likely because the erosive form may provoke a
treat minor manifestations or in combination with painful or burning sensation; hence, the patients seek
steroids to minimize steroid dose. High-dose steroid treatment. The buccal mucosa is most commonly affect-
therapy should be limited, if possible, to four to –six ed by the reticular form, although the lateral and dorsal
weeks, and maintenance therapy should be of the tongue, the gingiva, and the palate may also be
lowest dose possible, preferably alternate-day therapy. involved (Fig. 19) (4). The typical reticular pattern
For acute episodes, immunosuppressive agents,
including cyclophosphamide, chlorambucil, and
azothioprine have been used, but are associated with
significant toxic effects. Antimalarials, most common-
ly hydroxychloroquine, are effective for cutaneous,
musculoskeletal, and mild systemic symptoms.
The treatment of CCLE is usually confined to
topical corticosteroid administration to both the cuta-
neous and oral lesions. Those patients who fail to
respond to corticosteroids may improve with systemic
antimalarials. As with SLE, patients with CCLE
should avoid exposure to sunlight.
The clinical course of SLE is highly variable;
therefore, so is the prognosis. The disease is charac-
terized by periods of flare-ups and remissions over a
period of years and even decades. Over the years,
prognosis has improved significantly. The five-year
survival rate is 95% and then falls to 75% by 15 years.
The most common causes of death are renal failure,
intercurrent infections, and central nervous system
complications (1,5–7). Figure 19 Lichen planus of the buccal mucosa exhibiting a
The prognosis for patients with CCLE is quite white, reticulated lace-like pattern.
good. For most patients, the lesions remain confined
Figure 20 Lichen planus with typical plaque-like presentation

on the dorsal tongue.
Figure 22 Erosive lichen planus presenting as generalized
desquamative gingivitis.
Figure 21 Erosive lichen planus of the buccal mucosa. Note the

central ulceration surrounded by the white lace-like stria.
Figure 23 Lichenoid reaction to dental amalgam with lace-like
reticulations (arrows). Note the large amalgam restoration which
comes in direct contact with the affected mucosa (circled arrow).
seen on the buccal mucosa is usually replaced by a

more keratotic plaque when lichen planus occurs on
produce a lichenoid reaction that mimics lichen pla-
the dorsal tongue (Fig. 20) (4).
nus (Fig. 23) (3,5). Biopsy material from these lesions
Erosive lichen planus clinically shows varying
is very similar to that seen in lichen planus; however,
degrees of erythematous areas with central ulcerations.
unlike lichen planus, these lesions resolve after
On the periphery of these erosive areas, more typical
removal of the adjacent amalgam filling.
Wickham’s striae can be observed (Fig. 21). When the
Numerous drugs can produce a lichenoid muco-
gingiva is involved, a picture of desquamative gingivi-
sal reaction (Table 2) (1,5). Clinically, the lesions may
tis may present, and biopsy specimens should be
present as either reticular or erosive or both. Unlike
obtained to rule out other lesions that may present in
typical lichen planus, the lesions may be unilateral.
a similar fashion (Fig. 22) (see discussion on MMP).
The cause of lichenoid drug eruptions is unclear.
Histology may help distinguish lichenoid lesions
C. Lichenoid Drug Eruptions from classic lichen planus.
The use of cinnamon-flavored agents, including
Other entities can share both clinical and histopatho- candy, chewing gum, mouthwash, toothpaste, and
logical similarities to lichen planus. In some patients, volatile oils, can result in an adverse mucosal reaction
oral mucosa in direct contact with dental amalgam can (6). The clinical presentation can vary, including
256 Müller
Table 2 Drugs Associated with Lichenoid Reactions

Antibiotics Psychotropic
Ketoconazole Lorazepam
para-Amino salicylic acid Carbamezepine
Streptomycin Nonsteroidal anti-
Tetracycline inflammatory drugs
Sulfonylureas Naproxen
Chlorpropamide Indomethacin
Tolbutamide Diflunisal
Antimalarials Ibuprofen
Chloroquine Fenclofenac
Quinacrine Miscellaneous
Quinidine Arsenicals
Antihypertensives Bismuth
Chlorothiazide Gold
Hydrochlorothiazide Mercury
Methyldopa Pallidium
Propranolol Penicillamine
Spironolactone Allopurinol
Mercaptopropionylglycine
Source: From Refs. 5, 7, 9; Sec. V (LICHEN PLANUS). Figure 25 Lichen planus, oral mucosa. The lesion shows acan-
thosis, hyperparakeratosis, and sawtooth rete ridges. Occasional
dyskeratotic cell is noted (arrow). A dense band-like lymphocytic
infiltrate immediately subjacent to the epithelium is present.
Figure 24 Lichenoid reaction to cinnamon-flavored chewing

gum. This lesion resolved after gum chewing stopped.
erythema, ulceration, sloughing, and red and white

lesions that clinically resemble lichen planus (Fig. 24).
Because the histopathology of these lichenoid Figure 26 Lichen planus of the oral mucosa showing hydropic
lesions is similar to lichen planus, clinical correlation degeneration of basal cells. Civatte bodies are seen at the
is imperative. Recent history of drug therapy or a new epithelium-connective tissue interface (arrows).
amalgam restoration may aid in arriving at the correct
diagnosis. If symptomatic lichenoid reactions are a
result of a drug reaction, then discontinuation or
substitution of the medication is warranted. atinocytes that have undergone premature keratiniza-
tion, can be seen at the epithelium-connective tissue
D. Pathology interface. Another dominant feature is the band-like
inflammatory infiltrate of predominately T lympho-
The histopathological features of OLP show varying cytes that hug the basal layer. Cytological atypia
degrees of orthokeratosis and parakeratosis. The epi- should not be encountered in oral lichen planus; how-
thelium may show atrophy or acanthosis, and often the ever, lesions superimposed with candidal infections
rete ridges demonstrate a sawtooth pattern (Fig. 25). may appear dysplastic. Biopsies of these lesions should
The BMZ figures prominently in the pathogenesis of be taken for re-evaluation after the candidal infection is
lichen planus. The basal cell layer of the epithelium treated. When dysplasia is noted, this should not be
exhibits liquefaction (hydropic degeneration) (Fig. 26). interpreted as lichen planus but rather as lichenoid
Civatte bodies, which represent dyskeratotic basal ker- dysplasia which is a potentially premalignant lesion.
E. Immunopathology
The direct immunofluorescence pattern seen in lichen
planus is not specific or diagnostic. Most lesions
demonstrate the presence of fibrin or fibrinogen in a
granular or linear pattern along the basement mem-
brane (8). Although this finding is not diagnostic for
lichen planus, it is useful in eliminating other vesi-
culo-ulcerative diseases. Occasionally, deposits of
IgM, C3, IgG, and IgA are seen.
F. Immunology
The exact pathogenesis of lichen planus is unknown,
although both antigen-specific and nonspecific mech-
anisms are proposed (9). The disease appears to
represent a T cell–mediated immune response, and
the majority of T cells within the epithelium and
adjacent to the damaged basal cell are activated CD8
Figure 27 Lichenoid reaction to dental amalgam. Note the
lymphocytes. In one hypothesis, intraepithelial, anti-
formation of lymphoid follicles within a dense lymphocytic infiltrate.
gen-specific CD8 T cells trigger apoptosis of basal cell
keratinocytes in OLP (9). Other research points to
nonspecific events, including mast cell chemotaxis
Although there are many microscopic similarities
and degranulation, basement membrane disruption
to lichen planus, lichenoid lesions have some notable
by matrix metalloproteinases, as well as T cells
differences. At times, the lymphocytic infiltrate is so
recruited by keratinocye-derived chemokines.
dense that lymphoid follicles can be identified, which is
particularly true in amalgam reactions (Fig. 27). Lichen-
oid drug reactions may have a more diffused lympho-
cytic infiltrate and contain eosinophils and plasma G. Treatment and Prognosis
cells, and there may be more colloid bodies than in The treatment of OLP is dependent on disease extent.
classic LP, but there are no specific features. The In patients with the reticular form of lichen planus, no
microscopic features of cinnamon-induced stomatitis therapy is required because this form rarely produces
share many of the features of lichen planus; however, symptoms. At times, secondary candidiasis can cause
the lichenoid band-like infiltrate contains a higher a burning sensation, and antifungal therapy effectively
proportion of plasma cells than are expected in lichen relieves these symptoms. When patients present with
planus. In addition, perivascular chronic inflammatory limited oral erosive lichen planus, topical corticoste-
cell infiltrate is frequently seen (Fig. 28) (7). roids are recommended. For patients with extensive
oral lesions, treatment with systemic corticosteroids,
administered in tapering dosage; is effective.
Cyclosporine, dapsone, azathioprine, and psora-
len and ultraviolet light A (PUVA) have also been
used to treat symptomatic oral lesions of lichen pla-
nus; however, these reports are not controlled studies
and include only a few patients (1). OLP is a chronic
condition and can persist for up to 20 years (1,3). The
erosive form is least likely to undergo spontaneous
remission, whereas half of the reticular lesions will
eventually resolve.
H. OLP and Malignant Potential

Controversy exists over the potential malignant trans-
formation of OLP. Many reported cases of cancer
arising in OLP were never documented histopatho-
logically, or the histology demonstrated epithelial
dysplasia. The malignant transformation cases that
Figure 28 Lichenoid reaction to cinnamon. The lesion shares were reported occurred in patients with the atrophic,
many similarities to lichen planus, although a perivascular chron- erosive pattern of OLP. Therefore, microscopic docu-
ic inflammatory cell infiltrate is frequently seen in cinnamon- mentation of erosive, nonclassical forms of OLP as
induced stomatitis (arrow). well as long-term clinical follow-up of patients with
symptomatic OLP would be prudent.
258 Müller
VI. GRAFT-VERSUS-HOST DISEASE

Chronic graft-versus-host disease (GVHD) is a major
cause of morbidity and mortality following allogeneic
bone marrow transplantation (1). The median onset of
chronic GVHD is six months posttransplantation. If
symptoms appear within 100 days after bone marrow
transplant, the condition is commonly referred to as
acute GVHD. Primarily, the skin, liver, and gastroin-
testinal tract are involved in acute GVHD. This is in
contrast with chronic GVHD that presents with a
variable clinical picture, including dermal, ocular,
hepatic, pulmonary, and gastrointestinal manifesta-
tions (1).
Oral complications of chronic GVHD can be seen
in up to 80% of patients (1,2). Symptoms include
xerostomia, with minor salivary glands that exhibit
the histopathological features of Sjogren’s syndrome.
Oral lesions and infections are other common find-
ings, and viral and fungal cultures are needed to
Figure 30 Graft-versus-host disease. Within the mucosa,
institute appropriate therapy. Lichen planus–like groups of dyskeratotic keratinocytes can be seen (arrow).
lesions can appear as white, lacy, reticular striae, to Hydropic degeneration of the basal cells overlying a moderate
more dense plaques on the buccal mucosa and tongue lymphocytic infiltrate is present.
(Fig. 29).
Histological features of these lichenoid lesions
show basal cell degeneration, intracellular edema of
epithelial cells, dyskeratosis, and lymphocytic infiltra-
tion in the submucosa (Fig. 30). The lymphocytic VII. ERYTHEMA MULTIFORME
infiltration is usually not as intense as seen in lichen
A. Introduction
planus, although a band-like lymphocytic infiltration
can be seen. In addition, a few plasma cells and Over 130 years ago, von Hebra first described EM as a
eosinophils can occasionally be seen. Immunological- disease of fever, malaise, and multiform lesions of the
ly, the lymphocyte population is composed of CD4 skin and mucous membranes. Stevens and Johnson in
and CD8 T lymphocytes in the same ratio found in 1922 described a much more severe, acute febrile
lichen planus (2,3). The diagnosis of GVHD is based illness in two young boys, characterized by stomatitis,
on the clinical and histopathological findings because purulent conjunctivitis, and skin lesions similar to EM.
each patient may present with varied symptoms. There is some disagreement whether this mucocuta-
neous syndrome, subsequently called the Stevens–
Johnson syndrome (SJS), represents a more severe
variant of EM, also called EM major or represents a
distinct disease (1).
In 1956, Lyell described a condition he termed
toxic epidermal necrolysis (TEN), characterized by
extensive detachment of full-thickness epidermis, par-
tially or totally necrotic. Some patients with apparent
SJS eventually developed detachment and sloughing
of the epidermis, whereas other patients with TEN
developed typical target lesions seen in EM. Some
authors believe that TEN represents the most severe
form of EM, whereas others prefer to recognize TEN
as a distinct entity (2,3). The diagnostic criteria for EM,
SJS, and TEN are listed in Table 3.
B. Clinical Presentation
EM minor typically develops in young adults (aged
20–40 years) and accounts for 80% of patients with EM
(2,4). Skin lesions resembling a target or bull’s eye are
Figure 29 Graft-versus-host disease. Involvement of the the hallmark of EM (Fig. 31). The skin lesions typically
tongue in a patient who underwent a bone marrow transplant begin as flat, round, and dusky-red, then become
for chronic myelogenous leukemia. Note the ulcerations that slightly elevated. The most common sites are the
resemble erosive lichen planus. extremities, with the dorsum of the hand a prevalent
site. The cutaneous lesions are typically symmetrical
Table 3 Diagnostic Criteria for Erythema Multiforme, Stevens-

Johnson Syndrome, and Toxic Epidermal Necrolysis
Erythema multiforme
Symmetrical involvement of the extremities
Target (bull’s eye) lesions
Individual lesions <3 cm in diameter
Mucous membrane involvement absent or confined to
one site
<20% of body surface area affected
Biopsy specimen compatible with erythema multiforme
Stevens–Johnson syndrome
Widespread involvement of the body surface
Target lesions (typical or raised or flat atypical targets)
Individual lesions <3 cm in diameter, poorly defined
border, often confluent
Extensive mucous membrane involvement of at least
two sites
<20% of body surface affected
<10% of epidermal detachment
Figure 32 Characteristic hemorrhagic crusting of the lips in a
Toxic epidermal necrolysis patient with erythema multiforme.
Widespread involvement, prominent on trunk and proximal
limbs
Erythematous or purpuric macules, or flat, atypical target
lesions SJS represents approximately 20% of EM cases.
Bullae Severe mucosal lesions develop in at least two muco-
>30% of epidermal detachment sal sites—most commonly the oral mucosa and the
Mucosal erosions common, primarily oral and ocular mucosa eyes—although genitalia are also affected. The cuta-
neous lesions are similar to EM, although the erup-
Source: From Refs. 2–4, 7; Sec. VII (ERYTHEMA MULTIFORME).
tions are more often vesicular or bullous. These oral
lesions are quite painful and are covered with a white
or yellow exudate. When the gingiva is involved, a
clinical picture of acute necrotizing ulcerative gingivi-
tis (ANUG) is seen. The lip lesions show a character-
istic hemorrhagic crusting (Fig. 32). In many cases of
SJS, a prodromal period, consisting of an upper respi-
ratory illness, with fever, cough, headache, and mal-
aise, is noted before the onset. It is not entirely clear
whether these symptoms are a primary manifestation
of EM or are secondary to the disease that triggers EM.
The mortality rate of SJS is reported to be between 0%
and 10% (4).
The cutaneous lesions seen in TEN begin abruptly,
with burning or painful eruptions located symmetrical-
ly on the face and chest, rapidly extending over the skin
surface, prominently involving the trunk and proximal
limbs (3). A positive Nikolsky sign (epidermal loss with
lateral shearing), widespread, sheet-like loss of the
epidermis, and oozing dermis are characteristic of
Figure 31 Typical target or ‘‘bull’s eye’’ skin lesion characteris- TEN. Massive fluid loss through the denuded epider-
tic of erythema multiforme. mis and bacterial colonization of the skin leading to
systemic sepsis are major causes of mortality in TEN.
Approximately 30% of patients with TEN die.
and are generally a few centimeters or less in diameter Mucosal involvement is present in 80% to 95%
(3). EM primarily involving the skin, with no more of cases of TEN, and in one-third of patients, it
than one area of mucous membrane involvement, is precedes cutaneous lesions by one to three days
usually termed EM minor. The lips are the most (3,4). The oral mucosa is most frequently involved,
frequent site of oral involvement, followed by the with extension into the pharynx. The eyes, genitalia,
buccal mucosa, labial mucosa, tongue, soft palate, and anus may also be affected in TEN. Severe ocular
and fauces (5). The oral lesions start as erythematous involvements include corneal vesicles and acute iritis
patches, which undergo necrosis, become ulcerated, that can result in scarring of the lids and conjuncti-
and may hemorrhage. These oral lesions are quite vae. The sequelae of ocular lesions are especially
painful, and dehydration may occur because of the serious, affecting 30% to 40% of survivors, and
inability of the patient to ingest liquids. early intervention is crucial.
260 Müller
C. Pathology keratinocytes are also called Civatte bodies or colloid

bodies. Adjoining these necrotic keratinocytes are
There is no specific histopathological picture for EM, mononuclear cell infiltrates, an indication of satellite
reflective of the varied clinical presentations. Pro- cell necrosis.
nounced edema in the upper dermis can result in Deposits of IgM and C3 are found in the walls of
subepidermal blisters. A mixed inflammatory infil- blood vessels and along the BMZ on routine immu-
trate, composed of lymphocytes, neutrophils, and nofluorescence examination (6). The finding of
occasionally, eosinophils, is present at times in a immune complexes on dermal vessels, although at
perivascular location and along the junction of the one time was thought to denote immune complex
dermis and epidermis (Fig. 33). The inflammatory vasculitis, is nonspecific.
cells can migrate into the epidermis, and mild spon-
giosis and intracellular edema may result. Basal cells
may show hydropic degeneration, and scattered D. Etiology
throughout the epidermis, individually necrotic kera-
tinocytes are seen (Fig. 34). These eosinophilic necrotic The etiopathogenesis of EM is obscure, although a
wide range of factors have been suggested as trigger-
ing agents. Herpes simplex virus (HSV) infection type
1 and 2, with the subsequent development of EM, has
been recognized for many years and accounts for over
half of the cases of EM (6). Typically, a recurrent HSV
lesion, usually herpes labialis, precedes EM by about
10 days. Of interest is that EM occurs after recurrent
HSV infection, but not after a primary HSV infection.
The clinical features of herpes-associated EM are
consistent with a delayed-type hypersensitivity reac-
tion. Helper T cells involved in cell-mediated immu-
nity are recruited by keratinocytes and respond to
viral antigens with production of interferon-l initiat-
ing an inflammatory cascade.
Other agents implicated in the development of
EM include Mycoplasma pneumoniae, drug reactions,
mycotic infections, and less commonly, vaccinations,
skin allergens, and protozoan infections. Mycoplasma
infection, documented by both cultures and serology,
is the most commonly recognized bacterial infection
Figure 33 Erythema multiforme. Older lesion showing interface
associated with EM (7). Because this infection is
change with overlying necrotic keratinocytes. A mixed inflamma- usually treated with antibiotics, it is often difficult to
tory infiltrate is seen in both the superficial and deep dermis. determine whether the antibiotic or the infection is the
etiological factor.
Drug reactions cause the majority of SJS and
TEN cases. Numerous drugs are associated with the
onset of SJS and TEN, including the sulfonamides,
anticonvulsants, nonsteroidal anti-inflammatory
drugs, and antibiotics, such as amoxicillin and eryth-
romycin (8). Drug-associated EM major and TEN may
begin one to three weeks after drug initiation,
although incidences where months have elapsed
from the first dose of drug to the onset of symptoms
have been documented.
The diagnosis of recurrent EM of the oral mucosa in
the absence of cutaneous lesions may be difficult.
Other mucocutaneous, ulcerative diseases, including
aphthous ulcers, primary herpes, pemphigus, pem-
phigoid, and ANUG must be considered. Recurrent
aphthous ulcers are generally restricted to nonkerati-
Figure 34 Erythema multiforme. The basal cells show hydropic nized sites, whereas EM affects both keratinized and
degeneration and migrating into the epithelium are inflammatory nonkeratinized tissue.
cells. Multiple, individually necrotic keratinocytes can be seen Primary herpetic stomatitis shares many of the
(arrows). clinical features of EM. However, primary herpetic
stomatitis is not recurrent and usually involves the
gingiva, which is an unusual location for recurrent EM

(5). Other vesiculoerosive diseases, including pemphi-
gus and pemphigoid, occur in an older population,
and immunofluorescence studies are diagnostic.
When ocular involvement is present along with oral
lesions, both Reiter’s syndrome and Behçet’s disease
need to be ruled out.

Treatment of EM varies with the severity of the
outbreak. Usually, EM is treated symptomatically
with analgesics and antipruritics. Antibiotics for
lesions that become secondarily infected are also
used. The use of systemic corticosteroids for EM is
controversial (1,4). Some clinicians feel it reduces
symptoms and slows the spread of eruption. However, Figure 35 Minor recurrent aphthae on the lip (arrows). A white
extended use of these drugs may lower host resistance fibrinopurulent membrane is surrounded by erythema.
to HSV causing recurrent HSV and, subsequently,
recurrent EM.
The use of acyclovir as a prophylactic agent in
patients with a history of herpes-associated EM has
been effective (4–6). This therapy is not effective in all
patients, and reactivation of EM has occurred, even in
the absence of a preceding HSV lesion.
Other treatments for severe outbreaks of EM
have included cyclosporine, levamisole, thalidomide,
dapsone, and cyclophosphamide. TEN is treated sim-
ilarly to a major burn, with adequate antisepsis and
fluid management.
VIII. RECURRENT APHTHOUS STOMATITIS

Recurrent aphthous stomatitis (RAS), also known as
canker sores, are the most common oral ulcer estimated
to affect up to 30% of adults and 37% of school-aged
children (1). These painful ulcers generally last for
7 to 30 days and range in size from 1 mm to greater
than 1 cm. Figure 36 Herpetiform aphthous ulcerations present on the lip.
Generally, RAS is divided into three classes. Numerous small ulcers surrounded by erythema are seen.
Minor aphthous ulcers, the most common form,
accounting for 80% of all aphthae, measure less than
1 cm and usually heal within 7 to 10 days. The minor
aphthae may occur as a solitary lesion or in groups on A. Etiology
movable, nonkeratinized tissue (Fig. 35). Major aph-
thae are characterized by large, deep ulcers larger The search for the underlying cause of aphthous
than 1 cm in diameter. These painful lesions may stomatitis has been investigated for many years (1,2).
take several weeks to heal, sometimes with submuco- The etiology of RAS is thought to be multifactorial.
sal scarring. Generally, major aphthae occur on the Allergens have been reported to play an important
movable mucosa as well, particularly in the region of role in triggering aphthae. Reported allergens include
the soft palate and tonsillar fauces. The third type, cinnamon, cereal products, tomatoes, nuts, chocolates,
herpetiform aphthae are small, about 1 or 2 mm in citrus as well as other fruits. Stress, anxiety, local
diameter, and usually occur as multiple ulcers, some- mechanical trauma, nutritional deficiencies, and hor-
times as many as 100 ulcers (Fig. 36). These ulcers can mones are also reported to be associated with RAS.
coalesce, and healing time is generally 7 to 10 days. There are no known bacterial or viral infections asso-
Because of the small size and the large number of ciated with RAS, including HSV, Helicobacter pylori,
ulcers present, RAS can resemble primary HSV infec- and Streptococcus. Attempts to associate certain HLA
tion, however there is no association with herpes. A types with aphthous stomatitis are not consistent,
regional lymphadenitis may accompany an outbreak although a familial association has been observed in
of any of these oral ulcers. about 40% of cases.
262 Müller
Figure 37 Recurrent aphthous ulcer of lip showing a central

area of ulceration covered by a fibrinopurulent membrane. A
mixed inflammatory cell infiltrate is seen in the lamina propria.
This is essentially a nonspecific ulcer and diagnosis depends on Figure 38 Herpes simplex virus. Cells exhibiting a viral cyto-
clinical presentation. pathic effect with multinucleated giant cells with condensation of
the chromatin at the periphery (arrows).
B. Pathology
major recurrent ulcers can be seen in the vulva or
There are no diagnostic histological features of aph-
scrotum. Because the histopathological features of oral
thous ulcers. Early lesions show a central area of
ulcers in Behçet’s disease are nonspecific, the diagno-
ulceration covered by a fibrinopurulent membrane.
sis remains clinical.
The underlying lamina propria shows increased vas-
Intraoral herpes simplex virus type I (HSV I) can
cularity and a mixed inflammatory cell infiltrate,
often be clinically mistaken for aphthous ulcers. How-
composed of lymphocytes, histiocytes, and neutro-
ever, both the etiology and the clinical location of these
phils (Fig. 37). Definitive diagnosis is made from the
two types of ulcers are different. The most common
clinical presentation and from exclusion of other dis-
location of recurrent HSV1 is the vermilion border of
eases that mimic oral aphthae.
the lip (herpes labialis), also called a ‘‘fever blister’’ or
‘‘cold sore.’’ However, recurrent HSV1 can also occur
C. Immunopathology intraorally on keratinized tissue such as the hard palate
and attached gingiva. Histological examination of an
The immunopathogenesis of RAS has become more early HSV1-associated ulcer does show marked acan-
defined in recent years with similarities to the tholytic epithelial cells termed ‘‘Tzanck cells.’’ The
pathogenic mechanisms seen in oral lichen planus. infected cells show nuclear enlargement (ballooning
Increased numbers of activated cytotoxic T lympho- degeneration) and condensation of the chromatin
cytes and natural killer (NK) cells are present in around the periphery of the nucleus (Fig. 38). The
patients with active disease, whereas CD4 T lympho- infected epithelial cells can fuse to form multinucleated
cytes are depressed (3). The cytotoxic T cells respond cells. The adjacent mucosa is edematous with second-
to a target antigen within the epithelium. The resul- ary inflammation. Older lesions may show nonspecific
tant lysis occurs, by the release of cytokines, including findings similar to RAS.
tumor necrosis factor. Similar to lichen planus, adhe- Another oral ulcer that may be clinically mistaken
sion molecules probably regulate the movement of for RAS is traumatic ulcerative granuloma [traumatic
lymphocytes, although in RAS, the keratinocyte lysis ulcerative granuloma with stromal eosinophilia
occurs throughout the epithelium and not just at the (TUGSE), eosinophilic granuloma]. These ulcers most
basal cell layer, which is seen in lichen planus. often occur on the lateral tongue or buccal mucosa
adjacent to an identifiable source of irritation, such as a
D. Differential Diagnosis broken tooth (Fig. 39). Histologically traumatic ulcera-
tive granulomas have a unique appearance. The gran-
The oral ulcers seen in Behçet’s disease clinically ulation tissue extends into the deeper tissue including
resemble RAS. In addition to oral ulceration, either muscle and contains sheets of lymphocytes and histio-
genital or ocular lesions can occur. Usually, the oral cytes with scattered eosinophils (Figs. 40, 41). Often the
ulcers are minor (i.e., smaller than 1 cm), however, epithelium exhibits hyperplasia.
Figure 39 Nonhealing ulcer on the lateral tongue. Biopsy

Figure 41 High power photomicrograph of Figure 40 demon-
proved to be a traumatic ulcerative granuloma.
strating a mixed inflammatory cell infiltrate including eosinophils
extending into the skeletal muscle.
tetracycline, dapsone, and levamisole, but either con-

flicting results or questionable benefits compared with
placebos exist (1,2,4). Cauterization and freezing
agents should not be used to treat RAS, because
further tissue damage ensues, with prolonged healing
time.
Aphthae have a typical onset after puberty, and
recurrences can occur sporadically for many years. As
there is no cure for RAS, effective management is
achieved with the foregoing agents.
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VI. GRAFT-VERSUS-HOST DISEASE

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6
Premalignant Lesions of the Oral Cavity
Pieter J. Slootweg
Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The
Netherlands
Thijs A.W. Merkx
Department of Oral and Maxillofacial Surgery, Radboud University Nijmegen Medical
Center, Nijmegen, The Netherlands
I. DEFINITION size and shape. In addition, the nuclei also show

marked variation in size and may have enlarged
Premalignant lesions of the oral cavity are conditions nucleoli. An increase in mitotic activity can also be
of the epithelial part of the oral mucosal lining that seen in many reactive lesions but abnormal mitoses as
carry an increased risk for the development of oral well as mitotic figures found in unusual locations
squamous cell carcinoma (OSCC) in that area. This above the basal cell layer indicate premalignant cellu-
group encompasses a mixture of lesions that are lar alterations. Individually keratinized cells or con-
defined by clinical appearance, histology, or etiology centric rings of flattened keratinocytes below the
(Table 1) (1). For some of these lesions, the premalig- surface layer also distinguish epithelial dysplasia
nant character is doubtful as will be elaborated when from hyperplasia (Fig. 1A, B).
discussing them. Moreover, it should be realized that
lesions may not only be premalignant in the sense
defined above but could also be risk factors, indicating B. Tissue (Architectural) Alterations
an increased risk for developing OSCC anywhere in Dysplasia
in the upper aerodigestive tract (2,3). Moreover,
other lesions could indicate an increased risk for the Tissue alterations in dysplasia can be summarized as
development of OSCC without being premalignant loss of the orderly cellular maturation from basal cells
themselves. to flattened superficial cells that may keratinize or not,
Before going into detail about the various enti- depending on the site in the oral cavity (Fig. 2).
ties, histological items emanating when discussing Thickening of one of these epithelial layers without
mucosal premalignancies will be addressed. disturbance of this orderly layered architecture should
not be interpreted as dysplastic (Fig. 3A, B). A grading
system for dysplastic oral epithelium must take into
II. DYSPLASIA consideration both the degrees of cellular atypia, in
addition to the extent of structural tissue alterations as
‘‘Dysplasia’’ is the term that is used within the context described above.
of mucosal premalignancies. For the sake of clarity,
one has to distinguish between cellular changes and
architectural changes. The combination of both leads
to a diagnosis that is communicated to the clinician III. CLASSIFICATION/GRADING OF
with the aim to have a guide in management of the INTRAEPITHELIAL ALTERATIONS
individual patient. This aim however is only poorly In spite of shortcomings such as inter- and intraob-
attained in a lot of instances, either because of lack of server variability and absence of clear-cut prognostic
adequate and reproducible histological criteria or significance, traditional light microscopic examination
because of poor correlations between dysplasia and still remains the most reliable method for determining
risk for malignant degeneration (1). the grade of intraepithelial alterations summarized
under the designation dysplasia. Possibly because of
A. Cellular Alterations in Dysplasia these above-mentioned problems, competing classifica-
tion systems exist and therefore there are no worldwide
When assessing epithelial dysplasia, one should eval- generally accepted criteria for a histological grading
uate the presence of alterations of individual epithelial system in the head and neck region. As a result of this
cells (4). Cells show dark-staining nuclei, an increased lack of unanimity, three schemes are currently used,
nuclear-to-cytoplasmic ratio, as well as variation in which will be discussed in more detail. They are the
268 Slootweg and Merkx
Table 1 Potentially Malignant Lesions of the Oral Mucosa

Malignant
Disease name transformation potential
Proliferative verrucous leukoplakia ******
Erythroplakia ******
Nicotine palatinus in reverse *****
smokersa
Oral submucous fibrosis ****
Speckled, granular ****
(nonhomogeneous) leukoplakia
Actinic cheilitis ***
Smooth, thick (homogeneous) **
leukoplakia
Smokeless tobacco keratosis *
Lichen planus *
a
Reverse smoking: smoking with the lit end of the cigarette in one’s mouth.
Figure 2 Disordered maturation indicating dysplasia may alter-

nate with hyperplastic epithelial areas.
Figure 1 Photomicrograph to show cytonuclear atypia, both

due to nuclear atypia as well as to increased cytoplasmic
eosinophilia, indicating premature keratinization. (A) Low power Figure 3 Hyperkeratosis may occur (A) with epithelial hyper-
view. (B) Higher magnification. plasia as well as (B) without epithelial hyperplasia.
Chapter 6: Premalignant Lesions of the Oral Cavity 269
World Health Organization (WHO) dysplasia criteria

for classifying intraepithelial alterations in the oral
cavity and larynx, the squamous intraepithelial neopla-
sia system, and the Ljubljana classification, the latter
initially devised not only for the interpretation of
laryngeal lesions but also being thought to be applica-
ble for lesions in the oral cavity (4–7).
A. WHO Dysplasia Classification

The WHO dysplasia system includes the following
categories.
Hyperplasia with Increased Number of Cells

There may be an increased number of cells in the
spinous layer (acanthosis) (Fig. 3) or in the basal and
parabasal cell layers (basal cell hyperplasia). The
architecture of epithelium is preserved; there is no
cellular atypia.
Dysplasia with Three Grades

Mild Dysplasia Architectural disturbance is limited
to the lower third of the epithelium and is accompanied
by cytological atypia (Fig. 4).
Moderate Dysplasia Architectural disturbance that
extends into the middle third of the epithelium is the
initial criterion for recognizing this category of dys-
plasia (Fig. 5A, B). However, consideration of the
degree of cytological atypia may require upgrading
to severe dysplasia.
Severe Dysplasia Architectural disturbance with
associated cytological atypia is greater than two-thirds
Figure 5 In moderate dysplasia, the epithelial alterations

extend into the upper part of the epithelial thickness. They may
occur (A) without an increase in the epithelial width or (B) with an
increase in the epithelial width.
of the epithelium (Figs. 6A, B, C). However, as noted

when discussing moderate dysplasia, architectural
disturbance limited to the lower and middle third of
the epithelium but with sufficient cytological atypia
may be included in this category.
Carcinoma In Situ
Carcinoma in situ is represented by full or almost full
Figure 4 Photomicrograph showing mild dysplasia, epithelial thickness architectural abnormalities in the viable
alterations being confined to the lower third of the epithelial cellular layers accompanied by pronounced cytologi-
thickness. cal atypia (Fig. 7A, B). Atypical mitotic figures and
abnormal superficial mitoses are commonly present.
Figure 7 In in situ cancer, not only the whole epithelial thick-

ness is involved but also the epithelial flattening at the surface is
rudimentary or absent. In (A), there are also bulb-shaped rete
ridges, and in (B), there is intercellular edema in the upper part of
the epithelial covering.
upgrade from moderate-to-severe dysplasia makes

this latter criterion rather equivocal, thus the drawing
of a distinct line between both categories, making a
subject of debate in individual cases.
Figure 6 In severe dysplasia, atypical cells are dispersed
throughout the entire epithelial thickness. This may occur togeth- B. Squamous Intraepithelial Neoplasia
er (A) with hyperkeratosis, (B) with an increase of epithelial Classification
thickness, or even (C) with thinning of the epithelium.
In this classification scheme, oral intraepithelial neo-
plasia grade 1, 2, and 3 are synonymous with the
categories mild dysplasia, moderate dysplasia, and
Although the architectural alterations for the vari- severe dysplasia as defined in the WHO. The most
ous WHO stages are clearly defined, a lack of consensus severe intraepithelial alterations are called carcinoma
on the extent of cytological atypia necessitating an in situ in both classifications (4).
C. Ljubljana Classification
Within the Ljubljana grading system, the following
categories are distinguished (4,5).
Reactive Lesions Having a Minimal Risk of Progression to

Invasive Carcinoma
Squamous (Simple) Hyperplasia This is a benign
hyperplastic process with retention of the normal
architectural and cytological pattern of the squamous
epithelium. The epithelium is thickened as a result of
an increased prickle cell layer. The cells of the basal
and parabasal region, which comprise one to three
layers, remain unchanged. There is no cellular atypia;
infrequent, regular mitoses are seen in the basal layer
(Fig. 8).
Basal and Parabasal Cell Hyperplasia (Abnormal
Hyperplasia) This can be defined as a benign augmenta-
tion of basal and parabasal cells in the lower part of the
epithelial layer, while the upper part, containing regular
prickle cells, remains unchanged. The thickened epithe-
lium consists of an increased number of basal and
parabasal cells without significant nuclear changes
and occupying up to one-half or occasionally slightly
more of the entire epithelium (Fig. 9). Rare, regular
mitoses may be seen, always located in or near the basal Figure 9 Photomicrograph showing abnormal hyperplasia as
layer. Less than 5% of epithelial cells show dyskeratosis, defined in the Ljubljana classification. The thickened epithelium
a premature and abnormal keratinization of individual consists of an increased number of basal and parabasal cells
cells or groups of cells that have no prickles and without significant nuclear changes and occupying up to one-half
strongly eosinophilic cytoplasm. or occasionally slightly more of the entire epithelium. Source:
Picture courtesy of Prof. N. Gale, Institute of Pathology, Faculty
of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Potentially Malignant Lesions

Atypical Hyperplasia (Risky Epithelium) This is a
lesion with a definitely increased risk of progressing
to invasive carcinoma that is characterized by the
following histological appearances.
Stratification is still preserved in the epithelium.
There is an increased number of epithelial cells with
atypical features that may occupy the lower half or
more of the entire epithelial thickness. Mitoses are
moderately increased. They are usually found in the
lower two-thirds of the epithelium, although they may
occasionally appear at a higher level (Figs. 10, 11).
Mitoses are rarely, if ever, abnormal. Dyskeratotic
cells are frequent within the entire epithelium. Two
subdivisions of atypical hyperplasia are recognised:
(i) the more frequent ‘‘basal cell type’’ with no inter-
cellular prickles and no cytoplasmic eosinophilia and
the cells aligned perpendicularly or at an acute angle
to the basement membrane and (ii) the less frequent
‘‘spinous cell type’’ [analogous to so-called ‘‘keratiniz-
ing dysplasia,’’ as defined by Crissman and Zarbo (8)]
Figure 8 Photomicrograph showing squamous (simple) hyper- with intercellular prickles and increased cytoplasmic
plasia as defined in the Ljubljana classification. It concerns a benign eosinophilia.
hyperplastic process with retention of the normal architectural and
cytological pattern of the squamous epithelium. The epithelium is
Actually Malignant Lesions
thickened as a result of an increased prickle cell layer. Source:
Picture courtesy of Prof. N. Gale, Institute of Pathology, Faculty of This group comprises carcinoma in situ, a lesion
Medicine, University of Ljubljana, Ljubljana, Slovenia. showing the features of carcinoma without invasion.
There is loss of stratification or maturation of the
Figure 10 In atypical hyperplasia, according to the Ljubljana

classification, an increased number of epithelial cells with atypi-
cal features may occupy the lower half, or more of the entire
epithelial thickness. Mitoses are moderately increased. They are
usually found in the lower two-thirds of the epithelium, although
they may occasionally appear at a higher level. Source: Picture Figure 12 Photomicrograph showing carcinoma in situ. On this
courtesy of Prof. N. Gale, Institute of Pathology, Faculty of topic, there are no discrepancies between the WHO and the
Medicine, University of Ljubljana, Ljubljana, Slovenia. Ljubljana classification. Abbreviation: WHO, World Health Orga-
nization. Source: Picture courtesy of Prof. N. Gale, Institute of
Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana,
Slovenia.
epithelium as a whole, although at the surface of the

epithelium compressed, horizontally stratified, and
sometimes keratinized cells may occur. Moreover,
epithelial cells may show all the cytological character-
istics of invasive squamous cell carcinoma, and mitot-
ic figures are usually markedly increased throughout
the whole epithelium, often more than five in one
high-power field (Fig. 12). Abnormal mitoses are also
frequently seen.
IV. CORRELATION BETWEEN DYSPLASIA

GRADES AND MALIGNANT
TRANSFORMATION
The association between dysplastic alterations in the
oral mucosal lining and the subsequent development
of OSCC has been known since long. In fact, the
existence of such an association is the only point that
can be stated firmly, other more precise data on this
issue widely diverging or lacking.
Figure 11 Another example of atypical hyperplasia, as defined The time span between diagnosing the presence
in the Ljubljana classification. Atypical cells occupy the major of a cancer developing from a dysplastic lesion usually
part of the epithelium. In the WHO classification, such a picture lasts two to five years from the moment the dysplasia
would qualify as severe dysplasia or carcinoma in situ. Abbrevi- is diagnosed, but may also be much longer (1,9,10).
ation: WHO, World Health Organization. Source: Picture courtesy Malignant transformation rates for oral carcinoma in
of Prof. N. Gale, Institute of Pathology, Faculty of Medicine, situ or combined carcinomas in situ and severe dys-
University of Ljubljana, Ljubljana, Slovenia. plasia varies between 7% and 50% (1). So, there
appears to be a long period of time during which
malignant transformation may occur, and figures VI. LEUKOPLAKIA

about the risk of malignant transformation of even
the lesions with the more severe intraepithelial alter- A. Definition
ations diverge widely. This wide range of data on time Leukoplakia is defined as a ‘‘white patch’’ or plaque
evolving before malignancy occurs and on risk of that cannot be characterized clinically or pathological-
malignant degeneration may be related to different ly as any other disease and is not associated with any
patient populations and gaps in our knowledge con- physical or chemical causative agent except the use of
cerning the relationship between premalignant muco- tobacco (25). This time-honored definition may need
sal changes and risk for development of malignancy. some updating as there are currently indications that
It might also be possible that different risk factors are human papilloma virus (HPV) may also play a role
operative in dysplasia and carcinoma in situ than are (26–29). In this context, it may be useful to mention
responsible for development of frank malignancy. that in oral cancer and precancer, in contrast with the
The lack of data from comparable well-defined uterine cervix, overexpression of p16 cannot be equal-
patient groups and the lack of a consensus on the ized with HPV infection (30), neither does this protein
grading and reproducibility of dysplasia are addition- qualify as a marker for dysplasia (31,32). This is not
al factors that have a negative impact on its predictive surprising as there are a lot of triggers that could
value, as is also exemplified by two recent studies. cause overexpression of this protein that participates
One study reports that a binary system of grading oral in major tumor suppressor networks disabled in
epithelial dysplasia may have an increased power in human cancer and influences key physiological pro-
predicting malignant transformation (11), whereas the cesses such as replicative senescence, apoptosis, and
other indicates that lesions with slight, moderate, stem cell self-renewal (33).
severe, and no dysplasia developed carcinoma with
similar frequencies (12). Such opposing views
attempting to correlate the degree of dysplasia with B. Clinical Features
the likelihood of malignant transformation are frus-
trating and underscore the need for more precise Leukoplakia is a condition associated with a middle-
prognosticators. The potential usefulness of molecular aged and older population, with the vast majority of
methods will be discussed in the next section. cases occurring after the age of 40 years. The floor of
the mouth is the most common site in smokers,
whereas the border of the tongue is a more common
V. GENETIC CHANGES IN DYSPLASIAS AND site among nonsmokers (34,35).
THEIR DIAGNOSTIC USEFULNESS On visual examination, leukoplakia may vary
from a barely evident, vague whiteness on the base
Because of the subjective nature of dysplasia assess- of uninflamed, normal-appearing tissue to a definitive
ment, molecular analysis has been introduced in the white, thickened, leathery, fissured, verrucous, or
field with the aim that it would be helpful in obtaining wart-like lesion (Fig. 13). Red zones may also be
a more accurate prognosis. Investigations showed that seen in some leukoplakias, prompting use of the
the spectrum of chromosomal changes increases at term ‘‘speckled leukoplakia’’ (Fig. 14). On palpation,
each histological step from benign hyperplasia to some lesions may be soft, smooth, or finely granular in
dysplasia to carcinoma in situ to invasive carcinoma, texture. Other lesions may be roughened, nodular, or
with losses at chromosomes 9p bearing the p16/p14ARF indurated (34).
tumor-suppressor gene, 3p bearing the FHIT tumor-
suppressor gene, and 17p bearing the well-known p53
tumor-suppressor gene already found at the dysplasia
stage (13,14). All these data make sense in that they
show how malignant transformation of oral epithelial
cells into OSCC is associated with loss of tumor-
suppressor abilities.
Although preliminary translation of these data
in clinical practice has shown that chromosomal
losses at loci 3p and 9p occurring in mucosal lesions
may evolve into carcinoma, not all lesions, however,
with these genetic alterations progress; other changes
also play a role: additional chromosomal losses,
chromosomal polysomies, suprabasal p53 protein
expression, and loss of expression of fragile histidine
triad (15–21). Currently, none of these approaches
have found its way into routine diagnostic applica-
tions. Moreover, the development of oral cancer may Figure 13 White patch in the left cheek. This picture is typical
follow different pathways (22–24). This obviously for homogeneous leukoplakia. Histology is needed to determine
will make the identification of molecular markers the nature of the underlying epithelial alterations causing this
that may solve the problem of predicting malignant clinical appearance.
change complicated.
Nonleukoplakic tobacco-induced white lesions

of the oral mucosa include nicotine stomatitis and
smoker’s keratosis, which will be discussed later in
this chapter. Also included in a differential diagnosis
for tongue leukoplakia would be hairy or geographi-
cal tongue.
If the lesion is not removable and is not clinically
diagnostic, it can be generally classified as idiopathic,
and biopsy becomes mandatory. In extensive lesions,
multiple biopsies may be necessary to avoid sampling
error. The clinically most heterogeneous (speckled)
areas should be included in the biopsy (34).

There is general clinical consensus that oral leukopla-
kia should be treated either to alleviate the patient’s
complaints or to prevent the future development of
OSCC (Fig. 15A, B). The latter aim, however, appears
to be difficult to attain, considering the previous
discussion.
Dysplasia grading in selecting patients at risk for
progressing is of debatable value as already outlined.
More importantly, prognosis appears to be the size of
Figure 14 In ‘‘speckled’’ (inhomogeneous) leukoplakia, white
the lesion as well as its clinical appearance, speckled
areas alternate with red ones. In general, these lesions histologi- leukoplakias being more prone to malignant degener-
cally show more severe epithelial alterations than the homoge- ation (12). In fact, in a long-term follow-up study, 15%
neous ones. of cases with nonhomogeneous leukoplakia devel-
oped into OSCC as opposed to 3% of those with
homogeneous leukoplakia (12).
C. Pathology
Histological examination of a leukoplakic lesion
invariably shows a hyperkeratotic surface, which
causes the clinical appearance. The underlying epithe-
lium may show a spectrum of histological appearan-
ces that includes either normal epithelium, various
grades of dysplasia, or even carcinoma in situ or
OSCC. A histological report on a leukoplakic lesion
should leave no doubt on the nature of these epithelial
histomorphologies (1,34).
The first step in developing a differential diagnosis for
a white patch (leukoplakia) in the oral mucosa is
determining whether the lesion can be eliminated
with gauze or spatula. If the lesion can be removed,
it represents a pseudomembranous lesion, fungal col-
ony, or debris.
If there is evidence of bilateral buccal mucosal
disease, conditions not to be discussed further in this
chapter such as leukedema and white sponge nevus,
cheek biting, lichen planus, and lupus erythematosus
(LE) should be considered. The latter two can be
associated with cutaneous lesions.
If either chronic trauma or tobacco use is excluded
in the patient’s history and the lesion is predominantly
situated at the gingival margin, the white lesion could
represent frictional hyperkeratosis. Elimination of a Figure 15 In an area of (A) homogeneous leukoplakia, (B) a
suspected cause then should result in some clinical squamous cell carcinoma was diagnosed six months later.
improvement.
Whether the lateral border of the tongue and the plakia as malignant transformation to verrucous or
floor of the mouth are high-risk regions for develop- squamous cell carcinoma is almost always the out-
ment of malignancy is a debated subject (10,34,36). come for patients with PVL (41,43). The aggres-
Sometimes, leukoplakias may regress, especially siveness is not only demonstrated by a high
when patients quit smoking (37). recurrence rate after surgical excision but also by
Treatment may be effective in the removal of a development of multiple OSCCs (46).
lesion but relapses and adverse effects are common.
Moreover, to date, there is no evidence that treatment C. Pathology
is effective in preventing malignant transformation
(38). In spite of the limited ability of any treatment There is no histological feature that is pathognomonic
in preventing malignancy, various intervention for PVL. As this disease encompasses a spectrum
modalities have been advocated, such as surgical ranging from flat homogeneous leukoplakia to
excision and CO2-laser surgery. Also, agents such as conventional OSCC with various grades of dysplasia
b-carotene, a-tocopherol, and ascorbic acid have been and verrucous carcinoma as intermediate stages, the
attempted but until now none has been proven safe histopathology of an individual lesion from a patient
and effective in large-scale randomized trials (39). with PVL may show a morphology compatible with
any of these diagnoses, depending on the stage of the
disease (Fig. 17). The initial classification in 10 stages
VII. PROLIFERATIVE VERRUCOUS has been reduced to four stages: clinically flat leuko-
LEUKOPLAKIA plakia without dysplasia, verrucous hyperplasia, ver-
A. Definition rucous carcinoma, and conventional squamous cell
carcinoma (40,42). Probably, the number of stages
Proliferative verrucous leukoplakia (PVL) is a variant can be reduced to three as verrucous hyperplasia
of leukoplakia that shows white mucosal plaques that has much in common with verrucous carcinoma, the
virtually always develop nodular, papillary, or verru- only difference being an exophytic growth pattern in
ciform surface projections, that gradually, sometimes verrucous hyperplasia as opposed to an endophytic
rapidly, spreads to encompass large regions of the oral growth pattern in verrucous carcinoma (42). There-
mucosa, and that is associated with a very high rate of fore, it is debatable if there is any need to make this
malignant transformation (40–43). The cause is distinction between verrucous hyperplasia and verru-
unknown. Neither tobacco usage nor infection with cous carcinoma (47).
HPV has been demonstrated to be of any etiological
significance (43–45).
B. Clinical Features The typical clinical appearance of PVL does not leave
any room for consideration of another lesion. However,
This type of leukoplakia begins in most instances as a the diagnosis cannot be made unless the patient has
simple keratosis, slow growing, persistent, and irre- developed the complete clinical picture as outlined
versible, and eventually becomes verrucous in nature above.
(Fig. 16). The diagnosis is determined clinicopatholog-
ically and is usually made in retrospect. PVL behaves
far more aggressively than other forms of oral leuko- E. Treatment and Prognosis
Treatment procedures employed for PVL have been
surgery, CO2-laser evaporation, and photodynamic
therapy. It is commonly resistant to all forms of
therapy. Early recurrence of the lesion in the same
area is the rule, usually accompanied by greater
extension and by an increase of epithelial changes
including dysplasia (40). It has been reported that in
case of an HPV-related PVL, the use of an antiviral
agent appears to offer a significant enhancement to the
surgical management of PVL (48). Recent data deny-
ing any etiological significance of HPV, however,
make the purported result of this therapeutic
approach difficult to understand (44,45).
VIII. ERYTHROPLAKIA
A. Definition
Erythroplakia is the clinical term for ‘‘a fiery red
Figure 16 Proliferative verrucous leukoplakia showing thick, patch’’ that cannot be characterized clinically or path-
irregular keratotic plaques involving large mucosal areas. ologically as any other definable lesion (49,50). The
term is used analogously to leukoplakia.
Figure 17 Photomicrographs showing various appearances that may be shown by patients suffering from proliferative verrucous
leukoplakia. (A) Papillary epithelial projections covered with a hyperkeratotic surface. (B) Cellular alterations in the epithelium are not
very conspicuous [detail from (A)]. (C) Hyperplastic epithelium with a hyperkeratotic surface forming spires. (D) Detail from (C) showing
increased mitotic activity and slight cytonuclear atypia.
B. Clinical Features Individuals aged between 50 and 70 years are

usually affected, and there appears to be no gender
Erythroplakia is less frequently seen than its leukopla- predilection.
kic counterpart with a prevalence of between 0.02% and There is a strong association with tobacco con-
0.83% from different geographical areas. The lesions sumption and the use of alcohol (50).
appear either as a red smooth patch or, alternatively, as
an irregular granular patch with fairly well-defined
margins with the adjacent mucosa of normal appear- C. Pathology
ance. Sites of occurrence are the buccal mucosa, floor of
the mouth, and the soft palate (Fig. 18, 19). The tongue Histologically, erythroplakia shows invasive OSCC in
is rarely involved (50). There may be concomitant over 50% of cases, in situ cancer in 40% of cases, and
leukoplakia, which may make the distinction between in only 10% of cases mild or moderate dysplasia is
speckled leukoplakia and erythroplakia equivocal. observed (50). This high incidence of neoplasia
Figure 18 Localized erythroplakia in the anterior floor of the

mouth.
Figure 20 The dysplastic epithelial changes underlying a leu-

koplakic lesion may extend to deeper levels by replacing duct
lining epithelium.
studies. In case of surgical therapy in dysplastic and in

situ lesions, it is generally more important to excise
widely than deeply because of their superficial nature.
However, because the epithelial changes may extend
into the salivary gland excretory ducts, the excision
should not be too superficial. Extensive histological
sampling may be necessary to assess adequately the
involvement of ducts (Fig. 20).
Prognosis depends on the underlying histomor-
phology that ranges from mild dysplasia to OSCC.
Figure 19 More extensive erythroplakia in the floor of the
mouth.
IX. NICOTINE STOMATITIS
A. Definition
This is a particular form of keratosis occurring on the
emphasizes the need to take biopsies from each eryth- palate and seen in pipe or cigar smokers. A related
roplakic lesion. palatal lesion is caused by the habit of placing the
lighted end of cigarettes and cigars inside the mouth,
D. Differential Diagnosis which is practiced by certain rural populations in the
Indian subcontinent, New Guinea, and the Amazon
The clinical features of erythroplakia may occasionally basin. As the literature does not always draws a sharp
be shared by several other red lesions. Erythematous distinction between these two modes of tobacco usage,
candidiasis and atrophic oral lichen planus result in a both will be discussed under this heading, emphasiz-
red mucosal lesion. A more extensive differential ing specific features of each.
diagnosis would include Kaposi’s sarcoma, ecchymo-
sis, contact allergic reaction, vascular malformation, or
psoriasis. A careful clinical history and examination B. Clinical Features
should distinguish most of these lesions. Biopsy is Nicotine stomatitis shows raised umbilicated papules
required if there is any doubt. (representing blocked palatal mucous glands) with
red central depressions (their inflamed duct orifices).
E. Treatment and Prognosis These papules are found mainly in the posterior
regions of the hard palate and on the soft palate
The treatment of choice for erythroplakia is surgical (Fig. 21). The background mucosa may vary from
excision, although the effectiveness of this interven- clinically normal to gray leukoplakic (51). When spe-
tion, including laser therapy and cryotherapy, has cifically distinguishing between palatal changes
until now never been analyzed in controlled clinical induced by smoking versus reverse smoking, the
X. ORAL SUBMUCOUS FIBROSIS

A. Definition
Oral submucous fibrosis (OSF) is a chronic progres-
sive disorder characterized by subepithelial fibrosis
that interferes with oral functioning (58,59). Chewing
areca nut is the major etiological factor (58).
This disease is rarely seen in western countries but
generally occur in India and Southeast Asia. People of
any age may be affected. Symptoms include a burning
sensation of the oral mucosa, occasional mucosal
Figure 21 Clinical picture of nicotine stomatitis. Raised umbili- ulceration, a peculiar marble-like blanching of the
cated papules on a leukoplakic background and with a mucosa, and palpable fibrous bands of the buccal
depressed red center are quite typical for this mucosal lesion. mucosa, soft palate, and lips (Figs. 22, 23). Fiery red
erythroplakic areas are also occasionally present.
latter category shows more severe changes than the

former. In conventional smokers, palatal pigmentation
and erythema are seen, whereas in reverse smokers
leukoplakia, mucosal thickening, fissuring, pigmenta-
tion, nodularity, and ulceration are common (52,53).
C. Pathology
Histologically, nicotine stomatitis is characterized by
hyperkeratosis, acanthosis, and dilatation of the
underlying salivary gland ducts that show chronic
inflammatory alterations (51,54). Concomitant dys-
plastic alterations have been reported to occur in
nicotine stomatitis induced by reverse smoking (55). Figure 22 Oral submucosal fibrosis. Note limited mouth open-
Another tobacco-induced histological alteration, ing and fibrous white appearance of right cheek mucosa. Source:
the so-called ‘‘chevron-like’’ keratinization does not Picture courtesy of Prof. Tien-Yu Shieh and Dr. Connie Yang,
occur on the palate and so is not included in the Oral Health Research Center, Kaohsiung Medical University,
spectrum of histological alterations that characterize Kaohsiung, Taiwan.
nicotine stomatitis (56). This tissue alteration will be
discussed more extensively under the heading
‘‘Smokeless Tobacco Keratosis’’ (vide infra).
Because of the characteristics of its appearance and the
smoking habits of the patient, hardly any other diag-
nosis could interfere with diagnosing this mucosal
disorder.

Nicotine stomatitis does not evolve into malignancy in
conventional smokers but it may in individuals who
smoke reversely (34,55,57). Nevertheless, patients
should be encouraged to quit smoking to alleviate
the symptoms of nicotine stomatitis as well as to Figure 23 Oral submucosal fibrosis. Note the white appearance
prevent development of mucosal (pre-) malignancies of the inner side of the reflected upper lip. Source: Picture courtesy
elsewhere in the upper aerodigestive tract. There of Prof. Tien-Yu Shieh and Dr. Connie Yang, Oral Health Research
appears to be no room for surgical intervention unless Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
biopsies have shown concomitant dysplasia.
OSF may occasionally be preceded by or associ- D. Etiology

ated with vesicle formation. Rupture of these vesicles
leaves small superficial ulcerations. In time the affect- The main etiological factors are the constituents of
ed mucosa, especially the soft palate and buccal areca nut. These appear to interfere with the deposi-
mucosa, loses its resilience and elasticity, with resul- tion and/or degradation of extracellular matrix mol-
tant trismus and considerabe difficulty in eating (58). ecules such as collagen. Inflammatory cytokines also
may influence this process of ongoing fibrosis (58).
C. Pathology E. Differential Diagnosis

In cases starting with vesicle formation, it is shown that The clinical differential diagnosis of OSF is limited.
the vesicles are due to a subepithelial fluid accumula- Radiation-related subepithelial fibrosis and mucosal
tion. The adjacent lamina propria contains eosinophilic scarring secondary to thermal or chemical burns may
granulocytes. More typical, OSF shows the first changes produce similar clinical features.
in the connective tissue. Four consecutive stages are
distinguished, the disease starting with development of
edema and presence of a fibroblastic proliferation as F. Treatment and Prognosis
well as an inflammatory infiltrate mainly composed of Treatment has included stretching exercises and
neutrophilic granulocytes. Blood vessels may be dilated intralesional injections of corticosteroids. Surgical-
but not unvaried. Then, thickened collagen fibers occur releasing procedures likewise have been used. Suc-
together with juxtaepithelial hyalinization. The fibro- cess has been reported using a combination of both
blastic response is less pronounced. Blood vessels are local injections and local surgical excision of bands
more prominent and the inflammatory infiltrate now and submucosal application of placental grafts. All
also contains lymphocytes and occasionally plasma methods of treatment, however, have proved to be of
cells. The third stage is characterized by hyalinization only modest help in this essentially irreversible
of the collagen, edema is disappearing as is the fibro- condition.
blastic proliferation, and the blood vessels return to a The primary importance of OSF lies in its pre-
normal diameter or even are constricted because of malignant nature. Epithelial dysplasia in OSF has
increased surrounding fibrous tissue. The inflammatory been reported to vary from 7% to 26% and the malig-
infiltrate is now mainly composed of lymphocytes and nant transformation rate appears to vary from 7% to
plasma cells. In the final stage, the picture is dominated 13%. It has been speculated that fibroblastic degener-
by dense hyalinized collagen replacing the lamina ation and epithelial atrophy form the physical basis
propria (Fig. 24). The overlying epithelium is atrophic for carcinogenic penetration through the epithelium.
with loss of rete pegs, and there may be abnormal The restriction or elimination of areca nut use should
keratinization (59). be attempted and etiological dietary agents should be
withdrawn (58).
XI. ACTINIC CHEILITIS

A. Definition
Actinic cheilitis, also known as solar cheilosis, solar
cheilitis, or actinic keratosis of the lip, represents an
accelerated tissue degeneration of the vermillion por-
tion of the lip, especially the lower lip, secondary to
regular and prolonged exposure to sunlight. This par-
ticular condition occurs almost exclusively in whites
and is especially prevalent in those with a fair skin. It is
closely correlated with total cumulative exposure to
sunlight and amount of skin pigmentation (60).
The affected vermillion portion of the lips acquires an
atrophic, pale-to-silvery gray, glossy appearance,
often with fissuring and wrinkling at right angles to
Figure 24 Photomicrograph showing compact collagen cov- the cutaneous-vermillion junction (Fig. 25). In advanced
ered with a thin squamous epithelial layer typical for oral sub- cases, the junction is irregular or totally blurred, with a
mucous fibrosis. Source: Photomicrograph courtesy of Dr. Yuk- degree of epidermalization of the vermillion evident.
Kwan Chen, Department of Oral Pathology, Kaohsiung Medical Mottled areas of hyperpigmentation and keratosis are
University, Kaohsiung, Taiwan. often noted as well as superficial scaling, cracking,
erosion, ulceration, and crusting.
Chronic sun damage mandates periodic exami-

nation and biopsy if ulceration persists or if indura-
tion becomes evident. If atypical changes are noted
within the epithelium, a vermillionectomy may be
performed in association with mucosal advancement
to replace the damaged vermillion. Acceptable results
are also obtainable with the use of laser evaporation or
cryosurgery.
XII. SMOKELESS TOBACCO KERATOSIS

A. Definition
Smokeless tobacco keratosis (snuff pouch, snuff dip-
Figure 25 Actinic cheilitis characterized by whitish hue on the per’s lesion, tobacco pouch) is a chronic white or
vermillion border of the lower lip. gray/translucent mucosal macula localized in areas
of direct contact with smokeless tobacco (63). The
lesion cannot be scraped off and disappears with
cessation of the tobacco habit.
C. Pathology
Histologically, actinic cheilitis shows hyperkeratosis, B. Clinical Features
increased thickness of the prickle cell layer, basophilic
connective tissue changes, and perivascular inflamma- The white lesions of the oral mucosa associated with
tory alterations. Epithelial dysplasia is almost invari- smokeless tobacco use develop in the immediate area
ably present and varies from mild to severe (61,62). where the tobacco is habitually placed (Fig. 27). The
most common area of involvement is the mucobuccal
fold of the mandible or the maxilla, in either the
D. Differential Diagnosis incisor or the molar region. The altered mucosa gen-
Although the clinical appearance together with the erally has a granular-to-wrinkled appearance. In
history of UV exposure makes a diagnosis evident, advanced cases, a heavy folded character may be
erosive lichen planus, lupus erythematosus of the lip seen. Less frequently, an erythroplakic or red compo-
mucosa, and congenital dyskeratosis have to be men- nent may be admixed with the white keratotic com-
tioned in the differential diagnosis. ponent. In a Swedish population using moist snuff,
four different clinical degrees of mucosal alterations
have been discerned. Degree 1 is characterized by a
E. Treatment and Prognosis superficial lesion with a color similar to the surround-
ing mucosa and a slight wrinkling. In degree 2, there
Because of the positive relationship between exposure
is a superficial whitish or yellowish lesion with wrin-
of UV light and carcinoma (Fig. 26), lip protection is
kling. In degree 3, a whitish-yellowish-to-brown wrin-
indicated. The use of lip balm containing the sunscreen
kled lesion with intervening furrows of normal
agent para-aminobenzoic acid (PABA) or its derivates
mucosal color is present together with obvious thick-
should be used during periods of sun exposure in high-
ening. Degree 4 shows the same changes as described
risk patients. Sun-blocking opaque agents also boost the
effectiveness of the balm.
Figure 27 Smoker’s keratosis induced by snuff dipping in the

upper labial fold. Source: Picture courtesy of Prof. Jesper Reibel,
Department of Oral Medicine, Clinical Oral Physiology, Oral
Figure 26 Actinic cheilitis complicated by development of squa- Pathology and Anatomy, School of Dentistry, University of
mous cell carcinoma on the vermillion border of the lower lip. Copenhagen, Copenhagen, Denmark.
for degree 3 with the exception that the furrows have by areas of atrophy and inflammation (67). Epithelial
changed their color from normal to red (64). This dysplasia does not form part of the spectrum of
clinical classification is supported by corresponding histological alterations shown in Swedish moist
histological alterations as outlined below. snuff users (67). In other populations, it may occasion-
ally occur (66). It is however debatable if such lesions
with dysplasia should be considered as smoker’s
C. Pathology keratosis or should be placed in the category of
Histological changes in smokeless tobacco users leukoplakia. Probably, it is wise to reserve the term
include hyperparakeratosis, hyperorthokeratosis, a ‘‘smoker’s keratosis’’ for lesions because of the use of
pale eosinophilic zone of hyperkeratosis, and basal smokeless tobacco and with the typical histological
cell hyperplasia (65,66). Moreover, a particular kerati- appearances as outlined above and to put any tobac-
nization pattern consisting of parakeratinized streaks co-induced lesion that combines hyperkeratosis with
with an appearance similar to a pine tree, the so-called dysplastic epithelial alterations within the category of
chevron-like pattern of keratinization, does occur, this leukoplakia.
feature being part of the mucosal changes associated
with the use of smokeless tobacco (Fig. 28) (56,65) as
well as appearing as a result of other types of tobacco D. Differential Diagnosis
usage (56). Following are the various histological
alterations seen in Swedish snuff dippers that corre- Confusing smoker’s keratosis with other oral mucosal
spond to the clinical alterations as detailed above. In disorders with a whitish appearance can easily be
degree 1 lesions, there is slight inflammation but avoided when taking into account the patient’s
no epithelial changes. Degree 2 shows a thickened history and habits. In doubtful cases, histological
surface layer of the epithelium with or without an examination is indicated to rule out more serious
accompanying surface of necrosis. A considerably epithelial alterations.
thickened surface layer composed of vacuolated cells
and chevron-type keratinization characterizes degree
3 clinical mucosal alterations, and in degree 4, a marked E. Treatment and Prognosis
thickening of the surface layer may be accompanied
With discontinuation of smokeless tobacco use, some
lesions may disappear after several weeks, indicative
of an excellent prognosis (67). Persistent lesions
should be removed and examined histologically.
Moreover, patients who use smokeless tobacco have
a slightly increased risk for development of oral
cancer, this also warranting follow-up for those who
persist in this habit (66,68,69). The risk for malignant
change, however, may vary among patient popula-
tions, type of smokeless tobacco used, and mode of
application, as for some populations, this risk has
been reported to be zero (67). These conflicting data
may be due to confusing genuine smoker’s keratosis
with leukoplakia, an issue already alluded to in the
previous text devoted to the pathological features.
XIII. LICHEN PLANUS

Lichen planus typically presents as intertwining thin
strands or streaks of white keratosis (Wickham’s
striae) of the bilateral buccal mucosa. Its potential
for malignant transformation is questioned as it is
stated that reports of malignant progression could be
due to confounding lichen planus with the so-called
lichenoid dysplasia, a lesion probably representing
leukoplakia but resembling lichen planus clinically
and histologically (70–72).
Figure 28 Epithelial alterations due to snuff dipping. Note the
specific chevron-like keratinization and the band of pale cells in
the upper part of the epithelium. Source: Photomicrograph
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7
Cancer of the Oral Cavity and Oropharynx
Samir K. El-Mofty and James S. Lewis, Jr.

Department of Pathology and Immunology, Washington University, St. Louis,
Missouri, U.S.A.
I. INTRODUCTION 4. Adenoid squamous carcinoma

5. Verrucous carcinoma (VC)
The most common type of cancer affecting the oral 6. Papillary squamous carcinoma
cavity and oropharynx is squamous cell carcinoma 7. Spindle cell (sarcomatoid) carcinoma
(SCC), which is estimated to constitute approximately
94% of all oral malignancies (1). Because of this
dominance, the term ‘‘oral cancer’’ is used synony-
mously with oral SCC (2). Others, less commonly II. ANATOMY OF THE ORAL CAVITY
encountered carcinomas, are malignant melanoma AND OROPHARYNX
and neuroendocrine carcinoma, which will be dis- According to the American Joint Committee on Can-
cussed later in this chapter. Carcinomas of minor cer Staging, the oral cavity extends from the skin
salivary glands are detailed in the respective chapter vermilion junction of the lips to the junction of the
in the text. hard and soft palate above and to the line of the
SCC occurring at different anatomic subsites in circumvallate papillae of the tongue below (Fig. 1). It
the oral cavity and oropharynx vary considerably in can be divided into eight areas: lip mucosa, buccal
their epidemiologic, demographic, pathologic, and mucosa, lower alveolar ridge, upper alveolar ridge,
clinical features. Consequently, it is not possible to retromolar gingival [retromolar trigone (RMT)], FOM,
address these various tumors collectively. The follow- hard palate, and anterior two-thirds of the tongue
ing discussion will address in details each individual (the OT) (Figs. 1, 2).
carcinoma by its respective site of incidence. The The oropharynx extends from the plane of the
following is a list of these entities: hard palate superiorly to the plane of the hyoid bone
SCC of the oral cavity: inferiorly (Fig. 3), and is continuous with the oral
1. SCC of the lip cavity through an opening called the faucial isthmus.
2. SCC of the buccal mucosa The oropharynx is separated from the oral cavity
3. SCC of the floor of the mouth (FOM) and oral by the junction of the soft and hard palates superiorly,
tongue (OT) the line of the circumvallate papillae inferiorly, and
4. SCC of the gingival and alveolar mucosa the anterior pillars of the faucies laterally.
5. SCC of the hard palate The oropharynx encompasses three main
6. SCC of the retromolar trigon regions—the palatine arch, the base of tongue, and
the lateral and posterior pharyngeal walls. The palatine
SCC of the oropharynx: arch constitutes the inferior surface of the soft palate
1. SCC of soft palate and uvula and uvula, the palatine tonsils, and their anterior and
2. SCC of the oropharyngeal wall posterior pillars (Fig. 4). Although the RMT is techni-
3. SCC of tonsils and base of tongue cally a component of the oral cavity, carcinomas in this
location often involve adjacent oropharyngeal sites and
Keratinizing squamous cell carcinoma (KSCC) is behave more like oropharyngeal tumors (Fig. 4).
the prototype and the most common SCC. However,
there is a range of distinct morphologic variants, of this
neoplasm, that are of clinical significance. Differences
in clinical, pathologic, demographic and epidemiolog- III. EPIDEMIOLOGY AND ETIOLOGY
ic features of these variants will be addressed here.
Oral cancer is an important global health concern
The following is a list of these variants:
accounting for an estimated 275,000 cases and
1. Nonkeratinizing squamous cell carcinoma (NKCa) 128,000 deaths annually (3–5). Cancer of the mouth
2. Basaloid squamous carcinoma (BSC) and pharynx ranks sixth overall in the world. Its
3. Adenosquamous carcinoma (ASC) incidence varies markedly by geographic region.
286 El-Mofty and Lewis
Figure 1 Diagram showing the relationships of the oral

cavity anatomic subsites.
disease 10 years later than men (8). Changes in

incidence-age have been observed during an approxi-
mately 30-year period. Using the 1973–2001 surveil-
lance, epidemiology, and end results (SEER) database,
a statistically significant increase in oropharyngeal
carcinoma in young patients of 20 to 44 years was
observed. No similar increase was evident in oral SCC
(9). Another study found a significant annual increase
in tonsillar SCC in men, but not women, who are
younger than 60 years. Again, no similar increase was
observed in oral nontonsillar sites (10). The total
incidence rates of oral cavity and oropharynx are
found to be higher among blacks than whites. Con-
siderable racial and ethnic differences in the preva-
lence of oral/pharynx cancer may be related to social
and cultural practices as well as socioeconomic
factors.
Risk factors for oral/pharynx cancer can be
generally classified into several categories including
Figure 2 Diagram illustrating the anatomic relationship of the
OT, FOM, alveolar ridge, and lower lip. Abbreviations: OT, oral chemical carcinogens, oncogenic viruses, sunlight,
tongue; FOM, floor of the mouth. oral hygiene, nutritional factors, genetic predisposi-
tion, and immunocompromise.
A. Chemical Carcinogens
Two-thirds of all cases are observed in developing
countries. The Indian subcontinent accounts for one- The most important chemical carcinogens are related
third of the global burden. Men are affected two-to- to tobacco and alcohol abuse. Through a large number
three times as often as women. The oral cavity/ of epidemiologic studies, a strong link has been estab-
oropharynx is the third most common site for cancer lished between the use of tobacco and oral/pharynx
among males in developing countries (3–5). However, SCC. Alcohol is an independent risk factor for the
the incidence of oral cancer for women can be equal disease, but it may have synergistic effect when com-
to, or even greater than, that of men in high incidence bined with tobacco (7). The risk of development of
areas where both sexes are equally exposed to the cancer is three to nine times greater in those who
same risk factors (4). smoke or drink, and as much as 100 times greater in
In the United States, approximately 24,000 men those who smoke and drink heavily, than those who
and 10,000 women are diagnosed with oral and oro- neither smoke nor drink (11). It has been estimated
pharyngeal carcinomas annually, representing 3.2% of that approximately 75% of oral cancers are related to
all newly diagnosed cancers (6,7). The majority of the prolonged and heavy smoking and alcohol abuse (12).
carcinomas develop predominantly between the fifth Cigar and pipe smoking pose similar risk as cigarette
and eight decades of life. Women tend to develop the smoking. Tobacco and alcohol abuse has been
Chapter 7: Cancer of the Oral Cavity and Oropharynx 287
Figure 3 Anatomical boundaries of the orophar-

ynx as defined by the American Joint Committee on
Cancer staging. The tip of the epiglottis is consid-
ered the inferior border of the oropharynx by some
surgeons.
Figure 4 Diagram showing the relationship of the

RMT to the various components of the oropharynx.
Abbreviation: RMT, retromolar trigone.
implicated in the higher rates and earlier onset of which may include cloves and cardamom. Betel chew-
cancer among men in general and African American ing is a tradition that goes back thousands of years.
men in particular (8,12,13). Tobacco was added to betel quid sometime after its
In addition to cigarettes, cigars, and pipes, introduction to South Asia by Europeans in the seven-
tobacco is commonly smoked in other forms, in par- teenth century. Although Areca nut is carcinogenic in
ticular in parts of India and South Asia. Bidi, made of itself, the addition of tobacco increased the risk (17,18).
low-grade tobacco wrapped in tender leaf tobacco is As in the case of smoking, the risk for oral cancer
popular among rural folk and urban poor. The con- is dependent on dose and duration of use (19). Much
centrations of nicotine, tar, and other toxic agents in of the tobacco consumption in the world is without
the smoke are higher in bidi than other cigarettes, with combustion. In India, up to 40% of tobacco use is in
a higher risk for development of oral cancer (14). smokeless forms, mostly of the species Nicotiana rus-
Reverse chutta smoking, with the lighted end of the tica, while most smoking tobacco is Nicotiana tabacum
cigar placed inside the mouth, is associated with (20). Samples of N. rustica have been found to contain
particularly high rates of oral cancer of the palatal higher concentrates of tobacco-specific nitrosamines
mucosa (1,15), a site with otherwise very low cancer than N. tabacum (21). The tobacco is placed in direct
incidence. contact with the mucosa. In the developing countries,
The primary cause of the very high incidence of tobacco is mostly consumed mixed with other ingre-
oral cancer in South Asia is, however, the widespread dients, in addition to betel nut. Lime, molasses, oils,
habit of chewing betel quid or paan and related Areca and spices are used. Snuff is common in Scandinavia
nut use. An estimated 200 to 400 million people prac- and the United States. Tobacco is also prepared in
tice the habit worldwide (16). The components of the blocks or flakes for chewing. ‘‘Snuff dipper cancer’’
betel quid vary between different populations, but the described in the southeastern United States is due to
main ingredients are the leaf of the vine Piper betel— the habit of placing snuff in the labial sulcus (22,23).
which is not botanically related to the Betel palm, Areca Females in this geographic area have high prevalence
nut, slaked lime (calcium hydroxide), and spices, of snuff dipping and oral cancer (24).
Traditional values in some countries do not the subject did not corroborate earlier reports. It is
favor smoking by women and the young, but there concluded that the risk of developing oral cancer
is no such taboo against using smokeless tobacco. because of the use of alcohol-containing mouthwash is
Most women who use tobacco use it in its smokeless unlikely (38). Interestingly, however, dental products
form. The acquisition of tobacco habits, in whatever such as toothpaste and mouthwash containing sangui-
form, starts at an early age. In one study, one-third to narine (such as Viadent), which is the principle alkaloid
one-half of children younger than 10 years in three extract of the bloodroot plant (Sanguinaria Canadensis
rural areas in India had experimented with smoking L.), an antibacterial agent, is found to increase the risk of
or smokeless tobacco (25). Children have been known leukoplakia of the maxillary vestibule (39,40).
to choke to death on betel nuts. Pakistan’s new laws
forbid the selling of betel nut to children younger than
five years. B. Ultraviolet Light
More than 300 carcinogens have been identified Chronic exposure to sunlight (actinic radiation) is
in tobacco smoke or in its water-soluble components considered to be the most important factor in causa-
that will leach into saliva (26). The most important of tion of lip cancer, the vast majority of which occurs in
these is the aromatic hydrocarbon benz-pyrene and the lower lip (41–46). This proposal is supported by
other tar derivatives as well as the tobacco-specific the observations that cancer of the lip is more common
nitrosamines such as nitroso-nor-nicotine (NNN), in individuals who have fair complexion and who are
nitrosopyrrollidine (NPYR), nitrosodimethylamine. more exposed to sunlight because of outdoor occupa-
These aromatic hydrocarbons are identifiable in tions or who live near the equator. The propensity of
tobacco smoke as well as in smokeless tobacco. They the lip vermilion border for solar damage is attribut-
damage DNA by producing adducts, principally O6- able to lack of a pigmentary layer that protects against
methylguanine. UV radiation (47). Other risk factors may play a role in
Metabolism of these carcinogens usually involves the causation of cancer of the lip, most notably pipe
oxygenation by p450 enzymes in cytochromes, and smoking (45,48–50). It is suggested that the heat and
their conjugation, in which the enzyme glutathione S trauma of the pipe stem as well as the tobacco
transferase (GST) is involved. Polymorphism of the combustion products may play a role in the induction
p450 and GST genes is under active study in search of malignancy.
of genetic markers of susceptibility to head and neck
cancer and other tobacco-related cancers (27).
Alcohol is the second major risk factor for oral C. Oncogenic Viruses
cancer. In the West, 75% to 80% of patients frequently Accumulating evidence during the last two decades
consume alcohol. For nonsmokers, it is the most impor- has linked high-risk human papillomavirus (HPV),
tant risk factor. If above 30 g of alcohol is consumed per particularly type 16, with some upper aerodigestive
day, the risk increases linearly with the amount of tract carcinomas. The virus, which is a prerequisite for
alcohol consumed (28,29). As mentioned before, people cervical cancer, is also found to be an important
who smoke and drink have much greater risk of oral etiologic factor for a distinct, nonkeratinizing type of
cancer than those who only smoke or drink. The risk in SCC, which occurs in the oropharynx and more spe-
all cases is dose dependent. cifically in the palatine tonsils and base of tongue. The
Pure ethanol has never been shown to be carci- virus is very rarely identified in carcinoma of the oral
nogenic in vitro or in animal studies (30). It is pre- cavity proper (51–57). Substantial epidemiologic, clin-
sumed to act in concert with other, more direct ical, microscopic, and molecular evidence strongly
carcinogens, so called congeners that are found in support the connection between oropharyngeal cancer
the liquor, or from other sources such as tobacco. and HPV. HPV-related oropharyngeal carcinoma is
Nevertheless, alcohol drinking alone is an indepen- identified in subjects, with or without the established
dent risk for upper aerodigestive tract carcinoma (29). risk factors of tobacco and alcohol use (51–57). No
The increase in oral cancer in the Western world other type of oncogenic viruses has been convincingly
has been related to rising alcohol use. In England and shown to play a strong and direct role in the etiology
Wales, alcohol consumption more than doubled dur- of oral/pharyngeal SCC.
ing the second half of the 20th century, which closely
matched oral cancer mortality and, by inference, inci-
dence. There is strong circumstantial evidence that D. Dental Factors and Chronic Inflammation
alcohol rather than tobacco is the major factor in the
observed trend (4,31). Similar data have been reported An association between poor oral hygiene and poor
from Denmark (32). All forms of alcoholic drinks are dentition and oral cancer has been reported in several
dangerous if heavily consumed with evidence for the studies (4,36,58,59). Experimental evidence in animals
role of beer, wine, and spirits (12,33–36). The risk shows localization of chemical carcinogens–induced
becomes detectable when consumption exceeds 50 tumors to the sites of repeated mucosal traumatization.
drinks per week. An increase in yield and shortened latent period for
In 1979, a combined case-control study and case the development of the cancers are also observed in
series raised concern that alcohol-containing mouth- these sites (4). Clinical observations in human cases
wash is a risk for oral/pharyngeal cancer (37). More describe carcinomas developing at sites of chronic trauma
recently, extensive reviews of epidemiologic studies on caused by a broken teeth or ill-constructed dental
appliances (4,59,60). It is certain that the role of inflam- of AIDS-defining cancers: Kaposi’s sarcoma, non-
mation, whether caused by poor hygiene, infections or Hodgkin’s lymphoma, and cervical cancer as well as
mechanical trauma, in the etiology of carcinoma, is all HPV-related cancers and Hodgkin’s lymphoma.
compounded by known carcinogens such as tobacco An increased incidence in oral/pharyngeal cancer is
and alcohol abuse, nutritional deficiencies, and other observed in both HIV/AIDS patients as well as in
risks. However, during the current decade, the possibil- transplant recipients (73). Although incidence of can-
ity of a connection between chronic inflammation and cer of the lower lip is increased in both populations,
cancer has received intensive scrutiny and has moved to the increase was more marked in the transplant-
center stage in cancer research. It has been stated by recipient group (73). A similar pattern is observed in
some researchers that ‘‘genetic damage is the match that nonmelanoma skin cancer. While there is no known
lights the fire of the malignant process, and inflamma- connection between lip cancer in renal transplant
tion is the fuel that feeds it’’ (61). Recent clinical studies recipients and HPV or other viral infections, the risk
and experimental mouse models highlight a paradoxi- factors were found to be related to exposure to UV
cal role for the immune system as crucial regulator of radiation and tobacco products (74,75).
cancer development (62). Tumor-associated macro-
phages (TAM), which are ubiquitous in the stroma of IV. MOLECULAR BIOLOGY AND GENETICS
virtually all tumors, release a distinct repertoire of OF ORAL CANCER
growth factors, cytokines, chemokines, and enzymes
that are known to regulate tumor growth, angiogenesis, Oral SCC, like many other epithelial cancers, evolves
invasion, and/or metastasis (61–64). through the accumulation of multiple genetic and
The risk for malignancy associated with oral epigenetic alterations in a multistep process (7,76).
lichen planus, a chronic inflammatory dermatologic Genetic changes commonly involved in oral cancer
disease, remains a subject of debate (1,65). Candidal include loss of heterozygosity (LOH) at the sites of
hyphae are commonly observed to superficially known or suspected tumor suppressor genes, muta-
invade premalignant and malignant oral lesions. tion, and de novo promoter methylation of tumor
That such an association may be causally related, suppressor genes, amplification or overexpression of
rather than an effect of the malignant process, has oncogenes, and alterations in expression of DNA
been suggested (4,63,66). Some strains of candida repair genes. Common LOHs are observed at 3p, 9p,
were shown to produce hyperkeratotic lesions in the and 17p. The deletion of two genes located on the
dorsal rat tongue (1). In other studies, it was demon- short arm of chromosome 3; FHIT tumor suppressor
strated that some strains of Candida albicans produce gene and retinoic acid receptor (RAR)-b may play a
the chemical carcinogen nitrosamine from dietary role in development of oral cancer (77). P16INK4a
amines substrates (1,67). (p16), which is a tumor suppressor gene and a mem-
ber of the retinoblastoma pathway, is located at 9p21.
E. Nutritional Deficiencies High frequencies of deletions and mutations affecting
this gene are observed in oral SCC (77,78). p16 is also
Numerous studies report a significant preventive effect subject to epigenentic control through hypermethyla-
of proper diet on oral/pharyngeal cancer (68–72). The tion of its promoter. TP53 (p53), a tumor suppressor
antioxidant or free radical-scavenging vitamins A, C, gene located on the short arm of chromosome 17, is
and E as well as iron and trace elements, such as zink and mutated in the majority of oral cancers and is also
selenium, share a proven protective effect. High inci- frequently deleted (58,77). Gene amplification and
dence of upper gastrointestinal tract carcinoma is seen protein overexpression have also been found in head
in middle-aged women with chronic iron deficiency and neck carcinomas. Of special significance is epi-
anemia, glossitis, and mucosal atrophy, a condition dermal growth factor receptor (EGFR), which has
known as the Plummer-Vinson syndrome. In animals been targeted as a treatment strategy for oral SCC.
rendered iron deficient by venesection and low-iron Cyclin D1 and p63 are other genes that are amplified
diets, there developed epithelial atrophy and increased (79,80). Overexpression of cyclooxygenase-2 (COX-2)
cancer risk, which was clearly shown when such animals is important in carcinogenesis and may provide
were challenged with chemical carcinogens (71). molecular target for treatment (81).
An important study in China found a strong Increased susceptibility to oral cancer is associ-
protective effect for carotenoid and vitamin C and ated with a number of inherited cancer syndromes,
fiber intake in oral cancer risk (72). including Li-Fraumeni syndrome, Fanconi’s anemia,
and xeroderma pigmentosum (82). Polymorphism in
F. Altered Immunity genes involved in the metabolism of carcinogens con-
tained in tobacco and alcohol have been linked to
A similarity in the pattern of increased risk for cancer individual susceptibility. These genes encode for such
in both HIV/AIDS populations and immunosup- enzymes as the glutathione-s-transferase, which are
pressed organ transplant recipients suggests that the involved in detoxifying some carcinogens in tobacco.
immune deficiency rather than other risk factors for Other enzymes that metabolize carcinogens have also
cancer is responsible for the increased risk (73). In both been implicated in oral cancer such as cytochrome
of these two populations, there is significant increase p450, N-acetyltransferase and alcohol dehydrogenase
of incidence, predominantly in cancers with known (77,83). There is increasing evidence for an inherited
infectious cause (73–75). These include all three types genetic component in oral cancer, possibly associated
with a greater susceptibility to genetic damage by borders, intercellular bridges, and hyperchromatic
environmental mutagens. Those individuals may be nuclei. Varying degrees of nuclear and cellular pleo-
more likely to develop multiple tumors (81,84). morphism are seen. A characteristic feature of KSCC
is formation of keratin pearls (round cellular nests
with central keratinization). Traditionally KSCC is
A. Molecular biology in HPV-Related graded as well, moderate, and poorly differentiated
Carcinomas variants. Previously, the grading system, which was
Molecular changes in HPV-related carcinomas may proposed by Broder (90), was based on the amount of
differ from those induced by other carcinogens. A keratin production and pleomorphism of the tumor
large body of studies in cervical, as well as HIV- cells. Four grades are described, grade I being the
positive oropharyngeal carcinomas, shows that HPV most differentiated with the highest keratin produc-
oncogenes E6 and E7 act through inactivation of P53 tion and minimal cellular pleomorphism (Fig. 5),
and retinoblastoma tumor suppressor genes, respec- while grade IV is poorly differentiated with little or
tively. In addition, E6 can directly activate telomerase, no keratin formation and marked cellular pleomor-
and E7 induces abnormal centrosome duplication. phism (Fig. 6). Grades II and III have intermediate
Consequent cell cycle deregulation and genomic insta- levels of these characteristics (Fig. 7). The purpose of
bility are instrumental factors for the developments of tumor grading is to provide a tool for predicting its
these distinct carcinomas, see infra (Fig. 35) (85–88). biologic behavior. However, because the histologic
features may vary considerably from area to area
within the same tumor, the Broders grading system
V. CLINICOPATHOLOGIC CONSIDERATION was found to lack significant prognostic value (91).
Several authors suggested that more useful prognostic
As stated above, SCC of the oral/pharyngeal mucosa information may be deduced from the invasive fronts
constitutes a range of variants. Differences between of the tumor where the deepest and presumably most
these entities are not only morphologic but also clini- aggressive cells reside (91–94). An invasive front grad-
cal and in some cases molecular. The clinical and ing system has been devised in which five histologic
pathologic features of the following variants of SCC features are graded and assigned points from one to
will be considered in some detail later in this chapter: four. The score for each variant is summed to provide
1. KSCC a total malignancy score for each tumor. The param-
2. Nonkeratinizing carcinoma eters used are degree of keratinization, nuclear pleo-
3. BSC morphism, number of mitoses per high-power field,
4. ASC pattern of invasion, and host response. Accordingly,
5. Adenoid squamous carcinoma the lower score is given to tumors with high keratini-
6. VC zation (>50% of cells), little nuclear pleomorphism,
7. Papillary squamous carcinoma (>75% mature cells), 0–1 mitotic figures/HPF, push-
8. Spindle cell carcinoma (SpCC) (sarcomatoid ing well-defined invasive front and marked host
carcinoma) response. On the other hand, the highest scores are
given to tumors with little or no keratinization,
Staging of Oral/Pharyngeal Carcinoma: extreme nuclear pleomorphism, more than five mito-
Regardless of morphologic type, all variants of ses/HPF, marked cellular dissociation in small nests
SCC are staged similarly using the TNM system or single cells, and no host response. The intermediate
(Table 1 and 2). grade tumors have moderate levels of these features.
This system has been found to be of high prognostic
value for oral cavity carcinomas (91,92,95,96). This
VI. KERATINIZING SQUAMOUS CELL histologic grading of malignancy at deep tumor inva-
CARCINOMA sive front was also found to have significant positive
KSCC is the prototype of SCC and is its most common relationship with Ki-67 cell proliferative index (97,98).
type. It may occur at any of the anatomic sites of the Other morphologic features that are found to
oral cavity and oropharynx. Variations in clinical have independent prognostic significance are pres-
presentation, symptomatology, treatment outcome, ence of perineural invasion and intralymphatic
and prognosis may to some extent depend on the tumor emboli (99–101). It has also been shown that
anatomic location of the tumors. Because of such the pattern of invasion, at the advancing front of the
variations, the clinical aspects of carcinomas at vari- tumor, is a significant and independent predictor of
ous sites will be addressed separately. both local recurrence and overall survival. The most
unfavorable pattern is described as diffuse infiltration
A. Pathologic Features with cellular dissociation, while the most favorable is
well defined with ‘‘pushing’’ border (118).
KSCC bears some resemblance to keratinizing strati- Many studies have advocated the use of tumor
fied squamous epithelium. The similarities vary thickness as a measurable prognostic indicator in
depending on the degree of differentiation. Micro- small tumors (T1–T2) (101–104). Tumor thickness was
scopically, KSSC is composed of sheets, strands, and found to be significant in predicting local recurrence,
nests of squamous cells. The tumor cells show nodal metastasis, and survival. However, a ‘‘cut off’’
abundant eosinophilic cytoplasm, well-defined cell thickness level that can be used to discriminate
Table 1 TNM—Staging System for Oral Cavity Cancer
Definition of TNM
Primary tumor (T)
T1 Tumor 2 cm or less in greatest dimension
T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension
T3 Tumor more than 4 cm in greatest dimension
T4 (lip) Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of
face, i.e., chin or nose
T4a Tumor invades adjacent structures [e.g., through cortical (oral cavity) bone, into deep
muscles of the tongue (genioglossus, hyoglossus, palatoglossus, and styloglossus),
maxillary sinus, skin of face]
T4b Tumor invades masticator space, pterygoid plates, or skull base and/or encases
internal carotid artery
Note: Superficial erosion alone of bone/tooth
socket by gingival primary is not sufficient to
classify a tumor as T4.
Regional lymph nodes (N)

N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2 Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm
in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in
greatest dimension; or in bilateral or contralateral lymph nodes, none more than
6 cm in greatest dimension
N2a Metastasis in single ipsilateral lymph node more than 3 cm but not more than 6 cm in
greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest
dimension
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest
dimension
N3 Metastasis in a lymph node more than 6 cm in greatest dimension
Distant metastasis (M)

Stage grouping
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
T1 N1 M0
T2 N1 M0
T3 N1 M0
Stage IVA T4a N0 M0
T4a N1 M0
T1 N2 M0
T2 N2 M0
T3 N2 M0
T4a N2 M0
Stage IVB Any T N3 M0
T4b Any N M0
between favorable and unfavorable prognosis has variations were related to the size and peculiarity of
varied from 1.5 to 6 mm in various studies (102– the tumors. Studies on FOM and OT tumors showed
106). The variation in results reported in these studies cutoff thicknesses of 1.5 and 2.0 mm, respectively
might be related to several factors, such as using the (107,108), while in the case of buccal mucosal carcino-
surface of the tumor or the adjacent normal mucosa as mas with marked keratinization, the prognosis was
the point for measuring the thickness. More likely, the significantly worse for thicker tumors of more than or
Table 2 TNM Staging System for Oropharyngeal Cancer
Primary tumor (T)

T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension
T4a Tumor invades the larynx, deep/extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible
T4b Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base, or encases carotid
artery
N2 Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in
multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, or in bilateral or contralateral
lymph nodes, none more than 6 cm in greatest dimension
N2a Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N3 Metastasis in lymph node more than 6 cm in greatest dimension
Distant metastasis (M)

Stage grouping: Oropharynx

Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
T1 N1 M0
T2 N1 M0
T3 N1 M0
Stage IVA T4a N0 M0
T4a N1 M0
T1 N2 M0
T2 N2 M0
T3 N2 M0
T4a N2 M0
Stage IVB T4b Any N M0
Any T N3 M0
equal to 6 mm in thickness (106). In a study of 145 who are involved in outdoor occupations, particularly
cases of oral carcinomas of all sites, O’Brian et al. (102) those with ruddy or fair complexions. It is also more
found that a 4-mm cutoff for good and poor prognosis prevalent in the Caucasian populations that live near
applied to all sites. the equator and is rare in blacks and dark-skinned
KSCC is the most common type of oral/pharyn- persons (44,45,109–112). The incidence of carcinoma of
geal carcinoma of all anatomic subsites. Clinical pre- the lip varies from 24% to 30% of oral cancers (113–
sentation and etiologic factors may vary according to 115) and 12% of head and neck cancers (114,115). The
anatomic locations. lower lip is involved in 85% to 98% of cases
(45,112,114,116,117) with a male predominance. The
male-to-female ratio varies considerably in different
VII. SQUAMOUS CELL CARCINOMA OF THE series from 2:1 to 45:1 (45,113,116–118). The patients’
ORAL CAVITY age ranges from the fifth through the eighth decades
A. Squamous Cell Carcinoma of the Lip of life (110,116,117,119–121) with a mean age of
between 60.5 and 70 years (113,116,117,119–121).
As stated above, chronic exposure to sunlight is the SCC of the upper lip accounts for 1.8% to 7.7% of
most important etiologic factor. Lip cancer is more all lip cancers (122,123). Upper lip carcinoma is seen
common in individuals who live in rural areas and more frequently in women than in men (121,124). The
Figure 6 Poorly differentiated SCC. Although no keratin identi-

fied, the cells show keratinocytic phenotype (200). Abbrevia-
tion: SCC, squamous cell carcinoma.
Figure 5 Well differentiated, KSCC (100). Abbreviation:

KSCC, keratinizing squamous cell carcinoma.
relative overall paucity of lip cancer in women has

been attributed to the use of lipstick and less outdoor Figure 7 Moderately differentiated KSCC (100). Abbreviation:
KSCC, keratinizing squamous cell carcinoma.
exposure, both of which make women less susceptible
to the cumulative effects of actinic damage (124). Lip
cancer is also virtually unknown in blacks and people
with dark complexions (110). This apparent immunity
is presumably due to the protective effects of melanin Carcinomas of the lower lip, unlike that of the
pigmentation against UV light (41,125). upper lip, tend to grow slowly. A considerable amount
Typically, carcinoma of the lower lip occurs at of time may elapse before a diagnosis is made (127). If
the vermilion border at a point midway between the untreated, the tumor may extend to contiguous struc-
midline and commissure area (1,23,126). Clinical pre- tures such as skin, muscles, oral mucosa, and bone.
sentations of the carcinomas vary considerably. Early Some carcinomas have a propensity for involvement of
lesions may be focal, white, and thick, diffuse mixed nerves. These may be associated with numbness of the
erythematous and white, have areas of chapping and lip. Involvement of the mental nerve may be limited,
crusting or fissures that do no heal. More advanced but on occasions, proximal extension of the malignant
lesions may present as exophytic, infiltrating masses cells may follow the course of the inferior alveolar
but more commonly as an ulcer (1,125–128) (Fig. 8). nerve within the mandibular canal and even along
Palpable induration around the area of the lesion is an the mandibular branch of the trigeminal nerve through
important diagnostic feature in all forms of the tumor the foramen ovale and eventually intracranially. Such
(126,128). neurotropic behavior may be observed even when
solar keratosis affecting the rest of the vermilion

border (140).
Surgical management of smaller lesions is usually
in the form of a wedge or V-shaped resection with
primary closures. Larger defects require reconstructive
procedures. Lip shave and vermilionectomy, in addi-
tion to the simple resection, are recommended in
patients with demonstrable premalignant actinic
changes (117,141). Cases in which tumor involves the
mental nerve, efforts are made to prevent the progres-
sion of cancer cells along the inferior alveolar nerve
back to the base of the skull. This may involve a
hemimandibulectomy or, if possible, unroofing of the
nerve in the inferior alveolar canal and resecting it with
a free proximal margin (129). In such cases, surgery is
Figure 8 SCC of the lower lip presenting as an ulcer. Abbrevi-
ation: SCC, squamous cell carcinoma.
followed by radiation therapy (142,143).
Routine elective node dissection in patients with
clinically negative neck has been largely abandoned
because of low yield of nodal metastasis. A cure rate
of 90% is reported in T1 to T2, N0 carcinomas of the
other risk factors, such as tumor grade and stage, are lower lip (47,116,117,119). However, supraomohyoid
favorable (129–134). The mechanisms involved in neu- neck dissection is advocated in large T3 and T4
rotropic behavior of some SCCs are currently tumors, clinically positive nodes, and carcinomas at
unknown. Neural involvement in lip carcinoma can the oral commissure (144).
be determined clinically by sensory complaints such as Neck dissection combined with postoperative
burning, stinging pain, or numbness along the course irradiation has been highly successful in regional
of the affected nerve and by radiographic findings of control (138,141). Cases in which lymph node metas-
widening of the osseous canals or erosion of skull tasis is pathologically proven, the average five-year
foramina with which the affected nerves are associated survival rate is estimated to be 50% (47,116,119,
(129). Lymph node metastases from carcinoma of 120,122,124).
the lower lip develop late in the course of the Frierson and Cooper developed a cytologic grad-
disease. It is identified in 12% or fewer of the cases ing system for lip cancer similar to the grading system
(116,117,121,122,124,127). The submental and subman- of the advancing front alluded to above. Four grades
dibular lymph nodes (levels Ia and b) are most com- are described, which have prognostic implications.
monly involved. Contralateral metastasis occurs when They show a three-year cure rate of 95% for grade I
the tumor is near the midline, because of cross- lip tumors but only 46% and 38% for grades II and III,
drainage of lymphatics present in this location. The respectively (120).
size of the tumor is an important risk factor for lymph
node metastasis. Carcinomas that are smaller than 2 cm B. Squamous Cell Carcinoma of the Buccal
rarely metastasize, whereas those that are larger dis- Mucosa
seminate to lymph nodes with the same frequency as
carcinomas of the FOM and tongue (126). In one study, Many of the etiologic factors described above have
only 5% of T1 and T2 lesions demonstrated nodal been implicated in the causation of cancer of the
metastasis. In contrast, 67% of T3 and T4 carcinomas buccal mucosa, in particular, tobacco habits, both
spread to the cervical lymph nodes (135). In another smoked and nonsmoked, and alcohol abuse. The inci-
series, 7% of 757 patients with T1 cancer demonstrated dence of SCC of the buccal mucosa varies in different
cervical metastasis as compared with 16% of 249 of reports from 1% to 10% of oral/oropharyngeal carci-
patients with T2 to T4 tumors (124). noma (145–147).
Distant metastasis from lip carcinoma is quite In India, where betel nut and other chewing
rare. In a review of 845 cases, systemic spread was habits are prevalent, it constitutes 44% of all SCC of
noted in 1.6% of the cases. The lung, liver, heart, and the oral cavity (148). In a recent study from India
spleen were the sites most frequently involved (136). of 100 cases of carcinomas of the buccal mucosa, 95%
of the patients gave a history of abuse of oral tobacco
products (149).
Most cases occur in the sixth and seventh deca-
Surgery and/or radiation therapy are used with good des of life (147,150,151). The male-to-female ratio
results in managing smaller tumors of the lower lip, ranges from 2:1 to 9:1 in most investigations
both achieving equally high local control rates of more (145,149,150,152). However, in southeastern and
than 90% (122,137–139). southwestern United States, carcinoma of the buccal
Radiotherapy is contraindicated in the following mucosa has occurred as often, if not more frequently,
conditions: young patients, recurrence following ini- in women. This has been attributed to the excessive
tial radiation therapy, large tumors with possible use of snuff and chewing tobacco by females in those
neural involvement, and where there is extensive areas (22,153). Early SCC of the buccal mucosa may
present as a white plaque (leukoplakia), red plaque or a potential complication. Paralysis of branches of the
macule (erythroplakia) (Fig. 9), or exophytic verru- facial nerve may also occur (155,156). Invasion of the
cous hyperplasia (VH). The advanced lesions may mandible or maxilla may be present in advanced
appear as a fungating mass with a granular red cases. Death occurs from combination of infection,
surface or as ulcerating infiltrative cancer (Fig. 10). malnutrition, and hemorrhage.
Marked infiltration of the lamina propria and into the
underlying buccinators muscle and buccal fat is a Treatment and Prognosis
characteristic feature even in small T1 lesions
(153,154). VC commonly occurs in the buccal mucosa Primary radiation therapy is a good therapeutic
and is discussed independently later in this chapter. option for early buccal carcinoma (154,155,157).
The signs and symptoms of the disease are Patients with larger tumors show higher rates of
dependent on the degree to which the cancer has recurrence. Wide local resection even in small T1 to
progressed. Early lesions tend to be asymptomatic T2 tumors is associated with high recurrence rates
but eventually ‘‘soreness’’ becomes the most promi- (154,157), while aggressive composite resection has
nent initial complaint. As the tumor enlarges, trauma, better results (157). An improvement of the determi-
superimposed infection, and swelling result in nate cure rate from 28% to 42%, when surgery
increased pain. Involvement of the masticator spaces replaced radiation therapy as the preferred treatment,
in the process may lead to trismus. The tumor may was reported in a study from Memorial Sloan-Ketter-
slough and form a foul-smelling mass in the mouth or ing Cancer Center (145). In this study the presence or
may ulcerate and appear externally on the skin. Hem- absence of nodal enlargement was the most significant
orrhage from the internal maxillary or facial arteries is prognostic factor. Patients treated surgically for resid-
ual or recurrent buccal carcinoma have extremely
poor prognosis (155). The question of whether or not
to use surgery or irradiation to manage the neck with
clinically negative nodes has not been resolved. It is
suggested that prophylactic intervention is unwar-
ranted because of the low yield of occult nodal metas-
tasis (157,158).
Chemotherapeutic treatment of buccal carcinoma
using a variety of agents has not been very promising.
Use in larger tumors, T3 to T4, resulted in some tumor
regression in a minority of cases (155,159–161). The
vast majority needed surgical salvage, and nodal
regression was not significant in any case.
Regardless of the type of treatment, locoregional
recurrences are common, usually occurring within
18 months (155,161,162). Several factors affect the
prognosis: tumor size, location, and thickness as well
as presence or absence of nodal metastasis. Carcino-
Figure 9 SCC of the buccal mucosa presenting as erythropla- mas located anteriorly near the commissure area have
kia with leukoplakic areas. Abbreviation: SCC, squamous cell more favorable prognosis than those present posteri-
carcinoma. orly. The latter have a tendency to invade the oro-
pharynx and bone of the mandible and maxilla (163).
Tumor size is useful in predicting outcome only at the
extremes; (T1 and T4), but that discrimination is lost in
the intermediate sizes T2 and T3 (106). Tumor thick-
ness is suggested as a significant independent variable
in prognosis. The cutoff thickness for buccal cancer is
believed to be 6 mm, with five-year survival rates
significantly better for tumors less than 6-mm thick.
Patients presenting with cervical lymph node metas-
tasis are found to have a five-year cure rate of only
23% compared with 56% for those patients without
nodal disease (164).
C. Squamous Cell Carcinoma of the Floor

of the Mouth and Oral Tongue
The FOM and the anterior two-thirds of the tongue
(OT) are the most common sites of oral SCC. They
Figure 10 SCC of the buccal mucosa presenting as an exo- account for more than 60% of all oral carcinomas
phytic mass. Abbreviation: SCC, squamous cell carcinoma. excluding the lips (165). The frequency of carcinoma
of the OT exceeds that of the FOM (165–167). In a
review of 58,976 cases of oral cancer extracted from

the National Cancer Database (NCDB), the OT
accounted for 31.9% and the FOM 28.4% of the
cases. These tumors demonstrate locally aggressive
behavior related to lack of anatomic barriers to spread
and a propensity for cervical metastasis (168).
Etiology
Excessive smoking and alcohol abuse are the main
etiologic factors. Prolonged contact of the potential
carcinogens in the salivary reservoir with FOM and
OT mucosa may play a role in targeting these sites
specifically (169). These usual risk factors are not
always apparent, particularly in cases of OT cancer
in patients younger than 40 years. In this population, Figure 11 SCC of the tongue in a 19-year-old woman with no
other risk factors may be involved, particularly genetic history of smoking or excessive drinking. Abbreviation: SCC,
squamous cell carcinoma.
predisposition (170–172). Many younger patients with
tongue cancer have never smoked or consumed alco-
hol, and in any case, the exposure to those carcinogens
might be of too short duration for malignant transfor-
mation to occur (172,173).
Clinical Features
Carcinoma of the OT and FOM are predominantly
diseases of the elderly with the greatest majority of
cases occurring in the sixth to the eighth decades of
life with a median age of about 60 years (165,169,
174,175). A small minority of cases occur in young
patients in the second and third decades of life. It has
been estimated that about 3% of carcinomas of the OT
occur in young patients but an increase to 6% to 7%
has been recently recognized (176–178). In the United
States, the incidence of OT cancer has increased in
adults aged 20 to 44 years during the last three
decades (177).
In general, men are affected two to three times as Figure 12 Early SCC of the tongue seen as an area of
erythroplakia on the lateral border. Abbreviation: SCC, squa-
much as women. However, the gap appears to be
mous cell carcinoma.
closing during the last several decades in various
parts of the world. The difference seen previously
was probably a reflection of the differences in habits
between males and females. As habits such as smok-
ing and drinking became more socially acceptable
among women, the gap has narrowed (166,172,179–
182). Among young patients with OT cancer, it is
particularly noticeable that the proportion of women
is greater than in the general population of tongue
malignancies, yet a history of smoking and drinking is
less frequently reported (183–187) (Fig. 11). Tongue
carcinoma in patients younger than 40 years may be a
distinct biologic entity but as alluded to above, the
underlying causes remain unknown (170–172).
Early asymptomatic carcinomas clinically pres-
ent as either leukoplakia or, more commonly, eryth-
roplakia (Fig. 12). Shafer and Waldron found that 50%
of erythroplakia of the FOM were histologically
proven to be invasive carcinoma. The remainder
were either severe dysplasia or carcinoma in situ
(188). However, the typical patient presents with a Figure 13 Typical SCC of the lateral border of the tongue
painless, indurated ulcer of several months’ duration presenting as a painless indurated ulcer. Abbreviation: SCC,
(Fig. 13). The lesions are frequently more than 2 cm in squamous cell carcinoma.
diameter at the time when the true nature of the
metastasis (101–104,107,108,208). In any case, most of

the patients have stages III or IV disease at presentation
(181,209).
Distant metastases are unusual, occurring only
in 10% of the patients, with the lungs, liver, and bone
as the sites most commonly affected (181,190,192,205).
Secondary primary carcinomas are known to be asso-
ciated with FOM and OT carcinomas in 4% to 54% of
the cases. The secondary primary carcinomas may be
synchronous or asynchronous and occur mostly in the
head and neck area (181,189,192,194,205,207,210–212).
Half of these second primaries are detected by two
years from the index tumor presentation, but non-
aerodigestive tract tumors are common beyond five
years (213).
Figure 14 SCC of the anterior FOM near the lingual frenulum.
Abbreviations: SCC, squamous cell carcinoma; FOM, floor of the
mouth. Treatment and Prognosis
Surgery and radiation, either alone or in combination,
are the prime modalities used in the treatments of
disease is established (188–191). In cases of FOM carcinomas of the OT and FOM. Chemotherapy has
tumors, the most common site is anteriorly, near the been used as initial treatment concurrently with radio-
lingual frenulum (Fig. 14). Seventy-two percent of all therapy or as adjuvant treatment following surgery or
tumors occur in this location, whereas 15% to 30% irradiation. For the most part, early carcinomas (stages
develop in the middle third and posterior third, I and II) are treated effectively with either surgery or
respectively (189,191–193). However, restriction of radiotherapy alone (174,175,181,200,205).
the tumor to the confines of the FOM is generally Involvement of the mandible by carcinoma is an
found only in the initial stages of the disease. Exten- important consideration in selecting appropriate ther-
sion to contiguous structures occur in 50% to 70% of apy. Assessment of bone involvement by tumor may
the cases at the time of diagnosis (194–196). In the case be done by clinical examination and radiographic
of the OT, the most common site is the lateral border studies. Plain radiographs may be helpful in judging
of the middle third. About 75% of all tumors occur in the gross extent of mandibular invasion, but they are
the lateral border followed, in descending order, by of little or no help in determining early or minimal
the ventral surface, dorsum, and the tip. intraosseous invasion (214–216). Computed tomogra-
The ulcerated lesions are often only the ‘‘tip of the phy (CT) scans provide good cortical bone detail.
iceberg.’’ Manual palpation helps in appreciating the Magnetic resonance imaging (MRI) is generally more
third dimension of the lesion. Some tumors have exo- reliable in detecting changes within the marrow cavi-
phytic components. More advanced carcinomas are ty. Both of the foregoing procedures have produced
symptomatic. The patients may experience feelings of false-negative and false-positive results as well as
discomfort, pain, excessive salivation, or hemorrhage. under- or overestimation of the depth and width of
Tongue involvement produces some limitation of the invasion (214,217,218). The concomitant use of
movement, resulting in slurred or difficulty in speech. both MRI and CT scans has been suggested (219).
Involvement of the base of the tongue may lead to If the mandibular bone is minimally involved, a
dysphagia and referred otalgia (188,197,198). Weight marginal resection (excision of the alveolar process
loss is reported by one-third of the patients (198). At the above the mandibular canal) is considered. In patients
time of diagnosis, the majority of OT and FOM tumors with clearly demonstrable clinical or radiographic
are classified as T1 and T2 (54–67%) (175,198–201). The evidence of mandibular invasion, a segmental man-
percent of patients presenting with clinically positive dibulectomy is needed with a 1 to 2 cm resection
cervical lymph node metastasis varies from 30% to 63% margin (190,195,196,215) (Fig. 15). Tumors that exten-
(174,175,198,200,202,203). In general, the nodes most sively invade bones are usually less amenable to cure
commonly involved are those of the submandibular by irradiation alone and are complicated by high
and upper jugular (levels I and II). Dissemination to incidence of osteoradionecrosis.
lymph nodes of levels III, IV, and V occur less often Treatment of the neck is recommended in
(195,204,205). Anterior lateral and midline lesions have patients with clinically positive cervical lymph nodes
a propensity for contralateral nodal involvement (206). at presentation. For N1 metastasis, neck dissection
The orderly progression of metastasis from upper to alone is appropriate. For more advanced neck metasta-
lower lymph nodes is not always apparent; skip metas- sis, a neck dissection with or without radiotherapy is
tases are common. Although some studies have found needed (220). On the other hand, the question of
a positive correlation between tumor size and meta- treatment of the clinically negative neck is controver-
static potential (206), others have found that T stage is sial. Recommendations for management of the nega-
of little predictive value (101,207,208). On the other tive neck in stages I and II disease have included
hand, as mentioned before, tumor thickness has been observation alone or prophylactic neck dissection and
advocated as a significant predictor of lymph node prophylactic irradiation. On the other hand, there is
Figure 15 Diagrams illustrating (A) marginal and

(B) segmental mandibulectomy.
general agreement on the need to treat the neck in all T3 covering of the mandibular and maxillary ridges in
and T4 tumors (180,181,220–223). Other considerations edentulous areas is the alveolar mucosa. For the
that are taken into account in deciding whether or not purpose of the current discussion, both the gingival
to treat the neck prophylactically in cases of T1 and T2 and alveolar mucosa will be referred to as gingival
tumors include depth and pattern of invasion, lymph mucosa. Gingival SCC is the third most common
vascular involvement, perineural invasion, and intraoral carcinoma after cancers of the tongue and
patients who are not amenable to follow-up. FOM. It constitutes 4% to 25% of all oral cancers
The most common causes of treatment failure (166,167,241–248).
are the usual events: large tumors, tumor thickness, Of particular significance is that gingival SCCs
positive margins of excision, perineural invasion, may clinically simulate inflammatory gum diseases
infiltrating pattern of the advancing front, lymph such as chronic gingivitis, periodontal disease, and
node metastasis, extranodal spread of tumor, and periodontal abscess. Consequently, misdiagnosis and
distant metastasis (95,118,224–229). The incidence of delayed diagnosis are not uncommon (241,248–251). In
local recurrence following surgery or irradiation addition, gingival carcinoma is characterized by early,
varies from 10% to 40%. Over 90% of the patients and sometimes extensive, involvement of underlying
who fail therapy, regardless of the modality bone with impending poor outcome (250–256).
employed, will manifest local or regional recurrence
within two years (181,189,190). Etiology
Several reports of large series of cases have
Several investigators have indicated that tobacco use
emphasized the importance of early detection for more
and, in particular, snuff dipping is a major risk factor in
favorable prognosis. Figures based on clinical stage of
the etiology of gingival carcinoma (22,241,245,257,258).
the tumors have shown a five-year survival rate of 69%
Alcohol consumption (246,259) and poor oral hygiene
to 90% in stage I disease and 0% to 26% for stage IV
(245,258) are also important considerations. Other
disease (165,174,181,190,192,194–196,200,230–232). As
studies, on the other hand, have suggested that the
previously mentioned, some investigators have found
risk of alcohol and tobacco usage is not as significant
that young patients, less than 40 years of age, with OT
for gingival carcinoma when compared with that of the
cancer tend to have poorer prognosis (171,172,176,178,
tongue and FOM tumors (12,166,259–261).
183–185,187,233) even when presenting with early-stage
The occurrence of gingival SCC in young
disease, with a locoregional recurrence of 57% and death
patients with HIV/AIDS and in patients with graft-
caused by disease in 47% of the cases (234). It was
versus-host disease following marrow transplants, in
therefore recommended that an aggressive therapeutic
the absence of the usual risk factors, suggests an
approach be taken in young patients with carcinoma of
etiologic role for immune disorders (262–264). A
the anterior two-thirds of the tongue.
genetic bases for gingival carcinoma is postulated on
Distant metastasis, usually to the lung and bone,
the basis of the detection of p53 mutations and over-
is estimated to occur in 5% to 15% of the cases, and of
expression in many cases (58,77,265). The high inci-
these, 90% expire within two years. Larger estimates
dence of gingival SCC in patients with proliferative
of distant metastasis below the clavicles are reported
verrucous leukoplakia (PVL) (266) may also suggest a
on the basis of autopsy studies (228,235–239). About
genetic basis (see infra).
20% to 30% of patients will develop a second primary
malignancy during the course of their disease Clinical Features
(220,228,240).
Gingival carcinoma is primarily a disease of the elderly,
D. Squamous Cell Carcinoma of the Gingiva with the vast majority of cases occurring in indi-
and Alveolar Mucosa viduals of 50 years or older (241,246,267,268). Only a
few cases of gingival carcinoma have been reported in
The gingiva is the part of the oral mucosa that covers patients younger than 40 years, (269,270) including
the alveolar process of the dentate jaws. Mucosal one adolescent patient (271). Data derived from several
earlier series indicated that this disease usually

involves the mandibular gingival and affects men
more often than women (147,167,241,245–247,268,
269,272). However, more recent findings have shown
a decrease in the male-to-female ratio and even a
reversal in gender presentation (166,243,267,273,274).
Gingival carcinoma can present as an area of
erythema, an ulcer, or an exophytic mass, resembling
hyperplastic granulation tissue and mimicking focal
inflammatory gingival hyperplasia (188,275–277). The
carcinoma is more prevalent posterior to the canine
area, most commonly the mandibular molar area
(278,279). Quite often the lesion is asymptomatic
(246,278). More advanced cases may present with
soreness and pain of the gingiva, toothache, or bleed-
Figure 17 SCC of the lingual alveolar mucosa of edentulous
ing (246,278,280). Typically, this cancer extends along mandibular ridge, resembling inflammatory fibrous hyperplasia.
the periodontal membrane with destruction of the Abbreviation: SCC, squamous cell carcinoma.
supporting bone, resulting in loosening of the teeth,
closely resembling advanced periodontal disease
(242,277) (Fig. 16). Consequently, it is not unusual
for the involved teeth to be extracted, and the true
nature of the disease becomes apparent when the
tooth sockets and surrounding tissue fail to heal
(241,242,246,278). On the alveolar ridge, the carcinoma
often grows in the form of a flat elongated ulcer (281).
The duration of the symptoms in 187 patients, ana-
lyzed by Soo et al. (246), varied from three to more
than six months.
The tumors may spread laterally to involve the
mucobuccal folds, cheek, and lower lip (Fig. 16) or
medially leading to invasion of the hard palate, FOM,
and ventral surface of the tongue (278,282). Involve-
ment of the mandibular or maxillary mucobuccal fold
in edentulous patients who wear dentures may give
rise to a mass that lies in close proximity to the flange
of the denture. The clinical appearance of these lesions
may be identical to inflammatory fibrous hyperplasia
(epulis fissuratum) (279) (Fig. 17). Figure 18 Dental radiograph showing bone destruction at the
Because of its proximity to alveolar bone, gingi- site of gingival SCC in the mandibular molar area. Abbreviation:
SCC, squamous cell carcinoma.
val carcinoma commonly shows evidence of bone
invasion (Fig. 18). Bone is usually involved early in
the course of the disease. Clinical and radiographic
evidence of osseous invasion has been noted in up to

75% of patients (246,253,255,256,283,284). This process
does not appear to correlate with the site of the lesion
or the stage of the disease but is dependent on the
proximity to bone (284,285). Mandibular tumors may
extend to the mandibular canal and the inferior alve-
olar nerve. Paresthesia of the lower lip may develop.
In the maxilla, penetration of the antrum is a frequent
occurrence (252,253,256,278).
Metastasis to cervical lymph nodes may be influ-
enced by the location of the tumor and the T stage of
the disease. Mandibular tumors metastasize more
readily than maxillary ones. Clinically involved
nodes were found in 30% to 32% of the patients
with mandibular tumors and 9% to 14% in patients
Figure 16 Gingival SCC in the maxillary molar area extending with maxillary carcinomas (246,286).
into the buccal mucosa. Notice destruction of the periodontium The relationship between cervical metastasis and
and resemblance to advanced periodontal disease. Abbreviation: tumor stage was investigated in 109 individuals. The
SCC, squamous cell carcinoma. incidence of nodal involvement was found to increase
with the T stage of the disease (246). Dissemination to
distant sites developed most often in the presence of E. Squamous Cell Carcinoma of
extensive cervical metastasis or in the presence of the Hard Palate
bone involvement (246).
The hard palate is the rarest site of intraoral SCC. It is,
however, the most common site for minor salivary
Radiography gland adenocarcinoma of the mouth. As previously
alluded to, SCC of the hard palate is rather common in
Although radiography generally provides relatively some parts of India where reverse Chutta smoking is
reliable indication of bony involvement (Fig. 18), the prevalent (1,15,297,298). The hard palate is, however,
absence of detectable changes does not completely not uncommonly involved by extension of maxillary
exclude the possibility of invasion. Microscopic evi- gingival and alveolar ridge SCC (253,256).
dence of bone invasion is frequently seen in spite of In the United States, the peak incidence of occur-
radiographic findings (252,287). Additional techni- rence is between 60 and 70 years of age. Although
ques, other than intraoral and extra oral plain film some studies have found that it is more common in
radiography, are usually needed. CT scans, MRI, and men, other studies have indicated that women are
bone scans are all used for ascertaining bone involve- more often involved (299,300). The first sign of the
ment (252,253,256). CT scans are the most frequently disease is a lump or an ulcer (Fig. 19) that may or may
used and are usually the only necessary radiologic not be painful but occasionally bleeds. Exophytic
examination. CT can usually predict areas of bone growths are most common and can result in denture
invasion with a degree of accuracy (254). MRI has an malfunction in individuals who wear a maxillary
advantage in demonstrating malignancy in the bone prosthesis. Leukoplakia is detected in one-fourth of
marrow and perineural sheath. MRI can also aid in the patients in association with the tumor (301). The
delineating fluid from soft tissue when the paranasal average delay from onset of symptoms to diagnosis
sinuses are involved (254). Severe bone destruction has been as long as four to five months (299,302). The
may result in displacement of teeth and their isolation tumors are fairly well distributed between the two
producing ‘‘floating teeth’’ effect and may induce sides and the center of the palate (301). In reverse
pathologic fractures (288). smokers, however, the cancer usually develops as an
ulcer, lateral to the midline in the glandular zone of
the hard palate (297).
Treatment and Prognosis At the time of diagnosis, about half of the tumors
Surgery is the mainstay treatment of gingival carcinoma. are localized to the hard palate, 30% have invaded
Marginal mandibulectomy in appropriately selected adjacent structures, and 15% to 30% are associated
cases is as effective as segmental jaw resection with positive cervical lymph nodes, 5% of which are
(246,289–292), and maintenance of the mandibular con- bilateral (299,300,302). Close to one-half of the tumors
tinuity results in significant reduction in patient mor- are less than 4 cm in diameter. From the hard palate,
bidity and good long-term functional results (246,291). the cancer may spread to invade the underlying bone,
Segmental jaw resection is reserved for cases in which floors of the maxillary sinus and nasal cavity, gingiva,
bone destruction extends to the inferior alveolar canal and soft palate. Invasion through the bone and into
on imaging examination (Fig. 15). Hemimandibulec- the maxillary sinus or nasal cavity is usually a late
tomy is done in patients with unilateral involvement event. The submandibular and subdigastric lymph
of the entire inferior alveolar canal (252,290,293,294). nodes are the first to be involved with metastatic
Clinically positive cervical nodes N1 to N3 are carcinoma (301,303). Distant metastases are rare.
treated with modified or radical neck dissection. For
clinically N0 necks, a supraomohyoid neck dissection
is recommended (246,290). Postoperative radiothera-
py is used in patients with cervical metastasis as well
as in patients in whom tumor margins are inadequate
or who have advanced stage disease (i.e., stages III
and IV) (246,290,295). Chemotherapy has been used in
advanced cases (249,295).
Several factors play a determinant role in the
prognosis of gingival SCC. These include the size and
site of the tumor, presence or absence of bone involve-
ment and its extent, the adequacy of the surgical
margins, and presence or absence of metastasis
(241,245,269,291,296). Maxillary carcinomas have bet-
ter outcomes than mandibular ones with five-year
cures of 52% and 45%, respectively (22).
The main predictor of survival is considered to
be the stage of the tumor at the time of diagnosis
(246,253,256,280). Five-year survival rates decline Figure 19 Ulcerated, exophytic SCC of the hard palate in an
from 55% to 75%, for stages I and II patients, to 24% edentulous patient. Abbreviation: SCC, squamous cell carcinoma.
to 44% in more advanced cases (246,280).

Some clinicians prefer surgery over radiotherapy as
the prime therapeutic modality for SCC of the hard
palate (254,302). Others, however, have found irradia-
tion to be equally effective and without significant
complications (299,304). Kovalic and Sympson (305)
were able to achieve good 10-year local control and
disease-free survival rates when surgery was com-
bined with irradiation. The mean overall five-year
determinant survival has ranged from 31% to 59%
(300–302,306). For stages I to IV, the five-year survival
rate was found to be 75%, 46%, 36%, and 11%,
respectively (300), almost 80% of these patients who
fail therapy do so within 18 months after treatment.
Fifty-three percent of the treatment failure occurs in Figure 20 Ulcerated SCC of the RMT, involving the soft palate
the primary site, 30% in the neck alone, 10% at both and mandible. Abbreviations: SCC, squamous cell carcinoma;
primary site and neck, and 7% at distant sites along RMT, retromolar trigone.
with locoregional recurrence (300). Because of signifi-
cant prevalence of cervical metastasis from cancer of
the palate, it is recommended that selective elective
neck dissection should be offered to the patients (307).
absence of early symptoms. The prognosis tends to be
poor because of late stage at the time of presentation
VIII. SQUAMOUS CELL CARCINOMA OF THE (308–310). Advanced disease is symptomatic, com-
OROPHARYNX monly associated with pain and trismus. The symp-
toms may result from invasion of the branches of the
As previously indicated, the oropharynx encompasses mandibular nerve and muscles of mastication.
five anatomic areas: palatine tonsils, base of tongue, Referred otalgia is also common. At the time of
soft palate and uvula, oropharyngeal walls, and RMT. diagnosis, 27% to 60% are associated with clinically
Although the latter is technically a component of the positive lymph nodes, especially those of levels I and
oral cavity, carcinomas of this area often involve II (309–314). In one study of 31 patients with RMT
adjacent sites of the oropharynx and behave more carcinoma, occult metastasis was found in 64% of
like oropharyngeal tumors and thus will be discussed clinically N0 necks (308). Histologically documented
in this section. invasion of the underlying mandibular bone was
reported in 14% of the cases in one study and 50%
A. Squamous Cell Carcinoma of the RMT in another (310,314). MRI was found to be more
sensitive than CT scan in predicting infiltration of
The RMT is anatomically a part of the oral cavity the mandibular marrow by tumor. The respective
rather than the oropharynx. It consists of a roughly sensitivity was 100% and 50% (314,315).
triangular strip of mucosa that covers the ascending
ramus of the mandible immediately posterior to the Treatment and Prognosis
last molar tooth and ends at the apex of the tuberosity
of the maxilla (Figs. 1, 4). Laterally it merges with the The optimal management of carcinoma of the RMT is
buccal mucosa, and medially it blends with the ante- not yet clearly determined. While some studies advo-
rior tonsillar pillar, soft palate, and FOM. Anteriorly it cate surgical management, others recommend radio-
is in contact with the mandibular gingiva and posteri- therapy. However, it is generally agreed that small T1
orly relates to the muscles of mastication (pterygoid and T2 lesions can usually be treated effectively with
and masseter) and mandibular bone. radiation or surgery (316–320). Wide excision is neces-
Tumors involving the RMT may be extensions sary even in the absence of bone invasion. When bone
from subjacent sites such as the buccal mucosa, FOM, is involved, marginal or segmental mandibulectomy is
posterior tongue, soft palate, or tonsils. These tumors required. Adequate surgical margins improve surviv-
are described under their respective sites. Carcinomas al (309,316).
primarily of the RMT are relatively uncommon and Huang et al. (321) in their review of 65 patients
will be discussed here. The tumors have been linked showed a five-year disease-free survival of 31% with
etiologically to tobacco and alcohol abuse (308,309). radiation alone, compared with 90% and 63% with
surgery and pre- or postoperative radiation, respec-
Clinical Features
tively. These authors recommended combined sur-
gery and radiotherapy for all stages of disease. In
SCC of the RMT occurs primarily in men of 55 to 70 another study, the five-year overall survival was
years of age (309–311). Tumors in this region are 40% in patients managed with radiation alone and
characterized by early invasion of the buccal mucosa, 56% managed with surgery and radiotherapy (322).
soft palate, and mandible (309,310) (Fig. 20). They are Using multivariate analysis, they found that stage and
often diagnosed at an advanced stage owing to the treatment modality were significant predictors of
survival. Concurrent chemotherapy and radiation

therapy are occasionally used for advanced stages,
with some increase in survival rates (316). Distant
metastasis eventually occurs in 8% to 18% of the
patients (312,313). Lymph node status is reported to
significantly influence disease-free survival and dis-
tant metastasis rate (321).
B. Squamous Cell Carcinoma of the Soft Palate

and Uvula
The soft palate is an oropharyngeal structure. It is
contiguous with the tonsillar pillars inferiorly and the
hard palate anteriorly. It separates the nasopharynx
from the oral cavity and oropharynx. It approximates Figure 21 Early SCC of the soft palate presenting as erythro-
the posterior pharyngeal wall during swallowing, to plakia. Abbreviation: SCC, squamous cell carcinoma.
prevent nasopharyngeal regurgitation, and during
speech, to prevent nasal escape of air.
Clinical Features
The soft palate represents 5% to 12% of all oropharyn-
geal carcinomas (323,324). Although the soft palate is
not an uncommon site for malignant tumors of minor
salivary gland, SCC is the most common malignancy
(324). The majority of the lesions develop on the oral
surface. Epidemiologically, these tumors are associated
with tobacco and alcohol use. SCC of the soft palate
and uvula is two-to-three times more abundant in men
than women and in blacks more than whites and tends
to occur in older individuals with an average age of
about 60 years (323–329). Because of its abundant nerve
supply, most patients (60–80%) present within three
months of onset of symptoms and typically complain
of a persistent sore throat, pain on swallowing, or
referred otalgia (330,331). In a review of 188 cases of
SCC of the soft palate and uvula, Weber et al. (329) Figure 22 Ulcerated SCC of the soft palate extending into the
observed that 80% were unilateral and 20% were either mucobuccal fold. Abbreviation: SCC, squamous cell carcinoma.
midline or bilateral. The uvula was the site of the
primary in 2.7% of the cases (329). Approximately
30% to 35% of patients (range 23–50%) will have
positive cervical lymph nodes at diagnosis, and of
these, 3% to 13% may be bilateral, especially if the
lesion approaches or crosses the midline (326,327,
329–333). The subdigastric and midjugular lymph
nodes are most often involved.
As the tumor enlarges, it is not uncommon for it
to spread beyond the soft palate to involve other sites,
especially the tonsils, RMT, base of tongue, and pha-
ryngeal wall. The lesions may present as an exophytic
growth, an ulcer, a slightly elevated plaque, or as a
diffuse area of erythroplakia (Figs. 21–23).

The tumor can be treated either by irradiation, sur-
gery, or both. In general, early well-localized lesions
can be safely excised without causing significant func-
tional disability, whereas more diffuse or poorly
defined lesions are best treated with radiation.
Advanced tumors associated with regional lymphade- Figure 23 Exophytic SCC of the soft palate. Abbreviation: SCC,
nopathy generally require a combination of both squamous cell carcinoma.
modalities.
The five-year determinant survival ranges from Treatment and Prognosis

55% to 77% (325,327,329,330,332). Morse and Kerr
(334) found significant disparities in survival between Management of pharyngeal wall carcinomas varies
black males compared with white males. The differ- significantly by institution with some advocating pri-
ence in mortality rates for white and black females mary surgical resection, if possible, and others favor-
was small. ing combined surgery with pre- or postoperative
Local recurrence occurs in 25% to 37% of the irradiation in advanced lesions (340,347,348,353).
cases, and second primary malignant tumors are not Definitive irradiation alone for tumors of all stages
uncommon (24–42% of the cases) (325,326,328–332). has also been advocated (340,354–356). It has been
The incidence of distant metastasis during the course suggested that surgery with or without radiation
of the disease has varied from 0% to 22%. Most of does not produce improved results over radiation
these are to either bones or lungs. It has been pointed alone but is associated with higher morbidity (340,354).
out that despite combined modality therapy with The literature regarding use of chemotherapy is
surgery and radiation, the five-year survival for stages broad and inconclusive. However, in a study on a
III and IVa resectable tumors is poor (33–47%) group of patients receiving concurrent chemotherapy
(329,331,335–337). It has been recently shown that with irradiation (all of whom had stages T3 and T4
the reason for the poor outcome in those patients tumors), the patients appeared to fare better in overall
relates to occult metastatic disease in the paraphar- two-year local control rate than all patients with stages
yngeal space (324). The parapharyngeal space is out- T3 and T4 tumors (340). The prognosis of pharyngeal
side the surgical boundaries of a peroral resection and wall carcinoma is extremely poor, regardless of the
neck dissection. Furthermore, the risk of transverse method of treatment. The average overall five-year
myelitis limits the amount of adjuvant radiation that survival from several series of cases is 23% (range 3–
can be given to this area, in a standard opposing field 38%) (339,345–348,352,356). The incidence of second
anterior-posterior technique (324). primary malignancies in these patients is significant,
The use of neoadjuvant chemoradiation offers varying from 17% to 57% (339,347,348,352). Because of
another therapeutic regimen that may be of benefit in dismal survival rates, only 10% to 20% of the patients
advanced stage disease (338). Intensity-modulated live long enough to develop distant metastasis
radiation therapy (IMRT) may provide higher doses (347,349).
to and better control of the occult metastatic disease in
the parapharyngeal space without the risk of trans- D. Squamous Cell Carcinoma of the Palatine
verse myelitis (324). Tonsils and Base of Tongue
The palatine tonsils join the posterior third of the
C. Squamous Cell Carcinoma of the tongue inferiorly through their inferior poles and
Oropharyngeal Wall form the inferior and anterior component of the oro-
pharynx. The base of the tongue harbors the lingual
The posterior and lateral walls of the oro- and hypo- tonsils. Both of the palatine and lingual tonsils are
pharynx are anatomically and functionally one struc- components of the Waldeyer’s ring. Microscopically,
ture. Tumors in this location have similar risk factors, the tonsils show fissures or crypts, lined with non-
lymphatic drainage, clinical behavior, and prognosis keratinized stratified squamous epithelium, that
and are normally treated in the same manner (339–346). extend into the lymphoid tissue from the surface
squamous mucosa of the oropharynx. The lymphoid
Clinical Features tissues are composed of germinal centers and diffuse
Tumors of the oropharyngeal walls are relatively rare. lymphocytes and plasma cells. The latter typically
They are more common in males and affect patients involve the epithelial crypt walls (Fig. 24). The inter-
with a median age of 60 to 65 years (339,342,345–349). mingling of lymphoid cells with the epithelium may
Tumors at this site are usually quite large when first obscure cytologic features of early carcinomas that
seen. They tend to have a pattern of submucosal may occasionally not be recognized on biopsy exami-
spread and a known propensity for multiple foci of nation. The oropharyngeal tonsils are common sites of
origin in the regional mucosa (340). Sixty percent to a distinct clinicopathologic variant of SCC, the NKCa,
80% are T3 or T4 at diagnosis (345,350,351). A sore which is etiologically related to high-risk HPV. This
throat, dysphagia, and odynophagia are the most variant of SCC will be discussed in some detail below.
common symptoms. Approximately 40% to 60% of
Clinical Features
the patients will either have, or subsequently develop,
positive cervical lymph nodes which may be bilateral SCC of the tonsil and base of tongue is two-to-five
(339,345–349,352). The subdigastric, midjugular, and times more common in men and occurs primarily in
retro- and parapharyngeal lymph nodes are those the 50–70 year age range (52). However, patients with
most often involved. HPV-related carcinomas are generally younger than
Tumors of the oropharyngeal wall are especially those who harbor HPV-negative tumors. Significantly,
prone to spread submucosally and through lympho- tonsillar carcinomas in patients younger than 40 years
vascular spaces into the nasopharynx above and hypo- are overwhelmingly HPV related (52).
pharynx below. They often invade prevertebral fascia Although SCC of the tonsils and base of tongue
but rarely extend into the anterior spinal ligament. has been known to be closely linked to alcohol and
inability to protrude the tongue. Tonsillar carcinomas

tend to involve the base of tongue, soft palate, and
pharyngeal wall. Earlier lesions may present as eryth-
roplakia or as a slight mucosal granularity.
At the time of presentation, 50% to 80% of the
patients have clinically positive lymph nodes, 20% to
30% base of tongue carcinomas, and those of the
palatine tonsils that involve the tongue base either
have or will develop bilateral or contralateral nodal
metastasis at some time during the course of the
disease (362,368–379).

Surgery and radiation either alone, or in combination,
are used for treatment of base of tongue and tonsillar
carcinomas. Numerous papers have been published
on the validity of different treatment modalities.
Generally speaking, a combination of surgery and
radiation and, in selected cases, surgery and chemo-
Figure 24 Section in a palatine tonsil showing germinal center
radiation are used for advanced disease (T3 and T4),
and diffuse lymphocytic infiltrate involving the epithelial lining of a
crypt wall (100). while T1 and T2 tumors can be safely managed with
either surgery or radiation (380–391).
Key factors in surgical treatment of large base of
tobacco use, it has been more recently shown that tongue carcinoma are the proper management of
sexual transmission may play an important etiologic the larynx and OT. Partial or total laryngectomy
role in patients with HPV-positive carcinomas. The may be required in some cases (392). The decision to
latter patients are three times as likely to report having remove the larynx is based on whether it is involved
had oral sex as those with HPV-negative tumors and with the tumor (Fig. 25), the amount of tongue to be
were more likely to have had multiple sex partners resected, the status of the hypoglossal nerves, and the
(357). It has also been demonstrated that husbands of general condition of the patient, especially for respira-
women with cervical cancer had a significantly tory function and ability to tolerate aspiration while
increased risk of developing tonsillar carcinoma trying to relearn to swallow (393).
(358). At the same time, many patients with HPV-
positive carcinoma have little or no exposure to the
chemical carcinogens from tobacco and alcohol. HPV
is less frequently detected in cancer biopsies of
patients who are tobacco smokers or paan chewers
(9,10,13,57,171,357,359,360). In a recent, large case-
control study of oropharyngeal cancer, it was reported
that HPV carcinomas were identified in patients with
and without the established risk factors of tobacco and
alcohol use (51).
The most common presenting symptom is sore
throat. More advanced disease may be associated with
dysphagia, referred otalgia, bleeding, trismus, sensa-
tion of a foreign body in the throat, and ‘‘hot potato’’
voice in the case of base of tongue carcinomas (361–
363). It is not uncommon in cases of HPV-related
nonkeratinizing carcinoma that the patient present
with cervical lymphadenopathy in the absence of
clinically identifiable primary tumor (364,365).
Indeed, identification of HPV by in situ hybridization
(ISH) and p16 immunoreactivity in SCC metastases to
cervical lymph nodes was shown to be a reliable way
to establish origin from the tonsils or base of tongue
(366,367). HPV-related nonkeratinizing carcinomas
typically arise within the tonsillar crypts and may
show no mucosal abnormality or any detectable Figure 25 Gross specimen showing SCC of the base of tongue
enlargement. On the other hand, conventional KSCC involving the supraglottic larynx, treated by combined glossec-
presents, on examination, as an ulcer with rolled, firm tomy and laryngectomy. Abbreviation: SCC, squamous cell
margins with infiltrative growth that is palpable. Deep carcinoma.
infiltration into the base of tongue is manifested by
If less than half of the tongue base is excised, E. Pathology of Squamous Cell Carcinoma
supraglottic laryngectomy can be performed in other- Variants
wise healthy individuals without significant operative
problems. If, on the other hand, a large portion of The following variants of KSCC are discussed:
the base of the tongue needs to be removed, 1. NKCa and nonkeratinizing undifferentiated carci-
with sacrifice of both hypoglossal nerves, a total noma
laryngectomy is generally indicated to prevent severe 2. BSC
aspiration (393). 3. ASC
Total glossectomy may be required in some 4. Adenoid squamous carcinoma
patients to achieve an adequate resection margin 5. VC
(394). In a few highly selected patients, total glossec- 6. Papillary squamous carcinoma
tomy without total laryngectomy can be performed 7. Spindle cell (sarcomatoid) carcinoma
(395). For these reasons, some clinicians prefer primary
radiation therapy over surgery. Better survival and
functional outcome is reported after radiation therapy IX. NONKERATINIZING SQUAMOUS CELL
or chemoradiation in patients with advanced disease CARCINOMA
(384,386,391). Radiation alone was also shown to pro-
duce significantly improved posttreatment function NKCa is a distinct type of carcinoma, which is HPV
and quality of life compared with other modalities related. It differs from conventional KSCC, not only
(391). microscopically but also molecularly and clinically.
In a study from Memorial Sloan-Kettering The role of HPV infection, as a prerequisite for the
Cancer Center, it was found that most patients obtain development of a great majority of carcinomas of the
long-term regional control, with no severe complica- uterine cervix, is well established (408) and supported
tions, after definitive radiation therapy, of base-of- by molecular, serologic, and epidemiologic evidence.
tongue carcinoma, followed by neck dissection for Similar documentation has also been, more recently,
those patients who present with lymphadenopathy provided for a role for HPV, particularly type 16, in
(386). On the other hand, a study from M.D. Anderson the pathogenesis of a subgroup of SCCs of the head
Cancer Center found that patients whose neck disease and neck (361,409–411). Genomic DNA of high-risk
responded completely to radiation, using accelerated HPV is detected in approximately 26% of all SCCs of
fractionated dose, did not appear to need a planned the head and neck worldwide (412). Rigorous and
neck dissection (388). consistent molecular evidence have shown viral inte-
Postoperative adjuvant radiation therapy for gration and the expression of viral oncogenes (E6 and
patients with stages III or IV SCC of the tonsils who E7) in nonkeratinizing oropharyngeal carcinomas of
have undergone complete surgical resection is the the tonsils and base of tongue (52,54,410,411,413). The
treatment of choice for many clinicians (380,382,390). prevalence of HPV DNA, particularly type 16, in
The overall five-year survival rate for tonsillar and oropharyngeal carcinomas has varied in different
base of tongue carcinomas has ranged from 20% to studies from 18% to 90% (52,54–57,411). A variety of
54% (361,362,369,372,375,380,382,384,391,394–400). techniques are used to identify HPV in the tumors,
The five-year disease-specific survival rates are stage including ISH, polymerase chain reaction (PCR), and
dependent. Survival rates for stages I to IV in tonsillar immunohistochemistry. The virus is less frequently
carcinoma are 93%, 57%, 27%, and 17%, respectively identified in laryngeal and sinonasal carcinomas and
(362). The five-year survival rates for stages I to IV rarely in oral SCC (52–54).
base-of-tongue carcinoma are reported as 100%, 57%, In a review of 235 oropharyngeal carcinomas in
20%, and 0%, respectively (371). Fifteen percent of the all age groups by El-Mofty and Patil (54), 36% of
patients develop distant metastasis (401). The most tonsillar and 32% of base of tongue carcinomas were
frequent sites of dissemination, in order of frequency, HPV-related NKCa. Alternatively, 91% of tonsillar
are lung, liver, bones, and brain. carcinomas in young patients (younger than 40
The overwhelming cause of treatment failure years) were HPV type 16 positive (52). The average
and death is local recurrence. Distant metastasis age for patients with NKCa of the tonsil and base of
accounts for only a few cases. The five-year actuarial tongue was found to be 53.6 and 56.6 years, respec-
risk of distant metastasis in patients whose disease tively. On the other hand, patients with conventional
was controlled locoregionally was 21% in one study KSCC are slightly older with an average age of 56.6
(388) and 7.5% in another (389). and 58.0 years, for tonsillar and base of tongue,
Accumulating body of evidence in the United respectively. The male-to-female ratio for patients
States, as well as the international literature, confirms with HPV-related NKCa of the tonsils and base of
that HPV-related carcinomas of the tonsils and base of tongue is 4:1 (54). Numerous epidemiologic and case-
tongue have a statistically significant better prognosis control studies provide support for the association of
than HPV-negative carcinomas. The favorable out- high-risk sexual behavior with HPV-related oropha-
come is evident in disease-free and overall survival ryngeal cancer (51,357,414–420).
of the patients and is independent of TNM stage, Patients with HPV-positive tumors were three
nodal status, age, or gender (402–407). It is suggested times as likely to report having had oral sex as those
that the favorable prognosis is attributable to higher with HPV-negative tumors and were also more likely
sensitivity toward radiotherapy. to have had multiple sex partners (51,357). An analysis
of the Swedish Cancer Registry data (1958–1996)

showed that husbands of women with cervical cancer
had significantly increased risk of developing tonsillar
cancer (358). Exposure to HPV increases the associa-
tion with oropharyngeal cancer, regardless of tobacco
and alcohol use. HPV is less frequently detected in
cancer biopsies from patients who are tobacco smok-
ers or paan chewers (9,10,357). These observations
suggest two distinct pathways for the development
of oropharyngeal cancers of the tonsils and base of
tongue. In the case of the KSCC, the process is driven
predominantly by the carcinogenic effects of tobacco
or alcohol (or both). The other pathway, as in the case
of the NKCa, is by HPV-induced genomic instability.
A. Microscopic Features
HPV-related SCCs are characterized by nonkeratiniz-
ing basaloid morphology. The tumor cells are generally
monomorphic, oval, or spindle shaped, with hyper- Figure 27 NKCa. Oval and spindle shaped cells with hyper-
chromatic basophilic nuclei, inconspicuous cytoplasm, chromatic nuclei, inconspicuous cytoplasm and indistinct cell
and indistinct cell borders. They form cords, sheets, borders (200). Abbreviation: NKCa, nonkeratinizing squamous
and nests with sharply defined borders (Fig. 26). Pali- cell carcinoma.
sading of the peripheral cells may be present (Fig. 27).
Excessive mitoses and apoptosis as well as comedo-
type necrosis are commonly observed (Fig. 28). Kerati-
nization and keratin pearl formations are generally
absent, although some trend toward keratinocytic mat-
uration may occasionally be present focally in some
tumors (Fig. 29). In these hybrid lesions, the basaloid
epithelial cells at the center or the periphery of the
neoplastic cell sheets may show keratinocytic rather
than basal cell morphology (Figs. 29, 30). The meta-
plastic change is manifested by a more prominent
cytoplasm, distinct cell membrane, and intercellular
bridges.
HPV-related nonkeratinizing carcinomas typi-
cally start deep in the tonsillar crypts of both the
Figure 28 NKCa showing excessive mitoses and apoptosis

(400). Abbreviation: NKCa, nonkeratinizing squamous cell
carcinoma.
palatine and lingual tonsils. Because of such location,

the early lesions may be inaccessible to cytologic
smears and superficial biopsies (Fig. 31). It is not
uncommon that small primary tumors, which are
undetectable on routine clinical and radiographic
examination, are associated with significant cervical
lymph node metastasis. These occult primary carcino-
mas are typically missed on multiple blind endoscopic
Figure 26 NKCa of the oropharynx. Sheets of neoplastic cells biopsies of suspect sites. However, it has been found
with sharp outline and comedo-type necrosis (100). Abbrevia- that microscopic identification of HPV-related NKCa
tion: NKCa, nonkeratinizing squamous cell carcinoma. or the detection of HPV by ISH and/or p16 immu-
nostaining in metastatic cervical lymph nodes are
Figure 29 NKCa with focal areas of keratinocytic maturation Figure 31 NKCa arising deep in the wall of a tonsillar crypt
(400). Abbreviation: NKCa, nonkeratinizing squamous cell (200). Abbreviation: NKCa, nonkeratinizing squamous cell
carcinoma. carcinoma.
Figure 30 NKCa. Notice maturation of the peripheral cells Figure 32 Cystic changes in NKCa metastatic to a cervical
(200). Abbreviation: NKCa, nonkeratinizing squamous cell lymph node (100). Abbreviation: NKCa, nonkeratinizing squa-
carcinoma. mous cell carcinoma.
reliable techniques for establishment of the origin of characteristic cystic change. The lining epithelium of
an occult tonsillar carcinoma. These primary carcino- the cystic structures may be so scant and bland
mas are best identified in excisional biopsies of the appearing that a misdiagnosis of benign cyst may be
palatine or lingual tonsils (366,367,421). Identification rendered (Fig. 32). Such an error is more likely made
of the site of a clinically occult primary carcinoma is in patients whose primary tumors are occult.
crucial for the proper management of the patients. In
the absence of a known primary tumor, patients with B. Immunohistochemistry
cervical metastasis are likely to be overtreated with
wide-field irradiation that includes the entire pharyn- The immunohistochemical profile of nonkeratinizing
geal axis and larynx. Such treatment protocols are carcinoma differs from that of the conventional KSCC
associated with severe morbidity (422–424). Nonker- in several aspects. A major distinction is that non-
atinizing carcinoma metastasis to lymph nodes com- keratinizing carcinoma shows a diffuse and strong
monly exhibits extensive central necrosis leading to reactivity to p16 antibodies (Fig. 33), while KSCC is
Figure 33 NKCa showing strong and diffuse nuclear and cyto- Figure 35 Schematic representation of the proposed interac-
plasmic reactivity for p16 immunostain (200). Abbreviation: tion of HPV E6 and E7 oncoprotein with cell cycle regulators p53
NKCa, nonkeratinizing squamous cell carcinoma. and Rb.
prevents the dissociation of E2F transcription factor

from pRb and the subsequent progression of S-phase
of the cell cycle (87,429,430). The paradoxical over-
expression of an inhibitory protein in actively repli-
cating neoplastic cells is thought to result from
feedback control secondary to pRb deregulation by
HPV E7 oncoprotein (427,431) (Fig. 35).
The increased mitotic activity of nonkeratinizing
carcinoma as compared with KSCC is well illustrated
microscopically (Fig. 28) and is documented by higher
Ki-67 labeling scores (52,54) (Fig. 34). Ki-67 is a nuclear
protein that is overexpressed in actively proliferating
cells. A high Ki-67 score has also been used as a
surrogate biomarker for HPV-related carcinoma of
the uterine cervix (427,432,433).
The inverse correlation between NKCa and p53
has also been documented in HPV-related carcinomas
in several studies, immunohistochemically as well as
Figure 34 High staining scores for Ki67 in an NKCa (200). by molecular-sequencing techniques (52–54,431,434). It
Abbreviation: NKCa, nonkeratinizing squamous cell carcinoma. is well known that p53 mutations play a significant
role in development of the majority of conventional
KSCC in patients with known environmental risk
factors, such as tobacco and alcohol abuse (434–436).
either negative or weakly and focally positive (52,54). However, in the case of HPV-related carcinomas, p53
More over, an inverse staining pattern is observed inactivation is achieved by a different process. HPV-E6
with p53 reactivity. KSCC is much more likely to react oncoprotein interferes with p53 function by targeting it
positively and strongly to this antibody than non- for ubiquitination and degradation (87,437).
keratinizing carcinoma. Another distinction is
observed in immunostaining for Ki67. Nonkeratiniz-
ing carcinoma shows much higher staining scores, X. NONKERATINIZING UNDIFFERENTIATED
with that marker, than KSCC (Fig. 34) (52,54). CARCINOMA
Overexpression of p16 has been extensively docu-
mented in HPV-related carcinomas of the uterine cer- Nonkeratinizing undifferentiated carcinoma is a vari-
vix and anorectal tract (425–428) and more recently, as ant of NKCa. It is also known as lymphoepithelioma
stated above, in nonkeratinizing carcinoma of the oro- and nasopharyngeal-type lymphoepithelial carcinoma.
pharynx. p16 is considered as a surrogate biomarker Undifferentiated carcinoma is rare, accounting for
for HPV-related carcinomas. 0.8% to 2% of all oral/pharyngeal carcinomas. More
p16 gene product INK4A protein is a cell cycle than 90% of this type of carcinoma occurs in the tonsils
protein associated with the retinoblastoma pathway. It and base of tongue (438–441). The patients may present
Figure 36 Undifferentiated carcinoma of the palatine tonsil. Figure 37 BSC. Dysplastic surface epithelium at upper right
Notice morphologic similarities to nasopharyngeal undifferentiated corner (100). Abbreviation: BSC, basaloid squamous carcinoma.
carcinoma (lymphoepithelial carcinoma) (200).
with an oropharyngeal mass or a neck mass. Cervical

lymph node involvement occurs in approximately 70%
of the cases at presentation (439,441,442).
Microscopically, undifferentiated carcinoma of
the oropharynx shows morphologic features that are
indistinguishable from that of the nasopharyngeal
undifferentiated carcinoma (WHO type III). The
tumor is composed of syncytial sheets and clusters of
carcinoma cells with vesicular nuclei and prominent
nucleoli and ill-defined cell borders. A rich lympho-
cytic infiltrate surrounds the tumor cells (Fig. 36). ISH
for Epstein-Barr virus (EBV)-encoded RNA is usually
negative in Caucasians but may be positive in Chinese
patients (443,444). A relationship of undifferentiated
carcinoma of the oropharynx to HPV is suspected but
presently unconfirmed. The tumor cells are positive for
pan-cytokeratin and epithelial membrane antigen
(EMA) immunostains and are negative for leukocyte
common antigen (CD45). Figure 38 BSC. Closely opposed lobules and sheets forming a
Undifferentiated carcinoma of the oropharynx is jigsaw puzzle pattern (100). Abbreviation: BSC, basaloid squa-
radiosensitive. Local, regional, and distant failure mous carcinoma.
occurs in 3%, 5% and 19%, respectively. Distant
metastasis is associated with poor prognosis.
XI. BASALOID SQUAMOUS CARCINOMA a pavementing pattern. The basaloid component is

described as having the following principle histologic
The histologic features of BSC were first defined in features: (i) solid groups of cells in a lobular configu-
1986 by Wain et al. (445). The tumor is an aggressive ration that are closely opposed, producing a jigsaw
variant of conventional SCC. It is described as having puzzle appearance (Fig. 38), (ii) small crowded cells
biphasic morphologic features: a basaloid pattern, with scant cytoplasm, (iii) dark hyperchromatic nuclei
which is intimately associated with KSCC, dysplastic without nucleoli, (iv) small gland-like cystic spaces
surface epithelium (Fig. 37), carcinoma in situ, or with (Fig. 39), (v) small and large foci of coagulative necro-
focal areas of squamous differentiation. The squa- sis within the central areas of the tumor lobules, (vi)
mous differentiation is identified by the presence of stromal hyalinization and intercellular hyaline depos-
two or more of the following histologic features: (i) its (Figs. 40, 41).
individual cell keratinization, (ii) intercellular bridges, BSC occurs predominantly in the upper aerodi-
(iii) keratin pearl formation, and (iv) cells arranged in gestive tract. Seven of the 10 cases originally described
Figure 39 BSC with pseudoglandular appearance reminiscent Figure 41 BSC showing deposits of intercellular hyaline mate-
of ACC (200). Abbreviations: BSC, basaloid squamous carci- rial (400). Abbreviation: BSC, basaloid squamous carcinoma.
noma; ACC, adenoid cystic carcinoma.
(451–458). Most oral and sinonasal BSC are reported as

single cases, and in some of them, the microscopic
features did not conform strictly to the histologic
criteria necessary for diagnosis of BSC, as originally
defined by Wain et al. (445). It is clear from review of
the literature that well-documented cases of BSC have
a predilection for the pyriform sinus, supraglottic
larynx, and base of tongue (445–450,459).
BSC of the upper aerodigestive tract affects,
overwhelmingly, male patients with male-to-female
ratio ranging from 7:1 to 11:1 (445,447,448). The
patients tend to be elderly, with a mean age varying
from 58.5 to 64 (range 49–88) (445–447,459). A history
of heavy smoking and alcohol abuse is reported in the
majority of cases (446,447,458,460). A possible role for
radiation in the etiology of BSC was suggested in a
case in which the tumor developed in the nose of a
Chinese patient 12 years after radiotherapy for naso-
pharyngeal carcinoma (449).
Figure 40 Peripheral palisading of the neoplastic cells, stromal
hyalinization, excessive mitosis, and apoptosis in BSC (400). A. Treatment and Prognosis
Abbreviation: BSC, basaloid squamous carcinoma.
BSC is a highly malignant variant of SCC with a
propensity to aggressive local behavior and early
regional and distant metastasis with subsequent
arose from the pyriform sinus of the hypopharynx, poor survival (445–447,459,461,462).
and/or the epiglottis, and three from the base of Most patients are managed with radical surgery
tongue. In a review of 40 cases of BSC (446), 13 supplemented with radiation and/or chemotherapy.
occurred in the pyriform sinus, 12 base of tongue, 8 The great majority of the patients present with stages
larynx, 5 tonsils, and 2 nasal cavities. Luna et al. (447) III or IV disease (446,447,463). Cervical lymph node
in their report of nine cases of BSC found seven cases metastasis is reported in 60% to 78% of the patients at
in the pyriform and pharyngeal wall and two in the initial diagnosis (445–447,450,459). Distant metastasis
base of tongue. is observed in 38% to 48% of cases. Metastatic lesions
In another study of 12 cases of BSC, 10 arose in are found more commonly in the lungs but may affect
the pyriform sinus, epiglottis, and base of tongue the liver, bones, and central nervous system (445,446,
(448). BSC is less frequently reported in the sinonasal 459). At least half of the patients die of the disease
tract (449,450) and rarely in the oral cavity proper, one-to-four years after presentation (445,446,450,
including the palate, FOM, buccal mucosa, and gingiva 459,462–464). Evidence for prognostic significance of
tumor cell ploidy as measured by flow cytometry is C. Differential Diagnosis

contradictory. One study found that patients with
aneuploid BSC had a better mean survival time Before its definition as a variant of SCC, BSC was often
(39.5 months) than those with diploid carcinoma confused with the solid variant of adenoid cystic
(16.3 months) (447). Alternatively, tumor ploidy pro- carcinoma (ACC). Features such as the basaloid cyto-
vided no additional prognostic information in anoth- logic morphology, cystic, glandular-like spaces and
er investigation (459). Comparing the clinical intercellular hyaline deposits are analogous to those
outcome of BSC and poorly differentiated SCC, seen in ACC. However, a major histopathologic fea-
Winzenburg et al. (465) found that patients with ture of BSC is the presence of definable elements of
BSC had had more advanced disease at presentation, squamous cell differentiation, which may be in situ or
less than half the survival rate, and more frequent invasive carcinoma, and as focal areas with squamous
distant metastasis. Distant metastasis, in this study, features. ACC lacks that characteristic. In addition,
occurred in 52% of patients as compared with 13% of BSC tends to exhibit higher-grade nuclear morphology,
patients in the poorly differentiated SCC group. An with more pleomorphism, mitoses and apoptosis, than
increase in the incidence of second primary carcino- seen in cases of ACC (459). Although these histopatho-
mas in the upper aerodigestive tract has been indi- logic differences may be sufficient for correct diagno-
cated as well (460). sis, occasionally, especially in small biopsies, the
distinction may be difficult. In such cases, immunohis-
tochemical evaluation may be required.
B. Immunohistochemistry The myoepithelial elements in ACC typically
react positively to vimentin, muscle actins, and S-100
Most immunohistochemical studies show positive protein, in addition to cytokeratin. BSC, on the other
reactivity of the tumor cells to keratin markers, includ- hand, lacks myoepithelial components and is typically
ing high– and low–molecular weight cytokeratins negative for those markers (409,448,471). Vimentin
(pancytokeratins) AE1/AE3, CAM 5.2, and to high immunoreactivity may be present in some BSC. In
molecular weight cytokeratin 34bE12 (409,446,448, these cases, the pattern of staining is peculiar, forming
450,466). The staining may be diffuse in the squamous a delicate perinuclear rim with a small dot (474).
and basaloid components of the carcinoma or may be Coletta et al. (454) reported positive staining with
more intense in the squamous or the basaloid areas laminin and type IV collagen, in the microcystic
(446,448,450). However, the staining pattern is never spaces of BSC, which was not found in ACC. In a
punctate paranuclear (409,446). EMA is reported to be more recent study, p63 immunostaining was used to
positive in most cases, but may vary in intensity and distinguish ACC from BSC (475). BSC consistently
focality (446). Strong and diffuse p63 immunoreactivi- displayed diffuse p63 positivity with staining of
ty was reported in 100% of the tumor cells (475). nearly 100% of tumor cells. On the other hand, ACC
Although neuron specific enolase (NSE) is reported showed either selective staining of single peripheral
to be reactive in up to 75% of cases of BSC in some layer or focal compartmentalization pattern of stain-
studies (446,448,450), others found it to be negative in ing. Distinction of BSC from ACC has important
all cases (466). Focal reactivity for S-100 protein is clinical and prognostic implications. Treatment of
reported by some investigators, in some of the cases BSC is usually surgery with neck node dissection in
(456,467). Others found no reactivity in the tumor cells addition to radiotherapy and, in advanced cases,
(467,468) or was limited only to the Langerhan’s cells chemotherapy. ACC is usually treated with only exci-
in the tumors (448). Other markers such as chromog- sion of the primary tumor.
ranin, synaptophysin, GFAP, LCA, HMB-45, and des- BSC may present many similarities to small cell
min are negative (446,450,466,469). Vimentin and neuroendocrine carcinomas, particularly in small
actins may either be negative or infrequently positive biopsies. Small cell neuroendocrine carcinoma uni-
(409,448,470). Cell cycle regulator biomarkers in BSC formly react to pancytokeratin antibodies AE1/AE3
were evaluated in several studies. High labeling and CAM 5.2 frequently (60–80%) in a paranuclear
scores for p53 and Ki67 were reported in the majority pattern, while BSC does not show such staining pat-
of cases studied (463,471–473). Low expression of p27, tern (409). The high molecular weight cytokeratin
a cyclin dependent kinase inhibitor, correlated inde- 34bE12 is positive in BSC but not in neuroendocrine
pendently with poor prognosis. Brisk labeling for carcinoma (409,471). Although some BSC show posi-
Ki67, p53, and low expression of E-cadherin also tive reactivity to NSE, none are reactive to other
corresponded to poor prognosis (463). More aggres- neuroendorine markers such as synaptophysin and
sive behavior, as compared with conventional SCC, chromogranin. Alternatively, as expected, neuroendo-
was found to be associated with overexpression of crine carcinomas show positive reactivity to all of the
matrix metalloproteins MMP-1 MMP-2, and MMP-9, neuroendocrine markers (409,469,471,474,476).
in addition to higher staining scores for p53 (472). HPV-related nonkeratinizing carcinoma shares
Using PCR, Cabanillas et al. (471) found no with BSC a basal cell morphology and the base of
evidence of HPV in nine cases of BSC. Similarly, ISH tongue as a common anatomic location. For these
for HPV failed to demonstrate the virus in another reasons, cases of nonkeratinizing carcinomas are oc-
nine cases of BSC (466). Other ISH studies also did not casionally misdiagnosed as BSC. Distinction between
show EBV RNA to be present in any of the 23 cases of these two variants of SCCs is of utmost importance for
BSC (409). proper management and accurate prognosis. When
compared with NKCa, BSC is rare, more biologically

aggressive, less responsive to radiation therapy, and
has a much worse prognosis.
Microscopically, NKCa shows basaloid mor-
phology, but unlike BSC, NKCa never shows the
microcystic glandular patterns seen in BSC, and it is
not associated with conventional SCC or areas or
frank keratinization. However, NKCa, as mentioned
above, may show areas of maturation, producing a
pattern that may be compared with BSC. NKCa is
consistently associated with high-risk HPV infection.
HPV DNA is invariable demonstrated in these tumors
by PCR, ISH, and other molecular techniques. So far,
HPV has not been documented in BSC (461,466,471),
using either PCR (471) or ISH (461,471) techniques.
XII. ADENOSQUAMOUS CARCINOMA

The term adenosquamous carcinoma (ASC) was pro-
posed by Gerughty et al. (477) to describe a biphasic Figure 43 ASC, higher magnification of the adenocarcinoma
neoplasm composed of two components, adenocarci- component (200).
noma and SCC (Figs. 42–44). The SCC can be in situ or
invasive, ranging from well-to-poorly differentiated.
Squamous differentiation is defined by pavemented
growth with intercellular bridges, keratin pearl forma-
tion, dyskeratosis, and/or individual cell keratiniza-
tion. The adenocarcinoma component can be tubular,
alveolar, or glandular. Mucous cells may be present
but are not a prerequisite for diagnosis. The two
carcinomas may be separate or intermixed, with
areas of commingling and/or transition of the squa-
mous carcinoma to adenocarcinoma (477–482). The
relative abundance of the two carcinomas varies in
different tumors, the squamous carcinoma may domi-
nate in some while, less frequently, adenocarcinoma
dominates. Equal distribution of the two components
may be observed in some cases (479).
Figure 42 Adenosquamous carcinoma of the soft palate. Sur- Figure 44 (A) ASC, notice areas of comingling of squamous
face poorly differentiated SCC with deeper adenocarcinoma carcinoma and adenocarcinoma. (B) ASC, mucicarmine stain
(20). Abbreviation: SCC, squamous cell carcinoma. (200). Abbreviation: ASC, adenosquamous carcinoma.
ASC develops from surface as well as glandular Mucoepidermoid carcinoma, unlike ASC, only
epithelium. In addition to the upper aerodigestive arises from glandular and not surface epithelium.
tract, ASC has been reported in the skin, lung, stom- Both mucoepidermoid carcinoma and ASC manifest
ach, ileum, colon, gallbladder, endometrium, liver, epidermoid and glandular features. However, sepa-
pancreas, kidney, thyroid, and prostate among other rate and definitive areas of squamous carcinoma and
sites (467,470,478,483–489). In the upper aerodigestive adenocarcinoma are not seen in mucoepidermoid
tract, the larynx is the most frequently reported site carcinoma. Keratin pearl formation and individual
followed by, in order of frequency, FOM, tongue, cell keratinization are extremely rare in mucoepider-
tonsil, nasal cavity, and alveolar mucosa, less com- moid carcinoma, as compared with ASC, and surface
monly the buccal mucosa, lip, palate, and nasophar- carcinomatous changes are never seen. Although
ynx (479). In a review of oral cases examined at the mucicarmine-positive cells may be found in ASC,
Armed Forces Institute of Pathology (AFIP), the they are not requisite for diagnosis as in the case of
tongue, FOM, tonsil, and soft palate accounted for mucoepidermoid carcinoma. Moreover, the distinct
85% of the cases. The buccal mucosa, RMT, and lip are aggregates and cyst-lining rows of mucous cells, typi-
the other sites of occurrence (490). In a review of 58 cal of mucoepidermoid carcinoma, are not present in
cases of ASC of the upper aerodigestive tract reported ASC (490).
in the English literature, Keelawat et al. (479) found
that the patients’ age range was 34–81 years, with a
median age of 61.5 years. The male patients outnum- XIII. ADENOID SQUAMOUS CARCINOMA
bered females by a ratio of 4.3:1. A history of smoking,
smokeless tobacco use, and alcohol was common in This variant of SCC is also known as pseudoglandular
the majority of cases (479). A history of radiation has SCC and acantholytic SCC. It occurs most commonly
also been suggested as a risk factor in a case that on the sun-exposed skin of the head and neck region.
involved the mandibular alveolar mucosa (481). It has been shown to develop in areas of actinic
Symptoms vary according to site and range from 1.5 keratosis (493,494). Several cases have been reported
to 12 months in duration. Patients with FOM and in the vermilion border of the lip, most commonly the
tongue tumors typically complain of mouth ulcers, lower lip (495–499). Of 22 cases of adenoid squamous
pain, indurations, ill-fitting dentures, and a painless carcinoma of the lip published in the English litera-
mass. Patients with tonsillar tumors may complain of ture, only three were in the upper lip and the rest
odynophagia, otalgia, and weight loss (479,486). developed in the lower lip (495–499). The lesions
In spite of relatively few number of cases of oral affected predominantly males, with a 4.5:1 male-to-
and oropharyngeal ASC reported with adequate female ratio. The mean age of the patients was 55.3
follow-up, there is general agreement that this variant years (range 41–75 years).
of SCC is extremely aggressive and treatment resistant Clinically, the lesions have been variously
(477,479–481,486,491,492). Most patients present with described as keratotic or hyperkeratotic (499), ulcerat-
advanced-stage disease, early nodal metastasis, later ed (500), exophytic (498), and ‘‘warty and irritated’’
distant metastasis, and generally fatal outcome. Sites (501). Pain was reported at presentation in some cases.
of distant metastasis include lungs, liver, bone, brain, The lesion size varies from 0.2 to 2.0 cm with an
and kidney. Radical surgery with neck dissection is average of 1.0 cm. The prominent position of the
the treatment of choice. Adjuvant radiation and/or lesions favors early detection and treatment (495).
chemotherapy, with few exceptions, do not appear to Microscopically, the superficial portion of the
offer any therapeutic advantages (477,479,491). tumor resembles a typical SCC. However, the deeper
extensions demonstrate gland-like structures lined by
a single or double layer of cuboidal epithelial cells that
A. Immunohistochemistry exhibit nuclear pleomorphism, hyperchromaticity,
and mitotic activity. Scattered acontholytic, dyskera-
Few studies have investigated the immunohistochem- totic cells are evident in these foci (Fig. 45). The
ical profile of oral/pharyngeal ASC (478,480,491). The fibrous connective tissue stroma may reveal solar
tumors show differences in staining patterns between elastosis in addition to an inflammatory cell infiltrate.
the squamous carcinoma and adenocarcinoma ele- Solar keratosis with acantholysis may be evident in
ments in the tumors. The former react positively to the adjacent stratified squamous epithelium.
high molecular weight cytokeratin and negative for Mucicarmine stains are negative for mucin
low molecular weight cytokeratin and carcinoem- (495,501). Cases that were evaluated immunohistoclin-
bryonic antigen, whereas the reverse is true of the cally showed strong positive reactivity to high molec-
glandular components. ular weight cytokeratins but were not reactive to S-100
protein, factor VIII-related antigen and vimentin
B. Differential Diagnosis (495,501).
The preferred treatment of the lip lesions is local
Two main entities are considered in the differential excision. Lymph node metastasis is rare, (495) and so
diagnosis for ASC: mucoepidermoid carcinoma and is death related to disease (501). The excellent progno-
adenoid squamous carcinoma. The later will be dis- sis may be due to early detection.
cussed in more detail below, in the section on adenoid Although quite uncommon, a few cases of
SCC. intraoral adenoid squamous carcinomas have been
Although VC is primarily a disease of men, between
50 and 80 years of age, it has been described in
individuals as young as 34 years (504,506,516,517).
There are also some variations in gender according
to geographic location. In the southern United States,
where the use of snuff is prevalent among women,
there is a relative increase of VC in female patients
(516). A higher prevalence of VC in women is also
observed in patients with proliferative verrucous leu-
koplakia (PVL) (524,525). PVL is a clinicopathologic
entity that was originally described by Hansen et al.
(524). It is a continuum of hyperkeratotic disease with
high prevalence among elderly women. The condition
is detailed in another section of this text.
The majority of oral VC occurs either on the
buccal mucosa or the gingiva. Other sites affected, in
descending order of frequency, are the labial mucosa,
palate, RMT, or anterior tonsillar pillars (505,526). In
Figure 45 Adenoid squamous carcinoma of the lip showing
acantholysis (200).
most patients, the lesion presents as a slow growing,
exophytic, warty mass (Figs. 46, 47) that may be tender
or painful. Bleeding is uncommon.
reported. These involved the tongue, maxillary gingiva,

and FOM (501–503). These tumors tended to be more
aggressive than those occurring in the lip. As previously
mentioned, adenoid squamous carcinoma must be dif-
ferentiated from ASC. Adenoid squamous carcinomas
exhibit pseudoglandular spaces that are caused by
acantholysis of the tumor cells. No sialomucin is pro-
duced and dyskeratotic and acantholytic cells can be
found within many of the pseudoluminal spaces. These
features contrast with positive mucicarmine staining
and the true lumina of the adenocarcinomatous portion
of ASC.
XIV. VERRUCOUS CARCINOMA

VC was first defined as a distinct clinicopathologic Figure 46 VC of the buccal mucosa involving the alveolar ridge
entity by Lauren Ackerman in 1948 (504). The tumor is and tongue. Abbreviation: VC, verrucous carcinoma.
described as a locally aggressive, nonmetastasizing
variant of well-differentiated SCC. It is characterized
by an exophytic, warty, slowly growing neoplasm
with pushing margins. VC is still referred to, by
some pathologists, as Ackerman’s tumor. The oral
cavity is the most frequent site of occurrence for VC,
accounting for about 75% of all cases (505–507). The
larynx is the second most common site constituting
10% to 15% of the cases (506,508). VC has been
diagnosed in numerous other anatomic locations
within the head and neck, besides the oral cavity
and larynx. These include the nasal cavity, maxillary
sinus, pyriform sinus, esophagus, middle ear, and
skin (482,506,509–515).
In the oral cavity, VC represents 2% to 8% of all
SCCs (505,516–518). It is known to be associated with
tobacco habits such as snuff, chewing tobacco, and
betel nut use (506,516). However, not all cases of VC of
the oral cavity are related to tobacco use. HPV types 6, Figure 47 VC of the palate involving the edentulous maxillary
alveolar ridge. Abbreviation: VC, verrucous carcinoma.
11, 16, and 18 have been identified in some but not all
VCs (506,519–523).
B. Pathology
Grossly the tumor is exophytic, broadly based, gray-
white, soft or firm. The lesions size varies from 1 to 10
cm. Microscopically, it is composed of multiple filiform
projections, which are thickened and lined with normal-
appearing stratified squamous epithelium without any
evidence of atypia, dysplasia, or other malignant fea-
tures. The cells are arranged in an orderly maturation
pattern towards the surface, which typically shows
abundant keratinization, commonly in the form of para-
keratin. Orthokeratin with sparse keratohyalin granules
may be present. Parakeratin crypting and plugging may
be seen. The advancing front of the tumor is broad and
pushing with bulbous rete ridges, which extend deeper
than the level of the subjacent normal mucosa but with
no evidence of invasion. An intense inflammatory cell
infiltrate often precedes the advancing front of the
tumor (Fig. 48).
Figure 49 Conventional invasive SCC arising in VC (200).
Abbreviation: VC, verrucous carcinoma; SCC, squamous cell
carcinoma.
VC differs from conventional SCC not only mor-

phologically, but also molecularly and cytokinetically.
Using immunohistochemical techniques, Wu et al.
(527) have shown that oral VC showed lower levels
of expression of p53 and EGFR than conventional
SCC. The difference was statistically significant. A
similar relationship was also noted for TGF-a and
cyclin D1; however, it was not statistically significant.
In another study, it was shown that expression of
cyclin D1 was significant when poorly differentiated
SCC was compared with oral VC (528). In VC, cells in
S phase of the cell cycle are limited to the basal layer
or within three cell layers of the basement membrane.
This is in distinct contrast to conventional SCC in
which S-phase cells are present in all layers of the
epithelium (529). Ogawa et al. (530) reported positive
reactivity for the cell-to-cell adhesion molecule
CD44v9 in 8 of 10 cases of VC but in only 2 of 10
metastasizing SCCs examined. However, VC can be a
precursor to conventional invasive SCC. Medina et al.
have called attention to the existence of VCs that
contain foci of conventional SCC, which are termed
hybrid tumors (531). In their review of 104 cases of VC
of the oral cavity, 20 (19.2%) were considered hybrid
tumors. This study underscores the need for thorough
microscopic sampling of VC for foci of invasive SCC
(Fig. 49). Such a discovery implies that the tumor has
acquired the ability to metastasize and should be
expected to behave as a conventional SCC.
Figure 48 (A) VC advancing below the surface mucosa and
showing keratin plugging (20). (B) Bland squamous epithelium Two lesions that bear some morphologic similarities
showing normal maturation. Intense chronic inflammatory cell to VC are considered here:VH (papillary keratosis)
infiltrate is present surrounding stroma (100). Abbreviation: VC, and papillary squamous carcinoma. The latter is dis-
verrucous carcinoma. cussed separately below as a variant of conventional
SCC.
frequent single modality, accounting for 77.8% of the

oral cases. The most likely sites to be treated with
radiation alone were the oropharynx, larynx, and
hypopharynx. The two sites most often receiving
combined surgery and radiation therapy were the
RMT (20.8%) and oropharynx (20%). Stage was also
a factor in determining the type of the treatment
modality used. Early-stage oral cavity disease was
treated by surgery alone in most cases (85.8%). How-
ever, patients with advanced disease were less likely
to be treated with surgery alone (56.9%). It is of
interest that across the years of this study, surgery
as a single modality increased from 66.4% in 1985 to
73.7% in 1996.
The common use of surgery as the dominant
treatment may reflect concern that irradiation of VC is
not only less effective but also more likely to result in
anaplastic dedifferentiation resulting in recurrence
and more aggressive cancer (531). Resistance to
radiotherapy and possible progression to invasive
Figure 50 VH. The rete pegs do not extend below the level of carcinoma was also suggested in review of 148 previ-
adjacent mucosa (100). Abbreviation: VH, verrucous hyperplasia. ously published cases (537). It is noteworthy, howev-
er, that more recent work argues against irradiation-
induced anaplastic transformation as a viable concern
(538,539). Controversy persists regarding the efficacy
of irradiation in managing VC. The NCDB identifies
The term ‘‘verrucous hyperplasia’’ was coined worse outcome among the cases treated with irradia-
by Shear and Pindborg in 1980 to describe an oral tion. Markedly better results favor the initial manage-
mucosal lesion that resembles VC, both clinically and ment of oral cavity tumors surgically, with 85.7% five-
microscopically (532). Microscopically, both VC and year survival, as compared with that of irradiation
VH exhibit exophytic papillary projections that may (41.8%) (526). These rates should be interpreted with
be hyperkeratinized. The main distinction between the understanding that management with irradiation
the two lesions is that in VH the rete pegs are alone is often chosen for patients with extensive
superficial to, or at least at the same level as, the cancers, considered ‘‘incurable,’’ and for patients
adjacent mucosa (Fig. 50), whereas in VC they extend with extensive morbidity precluding surgery.
deeper into the underlying stroma (532–534). The contemporary NCDB report represents the
Whether VH is a distinct lesion, an early VC, or a patterns of care for VC of the head and neck in the
progenitor of conventional invasive SCC, is controver- United States. Surgical excision alone is the most
sial (505,525,533,535). VH is not uncommonly found in common treatment of VC. Improved outcomes were
association with VC and/or conventional SCC not shown with the addition of radiation therapy to
(525,532–534,536). The simultaneous or metachronous surgery. Initial management with irradiation alone
existence of these three lesions in the same patient is resulted in notable worse survival compared with
notably encountered in patients with PVL. surgical treatment, for both laryngeal and oral cavity
Wu et al. have demonstrated that the level of VC. Despite these findings, a definitive statement
expression of p53 and EGFR in VH is analogous to cannot be made regarding treatment efficacy because
that of VC and is significantly lower than that of of the possibility that unknown selection bias may
invasive SCC (527). Poh et al. found that the pattern account for the differences observed (526).
of allelic loss (LOH) in VH is similar to that of VC and The more rigorous current pathologic practice to
differed from conventional SCC (536). exclude hybrid and other variants will likely result in
the reporting of improved survival rates for VC.
XV. PAPILLARY SQUAMOUS CARCINOMA
As discussed above, VC exists within a histologic
continuum from premalignant VH to invasive SCC. To our knowledge, one of the earliest reports on
Distinguishing VC from VH and from lesions with a papillary SCC (PSCC) in the upper aerodigestive
dominant VC component, which also contain small tract was published in the first series of the AFIP
foci of squamous carcinoma (hybrid tumors) may be Atlas of Tumor Pathology, in 1968 (540). Reviewing
difficult, but is essential for the proper assessment of 39 patients with tonsillar carcinoma who were treated
treatment modalities and prediction of outcomes. at the Mayo Clinic from 1941 to 1950, Parkhill identi-
In a review of the NCDB, Koch et al. (526) found fied seven patients who had what was described as
2350 cases of VC of the head and neck diagnosed nonkeratinizing PSCC (540). Microscopically, the
between 1985 and 1996. Sixty percent of these were tumors were composed of exophytic, filiform, finger-
located in the oral cavity. Surgery alone was the most like papillary projections supported with slender
clinicopathologic variant of squamous cell carcinoma

has, so far, not been established.
Confusion about the true identity of PSCC arose
in the subsequent literature, after its initial description,
which resulted from including other exophytic entities
of SCC with true papillary squamous carcinoma. In the
second edition of the World Health Organization
(WHO) Histological Typing of Tumors of the Upper
Respiratory Tract and Ear, published in 1991, PSCC
was not classified separately and the term PSCC was
applied to ‘‘invasive SCC, which have an exophytic
papillary component’’ (541).
In a review of exophytic squamous neoplasms of
the head and neck, Ishiyama et al. (542) described two
morphologic variants, which exhibited different archi-
tectural growth patterns: (i) an inverting verrucous
pattern characterized by prominent keratinization and
(ii) an exophytic papillary pattern with little or no
keratinization. Verrucous inverting lesions lacking
cellular dysplasia were classified separately as VCs
and were excluded. Those with cytologic atypia
were categorized as papillary squamous neoplasms.
These included both of the aforementioned groups:
the keratinizing inverting (31 cases) and the exophytic
nonkeratinizing papillary (21 cases). The latter is
histologically identical to papillary squamous carcino-
ma, as initially described in the first series of the AFIP
Atlas (540). In this study, the most common site for
these papillary squamous neoplasms was the oral
cavity, particularly the alveolar ridge and buccal
mucosa. No distinctions were made on the site speci-
ficity of each of the two types.
Thompson et al. (543) reviewed 104 cases of
exophytic SCCs and PSCC of the larynx, identified
in the AFIP files from 1971 to 1991. Similar to Ishiya-
ma’s study mentioned above (542), the tumors were
divided according to their growth pattern into broad-
based exophytic (92 cases) and papillary-frond (12
cases). The latter consisted of thin, delicate filiform,
finger-like papillary projections; the exophytic pattern
showed broad-based bulbous projections. All lesions,
irrespective of type, demonstrated atypical cytologic
features such as nuclear enlargement, loss of cellular
polarity, increased nuclear-cytoplasmic ratio and
increased mitosis. With an average follow-up of 8.6
Figure 51 (A) Papillary squamous carcinoma of the tonsils years for 87 patients, they reported that 17 patients
showing slim exophytic filiform finger-like projection (20).(B) with an exophytic pattern died of disease, while none
Higher magnification showing thin papillary projection supported of the patients with the papillary pattern did. They
with delicate fibrovascular cores and covered with surface epi- concluded that patients with PSCC and exophytic
thelium exhibiting top-to-bottom dysplasia (100). SCCs of the larynx have better prognosis than those
with conventional SCC and that the prognosis of those
with true PSCCs is even better.
In the most recent WHO classification of tumors
fibrovascular cores (Fig. 51). The surface epithelial of the head and neck, PSCC of the larynx was defined
cells had dark staining nuclei and scant cytoplasm as a variant characterized by a predominant papillary
and lacked keratinization. The tumors were described growth pattern, the papillae are covered by neoplastic,
as resembling transitional cell carcinoma of the immature basaloid cells and supported with thin fibro-
urogenital tract. The lesions showed small-to-large vascular cores. Keratinization is sparse or absent (444).
proportion of carcinoma in situ. Patients with non- The lack of familiarity with the clinicopathologic
keratinizing papillary squamous carcinoma had much features of PSCC of the oral cavity and oropharynx
better five-year survival rate (71%) as compared with may be due to the low incidence of these tumors.
those with the keratinizing-type carcinomas (30%) More importantly, however, is the imprecision of
(540). However, recognition of PSCC as a distinct diagnosis and definition of this type of carcinoma.
modalities and to predict prognosis. As alluded to

above, PSCC can be predominantly in situ. Lymph
nodes are characteristically negative. However, a case
of PSCC of the base of tongue was reported in a
patient, initially presenting with a large cervical
lymph node metastasis (549). From the limited number
of cases with follow-up information, it seems possible
to conclude that PSCC may have a better prognosis
than conventional SCC but a worse outcome than VC.
In a study on cellular proliferation activity in
PSCC, VC and conventional SCC, Takeda et al. found
that PSCC had considerably higher Ki67-labeling
scores than VC. However, there was no significant
difference in Ki67 expression among PSCC and con-
ventional SCC (550).
B. Differential Diagnosis
Morphologic differences between PSCC, VC, hybrid
Figure 52 Atypical VH. Notice the dysplastic changes (200). verrucous-SCC and atypical VH are detailed in the
Abbreviation: VH, verrucous hyperplasia. above discussion. Another lesion that must be distin-
guished from PSCC is nonkeratinizing squamous
papilloma. The latter lacks the full thickness of epithe-
Currently, reports dealing with PSCC exclude the lial dysplasia that characterizes PSCC.
other exophytic carcinoma (544), which is broad-based
with bulbous club-shaped ridges and excessive kerati-
nization and dysplastic cytologic features. Such an XVI. SPINDLE CELL (SARCOMATOID)
entity should be classified as either atypical VH, in CARCINOMA
the absence of invasion (Fig. 52), or SCC with verrucous
SpCC (1) is a variant of SCC characterized by spindled
features, if invasive elements are identified (Fig. 49).
or pleomorphic tumor cells, which simulate a true
The term papillary squamous carcinoma should
sarcoma. This tumor is one of the most unusual and
be reserved for those lesions with slender, finger-like
interesting lesions of the head and neck. Numerous
exophytic papillae containing delicate fibrovascular
alternate terms, several of which are preferred at other
cores. The surface epithelium shows full-thickness
specific body sites, have been used, including meta-
dysplasia. The epithelial cells have basaloid appear-
plastic carcinoma (2), anaplastic carcinoma (3), pleo-
ance and frequent mitoses. Surface keratinization is
morphic carcinoma (4), carcinosarcoma, and
characteristically sparse or absent (Fig. 51). Despite
pseudosarcoma, among others (5,6). These tumors
their large size, many of the tumors remain in situ or
have been described everywhere carcinomas arise,
only show superficial invasion of the lamina propria.
but are most common in the head and neck region,
In the absence of invasion, the tumor should be
lung, and urinary bladder. Many different theories for
termed PSCC in situ (545).
their pathogenesis have been put forward in the past,
A putative role for HPV in the etiology of PSCC
including divergent differentiation of carcinoma cells,
of oral and oropharyngeal cavity is unclear. Suarez et
so-called collision tumors where there are two sepa-
al. (546) using PCR techniques identified HPV in 5 of
rate neoplastic clones combined in the same lesion (5),
14 cases of PSCC of the upper aerodigestive tract.
or that the carcinoma ‘‘drives’’ a non-neoplastic (6)
HPV type 16 or 18 in three cases and types 6 of 11 in
stromal component to proliferate in the same lesion.
two. The exact site of the carcinomas was not identi-
Over time, from ultrastructural (7–10), immunohisto-
fied. The tumors were morphologically consistent
chemical (11–16), and genetic investigations (17,18), it
with the PSCC as described above. More recently,
has become abundantly clear that the first theory is
HPV type 16 was identified in PSCC of the tonsil in
correct, namely, that the sarcomatoid tumor repre-
a renal transplant recipient (547). Crissman et al. (548)
sents a line of differentiation or ‘‘dedifferentiation’’
showed that PSCC is unrelated to recurrent respirato-
of the carcinoma. Furthermore, there is ample evi-
ry papillomatosis. After a long period of follow up,
dence that squamous carcinoma cells can exhibit
none of the patients with recurrent papillomatosis
mesenchymal transformation (19,20). As such, SpCC
developed PSCC, and none of the patients with papil-
is regarded as a histologic variant of SCC. The tumor
lary squamous carcinoma had previous history of
is fundamentally a carcinoma, but is composed, in
recurrent respiratory papillomatosis.
large part or completely, of spindled or pleomorphic
A. Treatment and Prognosis cells, which simulate a sarcoma or other spindle cell
neoplasm. Most SpCCs are biphasic tumors, consist-
Because of a lack of studies on large series of PSCC of ing of the spindle cell component and also a typical
the oral cavity and oropharynx, it is not possible to squamous carcinoma component or at least focal
evaluate the effectiveness of various therapeutic carcinoma in situ. However, a significant number
are composed only of spindled or pleomorphic tumor

cells, making them very difficult to recognize as
carcinoma.
SpCC has similar demographics to conventional SCC.
It is strongly associated with smoking and drinking
and, for cases in the oral cavity and oropharynx, has a
2 to 3:1 male-to-female ratio (15,16,21,22). In other
head and neck sites, this ratio is skewed much more
toward males (10,11,13,22). In most series, it occurs
most commonly in the larynx, particularly in the
glottis (11), followed by the oral cavity, hypopharynx,
and nasal cavity (16,22). Some series, however, have
found a higher percentage of cases in the oral cavity
and, in particular, in the oropharynx (15). The typical
age range is from 55 to 65 years (21,22). A significant
minority of patients have a history of previous radia- Figure 54 Ulcerated (U) SpCC consisting of a sheet of spindled
tion to the originating site. Combining four major tumor cells with abundant mixed associated inflammatory cells
clinicopathologic studies, 17% of the 300 cases of (40). Abbreviation: SpCC, spindle cell carcinoma.
SpCC occurred in a previously irradiated field at an
average of seven years and as late as 16 years later
(11,14,21,22). This is a much higher rate than for
conventional SCC. Oral cavity tumors usually arise
in the lip, alveolar ridge, and tongue and present with
swelling, pain, a nonhealing ulcer, dysphagia, or
hemorrhage (21). A unique clinical and pathologic
feature of SpCC is its macroscopic growth pattern.
More than 90% of laryngeal tumors (11,15,16) and
approximately 50% of oral tumors (21) present as
polypoid and exophytic masses projecting into the
lumen (Fig. 53). Sometimes there is a narrow stalk.
B. Pathology
The polypoid growth pattern usually results in an
exophytic mass with a smooth and extensively ulcerated
Figure 55 Biphasic SpCC with nests of moderately differentiat-

ed SCC intermixed with sheets of fusiform spindle cells with a
fascicular growth pattern (100). Abbreviations: SCC, squamous
cell carcinoma; SpCC, spindle cell carcinoma.
surface (Fig. 54). 66 to 75 percent of SpCC are biphasic

tumors with areas of conventional SCC admixed with
areas of spindled and/or pleomorphic tumor cells
(11,12,16) (Fig. 55). The spindled component usually
predominates (21). The conventional squamous neo-
plasia may take the form of squamous dysplasia,
carcinoma in situ or invasive carcinoma. Since the
Figure 53 Gross photograph of a resected oral cavity SpCC, tumors are usually exophytic with extensive surface
which is extensively polypoid and ulcerated. There is hyperkera- ulceration, this can render a noninvasive component
totic white thickening of the intact alveolar mucosa, which very focal or absent. The spindled cells may be bland
showed severe squamous dysplasia on histology. Abbreviation: and regular or may be markedly pleomorphic with
SpCC, spindle cell carcinoma. multinucleated giant tumor cells. There may be a wide
variety of architectural patterns, including fascicular,
Figure 56 Hypocellular SpCC consisting of markedly atypical Figure 57 Focal positive cytokeratin immunostaining in the
spindled, stellate, and pleomorphic tumor cells sitting in an spindle cell (sarcomatoid) component of a SpCC (400).
edematous, loose submucosa (200). Abbreviation: SpCC, Abbreviation: SpCC, spindle cell carcinoma.
spindle cell carcinoma.
storiform, or lace-like (10,21). On occasion, the tumor traditional immunohistochemistry. Immunostaining

cells may be widely spaced apart in an edematous and for p63, another marker of epithelial differentiation,
inflamed stroma (Fig. 56), with tumor cells mimicking which is positive in the basal layer cells of normal
granulation tissue or reactive soft tissue such as fibro- squamous epithelium, is positive in approximately
blasts with radiation-related stromal cell atypia. This two-thirds of cases, including a significant number
is a common pitfall for the surgical pathologist, possi- where cytokeratin is negative (15) (Fig. 58). It retains
bly resulting in a benign misdiagnosis. the high specificity for carcinomas just like the cytoker-
Approximately 5% of tumors will have definable atins, so is also useful in diagnosis. Virtually 100%
(heterologous) sarcomatous differentiation, either of cases are positive for vimentin with strong staining
osteosarcomatous with osteoid production or chon- (10–13,16). There is also evidence of specific mesenchy-
drosarcomatous with cartilage formation (10– mal proteins with smooth muscle actin staining in
12,16,21,22). Rhabdomyosarcomatous differentiation approximately 30% of cases, muscle-specific actin in
has been reported very rarely (23,24). Finally, another approximately 10% to 15%, and desmin in approxi-
diagnostic pitfall is where the spindle cell component mately 2% to 5% (11).
demonstrates loss of cohesion of the tumor cells and Ultrastructural examination of SpCC shows
consequently mimics an angiosarcoma. This is well cytoplasmic tonofilament bundles and tonofilament-
described in other body sites as pseudoangiosarcom- associated desmosomes in the spindle cells, features
atous carcinoma (25,26) and also in the oral cavity as associated with epithelial differentiation (7–10).
pseudovascular carcinoma (27). When a conventional SCC component is present
Although any malignant spindle cell lesion along intermingled with the spindle cells, the diagnosis of
the mucosa of the upper aerodigestive tract should be SpCC is confirmed without the need for additional
considered a SpCC until proven otherwise, immunohis- studies. This can take the form of squamous dysplasia,
tochemistry is nonetheless very important to confirm carcinoma in situ, or frankly invasive carcinoma.
the epithelial/carcinomatous nature of the spindle cells. When the lesion is purely spindled or pleomorphic
Oral cavity and oropharyngeal SpCC stain exactly like cells, one must first decide if it is malignant. SpCC can
those occurring at other head and neck sites (13,15). appear deceptively bland with regular, fusiform spin-
Cytokeratins have been extensively studied in the spindle cells in fascicles (Fig. 59) or loosely embedded in a
dle cell component, and they show only variable posi- very hypocellular and edematous stroma with numer-
tivity. Commonly used pancytokeratin (AE1/AE3 with ous small vessels and with or without an associated
or without CAM 5.2) is positive in 25% to 60% of inflammatory infiltrate. The former pattern can mimic
tumors (10–13,15,16) (Fig. 57). With an extended panel a number of benign or low-grade spindle cell neo-
of keratin stains, this number can be modestly plasms. The latter pattern, particularly given the pen-
increased, up to 68% in the large series (187 laryngeal chant for these tumors to present as polypoid and
cases) by Thompson et al. (11) or 85.7% (5/6 cases) in ulcerated masses, can very closely mimic benign
oral cases reported by Takata et al. (28). EMA is positive granulation tissue (Fig. 60). This is a serious challenge
in 20% to 45% of cases (11,15,16). This leaves a signifi- for the surgical pathologist, particularly at the time of
cant minority of cases without evidence of epithelial frozen section. One must look closely to identify and
differentiation by hematoxylin and eosin (H&E) or recognize the atypical spindle cells. Cutting additional
Figure 58 Immunohistochemistry for p63 (B),

which is positive in SpCC, while the corresponding
pancytokeratin immunohistochemistry (A) is nega-
tive (200 for each panel). Abbreviation: SpCC,
spindle cell carcinoma.
sections of the tumor or deeper levels often will

demonstrate a conventional carcinoma component
(21). If this fails, then the differential diagnosis
becomes quite broad, including myriad spindle cell
lesions, most notably benign lesions such as nodular
fasciitis, inflammatory myofibroblastic tumor, inflam-
matory pseudotumor, and sinonasal polyps with stro-
mal atypia and malignant lesions such as
angiosarcoma, fibrosarcoma, melanoma, synovial sar-
coma, or leiomyosarcoma. Truly recognizing the
malignant nature of the spindle cells by morphology
and using epithelial marker immunostains will differ-
entiate SpCC from those benign lesions.
Fortunately, true sarcomas are exceedingly
uncommon along the head and neck mucosa, such
that, when faced with a malignant-appearing spindle
cell neoplasm at these sites, it is statistically more
likely a SpCC. Cytokeratin and p63 immunostains
will rule all of these other entities out with the excep-
Figure 59 SpCC showing bland spindle cells with relatively tion of angiosarcoma and synovial sarcoma (15,29).
abundant eosinophilic cytoplasm and growing in fascicles Muscle markers such as smooth muscle actin and
(200). Abbreviation: SpCC, spindle cell carcinoma. muscle-specific actin can be positive in SpCC (11), so
one cannot rely on them in this differential. Angiosar-
comas occur infrequently in the oral cavity and may
be exophytic just as SpCC (30). The vascular markers
CD31 and CD34 will be positive in angiosarcoma (30–
32) and are not expressed by SpCC (11,27). Synovial
sarcoma is probably the most difficult to differentiate
(33). It may present as a polypoid or sessile mucosal
mass with a similar histologic appearance and will
stain with epithelial markers (29). Subtle morphology
and molecular analysis for the t(X;18) translocation
characteristic of synovial sarcoma may be necessary.

Since SpCC is inherently a carcinoma, current treat-
ment recommendations are essentially identical to
those for conventional squamous carcinoma. But just
as with the histogenesis, terminology, and morphology
of SpCC, the prognosis is also somewhat a complex
and controversial topic. If one looks at all patients and
Figure 60 Markedly inflamed SpCC mimicking granulation tis- all sites together, the prognosis does not appear differ-
sue. The tumor cells are rounded and atypical and sit in a loose, ent from conventional SCC (14). However, this does
edematous stroma surrounded by mixed inflammatory cells and not tell the whole story. Critical to prognosis is the
with abundant intermixed capillaries with plump endothelial cells location of the tumor. Tumors of the oral cavity act
(400). Abbreviation: SpCC, spindle cell carcinoma. aggressively (6,21,22,34,35). Tumors of the larynx, par-
ticularly the glottis, do much better than those of the
oral cavity, hypopharynx, oropharynx, and sinonasal B. Pathology

region (6,11,14,22). As with conventional squamous
carcinoma, the depth of tumor invasion is important, The gross findings are not distinct. Masses usually are
but this seems accentuated in SpCC such that minimal- bulging and ulcerated but, where not ulcerated, are
ly invasive tumors do very well and those with any usually somewhat smooth-surfaced. Tumors may
significant degree of invasion do worse than conven- have a component of SCC. These mixed tumors are
tional squamous carcinoma of the same stage (22,35). usually more granular and ragged in appearance.
Interestingly, polypoid conformation, by itself, does Microscopically, there are poorly circumscribed sheets,
not confer a better prognosis (11,14,21), presumably cords, and nests of small blue undifferentiated tumor
because the degree of invasion beneath the polyp is the cells (Fig. 61). The cells have very little cytoplasm, and
critical factor. Finally, and curiously and for unknown their nuclei range from round and regular to more
reasons, lack of keratin immunoreactivity in the spin- angulated and fusiform. There is frequently significant
dle cells also has been correlated with a better progno- chromatin crush artifact. The cells that are preserved
sis (11,14). display nuclear molding and have a chromatin that is
finely stippled or granular (Fig. 62). Nucleoli, if present,
are small and inconspicuous (3,10,15). There is very
XVII. NEUROENDOCRINE CARCINOMA brisk mitotic activity, abundant apoptosis, and usually
areas of necrosis. Rarely, tumors will have cells with
Neuroendocrine carcinomas of the head and neck are
more cytoplasm, rosette-like structures, and peripheral
relatively rare, and when they do occur, it is predom-
palisading. Tumors with these features have been clas-
inantly in the larynx (1,2). Oral cavity and oropharyn-
sified, in other organ sites, as large cell neuroendocrine
geal neuroendocrine carcinomas are quite uncommon,
carcinoma (5,9).
with approximately 20 cases reported in the literature.
Immunohistochemistry is positive for pan
Neuroendocrine carcinomas of the head and neck, just
cytokeratin, usually with a characteristic, punctate,
as in the lung, are broadly classified into three catego-
or dot-like, perinuclear pattern (Fig. 63). The reactivity
ries: carcinoid tumor (low grade or well-differentiated
may be limited or focal in some cases. Since only a
neuroendocrine carcinoma), atypical carcinoid tumor
portion of the reported cases have been stained for
(intermediate grade or moderately differentiated neu-
cytokeratin 20, full conclusions cannot be made. Cer-
roendocrine carcinoma), and small cell carcinoma
tainly, some of the cases are positive for that marker
(high grade or poorly differentiated neuroendocrine
(3,7). Neuroendocrine stains such as synaptophysin
carcinoma – HGNEC). The latter group also includes
and chromogranin A are positive in most cases, but
rare HGNEC with large cells with generous
reactivity may be limited (3,4,5,6,7). The tumors are
eosinophilic cytoplasm (large cell neuroendocrine car-
negative for S-100 and leukocyte common antigen and
cinoma). All reported cases of primary oral neuroen-
are usually negative for high molecular weight cyto-
docrine carcinoma have been HGNEC, and they
keratins. Ultrastructurally, there are rare membrane-
frequently have an intermixed component of SCC.
bound, dense core neurosecretory granules (5,10) and
True carcinoid tumors have not been reported in the
occasional cell junctions.
oral cavity or oropharynx. As a final general point,
many authors have referred to oral cavity HGNEC as
Merkel cell carcinoma, which is the term traditionally
reserved for HGNEC of the skin (3,7,12). As the oral
mucosa develops from ectoderm just as the skin does,
Merkel cell carcinomas certainly could feasibly occur
in the mouth. However, while there may well be
phenotypically different neuroendocrine carcinomas
in the oral cavity, to date, the literature does not
clearly distinguish them. For purposes of this discus-
sion, they will all be considered together.
The overwhelming majority of oral cavity and oropha-
ryngeal neuroendocrine carcinomas occur in men
(3,4,5,6). Beyond this, the small number of cases
does not allow for broad generalization of the clinical
features. Of the reported cases, the majority have been
in the oral cavity with a few reported in the orophar-
ynx (3,4,5,6,7,8). Specific oral sites include the lip
(3,14,7), FOM (12), RMT (6), tongue (3), and alveolar
ridges (4,13). There is no significant difference in Figure 61 Low-power view of high-grade neuroendocrine car-
tumors among these subsites. Almost all of the cinoma of the oral cavity showing sheets of small, blue cell tumor
patients are heavy smokers (8). Presenting symptoms in the submucosa (100).
include mouth pain, bleeding, or a neck mass.
carcinomas (11), so cannot be relied upon to diagnose

metastasis from the lung.

HGNEC is an extremely aggressive neoplasm. The
majority of patients [more than 70% (8)] develop
metastatic disease to cervical lymph nodes and also
distantly to the liver, lungs, brain, or bones. Approxi-
mately one-third have nodal disease at presentation,
and most patients develop cervical nodal disease or
local recurrence within the first year (3,4,5,6). Wide-
spread metastatic disease is common (3) with spread
to the liver, bones, and brain (3,4,8). Because these are
such aggressive tumors, which have a very high
rate of distant failure, nonsurgical therapy has been
recommended (8). Surgical resection of the primary
tumor is performed only if it is of very low morbi-
Figure 62 High-power view of high-grade neuroendocrine car-
dity or for the very rare case of a well or moderately
cinoma of the oral cavity. The tumor consists of sheets and nests differentiated neuroendocrine carcinoma (8). If surgi-
of small, blue cells with granular ‘‘salt and pepper’’ chromatin, cal therapy is undertaken, neck dissection is recom-
little cytoplasm, and brisk mitotic activity with abundant apoptosis mended even in the absence of clinical nodal disease.
(400). Aggressive induction chemotherapy, akin to that used
for pulmonary small cell carcinoma, is used followed
by definitive radiation therapy (3,8). Two-thirds of the
reported patients with oral cavity or oropharyngeal
HGNEC have died of disease within one to two years.
XVIII. ORAL MALIGNANT MELANOMA

Mucosal melanoma is a neoplasm composed of mela-
nocytes or melanocytic precursors, which, perhaps to
the surprise of some, is not particularly uncommon in
the oral cavity. Interestingly, oral mucosa has the same
density of melanocytes as some skin sites (1,2),
although it is not normally pigmented, except in
Figure 63 Cytokeratin immunohistochemistry in high-grade darker-skinned individuals (3). Pigmentation does
neuroendocrine carcinoma showing punctate, dot-like positive occur in response to local trauma, systemic medica-
staining in the tumor cells (400).
tions, or related to race—the darker a person’s skin, the
more likely they are to have a pigmented lesion (3).
Also, benign melanocytic lesions such as melanotic
macule, melanoacanthoma, true melanocytic nevi, or
The differential diagnosis includes a number of the rare melanotic neuroectodermal tumor of infancy
tumors with a ‘‘blue-cell’’ appearance, including do occur, rarely, in the oral cavity (4–8). While the head
poorly differentiated SCC, lymphoma, BSC, solid- and neck is a common site in general for melanomas
type (grade III) ACC, melanoma, and Ewing’s sarco- (up to 30% of all cases), most of which are cutaneous
ma. The punctate cytoplasmic pattern of cytokeratin and ocular (9), the oral cavity and oropharynx repre-
reactivity is one of the most reliable diagnostic fea- sent the primary site for less than 1% of melanomas
tures of neuroendocrine differentiation, followed by across the board (1) and approximately 0.5% of all
immunohistochemistry for synaptophysin, chromog- cancers (1,10) in the oral cavity. 50 to 60 percent of all
ranin A, or CD56 (N-CAM). The distinction from BSC mucosal melanomas occur in the head and neck (11),
and solid-type ACC may be assisted by strong immu- divided roughly equally between the oral cavity and
nostaining for these tumors with high molecular the nasal cavity/paranasal sinuses (1,9). While the
weight cytokeratins such as 34bE12 and CK 5/6, incidence of cutaneous melanomas is markedly
which are usually negative in neuroendocrine carci- increasing (12), particularly in the Caucasian popula-
nomas (16,17). Also, although uncommon, metastatic tion, the incidence of mucosal melanomas is only
small cell carcinoma, particularly from the lung, must gradually increasing (9,13). The reason for this differ-
be considered (18,19) and ruled out clinically. ence may be that, unlike cutaneous melanoma, where
Although TTF-1 immunostaining is a specific marker there is a strong relationship with sun exposure and
of pulmonary carcinomas of other types, it is positive actinic damage, no such relationship exists for mucosal
in a significant minority of nonpulmonary small cell melanomas (9). In fact, no etiologic factors have been
ascertained for these lesions. Although a number of B. Pathology

benign oral melanocytic lesions occur, there are only
very rare examples that have progressed to malignant Just as with the clinical appearance, resected melano-
melanoma (14,15). For this reason, and because of mas grossly consist of variably pigmented black or
the small numbers of benign oral melanocytic lesions, gray, macular or nodular lesions ranging from 1.5 to
the risk of their transformation to melanoma is 4 cm. Eighty-five percent of tumors demonstrate mela-
unclear (16). nin pigment (1) so the cut surface is frequently dark-
colored to black. Histologically, oral melanomas show
identical features to cutaneous lesions. They can be in
A. Clinical Features situ or invasive. However, unlike in the skin, the vast
majority of oral melanomas (85%) are deeply invasive
Oral melanoma occurs in adults with an average age at presentation (1). Most invasive tumors (*2/3) also
of approximately 60 years (1,9,17–19), but there is a still have an in situ component as well (1,19), which
roughly even incidence from age 20 to 80 years (1). consists of atypical melanocytes with clear cytoplasm
Oral melanoma is very rare in children (17). There is a sitting singly or, less commonly, in nests, along the
slight male predominance with 60% occurring in men basal layer of the epithelium. This typically leads to a
(13,17). Unlike in cutaneous melanoma, where the vast ‘‘rarified’’ or vacuolated appearance. These cells have
majority of patients are Caucasian, oral melanomas scattered intracytoplasmic melanin and nuclei which
occur in dark-skinned individuals with relative fre- are round to oval and hyperchromatic or have vesicu-
quency (9). In a review of 93 patients, Chaudhry et al. lar chromatin with prominent nucleoli (19) (Fig. 65).
(20) reported 22% occurring in dark-skinned races. Occasionally, in situ melanoma can be seen involving
Three distinct clinical presentations and pathways are seromucinous glands. There is frequently upward
recognized (21): The first is as an incidental, asymp- migration of single melanocytes in the epithelium,
tomatic, pigmented lesion noted by a dentist or phy- but nests above the interface are quite uncommon,
sician. The second, seen in approximately one-third of and mitoses are scarce. In invasive tumors, cells
patients, is the patient noting a flat, pigmented lesion, invade the submucosa singly and in sheets, clusters,
which remains present for months to years before they or islands and are either epithelioid, spindled, or a
seek attention or before an actual mass develops mixture of both types. Epithelioid cells are more
(17,20,22). The remaining patients present with a common and have round contours with eosinophilic
recently developing mass. Patients complain of pain, to gray cytoplasm and central round nuclei with
ulceration, bleeding, or loose teeth (1). The most vesicular chromatin and prominent ‘‘cherry red’’
common oral site is the hard palate (*40%) followed nucleoli (Fig. 66). Intranuclear cytoplasmic inclusions,
by the maxillary alveolar ridge (*25%) and then the although commonly described in cutaneous and ocu-
buccal mucosa, mandibular gingiva, and lip. Rare lar melanomas, are only infrequently encountered in
cases occur in the tongue, FOM, and oropharynx oral melanoma. Occasional tumors may have plasma-
(1,17,19,23). Clinically, the lesions are heterogeneous cytoid cells (1,19,24). In tumors with mixed cell types,
with colors ranging from black to gray to purple or the spindle cell component is usually minor or focal.
red (Fig. 64). There can be intermixed white areas, Pure spindle cell lesions are least common (25). These
which may represent foci of regression (1,19). The
flatter lesions are irregular in outline. Nodular masses
may or may not be pigmented or ulcerated, and
sometimes satellite nodules can be seen (19) without
intervening pigmentation.
Figure 65 Melanoma in situ of the hard palate showing a

confluent proliferation of atypical melanocytes along the basal
Figure 64 Clinical photograph showing a patient with melanoma layer along with many single cells in the upper epithelium
of the maxillary alveolus and upper lip. (pagetoid spread) (200).
component may simply be termed ‘‘oral melanoma

with radial growth phase’’ (17) or as more recently
proposed the varying lesions should be termed simply
as ‘‘in situ melanoma,’’ ‘‘invasive melanoma,’’ or
‘‘invasive melanoma with an in situ component’’
(19). Borderline lesions may be termed ‘‘atypical mel-
anocytic proliferation’’ (1,15,19).
Most oral melanomas are deeply invasive at
presentation. The great majority have a Breslow thick-
ness of greater than 4 mm (36), with none of the cases
in a large review by Hicks et al. less than 1.5 millmeters
(1). For this reason, Breslow thickness measurements
have not proven prognostic in oral cavity melanomas
and need not be reported. By immunohistochemistry,
90% to 97% of tumors are positive for S-100 protein
(25,37), but this cell marker lacks specificity. Melan-A
(or MART-1) and tyrosinase are much more specific for
melanoma, and expression is present in almost 100% of
cases of epithelioid melanoma. However, a few cases of
Figure 66 Epithelioid malignant melanoma consisting of sheets spindle cell melanoma and many cases of desmoplastic
of rounded tumor cells with prominent eosinophilic cytoplasm melanoma are negative. HMB-45 and microopthalmia
and central, round nuclei with vesicular chromatin and prominent, transcription factor-1 are positive in approximately
eosinophilic nucleoli. There is prominent melanin pigment 75% (25) of melanomas as well.
(400). Melanoma is notorious for its mimicry of other
types of neoplasms. Since the vast majority of oral
melanomas are pigmented, it is important to look for
consist of sheets of fusiform cells with oval to cigar- melanin, which is quite specific for melanoma. The
shaped nuclei and cytoplasm which varies from eosin- differential diagnosis for epithelioid melanoma
ophilic to clear (Fig. 67). Desmoplastic-type melano- includes poorly differentiated or undifferentiated car-
mas with a dense collagenous background and more cinoma, rhabdoid tumor, and plasmacytoma. For
elongated nuclei have been rarely described, most of spindle cell melanoma, the differential includes sarco-
which are nonpigmented and demonstrate perineural matoid carcinoma and myriad soft tissue–type tumors
invasion (19,26–30). When considered as a whole, such as malignant peripheral nerve sheath tumor.
nuclear pleomorphism and mitotic activity in oral Positive immunohistochemistry for S-100 and at least
melanomas range from minimal to marked, but one of the more specific melanoma markers such as
frank necrosis is not commonly seen. Finally, more melan-A, tyrosinase, or HMB-45 is key to the diagno-
than 90% of tumors contain melanin pigment that can sis. Most importantly, metastatic melanoma must be
be seen on microscopic examination (17,19). ruled out. Virtually all patients with metastatic mela-
Melanomas of the oral cavity do not fit particu- noma to the oral cavity will have a history of a
larly well into the classification scheme for cutaneous previous primary lesion elsewhere, most will be ame-
melanomas (1,17,31). Early attempts to classify oral lanotic as opposed to primary oral melanomas, and all
melanomas in this way led to tumors being described lack an in situ component (38).
as lentigo maligna melanoma (LMM) (32) and others
as being of the acral lentiginous pattern/type (31,33– C. Treatment and Prognosis
35). Those lacking an in situ component resemble
nodular melanoma. Because no pattern has been asso- The prognosis for oral and oropharyngeal melanomas
ciated with a specific behavior or prognostic differ- is poor. Numerous studies examining this have dem-
ence, it has been proposed that these terms not be onstrated a collective five-year survival between 15%
used (22). Instead, oral melanomas with an in situ and 25% (1,4,9,17,20,21,39–41) with one series showing
Figure 67 Spindle cell melanoma showing sheets

of regular spindle cells in the submucosa (left),
which, on higher power, show fusiform nuclei,
inconspicuous nucleoli, and moderate amounts of
eosinophilic to clear cytoplasm (right). There is focal
melanin pigment (100 left and 400 right).
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8
Diseases of the Nasal Cavity, Paranasal Sinuses,

and Nasopharynx
Leon Barnes
Department of Pathology, University of Pittsburgh Medical Center, Presbyterian-
University Hospital, Pittsburgh, Pennsylvania, U.S.A.
I. RHINOSINUSITIS (RHINITIS, SINUSITIS) with a small admixed component of neutrophils. The

overlying ciliated respiratory mucosa may show focal
A. Introduction squamous metaplasia and/or ulceration or exhibit
Inflammation of the sinonasal tract may be limited to mild papillary hyperplasia. Goblet cells, both in the
the nasal cavity (rhinitis) or to the paranasal sinuses mucosa and mucoserous glands, are often increased,
(sinusitis) or, as in most cases, involve both sites and the basement membrane may be prominent, thick,
(rhinosinusitis). It may also be unilateral or bilateral and hyalinized. Occasionally, the glands are dilated or
and acute, subacute, chronic, or granulomatous, with cystic and filled with mucus. Lymphoid aggregates
or without polyps and radiographic air-fluid levels. are uncommon.
Rhinosinusitis affects all age groups and is one Unexpected findings might include large num-
of the most common health problems in the United bers of neutrophils, granulomas, or vasculitis, which
States, with an annual expenditure of millions of should then raise the possibilities of an infectious
dollars for over-the-counter medications. Signs and origin or a systemic disease such as sarcoid and
symptoms vary in severity and usually include one or Wegener’s granulomatosis.
more of those listed in Table 1. A classification of adult
rhinosinusitis based on severity and duration of dis- C. Complications
ease has been proposed by a Task Force of the
American Academy of Otolaryngology—Head and Considering its frequency, rhinosinusitis is a relatively
Neck Surgery (Tables 1 and 2) (1). innocuous disorder with few complications.
There are many causes of rhinosinusitis that are Nevertheless, when the inflammatory process extends
not always apparent, either clinically or on histologi- into adjacent structures, treatment can be challenging
cal evaluation (Table 3). Regardless of etiology, the and the end results sometimes deadly (3–5).
ostiomeatal complex plays a fundamental role in the Complications of rhinosinusitis can be divided
pathogenesis of most, if not all, cases of rhinosinusitis. into osseous, orbital, and intracranial. Osseous
The ostiomeatal complex is a functional unit that involvement is most often associated with frontal
consists of the maxillary sinus ostia, anterior ethmoid sinusitis but can involve any site. The inflammation
cells and their ostia, ethmoid infundibulum, hiatus may cause bone remodeling in the form of prolifera-
semilunaris, and middle turbinate. The key element is tion (osteoblastic osteitis) or lysis or result in osteo-
the maintenance of optimal sinus ventilation and myelitis (Fig. 2). Orbital or periorbital manifestations
drainage. Ostial obstruction creates an increasingly include cellulitis and abscess. Intracranial involvement
hypoxic environment within the sinus and a microbi- is the most feared and potentially life threatening and
ological flora that becomes more anaerobic. Secretions ranges from meningitis, subdural-epidural-intracranial
stagnate, ciliary and epithelial damage become more abscesses, and cerebritis to cavernous or superior sag-
severe, and inflammation and bacterial infection ittal sinus thrombosis.
supervene (2). Only by ensuring ostial patency, aera-
tion, and drainage can the cycle be broken. Allergic Rhinosinusitis
Allergic rhinosinusitis is the most common form of
B. Pathology atopic disease and affects 10% to 20% of the adult
population in the United States (6). The incidence is
With few exceptions, the pathology of rhinosinusitis is higher, about 30%, among those who have a parent
rather nonspecific (Fig. 1). The lamina propria, with a history of atopic disease, and even more so, if
depending on the stage of disease, may be either both parents have such a history (7). Approximately
edematous or fibrotic and typically contains a diffuse 20% to 40% of patients with allergic rhinosinusitis also
infiltrate of lymphocytes, histiocytes, and eosinophils have coexistent asthma (8,9).
344 Barnes
Table 1 Signs and Symptoms of Rhinosinusitis Table 3 Classification of Rhinosinusitis
Major factors Minor factors 1. Allergic

2. Infectious
Facial pain/pressure Headache
A. Bacterial
Facial congestion/fullness Fever (nonacute)
B. Viral
Nasal obstruction/blockage Halitosis
C. Fungal
Nasal discharge/purulence/ Fatigue
D. Mycobacterial
discolored postnasal drainage Dental pain
E. Others
Hyposmia/anosmia Cough
3. Vasomotor
Purulence in nasal cavity on Ear pain/pressure/fullness
4. Atrophic
Examination
5. Aspirin intolerance—Samter’s triad
Fever (acute rhinosinusitis only)
6. NARES syndrome
Source: From Ref. 1. 7. Rhinosinusitis medicamentosa
8. Rhinosinusitis of pregnancy
Table 2 Classification of Adult Rhinosinusitis A. Other hormonal
9. Occupational or environmental
Classification Duration Criteria 10. Structural or mechanical
Acute % 4 wk ^ 2 major factors, A. Immotile cilia (primary ciliary dyskinesia)
1 major factor and B. Septal deviation
2 minor factors, or C. Tumors
nasal purulence on 11. Factitial
examination (see A. Foreign bodies
Table 1)a B. ‘‘Nose-pickers’’
Subacute 4–12 wk Same as chronic 12. Systemic diseases
Recurrent ^ 4 episodes per yr, Same as acute A. Asthma
acute with each lasting B. Cystic fibrosis
^ 7–10 days and C. Kartagener’s syndrome
absence of D. Young’s syndrome
intervening signs E. Diabetes mellitus
and symptoms F. Yellow nail syndrome
of chronic G. Others
rhinosinusitis 13. Idiopathic
Chronic ^ 12 wk ^ 2 major factors, Abbreviation: NARES, nonallergic rhinosinusitis
1 major factor, and with eosinophilia.
2 minor factors or
nasal purulence
on examination
Acute Sudden worsening
exacerbations of chronic
of chronic rhinosinusitis, with
return to baseline
after treatment
a
See Table 1 for definition of major and minor factors.
The disease is mediated through a type I IgE

immunological reaction. The nose acts as a filter, effec-
tively preventing particles of 5 to 10 mm or more in
diameter from reaching the lungs (10). The particles are
in contact with the nasal mucosa for about 10 to 30
minutes before they are eliminated through the pharynx
by ciliary action (11). During transit some are digested
by lysozyme, releasing potential allergens. In a sensi-
tized individual, IgE antibodies attached to the surface
of mast cells and basophils in the nasal mucosa react
with the allergens, releasing various pharmacological
mediators (histamine, prostaglandins, leukotrienes, and
such) responsible for vasodilation, increased vascular Figure 1 Chronic nonspecific rhinosinusitis. The ciliated respira-
permeability, edema, smooth muscle contraction, eosin- tory epithelium is intact and rests upon a thin, delicate basement
ophilia, nasal congestion, rhinorrhea, sneezing, and membrane. The lamina propria is edematous and contains a
itching (12). The reaction begins within two to five marked infiltrate of chronic inflammatory cells. There is no thick-
minutes of antigen-antibody exposure, reaching its ening or hyalinization of the basement membrane, no significant
peak about 15 minutes later (13). This is followed four accumulation of eosinophils or neutrophils, and no evidence of
to six hours later by a second phase of mediator release organisms, granulomas, vasculitis, or tumor (H&E, 200).
from additional cells (neutrophils and eosinophils).
Chapter 8: Nasal Cavity, Paranasal Sinuses, and Nasopharynx 345
Acute bacterial rhinosinusitis most commonly

develops as a complication of a viral infection of the
upper respiratory tract. Approximately 0.5% to 2.0%
of cases of viral rhinosinusitis develop into bacterial
infections (17). If a mucopurulent discharge develops,
then a secondary bacterial superinfection has most
likely occurred as a result of swollen nasal mucosa
obstructing a sinus ostium. Decreasing sinus aeration
causes decreasing oxygen tension within the sinus,
and an alteration of the normal bacterial flora, ending
in an acute bacterial sinusitis. Clinically, bacterial
sinusitis is usually associated with the pain localized
over the affected sinus.
The most common pathogens are Streptococcus
pneumoniae (pneumococcus), Haemophilus influenzae,
and a-hemolytic streptococci. Rarely, Staphylococcus
aureus and Pseudomonas infections can occur (17).
Pathogenic anaerobes are a rare cause of acute sinusi-
tis. However, anaerobes predominate in cases of
Figure 2 Chronic rhinosinusitis associated with a peripheral chronic sinusitis with persistent low intrasinus oxygen
bony shell of reactive osteitis (H&E, 100). tension. These include peptostreptococci, Bacteroids
sp., and fusobacteria (18,19). In the case of the maxil-
lary sinus, it is estimated that 10% to 20% of the
infections are secondary to dental infection or comp-
The most common allergens are pollens of lication of a tooth extraction (19). Bacterial sinusitis
grasses, weeds, and trees; animal danders; dust often resolves within four to seven days of antibiotic
mites; mold spores; and food. The hallmark of the therapy.
disease is the temporal correlation of nasal symptoms As acute bacterial sinusitis results from sinus
with exposure to an allergen. On rhinoscopy, the ostial obstruction, it is in effect a sinus-by-sinus
allergic nasal mucosa appears pale, with clear or, if event, rather than a generalized process. Thus, it is
infected, purulent rhinorrhea. In addition to history, more common to find contiguous unilateral sinusitis,
the diagnosis is further supported by finding eosino- rather than pansinusitis. Even when both maxillary
phils in stained smears of nasal secretions. If more antra are affected, one is usually more severely
than 25% of the cells on the slide are eosinophils, afflicted than the other. Generally, asymmetrical
allergy is very likely and, especially so, if the total sinusitis is a hallmark of bacterial disease. By compar-
serum IgE level is also evaluated. ison, pansinusitis is usually found in patients with an
Patients who have allergic rhinosinusitis may, on allergic sinusitis, because the allergic process is typi-
occasions, have negative skin tests when challenged cally a systemic, rather than local, event.
with the offending allergen. The explanation for this Chronic sinusitis results from either persistent
paradox is that IgE antibodies can be synthesized acute inflammation or repeated bouts of acute or
locally in the nasal mucosa (14,15). The local tissue subacute sinusitis. Up to one-third of patients with
would be more sensitive to a heavy concentration of acute sinusitis may develop chronic sinusitis. Chronic
antibody than a distant skin site, resulting in rhinosi- disease can result in an atrophic, sclerosing, or hyper-
nusitis and negative skin tests, respectively. Local trophic polypoid mucosa. These varied mucosal
synthesis of IgE could also explain why some patients changes most often coexist with one another and
with low serum IgE levels still have atopic symptoms. with areas of acute inflammation of either an infec-
tious or allergic etiology. Because chronically inflamed
Infectious Rhinosinusitis and scarred mucosa loses some of its ciliary function,
it becomes vulnerable to future infection, initiating a
A variety of infectious agents may involve the sinonasal vicious cycle of infection and reinfection. The bony
mucosa, resulting in acute or chronic inflammation, sinus walls around a chronically infected sinus usually
with or without secondary polyp formation. The pres- become thickened and sclerotic with reactive new
ence of large numbers of tissue neutrophils should bone formation (Fig. 2). Reactive bone is found with
always suggest the possibility of a bacterial infection. all chronic sinus inflammation, regardless of etiology,
The ‘‘common cold’’ is the most frequent infec- and presumably, is a response to periosteal involve-
tious malady of the upper respiratory tract. The clinical ment by inflammation. Nasal polyposis is an uncom-
manifestations of this viral infection are primarily a mon sequel to routine bacterial sinusitis.
watery and profuse nasal discharge that usually per-
sists for less than one week. The most commonly Vasomotor Rhinosinusitis
implicated viruses are rhinoviruses, parainfluenza
and influenza viruses, adenoviruses, and respiratory Vasomotor rhinosinusitis is a chronic nonallergic,
syncytial virus (16). The typical cold remains primarily noninfectious form of rhinosinusitis caused by an
a viral rhinitis with little significant sinusitis. imbalance of the autonomic nervous system that
346 Barnes
governs the sinonasal mucosa (10,20,21). The imbal- and manifests with nasal obstruction, epistaxis, head-
ance results in overactive parasympathetic stimula- aches, nasal crusting, anosomia, halitosis, and the
tion, with subsequent vasodilation, edema, emission of the characteristic foul-smelling nasal
hypersecretion, nasal obstruction, sneezing, and head- odor (ozena) that is detectable by others at conversa-
aches localized over the bridge of the nose or frontal tional distances. The disease is nonfatal, but very
sinus area. Pruritus, in contrast to allergic rhinosinu- distressful. The patients often become social cripples
sitis, is not common. Some patients may have histories and may even commit suicide.
of additional autonomic dysfunctional states, such as Nasal biopsies of patients with ARS show chronic
the irritable bowel syndrome (22). nonspecific inflammation and edema with progres-
Many factors can exacerbate the symptoms. sive fibrosis, loss of cilia and goblet cells, squamous
Among these are included cigarette smoke, strong metaplasia, and atrophy of the mucoserous glands
perfumes or other odors, extremes of temperature, and turbinates. The blood vessels may be dilated, or
stress, anxiety, and fatigue. they may show signs of endarteritis (28). Whether the
Tissue removed from the sinonasal tract in latter is the cause or the result of ARS is open to
patients with vasomotor rhinosinusitis typically speculation. The end result of the atrophic process is
shows only chronic nonspecific inflammation, with or that nasal passages are widened and more air is
without retention cysts. Eosinophils and mast cells are inspired, which, with its drying effect, results in a
not increased, and neutrophils are sparse to absent, vicious cycle of more crusts being formed.
unless there has been superimposed infection (23). There is no known cure for ARS. A variety of
Patients respond to different treatments. Some medical and surgical procedures, however, may offer
may benefit from anticholinergic drugs administered some limited palliative effect. Among these are
either orally, topically, or both, or to local application included antibiotics, lubricating nasal drops, nasal-
of silver nitrate (24). Others may require partial cleansing procedures, correction of presumed defi-
removal of the turbinates, particularly the inferior. ciencies (iron, vitamin A, estrogen), surgical operation
This may be achieved either by surgery, electrocau- to narrow the air passages, and various techniques to
tery, cryosurgery, or laser (21). For those with severe disrupt the autonomic nerve supply of the nasal
intractable symptoms, interruption of the parasympa- mucosa (nerve blocks, neurectomies) (29,30).
thetic and sympathetic supply by a vidian nerve Shehata indicates that after the age of 40 years
section may be required (25). there is a tendency for some patients to show sponta-
neous arrest of the active disease in which the crusts
Atrophic Rhinosinusitis and odor disappear despite the presence of the wide
nasal passages (27).
Atrophic rhinosinusitis (ARS) is a chronic disease of
unknown etiology characterized by a triad of findings: Aspirin Intolerance: Samter’s Triad
(i) atrophy of the nasal mucosa, (ii) crust formation,
and (iii) the emission of a foul nasal odor, sometimes Samter has called attention to the fact that patients
referred to as ozena (stench) (26,27). It occurs world- who are intolerant to aspirin often have coexistent
wide, but is especially common in subtropical and nasal polyps and asthma (31,32). This constellation of
temperate climates, such as Southeast Asia, Africa, findings, referred to as the aspirin, acetylsalicylic acid
Egypt, India, China, Brazil, and the Mediterranean (ASA), or Samter’s triad, is relatively common, affect-
(26–29). Racial influence may also be a factor in that ing 2% to 3% of all asthmatics and 20% of severe
Asians, Latinos, and black Americans are more sus- asthmatics (33,34). In three series of 445, 127, and 154
ceptible than natives of equatorial Africa. The disease nasal polyps, the incidence of the complete triad was
is also more common among the poor who live in 2%, 19.7%, and 24%, respectively (35–37).
unsanitary conditions. The syndrome typically manifests during the
Rather than a single cause, multiple factors may third or fourth decade of life and begins with upper
be involved in the etiopathogenesis of ARS. Among respiratory signs of rhinitis. The asthma and aspirin
the possibilities that have been proposed include intolerance usually appears within one year of each
(i) chronic bacterial infection of the sinonasal tract, other and about 5 to 10 years after the onset of rhinitis
(ii) nutritional deficiencies, especially iron and vitamin A, (36,38,39). Nasal polyps, in turn, develop about
(iii) hypoestrogenemia, (iv) autonomic instability with 10 years after the other symptoms have started,
prolonged sympathetic stimulation and vasoconstric- although they can occur at any time. In most instan-
tion, (v) an autoimmune disease, (vi) chronic exposure ces, the syndrome appears sporadically. Rare reports
to irritants, (vii) end stage of a variety of chronic of familial occurrences, however, have been described
sinonasal infections, (viii) prior radiation exposure, (34,38,39).
and (ix) previous surgery (27,28). In the typical case, the patient starts to experi-
Although Klebsiella ozaenae, nontoxic Coryne- ence bronchoconstriction and rhinorrhea within
bacterium diphtheriae, and the Perez–Hofer bacillus minutes to three hours after ingesting aspirin, often
are often cultured from the sinonasal tract, it is uncer- accompanied by nausea, vomiting, intestinal cramps,
tain whether these organisms are responsible for the and diarrhea. In addition to aspirin, some individuals
disease or are just secondary invaders. may demonstrate an intolerance to other nonsteroidal
According to Shehata (27), the disease begins in anti-inflammatory drugs such as acetaminophen,
childhood, especially in girls at the onset of puberty, indomethacin, and ibuprofen (38).
Rather than an allergic reaction, aspirin sensitiv- After a careful history, the diagnosis can usually
ity represents a pharmacological effect that results be confirmed by intranasal examination. The nasal
when the ingested drug interferes with the metabo- mucosa is typically red and boggy and will not respond
lism of arachidonic acid (34). Normally, arachidonic to topical 4% cocaine, which normally produces vaso-
acid, which is released from phospholipids in cell constriction and shrinkage of the turbinates (45).
membranes, is metabolized along two alternative The management of rhinosinusitis medicamen-
pathways. One pathway is concerned with the forma- tosa, according to Mabry, involves four steps: (i) make
tion of prostaglandin derivatives by cyclooxygenase, the diagnosis, (ii) reverse the mucosal changes,
whereas the other forms leukotrienes by the action of (iii) withdraw the offending medication, and (iv) edu-
lipoxygenase. Aspirin inhibits cyclooxygenase and cate the patient (45). During drug withdrawal, the
thereby increases the production of more leukotrienes, obstruction often becomes worse, and as a result,
which are known to stimulate production of mucus, the patient may need additional medications (cortico-
cause vasodilation and edema, and act as chemotactic steroids) for temporary relief. After the patient has been
factors for inflammatory cells (34). weaned, a search should be made for the cause of the
The polyps are typically bilateral and, on histo- obstruction that led to the initial use of the nasal spray.
logical examination, show extensive thickening and
hyalinization of the basement membrane, increased Rhinosinusitis of Pregnancy
goblet cells, stromal edema, and chronic inflammatory
cells, including prominent eosinophils and mast cells Rhinosinusitis occurs in 30% of pregnant women,
(34,39,40). There are no histological features that dis- most notably in the second and third trimesters, and
tinguish the aspirin-intolerant polyp from the aspirin- usually disappears within five postpartum days (47).
tolerant polyp. Treatment consists of avoiding aspirin The changes are due to the stimulatory effect of
and other similar medications, aspirin desensitization, pregnancy-associated hormones on nasal mucoserous
palliative relief of symptoms, and possible polypec- glands and increased blood volume with nasal vascu-
tomy (41). lar pooling and resultant airway resistance.
Although pregnancy may specifically influence
Nonallergic Rhinosinusitis with Eosinophilia the nose, Schatz and Zeiger (47) indicate that most
women with rhinosinusitis during pregnancy actually
Nonallergic rhinosinusitis with eosinophilia syndrome, have other specific entities not unique to pregnancy,
or NARES, is a perennial form of rhinosinusitis charac- such as allergic rhinosinusitis, bacterial rhinosinusitis,
terized by the ‘‘on again–off again’’ symptoms of and so on. Emphasis, therefore, must be placed on
sneezing, profuse watery rhinorrhea, pruritus, and making the correct diagnosis so that therapy can be
lacrimation, in conjunction with nasal eosinophilia in directed as accurately, yet minimally, as necessary to
excess of 20% and negative intradermal skin tests (42). achieve the desired therapeutic outcome and not
The on again–off again symptomatology is one of damage the fetus.
the hallmarks of the disease. Although patients gener-
ally do not have prolonged symptom-free periods, Occupational-Environmental Rhinosinusitis
those with less severe disease may have symptoms
almost daily for several weeks to months interspersed Although occupational-environmental rhinosinusitis
with long periods without symptoms. In these instan- has been known for many years, it has only recently
ces, the patient is often mistaken for having ‘‘seasonal received significant attention among otolaryngologists
allergy.’’ Allergic rhinosinusitis, however, can be (48–52).
excluded on the basis of a family history of atopic The workplace may be the source of many
diseases and often positive skin tests. vapors or particulate matter that may result in rhino-
There is some evidence suggesting that NARES sinusitis by means of direct irritation or an allergic
may be a precursor of Samter’s triad (aspirin intoler- reaction. The list is long, but some of the noxious
ance, asthma, and nasal polyps) (43). As a group, agents include wood dust, formaldehyde, sulfur diox-
NARES patients respond well to topical corticoste- ide, flour, nickel, shoe dust, and passive cigarette
roids, supplemented, as needed, with decongestants smoke. Chronic exposure may not only result in
and antihistamines. chronic rhinosinusitis, with or without polyps, but
may also, in some instances, lead to malignant tumors.
Rhinosinusitis Medicamentosa
Structural-Mechanical Rhinosinusitis
Nasal obstruction caused by topical or systemic
medications is referred to as rhinosinusitis medicamen- Defects of the cilia, either structural or functional,
tosa (44–46). Most often the culprit is one of the many result in impaired mucociliary clearance, stagnation
over-the-counter nasal sprays or drops used for their of secretions, and inflammation. This topic [primary
vasoconstrictive action to alleviate nasal obstruction. ciliary dyskinesia (PCD), immotile cilia syndrome] is
Regular use, however, sometimes for as little as one discussed elsewhere in this chapter.
week, may result in the patient using more medication, Other mechanical derangements, such as a devi-
thereby establishing a vicious cycle of habitual depen- ated nasal septum or any benign or malignant tumor
dence. Systemic drugs that may cause similar effects may predispose the individual to infections. The pos-
include oral contraceptives, reserpine, hydralazine, thi- sibility of a tumor should always be considered in any
oridazine (Mellaril), and propranolol (10,45). patient who presents with unilateral rhinosinusitis.
348 Barnes
Factitial Rhinosinusitis Nasal polyps are found in a wide variety of

diseases, including CF, rhinosinusitis, asthma, aspirin
Some individuals are habitual ‘‘nose-pickers,’’ a prac- hypersensitivity as well as in various other conditions
tice that may result in significant squamous metaplasia, listed in Table 3. Although there has been much
focal loss of the mucociliary clearance function, muco- interest in their growth, development, and molecular
sal ulceration, and infection. Likewise, young children biology, it is still unknown why some patients with
and mentally challenged individuals may insert a rhinosinusitis develop polyps while others do not
variety of foreign bodies into their nose that, if not (3,6–20). It is possible that the polyp is a common
detected by those around them, might lead to infection. histological endpoint of a variety of diseases of
diverse etiology that happen to share a common
Systemic Causes of Rhinosinusitis bond—an inflammatory edematous mass (polyp).
There are a variety of systemic diseases that may be
associated with rhinosinusitis, with or without polyps.
Some of these include asthma, cystic fibrosis (CF) B. Clinical Features
(discussed elsewhere in this chapter), Kartagener’s They typically occur in individuals older than 20 years
syndrome, Young’s syndrome, diabetes mellitus, yel- and are more common in males by a ratio of 1.5:1 to
low nail syndrome, Wegener’s granulomatosis, allergic 2:1 (21,22). Occurrence in children is uncommon and,
granulomatosis, and vasculitis of Churg-Strauss (53,54). when found, should always raise the possibility of CF
Evidence suggesting a connection between nasal or an infectious etiology (23). The polyps may be
polyps and diabetes mellitus is intriguing. Smith, in single or multiple, unilateral or bilateral, and are
his series of 40 patients with nasal polyps, observed accompanied by nasal obstruction, headaches, sneez-
that 42% had abnormal glucose tolerance tests and ing, and rhinorrhea, which, at times, may be purulent.
57% had a family history of diabetes (55). He stated Exceptionally, they may also present with epistaxis,
that two conditions are necessary for their develop- proptosis, and visual disturbance and may even erode
ment: (i) local irritation, such as allergy or infection bone (24–26).
and (ii) fluctuating glucose levels.
The rationale for this association is as follows. As
insulin diminishes, blood glucose increases, but is C. Pathology
unable to cross cell membranes because this is an
insulin-dependent reaction. When insulin is restored, Grossly, polyps are soft, smooth, gray-pink, myxoid to
the cells are presented with an increased substrate of mucoid, and translucent and often exhibit a promi-
glucose, which, in the presence of hexokinase, is nent surface network of capillary-size vessels (Fig. 3).
phosphorylated into glucose-6-phosphate and then Microscopically, they display varying combinations of
metabolized into various polysaccharides (hyaluronic stromal edema, congestion, thickening, or hyaliniza-
acid, chondroitin sulfates, and heparin) and smaller tion of the epithelial basement membranes, goblet cell
hydrophilic colloids. Because nasal tissue lacks hyperplasia, increased production of mucus with
glucose-6-phosphate, this reaction is irreversible. The formation of mucous cysts and contain an infiltrate
excess molecules, predominantly colloids, are then of eosinophils, plasma cells, lymphocytes, and mast
deposited extracellularly in the nasal mucosa where cells. Unless the polyp is of infectious origin or sec-
they exert an osmotic pressure, resulting in the edem- ondarily infected, neutrophils are uncommon. The
atous appearance characteristic of polyps (‘‘polysac- surface epithelium is of the respiratory type, often
charide nose’’). Local irritation enhances this sequence with areas of squamous metaplasia (Fig. 4). With long
of events. duration, the stroma may become fibrotic (Fig. 5).
Ultrastructurally, thickening of capillary base- Nerves are rarely seen.
ment membranes has been observed similar to that
found in the microangiopathy of diabetes (56).
Idiopathic Rhinosinusitis
As the name implies, idiopathic rhinosinusitis is
inflammation of the sinonasal tract in which no
known or predisposing condition can be identified.
II. NASAL POLYPS

A. Introduction
Nasal polyps are nonneoplastic inflammatory swel-
lings of the nasal mucosa that affect 1% to 4% of the
general population (1–3). Most arise from the anterior Figure 3 The typical nasal polyp has an edematous-myxoid
ethmoid-middle meatus and only rarely on the nasal gross appearance, with delicate surface vascularity, and will
transilluminate.
septum (4,5). Similar polyps can occur in the para-
nasal sinuses (sinus polyp, sinonasal polyp).
‘‘allergic polyp’’ should not be used as a pathological

diagnosis. Likewise, the term ‘‘inflammatory polyp’’
is potentially misleading and might be misconstrued
that the polyp is of infectious origin and might result
in the patient being treated unnecessarily with anti-
biotics. The noncommittal term ‘‘nasal polyp’’ is,
therefore, preferred.
There is some controversy on whether all nasal
polyps should be submitted for routine histological
evaluation (29,30). The answer is an unequivocal
‘‘Yes!’’ Although clinicians are generally good at
recognizing polyps, there are certainly exceptions
that may be significantly more ominous than polyps
and require additional investigation and therapy
(30,31).
Pathologists should be aware of three important
histological findings in nasal polyps: (i) stromal aty-
pia, (ii) epithelial abnormalities, and (iii) granulomas.
Atypical stromal cells are especially common in nasal
polyps that have been previously biopsied or have
undergone surface ulceration and necrosis. The cells
are usually widely scattered throughout the stroma or
around the blood vessels or just beneath the surface
epithelium (Fig. 6) (32–35). These cells represent reac-
tive histiocytes, fibroblasts, or myofibroblasts, and
Figure 4 Nasal polyp with well-vascularazed edematous stroma they typically contain enlarged, hyperchromatic,
containing scattered inflammatory cells and a mucus-retention round, ovoid-to-spindled-shaped nuclei, and pink-to-
cyst (H&E, 50).
amphophilic, sometimes vacuolated cytoplasm.
Despite their pleomorphism, they rarely demonstrate
any appreciable mitotic activity (Fig. 7). Depending on
the cell of origin, they may be positive on immunos-
taining for a-1-antichymotrypsin, CD-68, vimentin,
and actin. They are important because they are often
mistaken for malignancy, especially embryonal rhab-
domyosarcoma. In rhabdomyosarcoma, the tumor
cells are, at least focally, densely concentrated and
may even form a cambium layer; mitoses are com-
mon, cross-striations may be found, and the cells are
positive for myoglobin, myogenin, or desmin. The age
Figure 5 Note the three smaller nasal polyps that are fibrotic.
With long duration, polyps often became fibrotic and will not
transilluminate.
Pathologists have used a variety of terms for

these lesions, including allergic, simple, mucous, and
inflammatory polyps. Although eosinophils and a
thickened epithelial basement membrane suggest an
allergic etiology, several reports have cautioned that
histological features do not always correlate with the Figure 6 Nasal polyp with stromal atypia. Note that the cells
atopic status of the patient nor indicate, even at the with prominent, hyperchromatic nuclei are widely scattered, not
local level, that the lesion is related to an antigen- densely concentrated as in some tumors (H&E, 50).
antibody reaction (6,7,21,27,28). Therefore, the term
350 Barnes
the percentage of cells expressing Ki-67 was very low.

Moreover, the bizarre cells were not associated with
hyperplasia of the basal cell layer. Rather, the atypical
cells were often found in the superficial layer of
the respiratory mucosa, sparing the basal cell
compartment.
Granulomas are identified in about 1% of all
nasal polyps (39). Some are clearly related to intrana-
sal corticosteroid injections, inhalation or application
of medicinals with oily bases (paraffinoma), ruptured
mucous cysts, or cholesterol granulomas (CGs)
(40,41). Others are due to sarcoid, tuberculosis, other
infectious granulomatous diseases, Wegener’s granu-
lomatosis, and so forth.

Effective treatment consists of relieving the nasal
Figure 7 Higher magnification of benign, reactive stromal cells
obstruction and identifying the etiology. The thera-
occasionally seen in nasal and antrochoanal polyps. The cells, in
this instance, have elongated, hyperchromatic nuclei but show
peutic armamentarium includes hyposensitization,
no mitotic activity. Such cells may be mistaken for strap cells of a antihistamines, decongestants, corticosteroids, antibi-
rhabdomyosarcoma (H&E, 400). otics, avoidance of aspirin, control of diabetes, envi-
ronmental manipulation, and surgery. Local
recurrences, however, are not uncommon.
of the patient may also be helpful, for polyps are
uncommon in individuals younger than 20 years, III. ANTROCHOANAL POLYPS
whereas embryonal rhabdomyosarcomas are seen
more often in children. A. Introduction
Nakayama et al. noted in their review of 29 nasal The antrochoanal polyp (ACP), also known as the
polyps with stromal atypia that some exhibited a Killian polyp, is a large, solitary, typically unilateral
variable, aberrant expression for cytokeratin (CK), polyp that arises in the maxillary sinus, usually on the
which might result in their being mistaken for a posterior wall, occasionally on the inferior, medial, or
spindle cell squamous carcinoma (35). In spindle cell lateral wall and rarely from the superior or anterior
carcinoma, the tumor cells will be densely concentrated, wall (1–6). It extends in an hourglass fashion through
mitotically active, and invasive. In addition, foci of the normal or accessory ostium of the maxillary sinus
dysplasia, in situ or invasive conventional squamous into the middle meatus and then into the posterior
cell carcinoma may also be seen if the biopsy is large choana where it accounts for 3% to 6% of all ‘‘nasal
enough or enough sections are examined. Also in polyps’’ (2,7). In some instances, it may be large
spindle cell carcinoma, the spindle cells may be posi- enough to obstruct the entire nasopharynx or even
tive for p63, while polyps with stromal atypia are extend beyond the level of the soft palate.
negative. Although some patients with ACPs have an
Epithelial dysplasia or carcinoma in situ may be allergic background, it is controversial whether this
seen focally in 1.1% to 1.8% of all nasal polyps (36). contributes to their formation (2–9). It is the consensus,
There is no apparent correlation between the duration however, that most are of an inflammatory rather than
of the disease and the severity of these epithelial an allergic origin.
alterations. Follow-up has shown simple polypectomy
to be curative. Hasegawa et al. have also reported a
case of a microinvasive squamous cell carcinoma B. Clinical Features
arising in a nasal polyp (37). The patient received no
further treatment, other than polypectomy, and was ACPs are more common in males (65%) and in patients
stated to be free of disease six months later. between 10 and 40 years of age (70%) (2–8). It accounts
Westra et al. have also observed that patients for 25% to 35% of all nasal polyps in children (9,10).
receiving chemotherapy, especially alkylating agents, Although rare instances of bilateral ACPs have been
may exhibit epithelial atypia of the sinonasal tract (38). described, the overwhelming majority present as
The distribution of the abnormal cells was distributed unilateral nasal obstruction associated with mouth
unevenly throughout the mucosa. In other areas, the breathing, snoring, rhinorrhea, protruding nasal mass,
cells occupied the full thickness of the epithelium and/or recurrent episodes of sinusitis (6,11,12).
reminiscent of high-grade dysplasia or carcinoma in
situ. In addition to the clinical history that should alert C. Imaging
the pathologist to chemotherapeutic-induced atypia,
Westra et al. noticed that the abnormal cells were not The presence of a posterior choanal or nasopharyngeal
associated with appreciable mitotic activity and that soft-tissue density in conjunction with unilateral
IV. PRIMARY CILIARY DYSKINESIA

(IMMOTILE CILIA SYNDROME)
A. Introduction
It is estimated that the human body contains about
3 trillion cilia, which are divided into eight categories:
(i) mucus-propelling cilia, (ii) water-propelling cilia,
(iii) nodal cilia, (iv) monocilia, (v) rudimentary cilia,
(vi) olfactory cilia, (vii) photoreceptor cilia, and
(viii) sperm flagella (1,2). Genetic errors of each result
in specific outcomes. For example, defective water-
propelling cilia, olfactory cilia, and sperm flagella may
result in hydrocephalus, anosmia, and infertility,
respectively.
The mucus-propelling cilia, the subject of the
remaining discussion, are concerned with cleansing
the upper and lower respiratory tract of particulate
Figure 8 Antrochoanal polyp with large mucous retention cyst. matter, noxious agents, and infectious organisms.
Observe the long, tortuous tail. Abnormalities of these are divided into two categories—
primary and secondary. Primary causes are congenital
or genetic and are typically associated with structural
changes that render the cilia immotile and/or dysfunc-
mucosal thickening, cloudiness, or opacification of the tional and predispose the individual to repeated epi-
maxillary sinus is highly suggestive of an ACP. sodes of rhinosinusitis, bronchitis, and/or pneumonia—
Approximately 30% to 40% of patients, however, a condition previously referred to as immotile cilia
have bilateral maxillary sinusitis, but even in these syndrome and, more recently, as PCD (3–9).
instances, the polyp is almost invariably unilateral Secondary causes (secondary ciliary dyskinesia) are
(2,3,7). ACPs do not erode or destroy contiguous soft acquired and are usually temporary and reversible.
tissue or bony structures (13). There is no significant Such changes are seen in persistent heavy smokers
lateralization to either maxillary sinus. and following viral infections of the upper respiratory
tract (10,11).
D. Pathology
Other than the presence of an occasional cyst, repre-
senting the maxillary component of the polyp, and the PCD occurs in 1 in 20,000 to 1 in 34,000 births and is
presence of a stalk or long pedicle, representing the not a life-threatening disease (1,6,12). Symptoms
maxillary attachment, ACPs are grossly identical with include rhinorrhea, a moist-sounding cough, rhinosi-
other nasal polyps (Fig. 8). Microscopically, there are nusitis often associated with polyps, bronchitis, and
only quantitative differences, at most, between the frequent ear complaints (otitis, decreased hearing).
two; ACPs tend to have fewer mucoserous glands About half the cases are also associated with situs
and fewer eosinophils than ordinary nasal polyps. inversus or Kartagener’s syndrome, an autosomal
Atypical stromal cells, representing a reactive recessive disorder characterized by sinusitis, bron-
phenomenon, are sometimes seen. Their presence chietasis, and situs inversus (13).
has no clinical significance, but pathologists should Although patients are symptomatic soon after
be aware of this finding so that they do not confuse birth (‘‘my baby was born with a cold’’), it is not
the change with evidence of malignancy (Figs. 6 and 7) unusual for some patients to be in adulthood before it
(14). Because of their long pedicle, ACPs are susceptible is recognized. Once PCD is entertained, it is essential
to torsion with compromise of their vascular supply that cilia be evaluated for motility and ultrastructural
resulting in histological changes that might be confused abnormalities. Cilia from the nose, rarely the trachea,
with a vascular neoplasm or even a malignant process. are usually obtained either by biopsy or brush tech-
Such polyps are sometimes referred to as angiomatous nique (14).
or angiectatic ACPs (15,16).
C. Pathology
The mucus-propelling cilia are approximately 6 mm in
ACPs treated intranasally by snare and avulsion diameter and there are 200 or more per cell (2). They
without due respect for their stalks have a 20% to exhibit a characteristic 9 þ 2 structure similar to
30% rate of recurrence; most of these reappear within the hubs and spokes of a wheel (Figs. 9 and 10).
two years of excision (2,3,7). If the maxillary sinus is At the center are two singlet microtubules (representing
entered and the pedicle of the polyp is removed with the hub), which are connected to nine peripheral
adjacent normal mucosa, the recurrence rate is practi- doublets (each representing two microtubules) by a
cally nil. series of nine spokes. The outer doublets are also
352 Barnes
Figure 9 Cross-sectional diagram of a single cilium showing components and organization.
Any loss of the structural units, as noted above,

may result in immotile or dyskinetic cilia. The most
common abnormalities are those of the dynein arms,
either one or both are absent or diminished in number (2).

As previously indicated, PCD is not a life-threatening
illness. Treatment is palliative and centered around
maintaining the airway with mucolytic agents and
anti-inflammatory medication as needed. Obstructive
nasal polyps may have to be removed and
the sinuses drained. Serous otitis may also require
myringotomies.
V. CYSTIC FIBROSIS
A. Introduction
CF (mucoviscidosis) is the most common lethal genetic
disease among whites. It was first described by
Franconi et al. in 1936 and was given its present
Figure 10 Electron microscopic view of normal nasal cilia name of CF by Anderson in 1938 (1,2).
obtained by brush microscopy. Compare with Fig. 9. The disease follows an autosomal recessive pat-
tern of inheritance. A child born to two heterozygous
carriers has a 1:4 risk of having the disease, a 1:2
chance of being a carrier, and a 1:4 chance of neither
connected to one another by two arms, inner and being a carrier nor having the disease. The disease
outer dynein, that are attached to the doublets in a does, however, vary among ethnic groups. It has the
counterclockwise fashion. It is the arms that produce highest frequency among those of white Northern
the actual motion (1). The cilia beat asymmetrically European extraction, affecting about 1:2000 to 1:2500
with a relatively stiff forward stroke to move the newborns in this population (3–6). The frequency of
mucus, while on the backstroke they flex so that the heterozygote carrier in this same group is 1:20 to
they are drawn through the mucus so as not to stir 1:25 (4,5). Blacks and Asians are seldom affected.
the mucus in the opposite direction. Current estimates indicate that there are approximately
25,000 to 30,000 persons with this disease in the Nasal polyps are common in patients with CF,
United States (6,7). with most large series reporting an incidence of 10%
The gene responsible for CF has been localized to 20% (range 6–48%) (11–13,15,21,22). The polyps
to the long arm of chromosome 7 (4,8). This is a large tend to be multiple and bilateral and often appear at
gene composed of more than 250,000 base pairs and an early age. Nasal polyps in children are relatively
27 exons that encodes for a protein of 1480 amino uncommon; therefore, if a child develops bilateral
acids (4,6). This protein, referred to as cystic fibrosis nasal polyps before the age of 10 years, CF should
transmembrane conductance regulator (CFTR), is always be considered. In a review of 120 children with
intimately involved in a cAMP-dependent pathway nasal polyps, Schramm and Effron observed that 29%
for the transport of chloride across cell membranes occurred in association with CF (23). However, polyps
(6,9). are rarely the first manifestation of CF. It is much
The most common mutation in CF is a three- more common for polyps to develop in patients with
base-pair deletion that results in the absence of one known CF (3).
amino acid (phenylalanine, abbreviated ‘‘F’’) in the 508 Once the diagnosis is entertained, it can usually
position of the CFTR protein (5,6). Except for the be verified by an elevated sweat chloride test in excess
missing phenylalanine, the CFTR protein remains of 60 nEg/L. According to Davis, there are very few
intact, yet the flaw changes its structure and function diseases in children that elevate the chloride concen-
enough to produce a fatal disease. This specific genetic tration to this level (6). Among these are included
deletion, referred to as DF508, occurs in approximately untreated adrenal insufficiency, ectodermal dysplasia,
70% of patients with CF and is associated with the most renal diabetes insipidus, some forms of glycogen
severe form of the disease (5,6,10). The remaining 30% storage disease, and, possibly, untreated hypothyroid-
of patients have mutations at any of more than 200 sites ism. The role of molecular testing for the CFTR gene is
in the gene for CFTR (6). also becoming more available (11,24,25).
The basic genetic abnormality in CF, in summary,
is a defect in a cell membrane protein (CFTR) involved
in the secretion and absorption of chloride. A decrease C. Imaging
in chloride permeability across the membrane of
Imaging almost invariably reveals panopacification
epithelial cells of exocrine glands, in turn, leads to an
of the paranasal sinuses, particularly the maxillary
influx of salt and water into the cells, resulting in
and ethmoid. The frontal sinus is not present at
dehydration of the extracellular fluid compartment,
birth and, in fact, often fails to develop in patients
an increased chloride concentration in sweat (the
with CF (17). Despite evidence of radiographic
basis of the diagnostic sweat test), and thickening of
involvement, only 11% to 57% of patients actually
exocrine secretions.
complain of symptomatic sinusitis (fever, purulent
rhinorrhea, tenderness, or pain) (13,15). Bacterial
B. Clinical Features colonization alone does not always lead to infection,
but when infection occurs, it tends to be severe.
More than 60% of patients with CF will be diagnosed
Fortunately, the complications of sinusitis, such as
during the first year of life and fewer than 5% after the
osteomyelitis and orbital or cerebral abscesses, are
age of 15 years (6). Virtually, all of the clinical man-
rare (17). This may be the result of the frequent use of
ifestations of the disease can be attributed to the thick,
antibiotics or thickening of the adjacent bone from
tenacious secretions that accumulate in the ducts of
chronic persistent inflammation, which might pre-
exocrine organs that lead to destructive, inflammatory
vent spread.
changes, especially in the pancreas and lungs (11).
Eighty-five percent to 90% of patients will experience
pancreatic dysfunction with steatorrhea, malnutrition, D. Pathology
and possible growth retardation. Pulmonary involve-
ment, which tends to be chronic and suppurative, There is controversy on whether or not nasal polyps
eventually leads to insufficiency, and this is the most removed from patients with CF show histological
common cause of death in patients with CF. Other changes that are diagnostic of this disorder.
manifestations include meconium ileus, cholelithiasis, Oppenheimer and Rosenstein indicate that nasal
biliary cirrhosis, and infertility. polyps associated with CF may be identified by a
The sinonasal tract is the most conspicuously distinct triad of histological findings: (i) a thin delicate
involved site in the head and neck (12–18). Salivary surface epithelial basement membrane, (ii) lack of
glands are also affected, but rarely become symptom- extensive tissue eosinophilia, and (iii) the presence of
atic. Otitis media, likewise, is also uncommon in CF acid mucin in the glands and cysts (acid mucin stains
(19,20). blue with the alcian blue–periodic acid–Schiff stain)
Sinus involvement in CF is initiated by accumu- (26). In contrast, polyps that are not due to CF,
lation of viscous secretions that block the draining according to these investigators, exhibit a reversal of
ostia. This, in turn, leads to hypoxia, damage or this triad: (i) a thick, hyalinized surface epithelial
functional loss of the ciliary-clearing mechanism, basement membrane, (ii) stromal eosinophilia, and
edema, inflammation, and colonization by bacteria, (iii) the presence of neutral mucin in glands and
especially Pseudomonas aeruginosa, S. aureus, H. influ- cysts (neutral mucin stains red with alcian blue–
enzae, or anaerobes (17). periodic acid–Schiff stain).
354 Barnes
Other investigators, on the other hand, contend Table 4 Classification of Fungal Infections of
that there are no significant histological differences the Sinonasal Tract
between those polyps associated with CF and those
I. Invasive
that are not (3,12). More specifically, Tos et al. studied
A. Acute, fulminant, immunocompromised
and compared 11 CF polyps with 102 non-CF polyps B. Chronic, indolent, immunocompetent
and found no difference in density, distribution, II. Noninvasive
or architecture of glands, nor found any in the surface A. Mycetoma: fungus ball
epithelium or stroma between the two types of polyps B. Allergic fungal rhinosinusitis
(12). From these studies, it is apparent that histological
evaluation of nasal polyps in CF is not entirely specific
and cannot be used alone to either establish or refute noninvasive group, is now being recognized with
the diagnosis. However, the presence of neutrophils, increased frequency.
sparse numbers of eosinophils, and lack of basement AFRS represents about 5% to 10% of all cases of
thickening in a nasal polyp removed from a child chronic sinusitis (1–5). It was probably first described
should make one at least think about CF. in 1976 by Saferstein who reported a 24-year-old
The pathogenesis of nasal polyps in CF appears woman with allergic bronchopulmonary aspergillosis
to be multifactorial. Some contend that they are clearly associated with nasal obstruction, nasal polyps, and
related to the thick mucus that distends the mucoser- nasal cast formation (6). Cultures of the sinus grew out
ous glands. The cystic glands, in turn, compress adja- Aspergillus fumigatus. In 1981, Miller et al. presented
cent blood vessels with subsequent stromal edema five additional cases and coined the phrase ‘‘allergic
and prolapse (17,27). The incidence of allergic rhinitis aspergillosis of the paranasal sinuses’’ (7). Katzenstein
is about the same in CF as in the general population et al. reported seven more cases in 1983 and also noted
(16). It is thought that allergy as well as infection may that the fungal hyphae resembled those of Aspergillus
also contribute to the formation of some polyps in CF and proposed the name ‘‘allergic Aspergillus sinusi-
(12,17). tis’’ (1). Subsequent reports revealed that fungi other
than Aspergillus could also cause the syndrome and,
accordingly, the more generic term of ‘‘allergic fungal
E. Treatment and Prognosis sinusitis’’ was proposed (3,8–12).
Sinonasal disease in CF may respond to medical More recently, it has been shown that allergic
therapy, whereas others will require surgery. In the mucus is not unique to AFRS and that it can be seen in
past, surgery was largely palliative and consisted a variety of other eosinophilic sinonasal disorders
primarily of simple polypectomy for nasal obstruc- [eosinophilic chronic rhinosinusitis (ECRS)], not nec-
tion. Recurrences were high, but acceptable, because essarily of allergic origin (Table 5) (4,5,13,14).
the risks associated with more extensive surgery and Accordingly, it has been proposed that the term
prolonged anesthesia were believed to be potentially ‘‘eosinophilic mucin’’ might be more accurate than
life threatening. More recent studies, however, have ‘‘allergic mucus’’ (13).
not supported this viewpoint and clearly point to the Ponikau et al. have observed that fungal organ-
advantages of combining polypectomy with additional isms can be demonstrated in almost all individuals,
sinus operations, such as the Caldwell–Luc proce- including normal controls as well as those suffering
dure, endoscopic sinus surgery, or ethmoidectomy from chronic rhinosinusitis (15). Why some individu-
(13–16). Cepero et al., for instance, observed a 61% als develop an immunological reaction to the fungi
recurrence rate for patients who underwent nasal and others do not is not entirely clear, but may be
polypectomy alone versus 9% for those who had related to genetic factors and the atopic status of the
both polypectomy and additional paranasal sinus patient.
surgery (13). The distinction between the various types of
Although there have been significant advances ECRS shown in Table 5 depends on clinical, physical,
in the recognition and symptomatic treatment of CF, it imaging, immunological, and pathological findings.
continues to be a lethal disease, with a median survival So what is the role of the pathologist? The pathologist
of about 30 years (6). With the advent of lung trans- can only report the presence or absence of allergic
plantation and the possibility of gene therapy on the (eosinophilic) mucus. If found, then he/she must
horizon, patients may live considerably longer or even report whether fungal organisms are seen and, if
be cured of their disease. possible, try to identify the fungus. All too often, it
is impossible for the pathologist to identify the fungal
organisms with certainty, and as a result, a diagnosis
VI. ALLERGIC MUCUS—ALLERGIC
FUNGAL RHINOSINUSITIS Table 5 Classification of ECRS
A. Introduction 1. Superantigen-induced ECRS

2. Allergic fungal rhinosinusitis
Fungal infections of the nasal cavity and paranasal 3. Nonallergic fungal ECRS
sinuses can be divided into two broad categories: 4. Aspirin-exacerbated ECRS
invasive and noninvasive (Table 4). Allergic fungal Abbreviation: ECRS, eosinophilic chronic rhinosinusitis.
rhinosinusitis (AFRS), the newest member of the Source: From Ref. 14.
of ‘‘allergic (eosinophilic) mucus containing fungi of

uncertain type’’ would be appropriate. It is then up to
the clinician to determine whether the patient has
AFRS or non-AFRS and, if necessary, the type of
fungus with appropriate cultures. If the IgE level is
elevated, he/she probably has AFRS and, if normal,
nonallergic fungal ECRS (Table 5).
The following discussion pertains only to the
AFRS.
AFRS is currently defined as fungal organisms associ-
ated with allergic (eosinophilic) mucus and an elevated
IgE (13,14).
AFRS should be suspected in any young adult
who presents with (i) recurrent sinonasal polyps, (ii) a
history of asthma, (iii) multiple involved sinuses on Figure 11 Image showing bilateral opacification of the nasal
imaging, (iv) poor response to medical treatment, (v) a cavity and paranasal sinuses in a patient with allergic fungal
history of multiple surgical procedures for chronic pol- rhinosinusitis. Note the erosion of bone, especially the medial
ypoid sinusitis, and (vi) a history of atopy with sinonasal wall of the right orbit.
polyps, and (vii) who is found to have thick inspissated
mucus at the time of surgical intervention (16).
AFRS affects both sexes equally and occurs in all
age groups. Most, however, are between 20 and
40 years of age at the time of diagnosis. Virtually, all
patients have sinonasal polyps, 41% have asthma, 70%
have peripheral eosinophilia, 13% have a history of
aspirin sensitivity, almost all have an increased serum
total IgE level, and 52% to 58% have positive skin tests
to fungal antigens (13).
C. Etiology
AFRS is thought to be mediated through a type I (IgE)
and possibly type III (immune complex) immunologi-
cal reaction. The disease begins by inhalation and
trapping of the fungi in the mucous blanket of the
sinonasal tract. Fungal antigens then react with IgE- Figure 12 Thick, tenacious mucus removed from a patient with
sensitized mast cells with a subsequent cascade of allergic fungal rhinosinusitis, often described as similar to peanut
immunological events that result in an inflammatory butter or wet clay.
response.
D. Imaging
retention cysts are additional findings. The most dis-
Computed tomography scans characteristically reveal tinguishing feature, however, is the character of the
opacification of the nasal cavity and one or more para- mucus that is grossly thick, white, yellow, green, or
nasal sinuses, either unilateral or bilateral (Fig. 11). brown, with the consistency of ‘‘peanut butter’’ or ‘‘wet
Erosion of bone (skull base and orbit) is seen in 20% to clay’’ (Fig. 12).
60% of cases and should not be mistaken for tumor
Microscopically, the mucus appears inspissated
(5,17–19). AFRS is almost always an isolated event; only or ‘‘dried out’’ and purple or basophilic. It contains
rarely does it coexist with allergic bronchopulmonary large collections of ‘‘smudged’’ eosinophils and
aspergillosis.
neutrophils with admixed sloughed ciliated respirato-
ry epithelial cells. At times, the mucus even appears
E. Pathology laminated (Fig. 13). The eosinophils are frequently
ruptured and their granules widely dispersed.
Pathologically, AFRS consists of edematous polypoid Charcot–Leyden crystals are universal (Fig. 14).
respiratory mucosa with numerous mononuclear Fungi (hyphae), however, are sparse and, if found at
inflammatory cells and prominent eosinophils. all, are always located in the mucus and never in the
Hyalinization and thickening of the basement mem- tissue (Fig. 14). The use of fungal stains (silver methe-
brane and goblet cell hyperplasia with mucous namine and periodic acid–Schiff are very useful.
356 Barnes
Caution must be exercised in trying to identify

fungi by their characteristics in tissue sections.
Cultures have shown that many of the septated
hyphal forms observed in biopsies are actually dema-
tiaceous or other fungi mislabeled as Aspergillus. In a
review of cultures from 139 patients with ‘‘AFRS,’’
Cody et al. observed that the cultures were positive in
63% of patients and negative in 37% (3). Of those with
positive cultures, the most commonly recovered fungi,
in descending order, were Bipolaris, Curvularia,
Aspergillus, and Alternaria.
The Fontana–Masson stain may be very helpful
in distinguishing some of the dematiaceous fungi
from an Aspergillus sp. The former group of fungi
produces a melanin-like pigment and, accordingly,
will be positive with this stain. Aspergillus sp., with
the exception of Aspergillus niger, will be negative.
Figure 13 Note the edematous, inflamed respiratory mucosa
with the thick, hyalinized basement membrane on the left and the F. Treatment and Prognosis
allergic mucus on the right with a purple inspissated and lami-
nated appearance with entrapped, degenerating inflammatory The treatment of patients with allergic mucus is the
cells (H&E, 100). same, regardless of the presence or absence of fungi.
This consists of complete endoscopic removal of the
mucus and inflamed tissue followed by intranasal or
systemic corticosteroids and possible maintenance
therapy with fungal desensitization vaccines
(5,11,16,20,21). Since the fungus is noninvasive,
systemic antifungal agents are not indicated. There
is, however, some evidence that topical antifungal
agents or irrigating the sinonasal tract with a solution
of these drugs may be beneficial by decreasing the
numbers of fungi and, thereby, lessening the antigenic
stimulus.
Persistence of disease is common, particularly
when there has been incomplete eradication of the
allergic mucin. Even when the patient is disease-free,
recurrences are possible, presumably from reexposure
to fungal antigens.
VII. MUCOCELES
A. Introduction
Figure 14 High-power magnification of allergic fungal rhinosi-

A mucocele of a paranasal sinus is a slowly enlarging,
nusitis. Note the Charcot-Leyden crystals and the degenerating epithelial-lined lesion, containing mucus. It fills the
eosinophils (H&E, 40). A Grocott stain revealed a few fungal sinus cavity and, if neglected, may erode bone and
hyphae that were positive on culture for Aspergillus (inset, involve contiguous structures. The mucus is usually
Grocott, 400). sterile, but secondary infection may lead to the devel-
opment of a mucopyocele.
Any condition that obstructs the draining ostium
of a sinus can lead to a mucocele. Among the various
Mucus with the foregoing characteristics is causes are included inflammation, allergies, previous
referred to as ‘‘allergic (eosinophilic) mucus.’’ Fungi surgery, trauma, or tumor. The distribution and fre-
are not always demonstrated histologically or by quency of mucoceles among the sinuses vary accord-
culture in patients who have allergic mucus. In fact, ing to medical center (Table 6) (1–7). All agree,
in about 35% to 40% of patients with allergic mucus, however, that the frontal sinuses are more often
no fungi will be found (3). The failure to demonstrate involved.
fungi might be related to tissue sampling or to Mucoceles are typically unilateral and limited
destruction of the fungus by the existing inflamma- to one sinus. Some, however, do involve two or
tion. Alternatively, allergens or conditions other than more sinuses. When multiple, the sinuses most
fungal may be responsible for the allergic mucus often affected are the frontoethmoid and sphenoeth-
(Table 5). moid (8–11).
Table 6 Distribution of Mucoceles of the Paranasal Sinuses VIII. CHOLESTEROL GRANULOMA

Bockmuhl (7) Natvig (1) Total (%) A. Introduction
Sinus (N ¼ 290) (N ¼ 112) (N ¼ 402)
Frontal 125 86 211 (52%)
CGs are relatively frequent in the middle ear–mastoid
Maxillary 72 3 75 (19%) but distinctly unusual in the paranasal sinuses. Most
Ethmoid 41 7 48 (12%) originate in the maxillary sinus, but any sinus can be
Sphenoid 29 0 29 (7%) involved (1–6). They may also arise in the orbital
Frontoethmoid 23 16 39 (10%) bones, especially the frontal bone in the region of the
superotemporal quadrant above the lacimal fossa.
Most orbitofrontal CGs, however, remain separate
from the frontal sinus but may on occasion involve
the sinus (7,8).
Mucoceles occur over a broad age range, but are B. Etiology
uncommon in children. Most patients are between
40 and 70 years of age (1). The gender distribution Hemorrhage, impaired drainage, and poor ventilation
varies from 1:1 to 2:1 in favor of males (1,7). are important etiological factors. Prior trauma and
Signs and symptoms depend on the involved severe episodes of chronic rhinosinusitis with mucosal
sinus but usually include headache, pain or pressure ulceration are thought to be the sources of bleeding.
over the sinus, nasal obstruction, periorbital swelling, Leon et al. have also suggested that increased intra-
exophthalmos, and disturbances of vision and smell. sinus pressure due to drainage obstruction may affect
About 10% of individuals are asymptomatic. venous and lymphatic drainage from the sinus cavity
Exceptional cases of sphenoethmoid mucoceles leading to venule microhemorrhages while still allow-
have been associated with amenorrhea and galactor- ing arterial blood in the sinus mucosa and further
rhea (11). Some mucoceles are ‘‘invasive’’ and may contributing to a larger localized hemorrhage (3).
extend into the orbit or anterior cranial cavity (8,10). Subsequent hemolysis of the blood leads to the
accumulation of cholesterol from the red blood cells
and an inflammatory giant cell reaction known as CG.
C. Imaging
Imaging studies show a normal or expanded sinus C. Clinical Features
with a diffuse, homogenous opacification. One or
more bony walls may appear thin or eroded (12,13). CGs are more common in men and occur over a broad
If the mucocele is related to previous surgery, imaging age range (26–65 years) with a mean age of 42 years
will reveal ‘‘footprints’’ of the prior procedure. Rarely, (1–6). They typically develop in patients with a history
gross calcific deposits may also be seen (14). of chronic rhinosinusitis or trauma. Signs and
symptoms are largely nonspecific, and, as a result,
the diagnosis is rarely suspected clinically. The most
D. Pathology frequent complaints are headache, facial pain or pres-
The diagnosis of a mucocele of a paranasal sinus is a sure, nasal congestion, periorbital swelling, visual
clinical and not a histological diagnosis. Characteristic disturbances, dysosmia, and even otalgia. Proptosis
imaging studies and the finding at surgery of a sinus is almost universal in patients with orbitofrontal
filled with mucus associated with a narrow ostium is CGs (7).
diagnostic.
The specimen sent to pathology consists only of D. Imaging
the lining of the mucocele—ciliated respiratory
mucosa—and no mucus. As a result, it is impossible Imaging studies are nonspecific and range from poly-
for the pathologist to determine whether the lining is poid mucosal thickening to opacification of the sinus.
simply normal mucosa, represents a case of rhinosi- Occasionally, one will see an expanding cyst-like
nusitis, or is the wall of a mucocele. lesion with erosion and/or destruction of one or
The ciliated respiratory lining may exhibit more of the bony walls, which may, in some instances,
increased inflammatory and goblet cells, focal squa- masquerade as a malignant neoplasm (4).
mous metaplasia, ulceration, granulation tissue, loss
of cilia, and/or thickening and hyalinization of base-
E. Pathology
ment membranes (9,15).
The gross appearance varies according to the duration
E. Treatment and Prognosis of the lesion. Some are bloody and resemble a lique-
fied hematoma, while others are more fibrotic, yellow
Treatment consists of surgically evacuating the mucus to golden brown.
content of the mucocele and reestablishing adequate Microscopically, a CG consists of a more or less
drainage of the sinus. This can usually be accom- circumscribed mass of inflammatory granulation
plished with an endoscope (7,16). Local recurrences and/or fibrous tissue containing numerous elongated
are rare and usually do not exceed 2% (7). clefts surrounded by foreign body giant cells. The
358 Barnes
Figure 15 Cholesterol granuloma composed of granulation- Figure 16 Myospherulosis. Note the pseudocysts surrounded
fibrous tissue containing cholesterol clefts, hemosiderin, inflam- by dense fibrous tissue with scattered inflammatory cells (H&E,
matory cells, and giant cells (H&E, 700). 40). Some of the pseudocysts contain altered erythrocytes that
agglomerate into sporangium-like sacs that may be mistaken for
a fungus (inset, H&E, 400).
clefts represent the footprints of cholesterol crystals

dissolved in tissue processing. Hemosiderin is always
present, and there may be evidence of recent hemor- grains, an observation that has been confirmed by
rhage (Fig. 15). electron microscopy (2,9).
The disease was first described in 1969, when
McClatchie et al. reported a series of seven patients
F. Treatment and Prognosis from East Africa suffering from solitary, indurative
soft-tissue lesions of the arms, legs, and buttocks (10).
Surgical excision, usually through a Caldwell–Luc
Unable to classify the fungus-like bodies present in
procedure, with restoration of drainage and ventila-
biopsies of these patients, they coined the descriptive
tion is the treatment of choice.
term ‘‘myospherulosis’’ for this disease. The disease
was not recognized in the United States until 1977,
IX. MYOSPHERULOSIS when Kyriakos described 16 patients from the
St. Louis metropolitan area (2). However, in contrast
Myospherulosis is basically an iatrogenic pseudomy- to the African patients, those in St. Louis had their
cotic disease caused by the interaction of red blood disease confined to the nose, paranasal sinuses, and
cells with petrolatum, lanolin, or traumatized human middle ear. The patients, eight men and eight women
adipose tissue (1–8). As a result, large, sporangium- ranging from 15 to 86 years of age, all had previous
like sacs filled with numerous spherules are produced operations, usually a Caldwell–Luc procedure, involv-
that are often mistaken for a fungus. However, these ing these areas of the body. The operations were
structures do not react with the usual fungus stains, performed for inflammatory conditions and a variety
do not grow in cultures, and are not compatible with of benign and malignant tumors. Kyriakos astutely
any known pathogenic fungus. Tissue removed from observed that at the termination of each of the surgical
these patients contains microscopic pseudocysts that, procedures, the wound was packed with gauze
when numerous, impart a Swiss cheese appearance. impregnated with petrolatum and an antibiotic (usu-
The pseudocysts are surrounded by dense fibrous ally tetracycline). He suggested that contaminated
tissue containing lymphocytes, plasma cells, histio- gauze might be the source of the myospherules.
cytes, and multinucleated foreign body giant cells Rosai, intrigued by the resemblance of the endo-
(Fig. 16). Within these spaces, one finds large, bodies to erythrocytes, observed that these structures
brown, sac-like structures (‘‘parent bodies’’) contain- were positive when stained for hemoglobin and per-
ing numerous endobodies (‘‘spherules’’) (Fig. 16). The oxidase (3). Furthermore, he noted that when eryth-
parent bodies are generally round, have a thick non- rocytes were incubated with a petrolatum-tetracycline
refractile wall, and range from 20 to 120 mm in ointment, typical parent bodies with spherules were
diameter (2). Budding yeasts, hyphae, or pseudohy- formed. These observations clearly established the
phae are not seen. The structures do not react with erythrocyte origin of the myospherules and laid to
methenamine silver or periodic acid–Schiff stains. rest the notion of an infectious disease. Wheeler and
They also give negative staining reactions for cellulose McGavran subsequently demonstrated that either pet-
and chitin, indicating that they are not inhaled pollen rolatum or lanolin, both components of the ointment,
and not the antibiotic, were the culprits responsible C. Clinical Findings
for the disease (4). In addition, they found that emul-
sified human fat could also induce formation of these In our review of 23 cases, 13 occurred in females and
structures and offered this as an explanation for the 10 in males who ranged in age from 25 to 79 years
disease in the African patients. Reasoning that it was (mean 50 years) (1–15). The disease most often involves
unlikely that all the African patients had been exposed the nasal cavity, either unilaterally or bilaterally, and
to antibiotic ointments, they suggested that fat necro- only rarely extends into the sinuses (usually the maxil-
sis secondary to trauma, injections, or infections might lary) or orbit (6,14,15). At least two cases have been
result in lipids responsible for the formation of described in the subglottic area of the larynx (2,3). In
myospherules. the nasal cavity, the preferred site is the septum
Although myospherulosis was initially thought followed by the lateral wall. As the disease evolves,
to be a totally innocuous iatrogenic disorder, subse- usually over many years, the nasal cavity becomes
quent reports have indicated that it may exceptionally progressively obstructed and multiple sites are
occur spontaneously (11,12) and, in many instances, involved.
often results in a chronic, painful inflammatory reac- Nasal obstruction is, by far, the most frequent
tion that requires surgical removal (13). The excised initial complaint. Pain and epistaxis are uncommon.
tissue is fibrotic and often has a brown or black On physical examination, the nasal mucosa and
discoloration from acid hematin, a degradation prod- adjacent soft tissue appear swollen, thickened, and
uct of hemoglobin (5,14). fibrotic, often resulting in fibrous tumor-like masses.
Myospherulosis must be recognized to avoid In more advanced cases, the entire nose may be
confusion with mycotic disease and the attendant enlarged and deformed.
morbidity of unwarranted antifungal therapy. The At least 4 (17%) of the 23 cases reviewed were
diseases most often confused with this disorder are found to have cutaneous lesions of granuloma faciale
coccidioidomycosis and rhinosporidiosis. In contrast (1,2,8,11). These appeared on the skin of the nose,
with myospherulosis, these two organisms are posi- malar prominence, temporal area, and forehead. In
tive with the usual fungal stains and are negative on two cases, the cutaneous lesions predated the appear-
immunostaining for hemoglobin. Furthermore, ance of EAF, while the other two developed during
Rhinosporidium is mucicarminophilic, whereas myo- the course of the disease.
spherulosis is not. Reports describing the synchronous
occurrence of both myospherulosis and Aspergillus sp., D. Imaging
however, have been published (15).
Imaging studies show thickening or polypoid hyper-
plasia of the nasal mucosa and soft tissue often
X. EOSINOPHILIC ANGIOCENTRIC FIBROSIS associated with opacification of one or more sinuses
A. Introduction and deviation of the nasal septum. Destruction of
cartilage and bone is not uncommon in more
Eosinophilic angiocentric fibrosis (EAF) is a chronic, advanced cases.
idiopathic disorder that characteristically involves the
upper respiratory tract, especially the nasal cavity, E. Pathology
which leads to progressive obstruction and airway
compromise over a course of many years (1–15). Roberts and McCann have identified two phases of
The disease was first described by Holmes and the disease, early (active) and late (quiescent), which
Panje in 1983 who regarded it as a intramucosal form may coexist (2). The active phase is characterized by a
of granuloma faciale (1). It was Roberts and McCann, prominent inflammatory infiltrate composed of
who in 1985, reported three more cases, described the numerous eosinophils with admixed plasma cells,
pathology in detail, and coined the term ‘‘eosinophilic lymphocytes, and few neutrophils centered around
angiocentric fibrosis’’ (2). capillaries, venules, and arterioles (Fig. 17). The
inflammatory cells may spill into the walls of blood
B. Etiology vessels, but vascular necrosis and thrombosis are rare
to absent. Small foci of stromal necrosis, however,
The etiology is unknown. Whether EAF represents a may be seen. Multinucleated giant cells and granulo-
mucosal form of the cutaneous lesion known as gran- mas are not observed.
uloma faciale or whether it has any relationship at all In the late stage, the inflammation becomes less
to this lesion remains uncertain. Some patients have a intense and fibrosis more apparent. The most charac-
history of allergic rhinosinusitis or allergies to other teristic feature of the disease, in addition to eosino-
substances, such as penicillin. This coupled with the phils, is the prominent deposition of collagen around
fact that large numbers of eosinophils are observed in blood vessels in an ‘‘onion skin’’ pattern (Fig. 18).
tissue samples have led some to speculate that EAF Even in the late stage, eosinophils are still usually
may have an allergic basis. On the other hand, most apparent, unless the patient has received prior
patients do not have allergies, and corticosteroids, corticosteroids.
thus far, are largely ineffective in controlling the The spindle cell fibrotic areas demonstrate dif-
disease. These features mitigate against allergy as an fuse strong positivity for vimentin but are negative
etiological factor. for smooth muscle actin, desmin, S-100 protein, and
360 Barnes
pseudotumor. The absence of multinucleated giant

cells, granulomas, prominent (geographic) necrosis
and peripheral eosinophilia, and negative cyto-
plasmic-staining antineutrophil cytoplasmic auto-
antibodies (c-ANCA) and perinuclear-staining
antineutrophil cytoplasmic autoantibodies (p-ANCA)
are sufficient to exclude the first two conditions.
Inflammatory pseudotumor typically does not contain
large numbers of eosinophils nor shows the typical
‘‘onion skinning’’ of blood vessels.
G. Treatment and Prognosis

Surgery is the treatment of choice. Although largely
untested, initial results indicate that corticosteroids
and cytotoxic agents are ineffective. Recurrences
over a course of many years are common, necessitat-
ing repeat excisions.
Figure 17 Eosinophilic angiocentric fibrosis, early phase. Note

the prominent component of eosinophils (H&E, 400). XI. RESPIRATORY EPITHELIAL
ADENOMATOID HAMARTOMA
A. Introduction
Hamartomas (from the Greek, hamartia, meaning
‘‘fault’’ or ‘‘defect’’) are benign, nonneoplastic over-
growths of tissue(s) indigenous to the area of their
occurrence. They may be composed entirely of epithe-
lial or mesenchymal elements or both and should be
distinguished from teratomas and dermoids (1–5).
Teratomas are composed of tissues from all three
germ layers and are capable of autonomous growth,
whereas dermoids are usually cystic and comprise
primarily of ectodermal and, to a lesser extent, meso-
dermal elements.
Hamartomas of the sinonasal tract are uncommon and
most often of the pure epithelial type. Wenig and
Heffner have described 31 cases composed of a benign
glandular proliferation of respiratory epithelial cells
Figure 18 Eosinophilic angiocentric fibrosis, late phase. The that they have designated as ‘‘respiratory epithelial
small blood vessels are surrounded by rings of collagen (‘‘onion- adenomatoid hamartomas (REAH)’’ (4).
skin’’ pattern), and fibrosis is more apparent (H&E, 400). These occurred in 27 men and 4 women who
ranged in age from 27 to 81 years (median 58 years).
Most were unilateral and arose from the nasal cavity
(22 cases, 71%), particularly the posterior nasal sep-
CD-34 (6). The inflammatory infiltrate is polyclonal, tum and, to a lesser extent, along the lateral nasal wall,
reacting with B- and T-cell markers without a specific middle meatus, and inferior turbinate. A few, how-
pattern of distribution and without light chain restric- ever, were bilateral. The remaining cases occurred in
tion (6). the nasopharynx and paranasal sinuses. Nasal stuffi-
Complete blood counts show no evidence of ness, obstruction, epistaxis, and chronic rhinosinusitis
peripheral eosinophilia. Antineutrophil cytoplasmic with or without coexistent nasal polyps were the most
autoantibodies (ANCA) are negative, and the erythro- common manifestations.
cyte sedimentation rate is normal or only slightly
elevated.
C. Pathology
F. Differential Diagnosis REAHs are typically polypoid or exophytic, rubbery,

tan-white to red-brown and range up to 6 cm in great-
The differential diagnosis includes Wegener’s granulo- est dimension (2,4) (Fig. 19). Histologically, they are
matosis, Churg-Strauss syndrome, and inflammatory composed of small-to-medium-sized, round-to-oval
Hamartomas composed entirely of mucoserous

glands (1) and mesenchymal components (2,3,5) have
also been described in the sinonasal tract.
REAHs are most often confused with ordinary nasal
polyps, inverted papilloma (IP), and adenocarcinoma.
The presence of excess glands readily distinguish this
lesion from a nasal polyp. In contrast with REAH,
which occurs primarily on the nasal septum, IPs arise
almost exclusively on the lateral nasal wall in the
vicinity of the middle turbinate and ethmoid sinus
area. IPs are also composed predominantly of hyper-
plastic islands of squamous epithelium with few
interspersed mucous (goblet) cells and a prominent
intraepithelial component of neutrophils. Respiratory
epithelium may also be seen, but is usually not domi-
Figure 19 Respiratory epithelial adenomatoid hamartoma com-
posed of small to medium-sized glands lined by ciliated, respira- nant. The basement membranes around the epithelial
tory epithelium (H&E, 100). islands in IPs are also thin and delicate, not thick and
hyalinized, as seen in REAH. Mucoserous glands are
also sparse to absent in IPs.
Adenocarcinomas are characterized by back-to-
back arrangement of their glands, occasional nuclear
pleomorphism, prominent mitotic activity, and a des-
moplastic response to stromal invasion. These features
are not seen in REAH.

Simple but complete surgical excision is curative.
Recurrences are practically nonexistent.
XII. SCHNEIDERIAN PAPILLOMAS

A. Introduction
The ectodermally derived, ciliated, respiratory mucosa
that lines the nasal cavity and paranasal sinuses, so-
called Schneiderian membrane, gives rise to three
Figure 20 Higher magnification of respiratory epithelial adeno-
morphologically distinct papillomas. These are
matoid hamartoma. Note that each gland tends to be surrounded referred to individually as the exophytic, inverted,
by a thick eosinophilic or hyalinized basement membrane (H&E, and oncocytic Schneiderian papillomas or, collective-
200). ly, as Schneiderian papillomas.
Ever since their first recognition by Ward in
1854, papillomas of the sinonasal tract have been the
center of controversy over their nomenclature, etio-
glands lined by ciliated respiratory epithelium, often logy, pathology, and biological behavior (1). Over the
with numerous, admixed mucin-secreting (goblet) years, no fewer than 53 different terms have been
cells. The glands arise from invagination of the surface applied to these lesions. It was Hyams who, in 1971,
epithelium into the lamina propria and, consequently, finally brought some order to this chaos when he
often maintain direct continuity with the surface. The reported the clinicopathological features of
glands are widely spaced and characteristically sur- 315 Schneiderian papillomas and proposed that they
rounded by thick, eosinophilic basement membranes be subclassified into the three types, as basically noted
(Fig. 20). The stroma is well vascularized, edematous, above (2). There are some, however, who still consider
or fibrous and contains scattered chronic inflammatory these three lesions as a single entity and group them
cells. together under such generic terms as ‘‘papilloma,’’
Small mucoserous (salivary) glands are also ‘‘papillomatosis,’’ or ‘‘Schneiderian papilloma’’ (3,4).
occasionally seen. Whether they are part of the hamar- We, as well as others, are firmly convinced that there
toma or just a reactive hyperplastic response to the are sufficient clinical, pathological, and potential etio-
inflammation is uncertain, although the latter is logical differences among these lesions to warrant
favored (4). their separation (5,6).
362 Barnes
As a group, Schneiderian papillomas are uncom-

mon, representing only 0.4% to 4.7% of all sinonasal
tumors (7). Nasal polyps, in turn, are 25 to 60 times
more common than papillomas (3,8).
Although the etiology is unsettled, a viral origin,
at least for the exophytic papilloma (EP) and IP, has
been suggested. This issue is discussed in more detail
later. An association with allergy, inflammation,
smoking, or other environmental noxious agents is
not convincing (2,9).
Although Fu et al. have reported a series of nine
patients with Schneiderian papillomas, who also had a
personal history of genital warts, it is generally con-
ceded that patients with sinonasal papillomas do not
exhibit an increased tendency for developing papillo-
Figure 21 Exophytic papilloma attached to the nasoseptal
mas in other sites (10).
cartilage by a broad base.
B. Exophytic Papilloma (Fungiform Papilloma,

Septal Papilloma, Squamous Papilloma) Imaging
Clinical Features Imaging evaluation of EP is generally not indicated.
At most, the lesion will appear as a soft-tissue density
Depending on the series, EP comprise 18% to 50% of
along the nasal septum, with little, if any, evidence of
all Schneiderian papillomas (Table 7) (2,5,11,12). They
nasal septal erosion.
are 2 to 10 times more common in men and occur
primarily in individuals between 20 and 50 years of
Pathology
age (range 21–87 years) (2,13). They characteristically
arise on the nasal septum, usually the anterior portion; Most EPs range from a few millimeters up to about
only 4% to 21% originate on or involve the lateral 2 cm. Microscopically, they are composed of papillary
nasal wall (2,14,15). Involvement of the paranasal fronds with delicate fibrovascular cores covered by
sinuses is distinctly unusual, if indeed, it occurs epithelium, 5- to 20-cells thick, that varies from squa-
at all. There is no significant lateralization to either mous to transitional (intermediate) to ciliated, pseu-
side of the nose. Generally solitary and discrete, they dostratified columnar (respiratory) (Fig. 22). Scattered
may be multifocal, but bilaterality is rare (3.6%) (13). mucin-containing cells, representing residual goblet
Epistaxis, nasal obstruction, or the presence of an cells, are common. Surface keratinization is absent or
asymptomatic mass are the typical presenting scant, unless the patient is a ‘‘nose picker’’ and irrita-
symptoms. tes the lesion or if the papilloma is unusually large
On physical examination, EPs appear as exo- and hangs into the nasal vestibule where it is more
phytic, papillary, or warty gray, pink, or tan, non- exposed to the drying effect of ambient air. In these
translucent growths attached to the nasal septum by a instances, surface keratin may be apparent. Mitoses
relatively broad base (Fig. 21). are rare and never atypical. The fibrovascular stroma
contains few, if any, mucoserous glands and, unless
Etiology infected or irritated, sparse inflammatory cells.
There is increasing evidence to suggest that EPs may Carcinoma and Exophytic Papilloma
be etiologically related to the human papillomavirus
(HPV), especially types 6 and 11, rarely 16 and 57b. In Carcinoma arising in or associated with EPs is excep-
a collective review of 79 EPs evaluated for the pres- tional. Buchwald et al. have described a case of a
ence of HPV by in situ hybridization or the polymer- 40-year-old man who developed a squamous cell
ase chain reaction, 45 (57%) were positive (Table 8) carcinoma in an EP that was first excised 16 years
(10,11,15–21). ago (23). HPV 6/11 was demonstrated by in situ
Table 7 Frequency of Various Types of Schneiderian Papillomas

No. of oncocytic
References Total no. of cases No. of exophytic papillomas No. of inverted papillomas Schneiderian papillomas
Hyams (2) 315 156 (50%) 149 (47%) 10 (3%)
Buchwald (11) 78 16 (21%) 57 (73%) 5 (6%)
Michaels (5) 191 36 (19%) 139 (73%) 16 (8%)
Weiner (12) 114 21 (18%) 90 (79%) 3 (3%)
Total 698 (100%) 229 (33%) 435 (62%) 34 (5%)
Table 8 Incidence of HPV in Exophytic Papillomas

References Test Total no. of cases Total no. positive for HPV Percent positive Type(s) of HPV
Hirschfield (16) DNA-ISH 10 7 70 6/11
Judd (17) DNA-ISH, PCR 3 3 100 6/11
Fu (10) RNA-ISH 5 4 80 6/11
Kashima (18) PCR 26 4 15 6,11
McLaughlin (19) DNA-ISH, PCR 5 3 60 6/11
Sarkar (20) PCR 2 1 50 6b/11
Wu (21) RNA-ISH, PCR 7 7 100 57b
Buchwald (11) DNA-ISH, PCR 16 11 69 6/11, 16
Gaffey (22) DNA-ISH, RNA-ISH 5 5 100 6, 11
Total 79 45 Average ¼ 72%
(100%) (57%) Median ¼ 70%
Range ¼ 15–100%
Abbreviations: DNA-ISH, deoxyribonucleic acid in situ hybridization; RNA-ISH, ribonucleic acid in situ hybridization; PCR, polymerase chain reaction;
HPV, human papillomavirus.

Complete surgical excision is the treatment of choice.
Because the majority of recurrences tend to occur in
the site of previous removal, inadequate excision,
rather than multiplicity of lesions, probably accounts
for most of the 22% to 50% incidence of local recur-
rence (2,8,13).
C. Inverted Papilloma
Clinical Features
IPs constitute 47% to 79% of all Schneiderian papillo-
mas (Table 7). They are two to five times more
common in men and are found primarily in the
40- to 70-year age group (2,3,9,14,15,24–31). The six-
year-old boy included in the series of Eavey is the
Figure 22 Exophytic papilloma composed of papillary fronds of youngest patient yet described with the disease (32).
squamous cells. Note the absence of surface keratin and scat-
They characteristically arise from the lateral
tered foci of clear cells within the epithelium, which represent
residual mucous cells (H&E, 40).
nasal wall in the region of the middle turbinate or
ethmoid recesses and often extend secondarily into
the sinuses, especially the maxillary and ethmoid and,
to a lesser extent, the sphenoid and frontal. Isolated
lesions of the paranasal sinuses without nasal involve-
hybridization and polymerase chain reaction in
ment, however, do occur (31,33). Only about 8% of IPs
the original papilloma as well as in the recurrent
arise on the nasal septum (34). Their rarity on the
papilloma and in the carcinoma.
nasal septum may be partly due to the fact that there
Norris described another possible case that
is little soft tissue in the septum for the lesion to invert
occurred in a 62-year-old man who experienced four
into before it meets the resistance of the underlying
recurrences of his EP over the course of nine years
septal cartilage which, in turn, would force the lesion
(13). He subsequently developed an invasive squa-
to grow exophytically.
mous cell carcinoma in the same area.
Although reported to be bilateral in 0% to 10% of
cases, such an occurrence should always arouse the
suspicion of septal erosion and perforation from uni-
EP must be distinguished from the much more com- lateral disease (2,3,15,25,30).
mon keratinizing cutaneous papillomas (e.g., verruca Exceptionally, IPs may arise in sites other than
vulgaris) occurring in the nasal vestibule. The lack of the sinonasal tract. They have been recorded in the
extensive surface keratinization and the presence of oropharynx (35), posterior pharyngeal wall (36), hypo-
mucous cells (accentuated by mucin stains) and pharynx (37), nasopharynx (35,38), lacrimal sac (39),
ciliated or ‘‘transitional’’ epithelium serve to distin- middle ear-mastoid (40), and possibly in the wall of a
guish EP from cutaneous papillomas. In addition, the branchial cleft cyst (41). It has been suggested that
presence of mucoserous glands and septal cartilage ectopic migration of the Schneiderian membrane dur-
further indicate that the lesion is of mucosal, rather ing embryogenesis could account for those aberrant
than cutaneous origin. papillomas in sites contiguous with the sinonasal tract
364 Barnes
(2). Whether all of these ectopic cases are bona fide IPs HPV genomes in IPs by in situ hybridization or the
is uncertain. polymerase chain reaction, particularly HPV 6 and 11,
Unilateral nasal obstruction is the most common sometimes 16 and 18, and exceptionally HPV 57. The
presenting symptom. Other manifestations include frequency of finding the virus by these specialized
nasal drainage, epistaxis (10–20% of cases), anosmia, techniques is highly variable, ranging anywhere from
headaches (especially frontal), epiphora, proptosis, 0% to 100% (Table 9) (10,11,16–21,42–52). In a collec-
and diplopia. Pain, on the other hand, is an uncom- tive review of 341 IPs evaluated for the presence of
mon initial complaint, occurring in only about 10% of HPV by a variety of sophisticated molecular techni-
cases. When present, it should always suggest second- ques, 131 (38%) were positive (Table 9).
ary infection or even a malignant change (25). Macdonald et al. have also found evidence of the
On physical examination, IPs present as pink, Epstein–Barr virus (EBV) DNA in 13 of 20 (65%) IPs by
tan, or gray nontranslucent, soft-to-moderately firm using the polymerase chain reaction and have raised
polypoid growths, with a convoluted or wrinkled the possibility that this virus might be involved in its
surface (Figs. 23 and 24). pathogenesis (53). Gaffey et al., on the other hand, in
an in situ hybridization study of 19 IPs (1 of which
Etiology was associated with squamous cell carcinoma) found
no evidence of EBV (22). Obviously, more studies are
Although IPs have long been suspected of being of needed to resolve these conflicting data and the rela-
viral origin, viral inclusions have never been unequiv- tion, if any, between IPs and EBV.
ocally demonstrated by either light or electron micros- If one assumes that the IPs is etiologically related
copy. In addition, they are almost invariably negative to the HPV, then several important questions need
when stained for the HPV by immunoperoxidase. to be addressed: (i) Why is the virus so site specific
Some investigators, however, have demonstrated (i.e., lateral nasal wall)? (ii) Why are IPs almost
invariably unilateral? (iii) Why are IPs so rare in
children who are, conceivably, more susceptible to
viral infections than adults? (iv) If the IP is related to
an HPV infection, why do we not see several members
of a family affected with the lesion? (e) If due to HPV,
could IPs be treated with antiviral medication, rather
than by surgery?
Imaging
Imaging findings vary with the extent of the disease
(54). Early on, there may be only a soft-tissue density
within the nasal cavity or paranasal sinuses. Later,
with more extensive disease, unilateral opacification
and thickening of one or more of the sinuses are
common, as are expansion and displacement of adja-
Figure 23 Gross appearance of an inverted papilloma of the cent structures (Fig. 25). Pressure erosion of bone may
lateral nasal wall removed intact by a medial maxillectomy. Note also be apparent and must be distinguished from
the polypoid growth and that each papillary structure is opaque osseous invasion associated with malignancy.
and will not transilluminate. Extensive bone destruction should always raise the
possibility of a carcinoma arising in, or associated
with, an IP.
Pathology
Microscopically, IPs are composed of hyperplastic
ribbons of basement membrane—enclosed epithelium
that grows endophytically into the underlying stroma
(Figs. 26 and 27). The epithelium is multilayered,
usually 5- to 30-cells thick, and formed of squamous
or ciliated, columnar (respiratory) epithelial cells
admixed with goblet cells. Nonkeratinizing squamous
epithelium tends to predominate, but occasionally a
case may be composed almost entirely of respiratory
epithelium (Figs. 28 and Fig. 29). Gradations between
these two extremes are not uncommon, resulting in a
Figure 24 Gross appearance of an inverted papilloma. Note the transitional epithelium reminiscent of that seen in the
convoluted surface, much like the gyri and sulci of the brain or a urinary tract. All of these epithelial types may be
wrinkled prune. present in the same lesion, and their proportions
may vary widely in different lesions or even in
Table 9 Incidence of HPV in Inverted Papillomas

Total no. Total no. positive
References Test of cases for HPV Percent positive Type(s) of HPV
Respler (42) Southern blot 2 2 100 11
Syrjanen (43) IP-PAP, DNA-ISH 14 11 79 11, 16
Weber (44) DNA-ISH 21 16 76 6b, 11
Brandwein (45) RNA-ISH 7 5 71 6/11, 16/18
Bryan (46) PCR 13 10 77 6, 11
Klemi (47) DNA-ISH 19 13 68 11, 16
Siivonen (48) DNA-ISH 21 13 62 11, 16
Hirschfield (16) DNA-ISH 9 2 22 6/11
Ishibashi (49) Southern blot 7 1 14 6
Furuta (50) Dot blot, ISH, PCR 26 5 19 11, 16
Judd (17) DNA-ISH, PCR 9 0 0 0
Fu (10) RNA-ISH 4 4 100 6/11
Kashima (18) PCR 29 7 24 6,11
McLachlin (19) DNA-ISH, PCR 17 4 24 6, 11, 16
Sarkar (20) PCR 24 0 0 0
Wu (21) RNA-ISH 15 12 80 57, 16
Beck (51) PCR 32 20 63 6, 11, 16, 18
Buchwald (11) DNA-ISH, PCR 52 3 6 6, 11
Ogura (52) Southern blot 1 1 100 57
Gaffey (22) DNA-ISH, RNA, ISH 19 2 11 11, 16
Total 341 131 Average ¼ 50%
(100%) (38%) Median ¼ 62.5%
Range ¼ 0–100%
IP-PAP, immunoperoxidase antiperoxidase; HPV, human papillomavirus.
Figure 26 Cut surface of an inverted papilloma. Note the

hyperplastic ribbons of epithelium that grow inward into the
stroma.
Figure 25 Image of a 46-year-old man with an inverted papilloma.

There is a soft-tissue density in the area of the left middle turbinate
(arrow) associated with opacification of the left frontal, ethmoid,
The stroma ranges from dense and fibrous to
and maxillary sinuses.
loose and myxoid, with or without an inflammatory
component (Fig. 27). The inflammatory cells, especial-
ly neutrophils, often transmigrate through the epithe-
lium (Fig. 29). Eosinophils and basement membrane
different areas of the same papilloma (Fig. 30). Mitoses thickening are not seen (Figs. 28 and 29). Mucoserous
are not numerous and, if present at all, are seen glands are also sparse to absent because the abnormal
primarily in the basal and parabasal epithelium. epithelium uses the salivary ducts and glands as
Ten percent to 20% of IPs may show focal surface scaffolds to extend into the stroma, thereby obscuring
keratinization and 5% to 20% varying degrees of their normal appearance.
dysplasia (2,9,24,51,55,56). These are not necessarily As IPs enlarge, they may obstruct the drainage of
signs of malignancy, but they should alert the pathol- nearby sinuses. As a result, it is not uncommon to also
ogist of the need for thorough evaluation of the find ordinary nasal polyps in IP specimens. They can
papilloma. usually be identified grossly by their more myxoid
366 Barnes
Figure 27 Patient with concurrent inverted papilloma and a

nasal polyp (arrow ). Polyps are smooth, glistening, mucoid to
Figure 29 Inverted papilloma composed of hyperplastic ciliated
myxoid, and transilluminate. Because of the mass effect of the
respiratory epithelium. Observe the thin basement membrane
epithelium growing inward, inverted papillomas will not
and characteristic epithelial transmigration of neutrophils (H&E,
transilluminate.
400).
Figure 28 Higher magnification of the advancing (inverted) Figure 30 Inverted papilloma composed of squamous and
edge of an inverted papilloma. The epithelium is of the squamous ciliated respiratory epithelium (H&E, 100).
type and the clear cells are mainly due to the accumulation of
glycogen. Note the thin basement membrane and sharp bound-
ary between epithelium and stroma (H&E, 200).
diagnosis of ‘‘IP with focal verrucous hyperplasia’’
might be appropriate. This change has no clinical
significance other than it might be mistaken for
appearance and the fact that they will transilluminate, a verrucous carcinoma (see sect. ‘‘Differential
whereas IPs will not (Fig. 27). Diagnosis’’).
Rarely, an IP will exhibit focal surface changes
reminiscent of a verruca vulgaris; that is, it will show Carcinoma and Inverted Papilloma
focal papillary squamous epithelial hyperplasia, with
marked keratosis or parakeratosis, with or without a IPs are occasionally complicated by carcinomas, espe-
prominent granular cell layer, and often contains cially squamous cell carcinoma and, to a much lesser
numerous vacuolated cells suggestive of koilocytes extent, verrucous (57,58), mucoepidermoid (3), spin-
(Fig. 31). Although this might be a viral effect, immu- dle cell, and clear cell carcinomas (8), as well as
nohistochemical stains for HPV, in my experience, are adenocarcinoma (54). The incidence of malignant
invariably negative. When this change is observed, the change in individual series of IPs has ranged
anywhere from 2% to 27% (Table 10) (2–4,9,11,14, primarily an IP with only a small focus of carcinoma,
26–31,47,51,55,56,59–62). In a collective review of (ii) those who have primarily a carcinoma with only a
1390 IPs reported in the literature, 150 (11%) were small focus of IP, and (iii) those who have an IP and
associated with carcinoma (Table 10). then years later develop a carcinoma in the area in
Patients with IPs that are associated with carci- which the papilloma arose.
nomas fall into three groups: (i) those who have Of all carcinomas associated with IPs, approxi-
mately 61% are synchronous and 39% metachronous
(Table 10). For metachronous carcinomas, Lesperance
and Esclamado observed the mean interval between
the onset of the IP and the development of carcinoma
to be 63 months (range 6 months–13 years) (63).
Carcinomas complicating IP vary from well- to
poorly differentiated and exhibit a broad range of
behavior. Some are in situ and of little consequence,
whereas others are locally aggressive or may even
metastasize (Fig. 32).
The carcinomas may actually arise within the
papilloma (carcinoma ex-IP), as evidenced by a gra-
dation of histological changes, ranging from dyspla-
sia, to carcinoma in situ, to frankly invasive
carcinoma; whereas in others, the carcinoma is merely
associated with a histologically bland IP. Once a
carcinoma is recognized, the pathologist should not
only indicate the histological type, the degree of inva-
sion and differentiation, and the adequacy of resection
Figure 31 Inverted papilloma with focal verrucous hyperplasia. margins (if possible) but also quantitate its volume
Note the papillary epithelial hyperplasia and marked surface (e.g., the specimen consists of 30% IP and 70% poorly
keratinization. Although not illustrated, a prominent granular differentiated squamous cell carcinoma).
cell layer and koilocytes are also occasionally seen. This change There is no correlation between the number of
may be mistaken for a verruca vulgaris or a verrucous carcinoma local recurrences of an IP and the subsequent devel-
(H&E, 40). opment of carcinoma (25). There is some evidence,
however, to suggest that HPV 16 and 18 may be more
Table 10 Incidence of Carcinoma in Inverted Papillomas
No. of carcinomas
Total no. of inverted Percent of
References papillomas No. of carcinomas Synchronous Metachronous carcinoma
Norris (55) 29 2 1 1 7
Skolnik (59) 33 5 1 4 15
Hyams (2) 149 19 ? ? 13
Snyder (3) 39 8 7 1 21
Lasser (60) 17 4 2 2 24
Woodson (61) 90 4 1 3 4
Abildgaard-Jensen (56) 21 3 2 1 14
Weissler (4) 223 11 8 3 5
Segal (62) 30 3 0 3 10
Christensen (14) 39 7 6 1 18
Klemi (47) 19 3 2 1 16
Phillips (27) 112 8 8 0 7
Myers (26) 33 7 5 2 21
Outzen (28) 67 1 0 1 2
Furuta (50) 26 7 5 2 27
Dolgin (29) 42 5 4 1 12
Bielamowicz (30) 61 10 5 5 16
Vrabec (9) 101 8 7 1 8
Beck (51) 39 10 3 7 26
Buchwald (11) 57 5 3 2 9
Lesperance (63) 51 14 6 8 27
Lawson (31) 112 6 4 2 5
Total 1390 150 80 51 Average ¼ 14%
(11%) (61%) (39%) Median ¼ 13.5%
Range ¼ 2–27%
368 Barnes
(IDP) of minor salivary gland origin, and invasive

carcinoma.
In nasal polyps with squamous metaplasia, one
will usually see thickening and hyalinization of the
basement membrane, prominent mucoserous glands
and, often, a large number of inflammatory cells,
especially eosinophils. These features are absent in
IP. In addition, the epithelium lining the mucoserous
glands in nasal polyps is not multilayered, contains
more mucous cells, and does not show the character-
istic epithelial transmigration of neutrophils.
Features that are useful in distinguishing respi-
ratory epithelial adenomatoid hamartoma from IP are
covered elsewhere in this chapter (see sect.
‘‘Respiratory Epithelial Adenomatoid Hamartoma’’).
Although IDP and IP share similar names, they should
not be confused. The former is innocuous compared
with the potentially locally aggressive behavior of the
Figure 32 Inverted papilloma with focal squamous cell carcinoma
latter. In contrast with IP, which arises from the
in situ. Note the pleomorphic cells and intact basement membrane
(H&E, 200).
surface epithelium and grows endophytically, IDP
arises from the excretory duct of minor salivary
glands; hence, it will grow intraluminally and be
confined by the duct. IP also arises in the sinonasal
carcinogenic than HPV 6 and 11 (47,48,51). In the tract, while the IDP occurs almost exclusively in the
study of Klemi et al. and Siivonen and Virolainen oral cavity.
(47,48), three of eight (38%) IPs that contained HPV 16 Invasive carcinoma can be distinguished from
also had carcinoma. Klemi et al. also studied 19 IPs by the ordinary IP by the presence of the following
flow cytometry (47). Six of 19 (32%) were aneuploid features in the former lesion and their absence in the
and of the six that were aneuploid, two (33%) were latter: cellular pleomorphism, atypical mitoses, kera-
associated with carcinomas. Only 1 of the 13 (8%) tin pearls, loss of basement membrane, and unequiv-
diploid IPs was associated with carcinoma. They ocal invasion associated with an inflammatory
indicated that if the papillomas were both HPV 16– desmoplastic stromal response.
positive and aneuploid, the incidence of malignant
transformation was even higher. Treatment and Prognosis
According to Schwerer et al., p53 expression as IPs are thought to enlarge by squamous metaplasia of
determined by immunohistochemistry can be the adjacent mucosa. Although histologically benign,
detected in the majority of IPs, but usually only in they have an unlimited growth potential and, if
the basal and parabasal cells (64). Strong diffuse neglected, can cause considerable morbidity or even
staining, however, is associated with a sixfold greater death by extending into contiguous structures (68).
chance for carcinoma (65). Attempts to remove these lesions intranasally by
Data also suggest that CD44s may also be useful snare and avulsion have resulted in ‘‘recurrence
in predicting which IP will become malignant. Ingle (persistence?)’’ rates of 0% to 74% (average 60%) (31)
et al. observed that CD44s is diffusely expressed (Fig. 33).
immunohistochemically in typical IPs, whereas an IP
with an invasive squamous cell carcinoma, the expres-
sion of CD44s in the malignant component is reduced
or absent (66).
In a molecular-genetic appraisal of IPs, Califano
et al. confirmed that the papillomas are monoclonal
proliferations but are not necessarily premalignant
(67). They concluded that ‘‘IPs do not fit the profile
of a prototypic precursor lesion in that they do not
harbor critical genetic alterations that are known to
drive malignant transformation of the upper respira-
tory tract. In some instances, concurrent IPs and
sinonasal squamous cell carcinoma my even arise
from entirely different progenitor cells.’’
Figure 33 Patient with an inverted papilloma of the lateral nasal
wall that was initially treated by a conservative intranasal
approach. Because of recurrence (?persistence), a medial max-
The differential diagnosis includes nasal polyps illectomy was necessary for complete removal. Note the random
with squamous metaplasia, respiratory epithelial small foci of residual papilloma on the turbinates.
adenomatoid hamartoma, inverted ductal papilloma
Table 11 Krouse Staging System for Inverted Papilloma D. Oncocytic Schneiderian Papilloma
(Cylindrical Cell Papilloma,
T1 Tumor totally confined to the nasal cavity, without Columnar Cell Papilloma)
extension into the sinuses. The tumor can be localized to
one wall or region of the nasal cavity or can be bulky and Clinical Features
extensive within the nasal cavity, but must not extend
into the sinuses or into any extranasal compartment. Oncocytic Schneiderian papilloma (OSP) is the rarest
There must be no concurrent malignancy. of the three morphological variants of Schneiderian
T2 Tumor involving the ostiomeatal complex, ethmoid papillomas, constituting only 3% to 8% of the total
sinuses, and/or the medial portion of the maxillary sinus, (2,5,11,12,73–75) (Table 7). It shows many features in
with or without involvement of the nasal cavity. There common with the IP. In fact, some consider it to be
must be no concurrent malignancy. only a variant of the IP. Microscopically, however, the
T3 Tumor involving the lateral, inferior, superior, anterior, or
two lesions are distinct.
posterior walls of the maxillary sinus, with or without
involvement of the medial portion of the maxillary sinus,
OSP is equally distributed between the sexes and
the ethmoid sinuses, or the nasal cavity. There must be most of the patients are older than 50 years at the time
no concurrent malignancy. of diagnosis. The youngest patient reported thus far in
T4 All tumors with any extranasal/extrasinus extension the literature has been a 33-year-old woman (76).
to involve adjacent, contiguous structures such Recently, however, I have seen a case in consultation
as the orbit, the intracranial compartment, or the that involved a 25-year-old woman.
pterygomaxillary space. All tumors associated with OSP occurs exclusively on the lateral nasal wall
malignancy. or in the sinuses, usually the maxillary or ethmoid,
Source: From Ref. 70. and presents as a fleshy pink, tan, red-brown, or gray
papillary or polypoid growth (Fig. 34). Unilateral
nasal obstruction and intermittent epistaxis are the
The ‘‘gold standard’’ of therapy for most IPs most common symptoms.
has been a lateral rhinotomy and medial maxillec-
tomy with meticulous removal of all mucosa in the
ipsilateral paranasal sinuses (26,57). With this Etiology
approach, the incidence of recurrence is 20% (range At least 22 cases of OSPs have been examined by in
0–37%) (69). More recently, a less aggressive situ hybridization or the polymerase chain reaction for
approach using endoscopic resection has gained the presence of HPV, and all have been negative
momentum. With this technique and proper patient (11,16,17,20,22) (Table 12). This is in contrast with
selection, the incidence of recurrence is 12% (range the exophytic and IPs in which HPV has been found
0–33%) (69). The choice of therapy depends on the in many instances. Although this may be a sampling
training and bias of the surgeon, extent of tumor, problem, it does raise the possibility that the OSP is
and possibility of coexistent malignancy. To com- not etiologically linked to this virus.
pare therapeutic modalities, Krouse has proposed a
staging system for IPs, which involves the use of
both CT-MRI imaging and endoscopic examination Imaging
(Table 11) (70). The imaging features are identical with those of the IP
Although surgery is, and should remain, the described in the foregoing section.
primary treatment modality for IP, Mendenhall et al.
have suggested (71) that radiation therapy may have
merit in a small subset of patients with advanced or
incompletely resected tumors. Radiation therapy
should also be considered as an adjunct in patients
who have carcinomas arising in IPs.
Recurrences typically appear within two to three
years of therapy but, in some instances, are delayed
for many years. Attempts to correlate histological
features with risk of recurrence have been unsuccess-
ful (2,31,55,72). Even those with prominent mitotic
activity or dysplasia do not invariably show an
increased incidence of recurrence or malignancy.
Nevertheless, dysplasia, especially if moderate to
severe, demands thorough microscopic evaluation of
all resected tissue to avoid overlooking small foci of
cancer.
Whether the demonstration of HPV in IPs is
associated with a greater risk of local recurrences
is also open to debate. Beck et al. noted (51) that Figure 34 Gross appearance of oncocyte Schneiderian papil-
patients whose IP contained HPV often developed loma. Note both the exophytic (white arrow ) and inverted growth
relapses, whereas Furuta et al. found (50) no relation (black arrow ).
between HPV infection and local recurrence.
370 Barnes
Table 12 Incidence of HPV in Oncocytic Schneiderian Papillomas

Total no.
References Test Total no. of cases positive of HPV Percent positive Type(s) for HPV
Hirschfield (16) DNA-ISH 2 0 0 0
Judd (17) DNA-ISH, PCR 3 0 0 0
Sarkar (20) PCR 9 0 0 0
Buchwald (11) DNA-ISH, PCR 5 0 0 0
Gaffey (22) DNA-ISH, RNA-ISH 3 0 0 0
Total 22 0 0 0
HPV, human papillomavirus.
Figure 35 Oncocytic Schneiderian papilloma showing both Figure 36 Oncocytic Schneiderian papilloma. Note the multi-
exophytic and inverted patterns of growth (left and right sides layered oncocytic epithelium, numerous intraepithelial mucin-
of illustration, respectively) (H&E, 40). filled cysts, and microabscesses (H&E, 200).
Pathology
Microscopically, OSP exhibits both exophytic and
endophytic patterns of growth (Fig. 35). The epithelium
is multilayered, two- to eight-cells thick, and is
composed of tall columnar cells, with swollen, finely
granular cytoplasm reminiscent of oncocytes (Figs. 36
and 37). Barnes and Bedetti have shown that the cells
not only resemble oncocytes but also possess a high
content of cytochrome-c oxidase and ultrastructurally
are distended with mitochondria, thus clearly estab-
lishing their oncocytic character (73). The nuclei are
either small, dark, and uniform or slightly vesicular,
with barely discernible nucleoli. Cilia in varying
stages of regression may be observed in a few of the
outermost cells.
The epithelium characteristically contains
numerous small cysts filled with mucin or neutrophils
(microabscesses) (Figs. 36 and 37). The stroma varies Figure 37 Higher magnification of the oncocytic Schneiderian
from edematous to fibrous and may contain modest papilloma shown in Figure 36 (H&E, 400).
numbers of lymphocytes, plasma cells, and neutro-
phils, but few eosinophils. Mucoserous glands are
sparse to absent.
but mucoepidermoid, ‘‘transitional,’’ sinonasal undif-
Carcinoma and Oncocytic Schneiderian Papilloma
ferentiated and small cell carcinomas have also been
described (77–79).
Approximately 4% to 17% of all OSPs may harbor a As in IP, the carcinoma complicating OSP may
carcinoma (2,73,77,78). Most of these are squamous, actually arise within the papilloma as evidenced by a
gradation of histological changes, ranging from originate in the maxillary sinus, 24% to 30% in the
dysplasia, to in situ, to invasive carcinoma, or it may nasal cavity and vestibule, 10% to 15% in the ethmoid
merely be associated with the OSP. Prognosis depends sinus, and 1% in the sphenoid and frontal sinuses
on the histological type, degree of invasion, and the (9,10).
extent of tumor. In some instances, the carcinoma is in
situ and of little consequence to the patient, whereas
others are locally aggressive and may even B. Etiology
metastasize. Multiple risk factors have been associated with a wide
variety of malignant tumors of the sinonasal tract.
Differential Diagnosis Among these are included (i) tobacco, (ii) ionizing
The intraepithelial mucin-filled cysts, because of their irradiation (radium dial painters, thorium dioxide),
spheroidal nature and mucicarminophilia, are often (iii) occupational exposure to wood dust, nickel, and
mistaken for rhinosporidiosis. In rhinosporidiosis, chromates (iv) boot and shoe manufacturing, (v) work-
however, the organisms are not only limited to the ing in the textile industry, (vi) formaldehyde expo-
epithelium but also involve the stroma and, moreover, sure, (vii) atmospheric pollutants, and (viii) history or
never induce a diffuse oncocytic change in the epithe- presence of an IP or OSP (2,11,12).
lium. The OSP is also occasionally mistaken for a low- Furuta et al. searched for the presence of HPV
grade papillary adenocarcinoma. The presence of 16 and 18 in 49 squamous cell carcinomas of the
intact basement membranes, the lack of nuclear pleo- sinonasal tract using polymerase chain reaction.
morphism and mitotic activity, and the absence of The virus was detected in 14% of the tumors, raising
extensive bone destruction on imaging are features the possibility that the virus might be etiologically
that point to the benignity of the tumor. Furthermore, related to some of the tumors (13). Interestingly, they
the stratified oncocytic epithelium of an OSP is in observed that the presence of HPV was not related to
distinct contrast to the single-layered, nononcocytic local progression, occurrence of metastases, or the
epithelium seen in a low-grade adenocarcinoma. prognosis of the patients. Paulino et al. studied
15 non-Asian patients with squamous cell carcinoma
of the anterior nasal cavity for the presence of EBV
using immunohistochemistry and in situ hybridiza-
The clinical behavior parallels that of the IP. Effective tion. All tumors were negative for the virus, leading
treatment consists of a lateral rhinotomy and medial the investigators to conclude that squamous cell
maxillectomy or, possibly, excision through an carcinoma in this site does not appear to be causally
endoscopic approach. If inadequately excised, at related to EBV (14).
least 25% to 35% will recur, usually within five years
of treatment.
The incidence of squamous cell carcinoma of the
XIII. SQUAMOUS CELL CARCINOMA sinonasal tract, adjusted for age and gender, is 0.3 to
OF THE NASAL CAVITY 1.0 case per 100,000 people per year in most countries
A. Introduction (11). After the age of 35, the incidence rises steadily,
reaching about five to seven cases per 100,000 people
Assessing the clinical and pathological features of by age 80. It is practically nonexistent in children.
primary squamous cell carcinoma of the nasal cavity Squamous cell carcinomas of the nasal cavity is
is an exercise fraught with frustration because (i) the more common in males (52–97% of all cases) and
disease is uncommon and very few institutions have occurs in individuals with a mean or median age of
acquired a sufficiently large series for evaluation, about 55 to 65 years (range 17–91 years) (Tables 13–15)
(ii) the tumors are usually considered jointly with (15–56). A nonhealing sore, ‘‘crusting’’ of the interior
those occurring in the paranasal sinuses, (iii) many of the nose, epistaxis, rhinorrhea, and unilateral
studies include a heterogeneous group of neoplasms obstruction are common presenting symptoms. Local
and report end results as if only a single histological pain is a feature in only about one-fourth of patients
entity were involved, (iv) some investigators include (21,32).
or exclude tumors arising in certain regions of On physical examination, the lesion presents as
the nasal cavity, whereas others include all sites, an ulcer or as a polypoid or sessile growth limited to
(v) there is no uniformly acceptable system for staging one area of the nose, or it may completely fill the
of tumors to compare the efficacy of various therapeu- cavity. Others, particularly those of the vestibule, may
tic modalities, and (vi) survival rates are variously manifest as an ‘‘infection,’’ with induration of the
reported as actuarial, absolute, or disease free, further upper lip. Benign lesions, on the other hand, tend to
complicating evaluation (1–5). be smooth, firm, localized, and mucosa covered (17).
With these limitations in mind, carcinomas of the There is no significant lateralization of carcino-
nasal cavity and paranasal sinuses account for 0.2% to mas to either side of the nose (Table 16). Although
0.8% of all malignancies and 3% of those occurring in 10% of tumors will present bilaterally, most of these
the head and neck (6,7,8). When broken down accord- are actually examples of unilateral disease that has
ing to site of origin, 58% to 60% of all sinonasal tumors perforated the nasal septum.
372 Barnes
Table 13 Squamous Cell Carcinoma of the Nasal Vestibule: Clinical Features

Age (mean Local Positive Distant
No. of and/or recurrence regional metastasis
References cases median) Males (%) (%) nodes (%) (%) Survival
Goepfert (22) 26 60 92 15 31 4 78% 5-yr absolute
Wang (24) 36 >50 61 26 16 10 74% NED at 3 yr
Johansen (34) 66 >50 74 35 19 5 77% 5-yr corrected
Schalekamp (35) 127 67 97 36 24 — 83% at 4-yr mean
Wong (36) 56 64 75 21 9 2 87% 5-yr specific
Barzan (44) 12 65 92 8 8 — 75% 5 yr
Poulsen (45) 29 >60 86 36 34 7 64% 5-yr actuarial
McCollough (46) 39 65 59 18 15 5 75% 5-yr absolute
Patel (43) 30 65 80 40 30 3 76% 5 yr
Mendenhall (50) 60 63 68 15 15 5 74% 5 yr
Horsmans (51) 66 68 52 24 8 2 85% 5-yr disease specific
Samaha (52) 14 67 64 36 21 — —
Kummer (53) 47 — 81 9 13 4 —
Langendijk (54) 56 68 80 20 12 0 66% 5 yr
Mean 664 62 76 24 18 5 —
Abbreviation: NED, no evidence of disease.
Table 14 Squamous Cell Carcinoma of the Nasal Septum: Clinical Features

No. of Age (Mean and/ Local Positive regional Distant
References cases or Males median) (%) recurrence (%) nodes (%) metastasis (%) Survival
Weimert (26) 14 56 71 21 7 14 80% at 5 yr
Beatty (32) 58 57 67 — 24 3 67% at 5 yr
LeLiever (33) 18 59 68 6 50 28 66% 5-yr absolute
DiLeo (55) 16 62 75 6 19 — 66% at 5 yr
Mean 106 59 70 11 25 15 —
Table 15 Squamous Cell Carcinoma of the Nasal Cavity, all Sites: Clinical Features
No. of Age (mean and/ Local Positive regional Distant
References cases or median) Males (%) recurrence (%) nodes (%) metastasis (%) Survival
Chung (30) 20 56 64 10 — — 70% 3-yr actuarial
Shidnia (37) 21 65 52 29 29 10 64% 5-yr NED
Hawkins (39) 46 61 71 34 22 11 55% at 5 yr
Sakashita (48) 5 40 80 20 20 40 60% at 4.3 yr
Fornelli (56) 32 65 66 16 41 — 50% 5 yr
Mean 124 57 67 22 28 20 —
Table 16 Lateralization of Cancer of the Nasal Cavity Although the interior of the nose can be divided
No. of Right N Left N Bilateral into five areas—roof, septum, lateral wall, floor, and
References cases (%) (%) N (%) vestibule—squamous cell carcinoma of the nose is
usually considered clinically under three categories:
MacComb (15) 60 25 (42) 31 (52) 4 (6)
Badib (21) 57 33 (58) 21 (37) 3 (5) vestibule, septum, and nasal cavity proper (the
Bosch (25) 40 12 (30) 17 (43) 11 (28) remaining part of the nasal cavity). A discussion of
Lederman (57) 154 54 (35) 73 (47) 27 (18) squamous cell carcinoma at each of these sites follows.
Robin (58) 129 67 (52) 62 (48) —
Total 440 191 (43) 204 (46) 45 (10) Nasal Vestibule
The vestibule is the dilated cavity just inside the nose
Less than 10% of patients (range 0–27%) will that is lined by skin and contains long hairs (vibrissae)
have positive regional lymph nodes at the time of (Fig. 38). It extends from the anterior opening of each
diagnosis (22–24,29,34–36,41,43,45,46,48). Because it nostril to the level of the limen nasi, a distinct ridge on
is a midline structure, nodal metastases may be ipsi- the lateral nasal wall that corresponds to the superior
lateral, contralateral, or bilateral and typically involve margin of the greater alar cartilage and the zone of
the submandibular and submental and occasionally, transition between the skin and the ciliated respiratory
the facial, preauricular, and parotid lymph nodes epithelium of the nasal mucosa. The lateral wall of the
(10,22,24,31). vestibule is formed by the lateral plate of the greater
Table 17 Staging of Carcinoma of the Nasal Vestibule

According to Wang
T1 The lesion is limited to the nasal vestibule, relatively
superficial, involving one or more sites within.
T2 The lesion has extended from the nasal vestibule to
adjacent structures, such as the upper nasal septum,
upper lip, philtrum, skin of the nose or nasolabial fold, but
not fixed to the underlying bone.
T3 The lesion has become massive, with extension to the hard
palate, buccogingival sulcus, large portion of the upper
lip, upper nasal septum, turbinate, or adjacent sinuses,
fixed with deep muscle and bone involvement.
Table 18 Staging of Carcinoma of the Skin (Vestibule)

According to the American Joint Committee
Figure 38 Diagram showing the internal anatomy of the nasal TX Primary tumor cannot be assessed
cavity and its relation to surrounding structures. TO No evidence of primary tumor
TIS Carcinoma in situ
T2 Tumor more than 2 cm, but not more than 5 cm,
in greatest dimension
T4 Tumor invades deep extradermal structures
(e.g., cartilage, skeletal muscle, or bone)
(Table 17) and the American Joint Committee on

Cancer (AJCC) classifications (Table 18) (24,59). In a
collective review of 222 vestibular carcinomas classi-
fied according to the Wang system, 60% were T1, 23%
T2, and 17% T3 (24,34,35). Of 25 tumors staged by the
AJC criteria, 52% were T1, 32% T2, none T3, and 16%
T4 (45).
On average, 24% (range 8–40%) of patients with
Figure 39 Diagram of inferior view of nose showing potential vestibular carcinomas will develop local recurrences
areas of growth of a vestibular carcinoma (hatched area): (1) following initial treatment, 18% (range 8–34%) will
laterally to invade the lateral alar cartilage or skin, (2) inferiorly to experience positive regional lymph nodes sometime
involve the upper lip or underlying bone, (3) medially to involve during the course of their disease, and 5% (range
the septum, and (4) superiorly either along the septum or lateral
nasal wall.
2–10%) will ultimately have distant metastases,
usually to the lungs, liver, or bones (Table 13).
Survival rates from various studies are also shown
in Table 13.
Signs of poor prognosis include the following:
alar cartilage and the medial wall by the caudal nasal (i) tumors larger than 1.5 cm; (ii) involvement of two
septum and columella. The intervening floor of the or more sites in the vestibule; (iii) extension to the
nose is also included as part of the vestibule. upper lip, columella, cartilage, or bone; (iv) local
Because the vestibule is lined by skin, some recurrence; and (v) positive regional lymph nodes,
consider it as part of the integument, rather than the especially at the time of diagnosis (22,27,34,36,43).
nasal cavity. Although vestibular tumors have a rela-
tion to skin cancers, they are more aggressive for the Septum
following reasons: (i) they frequently masquerade as
an infectious process, which results in a delay in Squamous cell carcinoma of the nasal septum most
diagnosis; (ii) they often invade nearby important often arises from the anterior (70–75% of all cases)
structures, such as the septum, cartilage, skin of the rather than posterior septum (26,32). In one series in
nose, upper lip, or underlying bone, which makes which the size of the tumor was given, five were
resection more difficult and imposes the need for between 0 and 0.9 cm, eight were 1.0 to 1.9 cm, and
cosmetic repair (Fig. 39); and (iii) the area is richly nine were larger than 2 cm (33).
endowed with lymphatics, and lymph node metasta- As the tumor enlarges, it may (i) ascend the
sis, therefore, is not uncommon. septum to involve the roof of the nasal cavity,
Although there is no uniform system for staging (ii) spread inferiorly along the septum toward the
vestibular tumors, two have been proposed: the Wang mucocutaneous junction, (iii) perforate the septum
374 Barnes
and grow in the contralateral nasal cavity, or laryngeal carcinoma certainly raises the question of
(iv) partially or totally fill the nasal cavity. possible seeding from the nasal lesions (32). The
On average, 11% (range 6–21%) of patients with remaining 60% of second primaries occur below the
septal squamous cell carcinomas will experience local clavicles, usually in the lungs, gastrointestinal tract, or
recurrences, 25% (range 7–50%) will develop positive breasts.
regional lymph nodes during the course of their
disease, and 15% (range 3–28%) will subsequently
have distant metastasis (Table 14). Survival rates are XIV. SQUAMOUS CELL CARCINOMA
also shown in Table 14. According to Beatty et al., OF MAXILLARY SINUS
there is no significant difference in the tendency to
A. Introduction
metastasize between anteriorly or posteriorly located
tumors (32). Tumors larger than 2 cm and positive The maxillary sinuses are paired, usually symmetrical
regional lymph nodes are signs of adverse prognosis hollow cavities that lie in the body of each maxilla
(26,33). (Fig. 40). Each cavity is shaped similar to a pyramid,
being based medially on the nasal cavity and projec-
Nasal Cavity ting laterally to an apex in the zygoma (Fig. 41). Each
sinus has a roof, a floor, and three walls—anterior,
Squamous cell carcinoma of the nasal cavity arises
posterolateral, and medial (1). The base of the orbit
most often from the lateral wall. From this site, the
forms the roof of the sinus, and the floor is formed by
tumor may spread, if neglected, in several potential
the alveolar process of the maxilla.
directions to involve the paranasal sinuses, orbit,
The anterior wall is the facial surface of the
cranial cavity, palate, or skin, and it may even invade
maxilla, whereas the posterolateral wall relates to
cranial nerves (39).
the infratemporal and pterygopalatine fossa. The
On average, 22% (range 10–34%) of patients with
medial wall forms part of the lateral wall of the
squamous cell carcinomas of the nasal cavity will
nasal cavity. Each sinus drains through an opening—
experience local recurrences, 28% (20–41%) will
the hiatus semilunaris—into the middle meatus of the
develop positive regional lymph nodes, and 20%
lateral nasal wall.
(range 10–40%) will eventually have distant metasta-
Ohngren’s line, a theoretical plane joining the
sis. Table 15 shows survival rates from various pub-
medial canthus of the eye with the angle of the
lished series.
mandible, is sometimes used to divide the maxillary
sinus into an anteroinferior portion (the infrastruc-
D. Pathology ture) and a superoposterior portion (the suprastruc-
ture) (2).
Squamous cell carcinomas of the nose, regardless of
the site of origin, are predominantly well to moder-
ately differentiated. Poorly differentiated tumors are B. Clinical Features
uncommon.
Patients with squamous cell carcinoma of the maxil-
lary sinus present late and die slowly. Fortunately, it is
E. Treatment and Prognosis a relatively rare disease. It occurs more often in men
(2–5 times) and affects individuals with a mean or
Cancer of the nasal cavity can be treated by radia- median age of 60 to 65 years (3–21).
tion, surgery, or both. Because of cosmetic concerns, Signs and symptoms depend on the stage of the
many clinicians initially favor radiation, especially disease and direction of tumor growth. Early on they
for vestibular tumors. The most common cause of are vague and often confused with sinusitis. This
death is uncontrolled tumor at the primary site.
Because regional and distant metastases without
local recurrence tend to be uncommon, adequate
local control is tantamount to cure. Most local fail-
ures appear within one year of treatment and only
rarely after two to three years (23,34–36,46,49). The
majority are due to underestimating the extent of the
disease or attempts by the surgeon or radiotherapist
to be less radical to preserve function and avoid risks
of complications.
Of all patients with carcinomas of the nasal
cavity, 15% (range 6–28) either have or will develop
a second primary malignancy (25,31,32). In the series
of Bosch et al., 42% of these other tumors were
discovered before, 16% at the same time, and 42%
after appearance of the nasal lesion (25). Approxi-
mately, 40% of the second primaries are found in the Figure 40 Coronal section through the maxillary sinuses show-
head and neck, with two-thirds of these occurring in ing relation of each sinus to other craniofacial structures.
the larynx or pyriform sinus. The high incidence of
Figure 41 Cross-section through maxillary sinus show-

ing anatomical relations.
Table 19 ‘‘T’’ Staging of Squamous Cell Carcinoma of the Approximately 10% to 15% (range 4–21%) of
Maxillary Sinus patients will present with positive regional lymph
nodes, usually the upper jugular, submandibular,
TO No evidence of primary tumor
and retropharyngeal (3,5,6,10,11,13,14,16–18,25).
TIS Carcinoma in situ Distant metastases at the time of diagnosis, however,
T1 Tumor limited to the antral mucosa, with no erosion or are uncommon (0–4%) (5,10,14,16,17,25).
destruction of bone There is no significant lateralization of tumors to
T2 Tumor with erosion or destruction of the infrastructure, either sinus (26,27). Bilateral primary squamous cell
including the hard palate or the middle nasal meatus carcinomas of the maxillary sinuses, though
T3 Tumor invades any of the following: skin of cheek, described, are extremely rare and are predominantly
posterior wall of maxillary sinus, floor of medial wall of metachronous, rather than synchronous (28–30). In a
orbit, anterior ethmoid sinus review of 351 patients with squamous carcinomas of
T4 Tumor invades orbital contents or any of the following: the maxillary sinus, Shibuya et al. observed five
cribriform plate, posterior ethmoid or sphenoid sinuses,
nasopharynx, soft palate, pterygomaxillary or temporal
patients (1.4%) who had bilateral carcinomas (28). In
fossae, or base of skull a similar study of 802 patients, Miyaguchi et al. noted
that 10 (1.2%) had bilateral tumors (29). Of the five
patients with bilateral carcinomas in the study of
Shibuya et al., the interval between the diagnosis of
results in an average delay of five to eight months the index and second primary tumor was more than
before the diagnosis is established and is largely five years in all patients (28). This is a unique experi-
responsible for the 60% to 97% of patients who present ence, because most patients with squamous carcino-
with advanced T3 and T4 tumors (5,7,10–13,17,22–24) mas of the maxillary sinus are usually dead of disease
(Table 19). within five years and attest to the success that the
Complaints can be grouped into five categories: Japanese have had in treating this deadly disease.
nasal, oral, ocular, facial, and neurological. Nasal man- Shibuya et al. also indicate that of those patients
ifestations include unilateral stuffiness, obstruction, who survive more than five years, the incidence of
rhinorrhea, and epistaxis. Oral findings include pain bilateral cancers may even be as high as 5% (28).
referred to the upper premolar and molar teeth; loos-
ening of the teeth; swelling or ulceration of the palate, C. Imaging
alveolar ridge, or gingivobuccal sulcus; or a fistula.
Common ocular features consist of swelling of the Computed tomography and MRI are indispensable,
eyelids, excessive tearing, visual disturbances, and not only in determining the extent of disease but also
proptosis. Facial symptoms result from involvement in assisting the surgeon in selecting the best operative
of the anterior wall of the sinus and are characterized approach (31–34). Unfortunately, squamous cell carci-
by swelling and asymmetry of the cheeks. Neurological nomas of the maxillary sinus are rarely diagnosed in
manifestations are often due to tumor infiltration of the an early stage. Most are advanced and, on imaging,
infraorbital branch of the fifth cranial nerve with sub- show the sinus to be either partially or totally filled
sequent numbness or paresthesia of the cheek. with a tumor, with destruction of one or more of the
376 Barnes
bony walls. Extension into adjacent structures, such as canine fossa or skin involvement, orbital edema,
the cheek, oral cavity, infratemporal fossa, and peri- and positive cervical lymph nodes (46). Tumors that
orbital soft tissue, is not uncommon. originate in the antral suprastructure and those that
recur following initial curative therapy, regardless
of the site of origin, are also associated with a poor
D. Pathology prognosis.
The vast majority of squamous carcinomas are either
well or moderately differentiated. Poorly differentiated XV. NONKERATINIZING CARCINOMA
tumors are uncommon.
A. Introduction
E. Treatment and Prognosis ‘‘Nonkeratinizing carcinoma’’ (NKC) is the official
term sanctioned by the World Health Organization
Because the tumors are generally advanced at the (WHO) for a distinctive variant of squamous cell
time of diagnosis, a combination of surgery and carcinoma derived from respiratory (Schneiderian)
radiation is used in most instances, with or without mucosa and composed of mitotically active epithelial
chemotherapy (10,11,13,14,35–37). The Japanese, cells arranged in a characteristic ribbon-like pattern
however, have had rather remarkable success, using (1,2) (Fig. 42). Synonyms include cylindrical cell
primary irradiation followed by intra-arterial chemo- carcinoma, transitional cell carcinoma, Schneiderian
therapy (5-fluorouracil and bleomycin), weekly cryo- carcinoma, respiratory epithelial carcinoma, and
surgery, and immunotherapy (4,15,38,39). Ringertz carcinoma.
One of the most difficult decisions in treating Although uncommon in our experience, it com-
maxillary carcinoma is deciding whether or not the prises in some series 10% to 20% of all sinonasal
orbit should also be excised (40–44). This is a signifi- carcinomas (2–4).
cant emotional burden for both the patient and
surgeon and has resulted, in some instance, in the
patient opting for less aggressive or even nonsurgi- B. Etiology
cal treatment. The surgical consensus on manage- El-Mofty and Lu studied 39 carcinomas of the sino-
ment of the orbit in cases of carcinoma approaching nasal tract [21 keratinizing squamous cell carcinoma, 8
the orbital floor has changed from almost routine NKCs and 10 sinonasal undifferentiated carcinomas
exenteration in the 1960s to a more current highly (SNUCs)] for the presence of HPV, using the polymer-
selective approach. Clinical evidence of invasion of ase chain reaction (4). They observed that four of the
the orbital fat or extraocular muscles, such as prop- eight NKCs (50%) contained HPV 16, 18, or 45, where-
tosis, diplopia, decreased visual acuity, and restri- as only 19% of the keratinizing squamous carcinomas
cted ocular mobility are clear indications for orbital and 10% of the SNUCs were positive for the virus.
exenteration. Invasion of the bone of the orbital floor Other than a possible link to HPV, its relationship to
is currently not an absolute indication for removal. other risk factors such as smoking and atmospheric
Stern et al., however, indicate that strong consider- pollutants is unknown.
ation should be given to orbital exenteration at the
time of surgery when the orbital floor is resected,
especially if postoperative radiation fields will
include the eye (44). Otherwise, the preserved, radi-
ated eye will almost assuredly be useless following
radiation and may have to be removed at a later
date.
Local recurrence, seen in about 30% to 45%
(range 18–75%) of cases, is the most common cause
of treatment failure and death (5,8,10,11,13,15–22,45).
Virtually, all recurrences appear within two years of
therapy and most within one year. During the course
of the disease, 25% to 30% of patients will develop
positive regional lymph nodes and 10% to 20% will
experience distant metastases (3,5,6,8,10,11,16–22).
Five-year survival rates, variously reported as actuar-
ial, determinant, cumulative, crude, and not otherwise
specified, average about 45% to 50% (range 22–72%)
(4,11,13,16–24,40,45).
According to Weymuller et al. (46), patients who
exhibit one or more of the following signs or symp-
toms have a greater than 75% chance of dying of their Figure 42 Nonkeratinizing carcinoma. Note the ribbons of
disease: facial numbness, facial swelling, diplopia, tumor cells. At low magnification, the tumor is often mistaken
epiphora, denture pain, a mass in the palate or naso- for an inverted papilloma (H&E, 40).
pharynx, proptosis, abnormal extraocular movement,
C. Clinical Features endodermal sinus tumor-like features (6). These

‘‘hybrid’’ NKCs tend to be more aggressive than the
NKCs have been described in patients from 23 to ‘‘pure’’ NKC; consequently, thorough microscopic
92 years of age (average about 55–65 years) and exhibit examination of the excised tumor is essential.
a gender distribution of 1:1 to 1.6:1 in favor of males
(2,4,5). Most arise in either the nasal cavity or maxil-
lary sinus and manifest as nasal obstruction and E. Immunohistochemistry
epistaxis.
They are typically unilateral and, on examina- NKCs are typically positive for CK 5/6, 8, 13, 14, and
tion, often appear polypoid masquerading as an ordi- 19 and negative for CK 4, 7, and 10 (7). They also show
nary sinonasal polyp or IP. Most are solitary, but in a strong and diffuse staining for p16, high labeling for
review of 52 cases, Auerbach et al. observed that 12 Ki-67, and negative or weak reactivity for p53 (4,8).
(23%) of their patients had multifocal intranasal
lesions (5).
F. Differential Diagnosis
At low magnification, NKC is very reminiscent of an
D. Pathology IP, and, indeed, the two are often confused (Fig. 42).
NKCs are frequently exophytic or polypoid with a On higher magnification, however, the cells of an
smooth, corrugated papillary surface. Microscopically, NKC, in contrast with those seen in IP, are more
they are composed of thick ribbons of multilayered pleomorphic and mitotically active, with frequent
nonkeratinized, mitotically active epithelial cells, loss of polarity (Fig. 43).
which appear as invaginations of the surface epithe-
lium (Fig. 42). Admixed mucous (goblet) cells and
even rare foci of keratinization may be apparent. G. Treatment and Prognosis
Elongated cells perpendicular to the basement Surgery, often supplemented with postoperative radi-
membrane at times create a ‘‘cylindrical’’ appearance ation, is the treatment of choice. Although NKC may
(Fig. 43). metastasize to regional lymph nodes (10% of cases) or
NKCs tend to have a pushing margin, and many to more distant sites, it tends to be a locally aggressive
of the ribbons of cells are surrounded by intact base- tumor (2). It also seems to have a better prognosis than
ment membranes, thus appearing in situ. However, conventional squamous cell carcinoma.
focal and sometimes diffuse invasion will often be
apparent if enough tissue is available for examination.
Most NKCs develop de novo, but a few may
arise from a concurrent IP. Exceptionally NKCs may XVI. SINONASAL UNDIFFERENTIATED
contain foci of additional malignant tumors. Manivel CARCINOMA
et al. have described two cases of NKCs with A. Introduction
SNUC was originally described by Frierson et al. in
1986 and was defined as a high-grade malignant
epithelial neoplasm of the nasal cavity and paranasal
sinuses of uncertain histogenesis with or without
neuroendocrine differentiation but without evidence
of squamous or glandular differentiation (1). More
recently, the WHO has defined it as ‘‘a highly aggres-
sive and clinicopathologically distinctive carcinoma of
uncertain histogenesis that typically presents with
locally extensive disease. It is composed of pleomor-
phic tumour cells with frequent necrosis, and should
be differentiated from lymphoepithelial carcinoma
and olfactory neuroblastoma’’ (2).
Although the histogenesis of SNUC is uncertain,
the presence of dysplasia or in situ carcinoma of the
overlying mucosa observed in a few tumors suggests
that it is derived from the Schneiderian membrane
and therefore is of ectodermal origin. Limited neuro-
endocrine differentiation as seen by immunohis-
tochemistry and electron microscopy has led some to
Figure 43 Nonkeratinizing carcinoma. The cells are mitotically speculate that SNUC may be a neuroendocrine neo-
active with loss of polarity. Note the absence of keratinization. plasm related to large cell neuroendocrine carcinoma
The cells along the basement membrane are elongated or as seen in the lung (3). More recently, Ejaz and Wenig
cylindrical, hence the synonym ‘‘cylindrical cell carcinoma’’ have proposed that the definition of SNUC should be
(H&E, 200). expanded to include those tumors that show limited
squamous differentiation (4).
378 Barnes
B. Etiology
Many of the patients with SNUC either are or have
been smokers. Whether or not there is a relation
between this habit and the development of the
tumor is unknown. Thus far, no specific occupational
exposure has been incriminated (1).
Lopategui et al. and Gallo et al. studied a com-
bined series of 35 SNUCs for the presence of the EBV,
using in situ hybridization, and found evidence of the
virus in 12 cases (34%) (5,6). The virus was found only
in those patients of Asian or Italian descent. None was
found in those patients tested from the United States.
At least some of their EBV-positive tumors on critical
review are, no doubt, examples of unrecognized pri-
mary lymphoepitheliomas of the sinonasal tract (7).
More recently, Cerilli et al., using strict criteria, stud-
ied 25 additional SNUCs for the presence of EBV,
using in situ hybridization. All of their patients were Figure 44 Sinonasal undifferentiated carcinoma growing as
from the USA, and all were negative for the virus (8). sheets and trabeculae of cells (H&E, 100).
It would thus appear that SNUC has little, if any,
relationship to EBV.
A few cases have also been observed in patients
who have a history of previous nasopharyngeal carci-
noma (NPC) treated with irradiation (7).
Another two cases of SNUC have been described
in patients with a past history of retinoblastoma (9,10).
Whether mutations of the retinoblastoma gene are
responsible for some cases of SNUC is also in need
of further studies.
SNUC is a rare, highly aggressive malignant tumor of
the nasal cavity and paranasal sinuses. In a collective
review of 116 cases, the male to female ratio was 3:1
with a mean age at diagnosis of about 55 to 58 years
(range 20–84 years) (7,8,11–14). It most often originates
in the nasal cavity, but at the time of presentation the
tumor is often found unexpectedly to be quite exten-
sive, involving not only the nasal cavity and one or
more of the paranasal sinuses but also the orbit and
Figure 45 Higher magnification of the sinonasal undifferentiat-
cranial cavity. ed carcinoma shown in Fig. 44 showing a sheet of cells associ-
As such, patients typically present with multiple ated with extensive necrosis. Mitoses are usually prominent
signs and symptoms of about three- to four-months (H&E, 200).
duration. Among these are included nasal obstruction,
epistaxis, facial pain, headaches, proptosis, visual dis-
turbances, cranial nerve palsies, impaired mental func-
tion, neck mass, and weight loss. Tumors localized to (HPFs)] and angiolymphatic invasion and necrosis are
the nasal cavity or a single sinus are uncommon. prominent.
Infrequently, one may see changes of dysplasia or
carcinoma in situ of the overlying mucosa (Fig. 46).
D. Pathology Strictly defined, squamous and glandular differentiation
Microscopically, the tumors are composed of small to should not be seen nor rosettes or a neurofibrillary
medium-sized polygonal cells that grow in sheets, stroma (see discussion in the sect. ‘‘Introduction’’).
nests, wide trabeculae, and/or ribbons (Figs. 44
and 45). The nuclei are round to oval, hyperchromatic, E. Immunohistochemistry
and mild to moderately pleomorphic, but on occasions,
may be vesicular. Nucleoli vary from inconspicuous to The immunoprofile varies from case to case. The
large. The cells tend to have mild to moderate amounts tumors are, however, consistently positive for epi-
of eosinophilic to amphophilic cytoplasm. Mitoses are thelial markers, including parakeratin and the simple
numerous [10–50 or more per 10 high-power fields CK 7,8, and 19 (4,7,8,15,16). They are negative for CK4,
F. Electron Microscopy
Ultrastructurally, the cell membranes are smooth to
moderately ruffled and exhibit small desmosomes and
poorly formed junctional complexes (1). Nuclear
membranes are smooth to mildly irregular. The cyto-
plasm contains small amounts of rough endoplasmic
reticulum, polyribosomes, and mitochondria. Golgi
complexes are usually prominent, and lyzosomes
and lipid droplets may be found; however, bundles
of tonofilaments are absent. A few neurosecretory
granules have been observed in rare cells, but only
after a prolonged search (1).
The differential diagnosis includes a myriad of round
Figure 46 Sinonasal undifferentiated carcinoma. Note the sur- cell tumors that can occur in the sinonasal tract (16,17).
face component of in situ carcinoma and compare with similar Among the more common ones are olfactory
cells invading the lamina propria (H&E, 400). neuroblastoma (ONB), NPC, malignant lymphoma,
malignant melanoma (MM), rhabdomyosarcoma,
small cell neuroendocrine carcinoma (SCNEC), and
peripheral neuroectodermal tumor/Ewing’s sarcoma.
5/6, and 14. Variable reactivity has been observed Immunohistochemical stains that are useful in sepa-
with p63. Less than half the cases are reported to be rating these tumors are shown in Tables 20 and 21.
positive for epithelial membrane antigen, neuron- The three tumors that are most often confused
specific enolase, and p53 (8). The cells rarely decorate with SNUC are the ONB, NPC (undifferentiated type),
for synaptophysin, chromogranin, and Leu-7 and then and SCNEC. In addition to their different immunohis-
only in a spotty or patchy distribution. A few cases have tochemical profiles, ONB does not exhibit the degree
also been positive for CD-99, but in these instances, the of necrosis, mitotic activity, nuclear pleomorphism, or
staining is cytoplasmic rather than membranous as tendency for angiolymphatic invasion as seen in
characteristically seen in peripheral neuroectodermal SNUC. Features that are useful in separating these
tumor/Ewing’s sarcoma (8). three tumors are shown in Tables 22, 23, and 24.
Table 20 Immunohistochemical Staining of Selected Round Cell Tumors of the Sinonasal Tract
Tumor CK EMA LCA Synaptophysin HMB-45 Desmin Vimentin CD99
SNUC þ þ/ /þ /þ
ONB a þ
NPC þ þ
Lymphoma þ þ /þ
Melanoma þ þ
Rhabdomyosarcoma þ þ /þ
SCNEC þ þ þ/
PNET/ES /þ /þ þ þ
a
ONB is typically negative for CK, but may infrequently focally express low-molecular weight CK.
Abbreviations: CK, cytokeratin; EMA, epithelial membrane antigen; LCA, leukocyte common antigen; SNUC, sinonasal undifferentiated carcinoma;
ONB, olfactory neuroblastoma; NPC, nasopharyngeal carcinoma; SCNEC, small cell neuroendocrine carcinoma; PNET/ES, peripheral neuroectodermal
tumor/Ewing’s sarcoma.
Table 21 Cytokeratin Expression in Sinonasal Tumors

Tumor 4 5/6 7 8 10 13 14 19
SCC (N ¼ 10) 30% 90% 60% 90% — 90% 80% 90%
NKSCC (N ¼ 10) — 90% — 90% — 80% 80% 90%
UNPC (N ¼ 5) — 80% — 80% — 80% — 100%
SNUC (N ¼ 6) — — 50% 100% — — — 50%
Abbreviations: SCC, squamous cell carcinoma; NKSCC, nonkeratinizing squamous cell carcinoma; UNPC, undifferentiated nasopharyngeal carcinoma;
SNUC, sinonasal undifferentiated carcinoma.
380 Barnes
Table 22 ONB Vs. SNUC H. Treatment and Prognosis

Feature SNUC ONB SNUC is a very lethal neoplasm. Although a few
Age (average) 55–58 40–45 individuals have survived for more than five years, the
Site Multiple sites Roof of nasal two-year survival rate is about 45% (range 10 months
cavity median survival to 63% at 5 years) (7,8,11–14). Most
Prognosis 45% 2 yr 60–80% 5 yr patients die of local disease, but cervical lymph node
Ocular-cranial nerve Common Uncommon (15–50% of cases) and distant metastases (20–45% of
involvement cases), primarily to lungs, liver and bones, do occur
Anaplasia Common Uncommon (7,8,11,13).
Mitoses Numerous Variable Current therapy consists of chemotherapy, radi-
Necrosis Prominent Uncommon ation, and surgery (18,19). Contradictions to surgery
Vascular invasion Prominent Uncommon
Neurofibrillary stroma Absent Common
include bilateral orbital involvement, optic nerve or
HW rosettes Absent Common optic chiasm extension, frank brain invasion, prever-
Keratin Most Focal at most tebral fascia involvement, distant metastasis at pre-
EMA Occasional 0% sentation, and poor medical condition (20).
NSE Occasional 100%
S-100 Rare Sustentacular
Synaptophysin Rare 100% XVII. NEUROENDOCRINE CARCINOMA
Neurosecretory granules Rare Numerous
The term ‘‘neuroendocrine carcinoma (NEC)’’ without
Abbreviations: SNUC, sinonasal undifferentiated carcinoma; ONB, further qualification should not be used as a specific
olfactory neuroblastoma; HW, Homer Wright; EMA, epithelial membrane
antigen; NSE, Neuron-specific enolase.
diagnosis because it is not only confusing but is also
meaningless. Some, for instance, have used it to
describe typical carcinoids (well-differentiated NEC),
atypical carcinoids (moderately differentiated NEC),
Table 23 SNUC Vs. UNPC and SCNECs (poorly differentiated NEC) (1–5). Silva
et al. and Ordonez and Mackay have also described a
Feature SNUC UNPC
group of tumors of the nasal cavity that they, unfor-
Location Sinonasal tract Nasopharynx tunately, have referred to as simply ‘‘neuroendocrine
Clinical Large primary, þ/ Small primary, carcinomas’’ (6,7). Whether their tumors are actually
cervical lymph þcervical
small cell carcinomas, as claimed by some (8); repre-
nodes lymph nodes
Imaging Marked destruction Little destruction sent a spectrum of ONBs, as suggested by others (7,9);
and spread beyond or spread or represent a new entity is uncertain.
site of origin beyond site of Noteworthy is that the most recent edition of the
origin WHO’s book on head and neck tumors does not
Growth Trabeculae, nests, Syncytial recognize NEC as a specific lesion (10). Because a
sheets variety of neuroendocrine tumors (ONB, invasive
Cells Hyperchromatic to Large, vesicular pituitary adenoma, and others) may involve the
vesicular nuclei nuclei with nasal cavity and paranasal sinuses, we strongly rec-
with or without prominent ommend that the classification and terminology pro-
nucleoli nucleoli
posed by the WHO be used to avoid any future
Mitoses Very prominent Not prominent
Necrosis Very prominent Not prominent confusion. If a neuroendocrine tumor does not con-
Vascular invasion Very prominent Not prominent form to the WHO classification, then the term ‘‘neu-
Lymphocytes Absent to mild Heavy infiltrate roendocrine carcinoma, not otherwise specified type’’
Epstein-Barr virus þ might be appropriate, and certainly less confusing.
(United States) The tumor can then be graded as well, moderately, or
Abbreviations: SNUC, sinonasal undifferentiated carcinoma; UNPC, poorly differentiated.
undifferentiated nasopharyngeal carcinoma.
XVIII. SMALL CELL NEUROENDOCRINE

CARCINOMA
Table 24 SNUC Vs. SCNEC
A. Introduction
Feature SNUC SCNEC
Small cell neuroendocrine carcinoma (SCNEC, small
Spindle cells þ
Nucleoli þ/
cell carcinoma, oat cell carcinoma, small cell undiffer-
Nuclear molding þ entiated carcinoma) similar to those seen in the lung is
DNA coating þ now being recognized with increased frequency in a
Dysplasia—CIS þ/ variety of extrapulmonary sites. In the head and neck,
Synaptophysin þ/ the two most common sites are the larynx and salivary
Thyroid transcription factor þ/ glands (1–3).
Dot-like keratin positivity þ/ They are distinctively uncommon in the sino-
Abbreviations: SNUC, sinonasal undifferentiated carcinoma; SCNEC, nasal tract, and in this location, lack of uniform
small cell neuroendocrine carcinoma; CIS, carcinoma in situ. terminology and confusion with other ‘‘round or
undifferentiated’’ tumors preclude an accurate assess-

ment of their behavior. For instance, cases 3 (with
multinucleated giant cells) and 4 (with prominent
nucleoli) reported by Kameya et al. do not conform
to our concept of SCNEC (4). Whether the ‘‘neuroen-
docrine carcinomas,’’ described by Silva et al. and
Ordonez and Mackay, are examples of SCNECs or
some other entity is uncertain, and, accordingly, they
too are not considered (5,6). For this discussion, we
have accepted 48 cases in the literature as possible
examples of SCNEC of the sinonasal tract (2,4,7–16).
SCNEC of the sinonasal tract has been described in
patients from 16 to 79 years of age, with an average of
about 50 to 55 years, and a gender distribution of 1:1
to 1.5:1 in favor of males. Figure 47 Small cell neuroendocrine carcinoma. Similar to their
It originates either within the nasal cavity or the counterpart in the lung, the small cells have poorly defined
paranasal sinuses, especially the ethmoid and maxil- cytoplasm and dense, hyperchromatic, round to short spindled
lary, and may remain localized to these sites, or it may nuclei devoid of nucleoli (H&E, 400).
spread to the orbit, cribriform plate, or cranial cavity.
Symptoms, therefore, depend on the extent of disease
and include intermittent epistaxis, nasal obstruction,
progressive swelling and deformity, proptosis, visual SCNECs characteristically grow in the lamina
disturbances, cranial nerve palsy, and pain. propria as sheets or small clusters of cells beneath
A few SCNECs have also been associated with an intact or ulcerated epithelial surface. If the latter is
paraneoplastic endocrine syndromes of ectopic adre- intact, it typically shows no significant dysplasia. In
nocorticotropic hormone production and in appropri- some instances, the tumor is intimately associated
ate secretion of antidiuretic hormone (4,13,17). One with mucoserous glands, often appearing to arise
tumor was found to contain a high content of calcito- from them.
nin on chemical examination, but was not associated
with hormonal symptoms (4). The occurrence of a
paraneoplastic syndrome is an ominous feature with E. Immunohistochemistry
death ensuing within six months of onset. The tumors are positive for AE1/3 and CAM5.2,
occasionally in a dot-like pattern. They are also usually
C. Imaging positive for neuron-specific enolase, chromogranin,
and synaptophysin and negative for S-100 protein
Imaging studies may show only a soft-tissue mass (14). Only about 40% of extrapulmonary SCNECs,
limited to the sinonasal tract, with or without obstruc- however, express thyroid transcription factor-1 (18).
tive opacification of the adjacent sinuses. Other At least one tumor has been reactive for 0-13. By in
tumors exhibit considerable osteodestruction, with situ hybridization, all tumors have been negative for
invasion of the orbit, cribriform plate, or cranial the EBV (14).
cavity.
F. Electron Microscopy
D. Pathology Neurosecretory granules may or may not be seen. Cell
SCNECs of the sinonasal tract presumably arise from junctions are present to a variable degree, ranging from
mucoserous glands or from an uncommitted (stem) absent to well-formed desmosomes. Occasionally,
cell of the surface epithelium (2). Microscopically, they bundles of tonofilaments are observed (19).
are identical with their pulmonary counterpart and, as
such, are composed of short, spindle cells, with G. Differential Diagnosis
sparse, poorly defined cytoplasm, and hyperchro-
matic nuclei without nucleoli (Fig. 47). Nuclear mold- The differential diagnosis includes ONB, SNUC, basa-
ing, frequent mitoses, and necrosis are common. loid squamous cell carcinoma (BSCC), and metastatic
Tumors composed of slightly larger cells, with pulmonary SCNEC.
round, hyperchromatic nuclei, and more abundant ONB is characteristically a low-grade neoplasm
cytoplasm have also been described (12). These are and does not show the prominent necrosis, mitotic
similar to the ‘‘intermediate’’ type of SCNEC seen in activity, or nuclear pleomorphism of SCNEC. It is also
the lung. A few may exhibit divergent differentiation, composed of ‘‘round’’ rather than short spindle cells
with foci of obvious squamous cell carcinoma or and frequently exhibits rosettes (Homer Wright,
adenocarcinoma. Flexner–Wintersteiner) and a neurofibrillary matrix.
382 Barnes
Moreover, in contrast to SCNEC, which is diffusely

positive for CK and often positive for thyroid tran-
scription factor-1, ONB is usually negative for both.
Features that separate SCNEC from SNUC are
shown in Table 24. BSCC is negative for chromogranin
and synaptophysin and, if the biopsy is large enough,
will exhibit areas of squamous differentiation. Although
the sinonasal tract is an uncommon site of metastasis for
pulmonary SCNEC, an origin from the lung should
always be excluded by appropriate imaging and
cytological studies.
H. Treatment and Prognosis

Despite multimodality therapy, SCNEC of the sino-
nasal tract is an aggressive neoplasm with a poor
prognosis. Approximately, 35% to 45% of patients
will experience local recurrence, 20% to 45% positive
cervical lymph nodes, and 20% to 75% distant metas-
tases, usually to the lungs, liver, bones, and brain Figure 48 Lymphoepithelial carcinoma composed of cells with
(14–17,20,21). The median survival is about two to poorly defined cytoplasm, large round nuclei, and prominent
nucleoli. Note the admixed lymphocytes. Compare with Fig. 68
three years, with a five-year survival of 29% (15,16). (H&E, 400).
XIX. LYMPHOEPITHELIAL CARCINOMA

to exclude local-regional spread from a primary naso-
A. Introduction pharyngeal carcinoma.
Lymphoepithelial carcinoma (LEC) is a rare, newly
recognized tumor of the nasal cavity and paranasal E. Pathology
sinuses that is often mistaken for SNUC (1–7). Other
than location (sinonasal tract vs. nasopharynx), it is LEC grows as large syncytial masses, small aggre-
otherwise histologically similar to the undifferentiated gates, and/or individual cells without a desmoplastic
variant of nasopharyngeal carcinoma. response. Individual cells have eosinophilic to
Additional terms that have been applied to this amphophilic cytoplasm and large round nuclei with
tumor include nasopharyngeal-type undifferenti- prominent nucleoli (Fig. 48). An intraepithelial
ated carcinoma, undifferentiated carcinoma with component is observed in some instances as well as
lymphoid stroma, undifferentiated carcinoma, and foci in which the tumor cells assume a spindled
lymphoepithelioma-like carcinoma. morphology. Mitoses and necrosis are infrequent to
absent, and keratinization is not evident. Although
lymphocytes and plasma cells permeate the tumor, a
B. Etiology few cases have been observed that are relatively
Regardless of geographic location and ethnicity, devoid of these cells (6).
almost all sinonasal LECs have been associated with
the EBV (1,4,6). F. Immunohistochemistry
LECs are positive for pankeratin and epithelial mem-
C. Clinical Features brane antigen and negative for leukocyte common
antigen, neuron-specific enolase, synaptophysin, and
The tumor is two to three times more common in males chromogranin. According to Franchi et al., they are
and, thus far, has occurred only in adults of 31 to also positive for CK 5/6, 8, 13, and 19 and negative for
75 years of age (mean about 45–55 years) (1,4,6). CK 4, 7, 10, and 14 (5) (Table 21).
Patients typically present with nasal obstruction,
blood-tinged rhinorrhea, or epistaxis. Orbital or intra-
cranial extension may also result in visual disturban- G. Differential Diagnosis
ces, proptosis, or cranial nerve dysfunction.
The tumor is most often mistaken for SNUC and a
primary NPC.
D. Imaging SNUC, in contrast to LEC, exhibits extensive
necrosis, mitoses, and angiolymphatic invasion and
The tumor originates most often in the nasal cavity is almost always negative for the EBV. SNUC is also
and only infrequently in the sinuses. If neglected, it usually negative for CK 5/6 and 13 (5). LEC, on the
may involve one or more of the sinuses or invade the other hand, is positive for the EBV and also usually
orbit or cranial cavity. Imaging is especially important positive for CK 5/6 and 13 (Table 21).
Primary NPC can only be excluded by demon- wood dust is 70 to 500 times that of the nonwood-
strating the absence of tumor in the nasopharynx. worker (28,29). Dust particles measuring 5 mm or more
and primarily from the hardwood trees, beech, oak,
and mahogany are thought to be responsible for the
H. Treatment and Prognosis disease, rather than the lacquers, varnishes, and adhe-
Effective therapy of LEC of the sinonasal tract is still sives applied to the furniture. The inhaled particles
evolving, but like its counterpart in the nasopharynx, are concentrated in the anterior part of the nasal
irradiation appears to be the mainstay. In a review of septum and the anterior end of the middle turbinate,
13 cases, Jeng et al. observed a 61% disease-free where they induce cuboidal or squamous metaplasia
survival at a median follow-up of 48 months (6). with impairment of the mucociliary clearance mecha-
Three (23%) of their patients had positive cervical nism (30,31). This results in prolonged mucosal con-
lymph nodes and one (8%) distant metastasis (bone). tact of the carcinogen present within the dust. The
potential chemical or physical carcinogen (i.e., wood
dust and its natural products or wood dust with both
XX. INTESTINAL-TYPE ADENOCARCINOMA natural products and chemical additives) has not been
adequately defined (26).
A. Introduction The average interval from first dust exposure to
Adenocarcinomas comprise 10% to 20% of all malig- the appearance of the carcinoma is 40 years (range
nant tumors of the nasal cavity and paranasal sinuses 7–69 years) (24). In one of Hadfield’s patients, the length
and can be divided into four types (Table 25) (1–3). of exposure to wood dust was only 18 months (30). In
The intestinal-type adenocarcinoma (ITAC) bears a other studies, the length of dust exposure has ranged
close resemblance to adenocarcinoma of the colon from 5 to 55 years (26). The risk for ITAC does not
and, in some instances, even to villous adenoma appear to decrease until at least 15 years after termina-
(4,5). A few may even resemble normal small intesti- tion of occupational exposure to wood dust (26).
nal mucosa (6). Although the majority of tumors associated with
In the past, ITAC has been referred to as ‘‘colonic- wood dust exposure are adenocarcinomas, there is
type adenocarcinoma, mucinous adenocarcinoma, also an increased incidence of squamous cell carcino-
heterotopic tumor with intestinal mucous membrane, mas, especially among woodworkers in Japan (21).
enteric-type adenocarcinoma, or nonspecific adeno- Interestingly, in contrast with ITACs, which are asso-
carcinoma’’ (7–10). Because they may have features ciated with hard wood exposure, squamous cell carci-
in common with either the large or small intestine and nomas are more common in those exposed to soft
because the term ‘‘enteric’’ is sometimes used as a woods (pine and spruce) (26).
synonym for the small intestine (e.g., enteritis vs. There is also an increase in nasal cancers among
colitis), the term ‘‘intestinal-type adenocarcinoma’’ individuals exposed to leather dust, especially in the
has been proposed and adopted by the WHO (11,12). shoe industry, and possibly to flour in the baking
profession (17,28). However, in these occupations,
the tumors are evenly distributed between ITAC and
B. Etiology squamous carcinomas. Not all ITACs, however, are
related to an occupational exposure. They may occur
Interest in the ITAC peaked in the 1960s when
sporadically (11).
Hadfield, a British otolaryngologist, astutely observed
It has also been suggested that patients with an
an increased incidence of this tumor among wood-
occupational exposure to wood dust may be at risk for
workers employed in the furniture industry of
developing other site-specific malignancies. Among
Oxfordshire and Buckinghamshire, United Kingdom.
these are Hodgkin’s disease and carcinomas of the
Her observation was initially reported by her colleague,
skin, gastrointestinal tract, and lungs (26). More stud-
Macbeth, in 1965 and subsequently by Acheson,
ies, however, are needed to substantiate these alleged
Cowdell, Hadfield, and Macbeth in 1968 (13,14). It
associations.
has since become apparent that the risk for developing
ITAC is not limited to England, but also occurs in the
wood industries of many countries (15–27). C. Clinical Features
In a review of 5785 patients with sinonasal
ITACs can be divided clinically into two categories:
malignancies from 17 countries, Mohtashamipur
those related to occupational exposure (O-ITAC), and
et al. observed that 23% were woodworkers, and of
those that occur sporadically (S-ITAC) without a
these, 64% had adenocarcinomas (24). The risk for
known history of occupational exposure. There are
developing ITAC in the furniture worker exposed to
differences between the two. O-ITAC arises primarily
in the nasal cavity and ethmoid sinus region, and 85%
to 95% of patients are men (11). The male predomi-
Table 25 Classification of Adenocarcinomas of
the Nasal Cavity and Paranasal Sinuses nance is probably related to the fact that very few
women are employed as woodworkers. S-ITAC, on
Salivary type the other hand, may also occur in the same site(s) as
Intestinal type the O-ITAC, but these tumors are relatively more
Nonintestinal type (seromucinous) common in the maxillary sinus. In addition, S-ITACs
Metastatic
occur equally between the two sexes. The average age
384 Barnes
at diagnosis for both types is about 58 years (range Table 26 Classification and Survival of Intestinal-Type
12–86 years) (11). Adenocarcinoma
Although most ITACs occur in the sinonasal Kleinsasser and 3-yr cumulative
tract, they are not unique to this site. Spiro et al. Barnes (11) Schroeder (19) survivala
have described three arising in the oral cavity: one
Papillary PTCC-I 82%
in the palate, one in the floor of the mouth, and one in
Colonic PTCC-II 54%
the cheek-lip area (32). Lopez and Perez have also Solid PTCC-III 36%
reported another case in the pharynx (33). Some of the Mucinous Alveolar goblet 48%
rare mucinous adenocarcinomas of the major salivary Signet ring 0%
glands described by Ellis and Aclair may be additional Mixed Transitional 71%
examples (34). a
Survival data derived from Ref.19.
The most common presenting symptom is uni- Abbreviation: PTCC, papillary tubular cylinder cell.
lateral nasal obstruction, followed by epistaxis and
purulent or clear rhinorrhea (4,7,11,25,35–39). Larger,
more extensive tumors result in facial pain, mass of
the cheek, proptosis, and visual or neurological symp-
toms. Cervical lymph node and distant metastases are
rarely present at the time of initial presentation.
On physical examination, the tumors are polyp-
oid, papillary, or nodular and dark red, gray-white, or
pink-gray. Most are friable. Some are ulcerated and
hemorrhagic, whereas others are mucoid.
Barnes has described one patient with an
advanced tumor of the maxillary sinus that was
associated with pretreatment borderline abnormal
serum level of carcinoembryonic antigen (11).
Whether this laboratory test has any role in monitor-
ing the course of the disease in uncertain.
D. Imaging
Imaging studies are essential in determining the Figure 49 Papillary variant of intestinal-type adenocarcinoma.
extent of disease and the operative approach. Early Note the highly branched papillae with thin fibrovascular cores
lesions show only a soft-tissue mass with little, if any, (H&E, 40).
evidence of bone destruction. Other tumors are asso-
ciated with considerable osteodestruction and inva-
sion of contiguous structures, such as the orbit and
cranial cavity. A few may even involve the contralat-
eral sinonasal tract.
As the tumor enlarges, it interferes with drain-
age of nearby sinuses. The ensuing obstructive sinusi-
tis then may interfere with optimal preoperative
evaluation and staging.
E. Pathology
There are two generally accepted histological classi-
fications of ITAC. Barnes, in 1986, proposed that they
be divided into five types: papillary, colonic, solid,
mucinous, and mixed (11). Kleinsasser and Schroeder,
in 1988, suggested four categories: papillary tubular
cylinder cell, alveolar goblet cell, signet ring cell, and
transitional (19). They further divided their papillary-
tubular cylinder cell variant into three additional Figure 50 High magnification of a grade I (well differentiated)
papillary variant of intestinal-type adenocarcinoma. Note the
subtypes: I (well differentiated), II (moderately differ-
uniform, basally located nuclei (H&E, 200).
entiated), and III (poorly differentiated). These two
classifications actually share many similarities, and
their use depends on personal preference. Table 26
shows their interrelations. nonciliated, columnar (cylinder) cells (Fig. 49). The
The papillary-type (papillary-tubular cylinder columnar cells may be polarized with their long axes
cell-I) is characterized by highly branched fibrovascu- perpendicular to the basement membrane, or they may
lar fronds and glands (tubules) covered or lined by tall be stratified, crowded, and disorganized (Fig. 50).
These cells have pink cytoplasm and round to oval

nuclei that vary from vesicular to hyperchromatic, with
or without nucleoli. In some tumors, goblet cells are
found admixed with columnar cells in a ratio similar to
that seen in the intestine. In others, the fronds are
covered exclusively by columnar or goblet cells.
Mitoses may or may not be prominent. The back-
ground of papillary tumors is often ‘‘dirty,’’ appearing
hemorrhagic, necrotic, and inflammatory (Fig. 49).
Although some papillary tumors are clearly
invasive, others remain noninvasive (in situ) over a
broad front much like papillary transitional cell carci-
noma in situ of the urinary bladder. A few are rather
bland cytologically and may resemble a villous ade-
noma or even normal intestinal mucosa, yet are locally
aggressive and destructive.
The colonic type (papillary tubular cylinder
cell-II) is composed of well- to moderately differenti-
Figure 52 Solid variant of intestinal-type adenocarcinoma. In
ated glands and more closely resembles adenocarci-
this type, there is a diffuse proliferation of cells, with only focal
noma of the large intestine than any of the other gland formation (H&E, 200).
variants (Fig. 51). At times, cystic (glandular) spaces
with intracystic papillary projections are apparent.
The solid variant (papillary tubular cylinder
cell-III) is composed of diffuse proliferation of smaller,
more cuboidal cells with amphophilic to pink cyto-
plasm, occasionally with mucin droplets, and round,
vesicular nuclei, often with nucleoli. There is little
attempt at gland formation (Fig. 52).
The mucinous variant (alveolar goblet cell and
signet ring) encompasses three patterns. One is that of
small solid clusters of cells, individual glands, signet-
ring cells, or short papillary-like fronds, with or
without fibrovascular cores, lying in a mucomyxoid
matrix. A second pattern is characterized by large,
well-formed glands distended with mucus, some of
which may rupture and evoke a brisk inflammatory
response. The third pattern consists of clusters of
Figure 53 Mucinous variant of intestinal-type adenocarcinoma.

Clusters of epithelial cells are lying in a mucinous matrix sur-
rounded by thin fibrous septa (alveolar goblet cell pattern) (H&E,
100).
tumors lying in a mucinous matrix surrounded by

thin fibrous septa, so-called alveolar-goblet cell vari-
ant (Fig. 53).
The mixed pattern (transitional), as the name
implies, is composed of two or more of the foregoing
growth configurations.
ITACs, regardless of histological type, may con-
tain Paneth and enterochromaffin cells as well as a
muscularis mucosa (Fig. 54). The enterochromaffin
Figure 51 Colonic variant of intestinal-type adenocarcinoma. cells can express a variety of peptides, including
This type resembles adenocarcinoma of the colon and is com- gastrin, glucagon, serotonin, cholecystokinin, and
posed of well- to moderately differentiated glands (H&E, 100). leu-enkephalin (5,7,25). Although Schmid et al.
describe an ITAC that was associated with an elevated
386 Barnes
bodies in their ultrastructural evaluation of an ITAC

of the nasal cavity (7). These structures are thought to
be important in identifying tumors of intestinal epi-
thelium or tumors arising from metaplastic intestinal-
type epithelium.
H. Molecular-Genetic Data
Despite the similarity of ITAC and adenocarcinoma
of the colon at the light microscopic and immuno-
histochemical level, there is controversy on whether
this relationship extends to the molecular level.
Depending on the study, 0% to 29% of ITACs have
exhibited K-ras mutations, 0% to 25% H-ras muta-
tions, and 14% to 44% p53 mutations (54–59).
Comparative genomic hybridization (CGH)
studies have revealed that ITACs carry a large number
Figure 54 Paneth cells in an intestinal-type adenocarcinoma of chromosomal gains and losses, including high-level
(H&E, 400). amplifications. The pattern of chromosomal abnor-
malities in these tumors differs from the pattern in
other tumors within the same anatomic area (e.g.,
squamous cell carcinomas, salivary gland tumors),
serum level of somatostatin, these tumors virtually which may be due to differences in etiology (60).
never produce a clinically significant endocrine syn-
drome (5).
Recurrent ITACs may manifest the histological I. Differential Diagnosis
identity of the original tumor, or they may recur or
convert into another histological pattern. If they do The differential diagnosis includes a primary non-
transform, the transformation is usually from papillary ITAC, papillary rhinosinusitis, papillary adenocarci-
to one of the more aggressive types. noma of the nasopharynx, and metastatic adenocarci-
The most common histological types of ITAC noma of the gastrointestinal tract.
seen in woodworkers as well as in sporadic cases are A primary non-ITAC typically consists of one
the papillary and colonic variants (11,19). cell population and, with the possibly exception of a
ITAC, particularly the papillary type, clearly few mucus cells, is devoid of goblet and Paneth cells.
arises from the mucosa of the sinonasal tract It is also positive for CK7 and negative for CK20,
(11,40,41). Whether others also arise from the mucosa CDX2, and villin (Table 27).
or from mucoserous glands or their ducts is uncertain. Sinusitis, at times, may have a papillary config-
On the basis of the work of Cheng and Leblond and uration, but in these instances, the papillae are short
Kirkland, it has been suggested that multidirectional and blunt and not highly branched as one sees in
differentiation of a common stem cell could account papillary ITAC. In addition, the background is
for the variety of cells (Paneth, endocrine, absorptive, ‘‘clean’’ in papillary rhinosinusitis, the basement
goblet) observed in ITAC (6,42,43). The stem cell, membrane is often thick and hyalinized, the surface
either by direct transformation or by induction of cells are ciliated and free of dysplastic changes, and
adjacent mesenchyme, might also give rise to the the stroma often has a prominent component of
muscularis mucosa noted in a few tumors. eosinophils.
Features that distinguish papillary ITAC from
papillary adenocarcinoma of the nasopharynx are
F. Immunohistochemistry discussed in section XXV of this chapter.
In a collective review of 97 ITACs, we observed that, if
performed, 66% were positive for the CK7, 89% for Table 27 Differential Diagnosis of Intestinal and Nonintestinal
CK20, 89% for CDX2, 96% for synaptophysin, and 53% Adenocarcinoma
for chromogranin (44–53). On the basis of these results
ITAC in two-thirds of the cases exhibits a characteris- Synaptophysin
þ Tumor CK7 CK20 CDX2 Villin or chromogranin
tic profile of CK7 , CK20þ, CDX2þ, villinþ; however,
in one-third of cases the profile is CK7–, CK20þ, Normal mucosa þ
CDX2þ, villinþ. ITAC þ/a þ þ þ þ/
Non-ITAC þ
Adenocarcinoma þ/b þ þ þ
G. Electron Microscopy of colon
a
Approximately 66% of ITAC are CK7-positive.
The similarity of ITAC to intestinal tumors extends b
Approximately 74% of adenocarcinomas of the rectum are CK7 positive,
beyond the light microscopic to the ultrastructural all other colon adenocarcinomas are usually CK7 negative.
level (5,7). Batsakis et al. have observed glycocalyceal Abbreviation: ITAC, intestinal-type adenocarcinoma.
Metastases to the nasal cavity and paranasal may have a slow, ‘‘smoldering’’ disease, only to die of
sinuses from a primary adenocarcinoma of the gastro- their tumor 10 or more years later.
intestinal tract are not common (61,62). In a study of Treatment consists of surgical excision using a
82 tumors metastatic to the nasal cavity and paranasal lateral rhinotomy or, at times, even a cranial base
sinuses, Bernstein et al. found the most common sites approach. The use of radiotherapy is dictated by the
of origin to be the kidney (40 cases), lung (10 cases), extent and resectability of the tumor. An elective neck
breast (8 cases), testis (6 cases), gastrointestinal tract dissection is not warranted.
(5 cases; 2 stomach, 2 colon, and 1 rectum), uterus Prognosis depends on the histological type,
(4 cases), thyroid (3 cases), adrenals (2 cases), cutane- degree of differentiation, stage of the disease, and
ous melanoma (2 cases), and pancreas (2 cases) (61). the adequacy of resection margins. Papillary ITAC,
The maxillary, ethmoid, and frontal sinuses, and the especially grade I or well differentiated, has the best
nasal cavity were involved in descending order. In prognosis. It may recur, but it rarely metastasizes. The
some of these patients, the head and neck metastasis other types are more virulent, with a greater propen-
was the initial manifestation of an otherwise clinically sity for dissemination. Over the course of time, a few
occult carcinoma. For this reason, consideration of a tumors may change from one histological type into
gastrointestinal tract adenocarcinoma in all patients another. This is an ominous finding, signaling a tumor
with ITACs, especially the colonic variant, would with increased aggressiveness.
seem prudent, although in the absence of relevant Woodworkers seem to have a better prognosis
signs and symptoms such studies will generally than those individuals with sporadic ITAC. This is
prove negative. probably because the woodworker is under height-
Immunohistochemistry offers little, if any, help ened surveillance for this tumor, and in this group, the
in distinguishing ITAC from a metastatic colorectal tumors are more often found in the nasal cavity or
adenocarcinoma (see sect. ‘‘Immunohistochemistry’’ ethmoid sinus and, therefore, can be detected earlier
above and Table 27). In the past, an immunoprofile by the patient. In contrast, patients with a sporadic
of CK7–/CK20þ was considered characteristic of a tumor are not in early detection programs and have
colonic adenocarcinoma. More recent studies have tumors that are relatively more common in the maxil-
shown that the presence or absence of CK7 positivity lary sinus, which are difficult to detect early.
in colon carcinomas varies according to the level of
tumor involvement. Zhang et al. observed in an
evaluation of 35 adenocarcinomas of the rectum that XXI. NONINTESTINAL-TYPE
26 (74%) expressed CK7 whereas only 3 of 11 (27%) ADENOCARCINOMA
colon adenocarcinomas proximal to the rectosigmoid
colon were positive for CK7 (63). A. Introduction
Since about two-thirds of sinonasal ITACs also
Nonintestinal-type adenocarcinomas (Non-ITAC) are
express CK7, one cannot rely on this stain entirely to
uncommon tumors of the nasal cavity and paranasal
separate ITAC from a metastatic colorectal adenocar-
sinuses that can be divided into low- and high-grade
cinoma. Immunostains for neuroendocrine markers
subtypes (1–5). By definition, they do not show histo-
may offer some possible aid since ITACs tend to
logical features of salivary-type neoplasms and do not
contain more endocrine-type cells than colorectal
contain the multiple cell types (absorptive, goblet,
adenocarcinomas and would be expected to stain
endocrine, Paneth) or exhibit the immunoprofile of
more extensively (44). When used in tandem, a strongly
an ITAC.
positive stain for both CK7 and synaptophysin and/or
Synonyms include low- or high-grade adenocar-
chromogranin would be more supportive of a primary
cinoma, nonenteric adenocarcinoma, seromucinous
ITAC. Also, if dysplasia or in situ carcinoma is
carcinoma, low-grade papillary adenocarcinoma, ter-
observed in the mucosa adjacent to an ITAC, this
minal tubulus adenocarcinoma, and sinonasal tubulo-
would imply that the tumor is primary rather than
papillary low-grade adenocarcinoma.
secondary.
B. Etiology
J. Treatment and Prognosis There are no known environmental or occupational
The clinical course is characterized by repeated local risk factors, although a few cases have occurred in
recurrences (53%), with ultimate invasion of the orbit patients with smoking histories.
and cranial cavity, but little tendency toward cervical
lymph node (mean 8%; range 0–22%) and systemic C. Clinical Features
metastases (mean 13%; range 0–29%) (11). Tumor
necrosis with sepsis is often a problem and may be Low-grade non-ITACs occur over a broad age range
life threatening. In a review of 213 ITACs, Barnes (9–89 years, mean about 55–65 years) and exhibit a
noted that at least 60% of the patients were known gender distribution of 1:1 to 1.3:1 in favor of males
to have died of their disease (11). Of those dying, 80% (1–5). They tend to predilect the nasal cavity and
did so within three years of diagnosis. The survival ethmoid sinus and manifest as nasal obstruction and
according to histological type is shown in Table 26. epistaxis. High-grade non-ITACs also occur over a
Some patients, especially those with papillary ITAC, broad age range (15–80 years, mean 59 years) but are
388 Barnes
more frequent in males by a ratio of 4 to 5:1 (1). They

also tend to be more common in the sinuses rather
than in the nasal cavity and are more often associated
with pain.
D. Pathology
Non-ITACs usually arise from the mucosa and exhibit
a glandular and/or papillary growth (Figs. 55–58).
The low-grade variant is composed of small glands,
lying back to back, lined by a single layer of epithelial
cells. Myoepithelial cells are not seen, mitoses are
sparse, and necrosis and perineural invasion are rare
to absent. Occasionally, the glands are dilated and/or
cystic with intracystic papillary projections. The
Figure 57 Nonintestinal-type adenocarcinoma, low grade, with

a papillary pattern (H&E, 100).
Figure 55 Nonintestinal-type adenocarcinoma, low grade, com-

posed of well-differentiated glands lying back to back (H&E,
40).
Figure 58 Higher magnification of the tumor shown in Fig. 57.

The tumor is composed of one cell type as opposed to several
different cells that may be seen in some intestinal-type adeno-
carcinomas. In this instance, the cells have pink cytoplasm and
large vesicular nuclei with prominent nucleoli. Mitoses are sparse
(H&E, 400).
surface of the tumor may be either sessile or papillary

(Figs. 55 and 57). Not infrequently, a tumor will show
focal areas suggestive of an acinic cell carcinoma or
exhibit oncocytoid changes. A few tumors may con-
tain small intracytoplasmic mucin vacuoles.
High-grade tumors, in turn, are more pleomor-
phic and exhibit increased mitoses, necrosis, and peri-
neural invasion. They are also less glandular or
papillary and often grow in a solid or sheet-like pattern.
Figure 56 Higher magnification of the tumor shown in Fig. 55.

The glands are lined by a single layer of epithelial cells.
E. Immunohistochemistry
Myoepithelial cells are absent (H&E, 400). Non-ITACs are positive for CK7 and negative for
CK20, CDX2, and villin (3,5,6). Although some tumors
stain for S-100 protein, they are otherwise negative for to date, Compagno and Wong noted that 25 originated
myoepithelial and neuroendocrine markers (3). from the bony or cartilaginous nasal septum, with
most having a broad base rather than a pedicle
attachment. Eight arose from the lateral wall, usually
F. Differential Diagnosis involving a turbinate, and in seven the exact site of
The differential diagnosis includes ITAC, inverted origin within the nasal cavity could not be determined
Schneiderian papilloma or OSP, and a salivary-type (3). The sinuses were not involved in any case, either
adenoma. primarily or secondarily.
Non-ITAC has a characteristic immunoprofile of Intranasal pleomorphic adenomas occur over a
CK7þ, CK20–, CDX2–, villin– which contrasts with broad age range (3–82 years, mean 42 years) and
the CK7þ/–, CK20þ, CDX2þ, villinþ profile of ITAC involve both genders about equally (3,4). Unilateral
(Table 27). ITAC is also occasionally positive for nasal obstruction and episodic epistaxis are the usual
neuroendocrine markers, while the non-ITAC is symptoms. On imaging, one sees an expanding, het-
negative. erogenous mass that fills the cavity and may even
The inverted Schneiderian papilloma is com- erode or destroy bone (3,6).
posed of squamous and/or respiratory epithelium, Grossly, the tumors appear exophytic, polypoid,
which is not seen in non-ITAC. The OSP is uniformly or dome shaped and have ranged from 0.5 to 7.0 cm in
composed of oncocytic epithelium, with prominent greatest dimension. Microscopically, they are more
intraepithelial mucin-filled cysts and microabscesses cellular than the ‘‘usual’’ pleomorphic adenoma.
(Figs. 36 and 37). While oncocytic cells may be seen in Rare examples, which have ossified or even exhibited
non-ITAC, intraepithelial cysts and microabscesses focal skeletal muscle differentiation have been
are not. Salivary-type adenomas contain myoepithelial described (5,7).
cells, which are not observed in non-ITACs. In the series of Compagno and Wong, 31 of
34 patients (90%) available for follow-up (mean
7.4 years) showed no evidence of local recurrence,
G. Treatment and Prognosis regardless of excisional procedure used (intranasal vs.
Low-grade non-ITAC can usually be managed by wide excision) (3).
surgery alone, either through an endoscope or a A few examples of carcinoma expleomorphic
medial maxillectomy, whereas high-grade tumors adenoma of the nasal cavity have been documented
often require both surgery and radiation. (8).
Low-grade non-ITACs are characterized by 20%
to 30% incidence of local recurrences (usually within
2–4 years of therapy) and rare to absent cervical C. Oncocytic Tumors
lymph node and distant metastases (1–5). Death
Oncocytic tumors of the nasal cavity and paranasal
from disease is rare (1). High-grade tumors, on the
sinuses, comparable to those seen in the major sali-
other hand, are aggressive, with a 30% incidence of
vary glands, are rare. They are more common in the
distant metastases and a 20% three-year survival (1).
nasal cavity than the sinuses and frequently predilect
the nasal septum.
In our review of 15 cases, nine occurred in males
XXII. SALIVARY-TYPE NEOPLASMS and five in females. The gender of one case was not
A. Introduction indicated (9–13). The ages ranged from 23 to 86 years
(mean 58 years). All presented with nasal stuffiness/
Mucoserous glands are present throughout the sino- obstruction, rhinorrhea, and/or epistaxis.
nasal tract and are particularly abundant in the nasal Some of the tumors have been as small as 5 mm
cavity along the lateral wall, including the turbinates, (9), and most on microscopic examination are of
and to a lesser extent on the nasal septum (1). They the solid type of oncocytoma. There are some who
are, however, relatively uncommon in the sinuses. state that all oncocytic lesions in this location should
Salivary-type neoplasms may arise not only from be considered as low-grade carcinomas, despite their
these glands but also the surface mucosa (2). Despite histological appearance. We wish to point out that
the abundance of glands, tumors derived from them, any benign tumor in this relatively closed environ-
with the exception of adenoid cystic carcinoma, are ment may erode bone and exhibit necrosis, e.g., IP,
scarce, and risk factors are largely unknown. angiofibroma, and are not absolute signs of malig-
A brief summary of some of these neoplasms nancy. In our opinion, an oncocytic lesion should
follows. A more detailed account of their clinicopatho- only be considered as malignant if it shows unequiv-
logical features can be found in the chapter ‘‘Diseases ocal invasion (not erosion of bone), increased mitotic
of the Salivary Glands.’’ activity (especially atypical mitoses), pleomorphism,
perineural invasion, and/or metastasis.
B. Pleomorphic Adenoma The differential diagnosis includes an oncocy-
toid/oncocytic carcinoid tumor, a metastatic renal cell
Pleomorphic adenoma of the sinonasal tract occurs carcinoma, and a metastatic oncocytic (Hurthle cell)
primarily in the nasal cavity and only rarely in the carcinoma of thyroid. A carcinoid tumor, in contrast to
sinuses (3–5). In a review of 40 cases, the largest series an oncocytoma, is positive for synaptophysin and/or
390 Barnes
chromogranin. Vimentin, CD10, and renal cell carci-

noma antigen are useful immunohistochemical
markers that aid in separating metastatic renal cell
carcinoma from an oncocytoma. Renal cell carcinoma
is positive for these stains while the oncocytoma is
negative (14). Oncocytic thyroid carcinoma is usually
positive for thyroglobulin and thyroid transcription
factor, while oncocytoma is negative for these
markers.
D. Acinic Cell Carcinoma

Acinic cell carcinomas occur primarily in the parotid
gland and only exceptionally in the sinonasal tract. In
a review of 14 cases, Neto et al. noted that the nasal
cavity was more often involved than the sinus and
that seven (50%) arose from either the inferior or
Figure 59 Image of an adenoid cystic carcinoma of the right
middle turbinate (15). The patients, eight females
maxillary sinus (arrow ). The tumor occupies most of the sinus
and six males, ranged in age from 42 to 76 years and involves the medial and posterior walls.
(median 59 years). Nasal obstruction was by far the
most frequent complaint.
The tumors ranged in size from 1 to 6 cm and
were most often treated by surgery alone. Three
patients also received postoperative radiation. None
underwent a neck dissection. At least one patient
developed local recurrence but was stated to be disease
free 12 years later after additional therapy.
The differential diagnosis might include a non-
ITAC (seromucinous), which infrequently shows a
focal (rather than diffuse) acinic cell pattern. Acinic
cell carcinoma, however, contains periodic acid–
Schiff, diastase-resistant granules that are not typically
seen in the non-ITAC.
E. Adenoid Cystic Carcinoma Figure 60 Gross picture of the resected adenoid cystic carci-
noma shown in Fig. 59. The tumor is solid and deceptively well
Adenoid cystic carcinoma (ACC) is the most frequent circumscribed.
salivary-type neoplasm of the sinonasal tract.
Although slowly growing, it is locally aggressive
and relentless in its progression with death from
disease often exceeding 10 years or more (16–19).
ACC of the sinonasal tract occurs over a broad
age range (18–82 years, mean about 45–55 years) and
exhibits a gender distribution of 1:1 to 2.5: 1 in favor of
males (17,19). In one series of 35 cases, 19 tumors arose
in the maxillary sinus, 10 in the nasal cavity, and 6 in
the ethmoid sinus (19). Symptoms include nasal
obstruction, epistaxis, toothache, swelling and pain
of the premaxilla and palate, paresthesias, proptosis,
visual disturbances, trismus, and/or headache.
Tumors, especially those of the maxillary sinus, are
often advanced at the time of diagnosis and staged as
T3 or T4 (Figs. 59–61).
Surgery with adjuvant radiation is the usual
treatment. Following therapy, approximately 50% to
75% of patients will experience local recurrence usu-
ally within five years, and 3% to 5% will experience
cervical lymph node metastasis, and 30% to 35% will Figure 61 Microscopic view of the adenoid cystic carcinoma in
have distant dissemination of tumors to the lungs and Figs. 59 and 60 showing the classic cribriform pattern of tumor
bones. The overall 10-year survival is about 40% to cells (H&E, 100).
55% at best (17,19).
F. Mucoepidermoid Carcinoma and paranasal sinuses are uncommon. They account

for less than 1% of all MMs and 2% to 8% of all
Mucoepidermoid carcinoma (MEC) is an uncommon malignant neoplasms of the sinonasal tract (7–14).
tumor in the sinonasal tract. In one review of 220 The incidence of cutaneous MMs is rising faster
carcinomas of the nasal cavity and paranasal sinuses, than any other cancer and, as such, has become an
only four (1.8%) were classified as MECs (20). The important public health issue. Between 1950 and 2000,
largest single series to date consists of 19 cases (21). the incidence rose an astonishing 697%! (15,16).
These occurred in 10 females and 9 males aged 15 to According to Rigel, the lifetime risk of an individual
75 years (mean 53 years). Ten cases arose in the nasal in the United States to develop MM was 1:1500 in 1935
cavity, six in the maxillary sinus, and in the remaining (17). By 1980, the risk had increased to 1:250 and by
three, both nasal cavity and sinus were involved. The 2000, it was 1:75. In contrast, the incidence of mucosal
tumors had a mean size of 2.4 cm and manifested MMs has remained remarkably stable over the last
clinically as a ‘‘mass,’’ nasal obstruction, or epistaxis. several decades (6,18).
Most of the tumors were low grade (N ¼ 10), with
intermediate (N ¼ 6) and high grade (N ¼ 3) compris-
ing the remainder. B. Etiology
Surgery, at times supplemented with radiation,
was the usual treatment. Of the 19 patients, six devel- Mucosal MMs of the sinonasal tract arise from mela-
oped a recurrence and five died of disease (mean nocytic precursors that originate in the neural crest.
2.4 years). The remaining 14 patients were either alive During migration these cells normally populate the
(N ¼ 9) or had died (N ¼ 5) of unrelated causes (21). mucus membranes but may also remain confined to
The differential diagnosis includes necrotizing the stroma (lamina propria). Accordingly, some pri-
sialometaplasia and adenosquamous carcinoma mary mucosal MMs may arise from these stromal
(ASC). In necrotizing sialometaplasia, in contrast to precursors and not exhibit any junctional or in situ
MEC, the lobular architecture of the mucoserous changes of the mucosa (19,20).
glands is maintained, and there is no perineural inva- Although excessive exposure to sunlight and
sion. The distinction between MEC and ASC in the genetic factors (dysplastic nevus syndrome) are
sinonasal tract is more problematic. In sites outside important in the etiology of cutaneous MM, there
the sinonasal tract, the presence of an in situ surface are no known risk factors for mucosal MM (21,22).
(mucosal) component generally indicates an ASC. In There are, however, sporadic reports of mucosal MMs
the sinonasal tract, MEC can arise from and/or involve associated with preexisting ‘‘melanosis’’ or occurring
the surface (mucosa) (2,21), and as a consequence, this somewhat more frequently in certain ethnic groups
discriminating feature is lost. MEC, as opposed to (Ugandan Africans), suggesting the possibility that
ASC, contains multiple cell-types—epidermoid, ectopic melanin production and race may be potential
mucous, intermediate, and clear—and shows little factors (23,25). Whether melanosis in some instances
evidence of keratinization or keratin pearls. represents a true focal increase in melanin production
or an unrecognized radial growth phase of a preexis-
tent melanoma is not always clear.
G. Other Tumors There is also a recent report raising the possibili-
Additional salivary-type neoplasms have also been ty of whether sinonasal MMs may be related to
described in the nasal cavity and paranasal sinuses, formaldehyde exposure (20).
though rarely. Among these are included myoepithe-
liomas, epithelial-myoepithelial carcinoma, polymor-
phous low-grade adenocarcinoma, and basal cell C. Clinical Features
adenocarcinoma (22–25). MMs occur more often in the nasal cavity than in the
sinuses. In a collective review of 604 cases in which
H. Nasopharynx the site of origin was indicated, 71% arose in the nasal
cavity, 16% in the sinuses, and 13% involved both
Salivary-type neoplasms of the nasopharynx are rare areas (Table 28) (7,9,24,26–48). In the nose, the most
and not well documented. Kuo and Tsang have common sites of origin are the anterior septum and
described 15 cases. These included eight MECs, two inferior and middle turbinates (Fig. 62). When con-
adenoid cystic carcinomas, four nonspecific adeno- fined to the sinuses, the maxillary is most often
carcinomas, and one composite adenocarcinoma— involved, followed by the ethmoid. The frontal and
undifferentiated carcinoma (26). sphenoid sinuses are rarely affected.
The vast majority of patients at the time of
diagnosis are older than 50 years (mean 60–70 years)
XXIII. MALIGNANT MELANOMA (19,26,27,32–39,43,46). Only 10% to 20% occur in indi-
A. Introduction viduals younger than 50 years. Although some studies
have shown either a male or female predominance, a
Fifteen to 25% of all MMs occur in the head and neck collective review of 268 cases reveals only a slight
and, of these, 6% to 8% involve the mucus membranes male predominance (54%; M/F ¼ 1.2:1) (9,26,27,
of the upper aerodigestive tract (1–7). Malignant mel- 32–39,43,46). Most patients are white, but 5% to 16%
anomas of the mucus membranes of the nasal cavity are black (20,26,35). Nasal obstruction and epistaxis,
392 Barnes
occasionally accompanied by swelling of the nose or diffusely hemorrhagic and fill the entire nasal cavity.
cheek, are the usual presenting complaints. Pain, Bone destruction may or may not be apparent on
however, is uncommon. radiological studies.
On physical examination, the tumors are sessile At the time of diagnosis, 0% to 20% of patients
or polypoid, pink, white, brown, or black and average will have positive cervical lymph nodes, especially
1 to 4 cm (Fig. 62). In some instances, they are around the submandibular gland (9,27,28,30,32,
34,35,38,40,42,43). Only 6%, however, will have distant
Table 28 Distribution of 604 Malignant Melanomas of the Nasal metastases (9,42).
Cavity and Paranasal Sinuses
Total D. Pathology
no. of
References cases Nose Sinus Sinonasal MMs of the sinonasal tract, histologically, resemble
their cutaneous counterparts and, as such, are com-
Moore (7) 10 9 1 0 posed of epithelioid or spindle cells arranged in small
Holdcraft (26) 39 21 7 11
clusters (thèques) or sheets (Figs. 63 and 64). Mitoses,
Freedman (27) 47 29 18 0
Conley (28) 18 12 6 0
Eneroth (29) 24 16 0 8
Shah (30) 45 39 6 0
Snow (31) 11 11 0 0
Cove (24) 1 0 0 1
Lund (9) 36 33 3 0
Bethelsen (32) 20 20 0 0
Blatchford (33) 6 6 0 0
Panje (34) 10 9 1 0
Trapp (35) 15 11 4 0
Suen (36) 1 1 0 0
Huntrakoon (44) 2 0 1 1
Going (37) 1 0 1 0
Gilligan (38) 28 16 4 8
Franquemont (39) 14 4 7 3
Stern (40) 20 12 8 0
Guzzo (41) 26 26 0 0
Thompson (42) 16 13 3 0
Kingdom (43) 17 10 7 0
Loree (45) 18 14 4 0
Brandwein (46) 21 12 5 4
Thompson (20) 106 64 3 39 Figure 63 Amelanotic malignant melanoma of the nasal cavity
Prasad (47) 39 29 4 6 composed of epithelioid cells arranged in an alveolar pattern
Manolidis (48) 13 10 3 0 (H&E, 200).
Total 604 427 96 81
(100%) (71%) (16%) (13%)
Figure 62 Deeply pigmented malignant melanoma involving Figure 64 Amelanotic malignant melanoma of the nasal cavity
the inferior nasal turbinate. The thick arrow shows small, mulifo- composed of spindle cells. Note the vague storiform pattern.
cal areas of additional melanoma. The thin arrow depicts an area Such tumors may be confused with a malignant fibrous histiocy-
of melanosis. toma or other soft-tissue sarcomas (H&E, 100).
distinct genetic-molecular pathways that lead to dif-

ferent types of MMs (52,53).
MM is one of the great mimickers in pathology. Under
appropriate conditions, it can be mistaken for a varie-
ty of tumors, including carcinomas, sarcomas, and
lymphomas (54,55). This is especially true in the
sinonasal tract where the tumor is rare, often fails to
show junctional activity, frequently is amelanotic, and
occasionally grows in a spindle pattern.
The biggest problem in differential diagnosis
rests, therefore, in simply failing to consider MM as
a possibility. Once considered, the diagnosis can
easily be established by appropriate immuno-
histochemical stains or ultrastructural evaluation.
Amelanotic spindle cell melanomas of the sino-
Figure 65 In situ malignant melanoma of the nasal cavity (H&E,
nasal tract often grow in large fascicles and are
400).
frequently mistaken for a fibrosarcoma or malignant
schwannoma. They may also exhibit a storiform pat-
tern and be confused with a malignant fibrous histio-
pleomorphism, intranuclear inclusions of cytoplasm, cytoma (Fig. 64). As a general rule, one should never
necrosis, and lymphatic, vascular, and perineural in- make a diagnosis of a soft-tissue sarcoma adjacent to a
vasion are additional, although inconsistent, features. mucous membrane in the head and neck without first
Because of extensive ulceration, junctional or excluding a spindle cell carcinoma, an amelanotic
pagetoid invasion of the overlying mucosa is seen in MM, and a myoepithelial neoplasm.
only 9% to 44% of cases (20,26,39,49) (Fig. 65). Ten to A metastasis from a cutaneous MM to the sino-
30% of tumors are also amelanotic, requiring special nasal tract must also be considered in the differential
tissue stains [S-100 protein, HMB-45 etc.] and a high diagnosis (56–60). The incidence of cutaneous MM
index of suspicion for diagnosis (26,27). metastasizing to the mucosal surfaces of the head
Desmoplastic mucosal MMs, though rare, have and neck is 0.2% to 0.7% if clinical data are used
also been described, primarily in the oral cavity but and 2% to 8% if autopsy studies are included
also in the sinonasal tract (50). (56,58,60–62). When cutaneous MMs disseminate to
the mucous membranes of the head and neck, the
primary is most often located on the trunk (55–62% of
E. Immunohistochemistry cases), followed by extremities (24–27%), and head
and neck (18–24%) (58,60). More than 60% of the
Immunohistochemical evaluation of sinonasal MMs
mucosal metastases will appear within two years of
using the standard melanoma markers have shown
diagnosis of the cutaneous lesion and about 60% to
that 91% to 95% are positive for S-100 protein, 76% to
65% of the patients will also have evidence of dissem-
98% for HMB-45, 78% to 100% for tyrosinase, 65% to
inated disease at the time of diagnosis of the mucosal
100% for melan-A, and 57% to 91% for microphthal-
lesion. Junctional activity in the overlying or adjacent
mic transcription factor (20,51). S-100 protein and
mucosa, if present, in conjunction with the clinical
tyrosinase are the best stains to identify desmoplastic
history, distinguishes primary mucosal MM from
mucosal MMs, while HMB-45 is negative in most
metastatic disease (60). However, as previously men-
desmoplastic and many spindle cell MMs (51).
tioned under ‘‘Etiology,’’ some primary sinonasal
MMs may also arise from stromal melanocytic pre-
F. Molecular-Genetic Data cursors and, accordingly, will not show junctional or
in situ mucosal changes.
Van Dijk et al. examined 14 sinonasal MMs by com-
parative genomic hybridization (CGH) and observed H. Treatment and Prognosis
two remarkably consistent alterations (52). First, chro-
mosome arm 1q was gained in all tumors, and all The treatment of choice for sinonasal MM is surgery.
tumors harbored a gain of 6p, a loss of 6q, or both. Once considered radioresistant, radiation is now
Second, gains of 1q, 6p, and 8q occurred frequently in considered by some and denied by others to be an
combination with a loss of copy number or a normal important adjuvant in achieving local control and may
copy number of the opposite chromosome arm, sug- even have merit as a prime modality in selected
gesting isochromosome formation. Comparing these patients (20,63–66). An elective neck dissection
CGH results, the authors concluded that sinonasal for sinonasal MM is usually not warranted (40).
melanomas harbor a more consistent CGH pattern Chemotherapy is, at present, employed principally
than other melanoma types and subtypes. This as in the treatment of disseminated disease and for
well as other studies suggest that there may be several palliation.
394 Barnes
Local recurrence (40–85%) and distant metastasis Table 30 Proposed TNM staging of Sinonasal and Nasophar-
(30–70%), rather than regional lymph node metastasis yngeal Mucosal Malignant Melanomas
(10–30%), are responsible for most treatment failures Stage Definition
and deaths (9,27,28,30,32,34,35,38,40,42,43,67). The
five-year survival rate is about 20% to 30% (range Primary tumor
6–48%) (9,26,28,30,32,34–36,40,41,67). The average inter- T1 Single anatomic
site
val from initial treatment to local recurrence in three T2 Two or more
reported series has ranged from 9 to 13 months anatomic sites
(34,40,43). Local recurrence following seemingly ade- Regional lymph node
quate excision is ascribed to the presence of intrale- N1 Any lymph node
sional lymphatic and blood vessel invasion seen in metastasis
many tumors. Distant metastasis
Local recurrence and distant metastasis are omi- M1 Distant metastasis
nous signs. Most patients who fail locally eventually Stage grouping
die of their disease, and of those who develop syste- Stage I T1, N0 M0
mic disease, the average survival after metastasis is Stage II T2, N0 M0
Stage III Any T, any N, M1
only six months (30,34,40). The lungs, liver, brain, Stage IV Any T, any N, M1
bones, and spinal cord are the most frequent sites of T, primary tumor.
dissemination, but occasionally unusual areas, such as TX, primary tumor cannot be assessed.
the small intestine and heart, may also be involved T0, no evidence of primary tumor
(62,68,69). T1, tumor limited to a single anatomic
Clark staging of mucosal MMs is not possible site. A single anatomic site is defined
because of the absence of comparable landmarks as one of the following: nasal cavity,
within the mucosa and lamina propria of the upper maxillary sinus, frontal sinus, ethmoid
respiratory tract that are present in the dermis. sinus, sphenoid sinus, nasopharynx.
The Breslow thickness, the single most important Subsites, such as septum, lateral
wall, turbinate, nasal floor, or nasal
histological prognostic factor in cutaneous MM, has vestibule are not separately
not been found to be useful in mucosal MMs of considered.
the head and neck (20,47). In lieu of these two param- T2, tumor involving more than one
eters, Prasad et al. have proposed a three-level micro- anatomic site. More than one
staging system that seems to correlate with prognosis anatomic site is defined by tumor
(Table 29) (47). In a review of 61 mucosal MMs (39 involvement of more than one
sinonasal, 20 oral, 1 pharyngeal, and 1 laryngeal), they anatomic site (although not subsite)
observed the median survival to be 138 months for as cited above, including any
Level I, 69 months for Level II, and 17 months for extension into subcutaneous tissues,
Level III (47). skin, palate, pterygoid plate, floor,
wall, or apex of the orbit, cribriform
The tumor-node-metastasis (TNM) classifica- plate, infratemporal fossa, dura, brain,
tions for nasal cavity, paranasal sinuses, and skin are middle cranial fossa, cranial nerves,
not readily applicable for mucosal MMs. As a result, clivus.
Thompson et al. have proposed a modification shown
Data derived from Ref. 20.
in Table 30 (20). Another more simplified clinical Abbreviation: TNM, tumor-node-metastasis.
staging system uses three stages—stage I (localized
disease), stage II (locoregional disease), and stage III
(distant disease at presentation) (70).
XXIV. NASOPHARYNGEAL CARCINOMA
Local recurrence, and tumors composed
of undifferentiated cells with a sarcomatoid and A. Introduction
pseudopapillary architecture, and more than 10 mito-
ses per 10 HPFs are indicators of a poor prognosis NPC is defined by the WHO as ‘‘a cancer arising in
(20,47). the nasopharyngeal mucosa that shows light or ultra-
structural evidence of squamous differentiation. It
encompasses squamous cell carcinoma, nonkeratiniz-
ing carcinoma (differentiated or undifferentiated) and
Table 29 Prasad’s Microstaging of Mucosal Malignant Melano- basaloid squamous carcinoma. Adenocarcinoma and
mas of the Head and Neck salivary gland carcinoma are excluded’’ (1).
Level Definition It has a very distinctive geographic and ethnic
distribution (see ‘‘Etiology’’ below). On a worldwide
I Melanoma in situ without evidence of invasion or with
only microinvasion (defined as invasive individual or
basis, it is a relatively rare tumor, with an estimated
clusters of <10 atypical melanocytes near the 65,000 new cases per year, or 0.6% of all cancers (1).
epithelial junction)
II Invasion limited to the lamina propria
B. Anatomy
III Deep tissue invasion into skeletal muscle, bone, or
cartilage Anatomically, the nasopharynx is a small, relatively
Source: From Ref. 47. inaccessible space that represents the cranialmost
portion of the pharynx. It averages 2 to 3 cm ante- and III) by the fact that high antibody titers to the
roposteriorly and 3 to 4 cm vertically and transver- virus are found in most patients regardless of geo-
sally, with considerable individual variation (2). graphic location. The association was strengthened
Anteriorly, it communicates with the nasal cavity when EBV DNA and EBV-associated nuclear antigens
through the posterior choanae. Superiorly, the roof is were found in the epithelial cells of NPC and not in
formed by the base of the skull and the undersurface of the lymphoid component of the tumor (13,14). As the
the sphenoid sinus. Posteriorly, the wall is composed of tumor burden increases so does the antibody titer.
the ventral surfaces of the first and second cervical It has been suggested that the HPV, as well as
vertebrae. Inferiorly, it communicates with the oro- cigarette smoking, alcohol, and formaldehyde expo-
pharynx, or if the soft palate is closed, the superior sure, may play a role in the etiology of the keratinizing
surface of the soft palate forms the floor. Laterally, the type of NPC (WHO I) (15–18). Other factors that may
orifices of the eustachian tubes are found, each partially impact on the risk of NPC include an occupational
surrounded by a cartilaginous elevation referred to as exposure to wood dust and a history of chronic nose
the torus tubarius. Medial to this elevation is the and throat problems (rhinosinusitis) (1,19–21).
pharyngeal recess or fossa of Rosenmuller, which is a
slit-like space of variable size and depth.
Histologically, the nasopharynx is lined by both D. Clinical Features
ciliated respiratory and stratified squamous epitheli-
um, with respiratory epithelium predominating near NPC occurs in all age groups with a peak incidence
the posterior choanae and squamous epithelium on between 30 and 50 years of age. Some regions have
the posterior and lateral walls, with areas of epithelial observed a bimodal distribution, with one peak
transition. The nasopharynx is part of Waldeyer’s ring between 10 to 20 years of age and another at 40 to
and, accordingly, contains abundant lymphoid tis- 60 years (22–33). The ratio of males to females is rather
sue, with occasional germinal centers and crypts. consistent, regardless of geographic location, and is
Mucoserous glands are seen but are not prominent. about 2 to 3:1.
Patients typically present with nasal obstruction,
epistaxis, serous otitis media, or an asymptomatic
C. Etiology neck mass (usually in the apex of the posterior cervical
triangle or superior jugular area). At the time of
The etiology of NPC is multifactorial and relates to the diagnosis, 10% to 20% will also have a cranial nerve
interaction of race, genetics, environment and the dysfunction (especially III, IV, V, and VI) and 60% to
EBV. Although the incidence is declining, it is still 85% will have positive cervical lymph nodes, of which
one of the most frequent cancers in Chinese, especially 35% to 45% will be bilateral (2,34–36). Less than 5%,
among those who reside in southern China in the however, will have distant metastasis. In rare instan-
province of Kwantung and in Hong Kong (20–30 ces, NPC may present with dermatomyositis or mani-
cases per 100,000 population per year), and also fest with inappropriate secretion of antidiuretic
occurs with increased frequency in North Africa and hormone or Cushing’s syndrome secondary to ectopic
among Alaskan Eskimos, Indians, and Aleuts (3,4). In adrenocorticotrophic hormone production (37–39).
most other countries, it is an uncommon tumor (less The most common site of origin in the nasophar-
than one case per 100,000 population per year) (5). As ynx is the lateral wall in the region of the fossa of
the Chinese immigrate to other low-frequency coun- Rosenmuller, adjacent to the opening of the eusta-
tries, the incidence of NPC diminishes with successive chian tube followed by the posterior-superior wall. In
generations, but even then, the risk of NPC remains a review of 437 patients, Skinner et al. observed that
greater than that of the new host population (6,7). 78% of the tumors were lateral in origin and equally
Human leukocyte antigens (HLA) may also be distributed between the right and left sides of the
important etiological or prognostic indicators in NPC. nasopharynx, 12% were central in origin, 5% were
The association, however, is sometimes confusing and occult with a normal-appearing nasopharynx, and 5%
contradictory and may vary with ethnic group and were too large to determine their origin (34).
country. In a meta-analysis of southern Chinese, The clinical appearance of the tumor, as viewed
Goldsmith et al. observed a positive association for through an endoscope, is highly variable. In a retro-
NPC risk and HLA-A2, HLA-B14, and HLA-B46 and a spective review of 209 patients, Dickson noted that
negative association for HLA-A11, HLA-B13, and 74% of the carcinomas were exophytic, 14.4% infiltra-
HLA-B22 (8). A genetic predisposition is also sup- tive, and 6.7% ulcerative; in the remaining 4.8%, the
ported by the observation that individuals who have a tumor was not described (7).
first-degree relative with NPC are also at risk for In countries where the incidence of NPC is low,
developing tumor (9). the diagnosis is often not considered. The symptoms
Dietary factors, especially preserved foods that are regarded as trivial and largely ignored, which
contain a high content of nitrosamines such as accounts for the advanced stage when first recognized.
Cantonese salted fish, are also implicated and espe- Once the diagnosis is entertained, the patient should
cially if the individual consumes such food on a have a thorough examination, including nasopharyngo-
regular basis during the first decade of life (10–12). scopy (40). Imaging studies are crucial for proper
The EBV has been incriminated in the etiology of staging, planning of treatment, and selecting the most
NPC (especially the nonkeratinizing tumors, WHO II appropriate site of biopsy. Plain radiography, however,
396 Barnes
lacks sensitivity and specificity. Computed tomography Table 31 AJCC Staging of Nasopharyngeal Carcinoma, 2002
and magnetic resonance imaging are much preferred
Primary tumor (T)
and very helpful in defining the extent of skull base TX Primary tumor cannot be assessed
invasion, present in about 25% to 30% of cases (41). T0 No evidence of primary tumor
Cytology, both exfoliative and fine needle aspi- Tis Carcinoma in situ
ration, may also have a role in the diagnosis of NPC. T1 Tumor confined to the nasopharynx
The value of exfoliative cytology is, however, contro- T2 Tumor extends to soft tissues
versial, with overall diagnostic accuracy rates ranging T2a Tumor extends to the oropharynx and/or nasal cavity
anywhere from 26% to 89% (42). Fine needle aspira- without parapharyngeal extension
tion of enlarged cervical lymph nodes has, on the T2b Any tumor with parapharyngeal extension
other hand, opened a new vista in diagnosis. It not T3 Tumor involves bony structures and/or paranasal sinuses
T4 Tumor with intracranial extension and/or involvement of
only provides material that may be diagnostic but also
cranial nerves, infratemporal fossa, hypopharynx, orbit,
provides cells or tissue fragments that can be analyzed or masticator space
by in situ hybridization and/or the polymerase chain
reaction for the presence of the EBV (43–46).
Patients with NPC frequently develop antibodies N0 No regional lymph node metastasis
to a variety of EBV antigens, particularly immuno- N1 Unilateral metastasis in lymph node(s), 6 cm or less in
globulin A (IgA) antibodies, to the viral capsid antigen greatest dimension, above the supraclavicular fossaa
and early antigen. As the tumor burden increases, N2 Bilateral metastasis in lymph node(s), 6 cm or less in
so does the antibody titer. Consequently, the viral greatest dimension, above the supraclavicular fossaa
titer can be used not only as a diagnostic tool to screen N3 Metastasis in lymph node(s)a>6 cm and/or to
populations at risk but also to monitor therapy supraclavicular fossa
(47–51). N3a Greater than 6 cm in dimension
More recently, it has been shown that the detec- N3b Extension to the supraclavicular fossab
tion of EBV genomic LMP-1 by nasopharyngeal cotton Distant metastasis (M)
swab and polymerase chain reaction amplification is a MX Distant metastasis cannot be assessed
valuable tool for screening and early detection of M0 No distant metastasis
NPC. Hao et al. indicate that the procedure has a
92% positive predictive value and a 97% negative Stage grouping: nasopharynx
predictive value (52). Stage 0 Tis N0 M0
Once the diagnosis is established, it then Stage I T1 N0 M0
becomes necessary to determine the extent or stage Stage IIA T2a N0 M0
of the tumor. In the past, there were two competing Stage IIB T1 N1 M0
staging symptoms—the AJCC and the Ho. Each had T2 N1 M0
its own advantages and disadvantages (53–56). The T2a N1 M0
new sixth edition (2002) of the AJCC Cancer Staging T2b N0 M0
Manual has incorporated the best features of both and T2b N1 M0
Stage III T1 N2 M0
is now emerging as the most preferred (Table 31) (57).
T2a N2 M0
T2b N2 M0
T3 N0 M0
E. Pathological Features T3 N1 M0
T3 N2 M0
To standardize the confusing histological terminology Stage IVA T4 N0 M0
of NPC, the WHO in 1978 proposed that these tumors T4 N1 M0
be divided into three categories: squamous cell carci- T4 N2 M0
noma, nonkeratinizing carcinoma (NKC), and undif- Stage IVB Any T N3 M0
ferentiated carcinoma (58). In 1991, the WHO slightly Stage IVC Any T Any N M1-
modified this classification and once again in 2005 a
Midline nodes are considered ipsilateral nodes.
(Table 32) (1,59). b
Supraclavicular zone or fossa is relevant to the staging of nasophar-
The term ‘‘squamous cell carcinoma,’’ also some- yngeal carcinoma and is the triangular region originally described by Ho.
It is defined by three points: (i ) the superior margin of the sternal end of
times referred to as WHO I, is used for those tumors the clavicle, (ii ) the superior margin of the lateral end of the clavicle, and
that show definite evidence of squamous differentiation (iii ) the point where the neck meets the shoulder. Note that this would
(intercellular bridges, keratinization) over most of its include caudal portions of Levels IV and V. All cases with lymph nodes
extent and is associated with a desmoplastic reaction (whole or part) in the fossa are considered N3b.
(Fig. 66). It can be graded as well, moderately, or poorly Abbreviation: AJCC: American Joint Committee on Cancer.
differentiated, has a weak relationship to EBV, tends to
remain localized, and has a variable response to irradi-
ation (60). It rarely occurs in individuals younger than
40 years. (Fig. 67). The cell margins are distinct and the junction
The differentiated NKC (WHO II), as the name between stroma and epithelium is sharp. This type has
implies, shows no evidence of keratinization. The cells a strong relationship to EBV, tends to disseminate
are stratified and have an appearance similar to that from its site of origin, and has a variable but usually
of transitional cell carcinoma of the urinary bladder good response to irradiation (60).
Table 32 Classification of Nasopharyngeal Carcinoma

World Health Organization (1978)
1. Squamous cell carcinoma
2. Nonkeratinizing carcinoma
3. Undifferentiated carcinoma
a. Differentiated nonkeratinizing carcinoma
b. Undifferentiated carcinoma
a. Differentiated nonkeratinizing carcinoma
b. Undifferentiated carcinoma
3. Basaloid squamous carcinoma
Figure 67 Nonkeratinizing (differentiated nonkeratinizing) car-

cinoma of the nasopharynx. This variant resembles transitional
cell carcinoma of the genitourinary tract. The nuclei are relatively
uniform and, for the most part, are devoid of prominent nucleoli
(H&E, 200).
Figure 66 Squamous cell carcinoma of the nasopharynx.

Observe the dyskeratotic cells (H&E, 200).
Undifferentiated carcinoma (WHO III) is com-

posed of cells with indistinct margins and round to
oval nuclei with prominent, round nucleoli (Fig. 68).
The cells tend to grow in a syncytium rather than
having a stratified or pavemented appearance. In
some instances, the tumor grows in well-defined Figure 68 Undifferentiated carcinoma of the nasopharynx. The
epithelial aggregates (Regaud pattern) easily recogniz- cells have a syncytial arrangement and contain large, vesicular
able as a carcinoma. In other instances, it grows as ill- nuclei with prominent nucleoli. Note the lymphocytes in the
background that also extend between tumor cells (H&E, 400).
defined sheets, small clusters, or individual cells
admixed with lymphocytes (Schmincke pattern), sim-
ulating a malignant lymphoma (61–65). The lymphoid
element, however, is not malignant and is rarely, if
ever, observed in sites of metastasis. The lymphocytes be so prominent as to mask small islands of tumor cells
are mainly T cells of CD8 subtype (66,67). (71). The undifferentiated carcinoma may also be mis-
Undifferentiated carcinomas are often designat- taken for immunoblastic sarcoma. Immunoperoxidase
ed as lymphoepitheliomas. Occasionally, they may be stains for keratin, leukocyte common antigen, and
associated with an exuberant infiltrate of eosinophils immunoglobulins now allow one to distinguish
(25–35% of cases in endemic areas and especially the between these entities with ease.
undifferentiated type) and masquerade as Hodgkin’s The undifferentiated carcinoma is the type most
disease or eosinophilic granuloma (68–70). The eosin- often found in children. It has a strong correlation
ophilia has no prognostic significance. A few cases with EBV, tends to disseminate, and has a good
may also contain epithelioid granulomas, which may response to irradiation (60) (Fig. 69).
398 Barnes
F. Immunohistochemistry
NPCs are positive pankeratin, AE1/3 and p63. They
are also positive for CK 5/6, 8, 13, and 19 and usually
negative for CK7 and 20 (1,75). CAM 5.2 and epithelial
membrane antigen are weak and patchy. The lymphoid
cells are mixture of the T and B cells, with the former
predominating (66,67). Plasma cells are polyclonal.
Some tumors also contain scattered S-100 protein-
positive dendritic cells, and the more of these cells
seen, allegedly the better the prognosis (76,77).
G. Viral Studies
If one employs in situ hybridization or the polymerase
chain reaction, EBV genomes can be detected in most
NPCs, especially the nonkeratinizing variants (WHO
II and III) (Fig. 69). The incidence of finding EBV in the
squamous cell carcinoma variant of NPC, however, is
Figure 69 Positive EBER stain for Epstein-Barr virus in an controversial and, if found at all, is usually limited to a
undifferentiated nasopharyngeal carcinoma. Abbreviation: few scattered cells in the dysplastic surface epithelium
EBER, Epstein-Barr virus–encoded RNA. or in the relatively ‘‘nonkeratinized’’ portion of the
tumor and then only low copies of the virus are found
(78–81).
According to Pathmanathan et al., EBV infection
is an early initiating event in the development of NPC.
It is generally agreed that the above three They observed evidence of the virus in 11 cases of
types of NPCs actually represent variants of preinvasive lesions of the nasopharynx and that the
squamous cell carcinoma. The histological distinc- EBV DNA was clonal, indicating that the preinvasive
tion among these three tumor types is by no lesions arose from a single EBV-infected cell.
means always sharp. In fact, in the series of Moreover, they noted that the EBV-induced clonal
Shanmugaratnam et al., 26% of 363 NPCs had fea- proliferation in these preinvasive lesions often pro-
tures of more than one of the above histological gressed to an invasive carcinoma within one year (82).
patterns (72). In such a case, the tumor is classified Pak et al., however, indicate that the interval from in
according to its dominant component. situ to invasive NPC may take as long as four or five
NPC may also contain amyloid. Prathap et al. years (83).
studied consecutive biopsies in 434 Malaysian patients Hording et al. studied 38 NPCs for the presence
with NPC and found amyloid in 12% of the tumors. of the HPV. Four of 15 squamous carcinomas were
The amyloid was present in all three histological types positive for HPV (1 HPV-11 and 3 HPV-16). None of
of NPC but was highest in nonkeratinizing carcinoma the remaining 23 undifferentiated and nonkeratiniz-
(NKC) (22%) followed by squamous cell carcinoma ing carcinomas harbored HPV. They suggested that
(12%) and undifferentiated carcinoma (7%). The amy- the HPV might be responsible for some EBV-negative
loid was patchy in distribution and often localized to a squamous cell carcinomas of the nasopharynx (15).
small part of the tumor. No significance was apparent
in patients with this finding (73). H. Molecular-Genetic Data
Basaloid squamous carcinoma is distinctly
unusual in the nasopharynx. Histologically, it is com- Cytogenetic studies of NPC have shown multiple
posed primarily of smooth contoured lobules of mitot- chromosomal abnormalities, most of which are non-
ically active basaloid cells with comedonecrosis and specific. The only somewhat consistent finding has
occasional peripheral palisading of nuclei. The squa- been a loss of genetic material at two loci (3p 14 and
mous component is generally small and, at times, 3p25) on the short arm of chromosome 3 in a series of
elusive due to surface ulceration. Three cases have 36 patients from China (84).
been described in the nasopharynx in Hong Kong, and The frequency of chromosomal damage varies
all three were associated with the EBV (74). with the stage of the tumor; early-stage tumors
The frequency of the above histological types (I and II) have fewer genetic changes than those
varies according to geographic location. In North observed in advanced stages (III and IV). Gains in
America, about 75% of cases are of the nonkera- genetic material have been observed, in decreasing
tinizing type (WHO II and III) and 25% squamous order of frequency, on 12p, 1q, 17q, 11q, and 12q.
cell carcinoma (60) (WHO I). In endemic areas, such Loss of genetic material has been observed at 3p, 9p,
as Hong Kong, almost all (99%) are of the nonkera- 11q, 13q, and 14q (1,85).
tinizing type (WHO II and III). The frequency of Whether DNA tumor ploidy has prognostic sig-
basaloid squamous carcinoma in the nasopharynx is nificance remains controversial. Costello et al. con-
unknown, but appears to be distinctly uncommon (1). cluded that tumor ploidy was not a significant
Table 33 UNPC Vs. SNUC

Feature UNPC SNUC
Location Nasopharynx Sinonasal tract
Clinical Small primary þ cervical lymph nodes Large primary, þ/ cervical lymph nodes
Imaging Little destruction or spread beyond site of origin Marked destruction and spread beyond site of origin
Growth Syncytial Trabeculae, nests, sheets
Cells Large, vesicular nuclei with prominent nucleoli Hyperchromatic to vesicular nuclei with or without nucleoli
Mitoses Not prominent Very prominent
Necrosis Not prominent Very prominent
Vascular invasion Not prominent Very prominent
Lymphocytes Heavy infiltrate Absent to mild
EBV þ (in United States)
CK5/6 and 13 þ
Abbreviations: UNPC, undifferentiated nasopharyngeal carcinoma; SNUC, sinonasal undifferentiated carcinoma.
determinant of prognosis, while Cheng et al. and Yip Primary LEC of the sinonasal tract should also
et al. observed that diploid tumors had a significant be distinguished from the undifferentiated NPC. Since
survival advantage over those that were aneuploid the two are identical histologically and both contain
(86–88). the EBV, separating the two depends on identifying the
P53 overexpression has been reported in 31% to location of the tumor either in the sinonasal tract or
95% of NPCs and, with few exceptions, does not nasopharynx (97) (Figs. 48 and 68).
appear to be a significant prognostic factor (89–91). Basaloid squamous carcinoma, in turn, is occa-
In a study of 30 NPCs, Roychowdhury et al. noted that sionally confused with adenoid cystic carcinoma.
intense angiogenesis and C-erb B2 overexpression These two can be distinguished by features shown
correlated with a tendency for distant metastasis in Table 34.
and/or shorter overall survival (92). Shi et al. in a
review of 87 NPCs found no association between
tissue angiogenesis (microvessel density count) and J. Treatment and Prognosis
clinical behavior (93). Because of the strategic location of the nasopharynx
In a review of 49 NPCs, Bar-Sela et al. observed and the tendency for the tumor to invade surrounding
that one-third were positive for C-Kit and none for tissues, the first line of therapy for NPC is irradiation
C-erb B2 (HER2) (94). The C-Kit positive tumors were (98–102). Surgery, if used at all, is reserved for radio-
all EBV-positive and nonkeratinizing type (WHO II resistant and/or locally recurrent tumors (103–107).
and III). Although the C-Kit-positive tumors tended to As the local and regional disease can be adequately
be associated with a slightly better prognosis, this was managed by radiotherapy, the role of chemotherapy is
not statistically significant. usually reserved for disseminated disease and, more
There is preliminary evidence to suggest that
patients with tumors that are Bcl-2-negative and
Table 34 BSCC Vs. ACC
C-Myc-positive have a better prognosis (lower rates
of recurrence and death from disease) compared Feature BSCC ACC
with those whose tumors are Bcl-2 positive and Lymph nodes þ
c-Myc-negative (95,96). Cribriform pattern focal often prominent
Nuclei Hyperchromatic to dark, angulated
vesicular, round
I. Differential Diagnosis Nucleoli þ/
The keratinizing NPC (squamous cell carcinoma, Mitoses þ þ/
Squamous carcinoma þ
WHO I) is easily recognized and resembles squamous
Perineural invasion rare frequent
cell carcinoma anywhere else in the body. The non- Comedonecrosis prominent rare
keratinizing variants (WHO II and III), on the other Muscle specific actin Neg. or focal diffuse
hand, may be more problematic and can be confused Myoepithelial cellsa þ
with a myriad of other small round cell tumors of the P53 þ
sinonasal tract, including malignant lymphoma, Ki-67 high low
malignant melanoma, ONB, extramedullary plasma- S-100 focal, dendritic diffuse
cytoma, and rhabdomyosarcoma. SNUC, especially, is cells
often confused with the undifferentiated NPC (WHO C-kit þ/ þ
III). Features that are useful in separating these two P63 diffuse, basaloid, myoepithelial
and squamous cells only
neoplasms are shown in Table 33. The other small
cells
round cell tumors can usually be excluded with an a
appropriate panel of immunostains [leukocyte com- Although in our experience myoepithelial cells are usually not seen in
BSCC, a recent abstract indicates that myoepithelial cells may be seen in
mon antigen, S-100 protein, HMB-45, synaptophysin, some BSCCs (36).
immunoglobulin G (IgG), Lambda and kappa light Abbreviations: BSCC, basaloid squamous cell carcinoma; ACC, adenoid
chains, myogenin, etc.]. cystic carcinoma.
400 Barnes
recently, has also been used in a neoadjuvant stetting The status of the regional lymph nodes also
(108–113). Newer therapeutic options are being affects prognosis. Lymph nodes confined to the
explored, including brachytherapy, interferon upper neck, regardless of size, and whether they are
gamma, immunization with EBV peptide-pulsed den- unilateral or bilateral, fixed or nonfixed, do not carry
dritic cells, and photodynamic therapy (114–116). the same weight as those present in the lower neck–
After treatment with radiation, it may take up to supraclavicular area (25,126). Positive lymph nodes in
10 weeks for the tumor to disappear histologically. If the latter location are associated with a poor
posttreatment biopsy is still positive for tumor after prognosis.
10 weeks, additional salvage therapy is warranted The prognosis for NPC is better in young patients
(117,118). (younger than 40 years) than old, and in females than
Screening for LMP-1 also seems to be a valuable in males. Cranial nerve involvement also adversely
test to monitor therapy and early recurrence of NPC affects prognosis, whereas erosion of the base of the
following radiotherapy. According to Tsang et al., skull does not (127). Keratinizing histology and
LMP-1 becomes undetectable at a median interval of absence of EBV indicate a poor prognosis.
4.3 weeks (range 1.3–28 weeks) after the beginning of In contrast to other patients with mucosal head
irradiation. If LMP-1 reappears, the patient is at risk and neck squamous carcinomas who have an
for recurrence. In their study, the median interval increased frequency for developing additional prima-
between the reappearance of LMP-1 and abnormal ry tumors (field effect of Slaughter), patients with
mucosal findings by endoscopy was 11.9 weeks (range NPCs do not exhibit an increased frequency of second
2.7–27.4 weeks) (119). primaries, probably related to different risk factors.
At times, it is often difficult to distinguish on Patients with NPCs, however, are at risk, though
biopsies radiation changes from recurrent NPC. If the small, for developing radiation-induced neoplasms
LMP-1 is positive, then the biopsy most likely repre- (128–130).
sents recurrent tumor rather than radiation-induced
atypia-dysplasia.
Sixty percent to 85% of patients with NPCs will XXV. PAPILLARY ADENOCARCINOMA
have positive cervical lymph nodes at the time of OF THE NASOPHARYNX
diagnosis, but less than 5% will demonstrate clinical
evidence of distant metastasis (4,25,34). However, A. Introduction
during the course of the disease, 20% to 60% (depend-
ing on whether clinical or autopsy data are used) will The vast majority of malignant tumors of the naso-
develop tumor dissemination below the clavicles, usu- pharynx are either keratinizing or nonkeratinizing
ally to the bones, distant lymph nodes, lungs, and liver squamous cell carcinomas or malignant lymphomas
(25,120–122). Ninety-eight percent of distant metasta- (1,2). Adenocarcinomas are uncommon, constituting
ses are detected within three years of diagnosis (122). no more than 6% of all malignancies, and, of these,
Their presence is an ominous sign of impending death. most are derived from the mucoserous (minor
The median survival following their appearance is only salivary) glands and can be classified according to
six months (121). According to Vikram et al., the standard categories (adenoid cystic carcinoma,
presence of distant metastases correlates with the N mucoepidermoid carcinoma (MEC), and such) (3).
stage but not T stage (120). The incidence of distant Exceptionally, adenocarcinomas may also arise from
metastasis in patients whose cervical lymph nodes the mucosa and, when they do, they are typically
measure less than 3 cm, 3 to 6 cm, and more than papillary and are referred to as papillary adenocarci-
6 cm is 10%, 25%, and 50%, respectively (123). nomas of the nasopharynx (PACN) (4–6).
In a review of 103 patients with NPCs treated by
radiation therapy, Bailet et al. observed the 5-, 10-, and B. Clinical Features
15-year overall survival rates were 58%, 47%, and
41%, respectively, with a median survival of 96 months PACNs are slightly more common in males (60%) and
(124). Local recurrences following radiation therapy occur in individuals from 11 to 64 years of age (medi-
continue to be a problem and range from approximately an 33 years) (4–6). Most present with airway obstruc-
30% to 45% (120,124,125). In general, the greater the tion. Other less common symptoms include serous
T stage the more likely that the patient will develop otitis media, with or without hearing loss, and post-
local failure (125). nasal drip with blood-tinged sputum. Rarely, the
Keratinizing carcinomas (squamous cell carcino- tumor may be an incidental finding following
ma; WHO 1) have a much worse prognosis than adenoidectomy.
nonkeratinizing carcinomas (nonkeratinizing carcino- PACNs are typically confined to the nasophar-
ma, WHO 2, undifferentiated carcinoma, WHO 3). ynx and, on physical examination, present as exo-
The overall five-year survival rate for patients with phytic or pedunculated masses, with a papillary,
NPCs in the United States is about 40% to 50%. For nodular, or cauliflower-like appearance. The tumors
specific histological types, the five-year survival is range from 0.3 to 4.0 cm, and most often they involve
20% to 40% for squamous cell carcinoma (WHO 1) the roof, lateral or posterior walls of the nasopharynx.
and about 65% for the nonkeratinizing carcinomas There are no known risk factors associated with
(WHO 2 and 3). the development of this tumor. None of the patients
thus far has had a significant history of tobacco or

alcohol abuse or occupational, environmental, or radi-
ation exposure (4).
There has been one case reported in a 29-year-
old female with Turner’s syndrome (6). Karkos, et al.
describe a 72 year-old man with an ‘‘aggressive papil-
lary tumor (papillary adenocarcinoma, endolymphatic
sac tumor)’’ of the right ear (7). Past history revealed
that seven years previously that he had a papillary
adenocarcinoma removed from the nasopharynx. The
two tumors were stated to be histologically similar.
Whether the tumor in the middle ear was a recurrence
of the nasopharyngeal tumor or a second primary
malignancy was uncertain.
C. Pathology
The tumors arise from the surface epithelium of the
nasopharynx and may remain in situ or become
invasive. They are characterized by papillary and Figure 71 Papillary adenocarcinoma of the nasopharynx. The
glandular growth patterns (Fig. 70). The papillae cells lining the papillae are often stratified and have nuclei that
vary from hyperchromatic to optically clear (H&E, 400).
have fibrovascular cores and often show arboriza-
tion, whereas the glands frequently have a back-to-
back, often cribriform arrangement. Both papillae
and glands are covered or lined by one or more
layers of cuboidal to columnar cells, with pink cyto- D. Immunohistochemistry
plasm and round to oval nuclei that vary from PACNs are positive for pankeratin, epithelial mem-
hyperchromatic to optically clear (Fig. 71). Mild to brane antigen, and CK7 and negative for CK20, CDX2,
moderate nuclear pleomorphism may be seen, but villin, glial fibrillary acidic protein, and S-100 protein
nucleoli, mitoses, and necrosis are uncommon. A few (4,8,9). They may also focally stain for carcinoem-
tumors may also contain psammoma bodies. bryonic antigen.
Vascular, lymphatic, or neural invasion are usually Carrizo and Luna have described two cases that
not seen. were positive for thyroid transcription factor-1 and
PACNs typically contain periodic acid–Schiff, positive for CK7 and 19 (10). The tumors are otherwise
diastase-resistant intracytoplasmic granules, and negative for thyroglobulin and have no association
stain focally positive for intracellular or luminal with the EBV (4).
mucin (4).
The differential diagnosis includes papillary thyroid
carcinoma, papillary variant of intestinal-type adeno-
carcinoma (P-ITAC), and low-grade papillary adenocar-
cinoma of salivary gland origin (LGPASO).
Because of the papillae and the occasional pres-
ence of psammoma bodies and optically clear nuclei,
PACN can easily be mistaken for metastatic papillary
thyroid carcinoma. Although a few are positive for
thyroid transcription factor-1, they are negative for thy-
roglobulin and will typically show dysplasia or in situ
changes of the surface epithelium (4,10).
P-ITAC, in contrast with PACN, occurs primari-
ly in the nasal cavity and paranasal sinuses and is
often (not invariably) associated with an occupation
exposure to wood dust (11,12). P-ITAC also tends to
be less glandular and more papillary. Rather than
cuboidal cells, the papillae are covered by tall colum-
nar and goblet cells, the latter of which are sparse to
Figure 70 Papillary adenocarcinoma of the nasopharynx. Note absent in PACN. P-ITAC may also contain Paneth
the extensive branching and that the tumor is arising from the cells and scattered endocrine cells that may express
mucosa (H&E, 40).
somatostatin, gastrin, serotonin, or other secretory
substances on appropriate staining. Such cells are
402 Barnes
not seen in PACN. P-ITAC also tends to be associated Table 36 Most Frequent Sites of Tumors to
with a hemorrhagic, inflammatory background and Metastasize to the Paranasal Sinuses
often recurs following therapy. PACN, in contrast, has Primary tumor Frequency
a ‘‘clean’’ background and rarely recurs.
Immunohistochemistry is also helpful. P-ITAC is Kidney 40%
typically CK7þ, CK20þ, CDX2þ, villinþ, while PACN Lung 9%
Breast 8%
is CK7þ, CK20–, CDX2–, villin–. Thyroid 8%
LGPASO occurs almost exclusively in the oral Prostate 7%
cavity, especially the palate (13–15). Furthermore, it Miscellaneous 28%
arises submucosally from minor salivary glands,
rather than from the surface, as does the PACN.
Staining for S-100 protein may also be helpful. Thus
far, PACNs have been S-100 protein-negative,
while LGPASOs are usually positive (4,15). B. Clinical Features
LGPASOs are also more aggressive, with frequent
local recurrence (27%) and, at times, lymph node Metastases may occur in any age group. In a review of
metastasis (17%) (15). 82 cases, Bernstein et al. observed the median age at
the time of diagnosis of the metastatic tumor to be
57 years (range 3 months–76 years) and that 60% of the
F. Treatment and Prognosis patients were males (3).
Metastases to the sinonasal tract may be solitary
PACN is a slow-growing, indolent neoplasm that may or multifocal and ordinarily produce symptoms
recur but thus far has not metastasized to either indistinguishable from those of a primary tumor.
cervical lymph nodes or more distant sites [with the Among these are included nasal obstruction, head-
possible case of Karkos et al. as noted above (7)]. ache, facial pain, visual disturbances, exophthalmos,
The treatment of choice is surgery. Wenig et al. facial swelling, cranial nerve deficits, and epistaxis
describe one case that was treated initially with full- (especially metastatic renal and thyroid carcinomas).
course radiotherapy (4). The tumor recurred within In some instances, the metastasis may be the first
months following treatment. The patient subsequently manifestation of an otherwise clinically occult
underwent surgical excision and was reported free of carcinoma.
disease 11 years later. This singular experience casts
doubts on the efficacy of radiation therapy.
Photodynamic therapy has also been successful for C. Prognosis
an incompletely resected PACN (16).
Although the eventual outcome is usually poor, prog-
nosis depends, in part, on whether the sinonasal
XXVI. METASTASES TO THE NASAL CAVITY metastasis is isolated or part of widespread dissemi-
AND PARANSAL SINUSES nated disease. If the metastasis to the nasal cavity and
sinuses is localized and treated aggressively, Kent and
A. Introduction Majumdar indicated that the average survival follow-
ing discovery of the metastasis may be as long as 20 to
Metastases to the nasal cavity and paranasal sinuses
30 months (1).
are rare and are hematogenously derived. Kent and
Majumdar identified only two metastatic tumors of
the maxillary sinuses in their review of 250 malignant
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9
Diseases of the External Ear, Middle Ear,

and Temporal Bone
Bruce M. Wenig
Department of Pathology and Laboratory Medicine, Beth Israel Medical Center,
St. Luke’s and Roosevelt Hospitals, New York, New York, U.S.A.
I. NORMAL DEVELOPMENT AND STRUCTURE pouch gives rise to the epithelium on the internal side,
and the mesoderm of the first and second branchial
The ear can be considered as three distinct regions or pouches gives rise to the connective tissue lying
compartments that include the external ear, the middle between the external and internal epithelia (2).
ear and temporal bone, and the inner ear. The external
ear consists of the auricle (pinna), external auditory Anatomy
canal (or meatus), and the tympanic membrane at the
medial end of the auditory canal. The middle ear cavity The outer portion of the external ear includes the
includes the ossicles, eustachian tube connecting the auricle or pinna leading into the external auditory
middle ear space to the nasopharynx, and expansion of canal. The skeleton of the auricle consists of a single
the middle ear cavity in the form of air cells in the plate of elastic cartilage conforming to the shape of the
temporal bone. The inner ear is embedded in the ear. The lobule is the only part of the auricle that is
petrous portion of the temporal bone and consists of devoid of skeletal support. The cartilage of the auricle
a membranous (otic) labyrinth that lies within a dense is continuous with that of the external auditory canal.
bone referred to as the otic capsule that is excavated to The auricle is anchored through its continuity with the
form the osseous (periotic) labyrinth (1). cartilage of the meatus and through the skin and
The ear is the sense organ for hearing and extrinsic muscles.
balance. The inner ear is the sense organ for both The external auditory canal or meatus extends
hearing and balance. The external and middle ears are from the concha (the part of the ear lying immediately
the sound-conducting apparatus for the auditory part outside the opening of the external auditory canal) to
of the inner ear. The embryology, anatomy, and its medial limit, which is the external aspect of the
histology of the ear are complex, and beyond the tympanic membrane. The lateral portion of its wall
scope of this chapter. A broad overview of these topics consists of cartilage and connective tissue (1). The
follows. For a more in-depth discussion of the embry- medial portion of its wall consists of bone. The carti-
ology, anatomy, and histology of the ear as well as the laginous part of the external auditory canal constitutes
role that the auditory and vestibular systems play in slightly less than half its total length. The bony part of
the physiological aspects of hearing and balance, the the canal is formed by both the tympanic part and the
reader is referred to additional texts (1–9). petrous part of the temporal bone. In adults, the
anterior and inferior walls of the cartilaginous canal
are closely related to the parotid gland. The anterior
A. External Ear wall of the bony canal is closely related to the man-
Embryology dibular condyle, the posterior wall to the mastoid air
cells, and the medial portion of the superior wall to
The external ear develops from the first branchial the epitympanic recess. The tympanic membrane (ear
groove. The external auricle (pinna) forms from the drum) is situated obliquely at the end of the external
fusion of the auricular hillocks or tubercles, a group of auditory canal sloping medially both from above
mesenchymal tissue swellings from the first and sec- downward and from behind forward.
ond branchial arches, which lie around the external
portion of the first branchial groove (2). The external
Histology
auditory canal is considered a normal remnant of the
first branchial groove. The tympanic membrane forms Histologically, the auricle is essentially a cutaneous
from the first and second branchial pouches and the structure composed of keratinizing, stratified squa-
first branchial groove (2). The ectoderm of the first mous epithelium with associated cutaneous adnexal
branchial groove gives rise to the epithelium on the structures that include hair follicles, sebaceous glands,
external side, the endoderm from the first branchial and eccrine sweat glands (6). In addition to the hair
424 Wenig
follicles and sebaceous glands, the outer third of the internal carotid artery; and (vi) posterior aspect delim-
external auditory canal is noteworthy because of the ited by the petrous portion of the temporal bone
presence of modified apocrine glands called cerumi- containing the mastoid antrum and mastoid air cells
nal glands that replace the eccrine glands seen in the (1,4–6). The tympanic cavity communicates anteriorly
auricular dermis. Ceruminal glands produce cerumen with the nasopharynx by way of the eustachian (audi-
and are arranged in clusters composed of cuboidal tory or pharyngotympanic) tube and posteriorly with
cells with eosinophilic cytoplasm often containing a the mastoid air cells by way of the aditus and mastoid
granular, golden-yellow pigment. These cells have antrum.
secretory droplets along their luminal border. Periph- The contents of the tympanic cavity include the
eral to the secretory cells are flattened myoepithelial ossicles (malleus, incus, and stapes), the ligaments of
cells. The ducts of the ceruminal glands terminate in the ossicles, the tendons of the ossicular muscles,
the hair follicle or on the skin. The ducts of ceruminal eustachian tube, tympanic cavity proper, epitympanic
glands lack apocrine or myoepithelial cells. In the recess, mastoid cavity, and the chorda tympani of the
inner portion of the external auditory canal, ceruminal facial (VII) nerve. The middle ear as well as the
glands, as well as the other adnexal structures are external ear function as conduits for sound conduc-
absent. The subcutaneous tissue is composed of fibro- tion for the auditory part of the internal ear.
connective tissue, fat, and elastic-type fibrocartilage,
which give the auricle its structural support. The ear Histology
lobe is devoid of cartilage and is replaced by a pad of
adipose tissue. The perichondrium is composed of Histologically, the epithelial lining of the tympanic
loose vascular connective tissue. cavity is a single layer of respiratory epithelium of
Similar to the auricle, the external auditory canal flattened to cuboidal epithelium (6). Under normal
is lined by keratinizing squamous epithelium that conditions, there are no glandular elements within the
extends to include the entire canal and covers the middle ear; the presence of glandular epithelium in
external aspect of the tympanic membrane. The the middle ear is abnormal and may represent part of
inner two-thirds of the external auditory canal contain a metaplastic response in the setting of chronic otitis
bone rather than cartilage. Because of the absence of media (COM) or can be seen in adenomatous neo-
adnexal structures, there is relatively close apposition plasms (6). Stratified squamous epithelium is not
of the epithelium to the subjacent bone. present in the tympanic cavity under normal condi-
tions nor does squamous metaplasia occur in the
middle ear (6). Ciliated pseudostratified columnar
B. Middle Ear epithelium may be found in limited patches among
the flattened or cuboidal epithelium.
Embryology The lining of the eustachian (auditory) tube is a
The middle ear space develops from invagination of low ciliated epithelium for much of its length, except
the first branchial pouch (pharyngotympanic tube) as it approaches its nasopharyngeal end, where it
from the primitive pharynx. The eustachian tube and becomes ciliated pseudostratified columnar epithelium
tympanic cavity develop from the endoderm of the containing goblet cells. In its cartilaginous portion, it
first branchial pouch; the malleus and incus develop also contains seromucinous glands. The eustachian
from the mesoderm of the first branchial arch (Meckel’s tubes contain a lymphoid component, particularly in
cartilage), while the incus develops from the children, that is referred to as Gerlach’s tubal tonsil.
mesoderm of the second branchial arch (Reichert’s Reactive hyperplasia of this lymphoid component
cartilage) (2). particularly in children may close off the eustachian
tube, providing a desirable milieu for otitis media. The
Anatomy cartilage of the nasopharyngeal portion of the eusta-
chian tube is hyaline type.
The middle ear or tympanic cavity lies within the
temporal bone between the tympanic membrane and
the squamous portions of the temporal bone laterally C. Inner Ear
and the petrous portion of the temporal bone sur- Embryology
rounding the inner ear medially. The anatomical
limits of the tympanic cavity include (i) lateral or The first division of the ear to develop is the inner ear,
internal aspect made up by the tympanic membrane which appears toward the end of the first month of
and squamous portion of the temporal bone; (ii) gestation (2,3). The membranous labyrinth, including
medial aspect bordered by the petrous portion of the the utricle, saccule, three semicircular ducts, cochlear
temporal bone; (iii) superior (roof) delimited by the duct, and endolymphatic sac arises from the placodal
tegmen tympani, a thin plate of bone that separates thickening of the ectoderm to become a closed otic
the middle ear space from the cranial cavity; (iv) vesicle (otocyst). The membranous labyrinth, which is
inferior (floor) aspect bordered by a thin plate of essentially tubular and saccular, in turn is filled with
bone separating the tympanic cavity from the superior fluid, the endolymph, or endolymphatic fluid. The
bulb of the internal jugular vein; (v) anterior aspect bony labyrinth, including the vestibule, semicircular
delimited by a thin plate of bone separating the canals, and cochlea, arises from the mesenchyme
tympanic cavity from the carotid canal housing the around the otic vesicle (4–6).
Chapter 9: Diseases of the External Ear, Middle Ear, and Temporal Bone 425
Anatomy A. Congenital Abnormalities of the Ear

The internal (inner) ear, or labyrinth, is embedded The ear, including the external, middle, and internal
within the petrous portion of the temporal bone and ear, is often the target for congenital anomalies. These
comprises the medial portion of the temporal bone congenital abnormalities occur as an isolated defect or
adjacent to the cranial cavity. The inner ear contains in combination with other aural and extra-aural
the membranous labyrinth, which is surrounded by abnormalities, and they vary from cosmetic defects
an osseous layer or bony shell termed ‘‘the osseous to complete hearing loss. A complete discussion of the
(bony) labyrinth.’’ The membranous labyrinth con- developmental defects of the ear is beyond the scope
tains the cochlea, which is the organ of hearing, and of this chapter; the interested reader is referred to
the vestibular system, which is the system of balance other texts that discuss this subject (10–12). This
(equilibrium). section includes some of the more common develop-
mental abnormalities that the surgical pathologist is
Histology likely to encounter in daily practice.
The histology of the inner ear to include the osseous
labyrinth and membranous labyrinth, including the 1. Accessory Tragi
organ of Corti and semicircular canals, is rather com-
plex and beyond the scope of this chapter. The histo- Clinical Features
logical evaluation of the inner ear contents rarely Accessory tragi, which are also referred to as accesso-
occurs in daily practice. For further details, the readers ry or supernumerary ears, accessory auricle, and
are referred to other texts (4–6). polyotia, appear at birth. They may be unilateral or
bilateral, sessile or pedunculated, and soft or cartilag-
inous skin-covered nodules or papules, which may be
II. NONNEOPLASTIC LESIONS OF THE EAR solitary or multiple. They are located on the skin
AND TEMPORAL BONE surface often anterior to the auricle, and clinically,
The classification of nonneoplastic lesions of the ear they may be mistaken for a papilloma (Fig. 1). Acces-
and temporal bone is detailed in Table 1. Many sory tragi are thought to be related to second branchial
cutaneous lesions occur in and around the external arch anomalies. While accessory tragi may occur
ear, including (although not limited to) keloids, epi- independent of other congenital anomalies, they may
dermal cysts, sebaceous cysts, and angiolymphoid occur in association with cleft palate or lip and man-
hyperplasia with eosinophilia and Kimura’s disease. dibular hypoplasia or in association with other
These entities will not be discussed in this chapter; anomalies such as Goldenhar’s syndrome (oculoaur-
readers are referred to the chapter on selected skin iculovertebral dysplasia) (10).
lesion for a complete discussion.
Table 1 Classification of Nonneoplastic Lesions of the Ear and

Temporal Bone
External ear
Developmental (accessory tragi; first branchial cleft anomalies;
others)
Infectious and inflammatory
Keloid
Epidermal and sebaceous cysts
Idiopathic cystic chondromalacia
Chondrodermatitis nodularis helicis chronicus
Angiolymphoid hyperplasia with eosinophilia/Kimura’s disease
Autoimmune systemic diseases:
Relapsing polychondritis
Gout
Wegener’s granulomatosis
Others
Exostosis
Synovial chondromatosis
Middle and inner ear, including temporal bone
Developmental and congenital anomalies
Infectious (otitis media) and inflammatory
Otic or aural polyp
Cholesteatoma
Langerhans cell histiocytosis (eosinophilic granuloma)
Heterotopias (central nervous system tissue; salivary gland)
Otosclerosis
Paget disease Figure 1 Accessory tragus appearing as papillomatous, skin-
Meniere disease covered nodules located anterior to the auricle.
Others
426 Wenig
inferior, or posterior to the concha and pinna. Sinuses

parallel the external auditory canal and end in a blind
sac at the level of the mesotympanum. The external
auditory canal is intact and hearing is normal. Type II
lesions typically localize to a point just below the
angle of the mandible. Sinus or fistula tracts extend
upward over the angle of the mandible through the
parotid gland toward the external auditory canal.
Rarely, cases of combined type I and type II lesions
have been reported (17).
Pathology
Gross. The majority of first branchial cleft anom-
alies are cysts representing over two-thirds (68%) of
these anomalies; (14,18) sinuses and fistulas equally
make up the remainder of these lesions. The first
branchial cleft cysts appear as solitary cystic lesions
Figure 2 Histologically, accessory tragic have the appearance without an associated sinus tract.
of the normal external auricle, as the presence of skin, including Microscopy. Type I contains only ectodermal ele-
keratinizing squamous epithelium, cutaneous adnexal structures, ments, including keratinizing squamous epithelium
and a central core of cartilage demonstrate.
without adnexal structures (i.e., hair follicles, seba-
ceous glands, sweat glands) or cartilage, thereby
duplicating the membranous external auditory canal.
Pathology Type II lesions have both ectodermal and mesodermal
elements, including keratinized squamous epithelium,
Microscopy. Histologically, accessory tragi reca- cutaneous adnexae, and cartilage, thereby duplicating
pitulate the normal external auricle and include the the external auditory canal and pinna. Type II anoma-
skin, cutaneous adnexal structures, and a central core lies are more intimately associated with the parotid
of cartilage (Fig. 2). gland than type I anomalies, although parotid tissue
may be found in association with type I sinus or
Differential Diagnosis fistula tracts. Tracts associated with type II defects
may terminate short of the external auditory canal or
In contrast to accessory tragic, squamous papillomas
may open up in the external auditory canal near the
lack cutaneous adnexal structures and cartilage (13).
junction of the cartilaginous portion and osseous
portion of the canal; communication with the middle
Treatment and Prognosis ear is uncommon. For either type I or type II defects,
Simple surgical excision is curative. an associated prominent lymphoid component is not
usually present contrasting with second branchial
anomaly; only when it is inflamed or infected will
2. Branchial Cleft Anomalies there be an associated lymphoid component. Olsen
a. First Branchial Cleft Anomalies and associates (14) believed that the histological fea-
tures of type I and type II lesions overlapped and
Clinical Features therefore recommended that these anomalies should
be classified into cyst, sinus, or fistula.
First branchial cleft anomalies typically occur in the
area of the external ear and include cysts, sinuses, and Differential Diagnosis
fistulas (14). In comparison to second branchial cleft
anomalies, first branchial cleft anomalies are uncom- The differential diagnosis includes epidermoid cysts
mon, representing only 1% to 8% of all branchial and dermoid cysts. See chapter on diseases of the skin
apparatus defects. First branchial cleft anomalies for a discussion of these lesions.
may be identified in a variety of locations, including Treatment and Prognosis
preauricular, postauricular, or infra-auricular sites, at
the angle of the jaw, associated with the ear lobe, and Irrespective of the histology, complete surgical exci-
in the external auditory canal or involving the parotid sion is the treatment of choice. Inadequate excision
gland. Involvement of the external auditory canal may results in recurrence and increased risk of infection
result in otalgia or otorrhea. Parotid involvement may (19). Recurrence rates are increased when there are
result in an intraparotid or periparotid mass. The multiple preoperative infections and when there is no
fistula tract in first branchial cleft anomalies may epithelial lining identified in the specimen (19). Inci-
extend from the skin over or through the parotid sion and drainage are indicated in cases where
and open in the external auditory canal. abscesses have developed, and in this situation com-
According to Work, first branchial lesions can be plete surgical excision must wait until resolution of
divided into two types: type I and type II lesions the infection. Type II anomalies are often intimately
(15,16). Type I lesions represent a first cleft anomaly associated with the parotid gland, necessitating a
only. Type I lesions are typically located medial, superficial parotidectomy to ensure complete excision.
Although there is no consistent relationship between glial cells, histiocytes, and mature lymphocytes. Reac-
the tract and the facial nerve as it courses through the tive alterations of the neuroglial tissue (gliosis) may be
parotid gland, exposure and dissection of the nerve present. In addition, granulation tissue and keratiniz-
and its branches are required in Work type II anoma- ing squamous epithelium (cholesteatoma) may be
lies (20,21). found. Immunohistochemical confirmation of neuro-
glial tissues includes reactivity for glial fibrillary
b. Heterotopias of the Middle Ear and Mastoid acidic protein (GFAP).
Clinical Features Differential Diagnosis

Heterotopias, which are also referred to as choristo- In COM, a fibrillary stroma is often present, which
mas and ectopias, are characterized by the presence of may simulate the appearance of the neurofibrillary
normal-appearing tissue(s) in an anatomical location matrix. Reactivity for GFAP assists in confirming or
in which they are normally not found. Heterotopias excluding neuroglial tissues. The differential diagno-
that occur in the middle ear include salivary gland sis also includes a glial neoplasm. Neuroglial tissues
tissue and neuroglial tissue. Salivary gland choristo- in the middle ear and mastoid generally represent an
mas may present with unilateral conductive hearing acquired encephalocele with herniation of the brain
loss; they tend to occur more often in women and are into the middle ear and mastoid via compromise of
seen over a wide age range (22–24). Salivary gland the tegmen, a thin bony shell that separates the middle
choristomas often arise in conjunction with facial ear and mastoid cavity from the temporal lobe. The
nerve and ossicular chain anomalies (25). The combi- tegmen may be compromised or destroyed secondary
nation of facial nerve and ossicular chain anomalies to trauma or prior surgery by a complication of otitis
may be explained as a second branchial arch develop- media or because of a congenital defect (28). Potential
mental abnormality. True neuronal heterotopias in complications include brain abscess.
which isolated neuroglial tissue is located in the
middle ear and temporal bone without continuity Treatment and Prognosis
with the central nervous system (CNS) are rare, but
they have been reported (26,27). The more common Conservative surgical removal is the treatment of
occurrence in which glial type tissue is present within choice. However, choristomas often adhere to dehis-
the middle ear/temporal bone is seen in association cent facial nerve. If complete surgical resection will
with an acquired encephalocele. compromise the integrity of the facial nerve, then
incomplete resection is justified. Biopsy for diagnostic
Pathology purposes followed by observation is an alternative to
surgical excision. Rarely, salivary gland ectopia may
Gross. Choristomas appear as lobulated, nonpul- produce a neoplastic proliferation (e.g., pleomorphic
satile soft tissue masses lying in the middle ear space adenoma) (29,30).
with an intact tympanic membrane.
Microscopy. Histologically, the salivary tissues
are composed of an admixture of seromucous glands B. Acquired Nonneoplastic Lesions/Diseases
(Fig. 3) and adipose tissue. A neuroglial heterotopia 1. Necrotizing ‘‘Malignant’’ External Otitis
includes a heterogeneous population of cells, with
Clinical Features
Necrotizing malignant external otitis (NEO) is a virulent,
potentially fatal form of external otitis related to Pseudo-
monas aeruginosa infection.
NEO primarily affects older patients. The typical
clinical setting is that of a diabetic patient or a patient
who is chronically debilitated or immunologically
deficient, although NEO may occur in nondebilitated
patients (31–33). NEO originates in the external audi-
tory canal with the initial symptoms of an acute otitis
externa. With the progression of disease, pain, puru-
lent otorrhea, and swelling occur (Fig. 4). If it is left
untreated, the infectious process may extend into the
surrounding soft tissue structures (cellulitis), the car-
tilage (chondritis), the bone (osteomyelitis), the base of
the skull, and the middle ear space, leading to cranial
nerve palsies, meningitis, intracranial venous throm-
bosis, or brain abscess.
Figure 3 Middle ear heterotopia comprised of normal-
appearing seromucous glands. The mass, which clinically Pathogenesis and Etiology
caused conductive hearing loss, was entirely located within the
middle ear space, including an intact tympanic membrane. Note The pathogenesis of NEO is related to tissue ischemia
the attenuated middle ear epithelium at the top of the illustration. secondary to an underlying predisposing pathological
state (diabetic angiopathy) and a migratory defect of
428 Wenig
Figure 5 The histological appearance of necrotizing external

Figure 4 Necrotizing external otitis in a diabetic patient complain- otitis includes showing thick, acellular collagen replacing the skin
ing of aural-related pain. Clinically, purulent otorrea was present. and subcutaneous tissues with inflammation and necrosis
extending within the depth of the tissue, including extension to
underlying bone (osteomyelitis).
polymorphonuclear leukocytes related to systemic Differential Diagnosis

disease. These host factors that impede the inflamma-
tory response to infection, when combined with the The infectious nature of NEO is usually evident from
destructive properties of P. aeruginosa, are thought to the clinical course and the histological findings. The
be responsible for the lethal potential of NEO (31). By presence of squamous pseudoepitheliomatous hyper-
virtue of its endotoxins and exotoxins, neurotoxins, plasia may suggest a squamous cell carcinoma (SCC). In
collagenases, and elastases, the organism is capable of general, the presence or absence of dysplastic changes
causing rapid extensive tissue necrosis and necrotiz- and/or infiltrative growth allow for differentiating
ing vasculitis, which compounds the destruction (31). NEO from SCC. Conversely, SCC, if it is associated
with extensive necrosis, may elude diagnosis by biopsy,
Pathology yielding only necroinflammatory material such as one
finds in NEO. Occasionally, the clinical presentation
Gross. The changes of NEO are most pro- of SCC of the external auditory canal may closely mimic
nounced in the osseous portion of the external canal NEO (35,36), or the two diseases may occur con-
where the destructive infection usually begins. In this currently (37).
area, the skin becomes ulcerated, leaving a layer of
thick granulation tissue covering the exposed and Treatment and Prognosis
irregularly eroded bone, usually along the anterior
and inferior surfaces of the external auditory canal Antibiotics, surgical debridement, and control of dia-
(34). Necrotic tissue is abundant in fully developed betes mellitus in patients suffering from that disease
NEO, and it may, along with purulent exudate, are the treatments of choice. Hyperbaric oxygen ther-
obstruct the canal. apy may be used as an adjunctive modality.
Microscopy. The histological appearance of NEO Mortality rates may exceed 75% if the diagnosis
is dominated by the presence of necrotic material and and treatment are delayed (38). Death may result from
exuberant granulation tissue. The squamous extensive spread of the infection to adjacent struc-
epithelium is commonly ulcerated; intact epithelium tures, including intracranial involvement. Cures can
may show marked reactive and/or atypical changes, be achieved with early recognition and aggressive
including pseudoepitheliomatous hyperplasia adja- treatment.
cent to denuded areas.
Diffuse, heavy acute and chronic inflammation is
seen in the subcutis, and a necrotizing vasculitis is 2. Otitis Media
commonly present. Thick, acellular collagen is seen Clinical features
replacing most of the tissue extending from the carti-
lage to the overlying dermis (Fig. 5). The bone and Otitis media is either acute or chronic infectious
cartilage are necrotic, with acute and chronic inflam- disease of the middle ear space. There is no gender
matory cells massively infiltrating the adjacent viable predilection. Otitis media may occur at any age but is
bone. Sequestra of nonviable bone or cartilage may be predominantly a childhood disease, particularly com-
seen. The dermis is eventually replaced by acellular mon in children younger than three years. Otoscopic
collagen. Gram-negative bacilli are easily demonstrated examination reveals a hyperemic, opaque, bulging
by tissue gram stain. tympanic membrane with limited mobility; purulent
otorrhea may be present. Bilateral involvement is not

uncommon. Symptoms include fever, otalgia, and
decreased hearing typically preceded by several
days of an upper respiratory tract infection.
Etiology
The most common organisms implicated in causing
disease are Streptococcus pneumoniae and Hemophilus
influenza. The middle ear infection is believed to result
from infection via the eustachian tube either at the
time of or following pharyngitis (bacterial or viral).
Pathology
Gross. There are no specific macroscopic fea-
tures. In general, otitis media is managed medically.
However, tissue is removed for histopathological
examination at times. The tissue specimens usually Figure 6 Chronic otitis media. The histological features of
are received as multiple small fragments of soft to chronic otitis media include a background of chronic inflamma-
rubbery granulation tissue. If tympanosclerosis is tion composed of lymphocytes with fibrosis and hemorrhage;
present, then the tissues may be firm to hard, consist- scattered, unevenly distributed (metaplastic glands) of variable
ing of calcific debris. In general, all of the tissue size and shape that contain thin (serous) fluid separated by
fragments should be processed for histological abundant stromal tissue. Foci of calcification (tympanosclerosis)
examination. are present. Although not identifiable at this magnification, cilia
Microscopy. The histology of otitis media varies were focally present in association with the glands, an indicator
depending on the disease state (39). Acute otitis media of a reactive (i.e., metaplasia) rather than neoplastic (i.e., ade-
noma) proliferation.
is virtually never a surgical disease. The middle ear
mucosa, which is also referred to as the mucoperios-
teum, responds to infection with inflammation, hyper-
emia, polypoid thickening, and edema. The
inflammatory infiltrate in acute otitis media is is confirmatory of middle ear glandular metaplasia
predominantly composed of polymorphonuclear leu- because this feature is not found in association
kocytes with a variable admixture of chronic inflam- with middle ear adenomas (MEAs). Furthermore, the
matory cells. Secretory otitis media refers to otitis haphazard arrangement of the glands in the back-
media in which associated effusion is present behind ground of changes of COM should allow the observer
an intact tympanic membrane. The exudate may be to differentiate metaplastic from neoplastic glands.
serous, hemorrhagic, fibrinous, mucoid, purulent, or In addition to the inflammatory cell infiltrate and
an admixture of types (40). Acute otitis media usually glandular metaplasia, other histopathological findings
heals by resorption by the mucoperisoteum. However, that usually are seen in association with COM or that
localized destruction of the middle ear ossicles may represent its sequelae include fibrosis, granulation
occur. Further, granulation tissue may develop, result- tissue, tympanosclerosis, cholesterol granulomas,
ing in scar formation. Fibrosing osteitis is seen in areas and reactive bone formation. Because of the presence
of bone destruction that may result in reactive of scar tissue, the middle ear ossicles may be destroyed
sclerotic bone. (partially or totally), or they may become immobi-
Acute inflammatory cells may be superimposed lized. Perforation of the tympanic membrane pars
in a case of COM. The histological changes in COM tensa may occur, with the resulting ingrowth of squa-
include a variable amount of chronic inflammatory mous epithelium potentially leading to the develop-
cells consisting of lymphocytes, histiocytes, plasma ment of cholesteatoma.
cells, and eosinophils. Multinucleated giant cells and
foamy histiocytes may be present. The middle ear low 3. Tympanosclerosis
cuboidal epithelium may or may not be seen. However,
glandular metaplasia (Fig. 6), a response of the middle Tympanosclerosis represents dystrophic mineraliza-
ear epithelium to the infectious process, may be tion (calcification or ossification) of the tympanic
present. The glands tend to be more common in non- membrane or middle ear that is associated with recur-
suppurative otitis media than in suppurative otitis rent episodes of otitis media (41). The incidence of
media. The metaplastic glands are unevenly distri- tympanosclerosis in otitis media varies from 3% to
buted in the tissue specimens, they are variably 33% (42). Tympanosclerosis of the tympanic mem-
shaped, and they are separated by abundant stromal brane can be seen in children following myringotomy
tissue. The glands are lined by columnar to cuboidal and tube insertion. In this setting, the tympanoscler-
epithelium, with or without cilia or goblet cell meta- otic foci may or may not be permanent. Tympanoscle-
plasia. Glandular secretions may or may not be pres- rosis of the middle ear typically affects older patients,
ent, so the glands may appear empty, or they may it represents the irreversible accumulation of mineral-
contain varying secretions, including thin (serous) or ized material, and it is associated with conductive
thick (mucoid) fluid content. The identification of cilia hearing loss (43,44).
430 Wenig
On gross examination, tympanosclerotic foci chronic infection, may occur and might be confused
may be localized or diffuse, and they appear as with a true gland-forming neoplasm. The differential
white nodules or plaques. Histologically, dense diagnosis of the glandular metaplasia seen in otitis
‘‘clumps’’ of mineralized, calcified, or ossified material media includes MEA. In MEAs, the histology is dom-
or debris can be seen within the stromal tissues or in inated by the presence of a diffuse glandular and/or
the middle (connective tissue) aspect of the tympanic solid cell proliferation rather than the haphazard
membrane (Fig. 6). Tympanosclerosis may cause scar- arrangement of the glands seen in a background of
ring and ossicular fixation. changes of COM. The haphazard arrangement of the
glands occurring in the background of COM and the
4. Cholesterol Granulomas identification of cilia confirmatory of middle ear glan-
dular metaplasia are features that are not found in
Cholesterol granulomas represent a foreign body association with MEAs. Other possible lesions in the
granulomatous response to cholesterol crystals that differential diagnosis of COM include cholesteatoma,
are derived from the rupture of red blood cells and the Langerhan cell histiocytosis, and rhabdomyosarcoma.
resulting breakdown of the lipid layer of the erythro- The absence of keratinizing squamous epithelium
cyte cell membrane. Cholesterol granulomas arise in within the middle ear space allows for differentiation
the middle ear and mastoid in any condition in which of COM from cholesteatoma. It should be noted that
hemorrhage occurs in combination with interference COM and cholesteatoma are not mutually exclusive,
in drainage and ventilation of the middle ear space; and in any given patient, findings diagnostic for both
otoscopic picture is referred to as ‘‘blue ear syn- COM and cholesteatoma may be present. In view of
drome’’ (45). Cholesterol granuloma of the middle the fact that the inflammatory cell infiltrate seen in
ear may present as idiopathic hemotympanum; cases of otitis media may be extremely dense, the
patients may also complain of hearing loss and tinni- pathologist must be vigilant in evaluating these speci-
tus. The involvement of the petrous apex is more mens; this is especially true in the pediatric age group
likely to be associated with sensorineural hearing as not to overlook the presence of a rhabdomyo-
loss; headaches, cranial nerve deficits, and, rarely, sarcoma or Langerhans cell histiocytosis (LCH).
bone erosion with the involvement of the posterior
or middle cranial fossa has been reported (46,47). Treatment and Prognosis
The histology of cholesterol granulomas includes
the presence of irregular clear-appearing spaces sur- Antibiotic therapy directed at the specific pathogen is
rounded by histiocytes or multinucleated giant cells the treatment of choice and often is curative. Recur-
(foreign body granuloma) and hemosiderosis (Fig. 7). rent infections of the middle ear are common espe-
Cholesterol granulomas are not related to cholestea- cially in the pediatric population. In adults, an
tomas, but they may occur in association with them. unresolving otitis media should warrant detailed
examination of the nasopharynx in order to rule out
Differential Diagnosis the presence of a (malignant) neoplasm (e.g., nasopha-
ryngeal carcinoma). SCCs of the middle ear are rare
The pathological alterations are generally straightfor- tumors, typically occurring in older adults suffering
ward, but secondary changes, such as glandular meta- from long-standing history of COM. In the antibiotic
plasia of the surface epithelium, which is the result of era, complications associated with otitis media are not
generally seen; however, if left unchecked, complica-
tions of otitis media occur, which can be divided into
intratemporal complications (e.g., mastoiditis, petrosi-
tis, labyrinthitis, facial nerve paralysis) and intracranial
complication (e.g., meningitis, brain abscess) (38).
5. Miscellaneous Infections
Specific causes. Uncommonly, otitis media may
be caused by tuberculosis (48); syphilis (49); fungi,
including Candida, Mucor, Cryptococcus, and Aspergil-
lus (50); and actinomycosis (51). The setting for some
of these infections, particularly mycoses, is often in
patients who are diabetic or debilitated. In patients
infected with human immunodeficiency virus (HIV)
or who suffer from acquired immunodeficiency syn-
drome (AIDS), Pneumocystis carinii may be seeded by
pulmonary lesions to the middle ear and temporal
Figure 7 Cholesterol granuloma in the middle ear associated with bone (52). In this setting, the initial clinical presenta-
chronic otitis media appears as empty, irregularly shaped clefts or tion may occur as an aural polyp that, on histological
spaces surrounded by histiocytes and multinucleated giant cells. examination, shows characteristic foamy exudate con-
Fresh hemorrhage and hemosiderin pigment are present. taining the causative organisms. Viruses, including
herpes, cytomegalovirus, rubella, rubeola, and
mumps, can infect this region, and they may result in

labyrinthitis and sensorineural hearing loss (53,54).
6. Inflammatory Otic Polyp

Clinical Features
Otic (aural) polyp is an inflammatory polypoid pro-
liferation that originates from the middle ear mucosa
secondary to COM. Otic polyps may occur at any age,
but they are most common in children. Symptoms
include otorrhea, conductive hearing loss, and/or a
mass protruding from the external auditory canal.
Despite its origin from the middle ear, otic polyps
may cause perforation of the tympanic membrane
with extension into the external auditory canal. In
this situation, the polyp may appear to be originating
from the external auditory canal (55). In large polyps
completely obstructing the external ear, radiographic
studies are an invaluable aid in identifying the origin
of the polyp. In long-standing cases, destruction (par-
tial or complete) of the ossicles may occur.
Pathology
Gross. The gross appearance of otic polyps is
that of a polypoid, soft to rubbery, tan—white– to
pink-red–appearing lesion.
Microscopy. The polypoid mass is composed of a
cellular infiltrate that primarily consists of a chronic
inflammatory cell infiltrate, including mature lympho-
cytes, plasma cells, histiocytes, and eosinophils (Fig. 8)
(55–57). Russell bodies or Mott cells containing large
eosinophilic immunoglobules can be seen, and they Figure 8 Otic (aural) polyp. (A) This polypoid lesion originated
are indicative of a benign plasma cell proliferation in the middle ear space, perforated the tympanic membrane, and
(Fig. 8). Polymorphonuclear leukocytes may be pres- protruded from the external auditory canal. Histologically, it has
ent. The stroma includes granulation tissue varying in an exophytic or polypoid appearance with surface ulceration, a
appearance from edematous and richly vascularized dense inflammatory cell infiltrate, and granulation tissue, includ-
to fibrous with a decreased vascular component. ing numerous blood vessels oriented perpendicular toward the
surface of the lesion. (B) At higher magnification, the polyp is
Multinucleated giant cells, cholesterol granulomas,
composed of a cellular infiltrate, primarily consisting of an
and calcific debris (tympanosclerosis) may be present. admixture of mature plasma cells and polymorphonuclear leuko-
An overlying epithelium may not be seen; however, cytes. Russell bodies, which are also referred to as Mott cells,
when it is present, it appears as pseudostratified containing large eosinophilic immunoglobules, are seen in the
columnar or cuboidal cells with or without cilia. Foci left side of the illustration.
of squamous metaplasia and a glandular metaplastic
proliferation may also be seen. Special stains for
microorganisms are indicated to rule out an infectious
etiology. lying neoplastic process (e.g., rhabdomyosarcoma,
Langerhans cell granulomatosis (LCG), carcinoma).
In general, the presence of a mixed cell population of
chronic inflammatory cells indicates that the polyp is In the absence of an infectious etiology, local surgical
benign, so a diagnosis of a malignant hematolymphoid excision is curative.
proliferation is not an issue. Rarely, lymphomatous or
leukemic involvement of the middle ear and temporal
bone occur secondary to systemic disease. The dense 7. Malakoplakia
plasma cell component may lead to consideration of a
Clinical Features
plasmacytoma. While plasma cell dyscrasia may occur
in this site in rare instances (58), the presence of mature Malakoplakia, which is derived from Greek, means
plasma cells, Russell bodies, and polyclonality by ‘‘soft plaque’’ and is an inflammatory disease that
immunohistochemistry should preclude a diagnosis usually involves the genitourinary tract. Malakoplakia
of plasmacytoma. The cellular component in otic pol- is an extremely uncommon lesion in the head and neck;
yps may be very dense, and it may obscure an under- the middle ear is one of the reported sites of occurrence
432 Wenig
Figure 9 Malakoplakia of the middle ear is characterized by the Figure 10 Chondrodermatitis nodularis chronicus helicis. The
presence of solid sheets of histiocytes with a slightly granular to lesion was painful and located along the lateral helix. Clinically, it
vacuolated cytoplasm (Hansemann cells) and a centrally located was considered to be a carcinoma.
intracytoplasmic targetoid basophilic inclusion (Michaelis-
Gutmann body).
portion of the helix; lateral helical, antihelical, and

(59,60). There are no specific demographics. Symptoms antitragal involvement are also seen. They typically
relate to COM and conductive hearing loss. appear as round, reddish, tender areas usually measur-
ing less than 1 cm in diameter (Fig. 10). Clinically, many
Pathology cases are considered carcinomas (62).
Histology. The light microscopical features Etiology
include the presence of solid sheets of histiocytes
with slightly granular to vacuolated cytoplasm (so- The etiology of CNCH is not known, but several
called Hansemann cells) admixed with inflammatory theories have been suggested, including cold expo-
cells, including lymphocytes, plasma cells, and neu- sure, actinic damage, local trauma, and degenerative
trophils. Intracytoplasmic diastase-resistant, periodic change with pressure necrosis. Because the skin of the
acid–Schiff (PAS)-positive targetoid inclusion bodies auricle is quite thin, with little subcutaneous fat, the
termed ‘‘Michaelis-Gutmann bodies’’ can be seen area may be unusually sensitive to injury. In addition,
within occasional cells (Fig. 9). These inclusions or the vascular supply to the area is somewhat deficient,
calcospherites can also be seen extracellularly, and with the avascular cartilage depending on the dermal
they contain calcium and, frequently, iron salts, thereby circulation for its sustenance. These anatomical fea-
showing reactivity to a von Kossa stain for calcium tures may predispose the auricle to the development
and a Prussian blue stain for iron. Malakoplakia is of CNCH. Winkler (63) considered the underlying
believed to represent an unusual host response to pathological event to be a cartilaginous-based process.
infection with a variety of organisms, and, ultrastruc- However, the etiology appears to be linked to a
turally, phagolysosomes that have ingested break- primary cutaneous alteration as the cutaneous
down products of bacteria, such as Escherichia coli, changes are more significant and they are a more
have been found. constant feature. The development of CNCH is likely
multifactorial, and it includes actinic damage.
Pathology
Curettage is curative.
Gross. CNCH usually appears as a dome-
shaped, discrete nodule with a scale crust covering a
8. Chondrodermatitis Nodularis Chronicus central area of ulceration that ranges in diameter from
Helicis (Winkler Disease) 3 to 18 mm, with an average of 7 mm. Rarely, CNCH
Clinical Features may achieve diameters of 2 to 3 cm.
Microscopy. Histologically, the central portion of
Chondrodermatitis nodularis chronicus helicis (CNCH) the involved epidermis is ulcerated, while the adjacent
is an idiopathic, nonneoplastic ulcerative lesion of epithelium shows acanthosis, hyperkeratosis, paraker-
the auricle. CNCH usually affects men in the late atosis, and pseudoepitheliomatous hyperplasia (Fig. 11).
middle-age and older age groups, and it is considered The base of the ulcer shows granulation tissue with a
uncommon in women (61,62). Patients present with pronounced capillary proliferation, edema, fibrinoid
spontaneously occurring unilateral painful nodules. necrosis, and an acute and/or chronic inflammatory
Even gentle manipulation may precipitate excruciating cell infiltrate (61). The granulation tissue and inflam-
pain, eventually prompting patients to seek treatment. matory process usually involves the perichondrium
CNCH most frequently occurs along the superior and cartilage. Pain is thought to result from this
adjacent epidermis, should help in excluding a squa-

mous neoplasm in cases of CNCH.

Complete surgical excision, including wedge excision
(65) or cartilage excision, alone (66) is the treatment of
choice, and it is curative. In a minority of patients,
trials with injection of glucocorticoids directly into the
lesion have been effective in eradicating the lesion.
Although the lesion has no malignant potential, dif-
ferentiating these from BCC and SCC frequently
requires biopsy.
9. Idiopathic Cystic Chondromalacia of the

Auricular Cartilage (Auricular or
Endochondral Pseudocyst)
Clinical Features
Idiopathic cystic chondromalacia (ICC) is a benign
cystic degeneration of the auricular cartilage that is of
unknown etiology. ICC typically occurs in young and
middle-aged adult males, but in uncommon instances,
Figure 11 Chondrodermatitis nodularis chronicus helicis. The it does occur in women (67,68). These lesions arise as
central portion of the involved epidermis is ulcerated, with the unilateral, painless swellings of the cartilage without
base of the ulcer comprised of granulation tissue that extends to overlying ulceration or erythema over weeks to years
the subjacent perichondrium and cartilage; perichondrial involve-
(Fig. 12). They are occasionally bilateral (69). Although
ment is associated with pain. The surface epithelium adjacent to
the ulcer shows acanthosis and hyperkeratosis
they may arise anywhere on the auricle, the scaphoid
fossa is the most common site (80%) (70).
Etiology
perichondrial involvement. The dermis lacks cutane- Although trauma has been implicated in causing these
ous adnexal structures in the area of the lesion, and the lesions, no definitive connection to a prior traumatic
vasculature appears telangiectatic. Foci of fibrinoid event has been made, and the origin(s) for this condi-
eosinophilic material or, in some cases, frank necrobio- tion remains unknown. Engel (71), the first to describe
sis of the collagen may be present. Occasionally, pali- them in the English literature, believed that these
sading histiocytes are seen in association with
necrobiotic collagen. The changes in the auricular car-
tilage deep into the ulcer range from mild perichon-
dritis through variable degrees of degenerative
changes that are characterized by edema and loss of
chondrocytes, with smudging (i.e., loss of basophilia)
and hyalinization of the chondroid matrix. The necrotic
material from the dermis and, even occasionally, frag-
ments of degenerated cartilage may protrude into the
ulcer crater. Calcification and ossification of the under-
lying cartilage may be present (64).
CNCH is frequently misdiagnosed as a cutaneous
malignancy, particularly as a basal cell carcinoma
(BCC) or SCC. Metzger and Goodman (61) noted a
clinical diagnosis of either a malignant or premalig-
nant lesion in 80% of the cases they reviewed. Unfor-
tunately, the same mistake may be perpetuated by
microscopical examination, particularly if the epider-
mal hyperplastic changes are misinterpreted as repre-
senting either SCC or a hypertrophic actinic keratosis.
Careful attention to the extensive dermal changes and Figure 12 Idiopathic cystic chondromalacia appearing as (pain-
usually some degree of cartilaginous alterations, along less) swelling of the auricular cartilage with intact overlying
with the well-demarcated nature of the epidermal erythematous-appearing skin.
proliferation and the lack of cytologic atypia in the
434 Wenig
lesions were secondary to repeated minor trauma. He

attributed them to the habit of sleeping on hard
pillows, although he could not substantiate his
claim. Others have also believed that these lesions
were traumatic in origin, citing the wearing of motor-
cycle helmets, stereo headphones, the Italian birthday
custom of having one’s auricle pulled, and the habit of
sleeping on hard pillows (67,72–75). Auricular pseu-
docysts may arise within the potential plane left
during embryonic fusion of the auricular hillocks.
Ischemic necrosis of the cartilage or the abnormal
release of lysosomal enzymes by chondrocytes may
also be cofactors (69,74).
Pathology
Gross. The gross appearance of ICC is that of a
fluid-filled distended mass. The excised tissue may
include only a fragment of the cyst wall, or, less often,
it is a full-thickness excision of the ear. An intact cyst
usually contains fluid that has been described as
‘‘olive oil–like’’ (71). The cyst wall consists of a 1- to
2-mm rim of cartilage. The cyst lining may be a
smooth and glistening cartilaginous surface or may
include roughened, rust-colored patches. The cyst is
usually an elongated cleft, but multifocal cystic degen-
eration may be seen.
Microscopy. Histologically, the changes are
restricted to the cartilage, within which irregular-
shaped cystic areas are seen (Fig. 13). The cysts lack a
cell lining, and they generally are devoid of content. An
epithelial lining is absent, hence the term ‘‘pseudo-
cyst.’’ The cyst is the result of the loss of cartilage. The
cystic cleft is often centrally placed in the cartilaginous Figure 13 Idiopathic cystic chondromalacia. (A, B) Histologi-
plate. A rim of fibrous tissue along the inner rim of the cally, idiopathic cystic chondromalacia is characterized by the
cyst or a granulation tissue reaction composed of cystic degeneration of the auricular cartilage. The cysts result in
fibrovascular tissue may be observed, and scattered the loss of cartilage. (B) The cysts, which lack a true epithelial
chronic inflammatory cells can be seen in association lining (pseudocysts), are composed of fibrous tissue along the
with the cysts. In long-standing cases, fibrous tissue inner rim of the cyst and granulation tissue within the wall
may essentially obliterate the cystic space. Some exam- adjacent to the cartilage.
ples of cystic chondromalacia are characterized by a
distinctly proliferative cartilaginous response in which
a thickened cartilaginous wall develops.
reaccumulation of fluid; however, when this is com-
bined with bolster suture compression, long-term
Differential Diagnosis follow-up has shown an absence of recurrences (76).
Slight cytologic atypia may be seen; however, the
orderly nature of the proliferation and the associated
central cystic degeneration facilitate the exclusion of 10. Exostosis
malignant neoplasia (68). The differential diagnosis Clinical Features
may also include relapsing polychondritis, subperi-
chondrial hematoma, and CNCH. Exostoses are localized overgrowths of bone that are
classically described as reactive lesions consisting of a
Treatment and Prognosis compact proliferation of layers of bone of varied size
and appearance, including nodular, mound-like,
Complete surgical excision without distortion of the pedunculated, or flat protuberances on the surface of
underlying cartilaginous framework is the treatment a bone. Broad-based lesions are referred to as exosto-
of choice, and is curative. Because of the potential for sis, while pedunculated lesions have been termed
surgical-related deformity, full-thickness resection is ‘‘osteoma.’’
not advocated. In addition to the obvious cosmetic Exostoses are broad-based outgrowths of bone
concerns, long-standing lesions may result in defor- arising from the wall of the external auditory canal.
mity of the ear. Steroid injection alone has been Exostoses usually are multiple and bilateral (77).
unsuccessful, and it may result in cartilage deformity. External auditory canal exostoses tend to remain
Incision and drainage or curettage has shown variable asymptomatic until they reach a size sufficient to
success. Needle aspiration alone results in the rapid interfere with the normal egress of cerumen and

Medical treatment resolves the symptomatic external
otitis and related hearing loss. For patients who do not
respond to medical treatment, transmeatal surgical
excision is the treatment of choice (78).
11. Synovial Chondromatosis of the

Temporomandibular Joint (TMJ)
Clinical Features
Synovial chondromatosis is a reactive process of
unknown pathogenesis that is characterized by the
formation of multiple cartilaginous nodules in the
synovium. Many become detached and float within
the joint space. Other terms for synovial chondroma-
tosis include ‘‘synovial osteochondromatosis’’ and
‘‘synovial chondrometaplasia’’ (83).
TMJ synovial chondromatosis affects women,
and it generally occurs in adults. Patients with TMJ
synovial chondromatosis may present with preauric-
ular swelling and limited motion of the joint with
deviation of the mandible. TMJ synovial chondroma-
tosis may involve the external auditory canal, result-
Figure 14 Exostosis of the external auditory canal appearing as ing in an asymptomatic mass lesion (84–87).
a broad-based, mound-like bony proliferation lacking trabecular
architecture or marrow spaces; the periosteal layers resemble Radiology
the skin of an onion. A layer of periosteum with overlying thin skin
covers the bone. The radiographic features of synovial chondromatosis
include the presence of numerous radiopaque loose
bodies within the region of the joint, but destruction of
bone is absent (88,89).
exfoliated skin. Most canal exostoses are asympto-
matic, but external auditory canal obstruction may
Etiology
occur, causing recurrent episodes of external otitis,
conductive hearing loss, and tinnitus (78). Exostoses of Synovial chondromatosis is a condition in which foci
the external auditory canal affect cold water of the cartilage develop in the synovial membrane of a
swimmers and surfers (77), with the highest incidence joint, apparently through metaplasia of the sublining
being found in Australia and New Zealand (79). connective tissue of the synovial membrane. Recent
studies have shown clonal chromosomal alterations in
Pathology synovial chondromatosis, suggesting that this is a
neoplastic lesion rather than a metaplastic and/or
Gross. The gross appearance of exostoses is usu- reactive process (90).
ally better appreciated by the surgeon because only
fragments are available to the pathologist in most Pathology
cases.
Microscopy. The intact exostosis is a broad- Gross. The synovium may be diffusely studded
based, mound-like bony proliferation that is similar with innumerable nodules. The nodules are polypoid or
in color and texture to the normal cortical bone pedunculated with a delicate stalk, and they vary in size
(Fig. 14). A layer of periosteum with overlying thin from as small as 1 mm to as large as 3 cm. The external
skin covers the bone. The periosteal layers resemble surface varies from smooth to convoluted and granular.
the skin of an onion, and they usually lack trabecular Microscopy. Histologically, synovial chondroma-
architecture or marrow spaces. tosis consists of nodules of mature cartilage of varying
cellularity that are found within the synovium and
Differential Diagnosis that lie loosely in the joint space. The cartilage may
appear atypical, with hypercellularity, hyperchroma-
The chief differential diagnosis is an osteoma, which is sia, binucleated chondrocytes, and an increased mitot-
much less common in this location. The distinction ic rate (Fig. 15). Calcification and ossification may be
between exostosis and osteoma usually is readily present.
made on the basis of the clinical presentation. Some
controversy exists regarding the ability to distinguish Differential Diagnosis
between the two lesions histologically. Some observers
consider the lesions to differ histologically (77,80,81), The presence of increased cellularity with atypical
while others do not find the microscopical features features, including binucleated chondrocytes, may
sufficiently distinctive to allow separation (82). suggest a diagnosis of chondrosarcoma. In such
436 Wenig
12. Acquired Cholesteatoma (Keratoma)

Cholesteatoma is a pseudoneoplastic lesion of the mid-
dle ear characterized by invasive growth and the pres-
ence of stratified squamous epithelium that forms a
saclike accumulation of keratin within the middle ear
space. Despite their invasive growth, cholesteatomas
are not considered to be true neoplasms. The term
‘‘cholesteatoma’’ is a misnomer in that it is not a
neoplasm nor does it contain cholesterol (96). As such,
the designation of keratoma would be more accurate
but the term ‘‘cholesteatoma’’ is entrenched in the
literature. Other designations include epidermal cyst
or epidermal inclusion cyst of the middle ear (97,98).
Clinical Features
Cholesteatomas occur more frequently in men than in
women and are most common in the third to fourth
decades of life. The middle ear space is the most
common site of occurrence. Most acquired cholestea-
tomas arise in the pars flaccida portion of the tym-
panic membrane and extend into Prussak’s space (98).
Prussak’s space is bordered laterally by the pars
flaccida (Schrapnell’s membrane), medially by the
neck of the malleus, superiorly by the attachment of
the pars flaccida to the tympanic ring near the scutum
and inferiorly by the lateral or short process of the
malleus (6). Initially, cholesteatomas may remain clin-
ically silent until extensive invasion of the middle ear
space and mastoid has occurred. Symptoms include
hearing loss, malodorous discharge, and pain, and
they may be associated with a polyp arising in the
attic of the middle ear or with the perforation of the
Figure 15 Synovial chondromatosis of the temporomandibular
tympanic membrane. Otoscopic examination may
joint. (A) The lesion extended to and involved the external
auditory canal histologically appearing as subcutaneous nodules
reveal the presence of white debris within the middle
of cartilage. (B) At higher magnification, the cartilage appears ear, which is considered diagnostic.
atypical with hypercellularity, nuclear hyperchromasia, pleomor- Acquired cholesteatomas may occur in the exter-
phism, and binucleated chondrocytes but in concert with the nal auditory canal (98). External ear canal cholestea-
clinical and radiographic imaging was diagnostic for a benign tomas generally occur in older individuals, present
lesion (i.e., synovial chondromatosis) rather than a low-grade with otorrhea and unilateral chronic pain, and does
malignancy (e.g., chondrosarcoma). not produce a conductive hearing loss.
Radiology
examples, correlation with the radiographic appear- Given the localization to Prussak’s space, most
ance is essential to differentiate these lesions. The acquired cholesteatomas displace the malleus medial-
radiographic features of synovial chondromatosis ly and erode the adjacent bony scutum; from there, the
include the presence of numerous radiopaque loose mass may extend posteriorly via the epitympanum in
bodies within the region of the joint (88,89). the superior incudal space to the posterolateral attic
and then via the aditus ad antrum to the antrum and
Treatment and Prognosis mastoid air spaces (47). Radiographic evidence of
widening of the aditus is an important diagnostic
Intraoperatively, the lesion is usually confined to the finding.
joint space, and it is easily enucleated. On occasion,
the tumor may extend beyond the joint capsule into Pathogenesis
the parotid gland, the auditory canal, the temporal
bone, or the cranium (91). Conservative surgical man- The majority of cholesteatomas are acquired and arise
agement is the treatment of choice (92). Reported cases either de novo without a history of middle ear disease
of synovial chondrosarcoma have suggested the pos- or following a middle ear infection. A small percent-
sibility of malignant transformation of synovial chon- age of cases are congenital. The latter have also been
dromatosis (93,94). Cell proliferation studies of referred to as epidermoid cysts (98,99). The pathogen-
synovial chondromatosis have shown proliferative esis is thought to occur via the migration of squamous
activity that is intermediate between enchondromas epithelium from the external auditory canal or the
and chondrosarcomas (95). external surface of the tympanic membrane into the
middle ear (99). The mechanism by which the epithe-

lium may enter the middle ear probably is by a
combination of events, including perforation of the
tympanic membrane, particularly in its superior
aspect, which is referred to as the pars flaccida or
Shrapnell membrane, following an infection, coupled
with the invagination or retraction of the tympanic
membrane into the middle ear as a result of long-
standing negative pressure on the membrane second-
ary to blockage or obstruction of the eustachian tube
(99–101). Other theories by which cholesteatomas are
thought to occur include traumatic implantation,
squamous metaplasia of the middle ear epithelium,
and congenital derivation.
13. Congenital Cholesteatoma

Clinical Features Figure 16 Cholesteatoma. The histological diagnosis of cho-
lesteatoma is based on the finding of keratinizing squamous
Congenital cholesteatoma is a cholesteatoma of the epithelium within the middle ear space. The keratinizing squa-
middle ear that exists in the presence of an intact mous epithelium shows cellular maturation and is cytologically
tympanic membrane presumably occurring in the bland, lacking dysplastic changes.
absence of COM that may result in perforation or
retraction of the tympanic membrane (102). Choles-
teatoma of the petrous apex is an epidermoid cyst of
this location, and it bears no relation to cholesteatoma
of the middle ear. It likely is of congenital origin, but
no cell rests have been discovered that may explain
the origin of these lesions. The symptoms usually
relate to the involvement of the VIIth and VIIIth
cranial nerves in the cerebellopontine angle (99).
There is no gender predilection, and most con-
genital cholesteatomas are found in infants and young
children. The majority of cases of congenital choleast-
eatomas are found in the antero-superior part of the
middle ear (102). In early lesions, there are no symp-
toms, and lesions are discovered by otoscopic exami-
nation; in later lesions, the signs and symptoms may
be the same as acquired cholesteatoma.
Pathogenesis
Small colonies of epidermoid cells referred to as
epidermoid formations are found on the lateral ante-
rior superior surface of the middle ear in temporal Figure 17 Cholesteatoma involving a middle ear ossicles.
bones after 15 weeks of gestation (6,102,103). During Although considered a nonneoplastic process and comprised
the first postpartum year, the epidermoid colonies of benign squamous epithelium, cholesteatomas may have infil-
disappear; however, if the epidermoid cells do not trative growth and destructive capability.
disappear but continue to grow, they will become
congenital cholesteatomas (102,103).
Pathology of Cholesteatoma
without evidence of dysplasia. In spite of its benign
Gross. Cholesteatomas appear as cystic, white- histology, cholesteatomas are ‘‘invasive,’’ and they
to pearly appearing masses of varying size that con- have widespread destructive capabilities (Fig. 17).
tain creamy or waxy granular material (100). The destructive properties of cholesteatoma result
Microscopy. The histological diagnosis is made from a combination of interrelated reasons, including
on the basis of the presence of stratified keratinizing mass effect with pressure erosion of the surrounding
squamous epithelium, subepithelial fibroconnective or structures and the production of collagenase, which
granulation tissue, and keratin debris (Fig. 16) (97,98). has osteodestructive capabilities (104). Collagenase is
The essential diagnostic feature is the keratinizing produced by both the squamous epithelial and the
squamous epithelium. It is important to note that the fibrous tissue components of the cholesteatoma.
presence of keratin debris alone is not diagnostic of a External auditory canal cholesteatomas are com-
cholesteatoma. The keratinizing squamous epithelium posed of loosely packed, irregularly arranged keratin
is cytologically bland, and it shows cellular maturation squames (105).
438 Wenig
Differential Diagnosis of inflammation, and expression of the angiogenic

factors, increased number of microvessels in choles-
The differential diagnosis for external canal cholestea- teatomas. Further, these authors suggest that angio-
toma includes keratosis obturans (KO). KO results genesis enables and supports the sustained migration
when the normal self-cleaning mechanism of keratin of keratinocytes into the middle ear cavity represent-
maturation and lateral extrusion from the external ing a pivotal factor in the destructive behavior of
auditory canal is defective, causing the accumulation middle ear cholesteatoma (109).
of keratin debris deep within the bony aspect of the
external auditory canal (105). The etiology of KO
remains unclear. KO most commonly occurs in the Treatment and Prognosis
first two decades of life, and the symptoms generally For acquired cholesteatomas, complete surgical exci-
relate to conductive hearing loss due to the keratin sion of all histological components of the cholestea-
plug. Pain is a common finding. The keratin debris toma is the treatment of choice (100). If the
may exert pressure effects on the bony canal wall, cholesteatoma is not completely excised, it can have
resulting in widening of the external auditory canal, progressive and destructive growth, including wide-
bone remodeling, and inflamed epithelium. The his- spread bone destruction, which may lead to hearing
tological appearance is that of tightly packed keratin loss, facial nerve paralysis, labyrinthitis, meningitis, or
squames in a lamellar pattern. The treatment for KO is brain abscess (110,111). Complete surgical resection is
debridement of the keratin plug. In contrast to KO, also the treatment of choice for congenital cholestea-
external ear canal cholesteatomas generally occur in tomas (112). However, in comparison to acquired
individuals who are older; they present with otorrhea cholesteatomas, there typically is an absence of recurrence
and unilateral chronic pain, do not produce a conduc- and complications association with congenital choles-
tive hearing loss, and are composed of loosely packed, teatomas (112,113). The most important factor in the
irregularly arranged keratin squames, histologically absence of recurrence and complications is early
(105). detection, but may also relate to a different patho-
Cholesterol granuloma is not synonymous with physiology as compared to acquired cholesteatomas
cholesteatoma. These are distinctly different patholog- (112).
ical entities that should not be confused with one
another (96).
The histological diagnosis of cholesteatomas is 14. Langerhans Cell Histiocytosis (LCH),
relatively straightforward in the presence of keratiniz- Langerhans Cell (Eosinophilic)
ing squamous epithelium. In contrast to cholesteato- Granulomatosis, and Eosinophilic
mas, SCC shows dysplastic or overtly malignant Granuloma
cytological features with a prominent desmoplastic
stromal response to its infiltrative growth. Cholestea- LCH is a clonal proliferation of LCs occurring as an
tomas do not transform into SCCs. isolated lesion or as part of a systemic (multifocal)
In an attempt to determine whether cholesteato- proliferation (114,115). The designation of LCH
mas were low-grade SCCs, Desloge and associates replaced the previous nomenclature of the group of
(106) performed DNA analysis on human cholestea- diseases termed ‘‘histiocytosis X,’’ which included
tomas to determine whether ploidy abnormalities eosinophilic granuloma, Letterer—Siwe syndrome,
were present. In 10 cases with interpretable data, 9 and Hand—Schüller—Christian disease. Lieberman
were euploid, and 1 was aneuploid. These authors and colleagues (116) suggested the designation of LC
concluded that, because of a lack of overt genetic (eosinophilic) granulomatosis to indicate that the LC
instability, cholesteatomas could not be considered represents a cellular component of the dendritic cell
to be malignant neoplasms. Molecular genetic evalua- system rather than a tissue macrophage (histiocyte).
tion has found genes induced or upregulated in
cholesteatoma, including genes involved in cell pro- Clinical Features
liferation and differentiation (e.g., calgranulin A, cal- LCH most commonly occurs in the second to third
granulin B, psoriasin, thymosin b-10) and genes decades of life, and it tends to arise in males. The
involved in cell invasion (e.g., cathepsin C, cathepsin lesions are most often osseous. The most frequent
D, cathepsin H) (107). Keratinocyte growth factor osseous sites involved are those in the skull, including
(KGF), a mesenchymal cell-derived paracrine growth the middle ear and the temporal bone (117–120). In
factor that specifically stimulates epithelial cell prolif- patients with middle ear and temporal bone involve-
eration is present in cholesteatomas with KGFR pro- ment, the symptoms include aural discharge, swelling
tein and mRNA localized in the epithelium in 72% of of the temporal bone area, otitis media, bone pain,
cases and with significant correlation between KGFþ/ otalgia, loss of hearing, and vertigo (118–120). Bilateral
KGFRþ expression and recurrence (108). KGF and temporal bone involvement may occur.
KGFR may play a role in enhanced epithelial cell
proliferative activity and recurrence of cholesteatomas Radiology
(108). Angiogenesis and angiogenic growth factors
have been reported to be present in cholesteatoma Radiographic imaging on computed tomography (CT)
(109). Sudhoff and colleagues (109) reported a close of the skull includes (single or multiple) sharply
relationship between the density of capillaries, degree circumscribed osteolytic lesions (120).
Figure 18 Langerhans cell histiocytosis. The cellular prolifera-

tion is characterized by a sheetlike proliferation of cells with
lobulations and/or indentations of the nuclear membrane (reni-
form nuclei) representing Langerhans cells.
Pathology
Microscopy. Histologically, LCH is characterized
by a proliferation of LCs, which are arranged in sheets,
nests, or clusters and are composed of cells with
reniform nuclei characterized by nuclear membrane
lobations or indentations (Fig. 18). The nuclei have
vesicular chromatin with inconspicuous to small, cen-
trally located basophilic nucleoli and a moderate
amount of eosinophilic cytoplasm. The LC may show
Figure 19 Langerhans cells are immunoreactive for (A) S-100
mild pleomorphism, and mitotic figures are uncom- protein and (B) CD1a.
mon. An inflammatory cell infiltrate that primarily
consists of eosinophils accompanies the LC. Other
inflammatory cells are present, including polymorpho-
nuclear leukocytes, plasma cells, and lymphocytes. In malignant lymphoma. Rosai-Dorfman disease may
addition, foamy histiocytes and multinucleated giant occasionally involve the ear and temporal bone region
cells may also be observed. These histiocytes may show (126). Like LC, the cells of Rosai-Dorfman disease are
phagocytosis of mononuclear cells. S-100 protein reactive; they differ from LCs in that they
The diagnosis of LCH is facilitated by an immu- are nonreactive for CD1a and Langerin (124). Differen-
nohistochemical evaluation. LCs are diffusely immu- tiating LCH from a malignant lymphoproliferative
noreactive with S-100 protein (121,122) and CD1a disease is usually not problematic by light microscopy.
(Fig. 19) (123). Langerin, a type II transmembrane If necessary, immunohistochemical stains help in differ-
C-type lectin associated with the formation of Birbeck entiating LCH from a malignant lymphoma.
granules in LC, represents a highly selective marker
for LCs and the lesional cells of LCH (124). Langerin Treatment and Prognosis
immunoreactivity (membranous and granular cyto-
Surgical excision (curettage) and low-dose radiation
plasmic pattern) assists in substantiating the diagnosis
therapy (500 to 1500 rads) are the treatments of choice.
of LCH and in differentiating LCH from other non-LC
The prognosis is considered very good (120). Recur-
histiocytic proliferations (124). On electron microsco-
rence, which may be part of a systemic or multifocal
py, elongated granules referred to as Langerhans or
process, generally occurs within six months of the
Birbeck granules can be seen within the cytoplasm of
diagnosis. Failure of a new bone lesion to occur within
the LC (125). The foamy histiocytes and multinucleat-
one year of diagnosis is considered a cure. Chemo-
ed giant cells are S-100 protein and CD1a-negative,
therapy is used for multifocal and/or systemic disease
but they do react for CD68 (KP1).
(120). In general, the younger the patient is at the onset
of disease and the more extensive the involvement
(i.e., multiple sites including bone and viscera), the
The histological differential diagnosis of LCG includes worse the prognosis. Survival rates for children with
extranodal sinus histiocytosis with massive lymphade- multifocal disease have been reported to be 60% to
nopathy (Rosai-Dorfman disease) and non-Hodgkin 100% (120).
440 Wenig
15. Acquired Encephalocele

Clinical Features
Acquired encephaloceles represent neuroglial tissues
located within the middle ear and mastoid. Acquired
encephaloceles are also referred to as ectopic or
heterotopic CNS tissue, brain prolapse, or brain
herniation.
There is no gender predilection. Acquired ence-
phaloceles may occur over a wide age range but tends
to occur in older individuals (127). Most often
acquired encephaloceles represent an incidental find-
ing in patients requiring surgery for COM. Associated
symptoms may include unilateral conductive hearing
loss, leakage of CNS tissue, and/or recurrent epi-
sodes of meningitis (127,128). In patients suspected
of having ectopic neuroglial tissue in this site, radio-
logical imaging (e.g., CT scans) may prove valuable in
identifying a defect and/or connection to the CNS
(128).
Pathogenesis
Generally (but not always), acquired encaphaloceles
represent herniation of the brain into the middle ear
and mastoid via compromise of the tegmen, a thin
bony shell that separates the middle ear and mastoid
cavity from the temporal lobe. The connection to the
CNS may not always be identified. The tegmen may
be compromised or destroyed secondary to trauma,
prior surgery, complication of otitis media, or congen-
ital defect (127,128). Fracture of the temporal bone
may also result in representing herniation of the brain
Figure 20 Acquired encephalocele in a patient with long-
into the middle ear and mastoid (129).
standing chronic otitis media who had undergone several oper-
ations. Histologically, (A) the excised tissue includes normal brain,
Pathology including all cellular components of CNS tissue, and (B) reactive
Histology. All components of CNS tissue are alterations of the neuroglial tissue (gliosis) may be identified.
present (Fig. 20); reactive alterations of the neuroglial
tissue (gliosis) may be present (Fig. 20). Meninges are
generally not present. The CNS tissue may be present
in association with findings of other pathological
16. Relapsing Polychondritis
processes, including COM, as well as cholesteatoma Clinical Features
(keratinizing).
Immunohistochemical confirmation of neurogli- Relapsing polychondritis (RP) is an uncommon sys-
al tissues includes reactivity with GFAP. temic episodic or relapsing disease that is character-
ized by the progressive degeneration of cartilaginous
structures throughout the body. RP is also referred to
Differential Diagnosis as polychondropathia (130).
RP primarily occurs in whites, and it affects men
COM in which a fibrillary stroma is often present may and women equally. RP may occur at any age, but the
simulate the appearance of neurofibrillary matrix. symptoms are most frequent in the fifth to seventh
Staining for GFAP will assist in confirming or exclud- decades of life. The auricular cartilage is involved,
ing neuroglial tissues. usually bilaterally, in nearly 90% of patients with RP
(131–137). The affected ear is erythematous, swollen,
Treatment and Prognosis and very tender (Fig. 21). In advanced cases, the pinna
may be distorted because of destruction of the carti-
Management of the condition is surgical. For defects lage. The overlying skin is not ulcerated. The disease
smaller than 1 cm in diameter, the transmastoid manifestations relapse with marked variability in both
approach can be used (127). For defects larger than the severity and frequency of occurrence. The pro-
1 cm, the combined transmastoid-minicraniotomy gression of disease may result in ‘‘cauliflower’’ ears
approach provides good access (127). Possible com- and ‘‘saddle’’ nose deformities. The involvement of
plications include brain abscess. the audiovestibular system may result in hearing loss
lupus erythematosus, rheumatoid arthritis, scler-

oderma, Sjögren syndrome, Reiter syndrome, glomer-
ulonephritis, autoimmune thyroid disease, ulcerative
colitis, pernicious anemia, and Raynaud syndrome
(132,141,142).
Patients with RP have been known to have
factors in their serum that react with cartilage (143).
Circulating antibodies to type II collagen (144) with
titers reflecting severity of disease and the documen-
tation of immunofluorescent localization of immune
complex components at the perichondral-cartilagi-
nous interface have been reported in patients with
RP (145,146). Patients with RP have immune com-
plexes of immunoglobulins and complement detected
in the biopsy specimens taken from the inflamed
cartilage of the involved ear(s) (147). No evidence
exists to support either a hereditary or familial
predisposition.
Pathology
The histological findings in RP include perichondrial
Figure 21 Relapsing polychondritis. The affected ear is ery- inflammation with a mixed infiltrate of lymphocytes,
thematous and swollen with intact (nonulcerated) overlying skin.
plasma cells, polymorphonuclear leukocytes, and
occasional eosinophils that blurs the interface between
the perichondrium and the auricular cartilage (Fig. 22).
(conductive, sensorineural, or mixed) (133). Other Loss of the usual basophilia occurs in the cartilage,
cartilaginous sites, as well as noncartilaginous loca- which assumes an eosinophilic appearance with hema-
tions of the body, may be involved, including arthrop- toxylin and eosin staining. At the advancing edge of
athy (large and small joints), laryngotracheal and the inflammation, loss of chondrocytes and destruction
bronchial chondritis, nasal chondritis, cardiovascular of the lacunar architecture are observed. As cartilage is
complications (valvular insufficiency, aneurysm), ocu- destroyed, it is eventually replaced by fibrous tissue.
lar manifestations (episcleritis, conjunctivitis, retinop- The immunomicroscopical findings include the
athy), and cutaneous involvement (oral and genital diffuse granular deposition of immunoglobulin G
ulcers) (131–147). (IgG) and complement protein 3 (C3) in the perichon-
The current clinical diagnostic criteria for RP are drial fibrous tissue (148).
defined by three or more of the following: (i) recurrent
chondritis of both auricles; (ii) nonerosive inflamma-
tory arthritis; (iii) chondritis of nasal cartilages;
(iv) ocular inflammation, including conjunctivitis,
keratitis, scleritis and/or episcleritis, and/or uveitis;
(v) chondritis of the upper respiratory tract that
involves the larynx and/or tracheal cartilages; and
(vi) cochlear and/or vestibular damage manifested by
sensorineural hearing loss, tinnitus, and/or vertigo.
The diagnosis can be confirmed when one or more of
the above criteria occur in association with histologi-
cal confirmation or by the presence of chondritis in
two or more separate anatomical locations that
respond to steroids and/or dapsone.
The laboratory findings are nonspecific, includ-
ing an elevated erythrocyte sedimentation rate; mild
leukocytosis; and normochromic, normocytic anemia.
Antineutrophil cytoplasmic antibodies (ANCA) titers
are usually negative in RP (138–140); however, elevated
ANCA titers have been reported (141).
Figure 22 Relapsing polychondritis. The histological features
Etiology associated with relapsing polychondritis include a mixed inflam-
matory cell infiltrate extending into the cartilage with blurring or
The etiology of RP has not been clearly elucidated; obliteration of the interface between the cartilaginous plate and
however, evidence has implicated an autoimmune the adjacent fibroconnective tissues. The involved cartilage
process. In association with RP, some patients suffer shows a loss of its normal basophilic appearance.
from other autoimmune disorders, including systemic
442 Wenig
Differential Diagnosis Etiology

A number of diseases may be included in the clinical Gout may occur as an inherited or acquired disease
differential diagnosis of RP, including external otitis, (149,150). Primary gout, which represents 90% of
acute (infectious) polychondritis, tophaceous gout, cases, is an inherited error of metabolism that results
systemic vasculitides [e.g., Wegener’s granulomatosis from either an enzymatic defect in purine synthesis or
(WG)], and rheumatoid arthritis. a defect in the renal excretion of uric acid. Secondary
or acquired gout, which comprises the remaining 10%,
Treatment and Prognosis occurs secondary to disorders that increase the pro-
duction of uric acid (e.g., leukemias) or that decrease
The treatment of RP depends on the stage. In the acute the excretion of uric acid (e.g., chronic renal failure).
stages of disease, corticosteroids are used (141). In
more advanced stages, immunosuppressive agents Pathology
may be used (136). The prognosis is variable and
unpredictable, with some patients having a prolonged Microscopy. Histologically, gouty tophi are com-
course and others suffering from a more aggressive posed of needle-shaped aggregates of urate crystals
and fulminant disease. Death may occur, and it is with a surrounding foreign body giant cell reaction
most often the result of respiratory tract or cardiovas- (Fig. 24). If a diagnosis of gout is suspected, the
cular system involvement. resected tissue should be fixed in absolute alcohol or
any nonaqueous fixative, as the urate crystals are
water soluble. Crystals demonstrate negative birefrin-
17. Tophaceous Gout and Pseudogout gence; when using a primary color compensator in
Clinical Features between two polarizing lenses, the crystals will
Gout is a disorder of purine metabolism or of the renal

excretion of uric acid. Monosodium urate precipitates
as deposits (tophi) throughout the body. One of the
more common sites of gouty tophi is the helix of the
ear (Fig. 23). In relationship to the ear, tophi may
present as painful skin-covered firm nodules; auricu-
lar gouty tophi may be nonpainful.
The laboratory findings include the presence of
elevated urinary uric acid. Additionally, leukocytosis
and an increased erythrocyte sedimentation rate are
often observed. The measurement of 24-hour urinary
uric acid excretion helps the clinician determine whether
uric acid overproduction is a cause of the hyperurice-
mia (149,150). In normal body tissues, sodium urate is
deposited (tophi), but, in urine with a lower pH, uric
acid is precipitated (149,150).
Figure 24 Histologically, (A) gout is characterized by the pres-

ence of foreign body giant cell reaction typically surrounding
needle-shaped crystals, and (B) in this example, a foreign body
giant cell reaction is present, but the crystals are not readily
Figure 23 Gouty tophus seen on the helix of the ear. The lesion identifiable as the tissue was not fixed in absolute alcohol or a
appears as a skin-covered nodule. nonaqueous fixative.
change color from yellow to blue when rotating the may be lost. A foreign body granulomatous reaction
polarizing lenses from parallel to perpendicular. can be seen in association with the crystal deposition.
Chondroid metaplasia is often present in and around
Differential Diagnosis the areas of CPPD deposition. Some evidence indi-
cates that metaplastic chondrocytes may play a role in
Tophaceous gout may share similar features with the initial precipitation of CPPD crystals. Synovial
tophaceous pseudogout. The designation of pseudog- chondrometaplasia may be seen in patients with
out was initially coined by McCarty and associates pyrophosphate arthropathy. The metaplastic chondro-
(151) to describe the presence of calcium pyrophos- cytes may show cytologic atypia that could lead to a
phate dihydrate crystal deposition in the synovial diagnosis of chondrosarcoma. This is particularly true
fluid of patients with gout-like symptoms but without in decalcified sections from which CPPD crystals are
sodium urate crystals. Other designations include lost. In contrast to pseudogout, radiographic calcifica-
tumoral calcium pyrophosphate dihydrate (CPPD) tion in gouty tophi is relatively uncommon. In addi-
deposition disease (152), chondrocalcinosis, and pyro- tion, the identification of the specific positive
phosphate arthropathy. More recently, this disease birefringence of the calcium pyrophosphate crystals
has been designated as CPPD crystal deposition dis- that is seen in tophaceous pseudogout is not a feature
ease (153). Histologically, tophaceous pseudogout is of gouty tophi.
characterized by the presence of a variably cellular,
chondroid-appearing tissue in which crystalline mate- Treatment and Prognosis
rial is found (Fig. 25). The crystalline material appears
rhomboid or needle shaped, and, under polarized The treatment is directed toward the systemic disorder.
light microscopy, the crystals show weak, positive
birefringence. In decalcified material, the crystals 18. Wegener’s Granulomatosis
Clinical Features
WG is a systemic necrotizing vasculitis that typically
involves the kidneys, lung, and upper aerodigestive
tract. Otologic involvement by WG occurs in 20% to
60% of patients who have disease at these more usual
sites (154–157). The most common otologic manifes-
tations include unilateral or bilateral otitis media
(serous or suppurative), perforation of the tympanic
membrane, and sensorineural hearing loss (158,159).
Cutaneous involvement of the external ear can include
perforation of the ear lobes and external otitis
(154,156–159). Facial palsy may occur as the initial
manifestation of disease (155). The involvement of
the middle ear may occur secondary to nasopharyn-
geal and sinonasal disease via the eustachian tube, or
it may be due to direct involvement by disease.
Antineutrophil cytoplasmic autoantibodies
(ANCA) should be elevated in the active phase of
WG. Two distinct staining patterns of ANCA posi-
tivity are found, including cytoplasmic (C-ANCA)
and perinuclear (P-ANCA). WG is associated with
C-ANCA and infrequently with P-ANCA; (160–162)
P-ANCA is more often associated with rheumatic
diseases. Patients with generalized WG have a 60%
to 100% C-ANCA positivity, while patients with lim-
ited WG have a 50% to 67% C-ANCA positivity
(160,161). C-ANCA results can be used in establishing
a diagnosis of WG in clinically suspect lesions in
which the biopsies are not entirely diagnostic; false-
positive results are uncommon. C-ANCA titers corre-
late with disease activity and recurrent disease.
Proteinase-3 (PR-3) is a neutral serine proteinase pres-
ent in azurophil granules of human polymorphonu-
Figure 25 Tophaceous pseudogout. (A) Variably cellular chon- clear leukocytes and monocyte lysosomal granules.
droid-appearing tissue within which are identifiable crystalline PR-3 serves as the major target antigen of ANCAs
material appearing rhomboid or needle shaped (under polarized with a cytoplasmic staining pattern (c-ANCA) in WG
light microscopy, the crystals showed weak positive birefrin- (163,164). ANCA with specificity for PR3 are charac-
gence, not shown). (B) Chondroid metaplasia is present, which teristic for patients with WG. Patients with WG dem-
may show cytological atypia. onstrate a significantly higher percentage of mPR3þ
neutrophils than healthy controls and patients with
444 Wenig
other inflammatory diseases. The detection of ANCA ening of the ear and is derived from Greek (ous, ear;
directed against PR-3 (PR3-ANCA) is highly specific skleros, hard; osis, condition), osseous ankylosis
for WG (163,164). ANCA positivity is found only in (Greek: ankoulon, to stiffen).
about 50% of the patients with localized WG, whereas Otosclerosis affects women more often than
PR3-ANCA positivity is seen in 95% of the patients men; it usually begins in the second and third decades
with generalized WG (164). The pathogenesis of vas- of life and is slowly progressive. The prevalence of
cular injury in WG is ascribed to ANCAs directed otosclerosis varies with race; it is more common in
mainly against PR-3, and the interaction of ANCA whites than in blacks, Asians, or Native Americans
with neutrophilic ANCA antigens is necessary for the (168). Otosclerosis primarily causes conductive hear-
development of ANCA-associated diseases. In ing loss that usually begins in the second and third
patients with WG, high expression of PR-3 on the decades of life and slowly progresses. The extent of
surface of nonprimed neutrophils is associated with the hearing loss directly correlates with the degree of
an increased incidence and rate of relapse. stapedial footplate fixation. For patients with otoscle-
rosis also to have vestibular disturbances is not
Pathology uncommon (169,170). Otosclerosis usually involves
both ears; however, unilateral disease can occur in
The histological features are similar to those described up to 15% of cases (171).
in the upper aerodigestive tract (see chapter on mid-
facial destructive diseases for the histological find- Radiology
ings). Elevated serum levels of ANCA are of great
assistance in those cases in which the diagnosis is Imaging studies can confirm the clinical consideration
suspected, but the histology may not be definitively of otosclerosis. High-resolution CT is the modality of
diagnostic of WG. choice for evaluating middle and inner ear structures,
including labyrinthine windows, stapes foot plate,
Differential Diagnosis and cochlear capsule (172,173).
Other autoimmune or systemic diseases that may Etiology
involve the middle or inner ear include polyarteritis
nodosa and rheumatoid arthritis. Polyarteritis nodosa Although many theories appear in the literature, the
is a necrotizing vasculitis of small and medium-sized etiology of otosclerosis is unclear. Hereditary factors
muscular arteries. The aural-related symptoms are often cited, although the mode of inheritance is
include otitis media with effusion (165,166). Sensori- still uncertain (174). A family history is present in a
neural hearing loss may be the initial presentation, or majority of cases. The majority of epidemiological
it may develop after the diagnosis has already been studies on families with otosclerosis suggest an auto-
established (166). The histological diagnosis is depen- somal dominant mode of inheritance with reduced
dent on the presence of necrotizing vasculitis. The penetrance of approximately 40% (174). Genetic link-
treatment includes corticosteroids and immunosup- age studies have demonstrated the presence of six loci
pressant agents. The manifestations of rheumatoid (OTSC1, OTSC2, OTSC3, OTSC4, OTSC5, and OTSC7)
arthritis of the audiovestibular system include con- located on chromosomes 15q, 7q, 6p, 16q, 3q, and 6q,
ductive hearing loss due to the involvement of the respectively. Although these loci have been mapped,
incudomalleal and incudostapedial articulations (167). no causative genes have been identified (174).
High-dose salicylates used in combination with ste-
roids and nonsteroidal anti-inflammatory agents are Pathology
the treatment of choice. Microscopy. Histologically, the initial alterations
Treatment and Prognosis include the resorption of bone around blood vessels.
Cellular fibrovascular tissue replaces the resorbed
Combined corticosteroid and immunosuppressive bone, resulting in the softening of the bone (otospon-
therapy may result in long-term remissions, and treat- giosis). Immature bone is laid down with continuous
ment is capable of reversing the hearing loss and facial active resorption and remodeling. The new bone is rich
palsy if the diagnosis can be established and manage- in ground substance and is deficient in collagen, but,
ment can be initiated early in the disease course. The over time, more mature bone with increased collagen
prognosis for hearing is poor when appropriate treat- and less ground substance is produced, resulting in
ment is not given in the early stages of the disease densely sclerotic bone. This process most often begins
(157). Early diagnosis and appropriate treatment are anterior to the oval window, eventually involving the
important to prevent irreversible changes in the mid- footplate of the stapes (Fig. 26). Stapedial involvement
dle ear and inner ear. causes fixation of the stapes and the inability to
transmit sound waves, resulting in conductive hearing
19. Otosclerosis loss. Similar pathological involvement of the inner ear
may produce sensorineural hearing loss.
Clinical Features
Otosclerosis is a disorder of the bony labyrinth and
stapedial footplate that exclusively occurs in humans The differential diagnosis includes Paget disease (see
and is of unknown etiology. Otosclerosis means hard- below).
Etiology
The etiology of Paget disease is unknown, but consid-
eration has been given for an infectious (viral) etiology
in genetically predisposed individuals.
Pathology
Paget disease is characterized by three histological
phases. In the first or osteolytic phase, excessive
osteoclastic activity results in bone resorption. In the
second mixed or combined phase, new bone forma-
tion (osteoblastic activity) predominates over bone
resorption (osteoclastic activity), with deposition of
new bone next to areas of bone resorption. In the third
or osteoblastic phase, increased new bone that is
characterized by dense irregular masses showing a
mosaic pattern of cement lines is observed.
Figure 26 Otosclerosis of the stapedial footplate. This entity is
characterized by densely sclerotic bone resulting in fixation of the
stapes. The differential diagnosis includes otosclerosis. Fea-
tures in Paget disease that assist in separating this
from otosclerosis include a later age of onset, greater
sensorineural hearing loss, enlarging calvaria, and
Treatment and Prognosis enlargement and tortuosity of the superficial temporal
artery and its anterior branches (176).
Surgical management of the conductive hearing loss
caused by stapes fixation (stapedectomy) is the treat- Treatment and Prognosis
ment of choice.
Treatment is directed at slowing or preventing pro-
gression of disease by suppressing increased bone
20. Paget Disease of Bone turnover using oral administration of biphosphanates,
Clinical Features which acts by decreasing the number of osteoclasts
with deposition of structurally normal bone as
Paget disease of bone, also referred to as osteitis opposed to less disordered bone deposition. Anti-
deformans, is a chronic progressive disorder of inflammatory medications are used in relieving bone
unknown etiology. The skull and temporal bone are and joint pain. Hearing loss is permanent and cannot
involved in approximately 70% of cases (175). Other be reversed by medical therapy. Sarcomatous trans-
sites of involvement include the external auditory formation occurs in roughly 1% of cases, usually as an
canal, the tympanic membrane, the eustachian tube, osteosarcoma. Osteosarcomas arising in Paget disease
the ossicles, the oval window, the round window, the are highly malignant, with five-year survival rates of
internal auditory canal, the cochlea, and the endolym- less than 10% (178,179).
phatic sac (175). It is slightly more common in men
than in women. Paget disease affects approximately
3% of the population older than 40 years and as high
as 11% of the population older than 80 years (176). The
21. Meniere Disease (Endolymphatic Hydrops,
symptoms include hearing loss, tinnitus, and vertigo.
Idiopathic Endolymphatic Hydrops, or
The facial nerve is spared. The hearing loss is sensori-
Lermoyez Syndrome)
neural; mixed sensorineural and conductive; or, less Clinical Features
often, only conductive. The hearing losses are pro-
gressive, and they are due to involvement of the Meniere disease is an idiopathic disorder of the inner
osseous portion of the external auditory canal, of the ear associated with a symptom complex of spontane-
ossicles, and/or of the cochlea and labyrinth. ous, episodic attacks of vertigo; sensorineural hearing
loss; tinnitus; and a sensation of aural fullness.
Radiology The incidence of Meniere disease varies in the
literature from 157 per 100,000 people in England to 46
High-resolution CT of the temporal bone may show per 100,000 in Sweden to 7.5 per 100,000 in France
mixed appearance of bone thickening and sclerosis (180). Meniere disease occurs slightly more frequently
(177). In the temporal bone, the disease begins at the in women than in men (1.6:1). The peak incidence is in
petrous apex and progresses inferolaterally; with pro- the fifth to seventh decades of life, but it may occur in
gression, demineralization of the otic capsule may children as well as in older individuals (9th and 10th
occur. The stapedial footplate may become involved decades). The onset of the vertigo is frequently sud-
(i.e., thickened) contributing to the (conductive) hear- den, reaching maximum intensity within a few
ing loss. Frequently, the central skull is also involved. minutes and lasting for an hour or more. It then either
446 Wenig
subsides completely or continues as a sensation of II. NEOPLASMS OF THE EAR

unsteadiness for hours to days. AND TEMPORAL BONE
Etiology The classification of neoplastic lesions of the ear and
temporal bone is detailed in Table 2. Among the more
The etiology is uncertain, although the incidence of common neoplasms of the external ear are those of
Meniere disease is noted to be increased in patients cutaneous origin, including keratoacanthoma, squa-
with certain genetically acquired major histocompati- mous papilloma, seborrheic keratosis (SK), BCC, SCC,
bility complexes (MHCs), including human leukocyte verrucous carcinoma, malignant melanoma, Merkel
antigen (HLA) B8/DR3 and Cw7, which suggest a cell carcinoma, dermatofibrosarcoma protuberans,
possible autoimmune etiology (181–183). Familial and others. These neoplasms will not be discussed
occurrences of Meniere disease have been reported
(184,185), although the role that genetic inheritance
plays in the mode of transmission is variable. Table 2 Classification of Neoplasms of the Ear and Temporal
Meniere disease appears to be due to changes Bone
in the anatomy of the membranous labyrinth as a
I. External ear
consequence of the overaccumulation of endolymph
(endolymphatic hydrops) at the expense of the peril- A. Benign
ymphatic space (185,186). Endolymph, which is pro- Epithelial/neuroectodermal/mesenchymal
Keratoacanthoma
duced by the stria vascularis in the cochlea and by Ceruminal gland neoplasms
cells in the vestibular labyrinth, circulates in a radial Seborrheic keratoses
and longitudinal fashion. In patients with Meniere Squamous papilloma
disease, the absorption of endolymph by the endo- Melanocytic nevi
lymphatic sac is believed to be inadequate (185). Dermal adnexal neoplasms
Pilomatrixoma (calcifying epithelioma of Malherbe)
Pathology Neurilemmoma/neurofibroma
Osteoma, chondroma
In the early stages of the disease, endolymphatic Hemangioma
hydrops primarily involves the cochlear duct and Others
saccule, but, in the later stages, the entire endolym- B. Malignant
phatic system is involved. Alterations of the membra- Epithelial/neuroectodermal/mesenchymal
nous labyrinth include dilatation, outpouching, Basal cell carcinoma
rupture, and collapse. Fistulae (unhealed ruptures) Squamous cell carcinoma and variants
may occur. Severe cytoarchitectural and atrophic (verrucous carcinoma, spindle cell squamous carcinoma,
changes may occur, including the loss of neurons in adenoid squamous cell carcinoma)
the cochlea. Ceruminal gland adenocarcinomas
Malignant melanoma
Treatment and Prognosis Merkel cell carcinoma
Atypical fibroxanthoma (superficial malignant fibrous
Medical management is the mainstay of therapy. The histiocytoma)
therapy is aimed at the reduction of symptoms, and it II. Middle and inner ear
therefore is empiric and supportive. Optimally, man- A. Benign
agement should resolve the vertigo, tinnitus, and
hearing loss. The current management is directed at 1. Epithelial
Middle ear adenoma
relieving vertigo, the most debilitating of symptoms.
Middle ear papilloma
Therapy includes prophylaxis via the reduction of Others
endolymph accumulation by dietary modification, 2. Neuroectodermal/mesenchymal
intermittent dehydration, diuretics; the enhancement Jugulotympanic paraganglioma
of the microcirculation of the ear using vasodilators Meningioma
(e.g., betahistidine, adenosine triphosphate, isosorbide), Acoustic neuroma
and reduction in immunoreactivity using steroids, Others
immunoglobulin, and allergy therapy (187). Symp- B. Indeterminant
tomatic therapies include antivertiginous medications, Endolymphatic sac papillary tumor
antiemetics, sedatives, antidepressants, and psychiat- C. Malignant
ric management. Improvements in 60% to 80% of 1. Epithelial
patients have been reported (182,188). Surgical treat- Middle ear adenocarcinoma
ment is reserved for those patients who have failed Primary squamous cell carcinoma
medical management (approximately 10% of 2. Mesenchymal
patients), and it includes shunting or decompression Rhabdomyosarcoma
Vascular (angiosarcoma; Kaposi’s sarcoma)
of the endolymphatic sac, labyrinthectomy, or section-
Lymphoproliferative (malignant lymphoma,
ing of the vestibular nerve (187). Combined cortico- plasmacytoma)
steroid and immunosuppressive therapy may result in
long-term remissions, and this combination is capable Secondary tumors:
Squamous cell carcinoma from other head and neck sites; breast
of reversing the hearing loss and facial palsy if the
carcinoma; pulmonary adenocarcinoma; malignant melanoma;
diagnosis can be established and the treatment is renal cell carcinoma, prostatic adenocarcinoma, others
initiated early in the disease course.
in this chapter; readers are referred to the chapter on Ulceration is uncommon, and it may suggest a malig-
selected skin lesion for a complete discussion of these nant neoplasm.
tumor types. However, selective cutaneous type neo- Microscopy. Histologically, ceruminal gland ade-
plasms of the ear will be discussed in this chapter, nomas are unencapsulated but well-demarcated glan-
including SCC and BCC of the pinna and external dular proliferations (Fig. 27). The glands vary in size,
auditory canal. Rhabdomyosarcomas (RMSs) occur in and they may have various combinations of growth
the head and neck, and in children, they represent the patterns, including solid, cystic, and papillary. A
most common aural-related malignant neoplasm. The cribriform or back-to-back glandular pattern is com-
reader is referred to the chapter on diseases of soft monly seen. The glands are composed of two cell
tissues for the discussion on RMS of the head and neck. layers (Fig. 27). The inner or luminal epithelial cell is
cuboidal or columnar with eosinophilic cytoplasm and
the decapitation-type secretion (apical ‘‘snouts’’) char-
A. Benign Neoplasms of the External Auditory acteristic for apocrine cells, while the outer cell layer,
Canal which is of myoepithelial differentiation, is spindled
1. Ceruminal Gland Neoplasms with hyperchromatic nucleic (Fig. 27). A golden yellow-
brown, granular-appearing pigment can be seen in the
Ceruminal gland neoplasms are benign tumors of cells of the inner lining, and this represents cerumen.
cerumen-secreting modified apocrine glands (cerumi- Cellular pleomorphism and mitotic figures can be seen,
nal glands) located in the external auditory canal. but they are not prominent.
These glands are located in the dermis of the cartilagi- Diastase-resistant, PAS-positive, or mucicarmine-
nous (inner) portion of the external auditory canal. In positive intracytoplasmic or intraluminal material
general, ceruminal gland neoplasms are uncommon, may be seen. Immuonhistochemical stains show the
but they represent one of the more common tumors of luminal cells to be strongly and diffusely immunore-
the external auditory canal. The generic designation of active with CK7 as well as with CD117 positivity (193).
ceruminoma should be avoided. Ceruminal gland neo- The basal cells are CK5/6, S-100 protein, and p63-
plasms should be specifically diagnosed according to positive (193). Ultrastructure evaluation includes the
the tumor type. The classification of ceruminal gland presence of epithelial (apocrine cell) and myoepithe-
neoplasms includes benign and malignant tumors lial cell differentiation. Epithelial cells show features
(Table 3). The benign ceruminal gland tumors include of apocrine cells, including apocrine caps, microvilli,
ceruminal gland adenoma (ceruminoma), pleomorphic cell junctions, secretory granules, vacuoles, lipid drop-
adenoma, and syringocystadenoma papilliferum (189). lets, and siderosomes (194).
The malignant ceruminal gland tumors include ceru-
minal gland adenocarcinoma, adenoid cystic carcino- b. Ceruminal Gland Pleomorphic Adenoma
ma, and mucoepidermoid carcinoma (189).
Ceruminal gland pleomorphic adenomas are uncom-
mon tumors. The histological composition is similar to
a. Ceruminal Gland Adenoma that of pleomorphic adenomas of salivary gland ori-
Clinical Features gin, including a variable admixture of epithelial and
myoepithelial components set in a myxoid to chon-
Ceruminal gland adenomas (ceruminomas) are dromyxoid stroma.
benign neoplasms of cerumen-secreting modified apo-
crine glands (ceruminal glands) located in the external c. Syringocystadenoma Papilliferum of
auditory canal. Ceruminal gland adenomas tend to Ceruminal Gland Origin
affect men more than women, and they occur over a
wide age range; but they are seen most frequently in Syringocystadenoma papilliferum is a benign tumor
the fourth to sixth decades of life. The symptoms of apocrine gland origin that usually occurs on the
include a slow-growing external auditory canal mass scalp and face area but may originate in the external
or blockage; hearing difficulty; and, infrequently, otic auditory canal from ceruminal glands. The histology
discharge (189–193). is similar to tumors of the more common cutaneous
sites and to the salivary gland tumor termed ‘‘siala-
denoma papilliferum’’ (for more details see the chap-
Pathology ters on diseases of the salivary glands and skin).
Gross. The gross appearance of ceruminal gland Differential Diagnosis
neoplasms includes skin-covered, circumscribed, pol-
ypoid, or rounded masses from 1 to 4 cm in diameter. The differential diagnosis for ceruminal gland adeno-
ma includes MEA and ceruminal gland adenocarcino-
Table 3 Classification of Ceruminal Gland Neoplasms ma. The origin from the middle ear should allow for
Benign ceruminal gland tumors the identification of a MEA. However, occasionally,
Ceruminal gland adenoma (ceruminoma) MEAs may perforate the tympanic membrane and
Pleomorphic adenoma (benign mixed tumor) appear to present as an external auditory canal
Syringocystadenoma papilliferum mass, creating some difficulty in differentiating from
Malignant ceruminal gland tumors a ceruminal gland adenoma. The histological features
Ceruminal gland adenocarcinoma diagnostic for ceruminal gland adenoma, including
Adenoid cystic carcinoma (but not limited to) the presence of apocrine type
Mucoepidermoid carcinoma secretion and intracytoplasmic cerumen should
448 Wenig
allow for differentiating tumor types. In contrast to

ceruminal gland adenomas, ceruminal gland adeno-
carcinomas are cytomorphologically malignant and/
or infiltrative in growth. Given the relative proximity
of the parotid gland to the external auditory canal,
before diagnosing a ceruminal gland pleomorphic
adenoma, an origin from the parotid gland should
be excluded, which requires clinical correlation.

For all benign ceruminal gland neoplasms, complete
surgical excision, which is curative, is the treatment of
choice. Recurrences can develop, and they are related
to inadequate surgical excision.
2. Benign Mesenchymal Tumors of the External

Auditory Canal
Mesenchymal tumors of the external auditory canal
are rare; they include osteoma (195), chondroma (196),
leiomyoma (197), Schwannoma (198), and myxomas
(199). In contrast to exostosis, osteomas are true neo-
plasms of bone that are capable of unlimited growth.
Osteomas occur in the external auditory canal and
present as an asymptomatic solitary mass. Histologi-
cally, osteomas are composed of mature bone with
associated intraosseous fibrovascular tissue. Surgical
excision is curative.
Myxomas of the external ear and external audi-
tory canal have been described in an autosomal domi-
nant syndrome complex that includes myxomas in
other locations, most notably cardiac sites; spotty
pigmentation; endocrine tumors; and schwannomas
(199). Myxomas are characterized by the presence of
sparse cellularity and a paucity of blood vessels
(Fig. 28). The lesion consists chiefly of mucoid material
in which a loose framework of reticulin fibers is
suspended. The cellular component consists of a pop-
ulation of spindled-to-stellate cells with tiny pyknotic
Figure 27 Ceruminal gland adenoma. (A) Ceruminal gland

adenomas are unencapsulated, well-delineated glandular prolif-
erations lacking infiltrative growth; the glands vary in size and
shape and may include a back-to-back glandular pattern of
growth. (B) The glands are composed of two cell layers, includ-
ing inner (luminal) epithelial cells that vary in appearance from
cuboidal to columnar with an eosinophilic cytoplasm and decapi-
tation-type secretion (apical ‘‘snouts’’) characteristic of apocrine-
derived cells and an outer layer of spindle-shaped cells, with Figure 28 Myxoma of the external auditory canal is histologi-
hyperchromatic nuclei representing myoepithelial cells. (C) Intra- cally characterized by sparsely cellular lesion that consists of a
cytoplasmic granular, golden yellow– to brown-appearing pig- bland-appearing spindled to stellate cells with associated myxoid
ment (cerumen) is seen within the inner (luminal) epithelial cells. stroma.
nuclei and delicate cytoplasmic process. Cellular pleo- Etiology

morphism is not seen. A pseudocapsule of condensed
reticulin fibers and compressed host tissue, parti- There are no known etiological factors related to the
cularly skeletal muscle, surrounds the periphery of development of MEA. MEAs are not associated with a
the tumor. The myxoid matrix in myxoma stains history of COM. Concurrent cholesteatomas may be
with Alcian blue, and it is hyaluronidase sensitive. seen with MEA, but no known association exists
Mucicarmine and colloidal iron also stain the material. between these two lesions.
The cellular component of myxomas is vimentin-
positive, but it does not express skeletal muscle anti- Pathology
gens or S-100 protein. Although soft tissue myxomas Gross. MEAs are gray-white to red-brown, rub-
lack a discrete capsule, they rarely recur after excision. bery to firm masses free of significant bleeding on
Myxoid change occurs in a variety of benign manipulation.
neoplasms, including neurofibroma, neurilemmoma, Microscopy. Histologically, MEAs are unencapsu-
and lipoma, and it may mimic myxoma, especially in lated lesions with gland or tubule formation as well as
limited biopsy material. Of greater concern is the solid, sheetlike, trabecular, cystic, and cribriform growth
histological pattern in myxomas, which may mimic patterns (Fig. 29). The neoplastic glands occur individu-
myxoid soft tissue malignancies. These, particularly ally or have back-to-back growth. The glands are com-
embryonal rhabdomyosarcomas, as well as myxoid posed of a single layer of cuboidal to columnar cells
malignant fibrous histiocytoma (MFH), myxoid lip- with a varying amount of eosinophilic cytoplasm and a
osarcoma, and myxoid chondrosarcoma, are much round to oval hyperchromatic nucleus. Nucleoli may be
more common in this location. In contrast to myxoma, seen, and, generally, they are eccentrically located. The
sarcomas display much greater cellularity and a richer cells may have a prominent plasmacytoid appearance
vascular pattern. Furthermore, the cytological features that is particularly evident in the more solid areas of
differ. Cellular pleomorphism and increased numbers growth but also in the cells forming the glandular
of mitotic figures are seen in sarcomas. Differentiated
cell types, such as multinucleated giant cells in myx-
oid MFH, lipoblasts in liposarcoma, rhabdomyoblasts
in rhabdomyosarcoma, and atypical chondroblasts in
chondrosarcoma, are distinctive features.
For myxomas, surgery is the treatment of choice.
Although soft tissue myxomas lack a discrete capsule,
they rarely recur after excision.
B. Benign Neoplasms of the Middle Ear and

Temporal Bone
1. Middle Ear Adenoma
Clinical Features
MEA is a benign glandular neoplasm originating from
the middle ear mucosa (200,201). MEA occurs equally in
both genders and over a wide age range, but it is most
common in the third to fifth decades of life. Any portion
of the middle ear may be affected, including the eusta-
chian tube, mastoid air spaces, ossicles, and chorda
tympani nerve. The most common symptom is unilat-
eral conductive hearing loss, but fullness, tinnitus, and
dizziness may also occur. Pain, otic discharge, and facial
nerve paralysis rarely occur, and, if they are present,
they may be indicative of a malignant process. In the
majority of cases, otoscopic examination identifies an
intact tympanic membrane with a tumor that is con-
fined to the middle ear space with possible extension to
the mastoid. Occasionally, the adenoma perforates
through the tympanic membrane with extension into
and presentation as an external auditory canal mass.
Figure 29 (A) Middle ear adenoma composed of a diffuse
Radiology
gland-forming proliferation. The glands may appear individually,
In its more typical radiological presentation, MEA or they may have back-to-back growth. (B) The neoplastic cells
appears as a relatively avascular soft tissue density have a prominent plasmacytoid appearance evident in the solid
without evidence of destructive, invasive, or erosive areas as well as in association with the glands.
properties (201).
450 Wenig
Table 4 Immunohistochemical Reactivity of selected Middle Ear and Temporal Bone Neoplasms
CK EMA CG SYN S100 NSE GFAP VIM DES Myf4
MEA þ þ
MEA-NE þ þ þ þ V þ
JTP þ þ þa þ
MEN þ þ
AN þ þ
ESPT v v v V v v
RMS þ þ þ
a
Positive in the peripherally situated sustentacular cells.
Abbreviations: MEA, middle ear adenoma; NE, neuroendocrine features; JTP, jugulotympanic paraganglioma; MEN, meningioma; AN, acoustic neuroma;
ESPT, endolymphatic sac papillary tumor; RMS, rhabdomyosarcoma; CK, cytokeratin; EMA, epithelial membrane antigen; CG, chromogranin; SYN,
synaptophysin; NSE, neuron-specific enolase; GFAP, glial fibrillary acidic protein; VIM, vimentin; DES, desmin; þ = positive; = negative; þ/ = variably
positive.
structures (Fig. 29). A paranuclear clear zone is not tivity for one or more neuroendocrine markers,
present. Cellular pleomorphism may be prominent, including chromogranin and synaptophysin, is pres-
but mitotic figures are uncommon. The stromal compo- ent (Fig. 31) (Table 4). In addition, NSE, serotonin, and
nent is sparse, and it may appear fibrous or myxoid. human pancreatic polypeptide also may be present.
Histochemical stains show the presence of intra- Despite the presence of vasoactive compounds in
luminal, but not intracytoplasmic, mucin-positive these tumors, carcinoid syndrome is extraordinarily
material. PAS-positive material is not present. On rare in association with these middle ear neoplasms.
immunohistochemical evaluation (Table 4), the neo- These MEAs with neuroendocrine differentiation have
plastic cells are cytokeratin-positive, including dif- been termed ‘‘carcinoid tumors of the middle ear’’
fusely positive for AE1/AE3, CAM 5.2, and CK7,
and focal and weak CK20 reactivity (203). Neuroen-
docrine differentiation may be seen (see below), as is
seen by chromogranin, synaptophysin, and neuron-
specific enolase (NSE) immunoreactivity. Serotonin
and human pancreatic polypeptide also may be pres-
ent. S-100 protein and vimentin staining may be
present. Desmin and actin are negative.
Middle Ear Adenomas with Neuroendocrine
Differentiation. In some MEAs, the cells may have
dispersed or stippled nuclear chromatin with the ‘‘salt
and pepper’’ pattern seen in neuroendocrine tumors
(Fig. 30) and/or demonstrate architectural characteristics
seen in association with neuroendocrine neoplasms
(e.g., ribbons, cords, organoid growth). Immunoreac-
Figure 30 Middle ear adenoma with neuroendocrine differenti-

ation showing (A) foci of solid cell nests with an organoid growth Figure 31 The immunoreactivity of middle ear adenomas with
pattern and (B) nuclei with dispersed nuclear chromatin suggest- neuroendocrine differentiation include (A) chromogranin and (B)
ing neuroendocrine differentiation. synaptophysin.
(203–207) as well as ‘‘neuroendocrine adenoma’’ (203).

However, these carcinoid tumors are better viewed as
part of the histological spectrum of MEA (208,209),
albeit one with neuroendocrine differentiation, rather
than as representing a distinct middle ear neoplasm
separate from MEA. El-Naggar and colleagues (209)
showed the presence of chromogranin-positive cells
within hyperplastic but not in nonneoplastic middle
ear epithelium overlying an MEA, which supports the
inclusion of middle ear glandular tumors with neuro-
endocrine differentiation within the spectrum of
MEA. Nevertheless, the issue whether to classify
these tumors as MEA with neuroendocrine differenti-
ation or carcinoid tumors (also referred to as well-
differentiated neuroendocrine carcinomas) remains
controversial. The controversy relates to the biological
behavior of these tumors. On the basis of long-term
follow-up, the overwhelming majority of these tumors
have a benign biological course supporting the classi-
fication of these tumors as part of the histological
spectrum of MEA, albeit with neuroendocrine differ-
entiation, rather than representing a distinct middle Figure 32 Middle ear adenoma that perforated the tympanic
ear neoplasm separate from MEA. However, Ramsey membrane presenting as an external auditory canal mass lesion.
et al. (210) have reported two locally recurrent tumors Given this history, the histological diagnosis of a ceruminal gland
(which may be a function of inadequate initial adenoma may be erroneously made. The histological features of
excision) with regional metastasis asserting that at middle ear adenoma and ceruminal gland adenoma are distinct,
least some of these middle ear neoplasms are carci- allowing for differentiation.
noid tumors/well-differentiated neuroendocrine
carcinomas.
Differential Diagnosis extensive structural involvement. Recurrent tumor

The differential diagnosis of MEA primarily includes may occur and is likely a function of inadequate
jugulotympanic paraganglioma (JTP), meningioma, excision. Some MEAs may be locally aggressive, and
and acoustic neuroma (AN). The pathological and may rarely invade vital structures, causing death. In
immunohistochemical features (Table 4) of these general, the clinical, radiological, and pathological
other tumor types are discussed in their respective findings are indicative of a benign tumor. The over-
sections. Glandular metaplasia may occur in the set- whelming majority of MEAs (with and without neu-
ting of COM. In contrast to MEA, the glandular roendocrine differentiation) do not metastasize.
proliferation in COM is focal or haphazardly arrayed, However, as reported by Ramsey et al. (210), rare
may show the presence of cilia (a feature not seen in examples of MEAs with neuroendocrine differentia-
MEA), and typically occurs in the presence of histo- tion may metastasize, raising the consideration that
logical features of COM, including chronic inflamma- there are exceptional cases that may represent carci-
tion with fibrosis and calcifications (tympanosclerosis). noid tumors (also referred to as well-differentiated
MEA may perforate the tympanic membrane, and it neuroendocrine carcinomas). The histological findings
may appear to represent a neoplasm of the external of MEAs with neuroendocrine differentiation reported
auditory canal (Fig. 32), such as a ceruminal gland to have metastasized are similar to ones that did not
adenoma. The histological features of these two tumor metastasize (210).
types are distinctly different, so they should allow easy
distinction. In contrast to the rare middle ear adeno- 2. Jugulotympanic Paraganglioma
carcinoma, MEA lacks marked cellular pleomorphism,
increased mitotic activity, necrosis, or invasion of the Clinical Features
bone and other soft tissue structures. JTP is a benign neoplasm that arises from the extra-
Some confusion exists in the literature regarding adrenal neural crest-derived paraganglia specifically
MEA and its relationship to the endolymphatic sac located in the middle ear or temporal bone region.
papillary tumor (ESPT). As is discussed later in this Synonyms include glomus jugulare tumor or glomus
chapter, the pathological features and clinical course tympanicum tumor.
of ESPT differ decidedly from those of MEA. JTPs are considered the most common tumors of
the middle ear (200,201). They affect women more
often than men, and they are most common in the fifth
The treatment for all MEAs is complete surgical exci- to seventh decades of life. The majority (85%) of JTPs
sion. Surgery may be conservative if the lesion is small arise in the jugular bulb, resulting in a mass lesion in
and confined to the middle ear or more radical (mas- the middle ear or external auditory canal (200).
toidectomy) for larger lesions associated with more Approximately 12% originate from the Jacobson
452 Wenig
nerve (tympanic branch of the glossopharyngeal Table 6 Glassock–Jackson Classification of Glomus Tumors
nerve) and present as a middle ear tumor (200).
Glomus tympanicum
Roughly, 3% begin from the Arnold nerve (posterior Type I Small mass limited to promontory
auricular branch of the vagus nerve) and arise in the Type II Tumor completely filling the middle ear
external auditory canal (200). The most common space
symptom is conductive hearing loss. Other symptoms Type III Tumor filling the middle ear and extending
include tinnitus, fullness, otic discharge, pain, hemor- into the mastoid
rhage, facial nerve abnormalities, and vertigo. JTPs are Type IV Tumor filling the middle ear, extending into
often locally invasive neoplasms that destroy the the mastoid or through the tympanic
adjacent structures, including the temporal bone and membrane to fill the external auditory
mastoid (200,211). Neurological abnormalities, includ- canal; may also extend anterior to the
internal carotid artery
ing cranial nerve palsies, cerebellar dysfunction, dys-
Glomus jugulare
phagia, and hoarseness, may be seen, and these relate Type I Small tumor involving the jugular bulb,
to the invasive capabilities of this neoplasm. middle ear, and mastoid
Type II Tumor extending under the internal
Radiology auditory canal; may have intracranial
Computed tomography scan shows a soft tissue mass extension
Type III Tumor extending into petrous apex; may
often with evidence of extensive destruction of adja-
have intracranial extension
cent structures. Since JTPs are vascularized lesions, Type IV Tumor extending beyond the petrous
carotid angiography will show the lesion fed by apesx into the clivus or infratemporal
branches of nearby large arteries (211,212). By mag- fossa; may have intracranial extension
netic resonance imaging (MRI), tumors larger than 2
cm have a unique salt and pepper pattern of hyper-
intensity and hypointensity on T1-weighted and T-2 the basis of site of origin and extent of tumor involve-
weighted imaging (212). ment have been developed (Table 6) (212).
Etiology Pathology
JTPs may be familial (213). Familial JTPs may be Gross. Grossly, JTPs are polypoid, red, friable
multifocal, including jugulotympanic and carotid masses that are identified behind an intact tympanic
body. An autosomal dominant pattern of inheritance membrane or within the external auditory canal
is favored. Genetic analysis has shown linkage with (Fig. 33). They vary in size from a few millimeters to
two different loci, including 11q13.1 and 11q22.3–q23 a large mass that completely fills the middle ear space.
(214,215). Microscopy. The histological appearance of all
extra-adrenal paragangliomas is the same. The hall-
Classification mark feature is the presence of cell nests or a so-called
zellballen pattern (Fig. 34). The stroma surrounding
Jugular and tympanic paragangliomas have been
and separating the nests is composed of prominent
reported as a single entity (i.e., temporal bone para-
fibrovascular tissue. While this pattern is characteris-
gangliomas), but their distinction has important clini-
tic of paragangliomas, it can be seen in other tumors,
cal and therapeutic implications; as such, classification
including other neuroendocrine tumors, melanomas,
schemes on the basis of site of origin (Table 5) or on
Table 5 Classification of Temporal Bone Paragangliomas

Class A Tumors arising along the tympanic plexus on the
middle ear promontory
Class B Tumors arising from the inferior tympanic canal of the
hypotympanum; may invade the middle ear and
mastoid; cortical bone over jugular bulb is intact;
carotid canal is intact
Class C Tumors arising in dome of jugular bulb and involving
the overlying cortical bone
C1 Tumors eroding the carotid canal but not involving the
carotid artery
C2 Tumors involving the vertical carotid canal
C3 Tumors involving the horizontal carotid canal;
foramen lacerum is free of tumor
C4 Tumors involving the foramen lacerum and the
cavernous sinus
Class D Tumors with intracranial extension of posterior fossa
De1 Extradural tumor of <2 cm medial dural displacement Figure 33 Jugulotympanic paraganglioma appearing as a pol-
De2 Extradural tumor of >2 cm medial dural displacement ypoid, red mass that perforated the tympanic membrane and
Di1 Intradural tumor of <2 cm protruding into the external auditory canal from its origin in the
Di2 Intradural tumor of >2 cm middle ear.
Di3 Neurosurgically unresectable tumor
Figure 34 Jugulotympanic paraganglioma. This lesion shows Figure 35 The immunohistochemical antigenic profile of all
the classic organoid or the cell nest growth pattern, including paragangliomas irrespective of site, including this jugulotympanic
round or oval cells with uniform nuclei, a dispersed chromatin paraganglioma includes chromogranin positivity in the chief cells
pattern, and abundant eosinophilic granular or vacuolated cyto- (left) and S-100 protein staining localized to the peripheral
plasm. The sustentacular cells are located at the periphery of the sustentacular cells (right).
cell nests, but these are difficult to identify by light microscopy.
and carcinomas. Paragangliomas are predominantly

composed of chief cells, which are round or oval cells
with uniform nuclei; a dispersed chromatin pattern;
and abundant eosinophilic, granular, or vacuolated
cytoplasm. The sustentacular cells, which represent
modified Schwann cells, are located at the periphery
of the cell nests, appearing as spindle-shaped, baso-
philic cells, but these are difficult to identify by light
microscopy. Cellular and nuclear pleomorphism can
be seen, but these features are not indicative of malig-
nancy. Mitotic figures and necrosis are infrequently
identified. Paragangliomas lack glandular or alveolar
differentiation.
The diagnosis of JTP is facilitated by immuno-
histochemical stains. The immunohistochemical pro-
file includes chromogranin and synaptophysin
positivity in the chief cells and S-100 protein staining
localized to the peripheral sustentacular cells (Fig. 35). Figure 36 Jugulotympanic paraganglioma. The typical orga-
Vimentin is variably reactive in both the chief cells noid growth pattern is absent, and the lesion is associated with
densely fibrotic stroma. The absence of the typical light micro-
and sustentacular cells. Epithelial markers, including
scopical findings may suggest alternative diagnoses.
cytokeratin as well as HMB-45 and mesenchymal
markers (desmin and other markers of myogenic
differentiation) are negative. Rare examples of appar-
ently cytokeratin-reactive paragangliomas have been
reported (216). The ultrastructural evaluation shows an organoid pattern of growth, JTPs may be associated
the presence of neurosecretory granules (217). with a dense fibrous stroma and an appearance of
Paragangliomas are often readily identified by infiltrative growth. Special stains may aid in the
light microscopical evaluation. However, in certain diagnosis. Reticulin staining may better delineate the
instances, they may be difficult to differentiate from cell nest growth pattern, with staining of the fibrovas-
other tumors. Not infrequently, middle ear and tem- cular cores surrounding the neoplastic nests (Fig. 37).
poral paragangliomas do not show the characteristic In addition, the tumor cells are argyrophilic (Churu-
cell nest appearance. This ‘‘loss’’ of the organoid kian—Schenk). Argentaffin (Fontana), mucicarmine,
growth may be artifactually induced by surgical and PAS stains are negative. These findings may result
manipulation (‘‘squeezing’’) of the tissue during in an erroneous interpretation as a malignant neoplasm.
removal (Fig. 36). The absence of the typical growth Typical immunoreactive staining patterns for chromog-
pattern may result in diagnostic confusion with other ranin and S-100 protein should allow for a correct
middle ear tumors (Fig. 36). In addition to the loss of diagnosis.
454 Wenig
mon. Malignant JTPs do occur; they are associated

with histological criteria of malignancy, including
increased mitotic activity; necrosis that is usually
seen within the center of the cell nests; and vascular
invasion, and they may metastasize to the cervical
lymph nodes, lungs, and liver (221,222). In general,
DNA ploidy studies by image analysis are not predic-
tive of the behavior of paragangliomas (219).
3. Acoustic Neuroma
Clinical Features
AN is a benign neoplasm that originates from
Schwann cells, specifically from cranial nerve VIII.
Synonyms include neurilemoma, acoustic Schwan-
noma, and benign peripheral nerve sheath tumor.
Figure 37 Jugulotympanic paraganglioma. The typical orga- AN accounts for up to 10% of all intracranial
noid growth pattern is obscured (left); reticulin stain is helpful in neoplasms and represents up to 90% of all cerebello-
delineating the cell nest growth pattern (right). pontine angle tumors (200,201). ANs are more com-
mon in women than in men, and they may affect any
age; they are, however, most common in the fourth to
seventh decades of life. The majority of ANs involve
Differential Diagnosis the superior or vestibular portion rather than the
The differential diagnosis of JTP primarily includes cochlear portion of cranial nerve VIII. Symptoms
MEA, meningioma, and AN. If the histology is not include progressive (sensorineural) hearing loss, tin-
distinctive in separating JTP from these other tumors, nitus, and loss of equilibrium. With progression, the
the immunohistochemical reactivity differentiates these tumor enlarges, and it may compress adjacent cranial
tumors (Table 4). nerves (V, VII, IX, X, XI), the cerebellum, and the brain
stem, leading to facial paresthesia and numbness,
Treatment and Prognosis headaches, nausea, vomiting, diplopia, and ataxia.
Up to 8% may be bilateral (223–227), a potential
Complete surgical excision is the treatment of choice; indicator of neurofibromatosis type 2 (226,227).
however, the location and invasive nature of these
lesions often preclude complete resection. Unresect- Radiology
able paragangliomas include those with extensive
skull base involvement or intracranial extension, and The radiological features of AN include flaring, asym-
patients who might be poor surgical candidates, metric widening, or erosion of the internal auditory
including medically infirm and elderly. In such canal (200,201). Tumors as small as 1 cm or less are
cases, radiation therapy is a useful adjunct to surgery. capable of being detected with CT or MRI.
Radiotherapy results in a decrease or ablation of
vascularity and promotes fibrosis. Radiotherapy has Etiology
been primarily used to treat jugular paragangliomas NF-2 is an autosomal dominant condition. The gene
of the temporal bone. As there is rarely total resolution for NF-2 has been mapped to the long arm of chromo-
of the tumor following radiotherapy, successful treat- some 22 (22q12) (227). The hallmark of NF-2 is bilat-
ment of paragangliomas with radiotherapy is defined eral ANs (228). Patients with NF-2 also experience an
as local control in the form of stability or regression of increased incidence of multiple, separate-occurring
tumor size and nonprogression or improvement of meningiomas in intra- and extracranial sites. Symp-
neurological symptoms (218,219). Preoperative embo- toms of neurofibromatosis may be seen in up to 16%
lization is useful in decreasing the vascularity of the of patients and those with neurofibromatosis who
tumor and facilitating surgical resection. Postemboli- develop ANs generally are symptomatic at an earlier
zation angiography should document absence of age (2nd decade) and have a higher incidence of
tumor ‘‘blush’’ with continued patency of the external bilateral ANs. Patients with AN (or meningioma)
carotid systems; not all paragangliomas should be who are younger than 30 years should raise concern
embolized. The decision is dependent on the location for a diagnosis of NF-2.
and extent of tumor, and the experience of the surgeon
and interventional radiologist. Local recurrences can
Pathology
be seen in up to 50% of cases. The histological appear-
ance of paragangliomas does not correlate to the Gross. The gross appearance of AN includes a
biological behavior of the tumor. Intracranial exten- circumscribed, tan-white, rubbery-to-firm mass that
sion may occur in up to 15% of cases (220). Function- may appear yellow and show cystic change. The
ing JTPs, which are evidenced by endocrinopathic tumor ranges in size from a few millimeters up to 4
manifestations, occur, but they are extremely uncom- to 5 cm at its greatest diameter.
Figure 39 Acoustic neuroma. Diffuse and intense S-100 protein

immunoreactivity is present.
The differential diagnosis includes MEA, JTP, and
meningioma. The differentiation of these tumor types
can be achieved by the light microscopical and immu-
nohistochemical features for each tumor type (Table 4).

Complete surgical excision is the treatment of choice,
and it usually is curative. AN may result in death
Figure 38 Acoustic neuroma. (A) The tumor is unencapsulated secondary to the herniation of the brain stem in
and has fascicular growth comprised of of spindle-shaped cells; patients with untreated or large neoplasms. Malignant
vascular hyalinization is present. (B) The cellular component ANs are exceedingly rare, and, if they are present,
includes elongated and twisted-appearing nuclei with indistinct
neurofibromatosis should be suspected.
cytoplasmic borders.
4. Meningioma
Clinical Features
Microscopy. Histologically, the tumors are unen-
capsulated, and they are similar in appearance to Meningiomas are benign neoplasms arising from
benign schwannomas of all other locations. The cellu- arachnoid cells forming the arachnoid villi that are
lar component includes elongated and twisted nuclei seen in relation to the dural sinuses.
with indistinct cytoplasmic borders. The cells are Meningiomas represent from 13% to 18% of all
arranged in short, interlacing fascicles, and whorling intracranial tumors, and they are the second most
or palisading of nuclei called Verocay bodies may be common tumors of the cerebellopontine angle
seen (Fig. 38). The cellularity varies, and some benign (200,201). Meningiomas are more common in women
schwannomas can be highly cellular (so-called cellular than in men, and they are most often seen in the fifth
schwannoma). Mitotic figures are usually sparse in decade of life (229). They infrequently occur in children.
number. Cellular pleomorphism with hyperchromasia The occurrence of a meningioma outside the CNS is
can be identified, but it is not a feature of malignancy. considered ectopic, and it can be divided into those
Retrogressive changes, including cystic degeneration, tumors with no identifiable CNS connection (primary)
necrosis, hyalinization, calcification, and hemorrhage, and those with a CNS connection (secondary). The
may also be seen. Schwannomas have prominent development of primary meningiomas in the middle
vascularity composed of large vessels with thickened ear and temporal bone results either from direct exten-
(hyalinized) walls. sion or the presence of ectopic arachnoid cells. The
Immunohistochemical staining shows the pres- middle ear and temporal bone are the most common
ence of diffuse, intense S-100 protein reactivity (Fig. 39). sites of ectopically located meningiomas in the head
No immunoreactivity for cytokeratin or the neuroen- and neck region. Sites of involvement include the
docrine markers chromogranin and synaptophysin is internal auditory canal, jugular foramen, geniculate
present. ganglion, the roof of the eustachian tube, and the sulcus
456 Wenig
of the greater petrosal nerve (200). The clinical presen-

tation of middle ear meningiomas includes progressive
hearing loss, loss of equilibrium, headaches, cerebellar
dysfunction, and cranial nerve abnormalities.
Etiology
Meningiomas may be associated with neurofibromato-
sis type 2. Mutations in the NF2 gene probably account
for the formation of more than half of all meningiomas
(230). Patients with NF-2 also experience increased
incidence of multiple, separate-occurring meningiomas
in intra- and extracranial sites. Patients with a meningi-
oma (or AN) who are younger than 30 years should
raise concern for a diagnosis of NF-2.
Radiology
The radiological findings include a soft tissue mass Figure 41 Immunoreactivity of meningiomas include epithelial
with variable vascularity. A pathognomonic feature membrane antigen (EMA) (left) and vimentin (right).
for meningioma in this location is the presence of
speckled calcification in a soft tissue mass (200).
Pathology
achieved by the light microscopical and immunohis-
Microscopy. The histological features of middle tochemical features for each tumor type (Table 4).
ear and temporal bone meningioma are similar to
their intracranial counterparts (Fig. 40). The immuno- Treatment and Prognosis
histochemical antigenic profile of meningiomas
includes reactivity for EMA and vimentin (Fig. 41). In Complete surgical excision is the treatment of choice,
contrast to MEAs, meningiomas are generally nonreac- and it is curative. Malignant change rarely, if ever,
tive for cytokeratin, and, in contrast to JTPs, meningio- occurs. A diagnosis of middle ear meningioma should
mas are nonreactive for neuroendocrine markers (i.e., be made only after clinical evaluation has excluded
chromogranin and synaptophysin) (Table 4). secondary extension from an intracranial neoplasm
(231).
The differential diagnosis includes MEA, JTP, and 5. Other Benign Neoplasms of the Middle Ear
AN. The differentiation of these tumor types can be and Temporal Bone
While uncommon, a number of other primary benign
neoplasms can be found in the middle ear or temporal
bone. Among these uncommon middle ear neoplasms
are the Schneiderian-type mucosal papillomas of the
middle ear, which are histologically identical to sino-
nasal or Schneiderian papillomas (232). Such neo-
plasms are more common in women than in men.
They occur over a wide age range with an average
age of occurrence in the fifth decade of life, and present
with conductive hearing loss, otalgia, and otorrhea,
and often occur in patients with a history of COM.
Schneiderian-type mucosal papillomas of the middle
ear arise de novo without evidence of sinonasal tract
papillomas, although some have occurred in patients
with sinonasal tract papillomas (232). Their histology is
identical to that of inverted Schneiderian papillomas of
the sinonasal tract (Fig. 42). Rarely, an associated SCC
has been reported (232). Complete excision usually
Figure 40 Meningioma of the internal auditory canal showing a necessitating radical tympanomastoidectomy is the
cell nest or lobular growth separated by fibrovascular tissue. The treatment of choice.
cells are composed of round to oval or spindle-shaped nuclei Other uncommon primary benign tumors of the
with pale-staining cytoplasm and indistinct cell borders; the middle ear and temporal bone are primarily mesen-
nuclei show a characteristic punched-out or empty appearance chymal, including hemangiomas (233–235), lipoma
because of intranuclear cytoplasmic inclusions. (236,237), osteoma (238–240), osteoblastoma (241),
chondroblastoma (242), and teratomas (243).
Table 7 Neoplasms Associated with von Hippel–Lindau Syndrome

Retinal angiomas
Cerebellar and spinal hemangioblastomas
Endolymphatic sac papillary tumor
Renal cysts and cystadenomas
Pancreas: microcystic adenoma; endocrine tumors
Pheochromocytoma
Epididymal cyst and cystadenoma
Etiology
A diagnosis of ESPT should prompt the clinician to
consider the possibility that the patient has VHL
syndrome (244,245). VHL is an autosomal dominant
disorder with variable expression. Tumor suppressor
gene for VHL has been identified at chromosome
3p25–p26 (249). Patients with VHL have a predisposi-
Figure 42 Middle ear papilloma with histological features of a
sinonasal (Schneiderian)-type cylindrical cell papilloma.
tion to the development of numerous CNS and
abdominal organ tumors (Table 7).
Histogenesis
An endolymphatic sac origin for these tumors is
C. Middle Ear and Temporal Bone Tumors of supported by the following: (i) early clinical manifes-
Indeterminant Biologic Behavior tations of vestibular disease, including sensorineural
hearing loss, tinnitus, and episodic vertigo; (ii) radio-
1. Endolymphatic Sac Papillary Tumor graphic features showing a tumor in the posterior-
medial petrous ridge, a site where the endolymphatic
Clinical Features sac is located; (iii) identification of an in situ tumor (i.
The ESPT is an uncommon but distinct neoplasm that e., originating from within the endolymphatic sac);
possibly is a manifestation of von Hippel–Lindau and (iv) the morphological, immunohistochemical,
(VHL) syndrome (244,245). ESPT has had a variety and ultrastructural similarities of the tumor with the
of names, including adenoma of endolymphatic sac; normal endolymphatic sac epithelium (246).
adenoma and/or adenocarcinoma of temporal bone or
mastoid; low-grade adenocarcinoma of probable Pathology
endolymphatic sac origin; papillary adenoma of tem- Microscopy. The histopathological appearance of
poral bone; aggressive papillary tumor of temporal ESPT is quite variable. The papillary structures are
bone; aggressive papillary middle ear tumor; and, generally not complex in their growth. The neoplastic
more recently, the Heffner tumor (246,247). cells vary from flattened- or attenuated-appearing
There is no gender predilection. ESPT occurs cells to columnar-appearing cells (Fig. 43). Most
over a wide age range from the second to eighth often, only a single row of cells is present. Occasional-
decades of life. The most common symptom is unilat- ly, the surface epithelial cells may have an appearance
eral hearing loss ranging from 6 months to 18 years; that suggests a double layer of cells (epithelial and
the hearing loss is most frequently sensorineural myoepithelial); however, the ‘‘outer’’ row of cells in
rather than conductive, but mixed types of hearing all probability represents a stromal element, as these
loss also occur. Other symptoms include tinnitus, cells have not been shown to be immunoreactive with
vertigo, ataxia, and cranial nerve deficits. myoepithelial markers (248). The epithelial cells have
uniform nuclei that are usually situated either in the
center of the cells or toward the luminal aspect, and
Radiology
they have a pale eosinophilic- to clear-appearing
CT scan and MRI may show a lytic temporal bone cytoplasm. The latter may predominate in any given
lesion measuring from 4 to 6 cm (248). The center of tumor. Cell borders may be seen, but, not infrequent-
the lesion most often is seen at or near the posteriorly, the neoplastic cells lack a distinct cell membrane. In
medial face of the petrous bone. Extension of tumor to some cases, hypercellular areas with crowded, vari-
the posterior cranial cavity has led to suggestions that ably sized cystic glandular spaces that contain eosino-
the tumor took origin from the cerebellopontine angle; philic (colloid-like) material are noted (Fig. 44). The
extension results in cerebellar involvement and evi- latter appear remarkably similar to thyroid tissue. In
dence of compression and/or shifting of the fourth all cases, pleomorphism is minimal, and mitotic activ-
ventricle, brain stem, or pineal gland. Angiographic ity and necrosis are rarely present.
studies show a vascular or hypervascular lesion (244). A granulation tissue reaction is seen in associa-
The diagnosis of this tumor is based on clinical, tion with the neoplastic cells, and it includes the small
radiographic, and pathological correlation. vascular spaces lying in close proximity to the surface
458 Wenig
epithelium and/or within the stroma of the papillary

fronds. Because of the absence of a distinct cell mem-
brane around the neoplastic cells, a sharp demarcation
separating the neoplastic cells from the subjacent
granulation tissue is not observed. This appearance
may create diagnostic confusion so that the neoplastic
proliferation is not appreciated and the entire process
is viewed as reactive. This interpretation is further
enhanced by the stromal presence of a mixed inflam-
matory cell infiltrate, fibrosis, vascular proliferation,
fresh hemorrhage, and/or hemosiderin (within the
neoplastic cells or within macrophages), cholesterol
granulomas, and dystrophic calcification. Dystrophic
calcification does not include laminated calcific con-
cretions (psammoma bodies).
Intracytoplasmic diastase-sensitive, PAS-positive
material may be present. The colloid-like luminal
material stains strongly with PAS either with or
without diastase digestion. Intracytoplasmic and
intraluminal mucin staining is rarely positive. Iron
stains are positive. ESPTs are diffusely cytokeratin-
positive, and they also show variable reactivity for
EMA, S-100 protein, vimentin, NSE, GFAP, Ber-EP4,
synaptophysin, and Leu-7 (Table 4). Thyroglobulin
immunoreactivity is not seen. Ultrastructurally,
ESPTs show the presence of intercellular junctional
complexes, microvilli, basement membrane material,
rough endoplasmic reticulum, intracytoplasmic glyco-
gen, and secretory granules (248).
The differential diagnosis includes MEA. However,
Figure 43 Endolymphatic sac papillary tumor. (A) The lesion is the clinical, radiographic, and pathological features
characterized by a papillary growth pattern. (B) In this example, that are unique to ESPT should allow for distinction.
the epithelial component is composed of a distinct layer of cuboi- The same would apply for the other common neo-
dal- to columnar-appearing cells with delineated cell borders. plasms of the middle ear and temporal bone. The
differential diagnosis also includes choroid plexus
papilloma and metastatic carcinoma of thyroid or
renal origin. Choroid plexus papillomas are intracra-
nial (i.e., intraventricular) tumors with histological
features that are different from those of ESPT (246).
The absence of thyroglobulin reactivity and thyroid
transcription factor 1 (TTF1) differentiates ESPT from
metastatic thyroid papillary carcinoma. Metastatic
renal cell carcinoma is immunoreactive for renal cell
marker and CD10, markers not identified in ESPT.
Further, the immunohistochemical antigenic features
seen in ESPT are not found in renal cell carcinoma.

Radical surgery, including mastoidectomy and tem-
poral bone resection that may necessitate sacrifice of
cranial nerves, is the treatment of choice, and it is
potentially curative. Local recurrence results follow-
ing inadequate surgical removal, and operative mor-
Figure 44 Endolymphatic sac papillary tumor. This inner ear bidity may be high. Despite its relatively slow growth,
tumor localized to the petrous apex shows the appearance of a these neoplasms are capable of widespread infiltration
thyroid lesion, including variably sized cystic spaces contain and destruction, and they may be lethal (248). The
eosinophilic (colloid-like) material and nuclear alterations simu- prognosis is dependent on the extent of disease and
lating those seen in association with thyroid papillary carcinoma. the adequacy of the resection. Earlier detection when
Thyroglobulin and thyroid transcription factor 1 staining were the tumors are relatively small and confined may
negative (not shown). decrease the operative-associated morbidity, and it
may be curative.
D. Malignant Neoplasms of the External Ear BCCs may be inherited in the autosomal domi-
and Auditory Canal nant disorder called nevoid BCC syndrome caused by
mutations in patched (PTCH), a tumor suppressor
1. Basal Cell Carcinoma gene mapped to chromosome 9q22.3q31 (252,253). In
Clinical Features few cases, the syndrome is due to a microdeletion at
9q22 (254,255). The nevoid BCC syndrome includes
BCC is a slow growing, locally infiltrative malignant multiple BCCs most commonly involving the nose,
neoplasm of the skin and subcutaneous adnexal tis- mouth, eyes, and ear regions, occurrence in childhood,
sue. BCCs take origin from a pluripotential cell in association with palmar and plantar pitting, odonto-
either the basal cell layer of the surface epithelium or genic keratocysts of the jaws, skeletal developmental
the epithelium of the subcutaneous adnexae. abnormalities (bifid ribs, brachymetacarpalism, and
BCC represents the most common cutaneous vertebral anomalies), ectopic calcification in dermal
malignancy. BCC is more common in men than in and soft tissue sites, and neurological abnormalities
women; generally, a tumor affecting adults and is most (mental retardation).
commonly seen in the seventh decade of life. The sun-
exposed areas of the head and neck are the most Pathology
frequent sites of occurrence. BCC may occur in virtu-
ally all cutaneous sites of the head and neck but among See the chapter on diseases of the skin for a discussion
the more common locations include the nose, eyelids, of the pathology of BCCs.
nasolabial area, and the auricular area (pinna). In
general, BCCs are asymptomatic; presentation usually Differential Diagnosis
occurs because the patient notices a growth. BCCs of See the chapter on diseases of the skin for a discussion
the external auditory canal are uncommon (250). How- of the differential diagnosis of BCCs.
ever, when this area is involved, it typically has
extensive subcutaneous involvement, which may not Treatment and Prognosis
be clinically appreciated (250).
Initially, the lesion is a raised papule or nodule Complete surgical excision is the treatment of choice.
with a waxy or translucent appearance covered by a Electrodessication and irradiation may be used, the
fine capillary network (telangiectasia) (Fig. 45). With latter particularly in cases that cannot be completely
time, the central portion ulcerates and is surrounded excised. The prognosis is excellent following complete
by raised, pearly appearing borders, creating a typical excision. Local recurrence is not uncommon and is
papulonodular ulcerative lesion referred to as ‘‘rodent especially high in the morphea or sclerosing type of
ulcer’’ (Fig. 45). BCC. Metastases are rare except for neglected or long-
standing tumors, which attain large size and become
Etiology deeply and extensively infiltrative (256,257), as well as
in association with the basosquamous (metatypical)
The development of BCC is related to prolonged sun carcinoma, which for all intents and purposes behaves
exposure with resulting actinic damage (251). as an SCC, including metastatic rates seen in approxi-
mately 7% of patients (258,259). This form of BCC
requires a more aggressive surgical approach and a
closer follow-up than other types of BCCs. When metas-
tases occur, they usually spread to regional lymph
nodes and to the lungs; metastatic disease is associated
with poor prognosis irrespective of any therapeutic
intervention. BCCs of the external auditory canal are
notorious for extensive local invasion and extension to
the middle ear, mastoid region, temporal bone, and
potentially into the cranial cavity. For BCC of the exter-
nal auditory canal, radical surgical excision may be
necessary to eradicate tumors in this location (250).
2. Squamous Cell Carcinoma of the Ear,

Including the Pinna and External Auditory
Canal
Clinical Features
Figure 45 The clinical appearance of basal cell carcinoma of SCC accounts for approximately 25% of all SCCs of
the external ear may include (A) a raised papule or nodule on the the head and neck, and 15% of all primary cutaneous
helix as well as involving the concha of the ear and (B) ulcerated carcinomas of external ear and auditory canal (260).
lesion surrounded by raised borders, creating a papulonodular SCC of the external ear (i.e., auricular skin or
ulcerative (‘‘rodent ulcer’’) lesion on the cutaneous surface pinna) is more common in men than in women and is
behind the ear. Source: Images courtesy of Mark Persky, M.D. most frequently seen in the sixth to eighth decades of
life and presents as a nonhealing sore (261–263).
460 Wenig
SCCs of the external auditory canal are more servative (limited) local resection can be performed
common in women than in men, most frequently seen for small lesions limited in extent without osseous
in the sixth to seventh decades of life and present with invasion or invasion of the middle ear. Ogawa et al.
symptoms mimicking those of COM, including pain, (266) recommended radiotherapy in the treatment of
hearing deficits, and otorrhea (bloody or purulent) early (T1) lesions. For advanced (higher stage) SCCs,
(261,262). Suspicion for the presence of a malignancy more aggressive management is recommended,
should be considered in patients with chronic ear including radical surgical resection plus radiotherapy
infections who suddenly have a change in symptoms, and/or chemotherapy (263,266–269). Elective paroti-
including pain, bleeding, or facial paralysis. dectomy for control of occult parotid node metastasis
SCCs of the external ear often are polypoid, is necessary only in advanced SCC, whereas parotid
rubbery to firm nodules that frequently have ulcera- management to secure adequate safety margins is
tion (Fig. 46). Given difficulties in their visualization mandatory for advanced SCC (270).
due to location within the external auditory canal and For SCC of the external auditory canal, complete
concealment by purulent or hemorrhagic exudates, surgical excision is the treatment of choice; this often
the gross characteristics of external auditory canal requires a radical procedure (mastoidectomy or tem-
SCCs are not fully appreciated. Further, the extent of poral bone resection). Radiotherapy may be indicated
invasiveness may be underestimated on the basis of depending on the extent of disease. Prognosis is
the gross appearance, making radiological assessment considered poor. SCCs in this location often go unde-
imperative in determining the extent of disease. tected for long periods of time and often present with
advanced disease involving the mastoid and/or mid-
Radiology dle ear. In general, early detection and complete
removal result in good prognosis (263,266–269).
Radiological assessment is helpful in the diagnosis of Nakagawa et al. (269) reported a three-year estimated
SCC of the external auditory canal. In the face of lesion survival for T1 and T2 lesions to be 100% and a five-
that may appear to be limited to the canal belying its year estimated survival for T3 and T4 to be 80% and
invasive nature, radiological imaging (e.g., CT scan) 35%, respectively. Prognosis is dependent on the
accurately assesses the extent of the tumor (264,265). extent of disease (i.e., stage), completeness of surgery
Evidence of destruction of adjacent structures can be with tumor-free margins, recurrence, and metastasis
seen, including bone and other soft tissue structures, (263,266–269). Local recurrence may occur in up to
extension into the middle ear and growth into the 25% of patients and may correlate with tumor size
middle cranial fossa, mastoid, and soft tissues beneath (268). Owing to the low risk of nodal metastasis occur-
the temporal bone. ring in less than 20% of patients (260,265,271–273),
elective neck dissection is not advocated.
Pathology In a large study of SCCs of the skin by Rowe and
colleagues (268), several pathological factors were
See the chapter on diseases of the skin for a discussion linked to a propensity for local recurrence and metas-
of the pathology of SCCs. tases. These factors included a diameter greater
than 2 cm, a depth greater than 4 mm, poor differen-
Differential Diagnosis tiation, perineural invasion, development within a
Relative to external auditory canal SCCs, a key con- scar, previously treated squamous carcinoma in the
cern is differentiating SCC from SK, especially those site, and host immunosuppression. Death is generally
SKs that are inflamed. Histologically, the diagnostic attributed to invasion of regional structures, particu-
challenges in differentiation of SK from SCC may larly intracranial extension. Histological differentia-
directly relate to limited tissue sampling as well as tion does not correlate with prognosis.
the presence of cytological atypia in SK that are On the basis of clinical radiographic-histopatho-
irritated. The key differentiating feature is the absence logical correlation, a TNM staging system for external
(SK) or presence (SCC) of stromal invasion, which is auditory meatus carcinoma was proposed (Tables 8
not as simple to determine in practice as it is in theory. and 9) using preoperative CT and physical examina-
In equivocal cases, identification of lesion extent by tion (274). Arriaga et al. (274) found two-year deter-
radiological imaging may be the critical determinant minant survivals as follows: stage A, 100%; stage B,
in the diagnosis. Further, tissue sampling, including 50%; and stage C, 18%. Using the T system, Arriaga
deeper tissues, is recommended. Presumptively, if et al. (274) found mortality rates at two years to be as
tissue is sampled from deeper portions of the canal follows: T1 and T2, 0%; T3, 44%; and T4, 83%. More
and/or deeper to the lesion itself, then the presence of recently, Moody and colleagues (275) conducted a
squamous epithelium even with limited cytological review of the staging system proposed by the University
atypia likely represents well-differentiated SCC, as of Pittsburgh (274) for temporal bone cancer to
such epithelia should would not be expected to be evaluate survival status according to stage, treatment,
so located in the setting of SK. and other certain prognostic factors. On the basis of
T staging, these authors found that the two-year
survival rates for primary SCC of the temporal bone
were T1 lesions, 100%; T2, 80%; T3, 50%; and T4, 7%.
For SCC of the external ear, complete surgical excision Survival for T3 tumors was 75% with postoperative
is the treatment of choice and/or radiotherapy. Con- radiotherapy, compared with 0% with surgery alone.
Figure 46 (A–H) The spectrum of clinical appearances of squamous cell carcinoma of the external ear involving a variety of primary
sites on the pinna, as well as in the external auditory canal. Source: Images courtesy of Mark Persky, M.D.
462 Wenig
Table 8 TNM Staging of Squamous Cell Carcinoma of the

External Auditory Canal
Stage Definition
A Tumor limited to external auditory canal without erosion
B Tumor eroding the osseous external auditory canal or
involving the middle ear or mastoid, or both
C Tumor involving the cochlea, dura, medial wall of the
middle ear, petrous apex or surrounding soft tissue
Table 9 T Staging of Squamous Cell Carcinoma of the

External Auditory Canal
Stage Definition
T1 Tumor limited to external auditory canal without erosion
of bone or extension into soft tissue
T2 Tumor with limited bone erosion (not full thickness) of
the external auditory canal or radiographic evidence of
limited (<0.5 cm) of soft tissue involvement (includes
tumors extending through cartilaginous fissures or
bone-cartilaginous junction of the external auditory
canal
T3 Tumor eroding the osseous external auditory canal (full
thickness) with limited (<0.5 cm) of soft tissue
involvement or tumor involving the middle ear or
mastoid, or presentation with facial paralysis
T4 Tumor involving the cochlea, dura, medial wall of the
middle ear, petrous apex or surrounding soft tissue
They concluded that the two-year survival data

directly correlated with the staging system and that
the use of adjuvant radiotherapy increased survival
rate in patients with a T3 lesion (275).
3. Ceruminal Gland Adenocarcinoma

Clinical Features
Ceruminal gland adenocarcinoma is a malignant neo-
plasm of cerumen-secreting modified apocrine glands
(ceruminal glands) located in the external auditory
canal.
The demographics of ceruminal gland adenocar-
cinomas are similar to those of ceruminal gland ade-
nomas. In contrast to ceruminal gland adenoma,
patients with ceruminal gland adenocarcinomas
have associated pain more often (276,277).
Pathology
Microscopy. Histologically, features that may Figure 47 Ceruminal gland adenocarcinoma. (A) This external
assist in differentiating the ceruminal gland adenocar- auditory canal glandular lesion is extensively infiltrative with a
complex growth, including cribriform and solid patterns. (B) At
cinomas from the adenomas include a loss of the higher magnification, the glands are characterized by the pres-
glandular double cell layer, with identification of ence of cellular pleomorphism with nuclear anaplasia and by the
only the inner or luminal epithelial cell, the presence loss of the dual cell layers seen in ceruminal gland adenomas,
of cell pleomorphism with nuclear anaplasia, although on the outer aspects there is retention of apocrine type
increased mitotic activity, and invasive growth differentiation. (C) Perineural invasion and invasion of cartilage
(Fig. 47). However, well-differentiated ceruminal gland are present.
adenocarcinomas may appear similar to their benign
counterparts, and these are differentiated only on the
basis of invasive growth. At the other end of the addition to the more ‘‘conventional’’ type of cerumi-
spectrum, poorly differentiated ceruminal adenocarci- nal gland adenocarcinomas, other types of ceruminal
nomas do occur; these are recognized on the basis of gland malignant tumors include adenoid cystic carci-
their localization in the external auditory canal. In noma and mucoepidermoid carcinoma. These tumors
are morphologically identical to their salivary gland

counterparts.
Given the proximity of the parotid gland to the external
auditory canal, the differential diagnosis for ceruminal
gland adenoid cystic carcinoma and mucoepidermoid
carcinoma includes the direct extension of similar
tumors of primary parotid origin. Therefore, parotid
gland adenoid cystic carcinoma and mucoepidermoid
carcinoma should be excluded before such tumors are
diagnosed as being of primary ceruminal gland origin.
The same applies for ceruminal gland pleomorphic
adenoma. Wolf and associates (192) have also cautioned
about misdiagnosing a benign dermal eccrine cylin-
droma of the external auditory canal as an adenoid
cystic carcinoma.

Figure 48 Atypical fibroxanthoma (AFX) of the external ear
For ceruminal gland adenocarcinoma, en bloc surgical
appearing as a solitary, delineated polypoid mass.
resection is the treatment of choice. Middle ear or
temporal bone involvement necessitates more radical
surgery (276). Supplemental radiation therapy is rec-
ommended. Metastases are rare, and they include Etiology
regional lymph nodes and the lung (191,276). For
ceruminal gland adenoid cystic carcinoma and The etiology is related to actinic damage. The presence
mucoepidermoid carcinoma, wide surgical resection of p53 mutations supports the role of ultraviolet
with or without supplemental radiation therapy is the radiation damage in the development of AFX (279).
recommended treatment (277). The prognosis for cer- Therapeutic irradiation is also considered a predis-
uminal gland adenoid cystic carcinoma generally is posing factor in the development of AFX.
similar to its salivary gland counterpart, including Latent periods between radiation exposure and the
relatively good short-term survival (i.e., 5-year surviv- development of AFX being more than 10 years repre-
al) but poor long-term survival (i.e., 10- to 20-year sent an appropriate interval for a radiation-induced
survival) (276,277). neoplasm (278).
Pathology
4. Atypical Fibroxanthoma (Pleomorphic Gross. AFX of the ear presents as an asymptom-
Undifferentiated Sarcoma of Skin) atic, firm nodule measuring from 1 to 2 cm in diame-
Clinical Features ter, often associated with ulceration.
Microscopy. Histologically, AFX is an unencap-
Atypical fibroxanthoma (AFX) is a pleomorphic, pre- sulated, but generally circumscribed, spindle cell neo-
dominantly dermal mesenchymal tumor found primar- plasm arising in the dermis. The cellular component is
ily on actinic-damaged cutaneous sites of older patients varied, including a spectrum of elongated spindle-
or occasionally in younger patients involving the shaped to pleomorphic cells with hyperchromatic
superficial soft tissues of the extremities and trunk nuclei and bizarre multinucleated cells (Fig. 49). The
(278). Synonyms have included superficial (low larger cells may have foamy cytoplasm and are remi-
grade) MFH, pseudosarcoma of skin, and pseudosar- niscent of lipid-rich histiocytic cells. In some AFXs, a
comatous dermatofibroma. pleomorphic component may be absent and the
AFX occurs in two clinical forms, neither having tumors appear as a predominantly spindle cell, non-
a specific gender predilection. The most common pleomorphic lesion (280). Increased mitotic figures,
form, accounting for approximately 75% of cases, including atypical forms, are readily identified.
affects elderly patients and commonly involves the Areas may exhibit a storiform pattern, but this is not
head and neck (ears, cheeks, nose). A less common usually prominent. Junctional activity is absent.
form, accounting for approximately 25% of cases, Superficial areas adjacent to the tumor show solar
affects younger patients, commonly involving super- elastosis and vascular proliferation; prominent stro-
ficial sites on the limbs and trunk. However, more mal sclerosis may be present (281). A chronic inflam-
recently, the latter form of AFX is now thought to matory infiltrate may present. Vascular invasion may
represent atypical fibrous histiocytomas (278). AFX be seen, but necrosis is uncommon.
most often presents as an asymptomatic solitary Unusual variants include clear cell and granular
growth on the affected body site (Fig. 48). Patients cell (282,283). The clear cell variant of AFX is charac-
may complain of bleeding, pruritus, and pain. terized by sheets of large cells with foamy cytoplasms
464 Wenig
Immunohistochemistry is extremely valuable in

the differential diagnosis of AFX. In AFX, there is
variable staining for CD68 (KP1), muscle-specific
actin, and smooth muscle actin (286,287). CD99 reac-
tivity is present (288). No immunoreactivity is seen for
cytokeratins, S-100 protein (except for scattered non-
neoplastic dendritic cells), desmin, and melanoma
markers (e.g., HMB-45, Melan-A) (280,286,287). Aber-
rant HMB-45 and MART-1 (melanoma antigen recog-
nized by T cells-1) staining have been reported limited
to the large, multinucleated cells with vacuolated
cytoplasm (289). Ultrastructural studies have shown
evidence of fibrohistiocytic and myofibroblastic fea-
tures and, to a lesser extent, features of Langerhans’
cells (290). Features indicative of epithelial differenti-
ation (e.g., prominent intercellular bridges, tonofibrils)
or melanocytic differentiation (e.g., premelanosome,
melanosomes) are absent.
Deletions on chromosomes 9p and 13q have
been identified representing similar genetic alterations
as seen in undifferentiated high-grade pleomorphic
sarcoma, suggesting common pathogenetic pathway
(291). However, statistically significant differences of
genetic alterations between AFX and undifferentiated
high-grade pleomorphic sarcoma concerning dele-
tions on 1q, 3p, 5q, 11p, and 11q, gains on 7q and
12q, and high-level gains on 5p and 11q have been
found (291). In addition, the absence of H-ras and K-
ras mutations in AFX compared to undifferentiated
pleomorphic sarcoma (MFH) have been reported
(292). These genetic differences may contribute to
the different biological behavior of these two tumors.
Figure 49 Atypical fibroxanthoma (AFX) of the ear. (A) An

ulcerated, circumscribed cellular lesion is seen in the superficial
aspect of the auricular skin. (B) The cellular component includes The differential diagnosis of AFX includes spindle cell
markedly pleomorphic cells with hyperchromatic nuclei, bizarre squamous carcinoma and spindle cell malignant mela-
multinucleated cells, and increased mitotic figures, including noma. This distinction has been previously discussed
atypical mitoses. Cells with foamy-appearing cytoplasm that
above. AFX must be differentiated from leiomyosar-
are reminiscent of lipid-rich histiocytic cells are present.
coma. Immunohistochemical stains should allow the
pathologist to separate AFX from leiomyosarcoma,
with the latter tumor showing reactivity for desmin
and hyperchromatic, polypoid nuclei with frequent (289). The relationship of AFX to superficial MFH may
mitoses, including atypical mitoses (282). The clear be academic as both are associated with a good
cells express CD68 but not CD3, CD20, CD34, S-100 prognosis following complete surgical resection
protein, muscle-specific actin, factor XIIIa, Melan-A, (293). If a tumor has the histological features of AFX
carcinoembryonic antigen, or cytokeratin (282). Differ- but is large (>2 cm in diameter) and extensively
entiation from balloon cell melanoma, sebaceous car- infiltrative and has necrosis or vascular invasion,
cinoma, pleomorphic liposarcoma, chordoma, then it should be considered an MFH (278). This
parachordoma, tricholemmal carcinoma, and clear distinction is important as therapy for MFH includes
cell SCC depend on appropriate immunohistochemi- surgery with supplemental irradiation.
cal stains.
Multinucleated, ‘‘osteoclastic-like’’ giant cells as
well as osteoid may rarely be present (284). Uncom-
monly, pigmentation may occur. These lesions have Conservative but complete surgical excision is the
been termed ‘‘pigmented atypical fibroxanthoma’’ treatment of choice. The prognosis is excellent. Local
(285). Pigmented AFX can be easily mistaken for recurrence, which is uncommon, is related to incom-
malignant melanoma, clinically and histopathologi- plete excision. Recurrent tumors may present as a
cally. The pigmentation is felt to represent hemor- large mass in the deep soft tissue, and these neo-
rhage, with neoplastic cells ingesting and degrading plasms should be considered and treated as a bona
erythrocytes following intratumoral hemorrhage and fide MFH (278). AFX have been reported to metasta-
accumulation of hemosiderin in their cytoplasm; the size, but these cases may, in fact, represent MFH
pigment stains for iron. (278).
E. Malignant Neoplasms of the Middle Ear

1. Middle Ear Squamous Cell Carcinoma
Clinical Features
Middle ear SCC is a rare primary malignant neoplasm
with squamous differentiation that originates from the
middle ear mucosal epithelium.(294,293) Middle ear SCC
(ME-SCC) is most common in the sixth to seventh
decades of life. There is no gender predilection. The
majority of patients have a long history of COM, which
is usually longer than 20 years. Early symptoms include
pain with radiation to the scalp and face and hearing
impairment. Late symptoms include facial palsies and
vertigo. ME-SCC should be suspected in patients with
long-standing COM who suddenly present with pain out
of proportion to the clinical extent of disease and/or with
an onset or increase of otorrhea that is often hemorrhagic
and/or in those patients in whom clinical resolution
following therapeutic doses of antibiotics is lacking.
Etiology
The development of ME-SCC is also linked to radia-
tion treatment for intracranial neoplasms and radia-
tion therapy for middle ear inflammatory conditions,
although the latter is no longer used. High-risk human
papillomavirus types 16 and 18 identified in ME-SCC
raises HPV as a possible etiological factor, although a
direct cause and effect has not been established (295).
Although concomitant cholesteatomas can be seen in
up to 25% of cases, there is no correlation between
cholesteatomas and the development of an ME-SCC.
Pathology
Microscopy. The histology of ME-SCC is similar
to that of squamous carcinomas of other sites. The Figure 50 Squamous cell carcinoma of the middle ear. (A)
Infiltrative nests and cords of squamous epithelium is present in
tumors vary from well to poorly differentiated, and
association with histological findings of chronic otitis media,
they include infiltrative malignant cells with associated including dense inflammatory cell infiltrate, glandular metaplasia,
keratinization and/or intercellular bridges (Fig. 50). A and tympanoscleortic foci. (B) At higher magnification, their
background of COM, including chronic inflammation, nests are irregularly shaped with associated nuclear pleomor-
tympanosclerosis, glandular metaplasia, and fibrosis, phism and hyperchromasia and keratinization. The findings are
can be identified. those of a well-differentiated keratinizing squamous cell carcinoma
arising in the background of chronic otitis media.
The differential diagnosis includes cholesteatoma and
metastatic SCC. Cholesteatomas are characterized by Treatment and Prognosis
the presence of keratinizing squamous epithelium lack-
ing prominent rete pegs and an absence of dysplastic Radical surgery (i.e., radical mastoidectomy, temporal
cytological changes. In contrast, SCC (even well-differ- bone resection) with postoperative radiation therapy
entiated cancers) has dysplastic cytological changes, is the treatment of choice. In advanced disease, che-
increased mitotic activity, and possibly dyskeratotic motherapy may be beneficial. The prognosis has gen-
cells. Further, in adequately sampled tissue, an infiltra- erally been poor with 5- and 10-year survival rates of
tive growth with associated desmoplasia and scattered 39% and 21%, respectively (294). More recently,
irregular shaped nests of squamous epithelium is a Moore et al. (296) reported a five-year overall survival
growth pattern not seen in cholesteatomas. (OS), disease-specific survival (DSS), and disease-free
Metastatic SCC from a distant site must also be survival (DFS) of 77%, 79%, and 52%, respectively.
considered. Alternatively, a cutaneous SCC from an These authors found that upfront complete resection
adjacent site (e.g., external ear, nasopharynx, parotid (i.e., lateral temporal bone resection) when combined
gland, skin) can directly invade the middle ear or with postoperative radiation therapy may improve
temporal bone. These possibilities must be excluded survival and decrease recurrence. They reported an
before accepting an SCC as primary in the middle ear. improved OS, DSS, and DFS (p < 0.004 for each) and
466 Wenig
reduced local recurrence (p < 0.001). While combined Pathology

radical surgery and radiotherapy are the preferred
treatment modalities for ME-SCC, Pemberton et al. Gross. Variation in appearance ranges from
(297) reported that radical radiotherapy (55 Gy in 20 gray-white to red-brown, rubbery to firm, and spongy
daily fractions) alone achieves comparable results in to cystic. The neoplasm may attain large sizes filling
terms of local control and cancer-specific survival and the middle ear space and encasing the ossicles.
is a viable option in the treatment of ME-SCC. Meta- Microscopy. Histologically, middle ear adenocar-
stastic disease from ME-SCC may occur, but is con- cinomas are similar in many respects to MEAs. Like
sidered uncommon. MEAs, adenocarcinomas are unencapsulated glandular
lesions in which there is a diffuse glandular prolifera-
tion, including complex gland-in-gland (cribriform)
2. Middle Ear Adenocarcinoma growth. Typically, mucocytes are not identified. In
contrast to adenomas, adenocarcinomas show the pres-
Clinical Features ence of marked nuclear pleomorphism with increased
Middle ear adenocarcinomas are extremely rare mitotic activity and infiltrative growth (Fig. 51). The
malignant glandular neoplasms arising from the mid- latter includes invasion of soft tissue structures with
dle ear mucosa (298). Middle ear adenocarcinomas perineural and perivascular invasion, and invasion of
have no gender predilection and occur over a wide bone. A papillary and cystic variant (papillary cysta-
age range between the second to sixth decades of life. denocarcinoma) lined by cells with hyperchromatic
Symptoms are typically present for many years and nuclei and vacuolated cytoplasm can be identified.
include progressive hearing loss and a unilateral Histochemical stains for epithelial mucin show
draining ear; pain and vestibular manifestations are the presence of intraluminal but not intracytoplasmic
uncommon. Otoscopic examination in the majority of mucin-positive material. Lesional cells are immunore-
cases will identify an intact tympanic membrane with active for cytokeratins and epithelial membrane
tumor confined to the middle ear space with possible antigen. Immunoreactivity is not identified for neuro-
extension to the mastoid; occasionally, and similar to endocrine markers, for organ-specific markers,
the MEA, the adenocarcinoma will perforate through and/or for markers reactive in other adenocarcinomas
the tympanic membrane with extension into and as might be seen in metastatic carcinomas such as
presentation as an external auditory canal mass. those of thyroid origin (thyroglobulin and TTF-1),
Middle ear adenocarcinomas may attain a large prostate origin (prostate-specific antigen and prostatic
size, filling the middle ear space and encasing the acid phosphatase), renal origin (renal cell marker and
ossicles. CD10), and breast origin (BRST-2).
Etiology Differential Diagnosis

The etiology for middle ear adenocarcinoma is The differential diagnosis includes MEA and meta-
unknown. There is no association between COM and static adenocarcinoma. Differentiation from MEA is
the development of these adenocarcinomas. based on light microscopical features (see above).
Figure 51 Middle ear adenocarcinoma. (A) Infiltrating

glandular neoplasm showing complex growth pattern
(left). (B) At higher magnification, the tumor complexity
of growth is evident, including cribriform or back-to-back
pattern with cellular pleomorphism.
Before rendering a diagnosis of primary middle

ear adenocarcinoma, a metastasis to this region from a
separate primary adenocarcinoma should be excluded.
Metastases to the middle ear and temporal bone can be
seen from virtually all sites but are most common from
the breast, lungs, and kidneys. Clinical history and
immunohistochemical staining should allow for this
differentiaion.

Complete surgical excision is the treatment of choice.
In general, these are slow-growing neoplasms that are
locally aggressive but do not metastasize. Death may
occur as a result of direct intracranial extension (298).
3. Other Malignant Tumors of the Middle Ear

and Temporal Bone
While uncommon, a number of other malignant
tumors can originate in the middle ear or temporal
bone. These tumors are primarily of mesenchymal
origin, including matrix forming such as osteosarcoma
and chondrosarcoma. Osteosarcomas of the skull,
including the temporal bone, are uncommon with
only approximately 1% to 2% of all osteosarcomas
occurring in this location (299). In this setting, osteo-
sarcomas often arise in the setting of Paget disease of
bone, fibrous dysplasia, or secondary to radiotherapy
(299). Osteosarcomas of the skull are aggressive
tumors with a tendency to metastasize to the lungs
and brain and with a five-year survival of less than
15% (300,301). Chondrosarcomas of the temporal bone
are rare. The petrous apex and posteromedial aspect Figure 52 Metastastic disease to the ear and temporal bone
of the temporal bone are perhaps the most common may include (A) prostatic adenocarcinoma (confirmed immuno-
sites of occurrence (302). Chondrosarcomas of the reactivity with prostate markers, not shown) and (B) renal cell
temporal bone are not necessarily lethal tumors as carcinoma (confirmed immunoreactivity with CD10 and renal cell
with one study reporting 76% DFS over periods marker, not shown). In both examples, the primary carcinoma
ranging up to eight years (302). was not known, but once the diagnosis was suggested on the
Other malignancies of the middle ear and tem- basis of light microscopic and immunohistochemical findings
associated with the temporal bone lesions, respective primary
poral bones include hematolymphoid lesions, includ-
carcinomas in the prostate and kidney were found.
ing malignant lymphomas (non-Hodgkins and
Hodgkins), leukemia, and plasma cell dyscrasias
(303). Middle ear and temporal bone involvement by
a malignant hematolymphoid neoplasm often is sec-
ondary to primary disease elsewhere.
nearby primary tumor (e.g., SCC), meningeal carcino-
matosis, or leptomeningeal extension from an intra-
4. Metastatic Tumors to the Middle Ear and cranial primary neoplasm.
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10
Diseases of the Salivary Glands
John Wallace Eveson

Department of Oral and Dental Science, Bristol Dental Hospital and School, Bristol, U.K.
Toshitaka Nagao
Department of Diagnostic Pathology, Tokyo Medical University, Tokyo, Japan
I. ANATOMY variable in morphology and are inconspicuous in

hematoxylin and eosin–stained sections. Myoepithelial
Salivary glands are tubulo-acinar exocrine organs cells can be visualized with varying degrees of speci-
responsible for the production and secretion of saliva. ficity by immunohistochemical staining for a wide
They comprise the three-paired major glands, the range of antigens including S-100 protein, calponin,
parotid, submandibular, and sublingual. There are smooth muscle actin, smooth muscle myosin heavy
also several hundred minor glands, which are widely chain (5–7) cytokeratin 14 (8), glial fibrillary acidic
distributed throughout the oral and oropharyngeal protein (9), h-caldesmon (10), maspin (11), metallothio-
submucosa and, in some cases, the underlying muscle. nein (12), and p63 (13). Although not specific, staining
Similar seromucous glands are present in the upper for p63, which is nuclear, is one of the most useful
respiratory and sinonasal tracts. markers of myoepithelial cells in both normal and
The functional unit of salivary glands is the neoplastic tissue. Staining with myoid markers and
secretory acinus and related ducts and myoepithelial cytokeratin 14 highlights the stellate shape of the
cells (Fig. 1A). Acini may be serous, mucous, or myoepithelial cells (Fig. 1C). They have long dendritic
mixed. Serous acini form wedge-shaped secretory processes that embrace the secretory acini. Myoepi-
cells with basal nuclei. They surround a lumen that thelial cells also surround the intercalated ducts.
becomes the origin of the intercalated duct. The cyto- Although cells in the abluminal layer of the striated
plasm of serous cells contains densely basophilic, ducts can be highlighted by ‘‘myoepithelial markers,’’
refractile zymogen granules that are periodic acid– such as cytokeratin 14, the presence of true myoepi-
Schiff (PAS) positive and diastase resistant. Their thelial cells in this location is not firmly established.
principal secretion is amylase. Mucous acinar cells Ultrastructurally, the cytoplasm of typical myoepithe-
also have basally placed nuclei, and their cytoplasm lial cells contains actomyosin microfilaments running
is clear and contains vacuoles of sialomucin (Fig. 1B). parallel with the outer surface of the cell, glycogen
The secretions of these cells pass through the interca- granules and lipofuscin, and pinocytotic vesicles may
lated ducts. These are often inconspicuous in routine also be a conspicuous feature. Cells with these ultra-
histologic sections. They are lined by a single layer of structural features are not seen in the striated ducts.
cuboidal cells with relatively large, central nuclei. The parotid gland is almost purely serous and
They are continuous with the much larger striated the parenchyma is divided into lobules by fibrous
ducts. These are lined by tall, columnar, eosinophilic septa. There is abundant intralobular and extralobular
cells that are rich in mitochondria. They have parallel adipose tissue, which increases in relative volume
infoldings of the basal cytoplasm and are responsible with age. In addition, the parotid gland contains
for modifying the salivary secretions. The striated lymphoid tissue in the form of about 3 to 24 lymph
ducts join the interlobular and excretory ducts. nodes and less structured lymphoid aggregates (14).
These are lined by pseudostratified columnar epithe- The lymph nodes often contain salivary gland ducts or
lium, which often contains scattered mucous cells. occasionally acini (Neisse Nicholson rests). Sebaceous
Luminal ductal cells are immunohistochemically pos- glands, either individually or in small groups, are
itive for cytokeratins by CAM5.2 (1) and AE1/AE3, frequently seen in the parotid if the tissue is widely
cytokeratin 1 (2), epithelial membrane antigen (3), and sampled (*40%) (Fig. 1D) (15). The presence of mel-
carcinoembryonic antigen (4). anocytes has been reported in a single case (16). The
Myoepithelial, or basket cells, are contractile and submandibular gland is mixed serous and mucous,
are located between the basement membrane and the although the serous element predominates (*90%). In
basal plasma membrane of the acinar cells. They are mixed acini, the serous cells form caps, or demilunes,
476 Eveson and Nagao
Figure 1 (A) Parotid gland showing purely serous acinar cells and conspicuous striated ducts. (B) Submandibular gland showing serous
acinar cells forming demilunes over the mucous acinar cells. (C) Dendritic myoepithelial cells. Cytokeratin 14 stain. (D) Sebaceous gland
in parotid gland.
on the periphery of the mucous cells. The intercalated the tongue especially can be deeply located in the
ducts are shorter and the striated ducts more conspic- underlying muscle.
uous than those of the parotid gland. Sebaceous cells
are seen much less frequently in this gland (*5%)
(15). The sublingual gland is predominantly mucous II. NONNEOPLASTIC DISORDERS
in type. The mucous acini form elongated tubules
with peripheral seromucous demilunes. Sebaceous A. Developmental Defects
glands are only occasionally seen (*4%) (15). Aplasia, Hypoplasia, Atresia
Minor salivary glands are most numerous at the
junction of the hard and soft palate, lips, buccal Congenital aplasia of salivary glands, particularly the
mucosa, tongue, floor of the mouth, and retromolar parotid gland, is very rare (1). It may be associated
pad. They are present on the lateral aspects of the with other developmental abnormalities of the head
tongue, particularly in relation to the foliate papillae. and neck, especially those involving the first branchial
In addition, minor glands are present in the ventral arch. These include the lacrimo-auriculo-dento-digital
surface (glands of Blandin and Nuhn). These are (LADD) syndrome and aplasia of the lacrimal and
typically located toward the midline and extend salivary glands (ALSG), both of which appear to be
from the insertion of the tongue into the floor of the caused by FGF10 mutations (2). An association
mouth to the tip. Glands in the lips and buccal mucosa between salivary gland aplasia and ectodermal dyspla-
are seromucous, whereas those in the ventral tongue, sia has also been described (3). Aplasia may be unilat-
palate, glossopharyngeal area, and retromolar pad are eral or bilateral and can cause severe xerostomia,
predominantly mucous. Minor glands opening into candidosis, and accelerated dental caries. Hypoplasia
the groove surrounding the circumvallate papillae of one or more glands may be less uncommon than
(von Ebner’s glands) are purely serous in type. previously considered, as cases are usually asymptom-
The minor glands are not encapsulated, and those in atic and are sometimes detected fortuitously in
Chapter 10: Diseases of the Salivary Glands 477
These are termed ‘‘Neisse Nicholson rests,’’ and they

may be important in the pathogenesis of Warthin’s
tumor and lymphoepithelial cysts (LECs). Heterotopic
salivary tissue in other sites, however, is rare, and
most cases involve the lower neck and middle ear.
However, occasional examples have been described in
a very wide range of sites, including the mandible and
maxilla (3), gingiva (4,5), external auditory meatus (6),
upper neck (7), thyroid and parathyroid gland and
capsule (7–9), thyroglossal duct cyst (1), cerebellopon-
tine angle (10), pituitary gland (11), mediastinum (12),
stomach (1), skin (13), prostate gland (14), vulva (15),
and rectum (16). The accessory salivary gland tissue
that lies along the ducts of the major salivary glands,
particularly the parotid, is considered to be a variation
of normal anatomy rather than heterotopia (17,18).
Heterotopic salivary glands in the lower neck. Het-
erotopic salivary tissue in the lower neck is uncom-
mon (19–21). Lesions typically present in the
Figure 2 Magnetic resonance imaging scan showing a patient anterolateral border of the sternocleidomastoid mus-
with an enlarged parotid gland due to sialosis and hypoplasia of cle, usually close to the manubriosternal joint. They
the contralateral gland. are frequently noticed shortly after birth but some
cases may not present until much later in life. There is
a single case report showing a familial association
magnetic resonance imaging (MRI) scans (Fig. 2). Rare (22). Most cases are unilateral, and there is a predilec-
cases of salivary gland duplication have also been tion for the right neck. Rare, bilateral cases have also
reported (4). Ductal atresia is also uncommon and been reported. Some cases may be associated with a
affects Wharton’s duct most frequently (5). In that branchial cleft remnant on the contralateral side (2,21).
site, it may cause cystic swellings in the floor of the The typical clinical presentation is the presence of a
mouth (6). small sinus that may emanate from a cutaneous nod-
ule. The sinus intermittently exudes small quantities
Heterotopia of mucoid or watery, saliva-like fluid, particularly
during meals.
Salivary gland tissue in sites other than its normal Grossly, the sinus is usually less than 2 cm in
distribution is variously described as ectopic, hetero- length, and it communicates with a nodular or lobu-
topic, or salivary gland choristoma (1). It is very lated, gray-to-yellow mass that resembles normal sali-
common to see salivary ductal and acinar inclusions vary tissue (1). Microscopically, the tissue usually
in the intra- and paraparotid lymph nodes (Fig. 3) (2). consists predominantly of anatomically normal
mixed mucous and serous salivary acini, although
occasionally it is purely serous. The salivary acini
are surrounded by myoepithelial cells (21). There
can be chronic inflammation and interstial fibrosis
due to extravasated mucus, and the associated ducts
may show ectasia or squamous metaplasia. Occasion-
ally there is cystic change (21). Very rarely, pleomor-
phic adenomas have developed in this tissue (23,24).
The embryologic origin of this heterotopic sali-
vary tissue in the lower neck is contentious. In the
branchiogenic theory, it is proposed that the tissue
arises from the precervical sinus of His within the
branchial arch system (19). This theory is supported
by the anatomic location, congenital presentation,
right-sided predilection with occasional bilateral
cases, and the presence of predominantly mucous or
mixed salivary acini (17,20,25). An alternative pro-
posed origin is from a residue of the vagus nerve
placodal duct (26,27).
Heterotopic salivary glands in the middle ear. Het-
erotopic salivary tissue in the middle ear is frequently
termed salivary gland choristoma. It is rare, and
Figure 3 Intraparotid lymph node containing heterotopic sali- since it was first described by Taylor and Martin in
vary ducts and acini (Neisse Nicholson rests). 1961 (28), less than 30 cases have been reported
(29–35). They present in a wide age range (1–52 years)
with a mean of about 17 years (32). There is a female predominantly mucous salivary tissue that is usually
predominance of approximately 2:1. In addition, there is in continuity with the adjacent sublingual gland.
a striking left-sided prevalence. The most common Heterotopic salivary gland tissue elsewhere in the
presenting features are unilateral conductive hearing jaws, particularly within marrow spaces, has rarely
loss, otorrhea, and tinnitus. There is frequent ossicular been reported. In a study of 5034 marrow samples,
deformity or absence, mainly affecting the incus and 13 cases (0.3%) contained heterotopic salivary tissue (3).
stapes, and abnormalities in the horizontal portion of An additional four cases were found in the condyle.
the facial nerve, which may show dehiscence. Less Sampling limitations in such a study mean that the true
common associated abnormalities include absence of frequency of intraosseous heterotopic salivary tissue is
the oval window, cholesteatomas (36), and malforma- likely to be much higher. Although uncommon and
tions of the external ear (36,37). typically symptomless, intrabony heterotopic salivary
Macroscopically, the lesion forms a smooth or tissue may be the source of primary intraosseous
bosselated, gray-to-yellow mass (1). It usually lies (central) salivary gland tumors (3). [See the section
against, or close to, the facial nerve, which can make ‘‘Intraosseous (Central) Tumors.’’]
surgical excision challenging. Microscopically, it is
composed of mixed mucous and serous acini and Polycystic (Dysgenetic) Disease
adipose tissue and variably present excretory ducts.
The tissue is usually covered by normal respiratory This is a very rare condition of developmental origin
type mucosa. Even incomplete excision is not associ- characterized by the formation of multiple cysts, usu-
ated with recurrence (31). Rare pleomorphic adeno- ally in one or both parotid glands (1–4). A single case
mas reported in the middle ear may have arisen from has been reported bilaterally in the submandibular
this tissue (38,39). glands (5). Most patients (90%) are female, and there
The pathogenesis of middle ear salivary chori- are two case reports of a familial association (1,4),
stoma has been linked with anomalous development suggesting an autosomal dominant mode of transmis-
of the first and second branchial arches before the sion. Symptoms typically begin in childhood and
fourth month of intrauterine development (40–43). include recurrent, painless parotid gland swellings
Primordial salivary tissue becomes enclosed within at mealtimes. There is no associated clinical abnormal-
the temporal bone and then grows within the middle ity of salivation.
ear until somatic growth ceases (37). Microscopy shows preservation of the lobular
Intraosseous heterotopic salivary gland tissue. Sali- architecture, but the salivary parenchyma is extensive-
vary gland tissue is occasionally present within the ly replaced by a honeycomb of cysts of varying sizes.
mandible, and more rarely, the maxilla. The most These appear to be derived from the intercalated
common location is in the medial aspect of the man- ducts. Between the cysts, there is residual parenchy-
dible, anterior to the angle and below the mylohyoid ma, excretory ducts, and interlobular septa. The cysts
line. An extension of the submandibular gland are lined mainly by cytologically bland cuboidal or
becomes partially incarcerated in a bony invagination. more flattened cells. Some lining cells may be onco-
Less commonly, the defect contains only fat and cytic or vacuolated, and there may be luminal apo-
fibrous tissue. This is symptomless and is usually crine blebbing. Foci of mural thickening can give a
detected fortuitously during radiographic investiga- pseudopapillary appearance. Some cysts show nar-
tions and a radiographic frequency of 0.48% has been rowing, producing an hourglass shape (Fig. 4). Incom-
reported (44). It appears as a sharply demarcated, plete septa extending into the cystic lumina are
cyst-like, radiolucent area with a corticated periphery another characteristic appearance (Fig. 5). The cyst
and is known as a Stafne or static bone cavity (45–48). lining may fuse with striated ducts or distended
These defects are seen much more frequently in men acini. The cysts may contain amorphous eosinophilic
(over 80%) and are typically discovered in the fifth and material or concentrically laminated spheroliths.
sixth decades. The pathogenesis of these lingual man- There is usually no inflammatory component.
dibular bone defects is uncertain. It has been suggested The microscopic differential diagnosis includes
that part of the submandibular gland becomes sclerosing polycystic adenosis, cystadenoma, and cys-
entrapped within the mandible during development tadenocarcinoma. The generalized nature of polycys-
(49). However, this does not explain the age distribu- tic (dysgenetic) disease, the clinical history, and
tion of the patients. An alternative theory is that a lobe characteristic microscopic features mean that making
of the submandibular gland becomes hyperplastic and a definitive diagnosis is unlikely to be problematic.
produces pressure atrophy of the adjacent mandible The condition is benign, and treatment need only
(50). Analogous defects are seen much less frequently be used for cosmetic reasons.
in the lingual aspect of the anterior mandible (51,52).
These also typically manifest in middle life with an
unexplained 80% male predominance. They mostly Cystic Fibrosis (Mucoviscidosis)
present as unilateral radiolucent areas below or cover- Cystic fibrosis is a life-threatening disease that is
ing the roots of the canine or premolar teeth and can inherited as an autosomal recessive trait. It involves
mimic a radicular cyst (53). A small number form most exocrine, mucous-secreting glands including the
midline radiolucencies associated with the incisor salivary glands. There is secretion of abnormally viscid
teeth. There is a bony depression containing mucus that produces duct obstruction and consequent
Figure 4 Polycystic (dysgenetic) disease showing parotid Figure 6 Mucoviscidosis. Minor salivary gland biopsy shows
tissue extensively replaced by multiple cysts, some of which ductal dilatation, eosinophilic plugs, and acinar atrophy.
show central constrictions (hourglass shape). In addition there
are concentrically laminated spheroliths.
Sebaceous Glands
Sebaceous differentiation is common in normal major
parenchymal atrophy. The submandibular, sublin- salivary glands, with an incidence of 10% to 42% in
gual, and minor salivary glands may be involved, parotid glands, 5% to 6.4% in submandibular glands,
but the purely serous parotid gland is rarely, if ever, and 4.2% of sublingual glands (1–3). The higher inci-
affected (1). The sublingual gland is the most severely dence of sebaceous elements in the parotid gland has
affected, but most histologic studies have been under- been related to its origin from ectoderm compared
taken on minor labial glands where the changes are with the probable endodermal origin of the subman-
extremely variable and many glands appear normal dibular and sublingual glands (1). The frequency of
(2–4). There is occlusion of the dilated ducts and sebaceous foci varies with age with bimodal peaks
glandular acini by inspissated, eosinophilic material, between the ages of 10 and 20 years and individuals
which may be concentrically laminated (Fig. 6). Some over 70 years of age (2,4,5). There is no sex predilec-
of the ducts, especially in the sublingual gland, contain tion. Sebaceous cells may appear as isolated cells in
microliths consisting of mucoprotein and calcium the walls of intercalated or striated ducts or form
complexes. There is chronic inflammation and inter- recognizable sebaceous glands that are connected to
stitial fibrosis, together with acinar atrophy. Despite these intralobular ducts (Fig. 7). Cells at the periphery
the sometimes striking histologic changes in these of the gland are flattened and have round or oval
glands, oral symptoms are uncommon and mild. nuclei, and central cells have abundant, vacuolated
cytoplasm, rich in lipids, and irregular or pyknotic
nuclei (1). The holocrine secretion eventually
Figure 5 Polycystic (dysgenetic) disease showing incomplete

septa extending into the cysts, and residual salivary acini. Figure 7 Sebaceous cells in submandibular gland.
discharges into the duct and is mixed with saliva.

Sebaceous foci have been described in chronic siala-
denitis and in salivary gland tissue adjacent to sali-
vary tumors, but this association is probably
coincidental. The increased frequency of sebaceous
glands during and after puberty may result from
hormonal factors (3); however, the functional signifi-
cance of these sebaceous elements is not known.
B. Salivary Gland Cysts

Mucoceles
Mucoceles are the most common cystic lesions of
salivary glands, and almost all form in the minor
glands. The main types are extravasation, retention,
and superficial.
Extravasation mucoceles account for the large
majority of mucoceles (*90%). They are seen most Figure 8 Extravasation mucocele showing cyst lined by cellular
frequently in children and young adults. Although fibrous tissue and macrophages (muciphages) with adjacent
minor salivary gland.
they are considered to be caused by trauma to a gland
or an excretory duct with escape of salivary secretions
into the surrounding tissues, only a minority of
patients can recall a traumatic episode. It has recently
been suggested that rupture of adjacent lymphatic
vessels may play a role in the pathogenesis (1). The
most frequent site is the lower lip (*50%). Other
common sites include the buccal mucosa, floor of the
mouth and ventrum of the tongue (glands of Blandin
and Nuhn), and palate and buccal mucosa (2). They
occasionally present in the retromolar pad and gingi-
va. Mucoceles usually present as a bluish, domed
swelling, which rarely exceeds 1 cm in diameter
except in the floor of the mouth. The cysts may
fluctuate in size, and in some cases, there is spontane-
ous regression due to progressive scarring of the
affected gland. Mucoceles in the floor of the mouth
are termed ‘‘ranulae’’ and can be several centimeters
in diameter. The peak incidence of extravasation
mucoceles is in the second and third decades, and
occasional cases are multiple (3).
Figure 9 Extravasation mucocele: higher power showing com-
In the early stages of development, microscopy pressed fibrous tissue, and mucocytes in the wall and floating
shows ill-defined pools of mucus and acute inflamma- freely in the cyst cavity.
tion. Occasionally, a portion of damaged excretory duct
is visible. A central cavity becomes more defined, and
the cyst becomes lined by granulation tissue, which
undergoes progressive fibrosis (Fig. 8). The cyst eventu- Mucous retention cysts are relatively uncommon
ally becomes lined by compressed macrophages, many and are usually seen in older individuals (4). The
containing abundant mucus (muciphages), and similar cause is uncertain but may be related to intermittent
cells can be seen floating freely in the cyst cavity duct obstruction. They form unicystic cavities that are
(Fig. 9). In developing mucoceles, the true character lined by modified duct epithelium, which may be
of the process may not be immediately apparent unless cuboidal or columnar and occasionally shows squa-
muciphages are identified, either as foamy macro- mous or mucous metaplasia (Fig. 10) (4). Rarely there
phages in hematoxylin and eosin–stained sections or is oncocytic metaplasia (5).
by histochemical stains. Treatment is by excision of the Some mucoceles are located immediately below
cyst and related salivary gland or by cryosurgery. the epithelium and raise a small blister (6). These
Cysts in the tongue, especially, have a significant are known as superficial or subepithelial mucoceles
tendency to recur, probably because the associated (Fig. 11). They are seen most frequently in the region
minor glands are mainly located deeply within the of the palatoglossal fold, but they can be found
lingual musculature. Mucoceles in the upper lip are elsewhere in the mouth, including the gingiva. They
uncommon (*5%), and the possibility of a cystic are often multiple and appear to be much more
salivary gland neoplasm should always be considered common in women rather than men. Cases have
when examining cystic lesions from this site. been reported in association with lichen planus and
Figure 10 Retention mucocele lined by attenuated

epithelium.
graft-versus-host disease (7,8). In clinical practice, Microscopically, they usually have a patchily inflamed,
these lesions are not uncommon. Because they form thick, fibrous wall lined by stratified squamous,
subepithelial blisters, they are sometimes confused columnar, or cuboidal epithelium (Fig. 12). There
with mucocutaneous vesiculating disorders, especial- may be focal mucous or oncocytic metaplasia. Occa-
ly mucous membrane pemphigoid and bullous lichen sionally, there is partial calcification of the cyst con-
planus, both clinically and microscopically. tents, and granulomatous inflammation may be
present in the cyst wall and adjacent gland. Complete
surgical excision is curative.
Salivary Duct Cyst
Salivary duct cysts (sialocysts) are a rare type of reten- Lymphoepithelial Cyst
tion cyst seen in the major salivary glands, particularly
the parotid (9). They may be associated with an obvi- Lymphoepithelial cysts (LECs) are uncommon, and
ous duct obstruction, and occasionally, the cyst itself most arise in the parotid gland although microscopi-
leads to obstructive symptoms. There is no sex predi- cally similar lesions have been described in the ante-
lection, and most patients are in their fourth decade or rior floor of the mouth (10,11).
older. The cyst usually presents as a unilocular, pain- The proposed origin of these cysts from the
less swelling that rarely exceeds 3 cm in diameter. branchial arch system (12) has been disputed and an
Figure 11 Superficial mucocele. There is a subepithelial blister Figure 12 Salivary duct cyst. Low-power view showing a thick,
with overlying attenuated epithelium. The duct of a minor salivary fibrous-walled cyst lined by a double-layered columnar
gland is visible under the floor of the blister. epithelium.
Figure 13 Lymphoepithelial cyst lined by irregular stratified Figure 14 Obstructive sialadenitis with acinar atrophy, interstial
squamous epithelium with a dense lymphoid infiltrate in the fibrosis and extensive fatty infiltration.
cyst wall.
origin from Neisse Nicholson rests appears to be more cells are characterized by abundant granular and
likely (13,14). They resemble salivary duct cysts in brightly eosinophilic cytoplasm, which contains
clinical presentation, and the average age of patients is increased numbers of mitochondria. The nuclei are
45 years. Microscopy shows an epithelial-lined cyst typically round and centrally placed, and the nucleoli
with dense lymphoid aggregates containing promi- are usually single and conspicuous. The cells are
nent germinal centers in the cyst wall (Fig. 13). The generally cuboidal or polygonal, and there is a low
epithelial lining is usually stratified squamous, but nuclear-cytoplasmic ratio. In contrast to this type of
there may be focal areas of cuboidal or respiratory- ‘‘light’’ form of oncocytic cell, some oncocytes have
type epithelium, and both mucous and sebaceous more intensely staining, eosinophilic cytoplasm and
metaplasia have been reported (15,16). densely basophilic, shrunken nuclei. These are termed
‘‘dark’’ cells, or pyknocytes; they are probably a
degenerative form of the light cell. Oncocytic cyto-
C. Infiltrations plasmic granules stain positively with phosphotungs-
Lipomatosis tic acid hematoxylin after 48 hours incubation. The
mitochondrial nature of the granules has been con-
Fat is a normal but highly variable component of the firmed by staining with antimitochondrial antibodies
parotid gland and, to a much lesser extent, the sub- (2) and electron microscopy (3). It has been speculated
mandibular, sublingual, and minor salivary glands. that oncocytosis and oncocytic neoplasia are the result
The fat content appears to increase with age, in obese of progressively acquired mitochondriopathies due to
individuals and those with diabetes. The fat is distrib- mtDNA errors (4).
uted interstially and separates the salivary parenchyma. Focal and diffuse oncocytosis. Focal oncocytosis of
There may be fatty infiltration and replacement of ducts, and less commonly acini, is common in both
atrophic parenchyma for any cause, but this is most major and minor salivary glands with increasing age
commonly seen in chronic obstructive sialadenitis (Fig. 15A). It is rare in patients younger than 50 years,
(Fig. 14). Increased fat deposition has also been common in patients between 50 and 70 years and
reported in Sjögren’s syndrome using in vivo techni- virtually always present in older individuals (5,6).
ques (1). Occasionally, almost the whole of the parotid Diffuse oncocytosis of the parotid gland, however, is
or submandibular gland is replaced by fat (lipomatous rare and may be bilateral (Fig. 15B) (7–10). The entire
salivary atrophy). Seifert (2) described a case of lipo- gland, including both ducts and acini, can be
matous parotid atrophy in a child with lipomatous involved. There are both light and dark oncocytic
pancreatic atrophy and speculated on an association cells. This condition affects elderly patients and
with coxsackie B virus. Some cases in infants have may be associated with fatty infiltration and acinar
been rapidly progressive (3). A case of salivary lip- atrophy (11).
omatosis has also been reported in a minor gland (4). Ductal oncocytosis. There may be extensive ductal
oncocytosis with associated dilatation in minor
glands, particularly in the larynx (Fig. 15C) (see Chap-
Oncocytic Lesions
ter 3). This is less common in the oral cavity, where the
Introduction. The term ‘‘oncocyte,’’ which is floor of the mouth is the usual location. It usually
derived from the Greek word oukoustai meaning ‘‘to presents clinically as a small, painless mass. Micros-
swell,’’ was first coined by Hamperl in 1931 (1). These copy shows unilocular or multilocular dilated ducts
Figure 15 (A) Focal oncocytosis. (B) Diffuse oncocytosis involving the entire parotid gland and showing characteristic light and dark
cells. (C) Ductal oncocytosis and hyperplasia in minor salivary gland. (D) Multifocal nodular oncocytic hyperplasia that gives an
erroneous impression of invasion of surrounding salivary parenchyma.
lined by cytologically bland, oncocytic, and columnar

epithelium. There may be luminal papillary
ingrowths. The lesions are not encapsulated and can
be multifocal. There is often a stromal chronic inflam-
matory component, and in some cases, this can result
in a Warthin-like appearance of the lesion.
Multifocal nodular oncocytic hyperplasia. Multifocal
nodular oncocytic hyperplasia (MNOH) is a rare
condition that is characterized by the presence of
multiple nodules of oncocytic cells (11,12). The nod-
ules have a lobular distribution, and at the edges of
the nodules, cells may appear to engulf or invade
the surrounding normal salivary gland parenchyma
(Fig. 15D). In addition, islands of oncocytic cells can
pervade the hila of intraparotid lymph nodes giving
the erroneous impression of metastatic spread
(Fig. 16). Some or all of the oncocytic cells can have Figure 16 Multifocal nodular oncocytic hyperplasia involving
clear cytoplasm, and this appearance has been termed the hilum of an intraparotid lymph node.
clear cell oncocytosis (13). MNOH can be seen in
association with an oncocytoma, and the distinction
from a large hyperplastic nodule may be difficult or
impossible. partial fibrous capsule (11). MNOH may also be seen
It has been postulated that hyperplastic nodules in combination with other benign or malignant
are less organized and circumscribed than oncocyto- salivary gland tumors, particularly pleomorphic ade-
mas (14) and that oncocytomas should have at least a noma (11).
Amyloidosis
Amyloidosis of salivary glands appears to be rare, and
in some large series, no cases of clinical salivary
involvement were found (1,2). Localized amyloidosis
has been reported in the parotid (3), submandibular
(4) and sublingual glands (5). Both major and minor
salivary gland involvement can be seen in systemic
amyloidosis, which can be primary or secondary. In
primary amyloidosis, there is an immunocyte dyscra-
sia that results in excess production of abnormal light
chain immunoglobulin (AL-type amyloid). This over-
production is usually associated with multiple myeloma
or is idiopathic. Extensive amyloid deposition has been
reported in association with an extramedullary plasma-
cytoma within the parotid gland (6). Amyloidosis is
occasionally seen in patients presenting with primary
Sjögren syndrome (7,8). Secondary or reactive amyloid- Figure 18 Hemochromatosis in minor labial gland biopsy show-
osis (AA-type amyloid) is due to long-standing chronic ing granular, golden-brown hemosiderin deposition.
inflammatory diseases such as rheumatoid arthritis and
tuberculosis and can be associated with a variety of
carcinomas. Although there are few cases of clinical
salivary gland involvement in secondary amyloidosis,
deposits of amyloid have been detected in labial salivary Sjögren syndrome (1–3). It can also be a feature of
glands in the large majority of cases (9,10). thalassemia major, with or without secretory
Microscopy shows replacement of salivary impairment, usually in patients receiving multiple
parenchyma by homogeneous, eosinophilic material, transfusions (4–6). Histologic changes include acinar
patchy chronic inflammation, and sporadic multinu- atrophy, duct dilatation, interstitial fibrosis, and mild
cleated giant cells (Fig. 17). The amyloid shows orange chronic inflammation. Reddish-brown hemosiderin
staining with Congo and Sirius red stains, and there is deposits are seen in ducts and at the periphery of acinar
characteristic green/orange birefringence under cells (Fig. 18). They can be visualized more easily by
polarized light. In minor salivary glands, the amyloid using a Perl’s Prussian blue stain. Iron deposition in
deposition is predominantly periductal or periacinar, lower labial salivary gland biopsies has been used to
with less frequent perivascular or interstitial deposi- establish early diagnosis in neonatal hemochromatosis
tion (9). (7), allowing prompt medical intervention. In these
patients, the histologic features are more subtle, as the
Iron Deposition gland structure is relatively unchanged and the amount
of intracellular hemosiderin deposition may be
In hemochromatosis, iron can be deposited as hemo- minimal.
siderin in both major and minor salivary glands,
leading to a clinical presentation similar to primary
D. Sialadenitis
Acute Suppurative Sialadenitis
Acute suppurative sialadenitis most frequently involves
the parotid gland followed by the submandibular
gland. This may be explained because the serous
saliva produced by the parotid gland has less bacteri-
ostatic activity than that of the mucinous saliva of the
submandibular gland. The reduction of the secretory
flow and stasis of saliva, typically as a result of
dehydration, is an integral pathogenetic factor of
acute suppurative sialadenitis (1–5). Acute bacterial
submandibular infection often is associated with
obstruction of Wharton’s duct by stones or strictures.
Although acute suppurative parotitis can occur
in individuals of any age, patients aged from 50 to
70 years are the most frequently affected, with an equal
sex distribution. Parotid infections are occasionally
Figure 17 Amyloidosis of submandibular gland showing exten- observed in premature infants who have a greater
sive acinar destruction by globular hyaline deposits and patchy propensity for dehydration than term infants. Acute
chronic inflammation. suppurative sialadenitis accounts for 0.03% of hospital
admissions, with 30% to 40% of these occurring in
postoperative patients (5). Acute postoperative parotitis accumulation of bacteria and neutrophils. As the
is often observed in patients with debilitating disease or inflammatory process progresses, marked periductal
postoperative complications, particularly after major and interstitial neutrophilic infiltration with develop-
gastrointestinal surgery. Predisposing factors are dehy- ment of microabscesses leads to destruction of the
dration, malnutrition, oral neoplasms, liver cirrhosis, ductal epithelium with necrosis and loss of the
and diabetes mellitus (1–5). The use of drugs with an acinar tissue and eventually macroabscess and fistula
antisialogogue action, the most common being tricyclic formation.
antidepressants and diuretics, has been also associated
with acute suppurative sialadenitis. Obstructive Sialadenitis and Sialolithiasis
In acute suppurative sialadenitis, bacterial
organisms usually enter from the oral cavity in a Introduction. Obstructive sialadenitis is the
retrograde fashion. Staphylococcus aureus is the most most frequent type of chronic sialadenitis, accounting
common causative agent, and accounts for 50% to 90% for about 30% of all chronic sialadenitis cases and
of cases (1–5). Other aerobic organisms cultured approximately 1% of all salivary gland diseases (1,2).
from the disease include Streptococcus pneumoniae, Although sialolithiasis is by far the most common
Streptococcus pyogenes (b-hemolytic Streptococcus), cause of obstructive sialadenitis, there are two major
Streptococcus viridans, Hemophilus influenzae, Klebsiella factors playing a role in the pathogenesis of the
pneumonia, and Escherichia coli, and Pseudomonas aeru- disease (2). One is a mechanical obstruction by sialo-
ginosa. Methicillin-resistant Staphylococcus aureus liths, salivary gland cysts and tumors, and lesions of
(MRSA) has also been reported. More recently, anaer- the oral mucosa. The other factor is a disturbance of
obic organisms in acute salivary infections have been the electrolyte concentration of saliva, resulting in the
recognized, including Bacteroides, Peptostreptococcus, development of viscous secretory products. Most sia-
and Fusobacterium species. Acute suppurative parotitis loliths, also referred to as salivary calculi or stones, are
is usually a unilateral disease, but 10% to 25% of cases composed primarily of calcium phosphate together
have been bilateral involvement (3). The usual clinical with an organic matrix of various amino acids and
presentation is sudden onset of diffuse swelling of the carbohydrates (1,3,4). Sialoliths develop as a result of
affected gland associated with tenderness, induration, deposition of calcium salts around a nidus such as
erythema, and pain. Some patients complain of limited bacterial colonies, cellular debris, mucous plugs, or
movement of the mandible and difficulty in swal- foreign bodies. The precise cause of the development
lowing. Patients frequently have systemic signs of of sialoliths has not been fully elucidated, but infec-
toxemia, including delirium, high fever, and leukocy- tion or inflammation of the ducts as well as increased
tosis. Association with systemic sepsis is far more viscosity and stasis of saliva have been suggested as
common in infections of the parotid gland than in predisposing factors (3,4). Gout is associated with the
those of the submandibular gland. The respective formation of sialoliths, in which case, they are com-
intraoral duct orifice may become red and swollen posed of uric acid.
with purulent discharge recognized on massage of the Clinical features. The peak age of incidence of
gland. Fluctuation of the parotid gland does not occur sialolithiasis is between 30 and 60 years, with a mean
until late in the course of the disease because of the of about 45 years (1). Its occurrence in patients youn-
presence of multiple investing fascias enveloping the ger than 20 years, or older than 70 years, is rare. There
gland. The infection can extend locally by rupture of is a slight male preponderance. About 80% of cases of
the abscess into surrounding tissues, resulting in sialolithiasis develop in the submandibular gland,
osteomyelitis and fistula formation. The diagnosis of followed by less than 20% in the parotid gland.
acute suppurative sialadenitis is based on the clinical Involvement of the sublingual and minor salivary
presentation with culture of the purulent material glands is relatively rare (1). The upper lip and buccal
from the duct. Any abscess formation can be located mucosa are the most common minor salivary gland
using ultrasound or computerized tomography (CT) sites. The submandibular gland is more susceptible to
scanning. Sialograms are contraindicated in cases of sialolithiasis than the other salivary glands because its
acute suppurative infection of the salivary glands. saliva has higher mucin content, increased viscosity, a
Patients with acute suppurative sialadenitis may more alkaline pH, higher concentrations of calcium
eventually develop profound dehydration, sepsis, and phosphate, and antigravity flow within the duct
and multiorgan system failure. (5). In the majority of patients with sialolithiasis, only
Initial treatment of acute suppurative sialadeni- a single stone is found. Multiple stone formation
tis should be conservative, with eliminating the involving unilateral or bilateral glands is uncommon.
causes, improved oral hygiene, adequate hydration Sialoliths may be present both within the main ducts
to increase the salivary flow, repeated massage of the and within the gland parenchyma. In the submandib-
affected gland, and administration of appropriate ular gland, 57% of stones are localized near the hilum,
oral or intravenous systemic antibiotics, usually for a 34% in the distal area of the submandibular duct
penicillinase-resistant Staphylococcus. Irradiation of the (Wharton’s duct), and 9% in the intraglandular ducts
glands is no longer recommended. In cases involving (6). The formation of sialoliths in the main ducts
abscess formation, incision and drainage by surgical produces swelling of the distal salivary gland tissue
intervention are indicated. with or without pain. The episodes of the symptoms
Histologically, early acute suppurative sialade- are frequently recurrent and exacerbated by eating.
nitis is characterized by edema, hyperemia, and an There are distinct correlations between the severity of
the symptoms and the degree of obstruction. When

sialoliths occur in the submandibular gland duct,
induration can be observed in the floor of the
mouth, and the duct orifice becomes erythematous
and swollen. Sialoliths in the minor salivary glands
are mostly asymptomatic presenting as a small, firm
nodule. Sialoliths of intraglandular ducts of the major
salivary glands also may not cause significant clinical
symptoms. The complications of sialolithiasis include
acute suppurative sialadenitis, ductal ectasia, and
stricture. Ductal obstruction blocks secretion and
leads to stasis of the saliva within the duct, which
becomes predisposed to retrograde bacterial infection;
Streptococcus viridans is a commonly involved patho-
gen. In such instances, mucopurulent material may be
produced from the duct orifice by massaging the
involved gland.
The diagnosis of sialolithiasis is principally
based upon clinical and imaging examinations (3,6).
Sialoliths of the distal area of Wharton’s duct and the Figure 19 Obstructive sialadenitis of the submandibular gland.
hilum can be detected by bimanual palpation of the Ductal ectasia with periductal fibrosis accompanied by chronic
affected area. Plain radiography is a helpful method to inflammatory cell infiltrate and acinar atrophy.
diagnose sialolithiasis, but 90% of submandibular
stones are radiopaque while most parotid stones are
radiolucent. In addition, intraparenchymal sialoliths
may be difficult to visualize. Sialography is very
accurate in the diagnosis of sialolithiasis but is usually contents into the interstitial tissue. Complications of
unnecessary and is contraindicated in the acute setting obstructive sialadenitis include acute suppurative
of sialadenitis. Instead, high-resolution ultrasound inflammatory change with abscess formation, in addi-
and CT are the most useful diagnostic tools. tion to sinus tract and salivary fistulae.
The first steps of management of sialolithiasis in On immunohistochemistry, CD4-positive lym-
the submandibular and parotid glands include con- phocytes, which are the predominant subsets, are
servative methods, such as adequate hydration, siala- located mainly periductally (9). Isolated intraepithelial
gogues, and gland massage as well as minimally CD8-positive cytotoxic T cells are associated with
invasive approaches, such as basket retrieval and ductal epithelial cell destruction. B lymphocytes are
interventional sialendoscopy to remove the stones, restricted to lymphoid follicles located periductally
depending on their location and size (3,6). When and around intralobular ducts.
these measures fail, extracorporeal shock wave litho-
tripsy may be the treatment of choice. Extirpation of uttner Tumor)
Chronic Sclerosing Sialadenitis (K€
the affected gland is recommended only in the minor-
ity of recalcitrant cases. Introduction. Chronic sclerosing sialadenitis is
Pathology. Histologically, obstructive sialadeni- an inflammatory disease of the salivary glands, which
tis is characterized by ductal obstruction accompanied was first described by Küttner in 1896 (1). It has also
by a periductal chronic inflammatory cell infiltrate been referred to as Küttner tumor, because chronic
and fibrosis, ductal ectasia, and varying degrees of sclerosing sialadenitis produces a hard swelling of the
acinar atrophy (Fig. 19) (1,2,7,8). The initial alterations salivary gland that cannot be easily distinguished
are duct ectasia containing viscous masses of secretory clinically from neoplasia. This inflammatory process
products and development of microliths. The persis- almost exclusively affects the submandibular gland.
tence and progress of the obstructive process cause Although chronic sclerosing sialadenitis is a fairly
periductal sclerosis, increased acinar atrophy, and common type of chronic sialadenitis in the subman-
eventually destruction of the lobular architecture, dibular gland, it has been underrecognized by many
resulting in loss of secretory function of the gland. clinicians and pathologists for many years because of
There may be squamous, mucous cell, and oncocytic few reports in the English literature (2).
metaplasia of the duct epithelium. These features can The exact etiology of chronic sclerosing sialadeni-
simulate mucoepidermoid carcinoma, but obstructive tis remains unknown. While sialolithiasis is frequently
sialadenitis lacks an infiltrative nature and the pres- associated with chronic sclerosing sialadenitis, occur-
ence of intermediate cells characteristic of mucoepi- ring in 29% to 83% of cases, the progression of the
dermoid carcinoma. Ducts may contain sialoliths, inflammatory process, such as the intense lymphocytic
which vary in color from white to yellow-tan infiltration, the formation of lymph follicles, and the
(Fig. 20A) and consist of concentric laminations of destruction of salivary ducts in the submandibular
calcification (Fig. 20B), often with organic debris at the gland could not be explained pathogenetically by purely
center. A foreign body granulomatous reaction is obstructive mechanisms (2–4). Thus, sialolithiasis may
commonly caused by extravasation of secretory ductal be a secondary response by a functional abnormality
IgG4-related sclerosing diseases include sclerosing

pancreatitis, also called autoimmune pancreatitis or
lymphoplasmacytic sclerosing pancreatitis, sclerosing
cholangitis, retroperitoneal fibrosis, sclerosing media-
stinitis, and tubulointerstitial nephritis. The close asso-
ciation suggests that at least some cases of chronic
sclerosing sialadenitis share a common pathogenesis
with other sclerosing diseases involving disturbance
of IgG4 as a systemic disorder.
Clinical features. Chronic sclerosing sialadenitis
can occur at any age between 12 and 83 years, but
most patients are in the third-to-seventh decades with
a mean age of 42 to 44 years (2,4). Some investigators
have reported a slightly higher incidence in males,
whereas others have reported a slight female predom-
inance (2). Clinically, the patients typically present
with a firm swelling of the submandibular gland
with or without recurrent pain associated with eating.
This presentation of an enlarging, firm growth can
lead to the erroneous clinical diagnosis of a salivary
gland neoplasm, particularly carcinoma. Duration of
symptoms before patients receive treatment is highly
variable. The glandular involvement is usually unilat-
eral, but it can be bilateral. Cases with swelling of
bilateral submandibular glands and lacrimal glands,
similar to Mikulicz’s disease, have been reported (12).
As mentioned above, chronic sclerosing sialadenitis
is sometimes associated with the extrasalivary IgG4-
related sclerosing diseases; therefore, a systemic
examination is recommended for patients with chronic
sclerosing sialadenitis.
The serum concentrations of IgG4 in patients
with chronic sclerosing sialadenitis are typically ele-
vated (7). Autoantibodies specific for Ro (SS-A) and La
(SS-B) associated with Sjögren’s syndrome are usually
negative. The involved submandibular gland is often
removed for the purpose of diagnosis and/or treat-
Figure 20 Sialolithiasis. (A) Duct near the hilum of the sub- ment, while there have been several reports of chronic
mandibular gland contains yellow-tan sialolith (arrow). (B) Sialo- sclerosing sialadenitis responding well to corticoste-
lith consists of concentric laminations of calcification. roid therapy. Chronic sclerosing sialadenitis itself is
an entirely benign inflammatory process, and no
additional measures are warranted after removal,
but a case of extranodal marginal zone B-cell lymphoma
[mucosa-associated lymphoid tissue (MALT) lympho-
leading to inspissated secretion in the ducts. Seifert and ma] in the setting of chronic inflammation in chronic
Donath have suggested that a disorder of secretion sclerosing sialadenitis has been reported (13).
causes changes in the electrolyte content resulting in Pathology. Grossly, the involved glands are
increased viscosity of salivary secretions (5). Monoclo- enlarged and firm but maintain their configuration.
nal and oligoclonal cytotoxic T-cell populations found in Histologically, chronic sclerosing sialadenitis is char-
the affected salivary gland of patients with chronic acterized by dense periductal lymphoplasmacytic
sclerosing sialadenitis may suggest immune-mediated infiltrate with lymphoid follicle formation, prominent
reactions against the ductal system (6). fibrosis, and irregular ectasis of the ducts accompa-
On the other hand, recently it has become nied by inspissated secretion (Figs. 21, 22). The histo-
increasingly recognized that chronic sclerosing siala- pathologic features are quite variable depending on
denitis belongs to the group of immunoglobulin G4 the degree of inflammation, fibrosis, and parenchymal
(IgG4)–related sclerosing (systemic/autoimmune) dis- involvement and are also different from case to case
eases (7–11). This notion is further supported by the and from lobule to lobule within the same gland. The
fact that chronic sclerosing sialadenitis has been asso- lobular architecture is usually preserved, but in the
ciated with one or more extrasalivary IgG4-related advanced stage, it is distorted and disrupted by
sclerosing diseases, which are characterized by a prominent fibrosis and parenchymal destruction or
chronic inflammatory cell infiltrate containing abun- atrophy. Ductal hyperplasia often occurs with peri-
dant IgG4-positive plasma cells, accompanied by atro- ductal fibrosis and proliferation of lamellar collagen
phy of the normal parenchyma and sclerosis. Such fibers whorled around the ducts in an onionskin
Figure 21 Chronic sclerosing sialadenitis (Küttner tumor) of the

submandibular gland. Prominent lymphoid infiltration accompa-
nied by well-developed lymphoid follicle formation and marked
parenchymal loss.
arrangement. Sialolith and/or inspissated secretion

within ducts are observed in some cases. Small clus-
ters of epithelioid cells and isolated Langhans-type
giant cells may be present, and occasionally these
areas of granulomatous inflammation are conspicuous
(14). Obliterative phlebitis, with vein occlusion caused
by inflammatory infiltration and fibrosis, may also be
identified (7).
According to Seifert and Donath, the severity of
inflammation and fibrosis covers a spectrum that
evolves through the following four stages (5,15): Figure 22 Chronic sclerosing sialadenitis (Küttner tumor), end-
stage, of the submandibular gland. (A) Marked parenchymal
l Stage 1: Focal chronic inflammation with periduc- loss, septal fibrosis, and moderate degree of lymphoid infiltrate.
tal nests of lymphocytic infiltrate and moderately (B) There is periductal fibrosis accompanied by complete acinar
dilated ducts containing inspissated secretion. loss and mild lymphoid infiltrate.
l Stage 2: More marked diffuse lymphocytic infil-
tration and more severe periductal fibrosis. Duct
system exhibits inspissated secretion and focal
metaplasia with proliferation of ductal epithelium.
Periductal lymphoid follicles are well developed. University of Hamburg, Germany, is as follows:
There is fibrosis in the centers of the lobules and Stage 1: 40%; Stage 2: 18%; Stage 3: 33%; Stage 4: 9% (15).
atrophy of acini. Immunohistochemically, abundant cytotoxic
l Stage 3: Even more prominent lymphocytic infil- T cells are found, especially in close association with
tration, with lymph follicle formation with reac- ducts and acini (6). The B-cell population is less
tive germinal centers, reduction of the secretory pronounced and largely restricted to lymph follicles.
gland parenchyma, periductal fibrosis with hyali- Marked infiltration of IgG4-positive plasma cells is
nization, and ductal proliferation (Fig. 21). Squa- detected within the lesions (Fig. 23). Recently, Kita-
mous and goblet cell metaplasia in the ductal gawa et al. reported that the proportion of IgG4/IgG-
system may be present. positive plasma cells in chronic sclerosing sialadenitis
l Stage 4 (end stage): Destruction of the lobular cases ranged from 45.8% to 92%, whereas the percent-
architecture with marked parenchymal loss and age in cases of sialolithiasis and Sjögren syndrome
sclerosis, described as salivary gland cirrhosis (the was 0% to 4.9% (7).
‘‘burnt out’’ phase) (Fig. 22). Sometimes epimyoe- Differential diagnosis. Chronic sclerosing sialade-
pithelial islands can be observed. nitis should be differentiated from obstructive sialade-
The frequency of each stage based on more than nitis due to primary sialolithiasis, lymphoepithelial
1000 cases in the Salivary Gland Registry at the sialadenitis (LESA) (‘‘benign lymphoepithelial lesion’’),
Radiation Sialadenitis
Radiotherapy is the most commonly used modality
for treatment of the head and neck cancers (1). When
the major salivary glands are included within the
fields of radiotherapy, many patients develop swell-
ing and tenderness of the irradiated glands as well as
elevation of the serum amylase level within hours of
receiving even the first treatment in a course of
fractionated radiotherapy. These symptoms may be
transient, but a significant proportion of the patients
will suffer persistent salivary gland dysfunction,
resulting in xerostomia accompanied by a variety of
complications, such as dysphagia, abnormal taste
sensations, oral mucositis, dental caries, and peri-
odontal disease (2). These complaints may persist as
a long-term consequence of the radiation damage to
the salivary glands, even after cessation of radiotherapy.
In addition to the reduction in quantity, the composi-
Figure 23 Chronic sclerosing sialadenitis (Küttner tumor) of the tion of the secreted saliva also changes because of the
submandiular gland. Immunohistochemistry. Many IgG4-positive influence of radiotherapy. Saliva secreted from irradi-
plasma cells are seen within the lesion. ated salivary glands has a lower pH, lower protein
and secretory antibody contents, higher salinity,
and increased numbers of cariogenic microorganisms
(3). The severity of salivary gland damage and dys-
function depends on the dose and the duration of
Kimura’s disease, malignant lymphoma including irradiation.
extranodal marginal zone B-cell lymphoma (MALT The important pathogenetic factor of radiation
lymphoma), sclerosing variant of follicular lymphoma, sialadenitis is the direct irradiation effect on the sali-
and inflammatory pseudotumor (inflammatory myofi- vary gland tissue rather than the result of radiation-
broblastic tumor) (2). induced changes in the vasculature (4). Serous acinar
Obstructive sialadenitis due to primary sialoli- tissue of the parotid gland is considerably more
thiasis exhibits more prominent ductal ectasia and less radiosensitive than mucous glandular tissue of
evident lymphocytic infiltrate and fibrosis than chronic the submandibular gland (5). The radiosensitivity of
sclerosing sialadenitis. Lymphoepithelial islands the acinar cells depends on the content of secretory
(‘‘epimyoepithelial islands’’) characteristic of LESA granules, which contain a large amount of heavy
(benign lymphoepithelial lesion) are scarce or absent metals limited by the membrane (6). Released
in chronic sclerosing sialadenitis. In addition, chronic heavy metals as a result of the irradiation may cause
sclerosing sialadenitis is typically much more fibrous membrane lipid peroxidation by means of a redox
than LESA. Furthermore, obstructive sialadenitis and system, thus enhancing the process of apoptotic cellu-
LESA lack the feature of abundant IgG4-positive lar death (6).
plasma cells seen in chronic sclerosing sialadenitis. Generally, the acute alterations progress to a
Eosinophilic infiltration can be present in chronic chronic stage, with depletion of acinar structures, and
sclerosing sialadenitis, but it is much less common resulting interlobular and periductal fibrosis and chron-
than in Kimura’s disease. ic inflammatory cellular infiltrate. It has been suggested
Chronic sclerosing sialadenitis is distinguished that the histologic changes in the irradiated salivary
from extranodal marginal zone B-cell lymphoma glands can be divided into three stages according to the
(MALT lymphoma) by the absence of true lymphoe- degree of severity of the inflammatory process and the
pithelial lesions permeated by monocytoid B cells destruction of gland structure (7). These correlate close-
and the polytypic nature of lymphocytes proved by ly with the clinical symptoms and the outcome of late
means of immunohistochemistry and polymerase radiation-induced sequelae (7).
chain reaction (16). Follicular lymphoma can also Stage I is characterized by marked swelling and
histologically mimic chronic sclerosing sialadenitis, vacuolization of the serous glandular acinar cells with
especially its sclerosing variant. Unlike chronic sclerosing a reduction of secretory granules. However, mucous
sialadenitis, however, follicular lymphoma contains a glands may manifest few histologic changes. There is
monoclonal tumor population with CD10-positive also moderate atrophy of isolated glandular acini
and bcl-6-positive immunophenotypes (17). with a scant lymphocytic infiltration and moderate
Both chronic sclerosing sialadenitis and inflam- fibrosis. Stage I corresponds to an acute response to
matory pseudotumor possess extensive fibrosis with relatively low-level irradiation that lasts only several
chronic inflammatory cell infiltration. However, days.
inflammatory pseudotumor forms a discrete mass In Stage II, significant atrophy of the glandular
with proliferation of myofibroblastic cells and lacks acini is accompanied by ectasia of the excretory ducts
a lobulated architecture. filled with secretion. Goblet cell and squamous cell
metaplasia may be seen focally in the ductal epitheli- or mucoepidermoid carcinoma. These histologic fea-
um. Moderate periductal fibrosis and significant tures are observed most frequently after more than
lymphocytic infiltration are usually also present. Inter- three months of irradiation and after high irradiation
stitial lipomatosis may develop in some areas. Stage II doses. The resultant changes are completely irrevers-
corresponds to changes observed after higher irradia- ible and are associated with permanent damage and
tion doses in experimental studies. The resultant impaired glandular secretory function.
changes are no longer completely reversible and On immunohistochemistry, a loss of amylase reac-
cause functional loss of the glandular tissue. tion and an increasing expression of lysozyme, lacto-
Stage III is characterized by marked parenchy- ferrin, and secretory component may be observed in the
mal loss with destruction of the lobular structure, salivary ducts (7). The great majority of periacinar
extensive lymphocytic infiltration, interstitial fibrosis, lymphocytic infiltrates are CD8-positive cytotoxic
and ductal ectasia with intraluminal accumulation of T cells associated with acinar cell destruction (8).
secretions (Fig. 24A). Metaplastic changes of the duc-
tal epithelium may be prominent, sometimes together Cheilitis Glandularis
with cellular atypia (Fig. 24B), and may potentially be
difficult to distinguish from squamous cell carcinoma Introduction. Cheilitis glandularis is a rare
inflammatory disease affecting the minor salivary
glands of the lip that was first described by von
Volkman in 1870 (1). He described a suppurative
chronic inflammatory condition of the lower lip char-
acterized by mucopurulent discharge through the
ductal orifices of the labial minor salivary glands.
Cheilitis glandularis is a poorly understood enti-
ty, and its etiology is still unknown, but various
predisposing factors have been suggested, including
genetic predisposition (autosomal dominant pattern
of inheritance), chronic exposure to sunlight and
wind, smoking, poor oral hygiene, mouth breathing,
trauma (habitual lip licking), and a compromised
immune system human immunodeficiency virus
(HIV) infection (2–11).
Clinical features. The condition is seen most
frequently in adult men between the fourth and sev-
enth decades. However, a few cases have been
reported in women and children. It is most commonly
seen in the lower lip, although it has also been reported
in the upper lip and the palate. When the lesion
extends to the buccal mucosa, the term ‘‘suppurative
stomatitis glandularis’’ may be applied (12,13).
According to the clinical stages of progression of
the disease, cheilitis glandularis has historically been
subclassified into three types: simple, superficial
suppurative, and deep suppurative (8). Each subtype
represents part of a continuous spectrum of the
same disease category wherein, in the simple type,
the disease may progress from the superficial to the
deep suppurative types. The simple type is described
as multiple, painless, papular surface lesions with
central depressions and red or black puncta. The
lesions may extrude clear mucinous material upon
manipulation. The superficial suppurative type, also
referred to as Baelz’s disease, presents as multiple,
painless, indurated swellings of the lip with ulceration
and crust formation. Digital palpation of the lip will
Figure 24 Radiation sialadenitis of the submandibular gland.
produce clear-to-cloudy fluid from the ductal orifices.
(A) Marked parenchymal loss with destruction of the lobular The deep suppurative type, also called cheilitis glan-
structure, interstitial fibrosis, lymphocytic infiltration, and ductal dularis apostematosa, cheilitis glandularis suppura-
ectasia with intraluminal accumulation of secretions containing tive profunda, or myxadenitis labialis, demonstrates a
cell debris are evident. (B) Prominent squamous and goblet cell deep-seated infection accompanied by formation of
metaplasia of the ductal epithelium, together with cellular atypia. abscesses, sinus tracts and fistulae, and scarring,
Source: Courtesy of Dr. Jean E. Lewis, Mayo Clinic, Rochester, resulting in nodular enlargement of the lip. Viscous
Minnesota, U.S.A. secretion and mucopurulent material may spontane-
ously exude onto the mucosal surface.
Cheilitis glandularis, especially its deep suppura- In an experimental study using a rat model, local
tive type, has been closely associated with the develop- anesthetic injections and ligation of the arteries
ment of squamous cell carcinoma. The incidence of induced histologic changes similar to those of necro-
malignant transformation of cheilitis glandularis has tizing sialometaplasia (8).
been reported to range from 18% to 35% (3). Clinical features. Necrotizing sialometaplasia is
Pathology. Incisional biopsy consisting of sur- a rare disorder, involving an estimated 0.3% of all
face epithelium and an adequate amount of minor biopsied lesions from the oral cavity (2). Most cases
salivary glands is often recommended to establish a occur in the intraoral minor salivary glands, especially
definitive diagnosis and to rule out other specific the palate (77.2% of the cases) (3). Other salivary gland
granulomatous diseases, actinic cheilitis, or carcinoma. sites include the minor glands of the lower lip, retro-
The histologic features of cheilitis glandularis have molar pad area, tongue and buccal mucosa (9.8%), and
been described as nonspecific inflammation of minor the major salivary glands (8.7%) (10), particularly the
salivary gland tissue with broad variations. The histo- parotid. Necrotizing sialometaplasia has also rarely
logic changes can include ductal ectasia or hyperplasia been reported in the extrasalivary seromucinous
with or without squamous metaplasia, atrophy or glands of the nasal cavity, nasopharynx, paranasal
distention of acini, periductal acute and chronic inflam- sinuses, larynx, and trachea (3). Similar lesions have
matory infiltration, and interstitial fibrosis. Suppura- been recognized in the skin, breast, and lung (11–13).
tion and sinus tracts may be present in cases that The average age of the patients with necrotizing
involve bacterial infection. Oncocytic metaplasia and sialometaplasia is 45.9 years, with a range of 1.5 to
mucous cell metaplasia of the duct epithelium may be 83 years (3). There is a male preponderance; the male-
observed and are sometimes prominent. Oncocytic to-female ratio being approximately 2:1 (3).
metaplasia with papillary projections can be confused The typical clinical presentation is that of a deep,
with oncocytic variant of papillary cystadenoma (11). crater-like ulcer of the palate that resembles a malig-
Other histologic findings include surface hyperkerato- nant process. These ulcerated lesions range from 0.7 to
sis, erosion, or ulceration. 5.0 cm, with an average size of 1.8 cm (3). Palatal
Treatment of cheilitis glandularis ranges from a lesions are usually unilateral, but bilateral synchro-
preventive approach to surgical intervention. Reduc- nous lesions and metachronous lesions can occur.
tion or elimination of predisposing factors is the first Some lesions of necrotizing sialometaplasia may pres-
step in management. Conservative treatment includes ent as a submucosal swelling, without ulceration of
the usage of topical or intralesional corticosteroids the overlying mucosa. Patients with necrotizing sialo-
combined with antibiotic therapy. Patients with the metaplasia often complain of pain (63% of patients) or
deep suppurative type of cheilitis glandularis should numbness (13%) (3). Erosion of the palatal bone may
be considered for surgical excision because of the high occur in both ulcerated and nonulcerated lesions.
risk of developing squamous cell carcinoma. Recur- The average duration of the symptoms is three
rence after surgery is rare. weeks with an upper range of up to six months.
Most cases of necrotizing sialometaplasia appear to
Necrotizing Sialometaplasia arise spontaneously, whereas others are associated
with a history of trauma, vomiting, radiation therapy,
Introduction. Necrotizing sialometaplasia is a surgery, inflammatory disease, and either benign or
benign, self-limiting, reactive inflammatory condition malignant neoplasms.
of the salivary glands. It was first reported as a The suggested evolution of the lesions of necro-
distinct clinicopathologic entity of the minor salivary tizing sialometaplasia includes five stages: infarction,
gland of the hard palate by Abrams et al. in 1973 (1). sequestration, ulceration, reparation, and eventual
Since the clinical and histopathologic features of nec- healing (14). The prognosis for necrotizing sialometa-
rotizing sialometaplasia often simulate those of malig- plasia is excellent and spontaneous complete healing
nancies, including squamous cell carcinoma and occurs within 3 to 12 weeks, with an average healing
mucoepidermoid carcinoma, the report of Abrams time of approximately five weeks, depending on the
et al. and subsequent reports have emphasized the size of the lesion and the presence or absence of bony
importance of its correct diagnosis (1–6). Familiarity perforation. No specific treatment is necessary, but
with this disease can avoid misdiagnosis and inappro- biopsy of the lesion may be required to establish a
priate treatment. Ischemia caused by the impairment correct diagnosis.
of the vasculature supplying the salivary gland tissue Pathology. The principal histologic features of
has been implicated as the most likely etiology for necrotizing sialometaplasia are described as follows:
necrotizing sialometaplasia by both clinical and exper- (i) lobular infarction or necrosis of salivary gland
imental evidence (7,8), but the predisposing cause is tissue, (ii) simultaneous squamous metaplasia of
unclear in many cases. The factors believed to lead to ducts and acini, (iii) bland-appearing nuclear mor-
ischemia include traumatic injury, administration of phology of squamous cells, (iv) prominent granulation
local anesthetics, smoking, alcohol consumption, radi- tissue and inflammatory components, and (v) mainte-
ation, infection, intubation, and surgical procedures nance of the general lobular architecture in spite
(3). Necrotizing sialometaplasia has also been of fairly extensive inflammatory and metaplastic
described in a patient with embolization from carotid changes, often involving more than one lobule (1)
endarterectomy, Buerger’s disease, or Raynaud phe- (Fig. 25). The last feature is most helpful in distin-
nomenon, supporting this pathogenic mechanism (9). guishing necrotizing sialometaplasia from a malignant
process, but may be of little benifit if submitted

surgical material is scanty.
At low magnification, the lesion is composed of a
mixture of necrotic and metaplastic lobules (Fig. 25A).
There is a spectrum of histologic findings in necrotiz-
ing sialometaplasia depending on the duration of the
lesion, ranging from a dominant feature of complete
or partial coagulative necrosis of the acini, with mini-
mal or almost no inflammation in the early stages to
extensive squamous metaplasia of the ducts and reac-
tive fibrosis with edema and marked inflammation
being predominant in the late stage. Thus, although
necrosis is a defining hallmark of necrotizing sialome-
taplasia, it may not always be seen in the biopsy.
Mucous escape reaction and mucin pooling may be
present within the areas of necrosis and granulation
tissue (Fig. 25B). The inflammatory infiltrate consists
mainly of neutrophils and foamy macrophages and,
less commonly, of lymphocytes, plasma cells, and
eosinophils. On the other hand, squamous metaplasia
of the ducts and acini is a consistent finding in necro-
tizing sialometaplasia. The outline of the metaplastic
squamous nests is generally smooth, and they are
distributed within the lobular architecture (Fig. 25C).
Ductal luminal structures and mucous cells can remain
and be enclosed within the solid squamous nests.
Squamous cells usually have no significant cellular
atypia, but in some parts, the nests may be predomi-
nantly composed of basaloid cells with hyperchromatic
nuclei or exhibit reactive atypia with a high rate of
mitosis. In minor salivary gland or seromucinous gland
sites, pseudoepitheliomatous hyperplasia of the surface
epithelium overlying the lesion or adjacent to the ulcer
is commonly present.
Differential diagnosis. The main differential
diagnoses of necrotizing sialometaplasia are squa-
mous cell carcinoma and mucoepidermoid carcinoma.
The distinction is important to avoid unnecessary
radical surgery. Florid pseudoepitheliomatous hyper-
plasia of the overlying mucosa and squamous meta-
plasia can be misinterpreted as squamous cell
carcinoma, while the presence of residual mucous
cells entrapped within the squamous nests may be
confused with mucoepidermoid carcinoma.
Necrotizing sialometaplasia is distinguished
from these malignant processes by the recognition of
the maintenance of the lobular architecture, absence of
infiltrative growth pattern, presence of lobular infarc-
tive necrosis, lack of frankly malignant cytology, and
the evidence of residual ductal lumina. In a small
biopsy specimen, however, the differential diagnosis
is often problematic because the lobular pattern may
not be apparent. Therefore, an adequate amount of
biopsy material is required to ensure a correct diagno-
Figure 25 Necrotizing sialometaplasia. (A) Low-magnification sis. Identification of myoepithelial cells surrounding
view shows that a palatal lesion is composed of a mixture of squamous nests by immunostaining for calponin
necrotic and metaplastic lobules. Note the maintenance of the
general lobular architecture. (B) Squamous metaplasia of the
and/or smooth muscle actin may help to distinguish
ducts and acinar necrosis with mucin pooling are evident. necrotizing sialometaplasia from squamous cell carci-
(C) Metaplastic squamous nests with remaining ductal luminal noma and mucoepidermoid carcinoma (6). In addition,
structures and a few mucous cells. The outline of the nests is necrotizing sialometaplasia lacks the intermediate cells
smooth, and squamous cells have no significant cellular atypia. and cystic structures of mucoepidermoid carcinoma.
Source: Courtesy of Dr. Jean E. Lewis, Mayo Clinic, Rochester, Another lesion of the minor salivary glands that
Minnesota, U.S.A. should be considered for the differential diagnosis
is subacute necrotizing sialadenitis, which is a rare
Table 1 Comparison of Clinicopathologic Features Between Necrotizing Sialometaplasia and Subacute Necrotizing Sialadenitis
Necrotizing sialometaplasia Subacute necrotizing sialadenitis
Clinical features:
- No. of cases Approximately 200 31
- Age range (yr) 1.5–83 (mean, 45.9) 15–70 (mean, 26.7)
- Gender (M:F) 3:1 3:1
- Site Palate: 142 Palate: 24
Other locations: 58 Other locations: 7
- Lesion size, cm 0.7–5.0 0.3–2.5
- Symptoms 67 of 200 cases had pain Painful
- Appearance Usually ulcerated Nonulcerated
- Duration 4 days–3 mo (mean, 21 days) 1 day–1 wk
- Healing time /recurrence Healing usually after excisional biopsy/none 3 wk/none
Pathologic features:
- Surface ulcer Deep ulcer Absent
- Pseudoepitheliomatous hyperplasia Usually present Absent
- Necrosis/pattern All stages/usually lobular Early and moderate/focally acinar
- Ductal squamous metaplasia Always present Mild or absent
- Atrophy of ducts Severe Mild
- Inflammatory cells Chronic Mixed/subacute
- Eosinophils Usually absent Conspicuous
Source: From section ‘‘Necrotizing Sialometaplasia’’ Refs. 3 and 18.
self-limiting inflammatory condition characterized by there was an association with upper respiratory tract
a diffuse inflammatory infiltrate and acinar necrosis infection, with a peak incidence in the fall and winter
similar to necrotizing sialometaplasia, but without seasons. The palate, particularly the hard palate, is
squamous metaplasia of the salivary ducts (15). The most commonly involved, as in the case of necrotizing
relationship between subacute necrotizing sialadenitis sialometaplasia (6). Other sites of occurrence include
and necrotizing sialometaplasia is still under discus- the tonsillar area, buccal mucosa, ventral surface of
sion (16). The clinicopathologic features of these enti- the tongue, and the upper lip. Clinically, the lesion
ties are summarized in Table 1 (17,18). typically presents as a nonulcerated, erythematous,
nodular swelling accompanied by an abrupt onset of
pain. The size ranges from 0.3 to 2.5 cm. The duration
Subacute Necrotizing Sialadenitis of the symptoms before diagnosis is usually less than
Introduction. Subacute necrotizing sialadenitis is a week. The lesions generally heal within two to three
a rare, self-limiting, nonspecific inflammatory condi- weeks after incisional or excisional biopsy, without
tion of the intraoral minor salivary glands. It was first any additional medications. Clinical differences
described by Werning et al. in 1990 (1), and there have between subacute necrotizing sialadenitis and necro-
been 31 cases reported to date (1–6). Although there are tizing sialometaplasia include age distribution, pres-
considerable clinical and histologic differences between ence or absence of pain and ulceration, length of
the two conditions (Table 1) (3,6), it remains controver- duration, and healing time (Table 1) (3,6).
sial whether subacute necrotizing sialadenitis is a Pathology. Histologically, subacute necrotizing
distinct, specific entity, or whether it belongs to the sialadenitis is characterized by marked acute and
spectrum of necrotizing sialometaplasia (5). Even if the chronic inflammatory cell infiltration accompanied
latter is the case, subacute necrotizing sialadenitis and by focal necrosis and loss of acinar cells (Fig. 26).
early lesions of necrotizing sialometaplasia share some The inflammatory infiltrate is composed of neutro-
common histologic features, suggesting a possible rela- phils, lymphocytes, histiocytes, and eosinophils. Eosi-
tionship between them (5). The exact etiology of sub- nophils are sometimes a predominant element. The
acute necrotizing sialadenitis has not been defined, but inflammation may appear to be the earliest event,
an infectious process or immune responses to an occurring before the development of acinar necrosis.
unknown allergen have been postulated (1,3). Acinar necrosis is identified in only a part of the
Clinical features. The age of the patients ranges lesion, and the lobular-type acinar necrosis, typical
between 15 and 70 years, with a mean age of of necrotizing sialometaplasia, is not seen. Residual
26.7 years and the majority of cases occurring in the ducts may show slight atrophy and mild dilatation.
second and third decades (6). Subacute necrotizing Acinar and/or ductal squamous metaplasia, a defin-
sialadenitis shows a male predominance with male-to- ing criterion of necrotizing sialometaplasia, is not the
female ratio of 3:1 (6). These epidemiologic descrip- feature of subacute necrotizing sialadenitis. No signif-
tions might have a case selection bias since a signifi- icant fibrosis is observed. There is no pseudoepithe-
cant number of the reported patients belonged to a liomatous hyperplasia of the overlying mucosal
military population (1,3). Many patients with subacute epithelium. Ultrastructurally, electron-dense, virus-
necrotizing sialadenitis in previous reports shared like particles have been reported in some cases of
close living quarters such as military barracks, and subacute necrotizing sialadenitis (1).
infections ascending from the mouth after dehydra-

tion of the affected children, which provides a ground
for bacterial infection (1,2). However, the sialectasis
may be both the cause and the result of the recurrent
exacerbations of the parotitis (4).
Clinical features. The age of onset of recurrent
parotitis has been reported to be between 3 months
and 16 years, but it mostly starts between three and six
years with a peak during the first year of school (1).
There is a male predilection. Recurrent parotitis
presents as an intermittent, painful swelling of either
unilateral or bilateral parotid glands during mastica-
tion and/or swallowing, generally accompanied by
fever and malaise. The disease is often clinically mis-
diagnosed initially as mumps. The number of attacks
varies individually, but most commonly occurs every
three to four months (1–3). The swelling lasts from
several days to two weeks, and typically resolves
spontaneously, regardless of the treatment. Between
the episodes, the patient is free from symptoms.
Recurrent parotitis is generally self-limiting, and
after puberty, by age between 10 and 15 years, the
exacerbations usually subside and may disappear
completely, but there are persistent cases (2).
Although it usually is not accompanied by purulent
secretion, the majority of affected glands grow bacte-
ria on culture of saliva.
Sialography has been considered the most
important and accurate diagnostic tool, though its
role is now becoming secondary to ultrasonography
(5). The typical changes in recurrent parotitis on sialo-
gram are punctate and globular sialectasis, measuring
1 to 2 mm in diameter, scattered throughout the gland.
Ultrasonographic examination shows multiple small
hypoechogenic areas, corresponding to the punctate
sialectases demonstrated by sialography. These
changes are usually bilateral, even if the clinical
Figure 26 Subacute necrotizing sialadenitis of the palate. (A) manifestations are unilateral. These abnormalities
Low-power view shows focal acinar necrosis with an inflamma-
tend to diminish and sometimes disappear after the
tory cell infiltration. Note the lack of acinar and/or ductal squa-
mous metaplasia. (B) High magnification reveals the evidence of
disease becomes quiescent, but they may persist even
focal necrosis of acinar cells. after all other symptoms have resolved.
Pathology. The histologic findings of recurrent
parotitis are characterized by cystic dilation of inter-
lobular ducts accompanied by massive periductal
lymphocytic infiltration (Fig. 27) (1). The dilated
ducts correspond to the sialectases seen on sialo-
Recurrent Parotitis grams, and there seems to be no element of obstruc-
tion in most cases. The lymphocyte infiltrate usually
Introduction. Recurrent parotitis is a well-recog- contains well-formed lymphoid follicles. The ductal
nized entity in children, characterized by recurring epithelium is commonly hyperplastic and metaplastic
episodes of swelling of the parotid gland. Although it and is often permeated by lymphocytes. Some inves-
is relatively rare, it is still the second most common tigators proposed that this lymphocytic infiltration
inflammatory salivary gland disease in children, next damages the duct wall reticulum, allowing extravasa-
to mumps (1–3). Recurrent parotitis is generally asso- tion of secretions into the gland parenchyma, thus
ciated with nonobstructive sialectasis of the parotid exacerbating the inflammation (6). In the later stage of
gland. Although a number of etiologies have been the disease, there may be various degrees of atrophy
suggested, the exact causative factor of the disease has of the acini with interstitial fibrosis. Resolution of
yet to be determined. Candidates include congenital symptoms with age may be due to regeneration of
sialectasis of the salivary duct, genetic inheritance, glandular elements.
viral or bacterial infection, allergy, and a local mani- The main treatments of an acute phase of recur-
festation of an autoimmune disease (1–3). The most rent parotitis are either conservative observation or
probable theory is a combination of a congenital antibiotic treatment. Penicillin V is a good choice for
malformation of portions of the salivary ducts and acute infections. Performing sialography itself may
incidence is between the ages of four and six years,

but the infection can be seen in other age groups. The
incubation period is two to three weeks, with a clinical
onset characterized by pain and swelling of one or
both parotid glands. Systemic symptoms include
fever, malaise, myalgia and headache, and usually
resolve before the parotid swelling. While symptoms
are generally not severe in children, adults infected
with mumps are more likely to develop severe symp-
toms and complications. The diagnosis is usually
made on clinical presentation. Demonstrating anti-
bodies to the mumps S and V antigen by enzyme-
linked immunoadsorbent assay can confirm the diag-
nosis. Some laboratories use molecular methods that
are based on nested polymerase chain reaction.
Many cases are subclinical, and studies have
shown that more than 95% of adults have neutralizing
antibodies. Orchitis occurs in 10% to 20% of infected
males, but it is usually unilateral, and sterility only
Figure 27 Juvenile recurrent parotitis. Low-power view demon- rarely ensues; aseptic meningitis occurs in about 5% of
strates cystic dilation of interlobular ducts accompanied by those infected. In older people, the central nervous
massive periductal lymphocytic infiltration with well-formed lym- system, pancreas, prostate, breast, and other organs
phoid follicles. may be involved. Viral infections can cause severe
degrees of sensorineural hearing loss in one ear, and
sometimes in both, at any age. The disease is generally
self-limiting, and the outcome is usually good. Swell-
be useful in improving the symptoms. No preventive
ing and other acute symptoms usually subside within
therapy against recurrent parotitis is available. Other
treatments are much more invasive when applied to the two weeks. There is no specific treatment apart from
controlling the symptoms with analgesics.
adults with persistent severe disease, including duct
The opportunity for histologic examination of
ligation, parotidectomy, and tympanic neurectomy.
infected glands is exceedingly rare. The histologic
features of the swollen parotid glands include diffuse
Viral Sialadenitis Including Mumps, Cytomegalovirus, interstitial edema, intense hyperemia, and a dense
and HIV-Associated Lymphoepithelial Cyst inflammatory infiltrate composed of histiocytes, lym-
phocytes, and plasma cells. This infiltrate may com-
Viral infections involving the salivary glands are more press the salivary gland parenchyma resulting in
common than those of bacterial origin. Viral sialade- acinar cell vacuolization and ductal dilatation.
nitis is a manifestation of a systemic infection, and the Cytomegalovirus. Cytomegalovirus (from the
salivary glands are affected by a hematogenous Greek cyto-, ‘‘cell,’’ and -mega-, ‘‘large’’) is a member
spread of virus rather than direct infection to the of Betaherpesvirinae in the subfamily of Herpesvir-
organ as in bacterial sialadenitis. A variety of viruses idae. Most people are infected with cytomegalovirus
are known as causative agents of sialadenitis, includ- at some point in their life, although the age of infec-
ing the paramyxovirus (mumps), cytomegalovirus, tion varies worldwide. In developing countries, most
HIV, coxsackie A virus, Epstein–Barr virus (EBV), infections are acquired during childhood, whereas, in
echovirus, herpes virus, lymphocytic choriomeningitis developed countries, up to 50% of young adults
virus, adenovirus, and influenza A and parainfluenza are seronegative. Cytomegalovirus is not highly con-
viruses (1). A comprehensive discussion of all cases of tagious, thus the infection requires close, intimate
these viral-associated sialadenitis is beyond the scope contact with a person excreting the virus in their
of this chapter; however, several diseases that merit saliva, urine, or other bodily fluids. Cytomegalovirus
mention in this context are mumps (2), cytomegalovi- can be sexually transmitted and can also be transmit-
rus (3), and HIV-associated lymphoepithelial cysts ted via breast milk, transplanted organs, and, rarely,
(4–10). from blood transfusions. Diagnostic procedures
Mumps. Mumps is by far the most common include the enzyme-linked immunosorbent assay for
cause of parotid swelling and is the most common measuring the antibody to cytomegalovirus.
viral agent involving the salivary glands (2). Mumps Cytomegalovirus infection without symptoms is
is caused by a highly contagious paramyxovirus that common in infants and young children. Clinically
is transmitted by saliva droplets or direct contact with significant cytomegalovirus disease frequently devel-
articles that have been contaminated with infected ops in patients immunocompromised by HIV infection,
saliva. A vaccine made from attenuated live mumps organ transplantation, or bone-marrow transplantation
virus has reduced the frequency. Before the develop- (3). Symptomatic disease in immunocompromised
ment of effective vaccination, mumps was a common individuals can affect almost every organ of the body,
childhood disease worldwide and is still a significant resulting in fever of unknown origin, pneumonia,
threat to health in developing countries. The peak hepatitis, encephalitis, myelitis, colitis, uveitis, retinitis,
observed in HIV-negative patients (7). HIV-associated

LEC may develop either from preexisting salivary
gland inclusions in the intraparotid lymph nodes or
from a secondary lymphocytic infiltration of the sali-
vary gland parenchyma provoking LECs and lesions.
A computer-assisted three-dimensional reconstruction
study supports the latter hypothesis regarding its
pathogenesis (6).
Clinical Features. About 1% to 10% of adult
patients with HIV infection develop HIV-associated
LEC (4,10). The age distribution of patients with HIV-
associated LEC falls into two groups: children born to
HIV-infected mothers and adults aged between 20 and
60 years, but most are in the 25- to 50-year age group.
HIV-associated LEC has a distinct male predominance
of nearly 7:1 (4). Patients have been intravenous drug
users, homosexual males, transfusion recipients, and
hemophiliacs. The lesion almost exclusively arises in
the parotid gland, and the occurrence in the other
Figure 28 Cytomegalovirus infection. Several enlarged parotid salivary glands, including submandibular gland and
gland duct cells exhibit intranuclear viral inclusion bodies. minor salivary glands, is rare. Involvement may be
unilateral but is most commonly bilateral. The main
symptom is painless, slow-growing swellings of the
affected glands with or without the manifestation of
and neuropathy. Cytomegalovirus infections are fre- dry mouth. HIV-associated LEC usually develops early
quently associated with salivary glands, but significant in the course of HIV infection and sometimes is the
clinical manifestations of cytomegalovirus-infected first clinical manifestation. Patients almost invariably
patients are usually seen in other organs. Cytomega- have accompanying cervical lymphadenopathy. HIV-
lovirus infection is a major cause of death in immuno- associated LEC is thought to reflect a localized form of
compromised patients. persistent generalized lymphadenopathy. Fevers,
Additionally, congenital transmission from a fatigue, night sweats, diarrhea, or weight loss may
mother with acute infection during pregnancy is an also be present. Patients with HIV-associated LEC are
important cause of a variety of abnormalities in new- negative for the serologic markers commonly present
borns. Congenital cytomegalovirus infection is one of in Sjögren’s syndrome, such as anti-SS-A and SS-B,
the TORCH infections (toxoplasmosis, other infections antinuclear antibodies, or rheumatoid factor. HIV-
including syphilis, rubella, cytomegalovirus, and her- associated LEC has a characteristic appearance on CT
pes simplex virus). The clinical syndrome of congeni- and MRI as well as ultrasonography, where the salivary
tal cytomegalic inclusion disease includes jaundice, swellings are recognized as muticentric cysts or larger
splenomegaly, thrombocytopenia, intrauterine growth cysts ranging from 0.5 to 4.0 cm in diameter (6).
retardation, microcephaly, and retinitis. No treatment Although the salivary gland swelling may fluctu-
is generally necessary for cytomegalovirus infection in ate, they are generally persistent and long standing.
the healthy individual since the majority of infections Patients with HIV-associated LEC are at increased risk
resolve spontaneously. Antiviral drug therapy is now of developing aggressive B-cell lymphomas, most com-
being evaluated in infants. monly of the Burkitt-type and diffuse large cell lym-
The pathologic hallmark of cytomegalovirus phoma. No definitive treatment has been established
infection in the salivary glands is an enlarged duct for HIV-associated LEC. The clinical progression of the
cell with characteristic intranuclear viral inclusion salivary gland swelling may require surgical interven-
bodies (Fig. 28). The microscopic description given tion for cosmetic reasons. Steroid, antiretroviral medi-
to these cells is most commonly an ‘‘owl’s eye.’’ cations, and radiation therapy may reduce the size of
HIV-associated lymphoepithelial cyst the lesion. Therapy for the symptom of dry mouth is
(HIV–salivary gland disease). essential for the clinical control.
Introduction. HIV is currently the leading Pathology. Grossly, multiple cysts of variable
cause of death in Africa and the fourth leading diameters up to 5 cm can be seen usually in the
cause of death worldwide. Cystic lymphoepithelial superficial lobe of the parotid glands. The lobular
lesions of the salivary glands showing nodular or architecture of the glands is preserved.
diffuse enlargements can occur in patients with HIV Histologically, the lesion is characterized by
infection, with variable designations as HIV-associated poorly circumscribed multinodular areas composed
lymphoepithelial cyst (LEC), HIV–salivary gland dis- of multicystic structures surrounded by dense lym-
ease, benign lymphoepithelial lesion, cystic lymphoe- phoid infiltrates with florid lymphoid follicular
pithelial lesion, and diffuse infiltrative lymphocytosis hyperplasia and lymphoepithelial lesions (Fig. 29A).
syndrome (10). HIV-associated LEC and lymphoepi- The cysts are lined predominantly by nonkeratinized
thelial sialadenitis in Sjögren’s syndrome share some stratified squamous epithelium and focally by cuboi-
common morphologic features. Lesions that morpho- dal-type cells, permeated by mainly monocytoid and/
logically resemble HIV-associated LEC are also or marginal zone B cells and also sparsely by T cells
be present within the lymphoid infiltrate. The lym-

phoid follicles with germinal centers are large and
sometimes confluent (Fig. 29C). The appearance of
follicle lysis may be seen in the germinal centers,
similar to that in lymph nodes of persistent general-
ized lymphadenopathy in HIV-positive patients.
The lymphoid follicles show a prominent net-
work of CD21- and CD35-positive dendritic reticular
cells. The HIV-1 major core protein (p24) and HIV-1
RNA are detected within the follicular reticular den-
dritic cells, indicating that there is active replication of
the virus within them, but not in the salivary acinar
cells or duct epithelial cells (5). Interfollicular regions
consist of a mixture of small lymphocytes of both
B- and T-cell types, plasma cells, and immunoblasts.
T-cell population is dominated by CD8-positive cells
rather than CD4-positive cells; this feature is contrary
to HIV-negative LECs and LESA in Sjögren’s syn-
drome (7). The lymphoid and plasma cell population
is polyclonal in nature, revealed by immunohisto-
chemical staining for immunoglobulin light chains
and/or molecular analysis for immunoglobulin
heavy chain rearrangement (7,8). Labial salivary
gland biopsy of the patients with HIV-associated
LEC most often discloses a focal lymphocytic sialade-
nitis with a focus score of more than 1, as in Sjögren’s
syndrome.
E. Tumor-Like Lesions
Sclerosing Polycystic Adenosis
This is a recently described, rare lesion of salivary
glands of uncertain histogenesis that can simulate
neoplasia clinically, radiographically, and histologi-
cally (1). The appearances resemble those of benign
fibrocystic disease and sclerosing adenosis of the
breast. There have been over 40 reported cases: four
involved minor glands, including the buccal mucosa,
hard palate, and floor of mouth (2,3), two the sub-
mandibular gland, and the remainder affected the
parotid gland (1–8). The typical history is the presence
of a slow-growing mass of less than two years dura-
tion with occasional pain and tenderness. The age
range is from 9 to 80 years (3,6). Macroscopically,
most lesions are well circumscribed but unencapsu-
lated, with a minority forming multifocal nodules.
They may contain multiple, small cysts. The maxi-
mum reported size is 7 cm in diameter. Microscopi-
cally, the lesions show a diverse range of appearances.
They are characterized by densely collagenized,
sparsely cellular fibrous tissue surrounding ill-defined
Figure 29 HIV-associated lymphoepithelial cyst of the parotid salivary gland ductal and acinar lobules, and areas of
gland. (A) A cystic structure surrounded by dense lymphoid cystically dilated ductal structures (Fig. 30). The latter
infiltrates with florid lymphoid follicular hyperplasia. (B) The are lined by epithelium, which can be attenuated or
cyst is lined by non-keratinized stratified squamous epithelium hyperplastic and may show intraluminal papillary
permeated by monocytoid lymphoid cells. (C) Irregularly shaped,
projections. In addition, the lining may contain muco-
large lymphoid follicle with germinal center. Source: Courtesy of
Dr. Jean E. Lewis, Mayo Clinic, Rochester, Minnesota, U.S.A. cytes, vacuolated cells, sebaceous-like cells, apocrine
cells, and foci of squamous metaplasia (Fig. 30D). In
some areas, interconnecting cellular bridges form a
cribriform pattern (Fig. 30C), and this is occasionally
(Fig. 29B) (8). Monocytoid and/or marginal zone B associated with hyaline globules of basement mem-
cells do not expand into the interfollicular region, brane material forming collagenous spherules. Areas
forming broad sheets. Lymphoepithelial lesions may of atypical hyperplasia of densely granular,
Figure 30 Sclerosing polycystic adenosis. (A) Well-circumscribed tumorous lesion composed of dilated ductal structures and fibrous
stroma. (B) Densely collagenized fibrous tissue surrounding salivary gland ductal and acinar lobules. (C) Cystically dilated ductal
structures and foci of cribriform areas accompanied by intervening collagenous stroma. (D) Ductal structures consisting of various cell
types, including apocrine, acinar-like, vacuolated, and sebaceous-like cells. Note acinar-like cells exhibiting intracytoplasmic eosinophilic
granules and conspicuous nucleoli.
eosinophilic, acinar cells can be readily mistaken for The most important differential diagnoses are
acinic cell carcinoma (Fig. 30D). In addition, there may acinic cell carcinoma, adenocarcinoma [not otherwise
be islands of more basophilic acinar cells in micro- specified (NOS)] and cystadenocarcinoma. The lobular
cystic and solid configurations. In some cases, ducts nature of polycystic sclerosing adenosis, together with
show dysplastic changes resembling in situ carcino- the presence of a peripheral myoepithelial layer and the
ma, and focal islands of similar cells have also been lack of evidence of infiltration, should prevent confusion.
described (4). However, the lobular architecture is The treatment of choice appears to be a complete
preserved, and staining with markers such as calpo- but conservative local excision. About 30% of cases
nin (Fig. 31), smooth muscle actin, and muscle-specific with adequate follow-up, however, have recurred
actin shows a layer of myoepithelial cells surrounding with intervals ranging from approximately 5 to
the ducts and lobules (6). There is a variable mixed 22 years, and in a few cases, the recurrences were
chronic inflammatory infiltrate, and in some areas multiple. Although these recurrences are probably
xanthomatous macrophages are a conspicuous feature due to the presence of multifocal disease, the relatively
(Fig. 32). Two cases with a significant lipomatous high rate, together with the presence of dysplasia
component have been reported, and oncocytic change and/or carcinoma in situ means that the possible
may also be seen (6). Immunoreactivity for estrogen neoplastic potential of this process has yet to be
and progesterone receptors has been demonstrated, fully characterised (4). A recent study using the poly-
suggesting the possible participation of hormone stim- morphism of the human androgen receptor
ulation in the pathogenesis (4). (HUMARA) locus as a marker has shown sclerosing
Figure 31 Sclerosing polycystic adenosis. Immunohistochem-

istry. Calponin-positive myoepithelial cells surrounding the
hyperplastic ducts.
Figure 32 Sclerosing polycystic adenosis. Conspicuous aggre-

gation of xanthomatous macrophages.
Figure 33 (A) Sialosis. Diabetic patient with bilateral parotid
enlargement. (B) Sialosis. Enlarged granular serous cells and
compressed striated ducts. (C) Sialosis. Enlarged serous cells
have vacuolated cytoplasm.
polycystic adenosis is clonal (9). This adds further

support to the concept that it is a neoplastic rather
than reactive process.
been reported rarely in the submandibular gland (2)

Sialosis
and intraoral minor glands in the palate (5). Although
Sialosis (sialadenosis) is a noninflammatory and non- there are few major series, sialosis is probably more
neoplastic, typically bilateral, salivary enlargement, common than these would suggest, as many cases are
usually involving the parotid glands (Fig. 33A) (1). regarded merely as facial adiposity.
Unilateral cases have been described (2), and in some The condition is usually painless, but occasionally
patients, aplastic or hypoplastic parotid glands are the glands are tender or mildly painful. There is no sex
present on the contralateral side (3,4). Sialosis has predilection (6,7). The peak incidence is in the fifth and
Table 2 Causes of Sialosis to diabetes and chronic alcohol misuse, sialosis usual-
ly persists despite treatment (22). Superficial paroti-
Drugs induced Endocrine/metabolic Nutritional
dectomy is sometimes undertaken to correct
Antihypertensives Acromegaly Beriberi unacceptable cosmetic deformity (2).
Guanacline Alcoholism Bulimia
Iodine Diabetes insipidus Gastrointestinal
disease Salivary Gland Hyperplasia
Isoprenaline Diabetes mellitus Malnutrition
Lead Hypothyroidism Pellagra The terminal duct of salivary glands is a unit consist-
Mercury Cirrhosis of the liver Amylophagia ing of the secretory acinus, intercalated duct, and
Naproxen Uremia Vitamin A associated myoepithelial cells. Hyperplasia of this
deficiency complex can result in two distinct forms: acinar
Oxphenbutazone adenomatoid hyperplasia and ductal adenomatoid
Phenylbutazone hyperplasia (1,2).
Sulfisoxazole Acinar adenomatoid hyperplasia is a rare, idiopathic
Thiocyanate
condition, which usually affects the intraoral minor
Thiouracil
Valproic acid
salivary glands, with the palate accounting for the
majority of cases (3). It typically presents as a painless,
sessile swelling at the junction of the hard and soft
palates and clinically it can mimic a salivary gland
tumor. The sex ratio is equal, and the majority of
patients are middle aged or elderly. Most cases have
sixth decades, and the main complaint is a slowly been reported in Caucasians, and the condition
enlarging and cosmetically unsightly swelling of the appears to be very uncommon in Asians (4). There is
parotids. Occasionally, patients may experience a dry no association with sialosis (sialadenosis) of the major
mouth or sialorrhea. Although raised salivary levels of salivary glands.
potassium and amylase have been reported, this is of Microscopy shows lobules of hyperplastic but
limited, if any, practical value in diagnosis (4). Sialosis otherwise unremarkable mucous acinar cells and
has been associated with a wide variety of factors that essentially normal-appearing ducts (Fig. 34). In most
are predominantly nutritional, metabolic or pharmaceu- cases, the overlying palatal epithelium is normal, but
tical (4,8) (Table 2). It is thought that a unifying etiopa- one case showed a lichenoid reaction, and in another,
thogenesis could be related to peripheral autonomic pseudoepitheliomatous hyperplasia was reported.
nerve dysfunction (9). A relationship with salivary aqua- Occasionally, there are areas of interstitial mucous
porin water channels has been recently suggested (10). extravasation with an associated inflammatory reac-
The most common causes are diabetes mellitus tion. The condition is entirely benign, and excision is
and alcohol misuse. The reported prevalence of sialo- curative. A similar condition causing swelling in the
sis in diabetes ranges from 10% to 80% (11), and in sublingual region has been called ‘‘idiopathic hyper-
recent study, nearly half the patients with sialosis plasia of the sublingual gland’’ (5,6) or ‘‘pouting’’
were diabetic (4). Sialosis can occasionally precede sublingual glands. This is seen as an enlargement in
clinically detectable hyperglycemia. Alcohol misuse, the floor of the mouth in totally or partially edentu-
particularly when associated with cirrhosis, has been lous patients. The sublingual glands may be otherwise
reported to lead to sialosis in 30% to 60 % of these normal or show nonspecific chronic inflammation.
patients (7,12–14), but this high frequency has been Ductal adenomatoid hyperplasia (also known as
questioned (4). Any long-standing nutritional disor- intercalated duct hyperplasia) is also very rare and
der can result in sialosis, and this may also be a factor is usually seen as a chance finding in surgical speci-
in some alcoholic patients. A number of cases related mens from major salivary glands, especially tumor
to patients with bulimia or anorexia nervosa have resections. There is a 3:1 male predominance, and
been reported (15,16), and these may also be associat- most cases are seen in the sixth decade.
ed with palatal necrotising sialometaplasia (17). How- Microscopy shows one or several unencapsu-
ever, in a significant number of patients with sialosis, lated foci of proliferation of ducts with structural
no cause is found (18). similarities to the normal intercalated ducts (Fig. 35).
Sialosis is rarely biopsied. Microscopy shows These are densely packed with little supporting stro-
acinar cell hypertrophy, and the cells can be two or ma and consist of an inner layer of cuboidal cells and
three times the normal size (19). The enlarged cells can an outer layer of myoepithelial cells. There may be
have granular cytoplasm packed with densely stain- residual areas showing acinar differentiation with
ing zymogen granules (Fig. 33B), or the cytoplasm can cells containing basophilic zymogen granules.
be vacuolated (Fig. 33C). Some cases show a mixed The salivary gland tumor most frequently
population. Compression of the striated ducts has associated with ductal adenomatoid hyperplasia is
been described (20), but inflammation is not a feature. epithelial-myoepithelial carcinoma. This has raised
In long-standing cases, parenchymal atrophy and speculation that it may be a precursor of this tumor.
fatty replacement can be seen (21). Nutritional and This could also explain the frequent presence of an
drug-related sialosis will often regress if the underly- element of epithelial-myoepithelial carcinomas in
ing causative factors are eliminated, but in cases due hybrid salivary tumors (2,7).
Figure 34 Adenomatoid hyperplasia of palate

showing hyperplastic but otherwise normal mucous
acini.
Conversely, almost all patients with Sjögren’s syn-

drome manifest LESA.
Historically, the pathologic entity now called
LESA was first described by Mikulicz in 1892 (2). He
reported a 42-year-old man with bilateral, painless
enlargement of the salivary and lacrimal glands asso-
ciated with an infiltration of small round cells. Later,
the cases with bilateral salivary or lacrimal enlarge-
ment were diagnostically divided into two groups:
‘‘Mikulicz’s disease’’ and ‘‘Mikulicz’s syndrome’’ (3).
The term Mikulicz’s disease has been used when the
cause of the lesion is not defined, while the term
Mikulicz’s syndrome encompasses cases with many
known different underlying entities, including tuber-
culosis, sarcoidosis, and lymphoma. However, the
separation of these two categories is ambiguous and
does not provide any meaningful prognostic or thera-
Figure 35 Ductal adenomatous hyperplasia showing duct-like peutic information; to prevent confusion, they should
structures and residual serous acini. no longer be used. In 1933, Sjögren described detailed
clinical and histologic findings in women presenting
with xerostomia (dry mouth) and keratoconjunctivitis
sicca (dry eyes) (4). In 1953, on the basis of the
observation of cases diagnosed as Mikulicz’s disease,
F. Lymphoepithelial Sialadenitis Morgan and Castleman reported that there are many
and Sjögren’s Syndrome similarities between their cases and those described in
Sjögren’s syndrome and concluded that Mikulicz’s
Introduction disease is only one manifestation of the generalized
symptom complex of Sjögren’s syndrome (5). On the
Lymphoepithelial sialadenitis (LESA) is histologically other hand, recently Mikulicz’s disease has been
characterized by conspicuous interstitial lymphocytic reported to be associated with elevated IgG4 concen-
infiltration accompanied by atrophy of the salivary trations in the serum (6).
gland parenchyma and formation of lymphoepithelial The term LESA was formerly referred to as
lesions (epimyoepithelial islands). This pathologic benign lymphoepithelial lesion or ‘‘myoepithelial sia-
condition often, but not always, occurs in the patients ladenitis’’ (7), but these two names are not appropriate
who fulfil the clinical criteria of Sjögren’s syndrome, from the clinicopathologic point of view (1). It has
but up to 50% of LESA also develops in the patients become evident that some of the cases described as
without the clinical features of Sjögren’s syndrome; benign lymphoepithelial lesion, a term first intro-
they may or may not be associated with other connec- duced by Godwin in 1952 (8), on the basis of the
tive tissue disease, especially rheumatoid arthritis (1). recent advances of immunohistochemical, flow
cytometric, and molecular genetic studies, were actu- on the underlying cause of Sjögren’s syndrome, the
ally lymphomas (1,9,10). Furthermore, the term myoe- exact etiology and pathogenesis remain unresolved.
pithelial sialadenitis, alternatively applied for the Comprehensive reviews of recent progress on the
lesion later, is also misleading from the morphogenetic clinical aspects and the putative pathogenetic mecha-
aspects; the constituting nonlymphoid cells are mainly nism operating in the development of Sjögren’s syn-
basal type of epithelial cells rather than myoepithelial drome are available elsewhere (16,17).
cells (11,12). LESA, introduced by Harris in 1999, Until recently, several schemes of diagnostic
seems to be an accurate term that refers to the specific criteria for primary Sjögren’s syndrome have been
histopathologic features, and it has now become proposed. In 2002, an American-European consensus
generally accepted (1). group suggested a set of diagnostic criteria (Table 3)
(18). Diagnosis of primary Sjögren’s syndrome
Clinical features requires four of six criteria, including subjective or
objective signs and symptoms of dryness, a character-
Patients with LESA and Sjögren’s syndrome are typi- istic appearance of a biopsy sample from a minor
cally women, with the female-to-male ratio being 9:1. salivary gland, and the presence of an autoantibody
The disease can present at any age, with a significant such as anti-SS-A/SS-B. Exclusions from the assess-
peak incidence from fourth to sixth decades. The ment of the criteria include previous radiotherapy to
lesion presents as unilateral or bilateral diffuse, pain- the head and neck, lymphoma, infection with HCV,
less or mildly painful, firm enlargement of the salivary human T-lymphotropic virus type I, or HIV, sarcoido-
glands and/or lacrimal glands. LESA most frequently sis, and graft-versus-host disease. Also, measurements
involves the parotid gland (80–85%), followed by the of tear and saliva flow must be made in the absence of
submandibular gland (10–15%) usually in combina- drugs that have anticholinergic side effects.
tion with the parotid enlargement (7). Swellings of the The majority of LESA cases are of a chronic and
minor glands are rare, but subclinical focal periductal indolent nature. However, patients with LESA, wheth-
lymphocytic infiltrates are almost always seen in the er or not associated with Sjögren’s syndrome, have a
labial salivary glands in patients with Sjögren’s 44-fold increased risk of developing lymphoma, of
syndrome. which 80% are extranodal marginal zone B-cell lym-
Population prevalence of Sjögren’s syndrome is phoma (MALT lymphoma) (1). The rate of develop-
about 0.5%; it is one of the most common autoimmune ment of lymphoma is estimated to be approximately
disorders together with rheumatoid arthritis and sys- 4% to 7% of the patients with LESA (1). The presence of
temic lupus erythematosus (13). Sjögren’s syndrome is progressive unilateral swelling of an enlarged parotid
clinically characterized by the presence of keratocon- gland, lymphadenopathy, splenomegaly, anemia, lym-
junctivitis sicca or xerophthalmia (dry eyes) and xero- phopenia, peripheral neuropathy, cutaneous vasculi-
stomia (dry mouth), caused by the involvement of the tis, and type II mixed monoclonal cryoglobulinemia is
lacrimal and salivary glands. Sjögren’s syndrome is suggestive of lymphoma (16). Therefore, careful obser-
classified into two forms: primary (or sicca complex) vation with close follow-up is required for patients
and secondary. Both types have dry mouth and eyes, with LESA and Sjögren’s syndrome. Therapy for
but in secondary Sjögren’s syndrome, there is the symptomatic control includes topical agents to
presence of one or more additional autoimmune dis- improve moisture and decrease inflammation for dry
orders, including rheumatoid arthritis, systemic lupus mouths. Systemic steroids may be used, but at present
erythematosus, progressive systemic sclerosis, poly- there are no established medication strategies for
myositis, primary biliary cirrhosis, and others. The the treatment of patients with severe systemic
involvement of the lacrimal and salivary glands by manifestations.
lymphocytic infiltration impairs the production of
tears and saliva, leading to dry eyes and dry mouth. Pathology
Dry mouth is accompanied by difficulty in swallow-
ing and speaking, alterations in taste, dental caries, Grossly, LESA presents as a diffuse enlargement of
and candidiasis. One-third of the patients also present the salivary glands or a nodular formation, which is
with systemic extraglandular manifestations involv- yellow to tan and resembles lymph node tissue. The
ing predominantly skin, lung, heart, kidneys, nervous latter appearance is sometimes mistaken for a true
and hematolymphoid systems. neoplasm. The overall lobular architecture and the
Autoantibodies specific for Ro (SS-A) and La capsule of the major salivary glands are maintained.
(SS-B) are strongly associated with Sjögren’s syn- The histologic hallmarks of LESA are dense
drome and are of major importance in diagnosis. lymphocytic infiltration, acinar atrophy, and areas of
Clinically, the Ro/La immunoglobulin A (IgA) titers lymphoepithelial lesion, previously referred to by the
are proven to be positively correlated with sicca inaccurate term epimyoepithelial islands, which show
symptoms and anti-Ro levels with the occurrence of various developmental stages (Figs. 36, 37). Initially,
diverse systemic disease manifestations. Rheumatoid small lymphocytic infiltrates are limited to around the
factors are also positive in approximately 60% of the intralobular salivary ducts (Fig. 36). Subsequently,
patients. Several viruses and genetic predispositions lymphocytic infiltration gradually increases and
have been implicated in the development of Sjögren’s replaces the parenchyma, resulting in marked acinar
syndrome. Histologically similar changes to LESA can atrophy or loss (Fig. 37A). The lobular architecture of
occur in HIV- and hepatitis C virus (HCV)-infected the normal glands and interlobular septa are generally
patients (14,15). However, despite extensive research preserved. Lymphoid follicles with germinal center
Table 3 International Classification Criteria for Sjögren’s Syndrome Proposed by the American-European Consensus Group
I. Ocular symptoms:
— A positive response to at least one of the following questions:
1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?
2. Do you have a recurrent sensation of sand or gravel in the eyes?
3. Do you use tear substitutes more than 3 times a day?
II. Oral symptoms:
— A positive response to at least one of the following questions:
1. Have you had a daily feeling of dry mouth for more than 3 months?
2. Have you had recurrently or persistently swollen salivary glands as an adult?
3. Do you frequently drink liquids to aid in swallowing dry food?
III. Ocular signs:
— That is, objective evidence of ocular involvement defined as a positive result for at least one of the following two tests:
1. Schirmer’s I test, performed without anaesthesia (5 mm in 5 min)
2. Rose Bengal score or other ocular dye score (4 according to van Bijsterveld’s scoring system)
IV. Histopathology:
— In minor salivary glands (obtained through normal-appearing mucosa) focal lymphocytic sialadenitis, evaluated by an expert
histopathologist, with a focus score 1, defined as a number of lymphocytic foci (which are adjacent to normal-appearing mucous
acini and contain more than 50 lymphocytes) per 4 mm2 of glandular tissue
V. Salivary gland involvement:
— Objective evidence of salivary gland involvement defined by a positive result for at least one of the following diagnostic tests:
1. Unstimulated whole salivary flow (1.5 mL in 15 min)
2. Parotid sialography showing the presence of diffuse sialectasias (punctate, cavitary, or destructive pattern), without evidence of
obstruction in the major ducts
3. Salivary scintigraphy showing delayed uptake, reduced concentration, and/or delayed excretion of tracer
VI. Autoantibodies:
— Presence in the serum of the following autoantibodies:
1. Antibodies to Ro(SSA) or La(SSB) antigens, or both
Rules for classification
- For primary Sjögren’s syndrome:
— In patients without any potentially associated disease, primary Sjögren’s syndrome may be defined as follows:
a. The presence of any 4 of the 6 items is indicative of primary Sjögren’s syndrome, as long as either item IV (Histopathology) or VI
(Serology) is positive.
b. The presence of any 3 of the 4 objective criteria items (i.e., items III, IV, V, VI).
c. The classification tree procedure represents a valid alternative method for classification, although it should be more properly
used in clinical-epidemiologic survey.
- For secondary Sjögren’s syndrome:
— In patients with a potentially associated disease (for instance, another well defined connective tissue disease), the presence of
item I or item II plus any 2 from among items III, IV, and V may be considered as indicative of secondary Sjögren’s syndrome.
Exclusion criteria:
- Past head and neck radiation treatment
- Hepatitis C infection
- AIDS
- Preexisting lymphoma
- Sarcoidosis
- Graft-versus-host disease
- Use of anticholinergic drugs (since a time shorter than 4-fold the half life of the drug)
Abbreviation: AIDS, acquired immunodeficiency syndrome.
formation may be present in areas of dense lymphoid marginal zone B cells are confined within the lymphoe-
infiltration. The interfollicular lymphoid infiltrate con- pithelial lesions. Monoclonality of lymphocytes by
stitutes a mixed population of polyclonal small B- and means of gene rearrangement analysis using polymer-
T-cell lymphocytes, scattered immunoblasts, histio- ase chain reaction can be demonstrated in LESA with-
cytes, and sometimes considerable numbers of plasma out any histologic evidence indicative of lymphoma
cells. (1,15,19,20). The irregularly shaped epithelial compo-
Residual ductal epithelium, on the other hand, nent of the lymphoepithelial lesions consists of polygo-
proliferates together with the permeation of lympho- nal or plump spindle cells exhibiting uniform elongated
cytes into the epithelium (Fig. 37B). Eventually, there nuclei with fine chromatin and indistinct nucleoli. The
is luminal obliteration, and the characteristic lym- epithelial cells exhibit no atypia, and mitoses are rare.
phoepithelial lesions develop. The permeating lym- The lymphoepithelial lesions may undergo squamous
phocytes are monocytoid and/or marginal zone B metaplasia, in rare cases being accompanied with kera-
cells. They are intermediate in size with irregularly tinization. Foci of hyaline basement membrane-like
shaped nuclei and abundant pale cytoplasm, some- material may be occasionally observed among the
what resembling centrocytes. The monocytoid and/or cells of the lesions. These lymphoepithelial lesions
Figure 36 Lymphoepithelial sialadenitis of the parotid gland.

Marked small lymphocytic cell infiltration is evident around the
salivary ducts accompanied by the formation of lymphoepithelial
lesions (epimyoepithelial islands).
were previously considered to be composed of both

ductal epithelial cells and myoepithelial cells; thus the
term epimyoepithelial islands has been used for a long
time. However, recent immunohistochemical studies
suggest a lack of myoepithelial cell participation, as
mentioned above (11,12). Cystically dilated salivary
ducts may uncommonly be observed.
The histologic feature of LESA seen in the major
salivary glands can occur in the minor salivary glands
of the patient with Sjögren’s syndrome. In the minor
salivary glands, however, the typical histologic picture Figure 37 Lymphoepithelial sialadenitis of the parotid gland.
(A) Several well-developed lymphoepithelial lesions (epimyoepi-
is described as focal lymphocytic sialadenitis, and lym-
thelial islands) are present within a dense lymphoid infiltration.
phoepithelial lesion, an essential finding of LESA in the (B) The lymphoepithelial lesion is characterized by the prolifera-
major salivary glands, is rarely encountered (Fig. 38). tion of ductal epithelium and the permeation of monocytoid type
The histologic appearance of a labial biopsy sample is lymphocytes. Foci of hyaline basement membrane-like material
one of the important features for diagnosis of Sjögren’s are also observed among the cells of the lesions. Note that the
syndrome (21). In the patients with Sjögren’s syndrome, formation of a halo of monocytoid cells around the lymphoepi-
even without apparent clinical enlargement, character- thelial lesions is not evident. Monoclonality of the lymphoid cells
istically there are greater than or equal to one focus was not proven by means of immunohistochemical and molecu-
score, where a focus is defined as a focal lymphocytic lar genetic studies in this case.
aggregate consisting of more than 50 lymphocytes per
4 mm2 of salivary gland tissue adjacent to normal-
appearing mucous acini (18). At least four lobules in
the biopsy sample are required for the assessment. and/or marginal zone B cells may be prominent
inside the lymphoepithelial lesions in LESA, but if
Differential Diagnosis these cells are present outside the lymphoepithelial
lesions and form either broad halos or confluent areas
Differential diagnoses of LESA include malignant in interfollicular regions, MALT lymphoma should be
lymphoma, lymphoepithelial carcinoma, lymphade- considered (1). In addition, the presence of sheetlike
noma, chronic nonspecific sialadenitis, and HIV- proliferation of plasma cells, with or without Dutcher
associated lymphoepithelial cysts (LECs). bodies, also favors a diagnosis of lymphoma. Further-
The distinction between LESA and malignant more, the demonstration of monoclonality by immu-
lymphoma, especially of extranodal marginal zone nohistochemistry or flow cytometry gives supportive
B-cell type (MALT lymphoma), may be difficult and evidence of MALT lymphoma rather than LESA.
is still a controversial issue (see also the section Both lymphoepithelial carcinoma, formerly
‘‘Malignant Lymphomas’’) (1,5,19,20,22). Monocytoid sometimes referred to as ‘‘malignant lymphoepithelial
lesion,’’ and LESA are composed largely of two ele-

ments: epithelial nests and lymphoid infiltrate.
Lymphoepithelial carcinoma may rarely arise in the
setting of a LESA-like lesion. Unlike lymphoepithelial
carcinoma, however, epithelial cells constituting lym-
phoepithelial lesion in LESA lack nuclear atypia,
coarse chromatin pattern, and mitotic activity.
Lymphoepithelial carcinoma often infiltrates into the
surrounding salivary gland tissues accompanied by
lymphoid stroma. Additionally, epithelial nests of
lymphoepithelial carcinoma are larger and have a
more irregular outline than those of LESA. Moreover,
the presence of EBV revealed by EBV-encoded small
RNA (EBER) in situ hybridization, over-expression of
p53, and high–cell proliferative activity may be useful
for distinguishing lymphoepithelial carcinoma from
LESA (23). Lymphadenoma is a rare benign neoplasm
composed of variable-sized islands of epithelial cells
enclosed within a prominent lymphocytic infiltrate
similar to LESA, but in contrast to LESA, lymphade-
noma is a well-circumscribed lesion (24).
Chronic nonspecific sialadenitis is sometimes
confused with LESA, but in the former, the inflamma-
tory infiltrate usually consists of a mixture of lympho-
cytes, plasma cells, and macrophages, as well as
neutrophils, and is associated with prominent fibrosis.
In addition, there are no well-developed lymphoepi-
thelial lesions (14,21,25). Lymphoid hyperplasia can
develop in the salivary glands, especially the parotid
gland, in the patients with HIV infection. In such
instances, referred to as HIV-associated LECs, dilata-
tion of the residual ducts is more pronounced than in
LESA (26).
G. Introduction to Salivary Gland

Tumors
Epidemiology
There have been few large-scale studies on the epide-
miology of salivary gland neoplasms (1). In addition,
there has been considerable variation in how data
have been interpreted. For example, some studies
have included only parotid tumors, or tumors in the
major salivary glands. In some cancer registries only
malignant salivary tumors are recorded. In one study,
Warthin’s tumor, which is the second most common
salivary neoplasm, was excluded from the series (2).
Several investigators have highlighted the possibility
that their quoted incidence rates, for benign tumors
particularly, were underestimates (1,3,4). When all
Figure 38 Sjögren’s syndrome. Labial biopsy specimen. (A) Low- salivary gland tumors are included, the global annual
power view shows several foci of periductal lymphoid aggregates in incidence rates have ranged from 0.4 to 13.5 cases per
the labial minor salivary gland. (B) Foci of small lymphocytic 100,000 patients (5). The annual incidence for malig-
aggregation around the intralobular ducts accompanied by lym- nant salivary gland tumors only, varied from 0.4 to
phoepithelial lesions (epimyoepithelial islands) are evident. In 2.6 cases per 100,000 population (1,6–8). Malignant
general, lymphoepithelial lesions characteristic of lymphoepithelial
salivary gland tumors accounted for 6% of head and
sialadenitis in the major salivary glands are uncommonly observed
in the minor salivary glands. (C) High-power view demonstrates neck cancers and 0.3% of all malignant neoplasms in
small lymphocytes and plasma cells infiltrating periductal area and the United States between 1973 and 1988 (9). There
the formation of the early stage of lymphoepithelial lesion consisting have been a limited number of studies reporting time
of the duct epithelium permeated by monocytoid lymphoid cells. trends in the incidence, but several have suggested an
increasing frequency since the 1980s, particularly in
the elderly population (10–13). In the United States, in nonendemic regions (32). Most studies have not
there appears to have been a significant increase in detected EBV in other salivary gland tumors or nor-
the incidence of malignant salivary gland tumors mal parotid gland (28,33). However, EBV has been
during the period 1974 to 1999 (1.0–1.1/100,000 pop- reported in several cases of intranasal pleomorphic
ulation). In addition, salivary neoplasms accounted adenoma (34). No etiologic role has been found for
for 8.1% of all head and neck tumors during this cytomegalovirus in benign parotid tumors (33).
period (14). In the older literature there is an equal Pleomorphic adenomas have been shown to contain
sex incidence in white Americans and a slightly Simian virus 40 (SV40) DNA sequences and express
increased incidence in the black population (15). the SV40 large T antigen (35), but no association has
However, a more recent study showed a slight male been found with polyoma virus or papillomavirus in
predominance (M:F 1.5:1) (6). Although the data on human salivary tumors.
geographic distribution and ethnicity are limited, in Radiation. There is strong evidence for a close
most reports there appears to be minimal variation in association between ionizing radiation and salivary
incidence or the distribution of individual tumor gland tumors. In survivors of the atom bomb explo-
types. One exception to this was the very high inci- sions in Hiroshima and Nagasaki, there was a 3.5
dence of lymphoepithelial carcinomas in the North relative risk of developing benign salivary tumors
American Inuit population in the middle of the twen- and an 11 increased risk for malignant tumors
tieth century (16,17). At that time these tumors (36–39). In addition, the relative risk was directly
accounted for 25% of all malignancies in this popula- related to the distance from the epicenter of the
tion. Since then there has been a significant decline in explosions and the level of exposure to ionizing
its frequency. In Malaysia there is a higher frequency radiation. There was a high frequency of both War-
of salivary tumors in ethnic Malays than Indians or thin’s tumor and mucoepidermoid carcinoma in
Chinese (18). A higher relative frequency of malignant these patients (40). Therapeutic radiation of the
intraoral salivary gland tumors has been reported in a head and neck has also been implicated in salivary
Chinese population (19). gland neoplasia. This is typically a late consequence
and can result in both benign and malignant tumors
Site, Age, and Sex Distribution (41–44). Iodine131 used to treat thyroid disease is also
concentrated in salivary glands and increases the risk
In major series, the parotid gland is the site of between of salivary tumors (45). Routine dental diagnostic
64% and 80% of all salivary primary epithelial tumors radiographs may also be associated with an
(20). Seven percent to eleven percent of tumors increased risk (46,47). There is also evidence of an
involve the submandibular glands, and less than 1% association between cutaneous and salivary neo-
occur in the sublingual glands. Tumors in the minor plasms, with both showing a pattern of incidence
glands account for 9% to 23% of cases (5,21–24). Fifty- suggestive of susceptibility to ultraviolet radiation
four percent to seventy-nine percent of these are exposure (48,49). There is an increased risk of pre-
benign and 21% to 46% are malignant. There are dominantly malignant salivary tumors in survivors
striking variations in the ratio of benign to malignant of childhood cancer in the head and neck region that
tumors in different sites. For example, malignant had been treated by a combination of chemotherapy
tumors comprise 15% to 32% of parotid tumor, 41% and radiotherapy (50). The relationship, in any,
to 45% of submandibular tumors, and the large major- between salivary tumors and high-frequency electro-
ity of sublingual tumors (*90%). About half of minor magnetic fields from cellular telephones is conten-
gland tumors are malignant (19,25), and there appears tious, but most large-scale studies show no increased
to be variations in the frequency, age distribution, and risk (51,52). However, a recent study of a population
sex ratio in different populations (26). In the floor of with higher than average mobile telephone use
the mouth, tongue, and retromolar trigone between appears to show a higher frequency of benign parotid
80% and 90% of salivary tumors are malignant (5). tumors (53). There in no excess incidence of salivary
Although there is a slight overall female predomi- tumors in those exposed to radon gas (54).
nance, the sex ratio varies in different tumor types. Occupation. There is increased risk of develop-
There is a wide age distribution with a peak incidence ing salivary gland tumors in a diverse range of indus-
in the fifth decade. Pleomorphic adenoma is the most tries, including rubber manufacturing (55,56),
common tumor and accounts for over half of salivary plumbing (57), and woodworking in the automobile
tumors in most large series. The second most common industry (58). Exposure to nickel compounds (56),
neoplasm is Warthin’s tumor, which typically forms formaldehyde, and solvents has been implicated
about 10% to 15% of cases. (59). There appears to be a higher incidence of salivary
gland cancer in women working in hairdressing and
Etiology beauty shops (60,61). However, there is no increased
risk from the personal use of hair dyes (62). In Quebec
Viruses. Several viruses have been implicated there was an increased risk in populations living close
in the development of salivary tumors. However, the to asbestos mines, and the risk was directly related to
only strong association is between EBV and lymphoe- the distance from the mines (63).
pithelial carcinoma (27–29). Although the large major- Lifestyle and nutrition. The majority of studies
ity of cases of this tumor affect Asians (30) and have failed to demonstrate an association between
Greenlandic Inuits (31), sporadic cases are reported most salivary gland tumors and either cigarette
smoking or alcohol consumption (64–66). One study Imaging

showed an elevated risk in men but not women (56).
However, there is a close association between cigarette When dealing with salivary gland diseases, a detailed
smoking and Warthin’s tumor, and this is discussed in clinical history and physical examination will usually
section ‘‘Warthin’s tumor, ’’ page 525. There has only lead to a reasonable clinical diagnosis. Salivary gland
been one study on the relationship, if any, between diet diseases such as self-limiting entities like viral paroti-
and the development of salivary tumors (67). This tis may not require any imaging studies. However,
appeared to show an inverse relationship between imaging is often necessary to confirm the clinical
salivary gland tumors and consumption of antioxidant findings and determine the location and extent of
vitamins, beans, and carotenoids. It was suggested that pathologic changes.
high blood cholesterol was associated with an Ultrasound, CT, and MRI are the most common
increased risk. Exposure to silica dust and kerosene imaging procedures for the diagnosis of mass-forming
as a cooking fuel appeared to increase the risk lesions of the salivary glands (1–8). In Europe and
of salivary gland cancers in a Chinese population Japan, ultrasound is frequently the first imaging
(68). In a European study, a higher level of malignant modality used to assess superficial salivary gland
salivary gland tumors has been associated with expo- lesions, with accuracy similar to that of CT and MRI
sure to nickel, chromium, asbestos, and cement dust (3,4,7). Neoplasms are always hypoechoic relative to
(69). There is a single retrospective controlled study the normal hyperechoic glandular tissue. Although
suggesting an increased prevalence of type II diabetes ultrasound can also be used to guide fine-needle
and obesity in patients with salivary gland tumors (70). aspiration cytology or core needle biopsy to confirm
Hormones. Although sex steroid hormone their benign or malignant nature, it cannot evaluate
receptors have been described in normal and neo- the deep lobe of the parotid gland and the extent of
plastic salivary glands, there have been conflicting large tumors. In such circumstances, CT and MRI play
reports. Estrogen receptors were found in normal an important role instead. MRI is particularly useful in
salivary glands in both men and women (71). It was assessing perineural, vascular, meningeal, and skull
also reported that half of the salivary tumors in base invasion (5). Additionally, CT and MRI are
women had estrogen receptor levels comparable helpful in the evaluation of cervical lymph nodes for
with those seen in hormonally dependent breast metastasis. Minor salivary gland neoplasms are often
tumors. However, other workers have failed to con- difficult to assess on clinical examination, and the use
firm these finding and the methodology has been of preoperative CT or MRI is important for the deter-
questioned (72). Estrogen receptors have been mination of the tumor extent. In many cases, however,
reported in a minority of mucoepidermoid carcino- accurate discrimination between benign and malig-
mas, acinic cell carcinomas (73), and salivary duct nant tumors and the prediction of the histology of
carcinomas (73). No estrogen receptors have been tumors are not possible on ultrasound and/or CT as
reported in adenoid cystic carcinomas (72–76). Estro- well as MRI studies.
gen receptors have been reported in some pleomor- Almost all parotid gland tumors are readily
phic adenomas (73,77,78), but others have failed to identified on T1-weighted MRI as a lesion with low
confirm this finding (79). Reduced expression of signal intensity relative to the high signal intensity of
estrogen receptor-b in salivary duct carcinoma was the background. Pleomorphic adenomas generally
associated with adverse clinical features (80). Proges- have high signal intensity on T2-weighted images,
terone receptors have been reported in normal sali- whereas a mass of intermediate or low signal intensity
vary glands (74,81) and in a minority of pleomorphic on T2-weighted images raises the possibility of malig-
adenomas (73,81). Interestingly, high levels of pro- nancy. The high signal intensity of pleomorphic ade-
gesterone receptors have been reported in recurrent noma on T2-weighted images is attributed to myxoid
pleomorphic adenomas (81). However, another study tissue within the tumor. In addition, pleomorphic
failed to show evidence of these receptors in any of adenomas usually show homogeneous enhancement
the benign salivary gland tumors examined (79). following gadolinium administration, although het-
Progesterone receptors were found in 2 of 10 acinic erogeneous enhancement may be observed in large
cell carcinomas and 3 of 10 mucoepidermoid lesions or cystic tumors (9).
carcinomas, but were not detected in salivary duct Warthin’s tumors typically show complex lesions
carcinomas (82). Adenoid cystic carcinomas have on T1- and T2-weighted images, containing areas that
been positive for progesterone receptors in some are solid and cystic. The cystic foci appear as areas of
studies (74,83), but either infrequent or negative in high signal intensity on T2-weighted images. Unlike
others (72,73). Androgen receptors are seen in the pleomorphic adenomas, Warthin’s tumors lack
large majority (*90%) of salivary duct carcinomas enhancement following gadolinium administration.
(84–86). In addition, androgen receptors were Nuclear scintigraphy may be useful in diagnosing
detected in all the cases of salivary duct carcinoma, Warthin’s tumor and oncocytoma. These neoplasms
carcinoma ex pleomorphic adenoma, and basal cell are unique in that they show increased isotope uptake
carcinomas examined in one study (79). A fifth of the on 99m technetium (Tc) scintigraphic studies (10).
acinic cell carcinomas, mucoepidermoid carcinomas, Nonneoplastic cystic lesions commonly have high sig-
and adenoid cystic carcinomas were positive for nal intensity on T2-weighted images.
androgen receptors but all the benign tumors were High-grade malignancies tend to have irregular
negative. margins along the glandular parenchyma and/or
infiltration into the adjacent extraglandular spaces, widely used among clinicians and pathologists in the
which can be detected by both MRI and CT. Color diagnosis of salivary gland tumors. The main pur-
Doppler ultrasound may also be useful, as malignant poses of FNAC of the salivary gland lesions are to
salivary gland neoplasms frequently show a higher determine whether a process is inflammatory or neo-
grade of vascularity compared with benign neoplasms plastic; is benign or malignant; represents a carcinoma
(11). Positron emission tomography can be used to or a malignant lymphoma; to render a specific diag-
diagnose and plan treatment of salivary gland malig- nosis, if possible (3). In about one-third of cases,
nancies by detecting lymph node metastases and/or unnecessary surgery can be avoided by means of
distant metastases. FNAC diagnosis, especially when the lesions are
Ultrasound or CT is the examination of choice in inflammatory, lymphoproliferative disease including
patients with inflammatory salivary gland diseases malignant lymphoma, generalized disease, or metas-
(12). Plain radiography is still a helpful method to tasis to a salivary gland or adjacent lymph node (1,3).
diagnose sialolithiasis; 90% of submandibular stones FNAC of salivary gland tumors can be challeng-
are radiopaque, while most parotid stones are radio- ing. Factors causing diagnostic difficulties in cytopa-
lucent. Ultrasound and CT also easily detect calcified thologic evaluation of salivary gland neoplasms
stones. The latter is often the best initial study for the include diverse cytomorphology, scanty structural
evaluation to identify the calculi in the gland. On information as to cell to cell or cell to stromal compo-
ultrasound, sialolithiasis is always hyperechogenic nent, sampling problems, and the infrequency of
enclosed in a hypoechogenic halo representing the many tumor types resulting in limited experience
dilation of the duct. However, ultrasound is less and lack of familiarity by cytotechnologists and path-
accurate than CT in distinguishing multiple clusters ologists. The salivary gland tumors are unique in their
of stones from single large stones. Sialography is histologic complexity and morphologic variability,
contraindicated in the acute setting of sialadenitis reflecting in the cytologic material. While architecture
because of the possibility of exacerbating the symp- and circumscription are frequently helpful in the
toms associated with the infection. histopathologic differential diagnosis of salivary
Conventional and/or MR sialography are useful gland neoplasms, these clues are usually lacking in
in staging Sjögren’s syndrome, since patients’ symptoms cytologic preparations. If necessary, a cell block is
may not correlate well with severity of the disease. On prepared from cells entrapped in a blood clot or tiny
conventional sialography, the gland texture of patients tissue particles obtained by FNAC. The cell block
with Sjögren’s syndrome becomes heterogeneous and enables the pathologist to examine the tissue like a
reticulated, and multiple cysts may also be observed biopsy, and multiple sections can be obtained from
corresponding with sialectatic changes. MR sialography paraffin-embedded material for immunohistochemi-
may replace conventional sialography because MR sia- cal study. The cytologic examination is very limited
lography has the advantage of not requiring cannulation because the needle targets only a small area of the
of the duct (13,14). Salivary glands in patients with neoplasm. The sampled area in an aspiration biopsy
Sjögren’s syndrome show punctate, globular, and may represent only one of the patterns if a given
destructive patterns by MR sialography. However, in neoplasm shows diverse morphology.
most cases, the diagnosis of Sjögren’s syndrome is Because of the relatively high false-negative rate,
clinically based on the sicca syndrome, association ranging from 5% to 48% in the literature, treatment
with other connective tissue disorders, serology of anti- and follow-up of patients with salivary gland tumors
nuclear antibodies, and a lip biopsy. should not be based on FNAC results alone (2,4–6).
Negative FNAC findings alone should not prevent
Fine-Needle Aspiration Cytology surgical intervention when it is otherwise clinically
indicated. Fine-needle aspiration cytology combined
Since major salivary glands are superficially located with careful clinical examinations and imaging stud-
and easily accessible organs, they are optimal targets ies can lead to correct diagnosis and may help avoid
for fine-needle aspiration cytology (FNAC). This is a unnecessary surgery. False-negative results can be
quick, minimally invasive, and technically simple attributed to various factors including the quality
procedure that can be performed in any outpatient and quantity of FNAC material and sampling errors.
setting. However, there are some controversies about Ultrasonographic or CT guidance may help reduce
the use of FNAC in the diagnosis of salivary gland these problems.
tumors. The issues include rare but potentially serious Generally, FNAC is considered to have high
complications arising from the procedure, such as sensitivity and specificity in detecting salivary gland
tumor seeding along the needle tract, tumor dissemi- lesions (2,4–9). The diagnostic sensitivity and specifici-
nation, injury to the seventh cranial nerve and hemor- ty for neoplastic or nonneoplastic lesions have been
rhage. In addition, the FNAC procedure itself can reported as 62% to 98% and 85% to 100%, respectively
induce traumatic tissue injury and infarcts, causing (2). The reported overall accuracy rate of FNAC in
reactive pseudomalignant changes, which may be establishing a diagnosis as benign or malignant has
misdiagnosed as malignant (1). Despite these misgiv- been reported to be from 81% to 100% (2,3,6). However,
ings, it has been shown that FNAC of the salivary the rate of a correct specific diagnosis falls into the
gland lesions is a basically safe and effective diagnos- range from 48% to 75% (1,6). The benign lesions that are
tic technique (1,2). Thus, FNAC has gained wide most often misdiagnosed as malignant are basal cell
acceptance as a first-line diagnostic procedure and is adenoma, intraparotid lymph node, oncocytoma, and
granulomatous sialadenitis (6). The malignant lesions Frozen section diagnosis depends on both the
that are most frequently misdiagnosed as benign are ability of the pathologist to give an accurate histologic
lymphoma, acinic cell carcinoma, low-grade mucoepi- diagnosis and the experience of the surgeon to inter-
dermoid carcinoma, adenoid cystic carcinoma, and pret the results and provide optimal surgical therapy.
polymorphous low-grade adenocarcinoma. Although frozen section diagnosis of salivary gland
Since many benign and malignant salivary gland neoplasia frequently is challenging for the general
tumors share similar or overlapping cytologic features, pathologist, it is reported to be highly reliable in
FNAC may occasionally suffer from certain pitfalls in differentiating between benign and malignant dis-
the diagnosis of these tumors (6,9,10). The most com- eases. According to a review of 2460 frozen section
mon difficulty in FNAC is the distinction of benign diagnoses from 24 series, an overall accuracy rate for
neoplasms, such as cellular pleomorphic adenoma, identifying lesions as a benign or malignant, excluding
basal cell adenoma, and myoepithelioma, from malig- deferred diagnoses, was 96.3% (2). However, frozen
nant neoplasms, such as polymorphous low-grade section diagnosis for malignant salivary gland tumors
adenocarcinoma, adenoid cystic carcinoma, and epithe- is more difficult and less accurate than for benign
lial-myoepithelial carcinoma. These lesions have very tumors, the accuracy rate for benign and malignant
similar nuclear features of relatively small, bland, nuclei tumors being 98.7% and 85.9%, respectively. Therefore,
of the epithelial and/or myoepithelial-type cells and a therapeutic decision should never be made on the
basement membrane–like stromal material. The distinc- basis of a frozen section diagnosis alone, but always in
tion between different subtypes of pleomorphic aden- conjunction with the clinical findings. False-positive
oma, basal cell adenoma, and myoepithelioma is not rates (benign tumors initially diagnosed as malignant)
critical, as the clinical management is identical and the and false-negative rates (malignant tumors initially
clinical course is benign. However, it is especially diagnosed as benign) were 1.1% and 2.6%,
important for proper surgical management to distin- respectively.
guish adenoid cystic carcinoma from the other lesions The most common benign tumor overdiagnosed
in this group because adenoid cystic carcinomas often as malignant was pleomorphic adenoma, which
require more radical treatment. Other common diag- was frequently misdiagnosed as mucoepidermoid
nostic dilemmas in salivary gland FNAC include carcinoma or adenoid cystic carcinoma (2). Oncocy-
mucoepidermoid carcinoma versus reactive processes, toma, basal cell adenoma, Warthin’s tumor, lymphoe-
such as necrotizing sialometaplasia and chronic siala- pithelial sialadenitis, lymphoepithelial cyst, and
denitis with squamous or goblet cell metaplasia of the sarcoidosis have also caused difficulty. On the other
salivary ductal epithelial cells and acinic cell carcinoma hand, mucoepidermoid carcinoma was the tumor
versus normal salivary gland acinar cells. most commonly involved in false-negative diagnosis,
followed by acinic cell carcinoma, adenoid cystic
Frozen Section Diagnosis carcinoma, carcinoma ex pleomorphic adenoma, and
malignant lymphoma. Chronic sialadenitis and necro-
Preoperative imaging examinations, such as ultra- tizing sialometaplasia were most important
sound, CT, and MRI, are frequently employed to in the differential diagnosis for mucoepidermoid
characterize a salivary gland lesion before surgery. carcinoma (1).
However, while certain imaging features can favor or The main reason for the false-negative errors is
suggest a diagnosis of malignancy, they are often not inadequate sampling, by either the surgeon or by the
sufficiently characteristic or reliable to make a specific pathologist (2). Sampling errors can be minimized if
diagnosis. FNAC has also been widely used for the pathologists receive and examine the entire speci-
assessing salivary gland lesions preoperatively. men. Since several types of salivary gland malignancy
Although high sensitivity and specificity of the proce- can be identified only on the basis of their invasive
dure are reported, there are some controversies regard- nature rather than cellular or architectural features,
ing the accuracy in the diagnosis of salivary gland frozen sections should always include the neoplasm,
tumors, especially that of malignant lesions. Histologic tumor capsule if present, and surrounding salivary
diagnosis of the major salivary gland lesions by inci- gland tissue and/or soft tissue to evaluate tumor
sional biopsy is generally contraindicated because of circumscription as possible. Sampling should never
the possibility of facial nerve injury and tumor seed- be limited to the middle of the tumor. Benign tumors
ing. On the other hand, frozen section diagnosis is a with multinodularity, such as recurrent pleomorphic
potentially useful modality for the surgical manage- adenoma, oncocytoma, the membranous type of basal
ment of salivary gland lesions (1–7). The role of frozen cell adenoma, and canalicular adenoma, must not be
section diagnosis of salivary gland lesions is to provide misinterpreted as malignancy.
information that would influence immediate surgical Finally, if a definite diagnosis cannot be made by
treatment. When the preoperative diagnosis is disput- frozen section assessment, further surgery should be
ed, frozen section diagnosis is often requested to deferred until a final histopathologic diagnosis on
determine whether the lesion is benign or malignant. permanent sections is obtained (1). However, the
If the lesion is malignant, frozen section diagnosis is surgeon often has immediate need of the information
recommended to establish the exact type of malignan- whether the tumor is benign or malignant. Close
cy. Frozen section diagnosis is also performed to discussion between the pathologist and surgeon is
examine the extent of tumors, status of resection essential to reach an accurate diagnosis and to prevent
margins, and the involvement of lymph nodes. any unnecessary extensive surgery.
Genetics leiomyomas, and myeloid malignancies (15). How-

ever, because the PLAG1- or HMGA2-containing
Recent molecular genetic studies have provided fusion genes described above have so far been identi-
important information on genetic and epigenetic alter- fied only in pleomorphic adenomas, their detection
ations in salivary gland tumors, especially on impli- using reverse transcriptase-polymerase chain reaction
cations of their tumorigenesis, differential diagnosis, or fluorescence in situ hybridization may be potentially
and therapeutic strategies (1,2). useful in cases of difficult differential diagnoses.
Specific chromosomal translocations have been In mucoepidermoid carcinomas, a specific
reported in pleomorphic adenomas and mucoepider- chromosomal translocation, t(11;19)(q21;p13), which
moid carcinomas. In approximately 70% of cases of creates a fusion transcript of MECT1 (mucoepider-
pleomorphic adenoma, cytogenetic aberrations can be moid carcinoma translocated-1) at 19p13 with
demonstrated in one of the following three patterns: MAML2 (mastermind-like gene family) at 11q21,
(i) chromosomal rearrangement of 8q12 (39% of cases), has been found in up to 70% of cases (16–18). The
such as t(3;8)(p21;q12), t(5;8)(p13;q12); (ii) chromo- MECT1-MAML2 fusion transcript acts as a coactiva-
somal rearrangement of 12q13–15 (8% of cases), such tor for Notch receptor transcriptional activation and
as t(9;12)(p24;q14–15), ins(9;12)(p24;q12q15); (iii) spo- signalling (19). This translocation is frequently asso-
radic, clonal changes not involving 8q21 or 12q13–15 ciated with a low-grade histology, and the presence
(23% of cases) (3,4). The target gene in pleomorphic of the transcript appears as an independent prognos-
adenomas with 8q12 abnormalities is PLAG1 (pleo- tic factor of mucoepidermoid carcinoma (16,17).
morphic adenoma gene 1), which is a developmentally Recently, a fusion between EWSR1 and POU5F1 has
regulated zinc finger gene (5). The partner genes also been reported in a single case of high-grade
include CTNNB1 (b-catenin) in t(3;8)(p21;q12) (5), mucoepidermoid carcinoma with the translocation,
LIFR (leukemia inhibitory factor receptor) in t(5;8) t(6;22)(p21;q12) (20). These fusion transcripts can
(p13;q12) (6), and SII (transcription elongation factor potentially be utilized to establish the diagnosis and
SII) in a cryptic translocation (7). Fusion products expected to be useful in the development of novel
CHCHD7–PLAG1 or TCEA1–PLAG1 can also occur molecular therapeutic strategies for mucoepidermoid
resulting from cryptic, intrachromosomal 8q rear- carcinoma.
rangements (8). Translocations involving 8q12 result The most frequent cytogenetic aberrations in
in promoter swapping between PLAG1 and a ubiqui- adenoid cystic carcinomas involve chromosomes 6q,
tously expressed translocation partner gene, leading 9p, 12q, 17p, and 19q regions (21). Loss of heterozy-
to ectopic PLAG1 over-expression and reduced gosity at 6q 23–25 correlated with histologic grade and
expression of the partner gene (5–8). The PLAG1 clinical behavior in this tumor (22). On the other hand,
protein is a nuclear oncoprotein that functions as a in one study of 25 acinic cell carcinomas, 84% of the
DNA-binding transcription factor, which has been tumors had alteration in at least one of the 20 chromo-
postulated to play an important role in the oncogene- somal loci on 1, 4, 5, 6, and 17, most frequently at
sis of pleomorphic adenomas (9,10). This was estab- chromosomes 4p, 5q, 6p, and 17p regions (23). Con-
lished by microarray analysis, which indicated that current analysis of the benign and malignant compo-
the oncogenic capability of PLAG1 is mediated, at nents of carcinoma ex pleomorphic adenoma showed
least partly, by the IGF-II mitogenic signaling path- alterations of chromosome 8q and/or 12q in both
way (9). However, oncogenic activation of PLAG1 components and additional alterations in 17p only in
itself is also a crucial event in other human tumors, the carcinoma (24). The same cytogenetic abnormality
including lipoblastoma, hepatoblastoma, and acute in the chromosome 16q12–13 region, the CYLD (cylin-
myeloid leukemia (10). dromatosis gene) between dermal cylindromas, and
The target gene in pleomorphic adenomas with membranous basal cell adenomas has been reported
rearrangements on chromosome 12q13–15 is the high- in two familial cases (25).
mobility group protein gene, HMGA2 (previously Mutation and over-expression of p53 are found
known as HMGIC). The partner genes are FHIT (frag- in a relatively high proportion of high-grade salivary
ile histidine triad gene) in t(3;12)(p14.2;q14-15) (11), gland carcinomas, such as salivary duct carcinoma,
NFIB (nuclear protein involved in transcriptional reg- carcinoma ex pleomorphic adenoma, large cell carci-
ulation) in ins(9;12)(p23;q12q15) (12), and WIF1 (Wnt noma, dedifferentiated carcinoma, and hybrid carci-
inhibitory factor 1) (13). The gene fusion results in noma. Salivary duct carcinomas are usually distinctly
separation of the DNA-binding domains from poten- positive for HER-2/neu protein with or without the
tial mRNA-destabilizing motifs, leading to deregula- gene amplification by means of fluorescence in situ
tion of HMGA2 expression. The HMGA2 protein acts hybridization (26–28).
as an architectural transcription factor that promotes Oligonucleotide microarray analysis identified
activation of gene expression by modulating the con- several genes that were associated with adenoid
formation of DNA (12,13). High-level expression of cystic carcinoma (29). The most overexpressed
HMGA2 resulting from gene amplification was sug- genes encoded by adenoid cystic carcinoma included
gested to be of importance for malignant transforma- basement membrane and extracellular matrix proteins
tion of pleomorphic adenomas (14). Cytogenetic of myoepithelial differentiation, such as laminin-b1,
abnormalities on 12q14 involving the HMGA2 gene versican, biglycan (BGN), and type IV collagen-a1.
can also be identified in other variety of benign and Other genes, which were highly expressed in adenoid
malignant tumors as well, such as lipomas, uterine cystic carcinoma compared with the other carcinomas,
included transcription factors SOX-4 and AP-2 family, Table 4 WHO Histologic Classification of Tumors of the
and members of the Wnt/b-catenin signaling pathway, Salivary Glands, 2005
such as casein kinase 1, epsilon, and frizzled-7. Compar- Malignant epithelial tumors Benign epithelial tumors
ative gene expression profiles were studied in mucoe- Acinic cell carcinoma Pleomorphic adenoma
pidermoid carcinoma, acinic cell carcinoma, and Mucoepidermoid Myoepithelioma
salivary duct carcinoma (30). Only 5 out of 162 carcinoma Basal cell adenoma
genes were overexpressed in all carcinomas, including Adenoid cystic carcinoma Warthin’s tumor
fibronectin 1 (FN1), tissue metalloproteinase inhibitor Polymorphous low-grade Oncocytoma
1 (TIMP1), BGN, tenascin-C (HXB), and insulin-like adenocarcinoma Canalicular adenoma
growth factor binding protein 5 (IGFBP5), whereas 16 Epithelial-myoepithelial Sebaceous adenoma
genes, which are related to cell-cycle proteins, proteins carcinoma Lymphadenoma
Clear cell carcinoma, not Sebaceous
of signal transduction and translation, were underex- otherwise specified Nonsebaceous
pressed. Other microarray studies demonstrated dif- Basal cell Ductal papillomas
ferential gene expression profiles in pleomorphic adenocarcinoma Inverted ductal
adenoma, adenoid cystic carcinoma, mucoepidermoid Sebaceous carcinoma papilloma
carcinoma, clear cell carcinoma, acinic cell carcinoma, Sebaceous Intraductal papilloma
and salivary duct carcinoma (31). lymphadenocarcinoma Sialadenoma
Methylation is one of the epigenetic modifica- Cystadenocarcinoma papilliferum
tions that play an important role in the transcriptional LGCCC Cystadenoma
inactivation of tumor suppressor genes in human Mucinous Soft tissue tumors
cancer. Recent methylation studies revealed that adenocarcinoma Haemangioma
Oncocytic carcinoma Hematolymphoid tumors
methylation in promoter regions at E-cadherin gene Salivary duct carcinoma Hodgkin’s lymphoma
has been often identified in adenoid cystic carcino- Adenocarcinoma, not Diffuse large B-cell
mas (32,33). Also, in adenoid cystic carcinomas, otherwise specified lymphoma
frequent promoter methylation was found in cyclin- Myoepithelial carcinoma Extranodal marginal
dependent kinase inhibitors genes; such as p15, Carcinoma ex pleomor- zone-B cell lymphoma
p16INK4a, p18, p19, and p21; ras-association domain phic adenoma Secondary tumors
isoform A (RASSF1A); and the death-associated pro- Carcinosarcoma
tein kinase (DAPK) (34,35). About one-third of Metastasizing
mucoepidermoid carcinomas showed methylation pleomorphic adenoma
of the p16INK4a gene–promoter region (36). High Squamous cell
carcinoma
percentage of methylation occurred at RASSF1 and Small cell carcinoma
retinoic acid receptor b2 (RARb2) genes in salivary Large cell carcinoma
duct and acinic cell carcinomas (37). Furthermore, Lymphoepithelial
relatively high frequency of promoter methylation in carcinoma
tumor suppressor gene RB1 was detected in salivary Sialoblastoma
gland carcinomas (38). Abbreviation: LGCCC, Low-grade cribriform cystadenocarcinoma.
Classification
Salivary gland tumors can show a strikingly diverse Staging
range of histomorphologic differentiation and archi-
tectural configurations. This has led to a plethora of The TNM Classification only applies to carcinomas of
individual tumor types and a frequently changing the major salivary glands: parotid (C07.9), submandib-
terminology. In addition, this variability is seen within ular (C08.0), and sublingual (C08.1) glands (1, 2, 3).
many of these tumor entities, each of which may have Tumors arising in minor salivary (mucus-secreting
several named subtypes. Classification is further com- glands in the lining membrane of the upper aerodiges-
plicated by the presence of dedifferentiated and tive tract) are not included in this classification but at
hybrid tumors. As emphasized by Ellis and Auclair their anatomic site of origin. There should be anatomi-
(1), the classification of salivary tumors, as with any cal confirmation of the disease. The regional lymph
other type of neoplasm, is a dynamic rather than a nodes are the cervical nodes. The TNM Clinical Classi-
static process. Any tendency to regard a classification fication of salivary gland tumors is shown in Table 5.
as immutable should be firmly resisted. Formal clas-
sifications merely represent the consensus of a group
of individuals at a given moment in time. In this H. Benign Tumors
chapter we will follow closely the classification pro-
Pleomorphic Adenoma
posed by the World Health Organization (WHO) in
2005 (Table 4) (2). However, several entities, including Introduction. Pleomorphic adenoma has been
keratocystoma and sialolipoma, that were not includ- defined as ‘‘a tumor of variable capsulation character-
ed in the WHO classification will be discussed to ized microscopically by architectural rather than cel-
broaden awareness and promote discussion. In addi- lular pleomorphism. Epithelial and modified
tion, we have included sections on intraosseous (cen- myoepithelial elements intermingle most commonly
tral) and hybrid tumors. with tissue of mucoid, myxoid or chondroid
Table 5 TNM classification of carcinomas of the salivary gland
T – Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour 2 cm or less in greatest dimension without extraparenchymal extension*
T2 Tumour more than 2 cm but not more than 4 cm in greatest dimension without extraparenchymal extension*
T3 Tumour more than 4 cm and/or tumour with extraparenchymal extension*
T4a Tumour invades skin, mandible, ear canal, or facial nerve
T4b Tumour invades base of skull, pterygoid plates, or encases carotid artery
Note: *Extraparenchymal extension is clinical or macroscopic evidence of invasion of soft tissues or nerve, except those listed under T4a
and 4b. Microscopic evidence alone does not constitute extraparenchymal extension for classification purposes.
N – Regional lymph nodes#
N2 Metastasis as specified in N2a, 2b, 2c below
N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N3 Metastasis in a lymph node more than 6 cm in greatest dimension
Note: Midline nodes are considered ipsilateral nodes.
M–Distant metastasis
Stage Grouping
Stage 1 T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
T1, T2, T3 N1 M0
Stage IV A T1, T2, T3 N2 M0
T4a N0, N1, N2 M0
Stage IV B T4b Any N M0
Any T N3 M0
Stage IV C Any T Any N M1
#
The regional lymph nodes at the cervical nodes.
appearances’’ (1). Synonyms include mixed tumor accessory parotid gland. The most common minor
and benign mixed tumor. salivary gland sites are the palate, lip, and buccal
Clinical features. Pleomorphic adenoma is the mucosa. Pleomorphic adenomas have been reported
most common salivary neoplasm and accounts for in a wide variety of other sites, including cervical
60% to 70% of all parotid tumors, 40% to 60% of lymph nodes, mandible, lung, breast, pituitary fossa,
submandibular tumors, and 40% to 70% of all minor lacrimal gland and sac, ear, and lung (19–27). Histo-
salivary neoplasia (2–6). There is an annual incidence logically similar tumors in the skin are termed ‘‘chon-
rate of approximately 2.4 to 3.05 per 100,000 persons droid syringomas.’’ Pleomorphic adenoma may show
(7,8). Pleomorphic adenoma can also arise in the nasal a synchronous or metachronous association with other
cavity, paranasal sinuses, and larynx (9–11). The mean salivary neoplasms, particularly Warthin’s tumors, in
age at presentation is 46 years (2), but cases occur over the same or other glands (12).
a wide age range and can occasionally be seen in Pleomorphic adenoma in the major glands usual-
young children (6,12). Some studies have shown a ly presents as a slow-growing, painless mass. Small
bimodal age distribution (13). There is a female pre- tumors typically form smooth, firm, and mobile lumps,
ponderance of 1.9:1 (6). Familial cases of pleomorphic but larger tumors tend to be bosselated and may
adenoma are rare, with only four case reports in the attenuate and discolor the overlying skin. Deep-lobe
literature (14–17). The large majority (*80%) of parotid tumors may present as an intraoral or para-
tumors arise in the parotid gland, with most of the pharyngeal mass (28). Pain or facial nerve palsy may
remainder involving the submandibular gland occasionally be seen in tumors that are infected or have
(*10%) and minor seromucous glands (*10%). infarcted. Pleomorphic adenomas of the minor salivary
Pleomorphic adenomas of the sublingual gland are glands usually present as painless, submucosal swel-
exceptionally rare (18). Parotid tumors usually arise lings. The most common site is the junction of the hard
within the superficial lobe, especially its lower pole, and soft palate unilaterally, and here the tumors are
but 10% may occur in the deep lobe, or from an often adherent to the adjacent mucoperiosteum.
Figure 39 Pleomorphic adenoma showing a discrete fibrous Figure 40 Pleomorphic adenoma showing ‘‘satellite’’ nodule
capsule, cartilage, and duct-like structures. that is typically attached to the main tumor mass.
Most pleomorphic adenomas range from 2 to 6 cm in

greatest diameter, but some tumors are massive (29).
Pathology. Grossly, pleomorphic adenomas are
usually solitary, well-defined, ovoid or round masses.
Larger neoplasms may have a characteristic bosselated
surface. Their consistency varies from hard to rubbery
or soft and fluctuant. The cut surface of the tumor is
characteristically solid and the color varies from gray-
blue, pale yellow to tan. There may be gritty areas, and
gelatinous or glistening foci may be present when
there is cartilaginous or myxochondroid differentia-
tion. Necrotic or cystic regions may be a feature of
larger tumors. Recurrent tumors appear as multifocal
soft tissue masses that may be widely dispersed.
Most tumors are encapsulated, but there is wide
variation in both the thickness and presence of the
capsule (Fig. 39). There may be a complete lack of Figure 41 Pleomorphic adenoma showing capsular invasion.
capsule, especially in predominantly mucoid tumors.
In many tumors there is a distinct tendency for the
tumor to split away from the overlying capsule when
handling the specimen. This may be a factor in pro-
ducing an illusory plane of cleavage during surgery. Many tumors show local extension of fingerlike pro-
Nodules of tumor may bulge through the capsule and cesses into the capsule (Fig. 41). Tumor may also bulge
give a false impression of multifocality in some planes through the capsule and form pseudosatellite nodules.
of section (Fig. 40). The capsule in minor gland pleo- This is also particularly common in predominantly
morphic adenomas is often poorly formed or absent. myxoid tumors. Serial sectioning has shown that these
Pleomorphic adenomas are characterized by a nodules are invariably attached by an isthmus to the
remarkable degree of morphologic diversity between main tumor mass (32,33). Microscopically, it can be
individual tumors and often within a single tumor shown that the macroscopic parallel clefts seen
mass. The most important histologic components of between the tumor and capsule are, in fact, within
the tumor are the capsule, the epithelial and modified the tumor itself, leaving tumor cells attached to the
myoepithelial cells, and the mesenchymal or stromal capsular wall. Minor salivary gland pleomorphic ade-
elements. There is evidence using a HUMARA assay nomas characteristically lack encapsulation and may
that the epithelial and stromal cells of pleomorphic incorporate normal host tissue as they expand, giving
adenoma have a common origin (30). a false impression of invasion.
The capsule varies in both thickness and pres- The epithelial component of pleomorphic adeno-
ence. A quantitative study showed the capsular thick- mas shows a wide variety of cell types, including
ness ranging from 15 to 1750 mm (31). In predominantly cuboidal, basaloid, and squamous, and the myoepi-
mucoid tumors, there are usually areas where the thelial cells may be spindle cell, plasmacytoid, or
capsule is virtually absent and the tumor then abuts clear. Rarely, mucous, sebaceous, or serous acinar
onto adjacent normal salivary parenchyma or fat. cells are also present. The epithelium can form sheets,
Figure 42 (A) Duct-like structures in fibromucinous stroma. (B) Double-layered duct-like structures with a conspicuous abluminal layer
of clear myoepithelial cells. (C) Sheets of epithelioid and clear myoepithelial cells in mucoid stroma. (D) Pleomorphic adenoma showing a
focus of mucous metaplasia.
cords, or ductal structures (Fig. 42). The latter are may be myxoid, cartilaginous, or hyalinized, is a
composed of an inner layer of cytologically bland, product of the modified myoepithelial cells. These
large, cuboidal cells with vacuolated nuclei without cells have a wide range of appearances, which
prominent nucleoli, surrounded by an outer layer of includes polygonal, plasmacytoid (hyaline cell), spin-
myoepithelial cells. The myoepithelial cells may be dle-shaped, or clear cell (Fig. 44) (36). Polygonal cells
morphologically similar to the duct lining cells or may a have a fine reticular arrangement, and a promi-
have variably eosinophilic to clear cytoplasm and nent spindle cell component can occasionally display
condensed, small, hyperchromatic nuclei, which are a schwannoma-like palisading growth pattern. Plas-
flattened or triangular. The ducts may contain eosino- macytoid myoepithelial cells are distinctive round to
philic secretory material and, although usually small, oval cells with eccentric nuclei and dense eosinophilic
they may become distended to form microcysts. More cytoplasm. They usually form sheets and small islands
solid areas of epithelial cells lacking ductal lumini within a hyalinized stroma. Plasmacytoid cells have a
may be seen admixed with myoepithelial cells. There distinct tendency to separate from one another. Squa-
can be moderate degrees of nuclear atypia and an mous metaplasia, sometimes with keratin pearl forma-
increased mitotic frequency, particularly in dense, tion, is a common feature, which can involve both ducts
cellular foci. Occasionally tumors contain multinucle- and sheets of cells (Fig. 45). Extensive areas of squa-
ated and other bizarre neoplastic cells (34). This find- mous metaplasia are uncommon unless there has been
ing does not appear to have any prognostic surgical intervention or infarction (Fig. 46). Infrequent-
significance. Crystalloids, including collagenous mately, tumors have areas of sebaceous metaplasia, clear cell
rial, tyrosine-rich crystals, which form flowerlike change, and mucoepidermoid-like metaplasia. Focal
(‘‘daisy head’’) structures (Fig. 43A,B), and oxalate- oncocytosis is relatively common but occasionally the
like crystals, may be present (6). Intraductal, concen- entire tumor can be affected, making diagnosis difficult
trically laminated, corpora amylacea–like condensa- (Fig. 47) (37,38).
tions (Fig. 43C), and stromal amyloid are occasional The mesenchymal component is myxoid, carti-
features (35). The mesenchymal component, which laginous, or hyalinized and sometimes forms the
ossification (Fig. 48B,C). Some tumors show deposi-

tion of eosinophilic, hyaline material within islands of
tumor cells and within the stroma. The material is
positive with collagen and elastin stains, and in some
cases it can form the bulk of the tumor. It can attenu-
ate the epithelial elements to give a cylindromatous or
cribriform appearance that can be mistaken for ade-
noid cystic carcinoma (Fig. 48D). Some tumors show
progressive scarring with destruction and loss of
much of the epithelial component. It is important to
examine such tumors closely for residual epithelial
elements, as there is a higher risk of malignant pro-
gression in these old, scarred pleomorphic adenomas.
In a study of 65 pleomorphic adenomas, 9 tumors
(13.8%) showed malignant progression (39). It was
found that a prominent hyalinized stroma correlated
(p < 0.5) with malignant progression. Fat cells are
common in the stroma of pleomorphic adenoma,
particularly in minor glands. Tumors that have a
lipomatous stromal component of 90% or more have
been called lipomatous pleomorphic adenomas
(40,41), and a myxolipomatous variant has been
described (Fig. 49) (42).
There can be significant variations in the cellu-
larity of pleomorphic adenoma, with some tumors
being sparsely cellular and composed predominantly
of a mucoid component and others consisting of
densely packed, solid sheets of epithelial or myoepi-
thelial cells. The latter tumors have been called cellular
pleomorphic adenomas.
Areas of lymphocytic and plasma cell infiltration
are common, even when there has been no previous
surgical manipulation (31). They are usually seen in
the subcapsular region. Rarely, a lymphoplasmacytic
infiltrate appears to virtually destroy the bulk of the
epithelial component of the tumor, leaving residual
islands resembling those seen in lymphoepithelial
lesions. Occasionally there is extensive, acute, and
chronic inflammatory infiltration and prominent cen-
tral necrosis (43). This may be the result of spontane-
ous infarction or, increasingly, fine-needle aspiration
biopsy (44,45). Clinically, these tumors may be symp-
tomless or there can be an episode of sudden pain and
rarely facial nerve palsy. Such tumors can occasionally
show florid squamous metaplasia that can easily be
confused with malignancy (46–49). Occasionally, there
is extensive cystic degeneration, with residual tumor
Figure 43 (A) Tyrosine crystals in characteristic ‘‘daisy-head’’ forming no more than a cellular rim surrounding a
pattern. Mayer’s hemalum and tartrazine stain. (B) Collagenous central cystic cavity. Rare, truly multicentric pleomor-
crystalloids. (C) Pleomorphic adenoma showing intraductal cor- phic adenomas have been reported (50–52). Exception-
pora amylacea–like condensations. ally, multifocal pleomorphic adenoma may be the
result of nonsurgical physical injury.
Occasionally, small nests or more solid aggre-
gates of tumor cells can be seen within vascular spaces
(Fig. 50). Although these are usually present within
predominant element of the tumor. Cells within the the body of the tumor, or close to its periphery,
myxoid areas are myoepithelial in origin and their intravascular tumor can sometimes be seen in more
cellular periphery tends to blend into the surrounding distant vessels. This phenomenon appears to be
stroma. The cartilage-like material has similar bio- extremely rare in the United States, but it was a
chemical properties to true cartilage and is positive feature seen in 8.9% of intraoral pleomorphic adeno-
for both type II collagen and keratan sulfate (Fig. 48A). ma in a report from South Africa (53). This unusual
Bone may form directly by stromal osseous metaplasia phenomenon does not appear to represent true intra-
or, more rarely, by a process similar to endochondral vascular invasion and is probably the result of
Figure 44 (A) Plasmacytoid (hyaline) myoepithelial cells. (B) Spindle-shaped myoepithelial cells forming a neurilemmoma-like pattern.
(C) Numerous clear myoepithelial cells. (D) Myoepithelial cells forming a reticular pattern.
Figure 45 Pleomorphic adenoma showing focal squamous Figure 46 Infarcted pleomorphic adenoma showing florid squa-
metaplasia. mous metaplasia.
intraoperative surgical manipulation. It does not seem

to have any clinical consequences, including the risk
of metastatic disease.
Immunohistochemistry. As with many other sali-
vary gland tumors, the immunocytochemical profile
of pleomorphic adenoma is rarely of value in differ-
ential diagnosis. However, a number of immunocyto-
chemical studies have given valuable insights into the
histogenesis of this unique tumor. The luminal cells of
tubuloglandular elements of pleomorphic adenoma
are positive for cytokeratins 3, 6, 10, 11, 13, and 16.
Modified myoepithelial cells are irregularly positive
for cytokeratins 13, 14, and 16 and pan-cytokeratin
(54). They are also positive for vimentin, S-100 protein,
glial fibrillary acidic protein, a-smooth muscle actin,
HHF-35, calponin, and smooth muscle myosin, espe-
cially in the myxoid areas and/or in the solid areas
Figure 47 Pleomorphic adenoma showing extensive oncocytic (55–58). Tumoral myoepithelial cells are also reactive
metaplasia.
for p63 (59). There is moderately intense c-kit (CD117)
staining in the luminal cells of pleomorphic adenoma
Figure 48 (A) Cartilaginous differentiation. The inset shows staining for keratan sulfate. (B) Pleomorphic adenoma showing bone
formation by endochondral ossification. (C) Pleomorphic adenoma showing bone forming by osseous metaplasia in stroma.
(D) Pleomorphic adenoma with cribriform areas resembling adenoid cystic carcinoma.
pleomorphic adenomas with abnormal karyotypes.

Patients with karyotypically normal pleomorphic ade-
nomas are reported to be significantly older than those
with rearrangements of 8q12 (51.1 vs. 39.3 years, p <
0.001). In addition, adenomas with normal karyotypes
tend to be more stroma-rich than tumors with 8q12
abnormalities (67).
PLAG1, a developmentally regulated zinc finger
gene, appears to be the target gene in pleomorphic
adenoma with 8q12 abnormalities (68–70). Transloca-
tions involving 8q12 can result in promoter swap-
ping/substitution between PLAG1 and translocation
partner genes such as CTNNB1-PLAG1 and LIFR-
PLAG1. This in turn leads to activation of PLAG1
expression. It has been postulated that deregulation
of PLAG1 target genes, including IGF2, may have a
significant role in the genesis of pleomorphic adeno-
Figure 49 Lipomatous pleomorphic adenoma. ma (71). The finding of PLAG1 rearrangements in cells
with both epithelial and myoepithelial phenotypes,
reinforces the pluripotent single-cell theory of the
histogenesis of pleomorphic adenoma (72).
RAS mutation and activation are common in
pleomorphic adenoma, particularly in tumors show-
ing PLAG1 activation (73,74). However, amplification
and/or over-expression of ERBB2 is rare (75,76), and
TP53 alterations are infrequent in adenomas (76–78).
In addition, TP53-related genes TP63 and TP73, which
are putative myoepithelial markers, are overexpressed
in basal and myoepithelial cells in pleomorphic ade-
nomas (59,78).
Pleomorphic adenomas contain SV40 DNA
sequences and express the SV40 large T antigen.
This suggests that the virus may play a role as a
cofactor in the pathogenesis of pleomorphic adenoma
(79).
Differential diagnosis. In most cases of surgical-
ly excised pleomorphic adenoma the diagnosis is
relatively easy as there are characteristic combina-
Figure 50 Tumor in a vascular space close to the margin of a tions of epithelial and mesenchymal elements. How-
pleomorphic adenoma.
ever, particularly when confronted with limited
biopsy material from minor salivary glands, the
diagnosis can be more challenging. The main differ-
ential diagnoses of minor salivary gland pleomorphic
(60). The nonlacunar cells in the chondroid areas are adenoma are polymorphous low-grade adenocarci-
positive for both vimentin and pan-cytokeratin, noma and adenoid cystic carcinoma. Sharply circum-
whereas the lacunar cells are positive only for vimen- scribed cribriform or cylindromatous structures,
tin (61). Lacunar cells in the chondroid areas are also although characteristic of adenoid cystic carcinoma,
positive for S-100 protein. The modified myoepithelial can also be seen with polymorphous low-grade ade-
cells in the myxoid areas and the luminal cells express nocarcinoma and pleomorphic adenoma. These
transforming growth factor (TGF)-b2, whereas the tumors may be indistinguishable in limited surgical
lacunar cells in the chondroid areas weakly express material. In resection specimens, however, the pres-
TGF-b3 (62). Spindle-shaped myoepithelial cells adja- ence of more typical areas and the absence of features
cent to these chondroid areas also express bone mor- such as infiltration and perineural invasion usually
phogenetic protein (BMP) (63), whereas the inner facilitates diagnosis. Pleomorphic adenoma can show
ductal cells and lacuna cells in the chondroid areas double-layered, duct-like structures with an inner
express BMP-6 (64). Type II collagen and chondromo- layer of dark, cuboidal cells and an outer layer of
dulin-1 are present in the chondroid matrix, mirroring clear cells. Similar biphasic features may be a feature
the composition of normal cartilage (65). of the tubular variant of adenoid cystic carcinoma
Molecular-genetic data. About 70% of pleomor- and epithelial-myoepithelial carcinoma. In pleomor-
phic adenomas show karyotypic abnormalities, and phic adenoma and adenoid cystic carcinoma the
rearrangements involving 8q12–15 (39%), and 12q13– abluminal clear cells usually have small, hyperchro-
15 are the most common (8%) (66). Secondary chromatic and angular nuclei. Those in epithelial-
mosomal alterations are seen in about a third of myoepithelial carcinoma are typically larger and
more vesicular. However, in small biopsies it may however, may remain necessary for deep-lobe tumors
not be possible to make a confident distinction (94). There is a particular tendency for predominantly
between these tumors, and a circumspect report myxoid pleomorphic adenomas to recur. These
should be considered. In such specimens, the value tumors are diffluent, have thinner capsules, and nod-
of c-kit expression in differentiating pleomorphic ules of tumor may bulge through the capsule. There is
adenoma from adenoid cystic carcinoma is yet to be a higher risk of rupture during surgery, and these
established (80). neoplasms appear to have a greater rate of recurrence
Squamous cell carcinoma or mucoepidermoid than predominantly cellular tumors (81,85). In this
carcinoma may need to be considered in the differen- context, a recent study showed that expression of the
tial diagnosis, particularly in limited biopsy tissue of mucin MUC1/DF3 in pleomorphic adenoma was a
a pleomorphic adenoma showing squamous or potential marker of the risk of recurrence (95).
mucoepidermoid metaplasia. This is especially the Patients with more than one recurrence usually had
case in pleomorphic adenomas of minor glands such their first recurrence earlier than patients who were
as the palate, as tumors in this location can be partic- cured after re-excision of their only recurrence (47 vs.
ularly cellular and often lack cartilaginous or myxoid 105 months) (83). It appears that recurrences are more
differentiation. The presence of plasmacytoid myoe- likely in young patients (81,96). Radiotherapy has
pithelial cells provides strong support for a diagnosis been used to treat recurrences and sometimes follow-
of pleomorphic adenoma and effectively eliminates ing rupture of the tumor during surgery, but its value
the possibility of mucoepidermoid carcinoma and remains uncertain (97,98).
squamous carcinoma.
Treatment and prognosis. The main problems in Myoepithelioma
the clinical management of pleomorphic adenoma
are the tendency of tumors to recur following surgery Introduction. Myoepithelioma is defined as ‘‘a
and the risk of malignant transformation. Recurrent benign salivary gland tumor composed almost exclu-
tumor is usually multifocal and occasionally becomes sively of sheets, islands or cords of cells with myoepi-
inoperable (Fig. 51) (81,82). In addition, treatment of thelial differentiation that may exhibit spindle,
recurrent tumors carries a high risk of facial nerve plasmacytoid, epithelioid or clear cytoplasmic features’’
injury, further recurrences, and an increased risk of (1). While myoepithelioma can be accepted as a separate
malignant progression (80). In pleomorphic adenoma and distinct entity (1,2), this tumor may represent one
of minor salivary glands recurrences are rare, and end of the histologic spectrum of pleomorphic adenoma
most of the problems are seen in tumors of the (3–7).
parotid gland. A meta-analysis of parotid pleomor- Clinical features. The incidence of myoepithe-
phic adenoma showed 3.4% of tumors recurred after lioma is 1.5% of all salivary gland neoplasms and it
five years and 6.8% after 10 years (83). Since superfi- accounts for 2.2% and 5.7% of all benign major and
cial parotidectomy, either total or partial, became a minor salivary gland tumors, respectively (2). How-
more widely used treatment, the recurrence rate has ever, myoepithelioma is probably not as rare as has
usually been less than 5% (84–87). In recent years, been previously suggested. The age of patients ranges
more conservative surgical techniques have been from 9 to 85 years, with an average of 44 years, but
adopted in an attempt to avoid the risks of facial there is no significant gender predilection (1). Myoe-
nerve palsy and Frey syndrome (88–93). Total paroti- pithelioma occurs most frequently in the parotid
dectomy with preservation of the facial nerve, gland (40%), followed by the palate (21%) and sub-
mandibular gland (10%) (1). Other minor salivary and
seromucinous gland sites can also be affected. The
skin, lung, and soft tissue have rarely been reported as
the primary site of myoepithelioma (8–10). It presents
as a slow-growing, painless mass, which is clinically
indistinguishable from pleomorphic adenoma. Rarely,
myoepithelial carcinoma arises from a preexisting
myoepithelioma (11).
Pathology. Grossly, myoepithelioma presents as a
well-circumscribed solid mass with a white to tan col-
ored cut surface (Fig. 52). The size of the tumor ranges
from 1 to 5 cm in diameter, but is usually less than 3 cm.
Microscopically, the tumor is surrounded by a
thin fibrous capsule in the parotid gland but is often
not encapsulated when located in the minor salivary or
seromucinous gland sites. As with pleomorphic adeno-
ma, a pushing margin with pseudopodia can be seen in
myoepithelioma, but the tumor does not show destruc-
tive invasive growth. It is composed of solid, sheetlike,
Figure 51 Multifocal recurrent pleomorphic adenoma in peri- myxoid, microcystic, or reticular growth patterns of
parotid adipose tissue. neoplastic myoepithelial cells exhibiting variable mor-
phologies (Fig. 53) (4). In many myoepitheliomas,
combinations of these patterns may be present within

the same tumor mass. Collagenous crystalloids in the
form of radially arranged and intercellular hyaline
material can occasionally be observed (12).
The neoplastic cells may be spindle, plasmacy-
toid, epithelioid, or clear type (Fig. 54). The spindle-
cell type is the most common, but a mixture of several
types of the cell within a tumor is often seen (4).
Tumors with predominant spindle cells are frequently
observed in the parotid gland, whereas palatal tumors
consist mainly of plasmacytoid cells. The spindle cells
have centrally located nuclei and are usually arranged
in an interlacing fascicular pattern (Fig. 54A). A case
of spindle-cell type of myoepithelioma with extensive
lipomatous metaplasia has been reported (13). The
plasmacytoid cells, also referred to as ‘‘hyaline
cells,’’ have eccentrically located nuclei and abundant
eosinophilic cytoplasm, bearing a superficial resem-
blance to plasma cells, but these lack perinuclear halos
Figure 52 Myoepithelioma. The cut surface of a tumor presents
as a well-circumscribed, yellow-tan colored, solid mass in the
(Fig. 54B) (14). In addition, the plasmacytoid cells of
parotid gland. myoepithelioma are much larger than plasma cells.
Aggregations of plasmacytoid cells are often sur-
rounded by a myxoid matrix. The epithelioid cells are
polygonal, possessing central nuclei and pale eosino-
philic cytoplasm (Fig. 54C). These cells may be arranged
in patternless sheets, cords, reticular configurations, or
trabeculae. The clear cells are polygonal in shape and
have abundant glycogen revealed by PAS stain, with or
without diastase digestion (Fig. 54D). Tumors with
predominant clear cells are extremely rare. Oncocytic
variants of myoepithelioma have also been reported
(15). Cells of intermediate appearance are sometimes
present among cells of different types. Cellular pleo-
morphism is usually absent but may be observed to a
mild degree in some tumors. Mitoses are generally
scanty [up to 6 mitotic figures/10 HPFs (high-power
fields)]. The stroma may be hyalinized or myxoid.
Intercellular hyaline deposition is occasionally seen.
Although some investigators accept chondroid
differentiation in myoepithelioma (4), we prefer that
typical chondroid area of a pleomorphic adenoma
should not present in myoepithelioma. Ductal differ-
entiation is usually absent, but the presence of very
rare foci of ductal structures (up to 5%), usually at the
periphery of the tumor, does not preclude a diagnosis
of myoepithelioma (1,4,7).
Ultrastructural studies indicate both the epithelial
and smooth muscle nature of the tumor cells in myoe-
pithelioma (4). The tumor cells contain microfilaments,
usually without focal densities in their cytoplasm and
have desmosome-like junctions (Fig. 55).
Immunohistochemistry. Myoepitheliomas are
consistently immunoreactive for pan-cytokeratin
(Fig. 56A), S-100 protein (Fig. 56B), vimentin, and
p63 (16–19). Positivity for calponin (Fig. 56C), smooth
muscle actin, cytokeratin 14, caldesmon, muscle-
specific actin, glial fibrillary acidic protein, and smooth
muscle myosin-heavy chain vary according to the case
or cell type (16–19). Generally, smooth muscle actin is
often expressed in spindle cells but not in plasmacy-
Figure 53 Myoepithelioma. Solid (A) and reticular (B) growth toid cells (12). Calponin is considered the most specif-
patterns of neoplastic myoepithelial cells. ic and generally sensitive marker for neoplastic
myoepithelial cells (19). Epithelial membrane antigen
Figure 54 Myoepithelioma. (A) Spindle cell type. The spindle cells are arranged in an interlacing fascicular pattern. (B) Plasmacytoid
cell type. The plasmacytoid cells exhibiting eccentrically located nuclei and abundant eosinophilic cytoplasm are surrounded by a myxoid
matrix. Note the lack of perinuclear halos seen in the true plasma cells. (C) Epithelioid cell type. Solid and trabecular growth patterns of
polygonal epithelial cells with central nuclei, and eosinophilic cytoplasm. (D) Clear cell type. Solid growth of polygonally shaped clear
cells with intercellular hyaline depositions.
is usually negative. Positive immunoreactivity for and spindle cell mesenchymal tumors or plasmacytoma.
pan-cytokeratin in conjunction with one or more In addition, myoepithelioma should be differentiated
myoepithelial markers may be required for the diag- from its malignant counterpart, myoepithelial carcino-
nosis of myoepithelioma. ma. In most instances, these two neoplasms can easily
Differential diagnosis. Since neoplastic myoepi- be distinguished by histologic hallmarks such as
thelial cells exhibit considerable morphogenic hetero- invasiveness, cellular pleomorphism, necrosis, and
geneity, myoepithelioma must be distinguished frequency of mitosis. Immunohistochemical assess-
from various other tumor types. Spindle cell mesen- ment of the Ki-67 labeling index is helpful in the
chymal tumors, such as extracranial meningioma, differential diagnosis between myoepithelioma
schwannoma, leiomyoma, benign fibrous histiocy- (range: 0.9–9.1%, mean: 5.4%) and myoepithelial
toma, and synovial sarcoma, should be considered carcinoma (range: 15.6–65.3%, mean: 35.0%) (11).
in the differential diagnosis of spindle cell variant of Treatment and prognosis. The treatment and
myoepithelioma. prognosis of myoepithelioma are essentially the
The plasmacytoid variant must not be misdiag- same as those of pleomorphic adenoma, because
nosed as plasmacytoma. Immunohistochemical exam- both tumors have a similar biologic behavior. Com-
ination for cytokeratin and specific myoepithelial plete surgical excision is the treatment of choice for
markers, including calponin and smooth muscle actin, myoepithelioma. Recurrence after appropriate treat-
is useful in distinguishing between myoepithelioma ment is unusual and the prognosis is excellent. Rarely,
Figure 55 Myoepithelioma. Electron microscopy of the tumor

cell reveals abundant microfilaments without focal densities in
the cytoplasm.
long-standing or recurrent myoepitheliomas undergo

malignant transformation (20).
Basal Cell Adenoma

Introduction. In normal salivary glands, basal
cells are localized to ducts and have a relatively
isomorphic appearance, with palisade-like, polarized
nuclei (1). Unlike myoepithelial cells, basal cells do
not have myofilaments and their functional role is
poorly understood. Although basal cells are found in
several salivary gland tumors, those composed pre-
dominantly of basal cells are relatively uncommon.
In 1967, Kleinsasser and Klein first described basal
cell adenoma, which was an encapsulated, slow-
growing, purely epithelial neoplasm composed of
what appear to be basal cells (2). Basal cell adenoma
is distinctly separate from pleomorphic adenoma
because of its uniform population of tumor cells, in
contrast to the diverse histopathologic features com-
monly seen in the latter tumor. Basal cell adenoma
was categorized as other types of monomorphic adeno-
mas in the first edition of the WHO Classification of
Salivary Gland Tumors (3–8). However, it was placed in
a specific category in the second, and, as in the 2005
WHO classification (9,10), the term ‘‘monomorphic ade-
noma’’ did not appear. Formerly, some authors includ-
ed canalicular adenoma as a variant of basal cell
adenoma (11), but now it is regarded as a separate
entity because of its characteristic clinical and histo-
Figure 56 Myoepithelioma. Immunohistochemically, tumor
pathologic features (9–13). cells are diffusely positive for pan-cytokeratin (A) S-100 protein
Clinical features. Basal cell adenoma is an (B) and calponin (C).
uncommon benign tumor with the reported incidence
varying from 1.0% to 7.5% of all salivary gland tumors
(11,14). It occurs mainly in the major salivary glands,
especially the parotid gland (8), and only a few Basal cell adenomas develop most frequently in
examples have been described in the minor salivary patients older than 50 years, and the average is 58
glands, the upper lip being the most common site. years, being 10 years higher than for pleomorphic
Figure 57 Basal cell adenoma. Cut surface of the parotid gland Figure 58 Basal cell adenoma. Typical feature of the tumor
tumor shows well-circumscribed, grayish-white, solid mass. composed of basaloid cells forming solid islands, cords, and
ducts within a fibrous stroma. Note that each nest is sharply
demarcated from the stroma by basement membrane-like mate-
rial, and the myxochondroid stroma characteristically observed in
adenoma (14). Although rare examples of congenital pleomorphic adenoma, is absent.
basal cell adenoma have been described, these tumors
are best classified as sialoblastoma rather than as a
special form of basal cell adenoma (11,15). There is a
2:1 female predominance for most subtypes of basal
cell adenomas, although the membranous variant has Importantly, the myxochondroid stroma characteristi-
no gender predilection (11). Clinically, typical basal cally observed in pleomorphic adenoma is absent in
cell adenomas present as a solitary and freely mobile, basal cell adenoma. Scattered tubular structures are
superficial parotid tumor indistinguishable from pleo- seen within the cell nests with occasional squamous
morphic adenomas. However, they tend to be smaller eddies. The tumor cells have two basic cell types; one
than pleomorphic adenomas, usually not exceeding has scant cytoplasm and a round, basophilic nucleus
3 cm in diameter (14). with indistinct nucleoli, and the other has a larger,
Pathology. Basal cell adenoma is a well- paler nucleus and more abundant cytoplasm. The
circumscribed round or ovoid tumor with a distinct former cells tend to be located at the peripheral portion
fibrous capsule, except for the membranous type, of the nests, whereas the latter form tubular structures.
which has a multifocal or multinodular growth pat- The tumor cells are isomorphic without nuclear pleo-
tern. The cut surface is typically uniform and solid morphism. Mitotic figures and apoptotic cells may be
and varies from grayish-white to brown (Fig. 57). encountered but are scanty.
Their appearance has been described as similar to The solid variant of basal cell adenoma is char-
that of an enlarged lymph node. Formation of cysts acterized by large sheets, broad bands, and islands of
filled with brown, mucinous material is not uncom- basaloid cells with peripheral palisading (Fig. 59A).
mon, though its histogenesis has not yet been eluci- Whorling patterns or squamous eddies and occasional
dated. Basal cell adenomas tend to be under keratin pearl formation may be observed within the
3 cm in diameter with a range of 1.2 to 8 cm. cell nests. Only a few ductal structures are seen in this
Microscopically, basal cell adenoma is composed variant of basal cell adenoma. Cystic change is com-
of basaloid cells that form solid sheets, nests, cords, mon. An adenoid cystic pattern with multiple, pseu-
and ducts within a fibrous stroma (Fig. 58). Basal cell docystic formations may sometimes be observed in
adenomas are histologically subclassified into solid, basal cell adenoma, in which dilated lumina usually
trabecular, tubular, and membranous (dermal ana- contain Alcian blue–positive material (Fig. 60) (14,16).
logue) types, according to their cellular growth pattern The stroma is usually loose and scanty.
(Fig. 59). Although the most common type of basal cell In the trabecular variant, cellular features are the
adenoma is the solid variant, a mixture of several same as those seen in the solid variant, but the epithe-
architectural growth patterns is commonly seen. lial islands are narrower and form an interconnecting
Despite these different growth patterns, there are cordlike architecture (Fig. 59B). Rarely, a richly cellular
basic underlying histologic features that facilitate the stroma composed of S-100 protein-positive, modified
diagnosis. The peripherally located cells in the basa- myoepithelial cells is seen between tumor cords (17).
loid cell nests frequently show a palisading arrange- The tubular variant has prominent duct-like
ment and each nest is sharply demarcated from the structures with luminal cuboidal cells surrounded by
stroma by basement membrane–like material. one or more layers of basaloid cells (Fig. 59C).
Figure 59 Basal cell adenoma. (A) Solid type. Large sheets and broad bands of basaloid cells with peripheral palisading.
(B) Trabecular type. Narrow epithelial islands forming an interconnecting cordlike architecture. (C) Tubular type. Prominent duct-like
structures with intraluminal eosinophilic secretion. (D) Membranous type. Thick, hyaline, basement membrane–like material surrounds
large lobules. This material is also present within the epithelial nests forming coalescing, hyaline droplets.
Eosinophilic secretion is present within the ductal Electron microscopy. Ultrastructural observa-
lumina. Since a tubular pattern may often be seen in tions have confirmed both ductal and myoepithelial
conjunction with the trabecular pattern, some authors differentiation of the tumor cells (11,18). Luminal cells
merge the tubular and trabecular variants into a exhibit microvilli, tight junctional complexes, and
tubulotrabecular variant. Occasionally, focal or exten- occasional secretory granules characteristic of ductal
sive oncocytic change may be observed. differentiation. Abluminal cells include centrally
The membranous (dermal analogue) variant placed squamous cells, intermediate cells, and periph-
histologically resembles eccrine dermal cylindroma eral myoepithelial-type cells. In the membranous vari-
(Fig. 59D). Although the growth pattern and cellular ant, abundant stroma and intercellularly reduplicated,
features are similar to those of the solid variant, multilayered basal lamina are evident.
membranous basal cell adenoma is usually multinod- Immunohistochemistry. Basal cell adenomas
ular and is often not encapsulated. This multinodular show both ductal and myoepithelial differentiation
growth pattern should not be misinterpreted as malig- of variable degrees (19–21). Cytokeratin is detected
nancy. The tumor cell nests tend to be arranged in in luminal as well as abluminal cells in all tumors.
large lobules surrounded by thick, PAS-positive, hya- Epithelial membrane antigen is also expressed in
line, basement membrane–like material, forming nearly all tumors, but its distribution is confined to
‘‘jigsaw puzzle’’-like patterns. This material is also the apical portions of the luminal cells. The luminal
present within the epithelial nests forming coalescing, aspect of cell borders and the intraluminal secretion
hyaline droplets. show positive reaction for carcinoembryonic antigen.
salivary glands, and four histopathologic growth pat-

terns have been described for each lesion. Moreover,
they are characterized by similar proliferation of two
morphologic variants of basaloid cells. The most
important diagnostic feature for separating basal cell
adenomas from basal cell adenocarcinomas is the
absence of infiltrative growth pattern. However, since
cellular pleomorphism of basal cell adenocarcinomas is
usually slight, differential diagnosis between the two is
difficult in limited biopsy material. Immunohistochem-
ical markers, demonstrating ductal epithelial and
myoepithelial differentiation, display a striking similar-
ity in basal cell adenomas and basal cell adenocarcino-
mas, so that they are of little value in the differential
diagnosis. However, a higher rate of cell proliferation
(>4 mitotic figures/10 HPFs or over 5% of Ki-67
labeling index) and apoptosis (>0.4% of apoptotic
index determined by terminal deoxynucleotidyl
transferase-mediated dUTP-digoxigenin nick end label-
ing method), along with strong expression of p53 and
epithelial growth factor receptor, and loss of bcl-2
expression may be diagnostic for basal cell adenocarci-
nomas rather than basal cell adenomas (21).
Because cribriform structures may sometimes be
observed in basal cell adenomas, it is necessary to
distinguish it from adenoid cystic carcinoma (14).
These appearances can be differentiated from adenoid
cystic carcinoma on the basis of the gradual structural
alteration from areas typical of basal cell adenoma. In
addition, other features characteristic of adenoid cys-
tic carcinoma, such as cells with irregular, angular-
shaped hyperchromatic nuclei, mitoses, or invasive
growth are absent in the adenoid cystic carcinoma-like
areas of basal cell adenoma. Furthermore, the periph-
eral palisading arrangement and focal squamous dif-
ferentiation with whorling pattern present in basal cell
adenoma are not usually encountered in adenoid
Figure 60 Basal cell adenoma with a prominent adenoid cystic cystic carcinoma.
pattern. (A) Well-circumscribed tumor is composed of large Although basal cells are one of the components
sheets with multiple pseudocysts forming adenoid cystic type of pleomorphic adenoma, myxochondroid stroma and
cribriform pattern, which imparts a ‘‘Swiss cheese’’–like appear-
ance. Pseudolumina contain slightly basophilic material. (B) The
the plasmacytoid cells characteristically observed in
peripherally located cells in the basaloid cell nests frequently pleomorphic adenoma are absent in basal cell adeno-
show a palisading arrangement. A few true glandular lumina, ma. Canalicular adenomas can be distinguished by
some of which contain eosinophilic secretion and pseudocysts in their double row of low columnar cells arranged in
the solid and trabecular nests. parallel branching cords. In addition, canalicular ade-
noma shows exclusively duct luminal differentiation
by immunohistochemistry, whereas dual ductal and
myoepithelial differentiation can be seen in basal cell
adenoma (22).
Conversely, smooth muscle actin, calponin, p63, S-100 Treatment and prognosis. Basal cell adenoma
protein, and vimentin, indicators of myoepithelial cell usually behaves in a benign fashion, analogous to
differentiation may be positive and tend to localize at that of pleomorphic adenoma, and recurrence is
the periphery of the nests, adjacent to the connective rare. However, the membranous form of basal cell
tissue. Rarely, S-100 protein is strongly expressed in adenoma, also known as dermal anlage tumor, is
spindle-shaped ‘‘stromal’’ cells (17). associated with a higher recurrence rate (25–37%)
Differential diagnosis. The main differential after surgical removal (8,23). It has particular clinical
diagnoses of basal cell adenoma include basal cell associations with tumor diathesis and its histology.
adenocarcinoma, adenoid cystic carcinoma, pleomor- There have been cases of membranous basal cell
phic adenoma, and canalicular adenoma (also see the adenomas in the parotid gland coexisting with multi-
section ‘‘Basal Cell Adenocarcinoma’’) (1). ple dermal cylindromas (turban tumors), trichoepithe-
Basal cell adenomas and basal cell adenocarci- liomas, eccrine spiradenomas, trichilemmomas, or
nomas share common clinical and histologic similari- basal cell carcinomas in the same patients (23–26).
ties. Both tumors predominantly occur in the major Furthermore, the same cytogenetic abnormality in
epithelial tumors in the United States and 5.3% of

parotid tumors (3). Higher percentages in the parotid
gland have been reported in the United Kingdom
(14.4%) (4), Denmark (27.5%) (5), and Pennsylvania
(30%) (6). There appears to be a much lower incidence
of Warthin’s tumor in ethnic groups with dark skin,
including Asian populations (7), black Africans (8),
and African-Americans (3), although the incidence
appears to be increasing in the latter group (9). The
mean age at diagnosis is 62 years, (range 2.5–92) (3),
and tumors are rarely seen in the first three decades of
life. There has been a striking change in the relative
sex incidence over the last 50 years (10). In 1953 the
male to female ratio was 10:1 (10), whereas in 1996 it
was 1.2:1 (3), and in 1992 it was equal (6). This change
in sex incidence coincides with an increased preva-
lence of smoking in women. Familial cases are rare
and may be due to coincidence (11,12).
Figure 61 Carcinoma arising in basal cell adenoma. Salivary Warthin’s tumor is almost exclusively limited to
duct carcinoma composed of solid tumor nests with comedonec- the parotid glands and the periparotid lymph nodes
rosis (right) develops from basal cell adenoma (left) through the (13). Most cases involve the lower pole, although 10%
transitional zone seen in the middle. are in the deep lobe. Very rare examples have been
reported in other glands (14), but many tumors
thought to arise within the submandibular gland
have usually developed within the anterior tail of
the chromosome 16q12–13, the CYLD between dermal the parotid or from adjacent lymph nodes (3). Unusual
cylindromas and membranous basal cell adenomas locations for the tumor include the mouth (15), naso-
has been reported in two familial cases (23). However, pharynx (16), larynx (15), and lacrimal gland (17).
the majority of the parotid membranous basal cell However, it is important to exclude oncocytic meta-
adenomas occur independently of such associations. plasia of ductal epithelium of the minor glands with
Nevertheless, it has been suggested that individuals associated reactive lymphocytic infiltration. Warthin’s
with salivary basal cell adenomas should be screened tumor is the most common salivary neoplasm show-
for skin lesions. Malignant transformation of basal cell ing multifocality (12–20%, either synchronous or
adenoma is an exceedingly rare event (8,27–30). It is metachronous) or bilaterality (5–14%) (18,19). How-
reported, however, that the incidence of basaloid ever, the incidence of multifocal Warthin’s tumors
carcinoma arising from basal cell adenoma is higher rose to 50% when parotid glands were serially sec-
in the membranous type with the salivary-dermal tioned (20).
tumor diathesis (8,28). A few examples of nonbasaloid Most patients present with a slow-growing, soft
tumors, including salivary duct carcinoma and ade- mass, usually 2 to 4 cm in size; large tumors are
nocarcinoma (NOS), arising in basal cell adenoma exceptional (21). The mean duration of symptoms is
have been described (Fig. 61) (29). 21 months, but in 41% of patients it is less than six
months (10). There may be fluctuations in the size of
Warthin’s Tumor the tumor, especially when eating (22). Pain or dis-
comfort is relatively uncommon (9–18% of cases)
Introduction. Warthin’s tumor was first described (10,24) and is usually seen in the infarcted (metaplas-
comprehensively by the American pathologist Aldred tic) variant (23). Occasionally pain may be severe and
Scott Warthin in 1929. Over the years, this tumor has cause otalgia. Facial nerve palsy is rare, and again, is
been known by over 20 different names, including usually due to inflammation and fibrosis in infarcted
adenolymphoma, cystadenolymphoma, and papillary tumors (24–26).
cystadenoma lymphomatosum. ‘‘Warthin’s tumor’’ is Imaging. Warthin’s tumors are able to concen-
the preferred term as this avoids possible confusion trate 99m Tc pertechnetate and appear as hot spots.
with lymphoid malignancy, and with the separate However, scintigraphy has been found to be less
entity, lymphadenoma (1). It is defined as ‘‘a tumor useful than conventional MRI in the evaluation of
composed of glandular and often cystic structures, Warthin’s tumors (27). The tumor is usually well
sometimes with a papillary cystic arrangement, lined circumscribed, but secondary inflammation can
by characteristic bilayered epithelium, comprising cause blurring of the edges.
inner columnar eosinophilic or oncocytic cells sur- Etiology. There is a strong link between War-
rounded by smaller basal cells. The stroma contains thin’s tumor and cigarette smoking (28,29)—the inci-
a variable amount of lymphoid tissue with germinal dence is eight times that of nonsmokers (30). There
centers’’ (2). appears to be a higher risk of bilateral Warthin’s
Clinical features. Warthin’s tumor is the second tumor in heavy cigarette smokers (31). In addition,
commonest neoplasm of the salivary glands in most the increased numbers of female smokers during the
large series. It comprised about 3.5% of all primary second half of the 20th century closely parallels the
increase in Warthin’s tumor in women and largely

explains the change in sex incidence during this peri-
od (8,32). The mechanisms are not clear, but it has
been speculated that irritants in tobacco smoke cause
metaplasia in the parotid (33). However, Warthin’s
tumor develops in only a small proportion of smokers
(including black Africans and African-Americans),
and therefore, smoking is likely to be a promoting
factor rather than the main etiologic agent (33).
Radiation exposure may be relevant as there is
an increase in Warthin’s tumor among atomic bomb
survivors (34). There appears to be an association
between Warthin’s tumor and organ-specific autoim-
mune disease, especially insulin-dependent diabetes
mellitus, Hashimoto’s thyroiditis, autoimmune hyper-
thyroidism, and hypothyroidism (35).
The possible role of EBV in the pathogenesis of
Figure 62 Warthin’s tumor showing papillary cystic tumor with
Warthin’s tumor is unclear. In some cases, especially
dense lymphoid stroma.
where there are multiple tumors, the EBV genome has
been isolated from the cytoplasm of the luminal cells
(36), but not in other studies (37). Also, EBV exposure
during childhood or adolescence is widespread (38),
and thus any possible etiologic role has not yet been
established. At present, the balance of probabilities is
that EBV does not play a significant role in the etiolo-
gy of Warthin’s tumor (39).
The infarcted (metaplastic) variant can follow
trauma, particularly from fine-needle aspiration biop-
sy (39–44).
Pathology. Grossly, most Warthin’s tumors are
encapsulated, spheroidal to ovoid masses with a
smooth and sometimes bosselated surface. Despite
the circumscription, the capsule is often thin, may be
incomplete, and is easily ruptured during surgical
removal. The size ranges from 1 to 10 cm (mean 3.5
cm) in greatest diameter (10). Sectioning typically
shows papillary cystic spaces of variable sizes that
contain mucoid, clear or brown, glary fluid. In some
Figure 63 Warthin’s tumor showing oncocytic palisaded luminal
cases, papillary infoldings are inconspicuous grossly
cells and less numerous and regular abluminal basal cells.
and the tumor appears either as a unilocular cyst or as
a more solid mass. The solid areas are tan to white,
and may be firm and fibrous in inflamed tumors.
The microscopic appearance of a typical
Warthin’s tumor is very characteristic and readily some appear to be extruding into the luminal space
recognisable. It is sharply demarcated with a thin (Fig. 65). Small foci of squamous and mucous meta-
capsule. There are cystic and solid areas, and both plasia are relatively common (Fig. 66), and very
epithelial and lymphoid components (Fig. 62). The occasionally sebaceous differentiation is seen (45).
cysts vary considerably in size and shape, and papil- The cystic spaces may contain eosinophilic secre-
lary structures project into the lumina. The papillae tions with occasional cholesterol cleft formation
have fibrovascular cores, often with lymphoid and rarely laminated structures resembling corpora
stroma. The epithelium is double layered with tall, amylacea.
columnar, luminal cells that are granular and onco- The stroma consists of lymphoid tissue with
cytic. There is palisading of their bland, single, ovoid varying degrees of reactivity, and germinal centers
nuclei located centrally or toward the luminal end of are present in the majority. Mast cells, histiocytes, and
the cell (Fig. 63). The surface often shows apocrine plasma cells may also be seen. The ratio of epithelium
blebbing, and cilia, as first described by Warthin, are to lymphoid stroma varies between different tumors,
occasionally identified (Fig. 64) (10). The abluminal and Warthin’s tumors have been subclassified into
layer consists of less numerous, smaller, flattened, or typical (both components approximately equal),
cuboidal basal cells. Their cytoplasm is similar to stroma-poor (epithelial component >70%) and
luminal cells but less abundant. No significant stroma-rich forms (epithelial component of <30%)
nuclear atypia or mitotic activity is identified. Occa- (46). However, this subdivision has no prognostic value.
sionally, the luminal cells are intensely oncocytic Microscopic foci of inflammation, necrosis, and
with pyknotic nuclei (dark cells; pyknocytes) and fibrosis are common, and minor degrees of squamous
Figure 64 Warthin’s tumor with ciliated epithelium.

Inset: Scanning electron micrograph. Source: Cour-
tesy of Professor Hwang.
and mucous metaplasia were reported in 51% and

27%, respectively, of typical Warthin’s tumors (39).
However, in some cases there is almost complete
replacement of the lymphoid and, occasionally, the
epithelial component by fibrous and inflammatory
tissue. This subtype has been variously termed
‘‘infarcted,’’ ‘‘infected,’’ or ‘‘metaplastic,’’ and it
accounts for 6% to 7% of Warthin’s tumors (24,46).
Although such necrosis may be spontaneous, it is
likely that this variant will be seen more frequently
with the increasing use of preoperative fine-needle
aspiration. There is extensive necrosis but in some
cases the ghost outlines of papillary structures may
be seen and highlighted by a reticulin or keratin stain.
There may be conspicuous squamous metaplasia,
which can produce a pseudoepitheliomatous appear-
ance. Such florid squamous change was a common
Figure 65 Warthin’s tumor with epithelium showing light and feature of the ‘‘metaplastic’’ variant of Warthin’s
dark (pyknocytes) cells. tumor described by Seifert et al. (46). However, 40%
of these cases had received radiotherapy, a form of
treatment virtually never used for these tumors cur-
rently. Focal areas of mucous metaplasia or solitary
mucocytes can be present. Cytologic atypia can be
prominent, and although mitotic figures may be
numerous, they are normal. There is often extensive
fibrosis, particularly at the periphery of the tumor,
with dense collagen and myofibroblastic proliferation.
There is a heavy mixed inflammatory infiltrate, often
with sheets of macrophages, some with foamy cyto-
plasm. Lipogranulomas, cholesterol clefts, and hemo-
siderin deposition may be present. Epithelioid
granulomas, with or without multinucleated giant
cells (47), can lead to confusion with sarcoidosis and
tuberculosis (Fig. 67). This differential diagnosis can
be difficult, as cases of Mycobacterium tuberculosis
infection have been reported in Warthin’s tumor and
confirmed by polymerase chain reaction (48). In some
infarcted tumors, areas of residual Warthin’s tumor
Figure 66 Warthin’s tumor showing mucous metaplasia. may be absent, and the diagnosis then becomes
implicit (24,40).
are positive with antimitochondrial antibodies (57),

and the inner cells express epithelial membrane anti-
gen (59). Amylase, vimentin, S-100 protein, and myoe-
pithelial markers are negative in both basal and
luminal cells. The MIB1 index is low in the usual
forms, but high in regenerative squamous epithelium
in the metaplastic variant.
Lymphoid marker studies have shown B (CD20),
NK (CD56), and T (CD3) cells, including helper (CD4)
and suppressor (CD8) subtypes. This profile of lym-
phocyte subsets is similar to that in normal or reactive
lymph nodes (60).
However, in practice, special stains and immu-
nohistochemistry have little to offer in the diagnosis of
typical type of Warthin’s tumor, although there may
be a role in diagnosing the metaplastic variant, partic-
ularly when no residual viable Warthin’s tumor can
Figure 67 Warthin’s tumor. An area close to infarcted tumor be identified in hematoxylin and eosin–stained speci-
showing epithelioid granuloma formation. mens (40,58).
Electron microscopy. The luminal cells, and to a
lesser extent the basal cells, contain abundant, vari-
ably sized mitochondria, ranging from normal to
There are two principal theories of the histogene- enlargement by threefold. Many display long cristae,
sis (3): The more favored is an origin from intercalated which form lamellar sheaves, rouleaux, or concentric
and basal cells of heterotopic salivary ductal inclu- rings (61). The luminal cells have surface microvilli
sions in intra- or periparotid lymph nodes. In particu- and sometimes cilia (Fig. 64) (22), and the basal cells
lar, this explains the distribution of Warthin’s tumor have prominent tonofilament bundles and desmosom-
and its absence from other salivary tissue lacking al attachments to each other and overlying luminal
incorporated lymph nodes. It has been suggested cells. These are particularly plentiful in the metaplas-
that Warthin’s tumor initially develops in a parotid tic subtype. Beneath the basal cells there is a narrow,
lymph node as an adenomatous epithelial prolifera- discrete, basal lamina (62).
tion responding to as yet unidentified stimuli (proba- Molecular-genetic data. Cytogenetic studies
bly including tobacco, either as a direct stimulus or a have shown Warthin’s tumor to have three main
promoter). This attracts a heavy lymphoid reaction, stemline groups, one with a normal karyotype, a
similar to that seen in certain other salivary neoplasms second with numerical changes only (loss of Y chro-
(49–51). The stage of this process seen at the time of mosome or trisomy or monosomy 5), and a third
surgery determines the proportions of epithelial and group involving structural changes with one or two
lymphoid elements (52). reciprocal translocations (22). Damage to the mito-
Analysis of the X chromosome–linked HUMARA chondrial DNA may account for the ultrastructural
showed that Warthin’s tumor is nonclonal, and thus changes seen in the mitochondria, as well as the
likely to be nonneoplastic (53). It has therefore been oncocytic change seen morphologically (63). There
suggested that Warthin’s tumor should be classified in appears to be no evidence of DNA mismatch repair
the group of tumorlike lesions rather than adenomas defects, and tumors do not show microsatellite insta-
(54). This finding supports morphologic observations bility (64). The chromosomal translocation t(11;19)
that have suggested Warthin’s tumor (as well as (q21;p12–13) is seen in both Warthin’s tumor and
various thymic and head and neck cysts) results mucoepidermoid carcinoma (65). In addition, a
from the induction of cystic changes in branchial novel gene of unknown function designated
cleft epithelium by an inflammatory infiltrate, accom- WAMTP1 (Warthin and Mucoepidermoid tumor
panied by oncocytic change in the epithelium (55). Translocation Partner gene 1) has been described
Immunohistochemistry. All epithelial cells stain (66). This links with the mastermind-like Notch coor-
with broad spectrum cytokeratin antisera such as dinator gene MAML2, and the fusion product has
AE1/AE3 and MNF116, and the luminal cells are been shown to alter the Notch-signaling pathway,
positive for cytokeratins 7, 8, and 18. Results with suggesting this may be important in the genesis of
other cytokeratin markers are inconsistent; one study both mucoepidermoid carcinoma and Warthin’s
found cytokeratins 5/14 and 17 largely restricted to tumor.
the basal cells, except in the metaplastic variant Differential diagnosis. The typical type of War-
when they were also expressed by regenerative sur- thin’s tumor is easily diagnosed. Papillary cystadenoma
face cells (56). However, other investigators have has a similar epithelial component but lacks the lym-
found more widespread reactivity for cytokeratin 14 phoid elements. There is some resemblance to other
in the typical type, including the surface cells (57). lymphoepithelial cystic lesions such as simple benign
Cytokeratins 10/13, 1/2/11/12, and 20 were all nega- lymphoepithelial cyst (unrelated to AIDS), LESA with
tive, although a more recent study identified cytoker- cystically dilated ducts, cystic lymphoid hyperplasia
atin 10 staining in four of six tumors (58). Both layers of AIDS, and MALT lymphoma with cystically dilated
ducts (49). All lack the characteristic bilayered onco- bright eosinophilic granular cytoplasm (oncocytic
cytic epithelium of Warthin’s tumor, and lymphoepi- cells)’’ (1). Synonyms include oncocytic adenoma
thelial lesions (epimyoepithelial islands) are usually and oxyphil adenoma.
found in LESA, MALT lymphoma, and cystic lym- Clinical features. Oncocytoma is an uncommon
phoid hyperplasia of AIDS, but not in Warthin’s tumor and accounted for about 1.4% of primary epithe-
tumor. An important differential is from cystic metas- lial salivary gland neoplasms in an Armed Forces Insti-
tases in intra- and periparotid lymph nodes. The tute of Pathology (AFIP) series (2). It is seen
malignant nature of most should be obvious, but a predominantly in elderly patients, with an average age
recently reported variant of papillary thyroid carcino- of about 64 years. There is no racial or gender predilec-
ma has been described as ‘‘Warthin-like’’ (67,68). It is tion. In one major study 20% of patients gave a history of
characterized by a heavy lymphoid stroma and onco- previous radiotherapy to the head and neck or upper
cytic metaplasia of the epithelium. The best guide to torso or long-term occupational exposure (3). The aver-
its true nature is that the nuclei display typical chro- age age of these patients was 20 years younger than
matin clearing, inclusions and groove formation, and those not exposed to radiation (43 vs. 63 years) (3). The
the epithelial cells show immunohistochemical large majority of oncocytomas arise in the parotid (78%)
expression of thyroglobulin. and submandibular (9%) glands (2,4). Less commonly
If there is marked cytologic atypia and mitotic they occur in the minor salivary glands of the buccal
activity, the metaplastic variant can be mistaken for mucosa, palate, lip, tongue, and elsewhere (2,5–7). They
squamous or mucoepidermoid carcinoma, either pri- usually present as a unilateral painless swelling. Rare
mary or metastatic (40). The resemblance is particu- bilateral tumors have been reported (8–10).
larly close if there has been total infarction of the Pathology. Grossly, oncocytomas in major
original Warthin’s tumor. Also, the squamous meta- glands form a single, well-circumscribed but often
plasia lacks keratinization (seen in most squamous lobulated mass, which rarely exceeds 4 cm in diame-
carcinomas), and mucocytes are usually much less ter. The cut surface is uniform pink to rust-colored,
numerous than in low-grade cystic mucoepidermoid and occasionally there are small cysts or central stel-
carcinoma. late scarring.
Treatment and prognosis. In some cases, if the Microscopically, oncocytomas are encapsulated
diagnosis can be confidently established, active treat- and are solid with a variable cystic component. They
ment may not be necessary. Surgery, either superficial are composed predominantly of typical ‘light’ onco-
or limited parotidectomy, or local resection, is usually cytes with smaller numbers of dark cells (pyknocytes)
curative (69). The low reported rate of recurrence in (Fig. 68). These cells are arranged in sheets, nests,
most series (about 2–5.5%) (3,10) is probably the result trabeculae, or duct-like structures separated by thin,
of multifocal tumors. fibrovascular stroma. Microcysts or macrocysts are
Malignant change is seen in less than 1% of cases occasionally seen. Focal clear cell change is common
(46,70). It can involve the epithelial or lymphoid and occasionally the entire tumor consists of clear cells
components and in some cases there is a history of (Fig. 69) (11). It has been shown that the clear cell
previous radiation (34,46). Carcinomas that have been change is due to a combination of fixation artefact and
reported include squamous (71), adenocarcinoma (46), intracytoplasmic glycogen accumulation (11,12). Occa-
mucoepidermoid (72,73), oncocytic (74), Merkel cell sionally there may be binucleated or atypical nuclear
(75), and undifferentiated. Lymphoproliferative disor- forms. Foci of sebaceous and squamous metaplasia
ders associated with Warthin’s tumor include follicu- may also be apparent (3). Areas of chronic
lar lymphomas (76,77), Hodgkin’s lymphoma (78,79)
and peripheral T-cell lymphoma (80). Unique cases of
a MALT-type lymphoma and Warthin’s tumor pre-
senting in the same parotid gland (81), and a small
lymphocytic lymphoma forming a collision tumor,
have been reported (82).
Warthin’s tumor is the most common neoplasm
seen in association with other salivary tumors, par-
ticularly pleomorphic adenoma (14,83–85). In addi-
tion, there may be an increased association with the
development of extrasalivary neoplasms. This may
be due to a common etiology of cigarette smoking in
carcinomas of the lung, larynx, and possibly the
bladder, but in sites such as the hematolymphoid
system, kidney, and breast, the relationship could be
coincidental (17).
Oncocytoma
Introduction. Oncocytoma is defined as ‘‘a Figure 68 Oncocytoma consisting of characteristic light and
benign tumor of salivary gland origin composed dark cells.
exclusively of large epithelial cells with characteristic
treated by surgical excision. Oncocytes are radio-

resistant and although radiotherapy has been used in
the past (24), it should play no role in the management
of oncocytoma.
Canalicular Adenoma
Introduction. Canalicular adenoma is defined as
‘‘a tumor composed of columnar epithelial cells
arranged in thin, anastomosing cords with a beaded
pattern. The stroma is characteristically paucicellular
and highly vascular’’ (1). Synonyms include basal cell
adenoma (canalicular type), monomorphic adenoma
(canalicular type), and adenomatosis of minor salivary
glands.
Clinical features. Canalicular adenoma is an
uncommon, benign salivary tumor that arises almost
Figure 69 Oncocytoma with clear cell change. exclusively in minor glands where it accounts for 4%
to 6% of all tumors (2,3). It is seen predominantly in
adults, with a mean age of 65 years and a range from
33 to 88 years; it is uncommon before the sixth decade
inflammation are occasionally present. Oncocytomas (2–5). The sex ratio has varied from a definite female
may be seen in combination with multifocal nodular preponderance of 1.8:1 (2) to a slight male predomi-
oncocytic hyperplasia (13). nance (5) or no significant gender difference (6). The
Differential diagnosis. The differential diagnosis upper lip is the most common site, accounting for
of oncocytoma includes other salivary gland tumors about 70% to 80% of cases (2,4,5). The buccal mucosa
with an oncocytic component, salivary tumors con- and palate are the next most common sites (3,7). It is
sisting of large cells with granular cytoplasm, and rare in the parotid gland (3–9) and no cases have been
clear cell neoplasms. Oncocytic metaplasia can be reported in the submandibular or sublingual glands
seen in a wide range of salivary gland tumors, includ- (3). Canalicular adenomas are occasionally bilateral
ing pleomorphic adenoma, basal cell adenoma, (10,11) or multifocal, usually in the upper lip and
mucoepidermoid carcinoma, epithelial-myoepithelial buccal mucosa (6,12–14). Tumors typically present as
carcinoma, adenoid cystic carcinoma, polymorphous slow-growing, painless masses but infarcted (15) or
low-grade adenocarcinoma, and adenocarcinoma traumatically ulcerated tumors (4,16) may be painful.
(14–16). This metaplasia is usually focal and rarely The mass is usually mobile and can be solid or
causes diagnostic difficulties. However, occasionally fluctuant. The overlying mucosa may be normal in
in pleomorphic adenoma (17) and mucoepidermoid color, or bluish, when the tumor resembles a salivary
carcinoma (18–20) almost the entire tumor may show mucocele. Canalicular adenomas rarely exceed 2 cm in
oncocytic change. Careful examination usually reveals diameter and the mean size is 1.7 cm (2). The duration
more specific features of these tumors such as hyaline of the tumor has varied from a few months to 15 years,
cells and myxochondroid matrix in pleomorphic ade- with a mean of 8.4 years (2).
noma and mucocytes in mucoepidermoid carcinoma. Pathology. Grossly, most canalicular adenomas
An ‘‘oncocytoid’’ artefact due to diathermy used range between 0.5 and 2 cm in maximum diameter,
during surgery has been described, and this can be and they are well circumscribed and variably encap-
confused with oncocytosis or oncocytoma (21). sulated. In one series nearly a quarter of tumors had
Tumors with a significant granular cell component multifocal nodules (5). The cut surface varies from
include acinic cell carcinoma and granular cell tumor. light yellow to tan, and there are frequently cystic
Staining with PAS with prior diastase digestion spaces filled with clear or lightly stained gelatinous
shows that the intracytoplasmic granules of acinic material. Microscopy of larger tumors usually con-
cell carcinoma are positive, whereas those in oncocy- firms the circumscribed and encapsulated nature of
tomas are negative. Staining with PTAH may also aid the neoplasm but smaller tumors and multifocal nod-
distinction. Granular cell tumors have been rarely ules frequently lack a capsule (2,12). Small foci of
reported in salivary glands (22). The cells of this adenomatous change may be seen in adjacent minor
tumor are S-100 protein-positive, and distinction glands. The most distinctive feature of canalicular
from oncocytoma should not be difficult. The differ- adenoma is the formation of parallel rows of cuboidal
ential diagnosis of clear cell salivary neoplasms is or columnar cells forming a single layer (Fig. 70). The
considered on page 562. rows of cells may be closely opposed or show focal
Treatment and prognosis. Although oncocyto- areas where they separate to form a characteristic
mas are benign tumors, reported rates of recurrence beaded pattern. The cells are cytologically bland and
vary from 0% to 30% within periods ranging from have moderate amounts of eosinophilic cytoplasm
6 months to 13 years (23). Recurrences are probably and uniform, oval, or round basophilic nuclei. The
due to incomplete resections or multifocal disease. latter contain diffuse, finely granular chromatin, and
Both primary and recurrent oncocytomas should be prominent nucleoli are uncommon. Mitoses are rarely
Figure 70 Canalicular adenoma showing bilayered

trabeculae of columnar cells in degenerative stroma.
seen in the absence of an inflammatory overlay (15). trabecular or tubulotrabecular basal cell adenomas. In
There may be foci of mucous, or more rarely onco- addition, the tumors have distinctive immunohisto-
cytic, metaplasia (2,16). The cellular strands are usu- chemical profiles, particularly in regard to myoepi-
ally sharply demarcated from the surrounding thelial differentiation (21). However, occasional
stroma. This may be loosely collagenized but it is tumors show a hybrid morphology making meaning-
frequently sparsely cellular and myxoid, producing ful distinction impossible (23). As both tumors
a microcystic appearance. In addition, the stroma may behave in a similar fashion, the separation has little
contain a conspicuous network of congested capillar- clinical importance. Notable features that help dis-
ies with surrounding cuffs of eosinophilic collagen (1). tinguish canalicular adenoma from adenoid cystic
There may be areas of hemorrhage and associated carcinoma include its circumscribed nature, with no
hemosiderin deposition, together with patchy inflam- evidence of invasion, and the characteristic vascular-
matory infiltration. Extensive necrosis may follow ity of the stromal component (24). In equivocal cases,
infarction of the tumor (15). Occasionally, the solid or when there is evidence of multifocality, the
tumor element forms no more than a mural thickening absence of staining with myoepithelial markers may
projecting into a unilocular cystic space. There may be aid distinction.
papillary epithelial projections into the cystic spaces, Treatment and prognosis. Complete but conser-
and this is sometimes associated with the presence of vative surgical removal usually results in a cure.
psammoma bodies (2,16). When there is recurrence it is difficult to know if
Immunohistochemistry. Canalicular adenomas this is merely a manifestation of multifocal disease
are positive for cytokeratins and S-100 protein and (4,7,25). Indeed, given the frequency of multifocal
may show more variable staining for vimentin and tumor, it is surprising that the recurrence rate is so
glial fibrillary acid protein (17–20). They are negative low (26). An exceptional case of a histologically con-
for more sensitive markers of myoepithelial differen- ventional canalicular adenoma of the palate behaved
tiation such as calponin, a smooth muscle actin, and aggressively and invaded into the maxillary sinus and
smooth muscle myosin heavy chain (21). In addition, nasal cavity (27).
the tumor is negative for carcinoembryonic antigen,
p53, p63, and p73 (18,22). Analysis of the cytokeratin Sebaceous Adenoma
subsets showed that most of the cells stained strongly
for cytokeratins 7 and 13, but staining for cytokeratin Introduction. Sebaceous adenoma is defined as
19 was weak (20). Cytokeratins 8 and 19 were only ‘‘a rare, usually well-circumscribed tumor composed
found in occasional cellular aggregates or scattered of irregularly sized and shaped nests of sebaceous
individual cells. cells without cytologic atypia, often with areas of
Differential diagnosis. The main differential squamous differentiation and cystic change’’ (1).
diagnoses are basal cell adenoma and adenoid cystic Clinical features. Sebaceous adenoma is very rare
carcinoma. The characteristic bilayered cellular and accounts for only 0.1% of all salivary tumors (2). It
strands and distinctive stromal degeneration of is typically seen in adults with a mean age at diagnosis
canalicular adenoma should aid the separation from of 58 years and a range of 22 to 90 years. There is a
slight male preponderance (M:F, 1.6:1) (3,4). About half Striking oncocytic metaplasia is occasionally seen,
of reported cases involved the parotid gland (5) with and there may be small areas of xanthogranuloma-
buccal mucosa (6), retromolar trigone (7), and subman- tous inflammation (1). Very rarely, sebaceous adeno-
dibular gland in that order accounting for the remain- mas form part of a hybrid tumor (8).
der (4). They usually present as painless masses. Treatment and prognosis. Sebaceous adenoma is
Pathology. Tumors have ranged in size from a benign tumor that is easily eradicated by complete
0.4 to 3 cm in diameter and are usually circumscribed surgical excision.
or encapsulated. The cut surface is yellow or grayish
white and can be solid or cystic (3,4). Microscopically Lymphadenomas
they consist of nests of cytologically bland sebaceous
cells often with foci of squamous differentiation, Lymphadenomas are rare benign salivary gland
aggregated into nests and surrounded by fibrous neoplasms that are histologically characterized by
stroma (Figs. 71, 72). The tumor cells show positive well-circumscribed tumors composed of proliferating
reactivity for cytokeratin and epithelial membrane epithelial nests in a lymphocytic background. In the
antigen but are not reactive with myoepithelial 2005 WHO Classification of Salivary Gland Tumors, they
markers such as vimentin, S-100 protein, or smooth were subclassified into sebaceous and nonsebaceous
muscle actin (7). The cell nests may be microcystic, types, depending on the presence or absence of seba-
and some tumors consist mainly of dilated ductal ceous differentiation (1); the former has been generally
structures with focal sebaceous differentiation. called a ‘‘sebaceous lymphadenoma’’ and the latter is
often referred to as simply ‘‘lymphadenoma.’’
Sebaceous lymphadenoma. Sebaceous cells are
commonly found within normal salivary gland paren-
chyma, and sebaceous differentiation can be seen
infrequently in a wide variety of well-recognized
salivary gland tumors (2). However, primary seba-
ceous neoplasms arising in the salivary glands are rare
and are histologically classified into sebaceous adenoma,
sebaceous lymphadenoma, sebaceous carcinoma, and
sebaceous lymphadenocarcinoma (2,3). The term
sebaceous lymphadenoma was designated by McGav-
ran and Bauer in 1960 (4), but a similar tumor was first
described by Rawson and Horn in 1950 (5).
Clinical Features. Sebaceous lymphadenoma
presents as a slowly enlarging, painless mass, almost
exclusively in or around the parotid gland. One tumor
occurred in the anterior midline of the neck. Slightly
over 50 cases of sebaceous lymphadenoma have been
reported to date (6,7). The majority of the patients
Figure 71 Sebaceous adenoma showing nests of sebaceous are adults in the sixth to eighth decade, with an age
cells with peripheral squamous differentiation. range of 25 to 89 years (6). There is no gender
predilection. Synchronous presentation with other
salivary gland tumors, such as squamous cell carcino-
ma, acinic cell carcinoma, and Warthin’s tumor, has
been reported (2).
Pathology. Grossly, the tumor appears as a
well-defined and usually encapsulated mass, ranging
in size from 1.3 to 6.0 cm in greatest dimension. It
presents as a yellow to tan, solid, microcystic or,
uncommonly, unicystic lesion on the cut surface.
Sebum is commonly observed in the cystic tumor.
Microscopically, sebaceous lymphadenoma is a
well-circumscribed tumor composed of uniformly
distributed, variably shaped epithelial nests contain-
ing sebaceous cells, salivary duct-like structures, and
cystic formations with a lymphoid background
(Fig. 73). Cysts consist of numerous haphazardly
arranged spaces lined by squamous, cuboidal to
columnar, or sebaceous-type epithelium. Oncocytic
change may be present. In addition, scattered mucous
cells may also be found in ductal epithelial structures.
Figure 72 Sebaceous adenoma consisting solely of sebaceous The surrounding lymphoid stroma often shows reac-
cells of varying sizes. tive follicles with germinal centers. Foreign body giant
cell reactions against the extravasated sebum are
tumor. Like sebaceous lymphadenoma, low-grade

mucoepidermoid carcinoma can present as a multi-
cystic tumor with a dense lymphoid stroma. However,
sebaceous lymphadenoma lacks intermediate cells
and the invasive characteristics of mucoepidermoid
carcinoma. Although a few mucous cells can be found
in sebaceous lymphadenoma, these are restricted to
the salivary duct–like epithelial cells, while clear seba-
ceous cells are always negative with mucin stains.
Furthermore, the presence of a foreign body reaction
in the lymphoid stroma, often seen in sebaceous
lymphadenoma, is unusual in mucoepidermoid carci-
noma (1). Oncocytic cells can be identified in seba-
ceous lymphadenoma, but the bilayered oncocytic
epithelium and papillary-cystic configuration typical
of Warthin’s tumor are absent.
Treatment and Prognosis. The treatment for
sebaceous lymphadenoma is a complete surgical exci-
sion. Recurrence is exceptional and an excision with
an adequate margin is curative (6).
Lymphadenoma. Lymphadenoma is a recently
described, extremely rare benign salivary gland
tumor consisting of an epithelial component accom-
panied by lymphoid stroma but lacking sebaceous
differentiation (1). This tumor was first described by
Auclair et al. as ‘‘cystadenoma with prominent lym-
phoid element’’ in their textbook in 1991 (6), and then
four years later, they introduced lymphadenoma as a
variant of sebaceous lymphadenoma (lymphadenoma
that lacks sebaceous differentiation) in the Armed
Forces Institute of Pathology fascicle on salivary
gland tumors (9). Lymphadenoma was newly includ-
ed in the 2005 WHO Classification of Salivary Gland
Tumors (1). Some investigators speculate that lympha-
denoma may be a basal cell adenoma or cystadenoma
accompanied by a tumor-associated lymphoid prolif-
eration rather than a distinct tumor entity (11).
Figure 73 Sebaceous lymphadenoma. (A) Variably shaped Clinical Features. Only 10 cases have been
epithelial nests with multiple cystic formations, containing seba- reported in the literature (10–17). Lymphadenoma
ceous cells, in a lymphoid stroma. (B) Sebaceous glands in a
has been reported to exhibit a male predominance
diffuse lymphoid background.
and the age ranges from 13 to 74 years with a mean of
48 years. Lymphadenoma occurs almost exclusively in
the parotid gland. One case has been described as a
preauricular mass (11). The patients typically present
common. A subcapsular marginal sinus, similar to a with a slowly growing, painless, solitary mass.
true lymph node, may be found in smaller tumors. Pathology. Grossly, the tumor is a well-
Malignant transformation in sebaceous lymphadenoma, demarcated, solid white to gray mass, ranging in
referred to as ‘‘sebaceous lymphadenocarcinoma,’’ is size from 1.0 to 8.0 cm in greatest dimension.
exceptionally rare, and only five such examples have Histologically, the tumor is well circumscribed
been described to date (2,3). and sometimes encapsulated (Fig. 74A). It is com-
The histogenesis of sebaceous lymphadenoma is posed of variably sized islands of epithelial cells
unclear (2,8,9). One highly plausible theory is that this enclosed within a prominent lymphocytic infiltrate
lesion, similar to Warthin’s tumor, arises from ectopic (Fig. 74B). These features are similar to sebaceous
salivary gland inclusions entrapped in intraparotid lymphadenoma but lack sebaceous differentiation.
or periparotid lymph nodes (2,8). However, another The epithelial islands show anastomosing trabeculae,
theory that the lymphoid component represents a solid nests, and duct-like structures containing eosin-
secondary, reactive response to the epithelial prolif- ophilic secretion, with or without cyst formation,
eration, referred to as tumor-associated lymphoid surrounded by PAS-positive basement membrane–
proliferation (10), cannot be completely excluded in like material. The epithelial component may not be
some tumors. easily recognized due to masking by dense lympho-
Differential Diagnosis. The main differential cytic infiltrate. In such instances, PAS stain is helpful
diagnoses of sebaceous lymphadenoma include low- in highlighting the basement membrane–like material
grade mucoepidermoid carcinoma and Warthin’s around the epithelial nests (1). Droplets of similar
negative for smooth muscle actin (11). The lymphoid

cells comprise a mixture of B cells and T cells. In situ
hybridization for EBER is negative in both epithelial
tumor cells and infiltrating lymphoid cells (11).
Differential Diagnosis. The main differential
diagnoses of lymphadenoma include lymphoepithe-
lial sialadenitis (LESA), metastatic adenocarcinoma
in lymph nodes, lymphoepithelial carcinoma, and
acinic cell carcinoma with a tumor-associated lym-
phoid tissue. Unlike LESA, lymphadenoma forms a
well-circumscribed lesion. In addition, the epithelial
component in lymphadenoma is proliferative and
much more prominent than epimyoepithelial islands
in LESA. Metastatic adenocarcinoma in the lymph
nodes can be distinguished from lymphadenoma by
the presence of definite nuclear atypia and lymph node
structure. The most important differential diagnosis of
lymphadenoma is lymphoepithelial carcinoma. Since
cellular atypia in lymphoepithelial carcinoma may be
mild, cellular features alone may not be enough to
allow differentiation from lymphadenoma. Features
such as lack of mitotic activity, lack of invasive growth
with desmoplastic stroma, presence of ductal differen-
tiation, and negativity for EBER in situ hybridization
favor a diagnosis of lymphadenoma rather than lym-
phoepithelial carcinoma. Acinic cell carcinoma is some-
times accompanied by a dense lymphoid stroma that
can pose difficulty in the differential diagnosis of
lymphadenoma. However, in acinic cell carcinoma
the lymphoid component is usually more prominent
in the peripheral portion. Additionally, the epithelial
component of lymphadenoma does not show a micro-
cystic growth pattern and lacks cells possessing dia-
stase-resistant PAS-positive zymogen secretory
granules.
Treatment and Prognosis. Complete surgical
excision is the choice of the treatment for lymphade-
Figure 74 Lymphadenoma. (A) A well-circumscribed tumor in noma. No recurrences have been reported.
the parotid gland. (B) Irregularly-shaped islands of epithelial cells
enclosed within a prominent lymphocytic infiltrate with lymphoid
follicle. Note the lack of sebaceous differentiation. Ductal Papillomas
Although many salivary gland tumors arise from
ductal units and exhibit papillary configuration,
benign papillary tumors confined to the ducts are
material can also be found within tumor islands. The rare. They are largely categorized under the term
epithelial component consists of cuboidal to columnar ‘‘ductal papillomas’’ and generally further classified
cells as well as basaloid cells. These cells are usually as three distinct types of tumors: intraductal papilloma,
bland but sometimes have mild atypia with vesicular sialadenoma papilliferum, and inverted ductal papil-
nuclei and distinct, small nucleoli. Mitotic figures are loma (1,2). These tumors occur predominantly in the
rare. Neither sebaceous nor oncocytic cells have been intraoral minor salivary glands and develop in associ-
identified. The lymphoid stroma, which is generally ation with the salivary excretory duct system.
considered to represent tumor-associated lymphoid Intraductal papilloma. Intraductal papilloma is
proliferation (10), consists of small mature lympho- histologically characterized by papillary proliferations
cytes often accompanied by lymphoid follicles with of bland cuboidal-to-columnar epithelial cells; the
germinal centers. The subcapsular sinuses seen in proliferations have fibrovascular cores and protrude
lymph nodes are not observed. into the cystically dilated ductal space (1,2).
Immunohistochemistry. Immunohistochemi- Slightly over 40 cases of intraductal papilloma
cal findings indicate dual luminal cell and abluminal have been reported to date (3–11). This rare tumor
cell differentiation without myoepithelial cell participa- mostly occurs in the minor salivary glands and only a
tion in the epithelial elements of lymphadenoma. The few have been described in the major salivary glands
luminal cells are positive for epithelial membrane anti- (1). Of the minor salivary gland cases, the lips fol-
gen and low-molecular weight cytokeratin, whereas lowed by the buccal mucosa and palate are the most
the abluminal cells are immunoreactive for p63 but frequent sites (9). In the major salivary glands, the
parotid gland is the most common site, but develop-

ment in the submandibular and sublingual glands has
also been reported (8,9). Clinically, the patients typi-
cally present with a painless oral submucosal mass.
The majority of the patients are in their sixth or
seventh decades with a mean age of 63 years (9).
Men and women are affected almost equally.
Grossly, the cut surface of the tumor reveals
a unilocular cystic lesion somewhat removed from
the mucosal surface. Tumor size ranges from 0.5 to
2.0 cm (2).
Microscopically, there is a cystically dilated
duct with papillary epithelial projections into the
cystic space; each projection is composed of a
branching and anastomosing proliferation of a sin-
gle or double layer of high columnar epithelial cells,
with a fibrovascular core (Fig. 75). The tumor cells
show no proliferation beyond the cyst wall. They
have uniform and basally located nuclei with no
evidence of atypia. A few PAS- and Alcian blue–
positive mucous cells are seen. There are few mitotic
figures. The cystic lesion is usually surrounded by
thick fibrous tissue.
Intraductal papilloma has immunohistochemical
properties of ductal luminal cells (5,8). The tumor cells
express pan-cytokeratin and epithelial membrane
antigen but are negative for smooth muscle actin
and the Ki-67 labeling index is low (8).
Before establishing a diagnosis of intraductal
papilloma, it is necessary to rule out several papillary
and cystic salivary gland tumors, including papillary
cystadenoma, low-grade cribriform cystadenocarci-
noma (LGCCC) (formerly referred to as ‘‘low-grade
salivary duct carcinoma’’) (12), and the papillary-
cystic variant of acinic cell carcinoma (2).
Papillary cystadenoma is characterized by a
benign neoplastic papillary proliferation of salivary
gland duct epithelium in the form of multiple epithelial-
lined cystic structures. Papillary cystadenoma does not
involve the native duct system, whereas intraductal
papilloma proliferates within a cystically dilated duct
and does not form cysts separated from the duct
system. LGCCC is characterized by multiple ductal
in situ lesions with micropapillary, tufted, and plaque-
like intraluminal projections, rather than frank papil-
lary projections with fibrovascular cores protruding
into a cystically dilated duct (12). Acinic cell carcino-
mas rarely show prominent papillary and cystic fea-
tures; they predominantly have a proliferating
epithelium resembling intercalated ductal cells
admixed with acinar cells at least focally. Usually,
the papillary-cystic variant of acinic cell carcinoma
shows a more delicate fibrovascular core, if present,
and occasionally contains a microcystic or follicular
structure, a feature absent in intraductal papilloma.
The lack of acinar differentiation, as well as the nega-
tive granular staining pattern of the tumor cells with
PAS/D stain, helps to exclude the possibility of acinic Figure 75 Intraductal papilloma. (A) A cystically dilated duct with
cell carcinoma. papillary epithelial projections into the cystic space. (B) A projection
Excision is curative without recurrence having is composed of a branching and anastomosing proliferation of
been reported. One case each of the malignant coun- epithelial cells with a fibrovascular core. (C) Columnar tumor cells
terpart of the intraductal papilloma (intraductal pap- have uniform and basally located nuclei with no evidence of atypia.
illary carcinoma with an invasive component) and
papillary adenocarcinoma possibly arising from an

intraductal papilloma has been described (6,8).
Sialadenoma papilliferum. Sialadenoma papillife-
rum is characterized by a biphasic growth pattern of
exophytic squamous and endophytic glandular com-
ponents, closely resembling syringocystadenoma pap-
illiferum of the skin (1,2).
Since it was first described by Abrams and Finck
in 1969 (13), slightly less than 50 cases have been
reported in the literature (9,13–25). The incidence of
sialadenoma papilliferum is approximately 1% of all
minor salivary gland tumors, and almost all of them
affect intraoral minor salivary glands, mostly the
palate (9). Other intraoral sites include the buccal
mucosa, upper lip, retromolar pad, and pillars of
fauces (1). It has also been reported in the esophagus
and bronchus (18,21). The age of the patients ranges
from 18 to 87 years with a mean of 59 years (1). Men
are slightly more commonly affected. Clinically, the
lesion presents a painless, exophytic papillary growth
from the surface of the mucosal epithelium and is
often mistaken for squamous papilloma.
Grossly, the cut section of the tumor reveals a
well-defined, exophytic lesion with papillary or ver-
rucous structures in the center. The size generally
ranges from 0.3 to 2.0 cm with a mean of 0.7 cm (9).
Histologically, at low magnification, the lesion
shows biphasic exophytic and endophytic growth
patterns around the orifice of the excretory duct
close to the oral mucosal surface (Fig. 76A). The
exophytic component projecting above the mucosal
surface is composed of papillary proliferations of
well-differentiated stratified squamous epithelium
enclosing fibrovascular cores. At the deeper portion
of the exophytic lesion, the stratified squamous papil-
lary projections merge into ductal epithelial prolifera-
tion displaying an irregular outline along a dilated Figure 76 Sialadenoma papilliferum. (A) A well-defined, pedun-
excretory duct with infolding in the glandular struc- culated lesion with biphasic exophytic and endophytic growth
tures (Fig. 76B). On higher magnification, the stratified patterns around the orifice of the excretory duct close to the oral
squamous epithelium in the exophytic portion is mucosal surface. (B) Papillary proliferations of the lesion are
hyperplastic with hyperkeratosis, parakeratosis, and composed of both well-differentiated stratified squamous epithe-
focal hypergranulosis. The ductal epithelium consists lium and a double layer of ductal epithelium.
of a distinct double layer of outer cuboidal and inner
columnar cells. Scattered mucous cells can also be
seen. The supporting fibrovascular cores often contain
numerous plasma cells with a few lymphocytes. Squamous papilloma and verrucous carcinoma
Immunohistochemical studies suggest that siala- are composed exclusively of a squamous component
denoma papilliferum exhibits both ductal and myoe- and lack the deeper ductal proliferation of sialade-
pithelial differentiation (17,20,22). The luminal noma papilliferum. Papillary cystadenoma shows
columnar cells of the ductal structures express pan- duct cell lining multicystic structures similar to the
cytokeratin, carcinoembryonic antigen, and epithelial deeper portion of sialadenoma papilliferum but does
membrane antigen, whereas the basally located cells not have an exophytic component consisting of papil-
show immunoreactivity for vimentin, cytokeratin 14, lary proliferation of squamous cells. Unlike sialade-
and smooth muscle actin. Polymerase chain reaction noma papilliferum, inverted ductal papilloma is
examination failed to detect human papillomavirus characterized by an entirely endophytic growth with-
DNA in sialadenoma papilliferum (19). out ductal proliferation. In sialadenoma papilliferum,
The characteristic histological features of sialade- the biphasic patterns of exophytic squamous compo-
noma papilliferum with a biphasic pattern with an nent and endophytic ductal component are distinct,
exophytic and endophytic proliferation may pose while a mixture of squamous, mucous, and interme-
some problems in the histologic diagnosis. The differ- diate cells is a typical feature of mucoepidermoid
ential diagnosis includes squamous papilloma, verru- carcinoma.
cous carcinoma, papillary cystadenoma, inverted ductal Careful and complete surgical excision is the
papilloma, and mucoepidermoid carcinoma (2,9). recommended treatment for sialadenoma
papilliferum, because it has a high (10–15%) risk of

postoperative recurrence (1,16). This is in contrast to
intraductal papilloma and inverted ductal papilloma,
which are nonrecurrent tumors. One case of malignant
transformation into epithelial-myoepithelial carcino-
ma and high-grade invasive micropapillary carcinoma
from sialadenoma papilliferum has been reported
(23). Recently, a case of sialadenoma papilliferum
with epithelial dysplasia and carcinoma in situ in
the exophytic component has also been described (24).
Inverted ductal papilloma. The term ‘‘inverted
ductal papilloma’’ of minor salivary glands was initially
proposed in 1982 by White et al. for a tumor histologi-
cally resembling inverted papilloma of the sinonasal
tract (26). In contrast to the nasal inverted papilloma,
which arises from the surface epithelium, inverted
ductal papilloma develops at the junction of the salivary
excretory duct and the oral mucosal epithelium.
Inverted ductal papilloma is the rarest form of
the ductal papillomas. Slightly more than 30 cases
have been reported to date, arising exclusively in the
minor salivary glands (9,26–31). The lip and buccal
mucosa are more frequently involved, but this tumor
less commonly arises at other oral sites including the
palate and the floor of the mouth (9). Inverted ductal
papilloma has a slight male predominance. The age
ranges from 28 to 77 years, with a mean age of over 50
years (9). Clinically, inverted ductal papilloma
presents as a painless, submucosal, nodular swelling,
often with a central punctum.
Grossly, the lesions form a well-circumscribed
mass, with occasional cystic change, communicating
with the oral mucosal surface. Tumor size ranges from
0.5 to 1.5 cm with an average of 0.9 cm (9).
Microscopically, the lesion is located at or near
the orifice of salivary excretory ducts and is sharply
demarcated from the adjacent lamina propria. It
appears as a dilated duct of a minor salivary gland Figure 77 Inverted papilloma. (A) A dilated duct of the minor
salivary gland filled with papillary structures. (B) High magnifica-
filled with papillary structures supported by fibrovas-
tion of papillary proliferations reveals a thick layer of predomi-
cular cores (Fig. 77A). It is lined by a thick layer of nantly non-keratinizing stratified squamous and basaloid
predominantly nonkeratinizing stratified squamous epithelium. The papillary fronds contain columnar duct cells
and basaloid epithelium with numerous invaginations with occasional mucous goblet cells.
and cleft-like narrow spaces (Fig. 77B). The proliferat-
ing tumor epithelium is continuous to the surface
epithelium. The papillary fronds contain cuboidal or
columnar duct cells with occasional mucous goblet latter component consists of a proliferation of ductal
cells and microcysts. The epithelial cells do not have epithelium but not squamous and basaloid epithelium
atypia, and mitotic figures are rare. of inverted ductal papilloma. Mucoepidermoid carci-
Immunohistochemical investigations indicate noma is the most important lesion to be distinguished
that the origin of inverted ductal papilloma is in the from inverted ductal papilloma, because they both
excretory ductal cells of minor salivary glands (28). have squamous and mucous goblet-type cells.
The tumor cells react with pan-cytokeratin, epithelial Inverted ductal papilloma lacks intermediate cells
membrane antigen, and carcinoembryonic antigen. and the invasive growth characteristic of mucoepider-
S-100 protein, vimentin, and smooth muscle actin are moid carcinoma.
negative. The presence of human papillomavirus Simple excision is the choice of treatment. Recur-
DNA using in situ hybridization has been reported rence or malignant transformation has not been
in the tumor (29). reported (9).
Inverted ductal papilloma should be differentiated
from other intraoral minor salivary gland tumors, espe- Cystadenoma
cially sialadenoma papilliferum and mucoepidermoid
carcinoma (2,9). Unlike the exophytic growth of inverted Introduction. Cystadenoma is defined as ‘‘a rare
ductal papilloma, sialadenoma papilliferum exhibits benign epithelial tumor characterized by predominantly
biphasic exophytic and endophytic components. The multicystic growth in which the epithelium
demonstrates adenomatous proliferation. The epithelial

lining is frequently papillary and rarely mucinous’’ (1).
Previously, some investigators interpreted this lesion to
be reactive cystic hyperplasia of the salivary gland duct
rather than a true neoplasm and used corresponding
terms such as ‘‘duct ectasia,’’ ‘‘salivary duct cyst,’’ and
‘‘intraductal papillary hyperplasia’’ (2,3). However,
now cystadenoma is generally believed to be neoplastic
because of its proliferative properties (2).
Clinical features. The incidence of cystadenoma
varies from 1.2% to 6.3% of all intraoral minor salivary
gland neoplasms (4–7), and it accounts for 4.1% of all
benign epithelial salivary gland tumors based on the
large files of the AFIP (3). These tumors represent 7%
and 3.1% of minor and major salivary gland neo-
plasms, respectively (3). Patient ages range from 12
to 89 years, with a mean of about 57 years (3). There is
a female predominance of between 2:1 and 3:1 (3,4,7).
The major and minor salivary glands are almost
equally involved. In the major salivary glands, cysta-
denoma occurs frequently in the parotid gland (45%),
followed by the submandibular gland (7%) (3). The
lips and buccal mucosa are the most frequent loca-
tions for this tumor in the intraoral minor salivary
gland sites (3,4). The palate is less commonly involved
compared with other minor salivary gland tumors.
Cystadenoma can also arise in the larynx or in the
sinonasal tract (8,9).
Cystadenoma typically presents as a slow-
growing, painless mass, usually less than 1 cm in great-
est dimension when arising in the minor salivary
glands. The clinical appearance is similar to a mucocele.
Pathology. Grossly, cystadenoma is a well-
circumscribed tumor with multiple small cystic spaces
or rarely a single large cyst formation on the cut surface.
Microscopically, the tumor is usually composed
of variably sized, multiple cysts with or without a
fibrous capsule (Fig. 78A). Each cystic space is sepa- Figure 78 Cystadenoma. (A) Well-circumscribed tumor com-
posed of variably sized, multiple cysts with focal papillary con-
rated by limited, dense, fibrous stroma. Although
figurations. (B) The cyst lining epithelium consists of columnar or
papillary configurations are commonly seen in this cuboidal cells. The cysts contain eosinophilic, proteinaceous
tumor, the term ‘‘papillary cystadenoma’’ is applied material.
only when the lesion has multilocular cyst formations
with conspicuous multiple papillary projections into
the cystic spaces (10,11). Cyst formation may appear
as a single space in cystadenoma, but unicystic lesions
with intracystic papillary proliferations with fibrovas- Warthin’s tumor without lymphoid stroma (Fig. 79)
cular cores should be included in the category of (3,14). The oncocytic epithelial cells are stained by
intraductal papilloma rather than unicystic cystade- phosphotungstic acid hematoxylin, and their cyto-
noma. The cysts contain eosinophilic, proteinaceous plasm strongly reacts with an antimitochondrial anti-
material, sometimes with a few epithelial and inflam- body (14). One oncocytic cystadenoma had a
matory cells. Psammoma bodies or crystalloids prominent signet-ring cell component (15). Lining
(tyrosine-rich crystals) are rarely present within the epithelial cells have no cellular atypia, and mitoses
luminal secretions (12,13). The cyst-lining epithelium are rare. The thickness of the lining epithelium may
consists of mostly cuboidal or columnar cells (Fig. 78B). vary between cases or within a single tumor, but
Mucous, oncocytic, squamous, and apocrine cells are cystadenoma usually lacks an extraluminal, solid epi-
also present in the epithelium focally or occasionally thelial component. Foci of lymphocytic cell aggrega-
extensively; a mixture of several cell types may com- tions are sometimes evident in the fibrous stroma.
monly be seen. In ‘‘mucinous cystadenoma,’’ multiple Differential diagnosis. The main differential
cysts are predominantly lined by mucous columnar diagnoses include salivary duct cyst, duct ectasia
epithelium. due to obstruction, polycystic (dysgenetic) disease,
‘‘Oncocytic cystadenoma’’ is composed of papillary- Warthin’s tumor, low-grade mucoepidermoid carci-
cystic proliferation of a single- or double-layered noma, the papillary-cystic variant of acinic cell carci-
oncocytic epithelium, superficially resembling a noma, and cystadenocarcinoma.
mimic cystadenoma. However, solid nests composed

of a mixture of epidermoid, mucous, and intermediate
cells characteristic of mucoepidermoid carcinoma are
absent in cystadenoma. The papillary-cystic variant of
acinic cell carcinoma can be difficult to distinguish
from cystadenoma. In acinic cell carcinoma, at least
some cells containing diastase-resistant PAS-positive
zymogen secretory granules can be identified in the
proliferating epithelium. In addition, characteristic
microcystic growth patterns may be seen in the intra-
luminal papillary fronds in acinic cell carcinoma.
Cystadenocarcinoma usually has obvious cellular aty-
pia and shows invasive growth into surrounding
salivary gland parenchyma (16). The overall appear-
ance of low-grade cribriform cystadenocarcinoma
(LGCCC) (17), originally called low-grade salivary
duct carcinoma (18), is very similar to that of cysta-
denoma. However, LGCCC is a purely intraductal
carcinoma lesion.
Treatment and prognosis. Complete surgical
excision with a good safety margin is the choice of
treatment for cystadenoma. Although recurrence after
appropriate treatment is rare and the prognosis is
excellent, a case of malignant transformation to invasive
micropapillary adenocarcinoma from mucinous cysta-
denoma has been reported (19).
Keratocystoma
Introduction. Squamous cells are known to be
present in a variety of salivary gland diseases. How-
ever, benign salivary gland tumors composed of purely
squamous cells are quite unusual. Keratocystoma is a
rare, benign salivary gland tumor characterized by
multicystic spaces lined by stratified squamous epi-
thelium containing keratotic lamellae and focal solid
epithelial nests (1,2). In 1999, Seifert et al. reported the
Figure 79 Oncocytic cystadenoma. (A) Papillary-cystic prolifer- first example of this tumor, which they called ‘‘chori-
ation of oncocytic epithelium in the parotid gland. Note the stoma,’’ resembling trichoadenoma (1). In 2002, Nagao
absence of lymphoid infiltration in fibrous stroma separating et al. described two histologically identical cases and
cystic spaces. (B) The cysts are lined by a double-layered
designated them ‘‘keratocystoma,’’ a term that refers
oncocytic epithelium, resembling that seen in Warthin tumor.
Source: Courtesy of Dr. Jean E. Lewis, Mayo Clinic, Rochester, to the specific histopathologic features of the tumor
Minnesota, U.S.A. (2). In the 2005 WHO Histological Classification of Sali-
vary Gland Tumors, keratocystoma was not adopted as
an independent entity, and instead was briefly men-
tioned in the section of squamous cell carcinoma (3).
Salivary duct cyst is a unilocular lesion lined by Clinical features. Only three cases of keratocys-
a smoothly outlined epithelium without intracystic toma have been reported (1,2). The patients, two
papillary proliferations. Duct ectasia secondary to males and one female, were from 8 to 38 years old.
obstruction often displays a multicystic appearance, However, increased recognition of the tumor may
but this lesion involves several duct segments usu- alter the epidemiologic characteristics. All three
ally associated with acinar atrophy, fibrosis, and reported tumors arose in the parotid gland. Clinically,
chronic inflammatory cell infiltration in the adjacent the tumor manifests as a painless, slowly growing
salivary gland. Unlike the well-circumscribed tumor mass in the parotid gland. CT shows a low-density
formation of cystadenoma, polycystic disease is a multilocular cystic mass with enhanced septa. Kera-
diffuse lesion throughout the affected salivary tocystoma is a completely benign tumor. After subto-
gland. tal parotidectomy, no additional therapy is needed.
The oncocytic variant of papillary cystadenoma Pathology. The cut surface of the tumor shows a
lacks a dense lymphoid stroma characteristic of War- multilocular cystic lesion filled with a keratin-like
thin’s tumor. Additionally, the lining epithelium of substance (Fig. 80A). The three reported tumors had
oncocytic cystadenoma may focally be admixed with a maximum dimension of 1.3 to 4.0 cm.
cuboidal or columnar cells. Multicystic and papillary Histopathologically, the tumor consists mainly
pattern of low-grade mucoepidermoid carcinoma can of multiple cysts that contain keratotic lamellae
(Fig. 80B). Stratified squamous epithelium lines the

cystic spaces and shows a parakeratotic or orthoker-
atotic surface without a granular cell layer (Fig. 80C).
The stratification of the epithelium is oriented regu-
larly from the outer basal to the inner keratotic cell
layers. Focally, the outer layer demonstrates budlike
protrusions. In some areas, solid squamous cell
islands with sharply defined margins are surrounded
by collagenous stroma. The tumor does not have a
definite lobular architecture. The solid areas of squa-
mous cell nests are localized partly within the paren-
chyma of the parotid gland adjacent to an excretory
duct and should not be interpreted as invasive
growth. Cells of the neoplastic squamous epithelium
have uniform, bland nuclei, and abundant eosinophil-
ic cytoplasm. There is no oncocytic or mucous cell
differentiation. The few scattered mitotic figures are
limited to the outer epithelial layer. The transformation
from parotid ductal epithelium to neoplastic cells
through a squamous-metaplasia-like process may be
evident. Foci of giant cell reaction against extravasated
keratin may be apparent.
Squamous differentiation of the tumor cells is
confirmed by immunohistochemical stains positive
for cytokeratins by AE1/AE3 and cytokeratin 14 but
negative for cytokeratins 8 and 18 (2). Staining for
smooth-muscle actin and S-100 protein is negative.
Ki-67 immunoreactive cells may be limited to the area
along the outer basal layer of the neoplastic epithelium.
Collagen type IV-positive material surrounds the
epithelium lining the cysts and the solid cell nests.
Differential diagnosis. Several salivary gland
tumors and tumor-like lesions containing squamous
cells should be ruled out before the diagnosis of
keratocystoma, including primary and metastatic
squamous cell carcinomas, mucoepidermoid carcino-
ma, squamous metaplasia in certain benign neoplasms
and conditions, and cysts (2). Primary squamous cell
carcinoma of the parotid gland is an aggressive malig-
nancy with frequent facial nerve involvement or cer-
vical metastases (3). Cystic changes are a well-known
finding in metaplastic nodal squamous cell carcino-
mas and are also noted in primary squamous cell
carcinoma of the parotid gland. In keratocystoma,
the consistent absence of metastasis, necrosis, inva-
sion, and perineural or intravascular growth, as well
as the lack of cytological atypia and minimal cell
proliferative activity, weighs against malignancy.
The solid areas of squamous cell formation partly
localized within the parotid gland parenchyma in
the vicinity of an excretory duct should not be inter-
preted as invasive growth. In addition to the benign
characteristics described above, the absence of incor-
porated mucous cells and the presence of marked
Figure 80 Keratocystoma. (A) Cut surface of the parotid tumor, keratinization are important for distinguishing this
showing multiple cystic formations filled with keratin material. (B) tumor from mucoepidermoid carcinoma.
Low-power view showing multilocular cystic lesions filled with Squamous metaplasia is known to occur in
lamellar keratin material. (C) Portion of the cyst wall consists of several benign salivary gland tumors. In pleomor-
stratified squamous epithelium with keratinization through para- phic adenoma, squamous elements usually coexist
keratotic cells. Note the lack of a granular cell layer. Tumor cells with variable myxochondromatous, myoepithelial, or
exhibit uniform, bland nuclei and abundant eosinophilic glandular components. Warthin’s tumors sometimes
cytoplasm. show areas of squamous metaplasia, for example, in
metaplastic (infarcted) Warthin’s tumor (4,5). These
areas, however, are usually accompanied by exten- Acinic cell carcinoma usually presents as a slow-
sive necrosis, and immunoreactivity for cytokeratins growing, painless, mobile mass, although some cases
may reveal columnar cell phenotypes but no squa- may be fixed and nodular. The duration ranges from a
mous differentiation (5). In addition, foci with few weeks to over 40 years with an average of 6 to
characteristic double cell layer of oncocytic cells are 7 years (2,15,21–23). Pain or tenderness is present in
present at least focally even in such type of Warthin’s about half of the cases and facial nerve involvement is
tumor. seen in 5% to 10% of patients (15,22,24,25).
Other lesions that can be mistaken for keratocys- Pathology. Grossly, tumors form rubbery or
toma are necrotizing sialometaplasia and epidermal firm, round or lobulated, circumscribed masses that
and dermoid cysts. Necrotizing sialometaplasia is an are usually less than 3 cm in diameter. A minority of
inflammatory and usually self-limiting disorder of the tumors have ill-defined margins or appear multifocal.
salivary glands that occurs commonly in the hard or The cut surfaces vary from white to yellow to tan and
soft palate but can also be found in the parotid gland red. They may be homogeneous or show extensive
(6–8). In keratocystoma, the lack of the lobular infarc- cystic change. Recurrent tumors form multifocal and
tion or necrosis and the general lobular morphology, often poorly defined nodules.
the formation of much larger cysts, and the absence of Microscopically, there is a surprisingly wide
a granular layer in the squamous lining may be range of cell types and architectural configurations
helpful for distinguishing it from necrotizing sialome- with a unifying feature of serous acinar differentiation
taplasia. Rarely, epidermal and dermoid cysts may in some part of the tumor. The cell types present, other
occur in the parotid gland (9,10). Most epidermal cysts than serous acinar cells, include intercalated ductal,
show unilocular cystic formation with a granular layer nonspecific glandular, vacuolated, and clear cells.
in their lining. Unlike in dermoid cysts, skin appen- Acinar cells (Fig. 81) are the commonest and most
dages such as hair follicles and sebaceous glands are characteristic cells. They resemble the normal serous
absent in keratocystoma. acinar cells and are round or polyhedral and have
abundant, pale, basophilic cytoplasm. These contain
dense, grayish, or blue zymogen granules that may be
I. Malignant Tumors fine or moderately coarse and are PAS positive and
Acinic Cell Carcinoma diastase resistant (Fig. 82). The nuclei are round,
uniform, and typically located peripherally. They are
Introduction. Acinic cell carcinoma is defined as usually darkly stained and basophilic or occasionally
‘‘a malignant epithelial neoplasm of salivary glands in more vesicular. Intercalated duct-type cells are
which at least some of the neoplastic cells demonstrate smaller, cuboidal in shape, and have less cytoplasm
serous acinar differentiation, which is characterized that, in contrast, is eosinophilic or amphophilic. The
by cytoplasmic zymogen secretory granules. Salivary nuclei are usually centrally located. These cells sur-
ductal cells are also a component of this neoplasm’’ round duct-like spaces of variable sizes. Vacuolated
(1). Synonyms include acinic cell adenocarcinoma and cells are a common and sometimes conspicuous com-
acinous cell carcinoma. ponent of the tumor (26). They contain clear, PAS/D-
Clinical features. Acinic cell carcinoma accounts negative cytoplasmic vacuoles of variable sizes or, less
for about 3% to 6% of all salivary gland tumors and frequently, occasional zymogen granules can also be
between 7% and 17.5% of malignant salivary neo- identified. The nuclei have an open chromatin pattern
plasms in major series (2–5). The parotid gland is the and may show more pleomorphism than acinar or
most common site accounting for about 80% to 90% of
cases (2), with tumors of the minor glands of the oral
cavity forming the second most common site (2,5).
Intraoral tumors are most frequent in the upper lip,
buccal mucosa, and palate. Acinic cell carcinoma is
relatively uncommon in the submandibular gland
(*4%) and rare in the sublingual gland (2). Occasional
cases are reported in the lacrimal gland (6) and sero-
mucous glands of the upper and lower respiratory tract
(7,8). Central tumors in the mandible have also been
described (9). It is the most common malignant salivary
gland tumor to arise bilaterally (3%) (10,11). Acinic cell
carcinoma may be a component of a hybrid tumor (12).
There is a slight female predominance in most
published series (2,4,13–15), and tumors are seen over
a wide age range (3–91 years) with a fairly uniform
age distribution from the third to seventh decades (2).
The mean age in the largest series was 44 years (2). It
is the second most common salivary malignancy in
children (16–19). There is no ethnic predilection, and Figure 81 Acinic cell carcinoma showing basophilic, granular
there are only two case reports suggesting a familial cells that resemble normal serous acinar cells.
association (11,20).
Figure 82 Acinic cell carcinoma. Periodic acid Schiff stain Figure 84 Acinic cell carcinoma with solid and microcystic
highlighting zymogen granules on the luminal aspect. pattern.
Figure 83 Acinic cell carcinoma showing focal clear cell Figure 85 Acinic cell carcinoma with microcystic pattern and
change. lymphocyte-rich stroma.
the tumor usually consists of sheets or nodules of

intercalated ductal cells. Cells that have clear cyto- closely aggregated, cytologically bland acinar cells
plasm and conspicuous cell membranes are seen and sometimes smaller numbers of nonspecific glan-
singly or in small foci. They do not contain glycogen dular cells or intercalated ductal cells (Fig. 84). The
and in some cases may be a fixation or processing microcystic pattern is the most common subtype and
artifact (Fig. 83) (21,27). They are seen in only 6% of numerous small spaces within the tumor give it a
acinic cell carcinomas (15). Nonspecific glandular cells lattice-like pattern (Fig. 85). In addition to the serous
are round or polygonal and are smaller than acinar acinar cells, this variant often contains significant
cells. They have amphophilic cytoplasm and aggre- numbers of intercalated ductal cells and vacuolated
gate as sheets of cells with indistinct cytoplasmic cells. In some cases the cystic spaces enlarge, and there
borders. The nuclei are larger and more vesicular is papillary intracystic proliferation (Fig. 86A,B). In
than in the other cell types and in addition are more this papillary-cystic variant, cells on the luminal layer
likely to show pleomorphism and mitotic figures. may show prominent hobnailing, and classical acinic
Acinic cell carcinomas show a variety of growth cells may be very infrequent. In addition, this variant
patterns that include solid, microcystic, papillary- often shows intratumoral and intracystic hemorrhage,
cystic, and follicular, and tumors may contain one or and phagocytosis of hemosiderin by tumor cells is
several of these architectural subtypes. This morpho- sometimes a conspicuous feature. The follicular pat-
logic diversity, together with the heterogeneity of the tern (Fig. 86C) is the least common variant and con-
cellular component, contributes to the widely variable sists of multiple cystic spaces of varying sizes. These
histologic appearances of this tumor. In the solid type, are lined predominantly by cells of the intercalated
Figure 86 (A) Acinic cell carcinoma. Papillary-cystic variant consisting of basophilic cells. (B) Acinic cell carcinoma. Papillary-cystic
variant consisting of nonspecific glandular and clear cells. In this variant there is characteristic luminal blebbing. (C) Acinic cell carcinoma
with basophilic acinar cells forming follicles. (D) Acinic cell carcinoma with nonspecific glandular cells forming follicles containing colloid
material and resembling thyroid tissue.
duct type and contain homogeneous, eosinophilic,

and proteinaceous material. The intercystic areas con-
sist predominantly of nonspecific glandular cells. The
follicular variant often shows a striking similarity to
follicular carcinoma of the thyroid gland (Fig. 86D).
Psammoma bodies are sometimes a conspicuous fea-
ture of acinic cell carcinoma and have been described
in fine-needle aspiration biopsies (Fig. 87) (28). The
stroma of acinic cell carcinoma is usually scanty and
composed of delicate fibrovascular tissue. Occasional-
ly there is denser, hyalinized stroma. There may be
extensive intratumoral hemorrhage, degeneration,
and necrosis following fine-needle aspiration or spon-
taneous infarction (29). Stromal infiltration by lym-
phocytes is common but in some cases there is
conspicuous tumor-associated lymphoid proliferation
often together with germinal center formation (30).
These tumors tend to be of the solid or microcystic
type, have a low Ki-67 proliferation index, and are
encapsulated. This variant has been termed well- Figure 87 Acinic cell carcinoma with extensive psammoma
differentiated acinic cell carcinoma with abundant body formation.
lymphoid stroma (Fig. 88) (31). Preliminary data
Although about 10% of acinic cell carcinomas are

positive for S-100 protein (39), there appears to be no
evidence of basal cell or myoepithelial differentiation
(48,49). In a recent study, cytokeratin 14, which has
been used as a myoepithelial marker, was detected in
a wide range of salivary tumors but was not a feature
of acinic cell carcinomas (50).
Differential diagnosis. The degree of variability
can lead to considerable difficulty in diagnosis of
some acinic cell carcinomas by less experienced his-
topathologists. Well-differentiated tumors need to be
distinguished from normal salivary serous acini or
sialadenitis, particularly in biopsy material and frozen
sections. The lack of other structures such as striated
ducts should assist recognition. Microcystic and
papillary-cystic acinic cell carcinomas need to be dif-
ferentiated from cystadenocarcinomas, particularly the
Figure 88 Well-differentiated acinic cell carcinoma with abun- papillary variant. The presence of characteristic zymo-
dant lymphoid stroma. gen granules, vacuolated cells, and intercalated ductal
differentiation aids distinction. The characteristic hob-
nail appearance of luminal cells and the vascularity of
papillary-cystic acinic cell carcinoma are also useful
distinguishing features. Microcystic variants can also
be confused with mucoepidermoid carcinoma due to
the mucicarmine positivity of the small cystic spaces
being interpreted as mucocytes (51). However, there is
a lack of other characteristic features of mucoepider-
moid carcinoma such as intermediate and epidermoid
cells, and close scrutiny shows an absence of typical
goblet cells. When there is difficulty separating adeno-
carcinoma (NOS) and acinic cell carcinoma, staining for
cytokeratin 7 and cytokeratin 18 may be helpful (52).
Cytokeratin 7 is strongly positive in adenocarcinoma
(NOS) but completely or predominantly negative in
acinic cell carcinoma. In addition, cytokeratin 18 shows
characteristic membranous staining in acinic cell carci-
nomas but there is diffuse cytoplasmic staining in
adenocarcinoma (NOS). The follicular variant of acinic
Figure 89 Area of high-grade tumor with extensive necrosis. cell carcinoma can be mistaken for follicular thyroid
carcinoma but in equivocal cases staining for thyro-
globulin quickly resolves the dilemma. The differential
diagnosis when significant numbers of clear cells are
suggest that this subgroup has a very good prognosis. present is discussed in page 563. It is important that
Dedifferentiated acinic cell carcinomas have also been acinic cell carcinomas with a prominent lymphoid
reported (32–35). They are composed of typical acinic stroma are not misinterpreted as lymph node
cell carcinoma with areas of poorly differentiated, high- metastases.
grade tumor (Fig. 89); this component is usually ade- Molecular-genetic data. There have been few
nocarcinoma (NOS) or undifferentiated but a carcino- cytogenetic or molecular genetic studies on acinic
matous element showing myoepithelial differentiation cell carcinomas, and some results are conflicting so
has been described (36). Extensive oncocytic change that any interpretation should be circumspect. Dele-
has rarely been reported (37). tion of chromosome 6q, loss of the Y chromosome, and
Immunohistochemistry. The immunohistochemi- trisomy 21 have been described, but these abnormali-
cal profile of acinic cell carcinoma is nonspecific and is ties are neither constant nor specific (53,54). Analysis
rarely of diagnostic value (38,39). Although the zymo- of a single tumor has shown cytogenetic and genetic
gen granules of normal salivary glands stain consis- evidence of polyclonality (55). In the largest study on
tently for anti–alpha amylase, those in acinic cell genetic alterations in acinic cell carcinoma, the highest
carcinoma show very variable reactivity (40,41). incidence of loss of heterozygosity was found at 4p15-
Immunoreactivity has been reported for cytokeratins, 16, 6p25qter and 17p11, suggesting the presence of
carcinoembryonic antigen, Leu M1, a1 antichymotryp- tumor suppressor genes (56). Twenty-one out of
sin (39,42), vasoactive intestinal polypeptide (43), 24 cases showed alteration in at least one locus tested,
COX-2 (44), and bone morphogenic protein 6 (45). with the most frequent involvement on chromosomes
Some tumors are positive for estrogen and progester- 1p and 1q and 4q, 5p and 6q. It has been shown that
one receptors (46), and prostate-specific antigen (47). Rb protein is expressed in significant levels in acinic
cell carcinomas suggesting that it is not commonly In 1945, Stewart et al. were the first to describe
mutated (57). However, phosphorylation of serine 795 this neoplasm as ‘‘mucoepidermoid tumor’’ (3). They
resulting from cyclin D over-expression was more divided this tumor into two varieties: ‘‘relatively
frequent in tumors than normal salivary gland tissue. favorable’’ (benign) and ‘‘highly unfavorable’’ (malig-
In addition, there appeared to be no changes in nant). In 1953, Foote and Frazell reported that some
p16INK4a expression in the tumors compared with patients with ‘‘relatively favorable’’ tumors, included
normal tissue. This observation correlates with those in the previous citation, developed distant metastases
reports showing there was no loss of heterozygosity in (4). Nevertheless, the 1st edition of the WHO Histolog-
these tumors (58). ical Classification of Salivary Gland Tumors, published in
Treatment and prognosis. There is considerable 1972, retained the term mucoepidermoid tumor, for
variation in the reported rates of local recurrence (8– the reason that only minority do eventually metasta-
60%) and both regional and distant metastasis (7–29%) size and in only a very few does invasiveness assume
(59). The wide range of incidence may reflect inappro- a serious degree, though these tumors must be
priately conservative initial management in earlier regarded as potentially malignant (5). Now, all of
cases. The average recurrence rate is about 35%, and these tumors are considered to be malignant with
the average rate of metastasis and disease-associated the capability to recur or metastasize to regional
death is about 16% (2). In a meta-analysis of over lymph nodes or to distant viscera, regardless of their
2000 cases, the 5- and 10-year survival was 82% and macroscopic or microscopic appearances. Thus, the
68%, respectively (60). Multiple recurrences, locore- 2nd and 2005 editions of the WHO classification
gional or distant metastases, usually to lung or bone, adopted the term mucoepidermoid carcinoma (2,6).
are associated with a very poor prognosis (23,61). Mucoepidermoid carcinoma has been defined as ‘‘a
Tumors in the minor glands have a better outcome malignant glandular epithelial neoplasm character-
than those in major glands (24,62–65), and subman- ized by mucous, intermediate, and epidermoid cells,
dibular gland tumors have the worst prognosis. His- with columnar, clear cell and oncocytoid features (2).
tologic grading is of limited value in assessing Clinical features. Mucoepidermoid carcinoma is
outcome (15,59). Features associated with more clini- the most common malignant salivary gland tumor in
cally aggressive tumors include a high mitotic fre- both major and minor salivary gland sites, accounting
quency, cellular pleomorphism, necrosis, perineural for about 2% to 16% of all salivary gland tumors and
or vascular invasion, stromal desmoplasia, and wide- 12% to 29% of all salivary gland malignancies (1,7,8).
spread invasion (14,39,59,61,66). Attempts to devise a Slightly over half of the tumors arise in the major
histopathologic grading system based on architectural salivary glands. In the major salivary glands, the
characteristics, invasion, and vascular involvement parotid gland is the most frequent site (45%), followed
have not received universal acceptance (66). One by 7% in the submandibular gland and 1% in the
study found that a predominantly solid architecture sublingual gland (1). The palate is the most frequently
was a strong predictor of recurrence (67). Ki-67 pro- involved minor salivary gland site, but the buccal
liferation index may be a useful predictor of clinical mucosa, upper and lower lips, retromolar region,
behavior (68,69). DNA studies have produced con- and tongue may be affected (1,7).
flicting results in predicting likely outcome (70–73). Mucoepidermoid carcinoma can arise from
Dedifferentiated acinic cell carcinoma is associated ectopic salivary gland tissue in periparotid lymph
with a particularly poor prognosis. Clinical staging nodes as well as in the larynx, lacrimal gland, nose,
appears to be the best indicator of clinical outcome. paranasal sinuses, lung, and trachea (9). Rarely, it
Large tumors (>6 cm diameter) and involvement of originates in the mandible and maxilla as an intra-
the deep lobe of the parotid gland (4,15,21,61) are osseous tumor, referred to as ‘‘central mucoepider-
associated with a worse outcome. moid carcinoma’’ (1,10–13). The histogenesis of central
Surgical excision is the treatment of choice, and mucoepidermoid carcinoma remains controversial,
failure to excise the tumor completely in the initial but one highly possible theory is that this malignancy
operation is an indicator of poor prognosis (22). arises from the lining epithelium of odontogenic cysts
Superficial parotidectomy is the most commonly (1,10–13).
employed surgical procedure, and neck dissection is The majority of mucoepidermoid carcinoma
not undertaken unless there is a specific indication, as occurs between the third and sixth decades of life
there is a low reported incidence of regional metasta- with a mean patient age of about 45 years, but it may
ses. Radiotherapy appears to be of limited value present at any age (2). Patients with palatal tumors are
(59,61). about 7 years younger than those with other intraoral
minor salivary gland tumors (1). It is the most com-
Mucoepidermoid Carcinoma mon salivary gland malignancy of children, and most
tumors in this age group are low grade (14,15). There
Introduction. Mucoepidermoid carcinoma is a is a slight female predominance with a 3:2 female to
malignant epithelial neoplasm characterized by the male ratio (1).
proliferation of epidermoid, mucous, and intermedi- Prior exposure to ionizing radiation is the most
ate type cells in various proportions (1,2). This malig- common etiologic factor associated with the devel-
nancy exhibits varying degrees of differentiation and opment of mucoepidermoid carcinoma. Atomic
histologic grade as well as widely diverse biologic bomb survivors exposed to radiation in Hiroshima
behavior. and Nagasaki have suffered mucoepidermoid
carcinoma in high incidence with a relative risk of

9.3 times (16). In addition, the occurrences of mucoe-
pidermoid carcinoma have been reported in the
patients after radiation treatment for leukemia, lym-
phoma, brain tumor, sarcoma, retinoblastoma, or
thyroid carcinoma (17).
Clinically, patients with mucoepidermoid carci-
noma typically complain of a slowly growing, firm,
and painless swelling, but a high-grade tumor may
present as a rapidly enlarging mass accompanied by
pain, fixation, otorrhea, paresthesia, facial nerve palsy,
dysphagia, hemorrhage, or trismus (1). Many palatal
tumors appear as fluctuant, bluish, smooth-surfaced
swellings resembling mucoceles.
Pathology. Macroscopically, mucoepidermoid
carcinoma typically manifests as a circumscribed but
unencapsulated or incompletely capsulated, firm
mass. High-grade tumors are poorly circumscribed
and have infiltrative borders, often with fixation to
the adjacent tissue. The cut surface commonly has Figure 91 Mucoepidermoid carcinoma. Tumor is composed of
conspicuous cystic structures accompanied by grayish a mixture of three cell types: epidermoid, mucous (mucus-
white to tan solid areas (Fig. 90). Cystic spaces may producing), and intermediate.
contain brownish and mucinous material. Hemor-
rhage or necrosis is frequently present in high-grade
tumors, and these tumors tend to be solid. In the AFIP
series, the tumor size ranges from less than 1 cm to
over 12 cm in the major salivary glands and as large as mucoepidermoid carcinoma and if present, usually
5 cm in the minor salivary glands (1). occur in inflamed portions. Epidermoid cells are neg-
Microscopically, mucoepidermoid carcinomas ative for mucicarmine but may show faint positivity
are characteristically composed of varying propor- for PAS stain. Mucous cells are large and have pale to
tions of three basic cell types: epidermoid (squamous), slightly basophilic, fine cytoplasm with positive reac-
mucous (mucus-producing), and intermediate tions to PAS, Alcian blue, and mucicarmine stains.
(Fig. 91). Furthermore, columnar cells, clear cells, Their nuclei are compressed and located at the periph-
and oncocytic cells may also be components of these ery of the cell. Intermediate cells are ovoid in shape
tumors. Epidermoid cells are polygonal in shape with with scanty cytoplasm and the size ranges from small,
ovoid to elongated, vesicular nuclei, and abundant resembling basal cells, to about three times larger than
eosinophilic cytoplasm. Individual cell keratinization lymphocytes. These cells exhibit a small, centrally locat-
and keratin pearl formation are only rarely seen in ed, darkly stained nucleus and pale eosinophilic cyto-
plasm, which is negative for mucin stains. Larger
intermediate cells transitionally merge into epidermoid
or mucous cells.
Columnar cells superficially mimic duct lumi-
nal cells of the excretory salivary duct and can
transform into mucous cells. Clear cells are large
and polygonal in shape with sharply demarcated
borders that contain largely glycogen and occasion-
ally mucin as well. These cells are present in many
mucoepidermoid carcinomas and uncommonly are a
dominant component of the tumor (clear cell variant)
(Fig. 92A) (18,19). Oncocytic differentiation may be a
focal feature of some mucoepidermoid carcinomas,
but it is rarely extensive ‘‘oncocytic variant,’’ with
only 14 such cases reported (Fig. 92B) (20,21). The
majority of oncocytic mucoepidermoid carcinoma are
low-grade tumors and should not be misdiagnosed
as oncocytoma. In addition, a few cases of intraoral
mucoepidermoid carcinoma have been associated
with melanin pigmentation (22).
Mucoepidermoid carcinoma is characterized by
Figure 90 Mucoepidermoid carcinoma. Cut surface of the a variety of tumor-cell types arranged in a combina-
intermediate-grade tumor shows gray-white, solid mass accom- tion of cystic or ductal structures and solid nests in
panied by multiple small cystic structures and infiltrative borders. various proportions. The cystic structures are lined by
mucous, intermediate, epidermoid, or columnar cells.
Figure 92 Mucoepidermoid carcinoma. (A) Clear cell variant. Figure 93 Mucoepidermoid carcinoma. (A) Abundant hyali-
(B) Oncocytic variant. nized stroma is evident. (B) Extensive secondary lymphoid cell
infiltration, referred to as tumor-associated lymphoid
proliferation.
Cystic spaces contain mucinous material, which occa- into low grade, intermediate grade, or high grade.
sionally leaks into the stromal tissue, forming mucin Low- and intermediate-grade mucoepidermoid carci-
pools. The ductal structures are formed by clear and nomas tend to have a more favorable outcome than
columnar cells. The solid nests are composed mainly high-grade tumors, which have a greater tendency to
of intermediate cells admixed with epidermoid, recur and metastasize.
mucous, clear, and uncommonly oncocytic cells. The Many investigators have tried to define histolog-
fibrous stroma is usually abundant and sometimes ic features that have prognostic significance and pro-
hyalinized (Fig. 93A). Hyalinization may be proposed various grading schemes (3,4,27–33). In the
nounced and rarely is accompanied by dense eosino- literature, the histopathologic grading criteria of
philic cell infiltration (sclerosing mucoepidermoid mucoepidermoid carcinoma remain controversial.
carcinoma with eosinophilia) (23–25). Extensive sec- However, the AFIP scoring system offers good corre-
ondary lymphoid cell infiltration, referred to as lation with clinical outcome and high reproducibility
tumor-associated lymphoid proliferation (26), is com- (1,29,31,34) (Table 6). The grading is based on a
monly present (Fig. 93B); the feature may be confused scoring system of five histologic features: intracystic
with metastasis to or origin from ectopic salivary component <20% (þ2), neural invasion (þ2), necrosis
gland tissue in intraparotid lymph nodes. (þ3), 4 or more mitotic figures per high-power fields
The histopathologic features of mucoepidermoid (þ3), and anaplasia (þ4); and based on the total score
carcinoma are complex and largely depend on the a case is categorized as low grade (score 0–4), interme-
histologic grade; these tumors are generally classified diate grade (score 5–6), or high grade (score > 6)
Table 6 Histologic Grading System (Armed Forces Institute of Table 7 Histologic Grading System Proposed by Brandwein
Pathology) et al.
Parameter Point value Characteristic features Defining features
Intracystic component <20% þ2 Grade I – Prominent goblet cell – Lack of grade III defining
Neural invasion present þ2 component features
Necrosis present þ3 – Cyst formation and – Lack of aggressive
Four or more mitoses per 10 HPFs þ3 intermediate cells may invasion pattern
Anaplasia þ4 be prominent
– Circumscribed growth
Grade Total score Death of diseasea pattern
Low grade 0–4 3.3%
Grade II – Intermediate cells – Aggressive invasion
Intermediate grade 5–6 9.7%
predominate over pattern
High grade 7 or more 46.3%
mucinous cells
a – Mostly solid tumor – Lack of grade III defining
Five-year mortality rate.
Abbreviation: HPFs, high-power fields. features
Source: From Ref. 31. – Squamous cells may be
seen
Grade III – Squamous cells – Necrosis, perineural
(Table 6). The cellular anaplasia is represented by
predominate spread, vascular
cellular and nuclear pleomorphism, increased nuclear- – Intermediate and invasion, bony
cytoplasmic ratio, prominent or multiple nucleoli, and mucinous cells must invasion, >4 mitosis/10
hyperchromasia. This system is applicable to the parotid also be present HPFs, high-grade
gland and intraoral minor salivary gland tumors, but it – Mostly solid nuclear pleomorphism
does not predict outcome of submandibular tumors,
which have a significant metastatic potential irrespec- Features Points
tive of histologic grade (29,31). On the other hand, Intracystic component < 25% 2
Brandwein et al. noted that the AFIP scoring system Tumor front invades in small nests and islands 2
tends to downgrade mucoepidermoid carcinomas (32) Pronounced nuclear atypia 2
(Table 7). Their modified grading system adds three- Lymphatic or vascular invasion 3
additional parameters (invasion in the form of small Bony invasion 3
nests or islands, lymphovascular invasion, and bony > 4 mitoses/10 HPFs 3
invasion). Perineural spread 3
Necrosis 3
Low-grade tumors are characteristically composed
of multiple cystic structures of variable sizes that are Grade Total points Death of diseasea
lined predominantly by mucous cells (Fig. 94). Some I 0 0%
cysts may have focal papillary projections of lining II 2 or 3 5%
epithelial cells. Usually, mucous cells are more com- III 4 or more 63%
mon than intermediate- and high-grade tumors. Solid a
nests are a minor component and are composed Mortality rate at 36 months.
Abbreviation: HPFs, high-power fields.
mainly of intermediate cells. Squamous cell differenti- Source: From Ref. 32.
ation and clear cell change may be present, at least
focally. In low-grade tumors, cellular or nuclear pleo-
morphism is absent, and mitotic figures are rare.
Tumor borders are generally well circumscribed and
minimally invasive. However, a case of dedifferentia- tumors are composed primarily of epidermoid cells
tion to anaplastic, undifferentiated carcinoma from and a small proportion of intermediate cells, which
histologically low-grade mucoepidermoid carcinoma usually have marked cellular pleomorphism and high
has been reported (35). mitotic activity. Necrosis may be present, and peri-
Intermediate-grade tumors have less tendency to neural and lymphovascular invasion is common.
form cystic structures and contain smaller cystic Some areas of high-grade mucoepidermoid carcinoma
spaces (Fig. 95). In most cases, cyst-lining cells are may resemble nonkeratinizing squamous cell carcino-
mainly columnar cells with occasional mucous cells. ma. Since mucous cells are few and are scattered
Solid sheets or nests, consisting of intermediate cells within the tumor cell nests, mucin stains are often
as well as epidermoid cells, become a conspicuous required to identify them. Foci of low-grade mucoe-
component in intermediate-grade tumors compared pidermoid carcinoma are rarely present within high-
with low-grade tumors. Intermediate-grade tumors grade tumors. In addition, a case of high-grade
show an invasive growth pattern, at least focally. mucoepidermoid carcinoma with a spindle cell sarco-
Mild to moderate cellular pleomorphism and a few matoid component has been reported (36).
mitotic figures may be seen. A few examples of mucoepidermoid carcinoma
High-grade tumors manifest as predominantly arising in or associated with Warthin’s tumor (37),
solid nests with scanty cystic structures (Fig. 96). pleomorphic adenoma (38), salivary duct cyst (39),
They have markedly infiltrative borders. These and odontogenic cyst (10) have been reported.
Figure 95 Intermediate-grade mucoepidermoid carcinoma.

Solid nests with focal cystic structures consisting of intermediate
cells as well as epidermoid cells and a few mucous cells. Note
mild to moderate cellular pleomorphism.
Immunohistochemistry. Tumor cells are positive

for pan-cytokeratin and are variably immunoreactive
for epithelial membrane antigen, carcinoembryonic
antigen, and S-100 protein. Intermediate, epidermoid,
and clear cells may be positive for p63 but completely
negative for smooth muscle actin and calponin (40).
Molecular-Genetic data. A chromosomal translo-
cation, t(11;19)(q21;p13), has been found in mucoepi-
dermoid carcinoma as a sole-specific cytogenetic
alteration (41). Molecular analysis demonstrates that
the fusion transcript, resulting in the binding MECT1
at 19p13 with MAML2 at 11q21, is detected in 38% to
81% of mucoepidermoid carcinoma cases (42–44). The
MECT1-MAML2 fusion transcript acts as a coactivator
for Notch receptor transcriptional activation and sig-
naling (45). This translocation is frequently associated
with a low-grade histology, and the presence of this
transcript appears as an independent prognostic fac-
tor (42,43). The fusion transcript has been detected
using reverse transcription-polymerase chain reaction
assay also in some cases of Warthin’s tumor but not in
any cases of adenoid cystic carcinoma, basaloid carci-
noma, salivary duct carcinoma, and adenocarcinomas
(NOS) (44). Recently, fusion between EWSR1 and
POU5F1 has also been reported in a single case of
high-grade mucoepidermoid carcinoma with the
translocation t(6;22)(p21;q12) (46). The fusion tran-
script is expected to be useful in the development of
novel molecular therapeutic strategies for patients
with mucoepidermoid carcinoma (47).
Figure 94 Low-grade mucoepidermoid carcinoma. (A) Multiple Differential diagnosis. The main differential
cystic structures of variable sizes with focal papillary projections. diagnoses include necrotizing sialometaplasia, pleo-
(B) The cyst linings and papillary projections are mainly com-
morphic adenoma, cystadenoma, and cystadenocarci-
posed of mucous cells. (C) High-magnification view shows
mucous, intermediate, and columnar cells with minimal atypia.
noma for low-grade mucoepidermoid carcinoma,
squamous cell carcinoma and adenosquamous carci-
noma for high-grade mucoepidermoid carcinoma, and
clear cell tumors for the clear cell variant of mucoepi-

dermoid carcinoma (1,33).
Necrotizing sialometaplasia exhibits squamous
metaplasia of ducts and acini with adjacent lobules
containing mucus or necrotic debris. While these
features can be confused with mucoepidermoid carci-
noma, in necrotizing sialometaplasia, the lobular
architecture is maintained, and the cystic structures
and intermediate cells of mucoepidermoid carcinoma
are absent. In addition, identification of myoepithelial
cells demonstrated by calponin and/or smooth mus-
cle actin in necrotizing sialometaplasia may help to
distinguish it from mucoepidermoid carcinoma (40).
The epithelioid type of neoplastic myoepithelial
cells seen in pleomorphic adenoma may mimic inter-
mediate cells in mucoepidermoid carcinoma. The
presence of myxochondroid areas, plasmacytoid-type
myoepithelial cells, and small, well-defined ductal
structures is diagnostic for pleomorphic adenoma
but not for mucoepidermoid carcinoma. Cystadenoma
and cystadenocarcinoma and low-grade mucoepider-
moid carcinoma share conspicuous multicystic and
papillary structures. Cystadenoma and cystadenocar-
cinoma lack solid nests consisting of a mixture of
epidermoid, mucous, and intermediate cells charac-
teristic of low-grade mucoepidermoid carcinoma.
The distinction between high-grade mucoepider-
moid carcinoma with extensive squamous differentia-
tion and squamous cell carcinoma is based on the
presence or absence of mucous cells revealed by
mucin stains. Also, marked intracellular keratinization
and keratin pearl formation are much more commonly
seen in squamous cell carcinoma than in mucoepider-
moid carcinoma. Positive immunostaining for MUC1
and MUC5AC in high-grade mucoepidermoid carcino-
ma can be helpful in distinction from squamous cell
carcinoma (48,49). In addition, most mucoepidermoid
carcinomas stain positively for cytokeratin 7 and nega-
tively for cytokeratin 20, while squamous cell carcino-
mas generally stain negatively for these cytokeratin
subtypes (50). Adenosquamous carcinoma is composed
of two separate carcinomatous components showing
squamous and glandular differentiation. By contrast,
the squamous and mucinous glandular components of
mucoepidermoid carcinoma are usually markedly
admixed with each other in the same tumor nests.
The clear cell variant of mucoepidermoid carci-
noma should be distinguished from various types of
salivary gland tumors composed predominantly of
clear cells, such as sebaceous carcinoma, clear cell
adenocarcinomas (NOS), epithelial-myoepithelial car-
cinoma, oncocytoma, acinic cell carcinoma, and meta-
static renal cell carcinoma (see the section ‘‘Clear Cell
Carcinoma, NOS’’) (19,51). Only mucoepidermoid
carcinoma displays both epidermoid and mucous
cell differentiation.
Figure 96 High-grade mucoepidermoid carcinoma. (A) Solid
nests accompanied by focal necrotic area and scanty cystic Treatment and prognosis. The biologic behavior
structures. (B) Tumor is composed primarily of markedly pleo- of mucoepidermoid carcinoma varies depending on
morphic epidermoid cells and a small proportion of mucous cells. the clinical stage, the histologic grade, tumor location,
(C) Periodic acid–Schiff (PAS) stain showing scattered positive and the adequacy of treatment, but the majority is
mucous cells in the solid nests. low-grade and the prognosis is generally favorable.
Overall, 75% of patients with mucoepidermoid carci-
noma are tumor free after the initial treatment, 9%
have local recurrence only, 5% develop metastasis and b-catenin is correlated with adverse outcome (59).
survive, and 11% die of disease (31). High expression of MUC1 is related to high histologic
The clinical stage appears to be the most signifi- grades, high recurrence and metastasis rates, and a
cant prognostic indicator of mucoepidermoid carcino- shorter disease-free interval (48,49). On the other
ma. Five-year survival rates of the patients have been hand, high MUC4 expression is associated with low-
reported to be 97% to 100%, 70% to 83%, and 20% to grade tumors, lower recurrence rates, and a longer
37% for stage I, II, and III cases, respectively (7,33,52). disease-free interval (49).
Histologic grade also closely correlates with patient Complete surgical excision is the treatment of
outcome. However, the clinical stage is a stronger choice for mucoepidermoid carcinoma. Adequate
prognostic indicator than the histologic grade. excision is important in all grades of tumor, with
There are some differences in survival rate much higher recurrence rates reported with positive
among the histologic grades reported in the literature, surgical margins (27). Radiation therapy should be
because of the variable histologic grading criteria used added in high-grade tumors and for patients with
(3,4,27–32) (Tables 6 and 7). Low-grade tumors rarely questionable or positive surgical margins or for
recur or metastasize. According to the AFIP, 5% of those with positive lymph nodes. For the patients
major gland and 2.5% of minor gland low-grade with positive surgical margins, postoperative radio-
mucoepidermoid carcinomas metastasized to regional therapy may improve local control. Neck dissection is
lymph nodes or resulted in death of the patient (1). indicated when there is clinical evidence of regional
Most investigators have indicated that the five-year metastasis, high clinical stage, high histologic grade,
survival rate is over 92% in the low-grade tumor or proximity of tumor to regional lymph nodes.
group. Intermediate-grade tumors have a slightly
higher tendency of recurrence and metastasis than
low-grade tumor. Healey et al. reported that recur- Adenoid Cystic Carcinoma
rence rate following surgery of intermediate tumor is
20% compared with 6% for low-grade tumor (27). The Introduction. Adenoid cystic carcinoma is
five-year survival rate of intermediate-grade mucoe- defined as ‘‘a basaloid tumor consisting of epithelial
pidermoid carcinoma ranges from 62% to 92%. and myoepithelial cells in variable morphologic con-
High-grade tumors are much more likely to have figurations, including tubular, cribriform, and solid
recurrence and metastases than low- and intermediate- patterns’’ (1). Synonyms include cylindroma, adeno-
grade tumors. The recurrence rate has been reported cystic carcinoma, adenoepithelioma, and basaloma.
as 59% in high-grade tumors (31). Common sites for Clinical features. Adenoid cystic carcinoma
distant metastasis include the lungs, bones, liver, and accounted for 4.4% of all salivary gland tumors and
brain. Distant metastases imply a poor prognosis; 11.8% of malignant salivary neoplasms in the largest
patients with minor and major salivary gland tumors reported series (2). It affects a wide age range (9–103
with distant metastases survive 2.3 and 2.6 years on years) with a peak incidence in the fifth to seventh
average, respectively (1). The five-year survival rate of decades, but it is very rare in children (3,4). There is a
high-grade mucoepidermoid carcinoma is up to 53%. slight female preponderance in most large series,
Regarding the tumor location, submandibular gland particularly in the submandibular gland (5–10). In a
tumors metastasize to the regional lymph nodes more combined series of adenoid cystic carcinoma of the
frequently than other major and minor salivary gland upper aerodigestive tract where the site was recorded,
tumors (7). The margin status of the initial excision 42% involved the major glands and 58% the minor
closely correlates with the recurrence rate, regardless glands (2,11–15). The most common sites were the
of tumor grade (27). parotid (21%), palate (17%), and submandibular gland
Many investigators have attempted to correlate (13%). The tumor is rare in the sublingual gland (16).
nuclear DNA content and immunohistochemical The palate accounts for nearly half of the cases in the
markers of salivary gland mucoepidermoid carcinoma glands of the mouth and the upper aerodigestive tract
with prognosis. DNA ploidy pattern analysis has (17), and the sinonasal tract is the next most common
demonstrated that aneuploid tumors have a poorer site (18). Rare central (intraosseous) cases have been
clinical outcome than diploid tumors (52). Immuno- reported, the large majority involving the body and
histochemical prognostic factors include expression of angle of mandible (19). Adenoid cystic carcinomas
Ki-67 (53-56), HER-2/neu (55), p53 (56), p27 (54), bcl-2 have been reported in wide range of other anatomical
(57), caveolin-1 (58), b-catenin (59), and certain types sites including the lacrimal gland (20), ceruminous
of mucins (48,49). A Ki-67 labeling index higher than glands of the external ear (21), esophagus (22), trachea
10% is associated with high histologic grade, increas- (23), bronchus (24), peripheral lung (25), breast (26),
ing rate of recurrence and metastasis, and decreasing skin (27), uterine cervix (28), ovary (29), Bartholin
survival rates in patients with mucoepidermoid carci- gland (30), and prostate (31).
noma (53). Over-expression of HER-2/neu and p53 Tumors usually present as a slow growing but
correlates with poor prognosis (55,56); conversely, widely infiltrative mass of long duration, and they can
high expression for p27 and bcl-2 is associated with be mobile or fixed. They may be tender or painful, and
a favorable outcome (54,57). Downregulation of cav- cranial nerve lesions, particularly facial nerve palsy,
eolin-1, which has been proposed as a candidate can be the presenting feature (9,20). Patients with
tumor suppressor, is identified as a negative prognos- tumors involving the deep lobe of the parotid gland
tic factor (58). Nuclear/cytoplasmic accumulation of can present with trismus. It is common for tumors of
minor glands to show ulceration of the overlying

mucosa. Occasionally, distant metastases are the pre-
senting feature (32).
Pathology. Macroscopically adenoid cystic car-
cinoma typically forms a solid, light gray to tan colored
mass. It may appear circumscribed, particularly in
smaller tumors, but is rarely encapsulated. Cytolog-
ically, the tumor is composed of luminal ductal cells
and abluminal, modified myoepithelial cells. The lat-
ter predominate and have indistinct cell borders and
frequently sparse, amphophilic, or clear cytoplasm.
The nuclei are uniform in size, basophilic, and may be
round or angular (peg shaped). The ductal cells sur-
round small and sometimes indistinct lumina; they
are cuboidal and have more abundant, eosinophilic
cytoplasm, and round, uniform nuclei that may con-
tain small nucleoli. There are three main morphologic
patterns: cribriform (cylindromatous), tubular, and Figure 98 Adenoid cystic carcinoma showing prominent hyali-
solid in that order of frequency. A mixture of these nization of the stromal component.
patterns may be seen. The cribriform variant consists
of islands of modified myoepithelial cells containing
rounded, pseudocytic areas forming a characteristic
‘‘Swiss cheese’’ appearance (Fig. 97). The pseudocysts cribriform and tubular patterns but may be frequent,
are basophilic and mucoid or consist of hyaline, often together with extensive apoptosis, in the solid
eosinophilic material (Fig. 98). They are composed of type. Rare but clinically aggressive adenoid cystic
glycosaminoglycans and reduplicated basement mem- carcinomas showing high-grade transformation
brane material. Foci of ductal cells are present within (dedifferentiated variant) are characterized histologi-
the myoepithelial areas but may require careful exam- cally by the combination of a conventional adenoid
ination to detect. The tubular variant is double layered cystic carcinoma and a high-grade carcinoma (35–39).
and has conspicuous ductal differentiation (Fig. 99A). In addition, adenoid cystic carcinoma may form part
There is an inner layer of eosinophilic, duct-lining of a hybrid tumor, most commonly in association with
cells, and the abluminal myoepithelial cells may salivary duct carcinoma or epithelial-myoepithelial
show clear cytoplasm and irregular, angular nuclei carcinoma (40). The stroma of adenoid cystic carcino-
or be morphologically similar to the luminal layer ma is usually fibrous and may contain abundant
(Fig. 99B). Occasionally, foci of squamous (Fig. 99C) elastic tissue (41,42). Some cases where hyalinization
(33), sebaceous (34), or oncocytic metaplasia (Fig. 99D) is so abundant that tumor cells are attenuated into
are present. The least common solid variant consists of strands have been reported as a sclerosing variant
islands or sheets of basaloid cells with larger and less (Fig. 100D) (43). Perineural or intraneural invasion is
angular nuclei (Fig. 100A). Duct-lining cells may be common and frequently conspicuous, and the tumor
few (Fig. 100B) and inconspicuous, and comedonec- can extend along nerves and their branches over a
rosis is common (Fig. 100C). Mitoses are sparse in the wide area (Fig. 101A). The tumor may invade bone
extensively before there is any radiologic evidence
bone destruction (Fig. 101B). Lymph node involve-
ment is uncommon (*5% of cases) and is usually due
to contiguous spread rather than lymphatic perme-
ation or embolization (Fig. 101C) (44).
Immunohistochemistry. The pseudocysts are
positive for PAS and Alcian blue and contain base-
ment membrane components such as type IV collagen,
heparin sulfate proteoglycan, and laminin isoforms
(45,46). The epithelial cells, particularly in areas of
ductal differentiation, are positive for low–molecular
weight keratins, carcinoembryonic antigen, and epi-
thelial membrane antigen (47). Duct-lining cells are
also positive for c-kit (CD117) (48–50), and the myoe-
pithelial cells are variably positive for a variety of
markers including S-100 protein, calponin, smooth
muscle actin, smooth muscle myosin heavy chain,
maspin, metallothionein, and p63 (Fig. 101D) (47,51–
53). Expression of S-100 protein, glial fibrillary acidic
Figure 97 Adenoid cystic carcinoma showing characteristic protein (54), and neural cell adhesion molecule (55)
cribriform (cylindromatous) pattern. have been correlated with the presence of perineural
invasion. High expression of both p53 and bcl-2 has
Figure 99 (A) Adenoid cystic carcinoma. Tubular variant showing morphologically similar luminal and abluminal cells. (B) Adenoid
cystic carcinoma. Tubular variant showing morphologically clear abluminal cells. (C) Adenoid cystic carcinoma showing squamous
metaplasia. (D) Adenoid cystic carcinoma showing oncocytic metaplasia.
been reported, but there is no consistent relationship RASSF1A promotor methylation in high-grade tumors
between these observations and the histologic tumor (70). Mutations of p53 are relatively uncommon
types, clinical stage or survival (56–58). CD43, a sialo- (71,72). Alterations in p53 and RB genes have been
glyoprotein that is typically expressed by hemopoietic reported and correlated with behavior (73).P53 muta-
cells, has been shown to be differentially and selection, loss of expression of RB, and overexpression of
tively expressed in adenoid cystic carcinoma (59,60). both Her2/neu and cyclin D1 have been reported in
Molecular-genetic data. Alterations in chromo- adenoid cystic carcinomas showing high-grade trans-
somes 6q, 9p, and 17p12-13 are the most frequent formation (37,38). Frequent and plural methylation of
cytogenetic alterations reported (61,62). t(6;9)(q21-24; the cyclin-dependent kinase inhibitor genes promotor
p13-23) appears to be a nonrandom, primary aberra- regions has recently been reported (74). Microarrays
tion (63). There are frequent losses at 12q, 6q23-qter, and comparative genomic hybridization have been
13q21-q22, and 19q regions (64). A high frequency of used to identify candidate genes for adenoid cystic
loss of heterozygosity at 6q23-25 has been reported carcinoma (75).
and, although not specific for adenoid cystic carcino- Differential diagnosis. It is particularly important
ma, this has been correlated with both tumor grade to distinguish adenoid cystic carcinoma from poly-
and behavior (65,66). Over half of cases show genomic morphous low-grade adenocarcinoma in tumors from
deletions of chromosome 6 (67), and candidate sup- minor salivary glands. Polymorphous low-grade ade-
pressor genes have also been mapped to chromosome nocarcinoma consists of a uniform cell population
12 (68). Hypermethylation of the promotor region of with cytologically bland, round or oval and vesicular
the p16 gene was found in 4/22 of adenoid cystic nuclei and pale, eosinophilic cytoplasm, whereas cells
carcinoma and was associated with higher histologic in adenoid cystic carcinoma often have clear cyto-
grades of malignancy (69). In addition, promotor plasm and angular, hyperchromatic nuclei and may
methylation of p16INK4a, RASSF1A, and DAPK has show mitotic activity (76,77). The Ki-67 proliferative
been reported, and there was a high frequency of index is reported to be nearly 10 higher in adenoid
Figure 100 (A) Adenoid cystic carcinoma. Solid variant. (B) Adenoid cystic carcinoma. Solid variant higher power showing scattered
duct-like structures within the tumor sheet. (C) Adenoid cystic carcinoma. Solid variant showing extensive comedo necrosis. (D) Adenoid
cystic carcinoma showing extensive stromal hyalinization attenuated the tumor into thin strands.
cystic carcinoma than polymorphous low-grade ade- distinction between polymorphous low-grade adeno-
nocarcinoma with no overlap zone (78). Smooth mus- carcinoma and adenoid cystic carcinoma, but recent
cle markers of myoepithelial differentiation are studies suggest the value of these immunoagents is
positive in adenoid cystic carcinoma but negative in limited (48,49). In addition, c-kit expression in ade-
polymorphous low-grade adenocarcinoma. In a hier- noid cystic carcinoma does not appear to correlate
archical cluster analysis of myoepithelial/basal cell with behavior (50,79). Occasional foci in pleomorphic
markers, the diffuse expression of smooth muscle adenoma can resemble adenoid cystic carcinoma but
actin was the most reliable marker in support of a the presence of typical myxochondroid matrix and
diagnosis of adenoid cystic carcinoma (53). In addi- plasmacytoid or spindle-shaped cells helps to avoid
tion, polymorphous low-grade adenocarcinoma confusion (80). Basaloid squamous cell carcinoma
shows a much wider spectrum of histomorphologic can resemble solid variants of adenoid cystic carci-
differentiation. Even when cribriform areas are pres- noma but typically involves the hypopharynx and
ent in polymorphous low-grade adenocarcinoma, they larynx, which are uncommon sites for adenoid cystic
are typically focal, and adenoid cystic carcinoma does carcinoma. Both can show islands with cribriform
not show papillary differentiation or the single cord configurations, hyaline material surrounding tumor
arrangement of cells seen in polymorphous low-grade nests, and solid areas with comedonecrosis, but
adenocarcinoma. Although both adenoid cystic carci- basaloid squamous carcinoma also has evidence of
noma and polymorphous low-grade adenocarcinoma squamous differentiation and usually involves the
show neural invasion, in polymorphous low-grade overlying mucosa. In addition, the different patterns
adenocarcinoma this is often associated with a striking of p63 staining may aid distinction (51). Both epithelial-
whorling arrangement of single-file cords of cells or myoepithelial carcinoma and the tubular variant of
small ducts, and is seen predominantly within, or very adenoid cystic carcinoma can show double-layered,
close to, the main tumor mass. It has been postulated duct-like structures with an abluminal layer of clear
that staining with c-kit or galectin 3 aids the cells (see page 563).
Figure 101 (A) Adenoid cystic carcinoma showing perineural invasion. (B) Adenoid cystic carcinoma showing bone invasion but
absence of osteoclastic bone resorption. (C) Adenoid cystic carcinoma showing contiguous spread into a lymph node. (D) Adenoid cystic
carcinoma. P63 staining of myoepithelial component.
Treatment and prognosis. The average 5- and 10- The relationship between perineural invasion and
year survival rates are about 80% and 50%, respectively, survival is also contentious, but invasion of larger
but the majority of patients usually die of, or with, the nerves appears to correlate with more aggressive
tumor (81). Local recurrence is very common, espe- behavior (14,85). In a review of the literature, Barrett
cially in the first 5 years after surgery. The main and Speight (91) found 23% (range 2–86%) of patients
prognostic factors are site, clinical stage, and histologic had clinical evidence of neurologic deficit. Histologic
pattern (9,12,82). Tumors in the submandibular gland evidence of perineural invasion was reported in 51%
have a poorer prognosis than those in the parotid (83). (range 8–86%) of cases. Clinical evidence of nerve
Bone involvement and failure of primary surgery are involvement such as facial nerve palsy was an indica-
associated with poor prognosis. Correlations between tor of poor prognosis, but histologic evidence of
tumor morphology, grading, and outcome have perineural invasion appeared not to be an indepen-
yielded conflicting results, particularly after 10-year dent factor but was associated with other adverse
follow-up due to the overall poor long-term progno- features such as clinically large and more aggressive
sis (81,83). The tubular and cribriform variants have tumors. In addition, Spiro et al. in large follow-up
been reported to have a better outcome than studies of patients with adenoid cystic carcinoma
tumors with a solid component, especially if this found that both histologic grade and perineural inva-
exceeds 30% of the tumor volume (6,8,58,83–86). sion are unreliable predictors of behavior (9,82). Clini-
DNA studies have shown that there is a higher inci- cal stage is a better guide to prognosis (12,58). Lymph
dence of aneuploidy in solid tumors and this, not node involvement is relatively uncommon but distant
surprisingly, correlates with more aggressive behavior metastases to lung, bone, brain, and liver are seen in
(87–89). High Ki-67 expression is also associated with 40–60% of cases (92).
solid and clinically more aggressive tumors (90). Wide local excision, together with adjuvant
Tumors showing high-grade transformation (dediffer- radiotherapy, offers the best hope of local control
entiation) usually have a very poor prognosis (35–39). (93,94). Elective neck dissection is not indicated. The
use of the tyrosine kinase receptor (CD117) inhibitor, carcinoma (5). Although there are several reports
Imatinib mesylate (95), and the dual inhibitor of the describing polymorphous low-grade adenocarcinoma
tyrosine kinase domains of the epidermal growth of the major salivary glands, most of them are single
factor receptor and erbB2, Lapatinib (96), have not cases, and there are very few histologically convincing
shown any significant clinical benefit. examples. Only eight possibly acceptable polymor-
phous low-grade adenocarcinoma cases of major sali-
Polymorphous Low-Grade Adenocarcinoma vary gland origin, including three of our own proven
cases, have been identified to date as far as we can
Introduction. Polymorphous low-grade adeno- judge from reviewing the literature (7). In the major
carcinoma was first described as a distinctive minor salivary glands, polymorphous low-grade adenocarci-
salivary gland tumor by Evans and Batsakis in 1984 noma occurred in the parotid (5 cases), submandibu-
(1). Almost at the same time, this neoplasm was lar (2 cases), and sublingual (1 case) glands. The
reported in two other publications as ‘‘terminal duct lacrimal glands, nasopharynx, and sinonasal cavity
carcinoma’’ (2) and ‘‘lobular carcinoma’’ (3). The WHO have also been rarely described as the site of the
Classification of Salivary Gland Tumors adopted the term occurrence of polymorphous low-grade adenocarcino-
polymorphous low-grade adenocarcinoma for this ma (15,16).
tumor, and it is now a well-recognized entity in the In the minor salivary glands, polymorphous
minor salivary glands (4). It has been defined as ‘‘a low-grade adenocarcinoma has been reported to
malignant epithelial tumor characterized by cytologic exhibit a nearly 2:1 female to male ratio and a wide
uniformity, morphologic diversity, an infiltrative age range (16–94 years) with a mean of 59 years (4).
growth pattern, and low metastatic’ potential’’ (4). Several reports indicate that there are some differ-
Polymorphous low-grade adenocarcinoma is the sec- ences in the occurrence of polymorphous low-grade
ond most common type of malignant neoplasm of adenocarcinoma among ethnic groups: there is a pre-
minor salivary glands, after mucoepidermoid carcinoma dilection for this tumor in blacks, while it is rare
(5,6), but is exceedingly rare in the major glands (7). among Japanese (5,17). Polymorphous low-grade ade-
The 2005 WHO Blue Book introduced a recently nocarcinoma is generally an asymptomatic, slow-
described tumor, ‘‘cribriform adenocarcinoma of the growing mass or swelling of the palate, cheek, or
tongue,’’ as a possible variant of polymorphous low- upper lip, occasionally associated with bleeding, tel-
grade adenocarcinoma, but its relationship to this angiectasia, or ulceration of the overlying mucosa.
tumor remains controversial (4). The authors hypoth- Multiple, synchronous occurrence has been reported
esized that this tumor might be derived from the (18). Polymorphous low-grade adenocarcinoma may
thyroglossal duct anlage. Only one series consisting occur as a malignant component of carcinoma ex
of eight such cases has been reported (8). The tumor pleomorphic adenoma (19).
occurred in adults with a mean age of 50 years, and Pathology. Grossly, the tumor typically appears
there was no gender predilection. Unlike typical poly- as a relatively well-circumscribed, tan-to-gray mass
morphous low-grade adenocarcinoma, all patients but with infiltrative margins. Tumor size ranges from
with this neoplasm had cervical lymph node metasta- 0.4 to 6 cm with an average of 2.2 cm (12).
ses at the time of clinical presentation, but all were Microscopically, the tumor invades into the sali-
reported to be alive with no distant metastases after vary gland parenchyma (Fig. 102) and surrounding
the initial surgery. Histologically, the tumor is charac-
terized by predominantly solid and microcystic
growth patterns composed of cells with pale, vesicular
ground glass nuclei, closely resembling solid, and
follicular variant of papillary carcinoma of the thy-
roid. On immunohistochemistry, cytokeratins and
S-100 protein are strongly positive, whereas myoepi-
thelial markers show only limited patchy positivity.
Clinical features. Polymorphous low-grade ade-
nocarcinoma is one of the most common malignant
neoplasms of the minor salivary glands. Over 400
cases of minor salivary gland, polymorphous low-
grade adenocarcinoma have been reported (1,9–14).
It accounts for approximately 10% of all intraoral
minor salivary gland tumors, and 26% of all malig-
nancies in these sites (6). Of the minor salivary gland
cases, the palate is the most frequent site (12). Other
minor salivary sites include the buccal mucosa, upper
lip, retromolar region, and the base of the tongue.
Among AFIP cases of minor salivary gland tumors,
only pleomorphic adenoma and mucoepidermoid car-
cinoma are more common than polymorphous low- Figure 102 Polymorphous low-grade adenocarcinoma. Tumor
grade adenocarcinoma, and polymorphous low-grade invades into the minor salivary gland parenchyma.
adenocarcinoma is twice as frequent as adenoid cystic
The cytologic features of the tumor cells are

uniform throughout the mass. They have small- to
medium-sized, round to oval, fusiform nuclei without
pleomorphism. Fusiform cells are often arranged in a
fascicular pattern. The chromatin texture of the tumor
cells is finely dispersed, and nucleoli are small and
inconspicuous. The cytoplasm is relatively abundant
and typically pale eosinophilic, but clear or oncocytic
change may be focally observed, mainly in papillary
areas. A few mucous cells, highlighted by mucin
stains, may also be found. Mitotic figures are rare
and atypical mitoses are absent. The tumors have
hyalinized or mucoid stroma often with a blue-gray
hue (Fig. 106), but no chondroid differentiation is
demonstrated. Psammoma body-like microcalcifica-
tions and tyrosine-rich crystalloids may be present
(21). A few examples of undifferentiated carcinoma or
high-grade adenocarcinoma, evolving within a poly-
morphous low-grade adenocarcinoma, have been
Figure 103 Polymorphous low-grade adenocarcinoma. Low- reported (22,23).
power view showing histologic diversity within the tumor. Mainly Immunohistochemistry. The tumor cells are posi-
solid and tubular growth patterns with focal cribriform and papil- tive for epithelial markers including low- and high-
lary areas. molecular weight cytokeratins and epithelial mem-
brane antigen. Polymorphous low-grade adenocarci-
nomas are diffusely and strongly immunoreactive for
S-100 protein and vimentin, whereas smooth muscle
actin, muscle-specific actin, calponin, and glial fibril-
connective tissue close to the overlying mucosal epi- lary acidic protein are variably but usually uncom-
thelium and may even involve the underlying bone. monly and focally expressed (11,12,24–27). Most
The surface epithelium is usually intact, but is occa- tumors are diffusely positive for bcl-2 (11,12). The
sionally ulcerated. Polymorphous low-grade adeno- proliferative activity of the tumor cells assessed by
carcinoma is often described as an architecturally Ki-67 labeling index is low (12,28).
diverse but cytologically uniform neoplasm within Differential diagnosis. The most important dif-
each case (Fig. 103). The tumor has a polymorphous ferential diagnoses of polymorphous low-grade ade-
growth architecture showing predominantly solid nocarcinoma in the minor salivary glands are
(Fig. 104A,B), tubular (Fig. 104C), fascicular pleomorphic adenoma and adenoid cystic carcinoma.
(Fig. 104D), and cribriform (Fig. 104E) configurations Both polymorphous low-grade adenocarcinoma
with transitions between different patterns. Although and pleomorphic adenoma share similar histologic
papillary areas may also be observed focally features in terms of the diversity of growth patterns
(Fig. 104F), we recommend that tumors consisting and the bland cytology. Although pleomorphic ade-
almost exclusively of papillary areas should not be nomas of the minor salivary glands are often nonen-
included in the category of polymorphous low-grade capsulated, they do not invade the surrounding
adenocarcinoma to prevent confusion with other enti- salivary gland parenchyma and connective tissue. In
ties, especially papillary cystadenocarcinoma, because addition, perineural invasion, a typical feature of
they may have a different biologic behavior (20). polymorphous low-grade adenocarcinoma, is not
The solid portions often assume a lobular con- seen in pleomorphic adenomas. If only limited biopsy
figuration, with nuclear palisading along the periph- material is available for examination, the differential
ery of the tumor-cell nests. Tubular structures are diagnosis between the two neoplasms can be chal-
predominantly lined by a single layer of small cuboi- lenging. Polymorphous low-grade adenocarcinoma
dal cells. Both true tubular structures and pseudocys- commonly exhibits hyalinizing or mucoid stroma as
tic spaces, with or without pale-staining amphophilic seen in pleomorphic adenoma, but plasmacytoid-type
mucoid contents, result in a cribriform appearance. neoplastic myoepithelial cells and chondroid differen-
The areas showing a cribriform pattern are usually tiation characteristic of pleomorphic adenoma are not
limited and do not predominate in polymorphous a feature. Furthermore, tubular structures in pleomor-
low-grade adenocarcinoma. Single-cell arrays of the phic adenoma are bilayered with ductal and myoepi-
tumor cells, termed an ‘‘Indian-file’’ arrangement, thelial differentiation, whereas they are usually
may be seen (Fig. 105A). Perineural invasion and formed by a single layer of cells in polymorphous
association with small blood vessels, though true low-grade adenocarcinoma. Immunohistochemical
intravascular involvement is rare, are often detected expression of glial fibrillary acidic protein is almost
as a concentric targetoid pattern consisting of stream- always observed in pleomorphic adenoma, while
ing cords and narrow tubules of tumor cells (Fig. 105B). positivity is limited in cases of polymorphous low-
Tumor necrosis is absent or minimal. grade adenocarcinoma (24,26).
Figure 104 Polymorphous low-grade adenocarcinoma. Variable morphologic combinations of solid (A and B), tubular (C), fascicular
(D), cribriform (E), and papillary (F) growth patterns. (A) Sheet-like solid growth of the tumor cells exhibiting uniform oval nuclei without
any pleomorphism. (B) Lobular configuration with peripheral palisading arrangement. (C) Tubular structures are predominantly lined by a
single layer of small cuboidal cells. (D) Fusiform cells are arranged in a fascicular pattern. (E) Multiple pseudocystic spaces with pale-
staining amphophilic mucoid contents resulting in a cribriform appearance. (F) Papillary configurations of columnar or cuboidal cells.
Figure 106 Polymorphous low-grade adenocarcinoma. Abun-

dant mucoid stroma with a blue-gray hue.
carcinoma. One study has shown that the Ki-67 label-

ing index of adenoid cystic carcinoma (range 11.3–
56.7%, mean 21.4%) is significantly higher than that of
polymorphous low-grade adenocarcinoma (range 0.2–
6.4%, mean 2.4%) without an overlap zone in their
ranges (28). Immunoreactivity for S-100 protein is
more diffuse and stronger in polymorphous low-
grade adenocarcinoma than in adenoid cystic carcino-
ma. The value of c-kit expression in the differential
diagnosis between polymorphous low-grade adeno-
carcinoma and adenoid cystic carcinoma remains con-
Figure 105 Polymorphous low-grade adenocarcinoma. (A) troversial (29,30).
‘‘Indian-file’’ growth pattern. (B) Perineural invasion with concen- Treatment and prognosis. Minor salivary gland
tric targetoid appearance.
polymorphous low-grade adenocarcinoma recurs
locally and metastasizes to the cervical lymph nodes
in 9% to 17% and in 9% to 15% of the patients,
respectively, but very few patients have died from
the disease (12,13). Local recurrence itself does not
The distinction between polymorphous low- seem to be a major prognostic factor because no
grade adenocarcinoma and adenoid cystic carcinoma patients have died as a consequence. Distant organ
is also essential because of the significant difference in metastasis is extremely rare (12,13). Polymorphous
biologic behavior between these two entities. The low-grade adenocarcinoma arising in the major sali-
distinction is mainly based on cytologic and architec- vary glands shares common clinical characteristics
tural features. Round to oval, uniform nuclei with with tumors of minor salivary gland origin (7).
finely dispersed chromatin and more abundant cyto- Surgical resection with an appropriate safety
plasm in polymorphous low-grade adenocarcinoma margin is the treatment of choice for polymorphous
contrast with the angular and hyperchromatic irregu- low-grade adenocarcinoma. Elective neck dissection is
lar nuclei and scant cytoplasm seen in adenoid cystic not warranted unless the patients have clinical evi-
carcinoma. The cribriform pattern of adenoid cystic dence of lymph node metastasis. There can be pro-
carcinoma is more rigid and commonly present than tracted periods between initial resection and
that of polymorphous low-grade adenocarcinoma. In recurrence, indicating the need for a long-term
addition, polymorphous low-grade adenocarcinoma follow-up. Tumors with a predominant papillary con-
lacks large pseudocystic spaces containing pools of figuration have been reported to have a higher inci-
basophilic glycosaminoglycans. Furthermore, tubules dence of cervical lymph node metastasis. Whether
in polymorphous low-grade adenocarcinoma are typ- such tumors should be considered within the
ically lined by unilayered tumor cells, which contrast spectrum of polymorphous low-grade adenocarcinoma
with the bilayered tumor cells seen in adenoid cystic or deemed to be a separate entity, such as papillary
cystadenocarcinoma, remains controversial

(10,12,13,31). Polymorphous low-grade adenocarcino-
ma rarely can transform to a high-grade carcinoma if
untreated or radiated (22,23). These patients have a
less favorable clinical outcome.
Epithelial-Myoepithelial Carcinoma
Introduction. Epithelial-myoepithelial carcinoma
is defined as ‘‘a malignant tumor composed of vari-
able proportions of two cell types, which typically
form duct-like structures. The biphasic morphology is
represented by an inner layer of duct-lining, epithelial-
type cells, and an outer layer of clear, myoepithelial-
type cells’’ (1). It has many synonyms that cover
a wide variety of benign and malignant tumors
including: clear cell adenoma (2,3), glycogen-rich
adenoma (4), tubular carcinoma (5), clear cell myoe- Figure 107 Epithelial-myoepithelial carcinoma showing double
pithelioma (5), glycogen-rich adenocarcinoma (6), layered duct-like structures separated by acellular fibrous tissue.
clear cell carcinoma (7), epithelial-myoepithelial carci-
noma of intercalated duct origin (8), and adenomyoe-
pithelioma (9).
Clinical features. Epithelial-myoepithelial carci-
noma is uncommon and represents about 0.5% to 1%
of salivary gland tumors. There is a female predomi-
nance of about 2:1 and the age range is wide (6–92
years) with a mean age at diagnosis of about 60 years
(8,10–14). The tumor is rare in children (12,14,15).
The parotid gland (75%) and submandibular
gland (10–12%) account for most cases. In the
major glands, the tumor usually presents as a slow-
growing, painless mass and facial nerve palsy is
uncommon. It occasionally arises in oral minor
salivary glands, particularly in the palate and tongue,
and very rarely involves seromucous glands in the
upper (8,11–13) and lower respiratory tracts (16–19); in
these sites there is a tendency for the tumors to
ulcerate. Involvement of the sublingual and lacrimal
glands is exceptional. Adenomyoepithelioma is a
Figure 108 Epithelial-myoepithelial carcinoma with trabecular
histologically identical tumor that arises in the arrangement and predominantly noncanalized ducts.
breast (20).
Pathology. Macroscopically, epithelial-
myoepithelial carcinomas are usually well defined,
firm swellings that are frequently nodular or multi-
nodular. About a third of cases are encapsulated and
areas invading the surrounding gland are not com-
monly seen. The cut surface is yellow to gray-white and
cystic areas are common. Most tumors are 2 to 8 cm in
diameter with a mean of about 3 cm (14) but larger
examples have been reported (13).
The characteristic microscopic feature of epithelial-
myoepithelial carcinoma is the formation of double-
layered, duct-like structures. The luminal cells are
typically arranged as single, cuboidal, or columnar
luminal cells that have a central round or oval nucleus
with finely granular, densely eosinophilic cytoplasm
(Figs. 107–109). The polygonal abluminal cells form
single or multiple layers and have clear cytoplasm
and vesicular, eccentrically placed nuclei. The propor-
tion of these two cell types and their morphologic
distribution is widely variable. The duct-like struc- Figure 109 Epithelial-myoepithelial carcinoma consisting pre-
tures may be separated by dense fibrous tissue but dominantly of nests of clear cells with scanty luminal cells.
aggregated into theques or nests. In other areas,
although the nesting arrangement persists, the tumor

forms cohesive sheets. Where the clear cell component
predominates, the ductal configuration may not be
initially obvious. In some tumors, the inner duct-
lining cells do not canalize and are solid. Sometimes
the inner and outer layers are composed of morpho-
logically similar cells that do not have clear cytoplasm.
Conversely, double clear cell–layered epithelial-
myoepithelial carcinomas have recently been
described (14). Cystic or papillary areas are present
in about 20% of cases. Uncommonly there is squa-
mous or oncocytic metaplasia, usually of the duct-
lining cells. Very rarely spindle cell proliferation and
‘‘Verocay-like’’ palisading, similar to that occasionally
seen in pleomorphic adenomas, has been reported.
Sebaceous differentiation was described in 8/61 cases
of epithelial-myoepithelial carcinoma in a recent study
Figure 111 (A) Cytokeratin stain highlighting the luminal cells.
and was often associated with areas of oncocytic (B) Calponin staining highlighting abluminal myoepithelial cells.
metaplasia (14). Several cases of epithelial-myoepithe-
lial carcinoma showing sebaceous differentiation have
been reported, and termed ‘‘sebaceous epithelial-
myoepithelial carcinoma’’ (21). Mitoses are usually
sparse in epithelial-myoepithelial carcinoma and rare-
ly exceed 2 to 3 per 10 HPFs. Despite the relatively myoepithelial carcinoma is the tumor most commonly
bland cytologic features, tumor necrosis is not uncom- associated with ductal adenomatoid hyperplasia
mon. Only a small minority of tumors shows an (intercalated ductal hyperplasia) (33,34).
infiltrative growth pattern but perineural invasion is Immunohistochemistry. The immunoprofile of
present in about 30% of cases (Fig. 110) and angio- epithelial-myoepithelial carcinoma corresponds to
lymphatic involvement is seen in about 10%. Dedif- the biphasic nature of the tumor. Low–molecular
ferentiated epithelial-myoepithelial carcinomas show weight cytokeratins such as AE1/AE3 and CAM 5.2
greater cytologic atypia, higher mitotic frequency, are strongly positive in the duct-like cells (Fig. 111A).
and may have extensive areas of necrosis (14,22–25). They can also be detected in the clear cell population,
There are two reported examples of epithelial- though with lower staining intensity. ‘‘Myoepithelial
myoepithelial carcinomas with myoepithelial cell ana- markers’’ (p63, S-100 protein, alpha smooth
plasia characterized by severe nuclear atypia, muscle actin, calponin (Fig. 111B), vimentin, glial
pleomorphism, and hyperchromasia (14). Epithelial- fibrillary acidic protein, smooth muscle myosin
myoepithelial carcinoma can develop in a pleomor- heavy chain) stain the clear cell compartment variably,
phic adenoma (26) and may be a component of a with p63 probably being the best marker for these
hybrid tumor, particularly in combination with ade- tumors (14). Bcl-2 is frequently positive and stains
noid cystic carcinoma (27–32). In addition, epithelial- both duct-lining and myoepithelial cells, and c-kit,
when positive, only stains the epithelial component
(14). Tumors may show a relatively high Ki-67 prolif-
eration index (*17%), typically in the myoepithelial
component.
Molecular-genetic data. There are very few stud-
ies on the molecular-genetic characteristics of epithe-
lial-myoepithelial carcinoma. Of those tumors
karyotyped, half were normal and the remainder
showed nondistinctive chromosomal abnormalities
(35–37). Loss of heterozygosity has been shown in a
single case of epithelial-myoepithelial carcinoma, in
both the primary tumor and a metastatic deposit (38).
The tumor examined had a double-layered, tubular
growth pattern and a solid, predominantly myoepi-
thelial component. Loss of heterozygosity at 13q12
and 18q21 was found in both architectural areas of
the primary tumor and lymph node metastasis. In
addition, loss of heterozygosity at 9p22-p21 and
10q23-q24 was shown predominantly in the solid
Figure 110 Epithelial-myoepithelial carcinoma showing neural part of the primary tumor and the metastasis, which
invasion.
was also solid, underlining distinct biologic differ-
ences in the two parts of the tumor.
Differential diagnosis. The differential diagnosis associated with recurrence and metastasis (8,10–14).
of epithelial-myoepithelial carcinoma includes tumors The poorer prognosis seen in tumors located in minor
showing the formation of double-layered, duct-like salivary and sero-mucinous glands may be because of
structures and those consisting predominantly of a higher frequency of recurrences resulting from
clear cells. Double-layered, duct-like structures can incomplete excision (1). In a recent large study, no
be seen in pleomorphic adenoma and the tubular cases that were encapsulated or were minimally inva-
variant of adenoid cystic carcinoma. In these tumors sive recurred (14). Size and rapid tumor growth may
the clear cells tend to have less abundant cytoplasm be associated with a worse prognosis (20,22) but some
and their nuclei are usually hyperchromatic and studies have failed to show this correlation (14). No
angular. However, these variants usually only form correlation was found between proliferative activity
focal areas of more typical tumors and the main and histologic pattern and prognosis in a cytophoto-
problem arises in the interpretation of limited biopsy metric study (39). Other factors associated with poorer
material. In such circumstances it may not be possible prognosis include angiolymphatic invasion, necrosis,
to distinguish between these three tumor-types with and myoepithelial anaplasia. The presence of nuclear
confidence and a circumspect report may be neces- hyperchromasia and irregularity in over 20% of tumor
sary. Some epithelial-myoepithelial carcinomas con- cells has been associated with more aggressive behav-
sist almost entirely of clear cells and it may require ior (13). In addition, aneuploidy and high mitotic
extensive sampling to identify characteristic double- counts have been reported in cases with unfavorable
layered ducts or obvious duct-lining cells. A wide prognosis (13). Although areas of dedifferentiation
range of benign and malignant salivary tumors can have been related to poor prognosis (22,23), this has
show focal or extensive areas consisting predominant- not been universally confirmed (14); the size and
ly of clear cells. These include clear cell variants of distribution of such areas may be important in deter-
pleomorphic adenoma, myoepithelioma, oncocytoma, mining outcome.
mucoepidermoid carcinoma, acinic cell carcinoma, The treatment of choice is complete surgical
sebaceous neoplasms, and clear cell carcinoma removal with neck dissection only when there is
(NOS). Clear cells in pleomorphic adenoma are usually evidence of regional lymph node metastases. Adju-
focal and readily identified, but epithelial-myoepithelial vant radiotherapy has no proven role.
carcinoma may be a component of carcinoma ex
pleomorphic adenoma. In epithelial-myoepithelial
carcinomas the clear cells are positive for glycogen Clear Cell Carcinoma, Not Otherwise Specified
and myoepithelial markers and unlike mucoepider-
moid carcinomas they are mucicarmine negative and Introduction. Clear cell carcinoma, not otherwise
intermediate cells are not seen. Clear cells in acinic cell specified (NOS), has been defined as ‘‘a malignant
carcinoma are usually focal and the distinction is epithelial neoplasm composed of a monomorphous
rarely problematical. Similarly, in sebaceous tumors, population of cells that have optically clear cytoplasm
most of the cells have foamy rather than clear cyto- with standard hematoxylin and eosin stains. Because
plasm, although focally there may be genuinely clear many types of salivary gland neoplasms commonly or
cells. In clear cell oncocytomas, phosphotungstic acid consistently have a component of clear cells, clear cell
hematoxylin positive granules can usually be identi- carcinoma is distinguished by the absence of features
fied in at least some of the cells. Clear cell carcinoma characteristic of these neoplasms and its monomor-
(NOS), including the hyalinizing variant, lacks the phous population of clear cells’’ (1). Synonyms include
biphasic pattern of epithelial-myoepithelial carcinoma clear cell adenocarcinoma, glycogen-rich clear cell car-
and usually stains negatively, or weakly, for myoepi- cinoma, and hyalinizing clear cell carcinoma.
thelial markers. In addition, metastases from the kid- Clinical features. Clear cell carcinoma is an
ney and thyroid gland may need to be considered by uncommon salivary tumor that is found predomin-
staining for CD10, renal cell carcinoma marker or antly in the minor glands of the mouth (*60%),
thyroglobulin, or by using ultrasound as appropriate. particularly in the base of tongue and palate (2–4).
Myoepithelial markers are helpful in distinguishing Other sites include the lip, buccal mucosa, floor of the
epithelial-myoepithelial carcinoma showing seba- mouth, retromolar trigone, and tonsil. There is a single
ceous differentiation from sebaceous carcinoma (21). reported case involving the gingiva (4). The tumor is
Treatment and prognosis. Despite its relatively less common in the parotid (*28%) and submandib-
bland cytologic features, epithelial-myoepithelial car- ular (*12%) glands (2,5,6). Cases developing intra-
cinoma is a low- to intermediate-grade tumor. Local osseously within the maxilla and mandible have been
recurrence is common but rates in the literature are reported (7). Clear cell carcinoma can form the malig-
variable and range from 23% to 80% (14) with a mean nant component of carcinoma ex pleomorphic adeno-
of about 30%. The incidence of metastasis to regional ma (8). The majority of clear cell carcinomas arise in
lymph nodes and distant sites such as lung, liver, and the 40 to 70 year age range with a mean of 58 years
kidney, also shows a wide range, varying from 5% to and they are rare in children (2,9). There appears to be
25% of cases. Despite this, the prognosis is relatively no significant sex predilection. Tumors usually pres-
good and in one large study the disease-specific sur- ent as a nondescript, painless swelling but there may
vivals were 93.5% at 5 years and 81.8% at 10 years be ulceration and pain in tumors involving mucosal
(14). Margin status is the most significant pathologic glands. Palatal tumors can invade the underlying
prognostic factor. Incomplete surgical excision is bone (10).
Pathology. Most tumors are 3 cm or less in of basement membrane-type material, as it is composed

maximum diameter and the cut surface is typically mainly of type I collagen and fibronectin (17).
grayish white. The tumor may appear well or poorly Differential diagnosis. The differential diagnosis
circumscribed but they are not encapsulated and they of clear cell carcinoma (NOS) is considered in detail in
infiltrate the surrounding tissue. Microscopically, the the section covering epithelial-myoepithelial carcinoma
tumor consists of a predominant population of round (see page 562).
to polygonal cells of variable sizes with optically clear Treatment and prognosis. Most cases of clear cell
cytoplasm. The nuclei are usually round, have con- carcinoma are low grade and the prognosis is excel-
densed chromatin, and may contain small nucleoli. lent. They may show local recurrence but locoregional
They are eccentrically located. There may be mild-to- metastasis and distant spread are uncommon
moderate nuclear atypia and a relatively high nuclear- (4,6,11,18,19). A case of clear cell carcinoma with foci
cytoplasmic ratio, but mitoses are uncommon. The of less well-differentiated tumor showed widespread
presence of intracytoplasmic glycogen can be demon- metastasis and death within a year of initial diagnosis
strated by staining with PAS, with and without dia- (12). Complete surgical excision is the treatment of
stase digestion, but the staining is variable in both choice in the large majority of cases. Chemotherapy
distribution and intensity. Mucin stains are negative. and radiotherapy have been occasionally used but
In addition to the characteristic clear cells, there may their value is uncertain (12,19).
be a minor population of smaller cells with pale,
eosinophilic cytoplasm. The cells are aggregated into
a variety of configurations including solid sheets, Basal Cell Adenocarcinoma
nests and trabeculae, and ductal differentiation is
absent. Focal squamous metaplasia is an uncommon Introduction. Until recently, malignant basaloid
feature (6). In some tumors, the islands and nests are salivary gland tumors have been variously referred to
separated by thin, variably cellular, fibrous septa but as basaloid salivary carcinoma (1), hybrid basal cell
many show densely sclerosed bands of collagen and adenoma and adenoid cystic carcinoma (2), basal cell
constitute the ‘‘hyalinizing clear cell carcinoma’’ vari- adenocarcinoma (3–11), basal cell carcinoma (12),
ant (Fig. 112) (11). The tumor invades the surrounding basaloid carcinoma (13), and carcinoma ex monomor-
tissue, although this may only be in focal areas, and phic adenoma (14). Of these, there is now a clear
can show evidence of neural invasion. An aggressive consensus for the term basal cell adenocarcinoma,
variant of clear cell carcinoma with areas showing which is a distinct low-grade entity defined as a
cytologic atypia, high mitotic frequency, and necrosis, malignant counterpart of basal cell adenoma, desig-
has been reported (12). nated by Ellis and Wiscovitch in 1990 (4). Further-
Immunohistochemistry. Clear cell carcinomas more, the basaloid tumor occurring in infants is
have variable immunohistochemical profiles. They usu- probably best classified as sialoblastoma (15). Basal
ally show diffuse or focal low–molecular weight cytoker- cell adenocarcinoma has similar demographic features
atin staining but reactivity for vimentin, S-100 protein, and cytologic and architectural characteristics to those
glial fibrillary acidic protein, calponin, and actin is less of basal cell adenoma but is an invasive tumor with
predictable and often negative (4,6,10,11,13–16). It potential for metastasis. The majority of basal cell
appears that the densely fibrous stroma seen in the adenocarcinomas arise de novo (4,7), but some devel-
hyalinizing variant is not formed by the accumulation op via evolution from a preexisting basal cell adeno-
ma, usually of the membranous variant (6,14,16).
Clinical features. Basal cell adenocarcinoma is a
rare tumor, and slightly over than 100 cases have been
reported (4–11). It accounts for less than 2% of all
salivary gland tumors (15). Most basal cell adenocar-
cinomas have been reported to occur in the parotid
and submandibular glands (4,6–8) but a few minor
salivary gland cases have also been documented (5,9–
11). There is no gender predilection and the peak
incidence is in the sixth and seventh decades (range,
27–92 years; median, 60 years) (3). Most patients
present with long-standing, painless swellings, but
occasionally complain of pain or tenderness. Similar
to membranous variant of basal cell adenoma, a
diathesis of concurrent dermal tumors, especially
eccrine cylindromas and trichoepitheliomas, has
been documented in patients with basal cell adeno-
carcinoma, but its frequency is lower than that seen in
individuals with basal cell adenoma (4).
Figure 112 Hyalinizing clear cell carcinoma. Uniform popula- Pathology. The tumor size of basal cell adeno-
tion of cells with clear cytoplasm forming discrete nests in a carcinoma ranges from 0.7 to 7.0 cm with a mean size
dense fibrous stroma. of 2.4 to 3.4 cm (3–11). Basal cell adenocarcinomas are
usually unencapsulated with focal invasion into the
pattern or eddies, or even forming keratin pearls, is

sometimes seen (Fig. 116).
Two distinct cell populations, dark-staining
basaloid cells and larger pale cells, are recognized in
every case to varying extents depending on the
growth pattern; the former cells are evident in solid
and membranous variants and the latter cells mainly
form ductal structures. Some basaloid tumor cells can
evolve into spindle-shaped cells. Nuclear and cellular
pleomorphism is usually slight but varies from case to
case. Sometimes, the nuclear and cellular features are
virtually indistinguishable from basal cell adenoma.
In general, however, mitotic figures are easily identi-
fied in basal cell adenocarcinoma and the mitotic
count is usually more than 4/10 HPFs. Necrosis is
seen in a half of the tumors, either the comedo or
spotty type. Vascular involvement is common and
perineural invasion can also be identified.
Immunohistochemistry. Immunohistochemical
Figure 113 Basal cell adenocarcinoma. Low-power view show- and ultrastructural studies have shown that basal
ing tumor cell islands invading into the salivary gland cell adenocarcinomas are composed of similar cell
parenchyma. populations as basal cell adenomas with the dual
ductal and myoepithelial phenotypes (8,17). Tumors
are positive for cytokeratin and often focally immuno-
reactive for epithelial membrane antigen and
adjacent salivary gland or soft tissue, but some are carcinoembryonic antigen, indicating ductal differen-
well circumscribed. tiation. Myoepithelial markers, smooth muscle actin
Microscopically, the essential architectural pat- as well as S-100 protein and vimentin, are frequently
tern and cytologic appearance of basal cell adenocar- expressed by abluminal cells located at the periphery
cinoma resemble those of basal cell adenoma. of the tumor nests. The Ki-67 labeling index is usually
However, unlike basal cell adenomas, which are higher in basal cell adenocarcinoma (more than
always well circumscribed and encapsulated, all 5%) than in basal cell adenoma (less than 2.7%)
basal cell adenocarcinomas invade into the surround- (7). Expression of p53 and epidermal growth factor
ing normal salivary gland parenchyma (Fig. 113) or receptor may be observed in basal cell adenocarcino-
adjacent soft tissue, though a few cases are focally ma, whereas these are both negative in basal cell
encapsulated. As in basal cell adenoma, they can be adenoma (7).
generally divided into four subtypes: solid, trabecular, Differential diagnosis. The differential diagnosis
tubular, and membranous, according to its predomi- of basal cell adenocarcinoma includes basal cell adeno-
nant histologic features (Fig. 114). The solid type of ma, adenoid cystic carcinoma (especially of the solid
growth is the most common feature. Tumors with type), small cell carcinoma, large cell neuroendocrine
predominantly trabecular, tubular, or membranous carcinoma, and basaloid squamous cell carcinoma (18).
pattern are uncommon. A palisade-like arrangement Because of the frequent bland cytology of basal
of the carcinoma cells is characteristic at the periphery cell adenocarcinoma, it is often distinguished from
of the tumor cell nests (Fig. 115), but this feature is less basal cell adenoma by other histologic hallmarks
conspicuous than in basal cell adenoma. In the mem- such as invasive outgrowth, perineural and vascular
branous type, PAS-positive basement membrane-like invasion, necrosis, and mitosis (Table 8). Although
material surrounds individual tumor islands and is immunohistochemical markers for myoepithelial dif-
sometimes deposited within the tumor cell nests. ferentiation are not useful in the differential diagnosis
Focal squamous differentiation with a whorling between the two neoplasms, demonstrating cell
Table 8 Comparison of Clinicopathologic Features of Basaloid Salivary Gland Tumors

BCA BCAC Solid AdCC
Growth pattern Encapsulated Invasive Invasive
P/eripheral palisading Distinct Distinct to vague Inconspicuous
Atypia Mild Mild to marked Marked
Mitosis Few Frequent Numerous
Necrosis No Common (spotty) Common (comedo)
Squamous differentiation Occasional Common (1/3) No
Perineural invasion No Occasional (1/4) Frequent
Vascular involvement No Occasional (1/4) Frequent
Biologic behavior Benign Low-grade malignancy High-grade malignancy
Abbreviations: BCA, basal cell adenoma; BCAC, basal cell adenocarcinoma; Solid AdCC, solid type of adenoid cystic carcinoma.
Figure 114 Basal cell adenocarcinoma. (A) Solid type. Note a palisade-like arrangement of the carcinoma cells at the periphery of the
tumor cell nests. (B) Trabecular type. Cordlike architecture of the atypical basaloid cells. (C) Tubular type. Duct-like structures with
intraluminal eosinophilic secretion. (D) Membranous type. Thick, hyaline, basement membrane-like material surrounds individual tumor
islands.
proliferation index, apoptosis, expression of p53, cell adenocarcinoma are points of difference from
epidermal growth factor receptor, and bcl-2 may be small or large cell neuroendocrine carcinoma, which
helpful (see the section ‘‘Basal Cell Adenoma’’) (7). may exhibit peripheral palisading patterns and comedo
The distinction between basal cell adenocarcino- necrosis (19).
mas and the solid type of adenoid cystic carcinoma is Basaloid squamous cell carcinoma is a specific
also essential because of the significant difference in clinicopathologic entity of high-grade malignancy,
prognosis between these two entities (Table 8). The mainly arising in the hypopharynx, base of tongue,
presence of peripheral palisading and foci of squa- and supraglottic regions (20). Similar to basal cell
mous metaplasia favor the diagnosis of basal cell adenocarcinoma, this malignancy may exhibit lobular
adenocarcinoma. Even in the solid type, cribriform growth pattern with peripheral nuclear palisading
growth pattern and pseudocysts with amorphous and often displays comedo necrosis. In basaloid squa-
basophilic material characteristic of adenoid cystic mous cell carcinoma, however, the tumor shows
carcinoma is only rarely encountered in basal cell multiple attachments to the overlying epithelium.
adenocarcinoma. In addition, tumor cell nuclei of Definitive differential diagnosis is possible when
adenoid cystic carcinoma tend to be more hyperchro- absence of dual ductal and myoepithelial differentia-
matic and angular when compared with polygonal tion is confirmed immunohistochemically. Moreover,
nuclei found in basal cell adenocarcinomas. most basal cell adenocarcinomas arise in the major
The lack of neuroendocrine differentiation and salivary glands, a site where basaloid squamous cell
the presence of myoepithelial differentiation in basal carcinoma does not occur.
Figure 115 Basal cell adenocarcinoma. Solid nests of mildly Figure 116 Basal cell adenocarcinoma. Focal squamous dif-
atypical basaloid cells with peripheral palisading. ferentiation with keratin pearl formations.
Treatment and Prognosis. In general, basal cell bimodal age distribution with the incidence peaking
adenocarcinoma is considered to be a low-grade in the third and seventh and eighth decades and there
malignancy with a relatively high recurrence rate is a wide age range (17–93 years) (5). The mean age is
but good prognosis (4,6–8). Local recurrence in the 69 years and the sex distribution is equal. The dura-
major salivary gland cases occurs in about 40% of tion of the tumor ranges from a few months to
cases, but locoregional and distant metastases are 20 years (8,15). Tumors typically present as slow-
infrequent, with less than 10% occurrence, and death growing swellings with variable pain, facial nerve
from tumor is extremely rare. Basal cell adenocarcino- involvement, and fixation to the overlying skin. Rare
ma arising in intraoral minor salivary glands or sino- cases have arisen from a preexisting pleomorphic
nasal sero-mucinous glands appears to have a adenoma (9).
somewhat higher recurrence rate, and is accompanied Pathology. Grossly, tumors range in size from
by worse prognosis (5,9–11). Complete surgical exci- 0.6 to 8.5 cm and frequently appear to be well circum-
sion is the recommended treatment. In major salivary scribed or partially encapsulated (1). The color of the
gland cases, with proper surgical resection and ade- cut surface varies from yellow to pink, gray, or white.
quate margins, additional therapy may not be Microscopically, the tumor consists of sheets, nests, or
required. Cervical lymph node dissection is not war- cords of pleomorphic cells with variable degrees of
ranted, except for patients with clinical evidence of cytologic atypia. In well-differentiated tumors, the
lymph node metastasis. cells have hyperchromatic nuclei and abundant, vac-
uolated cytoplasm giving a typical sebaceous appear-
Sebaceous Carcinoma ance (Fig. 117). More poorly differentiated tumors
have greater degrees of pleomorphism and may
Introduction. Sebaceous carcinoma is defined as have clear or eosinophilic cytoplasm, making recogni-
‘‘a malignant tumor composed of sebaceous cells of tion of the sebaceous phenotype more difficult
varying maturity that are arranged in sheets and/or (Fig. 118). Duct-like structures may be numerous
nests with different degrees of pleomorphism, nuclear and cystic spaces of varying sizes are occasionally
atypia, and invasiveness’’ (1). The term sebaceous present. Scattered mucous cells are a rare feature.
adenocarcinoma has also been used (2). Squamous differentiation is common and basaloid
Clinical features. Sebaceous carcinomas of sali- differentiation can be seen, particularly in cells at the
vary glands are very uncommon with about periphery of cellular islands. Spindle cell myoepithe-
30 reported cases arising from major glands (2–10). lial differentiation has also been reported (7). A xan-
The large majority of these tumors developed in the thogranulomatous reaction to extravasated sebum and
parotid gland, with two cases in the submandibular oncocytic metaplasia are occasional findings. In
gland (7,10) and a single case in the sublingual gland higher-grade tumors, particularly, there may be
(1). Sebaceous carcinomas in the oral cavity may areas of necrosis and fibrosis. The tumor has infiltra-
develop from Fordyce granules rather than intraoral tive margins and perineural invasion is seen in about
minor glands (11) and probably should not be 20% of cases but vascular invasion is exceptional (5).
recorded as salivary tumors. Similarly, the histogene- Treatment and Prognosis. There are too few
sis of rare cases reported in the vallecula, epiglottis, recorded cases to make accurate prognostic state-
and hypopharynx is uncertain (12–14). There is a ments. However, most tumors appear to be
Figure 117 Well-differentiated sebaceous carcinoma consist-

Figure 119 Sebaceous carcinomatous elements in dense lym-
ing of non-specific glandular cells and cells showing conspicuous
phoid stroma.
sebaceous differentiation.
Clinical features. Sebaceous lymphadenocarci-

noma is the rarest salivary gland neoplasm with
only five reported cases (2–5). Four cases arose in
the parotid gland and one case involved a periparotid
lymph node. There were four men and one woman
and ages ranged from 55 to 70 years. The tumors were
present from 1 month to more than 20 years and most
formed painless masses.
Pathology. The tumors are grossly well circum-
scribed but show foci of local infiltration. The cut
surface varies from yellow-tan to gray.
Microscopy of these cases has shown variable
appearances. The tumors are partially encapsulated
with areas of invasive growth and one case showed a
subcapsular marginal sinus. They are usually com-
posed of areas of typical sebaceous lymphadenoma
Figure 118 Another field from the tumor in Figure 117 showing
with intermingled or sharply demarcated carcinoma-
clear cell change.
tous elements showing cytologic atypia with increased
and atypical mitoses (Fig. 119). In one case the tumor
appeared to arise from a lymphadenoma (2). The
intermediate grade and have been treated by surgical carcinomatous component has included sebaceous
excision, with or without postoperative radiotherapy. carcinoma with ductal differentiation or focally areas
In tumors with a high microscopic grade or clinical of poorly differentiated carcinoma, salivary duct car-
stage, chemotherapy has occasionally been used in cinoma, adenoid cystic carcinoma, and epithelial-
addition to adjuvant radiotherapy, but its value is myoepithelial carcinoma (1).
debatable (4,5). It has been suggested that radical There may be areas of xanthogranulomatous
parotidectomy, together with elective neck dissection, inflammation. A single case showed evidence of neu-
should be considered in such tumors (2). About a third ral involvement.
of tumors recur and the overall five-year survival Treatment and Prognosis. Sebaceous lymphade-
rate is 62% (1). nocarcinoma appears to be a low-grade malignant
tumor with a strong tendency to local recurrence;
Sebaceous Lymphadenocarcinoma distant metastasis is uncommon. It has been treated
with wide surgical resection, with or without adjuvant
Introduction. Sebaceous lymphadenocarcinoma radiotherapy.
has been defined as ‘‘the malignant counterpart of
sebaceous lymphadenoma. It is a carcinoma arising in Cystadenocarcinoma
a sebaceous lymphadenoma’’ (1). However, since this
tumor was defined by the WHO, a case has been Introduction. Carcinomas manifesting papillary-
reported where the tumor developed from a lympha- cystic morphology are relatively common in the
denoma (2). ovary, bile duct, pancreas, breast, and thyroid.
However, cystadenocarcinoma arising in the salivary

gland is a rare neoplasm that was first defined in the
2nd edition of WHO classification as a low-grade
malignant tumor characterized by invasive growth
and cystic architecture with papillary endocystic pro-
jections and was termed ‘‘papillary cystadenocarci-
noma’’ (1). It has also previously been given various
other names, including ‘‘malignant papillary cystade-
noma’’ (2), ‘‘mucus-producing adenopapillary (non-
epidermoid) carcinoma’’ (3,4), ‘‘low-grade papillary
adenocarcinoma of the palate’’ (5,6), and ‘‘papillary
adenocarcinoma’’ (7). In the 2005 WHO classification,
this tumor was simply designated ‘‘cystadenocarci-
noma’’ (8), because not all lesions have papillary
configurations. It was defined as ‘‘a rare malignant
tumor characterized by predominantly cystic growth
that often exhibits intraluminal papillary growth. It
lacks any specific histopathologic features that char-
acterize the other types of salivary carcinomas show-
ing cystic growth. Conceptually it is the malignant
counterpart of the benign cystadenoma’’ (8).
Additionally, in the 2005 WHO classification, the
tumor formally described as low-grade salivary duct
carcinoma was included as a variant of cystadenocar-
cinoma and given the term low-grade cribriform
cystadenocarcinoma (LGCCC) (9). This tumor type is
discussed as a separate entity in this section.
Clinical features. Cystadenocarcinoma is rare,
accounting for less than 1% of all salivary gland
tumors. Approximately 65% arise in the major sali-
vary glands, mostly in the parotid gland (10). The
remaining 35% involve the minor salivary glands,
including the lip, buccal mucosa, palate, tongue, ret-
romolar area, and floor of the mouth, in descending
order of frequency. There is a wide age range (20–86
years) with an average of about 59 years, and more
than 70% of patients are over 50 years of age (10). Men
and women are affected equally.
Most patients present with a slowly growing and
asymptomatic mass, but rarely there may be pain and
ulceration. When the tumor arises in minor salivary
gland sites, the mucosal surface is usually intact, and
the appearance clinically resembles a mucocele. Pala-
tal tumors may erode the bone and infiltrate into the
nasal cavity and maxillary sinuses.
Pathology. Macroscopically, cystadenocarci-
noma appears as a partially circumscribed, multicystic
mass, ranging in size from 0.4 to 6.0 cm with an
average size of 2.4 and 2.2 cm in the major and
minor salivary glands, respectively (10). Cystic spaces
may contain clear-to-brownish or mucinous material.
As the malignant counterpart of cystadenoma, micro-
scopically, the essential architectural pattern of cysta-
denocarcinoma resembles that of cystadenoma.
However, unlike cystadenomas, all cystadenocarcino-
mas invade into the surrounding normal salivary Figure 120 Cystadenocarcinoma. (A) Tumor with multiple pap-
gland parenchyma (Fig. 120A) or adjacent soft tissue. illary-cystic structures invades into the surrounding salivary gland
Minor salivary gland tumors can infiltrate bone. Peri- parenchyma. (B) Cyst formations accompanied by prominent
neural and vascular invasion is uncommon. intracystic papillary projections of columnar cells. (C) Columnar
The tumor is composed of multiple cysts. Each tumor cells exhibiting mild nuclear pleomorphism. Source: Cour-
cystic space is separated by fibrous stroma, commonly tesy of Dr. Jean E. Lewis, Mayo Clinic, Rochester, Minnesota,
U.S.A.
with hemorrhage and inflammation because of cyst
rupture. Psammoma bodies and microcalcifications
may be present. Cysts vary in size and shape and are The papillary-cystic variant of acinic cell carci-
usually accompanied by intracystic papillary projec- noma may be difficult to distinguish from cystadeno-
tions with or without branching fibrovascular cores at carcinoma. Cystadenocarcinoma lacks microcystic or
least focally (Fig. 120B). About 75% of cases have a follicular growth pattern and the presence of cells
conspicuous papillary growth pattern (8). The term with diastase-resistant PAS-positive secretory gran-
papillary cystadenocarcinoma is often applied to these ules in the cytoplasm that are characteristic of acinic
tumors. Limited areas of ductal structures or small solid cell carcinoma.
cells nests are seen in minority of the cases. The lining The tumor cells of salivary duct carcinoma are
epithelium of the cysts, papillary fronds, and ductal larger and have more pleomorphic nuclei with promi-
structures are usually composed of a single cell layer, nent nucleoli and abundant eosinophilic cytoplasm and
but may be double cell layered or pseudostratified. higher mitotic activity than those of cystadenocarci-
In the majority of cases, the lining cells consist noma. Furthermore, marked necrosis and a scirrhous
predominantly of small cuboidal cells, but large cuboi- invasive growth pattern are features distinguishing
dal, tall columnar, mucous, clear, oncocytic, and simple salivary duct carcinoma from cystadenocarcinoma.
squamous cells can be seen, frequently with an admix- Metastatic papillary thyroid carcinoma can be
ture of these cell types. Usually, nuclear pleomorphism distinguished from cystadenocarcinoma by its charac-
is mild to moderate and mitotic activity is low teristic ground-glass tumor cell nuclei, often with
(Fig. 120C). However, occasional tumors have marked nuclear grooves and pseudonuclear inclusions, as
nuclear pleomorphism with prominent nucleoli and well as positive immunostaining for thyroglobulin or
numerous mitotic figures (11,12). The columnar cells thyroid transcription factor-1.
tend to show more nuclear atypia, suggestive of a Treatment and prognosis. According to the AFIP
relatively higher-grade malignancy than tumors con- series, in which follow-up data were available in 39
sisting predominantly of cuboidal cells (10). Therefore, out of 57 cases of cystadenocarcinoma, no patients
cystadenocarcinomas present a broader histologic spec- died of disease at a mean interval of 52 months after
trum than is generally thought, and at least some may the initial surgery, 10% developed regional lymph
be considered as high-grade malignancies. nodal metastases at the time of diagnosis, and 7.7%
Immunohistochemistry. The immunohistochemi- had local recurrences at an average of 76 months after
cal features indicate that cystadenocarcinoma is com- the initial treatment (10). These data suggest that
posed of cells with ductal differentiation. The tumor cystadenocarcinoma is a low-grade malignancy. How-
cells are usually positive for pan-cytokeratin, epithelial ever, despite this there have been several reports
membrane antigen, and carcinoembryonic antigen (13). indicating that some cases of cystadenocarcinoma
CA19-9 and CA125 may be expressed in cystadenocar- may have more aggressive behavior and higher-grade
cinoma (14). pathologic features (11,12). The general therapeutic
Differential diagnosis. The differential diagnosis approach is complete local resection with cervical
of papillary cystadenocarcinoma includes salivary lymph node dissection, if there is lymphadenopathy,
gland tumors with predominantly papillary and cystic together with postoperative radiotherapy for high-
pattern of growth, such as cystadenoma, low-grade grade or recurrent, inoperable tumors.
mucoepidermoid carcinoma, polymorphous low- Low-Grade Cribriform Cystadenocarcinoma.
grade adenocarcinoma, the papillary-cystic variant of LGCCC is a rare tumor first reported by Delgado
acinic cell carcinoma, salivary duct carcinoma, and et al. in 1996 as a variant of salivary duct carcinoma,
metastatic papillary thyroid carcinoma (8). termed low-grade salivary duct carcinoma (15). There
Cystadenocarcinoma can have bland cytology are considerable histologic and biologic differences
and low mitotic activity, hardly distinguishable from and controversies regarding the relationship between
cystadenoma, but unlike cystadenoma, cystadenocar- this tumor entity and conventional salivary duct car-
cinoma always shows invasive growth. cinoma, which is a much more aggressive neoplasm
Low-grade mucoepidermoid carcinoma is often (16,17). The 2005 WHO classification categorized low-
composed of conspicuous multicystic and papillary grade salivary duct carcinoma as a variant of cysta-
structures, resembling cystadenocarcinoma. However, denocarcinoma and adopted a new term LGCCC in an
in contrast to cystadenocarcinoma, low-grade mucoe- attempt to avoid confusion (9). However, because it
pidermoid carcinoma has solid nests consisting of a bears a striking resemblance to atypical ductal hyper-
mixture of epidermoid, mucous, and intermediate plasia or low-grade ductal carcinoma in situ of the
cells at least focally. breast, some investigators have strongly recom-
Like cystadenocarcinoma, areas of papillary and mended that the term LGCCC should be replaced by
cystic proliferation are sometimes seen focally in ‘‘(low-grade) intraductal carcinoma’’ (18,19).
polymorphous low-grade adenocarcinoma, but the LGCCC almost exclusively occurs in the parotid
predominant features of polymorphous low-grade gland, but in rare cases the submandibular gland and
adenocarcinoma are characterized by the admix- minor salivary glands may be affected (15,16,20). The
ture of variable histologic architectures, such as majority of patients are in the sixth and seventh
solid, tubular, fascicular, and cribriform patterns. In decades. Unlike salivary duct carcinoma, this tumor
addition, perineural invasion is frequent in polymor- has a female predominance, the female to male ratio
phous low-grade adenocarcinoma, often with a con- being 2:1 (9). Histologically, LGCCC is generally a
centric, targetoid pattern, but is uncommon in well-circumscribed, but not encapsulated, tumor
cystadenocarcinoma. composed of multicystically dilated duct-like
to-brown pigment resembling lipofuscin. Mitotic fig-

ures are rare and necrosis is minimal or absent.
Cellular pleomorphism is generally absent, but infre-
quently, a transition from low- to intermediate- or
high-grade cytology with increased mitotic activity
may be seen. These lesions may also be accompanied
by focal invasion into surrounding tissue with small
solid nests, reactive inflammation, and desmoplasia
(16). The presence of microinvasion does not seem to
affect prognosis. Usually there is no perineural or
vascular invasion.
Unlike salivary duct carcinoma, LGCCC diffusely
and strongly expresses S-100 protein on immunohis-
tochemistry (Fig. 122A) (15,16). Intraductal tumor cell
proliferation is outlined by myoepithelial markers
(smooth muscle actin, calponin, cytokeratin 14, and
p63)-positive nonneoplastic, myoepithelial cells
(Fig. 122B) (16). The tumor cells are negative for both
androgen receptor and HER2/neu.
Figure 121 Low-grade cribriform cystadenocarcinoma. (A)

Tumor composed of multicystically dilated duct-like structures
accompanied by intraductal papillary proliferations and cribriform
patterns. (B) Intraductal cribriform growth pattern of small and
cuboidal or polygonal cells. Note that they are cytologically bland
with finely dispersed chromatin and small nucleoli.
structures accompanied by varying degrees of intra-

ductal proliferations (Fig. 121A). The lining cells of
the dilated ducts are usually multilayered and form a
combination of anastomosing micropapillae, plaque-
like projections, tufts with thin delicate fibrovascular
cores, and ‘‘floppy’’ fenestrated cribriform patterns
(15,16). Separate, smaller ductal lesions tend to be
filled with solid proliferation and cribriform struc-
tures of tumor cells.
Proliferating ductal cells are typically small and
cuboidal or polygonal. They are cytologically bland
with finely dispersed chromatin and small nucleoli
(Fig. 121B). These histologic appearances are similar to Figure 122 Low-grade cribriform cystadenocarcinoma. Immuno-
those seen in atypical ductal hyperplasia or intraductal histochemistry. (A) Tumor cells diffusely and strongly express
carcinoma of the breast. Tumor cells may show focal S-100 protein. (B) Intraductal tumor cell proliferation is outlined
apocrine differentiation and the cytoplasm frequently by calponin-positive non-neoplastic, myoepithelial cells.
has multiple, clear microvacuoles and a fine yellow-
The differential diagnosis of LGCCC includes

the papillary-cystic variant of acinic cell carcinoma
and conventional cystadenocarcinoma. It is often chal-
lenging to distinguish between the papillary-cystic
variant of acinic cell carcinoma and LGCCC. Both
tumors contain cells with vacuolar cytoplasm, but
the vacuoles of LGCCC are smaller and refractile
and are frequently associated with yellow-to-brown
pigment. In addition, cells with diastase-resistant
PAS-positive finely granular cytoplasm are only
found in the papillary-cystic variant of acinic cell
carcinoma, though the microvacuoles in LGCCC
may also show diastase-resistant PAS staining. Cys-
tadenocarcinoma does not resemble mammary atypi-
cal ductal hyperplasia or low-grade ductal carcinoma,
and tends to be more invasive, while LGCCC is a
usually a noninvasive lesion.
Complete surgical excision is the treatment of Figure 123 Mucinous adenocarcinoma. Nests of tumor cells
choice. The prognosis is excellent and none of the floating in mucous filled, cystic space.
cases with follow-up have recurred (15,16,20).
Mucinous Adenocarcinoma
Introduction. Mucinous adenocarcinoma is amounts of intracellular mucin. Mucin-containing
defined as ‘‘a rare malignant tumor composed of cells may form papillary projections into the mucous
epithelial clusters with large pools of extracellular pools or form acinus-like clusters. Focal necrosis is
mucin. The mucin component usually occupies the sometimes present. In a unique case of mucinous
bulk of the tumor mass’’ (1). A commonly used adenocarcinoma involving mandibular bone, neuro-
synonym is colloid carcinoma. endocrine differentiation was demonstrated (7). The
Clinical features. This is a very rare salivary intra- and extracellular mucus stains positively with
tumor and most examples have been reported as PAS, Alcian blue, and mucicarmine.
single cases or as short series. An analysis of Immunohistochemistry. The limited number of
10 cases, including five from the literature (2), and a immunocytochemical studies of mucinous adenocar-
series of six cases published in the Chinese literature cinoma show that the tumor is strongly positive for
(3), together with four further cases (4–7) shows that pan-cytokeratin (AE1/AE3) and cytokeratin 7 (3,4).
patients’ ages ranged from 42 to 86 years with a mean Most tumor cells also express keratins 8, 18, and 19.
age of about 65 years. There is no consistent sex There is minimal expression of keratins 4 and 13 and
predilection. About half the cases involved minor no expression of keratins 5/6, 10, 14, and 17. The
glands, particularly the palate; there were three cases tumor is also negative for smooth muscle actin, estro-
each in the sublingual and parotid glands and two gen, and progesterone (4).
cases affected the submandibular glands (8). The Differential diagnosis. The tumors to be consid-
usual presentation is a slow-growing mass of several ered in the differential diagnosis include mucoepider-
months’ duration, but in one case the tumor had been moid carcinoma, cystadenocarcinoma, and the mucin-
present for 11 years. In the minor glands, tumors are rich variant of salivary duct carcinoma (9). Although
firm and elevated and some are ulcerated. In tumors low-grade mucoepidermoid carcinomas frequently
arising in the sublingual gland, a presumptive diag- show extravasated mucous pools, the other character-
nosis of salivary calculi may be made. istic features of the tumor make diagnostic confusion
Pathology. Tumors range in size from 2.5 to unlikely. The distinction from cystadenocarcinoma
7.6 cm and are usually bosselated and ill defined. can be more problematical but in the latter, the
The cut surface is grayish white and shows multiple tumor cells tend to line the cystic spaces and there is
cystic spaces containing gelatinous fluid. a lack of cell clusters floating in the mucous compo-
Microscopically, the epithelial component con- nent. In the mucus-rich variant of salivary duct carci-
sists of cells, which may be single or form duct-like noma, there are mucin lakes but there are also areas
structures or solid clusters of variable sizes. These are composed of the high-grade carcinoma cells typical of
floating in abundant, mucus-filled lakes that are sepa- this tumor.
rated by fibrous septa (Fig. 123). The epithelial cells Treatment and prognosis. Surgery, with or with-
may be cuboidal, columnar, or irregular in shape (1). out adjuvant radiotherapy, has been the treatment of
The cytoplasm is typically clear and there is a central- choice in most cases, although the efficacy of radio-
ly placed, hyperchromatic nucleus. Although cells therapy has been questioned (1). There is a strong
may show nuclear atypia, mitoses are infrequent. tendency for local recurrence and metastasis to
Some of the solid clusters of tumor cells may develop regional lymph nodes. The tumor is aggressive, with
secondary lumina and scattered cells may have small about half the reported cases dying from the disease.
Oncocytic Carcinoma
Introduction. Oncocytic carcinoma is defined as
‘‘a proliferation of cytomorphologically malignant
oncocytes and adenocarcinomatous architectural phe-
notypes, including infiltrative qualities. These may
arise de novo, but are usually seen in association
with preexisting oncocytoma’’ (1). Synonyms include
oncocytic adenocarcinoma, malignant oncocytoma,
and malignant oxyphilic adenoma.
Clinical features. Oncocytic carcinoma is one
of the rarest salivary gland tumors with about
60 reported cases (2–21). The mean age is about
60 years and there is a wide age range (25–91 years).
There is a male predominance of about 2:1 (3,7). The
large majority arise in the parotid (*80%) and sub-
mandibular glands (*10%), with the remainder
reported in a wide range of intraoral and upper Figure 125 Oncocytic carcinoma showing neural invasion.
respiratory tract sites. Clinically, oncocytic carcinomas
usually present as painless, slow-growing swellings,
but in about a third of cases there is pain or facial
nerve palsy. In carcinomas arising in preexisting and surrounding tissue, and many cases show evi-
oncocytomas, there may be a history of a recent dence of neural and vascular invasion (Fig. 125).
rapid enlargement of a long-standing swelling. Immunohistochemistry. There is usually a higher
Pathology. Grossly, oncocytic carcinomas can Ki-67 proliferative index in oncocytic carcinoma than
appear as single or multifocal masses, which are oncocytoma and this may be useful in differentiating
firm, tan to gray-brown, and may show areas of the tumor from an atypical oncocytoma (21). Staining
necrosis. Some cases have variable capsulation but for alpha-1-antitrypsin (5) and antimitochondrial anti-
many tumors show extensive local invasion. bodies (22) has been reported.
Microscopically, oncocytic carcinoma shows var- Differential diagnosis. The main differential
iable pleomorphism. Most consist of large tumor cells, diagnoses include multifocal nodular oncocytic hyper-
which are round or polyhedral (Fig. 124). The cyto- plasia, oncocytoma, mucoepidermoid carcinoma, and
plasm is granular and eosinophilic and the round, salivary duct carcinoma. Multifocal nodular oncocytic
vesicular, and centrally placed nuclei often contain hyperplasia can simulate an infiltrative tumor. This
one or more prominent nucleoli. There is usually a impression may be reinforced when there is age-
moderate mitotic frequency but in some cases, mitoses related fatty change or when the oncocytic cells
are numerous and there may be abnormal forms. involve the hila of intraparotid lymph nodes. The
Occasionally, multinucleated tumor cells are present. multifocal nature of the hyperplasia and the presence
The tumor is arranged in sheets, nests, and trabeculae of cytologically bland cells should prevent confusion.
and infrequently there may be ductal differentiation. Oncocytomas show variable capsulation and occa-
Some cases show focal areas of necrosis. There is sionally there are atypical nuclei. In one study, benign
usually widespread infiltration of the salivary gland oncocytomas were diploid but oncocytic carcinomas
were associated with aneuploidy (23). In addition,
oncocytomas show minimal or no mitotic activity
and there is no evidence of invasion into salivary
parenchyma. Although perineural invasion has been
reported in benign oncocytomas (4), this observation
has been disputed (3). Some mucoepidermoid carci-
nomas are almost entirely oncocytic (24,25) but the
presence of intermediate cells and mucocytes aids
diagnosis. Salivary duct carcinoma often consists of
large, pleomorphic cells with eosinophilic, granular
cytoplasm. However, there are duct-like structures
and frequently luminal papillary ingrowths or cystic
structures. In addition, the cells of salivary duct carci-
noma are PTAH negative and are frequently androgen
receptor positive (26).
Treatment and prognosis. Oncocytic carcinomas
of the major salivary glands appear to be high-grade
and aggressive from the outset, except in the rare
Figure 124 Oncocytic carcinoma showing cellular atypia and cases where there was preexisting benign oncocytoma
focal necrosis. or multifocal nodular oncocytosis (8,27). They are
locally infiltrative (8,9) and can show locoregional
lymph node metastases or widespread dissemination

to the central nervous system, bone, liver, and lung
(2,8–10,28). Some cases have a prolonged course with
multiple local recurrences and distant metastases
(8–10,27). In a review of the literature, 32% developed
local recurrence and nearly 85% of oncocytic carcino-
mas developed regional or distant metastases (5).
There is a high mortality (8), and in one survey, the
average survival for patients with metastases was
3.8 years (4). Distant metastasis is the most important
sign of poor prognosis, with all affected patients in
one review dying of disease (7).
Oncocytic carcinomas should be treated by wide
surgical excision. Due to the relative rarity of this
tumor, the role of adjuvant radiotherapy is not firmly
established. However, as the prognosis is known to be
so poor, it should be strongly considered, together
with the need for neck dissection.
Salivary Duct Carcinoma Figure 126 Salivary duct carcinoma. Cut surface of the tumor
shows gray-white, solid mass with foci of necrosis.
Introduction. Salivary duct carcinoma is defined
as ‘‘an aggressive adenocarcinoma that resembles
high-grade breast ductal carcinoma’’ (1). It has intra-
ductal and invasive components. Although many
salivary carcinomas are postulated to originate from
ductal cells and often demonstrate ductal structures, growth pattern (Fig. 127B). However, cribriform ductal
the term salivary duct carcinoma should be restricted structures may also be seen in the invasive portion as
only to those tumors histologically resembling mam- well as in the metastatic foci. Cribriform carcinoma
mary ductal carcinomas. They were originally epithelium may form tumor cell arches over relatively
described by Kleinsasser et al. in 1968 (2) and were large intercellular spaces, called ‘‘Roman-bridge’’
included in the 2nd edition of the WHO Classification architecture. The central portion of the ductal cell
of Salivary Gland Tumors in 1991 (3). nests often undergoes comedo-like necrosis. Psam-
Clinical features. Salivary duct carcinomas are moma bodies and focal squamous differentiation,
an uncommon but not a rare tumor. More than 200 some with keratinization, can be seen in the carcinoma
such cases have been reported (2,4–10). They account nests.
for 2% of all salivary gland tumors and 9% of all The invasive component consists of irregular
salivary gland malignancies (1). Salivary duct carci- glands and cords of cells that frequently elicit a
noma has been reported to exhibit a distinct male prominent desmoplastic reaction (Fig. 127C). Salivary
predominance of nearly 4:1 and an age range from 22 duct carcinomas exhibiting a purely intraductal or
to 91 years, with a peak incidence in the sixth and minimally invasive form may be associated with a
seventh decades (1,11). Most tumors arise from the better prognosis. A preexisting pleomorphic adenoma
parotid gland, but a few have been described in the component, often hyalinized, may be present in the
submandibular gland and intraoral minor salivary minority of cases. It has been rarely reported that
glands as well as the sinonasal tract and larynx (1). salivary duct carcinomas coexist with other specific
Salivary duct carcinoma presents as a rapidly growing types of salivary gland carcinoma component within
tumor with frequent pain and facial nerve palsy. the same topographical area, those being referred to as
Many salivary duct carcinomas occur de novo, but hybrid carcinomas (13). Cytologic features of the sali-
some develop as the malignant component of carcino- vary duct carcinoma are characterized by large pleo-
ma ex pleomorphic adenoma (12). morphic nuclei with coarse chromatin and prominent
Pathology. Grossly, most tumors are unencap- nucleoli (Fig. 127D). The cytoplasm is abundant and
sulated, highly infiltrative, and gray to white solid granularly eosinophilic. Mitotic figures are frequently
masses with occasional small areas of cystic change observed in most cases. Apocrine-like metaplasia is
and foci of necrosis on their cut surfaces (Fig. 126). seen when they display papillary arrangement along
Mean tumor size is about 3.0 cm, with a range of 1.0 the dilated cystic wall. Usually, no goblet-type
cm to over 6.0 cm in diameter (11). mucous cells are seen in the conventional salivary
Histologically, infiltration into adjacent salivary duct carcinoma. Both lymphovascular and perineural
gland tissue and soft tissue is usually evident. The invasion are a frequent feature.
tumor bears a striking resemblance to high-grade Immunohistochemistry. Similar to breast carcino-
ductal carcinoma of the breast, with a mixture of two mas, both electron microscopy and immunohis-
components: intraductal and invasive (Fig. 127A). The tochemistry show that salivary duct carcinoma cells
intraductal component is described as multiple large exhibit purely ductal cell differentiation with immu-
ductal structures with a cribriform, papillary, or solid noreactivity for cytokeratin, carcinoembryonic
Figure 127 Salivary duct carcinoma. (A) A mixture of both intraductal and invasive growth patterns, which bears a striking resemblance
to high-grade mammary ductal carcinoma of the breast. (B) Intraductal component comprised of cribriform structures with ‘‘Roman-
bridge’’ architecture. Note that the central portion of the ductal cell nests undergoes comedo-like necrosis. (C) The invasive component
consists of irregular glands and cords of cells that elicit a prominent desmoplastic reaction. (D) Carcinoma cells exhibiting large
pleomorphic nuclei with coarse chromatin and prominent nucleoli. The cytoplasm is abundant and granularly eosinophilic.
antigen, epithelial membrane antigen, and gross cystic myoepithelial cells rimming carcinoma cell nests, con-
disease fluid protein-15 (5,7,14). However, unlike firming their intraductal nature (21).
breast carcinomas, salivary duct carcinomas are Histologic variants. Several histologic variants
almost always positive for androgen receptor (Fig. of salivary duct carcinoma have already been
128A), and negative for estrogen receptor and proges- described, including sarcomatoid (22–26), mucin-rich
terone receptor (7,14–16). Prostate-specific antigen is (27,28), and invasive micropapillary carcinomas
detectable in some cases (16). The Ki-67 labeling index (Fig. 55) (29). The tumor originally reported as low-
is high (average 43%) (1). Diffuse p53 immunoreactiv- grade salivary duct carcinoma has been renamed low-
ity and mutation of p53 gene are frequent (7,10,13). grade cribriform cystadenocarcinoma in the 2005 WHO
Most salivary duct carcinomas show diffuse and classification (see the section ‘‘Cystadenocarcinoma’’),
strong membranous staining for HER-2/neu (Fig. because it differs from conventional salivary duct car-
128B) with or without amplification of the gene dem- cinoma in some of its clinical and histopathologic
onstrated by fluorescence or chromogenic in situ features, has a good prognosis, and is a purely intra-
hybridization analysis (17–20). The tumor cells them- ductal carcinoma lesion composed of bland tumor cells
selves are negative for S-100 protein and any other (30–32). The question of a relationship between the two
myoepithelial markers. However, the myoepithelial neoplasms remains controversial.
markers, such as cytokeratin 14, smooth muscle The sarcomatoid variant is characterized histolog-
actin, calponin, and p63, clearly highlight supportive ically by a biphasic neoplasm with both typical salivary
‘‘carcinosarcoma’’ is widely used for biphasic carcino-

matous and mesenchymal neoplasms in the field of
salivary gland pathology, we recommend the term
‘‘sarcomatoid variant of salivary duct carcinoma’’
instead of carcinosarcoma when the carcinomatous
component of the lesion has histologic features fulfill-
ing the criteria for typical salivary duct carcinoma and
the term ‘‘sarcomatoid carcinoma, NOS’’ for lesions in
which the carcinoma component is not a distinct type
of salivary gland carcinoma (24).
In the mucin-rich variant of salivary duct carci-
noma, the tumor is composed of mucin lakes contain-
ing islands of carcinoma cells, resembling mucinous
(colloid) adenocarcinoma, in addition to the typical
salivary duct carcinoma component (Fig. 55B) (27,28).
The cellular and nuclear features of carcinoma cells in
the mucinous component are comparable to those in
the salivary duct carcinoma portion. Clinical outcome
for patients with this variant appears similar to that of
conventional salivary duct carcinoma.
In the invasive micropapillary variant of salivary
duct carcinoma, the tumors have an invasive micro-
papillary architecture admixed with features typical of
salivary duct carcinoma (Fig. 129C) (15). Its incidence
has been reported as 17% of all salivary duct carcino-
mas. This is a highly aggressive variant of salivary
duct carcinoma, with a propensity for extensive
lymph node metastasis and rapid disease progression,
similar to that noted in mammary, urothelial, ovarian,
and pulmonary tumors (33). The invasive micropapil-
lary pattern is characterized by morula-like small cell
clusters without fibrovascular cores, surrounded by a
clear space. Residual pleomorphic adenoma may be
present. Epithelial membrane antigen-positive reac-
tion rimming cell clusters shows a distinctive
‘‘inside-out’’ staining pattern (Fig. 129D).
Differential diagnosis. Although the intraductal
Figure 128 Salivary duct carcinoma. Immunohistochemistry. lesions are characteristic of salivary duct carcinoma,
(A) Carcinoma cells are diffusely positive for androgen receptor tumors with papillary-cystic or cribriform growth
in their nuclei. (B) Diffuse and strong membranous staining for
patterns and/or eosinophilic cells are considered in
HER-2/neu.
the differential diagnosis (11). These include high-
grade mucoepidermoid carcinoma, papillary-cystic
variant of acinic cell carcinoma, cystadenocarcinoma,
oncocytic carcinoma, and metastatic breast carcinoma.
duct carcinoma and sarcomatoid elements (Fig. 129A) The presence of goblet-type mucous cells as well
(22–26). This tumor has clinical features similar to as intermediate-type cells and the absence of a cribri-
conventional salivary duct carcinoma with a highly form pattern distinguish high-grade mucoepidermoid
aggressive behavior. A transitional zone between car- carcinoma from salivary duct carcinoma. Also, high-
cinomatous and sarcomatoid elements may be present. grade mucoepidermoid carcinoma usually does not
The sarcomatoid components show various histologic express androgen receptor. Papillary areas can superfi-
features such as a fascicular pattern of spindle cells, cially mimic the papillary-cystic variant of acinic cell
myxoid stroma, malignant osteoid formation, and carcinoma and cystadenocarcinoma, but the cellular
rhabdoid cells. A residual pleomorphic adenoma com- atypia of these tumors is much milder than that of
ponent is commonly identified. Generally, the carcino- salivary duct carcinoma. These two low-grade tumors
matous and sarcomatoid elements are diffusely lack comedo-type necrosis within the tumor character-
immunoreactive for cytokeratin and vimentin, respec- istic of salivary duct carcinoma. Additionally, diastase-
tively. However, the sarcomatoid elements also express resistant PAS-positive zymogen secretory granules
epithelial markers, showing occasional staining for should be present at least focally in the papillary-cystic
cytokeratin and consistent, focal positivity for epithelial variant of acinic cell carcinoma. Oncocytic carcinomas
membrane antigen. The diagnostic criteria and nomen- usually show diffuse and strong immunoreactivity for
clature for the entity ‘‘sarcomatoid salivary duct carci- mitochondrial antigen along with positivity for phos-
noma’’ are controversial, especially concerning its photungstic acid hematoxylin stain. Furthermore, this
distinction from carcinosarcoma. Although the term tumor typically lacks a cribriform growth pattern.
Figure 129 Histologic variants of salivary duct carcinoma. (A) Sarcomatoid variant. A biphasic neoplasm with both typical salivary duct
carcinoma and sarcomatoid elements with a fascicular pattern of spindle cells. (B) Mucin-rich variant. Mucin lakes containing islands of
carcinoma cells (right) in addition to the typical salivary duct carcinoma component (left). (C) Invasive micropapillary variant. Morula-like
small cell clusters without fibrovascular cores, surrounded by a clear space. (D) Invasive micropapillary variant. Immunohistochemistry.
Epithelial membrane antigen-positive reaction rimming cell clusters showing a distinctive ‘‘inside-out’’ staining pattern.
Since salivary duct carcinoma is histologically patients with salivary duct carcinoma had local recur-
almost indistinguishable from the mammary ductal rence, 60% had regional lymph node metastasis, and
carcinoma, the possibility of primary breast carcinoma 50% had distant metastasis (6,8,10). Sites for distant
metastatic to salivary gland must be excluded. In metastasis include lungs, bones, liver, brain, and skin.
contrast to breast cancer, salivary duct carcinoma is Of the reported patients with salivary duct carcinoma,
more common in males. The presence of the true 55% to 65% died of disease between 5 months and
intraductal components revealed by immunohisto- 10 years after diagnosis, usually within 4 years (mean
chemical staining for the myoepithelial markers in survival, 29 months) (6,8,10).
the salivary gland tumor suggests the primary origin. The putative prognostic factors of salivary duct
In addition, androgen receptor positive, estrogen carcinoma include tumor size (tumors less than 3 cm in
receptor negative, and progesterone receptor negative diameter having a better outcome), distant metastasis,
immunophenotype favor a diagnosis of salivary duct lymph node metastasis, surgical margins, HER2/neu
carcinoma rather than metastatic breast carcinoma over-expression, Ki-67 labeling index, expression of
(15). However, clinical examinations to identify a estrogen receptor-b (estrogen receptor-b downregula-
breast mass are most important for accurate diagnosis. tion being associated with adverse clinical features),
Treatment and Prognosis. It should be empha- invasive micropapillary morphology, and proportion
sized that salivary duct carcinoma is one of the most of intraductal component (5,7,10,17,29,34,35). The prog-
aggressive malignant salivary tumors. A review of the nostic significance of the expression of p53 and DNA
literature confirmed that approximately 30% of the ploidy pattern is controversial (10,35). Treatment
usually consists of total glandectomy, accompanied by predominance (9). The major salivary glands, mostly
radical neck dissection and radiotherapy. Although the parotid gland, are more frequently affected than
sufficient conclusive data are lacking, anti-androgen the minor salivary glands. Patients with adenocarci-
and transtuzumab (Herceptin) might provide hope noma NOS usually present with a solitary painless
for systemic therapy for patients with advanced stage mass, but approximately 20% of the patients with
salivary duct carcinoma (36,37). parotid tumors complain of pain or facial nerve weak-
ness, and nearly half of the tumors are fixed to the
Adenocarcinoma, Not Otherwise Specified skin or deep tissues (11). Palatal tumors may ulcerate
and involve the underlying bone.
Introduction. Adenocarcinoma, not otherwise Pathology. Grossly, the tumor shows ill-defined
specified (NOS), is defined as ‘‘a malignant salivary infiltrative borders, but it may be focally circum-
gland tumor that exhibits ductal differentiation but scribed. The cut surface is mostly tan to gray-white,
lacks any of the histomorphologic features that charac- and the tumor forms a solid mass, often with foci of
terize the other defined types of salivary carcinoma’’ (1). hemorrhage or necrosis.
Although many salivary gland carcinomas originate Histologically, the tumors are characterized by
from the salivary duct unit and generically belong to variable glandular or duct-like structures and inva-
the large category of ‘‘adenocarcinoma,’’ the modifying sion into the adjacent salivary gland parenchyma and
term ‘‘NOS’’ is only applied to those tumors that lack sometimes surrounding connective tissue, as well as
sufficient histologic features of the specific categories of muscle or bone. Apart from the glandular structures,
salivary gland carcinoma (1). adenocarcinoma NOS exhibits a variety of architectural
Various types of adenocarcinomas have been patterns, including solid sheets, papillary, cystic, crib-
recognized and separated from the adenocarcinoma riform, cords, lobular, and trabecular (Fig. 130). A
NOS group since the 1st edition of the WHO Classifi- mixture of several architectural growth patterns is
cation of Salivary Gland Tumors appeared in 1972 (2). common, but one architectural pattern may predomi-
Accordingly, the second edition of the WHO classifi- nate. Diverse tumor-cell types can be seen in adenocar-
cation published in 1991 significantly increased the cinoma NOS. In most tumors, cuboidal-, oval-, or
numbers of the tumor entities (3). In particular, the polygonal-cell type dominates, but scattered oncocy-
recognition of polymorphous low-grade adenocarci- toid-, clear-, melanoma-like-, mucinous-, or sebaceous-
noma, salivary duct carcinoma, epithelial-myoepithe- cell types may occasionally be present. Tumor necrosis
lial carcinoma, basal cell adenocarcinoma, and and perineural and vascular invasion are common. By
papillary cystadenocarcinoma have probably greatly definition, adenocarcinomas NOS lack the characteris-
contributed to the decrease in the number of cases tic histologic features of other recognized salivary
included in adenocarcinoma NOS group (4–8). How- adenocarcinomas, but limited foci that resemble specif-
ever, according to the AFIP series, for example, ade- ic tumor entities, such as adenoid cystic carcinoma,
nocarcinoma NOS still constitutes a considerable acinic cell carcinoma, epithelial-myoepithelial carci-
proportion, being only the second most common noma, cystadenocarcinoma, or salivary duct carcinoma,
type of all salivary gland malignancies next to mucoe- may be seen and the presence of these features does not
pidermoid carcinoma (9). Because the 2005 WHO preclude a diagnosis of adenocarcinoma NOS.
classification added only three relatively rare tumor Generally, the histologic grading system of low,
entities, namely, clear cell carcinoma NOS, low-grade intermediate, and high is applied to adenocarcinoma
cribriform cystadenocarcinoma, and sialoblastoma, it NOS and is based on differentiation or degree of gland
seems likely that the frequency of adenocarcinoma formation, cytologic atypia, mitotic count, and tumor
NOS has not been substantially decreased after the necrosis (Fig. 130) (11,13). Gland formation tends to be
recognition of the scheme (1). prominent in low-grade tumors but not in high-grade
In 2004, Ghannoum and Freedman introduced a tumors, but the extent of gland formation alone may
new type of salivary gland carcinoma they called not be enough for the assessment of the grade of
‘‘signet-ring cell (mucin-producing) adenocarcinoma adenocarcinoma NOS. It has been proposed that
of minor salivary glands,’’ and distinguished it from high-grade tumors should be distinguished from
the adenocarcinoma NOS group (10). This tumor low-grade tumors by the presence of one or more of
entity is not included in the 2005 WHO Classification the following features: nuclear atypia, high mitotic
of the Salivary Gland Tumors; thus it will be briefly rate, atypical mitotic figures, necrosis, perineural inva-
described later in this section. sion, bony invasion, angiolymphatic invasion, or
Clinical features. The incidence of adenocarci- aggressive invasion pattern. An aggressive pattern of
noma NOS is variable in several major series (5–9,11– invasion is seen as infiltration at the tumor interface
14). Based on recent series data, adenocarcinoma NOS composed of small islands or strands, or 1 mm or
represents an uncommon, but not rare, salivary gland more of normal tissue between tumor islands (8). Most
malignancy, accounting for approximately 3% to 9% adenocarcinomas NOS are considered to be high-
of all salivary gland tumors and 8% to 17% of all grade histologically.
salivary gland carcinomas (5–9,14). Age ranges from Immunohistochemically, the tumor cells are
10 to 93 years, with a peak incidence in the sixth and usually positive for pan-cytokeratin and negative for
seventh decades. Reported gender differences of ade- S-100 protein, smooth muscle actin, and calponin.
nocarcinoma NOS are inconsistent. The AFIP files Differential diagnosis. The diagnosis of adeno-
show these tumors to have a slight female carcinoma NOS is essentially based on the exclusion
of specific types of all gland-forming carcinomas

occurring in the salivary glands. Selected possible
differential diagnoses include polymorphous low-
grade adenocarcinoma, epithelial-myoepithelial carci-
noma, cystadenocarcinoma, salivary duct carcinoma,
and metastatic adenocarcinomas.
Polymorphous low-grade adenocarcinoma and
low-grade adenocarcinoma NOS share bland nuclear
morphology and numerous ductal and tubular struc-
tures. However, polymorphous low-grade adenocar-
cinoma shows a mixture of other features, such as
solid, fascicular, and cribriform patterns as well as a
concentric, targetoid appearance. Adenocarcinomas
NOS lack the biphasic pattern of duct-lining and myoe-
pithelial cells characteristic of epithelial-myoepithelial
carcinoma. The extensive papillary and cystic archi-
tecture of cystadenocarcinoma is not the feature of
adenocarcinoma NOS. The presence of an ‘‘intraduc-
tal’’ cribriform growth pattern of large pleomorphic
eosinophilic cells resembling mammary ductal carci-
noma leads to a diagnosis of salivary duct carcinoma
rather than high-grade adenocarcinoma NOS. The
possibility of metastatic adenocarcinomas should be
ruled out before the diagnosis of adenocarcinoma
NOS is made, based on the clinical information and,
where appropriate, immunohistochemical profile.
However, interpretation should be cautious, as immu-
noreactivity for prostate-specific antigen in adenocar-
cinoma NOS has been reported.
Treatment and prognosis. Because of the differ-
ences of classification schemes in various series, reli-
able data on the biologic behavior of adenocarcinoma
NOS are sparse (11,13,14). Clinical stage, histologic
grade, and the site of involvement appear to be the
major prognostic factors (11,13). Generally, adenocar-
cinoma NOS is a high-grade lesion with an aggressive
clinical behavior (11,13). According to the data of the
largest series (11), even if the reported patients com-
prise a possible case mixture of ‘‘true’’ adenocarcinoma
NOS and specific adenocarcinoma entities, the fre-
quency of local recurrence, cervical lymph nodal
metastases, and distant metastases were 51%, 27%,
and 26% of the patients, respectively (11). Overall cure
rates at 5, 10, and 15 years were 41%, 34%, and 28%,
respectively. Regarding the clinical stage, the 15-year
cure rates for stages I, II, and III tumors are 67%, 35%,
and 8%, respectively. Histologic grade is also strongly
correlated with survival; the 15-year cure rates for
low-, intermediate-, and high-grade tumors are 54%,
31%, and 3%, respectively. Survival was also depen-
dent on tumor site; tumors involving the oral cavity
had a more favorable prognosis than those of the
parotid or submandibular glands. The treatment of
choice is complete surgical excision. Additionally,
higher-stage or higher-grade tumors require wide
Figure 130 Adenocarcinoma, not otherwise specified. (A) Low- surgical excision with neck dissection and adjuvant
grade tumor. Prominent well-formed glandular formations. (B) radiation therapy.
Intermediate-grade tumor. Fused glandular formations with focal Signet-Ring Cell (Mucin-Producing) Adenocarcino-
solid areas. (C) High-grade tumor. Irregularly shaped islands and ma of Minor Salivary Gland. Only one series consist-
strands of anaplastic carcinoma cells. Glandular formations are ing of seven cases has been reported (10). The tumor
inconspicuous in this figure. occurred in adults, ranging in age from 32 to 72 years
with a mean age of 56.4 years (two men, five women).
All cases developed in the minor salivary glands of
the oral cavity. The patients presented with an asymp-

tomatic mass and neither bone invasion nor cervical
lymph node or distant metastases after excision was
found.
Histologically, the tumor is unencapsulated and
infiltrates into the adjacent minor salivary gland tis-
sue. It lies close to the overling mucosal epithelium,
which may show pseudoepitheliomatous hyperplasia.
Variable growth patterns, including narrow parallel
strands, interconnecting cords, small nests, microcys-
tic, or individually infiltrating cells, are seen in the
tumor. A few duct-like structures may also be seen.
The tumor is predominantly composed of signet-ring
cells with intracytoplasmic mucin and eccentric,
indented nuclei. Signet-ring cells mingle with minor
populations of polygonal cells with eosinophilic or
clear cytoplasm. Generally, nuclear atypia is absent
and mitotic figures are rare, but focal nuclear pleo-
morphism and occasional mitoses can be present.
Unlike mucinous adenocarcinoma, pools of extracel- Figure 131 Myoepithelial carcinoma. Carcinoma irregularly
lular mucin are an uncommon finding and if present invades into the surrounding salivary gland.
are limited. Perineural invasion may be observed, but
vascular invasion is infrequent.
evolution from a preexisting pleomorphic adenoma or

Myoepithelial Carcinoma myoepithelioma (5,7,11).
Pathology. Macroscopically, the cut surface of
Introduction. Myoepithelial carcinoma, also the tumor typically shows an unencapsulated, gray-
referred to as malignant myoepithelioma, is a rare white solid mass with nodules. A gelatinous appear-
salivary gland tumor, which is the malignant counter- ance is common and yellow foci of necrosis and cystic
part of myoepithelioma. The entity was first described degeneration may be seen. The size of the tumor
by Stromeyer et al. in 1975 (1) and was added to the 2nd varies and it ranges from 2 to 20 cm in greatest
edition of the WHO Classification of Salivary Gland dimension with a mean of 3.5 cm (5).
Tumors (2). Myoepithelial carcinoma is defined as ‘‘a Histologically, the tumor invades into the sur-
neoplasm composed almost exclusively of tumor cells rounding normal salivary gland (Fig. 131), or adjacent
with myoepithelial differentiation, characterized by adipose or muscular tissue; the extent of invasion
infiltrative growth and potential for metastasis’’ (3,4). varying according to case. A multinodular outline
However, the determination of the myoepithelial nature with tongue-like pushing margins is a common type
of the neoplasm may be difficult by light microscopy of invasion in this tumor. The multinodular architec-
alone because of the wide variety of histologic as well as ture consists of solid, sheet-like, trabecular, reticular,
cellular features of the tumor cells. A combination of and lace-like growth patterns of tumor cells
histomorphologic, immunohistochemical, and ultra-
structural criteria is often required to delineate myoe-
pithelial differentiation of the tumor cells. Therefore,
this tumor may have been misdiagnosed as various
other salivary gland entities in the past, such as the
broader category of ‘‘malignant mixed tumor’’ (5).
Clinical features. Myoepithelial carcinoma is
considered extremely rare, but it may be more com-
mon than previously thought (5). Approximately
90 cases of myoepithelial carcinoma have been
reported (1,5–14). It accounts for less than 0.4% of all
salivary gland tumors. The age range is from 14 to
86 years, and the mean age of 55 years is about
10 years older than that of myoepithelioma, and no
gender predilection is noted (3). Myoepithelial carci-
noma arises preferentially in the parotid gland (75%),
but it also occurs in the minor salivary glands (25%),
especially the palate, and submandibular gland (10%)
(3). The maxillary sinus, larynx, and bronchus have
been rarely reported as the primary site of this neo-
plasm (15). Most patients present with a chief com- Figure 132 Myoepithelial carcinoma. Low-power view showing
plaint of a painless mass. Myoepithelial carcinomas multinodular architecture.
may arise de novo, but a half or more may develop via
Figure 133 Myoepithelial carcinoma. (A) Epithelioid cell type. The epithelioid cells forming solid nests, cords, or trabeculae in a
hyalinized stroma. (B) Spindle cell type. The spindle cells arranged in a vaguely interlacing fascicular pattern. (C) Plasmacytoid cell type.
The plasmacytoid cells exhibiting eccentrically located nuclei and abundant cytoplasm in a myxoid background. (D) Clear cell type. Solid
nests of epithelioid type carcinoma cells with clear cytoplasm.
intermixing with variable amounts of myxoid or hya- is the most common cell type, a mixture of several cell
line material (Fig. 132). The center of the tumor cell types within a tumor is frequently seen. The epitheli-
nests often undergoes necrosis or paucicellular myxoid cells are polygonal, with central nuclei, coarse
oid degeneration, sometimes creating a pseudocystic chromatin and prominent nucleoli (Fig. 133A). These
appearance. It is unclear whether a tumor exhibiting cells may be arranged in patternless sheets, cords, or
predominantly myoepithelial differentiation with trabeculae in hyalinized stroma. Loose clusters in a
focal ductal differentiation can be diagnosed as myoe- myxoid background with pseudoglandular structures
pithelial carcinoma or should be considered in the forming cleft-like spaces can also be observed. The
category of epithelial-myoepithelial carcinoma. In spindle cells have centrally located nuclei and are
addition, recent reports have broadened the histomor- sometimes arranged in a vaguely interlacing fascicular
phologic spectrum of epithelial-myoepithelial carcino- pattern (Fig. 133B). The plasmacytoid cells have eccen-
ma (16). Although very limited foci of ductal trically located nuclei and abundant cytoplasm, super-
differentiation may not preclude the diagnosis of ficially mimicking plasma cells (Fig. 133C). Clear
myoepithelial carcinoma (4), in order to avoid confu- cytoplasm, because of accumulation of granular
sion, we propose that any true ductal structures PAS-positive glycogen, is usually seen in the epitheli-
should not be present in this tumor. oid type cells (Fig. 133D) (10,14). The clear-cell type
As in myoepithelioma, the tumor cells in myoe- may resemble a vacuolated signet-ring cell or lip-
pithelial carcinoma show wide morphologic variation, oblast-like cell (5). Sometimes, cells of intermediate
consisting of epithelioid, spindle, plasmacytoid and appearance are present among the cells of different
clear cell subtypes (Fig. 133). Although epithelioid cell types. Small foci of squamous differentiation with or
Figure 135 Myoepithelial carcinoma. Electron micrograph of

the carcinoma cell showing abundant microfilaments and des-
mosome-like junctions.
Immunohistochemistry. The immunohistochemi-

cal characteristics of myoepithelial carcinoma indicate
that these tumors are composed of modified neoplas-
tic myoepithelial cells showing various stages of dif-
ferentiation (5,7,9,11). Myoepithelial carcinomas are
almost always positive for pan-cytokeratin, S-100 pro-
tein, vimentin, and p63. The tumor cells are variably
immunoreactive for calponin (75–100%), smooth mus-
cle actin (50–80%), cytokeratin 14 (53–80%), caldesmon
(50%), muscle-specific actin (31–70%), glial fibrillary
acidic protein (31–50%), smooth muscle myosin heavy
chain (30%), and epithelial membrane antigen (20–
Figure 134 Myoepithelial carcinoma. (A) Several foci of squa- 100%) (5,11). Positivity for pan-cytokeratin, together
mous differentiation with keratinization. (B) Chondroid with one or more myoepithelial markers, is required
differentiation. for the diagnosis of myoepithelial carcinoma. Tumors
do not stain with carcinoembryonic antigen, HMB45,
or desmin.
Differential diagnosis. Because of the diverse
without keratinization as well as chondroid features histologic features of myoepithelial carcinoma, a vari-
may be seen (Fig. 134). Cellular pleomorphism varies ety of neoplasms must be included in the differential
from mild to severe. In rare cases, the cytologic diagnosis. These include myoepithelioma, various
features are virtually indistinguishable from those of types of sarcoma such as leiomyosarcoma, malignant
myoepithelioma. On the other hand, tumor exhibiting fibrous histiocytoma, malignant nerve sheath tumor,
marked cellular pleomorphism with cells showing and synovial sarcoma, plasmacytoma, and melanoma.
giant and bizarre nuclei is occasionally observed. Myoepithelial carcinoma is principally distin-
Mitotic figures are easily identified and are sometimes guished from myoepithelioma by several histologic
frequent. Perineural or vascular invasion is present in features such as invasive growth (being the most
44% and 16%, respectively (5). A preexisting pleomor- important hallmark), necrosis, cellular pleomorphism,
phic adenoma or myoepithelioma component is com- and mitosis. Assessment of cell proliferative activity is
monly seen. In addition, a case of dedifferentiation to helpful in the differential diagnosis between myoepi-
undifferentiated carcinoma from histologically low- thelioma and myoepithelial carcinoma, and more than
grade myoepithelial carcinoma has been reported (17). 7 mitotic figures/10 HPFs or a Ki-67 labeling index
Ultrastructurally, tumor cells contain microfila- over 10% is diagnostic for myoepithelial carcinoma
ments with or without focal densities in their cyto- (11). Malignant nerve sheath tumor and melanoma
plasm and have frequent desmosome-like junctions express S-100 protein, but unlike myoepithelial carci-
(Fig. 135) (5,11). Abundant glycogen deposits are nomas, all sarcomas, plasmacytoma, and melanoma
evident in the clear-cell type (5). A basal lamina may are negative for cytokeratin and specific myoepithelial
be focally present. markers such as calponin and smooth muscle actin.
The clear cell variant of myoepithelial carcinoma 2.8–42.4%), and 6.2% of all pleomorphic adenomas
should be distinguished from various types of salivary (range, 1.9–23.3%) (2). It is probable that the true
gland tumors with predominant clear cell morphology, incidence of carcinoma ex pleomorphic adenoma is
including epithelial-myoepithelial carcinoma, clear cell higher because the malignant component may over-
carcinoma (NOS), mucoepidermoid carcinoma, onco- grow and efface the original pleomorphic adenoma
cytoma, acinic cell carcinoma, sebaceous carcinoma, masking the origin of the tumor (4). The parotid gland
and metastatic renal cell carcinoma (see the section is the most frequent major gland site (82%) but tumors
‘‘Clear Cell Carcinoma, NOS’’) (10,18,19). The distinc- may also develop in the submandibular gland (18%)
tion between myoepithelial carcinoma and epithelial- and very rarely the sublingual gland (0.3%) (2). In the
myoepithelial carcinoma is based on the presence or minor salivary glands, about 60% of carcinoma ex
absence of the true ductal formation. pleomorphic adenoma involve the palate with lesser
Treatment and prognosis. The clinical behavior of numbers forming in the lips, tongue, buccal mucosa,
myoepithelial carcinoma varies, but it is generally and tonsil (5). There is a wide overall age distribution
considered to be of intermediate- to high-grade malig- but tumors rarely present before the age of 20 and
nancy (5,7,11). Approximately, one third of the most cases are seen in the sixth or seventh decades of
patients die of the disease, usually with distant metas- life. This is approximately a decade later than in
tases, another third develop recurrences but do not die patients with benign pleomorphic adenomas. The
of disease, and the remaining third are free of disease typical history is a rapid increase in size of a mass
(4). Common sites for metastasis include the cervical that has been present for many years. However,
lymph nodes and distant organs, such as the lungs, occasionally the initial presentation may be a rapidly
liver, bones, kidney, and brain (5,11). enlarging tumor with no history of a preexisting mass
Myoepithelial carcinomas exhibiting high prolif- (2,6). The risk of malignant transformation in pleo-
erative activity assessed by mitotic count and/or Ki-67 morphic adenoma appears to increase progressively
labeling index, histologic aggressiveness such as peri- with time (7). However, a significant proportion of
neural permeation and extensive invasion into the patients, particularly those in the younger age groups,
surrounding tissue, and marked cellular pleomor- have a clinical history of less than three years (2,8).
phism have a poor prognosis (11). p53 over-expression Carcinoma ex pleomorphic adenoma usually forms a
suggests an unfavorable course (11). DNA content and painless mass but pain, nerve palsy, and skin fixation
S-phase fraction of tumor cells are good predictors of or ulceration may be seen in progressive disease.
aggressive biologic behavior (20). There is no differ- Regional metastases are common at presentation
ence in outcome with regard to the presence or and the tumor often becomes more widely dissemi-
absence of preexisting pleomorphic adenoma or nated (9).
myoepithelioma (5,11). No correlation between Pathology. The size of carcinoma ex pleomor-
nucleolar organizer regions (an indicator of cell pro- phic adenoma ranges from 1.5 to 25 cm in greatest
liferative activity) and clinical outcome has been diameter (4,10). On average, this is twice the size of
reported (21). There is no apparent association benign pleomorphic adenomas. Large or densely
between the cell type and clinical behavior of myoe- hyalinized tumors and the presence of necrosis,
pithelial carcinoma (5,11). hemorrhage, or cystic degeneration should raise
Complete wide surgical excision is the recom- the suspicion of malignancy and such tumors may
mended treatment for myoepithelial carcinoma. The require extensive sampling. Grossly, carcinoma
effectiveness of chemotherapy or radiation therapy, or ex pleomorphic adenomas are usually poorly cir-
both, for this tumor remains unknown. cumscribed and many are extensively infiltrative.
Occasional tumors resemble their benign counter-
Carcinoma Ex Pleomorphic Adenoma part and are well circumscribed or completely
encapsulated (10,11). Sometimes the preexisting
Introduction. Carcinoma ex pleomorphic adeno- pleomorphic adenoma is represented by no more
ma has been defined as ‘‘a pleomorphic adenoma than an area of scarring. About 40% of carcinoma
from which an epithelial malignancy is derived’’ (1). ex pleomorphic adenomas show macroscopic evi-
Synonyms include carcinoma arising in a benign dence of facial nerve involvement (9).
mixed tumor, carcinoma ex benign mixed tumor, The most common malignant component is a
carcinoma arising in pleomorphic adenoma, and poorly differentiated adenocarcinoma (NOS) or sali-
malignant mixed tumor. In the past, the term malig- vary duct carcinoma (Figs. 136,137). Other malignant
nant mixed tumor has also included carcinosarcoma elements include mucoepidermoid, polymorphous
and metastasizing pleomorphic adenoma. This is a low-grade adenocarcinoma, adenoid cystic carcinoma,
particularly unhelpful name as these tumors are now clear cell or myoepithelial carcinoma (9,12). In addi-
regarded as independent entities. tion, carcinoma ex pleomorphic adenoma can show
Clinical features. Carcinoma ex pleomorphic multiple distinct carcinoma types in the same tumor
adenoma forms the large majority of malignant mass. Occasionally, no histologically benign remnant
tumors associated with pleomorphic adenoma can be found. If there is extensive scarring or calcifi-
(>95%) (2–4). In a major review of the literature, cation or if there is evidence of a previously excised
carcinoma ex pleomorphic adenoma accounted for pleomorphic adenoma at that site, a diagnosis of
approximately 3.6% of all salivary tumors (range, carcinoma ex pleomorphic adenoma is probable.
0.9–14%), 12% of all salivary malignancies (range, Some consider the history of a long-standing mass in
Figure 136 Carcinoma ex pleomorphic adenoma showing ade- Figure 138 Perineural invasion next to remnant of scarred
nocarcinoma developing next to cartilaginous area. pleomorphic adenoma.
Figure 137 Carcinoma ex pleomorphic adenoma showing poorly

differentiated carcinoma developing next to cartilaginous area.
Figure 139 Noninvasive carcinoma ex pleomorphic adenoma

showing dysplastic cells replacing the inner duct layer leaving a
these circumstances is insufficient to justify a diagno- benign myoepithelial layer.
sis of carcinoma ex pleomorphic adenoma (9). The
most reliable criterion for the diagnosis of carcinoma
ex pleomorphic adenoma is an infiltrative, destructive carcinoma, dysplastic pleomorphic adenoma, and car-
growth pattern (Fig. 138). Nuclear hyperchromasia cinoma in situ in pleomorphic adenoma. None of
and pleomorphism are frequent, although occasional these terms is entirely satisfactory and the preferred
tumors may show minimal cytologic atypia. The designation is noninvasive carcinoma ex pleomorphic
tumor grade shows a positive correlation with prog- adenoma. Atypical changes may be focal or diffuse
nosis. Necrosis is a common feature and mitoses may and multifocal dysplastic elements may overgrow and
be frequent. Carcinoma ex pleomorphic adenomas can replace much of the benign tumor. In the early stages,
be subclassified into noninvasive, minimally invasive tumor cells replace the normal inner duct epithelial
(1.5 mm penetration of the malignant component layer, leaving the normal peripherally located myoe-
into extracapsular tissue) and invasive (>1.5 mm of pithelial layer intact (Figs. 139,140). It has been postu-
invasion). The first two groups appear to have an lated that this represents intraductal carcinoma (13)
excellent prognosis (11) but the outlook is much and this has been associated with genetic and mor-
poorer in the latter group. phologic evidence of dysfunctional p53 (14). If there is
Some pleomorphic adenomas have foci of cells any evidence of destructive invasion through the
showing variable degrees of dysplasia but confined capsule into peritumoral tissues, the tumor is
within the main tumor mass. These tumors have been regarded as a noninvasive carcinoma ex pleomorphic
given a variety of names including intracapsular adenoma.
Rearrangements of 8q12 are the most frequent finding,

and alterations at 12q13-15 with amplifications of
HMGIC and MDM2 genes have been described (17).
These findings suggest that amplification and over-
expression of HMGIC and possibly MDM2 might be
important genetic events in the malignant transforma-
tion of pleomorphic adenomas (18,19). Microsatellite
analysis has shown that loss of heterozygosity (LOH)
is common on chromosome 8q and 12q in both pleo-
morphic adenoma and carcinoma ex pleomorphic
adenoma, suggesting the presence of one or more
tumor suppressor genes at these locations (19,20).
LOH at chromosome 17p has been reported in carci-
noma ex pleomorphic adenoma. In addition, chro-
mosome 17p alterations have been correlated with an
increased proliferative rate and a high disease stage
(19). It has therefore been proposed that changes in
Figure 140 Noninvasive carcinoma ex pleomorphic adenoma 8q and/or 12q are early events in the progression of
showing more extensive dysplastic change. pleomorphic adenoma to carcinoma ex pleomorphic
adenoma and that LOH at 12q might identify a subset
of pleomorphic adenomas that is more likely to
undergo metastasis (20). LOH at 17q may be a sepa-
Differential diagnosis. An important differential rate event that precedes malignant transformation
diagnosis for carcinoma ex pleomorphic adenoma is and progression. These late events may relate to
from tumors showing areas of extensive areas of loss or mutation of p53, which resides on 17p, and
hyalinization such as adenoid cystic carcinoma, sali- P53 over-expression has been reported in noninva-
vary duct carcinoma, and polymorphous low-grade sive carcinoma ex pleomorphic adenoma (21). Anoth-
adenocarcinoma. Finding remnants of pleomorphic er study concluded that p53 and c-erbB1 proteins
adenoma with myxoid, chondroid, or bland ductal/ were involved in the early stages of malignant trans-
myoepithelial components should allow appropriate formation of pleomorphic adenoma (22). Homozy-
classification of carcinoma ex pleomorphic adenoma. gous deletion of p16 on chromosome 9q21 has also
Carcinomas may rarely arise in a histologically benign been reported in the malignant but not the benign
adenoma (monomorphic adenoma) and these must be component of one of four cases of carcinoma ex
differentiated from carcinoma ex pleomorphic ade- pleomorphic adenoma (23). Microsatellite instability
noma because they appear to have a more favorable was found in the malignant elements of 2 cases and
prognosis (15). Tumors showing several distinctive in one case it was detected in the benign component,
malignant components need to be distinguished suggesting premalignant genetic instability.
from hybrid tumors by identifying remnants of pre- Treatment and prognosis. The treatment of choice
existing pleomorphic adenoma. The most important for carcinoma ex pleomorphic adenoma is radical
differential diagnosis, however, is between non- and local excision. Locoregional lymph node dissection
minimally invasive carcinoma ex pleomorphic ade- and adjuvant radiation therapy is recommended for
noma and the more typical invasive carcinoma ex widely invasive tumors. If the carcinomatous compo-
pleomorphic adenoma, as this has important thera- nent is cytologically low grade or minimally invasive
peutic and prognostic significance. It affects decisions and the tumor appears to have been completely
regarding neck dissections and the use of adjuvant excised, then adjuvant radiation therapy may not be
radiotherapy. In this respect, HER-2/neu amplifica- necessary.
tion has been reported in focal dysplastic cells in It appears that patients with noninvasive or
noninvasive carcinoma ex pleomorphic adenoma but minimally invasive carcinoma ex pleomorphic adeno-
not in the surrounding maternal pleomorphic adenoma have a prognosis similar to that of benign pleo-
ma (16). In addition, foci of noninvasive carcinoma ex morphic adenoma (9). There is only one report of a
pleomorphic adenoma showed a higher MIB1 prolif- noninvasive carcinoma ex pleomorphic adenoma
erative index when compared with the surrounding leading to a regional lymph node metastasis (24).
pleomorphic adenoma. Invasive carcinomas ex pleomorphic adenomas, how-
Molecular-genetic data. Deletions of chromo- ever, are usually high-grade and are associated with a
some 5(q22-23, q32-33) and t(10;12) (p15;q14-15) have poor prognosis. About 40% to 50% of patients develop
been reported. There is a breakpoint of the high one or more recurrences (2,4,7,9). As many as 70% of
mobility group protein HMGIC and translocations to patients develop local or distant metastases (6). The
the 10 marker protein have resulted in deletions/ sites of metastatic spread, in order of frequency, are
amplifications of segments containing both HMGIC lung, bone (especially spine), abdomen, and central
and MDM2 genes (1). Abnormalities in chromosome 8 nervous system (4,25). Carcinoma ex pleomorphic
are the most commonly encountered aberration in adenoma with capsular penetration of more than
both pleomorphic adenoma and carcinoma ex pleo- 1.5 mm is associated with a poor prognosis; survival
morphic adenoma, and this probably indicates an rates at 5, 10, 15, and 20 years range from 25% to 65%,
early event in the genesis of these tumors. 18% to 50%, 10% to 35%, and 0% to 38%, respectively
(4,6,7,9,10,25). It is important, therefore, to identify with a range of 14 to 90 years and there appears to be
carcinomas ex pleomorphic adenoma that are intra- no significant sex predilection (2). Most cases appear
capsular and those invading through the capsule as to arise de novo but occasionally there is a history of a
noninvasive or invasive, respectively, and to separate concurrent or recurrent pleomorphic adenoma (6). In
within the latter group minimally and widely invasive these cases, the tumor should strictly be termed carci-
tumors. nosarcoma ex pleomorphic adenoma. Carcinosarcoma
Several other studies have shown that depth of usually presents clinically as a mass, which may be
invasion is an important indicator of prognosis. painful. Nerve palsy, fixation, and ulceration are
However, the depth chosen varies widely in differ- common, but regional lymph node involvement is
ent studies making interpretation of the data prob- infrequent (8).
lematical. One study found that no patients with less Pathology. Carcinosarcoma is a biphasic tumor
than 8 mm invasion from the capsule died from the composed of a mixture of carcinomatous and sarco-
tumor, whereas all patients with invasion greater matous elements, usually with a predominance of
than 8 mm beyond the capsule ultimately died of the sarcomatous component. The most common sar-
disease (10). The local recurrence rate in this series comatous elements are chondrosarcoma, osteo-
also correlated with extent of invasion. There was a sarcoma (Fig. 141), and fibrosarcoma; moderate to
local recurrence rate of 70.5% in tumors with inva- poorly differentiated adenocarcinoma (NOS)
sion beyond 6 mm from the capsule, as compared (Fig. 142), or an undifferentiated carcinoma are the
with 16.6% for tumors with invasion of less than 6 most common carcinomatous components. More
mm. Another study showed that of four patients
with carcinoma ex pleomorphic adenoma invading
5 mm beyond the capsule, two died of the disease.
Two patients with invasion less than 5 mm had no
tumor progression (9). The improved prognosis for
minimally invasive tumors (1.5 mm) has been
shown by eight patients having recurrence-free peri-
ods ranging from 1 to 4 years (mean, 2.5 years) (11).
Further studies using larger numbers of patients and
more exact histologic criteria are necessary to estab-
lish more clearly the relationship between depth of
invasion and prognosis.
The reported effect of tumor size on prognosis
has also been variable. Some studies have shown a
poorer prognosis in larger tumors (3,9) whereas others
could find no significant relationship between size
and survival (7,10). Lewis et al. (9) could find no
correlation with tumor subtype, unlike Tortoledo et
al. (10) who reported a correlation between the sub-
type of the carcinomatous component and the five-
year survival rates. In their study there was a 30% Figure 141 Carcinosarcoma showing mixture of adenocarcino-
survival rate for undifferentiated carcinomas, 50% for matous and osteosarcomatous differentiation.
myoepithelial carcinomas, 62% for adenocarcinomas
(NOS), and 96% for polymorphous low-grade adeno-
carcinomas (10). Additional factors reported to be of
prognostic significance have included pathologic
stage, grade, proliferation index, and the proportion
of benign to malignant tumor (9).
Carcinosarcoma
Introduction. Carcinosarcoma is defined as ‘‘a
malignant tumor composed of a mixture of both
carcinomatous and sarcomatous elements’’ (1). Syno-
nyms include true malignant mixed tumor and sarco-
matoid carcinoma (see discussion of terminology in
the section ‘‘Salivary Duct Carcinoma’’.
Clinical features. Carcinosarcoma is a very rare
tumor, which accounts for only 0.2% of malignant
tumors of major salivary glands (2) and to
date, there have been over 70 published cases (2–22).
Two-thirds have arisen in the parotid, approximately
19% in the submandibular glands and 14% in the Figure 142 Carcinosarcoma showing poorly differentiated ade-
nocarcinoma and sarcomatoid stroma.
palate (1) and a single case has been reported in the
tongue (5). The mean age at presentation was 58 years
defined carcinomatous elements such as salivary duct Metastasizing Pleomorphic Adenoma

carcinoma (8) (see page 573), adenoid cystic carcinoma
(19), and squamous cell carcinoma (17) can also be Introduction. Metastasizing pleomorphic ade-
present. An unusual and unique case of a carcinosar- noma has been defined as ‘‘a histologically benign
coma composed of a large cell neuroendocrine carci- pleomorphic adenoma that inexplicably manifests
noma and a rhabdomyosarcoma has been reported local or distant metastasis’’ (1). Synonyms include
(10). Carcinosarcoma is characterized by local tissue metastasizing benign mixed tumor and malignant
infiltration and destruction (1). mixed tumor.
Molecular-Genetic data. There have been few Clinical features. The metastasizing pleomor-
studies on the genetic profile of salivary carcinosarco- phic adenoma is rare. In a recent review of the English
mas. Loss of heterozygosity (LOH) at 17p13.1, 17q21.3, literature, 42 cases of metastasizing pleomorphic ade-
and 18q21.3 has been reported in a single tumor, noma were identified (2) and further cases have been
indicating allelic loss in both components of a carci- reported (3,4). It is the least common of the three types
nosarcoma (11). P53 did not appear to be the target of malignancy associated with pleomorphic adenoma
gene affected by the LOH at 17p13.1. However, in an (2,5). The average age at presentation is 33 years and
immunohistochemical study, both components of a there appears to be no significant sex predilection.
carcinosarcoma strongly expressed p53 (17). LOH at Most cases arise in the parotid gland, with the remain-
17q21 and 9q21 has also recently been reported in der involving the submandibular gland and palate
several other carcinosarcomas, and the mutational (6–11). There is usually a long history of a pleomor-
profile was conserved between the carcinomatous phic adenoma with multiple recurrences before the
and sarcomatous elements (18). These observations development of locoregional and/or distant metastases.
support the concept that the sarcomatous and carci- The mean time from initial presentation to the develop-
nomatous elements of carcinosarcoma are derived ment of metastatic disease was 16 years (2) with a range
from a common clonal precursor and do not represent from 1.5 to 55 years.
a collision tumor. It has been suggested that the Pathology. Both the primary tumor and the
myoepithelial cell is the most likely common stem metastatic deposits consist of histologically typical
cell (11). benign pleomorphic adenoma (Fig. 143). There is no
Treatment and prognosis. Treatment is usually relationship between the histologic subtype type of
wide surgical excision combined with adjuvant radio- pleomorphic adenoma and its propensity for malig-
therapy. There is a high mortality with almost 60% of nant dissemination. Although mitotic figures and
patients dying from the disease with an average nuclear pleomorphism can be present, by definition,
survival period of only 2.5 years (2). Two-thirds of there is no evidence of frank malignancy although this
patients develop local recurrence, and metastatic dis- assertion has been questioned (12). It has been postu-
ease to lungs, bones, and central nervous system is lated that the multiple recurrences and subsequent
seen in about half the patients (2,6–8,15). surgical interference result in the tumor gaining
Figure 143 Metastasizing pleomorphic adenoma. Cytologically benign pleomorphic adenoma metastatic to supraclavicular lymph node.
lymphatic or venous access and allowing the cytolog- reported. There is a male-female ratio of about 2:1.
ically benign tumor metastasize. Most cases arise in the 50- to 70-year age range with a
Immunohistochemistry. The immunohistochemi- mean of 60 to 65 years (1); tumors in children are
cal features are similar to those of conventional pleo- exceptional (12,13). Some tumors are associated with
morphic adenoma. previous radiotherapy, often following a long latent
Molecular-genetic data. There have been limited period (5,7,14). About half of the patients present with
genetic studies on these tumors. The majority of cases a painless mass (5–7), and others give a history of a
are found to have a normal diploid complement but in rapidly enlarging mass, which may be associated with
one study 2/11 cases showed aneuploid DNA (9). pain, fixation, and facial nerve palsy. Many cases
Karyotypic chromosomal analysis and fluorescent in present with a high clinical staging (5–7).
situ hybridization in a single case have shown numer- Pathology. Grossly, most tumors form firm
ous translocations. These have included unbalanced masses that are larger than 3 cm in diameter and
rearrangements of chromosomes 1-13 and 9-21 and show evidence of invasion. The cut surface is usually
monosomy 22. These differ from the typical balanced white or light gray, and there may be areas of necrosis.
8q or 12q translocations associated with conventional Histologically, the tumor is similar to other squamous
pleomorphic adenoma (13). It has been suggested that cell carcinomas of the head and neck region
genetic factors rather than coincidence or mechanical (Figs. 144,145). Most are well or moderately differen-
dislodgement may be involved in the metastatic pro- tiated, with less than 10% of poorly differentiated
gression in these tumors. tumors (14). There may be ductal dysplasia and squa-
Treatment and prognosis. The main sites of mous metaplasia. There is usually extensive local
metastasis are bone (45%), locoregional head and invasion, and perineural involvement is common.
neck (43%), and lung (36%) (2). Distant spread is
associated with a significantly adverse outcome with
five-year disease-specific and disease-free survivals of
only 58% and 50%, respectively. Other indicators of
poor prognosis include the development of distant
metastases within 10 years of the initial diagnosis of
pleomorphic adenoma and the presence of metastases
in multiple sites. Radical surgery is the treatment of
choice as the evidence for the value of radiotherapy or
chemotherapy is minimal.
Squamous Cell Carcinoma

Introduction. Squamous cell carcinoma has been
defined as ‘‘a primary malignant epithelial tumor
composed of epidermoid cells, which produce keratin
and/or demonstrate intercellular bridges by light
microscopy’’(1). The diagnosis of a primary squamous
Figure 144 Moderately well-differentiated squamous cell carci-
cell carcinoma of salivary glands is often restricted to noma of the parotid gland.
the major glands as there may be no reliable way of
distinguishing tumors developing in minor glands
from those of mucosal origin (1). In addition, it is
essential to exclude metastases from the skin of the
scalp, external ear, and face, or rarely, tumors arising
in the upper aerodigestive tract. Similarly, direct
extension from the overlying skin or external auditory
meatus should be excluded (2).
Clinical features. Primary squamous cell carci-
noma of the major salivary glands is uncommon and
probably accounts for less than 1% of salivary gland
tumors. There is a wide range of reported incidence,
varying from 0.3% to 9.8% of all parotid malignancies
and 2.1% to 11.4% of malignant submandibular gland
tumors (3–8). The higher incidence rates for parotid
tumors are probably due to the inclusion of cutaneous
metastases (8–10). In addition, the possibility of direct
extension from a squamous cell carcinoma of the floor
of the mouth needs to be excluded in submandibular
tumors. About 80% of cases involve the parotid gland,
and 20% arise in the submandibular gland. Rare Figure 145 Well-differentiated squamous cell carcinoma aris-
squamous cell carcinomas of Stensen’s duct (11) and ing from Stensen’s duct.
the accessory parotid duct epithelium (2) have been
Table 9 Differences in Clinicopathologic Characteristics of Three Types of ‘‘Undifferentiated Carcinomas’’

Small cell carcinoma Large cell carcinoma Lymphoepithelial carcinoma
Incidence Rare (No ethnic Rare (No ethnic Rare (High in Inuit and
predilection) predilection) Southern Chinese)
Association with EBV No No Yes
Histopathology
Cell size Small Large Large
Nucleolus Inconspicuous Prominent Prominent
Lymphoid stroma No No Yes
Neuroendocrine differentiation Yes Sometimes No
Prognosis Poor Poor Fair
Abbreviation: EBV, Epstein–Barr virus.
Molecular-genetic data. There have been few ‘‘Undifferentiated Carcinomas’’

cytogenetic studies of primary squamous cell carcino-
mas of salivary glands. However, deletions at 6q have Undifferentiated carcinomas of the salivary glands are
been reported by several groups (15–17). This deletion uncommon high-grade malignant tumors that include
has been noticed in other salivary gland tumors, but is malignant epithelial neoplasms too poorly differenti-
uncommon in squamous cell carcinomas from else- ated by their light microscopic features to be placed in
where in the aerodigestive tract. a specific category of carcinoma (1). They are general-
Differential diagnosis. The main differential ly subclassified into three groups: small- and large-cell
diagnoses are metastatic squamous cell carcinoma types of undifferentiated carcinomas (2) and lymphoe-
and mucoepidermoid carcinoma. Occasionally, sali- pithelial carcinoma. However, since epidemiologic,
vary duct carcinomas and oncocytic carcinomas may etiologic, and clinical features among these entities
have an epidermoid appearance, but there are usually are different, each of them should be regarded as an
more typical areas elsewhere in the tumors. Mucoepi- independent tumor group (3–6) (Table 9).
dermoid carcinoma shows a wider range of cell types
that include mucocytes, which can be demonstrated Small Cell Carcinoma
by appropriate stains. In addition, conspicuous
keratinization is extremely uncommon in mucoepi- Introduction. The small-cell type of undifferen-
dermoid carcinomas. There can be striking pseudoe- tiated carcinoma, usually simply called small cell
pitheliomatous hyperplasia and, occasionally, carcinoma, of the salivary glands is rare. Small cell
necrotizing sialometaplasia in surgically treated or carcinomas are defined as ‘‘malignant epithelial
infarcted tumors. Careful examination and an accu- tumors characterized by a proliferation of small ana-
rate clinical history should prevent confusion. In plastic cells with scant cytoplasm, fine nuclear chro-
addition, squamous cell carcinoma may be a compo- matin, and inconspicuous nucleoli’’ (4). On the basis
nent of carcinomas arising in both pleomorphic ade- of immunohistochemical and/or ultrastructural fea-
noma and Warthin’s tumor. Keratocystoma, a rare tures, these tumors may be subclassified into two
salivary gland neoplasm, should also be considered main types: neuroendocrine and nonneuroendocrine
in the differential diagnosis (18). Keratocystoma is (ductal) types (1). However, most small cell carcino-
composed of multiple cysts lined by cytologically mas exhibit neuroendocrine differentiation (7,8). Neu-
bland stratified squamous epithelium and filled with roendocrine carcinomas may be further subdivided
laminated keratin. There may be solid nests of squa- into cutaneous (Merkel cell) and pulmonary varieties
mous epithelium, but there is no evidence of invasion on the basis of cytokeratin 20 immunoreactivity (8,9).
(see page 539). Metastatic small cell carcinoma or cutaneous neuro-
Treatment and prognosis. Primary squamous cell endocrine carcinoma (Merkel cell carcinoma) should
carcinoma is usually a high-grade tumor. There is be ruled out before making a diagnosis of salivary
widespread invasion and frequent lymph node gland small cell carcinoma.
involvement at the time of presentation (5,7,10,19). Clinical features. Small cell carcinoma most fre-
About half the patients develop locoregional recur- quently arises in the lung. An extrapulmonary origin is
rence, and the five-year survival rates varied from uncommon, and small cell carcinomas originating in the
21% to 50% in two major series (5,7). Patients have salivary glands are extremely rare, accounting for less
usually been treated by surgery, with or without than 1% of all salivary gland tumors and approximately
adjuvant radiotherapy. Because of the high rate of 2% of salivary gland malignancies (3). Less than 80
regional lymph node metastasis, elective neck dissec- cases of major salivary gland small cell carcinoma have
tion should be considered. The most important prog- been reported (2,8–23). Small cell carcinoma occurs
nostic factor is clinical stage. Other reported adverse slightly more commonly in males, with peak incidences
factors include patients over 60 years, ulceration, and in the fifth and seventh decades of life; however, these
fixation (7). In parotid gland tumors, facial nerve palsy tumors have also been described in younger patients.
and treatment modalities were also considered to be Most involve the parotid gland, but a few cases in the
prognostic indicators (4,10). submandibular gland and minor salivary glands have
also been reported. Patients typically present with a

painless, rapidly growing mass of several months’
duration. Cervical lymphadenopathy and facial nerve
palsy are common findings. Paraneoplastic syndromes
accompanied by the production of ectopic hormones
are unusual in this tumor (22).
Pathology. Macroscopically, small cell carci-
noma is a firm, poorly circumscribed tumor that
often infiltrates the surrounding salivary gland paren-
chyma and adjacent soft tissues. The tumor is usually
gray to white and commonly accompanied by necrosis
and hemorrhage.
Histopathologically, all small cell carcinomas
invade the surrounding normal salivary gland or
adjacent adipose or muscular tissue. Small cell carci-
noma is characterized by sheets, cords, or irregular
nests of anaplastic, small-sized tumor cells and a
variable amount of fibrous stroma. Tumor cell nests
may exhibit a peripheral palisading pattern. An orga-
noid pattern and rosette-like structures are occasion-
ally seen. Tumor cells are usually roughly two times
larger than mature small lymphocytes and contain
round to fusiform hyperchromatic nuclei with scanty
cytoplasm (Fig. 146A). These cytologic features closely
resemble those of ‘‘oat cell carcinoma’’ of the lung.
Some tumor cells are slightly larger and exhibit polyg-
onal nuclei with more cytoplasm (although the tumor
cells are still <30 mm in diameter) (Fig. 146B). They are
similar to the intermediate cell variant of pulmonary
small cell carcinoma or typical Merkel cell carcinoma.
Regardless of cellular size, the nuclear chromatin is
finely granular, and nucleoli are absent or inconspic-
uous. Cell borders are ill defined, and nuclear mold-
ing is common. Numerous mitotic figures are usually
present. Crush artifacts are observed in most of the
tumors. The tumor may have small foci of ductal
differentiation or squamous differentiation. Extensive
necrosis and vascular and perineural invasion are Figure 146 Small cell carcinoma. High-power view showing the
tumor cells with scant cytoplasm and inconspicuous nucleoli.
common.
Mitotic figures are readily identified. (A) The tumor cells have
Immunohistochemistry. In most small cell carci- elongated nuclei with granular, dense chromatin. These cytologic
nomas, the tumor cells express neuroendocrine features closely resemble those of ‘‘oat cell carcinoma’’ of the
markers. The tumors usually stain positively for, in lung. (B) The tumor cell nuclei are round to oval, with pale,
descending frequency, neuron-specific enolase, chro- dispersed chromatin and a well-defined nuclear membrane. They
mogranin A (Fig. 147A), synaptophysin, neurofila- are similar to typical Merkel cell carcinoma of the skin.
ment, and CD56. However, immunoreactivity for
neuron-specific enolase alone is insufficient evidence
to confirm the neuroendocrine differentiation of the
tumor. Most small cell carcinomas are positive for pan- Electron microscopy. Membrane-bound neuro-
cytokeratins, which sometimes have a characteristic endocrine granules are seen in about one-third of
paranuclear dot-like pattern of reactivity. About small cell carcinomas (7). The tumor cells contain
three-fourths of the tumors are immunoreactive for sparse cytoplasmic organelles, and either poorly or
cytokeratin 20, frequently with a characteristic dot- well-formed desmosomes interconnect the cells.
like pattern (Fig. 147B) (8). They stain positively for Multidirectional differentiation with the presence of
cytokeratin 20 in the Merkel cell variety and negatively myofilament-like microfilaments and tonofilaments
in the pulmonary variety. Positive neurofilament has been reported (15,19).
immunoreactivity, with a dot-like pattern, is seen in Differential diagnosis. Before making a diagnosis
some cytokeratin 20–positive tumors. The majority of of salivary gland small cell carcinoma, other types of
the tumors are also positive for epithelial membrane small ‘‘blue cell’’ tumors should be excluded. These
antigen. A few tumors express thyroid transcription include the solid type of adenoid cystic carcinoma,
factor 1 (8,24). Small cell carcinomas are negative for S- malignant lymphoma, malignant melanoma, and met-
100 protein, HMB-45, and myoepithelial and lymphoid astatic pulmonary small cell carcinoma or Merkel cell
markers. carcinoma.
positive immunoreactivity for cytokeratin 20 and neu-

rofilament strongly favors salivary small cell carci-
noma or Merkel cell carcinoma, features that are not
detected in pulmonary small cell carcinoma, which is
the most likely metastatic neoplasm (9).
Treatment and Prognosis. Small cell carcinoma of
major salivary glands is a highly aggressive tumor,
although the prognosis may be better than that for
small cell carcinoma of bronchogenic or laryngeal
origin. The two- and five-year survival rates for
patients with salivary gland small cell carcinomas
are 38% to 70% and 13% to 46% (8,13,18), respectively,
compared with 16% and 5% for patients with similar
tumors of the larynx (25). Distant metastases develop
in more than 50% of patients after the initial diagnosis.
Even though the incidence of cervical lymph node
involvement is high, it may be exceeded by hematog-
enous metastasis. Overall survival is significantly
reduced in patients with a primary tumor larger
than 3 cm in diameter, a negative immunostain reac-
tion for cytokeratin 20, and decreased immunoreactiv-
ity for neuroendocrine markers (8,17). Therefore, the
immunohistochemical determination of the cytokera-
tin 20 expression of salivary gland small cell carcino-
mas is recommended, since the result could affect the
prognosis. The treatment of choice is wide local exci-
sion with cervical lymph node dissection. Adjuvant
chemotherapy and radiation therapy may be
warranted.
Large Cell Carcinoma

Introduction. Large cell carcinomas are defined
as ‘‘rare, high-grade malignant salivary gland epithe-
lial tumors composed of large-sized pleomorphic cells
with abundant cytoplasm’’ (1). This tumor lacks his-
tologic features of other specific types of salivary
Figure 147 Small cell carcinoma. (A) Tumor cells are diffusely gland carcinomas and was formerly called large cell
immunopositive for chromogranin A. (B) Paranuclear dot-like
undifferentiated carcinoma, a subtype of undifferenti-
pattern of immunoreactivity for cytokeratin 20.
ated carcinomas (2–7). Salivary gland neuroendocrine
carcinomas other than the small-cell type have
received little attention until recently and were not
recognized as a specific entity in the 2nd edition of
Distinction of solid adenoid cystic carcinoma WHO classification (7). Rarely, large cell carcinomas
from small cell carcinoma may be difficult. The solid exhibit neuroendocrine differentiation, and these are
type of adenoid cystic carcinoma has a focal cribriform now referred to as ‘‘large cell neuroendocrine carcino-
architecture and lacks neuroendocrine differentiation mas’’ (3,8–10). The absence of the components of any
and paranuclear dot-like cytokeratin positivity of other specific tumor type should be confirmed by
small cell carcinoma. The presence of myoepithelial careful examination before making the diagnosis of
differentiation in this neoplasm also distinguishes it salivary gland large cell carcinoma.
from small cell carcinoma. Positive cytokeratin stain- Clinical features. Large cell carcinomas account
ing and negative CD45 (leukocyte common antigen) for less than 1% of all epithelial salivary gland neo-
expression exclude malignant lymphoma. Malignant plasms (1). In one report, 2 out of 13 cases of large cell
melanoma can also show a small-cell morphology, but carcinoma had neuroendocrine differentiation. To
positive immunoreactivity for S-100 protein, HMB-45, date, only five cases of large cell neuroendocrine
Melan-A, and vimentin, and a lack of cytokeratin carcinoma of the salivary glands have been reported
staining do not favor a diagnosis of small cell (3,8–10). In the majority of cases, the patients are older
carcinoma. than 60 years when the initial diagnosis is established.
Metastasis from small cell carcinoma of extra- Men and women are affected equally. Unlike lym-
salivary origin or Merkel cell carcinoma must also be phoepithelial carcinoma, no ethnic predilection, famil-
excluded. A negative medical history of a previous or ial occurrence, or association with EBV has been
coexisting malignancy assists in resolving this diag- documented. The majority of large cell carcinomas
nostic dilemma. In addition, a dot-like pattern of arise in the major salivary glands, especially the
Figure 148 Large cell carcinoma. Sheet-like growth pattern of

large pleomorphic cells with abundant eosinophilic cytoplasm
and prominent nucleoli.
parotid. A few tumors of minor salivary gland origin

have also been reported. Many patients present with a
rapidly growing firm mass that is often fixed to
adjacent tissue. Facial nerve paralysis and cervical
lymph node enlargement are common findings.
Pathology. Large cell carcinoma is usually a
poorly circumscribed, solid tumor with a grayish
white or tan cut surface. The tumor is often over
3 cm in diameter, and necrosis and hemorrhage are
frequent. Invasion into the adipose and muscular
tissue adjacent to the salivary gland is common.
Microscopically, the tumor growth pattern con-
sists of sheets (Fig. 148) and trabeculae, with a con- Figure 149 Large cell neuroendocrine carcinoma. (A) Organoid
growth pattern. (B) Solid growth with peripheral palisading and
spicuous tendency for necrosis. Organoid, rosette-like,
several rosette-like structures. The tumor cells have large and
and peripheral palisading patterns characterize large polygonal nuclei with vesicular chromatin and prominent nucleoli.
cell neuroendocrine carcinomas (Fig. 149). By defini-
tion, large cell carcinoma is too poorly differentiated
to allow more specific classification, but very rare foci
of ductal or squamous differentiation may be identi-
fied, and the presence of these features do not pre- undifferentiated carcinoma with large cells can occur
clude the diagnosis of large cell carcinoma. in association with various benign and malignant
The tumor is composed of large pleomorphic neoplasms, including pleomorphic adenoma (12),
cells (>30 mm in diameter) with an abundance of acinic cell carcinoma (13), mucoepidermoid carcinoma
eosinophilic or occasionally clear cytoplasm. The (14), adenoid cystic carcinoma (15), epithelial-myoepi-
tumor cell nuclei have a polygonal or fusiform thelial carcinoma (16), polymorphous low-grade ade-
shape, prominent nucleoli, and coarse chromatin nocarcinoma (17), and salivary duct carcinoma.
with vesicular distribution. While cell borders are Immunohistochemistry. Large cell carcinoma
usually well defined, bizarre or osteoclast-like giant cells are usually positive for cytokeratins and epithe-
cells may be present (11). Cytoplasmic glycogen can lial membrane antigen but never positive for lym-
be shown by PAS staining, but there are no mucicar- phoid markers, HMB45, or smooth muscle actin. In
mine-positive goblet-type mucous cells. Mitotic large cell neuroendocrine carcinomas, tumor cells
figures are readily identified and are frequently should be positive for at least one neuroendocrine
numerous. The amount of fibrous stroma varies, and marker, including chromogranin A, synaptophysin, or
unlike lymphoepithelial carcinoma, lymphoid cell CD56 in addition to neuron-specific enolase. No
infiltration is usually focal and patchy. Perineural immunoreactivity for cytokeratin 20 is found. The
and vascular invasion is prominent. Ki-67 labeling index is high and often greater than
Components of other categories of salivary gland 50%. In two reported cases of large cell neuroendo-
neoplasms must not be present because an crine carcinoma, the tumor cells showed diffuse
immunoexpression of bcl-2 protein, epidermal growth carcinoma accompanied by a prominent nonneoplas-

factor receptor, and cyclin D1, and reduced immu- tic lymphoplasmacytic infiltrate’’ (7). Lymphoepithe-
noexpression of p21/waf1 and p27/kip1 (9). Diffuse lial carcinomas of the salivary glands show histologic
p53 nuclear immunoexpression has been found in features that are almost identical with those of naso-
four of five cases (9,18,19). Expression of c-erbB-2 pharyngeal origin.
has been identified in the majority of tumors. Most lymphoepithelial carcinomas develop de
Electron microscopy. Tumor cells occasionally novo (10), but an association with a preexisting lym-
have a squamous or glandular differentiation not phoepithelial sialadenitis (LESA) or ‘‘benign lympho-
apparent on conventional light microscopic examina- epithelial lesion’’ may rarely be encountered (20).
tion (20). Neuroendocrine differentiation with the However, the issue concerning the pathogenetic cor-
presence of neurosecretory granules has rarely been relation between these lesions needs to be resolved,
described (3,8,9). Prominent desmosome-like junc- and whether malignant transformation of LESA actu-
tions connect the tumor cells. ally occurs has not been established (10).
Differential diagnosis. Metastatic undifferentiat- Clinical features. Lymphoepithelial carcinomas
ed carcinoma, particularly from the nasopharynx to are rare, usually accounting for less than 1% of all
the parotid gland, must first be excluded. Clinical salivary gland tumors, although an exceptionally high
information is necessary in differentiating between a incidence has been reported among Mongolians, par-
primary and a metastatic origin. Since an undifferen- ticularly Inuit (15,17,18,21–24) and Southern Chinese
tiated carcinoma with large cells can be found in populations (1,2,6,12,16,19,25,26). Approximately 75%
carcinoma ex pleomorphic adenoma and various of reported cases have occurred in these races.
types of dedifferentiated carcinomas, the absence of Familial clustering of salivary gland lymphoepithelial
a component of other specific tumor types should be carcinoma has been reported (27,28). Although Japa-
confirmed by a careful search before arriving at the nese are also ethnic Mongolians, lymphoepithelial
diagnosis of salivary gland large cell carcinoma. The carcinoma is quite rare in Japan (10).
epithelioid-cell type of myoepithelial carcinoma can The tumor occurs in patients of a wide age
be distinguished from large cell carcinoma by immu- range, from the first to the ninth decades (median,
nostaining for smooth muscle actin and calponin. 40 years), with a slightly higher incidence in females.
Metastatic malignant melanoma must also be differ- Lymphoepithelial carcinomas most frequently involve
entiated from large cell carcinoma (21). Immuno- the parotid gland (over 90% of the cases), followed by
histochemical staining for cytokeratin, S-100 protein, the submandibular gland. Rarely, the intraoral minor
HMB-45, and Melan-A distinguishes these tumors. salivary glands are affected (5,11). Patients present
Anaplastic large cell lymphoma involving parotid with an enlarging, firm mass, which may have a
gland lymph nodes may be necessary for a differential long-standing history with a recent rapid increase in
diagnosis with large cell carcinoma. Immunohisto- size. Facial nerve palsy is seen in up to 20% of the
chemical staining for cytokeratin and lymphoid cases, and cervical lymph node enlargement is present
markers including CD30 can resolve this diagnostic in about 40% of the patients (7). There is no clinical
problem. Negative immunoreactivity for cytokeratin association with Sjögren syndrome or malignant
20 in large cell neuroendocrine carcinoma helps to lymphoma.
exclude the possibility of Merkel cell carcinoma. Lymphoepithelial carcinoma in the salivary
Treatment and Prognosis. Large cell carcinoma is gland is consistently associated with EBV in Mongo-
an aggressive tumor with a propensity for local recur- lian patients but usually not in Caucasian patients (1–
rence, cervical lymph node metastasis, and distant 6,10,12,18,19,23,25,26,29,30). More than 50% of these
spread. One series has shown that the two-year sur- patients (all Mongolian) have elevated titers of serum
vival rate is only 36% (22). Large cell neuroendocrine immunoglobulin A against EBV capsid antigen (7).
carcinoma is also a high-grade tumor. Tumor size is a Therefore, ethnic, geographic, and genetic factors may
prognostic indicator; all patients with tumors larger influence EBV infection, which leads to the develop-
than 4 cm died from their disease after developing ment of lymphoepithelial carcinoma of the salivary
distant metastases (3). An age of more than 50 years is glands. The presence of the virus in a clonal episomal
also associated with a significantly poorer prognosis form suggests that EBV may have an etiologic role in
for patients with large cell carcinoma (3). One study the development of lymphoepithelial carcinoma (2).
has shown that cell size (small- vs. large-cell type of Pathology. Macroscopically, the tumors are a
undifferentiated carcinoma) has no influence on prog- solid and firm mass ranging in size from 1 to 10 cm.
nosis (3). Radical surgical excision with neck dissec- On cut section, they may be circumscribed and even
tion and postoperative radiotherapy is the treatment partially encapsulated, but typically extensive infiltra-
of choice. tion of salivary gland and adjacent soft tissues is
evident.
Lymphoepithelial Carcinoma Histologically, lymphoepithelial carcinoma is
characterized by cluster formation of large anaplastic
Introduction. Lymphoepithelial carcinoma (1–7) carcinoma cells enclosed within a prominent sheet of
is also known as undifferentiated carcinoma with lymphoid cells (Fig. 150A, B). Although the lesions are
lymphoid stroma (8–10), lymphoepithelioma-like car- sometimes circumscribed, carcinoma cells often infil-
cinoma (11,12), and malignant lymphoepithelial lesion trate into the surrounding salivary gland tissues
(13–19). It has been defined as ‘‘an undifferentiated accompanied by a lymphoid stroma. The carcinoma
cells show solid, trabecular or irregular arrangements.

Their cytoplasmic borders are indistinct and frequent-
ly create a syncytial appearance. Reactive histiocytes
have been reported to impart a ‘‘starry sky’’ pattern
within tumor islands (16).
Usually, the carcinoma cells are large and polyg-
onal or sometimes spindled (18). Nuclear chromatin is
vesicular or clumped, and there are prominent eosin-
ophilic nucleoli. The cytoplasm of the tumor cells may
be relatively abundant and slightly amphophilic. A
number of mitotic figures are usually evident.
Although ductal structures are absent and no intra-
cytoplasmic mucin is identified in the tumor cells,
focal squamous differentiation with keratinization
may be present.
Lymphoid follicles, each with a germinal center,
are occasionally observed in the lymphoid tissue. A
fibrous stroma is sometimes seen. Rarely, carcinoma
cells form clearly defined islands, which show periph-
eral palisading with PAS-positive hyaline material
(10,24). Perineural invasion is a common finding.
Generally, the residual salivary gland shows various
degrees of lymphocytic infiltration. Benign epimyoe-
pithelial islands may be identified in the surrounding
salivary gland tissue in occasional cases (20).
Electron microscopic features indicate that lym-
phoepithelial carcinoma is a poorly differentiated squa-
mous cell carcinoma with variable amounts of
tonofilament bundles and well-formed desmosomes
(10,31).
Immunohistochemistry. Carcinoma cells are pos-
itive for pan-cytokeratin and epithelial membrane
antigen but are negative for lymphoid markers. They
usually show diffuse expression of p53 and high Ki-67
labeling index with over 40% (10). The lymphoid cells
are polyclonal in nature with a mixture of B cells and
T cells. Expression of EBV latent membrane protein
1 varies (2,32). In Mongolians, EBER can almost
always be detected in the nuclei of almost all car-
cinoma cells using in situ hybridization technique
(Fig. 150C) (1–6,10,12,18,19,25,26,29,30). No hybridiza-
tion signals are identified in the lymphoid stroma or
the surrounding non-tumorous salivary gland tissue.
BamHI H left frame 1 (BHLF1) mRNA signals, on the
other hand, are not detectable in any tumors (10).
Differential diagnosis. The differential diagnosis
should include metastatic lymphoepithelial carcinoma,
LESA, large cell carcinoma, malignant lymphoma, and
lymphadenoma.
Since lymphoepithelial carcinoma of the salivary
glands is histologically indistinguishable from lym-
phoepithelial carcinoma of nasopharyngeal origin,
which is much more commonly seen, nasopharyngeal
lymphoepithelial carcinoma should be excluded by
Figure 150 Lymphoepithelial carcinoma. (A) Solid, trabecular, careful clinical examination along with multiple ran-
or irregular arrangements of carcinoma cells enclosed within a dom biopsies at the site. However, nasopharyngeal
lymphoid stroma. (B) The carcinoma cells are large and create a lymphoepithelial carcinoma metastatic to the salivary
syncytial appearance. Nuclear chromatin is vesicular and there glands is an extremely rare event.
are prominent nucleoli. (C) In situ hybridization for EBV-encoded LESA has a histologic architectural structure,
small RNA (EBER). Almost all of the carcinoma cells express with epithelial and lymphoid components similar to
strong nuclear EBER hybridization signals. Note complete those of lymphoepithelial carcinoma. Bland cytologic
absence of signal in the surrounding lymphoid stroma.
features, low mitotic activity, the presence of hyaline
material deposition, and the absence of invasive
growth pattern favor a diagnosis of LESA, rather than

lymphoepithelial carcinoma. Especially when only
small tissue fragments are available for histologic
examination, the presence of EBV demonstrated by
EBER in situ hybridization, the diffuse expression of
p53, and a high cell proliferative activity assessed by
Ki-67 immunostaining may be useful for distinguish-
ing lymphoepithelial carcinoma from LESA (10).
The distinction of lymphoepithelial carcinoma
from large cell carcinoma is important because the
prognosis of these two entities is quite different (6).
Large cell carcinomas are not associated with any
significant degree of lymphoid infiltrate and do not
show intermingling pattern of the carcinoma cells and
lymphoid cells as seen in lymphoepithelial carcinoma.
Malignant lymphoma, especially of diffuse
large-cell type, can be distinguished from lymphoe-
pithelial carcinoma by immunostaining for pan-cyto- Figure 151 Sialoblastoma (embryoma). Well-differentiated
tumor consisting of solid basaloid, duct-like structures, and
keratins and lymphoid markers, such as CD45
clusters of acinar type cells in fibrous stroma.
(leukocyte common antigen), CD20, CD79a, and
CD30. Lymphadenoma, a recently defined rare
tumor entity, shows ductal formation without cyto-
logic atypia and is negative for EBER in situ hybrid- (19). A single tumor was associated with a high level
ization (33). of serum a-fetoprotein and premature centromere
Treatment and Prognosis. The five-year survival division (16).
rate of patients with lymphoepithelial carcinoma of Pathology. Macroscopically, the tumors range
the salivary glands is between 75% and 86% (7), which from 1.5 to 15 cm and appear to be partially encapsu-
is much better than the outcome of patients with large lated, firm swellings that may show local infiltration
cell carcinoma (6). Lymph node metastases are a (26). They are multilobulated, and the cut surface is
common finding, and distant metastasis can be usually tan or yellow and solid. Occasionally, there are
found in 20% of the patients (7). Prognostic factors areas of hemorrhage or necrosis. Microscopically, the
include tumor stage and histologic features. One tumor consists of primitive, basaloid epithelial cells
study on Alaskan natives subclassified the tumor (Fig. 151). The nuclei are round or oval and vesicular
into low- and high-grade types on the basis of histo- with occasional nucleoli. The eosinophilic cytoplasm
logic features and prognosis (24). Radical surgical varies from scanty to abundant and usually has indis-
excision with postoperative radiation therapy is the tinct borders. There is variable pleomorphism, and
best choice of treatment. Most lymphoepithelial carci- some cells have hyperchromatic nuclei, a high nucle-
nomas are radiosensitive. ar-cytoplasmic ratio, and numerous, typically normal
mitoses (Fig. 152). Apoptosis and necrosis may be
Sialoblastoma present. The cells are usually arranged in solid,
Introduction. Sialoblastoma has been defined as

‘‘a rare, potentially aggressive, parotid or submandib-
ular gland tumor that is usually present at birth and
recapitulates the primitive salivary anlage’’ (1).
Synonyms include congenital basal cell adenoma,
basaloid adenocarcinoma, congenital hybrid basal
cell adenoma–adenoid cystic carcinoma, and embry-
oma (2–5).
Clinical features. Sialoblastomas are very rare,
with about 40 cases in the literature (2–24). Most have
been reported as single cases, but there is a short series
of seven cases from the files of the AFIP (23). Most
tumors are evident at birth or within the first few
months of life, with occasional cases in the second and
third years of life (4,7,12,21). Cases have been detected
in utero (16). There is no significant sex predilection.
Three quarters of tumors have arisen in the parotid
gland, with the remainder in the submandibular
gland. A similar tumor has been reported in the eyelid
(25). Sialoblastoma usually presents as a painless, firm
swelling, but some have shown ulceration and facial Figure 152 Sialoblastoma (embryoma). Poorly differentiated
nerve involvement. Cases of coexistent congenital tumor consisting of solid nests of basaloid cells.
nevi (7,9) and hepatoblastoma have been reported
hypercellular nests, and the outer layer may show more histologically distinct types of tumor within the
nuclear palisading. There may be small, duct-like same topographical area and proposed the term
structures lined by cuboidal cells, occasionally associ- ‘‘hybrid tumor’’ (1). Examples of both benign and
ated with solid, acinar-like nests resembling the anlage malignant hybrid tumors have been reported, most
of the developing salivary gland. Myoepithelial cells being the latter and referred to as hybrid carcinomas.
have been associated with these structures, and focal Some controversial issues regarding the criteria
areas of sebaceous or squamous differentiation may be for hybrid carcinomas have been raised. Since in the
present (17,18). Cribriform areas may be seen focally, salivary glands, shared foci of similar phenotypic
and occasionally, calcospherites are present. The stro- differentiation may be seen among the different histo-
ma is variable and can consist of thin, fibrous septa, logic tumor types, Gnepp et al. proposed that in
sparsely cellular myxoid tissue or more primitive, hybrid carcinomas, each element needs to differentiate
abundant, and cellular fibroblastic areas. toward distinctly different salivary gland elements:
Immunohistochemistry. Sialoblastoma is positive for example, excretory duct versus acini or excretory
for a variety of keratin markers, including pan- duct versus intercalated duct (2). Grenko et al.
cytokeratin cocktail, epithelial membrane antigen, cyto- described three adenoid cystic carcinomas and two
keratins 5/6, 7, and 14, but negative for cytokeratin epithelial-myoepithelial carcinomas that focally
20 (3,11,18,23). The abluminal cells stain with a variety shared both histologic features (3). They suggested
of myoepithelial markers including smooth muscle that these two entities shared common differentiation
actin, calponin, S-100 protein, cytokeratin 14, p63, and pathways and did not categorize these examples as
pan-cytokeratin (18). a-fetoprotein reactivity has been hybrid carcinomas. On the other hand, Seifert and
reported (16,23), but tumors are negative for glial Donath, and Croitoru et al. did not take account of the
fibrillary acidic protein (11,23). There is a wide varia- cellular phenotypes constituting hybrid tumors (1,4).
tion in Ki-67 expression (3–80%) (23). Chetty et al. suggested that completely divergent
Differential diagnosis. Sialoblastoma needs to differentiation may lead to the appearance of two
be distinguished from other basaloid neoplasms, distinct tumor entities (hybrid tumors), whereas
including basal cell adenoma, basal cell adenocarci- incomplete divergence may lead to tumors harboring
noma, and adenoid cystic carcinoma. The degree of overlapping histologic features (5). It has been postu-
cytologic atypia, primitive cellular features, mitotic lated that the two tumor components have an identi-
frequency, and local infiltrative growth pattern are cal origin because of the consistent presence of a
not seen in basal cell adenoma, and this tumor is transitional zone between the two. We recommend
exceptional in children. Basal cell adenocarcinoma that in hybrid carcinomas, each carcinoma component
and adenoid cystic carcinoma are also not seen in the should occupy at least 10% of the tumor mass and
perinatal period. should be separated from the other component (6).
Treatment and Prognosis. Sialoblastoma is an
aggressive and potentially low-grade malignant neo- Clinical Features
plasm. About 20% of cases recur, and occasionally, the
tumor metastases to regional lymph nodes or distant Hybrid carcinomas are very rare and, to the best of our
sites (12,23,27). Their relative rarity makes it difficult knowledge, only 26 such cases have been described
to make accurate prognostic statements. However, on (1,3–13). The prevalence is up to 0.4% of all salivary
the basis of an admittedly small series, it has been gland tumors. In hybrid carcinomas, there is no gender
suggested that sialoblastomas can be divided into predilection and an age range from 28 to
favorable and unfavorable subtypes on the basis of 81 years (mean 59 years). In terms of tumor location,
their histology (23). Favorable tumors are partially most hybrid carcinomas (17 cases) arise in the parotid
capsulated, cytologically relatively bland, and have gland with additional cases from the palate (5 cases),
abundant stroma. Unfavorable tumors consist of ana- submandibular gland (2 cases), and lacrimal gland (1 case).
plastic, basaloid cells, have minimal stroma, and may
show evidence of vascular or perineural invasion. In Pathology
addition, they may express a-fetoprotein reactivity
and have a high Ki-67 proliferative index. Complete Tumor size of hybrid carcinomas ranges from 2 to
surgical excision appears to be the treatment of choice. 10 cm (mean 4 cm). Microscopically, hybrid carcinoma
Although the successful treatment of metastatic dis- shows a single tumor mass consisting of two distinct
ease with adriamycin has been reported (20), the histologic types with invasion into the surrounding
overall role of radiotherapy and chemotherapy is salivary gland tissue (Fig. 153). Various carcinoma
difficult to assess (17,23,27). combinations have been described in hybrid carcino-
mas (1,3–13); salivary duct carcinoma, epithelial-
myoepithelial carcinoma, and adenoid cystic carcinoma
J. Hybrid Tumors are frequently involved. Others include mucoepider-
Introduction moid carcinoma, acinic cell carcinoma, squamous cell
carcinoma, basal cell adenocarcinoma, myoepithelial
Salivary gland tumors are known to have diverse carcinoma, and polymorphous low-grade adeno-
histologic features, sometimes exhibiting combined carcinoma. Rare hybrid adenomas show combinations
histologic patterns observed in different tumor enti- of basal cell adenoma with canalicular adenoma,
ties. In 1996, Seifert and Donath defined a salivary Warthin’s tumor with sebaceous adenoma, and
gland tumor entity characterized by containing two or Warthin’s tumor with oncocytoma (1).
from collision tumors, which are a meeting of two

carcinomas arising from independent topographical
sites, and from synchronous and multiple tumors. It
has been reported that some salivary gland carcino-
mas may exhibit focal squamous, oncocytic, or seba-
ceous metaplasia (16–18). Obviously, such carcinomas
with metaplastic changes should not be considered as
containing two different carcinoma types. Some sali-
vary gland carcinomas such as acinic cell carcinoma
(19), adenoid cystic carcinoma (20–22), epithelial-
myoepithelial carcinoma (23), and polymorphous
low-grade adenocarcinoma (24,25) may rarely contain
a dedifferentiated carcinoma component with aggres-
sive growth. In contrast to the dedifferentiated ele-
ment, which may be either undifferentiated carcinoma
or poorly differentiated adenocarcinoma, hybrid car-
cinomas are composed of two forms of carcinoma
that fall into the exactly defined tumor categories of
the salivary glands. Carcinomas associated with pleo-
morphic adenoma include three distinct pathologic
Figure 153 Hybrid carcinoma. Tumor consists of two distinct entities: carcinoma ex pleomorphic adenoma, carcino-
histologic types: salivary duct carcinoma composed of solid sarcoma, and metastasizing pleomorphic adenoma.
tumor nests with comedonecrosis (right) and myoepithelial car-
Unlike these tumors, hybrid carcinomas are composed
cinoma with myxoid stroma (left).
of two distinct malignant epithelial tumor elements.

The proportion of each carcinoma component in
a tumor mass varies from case to case, but, as noted Of the 18 patients with hybrid carcinoma who were
above, the minor component should occupy at least followed up, 1 died of disease, 5 were alive with
10% of the area. Although two distinct carcinoma disease, and 12 were alive with no evidence of disease,
components are recognized, a transitional zone although the follow-up period was often short. Several
between them is always present. investigators have suggested that the aggressiveness
of hybrid carcinomas is determined by the histologi-
Immunohistochemistry cally higher-grade element, and the management
should be targeted at this tumor component.
Immunohistochemically, Ki-67 labeling index com-
monly differs between the two carcinoma elements
(6,8). It has been reported that diffusely positive p53 K. Intraosseous (Central) Salivary
immunoreactivity was observed only in the histologi- Gland Tumors
cally more aggressive component in each pair (6,8).
Furthermore, these p53-positive cases demonstrated Introduction
frequent loss of heterozygosity at p53 microsatellite
loci and p53 gene point mutations, which were Salivary gland tumors can rarely develop as intra-
detected only in the p53-immunoreactive carcinoma osseous neoplasms within the mandible and, less
component (6). Therefore, there is a possibility that commonly, the maxilla. Before a central origin can
such molecular-genetic events take an integral part be accepted, strict exclusion criteria need to be
for inducing the transformation from histologically applied. First, there should be no evidence of a prima-
lower to higher-grade tumor during the hybrid carci- ry salivary gland tumor elsewhere. In addition, there
noma oncogenesis. should be radiographic evidence of bone destruction
within intact cortical plates and a definite diagnosis of
Differential Diagnosis a salivary neoplasm (1,2). Proposed origins for these
tumors include heterotopic salivary tissue within the
The concept of hybrid carcinoma is subject to some maxillofacial skeleton, seromucous glands displaced
confusion, and careful diagnosis is required. Several from the maxillary antrum, and neoplastic transfor-
salivary gland tumor entities that exhibit two or more mation of odontogenic rests or cysts (3,4).
different morphologies should be ruled out before a
diagnosis of hybrid carcinoma is made (1,14). These
entities include collision tumors, synchronous and
Clinical Features
multiple tumors (14,15), carcinomas with metaplastic Intraosseous salivary gland tumors form about 3% of
change, dedifferentiated carcinomas, and carcinomas all minor gland neoplasms (2). The large majority
arising from pleomorphic adenomas. (*75%) arise in the mandible, where the posterior
The presence of a transitional zone between the body and angle are the most common sites. There is a
two carcinomatous components, suggesting their single case report of bilateral intramandibular adenoid
identical origin, differentiates hybrid carcinomas cystic carcinoma (5). About a third of cases are found
in association with a radicular cyst or an impacted treatment was 13% (1). However, this increased to
tooth (1), and these may be mistaken for dental 40% when conservative treatments such as marginal
pathology (6,7). There is a wide age distribution (1– resection or curettage were used (1). The rate of
85) years, with a mean age of about 50 years (1,4). metastatic disease is 9% in mucoepidermoid carcino-
Many cases are symptomless and are discovered ma but rises to 50% in adenoid cystic carcinoma.
during routine radiographic investigations. The most
common presenting complaint is swelling, and other
symptoms include pain, paresthesia or anesthesia, L. Soft Tissue Tumors
loosening or spontaneous avulsion of teeth, discharge,
and hemorrhage. Mesenchymal soft tissue tumors, other than hemato-
lymphoid tumors, are uncommon in the salivary
glands, accounting for 1.9% to 5% of all salivary
Pathology
gland tumors (1–5). Benign soft tissue tumors occur
The overwhelming majority of central salivary gland more commonly than sarcomas, with the ratio varying
tumors are malignant (*95%) (1,4). Mucoepidermoid from 18:1 to 2.4:1 (5). They are observed mainly in the
carcinoma is the most common tumor, forming 64% to major salivary glands, mostly the parotid gland, and
77% of the cases in two major series (1,4). The second only a few have been described as minor salivary
most frequent tumor is adenoid cystic carcinoma gland in origin. Virtually any entity of benign and
(11–18%) (8), with smaller numbers of adenocarcino- malignant soft tissue tumors can originate from the
ma NOS (3–4%), carcinoma ex pleomorphic adenoma salivary glands, but the frequency may differ accord-
(3–5%), and acinic cell carcinoma (2–3%). Other rare ing to the tumor types (1–7). Pathologic and biologic
central malignant salivary gland tumors include hya- features of each tumor are essentially identical to
linizing clear cell carcinoma (9), epithelial-myoepithe- those arising in other sites in the body, with a few
lial carcinoma (10), and salivary duct carcinoma (11). exceptions.
Benign tumors, which include pleomorphic adenoma Of the 220 cases of benign soft tissue tumors of
(12), myoepithelioma (13), and monomorphic adeno- the salivary glands deposited in the AFIP files, about
ma, are uncommon and account for about 5% of 40% are vascular tumors, followed by 30% neural
reported cases (1,4). tumors, 19% fibrous tumors, and 9% lipomas (2).
The most common vascular tumors are hemangiomas,
Differential Diagnosis especially the juvenile type in infants (8–10), followed
by lymphangiomas. Schwannoma and neurofibroma
The differential diagnosis of central mucoepidermoid are the two major neural tumors (Fig. 154), and other
carcinomas includes glandular odontogenic cyst rare tumors include extracranial meningioma (2).
(sialo-odontogenic cyst), clear cell odontogenic carci- Among the fibrohistiocytic/myofibroblastic tumor
noma, calcifying epithelial odontogenic carcinoma, groups, nodular fasciitis, fibrous histiocytoma, fibro-
and metastatic renal cell carcinoma. Both mucoepider- matosis, myofibromatosis, fibroma, desmoid tumor,
moid carcinoma and glandular odontogenic cyst can solitary fibrous tumor (Fig. 155) (11,12), and inflam-
have cystic components and may have areas showing matory pseudotumor (inflammatory myofibroblastic
nonkeratinized squamous epithelium and goblet cells. tumors) (13–15) have been described (2). However, the
However, glandular odontogenic cysts lack the inter- latter two tumors encompass a wide spectrum, rang-
mediate cells that are frequently a predominant com- ing from benign to low-grade malignancy, with a risk
ponent of mucoepidermoid carcinoma and may show of local recurrence but no significant metastatic poten-
characteristic whorled epithelial plaques. In addition, tial. Although lipoma is generally a quite common soft
the epithelium lining glandular odontogenic cysts is tissue tumor, salivary gland origin is rare, accounting
often columnar or pseudostratified columnar in type for less than 0.5% of all salivary gland tumors (4).
and frequently shows luminal blebbing or filiform Several microscopic variants of lipoma of the salivary
extensions. Furthermore, although glandular odonto- glands, such as angiolipoma, fibrolipoma, pleomor-
genic cyst is multilocular, it does not show the infil- phic lipoma, spindle cell lipoma, and sialolipoma,
trative growth pattern of mucoepidermoid carcinoma. have been reported (16–19). Miscellaneous other
In difficult cases, the differential staining of cytoker- tumors include granular cell tumor (Fig. 156), angio-
atin 18 in mucoepidermoid carcinoma and cytokeratin myoma (vascular leiomyoma), glomangioma, and
19 in glandular odontogenic cyst may aid distinction osteochondroma (2,5).
(14,15). The clear cell variant of calcifying epithelial Salivary gland sarcomas are very rare, accounting
odontogenic tumor usually contains either amyloid or for 0.5% of all salivary gland tumors and 1.5% of all
calcospherites or both. Clear cell odontogenic carci- salivary gland malignancies (4). Because of their rarity,
noma and metastatic renal carcinoma do not have a before making a diagnosis of salivary gland sarcomas,
squamous or intermediate cell component and lack many primary or metastatic neoplasms, such as ana-
evidence of intracellular mucin. plastic undifferentiated carcinoma, carcinosarcoma,
myoepithelial carcinoma, and metastatic malignant
Treatment and Prognosis melanoma, must first be excluded by careful clinical
and pathologic examinations, including extensive
Malignant intraosseous salivary gland tumors should immunohistochemical analysis. The 85 cases of salivary
be treated by radical surgical excision. The recurrence gland sarcomas in the AFIP files include hemangioper-
rate for mucoepidermoid carcinoma following such icytoma, malignant schwannoma (malignant peripheral
Figure 155 Solitary fibrous tumor arising in the parotid gland.

Tumor is composed of haphazardly arranged bland spindle cells
and occasional branched hemangiopericytoma-like vessels.
Figure 154 Benign neural tumors arising in the parotid gland.

(A) Schwannoma. Encapsulated, well-circumscribed tumor com-
posed of spindle cells arranged in an interlacing fascicular
pattern. (B) Neurofibroma. Multilobular appearance of the myx-
oid tumor is evident. Note the lack of a capsule.
Figure 156 Granular cell tumor arising in the parotid gland.

nerve sheath tumor), fibrosarcoma, malignant fibrous Note the large tumor cells with granular eosinophilic cytoplasm
histiocytoma (Fig. 157), rhabdomyosarcoma, malignant (inset).
hemangioendothelioma (angiosarcoma) (20), synovial
sarcoma, Kaposi’s sarcoma (21), leiomyosarcoma, lip-
osarcoma (22), and alveolar soft part sarcoma, in
descending order of frequency (3). However, there is reported: 16 such cases can be found in the literature
controversy as to whether hemangiopericytoma is a (Fig. 158) (23,24). Nine out of 16 cases (56%) of these
distinct clinicopathologic entity or only represents a salivary giant cell neoplasms were associated with a
histologic pattern, as hemangiopericytoma-like appear- carcinomatous component. Although it remains to be
ance may be observed at least focally in various tumors, determined whether giant cell neoplasms are an
including primarily solitary fibrous tumors. unusual type of carcinoma or a distinct mesenchymal
A few examples of epithelioid sarcoma, extra- tumor entity (extraskeletal giant cell tumor of bone), a
osseous chondrosarcoma, osteosarcoma, angiosar- recent immunohistochemical and genotypical study
coma, synovial sarcoma, desmoplastic small round supports the former hypothesis (23). The age range of
cell tumor, and primitive neuroectodermal tumor salivary sarcomas is from 1 to 93 years, with an
have also been described (3,7). Primary salivary average of about 50 years, which is generally older
gland tumors resembling giant cell tumor of the than that of benign soft tissue salivary tumors (23,24).
bone, consisting of mononuclear cells and scattered Many salivary gland sarcomas are high-grade
multinucleated giant cells, are rare but have also been neoplasms; the incidence of local recurrence is 40% to
cavernous types (4,10). Juvenile hemangioma is a

histologically immature form of capillary hemangio-
ma and has been previously referred to by various
terms, including benign infantile hemangioendothe-
lioma (8), infantile hemangioma, cellular hemangioma
of infancy, invasive hemangioma, immature capillary
hemangioma, juvenile hemangioma, and congenital
capillary hemangioma (9). Juvenile hemangioma is
the most common salivary gland tumor in infants.
Clinical features. Juvenile hemangioma occurs at
birth or in patients under the age of 12 months, most
commonly, in females. This contrasts with the much
older patients with average of 26 years and no gender
difference in the incidence of cavernous hemangioma
(8). Most juvenile hemangiomas involve the parotid
gland. Bilateral involvement is found in some
patients. Clinically, the patients usually present with
a progressively enlarging parotid swelling with no
sign of pain or tenderness, giving an erroneous
Figure 157 Malignant fibrous histiocytoma involving the parotid impression of malignancy. The overlying skin may
gland parenchyma. show blue discoloration that is accentuated when the
patient cries. Rarely, patients with juvenile hemangio-
ma have been associated with extensive hemangioma
development with thrombocytopenia and consump-
tive coagulopathy known as Kasabach-Merritt syn-
drome (4).
The majority (75–90%) of juvenile hemangiomas
spontaneously involute by the age of seven years (4).
In the past, the treatment of juvenile hemangioma was
primarily surgical removal of the tumor, including
total parotidectomy with sacrifice of the facial nerve.
Currently, however, it is recommended to delay oper-
ation as long as possible in the hope of seeing sponta-
neous regression, unless surgical intervention is
necessitated by clinical considerations (4). Corticoste-
roid and interferon therapy may be able to reduce the
tumor growth (9).
Pathology. Grossly, the tumor is characteristi-
cally composed of many hypertrophic lobules of sali-
vary gland with a gray-reddish color separated by fine
connective tissue. In most cases, the basic structure of
the parotid gland is maintained, and a tumor mass is
indistinct.
Microscopically, the tumor diffusely and uni-
Figure 158 Giant cell tumor arising in the parotid gland. Tumor formly involves the salivary gland lobules (Fig. 159A).
is composed of round or polygonal mononuclear cells admixed
The tumor cells produce solid cellular sheets with
with scattered multinucleated giant cells.
scattered vascular structures containing a few red
blood cells (Fig. 159B). Normal acini and intercalated
ducts are widely replaced by tumor cells, leaving only
scattered islets of these elements, while striated ducts
64%, distant metastases occur in 38% to 64%, and the are well preserved. The tumor consists of two types of
mortality rate is 36% to 64% (6,25). Complete and wide cells: endothelial cells and pericytes. The endothelial
surgical excision is the treatment of choice for salivary cells occasionally become plump, with mild nuclear
gland sarcomas. Postoperative radiation therapy and atypia (Fig. 159C). The pericytes are located outside the
chemotherapy may improve the outcome. endothelial basement membrane and have an oval or
In this section, two selected benign soft tissue rounded nucleus with relatively sparse chromatin.
tumors, juvenile hemangioma and sialolipoma, will be Mitotic figures range from rare to moderate in number,
discussed. Clinicopathologic details of other soft tis- but atypical mitoses are never seen. Reticulin fiber
sue neoplasms are available elsewhere (Chapter 13). staining is helpful in highlighting the small separated
cell clusters forming a vascular structure even in a solid
Juvenile Hemangioma cellular area (8).
Immunohistochemically, the endothelial tumor
Introduction. Hemangiomas of the salivary cells of juvenile hemangioma express factor VIII–related
glands are generally divided into capillary and antigen, CD31 (Fig. 159D), CD34, and glut-1 (26).
Figure 159 Juvenile hemangioma in the parotid gland. (A) Tumor diffusely and uniformly involves the parotid gland lobules, leaving
scattered striated ducts. (B) The tumor cells produce solid cellular nests with scattered vascular structures containing red blood cells.
(C) Proliferation of the plump endothelial cells with mild nuclear atypia. (D) Endothelial tumor cells are immunoreactive for CD31.
Differential diagnosis. The most important dif- conventional lipomas of the salivary glands. The
ferential diagnosis of juvenile hemangioma is angio- patients have been from birth to 84 years old, with
sarcoma. The presence of plump cells in juvenile an average of 55.7 years except for two congenital
hemangioma may cause confusion. In angiosarcomas, cases (19,27–29). Male cases are slightly more common
even in well-differentiated cases, plump cells exhibit than female ones. It occurs in both major and minor
more frequent mitotic figures and higher nuclear salivary glands. Eleven of the reported tumors arose
atypia than juvenile hemangioma. In addition, in the parotid gland, and eight in intraoral minor
clinically, angiosarcoma is extremely rare in infants. salivary glands including four involving the palate;
one case each occurred in the floor of the mouth,
tongue, and buccal mucosa.
Sialolipoma Sialolipoma presents as a slow-growing, painless
mass with the duration varying from 2 months to
Introduction. Sialolipoma is a recently described 10 years. CT and MRI show a well-circumscribed
variant of salivary gland lipoma defined by Nagao tumor with a low-intensity CT signal and high-inten-
et al. (19). It is histologically characterized by islands sity MRI signal. MRI may show scattered or heteroge-
of salivary gland parenchyma enclosed in mature neous glandular elements. No concurrent history of
lipomatous tissue. diabetes mellitus or chronic alcoholism has been
Clinical features. Sialolipoma is a rare, benign reported for any patient with sialolipoma. Superficial
neoplasm; at least 19 cases of a tumor with similar parotidectomy or, in the case of minor salivary gland
histologic features have been reported (19,27–29). Sia- origin, surgical excision is the appropriate treatment
lolipomas share similar clinical features with for this benign tumor.
Figure 160 Sialolipoma. (A) A well-circumscribed, yellow mass in the parotid gland. (B) Low-power view showing a tumor sharply
separated from the surrounding normal parotid gland tissue. The tumor is composed of mature lipomatous tissue with enclosed islands of
salivary gland parenchyma. (C) The glandular components closely resemble the cellular and structural features of a normal salivary
gland. (D) Oncocytic change in glandular component.
Pathology. Grossly, sialolipomas are well- with some minor variations. The salivary gland paren-
circumscribed, soft, and yellow or yellow-white, chymal tissue elements are either distributed sparsely
with a maximum dimension of 1 to 6 cm in the parotid or clustered throughout the tumor. Generally, the
gland (Fig. 160A) and 1 to 3 cm in the minor salivary glandular components are atrophic. Rarely, a small
glands. lymph node, peripheral nerve, or dense lymphoid
Histopathologically, the tumor is a well-circumscribed infiltration is seen at the tumor’s periphery. Focal
mass confined by a fibrous capsule and composed of oncocytic (Fig. 160D), sebaceous, and squamous meta-
mature adipose tissue and islands of salivary gland plasia may be observed in the glandular component.
parenchymal tissue (Fig. 160B). The amount of fatty Occasionally, marked ductal dilatation with fibrosis is
tissue in the tumor is higher than that observed in evident. Myxoid change can occur in the adipose
adjacent nontumorous salivary gland tissue. However, element. It is likely that the glandular components in
the area occupied by the lipomatous component may sialolipoma become entrapped during lipomatous
differ, depending on the site of origin. Tumors in the proliferation, rather than representing true neoplastic
parotid gland have a greater abundance of adipose elements.
tissue, usually constituting 90% or more of the tumor, Ultrastructurally, the glandular elements, con-
than those in minor salivary glands. sisting of ductal, acinar, basal, and myoepithelial
The glandular component consists of ductal, cells have features compatible with those observed
acinar, basal, and myoepithelial cells without atypia, in the parenchyma of normal parotid gland. The
and closely resembles the cellular and structural fea- adipose cells have lipid droplets without tonofila-
tures of a normal salivary gland (Fig. 160C), albeit ments or myofilaments.
Immunohistochemical studies confirm that the with approximately 70% of cases, but the submandib-
glandular components within the tumor are com- ular glands and minor salivary glands are also
posed of regularly organized ductal, acinar, and involved in the incidence of 20% to 25% and 5% to
myoepithelial cell elements that have cell-specific 10%, respectively (1). About 10% of the tumors arise in
phenotypes of normal glands. Focally observed onco- multiple glands (1). Usually, the salivary gland lym-
cytic cells are strongly immunoreactive for mitochon- phoma presents clinically as a slow-growing salivary
dria. The adipose cells stain positively for S-100 gland swelling in a patient over 50 years old.
protein. Cell proliferative activity, as assessed by The majority of the primary salivary gland lym-
Ki-67 immunostaining, is low. phomas are non-Hodgkin lymphomas of B-cell type;
Differential diagnosis. Several salivary gland both Hodgkin lymphomas and T-cell lymphomas are
conditions or tumors with lipomatous components extremely rare (5,6). The most common non-Hodgkin
might be confused with sialolipoma (19). The presence lymphomas arising in the salivary glands are extra-
of a fibrous capsule distinguishes sialolipomas from nodal marginal zone B-cell lymphomas (MALT lym-
lipomatosis, which constitutes a nontumoral deposi- phomas), which account for up to 80% of lymphoma
tion of adipose tissue throughout the gland, resulting cases (5,7). This type of non-Hodgkin lymphoma
in its diffuse enlargement. Lipomatosis may occur in develops in the setting of acquired lymphoid tissue
association with diabetes mellitus, liver cirrhosis, secondary to long-standing chronic inflammation or,
chronic alcoholism, malnutrition, and hormonal dis- more commonly, to an autoimmune process, such as
turbance, although the exact pathophysiology is still Sjögren’s syndrome (7–11). Other non-Hodgkin lym-
unclear. Unlike lipomatosis, the patients with sialoli- phomas involving the salivary glands are usually
poma do not have any of these conditions. In the considered to arise in lymph nodes adjacent to or
parotid gland, advancing age is accompanied by aci- embedded within the gland and extending into the
nar atrophy together with the increase in adipose glandular parenchyma (5). These include follicular
tissue. Sialolipoma, however, shows that the propor- lymphoma (Fig. 161), diffuse large B-cell lymphoma,
tion of adipose tissue elements in the tumor is obvi- and small lymphocytic lymphoma, with the former
ously higher than that in nontumorous salivary gland two tumors being the most commonly reported, but
tissue, regardless of age. almost all types of nodal lymphomas can occur (5). It
Recently, a few case reports of similar tumors is important to recognize that the natural history and
have been published; these were categorized as ‘‘lip- the therapeutic approaches of these nodal-type lym-
oadenomas’’ (30) and ‘‘oncocytic lipoadenomas’’ (31). phomas are different from those of MALT lymphoma
In the former, the glandular tumor components are (5). Diffuse large B-cell lymphomas may develop de
described as tubules showing a sertoliform pattern novo or secondarily by transformation from either
without myoepithelial cells and acinar differentiation. MALT lymphoma or follicular lymphoma. Rarely,
Such unique findings are absent, while both myoepi- low-grade lymphomas, in particular, follicular lym-
thelial and acinar cells are present in sialolipomas. phoma, may arise in the lymphoid tissue of Warthin’s
Unlike sialolipomas, the latter tumors are character- tumors (12). The histopathologic features and progno-
ized by diffuse oncocytic metaplasia of the glandular sis of these other non-Hodgkin lymphomas in the
elements. In contrast, the metaplastic change is only salivary glands are identical to those of primary
focally observed, if at all, in sialolipomas. However, nodal disease of the same type (5).
since sialolipoma and lipoadenoma share many com- Comprehensive reviews and textbooks dealing
mon histologic features, it is a subject of debate with these fields are currently available elsewhere
whether these are distinct salivary gland tumors or
belong to the same tumor spectrum.
Pleomorphic adenomas rarely contain extensive
fatty components, but if these components are present,
they may derive from the pluripotential reserve cells
of pleomorphic adenoma via a metaplastic process
(32). Such a rare variant of pleomorphic adenoma
should also be considered in the differential diagnosis
of sialolipoma. In sialolipoma, however, the epithelial
components are sharply separated from the adipose
element. In addition, the presence of normal-
appearing acinar cells may exclude the possibility of
pleomorphic adenoma.
M. Malignant Lymphomas
Primary salivary gland lymphomas are uncommon,
accounting for less than 5% of lymphomas of all sites,
10% of lymphomas arising in the head and neck, and
2% of all salivary gland tumors (1–5). The most Figure 161 Follicular lymphoma involving the parotid gland.
common sites of occurrence are the parotid gland,
(5,7,10,13). In this section, only extranodal marginal hepatitis C virus (HCV) infection and in immunocom-
zone B-cell lymphoma (MALT lymphoma) is petent children (7–11). However, the role of hepatitis
discussed. C virus (HCV) in the pathogenesis of MALT lympho-
ma remains to be defined (21). Monoclonal gammop-
Extranodal Marginal Zone B-Cell Lymphoma athy may be present.
(MALT Lymphoma) MALT lymphoma occurs predominantly in
patients aged 55 to 65 years, with an average of
Introduction. Since Isaacson and Wright first 61 years, mainly in women (5). Most MALT lympho-
described MALT lymphoma of the gastrointestinal mas arise in the parotid gland, but small numbers of
tract in 1983 (14), this type of lymphoma has been cases have been reported in the submandibular, sub-
found in many other organs, such as the salivary lingual, and minor salivary glands (5). Bilateral parot-
gland, thyroid gland, lung, skin, conjunctiva, breast, id involvement of MALT lymphoma may occur. The
and larynx (13,15). The salivary gland is the second patients typically present with a painless, slowly
most common site of involvement of MALT lympho- progressive swelling of the parotid area. The regional
ma following the stomach, which is far more frequent- lymph nodes may be enlarged because of involve-
ly affected, accounting for 70% of all cases (13,15). ment, but general lymphadenopathy and bone mar-
The characteristic feature of MALT lymphoma is row involvement are unusual in MALT lymphoma.
the proliferation of small- to medium-sized marginal Pathology. Grossly, the tumor presents as an ill-
zone cells that infiltrate the ductal epithelium, forming defined, firm mass, yellow to tan on the cut surface. It
lymphoepithelial lesions. Thus, MALT lymphomas is usually homogeneous, but microcysts may be
are now definitively considered as extranodal margin- observed.
al zone B-cell lymphomas (5,9,13). MALT is not nor- Histologically, the tumor entirely or partially
mally present in salivary glands, but it may be replaces the salivary gland parenchyma by a dense
acquired as a result of chronic inflammatory or auto- lymphoid infiltrate (Fig. 162), but in either case, lobu-
immune processes that leads to the pathologic condi- lar structure may be maintained. Features of LESA are
tion referred to as lymphoepithelial sialadenitis usually present. MALT lymphoma is characteristically
(LESA), which was formerly reported as myoepithe- composed of a diverse range of lymphoid cells with
lial sialadenitis or benign lymphoepithelial lesion. reactive lymphoid follicles and formation of lymphoe-
MALT lymphomas usually arise in the context of pithelial lesions. The neoplastic cells infiltrate sur-
LESA in patients with Sjögren’s syndrome. The trans- rounding reactive secondary lymphoid follicles in a
formation from LESA to MALT lymphoma is postu- marginal zone distribution and spread outward to
lated to be a multistep process (7,17). Chronic long- form diffuse interfollicular sheets or, in some cases,
term immune stimulation will promote proliferation a vaguely nodular pattern.
of the lymphoid cells, and there may be selection or The neoplastic lymphoid cells include centrocyte-
emergence of one or more dominant B-cell clones. like (cleaved) cells, monocytoid B cells, small lymphoid
Sequentially, sufficient genetic alterations may lead cells, lymphoplasmacytic and plasma cells, and large
to clonal escape from control of proliferation, and transformed cells in varying numbers. Monocytoid B
overt lymphoma could eventually develop. Therefore, cells are described as medium-sized cells with lobated
the monoclonality in itself could be identified in or indented nuclei and abundant, pale cytoplasm,
lymphoproliferative disorders with lack of morpho- often with distinct cell borders. Centrocyte-like cells
logic features of lymphoma (7–10,16–20). These lesions are slightly smaller cells with less cytoplasm than
are considered by different authors as pseudolympho- monocytoid B cells, resembling marginal zone B cells
mas or prelymphomas, as neoplasms of ‘‘uncertain (7). In some cases, plasma cell differentiation may be
malignant potential’’ or as early true lymphomas. prominent. In about half of the cases, the neoplastic
Various criteria have been utilized to define lymphoplasma and lymphoplasmacytic cells may contain
ma, although none is universally accepted (7–10,16– PAS-positive Dutcher bodies in their nuclei.
20). Whatever the event, MALT lymphomas are often One of the most important histologic hallmarks
localized at presentation and are usually indolent of MALT lymphoma is the presence of lymphoepithe-
disease entities with a prolonged course; sometimes lial lesions, defined by the infiltration and distortion
they involve different anatomic sites and, after some of epithelial structures by aggregates of neoplastic
years, may develop into high-grade lymphoma (7,9). lymphoid cells, usually monocytoid B cells or centrocyte-
Clinical features. MALT lymphoma usually like cells (Fig. 162C). The affected ducts are often
arises in the patients with a preceding history of hyperplastic with luminal obliteration or, occasional-
LESA induced by an autoimmune disease, most ly, cystic dilatation, causing a multicystic appearance.
often Sjögren’s syndrome. The period of LESA pre- The early histologic manifestation of the emergence
senting prior to the development of MALT lymphoma of MALT lymphoma in LESA is the presence of haloes
varies, ranging from 6 months to 29 years (9). About or collars of pale monocytoid B cells and centrocyte-
4% to 7% of patients with Sjögren’s syndrome will like cells around the epimyoepithelial islands (lym-
develop lymphoma, and the risk of MALT lymphoma phoepithelial lesion) (Fig. 162A) (5). Areas of these
in Sjögren’s syndrome is 44 times higher than in the tumor cells gradually expand and form broad bands,
normal population (7,10). Development of salivary often linking together several lymphoepithelial lesions
gland MALT lymphoma has also been described in or diffuse sheets, which eventually replace reactive
patients with human immunodeficiency virus and follicles (Fig. 162B). On the other hand, some reactive
follicles may be infiltrated by monocytoid B cells (‘‘fol-

licular colonization’’). Additionally, there may be aggre-
gation of epithelioid histiocytes and foci of sclerosis.
Large centroblast- or immunoblast-like cells are
typically scattered throughout the tumor. However, in
some cases, there are considerably increased numbers
of large cells within a typical MALT lymphoma. The
exact criteria for the diagnosis of large-cell transfor-
mation of MALT lymphoma are not well defined, but
the presence of sheets of large transformed cells is
thought to represent high-grade transformation (7,9).
Although diffuse large B-cell lymphoma can occur de
novo or from preexisting MALT lymphoma, with an
aggressive behavior, the prognostic significance of the
large-cell transformation in MALT lymphoma still
remains to be elucidated (7,9). The current WHO
classification of tumors of hematopoietic and lym-
phoid tissues recommends that cases showing trans-
formation to large cell lymphoma should be
diagnosed as diffuse large B-cell lymphomas, and
the presence of accompanying MALT lymphomas
should be noted (13). The term ‘‘high-grade MALT
lymphoma’’ is confusing and should be avoided.
Immunohistochemistry. The lymphoid tumor
cells of MALT lymphoma express B-cell markers, such
as CD19, CD20 (Fig. 163A, left), CD22, and CD79a, but
are negative for CD3 (Fig. 163A, right), CD5, CD10,
CD23, bcl-6, and cyclin D1 (5,9). Demonstration of
immunoglobulin light-chain restriction is helpful to
prove the neoplastic nature of the lesion; monotypic
immunoglobulin light chain with kappa is seen more
often than that with lambda (Fig. 163B) (9). The B cells
of MALT lymphoma may be aberrantly positive for
CD43 (9). The intrafollicular neoplastic, colonizing B
cells are often immunoreactive for bcl-2, but residual,
reactive germinal center cells are negative (5). Staining
for cytokeratin is useful to reveal lymphoepithelial
lesions or scattered epithelial cell remnants.
Differential diagnosis. The differential diagnoses
of MALT lymphoma include LESA and certain types
of nodal non-Hodgkin lymphomas, such as follicular
lymphoma, small lymphocytic lymphoma, and mantle
cell lymphoma (5,9).
Distinguishing LESA from MALT lymphoma
remains controversial and may be challenging on the
basis of histologic examination alone. In such circum-
stances, immunophenotypic analyses for monoclonal-
ity or molecular studies are often required. The
presence of haloes of monocytoid B cells surrounding
the epimyoepithelial islands (lymphoepithelial lesion)
and coalescence of centrocyte-like and monocytoid B
cells into broad bands or sheets support the diagnosis
of MALT lymphoma rather than LESA. Cytologic
atypia, plasma and lymphoplasmacytic cells with
Figure 162 MALT lymphoma. (A) The early stage of MALT Dutcher bodies, and epithelioid histiocytes are associ-
lymphoma. Note the presence of haloes or collars of pale ated with lymphoma rather than LESA. Detection of
monocytoid cells around the lymphoepithelial lesions. (B) The immunoglobulin light-chain restriction by immuno-
well-developed stage of MALT lymphoma showing scattered histochemistry or flow cytometry is considered diag-
lymphoepithelial lesions in diffuse sheets of monocytoid cells. nostic of MALT lymphoma. However, LESA may
(C) Lymphoepithelial lesion formed by the infiltration of mono- show evidence of oligoclonality or monoclonality
cytoid cells in the proliferation of duct epithelial cells. Abbrevia- revealed by gene rearrangement analysis, suggesting
tion: MALT, mucosa-associated lymphoid tissue.
that the monoclonal populations may arise within this
process and eventually emerge in the development of
Figure 163 MALT lymphoma. Immunohistochem-

istry. (A) The lymphoid tumor cells at both inside
and outside of the lymphoepithelial lesion diffusely
express CD20 (left) but are negative for CD3 (right).
(B) Immunoglobulin light chain restriction. Many
kappa light chain-positive cells are seen in the left,
whereas only scattered lambda-positive cells are
identified in the right. Abbreviation: MALT, mucosa-
associated lymphoid tissue.
frank lymphoma. Therefore, demonstration of mono- lymphomas (7–10,16–20). In the literature, trisomies 3
clonality by molecular methods is not sufficient to and 18, and four distinct chromosomal translocations
establish a diagnosis of lymphoma. An extensive, have been demonstrated in MALT lymphoma of vari-
dense infiltrate of B cells and aberrant expression of ous anatomic sites: t(11;18)(q21;q21): API2-MALT1, t
CD43 in the neoplastic B cells are also highly sugges- (14;18)(q32;q21): IGH-MALT1, t(1;14)(p22;q32): BCL10-
tive of lymphoma. IGH, and t(3;14)(p14.1;q32): IGH-FOXP1 (22–28). These
The infiltration of neoplastic B cells into reactive different chromosomal translocations share the final
follicles in MALT lymphoma may produce a promi- common pathway leading to the activation of nuclear
nent nodular appearance, leading to confusion with factor-kB, a transcription factor that regulates the
follicular lymphoma. Although both colonized B cells expression of genes associated with lymphocyte pro-
in MALT lymphoma and tumor cells of follicular liferation and survival. The specific translocations
lymphoma may be positive for bcl-2, only the latter occur at variable frequencies in MALT lymphomas
express germinal center cell markers, such as CD10 depending on the sites. The t(11;18)(q21;q21): API2-
and bcl-6. Alternatively, small lymphocytic lympho- MALT1 is the most common chromosomal transloca-
ma and mantle cell lymphoma are characteristically tion, found most often in gastric and pulmonary cases
immunoreactive for CD5 coexpressing CD23 and but uncommonly in MALT lymphomas of the salivary
cyclin D1, respectively, but MALT lymphoma is con- glands. The t(14;18)(q32;q21): IGH-MALT1 is found
sistently negative for these markers. most often in MALT lymphomas arising at nongastric
Molecular-genetic data. Monoclonal rearrange- sites including the salivary glands and is identified in
ments of both heavy- and light-chain immunoglobulin approximately 20% of cases. The t(1;14)(p22;q32):
genes are detected in the majority of MALT BCL10-IGH is rarely detected in salivary MALT
lymphomas, resulting in strong aberrant nuclear bcl- or paraparotid lymph nodes or the salivary gland
10 immunostaining. MALT lymphomas harbor t(3;14) parenchyma. The most common primary tumors are
(p14.1;q32): IGH-FOXP1–comprising tumors of the squamous cell carcinomas and malignant melanomas,
thyroid, ocular adnexa, and skin but not those of the which together account for nearly half of parotid
salivary glands. metastases. Other relatively less common tumor
Treatment and prognosis. Most MALT lympho- types include poorly or undifferentiated carcinomas,
mas have a favorable outcome with five-year survival adenocarcinomas, and carcinomas or malignant
of 85%, and the tumor usually remains localized to the tumors (NOS). Metastases from sarcomas and neural
salivary gland, often for many years (5,9). Lymph malignancies are exceptionally rare. Clear cell carcino-
node involvement is usually a late event and may mas, including tumors from the kidney and thyroid
involve intraglandular lymph nodes or adjacent cervi- gland, may be difficult to distinguish from primary
cal lymph nodes. The prognosis of the patients with salivary neoplasms. The differential diagnosis of clear
lymph node involvement is similar to that of primary cell malignancies is discussed in page 562. Some sali-
nodal low-grade B-cell lymphomas. Dissemination to vary gland tumors, particularly acinic cell carcinoma
other sites is uncommon in MALT cases, but can and mucoepidermoid carcinoma, can have abundant
include the lung, conjunctiva, or stomach. Typical tumor-associated lymphoid proliferation. This should
low-grade MALT lymphoma may undergo transfor- not be interpreted as lymph node metastases (5).
mation into frank diffuse large B-cell lymphoma.
Although the optimal management of MALT
lymphoma remains to be established, local treatment Treatment and Prognosis
with surgical excision, if possible, or radiotherapy
Metastatic tumors in the parotid region are often
seems appropriate. Subsequent chemotherapy may
associated with a very poor prognosis, with five-year
be necessary in case of disseminated disease.
survival rates of 11.5% and 14.5% for melanoma and
squamous cell carcinoma, respectively (6). The prog-
N. Secondary Tumors nosis for noncutaneous metastases appears to be even
worse (7). In more recent studies, there appears to
Introduction have been an improvement in the survival rates (8).
A secondary tumor of salivary glands is defined as ‘‘a
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Index
AAD. See Acroangiodermatitis (AAD) Acyclovir, 1673 ALCD. See Anterior lingual cortical defect
ABC. See Aneurysmal bone cyst (ABC) Addison’s disease, 1460 (ALCD)
ABCD. See Anterior buccal cortical defect Adenocarcinoma, 578–580 ALCL. See Anaplastic large cell lymphoma
(ABCD) of left supraclavicular lymph node, 1151 (ALCL)
AC. See Atypical carcinoid (AC) Adenocarcinomas Alcohol, oral cancer, 288
Acanthamoeba keratitis, 1571–1572 ceruminal gland, 462–463 ALHE. See Angiolymphoid hyperplasia
Acantholytic actinic keratosis (AK), 1491 intestinal-type, 383–387 with eosinophilia (ALHE)
Acantholytic squamous cell carcinoma middle ear, 466–467 ALK+ anaplastic large cell lymphoma,
(ALSCC), 159–160 of nasal cavity/paranasal sinuses, 1065–1068
clinical features, 160 classification, 383 clinical features, 1066
diagnosis, 160 nonintestinal-type, 387–389 differential diagnosis, 1068
etiology, 159–160 Adenoid cystic carcinomas (ACC), 23, immunohistochemistry, 1066–1067
overviews, 159 24–25, 76, 168–169, 178, 390, molecular genetic data, 1067–1068
pathology, 160 552–557 pathology, 1066
treatment, 160 Adenoid hyperplasia, 225–226 ALK- anaplastic large cell lymphoma, 1068
Acanthosis, 253 pathology, 226 ALK+ DLBCL, 1042
ACC. See Adenoid cystic carcinomas (ACC) treatment, 226 ALK gene, 1042
Accessory tragi, 425–426 Adenoid squamous carcinomas, 313–314 Allergic fungal rhinosinusitis (AFRS),
Acinar cells, 20, 27 Adenomatoid nodules. See Hyperplastic 354–356
Acinic cell carcinomas, 29–30, 390, 542–546 nodules clinical features, 355
Acne keloidolis, 1342 Adenomatoid odontogenic tumor (AOT) etiology, 355
Acoustic neuromas, 454–455, 691–692 AMBN mutation, 1240 pathology, 355–356
Acquired cholesteatomas, 436–437 differential diagnosis, 1240 treatment, 356
Acquired encephalocele, 440 electron microscopy of, 1239–1240 Allergic fungal sinusitis (eosinophilic mucin
Acquired melanosis, 1560–1561 imaging, 1236–1237 rhinosinusitis)
Acquired nonneoplastic lesions, 427–432 immunohistochemistry, 1238–1239 clinical presentation, 1633
cholesterol granulomas, 430 pathology and pathogenesis, 1238 etiology, 1633
inflammatory otic polyps, 431 patterns of, 1237 histopathology, 1633–1634
malakoplakia, 431–432 prevalence and incidence, 1235–1236 treatment, 1634
necrotizing malignant external otitis treatment and prognosis, 1240 Allergic granulo matosis and vasculitis
(NEO), 427–428 Adenosine triphosphate–binding cassette (AGV). See Churg-Strauss syndrome
otitis media, 428–429 transporter A1 (ABCAL1), 1730 Allergic mucus, 354–356
tympanosclerosis, 429–430 Adenosquamous carcinomas, 158–159, Allergic rhinosinusitis, 343–345
Acroangiodermatitis (AAD), 1522 312–313 Alopecia, 252
Actinic cheilitis, 279–280 clinical features, 158 ALSCC. See Acantholytic squamous cell
clinical features, 279 diagnosis, 159 carcinoma (ALSCC)
defined, 279 etiology, 158 Alternaria, 1640
diagnosis, 280 immunohistochemistry, 159 Alveolar cysts, 1343
pathology, 280 overviews, 158 Alveolar mucosa, squamous cell carcinomas
treatment, 280 pathology, 158–159 of, 298–300
Actinic keratosis (AK) treatment, 159 Alveolar RMS (ARMS), 869, 872–873
clinical features, 1489–1490 Adipose tissue, 20 Alveolar soft part sarcoma (ASPS), 901–904,
differential diagnosis, 1490–1491 Adult onset laryngeal papillomas, 1677 1363
histologic features, 1490 Adult T-cell leukemia/lymphoma, 1072 in children, 1346
imaging studies, 1490 AFD. See Ameloblastic fibrodentinoma Amalgam tattoo, 204–205
immunohistochemical studies, 1490 (AFD) clinical features, 205
treatment and prognosis, 1491 AFIP. See Armed Forces Institute of pathology, 205
Actinomyces, 1621 Pathology (AFIP) treatment, 205
Actinomyces spp, 953, 1013 Afipia felis, 1011 AMCA. See Ameloblastic carcinoma (AMCA)
Actinomycoses AFOD. See Ameloblastic fibro-odontoma Ameloblastic carcinoma (AMCA), 1292
clinical background, 1620–1621 (AFOD) differential diagnosis, 1295
etiology, 1621 Aggressive osteoblastoma, 970 DNA microarray study, 1295
histopathology, 1621 AIDS, 50 etiology of, 1293–1294
treatment, 1621 AIDS-related lymphomas, 1667 frequency of, 1293
Acute bacterial rhinosinusitis, 345 AIDS-related nasopharyngeal lesions, 1661 gender ratio, 1293
Acute bacterial sinusitis, 345 AIDS-related parotid cysts (ARPC), growth rate, 1293
Acute exacerbation of chronic sinusitis 1660–1661 immunohistochemistry, 1294
(AECS), 1609 AIDS toxoplasmosis, 1688 locations of, 1293
Acute myeloid leukemia, 1355 AIF. See Apoptosis inducing factor (AIF) ultrastructure of, 1294
Acute necrotizing ulcerative gingivitis and apoptotic cell death Ameloblastic fibrodentinoma (AFD)
(ANUG), 259 AJCC. See American Joint Committee on clinical features, 1247
Acute suppurative osteomyelitis Cancer (AJCC) immunohistochemistry
pathologic features, 958–959 AJCC 2002 melanoma staging, 1508 neural tissue markers, 1248
radiologic features, 958 AK. See Actinic keratosis (AK) pathogenesis of, 1247–1248
Acute suppurative sialadenitis, 484–485 Albendazole, 1690 treatment and prognosis, 1248
Acute thyroiditis, 4, 1391–1392 Albright’s hereditary osteodystrophy, 1460 ultrastructure of, 1248
I-2 Index Volume 1: 1–648; Volume 2: 649–1200; Volume 3: 1201–1734
Ameloblastic fibroma (AMF) Anaplastic large cell lymphoma (ALCL), Apocrine hidrocystomas, 1484
clinical features, 1241–1242 42–43 Apoptosis inducing factor (AIF) and
differential diagnosis, 1245–1246 ALK+, 1065–1068 apoptotic cell death, 1212
etiology of, 1242–1244 ALK-, 1068 Apoptotic protease activating factor-1
imaging of, 1242 ANCA. See Antineutrophil cytoplasmic (APAF-1) and apoptotic cell death,
immunohistochemistry, 1244 autoantibodies (ANCA) 1212
molecular-genetic data, 1245 ANCA titers. See Antineutrophil AR. See Androgen receptor (AR)
treatment and prognosis, 1246–1247 cytoplasmic antibodies (ANCA) titers Argyrophilic nucleolar organizer regions
ultrastructure of, 1245 Ancillary studies, of lymph nodes, 39–40 (AgNORs), 1479
Ameloblastic fibro-odontoma (AFOD) cell block, 39 Armed Forces Institute of Pathology (AFIP),
clinical features, 1248–1249 core needle biopsy, 39 976
differential diagnosis, 1252 FISH studies, 40 ARMS. See Alveolar RMS (ARMS)
etiology of, 1249–1250 flow cytometry, 39–40 Arteriovenous hemangioma (arteriovenous
immunohistochemistry PCR studies, 40 malformation)
CK in epithelial component of, 1250 Androgen receptor (AR), 31 clinical findings, 776–777
enamel proteins in, 1251 Aneuploidy, 713 differential diagnosis, 778–779
growth factors, 1251 Aneurysmal bone cyst (ABC), 963, 986–987 imaging, 777
MIB-1 antibody, 1251 Angiofibroma immunohistochemistry, 778
nestin and vimentin, 1251 clinical features, 834 pathologic findings, 777–778
molecular-genetic data, 1252 differential diagnosis, 836 prognosis and treatment, 779
osteocalcin transcripts and, 1252 electron microscopy, 836 Arthralgia, 253
radiographs, 1249 imaging, 834–835 Aspergillosis
treatment and prognosis, 1252 immunohistochemistry, 836 acute fulminant invasive, 1630
ultrastructure of, 1251–1252 molecular-genetic data, 836 chronic invasive/chronic granulomatous,
Ameloblastomas, 69 pathology, 835–836 1631–1632
ameloblastin (AMBN) gene mutations in, treatment and prognosis, 836–837 histopathology, 1630–1631
1213 Angiofibromas, 64 historical background, 1629–1630
amelogenin and, 1213 Angioimmunoblastic T-cell lymphoma, 1064 serology, 1631
differential diagnosis, 1214 Angiolymphoid hyperplasia with treatment, 1631
molecules involved in progression of eosinophilia (ALHE) Aspergillus flavus, 1630
angiogenic factors, 1214 clinical features, 1528 Aspergillus fumigatus, 354
cell adhesion molecules, 1213 defined, 1528 Aspirin, 968
matrix-degrading proteinases, differential diagnosis, 1529 intolerance, 346–347
1213–1214 electron microscopy, 1529 ASPS. See Alveolar soft part sarcoma
osteolytic cytokines, 1214 imaging studies, 1528 (ASPS); Alveolar soft part sarcoma
treatment and prognosis, 1214–1215 immunohistochemistry, 1529 (ASPS)
tumorigenesis and/or cell differentiation, molecular genetics, 1529 Asteroid bodies, 1693
molecules involved in pathology, 1528 Ataxia-telangectasia (AT), 1667
apoptosis-related factors, 1212 treatment and prognosis, 1529 Ataxia-telangiectasia syndrome, 1523
cell cycle-related factors, 1212 Angiomatoid fibrous histiocytoma (AFH). AT-mutated (ATM) gene, 1667
DNA-repair genes, 1211 See Malignant fibrous histiocytoma Atrophic rhinosinusitis (ARS), 346
gene modifications and, 1210–1211 Angiosarcoma, 867–869, 982–983, 1415–1416 Atypia, 130
growth factors, 1211–1212 Angle recession, 1584 Atypical carcinoid (AC), 164–166
hard tissue-related proteins, 1213 Annexin V activity and apoptotic cells clinical features, 164
oncogenes, 1210 detection, 1212 diagnosis, 165
oncoviruses, 1211 Anterior buccal cortical defect (ABCD), 963 electron microscopy, 165
telomerase activity, 1212 Anterior lingual cortical defect (ALCD), 963 immunohistochemistry, 165
tooth development, regulators of, 1213 Anthelmintics, 1690 pathology, 164
tumor suppressor genes, 1211 Anthracosis, 1444 treatment, 165–166
Amelogenin and calcifying odontogenic cyst Antibiotics, 260 Atypical fibroxanthoma (AFX), 463–464,
(COC), 1265 Anticonvulsants drugs, 260 1494–1495
American College of Rheumatology, 253, Antifungal therapy, 257 clinical features, 1520
652 Antigen, 249 differential diagnosis, 1521
American Joint Committee on Cancer Antimalarial drugs, 254 electron microscopy, 1521
(AJCC), 863 Antimicrobial therapy, 37 immunohistochemistry, 1521
staging of nasopharyngeal carcinomas, Antineutrophil cytoplasmic antibodies molecular genetics, 1521
396 (ANCA) titers, 441 pathology, 1520–1521
staging of vestibular carcinomas, 373 Antineutrophil cytoplasmic antibodies/ treatment and prognosis, 1521
AMF. See Ameloblastic fibroma (AMF) autoantibodies (ANCA), 649, 650 Atypical keratinocytes, 1489
5-aminolevulinic acid, 1488 cytoplasmic (C-ANCA), 650 Atypical lymphoid hyperplasia, 1081
Amiodarone drugs, 1386 perinuclear (P-ANCA), 650 Atypical lymphoreticular cells, 652
Amphotericin B, 1631, 1637, 1652 Antineutrophil cytoplasmic autoantibodies Atypical marginal zone hyperplasia, of
Ampicillin-sulbactam, 1611 (ANCA) tonsil, 1093
Amputation neuroma. See Traumatic in Wegener’s granulomatosis, 443–444 Atypical teratoid/rhabdoid tumor, 1363
neuroma Antinuclear antibodies (ANA), 252 Auditory canal
Amyloid, 14 Anti-PTH immunohistochemistry, 1434 external. See External auditory canal
Amyloid goiter, 1391 Antoni type A, 679 mlignant neoplasms of, 459–464
Amyloidosis, 484, 1027–1029 Antrochoanal polyps (ACP), 350–351 Auricular cartilage
classification, 1028 ANUG. See Acute necrotizing ulcerative of idiopathic cystic chondromalacia,
clinical features, 1028–1029 gingivitis (ANUG) 433–434
pathology, 1029 AOT. See Adenomatoid odontogenic tumor Autoimmune diseases, 952
ANA. See Antinuclear antibodies (ANA) (AOT) Autoimmune hypoparathyroidism, 1460
Anaplastic carcinoma, 14–15 APAF-1. See Apoptotic protease activating Autoimmune lymphoproliferative
clinical features, 1407 factor-1 (APAF-1) and apoptotic cell syndrome, 1024–1025
molecular genetics, 1408–1409 death Autoimmune polyendocrinopathy-
pathology, 1408 Aplasia, of salivary glands, 476–477 candidiasis-ectodermal dystrophy
treatment and prognosis, 1409 Aplasia cutis congenital (ACC), 1537 (APECED), 1460
Volume 1: 1–648; Volume 2: 649–1200; Volume 3: 1201–1734 Index I-3
Autoimmune polyglandular Basosquamous cell carcinoma (BSCC) Biphasic synovial sarcoma. See Synovial
syndrome-1, 1460 clinical features, 1498–1499 sarcoma
Autotransplantation, of parathyroid glands, differential diagnosis, 1499 Bipolaris, 1639–1640
1462–1463 imaging studies, 1499 Birefringent oxalate crystals, 954
Azathioprine, 257, 1693 immunohistochemistry, 1499 Blastic plasmacytoid dendritic cell
Azithromycin, 1689 pathology, 1499 neoplasm, 1077–1078
treatment and prognosis, 1499 Blastomycosis, 1642, 1648–1651
B-cell lymphoma Blue rubber bleb syndrome, 1523
Bacillary Angiomatosis (BA) intravascular large, 1042 B- lymphocytes, 952, 953
clinical presentation, 1628 primary mediastinal (thymic) large, BMP. See Bone morphogenetic protein
culture, PCR, and serological 1041–1042 (BMP), in ameloblastomas
identification, 1628 T-cell/histiocyte-rich large, 1042 BMZ. See Basement membrane zone (BMZ)
differential diagnosis, 1628 B-cells, 39 Bohn’s nodules, 1343. See also Oral cavity
etiology, 1628 lymphoblastic leukemia/lymphoma, 1060 Bone, hematolymphoid lesions of, 1108–
histopathology, 1628 Bcl-2 and inhibitor of apoptosis (IAP) family 1109
treatment, 1628 proteins, modulators of Bone morphogenetic protein (BMP), in
Bacilli Calmette-Guerin (BCG), 1623 mitochondrial apoptotic pathway, ameloblastomas, 1213
Bacterial conjunctivitis, 72 1212 Bone sialoprotein (BSP), in ameloblastomas,
Bacterial meningitis, 654 BCL2 protein expression, follicular 1213
Bacterial sinusitis lymphoma, 1049 Borrelia burgdorferi, 953, 1692
acute, 1609 Beckwith-Wiedemann syndrome, 1523 Botryoid rhabdomyosarcoma, 871
chronic, 1609–1610 Behcet’s disease, 261 Botulinum toxin, 1485
Band keratopathy, 1580 Benign epithelial neoplasms Bowenoid papulosis, 1676
Bartonella henselae, 51, 1011 actinic keratoses (AKs), 1489–1491 Bowen’s disease. See Squamous cell
Basal cell adenocarcinoma, 25, 564–567 cutaneous lymphadenoma (CL), 1482–1484 carcinoma (SCC)
Basal cell adenoma, 23–24, 34 hidrocystomas, 1484–1485 BP-antigen, 249
clinical features, 522–523 pilar cysts (PCs), 1477–1478 BRAF mutations, 1488, 1510
differential diagnosis, 525 pilomatricoma, 1479–1481 Branchial cleft anomalies, 426–427
electron microscopy, 524 proliferating pilar cyst (PPC), 1478–1479 Branchial cleft cyst, 21, 1351–1352
immunohistochemistry, 524–525 sebaceous adenoma, 1488–1489 Branchial complexes, 1429
overview, 522 sebaceous hyperplasia, 1487–1488 Branchiogenic carcinoma, 1155–1156
pathology, 523–524 seborrheic keratoses (SKs), 1475–1477 BRD4-NUT fusion product, 1730
treatment, 525–526 syringoma, 1485–1487 BRD4 tumors, 1730
Basal cell carcinoma (BCC), 75–76, trichilemmomas (TLs), 1481–1482 BSP. See Bone sialoprotein (BSP), in
459, 1342 Benign FHH, 1438 ameloblastomas
clinical features, 1496 Benign lymphoepithelial lesion (BLEL), 1661 Buccal mucosa
differential diagnosis, 1498 Benign lymphoepithelial tumor, of the skin. squamous cell carcinomas, 294–295
eyelids, 1552–1553 See Cutaneous lymphadenoma (CL) Buccal nerve, 669
imaging studies, 1496 Benign mesenchymal tumors Buccinator muscle, 669
immunohistochemistry, 1497–1498 of external auditory canal, 448–449 Bullous keratopathy, 1564–1565
molecular genetics, 1498 Benign mesenchymomas, 895 Bullous pemphigoid, 248–249
pathology, 1496–1497 Benign migratory glossitis, 205–207 clinical presentation, 248
treatment and prognosis, 1498 clinical features, 206 immunology, 249
Basal cell nevus syndrome, 1342 diagnosis, 206 immunopathology, 249
Basal cell type ameloblastoma, 1206–1207 pathology, 206 pathology, 248–249
Basal encephaloceles, 652 treatment, 207 treatment, 249
Basaloid cells, 23 Benign neoplasms, 1481 Bulls eye, skin lesion, 258, 259
Basaloid keratinocytes, 1475 external auditory canal, 447–449 Burkitt’s lymphoma, 40–41, 1056–1057, 1355,
Basaloid squamous carcinomas, 309–312, middle ear and temporal bone, 449–456 1667–1668
398. See also Squamous cell Benign odontogenic tumors
carcinomas adenomatoid odontogenic tumor,
differential diagnosis, 311–312 1235–1240 Calcification, 1477, 1594
histologic features, 309–310 ameloblastoma Calcifying cystic odontogenic tumor
immunohistochemistry, 311 desmoplastic ameloblastoma, (CCOT)
treatment and prognosis, 310–311 1218–1221 adenomatoid odontogenic tumor-
Basaloid squamous cell carcinoma, keratoameloblastoma, 1225–1226 associated, 1268
62, 155–158 papilliferous keratoameloblastoma, ameloblastic fibroma-associated, 1268
clinical features, 155 1226–1228 ameloblastic fibro-odontoma-associated,
diagnosis, 157 solid/multicystic ameloblastoma– 1268
electron microscopy, 157 central, 1202–1215 clinical features, 1269–1270
etiology, 155 solid/multicystic ameloblastoma– immunohistochemically studies, 1271
immunohistochemistry, 157 peripheral, 1215–1218 odonto-ameloblastoma-associated, 1269
overviews, 155 unicystic ameloblastoma, 1221–1225 odontogenesis stages of, 1270–1271
pathology, 155–157 calcifying epithelial odontogenic tumor, odontogenic fibromyxoma-associated,
treatment, 157–158 1230–1235 1269
Basaloid tumors, 25 squamous odontogenic tumor, 1228–1230 odontoma-associated, 1269
Basement membrane-associated molecules Benign thyroid inclusions, in lymph node, solid/multicystic ameloblastoma–
AOT and, 1238 230–231 associated, 1267
and CEOT, 1234 Benzoylmethylecgonine. See Cocaine treatment and prognosis, 1272
Basement membrane zone (BMZ), 246 Ber-EP4 expression, 1499 ultrastructure of, 1271
Basement-type heparan sulfate Bethanechol chloride, 1691 unicystic ameloblastoma–associated,
proteoglycan (HSPG) and solid/ Bilateral acoustic neuroma. See 1267–1268
multicystic ameloblastoma–central, Neurofibromatosis 2 Calcifying epithelial odontogenic tumor
1209 Biopsy (CEOT)
Base of tongue, squamous cell carcinomas, ABCD, 963 calcification and, 1233
303–305 osteoblastoma, 970 clear-cell variant of, 1231–1233
Basidiobolus, 1638 PLCD, 963 differential diagnosis, 1235
[Calcifying epithelial odontogenic tumor [Carcinomas] Central odontogenic fibroma (COF), 1276
(CEOT)] spindle cell. See Spindle cell carcinomas differential diagnosis, 1278–1279
etiology and source, 1232–1233 (SPCC) etiology of, 1277
extraosseous variant of, 1233 squamous cell. See Squamous cell histochemical studies, 1278
immunohistochemistry carcinomas treatment and prognosis, 1280
CK antibody reaction, 1234 staging in nasal vestibule, 373 ultrastructure of, 1278
epithelial membrane antigens (EMAs), verrucous. See Verrucous carcinomas CEOT. See Calcifying epithelial odontogenic
1234 Carcinosarcoma, 586–588. See also Spindle tumor (CEOT)
proliferation marker Ki-67, 1234 cell carcinomas (SPCC) Cerebrospinal fluid (CSF), 672
tenascin, 1234 Cardiac myxomas, 1727 leak, 675
molecular-genetic data, 1235 Cardiovascular complications, associated rhinorrhea, 675
prevalence and incidence, 1230 with hyperparathyroidism, 1442 Ceruminal gland adenocarcinomas, 462–463
radiograms of, 1231–1232 Carney complex (CNC), 1726–1727 Ceruminal gland adenomas, 447
radiolucent–radiopaque type, 1231 Carotid body paraganglia (CBPG), 718–721 Ceruminal gland neoplasms, 447–448
treatment and prognosis, 1235 Cartilaginous lesions, 974 Ceruminal gland pleomorphic adenomas, 447
ultrastructural studies, 1234–1235 Caseating granulomas, 1012 Ceruminal glands, 424
Calcifying odontogenic cyst (COC), Caspase-8 apoptosis initiator, role in Cervical adenopathy location, 1147–1148
1262–1263 ameloblastomas, 1212 Cervical lymphadenitis, 1623
etiology of, 1263 CaSR gene, 1458 Cervical lymph nodes, 144, 1147, 1148
immunohistochemical studies, 1264 Castleman disease deep, 1135
treatment and prognosis, 1267 hyaline-vascular, 1019–1021 levels, 1135
Calcimimetics, 1456 localized plasma cell, 1021–1022 metastasis to, 299–300
Calcitonin-producing C cells, 1385 multicentric, 1009, 1022–1023 superficial, 1135
Calcium channel blocking agents, 217–218 Cataract, 72 Cervical thymoma
Calcium pyrophosphate crystal deposition B-catenin stabilization, 1481 clinical features, 1724
disease (CPCDD) Cat scratch disease (CSD), 51 imaging studies, 1724
pathologic features, 954 clinical features, 1627 pathology, 1724
radiologic features, 954 etiology, 1627 treatment and prognosis, 1724–1725
Calcium pyrophosphate dihydrate (CPPD), histopathology, 1627–1628 CFP-10 (culture filtrate protein 10), 1623
gout, 443 of lymph node, 1011–1012 CFS. See Chronic fatigue syndrome (CFS)
Calcium-sensing receptor (CaSR), 1435 serology and PCR, 1628 CFTR. See Cystic fibrosis transmembrane
Calcium supplements, 1456 treatment, 1628 conductance regulator (CFTR)
Calretinin and ameloblastic epithelium, Cavernous hemangiomas, 74, 1596–1597 CGH. See Comparative genomic
1223 CBPG. See Carotid body paraganglia hybridization (CGH)
Canalicular adenoma, 24 (CBPG) Chalazions, 73, 1553
clinical features, 531 CCC. See Clear cell carcinoma Charcot-Leyden crystals, 355
defined, 531 C cells tumors Cheilitis glandularis, 490–491
differential diagnosis, 532 hyperplasia, 1409–1410 Chemical carcinogens, oral cancer, 286–288
immunohistochemistry, 532 medullary thyroid carcinoma, 1410 metabolism, 288
pathology, 531–532 mixed medullary-follicular carcinoma, Chemodectoma, 717
treatment, 532 1411 Chemoreduction, 1594
Cancer, 1438 mixed medullary-papillary carcinoma, Chemotherapy, 983
sarcoma staging, AJCC on, 863 1411–1412 Chemotherapy-induced atypia, 1491
Candida albicans, 289 CCLE. See Chronic cutaneous lupus Cherubism, 966–967
Candida albicans pseudohyphae, 59 erythematosus (CCLE) Chlamydia, 72
Candidiasis, 1645–1646 CCOC. See Clear cell odontogenic carcinoma Chlamydial conjunctivitis, 72
Canker sores. See Recurrent aphthous (CCOC) Chlorhexidine, 263
stomatitis (RAS) CCOT. See Calcifying cystic odontogenic Cholesteatomas
Capillary hemangioma in soft tissues of tumor (CCOT) acquired, 436–437
neck, 1358 CD31, 866, 867 congenital, 437–438
Capillary malformations, 1522 CD34, 866, 867 Cholesterol granulomas, 30, 357–358
Carboxyterminal fragments, 1436 CD3 and CD4-like moieties, 1435 versus congenital cholesteatomas, 438
Carcinoembryonic antigen (CEA), 14, 1483 CD99 immunoreactivity, in ES/PNET, 737 Chondroblastomas, 69, 978–979
Carcinoma ex pleomorphic adenoma, 583– CD3 immunostains, 39 Chondrocalcinosis. See Calcium
586 CD20 immunostains, 39 pyrophosphate crystal deposition
Carcinoma in situ (CIS), 130, 133–135, 269 CD44s, inverted papilloma, 368 disease (CPCDD)
clinical features, 133 CE. See Congenital epulis (CE) Chondrodermatitis nodularis chronicus
introduction, 133 CEA. See Carcinoembroyonic antigen (CEA) helicis (CNCH), 432–433
molecular-genetic data, 134 Cefixime, 1618 Chondrodermatitis nodularis helicis (CNH)
pathology, 133 Cell block, 39 clinical features, 1534
treatment, 134–135 Cellular alterations, in dysplasia, 267 differential diagnosis, 1535
Carcinoma of unknown primary (CUP), Cellular hemangioma of infancy. See histologic features, 1534
1147 Infantile hemangioma (IH) immunohistochemistry, 1534
frequency, 1148 Cellular neurothekeomas, 694, 695 treatment and prognosis, 1535
metastase histology, 1150 Cellular PA, 34–35 Chondroid metaplasia, 975–976
Carcinomas. See also Granulomas Cellular schwannomas, 680 Chondroma, 976
adenoid squamous, 313–314 CEMBLA. See Cementoblastoma (CEMBLA) Chondromatosis, synovial
adenosquamous, 312–313 Cementoblastoma (CEMBLA) of temporomandibular joint, 435–436
exophytic papilloma and, 362–363 differential diagnosis, 1290 Chondromyxoid fibroma, 978
inverted papilloma and, 366–368 etiology of, 1289 Chondrosarcoma, 976–978
incidence, 367 growth rate, 1288 larynx, 977
molecular biology in HPV-related, 290 immunohistochemistry, 1290 law, 977
neuroendocrine, 322–323 prevalence and incidence, 1288 Chordoid meningioma, 706
and OSP, 370–371 radiographic examination, 1288–1289 Chordoma, 979–981
papillary squamous, 316–318 treatment and prognosis, 1290 Choroidal melanoma, 1589
showing thymus-like Cemento-osseous dysplasia, 965–966 Choroid plexus, 675
differentiation, 1413 Cemento-ossifying fibroma, 1279 Choroquine, 1693
Chromogranin, 67, 1452 Clofaimines, 1691 Conjunctiva

Chromosome 22q11 microdeletion Clofazimine, 1620, 1627 anatomy, 1557
syndrome, 1460 CMN. See Congenital melanocytic nevi diseases
Chronic bruxism, 958 (CMN) conjunctival intraepithelial neoplasia
Chronic cutaneous lupus erythematosus CMV. See Cytomegalovirus (CMV) (CIN), 1558–1559
(CCLE), 252 CNB. See Core needle biopsy (CNB) limbal dermoid, 1562–1563
Chronic diffuse sclerosing osteomyelitis, 960 COC. See Calcifying odontogenic cyst melanoses and melanocytic
Chronic fatigue syndrome (CFS), 1666 (COC) proliferations, 1559–1562
Chronic granulomatous fungal sinusitis, Cocaine specimen handling, 1557–1558
1631 chronic intranasal inhalation, 663 Conjunctival intraepithelial neoplasia (CIN),
Chronic hyperphosphatemia, in children, clinical features, 663–664 1558–1559
963 crack cocaine, 663 Contact granuloma, 111–112
Chronic invasive fungal sinusitis, 1632 pathology, 664 Contact ulcers, 111–112
Chronic lymphocytic leukemia/small treatment and prospect, 664 Conventional chordoma, 980
lymphocytic lymphoma (CLL/SLL), Coccidioidomycosis, 1646–1648 Conventional osteosarcoma, 972
1059 COF. See Central odontogenic fibroma Convexity meningioma, 703
Chronic sclerosing osteomyelitis, 959–960 (COF) Cookie-bite appearance, of ASPS, 902
Chronic sclerosing sialadenitis, 486–490 CO2-laser evaporation, 275 Core needle biopsy (CNB), 39
of submandibular gland, 1097–1098 Collagen-1a1 gene, 1517, 1519 Cornea
Chronic sinusitis, 345 Collagenous fibroma (desmoplastic anatomy, 1563–1564
Chronic suppurative osteomyelitis, 959 fibroblastoma) biopsy of
Chronic suppurative otitis media (CSOM), clinical features, 843 acanthamoeba keratitis, 1571–1572
1612 differential diagnosis, 845–846 pterygium, 1573–1574
Churg-Strauss syndrome, 650, 657–660, electron microscopic findings, 845 stains for, 1571
1610 immunohistochemistry, 844–845 diseases
clinical features, 658 molecular findings, 845 bullous keratopathy, 1564–1565
criteria for diagnosis, 658 pathologic findings, 843–844 Fuchs dystrophy, 1566–1567
limited form, 657 prognosis and therapy, 846 graft failure, 1567–1569
pathology, 658–659 radiologic findings, 843 keratoconus, 1569–1570
treatment and prospect, 660 Colloid cyst, of the thyroid pseudophakia, 1565–1566
Chvostek’s sign, 1460 glands, 1457 stromal dystrophies, 1570–1571
Cidofovir, 1663 Colloid nodule. See Nodular goiter specimen handling, 1564
Cigarette smoking, and salivary gland Combined small cell neuroendocrine Cortex, lymphoid follicles in, 997
tumors, 506–507 carcinoma, 167 Cortical defects of mandible
Ciprofloxacin, 1612 Common cold, 345 anterior buccal cortical defect (ABCD), 963
Circumferential margin preparation, 98 Comparative genomic hybridization anterior lingual cortical defect (ALCD), 963
CIS. See Carcinoma in situ (CIS) (CGH), 685 posterior buccal cortical defect(PBCD),
Civatte bodies, 260 malignant melanomas, 393 963
CK. See Cytokeratin (CK) studies of ITAC, 386 posterior lingual cortical defect (PLCD),
CK 5/6 expression, 1481 Computed tomography (CT), 1 962–963
CK 20-positive Merkel cells, 1483 Condyloma acuminatum, 212–214 Corticosteroids
Cladosporium, 1640–1641 clinical features, 212 as drug, 1390
Clark level of invasion, 1507 diagnosis, 213 therapy, 1584, 1600, 1693, 1719
Classical Hodgkin lymphoma, 45 electron microscopy, 213 Corynebacterium diphtheriae, 346
clinical features, 1032 molecular genetic data, 213–214 Cowden syndrome, 1348, 1481
differential diagnosis, 1035 overviews, 212 CPCDD. See Calcium pyrophosphate crystal
immunohistochemistry, 1034–1035 pathology, 213 deposition disease (CPCDD)
lymphocyte-rich, 1033–1034 treatment, 214 Cranial fasciitis, 966, 1359
molecular genetic data, 1035 Condylomas, 1676 Craniopharyngioma
oral cavity and oropharynx, 1089 Congenital abnormalities, ear, 425–427 clinical features, 714
pathology, 1032–1034 Congenital cholesteatomas, 437–438 diagnosis, 716
treatment and prognosis, 1035 versus cholesterol granulomas, 438 overview, 714
Classic butterfly rash, malar region, 252 Congenital epibulbar melanocytic pathology, 715–716
Clear cell carcinoma (CCC), 563–564, 1729 proliferations, 1560 radiography, 714–715
Clear cell myoepithelial carcinoma Congenital epulis. See Gingival GCT of somatic genetics, 716
(CMEC), 1729 newborn treatment, 716–717
Clear cell odontogenic carcinoma (CCOC) Congenital epulis (CE), 701 Craniotomy, 957
differential diagnosis, 1304 Congenital granular cell tumor, 1345 Cribriform, 24
etiology and pathogenesis, 1302–1303 Congenital hemangioendothelioma. Cricoarytenoid joints, 953
gender ratio, 1302 See Kaposiform Cricothyroid joints, 953
histochemical and immunohistochemical hemangioendothelioma Crohn disease, 228–229
studies, 1303 Congenital hemangiopericytoma, 1358 Cryopreservation, of parathyroid tissue,
molecular-genetic data, 1304 Congenital hereditary lymphedema 1462–1463
prevalence and incidence, 1301 syndrome, 1523 Cryotherapy, 277
treatment and prognosis, 1304 Congenital herniations, 674 Cryptococcosis, 1642, 1651–1652
ultrastructural studies, 1303 Congenital-infantile fibrosarcoma with Cryptococcus, 1013
Clear cells spindle cell, 1361 CSD. See Cat scratch disease (CSD)
change, 31–32 Congenital melanocarcinoma. See CSF. See Cerebrospinal fluid (CSF)
lesions, 16–17 Melanocytic neuroectodermal tumor CT. See Computed tomography (CT)
meningiomas, 703 of infancy (MNTI) CT scan
of parathyroid glands, 1432 Congenital pleomorphic adenoma. See acute supprative osteomyelitis, 958
Clindamycin plus surgical drainage, 1611 Salivary gland anlage tumor chondroblastomas, 978
Clinical staging system, for Congenital teratoid cyst, 1343 chondromyxoid fibroma, 978
rhabdomyosarcoma, 876 Congo red stain, 14 chondrosarcoma, 977
CLL/SLL. See Chronic lymphocytic Conidiobolus, 1638 chordoma, 980
leukemia/small lymphocytic Conidiobolus coronatus, 1638 chronic suppurative osteomyelitis, 959
lymphoma (CLL/SLL) Conidiobolus incongruous, 1638 extragnathic osteosarcoma, 972
[CT scan] Cytomegalovirus lymphadenitis, 1007–1008 Desmoplastic fibroma, 987–988, 1279

hemangioma, 981 Cytometry, 15 Desmoplastic trichoepithelioma, 1500
ossifying fibroma, 970 Desquamative gingivitis, 249, 255
osteoblastoma, 969 DFSP. See Dermatofibrosarcoma
osteoid osteoma, 968 Dalen-Fuchs nodules, 1584 protuberans (DFSP)
parosteal osteosarcoma, 973 Dapsone, 251, 263, 1627 DG1. See Desmoglein 1 (DG1)
PLCD, 963 Debridement, of infected tissues, 1637 DG3. See Desmoglein 3 (DG3)
PVNS, 934 Dedifferentiated liposarcoma, 884 DGCT. See Dentinogenic ghost cell tumor
relapsing polychondritis, 961 Deep lymph nodes (DGCT)
rheumatoid arthritis, 952 lateral, 1135 Diabetic microangiopathy, 1637
CUP. See Carcinoma of unknown medial, 1135 Diff-Quik, 1445
primary (CUP) Deep or subcutaneous granuloma annulare Diffuse infiltrative lymphocytosis syndrome
Curvularia, 1640 (DSGA), 1367 (DILS), 1660
Cutaneous angiofibroma. See Fibrous Dendritic cell neoplasm Diffuse large B-cell lymphoma
papules (FP) blastic plasmacytoid, 1077–1078 (DLBCL), 15, 41–42, 1039–1045. See
Cutaneous intravascular large B-cell Dendritic cell sarcoma, 1075–1079 also Large cell lymphoma
lymphoma, 1111 in cervical lymph node, 1153 with chronic inflammation, 1043
Cutaneous leiomyosarcoma, 877, 879 follicular, 1075–1076 clinical features, 1039
Cutaneous lymphadenoma (CL) interdigitating, 1076–1077 differential diagnosis for, 1044–1045
clinical features, 1482 rare types of, 1078–1079 elderly population with EBV-positive,
differential diagnosis, 1483–1484 De novo malignancies, 958 1043–1044
immunohistochemistry, 1483 Dental factors, oral cancer, 288–289 immunohistochemistry, 1041
molecular genetics, 1483 Dental lamina cyst, 1343 large B-cell lymphoma, 1041–1043
pathology, 1482–1483 Dentinogenic ghost cell tumor (DGCT), 1272 molecular genetic data, 1041
treatment and prognosis, 1484 b-catenin gene mutation, 1275 pathology, 1039–1041
Cutaneous mastocytosis, 1112, 1113 etiology of, 1273–1274 primary cutaneous, 1043
Cutaneous pseudolymphoma, 1112 histomorphological pattern of, 1275 primary effusion lymphoma, 1044
Cyclic adenosine monophosphate imunohistochemistry, 1274–1275 of thyroid, 1102
(cAMP), 688 treatment and prognosis, 1275 primary cutaneous, leg-type, 1110–1111
Cyclin-dependent kinase inhibitor 2A ultrastructure of, 1275 of tonsil, 1094
(CDKN2A), 1510 Dentinoid, and COC, 1265 treatment and prognosis., 1045
Cyclophasphamide, 1693 Denture-induced fibrous hyperplasia. See Diffuse neurofibroma (DNF), 686–687
Cyclosporine, 217, 257 Fibrous hyperplasia, denture-induced DiGeorge syndrome, 1387, 1460
therapeutic agents, 1344 Depositional diseases, of joints. See Dilantin. See Diphenylhydantoin
Cystadenocarcinoma, 568–572 Inflammatory diseases, of joints antiepileptic drug
Cystadenoma, 538–540. See also De Quervain’s thyroiditis, 1392 Dilator pupillae smooth muscle
Hidrocystomas Dermatofibroma (DF), 1482 fibers, 1586
Cystic fibrosis, 352–354 clinical features, 1515 Diphenylhydantoin antiepileptic
clinical features, 353 differential diagnosis, 1517 drug, 1386
nasal polyps with, 353 electron microscopy, 1517 Discoid lupus erythematosus, 1491. See also
pathology, 353–354 immunohistochemistry, 1516–1517 Chronic cutaneous lupus
of salivary glands, 478–479 molecular genetics, 1517 erythematosus (CCLE)
treatment, 354 pathology, 1515–1516 Distant metastases from SCC, 1158–1159
Cystic fibrosis transmembrane conductance treatment and prognosis, 1517 DLBCL. See Diffuse large B-cell lymphoma
regulator (CFTR), 353 Dermatofibrosarcoma protuberans (DFSP), (DLBCL)
Cystic hygroma-lymphangioma and cystic 687, 697, 880 Dopamine agonist medications, for pituitary
hygroma colli, 1357 clinical features, 1518 adenomas, 712
Cystic lesions, 15–16, 21–22 defined, 1517 Down syndrome, 1342, 1388, 1486
Cystic nests, 1552 differential diagnosis, 1519 Doxycycline, 1628
Cystogenic type SCC, 1299 electron microscopy, 1519 DQ stain, 5
histopathology of, 1300 imaging studies, 1518 Drug-induced gingival hyperplasia. See
treatment and prognosis, 1301 immunohistochemistry, 1519 Gingival hyperplasia, drug-induced
ultrastructure of, 1301 molecular genetics, 1519 DSGA. See Deep or subcutaneous
Cysts, 115–119 pathology, 1518–1519 granuloma annulare (DSGA)
ductal, 116 treatment and prognosis, 1519–1520 Ductal cells, 20, 27
epithelial, 117 Dermatopathic lymphadenopathy, 1005 Ductal cysts, 116
oncocytic, 117 Dermoid cysts, 73, 957, 1596 Ductal eccrine carcinoma. See Microcystic
saccular, 116 in periorbital nodule in infant, adnexal carcinoma (MAC)
tonsillar, 117 1342–1343 Ductal papillomas
Cytochrome c oxidase defects, 1433 DESAM. See Desmoplastic ameloblastoma intraductal, 535–537
Cytokeratin 8, 18, and 19, 1434 (DESAM) inverted ductal papilloma, 538
Cytokeratin (CK), 31, 983 Desmin, 903, 904 sialadenoma papilliferum, 537–538
expression in sinonasal tumors, 379 Desmoglein 1 (DG1), 246 Dyshormonogenetic goiters, 1391
Cytologic atypia, 1475, 1476 Desmoglein 3 (DG3), 246 Dyskeratosis, 130
in ASPS, 902 Desmoid fibromatosis, 1360 Dysphagia, 243
Cytomegalovirus (CMV), 495–497, 1661 Desmoplastic ameloblastoma (DESAM) Dysplasia, 267
in AIDS, 1662 Akt-signaling pathway and MAPKs, role cellular alterations, 267
congenital, 1661–1662 in, 1220 genetic changes in, 273
epidemiology, 1661 differential diagnosis, 1221 malignant transformation, corelation
in the head and neck, 1662–1663 etiology of, 1219 with, 272–273
histopathology, 1663 immunohistochemistry, 1219 mild, 269
infection, 1007–1008 intraosseous cystic/solid and, 1220 moderate, 269
infection in organ transplant prevalence and incidence, 1218 severe, 269
recipients, 1662 radiological study, 1218–1219 with three grades, 269
pathogenesis, 1663 treatment strategy for, 1221 tissue alterations, 267
serology, 1663 Wingless type 1 glycoprotein (Wnt1) and WHO classification, 269–270
treatment, 1663 SDC-1, 1220–1221 Dystrophic calcifications, 715, 954–955, 1344
EAF. See Eosinophilic angiocentric fibrosis Enamel proteins [Epstein-Barr virus (EBV)]
(EAF) in AFOD, 1251 disease associated with, 1664
Ear, 953 and AOT, 1238 EBV-lymphoproliferative disorders,
external, 423–424 CEOT, 1234 1667–1668
hematolymphoid lesions of, 1107–1108 Enamelysin and calcifying odontogenic cyst infectious mononucleosis, 1666–1667
inner, 424–425 (COC), 1265 inverted papilloma, 363
middle, 424 Encephalocele, acquired, 440 latent infections, 1664–1665
neoplastic lesions of, 446–467 Encephaloceles, 674 nasopharyngeal carcinoma, 1668–1669
benign neoplasms, 447–456 nasal. See Nasal encephalocele nasopharyngeal carcinomas, 398
endolymphatic sac papillary tumor, Endemic goiters, 1391 oral hairy leukoplakia, 1669–1670
457–458 Endodermal sinus tumor, 1365–1366 overview and pathobiology, 1663–1664
malignant neoplasms, 459–467 Endodontic therapy, 959, 960 proteins, 1665–1666
nonneoplastic lesions, 425–432 Endolymphatic sac papillary tumor, 457–458 severe chronic active EBV infection,
acquired, 427–432 Endoneurial fibroblasts, 677 1667
congenital abnormalities, 425–427 Endophytic growth, of the tumor, 1593 sinonasal NK/T-Cell lymphoma,
squamous cell carcinomas, 459–460 Endoscopic sinus surgery, 1609 1670–1671
EBA. See Epidermolysis bullosa acquisita Endothelial cells, 981, 983 strains of, 1664
(EBA) Enneking staging system, for undifferentiated salivary
EBV. See Epstein-Barr virus (EBV) musculoskeletal sarcoma, 863 lymphoepithelial carcinoma, 1669
EBV nuclear antigens (EBNA), 1665 Entomophthorales Epstein-Barr virus–encoded RNA (EBER), 398
EBV-positive DLBCL, of elderly, clinical course, 1637 Epstein’s pearls, 1343. See also Oral cavity
1043–1044 epidemiology, 1637 ER. See Estrogen receptor (ER)
Eccrine hidrocystomas, 1484 histopathology, 1637 ERMS. See Embryonal RMS (ERMS)
Eccrine poroma, 1476, 1482 serology, 1637 Erosive lichen planus, 250
ECRS. See Eosinophilic chronic treatment, 1637 Eruptive vellus hair cyst, 1343, 1363
rhinosinusitis (ECRS) Enucleation Erythema, 250
ECS. See Extracapsular spread categorizations for, 1577 Erythema multiforme (EM), 258–261
Ectopic acinic cell carcinoma, 1152 indications, 1577 clinical presentation, 258–259
Ectopic benign thyroid tissue, in phthisis bulbi diagnosis, 260–261
nonlymphoid tissues, 231–232 clinical features, 1579 etiology, 260
clinical features, 231–232 pathology, 1579–1582 pathology, 260
pathology, 232 specimen handling, 1577–1579 treatment, 261
treatment, 232 sympathetic ophthalmia, 1583–1586 Erythromycin, 1628
Ectopic hamartomatous thymoma–branchial traumatic injury, 1582–1583 Erythroplakia, 131, 275–277
anlage mixed tumor Enzyme activity, 669 clinical features, 276
clinical features, 1725 Enzyme-linked immunoabsorbant assay defined, 275
differential diagnosis, 1726 (ELISA), 246, 650 diagnosis, 277
imunohistochemistry, 1726 Eosinophilic angiocentric fibrosis (EAF), pathology, 276–277
pathology, 1725–1726 359–360 treatment, 277
treatment and prognosis, 1726 Eosinophilic chronic rhinosinusitis (ECRS), ESAT-6 (early secretory antigenic target
Ectopic lacrimal glands, 74 354–355 protein 6), 1623
Ectopic protrusion, 676 Eosinophilic granulomas, 438–439, 989 ES/PNET. See Ewing’s sarcoma and
Ectopic thyroid, 229–232 Eosinophilic ulcer, of tongue, 1093 primitive neuroectodermal tumor
benign thyroid inclusions, in lymph node, Eosinophils, 660 (ES/PNET)
230–231 Eosin stains, 1445 Estrogen receptor (ER), 31
benign thyroid tissue, in nonlymphoid Ependyma, 675 Eustachian tube, 424
tissues, 231–232 Epibulbar conjunctival stroma, 1557 Evan’s tumor. See Low-grade fibromyxoid
lingual thyroid, 229–230 Epidermal nevus, congenital and acquired sarcoma (LGFMS)
Edema, 250 lesions, 1341 Ewing sarcoma–primitive neuroectodermal
EH. See Epithelioid hemangioendothelioma Epidermolysis bullosa acquisita (EBA), 243 tumor (EWS-PNET), 1347
(EH) Epistaxis, 1157 Ewing’s sarcoma, 55, 989
EKH-6, 1486 Epithelial atrophy, 253 Ewing’s sarcoma and primitive
Electron microscopy Epithelial cysts, 117 neuroectodermal tumor (ES/PNET)
of ITAC, 386 Epithelial dysplasia, nasal polyps, 350 clinical features, 735
of SCNEC, 381 Epithelial-lined cysts, 1342 diagnosis, 737–738
of SNUC, 379 Epithelial membrane antigen (EMA), 42–43, histopathology, 736
ELISA. See Enzyme-linked immunosorbent 1483 imaging, 735–736
assays (ELISA) Epithelialmyoepithelial carcinoma (EMC), immunohistochemistry, 736–737
EM. See Erythema multiforme (EM) 31, 561–563 macroscopy, 736
EMA. See Epithelial membrane antigen Epithelial-myoepithelial carcinoma (EMEC), overview, 735
(EMA) 1729 somatic genetics, 737
Embryology Epithelioid cell sarcomas. See Polygonal cell treatment, 738
of external ear, 423 sarcomas ultrastructure, 736
of inner ear, 424 Epithelioid hemangioendothelioma (EH), EWS-PNET. See Ewing sarcoma-primitive
of middle ear, 424 61, 863–867, 981–982 neuroectodermal tumor (EWS-PNET)
Embryonal rhabdomyosarcoma, Epithelioid hemangioma, 61, 1357 Excision, 677
1361–1362 in dermis and soft tissues of temporal Excisional biopsy, hematolymphoid
Embryonal RMS (ERMS), 869, 870–871 region, 1359 neoplasms, 1031
EMC. See Epithelialmyoepithelial carcinoma Epithelioid histiocytes, 1584 Exophytic growth, of tumor, 1593
(EMC) Epithelioid tumor cells, 864 Exophytic papilloma, 362–363
EMC-degrading serine proteinases role in E-2 promotor-bindingfactor-1(E2F-1) and and carcinomas, 362–363
ameloblastomas, 1214 phosphorylated RB role in HPV incidence in, 363
EMMPRIN. See Extracellular matrix ameloblastomas, 1211 Exostosis, 967
metalloproteinase inducer Epstein-Barr virus (EBV), 41, 155, 160, 660, external auditory canal, 434–435
(EMMPRIN) 1150, 1483, 1661. See also Human Explosive follicular hyperplasia, of lymph
Enamelin and calcifying odontogenic cyst papillomavirus (HPV) node, 1009
(COC), 1265 clonal infections, 1665 Exserohilum, 1639–1640
External auditory canal Fabry’s syndrome, 1523 [Fibrous papules (FP)]

benign mesenchymal tumors of, 448–449 Facial bones. See Jaw electron microscopy, 1514
benign neoplasms, 447–449 Factitial rhinosinusitis, 348 immunohistochemistry, 1514
cholesteatomas of, 437 Familial hypocalciuric hypercalcemia pathology, 1513
exostosis, 434–435 (FHH), 1436 treatment and prognosis, 1514
squamous cell carcinomas of, 460–462 clinical features, 1457 Fibrous septa, 1487
squamous cell carcinomas staging in, 462 differential diagnosis, 1458 Fibrous stromal cells, 965
External ear, 423–424 molecular biology, 1458 Fibrovascular proliferation, 1579
mlignant neoplasms of, 459–464 pathologic features, 1457 Fibroxanthoma, atypical, 463–464
Extracapsular spread (ECS), 1137, 1138–1140 treatment and prognosis, 1458 FIHH. See Familial hypocalciuric
Extracellular matrix metalloproteinase Familial isolated hyperparathyroidism hypercalcemia (FHH)
inducer (EMMPRIN), and (FIHP), 1437–1438 FIHP. See Familial isolated
ameloblastomas, 1214 Fat stains, 1446 hyperparathyroidism (FIHP)
Extracellular matrix proteins FD. See Fibrous dysplasia (FD) Filaggrin, and COC, 1265
in AMFs, 1244 Federation Nationale des Centres de Lutte Filobasidiella neoformans, 1651
and AOT, 1238 Contre le Cancer (FNCLCC), Fine needle aspiration biopsy (FNAB), 37,
Extracranial teratomas, 674 France, 862 1149
Extragnathic osteosarcoma, 972–973 Fetal development and thyroid gland Hodgkin lymphoma, 45–46
Extramedullary hematopoietic tumor, growth, 1429 Fine-needle aspiration (FNA), 1, 101, 1599
1026–1027 Fetal rhabdomyoma, 1361–1362 cytology, hematolymphoid neoplasms,
Extramedullary plasmacytoma, 1057–1059 FGF. See Fibroblast growth factors (FGF), in 1031
clinical features, 1057 ameloblastoma FISH. See Fluorescence in situ hybridization
differential diagnosis, 1057–1059 FHH. See Familial hypocalciuric (FISH)
ectopic pituitary adenoma, 1059 hypercalcemia (FHH) FISH studies, 40
immunohistochemistry, 1057 Fibrinogen, 257 Flexner-Wintersteiner rosettes, 78
molecular genetic data, 1057 Fibroblast growth factors (FGF), in Floor of the mouth, squamous cell
pathology, 1057 ameloblastoma, 1211 carcinomas, 295–298
treatment and prognosis, 1059 Fibroblastic-myofibroblastic Florid interfollicular immunoblastic
Extranodal marginal zone B-cell lymphoma, tumors, 1358 proliferation, 1355
604–607, 1600–1601 Fibrodysplasia ossificans progressive Flow cytometry, in lymph nodes, 39–40
Extranodal metastases (myositis ossificans progressive) Fluorescence in situ hybridization (FISH), 728
head and neck skin, 1157 clinical findings, 820–821 Fluoroquinolone-resistant gonorrhea, 1618
laryngeal, 1157–1158 differential diagnosis, 821 FLUS. See Follicular lesion of undetermined
metastatic tumors, to eyes, 1157 immunohistochemistry, 821 significance (FLUS)
metastatic tumors, to nasal cavity, 1157 pathologic findings, 821 FN. See Follicular neoplasm (FN)
metastatic tumors, to oral regions prognosis and treatment, 821–822 FNA. See Fine needle aspiration (FNA)
jaw metastases, 1156 radiologic imaging, 821 FNAB. See Fine needle aspiration biopsy
oral soft tissue metastases, 1156–1157 Fibromatosis colli (Torticollis), 1359 (FNAB)
metastatic tumors, to paranasal sinuses, clinical features, 828 FNA biopsy. See Fine-needle aspiration
1157 differential diagnosis, 830 biopsy (FNAB)
salivary glands, 1156 electron microscopy, 830 FNCLCC. See Federation Nationale des
temporal bones, 1157 imaging, 828 Centres de Lutte Contre le Cancer
Extranodal NK/T-cell lymphoma immunohistochemistry, 830 (FNCLCC), France
nasal, 1060–1064 molecular findings, 830 Focal epithelial hyperplasia, 211–212. See
clinical features, 1061 pathology, 828 also Heck’s disease
differential diagnosis, 1062–1063 treatment and prognosis, 830 Focal lymphocytic thyroiditis, 1389
immunohistochemistry, 1061 Fibromatosis (desmoid) Focal myositis
molecular genetic data, 1061–1062 clinical findings, 832 clinical features, 797
pathology, 1061 differential diagnosis, 833–834 definition, 796
treatment and prognosis, 1063–1064 imaging, 832 differential diagnosis, 798
of oral cavity and oropharynx, 1089 immunohistochemistry, 833 immunohistochemistry, 797–798
of skin, 1111, 1112 molecular findings, 833 laboratory studies, 797
Extranodal sites pathologic findings, 832–833 pathology, 797
head and neck, 1001 prognosis and treatment, 834 radiologic imagery, 798
HIV-associated lymphoid hyperplasia in Fibro-osseous lesions, 68 treatment and prognosis, 798
head and neck, 1010–1012 Fibrosarcoma, 885–892, 988–989 Focal osteoporotic bone marrow
reactive lymphoid hyperplasia of, 1001 Fibrosis, 1367 defect, 961–962
Extraosseous odontomas, 1253 in osteoradionecrosis (ORN), 961 Follicular carcinoma, 7
Extraosseous osteosarcoma, 974 Fibrous dysplasia (FD), 960, 964–965 Follicular cells, 3, 4
Extravascular proliferation, of atypical Fibrous hamartoma of infancy in thyroid gland, 1385
endothelial cells, 868 clinical findings, 825 Follicular dendritic cell sarcoma, 1075–1076
Eye, hematolymphoid lesions of, 1103–1107 differential diagnosis, 826–828 Follicular hyperplasia, 1355
clinical features, 1104 electron microscopy, 826 Follicular lesion of undetermined
diagnostic considerations, 1107 imaging, 826 significance (FLUS), 9
neoplasms, 1103–1105 immunohistochemistry, 826 Follicular lesions, 6–9
reactive/inflammatory, 1105–1107 molecular findings, 826 Follicular lymphoma, 44–45
Eyelids pathologic findings, 826 clinical features, 1045–1046
anatomy, 1551 prognosis and treatment, 828 differential diagnosis, 1050
diseases Fibrous hyperplasia, denture-induced, histologic grading and growth pattern,
basal cell carcinoma, 1552–1553 218–220 1047–1049
reactive inflammatory processes, clinical features, 219 immunohistochemistry, 1049
1553–1554 pathology, 219 molecular genetic data, 1049
sebaceous neoplasms, 1554–1556 treatment, 220 pathology, 1046
sebaceous tumefactions, 1553 Fibrous papules (FP) pediatric, 1050
squamous cell carcinoma, 1553 clinical features, 1513 primary cutaneous follicle center
xanthelasma, 1557 defined, 1513 lymphoma, 1050
specimen handling, 1551–1552 differential diagnosis, 1514 versus reactive follicular hyperplasia, 1051
[Follicular lymphoma] Germinal centers, progressive [Gonorrhea]

in situ, 1051 transformation of, 1004–1005 transmission and epidemiology,
of tonsil, 1090 Ghost cell glaucoma, 72 1617–1618
transformation to high-grade lymphoma, Ghost cell odontogenic carcinoma (GCOC), treatment, 1618
1049–1050 1212, 1304. See also Ameloblastomas Gorham-Stout syndrome, 981
treatment and prognosis, 1050 differential diagnosis, 1306 Gorlin–Goltz syndrome, 1344
Follicular neoplasm (FN), 7 etiology of, 1305 Gout, 442–443
diagnosis, challenges, 7–8 immunohistochemistry, 1306 pathologic features, 953–954
Follicular thyroid tumors molecular-genetic data, 1306 radiologic features, 953
follicular adenomas, 1402 prevalence and incidence, 1305 Grading
follicular carcinoma, 1402–1404 radiographic picture, 1305 of follicular lymphoma, 1047–1049
Follicular variant of papillary carcinoma treatment and prognosis, 1306 histologic, of sarcoma, 863
(FVPC), 7 Giant cells, 47 of malignant mesenchymal tumors,
Folliculosebaceous cystic hamartoma, 1488 fibroma, 222 862–863
Fomivirsen, 1663 lesions, 69 Graft failure, 1567–1569
Fordyce granules, 201 Giant cell angiofibroma (GCA), 1728 Graft-versus-host disease (GVHD), 258
Foregut duplication cyst, 1348 Giant cell arteritis (GCA) Gram-negative bacteria, 64
Foreign body granuloma, 73 angiography and ultrasonography, Granular cell ameloblastoma, 1206–1207
Formalin, 10 1717–1718 Granular cell odontogenic tumor (GCOT),
Foscarnet, 1663 clinical features, 1717 1214, 1281
Frontal encephaloceles, 674 differential diagnosis, 1719 clinical features, 1282
Frontofacionasal dysplasia, 674 laboratory tests, 1718 differential diagnosis, 1283
Frozen-section diagnoses, 95–105 pathology, 1718–1719 histopathology of, 1282
accuracy, 96 treatment and prognosis, 1719 immunohistochemical technique,
contraindications, 97 Giant cell carcinoma (GCC), 161–162 1282–1283
errors, 96–97 Giant cell granuloma, 984–985 surgical removal, 1283
handling tissue sample, 95 Giant cell-rich malignant fibrous ultrastructure of, 1283
indications, 97 histiocytoma, 889 Granular cell tumor (GCT), 54, 60–61,
intraoperative cytology, 97 Giant cell–rich osteosarcomas, 984 698–701, 1344
overviews, 95 Giant cell tumor (GCT), 171–172, 984 CE, 701
preparation technique, 95–96 Gierke disease, 1392 malignant GCT, 700–701
regional applications, 97–105 Gingiva, squamous cell carcinomas of, Granulomas. See also Carcinomas
lymph nodes, 100–101 298–300 cholesterol, 30, 357–358
mucosal surfaces, 101 Gingival carcinoma, 300 eosinophilic, 438–439
parathyroid gland, 104–105 Gingival fibromatosis nasal polyps, 350
peripheral nerves, 100 clinical features, 830–831 Granulomatosis, 438–439
salivary gland, 101–103 differential diagnosis, 831–832 Wegener’s. See Wegener’s granulomatosis
surgical margins, 97–100 electron microscopy, 831 Granulomatous inflammation, 1598
thyroid gland, 103–104 imaging, 831 Granulomatous lesions, 73
Frozen section interpretation, of immunohistochemistry, 831 chalazions, 73
parathyroid, 1444–1446 molecular-genetic data, 831 dermoid cyst, 73
Fuchs dystrophy, 1566–1567 pathology, 831 foreign body granuloma, 73
Fungal conjunctivitis, 72 treatment and prognosis, 832 sarcoidosis, 73
Fungal infection, 1013 Gingival GCT of newborn, 1344 Wegener’s granulomatosis, 73
Fungus ball/mycetoma Gingival hyperplasia, drug-induced, Whipple’s disease, 73
clinical presentation, 1632 217–218 Granulomatous lymphadenitis, 50
etiology, 1632 Glassock–Jackson classification, of glomus Granulomatous thyroiditis, 1390, 1392
histopathology, 1632 tumors, 452 Graves’ disease, 5–6, 1388–1389, 1484
PCR techniques, 1632–1633 Glaucoma, 1574–1575 Gross cystic disease fluid protein-15
treatment, 1633 Glaukomflecken, 1585 (GCDFP-15), 31
Furstenberg test, 672 Glial cells missing gene (GCMB), Gross-sampling errors, 96
Fusarium, 1641 1435, 1460 Gross total resection (GTR), 681
Fusobacterium necrophorum, 1611 Glial heterotopias, 672 Growth factors
FVPC. See Follicular variant of papillary Gliosis of the inner retina, 1580 and AFOD, 1251
carcinoma (FVPC) Glomus jugulare. See Jugular in ODOMYX, 1286
paraganglioma GTPase-activating protein (GAP), 688
Glomus tumors, 717 GTR. See Gross total resection (GTR)
Ganciclovir, 1663 clinical findings, 793 GVHD. See Graft-versus-host disease
Ganglion, 957 differential diagnosis, 794–795 (GVHD)
GAP. See GTPase-activating protein (GAP) electron microscopy, 793
Gardner’s syndrome, 967, 1480 Glassock–Jackson classification, 452
GCA. See Giant cell angiofibroma (GCA); immunohistochemistry, 794 Haemophilus influenza, 953
Giant cell arteritis (GCA) molecular findings, 794 Haemophilus influenzae, 345
GCDFP-15. See Gross cystic disease fluid pathologic findings, 793 Hairy polyp, 1348–1349
protein-15 (GCDFP-15) prognosis and treatment, 795–796 Hairy tongue, 209–210
GCOC. See Ghost cell odontogenic radiologic imaging, 793 clinical features, 209
carcinoma (GCOC) Glomus tympanicum. See Tympanic pathology, 210
GCOT. See Granular cell odontogenic tumor paraganglioma treatment, 210
(GCOT) Glottic carcinoma, 139–142 Hamartomas, 1348, 1536–1538
GCT. See Giant cell tumor (GCT); Granular GLUT-1 expression, 1522 respiratory epithelial adenomatoid,
cell tumor (GCT); Granular cell GLY382Asp, 1487 360–361
tumor (GCT) Glycosaminoglycans in ODOMYX, 1286 Hamazaki-Wesenberg inclusions, 1693
Genetic abnormality, in cystic fibrosis, 353 Gnathic osteosarcoma, 971–972 Hansen’s disease, 1625
Genetic linkage analyses, of hereditary Goiterous thyroids, 1390 Haphazard tangles, of nerve
PGL, 718 Gonorrhea fascicles, 677
Genetic mutations, in SH3BP2 gene, 966 diagnosis of, 1618 Hard palate, squamous cell carcinomas of,
Germ cell neoplasms, 1364–1365 histopathology, 1618 300–301
Hard tissue–related proteins [Hematolymphoid neoplasms] Horn cysts, 1476

and AMFs, 1244 of skin, 1109–1115 HPV. See Human papilloma virus (HPV)
AOT, 1238 of thyroid, 1100–1103 HRPT2 mutations, 1453, 1457
and CEOT, 1234 of trachea, 1100 HSV. See Herpes simplex virus (HSV);
Hashimoto’s thyroiditis, 4, 1101–1102, 1102, Hematopoietic tumor, extramedullary, Herpes simplex virus (HSV)
1103, 1387–1388 1026–1027 HSV-1 exposure/infection, 1671
Hassal’s corpuscles, 1457 Hematoxylin, 1445 HSV-2 exposure/infection, 1672
Haversian canals, 960, 967 Hematoxylin and eosin (H&E) stain, 95, 961 HSV I. See Herpes simplex virus type I (HSV I)
H&E. See Hematoxylin and eosin (H&E) Hemidesmosomal proteins, 251 Human herpesvirus 6 (HHV6) lymphadenitis,
Heck’s disease, 1675. See also Focal epithelial Hemophilus influenza, 429, 1609 1009
hyperplasia Hemorrhagic detachment, of the choroid, Human immunodeficiency virus (HIV), 38,
Heerfordt’s syndrome, 1692 1586 1657–1658
Helicobacter pylori, 261 Heparanase, and ameloblastomas, 1214 clinical categories of, 1657
Hemangiomas, 126–127, 779–780, 981, 1355 Hepatocyte growth factor (HGF) role in criteria for infection for adolescents and
in adults, 127 ameloblastomas, 1211 adults, 1657
clinical features, 780–782 Hereditary gingival overgrowth, 1344 epidemiology, 1655
differential diagnosis, 786–788 Her-2 expression, 1485 primary infection and latency, 1656–1657
imaging, 782 Herpes simplex virus (HSV), 121, 260, transmission, 1655
immunohistochemistry, 786 1008–1009, 1661 treatment, 1658
of infancy. See Infantile hemangioma (IH) clinical course, 1671–1673 tropism, 1656
in infants, 126–127 epidemiology, 1671 virion and genome, 1655–1656
pathology, 782–786 interference with cell-mediated Human leukocytes antigens (HLA), 122, 649
prognosis and treatment, 788 immunity, 1672–1673 nasopharyngeal carcinomas, 395
Hemangiopericytoid vascular pattern treatment, 1673 Human milk fat globulin-1 (HMFG1), 1485
in mesenchymal chondrosarcoma, 896 Herpes simplex virus type I (HSV I), 262 Human papilloma virus (HPV), 211, 273
in monophasic synovial sarcoma, 897 Herpetic whitlow, 1671–1672 in benign vs. dysplastic vs. malignant IP,
Hemangiopericytomas, 74, 707 Heterophil test, 1666 1681
Hemangiopericytoma/solitary fibrous Heterotopia detection rates
tumor of middle ear and mastoid, 427 in laryngeal SCC, 1683
clinical features, 848 of neuroglial tissue, 68 in oral cavity SCC, 1683
differential diagnosis, 849–850 of salivary glands, 477–478 in oropharyngeal SCC, 1682
electron microscopy, 849 HGF. See Hepatocyte growth factor (HGF) diseases, 1675–1684
imaging, 848 HHM. See Humoral hypercalcemia of genome, 1675
immunohistochemistry, 848 malignancy (HHM) incidence
molecular findings, 848–849 HHV-8 DNA, 1659–1660 in exophytic papillomas, 363
pathologic findings, 848 Hidrocystomas in oncocytic schneiderian papillomas
prognosis and treatment, 850 clinical features, 1484 (OSP), 370
Hematolymphoid neoplasms differential diagnosis, 1485 in inverted papaillomas, 1679–1681, 1681
of bone, 1108–1109 imaging, 1484 inverted papilloma, 364
of ear, 1107–1108 immunohistochemistry, 1485 life cycle, 1675
of eye, 1103–1107 pathology, 1484–1485 molecular biology carcinomas related to,
of head and neck treatment and prognosis, 1485 290
etiology, 1031 High-grade MEC, 28 nasopharyngeal carcinomas, 398
general features, 1029–1031 Highly active antiretroviral therapy nonkeratinizing carcinomas, 376
Hodgkin lymphomas, 1032–1039 (HAART), 1532, 1657 pathobiology, 1674–1675
myeloid/histiocytic/dendritic cell Histiocytic necrotizing lymphadenitis, 1355. subtypes 16 and 18, 1559
tumors, 1073–1079 See also Kikuchi lymphadenitis transmission, 1673–1674
non-Hodgkin lymphomas, 1039–1073 Histiocytic sarcoma, 1073–1074 Humoral hypercalcemia of malignancy
patholgy, 1031 Histiocytosis, Langerhans cell, 438–439 (HHM), 1459
staging, 1031–1032 Histologic frozen-section slide, of surgical Hurthle cell. See also Oncocytic neoplasms
WHO classification, 1030 margin, 99 lesions, 1441
of hypopharynx, 1099–1100 Histologic grading, of sarcoma, 863 tumors
of larynx, 1099 Histoplasma capsulatum, 1652 adenoma, 1404
of lymph node, 1079–1081 Histoplasmosis, 1652–1654, 1691 carcinomas, 1404–1406
diagnostic considerations, 1079–1081 HIV. See Human immunodeficiency virus Hyaline cartilage metaplastic, in
nasal cavity and paranasal sinuses, 1081– (HIV) mesenchymal chondrosarcoma, 896
1086 HIV-associated lymphadenopathy, Hyaline PA, 35–36
clinical features, 1081 1009–1012 Hyaline-vascular Castleman disease,
diagnostic considerations, 1085–1086 lymphocyte depletion in, 1009 1019–1021
reactive/inflammatory HIV-associated lymphoepithelial, of clinical features, 1019
hematolymphoid lesions, 1082–1085 salivary glands, 1096 differential diagnosis, 1021
nasopharynx, 1086–1088 HIV-associated lymphoid hyperplasia, in pathology, 1019–1021
diagnostic considerations, 1088 head and neck extranodal sites, Hyalinization, 703
features of, 1086–1087 1010–1012 Hyalinizing trabecular tumor
reactive/inflammatory HL. See Hodgkin’s lymphoma (HL) clinical features, 1400
hematolymphoid lesions, 1087–1088 HLA. See Human leukocyte antigens differential diagnosis, 1401–1402
of ocular adnexa, 1103–1107 Hoarseness, as symptom of contact immunohistochemistry, 1401
oral cavity and oropharynx, 1088–1094 ulcers, 112 microscopic features, 1401
diagnostic considerations, 1093–1094 Hodgkin lymphomas, 1032–1039, 1354 molecular genetics, 1401
features, 1088–1090 classical, 1032–1035 pathology of, 1400–1401
reactive/inflammatory nodular lymphocyte–predominant, treatment and prognosis, 1402
hematolymphoid lesions, 1091–1093 1035–1039 Hyalohyphomycosis, 1641
of salivary gland, 1094–1099 versus PTGC, 1005 Hyams grading system, for ONB, 731
diagnostic considerations, 1098–1099 post transplant, 1073 Hybrid cysts, 1478
features of, 1094–1096 Hodgkin’s disease, 15 Hybrid tumors, of salivary gland, 596–597
reactive/inflammatory Hodgkin’s lymphoma (HL), 33, 38 Hydralazine, 252
hematolymphoid lesions, 1096–1098 Hordeolum (stye), 1553 Hydroa vacciniforme–like lymphoma, 1072
Hydrochloroquine, 1693 Immotile cilia syndrome. See Primary ciliary [Inflammatory diseases, of joints]
Hydroxylysylpyridinoline, urine dyskinesia (PCD) dystrophic calcification, 954–955
concentrations, 959 Immunoblastic lymphomas, 42 ganglion, 957
Hyoid bone, 16 Immunocytochemical stains, 14 gout, 953–954
Hyperbaric oxygen therapy, 961 Immunocytochemical techniques, 1433 infectious arthritis, 953
Hypercalcemia, non-PTH causes of. See Immunocytochemistry. See Cytometry oxalosis, 954
Non-PTH-related hypercalcemia Immunodeficiency-associated pigmented villonodular synovitis, 956–957
Hyperfunctioning parathyroid glands lymphoproliferative disorders, rheumatoid arthritis, 952–953
multigland and multifocal disease, 1072–1073 synovial chondromatosis, 955–956
1453–1455 Immunoglobulin G (IgG), 245, 650 synovial cysts, 957
single-gland disease Immunohistochemistry (IHC), 14 tumoral calcinosis, 954–955
adenoma, 1446–1449 ALK+ anaplastic large cell lymphoma, Inflammatory lesions
atypical adenoma, 1449–1450 1066–1067 chondrodermatitis nodularis helicis,
carcinoma, 1450 Burkitt lymphoma, 1056–1057 1534–1535
differential diagnosis and molecular classical Hodgkin lymphoma, 1034–1035 rhinophyma, 1532–1534
pathology, 1450–1453 of DLBCL, 1041 rosacea, 1532–1534
Hyperkeratosis, 1677 extramedullary plasmacytoma, 1057 weathering nodule of the ear,
Hyperorthokeratosis, 253 extranodal NK/T-cell lymphoma, 1061 1535–1536
Hyperparakeratosis, 253 follicular lymphoma, 1049 Inflammatory malignant fibrous
Hyperparathyroidism, 985–986. See also of hyaline-vascular Castleman disease, histiocytoma, 890
Primary hyperparathyroidism; 1021 Inflammatory myofibroblastic tumor,
Secondary hyperparathyroidism intestinal-type adenocarcinomas (ITAC), 172–173
Hyperparathyroidism-jaw tumor (HPT-JT) 386 Inflammatory otic polyps, 431
syndrome, 1437–1438 of Kikuchi lymphadenitis, 1016 Inflammatory papillary hyperplasia,
Hyperplasia, 130 lymphoepithelial carcinomas (LEC), 382 220–221
adenoid, 225–226 malignant melanomas, 393 Inflammatory process, 661
atypical, 271 MALT lymphoma, 1055 Inflammatory pseudotumor, of lymph node,
basal, 271 mantle cell lymphoma, 1053 1025–1026
fibrous. See Fibrous hyperplasia, nasopharyngeal carcinomas, 398 Infliximab, 1693
denture-induced nodular lymphocyte–predominant INF-a therapy, 1677
gingival. See Gingival hyperplasia, Hodgkin lymphoma, 1037 Infundibular cyst, 1342
drug-induced nonintestinal-type adenocarcinomass Inner ear, 424–425
papillary. See Inflammatory papillary (non-ITAC), 388–389 Meniere disease, 445–446
hyperplasia nonkeratinizing carcinomas, 377 Insular carcinoma, 14
parabasal cell, 271 papillary adenocarcinomas of Insulinlike growths factors (IGFs)
squamous, 271 nasopharynx, 401 expression and stroma of
tonsillar, 222–225 of Rosai-Dorfman disease, 1024 ameloblastomas, 1212
Hyperplastic dental follicles, 1279 sinonasal undifferentiated carcinomas Integrin
Hyperplastic nodules, 5, 7 (SNUC), 378–379 and AOT, 1238
diagnosis, challenges, 7–8 small cell neuroendocrine carcinomas solid/multicystic ameloblastoma–central,
Hyperuricemia, 953 (SCNEC), 381 1209
Hypervascular follicular hyperplasia, 1009 Immunostains, on synovial sarcoma, 898 Interdigitating dendritic cell sarcoma,
Hypointense meningiomas, 702 Immunosuppressive drugs, 251 1076–1077
Hypopharynx, hematolymphoid lesions of, Immunosuppressive therapy, 249 Intergroup Rhabdomyosarcoma Study
1099–1100 Incidental pituitary adenoma, 709 Postsurgical Clinical Grouping
Hypophysis. See Pituitary gland Indirect immunofluorescence (IIF), 650 System, on RMS staging, 876
Indolent T-lymphoblastic proliferation, of Interleukin-1, 958
oral cavity and oropharynx, 1093 International Classification Of
Iatrogenic KS, 1660 Infantile fibrosarcomas, 885, 886 Rhabdomyosarcoma (ICR), 54
ICR. See International classification of Infantile hemangioma- International Prognostic Index (IPI) Scoring
rhabdomyosarcoma (ICR) hemangioendothelioma, 1355 System, 1031
Idiopathic cervical fibrosis Infantile hemangioma (IH) International Prognostic Index score, 1032,
clinical features, 824 clinical features, 1525 1045, 1054, 1063
differential diagnosis, 825 defined, 1524 Intestinal-type adenocarcinomass (ITAC),
electron microscopy, 825 differential diagnosis, 1526 383–387
imaging, 824 imaging studies, 1525 classification and survival, 384
immunohistochemistry, 824 immunohistochemistry, 1526 clinical features, 383–384
pathology, 824 molecular genetics, 1526 differential diagnosis, 386–387
treatment and prognosis, 825 pathology, 1525–1526 electron microscopy, 386
Idiopathic cystic chondromalacia, auricular treatment and prognosis, 1526 etiology, 383
cartilage, 433–434 Infantile myofibroma, 1355 imaging, 384
Idiopathic midline destructive disease desmoid and diffuse type, 1360 immunohistochemistry, 386
(IMDD), 660 Infantile systemic hyalinosis, 1344 molecular-genetic data, 386
Idiopathic orbital inflammation, 73, 1598 Infectious arthritis, 953 Paneth cells in, 386
IgE antibodies in allergic rhinosinusitis, Infectious mononucleosis, 51, 1007, pathology, 384–386
344–345 1666–1667 treatment and prognosis, 387
IgG. See Immunoglobulin G (IgG) versus large cell lymphoma, 1088 variants of, 384–385
IgG4-related sclerosing disease, nasopharynx, 1087 Intracranial extension, 676
1014–1015 tonsil, 1091–1092 Intracytoplasmic lumen formation, 1486
of nasopharynx, 1087–1088 Infectious rhinosinusitis, 345 Intraepithelial alterations, classifications,
of ocular adnexa, 1105–1106 Infiltration, fatty, 20 267–272
of parotid gland, 1097–1098 Infiltrative BCC, 1496 dysplasia classification, by WHO, 269–270
IHC. See Immunohistochemistry (IHC) Infiltrative fibroblastic disorders, 1344 Ljubljana classification, 271–272
IIF. See Indirect immunofluorescence Inflammatory diseases, of joints, 952–957 squamous intraepithelial neoplasia
IMDD. See Idiopathic midline destructive calcium pyrophosphate crystal deposition classification, 270
disease disease (CPCDD), 954 Intralesional mineralization, 1478
Immature teratoma, 1365 dermoid cysts, 957 Intralymphatic growth, in ASPS, 902
Intraneural perineurioma, 697 Kaposiform hemangioendothelioma, 1357–1358 Keratosis obturans (KO), congenital
Intraocular conditions, 1576–1586 clinical features, 1527 cholesteatoma, 438
Intraocular lymphoma, 1104–1105 defined, 1526–1527 Keratosis with dysplasia (KWD), 131
Intraoperative cytologic evaluations, 1445 differential diagnosis, 1527 Keratosis without dysplasia (KWOD), 131
Intraoperative parathyroid hormone testing electron microscopy, 1527 Keratotic plugging, 253
(IOPTH), 1455 imaging studies, 1527 Kikuchi-Fujimoto disease. See Histiocytic
Intraosseous basal cell ameloblastoma, immunohistochemistry, 1527 necrotizing lymphadenitis; Kikuchi
1214 pathology, 1527 lymphadenitis
Intraosseous tumors, of salivary gland, treatment and prognosis, 1527–1528 Kikuchi histiocytic necrotizing
597–598 Kaposi-like infantile lymphadenitis, 1354
Intrathyroidal parathyroid glands, 1430 hemangioendothelioma. See Kikuchi lymphadenitis, 52, 1015–1016
Intravascular large B-cell lymphoma, Kaposiform hemangioendothelioma Ki-67 labeling in, 1452
cutaneous, 1111 Kaposi sarcoma (KS), 63, 277, 1659–1660 Killian polyps. See Antrochoanal polyps
Intraventricular meningioma, 703 clinical features, 1530 (ACP)
Intubation granuloma, 111–112 differential diagnosis, 1532 Kimura disease, 1016–1018
Inverted papilloma, 363–369 electron microscopy, 1532 clinical features, 1016–1017
carcinomas and, 366–368 imaging studies, 1530–1531 differential diagnosis, 1017–118
clinical features, 363–364 immunohistochemistry, 1531–1532 pathology, 1017
differential diagnosis, 368 molecular genetics, 1532 of salivary glands, 1098
etiology, 364 pathology, 1531 KIT mutations, 1510
imaging, 364 treatment and prognosis, 1532 Klebsiella ozaenae, 346
Krouse staging system for, 369 in vascular transformation of sinuses, Klebsiella pneumoniae, 64
pathology, 364–366 1005–1006 Klebsiella rhinoscleromatis, 1085
treatment and prognosis, 368–369 Karyotypes, 727 Klippel-Trenaunay syndrome, 1523
Inverting papilloma, 1678 Kassabach-Merrit syndrome, 1357, 1523 Koch’s bacillus, 1621
Involucrin and calcifying odontogenic cyst Kawasaki disease, 1018–1019 Koplick’s spots, 1685
(COC), 1265 KCOT. See Keratocystic odontogenic tumors Krouse staging system, inverted papilloma,
Involucrin expression, in TL, 1481 (KCOT) 369
Iodine therapy, 6 Keloids KS. See Kaposi sarcoma (KS)
Iridocyclectomy, 1587 clinical features, 1512 Kursteiner’s canals, 1431
Iris root, 1587 defined, 1511 Kuttner tumor. See Chronic sclerosing
Iron pigment in thyroid follicular cells, 1393 differential diagnosis, 1512–1513 sialadenitis
Irritation fibroma, 221–222 electron microscopy, 1512 Kviem test, 1693
Isoniazid, 252 immunohistochemistry, 1512 KWD. See Keratosis with dysplasia (KWD)
Isthmus-catagen cyst. See Pilar cysts (PCs) molecular genetics, 1512 KWOD. See Keratosis without dysplasia
ITAC. See Intestinal-type adenocarcinomass pathology, 1512 (KWOD)
(ITAC) treatment and prognosis, 1513
Itraconozole, 1637 Kenny–Caffey syndrome, 1460 Lacrimal gland
Keratin-filled clefts, 1678 clinical findings, 1599–1600
Jaw, 68–70 Keratinization, 715 extranodal marginal zone B-cell
metastases, 1156 in MCE, 28 lymphoma, 1600–1601
Jeryl Lynn vaccine substrain, 1687 Keratinized cells, 267 lymphoproliferative processes, 1599
JHF. See Juvenile hyaline fibromatosis (JHF) Keratinized papilloma, 123–124 Laminin and solid/multicystic
JNA. See Juvenile nasopharyngeal Keratinizing squamous carcinoma, 100 ameloblastoma–central, 1208
angiofibroma (JNA) Keratinizing squamous cell carcinomas Langerhans cell histiocytosis (LCH), 438–
JOC. See Juxtaoral organ of Chievitz (KSCC), 285, 290 439, 966, 1074–1075, 1351, 1415
(JOC) pathologic features, 290–292 of bone, 1109
JOC vs Carcinoma, microscopic features, variants of, 285 dermatopathic lymphadenopathy, 1005
671 Keratinocyte growth factor (KGF), Kimura disease, 1018
JTPG. See Jugulotympanic paragangliomas congenital cholesteatomas, 438 of skin, 1112
(JTPG) Keratinocytes, in seborrheic keratoses (SK), Langerhan’s cells, 52, 438–439
Jugular paraganglioma, 721 1475 and CEOT, 1234
Jugulotympanic paragangliomas, 451–454 Keratinocytic intraepithelial neoplasia sarcoma, 1075
classification, 452 (KIN). See Actinic keratoses (AKs) Langerhan’s histiocytes, 52
Jugulotympanic paragangliomas (JTPG), Keratinous cysts of infundibular type, 1342 Large cell carcinoma, 591–593
721–722 Keratoacanthoma, 1493–1494 Large cell infiltrates, diffuse/nodular
Juvenile hemangioma. See Infantile Keratoameloblastoma, 1225–1226 diagnosis, of hematolymphoid lesions of
hemangioma (IH) Keratoconus, 1569–1570 skin, 1113–1114
Juvenile hyaline fibromatosis (JHF), 1344 Keratocystic odontogenic tumors (KCOT), Large cell lymphoma. See also Diffuse large
Juvenile melanoma, 1340 1209, 1240 B-cell lymphoma (DLBCL)
Juvenile nasopharyngeal angiofibroma Keratocystoma, 540–542 anaplastic. See Anaplastic large cell
(JNA), 1360–1361 Keratohyaline granules, 1486 lymphoma
Juvenile onset laryngeal papillomatosis, Keratoma. See Cholesteatomas, acquired versus infectious mononucleosis, 1088
1677 Keratosis, 129–133 problems in diagnosis of, 1093–1094
Juvenile xanthogranuloma, nasal cavity, atypia, 130 Laryngeal candidiasis, 1645
1085 CIS, 130 Laryngeal carcinoma, 144–145
Juxtaoral organ of Chievitz (JOC) clinical features, 131 Laryngeal cartilages invasion, 144
clinical features, 669 dyskeratosis, 130 Laryngeal kaposi sarcoma (KS), 1660
diagnosis, 671 erythroplakia, 131 Laryngeal leiomyosarcoma, 876
embryology, 669 histology, 129–130 Laryngeal metastases, 1157–1158
histopathology, 670 hyperplasia, 130 Laryngeal papilloma, 1677
immunohistochemistry, 671 KWD, 131 Laryngeal paragangliomas (LPG), 723–724
macroscopy, 670 KWOD, 131 Laryngeal TB, 1622
overview, 669 leukoplakia, 131 Laryngoceles, 117–119
physiology, 669 overviews, 129 Larynx, 953
ultrastructure, 670–671 parakeratosis, 130 hematolymphoid lesions of, 1099
treatment, 132–133
Laser therapy, 277 Lipoma, 128 Lymph nodes, 37–52, 100–101

Latent membrane proteins (LMP), 1664, Lipoma, lipoma variants, and reactive ancillary studies, 39–40
1665 lipomatous lesions B-Cell, non-Hodgkin lymphoma, 43–45
Lateral aberrant thyroid tissue, 230 clinical and pathology, 806–812 biopsy, 1150
Lateralization of cancer in nasal cavity, 372 differential diagnosis, 812 causes of enlargement of head and
LCH. See Langerhans cell histiocytosis immunohistochemistry, 812 neck, 998
(LCH); Lobular capillary molecular findings, 812 clinical symptoms, 38
hemangioma (LCH) prognosis and treatment, 812 diagnosis, 38–39
LE. See Lupus erythematosus (LE) radiologic imaging, 812 FNA, non-Hodgkin lymphomas, 39
LEC. See Lymphoepithelial carcinomas Lipomatosis, 482 FNAB, Hodgkin lymphoma, 45–46
(LEC); Lymphoepithelial cysts (LEC) Liposarcomas, 881–885 FNAB, non-Hodgkin lymphomas, 40–43
Leg-type, primary cutaneous DLBCL, Lithium, 1438 hematolymphoid neoplasms, 1079–1081
1110–1111 and hypercalcemia/ infarction, 1006
Leiomyomas, 128–129, 1416 hyperparathyroidism, 1458–1459 inflammatory pseudotumor, 1025–1026
clinical findings, 802–803 Ljubljana classification, 269, 271–272 lymphadenopathies, 49–52
differential diagnosis, 805–806 basal hyperplasia, 271 metastatic neoplasms to cervical
electron microscopy, 805 malignant lesions, 271 lymph nodes, FNAB, 46–49
imaging, 803 parabasal cell hyperplasia, 271 nonspecific reactive lymphoid
immunohistochemistry, 804 squamous hyperplasia, 271 hyperplasia, 997–1003
molecular findings, 804–805 LMP. See Latent membrane proteins (LMP) normal, 997
pathologic findings, 803–804 LMP-1, nasopharyngeal carcinomas, 400 patterns and etiology of reactive, 1080
prognosis and treatment, 806 Lobectomy, 13, 15 reactive lymphoid hyperplasia of, 997
Leiomyosarcomas, 58, 876–881 Lobular capillary hemangioma, 227–228 Lymphoblastic leukemias/
Leishmania, 1013, 1653, 1654 clinical features, 227–228 lymphomas, 1060
Leishmaniasis, 1013 diagnosis, 228 Lymphoblastic lymphoma, 40
Lemiere’s disease, 1611 pathology, 228 Lymphocyte depletion
Lens treatment, 228 classical Hodgkin lymphoma, 1034
anatomy, 1575 Lobular capillary hemangioma in fine fibrosis, 1009
cataract, 1575–1576 (LCH), 1340 Lymphocyte-rich classical Hodgkin
Lentigo maligna, 1507 Localized plasma cell Castleman disease, lymphoma, 1033–1034
melanoma, 1507–1509 1021–1022 Lymphocytic/histiocytic (L&H) cells, 1005
Lepromatous lymphadenitis, 1012 LOH. See Loss of heterozygosity (LOH) nodular lymphocyte–predominant
Leprosy Loss of heterozygosity (LOH), 685 Hodgkin lymphoma, 1037
clinical features, 1625 Low-grade fibromyxoid sarcoma (LGFMS), Lymphocytic thyroiditis, 3
culture and PCR identification, 1627 886, 888 Lymphoepithelial carcinomas (LEC), 33,
differential diagnosis, 1627 Low grade malignancies vs. PA, 36–37 160–161, 382–383, 593–595
head and neck manifestations, 1626 Low-grade MEC, 26 Lymphoepithelial cysts (LEC), 22, 481–482
histopathology, 1626–1627 LPG. See Laryngeal paragangliomas (LPG) Lymphoepithelial lesions, 33
immunological considerations, 1625 LPL. See Lymphoplasmacytic lymphoma Lymphoepithelial sialadenitis (LESA),
Ridley Joplin criteria classification, 1625 (LPL) 501–505
treatment, 1627 Lupus erythematosus (LE), 252–254, 274 of salivary glands, 1096
LESA. See Lymphoepithelial sialadenitis chronic cutaneous lupus erythematosus, Lymphoepithelial sialadenitis versus MALT
(LESA) 252 lymphoma, 1100
Leser-Trelat, 1477 diagnosis, 253–254 Lymphoepithelial tumor. See Cutaneous
Lesions histopathology, 253 lymphadenoma (CL)
containing squamous cells, 27–28 subacute cutaneous lupus erythematosus, Lymphoepithelioma, in children, 1355
in ocular adnexa, 72–74 252–253 Lymphoepithelioma-like carcinoma
Leukoplakia, 59–60, 131, 273–275 systemic lupus erythematosus, 252 (LE-LC), 1483
clinical features, 273 treatment, 254 Lymphoid cells, 3, 32
defined, 273 Lupus lymphadenitis, 1014 Lymphoid hyperplasia, 33
diagnosis, 274 Lupus vulgaris (LV), 1622 Lymphoid proliferations, 1079–1081
pathology, 274 LWG. See Limited form of Wegener’s atypical lymphoid hyperplasia in,
treatment, 274–275 granulomatosis 1081
Levamisole, 263 Lymphadenomas Lymphoid tissues, of Waldeyer ring, 1001
LGFMS. See Low-grade fibromyxoid lymphadenoma, 534–535 Lymphoma, 15
sarcoma (LGFMS) sebaceous lymphadenoma, 533–534 Lymphoplasmacytic lymphoma (LPL), 43,
Lichenoid drugs, 255–256 Lymphadenopathies, 37, 49–52, 1627 1059–1060
Lichen planus, 254–257, 281 cat-scratch disease, 51 Lymphoproliferative disorders,
clinical presentation, 254–255 dermatopathic, 1005 immunodeficiency-associated,
immunology, 257 granulomatous lymphadenitis, 50 1072–1073
immunopathology, 257 HIV-associated, 1009–1012 Lymphoproliferative processes, 1599
lichenoid drugs, 255–256 infectious mononucleosis, 51
pathology, 256–257 Kikuchi lymphadenitis, 52 Macroadenoma, 709
treatment, 257 reactive lymphoid hyperplasia, 49–50 Maffucci syndrome, 1523
Limbal dermoid, 1562–1563 Rosai-Dorfman disease, 51–52 Magnet resonance imaging (MRI), 1
Limited form of Wegener’s granulomatosis suppurative lymphadenitis, 50 MAI. See Mycobacterium avium-
(LWG), 654. See also Wegener’s toxoplasmosis, 50–51 intracellulare (MAI); Mycobacterium
granulomatosis Lymphangioma, 788, 983–984 avium-intracellulare (MAI)
Lingual thyroid, 229–230 clinical and molecular features, 789 Mainstay therapy, 976, 983
clinical features, 230 differential diagnosis, 792 Major aphthae, 261
pathology, 230 electron microscopy, 792 Malakoplakia, 431–432
primordium of thyroid, 1346 imaging, 789–790 clinical course, 1690
treatment, 230 immunohistochemistry, 792 etiology, 1690
Lip cancer, 292–294 pathology, 790–792 histopathology, 1690–1691
Lipoadenomas, 1449 prognosis and treatment, 792–793 treatment, 1691
Lipoblastoma, 1364 Lymphatic malformations (LM), 1522, Malignant ectomesenchymoma, 1363
Lipoid proteinosis, 1344 1597–1598
Malignant epithelial neoplasms Malignant oral lesions, 61–63 Median rhomboid glossitis, 207–208
basal cell carcinoma, 1495–1498 basaloid squamous cell carcinoma, 62 clinical features, 207
basosquamous cell carcinoma, 1498–1499 metastatic squamous cell carcinoma, diagnosis, 208
merkel cell carcinoma (MCC), 1502–1504 62–63 pathology, 207–208
microcystic adnexal carcinoma, 1499–1501 nonepithelial tumors, 63 treatment, 208
squamous cell carcinoma, 1491–495 PLGA, 63 Medium-sized cell infiltrates
trichilemmal carcinoma (TLC), 1501–1502 salivary gland lesions, 63 diagnosis, of hematolymphoid lesions of
Malignant extrarenal rhabdoid tumor, squamous cell carcinoma, 61–62 skin, 1114
900–901 Malignant peripheral nerve sheath tumor Medullary carcinoma, 13–14
Malignant fibrous histiocytoma (MFH), 57, (MPNST), 58, 688. See also Malignant Medullary thyroid carcinoma (MTC), 1355,
885–892 triton tumor 1356, 1391, 1441, 1451
Malignant GCT, 700–701 clinical features, 726 Medullary thyroid carcinoma (MTC), 685
Malignant lesions, in nasal cavity sinuses, diagnosis, 728 Meibomian gland, 73
64–68 histopathology, 727 Meige disease, 1523
Malignant lymphomas, 32–33, 38 imaging, 726–727 Melanin, 48
Malignant melanomas, 47–48, 80–81, immunohistochemistry, 727 Melanocytic lesions, in ocular adnexa, 79–81
170–171, 391–394, 1587 macroscopy, 727 malignant melanoma, 80–81
amelanotic, 392 overview, 725–726 melanocytoma, 79–80
in children, 1341 somatic genetics, 727–728 melanotic neuroectodermal tumor of
clinical features, 391–392 treatment, 728 infancy, 79
differential diagnosis, 393 ultrastructure, 727 Melanocytic neoplasms
etiology, 391 Malignant rhabdoid tumor (MRT), 1363 melanomas, 1507–1511
immunohistochemistry, 393 in floor of mouth, 1364 spitz nevus, 1504–1507
molecular-genetic data, 393 Malignant round cell neoplasms, 1363 Melanocytic neuroectodermal tumor of
oral, 323–326 Malignant syringoma. See Microcystic infancy (MNTI)
pathology, 392–393 adnexal carcinoma (MAC) clinical features, 733
treatment and prognosis, 393–394 Malignant triton tumor, 726, 892–894 diagnosis, 734
Malignant mesenchymal tumors Malignant tumors, in ocular adnexa, 75–79 histopathology, 733–734
ASPS, 901–904 ACC, 76 imaging, 733
fibrosarcoma, 885–892 basal cell carcinomas, 75–76 immunohistochemistry, 734
grading, 862–863 Merkel cell tumor, 77 macroscopy, 733
malignant extrarenal rhabdoid tumor, metastatic carcinoma, 78–79 overview, 733
900–901 orbital teratomas, 77 somatic genetics, 734
malignant fibrous histiocytoma, 885–892 retinoblastoma, 77–78 treatment, 734–735
malignant lipomatous, liposarcomas, sebaceous carcinoma, 76–77 ultrastructure, 734
881–885 squamous cell carcinoma, 76 Melanocytic nevi, cutaneous tumefactions
malignant mesenchymoma, 894–895 MALT. See Extranodal marginal zone B-cell from children
malignant skeletal muscle lymphoma (MALT) atypical pattern of lentiginous
leiomyosarcomas, 876–881 MALT lymphoma, 33 proliferation, 1341
RMS, 869–876 Manchester clinical diagnostic criteria, for congenital melanocytic nevi (CMN), 1339
malignant triton tumor, 892–894 NF2, 690 giant CMN, 1341
malignant vascular Mandible, cortical defects. See Cortical nested and lentiginous junctional
angiosarcoma, 867–869 defects of mandible component, 1340
epithelioid hemangioendothelioma, Mandibular margin, 99 neurocytic hamartoma, 1340–1341
863–867 Mantle cell lymphoma risk of a malignancy in, 1340
mesenchymal chondrosarcoma, 895–897 clinical features, 1051–1052 single cell pattern, 1340
staging, 863 differential diagnosis, 1053–1054 spitz-like features, 1340
synovial sarcoma, 897–899 immunohistochemistry, 1053 Melanocytoma, 79–80
Malignant mesenchymoma, 894–895 molecular genetic data, 1053 Melanomas
Malignant neoplasms, 9–15 pathology, 1052–1053 clinical features, 1507–1508
anaplastic carcinoma, 14–15 treatment and prognosis, 105 differential diagnosis, 1511
of external ear and auditory canal, 459–464 Mantle cell lymphoma (MCL), 40, 44 electron microscopy, 1510
insular carcinoma, 14 Marginal zone lymphoma (MZL), 43 imaging studies, 1508
lymphoma, 15 Massachusettes General Hospital, 982 immunohistochemistry, 1510
medullary carcinoma, 13–14 Masson trichrome histochemical stain, 878 molecular genetics, 1510
of middle ear, 465–467 Masson vegetant hemangioma. See Papillary pathology, 1508–1510
papillary thyroid carcinoma, 9–11 endothelial hyperplasia staging, 1507
Malignant odontogenic tumors Mastocytosis, cutaneous, 1112, 1113 treatment and prognosis, 1511
ameloblastic carcinoma (AMCA), 1292 Mastoid, heterotopias of, 427 Melanoses and melanocytic proliferations,
differential diagnosis, 1295 Matrix metalloproteinase (MMP), 685 1559–1562
DNA microarray study, 1295 Matrix metalloproteinases (MMP), and Melanosis, 170
etiology of, 1293–1294 ameloblastomas, 1213–1214 Melanotic ameloblastoma. See Melanocytic
frequency of, 1293 Matrix-rich microcirculation architecture, neuroectodermal tumor of infancy
gender ratio, 1293 1587 (MNTI)
growth rate, 1293 Maxillary sinuses, squamous cell Melanotic lesions, 170–171
immunohistochemistry, 1294 carcinomas of, 374–376 Melanotic neuroectodermal tumor of
locations of, 1293 Mayo Clinic, 96 infancy, 1346
ultrastructure of, 1294 Mazabraud myxomas, 1728 Melanotic neuroectodermal tumor of
metastasizing ameloblastoma Mazabraud syndrome, 964, 1727–1728 infancy, 79
(METAM), 1290 McCoy cell culture, 72 Melanotic neuroectodermal tumor of
age range, 1291 McCune Albright syndrome, 964 infancy (MNTI), 1346
growth rate, 1291 MCL. See Mantle cell lymphoma (MCL) vimentin and HMB45, 1347
histopathological features of, 1291 Measles (rubeola), 1685–1687 Melanotic progonoma. See Melanocytic
immunohistochemistry, 1291–1292 Mebendazole, 1690 neuroectodermal tumor of infancy
location of, 1291 MEC. See Mucoepidermoid carcinomas (MNTI)
treatment and prognosis, 1292 (MEC) Mel-CAM glycoprotein and calcifying
secondary (Dedifferentiated) AMCA, 1295 Medial pterygoid muscle, 669 odontogenic cyst (COC), 1265
Membrane type 1-matrix metalloproteinase Metastatic tumors, to oral regions Mohs surgery, 1495, 1504, 1510, 1511, 1519
(MT1-MMP), and ameloblastomas, jaw metastases, 1156 Molecular genetic data
1214 oral soft tissue metastases, 1156–1157 ALK+ anaplastic large cell lymphoma,
Membranous labyrinth, 424–425 Metastatic tumors to middle ear and 1067–1068
Memorial Sloan-Kettering Cancer Center, temporal bone, 467 Burkitt lymphoma, 1056–1057
295, 305 Metastatic tumors to thyroid, 1416–1417 classical Hodgkin lymphoma, 1035
MEN. See Multiple endocrine neoplasia Metastatic undifferentiated nasopharyngeal DLBCL, 1041
(MEN); Multiple endocrine neoplasia type, of carcinoma, 1151 extramedullary plasmacytoma, 1057
(MEN) Methimazole antithyroid drugs, 1386 extranodal NK/T-cell lymphoma,
Meniere disease, inner ear, 445–446 Methotrexate, 1693 1061–1062
Meningeal sarcoma, 706 Methylene diphosphonate bone of hyaline-vascular Castleman disease,
Meningioma scintigraphy, 961 1021
clinical features, 701–702 Metronidozole, 1611 MALT lymphoma, 1055–1056
diagnosis, 707 MFH. See Malignant fibrous histiocytoma mantle cell lymphoma, 1053
imaging, 702 (MFH) nodular lymphocyte–predominant
immunohistochemistry, 705 MIB-1 antibody in AFOD, 1251 Hodgkin lymphoma, 1037
malignant, 704–705 Microcystic adnexal carcinoma (MAC), Molecular-genetic data
overview, 701 1486–1487 ITAC, 386
pathology, 702–704 clinical features, 1499 malignant melanomas, 393
somatic genetics, 705–707 differential diagnosis, 1500 nasopharyngeal carcinomas, 398–399
treatment, 707–708 immunohistochemistry, 1500 Molecular genetic data, follicular
WHO classification, 701 molecular genetics, 1500 lymphoma, 1049
Meningioma of the ocular adnexa, 1602 pathology, 1499–1500 Moll’s gland cyst. See Hidrocystomas
Meningiomas, 75, 455–456 treatment and diagnosis, 1500–1501 Molluscum contagiosum, 1684–1685
Meningitis, bacterial, 676 Microinvasive carcinoma (MIC), 135–136 Monocytoid B cells, 999
Meningoceles, 674 clinical features, 136 Mononucleosis, 1355
Meningothelial cells, 704 overviews, 135–136 Monophasic synovial sarcoma. See Synovial
Merkel cell carcinoma (MCC) treatment, 136 sarcoma
clinical features, 1502 Microlaryngoscopy with laser excision, 1677 Monosodium urate crystals, in gout, 953
differential diagnosis, 1503–1504 Micronodular BCC, 1496 Monospot test, 1666
electron microscopy, 1503 Microscopic polyangiitis (MPA) Monostotic fibrous dysplasia, 964–965
immuhistochemistry, 1503 clinical features, 655 MPA. See Microscopic polyangiitis
molecular genetics, 1503 diagnosis, 655 MPNST. See Malignant peripheral nerve
pathology, 1503 pathology, 655 sheath tumor (MPNST)
treatment and prognosis, 1504 treatment and prospect, 655–656 MPO. See Myeloperoxidase
Merkel cell tumor, 77 Middle ear, 424 MRI. See also Magnet resonance imaging
Mesenchymal chondrosarcoma, 895–897 adenocarcinomas, 466–467 (MRI)
Mesenchymal tumors adenomas. See Middle ear adenomas acute supprative osteomyelitis, 958
angiosarcoma, 1415–1416 benign neoplasms of, 449–456 chondrosarcoma, 977
aytpical fibroxanthoma, 1520–1521 cholesteatomas of, 436–438 chordoma, 980
dermatofibroma, 1515–1517 endolymphatic sac papillary tumor, chronic suppurative osteomyelitis, 959
dermatofibrosarcoma protuberans, 457–458 gout, 953
1517–1520 heterotopias of, 427 osteoblastoma, 969
fibrous papules (FPs), 1513–1514 malignant neoplasms of, 465–467 parosteal osteosarcoma, 973
keloids, 1511–1513 metastatic tumors, 467 PVNS, 956
leiomyomas, 1416 squamous cell carcinomas, 465–466 MRT. See Malignant rhabdoid tumor (MRT)
nuchal-type fibroma, 1514–1515 Middle ear adenomas, 449–451 MTC. See Medullary thyroid carcinoma
Mesenchymal tumors, benign with neuroendocrine differentiation, (MTC); Medullary thyroid carcinoma
of external auditory canal, 448–449 450–451 (MTC)
Metastases, 179 Middle ear squamous cell carcinomas, MT1-MMP. See Membrane type 1-matrix
cervical lymph nodes, 299–300 465–466 metalloproteinase (MT1-MMP) and
clinical features, 179 Midfacial destructive diseases, diagnosis of, ameloblastomas
nasal cavity/paransal sinuses, 402 664 Mucinous adenocarcinoma, 572
overviews, 179 Midline carcinoma with NUT rearrangement Mucinous carcinoma, 100
prognosis, 179 (MCNUTR), 1729–1730 Mucoceles, 74, 356–357
Metastases , of orbit, 1603 Mild dysplasia, 269 Mucoceles, of salivary gland, 480–481
Metastasizing ameloblastoma (METAM), Milial cysts, 1342 Mucoepidermoid carcinoma, 546–552
1290 Milk alkali syndrome, 1438 Mucoepidermoid carcinoma (MEC), 1352,
Metastatic adenocarcinoma, 1150 Minimally invasive techniques, 1455 1412
Metastatic carcinoma, 25, 78–79, 1138 Minocycline, 1693 Mucoepidermoid carcinomas (MEC), 17, 23,
Metastatic cystic squamous carcinoma, 1151, Minocycline ingestion and pigment 102, 169, 391
1152 accumulation in thyroid, 1393 Mucorales
Metastatic malignancies, 17–18, 31 Minor aphthae, 261 clinical presentation, 1636
Metastatic melanoma, 1591 Minor aphthous ulcers, 261 etiology, 1635–1636
Metastatic neoplasms to cervical lymph Mitomycin-C, 1556 histopathology, 1636–1637
nodes, FNAB, 46–49 Mitoses, 1480, 1726 serology, 1637
malignant melanoma, 47–48 Mitotic activity, 1493 treatment, 1637
nasopharyngeal carcinoma, 47 Mixed mesoneuroectodermal hamartoma, Mucor hyphae, 1637
squamous cell carcinoma, 46–47 1348 Mucormycosis, 1637
supraclavicular lymph node metastases, MMP. See Matrix metalloproteinase (MMP); Mucosa-associated lymphoid tissue (MALT)
48–49 Mucous membrane pemphigoid lymphoma. See also Extranodal
thyroid carcinoma, 47 (MMP) marginal zone B-cell lymphoma
Metastatic neuroblastoma, to skull, 1363 MMPs. See Matrix metalloproteinases clinical features, 1054
Metastatic papillary carcinoma, of thyroid, (MMPs) and ameloblastomas of conjunctiva, 1105
1151 MNTI. See Melanotic neuroectodermal differential diagnosis, 1056
Metastatic squamous cell carcinoma, 62–63 tumor of infancy (MNTI) immunohistochemistry, 1055
Metastatic thymoma, 1725 Moderate dysplasia, 269 of lacrimal gland, 1106
[Mucosa-associated lymphoid tissue Myoepithelioma, 519–522 [Nasal encephalocele (NE)]

(MALT)] clinical features, 519 diagnosis, 675–676
large cell transformation in, 1055 defined, 519 imaging, 675
lymphoepithelial sialadenitis versus, 1100 differential diagnosis, 521 overview, 674
molecular genetic data, 1055–1056 immunohistochemistry, 520–521 pathogenesis, 676
of orbit, 1105 pathology, 519–520 pathology, 675
immunostaining, 1108 treatment, 521–522 treatment, 676
pathology, 1054–1555 Myofibroblastoma, 1152 Nasal glioma (NG), 1348
of salivary glands, 1094–1095 Myofibroma clinical features, 671–672
of skin, 1111 clinical features, 837 diagnosis, 673–674
of thyroid, 1102, 1103 differential diagnosis, 841–842 imaging, 672
in situ hybridization for electron microscopic findings, 840–841 overview, 671
immunoglobulin mRNA, 1104 immunohistochemical findings, 840 pathogenesis, 674
of tonsil, 1091 molecular findings, 840 pathology, 672–673
treatment and prognosis, 1056 pathologic findings, 838–840 treatment, 674
Mucosal neuromas, 692–694 prognosis and treatment, 842–843 Nasal heterotopia. See Nasal glioma (NG)
Mucosal surfaces, 101 radiologic imaging, 837–838 Nasal mucosa, 672
Mucosal ulcerations, 1657 Myofibromatosis. See Infantile myofibroma Nasal obstruction, rhinosinusitis
Mucoserous (salivary) glands, Myofibromatosis-myofibroma, 1358 medicamentosa and, 347
hamartomas, 361 Myogenic neoplasms, 1361 Nasal polyps, 348–350
Mucous cell metaplasia, 1207 Myosin heavy chain genes (MYH), 1487 clinical features, 348
Mucous membrane pemphigoid (MMP), Myositis ossificans (MO) circumscripta with cystic fibrosis, 353
243, 249–251 clinical findings, 818–819 pathology, 348–350
clinical presentation, 249–250 differential diagnosis, 820 with squamous metaplasia, 368
diagnosis, 251 electron microscopy, 820 treatment, 350
immunology, 251 immunohistochemistry, 820 Nasal septum, 953
immunopathology, 250–251 pathologic findings, 819–820 squamous cell carcinomas, 373–374
pathology, 250 prognosis and treatment, 820 Nasal vestibule
treatment, 251 radiologic imaging, 819 squamous cell carcinomas, 372–373
Mucous retention cysts, 59 Myospherulosis, 64, 358–359 staging of carcinomas, 373
antrochoanal polyp with, 351 Myospherulosis, 1643–1644 Nasopharyngeal carcinoma (NPC), 47,
Mucus, allergic, 354–356 Myotonic dystrophy, 1480 64–65, 394–200, 1668–1669
Mucus-propelling cilia, 351–352 Myxofibrosarcoma, 886–887, 889 anatomy, 394–395
Muir-Torre syndrome, 1488, 1489, 1493, 1553 Myxoid liposarcoma, 881, 882 classification of, 397
Multicentric Castleman disease, 1009 Myxoid liposarcomas, 58–59 clinical features, 395–396
clinical features, 1022 Myxoid malignant fibrous histiocytoma. differential diagnosis, 399
pathology, 1023 See Myxofibrosarcoma Epstein–Barr virus (EBV) genome
Multimodality therapy, for ONB, 732 Myxoid neurothekeomas, 695 detection in, 1355
Multinodular goiter, 1390–1391 Myxoid soft tissue sarcomas, 58–59 etiology, 395
Multiple endocrine neoplasia, 1437 Myxomas, 1279 immunohistochemistry, 398
Multiple endocrine neoplasia (MEN), 1348 external auditory canal, 448–449 molecular-genetic data, 398–399
Multiple endocrine neoplasia (MEN), 677, 692 MZL. See Marginal zone lymphoma (MZL) pathology, 396–398
Multiple odontomas, 1253 treatment and prognosis, 399–400
Multiple primary malignancies, 145 undifferentiated nasopharyngeal
NARES. See Nonallergic rhinosinusitis with
Multiple syringomas, 1342 nonkeratinizing carcinoma, 1357
eosinophilia syndrome (NARES)
Mumps, 495, 1687 viral studies, 398
Nasal biopsy, in ARS, 346
Murine double minute 2 (MDM2) and p14 Nasopharynx
Nasal cavity
(ARF) expression in ameloblastomas, carcinomas. See Nasopharyngeal
extranodal NK/T-cell lymphoma,
1211 carcinomas
1060–1064
Murk Jansen’s chondrodysplasia, 1458 hematolymphoid neoplasms, 1086–1088
hematolymphoid neoplasms, 1081–1086
Myalgia, 252 papillary adenocarcinomas, 400–402
lateralization of cancer of, 372
MYC gene translocation, DLBCL, 1041 salivary-type neoplasms, 391
metastases to, 402
Mycobacterial cervical lymphadenitis, National Cancer Institute (NCI), 1
sinternal anatomy of, 373
1624–1625 National Institute on Drug Abuse, 663
squamous cell carcinomas of, 371–374
Mycobacterial (tuberculous) lymphadenitis, Natural killer (NK) cells, 262
Nasal cavity sinuses, 63–68
1012 NBCCS. See Nevoid BCC syndrome (NBCCS)
lesions, 64
Mycobacterium avium-intracellulare NCI. See National Cancer Institute (NCI)
angiofibromas, 64
(MAI), 38 NCMH. See Nasal chondromesenchymal
myospherulosis, 64
Mycobacterium avium-intracellulare hamartoma (NCMH)
paranasal sinus mucoceles, 64
(MAI), 1624 NE. See Nasal encephalocele (NE)
rhinoscleroma, 64
Mycobacterium tuberculosis, 1012 NEC. See Neuroendocrine carcinomas (NEC)
sinonasal hemangiopericytoma, 64
clinical stages, 1621 Neck dissections
malignant lesions, 64–68
epidemiology, 1621 adjuvant chemotherapy, 1144–1145
heterotopia, of neuroglial tissue, 68
in the head and neck, 1622 extended radical, 1136
nasopharyngeal carcinoma, 64–65
laryngeal, 1622–1625 gross examination of
olfactory neuroblastoma, 65–67
mucocutaneous, 1622 radiologic examination, 1137
paraganglioma, 67–68
primary sinonasal tract, 1622 technique, 1137–1138
sinonasal adenocarcinoma, 67
reactivation, 1621–1622 microscopic examination, 1138
sinonasal neuroendocrine carcinoma, 67
Mycoplasma pneumoniae, 260 modified radical, 1136
sinonasal undifferentiated carcinoma,
Mycosis fungoides, 1069–1070 radical, 1136
66–67
Myeloid sarcoma, 1073 selective, 1136
Nasal cerebral heterotopia, 1348–1349
of salivary glands, 1095 unexpected pathology
Nasal chondromesenchymal hamartoma
Myeloperoxidase (MPO), 650 granulomatous lesions, 1142
(NCMH), 974–975, 1351
MYH-associated polyposis, 1487 lymph node heterotopias, 1142, 1143
Nasal encephalocele (NE)
Myoepithelial carcinoma, 580–583 anatomy, 674–675 metastatic papillary thyroid
Myoepithelial carcinoma, 36 clinical features, 675 carcinoma, 1142
Myoepithelial cells, 35
Necrobiosis with palisading mantle of Neuroendocrine differentiation, middle ear Nodular lymphocyte–predominant
histiocytes, 1367 adenomas, 450–451 Hodgkin lymphomas, 1035–1039
Necrosis, 1591 Neuroendocrine tumors, 162–167 clinical features, 1036
Necrotizing external otitis, 427–428 AC, 164–166 differential diagnosis, 1038–1039
Necrotizing granulomatous combined small cell neuroendocrine immunohistochemistry, 1037
lymphadenitis, 1354 carcinoma, 167 molecular genetic data of, 1037
Necrotizing granulomatous nodules, 952 overviews, 162 pathology, 1036–1037
Necrotizing sialometaplasia, 491–493 paraganglioma, 167 versus PTGC, 1005
Neisseria gonorrhea, 953 SCNEC, 166–167 transformation to non-Hodgkin
Neonatal hyperparathyroidism, 1458 TC, 162–164 lymphoma, 1037
Neoplasm, in ocular adnexa, 74–75 Neurofibroma, 63, 127–128, 681–683 treatment and prognosis, 1039
cavernous hemangiomas, 74 Neurofibromatosis 1, 687–689 Nodular melanoma, 1509
hemangiopericytoma, 74 Neurofibromatosis 2, 689–691 Nodular sclerosis, classical Hodgkin
meningioma, 75 Neurofibromatosis (NF), 676, 1344 lymphoma, 1032–1033
mucoceles, 74 Neurofibromatosis type 1 (NF1), 1601 Nodulosis—arthropathy—osteolysis
pilomatrixoma, 74 Neurofibrosarcoma. See Malignant syndrome, 1344
pleomorphic adenoma, 74–75 peripheral nerve sheath tumor Nonallergic rhinosinusitis with eosinophilia
schwannoma, 75 (MPNST) syndrome (NARES), 347
Neoplasms Neurogenic sarcoma. See Malignant Noncutaneous leiomyosarcoma, 876
of bone, hematolymphoid, 1108–1109 peripheral nerve sheath tumor Nonepithelial larynx tumors, benign,
of eye, hematolymphoid, 1103–1105 (MPNST) 126–129
of ocular adnexa, hematolymphoid, Neurothekeoma, 694–696 hemangioma, 126–127
1103–1105 Neutrophilic abscesses, 1493–1494 leiomyoma, 128–129
of skin, hematolymphoid, 1109–1112 Neutrophilic microabscess, 652, 653 lipoma, 128
of thyroid, hematolymphoid, 1100–1101 Nevoid BCC syndrome (NBCCS), 1344 neurilemoma, 127–128
Neoplastic cells, 13, 661 Nevus, 170 neurofibroma, 127–128
Neoplastic diseases, condroid. See Nevus sebaceous of Jadassohn (NSJ), overviews, 126
Neoplastic diseases, osseous 1341–1342 Nonepithelial tumors, 63
Neoplastic diseases, mesenchymal clinical features, 1536 Non-Hodgkin lymphoma (NHL), 15, 39,
aneurysmal bone cyst, 986–987 differential diagnosis, 1537 1039–1073, 1354
angiosarcoma, 982–983 imaging, 1536 adult T-cell leukemia/lymphoma, 1072
desmoplastic fibroma, 987–988 molecular genetics, 1537 anaplastic large cell lymphoma, 1065–1068
eosinophilic granuloma, 989 pathology, 1536–1537 angioimmunoblastic T-cell lymphoma,
epithelioid hemangioendothelioma, treatment and prognosis, 1537–1538 1064
981–982 NF. See Neurofibromatosis (NF) in B-cell, 43–45
Ewing’s sarcoma, 989 NF-2 follicular lymphoma, 44–45
fibrosarcoma, 988–989 in acoustic neuroma, 454 mantle cell lymphoma, 44
giant cell granuloma, 984–985 in meningiomas, 456 small lymphocytic lymphoma, 44
giant cell tumor, 984 NG. See Nasal glioma (NG) Burkitt lymphoma, 1056–1057
hemangioma, 981 NHL. See Non-Hodgkin’s lymphoma (NHL) CLL/SLL, 1059
hyperparathyroidism, 985–986 Nicotiana rustica, 287 DLBCL, 1039–1045
lymphangioma, 983–984 Nicotiana tabacum, 287 extramedullary plasmacytoma, 1057–1059
Neoplastic diseases, nonchondroid. See Nicotinic stomatitis extranodal NK/T-cell lymphoma,
Neoplastic diseases, mesenchymal clinical features, 208–209, 277–278 1060–1064
Neoplastic diseases, nonosseous. See defined, 277 FNA, 39
Neoplastic diseases, mesenchymal diagnosis, 278 FNAB, 40–43
Neoplastic diseases, osseous pathology, 209, 278 anaplastic large cell lymphoma, 42–43
cartilaginous lesions, 974 treatment, 209, 278 Burkitt’s lymphoma, 40–41
chondroblastomas, 978–979 NIH diagnostic criteria, for NF1, 687 diffuse large B-cell lymphoma, 41–42
chondroid metaplasia, 975–976 Nikolsky sign, 250, 259 immunoblastic lymphomas, 42
chondroma, 976 NK. See Natural killer (NK) cells lymphoblastic lymphoma, 40
chondromyxoid fibroma, 978 NK/T-cell lymphomas follicular lymphoma, 1045–1051
chondrosarcoma, 976–978 clinical features, 660–661 hydroa vacciniforme-like lymphoma,
chordoma, 979–981 immunohistochemistry, 662 1072
exostosis, 967 pathology, 661 immunodeficiency-associated
extraosseous osteosarcoma, 974 treatment and prospect, 662 lymphoproliferative disorders,
nasal chondromesenchymal hamartoma, Nodal and extranodal lymphoma, 63 1072–1073
974–975 Nodal marginal zone lymphoma, 1060 lymphoblastic leukemia/lymphoma, 1060
ossifying fibroma, 970–971 Nodular BCC, 1496 lymphoplasmacytic lymphoma,
osteoblastoma, 969–970 Nodular/diffuse dermal infiltrate diagnosis, 1059–1060
osteochondroma, 968 of hematolymphoid lesions of skin, MALT lymphoma, 1054–1056
osteoid osteoma, 968–969 1113–1114, 1115 mantle cell lymphoma, 1051–1054
osteosarcoma, 971–974 Nodular fasciitis, 54 mycosis fungoides, 1069–1070
Nephrolithiasis, 1455 in children, 1359 nodal marginal zone lymphoma, 1060
Nephrotic syndrome, 252 Nodular fasciitis and related lesions peripheral T-cell lymphoma, 1064–1065
Nerve sheath myxomas, 694 including cranial fasciitis, 812 primary cutaneous CD8+ aggressive
Nestin antibodies clinical findings, 813 epidermotropic cytotoxic T-cell
AFOD, 1251 differential diagnosis, 813–815 lymphoma, 1071–1072
AMF, 1244 electron microscopy, 813 primary cutaneous CD4+ small/medium
and AOT, 1238 imaging, 813 T-cell lymphoma, 1071
and ODOMYX, 1286 immunohistochemistry, 813 primary cutaneous CD30+ T-cell
Neurilemoma, 127–128 molecular findings, 813 lymphoproliferative disorders,
Neuroblastoma (NB), 1347, 1355 pathologic findings, 813 1068–1069
Neuroendocrine carcinomas (NEC), 322– prognosis and treatment, 815 Sézary syndrome, 1070–1071
323, 380. See also Primary small cell Nodular goiter, 4–5 subcutaneous panniculitis-like T-cell
carcinoma Nodular KS, 1660 lymphoma, 1071
Noniatrogenic hypoparathyroidism OaCCOT. See Odontoma-associated [Odontogenic myxoma and myxofibroma

clinical features, 1460 calcifying cystic odontogenic tumor (ODOMYX)]
differential diagnosis, 1460 (OaCCOT) [immunohistochemistry]
gene alterations in, 1461 Obstructive sialadenitis, 485–486 glycosaminoglycans, 1286
molecular biology, 1461 Obstructive sleep apnea, 226–227 nestin and vimentin antibodies, 1286
pathologic features, 1460 clinical features, 227 molecular-genetic data, 1287
treatment and prognosis, 1461 pathology, 227 radiographic appearance of, 1284–1285
Nonintestinal-type adenocarcinomass treatment, 227 rate of growth, 1284
(Non-ITAC), 387–389 Occlusive phlebitis, 1390 treatment and prognosis, 1288
Nonkeratinizing carcinomas (NKC), Occult primary ultrastructure of, 1287
376–377 to cervical nodes Odontogenic sarcomas
of nasopharynx, 397 adenopathy site, 1147–1148 ameloblastic fibrodentino- and
Nonkeratinizing squamous cell carcinomas, clinical data, 1147 fibro-odontosarcoma, 1310–1311
305–308 diagnosis, 1150–1152 ameloblastic fibrosarcoma, 1307–1310
immunohistochemistry, 307–308 lymphatic region, of neck, 1147 odontogenic fibrosarcoma, 1311–1312
microscopic features, 306–307 lymph node biopsy, 1150 odontogenic myxosarcoma, 1312–1313
Nonkeratinizing undifferentiated primary lesion search, 1148–1150 Odontomas
carcinomas, 308–309 immunohistochemistry complex and compound odontomas,
Nonneoplastic bone diseases primary tumor discovery, 1154 1256–1258
cemento-osseous dysplasia, 965–966 treatment, 1154–1155 complex odontoma (ODTx)
cherubism, 966–967 Ococytoma etiology, 1253–1255
cortical defects of mandible, 962–963 clinical features, 530 imaging of, 1253
cranial fasciitis, 966 defined, 530 prevalence and incidence, 1252–1253
fibrous dysplasia, 964–965 differential diagnosis, 531 compound odontoma (ODTp)
focal osteoporotic bone marrow defect, pathology, 530–531 etiology of, 1256
961–962 treatment, 531 prevalence and incidents, 1255–1256
osteoarthritis, 958 Octreotide scintigraphy, for PGL, 718 radiographs, 1256
osteomyelitis, 958–960 Ocular adnexa, 70–81 odontoma-associated calcifying cystic
osteoradionecrosis, 960–961 diagnosis, 71–72 odontogenic tumor (OaCCOT), 1253
Paget’s disease, 963–964 hematolymphoid lesions of, 1103–1107 Odynophagia, 243
relapsing polychondritis, 961 clinical features, 1104 Oil red O stains, 77
Nonneoplastic disease, 3–6 diagnostic considerations, 1107 Olfactory neuroblastoma (ONB), 65–66,
Nonneoplastic joint disease. See neoplasms, 1103–1105 65–67, 1363
Nonneoplastic bone disease reactive/inflammatory, 1105–1107 clinical features, 728–729
Nonneoplastic lesions lesions, 72–74 diagnosis, 731–732
acquired. See Acquired nonneoplastic malignant tumors, 75–79 imaging, 729
lesions ACC, 76 immunohistochemistry, 731
of ear and temporal bone, 425–432 basal cell carcinomas, 75–76 overview, 728
classification, 425 Merkel cell tumor, 77 pathology, 729–731
Nonneoplastic salivary gland lesions, 20–21 metastatic carcinoma, 78–79 versus SNUC, 380
infiltration, fatty, 20 orbital teratomas, 77 treatment, 731–733
sialadenitis, 20–21 retinoblastoma, 77–78 ultrastructure, 731
Non-PTH-related hypercalcemia sebaceous carcinoma, 76–77 OLP. See Oral lichen planus (OLP)
clinical features, 1459 squamous cell carcinoma, 76 ‘‘On again–off again’’ symptoms, NARES, 347
differential diagnosis, 1459 melanocytic lesions, 79–81 ONB. See Olfactory neuroblastoma (ONB);
molecular biology, 1460 malignant melanoma, 80–81 Olfactory neuroblastoma (ONB)
pathologic features, 1459 melanocytoma, 79–80 ONB vs ES/PNET, 732
treatment and diagnosis, 1459–1460 melanotic neuroectodermal tumor of ONB vs SNUC, 732
Nonspecific reactive lymphoid hyperplasia infancy, 79 Oncocytic carcinoma, 573–574
lymph node, 997–1003 neoplasm, 74–75 Oncocytic cysts, 117
nasopharynx, 1087 orbital cytology, 70 Oncocytic lesions, 168, 482–483
of ocular adnexa, 1106–1107 overviews, 70–72 Oncocytic neoplasms, 9
of oral cavity and oropharynx, 1091 Ocular adnexal lymphoproliferative Oncocytic schneiderian papilloma (OSP),
Nonsteroidal anti-inflammatory drugs, 260 disorders, 1599 369–371
Nonsuppurative osteomyelitis. See Chronic Oculodermal melanocytosis, 1560 carcinomas and, 370–371
sclerosing osteomyelitis ODOMYX. See Odontogenic myxoma and incidence of HPV in, 370
Noonan syndrome, 1523 myxofibroma (ODOMYX) Oncocytic tumors, 389–390
NSJ. See Nevus sebaceous of Jadassohn Odonto-ameloblastoma Oncocytoma, 30
(NSJ) clinical features, 1258–1259 Oncogenic viruses, ora cancer, 288
Nuchal fibrocartilaginous pseudotumor etiology of, 1259 Onion skinning. See Proliferative periostitis
(NFP), 1728–1729 immunohistochemistry, 1260 OPG. See Orbital paragangliomas (OPG);
Nuchal fibroma radiographs, 1259 Osteoprotegerin (OPG) and
clinical features, 846 treatment and prognosis, 1260 osteoclastogenesis
differential diagnosis, 847 Odontogenic cysts, 69–70 Ophthalmoscopy, 78
electron microscopy, 847 Odontogenic fibroma, 1276 Optic nerve glioma (juvenile pilocytic
imaging, 846 Odontogenic ghost cell lesions, astrocytoma), 1601–1602
immunohistochemistry, 847 1260–1262 Optic nerve neoplasms, 1601–1602
pathology, 846–847 Odontogenic keratocysts, 1344 Oral cancer. See also Squamous cell carcinomas
treatment and prognosis, 847 Odontogenic myxoma, 68–69 altered immunity, 289
Nuchal-type fibroma Odontogenic myxoma and myxofibroma clinicopathologic consideration, 290
clinical features, 1514 (ODOMYX), 1283 dental factors and chronic inflammation,
differential diagnosis, 1515 age range and gender ratio, 1284 288–289
imaging studies, 1514 differential diagnosis, 1287–1288 epidemiology/etiology, 385–389
immunohistochemistry, 1514 etiology of, 1285 risk factors, 386–389
pathology, 1514 HRAS- and KRAS-encoded gene incidence
treatment and prognosis, 1515 products, 1287 in South Asia, 287
Nuclear atypia, 7 immunohistochemistry in United States, 286
Nutritional deficiencies, oral cancer, 289 CK antibodies, 1286 molecular biology/genetics, 289–290
[Oral cancer] Osteoblastoma, 969–970 Papillary keratosis. See Keratinized

nutritional deficiencies, 289 Osteoblasts, 959, 965 papilloma
TNM—staging system for, 291 Osteochondroma, 968 Papillary squamous carcinomas,
Oral candidiasis (OC), 1645 Osteoclasts, 959 316–318
Oral cavity, 59–63 Osteoclasts-like giant cells, 979 Papillary squamous cell carcinoma
anatomy, 285 Osteoid, 972 (PSCC), 153–155
developmental and/or congenital lesions, osteoma, 968–969 Papillary thyroid carcinoma (PTC),
1343 Osteoma, 967 4, 9–11, 1352
hematolymphoid neoplasms, 1088–1094 Osteomyelitis, 958–960 clinical features, 1393
malignant oral lesions, 61–63 Osteonecrosis, 958 differential diagnosis, 1399–1400
mucocele of lip and ranulas, 1343 Osteoprotegerin (OPG) and immunohistochemical markers, 1399
oral lesions, 59–61 osteoclastogenesis, 1212 lipomatous stroma with, 1399
overviews, 59 Osteoradionecrosis (ORN) with nodular fasciitis like
squamous cell carcinomas of, 292–301 fibrosis, 961 stroma, 1399
Oral hairy leukoplakia, 210–211, 1669–1670 persistent carcinoma, 961 pathology, 1393–1394
clinical features, 210–211 radiation damages, 960 RET/PTC rearrangement, genetic
electron microscopy, 211 treatment, 961 alteration in, 1399
pathology, 211 wound-healing defect, 961 treatment and prognosis, 1400
treatment, 211 Osteosarcoma, 57 variants of, 11–13, 1395
Oral lesions, ulcerations, 59–61 extragnathic, 972–973 clear cell, 1399
Oral lichen planus (OLP), 254 extraosseous, 974 cribriform-morular, 1398–1399
Oral malignant melanomas, 323–326 gnathic, 971–972 diffuse sclerosing, 1397
clinical features, 324 paget’s disease, 963, 974 follicular, 1396–1397
pathology, 324–325 parosteal, 973 oxyphilic (oncocytic/Hurthle cell),
treatment and prognosis, 325–326 radiation-associated, 974 1398
Oral melanocytic nevi, 203–204 secondary, 974 solid, 1397–1398
Oral radiation, 59 syndrome-associated, 974 tall cell, 1397
Oral soft tissue metastases, 1156–1157 telangiectatic, 973–974 Warthin-like, 1398
Oral squamous cell carcinoma (OSCC), 267 Otic polyps, inflammatory, 431 Papilliferous keratoameloblastoma,
Oral submucous fibrosis (OSF), 278–279 Otitis externa, 1611 1226–1227
Oral tongue, squamous cell carcinomas, Otitis media, 428–429, 1611–1612 Papillomas, 119–124, 215–216, 1676
295–298 in children, 958 clinical features, 215
Orbit Otosclerosis, 444–445 diagnosis, 215–216
anatomy, 1595–1596 Overgrowth syndromes, 1344 keratinized, 123–124
extramedullary hematopoiesis in, 1027 Owen, Sir Richard, 1429 nonkeratinized. See Recurrent respiratory
malformations Oxalosis papillomatosis (RRP)
dermoid cysts, 1596 pathologic features, 954 pathology, 215
inflammation, 1598 radiologic features, 954 treatment, 216
lymphatic malformation Oxyphil cells, of parathyroid glands, Papulomatosis, 1675–1677
(lymphangioma), 1597–1598 1432–1433, 1435 Para-aminobenzoic acid (PABA), 280
venous malformation (cavernous Oxyphilic adenomas, 1448 Paracoccidioidomycosis, 1648
hemangioma), 1596–1597 Oxyphil-rich carcinomas, 1450 Paracortex
melanomas involving, 1603 lymphoid cells in, 997
metastases to, 1603 PA. See Pleomorphic adenoma (PA) reactive paracortical hyperplasia,
specimen handling, 1596 PABA. See Para-aminobenzoic acid (PABA) 999–1000
Orbital cytology, 70 Paget’s disease, 963–964 Paragangliomas (PGL), 67–68, 167
Orbital meningiomas, 702 of bone, 445 CBPG, 718–721
Orbital paragangliomas (OPG), 724 Palatal cysts, 1343 genetics, 718
Orbital teratomas, 77 Palatine tonsils imaging, 717–718
Orbital tumors, 1728 reactive follicular hyperplasia of, 1001–1003 immunohistochemistry, 718
ORN. See Osteoradionecrosis (ORN) squamous cell carcinomas, 303–305 JTPG, 721–722
Orofacial TB, 1622 Palpation thyroiditis, 1392 LPG, 723–724
Oropharyngeal cancer, TNM—staging PAN. See Polyarteritis nodosa OPG, 724
system for, 292 Pancytokeratin, 973 overview, 717
Oropharyngeal wall, squamous cell Paneth cells, in intestinal-type pathology, 718
carcinomas, 303 adenocarcinomas, 386 SNPG, 724–725
Oropharynx Panhypopituitarism, 717 terminology, 717
anatomy, 285 PAP. See Prostate acid phosphatase (PAP) TPG, 725
hematolymphoid neoplasms, 1088–1094 Papanicolaou Society of Cytopathology VPG, 722–723
squamous cell carcinomas of, 301–305 (PSC), 1 Paramyxoviral transcripts, in
OSCC. See Oral squamous cell carcinoma Papanicolaou stain, 5, 33 osteoclasts, 963
(OSCC) Papillary adenocarcinomas, nasopharynx, Paranasal sinuses. See also Nasal cavity
OSF. See Oral submucous fibrosis (OSF) 400–402 sinuses
Osler-Rendu-Weber syndrome, 1523 clinical features, 400–401 hematolymphoid neoplasms of,
Osseous and cartilaginous choristomas differential diagnosis, 401–402 1081–1086
clinical findings, 823 immunohistochemistry, 401 metastases to, 402
differential diagnosis, 824 pathology, 401 Paranasal sinus mucoceles, 64
imaging, 823 treatment and prognosis, 402 Paraneoplastic pemphigus (PNP),
immunohistochemistry, 824 Papillary carcinoma, 100 246–248
pathologic findings, 823 Papillary cystadenocarcinoma (PCA), 29 diagnosis, 248
prognosis and treatment, 822, 824 Papillary dermal fibrosis, 1476 immunology, 247–248
radiologic imaging, 823 Papillary endothelial hyperplasia, 1357 immunopathology, 247
Osseous labyrinth, 425 clinical features, 774 pathology, 247
Osseous metaplasia, of the retinal pigment differential diagnosis, 776 Paraneurofibroma. See Diffuse
epithelium (RPE), 1582 immunohistochemistry, 776 neurofibroma (DNF)
Ossifying fibroma, 970–971 pathologic findings, 774–775 Parapharyngeal meningiomas, 702
Osteitis deformans. See Paget’s disease prognosis and treatment, 776 Parapharyngeal neurofibromas, 682
Osteoarthritis, 958 ultrastructure, 775 Parathyroid aspirates, 1441
Parathyroid cysts Pentoxifyline, 1693 Pilomatricoma

clinical features, 1456 PERAM. See Solid/multicystic clinical features, 1480
differential diagnosis, 1457 ameloblastoma-peripheral (PERAM) differential diagnosis, 1481
molecular biology, 1457 Perchlorate antithyroid drugs, 1386 electron microscopy, 1480
pathologic features, 1456–1457 Perineurioma, 696–698 imaging studies, 1480
treatment and prognosis, 1457 Periodic acid-Schiff (PAS), 60, 253, 670 immunohistochemistry, 1480
Parathyroid embryogenesis, 1429 Peripheral eosinophilia, 658 molecular genetic data, 1481
Parathyroid glands, 19, 104–105 Peripheral nerves, 100 pathology, 1480
Parathyroid glands, normal Peripheral nerve sheath tumors treatment and prognosis, 1481
anatomy, 1429–1430 acoustic neuromas, 691–692 Pilomatrixoma, 26, 74
microscopic, 1431–1433 DNF, 686–687 from neck, 1342–1343
ultrastructural, 1433 GCT, 698–701 Pinna, squamous cell carcinomas of, 460–462
distribution of, 1430 mucosal neuromas, 692–694 PIOSCC. See Primary intraosseous
embryology, 1429 neurofibroma, 681–683 squamous cell carcinoma (PIOSCC)
fat surrounding, 1430 neurothekeoma, 694–696 Piperacillin, 1612
gross appearance, 1430 NF1, 687–689 Pituitary adenomas
histochemistry/immunohistochemistry, NF2, 689–691 clinical features, 708–709
1433–1435 perineurioma, 696–698 diagnosis, 712
molecular biology, 1435 PNF, 683–686 imaging, 709–710
physiology and biochemistry, 1435–1437 schwannoma, 678–681 incidental, 709
receptors, 1435 Peripheral odontogenic fibroma (POF) overview, 708
stroma of, 1431 differential diagnosis, 1281 pathogenesis, 714
venous drainage, 1430 immunohistochemistry, 1281 pathology, 710–712
weight distribution, 1430 local surgical excision, 1281 treatment, 712–713
Parathyroid hormone (PTH), 1429. See also pathology, 1280–1281 Pituitary carcinoma, 713
Primary hyperparathyroidism prevalence and incidence, 1280 Pituitary gland, 708
action on renal tubular cells, 1436 ultrastructure of, 1281 Plasmablastic lymphoma, 1042–1042
analytic methods for, 1436–1437 Peripheral T-cell lymphoma, 1064–1065 Plasma cells, 952
Parathyromatosis, 1454 Peritonsillar abscess, 225, 1610 Plasmacytoma, 1108
Parenchyma, 669 Periungual fibroma. See Fibrous papules extramedullary, 1057–1059
Parenchymal cells, 669 (FPs) Platelet-derived growth factor (PDG)
Parkes-Weber syndrome, 1523 PET. See Positron emission tomography expression and stroma of
Parosteal osteosarcoma, 973 (PET) ameloblastomas, 1211–1212
PAS. See Periodic acid-Schiff (PAS); Periodic PGL. See Paragangliomas (PGL) PLCD. See Posterior lingual cortical defect
acid-Schiff (PAS) Phacoanaphylactic endophthalmitis, 73, (PLCD)
Patched (PTCH) gene underexpression in 1576 Pleomorphic adenoma (PA), 33–37, 74–75,
ameloblastomas, 1213 Phacolytic cells, 73 168, 389, 511–519, 1722
Patch KS, 1660 Phaeohyphomycosis, 1639 cellular PA, 34–35
Pathogens, in infectious rhinosinusitis, 345 Phakomatous choristoma, 1367–1368 clinical features, 512–513
Pathologic examination, in Pharyngeal hypophysis, 708 differential diagnosis, 518–519
hyperparathyroidism, 1443–1445 Pharyngoesophageal diverticulum (PED), hyaline PA, 35–36
Paul-Bunnell IgM test, 1666 1720–1721 immunohistochemistry, 517–518
PBCD. See Posterior buccal cortical Pharyngoesophageal (Zenker’s) myoepithelioma, 36
defect(PBCD) diverticulum pathology, 513–517
PCA. See Papillary cystadenocarcinoma clinical features, 1720–1721 spindle cell lesions, 35
(PCA) pathology, 1719–1720 vs. low grade malignancies, 36–37
PCNA. See Proliferating cell nuclear treatment and prognosis, 1721 Pleomorphic cells, 28
antigen (PCNA) Phenylbutazone antithyroid drugs, 1386 Pleomorphic liposarcoma, 884
PCNA L.I. and calcifying odontogenic cyst Phenytoin, 217 Pleomorphic RMS, 869, 873
(COC), 1265 therapeutic agents, 1344 Pleomorphic sarcoma NOS. See Storiform
PCR studies, 40 Phosphate-binding agents, 1456 pleomorphic malignant fibrous
PD-ECGF/TP. See Thymidine Phospho-retinoblastoma protein (pRb) histiocytoma
phosphorylase (PD-ECGF/TP) immunohistochemistry, 1453 Pleomorphic sarcomas, 57
expression and stroma of Phosphotungstic acid–hematoxylin (PTAH), Plexiform neurofibroma (PNF), 677, 683–
ameloblastomas 1433 686, 1363
PDS. See Pendred’s syndrome (PDS) Photodynamic therapy, 275, 1488 and parotid gland, 1365
Pearly penile papule. See Fibrous papules Phthisical eye, 1583 Plexiform schwannomas, 680
(FPs) Phthisis bulbi PLGA. See Polymorphous low-grade
Pemphigoid, 248–250 clinical features, 1579 adenocarcinoma (PLGA)
bullous pemphigoid, 248–249 pathology, 1579–1582 Plummer-Vinson syndrome (PVS), 175
mucous membrane MMP, 249–251 Pigmented congenital epulis. See PMML. See Malignant melanomas
Pemphigus, 243–248 Melanocytic neuroectodermal tumor Pneumocystis carinii, 430
drug induced, 248 of infancy (MNTI) Pneumocystosis, 1658–1659
paraneoplastic pemphigus, 246–248 Pigmented hidrocystomas, 1485 Pneumonia, interstitial giant cell
vegetans, 246 Pigmented villonodular synovitis (PVNS) pneumonia, 1685
vulgaris, 243–246 immunohistochemistry, 956–57 PNF. See Plexiform neurofibroma (PNF)
Pemphigus vegetans, 246 pathologic features, 956 Podoplanin, immunohistochemical stain,
Pemphigus vulgaris (PV), 59, 243–246 radiologic features, 956 984
clinical presentation, 243–244 Pilar cysts (PC), 1342 POF. See Peripheral odontogenic fibroma
immunology, 246 clinical features, 1477 (POF)
immunopathology, 245–246 differential diagnosis, 1478 Polyarteritis nodosa (PAN), 655, 656–657
overviews, 243 electron microscopy, 1478 clinical features, 656–657
pathology, 244–245 imaging studies, 1477 pathology, 657
treatment, 246 immunohistochemical studies, 1478 treatment and prospect, 657
Pendred’s syndrome (PDS), 1391 molecular-genetic data, 1478 Polychondritis,relapsing, 440–442
Penicillins, 1621, 1691 pathology, 1477–1478 Polyclonal carcinoembryonic antigen (CEA)
Penicillium marneffei, 1013 treatment and prognosis, 1478 immunoreactivity, 1386
Polycystic disease, of salivary glands, 478 [Primary intraosseous squamous cell Pseudophakia, 1565–1566
Polygonal cell sarcomas, 55–56 carcinoma (PIOSCC)] Pseudovasculitis, 660
Polyhydraminios, 1364–1365 molecular-genetic data, 1299 Psoralen and ultraviolet light A
Polymethylmethacrylate (PMMA), 1576 radiograms, 1298 (PUVA), 257
Polymicrobial infections, 958 treatment and prognosis, 1299 Pterygium, 1573–1574
Polymorphous low-grade adenocarcinoma, Primary lymphomas and plasmacytomas, PTGC. See Progressive transformation of
557–561 1414–1415 germinal centers (PTGC)
Polymorphous low-grade adenocarcinoma Primary malignant melanoma of the larynx PT stage grouping, 98
(PLGA), 26, 27, 63 (PMML). See Malignant melanomas Pulmonary cryptococcosis, 1652
Polyostotic fibrous dyspalsia, 965 Primary oral CD30+ T-cell Pulsion diverticula, 1720
Polypoid nasal mass, 672 lymphoproliferative disorders, 1069 PUVA. See Psoralen and ultraviolet light A
Pompe disease, 1392 Primary small cell carcinoma, 25–26 (PUVA)
Poorly differentiated carcinoma Primary systemic amyloidosis, 1391 PV. See Pemphigus vulgaris (PV)
clinical features, 1406 Priming, 649 PVL. See Proliferative verrucous leukoplakia
pathology, 1406 Primitive neuroectodermal tumors (PNET), (PVL)
TP53 and BRAF mutations, 1407 1503 PVNS. See Pigmented villonodular synovitis
treatment and prognosis, 1407 Procainamide, 252 (PVNS)
Positron emission tomography (PET), 1 Progesterone receptor (PR), 31 Pyogenic bacterial infections, 1013
Postcricoid carcinoma, 176–177 Progressive transformation of germinal Pyogenic granuloma. See Lobular capillary
Posterior buccal cortical defect(PBCD), 963 centers (PTGC), 1004–1005 hemangioma; Lobular capillary
Posterior hypopharyngeal wall Proliferating cell nuclear antigen (PCNA), hemangioma (LCH)
carcinoma, 176 697 Pyriform sinus carcinoma, 175–176
Posterior lingual cortical defect (PLCD), Proliferating follicular-cystic neoplasm. See Pyrimethamine, 1689
962–963 Proliferating pilar cyst (PPC)
Postpartum thyroiditis, 1389 Proliferating pilar cyst (PPC) QPTH. See Quick parathyroid hormone
Posttransplant lymphoproliferative clinical features, 1478 (QPTH)
disorders, 1073, 1667 differential diagnosis, 1479 QuantiFERON-TB Gold, 1623
Postvaccination fatal disseminated genetic association, 1479 Quick parathyroid hormone (QPTH), 104
infection, 1686 imaging studies, 1478 Quinidine, 252
Potassium iodide, 1638 immunohistochemical studies, 1479 Quinolones, 1691
Pouch–derived cysts, 1457 pathology, 1478–1479
P53 protein treatment and prognosis, 1479
and AOT, 1238 Proliferating tricholemmal cyst. See Radiation-associated osteosarcomas, 974
p53 mutations in ameloblastomas, 1211 Proliferating pilar cyst (PPC) Radiation therapy, 14, 31, 976
PR. See Progesterone receptor (PR) Proliferative myositis, 54 Radiography, FD, 964
PR3. See Proteinase 3 Proliferative myositis/fasciitis and atypical RANKL. See Receptor activator of nuclear
Prasad’s microstaging, mucosal malignant decubital fibroplasia (ischemic factor-kB ligand (RANKL) and
melanomas, 394 fasciitis) osteoclastogenesis
Precancerous keratosis. See Actinic keratoses differential diagnosis, 817–818 RAS. See Recurrent aphthous stomatitis
(AKs) electron microscopy, 817 (RAS)
Pregnancy, rhinosinusitis during, 347 immunohistochemistry, 816 RCC. See Renal cell carcinoma (RCC)
Primary acquired melanosis, 1561 molecular, 817 Reactive follicular hyperplasia, 997–999
Primary bone lymphoma, 1108–1109 pathologic findings, 816 versus follicular lymphoma, 1051
Primary ciliary dyskinesia (PCD), 351–352 prognosis and treatment, 818 monocytoid B cells in, 999
Primary cutaneous CD8+ aggressive radiologic imaging, 815–816 of palatine tonsils, 1001–1003
epidermotropic cytotoxic T-cell Proliferative periostitis, 960 Reactive/inflammatory hematolymphoid
lymphoma, 1071–1072 Proliferative verrucous leukoplakia (PVL), lesions
Primary cutaneous CD4+ small/medium 275 of eyes and ocular adnexa, 1105–1107
T-cell lymphoma, 1071 Proptosis, 1596 of skin, 1112–1113
Primary cutaneous CD30+ T-cell Propylthiouracil antithyroid drugs, 1386 of thyroid, 1101–1102
lymphoproliferative disorders, Prosecretory granules, 1433 Reactive lymphoid hyperplasia, 49–50
1068–1069 Prostate acid phosphatase (PAP), 31 of extranodal sites, 1001
Primary cutaneous DLBCL, leg-type, Prostate-specific antigen (PSA), 31 nonspecific, 997–1003
1110–1111 Proteinase 3 (PR3), 650 specific, 1003–1029
Primary cutaneous follicle center Proteus syndrome, 1523 of tonsil, 1002, 1003
lymphoma, 1050, 1109–1110 Pruritus, 248 Reactive paracortical hyperplasia,
Primary cutaneous MALT lymphoma, 1111 Prussak’s space, 436 999–1000
Primary effusion lymphoma, 1044 PSA. See Prostate-specific antigen (PSA) Reactive periostitis, BPOP, and turret
Primary follicular lymphoma of thyroid, Psammoma bodies, 10 exostosis
1101 PSC. See Papanicolaou Society of clinical findings, 818
Primary herpetic stomatitis, 59 Cytopathology (PSC) differential diagnosis, 818
Primary hyperparathyroidism PSCC. See Papillary squamous cell immunohistochemistry, 818
clinical differential diagnosis, 1438 carcinoma (PSCC) pathologic findings, 818
clinical presentation, 1438–1439 Pseudoallescheriasis, 1637–1638 prognosis and treatment, 818
definition, 1437 Pseudoepitheliomatous hyperplasia, 1345 radiologic imaging, 818
epidemiology, 1437–1438 Pseudogout, 442–443. See also Calcium Receptor activator of nuclear factor-kB
FNA cytology, 1440–1442 pyrophosphate crystal deposition ligand (RANKL) and
imaging studies, 1439–1440 disease (CPCDD) osteoclastogenesis, 1212
preoperative localization, 1439–1442 Pseudohyperparathyroidism Recurrent aphthous stomatitis (RAS),
selective venous sampling (SVS) for PTH clinical features, 1460 261–263
levels, 1440 differential diagnosis, 1460 diagnosis, 262
treatment and prognosis, 1455–1456 gene alterations in, 1461 etiology, 261
Primary intraosseous squamous cell molecular biology, 1461 immunopathology, 262
carcinoma (PIOSCC), 1235, 1297 pathologic features, 1460 pathology, 262
frequency, 1298 treatment and prognosis, 1461 treatment, 263
histomorphology of, 1298 Pseudolymphoma, cutaneous, 1112 Recurrent laryngeal nerve paralysis, 1721
immunohistochemistry, 1299 Pseudomonas aeruginosa, 1609 Recurrent parotitis, 494–495
Recurrent respiratory papillomatosis (RRP), [Rhinoscleroma] [Salivary gland neoplasm]

119–123 epidemiology, 1618–1619 [by large cells]
clinical features, 120 histopathology, 1619–1620 metastatic malignancies, 31
etiology, 119–120 immunological considerations, 1619 oncocytoma, 30
immunohistochemistry, 122 nasal cavity, 1085 radiation therapy, 31
molecular-genetic data, 122 treatment, 1620 salivary duct carcinoma, 28–29
pathology, 121–122 Rhinosinusitis, 343 Warthin tumor, 30–31
terminology, 119 in adults, classification, 344 Salivary glands, 20–37, 101–103
treatment, 122–123 allergic, 343–345 aplasia, 476–477
Reed-Sternberg cells, 44 atrophic. See Atrophic rhinosinusitis (ARS) choristomas, 427
classical Hodgkin lymphoma, 1032–1035 complications, 343–348 cystic fibrosis, 478–479
in cytomegalovirus lymphadenitis, 1008 factitial, 348 cystic lesions, 21–22
in infectious mononucleosis, 1007 idiopathic, 348 cysts
in Kimura disease, 1018 infectious, 345 LEC, 481–482
Regaud type, 1355 occupational-environmental, 347 mucoceles, 480–481
Reiter’s syndrome, 261 pathology, 343 salivary duct cysts, 481
Relapsing polychondritis, 440–442, 961 during pregnancy, 347 functional unit, 475
ANCA titers in, 441 signs and symptoms, 344 hematolymphoid neoplasms, 1094–1099
Renal cell carcinoma (RCC), 9, 16, 1459, 1729 structural-mechanical, 347 heterotopia, 477–478
Renal cell-like sinonasal adenocarcinoma systemic causes, 348 HIV-associated lymphoid hyperplasia
(RCSA), 1729 vasomotor, 345–346 in, 1010
Renal disease, 253 Rhinosinusitis medicamentosa, 347 hyperplasia, 500
Resection margins, 144 Rhinosporidiosis, 1642–1643 infiltrations
Respiratory epithelial adenomatoid Rhizopus, 1637 amyloidosis, 484
hamartomas, 360–361 Riedel thyroiditis, 1388–1390 iron deposition, 484
Retention cyst, 21 Rifampin, 1627 lipomatosis, 482
Retina Rituximab, for DLBCL, 1045 oncocytic lesions, 482–483
anatomy, 1591 RMS. See Rhabdomyosarcoma (RMS) lesions, 63
retinoblastoma, 1592–1595 RMT. See Retromolar trigone (RMT) nonneoplastic salivary gland lesions, 20–21
specimen handling, 1592 Robinson type lesion, 1484 parotid gland, 475
Retinal anlage tumor. See Melanocytic Romanowsky-type stains, 41 sebaceous glands, 475, 479–480
neuroectodermal tumor of infancy Rosacea sialadenitis. See Sialadenitis
(MNTI) clinical features, 1532–1533 submandibular gland, 475–476
Retinal pigment epithelium (RPE), 1580 defined, 1532 tumors. See Tumors
Retinoblastoma, 77–78 differential diagnosis, 1533 Salivary gland tumors, 26–28, 70
clinical features, 1592–1593 immunohistochemistry, 1533 lesions containing squamous cells, 27–28
pathology, 1593–1594 molecular genetics, 1533 low-grade MEC, 26
treatment, 1594 pathology, 1533 in lymphocytes, 32–33
Retinoblastoma (RB) tumor suppressor gene treatment and prognosis, 1533–1534 polymorphous low-grade
in ameloblastomas, 1211 Rosai-Dorfman disease, 51–52, 439, adenocarcinoma, 27
Retinocytoma, 1594 1023–1024. See also Sinus, Salivary gland-type neoplasms, 167–170
Retinoids, 1678 histiocytosis with lymphadenopathy adenoid cystic carcinoma (ACC), 168–169
Retromolar trigone (RMT), squamous cell of nasal cavity, 1083–1085 mucoepidermoid carcinoma (MEC), 169
carcinomas, 301–302 of skin, 1113, 1114 oncocytic lesions, 168
Rhabdoid meningioma, 706 Round cell liposarcoma, 881, 882 overviews, 167–168
Rhabdomyoblasts, 726 Round cell sarcomas, 54–55 pleomorphic adenoma, 168
in malignant triton tumor, 893 Rovamycin, 1689 Salivary-type neoplasms, 389–391
Rhabdomyoma, 54, 60 RRP. See Recurrent respiratory Samter’s triad, 346–347
clinical features, 798–799 papillomatosis (RRP) Sarcoid granulomas, 1693
differential diagnosis, 801–802 Rudimentary lumen formation, 865 Sarcoidosis, 50, 73, 1354, 1438
imaging, 799 Rudimentary meningocele, 1349–1350 causes, 1692–1693
immunohistochemistry, 800–801 clinical features, 1691–1692
molecular findings, 801 diagnosis, 1693
pathology, 799–800 Sabin Feldman Dye test, 1688 histopathology, 1693
treatment and prognosis, 802 Saccular cysts, 116 predispositions, 1691
Rhabdomyomatous mesenchymal Sac papillary tumor, endolymphatic, 457–458 treatment, 1693
hamartoma, 1362 Saksenea vasoformis, 1638 Sarcomas, 52–59, 63
Rhabdomyosarcoma (RMS), 869–876, 1603 Salivary duct carcinoma (SDC), ancillary studies, diagnosis, 53–54
nasal polyps, 349–350 28–29, 574–578 of larynx, 173–174
Rheumatoid arthritis, 1013–1014 Salivary duct cysts, 481 overviews, 52–53
ear, 953 Salivary gland anlage tumor, 1350 soft tissue lesions, 54
larynx, 953 Salivary gland heterotopias, 1352 soft tissue sarcomas, in head and neck
nasal septum, 953 Bartonella henselae causative organism, 1354 region, 54–59
pathologic features, 952–953 mycobacterial and Bartonella (cat scratch Sarcomatoid carcinoma. See Spindlecell
temporomandibular joint, 953 disease) infection, 1353 carcinomas (SPCC)
Rhinophyma Salivary gland neoplasm Sarcomatoid SCC, 1492
clinical features, 1532–1533 with besaloid cell, 23–26 SCC. See Squamous cell carcinoma (SCC)
defined, 1532 adenoid cystic carcinoma, 24–25 Schistosoma, 1638
differential diagnosis, 1533 basal cell adenocarcinoma, 25 Schneiderian mucosa, 1609
immunohistochemistry, 1533 basal cell adenoma, 23–24 Schneiderian papillomas, 361–371
molecular genetics, 1533 pilomatrixoma, 26 exophytic papillomas, 362–363
pathology, 1533 primary small cell carcinoma, 25–26 frequency of, 362
treatment and prognosis, 1533–1534 challenges, diagnosis, 22–23 inverted papilloma. See Inverted papilloma
Rhinoscleroma, 64, 1691 by large cells, 28–32 oncocytic schneiderian papilloma (OSP),
clinical features, 1619 acinic cell carcinoma, 29–30 369–371
clinicopathological stages, 1619 clear cell change, 31–32 Schopf-Schulz-Passarge syndrome, 1484
differential diagnosis, 1620 high-grade MEC, 28 Schwann cells, 678
Schwannoma, 75, 678–681, 1363–1365 Severe dysplasia, 269 [Skin]

SCLE. See Subacute cutaneous lupus Sézary syndrome, 1070–1071 hematolymphoid lesions of, 1109–1115
erythematosus (SCLE) Sheathlin and calcifying odontogenic cyst diagnostic considerations, 1113–1115
Sclerosing epithelioid fibrosarcoma, 886, 887 (COC), 1265 neoplasms, 1109–1112
Sclerosing mucoepidermoid carcinoma with Short tau inversion recovery (STIR) reactive/inflammatory, 1112–1113
eosinophilia, 1412 sequences, 1518 pigmented lesions, 1339–1341
Sclerosing polycystic adenosis, 497–499 Sialadenitis, 20–21 tag, 1352. See also Branchial cleft cyst
Sclerosing sweat duct carcinoma. See acute suppurative sialadenitis, 484–485 Skull meningioma, 703
Microcystic adnexal carcinoma cheilitis glandularis, 490–491 SLE. See Systemic lupus erythematosus (SLE)
(MAC) chronic, 21, 33 SLL. See Small lymphocytic lymphoma
Sclerosing type BCC, 1496 chronic sclerosing sialadenitis, 486–489 (SLL)
SCNEC. See Small cell neuroendocrine cytomegalovirus, 495–497 SLN. See Sentinel lymph node (SLN)
carcinomas (SCNEC) mumps, 495 Small cell carcinoma, 589–591
Scrofula, 1623 necrotizing sialometaplasia, 491–493 Small cell/mixed cell infiltrates
SDC. See Salivary duct carcinoma (SDC) obstructive sialadenitis, 485–486 diagnosis, of hematolymphoid lesions of
Sebaceous adenoma (SA), 32, 532–533, 1554 radiation sialadenitis, 489–490 skin, 1114–1115
clinical features, 1488 recurrent parotitis, 494–495 Small cell neuroendocrine carcinomas
differential diagnosis, 1489 subacute necrotizing sialadenitis, 493 (SCNEC), 166–167, 380–382
immunohistochemistry, 1489 Sialoadenitis, chronic, 102 versus SNUC, 380
molecular genetics, 1489 Sialoblastoma, 595–596 Small lymphocytic lymphoma (SLL), 33, 44
pathology, 1488 Sialometaplasia, 102 Smith type lesion, 1484
treatment and prognosis, 1489 Sialosis, 20, 499–500 Smokeless tobacco keratosis, 280–281
Sebaceous carcinoma, 32, 76–77, 567–568, Sincipital encephaloceles, 674 clinical features, 280–281
1554–1556 Sinonasal adenocarcinoma, 67 defined, 280
Sebaceous differentiation, of salivary Sinonasal fungal disease diagnosis, 281
glands, 479–480 alternaria, 1640 pathology, 281
Sebaceous hyperplasia (SH), 1482 aspergillosis, 1629–1632 treatment, 281
clinical features, 1487 bipolaris and exserohilum, 1639–1640 Smoking, oral cancer, 286–288
differential diagnosis, 1488 blastomycosis, 1642 SND. See Selective neck dissection
immunohistochemistry, 1487 cladosporium, 1640–1641 SNPG. See Sinonasal paragangliomas
molecular genetics, 1487–1488 clinicopathological classifications, (SNPG)
pathology, 1487 1628–1629 SNUC. See Sinonasal undifferentiated
treatment and prognosis, 1488 cryptococcosis, 1642 carcinoma (SNUC); Sinonasal
Sebaceous lymphadenocarcinoma, 568 curvularia, 1640 undifferentiated carcinomas (SNUC)
Sebaceous trichofolliculoma, 1488 fungus ball/mycetoma, 1632–1634 Soft palate, squamous cell carcinomas,
Seborrheic keratoses (SK) hyalohyphomycosis, 1641 302–303
associated syndromes, 1477 mucormycosis and Soft tissues
clinical features, 1475 entomophthoromycosis, 1634–1637 developmental cysts of neck, 1351
differential diagnosis, 1476–1477 myospherulosis, 1643–1644 lesions, 54
imaging studies of, 1475 phaeohyphomycosis, 1639 lymph node(s), 1353–1355
immunohistochemical studies, 1475 pseudoallescheriasis, 1637–1638 metastases, 1140
treatment and prognosis, 1477 rhinosporidiosis, 1642–1643 neoplasms, 1603
Secondary (dedifferentiated) AMCA, 1295 sporotrichosis, 1641–1642 perineurioma, 697
etiology of, 1296 Sinonasal hemangiopericytoma, 64 tumors and, 1355–1367
histochemical study, 1296 clinical features, 850 like lesions of, 1367
molecular-genetic data, 1296 immunohistochemistry, 850 Soft tissue sarcomas, in head and neck
radical surgical resection, 1296 molecular findings, 850 region, 54–59
Secondary (dedifferentiated) peripheral pathology, 850 Ewing’s sarcoma, 55
(arising in preexisting benign treatment and prognosis, 850 leiomyosarcomas, 58
ameloblastoma), 1296 Sinonasal leiomyosarcoma, 876 myxoid soft tissue sarcomas, 58–59
clinical features, 1297 Sinonasal neuroendocrine carcinoma, 67 osteosarcomas, 57
differential diagnosis, 1297 Sinonasal NK/T-Cell lymphoma, 1670–1671 pleomorphic sarcomas, 57
etiology of, 1297 Sinonasal paragangliomas (SNPG), 724–725 polygonal cell sarcomas, 55–56
radiograms, 1297 Sinonasal polyposis, 1610 round cell sarcomas, 54–55
treatment and prognosis, 1297 Sinonasal polyps, 674 spindle cell sarcomas, 58
Secondary hyperparathyroidism Sinonasal tumors, cytokeratin synovial sarcomas, 56–57
clinical presentation, 1442 expression, 379 Soft tissue tumors, of salivary gland,
definition, 1442 Sinonasal undifferentiated carcinoma 598–600
epidemiology, 1442 (SNUC), 731 juvenile hemangioma, 600–601
imaging studies, 1442–1443 Sinonasal undifferentiated carcinomas sialolipoma, 601–603
preoperative localization, 1442–1443 (SNUC), 66–67, 377–380 SOHLs. See Squamous odontogenic
selective venous sampling, 1443 histogenesis, 378 hamartoid lesions (SOHLs)
treatment and prognosis Sinuses, 1351 Solar elastosis, 1489
standard medical therapy, 1456 histiocytosis with lymphadenopathy, 1415 Solar keratosis. See Actinic keratoses (AKs)
surgical management, 1456 vascular transformation of, 1005–1006 Solid cell nests in thyroid, 1386
Secondary malignancies, of eyes, 1603 Sinus histiocytosis, 1000–1001 Solid/multicystic ameloblastoma–central
Secondary osteosarcoma, 974 with massive lymphadenopathy, etiology of
Secretory meningioma, 705 1023–1024 basaloid pattern, 1206–1207
Selective neck dissection (SND), 1135 Sinusitis plexiform growth pattern, 1205
Senile keratosis. See Actinic keratoses (AKs) acute bacterial, 345 immunohistochemistry
Sentinel lymph node (SLN), 101, 1137 chronic, 345 basement-type heparan sulfate
Serous otitis media (otitis media with Sjögren’s syndrome, 32, 1014, 1660 proteoglycan (HSPG), 1209
effusion), 1612 SJS. See Stevens–Johnson syndrome (SJS) cell proliferation markers, 1209
Serum calcitonin analysis, 1150 Skeletal muscle hemangioma, 1356 CKs and vimentin, 1208
SETTLE. See Spindle epithelial tumor with Skin collagen types, 1208–1209
thymus-like differentiation (SETTLE) epidermal and cutaneous adnexal lesions, extracellular matrix proteins and
Severe chronic active EBV infection, 1667 1341–1342 basement membrane, 1208
[Solid/multicystic ameloblastoma–central] [Squamous cell carcinoma (SCC)] Stevens–Johnson syndrome (SJS), 258
[immunohistochemistry] [metastasis determinants] Stomal recurrence, 144–145
integrin, 1209 soft tissues, 1140 Storiform pleomorphic malignant fibrous
laminin, 1208 stromal reactions, 1141 histiocytoma, 886, 888
mitogen-activated protein kinases Squamous cell carcinomas (SCC), 46–47, Stratum fibrosum externum, 672
(MAPKs), roles of, 1209 61–62, 76, 1413–1414, 1476. See also Stratum fibrosum internum, 670
tenascin, 1208 Oral cancer Stratum nervosum, 670
prevalence and incidence clinical features, 1491 Streptococcus, 261
age range, 1203 differential diagnosis, 1494–1495 Streptococcus pneumoniae, 345, 429, 1392, 1609
frequency of, 1202–1203 of ear, 459–460 Stromal atypia, nasal polyps, 350
location of, 1203 eyelids, 1553 Stromal dystrophies, 1570–1571
plexiform growth pattern, 1204 of hypopharynx, 174–177 Stucco keratosis. See Seborrheic keratoses
radiological appearance and, 1204 clinical features, 175–177 (SKs)
Solid/multicystic ameloblastoma– etiology, 175 Sturge-Weber syndrome, 1523
peripheral (PERAM) overviews, 174 Subacute cutaneous lupus erythematosus
CK-19 and Ber-EP4, 1217 treatment, 177 (SCLE), 252–253
differential diagnosis, 1217 keratinizing. See Keratinizing squamous Subacute granulomatous thyroiditis, 4
gender distribution of, 1215 cell carcinomas (KSCC) Subacute necrotizing sialadenitis, 493
immunohistochemical studies, 1216–1217 of larynx, 137–145 Subacute sclerosing panencephalitis
molecular-genetic data, 1217 glottic carcinoma, 139–142 (SSPE), 1685
pathology, 1216 laryngeal carcinoma, 144–145 Subacute thyroiditis, 1392
prevalence and incidence, 1215 molecular genetic data, 145 Subcutaneous lymphoid infiltrate
radiological changes, 1216 overviews, 137–139 diagnosis, of hematolymphoid lesions of
treatment and prognosis, 1217–1218 subglottic carcinoma, 142–143 skin, 1115
ultrastructure of, 1217 supraglottic carcinoma, 139 Subcutaneous panniculitis-like T-cell
Solid parathyroid adenomas, 19 transglottic carcinoma, 143 lymphoma, 1071
Somatostatin analogue octreotide, 712 maxillary sinuses, 374–376 Subglottic carcinoma, 142–143
Sonic Hedgehog (SHH) gene underexpression T staging, 375 Subglottic stenosis, 114
in ameloblastomas, 1213 of middle ear, 465–466 Sulfodiazine, 1689
SOT. See Squamous odontogenic tumor (SOT) molecular genetics, 1494 Sulfonamides, 260
South Asia, oral cancer incidence in, 287 nasal cavity, 371–374 Superficial extending carcinoma (SEC),
SPCC. See Spindlecell carcinomas (SPCC) of nasopharynx, 397 136–137
Sphenoethmoidal, through sphenoethmoid nonkeratinizing. See Nonkeratinizing Superficial lymph nodes
junction, 674 squamous cell carcinomas lateral, 1135
Sphenomaxillary, through sphenoid, 675 oral cavity, 292–301 medial, 1135
Spheno-orbital though superior orbital buccal mucosa, 294–295 Supernumerary parathyroid glands, 1429,
fissure, 674 floor of mouth and oral tongue, 295–298 1430
Spindle cell carcinomas (SPCC), 146–151, gingiva and alveolar mucosa, 298–300 Suppurative granulomas, 1012
318–322, 1492 hard palate, 300–301 Suppurative lymphadenitis, 50
clinical features, 147, 319 lip, 292–294 Suprabasal bullae formation, 244
diagnosis, 150 oropharynx, 301–305 Supraclavicular lymph node metastases,
etiology, 147 oropharyngeal wall, 303 48–49
immunohistochemistry, 149–150 palatine tonsils and base of tongue, Supraglottic carcinoma, 139
molecular genetic data, 150 303–305 Surgical margins, 97–100
overviews, 146–147 retromolar trigone (RMT), 301–302 Surgical resection, of cancer, 98
pathology, 147–149, 319–321 soft palate and uvula, 302–303 Sympathetic ophthalmia, 1583–1586
treatment, 150–151 pathology, 1492–1494 Synaptophysin, 67
treatment and prognosis, 321–322 of trachea, 178 Syndecan-1 (SDC-1) for Wnt induced
Spindle cell lesions, 35 glottic carcinoma, 139–142 carcinogenesis, 1213
Spindle cell melanoma, 1509–1510 laryngeal carcinoma, 144–145 Syndrome-associated osteosarcoma, 974
Spindle cell rhabdomyosarcoma, 871–872 molecular genetic data, 145 Synovectomy, 956
Spindle cell sarcomas, 58 overviews, 137–139 Synovial chondromatosis
Spindle epithelial tumor with thymus-like subglottic carcinoma, 142–143 pathologic features, 955–956
differentiation (SETTLE), 1412–1413 supraglottic carcinoma, 139 radiologic features, 955
Spindle-pleomorphic lipoma (SPL), 1728 transglottic carcinoma, 143 Synovial chondromatosis of
Spitz nevus treatment and prognosis, 1495 temporomandibular joint, 435–436
clinical features, 1504 of upper aerodigestive tract, 1459 Synovial cysts, 957
differential diagnosis, 1506 variants, 1492–1494 Synovial sarcomas, 56–57, 897–899, 1360
electron microscopy, 1506 Squamous eddies, 1479 biphasic, 897
immunohistochemistry, 1506 Squamous intraepithelial neoplasia monophasic, 897
and melanocytic proliferation, 1340 classification, 270 Syphilis
molecular genetics, 1506 Squamous metaplasia, nasal polyps with, 368 congenital, 1615, 1616
pathology, 1504–1506 Squamous odontogenic hamartoid lesions differential diagnosis, 1617
treatment and prognosis, 1506–1507 (SOHL), 1229 epidemiology and historical perspective,
Spitzoid melanoma, 1340 Squamous odontogenic tumor (SOT) 1612–1613
Sporothrix, 1638 etiology and pathogenesis, 1228–1229 head and neck manifestations, 1613–1614
Sporotrichosis, 1641–1642 histochemical markers for, 1229 oral manifestations, 1613
S-100 protein, 1286, 1500, 1729 hyperplastic islands, 1229 otosyphilis, 1614
S-100 protein-positive cells, 683 molecular-genetic data, 1230 primary, 1615–1616
Squamous carcinoma, 21–22 prevalence and incidence, 1228 secondary, 1616
Squamous cell carcinoma (SCC), 588–589, radiograms of, 1228 serologic identification, 1617
958, 1147 treatment and prognosis, 1230 and spirochetes, 1616–1617
metastasis determinants Stafne cyst, 962 tertiary, 1614–1615, 1616
extracapsular spread, 1138–1140 Stapedial footplate, otosclerosis of, 445 treatment, 1617
histologic prognostic factors, 1141–1142 Staphylococcus aureus, 50, 953, 1609 Syphilitic (luetic) lymphadenitis, 1012
micrometastases, 1140–1141 Sternomastoid tumor. See Fibromatosis colli Syringocystadenoma papilliferum,
positive lymph nodes, 1140 Steroid therapy, 254 ceruminal gland, 447–448
Syringomas, 1342 Thorotrast-related neoplasms, 1723 [Thyroid gland]

clinical features, 1485–1486 Thymidine phosphorylase (PD-ECGF/TP) [tumors]
differential diagnosis, 1486–1487 expression and stroma of primary lymphomas and
electron microscopic studies, 1486 ameloblastomas, 1211 plasmacytomas, 1414–1415
immunohistochemistry, 1486 Thymomas, 1724 sclerosing mucoepidermoid carcinoma
molecular genetics, 1486 Thyroglobulin, 1386 with eosinophilia, 1412
pathology, 1486 Thyroglossal duct cyst (TGDC), 16, sinus histiocytosis with massive
treatment and prognosis, 1487 1351–1352, 1387 lymphadenopathy, 1415
Systemic lupus erythematosus (SLE), 252 Thyroid, hematolymphoid lesions of, smooth muscle tumors, 1416
1100–1103 solitary fibrous tumor, 1415
Tachyzoites, 1688 diagnostic considerations, 1102–1103 spindle epithelial tumor with
Tamoxifen, 1390 neoplasms, 1100–1101 thymus-like differentiation, 1412–1413
Tangier disease (TD), 1730 reactive/inflammatory, 1101–1102 squamous cell carcinoma, 1413–1414
Tapered stroma, of the ciliary body, 1587 Thyroid carcinoma, 47 teratoma, 1414
Tartrateresistant acid phosphatase Thyroid cyst fluid, 16 Thyroiditis, 3–4
(TRAP), 557 Thyroidectomy, 13, 15, 1429, 1432 Thyroid nodule, 1
TC. See Typical carcinoid (TC) Thyroid gland, 103–104 Thyroid parangliomas (TPG), 725
T-cell intracellular antigen (TIA)-1, 43 adequasy criteria, 2–3 Thyroid transcription factor (TTF)-1, 1503
T-cells, 39, 257, 260 clear cell lesions, 16–17 Thyroid transcription factor-1 (TTF-1), 15
lymphoblastic leukemia/lymphoma, 1060 clinical implications of, 17 Ticarcillinclavulanate, 1611
receptor gene, 40 cystic lesions, 15–16 Tissue alterations, in dysplasia, 267
rich B-cell lymphomas, 660 developmental and hereditary Tissue culture, in cranial fasciitis, 966
Teflon granulomas, 113–114, 1393 abnormalities Tissue eosinophilia, 658
Teflon injections, 976 aplasia and hypoplasia, 1387 TLA-1. See T-cell intracellular antigen (TIA)-1
Teflonoma. See Teflon granuloma ectopic thyroid tissue, 1387 T- lymphocytes, 952, 953
Telangectasias, 1533 hereditary abnormalities, 1387 TMJ. See Temporomandibular joint (TMJ)
Telangiectatic osteosarcoma, 973–974 parasitic nodule, 1387 TNF-related apoptosis-related ligand
Temporal bone thyroglossal duct cyst, 1387 (TRAIL) 1 and 2, role in
benign neoplasms of, 449–456 diagnostic accuracy, 2 ameloblastomas, 1212
endolymphatic sac papillary tumor, diagnostic categories, 1–2 TNM classification scheme, 1507–1508
457–458 disorders Tobramycin, 1612
metastases, 1157 autoimmune thyroid diseases, 1390 Tonsillar cysts, 117
metastatic tumors, 467 crystals, 1393 Tonsillar hyperplasia, 222–225, 1610
neoplastic lesions of, 446–467 goiters, 1390–1391 Tonsillectomy, 1610
benign neoplasms, 447–456 hypothyroidism, 1392–1393 Tonsillitis, 222–225, 1610
endolymphatic sac papillary tumor, infections and granulomatous diseases, clinical features, 223
457–458 1391–1392 overviews, 222–223
malignant neoplasms, 459–467 levothyroxine therapy, 1390 pathology, 223–224
nonneoplastic lesions, 425–432 metabolic diseases, 1392 treatment, 224–225
Temporomandibular joint (TMJ), 953 pigment deposition, 1393 Tophaceous gout, 442–443
synovial chondromatosis of, 435–436 teflon, 1393 Tophus, 953
Tenascin drugs effects of, 1386 Topical 5-aminolevulinic acid-mediated
and calcifying odontogenic cyst (COC), embryology and development, photodynamic therapy, 1678
1265 1385–1386 Torg syndrome, 1344
CEOT, 1234 follicular lesions, 6–9 Torus mandibularis, 967
and DESAM, 1220 invasion, 145 Torus palatinus, 967
solid/multicystic ameloblastoma–central, malignant neoplasms, 9–15 Toxic multinodular goiter, 1391
1208 metastatic malignancies, 17–18 Toxoplasma gondii, 50
Teratocarcinosarcoma, 1366 nonneoplastic disease, 3–6 Toxoplasmic lymphadenitis, 1012–1013
Teratoma, 1414 oncocytic neoplasms, 9 Toxoplasmosis, 50–51
Terminal deoxynucleotidyl transferase overviews, 1 clinical course, 1687–1688
biotin-dUTP-nick-end labeling physiology epidemiology, 1687
(TUNEL) for apoptosis detection, thyroid-stimulating hormone (TSH), histopathology, 1688
1212 1386 IHC, PCR, and serology, 1688–1689
Tertiary hyperparathyroidism thyroxine (T4) and triiodothyronine treatment, 1689
clinical presentation, 1442 (T3), hormones, 1386 TPG. See Thyroid parangliomas (TPG)
definition, 1442 radiation changes in, 1386–1387 TP53 gene family in ameloblastomas, 1211
epidemiology, 1442 thyroid parenchyma, 1365 TPO. See Tracheopathia
imaging studies, 1442–1443 thyroid transcription factor-I (TTF-1), osteochondroplastica (TPO)
preoperative localization, 1442–1443 1385 Trachea, hematolymphoid lesions of,
selective venous sampling, 1443 thyrotropin receptor gene, genetic 1100
treatment and prognosis, 1456 alterations of, 1387 Tracheopathia osteochondroplastica (TPO),
Tetracycline, 263 tumors 114–115
TGF-b. See Transforming growth factor beta anaplastic carcinoma, 1407–1409 TRAIL/Apo2L. See Tumor-necrosis-factor-
(TGF-b) role in ameloblastomas carcinoma showing thymus-like related apoptosis-inducing ligand
Thalidomide, 1693 differentiation, 1413 (TRAIL/Apo2L) expressions and
Thiabendazole, 1690 of C Cells, 1409–1412 ameloblastomas
Thiazide diuretics, 1438 follicular thyroid tumors, 1402–1404 Transcription factor deficiency, 1387
Thiocyanate antithyroid drugs, 1386 hurthle cell tumors, 1404–1406 Transethmoidal, through cribriform
Thorotrast granulomas hyalinizing trabecular tumor, 1400–1402 plate, 674
background, 1722–1723 langerhans cell histiocytosis, 1415 Transforming growth factor beta (TGF-b)
clinical features, 1723 mesenchymal tumors, 1415–1416 role in ameloblastomas, 1211
pathology, 1723–1724 mucoepidermoid carcinoma, 1412 Transglottic carcinoma, 143
treatment and prognosis, 1724 papillary thyroid carcinoma (PTC), Transillumination, of the eye, 1583
Thorotrast injection, 1723–1724 1393–1400 Transsphenoidal, through sphenoid, 675
Thorotrast-related hepatic malignancies, 1724 poorly differentiated carcinomas, TRAP. See Tartrateresistant acid
1406–1407 phosphatase (TRAP)
Traumatic neuroma Tumors, of trachea, 177–178 Urbach-Wiethe syndrome. See Lipoid

clinical features, 676–677 adenoid cystic carcinoma, 178 proteinosis
diagnosis, 677 anatomy, 177–178 Uremia, 252
histopathology, 677 overviews, 177 US. See Ultrasound (US)
immunohistochemistry, 677 squamous cell carcinoma, 178 UV. See Ultraviolet light (UV)
macroscopy, 677 Tumors, salivary gland Uveal tract
overview, 676 age distribution, 506 anatomy, 1586–1587
treatment, 677–678 cigarette smoking and, 506–507 clinical features, 1587–1588
ultrastructure, 677 classifications, 511 pathology, 1588–1591
Traumatic retinal detachment, 1585 epidemiology, 505–506 specimen handling, 1587–1591
Treponema pallidum, 1012 fine-needle aspiration cytology UV light–induced SCCs, 1494
Trichilemmal carcinoma (TLC), 1479 for, 508–509 Uvula, squamous cell carcinomas, 302–303
clinical features, 1501 frozen section diagnosis, 509
differential diagnosis, 1502 genetics, 510–511 Vagal paragangliomas (VPG), 722–723
immunohistochemistry, 1502 imaging procedures of, 507–508 Varicella Zoster virus (VZV), 1661
pathology, 1501–1502 occupation and, 506 Vascular endothelial growth factor (VEGF)
treatment and prognosis, 1502 radiation and, 506 role in ameloblastomas, 1214
Trichilemmal cyst. See Pilar cysts (PCs) sex ratio, 506 Vascular malformations
Trichilemmal keratinization, 1477 site, 506 clinical features, 1522
Trichilemmomas (TL) viruses and, 506 differential diagnosis, 1522–1524
clinical features, 1481 TUNEL. See Terminal deoxynucleotidyl electron microscopy, 1522
differential diagnosis, 1482 transferase biotin-dUTP-nick-end genetics, 1522
imaging studies, 1481 labeling (TUNEL) for apoptosis imaging studies, 1522
immunohistochemistry, 1481–1482 detection immunohistochemistry, 1522
molecular genetics, 1482 Turner syndrome, 1357, 1523 pathology, 1522
pathology, 1481 T1-weighted images, 980 treatment and prognosis, 1524
treatment and prognosis, 1482 T2-weighted images, 980 Vascular neoplasms, in children, 1355
Trichinella, 1689 Tympanic cavity, 424 Vascular proliferations
Trichinosis Tympanic paraganglioma, 721 angiolymphoid hyperplasia with
clinical course, 1689 Tympanosclerosis, 429–430 eosinophilia (ALHE), 1528–1529
etiology, 1689 Typical carcinoid (TC), 162–164 infantile hemangioma (IH), 1524–1526
histopathology, 1689–1690 clinical features, 162–163 kaposiform hemangioendothelioma,
serology, 1690 diagnosis, 164 1526–1528
treatment, 1690 electron microscopy, 164 kaposi sarcoma, 1530–1532
Trichloracetic acid treatment, 1487 immunohistochemistry, 163–164 syndromes associated with, 1523
Trimethoprim sulfamethoxazole, 1691 pathology, 163 vascular malformations, 1521–1524
Trimethoprin-sulfamethoxazole (TS), 655 treatment, 164 vascular tumors, 1524
Trousseau’s sign, 1460 Tyr165Cys, 1487 Vascular transformation of
Trypanosome, 1654 Tzanck cells, 245, 262 sinuses, 1005–1006
TS. See Trimethoprin-sulfamethoxazole Vasomotor rhinosinusitis, 345–346
T-SPOT-TB, 1623 UDCs. See Undifferentiated carcinomas VCA. See Viral capsid antigen (VCA)
T staging of squamous cell carcinomas Ulceration, 1478 VCNP. See Vocal cord nodule and polyp
external auditory canal, 462 Ultrasonography, 78 (VCNP)
in maxillary sinus, 375 Ultrasound (US), 1, 953 VEGF. See Vascular endothelial growth
TTF-1. See Thyroid transcription factor-I Ultraviolet light (UV), 252 factor (VEGF)
(TTF-1) oral cancer, 288 Venous drainage, of parathyroids, 1430
Tuberculin skin test, 1623 Ultraviolet (UV) B radiation, 1491 Venous malformations, 1522
Tuberculosis and thyroiditis, 1392 UNAM. See Unicystic ameloblastoma Vernal conjunctivitis, 72
Tuberous sclerosis, 1348 (UNAM) Verruca vulgaris, 214–215, 1476
Tumefactive fibroinflammatory Undifferentiated carcinomas (UDCs), 1141 Verruca vulgaris of larynx (VVL), 124–125
pseudotumor, 1367 nonkeratinizing, 308–309 Verruciform xanthoma, 216–217
Tumoral calcinosis, 954–955 of salivary glands, 589 Verrucous carcinomas, 151–153, 314–316,
Tumor necrosis factor a(TNF-a), 655, 958 Undifferentiated nasopharyngeal 1492
Tumor-necrosis-factor-related apoptosis- carcinomas (UNPC), 397 clinical features, 151, 314
inducing ligand (TRAIL/Apo2L) versus SNUC, 380 diagnosis, 153
expressions and ameloblastomas, 1212 Unencapsulated parathyroid cells, 1431 differential diagnosis, 315–316
Tumor-node-metastasis (TNM) staging, Unicystic ameloblastoma (UNAM) etiology, 151–152
1495 AgNOR activity, 1224 molecular-genetic data, 152–153
malignant melanomas, 394 differential diagnosis, 1224 overviews, 151
for oral cavity cancer, 291 etiology of, 1222–1223 pathology, 152, 315
for oropharyngeal cancer, 292 histological variants of, 1223 treatment, 153
of squamous cell carcinomas in external immunohistochemistry, 1223–1224 treatment and prognosis, 316
auditory canal, 462 molecular-genetic data, 1224 and verrucous hyperplasia, 1677–1678
Tumors multilocularity and, 1222 Verrucous hyperplasia (VH), 1678
of parapharyngeal space PCNA and Ki-67 expression, 1224 Versican and calcifying odontogenic cyst
anatomy, 1721–1722 prevalence and incidence, 1221–1222 (COC), 1265
clinical features, 1722 treatment and prognosis, 1224–1225 Vesiculoerosive lesions, 243
histology, 1722 type 1 (intralining) and type 2 Vimentin antibodies
pathology, 1722 (intraluminal), 1225 AFOD, 1251
treatment and prognosis, 1722 United States, oral cancer incidence in, 286 and AMF, 1244
of parathyroid glands UNPC. See Undifferentiated AOT, 1238
clinical features, 1461–1462 nasopharyngeal carcinomas (UNPC) and (ODOMYX), 1286
differential diagnosis, 1462 Upper aerodigestive tract Viral capsid antigen (VCA), 1150
pathologic features, 1462 nasal cavity and nasopharynx, Viral diseases, 72
treatment and prognosis, 1462 1343–1351 Vitamin C, 1691
ploidy, 145 oral cavity and oropharynx, 1343–1348 Vitamin D analogues, 1456
thyroid glands. See Thyroid gland, tumors
Vitamin D receptor (VDR), 1435 WDLS. See Well-differentiated liposarcoma Wiskott-Aldrich syndrome (WAS), 1667
Vitrectomy, 70 (WDLS) Wnt signaling pathway in ameloblastomas,
Vocal cord nodule and polyp (VCNP), 109– Weathering nodule of the ear (WNE) 1213
111 clinical features, 1535 World Health Organization (WHO), 37, 43,
clinical features, 109 differential diagnosis, 1536 269
diagnosis, 111 immunohistochemistry, 1536 classification
etiology, 109 pathology, 1535 ossifying fibroma, 970
overviews, 109 treatment and prognosis, 1536 osteosarcoma, 972
pathology, 109–110 Wegener’s granulomatosis (WG), 73, dysplasia classification by, 269–270
treatment, 111 443–444, 961, 1392, 1610 histological classification of odontogenic
Vogt-Koyanagi-Harada syndrome (VKH), clinical features, 650–652 tumors, 1202
1584 criteria for diagnosis, 652
Von Hippel–Lindau (VHL) syndrome, 457 ELK classification, 654 Xanthelasma, 1557
Vossius ring, 1586 etiology, 649–650 Xanthogranuloma, juvenile, 1085
VPG. See Vagal paragangliomas (VPG) limited form of(LWG), 653–654 X chromosome-linked IAP (XIAP), and
VVL. See Verruca vulgaris of larynx (VVL) nasal cavity, 1083 odontogenic epithelial cells, 1212
pathology, 652–654 Xeroderma pigmentosa, 1341
treatment and prospect, 654–655 Xeroderma pigmentosum, 76
Waldeyer’s ring, 1147 Well-differentiated liposarcoma (WDLS), XIAP. See X chromosome-linked IAP (XIAP)
normal lymphoid tissues of, 1001 862 and odontogenic epithelial cells
Warthin-Starry stain, 64 ‘‘Western’’ sinonasal lymphomas, 1670 X-linked idiopathic hypoparathyroidism,
Warthin’s tumor, 505 Wet keratin, 715 1460
cigarette smoking and, 507 WG. See Wegener’s granulomatosis X-linked lymphoproliferative syndrome,
clinical features, 526 Whipple’s disease, 73, 1691 1667
differential diagnosis, 529–530 White sponge nevus
electron microscopy, 529 clinical features, 201–202
etiology, 526–527 diagnosis, 203 Yolk sac carcinoma, 1365
imaging, 526 molecular and genetic data, 203
immunohistochemistry, 529 pathology, 202 ZEBRA, 1665
molecular-genetic data, 529 treatment, 203 Ziehl-Neelsen stain, 1623
overview, 526 WHO. See World Health Organization Zimmerman tumor. See Phakomatous
pathology, 527–529 (WHO) choristoma
treatment, 530 Wickham’s striae, 254 Zygomycetes, 1638
Warthin tumor, 22, 30–31 Winkler disease. See Chondrodermatitis
Water-clear cells, 1448, 1454 nodularis chronicus helicis (CNCH)
Pathology
about the book…

Surgical Pathology of the Head and Neck, Third Edition is a complete stand-alone reference covering
all aspects of head and neck pathology. Providing an interdisciplinary approach to the diagnosis,
treatment, and management of head and neck diseases, this source promotes clear communication
between pathologists and surgeons. This is the reference of choice for a variety of clinicians, including:
oral and general pathologists; oral and maxillofacial, plastic, reconstructive, head and neck, orthopedic,
and general surgeons; otolaryngologists; radiologists; and dentists.
Topics covered include:
• incidence
• etiology
• clinical presentation
• pathology
• differential diagnosis
• prognosis for each disorder
With an improved format and design as well as an easy-to-use, quick reference index, the updated and
expanded Third Edition contains more than 1,400 images—200 more full-color images than in previous
editions—for optimal illustrations of head and neck lesions.
about the editor...
LEON BARNES is Professor of Pathology and Otolaryngology, Chief of the Division of Head and Neck–
Endocrine Pathology and Director of the Head and Neck–Endocrine Pathology Fellowship Program at
the University of Pittsburgh Medical Center, and Professor of Oral and Maxillofacial Pathology at the
University of Pittsburgh School of Dental Medicine. Dr. Barnes obtained his M.D. degree from the
University of Arkansas, Little Rock, Arkansas. He is a founding member of the North American Society of
Head and Neck Pathology and has been a frequent honoree on the “Best Doctors in America” list for
head and neck pathology. He has contributed numerous peer-reviewed publications, is a co-editor of
the most recent World Health Organization “Blue Book” on the Pathology and Genetics of Head and
Neck Tumors, and is the editor of the two previous editions of Informa Healthcare’s Surgical Pathology
of the Head and Neck.
Printed in India
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Volu m e 1

Preface to Third Edition . . . . iii

2. Uses, Abuses, and Pitfalls of Frozen-Section Diagnoses of Diseases

3. Diseases of the Larynx, Hypopharynx, and Trachea . . . . . . . . . . . . . . . . . . . . . . 109

6. Premalignant Lesions of the Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

7. Cancer of the Oral Cavity and Oropharynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

10. Diseases of the Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475

14. Diseases of the Bones and Joints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951

15. Hematolymphoid Lesions of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . 997

17. The Occult Primary and Metastases to and

18. Cysts and Cyst-like Lesions of the Oral Cavity,

22. Pathology of the Parathyroid Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429

25. Infectious Diseases of the Head and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1609

Kristen A. Atkins Department of Pathology, University of Virginia Health

Aaron Auerbach Department of Hematopathology, Armed Forces Institute of

Leon Barnes Department of Pathology, University of Pittsburgh Medical

Margaret Brandwein-Gensler Department of Pathology, Albert Einstein

Harry H. Brown Departments of Pathology and Ophthalmology, Harvey and

Steven D. Budnick Emory University School of Medicine Atlanta, Georgia, U.S.A.

Alexander C. L. Chan Department of Pathology, Queen Elizabeth Hospital,

John K. C. Chan Department of Pathology, Queen Elizabeth Hospital,

Louis P. Dehner Lauren V. Ackerman Laboratory of Surgical Pathology,

Samir K. El-Mofty Department of Pathology and Immunology, Washington

Samir K. El-Mofty Lauren V. Ackerman Laboratory of Surgical Pathology,

Tarik M. Elsheikh PA Labs, Ball Memorial Hospital, Muncie, Indiana, U.S.A.

Lori A. Erickson Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A.

Julie C. Fanburg-Smith Department of Orthopaedic and Soft Tissue Pathology,

Robert D. Foss Department of Oral and Maxillofacial Pathology, Armed Forces

Kim M. Hiatt Department of Pathology, University of Arkansas for Medical

William B. Laskin Surgical Pathology, Northwestern Memorial Hospital,

Jerzy Lasota Department of Orthopaedic and Soft Tissue Pathology, Armed

James S. Lewis, Jr. Department of Pathology and Immunology, Washington

Ricardo V. Lloyd Mayo Clinic College of Medicine, Rochester, Minnesota,

Mario A. Luna Department of Pathology, The University of Texas,

Susan Müller Department of Pathology and Laboratory Medicine and

Panna Mahadevia Department of Pathology, Albert Einstein College of

Thijs A.W. Merkx Department of Oral and Maxillofacial Surgery, Radboud

Stacey E. Mills Department of Pathology, University of Virginia Health System,

Mark D. Murphey Department of Radiologic Pathology, Armed Forces

Toshitaka Nagao Department of Diagnostic Pathology, Tokyo Medical

Daisuke Nonaka Department of Pathology, New York University School of

Jennifer B. Ogilvie University of Pittsburgh Medical Center, Pittsburgh,

Shayesteh Pashaei Department of Pathology, University of Arkansas for

Finn Prætorius Department of Oral Pathology, University of Copenhagen,

Robert A. Robinson Department of Pathology, The University of Iowa, Roy

Reda S. Saad Sunnybrook Hospital, University of Toronto, Toronto, Ontario,

Raja R. Seethala University of Pittsburgh Medical Center, Pittsburgh,

Jan F. Silverman Department of Pathology and Laboratory Medicine,

Harsharan K. Singh University of North Carolina-Chapel Hill School of

Pieter J. Slootweg Department of Pathology, Radboud University Nijmegen

Bruce R. Smoller Department of Pathology, University of Arkansas for Medical

Steven D. Vincent Department of Oral Pathology, Oral Radiology and Oral

Mohamed A. Virji University of Pittsburgh Medical Center, Pittsburgh,

Beverly Y. Wang Departments of Pathology and Otolaryngology, New York

Bruce M. Wenig Department of Pathology and Laboratory Medicine,

David Zagzag Department of Neuropathology, New York University School of

Fine Needle Aspiration of the Head and Neck

I. THYROID GLAND provide a relative risk of malignancy from which they