Ajcpath125 0555

Anatomic Pathology / OSTEOSARCOMA
Osteosarcoma
Anatomic and Histologic Variants
Michael J. Klein, MD, and Gene P. Siegal, MD, PhD
Key Words: Osteosarcoma; Malignant bone tumors; Bones; Imaging
DOI: 10.1309/UC6KQHLD9LV2KENN
Downloaded from https://academic.oup.com/ajcp/article/125/4/555/1759835 by guest on 19 October 2022

Abstract At an estimated incidence of 2 cases per million persons
Osteosarcoma is the most common primary tumor per year, osteosarcoma is the most common malignant pri-
of bone, yet its absolute incidence among malignant mary bone tumor excluding hematopoietic intraosseous
tumors is low. Within its strict histologic definition, tumors. Although it occurs at any age, its peak incidence is in
osteosarcoma comprises a family of lesions with the second and third decades. Its statistical distribution rough-
considerable diversity in histologic features and grade. ly parallels skeletal growth; it is more frequent in tall people
Its prognosis is dependent not only on these parameters than in short people and in larger animals than in smaller ani-
but also on its anatomic site. It may occur inside the mals.1 Bones having the fastest rates of growth have the high-
bones (in the intramedullary or intracortical est frequency of occurrence. When osteosarcoma appears ear-
compartment), on the surfaces of bones, and in lier than the second decade or after the cessation of skeletal
extraosseous sites. Information of diagnostic or growth, there is often an association with another osseous
prognostic significance has not been elucidated from abnormality. This may be a genetic predisposition such as the
studies of its cytogenetics. This review summarizes the Li-Fraumeni or Beckman-Wiederman syndrome,2,3 an under-
anatomic and histologic variations of osteosarcoma lying abnormality such as Paget disease4 or fibrous dysplasia
and offers a schema for its subclassification. that has a predilection for the development of osteosarcoma,5
or previous radiation of the bone involved.
The definition of osteosarcoma is deceptively straightfor-
ward. It is a malignant tumor of connective tissue (mesoder-
mal) origin within which the tumor cells produce bone or
osteoid (often referred to as “tumor bone” or “tumor osteoid”
in the vernacular). Although this makes it seem as though the
cells giving rise to osteosarcoma must be of osteoblastic deri-
vation, there is no evidence that osteoblasts, once they differ-
entiate from osteoprogenitor cells, can actually revert to more
primitive cells, let alone malignant ones. This implication is
inherent in the more arcane term osteogenic sarcoma, which
has fallen into disuse.
An additional feature often encountered in osteosarcomas
is their propensity to produce variable amounts of cartilage
matrix and fibrous tissue. In some cases, the cartilage matrix
or fibrous tissue may so strikingly dominate the tumor tissue
that the actual production of bone must be carefully sought to
© American Society for Clinical Pathology Am J Clin Pathol 2006;125:555-581 555

555 DOI: 10.1309/UC6KQHLD9LV2KENN 555
Klein and Siegal / OSTEOSARCOMA
make the correct diagnosis. Because osteosarcoma may differ- so-called Codman angle. Other kinds of periosteal reac-
entiate along all or any of these pathways of matrix synthesis, tions may cause so-called sunburst or hair-on-end radi-
it has more of a histologic similarity to fracture callus or ographic densities ❚Image 1❚.
fibrous dysplasia than it does to differentiated bone Although periosteal new bone formation sometimes is
matrix–producing tumors such as osteoid osteoma or associated with benign conditions, periosteal reactions associ-
osteoblastoma. This has given rise to the 3 traditional subdivi- ated with malignant tumors usually are discontinuous, imply-
sions of osteoblastic, chondroblastic, and fibroblastic ing that the tumor growth is too rapid for periosteal contain-
osteosarcoma. In actuality, most osteosarcomas demonstrate ment.6 In some cases, conventional radiographs may suggest a
varying amounts of all 3 cell types and matrix. Consequently, malignant tumor that is not osteosarcoma.7 This is especially
division into any one of these types is arbitrary and capricious true when a large proportion of the osteoid matrix in an
but generally is meant to signify greater than 50% predomi- osteosarcoma is not well mineralized. In rarer cases, the radi-
nance of any histologic type. ograph may not even appear to represent a malignant tumor.8

Although osteosarcoma usually arises in the medullary It must be kept in mind that although radiographs usually cor-
cavity of the metaphysis of a growing long tubular bone, it relate well with histologic studies of bone tumors, radiographs
also may arise on the surface of a bone, it may be confined to merely reflect statistical odds ratios and, thus, the likelihood
the cortex, or it even may arise in an extraskeletal site. The that a lesion is, first, a tumor, and second, malignant or benign.
osteosarcomas arising on the bone surfaces are about 20 times Like all statistics, there are some lesions of bone that are out-
less frequent than their medullary counterparts. Interestingly, liers and may not correlate well with the radiographic appear-
the majority of osteosarcomas of medullary origin are high- ance; this is precisely the reason that even classically appear-
grade, whereas most arising on the surfaces of bones are of ing bone lesions must be biopsied ❚Image 2❚.
lower grade. Patients with surface osteosarcomas are often a Historically, the malignant nature of osteosarcoma
decade or more older than typical patients with central became obvious with the appearance of lung metastases, usu-
osteosarcomas. Occasionally, high- and low-grade elements ally in about 18 months to 2 years after first diagnosis, and the
may be present in any given case of osteosarcoma. In these
cases, the biologic behavior is usually that of the histological-
ly highest grade area of the neoplasm. A B
Patients with osteosarcomas usually have nonspecific
clinical symptoms, the most common of which is pain for sev-
eral weeks or months. The pain often begins insidiously, but
by the time patients come to medical attention, their pain is
present at rest or even disturbs their sleep. The most common
sign is a mass that is almost always firm and tender. There
may be superficial erythema, venous distension, or other signs
of hypervascularity. There may be a limp, loss of function, or
even decreased range of motion. Any of these symptoms or
signs is cause for further clinical investigation.
The imaging studies usually suggest a malignant
tumor; at least half the time the specific diagnosis can be
made from conventional radiographs. Especially character-
istic is an ill-defined radiodensity occupying the metaphy-
seal region of a long bone. The intraosseous density often
has a diffusely cloudy or fluffy appearance. Although there ❚Image 1❚ A, Lateral radiograph of the distal femur
is seldom a fracture or cortical infraction in osteosarcoma, demonstrates typical radiographic features of osteosarcoma.
it is usual for the tumor to permeate the extant passages Radiodense, cloudy bone lies within an ill-defined
not only between osseous trabeculae but also of the radiolucency of the femoral metadiaphysis. The arrows delimit
Haversian systems and Volkmann canals. As the tumor a very large soft tissue mass containing bone matrix. A
reaches the outer cortical surface, the periosteum is dis- Codman angle periosteal reaction is highlighted with an
sected from the bone. The cambium layer of the inner arrowhead. B, Lateral radiograph in a different case
periosteum reacts to separation from the cortex by produc- demonstrating a very large extraosseous, radiodense mass
ing new bone, which is sometimes visible as an incomplete that contains extensively interrupted periosteal “streamers,”
bony shell that appears attached to the bone surface on forming a “sunburst” periosteal reaction.
only one end and is open or discontinuous in the middle, a
556 Am J Clin Pathol 2006;125:555-581 © American Society for Clinical Pathology

556 DOI: 10.1309/UC6KQHLD9LV2KENN
Anatomic Pathology / REVIEW ARTICLE
5-year survival was on the order of 20%. Although its degree Conventional Osteosarcoma
of malignancy has not changed, modern adjuvant chemother-
apy has increased this survival more than 3-fold,9 and even Osteosarcoma is diagnosed most easily when it appears
people with metastatic disease sometimes can be saved.10,11 in its classic, or conventional, form. The tumor cells vary from
Because osteosarcoma may produce various kinds of spindled to polyhedral; their nuclei are pleomorphic and
extracellular matrix and have different degrees of differen- hyperchromatic. Mitotic figures are easily demonstrable, and
tiation, its histologic pattern may vary significantly, not atypical mitotic figures also may be identified. The tumor cells
only from case to case but also from area to area in the same are engaged in the production of extracellular matrix that may
case. Its classification into various subtypes is not only by be osseous, cartilaginous, or fibrous in various proportions.
the predominant histologic pattern, but also by its anatomic The production of bone or osteoid directly by tumor cells at
location and sometimes by its histologic grade ❚Table 1❚ and least somewhere in the tumor is the absolute requirement for
❚Table 2❚. diagnosis ❚Image 3❚.

The tendency to subclassify osteosarcomas in this way As noted previously, conventional osteosarcoma histor-
makes it seem that there are as many variations of this tumor ically has been divided into osteoblastic, chondroblastic, and
as any tumor in the oncologic realm. The tendency to subdi- fibroblastic subtypes depending on the predominant type of
vide so rare a tumor into many such compartments also extracellular matrix ❚Image 4❚. This separation is largely arti-
makes straightforward diagnosis more difficult for the gener- ficial because there is no statistical difference in the survival
al surgical pathologist. In a significant number of cases, how- of patients with high-grade tumors of these 3 histologic
ever, the subclassification of osteosarcoma matters only if a types and the treatment for all types is the same. Of some
given subtype behaves or responds to treatment in a consis-
tently different way. The remainder of this review is dedicat-
ed to the comparison of these subtypes histologically, ❚Table 1❚
anatomically, and biologically. Osteosarcoma Types
Central
High-grade
Conventional
A B Telangiectatic
Small cell
Epithelioid
Osteoblastoma-like
Chondroblastoma-like
Fibrohistiocytic
Giant cell–rich
Low-grade
Low-grade central
Fibrous dysplasia–like
Desmoplastic fibroma–like
Surface
Low-grade
Parosteal
Intermediate-grade
Periosteal
High-grade
Dedifferentiated parosteal
High-grade surface
Intracortical
Gnathic
Extraskeletal
High-grade
❚Image 2❚ A, An osteosarcoma that appears completely Low-grade
radiolucent and has a sclerotic, fairly circumscribed upper
border, mimicking a benign lesion. Although the radiographs
❚Table 2❚
show little intraosseous radiodensity apart from a vague Osteosarcoma by Anatomic Site
haziness near the sclerotic area, the lateral tibial border
Osseous
shows that the cortex is interrupted and there is a small Central
interrupted periosteal reaction. B, Biopsy of the radiolucent Surface
Gnathic
mass demonstrates an osteosarcoma in which there is little
Multifocal
bone/osteoid matrix (upper left) but obviously bizarre, Soft tissue
pleomorphic malignant polyhedral tumor cells, apparent to Intramuscular
Other
the trained observer as malignant (H&E, ×400).

of this bone (and the fact that the thick interlobular septa are,
in fact, bone matrix) is obscured. The diagnosis becomes
obvious if radiopathologic correlation is performed, because
these tumors usually are radiodense and not circumscribed
❚Image 7❚. In addition, this type of tumor may have soft tis-
sue extension on the imaging studies that is not obvious in a
small bone biopsy specimen.
Histologic grading in osteosarcomas is important in the
oncologic staging of the tumor and for determining adjuvant
treatment in addition to surgery. There are several grading sys-
tems for osteosarcoma, but there is a variable degree of sub-
jectivity in each. The 4-tiered grading system popularized by

the Mayo Clinic group is based on the original Broders grad-
ing of squamous cell carcinomas of the lip.14 In Broders’
schema, the numeric grade of the tumor from 1 to 4, was
equated to the percentage of anaplasia in the tumor (from
≤25% to 100%). Assuming that the most important factor in
❚Image 3❚ Classic osteosarcoma in which there is abundant
grading is the cytologic atypia of tumor cells,14 any significant
production of osteoid and bone matrix in a lacy pattern into
focus of anaplasia in an osteosarcoma would itself represent
which the malignant cells are incorporated. Because these
grade 4 disease.
sections usually are decalcified, the terms osteoid and
In practice, almost all conventional central osteosarco-
immature bone are interchangeable, especially if the imaging
mas are assigned a grade of 3 or 4; ie, they are high grade.
studies do not reveal the precise biopsy site (H&E, ×250).
The osteosarcomas assigned a histologic grade of 1 are low-
grade central osteosarcoma and the usual form of parosteal
diagnostic interest is that occasionally, purely sclerosing osteosarcoma. In the low-grade osteosarcomas, there not
osteosarcoma is difficult to diagnose with a small biopsy only is absence of anaplasia, but also on a cytologic basis
specimen alone because of “normalization,” a phenomenon alone, it is difficult to recognize these entities as neoplasms.
first described by Jaffe.12 In this process, the production of Should a focus of anaplastic tumor be identified within what
osseous matrix is in excess to the proportion of tumor cells, is otherwise a grade 1 tumor, the tumor is termed dedifferen-
which become incorporated into the bone matrix and resem- tiated, and it is assumed that its biologic behavior will fol-
ble normal osteocytes. The production of bone matrix may low a highly malignant course consistent with conventional
be so excessive in sclerosing osteosarcoma that the cellular osteosarcoma.15
component of the tumor is difficult to identify; usually In the bone and soft tissue staging schema outlined by
tumor cells are most obvious at the advancing edge of the the Society of Musculoskeletal Oncology, without demon-
tumor ❚Image 5❚. Of additional importance is the knowledge strable metastatic disease, the staging depends on whether
that chemotherapy given after a biopsy and before definitive the tumor is high or low grade.9 For the purposes of treat-
surgery, if successful, often causes a similar normalization ment with neoadjuvant chemotherapy (given before defini-
effect along with necrosis. This phenomenon has been tive resection), an orthopedic oncologist needs to know only
referred to as maturation, and the challenge becomes accu- whether the grade is sufficiently high to offer chemotherapy
rately quantifying the degree of tumor necrosis for prognos- in the treatment regimen. Because almost all conventional
tication and postsurgical therapeutic manipulation.13 osteosarcomas are high-grade tumors and almost all surface
Occasionally, the pattern of tumor advancement in scle- osteosarcomas are low-grade tumors, it may make more
rosing osteosarcoma is the deposition of bone matrix along sense from a treatment standpoint to report osteosarcomas
the interseptal spaces between adipocytes in the marrow cav- as high or low grade in a 2-tiered system. The reported
ity. In this case, the surface tension of the fat globules in the exceptions to this are some gnathic osteosarcomas and
marrow adipocytes forces the tumor cells and their matrix periosteal osteosarcomas in which the degree of atypia is
production to follow the path of least resistance between higher than that usually seen in grade 1 tumors but insuffi-
adipocytes. The low-power appearance of this type of tumor cient for the diagnosis of grade 2 or 3 tumors.14 These
spread resembles adipose tissue but with thicker than normal tumors would be called intermediate grade if they were
septa ❚Image 6❚. These thick septa actually are composed of inserted into a 2-tiered system, and the decision to add sys-
delicate immature bone that surrounds the adipocytes; how- temic therapy would be subject to the experience of the
ever, because sections usually are decalcified, the presence orthopedic oncologist.

A B

C D
❚Image 4❚ Conventional osteosarcoma. A, So-called osteoblastic osteosarcoma is dominated by the production of extracellular
bone matrix. This medium-power field demonstrates immature bone deposition in a pattern resembling lace into which tumor
cells are incorporated (H&E, ×100). The clinical radiograph (not shown) was radiodense in the area from which the biopsy was
obtained. B, So-called chondroblastic osteosarcoma. This medium-power field is dominated by cellular hyaline cartilage but
shows a few wisps of osteoid formation at the upper right (H&E, ×100). The radiographic appearance depends on the
predominant matrix type in the tumor; noncalcified cartilage portions are radiolucent. C, So-called fibroblastic osteosarcoma is
dominated by spindle cells resembling atypical fibroblasts, usually contains little bone matrix (H&E, ×250), and is radiolucent.
D, Pleomorphic osteosarcoma might appear fibrohistiocytic or epithelioid and sometimes poses a difficult diagnostic problem
because extracellular matrix is scant (H&E, ×250) and the lesion is radiolucent. Pleomorphic bone sarcomas in children usually
fall into this category.
Telangiectatic Osteosarcoma the bone involved. Unlike in aneurysmal bone cyst, a thin shell
of periosteal neocortex may not be observed. There is some-
Telangiectatic osteosarcoma is a type of osteosarcoma times an interrupted periosteal reaction, which is a clue to the
that resembles aneurysmal bone cyst radiographically and his- correct diagnosis; however, because little bone is formed in
tologically.16 The lesion almost always produces radiolucent this lesion, it is not unusual for new bone to be absent radi-
bone destruction, and there is often asymmetric expansion of ographically. On the other hand, the increased sensitivity of

❚Image 5❚ “Normalization” of conventional osteosarcoma. A,

A B
Low-power view of cancellous bone spicules (blue and yellow)
shows marrow replacement by osteosarcomatous bone matrix
that appears compact (including Haversian systems) using
partially polarized light with a first-order compensator (H&E,
×20). B, Higher magnification of normalized area demonstrates
somewhat immature bone matrix in which tumor cells seem to
be compressed into the appearance of osteocytes
(hematoxylin-phloxine-safranin [HPS], ×50). If this field were
C
taken out of context (ie, if it were not understood that this
matrix was displacing normal marrow adipose tissue),
malignancy of the lesion might not be detected. C, The

advancing edge of the bone matrix demonstrates a greater
number of pleomorphic enlarged tumor cell nuclei that do not
appear to be osteocytes (HPS, ×250).
A B C
D E F
❚Image 6❚ Sclerosing osteosarcoma. A, Low-power magnification demonstrating subtle marrow septal permeation pattern.
The adipocyte shapes are clearly visible, but the interadipocytic septa are thickened (H&E, ×25). B, At higher magnification,
the outlines of the fat vacuoles are preserved, but the septa are thick and eosinophilic. A small bone trabecula is present in
the center (H&E, ×100). C. The same photograph in polarized light reveals that the pink septa are composed of anisotropic
immature collagen, which is bright in polarized light, whereas normal adipocyte septa are invisible. In the center of the field is a
small preexistent bone trabecula that is lamellar (arrows) surrounded by the immature neoplastic bone (H&E, ×100). D, Another
field in the same tumor stained by the hematoxylin-phloxine-safranin (HPS) method demonstrates that the immature osteoid
surrounding the adipocytes is safranophilic (yellow), whereas the preexistent mature bone trabecula is phloxiphilic (pink) and
lamellar. At this magnification, normalizing tumor cells can just be discerned (HPS, ×100). E, At higher magnification, normalizing
tumor cells are discerned more easily (HPS, ×250). F, Later in the process, the sclerotic bone matrix has overwhelmed the
architecture of the adipose tissue and its normalization belies its malignant nature if taken out of context (H&E, ×100).

computed tomography (CT) scanning has resulted in a detect- A B

ed incidence of some bone matrix in 85% of tumors, and
magnetic resonance imaging (MRI) has detected fluid levels
in 74% of tumors examined.17 The lesion usually is com-
posed of multiple blood-filled sinusoids, and there is little
solid tissue to evaluate. Consequently, at low power, telan-
giectatic osteosarcoma bears a striking resemblance to
aneurysmal bone cyst. At higher power, the presence of
nuclear pleomorphism and a high mitotic rate usually are
obvious. In contrast, the sinusoidal lining cells are bland or
even inapparent in aneurysmal bone cysts. In telangiectatic
osteosarcoma, there usually is local destruction manifest by

permeation of the process into adjacent marrow or cortical
Haversian spaces. The replacement of normal anatomic
spaces by a growing process is a usual histologic feature of
malignancy ❚Image 8❚. Although the production of bone or
osteoid by the tumor cells helps considerably in formulating
❚Image 7❚ Radiographic examples of sclerosing
the diagnosis, extracellular matrix tends to be histologically
osteosarcoma. A, The lesion is cloudy, radiodense, and
sparse in telangiectatic osteosarcoma.
metaphyseal. The inferior border is not distinct, and there is
Giant cell–rich osteosarcoma (see later below) seems to
lateral extension outside the bone. B, Diaphyseal lesion from
be linked to telangiectatic osteosarcoma at a rate greater than
which the sections in Image 6 are derived. Note the very
chance. In addition, telangiectatic osteosarcoma, like
radiodense lesion that not only has poorly defined osseous
aneurysmal bone cyst, often contains foci of such osteoclast-
confines but also produces interrupted, bulky, cloudy, and
like giant cells. We speculate that an element in blood or a
trabeculated bone in the soft tissues.
breakdown product may serve as a giant cell stimulus to the
region in all 3 conditions.
Before the institution of neoadjuvant chemotherapy, the
prognosis for telangiectatic osteosarcoma was statistically high-grade osteosarcoma. Close observation sometimes
more dismal than that for conventional osteosarcoma.16 With reveals spindling of tumor cells. This finding is not character-
the advent of chemotherapy, the prognosis for telangiectatic istic of the Ewing/PNET group of tumors. In addition, the pro-
osteosarcoma has been reported as being as good as or even duction of osteoid by tumor cells is not a characteristic feature
better than that associated with the conventional types of of Ewing sarcoma, whereas it always is identified to confirm
osteosarcoma.9 Although the reasons for this are unclear, most a diagnosis of osteosarcoma ❚Image 9❚.
of the chemotherapy regimens for osteosarcoma are active Several features reported in small cell osteosarcoma
during the proliferative (S) phase of the cell cycle; a histolog- make it a controversial diagnosis. First, many, if not all, small
ic comparison of conventional and telangiectatic osteosarco- cell osteosarcomas display a similar immunohistochemical
ma often suggests fewer total tumor cells with a higher growth profile to that of Ewing sarcoma/PNET. The most important
fraction in the latter. of these is positive membrane staining for CD99, a marker of
expression of the MIC-2 gene product. This marker is typical
for tumors in the Ewing sarcoma/PNET group, mesenchymal
chondrosarcoma, and some primitive hematopoietic tumors,
Small Cell Osteosarcoma
but it is not found in other types of osteosarcoma.
Small cell osteosarcoma is a rare histologic variant of Furthermore, the reciprocal translocation between chromo-
osteosarcoma with histologic features combining those of somes 11 and 22, the most common one found in the Ewing
osteosarcoma and Ewing sarcoma.18 It constitutes between sarcoma/PNET tumor family, occasionally has been reported
1% and 2% of all osteosarcomas.19 The radiologic features in a small cell osteosarcoma, whereas it is not a feature of
are not consistently typical for osteosarcoma because there other subtypes of osteosarcoma. Some authors believe that
often is very little mineralized matrix produced. tumors showing this translocation should be considered
Histologically, it may be mistaken for Ewing sarcoma/primi- Ewing sarcoma/PNET regardless of whether they produce
tive neuroectodermal tumor (PNET) because its cells are osteoid, implying that it is possible that some of the tumors
small and have round, hyperchromatic nuclei with very little classified as small cell osteosarcomas actually are Ewing sar-
of the nuclear pleomorphism characteristic of conventional coma family tumors with divergent differentiation.9 The matter

A B C D

E F G H
❚Image 8❚ Telangiectatic osteosarcoma. A, B, and C, A radiolucent destructive lesion originally thought to be an aneurysmal bone
cyst because of the eccentric radiolucent expansion (A). Curettings were thought to represent aneurysmal bone cyst (E, H&E, ×50).
One month later, the patient returned with pain and increasing size of mass, and there was virtual destruction and expansion of the
entire metaphyseal region of the right humerus. Retrospectively, the radiographs in A were noted to have a medial interrupted
periosteal reaction. A portion of the cortex from the second procedure demonstrated permeation of Haversian canals by a vascular,
osteoid-producing tumor (F, H&E, ×50), and the diagnosis of telangiectatic osteosarcoma was made. The patient returned after 2
cycles of neoadjuvant chemotherapy. The mass had continued to grow and was excised owing to lack of clinical response (C and D).
The radiograph demonstrates virtually no humeral structure proximal to the diaphysis (C). D, The gross specimen demonstrates a
hemorrhagic, necrotic mass sparing only the medial articular cartilage. Although the histologic sections demonstrated significant
necrosis after 2 cycles of chemotherapy, viable tumor with obvious pleomorphism was still demonstrable (G, H&E, ×250), and the
hypervascular and sinusoidal architecture responsible for its initial misdiagnosis were still present (H, H&E, ×250).
is not entirely trivial because response to adjuvant chemother- Epithelioid Osteosarcoma

apy for osteosarcoma has been variable and less successful in
patients with small cell osteosarcoma.19 Moreover, Ewing sar- Epithelioid osteosarcoma is an osteosarcoma in which the
comas, which are exquisitely radiosensitive, may require radi- tumor cells are so poorly differentiated that it is difficult to deter-
ation for local control, but osteosarcomas are almost always mine histologically whether the tumor is a sarcoma or a carcino-
insensitive to that approach. ma.14 If there are areas of histologically typical osteosarcoma

A B C

D E
❚Image 9❚ Small cell osteosarcoma. The lesion is highly destructive and has no obvious radiodensity suggestive of osteosarcoma
on routine radiograph (A) and computed tomography scan (B). C, The tumor above the bone trabecula appears to be composed
of small cells dominated by round, blue nuclei suggestive of Ewing sarcoma/primitive neuroectodermal tumor. The tumor below
the trabecula demonstrates that the tumor cells are separated by pink matrix (H&E, ×50). D, At higher magnification, the tumor
cells above the trabecula are indistinguishable from Ewing sarcoma (H&E, ×250). E, At the same magnification, the tumor cells
below the trabecula are clearly producing osteoid matrix (H&E, ×250).
with obvious matrix formation elsewhere, the diagnosis is made If tumors like these are observed in the bones of young
easily. On the other hand, if the tumor cells resemble epithelial patients, osteosarcoma should be considered strongly as the
cells and there is little osteoid, the diagnosis becomes more com- diagnosis. In older patients, the diagnosis of a poorly differen-
plicated. The tumor cells often are round or polyhedral rather tiated metastatic carcinoma is more likely.14 A diligent, care-
than spindle-shaped. Their round or ovoid enlarged nuclei may ful search for osteoid matrix should be carried out, particular-
contain 1 or more prominent nucleoli, and the tumor cells may ly in young patients, because immunohistochemical analysis
even appear as cohesive as in some poorly differentiated carci- may demonstrate keratins even in usual osteosarcomas. The
nomas. The cells may demonstrate gland-like structures14 or effectiveness of this technique may be observing the tissue
even contain cells arranged in papillary configurations. Although through crossed polarizers for woven bone after staining the
the association has yet to be validated scientifically, we have sections with Sirius red or some other enhancer of collagen
seen this pattern more often in postradiation osteosarcomas. anisotropism ❚Image 10❚.20

A B C

D E F
❚Image 10❚ Epithelioid osteosarcoma. The anteroposterior (A) and lateral (B) radiographs demonstrate an ill-defined process
showing a few indistinct, cloudy densities and a small posterior soft tissue mass. C, The coronal T1-weighted magnetic
resonance image demonstrates that the mass is in the lateral femoral condyle and extends into the overlying subperiosteal soft
tissue. D, Histologic sections reveal clusters of polyhedral cells aggregated about central cores resembling papillary structures;
some of these contain osteoid rather than vessels (H&E, ×150). E, Higher magnification demonstrates epithelioid round cells
loosely disposed among a few wisps of osteoid (H&E, ×250). F, An area similar to that in E stained with Sirius red F3BA and
photographed in polarized light (×500). This technique emphasizes the osteoid.
Osteoblastoma-like and no constant radiographic pattern for osteoblastoma, which

Chondroblastoma-like Osteosarcoma occasionally has the radiographic signs of malignancy.
To make matters more complicated, some osteoblas-
Osteosarcomas occasionally may be similar histological- tomas may contain atypical-appearing osteoblasts,22 and a
ly to other types of benign matrix-producing tumors. spectrum of histologically overlapping lesions ranging from
Osteoblastoma-like osteosarcoma resembles osteoblastoma biologically quiescent to aggressive has been described.23
histologically in that it produces the same sort of microtrabec- The most important histologic parameters for malignancy
ular bone lined by osteoblasts as does osteoblastoma. The include permeation of architecturally normal bone at its inter-
radiographic appearance often suggests a malignant tumor21; face with tumor24 and aneuploid mitotic activity ❚Image 11❚,
however, this may not be completely helpful because there is whereas benign osteoblastic tumors tend to show maturation

A B C

D E F
❚Image 11❚ Osteoblastoma-like osteosarcoma. A, The anteroposterior radiograph demonstrates a well-circumscribed tumor. B, The fat-
suppressed T2 coronal magnetic resonance image demonstrates that the tumor has a bright signal, focally involves the growth
plate, and may involve the overlying soft tissues and cause edema. C, The resected specimen demonstrates obliteration of the growth
plate medially and an organized periosteal reaction. Tumor external to the cortex is not present following neoadjuvant chemotherapy.
D, E, and F, Representative histologic features before specimen resection. D, Microtrabecular osteoid lined by osteoblast-like cells
as seen in osteoblastomas (H&E, ×100). E, Foci of lace-like osteoid and hyaline cartilage in other microscopic fields from the same
lesion (H&E, ×250). F, Focal permeation of normal cancellous bone and marrow adjacent to the tumor mass (H&E, ×150).
and circumscription at their edges.21 Because of this, differen- its difference from chondroblastoma may be extremely subtle
tiating this type of osteosarcoma from osteoblastoma may be because despite its clinically benign behavior, chondroblas-
extremely difficult, especially in small biopsy samples.25 toma itself is a mitotically active, primitive tumor. This type of
Rarely, osteosarcomas may appear histologically to be a osteosarcoma is best distinguished by its osteoid or bone for-
chondroblastoma.26 Chondroblastoma-like osteosarcoma mation, atypical mitotic activity, and infiltration of adjacent
may or may not be epiphyseal. When it is epiphyseal and intertrabecular spaces ❚Image 12❚.
well circumscribed, it is a very difficult diagnosis to make Both osteoblastoma-like and chondroblastoma-like
because radiologic studies specifically suggest a benign diag- osteosarcomas are extremely rare, but their accurate diagnosis
nosis. In these cases, the diagnosis must be made histological- is important because like their more common conventional
ly in the face of conflicting radiographic data. Histologically, counterparts, they may metastasize.

A B C

D E
❚Image 12❚ Chondroblastoma-like osteosarcoma. The lateral (A) and anteroposterior (B) radiographs demonstrate a well-
circumscribed radiolucency centered in the end of the bone. C, The computed tomography scan demonstrates that the borders
are indeed well circumscribed and the lesion is confined to the bone. D, Most of the histologic features are that of a monotonous
lesion composed of uniform cells with demarcated cytoplasmic borders and with bean-shaped, ovoid nuclei and rather fine,
lattice-like calcifications in a chondroid background (H&E, ×400). The overall initial biopsy impression was chondroblastoma;
however, a few atypical mitoses raised suspicions of osteosarcoma. E, A more thorough sampling revealed foci of typical lace-like
osteoid infiltrating cancellous bone at the periphery (H&E, ×150), and the diagnosis of osteosarcoma was made.
Giant Cell–Rich Osteosarcoma osteosarcoma are less apparent than in long bones, where the
radiographic differences are more conventional and osteosar-
About 25% of osteosarcomas contain benign multinucle- comas are more common. As noted previously, multinucleat-
ated giant cells resembling osteoclasts.14 Rarely, an osteosar- ed giant cells tend to be more numerous in telangiectatic
coma may contain so many benign giant cells that the malig- osteosarcomas than in other types of osteosarcomas, but they
nant elements in the background are obscured; in these cases, are not distributed uniformly in any of the solid areas of tumor
the lesion may be mistaken histologically for a giant cell tissue. In addition, there usually is a great deal of nuclear pleo-
tumor.26 This is more apt to occur in the sacrum, where giant morphism evident in telangiectatic osteosarcomas ❚Image 13❚.
cell tumor is much more common than osteosarcoma and the By comparison, the usual giant cell tumor tends to arise
radiographic differences between giant cell tumor and in skeletally mature people and extends from the area that

A B C

D E F
❚Image 13❚ Giant cell–rich osteosarcoma. The anteroposterior (A) and lateral (B) radiographs reveal a locally destructive tumor
extending from the metaphysis to the articular end of the bone. There is internal circumscription and no discernible periosteal
reaction. C, The coronal fat-suppressed magnetic resonance image demonstrates that the lesion has a heterogeneous
isointense to hyperintense signal. The clinical diagnosis was giant cell tumor. D and E, Histologic sections demonstrate a giant
cell rich lesion with mononuclear background; however, nuclear atypia and atypical mitotic activity are clearly shown (E) (D, H&E,
×200; E, H&E, ×400). F, Individually malignant mononuclear cells and even polyploid giant cells within a collagenized matrix
focally having the properties of osteoid (H&E, ×250).
corresponds to the metaphyseal side of the growth plate to the tissue of an otherwise atypical giant cell tumor, the diagnosis
ends of the long bones. In the absence of a fracture, a often made to describe this event is a “primary malignant giant
periosteal reaction also is uncommon in an uncomplicated cell tumor.” A histologically typical giant cell tumor previous-
giant cell tumor. A tumor that appears to be a giant cell tumor ly curetted that recurs and histologically shows sarcomatous
histologically but arises in a skeletally immature person, tissue often is described as a “secondary malignant giant cell
therefore, should be regarded with great suspicion and sam- tumor.” Primary malignant giant cell tumor is clinically half as
pled widely to rule out osteosarcoma. This is particularly true common as secondary malignant giant cell tumor. The type of
if it is accompanied by a visible periosteal reaction. sarcoma associated with both may be a spindle cell sarcoma
True giant cell tumors also may develop malignant with little or no extracellular matrix, but it may, in fact, contain
tumors within them. When a sarcoma is identified within the osteoid matrix. If the malignant component replaces otherwise

typically conventional areas of giant cell tumor without Gnathic Osteosarcoma

replacing all of the giant cells, it would be easy to mistake the
lesion for a giant cell tumor if there is little matrix present. It Osteosarcomas of the mandible and maxilla usually man-
is possible that this also is a source of some of the giant ifest with swelling or pain. Radiographically, they often are
cell–rich osteosarcomas reported in the literature. radiolucent or a mixture of radiolucent and radiodense areas.28
Osteosarcomas that appear fibrohistiocytic resemble Anecdotally, we have seen several cases in which the conven-
fibroblastic osteosarcoma histologically and, in addition, tional radiographs appear unremarkable, creating a dichotomy
have a storiform arrangement and histiocytic giant cells in clinical symptomatology, radiographic presentation, and
❚Image 14❚. They contain smaller amounts of detectable histopathologic appearance. Gnathic osteosarcomas tend to be
bone matrix and tend to arise at a later age than convention- predominantly chondroblastic in matrix production ❚Image
al osteosarcomas.27 15❚, but osteoblastic, fibroblastic, and even small cell types

A B C
D E
❚Image 14❚ Osteosarcoma, so-called fibrohistiocytic variant. A, The conventional radiograph demonstrates a destructive lesion of
the proximal humerus extending to the articular end. There is some sclerosis in the humerus just distal to the humeral head.
Coronal magnetic resonance imaging studies in T1 (B) and T2 (C) demonstrate hypointensity in T1 and hyperintensity in T2. There
is a soft tissue mass and periosteal reaction inferolaterally. D, Most of the lesion has a fibrohistiocytic pattern with a cellular
stroma and storiform arrangement of tumor cells (H&E, ×150). E, Areas of definite osteoid production are identified focally
juxtaposed to the tumor cells (H&E, ×400).

have been described.29 Although they often are high-grade Low-Grade Central Osteosarcoma
tumors histologically, they tend to give rise to uncontrolled
local disease, with a small minority of patients developing dis- This unusual variant of osteosarcoma constitutes a very
tant metastatic disease. For this reason, and not on a histolog- small percentage of osteosarcomas. Its microtrabecular
ic basis, they usually are thought of as pathologic entities dif- osseous matrix architecture in a bland fibrous stroma bears
ferent from conventional osteosarcoma.30 some resemblance to fibrous dysplasia and other benign
Osteosarcomas arising in nongnathic craniofacial bones lesions,32,33 but most often it resembles the histologic features
tend to arise in older patients, often are associated with an of low-grade parosteal osteosarcoma. If bone formation is
underlying predisposing condition such as Paget disease or scant, there also is a histologic resemblance to desmoplastic
previous radiation, and have a biologic potential more like that fibroma,34 and 2 reported cases were misdiagnosed initially as
of conventional osteosarcoma.31 Paget disease.35

A B
C D
❚Image 15❚ Gnathic osteosarcoma. A, The Panorex radiograph demonstrates a radiolucent space-occupying lesion under the area
of the missing right lower second molar tooth. B, The gross specimen demonstrates rather soft tumor matrix filling the area
under the missing molar and causing erosion of the underlying mandible. Histologic sections at medium (C, H&E, ×100) and
high (D, H&E, ×250) magnifications demonstrate a mostly cartilaginous, highly cellular tumor that contains foci of immature
osteoid production.

Accurate diagnosis is predicated on satisfactory correlation demonstrate woven microtrabeculae of bone in a moderately
with clinical imaging studies and very careful evaluation of his- cellular, fibrous stroma. If sections include the interface of
tologic findings ❚Image 16❚. The imaging features are not invari- the lesion with normal bone, fibrous tissue within Haversian
ably diagnostic, but they often suggest a lesion of greater local canals or between mature cancellous trabeculae is a telltale
aggressiveness than fibrous dysplasia or other benign sign of malignancy.32 In the absence of these findings, atypi-
lesions.36 These features may include indistinct circumscrip- cal mitotic activity may lead to the correct diagnosis.
tion, dense sclerosis, an interrupted periosteal reaction, or corti- Although patients usually are treated with surgery alone and
cal infraction. Sections through the center of the lesion usually their prognosis is significantly better than in conventional
A B C

D E F
❚Image 16❚ Low-grade central osteosarcoma. The anteroposterior (A) and lateral (B) radiographs demonstrate a rather mottled,
deceptively circumscribed lesion that resembles fibrous dysplasia except for the very focal area of cortical erosion of the lateral
femoral metadiaphysis. C, The fat-suppressed magnetic resonance image in coronal view demonstrates actual extension of the
hyperintense mass into the soft tissue. This finding is never seen in uncomplicated fibrous dysplasia. D, The majority of the
histologic features are immature, poorly formed, woven trabeculae without appositional osteoblastic activity in a modestly
cellular fibrous stroma (H&E, ×250). This greatly imitates fibrous dysplasia except for the atypical features in the radiographs. E,
A search of nuclei at higher magnification revealed not only mitotic activity but also atypical mitoses (H&E, ×787). A diagnosis of
low-grade central osteosarcoma prompted removal of the distal femur. F, A section through the cortex demonstrated
permeation of the Haversian systems by tumor matrix (asterisk) (H&E, ×100).

osteosarcoma,37 a certain number of patients develop a sec- In localized heterotopic ossification (so-called myositis
ondary high-grade osteosarcoma (dedifferentiation) within ossificans circumscripta) arising near the bone surface, the
the original low-grade tumor or at its previous anatomic site ossification pattern is exactly the opposite radiographically,
of origin in local recurrences.33,38,39 It is probable that some with the densest bone being outside and the least dense
cases of fibrous dysplasia associated with secondary develop- being inside.
ment of osteosarcomas are, in fact, low-grade osteosarcomas In parosteal osteosarcoma, there often is an incomplete
that later became higher grade. radiolucent line separating most of the sclerotic mass from
the underlying cortex ❚Image 17❚. When a resected specimen
is examined carefully, especially with specimen radiography,
this radiolucent line corresponds to the underling perios-
Surface Osteosarcomas
teum, to which the mass usually is fixed at one point on the
Surface osteosarcomas are osteosarcomas whose epicen- outside. An underlying periosteal reaction is very unusual

ters are outside the cortex of the underlying bone. They usual- because to produce such a reaction, the tumor would have to
ly arise in relation to the periosteum or the cortex of the bone lift the inner cambium layer of the periosteum away from the
with minimal or no involvement of the medullary cavity. cortex. Parosteal osteosarcoma usually is not locally aggres-
Unlike conventional osteosarcomas, which are tumors of ado- sive enough to do this.
lescents, these lesions usually arise in patients in the third and Histologically, parosteal osteosarcomas consist of
fourth decades. streamers of bone trabeculae that often show a high degree
There are several types of surface osteosarcomas, which of parallel orientation similar to what might be observed in a
have been characterized by exact anatomic location, by the pre- periosteal new bone reaction ❚Image 18❚. This concentration
dominant type of matrix, and by histologic grade. The majori- and arrangement of bone is what gives rise to the typically
ty of surface osteosarcomas are low-grade neoplasms with a sclerotic trabecular architecture seen in radiographs, and the
propensity for local recurrence and a real but very limited trabecular orientation may be discerned in a specimen radi-
capacity for distant metastasis. A relatively small number ograph of a thinly cut slice of the lesion. Mirra26 has noted
(approximately 10%) of surface osteosarcomas are high-grade the histologic resemblance of this bone formation to “flow-
tumors. The current classification system identifies indolent ing steel wool.” When the bone spicules become thicker at
and high-grade tumors, so it is able to group the lesions need- the base of the lesion, there usually is very little actual mat-
ing specific kinds of therapy.40 uration of the matrix into a lamellar architecture, and the
lesion does not become enveloped within the cortex. There is
Parosteal Osteosarcoma a cellular cartilage cap external to the osseous portion of the
Geschicter and Copeland41 first described the most com- lesion in about 25% to 30% of cases. This occurrence histor-
mon form of surface osteosarcoma, parosteal osteosarcoma, ically has resulted in the pathologic misdiagnosis of some
although the term currently used for it was formulated by parosteal osteosarcomas as osteochondromas, particularly if
Dwinnell et al.42 This lesion often had been confused with the radiographic findings showing a lack of cortical and
osteochondroma and osteoma; however, its local recurrence medullary continuity are not correlated with the histologic
rate when incompletely excised and its small but definite features. There are even descriptions of so-called osteochon-
propensity for distant spread made it clear that it behaved clin- droma-like parosteal osteosarcomas that not only call atten-
ically as a uniquely different entity. Parosteal osteosarcoma tion to this phenomenon, but also propose that it be given a
accounts for fewer than 1 in 20 osteosarcomas, and its average separate nomenclature.43
incidence is about a decade later than the usual type of central The histologic key to the correct diagnosis is that a
osteosarcoma. It has a unique presentation and anatomic distri- growing osteochondroma has the same internal develop-
bution because 75% to 80% of cases arise as densely ment as a growing bone. There is a medullary cavity with
radiopaque masses attached to the distal posterior femur. fat or hematopoietic marrow in the intertrabecular spaces
Although parosteal osteosarcoma may give rise to a sensa- of normal bone and osteochondroma, whereas the inter-
tion of fullness, prevent complete range of flexion, and even be trabecular spaces of parosteal osteosarcomas contain cel-
perceived as a mass through the overlying soft tissues, it is lular fibrous tissue. This fibrous tissue is deceptively
unusual for the entity to be spontaneously painful. Its radioden- bland, and without radiographic correlation, it would be
sity often is not uniform, often being more radiodense centrally difficult to say that it represents a malignant condition.
as it approaches the bone surface and less dense at its periphery. Occasionally, there is immature osteoid or osseous matrix
In contrast with osteochondroma, there is no usual continuity of found between the parallel bone spicules, and this helps in
the exterior of the mass with the adjacent cortex, and its inside the definitive assessment of ordinary low-grade parosteal
is not in continuity with the underlying medullary cavity. osteosarcoma.

A B C D

❚Image 17❚ Parosteal osteosarcoma. A, The lateral radiograph demonstrates a radiodense lesion attached to the posterior cortex
of the femur; the density decreases peripherally, and there is a radiolucent line outside the cortex that corresponds to the
periosteum. The specimen radiograph (B) and specimen (C) demonstrate that the radiodensity is due to rather compact bone. The
radiolucent line corresponding to the periosteum can be seen between the dense overlying mass and the bone in the radiograph
and corresponds to the dark linear area between the thin metaphyseal cortex and overlying mass in the specimen photograph. D,
The diagonally oriented periosteum (lower left to upper right) interposed between the low-grade bone-producing tumor (left) and
underlying bone (right) (H&E, ×250).
The majority of parosteal osteosarcomas are associated Dedifferentiated Parosteal Osteosarcoma

with the outer fibrous layer of the periosteum, which does not Wold and associates46 first described cases of histologi-
produce typical periosteal reactions. Exceptions are rarely seen cally high-grade osteosarcoma arising in the clinical setting of
when an otherwise slowly growing tumor eventually penetrates recurrent parosteal osteosarcoma of the usual low-grade vari-
the periosteum externally and gradually dissects apart the cortex ety. In the first published series, the dedifferentiation took
and inner periosteum. Rarely, a typical low-grade parosteal place over time in recurrences of well-documented tumors
osteosarcoma demonstrates invasion of the underlying bone that previously were diagnosed as typical low-grade parosteal
❚Image 19❚. This event has been thought to have an adverse role osteosarcomas.47 With the discovery and description of more
in prognosis; however, so long as the tumor remains low grade, cases of this disease, it became clear that the dedifferentiation
the outlook for this event probably is not significantly worse. may, in fact, have been present at the time of first resection of
the tumor. This event may be heralded by changing clinical
Periosteal Osteosarcoma signs and symptoms, such as a difference in the quality of pain
Unni and associates44 first described this surface tumor, or an area of radiolucency in an otherwise radiodense lesion.
which is considerably less common than parosteal osteosarco- It may, on the other hand, be clinically unsuspected.
ma and has a matrix component that is mainly cartilaginous. Grossly, the area of dedifferentiation often is discernible
Although the lesion is associated with the bone surface, it from the typically sclerotic areas of parosteal osteosarcoma. This
tends to arise between the cortex and the cambium layer of the may be because the higher-grade component is more cellular with
periosteum, so that there often is a periosteal reaction visible respect to its matrix or because its bone matrix is less mineralized
radiographically. There also often is underlying cortical thick- than in the lower grade areas. Less often, a higher grade area may
ening or erosion, and it usually occurs along the tibial or result in cortical invasion and call attention to itself by its locally
femoral diaphysis rather than posterior to the metaphysis of aggressive behavior. At least 1 study correlating CT and MRI
the distal femur.45 Its histologic grade is intermediate between with grade suggested that the presence of a soft tissue mass with-
that of the usual grade 1 parosteal osteosarcoma and that of out osseous matrix is typical of dedifferentiation, particularly if it
conventional grade 3 or 4 osteosarcoma ❚Image 20❚. There is of high signal intensity on T2-weighted MR images.47
rarely is extension into the underlying cortex, but there almost Histologically, the tissue is composed of an admixture of
never is extension into the underlying endosteum. typical appearing low-grade parosteal osteosarcoma and high-

A B C

❚Image 18❚ Parosteal osteosarcoma. A, Low-power
D
magnification demonstrates the typical “pulled steel wool”
pattern of bony trabeculae (H&E, ×25). B, The cartilage cap is
identified in approximately 1 in 3 cases of parosteal
osteosarcoma (H&E, ×40). This is distinguished from
osteochondroma because normal endochondral ossification
gives rise to fatty or hematopoietic bone marrow in the
intertrabecular spaces. Parosteal osteosarcoma has fibrous
tissue between the trabeculae. C, Higher magnification
demonstrates thickening and maturation of bone spicules at the
base of the tumor (H&E, ×250). D, Although the fibrous tissue
between the bone spicules is bland, there is no marrow evident.
A careful search in the fibrous component sometimes reveals
focal hypercellularity and early immature bone formation, but
this is usually not a frequent feature (H&E, ×400).
grade conventional parosteal osteosarcoma ❚Image 21❚. The with dense sclerosis. Alternatively, it may have mixed sclero-
dedifferentiated component has at least once been reported as sis and radiolucency, or, occasionally, it may form a soft tissue
being telangiectatic,48 and it is possible that other varieties may mass with relatively little radiodensity. Because it is a higher
be described as larger series are obtained. The prognosis is grade lesion than ordinary parosteal osteosarcoma, its local
related to that of the least differentiated tumor component; it is growth and aggressiveness are more accelerated.
worse than that of low-grade parosteal osteosarcoma but seems Consequently, patients with this disease are more likely to
to be somewhat better than that of pure high-grade surface have more distressing symptoms and signs than those with
osteosarcomas.49 At least 1 series suggests that patients with usually low-grade parosteal osteosarcomas.
this disease derive benefit from adjuvant chemotherapy.50 Microscopically, the tumor is entirely high grade ❚Image
According to the recently published experience from the 22❚. It is possible that some high-grade surface osteosarcomas
Rizzoli Institute, dedifferentiation occurs in approximately 1 in represent dedifferentiated parosteal osteosarcomas in which
4 low-grade parosteal osteosarcomas.49 the high-grade component has replaced entirely the low-grade
component. There usually is very little or no medullary inva-
High-Grade Surface Osteosarcoma sion by the tumor in conventional radiography, although CT
This tumor, which manifests as a surface lesion of bone, and MRI demonstrate occasional small foci of marrow
is entirely high grade histologically.51 It may appear radi- involvement.52 If medullary invasion were a constant feature,
ographically as an ordinary low-grade parosteal osteosarcoma it would be more difficult to make a case pathologically for the

A B C

❚Image 19❚ Parosteal osteosarcoma, low grade, with intramedullary invasion. A, A specimen radiograph showing the typical
striate radiodensity increased at the base of the lesion. Note that although there is no visible radiolucent line between the mass
and the underlying bone, there is dense sclerosis adjacent to the surface mass that obliterates the trabecular architecture of the
medullary cavity and obscures the cortex. B, The corresponding gross specimen. Although the intraosseous component is as
large as the surface lesion, there is no periosteal reaction, strongly favoring a surface origin. C, Representative histologic
features demonstrate that the lesion is entirely low grade and resembles fibrous dysplasia (H&E, ×40).
lesion to have originated from the bony surface. On the other Multifocal Osteosarcoma
hand, because this tumor is considered to have the same
malignant potential as conventional osteosarcoma, it is logical This extremely unusual condition affects multiple
to occasionally have some degree of localized invasion of the osseous sites simultaneously at the time of presentation (syn-
cortex and endosteum. However, the radiographic epicenter chronous form) or multiple skeletal sites at varying intervals
and the great bulk of surface lesions must be external to the (metachronous type) ❚Image 24❚. The former variant tends to
bone. In the case of high-grade surface osteosarcoma in par- affect children and adolescents, whereas the latter type usual-
ticular, the lack of periosteal reaction to the tumor indicates ly occurs in adults.9 The childhood form is radiodense, usual-
that the neoplasm did not begin within the medullary cavity. ly symmetric, and a high-grade sarcoma with a rapidly fatal
course.9 In the adult metachronous form, after the appearance
of the first osteosarcoma, there is a disease-free interval of
several months to several years followed by the development
Intracortical Osteosarcoma
of one or several skeletal osteosarcomas.26 These lesions are
Jaffe12 first described this very rare anatomic variant of not symmetric, they may have variable degrees of sclerosis,
osteosarcoma, a high-grade osteosarcoma entirely confined and their histologic features may vary from high to low grade.
within the bony cortex. It usually manifests as an area of cor- The patients have a longer survival interval than children with
tical radiolucency with perilesional sclerosis. Depending on the synchronous form, and a few long-term survivors have
its size, it may be confused with osteoid osteoma and been reported.26 This could argue for their not being osseous
osteoblastoma, but its cellular atypia and local aggressiveness metastases, but an independent test to separate multifocality
distinguish it from those entities. Histologically, there usually from metastasis continues to remain out of reach.
is abundant osteoid or bone formation. Formation of cartilage
is unusual but helps to distinguish the lesion from osteoblas-
toma and osteoid osteoma. Follow-up of the small number of Extraskeletal Osteosarcoma
cases thus reported reveals that although aggressively treated Osteosarcoma in an extraskeletal site accounts for
patients have favorable results, this lesion may give rise to sys- fewer than 2% of all soft tissue sarcomas. Unlike conven-
temic disease53 and is best approached biologically like any tional osteosarcoma, it tends to occur in late adulthood, and
conventional osteosarcoma ❚Image 23❚. most patients are in the fifth to seventh decades at the time of

A B C D

E F G H
❚Image 20❚ Periosteal osteosarcoma. A, The lateral radiograph demonstrates a localized, interrupted, hair-on-end periosteal
reaction without intramedullary abnormalities. The corresponding axial T1 (B) and T2 (C) magnetic resonance images
demonstrate a partially circumferential hypointensity in T1 and hyperintensity in T2; this indicates a water-containing tissue
consistent with cartilage. The base of the lesion is “signal void” in both studies, corresponding to the bony reaction in the plain
radiograph. The marrow is bright in both sequences, indicating no tumor inside the medullary cavity. D, A partial diametric
section reveals a circumferential mass confined to the space between the cortex and the periosteum. The color and partial
translucency is consistent with calcifying cartilage. E, A scanning micrograph reveals the pink periosteal membrane overlying
the bluish white cartilage matrix; at this power, pink streamers of periosteal new bone are seen within the cartilage (H&E, ×25).
F, A low-power micrograph from the base of the lesion demonstrates not only cartilage and periosteal bone streamers, but also
bone formation (H&E, ×40). G and H, Higher power magnifications from the base of the tumor show convincing bone formation
in which tumor cells are entrapped (G, H&E, ×100; H, H&E, ×250).
diagnosis.54 Most cases arise in the deep soft tissues with a Histologically, the tumors demonstrate all types of
predilection for the thigh followed by the buttocks, upper extrem- osteosarcoma seen in tumors that arise in bone ❚Image 25❚. The
ities, and the retroperitoneum.55 Patients usually have an enlarg- most unusual histologic subtype is that of low-grade osteosar-
ing soft tissue mass, and the mass may be painful. Radiographs coma. When the latter occurs, it has been described as the
show a mass that may demonstrate mineralization, and CT scans “soft tissue homologue of parosteal osteosarcoma,”15
increase the yield of cases that demonstrate mineralization. although it could as easily have been described as the soft tissue

A B C

D E F
❚Image 21❚ Dedifferentiated parosteal osteosarcoma. A, The anteroposterior radiograph demonstrates cloudy, radiodense tumor
matrix in the soft tissues. Note that the portion of lateral femoral condyle that does not overlap the patella and the upper medial
metaphysis are markedly radiolucent compared with the bone of the metadiaphysis. B, The axial computed tomography scan
demonstrates radiolucency and underlying cortical interruption at the base of the mass. The radiolucency also replaces the
slightly denser cancellous bone. C, The gross specimen viewed coronally demonstrates that most of the surface tumor appears
bony grossly and most of the tumor in the medullary cavity is hemorrhagic. There is no periosteal reaction, indicating that the
mass began external to the bone and then invaded the bone. D, A low-power micrograph at the junction of external mass and
invasive component demonstrates the typical trabecular pattern with intertrabecular fibrosis of low-grade parosteal
osteosarcoma at the left and a more cellular, high-grade tumor within the underlying bone at the right (H&E,×25). There is no
recognizable residual cortex in this photograph. E and F, Higher power photographs of the high-grade tumor components reveal
sheet-like osteoid formation in an area of cortical disruption (E, H&E, ×50) and an area of undifferentiated high-grade tumor
without bone formation (F, H&E, ×250).
homologue of low-grade central osteosarcoma. Recently, The prognosis is poor in soft tissue osteosarcoma of
there was a reported case of high-grade dedifferentiation in a the high-grade type, with about 75% of patients dying of
low-grade extraskeletal osteosarcoma analogous to that seen the tumor within 5 years of diagnosis.7 Anecdotally,
in parosteal and low-grade central osteosarcomas.56 patients with the low-grade variant seem to have a better

A B

C D
❚Image 22❚ High-grade surface osteosarcoma. A, A lateral radiograph demonstrates a radiodense tumor mass posterior to the
tibia. B, A computed tomography scan demonstrates separation of the mass from the underlying bone by a dark periosteal line.
The mass is progressively less radiodense away from the bone. C, The resected specimen demonstrates that the underlying
tibia shows no gross invasion by the tumor. The patient died of metastatic disease less than a year after resection. D, The mass
was biopsied at its periphery and found to be a high-grade neoplasm producing wispy osteoid (H&E, ×200).
prognosis, although the total number of cases in the liter- Address reprint requests to Dr Klein: Section of Surgical
ature may still be too small to make accurate statistical Pathology, Department of Pathology, KB 506, University of
analyses.56,57 Alabama at Birmingham, Birmingham, AL 35233.
From the Departments of Pathology, Cell Biology, and Surgery, References

University of Alabama at Birmingham and the Birmingham
1. Cotterill SJ, Wright CM, Pearce MS, et al. Stature of young
Veterans Affairs Medical Center. people with malignant bone tumors. Pediatr Blood Cancer.
2004;42:59-63.
Funded in part by grants AR46031, CA93796, and CA98543
2. Porter DE, Holden ST, Steel CM, et al. A significant
from the National Institutes of Health, Bethesda, MD, and the
proportion of patients with osteosarcoma may belong to Li-
Haley’s Hope Memorial Support Fund for Osteosarcoma Fraumeni cancer families. J Bone Joint Surg Br. 1992;74:883-
Research, University of Alabama at Birmingham. 886.

A B

C D E
❚Image 23❚ Intracortical osteosarcoma. A, The lateral radiograph demonstrates a radiodense mass attached to the midshaft of
the radius. The patient had a painless bump on the lateral arm. B, The computed tomography (CT) scan demonstrates eccentric
thickening of the cortex. There was no history of trauma or radial deformity suggestive of a healed fracture. A biopsy specimen
at medium (C, H&E, ×150) and high (D, H&E, ×250) power demonstrates highly cellular immature bone and cartilage formation.
There is no appositional osteoblast activity and no maturation suggestive of a repair reaction. The process was considered an
intermediate-grade osteosarcoma, and a CT scan performed at the same time (E) demonstrated multiple lung metastases.
3. Ragland BD, Bell WC, Lopez RR, et al. Cytogenetics and 6. Ragsdale BD, Madewell JE, Sweet DE. Radiologic and
molecular biology of osteosarcoma. Lab Invest. 2002;82:365- pathologic analysis of solitary bone lesions, part II: periosteal
373. reactions. Radiol Clin North Am. 1981;19:749-783.
4. McNairn JDK, Damron TA, Landas SK, et al. Inheritance of 7. Rosenberg Z, Lev S, Schmahmann S, et al. Osteosarcoma:
osteosarcoma and Paget’s disease of bone. J Mol Diagn. subtle, rare, and misleading plain film features. AJR Am J
2001;3:171-177. Roentgenol. 1995;165:1209-1214.
5. Jhala DN, Eltoum I, Carroll AJ, et al. Osteosarcoma in a 8. deSantos LA, Edeiken B. Purely lytic osteosarcoma. Skeletal
patient with McCune-Albright syndrome and Mazabraud’s Radiol. 1982;9:1-7.
syndrome: a case report emphasizing the cytological and 9. Dorfman HD, Czerniak B. Bone Tumors. St Louis, MO: Mosby;
cytogenetic findings. Hum Pathol. 2003;34:1354-1357. 1998.

A B C D

E F
❚Image 24❚ Multifocal osteosarcoma. A 50-year-old woman had no history of radiation, Paget disease, or any other known familial
condition that would predispose her to osteosarcoma. B and C, Pain in the left leg resulted in radiographs demonstrating multiple
disparate osteosclerotic lesions of the femur. Because there were multiple lesions, she underwent a skeletal series that revealed
multiple lesions of the medullary right femur shown in the anteroposterior radiograph (A) and the computed tomography scan (D).
The right femur resection was performed because of intractable pain; there are at least 4 discrete lesions, 2 involving the cortex
with remodeling changes. E, Midfemur scan demonstrating cloudy radiodensity of osteosarcoma matrix within the medullary
cavity. F, The histologic features were those of a conventional osteosarcoma (H&E, ×250). The diagnosis was presumed to be
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A B

C D
❚Image 25❚ Extraskeletal osteosarcoma. The patient had a 4-cm mass anterior to the left clavicle. The lesion was thought to be
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Anatomic Pathology / OSTEOSARCOMA

Key Words: Osteosarcoma; Malignant bone tumors; Bones; Imaging

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❚Image 5❚ “Normalization” of conventional osteosarcoma. A,

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computed tomography (CT) scanning has resulted in a detect- A B

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is not entirely trivial because response to adjuvant chemother- Epithelioid Osteosarcoma

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Osteoblastoma-like and no constant radiographic pattern for osteoblastoma, which

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typically conventional areas of giant cell tumor without Gnathic Osteosarcoma

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The majority of parosteal osteosarcomas are associated Dedifferentiated Parosteal Osteosarcoma

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From the Departments of Pathology, Cell Biology, and Surgery, References

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