Frozen Section Library

Series Editor
Philip T. Cagle, MD
Houston, Texas, USA

For other titles published in this series, go to

http://www.springer.com/series/7869
wwwwwwwwwwwww
 Frozen Section
Library:
Bone

Omar Hameed, MBChB

University of Alabama at Birmingham, AL, USA

Shi Wei, MD, PhD

University of Alabama at Birmingham, AL, USA

Gene P. Siegal, MD, PhD

University of Alabama at Birmingham, AL, USA
Omar Hameed, MBChB
Associate Professor of Pathology and Surgery
Department of Pathology
University of Alabama at Birmingham
Birmingham, AL, USA
ohameed@uab.edu

Shi Wei, MD, PhD

Assistant Professor
Department of Pathology
University of Alabama at Birmingham
Birmingham, AL, USA
swei@uab.edu

Gene P. Siegal, MD, PhD

R. W. Mowry Endowed Professor of Pathology
Director, Division of Anatomic Pathology
Executive Vice-Chair – Pathology, UAB Health System
Department of Pathology
University of Alabama at Birmingham
Birmingham, AL, USA
gsiegal@uab.edu

ISSN 1868-4157 e-ISSN 1868-4165

ISBN 978-1-4419-8375-6 e-ISBN 978-1-4419-8376-3
DOI 10.1007/978-1-4419-8376-3
Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2011921258

© Springer Science+Business Media, LLC 2011

All rights reserved. This work may not be translated or copied in whole
or in part without the written permission of the publisher (Springer
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except for brief excerpts in connection with reviews or scholarly analysis. Use
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The use in this publication of trade names, trademarks, service marks,
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Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

To my parents, my dearest wife, Chura, and my daughters,
Shilan and Sara
OH

To my loving wife, Mei, for her unending support,

and my wonderful children, Johnny and Erica
SW

To all those who have taught me...my mentors,

my trainees and most assuredly my family
- from Sandy to Marley and all those in between.
GPS
wwwwwwwwwwwww
Series Preface

For over 100 years, the frozen section has been utilized as a tool for
the rapid diagnosis of specimens while a patient is undergoing sur-
gery, usually under general anesthesia, as a basis for making immedi-
ate treatment decisions. Frozen section diagnosis is often a challenge
for the pathologist who must render a diagnosis that has crucial
import for the patient in a minimal amount of time. In addition to the
need for rapid recall of differential diagnoses, there are many pitfalls
and artifacts that add to the risk of frozen section diagnosis that are
not present with permanent sections of fully processed tissues that
can be examined in a more leisurely fashion. Despite the century-long
utilization of frozen sections, most standard pathology textbooks,
both general and subspecialty, largely ignore the topic of frozen sec-
tions. Few textbooks have ever focused exclusively on frozen section
diagnosis and those textbooks that have done so are now out-of-date
and have limited illustrations.
The Frozen Section Library Series is meant to provide conven-
ient, user-friendly handbooks for each organ system to expedite
use in the rushed frozen section situation. These books are small
and lightweight, copiously color illustrated with images of actual
frozen sections, highlighting pitfalls, artifacts, and differential
diagnosis. The advantages of a series of organ-specific handbooks,
in addition to the ease-of-use and manageable size, are that (1) a
series allows more comprehensive coverage of more diagnoses,
both common and rare, than a single volume that tries to high-
light a limited number of diagnoses for each organ and (2) a series
allows more detailed insight by permitting experienced authorities
to emphasize the peculiarities of frozen section for each organ
system.

vii
viii   Series Preface
viii

As a handbook for practicing pathologists, these books will

be indispensable aids to diagnosis and avoiding dangers in one
of the most challenging situations that pathologists encounter.
Rapid consideration of differential diagnoses and how to avoid
traps caused by frozen section artifacts are emphasized in these
handbooks. A series of concise, easy-to-use, well-illustrated hand-
books alleviates the often frustrating and time-consuming, some-
times futile, process of searching through bulky textbooks that
are unlikely to illustrate or discuss pathologic diagnoses from
the perspective of frozen sections in the first place. Tables and
charts will provide guidance for differential diagnosis of various
histologic patterns. Touch preparations, which are used for some
organs such as central nervous system or thyroid more often than
others, are appropriately emphasized and illustrated according to
the need for each specific organ.
This series is meant to benefit practicing surgical pathologists,
both community and academic, and to pathology residents and
fellows; and also to provide valuable perspectives to surgeons,
surgery residents, and fellows who must rely on frozen section
diagnosis by their pathologists. Most of all, we hope that this series
contributes to the improved care of patients who rely on the frozen
section to help guide their treatment.

Philip T. Cagle, MD
Preface

This monograph attempts to provide for the trainee, as well as

the seasoned pathologist with limited exposure to bone lesions,
an introduction to the most common forms of tumor and tumor-
like conditions of bone seen in North American clinical practice.
We have purposely avoided demonstrating exotica which few,
if any of us, would hope to see in a lifetime of experience even
in an academic medical center. For example, we have purposely
avoided demonstrating examples of primary smooth and striated
muscle tumors of bone; likewise the lipogenic tumors and neural
tumors of bone have not been reported. Rather, we have focused,
in eight chapters, on the common cartilaginous and osteogenic
tumors, fibrogenic tumors, small cell tumors, giant cell tumors,
epithelial tumors, and vascular tumors. We have also highlighted,
where appropriate, reactive, cystic, and reparative conditions that
are often mistaken for primary neoplasms in their presentation
and have further supplemented the actual frozen section in many
cases with representative radiographic images to help the patholo-
gist in understanding the breadth and depth of such lesions.
Furthermore, although a particular interest of ours, we have
avoided discussing the cytogenetic and molecular genetic charac-
teristics of many of the demonstrated lesions as well as avoided
the ultrastructural and immunophenotypic characteristics, leaving
these for the primary literature or the many outstanding themed
textbooks in the field which we have selectively highlighted at the
end of this monograph. In an attempt to be consistent with the
other books in this series, we have tried to minimize the text and
rather provided full color images of the histopathology, often at
different magnifications, to the help serve as an atlas for those con-
fronted with an unknown lesion. Lastly, rather than attempting to

ix
x   Preface
x

take photomicrographs of the most idealized fields in a tumor or

tumor-like condition, we have purposely tried to mix such images
with those that are less than ideal to give the reader a sense of the
challenges faced in the actual practice of frozen section interpreta-
tion of such lesions. We hope you benefit from this approach and
benefit from this treatise.

Birmingham, 2011 Omar Hameed

Shi Wei
Gene P. Siegal
Contents

1 Introduction........................................................................... 1

2 Bone/Osteoid Producing Lesions......................................... 5

3 Cartilage-Producing Lesions................................................. 25

4 Fibrous and Fibrohistiocytic Lesions.................................. 47

5 Giant Cell-Rich Lesions........................................................ 67

6 Small/Round Cell Lesions..................................................... 85

7 Cystic and Vascular Lesions................................................. 99

8 Epithelial Lesions.................................................................. 105

Suggested Readings.................................................................... 117

Index............................................................................................ 131

xi
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Chapter 1
Introduction

Orthopedic Pathology, specifically tumors of bone and related

conditions, has a reputation as a diagnostically difficult area of
practice. The reasons for this are multiple and probably include
the reality that such lesions are quite rare (representing <1% of
all cases seen in typical community practices) so the “average”
pathologist may have limited experience in dealing with such cases
and may not develop a sense of confidence in recognizing these
lesions. The second cause is the realization that bone has only a
limited number of ways to respond to an insult and thus many
lesions overlap morphologically at the gross, microscopic, and
ultrastructural levels. Thirdly, pathologists have developed a keen
insight into what to expect histologically when observing the gross
features of a pathologic condition. In bone, the radiograph or spe-
cial radiographic study (MRI, CT scan, bone scan, and PET scan)
acts invariablely as the “gross pathology.” Pathologists, although
highly trained, have minimal exposure to radiologic practice and
might be helpless in interpreting the images themselves, and with
lack of immediate access to musculoskeletal radiologists, usually
do not know what the “gross pathology” looks like. This series
of challenges is heightened by the isolation of the frozen section
suite in many North American hospitals. One further cause for the
uncomfortable state many pathologists find themselves in when
having to deal with lesions of bone is the incorrect notion that such
tumors are by their nature invariably “bone hard” and thus not
susceptible to interpretation by frozen section analysis. Nothing
could be further from the truth; virtually all lesions of bone including
those that are “bone producing” have tissue soft enough to cut on
a cryostat, as has been demonstrated for more than 100 years at

O. Hameed et al., Frozen Section Library: Bone, Frozen Section Library,

DOI 10.1007/978-1-4419-8376-3_1, © Springer Science+Business Media, LLC 2011
2   Frozen Section Library: Bone

the Mayo Clinic (which has perhaps the largest collection of bone
tumors in the world). Thus, diagnoses obtained by intraoperative
consultation, i.e., by frozen sections, are readily possible.
We remain at a point in time, more than half a century since
Jaffe defined the so-called triad for the diagnosis of tumors of
bone, where a partnership still is required between the clinician
who has knowledge of the demographic and clinical features of the
patient presenting to him, the radiologist with his ever expanding
armamentarium of techniques and instruments, and the patholo-
gist who bring his unique skill set to reach the proper diagnosis.
This becomes even more critical in the high-pressure environment
of the frozen section room. It is requisite that this triad of coopera-
tion be in place either before the operation begins or depending
on the emergent nature of the presentation, during the operation.
One would be severely remiss, if one failed to personally review the
radiographic images and/or radiology reports or, if not possible, to
ask the clinician or radiologist what the appropriately radiographic
images revealed. Although it seems easy and simple to say, we find
often in our consultation practice failure to follow this most simple
of rules. Such failure invariably leads the pathologist down a path-
way from which he or she cannot easily recover; so for example,
without the knowledge of the patient’s demographics, it might result
in the pathologist pontificating that in this 65-year-old patient with
a small blue round cell tumor that neuroblastoma is a reasonable
choice in the differential diagnosis. Similarly, a pure cartilaginous
lesion in the phalange of a 12-year old is probably not going to be
a chondrosarcoma. Giant cell tumor of bone, giant cell reparative
granuloma, and so-called brown tumor of hyperthyroidism often
have extensive overlapping histopathologic features and is it only
by knowing the patient’s age, gender, presentation, clinical and
laboratory studies, and radiographic appearances can one hope to
reach a reasonable and appropriate diagnosis. More subtle, if one
has a lesion that appears to be benign fibrous histiocytoma, one
best be sure it is not, in fact, really a case of metaphyseal fibrous
defect/non-ossifying fibroma that was in inadvertently biopsied as
the histology is essentially identical.
By following the standard rules of good practice as defined by
Jaffe, it should be relatively easy to reach a very narrow differen-
tial diagnosis or the one “correct” diagnosis on the frozen section
biopsy interpretation; however, it is also important to realize that
sometimes it is not wise or even possible to do so and here the expe-
rience of the pathologist is critical in being able to share his or her
uncertainty honestly with the surgeon. It goes without saying that
calling a benign osseous lesion an osteosarcoma is not acceptable
 Introduction   3

and could lead to rapid consequences from which one could not
recover. Thus, whenever there is even a reasonable doubt, it is often
best to say you favor such and such but need to do further analysis
or more definitive studies and the final diagnosis will be deferred.
Lastly, often times the surgeon does not really need or want the
final diagnosis but really wants to know whether there is sufficient
material to reach that diagnosis in a one-step operation. Here again
experience and judgment are critical so if, for example, one is sus-
pecting primary lymphoma of bone, one will need to perform flow
cytometry, perhaps touch preps and molecular diagnostics, and
one cannot reasonably do that on a limited sample provided for
frozen sectioning. One would hopefully be perfectly comfortable
in saying that there is a high degree of suspicion for lymphoma or
a malignant lymhoreticular process, but that additional tissues are
requested for special studies.
In this treatise, we follow a simple decision tree which has as
its center six key questions:

1. What are the key demographic features (age, sex, and race) of
the patient and does the patient have a relevant past history
(previous cancer diagnosis, genetic disease, radiation history,
etc.) or altered laboratory values?
2. What do the radiographic images show and what is the radio-
logic differential diagnosis?
3. Which bone or bones are involved and where in the bone (sur-
face, cortex, or intramedullary)?
4. Is it a long bone or flat bone and if the former is it epiphyseal,
diaphyseal, or metaphyseal in location?
5. Is it solid or cystic (or both); what are the main features of the
lesion and is it producing a particular extracellular matrix (e.g.,
osteoid, chondroid, or myxoid); and what are the principal cell
types involved (e.g., small cells, giant cells, and epithelial cells)?
6. Do the clinical data, radiologic findings and histopathologic
features come together into a logical picture?

Sure it is possible that you are seeing in the frozen section room
the first reported case of a chordoma in the metatarsal of a teen-
ager but really how reasonable a diagnosis is that? By following
this strategy, we believe that one stays out of trouble, can create a
reasonable differential diagnosis and will not be operating on luck.
Indeed you will be engaged in the best of good practice.
Chapter 2
Bone/Osteoid Producing Lesions

Introduction
There are many lesions that are associated with reactive new bone
formation; this chapter predominantly covers those in which depo-
sition of osteoid/bone matrix represents the primary pathological
process. The key in recognizing these lesions is the identification
of osteoid or woven bone (vs. lamellar bone) on the frozen section
slide. Osteoid is the organic nonmineralized matrix of bone and,
being predominantly composed of type I collagen fibers, appears
homogeneously eosinophilic and almost keloid-like in nature. This
matrix is almost always associated with osteoblasts within clear
spaces or halos. Bone matrix is further classified as lamellar or
woven depending upon the predominant fiber arrangement of its
collagen. In lamellar bone, the bone collagen fibers are arranged
in tightly packed stacks that are parallel to one another but run
at slightly different angles so that the bone appears to be layered.
Moreover, the osteoblasts/osteocytes within lamellar bone also
run parallel to the collagen fibers. After about 3 years of age,
normal compact (cortical) and cancellous (trabecular, spongy, and
medullary) bone exclusively consist of lamellar bone. In contrast,
woven bone is found in the fetal skeleton, in the growing parts of
the skeleton in infants and adolescents, and in processes in which
there is very rapid bone production secondary to neoplastic or
nonneoplastic conditions. Accordingly, identification of lesional
woven bone and its distinction from adjacent lamellar bone is
crucial during frozen section evaluation. This is based on the fact
that, in contrast to lamellar bone, woven bone is characterized by
the random distribution of its collagen fibers and the irregular dis-
tribution of osteoblasts within it. Although the distinction between

O. Hameed et al., Frozen Section Library: Bone, Frozen Section Library,

DOI 10.1007/978-1-4419-8376-3_2, © Springer Science+Business Media, LLC 2011
6   Frozen Section Library: Bone

lamellar and woven bone can, for the most part, be made using
regular bright-field microscopy, the process can be facilitated with
the use of polarized light.
Once the presence of bone matrix has been established, one
has to determine if its presence is primary or secondary in nature,
a determination often compounded by the fact that many frozen
section samples include intermixed curettings from the lamellar
bone immediately adjacent to the lesion in question. In most cases,
where the production of new bone is secondary, its presence tends
to be focal in nature and closely intermixed with other reactive ele-
ments including hemorrhage and osteoclast giant cells. Moreover,
there is usually a zonal distribution which may not be easily appre-
ciated in curetting specimens. On the other hand, bone production
in most cases of primary bone-producing lesions tends to more
extensive and generally not intimately associated with reactive ele-
ments, that, if present, also tend to be peripherally located.
As stated throughout this book, evaluation of any bone lesion
(intraoperatively or otherwise) should not be made independently
from the clinical (age of the patient, bone involved, and portion
of bone involved) and radiological findings. This is no less true
for the bone-producing lesions discussed in this chapter, which,
although having overlapping histological features, can have quite
distinct clinical and/or radiological features that are crucial to
arriving at the correct diagnosis.

Fracture Callus
Although fractures are numerically one of the most frequent bone
“disorders,” intraoperative consultation is infrequently requested
unless the fracture is thought to be pathological in nature. Although
acute fractures can be hemorrhagic and display some fragmented
bone trabeculae, these changes are nonspecific and are very diffi-
cult to evaluate in the setting of the artifacts associated with frozen
sections. Subacute fractures (meaning a few days old, rather than
hours or weeks) may also display empty osteocyte lacunae and
necrosis of marrow. Older fractures that do not readily heal and,
as noted above, those that are thought to be pathologic, are more
frequently sampled to rule out the presence of an occult neoplasm
or infection. In the absence of these etiologies mimicking the natu-
ral healing process that moves from fibrosis to chondrogenesis
to osteogenesis in long bones, one observes irregular islands and
trabeculae of osteoid with an intervening, variably cellular reactive
spindle-cell stroma. Scattered osteoclasts are frequently present
(Figs. 2.1 and 2.2) as are islands of cartilage (Fig. 2.3). It is very
important to know that there is a history of trauma, otherwise
 Bone/Osteoid Producing Lesions   7

Figure 2.1 Low power view of a fracture callus showing a cellular infil-
trate in which scattered eosinophilic islands of osteoid are evident.

Figure 2.2 On higher magnification, this fracture callus shows a predomi-

nantly spindle-cell component in which scattered osteoclasts are evident.
Notice that although the osteoid islands are mostly irregular in shape,
one starts to appreciate the somewhat parallel alignment of these islands
(running downwards and to the right in this field). Such an appearance is
strongly in favor of reactive, nonneoplastic osteoid deposition.
8   Frozen Section Library: Bone

Figure 2.3 Hyaline cartilage is frequently a component of fracture callus

(a). The presence of orderly endochondral ossification (b) is another help-
ful feature of benignity.

one might misinterpret the osteoid as being neoplastic in nature.

Of note, primary bone-producing neoplasms are rarely the sites of
fracture unless radiographically evident and quite large.
There are a few histological parameters that help to distin-
guish bone (and cartilage) formation by tumor from that second-
ary to trauma; however, it might be difficult to appreciate
 Bone/Osteoid Producing Lesions   9

them in frozen sections. Although reactive osteoid may start

off focally lacelike in appearance (Fig. 2.4), it rapidly acquires
a microtrabecular to trabecular architecture as it matures, and
there is almost always a zonation of orderly maturation (Fig. 2.5).

Figure 2.4 The presence of focal lace-like areas of osteoid deposition in

a fracture callus can be worrisome for neoplasia. However, this focus also
displays an edematous spindle-cell stroma with scattered inflammatory
cells and osteoclasts and no evidence of cytological atypia.
10   Frozen Section Library: Bone

Figure 2.5 With time, there is progressively more bone deposition in a

fracture callus and the orderly trabecular pattern of deposition is one of
the best clues to suggest a nonneoplastic process.

In contrast, neoplastic osteoid invariably has a lace-like or sheet-like

appearance (see below) and there is no orderly maturation.

Reactive Bone
In addition to being a component of fracture callus, as noted
earlier, reactive bone may be seen accompanying a variety of bone
infections with secondary attempts at healing/repair. As such,
this often surrounds the lesion in question or is part of an accompa-
nying reactive periosteal new bone formation. The orderly parallel
arrangement of the trabeculae/microtrabeculae in reactive bone
(Fig. 2.6) is characteristic.

Osteoma
The characteristic clinical and radiographic findings of this benign
lesion, when linked to its classic location in the skull and sinuses,
make it an unlikely frozen section sample. Moreover, its dense
bony nature would make sectioning virtually impossible.

Osteoid Osteoma
This bone-forming tumor is relatively common, representing at
least 10% of all benign bone neoplasms. Most patients are between
10 and 30 years of age and the lesion most frequently involves
the cortex of long bones. One of osteoid osteoma’s characteristic
 Bone/Osteoid Producing Lesions   11

Figure 2.6 The pattern of bone deposition in reactive bone is very similar
to that seen in fracture callus.

symptoms is progressive pain, easily relieved by ingestion of

nonsteroidal anti-inflammatory drugs. Radiologically, a radiolu-
cent “nidus” surrounded by sclerotic bone is quite characteristic
(Fig. 2.7). Histologically, the nidus is composed of vascularized
fibroconnective tissue in which osteoid or mineralized new bone
is evident. This new bone is usually arranged in microtrabecular
arrays, lined by plump appositional osteoblasts, and surrounded
by sclerotic bone. Given its characteristic clinical and radiologi-
cal features, osteoid osteoma is rarely sampled intraoperatively.
Moreover, definitive treatment by radiofrequency ablation or cryo-
therapy is not infrequently performed prior to pathological con-
firmation of the diagnosis. Unfortunately, in most of these cases,
one sees only markedly fragmented nonviable bone (sometimes
referred to as “bone dust”) that is nondiagnostic histologically.

Osteoblastoma
The histological features of this neoplasm are identical to those of
osteoid osteoma except for the fact that it has an expanded growth
potential. It also arises in adolescence and young adulthood and
frequently involves the cortices of long bones; however, spinal ver-
tebrae are also a common site of involvement (Fig. 2.8). As noted
above, microtrabecular arrays of osteoid or woven bone lined by
plump osteoblasts dominate the histological appearance (Fig. 2.9).
Some cases can be significantly more cellular being composed of
12   Frozen Section Library: Bone

Figure 2.7 An osteoid osteoma of the humerus showing the characteristic

lucent nidus (arrow) surrounded by sclerotic bone.

Figure 2.8 An osteoblastoma appearing on plain radiograph (a) as an

expansile lesion in the transverse process of the third lumbar vertebra
(arrows). The expansile nature of the lesion is also quite apparent on the
CT scan (b) (images courtesy of Dr. Michael J. Klein, Hospital for Special
Surgery, New York, NY).
Bone/Osteoid Producing Lesions   13
14   Frozen Section Library: Bone

Figure 2.8 (continued)

sheets of tumor cells with less easily discernable osteoid (Fig. 2.10).
Lack of nuclear pleomorphism in the conventional forms of this
neoplasm is one feature that is useful to distinguish them from
other variants including the “aggressive” and “epithelioid” types.
Pathologists need to be aware that there is a histologic continuum
between conventional osteoblastoma and osteosarcoma, with the
osteoblastoma variants in the middle. Considering the histological
(and radiological) difficulty in recognizing these variants and
distinguishing them from osteosarcoma, it is prudent to defer the
diagnosis of atypical cases to permanent sections.

Osteosarcoma
Excluding hematopoietic tumors, osteosarcoma is the most com-
mon primary malignant neoplasm of bone. The peak incidence is
late childhood and adolescence, but there is another peak in patients
over 50 years where most cases develop secondarily in preexisting
bone lesions, such as Paget’s disease or following irradiation. The
metaphyses of long bones (femur, tibia, and humerus) are the most
common sites of involvement, isolated diaphysial involvement is rare,
while involvement of the epiphyses of long bones or small bones of
the hands and feet is exceptionally uncommon. The tumor may also
involve the jaws, skull and axial skeleton. A significant proportion of
patients presents with pain (often dull and unremitting) with or with-
out a palpable mass. Radiologically, there is almost always evidence of
a destructive bony lesion, often with evidence of new bone formation.
There may also be an interrupted periosteal reaction (Fig. 2.11).
 Bone/Osteoid Producing Lesions   15

Figure 2.9 Although not very cellular, one can appreciate a somewhat
monotonous cell population in this osteoblastoma. The faintly staining
microtrabecular osteoid in the upper right portion of the image is sur-
rounded by appositional osteoblasts.

The histological hallmark of osteosarcoma is the presence of

tumor osteoid or bone being formed directly by tumor cells. Similar
to that seen in fracture callus and osteoblastoma, tumor osteoid
has unique tinctorial properties on hematoxylin and eosin-stained
sections appearing as dense, pink, amorphous material that is often
described as “hard.” As noted above, osteoid may have a lace-like
(Fig. 2.12) or sheet-like (Fig. 2.13) appearance in osteosarcomas.
Although subclassification of osteosarcomas as osteoblastic, chon-
droblastic, or fibroblastic based upon the predominant matrix
produced has no prognostic impact, identification of a significant
16   Frozen Section Library: Bone

Figure 2.10 This osteoblastoma was markedly cellular (a) to the extent
that osteoid could only be focally identified (arrowheads). Higher magni-
fication (b) confirms the hypercellular nature of the neoplasm and better
displays the osteoid matrix. One should always remember that nuclear
atypia is exaggerated on frozen sections and thus be careful not to make a
diagnosis of osteosarcoma based solely on that feature.

chondroid or spindle-cell component independent of the osteoid

matrix may also be a useful clue toward the diagnosis. The neoplas-
tic tumor cells are usually seen intermixed within the osteoid
matrix but occasionally may appear to be in direct opposition to it;
they may even be condensed around it in a palisaded fashion
 Bone/Osteoid Producing Lesions   17

Figure 2.11 An osteosarcoma of the lower tibia that is predominantly

osteoblastic and also shows lucent areas. Notice the irregular cortex and
slightly lifted periosteum (arrowheads).

(Fig. 2.13). Morphologically, the tumor cells are usually round to

polyhedral in shape and significant pleomorphism is usually
present (Figs. 2.12 and 2.14). In other cases, the tumor cells can
have a predominantly spindle-cell morphology (Fig. 2.15). It is
important to note, however, that significant nuclear atypia may not
always be present in conventional high-grade lesions, in that case
18   Frozen Section Library: Bone

Figure 2.12 A typical appearance of osteosarcoma on frozen section

where one sees a very cellular lesion with characteristic irregular lace-like
osteoid deposition. Notice to the hyperchromatic nature of the tumor cells.

the radiological evidence of a destructive bony lesion can be one of

the most useful clues to suggest the diagnosis of osteosarcoma.
In addition to conventional intramedullary osteosarcoma, the
prototypical central osteosarcoma discussed above, there are other
variants of osteosarcoma, including some that are potentially
more challenging diagnostically.
 Bone/Osteoid Producing Lesions   19

Figure 2.13 Another osteosarcoma in which the neoplastic osteoid had

more of a sheet-like pattern of deposition (a). There is also prominent
palisading of tumor cells around the osteoid matrix (a, b).

Low-grade central osteosarcoma is composed of a variably

cellular spindle-cell/fibroblastic proliferation that, as the name
suggests, lacks the degree of cytological atypia seen in conven-
tional osteosarcoma. Moreover, bone production within this
spindle-cell proliferation appears as irregular, somewhat thick,
anastomosing or branching bony trabeculae that simulate the
20   Frozen Section Library: Bone

Figure 2.14 Hyperchromasia and nuclear atypia can be appreciated in

this osteosarcoma, even at this low power.

woven bone of fibrous dysplasia, or the longitudinal seams of

bone seen in parosteal osteosarcoma (see below). Although
review of the radiological findings often reveals subtle signs of
malignancy and helps to exclude a benign lesion such as fibrous
dysplasia or desmoplastic fibroma, it is best to defer the diagno-
sis of this rare variant to the permanent sections.
Telangiectatic osteosarcoma is characterized by large blood-filled
spaces separated by hypercellular fibrous septae that contain
 Bone/Osteoid Producing Lesions   21

Figure 2.15 Some osteosarcomas can be composed almost entirely of

spindle cells. Notice the osteoid in the center (a). Significant nuclear atypia
is also present (b).

variable amounts of tumor osteoid and markedly pleomorphic cells.

Although one might not readily see the osteoid on a single frozen
section slide, the degree of pleomorphism present in the cells lining
the blood lakes usually makes the diagnosis of malignancy relatively
straightforward. This, along with the tumor’s characteristic
radiolucent and expansile appearance on radiological examina-
tion, should strongly suggest the diagnosis.
22   Frozen Section Library: Bone

Small cell osteosarcoma histologically resembles Ewing’s

sarcoma, except that there is at least focal evidence (usually scant)
of osteoid formation (Fig. 2.16).
In contrast to central osteosarcomas that arise in the medullary
cavity, the much less common surface osteosarcomas arise on the

Figure 2.16 Small-cell osteosarcoma (a, b) may be very difficult to distin-

guish from other round cell tumors of bone (such as lymphoma or Ewing’s
sarcoma) and may not be correctly diagnosed in frozen section material
unless direct osteoid production by tumor cells is identified. In this case,
this was only found on permanent sections.
 Bone/Osteoid Producing Lesions   23

cortical surface. Of these, high-grade surface osteosarcoma is his-

tologically identical to conventional intramedullary osteosarcoma;
parosteal osteosarcoma (the commonest surface osteosarcoma)
resembles low-grade central osteosarcoma, whereas periosteal
osteosarcoma characteristically has abundant cartilaginous matrix
and cytomorphologically falls between the low- and high-grade
variants.
Again, it should be stressed that although awareness of the par-
ticular features of the osteosarcoma variants is useful especially to
avoid a misdiagnosis, subclassification of osteosarcoma is seldom
necessary on frozen section interpretation and is best deferred to
permanent sections.
Chapter 3
Cartilage-Producing Lesions

Introduction
Tumors that produce a chondroid matrix are traditionally grouped
together regardless of their histogenesis. There are three types of
cartilage: hyaline cartilage, fibrocartilage, and elastic cartilage. In
the adult, hyaline cartilage is present in the joints; fibrocartilage
is mostly found in the spine; and elastic cartilage is seen in the
external ear, epiglottis, and a few other places. The vast majority
of cartilaginous matrix encountered in frozen sections is hyaline
cartilage, which is easily recognizable based on its amorphous
basophilic quality. Mature chondrocytes reside within sharp-edged
lacunar spaces embedded in the matrix and have finely granular
eosinophilic cytoplasm that is often vacuolated. The nuclei are typ-
ically small and round with condensed chromatin (“tight nuclei”).
The nuclear detail is usually not appreciated. The presence of
small clusters of chondrocytes, more than one cell per lacuna, and
occasional binucleation is not uncommon. Mitotic activity is usu-
ally not discernable.
As for all bone lesions, evaluation of cartilaginous lesions
necessitates adequate correlation with radiographic findings.
This is extremely important during intraoperative consultation
(frozen section), when the diagnosis may dictate the immediate
subsequent surgical procedure, i.e., curettage with bone grafting
vs. amputation. Oftentimes, conventional radiographic images are
sufficient to guide the diagnosis. Computed tomography (CT) and
magnetic resonance imaging (MRI) are useful in determining cor-
tical or soft tissue involvement and possible coexistent secondary
lesions [e.g., aneurysmal bone cyst (ABC)].

25

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DOI 10.1007/978-1-4419-8376-3_3, © Springer Science+Business Media, LLC 2011
26   Frozen Section Library: Bone

Osteochondroma
Osteochondroma is the most common benign tumor of bone and
is characterized by a hyaline cartilage-capped, exophytic, bony
projection arising on the surface of bone. The tumor is more com-
monly seen in males and peaks in the second decade of life. The
most common location is the metaphysis of long bones, especially
around the knee. On imaging, osteochondroma demonstrates
continuity of marrow and cortex with the underlying parent bone.
These lesions are usually easily diagnosed by radiographic modali-
ties with the cartilage cap pointing away from the nearest joint.
However, in cases clinically concerning for malignancy (e.g., pain,
rapid growth, thick and irregular cartilage cap), an open biopsy
with frozen section interpretation may be performed to determine
the immediate surgical strategy.
An osteochondroma may be sessile or pedunculated with a
smooth and thin cartilage cap (normally <1 cm, decreasing with
age). A cartilage cap of greater than 2–3 cm raises suspicion of
malignant transformation. The chondrocytes in an osteochon-
droma are organized and undergo endochondral ossification,
mimicking that of growth plate. However, these features are best
appreciated in permanent sections of excisional specimens. The
diagnostic challenge is mostly during frozen section interpreta-
tion, where the nature of the lesion often needs to be determined
from a small biopsy specimen.
While loss of architecture, myxoid change, nuclear atypia,
mitotic activity, and necrosis are all features indicative of malig-
nant transformation, the cartilage cap in an osteochondroma may
be more cellular than ordinary chondromas. Thus, the threshold
of cellularity for malignancy in the setting of osteochondroma
should be higher in the absence of other worrisome features
(Fig. 3.1).
Although surface chondrosarcoma may be histologically indis-
tinguishable from chondrosarcoma arising in an osteochondroma,
the former is characterized by the absence of a stalk radiographi-
cally and grossly. Although a parosteal osteosarcoma may have
a zone of cartilage simulating a “cap,” it can be histologically
separated from an osteochondroma by an atypical fibroblastic
proliferation and tumor osteoid formation.
Bizarre parosteal osteochondromatous proliferation (Nora’s
lesion) may also be encountered in the differential diagnosis. This
lesion predominantly affects small tubular bones of the hands and
feet but has been well described in long bones and is not continu-
ous with the underlying bone. Histologically, the lesion consists
of seemingly random mixture of bone, cartilage, and proliferative
 Cartilage-Producing Lesions   27

bizarre fibroblasts and is frequently very cellular. Furthermore,

the hyaline cartilage in Nora’s lesion is typically disorganized,
with patchy ossification, but no “columnation” of the cartilage as
is seen in osteochondromas.

Figure 3.1 A 48-year-old woman, with history of multiple hereditary exos-

toses, presented with a large left proximal femoral mass, consistent with
osteochondroma (a). While the frozen section shows increased cellularity
in the cartilage cap, there is no significant nuclear pleomorphism, mitotic
activity, or necrosis (b), which, in combination of the thickness of the
cartilage cap (0.5 cm), warrants a diagnosis of osteochondroma.
28   Frozen Section Library: Bone

Figure 3.1 (continued)

Chondromas
This group of benign tumors of hyaline cartilage consists of
enchondroma, periosteal chondroma, and enchondromatosis.
While they share many histologic features, these lesions differ with
respect to location and clinical manifestation.
Enchondromas arise from the medullary cavity, with a wide age
distribution, but peak in the second through fourth decades. They
frequently occur in the small bones of hands and feet and may
present with pain and pathologic fracture. Long bone tumors are
less common and are more often asymptomatic. Radiographically,
enchondromas are typically well-demarcated radiolucencies with
variable amounts of mineralization. Rings and arcs or popcorn-like
calcifications, when present, are the most characteristic findings.
Lesions of small tubular bones may be expansile or replace the
medullary cavity. In contrast, the presence of bony expansion and
scalloping in long bones suggests low-grade chondrosarcoma.
Curettage specimens received for frozen section evaluation are
typically pale blue or translucent hyaline cartilage fragments, which
may be associated with intermixed bony spicules representing
endochondral ossification. Histologically, enchondromas are
typically composed of hypocellular lobules with abundant pale
blue hyaline cartilage matrix, which may be associated with endo-
chondral ossification at the periphery. The lesional cells are
round to ovoid and situated within lacunae, similar to the normal
 Cartilage-Producing Lesions   29

chondrocytes of the growth plate. The nuclei are small and dark,
and the nuclear details are usually difficult to appreciate. Binucleated
forms are rare (Fig. 3.2). It should be noted that enchondromas of
small bones in the hands and feet may have increased cellularity,
cytologic atypia, binucleation, and myxoid change. Thus, the pres-
ence of these features should not be regarded a priori as low-grade
chondrosarcoma especially if they appear nonaggressive radio-
graphically (Fig. 3.3). On the other hand, chondrosarcomas of long

Figure 3.2 Enchondroma. A 14-year-old boy presented with a minimally

expansile lytic lesion involving the proximal left clavicle. No obvious
aggressive features are seen (a). The frozen section shows hypocellular lob-
ules with abundant hyaline cartilage matrix. No atypical cytologic features
are present (b). The findings are consistent with an enchondroma.
30   Frozen Section Library: Bone

Figure 3.3 Enchondroma. This elongated lucent lesion in the right fifth
metatarsal of a 30-year-old female has no aggressive radiographic features
(a). The frozen section showed a hypercellular cartilage lesion with focal
myxoid change (b), features that may otherwise represent malignancy;
however, given the location and the nonaggressive appearance on imaging,
the lesion is mostly consistent with enchondroma.
 Cartilage-Producing Lesions   31

Figure 3.3 (continued)

bones may have hypocellular areas that mimic enchondroma.

Thus, radiologic–pathologic correlation is critical in diagnosing
any hyaline cartilage lesion. If radiographic information is not
accessible or not provided, the diagnosis should be deferred until
obtained during permanent section signout.
Periosteal chondromas (also known as juxtacortical chon-
droma) arise on the cortical surface and most commonly occur
in the metadiaphysis of long bones (about two-thirds involve the
humerus and femur). These lesions are usually small (less than
3 cm), well-circumscribed, with “saucerization” (partial cortical
erosion) of the underlying bone and “buttressing” (lifted perios-
teum by the lesion that appears to project out from the axis of
the bone) on radiographs. The gross and microscopic features
of periosteal chondromas closely resemble those of enchondro-
mas of the small bones in the hands and feet. The tumors are
typically hypercellular with increased binucleated forms. Nuclear
atypia may be prominent. However, the tumor does not perme-
ate Haversian canals or the medulla. The differential diagnosis
includes periosteal chondrosarcoma, periosteal osteosarcoma,
and Nora’s lesion. Thus, a definitive diagnosis on frozen (or per-
manent) sectioning cannot be rendered with certainty without
radiological correlation.
Enchondromatosis is rare and mostly arises in the setting of
Ollier’s disease (multiple enchodromas) and Mafucci’s syndrome
32   Frozen Section Library: Bone

(multiple enchondromas with associated soft tissue hemangiomas).

The hand is the most common site. Both of these developmental
disorders are associated with significantly increased risk of sec-
ondary chondrosarcoma. While the histological features overlap
those of other cartilaginous lesions as described above, it should
be noted that the enchondromas in these patients tend to be more
cellular than solitary enchondromas, thus the histomorphologic
appearance alone cannot always be used to assess malignant
transformation.

Chondroblastoma
Chondroblastoma is a rare, benign cartilage-producing tumor
that mostly affects skeletally immature patients. Most patients are
between 10 and 25 years of age, with a slight male predominance.
It usually arises in the epiphysis (or apophysis) of long bones, most
commonly around the knee, and in the proximal humerus. The
skull may also be involved but usually at an older age.
Radiographically, chondroblastoma is typically a small and
sharply demarcated lytic lesion with a sclerotic rim (Fig. 3.4).
Spotty matrix calcifications may also be present. The lesion may
extend into the metaphysis. The classic microscopic findings of
chondroblastoma at lower magnification include randomly dis-
tributed osteoclast-type multinucleated giant cells and variably
sized, amorphous or eosinophilic fibrochondroid islands that
may be focally calcified. Calcification may take the form of a
fine network of pericellular highlighting (so-called “chicken wire”
calcification). At higher magnification, the cellular component
consists of oval, polygonal mononuclear cells (chondroblasts) with
well-defined cell borders and eosinophilic cytoplasm. The nuclei
have longitudinal grooves, resulting in a “coffee bean” appearance
(Fig. 3.4) similar to that of the principle cells in Langerhans cell
histiocytosis (LCH). Mitotic activity may be present but is usually
low (<3/10 high power fields). True hyaline cartilage is almost

Figure 3.4 Chondroblastoma. A 14-year-old young man presented with hip

pain. Conventional radiographs demonstrated a lucent lesion in the devel-
oping apophysis of the left greater trochanter with sclerotic margins (a).
There is no periosteal reaction. The radiographic differential diagnosis
includes chondroblastoma and osteoblastoma. On frozen sections, the tis-
sue contains fibrochondroid islands and “chicken wire”-type pericellular
calcifications (b), as well as sheets of polygonal mononuclear cells with
well-defined cell borders and eosinophilic cytoplasm (c). The findings are
characteristic of a chondroblastoma.
Cartilage-Producing Lesions   33
34   Frozen Section Library: Bone

Figure 3.4 (continued)

never found. It is important to note that such lesions may show

varying degrees of the aforementioned features, but only a small
proportion of cases demonstrates all of the histologic characteris-
tics, especially during frozen section evaluation, as the material is
often limited and/or detailed microscopic examination is hindered
by prominent calcification.
The histologic differential diagnosis of chondroblastoma
includes giant cell tumor (GCT) of bone, chondromyxoid fibroma
 Cartilage-Producing Lesions   35

(CMF), LCH, and ABC. GCT (Chap. 5) is seldom seen in skeletally

immature individuals. Histologically, the GCT typically shows
numerous, evenly distributed osteoclast-like giant cells in a back-
ground of mononuclear cells with similar appearing nuclei. CMF
(next entity) typically occurs in the metaphysis and consists of
zonated lobules of spindled and stellate cells in a background of
myxoid stroma. LCH (Chap. 6) has a predilection for flat bone
involvement and typically shows a variety of inflammatory cells
(especially eosinophils). The Langerhans cells may mimic chon-
droblasts, but the lesion typically lacks matrix formation and
calcifications. ABC (Chap. 5) may occur anywhere within the bone,
although primary ABC usually spares the epiphysis. CT or MRI,
if performed preoperatively, typically shows fluid–fluid levels.
Although the presence of osteoclast-like giant cells and basophilic
calcifications overlaps with chondroblastoma, the presence of
blood-filled spaces and fibroblastic proliferation along with the
absence of sheets of chondroblasts should help point to the diag-
nosis of ABC. It should be noted, however, that secondary ABC
commonly coexists with chondroblastoma. Thus, care should be
taken when features of ABC are seen in a specimen from an epi-
physeal lesion or when radiographic information is not provided.
In such cases, communication with the surgeon is imperative prior
to providing the diagnosis.

Chondromyxoid Fibroma
CMF is one of the least common tumors of bone. It has a wide
age range but peaks in the second and third decades. In its typi-
cal presentation, CMF occurs in the intramedullary portion of the
metaphysis of long bones, most commonly in the proximal tibia.
Imaging studies typically show sharp, sclerotic margins with scal-
loping. Matrix calcification is rare, except when present in the
juxtacortical location.
Histologically, the lesion has a vaguely lobular pattern caused
by hypocelluar centers and increased cellularity at the periph-
ery. The lobules are composed of varying proportions of fibrous,
myxomatous, and chondroid tissue containing spindled and stel-
late cells which are more zonally numerous at the periphery of
the lobules. Osteoclast-like giant cells are also often present at the
periphery. Well-formed hyaline cartilage is only rarely present. It
should be noted that the zonated configuration of CMF may not be
well preserved in the limited frozen material sent for examination,
especially when the curetting specimen is largely fragmented. The
myxoid matrix may appear edematous and mimic freezing artifact
(Fig. 3.5).
Figure 3.5 Chondromyxoid fibroma. There is an eccentric osteolytic lesion
in the distal humerus of this 53-year-old man which involves the lateral cortex
(a). Frozen sections of the curettage specimen revealed spindled and stellate
cells embedded in somewhat myxoid matrix that mimics edema or freez-
ing artifact (b). The cells are arranged in a lobulated pattern with increased
cellularity at the periphery. Although cortical involvement is not a common
finding, the histologic features are typical for chondromyxoid fibroma.
 Cartilage-Producing Lesions   37

Figure 3.5 (continued)

The cytomorphology of CMF may mimic chondroblast-

oma. However, the latter occurs almost exclusively in the epi-
physis and histologically does not have lobular configuration.
Chondroma is also a differential diagnostic consideration but
usually can be excluded by the presence of predominant hyaline
cartilage. Chondroblastic osteosarcoma may have overlapping
38   Frozen Section Library: Bone

histolomorphology with CMF especially as related to the matrix.

Chondroblastic osteosarcoma, however, typically demonstrates
an aggressive radiographic appearance and the presence of, at
least focally, hyaline cartilage and tumor-producing osteoid.
Chondro-sarcoma usually occurs in the older patients and can be
excluded by the presence of permeation of bone radiographically
and microscopically.

Chondrosarcoma
Chondrosarcoma is the second most common malignant neoplasm
of bone. The tumor usually occurs in adults and peaks between the
fifth and sixth decades. Chondrosarcoma may affect any bone; the
most frequent sites of involvement include the bones of the pel-
vis, proximal femur, and rib. Rarely, the tumor arises de novo in
extraskeletal sites. On imaging, chondrosarcoma typically presents
as a rapidly growing, large radiolucency with punctate or ring-like
calcifications and cortical erosion (scalloping). Cortical disrup-
tion and soft tissue extension may be seen in advanced lesions
(Figs. 3.6 and 3.7).
The fresh tissue of chondrosarcoma received for frozen
sectioning is typically pale blue with a mucoid or myxoid
matrix. A lobular growth pattern may be appreciated in a larger
specimen but is replaced by sheet-like growth in high-grade
lesions. Chalky white calcium deposits are commonly present.
Microscopically, the tumor grows in nodules separated by
fibrous bands and produces abundant blue-gray cartilaginous
matrix on H&E staining.
Conventional chondrosarcoma varies in cellularity from field to
field but is typically hypercellular when compared with an enchon-
droma of the same site. The chondrocytes are variable in size and
shape accompanied by hyperchromasia and discernible nuclear
details (“open-nuclei”); binucleation is also frequent. Myxoid
changes and matrix liquefaction are other common features,
whereas necrosis and atypical mitoses are rare and indicative
of a high-grade lesion. Another important feature to distinguish
chondrosarcoma from enchondroma is permeation through the
cortex or invasion and overrunning of the bone trabeculae in
the medulla. It should be noted that endochondral ossification
is commonly seen at the periphery of tumor lobules and should
not dissuade one from the diagnosis of chondrosarcoma if all the
other features are present. On the other hand, the identification
of tumor osteoid or bone formation directly by tumor cells should
point to the diagnosis of (chondroblastic) osteosarcoma, rather
than chondrosarcoma.
 Cartilage-Producing Lesions   39

Figure 3.6 Chondrosarcoma. The conventional radiograph shows a cen-

trally placed lesion in the proximal fibula of a 59-year-old man. The lesion
contains chondroid matrix and demonstrates endosteal scalloping with
associated pathologic fracture. The most likely consideration is a low-grade
chondrosarcoma.
40   Frozen Section Library: Bone

Figure 3.7 A CT scan showing a 4.5 cm mixed densely sclerotic and lytic
right iliac wing lesion with cortical breakthrough, concerning for chon-
drosarcoma versus osteosarcoma or less likely a metastatic lesion. The
histologic sections demonstrated a grade II chondrosarcoma.

Given that increased cellularity, binucleation, hyperchro-

masia, and myxoid change all may be seen in enchondromas of the
small bones of hands, only the presence of unequivocal radiologic
or histologic evidence of tumor permeation through the cortex
can the diagnosis of chondrosarcoma in these locations be made.
Conversely, one should also bear in mind that curettage specimens
do not always have preserved geographic relationships maintained
with the adjacent bony structures, and lack of permeation in the
histologic sections examined (frozen or permanent) does not auto-
matically exclude malignancy.
Grading is most useful to predict clinical outcome in chon-
drosarcoma, except for those arising in the bones of the fingers
and toes. Nevertheless, accurate assessment is also critical during
frozen section diagnosis, as it often determines the subsequent
management. Chondrosarcoma is graded on a scale of I–III, pri-
marily based on cellularity, nuclear size and details, as popularized
by Evans. However, other competing systems exist yielding no
universally accepted strict scoring system.

• Grade I: similar to enchondroma except mildly increased cellu-

larity, occasional binucleation and hyperchromasia, and permea-
tive growth pattern (Fig. 3.8).
• Grade II: increased cellularity, myxoid changes, cytologic atypia
including visible nuclear detail, hyperchromasia, and frequent
binucleation (Fig. 3.9).
 Cartilage-Producing Lesions   41

Figure 3.8 An example of grade I chondrosarcoma of a long bone as seen

on frozen section. Note the mildly increased cellularity and binucleated
forms but minimal nuclear atypia that overlap substantially with enchon-
droma. However, the myxoid changes and chondroid matrix liquefaction
are common features of chondrosarcoma.

Figure 3.9 Grade II chondrosarcoma. In addition to myxoid changes, note

the markedly increased cellularity, cellular pleomorphism, and hyperchro-
masia that are appreciated even at intermediate magnification.
42   Frozen Section Library: Bone

• Grade III: high cellularity, significant nuclear pleomorphism;

mitoses and/or necrosis may be present (Fig. 3.10).
It should be emphasized that high-grade chondrosarcomas
(grade II and III) often have low-grade areas. This is particularly
important in frozen section evaluation when only limited amounts
of tissue are made available for histologic evaluation. Thus, when
facing a radiographically aggressive lesion but no histologic evi-
dence of malignancy, it is appropriate to defer the frozen section
diagnosis. An example of how we report such a case is as follows:
“cellular cartilaginous lesion, further diagnosis deferred to perma-
nent section.” On the other hand, sometimes cartilaginous lesions
may represent some worrisome radiographic features (e.g., large
size) but are not associated with apparent aggressive character-
istics (e.g., scalloping, cortical breakthrough), and the histologic
features may be similarly borderline. Again, deferral is appropriate
in such a case (Figs. 3.11 and 3.12).
The histologic caveats for diagnosing periosteal chondrosar-
coma (arising on surface of bone) and secondary chondrosarcoma
(arising in a benign precursor, either osteochondroma or enchon-
droma, or in Ollier disease or Maffucci syndrome) are similar to
those of conventional chondrosarcoma.

Figure 3.10 Grade III chondrosarcoma. Note the infiltrative growth pattern,
diffuse hypercellularity, and significant pleomorphism including hyper-
chromasia, irregular nuclear membrane, and visible nuclear details.
 Cartilage-Producing Lesions   43

Figure 3.11 Borderline cartilage tumor. The curetting specimen was from
a proximal humeral lesion in a 59-year-old woman. The radiologist noted
a 7 cm intramedullary cartilagenous lesion with no apparent aggressive
features. Frozen sections showed moderately cellular hyaline cartilage
intermixed with bone dust. There was no significant nuclear pleomor-
phism, hyperchromasia, or mitotic activity. The radiologic findings and
histomorphologic features (frozen and permanent) did not fulfill those
either for an enchondroma or a low-grade chondrosarcoma. A diagnosis of
“cartilaginous tumor of indeterminate biological potential” was eventually
rendered, and close clinical follow-up was recommended.

Chondrosarcoma Variants
Dedifferentiated chondrosarcoma is characterized by a bimorphic
lesion composed of a well-differentiated cartilage tumor (enchon-
droma or low-grade chondrosarcoma) juxtaposed to a high-grade,
noncartilaginous sarcoma. The radiographic findings are also
commonly biphasic, with a more “aggressive” component super-
imposed on what is otherwise typical of chondrosarcoma. Grossly,
both components are usually easily identified. The cartilaginous
portion (often centrally located) is blue-gray and lobulated, and
the high-grade component commonly has a soft fleshy consist-
ency with hemorrhage and necrosis. However, the abrupt transi-
tion may not be appreciated in a frozen specimen obtained from
curettings.
On histologic sections, there is similarly a distinct zone
of abutment where the two components are interface. The
44   Frozen Section Library: Bone

Figure 3.12 Similarly, this frozen section was from a mass arising from
a sessile osteochondroma with a cartilage cap whose maximum thick-
ness was 2.5 cm. The section shows prominently cellular cartilage with
mild-to-moderate pleomorphism and hyperchromasia that may otherwise
indicate a grade II chondrosarcoma in a long bone. However, given that
the cartilage cap within an osteochondroma often shows higher cellular-
ity and a degree of cytologic atypia greater than that of a cartilage tumor
elsewhere, the diagnosis was deferred to permanent sectioning and a final
diagnosis of “cartilaginous tumor of indeterminate biological potential”
was rendered.

dedifferentiated area may have features of malignant fibrous

histiocytoma (most frequent), osteosarcoma, fibrosarcoma,
and/or rhabdomyosarcoma (Fig. 3.13). It should be noted that
although by definition the dedifferentiated component is a
high-grade sarcoma, we have experienced two cases where the
noncartilage portion represented a predominantly giant cell-
rich lesion reminiscent of a cytologically atypical GCT of bone.
Thus, in our opinion, the presence of any “high-grade” mesen-
chymal component in association with a separate “low-grade”
cartilage tumor would raise the possibility that this lesion was
a dedifferentiated chondrosarcoma. Dedifferentiated chondro-
sarcoma is highly aggressive and has a poor prognosis.
Mesenchymal chondrosarcoma is a rare variant of chondrosa-
rcoma that affects younger patients with a peak incidence in the
second and the third decades of life. This highly malignant tumor
is characterized by a bimorphic appearance in which islands of
 Cartilage-Producing Lesions   45

Figure 3.13 Dedifferentiated chondrosarcoma. The frozen section was

made from tissue derived from a chest wall mass of a patient with hereditary
multiple exostoses. Note the abrupt transition of a high-grade osteosarcoma
(center) from the adjacent conventional relatively low-grade chondrosar-
coma, most likely representing its dedifferentiated component.

mostly bland-appearing hyaline cartilage are embedded within

solid, hypercellular areas of primitive small, round, blue cells
(simulating Ewing sarcoma) commonly arranged in a hemangi-
opericytoma-like pattern (Fig. 3.14).
46   Frozen Section Library: Bone

Figure 3.14 A section of mesenchymal chondrosarcoma with character-

istic bimorphic appearance consisting of islands of hyaline cartilage and
solid, hypercellular areas of primitive small, round, blue cells. Note that
the cartilage in mesenchymal condrosarcoma appears benign because it
represents all stages of chondrogenesis that are seen in the growth plate.

Clear cell chondrosarcoma is a rare, low-grade variant of chon-

drosarcoma with a predilection for the epiphyseal region of long
bones. It also affects a younger age group than conventional chon-
drosarcoma and peaks in the third decade. Approximately two-
thirds of lesions involve either the femoral or the humeral heads.
The tumor consists primarily of plump cells with large, centrally
located nuclei with a clear-to-pale eosinophilic cytoplasm and
well-defined cell borders. Zones of low-grade chondrosarcoma,
formation of woven bone and osteoclast-like multinucleated giant
cells are variably present. Areas of aneurysmal bone cyst are often
also identified.
Chapter 4
Fibrous and Fibrohistiocytic Lesions

Introduction
Most tumors of fibrous and fibrohistiocytic origin generally produce
collagen but do not form a mineralizing matrix, whereas high-grade
tumors may have little to no matrix. Fibro-osseous lesions [fibrous
dysplasia (FD) and osteofibrous dysplasia (OFD)] are composed of
large volumes of fibrous connective tissue, principally collagens
type I and III, as well as osseous areas. Fibrous and fibrohistio-
cytic lesions span the entire spectrum of clinical behaviors: benign,
locally aggressive, and malignant. While with radiologic input, it is
usually not difficult to distinguish the benign and malignant ends
of the spectrum, some of these lesions have significant overlapping
histologic features and necessitate incorporating clinical and demo-
graphic information to arrive at the correct diagnosis.

Nonossifying Fibroma (Metaphyseal

Fibrous Defect)
Nonossifying fibromas (NOFs) are exclusively seen in young
patients with an age range of 5–20 years. It is extremely unusual
to see an NOF in individuals with fused growth plates. The most
common site is the metaphysis around the knee (distal femur and
proximal tibia). It is still debatable whether NOF represents a true
neoplasm. Hence, some authorities prefer to use the term meta-
physeal fibrous defect (MFD).
NOFs are mostly asymptomatic and typically incidental find-
ings. Patients may present with a pathologic fracture if lesions
are larger. Radiography they typically show an eccentric, sharply
circumscribed, purely lucent, expansile process in the metaphysis of

47

O. Hameed et al., Frozen Section Library: Bone, Frozen Section Library,

DOI 10.1007/978-1-4419-8376-3_4, © Springer Science+Business Media, LLC 2011
48   Frozen Section Library: Bone

a long bone. The lesion may appear multilocular and has a­

scalloped border and a narrow rim of marginal sclerosis (Fig. 4.1a).
The association of multiple NOFs with café-au-lait skin patches
has been named Jaffe–Campanacci syndrome.
Curetted fragments of lesional tissue are fibrous and fleshy
and may vary from tan yellow to brown in color, depending on the
proportions of fibrous tissue, lipid-laden histiocytes and hemo-
siderin deposition/hemorrhage in association with the stroma.
Histologically, NOFs typically show a highly cellular spindle cell
proliferation arranged in a characteristic storiform pattern in a
background of collagenized stroma (Fig. 4.1b). The pattern may
vary from area to area. Multinucleated giant cells are scattered
throughout the lesion and thus may share many microscopic fea-
tures with giant cell tumors of bone (Fig. 4.1c). However, the giant
cells in NOFs are generally smaller and contain fewer nuclei than
the giant cells in giant cell tumors. Lipid-laden foamy histiocytes
are almost always present and so is hemosiderin deposition. On
higher magnification, the spindled cells are fibroblastic in nature,
without significant pleomorphism. Mitotic figures may be present
but no atypical forms are seen. Reactive new bone formation
is not an uncommon finding, especially at the periphery of the
lesion or if pathologic fracture is present. Rarely, a superimposed
secondary aneurysmal bone cyst (ABC) may occur and is clinically
manifested as a rapidly enlarged mass (Fig. 4.2). This may lead to a
diagnostic challenge and careful radiologic–pathologic correlation
is required.

Figure 4.1 Nonossifying fibroma. This lesion was from a 13-year-old boy,
which demonstrated a multilocular, expansile, lytic lesion in the distal
fibula, with a scalloped border and a sclerotic ­margin. The radiologic features
are those of a typical nonossifying fibroma (a). Microscopically, the lesion
consists of cellular spindle cell proliferation in a storiform fashion (b) with
Scattered multinucleated giant cells and scattered or clustered foamy his-
tiocytes are typical (c). These cells, mimicking those seen in giant cell
tumor of bone, may be misinterpreted as freezing artifacts.
Fibrous and Fibrohistiocytic Lesions   49
50   Frozen Section Library: Bone

Figure 4.1 (continued)

Benign Fibrous Histiocytoma

Benign fibrous histiocytoma (BFH) of bone is histologically indis-
tinguishable from NOF, being separated from the latter only on
clinical and radiological grounds. BFH may affect any bone, occur
at any age, and present with local pain even in the absence of
pathologic fracture.
 Fibrous and Fibrohistiocytic Lesions   51

Figure 4.1 (continued)

Radiographically, BFH typically has a sharp margin, often with

a sclerotic rim such as NOF, but may also lack a well-defined
margin, destroy the cortex, and extend into soft tissue, thus mim-
icking a malignant process (Fig. 4.3a). When a lesion with histo-
logic features of NOF (Fig. 4.3b, c) is seen in a skeletally mature
52   Frozen Section Library: Bone

Figure 4.2 Nonossifying fibroma. This is a large (8.3 cm), multilocu-

lated, cystic lesion in the distal tibial metaphysis of another 13-year-old
boy. There are multiple internal bony septations (a). Histologic sections
show a cellular spindle cell lesion with a storiform growth pattern and
scattered giant cells, features of those of a typical nonossifying fibroma
(b). However, a cyst wall with no apparent lining (right upper corner) is
present, with new bone formation in a lace-like pattern in parallel to the
cyst wall. The histologic features, along with the radiologic findings, are
mostly consistent with a nonossifying fibroma with secondary aneurysmal
bone cyst formation.
 Fibrous and Fibrohistiocytic Lesions   53

Figure 4.2 (continued)

patient, in a location other than metaphysis of a long bone or with

associated local pain, the diagnosis of BFH is appropriate.
The differential diagnosis of NOF/BFH includes desmoplastic
fibroma of bone (intra-osseous counterpart of soft tissue fibroma-
tosis). This lesion tends to occur in younger patients, may involve
any bone but is most frequent in the mandible. Radiographically,
it is usually a well-defined, radiolucent lesion. If large, the lesion
54   Frozen Section Library: Bone
Figure 4.3 (continued)

Figure 4.3 Benign fibrous histiocytoma. A 29-year-old woman presented

with significant leg pain. CT scan showed an expansile, lytic, and sclerotic
lesion in the proximal diaphysis of the right fibula, with cortical thinning
(a). Frozen sections showed loosely proliferative fibroblasts in a background
of collagenized stroma, intermixed with small fragments of remodeled bone
which may represent fracture callus (right) (b). Permanent sections showed a
cellular spindle cell lesion with histologic features almost identical to those
seen in a typical nonossifying fibroma (c). However, the age of patient, the
presence of local pain, and the anatomic location of the lesion all point to a
diagnosis of benign fibrous histiocytoma.
56   Frozen Section Library: Bone

may breach the periostium and extend into the soft tissue.
Histologically, the lesion is typically composed of dense, bland
spindle cells in a background of richly collagenized matrix. The
separation of desmoplastic fibroma from NOF/BFH may be dif-
ficult on histologic grounds even on permanent sections and
especially in small curettage material. In these situations, the iden-
tification of its characteristic cytogenetic abnormalities (trisomies
8 and 20) and nuclear b-catenin accumulation, if present, can help
reach the diagnosis of desmoplastic fibroma.

Fibrosarcoma and Malignant Fibrous

Histiocytoma
Primary malignant fibrous/fibrohistiocytic lesions of bone
include fibrosarcoma and malignant fibrous histiocytoma (MFH).
Fibrosarcoma is far less common than previously thought, with
many of those so labeled relabeled as monomorphic synovial
sarcoma – thanks to advances in immunohistochemistry and
molecular genetics. MFH is much more common than fibrosar-
coma and may occur at any age, with a higher incidence in adults
over 40 years. This tumor may arise de novo in bone but may
also develop secondary to preexisting bone conditions such as
radiation therapy for an unrelated malignancy or as a malignancy
complicating Paget’s disease or FD, or as the end product of “dedif-
ferentiation” of a low-grade neoplasm. The aggressive behavior of
these lesions is usually demonstrated by their destructive nature
on imaging.
Histologically, fibrosarcoma is composed of a uniform popula-
tion of spindled cells arranged in a fascicular or herringbone-like
pattern, with a variable amount of collagenous matrix. The pres-
ence of readily discernable mitotic activity and hypercellularity in
well-differentiated fibrosarcoma can distinguish it from desmo-
plastic fibroma. The lesion should be classified as myxofibrosar-
coma in the presence of identifiable myxoid changes. Significant
cytologic atypia, brisk mitotic activity, the presence of tumor giant
cells, epitheloid type cells, and a storiform growth pattern are
typically not present in fibrosarcoma and their presence would
favor a diagnosis of MFH. Different histologic subtypes of MFH in
bone (and soft tissue) have been described, including pleomorphic
(Fig. 4.4), giant cell, and inflammatory. While MFH may have foci
of osteoid and bone formation at the periphery of the lesion, these
newly formed bony trabeculae are typically well organized and
most typically represent periosteal reactive bone/fracture callus.
Any unequivocal evidence of tumor cell-produced osteoid or bone
should lead to a diagnosis of osteosarcoma (MFH-like; Fig. 4.5),
Figure 4.4 Malignant fibrous histiocytoma. This curettage specimen was
from an aggressive lesion of femur in a 62-year-old man. Section showed
a cellular neoplasm containing numerous large, bizarre cells, some with
foamy cytoplasm. The tumor cells do not have apparent growth pattern or
identifiable differentiation. No osteoid or new bone formation by tumor
was present in either the frozen or the permanent sections. A diagnosis of
malignant fibrous histiocytoma was rendered.

Figure 4.5 In contrast to the previous case, this is a section from a 3.0 cm
lytic lesion in the distal third of tibia of a 60-year-old man. The section
shows a highly pleomorphic sarcoma consisting of fibroblastic and fibro-
histiocytic cells admixed with abundant bizarre multinucleated giant cells,
mimicking a malignant fibrous histiocytoma. However, one can appreciate
subtle but apparent tumor-produced bone matrix (center), thus rendering
a diagnosis of osteosarcoma.
58   Frozen Section Library: Bone

usually leading to neoadjuvant systemic chemotherapy prior to

definitive surgical treatment. Given that such foci may be very
subtle, a careful search of all sections is necessary.

Fibrous Dysplasia
FD is a benign medullary fibro-osseous lesion, which is tradition-
ally considered as a noninherited developmental disorder. However,
recent studies have suggested that this entity is neoplastic in nature
given the reproducible genetic abnormalities (activating mutations
in the GNAS1 gene and associated clonal chromosomal aberration).
Nevertheless, FD may be a solitary (monostotic) lesion or of the
polyostotic form. The latter is intimately associated with McCune–
Albright syndrome (FD, endocrinopathy, and skin pigmentation)
and Mazabraud syndrome (FD and intramuscular myxomas).
Although it can occur at any age, the majority of patients at
first presentation of FD are younger than 30 years. The polyostotic
form mostly presents in the first decade of life, while the monostotic
form peaks in the late teens and early 20s. It may involve any bone,
with long bones (femur and tibia), craniofacial bones, and ribs
being most affected sites. The typical radiographic appearance is an
expansile, lytic, or ground glass-like lesion with sharp margination
in the metadiaphyseal region (if in long bones) (Fig. 4.6a).
The gross appearance of lesional tissue is usually dense and
fibrous with a firm-gritty consistency. There may be cyst forma-
tion which may contain yellowish fluid. The classic microscopic
findings include proliferating cytologically bland fibroblasts in a
collagenous background, with bony trabeculae coursing irregu-
larly throughout the lesion. These bone trabeculae, which are
predominantly immature and woven in nature, are arranged in
a haphazard manner and are commonly thin, curved or branch-
ing without osteoblastic rimming (Fig. 4.6b, c). Occasionally, the
osteoid produced may take the form of rounded, cementum-
or psammomatous-like bone, especially in craniofacial bones.
Lipophages, multinucleated giant cells, and areas of cartilaginous
differentiation (so-called “fibrocartilaginous dysplasia”) may be
present. No cytologic atypia is seen.

Osteofibrous Dysplasia
OFD has been also called ossifying fibroma and Kempson–
Campanacci’s disease. It is a benign fibro-osseous lesion that
almost exclusively arises in the tibia, with or without involvement
of the fibula. OFD predominantly occurs in children during the
first two decades of life and typically involves the proximal or
Figure 4.6 Fibrous dysplasia. This CT scan shows multiple well-demarcated
lytic lesions in the proximal humerus, the largest involves the proximal
humeral metadiaphysis with cortical breakthrough but no associated soft
tissue mass or progressive periosteal reaction (a). Sections show a fibro-
osseous lesion composed of irregularly shaped trabeculae of immature bone
without rimming osteoblasts dispersed in a background of bland spindle
cells (b and c). These findings are most consistent with fibrous dysplasia.
60   Frozen Section Library: Bone

Figure 4.6 (continued)

middle-third of the tibial diaphysis. The majority of cases are

self-limited and regress spontaneously after puberty. Thus, OFD
represents a distinctly separate entity from FD.
On imaging, OFD most commonly affects the cortex anteriorly
and presents as well-demarcated, multiloculated lytic expansion
associated with a thin, sclerotic rim of cortex that separates the
lesion from the medullary bone (Fig. 4.7a). Thus, the radiographic
 Fibrous and Fibrohistiocytic Lesions   61

Figure 4.6 (continued)

appearance of OFD may closely mimic that of adamantinoma, a

low-grade malignant biphasic tumor that involves particularly the
anterior metadiaphysis of the tibia, although the latter typically
affects patients in their 20s and 30s. A significant body of literature
has emerged over the last few years, suggesting that the relation-
ship between OFD and adamantinoma is, in fact, not coincidental
and one may transform into the other over time. If the lesion
involves the medullary cavity by extension, it may also resemble
FD radiographically.
The histologic findings of OFD also resemble FD and are
characterized by irregular fragments of woven bone trabeculae
lying in variably cellular bland spindle cells with collagen produc-
tion. In contrast to typical FD, the trabecular bone is rimmed, at
least in part, by plump osteoblasts (Fig. 4.7b, c), which is also a
differentiating feature from parosteal osteosarcoma (see Chap. 2).
Osteoclasts may also be present. In contrast to adamantinoma,
epithelial islands are absent. Other nonspecific findings include
foamy histiocytes, hemorrhage, and cyst formation likely repre-
senting degenerative changes.

Central Ossifying Fibroma

Central ossifying fibroma (COF) is a benign fibro-osseous neo-
plasm composed of cellular fibrous tissue admixed with varying
amount of mineralized material, including bone and cementum, of
Figure 4.7 Osteofibrous dysplasia. This radiograph from an 11-year-old
girl revealed multiple areas of radiolucency with surrounding osteosclerosis
and a lack of a periosteal reaction in the cortical diaphysis of the right tibia
(a). Frozen sections of this lesion show irregularly arranged bony trabecu-
lae surrounded by a variably cellular fibroblastic proliferation (b). The bony
trabeculae exhibit prominent osteoblastic rimming and increased osteoclast
activity consistent with active remodeling (c). The spindle cells in the sur-
rounding stroma display minimal cytologic ­atypia. This case demon­strates
a perfect correlation between the radiologic and histopathologic findings
and point to the ­diagnosis of osteofibrous dysplasia.
 Fibrous and Fibrohistiocytic Lesions   63

Figure 4.7 (continued)

varying appearance. COF most commonly occurs in the second to

fourth decades of life, with a female predilection. It most frequently
affects the mandible, especially the molar or posterior region.
COF is generally asymptomatic and diagnosed incidentally.
Radiographs show a sharply demarcated or well-circumscribed
lesion with smooth contours. The lesion may have radiodense as
well as radiolucent areas, depending on the contributions of bone
and soft tissue components.
64   Frozen Section Library: Bone

Histologic sections of COF typically show randomly distributed

bony spicules surrounded by variably cellular fibrous tissue. The
mineralized trabeculae may consist of woven and/or lamellar bone
and spherules of cementoid tissue (hence cementifying fibroma or
cemento-ossifying fibroma). Psammomatoid OF, a unique variant
of COF that mainly involves the paranasal sinuses, is character-
ized by a fibroblastic stroma containing bony spicules that resem-
bles psammoma bodies (Fig. 4.8). The bony spicules of COF are
typically rimmed by osteoblasts, but there may be mixed bands
of cellular osteoid without osteoblastic rimming. The differential
diagnosis of COF is primarily with FD. Distinction between these
two lesions on histologic grounds only may be problematic. The
most important distinguishing feature is the presence of demarca-
tion and/or encapsulation in COF as opposed to the merging with
its surroundings in FD.
 Fibrous and Fibrohistiocytic Lesions   65

Figure 4.8 Central ossifying fibroma of the psammomatous type. This

biopsy is from a 2.0 cm, well-demarcated, expansile mass involving the
roof of the left orbit in a 64-year-old man. Frozen sections showed a fibro-
osseous lesion consisting of irregularly shaped immature bony spicules
admixed with variably cellular fibrous stroma (a). The permanent sec-
tions, however, revealed that the spicules were mostly spherical or curved
resembling psammoma bodies (b). Taken together, the features are mostly
consistent with central ossifying fibroma of the psammomatous type.
Chapter 5
Giant Cell-Rich Lesions

Introduction
Although almost all bone tumors contain giant cells, giant cell-rich
lesions of bone encompass a number of entities in which the giant
cells are an essential diagnostic component, chief among these are
giant cell tumor (GCT) of bone, giant cell reparative granuloma
(GCRG), and aneurysmal bone cyst (ABC). These lesions may have
overlapping histomorphologic features, yet each possesses its own
unique characteristics. Accordingly, clinical and radiologic input is
necessary for definitive classification of these lesions.
In addition, a spectrum of other bony lesions may have on occa-
sion prominent giant cell elements; these include principally giant
cell-rich osteosarcoma, cherubism, and the so-called brown tumor
of hyperparathyroidism. These lesions invariably have characteris-
tic clinical and radiologic characteristics, i.e., aggressive growth in
a non-epiphyseal location of a long bone (osteosarcoma), involve-
ment of a particular anatomic site (the mandible in cherubism),
unusual radiographic features (multifocal; subperiosteal bone
resorption) and typical serum chemistries (brown tumor), and
thus are frequently recognized prior to frozen section evaluation.
Lastly, other primary tumors of bone may be mistaken for GCTs
because the observer focuses on the osteoclast-like giant cells and
ignores the other clinical, radiologic, and/or histomorphologic fea-
tures; among these are chondroblastoma, nonossifying fibroma,
and both benign and malignant fibrous histiocytomas.

GIANT CELL TUMOR of Bone

GCT of bone was historically known as osteoclastoma. GCT
is a locally aggressive neoplasm affecting principally young
adults, with a slight female predominance. GCT is uncommon in

67

O. Hameed et al., Frozen Section Library: Bone, Frozen Section Library,

DOI 10.1007/978-1-4419-8376-3_5, © Springer Science+Business Media, LLC 2011
68   Frozen Section Library: Bone

skeletally immature individuals and very rarely seen in children

younger than 10 years.
Pain of variable severity is the most common and almost uni-
form presentation. GCT can affect any bone but typically involves
the ends of long bones, principally around the knee (distal femur
and proximal tibia). The sacrum is the most common site in the
axial skeleton. Conventional radiographs of GCT in long bones usu-
ally show an eccentric, purely lytic, and expansile lesion, almost
exclusively epiphyseal (or apophyseal) in location but may extend
to adjacent metaphysis and articular cartilage (Fig. 5.1a). The
margins may be well-defined with or without sclerosis, depending
on the activity of the tumor. Mineralization within the lesion is
distinctly uncommon. However, aggressive tumors may have ill-
defined margins, cortical destruction, and soft-tissue extension,
thus mimicking that of a biologically aggressive/malignant tumor.
The curetted fragments of tissue are typically soft and friable.
The characteristic histopathological appearance is of evenly dis-
tributed, numerous osteoclast-like multinucleated giant cells (often
containing 50–100 nuclei; Fig. 5.1b, c) in a background of sheets
of uniform, oval to polygonal mononuclear stromal cells which
resemble macrophages. It is now generally accepted that these
mononuclear cells represent the neoplastic component. At higher
magnification, the giant cell nuclei are similar to the nuclei of the
neoplastic mononuclear cells in that they have regular outlines with
open chromatin and small nucleoli. The cytoplasm is ill defined
(Fig. 5.2a, b). In select areas, the mononuclear cells can be more
spindle-shaped and may even be arranged in a storiform growth
pattern (Fig. 5.3). Collections of foam (xanthoma) cells may also be
present. This phenomenon, when dominating the histologic appear-
ance, may lead to a mistaken diagnosis of a benign fibrous histiocy-
toma (see Chap. 4). The stroma is typically rich in vasculature (but
not usually to the same degree as seen in GCRG) and intravascular
invasion in the form of “plugs of tumor cells” is frequently seen
(Fig. 5.4). Mitotic figures may be abundant, but atypical mitoses are
not seen and their presence should point to an alternative diagnosis
of a giant cell-rich sarcoma. There should be no cytologic atypia in a
typical GCT. The tumor typically lacks extensive matrix production;
however, in our experience, small foci of osteoid and woven bone
are invariably present, especially in lesions associated with patho-
logic fracture, at the periphery or at the leading edges of a soft tis-
sue recurrence resulting in a characteristic “egg-shell” appearance
on conventional radiographs. This is often difficult to appreciate
on frozen sectioning because the curettings have no preserved geo-
graphic relationship with the adjacent bone or soft tissue structures.
Figure 5.1 Giant cell tumor of bone. The conventional radiograph of a
46-year-old woman reveals a large lucent lesion occupying the right medial
femoral condyle (a). The lesion extends distally to the articular surface and
proximally into the diametaphyseal region. The lesion is sharply marginated
with a minimal periosteal reaction. There are no lesional contents. Frozen
sections from the lucent region displayed numerous, large osteoclast-type
multinucleated giant cells which lie uniformly in a syncytium of round to
oval mononuclear cells (b). There are areas suggestive of cyst formation but
these may also represent freezing artifact. At intermediate magnification,
the mononuclear cells as well as the multinucleated giant cells have eosi-
nophilic cytoplasm and indistinct cell borders, with vesicular nuclei and
small nucleoli. The nuclei of mononuclear cells and those of the multinucle-
ated cells are similar in appearance (c). The overall findings are typical for a
giant cell tumor with excellent radiologic–pathologic correlation.
70   Frozen Section Library: Bone

Figure 5.1 (continued)

When present, the new bone formation has the appearance of a

reactive process with prominent osteoblastic rimming of the bony
trabeculae, similar to that commonly seen in an ABC. Other com-
mon but nonspecific findings include focal necrosis, hemorrhage,
and hemosiderin deposition.
While most GCTs have characteristic clinical, radiologic, and
histopathologic manifestations allowing for a straightforward
diagnosis, a lesion that fulfills all the clinical and radiologic
 Giant Cell-Rich Lesions   71

Figure 5.2 High power views (a and b) of a giant cell tumor of bone. The
giant cells may be very large and contain 50–100 nuclei (b).

features of a GCT should be regarded as a GCT even if there is

only a minimal typical GCT component histologically, especially
during intraoperative consultation with limited material from
curettage specimens. On the other hand, as alluded to above,
virtually any tumor of bone may contain variable numbers of
multinucleated giant cells. However, both the presence of large,
confluent, osteoclast-like, multinucleated giant cells and the
72   Frozen Section Library: Bone

Figure 5.3 Giant cell tumor of bone with prominent spindled cells. These
areas are often devoid of giant cells and may resemble a benign fibrous
histiocytoma.

Figure 5.4 Giant cell tumor of bone with intravascular invasion in the
form of “plugs of tumor cells.”
 Giant Cell-Rich Lesions   73

cytologic resemblance of giant cell nuclei to ovoid or spindled

mononuclear cell nuclei are typically absent in lesions other than
GCT such as ABC, chondroblastoma, GCRG, and malignant bone
lesions with prominent giant cells.

ANEURYSMAL BONE CYST and Other Mimics

Primary ABC is a benign but locally aggressive cystic lesion that
commonly affects patients in the first two decades of life. It usually
arises in the metaphysis of long bones but less frequently involves
the vertebrae, characteristically situated in the dorsal elements.
Primary ABC typically presents as a lytic, eccentric, expansile
mass with well-defined margins on conventional radiographs.
CT and MRI studies frequently show internal septa and charac-
teristic fluid–fluid levels (Fig. 5.5a). Microscopically, pure ABC is

Figure 5.5 Primary aneurysmal bone cyst. A 15-year-old boy presented

with increasing pain involving his right hip. CT scan revealed a well-defined,
heterogeneous, expansile lytic lesion in his right acetabulum (a). The mass
was predominantly hypodense with internal septa and multiple fluid lev-
els. This appearance is mostly consistent with an aneurysmal bone cyst.
Although very unlikely, a telangiectatic osteosarcoma could not be entirely
excluded. Frozen sections showed a hemorrhagic lesion, of which the solid
component was composed of a fibrotic cyst wall devoid of apparent lining
(b). The cellular compartments included spindled fibroblasts, osteoclast-
type multinucleated giant cells, and hemosiderin (b). In addition, thin
strands of reactive woven bone formation were present along the cyst wall
and within the fibrotic stroma (c and d). The newly formed bone is rimmed
by flat, but more commonly plumped or plasmacytoid osteoblasts (d). No
significant cytologic atypia or other complicating lesional tissue was found.
Thus, a diagnosis of primary aneurysmal bone cyst was rendered.
74   Frozen Section Library: Bone

Figure 5.5 (continued)

composed of blood-filled, variably sized cystic spaces separated

by fibrous septa, which contain predominantly proliferative
fibroblasts, and scattered osteoclast-like multinucleated giant cells
(Fig. 5.5b). Reactive new bone formation, typically in the form of
thin strands, is almost invariably present, commonly along the
cyst wall (Fig. 5.5c, d). However, ABC may also arise secondarily
in association with other benign or malignant bone tumors.
 Giant Cell-Rich Lesions   75

Figure 5.5 (continued)

In fact, secondary ABC is not uncommonly associated with a GCT

(Fig. 5.6). While CT and MRI may show evidence of an underlying
primary lesion in such circumstances, a lesion with the histologic
appearance of an ABC but extending to the end of a long bone
should prompt the pathologist to conduct a thorough search for
even small foci of typical GCT.
Chondroblastoma, like GCT, classically also occurs in epiphy-
sis of long bones but typically affects skeletally immature patients.
The important histological features to distinguish GCT from a
chondroblastoma are lack of chondroid differentiation, no chicken
wire matrix, and uniformly distributed giant cells that are larger
and contain more numerous nuclei than typically appreciated in
chondroblastoma (see Chap. 3).
As noted previously, malignant bone tumors may also contain
giant cell elements. The nature of malignancy may be appreciated
by the aggressive growth and the histologic appearance (i.e., the
degree of cellular atypia, atypical mitotic figures, and necrosis).
Most of these lesions represent osteosarcoma (Fig. 5.7), malig-
nant fibrous histiocytoma, or sarcoma with a dedifferentiated
component (Fig. 5.8) resembling GCT. It should be noted, how-
ever, that malignancy in GCT (also known as malignant GCT) is
either a high-grade sarcoma arising in a GCT (primary) or at the
site of previously documented GCT (secondary). While a de novo
Figure 5.6 Secondary aneurysmal bone cyst. A 37-year-old man ­presented
with local pain. Conventional imaging shows an expanded lytic lesion
extending to the subarticular portion of the right distal radius with sharp,
nonsclerotic margins (a). There is no obvious cortical breakthrough or perio-
steal reaction. There are internal septations but no matrix is present. The
radiological differential diagnosis includes giant cell tumor and aneurysmal
bone cyst. Alternatively, this may also represent a giant cell tumor with a
secondary aneurysmal bone cyst. Upon frozen sectioning the lesion is that of
a giant cell tumor which consists, in most areas, of confluent osteoclast-like,
multinucleated giant cells in a background of mononuclear cells (b, right
upper, and c). However, nonendothelium-lined cyst spaces consisting of lakes
of blood are also present. Fibroblastic proliferation and formation of osteoid
and bone trabeculae are seen in areas (b, center, d, upper right and e). The
findings are mostly consistent with a giant cell tumor with secondary aneu-
rysmal bone cyst formation which was confirmed on permanent sections.
Figure 5.6 (continued)

malignant GCT may have the same radiographic appearance as

a benign GCT, there are areas of conventional GCT and concur-
rent high-grade spindle-cell sarcoma with an abrupt transition
in dedifferentiated forms. A secondary malignant GCT typically
arises in the same location several years after a previous GCT,
usually following radiation therapy.
78   Frozen Section Library: Bone

Figure 5.6 (continued)

Giant Cell Reparative Granuloma

GCRG was first described as a nonneoplastic fibrous lesion with
scattered osteoclast-like multinucleated giant cells of gnathic
bones in children and young adults. Thereafter, the concept of
GCRG of extragnathic sites (also known as giant cell reaction)
has been widely recognized. Meanwhile, given the significant
histopathologic overlap, GCRG of extragnathic sites has been
Figure 5.7 Giant cell-rich osteosarcoma. Note that without the nested
giant cell component, the tumor is otherwise a typical conventional
osteosarcoma, with tumor osteoid filling the upper half of the section.
Although many giant cell-rich osteosarcomas are similar to telangiectatic
osteosarcomas, this example has more of a fibroblastic appearance.

Figure 5.8 The permanent section of a dedifferentiated chondrosarcoma.

Note the abrupt transition of a well-differentiated chondrosarcoma from
its dedifferentiated component resembling giant cell tumor of bone.
80   Frozen Section Library: Bone

merged with the entity “solid variant of aneurysmal bone cyst

(solid ABC)” by many practitioners.
Characteristic radiographic features occurring in the GCRG
of maxilla and mandible are the presence of a round or
oval lucency with fine trabeculations and distinct borders.
Extragnathic GCRGs frequently occur in the small bones of
the hands and feet and very rarely in long tubular bones and
vertebrae. On imaging, lesions may be intramedullary or rarely
surface based and can be metaphyseal or diaphyseal, but do not
cross the open growth plate in skeletally immature patients.
The most characteristic radiologic features are purely lytic
and expansile lesions with sharp margination, regardless of
location. Soft tissue extension beyond the cortex is uncommon
but may be occasionally seen. On MRI, fluid–fluid levels among
solid components are often seen within the lesion, which
correspond to small cysts filled with blood akin to secondary
ABCs.
The curetted fragments of bone are tan or reddish brown, fri-
able, gritty tissues. Low-power microscopic examination typically
reveals a moderately to highly cellular spindle-cell proliferation
in the background of vascular-rich fibrous stroma that often con-
tains varying amount of collagen fibers. Numerous osteoclast-like
multinucleated giant cells are unevenly distributed throughout
the lesion and tend to be arranged in a vaguely clustered fashion
(Fig. 5.9a). Microscopic evidence of hemorrhagic cyst formation
reminiscent of an ABC, as well as hemosiderin deposition, is
­frequently seen. Newly formed reactive osteoid or bone trabeculae
rimmed by osteoblasts are an extremely common finding. The
spindled fibroblastic cells and the giant cells lack cytologic atypia.
Occasional mitotic figures may be present but not atypical forms
(Fig. 5.9b, c).
The major histological differential diagnostic consideration
for GCRG includes ABC, GCT, fibrohistiocytic lesions (nonossify-
ing fibroma and benign fibrous histiocytoma), and brown tumor
of hyperparathyroidism. The cellular components of an ABC are
similar, if not identical, to a GCRG. However, ABC is typically
composed of larger blood-filled cysts (lakes of blood) and has a
characteristic radiographic presentation. A GCT may rarely have
a prominent spindle-cell component. However, GCTs are almost
exclusively located in an epiphyseal region, and the giant cells
are typically larger, confluent, and evenly arranged. Nonossifying
fibroma and benign fibrous histiocytoma do not typically have
reactive new bone formation within the lesion, and the giant cells
Figure 5.9 Giant cell reparative granuloma. A 50-year-old man presented
with back pain. An MRI demonstrated a densely enhancing mass involving
the L4 vertebral body, displacing adjacent paravertebral structures. Frozen
sections reveal a densely cellular lesion consisting of spindled mononuclear
cells and abundant, randomly distributed osteoclast-like multinucleated
giant cells in a focally hyalinized stroma with intermixed hemosiderin dep-
osition (a). At higher magnification, one can appreciate the cellular details
of the mononuclear stromal cells and the giant cells which, as seen in
aneurysmal bone cyst, lack significant cytologic atypia (b and c). However,
cavernous spaces filled with lakes of blood, a feature characteristic of aneu-
rysmal bone cyst, are not present. The fibrous stroma is highly vascularized
and composed of reactive osteoid and new bone formation (b and c). Thus,
the features are those of a typical giant cell reparative granuloma.
82   Frozen Section Library: Bone

Figure 5.9 (continued)

 Giant Cell-Rich Lesions   83

are usually smaller and randomly distributed (see Chap. 4). Brown
tumor is almost indistinguishable microscopically from a GCRG
and historically has always been in the differential diagnosis, but
as this entity has become extremely uncommon or recognized
presurgically, it rarely causes a clinical problem. If in doubt, a
comment with a recommendation for clinical laboratory testing
is appropriate.
Chapter 6
Small/Round Cell Lesions

Introduction
Lesions considered in this chapter include traditional “small blue
round cell” neoplasms, specifically Ewing sarcoma/primitive
neuroectodermal tumor (ES/PNET) and lymphomas, solitary
plasmacytoma/multiple myeloma, and other lesions that tend to be
composed of a mixed population of rounded cells without epithe-
lial differentiation or significant extracellular matrix deposition.
These latter lesions include osteomyelitis and Langerhans cell
histiocytosis (LCH). As discussed earlier, however, there are other
lesions that can be composed predominantly of small round cells,
such as small cell osteosarcoma (Chap. 2), which may also need to
be considered in the differential diagnosis.

Ewing Sarcoma/Primitive
Neuroectodermal Tumor
Although ES/PNET has been described at various ages, most
patients present before their 20th birthday with pain and a mass
lesion. The classic location for this neoplasm is the diaphyses of
long bones, but it may also arise in the axial bones such as the
pelvis and ribs (as well as in soft tissues and other organs). Patients
may also present with fever and leukocytosis suggesting an infec-
tious picture, which is important to remember especially since
osteomyelitis often has overlapping clinical and radiological find-
ings (see below). Radiologically, a destructive permeative lesion is
usually evident within the diaphysis of a long bone (Fig. 6.1) often
with an overlying multilayered but discontinuous “onion-skin”
periosteal reaction. Occasionally, there is a large soft tissue mass
with no obvious bone destruction on the conventional radiographs,

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Figure 6.1 Ewing sarcoma involving the diaphysis of the fibula. Notice
the marked cortical destruction and the elevated periosteum (arrow)
(image courtesy of Mark J. Kransdorf, Mayo Clinic, Jacksonville, FL).

but the intraosseous component becomes evident on a CT scan or

MRI. Histologically, Ewing sarcoma is composed of sheets of small-
rounded cells, with amphophilic cytoplasm and uniform hyperchro-
matic nuclei (Fig. 6.2). Evidence of neuroectodermal differentiation
may be identified even on frozen section evaluation as extracellular
eosinophilic neuropil-like structures or Homer-Wright rosettes,
which are composed of groups of tumor cells that surround a cen-
tral core of the eosinophilic extracellular material. If these are very
prominent, metastatic neuroblastoma needs to be eliminated as a
diagnostic possibility. The histological differential diagnosis of ES/
PNET in this age group would also include lymphoma (see below)
as well as other small round cell tumors of childhood that have
metastasized to bone, most principally rhabdomyosarcoma.

Lymphoma
Most bone lymphomas are secondary to disease elsewhere, but pri-
mary bone lymphomas most certainly occur. The majority of pri-
mary bone lymphomas, and those that secondarily involve the bone
as tumorous masses, are diffuse large B-cell lymphomas and a few
other high-grade tumors, whereas most lower-grade lymphomas
and leukemias present with diffuse marrow involvement rather
 Small/Round Cell Lesions   87

Figure 6.2 An example of Ewing sarcoma (a, b) in which sheets of small

round blue cells are evident on frozen section. Even on high power (b), it
is very difficult to distinguish this from hematopoietic neoplasms.

than mass lesions. Radiologically, lymphomas usually present

as radiolucent lesions (Fig. 6.3), sometimes disproportionately
destructive when compared with the patient’s clinical symptoms.
The histological findings on frozen section evaluation are similar
to those seen in extraskeletal lymphomas and are characterized by
the presence of sheets of noncohesive, rounded, hyperchromatic
cells, usually with some (but minimal) pleomorphism (Fig. 6.4).
88   Frozen Section Library: Bone

Figure 6.3 On conventional radiographs, lymphomas usually appear as

destructive osteolytic lesions without a surrounding sclerotic rim, as seen
in the subtrochanteric area of this femur (image courtesy of Dr. Michael J.
Klein, Hospital for Special Surgery, New York, NY).
 Small/Round Cell Lesions   89

Figure 6.4 Bone lymphomas evaluated by frozen section. The first example
(a) is composed of sheets of large cells having indistinct cytoplasmic borders
and rounded nuclei with occasionally prominent nucleoli. Prominent apop-
tosis is present. A more polymorphic population is evident in the second
case (b) where significant nuclear crushing is also present. Although the
neoplasm is less cellular in the third case (c) with smaller tumor cells and
is potentially more suggestive of an inflammatory process (osteomyelitis),
the prominent hyperchromasia present (even at this magnification) helps
to point toward the diagnosis of lymphoma.
90   Frozen Section Library: Bone

Figure 6.4 (continued)

The latter is useful in distinguishing this lesion from its mimickers

including Ewing sarcoma and small cell carcinoma, which tend to
have more monotonous cytology (and more finely dispersed chro-
matin), and poorly differentiated carcinomas, which tend to be
more pleomorphic. Of note, a touch preparation of the submitted
material can be very useful in distinguishing between these lesions
and from plasma cell lesions (see below).

Solitary Plasmacytoma and Multiple Myeloma

Despite the quite variable presentation of myeloma, it is frequently
in the differential diagnosis on frozen sections because it accounts
for a large percentage of small, blue, round cell tumors arising
primarily in the bone of adults (as opposed to infants [neuroblas-
toma, rhabdomyosarcoma, and LCH], teenagers [ES/PNET], or
young adults [lymphoma, small cell osteosarcoma]). Involvement
of the skeletal system is usually manifested by bone pain and/
or pathological fractures. Radiologically, plasmacytoma and the
lesions of multiple myeloma are lytic, well-demarcated and with-
out a rim of sclerotic bone (Fig. 6.5); however, multiple myeloma
may also present with “generalized osteoporosis” without any
detectable foci of discrete bone destruction. As one would expect,
solitary plasmacytoma and bone lesions of multiple myeloma are
histologically composed of plasma cells and their precursors at
Figure 6.5 Lytic foci (arrows) without surrounding sclerosis in this femur
are typical of multiple myeloma lesions.
92   Frozen Section Library: Bone

Figure 6.6 Low (a), intermediate (b), and high (c) power magnification of
a case of multiple myeloma in which the sheets of neoplastic plasma cells
can be easily identified.

various stages of development (Fig. 6.6). The main differential

diagnosis is often other hematolymphoid neoplasms; however,
myeloma cells are occasionally quite anaplastic and, as such, can
easily mimic high-grade carcinoma and high-grade sarcoma.
 Small/Round Cell Lesions   93

Figure 6.6 (continued)

Given that plasma cells and precursors may be easier to discern on

intraoperative touch preparations stained by Romanowsky-type
stains (e.g., Diff-Quick), it is strongly recommended that such an
evaluation be always performed when plasmacytoma/myeloma
and its mimickers are in the differential diagnosis.

Osteomyelitis
Although this is a relatively common bone affliction, osteomyeli-
tis is infrequently submitted for intraoperative evaluation, as the
diagnosis is often made preoperatively based on the clinical and
radiological findings. Early cases are associated with increased
radionuclide uptake on bone scans; mixed sclerosis and radi-
olucency tend to appear later. Histologically, there is an acute
inflammatory infiltrate composed predominantly of polymorpho-
nuclear leukocytes with various degrees of marrow fibrosis; as
cases become more chronic an associated plasma cell infiltrate
is often also present (Fig. 6.7). Osteonecrosis, manifested as bone
trabeculae with empty lacunae, as well as new bone formation is
also frequently evident (Fig. 6.8), especially as these lesions age.
Differential diagnostic considerations include the small round cell
94   Frozen Section Library: Bone

Figure 6.7 A case of osteomyelitis in which one observes a sheet of mixed

inflammatory cells in between portions of mineralized bone (a–c).
 Small/Round Cell Lesions   95

Figure 6.7 (continued)

Figure 6.8 Another case of osteomyelitis in which there is new bone for-
mation. This is evident as trabeculae of woven bone in the upper portion
of the image.
96   Frozen Section Library: Bone

tumors discussed above as well as LCH. Apart from the clinical

and radiological findings and the fact that these conditions are
unlikely to be associated with osteonecrosis, a monotonous popu-
lation of cells would favor a round cell tumor, whereas intermixed
eosinophils, histiocytes, and cells with characteristic morphology
(see below) would favor LCH. Moreover, new bone formation
would also be unusual in these conditions unless a fracture has
occurred (see Chap. 2).

Langerhans Cell Histiocytosis

This comprises a group of neoplastic Langerhans cell prolifera-
tions, all of which being capable of producing bone lesions. Such
lesions can be unifocal (previously labeled solitary eosinophilic
granuloma), multifocal (Hand–Schuller–Christian disease), or
disseminated (Letterer–Siwe disease). The latter is thought by
most to be a different entity – malignant histiocytosis). The
craniofacial bones are most frequently affected, but LCH may
also involve other bones such as the femur, pelvis, and ribs.
Radiographically, lesions of LCH are radiolucent, often destruc-
tive and, in long bones, sometimes associated with exuberant
periosteal new bone formation. Histologically, there is a mixed
inflammatory infiltrate including neutrophils, eosinophils,
lymphocytes, and histiocytes (with or without giant cells) in
which Langerhans cells are identified (Fig. 6.9). These are cells
with eosinophilic to clear cytoplasm containing oval, grooved,
or multilobated nuclei (Fig. 6.10). Because of the histologic
similarity to chronic osteomyelitis, lesions should be cultured,
and the culture results should be known prior to formulating a
final diagnosis.
 Small/Round Cell Lesions   97

Figure 6.9 A case of Langerhans cell histiocytois characterized by abun-

dant eosinophilic infiltration (a, b) among other component cells.
98   Frozen Section Library: Bone

Figure 6.10 Another case of Langerhans cell histiocytois with less dense
inflammatory infiltrate and fewer eosinophils. Notice the grooved and
multinucleated Langerhans cells (arrows).
Chapter 7
Cystic and Vascular Lesions

Introduction
Since aneurysmal bone cyst has already been covered with other
giant cell-containing lesions, the other cystic lesions that will be
discussed in this chapter have been limited to simple bone cyst
and intraosseus ganglion. Given the rarity of true vascular lesions
of the bone only hemangioma, hemangioendothelioma, and angi-
osarcoma are referenced.

Unicameral (Simple) Bone Cyst

Patients with this lesion usually present within the first two dec-
ades of life, most frequently with a pathological fracture, with
the proximal humerus, femur, or tibia being the commonest sites
of involvement. Radiologically, the lesion is circumscribed, radio­
lucent, and, unless there has been a fracture with displacement
prior to healing, tends to be symmetric and without expansion
of the bone or deformity. Unicameral bone cysts are usually lined
by a thin fibrous membrane rarely covered by flattened cells of
unknown type (Fig. 7.1). Such cells are often not visible on frozen
section evaluation, but nonspecific findings including granula-
tion tissue with chronic inflammation, cholesterol crystals, and
hemosiderin deposition are usually evident (Fig. 7.1a, b). Because
of this, the diagnosis (even on permanent sections) is one of exclu-
sion and depends upon the presence of compatible radiological
and operative findings, and the absence of histological features
that might otherwise suggest an alternative diagnosis.

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Figure 7.1 A unicameral (simple) bone cyst showing a cyst wall structure
focally lined by flattened cells with underlying fibrosis and hemosiderin
deposition (a). Cholesterol clefts are also evident, more so elsewhere in
the lesion (b).
 Cystic and Vascular Lesions   101

Intraosseus Ganglion CYST

This is an intramedullary, mucin-filled lesion that usually involves
the epiphysis of select bones, most typically the tibia and femur
and can arise at any age. Similar to its soft tissue counterpart, one
may identify fibrous septae with myxoid matrix and mucin on
frozen sectioning (Fig. 7.2).

Hemangioma
Although incidental hemangiomas of bone are relatively common,
clinically symptomatic tumors account for less than 1% of primary
bone tumors. Such hemangiomas tend to present in late adult-
hood with the vertebral column being the most frequently involved
site followed by the craniofacial skeleton and metaphyses of long
bones. Hemangioma often appears on conventional radiographs
as a vertically striate, “corduroy pattern” lesion in intact verte-
brae, and as a radiolucent, often expansive lesion in long bones.
Histologically, it is composed of capillary sized or cavernous ves-
sels that permeate the marrow and are lined by bland endothelial
cells (Fig. 7.3). It should be noted that this lesion is closely related
to lymphangioma and it sometimes very difficult to distinguish
between the two even on permanent sections without the use of
immunohistochemistry.

Figure 7.2 Intraosseous ganglion cyst showing bland fibrous septa and
mucinous fluid.
102   Frozen Section Library: Bone

Figure 7.3 An example of an intraosseus hemangioma showing endothelial-

lined vascular spaces.

Angiosarcoma and Hemangioendothelioma

These two primary vascular neoplasms account for less than 1% of
all bone tumors. Although they may present at any age group, the
peak incidence is in young adulthood. They constitute a spectrum
of lesions ranging from locally destructive, indolent tumors with a
good response to surgery or local radiation to poorly differentiated
malignant tumors with a high-metastatic rate. Most tumors are
radiolucent with poor margination; however, a sclerotic rim is
occasionally identified. While angiosarcomas are often solitary,
hemangioendotheliomas tend to present as multifocal lesions in
the same bone or in the same limb and, as such, may be mistaken
for skeletal metastases. Histologically, angiosarcomas are usually
characterized by the presence of irregularly anastomosing vascular
channels lined by highly atypical endothelial cells, but, as do some
hemangioendotheliomas, may only appear as aggregates or sheets
of polyhedral or spindle cells without readily identified vascular
spaces, especially on frozen sections (Fig. 7.4). The presence of cords,
 Cystic and Vascular Lesions   103

Figure 7.4 A case of spindle-cell hemangioendothelioma in which frozen

sections (a, b) showed a cellular spindle-cell proliferation. The diagnosis
was deferred. The vascular nature of the lesion became apparent on per-
manent sections (c, d).

nests, or sheets of plump vacuolated cells (±  intracytoplasmic

red blood cells), especially when the characteristic extracellular
myxoid/hyalinized stroma is present, should suggest epithelioid
hemangioendothelioma.
104   Frozen Section Library: Bone

Figure 7.4 (continued)

Chapter 8
Epithelial Lesions

Introduction
Although metastatic carcinoma represents the commonest epithe-
lial lesion that can arise in bone, there are at least two primary
bone neoplasms, namely adamantinoma and chordoma, that one
should always consider these before making a diagnosis of meta-
static carcinoma.

Adamantinoma
This tumor comprises less than 1% of malignant bone tumors with
the tibia being the most frequently involved site, followed by the
fibula or both. There is a wide age distribution but the median
age of patients is between 25 and 35 years. The lesion appears
radiolucent and predominantly intracortical but may also involve
the medullary cavity. Histologically, classic adamantinoma is com-
posed of epithelial cells having a basaloid, tubular, or squamoid
appearance; a predominantly spindle-cell pattern as well as mix-
tures of the above cell types can also be seen. A storiform fibrob-
lastic proliferation that contains variable amounts of woven or
lamellar bone may also be present. Rarely, the tumor is predomi-
nantly composed of the latter component, with only rare scattered
epithelial cells. Thus, as discussed in Chap. 4, the findings can sig-
nificantly overlap with those of osteofibrous dysplasia, with such
cases described as having an “osteofibrous dysplasia-like pattern”
or as “differentiated adamantinomas.” As noted above, the main
issue is not to misdiagnose this lesion as metastatic carcinoma
and to keep this entity in mind when a tibial/fibular lesion with
the appropriate morphology is being evaluated.

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Chordoma
Although chordomas have traditionally been thought to be derived
from notochordal remnants, they display epithelial differentiation,
hence their inclusion in this chapter. Chordomas represent 4% of
malignant bone tumors with most cases presenting after 30 years
of age; the peak incidence is between 50 and 60 years. The “ends”
of the spinal column in the axial skeleton, particularly the sacrum
and the base of the skull, are usually affected. On imaging, they
appear radiolucent with scattered calcifications; an associated soft
tissue component is also frequently present. Histologically, chor-
domas are composed of lobules of tumor in which sheets, cords,
or nests of vacuolated, eosinophilic to clear cells with abundant
cytoplasm (physaliphorous cells) are seen embedded in myxoid
matrix (Fig. 8.1). These appearances, along with the characteristic
clinical and radiological findings, are usually sufficient to point
toward the correct diagnosis during intraoperative evaluation.
Because of the presence of areas that can mimic hyaline cartilage,
however, the correct identification of so-called “chondroid” chor-
domas during frozen section evaluation (Fig. 8.2) is often more
difficult. In fact, immunohistochemistry is frequently utilized in
this situation to arrive at the correct diagnosis. Of note, the focal
presence of a high-grade sarcomatous component should not
necessarily point to an alternative diagnosis as dedifferentiated
chordomas exist.

Metastatic Carcinoma
Metastatic carcinomas are the most common tumor affecting
the skeleton. Moreover, the skeleton is the third most common
site to be involved by metastatic tumor after the lungs and liver.
Radiologically, metastatic deposits can be radiolucent, radi-
odense, or display a mixed sclerotic–lytic pattern. Given their
high incidence, one should always consider metastatic carcinoma
in the differential diagnosis of solitary or multiple bone lesions
in patients over 40 years. Apart from the fact that metastatic
carcinomas usually show evidence of epithelial differentiation,
the histology usually resembles that of the primary carcinoma.
Those of the breast (Fig. 8.3), lung (Figs. 8.4 and 8.5), prostate,
kidney (Figs. 8.6 and 8.7), and thyroid gland (Fig. 8.8) comprise
more than 80% of all bone metastases, but obviously many other
 Epithelial Lesions   107

Figure 8.1 A frozen section of a chordoma (a, b) showing cords of tumor

cells embedded in a myxoid matrix. Notice the characteristically abundant
cytoplasm of the tumor cells (b).

malignant tumors (carcinomas or otherwise) can metastasize to

the bone and be encountered intraoperatively. Although the histol-
ogy is sometimes distinctive enough to suggest the primary origin
even in the absence of a prior history (e.g., renal cell carcinoma;
Fig. 8.6), in many cases the degree of frozen section artifacts
108   Frozen Section Library: Bone

Figure 8.2 As depicted in this case, the appearances of chordoid chor-

doma on frozen sections (a, b) can significantly overlap with those of
chondrosarcoma.

(Fig. 8.9) precludes making a more definitive diagnosis other than

metastatic carcinoma. Because a prominent inflammatory, fibrob-
lastic, osteoblastic, and/or vascular response may also obscure
tumor cells, there should always be a high index of suspicion of
 Epithelial Lesions   109

Figure 8.3 Low (a) and intermediate (b) power magnifications of a meta-
static breast carcinoma within bone. Although the morphology here is cer-
tainly consistent with a breast primary, it is not sufficiently distinctive for
such a definitive diagnosis in the absence of any prior history.

metastatic disease and, in the appropriate clinical and radiological

setting, a careful search for occult neoplastic cells should always be
undertaken, supplemented as necessary by immunohistochemical
evaluation of paraffin-embedded material.
110   Frozen Section Library: Bone

Figure 8.4 The morphology of this metastatic adenocarcinoma (a, b)

also does not suggest a specific primary site. Nevertheless, the presence of
intracellular mucin is compatible with the patient’s history of a primary
mucinous adenocarcinoma of the lung.
 Epithelial Lesions   111

Figure 8.5 Another metastatic carcinoma of lung origin but here with
squamous differentiation.
112   Frozen Section Library: Bone

Figure 8.6 Although the low-power view (a) of this lesion may suggest
an inflammatory process, the clear cell nature of its component cells and
the sinusoidal vascular pattern, both of which become evident on higher
magnification (b, c), should certainly suggest a diagnosis of metastatic
clear cell renal carcinoma.
 Epithelial Lesions   113

Figure 8.6 (continued)

Figure 8.7 Another metastatic renal cell carcinoma characterized by

dense eosinophilic cytoplasm rather than clear cells.
114   Frozen Section Library: Bone

Figure 8.8 Metastatic thyroid carcinoma. The frozen section (a) displays
scattered epithelial cells with some glandular formation; however, the
presence of colloid within the glandular structures was only identified on
permanent sections (b).
 Epithelial Lesions   115

Figure 8.9 Metastatic colonic adenocarcinoma. Although suspicious

for metastatic carcinoma, the degree of crushing/frozen section artifact
present here would make this a tough diagnosis to make. In such cases,
one should not hesitate to request for additional tissue and/or defer the
diagnosis to permanent sections where immunohistochemistry or other
special studies may help in identifying the correct site of origin.
Suggested Readings

General/Broad Topics
Abdul-Karim FW, Bauer TW, Kilpatrick SE, Raymond KA, Siegal GP, for
the Association of Directors of Anatomic and Surgical Pathology.
Recommendations for the reporting of bone tumors. Hum Pathol.
2004;35(10):1173–78.
Ackerman LV. Common errors made by pathologists in the diagnosis of
bone tumors. Recent Results Cancer Res. 1976;(54):120–38.
Ayala AG, Raymond AK, Ro JY, Carrasco CH, Fanning CV, Murray JA.
Needle biopsy of primary bone lesions. M.D. Anderson experience.
Pathol Annu. 1989;24 Pt 1:219–51.
Bovée JV, Hogendoorn PC. Molecular pathology of sarcomas: concepts and
clinical implications. Virchows Arch. 2010;456(2):193–99.
Brien EW, Mirra JM, Kerr R. Benign and malignant cartilage tumors of
bone and joint: their anatomic and theoretical basis with an emphasis
on radiology, pathology and clinical biology. I. The intramedullary
cartilage tumors. Skeletal Radiol. 1997;26(6):325–53.
Bui MM, Smith P, Agresta SV, Cheong D, Letson GD. Practical issues of
intraoperative frozen section diagnosis of bone and soft tissue lesions.
Cancer Control. 2008;15(1):7–12.
Dahlin DC. Seventy-five years’ experience with frozen sections at the Mayo
Clinic. Mayo Clin Proc. 1980;55(11):721–23.
Deyrup AT, Montag AG. Epithelioid and epithelial neoplasms of bone. Arch
Pathol Lab Med. 2007;131(2):205–16.
Dorfman HD, Czerniak B. Bone cancers. Cancer. 1995;75
(1 Suppl):203–10.
Horvai A, Unni KK. Premalignant conditions of bone. J Orthop Sci.
2006;11(4):412–23.
Huvos AG. Surgical pathology of bone sarcomas. World J Surg.
1988;12(3):284–98.

117

O. Hameed et al., Frozen Section Library: Bone, Frozen Section Library,

DOI 10.1007/978-1-4419-8376-3, © Springer Science+Business Media, LLC 2011
118   Suggested Readings

Johnson LC, Vinh TN, Sweet DE. Bone tumor dynamics: an orthopedic
pathology perspective. Semin Musculoskelet Radiol. 2000;4(1):1–15.
Khuu H, Moore D, Young S, Jaffe KA, Siegal GP. Examination of tumor and
tumor-like conditions of bone. Ann Diagn Pathol. 1999;3(6):364–69.
Li S, Siegal GP. Small cell tumors of bone. Adv Anat Pathol.
2010;17(1):1–11.
Miller TT. Bone tumors and tumorlike conditions: analysis with conven-
tional radiography. Radiology. 2008;246(3):662–74.
Romeo S, Hogendoorn PC, Dei Tos AP. Benign cartilaginous tumors of
bone: from morphology to somatic and germ-line genetics. Adv Anat
Pathol. 2009;16(5):307–15.
Rubin BP, Antonescu CR, Gannon FH, Hunt JL, Inwards CY, Klein
MJ, et al. Members of the Cancer Committee. College of American
Pathologists. Protocol for the examination of specimens from patients
with tumors of bone. Arch Pathol Lab Med. 2010;134(4):e1–7.
Schiller AL. Diagnosis of borderline cartilage lesions of bone. Semin Diagn
Pathol. 1985;2(1):42–62.
Shah MS, Garg V, Kapoor SK, Dhaon BK, Gondal R. Fine-needle
aspiration cytology, frozen section, and open biopsy: relative sig-
nificance in diagnosis of musculoskeletal tumors. J Surg Orthop Adv.
2003;12(4):203–7.
Stacy GS, Mahal RS, Peabody TD. Staging of bone tumors: a review with
illustrative examples. AJR Am J Roentgenol. 2006;186(4):967–76.
Unni KK. Cartilaginous lesions of bone. J Orthop Sci. 2001;6(5):457–72.
Unni KK, Dahlin DC. Grading of bone tumors. Semin Diagn Pathol.
1984;1(3):165–72.
Weatherby RP, Unni KK. Practical aspects of handling orthopedic speci-
mens in the surgical pathology laboratory. Pathol Annu. 1982;17(Pt
2):1–31.

Aneurysmal Bone Cyst [ABC]

Campanacci M, Cervellati C, Donati U, Bertoni F. Aneurysmal bone cyst
(a study of 127 cases, 72 with longterm follow up). Ital J Orthop
Traumatol. 1976;2(3):341–53.
Cottalorda J, Bourelle S. Modern concepts of primary aneurysmal bone
cyst. Arch Orthop Trauma Surg. 2007;127(2):105–14.
Martinez V, Sissons HA. Aneurysmal bone cyst. A review of 123 cases
including primary lesions and those secondary to other bone pathol-
ogy. Cancer. 1988;61(11):2291–304.
Oliveira AM, Perez-Atayde AR, Inwards CY, Medeiros F, Derr V, Hsi BL,
et al. USP6 and CDH11 oncogenes identify the neoplastic cell in pri-
mary aneurysmal bone cysts and are absent in so-called secondary
aneurysmal bone cysts. Am J Pathol. 2004;165(5):1773–80.
Vergel De Dios AM, Bond JR, Shives TC, McLeod RA, Unni KK.
Aneurysmal bone cyst A clinicopathologic study of 238 cases. Cancer.
1992;69(12):2921–31.
 Suggested Readings   119

Benign Fibrous Histiocytoma of Bone

Bertoni F, Calderoni P, Bacchini P, Sudanese A, Baldini N, Present D,
et al. Benign fibrous histiocytoma of bone. J Bone Joint Surg Am.
1986;68(8):1225–30.
Clarke BE, Xipell JM, Thomas DP. Benign fibrous histiocytoma of bone.
Am J Surg Pathol. 1985;9(11):806–15.
Grohs JG, Nicolakis M, Kainberger F, Lang S, Kotz R. Benign fibrous his-
tiocytoma of bone: a report of ten cases and review of literature. Wien
Klin Wochenschr. 2002;114(1–2):56–63.
Hamada T, Ito H, Araki Y, Fujii K, Inoue M, Ishida O. Benign fibrous
histiocytoma of the femur: review of three cases. Skeletal Radiol.
1996;25(1):25–9.
Matsuno T. Benign fibrous histiocytoma involving the ends of long bone.
Skeletal Radiol. 1990;19(8):561–66.
Roessner A, Immenkamp M, Weidner A, Hobik HP, Grundmann E. Benign
fibrous histiocytoma of bone. Light- and electron-microscopic obser-
vations. J Cancer Res Clin Oncol. 1981;101(2):191–202.

Bizarre Parosteal Osteochondromatous Proliferations

Abramovici L, Steiner GC. Bizarre parosteal osteochondromatous prolif-
eration (Nora’s lesion): a retrospective study of 12 cases, 2 arising in
long bones. Hum Pathol. 2002;33(12):1205–10.
Campanacci DA, Guarracino R, Franchi A, Capanna R. Bizarre paro-
steal osteochondromatous proliferation (Nora’s lesion). Description
of six cases and a review of the literature. Chir Organi Mov.
1999;84(1):65–71.
deLange EE, Pope Jr TL, Fechner RE, Keats TE. Bizarre parosteal osteo-
chondromatous proliferation vs. benign florid reactive periostitis. AJR
Am J Roentgenol. 1987;148(3):650.
Meneses MF, Unni KK, Swee RG. Bizarre parosteal osteochondro-
matous proliferation of bone (Nora’s lesion). Am J Surg Pathol.
1993;17(7):691–97.
Nora FE, Dahlin DC, Beabout JW. Bizarre parosteal osteochondro-
matous proliferations of the hands and feet. Am J Surg Pathol.
1983;7(3):245–50.

Brown Tumor of Bone [Hyperparathyroidism]

Diamanti-Kandarakis E, Livadas S, Tseleni-Balafouta S, Lyberopoulos K,
Tantalaki E, Palioura H, et al. Brown tumor of the fibula: unusual pres-
entation of an uncommon manifestation. Report of a case and review
of the literature. Endocrine. 2007;32(3):345–49.
Galvin AH. Osteitis fibrosa cystica occurring in a flat bone: report of a case.
Cal State J Med. 1923;21(6):244–45.
Pavlovic S, Valyi-Nagy T, Profirovic J, David O. Fine-needle aspiration of
brown tumor of bone: cytologic features with radiologic and histologic
correlation. Diagn Cytopathol. 2009;37(2):136–39.
120   Suggested Readings

Chondroblastoma
Bertoni F, Unni KK, Beabout JW, Harner SG, Dahlin DC. Chondroblastoma
of the skull and facial bones. Am J Clin Pathol. 1987;88(1):1–9.
Dahlin DC, Ivins JC. Benign chondroblastoma. A study of 125 cases.
Cancer. 1972;30(2):401–13.
Forest M, De Pinieux G. Chondroblastoma and its differential diagnosis.
Ann Pathol. 2001;21(6):468–78.
Huvos AG, Marcove RC. Chondroblastoma of bone. A critical review. Clin
Orthop Relat Res. 1973;(95):300–12.
Marcove RC, Alpert M. A pathologic study of benign osteoblastoma. Clin
Orthop Relat Res. 1963;30:175–81.
Springfield DS, Capanna R, Gherlinzoni F, Picci P, Campanacci M.
Chondroblastoma. A review of seventy cases. J Bone Joint Surg Am.
1985;67(5):748–55.

[En]Chondroma
Bonnevialle P, Mansat M, Durroux R, Devallet P, Rongières M.
Chondromas of the hand. A report of thirty-five cases. Ann Chir Main.
1988;7(1):32–44.
Jones KB, Buckwalter JA, Frassica FJ, McCarthy EF. Intracortical chon-
droma: a report of two cases. Skeletal Radiol. 2006;35(5):298–301.
Lewis MM, Kenan S, Yabut SM, Norman A, Steiner G. Periosteal chon-
droma. A report of ten cases and review of the literature. Clin Orthop
Relat Res. 1990;(256):185–92.
Marcozzi G, Messinetti S. Maffucci’s syndrome in its clinical, radiological,
anatomical, pathological and pathogenetic aspects; dyschondroplasia
with multiple angiomas. Ann Ital Chir. 1956;33(6):504–33.
McFarland Jr GB, Morden ML. Benign cartilaginous lesions. Orthop Clin
North Am. 1977;8(4):737–49.
Mirra JM, Gold R, Downs J, Eckardt JJ. A new histologic approach to the
differentiation of enchondroma and chondrosarcoma of the bones.
A clinicopathologic analysis of 51 cases. Clin Orthop Relat Res.
1985;(201):214–37.
Umansky AL. Dyschondroplasia with hemangiomata (Maffucci’s syn-
drome); report of an early case with mild osseous manifestations. Bull
Hosp Joint Dis. 1946;7(1):59–68.

Chondromyxoid Fibroma
Baker AC, Rezeanu L, O’Laughlin S, Unni K, Klein MJ, Siegal GP.
Juxtacortical chondromyxoid fibroma of bone: a unique variant: a case
study of 20 patients. Am J Surg Pathol. 2007;31(11):1662–68.
Jaffe HL, Lichtenstein L. Chondromyxoid fibroma of bone; a distinctive
benign tumor likely to be mistaken especially for chondrosarcoma.
Arch Pathol. 1948;45(4):541–51.
Nielsen GP, Keel SB, Dickersin GR, Selig MK, Bhan AK, Rosenberg AE.
Chondromyxoid fibroma: a tumor showing myofibroblastic, myo-
chondroblastic, and chondrocytic differentiation. Mod Pathol. 1999;
12(5):514–17.
 Suggested Readings   121

Rahimi A, Beabout JW, Ivins JC, Dahlin DC. Chondromyxoid fibroma:

a clinicopathologic study of 76 cases. Cancer. 1972;30(3):726–36.
Wu CT, Inwards CY, O’Laughlin S, Rock MG, Beabout JW, Unni KK.
Chondromyxoid fibroma of bone: a clinicopathologic review of 278
cases. Hum Pathol. 1998;29(5):438–46.
Yamaguchi T, Dorfman HD. Radiographic and histologic patterns of calcifica-
tion in chondromyxoid fibroma. Skeletal Radiol. 1998;27(10):559–64.
Zillmer DA, Dorfman HD. Chondromyxoid fibroma of bone: thirty-six cases
with clinicopathologic correlation. Hum Pathol. 1989;20(10):952–64.

Chondrosarcoma
Bjornsson J, Unni KK, Dahlin DC, Beabout JW, Sim FH. Clear cell chond-
rosarcoma of bone. Observations in 47 cases. Am J Surg Pathol. 1984;
8(3):223–30.
Chow WA. Update on chondrosarcomas. Curr Opin Oncol. 2007;19(4):
371–76.
Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondrosar-
coma of bone: a clinicopathologic analysis with emphasis on histologic
grading. Cancer. 1977;40(2):818–31.
Frassica FJ, Unni KK, Beabout JW, Sim FH. Dedifferentiated chondro­
sarcoma. A report of the clinicopathological features and treatment of
seventy-eight cases. J Bone Joint Surg Am. 1986;68(8):1197–205.
Gitelis S, Bertoni F, Picci P, Campanacci M. Chondrosarcoma of bone. The
experience at the Istituto Ortopedico Rizzoli. J Bone Joint Surg Am.
1981;63(8):1248–57.
Lichtenstein L, Jaffe HL. Chondrosarcoma of bone. Am J Pathol.
1943;19(4):553–89.
Pritchard DJ, Lunke RJ, Taylor WF, Dahlin DC, Medley BE.
Chondrosarcoma: a clinicopathologic and statistical analysis. Cancer.
1980;45(1):149–57.
Skeletal Lesions Interobserver Correlation among Expert Diagnosticians
(SLICED) Study Group. Reliability of histopathologic and radiologic
grading of cartilaginous neoplasms in long bones. J Bone Joint Surg
Am. 2007;89(10):2113–23.
Unni KK, Dahlin DC, Beabout JW, Sim FH. Chondrosarcoma: clear-
cell variant. A report of sixteen cases. J Bone Joint Surg Am.
1976a;58(5):676–83.

Chordoma
Chambers PW, Schwinn CP. Chordoma. A clinicopathologic study of
metastasis. Am J Clin Pathol. 1979;72(5):765–76.
Chugh R, Tawbi H, Lucas DR, Biermann JS, Schuetze SM, Baker LH.
Chordoma: the nonsarcoma primary bone tumor. Oncologist. 2007;
12(11):1344–50.
Dahlin DC, Unni KK. Chordoma. Arch Pathol Lab Med. 1994;
118(6):596–97.
Pamir MN, Ozduman K. Tumor-biology and current treatment of skull-
base chordomas. Adv Tech Stand Neurosurg. 2008;33:35–129.
122   Suggested Readings

Riopel C, Michot C. Chordomas. Ann Pathol. 2007;27(1):6–15.

Rosenberg AE, Bhan AK, Lee JM. Chondroid chordoma. Am J Clin Pathol.
1995;104(4):484.
Sundaresan N, Galicich JH, Chu FC, Huvos AG. Spinal chordomas.
J Neurosurg. 1979;50(3):312–19.

Ewing’s Sarcoma/PNET
Askin FB, Rosai J, Sibley RK, Dehner LP, McAlister WH. Malignant
small cell tumor of the thoracopulmonary region in childhood: a
distinctive clinicopathologic entity of uncertain histogenesis. Cancer.
1979;43(6):2438–51.
Bacci G, Longhi A, Ferrari S, Mercuri M, Versari M, Bertoni F. Prognostic
factors in non-metastatic Ewing’s sarcoma tumor of bone: an analy-
sis of 579 patients treated at a single institution with adjuvant or
neoadjuvant chemotherapy between 1972 and 1998. Acta Oncol.
2006;45(4):469–75.
Iwamoto Y. Diagnosis and treatment of Ewing’s sarcoma. Jpn J Clin Oncol.
2007;37(2):79–89.
Kissane JM, Askin FB, Foulkes M, Stratton LB, Shirley SF. Ewing’s sarcoma
of bone: clinicopathologic aspects of 303 cases from the Intergroup
Ewing’s Sarcoma Study. Hum Pathol. 1983;14(9):773–79.
Lichtenstein L, Jaffe HL. Ewing’s sarcoma of bone. Am J Pathol.
1947;23(1):43–77.
Llombart-Bosch A, Machado I, Navarro S, Bertoni F, Bacchini P,
Alberghini M, et al. Histological heterogeneity of Ewing’s sarcoma/
PNET: an immunohistochemical analysis of 415 genetically confirmed
cases with clinical support. Virchows Arch. 2009;455(5):397–411.
Maheshwari AV, Cheng EY. Ewing sarcoma family of tumors. J Am Acad
Orthop Surg. 2010;18(2):94–107.
Maygarden SJ, Askin FB, Siegal GP, Gilula LA, Schoppe J, Foulkes M,
et al. Ewing sarcoma of bone in infants and toddlers. A clinico­
pathologic report from the Intergroup Ewing’s Study. Cancer.
1993;71(6):2109–18.
Terrier P, Llombart-Bosch A, Contesso G. Small round blue cell tumors in
bone: prognostic factors correlated to Ewing’s sarcoma and neuroecto-
dermal tumors. Semin Diagn Pathol. 1996;13(3):250–57.
Ushigome S, Shimoda T, Nikaido T, Nakamori K, Miyazawa Y, Shishikura A,
et al. Primitive neuroectodermal tumors of bone and soft tissue. With
reference to histologic differentiation in primary or metastatic foci.
Acta Pathol Jpn. 1992;42(7):483–93.
Wilkins RM, Pritchard DJ, Burgert Jr EO, Unni KK. Ewing’s sarcoma of
bone. Experience with 140 patients. Cancer. 1986;58(11):2551–55.

Fibrosarcoma
Bertoni F, Capanna R, Calderoni P, Patrizia B, Campanacci M. Primary
central (medullary) fibrosarcoma of bone. Semin Diagn Pathol.
1984;1(3):185–98.
 Suggested Readings   123

Dahlin DC, Ivins JC. Fibrosarcoma of bone. A study of 114 cases. Cancer.
1969;23(1):35–41.
Huvos AG, Higinbotham NL. Primary fibrosarcoma of bone. A clinico-
pathologic study of 130 patients. Cancer. 1975;35(3):837–47.
Papagelopoulos PJ, Galanis EC, Trantafyllidis P, Boscainos PJ, Sim FH,
Unni KK. Clinicopathologic features, diagnosis, and treatment of fib-
rosarcoma of bone. Am J Orthop. 2002;31(5):253–57.

Fibrous Dysplasia
Chapurlat RD, Orcel P. Fibrous dysplasia of bone and McCune-Albright
syndrome. Best Pract Res Clin Rheumatol. 2008;22(1):55–69.
Jaffe HL. Fibrous dysplasia of bone. Bull NY Acad Med. 1946;22(11):588–
604.
Jhala DN, Eltoum I, Carroll AJ, Lopez-Ben R, Lopez-Terrada D, Rao PH,
et al. Osteosarcoma in a patient with McCune-Albright syndrome and
Mazabraud’s syndrome: a case report emphasizing the cytological and
cytogenetic findings. Hum Pathol. 2003;34(12):1354–57.
Kyriakos M, McDonald DJ, Sundaram M. Fibrous dysplasia with car-
tilaginous differentiation (“fibrocartilaginous dysplasia”): a review,
with an illustrative case followed for 18 years. Skeletal Radiol.
2004;33(1):51–62.
Pollandt K, Engels C, Kaiser E, Werner M, Delling G. Gs alpha gene muta-
tions in monostotic fibrous dysplasia of bone and fibrous dysplasia-like
low-grade central osteosarcoma. Virchows Arch. 2001;439(2):170–75.
Riminucci M, Robey PG, Bianco P. The pathology of fibrous dysplasia and
the McCune-Albright syndrome. Pediatr Endocrinol Rev. 2007;4 Suppl
4:401–11.

Giant Cell Reparative Granuloma/Solid Variant ABC

Auclair PL, Cuenin P, Kratochvil FJ, Slater LJ, Ellis GL. A clinical and
histomorpho logic comparison of the central giant cell granuloma and
the giant cell tumor. Oral Surg Oral Med Oral Pathol. 1988;66(2):197–
208.
Ilaslan H, Sundaram M, Unni KK. Solid variant of aneurysmal bone cysts
in long tubular bones: giant cell reparative granuloma. AJR Am J
Roentgenol. 2003;180(6):1681–87.
Ratner V, Dorfman HD. Giant-cell reparative granuloma of the hand and
foot bones. Clin Orthop Relat Res. 1990;260:251–58.
Sanerkin NG, Mott MG, Roylance J. An unusual intraosseous lesion
with fibroblastic, osteoclastic, osteoblastic, aneurysmal and fibro-
myxoid elements. “Solid” variant of aneurysmal bone cyst. Cancer.
1983;51(12):2278–86.
Wold LE, Dobyns JH, Swee RG, Dahlin DC. Giant cell reaction (giant cell
reparative granuloma) of the small bones of the hands and feet. Am J
Surg Pathol. 1986;10(7):491–96.
Yamaguchi T, Dorfman HD. Giant cell reparative granuloma: a com-
parative clinicopathologic study of lesions in gnathic and extragnathic
sites. Int J Surg Pathol. 2001;9(3):189–200.
124   Suggested Readings

Giant Cell Tumor of Bone

Aegerter EE. Giant cell tumor of bone: a critical survey. Am J Pathol.
1947;23(2):283–97.
Campanacci M, Baldini N, Boriani S, Sudanese A. Giant-cell tumor of
bone. J Bone Joint Surg Am. 1987;69(1):106–14.
Cummins CA, Scarborough MT, Enneking WF. Multicentric giant cell
tumor of bone. Clin Orthop Relat Res. 1996;(322):245–52.
Dahlin DC. Caldwell lecture. Giant cell tumor of bone: highlights of 407
cases. AJR Am J Roentgenol. 1985;144(5):955–60.
Gupta R, Seethalakshmi V, Jambhekar NA, Prabhudesai S, Merchant N,
Puri A, et al. Clinicopathologic profile of 470 giant cell tumors of
bone from a cancer hospital in western India. Ann Diagn Pathol.
2008;12(4):239–48.
Lichtenstein L. Giant-cell tumor of bone; current status of problems in
diagnosis and treatment. J Bone Joint Surg Am. 1951;33(A:1):143–50.
Wülling M, Engels C, Jesse N, Werner M, Delling G, Kaiser E. The
nature of giant cell tumor of bone. J Cancer Res Clin Oncol.
2001;127(8):467–74.
Wold LE, Swee RG. Giant cell tumor of the small bones of the hands and
feet. Semin Diagn Pathol. 1984;1(3):173–84.

Hemangioma/Hemangioendothelioma/Angiosarcoma of Bone
Dorfman HD, Steiner GC, Jaffe HL. Vascular tumors of bone. Hum Pathol.
1971;2(3):349–76.
Evans HL, Raymond AK, Ayala AG. Vascular tumors of bone: a study of
17 cases other than ordinary hemangioma, with an evaluation of the
relationship of hemangio endothelioma of bone to epithelioid heman-
gioma, epithelioid hemangioendothel ioma, and high-grade angiosar-
coma. Hum Pathol. 2003;34(7):680–89.
Kleer CG, Unni KK, McLeod RA. Epithelioid hemangioendothelioma of
bone. Am J Surg Pathol. 1996;20(11):1301–11.
Nielsen GP, Srivastava A, Kattapuram S, Deshpande V, O’Connell JX,
Mangham CD, et al. Epithelioid hemangioma of bone revisited: a study
of 50 cases. Am J Surg Pathol. 2009;33(2):270–77.
O’Connell JX, Nielsen GP, Rosenberg AE. Epithelioid vascular tumors
of bone: a review and proposal of a classification scheme. Adv Anat
Pathol. 2001;8(2):74–82.
Tsuneyoshi M, Dorfman HD, Bauer TW. Epithelioid hemangioendothe-
lioma of bone. A clinicopathologic, ultrastructural, and immunohisto-
chemical study. Am J Surg Pathol. 1986;10(11):754–64.
Unni KK, Ivins JC, Beabout JW, Dahlin DC. Hemangioma, hemangioperi-
cytoma, and hemangioendothelioma (angiosarcoma) of bone. Cancer.
1971;27(6):1403–14.
Wold LE, Unni KK, Beabout JW, Ivins JC, Bruckman JE, Dahlin DC.
Hemangioendothelial sarcoma of bone. Am J Surg Pathol. 1982;6(1):
59–70.
 Suggested Readings   125

Langerhans’ Cell Histiocytosis

Egeler RM, D’Angio GJ. Langerhans cell histiocytosis. J Pediatr.
1995;127(1):1–11.
Favara BE, McCarthy RC, Mierau GW. Histiocytosis X. Hum Pathol.
1983;14(8):663–76.
Jaffe R. Pathology of histiocytosis X. Perspect Pediatr Pathol.
1987;9:4–47.
Kilpatrick SE, Wenger DE, Gilchrist GS, Shives TC, Wollan PC, Unni
KK. Langerhans’ cell histiocytosis (histiocytosis X) of bone. A clin-
icopathologic analysis of 263 pediatric and adult cases. Cancer.
1995;76(12):2471–84.
Lichtenstein L. Histiocytosis X (eosinophilic granuloma of bone, Letterer-
Siwe disease, and Schueller-Christian disease). Further observations
of pathological and clinical importance. J Bone Joint Surg Am.
1964;46:76–90.
Lieberman PH, Jones CR, Steinman RM, Erlandson RA, Smith J, Gee T,
et al. Langerhans cell (eosinophilic) granulomatosis. A clinicopatho-
logic study encompassing 50 years. Am J Surg Pathol. 1996;20(5):
519–52.
Osband ME, Histiocytosis X. Langerhans’ cell histiocytosis. Hematol Oncol
Clin North Am. 1987;1(4):737–51.
Wester SM, Beabout JW, Unni KK, Dahlin DC. Langerhans’ cell granu-
lomatosis (histiocytosis X) of bone in adults. Am J Surg Pathol.
1982;6(5):413–26.

Leiomyosarcoma of Bone
Adelani MA, Schultenover SJ, Holt GE, Cates JM. Primary leiomyosar-
coma of extragnathic bone: clinicopathologic features and reevalua-
tion of prognosis. Arch Pathol Lab Med. 2009;133(9):1448–56.
Antonescu CR, Erlandson RA, Huvos AG. Primary leiomyosarcoma of
bone: a clinicopathologic, immunohistochemical, and ultrastruc-
tural study of 33 patients and a literature review. Am J Surg Pathol.
1997;21(11):1281–94.
Berlin O, Angervall L, Kindblom LG, Berlin IC, Stener B. Primary leiomy-
osarcoma of bone. A clinical, radiographic, pathologic-anatomic, and
prognostic study of 16 cases. Skeletal Radiol. 1987;16(5):364–76.
Khoddami M, Bedard YC, Bell RS, Kandel RA. Primary leiomyosarcoma
of bone: report of seven cases and review of the literature. Arch Pathol
Lab Med. 1996;120(7):671–75.
Peoc’h M, Vitetta F, Girard MH, Roux JJ, Plaweski S, Barnoud R, et al.
Primary bone leiomyosarcoma. Anatomo-clinical case with immuno-
histochem istry study and review of the literature. Arch Anat Cytol
Pathol. 1997;45(1):28–36.
Young MP, Freemont AJ. Primary leiomyosarcoma of bone. Histopathology.
1991;19(3):257–62.
126   Suggested Readings

Lymphoma of Bone
Bhagavathi S, Fu K. Primary bone lymphoma. Arch Pathol Lab Med.
2009;133(11):1868–71.
Gill P, Wenger DE, Inwards DJ. Primary lymphomas of bone. Clin
Lymphoma Myeloma. 2005;6(2):140–42.
Kitsoulis P, Vlychou M, Papoudou-Bai A, Karatzias G, Charchanti A,
Agnantis NJ, et al. Primary lymphomas of bone. Anticancer Res.
2006a;26((1A)):325–37.
O’Neill J, Finlay K, Jurriaans E, Friedman L. Radiological manifestations
of skeletal lymphoma. Curr Probl Diagn Radiol. 2009;38(5):228–36.
Ostrowski ML, Inwards CY, Strickler JG, Witzig TE, Wenger DE, Unni KK.
Osseous Hodgkin disease. Cancer. 1999;85(5):1166–78.
Pettit CK, Zukerberg LR, Gray MH, Ferry JA, Rosenberg AE, Harmon DC,
et al. Primary lymphoma of bone. A B-cell neoplasm with a high fre-
quency of multilobated cells. Am J Surg Pathol. 1990;14(4):329–34.

Malignant Fibrous Histiocytoma of Bone

Capanna R, Bertoni F, Bacchini P, Bacci G, Guerra A, Campanacci M.
Malignant fibrous histiocytoma of bone. The experience at the Rizzoli
Institute: report of 90 cases. Cancer. 1984;54(1):177–87.
Huvos AG, Heilweil M, Bretsky SS. The pathology of malignant fibrous
histiocytoma of bone. A study of 130 patients. Am J Surg Pathol.
1985;9(12):853–71.
Little DG, McCarthy SW. Malignant fibrous histiocytoma of bone: the
experience of the New South Wales Bone Tumour Registry. Aust N Z J
Surg. 1993;63(5):346–51.
McCarthy EF, Matsuno T, Dorfman HD. Malignant fibrous histiocytoma of
bone: a study of 35 cases. Hum Pathol. 1979;10(1):57–70.
MaNishida J, Sim FH, Wenger DE, Unni KK. Malignant fibrous his-
tiocytoma of bone. A clinicopathologic study of 81 patients. Cancer.
1997;79(3):482–93l.
Papagelopoulos PJ, Galanis EC, Sim FH, Unni KK. Clinicopathologic fea-
tures, diagnosis, and treatment of malignant fibrous histiocytoma of
bone. Orthopedics. 2000;23(1):59–65. quiz 66–7.

Metastasis
Berrettoni BA, Carter JR. Mechanisms of cancer metastasis to bone.
J Bone Joint Surg Am. 1986;68(2):308–12.
Bubendorf L, Schöpfer A, Wagner U, Sauter G, Moch H, Willi N, et al.
Metastatic patterns of prostate cancer: an autopsy study of 1, 589
patients. Hum Pathol. 2000;31(5):578–83.
Clezardin P, Teti A. Bone metastasis: pathogenesis and therapeutic implica-
tions. Clin Exp Metastasis. 2007;24(8):599–608.
Koyama T, Hasebe T, Tsuda H, Hirohashi S, Sasaki S, Fukutomi T, et al.
Histological factors associated with initial bone metastasis of invasive
ductal carcinoma of the breast. Jpn J Cancer Res. 1999;90(3):294–300.
 Suggested Readings   127

Roudier MP, Morrissey C, True LD, Higano CS, Vessella RL, Ott SM.
Histopatho logical assessment of prostate cancer bone osteoblastic
metastases. J Urol. 2008;180(3):1154–60.
Rougraff BT, Kneisl JS, Simon MA. Skeletal metastases of unknown origin.
A prospective study of a diagnostic strategy. J Bone Joint Surg Am.
1993;75(9):1276–81.
Rubin P, Brasacchio R, Katz A. Solitary metastases: illusion versus reality.
Semin Radiat Oncol. 2006;16(2):120–30.

Myeloma/Plasmacytoma
Edwards CM, Zhuang J, Mundy GR. The pathogenesis of the bone disease
of multiple myeloma. Bone. 2008;42(6):1007–13.
Frassica FJ, Beabout JW, Unni KK, Sim FH. Myeloma of bone. Orthopedics.
1985;8(9):1184–86.
Knobel D, Zouhair A, Tsang RW, Poortmans P, Belkacémi Y, Bolla M, et al.
Prognostic factors in solitary plasmacytoma of the bone: a multicenter
Rare Cancer Network study. BMC Cancer. 2006;6:118.
Meis JM, Butler JJ, Osborne BM, Ordóñez NG. Solitary plasmacytomas
of bone and extramedullary plasmacytomas. A clinicopathologic and
immunohistochemical study. Cancer. 1987;59(8):1475–85.
Pambuccian SE, Horyd ID, Cawte T, Huvos AG. Amyloidoma of bone, a
plasma cell/plasmacytoid neoplasm. Report of three cases and review
of the literature. Am J Surg Pathol. 1997;21(2):179–86.
Roodman GD. Pathogenesis of myeloma bone disease. Leukemia.
2009;23(3):435–41.
Shaheen SP, Talwalkar SS, Medeiros LJ. Multiple myeloma and immunose-
cretory disorders: an update. Adv Anat Pathol. 2008;15(4):196–210.

Non-ossifying Fibroma/Metapheal Fibrous Defect

Bullough PG, Walley J. Fibrous cortical defect and non-ossifying fibroma.
Postgrad Med J. 1965;41(481):672–76.
Campbell CJ, Harkess J. Fibrous metaphyseal defect of bone. Surg Gynecol
Obstet. 1957;104(3):329–36.
Hau MA, Fox EJ, Cates JM, Brigman BE, Mankin HJ. Jaffe-Campanacci
syndrome. A case report and review of the literature. J Bone Joint Surg
Am. 2002;84-A(4):634–38.
Mankin HJ, Trahan CA, Fondren G, Mankin CJ. Non-ossifying fibroma,
fibrous cortical defect and Jaffe-Campanacci syndrome: a biologic and
clinical review. Chir Organi Mov. 2009;93(1):1–7.

Osteoblastoma
Baker AC, Rezeanu L, Klein MJ, Pitt MJ, Buecker P, Hersh JH, et al.
Aggressive osteoblastoma: a case report involving a unique chromo-
somal aberration. Int J Surg Pathol. 2010;18(3):219–24.
Berry M, Mankin H, Gebhardt M, Rosenberg A, Hornicek F. Osteoblastoma:
a 30-year study of 99 cases. J Surg Oncol. 2008;98(3):179–83.
128   Suggested Readings

Della Rocca C, Huvos AG. Osteoblastoma: varied histological presenta-

tions with a benign clinical course. An analysis of 55 cases. Am J Surg
Pathol. 1996;20(7):841–50.
McLeod RA, Dahlin DC, Beabout JW. The spectrum of osteoblastoma. AJR
Am J Roentgenol. 1976;126(2):321–25.
Papagelopoulos PJ, Galanis EC, Sim FH, Unni KK. Clinicopathologic
features, diagnosis, and treatment of osteoblastoma. Orthopedics.
1999;22(2):244–47.
Ruggieri P, McLeod RA, Unni KK, Sim FH. Osteoblastoma. Orthopedics.
1996;19(7):621–24.
Zon Filippi R, Swee RG, Krishnan Unni K. Epithelioid multinodular oste-
oblastoma: a clinicopathologic analysis of 26 cases. Am J Surg Pathol.
2007;31(8):1265–68.

Osteochondroma
Bovée JV. Multiple osteochondromas. Orphanet J Rare Dis. 2008;3:3.
Kitsoulis P, Galani V, Stefanaki K, Paraskevas G, Karatzias G, Agnantis NJ,
et al. Osteochondromas: review of the clinical, radiological and patho-
logical features. In Vivo. 2008;22(5):633–46.
Porter DE, Simpson AH. The neoplastic pathogenesis of solitary and mul-
tiple osteochondromas. J Pathol. 1999;188(2):119–25.

Osteoid Osteoma
Gitelis S, Schajowicz F. Osteoid osteoma and osteoblastoma. Orthop Clin
North Am. 1989;20(3):313–25.
Greenspan A. Benign bone-forming lesions: osteoma, osteoid osteoma, and
osteoblastoma. Clinical, imaging, pathologic, and differential consid-
erations. Skeletal Radiol. 1993;22(7):485–500.
Jaffe HL. Osteoid-osteoma. Proc R Soc Med. 1953;46(12):1007–12.
Kitsoulis P, Mantellos G, Vlychou M. Osteoid osteoma. Acta Orthop Belg.
2006b;72(2):119–25.
O’Connell JX, Nanthakumar SS, Nielsen GP, Rosenberg AE. Osteoid
osteoma: the uniquely innervated bone tumor. Mod Pathol.
1998;11(2):175–80.

Osteosarcoma
Antonescu CR, Huvos AG. Low-grade osteogenic sarcoma arising
in medullary and surface osseous locations. Am J Clin Pathol.
2000;114(Suppl):S90–S103.
Ayala AG, Ro JY, Papadopoulos NK, Raymond AK, Edeiken J. Small cell
osteosarcoma. Cancer Treat Res. 1993;62:139–49.
Huvos AG, Rosen G, Bretsky SS, Butler A. Telangiectatic osteogenic sarcoma:
a clinicopathologic study of 124 patients. Cancer. 1982;49(8):1679–89.
Klein MJ, Siegal GP. Osteosarcoma: anatomic and histologic variants. Am
J Clin Pathol. 2006;125(4):555–81.
Nakajima H, Sim FH, Bond JR, Unni KK. Small cell osteosarcoma of bone.
Review of 72 cases. Cancer. 1997;79(11):2095–106.
 Suggested Readings   129

Rosen G, Caparros B, Huvos AG, Kosloff C, Nirenberg A, Cacavio A, et al.

Preoperative chemotherapy for osteogenic sarcoma: selection of post-
operative adjuvant chemotherapy based on the response of the primary
tumor to preoperative chemotherapy. Cancer. 1982;49(6):1221–30.
Sheth DS, Yasko AW, Raymond AK, Ayala AG, Carrasco CH, Benjamin RS,
et al. Conventional and dedifferentiated parosteal osteosarcoma.
Diagnosis, treatment, and outcome. Cancer. 1996;78(10):2136–45.
Unni KK, Dahlin DC. Osteosarcoma: pathology and classification. Semin
Roentgenol. 1989;24(3):143–52.
Unni KK, Dahlin DC, Beabout JW. Periosteal osteogenic sarcoma. Cancer.
1976b;37(5):2476–85.
Unni KK, Dahlin DC, Beabout JW, Ivins JC. Parosteal osteogenic sarcoma.
Cancer. 1976c;37(5):2466–75.
Unni KK, Dahlin DC, McLeod RA, Pritchard DJ. Intraosseous well-differ-
entiated osteosarcoma. Cancer. 1977;40(3):1337–47.

Unicameral/Solitary Bone Cyst

Boseker EH, Bickel WH, Dahlin DC. A clinicopathologic study of simple
unicameral bone cysts. Surg Gynecol Obstet. 1968;127(3):550–60.
Capanna R, Campanacci DA, Manfrini M. Unicameral and aneurysmal
bone cysts. Orthop Clin North Am. 1996;27(3):605–14.
Harnet JC, Lombardi T, Klewansky P, Rieger J, Tempe MH, Clavert JM.
Solitary bone cyst of the jaws: a review of the etiopathogenic hypoth-
eses. J Oral Maxillofac Surg. 2008;66(11):2345–48.
Index

A characteristic symptoms, 10–11

Adamantinoma, 105 nidus, 11, 12
Aneurysmal bone cyst (ABC) treatment, 11
chondroblastoma, 35, 75 osteoma, 10
dedifferentiated osteosarcoma
chondrosarcoma, 79 hyperchromasia, 17, 20
osteosarcomas, 75, 79 interrupted periosteal reaction,
primary, 73–75 14, 17
secondary, 76–78 irregular lace-like osteoid
Angiosarcoma, 102–104 deposition, 17, 18
lower tibia, 17
B low-grade central
Benign fibrous histiocytoma osteosarcoma, 19–23
(BFH), 50, 51, 53, 56 nuclear atypia, 17, 20
Bone/osteoid producing lesions Paget’s disease, 14
fracture callus parosteal and periosteal
endochondral ossification, 6, 8 osteosarcoma, 23
orderly trabecular pattern, 9–10 sheet-like pattern of osteoid
osteoid deposition, 9 deposition, 17, 19
scattered osteoclasts, 6–7 sites of involvement, 14
subacute fractures, 6 small cell osteosarcoma, 22
osteoblastoma spindle cells, 17, 21
expansile lesion, 11–12 subclassification, 15, 16
histological features, 11 telangiectatic osteosarcoma,
hypercellular nature, 11, 16 20–21
monotonous cell population, primary/secondary, 6
11, 15 reactive bone, 10, 11
nuclear pleomorphism, 14 woven vs. lamellar, 5–6
osteoid osteoma Borderline cartilage tumor, 42–43

131
132   Index

C Langerhans cell histiocytosis, 35

Cartilaginous lesions lucent lesion, apophysis, 32–34
chondroblastoma Chondromas
aneurysmal bone cyst, 35 enchondromas, 28–31
chicken wire calcification, 32 enchondromatosis, 31–32
fibrochondroid islands, 32–34 periosteal chondromas, 31
giant cell tumor, 34 Chondromyxoid fibroma (CMF)
Langerhans cell histiocytosis, 35 chondroblastic osteosarcoma,
lucent lesion, apophysis, 37–38
32–34 cytomorphology, 37
chondromas eccentric osteolytic lesion, 36
enchondromas, 28–31 lobular pattern, 35
enchondromatosis, 31–32 spindled and stellate cells,
periosteal chondromas, 31 35–37
chondromyxoid fibroma Chondrosarcoma
chondroblastic osteosarcoma, borderline cartilage tumor,
37–38 42, 43
cytomorphology, 37 clear cell chondrosarcoma, 46
eccentric osteolytic lesion, 36 dedifferentiated
lobular pattern, 35 chondrosarcoma, 43–45
spindled and stellate cells, grading, 40–42
35–36 mesenchymal chondrosarcoma,
chondrosarcoma 44, 46
borderline cartilage tumor, proximal fibula, 39
42, 43 sites of involvement, 38
clear cell chondrosarcoma, 46 Chordoid chordoma, 106, 108
dedifferentiated Chordoma
chondrosarcoma, 43–45 chordoid chordoma, 106, 108
grading, 40–424 myxoid matrix, 106, 107
mesenchymal Clear cell chondrosarcoma, 46
chondrosarcoma, 44, 46 CMF. See Chondromyxoid
proximal fibula, 39 fibroma
sites of involvement, 38 COF. See Central ossifying
elastic cartilage, 25 fibroma
fibrocartilage, 25 Colonic adenocarcinoma,
osteochondroma, 26–28 metastatic, 115
Cemento-ossifying fibroma, 64 Cystic and vascular lesions
Central ossifying fibroma (COF) angiosarcoma, 102–104
cementifying fibroma, 64 hemangioendothelioma,
differential diagnosis, 64 102–104
psammomatous type, 64–65 hemangioma
Chondroblastoma, 75 corduroy pattern lesion, 101
fibrochondroid islands and intraosseus hemangioma, 102
chicken wire calcification, intraosseus ganglion cyst, 101
32–34 unicameral bone cyst,
histologic differential diagnosis 99–100
aneurysmal bone cyst, 35
chondromyxoid fibroma, D
34, 35 Dedifferentiated chondrosarcoma,
giant cell tumor, 34 43–45
 Index   133

E Fracture callus
Enchondromas, 28–31 endochondral ossification, 6, 8
Enchondromatosis, 31–32 orderly trabecular pattern, 9–10
Epithelial lesions osteoid deposition, 9
adamantinoma, 105 scattered osteoclasts, 6–7
chordoma subacute fractures, 6
chordoid chordoma,
106, 108 G
myxoid matrix, 106, 107 Giant cell reparative granuloma
metastatic carcinoma (See (GCRG)
Metastatic carcinoma) characteristic radiographic
Ewing sarcoma/primitive features, 80
neuroectodermal tumor extragnathic sites, 78
(ES/PNET), 85–87 histological differential
diagnosis, 83
F low-power microscopic
Fibrosarcoma, 56 examination, 80
Fibrous and fibrohistiocytic osteoclast-like multinucleated
lesions giant cells, 80–82
benign fibrous histiocytoma, 50, Giant cell-rich lesions
51, 53, 56 aneurysmal bone cyst
central ossifying fibroma chondroblastoma, 75
cementifying fibroma, 64 dedifferentiated
differential diagnosis, 64 chondrosarcoma, 79
psammomatous type, 64–65 osteosarcomas, 75, 79
clinical behaviors, 47 primary, 73–75
fibrosarcoma, 56 secondary, 76–78
fibrous dysplasia, 58–60 clinical and radiologic
malignant fibrous histiocytoma, characteristics, 67
56, 57 giant cell reparative granuloma
non-ossifying fibromas characteristic radiographic
cellular spindle cell features, 80
proliferation, 48–50 extragnathic sites, 78
differential diagnosis, 53 histological differential
Jaffee-Campanacci diagnosis, 83
syndrome, 48 low-power microscopic
multilocular, expansile, lytic examination, 80
lesion, 48–50 osteoclast-like multinucleated
multinucleated giant cells, 48 giant cells, 80–82
secondary aneurysmal bone giant cell tumor
cyst, 48, 52 intravascular invasion, 72
osteofibrous dysplasia, 58, long bones, 68
61–63 mitotic figures, 68, 71
Fibrous dysplasia (FD) multinuclear and mononuclear
reproducible genetic cells, 68–70
abnormalities, 58 osteoclastoma, 67
fibro-osseous lesion, 59 plugs of tumor cells, 68, 72
lytic lesions, 59 radiologic–pathologic
monostotic form, 58 correlation, 69
polyostotic form, 58 spindled cells, 72
134   Index

Giant cell tumor (GCT) N

chondroblastoma, 32–34 Noninherited developmental
intravascular invasion, 72 disorder, 58
long bones, 68 Non-ossifying fibromas (NOFs)
mitotic figures, 68, 71 cellular spindle cell proliferation,
multinuclear and mononuclear 48–50
cells, 68–70 differential diagnosis, 53
osteoclastoma, 67 Jaffee-Campanacci syndrome, 48
plugs of tumor cells, 68, 72 multilocular, expansile, lytic
radiologic-pathologic lesion, 48–50
correlation, 69 multinucleated giant cells, 48
spindled cells, 72 secondary aneurysmal bone cyst,
48, 52
H
Hemangioendothelioma, O
102–104 Orthopedic pathology
Hemangioma decision tree, 3
corduroy pattern lesion, 101 diagnosis, 2–3
intraosseus hemangioma, 102 gross pathology, 1
Ossifying fibroma, 58
I Osteoblastoma
Intraosseus ganglion cyst, 101 expansile lesion, 11–12
histological features, 11
J hypercellular nature, 11, 16
Jaffee-Campanacci syndrome, 48 monotonous cell population, 11, 15
nuclear pleomorphism, 14
K Osteochondroma
Kempson-Campanacci’s disease, 58 multiple hereditary exostoses,
27–28
L Nora’s lesion, 26–27
Langerhans cell histiocytosis Osteoclastoma, 67
(LCH), 35, 96–98 Osteofibrous dysplasia (OFD), 58,
Lymphomas, 86–90 61–63
Osteoid osteoma
M characteristic symptoms, 10–11
Malignant fibrous histiocytoma nidus, 11, 12
(MFH), 56–58 treatment, 11
Mesenchymal chondrosarcoma, Osteoma, 10
44–46 Osteomyelitis
Metaphyseal fibrous defect (MFD), differential diagnostic, 93, 96
47, 48 mixed inflammatory cells, 94–95
Metastatic carcinoma new bone formation, 96
breast, 109 Osteosarcoma
colon, 115 hyperchromasia, 17, 20
lung interrupted periosteal reaction,
mucinous adenocarcinoma, 110 14, 17
squamous differentiation, 111 lower tibia, 17
renal cell, 112–113 low-grade central osteosarcoma,
thyroid gland, 106, 114 19–20
 Index   135

nuclear atypia, 20–21 S

osteoid Secondary aneurysmal bone cyst,
irregular lace-like deposition, 48, 52, 76–78
15, 18 Small cell osteosarcoma, 22
sheet-like pattern of Small/round cell lesions
deposition, 15, 19 Ewing sarcoma/primitive
Paget’s disease, 14 neuroectodermal tumor,
parosteal and periosteal 85–86
osteosarcoma, 23 Langerhans cell histiocytosis,
sites of involvement, 14 96–98
small cell osteosarcoma, lymphomas, 86–90
22, 23 osteomyelitis
spindle cells, 17, 21 differential diagnostic,
subclassification, 15 93, 96
telangiectatic osteosarcoma, mixed inflammatory cells,
20–21 94–95
new bone formation, 96
P solitary plasmacytoma and
Parosteal osteosarcoma, 23 multiple myeloma, 90–93
Periosteal chondromas, 31
Plasmacytoma, 90–93 T
Primary aneurysmal bone cyst, Telangiectatic osteosarcoma,
73–75 20–21
Psammomatous ossifying fibroma, Thyroid carcinoma, metastatic, 114
64, 65
U
R Unicameral bone cyst
Reactive bone, 10, 11 cholesterol clefts, 99–100
Renal cell carcinoma, metastatic, diagnosis, 99
112–113 flattened cells, 99–100