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8/4/2019 2011-01 Goldblum Common Morphologic Patterns
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COMMON MORPHOLOGIC PATTERNS
IN SOFT TISSUE TUMORS WITH AN EMPHASIS ON USEFUL
ANCILLARY DIAGNOSTIC TECHNIQUES
John R. Goldblum, M.D.
Chairman, Department of Anatomic PathologyCleveland ClinicProfessor of PathologyCleveland Clinic Lerner College of Medicine9500 Euclid Avenue L25Cleveland OH 44195Ph 216-444-8238Fx 216-445-2142
Common Morphologic Patterns in Soft Tissue Tumors
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Email [email protected]
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Recognizing patterns at low magnification is one of the keys to organizing differential diagnoses
in soft tissue sarcomas. Each pattern elicits a differential diagnosis, and often a combination of
light microscopic and immunohistochemical features will allow one to classify a neoplasm with a
given morphologic pattern. Below is a description of some of the more common morphologic
patterns seen in soft tissue sarcomas with some practical points on the approach to tumors with
these morphologic patterns.
MFH-Like Pattern
One of the more controversial issues in soft tissue pathology is whether a malignant fibrous
histiocytoma (MFH) is a pathologic entity or a morphologic pattern. The concept of MFH was
first introduced in the early 1960s by Dr. Stout and colleagues1,2 and was refined and accepted
as an entity in the early 1970s through the efforts of Drs. Kempson and Kyriakos.3 Thereafter,
several large studies supported the concept of MFH as a distinct clinicopathologic entity.4-6
Pleomorphic-storiform MFH is now regarded as the most common soft tissue sarcoma of
adulthood.7 However, it has become increasingly recognized that a variety of other neoplasms
may have focal MFH-like areas, and other tumors that resemble MFH in their entirety may show
some specific line of cellular differentiation through the use of immunohistochemistry or electron
microscopy. In 1986, Brooks suggested that at least a subgroup of neoplasms classified as
MFH represent a final common pathway indicative of tumor progression.8 In 1992, Fletcher
reassessed 159 cases of pleomorphic sarcoma that were classified originally as pleomorphic
MFH and found that only 13% of these tumors could not be assigned to some other specific
sarcoma category.9 Thus, in Fletcher’s opinion, if one uses a combination of morphologic,
immunophenotypic and ultrastructural data, one can almost always identify a specific line of
cellular differentiation in pleomorphic tumors resembling MFH, supporting the concept of MFH
as a morphologic pattern as opposed to a distinct clinicopathologic entity. One could also argue
that Dr. Fletcher eventually proved the point that he sought to disprove, that is, one is still left
with a subgroup of pleomorphic sarcomas that cannot be further subclassified, and thus may
truly represent MFH (as a diagnosis of exclusion). Regardless of this ongoing controversy,
which probably will never be definitively answered, the practicing pathologist is not infrequently
met with the challenge of classifying a pleomorphic malignant neoplasm, and the following
discussion raises some practical points in the approach to such tumors.
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When I encounter a soft tissue sarcoma with an MFH-like pattern, I first question whether that
could be a component of a “dedifferentiated” sarcoma, particularly when dealing with a sarcoma
in the retroperitoneum. For example, well-differentiated liposarcomas in the retroperitoneum are
typically not detected until they reach an enormous size, given the lack of space constraints for
their growth. Thus, it is not uncommon to find areas of dedifferentiation in liposarcomas in this
location, given the supposition that dedifferentiation is a time-dependent phenomenon.10
Similarly, when I encounter a lesion in the bone with an MFH-like pattern, I also consider the
possibility of that representing a portion of a dedifferentiated chondrosarcoma, as originally
described by Dahlin et al.11 Thorough sampling is often required in order to recognize the low-
grade sarcoma from which the dedifferentiated MFH-like areas arose.
More commonly, a variety of other sarcomas may have focal MFH-like areas or may be
composed virtually entirely of MFH-like areas. In both of these circumstances, it is important to
sample the tumor well and evaluate for lower grade areas that could allow for recognition of a
specific sarcoma type. For example, in most cases of pleomorphic leiomyosarcoma, one can
find lower grade areas recognizable as leiomyosarcoma that can be confirmed by
immunohistochemistry. Similarly, pleomorphic MPNST and pleomorphic rhabdomyosarcoma
may have lower grade areas that allow for their recognition. In the absence of these low-grade
areas, immunohistochemistry plays an important role in determining a specific line of cellular
differentiation. One could argue as to the necessity of this endeavor, given the similar
therapeutic and prognostic implications of all of these high-grade pleomorphic sarcomas.
However, for academic purposes, and possibly for future refinements in therapy, we attempt to
identify a specific line of cellular differentiation in all pleomorphic MFH-like sarcomas. The
following is a discussion of criteria for recognizing the various pleomorphic sarcomas.
Pleomorphic Liposarcoma
Immunohistochemistry is not necessary for recognizing this lesion. The only criterion for the
diagnosis is the presence of multivacuolated lipoblasts, defined as large cells containing
multiple punched-out intracytoplasmic vacuoles, typically indenting or scalloping an atypical
hyperchromatic nucleus. The major difficulty here is separating pleomorphic sarcomas that
infiltrate fat from those with true pleomorphic lipoblasts.
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Dedifferentiated Liposarcoma
Although it has become recently recognized that not all dedifferentiated liposarcomas have
high-grade sarcomatous areas,12 for the purposes of this discussion, the recognition of a high-
grade dedifferentiated liposarcoma requires recognition of a well-differentiated liposarcoma
either in the same neoplasm, or clearly antedating the presence of the high-grade sarcoma.
Pleomorphic MPNST
As with non-pleomorphic variants of MPNST, this tumor can be recognized when there is a
demonstrable origin from a major nerve, a demonstrable pre-existing benign peripheral nerve
sheath tumor or ultrastructural evidence of Schwann cell differentiation. S100 protein
immunoreactivity in a pleomorphic sarcoma should not be taken as definitive evidence of a
pleomorphic MPNST, as S-100 protein may be seen in a variety of other pleomorphic sarcomas.
However, S-100 protein immunoreactivity in a pleomorphic sarcoma in a patient with
neurofibromatosis may be taken as indirect evidence of that lesion being an MPNST.
Pleomorphic Leiomyosarcoma
The tumor cells tend to be arranged into more of a fascicular growth pattern, as opposed to a
storiform growth pattern typical of MFH. In addition, cells have blunt-ended vesicular nuclei,
often with a perinuclear vacuole as well as densely eosinophilic cytoplasm. One can confirm this
diagnosis by either ultrastructural or immunohistochemical (smooth muscle actin and/or desmin)
analysis.
Pleomorphic Rhabdomyosarcoma
Once one is sure that one is excluding the possibility of entrapped non-neoplastic skeletal
muscle, the presence of large cells with eosinophilic cytoplasm and cross striations should raise
the possibility of this diagnosis. Confirmation with immunohistochemical stains (muscle specific
actin, desmin, myoglobin, MyoD1 or myogenin) or ultrastructural analysis (alternating thick and
thin filaments with Z-bands) is necessary.
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Extraskeletal Osteosarcoma
The only criterion for recognizing this lesion is the presence of bone or osteoid that is produced
by cytologically malignant cells.
Probably even more important than being able to recognize a specific line of cellular
differentiation in an MFH-like tumor, one should also consider the possibility that one is dealing
with a pseudosarcoma, i.e., a non-mesenchymal malignant neoplasm that phenotypically
resembles an MFH. Certainly, melanoma should always be entertained in the differential
diagnosis, and an S-100 is probably always worth doing to exclude this diagnosis. In addition,
particularly in mucosal or organ-based MFH-like lesions, the possibility of a sarcomatoid
carcinoma should be strongly entertained and confirmed with the use of immunohistochemistry,
particularly cytokeratins.
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References1. Kauffman SL, Stout AP. Histiocytic tumors (fibrous xanthoma and histiocytoma)in children. Cancer 1961;14:469-482.
2. O’Brien JE, Stout AP. Malignant fibrous xanthomas. Cancer 1964;17:1445-1455.3. Kempson RL, Kyriakos M. Fibroxanthosarcoma of the soft tissues. A type of malignant fibrous histiocytoma. Cancer 1972;29:961-976.
4. Enjoji M, Hashimoto H, Tsuneyoshi M, Iwasaki H. Malignant fibrous histiocytoma.A clinicopathologic study of 130 cases. Acta Pathol Jpn 1980;30:727-741.5. Kearney MM, Soule EH, Ivins JC. Malignant fibrous histiocytoma. A retrospectivestudy of 167 cases. Cancer 1980;45:167-178.6. Weiss SW, Enzinger FM. Malignant fibrous histiocytoma. An analysis of 200cases. Cancer 1978;41:2250-2266.7. Enzinger FM, Weiss SW. Malignant fibrous histiocytic tumors. In: Soft TissueTumors, 3rd ed. St. Louis: C. V. Mosby, 1995.8. Brooks JJ. The significance of double phenotypic patterns and markers in humansarcomas. A new model of mesenchymal differentiation. Am J Pathol 1986;125:113-123.9. Fletcher CDM. Pleomorphic malignant fibrous histiocytoma: Fact or fiction? Acritical reappraisal based on 159 tumors diagnosed as pleomorphic sarcoma. Am J Surg
Pathol 1992;16(3):213-228.10. Weiss SW, Rao VK. Well-differentiated liposarcoma (atypical lipoma) of deep softtissue of the extremities, retroperitoneum and miscellaneous sites: A follow-up study of 92 cases with analysis of the incidence of “dedifferentiation.” Am J Surg Pathol1992;16(11):1051-1058.11. Dahlin DC, Beaubout JW. Dedifferentiation of low-grade chondrosarcomas.Cancer 1971;28:461-466.
12. Henricks WH, Chu YC, Goldblum JR, Weiss SW. Dedifferentiatedliposarcoma: A clinicopathological analysis of 155 cases with a proposal for anexpanded definition of dedifferentiation. Am J Surg Pathol 1997;21(3):271-281.
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Myxoid Soft Tissue Tumors and Tumor-Like Lesions
The pathologist need not panic when one comes across one of these lesions because these
entities can be separated from one another when one pays attention to certain key features
when evaluating these lesions. For example, evaluation of the cellularity of the lesion, as well as
the arrangement of the cells with respect to one another is absolutely critical in distinguishing
these lesions from one another. While some lesions are characterized by extremely low
cellularity (intramuscular myxoma), others are characteristically much more cellular (nodular
fasciitis). Similarly, these cells may stand apart from one another, with little cell-cell contact
(myxoid liposarcoma), or they may be arranged into nests or chains (myxoid chondrosarcoma).
Nuclear pleomorphism, although somewhat subjective, is also useful in this evaluation, given
that some lesions totally lack nuclear pleomorphism (intramuscular myxoma), whereas others
are characterized by a high degree of cytologic atypia (myxofibrosarcoma). Another often
underappreciated feature in this evaluation is the presence or absence of an underlying
vasculature. While some lesions are characteristically of low vascularity (intramuscular
myxoma), others are characterized by an intricate vascular network that allows one to recognize
the lesion as malignant (myxoid liposarcoma and myxfibrosarcoma). Occasionally, the
evaluation of the myxoid stroma using histochemical techniques may also be useful. Hyaluronic
acid and chondroitin sulfate are the most common mucosubstances found in these lesions, and
one or the other of these substances is often typical of a particular lesion. For example,
intramuscular myxoma, myxoid liposarcoma and myxofibrosarcoma are characterized by
hyaluronic acid-rich myxoid stroma, whereas myxoid chondrosarcoma and chordoma are
characterized by a chondroitin sulfate-rich myxoid stroma. Although Alcian blue (pH2.5) stains
both hyaluronic acid and chondroitin sulfate, pretreatment with hyaluronidase will result in the
loss of Alcian blue positivity if the stroma is made up of hyaluronic acid. In contrast, chondroitin
sulfate-rich stroma is hyaluronidase resistant. Benign myxoid soft tissue lesions that enter into
this differential diagnosis include nodular fasciitis, intramuscular myxoma and angiomyxoma,
among others. The malignant lesions may include myxoid liposarcoma, myxofibrosarcoma,
extra-skeletal myxoid chondrosarcoma and low-grade fibromyxoid sarcoma (Evans' tumor).
Nodular fasciitis is a self-limited, reactive lesion often mistaken for a sarcoma due to its high
cellularity, rapid growth and brisk mitotic activity.1 In Montgomery and Meis' series of 53 cases,
only 43% of the cases were correctly diagnosed, and 21% of these cases were misdiagnosed
as some type of sarcoma2. This lesion typically presents as a rapidly growing mass of short
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duration, and is most common in young patients (average age: 34 years), although essentially
any age group may be affected. The upper extremity is the most common site; other fairly
common sites include the trunk, lower extremities and head and neck region (although virtually
any superficial site in the body may be involved). Most lesions are less than 3.0 cm, but I have
seen examples as large as 6.0 cm. Most cases are subcutaneous, but some are in skeletal
muscle, causing further concern that the lesion is a sarcoma.
Histologically, nodular fasciitis has many appearances, varying dramatically in cellularity and
amount of myxoid stroma both between lesions, and within the same lesion. Most cells are
plump, immature “tissue culture” fibroblasts or myofibroblasts that show little nuclear
pleomorphism. Mitoses are characteristically numerous, but atypical mitoses are not present.
The cells are arranged into short, irregular bundles or fascicles, but never form long, sweeping
fascicles, and are deposited in a hyaluronic acid-rich myxoid matrix that occasionally forms
microcysts. Other helpful histologic features include cleft-like spaces, red blood cell
extravasation, rare giant cells and, occasionally, metaplastic bone or cartilage. In older lesions,
there is an increased amount of stromal fibrosis with a less prominent myxoid matrix.
Immunohistochemically, the majority of cells stain for smooth-muscle actin, which may be a
source of confusion if one is considering the possibility of leiomyosarcoma.2
The intramuscular myxoma typically occurs in middle-aged to elderly patients, and is extremely
rare in childhood. These lesions present as a painless, palpable fluctuant mass within the deep
soft tissues of the thigh, shoulder, buttocks or upper arm, although virtually any site may be
involved.3 In addition, lesions with similar histology can occur in a cutaneous and juxta-articular
location. Although usually solitary, multiple intramuscular myxomas have been found to be
associated with fibrous dysplasia, and generally occur in the same anatomic region as the bony
abnormalities.4 Rare patients also display melanotic pigmentation of the skin and endocrine
abnormalities (Albright's syndrome). Myxomas occurring in a cutaneous location may be
sporadic or associated with Carney's complex, characterized by an association with endocrine
abnormalities, spotty pigmentation, cardiac myxomas, and psammomatous melanoticschwannomas, inherited in an autosomal dominant manner.5 The juxta-articular myxoma is
another variant of myxoma, most commonly found in the area of the knee (90%).6 Males are
affected significantly more commonly than females, typically between the third and seventh
decades of life. In the series by Meis and Enzinger, 34% of the cases recurred, sometimes with
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multiple recurrences. Despite the tendency for these lesions to recur, these are best treated
conservatively by local excision.
Grossly, the intramuscular myxoma appears to be well-circumscribed, although a true fibrous
capsule is not present. Histologically, these lesions characteristically are of low cellularity,
composed of bland spindled or stellate cells with cytoplasmic processes. The cells tend not to
touch one another, but rather are separated by abundant myxoid stroma composed of
hyaluronic acid. Although some cells with vacuolated cytoplasm may be present and may
resemble lipoblasts, these are macrophages that have imbibed products of the myxoid stroma
resulting in cytoplasmic vacuolization. In addition, although grossly well circumscribed, there is
often some infiltration into the surrounding skeletal muscle, with entrapment of atrophic skeletal
muscle fibers. Although scattered blood vessels may be present, there is relatively little
vascularity, and the vascularity lacks the organization of many myxoid sarcomas. These lesions
are essentially cured by local excision, and have little tendency to recur, even if incompletely
excised.
Angiomyxoma (aggressive angiomyxoma) typically occurs as a large, ill-defined mass within the
pelvis, perineum, or genital tract in women.7,8 Rare cases have also been reported in men.9
Histologically, the lesion is composed of spindled or stellate cells that generally do not touch
one another, and are separated by an abundant myxoid stroma composed primarily of
hyaluronic acid. The cells lack nuclear atypia, and mitotic figures are difficult to identify. Mast
cells are frequently prominent. In addition, these lesions are characterized by a prominent
vascularity with vessels of different caliber, including thin-walled vessels and thick hyalinized
vessels. Although histologically bland, these lesions are characterized by a high rate of local
recurrence; metastases have not been reported.
Myxoid liposarcoma is the most common subtype of liposarcoma.10 This is a tumor of adult life
and typically occurs in the deep soft tissues of the extremity, especially the thigh and popliteal
region. At low power, the most striking feature is the very characteristic delicate plexiformcapillary pattern that is found throughout the neoplasm. The spindled cells between the
capillaries are primitive mesenchymal cells, and vary little from one another, without significant
nuclear pleomorphism. The cells are evenly distributed, and typically do not touch one another.
Interspersed between the primitive mesenchymal cells are the diagnostic lipoblasts, which occur
in varying numbers. By definition, a lipoblast is characterized by a sharply defined lipid droplet
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that usually pushes the nucleus to a peripheral location and indents or scallops the nucleus.
Vacuolated cells indistinguishable from lipoblasts may be found in a variety of benign and
malignant lesions. Therefore, an appropriate histologic background must be present in order to
establish that cell as a true lipoblast. Unless there is a significant round cell component, myxoid
liposarcomas are generally considered to be low-grade sarcomas.
Round cell liposarcoma is considered to be a poorly differentiated form of myxoid liposarcoma
for several reasons. First, it is not uncommon to see mixtures of both myxoid and round cell
liposarcoma within the same tumor. Furthermore, the characteristic translocation found in
myxoid liposarcoma, t(12;16)(q13;p11), is also present in round cell liposarcoma,11,12 and can be
detected by either fluorescence in-situ hybridization13,14 or polymerase chain reaction.15 At the
molecular level, this translocation results in fusion of the DDIT3 (CHOP) gene on 12q13 with the
FUS gene on 16p11.16-18 Rarely, the DDIT3 gene is fused to the N-terminal portion of the EWS
gene.19,20
It has been suggested that tumors that have “hypercellular” or “round cell” areas within an
otherwise typical myxoid liposarcoma pursue a more aggressive clinical course.21-24 However, it
is difficult to know where on the spectrum of cellularity these cases actually lie. Furthermore, it is
unknown whether there is a critical amount of these “round cell” areas that are predictive of a
worse prognosis. Smith et al studied 29 cases of myxoid/round cell liposarcoma of the
extremities and found that those patients whose tumors had greater than 5% round cell
component were more likely to develop metastases or die from their disease. 25 Round cell areas
were defined as those areas with a marked increase in cellularity in which the cells were round
and separated by little or no myxoid stroma. In these areas, the mitotic index was generally
increased, and a plexiform vascular pattern was difficult to recognize secondary to the
overgrowth of primitive round cells. In addition, transitional areas, defined as areas of increased
cellularity compared to typical myxoid liposarcoma, but in which the cells remained spindled, did
not have overlapping nuclear borders, and retained an easily discernible plexiform vascular
pattern, were not found to worsen clinical outcome in the absence of a round cell component.Kilpatrick et al. found similar findings, although they found a cut-off point of 25% round cell
component to be prognostically important by multivariate analysis.26
The myxoid variant of MFH was first characterized by Weiss and Enzinger in 1977, and was
defined as an MFH that has at least 50% of the tumor cells deposited in a hyaluronic acid-rich
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myxoid stroma.27 However, it is apparent that there is a wide spectrum of lesions ranging from
superficially located, hypocellular, low-grade myxoid lesions (low-grade myxofibrosarcoma) to
those that are more deeply located, of higher stage and more biologically aggressive. Mentzel et
al. recently evaluated the clinicopathologic features of 75 cases of so-called
myxofibrosarcoma,28 now the preferred term for this entity. Almost 70% of their cases were
superficially located, either in the dermis or subcutaneous tissues, usually on the upper or lower
extremities, and characterized by a nodular growth pattern, a myxoid matrix containing
elongated, curvilinear capillaries and spindled or stellate-shaped tumor cells with
hyperchromatic atypical nuclei. These superficially located low-grade lesions are the lesions that
are most likely to be confused with benign myxoid lesions. Some of the cases were more deeply
located and showed areas of increased cellularity and cytologic atypia, more typical of the
classic “myxoid MFH” described by Weiss and Enzinger. The latter group of lesions was
characterized by moderate cellularity in which the cells showed significant nuclear
pleomorphism and hyperchromatism, with easily identified mitotic figures. Similar to myxoid
liposarcoma, a characteristic vasculature was present throughout the neoplasm, although these
blood vessels tended to be more coarse than those seen in myxoid liposarcoma. Frequently, the
atypical cells condensed along the periphery of the blood vessels. Although the depth of the
primary lesion did not influence the incidence of local recurrence, only those neoplasms of
intermediate or high-grade metastasized. In addition, some cases of low-grade
myxofibrosarcoma progressed to higher-grade lesions in recurrences.
In 1987, Evans described a tumor that typically presents as a large, well-circumscribed mass in
the deep soft tissues, most commonly in the shoulder, thigh and inguinal region, which he
termed “low-grade fibromyxoid sarcoma.”29 Histologically, this lesion is composed of bland
spindled cells of low to moderate cellularity deposited in a fibrous and myxoid stroma. The cells
often have a swirling growth pattern and occasionally condense in a perivascular location.
Cytologically, there is little nuclear pleomorphism, and mitotic figures are difficult to identify.
Similar to other myxoid sarcomas, low-grade fibromyxoid sarcoma often has a rich, regular
vascular network that is useful in its distinction from a benign lesion. Also, despite the grosscircumscription, there is microscopic infiltration of the surrounding tissues. Of the twelve patients
described in Evans’ 1993 paper, nine had local recurrences, seven had evidence of distant
metastasis, and four died of disease.30 Some authors have also reported histologic progression
to a higher-grade lesion in recurrences.31 Low-grade fibromyxoid sarcoma (and the related
hyalinizing spindle cell tumor with giant rosettes) is characterized by a t(7;16) with fusion of the
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CREB3L2 gene on chromosome 12 with the FUS gene on chromosome 16. 32 Mertens and
colleagues reported the presence of CREB3L2-FUS fusion in 22 of 23 (96%) cases of low-grade
fibromyxoid sarcoma,33 and we utilize paraffin-embedded tissue for FISH, probing with a FUS
breakapart probe to confirm this difficult diagnosis.
Similar to myxoid liposarcoma, extraskeletal myxoid chondrosarcoma also occurs primarily in
the deep soft tissues of the extremities.34 Macroscopically, the neoplasm occurs as a
multinodular, well-circumscribed mass, which frequently shows large areas of hemorrhage.
Histologically, this is a lesion of moderate cellularity in which the cells tend to touch one another
and are arranged in small cords or strands. These cells show little nuclear pleomorphism, low
mitotic activity, and have a moderate amount of eosinophilic cytoplasm. The vascularity is not
prominent, in contrast to myxoid liposarcoma and myxofibrosarcoma. The myxoid matrix in this
case is composed of chondroitin sulfate. Immunohistochemically, these cells may be S-100
protein positive, although Dei Tos et al found that only 7 of 39 cases (18%) stained for this
antigen,35 although it is usually unnecessary to perform immunostains. In addition, this tumor
has been found to harbor a characteristic translocation, t(9;22)(q22;q12), which involves a
rearrangement of the EWS gene on 22q12 with the NR4A3 gene (formerly known was CHN or
TEC).36 The resultant NR3A3-EWS fusion transcript can be detected by RT-PCR or FISH. 37 In
the series by Meis-Kindblom et al, older patient age, larger tumor size and tumor location in the
proximal extremity or limb girdle were adverse prognostic factors identified by multivariate
analysis.38
Local recurrences and metastases were noted in 48% and 46% of patients,
respectively. Some patients had prolonged survival even after the development of metastasis,
although many of these patients eventually died as a result of tumor. Interestingly, this study did
not identify a relationship between tumor cellularity and prognosis.
In conclusion, despite the fact that numerous benign and malignant soft tissue lesions may have
a myxoid stroma, these lesions can be reliably separated from one another through the
systematic evaluation of certain parameters, in conjunction with clinical features including age,
site and rate of growth of the neoplasm, with little need for ancillary studies. However, molecular testing for translocations has become increasingly important.
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References
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2. Montgomery EA, Meis JM. Nodular fasciitis. Its morphologic spectrum andimmunohistochemical profile. Am J Surg Pathol 1991; 15:942-948.
3. Kindblom LG, Stener B, Angervall L. Intramuscular myxoma. Cancer 1974; 34;1734-1744.
4. Ireland DCR, Soule EH, Ivins JC. Myxoma of somatic soft tissues. A report of 58patients, three with multiple tumors and fibrous dysplasia of bone. Mayo Clin Proc 1973;48:401-410.
5. Carney JA, Headington JT, Su WPD. Cutaneous myxomas. A major component of thecomplex of myxomas, spotty pigmentation, and endocrine overactivity. Arch Dermatol1986; 122:790-798.
6. Meis JM, Enzinger FM. Juxta-articular myxoma. A clinical and pathological study of 65cases. Hum Pathol 1992; 23:639-646.
7. Steeper TA, Rosai J. Aggressive angiomyxoma of the female pelvis and perineum.Report of nine cases of a distinctive type of gynecologic soft tissue neoplasm. Am J Surg
Pathol 1983; 7:463-475.8. Begin LR, Clement PB, Kirk ME, Jothy S, McCaughey WTE, Ferenczy A. Aggressive
angiomyxoma of pelvic soft parts: A clinicopathologic study of nine cases. Hum Pathol1985; 16:621-628.
9. Tsang WYW, Chan JKC, Lee KC, Fisher C, Fletcher CDM. Aggressive angiomyxoma. Areport of four cases occurring in men. Am J Surg Pathol 1992; 16:1059-1065.
10. Weiss SW, Goldblum JR. Myxoid variant of liposarcoma. In: Soft Tissue Tumors, 4thEdition, CV Mosby, St. Louis, MO, 2001.
11. Gibas Z, Miettinen M, Limon J, et al. Cytogenetic and immunohistochemical profile of myxoid liposarcoma. Am J Clin Pathol 1995;103:20-26.
12. Tallini G, Akerman M, Del Cin P, et al. Combined morphologic and karyotypic study of 28 myxoid liposarcomas. Implications for a revised morphologic typing (a report from the
CHAMP group). Am J Surg Pathol 1996;20:1047-1055.13. Mezzelani A, Sozzi G, Pierotti MA, Pilotti S. Rapid differential diagnosis of myxoid
liposarcoma by fluorescence in-situ hybridization on cytological preparations. J ClinPathol 1996;49:308-309.
14. Aoki T, Hisaoka M, Kouho H, Hashimoto H, Nakata H. Interphase cytogenetic analysis of myxoid soft tissue by fluorescence in-situ hybridization and DNA flow cytometry usingparaffin-embedded tissue. Cancer 1997;79:284-293.
15. Kuroda M, Ishida T, Horiuchi H, et al. Chimeric TLS/FUS-CHOP gene expression andthe heterogeneity of its junction in human myxoid and round cell liposarcoma. Am JPathol 1995;147:1221-1227.
16. Aman P, Ron D, Mandahl N, et al. Rearrangement of the transcription factor gene CHOPin myxoid liposarcomas with t(12;16)(q13;p11). Genes Chromosomes Cancer
1992;5:278-285.17. Crozat A, Aman P, Mandahl N, Ron D. Fusion of CHOP to a novel RNA-binding protein
in human myxoid liposarcoma. Nature 1993;363:640-644.18. Rabbitts T, Forster A, Larson R, Nathan P. Fusion of the dominant negative transcription
regulator CHOP with a novel gene FUS by translocation t(12;16) in malignantliposarcoma. Nature Genet 1993;4:175-280.
19. Panagopoulos I, Hoglund M, Mertens F, et al. Fusion of the EWS and CHOP genes inmyxoid liposarcoma. Oncogene 1996;12:489-494.
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20. Dal Cin P, Sciot R, Panagopoulos I, et al. Additional evidence of a variant translocationt(12;22) with EWS/CHOP fusion in myxoid liposarcoma: clinicopathological features. JPathol 1997;182:437-441.
21. Azumi N, Curtis J, Kempson RL, Hendrickson MR. Atypical and malignant neoplasmsshowing lipomatous differentiation: A study of 111 cases. Am J Surg Pathol1987;11(3):161-183.
22. Enzinger FM, Winslow DJ. Liposarcoma: A study of 103 cases. Virch Arch Pathol Anat1962;335:367-388.
23. Evans HL. Liposarcoma: A study of 55 cases with a re-assessment of its classification.Am J Surg Pathol 1979;3(6):507-523.
24. Evans HL. Liposarcomas and atypical lipomatous tumors: A study of 66 cases followedfor a minimum of 10 years. Surg Pathol 1988;1(1):41-54.
25. Smith TA, Easley KA, Goldblum JR. Myxoid/round cell liposarcoma of the extremities: Aclinicopathologic study of 29 cases with particular attention to extent of round cellliposarcoma. Am J Surg Pathol 1996;20(2):171-180.
26. Kilpatrick SE, Doyon J, Choong PFM, Sim FH, Nascimento AG. The clinicopathologicspectrum of myxoid and round cell lipoma. A study of 95 cases. Cancer 1996;77:1450-1458.
27. Weiss SW, Enzinger FM. Myxoid variant of malignant fibrous histiocytoma. Cancer 1977;39;1672-1689.
28. Mentzel T, Calonje E, Wadden C, et al. Myxofibrosarcoma: Clinicopathologic analysis of 75 cases with emphasis on the low-grade variant. Am J Surg Pathol 1996;20(4):391-405.
29. Evans HL. Low-grade fibromyxoid sarcoma: A report of two metastasizing neoplasmshaving a deceptively benign appearance. Am J Clin Pathol 1987; 88:615-619.
30. Evans HL. Low-grade fibromyxoid sarcoma: A report of twelve cases. Am J Surg Pathol1993; 17(6):595-600.
31. Goodlad JR, Mentzel T, Fletcher CDM. Low-grade fibromyxoid sarcoma:Clinicopathological analysis of 11 new cases in support of a distinct entity.Histopathology 1995;26:229-237.
32. Panagopoulos I, Storlazzi CT, Fletcher CD, et al. The chimeric FUS/CREB3L2 gene isspecific for low-grade fibromyxoid sarcoma. Genes Chromosomes Cancer 2004;40:218-228.
33. Mertens F, Fletcher CD, Antonescu CR, et al. Clinicopathologic and molecular geneticcharacterization of low-grade fibromyxoid sarcoma and cloning of a novelFUS/CREB3L1 fusion gene. Lab Invest 2005;85:408-415.
34. Enzinger FM, Shiraki M. Extraskeletal myxoid chondrosarcoma: An analysis of 34 cases.Hum Pathol 1972;3:421-435.
35. Dei Tos AP, Wadden C, Fletcher CDM. Extraskeletal myxoid chondrosarcoma: Animmunohistochemical reappraisal of 39 cases. Appl Immunohistochem 1997;5(2):73-77.
36. Hinrichs SH, Jaramillo MA, Gumerlock PH, et al. Myxoid chondrosarcoma with atranslocation involving chromosomes 9 and 22. Cancer Genet Cytogenet 1985;14:219-
226.37. Brody, RI, Ueda T, Hamelin A, et al. Molecular analysis of the fusion of EWS to an
orphan nuclear receptor gene in extraskeletal myxoid chondrosarcoma. Am J Pathol1997;150:1049-1058.
38. Meis-Kindblom JM, Bergh P, Gunterberg B, Kindblom L-G. Extraskeletal myxoidchondrosacroma. A reappraisal of its morphologic spectrum and prognostic factorsbased on 117 cases. Am J Surg Pathol 1999;23:636-650.
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Fibrosarcoma-Like Pattern
Highly cellular spindled mesenchymal neoplasms arranged into a fascicular growth pattern are
not uncommonly encountered in the deep soft tissues, mediastinum or retroperitoneum. When
presented with such a lesion, the most common differential diagnosis usually includes cellular
schwannoma, MPNST, leiomyosarcoma, monophasic synovial sarcoma and fibrosarcoma.
Through a combination of light microscopy and immunohistochemistry, one can usually detect a
specific line of cellular differentiation in such tumors. As a matter of fact, a diagnosis of
fibrosarcoma, once a very common diagnosis to make in the realm of soft tissue pathology, has
become a diagnostic rarity.
Cellular Schwannoma
Cellular schwannoma is one of several variants of schwannoma that may cause diagnostic
confusion, in this case because of its high cellularity, mitotic activity, and presence of bony
destruction. These lesions typically occur in middle-aged patients (although the age range is
broad), with a slight female predilection. They are most commonly found within the
paravertebral region of the posterior mediastinum, retroperitoneum, and pelvis. A small number
of patients have been found to have neurofibromatosis.
Grossly, these lesions are typically encapsulated, and may or may not be associated with an
identifiable nerve, either grossly or microscopically. Degenerative changes, including cyst
formation, hemorrhage and necrosis may be seen. Histologically, the neoplasm is composed of
slender, elongated spindled cells with wavy contours that may be arranged in short intersecting
fascicles, or in longer sweeping fascicles reminiscent of the herringbone pattern seen in
fibrosarcoma. By definition, the lesion is composed almost entirely of Antoni A areas, and
although abortive nuclear palisades may be seen, true Verocay bodies are not formed. Although
at first glance this lesion may be difficult to differentiate from other spindle cell sarcomas, a
variety of histologic features may serve as useful diagnostic clues. This lesion typically has
cellularity that is disproportionate to the degree of mitotic activity and cytologic atypia that is
present. It should be noted that the cellular schwannoma can have some mitotic activity,
although it is typically less than that seen in MPNSTs (<4 MF/10 HPF). Similarly, focal cytologic
atypia has been identified in a small percentage of cellular schwannomas, but is typically not to
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the degree both in quality and quantity as is seen in MPNSTs. Other useful features to
recognize this lesion include (1) the presence of paracapsular and/or perivascular lymphoid
aggregates; (2) the focal presence of Antoni B areas; (3) prominent perivascular hyalinization
and, very importantly (4) diffuse and strong immunoreactivity for S-100 protein.
It is critical to distinguish the cellular schwannoma from a MPNST, given the differences in both
therapy and prognosis. Tumor cellularity is not useful in that both of these lesions are highly
cellular. As mentioned previously, although nuclear pleomorphism and mitotic activity may be
seen in cellular schwannoma, MPNSTs typically have more extensive nuclear pleomorphism
and mitotic figures, including atypical mitoses. Divergent differentiation, often in the form of
rhabdomyoblasts, is found in approximately 10% of MPNSTs1, but is not seen in cellular
schwannomas. Finally, S-100 protein immunoreactivity is a useful adjunct in this differential
diagnosis, as cellular schwannomas show diffuse and strong S-100 protein positivity, whereas
only about 60% of MPNSTs show S-100 protein positivity, typically in a focal distribution.2
Four large studies of cellular schwannoma with significant follow-up (total of 119 cases) have
been published.3-6 Although up to 5% of tumors have locally recurred, none of the patients have
developed metastatic disease or died due to their tumor. Importantly, erosion of adjacent bone
has been noted in approximately 13% of the patients in these series, and may contribute to the
erroneous diagnosis of a sarcoma.
Ultrastructurally, these cells have been found to have the characteristic features of schwann
cells, with elongated bipolar cytoplasmic extensions, interdigitating cytoplasmic processes, and
multilayering of basal lamina.7
Other Variants of Schwannoma
Ancient Schwannoma
Ancient schwannomas are recognized by their extensive degenerative changes, which include
cyst formation, hemorrhage, hyalinization and calcification. Significant nuclear atypia may also
be noted, but importantly, the degree of mitotic activity is not proportionate to the degree of
nuclear atypia that is present, suggesting a degenerative phenomenon.8 These degenerative
findings typically occur in lesions that have been present for a long duration, and thus are more
commonly found in more deeply situated tumors.
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Plexiform Schwannoma
Rare schwannomas may also be arranged in a plexiform architecture, reminiscent of what one
encounters in the plexiform neurofibroma. Frequently, the individual nodules closely resemble
those seen in the cellular schwannoma. It is important to distinguish these lesions from
plexiform neurofibroma, as they lack an association with neurofibromatosis type I, and also are
not known to undergo malignant transformation.9,10
Glandular Schwannoma
Rare peripheral nerve sheath tumors also contain clear-cut epithelial differentiation in the form
of glands. Although most of these lesions have been described in patients with
neurofibromatosis type I and presumably have arisen from neurofibromas, there have been
several reports of glandular differentiation in schwannomas.11,12 However, the existence of this
entity has been disputed, as some authors believe that these reports represent schwannomas
containing entrapped skin adnexal structures.13 Woodruff and Christensen identified 11 cases of
glandular peripheral nerve sheath tumors and found that 92% of the tumors were histologically
malignant and 74% of the patients had neurofibromatosis type I. The authors did not identify any
cases of glandular schwannoma.13
Multiple Schwannomas (schwannomatosis)
Rarely, schwannomas may occur multifocally, either in the form of multiple cutaneous
schwannomas coursing along a nerve14 or occurring in multiple different sites and often
associated with intracranial tumors.15,16 While some authors believe that this entity
(schwannomatosis) is distinct from neurofibromatosis type II (NF-2), others believe that this
might represent an unusual variant of NF-2.17
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Neuroblastoma-like Schwannoma
Another rare variant of schwannoma is one in which the cells have a rounded morphology and
are often centered around a collagen core forming rosette-like structures, giving a superficial
resemblance to neuroblastoma.18 However, both ultrastructural and immunohistochemical
examination reveal that these cells have the characteristic features of schwann cells, and this is
supported by the benign clinical outcome in all cases.
Melanotic Schwannoma
Another rare form of schwannoma has been variably referred to as the melanocytic
schwannoma19 or the psammomatous melanotic schwannoma.20 Interestingly, over 50% of the
patients with this unusual tumor have evidence of Carney's syndrome (myxomas in a variety of
sites, spotty pigmentation and endocrine overactivity).20 The most striking histologic features are
the heavy pigment deposits which stain positively for Fontana's stain and negatively for iron, as
well as the presence of psammoma bodies, which may be extensive in some cases.
Immunohistochemically, the cells strongly express S-100 protein and HMB-45. Ultrastructurally,
the cells resemble typical schwann cells, except for the presence of premelanosomes and
melanosomes. Although most of these tumors act in a benign fashion, rare cases may
metastasize.20
Finally, the issue of malignant transformation in a schwannoma is an interesting one, as
Woodruff et al could only find 9 acceptable cases reported in the literature.21 None of the
patients had evidence of neurofibromatosis type I, and the majority of the patients died of their
disease. Histologically, the benign component in these tumors was classical schwannoma,
whereas the malignant component consisted of an epithelioid malignant peripheral nerve sheath
tumor in 7 cases, and showed evidence of neuroepithelial differentiation in 2 cases. Thus,
although exceedingly rare, schwannomas do have the capacity to undergo malignant
transformation.
Synovial Sarcoma
Synovial sarcoma is the third most common type of sarcoma (after so-called MFH and
liposarcoma), and typically affects adolescents and young adults (most common between 15-40
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years).22 By far the most common location is the extremities, particularly in proximity to large
joints (especially the knees), but distal extremity synovial sarcomas are not uncommon. These
tumors can also occur on the upper extremities, head and neck region and the trunk. Although
these tumors are often intimately related to tendons, tendon sheaths and bursal structures, they
are exceedingly rare within joint cavities.
Histologically, synovial sarcomas are composed of variable mixtures of epithelial cells, spindled
cells and cells that have features intermediate between these two (transitional cells). Thus, the
classic biphasic synovial sarcoma is fairly easily recognized, as it is composed of a distinct
population of these three cell types. However, when the epithelial elements are predominant
(epithelial type of synovial sarcoma), these lesions may be extremely difficult to recognize and
separate from carcinomas, melanomas or mesotheliomas. At the other extreme, when the
epithelial elements are difficult to identify or completely absent (monophasic fibrous type of
synovial sarcoma), then this lesion becomes difficult to differentiate from other highly cellular
spindle cell sarcomas.
The monophasic fibrous type of synovial sarcoma is probably the most common subtype and
can usually be recognized through a combination of histologic and immunohistochemical
features. At low magnification, one is often impressed with a “marbled” appearance that is due
to alternating areas of low and high cellularity. The spindled cells are often arranged into
irregular fascicles, but typically lack the regular herringbone pattern seen in fibrosarcoma.
Although the cells are generally spindled, some may have more of an ovoid appearance.
Nuclear pleomorphism is typically minimal, and mitotic figures can be identified fairly easily.
Other features that should suggest a diagnosis of monophasic fibrous type of synovial sarcoma
include the presence of calcification or ossification, a conspicuous mast cell infiltrate, and a
hemangiopericytomatous vasculature.
Immunohistochemistry is extremely useful in arriving at this diagnosis. Virtually all monophasic
synovial sarcomas stain for cytokeratins, epithelial membrane antigen, or both.23-26
Guillou etal.26 found that all but one of 100 cases of synovial sarcoma stained for at least one of these
epithelial markers. In their hands, a significantly greater percentage of cases stained for EMA,
although in our laboratory, we have found AE1/AE3 or CAM 5.2 to be more consistently
positive. In addition, Guillou et al. noted the relative frequent S-100 protein immunoreactivity in
all subtypes of synovial sarcoma. Thus, not all spindle cell sarcomas that stain for S-100 protein
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are necessarily malignant peripheral nerve sheath tumors. Given the fact that rare cases of
MPNST stain for cytokeratins (and in fact may be S-100 protein negative), we have found
cytokeratin subsets useful in this regard. Smith et al.27 found that virtually all monophasic
synovial sarcomas stained for cytokeratins 7, 19, or both, whereas staining for either of these
antigens is extremely rare in cases of MPNST. More recently, gene expression profiling of
synovial sarcomas revealed consistent expression of the TLE1 gene.28 Subsequently, an
antibody to TLE1 was developed which, according to Terry et al, shows a high degree of
sensitivity and specificity for synovial sarcoma.29 In our experience, this antibody is exceedingly
useful in confirming a diagnosis of synovial sarcoma, and it is very easy to interpret, since, in my
experience, virtually all cells in every synovial sarcoma I have tested shows strong nuclear
immunoreactivity. Finally, it must be kept in mind that a significant percentage of synovial
sarcomas (including poorly differentiated synovial sarcomas) show membranous
immunoreactivity for CD99, a feature which can cause confusion with the Ewing's family of
tumors.30
A consistent, specific translocation, most commonly a balanced reciprocal translocation, t(X;18)
(p11;q11), is found in virtually all synovial sarcomas, regardless of subtype.31 This translocation
involves the fusion of the SYT gene (also known as SS18) on chromosome 18 with either the
SSX1 or SSX2 gene on the X chromosome (both at Xp11) or very rarely with SSX4 (also
Xp11).32-34 This fusion can be detected by RT-PCR or FISH. In our practice, we utilize an SYT
breakapart probe utilizing paraffin-embedded tissue, an ancillary test used in virtually any case
in which we suspect a diagnosis of synovial sarcoma.
Synovial sarcoma is generally viewed and treated as a high-grade sarcoma. However, in a large
series of cases reported by Bergh et al, the authors identified features that could place patients
in either low or high-risk groups.35 Adverse prognostic factors with regard to metastasis and
survival included older age, larger tumor size, the presence of poorly differentiated areas, high
Ki-67 values, the presence of necrosis, vascular invasion and prior local recurrence.
Malignant Peripheral Nerve Sheath Tumor
Another lesion that frequently enters into the differential diagnosis is malignant peripheral nerve
sheath tumor (MPNST). Unless this lesion clearly arises from a nerve trunk, a neurofibroma, or
occurs in a patient with von Recklinghausen's disease, it may be extremely difficult to recognize
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and differentiate from these other lesions. At low magnification, similar to the appearance of
monophasic synovial sarcoma and cellular schwannoma, there are alternating hypo- and
hypercellular regions resulting in a marbled appearance. The spindled cells are arranged into an
irregular fascicular pattern, similar to that seen in fibrosarcoma, but other architectural patterns
may be present, including areas of nuclear palisading, myxoid zones, and a perivascular
targetoid growth pattern. The tumor cells are wavy or angulated, but show more nuclear
pleomorphism than that seen in cellular schwannoma. Mitotic figures are usually numerous (>4
MF/10 HPF). Immunohistochemically, about 60% of MPNSTs stain for S-100 protein, typically
with only focal positivity.
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References
1. Ducatman BS, Scheithauer BW. Malignant peripheral nerve sheath tumors withdivergent differentiation. Cancer 1984;54:1049-1057.
2. Weiss SW, Langloss JM, Enzinger FM. Value of S-100 protein in the diagnosis of softtissue tumors with particular reference to benign and malignant schwann cell tumors.
Lab Invest 1983;49:299-308.3. Lodding P, Kindblom LG, Angervall L, Stenman G. Cellular schwannoma: A
clinicopathologic study of 29 cases. Virch Arch Pathol Anat 1990; 416:237-248.4. White W, Shiu MH, Rosenblum MK, Erlandson RA, Woodruff JM. Cellular schwannoma:
A clinicopathologic study of 57 patients and 58 tumors. Cancer 1990; 66:1266-1275.5. Fletcher CDM, Davies SE, McKee PH. Cellular schwannoma: A distinct
pseudosarcomatous entity. Histopathology 1987; 11:21-35.6. Woodruff JM, Godwin TA, Erlandson RA, Susin M, Martini N. Cellular schwannoma: A
variety of schwannoma sometimes mistaken for a malignant tumor. Am J Surg Pathol1981; 5:733-744.
7. Woodruff JM. Cellular schwannoma. Bone and Soft Tissue Specialty Conference, Case1. USCAP Meeting, Toronto, Canada, 1995.
8. Dahl I. Ancient neurilemmoma (schwannoma). Acta Pathol Microbiol Scand1977;85(6):812-818.
9. Fletcher CDM, Davies SE. Benign plexiform (multinodular) schwannoma: A rare tumor unassociated with neurofibromatosis. Histopathology 1986;19:971-980.
10. Hirose T, Scheithauer BW, Sano T. Giant plexiform schwannoma: A report of two caseswith soft tissue and visceral involvement. Mod Pathol 1997;10:1075-1081.
11. Brooks JJ, Draffen RM. Benign glandular schwannoma. Arch Pathol Lab Med1992;116:192-195.
12. Fletcher CDM, Madziwa D, Heyderman E, et al. Benign dermal schwannoma withglandular elements - true heterology or a local “organizer” effect? Clin Exp Dermatol1986;11:475-485.
13. Woodruff JM, Christensen WN. Glandular peripheral nerve sheath tumors. Cancer
1993;72:3618-3628.14. Buenger KM, Porter NC, Dozier SE, Wagner RF. Localized multiple neurilemmomas of
the lower extremity. Cutis 1993;51:36-38.15. Purcell SM, Dixon SL. Schwannomatosis: An unusual variant of neurofibromatosis or a
distinct clinical entity? Arch Dermatol 1989;125:390-393.16. Shishibo T, Niimura M, Ohtsuka F, Tsuru N. Multiple cutaneous neurilemmomas as a
skin manifestation of neurilemmomatosis. J Am Acad Dermatol 1984;10:744-754.17. Reith JR, Goldblum JR. Multiple cutaneous plexiform schwannomas: Report of a case
and review of the literature with particular reference to the association with types 1 and 2neurofibromatosis and schwannomatosis. Arch Pathol Lab Med 1996;120:399-401.
18. Goldblum JR, Beals TF, Weiss SW. Neuroblastoma-like neurilemmoma. Am J SurgPathol 1994;18:266-273.
19. Fu YS, Kaye GI, Lattes R. Primary malignant melanocytic tumors of the sympatheticganglia with an ultrastructural study of one. Cancer 1975;36:2029-2041.
20. Carney JA. Psammomatous melanotic schwannoma: A distinctive heritable tumor withspecial associations including cardiac myxoma and the Cushing syndrome. Am J SurgPathol 1990;14:206-222.
21. Woodruff RM, Selig AM, Crowley K, Allen PW. Schwannoma with malignanttransformation. A rare, distinctive peripheral nerve tumor. Am J Surg Pathol1994;18(9):882-895.
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22. Weiss SW, Goldblum JR. Synovial sarcoma. In: Enzinger and Weiss's Soft TissueTumors, 5th Ed. Elsevier, New York 2008.
23. Ordonez NG, Mahfouz SM, Mackay B. Synovial sarcoma. An immunohistochemical andultrastructural study. Hum Pathol 1990;21:733-749.
24. Schmidt D, Thum P, Med C, Harms D, Treuner J. Synovial sarcoma in children andadolescents. A report from the Kiel Pediatric Tumor Registry. Cancer 1991;67:1667-
1672.25. Fetsch JF, Meis JM. Synovial sarcoma of the abdominal wall. Cancer 1993;72:469-477.26. Guillou L, Wadden C, Kraus MD, Dei Tos AP, Fletcher CDM. S-100 protein reactivity in
synovial sarcomas - A potentially frequent diagnostic pitfall. Immunohistochemicalanalysis of 100 cases. Appl Immunohistochem 1996;4(3):167-175.
27. Smith TA, Machen SK, Fisher C, Goldblum JR. Utility of cytokeratin subsets indistinguishing monophasic synovial sarcoma from malignant peripheral nerve sheathtumor. Am J Clin Pathol 1999;112:641-648.
28. Nielsen TO, West RB, Linn SC, et al. Molecular characterization of soft tissue tumours: agene expression study. Lancet 2002;359:1301-1307.
29. Terry J, Saito T, Subramanian S, et al. TLE1 as a diagnostic immunohistochemicalmarker for synovial sarcoma emerging from gene expression profiling studies. Am J
Surg Pathol 2007;31:240-246.30. Folpe AL, Schmidt RA, Chapman D, Gown AM. Poorly differentiated synovial sarcoma:
immunohistochemical distinction from primitive neuroectodermal tumors and high-grademalignant peripheral nerve sheath tumors. Am J Surg Pathol 1998;22:673-682.
31. Dal Cin P, Rao U. Jani-Sait S, Karasousis C, Sandberg AA. Chromosomes in thediagnosis of soft tissue tumors. I. Synovial sarcoma. Mod Pathol 1992;5:357-362.
32. de Leeuw B, Balemans M, Olde Weghuis D, Geurts van Kessel A. Identification of twoalternative fusion genes, SYT-SSX1 and SYT-SSX2, in t(x;18)(p11.2;q11.2)-positivesynovial sarcomas. Hum Mol Genet 1995;4:1097-1099.
33. Fligman I, Lonardo F, Jhanwar SC, Gerald WL, Woodruff J, Ladayni M. Molecular diagnosis of synovial sarcoma and characterization of a variant SYT-SSX2 fusiontranscript. Am J Pathol 1995;147:1592-1599.
34. Argani P, Zakowski MF, Klimstra DS, Rosai J, Ladanyi M. Detection of the SYT-SSXchimeric RNA of synovial sarcoma in paraffin-embedded tissue and its application inproblematic cases. Mod Pathol 1998;11;65-71.
35. Bergh P, Meis-Kindblom JM, Gherlinzoni F, et al. Synovial sarcoma: identification of lowand high-risk groups. Cancer 1999;85:2596-2602.
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Round Cell Tumor Pattern
The differential diagnosis of small round cell tumors is broad. On occasion, one can encounter a
benign round cell tumor (e.g. glomus tumor, giant cell tumor of tendon sheath, cutaneous
adnexal tumors of various types), which can be mistaken for a high-grade round cell sarcoma.
However, most of the time when one encounters a round cell pattern, the differential diagnosis
includes a broad group of malignant round cell tumors which includes the Ewing's family of
tumors (EFT), alveolar rhabdomyosarcoma, neuroblastoma, lymphoblastic lymphoma, Merkel
cell carcinoma, small cell carcinoma, poorly differentiated synovial sarcoma, mesenchymal
chondrosarcoma, round cell liposarcoma, desmoplastic small round cell tumor, small cell
osteosarcoma and others. Although the light microscopic features are useful in narrowing this
differential diagnosis, in virtually every case, ancillary studies including immunohistochemistry
and molecular genetic studies are required in order to more precisely classify the round cell
tumor. Given that this has important therapeutic and prognostic implications, simply designating
a given tumor as a round cell tumor, not otherwise specified, is not acceptable in most cases.
However, there are rare cases that cannot be precisely classified.
Ewing’s/Peripheral Neuroectodermal Tumor (Ewing's Family of Tumors or EFT)
A review of the literature over the past twenty years reveals a remarkable evolution in the
concepts regarding classic osseous and extra-osseous Ewing's sarcoma. Through an
accumulation of data, it has become apparent there is a spectrum of tumors that ranges from
classic Ewing's sarcoma to classic peripheral neuroectodermal tumor (PNET). Since its initial
description by James Ewing in 1921, Ewing's sarcoma was felt to arise only in bone, and it was
not until 1975 when Angervall and Enzinger described the first cases of extra-osseous Ewing's
sarcoma.1 PNET, since its initial description by Arthur Purdy Stout in 1918 as a round cell tumor
of the ulnar nerve,2 has been documented in soft tissue unassociated with nerve,3 as well as
within bone.4 As discussed below, these entities have histologic, immunohistochemical,
ultrastructural, cytogenetic and molecular genetic features that are overlapping, supporting the
histogenetic relationship among these neoplasms.
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EFT: Clinical Features
Most patients with EFT are adolescents or young adults, the majority of whom are less than 30
years of age.5 Although the mean age for PNET is similar to that of ES, there tends to be a
broad age range for the former, with a significant number of patients over the age of 40 years. In
contrast, patients with classic extraskeletal ES are rarely over 40 years of age. Both tumors are
slightly more common in males than in females.
PNET most commonly arises in the extremities. In my experience, the most common anatomic
sites are the upper thigh and buttock, followed by the upper arm and shoulder. Tumors
intimately attached to a major nerve may give rise to signs and symptoms related to diminished
neurologic function. The principal sites of classic extraskeletal ES are the paravertebral region
and chest wall, generally in close association with the vertebrae or the ribs. These tumors may
also arise in the soft tissues of the lower extremities and rare in the pelvic and hip regions, the
retroperitoneum and the upper extremities. However, it is important to note that virtually every
anatomic site has been documented to be involved by this family of tumors. In general, the
tumor presents as a rapidly growing, deeply situated mass measuring between 5 and 10 cm.
Superficially located cases do occur but are quite rare.
EFT: Pathologic Findings
Classic ES is composed of solidly packed uniform small cells arranged in a lobular pattern
separated by dense fibrous septa. At low magnification, there is nuclear uniformity, and nucleoli
are inconspicuous, as are mitotic figures. The nuclear chromatin is fine and powdery, and there
is a thin rim of pale cytoplasm often filled with glycogen. Hemorrhage and necrosis are
prominent features. On the other end of the spectrum, classic PNET is characterized by more
irregularity in nuclear size and shape, as well as a coarsening of the chromatin, more prominent
nucleoli and increased mitotic figures. In addition, rosettes of varying types, including Homer
Wright, Flexner-Wintersteiner and perivascular rosettes are typically seen. However, in betweenthese ends of the spectrum is a variety of architectural and cytologic features in which it is
unclear whether the lesion is best classified as a classic ES or PNET. The entity of "atypical
Ewing's sarcoma" has been proposed to include some of these cases between the two ends of
the histologic spectrum.6 However, the cut-off between ES and atypical ES, and between ES
and PNET, is unclear and arbitrary. Fortunately, however, this distinction is not necessary since
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a number of more recent studies have shown that there is no significant difference in prognosis
based upon where a given tumor lies on this morphologic spectrum.7
Ultrastructurally, typical ES is a primitive neoplasm composed of uniform round cells devoid of
specific features and characterized by abundant deposits of cytoplasmic glycogen. On the other
hand, PNET shows ultrastructural evidence of some degree of neural differentiation, including
rare dense core granules, neuritic cell processes, neurofilaments and neural tubules. Similar to
that seen histologically, there is a spectrum of ultrastructural features between the two extremes
that can be seen.
EFT: Immunohistochemical Features
For many years, a diagnosis of either ES or PNET was essentially an immunohistochemical
diagnosis of exclusion. However, it is clear that the product of the MIC2 gene (CD99) is the
most sensitive marker on this family of tumors.8 The MIC2 gene is a pseudoautosomal gene
located on the short arms of the sex chromosomes, and its product is a membranous
glycoprotein that can be detected immunohistochemically using a variety of differenti antibodies
(including 12E7 and O13). Although initially believed to be highly specific for the EFT, it is
apparent that virtually all other round cell tumors in the differential diagnosis, on rare occasion,
show membranous immunoreactivity for the MIC2 gene product, including lymphomas,
particular T-lymphoblastic lymphoma and precursor B-lymphoblastic lymphoma, Merkel cell
carcinoma, small cell carcinoma, alveolar rhabdomyosarcoma, small cell osteosarcoma,
desmoplastic small round cell tumor and mesenchymal chondrosarcoma.9-12 Notably, however,
childhood neuroblastomas have not been reported to stain for this antigen. Thus, although
immunostains for CD99 are highly sensitive for recognizing the EFT, this marker should be used
as part of a panel of immunostains, given the lack of complete specificity.
There are a few other notable immunohistochemical findings that one should be aware of for
EFT. For example, up to 20% of tumors have focal immunoreactivity for low-molecular-weightcytokeratins,13 although these tumors do not express cytokeratins 7 or 19, a useful finding for
distinguishing EFT from poorly differentiated synovial sarcoma.14 Desmin may also rarely be
found in EFT, but there is no ultrastructural evidence of skeletal muscle differentiation in these
tumors.15
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Cytogenetic and Molecular Genetic Findings
Approximately 90-95% of EFT are characterized by rearrangements of the EWS gene on 22q12
and ETS-related oncogenes, most commonly FLI-1 on 11q24.16 Less commonly, the EWS gene
is fused with other ETS-related genes, including ERG on 21q22,17 ETV-1 on 7p22,18 E1AF on
17q1219 or FEV on 2q33.20 The translocation breakpoints are restricted to introns 7-10 of the
EWS gene and introns 3-9 on the ETS-related gene, with the most common fusion being
between exon 7 of EWS and exons 5 or 6 of FLI-1.21 These translocations result in a novel
chimeric gene that encodes for a chimeric transcript in protein, the function of which is largely
unknown. Given the limitations of traditional cytogenetic techniques for detecting these
translocations, the ability to detect fusion transcripts by molecular genetic techniques (including
RT-PCR and FISH) using fixed, paraffin-embedded tissues has greatly facilitated the diagnosis
of these tumors. In our practice, we utilize an EWSR1 breakapart probe as a routine part of the
work-up for a suspected EFT.
Alveolar Rhabdomyosarcoma
Alveolar rhabdomyosarcoma (ARMS) is another important lesion to distinguish from EFET,
given the different therapeutic modalities used to treat these tumors. Although there may be
some overlap in the age distribution, ARMS often occurs in patients younger than seen in EFT.
This tumor has a predilection for the deep soft tissues of the extremities, although it may arise in
many other sites, including the head and neck, trunk, perineum, pelvis and retroperitoneum.
Histologically, ARMS is composed largely of ill-defined aggregates of poorly differentiated round
or oval tumors cells that frequently show central loss of cellular cohesion and formation if
irregular "alveolar" spaces. The individual cellular aggregates are separated and surrounded by
a framework of dense, frequently hyalinized fibrous septa that surround dilated vascular
channels. The cells at the periphery of the alveolar spaces are well preserved and adhere in a
single layer to the fibrous septa, whereas those in the center of the alveolar spaces tend to be
more loosely arranged or freely floating. These centrally located cells are often poorly preserved
and show evidence of degeneration and necrosis. There are also "solid" forms of ARMS that
lack an alveolar growth pattern entirely and are composed of densely packed groups of tumor
cells resembling the round cell areas of EFT. These solidly cellular areas are more commonly
encountered at the periphery of the tumor and probably represent the most active and most
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cellular stage of growth. However, even in these solid areas, there is a regular arrangement of
fibrous septa that surround the primitive round cells. Rhabdomyoblasts may be found, but in
some cases, they may be extremely difficult to identify.
Immunohistochemistry is extremely useful in making the diagnosis of ARMS. Although it is true
that most of these tumors do express desmin and muscle-specific actin (HHF-35), there are
some ARMS that do not express either of these antigens. In my experience, myogenin is the
best marker in recognizing ARMS. Both MyoD1 and myogenin are members of the MyoD family
of genes, which encode a series of DNA binding proteins that are involved in the initiation of
myogenic differentiation.22 These genes are expressed at the earliest stages of commitment of a
mesenchymal cell to striated muscle, and antibodies to these genes appear to be the most
sensitive markers of skeletal muscle differentiation.23 Although myogenin is expressed by
virtually all subtypes of rhabdomyosarcoma, it is clear that ARMS tends to express this antigen
more diffusely and strongly than the other subtypes of rhabdomyosarcoma. It is also important
to recognize that some examples of ARMS may show membranous immunoreactivity for CD99.
Again, cytogenetic and molecular genetic features of ARMS may be extremely useful in
confirming this diagnosis. The most common translocation is a t(2;13)(q35;q14), resulting in the
fusion of the PAX3 gene on chromosome 2 with FOXO1a (formerly known as FKHR) gene on
chromosome 13.24 Less commonly, ARMS may show a t(1;13), resulting in a PAX7-FOXO1a
fusion. In our practice, we utilize a FOXO1a breakapart probe on fixed, paraffin-embedded
tissues to detect this translocation. However, it must be kept in mind that only about 75% of
ARMS have either a t(2;13) or t(1;13), and 25% of ARMS lack either of these translocations.
Once a diagnosis of rhabdomyosarcoma is established, it is important to properly subtype the
tumor, given the significant prognostic implications. However, pathologists are not particularly
good at subclassifying rhabdomyosarcomas, as there is a high degree of inter- and
intraobserver variation in classifying these tumors.25 The Intergroup Rhabdomyosarcoma Study
(IRS) has proposed the International Classification of Rhabdomyosarcoma (ICR), which seemsto be the most reproducible classification scheme as well as the scheme which predicts
prognosis best.26 Tumors having a superior prognosis include botryoid and spindle cell variants
of embryonal rhabdomyosarcoma. The usual type of embryonal rhabdomyosarcoma has an
intermediate prognosis, whereas ARMS has a poor prognosis.
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Desmoplastic Small Round Cell Tumor (DSRCT)
DSRCT is a relatively uncommon entity that typically involves the abdominal or pelvic
peritoneum of young males and pursues an aggressive clinica course. Most patients with this
tumor are 15 to35 years of age, although patients younger and older than this classic age range
have also been reported. In a study of 109 patients with this tumor by Gerald et al,27 the patients
ranged in age from 6 to 49 years, with a mean age of 22 years. Males far outnumber females at
a ratio of approximately 4:1.
Most patients present with a large abdominal and/or pelvic mass with extensive peritoneal
involvement, usually without an identifiable visceral site of origin. However, this tumor has been
noted to arise in virtually every other anatomic location and does not necessarily arise in
association with a mesothelial-lined surface. Although there was some speculation that this
lesion could be related to a mesothelial neoplasm (mesothelial blastoma), given the fact that
these tumors can arise in non-mesothelial locations and given the absence of convincing
immunohistochemical or ultrastructural evidence of mesothelial differentiation, the histogenesis
of this unusual tumors remains unknown.
Histologically, the neoplasm is composed of sharply outlined islands of tumor cells that are
separated by a desmoplastic stroma containing myofibroblasts and prominent vascularity. There
is often a suggestion of peripheral palisading, occasionally with central necrosis. The individual
cells are relatively uniform, small and round to oval with hyperchromatic nuclei, inconspicuous
nucleoli and scanty cytoplasm. Mitotic figures are easily identified. Rarely, cells with peripherally
located nuclei and increased eosinophilic cytoplasm with a perinuclear clear zone (rhabdoid
morphology) are seen. Despite this classic histology, the morphologic profile of this tumor
continues to expand, as Ordonez noted that up to one-third of these tumors have atypical
histologic features.28
Immunohistochemically, these lesions have a characteristic polyphenotypic profile with
coexpression of cytokeratins, vimentin, desmin and NSE. The pattern of desmin
immunoreactivity is quite unique with a characteristic perinuclear globular pattern of staining. An
antibody that recognizes the carboxyl terminus portion of the WT1 gene product has also been
developed and is highly sensitive and reasonably specific in recognizing this tumor.29 It is also
important to note that up to 20% of DSRCT do stain for CD99. Interestingly, a characteristic
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cytogenetic aberration has been associated with this neoplasm, t(11;22)(p13;q12), involving the
Wilms' tumor gene on chromosome 11 and the EWS gene on chromosome 22. In virtually all
suspected cases, we utilize an EWSR1 breakapart probe in an attempt to detect this
translocation.
Neuroblastoma
Neuroblastoma may also be difficult to differentiate from some of these other round cell tumors.
Patients with neuroblastoma are typically younger than those with the other tumors, as 90% of
patients are diagnosed before the age of 5 years. Neuroblastoma is exceedingly rare in
adolescents and adults. These patients often have elevated catecholamine metabolite levels in
their urine. Neuroblastomas arise from either the adrenal gland or extra-adrenal sympathetic
ganglia, although metastases may be seen in virtually any location.
Histologically, neuroblastomas are composed virtually entirely of small round undifferentiated
cells, typically with dark nuclei and clumped chromatin, inconspicuous nucleoli and scanty
cytoplasm. The tumor cells are divided into small lobules by fibrovascular septa. Typically, some
cells with peripherally located larger nuclei with vesicular chromatin and increased eosinophilic
cytoplasm (representing immature ganglion cells) are seen. Neuroblastomas are characterized
by rosettes of various types, including Homer Wright rosettes, with the cells deposited in a
fibrillary background. Calcifications are often seen, and mature ganglion cells may be present.
Immunohistochemically, neuroblastomas do not stain for CD99, actin, desmin or myogenin.
Although the vast majority of neuroblastomas do stain for neural markers, particularly NSE, the
expression of these neural markers is not specific. Miettinen et al reported a high degree of
sensitivity of the monoclonal antibody NB84 in recognizing neuroblastoma,30 but we have had
no experience utilizing this antibody in our clinical practice. Neuroblastomas are characterized
by a consistent cytogenetic abnormality with deletion of the short arm of chromosome 1 (1p-). 31
Amplification of the N-myc gene is frequently seen in neuroblastoma and is of important
prognostic value.32
Mesenchymal Chondrosarcoma
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Mesenchymal chondrosarcoma is a rare neoplasm that typically occurs in young adults with a
peak age in the second to third decade of life. Approximately 20% of these neoplasms arise in
an extraosseous location and are most common in the cranial or spinal meninges, orbit and soft
tissues of the thigh.33 Histologically, Histologically, the neoplasm is characterized by a biphasic
appearance of small nests or nodules of well-differentiated cartilage intimately admixed with
undifferentiated round or slightly spindled cells with hyperchromatic nuclei and scanty
cytoplasm. Frequently, a hemangiopericytoma-like vascular pattern is present. Although the
biphasic appearance is characteristic, this may not be appreciated on a small biopsy, making
distinction from other round cell tumors difficult. Immunohistochemically, mesenchymal
chondrosarcomas do not express cytokeratins or myogenic markers, but variably express neural
markers, including S100 protein. Membranous CD99 immunoreactivity is found in the majority of
these tumors.34 In addition, there have been rare reports of mesenchymal chondrosarcoma with
the identical t(11;22) identified in the EFT, raising the possibility that these tumors are
histogenetically related.35
Round Cell Liposarcoma
Round cell liposarcoma is a poorly differentiated form of myxoid liposarcoma and typically
behaves as a high-grade sarcoma. Histologically, the cells are relatively uniform, small and
round with vesicular nuclei. The fine plexiform vascular pattern that is so characteristic of
myxoid liposarcoma is inconspicuous in the round cell areas. This neoplasm may be very
difficult to recognize, particularly on a needle biopsy, without a component of myxoid
liposarcoma. In such cases, the application of FISH can be extremely useful, since (like myxoid
liposarcoma) round cell liposarcoma is characterized most commonly by a t(12;16) involving the
DDIT3 gene on chromosome 12 and the FUS gene of chromosome 16, for which breakapart
probes are commercially available. Like myxoid liposarcoma, some cases of round cell
liposarcoma may also harbor a t(12;22), and in such cases, using an EWSR1 probe can be
useful.
Poorly Differentiated Synovial Sarcoma
Poorly differentiated synovial sarcoma is composed of small round cells with little cytoplasm,
often separated by a hemangiopericytoma-like vascular pattern. Unless one identifies other
areas of classic biphasic or monophasic synovial sarcoma of lower grade, this lesion may be
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extremely difficult to separate from some of the other round cell sarcomas. In addition, the
poorly differentiated form of synovial sarcoma is less likely to express cytokeratins.36 Further
adding to the difficulty, some cases of poorly differentiated synovial sarcoma express
membranous CD99 immunoreactivity, making distinction from EFT difficult.37 We have found the
use to cytokeratin subsets useful in this regard, as a substantial portion of poorly differentiated
synovial sarcomas stain for CK7 and 19, while EFT rarely, if ever, stains for the antigens. 14
Detection of the t(X;18) using either RT-PCR or FISH (for the SYT gene) may be exceedingly
useful in recognizing this tumor.38
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