Non-mesenchymal Mimics of Sarcoma
CrossMark
Leona A. Doyle, MD
KEYWORDS
. Soft tissue . Tumor . Sarcoma . Melanoma . Sarcomatoid carcinoma . Immunohistochemistry
· Molecular genetics
ABSTRACT
A variety of different non-mesenchymal neo- plasms may mimic sarcoma, in particular sarcomatoid carcinoma and melanoma, but also mesothelioma and rarely some lym- phomas. This article reviews the key clinical and histologic features of such neoplasms in different settings, along with the use of ancillary studies to help identify the tumor types most frequently mis- diagnosed as sarcoma.
OVERVIEW
Soft tissue tumors encompass a broad group of clinically, histologically, and molecularly diverse tumor types. Many soft tissue tumors show signif- icant histologic overlap with one another (eg, spindle cell sarcomas, pleomorphic sarcomas), and distinguishing different sarcoma types often requires clinical correlation along with ancillary diagnostic tests, most often immunohistochem- istry (IHC) and fluorescence in situ hybridization (FISH). However, many non-mesenchymal tumor types can also show significant histologic overlap with sarcomas, and should be considered in the differential diagnosis of many different soft tissue neoplasms. In most cases, distinction can be made with a combination of clinical correlation, identification of certain diagnostic histologic fea- tures, and a relatively limited panel of immunohis- tochemical stains. This article reviews some of the most commonly encountered situations in which non-mesenchymal neoplasms may show signifi- cant histologic overlap with sarcoma and provides a practical approach to such cases, incorporating the use of ancillary studies.
MALIGNANT MELANOMA
Malignant melanoma, both primary and metasta- tic, frequently mimics sarcoma. Most primary cutaneous melanomas are readily recognizable as such due to the presence of an in-situ compo- nent, with the exception of desmoplastic or spindle cell melanoma, which may be difficult to distin- guish histologically from other intradermal spindle cell neoplasms, such as atypical fibroxanthoma/ pleomorphic dermal sarcoma, and nerve sheath neoplasms. However, the diverse histologic fea- tures (epithelioid, spindled, round cell, pleomor- phic, mixed) seen in metastatic melanoma accounts for the significant overlap with many different sarcoma types (Fig. 1). Although clinical history is clearly crucial, histologic clues to the diagnosis of metastatic melanoma include the presence of mixed architectural growth patterns, particularly a nested or theke-like growth pattern, cytologic pleomorphism, melanin pigmentation (often not present in metastatic tumors), and prom- inent “cherry-red” nucleoli. However, in many cases, and especially in small biopsy samples, IHC is needed to confirm the diagnosis and to exclude other entities. Most metastatic mela- nomas show at least focal nuclear and cyto- plasmic S100 protein expression, but expression of secondary melanocytic markers, such as melan-A/MART-1, HMB45, tyrosinase, and MiTF is highly variable, and many metastatic tumors are negative for all these markers. In addition, mel- anomas with a spindled morphology, both primary and metastatic, are usually negative for secondary melanocytic markers. Quite recently, however, SOX10 has been described as a highly sensitive and relatively specific marker of neuroectodermal differentiation, and has proven to be very useful
E-mail address: ladoyle@partners.org
http://dx.doi.org/10.1016/j.path.2015.05.010
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in clinical practice in the evaluation of melanocytic lesions, particularly those that lack expression of other secondary melanocytic markers (see Fig. 1D).1 Expression of SOX10 is seen in more than 99% of melanocytic and nerve sheath neo- plasms, as well as a subset of (usually benign) my- oepithelial tumors.2-4 Three relatively common
scenarios in which melanoma may be mistaken for sarcoma are described in the following sec- tions, and include the distinction of melanoma from malignant peripheral nerve sheath tumor (MPNST) and clear cell sarcoma, as well as the occurrence of metastatic melanoma in the absence of a known primary tumor.
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MELANOMA AND MALIGNANT PERIPHERAL NERVE SHEATH TUMOR
Malignant melanoma is occasionally mistaken for MPNST, due to shared S100 expression in both
tumors, in addition to overlapping histologic fea- tures (see Fig. 1A). MPNST is a variably cellular fascicular spindle cell neoplasm that shows S100 protein expression in approximately 50% of
cases.5,6 Importantly, however, the distribution of S100 expression in MPNST is usually focal or multifocal at most when present, and the presence of diffuse S100 expression is far more commonly seen in melanoma (see Fig. 1B). The presence of diffuse S100 positivity in MPNST is generally seen only in pediatric cases associated with neurofibromatosis.5 Anatomic location is also important in this differential diagnosis: “conven- tional” MPNST arises in deep soft tissues and virtually never in skin, and therefore the presence of an S100-positive cytologically atypical dermal tumor is far more likely to represent melanoma, with the exception of the very rare variant of epithelioid MPNST. Epithelioid MPNST is a clinico- pathologically distinctive neoplasm characterized by a multinodular growth pattern and composed of a relatively monomorphic population of epithe- lioid cells with distinct nucleoli. In contrast to con- ventional MPNST, this variant arises in the dermis and shows diffuse S100 positivity. It is distin- guished from melanoma by its multinodular growth pattern, relative cytologic monotony, loss of INI1 expression in 50% of cases, and absence of expression of secondary melanocytic markers, such as HMB-45 and melan-A.7
MELANOMA AND CLEAR CELL SARCOMA
Distinguishing malignant melanoma from clear cell sarcoma can be extremely difficult, particularly in core biopsy samples, again due to overlapping IHC features. Clear cell sarcoma classically in- volves tendons or aponeuroses of distal extrem- ities, usually around the ankle, and is composed of nests of spindled or epithelioid cells with prom- inent nucleoli and usually mild cytologic pleomor- phism. Similar to melanoma, the tumor cells show expression of S100, SOX10, and secondary melanocytic markers, but characteristically show more intense or diffuse staining for HMB-45 compared with S100, a finding that is uncommon in melanoma. However, this feature alone is generally not reliable enough in a given case to distinguish these tumor types, and distinction relies on a combination of clinicopathologic and molecular features. Clear cell sarcoma is a translocation-associated sarcoma that generally occurs in young to middle-aged adults, and is characterized by either a t(12;22)(q13;q12) result- ing in EWSR1-ATF fusion gene, or less commonly t(2;22)(q34;q12) resulting in EWSR1-CREB1 fusion,8-10 and identification of EWSR1 rearrange- ment by FISH is a reliable ancillary test to confirm this diagnosis. Histologic features that favor a diagnosis of clear cell sarcoma include lack of a superficial epidermal component, infiltration of
tendinous tissue by tumor in a nested pattern, multinucleate tumor cells, and the presence of only mild atypia and pleomorphism. However, in many cases, the histologic and immunohisto- chemical overlap is sufficient enough that FISH to identify the EWSR1 rearrangement of clear cell sarcoma is needed to exclude melanoma.
METASTATIC MELANOMA WITH NO KNOWN PRIMARY
In approximately 5% of cases of metastatic mela- noma a primary site is not identified, and given the overall incidence of metastatic melanoma, this is not an uncommon scenario. Axillary lymph nodes are frequently involved, followed by inguinal lymph nodes, and tumors may show epithelioid, spin- dled, or mixed features, usually with moderate to severe cytologic atypia and pleomorphism. In such cases, the diagnosis is usually suggested by the finding of S100 or SOX10 positivity, with or without expression of other melanocytic markers. Metastatic melanoma may also involve subcutaneous soft tissue sites, where it is usually well circumscribed, and shows a nested or “theke-like” growth pattern. Circumscription and lack of an overlying epidermal component are fea- tures suggestive of metastatic disease rather than primary tumor site.
Key Features METASTATIC MELANOMA
· For approximately 5% of metastatic mela- nomas, no primary site is identified
· Broad range of morphologies, including spindled, epithelioid, pleomorphic, or round cell; spindled or round cell morphologies commonly mimic sarcoma
· Clues to diagnosis include presence of nested growth pattern, which may be focal, cyto- logic and architectual pleomorphism
. Many metastatic melanomas, either primary or metastatic, and most with spindle cell morphology, lack expression of secondary melanocytic markers; however, SOX10 re- mains highly sensitive in this setting
. SOX10 expression is present in more than 95% of melanocytic neoplasms; expression is also seen in nerve sheath tumors and a sub- set of myoepithelial tumors
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Pitfalls METASTATIC MELANOMA
! Diffuse positivity for S100 protein or SOX10 in a spindle cell neoplasm is far more likely to represent melanoma than MPNST, which only very rarely shows diffuse expression of these two markers
! Distinction of malignant melanoma from clear cell sarcoma may be very difficult, especially in small biopsies: FISH to identify EWSR1 rearrangement characteristic of clear cell sarcoma is often needed to resolve this differential
CARCINOMA TYPES THAT MAY MIMIC SARCOMA (AND VICE VERSA)
Sarcomatoid carcinoma, or spindle cell carci- noma, can be present as a major or minor compo- nent of carcinomas at virtually any site, but is most often associated with primary breast carcinoma, renal cell carcinoma, and mucosal or cutaneous squamous cell carcinoma. At these sites and other primary sites, pure sarcomatoid carcinoma may be difficult to recognize as an epithelial neoplasm (Fig. 2), and sarcomatoid carcinoma is even more difficult to recognize at metastatic sites, such as in bone or somatic soft tissue (Fig. 3), un- less one has a high level of suspicion or can iden- tify more epithelioid-appearing areas. In addition, sarcomatoid carcinoma may show heterologous differentiation in the form of chondro-osseous/ osteosarcomatous or rhabdomyosarcomatous differentiation (Fig. 4A), which may result in an erroneous diagnosis of osteosarcoma or rhabdo- myosarcoma: the presence of either of these tumor types at visceral sites, or even at soft tissue sites, in an adult should prompt consideration of the possibility of heterologous differentiation within a carcinoma (see Fig. 4B). A panel of immu- nohistochemical markers to include several cytokeratins (both low-molecular weight and high-molecular weight) is usually needed to confirm the diagnosis of metastatic sarcomatoid carcinoma, and with the exception of TTF-1 and PAX-8, most “lineage-specific” markers or keratin subtypes are of little use in determining primary site. Three settings in which carcinoma may mimic different mesenchymal tumors are considered in the following sections.
SARCOMATOID CARCINOMA OF BREAST
Sarcomatoid or spindle cell carcinoma of the breast is often cytologically bland and thereby resembles desmoid fibromatosis or Phyllodes tumor11,12 (Fig. 5A), or may show significant cytologic atypia and pleomorphism and mimic high-grade sarcoma. 13 For this reason, most prac- titioners advocate the use of multiple cytokeratins to include broad-spectrum cytokeratins (AE1/ AE3, pan-cytokeratin) and those associated with a “basal” or myoepithelial phenotype (CK5, CK14, 34ßE12) along with p63,14 in the evaluation of any spindle cell lesion in the breast to exclude the possibility of sarcomatoid carcinoma, and this approach is generally optimal when dealing with most such lesions (see Fig. 5B). In some cases, small foci of epithelioid cells, gland formation, or in situ carcinoma are present, and therefore thor- ough sampling to identify any conventional compo- nent of adenocarcinoma is warranted. Desmoid fibromatosis is distinguished from low-grade spindle cell carcinoma of breast by the presence of nuclear beta-catenin expression and lack of cy- tokeratin expression. Sarcomatoid carcinoma of breast is typically negative for estrogen and pro- gesterone receptors, as well as Her2-neu.
Clinically, sarcomatoid carcinoma of breast shows a wide spectrum of biologic behavior, with histologically low-grade fibromatosis-like cases having a relatively indolent clinical course with local recurrences and infrequent lymph node spread, similar to low-grade sarcomas, 12,15 whereas higher-grade lesions show a clinical course more analogous to conventional adenocar- cinoma of breast. 13
Key Features SARCOMATOID CARCINOMA
. For any spindle cell neoplasm in the breast, consider a broad panel of keratins, as well as thorough sampling, to exclude possibility of sarcomatoid carcinoma
· The differential diagnosis of an atypical intra- dermal spindle cell neoplasm includes sarco- matoid carcinoma, melanoma, smooth muscle neoplasm, and spindle cell angiosar- coma; these tumors should be excluded before a diagnosis of atypical fibroxanthoma or pleomorphic dermal sarcoma is made
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Pitfalls SARCOMATOID CARCINOMA
! Sarcomatoid spindle cell carcinoma of breast can be morphologically low grade, resembling desmoid fibromatosis
! Keratin expression can be seen in many different soft tissue tumors, including leiomyosarcoma, in- flammatory myofibroblastic tumor, schwannoma arising in the mediastinum, epithelioid sarcoma, and epithelioid vascular tumors
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SARCOMATOID SQUAMOUS CELL CARCINOMA OF SKIN
Spindle cell/sarcomatoid squamous cell carci- noma falls into the differential diagnosis of virtually any atypical intradermal spindle cell neoplasm, commonly encountered in superficial skin biopsies
or shaves. In addition to carcinoma, diagnostic considerations for such specimens include spindle cell melanoma, atypical fibroxanthoma, pleomor- phic dermal sarcoma, and less often, atypical in- tradermal smooth muscle neoplasm (cutaneous leiomyosarcoma) or spindle cell angiosarcoma. The overlying epithelium should be evaluated
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for either squamous dysplasia to support a diag- nosis of sarcomatoid squamous cell carcinoma or atypical melanocytic proliferation for mela- noma. A useful initial IHC panel to evaluate such lesions therefore includes CK5, p63, S100, and SOX10. Sarcomatoid squamous cell carcinoma is typically positive for CK5 and p63. Spindle cell
melanoma shows variable expression of S100 and is usually negative for HMB-45 and melan-A/ MART-1, but SOX10 shows a higher sensitivity than all of these markers in this setting.1 For smooth muscle neoplasms, expression of smooth muscle actin and desmin helps confirm the diag- nosis, and for angiosarcoma, expression of
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endothelial markers CD31 and ERG is diagnostic. For those tumors that fail to show a line of differen- tiation, either morphologically or immunohisto- chemically, the differential diagnosis usually lies between atypical fibroxanthoma and pleomorphic dermal sarcoma16; distinction between these two
tumors requires complete excision to evaluate the depth of tumor involvement and determine whether invasion into subcutaneous tissue has occurred: atypical fibroxanthoma should be confined to the dermis or show only minimal extension into subcutaneous tissue.
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RENAL CELL CARCINOMA, ADRENOCORTICAL CARCINOMA, AND MESENCHYMAL MIMICS
Renal cell carcinoma may mimic several soft tissue tumors; in the kidney, anastomosing hemangioma
may be difficult to distinguish from renal cell carci- noma, and outside the kidney renal cell carcinoma most often resembles perivascular epithelioid cell tumor (PEComa), chordoma, and epithelioid variant of pleomorphic liposarcoma.
Anastomosing hemangioma is composed of small capillaries lined by bland endothelial cells, which may have an epithelioid appearance or clear cytoplasm.17 The capillaries are often com- pressed, resulting in a solid appearance and in combination with clear cell cytomorphology may mimic renal cell carcinoma.18 Histologic clues that suggest the diagnosis of anastomosing hem- angioma include a lobular growth pattern (may not be apparent on core biopsies), eosinophilic intra- cytoplasmic globules, stromal fibrosis, and hemor- rhage. Expression of ERG and CD31 confirms the endothelial nature of the lesion, and PAX8 is nega- tive, thereby distinguishing it from renal cell carcinoma.
Epithelioid variant of pleomorphic liposarcoma is composed of sheets, nests, or trabeculae of large epithelioid cells with variably clear, granular, or palely eosinophilic cytoplasm, thereby mimicking metastatic adrenocortical carcinoma or renal cell carcinoma (Fig. 6). Clinically, pleomor- phic liposarcoma usually arises on the extremities, but occasionally can occur in the retroperito- neum.19,20 Most adrenocortical carcinomas pre- sent with a large adrenal mass, and unlike renal cell carcinoma, occult adrenal cell carcinoma pre- senting with metastasis is exceptional, and there- fore knowledge of the presence of an adrenal mass or history of renal cell carcinoma is helpful. The histologic clue to the diagnosis of pleomorphic liposarcoma is the presence of true lipoblasts (ie, univacuolated or multivacuolated cells with in- dented or scalloped nuclei); these cells may be
numerous or present only focally within a given tu- mor (see inset in Fig. 6). Although there are no spe- cific IHC markers to confirm the diagnosis of pleomorphic liposarcoma, IHC for inhibin and melan-A/mart1, or PAX8 and EMA, can help exclude adrenocortical carcinoma or renal cell carcinoma, respectively. Epithelioid variant of pleomorphic liposarcoma shows focal expression of broad-spectrum cytokeratins (usually high- molecular weight) in 20% of cases. 19,20
Finally, it is important to remember that keratin expression can be seen in many different soft tissue tumors. Of those with spindle cell morphology, leiomyosarcoma21 and schwannoma arising in the mediastinum or retroperitoneum22 can show expression of cytokeratins, which is usu- ally at most multifocal in distribution. In addition, keratin expression is characteristic of some epithelioid soft tissue tumors, most notably epithe- lioid sarcoma23 and synovial sarcoma (biphasic and monophasic types), and also may be present in any epithelioid vascular tumor.24 Of round cell sarcomas, Ewing sarcoma can show focal expres- sion of cytokeratin as well as neuroendocrine markers, which may lead to an erroneous diag- nosis of neuroendocrine tumor.
HEMATOLYMPHOID NEOPLASMS
Although lymphoma is generally readily distin- guishable from sarcoma, several hematolymphoid neoplasms may mimic sarcoma and are discussed in the following sections.
ACUTE LYMPHOBLASTIC LYMPHOMA VERSUS ROUND CELL SARCOMA
Lymphoblastic lymphoma, both T-cell and B-cell types, is composed of sheets of relatively monotonous-appearing small to medium-sized
lymphocytes with minimal cytoplasm, finely dispersed nuclear chromatin, irregular nuclear con- tours, and frequent mitoses, and may mimic round cell sarcoma (Fig. 7A). These tumors usually arise in children, and may form tumors in bone but also frequently occur in somatic soft tissue and skin
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(and mediastinum for T lymphoblastic lymphoma), where they most frequently mimic Ewing sar- coma.25-27 This is not only because of their shared morphologic features, but also because up to 80% of cases show diffuse membranous expression of
CD99, the pattern usually appreciated in Ewing sar- coma (see Fig. 7B). Because of this, a high index of suspicion for the diagnosis of lymphoblastic lym- phoma should be maintained when faced with any round cell sarcoma. This is particularly
important from a prognostic and predictive stand- point, as the chemotherapeutic regimens and prognosis for Ewing sarcoma and lymphoblastic lymphoma differ greatly. Histologic features that favor a diagnosis of Ewing sarcoma include nested growth pattern, rosette formation, and clear cyto- plasm, whereas the presence of irregular nuclear membranes is more characteristic of lymphoblastic lymphoma. However, in a given case or in small biopsies, these features may not be identifiable. Fortunately, immunohistochemistry readily distin- guishes lymphoblastic lymphoma from its mimics: lymphoblastic lymphoma shows diffuse nuclear positivity for TdT (see Fig. 7C), which is not seen in Ewing sarcoma and is highly specific for lymphoid differentiation in this setting.28 Further subclassification is afforded by more specific IHC to identify T-cell and B-cell lineage (see Fig. 7D). Other round cell sarcomas that also may mimic lymphoblastic lymphoma include solid variant of alveolar rhabdomyosarcoma, and round cell sarcomas with CIC-DUX4 and BC0R-CCNB3 rearrangements.29-31
HISTIOCYTIC SARCOMA
The classification of histiocytic sarcoma as a sar- coma rather than a hematolymphoid neoplasm is somewhat controversial; in fact, many of these tu- mors were previously classified as lymphoma and they are currently classified in the World Health Organization Classification of Tumors of Hemato- poietic and Lymphoid Tissues. However, these tu- mors tend to show little response to conventional chemotherapeutic agents used in the treatment of lymphoma, and also show a broader range of anatomic sites of involvement, features that in part explain the shift in nomenclature. However, regardless of nosology, because of their rarity and potential to mimic other tumor types (in partic- ular sarcoma), recognition of these neoplasms is often difficult. Histiocytes are phagocytic cells that are derived from myeloid/monocytic cells, and correspondingly histiocytic tumors (including Langerhans cell histiocytosis, Langerhans cell sar- coma, histiocytic sarcoma, and Rosai-Dorfman disease) are considered to be of myeloid/mono- cyte lineage.
Histiocytic sarcoma is an aggressive malignant neoplasm composed of large pleomorphic cells that show morphologic and immunohistochemical features of mature histiocytes. Patients are usually middle-aged adults, but there is a wide age range. Most tumors arise in extranodal sites, including so- matic soft tissue, gastrointestinal tract, and skin, and present with solitary or multiple masses. 32,33 A subset of cases arises in association with
lymphoma (usually non-Hodgkin) or leukemia.34-36 Histiocytic sarcoma consists of sheets of large round to oval (Fig. 8A, B), and occasionally spin- dled cells (see Fig. 8C, D), with abundant eosino- philic cytoplasm that may be vacuolated.32,33 Nuclei are also large and round with irregular nu- clear membranes, vesicular chromatin, and vari- able atypia (see Fig. 8; Fig. 9). The tumor cells are usually pleomorphic, but in some cases may be monomorphic. A prominent inflammatory infiltrate is generally seen, comprising lymphocytes, plasma cells, non-neoplastic histiocytes, and neutrophils. Histiocytic sarcoma therefore may mimic many different tumor types (melanoma, carcinoma, lym- phoma), but of mesenchymal neoplasms the main diagnostic considerations include pleomorphic sarcomas, such as undifferentiated/unclassified type, pleomorphic liposarcoma or malignant PE- Coma, as well as other sarcomas that show a prominent inflammatory infiltrate such as dediffer- entiated liposarcoma. Immunohistochemistry is extremely helpful in resolving these differential di- agnoses. Histiocytic sarcoma shows membranous and/or cytoplasmic expression of CD163, LCA, and CD45RO, and cytoplasmic expression of CD68 and lysozyme.32,33 In addition, positivity for CD4, lysozyme, and CD31 is common (see Figs. 8 and 9). S100 protein positivity is found in 50% of cases.33 Markers of Langerhans cells, B-cells and T-cells are negative, as are CD21, CD35, kera- tins, and EMA. When arising in the retroperitoneum, the principal differential diagnosis is dedifferenti- ated liposarcoma; however, in addition to the above immunophenotypic findings, histiocytic sar- coma lacks coexpression of MDM2 and CDK4. At present, relatively little is known about the genetic pathogenesis of histiocytic sarcoma; for cases arising in association with lymphoma or leukemia, similar genetic changes can be seen in both components, but otherwise histiocytic sarcoma lacks clonal IgH or T-cell receptor gene rearrangements. 32
LYMPHOMA WITH SPINDLE CELL FEATURES
Rare cases of high-grade lymphoma, particularly diffuse large B-cell lymphoma, show a spindled morphology and may have a sclerotic stroma (see Fig. 9A). Recognition of such cases as lym- phoma can be extremely difficult, and is usually helped by knowledge of a preceding history of lymphoma or the presence of more conventional- appearing lymphoma within the tumor. Other his- tologic clues include a somewhat dyshesive growth pattern, convoluted nuclear membranes, and admixed small lymphocytes or other inflam- matory cells. Expression of LCA, CD20, and
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BSAP/PAX5 confirms B-lymphocytic differentia- tion (see Fig. 9B). The presence of PAX8 expres- sion in lymphoma, due to cross-reactivity with PAX5, should be kept in mind to avoid an erro- neous diagnosis of sarcomatoid renal cell
carcinoma. Other lymphomas that may show a spindled morphology include anaplastic lym- phoma kinase (ALK)-positive anaplastic large-cell lymphoma and primary cutaneous follicle center lymphoma. 37-39
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Pitfalls HEMATOLYMPHOID NEOPLASMS
! Lymphoblastic lymphoma may mimic round- cell sarcomas, in particular Ewing sarcoma due to the presence of diffuse membranous CD99 expression in both tumor types, and should be distinguished if any uncertainty re- mains, either by IHC for TdT or FISH/reverse- transcriptase polymerase cell reaction to identify fusion genes of Ewing sarcoma
! Rarely, diffuse large B-cell lymphoma has a spindled morphology and may mimic sarcoma
! Expression of PAX8 can be seen in lymphoid neoplasms due to cross reactivity for PAX5
! Histiocytic sarcoma may mimic high-grade pleomorphic sarcomas or spindle cell sar- comas, and should be considered in tumors that show a prominent admixed inflamma- tory infiltrate
MALIGNANT MESOTHELIOMA
Within the pleura and less commonly the abdom- inal cavity, malignant mesothelioma may mimic several different sarcoma types, most often when it shows spindled or sarcomatoid morphology. Most primary peritoneal mesotheliomas are epithelioid, and the main differential diagnosis is with papillary serous carcinoma of gynecologic origin or other carcinomas. Although epithelioid mesothelioma is usually readily recognizable, sar- comatoid mesothelioma is more difficult to recog- nize, and is less likely to be considered as a diagnostic possibility within the abdominal cavity. Sarcomatoid variants may mimic dedifferentiated liposarcoma, inflammatory myofibroblastic tumor (IMT), sclerosing mesenteritis, or sarcomatoid car- cinoma when occurring in the abdominal cavity (Fig. 10A).
Features suggestive of sarcomatoid mesotheli- oma include diffuse growth throughout the abdomen and keratin positivity in an otherwise nondescript spindle cell neoplasm without fea- tures of dedifferentiated liposarcoma, IMT, or other spindle cell mesenchymal neoplasms that occur in the retroperitoneum. Although mesotheli- oma generally shows consistent expression of cy- tokeratins, such as pancytokeratin or AE1/AE3, more specific “mesothelioma” markers (ie, CK5/6 and WT1) are usually negative in sarcomatoid var- iants (see Fig. 10B, C).40 Calretinin is expressed in 70% of sarcomatoid mesotheliomas, but expres- sion also is seen in 60% of sarcomatoid
carcinomas and up to 20% of sarcomas.40,41 Due to the variability of staining between different tumors, a panel of stains is usually needed. IHC for MDM2/CDK4 and ALK should distinguish meso- thelioma from dedifferentiated liposarcoma and IMT, respectively. The rare “deciduoid” variant of mesothelioma that arises within pleural or perito- neal cavities is composed of sheets of large cells with abundant eosinophilic cytoplasm and promi- nent nucleoli, resembling ectopic decidua.42,43 This variant of mesothelioma may mimic histiocyt- ic neoplasms, germ cell tumors, or carcinoma, and has an aggressive clinical course.
SUMMARY
Knowledge of the histologic overlap between non- mesenchymal neoplasms (melanoma, sarcoma- toid carcinoma, mesothelioma, and some hematolymphoid neoplasms) and different sar- coma types is essential in all areas of pathology to avoid erroneous diagnoses, which may have significant clinical implications. This article has re- viewed the most commonly encountered settings in which such differential diagnoses are encoun- tered, along with clinical and histologic clues to distinguish these different tumor types and to guide the appropriate use of ancillary tests.
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