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Spindle Cell Tumor SPINDLE CELL TUMOR / SARCOMA SUBTYPING SPINDLE CELL TUMOR / SARCOMA SUBTYPING S ubtyping of spindle cell tumors and sarcomas requires integration of histology, clinicopathologic parameters, Markers of nerve sheath differentiation: The principal markers of nerve sheath differentiation are antibodies to S100 and results of IHC and/or FISH studies. Three subgroups of spindle cell tumors/sarcomas can be identified: protein and the p75-NTR nerve growth factor receptor. They are most helpful in confirming the diagnosis of benign and malignant 1. Tumors showing cell-specific differentiation (e.g., leiomyoma/ leiomyosarcoma, peripheral nerve sheath tumors) nerve sheath tumors. None of these markers, however, is specific for nerve sheath differentiation and must be used in combination 2. Sarcomas with specific translocations (e.g., PNET/Ewing sarcoma, synovial sarcoma) with other markers. p75-NTR is also an excellent marker of spindle cell and desmoplastic melanomas, which are generally negative for 3. Sarcomas with single gene alterations, i.e., mutations, deletions, and amplification (e.g., rhabdoid tumor, dedifferentiated expression of melanoma-specific antigens. liposarcoma, etc.) IHC studies are most efficacious in identifying group 1, while a combination of IHC and FISH studies, or sometimes FISH studies alone, are most efficacious in identifying the latter two groups. The following cell type-specific IHC markers can be useful in the identification of sarcomas showing cell-specific differentiation: Markers of epithelial differentiation in soft tissue tumors: Some sarcomas display true epithelial differentiation (e.g., synovial sarcomas and epithelioid sarcomas) and concomitant cytokeratin expression. Other sarcomas (e.g., leiomyosarcomas, melanomas, and angiosarcomas) can display ‘anomalous’ cytokeratin expression. Markers of smooth muscle differentiation: The principal markers of smooth muscle differentiation are antibodies to the H&E p75-NTR intermediate filament, desmin, and to muscle-specific actin isoforms (e.g., antibodies 1A4 and HHF-35). Such antibodies are most useful in identifying tumors such as leiomyosarcomas, although smooth muscle actin expression can be seen in other tumors showing Case of peripheral nerve sheath tumor showing expression of the p75-NTR nerve growth factor receptor. myofibroblastic differentiation. Markers of endothelial differentiation: Endothelial markers include von Willebrand factor (the co-factor of the clotting factor VIII, often erroneously referred to as ‘F. VIII’), CD34, CD31, and the FLI-1 gene product, with varying sensitivities and specificities. As a practical issue, it is best to employ both a highly specific (e.g., CD31) and a highly sensitive (e.g., FLI-1) marker to assess the presence of endothelial differentiation in histologicand clinical settings where the diagnosis of a vasoformative tumor is being entertained. H&E SM actin A case of low-grade leiomyosarcoma showing strong expression of smooth muscle actin identified by the 1A4 clone. Markers of myofibroblastic differentiation: Myofibroblasts are distinguished from true smooth muscle cells by their ‘partial’ muscle immunophenotype, usually smooth muscle actin positive and desmin negative. Furthermore, smooth muscle actin is H&E CD31 generally expressed in a characteristic peripheral, wispy pattern. Soft tissue tumors characterized by myofibroblastic differentiation include nodular fasciitis and inflammatory myofibroblastic tumors; however, myofibroblastic differentiation can be seen in a wide Case of spindle cell angiosarcoma showing expression of the endothelial-restricted marker, CD31. range of soft tissue tumors. H&E 1A4 Case of abdominal fibromatosis showing characteristic myofibroblastic differentiation, with peripheral ‘tram-tracking’ pattern of smooth muscle actin expression. 28 © 2013 PhenoPath Laboratories, PLLC. All rights reserved. © 2013 PhenoPath Laboratories, PLLC. All rights reserved. 29 SPINDLE CELL TUMOR / SARCOMA SUBTYPING SPINDLE CELL TUMOR / SARCOMA SUBTYPING Other useful IHC markers in identifying soft tissue tumors: Chromosomal Translocations Type IV Collagen: While not specific for a cell or tumor type, the presence and even pattern of expression of type IV Approximately one-third of all sarcomas contain chromosomal translocations which result in the juxtapositioning of two different collagen can be helpful in identifying specific soft tissue tumor subtypes, as only a subset of sarcomas produce a type IV genes (one from each translocation partner) that form a ‘fusion gene’. An example is the EWSR-WT1 fusion which results from the collagen; furthermore, the pattern of type IV collagen expression can provide evidence to help identify selected spindle cell t(11;22)(p13;q12) translocation found in desmoplasic small round cell tumor. For detection of these translocations in tissue sections tumors. of the tumor, two different types of probes or probe sets can be employed: (a) dual fusion, dual color FISH probes, which identify the chromosomes participating in the translocation; a ‘positive’ result is one in which normally disparate red and green signals ‘fuse’ as a is normally a cell membrane-associated protein. However, alterations in the APC/beta catenin pathway result result of the translocation into a single yellow spot; (b) breakapart probes, in which two different-colored probes span the expected in abnormal nuclear localization of this protein. Only a restricted subset of spindle cell tumors, including fibromatoses, breakpoint region in one of the partner genes, with a ‘positive’ result yielding disparate (e.g., red and green) spots that would normally endometrial stromal tumors, solitary fibrous tumors, and synovial sarcomas, show this unique distribution of beta catenin. be a single yellow spot. DOG1 and CD117 (c-kit) are highly sensitive and specific markers for gastrointestinal stromal tumors. DOG1 is FISH for SYT translocations of synovial sarcoma: The histologic diagnosis of synovial sarcoma can be difficult as these particularly useful in identifying the subset of c-kit negative gastrointestinal stromal tumors (GISTs). tumors often resemble other spindle cell sarcomas. IHC studies are usually helpful in characterizing these tumors, but many of the is a marker of a unique subset of spindle cell tumors. In addition to vascular tumors, CD34 is expressed in marker studies (TLE-1 and beta catenin) used to confirm this diagnosis are not completely specific. Translocations involving the SYT dermatofibrosarcoma protuberans, solitary fibrous tumor/hemangiopericytoma, and a subset of nerve sheath tumors, gene on chromosome 18q11.2 are unique to, and ultimately define, synovial sarcomas, and confirmation of this diagnosis can be made among others. with high sensitivity and specificity using dual color, ‘breakapart’ FISH studies. In these assays, translocations involving the SYT gene lead to a breakapart of the normal red-(yellow)-green overlapping signal, resulting in distinct red and green signals, as illustrated below, is a highly sensitive and specific marker for synovial sarcoma. This protein, initially identified with gene expression which confirm the presence of the SYT translocation characteristic of synovial sarcoma. profiling, is best used as a ‘screening marker’ for synovial sarcoma and, if positive, followed by confirmatory FISH for the SYT translocation. Other spindle cell tumors may occasionally show high-level expression of TLE-1 such as peripheral nerve sheath tumors. is a tumor supressor gene product, the loss of which has been found to be a characteristic finding of the following tumors: rhabdoid tumors, atypical teratoid/ rhabdoid tumors of the CNS, epithelioid sarcoma, MPNST, myxoid chondrosarcoma, and soft tissue myoepitheliomas. is the glycoprotein to which the monoclonal antibody HMB-45 is directed. In addition to being a marker of melanoma and clear cell sarcoma, gp100 expression also characterizes the group of tumors known as PEComas (PEC = perivascular epithelioid cell), a family of spindle to epithelioid tumors that includes angiomyolipoma, sugar tumor of the lung, pulmonary lymphangioleiomyomatosis, clear cell myomelanocytic tumor of the falciform ligamentum teres, and others. H&E FISH for translocations of the SYT gene Monophasic synovial sarcoma characteristic of synovial sarcoma FUSION GENE TUMOR TRANSLOCATION TYPE FORMED Alveolar rhabdomyosarcoma t(2;13)(q35;q14) PAX3-FOXO1 Breakapart (FOXO1) t(12;22)(q13;q12) EWSR-ATF1 Breakapart (EWSR) Angiomatoid fibrous t(2;22)(q33;q12) EWSR-CREB1 Breakapart histiocytoma t(12;16)(q13;p11) FUS-ATF1 (FUS) Desmoplastic small t(11;22)(p13;q12) EWSR-WT1 Breakapart (EWSR) Beta catenin TLE-1 CD117 (c-kit) round cell tumor Nuclear localization of beta catenin is a Synovial sarcoma showing uniform Strong uniform expression of c-kit in a case of t(11;22)(q24;q12) EWSR-FLI-1 characteristic feature of the cells of abdominal expression of the nuclear protein, TLE-1. gastrointestinal stromal tumor. t(21;22)(q24;q12) EWSR-ERG PNET/Ewing sarcoma Breakapart (EWSR) fibromatosis. t(7;22)(q22;q12) EWSR-ETV1 and others EWSR partner for most Breakapart (EWSR) Extraskeletal myxoid t(9;22)(q22;q12) EWSR-NR4A3 chondrosarcoma Myxoid/round cell t(12;16)(q13;p11) FUS-DDIT3 Breakapart FUS liposarcoma t(12;22)(q13;q12) EWSR-DDIT3 Breakapart EWSR SS18-SSX1 Synovial sarcoma t(X;18)(p11.2;q11.2) SS18-SSX2 SYT breakapart SS18-SSX4 30 © 2013 PhenoPath Laboratories, PLLC. All rights reserved. © 2013 PhenoPath Laboratories, PLLC. All rights reserved. 31 .
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