Case 5 -

Myoepithelial Carcinoma of Soft Tissue Christopher Fletcher, Brigham and Women’s Hospital, Boston, MA

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Clinical History A 78 year old man presented with an enlarging mass in the triceps muscle. A well-circumscribed 19cm mass was excised. Case 5 - Figure 1 At low power, the lesion is well circumscribed and has a prominent myxoid matrix. Case 5 - Figure 2 Medium power demonstrates cords and strands of epithelioid cells with moderate amounts of eosinophilic cytoplasm arranged in a reticular fashion within a myxoid stroma. Case 5 - Figure 3 Closer examination demonstrates the epithelioid quality of these cells as well as irregular vesicular nuclei with focally notable nucleoli. Case 5 - Figure 4 In many areas, the tumor cells had more uniform smaller nuclei. Note the variably myxoid and hyaline stroma. Case 5 - Figure 5 Some areas of the tumor had strikingly clear cell morphology. Case 5 - Figure 6 In this field, trabeculae of eosinophilic and clear cells are admixed with one another. Case 5 - Figure 7 The tumor cells showed multifocal strong positivity for S-100 protein. Case 5 - Figure 8 There is also multifocally striking positivity for pan-keratin. Pathologic Findings This is a relatively circumscribed intramuscular neoplasm composed mostly of epithelioid but focally more ovoid or spindled cells with variably eosinophilic or clear cytoplasm. In areas, these tumor cells are arranged in a strikingly reticular or trabecular fashion within a prominent myxoid or, elsewhere, hyaline stroma. While the nuclei mostly have a quite uniform appearance, in areas, the lesional cells show nuclear enlargement and prominent nucleoli. There are scattered mitotic figures. Immunohistochemical stains show multifocal positivity for pan-keratin, EMA and S-100 protein, while GFAP, SMA and p63 are negative in this case. Differential Diagnosis Extraskeletal myxoid chondrosarcoma Soft tissue myoepithelioma Myoepithelial carcinoma of soft tissue Final Diagnosis Myoepithelial carcinoma of soft tissue Positivity for EMA and keratin argues strongly against extraskeletal myxoid chondrosarcoma. The plump atypical nuclei with prominent nucleoli warrant designation as myoepithelial carcinoma rather than soft tissue myoepithelioma. Discussion Myoepithelial lesions arising in non-cutaneous soft tissue have only been characterized quite recently, [1, 2, 3] probably because prior outdated concepts of histogenesis essentially excluded this possibility. In fact it seems that these lesions are not so rare (but may formerly have been mislabeled as myxoid chondrosarcoma or as an obscure metastasis) since, following publication of a relatively small series in early 1997, we have now seen over 300 additional examples, suggesting that pathologists are showing greater willingness to propose this diagnosis. These tumors affect all age groups but are most common before the age of 50; a significant subset (perhaps 10%) occur in young children. Limbs (including hands and feet) are the commonest site and, while most cases are subcutaneous, up to 35% are intramuscular or subfascial. As with their salivary gland counterparts, around 15-20% recur locally and experience has shown that 10-15% ultimately metastasize, albeit most of those show cytologically atypical features (see below). Given the relative rarity of epithelial malignancies in children, myoepithelial carcinomas appear to be disproportionately frequent in this age group and are often very aggressive. [4] Histologically, myoepithelial lesions in soft tissue show the same broad spectrum as in salivary gland. The only (questionably valid) distinction between mixed tumor and myoepithelioma is the presence of a ductal component, which is identified in 15-20% of cases. The relative proportions of the myxoid/chondromyxoid tissue and epithelial/ myoepithelial components are very variable; around 10–15% show overt chondro-osseous differentiation and rare examples show adipocytic differentiation. Occasional cases, as in salivary gland lesions, show transition to frank carcinoma or sarcoma, but the more usual clues to aggressive potential are nuclear atypia or prominent nucleoli. Mitotic rate and the character of the margin do not predict outcome. Immunohistochemically, most but not all cases are positive for keratin, along with S-100 protein in almost 90% or GFAP in approximately 45%. [3] Calponin stains most cases, while EMA stains 60% and SMA is positive in only 20-25%. p63 positivity is quite infrequent. Consistent S-100 positivity allows distinction from most metastatic carcinomas (except perhaps those of breast) and myxoid chondrosarcoma is excluded by keratin positivity, the greater morphologic heterogeneity, frequently very epithelial-like cytomorphology and the presence of ducts in some cases. Parachordoma [5, 6, 7] is an enigmatic neoplasm which has not become well-established as an 'entity'. Despite its partial morphologic overlap with chordoma, it shows important topographic, clinical and immunohistochemical differences from the latter. By contrast, however, it is essentially indistinguishable from myoepithelioma/mixed tumor other than in the minor fact that the tumor cell cytoplasm is often notably vacuolated [3] and, in the current WHO Classification, it is regarded as a variant of myoepithelioma. By contrast, extra-axial examples of chordoma, showing typical chordoma morphology and brachury immunopositivity, have now been convincingly demosntrated. [8] Ectomesenchymal chondromyxoid tumor, [9] which is most common in the tongue but may also occur elsewhere in the oral cavity, also appears to be a variant of myoepithelioma. Recent remarkable new data have shown that almost 50% of soft tissue myoepithelial neoplasms show EWSR1 gene rearrangement, [10] most often in cases occurring in children and young adults. Furthermore, preliminary data suggest that there may be a correlation between the specific type of gene fusion and distinct morphologic subsets (most notably EWSR1-POU5F1 in lesions with clear cell morphology). These new molecular data demonstrate that these soft tissue lesions have a quite different molecular pathogenesis from their salivary gland counterparts (which usually harbor rearrangements of PLAG1 or HMGA2). Conclusions Myoepithelial tumours arising in the soft tissue are now well recognized. They show a broad morphologic spectrum, comparable to their salivary gland counterparts, but, in contrast to the latter, a larger subset appears to be associated with aggressive behavior. The molecular pathogenesis of these recently recognized neoplasms is being unraveled and appears to be quite different from that of the salivary gland counterpart. References Kilpatrick S E, Hitchcock M G, Kraus M D, Calonje E, Fletcher C D M 1997 Mixed tumors and myoepitheliomas of soft tissue: a clinicopathologic study of 19 cases with a unifying concept. Am J Surg Pathol 21: 13–22 Michal M, Miettinen M 1999 Myoepitheliomas of the skin and soft tissues. Report of 12 cases. Virchow's Arch 434: 393–400 Hornick JL, Fletcher CDM. 2003. Myoepithelial tumors of soft tissue: a clinicopathologic and immunohistochemical study of 101 cases with evaluation of prognostic parameters. Am J Surg Pathol 27: 1183-1198 Gleason BC, Fletcher CDM. 2007. Myoepithelial carcinoma of soft tissue in children: an aggressive neoplasm analyzed in a series of 29 cases. Am J Surg Pathol 31: 1813-1824 Dabska M 1977 Parachordoma. A new clinicopathologic entity. Cancer 40: 1586–1592 Fisher C, Miettinen M 1997 Parachordoma: a clinicopathologic and immunohistochemical study of four cases of an unusual soft tissue neoplasm. Ann Diagn Pathol 1: 3–10 Folpe A L, Agoff S N, Willis J, Weiss S W 1999 Parachordoma is immunohistochemically and cytogenetically distinct from axial chordoma and extraskeletal myxoid chondrosarcoma. Am J Surg Pathol 23: 1059–1067 Tirabosco R, Mangham DC, Rosenberg AE et al. 2008. Brachyury expression in extra-axial skeletal and soft tissue chordomas: a marker that distinguishes chordoma from mixed tumor/myoepithelioma/parachordoma in soft tissue. Am J Surg Pathol 32: 572-580 Smith B C, Ellis G L, Meis-Kindblom J M, Williams S B 1995 Ectomesenchymal chondromyxoid tumor of the anterior tongue. Nineteen cases of a new clinicopathologic entity. Am J Surg Pathol 19: 519–530 Antonescu CR, Zhang L, Chang NE et al. 2010. EWSR1-POU5F1 fusion in soft tissue myoepithelial tumors. A molecular analysis of sixty-six cases, including soft tissue, bone, and visceral lesions, showing common involvement of the EWSR1 gene. Genes Chromos Cancer 49: 1114-1124