Case 1 -

Myoepithelial Carcinoma of Soft Tissue with Heterologous Chondrosarcomatous Differentiation Jason Hornick Brigham and Women's Hospital Boston, MA

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Clinical History A 42 year-old male presented with a painless mass in the left calf. MRI revealed a 9 cm nodular enhancing mass within the soleus muscle. Following incisional biopsy, the tumor was resected. Case 1 - Figure 1 - The tumor shows a multinodular growth pattern and variably prominent stroma. Case 1 - Figure 2 - Small foci of the tumor are composed of cytologically low grade cells set in abundant chondromyxoid stroma. Case 1 - Figure 3 - In other areas, cytologically atypical epithelioid cells grow in cords. Case 1 - Figure 4 - Epithelioid tumor cells within a variably prominent chondroid stroma. Case 1 - Figure 5 - Sheets of cytologically malignant epithelioid cells are punctuated by foci of cartilaginous differentiation. Case 1 - Figure 6 - In some areas, the cartilage shows relatively bland cytomorphology. Case 1 - Figure 7 - In other areas, the cartilage is frankly malignant (chondrosarcomatous). Case 1 - Figure 8 - Focal areas of the tumor are dominated by spindle cells. Case 1 - Figure 9 - Spindle cells showing scattered pleomorphism in a hyalinized collagenous stroma. Case 1 - Figure 10 - Sheets of high grade malignant epithelioid cells with abundant amphophilic cytoplasm. Immunohistochemical results: The tumor cells were positive for keratins CAM5.2 and AE1/AE3, EMA, S-100 protein, smooth muscle actin, and calponin, and were negative for GFAP and desmin. Diagnosis: Myoepithelial carcinoma of soft tissue with heterologous chondrosarcomatous differentiation ("malignant mixed tumor") Discussion/Differential diagnosis: Myoepithelial tumors were only recognized to arise primarily in soft tissue within the past decade. [1, 2, 3, 4] Most such tumors are pure myoepitheliomas, whereas mixed tumors (also showing ductal/epithelial differentiation) represent a small subset of these lesions. [4] This is in stark contrast to myoepithelial tumors of salivary glands, the vast majority of which are mixed tumors ("pleomorphic adenomas"). Most soft tissue myoepitheliomas are benign, although malignant variants (myoepithelial carcinoma) also occur. Criteria for malignancy have only very recently been established (see below). [4] Clinically, soft tissue myoepitheliomas show no gender predilection and occur over a wide age range (including in children) with a peak incidence in the third to fifth decades. The extremities are most often affected (lower limb > upper limb), although myoepitheliomas also occur in the trunk and head and neck. The most common presentation is a painless mass in the subcutis or deep somatic soft tissue. The median tumor size is 3.5 cm; occasional tumors are large (>10 cm). Morphologically, similar to their salivary gland counterparts, [5] soft tissue myoepitheliomas show considerable heterogeneity, in terms of cytomorphology, architecture, and stromal characteristics. [4] Most soft tissue myoepitheliomas are lobulated or multinodular, and a reticular growth pattern is the most common architecture with intersecting cords of cells set in a prominent chondromyxoid or hyalinized matrix. Myoepitheliomas often show mixed architectural patterns, with areas of reticular growth merging with solid sheets or nests of tumor cells. Tumor cells may be epithelioid, spindled, plasmacytoid (hyaline), or clear; many myoepitheliomas contain an admixture of cell types. Pure spindle cell myoepitheliomas (lacking a stromal component) are an uncommon variant. Ductal differentiation is seen in 15% of soft tissue myoepitheliomas ("mixed tumors"). Cartilaginous and/or osseous metaplasia is observed with a similar frequency as ductal differentiation. Occasional myoepitheliomas show features of so-called "parachordoma" (large epithelioid cells with eosinophilic, vacuolated cytoplasm and hyalinized stroma); given their overlapping histologic and immunophenotypic features, "parachordoma" likely falls within the spectrum of soft tissue myoepithelioma. By immunohistochemistry, virtually all myoepithelial tumors of soft tissue are positive for keratins and S-100 protein, two-thirds express EMA, and 50% are immunoreactive for GFAP. [4] In terms of myogenic markers, calponin is the most sensitive, staining nearly all myoepitheliomas, whereas immunoreactivity for SMA is seen in only one-third, and expression of desmin is uncommon. [4] Given their lack of specificity, myogenic markers are generally not particularly useful for diagnosing soft tissue myoepithelioma. The "myoepithelial" markers p63 and CK14 are detected in a minority of soft tissue myoepitheliomas, but may be helpful in some cases. Analogous to cutaneous mixed tumors ("chondroid syringomas"), "pure" myoepitheliomas may also arise primarily in the dermis. [3, 6, 7, 8, 9] Some cutaneous myoepitheliomas resemble their soft tissue or salivary gland counterparts, but the majority of cutaneous lesions are composed of histiocytoid or spindled cells showing a distinctive syncytial growth pattern with abundant palely eosinophilic cytoplasm. These syncytial myoepitheliomas usually lack keratin expression but are diffusely positive for EMA; S-100 and GFAP are also generally positive. [9] Prognostic parameters have only very recently been evaluated in myoepithelial tumors of soft tissue. [4] Since focally infiltrative margins are common in these lesions (including typical benign myoepitheliomas), infiltrative growth per se is unhelpful for prognostication. The most important histologic feature of malignancy is nuclear atypia, in the form of vesicular chromatin and prominent nucleoli. [4] The presence of at least moderate cytologic atypia should lead to a diagnosis of myoepithelial carcinoma. When heterologous mesenchymal (chondrosarcomatous or osteosarcomatous) differentiation is present in a myoepithelial carcinoma, an alternative diagnosis of "malignant mixed tumor" may also be rendered. Mitotic activity does not correlate well with clinical behavior, although the majority of tumors that recur or metastasize have 5 or more mitoses per 10 HPF. Morphologically benign myoepitheliomas have an approximately 20% risk for local recurrence. In contrast, myoepithelial carcinomas (or "malignant mixed tumors") recur in nearly 50% of cases, and at least one-third metastasize. [4] The chief differential diagnostic consideration for the most typical pattern of soft tissue myoepithelioma (i.e., reticular growth with chondromyxoid stroma) is extraskeletal myxoid chondrosarcoma (EMC). EMC are typically cytologically more uniformly spindled than myoepitheliomas, which instead often have more epithelioid cytomorphology and intratumoral cytologic and architectural heterogeneity. In some cases, however, histologic features are virtually indistinguishable, and immunohistochemistry is required. Focal staining for S-100 is seen in only a small subset of EMC, whereas virtually all myoepitheliomas are diffusely positive. Moreover, expression of keratins and GFAP favors myoepithelioma. Detection of EWS gene rearrangement can confirm the diagnosis of EMC. Spindle cell myoepitheliomas may mimic smooth muscle or nerve sheath tumors; by employing immunohistochemistry, the distinction among these diagnostic possibilities is usually straightforward. The primary differential diagnoses for myoepithelial carcinoma (particularly when dominated by epithelioid cells) are metastatic carcinoma, metastatic melanoma, proximal-type epithelioid sarcoma, and the epithelioid variant of malignant peripheral nerve sheath tumor (MPNST). The presence of cartilaginous differentiation (as in the case presented) should suggest the possibility of a myoepithelial neoplasm. Metastatic carcinoma lacks the multinodular architecture and myxoid stroma of myoepithelial carcinoma. Detection of S-100 protein and GFAP expression favor a myoepithelial tumor over metastatic carcinoma. Similarly, the presence of myxoid stroma is exceptional in metastatic melanoma, and immunoreactivity for epithelial and myogenic markers is very uncommon. Proximal-type epithelioid sarcoma is typically cytologically uniform, unlike myoepithelial carcinomas, which again often show significant heterogeneity. Expression of S-100 and GFAP is not a feature of epithelioid sarcoma. Epithelioid MPNST shares the multinodular architecture of myoepithelial carcinoma, but instead typically shows cytologic uniformity. Similar to myoepithelial carcinoma, MPNST may show heterologous chondrosarcomatous differentiation (although this is uncommon in the epithelioid variant). Unlike conventional MPNST (<50% of which show focal expression of S-100 protein), most epithelioid MPNSTs show extensive S-100 immunoreactivity (similar to myoepithelial neoplasms); however, epithelial markers are uncommonly detected in epithelioid MPNST. References Burke T, Sahin A, Johnson DE, et al. Myoepithelioma of the retroperitoneum. Ultrastruct Pathol 1995;19:269-74. Kilpatrick SE, Hitchcock MG, Kraus MD, et al. Mixed tumors and myoepitheliomas of soft tissue: a clinicopathologic study of 19 cases with a unifying concept. Am J Surg Pathol 1997;21:13-22. Michal M, Miettinen M. Myoepitheliomas of the skin and soft tissues: report of 12 cases. Virchows Arch 1999;434:393-400. Hornick JL, Fletcher CDM. Myoepithelial tumors of soft tissue: a clinicopathologic and immunohistochemical study of 101 cases with evaluation of prognostic parameters. Am J Surg Pathol 2003;27:1183-96. Dardick I, Cavell S, Boivin M, et al. Salivary gland myoepithelioma variants: histological, ultrastructural, and immunocytological features. Virchows Archiv A Pathol Anat 1989;416:25-42. Fernandez-Figueras MT, Puig L, Trias I, et al. Benign myoepithelioma of the skin. Am J Dermatopathol 1998;20:208-12. Kutzner H, Mentzel T, Kaddu S, et al. Cutaneous myoepithelioma: an under-recognized cutaneous neoplasm composed of myoepithelial cells. Am J Surg Pathol2001;25:348-55. Mentzel T, Requena L, Kaddu S, et al. Cutaneous myoepithelial neoplasms: clinicopathologic and immunohistochemical study of 20 cases suggesting a continuous spectrum ranging from benign mixed tumor of the skin to cutaneous myoepithelioma and myoepithelial carcinoma. J Cutan Pathol 2003;30:294-302. Hornick JL, Fletcher CDM. Cutaneous myoepithelioma: a clinicopathologic and immunohistochemical study of 14 cases. Hum Pathol 2004;35:14-24.