Epithelioid malignant peripheral nerve sheath tumor: clinicopathologic analysis of 63 cases

Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is rare and differs from conventional malignant peripheral nerve sheath tumor by showing diffuse S-100 protein positivity, infrequent association with NF1, and occasional origin in a schwannoma. Loss of INI1 expression is seen in a subset of tumors. The purpose of this study was to further define clinicopathologic features and outcome data in a large series of EMPNST. Sixty-three cases were identified in consultation files. The patient group consisted of 33 men and 30 women; the median age was 44 years (range, 6 to 80 y). One patient was reported to have NF1. One patient had 3 seemingly separate primary EMPNSTs during his 12-year clinical course. The median tumor size was 3.0 cm (range, 0.4 to 20 cm), and tumors were located most frequently on the lower extremity (30/63; 48%) and trunk (16/63; 25%). Most tumors were superficial (5 dermal, 38 subcutaneous); 15 were subfascial, and 5 were visceral. Microscopically, tumors comprised a relatively uniform but clearly atypical population of epithelioid cells. The majority of tumors demonstrated a multilobular growth pattern, with lobules and nests surrounded by myxoid and/or fibrous stroma. Tumor cells were round, polygonal, or ovoid and had round vesicular nuclei and abundant amphophilic to palely eosinophilic cytoplasm. Focal spindled morphology was seen in one third of cases. Most tumors (55/63; 87%) showed marked cytologic atypia with irregular vesicular nuclei and prominent nucleoli. Mitotic rate ranged from 1 to 46/10 HPF (median, 5/10 HPF); atypical mitotic figures were seen in 7 cases. Necrosis was present in 17 tumors. Twelve tumors were associated with a nerve. Nine tumors arose in a schwannoma (6 conventional type, 3 epithelioid) and 1 in a neurofibroma (in the NF1 patient). All tumors expressed S-100 protein, and the majority showed strong and diffuse staining (87%; 55/63). There was no expression of the melanocytic markers Mart-1/Melan-A (0/58), HMB-45 (0/57), and MiTF (0/9). Other immunohistochemical results included variable staining for GFAP (24/40; 60%) and EMA (4/29; 14%), whereas keratin was consistently negative (0/33). INI1 expression was lost in 67% of tumors examined (35/52). Most tumors were treated by surgical resection; 13 also received chemotherapy and/or radiation. Follow-up data were available for 31 cases and ranged in duration from 3 months to 20 years (median, 36 mo). Twenty-two patients have no evidence of disease at the time of follow-up. Nine patients developed local recurrence, 3 of whom were reported to be disease-free at the time of latest follow-up (44 mo, 19 y, and 20 y). Five patients developed distant metastases, and 4 patients died of disease (including 2 with unresectable recurrent tumors). Recurrence, metastasis, and disease-related death were observed independent of anatomic site or depth. In summary, EMPNST is a morphologically distinct variant that most commonly affects adults on the lower extremity or trunk, although a wide age range and site distribution are seen. Most tumors arise in superficial soft tissue, are diffusely S-100 positive, and two thirds show INI1 loss. On the basis of available follow-up information there is a comparatively low risk for recurrence and metastasis, irrespective of tumor depth.