SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): a clinicopathologic entity distinct from undifferentiated carcinoma

Small cell carcinoma of the ovary, hypercalcemic type is a rare, aggressive malignancy which usually occurs in young women and is characterized by mutations in SMARCA4, with few other alterations. We recently encountered uterine tumors with morphologic, immunohistochemical, and genetic similarities to small cell carcinoma of the ovary, hypercalcemic type. Herein we report the clinicopathologic and molecular features (using a targeted massively parallel sequencing [MPS] assay) of these tumors. The cases were diagnosed on cervical and endometrial biopsies (n = 2, 34, and 29 years) or hysterectomy and bilateral salpingo-oophorectomy (n = 3, 25, 33, and 58 years). The tumors were composed of sheets of large atypical epithelioid cells with prominent rhabdoid morphology, indistinguishable from the large cell variant of small cell carcinoma of the ovary, hypercalcemic type. In three cases, the ovaries were pathologically examined to exclude a primary ovarian malignancy. Immunohistochemically, four of four cases showed SMARCA4 loss, and were negative or only focally positive for keratins, EMA, and claudin-4. One of three cases was positive for WT-1. Targeted MPS was successfully performed on 4 of 5 tumors, and showed recurrent mutations in SMARCA4, with few other alterations. Of the cases diagnosed on hysterectomy, all had extensive lymphovascular invasion, extra-uterine spread, and marked infiltrative growth. These tumors were uniformly aggressive; all patients died of disease (median survival 7 months, range 1-43 months). We propose this entity be called SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus), a term which describes both the tumor's underlying molecular abnormality and its morphology. Its unique clinicopathologic and molecular features differentiate it from other related malignancies, including undifferentiated endometrial carcinoma, small cell carcinoma of the ovary (hypercalcemic type), and epithelioid sarcoma. We review and discuss previously reported rhabdoid tumors of the uterus; while they are a heterogenous group of tumors, some of them are likely examples of this entity. Correctly identifying cases of SMARCA4-deficient uterine sarcoma from histologic mimics is important as it may have prognostic, predictive, and germline implications.