High-grade transformation of low-grade endometrial stromal sarcomas lacking YWHAE and BCOR genetic abnormalities.

Abstract

High-grade histologic transformation of low-grade endometrial stromal sarcoma (LGESS) is rare. Here we describe the clinicopathologic features and gene fusion status of 12 cases (11 primary uterine corpus and 1 primary vaginal), 11 diagnosed prospectively from 2016 and one retrospectively collected. Targeted RNA sequencing and/or fluorescence in situ hybridization was employed in all cases. High-grade transformation was seen at the time of initial diagnosis in eight patients and at the time of recurrence in four patients, 4 to 11 years after initial diagnosis of LGESS. High-grade morphology consisted of generally uniform population of round to epithelioid cells with enlarged nuclei one to two times larger than a lymphocyte, visible nucleoli, and increased mitotic index (range, 6 to 30; median, 16 per 10 high power fields); there was often an associated sclerotic and/or myxoid stroma. Estrogen receptor, progesterone receptor, and CD10 expression was absent or significantly decreased (compared to the low-grade component) in the high-grade foci of five tumors. One tumor demonstrated positive (diffuse, strong) cyclin D1 and BCOR staining. p53 staining was wild-type in both components of all eight tumors tested. JAZF1-SUZ12 (n=6), JAZF1-PHF1 (n=3), EPC1-PHF1, (n=1), or BRD8-PHF1 (n=1) fusions were detected in 11 tumors; no fusions were found in one by targeted RNA sequencing. Patients presented with FIGO stages I (n=4), II (n=4), III (n=1) and IV disease (n=2). Median overall survival calculated from the time of histologic transformation was 22 months (range, 8 months to 8 years) with 5 patients who died of disease 8 to 18 months after transformation. High-grade transformation may occur in LGESS with JAZF1 and PHF1 rearrangements at the time of or years after initial diagnosis. Such high-grade transformation is characterized by nuclear enlargement, prominent nucleoli, and increased mitotic index compared to typical LGESS. Histologic high-grade transformation may herald aggressive behavior.