Undifferentiated round cell sarcoma with CRTC1::SS18 fusion: Expanding clinicopathologic features of a rare translocation sarcoma with prominent desmoplastic stroma.

Undifferentiated round cell sarcomas (URCS) represent a diverse group of tumors, including conventional Ewing sarcoma, round cell sarcoma with EWSR1/FUS-non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR alterations. Since 2018, three cases of URCS with a novel CRTC1::SS18 gene fusion have been reported in the literature. Herein, we report three additional cases of CRTC1::SS18 sarcoma, thereby doubling the number of described cases and expanding the clinicopathologic features of this rare translocation sarcoma. Together with the previously reported cases, we show that the male-to-female ratio is 1:2 with a median age of 34 years (range: 12 to 42 years). Tumors occurred primarily in intramuscular locations involving the lower extremity. Histologically, all tumors contained uniform round to epithelioid cells with a moderate amount of eosinophilic cytoplasm growing in sheets and nests with prominent desmoplastic stroma reminiscent of desmoplastic small round cell tumor (DSRCT). Immunohistochemical results were non-specific, demonstrating variable expression of CD99 (patchy), ALK, GATA3, and cyclin D1. RNA sequencing revealed CRTC1::SS18 gene fusions in all cases, involving exon 1-2 of CRTC1 (the 5' partner gene) on chromosome 19 and either exon 2 or exon 4 of SS18 (the 3' partner gene) on chromosome 18. The clinical course was variable. While one previously reported case demonstrated aggressive behavior with fatal outcome, two others had a relatively indolent course with gradual growth for 6-7 years prior to resection. Two cases developed metastatic disease, including one case with bilateral lung metastasis and one with locoregional spread to a lymph node. By analyzing the clinicopathologic features, we aim to improve recognition of this rare translocation sarcoma to better understand its biologic potential, optimize patient management, and expand the current classification of URCS.