EWS-CREB1: A recurrent variant fusion in clear cell sarcoma associated with gastrointestinal location and absence of melanocytic differntiation
Clear cell sarcoma (CCS) usually arises in the lower extremities of young adults and is typically associated with a t(12;22) that results in the fusion of EWS with ATF1, a gene encoding a member of the CREB family of transcription factors. CCS arising in the gastrointestinal (GI) tract is extremely rare and its pathologic and molecular features are not well defined.In the course of testing a CCS from the colon of an 81 year old woman for the EWS-ATF1 fusion by reverse transcriptase PCR (RT-PCR), we detected a novel variant fusion of EWS to CREB1, a gene at 2q32 encoding another CREB family member highly related to ATF1. We then studied additional cases with similar features for EWS-CREB1.We subsequently identified two additional GI CCS with the EWS-CREB1 fusion by RT-PCR, both arising in the small bowel, both in 42 year old women. In 2/2 cases tested, EWS gene rearrangement was also confirmed by FISH and the EWS-CREB1 genomic junction fragments were isolated by long range DNA PCR. Morphologically, all 3 lesions had a solid, nested, or pseudopapillary growth pattern, with an epithelioid and uniform cytology. No melanin pigmentation was noted. By immunohistochemistry (IHC), there was strong and diffuse S100 protein reactivity, while all melanocytic markers and CD117 were negative. Neural markers, such as NSE, CD56 and synaptophysin were positive. Ultrastructurally, electrondense granules were identified in 2/2 cases but they lacked the diagnostic features of melanosomes. Finally, RT-PCR for the melanocyte-specific transcript of MITF showed only weak expression in 1/3 cases. Comparison of these 3 cases to EWS-ATF1-positive GI CCS (previously published and additional unpublished cases from our institution) suggested that GI CCS show less melanocytic differentiation regardless of the fusion type.