EWSR1::WT1 fusions in neoplasms other than conventional desmoplastic small round cell tumor: three tumors occurring outside the female genital tract.

Desmoplastic small round cell tumor (DSRCT) is a high-grade, primitive round cell sarcoma classically associated with prominent desmoplastic stroma, co-expression of keratin and desmin, and a characteristic EWSR1::WT1 gene fusion. DSRCT typically arises in the abdominopelvic cavity of young males with diffuse peritoneal spread and poor overall survival. While originally considered to be pathognomonic for DSRCT, EWSR1::WT1 gene fusions have recently been detected in rare tumors lacking the characteristic morphologic and immunohistochemical features of DSRCT. Herein, we report three additional cases of non-conventional DSRCT tumors with EWSR1::WT1 gene fusions that occurred outside the female genital tract. Two occurred in the abdominopelvic cavities of a 27-year-old male and a 12-year-old female, while the third arose in the axillary soft tissue of an 85-year-old male. All cases lacked prominent desmoplastic stroma and were instead solid and cystic with peripheral fibrous pseudo capsules and occasional intervening fibrous septa. Necrosis was either absent (1/3) or rare (2/3), and mitotic activity was low (<1 to 3 per 10 hpf). On immunohistochemical study, there was expression of SMA (3/3) and desmin (3/3), rare to focal reactivity for EMA (2/3), and variable expression of CK AE1/AE3 (1/3). Myogenin and MyoD1 were negative, and C-terminus specific WT1 was positive in both cases tested (2/2). All three tumors followed a more indolent clinical course with two cases demonstrating no evidence of disease at 20 and 44 months post resection. The patient from case 3 died of other causes at 14 months with no evidence of recurrence. DNA methylation profiling showed that the three cases clustered with DSRCT; however, they demonstrated fewer copy number variations (CNVs) with two cases having a flat profile (0% CNV). Differential methylation analysis with hierarchical clustering further showed variation between the three cases and conventional DSRCT. While further study is needed, our results, in addition to prior reports, suggest that EWSR1::WT1 gene fusions occur in rare and seemingly distinctive, non-conventional DSRCT tumors with indolent behavior. Proper classification of these unusual soft tissue tumors with EWSR1::WT1 gene fusions requires direct correlation with tumor morphology and clinical behavior, which is essential to avoid overtreatment with aggressive chemotherapy.

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