Sweat gland tumors with NFATC3 gene fusions: a clinicopathological and molecular study of three cases.

Numerous cutaneous adnexal tumors have recently been characterized by specific molecular hallmarks, notably oncogenic gene fusions. Herein, we report three cases of a sweat gland tumor exhibiting a secretory morphology and harboring SFPQ::NFATC3 or NPM1::NFATC3 fusions. The cases presented in a 36-year-old woman (left thigh), a 55-year-old man (paraumbilical region), and a 65-year-old woman (scalp), and were dermal-based neoplasms. Histopathological examination revealed ill-defined tumors with an infiltrative growth pattern, predominantly centered in the dermis, with one case extending into the subcutis. Two cases were characterized by cords, small nodules, and nests of epithelioid cells with large hyperchromatic nuclei, while prominent glandular and cribriform structures were observed in the third case. Numerous round ductal structures filled with a dense eosinophilic secretory material were identified in all cases. Mitotic activity was very low (< 1/mm²). No lymphovascular or perineural invasion was observed. Immunohistochemistry demonstrated diffuse SOX10 positivity in one case and p63 expression in the remaining two. PanTRK and NUT were negative, and YAP1 expression was preserved. Molecular analysis revealed in-frame SFPQ::NFATC3 (n = 2) or NPM1::NFATC3 (n = 1) fusions with identical breakpoints within the NFATC3 gene. These three cases of sweat gland tumor harboring NFATC3 gene fusions may represent the first identified examples of a previously undescribed adnexal tumor.