Abstract

Gene fusions have emerged as crucial molecular drivers of oncogenesis in various cutaneous adnexal neoplasms, including NUTM1, YAP1, WWTR1 fusions in poroid neoplasms, and CRTC1::MAML2 fusions in hidradenomas and hidradenocarcinomas. We present the first-ever case of primary cutaneous adnexal carcinoma with RARA::NPEPPS fusion, a previously undescribed fusion in any human malignancies. The patient, a 77-year-old African American man, presented with a 5 cm ulcerated nodule on the left proximal thigh. Biopsy revealed adenocarcinoma predominantly involving the dermis, with focal epidermal involvement and occasional intraepidermal pagetoid spread. The neoplastic cells exhibited various growth patterns, including solid, papillary, micropapillary, and cribriform growth, along with central comedo-type necrosis, set in a desmoplastic and fibrotic stroma. Immunohistochemical analysis showed positive expression of CK7, CK19, GATA3, TRPS1, CK5/6 (patchy), calretinin (patchy), p63 (focal), and DPC4 (no loss). However, immunoreactivity for CK20, CDX2, TTF1, Napsin-A, PAX8, arginase-1, adipophilin, NKX3.1, uroplakin II, and D2-40 was absent. Next-generation sequencing revealed the presence of RARA::NPEPPS fusion, as well as amplifications of ERBB2 and SESN1, along with a high tumor mutational burden of 18 mut/Mb. The tumor was suspected to be of cutaneous origin given the presence of CK5/6, calretinin, and p63 immunoreactivities in the tumor cells. Further imaging studies did not reveal any internal malignancy, except for multiple lymphadenopathies. Subsequent lymph node biopsies from the left inguinal and supraclavicular lymph nodes confirmed metastases. This unique case represents an unclassifiable aggressive cutaneous adnexal carcinoma with a novel fusion, offering valuable insights into the molecular landscape of such neoplasms.