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Abstract

An 82-year-old male with a history of diffuse large B-cell lymphoma in remission and invasive squamous cell carcinoma (SCC) presented to the dermatology clinic for an annual skin examination. A 1 cm friable pink papule was noted on the left preauricular region, clinically concerning for SCC. Hematoxylin and eosin staining revealed a squamoid tumor arising within the epidermis and forming nests and islands that invaded the underlying dermis. Multiple dilated ductal spaces containing eosinophilic secretions and mucin were observed. Many ductal spaces were partially or completely lined by goblet cells, with scattered solitary goblet cells also interspersed among the squamoid cells. No definitive intermediate cells were identified. Immunohistochemical staining showed CK5/6 and p40 positivity in most squamoid cells but negativity in the majority of goblet cells. CK7 and CEA highlighted a minor subset of tumor cells, particularly goblet cells and those lining the ductal spaces. Mucicarmine stain highlighted goblet cell cytoplasm and mucin within the ducts. The differential diagnosis included cutaneous SCC with goblet cell differentiation, primary cutaneous mucoepidermoid carcinoma, and cutaneous adenosquamous carcinoma. Next-generation sequencing revealed a novel CLCN5::CCNB3 gene fusion, not previously reported in the literature and currently classified as a variant of uncertain significance. Based on histologic, immunophenotypic, and molecular findings, a final diagnosis of cutaneous SCC with goblet cell differentiation was rendered. To our knowledge, this is the first reported case of cutaneous SCC with goblet cell differentiation harboring a CLCN5::CCNB3 gene fusion, expanding the morphologic and molecular spectrum of cutaneous SCC.