When Morphology Misleads: The Diagnostic Challenge of Large-Cell Variant Merkel Cell Carcinoma

ABSTRACT: Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous neuroendocrine carcinoma classically characterized by small blue cell morphology and a distinctive perinuclear dot-like cytokeratin 20 (CK20) staining pattern. Rare histologic variants, however, may deviate from these defining features and pose significant diagnostic challenges. We report a diagnostically challenging case of large-cell variant MCC arising on the left distal dorsal forearm of a 61-year-old man, highlighting its distinctive morphologic and immunophenotypic features. Histopathologic examination revealed a predominantly dermal-based neoplasm composed of pleomorphic large epithelioid cells with abundant cytoplasm, enlarged nuclei, frequent mitotic figures, and focal architectural patterns mimicking adnexal differentiation, including tubule-like structures and sebocyte-like cells. Classic finely stippled "salt-and-pepper" chromatin was inconspicuous. Immunohistochemical analysis demonstrated diffuse pankeratin positivity and strong diffuse cytoplasmic CK20 staining, obscuring the characteristic perinuclear dot-like accentuation typically associated with MCC. The tumor also showed diffuse expression of neuroendocrine markers, including insulinoma-associated protein 1 (INSM1), neurofilament, chromogranin, and synaptophysin, with rare tumor cells exhibiting aberrant CK5/6 and CK7 expression. These findings expanded the differential diagnosis to include sebaceous carcinoma, porocarcinoma, and metastatic carcinoma. Integration of histomorphology with a comprehensive immunohistochemical panel supported a final diagnosis of large-cell variant MCC. This case underscores the importance of recognizing atypical morphologic and immunophenotypic presentations of MCC and reinforces the need for broad immunohistochemical evaluation to ensure appropriate management of this aggressive malignancy.