Melanomas confined to the lung: Integrated clinicopathological and molecular assessment of a case series.

Melanomas confined to the lung represent an exceptionally rare and diagnostically challenging entity. Whether these tumors constitute true primary pulmonary melanomas or metastases from occult or completely regressed cutaneous primaries remains controversial. We retrospectively analyzed the clinicopathologic, immunophenotypic, and molecular features of five melanomas confined to the lung diagnosed over a 10-year period at a tertiary referral center. Comprehensive clinical, radiologic, dermatologic, ophthalmologic, and gastroenterologic investigations excluded a cutaneous, mucosal, ocular, or visceral primary melanoma in all patients. Histopathologic review, immunohistochemistry, and targeted next-generation sequencing were performed. The series included three men and two women, aged 66-83 years. Four tumors showed predominantly epithelioid morphology and one displayed spindle-cell features with desmoplastic areas. All cases expressed S100 and/or SOX10, whereas expression of conventional melanocytic markers was variable. Targeted sequencing identified BRAF alterations in two cases, NRAS in one, and NF1 in one, with additional alterations involving the TERT promoter, TP53, and CDKN2A. No tumor demonstrated an intraepithelial or intramucosal melanocytic component in the adjacent bronchial mucosa or pulmonary parenchyma. During follow-up, all patients developed progressive disease and none achieved disease-free status. Melanomas confined to the lung harbor canonical MAPK-pathway driver alterations that are not specific to their anatomical origin, and none of the tumors showed an associated in situ melanocytic component. Although their histogenesis remains unresolved, these findings underscore the difficulty of distinguishing genuine primary pulmonary melanoma from metastasis arising from an occult or completely regressed extrapulmonary primary and support an integrated clinicopathologic and molecular diagnostic approach.