Mucosal melanoma: clinicopathological, molecular and prognostic features in a retrospective cohort

Mucosal melanoma represents a rare, aggressive malignancy with limited therapeutic options and sparse data on prognostic markers. Here, we assess histopathologic and molecular parameters influencing survival to identify features applicable in routine diagnostics. A retrospective single-centre clinicopathological study of 51 patients diagnosed with mucosal melanoma (genitourinary, head and neck and gastrointestinal) between 2016 and 2024 was performed. Histopathological parameters, including tumour-infiltrating lymphocytes, were assessed by pathologists with expertise on melanocytic lesions. Molecular data derived from previously performed next-generation sequencing panels targeting common oncogenic drivers were retrieved from pathology records. Molecular and histopathological findings were correlated with clinical data and survival outcomes. The findings highlight the prognostic relevance of proliferative activity and residual in situ disease. Disease-free survival was significantly reduced in patients with metastatic (M1) status, ulceration, ≥10 mitoses/mm² and amelanotic tumours on univariate analysis, although none of these variables remained significant in multivariate models. Overall survival (OS) was significantly lower in cases with M1 status and in the presence of an in situ component in both univariate and multivariate analyses; high mitotic activity showed a nonsignificant trend towards reduced OS in multivariate analysis. NRAS was the most frequent mutation, followed by ARID1A, CDK4, CDKN2A, JAK2 and MYC, without a significant association with survival. These results emphasise the prognostic value of mitotic index and surgical completeness, while confirming the marked molecular heterogeneity of mucosal melanoma and the lack of a single dominant actionable alteration.