Metastatic Undifferentiated Melanoma with Ultra-High Tumor Mutational Burden and UV Mutational Signature: A Diagnostic Challenge

Undifferentiated melanoma (UM) is a rare and diagnostically challenging subtype of malignant melanoma that often lacks traditional histological features and immunophenotypic expression. We report the case of a 58-year-old man with a history of a previously excised melanoma in-situ (lentigo maligna type) of the scalp who later developed a painful chest wall mass. Subsequent workup revealed a high-grade malignant neoplasm with only focal weak S100P positivity while molecular analysis with next-generation sequencing (NGS) revealed an ultra-high TMB tumor mutational burden (>150 mut/Mb), NF1 mutation, TERT promoter mutation, TP53 mutations, PTPRD mutations, and a UV mutational signature (100% SBS7a), supportive of a diagnosis of UM. This case highlights the diagnostic value of comprehensive molecular testing in UM and its role in informing immunotherapy decisions.