Undifferentiated and Dedifferentiated Melanoma of the Genitourinary Tract: A Case Series Demonstrating the Potential for Diagnostic Pitfalls

Undifferentiated/dedifferentiated melanomas typically lack all conventional melanocytic biomarkers and closely mimic non-melanocytic malignancies, risking misclassification and missed melanoma-directed therapy. We report four metastatic undifferentiated/dedifferentiated melanomas from 3 women and 1 man (median age 67 years) to genitourinary (GU) sites, involving the adrenal gland (n = 2), kidney (n = 1), and perirenal soft tissue (n = 1). Resected tumors (n = 3; median 5.4 cm) and one biopsy specimen showed high-grade epithelioid and/or spindle-cell morphology with brisk mitotic figures. All four tumors were S100/SOX10/MelanA/HMB45 negative. PAX8 was also negative. In contrast, pan-keratin/CAM5.2/cytokeratin AE1/AE3 and/or p63 showed focal/multifocal staining in all resected tumors. Additional pitfalls included focal weak TFE3 and scattered cathepsin K expression. PD-L1 was diffusely positive (70%-100% of tumor cells) in 2 tested tumors. Targeted next-generation sequencing showed a MAPK-pathway driver in all tumors: BRAF class-3 (D594N, G466R) in 2/4 tumors, NRAS Q61R in 1 tumor, and NF1 truncation (R440*) in 1 tumor, with frequent co-events ( TERT promoter mutations; CDKN2A loss; TP53 mutation). UV mutational signatures and high tumor mutational burden supported cutaneous origin. One patient showed clonal continuity between a prior liver metastasis and the subsequent adrenal gland lesion. All patients received PD-1-based immunotherapy (pembrolizumab n = 3; nivolumab n = 1). Three patients achieved complete responses and remain alive and disease-free (median follow-up 28 months; range, 1.8 months-10.5 years), while one patient was lost to follow-up at 2 months with progressive disease. Accurate recognition of these metastatic tumors enables effective therapy. To our knowledge, this is the first dedicated series of GU-site specific undifferentiated/dedifferentiated melanoma and provides a framework for work-up and management.