Undifferentiated and Dedifferentiated Melanoma of the Genitourinary Tract: A Case Series Demonstrating the Potential for Diagnostic Pitfalls
High PD‑L1 expression and MAPK‑pathway drivers in undifferentiated/dedifferentiated melanoma of genitourinary sites predict excellent response to PD‑1‑based immunotherapy.
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 to genitourinary sites, involving the adrenal gland, kidney, and perirenal soft tissue. Resected tumors 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 and PAX8 negative. 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.
Recognition of undifferentiated/dedifferentiated melanoma at genitourinary sites prevents misdiagnosis and allows timely initiation of effective PD‑1‑based immunotherapy, improving patient outcomes.
Evidence level: Korai humán adat. Kis vagy feltáró emberi adat.
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