Metastatic Melanoma with Rhabdomyosarcomatous Transdifferentiation: Two Tumors with Next-Generation Sequencing...

Metastatic melanoma can present significant diagnostic challenges when it undergoes both loss of differentiation and transdifferentiation, leading to the loss of melanocytic markers and acquisition of features mimicking other malignancies. We provide two case reports of metastatic melanoma with rhabdomyosarcomatous transdifferentiation, each demonstrating a small round blue cell morphology and expression of muscle markers such as MYOD1, desmin, and myogenin, with complete loss of melanocytic immunophenotype. The first patient developed bone metastasis 10 years after diagnosis of superficial spreading melanoma, while the second patient presented with pulmonary metastases within 6 months of desmoplastic melanoma resection. In both tumors, correlation with primary melanoma histology and immunohistochemistry failed to establish a diagnosis. Targeted next-generation sequencing (NGS) revealed genomic alterations characteristic of melanoma, including ultraviolet mutational signatures, and mutations in NF1, TERT promoter, NRAS, MITF, and TP53. Both were successfully treated with immune checkpoint inhibitors with 2 and 3 years of follow-up. These tumors underscore the diagnostic utility of NGS in resolving ambiguous presentations of melanoma with aberrant differentiation and highlight the importance of maintaining clinical suspicion in patients with a prior melanoma diagnosis.