Cutaneous Epithelioid/Pleomorphic Rhabdomyosarcoma, Melanoma in Disguise? An Immunohistochemical, Molecular, and Epigenetic Study of 13 Patients

Rhabdomyosarcomatous transdifferentiation is a rare but well-documented phenomenon in melanoma, and, in these cases, recognition of a conventional component by either morphology or immunophenotype is essential for the correct diagnosis. However, tumors that are entirely transdifferentiated can be impossible to distinguish from primary rhabdomyosarcoma. We analyzed a cohort of cases diagnosed as cutaneous epithelioid/pleomorphic rhabdomyosarcoma using genetic/epigenetic techniques and compared them with melanoma. Cases diagnosed as cutaneous epithelioid/pleomorphic rhabdomyosarcoma were retrieved, and clinicopathologic features were documented. NRAS p.Q61R and BRAF p.V600E immunohistochemistry, targeted DNA next-generation sequencing, and DNA methylation profiling were performed. A total of 13 cases of cutaneous epithelioid/pleomorphic rhabdomyosarcomas were identified in 10 males and 3 females (62-90 years; median, 83 years). Cases included tumors arising in the head and neck (n = 9), upper extremity (n = 2), lower extremity (n = 1), and back (n = 1). Using immunohistochemistry, 1 tumor (of 13) was positive for NRAS Q61R; all were negative for BRAF V600E expression (0/13). Targeted DNA next-generation sequencing revealed 1 case each to harbor HRAS c.34G>A p.G12S and BRAF c.1363G>A p.G455R mutations, respectively. Tumor mutation burden was interpretable in 5 cases and ranged from 3 to 80 Mut/Mb (median 38 Mut/Mb); 4 of 5 cases had tumor mutation burden > 10 Mut/Mb. A DNA UV light mutational signature was present in all cases with evaluable data (6/6). DNA methylation profiling showed 7 (of 9) cases to cluster with desmoplastic melanoma, whereas 1 case formed a partial match for head and neck squamous cell carcinoma, and the final case matched with TFCP2-rearranged rhabdomyosarcoma. At the last follow-up, 4 patients died from the disease, 2 died from unknown causes, 2 were alive without disease, and 1 was alive with disease. The majority of cutaneous epithelioid/pleomorphic rhabdomyosarcoma show clinical, genetic, and epigenetic profiles similar to melanoma, suggesting that a major subset represents transdifferentiated melanoma.