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

Abstract

Background: 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 which are entirely transdifferentiated can be impossible to distinguish from primary rhabdomyosarcoma. We analyzed a cohort of cases diagnosed as cutaneous epithelioid/pleomorphic rhabdomyosarcoma by genetic/epigenetic techniques and compared them with melanoma.

Design: 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 (NGS), and DNA methylation profiling were performed.

Results: 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 (1). By immunohistochemistry, 1 tumor (of 13) was positive for NRAS Q61R; all were negative for BRAF V600E expression (0/13). Targeted DNA NGS revealed one case each to harbor HRAS c.34G>A p.G12S and BRAF c.1363G>A p.G455R mutations, respectively. Tumor mutation burden (TMB) was interpretable in five cases and ranged from 3 to 80 Mut/Mb (median 38 Mut/Mb); four of five cases had TMB >10 Mut/Mb. A DNA ultraviolet light (UV) mutational signature was present in all cases with evaluable data (6 of 6). DNA methylation profiling showed 7 (of 9) cases to cluster with desmoplastic melanoma, while one case formed a partial match for head and neck squamous cell carcinoma and the final case matched with TFCP2-rearranged rhabdomyosarcoma. At last follow-up, four patients died from disease, two died from unknown causes, two were alive without disease, and one was alive with disease.

Conclusion: The majority of cutaneous epithelioid/pleomorphic rhabdomyosarcoma show clinical, genetic, and epigenetic profiles similar to melanoma, suggesting that a major subset represents transdifferentiated melanoma.

Keywords: BRAF; DNA methylation; NRAS; UV signature; epithelioid rhabdomyosarcoma; pleomorphic rhabdomyosarcoma; transdifferentiated melanoma; tumor mutation burden.