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Cutaneous Epithelioid/Pleomorphic Rhabdomyosarcoma, Melanoma in Disguise? An Immunohistochemical, Molecular and Epigenetic Study of 13 Patients
Journal article   Open access   Peer reviewed

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

Veronica Ulici, Baptiste Ameline, Ivy John, Josephine K. Dermawan, Arivarasan Karunamurthy, Carina A. Dehner, Anthony P. Fernandez, Elizabeth Azzato, Travis Hattery, Scott E. Kilpatrick, …
Modern pathology, Vol.39(5), 100983
05/2026
DOI: 10.1016/j.modpat.2026.100983
PMID: 41780801
url
https://doi.org/10.1016/j.modpat.2026.100983View
Published (Version of record) Open Access

Abstract

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. 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. 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. The majority of cutaneous epithelioid/pleomorphic rhabdomyosarcoma show clinical, genetic, and epigenetic profiles similar to melanoma, suggesting that a major subset represents transdifferentiated melanoma.
 BRAF DNA methylation epithelioid rhabdomyosarcoma NRAS pleomorphic rhabdomyosarcoma transdifferentiated melanoma tumor mutation burden UV signature

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