Many tumors diagnosed as cutaneous epithelioid or pleomorphic rhabdomyosarcoma may actually represent transdifferentiated melanoma, according to findings published in Modern Pathology.
In a retrospective study of 13 patients, researchers used immunohistochemistry, targeted next-generation sequencing, DNA mutational signature analysis, tumor mutation burden assessment, and DNA methylation profiling to evaluate rare cutaneous tumors originally diagnosed as epithelioid or pleomorphic rhabdomyosarcoma. The patients were aged 62 to 90 years, with a median age of 83 years, and most tumors arose on the head and neck.
The diagnostic challenge was notable because all tumors expressed desmin and myogenin, and all tumors tested for MyoD1 were positive, supporting skeletal muscle differentiation. However, standard melanoma markers were consistently negative, including S100 in 12 of 12 tested tumors, SOX10 in ten of ten, Melan A in nine of nine, and HMB45 in five of five.
Following comprehensive review, 10 of the 13 tumors were best reclassified as transdifferentiated melanoma. DNA methylation profiling was successful in nine cases, seven of which clustered with desmoplastic melanoma. Among tumors with evaluable mutational signature data, all six had a DNA ultraviolet light signature. Tumor mutation burden was interpretable in five cases and exceeded 10 mutations per megabase in four.
Targeted sequencing identified TERT promoter mutations in five of seven sequenced cases, further supporting melanoma lineage. One scalp tumor with an HRAS p.G12S mutation also had melanoma in situ, NF1/NF2 alterations, a TERT promoter mutation, high tumor mutation burden, and a UV signature, supporting reclassification as transdifferentiated melanoma.
Immunohistochemistry showed NRAS Q61R expression in one of 13 tumors, whereas all tumors were negative for BRAF V600E expression. Targeted sequencing identified a non-V600E BRAF p.G455R mutation in one case. PRAME immunohistochemistry was diffusely positive in three of eight transdifferentiated melanoma cases but negative in all three tumors without evidence of melanocytic derivation, suggesting possible diagnostic utility with important limitations.
Not all tumors showed evidence of melanoma derivation. One case partially matched head and neck squamous cell carcinoma by methylation profiling, and another clustered with TFCP2-rearranged rhabdomyosarcoma, highlighting diagnostic heterogeneity among tumors with similar histologic features.
The findings may have clinical implications because melanoma can lose conventional melanocytic markers and mimic sarcoma while retaining molecular and epigenetic evidence of melanocytic lineage. In the study cohort, two patients received immunotherapy; one experienced resolution of axillary metastasis following pembrolizumab and was alive without disease at 25 months.
The researchers emphasized that melanoma should remain in the differential diagnosis for poorly differentiated malignancies arising in sun-damaged skin, particularly when rhabdomyosarcomatous differentiation is present. They also suggested that comprehensive molecular testing and DNA methylation profiling may be useful before rendering a diagnosis of cutaneous epithelioid or pleomorphic rhabdomyosarcoma.
The study was limited by its small sample size, retrospective design, selected cohort, incomplete molecular testing across all cases, and biopsy-heavy specimen set. The researchers also noted that mutational signature analysis was not clinically validated for reporting, and that methylation profiling has limitations, as illustrated by the inconclusive partial squamous cell carcinoma match.
“In conclusion, we show that the majority of cutaneous epithelioid/pleomorphic rhabdomyosarcomas in our series have genetic/epigenetic phenotypes of transdifferentiated melanoma,” wrote lead study author Veronica Ulici, of Cleveland Clinic, and colleagues.
Disclosures: The researchers reported no relevant conflicts of interest.
Source: Modern Pathology