Cutaneous Rhabdomyosarcoma May Mask Melanoma

Molecular and epigenetic profiling suggested most tumors in a rare cutaneous sarcoma cohort were better classified as transdifferentiated melanoma.

Category	Detail
Condition	Cutaneous epithelioid or pleomorphic rhabdomyosarcoma often represents transdifferentiated melanoma
Key Mechanisms	Melanoma can lose conventional melanocytic markers and mimic sarcoma while retaining molecular and epigenetic evidence of melanocytic lineage
Target Population	Older adults (median age 83 years) with tumors primarily on head and neck
Care Setting	Pathology and oncology settings involving diagnosis and treatment of cutaneous tumors

Most tumors originally diagnosed as cutaneous rhabdomyosarcoma were reclassified as transdifferentiated melanoma based on molecular and epigenetic profiling
Standard melanoma immunohistochemical markers were negative despite molecular evidence supporting melanoma lineage
Comprehensive molecular testing including DNA methylation profiling and mutational signature analysis is critical for accurate diagnosis

Consider melanoma in differential diagnosis of poorly differentiated cutaneous malignancies with rhabdomyosarcomatous features, especially in sun-damaged skin
Use comprehensive molecular testing including immunohistochemistry, targeted next-generation sequencing, DNA methylation profiling, and mutational signature analysis before diagnosing cutaneous rhabdomyosarcoma

Immunotherapy may be effective in cases reclassified as melanoma, as evidenced by response to pembrolizumab in some patients

Monitor for metastatic disease and treatment response, particularly in patients receiving immunotherapy

Misdiagnosis may lead to inappropriate treatment due to overlapping histologic features between melanoma and rhabdomyosarcoma
Limitations exist in molecular testing and methylation profiling; clinical correlation is essential

Older adults with cutaneous tumors initially diagnosed as rhabdomyosarcoma

Immunotherapy such as pembrolizumab showed clinical benefit in some patients with transdifferentiated melanoma

Maintain high suspicion for melanoma in poorly differentiated cutaneous tumors with rhabdomyosarcomatous differentiation
Employ a multimodal diagnostic approach combining histology, immunohistochemistry, molecular genetics, and epigenetic profiling
Interpret molecular and methylation profiling results cautiously due to current limitations and lack of clinical validation
Consider immunotherapy options for patients with confirmed melanoma lineage tumors