Malignant melanoma (MM) is notorious for its wide range of morphologic variability. Rarely, MM may lose all melanocytic markers and adopt the morphologic and immunophenotypic characteristics of a different neoplasm in a process known as trans-differentiation (TMM). Distinguishing TMM from primary cutaneous neoplasms may be challenging and is often dependent on the identification of an adjacent conventional melanoma. In particularly difficult cases, molecular analysis may be helpful; TMMs are known to exhibit highly similar mutational landscapes to conventional melanomas (e.g., mutations in NF1, NRAS; variable BRAF V600E). Herein, we present an exceedingly rare case of likely TMM with rhabdomyosarcomatous differentiation in which high tumor mutational burden (TMB) was an important clue to the diagnosis. An 83-year-old woman presented with an 8.2 cm fungating mass on the upper arm. Biopsy revealed a sheet-like proliferation of mitotically active pleomorphic cells which were positive for myogenin/MyoD1 and negative for S100/SOX10. A diagnosis of epithelioid rhabdomyosarcoma was rendered. Subsequent axillary lymph node metastasis prompted whole exome sequencing, which revealed a molecular signature more indicative of MM, including: high TMB (19 mutations/Mb); ultraviolet mutational signature (i.e., preponderance of C>T base changes); TERT promoter mutation; and ARID2 mutation. After discussion at the interdisciplinary tumor board, a diagnosis of TMM was considered most likely, and the patient was initiated on pembrolizumab. Morphologic features more typical of MM than cutaneous sarcomas, such as tumor-infiltrating lymphocytes, junctional epidermal tumor nests, and satellitosis, may provide further clues to the accurate diagnosis of TMM, which has important prognostic and therapeutic implications for the patient.
© 2025 The Author(s). Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.