Case Report: Atypical pattern of pathologic response in cutaneous transdifferentiated melanoma with rhabdomyoblastic differentiation following neoadjuvant therapy

Transdifferentiated melanoma is a rare variant of melanoma characterized by phenotypic plasticity, loss of conventional melanocytic markers, and acquisition of features from other tissue lineages, often associated with aggressive biological behavior. Among these, melanoma with rhabdomyosarcomatous differentiation represents an exceptionally rare presentation that poses significant diagnostic and clinical challenges, particularly in the context of immunotherapy. We report the case of a 38-year-old male with a remote history of cutaneous melanoma who presented with an isolated left axillary nodal recurrence. Histopathological examination revealed a biphasic melanoma with a dedifferentiated component showing focal rhabdomyosarcomatous differentiation. The patient was treated with neoadjuvant immunotherapy using ipilimumab and nivolumab. Treatment was discontinued after two cycles due to immune-related hepatitis and aseptic meningitis requiring immunosuppressive therapy. Post-treatment imaging demonstrated a mixed metabolic response. Subsequent axillary lymphadenectomy revealed a complete pathological response of the melanocytic component, while a high-grade sarcomatoid/rhabdomyoblastic component remained viable, exhibiting high proliferative activity and loss of melanocytic markers. Molecular profiling identified NRAS Q61R and TERT promoter mutations, equivocal MYC amplification, and an elevated tumor mutational burden. The patient received adjuvant radiotherapy and remains under close oncologic surveillance. This case illustrates an atypical pattern of pathological response to neoadjuvant immunotherapy, characterized by eradication of the differentiated melanocytic component and persistence of a dedifferentiated, rhabdomyoblastic tumor population. These findings suggest phenotypic plasticity and immune escape as potential mechanisms of resistance, underscoring the need for integrated histopathological and molecular assessment when evaluating pathological response in rare melanoma variants. As neoadjuvant immunotherapy becomes increasingly incorporated into clinical practice, it is crucial to characterize its impact across the diverse presentations of melanoma and to understand the distinct patterns of pathological response.