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Case Reports

Abstract

De- and trans-differentiation in malignant melanoma to a divergent phenotype are being increasingly recognized at both primary and metastatic sites, most often occurring in the setting of systemic therapy. We report a case of a 69-year-old man diagnosed with lentigo maligna melanoma of the scalp with locoregional nodal disease (pT4aN3c) and an NRAS (p.Q61R) mutation, who was treated neoadjuvantly with PD1 inhibitor pembrolizumab. Due to interval enlargement, a wide local excision and lymph node dissection was performed revealing essentially no conventional melanoma morphology at either primary or metastatic sites; rather, the tumor consisted of variably SOX10-positive primitive undifferentiated round cells admixed with distinct islands of immature neuroblastic cells dispersed in a neuropil background and admixed with the ganglion cells with eccentric nuclei, prominent nucleoli, and abundant pale cytoplasm. By IHC, these areas expressed PHOX2B, neuron-specific enolase (NSE), and glial fibrillary protein (GFAP) while the rest of the tumor was negative for these markers. Both components were negative for HMB45, Melan A and S100. Mutation profiling of the post-treatment specimen revealed a new TERT promoter mutation and ARID2 loss-of-function mutation. Ganglioneuronoblastic differentiation in malignant melanoma is exceptionally rare, with less than ten cases reported in the literature. This case provides potential insight into the increasingly common de-/transdifferentiation phenomenon following anti-PD1 therapy, with discussion of the clinical features and treatment follow-up.