Spitz Melanocytoma With a Novel CPEB2::MAP3K2 Rearrangement: A Case Report

Most Spitz tumors exhibit recurrent gene fusions involving receptor tyrosine kinase or MAPK pathway genes. Here, we describe a Spitz tumor with a novel fusion involving MAP3K2. The lesion occurred on the penile shaft of an 18-year-old. Histopathologically, tumor cells were predominantly dermal, arranged in irregularly shaped nests and cords showing minimal maturation with dermal descent, and accompanied by pseudoepitheliomatous epidermal hyperplasia. Melanocytes displayed abundant eosinophilic to amphophilic cytoplasm, variably enlarged rounded nuclei, fine chromatin, and scattered nucleoli or chromocenters. There were occasional dermal mitotic figures (1/mm²). The lesion involved the deep aspect of the biopsy specimen. SOX10, S100 protein, and MITF immunohistochemical stains were diffusely positive, while Melan-A and HMB45 staining was only focal. PRAME was negative. FISH showed copy number gains at 6p25 (RREB1) and 11q13 (CCND1) narrowly exceeding cutoff values. Next-generation sequencing revealed a CPEB2::MAP3K2 fusion and a low tumor mutation burden (2.1/Mb). To our knowledge, this fusion has not been previously reported in melanocytic lesions or other human tumors. A conservative re-excision was performed, and a PET/CT scan showed no evidence of dissemination. With 16 months of follow-up available, longer-term monitoring will be required to determine the clinical behavior and biologic potential of this tumor.