Abstract

Most Spitz tumors exhibit recurrent gene fusions including receptor tyrosine kinase and MAP kinase 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. It was predominantly intradermal. Lesional melanocytes displayed abundant eosinophilic cytoplasm, enlarged nuclei with vesicular chromatin, and variably prominent nucleoli. The melanocytes were arranged in irregularly shaped nests and cords showing minimal maturation with dermal descent. There were occasional dermal mitotic figures. The deep aspect of the biopsy was involved. SOX10, S100 protein, and MITF immunohistochemical stains were diffusely positive; Melan-A and HMB45 showed only focal staining, reminiscent of CRTC1::TRIM11 and MED15::ATF1 cutaneous tumors. PRAME was negative. FISH showed copy number gains at 6p25 (RREB1) and 11q13 (CCND1) that narrowly exceeded cutoff values. Whole-transcriptome sequencing revealed CPEB2::MAP3K2. Cytoplasmic polyadenylation element binding protein 2 (CPEB2) is an mRNA-binding protein that regulates mRNA polyadenylation as a trans factor in oogenesis and spermatogenesis. MAP3K2 participates in the MAPK, NF-kB and protein kinase C signaling pathways. To our knowledge, this fusion has not been previously reported in melanocytic lesions or any other human tumor. Due to the presence of mitotic activity, the borderline positive chromosomal abnormalities, and potentially more aggressive behavior of Spitz tumors with MAP3K8 fusions, a conservative re-excision with negative margins was recommended, along with ultrasound monitoring of the regional lymph node basin. Minimal follow-up information is available. Longer-term follow-up and additional cases will be required to determine the biologic behavior of this tumor.