Genomic comparison of malignant melanoma and atypical Spitz tumor in the pediatric population

The diagnostic distinction between atypical Spitz tumor (AST) and malignant melanoma (MM) in pediatric tumors is challenging. Molecular tests are increasingly used to characterize these neoplasms; however, limited studies are available in pediatric patients. This study aimed to provide a genomic comparison of pediatric MM and AST in the context of comprehensive clinical annotation.

Pediatric patients diagnosed with MM (n=11) and AST (n=12) were compared to a cohort of 693 adult melanoma patients. DNA next-generation sequencing assessed kinase gene fusions, tumor mutational burden, sequence variants, copy number alterations, structural variants, microsatellite instability, and mutational signatures.

Seven AST cases and eight MM cases were successfully sequenced. Kinase gene fusions were identified in both the MM and AST cohorts (NTRK1, ROS1, and MET). MM cases had TERT, BRAF, and CDKN2A alterations, which were not identified in the AST cohort. Tumor mutational burden (TMB) analysis showed pediatric ASTs had an average of 2.82 mutations/Mb, pediatric MM had an average of 5.7 mutations/Mb, and adult MM cases averaged 18.8 mut/Mb. One pediatric MM case had an elevated TMB of 15 mutations/Mb and a UV mutational signature.

These data expand our understanding of pediatric malignant melanoma. The differences between the molecular signatures for AST and MM are not statistically significant, and histopathology remains the gold standard for the diagnosis of pediatric AST and MM at this time. With more data, molecular studies may provide additional support for diagnosis and targeted therapeutics.