A Clinical, Morphologic, and Molecular Comparison of Bonafide Spitz Melanomas and Atypical Spitz Tumors in the Pediatric Population

Pediatric Spitz melanoma (SM) with bonafide metastatic disease is rare. In this study, we assembled the largest cohort to date of pediatric SM with a verified Spitz-associated genomic driver and clinical follow-up demonstrating bonafide metastasis. We compared the clinical, morphologic, and molecular features of these SMs to a control cohort of 57 pediatric atypical Spitz tumors (ASTs). Pediatric SM patients were significantly older than AST patients (12 vs 8 years of age). While not statistically significant, SMs were more likely to be heavily pigmented (5/7 SMs vs 11/57 ASTs), to have a sheet-like growth pattern (3/7 SMs vs 8/57 ASTs), and have severe nuclear atypia (6/7 SMs vs 20/57 ASTs). SMs had significantly greater mitotic activity (avg of 4.3/mm 2 in SMs and 2.7/mm 2 in ASTs, P =0.008) and more frequent larger cell size ( P =0.006). However, none of these features were specific and could also be seen in ASTs. The presence of homozygous deletions of 9p21 in conjunction with TERT promoter hot spot mutations or PTEN deletions (n=2), as well as MYC overexpression or amplification (n=2) were only seen in the SMs and none of the ASTs. These findings were mutually exclusive in the SM group and mutually exclusive with the presence of complex chromosomal copy number aberrations, which were seen in the remaining 3 pediatric SMs. This study demonstrates that there are multiple pathways to malignancy for pediatric SMs and none of our commonly used biomarkers have a particularly high sensitivity. Hence, the optimal distinction of pediatric SM from ASTs will continue to require the integration of clinical, histologic, and molecular data.