Role of Targeted Sequencing in Routine Diagnostics of Spitz Melanocytic Neoplasms—An Analysis of 70 Cases

ABSTRACT Background There is growing evidence that the Spitz group of melanocytic neoplasms should be restricted to those harboring kinase receptor fusions and HRAS mutations/11p15 amplification. The presence of genomic alterations characteristic of conventional melanomas (BRAF and NRAS mutations) precludes a diagnosis of a Spitz neoplasm. It is often challenging to distinguish Spitz neoplasms from conventional melanomas with spitzoid morphology on histopathological grounds alone. Methods We report a series of 70 consecutive melanocytic tumors in which targeted sequencing was indicated to distinguish Spitz from spitzoid neoplasms and to classify Spitz neoplasms along the biological spectrum. Results Final diagnoses incorporating molecular results included 12 conventional melanomas (nine of which with NRAS mutations), five Spitz melanomas, 35 atypical Spitz tumors, eight Spitz nevi, three melanocytic tumors with a MAP2K1 mutation, and seven desmoplastic Spitz nevi/tumors. There were significant discrepancies between initial diagnoses and final diagnoses after incorporating molecular results in 24 (34%) cases, including nine conventional melanomas favored to be Spitz neoplasms and nine Spitz neoplasms favored to be conventional melanomas. Conclusions It is often not possible to reliably distinguish Spitz neoplasms from spitzoid melanocytic tumors without identifying their driver genomic alterations. Applying next‐generation sequencing in diagnostically problematic tumors improves diagnostic accuracy.