Abstract
NTRK3 fusions are a relatively common driver of Spitz neoplasms. This subset of Spitz neoplasms may have smaller cells without the typical abundant glassy eosinophilic cytoplasm seen in most Spitz neoplasms. This can make it difficult to recognize them as belonging to the Spitz family and potentially result in misdiagnosis as melanoma. In this study we assess the clinical, morphologic and genomic features of 60 NTRK3 fusion Spitz neoplasms (13 previously reported and 47 new cases) and perform a comprehensive review of the literature. We identified 5 characteristic morphologic patterns: 1) conventional Spitz nevus or tumor 2) spindle cell nevus of Reed 3) spindle cell tumor of Reed 4) dysplastic Spitz nevus 5) exclusively spindle cell variant of Spitz nevus/tumor. The most common fusion partners were MYO5A and ETV6. DNA copy number changes were infrequent (18% of cases) with an average of 1 CNV per case. Among 54 cases tested for a TERT promoter mutation, all were negative. One case had a homozygous deletion of 9p21. The majority of cases were diagnosed as Spitz or Reed nevi (n=37) rather than Spitz or Reed tumors (n=23) and none were diagnosed as Spitz melanoma. Among the 30 patients with outcome data, none experienced recurrence following excision (mean follow up time was 15 months). NTRK3 fusions can produce morphologic variants of Spitz neoplasms that may be difficult to recognize as belonging to the Spitz family. Familiarity with these morphologic patterns can facilitate identification of the NTRK3 fusion optimizing classification and distinction from melanoma.

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