ALK fusion Spitz neoplasms show distinct morphologic patterns and genomic correlates in meta-analysis

A comprehensive understanding of newly described tumors is often an evolutionary process. In this study, we describe the extended spectrum of morphologic patterns in a cohort of 144 ALK fusion Spitz neoplasms and provide the largest data set of ALK fusion Spitz with clinical follow-up. In addition to the most classic morphologic pattern of a nodular silhouette with wavy fascicles of spindle cells, these tumors may also form a desmoplastic pattern, a combined nevus of Reed-Spitz pattern, a predominantly epithelioid pattern, and a nevoid pattern. There are genomic correlates to some of these morphologic patterns, with Reed-Spitz cases frequently having TPM4 as the fusion partner ( P =0.001), epithelioid cases frequently having EHBP1 as the fusion partner ( P =0.0002), and nevoid cases frequently having KIF5B as the fusion partner. Two fusion partners, ZEB2 and EML4 , were only seen in Spitz melanoma (SM) cases. TERT promoter mutations and c-MYC amplification were only seen in SM. A meta-analysis of the literature suggests that adverse events tend to be associated with c-MYC amplification, CDKN2A homozygous deletion, and higher mitotic count (5.5 mitoses/mm 2 in metastatic cases vs. 2.2 mitoses/mm 2 in nonmetastatic cases). Our study expands the morphologic spectrum and the associated genomic correlates of ALK -rearranged Spitz neoplasms and identifies parameters associated with malignant behavior.