Cutaneous Non-Neural Granular Cell Tumors Harbor Recurrent ALK Gene Fusions

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Abstract

Non-neural granular cell tumor (NNGCT; also known as primitive polypoid granular cell tumor) is a rare neoplasm composed of large ovoid cells with abundant granular cytoplasm, variable nuclear pleomorphism, and the potential for regional lymph node spread. In contrast to conventional granular cell tumor (GCT), NNGCT lacks S100 expression and can exhibit greater nuclear atypia and mitotic activity. Therefore, we investigated clinicopathologic features of 12 NNGCT, and also used next-generation sequencing to identify potential driver events in a subset of NNGCT and 6 GCT. NNGCT demonstrated mild-to-moderate nuclear pleomorphism, variable mitotic activity (0 to 10/10 high-power fields), and were S100−. Genetic analysis of 5 cutaneous NNGCT revealed gene fusions involving the anaplastic lymphoma kinase gene (ALK) in 3 cases (60%). Specifically, an interstitial deletion of chromosome 2 resulting in an in-frame fusion of dyanactin 1 (DCTN1) to ALK was identified in 2 cases, and a translocation resulting in a fusion between sequestosome 1 (SQSTM1) on chromosome 5 and ALK was identified in one case. Two of 6 GCT (33%) showed gains of chromosome 7. No other molecular or chromosomal alterations were detected in NNGCT and GCT. ALK immunohistochemistry revealed weak-to-moderate positivity in 4/9 cutaneous NNCGT (44%) including all 3 tumors with ALK fusions. Three oral NNGCT lacked ALK expression. NNGCT with ALK immunostaining did not have morphologic features distinguishing them from those without ALK staining. Our results demonstrate that a subset of NNGCT harbor ALK fusions, suggest that NNGCT are molecularly diverse, and further substantiate NNGCT as distinct from GCT.

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