Utility of sequencing for ATP6AP1 and ATP6AP2 to distinguish between atypical granular cell tumor with junctional component and melanoma.

Abstract

Granular cell tumor (GCT) is a S100+ neoplasm with atypical and malignant variants. Similar to melanocytic neoplasms, the tumors make nests and can have junctional components raising a differential diagnosis of melanoma. Nevi and melanomas may also have granular cell cytoplasm. MelanA is useful in distinguishing melanocytic from granular cell lineage, but increasingly MelanA/SOX10 negative melanomas have been recognized by correlation with molecular methods. We encountered several cases with morphologic overlap between melanoma and atypical GCT necessitating additional molecular workup. We sequenced two cases and searched our archive for similar cases of GCT with overlapping features of melanocytic lineage. In our two index cases, we excluded melanoma driver mutations and identified frameshift or premature stop codons in ATP6AP1/2 pathognomonic of granular cell lineage. Data retrieved from Cosmic identified 24 melanomas with missense single nucleotide variants (SNVs) in ATP6AP1 but no frameshift or premature stop codons. Twenty-one melanomas had missense SNVs in ATP6AP2. One melanoma had a premature stop codon in ATP6AP2, but this lesion also had a melanoma-associated driver mutation NRASQ61K. We found 1 of 23 additional cases of GCT in our archives with a junctional component and no additional cases with maturation. Atypical and malignant GCT can have histopathologic overlap with melanoma. Frameshift and premature stop codons in ATP6AP1/2 are specific for granular cell lineage, and capable of excluding melanoma, in the absence of known melanoma-associated driver mutations.