NTRK Fusions in Xanthogranuloma, a Clinicopathologic and Molecular Analysis of 23 Cases.

Xanthogranuloma is the most common category of histiocytic neoplasia, with a range of clinical behaviors from solitary cutaneous lesions to multiple cutaneous lesions and less frequent cases with evolution to disseminated disease. Solitary lesions make up 78% to 81% of total cases. We encountered 2 consecutive index patients with solitary cutaneous xanthogranuloma with NTRK overexpression by immunostaining and confirmed the presence of an NTRK1 fusion with both RNA and DNA sequencing. We screened 55 additional patients by pan-TRK immunostain, and found that 26 of 48 (54%) with solitary xanthogranulomas had TRK overexpression, whereas 0 of 7 (0%) multifocal or disseminated xanthogranulomas had TRK overexpression. We sequenced a subset of 23 patients with solitary xanthogranuloma. In all 16 patients with a positive pan-TRK immunostain, we confirmed the presence of an NTRK1 fusion using RNA and DNA sequencing. In all 7 patients that were negative by immunostain we identified no NTRK fusion by sequencing. All patients with a fusion identified by sequencing had overexpression of the NTRK1 RNA transcript relative to wild-type tumors with a mean 58-fold increase over wild-type tumors (P=8.77e-15). Further, all cases with fusions had a loss of the extracellular portion of NTRK1, and fusion partners were limited to TPM3, PRDX1, IRF2BP2, LRRIP1, and SQSTM1. DNA sequencing identified additional recurrent loss of function mutations in DNA methylation genes DNMT3A, KDM5D, and SETD2, as well as the MTOR-PI3K pathway gene FLCN. Recurrent copy number gains were detected in MTOR-PI3K pathway genes PIK3CG, IL10Ra, as well as transcriptional regulator PAX8. The frequency of NTRK1 fusions appears markedly higher in solitary compared with multifocal and disseminated xanthogranuloma (54% vs. 0%). The reduced proportion of NTRK1 fusions in disseminated cases relative to solitary cases suggests that NTRK1 fusions are less efficient than MAP kinase pathway point mutations at driving tumor evolution towards disseminated disease. As NTRK1 fusions are uncommon in other histiocytoses, pan-TRK immunostain may have utility to confirm the diagnosis of xanthogranuloma in a histiocytic lineage tumor and to screen for low-risk xanthogranuloma.