Track

Basic Science

Abstract

The clinical spectrum of xanthogranuloma includes  solitary  (~80% of total) , multiple  and disseminated disease.  Mortality is 25% with disseminated disease. We encountered two  consecutive patients with solitary xanthogranuloma with pan-NTRK immunoreactivity and confirmed the presence of an NTRK1 fusion with both RNA and DNA sequencing.  We screened additional patients by pan-NTRK immunostain, and found that 26 of 48 (54%) with solitary xanthogranulomas had NTRK overexpression. We sequenced 23 patients. In all 16 patients with a positive immunostain we confirmed  NTRK1 fusion using RNA/DNA sequencing. In all 7 patients that were negative by immunostain we identified no NTRK fusion. Patients with  fusion had overexpression of NTRK1 RNA  relative to wild-type tumors with a mean 58-fold increase (p= 8.77e-15). Fusions demonstrated loss of the extracellular portion of NTRK1, and fusion partners limited to TPM3, PRDX1, IRF2BP2, LRRIP1, SQSTM1. We identified recurrent LOF  mutations in DNA methylation genes DNMT3A, KDM5D,  SETD2 as well as  MTOR-PI3K pathway gene, FLCN. Recurrent copy number gains were detected in MTOR-PI3K pathway genes PIK3CG,  IL10Ra . The frequency of NTRK1 fusions is higher in solitary compared to multifocal and disseminated xanthogranuloma (54% vs ~11%). 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-NTRK immunostain may have utility to confirm the diagnosis of xanthogranuloma in a histiocytic lineage tumor and to screen for low-risk xanthogranuloma.