A report of thirteen non-conventional FLCN-mutated (renal) tumors (FMT) and a discussion of proposed diagnostic criteria, convergent FLCN/TFEB and FLCN/MITF E318K signaling, and FLCN immunohistochemistry

BACKGROUND Recent studies have demonstrated that FLCN-mutated tumors (FMT) represent a unique tumor type with dual FOXI1+ and L1CAM+ cell populations. Low-grade, well-circumscribed eosinophilic tumors (conventional FMT, c-FMT) are typically indolent, whereas tumors exhibiting morphologic divergence from this pattern including tubulopapillary, microcystic, or tubulocystic architecture (non-conventional FMT, nc-FMT) may rarely demonstrate metastatic behavior. METHODS Thirteen new nc-FMTs were evaluated using histologic review, immunohistochemistry, and a kidney cancer-specific next-generation sequencing (NGS) panel. Analysis for TFE3/TFEB rearrangements (by FISH/NGS) and chromosomal copy number changes were performed in a subset of cases. Combined findings from an overall cohort of 77 c-FMTs and 21 nc-FMTs across 35 patients have been reported. RESULTS The most common morphologic pattern for nc-FMT was papillary/tubulopapillary (9/21, 43%), followed by microcystic (histiocyte-rich)/tubulocystic (7/21, 33%). GPNMB was an excellent immunohistochemistry screen showing diffuse positivity in all c-FMT (n=34) and nc-FMT (n=19), while L1CAM had less consistent expression in nc-FMT suggestive of a single cell population in some cases (H-score: 0, 3/20, 15%; H-score: 300, 4/20, 20%). Immunohistochemistry for FLCN failed to separate FMT (n=23) from morphologic mimics (n=13). Metastatic behavior was seen in 3/21 nc-FMT that had alterations of TFEB (amplification and gain, one case each) or an MITF p.E318K alteration (one case). CONCLUSIONS Our cohort provides insight into the natural history of FMT and helps define the histopathologic and molecular features of nc-FMT. Rare metastatic nc-FMTs demonstrate potentially convergent FLCN/TFEB and FLCN/MITF signaling, a finding that warrants prospective validation and may enable improved prognostication of clinically aggressive tumors.