GPNMB Expression Identifies FLCN-Associated Eosinophilic Renal Tumors With Heterogeneous Clinicopathologic Spectrum and Gene Expression Profiles

FLCN -associated eosinophilic renal tumors mainly refer to hybrid oncocytic/chromophobe tumors (HOCT) and other oncocytic tumors related to Birt-Hogg-Dubé (BHD) syndrome, which can sometimes occur sporadically. Accurate diagnosis of FLCN -associated tumors is challenging due to their morphologic heterogeneity and the lack of reliable biomarkers. We evaluated the clinicopathologic and IHC profiles of 18 eosinophilic renal tumors with targeted DNA sequencing-confirmed FLCN mutations, including 10 typical HOCT and 8 unclassified tumors. Fourteen of these, plus 45 cases from the control group, were profiled transcriptionally by RNA-seq. Ten typical HOCT displayed consistent mosaic morphology and immunohistochemical patterns. Eight unclassified FLCN -mutated tumors exhibited diverse morphologies, including chromophobe renal cell carcinoma (ChRCC)-like, succinate dehydrogenase-deficient renal cell carcinoma (SDH-RCC)-like, and histiocyte-rich patterns, lacking obvious hybrid cellular components and typical immunohistochemical features. Despite this heterogeneity, glycoprotein non-metastatic melanoma protein B (GPNMB) was identified as a highly sensitive biomarker for FLCN -mutated tumors, showing strong and diffuse positivity in both typical HOCT, unclassified FLCN -mutated tumors, and in the oncocytosis surrounding the tumors. RNA sequencing revealed that typical HOCT formed a unique gene expression cluster, distinct from recognized renal tumor types. Some unclassified FLCN -mutated tumors were grouped with HOCT, while others remained unclassified among known kidney tumors, existing independently. This study expanded the morphologic spectrum of FLCN -mutated renal tumors and highlighted GPNMB as a valuable diagnostic marker for both typical and unclassified FLCN -mutated tumors. GPNMB should be utilized to screen eosinophilic renal tumors that cannot be classified, aiding in the precise diagnosis and management of BHD or sporadic FLCN mutation-related patients.