Unlocking diagnostic potential: A retrospective analysis of GPNMB immunohistochemistry in nearly 1000 surgical pathology specimens

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a lysosomal transmembrane protein regulated by the TSC/mTOR-TFE pathway and has been proposed as a diagnostic immunohistochemical (IHC) marker for tumors associated with TSC/mTOR-TFE pathway alterations. However, its diagnostic performance in routine surgical pathology has not been systematically evaluated on a large scale. We retrospectively reviewed 934 cases from the Johns Hopkins pathology archives (2021–2025) in which GPNMB IHC was performed. Diagnoses were categorized into TSC/mTOR-TFE-related, non-TSC/mTOR/TFE-related, or undefined molecular groups. Correlation with fluorescence in situ hybridization (FISH) results and histologic features was performed to assess diagnostic utility. GPNMB was diffusely positive in 94.8 % (218/230) of TSC/mTOR-TFE-related neoplasms, including renal cell carcinomas with TFE3/TFEB rearrangements, perivascular epithelioid cell tumors (PECOMA/AML), and other related entities. In contrast, 83.3 % of non-TSC/mTOR-TFE-related tumors were negative for GPNMB. Discordant cases were seen in both groups, likely reflecting molecular heterogeneity, limitations of FISH, or the complex regulation of GPNMB expression. GPNMB outperformed cathepsin K in sensitivity in FISH-confirmed cases with TFE3 or TFEB alterations. Patchy or equivocal staining required careful histologic and ancillary correlation for interpretation. GPNMB IHC is a valuable ancillary tool in diagnosing TSC/mTOR-TFE-related neoplasms, particularly in renal and mesenchymal tumors. While not perfectly specific or sensitive, it offers a rapid and cost-effective alternative to molecular testing and can guide further diagnostic workup. Positive GPNMB staining in tumors without known TSC/mTOR-TFE alterations may suggest secondary pathway involvement, warranting additional molecular studies.