Immunoreactivity of GPNMB (glycoprotein nonmetastatic melanoma protein B) across the spectrum of uterine mesenchymal tumours.

BACKGROUND: GPNMB is a lysosomal transmembrane protein that has emerged as a diagnostic marker for tumours driven by the microphthalmia-associated transcription factor family (TFE3 and TFEB) and mTOR pathway activation. Diffuse, moderate-to-strong GPNMB positivity has been proposed as a surrogate marker for both translocation-driven and mTOR pathway-activated neoplasms, including PEComas. This study investigated the diagnostic utility of GPNMB immunohistochemistry in differentiating uterine PEComas from common morphological mimics among uterine mesenchymal tumours. MATERIALS AND METHODS: We analysed a cohort of 115 uterine mesenchymal tumours, which included nine PEComas and a broad panel of differential diagnoses, comprising leiomyosarcoma (LMS, n = 19), STUMP (n = 20), leiomyoma (n = 10), low-grade endometrial stromal sarcoma (LG ESS, n = 18), high-grade ESS (HG ESS, n = 13), adenosarcoma (n = 11), undifferentiated uterine sarcoma (UUS, n = 5), inflammatory myofibroblastic tumour (IMT, n = 3) and a collection of rare entities (1 UTROSCT, 3 KAT6B/A::KANSL1-, 2 PLAG1- and 1 NTRK-rearranged sarcomas). Immunohistochemistry (IHC) for GPNMB was performed, and a case was strictly defined as positive only if it showed diffuse staining (>75% of tumour volume) of moderate to strong intensity. RESULTS: All uterine PEComas (9/9; 100%) showed diffuse moderate to strong GPNMB positivity. However, diagnostically significant expression was also observed in LMS (9/19; 47%), UUS (2/5; 40%), IMT (2/3; 67%) and LG ESS (1/18; 6%). All other entities lacked diagnostic GPNMB expression, showing negative or only focal (1%-75% of tumour cells) or diffuse but weak staining. Low-level GPNMB expression was common, with focal or weak staining present in 65% of non-positive tumours (60/92), supporting the use of strict scoring criteria. CONCLUSIONS: Although highly sensitive for uterine PEComa, GPNMB lacks sufficient specificity for distinguishing PEComa from its principal uterine mesenchymal mimics, particularly LMS, IMT and UUS. Although strict scoring criteria (moderate-to-strong positivity in >75% of tumour cells) reduce false-positive interpretation, GPNMB should not be used as a standalone discriminatory marker but interpreted in conjunction with morphology and a broader immunohistochemical panel.