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.