GPNMB expression in clear cell papillary renal cell tumour: Limited specificity and a potential diagnostic pitfall in clear cell renal neoplasms.

GPNMB is considered a relatively specific marker for MiTF-associated renal cell carcinoma (RCC) and renal neoplasms with mTOR pathway alteration. However, more recent studies have broadened this view, demonstrating that its specificity is lower than previously thought due to expression in other renal tumour subtypes. In this study, we evaluated GPNMB expression in a cohort of clear cell papillary renal cell tumours (CCPRCT) and compared to a cohort of renal epithelial neoplasms with clear cell morphology. A total of 35 CCPRCTs were analysed, along with a control cohort of 50 renal tumours, comprising clear cell RCC (CCRCC; n = 32), multilocular cystic renal neoplasm of low malignant potential (MCRNLMP; n = 6), and RCC with fibromyomatous stroma (RCC FMS; n = 12). All CCPRCTs had typical morphologic features with strong and diffuse CK7 positivity. The majority of CCPRCTs (89%) showed GPNMB reactivity (diffuse weak/moderate in 20, and focal weak/moderate in 11 tumours). In the CCRCC and MCRNLMP group, 92% (35/38) did not show any GPNMB expression (29/32 CCRCCs and 6/6 MCRNLMPs). Among 12 RCC FMS, three tumours harbouring TSC1/2 alterations demonstrated diffuse strong GPNMB staining. In contrast, among 9 MTOR-mutated RCC FMS, diffuse moderate staining was observed in only 2 tumours; 6 tumours exhibited focal weak to moderate reactivity, and one showed diffuse weak staining. Weak to moderate GPNMB expression is frequently observed in CCPRCT. The GPNMB staining pattern identified in a substantial proportion of MTOR-mutated RCC FMS overlapped with that seen in CCPRCT. This finding underscores the limited specificity of GPNMB as a diagnostic marker.