Immunohistochemical expression of GPNMB in TFEB-rearranged and TFEB-amplified renal cell carcinomas

TFEB-altered renal cell carcinomas (RCCs) display a wide range of morphological features and variable immunohistochemical profiles, often overlapping with other RCC subtypes. This variability poses significant diagnostic challenges. Consequently, there is an ongoing search for reliable ancillary tests that can aid in identifying cases that warrant molecular testing. In this study, we focused on GPNMB immunohistochemistry expression in TFEB-rearranged and TFEB-amplified RCCs. A total of 25 TFEB-altered RCCs, including 16 TFEB-amplified RCCs and nine TFEB-rearranged RCCs, were included in the study. GPNMB immunohistochemistry was positive in all nine TFEB-rearranged RCCs, demonstrating strong, diffuse cytoplasmic staining. In the TFEB-amplified RCC cohort, GPNMB expression was also detected in all 16 tumors; however, the staining pattern differed from that seen in TFEB-rearranged RCCs. Diffuse staining was observed in eight tumors (50%), four of which showed variable staining intensity, while the remaining eight tumors (50%) exhibited focal GPNMB reactivity, with intervening negative areas. GPNMB was therefore positive in all 25/25 (100%) TFEB-altered RCCs by IHC, supporting its potential role as a sensitive screening marker for such RCCs. TFEB-rearranged RCCs typically exhibited strong, diffuse GPNMB immunoreactivity, whereas TFEB-amplified RCCs more often showed patchy or focal staining of lower intensity, interspersed with areas of GPNMB negativity. Variability of staining in TFEB-amplified RCCs underscores the need for cautious interpretation, particularly in limited biopsy specimens, taking into account the morphologic findings and other immunohistochemistry stains, such as Melan A and Cathepsin K.