Evaluation of nuclear pseudoinclusions, GATA3, 34βE12, and GPNMB performances in CK7 diffuse positive clear cell...

Recent studies have revealed histological diversity among clear cell renal cell neoplasms demonstrating diffuse CK7 positivity. While prior research established the utility of GATA3 and 34βE12 immunohistochemistry in clear cell papillary renal cell tumors (CCPRCT) and GPNMB in TSC/mTOR pathway-altered RCC with fibromyomatous stroma (TSC/mTOR RCC FMS), this study employed next-generation sequencing to analyze 36 CK7-diffuse positive clear cell renal neoplasms. These were classified as ELOC-mutated RCC (n = 17), TSC/mTOR RCC FMS (n = 12), CCPRCT (n = 4), and clear cell RCC (n = 3). Cystic architecture was uncommon in TSC/mTOR RCC FMS (2/12) and common in ELOC-mutated RCC (15/17), and nuclear pseudoinclusions were rare in ELOC-mutated RCC (1/17), but common in TSC/mTOR RCC FMS. GATA3 and 34βE12 expression was common in CCPRCT (2/4 and 4/4) and TSC/mTOR RCC FMS (5/11 and 8/11), though rare ELOC-mutated RCC exhibited focal expression (1/12 and 3/10). Limited weak cytoplasmic granular GPNMB expression occurred in one ELOC-mutated RCC and CCPRCT; however, diffuse GPNMB expression was exclusively identified in neoplasms with TSC/mTOR pathway alterations. These results emphasize that GATA3 and 34βE12 expression are not specific to CCPRCT, as they also occur in ELOC-mutated RCC and TSC/mTOR RCC FMS. While focal weak GPNMB expression may be observed in some ELOC-mutated RCC and CCPRCT, diffuse strong expression remains distinctive for TSC/mTOR pathway-altered neoplasms. The frequent nuclear pseudoinclusions observed in TSC/mTOR RCC FMS may aid differential diagnosis.