Diagnostic accuracy of TRIM63 RNA-ISH in MiTF-rearranged renal cell carcinomas: Results from a 331-tumor validation cohort.

The microphthalmia-associated transcription factor rearranged renal cell carcinoma (MiTF-rRCC) comprise very heterogenous group of tumors with variable histology mimiking other renal cell tumors and often present a diagnostic challenge. Tripartite Motif Containing 63 (TRIM63) has been proposed as a novel marker of MiTF-rRCC, but its sensitivity and specificity remain unknown. The study aimed to investigate TRIM63 expression in a large independent cohort of different renal cell tumors and determine its diagnostic value in detecting MiTF-rRCC. TRIM63 RNA in situ hybridization (RNA-ISH) was performed on 331 renal cell tumors, including 15 TFE3-translocation RCCs (TFE3-tRCC), 3 TFEB-amplified RCCs (TFEB-aRCC), 113 clear cell RCCs, 66 papillary RCCs, 27 oncocytomas, 23 chromophobe RCCs, 13 eosinophilic solid and cystic (ESC)-RCCs, 10 collecting duct carcinomas, 6 tubulocystic RCC, 4 fumarate hydratase (FH)-deficient RCCs, 51 other types of RCCs. TRIM63 overexpression was identified in 80 % (12/15) of TFE3-tRCC, 33.3 % (1/3) of TFEB-aRCC, while being positive only in 4 % of other renal cell tumor types (12/313). Among non-MITF-rRCC positive cases, significant incidence of TRIM63 overexpression was detected in 66.7 % of tubulocystic RCC (4/6), 38.5 % of ESC-RCC (5/13) and 25 % of FH-deficient RCC (1/4). The overall performance of TRIM63 RNA-ISH assay for detecting MITF-rRCC tumors showed high specificity (96.2 %) and negative predictive value (98.4 %) with relatively lower sensitivity (72.2 %) and positive predictive value (52.0 %). In conclusion, TRIM63 RNA-ISH can be a useful diagnostic marker of MiTF-rRCC. TRIM63 RNA-ISH could improve the diagnostic accuracy of recognizing MiTF-rRCC in an adequate histologic background and distinguishing them from other renal cell tumors.