Morphologic and Immunohistochemical Characteristics of Fluorescent In Situ Hybridization ConfirmedTFE3-Gene Fusion Associated Renal Cell Carcinoma A Single Institutional Cohort

TFE3-fusion associated renal cell carcinoma (TFE3-RCC) accounts for up to 5% adults and 40% of childhood RCC. Their comprehensive immunohistochemical (IHC) profile in correlation to fluorescence in situ hybridization (FISH) testing and their role in the diagnostic approach are not well documented because of lacking published data. FISH confirmedTFE3-RCC between years 2010 and 2020 were identified from institutional electronic database and retrospectively reviewed. Eighty-fiveTFE3-RCC were identified. Seventy-six of 85 (89.4%)TFE3-RCC cases had positiveTFE3expression, with diffuse and strong/moderateTFE3expression in 45 (54.2%). Three (3.5%)TFE3-RCC had negativeTFE3expression whereas 6 (7%) cases had equivocalTFE3expression. On the other hand, positiveTFE3-IHC expression was observed in 17/29 (58.6%)TFE3-FISH negative RCC cases, although only 8 (27.5%) had diffuse and moderate/strongTFE3expression. Diffuse and strongTFE3-IHC expression was statistically significant in predictingTFE3-FISH positivity (P<0.0001) regardless of morphologic features. After univariate and multivariate analyses,TFE3-IHC was the only parameter with significant predictive value for detecting positiveTFE3-FISH (P<0.0001). On univariate analysis, sex, classic morphology, age, negative AE1/AE3 or cytokeratin 7 were not predictive ofTFE3-FISH positivity. Diffuse and strong nuclearTFE3-IHC expression is significantly associated withTFE3-FISH positivity and can be used as a surrogate marker to confirm translocation associated cases.TFE3-rearranged RCCs show variable histomorphologic features andTFE3-FISH should be performed in cases presenting at a younger age or, regardless of the age, tumors with unusual morphology. Despite previous reports, negative pancytokeratin and positive cathepsin K expression may not be reliable markers forTFE3-RCC.