Aberrant HER2 Expression as a Specific and Feasible Diagnostic Marker for Fumarate Hydratase-Deficient Renal Cell...

The presence of human epidermal receptor 2 (HER2) in fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) remains unexplored. We investigated immunohistochemical staining for HER2 (clone 4B5), FH, 2SC, and AKR1B10 on 72 cases of FH-deficient RCC and 440 cases of other RCC subtypes. HER2 positivity was observed in 88.9% (64/72) of FH-deficient RCCs, manifesting as cytoplasmic only (6.9%), cytoplasmic and nuclear (47.2%), cytoplasmic and membranous (2.8%), or cytoplasmic, nuclear, and membranous (31.9%) patterns. Notably, all four cases of low-grade FH-deficient RCC exhibited cytoplasmic, nuclear, and membranous positivity. HER2 fluorescence in situ hybridization test showed no amplification in any of the 30 HER2-positive FH-deficient RCCs. Next, 27 FH-deficient RCCs stained with two additional N-terminal HER2 antibodies (A21248 and HA721178) revealed cytoplasmic and membranous positivity similar to those with 4B5 but lacked nuclear expression, and western blot confirmed recognition of the 185 kDa HER2 protein by all three antibodies. In contrast, HER2 (4B5) staining was absent in clear cell RCCs, chromophobe RCCs, typical papillary RCCs, papillary renal neoplasms with reverse polarity, and SMARCB1-deficient renal medullary carcinomas, whereas positivity was observed in 2.4% (2/83) of TFE3-translocation and 22.2% (2/9) of oncocytic papillary RCCs. HER2 achieved 88.9% sensitivity (superior to FH; inferior to 2SC and AKR1B10) and 99.1% specificity (superior to 2SC and AKR1B10; inferior to FH), with the HER2/FH combination yielding optimal diagnostic efficacy. In conclusion, FH-deficient RCCs are characterized by prevalent cytoplasmic HER2 staining with variable nuclear/membranous reactivity, and the combined HER2/FH panel may serve as an effective screening strategy.