Comprehensive analysis of six MED15::TFE3 renal cell carcinomas including two novel solid MED15::TFE3 renal cell carcinomas, highlighting their morphologic, immunohistochemical and molecular differences from their cystic counterparts

In 2017, the first case of TFE3-rearranged renal cell carcinoma (RCC) with MED15 as a novel fusion partner gene was reported. Since then, vast majority of MED15::TFE3 RCCs were reported to have characteristic extensively cystic appearance, with the septa being lined by tumor cells with optically clear cytoplasm and inconspicuous nucleoli, morphologically mimicking multilocular cystic renal neoplasm of low malignant potential and clear cell RCC with extensive cystic changes. IHC stains are helpful in such diagnostic scenario, as MED15::TFE3 RCCs are negative for carbonic anhydrase IX (CAIX) and are positive for melanocytic markers and TFE3. However, the current MED15::TFE3 RCCs case series includes two solid MED15::TFE3 RCCs, which are morphologically, immunohistochemically and molecularly different from the conventional MED15::TFE3 RCCs that are extensively cystic. One case is purely solid with nests of tumor cells with clear cytoplasm mimicking clear cell RCC. This purely solid MED15::TFE3 RCC is positive for TFE3, focally positive for CAIX with box-like membranous staining, and negative for Melan A. Another case is mostly solid and tubulopapillary with minor cystic components, is positive for TFE3, and negative for Melan A and CAIX. The non-cystic MED15::TFE3 RCCs also have unique fusion transcripts that are different from those seen in the conventional MED15::TFE3 RCCs. The phenotypic variation of MED15::TFE3 RCCs may be due to the property of the fusion transcripts, although additional studies are required to validate this finding.