Comprehensive analysis of 34 MiT family translocation renal cell carcinomas and review of the literature: investigating prognostic markers and therapy targets

Recently cabozantinib, a tyrosine kinase inhibitor with activity against VEGF, MET, AXL, and downregulating cathepsin K in vitro, has been proposed for the treatment of advanced clear and non-clear renal cell carcinomas. Since it is well known that cathepsin K is expressed in the majority of MiT family translocation renal cell carcinomas, we investigated cathepsin K, MET, AXL, and VEGF in a large series of those tumours, looking for possible predictive markers. We collected the clinicopathological features of 34 genetically confirmed MiT family translocation renal cell carcinomas [26 Xp11 and 8 t(6;11) renal cell carcinomas] and studied them using an immunohistochemical panel including PAX8, cathepsin K, HMB45, Melan-A, CD68 (PG-M1), CK7, CA9, MET, AXL and by FISH for VEGFA and MET. Cathepsin K was expressed in 14 of 26, HMB45 in 8 of 25, and Melan-A in 4 of 23 Xp11 renal cell carcinomas, whereas labelling for CK7 and CA9 was minimal. In t(6;11) renal cell carcinoma, cathepsin K and melanogenesis markers were constantly positive, whereas CK7 and CA9 were negative. None of the 34 carcinomas showed CD68 (PG-M1) and AXL expression. One aggressive Xp11 renal cell carcinoma showed increased VEGFA gene copy number (4-5 copies) with concurrent gains of TFE3 and TFEB. None of the 34 carcinomas showed MET gene amplification, whereas staining for MET was found in 7 of 8 t(6;11) and in 16 of 24 Xp11 renal cell carcinomas, and in the latter cases, when the expression was >50%, correlated with aggressiveness (p=0.0049). In Xp11 renal cell carcinomas, the aggressiveness was also correlated with larger tumour size (p=0.0008) and the presence of necrosis (p=0.027) but not nucleolar grading (p=1). Interestingly, in patients with tumours exhibiting two of three parameters (necrosis, larger tumour size and MET immunolabelling >50%) an aggressive clinical behaviour was observed in 88% of cases. In conclusion, cathepsin K, CD68 (PG-M1), CK7, CA9, and PAX8 is a useful panel for the