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 diagnosis. Larger tumour size, the presence of necrosis and MET immunohistochemical expression correlate with aggressive behaviour in Xp11 renal cell carcinomas, especially in combination. VEGF, MET, cathepsin K but not AXL may be potential predictive markers for targeted therapy in MiT family translocation renal cell carcinomas.
Pathology. 2020 Feb 24 [Epub ahead of print]
Anna Caliò, Matteo Brunelli, Diego Segala, Serena Pedron, Andrea Remo, Serena Ammendola, Enrico Munari, Francesco Pierconti, Alessandra Mosca, Enrico Bollito, Angelo Sidoni, Simona Fisogni, Cosimo Sacco, Luisa Canu, Steno Sentinelli, Anna Paola Fraccon, Michelangelo Fiorentino, Cathryn Scott, Michele Milella, Camillo Porta, Pedram Argani, Guido Martignoni
Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Italy., Department of Pathology, Pederzoli Hospital, Peschiera del Garda, Italy., Department of Pathology, Hospital 'Mater Salutis', Legnago, Italy., Department of Pathology, Sacro Cuore Hospital, Negrar, Italy., Division of Anatomic Pathology and Histology, Foundation 'A. Gemelli' University Hospital, Università Cattolica del Sacro Cuore, Rome, Italy., Medical Oncology, Maggiore della Carità University Hospital, Novara, Italy., Department of Pathology, San Luigi Gonzaga Hospital, University of Turin, Italy., Department of Experimental Medicine, Section of Pathology, University of Perugia, Italy., Department of Pathology, Spedali Civili, University of Brescia, Italy., Department of Oncology, University and General Hospital, Udine, Italy., Department of Pathology, ASL Nuoro, Nuoro, Italy., Department of Pathology, IRCCS-Regina Elena National Cancer Institute, Rome, Italy., Department of Oncology, Pederzoli Hospital, Peschiera del Garda, Italy., Laboratory of Oncological and Transplant Molecular Pathology - Pathology Unit, S.Orsola-Malpighi Hospital, University of Bologna, Italy., Department of Pathology, University and General Hospital, Udine, Italy., Medical Oncology, University of Verona, Italy., Department of Internal Medicine, University of Pavia, Italy., Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, USA., Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Italy; Department of Pathology, Pederzoli Hospital, Peschiera del Garda, Italy. Electronic address: .