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.