Tyrosine kinase inhibitor sunitinib targets the vasculature of clear cell renal cell carcinoma: A morphometrical study of treatment effect

Tyrosine kinase inhibitor sunitinib is thought to exert its anti-tumor effect by modulating angiogenesis in clear cell renal cell carcinoma (ccRCC). The pathological changes after sunitinib treatment have, however, rarely been studied in surgically resected ccRCC specimens. Such studies are important as they allow researchers to examine whether sunitinib targets the intended tissue and the effectiveness of treatment. We analyzed the pathological and immunohistochemical features of 14 surgically resected ccRCCs following sunitinib treatment and 25 untreated ccRCCs. Treated and untreated ccRCCs were similar in tumor size, nuclear grade and pathological stage. The treated tumors, however, showed significantly higher extent of tumor necrosis (32%) and more likely to have pericellular fibrosis (100%) and vasculopathy involving medium/large vessels (78.6%) compared with untreated tumors (23%, 20% and 40%, respectively, p<0.03). The treated tumors showed 47% reduction in microvessel density demonstrated on CD34 immunohistochemistry compared to the untreated tumors (64 vs 33, p=0.003). Architectural disruption, including vascular dilation and fragmentation, were significantly more common in treated tumors. VEGFR-2 expression (VEGFR-2/CD34 ratio) was higher on tumor microvessels in treated tumors than untreated tumors (0.95 vs 0.81, p=0.04). Our study confirms that tumor microvessels are the primary target of sunitinib treatment in ccRCCs. Sunitinib treatment significantly reduces the microvessel density and also produces significant structural disruption that lead to hypoxia, ischemia and necrosis in tumors. The treatment also increases the VEGFR-2 expression on the residual tumor microvessels and may contribute to the occurrence of resistance to sunitinib treatment.