Tyrosine Kinase Inhibitor Sunitinib Targets the Vasculature of Clear Cell Renal Cell Carcinoma: A Histological and Immunocytochemical Study of Treatment Effect
J Huang, A Thomas, K Simmerman, L Sercia, C Magi-Galluzzi, S Campbell, B Rini, M Zhou. Cleveland Clinic, Cleveland, OH
Background: Tyrosine kinase inhibitor sunitinib selectively inhibits several receptor tyrosine kinases, including those of VEGFR-2 and PDGFR-ß. It is used to treat patients with advanced stage clear cell renal cell carcinoma (CCRCC). Thought to primarily target tumor angiogenesis, its anti-tumor mechanism is not entirely clear. The pathologic and molecular changes after sunitinib treatment are not well studied in CCRCC. We analyzed the pathologic and immunohistochemical features of 18 CCRCC treated with neoadjuvant sunitinib.
Design: 9 primary and 9 metastatic CCRCC were treated with sunitinib before surgical resection. The resection specimens of these 18 tumors and 4 untreated CCRCC were evaluated for gross pathology, histology, microvessel density (MVD) by CD34 immunostain, and expression of VEGFR2 and CA9 protein.
Results: Sunitinib-treated tumors demonstrated varying degree of tumor necrosis (5-60%) and hemorrhage (5-50%). Prominent deposition of fibrinoid material around vessels, which may indicate leaky vessels, was present in 15/18 (83%) treated cases. Immunostain of CD34 revealed markedly reduced, moderately reduced and normal MVD in 7 (41.2%), 5 (29.4%) and 5 (29.4%) of 18 treated tumors and normal MVD in 4 untreated tumors. Fragmented and dilated vessels were found in 12/17 (70.6%) treated tumors and none of the 4 untreated tumors. VEGFR2 was expressed in tumor vasculature but not in tumor cells. Its expression, measured by multiplying the staining intensity and % of vessels positive for the staining, was not different between treated and untreated tumors (180 vs 181, p>0.05). CA9 expression was found in tumor cells. Its expression, measured by multiplying the staining intensity and % of cells positive for the staining, was not different between treated and untreated tumors (205 vs 202, p>0.05).
Conclusions: Our study suggests that the tumor vasculature is the primary target of sunitinib in CCRCC. It results in altered vascular morphology as well as a reduction in microvessel density. However, sunitinib does not seem to change VEGFR2 expression in tumor vasculature or CA9 expression in tumor cells.
Category: Genitourinary (including renal tumors)
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 90, Wednesday Morning