Expression of the vascular endothelial growth factor family in tumor dissemination and disease free survival in clear cell renal cell carcinoma

Abstract

4538 Background: The Vascular Endothelial Growth Factor (VEGF) family includes distinct pathways to signal either angiogenesis or lymphangiogenesis. We evaluated the ability of protein expression of the VEGF family to predict the pattern of spread and disease free survival in patients with clear cell renal cell carcinoma (RCC). Methods: A tissue microarray was constructed from paraffin-embedded clear cell (n=340) RCC specimens from patients treated with nephrectomy. Immunohistochemistry was performed with antibodies directed against VEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2 and VEGFR-3. The percentage of tumor cells expressing each marker was scored in 3 locations and averaged. Expression of the receptors was also scored in tumor associated endothelium. Logistic regression analysis was used to determine the ability of a marker to predict lymphatic or hematogenous metastases. Cox proportional hazards analysis was used to evaluate the association of each marker with disease-specific survival. Multivariate analysis included TNM stage, Fuhrman grade, and ECOG performance status. Results: Univariate predictors of hematogenous spread to distant metastases included VEGFR-1 (P=0.006) and VEGFR-2 (P=0.02). Neither marker remained significant in multivariate analysis. VEGF-A (P=0.009), VEGFR-1 (P=0.006) and low endothelial expression of VEGFR-3 (P=0.0003) were univariate predictors of lymph node involvement. Low VEGFR-3 expression remained independently significant in multivariate analysis (P=0.01). Univariate predictors of disease free survival included VEGF-A (P=0.0004), VEGFR-1 (P<0.0001), VEGFR-2 (P=0.01), and VEGFR-3 in tumor associated endothelium (P=0.008). VEGFR-3 remained an independent predictor of survival in multivariate analysis (P=0.02). Conclusions: Decreasing expression of VEGFR-3, thought to play a role in tumor escape to the lymphatic system, is an independent predictor of both nodal metastases and poor disease free survival. The relative expression of the VEGF mediated angiogenesis and lymphangiogenesis pathways offers a molecular explanation for the pattern of spread of clear cell RCC. No significant financial relationships to disclose.