Increased Expression of Vascular Endothelial Growth Factor-C and Nuclear CXCR4 in Hepatocellular Carcinoma Is Correlated With Lymph Node Metastasis and Poor Outcome

Abstract

Lymph node metastasis (LNM) is a chief cause of morbidity and mortality in patients with hepatocellular carcinoma (HCC) after hepatectomy. The aim of this study was to investigate the relationship between the expression of CXCR4 and vascular endothelial cell growth factor (VEGF)-C and the clinicopathological features of HCC with LNM. Immunohistochemical staining for CXCR4 and VEGF-C was performed on tissue microarrays that were constructed using tumor specimens from patients with HCC with (N = 123) or without (N = 145) LNM. The relationship between the clinicopathological features of HCC and the expression of CXCR4 and VEGF-C was analyzed using the Pearson chi(2) test, logistical regression analysis, and receiver operating characteristic analysis. Nuclear CXCR4 expression and VEGF-C expression were positively correlated with LNM and poor outcome in HCC. Moreover, nuclear CXCR4 expression was positively correlated with VEGF-C expression (correlation coefficient 0.256). Receiver operating characteristic analysis revealed that both factors were predictive of HCC LNM {CXCR4: area under the curve, 0.695 [95% confidence interval (CI), 0.630-0.759; VEGF-C: area under the curve, 0.629 (95% CI, 0.562-0.695]}. Patients with tumors exhibiting high nuclear CXCR4 expression or high VEGF-C expression had significantly poorer overall survival than those with low tumor expression of the corresponding factors. Multivariate analysis showed that UICC T stage [odds ratio (OR), 1.615, 95% CI, 1.306-1.997], nuclear CXCR4 expression (OR, 3.998; 95% CI, 2.706-5.907), and VEGF-C expression (OR, 1.903; 95% CI, 1.203-3.011) were independent risk factors for developing HCC LNM. These findings suggest that nuclear CXCR4 expression and VEGF-C expression can be used to identify patients with HCC at high risk for developing LNM.