Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: a prospective study

Abstract

Objective: To evaluate the correlation between serum vascular endothelial growth factor (VEGF) level and the clinicopathologic features in patients with hepatocellular carcinoma (HCC).

Summary background data: VEGF is an important angiogenic factor regulating tumor angiogenesis. A high serum VEGF level has been shown to be associated with tumor progression and metastasis in several human cancers, but its significance in HCC is unclear. The correlation between serum VEGF level and tumor pathologic features in patients with HCC has not been studied before.

Methods: Preoperative serum samples and tumor specimens were prospectively collected in 100 patients undergoing resection of HCC. Serum VEGF level was measured by enzyme-linked immunosorbent assay, and tumor VEGF expression was assessed by immunohistochemical study. Histopathologic examination was performed by a pathologist without prior knowledge of the serum VEGF level or tumor VEGF expression.

Results: Preoperative serum VEGF levels ranged from 15 to 1,789 pg/mL (median 269). When serum VEGF levels were compared between groups categorized by different clinicopathologic variables, significant correlation was found between a high serum VEGF level and absence of tumor capsule, presence of intrahepatic metastasis, presence of microscopic venous invasion, and advanced stage. There was a positive correlation between the serum VEGF level and tumor expression of VEGF as well as platelet count. When the 75th percentile serum VEGF level (500 pg/mL) was used as a cutoff level, the frequency of venous invasion in patients with a high serum VEGF level was significantly greater compared with patients with a low serum VEGF level. By multivariate analysis, a serum VEGF level of more than 500 pg/mL and tumor size more than 5 cm were independent preoperative factors predictive of microscopic venous invasion. During a median follow-up of 11.6 months, 48% of patients with a serum VEGF level of more than 500 pg/mL and 27% of those with a serum VEGF level of 500 pg/mL or less developed postoperative recurrence.

Conclusions: These results show that a high preoperative serum VEGF level is a predictor of microscopic venous invasion in HCC, suggesting that the serum VEGF level may be useful as a biologic marker of tumor invasiveness and a prognostic factor in HCC.

Figures

Figure 1. Immunostaining showing positive staining for vascular endothelial growth factor (VEGF; brownish staining) in the cytoplasm of the majority of tumor cells in a tumor specimen with high VEGF expression. (A) ×100. (B) ×400.

Figure 2. Scatter plot showing the correlation between the serum level of vascular endothelial growth factor (VEGF) and platelet count (r = 0.432, P = .001).

Figure 3. (A) Serum levels of vascular endothelial growth factor (VEGF) in patients with tumors of different stages. Values in each group were significantly different from the other groups (P < .05). The upper and lower quartiles and the median values (dotted line) are depicted as box plots. Error bars indicate data within 1.5 times the interquartile range. (B) Platelet count in patients with tumors of different stages. Values in the stage IVA group were significantly greater than values in the stage I, II, or IIIA groups (P < .05), but there were no significant differences between other tumor stages.

Figure 4. Correlation between serum levels of vascular endothelial growth factor (VEGF) and tumor expression of VEGF evaluated by immunohistochemical staining (P = .043). The upper and lower quartiles and the median values (dotted line) are depicted as box plots. Error bars indicate data within 1.5 times the interquartile range.

Figure 5. Cumulative disease-free survival curves of patients with serum levels of vascular endothelial growth factor (VEGF) less than and greater than 500 pg/mL (P = .085).