Vascular Endothelial Growth Factor C Induces Lymphangiogenesis In Adenocarcinoma Of Esophagogastric Junction And Correlates With Clinical Outcome After Curative Resection

Background and objectiveAdenocarcinoma of esophagogastric junction is one of the most common malignant diseases in southern China, especially in ChaoShan region. Lymphatic metastasis has been one of the major treatment failures for it. Many studies discover that lymphangiogenesis is one of the important factors for tumor lymphatic metastasis. Vascular endothelial growth factor C (VEGF-C) can induce lymphangiogenesis and angiogenesis, and promote tumor metastasis. The objective of this study is to investigate the impact of VEGF-C on lymphangiogenesis and clinical outcome in adenocarcinoma of esophagogastric junction.MaterialsWe collected 128 specimens of esophagogastric junction adenocarcinoma underwent curative resection in Cancer Hospital of Shantou University Medical College from October 2000 to October 2002. All patients were followed-up. The median follow-up period was 27 months(range 1 to 77 months), the mean follow-up time was 35.57±24.28 months.MethodsVEGF-C expression in the paraffin sections was detected immunohistochemically (Envision Labelled Peroxidase System 2 Steps Method). The mean optical density (MOD) was measured with digital image analysis (Leica IM50 image acquisition system, Image-pro(?) Plus6.0 software) to represent the expression level of VEGF-C. The lymphatic vessel was labeled with D2-40 antibody to calculate lymphatic vessel density (LVD).Statistical analysis All data were analyzed using SPSS17.0 statistical package. T-test and analysis of variance (one-way ANOVA) were used to compare the means of 2 and more than 2 independent samples respectively. Survival analysis was carried out using Kaplan-Meier and Log-rank test. Cox proportional hazard model was performed to explore the independent prognostic factors. Differences were considered statistically significant when p-value was less than 0.05.Results1. VEGF-C proteins were localized in the cytoplasm of tumor cells. The VEGF-C protein expression was positively correlated with N stage, clinical stage (p<0.05). No correlation was found between VEGF-C expression and other clinicopathological parameters, including age, sex, tumor size, macrographic type, histological type and T stage (p>0.05). D2-40-labelled lymph vessels were less often found at central portions than around the invasive borders. The levels of LVD in adenocarcinoma of esophagogastric junction were positively correlated with N stage and clinical stage (p<0.05). No correlations were found between LVD expression and other clinicopathological (p>0.05).2. The MOD median of 0.18 was used as a cut-off to define high and low VEGF-C expression. The number of positive resected lymph nodes was singnificantly fewer in low VEGF-C expression group than in high VEGF-C expression group (2.0±2.36 vs 2.9±2.44, p=0.025). The LVD median of 13 was used as a cut-off to define high and low LVD expression, the number of positive resected lymph nodes was singnificantly fewer in low level LVD group than in high level LVD group (1.9±2.43 vs 3.0±2.34,p=0.010).3. There was a positive correlation between VEGF-C protein expression and LVD level (T-test, p=0.002).4. High expression level of VEGF-C and High LVD level were all significantly associated with poor disease-free survival. (p<0.05).5. Multivariate analysis indicated that VEGF-C (MOD) as well as postoperative chemotherapy, depth of tumor invasion, lymph node metastasis, and resection margin were independent survival predictors. Conclusions1. The VEGF-C expression and the level of LVD were positively correlated with N stage, suggesting that VEGF-C expression, the level of LVD may associate with lymphatic metastasis in adenocarcinoma of esophagogastric junction.2. There was a positive correlation between the VEGF-C expression and LVD level which indicated that VEGF-C expression might induce lymphangiogenesis and promote tumor lymphatic metastasis.3. In univariate analysis, both high VEGF-C expression group and high LVD level group were associated with poor clinical outcome. The disease-free survival for low VEGF-C expression or low LVD group was superior than their corresponding control groups. Multivariate analysis indicated that high VEGF-C expression was unfavorable prognostic factor independence of other clinical factors, including TNM stage, Chemotherapy; surgical margin for adenocarcinoma of esophagogastric junction underwent curative resection.