| The incidence of esophageal carcinoma was higher in hebei province than other places because of different regional factors. It could not increase survival rate significantly even though combined treatment including surgical operation, radiotherapy, chemotherapy and et al. have been applied to clinical, 5-year survival rate of esophageal carcinoma was still about 10%-30%. Most patients have been in intermediate and advanced stage when first visiting hospital. Postoperative recurrence and lymph node metastasis were the most important factors affecting survival of esophageal carcinoma. In recent years, TNM stage, extent of lymph node dissection, clinical stage of non-operative patients and target region of postoperative radiotherapy in esophagus were focused on, in which lymph node status was very important to TNM stage, designing therapeutic scheme and the prognostic evaluation of patients. So accurate delineation of lymphatic drainage region was essential to the whole treatment planning and it could prolong survival time and improve quality of life to some extent. Study showed prophylactic postoperative radiotherapy in esophageal carcinoma could not increase survival rate but could reduce lymph node metastasis and improve local control. So our study aims at exploring the distribution of lymph node metastasis and analying the clinical-pathologic factors and prognosis with thoracic esophageal carcinoma after curative resection, on these basis supplying the criteria of irradiated region of radiotherapy for esophageal carcinoma.Vascular endothelial growth factor-c (VEGF-C) was found as first specific lymphatic endothelial growth factor. A lot of study showed its abnomal expression in some solid tumor was closely related to lymph node metastasis and TNM stage. Stromal derived factor-1 (SDF-1) and its receptor (CXCR4) pairs not only actively participate in inflammation, hematopoiesis, infection of HIV but also may play important role in tumor metastasis. Both SDF-1 and VEGF-C could activate downstrram signal molecules by PI3K/AKT and MEK/ERK pathway, which showed there were some connections between each other. Some study showed VEGF-C not only promoted lymphangion genesis but also produced SDF-1 through activating endothelial cells. However, few researchers have examined the expression of VEGF-C, SDF-1 and CXCR4 and influencing factors with clinical-pathologic and prognostic value in patients with esophageal carcinoma. So we investigated immunohistochenically the relationship within VEGF-C, SDF-1 and CXCR4 and clinicopathological factors especially lymph node metastasis and prognosis to try to find indicators for lymph node metasis and prognosis.Part 1Study on the characteristics of lymph node metastasis and influencing factors and the value in target region of postoperative radiotherapy in thoracic esophageal carcinomaObjective: To explore the distribution of lymph node metastases and to analyze the clinical-pathologic factors with thoracic esophageal carcinoma after curative resection, supply the criteria of irradiated region of radiotherapy for esophageal carcinoma.Methods: From Jun 2002 to Jun 2006, 763 patients have receiving esophagecotomy were retrospectively analyzed. The regularity of lymph node metastasis of thoracic esophageal cancer and clinical-pathologic factors were stratified and analyzed with SPSS13.0 software.Results: Of the 763 patients, a total of 5846 lymph nodes were dissected with an average of 7.66 lymph nodes in each case. Metastatic lymph nodes were 711, the ratio of metastatic lymph node was 12.16%, and 297 patients had lymph node involved, the lymph node metastasis rate was 38.93%. The metastases lymph node of upper-thoracic esophagus were mainly observed in the region of supraclavicular and paratrachea(lp<0.05), the metastases lymph node of middle-third thoracic esophagus were bidirectional, and the lower-third thoracic esophagus mainly metastasized to the region of lateral esophagus, lateral cardia and gastric artery(p<0.05). Both the lymph node metastasis ratio and rate of gastric artery in the lower-thoracic esophagus were significantly higher than those in the middle-third and upper-third thoracic esophagus (χ2=9.918,p=0.007,χ2=16.638,p=0.001). With multiple factors Logistic regression analysis showed that tumor length, depth of tumor invasion, vascular tumor embolus and distant metastasis have become the important factors for lymphatic metastasis(P<0.01). For total patients the lymphatic metastasic rate was 28.5% in upper-thoracic esophageal, which extremely lowed than the rate 38.8% and 43.4% in middle- and lower-thoracic esophageal (χ2=4.274,P =0.039;χ2=6.682,P=0.010).However, the lymphatic metastasic rates were 37.0%,37.9% and 41.4% in upper- , middle- and lower-thoracic esophageal carcinoma for 592 receiving left chest notches, and there were not significantly difference. (χ2=0.671,P=0.715).Conclusions: The lesion length, depth of tumor invasion, vascular tumor embolus and distant metastasis were the most important parameters for the metastases lymph node. Operative model had obvious influence on the distribution of regional lymph node metastasis. So according to lymph node dissective pattern select the indicated patients who need postoperative prophylactic radiotherapy.Part 2Impact of lymph node metastasis of esophageal carcinoma after curative resection on prognosisObjective:To investigate the related influence of lymph node metastases from thoracic esophageal carcinoma and the influence on patient survival after curative resectionMethods:From Jun 2002 to Jun 2006, Clinical data of 763 patients undergoing esophagecotomy were analyzed retrospectively in The Fourth Hospital of Hebei Medical University. The affecting factors of lymph node metastasis of thoracic esophageal cancer and were stratified and analyzed with SPSS11.5 software. Fourteen possible factors influencing survival were studied. A multivariate analysis of these variables was performed using the cumulative survival rate by the computer′s Cox proportional hazard model. Result:Of the 763 patients, A total of 5846 lymph nodes were dissected with an average of 7.66(0～29)lymph nodes in each case, metastatic lymph node ratio was 12.16%(711/5846), and the lymph node metastasis rates were 38.93%(297/763). Results of Multiple Factors Logistic Regression Analysis showed that lesions location, tumor diameter, vascular tumor embolus, depth of tumor invasion and distant metastasis influenced the lymphatic metastasis(P<0.001).The 1-year,2-year,3-year and 5-year survival rates of all patients were 85.18%,68.57%,54.13%,37.08%. According to multivariate analysis, tumor location, operative method, depth of tumor invasion, lymph node metastasis, degree of lymphatic metastasis, number of metastatic lymph nodes, and number of lymph nodes metastatic field were independent prognostic-factors(P<0.05). The 3-year survival rates of number of metastatic lymph nodes0,1 and≥2 were 63.82%,43.18%,31.75%(P<0.05).conclusions: 1. Factors including lesions location, tumor diameter, vascular tumor embolus, depth of tumor invasion and distant metastasis should be focus on in the selection of indications of postoperative prophylactic radiotherapy after radical surgery of thoracic esophageal carcinoma. 2. Lymph node metastasis significantly influences the survival of patients with esophageal cancer. The three grade classification (0, 1,≥2 positive nodes) can well suggest the relationship between the numbers of lymph node metastasis and the patient survival.Part 3Expression of VEGF-C, SDF-1, CXCR4 in esophageal carcinoma and relationship with lymph node metastasisObjective: To investigate the expression of VEGF-C, SDF-1 and CXCR4 in esophagral squamous cell carcinoma and relation to clinical pathology and their prognosis value.Methods: We investigated immunohistochemically expression of VEGF-C, SDF-1 and CXCR4 and the relationship within themselves and clinico-pathological factors including lymph node metastasis and prognostic value in surgical specimens of primary tumors in 95 patients with esophageal squamous cell carcinoma.Results: VEGF-C, SDF-1 and CXCR4 protein were mainly located in tumor cell cytoplasm and the positive expression rate of VEGF-C, SDF-1 and CXCR4 were 89.5%, 84.2% and 69.5% respectively. positive VEGF-C and SDF-1 expression were significantly correlated with cellular differentiation degree,depth of tumor invasion, lymph node metastasis, number of lymph node metastasis and TNM stage. The positive rate of VEGF-C and SDF-1 in patients with lymph node metastasis were 96.97% and 93.94%, higher than that in patients without lymph node metastasis 82.54% and 77.78%, and there were significantly difference(χ2=6.319,P =0.012;χ2=5.821,P=0.016). but positive CXCR4 expression was only correlated with cellular differentiation degree. Total patients mean survival time were 36.46 months, median survival time were 35.50 months.The 1-year, 2-year, 3-year survival rates of all patients were 90.53%, 68.42% and 47.44% respectively. Kaplan meier survival analysis showed depth of tumor invasion, lymph node metastasis, number metastatic lymph nodes, TNM stage and expression of VEGF-C, SDF-1 and CXCR4(P<0.05). According to multivariate analysis depth of tumor invasion, lymph node metastasis, number of metastatic lymph nodes, TNM stage and expression of SDF-1 were independent prognostic factors(P<0.05). there was significantly relationship between VEGF-C and SDF-1 expressions(r=0.475, P=0.000), and there was significantly relationship between VEGF-C and CXCR4 expressions(r=0.260, P=0.011), and there was significantly relationship between SDF-1 and CXCR4 expressions(r=0.214, P=0.037).Conclusions: The expression of VEGF-C and SDF-1 had correlation with clinico-pathological variables especially lymph node metastasis. To some extent evaluation of SDF-1 expression is useful for determing tumor properties including nodal metastasis and prognosis in patients with esophageal squamous cell carcinoma. VEGF-C and SDF-1/CXCR4 maybe have a synergistic effect on the lymph node metastasis of esophageal squamous cell carcinoma.
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