Expression Of Fluorouracil Metabolism Related Enzymes (Thymidylate Synthase,Dihydropyrimidine Dehydrogenase And Thymidine Phosphorylase) In Small Bowel Adenocarcinoma And Prognostic Analysis

Objective:1.To investigate the difference between duodenal adenocarcinoma and jejunoileum adenocarcinoma in clinicopathological features and prognosis.2.To investigate the relationship between expression of thymidylate synthase(TS),dihydropyrimidine dehydrogenase(DPD)and thymidine phosphorylase(TP)in small bowel adenocarcinoma tissues with clinicopathological features and prognosis.Methods:1.66 small bowel adenocarcinoma patients presenting with stage II-III were selected,all of whom had received 5-fluorouracil based adjuvant chemotherapy after curative surgical resection at our hospital from August 2007 to December 2010,and all of them had complete follow-up datas.The difference between duodenal adenocarcinoma and jejunoileum adenocarcinoma in the clinicopathological features and prognosis were analyzed.2.The postoperative paraffin-embedded tissues of small bowel adenocarcinoma patients and 15 paracancerous tissues were collected,the latter was regarded as negative control.The expression of TS,DPD and TP in tumor tissues and paracancerous tissues were assessed by standard immunohistochemistry(IHC).Chi-square test was used to analyze the difference between cancerous tissues and paracancerous tissues on the expression of TS,DPD and TP,the difference between duodenal adenocarcinoma tissues and jejunoileum adenocarcinoma tissues on the expression of TS,DPD and TP,and the relationship between clinicopathological features and the expression of TS,DPD and TP in tumors.3.Drawing the survival curves was constructed by Kaplan-Meier analysis.Univariate survival analysis was used to analyze the relationship betwwen clinicopathological features,5-FU metabolism related enzymes and the 5-year disease free survival(DFS),5-year overall survival(OS).COX proportional hazard model were used to analyze the relationship between different meaningful single factors and prognosis,then got the independent prognostic factor of 5-year DFS and 5-year OS for small bowel adenocarcinoma after radical surgery.Results:1.66 patients with small bowel adenocarcinoma were included into the study.Duodenal was the most common site of primary small bowel adenocarcinoma(86.4%).Abdominal pain and abdominal distension were the most common clinical manifestations.Misdiagnose rate was 68.2%,and the most common disease misdiagnosed was choledocholithiasis(34.8%).The degree of pathological differentiation and tumor type between duodenal adenocarcinoma and jejunoileum adenocarcinoma were statistical difference.The patients at poor differentiation of jejunoileum adenocarcinoma were more than duodenal adenocarcinoma patients(88.9% vs 29.8%,p=0.001).Jejunoileum adenocarcinoma patients with ulcerative type,infiltrating type and constrictive type were more than duodenal adenocarcinoma(respectively:44.4% vs 33.3%、33.3% vs 8.8%、22.2% vs 7.1%,p=0.023).The 5-year DFS bentween duodenal adenocarcinoma and jejunoileum adenocarcinoma were statistical difference.The 5-year DFS and 5-year OS of duodenal adenocarcinoma were longer than jejunoileum adenocarcinoma(5-year DFS:38.6% vs 11.1%,p=0.028;5-year OS:47.4% vs 22.2%,p=0.032).2.The expression of TS,DPD and TP between small bowel adenocarcinoma tissues and paracancerous tissues were statistical difference.The positive rate of TS,DPD and TP in small bowel adenocarcinoma tissues were higher than paracancerous tissues(TS:53.0% vs 20.0%,p=0.024;DPD:72.7% vs 26.7%,p=0.002;TP:59.1% vs 26.7%,p=0.042).The expression of TP between duodenal adenocarcinoma tissues and jejunoileum adenocarcinoma tissues was statistical difference.The positive rate of TP in the former was higher than the latter(66.7% vs22.2%,p=0.026).However,the difference expression of TS and DPD between them showed no statistical significance(p>0.05).TS expression was related to nerve vascular infiltration status.The small bowel adenocarcinoma patients with nerve vascular infiltration had higher positive rate of TS than those without nerve vascular infiltration(100% vs 36.7%,p=0.000).DPD expression was related to the degree of differentiation.The patients at poor differentiation of small bowel adenocarcinoma had higher positive rate of DPD than those at well differentiation(88% vs 63.4%, p=0.045).3.Univariate survival analysis showed that age,degree of differentiation,tumor type,lymphatic metastasis,TNM stage and TS expression of patients with 5-year DFS showed statistical difference.Small bowel adenocarcinoma patients with age≥55 years old had worse 5-year DFS than those age < 55 years old(14.3% vs 32.7%,p=0.000).The patients at poor differentiation of small bowel adenocarcinoma had worse 5-year DFS than those at well differentiation(8% vs 51.2%,p=0.000).Small bowel adenocarcinoma patients with protrude type had the best 5-year DFS compared to other types(p=0.006).Small bowel adenocarcinoma patients without lymph node metastasis had better 5-year DFS than those with lymph node metastasis(48.6% vs17.2%,p=0.002).The patients at stage II of small bowel adenocarcinoma had better5-year DFS than those at stage III(48.6% vs 17.2%,p=0.002).Small bowel adenocarcinoma patients with negative expression of TS had better 5-year DFS than those with positive TS expression(41.9% vs 28.6%,p=0.017).Multivariate survival analysis showed that advanced age and positive expression of TS were independent adverse prognostic factors for 5-year DFS of small bowel adenocarcinoma after radical surgery(age:p=0.000,HR=0.251;TS:p=0.003,HR=2.660).Age,degree of differentiation,tumor type,lymphatic metastasis,TNM stage and TS expression of patients with 5-year OS showed statistical difference.Small bowel adenocarcinoma patients with age≥55 years old had worse 5-year OS than those age<55 years old(17.1% vs 41.8%,p=0.000).The patients at poor differentiation of small bowel adenocarcinoma had worse 5-year OS than those at well differentiation(20% vs 58.5%,p=0.000).Small bowel adenocarcinoma patients with protrude type had the best 5-year OS compared to other types(p=0.007).Small bowel adenocarcinoma patients without lymph node metastasis had better 5-year OS than those with lymph node metastasis(51.4% vs 34.5%,p=0.005).The patients at stage II of small bowel adenocarcinoma had better 5-year OS than those at stage III(51.4%vs 34.5%,p=0.005).Small bowel adenocarcinoma patients with negative expression of TS had better 5-year OS than those with positive TS expression(48.4% vs 40%,p=0.02).Multivariate survival analysis showed that advanced age and positive expression of TS were independent adverse prognostic factors for 5-year OS of small bowel adenocarcinoma after radical surgery(age:p=0.025,HR= 0.446;TS:p=0.035,HR=1.372).Conclusion:1.The duodenum was the most common site of primary small bowel adenocarcinoma.The clinicopathological features of site-specific small bowel adenocarcinoma were different.They may be a heterogeneous diseases.The prognosis of duodenal adenocarcinoma was better than jejunoileum adenocarcinoma.2.The positive rate of TS,DPD and TP in small bowel adenocarcinoma tissues were higher than paracancerous tissues.The positive rate of TP in duodenal adenocarcinoma tissues was higher than jejunoileum adenocarcinoma tissues.3.Age,degree of differentiation,tumor type,lymphatic metastasis,TNM stage and TS expression were associated with 5-year DFS and 5-year OS of the small bowel adenocarcinoma patients after radical surgery.Independent predictors of poor survival for small bowel adenocarcinoma after radical surgery included advanced age and positive expression of TS.