【作者】 谢良喜；

【导师】 苏敏；

【作者基本信息】 汕头大学 ， 病理学， 2008， 博士

【摘要】 目的1.探讨肿瘤局部免疫细胞反应状态对贲门癌根治术预后的影响,以及细胞转化生长因子β1(TGF-β1)在肿瘤免疫中的可能作用。2.随访调查汕头大学医学院附属肿瘤医院胸外科贲门癌根治术病人的治疗结果,分析影响贲门癌预后的临床病理因素。方法收集2000年10月至2002年10月间在汕头大学医学院附属肿瘤医院胸外科行根治性手术治疗的137例贲门癌患者的临床病理资料,对所有病人治疗结果进行至少5年的随访。Kaplan-meier法分析病人生存资料和影响预后的临床因素,显著性预后因素利用比例风险模型(Cox模型)进行多因素分析。免疫组化检测其中133例(剔除4例手术并发症死亡病人)贲门癌标本瘤内和瘤周CD3+细胞(总浸润性T淋巴细胞)、CD8+细胞(细胞毒性T细胞)、CD68+细胞(肿瘤相关巨噬细胞)、CD20+细胞(肿瘤浸润性B淋巴细胞)的密度以及贲门癌细胞TGF-β1的表达情况。肿瘤免疫学因素对临床治疗预后的影响进行单因素分析,其中显著性预后因素和各种临床病理参数进行Cox模型多因素分析,以筛选独立预后因素;T检验分析肿瘤细胞TGF-β1的表达强度对免疫细胞浸润密度的影响。结果1.单因素分析中:除了TNM分期(T分期,N分期,临床分期),其他对贲门癌根治术预后有显著性影响的临床病理因素包括性别、年龄、肿瘤大小(最长径)、有否术后化疗、清扫(送检)淋巴结总数、上下切缘与肿瘤距离(上、下瘤距)以及瘤内和瘤周CD3+细胞、CD68+细胞计数,瘤内CD8+细胞计数。其中,TNM分期、年龄和肿瘤大小与预后负相关,清扫(送检)淋巴结数目、上、下瘤距、术后化疗、瘤内和瘤周CD3+细胞、CD68+细胞计数,瘤内CD8+细胞计数与预后正相关,男性病人预后好于女性。2.多因素分析:利用比例风险模型(Cox模型)对T分期,N分期,上瘤距、下瘤距、性别、有否术后化疗、送检淋巴结总数、瘤内CD8+细胞、CD3+细胞、CD68+细胞计数10个单因素分析中对预后有显著性影响的因素进行多因素分析,结果显示,T分期,N分期,性别、有否术后化疗、送检淋巴结总数、瘤内CD8+细胞计数、瘤内CD3+细胞计数为独立的预后影响因素。3. TGF-β1对肿瘤局部免疫反应的影响:TGF-β1高、低表达组平均瘤内CD68+细胞数分别为: 9.7±6.83和12.2±7.07,差别有统计学意义(p=0.04)。TGF-β1高、低表达组平均瘤内CD3+细胞数分别为: 24.2±21.52和32.6±27.47,差别有统计学意义(p=0.05)。结论1.肿瘤浸润性T淋巴和肿瘤相关性巨噬细胞计数,对临床治疗预后有正面影响,是独立于TNM分期的预后影响因素,反映了病人抗肿瘤免疫的潜能。2.随着TGF-β1表达增强,肿瘤浸润免疫细胞数量呈下降趋势,提示TGF-β1对宿主免疫系统有抑制作用,可能是肿瘤逃脱机体免疫监视的机制之一。3.贲门癌外科临床方面:送检淋巴结总数与预后正相关,术后需重视标本解剖,保证有足够的送检淋巴结数,以免影响淋巴结分期的准确性;肿瘤切除范围应包括6cm以上正常食管和胃组织,以减少切缘阳性。术后辅助化疗可明显提高病人治疗效果,是今后贲门癌治疗的方向。更多还原

【Abstract】 ObjectiveTo evaluate the impacts of tumor infiltrating immune cells on long-term survivals of gastric cardia carcinoma and the significances of Transforming Growth Factor-β1(TGF-β1) in the interaction between immune system and tumor.MethodsFrom October 2000 to October 2002, 137 patients with gastric cardia carcinoma underwent curative resection in Shantou University, Medical College, Cancer hospital. All patients were followed-up for at least 5 years. Detailed clinical and pathological data were collected. Intratumoral and peritumoral presence of various tumor-infiltrating immune cells, including CD3+、CD8+、CD68+、CD20+ cell, as well as the expression of tumor-deriving TGF-β1 were detected using immunohistochemistry in resection specimens from 133 patients(4 cases who died from severe surgical complications were excluded).Univariate analysis was used to determine the prognostic value of infiltrating immune cell counts as well as other clinical and pathological parameters. For those statistically significant factors in univariate analysis, a multivariate analysis (Cox proportional hazard model) was performed to explore the independent prognostic factors.The influence of TGF-β1 expressions on immune cell couts was evaluated using student T-test.Results1. univariate analysis:In univariate analysis, significant prognostic factors for Overall survival(OS) are: TNM stage(T stage, N stage, clinical stage),sex, age, tumor size, total number of examinated lymph nodes, distance from the upper and lower resection margins to macroscopic tumor borders(upper and lower resection margin distance). Intratumoral and peritumoral CD3+、CD68+cell counts and Intratumoral CD8+ cell counts. Among them, TNM stage, age, tumor size have reverse correlation to overall survival while number of examinated lymph nodes, extent of resection margins, Intratumoral and peritumoral CD3+、 CD68+cell counts and Intratumoral CD8+ cell counts have positive correlation to overall survival, Female patients have poor prognosis than male patients.2. Multivariate analysis: 11 significant prognostic factors were chosen for multivariate analysis,they were T stage, N stage, sex, age,with or without chemotherapy,numbers of examinated lymph nodes, upper and lower resection margin distance, intratumoral CD3+、CD68+、CD8+cell counts l。The results shows that T stage, N stage, sex, with or without chemotherapy,numbers of examinated lymph nodes, intratumoral CD3+、CD68+cell counts are independent prognostic factors for Overall survival.3. Impacts of TGF-β1 on local immune response: The means of intratumoral CD68+cell counts for low and high TGF-β1 groups were 12.2±7.07 and 9.7±6.83 respectively, and the difference was statistically significant. The means of intratumoral CD3+cell counts for low and high TGF-β1 groups were 32.6±27.47 and 24.2±21.52 respectively, and the difference was statistically significant. High level of TGF-β1 expression is correlative to poor treatment outcome, but the difference is not statistically significant(p=0.06)Conclusions1. The counts of TAM and tumor infiltrating T cell reflect the anti-caner potiental of immune system, and are independent prognostic factors.2. TGF-β1 can reduce the number of tumor infiltrating immune cell, especially macrophages and tumor infiltrating T lymphocyted, which may be one of the mechanisms by which tumor escapes from immune surveillance.3. The number of examinated lymph nodes is essentially needed for a correct N stage. Careful examination of the resection specimens for the lymph nodes is very important. Resection margin should include at least 6cm of normal esophagus and stomach to avoice tumor residence. Postoperative chemotherapy may improve the long-term survival and remains a better management for gastric cardia carcinoma.更多还原