食管鳞状细胞癌临床病理指标及分子指标预后相关性研究

发布时间：2019-02-18 15:26

【摘要】：食管癌是人类最常见的十大恶性肿瘤之一,在全世界癌症死亡率中位于第六位。中国食管癌的发病人口及死亡人口均居世界首位。在中国,食管鳞状细胞癌(esophageal squamous cell carcinoma,ESCC)是主要组织学亚型。尽管近年来手术和其它治疗有很大进展,但中晚期ESCC患者的预后仍然非常差,面临床上大多数ESCC患者就诊时已为中晚期。准确判断ESCC患者的预后是精准治疗的前提,是提高患者生存率和生存质量的关键。相关的临床病理指标和分子指标是预测预后的重要指标,是ESCC的重要研究方向。本研究的首要意义是通过对ESCC预后相关的临床病理指标及分子指标的研究,对ESCC患者预后因素有更加充分的认识,从而能够准确判断及改善患者的预后,同时望能找到有效的靶向治疗方法改善患者的预后。在食管癌诊断和治疗中,中晚期患者的预后有一定的差异,这个临床问题提示当前应用的指导治疗的预后指标尚不能满足个体化治疗的需要,寻找可有效预测预后相关的临床病理指标和分子指标,能够优化临床路径和治疗方案,制定有效合理的个体化治疗方案,减少毒副作用和额外的费用,为患者和国家节省花费。本课题后期的研究前景广阔,望能筛选出ESCC预后相关的标志物,对于促进和推动ESCC的靶向治疗临床应用进程发挥一定作用,本研究主要分两部分进行:第一部分:选取1999年至2003年行食管癌切除术且术前未进行任何治疗的T3期的ESCC病例289例进行HE切片的复阅,主要的观察内容有肿瘤距环周切缘(circumferential resection margin,CRM)的距离、淋巴结转移阳性的病例是否存在淋巴结被膜外侵犯,从而探讨环周切缘以及淋巴结被膜外侵犯与ESCC临床特征及病理因素的关系,并分析其与预后的相关性,为晚期ESCC患者的预后提供判断依据,进一步选择合适的治疗方案,从而提高患者的生存率和生存质量。结果显示根据CAP标准判断的环周切缘阳性的患者预后较差,根据CAP标准判断的环周切缘阳性与预后有显著的相关性,是ESCC患者独立的预后因素。此外,研究发现在141例淋巴结转移阳性的患者中,淋巴结被膜外侵犯与患者的年龄、性别、N分期有关,与OS及DFS有显著的相关性,但不是淋巴结转移阳性患者的独立的预后因素。第二部分:食管癌的发生发展是由多基因、多因素、多步骤协同作用的结果。近年来,分子生物学研究发展迅猛,与食管癌预后有关的分子生物学指标也成为研究的热点,希望通过对其分子指标的研究找到有效的靶向治疗方法改善患者的预后。肿瘤免疫逃逸是肿瘤发生、侵袭及转移的重要机制,PD-1/PD-L1途径介导的负性信号能有效抑制T、B细胞功能,在机体免疫应答后期的负性调节中发挥了至关重要的作用,并在肿瘤免疫、自身免疫和慢性病毒感染等疾病的发生发展中具有重要的生物学意义。本研究通过对1999年-2003年378例行食管癌切除术且术前未进行任何治疗的T2-T4a期ESCC患者PD-L1基因的蛋白表达情况的分析,探讨PD-L1表达的临床病理特征及与预后的相关性。结果显示在378例ESCC患者中,113例(29.99%)PD-L1出现肿瘤细胞的表达,152例(40.2%)出现浸润免疫细胞的表达。PD-L1在肿瘤细胞的表达与患者的发病年龄、分化程度、T分期、N分期及血行转移有一定的相关性,肿瘤分化程度低的ESCC患者,PD-L1表达率较高。PD-L1在浸润免疫细胞的表达则与N分期有关。Kaplan-Meier生存分析及单因素分析显示PD-L1在肿瘤细胞的表达与DFS显著相关,PD-L1表达的患者DFS较短,但多因素分析并没有显示PD-L1表达是独立的预后因素。同时研究发现PD-L1在浸润免疫细胞表达的患者DFS及OS更长,然而生存分析并没有显示其与预后有明显的相关性。本研究表明PD-L1在肿瘤细胞中的表达对进展期ESCC患者预后较差有一定的提示作用,针对PD-1/PD-L1通路的靶向治疗也许可以使进展期ESCC患者获益,改善患者预后。
[Abstract]:Esophageal cancer is one of the most common malignant tumors in the world, and is in the sixth place in the world's cancer mortality rate. The incidence and death of esophageal cancer in China are the first in the world. In China, esophageal squamous cell carcinoma (ESCC) is a major histological subtype. Although much progress has been made in the operation and other treatments in recent years, the prognosis of patients with advanced ESCC is still very poor. Accurate judgment of the prognosis of patients with ESCC is the premise of accurate treatment, which is the key to improve the survival rate and quality of the patients. The relevant clinico-pathological index and molecular index are the important indexes for predicting the prognosis, and it is the important research direction of ESCC. The primary significance of this study is to study the prognostic factors of ESCC patients by the study of the clinical and pathological indexes and molecular indices related to the prognosis of ESCC, so that the prognosis of patients can be accurately judged and improved, and the prognosis of patients can be improved by finding effective targeted treatment methods. In the diagnosis and treatment of esophageal cancer, the prognosis of the advanced patients has a certain difference, and the clinical problem is that the prognosis index of the current application can not meet the needs of the individual treatment, and the clinical and pathological indexes and molecular indexes related to the prognosis can be effectively predicted. can optimize the clinical path and the treatment scheme, establish an effective and reasonable individualized treatment scheme, reduce the toxic and side effect and the additional cost, and save the cost for patients and countries. The present study has a broad prospect and can be used to screen the markers related to the prognosis of ESCC and play a certain role in promoting and promoting the targeted treatment of ESCC. The main part of this study is that: From 1999 to 2003, 289 cases of ESCC with esophageal cancer resection and no treatment before operation were selected for HE section, and the main observations included the distance of the tumor from the circumferential margin (CRM). In the case of the positive cases of lymph node metastasis, there was a non-membrane invasion of the lymph nodes, so as to investigate the relationship between the peripheral edge of the ring and the invasion of the lymph node by the membrane and the clinical characteristics and the pathological factors of the ESCC, and to analyze the correlation between the prognosis and the prognosis of the patients with advanced ESCC. A suitable treatment regimen is further selected to improve the survival and quality of life of the patient. The results showed that the prognosis of the peripheral edge of the ring was poor according to the CAP criterion, and there was a significant correlation between the positive and the prognosis of the ring cycle, which was judged according to the CAP criterion, and was an independent prognostic factor in the ESCC patients. In addition, the study found that in the 141 patients with positive lymph node metastasis, the invasion of the lymph node was related to the age, sex and N stages of the patient, and there was a significant correlation with the OS and DFS, but not the independent prognostic factors for the positive patients with lymph node metastasis. The second part: The development of esophageal cancer is the result of multi-gene, multi-factor and multi-step synergy. In recent years, the research of molecular biology has developed rapidly, and the molecular biology index related to the prognosis of the esophagus cancer has also become the hot spot of the study, and it is hoped that the effective targeted treatment method can be found to improve the prognosis of the patients by finding effective targeted treatment methods for the study of its molecular index. The tumor immune escape is an important mechanism for tumorigenesis, invasion and metastasis, and the negative signal mediated by the PD-1/ PD-L1 pathway can effectively inhibit the function of T and B cells, plays an important role in the negative regulation of the late stage of the immune response of the organism, and is immune to the tumor, and has important biological significance in the development of diseases such as autoimmune and chronic viral infection. The clinical and pathological characteristics of PD-L1 expression and the correlation with the prognosis were discussed by the analysis of the protein expression of PD-L1 gene in the patients with T2-T4a ESCC who underwent esophagectomy in 1999-2003 and before the operation. The results showed that in the 378 ESCC patients, 113 (29. 99%) PD-L1 expression of the tumor cells, and 152 (40.2%) of the expression of the infiltration immune cells. The expression of PD-L1 in tumor cells was related to the age, degree of differentiation, T stage, N stage and blood line metastasis, and the expression rate of PD-L1 was higher in patients with ESCC with low degree of differentiation. The expression of PD-L1 in the infiltrating immune cells is related to the N stage. The Kaplan-Meier survival analysis and single factor analysis showed that the expression of PD-L1 in tumor cells was significantly related to DFS, and the DFS of PD-L1 expression was shorter, but the multi-factor analysis did not show that PD-L1 expression was an independent prognostic factor. At the same time, the DFS and OS of PD-L1 were found to be longer in the patients with infiltrative immune cells, but the survival analysis did not show a significant correlation with the prognosis. The study shows that the expression of PD-L1 in the tumor cells has a certain effect on the prognosis of the patients with advanced ESCC, and the targeted therapy for PD-1/ PD-L1 pathway may benefit the patients with advanced ESCC and improve the prognosis of the patients.
【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.1

【参考文献】