食管鱗狀細胞癌臨床病理指標及分子指標預后相關性研究
發(fā)布時間：2019-02-18 15:26
【摘要】：食管癌是人類最常見的十大惡性腫瘤之一,在全世界癌癥死亡率中位于第六位。中國食管癌的發(fā)病人口及死亡人口均居世界首位。在中國,食管鱗狀細胞癌(esophageal squamous cell carcinoma,ESCC)是主要組織學亞型。盡管近年來手術和其它治療有很大進展,但中晚期ESCC患者的預后仍然非常差,面臨床上大多數(shù)ESCC患者就診時已為中晚期。準確判斷ESCC患者的預后是精準治療的前提,是提高患者生存率和生存質量的關鍵。相關的臨床病理指標和分子指標是預測預后的重要指標,是ESCC的重要研究方向。本研究的首要意義是通過對ESCC預后相關的臨床病理指標及分子指標的研究,對ESCC患者預后因素有更加充分的認識,從而能夠準確判斷及改善患者的預后,同時望能找到有效的靶向治療方法改善患者的預后。在食管癌診斷和治療中,中晚期患者的預后有一定的差異,這個臨床問題提示當前應用的指導治療的預后指標尚不能滿足個體化治療的需要,尋找可有效預測預后相關的臨床病理指標和分子指標,能夠優(yōu)化臨床路徑和治療方案,制定有效合理的個體化治療方案,減少毒副作用和額外的費用,為患者和國家節(jié)省花費。本課題后期的研究前景廣闊,望能篩選出ESCC預后相關的標志物,對于促進和推動ESCC的靶向治療臨床應用進程發(fā)揮一定作用,本研究主要分兩部分進行:第一部分:選取1999年至2003年行食管癌切除術且術前未進行任何治療的T3期的ESCC病例289例進行HE切片的復閱,主要的觀察內容有腫瘤距環(huán)周切緣(circumferential resection margin,CRM)的距離、淋巴結轉移陽性的病例是否存在淋巴結被膜外侵犯,從而探討環(huán)周切緣以及淋巴結被膜外侵犯與ESCC臨床特征及病理因素的關系,并分析其與預后的相關性,為晚期ESCC患者的預后提供判斷依據(jù),進一步選擇合適的治療方案,從而提高患者的生存率和生存質量。結果顯示根據(jù)CAP標準判斷的環(huán)周切緣陽性的患者預后較差,根據(jù)CAP標準判斷的環(huán)周切緣陽性與預后有顯著的相關性,是ESCC患者獨立的預后因素。此外,研究發(fā)現(xiàn)在141例淋巴結轉移陽性的患者中,淋巴結被膜外侵犯與患者的年齡、性別、N分期有關,與OS及DFS有顯著的相關性,但不是淋巴結轉移陽性患者的獨立的預后因素。第二部分:食管癌的發(fā)生發(fā)展是由多基因、多因素、多步驟協(xié)同作用的結果。近年來,分子生物學研究發(fā)展迅猛,與食管癌預后有關的分子生物學指標也成為研究的熱點,希望通過對其分子指標的研究找到有效的靶向治療方法改善患者的預后。腫瘤免疫逃逸是腫瘤發(fā)生、侵襲及轉移的重要機制,PD-1/PD-L1途徑介導的負性信號能有效抑制T、B細胞功能,在機體免疫應答后期的負性調節(jié)中發(fā)揮了至關重要的作用,并在腫瘤免疫、自身免疫和慢性病毒感染等疾病的發(fā)生發(fā)展中具有重要的生物學意義。本研究通過對1999年-2003年378例行食管癌切除術且術前未進行任何治療的T2-T4a期ESCC患者PD-L1基因的蛋白表達情況的分析,探討PD-L1表達的臨床病理特征及與預后的相關性。結果顯示在378例ESCC患者中,113例(29.99%)PD-L1出現(xiàn)腫瘤細胞的表達,152例(40.2%)出現(xiàn)浸潤免疫細胞的表達。PD-L1在腫瘤細胞的表達與患者的發(fā)病年齡、分化程度、T分期、N分期及血行轉移有一定的相關性,腫瘤分化程度低的ESCC患者,PD-L1表達率較高。PD-L1在浸潤免疫細胞的表達則與N分期有關。Kaplan-Meier生存分析及單因素分析顯示PD-L1在腫瘤細胞的表達與DFS顯著相關,PD-L1表達的患者DFS較短,但多因素分析并沒有顯示PD-L1表達是獨立的預后因素。同時研究發(fā)現(xiàn)PD-L1在浸潤免疫細胞表達的患者DFS及OS更長,然而生存分析并沒有顯示其與預后有明顯的相關性。本研究表明PD-L1在腫瘤細胞中的表達對進展期ESCC患者預后較差有一定的提示作用,針對PD-1/PD-L1通路的靶向治療也許可以使進展期ESCC患者獲益,改善患者預后。
[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.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R735.1
本文編號：2425977
[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.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R735.1
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