肝细胞癌微血管侵犯新型分级系统的建立及其临床病理学意义的研究

发布时间：2018-04-18 06:52

本文选题：肝细胞癌 + 微血管癌栓　；参考：《第二军医大学》2016年硕士论文

【摘要】：背景:肝细胞癌(以下简称“肝癌”)是我国最常见的恶性肿瘤之一。肝癌微血管侵犯(Microvascular invasion,MVI)是影响肝癌术后生存的重要因素,已成为制约肝癌外科疗效的重要瓶颈。但是,MVI组织病理学分型国内外尚未明确提出,现有MVI风险分级系统尚未广泛应用于临床实践,经典肝癌分期系统也未能充分反应MVI在肝癌术后预后评估中的临床意义。目的:提出肝癌MVI组织病理学分型,并在此基础上建立一个以MVI组织病理学特点为核心的新型MVI分级系统。最终,在综合分析影响肝癌术后预后因素的基础上,建立一个更加准确、敏感、实用的预测肝癌术后远期生存及早期复发的评估模型。方法:回顾性分析2009年12月-2010年04月因“肝占位”在上海东方肝胆外科医院行肝肿瘤根治性手术治疗、且术后病理明确诊断为肝癌的686例病例(建模组)。在复阅所有病理切片并详细分析MVI的组织病理学特点的基础上,提出MVI组织病理学分型并建立新型MVI分级系统。继而,对建模组数据首先进行Kaplan-Meier单因素生存分析,筛选出相关预后危险因素后,再将这些危险因素进行Cox风险比例多因素生存分析,筛选影响肝癌预后的独立危险因素。根据多因素生存分析结果,分别建立总体生存和早期复发预后列线图预测模型。以一致性指数(C-index)和校正曲线图为主要评估指标,评价模型的预测效果,并与肝癌经典分期系统的预后预测情况做比较,包括巴塞罗那肝癌临床分期系统(Barcelona Clinic Liver Staging System,BCLC)、第七版肝癌TNM分期系统(Tumour-Node-Metastasis Staging System,TNM)、日本综合分期系统(Japan Integrated Staging System,JIS)、香港中文大学预后指数(Chinese University Prognostic Index,CUPI)和香港肝癌分期系统(Hong Kong Liver Cancer Staging System,HKLC)。同时,筛选2010年05月-2010年06月的225例病例作为外部验证队列(验证组)以验证模型预测效果。所有统计学分析均采用SPSS(版本22.0)和R统计软件(版本2.13.1)完成。结果:MVI组织病理学分型:根据癌栓与管壁之间的关系以及癌栓对管壁的侵犯程度,MVI可细分为游离型(26.0%)、黏附型(12.2%)、管壁侵犯型(22.9%)和管壁突破型(38.9%)四种类型(四分类),又可简要分为非侵犯型(包括游离型和黏附型,38.2%)和侵犯型(包括管壁侵犯型和管壁突破型,61.8%)两种类型(二分类)。Kaplan-Meier生存曲线表明该分型与肝癌术后生存与早期复发密切相关(P0.001)。MVI新型分级系统:Cox风险比例生存分析结果表明,MVI组织病理学分型(P0.017)和MVI数量(P0.001)是影响肝癌患者总生存期的独立预后因素,两者风险比值相近,分别为1.7(95%CI:1.1-2.5)和2.0(95%CI:1.4-2.9);而仅MVI数量是影响肝癌患者早期复发(P0.001)的独立预后因素。因此,MVI病理分型和数量成为MVI风险分层的主要危险因素。根据危险因素的累及数量,构建MVI分级系统:M1,无危险因素;M2,1项危险因素;M3,2项危险因素;同时,增加无MVI形成组M0。此种方法,将MVI分为M0-M3四种风险分级;生存分析表明,随着MVI分级增加,总生存时间和无瘤生存期均逐渐缩短。肝癌术后总生存期及早期复发预后列线图的建立与验证:Cox回归筛选出与总生存期相关的因素有8项,分别为:血清AFP水平、血清CA19-9水平、术中输血、肿瘤大小、肿瘤数量、MVI分级、肿瘤包膜和卫星结节;影响早期复发的独立危险因素有7项,分别为:年龄、血清AFP水平、肿瘤大小、肿瘤数量、MVI数量、肿瘤包膜和卫星结节。据此,绘制相应列线图,其中总生存预后模型C-index值为0.78,早期复发模型C-index值为0.72,均高于肝癌经典分期系统(BCLC分期:0.58/0.54;TNM分期:0.67/0.68;JIS分期:0.58/0.52;CUPI:0.52/0.55;HKLC分期:0.72/0.73),且差异具有统计学意义(P值均0.001)。同时,无论是建模组还是验证组,校正曲线均直观表明两种预测模型的实际概率和预测概率具有良好的一致性。在验证队列中,总体生存及早期复发列线图的C-index值均高于其他经典分期系统,但除HKLC分期系统外(P总体生存=0.234;P早期复发=0.749),列线图C-index值与其他经典分期系统的比较均具有统计学差异(P值均0.001)。结论:通过此次研究,我们首次明确提出了MVI组织病理学分型,并建立了更加实用、简洁的新型分级系统和预后列线图,对肝癌术后复发的早诊、早治提供了临床病理学依据。
[Abstract]:Background: hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. Invasion of tumor microvessel (Microvascular invasion MVI) is an important factor affecting the survival of hepatocellular carcinoma after operation, has become an important bottleneck restricting the curative effect of surgical liver cancer. However, MVI tissue pathological types at home and abroad is not yet clear put forward the existing MVI risk classification system has not been widely used in clinical practice, the classic staging system for hepatocellular carcinoma also failed to fully reflect the clinical significance of MVI in assessing the prognosis of hepatocellular carcinoma after operation. Objective: to put forward MVI HCC histological type, and on the basis of the establishment of a MVI histological features as the core of the new MVI classification system. In the end, based on the prognostic factors of hepatocellular carcinoma after operation in a comprehensive analysis, establish a more accurate, sensitive, practical assessment and prediction of long-term survival after liver resection for early recurrence model: Retrospective analysis of December 2009 -2010 years 04 months because of "liver occupying" radical surgery in Shanghai Oriental Hepatic Surgery Hospital, liver neoplasms, and postoperative pathological diagnosis of 686 cases of liver cancer (model group). Based on the review of all pathological and histopathological characteristics of a detailed analysis of MVI, put forward MVI pathology the credit and to establish a new MVI classification system. Then, the modeling data set firstly analyzed Kaplan-Meier univariate survival, screened prognostic risk factors, the risk factors of Cox risk ratio multivariate survival analysis, screening effect of independent risk factors for the prognosis of liver cancer. According to multivariate survival analysis results, establish overall the survival and prognosis of early recurrence nomogram prediction model. The consistency index (C-index) and calibration curve as the main evaluation index, evaluation model of prediction, Compare the situation and prognosis of liver cancer staging system classic prediction, including Barcelona liver cancer staging system (Barcelona Clinic Liver Staging System, BCLC), the seventh edition of TNM staging system for hepatocellular carcinoma (Tumour-Node-Metastasis Staging, System, TNM), the Japanese comprehensive system (Japan Integrated Staging System, JIS), Chinese University Prognostic (Chinese University Hong Kong prognostic index Index, CUPI) and the Hongkong staging system for hepatocellular carcinoma (Hong Kong Liver Cancer Staging System, HKLC). At the same time, the screening of 225 cases in 2010 05 months -2010 years 06 months as the external validation cohort (test group) prediction results to verify the model. All statistical analyses were performed using SPSS (version 22) and R software (version 2.13.1). Results: MVI histological classification according to the relationship between the tumor thrombus and the pipe wall and the pipe wall on the extent of tumor thrombus, MVI can be subdivided into Free type (26%), (12.2%), the adhesion type tube wall invasion type (22.9%) and wall breaking (38.9%) four types (four categories), and can be briefly divided into non aggressive (including free and adhesion type, 38.2%) and aggressive (including wall invasion and tube type break wall type, 61.8% (two) of two types of classification).Kaplan-Meier survival curves showed that the type of survival and early recurrence after resection of hepatocellular carcinoma and closely related to the new classification system (P0.001).MVI: Cox proportional hazards survival analysis showed that MVI histological type (P0.017) and MVI (P0.001) is the number of independent prognostic factors of overall survival in patients with hepatocellular carcinoma, the risk ratio is similar, respectively 1.7 (95%CI:1.1-2.5) and 2 (95%CI:1.4-2.9); and only MVI the number of early recurrence in patients with hepatocellular carcinoma (P0.001) of the independent prognostic factors. Therefore, the MVI pathological type and number of MVI become the main risk factors. The risk stratification of root According to the number of risk factors in construction of MVI classification system: M1, no M2,1 risk factors; risk factors; M3,2 risk factors; at the same time, no increase in MVI group M0. this method, MVI is divided into M0-M3 four risk classification; survival analysis showed that with the increase in the MVI grade, and tumor free survival time survival period was shortened gradually. Establishment and verification of overall survival and prognosis of early recurrence after resection of hepatocellular carcinoma: nomogram Cox regression analysis showed that the factors associated with overall survival of 8, respectively: the level of serum AFP, serum CA19-9 level, intraoperative blood transfusion, tumor size, tumor number, MVI grade, tumor capsule and satellite nodules; independent risk factors for early recurrence of 7, respectively: age, serum AFP level, tumor size, tumor number, MVI number, tumor capsule and satellite nodules. Accordingly, draw the corresponding nomograms, of which the total value of 0.7 C-index survival model 8, early recurrence model of C-index was 0.72, was significantly higher than that of tumor staging (BCLC staging system classic: 0.58/0.54; TNM: 0.67/0.68; JIS staging staging: 0.58/0.52; CUPI:0.52/0.55; HKLC staging: 0.72/0.73), and the difference was statistically significant (P < 0.001). At the same time, whether it is modeling group and validation group, calibration curve all show two kinds of prediction models and the actual probability prediction probability with good consistency. In the validation cohort, the overall survival and early recurrence of the nomogram C-index values were higher than those of other classic staging system, but in HKLC stage system (P =0.234 P early recurrence and overall survival; =0.749, C-index) nomogram with other classical staging system were compared with statistical difference (P < 0.001). Conclusion: through this study, we first proposed MVI histological classification, and established a new classification system is more practical, concise The prognosis and nomogram of postoperative recurrence of hepatocellular carcinoma early diagnosis, early treatment to provide clinical pathological basis.

【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R735.7

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