【作者】 徐敏晖；

【导师】 吴孟超；

【作者基本信息】 苏州大学 ， 普通外科学， 2014， 博士

【摘要】 第一部分：癌旁胆管反应与临床及病理学关系的研究目的：评估癌旁胆管反应与临床病理资料间的关系。方法：收集2001年1月到2003年6月期间第二军医大学附属东方肝胆外科医院原发性肝细胞癌根治性手术后病理标本106例。运用免疫组织化学方法检测癌旁胆管反应情况。整理肝细胞癌患者的临床及随访资料，分析癌旁胆管反应与肝细胞癌患者临床病理特征的关系。结果：癌旁胆管反应的程度与肿瘤患者血清AFP水平（p=0.01）、血清ALT (p=0.017)、血清ALP (p=0.007)、血清HBsAg (+)(p=4.9E-4)、肿瘤包膜(p=0.027)、肿瘤个数(p=0.004)、镜下血管侵犯(p=0.031)、早期复发(p=0.010)、BCLC分期(p=0.003)和TNM分期（p=0.002）显著相关。结论：癌旁组织中胆管反应的程度与肝细胞癌患者临床病理中肿瘤强侵袭性指标显著相关，癌旁胆管反应高的肿瘤表现出更强的侵袭性。第二部分：癌旁胆管反应与肝癌根治性切除术后预后关系的研究目的：分析肝细胞癌根治性切除术后预后的影响因素。方法：回顾性分析2001年1月到2003年6月期间第二军医大学附属东方肝胆外科医院106例肝细胞癌根治性手术患者临床资料。采用Log-rank法检验进行统计学比较，寿命表法进行生存率分析，运用Cox比例风险模型进行多因素分析。结果：全组患者1、3、5及7年总体生存率分别为71.7%、36.8%、32.1%及20.8%。多因素分析发现，肿瘤大小(﹥5vs≤5cm)、胆管反应（<2vs≥2）和BCLC分期(0/Avs B/C)是影响总生存的独立预后因素（p值分别为1.3E-04、9.3E-06及2.3E-04）。全组患者1、3、5及7年无瘤生存率分别为54.7%、24.5%、19.8%及8.5%。多因素分析发现，肿瘤大小(﹥5/≤5cm)、胆管反应（<2vs≥2）、TNM分期（I vs II/III）和炎症坏死分级(<9vs≥9)是影响无瘤生存的独立预后因素(p值分别为0.031、0.008、8.8E-06及0.023)。结论：癌旁胆管反应程度是影响肝癌患者术后总生存、无瘤生存的独立预后因素。第三部分：癌旁胆管反应与肝脏炎症坏死及肝硬化关系的研究目的：探讨癌旁胆管反应与肝脏炎症坏死及肝硬化的相关性。方法：收集2001年1月到2003年6月期间第二军医大学附属东方肝胆外科医院原发性肝细胞癌根治性手术后病理标本106例。运用免疫组织化学方法检测癌旁非肿瘤肝脏组织中胆管反应的水平，HE染色评价癌旁肝脏组织中炎症坏死及肝硬化情况，并对二者进行相关性分析。结果：癌旁胆管反应程度与癌旁肝脏炎症坏死及肝硬化情况有相关性。癌旁组织中高水平胆管反应的肝癌患者其癌旁肝脏炎症坏死及肝硬化相对较重（r=0.563, p=3.4E-10；r=0.435, p=3.1E-06）。结论：癌旁胆管反应与肝脏炎症坏死及肝硬化程度呈正相关，肝脏的炎症环境可能促进了胆管反应的升高。第四部分：癌旁胆管反应与肝癌细胞的EpCAM表达关系的研究目的：探讨癌旁胆管反应与肝癌细胞的EpCAM表达的相关性。方法：收集2001年1月到2003年6月期间第二军医大学附属东方肝胆外科医院原发性肝细胞癌根治手术后病理标本106例。运用免疫组织化学方法检测癌旁胆管反应的水平和肝癌细胞的EpCAM表达情况，并对二者进行相关性分析。结果：癌旁胆管反应与肝癌细胞的EpCAM的表达有密切相关性。癌旁组织中高水平胆管反应的肝癌患者其癌细胞的EpCAM表达也比较高（p=0.016）。结论：癌旁胆管反应与肝癌细胞的EpCAM表达呈正相关，癌旁胆管反应可能与肝脏祖细胞的激活、增殖有关。更多还原

【Abstract】 PartⅠStudy on the correlation between peritumoral DR andclinicopathology in hepatocellular carcinomaObjective: To evaluate the peritumoral ductular reaction (DR) in hepatocellularcarcinoma (HCC), and its relationship with the clinicopathological features.Methods: The clinicopathological features and DR were analyzed in106HCCpatients who received curative hepatectomy at the Eastern Hepatobiliary SurgeryHospital from January2001to June2003. Follow-up was completed in December2009. DR was performed by immunohistochemical analysis on peritumoral tissuesections. Relationship between peritumoral DR and clinicopathological features wasperformed by statistical analysis.Results: Increased DR correlated with advanced BCLC stage (p=0.003), TNMstage (p=0.002), with elevated serum ALT (p=0.017), ALP (p=0.007), AFP (p=0.010) and HBsAg (+)(p=4.9E-4). Increased DR was also tended to correlate withmultiple nodules (p=0.004), absence of tumor capsule (p=0.027), severemicroscopic vascular invasion (p=0.031) and early recurrence (p=0.010).Conclusions：Significantly peritumoral DR correlated with aggressive clinico-pathological features. It plays a critical role in the aggressiveness of HCC. PartⅡPeritumoral ductular reaction and survival analysis of hepato-cellular carcinoma after hepatectomyObjective: To appraise the relationship of risk factors with poor overall survivaland recurrence free survival in hepatocellular carcinoma after curative hepatectomy.Methods: The clinicopathological characteristics and DR was analyzed in106HCC patients who received curative hepatectomy at the Eastern HepatobiliarySurgery Hospital from Junuary2001to June2003. The Kaplan–Meier method wasused in overall survival rates and recurrence free survival rates. The Log-Rank testwas used in survival curves. Variables were subjected to multivariate Cox regressionmodeling using forward stepwise variable selection when they with p <0.05inunivariate analysis.Results: The1-,3-,5-,7-year RFS and OS rates were54.7%,24.5%,19.8%,8.5%and71.7%,36.8%,32.1%,20.8%respectively. Both DR and tumor size wereindependent prognostic factors for RFS and OS. DR was associated with elevatedrisks of recurrence (HR=2.380,95%CI=1.250-4.534, p=0.008) and death (HR=4.294,95%CI=2.255-8.177, p=9.3E-06). Tumor size was associated with elevatedrisks of recurrence (HR=1.804,95%CI=1.057-3.080, p=0.031) and death (HR=2.950,95%CI=1.694-5.137, p=1.3E-04). Besides, TNM and necroinflammatorygrade were demonstrated as independent predictors for RFS; while BCLC stage wasindependent prognostic factors for OS.Conclusions：Peritumoral DR is an independent factor which affects overallsurvival and recurrence free survival of HCC. PartⅢStudy on the correlation between peritumoral DR andNecroinflammatory grade, Fibrotic stageObjective: To evaluate association between the peritumoral DR andnecroinflammatory grade, fibrotic stage in the non-tumor liver tissue.Methods: The pathological specimens of liver tissues were obtained from106HCC patients who received curative hepatectomy at the Eastern HepatobiliarySurgery Hospital from January2001to June2003. Peritumoral DR was performed byimmunohistochemical analysis, necroinflammatory grade and fibrotic stage innon-tumor liver sections were scored by H&E. Association between peritumoral DRand necroinflammatory grade, fibrotic stage was performed by statistical analysis.Results: The relationship of peritumoral DR and necroinflammatory grade,fibrotic stage was found significantly. Peritumoral DR significantly correlated withnecroinflammatory grade (r=0.563, p=3.4E-10) and fibrotic stage (r=0.435, p=3.1E-06) in HCC patients.Conclusions： A necroinflammatory microenvironment perhaps promotedperitumoral ductular reactions in HCC. PartⅣStudy on the correlation between peritumoral DR and tumoralEpCAM expressionObjective: To evaluate the peritumoral DR in the non-tumor liver tissue and itsrelationship with expression of tumoral EpCAM in HCC.Methods: The pathological specimens of liver tissues were obtained from106HCC patients who received curative hepatectomy at the Eastern HepatobiliarySurgery Hospital from January2001to June2003. Peritumoral DR and tumoralEpCAM was performed by immunohistochemical analysis on non-tumoral liversections and tumoral tissues. Association between peritumoral DR and tumoralEpCAM expression was performed by statistical analysis.Results: The relationship of peritumoral DR and tumoral EpCAM expressionwas found significantly. Elevated peritumoral DR was closely associated with tumoralEpCAM expression in HCC patients (p=0.016).Conclusions：Elevated peritumoral DR was closely associated with tumoralEpCAM expression in HCC. Peritumoral DR was perhaps associated activation andproliferation of hepatic progenitor cell in HCC.更多还原