乙型肝炎病毒感染及抗病毒治疗对肝细胞癌微血管侵犯的影响
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摘要
目的:探讨乙型肝炎病毒(HBV)感染及抗病毒治疗对肝细胞癌微血管侵犯(MVI)形成的影响。方法:回顾性分析青岛大学附属医院2015年1月—2017年12月660例行根治性肝切除手术的肝细胞癌患者的临床及病理资料。结果:660例患者中,MVI发生率为46.8%(309/660)。单因素分析显示,MVI的形成与HBsAg阳性、可检测的HBV DNA载量以及是否行抗病毒治疗有关,此外,还与患者的年龄、性别、术前AFP、肿瘤标志物、肝功能指标、组织学分级、肿瘤大小与数目、包膜是否完整以及是否存在卫星结节有关(均P<0.05)。在HBV相关患者中,多因素Logistic回归分析结果显示:可检测的HBV DNA载量(OR=5.33,P<0.001)为MVI的独立危险因素,而抗病毒治疗半年以上(OR=0.37,P=0.002)为MVI的独立保护因素,MVI的其他独立影响因素还包括性别、AFP水平、肿瘤直径、组织学分级、包膜不完整、存在卫星结节(均P<0.05)。重度MVI患者有明显高的HBV感染、高HBV DNA载量(>100 IU/mL)以及未行抗病毒治疗的比例较轻度MVI及无MVI患者明显升高(均P<0.05),此外,轻度MVI患者中肝硬化比例较高(80.0%)。结论:HBV感染与HBV DNA水平是肝细胞癌MVI的形成的重要因素,抗病毒治疗可能对MVI的形成有预防作用。
Objective: To investigate the influence of hepatitis B virus(HBV) infection and antiviral treatment on the formation of microvascular invasion(MVI) in hepatocellular carcinoma.Methods: The clinical and pathological data of 660 patients with hepatocellular carcinoma who underwent radical hepatectomy from January 2015 to December 2017 in Affiliated Hospital of Qingdao University were retrospectively analyzed. Results: In the 660 patients, the incidence of MVI was 46.8%(309/660). Results of univariate analysis showed that MVI formation was significantly related to positive HBsAg, detectable HBV DNA load, and whether or not underwent antiviral treatment, and was also associated with the age, sex, preoperative levels of AFP, tumor markers and liver function parameters, histological grade, the size and number of lesions, capsule integrity and presence or absence of satellite nodules(all P<0.05). In the HBV-related patients, the results of multivariate Logistic regression analysis showed that detectable HBV DNA load was an independent risk factor for MVI(OR=5.33, P<0.001), while antiviral therapy for more than half a year was an independent protective factor against MVI(OR=0.37, P=0.002), and other independent influential factors for MVI were included sex, AFP level, tumor diameter, histological grade, incomplete capsule and presence of satellite nodules(all P<0.05). In patients with severe MVI, the proportions of HBV infection, high detectable HBV DNA load(>100 IU/mL) and cases without antiviral treatment were significantly increased compared with those with mild or without MVI(all P<0.05), moreover, the proportion of cases with liver cirrhosis was increased in patients with mild MVI(80.0%).Conclusion: HBV infection and HBV DNA level are independent factors for MVI formation in hepatocellular carcinoma and antiviral therapy may have a preventive effect against the formation of MVI.
Objective: To investigate the influence of hepatitis B virus(HBV) infection and antiviral treatment on the formation of microvascular invasion(MVI) in hepatocellular carcinoma.Methods: The clinical and pathological data of 660 patients with hepatocellular carcinoma who underwent radical hepatectomy from January 2015 to December 2017 in Affiliated Hospital of Qingdao University were retrospectively analyzed. Results: In the 660 patients, the incidence of MVI was 46.8%(309/660). Results of univariate analysis showed that MVI formation was significantly related to positive HBsAg, detectable HBV DNA load, and whether or not underwent antiviral treatment, and was also associated with the age, sex, preoperative levels of AFP, tumor markers and liver function parameters, histological grade, the size and number of lesions, capsule integrity and presence or absence of satellite nodules(all P<0.05). In the HBV-related patients, the results of multivariate Logistic regression analysis showed that detectable HBV DNA load was an independent risk factor for MVI(OR=5.33, P<0.001), while antiviral therapy for more than half a year was an independent protective factor against MVI(OR=0.37, P=0.002), and other independent influential factors for MVI were included sex, AFP level, tumor diameter, histological grade, incomplete capsule and presence of satellite nodules(all P<0.05). In patients with severe MVI, the proportions of HBV infection, high detectable HBV DNA load(>100 IU/mL) and cases without antiviral treatment were significantly increased compared with those with mild or without MVI(all P<0.05), moreover, the proportion of cases with liver cirrhosis was increased in patients with mild MVI(80.0%).Conclusion: HBV infection and HBV DNA level are independent factors for MVI formation in hepatocellular carcinoma and antiviral therapy may have a preventive effect against the formation of MVI.
引文
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[16]Imamura H,Matsuyama Y,Tanaka E,et al.Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy[J].J Hepatol,2003,38(2):200-207.
[17]Sumie S,Kuromatsu R,Okuda K,et al.Microvascular invasion in patients with hepatocellular carcinoma and its predictable clinicopathological factors[J].Ann Surg Oncol,2008,15(5):1375-1382.doi:10.1245/s10434-008-9846-9.
[18]Lim KC,Chow PK,Allen JC,et al.Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria[J].Ann Surg,2011,254(1):108-113.doi:10.1097/SLA.0b013e31821ad884.
[19]Yuen MF,Hou JL,Chutaputti A.Hepatocellular carcinoma in the Asia pacific region[J].J Gastroenterol Hepatol,2009,24(3):346-353.doi:10.1111/j.1440-1746.2009.05784.x.
[20]王煜,王峰,张爱芸,等.血清HBV-DNA载量与肝细胞癌患者手术风险的临床关系[J].中国普通外科杂志,2017,26(7):939-943.doi:10.3978/j.issn.1005-6947.2017.07.020.Wang Y,Wang F,Zhang AY,et al.Clinical relevance of quantity of serum HBV-DNA load and surgical risk of hepatocellular cancer patients[J].Chinese Journal of General Surgery,2017,26(7):939-943.doi:10.3978/j.issn.1005-6947.2017.07.020.
[21]姚豫桐,安志明,罗兰云,等.乙肝相关性肝癌术前乙型肝炎病毒DNA载量与围手术期并发症的关系[J].中国普通外科杂志,2016,25(1):19-24.doi:10.3978/j.issn.1005-6947.2016.01.004.Yao YT,An ZM,Luo LY,et al.Relationship between preoperative hepatitis B virus DNA level and perioperative complications in patients with hepatitis B-related hepatocellular carcinoma[J].Chinese Journal of General Surgery,2016,25(1):19-24.doi:10.3978/j.issn.1005-6947.2016.01.004.
[22]Wu CY,Chen YJ,Ho HJ,et al.Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection[J].JAMA,2012,308(18):1906-1914.
[23]Kim BK,Park JY,Kim DY,et al.Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection[J].Liver Int,2008,28(3):393-401.doi:10.1111/j.1478-3231.2007.01625.x.
[24]Huang G,Lai EC,Lau WY,et al.Posthepatectomy HBVreactivation in hepatitis B-related hepatocellular carcinoma influences postoperative survival in patients with preoperative low HBV-DNA levels[J].Ann Surg,2013,257(3):490-505.doi:10.1097/SLA.0b013e318262b218.
[25]李巨仕,刘国华,郑核.抗病毒治疗对行根治切除术肝癌合并乙肝病毒感染患者的应用价值[J].中国普通外科杂志,2013,22(7):880-884.doi:10.7659/j.issn.1005-6947.2013.07.013.Li JS,Liu GH,Zheng H.Application value of antiviral therapy for liver cancer patients infected with hepatitis B virus undergoing radical resection[J].Chinese Journal of General Surgery,2013,22(7):880-884.doi:10.7659/j.issn.1005-6947.2013.07.013.
[26]Wu JC,Huang YH,Chau GY,et al.Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma[J].JHepatol,2009,51(5):890-897.doi:10.1016/j.jhep.2009.07.009.
[27]陈凯,杨洪吉,邓小凡,等.肝癌根治性切除术后早期复发危险因素分析及预测模型构建[J].中华肿瘤防治杂志,2018,25(5):344-348.Chen K,Yang HJ,Deng XF,et al.Risk factors of primary hepatocellular carcinoma patients early term recurrence after radical resection and prediction model establishment[J].Chinese Journal of Cancer Prevention and Treatment,2018,25(5):344-348.
[28]Yin J,Li N,Han Y,et al.Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma:a two-stage longitudinal clinical study[J].J Clin Oncol,2013,31(29):3647-3655.doi:10.1200/JCO.2012.48.5896.
[29]中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015更新版)[J].中华肝脏病杂志,2015,23(12):888-905.doi:10.3760/cma.j.issn.1007-3418.2015.12.002.Society of Hepatology,Chinese Medical Association,,Society of Infectious Diseases,Chinese Medical Association.The guideline of prevention and treatment for chronic hepatitis B:a 2015 update[J].Chinese Journal of Hepatology,2015,23(12):888-905.doi:10.3760/cma.j.issn.1007-3418.2015.12.002.
[30]中华预防医学会肿瘤预防与控制专业委员会感染相关肿瘤防控学组,中华预防医学会慢病预防与控制分会,中华预防医学会健康传播分会.中国肝癌一级预防专家共识(2018)[J].中华肿瘤杂志,2018,40(7):550-557.doi:10.3760/cma.j.issn.0253-3766.2018.07.013.Group of Prevention of Infection Related Cancer,Specialized Committee of Cancer Prevention and Control,Chinese Preventive Medical Association,Society of Chronical Disease Control and Prevention,Chinese Preventive Medical Association,Society of Health Communication,Chinese Preventive Medical Association.Strategies of primary prevention of liver cancer in China:Expert Consensus(2018)[J].Chinese Journal of Oncology,2018,40(7):550-557.doi:10.3760/cma.j.issn.0253-3766.2018.07.013.
[2]Kim Y,Stahl C C,Makramalla A,et al.Downstaging therapy followed by liver transplantation for hepatocellular carcinoma beyond Milan criteria[J].Surgery,2017,162(6):1250-1258.doi:10.1016/j.surg.2017.08.007.
[3]Ziogas IA,Tsoulfas G.Advances and challenges in laparoscopic surgery in the management of hepatocellular carcinoma[J].World J Gastrointest Surg,2017,9(12):233-245.doi:10.4240/wjgs.v9.i12.233.
[4]Roayaie S,Blume IN,Thung SN,et al.A system of classifying microvascular invasion to predict outcome after resection in patients with hepatocellular carcinoma[J].Gastroenterology,2009,137(3):850-855.doi:10.1053/j.gastro.2009.06.003.
[5]Rodríguez-Perálvarez M,Luong TV,Andreana L,et al.A systematic review of microvascular invasion in hepatocellular carcinoma:diagnostic and prognostic variability[J].Ann Surg Oncol,2013,20(1):325-339.doi:10.1245/s10434-012-2513-1.
[6]丁光宇,朱小东,施国明,等.微血管侵犯对肝内胆管细胞癌根治性切除术患者预后的影响[J].中华肝胆外科杂志,2018,24(3):189-193.doi:10.3760/cma.j.issn.1007-8118.2018.03.012.Ding GY,Zhu XD,Shi GM,et al.The prognostic impact of microvascular invasion on patients with intrahepatic cholangiocarcinoma after R0 resections[J].Chinese Journal of Hepatobiliary Surgery,2018,24(3):189-193.doi:10.3760/cma.j.issn.1007-8118.2018.03.012.
[7]Yu MC,Yuan JM.Environmental factors and risk for hepatocellular carcinoma[J].Gastroenterology,2004,127(5 Suppl 1):S72-78.
[8]Iguchi T,Shirabe K,Aishima S,et al.New Pathologic Stratification of Microvascular Invasion in Hepatocellular Carcinoma:Predicting Prognosis After Living-donor Liver Transplantation[J].Transplantation,2015,99(6):1236-1242.d o i:10.1097/TP.0000000000000489.
[9]Qu LS,Zhang HF.Significance of viral status on prognosis of hepatitis B-related hepatocellular carcinoma after curative resection in East Asia[J].Hepatol Res,2016,46(1):40-49.doi:10.1111/hepr.12523.
[10]European Association For The Study Of The Liver.EASL clinical practice guidelines:Management of chronic hepatitis B virus infection[J].J Hepatol,2012,57(1):167-185.doi:10.1016/j.jhep.2012.02.010.
[11]Chen L,Zhang Q,Chang W,et al.Viral and host inflammationrelated factors that can predict the prognosis of hepatocellular carcinoma[J].Eur J Cancer,2012,48(13):1977-1987.doi:10.1016/j.ejca.2012.01.015.
[12]Yang P,Li Q J,Feng Y,et al.TGF-β-miR-34a-CCL22 signalinginduced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma[J].Cancer Cell,2012,22(3):291-303.doi:10.1016/j.ccr.2012.07.023.
[13]Lei Z,Li J,Wu D,et al.Nomogram for Preoperative Estimation of Microvascular Invasion Risk in Hepatitis B Virus-Related Hepatocellular Carcinoma Within the Milan Criteria[J].JAMASurg,2016,151(4):356-363.doi:10.1001/jamasurg.2015.4257.
[14]中华人民共和国卫生和计划生育委员会医政医管局.原发性肝癌诊疗规范(2017年版)[J].中华肝脏病杂志,2017,25(12):886-895.doi:10.3760/cma.j.issn.1007-3418.2017.12.002.Bureau of Medical Administration,National Health and Family Planning Committee.Diagnosis,management,and treatment of hepatocellular carcinoma(V2017)[J].Chinese Journal of Hepatology,2017,25(12):886-895.doi:10.3760/cma.j.issn.1007-3418.2017.12.002.
[15]中国抗癌协会肝癌专业委员会,中华医学会肝病学分会肝癌学组,中国抗癌协会病理专业委员会,等.原发性肝癌规范化病理诊断指南(2015年版)[J].中华肝脏病杂志,2015,23(5):321-327.doi:10.3760/cma.j.issn.1007-3418.2015.05.001.Specialized Committee of Liver Cancer,Chinese Anti-Cancer Association,Group of Liver Cancer,Society of Hepatology,Chinese Medical Association,Specialized Committee of Pathology,Chinese Anti-Cancer Association,et al.Evidence-based practice guidelines for standardized pathological diagnosis of primary liver cancer in China:2015 update[J].Chinese Journal of Hepatology,2015,23(5):321-327.doi:10.3760/cma.j.issn.1007-3418.2015.05.001.
[16]Imamura H,Matsuyama Y,Tanaka E,et al.Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy[J].J Hepatol,2003,38(2):200-207.
[17]Sumie S,Kuromatsu R,Okuda K,et al.Microvascular invasion in patients with hepatocellular carcinoma and its predictable clinicopathological factors[J].Ann Surg Oncol,2008,15(5):1375-1382.doi:10.1245/s10434-008-9846-9.
[18]Lim KC,Chow PK,Allen JC,et al.Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria[J].Ann Surg,2011,254(1):108-113.doi:10.1097/SLA.0b013e31821ad884.
[19]Yuen MF,Hou JL,Chutaputti A.Hepatocellular carcinoma in the Asia pacific region[J].J Gastroenterol Hepatol,2009,24(3):346-353.doi:10.1111/j.1440-1746.2009.05784.x.
[20]王煜,王峰,张爱芸,等.血清HBV-DNA载量与肝细胞癌患者手术风险的临床关系[J].中国普通外科杂志,2017,26(7):939-943.doi:10.3978/j.issn.1005-6947.2017.07.020.Wang Y,Wang F,Zhang AY,et al.Clinical relevance of quantity of serum HBV-DNA load and surgical risk of hepatocellular cancer patients[J].Chinese Journal of General Surgery,2017,26(7):939-943.doi:10.3978/j.issn.1005-6947.2017.07.020.
[21]姚豫桐,安志明,罗兰云,等.乙肝相关性肝癌术前乙型肝炎病毒DNA载量与围手术期并发症的关系[J].中国普通外科杂志,2016,25(1):19-24.doi:10.3978/j.issn.1005-6947.2016.01.004.Yao YT,An ZM,Luo LY,et al.Relationship between preoperative hepatitis B virus DNA level and perioperative complications in patients with hepatitis B-related hepatocellular carcinoma[J].Chinese Journal of General Surgery,2016,25(1):19-24.doi:10.3978/j.issn.1005-6947.2016.01.004.
[22]Wu CY,Chen YJ,Ho HJ,et al.Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection[J].JAMA,2012,308(18):1906-1914.
[23]Kim BK,Park JY,Kim DY,et al.Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection[J].Liver Int,2008,28(3):393-401.doi:10.1111/j.1478-3231.2007.01625.x.
[24]Huang G,Lai EC,Lau WY,et al.Posthepatectomy HBVreactivation in hepatitis B-related hepatocellular carcinoma influences postoperative survival in patients with preoperative low HBV-DNA levels[J].Ann Surg,2013,257(3):490-505.doi:10.1097/SLA.0b013e318262b218.
[25]李巨仕,刘国华,郑核.抗病毒治疗对行根治切除术肝癌合并乙肝病毒感染患者的应用价值[J].中国普通外科杂志,2013,22(7):880-884.doi:10.7659/j.issn.1005-6947.2013.07.013.Li JS,Liu GH,Zheng H.Application value of antiviral therapy for liver cancer patients infected with hepatitis B virus undergoing radical resection[J].Chinese Journal of General Surgery,2013,22(7):880-884.doi:10.7659/j.issn.1005-6947.2013.07.013.
[26]Wu JC,Huang YH,Chau GY,et al.Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma[J].JHepatol,2009,51(5):890-897.doi:10.1016/j.jhep.2009.07.009.
[27]陈凯,杨洪吉,邓小凡,等.肝癌根治性切除术后早期复发危险因素分析及预测模型构建[J].中华肿瘤防治杂志,2018,25(5):344-348.Chen K,Yang HJ,Deng XF,et al.Risk factors of primary hepatocellular carcinoma patients early term recurrence after radical resection and prediction model establishment[J].Chinese Journal of Cancer Prevention and Treatment,2018,25(5):344-348.
[28]Yin J,Li N,Han Y,et al.Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma:a two-stage longitudinal clinical study[J].J Clin Oncol,2013,31(29):3647-3655.doi:10.1200/JCO.2012.48.5896.
[29]中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015更新版)[J].中华肝脏病杂志,2015,23(12):888-905.doi:10.3760/cma.j.issn.1007-3418.2015.12.002.Society of Hepatology,Chinese Medical Association,,Society of Infectious Diseases,Chinese Medical Association.The guideline of prevention and treatment for chronic hepatitis B:a 2015 update[J].Chinese Journal of Hepatology,2015,23(12):888-905.doi:10.3760/cma.j.issn.1007-3418.2015.12.002.
[30]中华预防医学会肿瘤预防与控制专业委员会感染相关肿瘤防控学组,中华预防医学会慢病预防与控制分会,中华预防医学会健康传播分会.中国肝癌一级预防专家共识(2018)[J].中华肿瘤杂志,2018,40(7):550-557.doi:10.3760/cma.j.issn.0253-3766.2018.07.013.Group of Prevention of Infection Related Cancer,Specialized Committee of Cancer Prevention and Control,Chinese Preventive Medical Association,Society of Chronical Disease Control and Prevention,Chinese Preventive Medical Association,Society of Health Communication,Chinese Preventive Medical Association.Strategies of primary prevention of liver cancer in China:Expert Consensus(2018)[J].Chinese Journal of Oncology,2018,40(7):550-557.doi:10.3760/cma.j.issn.0253-3766.2018.07.013.