乙型肝炎病毒相关孤立性大肝癌手术切除的远期疗效及预后因素分析

白石磊; 项红军; 夏勇; 李俊; 杨平华; 沈锋

doi:10.3760/cma.j.issn.1673-9752.2017.02.009

乙型肝炎病毒相关孤立性大肝癌手术切除的远期疗效及预后因素分析

Long-term outcomes and prognostic factors of surgical resection of hepatitis B virus-related solitary large hepatocellular carcinoma

摘要

摘要: 目的:探讨乙型肝炎病毒相关孤立性大肝癌和小肝癌患者预后的情况，分析影响孤立性大肝癌预后的危险因素。
方法:采用回顾性病例对照研究方法。收集2008年1—12月第二军医大学东方肝胆外科医院收治的856例乙型肝炎病毒相关肝癌患者的临床病理资料。其中693例肝癌患者肿瘤直径≤ 5 cm，设为小肝癌组；163例肝癌患者肿瘤直径>5 cm、单发、呈膨胀性生长、包膜完整，设为孤立性大肝癌组。患者术前行实验室和影像学检查，行抗病毒治疗，依据术前检查结果制订手术方案。观察指标：(1)两组患者临床病理特征比较：性别、年龄、肝功能ChildPugh分级、HBeAg、HBV DNA载量、PLT、Alb、TBil、AFP、肿瘤直径、微血管侵犯、EdmondsonSteiner分级、肝硬化。(2)两组患者治疗情况：手术方式、手术时间、术中出血量、术中输血例数、肝门阻断时间。(3)两组患者生存情况分析。(4)孤立性大肝癌患者的预后因素分析。术后采用电话或门诊方式进行随访。术后2年内每3个月复查1次，2年后每6个月复查1次。复查内容包括肿瘤标志物、肝功能、HBV DNA载量以及腹部B超检查。每6个月或者怀疑肿瘤复发或转移时复查1次CT或MRI，两种影像学检查发现肝癌典型表现则认为肝内复发或转移，必要时行PET/CT检查明确诊断。随访时间截至2014年6月23日。无瘤生存时间为手术时间至患者肿瘤复发时间，患者总体生存时间为手术时间至患者死亡或最后一次随访时间。正态分布的计量资料以±s表示，连续变量采用t检验或MannWhitney U检验。偏态分布的计量资料以M(范围)表示。分类变量采用计数(百分比)表示，采用〖KG*4〗x²检验或校正x²检验。采用KaplanMeier法绘制生存曲线，生存分析采用Logrank检验。COX回归比例模型用于预后因素分析。
结果:(1)两组患者临床病理特征比较：小肝癌组和孤立性大肝癌组患者PLT< 100×109/L分别为197、28例，肿瘤直径分别为(3.1±1.1)cm、(8.9±3.3)cm，微血管侵犯阳性分别为133、53例，有肝硬化分别为447、79例，两组患者上述指标比较，差异均有统计学意义(x²=28.618，t=37.286，x²=213.773，214.325，P<0.05)。(2)两组患者治疗情况：856例肝癌患者均行肝切除术治疗，切除肝段≥ 3个326例，切除肝段<3个530例。693例小肝癌组患者手术时间为90 min(60～200 min)，术中出血量为200 mL(20～5 200 mL)，47例术中输血，125例肝门阻断时间>20 min；163例孤立性大肝癌组患者手术时间为110 min(60～230 min)，术中出血量为300 mL(50～3 200 mL)，31例术中输血，58例肝门阻断时间> 20 min。(3)两组患者生存情况分析：856例患者术后均获得随访，随访时间为32.5个月(1.0～72.3个月)。693例小肝癌组患者中位生存时间为56.2个月(1.6～75.8个月)，无瘤中位生存时间为39.5个月(1.0～75.0个月)；1、3、5年总体生存率和无瘤生存率分别为90%、71%、58%和70%、48%、38%。163例孤立性大肝癌组患者中位生存时间为50.3个月(1.1～76.0个月)，无瘤中位生存时间为30.7个月(1.0～72.0个月)；1、3、5年总体生存率和无瘤生存率分别为87%、59%、47%和65%、46%、33%。小肝癌组和孤立性大肝癌组患者术后无瘤生存率比较，差异无统计学意义(x²=0.514，P>0.05)；两组患者总体生存率比较，差异有统计学意义(x²=10.067，P<0.05)。进一步分层分析：将孤立性大肝癌组患者分为117例肿瘤直径5～ 10 cm和46例肿瘤直径>10 cm，肿瘤直径为5～10 cm的孤立性大肝癌患者1、3、5年总体生存率和无瘤生存率分别为91%、65%、53%和70%、48%、35%，与小肝癌组患者比较，差异均无统计学意义(x²=1.832，0.042，P>0.05)。肿瘤直径>10 cm的孤立性大肝癌患者1、3、5年总体生存率和无瘤生存率分别为78%、46%、31%和49%、39%、30%，与小肝癌组患者比较，差异均有统计学意义(x²=21.136，4.097，P<0.05)。(4)孤立性大肝癌患者的预后因素分析：单因素分析结果显示：HBV DNA载量、肿瘤直径、微血管侵犯是影响孤立性大肝癌患者术后5年无瘤生存率的危险因素(x²=5.193，3.377， 5.509，P<0.05)；性别、HBV DNA载量、肿瘤直径、微血管侵犯是影响孤立性大肝癌患者术后5年总体生存率的危险因素(x²=4.546，18.053，7.780， 10.569，P<0.05)。多因素分析结果显示：HBV DNA载量≥104 U/mL、肿瘤直径>10 cm、微血管侵犯阳性是影响孤立性大肝癌患者术后5年无瘤生存率的独立危险因素(HR=2.77,1.85, 1.86，95%可信区间：1.74～4.40，1.16～2.94， 1.17～2.96，P<0.05)；也是影响孤立性大肝癌患者术后5年总体生存率的独立危险因素(HR=2.73，1.98, 1.69，95%可信区间：1.72～4.33，1.23～3.17， 1.04～2.72，P<0.05)。
结论:肿瘤直径为5～10 cm的孤立性大肝癌预后和小肝癌相似，但肿瘤直径> 10 cm的孤立性大肝癌预后较小肝癌差。HBV DNA载量≥104 U/mL、肿瘤直径>10 cm、微血管侵犯阳性是影响孤立性大肝癌预后的独立危险因素。

Abstract: Objective:To investigate the prognosis of patients with solitary large hepatocellular carcinoma (SLHCC) and with small hepatocellular carcinoma (SHCC), and analyze the risk factors affecting the prognosis of patients with SLHCC.
Methods:The retrospective casecontrol study was conducted. The clinicopathological data of 856 patients with hepatitis B virus (HBV)related HCC who were admitted to the Eastern Hepatobiliary Surgery Hospital of the Second Military Medical University from January 2008 to December 2008 were collected. Of 856 patients, 693 HCC patients with tumor diameter ≤5 cm were allocated into the SHCC group and 163 HCC patients with tumor diameter >5 cm and with solitary, expansive growth and complete capsule tumors were allocated into the SLHCC group. Patients underwent preoperative antiviral therapy, laboratory and imaging examinations, and then surgical planning was determined based on the preoperative results. Observation indicators: (1) comparisons of clinicopathological features between the 2 groups: sex, age, ChildPugh grade, HBeAg, serum level of HBVDNA, platelet (PLT), albumin (Alb), total bilirubin (TBil), alphafetoprotein (AFP), tumor diameter, microvascular invasion, EdmondsonSteiner grade and liver cirrhosis; (2) treatment situations between the 2 groups: surgical procedures, operation time, volume of intraoperative blood loss, number of patients with blood transfusion and time of hepatic inflow occlusion; (3) survival analysis between the 2 groups; (4) prognostic analysis of patients with SLHCC. Followup using telephone interview and outpatient examination was performed once every 3 months within 2 years postoperatively and once every 6 months after 2 years postoperatively up to June 23, 2014. Followup included tumor marker, liver function, serum level of HBVDNA and abdominal Bultrasound examination. The patients received reexamination of computed tomography (CT) or magnetic resonance imaging (MRI) once every 6 months or when there was suspicion of tumor recurrence or metastasis. Tumor recurrence or metastasis was confirmed through typical HCC imaging findings of CT and MRI, and PET/CT examination was conducted if necessary. Tumorfree survival time was from operation time to time of tumor recurrence, and overall survival time was from operation time to death or the last followup. Measurement data with normal distribution were represented as ±s, and continuous variables were analyzed by the t test or MannWhitney U test. Measurement data with skewed distribution were described as M (range). Categorical variables were represented as count (percentage) and analyzed by the chisquare test or calibration chisquare test. The survival curve and survival rate were respectively drawn and calculated by the KaplanMeier method and Logrank test. COX regression model was used for prognostic analysis.
Results:(1) Comparisons of clinicopathological features between the 2 groups: number of patients with PLT<100×109/L, with positive microvascular invasion and with liver cirrhosis and tumor diameter were 197, 133, 447, (3.1±1.1)cm in the SHCC group and 28, 53, 79, (8.9±3.3)cm in the SLHCC group, respectively, with significant differences between the 2 groups x²=28.618, t=37.286, χ2=213.773, 214.325, P<0.05). (2) Treatment situations between the 2 groups: all the 856 patients underwent hepatectomy, including 326 with hepatic segments of resection ≥3 and 530 with hepatic segments of resection <3. Operation time, volume of intraoperative blood loss, number of patients with intraoperative blood transfusion and with time of hepatic inflow occlusion >20 minutes were 90 minutes (range, 60-200 minutes), 200 mL (range, 20-5 200 mL), 47, 125 in the SHCC group and 110 minutes (range, 60-230 min), 300 mL (range, 50-3 200 mL), 31, 58 in the SLHCC group, respectively. (3) Survival analysis between the 2 groups: all the 856 patients were followed up for 32.5 months (range, 1.0-72.3 months). The median survival time, median tumorfree survival time, 1, 3, 5year overall survival rates and 1, 3, 5year tumorfree survival rates were 56.2 months (range,1.6-75.8 months), 39.5 months(range,1.0-75.0 months), 90%, 71%, 58%, 70%, 48%, 38% in the SHCC and 50.3 months (range, 1.1- 76.0 months), 30.7 months (range, 1.0-72.0 months), 87%, 59%, 47%, 65%, 46%, 33% in the SLHCC group, respectively, with no significant difference in tumorfree survival between the 2 groups x²=0.514, P>0.05) and with a significant difference in overall survival between the 2 groups x²=10.067, P<0.05). Stratified analysis: there were 117 SLHCC patients with 5 cm < tumor diameter <10 cm and 46 SLHCC patients with tumor diameter >10 cm. The 1, 3, 5year overall survival rates and 1, 3, 5year tumorfree survival rates were 91%, 65%, 53%, 70%, 48%, 35% in 117 SLHCC patients with 5 cm < tumor diameter <10 cm, respectively, with no significant difference compared with SHCC group x²=1.832, 0.042, P>0.05). The 1, 3, 5year overall survival rates and 1, 3, 5year tumorfree survival rates were 78%, 46%, 31%, 49%, 39%, 30% in 46 SLHCC patients with tumor diameter >10 cm, respectively, with significant differences compared with SHCC group x²=21.136, 4.097, P<0.05). (4) Prognostic analysis of patients with SLHCC: results of univariate analysis showed that serum level of HBVDNA, tumor diameter and microvascular invasion were risk factors affecting postoperative 5year tumorfree survival rate of SLHCC patients x²=5.193, 3.377, 5.509, P<0.05); sex, serum level of HBVDNA, tumor diameter and microvascular invasion were risk factors affecting postoperative 5year overall survival rate of SLHCC patients x²=4.546, 18.053, 7.780, 10.569, P<0.05). Results of multivariate analysis showed that serum level of HBVDNA≥104 U/mL, tumor diameter >10 cm and positive microvascular invasion were independent risk factors affecting postoperative 5year tumorfree survival rate of SLHCC patients ［HR=2.77, 1.85, 1.86, 95% confidence interval (CI): 1.74-4.40, 1.16-2.94, 1.17-2.96, P<0.05］ and affecting postoperative 5year overall survival rate of SLHCC patients (HR=2.73, 1.98, 1.69, 95%CI: 1.72-4.33, 1.23-3.17, 1.04-2.72, P<0.05).
Conclusions:There are similar prognosis between SLHCC patients with 5 cm < tumor diameter <10 cm and SHCC patients, however, prognosis of SLHCC patients with tumor diameter >10 cm is worse than that of SHCC patients. Serum level of HBVDNA≥104 U/mL, tumor diameter >10 cm and positive microvascular invasion are independent risk factors affecting prognosis of SLHCC patients.

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