• 中国科技论文统计源期刊
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Volume 46 Issue 1
Feb.  2021
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Analysis of the risk factors of tumor recurrence in hepatocellular carcinoma patients with positive microvascular invasion treated with hepatectomy

  • Corresponding author: ZHOU Wu-yuan, 15564100001@163.com
  • Received Date: 2020-05-22
    Accepted Date: 2020-10-30
  • ObjectiveTo study the risk factors for tumor recurrence in hepatocellular carcinoma patients with positive microvascular invasion(MVI) treated with hepatectomy.MethodsSixty patients with liver cancer were divided into the MVI-positive group(20 cases) and MVI-negative group(40 cases) according to the surgical pathological results.The basic data, postoperative complications, and recurrence rate and mortality after 12-month of following-up were compared between two groups.The risk factors of tumor recurrence in hepatocellular carcinoma patients with positive MVI treated with hepatectomy were analyzed.ResultsThe differences of the gender, age, pathological type, surgical margin, anatomical hepatectomy, cirrhosis, hepatitis and liver function Child-Pugh classification between two groups were not statistically significant(P>0.05).The differences of the degree of tumor differentiation, maximum diameter of tumor, smooth edge of tumor, integrity of tumor envelope and level of α-fetoprotein(AFP) were statistically significant(P < 0.05 to P < 0.01).The postoperative complication rate in the MVI-positive group and MVI-negative group were 20.00% and 7.50%, respectively, and the difference of which between two groups was not statistically significant(P>0.05).After 12 months of following-up, the recurrence rate of tumor in MVI-positive group(25.00%) was higher that in MVI-negative group(5.00%)(P < 0.05).The difference of the mortality rate between the MVI-positive group(10.00%) and MVI-negative group(5.00%) was not statistically significant(P>0.05).The results of multivariate logistic regression analysis showed that the low differentiation, maximum diameter >5 cm, non-smooth edge, tumor-free capsule and AFP>400 g/L were the dependent risk factors of MVI-positive liver cancer(P < 0.05 to P < 0.01).ConclusionsThe recurrence rate of MVI-positive liver cancer patients after hepatectomy is higher than that of MVI-negative liver cancer patients, and mainly related to the degree of tumor differentiation, tumor diameter, tumor margin, capsule and AFP level.
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  • [1] 王伟强, 张伟, 李仁涛, 等. 单发大肝癌患者肝切除术后长期生存影响因素[J]. 中华肝胆外科杂志, 2018, 24(5): 299. doi: 10.3760/cma.j.issn.1007-8118.2018.05.003
    [2] LEE SY, KI SH, LEE JE, et al. preoperative cadoxetic acid-enhanced MRI for predicting microvascular invasion in patients with single hepatocellular carcinoma[J]. J Hepatol, 2017, 67(3): 526. doi: 10.1016/j.jhep.2017.04.024
    [3] 刘爱祥, 王海清, 薄文滔, 等. 肝细胞癌肝切除术的临床疗效及预后因素分析[J]. 中华消化外科杂志, 2019, 18(4): 368. doi: 10.3760/cma.j.issn.1673-9752.2019.04.012
    [4] 邹国华, 代春. 微血管侵犯对单发性小肝癌患者预后的影响[J]. 安徽医药, 2018, 22(11): 2119. doi: 10.3969/j.issn.1009-6469.2018.11.017
    [5] 赵泽明, 范跃祖, BECKER T, 等. 肝细胞肝癌肝移植术后复发因素分析——汉诺威经验[J]. 中华普通外科杂志, 2017, 32(11): 901. doi: 10.3760/cma.j.issn.1007-631X.2017.11.001
    [6] 王志明, 何东任, 钟鉴宏, 等. 以坏死并血管侵犯为关键要素的肝细胞癌T"N"M分期系统的建立及其准确性初步评估[J]. 中国普通外科杂志, 2019, 28(7): 790.
    [7] 张小晶, 王琳. 微血管侵犯在肝癌综合诊断与治疗中的临床意义[J]. 中华消化外科杂志, 2019, 18(4): 336. doi: 10.3760/cma.j.issn.1673-9752.2019.04.008
    [8] ZHENG J, SEIER K, GONEN M, et al. Utility of serum inflammatory markers for predicting microvascular invasion and survival for patients with hepatocellular carcinoma[J]. Ann Surg Oncol, 2017, 24(1691/700): 1.
    [9] 姜利伶, 陈海玲, 王光宪, 等. CT或MRI表现对小肝癌微血管侵犯的危险因素评估[J]. 临床放射学杂志, 2019, 38(5): 844.
    [10] AGOPIAN VG, HARLANDER-LOCKE MP, MARKOVIC D, et al. Evaluation of patients with hepatocellular carcinomas that do not produce α-fetoprotein[J]. Jama Surg, 2017, 152(1): 55. doi: 10.1001/jamasurg.2016.3310
    [11] 刘驰, 杨启, 秦长岭. 微血管侵犯对早期肝癌肝切除术切缘选择及患者预后的影响[J]. 肝胆外科杂志, 2017, 5(25): 353.
    [12] 张努, 荚卫东, 王润东, 等. 解剖性肝切除对肝细胞癌伴微血管侵犯病人预后的影响[J]. 中国实用外科杂志, 2018, 38(5): 555.
    [13] 张小晶, 刘静, 刘坤, 等. 微血管侵犯对肝癌肝切除术后预后的影响[J]. 中华消化外科杂志, 2018, 17(5): 483. doi: 10.3760/cma.j.issn.1673-9752.2018.05.012
    [14] WANG L, KE Q, LIN NP, et al. Does postoperative adjuvant transarterial chemoembolization benefit for all patients with hepatocellular carcinoma combined with microvascular invasion: a meta-analysis[J]. Scand J Gastroenterol, 2019, 54(5): 1.
    [15] 殷运林, 刘会春, 潘洪涛, 等. 射频消融与手术切除治疗原发性中小肝癌的疗效比较[J]. 蚌埠医学院学报, 2017, 42(2): 154.
    [16] 李自慧, 叶甲舟, 陈洁, 等. 解剖性肝切除术对合并微血管侵犯的肝癌患者早期复发的影响[J]. 中华肝胆外科杂志, 2018, 24(1): 18. doi: 10.3760/cma.j.issn.1007-8118.2018.01.005
    [17] CHOI HJ, KIM DG, NA GH, et al. The clinical outcomes of patients with portal vein tumor thrombi after living-donor liver transplantation[J]. Liver Transplantation, 2017, 23(8): 1023. doi: 10.1002/lt.24782
    [18] 王东旭, 丁国旭, 张天宇, 等. 肝细胞肝癌多层螺旋CT表现与微血管侵犯关系的研究[J]. 临床放射学杂志, 2017, 36(12): 1892.
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Analysis of the risk factors of tumor recurrence in hepatocellular carcinoma patients with positive microvascular invasion treated with hepatectomy

    Corresponding author: ZHOU Wu-yuan, 15564100001@163.com
  • Department of Hepatobiliary and Pancreatic Surgery, Xuzhou Cancer Hospital of Jiangsu, Xuzhou Jiangsu 221000, China

Abstract: ObjectiveTo study the risk factors for tumor recurrence in hepatocellular carcinoma patients with positive microvascular invasion(MVI) treated with hepatectomy.MethodsSixty patients with liver cancer were divided into the MVI-positive group(20 cases) and MVI-negative group(40 cases) according to the surgical pathological results.The basic data, postoperative complications, and recurrence rate and mortality after 12-month of following-up were compared between two groups.The risk factors of tumor recurrence in hepatocellular carcinoma patients with positive MVI treated with hepatectomy were analyzed.ResultsThe differences of the gender, age, pathological type, surgical margin, anatomical hepatectomy, cirrhosis, hepatitis and liver function Child-Pugh classification between two groups were not statistically significant(P>0.05).The differences of the degree of tumor differentiation, maximum diameter of tumor, smooth edge of tumor, integrity of tumor envelope and level of α-fetoprotein(AFP) were statistically significant(P < 0.05 to P < 0.01).The postoperative complication rate in the MVI-positive group and MVI-negative group were 20.00% and 7.50%, respectively, and the difference of which between two groups was not statistically significant(P>0.05).After 12 months of following-up, the recurrence rate of tumor in MVI-positive group(25.00%) was higher that in MVI-negative group(5.00%)(P < 0.05).The difference of the mortality rate between the MVI-positive group(10.00%) and MVI-negative group(5.00%) was not statistically significant(P>0.05).The results of multivariate logistic regression analysis showed that the low differentiation, maximum diameter >5 cm, non-smooth edge, tumor-free capsule and AFP>400 g/L were the dependent risk factors of MVI-positive liver cancer(P < 0.05 to P < 0.01).ConclusionsThe recurrence rate of MVI-positive liver cancer patients after hepatectomy is higher than that of MVI-negative liver cancer patients, and mainly related to the degree of tumor differentiation, tumor diameter, tumor margin, capsule and AFP level.

  • 肝癌是危害极大的消化系统恶性肿瘤,我国每年的肝癌新发病例约占全球新发病例的55%,死亡率约占全球的45%[1]。随着诊疗技术的提高,早期肝癌的检出率明显提高、死亡率明显下降,肝癌切除术后的1年生存率也从30%~40%上升至80%以上,但术后复发率仍处于较高水平[2]。临床研究[3]显示,肿瘤分化程度、肿瘤大小及边缘等均与肝癌切除术后复发有关。其中,微血管侵犯(microvascular invasion,MVI)主要表现为内皮细胞衬覆的血管腔内癌细胞巢团,邹国华等[4]认为其主要通过侵犯癌旁肝组织而引起复发,当肿瘤细胞沿血管迁徙,还可发生肝内或肝外转移。但肿瘤复发的因素较多[5],本研究对MVI阳性肝癌病人肝切除肿瘤复发的危险因素进行分析。现作报道。

1.   对象与方法
  • 选择2016年12月至2018年12月我科收治的60例肝癌病人作为研究对象。其中男36例,女24例,年龄35~78岁。纳入标准:(1)经血清甲胎蛋白(AFP)、影像学、病理学等检查,均符合肝癌诊断标准[6];(2)均符合肝切除术标准,肿瘤局限于肝的1叶或半肝内,第1、2肝门下腔静脉未受侵犯,可保留30%以上的正常肝组织等。排除标准:(1)肝硬化面积超过肝组织的70%;(2)多发性肿瘤且范围超过半肝、已有远处转移或广泛种植;(3)有明显腹水、下肢水肿等;(3)有消化道出血、顽固性肝性脑病等全身情况不耐受肝切除术;(4)预计生存期 < 3个月;(5)临床资料不全或随访时间 < 12个月。

  • 病人均根据临床检查结果制定肝切除方案,采取免疫核糖核酸、干扰素、维生素K1等提高免疫力、凝血功能,术中视肿瘤范围、浸润深度及周围组织粘连情况等进行肿瘤切除,并将切除的组织及时送检,术后密切监测病人生命体征、对症进行抗感染和保肝治疗,并通过电话、门诊随访12个月。

    本研究所有病例切除的组织均进行大体及镜下病理检查,根据手术病理结果将其分为MVI阳性组和MVI阴性组。MVI阳性标准[7]:显微镜下可见内皮细胞衬覆的血管腔内癌细胞巢团,且血管腔内出现悬浮癌细胞数目≥50个,癌细胞巢团主要出现在癌旁组织、门静脉小分支。

  • (1) 基本资料:性别、年龄、病理类型、肿瘤分化程度、手术切缘、肿瘤最大直径、肿瘤边缘、肿瘤包膜、解剖性肝切除、AFP、肝硬化、肝炎、肝功能Child-Pugh分级。(2)术后并发症。(3)随访12个月的复发率、死亡率。

  • 采用χ2检验、秩和检验和多因素logistic回归分析。

2.   结果
  • 根据手术病理结果,MVI阳性组20例,MVI阴性组40例。2组性别、年龄、病理类型、手术切缘、解剖性肝切除、肝硬化、肝炎、肝功能Child-Pugh分级差异均无统计学意义(P>0.05),2组肿瘤分化程度、肿瘤最大径、肿瘤边缘是否光滑、肿瘤包膜是否完整、AFP水平差异均有统计学意义(P < 0.05~ P < 0.01)(见表 1)。

    项目 MVI阳性组(n=20) MVI阴性组(n=40) χ2 P
    性别
      男
      女
    12(60.00)
    8(40.00)
    23(57.50)
    17(42.50)
    0.03 >0.05
    年龄/岁
      ≤60
      >60
    13(65.00)
    7(35.00)
    25(62.50)
    15(37.50)
    0.04 >0.05
    病理类型
      肝细胞型 14(70.00) 22(55.00)
      胆管细胞型 4(20.00) 13(32.50) 1.31 >0.05
      混合型 2(10.00) 5(12.50)
    肿瘤分化程度
      高分化 3(15.00) 16(60.00)
      中等分化 6(30.00) 18(45.00) 10.91 < 0.01
      低分化 11(55.00) 6(15.00)
    手术切缘/cm
      ≤1
      >1
    4(20.00)
    16(80.00)
    9(22.50)
    31(77.50)
    0.01* >0.05
    肿瘤最大径/cm
      ≤5
       >5
    5(25.00)
    15(75.00)
    22(55.00)
    18(45.00)
    4.85 < 0.05
    肿瘤边缘
      光滑
      不光滑
    6(30.00)
    14(70.00)
    25(62.50)
    15(37.50)
    5.64 < 0.05
    肿瘤包膜
      完整 3(15.00) 17(42.50)
      不完整 7(35.00) 15(37.50) 7.05 < 0.05
      无 10(50.00) 8(20.00)
    解剖性肝切除
      是
      否
    16(80.00)
    4(20.00)
    31(77.50)
    9(22.50)
    0.01* >0.05
    AFP/(μg/L)
      ≤400
      >400
    7(35.00)
    13(65.00)
    26(65.00)
    14(35.00)
    4.85 < 0.05
    肝硬化
      有
      无
    12(60.00)
    8(40.00)
    23(57.50)
    17(42.50)
    0.03 >0.05
    肝炎
      有
      无
    15(75.00)
    5(25.00)
    29(72.50)
    11(27.50)
    0.04 >0.05
    肝功能Child-Pugh分级
      A级
      B级
    13(65.00)
    7(35.00)
    27(67.50)
    13(32.50)
    0.04 >0.05
  • MVI阳性组病人术后并发症总发生率为20.00%,与MVI阴性组的7.50%比较差异无统计学意义(P>0.05)(见表 2)。

    分组 n 切+口感染 腹腔出血 胆汁瘘 膈下感染 胸腔积液 腹水 合计
    MVI阳性组 20 1(5.00) 0(0.00) 0(0.00) 0(0.00) 1(5.00) 2(10.00) 4(20.00)
    MVI阴性组 40 0(0.00) 0(0.00) 0(0.00) 0(0.00) 2(5.00) 1(2.50) 3(7.50)
    χ2 0.39 0.39 0.99
    P 0.33* >0.05 >0.05 >0.05
  • 随访12个月,MVI阳性组病人复发率25.00%(5/20),高于MVI阴性组的5.00%(2/40)(χ2=5.18,P < 0.05);MVI阳性组病人死亡率10.00%(2/20),与MVI阴性组的5.00%(2/40)差异无统计学意义(χ2=0.54,P>0.05)。

  • 经多因素logistic回归分析,肿瘤低分化、肿瘤最大径>5 cm、肿瘤边缘不光滑、无肿瘤包膜、AFP>400 μg/L均为MVI肝癌的独立危险因素(P < 0.05~P < 0.01)(见表 3)。

    因素 B SE Waldχ2 OR P 95%CI
    肿瘤低分化 1.422 1.212 6.264 5.672 < 0.01 1.417~13.478
    肿瘤最大径>5 cm 1.345 1.230 6.120 5.479 < 0.01 1.305~12.026
    肿瘤边缘不光滑 1.237 1.009 5.102 3.948 < 0.05 0.823~6.865
    无肿瘤包膜 1.316 1.207 5.815 5.158 < 0.05 1.214~10.875
    AFP>400 μg/L 1.178 0.935 4.886 4.274 < 0.05 1.148~8.463
3.   讨论
  • 手术是目前治疗肝癌的首选方式,一般认为无肝硬化肝癌,但可保留正常肝组织30%以上病人、有肝硬化肝癌,但可保留正常肝组织40%以上病人,均可通过手术获得较好的远期疗效[8]。但即使是适宜手术切除的肝癌,术后仍然会因MVI出现肝癌的复发与转移。如MVI发生在门静脉小分支时,可通过癌细胞的分裂增殖形成门静脉癌栓,进而在肝癌术后形成肝内转移灶,但MVI常难以在术前通过影像学检查或术中解剖时确认[9]。因此,笔者认为,对于术中无明显门静脉癌栓,但经手术病理结果证实存在MVI的病人,可给予术后门静脉化疗或预防性肝动脉化疗栓塞,以改善预后,减少复发。分化程度越低的肿瘤侵袭性越大,会引起原发性肝癌发生早期转移,从而导致肿瘤切除不彻底[10]。本研究中,MVI阳性组的肿瘤分化程度明显低于MVI阴性组,这提示分化程度越低,肝癌切除术后的疗效越差。刘驰等[11]认为,当肿瘤直径≥2 cm,低分化区会逐渐代替高分化区,促使肿瘤的恶性程度升高。其次,随着肿瘤的增大、浸润,肿瘤完整切除率和术后肝功能随之下降,且残肝易有微小灶,MVI的概率也相对更高[12]

    此外,我国85%左右的肝癌病人均合并有肝硬化、肝炎等慢性肝病,若手术性创伤过大不仅会导致肝功能衰竭、腹水等严重并发症,还会加速术后早期肿瘤复发[13]。如何在保证切除效果的同时,降低正常肝组织的切除量,还需结合影像学、分子技术对等进行研究。肿瘤越大,血供越丰富,边缘与正常肝组织的界限也越难区分清楚,易增加术中出血量;而肿瘤边缘不光滑者,肿瘤细胞的侵袭力相对较高,可逐渐促进肿瘤边缘正常肝组织的MVI[14]。有报道[15-16]称,在恶性肿瘤切除术中,有时会发现部分肿瘤有包膜,但大多不完整,这是因为恶性肿瘤多呈侵袭性生长,随着分化程度的降低或MVI的增多,可突破包膜,甚至破裂出血,引起坏死、感染等。但也有研究[17]认为,原发性肝癌本就会出现肿瘤周围纤维组织、受压小血管等组成的假性包膜,其形成受多种因素影响,且可通过影像学检查明确。所以,对于无肿瘤包膜或包膜完整的病人,还应结合其他检查,谨慎判断是否存在MVI阳性。AFP的升高,通常与肝细胞的死亡与再生有关,因此MVI及肿瘤浸润加快时,AFP常呈高水平[18]

    本研究中,2组病人的术后并发症发生率虽无明显差异,但MVI阳性组随访12个月的复发率高于MVI阴性组,提示MVI阳性对预测肝癌的复发有较高价值,而肿瘤低分化、肿瘤最大径>5 cm、肿瘤边缘不光滑、无肿瘤包膜、AFP>400 μg/L均为MVI阳性肝癌病人肝切除肿瘤复发的独立危险因素,临床可据此调整治疗方案。但本文并没有对病人不同时段的复发率、死亡率进行详细研究,且随访时间较短、研究病例较少,在今后的临床中还需扩大样本数量进一步研究。

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