Advances in Clinical Medicine
Vol. 09  No. 03 ( 2019 ), Article ID: 29240 , 9 pages
10.12677/ACM.2019.93047

Molecular Markers and Recurrence of Hepatocellular Carcinoma after Liver Transplantation

Wenyan Zhang, Shusen Zheng

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou Zhejiang

Received: Feb. 21st, 2019; accepted: Mar. 5th, 2019; published: Mar. 14th, 2019

ABSTRACT

Liver transplantation is a potentially curative treatment for hepatocellular carcinoma (HCC). But, the recurrence of HCC after transplantation has seriously affected the treatment effect. Despite stringent selection criteria, recurrence occurs in a high proportion of patients transplanted for HCC. With the development of molecular biology, there are more and more molecular markers related to the recurrence after liver transplantation. In this review, we focus on the tumor markers and inflammatory markers. Tumor markers mainly include Alpha-fetoprotein (AFP), Des-gamma-carboxyprothrombin (DCP), etc. Inflammatory markers include C-reactive protein (CRP), Neutrophil lymphocyte ratio (NLR) and Platelet lymphocyte ratio (PLR), etc. However, taking into account the limitations of these markers, multicenter prospective studies are essential to find a better combination of molecular markers, which means better prediction of recurrence and better transplant treatment effect.

Keywords:Hepatocellular Carcinoma, Liver Transplantation, Recurrence, Molecular Markers, Review

肝癌移植术后复发相关标志物的 研究进展

章文燕,郑树森

浙江大学医学院附属第一医院肝胆胰外科,浙江 杭州

收稿日期:2019年2月21日;录用日期:2019年3月5日;发布日期:2019年3月14日

摘 要

肝移植是治疗肝细胞肝癌(Hepatocellular carcinoma, HCC)的重要方法,但移植后的HCC复发影响了治疗效果,尽管有严格的纳入标准,但移植术后仍有较高的复发率。随着分子生物学的发展,HCC移植术后复发相关的分子标志物被不断提出并进行分析研究。在这篇综述中,我们重点关注肿瘤标志物和炎症标志物与HCC移植术后的相关性。HCC相关的肿瘤标志物主要有甲胎蛋白(Alpha-fetoprotein, AFP)、脱-γ-羧基凝血酶原(Des-gamma-carboxyprothrombin, DCP)等,相关的炎症标志物主要有C反应蛋白(C-reactive protein, CRP)、中性粒细胞淋巴细胞比值(Neutrophil lymphocyte ratio, NLR)、血小板淋巴细胞比值(Platelet lymphocyte ratio, PLR)等。但这些标志物都存在一定的缺陷,希望能通过更多的多中心的前瞻性研究,找着更好的分子标志物组合,从而更好地预测移植后复发,以希望获得更好的移植效果。

关键词 :肝细胞肝癌,肝移植,复发,分子标志物,综述

Copyright © 2019 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 引言

原发性肝癌是世界上最常见的恶性肿瘤之一,也是死亡率极高的全球疾病 [1]。据最新的国家癌症中心统计数据显示 [2],我国2015年原发性肝癌发病率高达26.92/10万,死亡率为23.72/10万,是我国第4常见恶性肿瘤,位居我国恶性肿瘤死亡病因第2位,严重威胁我国人民的生命和健康。病理学上,原发性肝癌主要可以分为肝细胞肝癌(Hepatocellular Carcinoma, HCC)、肝内胆管癌(Intrahepatic Cholangiocarcinoma, ICC)和混合型,其中HCC占到85%~90%以上 [3]。由于这三种病理类型在发病机制、临床表现及治疗等方面差异较大,因此,本文中主要讨论发病率最高的HCC。

在我国,大部分HCC患者合并有乙型病毒性肝炎导致的肝硬化,这部分患者的手术切除率往往不是很理想,肝移植是根治HCC的有效方法,特别是对失代偿期肝硬化且不适合手术切除的小肝癌患者 [3] [4]。肝移植不仅可以完整切除HCC,同时还可以去除肝硬化组织,恢复正常的肝脏功能。HCC患者肝移植后的5年生存率可达50%~81% [5] [6] [7] [8] [9],而根治性肝切除术后的5年生存率仅为25%~50% [5] [10] [11],肝移植在HCC的治疗中的重要性不言而喻。然而HCC患者移植术后复发问题仍然困扰着所有进行肝移植的患者以及肝移植治疗团队。

尽管有严格的纳入标准,但HCC患者进行肝移植后的复发率高达6%~18.3% [12] [13] [14],也有数据称不同中心HCC肝移植术后5年HCC复发率可达20.0%~57.8% [15],HCC复发多见于肺、骨和腹部淋巴结,肝外复发约占50%~70% [16],肝内复发比例约为30% [17],且多在移植后2年内复发。众所周知,肝移植后肿瘤复发明显减低了移植后生存率,及早发现和治疗移植后HCC复发显得十分重要。因此,一方面,移植后肝癌复发治疗受到极大关注,主要治疗方法包括免疫治疗,靶向药物治疗,手术再次切除,经动脉化疗栓塞术(Trans-arterial chemoembolization, TACE),射频消融术(Radiofrequency ablation, RFA),立体定向放射治疗术(Stereotactic body radiation therapy, SBRT)等 [12]。另一方面,国内外学者均希望提出更有效实用的预测模型,更合理地筛选患者进行肝移植,其中分子标志物是重要研究内容之一。目前已有多种分子标志物被用于HCC患者移植后复发的预测,包括肿瘤标志物,炎症标志物,各种蛋白(如血管内皮生长因子,VEGF),病毒及载量(如乙肝病毒,HBV),基因(如P53基因),液体活检(包括循环肿瘤细胞和无细胞DNA),循环RNA等。本综述将重点阐述HCC肝移植患者纳入标准及术后复发相关肿瘤标志物和炎症标志物的研究进展。

2. 常用的HCC肝移植患者纳入标准

为了更合理地利用供肝资源,降低肝移植术后HCC复发率,提高HCC患者的长期生存率,各大移植中心都严格掌握HCC肝移植的适应征。米兰标准 [18],USCF标准 [19] 和杭州标准 [20] 是最常用的三种HCC肝移植患者纳入标准。此外,2000年Pittsburgh等人改良了TNM分期标准 [21],2007年德国学者提出Berlin标准 [22],2007年日本学者提出东京5-5标准 [23],2008年韩国学者提出Asan标准 [24],2009年Mazzaffero等人提出了最多7个(Up-to-seven)标准 [25] 等。而在国内,除了杭州标准外,还有2009年樊嘉院士团队提出复旦标准 [26] 和2009年严律南教授团队提出的成都标准 [27] 等。

2.1. 米兰标准

米兰标准 [18] 由意大利的Mazzaferro等人在1996年提出,这是最早提出的HCC患者进行肝移植的标准,也是目前使用最为广泛的患者纳入标准 [28],1998年起,美国联合网络器官共享(UNOS)将米兰标准作为主要选择标准。米兰标准的主要内容为:① 单个肿瘤直径 ≤ 5 cm或者多发肿瘤不超过3个且最大直径 ≤ 3 cm;② 没有主要血管侵犯,没有淋巴结或肝外转移。该标准大大提高了HCC肝移植的术后生存率,Mazzaferro等报道的48名患者的术后4年生存率和无瘤生存率分别为85%和92% [18]。随后多个中心的研究也提示符合米兰标准的HCC患者肝移植后具有良好的预后,5年生存率可以高达75%~80% [9] [28] [29]。

然而,通过临床实践及总结分析,许多学者认为米兰标准存在局限性,一方面,米兰标准对肿瘤的大小限制过于严苛,许多需要进行肝移植的患者被排除在外,而临床实践证明,这些不符合米兰标准的患者进行肝移植后仍可以获得令人满意的预后 [30] [31] [32]。另一方面,米兰标准未考虑肿瘤的生物学特征:如组织病理学分级和血清AFP指标等。近年来,越来越多的国际肝移植中心对米兰标准及超过米兰标准的肝移植进行了进一步研究,其中就包括USCF标准和杭州标准的提出。

2.2. UCSF标准

2002年加州大学旧金山分校的研究人员提出了UCSF标准,将HCC肝移植的适应征适当放宽:①单个肿瘤,直径 ≤ 6.5 cm,或肿瘤数目 ≤ 3个,直径最大 ≤ 4.5 cm且肿瘤直径之和 ≤ 8 cm。② 没有主要血管侵犯或肝外转移。Yao等人报道 [19],米兰标准和USCF标准的HCC肝移植患者的5年生存率差异没有统计学意义,而且超过UCSF标准的HCC患者移植后5年生存率显著降低。USCF标准明显扩大了HCC肝移植受体范围,而且不影响其总体生存率。我国国家卫计委新发布的原发性肝癌诊疗规范(2017版)提出现阶段肝癌肝移植推荐使用UCSF标准 [3]。与米兰标准相同的是,USCF也未关注肿瘤的病理学特征或肿瘤标志物等因素。

2.3. 杭州标准

HCC是我国最常见的恶性肿瘤之一,位居死亡病因第2位。使用国际标准选择肝移植受体,将使许多HCC患者失去肝移植机会,因此建立新的HCC肝移植受体纳入标准势在必行。2008年,郑树森院士团体提出了HCC肝移植的杭州标准 [20] :① 肿瘤没有主要血管侵犯和肝外转移。② 所有肿瘤结节直径之和 ≤ 8 cm,或所有肿瘤结节直径之和 > 8 cm,但是满足术前AFP(血清甲胎蛋白)水平 < 400 ng/mL,且组织学分级为高、中分化。杭州标准不仅在肿瘤大小限制上超越了米兰标准和UCSF标准,而且首次引入了HCC的组织病理学分级和血清AFP指标,研究结果显示杭州标准和USCF标准的HCC肝移植患者的术后生存率和无瘤生存率差异无统计学意义,但杭州标准的入组HCC患者例数增加了37.5%,安全地扩大了HCC肝移植的受体池。Chen等人研究表明 [33],杭州标准的1年、5年生存率分别为92.3%、80.8%,1年、5年无瘤生存率分别为92.3%、76.1%。该研究结果发表后得到了移植界的肯定,杭州的标准也适用于其他国家和地区 [34] [35] [36]。

3. HCC复发相关肿瘤标志物

3.1. 甲胎蛋白(Alpha-Fetoprotein, AFP)

甲胎蛋白AFP是一种大小为67 kDa的糖蛋白,主要由胎儿肝细胞及卵黄囊合成,在正常成人血清中含量极低,它可以反映HCC的肿瘤分化和血管浸润情况,已被广泛应用于HCC肝移植患者的筛选,最典型的就是杭州标准。此外法国学者提出的AFP模型 [37] 主要基于肿瘤形态学数据和AFP数据,在米兰标准内,AFP > 1000 ng/mL其复发风险将明显提高(37.7% vs 13.3%);另一方面,超过米兰标准,但AFP小于100 ng/mL的患者其5年复发率仅为14.4%。该模型被成功应用于法国肝脏分配。另一项研究报告显示总肿瘤体积 ≤ 115 cm3和移植后AFP ≤ 400 ng/mL提示低移植后HCC复发风险 [38],且进行了多中心前瞻性的验证 [39]。

尽管AFP已经被证明是一种有用的肿瘤标志物,但其最佳临界值尚未达成共识,如上述提到的杭州标准的400 ng/mL、AFP模型的1000 ng/mL、日本学者提出的500 ng/mL [32] 等。此外,AFP的动态变化能更好反映肿瘤生物学行为变化。如果患者术前的每月AFP增加值 > 50 ng/mL [40],或者每天AFP增加值 > 0.1 ng/mL [41],这些都可能意味着移植预后不佳。

但AFP也存在不足之处,约80%的小HCC (<2 cm)患者的AFP在正常范围内 [42],另一方面,慢性肝病患者的AFP也会有不同程度升高 [43],在一些神经退行性疾病中也已描述了AFP水平的增加 [44]。而且AFP升高常意味着HCC预后不佳,目前,美国肝病研究协会(AASLD) [45] 、欧洲肝脏研究协会(EASL) [46] 、美国国家综合癌症网络(NCCN) [47] 等均已不再推荐AFP作为HCC筛查指标。因此,有学者提出使用AFP异质体——AFP-L3作为新的肿瘤标志物,它被认为是低AFP水平患者的HCC高度特异性标志物,可以更好预测低AFP水平患者的移植术后复发情况 [48],这个新的肿瘤标志物需要更多的研究。

3.2. 脱-γ-羧基凝血酶原(Des-Gamma-Carboxyprothrombin, DCP)

Des-γ-羧基凝血酶原DCP,也称为维生素K缺乏或拮抗剂-II诱导产生的蛋白(PIVKA-II),是由肝脏产生的无功能的凝血酶原形式。正常肝脏中通过维生素K依赖性羧化酶的催化作用将凝血酶原N-末端部分中的谷氨酸残基完全羧化,从而向外周血分泌正常的凝血酶原。而在异常肝细胞中,由于不存在产生这种羧化的维生素K依赖性羧化酶,因此会分泌异常凝血酶原,即DCP。DCP阳性已被证实与HCC的恶性程度相关,DCP阳性的HCC患者的肝内转移和门静脉浸润发生的概率明显增加 [49],也更容易术后复发 [50]。

日本学者提出了基于DCP的活体肝移植患者纳入标准——京都标准 [51],该标准要求肿瘤数目 ≤ 10个,肿瘤直径 ≤ 5 cm,DCP ≤ 400 mAU/mL,符合京都标准但不符合米兰标准的患者也能取得令人满意的生存期和无瘤生存率。

但DCP更常联合AFP用于HCC肝移植术后复发的预测,AP200 [52] 标准认为AFP ≤ 200 ng/mL和DCP ≤ 200 AU/mol可提示患者术后复发风险低,Kim等人 [53] 回顾性分析了77例复发的病例,认为肿瘤大小 > 5 cm,AFP > 150 ng/mL,DCP > 100 maul/mol是HCC肝移植术后复发的独立危险因素。但就目前的相关研究而言,DCP更多应用于活体肝移植,而DCD(公民逝世后器官捐献)肝移植较少。

3.3. 其他肿瘤标志物

除了上述提到的AFP、AFP-L3和DCP,α-L-岩藻糖苷酶(AFU)、糖链抗原19-9 (CA19-9)、癌胚抗原(CEA)等也是HCC相关的肿瘤标志物 [54] [55],但它们在HCC肝移植中的作用研究较少,目前它们对移植术后HCC复发的预测作用尚不明确。

4. 炎症标志物

4.1. C反应蛋白(C-Reactive Protein, CRP)

CRP作为急性和慢性炎症的标志物已经获得了显著的临床价值,它由肝细胞合成,且受到白介素-1和白介素-6的调节,它对感染,损伤或恶性肿瘤等都有反应。人们越来越关注CRP在预测恶性肿瘤中的作用 [56] [57],CRP被广泛用于HCC复发转移等相关研究,也被用于移植术后复发的预测。移植术前和术后的CRP水平均具有预测功能,是一种有价值的标志物。An等人 [58] 在2012年报道了一项85名接受肝移植的HCC患者(绝大多数是接受活体肝移植)的研究,所有患者均具有可用的移植前CRP水平,相关分析表明CRP ≥ 1 mg/dL是患者死亡和肿瘤复发的重要独立危险因素。有趣的是,术前CRP与移植后的生存率和无瘤生存率之间的相关性仅限于米兰标准以外的患者,换句话说,更高风险的人群需要更详细的风险分层,从而得到更安全的移植。

与术前CRP相似,移植术后的CRP也具有预测预后价值。Kornberg等人 [59] 回顾性分析了106例HCC肝移植受者,指出术后早期CRP峰值是肝移植术后复发的重要指标,术后早期CRP峰值(>3.5 mg/dL)的术后复发率为48.7%,而术后早期CRP峰值 ≤ 3.5 mg/dL的复发率仅为7.8%,同样的,这对米兰标准以外的患者意义更大。

4.2. 中性粒细胞淋巴细胞比值(Neutrophil Lymphocyte Ratio, NLR)

中性粒细胞淋巴细胞比值是指外周血中性粒细胞与淋巴细胞的比值,已经被证实在多种恶性肿瘤预后预测中扮演重要作用。升高的NLR意味着炎症或外周淋巴细胞减少导致的中性白细胞增多,这两者都与恶性肿瘤的不良预后有关。Halazun等人 [60] 首次将NLR与肝癌联系起来,分析了接受结直肠癌肝转移切除术的患者,并指出NLR升高与复发和死亡风险增加有关。

NLR在肝癌肝移植患者中已被广泛研究,Halazun等人 [61] 首先将NLR应用于肝癌肝移植患者,在150例肝癌肝移植患者中,有13例患者NLR升高(≥5),其中62% HCC复发,且5年生存率(28% vs 64%)和5年无瘤生存率(25% vs 75%)明显更差。另一项针对152例活体肝癌肝移植的研究指出NLR升高使肝细胞肝癌复发可能性增加7倍,并且在该队列中NLR比AFP更具预测性 [62]。另一项针对涉及865例患者的大型研究指出,随着NLR增加每个对数单位,HCC复发的风险几乎翻了一番 [7]。NLR已被认定为移植后HCC复发的独立危险因素,Najjar等人 [63] 系统评价分析显示升高的NLR与移植后无瘤生存期相关。但关于NLR的最佳临界值尚未有定论,不同文献的临界值范围从2.6到6不等,Xu等人 [64] 分析后建议将NLR最佳临界值指定为4。

4.3. 血小板淋巴细胞比值(Platelet Lymphocyte Ratio, PLR)

血小板淋巴细胞比值是指外周血小板与淋巴细胞的比值,PLR对移植后HCC预后的意义研究不如NLR广泛。升高的PLR通常意味着更大的肿瘤大小,多发性肿瘤和血管侵犯 [65]。2012年,Pinato等人首先将PLR应用于评估HCC患者移植预后评估,且分析得出PLR与NLR预测效果相当 [66]。一项Meta分析 [67] 指出高PLH与患者的术后HCC复发显著增加相关,但这项分析仅包括5项研究,899名患者,且具有中等异质性。Han等人 [68] 也发现PLR与HCC移植后复发相关,但该研究支持血小板绝对计数与HCC移植后复发相关性更高。也有文章指出PLR未能预测符合米兰标准的患者的HCC复发 [69]。虽然与NLR一样,PLR很容易获得,但其重要性有待研究,所以目前不推荐这项炎症标志物的广泛使用。

5. 总结与展望

尽管米兰标准等提出已经明显延长了HCC患者移植后的生存期,但移植后HCC复发仍明显影响患者术后生存率和生存质量。延伸和拓展米兰标准并结合相关分子标志物可以更安全地扩展移植受体范围,同时可以更好地预测移植后HCC复发,杭州标准就是一个典型的成功案例。本综述重点关注肿瘤标志物和炎症标志物与HCC移植术后的相关性,肿瘤标志物(包括AFP、DCP等)和炎症标志物(包括CRP、NLR、PLR等)均可以作为预测移植后HCC复发的分子标志物,但除AFP外,大部分标志物均未成功应用于临床。由于肿瘤的个体差异性较大,因此更多分子标志物组合使用可能更具临床意义。另外,目前大部分的研究都是回顾性研究,缺乏多中心前瞻性研究。未来需要更多的多中心前瞻性研究,以找着更合适的分子标志物组合,结合肿瘤形态学和病理学标准,更安全有效地筛选合适的HCC患者接受肝移植,实现预测复发风险,达到早期发现和治疗的目的,以获得更好的治疗效果。

文章引用

章文燕,郑树森. 肝癌移植术后复发相关标志物的研究进展
Molecular Markers and Recurrence of Hepatocellular Carcinoma after Liver Transplantation[J]. 临床医学进展, 2019, 09(03): 310-318. https://doi.org/10.12677/ACM.2019.93047

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