修回日期: 2019-06-04
接受日期: 2019-07-22
在线出版日期: 2019-10-28
肝细胞癌(hepatocellular carcinoma, HCC)合并癌栓是HCC研究的热点和难点, 许多焦点问题尚有争议, 临床指南和治疗推荐方面东西方差异巨大, 疗效仍不令人满意. 近年来, 随着肿瘤综合治疗理念的进步和手术技术, 围术期管理, 介入, 放疗, 靶向治疗等治疗手段的飞速发展, HCC合并癌栓的总体生存率明显延长, 取得令人鼓舞的疗效. 但是, 如何个体化选择治疗方案以达到最优化治疗, 以及如何预防术后复发等核心问题仍需不断研究和探讨. 本文就HCC合并门静脉癌栓, 下腔静脉癌栓和胆管癌栓的研究进展作一综述.
核心提要: 肝细胞癌(hepatocellular carcinoma, HCC)合并癌栓治疗上非常困难, 表现在指南推荐意见不统一, 治疗方案繁多, 疗效不明确, 总的生存率仍不令人满意, 核心问题争议不断. 本文就近年来HCC合并各类癌栓的治疗进展和预后情况作一综述.
引文著录: 赵健, 谢于. 肝细胞癌合并癌栓的研究进展. 世界华人消化杂志 2019; 27(20): 1239-1247
Revised: June 4, 2019
Accepted: July 22, 2019
Published online: October 28, 2019
Hepatocellular carcinoma (HCC) with tumor thrombus is a hot and difficult issue in the study of HCC, and many key issues concerning this condition are still controversial. Clinical guidelines and treatment recommendations vary widely between the East and the West, and efficacy remains unsatisfactory. In recent years, with the progress of comprehensive tumor treatment concept and the rapid development of surgical techniques, perioperative management, interventional therapy, radiotherapy, targeted therapy, and other treatment methods, the overall survival rate of HCC with tumor thrombus has been significantly extended and encouraging efficacy has been achieved. However, the core issues on how to select individualized treatment to achieve optimal treatment and how to prevent postoperative recurrence still need to be studied and discussed. This article reviews the progress in the research of hepatic carcinoma with portal vein thrombus, inferior vena cava thrombus, or bile duct thrombus.
- Citation: Zhao J, Xie Y. Progress in research of hepatocellular carcinoma with tumor thrombus. Shijie Huaren Xiaohua Zazhi 2019; 27(20): 1239-1247
- URL: https://www.wjgnet.com/1009-3079/full/v27/i20/1239.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v27.i20.1239
肝细胞癌(hepatocellular carcinoma, HCC)是一种恶性度和异质性非常高的肿瘤, 多数病人就诊时病情已属进展期, 其中常见的特征之一是合并癌栓. 在此, 我们对HCC合并各类癌栓的情况作一探讨.
合并门静脉癌栓(portal vein tumor thrombus, PVTT)可分为微血管癌栓(或称微血管浸润, microvascular invasion, MVI)和大血管侵犯(major portal vein tumor thrombus, MPVTT), 两者均是影响HCC预后的独立危险因素. MVI发生率随肿瘤增大而增加, 但即使在小HCC中发生率也高达15%-50%[1]. MVI意味着肿瘤生物学行为较差, 主要是显著增加术后复发风险降低远期生存率; 其发生原因尚不明确, 可能和肿瘤与微环境相互影响, 免疫, 内分泌, 代谢, 基因等多个因素有关[2]. 现行的检查及影像手段难以在术前发现, 仅能通过术前预测模型和相关指标推测其发生风险[3], 需术后病理才能明确诊断, 容易被忽视. MVI与MPVTT的生物学行为, 临床病理特征, 诊断, 治疗和预后均有不同, 因此本文讨论PVTT仅为肉眼可见的门静脉癌栓.
文献报道PVTT的发生率44%-62.2%[4], 在晚期HCC中可高达90%[5]. 无PVTT的HCC病人中位生存时间(median survival time, mST)24.4 mo, 发生PVTT但未予治疗的mST仅2.7-4 mo[6]. 近年来对PVTT发生机制的研究取得进展, 认为可能与肿瘤的分化浸润, 解剖学特点, 生长方式, 凝血异常, 门静脉逆流, 基因及分子机制如癌细胞间黏附降低, 癌细胞与基质间黏附升高, 细胞外基质降解, 癌细胞趋化运动等诸多因素相关[7-9]. 有研究表明KDM6A, CUL9, FDG6, AKAP3, RNFl39等基因突变[7], 趋化因子及受体CCR1, CXCR4, CCL22等与PVTT的发生发展相关[8].
PVTT往往预示HCC预后更差, 原因为: (1)癌细胞沿门静脉播散引起广泛肝内转移; (2)肝血流分布锐减使肝功能持续恶化导致肝衰; (3)加重门脉高压导致难治性腹水和食管胃底曲张静脉破裂出血. 其生物学特点表现为: (1)呈离心性生长, 生长偏慢; (2)预后与生长部位, 浸润程度, 病理类型关系密切; (3)肝硬化, 血清碱性磷酸酶>100 IU/L, 肿瘤包膜不完整, 邻近器官浸润是预后不良的独立危险因素[10]; (4)原发灶大小并不是PVTT发生的决定因素, 但原发灶直径>8cm时更容易发生一级门脉及门脉主干癌栓[11].
诊断方面以影像学检查为最常用方法. 增强电子计算机断层扫描(computed tomography, CT)应用最广, 3D-CT的确诊率可达87%[12]. PVTT与HCC原发灶有相同的病理学性质和血供特点, 结合是磁共振成像(magnetic resonance imaging, MRI)的T1WI, T2WI, 增强扫描和弥散成像, 表观扩散成像等可较好的诊断, 判断静脉壁是否受累以及与血栓鉴别. 血清学检测方面, 目前尚无单一标志物可以准确预测PVTT, 因敏感性和特异性均不高. 有研究表明, AFP, 异常凝血酶原, α-岩藻糖, 白细胞介素8, 外泌体microRNA等有望成为预测因子[13], 但尚需临床进一步验证.
目前国际上最常采用的临床分型包括: 日本HCC研究组提出的根据门静脉分级分型(VP分型)[14]和研究[15]提出的根据PVTT进展程度分型(程式分型). 分型的制定对PVTT进展度判断, 治疗策略选择, 预测和评价预后有重要意义. 但这两种分型均是以癌栓发生部位划分, 并未考虑肝脏功能和全身状态, 以及HCC原发灶的可切除性, 在实际应用中略显不足[16].
当前的治疗包括: (1)手术治疗; (2)全身辅助治疗: 包括经导管动脉化疗栓塞术(transarterial chemoembolization, TACE), 肝动脉灌注化疗(hepatic arterial infusion chemotherapy, HAIC), 外放射治疗, 系统化疗, 靶向治疗(索拉菲尼, 仑伐替尼), 免疫治疗; (3)局部治疗: 包括Ⅰ125粒子内放射治疗, 钇90(Y90)经动脉放射性栓塞(transarterial radioembolization, TARE), 门静脉支架植入, 腔内射频消融等.
PVTT的治疗是HCC的研究热点和争论焦点, 东西方差异很大. 以欧美国家为代表的巴塞罗那临床HCC分期(BCLC分期)将大血管侵犯划为进展期(C期), 推荐治疗仅有索拉菲尼, 其依据是这类病人生存率低(mST小于6.5 mo, 1年生存率低于25%)[17]和并发症发生率高(治疗带来的肝损害, 毒性和耐受力下降)[18]. 然而, 越来越多的研究证实, 索拉菲尼并非最佳的治疗选择. 基于SHARPE trial(欧洲和美国)[19]和Asian-Pacific study(Asia-Pacific regions)[20]两项随机对照试验(randomized controlled trial, RCT)研究证据: (1)索拉菲尼延长生存期仅有3 mo; (2)对不同PVTT分型仅推荐单一治疗方案而非个体化和最优化的治疗选择; (3)手术治疗和多种治疗方案的综合治疗的确延长了病人生存期和改善了生活质量; (4)基于MDT, 精准术前评估和围手术期管理, 手术安全性和有效性得以改善. 以中日韩三国为代表的亚太国家制定的共识意见[21]认为, 手术治疗是PVTT病人有效的治疗选择, 即使不能达到根治, 仍可以有效延长病人生存期和改善生活质量. 因此, 中国大陆, 香港和日本相继更新了本国指南[22-24].
1.6.1 手术切除: 手术切除是否有效呢? 一项来自欧洲(希腊)的系统回顾[25]分析了29项研究3659例PVTT患者手术治疗后的生存情况. 结果显示mST为15 mo, 3, 5年生存率33%和20%. 日本最新公布的一项汇总了6474例PVTT患者的全国多中心调查[26]显示, 手术组mST较对照组(索拉菲尼)延长1.77年, 1年, 3年, 5年生存率明显高于对照组. 来自中国的汇总1580例患者的大型队列研究也显示, 程式Ⅰ\Ⅱ型mST明显优于非手术组. 这些研究数据充分说明手术切除可带来明显的生存获益. 另外, 一项针对PVTT术后生活质量的研究显示[27], 手术治疗在提高生活质量方面较非手术治疗更有优势, 原因可能是PVTT的清除具有减轻肿瘤负担, 减轻门静脉高压及其相关并发症, 改善肝功能的优点.
手术切除是否安全呢? PVTT的手术死亡率文献报道较少且结果不一致, 为3.4%-9.3%[28], 术后30 d死亡率达2.3%. 主要死因多集中在术后肝衰竭和术后出血. 术后并发症发生率18%-33%[28,29]. 但这些文献统计的病例数均较少, 且不同中心不同医生存在技术差异和病人选择差异, 难以反映真实世界结果. 由此可见, PVTT手术治疗虽然已被广泛采用并证明是安全的, 但仍有一定风险性, 需要非常精细的技术和慎重决定.
不同PVTT分型如何选择手术呢? 日本一项多中心研究显示[26], 如仅限于一级分支(VP1-3, 程式Ⅰ-Ⅱ型), 手术切除与非手术相比具有更长的总生存期(overall survival, OS)和无病生存期(disease-free survival, DFS). 国内一项回顾性分析[11]1980-2012年手术治疗PVTT结果显示, VP1-3型(程式Ⅰ-Ⅱ型)行手术治疗后OS/DFS有上升趋势, 这可能得益于手术技术和评估手段的进步. 但VP4(程式Ⅲ-Ⅳ型)和癌栓延伸至对侧时并无获益. 由此可见, PVTT的位置和范围是影响手术疗效的关键因素, VP1-3(程式Ⅰ-Ⅱ型)应更积极的手术.
如何优化手术呢? 首先应强调适应症选择. 研究表明, 影响手术效果的不良因素除了进展度(临床分型), 还包括年龄, 肝功能储备, 肝纤维化程度, 全身状态, 肿瘤大小数量[26,30]. 安全实施PVTT手术尤其是行大范围肝切除时, 肝功能评估极其重要, 一般认为Child-Pugh A级才能安全实施手术; 三维可视化技术和肝脏与病灶精准评估可显著提高手术安全性和治疗效果[11]. 其次是手术技术的改进.对VP3-4病人术中搬动和离断肝脏之前先进行PVTT的清除, 结果显示mST和OS大幅提高, 显示出癌栓优先处理的明显优势[31]. 随后, 提出了"癌栓优先处理"的手术方案, 并报道了3例Ⅲ-Ⅳ型(VP4)病人行癌栓优先手术治疗+术后TACE治疗并获得长期生存(4.6-13年)[32]. 这种技术的改进一方面避免了术中挤压以减少肝内播散风险, 另一方面使健侧肝脏血流得以早期恢复对肝功能有保护作用, 从而提高手术效果和改善总体生存. Li等[33]回顾性研究了30例HCC合并门静脉左支癌栓行手术治疗的成绩, 显示联合尾状叶切除组治疗效果好于未切除组. 门静脉受累时建议予以切除后重建或异体血管置换, 但整块切除与取栓术哪个更好尚有争议, 应依据癌栓类型, 术者经验和吻合技术水平慎重决定[34,35]. 总之, 随着手术技术的发展和理念的进步, 手术疗效必将逐步提升.
1.6.2 TACE: TACE曾被欧美国家认为可能增加肝衰竭风险而被视为禁忌症. 近年来, 越来越多的研究探讨了TACE在PVTT治疗中的作用. 美国近期一项汇总2006/2016 13项研究中1933例采用TACE治疗PVTT病人的系统回顾并对总生存率, 应答率和并发症发生率进行Meta分析[29], 结果中位OS为8 mo, 1年, 3年, 5年生存率分别为29%, 4%和1%, 应答率14%-16%, 并发症率18%, 且分支癌栓较主干癌栓有更好的生存获益. 北京大学人民医院近期报道的一份回顾性分析了多个中心1040例PVTT病人的治疗资料[36], 其中TACE治疗675例(65%), 中位OS和1年生存率均优于索拉菲尼组(9 mo vs 6 mo和35.2% vs 26.9%), 死亡率TACE组也明显占优势(2.6% vs 7.7%). 由此可见, TACE不应被视为PVTT治疗禁忌, 而是安全有效且合理的治疗选择. 随着微球技术的进步, 以含有化疗药物的微球作为栓塞材料的载药微球(drug-eluting beads, DEB)-TACE迅速发展, 可以持续的局部输送高质量的药物, 在降低全身(血浆内)药物峰值水平的同时, 产生微球介导的栓塞效应. 研究证明DEB-TACE对于晚期不可切除PVTT患者是安全和有效的[37]. 一项PRECISION V前瞻性RCT研究[38]表明, TACE与DEB-TACE的疗效相似, 但后者的肝脏毒性明显轻. TACE与DEB-TACE哪个更好目前尚无定论, 仍缺少高质量RCT研究. 此外, 术前TACE与术后TACE应如何选择即TACE的时机问题, 以及如何筛选潜在获益人群等问题也没有定论, 同样缺少高级别循证医学证据.
1.6.3 手术与TACE如何选择: 一项国外META分析[39]中的分层研究表明, 接受手术切除的程式Ⅰ-Ⅱ型PVTT患者的生存率优于TACE , 而Ⅲ-Ⅳ型患者更适合TACE. 研究[7]比较了201例接受手术治疗和402例接受TACE治疗的病例后也得到相近的结果. 来自东方肝胆医院的两项研究: 一项是回顾性分析了11项3129例PVTT病人治疗资料, 一项是近期的汇总了中日韩三国2012/2016 7项研究的4810例PVTT病人治疗资料, 结果均显示, 手术切除较TACE的OS更长, 特别是程式Ⅰ-Ⅱ型, 可切除的PVTT病人能获得更好的生存获益.
1.6.4 放疗: 理论上讲, PVTT术后复发与癌栓脱落扩散有关, 因此术前灭活癌栓有利于预防转移和癌细胞扩散. 有研究表明, 癌栓的放射应答率高于原发灶(27% vs 13%), 作为新辅助治疗, 术前放疗可以有效提高生存率和降低半年-1年内复发率, 且耐受性良好, 1年, 2年总生存率有显著优势(69% vs 20.4%, 35.6% vs 0%)[40]. 同时研究还认为, 术前放疗可导致PVTT部分甚至全部坏死从而有机会达到降期, 且减少术中出血和缩短手术时间, 提高了手术安全性[40,41]. Minagawa等[42]观察研究外放射治疗PVTT的病例, 并没有发现放射性肝病和明显的放射相关并发症. 这得益于放射治疗技术的进步, 同时放射部位仅是癌栓而非HCC原发灶, 全身放射性损害被局限和最小化, 因而并没有显著增加肝功能和全身状态的损害. 由此可见, 术前外放射治疗对延长病人生存是有益的.
1.6.5 局部治疗: 这里着重介绍一种经动脉放射性粒子栓塞治疗, 即钇90(Y90)TARE. 钇90是一种发射β射线的放射性同位素, 其组织穿透率低(平均2.5 mm, 最大11 mm), 术后无需隔离[43]. 由于放射性树脂微球主要聚集于肿瘤组织富含的血管内, 对正常肝实质的影响小, 其体积仅20-60 μm, 对肝内血流分布影响小于传统TACE[44]. 一项来自美国的纳入185例钇90-TARE治疗晚期PVTT的数据显示其是安全, 有效的局部治疗手段[45]. 对于肝功能不良的晚期病人, 其有效率可达42%-57%[46]. 钇90-TARE对比索拉菲尼和传统TACE的多项研究表明, 其生存率明显优于单一索拉菲尼治疗[47], 无进展生存期(progression free survival, PFS)明显好于TACE(>26 mo vs 6.8 mo)[48], 但中位生存期和存活期并无显著差异. 由此可见, 钇90-TARE能为局部晚期病人带来生存获益, 且耐受性较好.
1.6.6 多学科联合, 序贯治疗: PVTT的治疗非常复杂, 肝硬化和其他潜在并发症进一步恶化了整体预后, 并使临床决策极具挑战[49]. 多学科评估和联合序贯治疗在近期的PVTT治疗中得到应用[49], 包括肿瘤学, 肝病内科, 外科, 放射介入治疗, 核医学和病理学等多个学科可以帮助优化病人管理和治疗决策. 近期, 基于多学科协作模式下开展联合-序贯治疗取得了令人鼓舞的成绩. 国内外多项研究表明[50-52], 手术切除+术后TACE的OS和PFS明显优于单纯手术, 认为术后TACE可有效延缓和预防肿瘤复发从而改善生存. 韩国一项纳入984例晚期PVTT患者(VP4)的回顾性多中心研究显示, 放疗联合TACE治疗的中位OS为10.2 mo, 有效率为52%[30]. Lee等[53]报道在16.9%的晚期病例通过同步放化疗(concurrent chemoradiothrapy, CCRT) +HAIC治疗后降期而成功实施了根治性切除. Chong等[54]报道98例局晚不可切除PVTT病人行相同的CCRT+HAIC治疗后降期再行手术治疗的效果和预后分析显示, 经CCRT+HAIC治疗转化率26.5%, 再经手术后中位生存率明显优于仅行CCRT和仅行手术者(62 mo vs 15 mo vs 13 mo). 日本一项系统回顾显示[28], 接受手术联合多学科治疗的PVTT患者OS明显优于未接受多学科治疗者. 其多学科治疗包括: 术前放疗, 术前TACE, 皮下注射干扰素治疗, 术后TACE, 经肝动脉\门静脉化疗等. 同时认为, 肝切除联合多学科序贯治疗可能是延长患者生存期的必要方法之一, 但如何合理选择序贯治疗方案尚无定论, 需进一步研究探讨.
综上所述, 笔者认为, PVTT治疗方案的选择应以精准评估为前提, 以手术切除为基础, 综合全身及肝功能情况, 严格把握适应症, 合理筛选病人, 结合自身技术条件恰当选择手术方式, 术后辅以综合治疗预防复发转移. 多学科联合序贯治疗, 治疗方案合理配置与时相选择以及转化治疗将是未来研究的方向.
HCC合并下腔静脉癌栓(inferior vena cava tumor thrombus, IVCTT)是HCC的晚期表现, 包括肝静脉内癌栓和下腔静脉主干癌栓, 发生率分别为3.8%和2.0%[55]. 一般认为癌栓从HCC原发灶侵入肝静脉或肝短静脉并沿静脉回流方向延展, 导致下腔静脉甚至右心房癌栓形成, 腔静脉完全阻塞时可引起布加综合征(Budd-Chiari), 癌栓脱落可导致肺内弥漫性肿瘤播散, 肺栓塞, 心脏停搏甚至猝死. 目前临床检查手段包括多普勒超声, CT和MRI. 三维重建及腔静脉造影等能非常直观显示癌栓的大小, 部位, 梗阻程度和下腔静脉壁浸润情况, 对术式选择, 手术风险评估, 可能出现的困难及应对策略等是十分有益的.
目前国际上尚无对IVCTT的分型标准, 国外各HCC治疗指南未将其分级分层研究. 东方肝胆医院根据下腔静脉内癌栓的蔓延部位将其分为3型[56], 即Ⅰ型膈下型, Ⅱ型膈上型, Ⅲ型心内型. 不同分型对应不同的治疗方案和手术策略.
以往认为IVCTT并不适合手术治疗. 主要考虑这类病人已处于终末期, 自然病程仅1-5 mo[57]. IVCTT属于大血管侵犯, 更易发生肺转移或癌栓栓塞, 按BCLC分期属于进展期(C期), 并不主张手术而是推荐索拉菲尼治疗. 但越来越多的证据表明, 手术可以使这类病人获益. 日本东京大学报道肝部分切除联合下腔静脉切开取栓术患者的1, 3年总生存率分别为81%和32%, mST为16.7 mo, 中位无复发生存期为3 mo[39]. 日本北海道大学报道术后患者的1和3年总生存率分别为80%和30%, mST明显优于索拉菲尼治疗(30.8 mo vs 10.7 mo)[58].
笔者对于IVCTT的治疗持积极态度. 理由是: (1)下腔静脉癌栓属于静脉内延伸, 血供丰富, 多不伴有静脉壁浸润和内膜改变, 呈铸型生长. 这是实施取栓术的理论基础; (2)这类手术均难以达到根治性切除. 但即便原发灶不能根治性切除, 下腔静脉取栓仍有意义, 目的是经手术取栓, 减少肿瘤负荷, 使肝静脉再通, 降低癌栓脱落引起栓塞的几率; (3)单纯局部治疗(消融或支架)和辅助治疗(TACE或放疗)均不能延长总体生存时间[59]. 因此, 在病人条件允许的情况下, 积极的手术治疗是可以获益的. 同时, 必须充分认清这类手术极高的风险性, 任何意外情况都有猝死在手术台上的可能. 既往文献报道手术相关并发症率为40%, 30 d内死亡率高达15%[55], 均提示手术取栓仍需慎重决定.
手术应注意以下问题: (1)术前准备很重要: 一是严格筛选病人, 把握手术适应症; 二是精准评估癌栓浸润程度和慎重评估手术风险. (2)手术操作是关键: 包括: ①术中再评估癌栓平面和静脉壁是否受侵犯; ②预防性血流控制, 流入, 流出道预置阻断带; ③前入路劈肝, 减少肿瘤挤压和搬动, 最后处理肝静脉和下腔静脉; ④下腔静脉游离后下拉, 可增加2-3 cm操作空间; ⑤术中超声, 食管内超声等手段实时监控, 直视下取栓. (3)做好应急处置和方预案. 术中最危险的是癌栓脱落导致急性肺梗塞和空气栓塞, 其次是大出血. (4)尾状叶来源的IVCTT常浸润肝后下腔静脉壁并引起阻塞, 需行切除后血管置换. (5)术后辅助治疗可能使病人获益, 但这类病人生存时间均较短, 难以判断术后辅助治疗的效果.
综上所述, IVCTT是HCC终末期表现, 治疗较为棘手. 在病人条件允许的情况下, 严格筛选病人, 慎重评估手术风险, 妥善做好术前术中准备和意外情况应急处置, 手术可以延长短期生存和改善生活质量. 术后最大的问题仍是高复发率和肺转移, 如何解决复发问题尚需进一步研究.
胆管癌栓(bile duct tumor thrombus, BDTT)发生率较低, 文献报道为1.2%-9%[60]. HCC合并BDTT并不是肿瘤晚期表现, 在肿瘤发生早期就可能有胆管内微小癌栓出现[61]. 因胆管内并不适合肿瘤生长, 癌栓仅呈膨胀性铸型状生长, 但较大的癌栓也可侵犯胆管壁并获取血供. 一旦癌栓阻塞胆管可引起胆汁排出障碍, 如胆总管阻塞可引起黄疸和肝功能持续性恶化. BDTT的发生机制尚无定论, 推测可能与肿瘤直接浸润, 血行转移, 胆道内癌栓脱落, 微小癌栓跳跃式侵犯胆管壁, 肿瘤微环境, 免疫状态, 肿瘤干细胞起源等相关[62].
BDTT的分型尚未统一, 临床应用较多的是根据Ueda等依据癌栓位置提出的分型[60]: Ⅰ型胆道癌栓位于胆管树2级分支内; Ⅱ型延伸至1级分支内; Ⅲ型延伸或种植至肝总管; Ⅳ型是癌栓或肿瘤碎片悬浮于胆总管内. 分型与手术方案的制定, 手术难度及风险等密切相关, 但各型的远期生存率无差别[60].
手术切除是BDTT治疗的关键. Oba等[63]的研究显示, BDTT术后1年, 3年和5年生存率分别为92%, 77%和48%, 与同时期切除的HCC患者的长期疗效一致. 东京大学附属医院回顾性分析1994年至2007年间19例BDTT病例结果显示[64], 1年, 3年, 5年生存率分别为82.3%, 38.8%, 32.4%, 平均复发时间6.4 mo, 复发率67%. 这充分说明手术治疗可使BDTT病人明显获益, 但高复发率问题目前没有好的解决方案. 对于不能耐受手术的BDTT病人, 常用的局部治疗手段包括TACE, 胆道支架, 放疗, 索拉菲尼等[65], 但效果均不理想. 研究[66]比较了27例行TACE治疗和40例经胆管穿刺引流的治疗效果, 两者远期生存均较差. 但随着技术的进步, TACE, HTAC, 腔内射频消融治疗均有一定进展, 逐渐出现非手术治疗后改善短期生存的个案报道[67,68], 但总的疗效尚不明确, 仍缺少大样本, 高质量的研究数据.
术式选择问题尚无定论. 对于Ueda Ⅰ, Ⅱ型BDTT病人行HCC原发灶及癌栓胆管一并切除以达到根治性已得到广泛认可. Ueda Ⅲ, Ⅳ型病人的术式选择是争论的焦点: 癌栓胆管的保留问题, 文献报道并不一致. 一方面, 国内一项回顾性研究[69]比较了不同术式治疗BDTT的疗效显示, HCC切除+胆总管切除+肝肠吻合术的总体生存时间优于HCC切除+胆管切开取栓术; 韩国一项多中心研究也支持行规则性肝切除同时进行肝外胆管切除长期生存良好, 术后1年, 3年, 5年, 10年生存率分别为76.5%, 41.4%, 32%和17%[70]. 另一方面, Satoh等[60]比较了5例行肝外胆管切除与17例未行肝外胆道切除患者的复发率和远期生存未有差别, 但前者生活质量较差, 复发后耐受辅助治疗和再手术的机会降低.
笔者认为: (1)生物学行为是肿瘤治疗的基础. 一方面, 胆管内缺少适合HCC肿瘤生长的环境, 扩散和转移均受限制, 这为尽可能手术治疗彻底清除癌栓创造了条件. 另一方面, BDTT表现出更高的血管侵袭性和更低的组织分化程度[71], 恶性程度高预后差. 这显著增加了根治性切除难度和术后复发率. (2)术式选择不是影响远期生存的因素. 因此, 对于一般情况和肝功能良好, 病变可切除的病人应适当扩大切除范围, 包括HCC原发灶+肝外胆管+尾状叶联合切除; 对于肝硬化重, 全身状态差, 或不能根治性切除的病人, 考虑到术后高复发率和术后接受辅助治疗的耐受问题, 应尽量选择相对简单的胆管切开取栓术以提高病人生存质量.
总之, BDTT并不是癌症晚期表现, 也不意味着丧失手术机会, 相反手术是可以获得长期生存的唯一选择. 术后复发是尚未解决的难题, 术后综合治疗和非手术治疗的效果尚需大样本, 高质量前瞻性研究验证.
HCC合并脉管癌栓并不是手术的绝对禁忌症, 多数病人可以从手术中获益. PVTT的整体预后差, 但通过以手术为主的综合治疗方案, 联合序贯各种辅助治疗手段可以获得较好的治疗效果; IVCTT属于HCC晚期事件, 应在条件允许的情况下积极尝试手术干预来延长短期生存和改善生活质量; BDTT的治疗争议多, 治疗效果不明确, 但仍需尽可能手术治疗来改善预后. 随着外科手术的进步, 手术方式的改进, 术前评估的重视和规范化, 影像学病理学的进步, 对HCC浸润转移, 复发再发, 脉管侵犯等生物学行为的研究逐步深入, 以及综合治疗理念和MDT的推广, HCC合并脉管癌栓的治疗成绩必将逐步提升, 个体化的综合治疗和术后辅助治疗将发挥越来越重要的作用.
学科分类: 胃肠病学和肝病学
手稿来源地: 北京市
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