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  • “中国科技期刊卓越行动计划”中文领军期刊
  • 百种中国杰出学术期刊
  • 中国百强报刊
  • RCCSE中国核心学术期刊(A+)
  • 中国自然科学类核心期刊
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中国研究型医院学会肝胆胰外科专业委员会, 《中华消化外科杂志》编辑委员会, 董家鸿, 等. 肝门部胆管癌诊断和治疗指南(2025版)[J]. 中华消化外科杂志, 2025, 24(1): 1-20. DOI: 10.3760/cma.j.cn115610-20250106-00010
引用本文: 中国研究型医院学会肝胆胰外科专业委员会, 《中华消化外科杂志》编辑委员会, 董家鸿, 等. 肝门部胆管癌诊断和治疗指南(2025版)[J]. 中华消化外科杂志, 2025, 24(1): 1-20. DOI: 10.3760/cma.j.cn115610-20250106-00010
Society for Hepato-pancreato-biliary Surgery of Chinese Research Hospital Association, Editorial Board of Chinese Journal of Digestive Surgery, Dong Jiahong, et al. Guideline for diagnosis and treatment of perihilar cholangiocarcinoma (2025 edition)[J]. Chinese Journal of Digestive Surgery, 2025, 24(1): 1-20. DOI: 10.3760/cma.j.cn115610-20250106-00010
Citation: Society for Hepato-pancreato-biliary Surgery of Chinese Research Hospital Association, Editorial Board of Chinese Journal of Digestive Surgery, Dong Jiahong, et al. Guideline for diagnosis and treatment of perihilar cholangiocarcinoma (2025 edition)[J]. Chinese Journal of Digestive Surgery, 2025, 24(1): 1-20. DOI: 10.3760/cma.j.cn115610-20250106-00010

肝门部胆管癌诊断和治疗指南(2025版)

基金项目: 

国家自然科学基金 92359301

中国科技期刊卓越行动计划(卓越二期⁃B1⁃090) 

详细信息
    通讯作者:

    董家鸿,清华大学临床医学院 清华大学精准医学研究院,北京 102218,Email:dongjiahong@mail.tsinghua.edu.cn

    李相成,南京医科大学第一附属医院肝胆中心,南京 210029,Emial:drxcli@njmu.edu.cn

Guideline for diagnosis and treatment of perihilar cholangiocarcinoma (2025 edition)

Funds: 

National Natural Science Foundation of China 92359301

The Excellent Action Plan for Chinese Scientific and Technological Journals (Zhuoyue phase Ⅱ‑B1‑090) 

More Information
    Corresponding author:

    Dong Jiahong, Institute for Precision Medicine, School of Clinical Medicine, Tsinghua University, Beijing 102218, China, Email: dongjiahong@mail.tsinghua.edu.cn

    Li Xiangcheng, Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China, Email:drxcli@njmu.edu.cn

  • 摘要:

    肝门部胆管癌是胆道恶性肿瘤的常见类型。肝门部胆管癌的诊疗涉及流行病学、临床诊断、影像学检查、临床分型分期、病理学、可切除性评估、围手术期管理、手术抉择、系统治疗以及随访监测等多个环节,是肝胆外科中诊疗难度最大、技术要求最高的领域之一。为指导我国肝门部胆管癌诊疗更规范、安全、有效地开展,中国研究型医院学会肝胆胰外科专业委员会和《中华消化外科杂志》编辑委员会组织全国肝门部胆管癌领域的专家共同制订《肝门部胆管癌诊断和治疗指南(2025版)》,旨在基于最新临床实践与循证医学原则,提供肝门部胆管癌的规范化诊断与治疗方案,以提升诊疗水平并改善患者预后,为我国开展肝门部胆管癌治疗的外科医师提供科学指导和参考。

    Abstract:

    Perihilar cholangiocarcinoma is the common type of malignant tumor in the biliary tract. The diagnosis and treatment of perihilar cholangiocarcinoma involve multiple aspects such as epidemiology, clinical diagnosis, imaging examination, clinical classification and staging, pathology, resectability evaluation, perioperative management, surgical planning, systematic treat-ment, and follow-up monitoring, which make it as one of the difficult and technically demanding fields in hepatobiliary surgery. In order to guide the more standardized, safe, and effective treatment of hilar cholangiocarcinoma in China, the Society for Hepato‑pancreato‑biliary Surgery of Chinese Research Hospital Association and Editorial Board of Chinese Journal of Digestive Surgery have organized experts in the field of hilar cholangiocarcinoma nationwide to develop the Guideline for diagnosis and treatment of hilar cholangiocarcinoma (2025 edition). The aim is to provide standardized diagnosis and treatment plans for perihilar cholangiocarcinoma based on the latest clinical practice and evi-dence-based medicine principles, to improve diagnosis and treatment levels and patient prognosis, and to provide scientific guidance and reference for surgeons in China.

  • 肝门部胆管癌是胆道恶性肿瘤的常见类型,起病隐匿,并具有多维度浸润性生长特点:既可沿胆管壁轴向浸润,也可突破胆管树向侧方浸润,导致邻近的门静脉、肝动脉和肝实质受累及,且易发生区域性淋巴结和神经丛转移[1]。根治性手术切除是治疗肝门部胆管癌的首选手段,肝门部胆管癌根治性手术实施涉及明确诊断、临床分期及分型、可切除性评估、手术规划、围手术期管理及系统治疗等多个环节,是肝胆外科中诊疗难度最大、技术要求最高的领域之一。

    为规范我国肝门部胆管癌的诊疗行为,2013年制订并颁布了《肝门部胆管癌诊断和治疗指南(2013年版)》。该版指南集中反映了当时我国在肝门部胆管癌诊断、治疗和研究方面的状况,在规范诊疗流程、改善患者预后、保障医疗质量和安全,以及优化医疗资源利用等方面发挥了重要作用。

    近年来,国内外在肝门部胆管癌的诊断、术前评估、手术策略和技术、围手术期管理以及综合治疗等方面均取得了显著进展。因此,中国研究型医院学会肝胆胰外科专业委员会和《中华消化外科杂志》编辑委员会,组织全国肝门部胆管癌领域专家,在结合最新临床实践经验和研究进展的基础上,根据循证医学原则,修订并更新为《肝门部胆管癌诊断和治疗指南(2025版)》(以下简称本指南),旨在为我国肝门部胆管癌的规范化治疗提供指导意见,提升诊治水平,进一步改善患者预后。

    循证医学证据等级评估参考证据评价与推荐意见分级、制定和评价方法学(grading of recommen⁃dations assessment,development,and evaluation,GRADE)的指导原则,采用《牛津循证医学中心分级2011版》作为辅助工具具体执行证据分级(证据等级1~5)[23]。专家组主要参考GRADE系统对推荐意见分级原则,融合美国临床肿瘤学会指南的分级方案,对推荐意见分级进行相应调整和优化[4]。推荐强度被划分为两个等级:强推荐和弱推荐。

    肝门部胆管癌是指起源于肝门周围胆管(肝总管、左右肝管及其汇合部胆管上皮细胞)的恶性肿瘤。为明确区分肝门部胆管癌与肝内胆管细胞癌、远端胆管癌,本指南以门静脉系统为参照界定其边界:左侧边界为门静脉左支水平部与矢状部转角处对应胆管(即U点);右侧边界为门静脉右后支起始部左侧对应胆管(即P点);下方边界为胆囊管和肝总管汇合点[5]

    由于肝内胆管和肝外胆管的边界界定不明确,第五版WHO消化系统肿瘤分类指出,具有肝内成分并累及肝门的大胆管型肝内胆管癌源于近肝门的肝内胆管,生物学特性近似肝门部胆管癌[6]。因此,针对该类型的胆管肿瘤,当肿瘤中心位于U点与P点间,并累及单侧或双侧肝门胆管时可被定义为肝门型肝内胆管细胞癌,其诊治应与肝门部胆管癌等同[7]

    鉴于肝门部胆管癌的流行病学研究中存在:(1)地区和人种差异大。(2)病例规模相对较小。(3)多数研究未明确区分胆道恶性肿瘤亚型。目前相关致病高危因素仍在研究探索中。

    目前,欧洲流行病学研究结果显示:原发性硬化性胆管炎与肝门部胆管癌发病密切相关[8]。东亚的研究结果显示:肝吸虫病是导致肝门部胆管癌的高危因素[9]。HBV和HCV感染相关的肝脏疾病与肝内胆管癌关系密切,但与肝门部胆管癌的关系尚需进一步验证[10]。此外,肝内外胆管结石、先天性胆道畸形也与肝门部胆管癌显著相关[11];糖尿病、吸烟、肥胖与肝门部胆管癌也存在相关性[1113]

    IgG4相关性硬化性胆管炎、胰胆管汇合异常、伤寒感染、胆汁幽门螺杆菌感染等疾病与肝门部胆管癌的关系需进一步探索[1415]。同时,酗酒、受亚硝胺污染的食品、石棉、二噁英、氯乙烯和乳化剂等毒性与环境因素也可能与之存在潜在联系[1620]

    推荐意见1:胆管扩张症、原发性硬化性胆管炎、寄生虫感染、肝内外胆管结石是肝门部胆管癌的明确危险因素(证据等级2,强推荐)。

    肝门部胆管癌的诊治应在具备相关专业技能的医疗中心进行,应首先进行多学科团队(multi⁃disciplinary team,MDT)会诊,MDT主要包括肝胆外科、影像科、消化内科及内镜中心、病理科、放疗科、肿瘤科等[2122]

    推荐意见2:建议肝门部胆管癌患者诊治都应进行MDT会诊;如无MDT条件,建议转诊至大容量、有治疗经验的中心进一步治疗(证据等级2,强推荐)。

    肝门部胆管癌患者主要临床表现为:上腹部不适、右季肋区疼痛、黄疸(可表现为反复黄疸)、乏力、发热、体质量下降。目前还没有针对肝门部胆管癌的特异性肿瘤标志物,临床上主要使用特异性相对较高的CA19‑9和通用肿瘤标志物CEA[23]

    胆道系统炎症(胆管炎、急性胆囊炎)可导致CA19‑9异常升高;当合并肝门胆管癌时,应充分减轻黄疸后再复查CA19‑9,避免胆道系统炎症干扰。如经术前充分减轻黄疸后,CA19‑9仍然>1 000 U/mL,提示肝门部胆管癌可能处于晚期或存在远处转移[24]

    ALT、AST可能正常或轻度升高。ALP水平通常与胆红素水平同时升高。肝功能生化检查(如Alb、凝血酶原时间)在病程早期正常。凝血酶原时间/国际标准化比率可能随着梗阻时间延长引起维生素K吸收不良而升高。

    IgG4相关硬化性胆管炎通常影响老年患者,且给肝门部胆管癌的诊断带来挑战[2527]。随着对该疾病认识加深,目前多项指南推荐对其进行相关检测[2829]

    推荐意见3:CA19‑9是一种广泛用于肝门部胆管癌诊断的血液肿瘤标志物,需谨慎解读检测结果(证据等级2,强推荐);疑似肝门部胆管癌患者,应行IgG4相关硬化性胆管炎检测(证据等级4,强推荐)。

    影像学检查是目前肝门部胆管癌临床诊断和鉴别诊断的重要方法,确诊仍需组织病理学检查[30]

    超声检查诊断胆管扩张敏感度高,可清晰展示肝内胆管扩张及肝门部胆管截断,明确肿瘤与正常组织界限,多普勒技术可发现肝动脉、门静脉受累情况。

    MDCT图像分辨率高,通过增强扫描,可清晰、直观显示增厚的胆管壁、形成的肿块、扩张胆管、局部淋巴结情况和肝内外转移灶。借助CT三维可视化技术,可立体准确显示肿瘤与胆管、大血管、周围脏器的关系以及各部分的肝脏体积[31]

    MRI检查具有良好的软组织分辨力,有助于清晰显示肿瘤边界和肿瘤侵犯肝实质情况,可有效评估肝门部血管和重要脏器的受累情况。MRCP检查能无创显示肝内外胆管的全貌,明确肿瘤阻塞位置和范围,有助于肝门部胆管癌的临床分型。以上检查均需在行胆道引流前进行[3233]

    ERCP可直接进行胆管造影从而评估肿瘤纵向侵犯程度,在胆管不全阻塞时可展现整个胆道的受累情况;胆管完全阻塞时,只能局限显示梗阻部位以下的胆管状况,同时ERCP可进行组织病理学检查[3435]

    PTC检查可显示胆管的梗阻部位、范围及梗阻部位上游胆管形态,并可辅助胆道减压与减轻黄疸治疗[36]

    PTC和ERCP都是有创检查,可能引发出血、胆道感染和急性胰腺炎等严重并发症。同时,因肿瘤促纤维增生特性,以上方法诊断特异度高,敏感度较低。因此,PTC和ERCP不被推荐为常规检查,适用于MRCP检查显示不清晰或无法施行的情况,或行术前经皮经肝胆管穿刺引流术(percutaneous transhepatic biliary drainage,PTBD)或内镜下鼻胆管置入引流术(endoscopic nasobiliary drainage,ENBD)时使用。

    EUS检查有利于评估肿瘤垂直和纵向侵犯程度以及是否合并血管侵犯,EUS检查引导穿刺与ERCP引导组织病理学检查有助于病理学确诊,但需注意肿瘤扩散风险[3739]。胆道子镜光纤直视系统可直接观察肿瘤并进行组织病理学检查,利于术前肿瘤评估与手术规划[4041]

    PET/CT检查可用于评估肝门部胆管癌淋巴结转移、远处转移和复发情况,其敏感度、特异度均优于单纯CT或MRI检查[42]。无其他病灶或病理学检查结果支持时,PET/CT检查不宜单独用于原发肿瘤诊断,对局部病变评估及可切除性判断的价值不优于其他影像学检查方法[43]

    推荐意见4:超声检查仅作为筛查手段。增强CT、MRI+MRCP检查是对肝门部胆管癌诊断、肿瘤分型和分期、可切除性评估和手术规划的主要手段和依据,且二者不可相互代替,建议有条件的单位同时行增强CT、增强MRI+MRCP检查(证据等级2,强推荐)。

    PTC、ERCP、EUS、胆道子镜光纤直视系统、PET/CT检查可作为肝门部胆管癌诊断中的补充手段(证据等级4,弱推荐)。

    目前肝门部胆管癌常用的分型和分期系统主要包括:Bismuth‑Corlette分型反映胆管癌在胆管树的轴向累及范围,是一种基于解剖学因素、可指导手术决策的分型系统,但未涵盖血管浸润、淋巴结转移等关键预后因素[44]。董氏改良分型在段肝管水平对Bismuth分型加以补充和修正,提高了手术决策的精准度[45]

    MSKCC T分期系统根据肿瘤累及胆管范围、门静脉侵犯和合并肝叶萎缩3个因素对肝门部胆管癌进行分期[46]。在评估可切除性和预测患者预后上优于Bismuth‑Corlette分型,但未体现肝动脉侵犯、淋巴结转移和远处转移等病理学要素,且涉及的相关变量在东西方人群中存在显著差异。

    AJCC TNM分期根据原发肿瘤(T)、淋巴结转移(N)和远处转移(M)3个因素进行分期[47]。该分期是基于术后病理学指标的一种分期系统,有助于患者预后判断以及指导术后辅助治疗,但在术前评估以及可切除性判断方面价值有限。

    推荐意见5:采用Bismuth‑Corlette分型可对肿瘤累及胆管的部位及范围进行初步评估(证据等级1,强推荐);MSKCC分期可评估胆管受累范围、血管受侵犯及肝叶萎缩,为评估手术切除提供参考(证据等级3,强推荐);AJCC TNM分期可应用于预测患者预后及术后生存时间(证据等级2,强推荐)。

    肝门部胆管癌按大体形态可分为硬化型(70%)、结节型(20%)和乳头型(10%)[48]。硬化型多见于低、中分化腺癌,呈环状缩窄性增厚,有时与慢性炎性疾病(硬化性胆管炎、自身免疫性胆管炎)难以鉴别。硬化型肿瘤常沿着黏膜下浸润,肿瘤边界在大体上很难精准确定,且容易侵犯肝实质、门静脉、肝动脉;结节型表现为明显的癌性胆管增厚;乳头型表现为胆管内明显的乳头状或息肉样生长,多为高分化腺癌,常沿黏膜层浸润,以浅表扩散为主,切除率高,预后好[4950]。常见亚型为胰胆管型,其他腺癌亚型包括肠型、胃小凹型、黏液型、印戒细胞型、透明细胞型、幽门腺型、肝样型、微乳头型。

    目前常用的胆道肿瘤免疫组织化学染色检测套组包括CK7、CK19、CK20、CDX2、MUC‑1、MUC‑2、MUC‑5AC、MUC‑6、CEA、CA19‑9、P53、Ki‑67等,其中CEA、CA19‑9、TP53、Ki‑67检测可用于肿瘤良恶性的筛选。此外,还可运用MLH1、MSH2、MSH6、PMS2辅助免疫治疗决策,运用HER‑2免疫组织化学染色检测指导靶向治疗。基因检测方面,MSI检测、NTRK融合突变、BRAF V600E突变、FGFR2融合或其他FGFR通路改变、IDH1突变、HER2/ERBB2过表达或扩增或激活突变等,可为免疫或靶向治疗提供依据。

    肝门部胆管癌具有多极化浸润特性,该疾病浸润行为除连续浸润外,还存在表浅播散及跳跃浸润[4952]。肝门部胆管癌常合并微血管及周围神经侵犯,与患者的不良预后相关[5358]。因此,精确评估肝门部胆管癌切缘状态对疾病分期及预后预测至关重要。

    病理学切缘评价中,纵向切缘评价应包括近端及远端胆管切缘;辐向切缘评价应包括肝脏切缘、血管切缘、肝十二指肠韧带切缘及肝门软组织。肝脏切缘面积较大,判定范围应主要以近端胆管周围2 cm肝脏断面为主[5961]。在非侵袭性浅表扩散型肝门部胆管癌切缘病理学状态评价上,高级别瘤变及原位癌应被视为R0切除[51,6264]

    推荐意见6:肿瘤组织病理学类型、分化程度、区域淋巴结转移、微血管和周围神经侵犯是影响预后的重要因素(证据等级2,强推荐)。肝门部胆管癌病理学切缘的评价应包括纵向切缘及辐向切缘(证据等级3,强推荐)。

    不可切除的肝门部胆管癌的判断标准包括(1)远处转移:肿瘤被证实存在远处器官、腹膜和远处淋巴结转移。(2)患者因素:患者无法耐受手术创伤,预留功能性肝体积小于患者必需功能性肝体积。(3)肿瘤局部累及情况:需进行MDT讨论,综合判断肿瘤对胆管及邻近区域组织内的累及情况,以及胆管、血管结构可否保持完整或重建[6566]。术前评估要点包括以下几个方面。

    胆管切离点指肝内近端胆管可安全切除并重建的最远点。右侧肝切除时,极限点在U点左缘B2与B3;左侧则在P点附近B6与B7。对于Bismuth Ⅳ型,若肿瘤超越两侧极限点,则视为不可R0切除[67]。胆管切离后需确保足够胆管长度以行重建和吻合。

    保留或重建血管结构是肝门部胆管癌手术的前提。血管切除指征仅限于术中确认血管壁受肿瘤浸润或癌性粘连,且无法钝性分离。一般认为门静脉切除的肝侧极限点为三级分支起始部,肝动脉切除的肝侧极限点则为二级分支[68]

    预留的功能性肝体积必须不小于患者的必需功能性肝体积,这是安全肝切除的前提条件[69]。持续重度梗阻性黄疸可导致肝脏功能损害,但对梗阻性黄疸状态下肝脏储备功能的评估及相应必需功能性肝体积的判断尚缺乏明确标准。可通过CT、MRI检查三维可视化计算剩余肝体积百分比,结合肝脏基础病变、胆道梗阻时程和范围、胆红素水平、胆道引流后吲哚菁绿清除试验、瞬时弹性成像测定肝脏硬度等综合评价[70]。对于需行半肝及以上大范围切除的肝门部胆管癌患者而言,建议当TBil<3 mg/dL(51 μmol/L)再行吲哚菁绿清除试验。梗阻性黄疸患者的预留肝体积应≥40%标准肝体积(证据Ⅳ级)。名古屋大学标准认为:预留剩余肝体积/全肝体积×吲哚菁绿清除率>0.05是大范围肝切除术的安全条件[6971]。肝叶萎缩也影响可切除性评估,单侧肝叶萎缩伴肿瘤侵犯对侧三级以上肝管或对侧门静脉三级分支则视为不可切除。

    重点关注区域淋巴结,如肝十二指肠韧带内、肝总动脉旁及胰头后上淋巴结。若术前PET/CT检查高度怀疑或组织病理学检查证实淋巴结转移范围超出区域范围,或转移至肝脏、肺、腹膜等远处脏器,则视为肿瘤已发生远处转移,提示不可根治性切除。

    术前需全面评估患者的全身状况及营养水平。采用美国东部肿瘤协作组体能状态评分系统评估全身功能状态,营养风险筛查2002或患者主观整体评估量表进行营养风险及营养状态筛查。对于存在营养不良的患者,建议术前给予营养支持治疗,以降低术后并发症风险[7273]

    推荐意见7:肝门部胆管癌的可切除性判断需行MDT讨论,应从肿瘤病理学边界与胆管切离极限点的关系、预留肝脏的功能性体积和血管结构完整性、淋巴结转移和远处转移状况、患者全身情况及营养状况5个方面做出全面评估和准确判断(证据等级3,强推荐)。

    合并梗阻性黄疸的肝门部胆管癌患者施行大范围肝切除术的手术死亡率高,其主要死亡原因为肝功能衰竭[7477]。对于高胆红素血症[TBil≥5.85 mg/dL(100 μmol/L)]、伴有胆管炎、营养不良[血清Alb<3 g/dL(30 g/L)]、拟行新辅助治疗、需行大范围肝切除术(切除肝叶>60%)、术前门静脉栓塞增加剩余肝体积的患者,推荐术前胆管引流[65,7880]。引流决策应基于MDT的综合评估[8182]

    肝门部胆管癌穿刺引流前的增强CT及MRCP等影像学检查有助于系统化判断肿瘤的梗阻部位和有无脉管侵犯,对肿瘤分期、分型进行精准评估。检查前已置入的穿刺管,可能会影响影像学评估。因此,在进行增强CT检查前,需要仔细考虑穿刺管的位置和其对图像质量可能产生的干扰,以确保评估结果的准确性。

    术前胆管引流常用的方式有:PTBD、ENBD、内镜下胆管支架置入术(endoscopic retrograde biliary drainage,ERBD)等。(1)PTBD操作简便,并发症发生率低,减轻黄疸效果好,但存在引流不畅并发胆道感染、引流管移位、门静脉损伤及潜在肿瘤种植转移风险[8385]。(2)ENBD优势是并发症(急性胆管炎、引流管移位、胆道出血等)较少,减轻黄疸效果与PTBD相当[8688]。ENBD手术难度大,技术要求高,有诱发胰腺炎的风险。(3)对于Bismuth‑Corlett Ⅲ型及Ⅳ型的患者,内镜下逆行操作需超选并通过病变胆管,且不易实现双侧引流,建议首选PTBD[8992]。(4)ERBD为内引流,其优点是更符合生理、患者更易耐受。但胆道支架会损伤十二指肠乳头括约肌功能,术后易致胆管炎,延长根治性手术等待时间,且支架移位、堵塞常见,影响引流[9394]。胆管支架建议选择塑料支架,不建议在根治性手术前应用金属支架减轻黄疸治疗[9596]

    胆道引流最佳方法仍存争议,需依据患者状况与医疗条件选择。根治性手术前胆道引流理想情况,TBil应<3 mg/dL(51 μmol/L)[73,78,92]。引流部位首选预留肝叶单侧,不仅可以有效减轻黄疸,还可增加预留侧肝叶功能代偿和肝脏容积[56,9798]。对手术方式难定或单侧引流效果不佳患者,考虑双侧胆管引流。术后常规胆汁细菌培养指导抗菌药物的使用,外引流患者可行胆汁回输,促进肠黏膜屏障功能恢复,改善营养状况。

    推荐意见8:对梗阻性黄疸且同时需行大范围肝切除术(切除肝叶>60%)、或合并胆管炎、或营养风险大、或拟行新辅助治疗、或需行门静脉栓塞的肝门部胆管癌患者应考虑给予术前胆道引流。对无症状轻度黄疸患者,可行MDT讨论,综合判断是否需要行术前胆道引流(证据等级2,强推荐)。胆道引流的方法应根据患者情况和医疗技术条件进行选择,优选ENBD或PTBD。胆道引流后,常规行胆汁细菌培养指导围手术期抗菌药物使用(证据等级3,强推荐)。

    门静脉栓塞术旨在促进拟切除肝段萎缩,并增大剩余肝体积,以优化肝叶切除条件。仅当预留肝脏具备足够体积与功能时,方考虑手术。门静脉栓塞能扩大手术适应证范围,提高患者手术耐受性,降低术后死亡率与肝衰竭风险[99100]。当预留功能性肝体积<40%全肝体积时,术前应行门静脉栓塞术,以降低手术死亡率和肝衰竭风险(证据Ⅳ级)[101]。为防延误手术时机,综合评估肝功能后,可同时实施胆管引流与门静脉栓塞术[102]

    门静脉栓塞术需行增强CT检查并结合肝功能生化指标,评估肝脏体积与功能[103105]。若肝再生显著(肝体积增大>5%或预留功能性肝体积≥40%),则并发症风险明显降低,可手术治疗[106]。门静脉栓塞范围直接影响剩余肝体积的增生程度,完全栓塞目标肝段可最大化发挥剩余肝增生效应。为减少门静脉栓塞术后无法手术的情况,干预策略包括:(1)考虑剩余肝体积非线性增长模式,缩短门静脉栓塞术效果评估的等待时间[103]。(2)缩短门静脉栓塞术和手术间隔,因剩余肝脏功能增长可能快于体积增长[107108]。(3)同步手术如行右侧门静脉栓塞术同时行同侧肝静脉栓塞,可促进更显著的剩余肝体积的增长[109110]

    推荐意见9:伴有黄疸的肝门部胆管癌患者若预留功能性肝体积<40%全肝体积,术前需行拟切除肝脏区段的选择性门静脉栓塞术(证据等级2,强推荐)。

    手术切除是肝门部胆管癌患者获得长期生存的首选治疗方法,目前公认的肝门部胆管癌标准根治性切除手术方式为肝叶切除和肝外胆管切除、区域淋巴结和神经丛廓清以及肝管‑空肠Roux‑en‑Y吻合术。

    肝门部胆管癌淋巴结转移常隐匿于常规病理学检查外,实际淋巴结转移率可能更高。主要淋巴引流途径:(1)沿胆总管至胰头后上方淋巴结及腹主动脉淋巴结。(2)循肝固有动脉经肝总动脉至腹腔干淋巴结。(3)沿门静脉左行至肠系膜上静脉淋巴结。前两者为主要引流路径[111]

    AJCC/UICC第8版指南规定,pN0期定义为区域淋巴结阴性;pN1期为1~3枚区域淋巴结转移;pN2期为≥4枚区域淋巴结转移。然而,该指南对肝门部胆管癌区域淋巴结范围界定模糊[47]

    日本《肝胆胰外科协会指南(第3版)》则明确定义肝门部胆管癌区域淋巴结包括肝十二指肠韧带内、肝总动脉旁和胰头后上淋巴结,但对淋巴结清扫数目无硬性规定[112]

    肿瘤细胞能沿神经纤维“跳跃”传播,导致远处转移。鉴于肝门区及肝十二指肠韧带内神经纤维在Glisson鞘内多沿肝动脉分布,应整块切除肝十二指肠韧带内除肝动脉和门静脉以外的全部组织,实现肝十二指肠韧带的“骨骼化”[113]。术中清理时应紧贴血管外膜剥离神经组织,确保彻底清除肿瘤浸润的神经组织,减少复发风险。胰腺侧清理需清晰分离胰头后部、胰颈上缘、胃十二指肠动脉、肝总动脉;肝脏侧则需完全剥离肝被膜外的所有结缔组织。

    推荐意见10:肝门部胆管癌根治性切除术中常规清扫淋巴组织和神经丛的范围应包括:肝门区、肝十二指肠韧带内淋巴结、肝总动脉旁淋巴结、胰头后上淋巴结和神经丛组织(证据等级2,强推荐)。

    肝尾状叶胆管支直接汇入肝门部胆管的特殊解剖,及肝门部胆管癌沿胆管上下蔓延浸润的侵袭特性,凸显了肝尾状叶切除在肝门部胆管癌手术治疗中的重要性。

    目前,肝叶切除联合肝尾状叶切除已成为治疗肝门部胆管癌的常规手段。肿瘤可经胆管上皮浸润、直接侵犯或沿胆管周围神经淋巴组织3种方式累及肝尾状叶[114115]。尽管术前难以准确判断肝尾状叶受累情况,但累及左右肝管汇合处的肿瘤(Bismuth Ⅱ型、Ⅲ型、Ⅳ型)侵犯肝尾状叶可能性极高。切除肝尾状叶能显著提升R0切除率,并可能带来更高的5年生存率[116117]

    推荐建议11:由于肿瘤易侵犯左右肝管汇合部和肝尾状叶胆管支,通常情况下应将全尾状叶切除作为肝门部胆管癌根治性切除手术的必要内容(证据等级2,强推荐)。

    肝门部胆管癌的病理学边界常超出影像和物理诊断范围,联合规则性肝段切除能提升R0切除率并减少复发已达成基本共识。对于Bismuth Ⅰ型、Ⅱ型患者(除特定情况:病理学分型为乳头状肿瘤,身体不能耐受等),推荐行肝外胆管+半肝切除术[114118]

    Bismuth Ⅲa型患者根据二级胆管侵犯范围,可能需行右半肝或扩大右半肝+肝尾状叶切除术[119];Bismuth Ⅲb型则可能需行左半肝或扩大左半肝+肝尾状叶切除术[120]。Bismuth Ⅳ型常需联合肝中央区域、右三区或左三区+肝尾状叶切除。Bismuth Ⅲ型、Ⅳ型常规需行全尾状叶切除术。肝中叶切除分完全和部分,前者适用于累及两肝段以上患者,切除肝Ⅰ+Ⅳ+Ⅴ+Ⅷ段;后者适用于肿瘤较小且仅累及肝中叶的一个肝段,切除范围包括完整的肝右前叶或肝左内叶全段联合另一叶的部分肝段以及肝尾状叶[121123]

    推荐建议12:肝门部胆管癌根治术应将受累的胆道系统、同侧半肝以及肝尾状叶一并切除,以实现切缘阴性(证据等级2,强推荐)。

    由于联合规则性肝切除术需要牺牲大量正常肝组织,术前常需行PTBD和门静脉栓塞术等预处理以提升预留肝脏的体积和功能,而预处理等待期可能出现肿瘤进展和扩散风险。

    围肝门部或联合部分肝段切除可达到根治性切除,同时最大限度保留肝实质[124125]。围肝门切除范围:腹侧距离肝门板1.5 cm,背侧包括全部肝尾状叶,右侧至右前及右后肝内胆管汇合处,左侧以Arantius管上缘至矢状部右侧缘为界,切除肝门区肝实质、肝尾状叶、肝外胆管、区域淋巴结以及神经组织[126127]。Bismuth Ⅰ型、Ⅱ型肝门部胆管癌行围肝门切除+胆管空肠吻合术;Bismuth Ⅲa型肝门部胆管癌行围肝门切除+肝S5、S8段切除+胆管空肠吻合术;Bismuth Ⅲb型肝门部胆管癌行围肝门切除+肝S4段切除+胆管空肠吻合术;Bismuth Ⅳ型肝门部胆管癌行围肝门切除+中肝切除+胆管空肠吻合术。

    Bismuth Ⅳ型因肿瘤广泛浸润左右肝管二级分支以上,通常需要行肝三叶联合肝尾状叶切除术,术后肝衰竭发生率高。而肝中叶切除术或改良肝中叶切除术(肝Ⅳb、Ⅴ、Ⅷ段切除联合肝Ⅰ段切除术),因其保留更多功能性肝实质、减少预处理需求、有降低手术风险的优势,在特定患者中展现出良好疗效。该手术方式对手术医师技术要求高,且需严格筛选适应证[128130]

    对于不耐受大范围肝切除术患者,单纯肝外胆管切除可作为姑息性治疗,尤其适合部分乳头型Bismuth Ⅰ型、Ⅱ型患者,能减少并发症,生命质量及预后与半肝切除术相当。

    推荐意见13:对于广泛浸润左右肝管二级分支以上但又不超过双侧胆管三级分支的部分可获得阴性切缘且不能耐受大范围肝切除的Bismuth Ⅳ型肝门部胆管癌,可行尽量保留功能性肝实质的肝中叶切除术(证据等级4,弱推荐)。

    联合切除受累血管是实现R0切除的重要保证。术前结合影像学技术有助于初步评估血管受累情况,但术中探查是判断血管是否受侵犯的关键。术中探查若发现能顺利剥离血管,即使术前怀疑血管侵犯也无需切除;同样,若肿瘤与血管关系密切,无法顺利剥离,即使术前评估无血管侵犯亦应行血管切除重建。此外,术中快速冷冻切片病理学检查有助于对血管切除进行精准判断。

    对于合并门静脉侵犯的肝门部胆管癌,联合门静脉切除重建能显著提升根治率,延长生存时间,且不增加并发症与死亡率[131134]。门静脉切除重建适用于Bismuth Ⅲa型或右侧侵犯为主的Bismuth Ⅳ型,肿瘤累及门静脉左支近汇合部者;也可应用于Bismuth Ⅲb型或左侧侵犯为主的Bismuth Ⅳ型(需保留右侧肝脏,但门静脉右支受侵犯而肝右动脉正常)[135138]。门静脉重建的方式,应根据肿瘤的具体位置和浸润范围选择合适的手术方式。

    血管壁部分切除修补:仅适用于门静脉管壁局部受累,吻合时要注意防止管腔狭窄;切除受累门静脉血管段后,可行端端吻合重建;若受累门静脉长度较长,直接吻合困难,则考虑自体血管或人工血管重建。门静脉重建采用血管内膜外翻缝合,以保证吻合口无张力、无扭曲,避免管腔狭窄。

    肝动脉切除重建能显著提高患者R0切除率,取得优于仅行姑息治疗的长期生存。通过显微外科技术和围手术期管理,手术并发症和死亡率可控。当肝动脉侵犯阻碍R0切除时,实施肝动脉切除重建至关重要[139140]

    肝动脉切除极限为拟保留侧二级分支,部分超出切除极限点的患者可考虑门静脉动脉化。肝动脉重建方式以显微镜下对端吻合为主;若动脉受累长度较长,直接吻合困难,可考虑采用自体血管重建。过程中应注意避免反复钳夹、牵拉损伤动脉壁,确保吻合口内膜对合好,无张力。吻合中持续肝素水冲洗,术后常规抗凝,以防血栓形成。当肝门部胆管癌患者无法行动脉切除重建时,不建议行根治性手术。

    推荐意见14:对于拟保留侧门静脉受累的肝门部胆管癌患者,推荐行门静脉切除重建(证据等级2,强推荐)。对于拟保留侧肝动脉受累的肝门部胆管癌患者,可考虑行肝动脉切除重建(证据等级2,弱推荐)。

    肝门部胆管癌根治术中,肝管残端数由切除方式和切离位点决定,常需吻合多支细小薄壁胆管,此类胆管空肠吻合技术要求高。胆管空肠吻合的基本原则是胆管空肠全周黏膜对黏膜吻合,确保黏膜上皮连续完整。吻合口应无张力,保证充分血供,选择可吸收缝线。缝合方式依显露情况、胆管直径及术者经验选择。

    胆管缝合后放置支撑管旨在预防胆漏和吻合口狭窄。当吻合口组织状况不佳、吻合不确定或存在张力不均时,建议放置支撑管。

    推荐意见15:肝门部胆管高位缝合需根据胆管断面情况选择合适方法,首选胆管空肠黏膜对黏膜缝合(证据等级2,强推荐)。在胆管断端血供良好、瘢痕组织清除彻底且吻合满意的情况下,通常无需放置支撑管。若吻合口组织不健康、吻合不确切或存在张力不均,则建议放置支撑管(证据等级2,弱推荐)。

    针对晚期、广泛侵犯的肝门部胆管癌,肝胰十二指肠切除术是实现R0切除、延长生存期的重要方法,优于姑息治疗,但术后并发症风险增加[141142]

    肝胰十二指肠切除术手术适应证主要包括:肝门部肿瘤侵犯胰腺段胆管、远端胆管癌侵犯肝门部、结节性肿瘤伴胰腺周围淋巴结转移,以及肝门部和胰腺段胆管存在广泛肝外胆管受累[143144]

    随着门静脉栓塞术与术前支持治疗的进步,肝胰十二指肠切除术得以实施,但手术风险与预后平衡仍是研究焦点。手术关键操作包括切除肿瘤上缘、清扫肝十二指肠韧带及周围淋巴结、肝门部血管骨骼化、切除远端受侵胆管与胰头十二指肠(注意清扫胰头后方、肝总动脉、腹腔干根部和(或)腹主动脉周围淋巴结),并重建消化道(常规行胰肠吻合术和胆管空肠吻合术)。血管切除仅在血管粘连严重、无法钝性分离时考虑。为降低术后并发症与死亡率,需严格谨慎筛选病例并优化手术流程。

    推荐意见16:部分肝门部胆管癌浸润范围广,可沿肝门区胆管侵犯至远端胆管,可行肝胰十二指肠切除术实现R0切除。肝胰十二指肠切除术的手术复杂且并发症风险较高,手术的决策需要综合考虑患者的具体情况、手术风险和潜在生存受益(证据等级3,弱推荐)。

    腹腔镜下肝门部胆管癌根治术可放大肝门部相对狭小的操作空间,更加近距离、立体显示肝门的解剖结构,同时对腹腔内环境刺激相对较小,术后腹腔内粘连少,创伤小,恢复快,住院时间短。多项研究证实了该技术在特定患者群体中的安全性,但腹腔镜手术并未体现出比传统开腹手术更为显著的长期生存价值[145148]

    相对于开腹手术,腹腔镜肝门部胆管癌根治术对患者选择更为严格,术前应仔细评估:(1)胆管受累程度包括胆管受累长度、范围及浸润深度。(2)血管侵犯评估:明确血管是否受侵犯及侵犯部位、范围。(3)淋巴结转移评估:同开腹手术,必要时行PET/CT检查。应严格把握手术适应证和禁忌证,其适应证包括Bismuth Ⅰ型、Ⅱ型以及部分Ⅲ型和Ⅳ型(无门静脉及肝动脉侵犯)肝门部胆管癌。禁忌证除开腹肝门部胆管癌根治性切除术的所有禁忌证外,还包括不能耐受或无法建立气腹;腹腔广泛粘连难以分离显露病灶;肿瘤侵犯门静脉或肝动脉;腹腔镜下暴露困难或肝门存在区域性门静脉高压等无法安全行肿瘤根治性切除患者[149]

    当出现难以控制的大出血、患者无法耐受气腹、病灶显露或切除困难、血管主干或拟保留侧肝脏血管受肿瘤侵犯(肿瘤侵犯肝门部血管,由于累及位置较高,腹腔镜下重建难度大,吻合质量不确定,一旦术中发现拟保留侧门静脉或肝动脉被侵犯或主干受侵犯,建议中转开腹手术行相应处理),胆管断端多且腹腔镜下整形及胆肠吻合困难或效果不满意,以及术者无法在腹腔镜下继续操作时,应及时中转开腹手术以确保手术安全与效果[150]

    机器人辅助手术在技术上比传统腹腔镜方法更灵活和稳定,在淋巴结清扫、细小胆管整形及胆肠吻合、血管吻合及重建方面表现优越[151154]。但机器人辅助手术同样存在许多障碍,包括技术门槛高、打孔位置对术野及操作影响明显、配套器械有限、缺乏力反馈、成本高昂。

    目前,机器人肝门部胆管癌手术的数据主要集中在Bismuth Ⅰ型、Ⅱ型、Ⅲb型患者。Ⅲa型和Ⅳ型胆管癌由于需要施行包括右半肝、肝尾状叶甚至更广泛区域的肝切除手术,手术难度和风险显著增加,术后并发症发生率也相对较高。因此,这类复杂手术目前仅由少数具备丰富机器人手术经验的医疗中心开展并报道。尽管多家医学中心对机器人辅助手术的短期治疗效果给予肯定,但对于复杂病例(尤其是Bismuth Ⅲ型、Ⅳ型)的长期临床效果,仍需要通过广泛的多中心、大样本研究进一步巩固和验证。

    推荐意见17:腹腔镜肝门部胆管癌根治术和机器人辅助肝门部胆管癌根治术在技术上安全、可行,但要求术者拥有丰富的开腹肝门部胆管癌根治手术经验和娴熟的腹腔镜或机器人操作技巧,远期疗效尚待更多大宗病例RCT进一步验证(证据等级4,弱推荐)。

    肝移植能彻底切除整个病肝,确保胆管的最佳切缘,其治疗肝门部胆管癌的优势包括:实现常规手术难以完成的根治性切除;适用于合并肝病、肝功能差及肝切除耐受性差患者;降低术中肿瘤播散风险。

    关于肝门部胆管癌肝移植的患者选择标准,NCCN指南给出了明确标准:肿瘤长径<3 cm、无淋巴结转移、无肝内和肝外转移。梅奥诊所的标准更加具体,包括影像学发现的恶性狭窄经病理学确认为肝门部胆管癌,或CA19‑9>100 ng/mL,以及肿瘤长径<3 cm,EUS‑FNA活检确认区域淋巴结阴性,无远处转移[155158]

    移植前新辅助治疗,旨在缩小肿瘤、降低转移风险,延长生存期。当前多采用梅奥诊所方案,包括3周的外放射治疗同时进行5‑氟尿嘧啶持续性静脉注射化疗,序贯2周的经导管近距离放射,序贯口服卡培他滨直至肝移植。移植前需行腹腔镜探查分期,确保无淋巴结和远处转移[159161]

    针对严格筛选的肝门部胆管癌患者,采用新辅助放化疗结合肝移植治疗策略,其5年生存率可>60%,且多项回顾性研究结果显示:其肿瘤学效果优于根治性肝切除术[162]。1项涉及304例患者的荟萃分析结果显示:符合肝移植标准的患者中,选择肝移植治疗相较于根治性肝切除术,前者5年生存率显著提升[163]

    推荐意见18:对于确诊的肝门部胆管癌,若肿瘤长径<3 cm、无淋巴结转移、无肝内和肝外转移,可考虑行肝移植治疗(证据等级2,弱推荐)。不可切除的局部进展期肝门部胆管癌,可考虑在新辅助放化疗后行肝移植。新辅助治疗方案应包括化疗与放疗的联合应用(证据等级2,弱推荐)。

    有关肝门部胆管癌的新辅助治疗临床研究较少,韩国1项关于局部进展期肝门部胆管癌的临床研究结果显示[164]:术前接受新辅助同步放化疗并未显著延长局部进展期肝门部胆管癌患者的无病生存期和总生存期,但可使肿瘤降期并提高肿瘤的R0切除率。2022年日本横滨大学的1项关于边界可切除肝门部胆管癌的临床研究结果显示:吉西他滨和替吉奥的新辅助治疗方案的疾病控制率可达91.3%,R0切除率达81%,并认为新辅助化疗对边界可切除肝门部胆管癌患者具有显著疗效和良好的耐受性[165]。Kuriyama等[166]报道吉西他滨联合替吉奥的新辅助方案治疗肝门部胆管癌的研究。该研究中将无远处转移的肝门部胆管癌分为可切除、边界可切除、局部进展期3组,3组切除率分别为89.7%、73.9%、30.0%。新辅助治疗可能会提高手术切除率,更可能实现肿瘤的R0切除,但仍需RCT证明新辅助治疗是否能改善患者的总生存期和无进展生存期。

    推荐意见19:没有证据表明新辅助治疗适用于可切除或临界可切除和局部晚期肝门部胆管癌患者;但是,新辅助治疗可能会提高手术切除率。因此,有必要进行RCT进一步验证新辅助治疗能否改善患者的总生存期和无进展生存期(证据等级2,弱推荐)。

    在ABC‑02试验中,吉西他滨与顺铂联合疗法相较于单独使用吉西他滨,前者可显著提高患者的中位总生存期和无进展生存期[167]。TOPAZ‑1试验结果显示:度伐利尤单克隆抗体(以下简称单抗)联合吉西他滨和顺铂联合疗法能显著改善总生存期和无进展生存期[168]。KEYNOTE‑966试验中,帕博利珠单抗联合吉西他滨和顺铂展现出生存期优势[169]。FUGA‑BT/JCOG1113研究结果显示:吉西他滨联合替吉奥的疗效与吉西他滨联合顺铂相当,且在无进展生存期方面表现出优势。两种疗法的耐受性均良好[170]。卡培他滨联合奥沙利铂疗法的中位无进展生存期为5.8个月,与吉西他滨联合奥沙利铂相当[171]

    KHBO1401‑MITSUBA试验结果显示:对于胆道肿瘤患者,行吉西他滨+顺铂+替吉奥三药联合疗法相较于吉西他滨联合顺铂,能显著提高中位总生存期和中位无进展生存期,且不良事件发生率无显著差异[172]。1项系统评价研究结果显示:对于晚期胆管癌患者,奥沙利铂联合吉西他滨与顺铂联合吉西他滨的治疗效果相近,加权生存期中位数分别为9.5个月和9.7个月[173]。1项单臂研究对晚期胆管癌患者使用白蛋白紫杉醇联合吉西他滨治疗,研究结果显示:该疗法具有可接受的安全性,虽然未达到主要疗效终点,但其总生存期和无进展生存期与吉西他滨联合顺铂和吉西他滨联合奥沙利铂治疗方案的结果相当[174]

    推荐意见20:晚期肝门部胆管癌推荐5个标准治疗方案,分别是度伐利尤单抗+吉西他滨联合顺铂、帕博利珠单抗+吉西他滨联合顺铂、吉西他滨联合顺铂、吉西他滨联合替吉奥以及卡培他滨联合奥沙利铂(证据等级2,强推荐)。对于体能状况良好的患者,可以考虑吉西他滨+顺铂+替吉奥三药联合化疗。此外还可以考虑吉西他滨或5‑氟尿嘧啶为基础的其他两药联合化疗方案。

    Ⅲ期ABC‑06试验中纳入吉西他滨联合顺铂治疗后进展的胆道肿瘤患者,其中FOLFOX组(亚叶酸钙+5‑氟尿嘧啶+奥沙利铂)的中位总生存期为6.2个月,而仅积极控制症状组为5.3个月[175]。Ⅱb期NIFTY试验中二线治疗使用脂质体伊立替康+氟尿嘧啶+亚叶酸钙组的中位无进展生存期为7.1个月,明显长于氟尿嘧啶+亚叶酸组的1.4个月,但接受脂质体伊立替康+氟尿嘧啶+亚叶酸钙患者严重不良事件发生率更高[176]。伊立替康联合卡培他滨方案(XELIRI)[177]、氟尿嘧啶联合伊立替康方案(FOLFIRI)[178],纳入肝门部胆管癌患者人数过少,需要更大规模的临床试验数据验证。

    晚期胆道癌诊疗已进入精准治疗时代,HER2突变在肝外胆管癌患者中突变率为4%~20%,目前主要有帕妥珠单抗联合曲妥珠单抗[179]、德曲妥珠单抗[180]、泽尼达妥单抗[181]等方案,均在早期临床试验阶段。针对NTRK融合突变的患者,主要有恩曲替尼[182]和拉罗替尼[183];针对RET融合突变的患者,主要有普拉替尼[184]和塞普替尼[185];针对KRAS G12C的主要靶向药物是阿达格拉西布[186]。上述基因在肝门部胆管癌患者中突变率均约1%,其临床研究均为不分瘤种的早期试验,均为后线治疗,但由于临床数据获益良好,也可用于肝门部胆管癌治疗。

    IDH1突变[187]、FGFR2突变[188]以及BRAF V600E突变[189]在肝门部胆管癌中基因突变频率极低,但相关临床试验显示这些突变的靶向药物在具有突变基因的患者中获益明显。

    免疫治疗方面,贝莫苏拜单抗联合安罗替尼[190]、阿替利珠单抗联合考比替尼[191]、瑞戈非尼联合阿维鲁单抗[192]、度伐利尤单抗联合曲美木单抗、纳武利尤单抗、帕博利珠单抗[193]、多塔利单抗[194]等免疫治疗方案均在早期临床试验阶段,需要更多生物标志物的探索选取合适患者。目前研究结果显示:高微卫星不稳定/错配修复缺陷是使用帕博利珠单抗[193]、多塔利单抗[194]的生物标志物,高肿瘤突变负荷也是使用帕博利珠单抗的生物标志物[193]

    推荐意见21:FOLFOX+积极症状控制为晚期肝门部胆管癌患者的二线标准治疗方案。其他可供选择的化疗方案和靶向治疗可根据患者既往治疗经过以及全身情况、营养状况、肝脏功能和肿瘤突变位点选用(证据等级3,弱推荐)。免疫治疗在晚期胆道癌二线治疗中缺乏高质量的循证医学证据,推荐患者参与相关临床试验(证据等级2,强推荐)。

    Ⅲ期BILCAP试验探索了卡培他滨组的术后辅助治疗价值,在意向治疗人群中,卡培他滨组的中位总生存期为49.6个月,而观察组的中位总生存期为36.1个月[195]。卡培他滨组的中位无复发生存期为24.3个月,而观察组的中位无复发生存期为17.4个月[195]。仅在卡培他滨组中测量了不良事件,其中最常见的是手足综合征、腹泻、疲劳[195]。Ⅲ期JCOG1202/ASCOT试验中,观察组的5年总生存率为52.2%,而替吉奥组的5年总生存率为64.1%;观察组的5年无复发生存率为45.9%,而替吉奥组为53.6%[196]

    推荐意见22:对于接受手术切除的肝门部胆管癌患者,建议进行为期6个月的氟嘧啶类药物辅助治疗(卡培他滨或替吉奥)。有必要开展以肝门部胆管癌患者,特别是高复发风险的肝门部胆管癌患者为研究对象的辅助治疗临床试验(证据等级2,强推荐)。

    放射治疗在肝门部胆管癌中的应用体现在:(1)对于无法手术或转移性肝门部胆管癌,放射治疗或放化疗联合治疗是潜在有效的治疗方法。(2)放疗在术后辅助治疗中具有价值,对于R1/R2切除或者存在淋巴结转移的肝门部胆管癌患者,术后辅助放化疗可以得到与R0切除相似的长期生存数据。

    1项Ⅱ期临床研究(SWOG S0809)结果显示:对于切除术后高复发风险患者行吉西他滨联合卡培他滨的辅助化疗,以及卡培他滨为基础的同步放化疗可以改善预后[197]。1项荟萃分析结果显示:对于术后存在阳性切缘或淋巴结阳性患者,术后辅助放疗组的5年总生存率高于无放疗组[198]。同时术后辅助放疗也可改善切缘阴性患者的5年生存率,术后辅助放疗组的局部复发率显著低于无放疗组,但两组之间的远处转移率无显著差异。肝门部胆管癌的放疗剂量应在周围小肠或十二指肠最大耐受剂量接受范围内[198]

    推荐意见23:对于术后存在阳性切缘(R1/R2)或淋巴结阳性患者,术后辅助放疗可以降低患者术后复发率以及改善患者总生存期,推荐放疗区域为原发肿瘤瘤床,肝脏切缘,吻合口以及区域淋巴结;需要严格考量放疗剂量与正常组织耐受性(证据等级4,弱推荐)。

    肝门部胆管癌姑息性治疗的核心在于胆道引流通畅,主要手段包括PTBD/经皮经肝穿刺胆道支架置入术、ENBD、ERBD及胆道手术引流。与非手术性引流比较,手术引流在疗效上无优势,且伴随胆瘘、感染、出血风险[199]。在姑息性胆道引流支架选择方面,有研究证实金属支架在改善患者肝功能、支架通畅时间及支架置入成功率等方面优于塑料支架,且金属支架并发症发生率低于塑料支架[200]

    针对肿瘤的介入治疗手段包括经动脉内治疗、胆管腔内RFA、光动力治疗等。经动脉内治疗包括TACE、肝动脉灌注化疗术和经动脉放射栓塞术。由于肝门部胆管癌乏血供及浸润性生长特点,血管造影肿瘤供血动脉多不明确,故推荐肝动脉灌注化疗术。多项研究结果显示:肝动脉灌注化疗术联合系统治疗可提高远期疗效,高胆红素血症患者在充分胆道引流后也可考虑行肝动脉灌注化疗术[201202]

    胆管腔内RFA能缓解胆道恶性狭窄,但安全性和远期疗效需更多研究验证。光动力治疗结合支架置入提高了患者的1年和2年生存率,且未增加胆管炎及其他治疗相关不良事件的发生率[203]

    推荐意见24:单纯姑息性胆道引流可选胆道支架置入或经皮胆道引流(证据等级3,强推荐);对于胆管癌姑息性治疗,可依据患者身体状况和意愿行肝动脉灌注化疗术联合系统治疗、光动力治疗或胆管腔内RFA(证据等级4,弱推荐)。

    肝门部胆管癌手术后复发的主要决定因素是切缘状态和淋巴结转移[204]。R1、R2切除和淋巴结阳性与早期复发和不良生存结局相关。肝门部胆管癌手术切除后的5年总生存率为20%~42%[205208]

    已证实的与预后密切相关的独立风险因素包括术前胆红素水平、术前CA19‑9水平、肿瘤大小、血管侵犯、T分期、淋巴结转移、病理学分级、切缘状态[207]

    因此,肝门部胆管癌术后患者需要密切监测。随访内容应包括血常规、肝功能检查、肿瘤标志物的评估以及相关的个体化检查,术后第1年每3个月进行1次影像学检查,之后每6个月进行1次,直至5年。影像学检查应包括每次就诊时的超声检查,以及每3个月进行1次的增强CT检查,或根据临床相关检查结果选择合适的检查手段(MRI、PET/CT或组织病理学检查)。这些患者应参加MDT会诊,讨论术后辅助治疗以获得更好预后[208210]

    推荐意见25:肝门部胆管癌患者术后第1年每3个月进行1次影像学检查(增强CT检查,或根据具体情况采用MRI、PET/CT、组织病理学等检查方法),之后每6个月进行1次复查,至术后第5年(证据等级2,弱推荐)。

    图  附图1  肝门部胆管癌的诊疗流程
    注:MDCT为多排螺旋CT;MRI为磁共振成像;MRCP为磁共振胰胆管成像;ERCP为经内镜逆行胆胰管成像;PTC为经皮穿刺肝胆道成像;PET/CT为正电子发射计算机体层显像仪;MDT为多学科诊疗
    《肝门部胆管癌诊断和治疗指南(2025版)》编审委员会名单

    主任委员:

    董家鸿 清华大学临床医学院 清华大学精准医学

    研究院

    组长

    李相成 南京医科大学第一附属医院

    项灿宏 清华大学附属北京清华长庚医院

    陈 敏 陆军军医大学第一附属医院

    《中华消化外科杂志》编辑委员会

    委员(按姓氏汉语拼音排序):

    陈亚进 中山大学孙逸仙纪念医院

    陈拥军 上海交通大学医学院附属瑞金医院

    陈勇军 华中科技大学同济医学院附属同济医院

    陈志宇 陆军军医大学第一附属医院

    程南生 四川大学华西医院

    崔云甫 哈尔滨医科大学附属第二医院

    戴朝六 中国医科大学附属盛京医院

    樊海宁 青海大学附属医院

    方驰华 南方医科大学珠江医院

    高 杰 北京大学人民医院

    耿小平 安徽医科大学第一附属医院

    耿智敏 西安交通大学第一附属医院

    龚 伟 上海交通大学医学院附属新华医院

    郭 伟 首都医科大学附属北京友谊医院

    洪德飞 浙江大学附属邵逸夫医院

    黄永辉 清华大学附属北京清华长庚医院

    金 烁 清华大学附属北京清华长庚医院

    清华大学临床医学院

    李德宇 河南省人民医院

    李富宇 四川大学华西医院

    李敬东 川北医学院附属医院

    李 强 天津医科大学肿瘤医院

    李 汛 兰州大学第一医院

    梁力建 中山大学附属第一医院

    梁廷波 浙江大学医学院附属第一医院

    刘 昌 西安交通大学第二附属医院

    刘 超 中山大学孙逸仙纪念医院

    刘付宝 安徽医科大学第一附属医院

    刘厚宝 复旦大学附属中山医院

    刘连新 中国科学技术大学附属第一医院

    刘青光 西安交通大学第一附属医院

    刘颖斌 上海交通大学医学院附属仁济医院

    卢绮萍 中国人民解放军中部战区总医院

    吕国悦 吉林大学第一医院

    秦 磊 苏州大学附属第一医院

    仇毓东 南京大学医学院附属鼓楼医院

    全志伟 上海交通大学医学院附属新华医院

    沈 锋 海军军医大学第三附属医院

    邰 升 哈尔滨医科大学附属肿瘤医院

    谭 广 大连医科大学附属第一医院

    王广义 吉林大学第一医院

    王宏光 中国医学科学院肿瘤医院

    王 坚 上海市第六人民医院

    王剑明 华中科技大学同济医学院附属同济医院

    王 琳 空军军医大学西京医院

    王 鲁 复旦大学附属肿瘤医院

    王秋生 北京大学人民医院

    吴 泓 四川大学华西医院

    夏 锋 陆军军医大学第一附属医院

    杨 剑 南方医科大学珠江医院

    杨尹默 北京大学第一医院

    尹洪芳 清华大学附属北京清华长庚医院

    袁玉峰 武汉大学中南医院

    曾永毅 福建医科大学孟超肝胆医院

    曾 勇 四川大学华西医院

    张雷达 陆军军医大学第一附属医院

    张雅敏 天津市第一中心医院

    张永杰 海军军医大学第三附属医院

    张宗明 国家电网公司北京电力医院

    郑树国 陆军军医大学第一附属医院

    郑卓肇 清华大学附属北京清华长庚医院

    清华大学临床医学院

    周 杰 南方医科大学南方医院

    邹英华 北京大学第一医院

    左 石 贵州医科大学附属医院

    执笔

    李相成 南京医科大学第一附属医院

    项灿宏 清华大学附属北京清华长庚医院

    赵 蕾 陆军军医大学第一附属医院

    《中华消化外科杂志》编辑委员会

    白志清 清华大学附属北京清华长庚医院

    清华大学临床医学院

    张耀东 南京医科大学第一附属医院

    所有作者声明不存在利益冲突
    中国研究型医院学会肝胆胰外科专业委员会, 《中华消化外科杂志》编辑委员会. 肝门部胆管癌诊断和治疗指南2025版)[J]. 中华消化外科杂志, 2025, 24(1: 1-20. DOI: 10.3760/cma.j.cn115610-20250106-00010.
    http://journal.yiigle.com/LinkIn.do?linkin_type=cma&DOI=10.3760/cma.j.cn115610-20250106-25010
  • 图  附图1   肝门部胆管癌的诊疗流程

    注:MDCT为多排螺旋CT;MRI为磁共振成像;MRCP为磁共振胰胆管成像;ERCP为经内镜逆行胆胰管成像;PTC为经皮穿刺肝胆道成像;PET/CT为正电子发射计算机体层显像仪;MDT为多学科诊疗

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  • 收稿日期:  2025-01-05
  • 刊出日期:  2025-01-19

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