远端胆管癌规范化诊治专家共识(2017)
中华肝胆外科杂志, 2018,24(1) : 1-8. DOI: 10.3760/cma.j.issn.1007-8118.2018.01.001

远端胆管癌是指位于围肝门区域之外的肝外胆管癌,即原发肿瘤起源于胆总管中下段的胆管恶性肿瘤。受限于流行病学调查及癌症登记等工作,目前远端胆管癌形成的发病原因及其确切的发病率等方面尚未完全清晰。由于解剖部位的原因,远端胆管癌的外科治疗方案及辅助治疗方案,临床多采用与胰头癌、壶腹癌等疾病相类似的治疗方案。但越来越多的研究发现,远端胆管癌与上述疾病存在诸多差异,其诊疗方案亦与之有所区别[1]。限于目前针对远端胆管癌开展的多中心研究、随机对照研究数量有限,远端胆管癌的治疗方案尚缺乏充分的高级别循证医学证据支持[2]。中国抗癌协会胆道肿瘤专业委员会专家组对远端胆管癌规范化诊疗方案达成此共识意见,以期聚焦争议、理清模糊问题、推动国内远端胆管癌临床规范化诊疗和相关研究工作的发展和不断进步。

一、定义及流行病学危险因素

远端胆管癌可定义为胆囊管汇入胆总管以远的肝外胆管癌。

1.已确定的危险因素

·胆管腺瘤

·胆管囊腺瘤

·胆管乳头状瘤病

·胆管上皮内瘤变

·胆管-胰管汇合异常

·胆管囊肿/残余胆管囊肿

·原发性硬化性胆管炎(PSC)

2.可能的危险因素

·细菌、病毒等病原体感染

·胆管结石

·环境或职业毒素暴露

·IgG4型胆管炎[3]

二、病理分型
1.大体类型:

包括硬化型、结节型、息肉型、弥漫浸润型[4]

·硬化型(缩窄型):胆管壁环形增厚、管腔狭窄,常伴管周组织的弥漫性浸润和纤维化。易于侵犯胆管壁周围组织。

·结节型:坚硬不规则瘤结节突入胆管腔,与硬化型特征可伴随出现,易于侵犯胆管壁周围组织。

·息肉型(乳头型):质软而易碎的息肉样组织占据胆管腔。

·弥漫浸润型,多沿胆管壁直线扩散。

2.显微镜下类型

·胆管腺癌:为主要组织学类型,中分化多见[4]

·其他组织学类型:其他类型少见,包括:肠型透明细胞腺癌、黏液癌、鳞状细胞癌、腺鳞癌、小细胞未分化癌、乳头状癌、浸润性癌等[4]

三、诊断
1.临床症状

·早期多无明显临床症状。

·进展期出现梗阻性黄疸、上腹胀痛不适、消化不良、胆管炎等症状。

2.实验室诊断(ⅡA推荐)

·肝功能异常:包括TBil、DBil、ALT、AST、AKP、GGT、TBA等。

·推荐肿瘤标志物CA19-9,联合CEA和CA125等多项肿瘤标志物,可提高其鉴别诊断率[5]及对动态监测肿瘤进展具有意义[6]

·出现梗阻性黄疸症状时,肿瘤标志物CA19-9诊断特异性低。胆道引流减黄后CA19-9仍维持高值,提示胆管癌可能性大。

3.影像学诊断
(1)超声(Ⅰ类推荐)

·无法对肿瘤作出有效的定性诊断。

·仅仅当合并胆道梗阻时提示肝内外胆管全程扩张、胆囊充盈增大,对判断胆道梗阻位置具有定位价值。

(2)CT(Ⅰ类推荐)[7,8]

·增强扫描,肿瘤部位胆管壁强化或占位病灶表现。

·可以提供如肿瘤位置与大小、胆管梗阻水平与范围、血管侵犯及区域淋巴结转移及远处器官转移等的信息。

·在评价肝动脉、门静脉、肠系膜上静脉、胰腺组织、十二指肠等胆管周围组织受侵方面具有较高价值。

·纵轴面成像可了解胆管腔内肿瘤侵犯长度和深度。

(3)MRI(Ⅰ类推荐)[7,8]

·MRCP对了解胆道系统具有独特的诊断价值,在胆道成像上可以替代PTC或ERC,并能显示梗阻且分离的胆管。

·MRCP在评价浸润型胆管癌纵向生长程度方面具有独特的价值。

·MRI成像结合MRI血管成像技术对于肿瘤血管侵犯的判断可以取得与血管造影相似的效果。

(4)PTC/ERCP(ⅡA类推荐)

·有创性检查手段。

·对合并梗阻性黄疸患者,可同时进行胆道引流减黄。

·ERCP引导下能够进行胆管腔内超声检查或组织活检,具有诊断价值[9]

·对于硬化性胆管炎、缩窄型胆管炎与胆管癌的鉴别,尽管ERCP胆道黏膜上皮细胞刷检检出率有限,但细胞学检查的病理诊断仍有巨大价值。

(5)超声内镜(Ⅰ类推荐)

·超声内镜对鉴别诊断远端胆管癌与胰头癌、壶腹癌的价值大;对明确肿瘤是否合并胆道结石、胆管囊状扩张等具有诊断价值[10,11]

·超声内镜引导下组织穿刺活检,具有重要的诊断价值,对明确诊断并确定实施创伤巨大的胰十二指肠切除术治疗方案意义重大。对区域内的肿大淋巴结,超声内镜具有影像学诊断价值,并具有引导定位进行细针穿刺、病理活检的技术优势[12]

·多普勒超声有助于评价门静脉等周围血管是否受肿瘤侵犯[12,13]

(6)PET-CT(ⅡA类推荐)[8]

·由于胆管癌的生物学特性及病理特点,正常大小的淋巴结可能已有转移,而增大的淋巴结可能是炎性增生,故PET-CT对于诊断肿瘤淋巴结转移或远隔器官转移具有价值。

·不建议常规应用于早、中期肿瘤的检查。

(7)腹腔镜探查(Ⅲ类推荐)

·鉴于无创影像学技术在远端胆管癌中的诊断价值明确,腹腔镜探查作为有创性诊断手段,不建议术前诊断时采用。

(8)病理诊断(Ⅰ类推荐)

·是目前最有价值的临床确诊手段。

·细胞学及组织活检对术前诊断价值巨大[14]

·荧光原位杂交(FISH)技术,可能在辅助细胞学诊断方面具有探索价值[14,15,16,17]

4.术前特殊准备

PTBD/ERCP胆道引流(ⅡA类推荐)。

·目前对恶性胆道梗阻术前是否需要常规胆道引流减黄存在争议[18,19,20]。鉴于胰十二指肠切除术手术范围较广泛、需进行彻底的区域淋巴结清扫术,对合并严重的黄疸患者或黄疸持续时间较久或高龄、全身一般情况差的患者,术前引流减黄能够有效改善腹腔内组织水肿、减少术中创面广泛渗血的风险,提高手术安全性、降低手术难度,对术前胆道引流的价值应予以肯定。

·对诊断明确并具有手术指征的患者,ERCP造影及胆道引流有可能引起胆管炎、肝十二指肠韧带炎症水肿明显,增加了术中实施区域淋巴结清扫的难度。经皮肝穿刺胆管引流术(PTBD)能迅速、有效地引流减黄并规避上述不利于根治性手术的干扰因素,但对于PTBD是否增加肿瘤细胞转移风险的争议,尚缺乏循证医学证据予以明确。应当根据所在中心条件选择,并进行多学科团队(MDT)讨论,共同制定胆道引流的策略和方式,并遵循胆道引流的共同原则[21,22]

·PTBD或ENBD胆道外引流者,当胆汁引流量较多时,建议将引流胆汁过滤后经鼻肠管或经口回输,恢复胆盐的肠肝循环、维护患者小肠黏膜的屏障功能,促进其肝功能及营养状况改善。

四、肿瘤组织病理分期

推荐美国癌症联合委员会(AJCC)和国际抗癌联盟(UICC)联合制定的肿瘤TNM分期标准(AJCC/UICC TNM分期,第8版[23],Ⅰ类推荐)。基于病理组织学的标准、术后评价局部和远处转移的情况,对远端胆管癌进行分期。分期对肿瘤预后具有指导意义。

(1)肿瘤分期(T分期)

·TX:原发肿瘤无法评估。

·T0:无原发肿瘤证据。

·Tis:原位癌。

·T1:肿瘤侵犯至胆管壁内,深度少于5 mm。

·T2:肿瘤侵犯至胆管壁内,深度为5~12 mm。

·T3:肿瘤侵犯至胆管壁内,深度超过12 mm。

·T4:肿瘤侵犯腹腔干、肠系膜上动脉,和/或肝总动脉。

(2)淋巴分期(N分期)

基于存在或无区域淋巴结转移。区域淋巴结包括:肝十二指肠韧带(12a、b、p、c、h组)、肝总动脉周围(8a、p组)、胰头部周围(13a、b组;17a、b组)、肠系膜上动脉根部周围淋巴结(14p、d)。

·NX:区域淋巴结无法评估。

·N1:1~3个区域淋巴结转移。

·N2:4个或以上区域淋巴结转移。

(3)远隔转移(M分期)

·M0:无远隔器官或部位转移。

·M1:远隔器官或部位转移。

(4)远端胆管癌TNM分期(AJCC/UICC第8版,Ⅰ类推荐)见表1

点击查看表格
表1

美国癌症联合会(AJCC)/国际抗癌联盟(UICC)远端胆管癌TNM分期(第8版)[23]

表1

美国癌症联合会(AJCC)/国际抗癌联盟(UICC)远端胆管癌TNM分期(第8版)[23]

分期 肿瘤分期 淋巴分期 远处转移
0期 Tis N0 M0
Ⅰ期 T1 N0 M0
ⅡA期 T1 N1 M0
  T2 N0 M0
ⅡB期 T2 N1 M0
  T3 N0-1 M0
ⅢA期 T1-3 N2 M0
ⅢB期 T4 N0-2 M0
Ⅳ期 T1-4 N0-2 M1

(5)pTNM病理分期:pTNM病理分期是世界卫生组织(WHO)制定的肿瘤分期标准。

·pT分期:原发肿瘤,与T分期对应。

pTX,原发肿瘤在组织学上无法评估;

pT0,无原发肿瘤的组织学证据;

pTis,原位癌:

pT1-4,组织学上原发肿瘤大小和(或)范围增加。

·pN分期与N分期对应:N0-1。

pNX,区域淋巴结转移无法评估;

pN0,区域淋巴结阴性(组织学检查要求,包括至少12个淋巴结)。如果淋巴结检查阴性,但检查的淋巴结数目没有达到要求,仍可归类为pN0分期;

pN1,区域淋巴结切除标本阳性。

·pM分期:

pM0和pMX,并不是有效分期;

pM1,镜下证实有远处转移。

五、治疗
1.手术治疗

·是目前治疗远端胆管癌最为积极、有效的手段,可彻底清除癌组织,为患者提供了唯一可能治愈和长期生存的机会[24,25,26]

·强调实施尽可能包括肝外胆管、胰头、十二指肠、血管等多切缘阴性的完整的肿瘤切除及彻底的区域淋巴结清扫术,并进行合理可靠的消化道重建[27]

·根治性手术切除范围应包括肝外胆管、胰头、远端胃大部、十二指肠、空肠上段及区域淋巴结的整块切除[28]

(1)根治性切除的原则(Ⅰ类推荐)

·术前评估为AJCC/UICC TNM ⅠA~ⅢA期的患者,均有实施肿瘤根治性切除方案的可行性。

·R0切除是远端胆管癌患者手术切除所追求的目标。建议胆管近端切缘和远端切缘(单纯肝外胆管切除时)术中行冰冻切片检查证实为阴性[29]

·门静脉/肠系膜上静脉受肿瘤侵犯可能是预后的不利因素[30,31,32],但不是手术的绝对禁忌证。当局部血管受侵犯范围局限,可联合行受侵的门静脉/肠系膜上静脉血管切除、重建[28,33,34]

·明确的转移淋巴结侵犯肠系膜上动脉,是手术的绝对禁忌证。

·组织学证实合并远处转移(腹腔、肝转移,肺、骨骼等远隔部位转移),或超出区域淋巴结(腹腔干、腹主动脉旁)等范围的淋巴结转移,是手术的禁忌证。

·对于胆管腺瘤癌变或胆管上皮内瘤变等胆管腔内生长的占位性肿瘤,或肿瘤位于胰腺段外胆管区域,可根据胆管肿瘤肿瘤生长范围及胆管上下切缘范围,个体化制定根治性手术方案。如癌变胆管壁下缘尚未延伸至胰腺段胆管,可行局段性肝外胆管切除、肝十二指肠韧带及胰头后上淋巴结清扫、胆肠吻合术,并应术中病理明确胆管上下切缘阴性及13a、b组、17a、b等区域淋巴结未发生转移。否则即应行胰十二指肠切除术[35,36]

(2)腹腔淋巴结清扫(Ⅰ类推荐)

·对远端胆管癌区域淋巴结的范围、淋巴结转移路径及清扫范围,尚需进行循证医学研究,以区别于胰头癌、十二指肠乳头癌、壶腹癌等其它壶腹周围恶性肿瘤淋巴转移路径,并相应制定更为精准、规范的远端胆管癌区域淋巴结清扫方案。

·由于对远端胆管癌淋巴结转移规律、路径尚未清晰,现阶段推荐根据日本胆道外科学会(JSBS)分期,将远端胆管癌的淋巴结转移分为区域淋巴结和非区域淋巴结[37]

·区域淋巴结包括:肝十二指肠韧带(12a、b、p、c、h组)、肝总动脉周围(8a、p组)、胰头部周围(13a、b组;17a、b组)、肠系膜上动脉根部周围的淋巴结(14p、d)。

·非区域淋巴结包括:腹主动脉旁(16a1,a2,b1,b2组)、腹腔动脉干旁(9组)、胰体尾部下缘除肠系膜上动脉根部周围以外的淋巴结(18组),以及其它远隔部位淋巴结。

·R0切除须同时进行规范的区域淋巴结骨骼化清扫术,以便为肿瘤分期提供准确的信息。

·如区域淋巴结未达到彻底的淋巴结清扫时,对清扫淋巴结数目作强制性规定的临床意义,尚待进一步的研究予以明确、支持[23,38,39,40,41]

·当已经确认区域淋巴结以外的淋巴结转移,扩大的淋巴清扫范围并不能改善预后,不建议常规实施。

(3)预后因素

淋巴转移是影响远端胆管癌预后的独立因素[1,24,25,35,36,38,42,43]。胆管旁神经侵犯[36,43,44]、血管侵犯[33]、胰头等周围组织侵犯[44,45,46]可能是影响远端胆管癌预后的危险因素。

(4)胰十二指肠切除术(Ⅰ类推荐)

·保留幽门的胰十二指肠切除术,能够达到足够的切除范围及区域淋巴结清扫,并能相应减少手术创伤范围。

·优先离断胃、十二指肠、胆管、血管及淋巴结清扫的多入路结合的手术操作路径,能够实施胰十二指肠区域的整块切除、受侵门静脉切除重建等,实现肿瘤非接触(No-Touch)切除,可能对规避术中肿瘤细胞的脱落转移、减少术后肿瘤复发具有价值。

2.肿瘤辅助治疗

对下述情况,肿瘤辅助治疗方案可能具有临床价值[47,48,49,50]

·根治性切除术后,为防范肿瘤复发。

·无法进行根治性手术的进展期肿瘤患者(AJCC/UICC Ⅲ期、Ⅳ期患者)。

·术后肿瘤复发的患者。

(1)化疗(ⅡA类推荐)

目前,胆道肿瘤化疗方案仍有待于更多的高级别循证医学证据支持,建议采用以下方案。

·吉西他滨+铂类方案[51,52,53,54,55]

·S1为基础的联合化疗方案[56,57,58,59,60]

·对于吉西他滨联合铂类药物化疗方案失败的患者,换用卡培他滨、5-氟尿嘧啶单药或联合5-氟尿嘧啶与伊立替康、奥沙利铂、顺铂的二线化疗方案,均未能在患者预后获益方面体现出更大的价值[61]

(2)癌基因靶向治疗(ⅡB推荐)

·截至2016年,已结束的多个胆道肿瘤癌基因靶向治疗临床药物试验,均尚未取得重大突破。

·部分临床前的基础研究,针对FEGR[62]、FGFR[63]、IDH[64]等胆管癌驱动基因的研究及靶向治疗,显示出对胆管癌可能成为有效治疗方案的效果[65,66,67,68,69]。随着精准医疗概念的提出及研究的深入,采用癌基因靶向治疗、免疫治疗等的肿瘤个体化治疗,可能会成为胆管癌患者治疗的重要手段[70,71]

(3)放疗(ⅡB推荐)

对无法行肿瘤根治性切除的进展期患者,及术后肝脏等实体脏器、腹腔淋巴结复发转移、肌肉及骨骼复发转移患者,结合化疗方案具有治疗价值[72,73,74]。单独实施或联合外照射放疗的胆管腔内内照射放疗,其治疗价值及安全性仍待更多的临床研究及高级别循证医学证据支持[75,76,77]

(4)介入治疗

·胆道内支架、解除梗阻性黄疸治疗,对预判生存期超过3个月的进展期患者,胆道置入金属内支架较塑料内支架对患者更为有利[78,79,80](ⅡA类推荐)。

·胆道腔内肿瘤光动力治疗或消融治疗,可以使胆管腔内肿瘤细胞坏死、脱落,已在肝门部胆管癌的临床研究中显现出治疗价值和较好的安全性[81,82,83,84,85,86]。但是,对于其在远端胆管癌的临床治疗价值和安全性,尚需更多高质量的临床研究结果支持(ⅡB推荐)。

·临床研究表明,腹腔转移灶热灌注化疗对控制肿瘤腹腔内广泛转移及恶性腹水具有一定效果[87,88,89],但其在胆管癌中治疗价值和安全性仍需高质量的临床研究结果支持(ⅡB推荐)。

本共识推荐的远端胆管癌诊疗流程见图1

点击查看大图
图1
远端胆管癌诊疗流程
图1
远端胆管癌诊疗流程

注:本专家共识中的诊断、治疗推荐标准,依照美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)对临床诊治指南的推荐级别分类方法:

Ⅰ类:基于高水平证据(如随机对照试验)提出的建议,专家组一致同意。

ⅡA类:基于包括临床经验在内的较低水平证据提出的建议,专家组达成共识。

ⅡB类:基于包括临床经验在内的较低水平证据提出的建议,专家组基本同意,无明显分歧。

Ⅲ类:基于任何水平证据提出的建议,专家组意见存在明显的分歧。

专家组成员

执笔:李 斌 邓侠兴 姜小清 彭承宏

专家组成员(依照姓氏拼音排序):

别 平 崔云甫 曹 宏 邓侠兴 顾万清 高 鹏 胡 冰 洪德飞 霍 枫 黄建钊 姜小清 江 艺 李 强 黎乐群 刘厚宝 刘景丰 刘颖斌 梁廷波 罗祥基 李升平 李 斌 彭承宏 仇毓东 王剑明 王顺祥 殷晓煜 尹 涛 易 滨 曾 勇 周家华 张学文 左朝晖

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