肝门部胆管癌治疗进展课件

1、Hilar Cholangiocarcinoma:Current Management 肝门胆管癌治疗进展目 录1定 义2病 因3病理分型4诊 断5治 疗 A Klatskin tumor (or hilar cholangiocarcinoma) is a cholangiocarcinoma occurring at the confluence of the right and left hepatic bile ducts 发生于肝总管或左、右肝管及其汇合处的恶性肿瘤Proliferation of malignant adenocarcinoma and fibroblast 组织学

2、特征是恶性腺癌细胞和周围的粗纤维细胞增生specific situation and infiltrated growth 发生部位特殊、呈浸润性生长 Low radical resection rate with high operation risk 根治性切除率低、手术风险大 A hard-to-treat disease 难以攻克的顽症之一Hilar Cholangiocarcinoma, Klatskin Tumor肝门胆管癌Etiology of Hilar Cholangiocarcinoma 肝门胆管癌的病因目前病因尚不清楚，与胆管慢性炎症、胆结石及胆汁淤积可能相关可能的病因：

3、PSC 原发性硬化性胆管炎Congenital biliary malformations 先天性胆道畸形，如多囊肝、胆总管囊肿、caloris病等Chronic ulcerative colitis 慢性溃疡性结肠炎Parasitic infections 化学致癌物，如麝猫后睾吸虫、华支睾吸虫等Chemical carcinogens 化学致癌物多囊肝溃疡性结肠炎PSC与胆道系统肿瘤263例原发性硬化性胆管炎，观察时间从19992009，胆管癌发生概率为14%Kristen MB等人发现，Mayo评分4，吸烟、酗酒、炎症性肠病病史患者更容易发生胆管癌Best Practice & Rese

4、arch Clinical Gastroenterology 2011Roles of Clonorchis Endemicus Infection as Risk Factor for CC华支睾吸虫是肝门胆管癌的易感因素John Z, et al. Journal of Hepato-Biliary-Pancreatic Sciences, 2014成虫卵沼螺、涵螺、豆螺（第一中间宿主）包囊终末宿主保虫宿主淡水鱼第二中间宿主尾蚴长约1025mmA history of eating raw freshwater fish and a positive serologic result fo

5、r C. sinensis were significantly associated with the development of CC食用淡水鱼史并且华支睾吸虫血清学试验阳性的患者，与肝门胆管癌的发生发展密切相关Freshwater Fish and Clonorchis Endemicus淡水鱼与华支睾吸虫淡水鱼是华支睾吸虫的第二中间宿主The Ways of Metastasis转移途径Roland. Z, Hepatology, 2012Hematogenous metastasis血行转移肝内血行转移发生最早，也最常见，可侵犯门静脉并形成瘤栓Lymphatic metastasi

6、s淋巴转移可局部转移到肝门，淋巴转移仅占转移总数的12.6%Contact metastasis接触转移一般较少发生邻近脏器的直接浸润，但偶尔也可直接蔓延、浸润至邻近组织器官，如膈、胃、结肠、网膜等Metastasis along nerve fibers 沿神经蔓延Hilar CholangiocarcinomaDiagnosis肝门胆管癌诊断方法 Hilar cholangio-carcinoma Clinical manifestation ：progressive painless jaundice进行性无痛性黄疸 Imaging： CT, MRCP, ERCP, B ultrason

7、ic, PET-CTTumor marker: CA199, CEApathology：ERCP brush cytology, biopsy 毛刷细胞学检查，活检Diagnosis-CTCT诊断Diagnosis-MRIMRI诊断MRCPDiagnosis-MRCPMRCP诊断The Role of Histological Diagnosis组织学诊断的作用Koea et al, world journal of surgery, 2004Buc et al, HPB, 2008ERCP brush cytology(毛刷细胞学检查):the first choiceForceps bio

8、psy and fine-needle aspiration is not mandatoryLow sensitivityRisk of metastasisResection remains the most reliable way to rule out biliary malignancyDistribution of Hilar Cholangiocarcinoma肝门胆管癌分布Murad Aljiffry, et al. World J Gastroenterol, 2009Hilar cholangiocarcinoma5%10%的胆管癌分布于肝内胆管60%70%的胆管癌位于胆

9、道系统的分叉处，即肝门胆管癌，是胆管癌的主要类型。20%30%的胆管癌位于肝外胆管Pathology of Hilar Cholangiocarcinoma病理分型Hayashi S, et al. Cancer, 1994sclerosing硬化型（70%）nodular结节型（20%）papillary乳头状（5%）Transmural invasion 横向浸润，侵犯胆管及周围组织Longitudinal extension 纵向浸润，粘膜和粘膜下的扩散 肿瘤可向上胆管上下侵犯Lymph node metastasis 淋巴结转移PathologySpreadmore favorable

10、 prognosis预后较好majority of cases主要类型名称分型或分期依据Bismuth-Corlette classification:the most common肿瘤解剖学部位Gazzaniga分期（加扎尼加分期、T分期法）肿瘤部位，门静脉是否侵犯及有无肝叶萎缩MSKCC改良T分期（Memorial Sloan-Kettering Cancer Genter） 肿瘤对肝动脉和门静脉的侵犯程度AJCC（pTNM）分期术后病理结果Claissification and Staging分型分期 Bismuth-Corlette 分型Henri Bismuth, Ann Surg,

11、 1992IIIaIIIbIV临床最常用，有助于计划手术方式，但肿瘤分级程度与肿瘤可切除性和术后生存期长短之间无相关性 ITumors below the confluence of the left and right hepatic duct 肿瘤位于胆总管上端IITumors reaching the confluence 肿瘤位于左右肝管分叉部IIIaTumors occluding the common hepatic duct and either the right duct肿瘤累及肝总管、汇合部和右肝管 IIIbTumors occluding the common hepat

12、ic duct and either the left duct 肿瘤累及肝总管、汇合部和左肝管IVTumors involving the confluence and boththe right and left hepatic ducts肿瘤累及肝总管、汇合部和同时累及左右肝管IIIIIIaIIIbIVBismuth-corlette classificationBismuth5种分型Gazzaniga分期（T分期法）T分期发展于Bismuth-Corlette 分期基础之上主要包括以下三个因素：1、肿瘤位置及胆管受累程度（参见Bismuth-Corlette 分期）2、有无门静脉侵犯3

13、、有无肝叶的萎缩T3: Tumors occluding the common hepatic duct or the secondary bile duct ,and involving the hepatic portal vein offside, or with the contra lateral liver atrophy, or involving the main hepatic portal vein肿瘤侵及肝管汇合部并且双侧都侵袭至二级胆管或肿瘤单侧侵袭至二级胆管同时合并对侧门静脉受累；或肿瘤单侧侵袭至二级胆管同时合并对侧肝叶萎缩；或肿瘤累及门静脉主干或者双侧门静脉均受累M

14、SKCC改良T分期Classification &CriteriaT1: Tumors occluding the common hepatic duct or the secondary bile duct肿瘤侵及肝管汇合部和（或）单侧侵袭至二级胆管T2: Tumors occluding the common hepatic duct or the secondary bile duct ,and involving the ipsilateral hepatic portal vein肿瘤侵及肝管汇合部和（或）单侧侵袭至二级胆管, 同时合并同侧门静脉受累和（或）同侧肝叶萎缩MSKCC i

15、s used for assessing the resectability of liver carcinoma.Jarnagin WR. Ann Surg，2011AJCC分期原发肿瘤（T） Tis：原位胆管癌；T1 : 浸润肌层或纤维层；T2a: 侵及胆管周围纤维组织；T2b: 侵及胆管邻近肝实质；T3: 侵犯单侧门静脉/肝动脉；T4: 侵犯门静脉主干或双侧分支；或肝总动脉；或双侧II级胆管；或单侧II级胆管加对侧门静脉或肝动脉浸润区域淋巴结（N）N0：无淋巴结转移；N1：局部淋巴结转移（胆囊管、胆总管、肝动脉、门静脉旁）N2: 远处淋巴结转移（主动脉、肠系膜上动静脉、下腔静脉、腹腔动脉

16、旁淋巴结转移；远处转移（M） M0 无远处转移；M1 发生远处转移 0期 Tis N0 M0A期 T1 N0 M0B期 T2 N0 M0A期 T3 N0 M0B期 T1、T2或T3 N1 M0期 T4 任何N M0 期 任何T 任何N M1American Joint Committee on Cancer. AJCC cancer staging manual. 7th edPrognostic Factors预后因素情况很好，恢复不错肿瘤病理类型术前胆道引流术前定位与剩余肝胆红素水平术前CA199水平肿瘤浸润深度手术切除类型下腔静脉侵犯Prognostic factor: preopera

17、tive serum CA19-9 levels1、术前CA19-9水平是肝门胆管癌术后的独立预后因素术前CA19-9低于150U/ml的胆管细胞癌患者组术后生存显著优于术前CA19-9高于150U/ml组（P=0.000）Wen-Ke Cai1, Int J Clin Exp Pathol, 2014术前CA199150U/ml术前CA199150U/ml Rocha FG, et al. J Hepatobiliary Pancreat Sci, 2010Preoperative serum total bilirubin 10mg/dl associated with poor prog

18、nsois术前胆红素10mg/dl,直接影响术后生存率Prognostic factor: preoperative serum total bilirubin2、术前胆红素与预后Prognostic factor: the volume of remnant liver3、准确的术前定位与剩余肝体积影响预后Precise visualization of anatomic structures Multidirectional assessment of biliary branches and vesselsAllowing improved operative planningRyoko

19、 Sasaki, The American Journal of Surgery ,2011The volume of remnant liver and prognosis剩余肝体积与预后关系Rocha FG, J Hepatobiliary Pancreat Sci, 2010通过48例患者的临床数据分析显示，剩余肝体积与预后具有显著相关性 P=0.012Liu F, et al. Dig Dis Sci, 2010YES：unrelieved biliary obstruction is associated with hepatic and renal dysfunction and

20、coagulopathyNO：Preoperative biliary drainage is associated with an increased risk of complicationPreoperative biliary drainage remains controversialRecently, Meta analysis indicated preoperative biliary drainage had no benefit Prognostic factor: preoperative Biliary Drainage4、术前胆道引流Preoperative bili

21、ary decompression in patient with cholangiocarcinoma肝门胆管癌患者术前胆道减压Case-comparison studyMajor liver resections without PBD are safe in most patients with obstructive jaundice. Transfusion requirements and incidence of postoperative complications, especially bile leaks and subphrenic collections, are h

22、igher in jaundiced patients. Whether PBD could improve these results remains to be determined肝门胆管癌术前胆道减压能减少并发症发生率，但是否能提高预后结果仍需进一步研究20例黄疸患者作了肝切除但未行术前胆道引流27例对照组患者肝切除但未黄疸患者结果发现：黄疸患者与无黄疸患者组病死率为（5% vs 0%），肝衰发生率（5% vs 0%），胆漏等并发症发生率（50% vs 15%）Preoperative biliary drainage of the FLR (future liver remnant)

23、 appears to improve outcome if the predicted volume is or = 30%, preoperative biliary drainage does not appear to improve perioperative outcomeRetrospective study研究显示，当剩余肝体积30%时，术前胆道引流能提升肝门胆管癌患者预后，当剩余肝体积30%时，术前胆道引流对预后影响无统计学差异从19972007年间的60例肝脏切除术后患者根据剩余肝体积选择性的使用术前胆道引流，65%的患者剩余肝体积30%（39/60）对照组中，肝体积30%

24、（21/60），其中有5人出现了肝体积不足，有4人死亡，并且缺少术前胆道引流（P=0.009）这篇meta分析包括10个研究711位肝门胆管癌，其中442位合并黄疸患者进行了术前胆管引流，233位黄疸患者未进行术前引流，临床数据分析不支持肝门胆管癌合并黄疸患者能从引流中获益Retrospective studyMeta-analyse 711 casesAdvantages and disadvantages of different methods of bile drainage不同胆管引流方法的优劣引流方法Maguchi H et al, J Hepatobiliary Pancreat

25、 Surg, 2007Prognostic factor: histological classification5、组织学分型影响预后分化程度与生存率Saxena A, The American Journal of Surgery, 2011高分化患者组中分化患者组低分化患者组Prognostic factor: Tumor depth6、肿瘤浸润深度及长期预后Tumor depth more accurately stratifies patients and is a better predictor of long-term outcome 肿瘤浸润深度是评估肝门胆管癌预后的一项重要

26、指标de Jong MC, et al. Arch Surg. 2011肿瘤浸润深度5mm组肿瘤浸润深度5mm组Prognostic factor: type of liver resection7、肝切除类型与预后关系 Konstadoulakis,The American Journal of Surgery, 2008Right hepatectomy had better survival19982006年间的73位肝门胆管癌患者51位患者进行了右半肝切除术22位患者进行了左半肝切除术5年生存率分别是48.9%和21.7%Invasion of IVC indicates poor p

27、rognosis8、下腔静脉侵犯预示不良预后Konstadoulakis, The American Journal of Surgery, 2008下腔静脉侵犯患者术后生存率显著低于未侵犯者纳入本研究的73例患者中有3例（4%）出现了下腔静脉侵犯统计结果提示严重的不良预后肝门胆管癌外科治疗方法Patients resected(solid line) had better overall 5-year survival (35%) than patients that were not resected. No unresected patient(dotted line) survived

28、 to 24 monthsAlan W. Hemming, Ann Surg, 2005手术切除组非手术治疗组Surgical resection外科切除Surgical resection is the best treatment for hilar cholangiocarcinomaT.M. van Gulik ,European Journal of Surgical Oncology, 2011手术切除组患者术后生存率显著优于非手术组及肝移植组Actuarial survival of patients underwent resectionversus those were no

29、t resected手术切除对生存率的影响Precise surgical resection for hilar cholangiocarcinoma 肝门胆管癌的外科治疗IIIV根治性切除手术的范围和术式的选择IVIII可切除性的判断和手术规划的制订精确评估肝门胆管癌的侵袭范围精确评估预留剩余肝脏功能和必需功能性肝脏体积明确围肝门部的脉管解剖肝门部胆管癌的诊断和治疗， 2013肝门胆管癌切除的根治程度肿瘤根治术按照肿瘤切缘有无癌细胞，分为以下几种切除R0指切缘无癌细胞，完整切除R1切除指镜下见切缘有癌细胞R2指肉眼可见切缘癌细胞在肝门部胆管细胞癌的治疗中，尽量做到R0切除R0 resect

30、ion significantly improved survival rate1、R0切除能显著提高术后生存率Junjie Xiong et al. Journal of Surgical Research, 2014 R0 resection improved survival rate(P=0.037)Negative resection margin is the key for R0 resection: the role of intraoperative frozen sectionR0切除的关键是阴性切缘：术中冰冻检测的关键部位Dario Ribero, et al. Ann

31、Surg, 2011术中冰冻检测切缘若切缘阳性,未达到R0切除此时如进一步切除并达到R0切除，可提高生存率Survival of patients resected negative margins versus those who resectedwith positive margins阴性切缘和阳性切缘患者生存率对比Patients resected with negative margins had a better 5-year survival of 45% than patients resected with positive margins, with no patient

32、resected with positive margins surviving longer than 40 monthsAlan W. Hemming, Ann Surg, 2005negative marginspositive margins2、No-touch-technique and en-bloc-resection不接触技术和整块切除Peter Neuhaus, et al. Ann Surg Oncol, 2012白线为切除线黑线为切除线Hilar en-bloc-resection优点：避免肿瘤周围肝门部血管解剖门静脉切除提高了R0切除率欧洲外科学会主席Peter Neu

33、haus教授提出：Bismutha和Bismuth 型，只有施行扩大右半肝和门静脉切除，才能达到理想的广泛切缘阴性和肿瘤不接触原则的目标Hilar en-bloc-resection incredibly increase the survival of CC肝门部整块切除显著提高肝门胆管癌生存率Peter Neuhaus, et al. Ann Surg Oncol, 2012不接触技术、整块切除和广泛的切缘肿瘤阴性的三大肝门胆管癌外科手术原则整块切除组显著优于普通肝切组Lymph node dissection improved prognosis 3、彻底淋巴结清扫能提高预后Young

34、LA, J Hepatobiliary Pancreat Sci, 2010范围：清扫肝十二指肠韧带的淋巴结和结缔组织（12,12p,12b组）,胰头上、后淋巴结（胰腺上、后13a组），及肝总动脉周围淋巴结（8组）彻底清扫淋巴结与预后显著相关Lymph nodes metastasis肝门胆管癌淋巴结转移名古屋大学附属医院110例肝门胆管癌手术切除患者 30%50%伴淋巴转移胆总管旁淋巴结（42.7%）门静脉旁（30.9%）肝总动脉旁（27.3%） 胰头十二指肠后（14.5%）Kitagawa Y, et al. Ann Surg, 2001Group I: 无淋巴结转移；Group II:

35、局部淋巴结转移；Group III: 腹主动脉旁淋巴结转移；A: 镜检阳性；B: 肉眼阳性+镜检阳性；C: 无法切除；Group III患者术后生存与淋巴结侵犯密切相关75cases cc lymph nodes metastasis and prognosis Verona university, Italy淋巴结转移及预后分析Alfredo Guglielmi, J Gastrointest Surg, 2013术中切除淋巴结3枚以上能提高生存期淋巴结阳性率0.25提示预后不良淋巴结阳性预后不良4、尾状叶切除是R0切除关键Gazzaniga GM, J Hepatobiliary Panc

36、reat Surg, 2000行尾状叶切除未行尾状叶切除肝门胆管癌尾状叶累及高达40%-98%，故尾状叶切除是R0切除的关键尾状叶胆管：可汇入左、右肝管及左、右肝管汇合处肝门胆管癌常累及肝尾状叶Resection of caudate lobe of liver greatly increase the survival肝尾状叶切除能显著提高生存率尾状叶切除显著提高患者术后总体生存与无瘤生存率，改善a 和 b期患者预后Kow AW, et al. World J Surg, 2012来自韩国Samsung Medical Center针对127例患者的回顾性分析：尾状叶切除组尾状叶切除组Inv

37、asion of the portal vein is not the operative contraindication5、门静脉侵犯不是手术禁忌征 肝门胆管癌门静脉侵犯较多见（36%）门静脉切除能提高R0切除率（P=0.003）Young AL, J Hepatobiliary Pancreat Sci, 2010 Mechteld C. de Jong, et al. Cancer, 2012There was no significant difference in survival between portal vein resection (PVR) and No PVR门静脉切

38、除并不增加死亡率Alan W Hemming, J Am Coll Surg, 2011门静脉切除组与非门静脉切除组术后生存无统计学差别238例肝门胆管细胞癌患者分别为R0、R0+PVR、R1、R2切除后，与其他三组相比，R0+PVR组生存情况不如单纯R0切除（P0.001），与R1组生存情况相似（P=0.606），但优于R2组（P=0.047）Wenlong Yu, Cell Biochem Biophys, 2014R0切除合并门静脉切除相比单纯R0切除降低了生存率合并门静脉切除的患者存在门静脉侵犯情况，情况较单独R0切除组差结论仍需大样本的临床病例验证Common types of th

39、e vessel reconstruction after PVR肝门静脉重建的常见类型PV - SMVPV重建方法例举利用Y形髂动脉行门静脉-脾静脉、门静脉-肠系膜上静脉吻合Hepatic artery resection and reconstruction6、肝动脉切除及重建肝动脉侵犯肝动脉重建后吻合口Male, 74ys，hepatic artery invasion, hepatic artery resection and reconstruction during operationde Santibaes E, HPB, 2012 acb离断左、右肝动脉及右肝后动脉将左肝动脉端

40、与右肝后动脉吻合重建完成后行左半肝切除两例肝门胆管癌Bismuth b期行左半肝切除+尾状叶切除，术中行肝动脉重建 保证胆管良好血供 无张力吻合 连续(后壁连续、前壁间断) 5/6/7-0 prolene或可吸收线 不放置支架或T管Reconstruction of bile duct胆管重建的经验三支胆管重建 胆肠吻合胆肠吻合结束典型病例1男，65岁，诊断为肝门胆管癌，行半肝切除术清扫淋巴结胆管重建典型病例2侵犯肝脏男性, 46岁，肝门胆管癌伴胰腺周围淋巴结转移，行胰十二指肠联合肝脏切除Bismuth IV After HPD 胰周淋巴结转移HPD术后 达芬奇机器人辅助外科手术系统医生操作台

41、床旁机械臂塔显示器达芬奇机器人与肝胆外科手术车器械护士术者巡回护士麻醉师助手显示器Palliative therapy姑息性治疗 大多数肝门胆管癌患者并没有接受手术治疗的机会，解除胆道梗阻成为主要治疗目的，主要包括胆肠吻合旁路手术、内镜胆道引流和经皮肝穿刺胆道引流。有效，并发症相对较多，适用于晚期患者，无法接受胆道支架患者ERCPPTCD胆肠吻合旁路手术安全，有效廉价，应用广泛有效，相对安全，适用于无法内镜胆道引流时Weber A, et al, World J Gastroenterol, 2007 Application of laparoscopy in the treatment of

42、 hilar cholangiocarcinoma field内镜治疗在肝门胆管癌领域的应用 Izbicki JR, J Gastrointest Surg, 2012术前探查：能发现隐匿转移灶又减少了手术创伤。应用腹腔镜探查结合MSKCC分期，发现36%的T2/T3 期存在隐匿病灶。提示对T2/T3 期患者选择性的应用腹腔镜探查具有一定价值手术治疗：技术上的局限性限制了采用微创技术治疗肝门胆管癌，目前报道较少有报道借助机器人腹腔镜手术系统行右半肝切除联合胆道重建Giulianotti PC. J Laparoendosc Adv Surg Tech A, 2010肝门胆管癌支架引流金属支架长

43、期通畅率和相对成本效益比塑料支架高，金属支架能保持通畅时间明显长于塑料支架者，尤其于不可切除性肿瘤患者金属支架组塑料支架组John Z, BMC Gastroenterol. 2012通畅率对身体的肿瘤进行手术治疗和放疗的前后，应用化疗，使原发肿瘤缩小，提高治愈率而进行的化学药物治疗辅助化疗Hepatobiliary Surg Nutr. 2014Kevin C等人分析了63例肝门胆管癌患者的临床数据其中29例患者做了术前化疗，和体外化疗接受辅助化疗患者组的五年生存率（33.9%）显著高于未辅助化疗组（13.9%）（P0.001）Liver transplantation for hilar

44、cholangiocarcinoma肝门胆管癌肝移植治疗Early StgagePoor prognosis，5-year survival rate :30%，tumor recurrence rate: 50%Relative contradiction of LTMeyer et al, Transplantation, 2000Poor prognosisIndication of liver transplantation for hilar cholangiocarcinoma in Mayo Clinic梅奥医学中心的肝门胆管癌肝移植指征Include入选指征Rea et al. Ann Surg, 20051、肝门胆管癌诊断：经导管活检或毛刷细胞学检查阳性CA199100mg/ml和（或）断层扫描有块状阴影并且胆管造影有恶性肿瘤结构FISH检测胆管染色体倍数并且胆管造影有恶性肿瘤结构2、胆囊管以上无法切除的肿瘤3、放射检查显示肿瘤直径3cm4、无肝内肝外转移5、肝移植的候选者Mayo Clinic Protocal外照射+5-Fu近距放射疗法 口服卡培他滨（希罗达） 移植前剖腹探查评估移植Rea et al