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胆管癌

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胆管癌
肝内胆管癌(右侧)和正常肝细胞(左侧)的组织切片,HE染色
症状腹痛黄疸体重下降全身搔痒、发热[1]
常见始发于约70岁[2]
类型肝内型(Intrahepatic)、肝门型(perihilar)、远端型(distal)[2]
风险因子原发性硬化性胆管炎溃疡性结肠炎、特定肝吸虫英语liver fluke感染、先天肝发育异常[1]
诊断方法显微病理切片[3]
治疗手术切除英语Surgical resection化学疗法放射线疗法、胆道支架肝脏移植英语liver transplantation[1]
预后通常很差[4]
盛行率约每年每10万人1–2例(西方国家)[5]
分类和外部资源
医学专科肿瘤学
OMIM615619
DiseasesDB2505
MedlinePlus000291
eMedicine277393365065
Patient UK英语Patient UK胆管癌

胆管癌Cholangiocarcinoma),又称胆道癌,是一种由胆道上皮细胞(或呈现上皮细胞分化特征的细胞)癌变所造成的癌症[6]。胆管癌主要的症状为肝功能异常、腹痛黄疸、全身搔痒、发热体重减轻[1];此外患者的粪便颜色可能变浅,尿液颜色变深[3]。同属胆道系统英语biliary tract癌症的疾病还包括胆囊癌十二指肠乳头癌英语ampulla of Vater[7]。胆管癌是一种罕见的腺癌英语adenocarcinoma[2]

胆管癌的风险因子包含原发性硬化性胆管炎溃疡性结肠炎肝硬化丙型肝炎乙型肝炎、特定肝吸虫英语liver fluke感染,以及先天肝脏结构异常等等[1][2][8]。但大多数胆管癌患者缺乏明确的风险因子背景可供辨识[2]。疾病的诊断须结合血液检查医学影像,和内视镜检查,有时需手术取出检体进行病理诊断[3]。确诊须经由显微镜检进行[3]

多数患者在诊断出胆管癌时,疾病已经进展至晚期,无法治愈[1]。在这些无法治愈的病人可进行和缓医疗,包含手术切除英语surgical resection化学疗法放射线疗法,以及置放胆道支架等等[1]。完全手术切除是唯一的治愈希望,但有约三分之一的病人肿瘤会进犯总胆管英语common bile duct,而此类肿瘤无法手术切除,因此仅有少数肿瘤可以进行完全切除[1]。完全切除后仍然建议继续进行化疗及放疗[1]。有些符合特定条件的病人可以进行肝脏移植英语liver transplantation[2],但术后的五年存活率仍不到五成[5]

胆管癌在西方世界相当罕见,大约每年每10万人仅 0.5–2 例[1][5]东南亚等肝吸虫流行的地区发生率较高[4],如泰国约每年每10万人60例[4]韩国上海的发生率甚至高于罕见癌症的标准[9]。胆管癌一般发生于70岁左右,但患有原发性硬化性胆管炎者常在40岁左右即发病[2]。现今西方国家的肝内型胆管癌比例比起过去较高[5]

症状和综合症

皮肤和眼睛变黄(黄疸和巩膜黄染)
皮肤和眼睛变黄(黄疸和巩膜黄染)

胆管癌最常见的生理变化为肝功能异常黄疸(胆管阻塞后,胆汁导致眼睛和皮肤变黄)、腹痛(30%–50%)、全身搔痒(66%)、体重减轻(30%–50%)、发热(小于20%)、粪便和尿液颜色改变[10][11]。症状的类别取决于肿瘤在胆管中的位置:位于肝外胆管者较可能发生黄疸;位在肝内胆者则较常发生腹痛,但不常伴随黄疸[12]

胆管癌患者的肝功能血液检验报告往往会呈现出各种“阻塞性”特征:意即胆色素碱性磷酸酶丙麸胺酸转移酶英语gamma glutamyl transferase浓度上升,但转氨酶浓度正常,此类检验结果排除了发炎或肝实质组织感染的可能,明确指出黄疸的病灶来自胆管阻塞[13]。多数的胆管癌患者CA19-9英语CA19-9浓度也会上升[14]

风险因子

中华肝吸虫的生活史,以下说明与图中数字一致: (1) 受精卵透过粪便离开人体。 (2) 卵被蜗牛食入后,依序发育为毛蚴、孢蚴、雷蚴、尾蚴。 (3) 自由游动的尾蚴离开蜗牛,在淡水鱼皮肤或肌肉内形成囊蚴。 (4) 淡水鱼被人类食用后,囊蚴进入人体。 (5) 囊蚴在十二指肠破出囊孢。 (6) 成体寄生在胆管。
中华肝吸虫的生活史,以下说明与图中数字一致: (1) 受精卵透过粪便离开人体。 (2) 卵被蜗牛食入后,依序发育为毛蚴、孢蚴、雷蚴、尾蚴。 (3) 自由游动的尾蚴离开蜗牛,在淡水鱼皮肤或肌肉内形成囊蚴。 (4) 淡水鱼被人类食用后,囊蚴进入人体。 (5) 囊蚴在十二指肠破出囊孢。 (6) 成体寄生在胆管。

虽然多数胆管癌患者形成肿瘤的原因并不明确,但目前已发现相当多的风险因子。西方国家最常见的风险因子为原发性硬化性胆管炎(PSC),这是一种和溃疡性结肠炎高度相关的胆道发炎疾病[15],流行病学统计指出PSC患者一生中罹患胆管癌的几率为10%–15%[16]法医病理的一系列研究则显示此比率可能高达30%[17]。PSC增加胆管癌罹患风险的机制目前尚未明了。

特定的肝吸虫疾病也是胆管癌的风险因子,香猫肝吸虫(分布于泰国老挝越南[18][19][20]或中华肝吸虫(分布于中国大陆台湾、东西伯利亚韩国越南[21][22]感染已证实和胆管癌有关。病毒感染(如乙型肝炎丙型肝炎[23][24][25]、酒精性肝炎、肝硬化或其他形式的慢性肝脏疾病,都会大幅提升患者罹患胆管癌的风险[26][27]。一份研究中指出艾滋病也可能是胆管癌的风险因子,但目前还不清楚此现象是艾滋病毒本身还是相关的干扰因子(如丙型肝炎感染)所造成的[26]胆型螺旋杆菌英语Helicobacter bilis肝型螺旋杆菌英语Helicobacter hepaticus等细菌感染也可能造成胆道癌症[28]

先天性肝内胆道囊肿英语Caroli's syndrome(五种胆道囊肿英语choledochal cysts中的一种)患者一生罹患胆管癌的概率为15%[29][30];罕见的遗传性非息肉结肠癌英语Lynch syndrome和胆道乳突瘤也可能和胆管癌有关[31][32]胆结石和胆管癌没有明显的关联;肝内胆管结石英语hepatolithiasis和胆管癌却强烈相关,后者在西方国家并不常见,但在亚洲部分地区(如台湾)却非常普遍[33][34][35]二氧化钍以前常用作放射造影的对比剂,但人体受暴露后的30至40年内可能会产生胆管癌,美国为此已于1950年代禁用此药品[36][37]

病理生理学

胆管在消化系统中的位置示意图。图中虚线膨大构造为胃,胃往下接着小肠。横线区块左上为肝脏,右下为胰脏,实心黑色树枝状线条即为胆管,胆管之后会汇入十二指肠(小肠的一部分)。
胆管在消化系统中的位置示意图。图中虚线膨大构造为胃,胃往下接着小肠。横线区块左上为肝脏,右下为胰脏,实心黑色树枝状线条即为胆管,胆管之后会汇入十二指肠(小肠的一部分)。

胆管癌可能影响胆管中的任何位置──包括肝脏内和肝脏外:发生在肝脏内者称肝内胆管癌;在肝脏外者称肝外胆管癌;在肝外胆管与肝脏相接处者称肝门胆管癌。胆管癌若发生在左右两肝管汇流形成总肝管处(即胆囊三角内),则称为克拉茨金瘤英语Klatskin tumor(Klatskin tumor)[38]

虽然胆管癌在胆道上皮腺癌英语adenocarcinoma的组织和分子特征,但细胞真正的来源仍属未知,有证据指出造成肿瘤的初始转型细胞可能来自多能性干细胞[39][40][41]。胆管癌的发展可分为以下几个阶段:早期的增生化生、接着异生、最后发展成肿瘤,这个过程和结肠癌的发展相似[42]。慢性发炎和胆管阻塞会造成胆汁流动受阻,这可能也会促进胆管癌发展[42][43][44]

组织学上,胆管癌的细胞可能以未分化型、分化型、或过渡型出现,它们通常由活化的纤维结缔组织促结缔组织英语desmoplastic包围,纤维化组织的存在使得分化型癌细胞和正常上皮细胞不易分辨。角蛋白癌胚抗原英语carcinoembryonic antigen粘蛋白染色或许能帮助诊断,但目前没有专门的免疫组织化学染色能区分恶性和良性的胆道组织[45]

诊断

肝内胆管癌(右侧)和正常肝细胞(左侧)的组织切片。组织学上,这个胆管癌 (1) 为沙斯型的类胆管细胞,由肝小叶中隔(肝内胆管正常会在的地方)的肿瘤延伸而来 (2) 肿瘤有很多促结缔组织形成的基质,如同在许多胆管癌案例中所见。图中肝门三体(英语:portal triad)(左上)中的胆管有正常的组织染色。HE染色
肝内胆管癌(右侧)和正常肝细胞(左侧)的组织切片。组织学上,这个胆管癌 (1) 为沙斯型的类胆管细胞,由肝小叶中隔(肝内胆管正常会在的地方)的肿瘤延伸而来 (2) 肿瘤有很多促结缔组织形成的基质,如同在许多胆管癌案例中所见。图中肝门三体英语portal triad(左上)中的胆管有正常的组织染色。HE染色

胆管癌的确切病程必须由病理检查来判定,意即必须进行组织切片或检验手术以取得肿瘤组织[46]。阻塞性黄疸的病人可能疑似患有胆管癌,其中原发性硬化性胆管炎是造成胆管癌的高风险因子,但它本身的症状和胆管癌难以分辨,在这种情形下,造影上显示的团状物或胆管扩张等诊断线索不具有代表性,因此要有效诊断出胆管癌相当困难[47]

血液检查

目前没有特定的血液检查方法能直接诊断出胆管癌。胆管癌患者血浆中的癌胚抗原英语carcinoembryonic antigenCA19-9英语CA19-9浓度通常会提高,但其专一度和敏感度都不足以成为常规的检查标准。血液检查常配合造影方法,在疑似胆管癌的案例中作为有用的判断依据[48]

腹部造影

CT显示出胆管癌。
CT显示出胆管癌。

针对可疑的阻塞性黄疸患者,肝脏胆道超音波常是首选的检查方法[49][50],超音波可以辨识出胆管阻塞和扩张,在某些案例中也足够诊断出胆管癌[51]X射线计算机断层成像(CT)在胆管癌的诊断中也充当重要角色[52][53][54]

胆管造影

胆管癌的ERCP(英语:Endoscopic retrograde cholangiopancreatography)影像显示出总胆管狭窄和总胆管近端舒张
胆管癌的ERCP英语Endoscopic retrograde cholangiopancreatography影像显示出总胆管狭窄和总胆管近端舒张

虽然腹部造影在胆管癌的诊断上很有用,但针对性的胆管造影也是必须的。最广泛使用的胆管造影术为内视镜逆行性胆胰管摄影术英语Endoscopic retrograde cholangiopancreatography(ERCP),此种内视镜必须由肠胃专科医师或受过训练的外科医师操作,虽然这是一种有风险的侵入性方法,但它同时能取得检体、放置支架、或进行其他能排除胆管阻塞的措施[13]内视镜超音波英语Endoscopic ultrasound可以与ERCP同时进行,如此将能更准确地取得检体、得知淋巴结的入侵情形、并评估手术切除的可行性[55]除了ERCP外,经皮肝穿刺胆道造影英语percutaneous transhepatic cholangiography(PTC)也是可行的选择;核磁共振胆胰管造影英语Magnetic resonance cholangiopancreatography(MRCP)则是一种非侵入性的替代方法[56][57][58],有些研究者建议以MRCP取代ERCP,因为MRCP能更精准地确认肿瘤并避免ERCP操作的风险[59][60][61]

手术

人类肝脏中的胆管癌照片
人类肝脏中的胆管癌照片

外科手术是取得组织切片和准确得知胆管癌病程的唯一方法,分期腹腔镜手术在特定情形下可以替代更具侵入性的剖腹手术英语laparotomy [46][62];以手术切除英语Segmental resection肿瘤是目前唯一能治愈胆管癌的方法,但只适用于尚未远端转移的病患[63]

病理

胆管癌在组织学上归类为中度到高度分化的腺癌英语adenocarcinoma免疫组织化学方法在诊断上很有用,能协助医师区别胆管癌、肝细胞癌与其他肠胃道癌的后期转移[64]细胞刮削英语Cytopathology通常对胆管癌诊断的精确度很低[65],这和癌细胞周围促纤维细胞英语desmoplasia产生的基质有关[66]

分期

目前至少有三种癌症分期系统用于胆管癌(Bismuth系统、Blumgart系统和美国癌症联合委员会英语American Joint Committee on Cancer的系统),但没有一种能有效预测患者存活率[67]。癌症分期最重要的问题在于肿瘤能否成功地以手术移除英语Segmental resection,但对胆管癌而言,答案通常要到手术进行当下才能判定。

一般而言,评估胆管癌手术可行性的原则如下[63][68]

  • 没有淋巴结肝脏转移
  • 没有影响到肝门静脉
  • 没有直接侵犯到邻近器官
  • 没有大范围的远端转移

治疗

胆管癌是个难以医治且快速致死的疾病,只有在肿瘤能以手术根除英语Segmental resection的情况下才有机会治愈。除非已有明确证据指出患者无法进行手术,多数案例要到手术进行当下才能评估手术成功率[69],因此患者多会先进行一次试探性手术[13]马约诊所使用标准化的肝脏移植手术和严格的手术筛选条件,在早期胆管癌治疗中取得显著的成功[70]肝脏移植英语Liver transplantation后的辅助性疗法在无法切除肿瘤的特定病例中有明显的作用[71]

辅助性化疗和放疗

由于有高达85%的胆管癌患者在手术后三年内复发,患者术后常会使用辅助性化疗放疗以期增加治愈机会[72]。若术后肿瘤组织边缘呈阴性反应(例如肿瘤已完全清除),辅助疗法不一定能带来好处,报告指出辅助性放疗可能产生正面[73][74]或负面[12][75][76]的结果;对于肿瘤已成功清除的病人而言,辅助性化疗似乎也没有意义[77]。结合化疗和放疗的效果目前并不清楚[78]。若术后肿瘤组织边缘呈阳性反应,代表肿瘤没有根除,一般会建议进行辅助性放疗和化疗[79]。目前的研究结果显示化疗的效果似乎有优于放疗的趋势[72],针对化疗药物吉西他滨/顺铂的第三期随机对照试验已经在2014年注册[80]

后期治疗

胆管癌绝大多数的病例都无法以手术根除[81],患者通常会接受缓和性化疗,也可能配合放射治疗随机对照试验的结果显示化疗在这些患者中能增进生活品质并延长寿命[82]。目前没有单一的化疗用药常规,若状况允许,也常会建议患者申请临床试验[79]。治疗胆管癌的化疗药物包括5-氟尿嘧啶/亚叶酸英语Leucovorin [83]、单用吉西他滨 [84]或吉西他滨加上顺铂 [85]爱莱诺迪肯[86]卡培他滨英语capecitabine[87]。一个小型的可行性研究指出酪氨酸激酶抑制剂厄洛替尼在后期胆管癌患者中可能是有益的[88]

病程

手术移除英语Segmental resection肿瘤是目前唯一可能治愈胆管癌的方法。由于癌细胞会透过淋巴结远端转移,无法切除肿瘤的患者五年存活率为0%[89];全部胆管癌患者的五年存活率则为5%[90]。若无法切除的肿瘤借由肝内胆管或肝门静脉侵犯肝脏,即使患者其余生理机能正常,其余命的中位数也小于6个月[91]

对能进行手术的病例而言,手术成功的几率取决于肿瘤的位置,以及肿瘤是否能加以根除。远端型胆管癌(肿瘤发生于总胆管英语Common bile duct)患者通常会进行胰十二指肠切除术英语Whipple procedure,长期存活率为15%–25%,另有一系列报告指出肿瘤未侵犯到淋巴结的患者有54%的五年存活率[92]。肝内胆管癌(肿瘤发生于肝内胆管)患者通常会将部分肝脏移除英语hepatectomy,不同的系列报告估计术后存活率为22%–66%,存活率差异取决于手术移除的完整度和癌细胞是否侵犯到淋巴结[93]。肝门型胆管癌(肿瘤发生于肝外胆管与肝脏相接处,又称克拉茨金瘤英语Klatskin tumor)通常无法进行手术,只有少数罕见的病例有开刀治疗的可能,手术过程通常会包括胆囊切除术英语cholecystectomy或部分肝脏移除,能进行手术的肝门型胆管癌患者五年存活率为20%–50%[94]

原发性硬化性胆管炎发展而来的胆管癌患者情况通常更糟,这或许是因为肿瘤在诊断出来前就已经恶化[17][95]。一些临床证据指出入侵性较高的手术和佐剂治疗可能会有较好的效果[96]

流行病学

胆管癌发生率的全球分布图。绿色代表胆管癌在该地区为罕见癌症 (年发生率小于每十万人6例),红色代表胆管癌在该地区非罕见癌症。数据来自 Bragazzi MC et al (2011)。[9]
胆管癌发生率的全球分布图。绿色代表胆管癌在该地区为罕见癌症 (年发生率小于每十万人6例),红色代表胆管癌在该地区非罕见癌症。数据来自 Bragazzi MC et al (2011)。[9]

胆管癌是一种相对少见的癌症,美国每年大约有2000到3000桩新病例,换算成年发生率约每十万人1至2例[97]法医病理研究指出盛行率约0.01% - 0.46%[98][99]。由于区域性流行病的缘故,胆管癌在亚洲有较高的流行率,在上海韩国泰国北部的发生率都已超过罕见癌症的标准(大于每年每十万人6例)[9],尤其是泰国北部的年发生率高达每十万人14.6例以上,统合分析研究指出中华肝吸虫香猫肝吸虫是最主要的风险因子[100]台湾的胆管癌年发生率为每十万人4.7例,属于罕见癌症,但发生率仍较西方国家高出许多,台湾的中华肝吸虫感染盛行率虽然已经大幅降低,但另一项西方国家很少见的风险因子——肝内胆管结石英语hepatolithiasis和台湾的胆管癌病例则有强烈关联[100]

胆管癌的发生率会随着年龄增加,男性发生的几率稍微较女性高(可能是因为男性有较高比例的原发性硬化性胆管炎患者)[101]。根据法医病理研究,带有原发性硬化性胆管炎的患者胆管癌流行率可能高达30%[17]。多份研究纪录指出截至二十世纪末为止,北美欧洲亚洲澳洲的肝内胆管癌发生率都有上升的趋势[102],并于2000年后逐渐趋于稳定[103],肝内胆管癌发生率上升的原因目前并不清楚,诊断方法的进步可能有关,但潜在风险因子的盛行率(例如艾滋病感染)在同个时期也有增加,因此可能也扮演一定的角色[26]。然而,近年来肝外胆管癌和肝门胆管癌的发生率却呈现下降的趋势[103]。美国可能由于有完善的医疗照护,胆管癌患者的住院人数和院内死亡率也都趋于降低。[104]

研究

近期研究显示不同患者的癌细胞具有高度的基因变异,这和肿瘤发生位置、造成疾病的风险因子等都有关联[106],研究者正尝试由手术切除的组织筛选患者肿瘤细胞的基因型,以施予患者特定的标靶药物[107]。随着胆管癌细胞生成和肿瘤微环境的可能分子路径正式提出,阻断这些路径的抑制剂也成为治疗胆管癌的候选药物[108]光动力治疗则是使用对特定光波长敏感的药物的新型疗法,随机对照试验的结果显示此疗法对无法手术切除肿瘤的患者而言能有效提高存活率[109][110]。另外,侦测肿瘤基质细胞副产物在血液中浓度的技术也正在发展,此方法可用于协助癌症诊断[111]

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  93. ^ 下列研究指出了肝内胆管癌的治疗结果:
  94. ^ 以下报告估算了肝门型胆管癌患者的术后存活率:
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