Advances in Clinical Medicine
Vol.4 No.04(2014), Article ID:14579,6 pages
DOI:10.12677/ACM.2014.44014

Typing, Risk Factors and Related Treatments of Cholangiocarcinoma

Xuehe Zhu1, Xudong Liu2

1Inner Mongolia Medical University, Hohhot

2Affiliated Hospital of Inner Mongolia Medical University, Hohhot

Email: 495747315@qq.com

Copyright © 2014 by authors and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

Received: Nov. 2nd, 2014; revised: Nov. 20th, 2014; accepted: Nov. 30th, 2014

ABSTRACT

Cholangiocarcinoma (CCA), is a highly malignant tumor, clinically rare and accounting for less than 1% of all malignant tumors. But the number of patients with cholangiocarcinoma in China increases year by year, so cholangiocarcinoma research has special significance in our country. Depending on the anatomical location, cholangiocarcinoma is divided into: hilar cholangiocarcinoma (PHC), the distal bile duct (DCCA) and intrahepatic cholangiocarcinoma (ICCA), among which hilar is the most common. Currently, surgery is the best treatment, but because early diagnosis is difficult, most cases are in the end-stage when diagnosed; therefore, less than 10% of patients are able to tolerate surgery. However the high recurrence rate and low survival rate are still unresolved. With clinical treatment of cholangiocarcinoma deepening, new treatments gradually formed. This article summarizes the results of the analysis of the cholangiocarcinoma typing, clinical manifestations, risk factors, molecular biological mechanisms and related treatment.

Keywords:Cholangiocarcinoma, Typing, Clinical Manifestations, Risk Factors, Treatment

胆管癌的分型、危险因素及其相关的
治疗手段

朱学河1,刘旭东2

1内蒙古医科大学,呼和浩特

2内蒙古医科大学附属医院,呼和浩特

Email: 495747315@qq.com

收稿日期:2014年11月2日;修回日期:2014年11月20日;录用日期:2014年11月30日

摘  要

胆管癌,是一种恶性程度较高的肿瘤,临床较少见,占所有恶性肿瘤不足1%,但在中国胆管癌患者数呈逐年增多的趋势,因而胆管癌研究在我国具有特殊意义。胆管癌根据解剖位置的不同分为:肝门部胆管癌(PHC)、远端胆管癌(DCCA)和肝内胆管癌(ICCA),肝门部胆管癌最为常见。目前,手术治疗是最佳的治疗手段,但由于早期诊断困难,确诊时多为晚期,因此只有不到10%的患者能够耐受手术治疗,但术后复发率较高,生存率低等问题仍然未能解决。随着人们对胆管癌临床治疗研究的不断深入,新的治疗手段逐渐形成。本文归纳分析了胆管癌的分型、临床表现、危险因素、分子生物学机制及其相关治疗手段的研究结果。

关键词

胆管癌,分型,临床表现,危险因素,治疗手段

1. 引言

胆管癌,是一种恶性程度较高的肿瘤,占所有恶性肿瘤不足1% [1] 。由于常用的肿瘤标记物在早期胆管癌中无明确的特异性表达,加之临床表现的多样性,使胆管癌早期的诊断十分困难,甚至无法明确诊断,大部分患者只有在晚期时才可诊断明确,故而大大降低了患者的生存率。通常根据解剖部位的不同将胆管癌分为三种类型:肝门部胆管癌、远端胆管癌和肝内胆管癌。其中以肝门部胆管癌(PHC)最常见,约占胆管恶性肿瘤的50%~67%。远端胆管癌(DCCA)和肝内胆管癌(ICCA),分别占27%~42%和6%~8% [2] [3] 。肝门部胆管癌首次以Klatskin瘤命名,至今仍在沿用[4] ,所以部分文章中也常以Klatskin瘤来描述肝门部胆管癌。

2. 胆管癌的临床表现

总体来说,胆管癌常见的临床症状包括瘙痒(66%),腹痛(30%~50%),体重减轻(30%~50%),及发热(20%)等[5] [6] 。但由于胆管癌的分型不同导致了胆管癌的临床表现不尽相同。

肝外胆管癌所致黄疸早期往往不伴腹痛,故称之为无痛性黄疸,患者不易察觉,就诊时多为晚期,失去治疗时机。肝外胆管癌又可分为远端胆管癌(中、下段胆管癌)和肝门部胆管癌。两者的临床表现也存在着区别:远端胆管癌的患者可表现为胆囊肿大,体征包括黄疸(90%)、肝肿大(25%~40%)和右上腹不适(10%) [6] ,由于胆总管中下段的阻塞,胆囊增大,临床上可触及肿大胆囊,但Murphy’s征可能阴性。而肝门部胆管癌尽管皮肤深度黄染,但胆囊常不增大,部分患者可能出现肝大。这两种不同类型的肝外胆管癌也常具有着相同的临床症状包括肝脏损害;肝功能失代偿期(多因黄疸时间较长)出现腹水,甚或双下肢水肿;肿瘤侵犯或压迫门静脉,造成门脉高压致消化道出血;晚期可并发肝肾综合征,出现尿少、无尿;瘤体破溃可导致上消化道出血,伴黑便、大便潜血(+)及贫血等。

肝内胆管癌患者通常以持续性上腹部疼痛为主要症状,有时会伴有乏力、恶心、食欲减退、黄疸、发热等。同原发性肝细胞肝癌相似,早期无明显临床症状,右上腹疼痛出现较晚,就诊时多为晚期。因此,无论是肝内或肝外胆管癌的早期诊断、早期治疗尤为关键。

3. 胆管癌的危险因素

胆管癌致病因素有多种,相关研究表明,丙型肝炎、乙型肝炎以及肝硬化已被确认为胆管癌的危险因素,尤其肝内胆管癌。丙型肝炎和乙型肝炎在不同地区对胆管癌的发展也不相同,在西方国家,丙型肝炎相对普遍。对亚洲国家地区,尤其是我国是公认的乙肝流行大国,所以乙肝成为了我国胆管癌患者重要的危险因素。相关的一些研究已经证实,在欧美地区丙型肝炎是胆管癌与肝内胆管细胞癌的相关性最强的危险因素[7] -[10] 。而来自于韩国和中国的研究结果证实了乙肝是肝内胆管癌的重要危险因素[11] -[13] 。随着肝硬化相关的致病性因素的确定(包括致病原,炎症性细胞因子的释放,细胞死亡耦合细胞增殖,以及肝脏的纤维性变等等) [13] 。这些因素同样为肿瘤在肝硬化患者肝脏内的发生提供了有利条件,然而,肝硬化并不是存在于所有的病毒性肝炎伴发胆管癌患者中[13] 。一项meta分析对肝内胆管癌的危险因素进行的几个病例对照研究显示如下关联:肝硬化患者比值比(OR) 22.92 (95%CI 18.24~28.79)、丙型肝炎患者4.84 (2.41~9.71),和乙型肝炎患者5.10 (2.91~8.95) [14] 。除了上诉的肝硬化及病毒性肝炎已被确认为胆管癌常见的危险因素外,Ben-Menachem [15] 等人总结出了胆管癌最常见的危险因素包括:肝吸虫,原发性硬化性胆炎[16] [17] ,胆总管囊肿[18] -[20] ,肝内胆管结石[21] [22] ,胆肠内引流术[23] 。2011年Tyson GL等人的研究证实了几种遗传基因的多态性会增加胆管癌发生的危险,这些基因根据影响因素的不同可分为参与细胞DNA修复的编码蛋白(MTHFR, TYMS, GSTO1, XRCC1),抗毒素并进行细胞保护的基因(ABCC2, CYP1A2, NAT2)及免疫监视的功能基因(KLRK1, MICA, PTGS2)等[18] 。

4. 胆管癌的治疗

4.1. 手术治疗及术后并发症

Zhang.W [24] 等人通过使用PubMed和MedLine以“肝门部胆管癌”、“肝门部胆管癌肿瘤”和“切除术”为关键词进行搜索,收集了不同时期不同类型胆管癌手术治疗的相关资料并进行分析,分析结果说明了胆管癌手术难度大,术后生存率低,一直是胆管癌手术治疗面临的难题,至今难以解决。近几年,另有一些研究表明胆管癌患者术后的并发症也日渐成为亟待解决的重点问题,其中以感染最为常见,约占所有并发症的50%或以上[3] [25] [26] 。肝功能衰竭,则是胆管癌术后最为严重的并发症,其次为创面脓毒症、腹腔脓肿、胆漏等等[27] 。

综上所诉,随着胆管癌危险因素的增加,胆管癌的发病率也在逐年上升。目前治疗胆管癌首选治疗手段仍为外科手术治疗,但此类手术对患者的创伤极大,术后复发率较高,生存率较低等已经成为胆管癌治疗的巨大难题。近几年胆管癌的术后并发症逐渐变得多样化和复杂化,使得胆管癌的术后风险进一步增加,患者生存率及生活质量难以保障。由此,姑息治疗逐渐引起研究者们的注意。

目前临床上常用内镜缓解BY支架置入术、经皮胆道引流、内镜超声引导下胆管引流、局部烧蚀疗法(光动力疗法)、射频消融、放疗/化疗等[28] 姑息治疗的手段。姑息治疗的应用指征也日渐明确,最近的研究数据表明,针对肝脏衰竭大于50%肝脏的胆管癌患者,采用支架植入术会得到更好的治疗效果。值得一提的是,目前非手术治疗中,超声内镜引导下胆管引流术也逐渐显出巨大优势。经皮或超声内镜引导下胆管引流适用于不能行ERCP检查的所有病人或病人自身不愿接受ERCP检查,但其中最为主要的原因是胆管系统解剖结构的改变或十二指肠肿瘤阻塞。另有一些文献的报道表明,光动力疗法和射频消融术也可以提高患者生存率,如配合胆道支架置入术,治疗效果更加明显,但这一过程仅仅适用于晚期肿瘤(III型和IV期) [29] 。

虽然姑息治疗被越来越多的医生认同和接受,治疗效果值得肯定,治疗前景也非常乐观,但姑息治疗的范围仅集中在胆管癌的中、晚期或患者无法耐受根治术,且姑息手术仅以减少并发症和降低死亡率为原则,以控制和减轻症状、延长患者寿命和提高生活质量为目的,而对于早期及胆管梗阻症状不明显的患者姑息手术意义不大。

4.2. 非手术治疗

细胞毒性药物治疗。吉西他滨(gmecitabine)是一种破坏细胞复制的二氟核苷类抗代谢物抗癌药,去氧胞苷的水溶性类似物,是对核糖核苷酸还原酶的一种抑制酶作用物的替代物,这种酶在DNA合成和修复过程中,对所需要的脱氧核苷酸的生成是至关重要的。吉西他滨已经成为晚期胰腺癌、晚期非小细胞肺癌、局限期或转移性膀胱癌及转移性乳腺癌的一线治疗药物。最近,由ABC-2建立了的标准实践研究,将410例晚期胆道癌患者中的63人随机分配,分别行吉西他滨单独治疗及顺铂联合吉西他滨治疗,接受联合治疗的患者平均存活时间约为11.7个月,而接受吉西他滨单独治疗的患者平均存活时间约为8.1个月(风险比[HR]0.64,95% CI为0.52~0.80) [30] ,显然联合疗法在很大程度上提供高了患者的生存时间,但该方案对于胆管癌的治疗仍未达到理想效果。值得肯定的是,这些结果不足以成为探索吉西他滨联合顺铂治疗试验前景的阻碍[31] [32] 。

然而该药物的副作用不容忽视,它可以引起:①骨髓抑制作用,患者使用后出现贫血、白细胞降低和血小板减少;②胃肠道的反应,部分患者出现肝脏转氨酶异常,恶心和呕吐反应;③肾脏损害,约有一半以上的患者出现轻度蛋白尿和血尿,有可能导致原因不明的肾衰;④过敏,患者出现皮疹、瘙痒,甚至可发生支气管痉挛;⑤其他不良反应还有类似“流感”表现、周围性水肿、脱发、嗜睡、口腔毒性及便秘等等。虽然患者的病变得到控制,但是生活质量及身心健康都会受到不同程度的消极影响。相信通过不断地改善药物的功效和安全性,不久的将来会提出更精确更有针对性的治疗方案。

分子生物学的靶向治疗。目前,RAS-MAPK信号通路是胆管癌的主要信号通路之一,有关其生物学意义的研究也屡见报道。例如,Sia和他的同伴[33] 使用综合分子分析技术与临床病理特征相结合的手段,通过对119例肝内胆管癌患者的治疗,得出了两种不同的基因标记类:分别是增殖类(proliferation class)和炎症类(inflammatory class)。其中增殖类(占研究病例的62%)与若干致癌基因表达变化有关,它们包括而不仅限于KRAS和BRAF,还包括RAS,MAPK和MET信号传导通路的其它基因。由这些基因编码的蛋白质是RAS-RAF-MEK-ERK信号轴刺激细胞增殖过程或PI3K-AKT-mTOR信号轴线促进细胞存活信号传导通路中的组成部分。在另一项研究中[34] ,研究者对欧洲,美国和澳大利亚收集的104例胆管癌切除术后的胆管癌标本进行转录学图谱分析表明,KRAS基因突变与表皮生长因子自由化(EGFR)和ErbB2(也称为HER2)信号通路(其中包括MET)存在一定的关联性,而且这些基因参与并导致蛋白酶体活性紊乱与胆管癌预后不良存在关联。此研究也显示了活化的EGFR和HER2的酪氨酸激酶抑制剂治疗胆管癌潜力[27] [34] 。尽管EGFR可能作为一个枢纽,用于发送下行信号,以激活RAS-MAPK,JAK-STAT,和PI3K-AKT-mTOR等信号通路[31] [35] ,但这也有可能是由于不同的受体酪氨酸激酶之间存在着互相干扰的现象,其有待于进一步的探究。

最近,Chung JY等人通过对221例肝外胆管癌进行微阵列研究得到如下结果,肿瘤抑制基因PTEN与AKT和(或)mTOR的激活中出现遗传学的改变与患者的预后差存在一定的关联性[36] 。并且在另一项对101例肝内胆管癌研究中,也证实了这些基因的变化和预后良好存在着联系,其中在不同分化程度的肿瘤都能检测到mTOR和AKT的活化[37] 。近年的研究表明,新型纤维细胞生长因子受体2(FGFR2)的重排和基因融合已被确定发生在患者的胆管癌细胞中,更为重要的是这些突变是具有靶向性的[38] 。

由此可见,越来越多的研究者通过基因组测序研究完善了基因与蛋白质的识别能力,对胆管癌发病机制与肿瘤表型认识的深入,为设计胆管癌的靶向药物、临床分子靶向治疗研究奠定坚实的基础。目前,临床靶向治疗研究主要集中在结直肠癌、乳腺癌、胰腺癌、胃肠道基质瘤、肝细胞癌、肺癌等原发性和转移性肿瘤。例如厄洛替尼(Erlotinib)的应用[39] [40] ,它是一种靶向治疗药物,可抑制人表皮生长因子受体(EGFR)的信号传导途径,并抑制与表皮生长因子受体(EGFR)相关的细胞内酪氨酸激酶的磷酸化,从而达到抑制肿瘤的目的。阿瓦斯汀(又称贝伐单抗,Bevacizumab,Avastin)是重组的人源化单克隆抗体。其作用机制是通过体内、体外检测系统证实IgG1抗体能与人血管内皮生长因子(VEGF)结合并阻断其生物活性。相关研究[41] [42] 证实,阿瓦斯汀与其他放、化疗药物或靶向治疗药物联合用药时,在抑制胆管癌转移方面也可获得良好的效果。索拉非尼(sorafenib)能同时抑制多种存在于细胞内和细胞表面的激酶,包括RAF激酶、血管内皮生长因子受体-2(VEGFR-2)、血管内皮生长因子受体-3(VEGFR-3)、血小板衍生生长因子受体-β (PDGFR-β)、KIT和FLT-3。由此可见,索拉非尼具有双重抗肿瘤效应,一方面,它可以通过抑制RAF/MEK/ERK信号传导通路,直接抑制肿瘤生长;另一方面,它又可通过抑制VEGFR和PDGFR而阻断肿瘤新生血管的形成,间接抑制肿瘤细胞的生长,该药物已被应用于胆管癌的治疗,2010年Bengala等[43] 总结了索拉非尼单药对胆管癌治疗作用相对较弱,对于患者状况好、肿瘤无进展的患者可提高生存期,且不良反应可控。

以上对靶向药物的研究说明,临床分子靶向治疗正逐步得到重视,药物靶向治疗在提高化疗药物疗效,降低毒副作用方面具有广阔前景。与传统的化疗药物相比,针对肿瘤的特异性分子靶点设计的抗肿瘤治疗手段具有特异性强、疗效明显、正常组织损伤少等优点。当然,靶向治疗的还存在着诸多问题,一些潜在的毒副作用仍需要进一步解决。尽管分子靶向治疗的发展步履艰难,但它仍然为肿瘤治疗开辟了新的道路。而且,随着部分靶向治疗药物的应用及推广,许多的癌症患者从中受益,这一观点是不可否认的。相信通过研究者们不断地钻研,不久的将来更好、更稳定、毒副作用更少的分子靶向治疗药物会被应用于临床。

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