Welcome to Visited Lingnan Modern Clinics In Surgery, Today is

Lingnan Modern Clinics in Surgery ›› 2020, Vol. 20 ›› Issue (02): 261-266.DOI: 10.3969/j.issn.1009-976X.2020.02.025

Previous Articles     Next Articles

Research status of commonality between cancerous and precancerous lesions of the biliary tract and the pancreas

  

  1. 1. Department of Hepatopancreatobiliary Surgery; 2. Nutrition Department, the Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, China
  • Contact: LI Le-qun

胆管癌、胰腺癌及其癌前病变共同特征的研究现状

  

  1. 广西医科大学附属肿瘤医院1. 肝胆胰外科;2. 临床营养科,广西南宁530021
  • 通讯作者: 黎乐群

Abstract: [Abstract] Neoplastic and preneoplastic lesions of the biliary tract and the pancreas share analogies in terms of molecular, histopathological and clinical features due to their anatomical proximity and common embryological origin. This review systematically illustrates similarities and differences between cancerous and precancerous lesions of the biliary tract and the pancreas with potential implications on a common origin from similar stem/progenitor cells, which will provides the theoretical basis for learning from each other on the related research, joint monitoring, common prevention and treatment, and individualized strategy under the comprehensive concept for the two types of diseases.

Key words: precancerous lesions, cholangiocarcinoma, commonality, pancreatic ductal adenocarcinoma, stem cell

摘要:

胆管癌、胰腺癌及其癌前病变共同特征的研究现状

彭宁福1, 钟鉴宏1, 朱少亮1, 廖迎阳2, 黎乐群1*

[摘要] 胆道、胰腺解剖毗邻,共享胚胎起源。胆、胰肿瘤及其瘤前病变在分子、组织病理学和临床结局等颇具相似性。本文系统阐述胆管癌与胰腺导管腺癌及其癌前病灶之间的相似性和差异性,可能对两者具有共同干细胞起源的研究具有潜在影响,同时为两类疾病研究互鉴,共同监测、防治及其综合理念下的个体化治疗提供理论依据。

[关键词]胆管癌;胰腺导管腺癌;癌前病变;共性;干细胞

胆道与胰腺具有共同的胚胎学起源,目前认为胆胰壶腹区域是原始胆道及胰腺的最近端。胆胰胚胎干细胞存在于胚胎早期,特定转录调控其胆、胰谱系的发育。成体胆道仍存胆道干细胞(biliary tree stem/progenitor cells,BTSCs),且位于大胆管(肝外胆管和肝内大胆管)周围腺体(peribiliary glands,PBGs)[1];而胰腺干细胞特性也存留于其中,尤其胆胰壶腹周围[2]。另外,较大胰管中的腺体主要为胰腺定向祖细胞,对应于PBGs中的BTSCs,但后者为前体细胞[3]

多年研究表明[1-4],胆、胰两类相关疾病,无论在流行病学、临床行为,还是组织病理、免疫表型、分子谱等,均存相应的类似甚至同一性,有力支持胆胰“共同干细胞起源”学说。本文主要阐述胆管癌(cholangiocarcinoma,CCA)与胰腺导管腺癌(pancreatic ductal adenocarcinoma,PDAC)及其各自癌前病变之间的相似和差异性,为两类疾病研究互鉴,共同监测、防治及其综合理念下的个体化治疗提供理论依据。

1 胆胰疾病共性的胚胎发育及起源细胞学基础

胆道与胰腺具有共同的胚胎学起源。在人胚期第4周,前肠末端腹侧内胚层形成肝憩室,膨大成头、尾两支,近肝憩室尾缘另增生为腹、背胰芽。憩室头侧形成肝脏和肝内小胆管(小叶间胆管和胆小管),而尾部形成肝外胆管和腹侧胰腺,肝内大胆管(段、亚段及中膈)则为后者在肝门部的分化、植入所成[5]

成体胆道仍存BTSCs。通过分析各年龄层正常大胆管组织中的内胚源干细胞特性,近年研究[1]提示BTSCs很可能位于其PBGs内,该结构由黏、浆液腺泡组成的管泡腺,呈腔周壁内及壁外各自的网络样,由导管通入邻近的胆管腔。解剖原位分析显示,PBGs密度以胆胰壶腹及肝总管最高、肝内大胆管最低,不存在于小叶间胆管及胆小管,偶见中膈胆管。

成体 PBGs表达 SOX17、SOX9、PDX1、SALL4等内胚源转录因子与EpCAM、NCAM、CD133、CXCR4等干细胞标志;且存在差异性腺体内分布,自基底、中部至濒临胆管腔,上述表达及增殖标记PCNA渐衰减、甚至消失,而成熟标志渐获取,至于具体的成熟标志与所处解剖位置相关(肝内、邻近肝脏抑胰腺)[2]。另外,自PBGs中获取的SOX17+/PDX1+/EpCAM+细胞,在某种微环境下保持表型稳态的未分化状达数月;体外特定培养呈多潜能,选择培养条件可单向分化为胆管细胞、肝细胞或胰岛细胞;SCID鼠肝包膜下注射发现,部分移植细胞主要参与肝内大胆管黏膜上皮的构建,并表达CK7、胰泌素受体等[2]。在糖尿病动物模型和II型糖尿病患者中研究显示,PBGs向胰岛素生成细胞分化、增殖并扩张,且达稳态胰岛再生平衡[6]。自胎儿样本的相继探索证实,PBGs中的BTSCs截然不同于胆管板中的hHpSCs(即:成体肝脏Hering管中的hHpSCshumanhepaticstermyprogenitor cells)[7]。此外,鼠模型中发现[8],PBGs上皮“春笋般”增殖常继发于邻近的胆管黏膜损伤;与近来有关肝移植的报道[9]一致:供肝PBGs及其血管丛的损伤程度,与移植后非吻合性胆道狭窄的发生存在显著相关。因此,大胆管中的PBGs存在BTSCs,为胆胰胚胎干细胞在成体后的残留,能始终负责邻近胆管黏膜上皮的更新、修复。

至于胰腺,较大胰管壁内存在胰腺定向祖细胞栖息的胰管腺体(pancreatic ductal glands,PDGs),以胰头主胰管居多,胰尾及较大小叶间导管较少,并最终消失于直径小于300 μm的小叶间导管,与PBGs在胆道树中的分布相似[10]。研究提示[3,6,10]

胰腺定向祖细胞的前体为胆道干细胞(BTSCs),且遵循由近(PBGs))及远(PDGs)的谱系发育、逐渐成熟,并担负修复慢性、广泛损伤[11]

2 胆、胰肿瘤癌前病变

2.1 胆胰上皮内瘤变

胆管上皮内瘤样变(biliary intraepithelial neoplasm,BilIN),主要发生于大胆管,胆囊偶见。镜下呈微乳头、假乳头、或扁平状生长,常伴慢性胆道疾病,部分CCA并存BilINs,提示可能参与多步骤癌变过程。目前,根据细胞及结构异型度,BilIN分为BilIN-1/-2/-3,与胰腺上皮内瘤变(pancreatic intraepithelial neoplasia,PanIN)相对应。近年,细胞周期相关分子研究显示[12],随BilIN异型增高,p21、cyclin D1逐渐上调,而SMAD4表达下调。另外,相比于BilIN-1/2,BilIN-3及侵袭性CCA中p53显著上调,提示p53在BilIN转化为CCA并获取侵袭性中的作用。此外,p21,cyclin D1和p53在胆管非肿瘤上皮中不表达。随BilIN异型性增加,胆管上皮胞质及腔面粘蛋白表达模式也发生改变。研究显示[13],MUC1表达随BilIN异型增加而增多,而MUC5AC表达在BilIN-1/-2/-3中均较高。另外,BilIN偶有肠上皮化生、MUC2呈局灶表达却未见于PanIN。此外,相比于胆管非肿瘤上皮,BilIN中S100蛋白表达增加;尤其S100P在BilIN-3及侵袭性CCA中特异表达,而在BilIN-1/-2中不表达,提示S100P参与胆管癌变的晚期阶段[14]。PBGs中也存在BilINs,并囊括BilIN-1/-2/-3。研究证实,胆道慢性炎症背景下,PBGs历经病理改变、最终形成CCA。而且,PBGs中的BilINs亦呈S100P、癌胚抗原、CA19-9等较强阳性反应[13]

PanIN为镜下扁平或微乳头非侵袭性病变,隆起高度通常小于5 mm,为PDAC最常见的癌前病变。同理,PanIN目前分为低级别(包括先前分类中的PanIN-1/-2)与高等级(即先前分类中的PanIN-3),与BilIN的内涵基本相似。研究证实[13,15],非肿瘤胰导管上皮中不存在cyclin D1、p21、p53等表达,而SMAD4表达丧失发生于高而非低级别PanIN中,属于癌变的典型晚期事件。粘蛋白表达情况,PanIN几近不表达MUC2外,余与BilIN相似:从PanIN至PDAC,MUC1呈逐渐过表达;MUC5AC在PanIN、尤其PDAC中表达,提示为癌变的早期事件,或许可尝试用于早期筛查[16]。另外,高级别PanIN与PDAC中的S100P表达较低级别PanIN增加。PanIN中最常见的突变基因为Kras(>90%),尤其见于低级别PanIN,提示Kras突变是PDAC发生的起始事件,但终究不能作为其浸润性发生的唯一因素。Hedgehog通路在胰腺胚胎发育及其干细胞调控中至关重要。对比正常胰腺,PanIN与浸润性癌Sonic Hedgehog(SHH)高表达,进一步发现Gli1作为Hedgehog途径中的转录激活靶点,其过表达与ICCA浸润及转移密切相关。而且Kras突变与SHH活化在肿瘤早期发展阶段存在协同作用[13,16]。对比 PanINs,约 30%BilINs发生Kras突变,显著较低,但类似PDAC的多步骤致癌历程,同样提示,至少部分CCA的形成最早始于低级别 BilIN[17]。同理,类似胆道 PBGs,慢性胰腺炎等疾病背景可激活PDGs中的胰腺定向祖细胞[11]。具体而言,PDGs中 MUC-6上调和MUC5AC重新表达,有利于其粘液化生,并伴PanIN样病变。

因此,BilIN和PanIN具有相似组织学、免疫组化特征,以及与CCA和PDAC多步骤致癌相关的类似分子改变。

2.2 胆管、胰管内乳头状瘤

胆管内乳头状瘤(intraductal papillary neoplasm of the bile duct,IPNB)属于胆道罕见疾病,主要发生于肝内胆管结石、华支睾吸虫病等流行的远东地区[18]。大体位于大胆管内,呈胆管内乳头状增生、内含纤细的纤维血管核心,有时伴阻塞性胆管扩张、粘液分泌,偶有囊性变,代表了不同于BilIN的另一致癌途径,与胰管内乳头状黏液性肿瘤(intraductal papillary mucinous neoplasm of the pancreas,IPMN)相对应。根据免疫表型及组织学,IPNB分为胰胆管型、胃型、肠型和嗜酸细胞型,其中以胰胆管型最常见,后依次为肠型、胃型、嗜酸细胞型[19]。研究显示[18],粘蛋白核心蛋白表达与IPNB的上皮亚型相关。MUC-1主要表达于胰胆管型,但不表达于其它亚型;MUC-2在肠型中表达;而MUC5AC表达于所有亚型,包括嗜酸细胞型,后者也显示MUC-1和/或MUC-2的局部表达,提示嗜酸细胞型可能是胰胆管型的变异体。另外,尽管高分泌粘蛋白为IPMN典型且常见特征,但它仅常见于IPNB中的胃型、肠型,而非胰胆管型[20]。此外,某些细胞角蛋白的表达也与IPNB亚型有关,尤其CK20表达与肠型有关,而CK7与胃型有关[18]

大胆管PBGs也常发生慢性囊样扩张、微乳头状或异型增生、瘤样变及癌变等改变,为不同组织形态学的有机组合,类似甚至等同于CCA合并IPNB 和/或 BilIN。2009年 Nakanishi等[21]率先报道1例源自左肝管旁壁外PBGs的IPNB合并原位癌,该瘤体基底部为原位癌,起始部与囊样腺体上皮相连,延续为乳头状瘤,沿已扩张的腺体导管延伸至左肝管内,而该处胆管黏膜上皮未见病变,此外其周围PBGs亦呈囊性扩张。往后他们又发现1例更为早期的典型小病灶(1.6 cm×1.4 cm),位于肝Ⅴ段胆管旁,另一胃型粘蛋白MUC6均高表达于 PBGs和 IPNB,但未表达于正常胆管上皮[22]。至今,多个报道重复上述观察,即:均以PBGs的慢性囊状扩张为前提,始于囊腔基底部、游离生长至邻近的大胆管腔内,犹如“参天大树、根深叶茂”,而该处胆管黏膜未见类似病变。

IPMN位于胰腺导管系统内,由产粘液细胞构成、肉眼可见的非侵袭性上皮肿瘤,可能来自主胰管(IPMN-main pancreatic duct,IPMN-MD)和/或分支胰管(IPMN-branch ducts,IPMN-BD)[23]。健康人群中,IPMN患病率约7%,多为IPMN-BD型,常为意外诊断[24]。IPMN-BD中胃型最常见,为MUC-1阴性、MUC5AC阳性和CK20阴性;而IPMN-MD最常见胰胆管型和肠型,前者为MUC-1/MUC5AC阳性和MUC-2阴性,后者MUC-2/MUC5AC阳性和MUC-1阴性。研究提示[25],粘蛋白表达模式与IPMN可能发生的两类肿瘤有关:导致管状腺癌的MUC1途径和演变成粘液腺癌的MUC2途径。特别是,胰胆管型与浸润性管状腺癌强相关,由于确诊多为晚期、术后高复发,预后最差[26]。由此MUC-1表达预示其较短生存,类似于IPNBs的有关报道。相似于IPNB可能源自PBGs,PDGs可能在IPMN的发展中起核心作用。IPMN中的TFF2高表达在PDGs中也观察到[27]。此外,粘蛋白及角蛋白在IPMN尤其IPMN-MD中的表达情况,与IPNB类似。

尽管IPMN和IPNB具有很大相似性,但也存在一些差异,包括:几乎所有IPMN均观察到粘蛋白的产生,而IPNB仅报道1/3;IPNB胃型较IPMN显著少见;CK20在IPNB中的表达较IPMN更为普遍,等等。特别是,IPNB和IPMN-MD具有更多相似的组织学和表型特征,且恶性转化率较高,支持“共同疾病实体”学说,但大部分IPMN-BD具有不同分子谱、生物学及临床行为。

3 胆管癌和胰腺导管腺癌

胆管癌按相应解剖原发部位,分为肝内(intra-hepatic)、肝门周(perihilar)及远端(distal)CCA。组织学上,p/d CCA主要为粘液腺癌或乳头瘤,而iCCA包括传统型腺癌、胆小管型、罕见变异型等。CCA并非统一实体,而是高度异质,主要集中于iCCA[28]。近年,大体依据肿瘤细胞呈高柱状组成的较大腺样还是乏胞质的立方或低柱状,或者与肝内大胆管黏液柱状上皮和小胆管非黏液立方上皮的形貌相似度等,多位学者相继提出不同的iCCA组织学分型,主要包括黏液型和混合型、胆管型和胆小管型、经典和非经典型、肝内大胆管型和小胆管型等。研究证实[28-30],上述iCCA二分亚型在疾病背景、伴随病变、临床病理、分子特征等均截然不同,前者趋同于p/d CCA,后者部分类似胆小管癌(cholangiolocellularcarcinoma),因此其内涵相似。基于胚胎学起源,iCCA亚型可能反映不同的起源细胞。后者如小胆管型等,可能起源于胆管末梢Hering管或胆小管中的肝干/祖细胞(hHpSCs),而前者如大胆管型等,与p/dCCA均源于大胆管PBGs中的BTSCs或胆管上皮细胞。综上所述[1,28-30],其依据包括:PBGs可形成癌前病变,其分布与上述相应肿瘤发生部位一致,还有仅在PBGs底部发现的干/祖细胞标志同样表达于相应肿瘤中的癌干细胞。

胰腺导管腺癌为胰腺恶性肿瘤的主体(约近90%)[31],可认为与p/dCCA及大胆管型亚类样的iCCA相对应。这两类肿瘤大体均呈坚实、灰白、浸润性结节硬化样;组织学上可产生粘蛋白,为分化良好的管状腺癌,有时伴微乳头,常有神经周围及淋巴血管浸润,且纤维间质丰富。基于上述组织学特性,尤其富含基质,反映在计算机断层扫描和磁共振成像上,也颇具特异的相似影像学特征。

免疫组化显示[32],正常胰管很少表达粘蛋白,但PDAC与p/dCCA均过表达,尤其MUC1、MUC4和MUC5A。约80%PDAC表达MUC1,且与肿瘤大小及异型性相关。MUC1高表达p/dCCA患者较MUC1低表达且MUC2高表达者预后更差,并与转移密切相关。至于MUC4[33],在肿瘤发生过程逐渐表达,并表达于最早期PanIN病变,且与其异型度及PDAC不良预后关系密切。同样,MUC4不表达于正常胆管上皮,但表达于CCA,且可预测不良预后。另外,p/dCCA较ICCA更频繁表达MUC5AC。PDAC中Kras和p53基因突变最为常见,其中前者接近100%,且起始于早期阶段[13]。而Kras突变在CCA中明显较少,但同样在BilIN早期即有Kras突变,提示可能属于CCA发生的早期事件[17]。另外,p53突变还常见于CCA,但似乎参与癌变的晚期阶段。关于免疫表型[34,35],PDAC和CCA均具有S100P等表型特征,以及CK-7,CK-17、CK-19 等肿瘤标志物[36]

近年来,高通量测序技术联合系统生物学分析证实PDAC和CCA具有显著的肿瘤间及瘤内异质性。迄今,多个研究机构相继提出不同的PDAC分子分型,各自病例研究中初步显示与临床结局密切相关,可指导系统化疗、分子靶向、免疫治疗等选择[37]。另外,Sia等提出分子谱相异的ICCA两亚类[38]:炎症型与增殖型,他们发现增殖型ICCA较炎症型预后更差。还有非编码RNA尤其microRNA(miRNA),在瘤细胞增殖、侵袭、转移、耐药等通路调控上作用较大而被广泛、深入研究。目前发现,miR-21、miR-25、miR-26a、miR-191、miR-221等参与 CCA 的发生、演进[13];miR-21、miR-196a、miR-221/222等参与PDAC恶性生物学的分子调控[13,39],miR-126、let-7等与PDAC侵袭及转移相关[13,40]

因此,PDAC与CCA具有较广泛的共同组织学和免疫表型特征,其分子特征可解释两者类似的不良预后,但部分也归因于晚期发现、常规放化疗不敏感等现状。

4 结 语

总之,CCA和PDAC及其癌前病变具有相似甚至某种程度上相同的致病因素、组织学、分子生物学、疾病演进、临床结局等,可能缘于共同的胚胎发育及干细胞起源,为将两类疾病当作共同体进行监测、防治奠定了部分理论基础。另外,临床实践中遇及的多样性,也提示胆胰肿瘤及其癌前病变的复杂性。鉴于可能的起源细胞谱系、疾病背景,及其特定分子发病机理(基因突变、表观遗传、通路紊乱等)存在相互作用[29],决定了两类相关疾病具体发生、发展的多种模式,即差异性,充分体现普遍性与特殊性的统一,有待深入探索,为综合理念下的个体化治疗进一步提供理论依据。

参考文献

[1] Nakagawa H,Hayata Y,Yamada T,et al.Peribiliary Glands as the Cellular Origin of Biliary Tract Cancer[J].Int J Mol Sci,2018,19(6):1745.

[2] Cardinale V,Wang Y,Carpino G,et al.Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes,cholangiocytes,and pancreatic islets[J].Hepatology,2011,54(6):2159-2172.

[3] Wang Y,Lanzoni G,Carpino G,et al.Biliary tree stem cells,precursors to pancreatic committed progenitors:evidence for possible life-long pancreatic organogenesis[J].Stem Cells,2013,31(9):1966-1979.

[4] Nakanuma Y,Harada K,Sasaki M,Sato Y.Proposal of a new disease concept“biliary diseases with pancreatic counterparts”.Anatomical and pathological bases [J].Histol Histopathol,2014,29(1):1-10.

[5] Cardinale V,Wang Y,Carpino G,et al.The biliary tree--a reservoir of multipotent stem cells[J].Nat Rev Gastroenterol Hepatol,2012,9(4):231-240.

[6] Carpino G,Puca R,Cardinale V,et al.Peribiliary Glands as a Niche of Extrapancreatic Precursors Yielding Insulin-Producing Cells in Experimental and Human Diabetes[J].Stem Cells,2016,34(5):1332-1342.

[7] Semeraro R,Carpino G,Cardinale V,et al.Multipotent stem/progenitor cells in the human foetal biliary tree[J].J Hepatol,2012,57(5):987-994.

[8] DiPaola F,Shivakumar P,Pfister J,et al.Identification of intramural epithelial networks linked to peribiliary glands that express progenitor cell markers and proliferate after injury in mice[J].Hepatology,2013,58(4):1486-1496.

[9] op den Dries S,Westerkamp AC,Karimian N,et al.Injury to peribiliary glands and vascular plexus before liver transplantation predicts formation of non-anastomotic biliary strictures[J].J Hepatol,2014,60(6):1172-1179.

[10] Carpino G,Renzi A,Cardinale V,et al.Progenitor cell niches in the human pancreatic duct system and associated pancreatic duct glands:an anatomical and immunophenotyping study[J].J Anat,2016,228(3):474-486.

[11] Yamaguchi J,Liss AS,Sontheimer A,et al.Pancreatic duct glands(PDGs)are a progenitor compartment responsible for pancreatic ductal epithelial repair[J].Stem Cell Res,2015,15(1):190-202.

[12] Nakanishi Y,Zen Y,Kondo S,et al.Expression of cell cyclerelated molecules in biliary premalignant lesions:biliary intraepithelial neoplasia and biliary intraductal papillary neoplasm[J].Hum Pathol,2008,39(8):1153-1161.

[13] Zaccari P,Cardinale V,Severi C,et al.Common features between neoplastic and preneoplastic lesions of the biliary tract and the pancreas[J].World J Gastroenterol,2019,25(31):4343-4359.

[14] Sato Y,Harada K,Sasaki M,Nakanuma Y.Clinicopathological significance of S100 protein expression in cholangiocarcinoma[J].J Gastroenterol Hepatol,2013,28(8):1422-1429.

[15] Sato Y,Harada K,Sasaki M,Nakanuma Y.Histological Characterization of Biliary Intraepithelial Neoplasia with respect to Pancreatic Intraepithelial Neoplasia[J].Int J Hepatol,2014.2014:678260.

[16] Guo J,Xie K,Zheng S.Molecular Biomarkers of Pancreatic Intraepithelial Neoplasia and Their Implications in Early Diagnosis and Therapeutic Intervention of Pancreatic Cancer[J].Int J Biol Sci,2016,12(3):292-301.

[17] Hsu M,Sasaki M,Igarashi S,et al.KRAS and GNAS mutations and p53 overexpression in biliary intraepithelial neoplasia and intrahepatic cholangiocarcinomas[J].Cancer,2013,119(9):1669-1674.

[18] Ohtsuka M,Shimizu H,Kato A,et al.Intraductal papillary neoplasms of the bile duct[J].Int J Hepatol,2014,2014:459091.

[19] Fukumura Y,Nakanuma Y,Kakuda Y,et al.Clinicopathological features of intraductal papillary neoplasms of the bile duct:a comparison with intraductal papillary mucinous neoplasm of the pancreas with reference to subtypes[J].Virchows Arch,2017,471(1):65-76.

[20] Rocha FG,Lee H,Katabi N,et al.Intraductal papillary neoplasm of the bile duct:a biliary equivalent to intraductal papillary mucinous neoplasm of the pancreas [J].Hepatology,2012,56(4):1352-1360.

[21] Nakanishi Y,Zen Y,Hirano S,et al.Intraductal oncocytic papillary neoplasm of the bile duct:the first case of peribiliary gland origin[J].J Hepatobiliary Pancreat Surg,2009,16(6):869-873.

[22] Nakanishi Y,Nakanuma Y,Ohara M,et al.Intraductal papillary neoplasm arising from peribiliary glands connecting with the inferior branch of the bile duct of the anterior segment of the liver[J].Pathol Int,2011,61(12):773-777.

[23] Tulla KA,Maker AV.Can we better predict the biologic behavior of incidental IPMN?A comprehensive analysis of molecular diagnostics and biomarkers in intraductal papillary mucinous neoplasms of the pancreas[J].Langenbecks Arch Surg,2018,403(2):151-194.

[24] Zerboni G,Signoretti M,Crippa S,et al.Systematic review and meta-analysis:Prevalence of incidentally detected pancreatic cystic lesions in asymptomatic individuals[J].Pancreatology,2019,19(1):2-9.

[25] Adsay NV,Merati K,Andea A,et al.The dichotomy in the preinvasive neoplasia to invasive carcinoma sequence in the pancreas:differential expression of MUC1 and MUC2 supports the existence of two separate pathways of carcinogenesis[J].Mod Pathol,2002,15(10):1087-1095.

[26] Distler M,Kersting S,Niedergethmann M,et al.Pathohistological subtype predicts survival in patients with intraductal papillary mucinous neoplasm(IPMN)of the pancreas[J].Ann Surg,2013,258(2):324-330.

[27] Yamaguchi J,Mino-Kenudson M,Liss AS,et al.Loss of Trefoil Factor 2 From Pancreatic Duct Glands Promotes Formation of Intraductal Papillary Mucinous Neoplasms in Mice[J].Gastroenterology,2016,151(6):1232-1244.e10.

[28] Kendall T,Verheij J,Gaudio E,et al.Anatomical,histomorphological and molecular classification of cholangiocarcinoma[J].Liver Int,2019,39(Suppl 1):7-18.

[29] Bragazzi MC,Ridola L,Safarikia S,et al.New insights into cholangiocarcinoma:multiple stems and related cell lineages of origin[J].Ann Gastroenterol,2018,31(1):42-55.

[30] Aishima S,Oda Y.Pathogenesis and classification of intrahepatic cholangiocarcinoma:different characters of perihilar large duct type versus peripheral small duct type[J].J Hepatobiliary Pancreat Sci,2015,22(2):94-100.

[31] Luchini C,Capelli P,Scarpa A.Pancreatic Ductal Adenocarcinoma and Its Variants[J].Surg Pathol Clin,2016,9(4):547-560.

[32] Suh H,Pillai K,Morris DL.Mucins in pancreatic cancer:biological role,implications in carcinogenesis and applications in diagnosis and therapy[J].Am J Cancer Res,2017,7(6):1372-1383.

[33] Gautam SK,Kumar S,Cannon A,et al.MUC4 mucin-a therapeutic target for pancreatic ductal adenocarcinoma[J].Expert Opin Ther Targets,2017,21(7):657-669.

[34] Ali A,Brown V,Denley S,et al.Expression of KOC,S100P,mesothelin and MUC1 in pancreatico-biliary adenocarcinomas:development and utility of a potential diagnostic immunohistochemistry panel[J].BMC Clin Pathol,2014,14:35.

[35] Hamada S,Satoh K,Hirota M,et al.Calcium-binding protein S100P is a novel diagnostic marker of cholangiocarcinoma[J].Cancer Sci,2011,102(1):150-156.

[36] Perysinakis I,Margaris I,Kouraklis G.Ampullary cancer--a separate clinical entity[J].Histopathology,2014,64(6):759-768.

[37] Ren B,Liu X,Suriawinata AA.Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions:Histopathology,Cytopathology,and Molecular Pathology[J].Am J Pathol,2019,189(1):9-21.

[38] Sia D,Hoshida Y,Villanueva A,et al.Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes[J].Gastroenterology,2013,144(4):829-840.

[39] Xu Q,Li P,Chen X,et al.miR-221/222 induces pancreatic cancer progression through the regulation of matrix metalloproteinases[J].Oncotarget,2015,6(16):14153-14164.

[40] Jiao LR,Frampton AE,Jacob J,et al.MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors[J].PLoS ONE,2012,7(2):e32068.

Research status of commonality between cancerous and precancerous lesions of the biliary tract and the pancreas

PENG Ning-fu1,ZHONG Jian-hong1,ZHU Shao-liang1,LIAO Ying-yang2,LI Le-qun1
1.Department of Hepatopancreatobiliary Surgery;2.Nutrition Department,the Affiliated Tumor Hospital of Guangxi Medical University,Nanning 530021,China

[Abstract] Neoplastic and preneoplastic lesions of the biliary tract and the pancreas share analogies in terms of molecular,histopathological and clinical features due to their anatomical proximity and common embryological origin.This review systematically illustrates similarities and differences between cancerous and precancerous lesions of the biliary tract and the pancreas with potential implications on a common origin from similar stem/progenitor cells,which will provides the theoretical basis for learning from each other on the related research,joint monitoring,common prevention and treatment,and individualized strategy under the comprehensive concept for the two types of diseases.

[Key words] cholangiocarcinoma;pancreatic ductal adenocarcinoma;precancerous lesions;commonality;stem cell

doi: 10.3969/j.issn.1009-976X.2020.02.025

中图分类号:R735.8;R735.9

文献标识码:A

基金项目: 国家自然科学基金地区项目(81560460/H1602);广西区卫计委项目(Z2016479)

作者单位:广西医科大学附属肿瘤医院1.肝胆胰外科;2.临床营养科,广西南宁530021

*通讯作者:黎乐群,Email:lilq2010@163.com

Corresponding author:LI Le-qun,lilq2010@163.com

(收稿日期:2020-02-13)

关键词: 癌前病变, 干细胞, 胰腺导管腺癌, 胆管癌, 共性

CLC Number: