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Pathology & Oncology Research
Published in: Pathology & Oncology Research 1/2020

01-01-2020 | Review

Cholangiocarcinoma: Classification, Histopathology and Molecular Carcinogenesis

Authors: Gábor Lendvai, Tímea Szekerczés, Idikó Illyés, Réka Dóra, Endre Kontsek, Alíz Gógl, András Kiss, Klára Werling, Ilona Kovalszky, Zsuzsa Schaff, Katalin Borka

Published in: Pathology & Oncology Research | Issue 1/2020

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Abstract

Cholangiocarcinoma (CC) is the second most common tumor of the liver, originating from the biliary system with increasing incidence and mortality worldwide. Several new classifications review the significance of tumor localization, site of origin, proliferation and biomarkers in the intrahepatic, perihilar and distal forms of the lesion. Based on growth pattern mass-forming, periductal-infiltrating, intraductal, undefined and mixed types are differentiated. There are further subclassifications which are applied for the histological features, in particular for intrahepatic CC. Recognition of the precursors and early lesions of CC including biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of the bile ducts (IPNB), biliary mucinous cystic neoplasm (MCNB) and the candidate precursors, such as bile duct adenoma and von Meyenburg complex is of increasing significance. In addition to the previously used biliary markers detected by immunohistochemistry, several new markers have been added to the differentiation of both the benign and malignant lesions, which can be used to aid in the subclassification in association with the outcome of CC. Major aspects of biliary carcinogenesis have been revealed, yet, the exact way of this diverse process is still unclear. The factors contributing to molecular cholangiocarcinogenesis include various risk factors, different anatomical localizations, multiple cellular origins, genetic and epigenetic alterations, tumor microenvironment, heterogeneity and clonal evolution. Driver mutations have been identified, implying that they are optimal candidates for targeted therapy. The most promising therapeutic candidates have entered clinical trials.
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Literature
1.
Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, Pawlik TM, Gores GJ (2014) Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 60(6):1268–1289PubMedCrossRef
2.
Dodson RM, Weiss MJ, Cosgrove D, Herman JM, Kamel I, Anders R, Geschwind JF, Pawlik TM (2013) Intrahepatic cholangiocarcinoma: management options and emerging therapies. J Am Coll Surg 217(4):736–750 e734PubMedCrossRef
3.
Rizvi S, Gores GJ (2013) Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 145(6):1215–1229PubMedCrossRef
4.
Javle M, Bekaii-Saab T, Jain A, Wang Y, Kelley RK, Wang K, Kang HC, Catenacci D, Ali S, Krishnan S, Ahn D, Bocobo AG, Zuo M, Kaseb A, Miller V, Stephens PJ, Meric-Bernstam F, Shroff R, Ross J (2016) Biliary cancer: utility of next-generation sequencing for clinical management. Cancer 122(24):3838–3847PubMedCrossRef
5.
Nakanuma Y, Sato Y, Harada K, Sasaki M, Xu J, Ikeda H (2010) Pathological classification of intrahepatic cholangiocarcinoma based on a new concept. World J Hepatol 2(12):419–427PubMedPubMedCentralCrossRef
6.
Nakanuma Y, Tsutsui A, Ren XS, Harada K, Sato Y, Sasaki M (2014) What are the precursor and early lesions of peripheral intrahepatic cholangiocarcinoma? Int J Hepatol 2014:805973PubMedPubMedCentralCrossRef
7.
Maemura K, Natsugoe S, Takao S (2014) Molecular mechanism of cholangiocarcinoma carcinogenesis. J Hepatobiliary Pancreat Sci 21(10):754–760PubMedCrossRef
8.
Cai Y, Cheng N, Ye H, Li F, Song P, Tang W (2016) The current management of cholangiocarcinoma: a comparison of current guidelines. Biosci Trends 10(2):92–102PubMedCrossRef
9.
Marcano-Bonilla L, Mohamed EA, Mounajjed T, Roberts LR (2016) Biliary tract cancers: epidemiology, molecular pathogenesis and genetic risk associations. Chin Clin Oncol 5(5):61PubMedCrossRef
10.
11.
Nakanuma Y, Harada K, Sasaki M, Sato Y (2014) Proposal of a new disease concept "biliary diseases with pancreatic counterparts". Anatomical and pathological bases. Histol Histopathol 29(1):1–10PubMed
12.
Simbolo M, Fassan M, Mafficini A, Lawlor RT, Ruzzenente A, Scarpa A (2016) New genomic landscapes and therapeutic targets for biliary tract cancers. Front Biosci (Landmark Ed) 21:707–718CrossRef
13.
Serafini FM, Radvinsky D (2016) The pathways of genetic transformation in cholangiocarcinogenesis. Cancer Genet 209(12):554–558PubMedCrossRef
14.
Jain A, Kwong LN, Javle M (2016) Genomic profiling of biliary tract cancers and implications for clinical practice. Curr Treat Options in Oncol 17(11):58CrossRef
15.
Edge SB, Byrd DR, Compton CC (2010) AJCC Cancer staging manual, 7th edn. Springer, New York
16.
Sobin LH, Gospodarowicz MK, Wittekind C (2009) TNM classification of malignant tumors, 7th edn. Wiley-Blackwell, Oxford
17.
Gandou C, Harada K, Sato Y, Igarashi S, Sasaki M, Ikeda H, Nakanuma Y (2013) Hilar cholangiocarcinoma and pancreatic ductal adenocarcinoma share similar histopathologies, immunophenotypes, and development-related molecules. Hum Pathol 44(5):811–821PubMedCrossRef
18.
Nemeth Z, Szasz AM, Somoracz A, Tatrai P, Nemeth J, Gyorffy H, Szijarto A, Kupcsulik P, Kiss A, Schaff Z (2009) Zonula occludens-1, occludin, and E-cadherin protein expression in biliary tract cancers. Pathol Oncol Res 15(3):533–539PubMedCrossRef
19.
Nemeth Z, Szasz AM, Tatrai P, Nemeth J, Gyorffy H, Somoracz A, Szijarto A, Kupcsulik P, Kiss A, Schaff Z (2009) Claudin-1, −2, −3, −4, −7, −8, and −10 protein expression in biliary tract cancers. J Histochem Cytochem 57(2):113–121PubMedPubMedCentralCrossRef
20.
Zhou Y, Zhao Y, Li B, Huang J, Wu L, Xu D, Yang J, He J (2012) Hepatitis viruses infection and risk of intrahepatic cholangiocarcinoma: evidence from a meta-analysis. BMC Cancer 12:289PubMedPubMedCentralCrossRef
21.
Hu J, Yin B (2016) Advances in biomarkers of biliary tract cancers. Biomed Pharmacother 81:128–135PubMedCrossRef
22.
Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ (2018) Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol 15(2):95–111CrossRefPubMed
23.
Dong LQ, Shi Y, Ma LJ, Yang LX, Wang XY, Zhang S, Wang ZC, Duan M, Zhang Z, Liu LZ, Zheng BH, Ding ZB, Ke AW, Gao DM, Yuan K, Zhou J, Fan J, Xi R, Gao Q (2018) Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma. J Hepatol 69(1):89–98PubMedCrossRef
24.
Palmer WC, Patel T (2012) Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol 57(1):69–76PubMedPubMedCentralCrossRef
25.
Wei M, Lu L, Lin P, Chen Z, Quan Z, Tang Z (2016) Multiple cellular origins and molecular evolution of intrahepatic cholangiocarcinoma. Cancer Lett 379(2):253–261PubMedCrossRef
26.
Raggi C, Invernizzi P, Andersen JB (2015) Impact of microenvironment and stem-like plasticity in cholangiocarcinoma: molecular networks and biological concepts. J Hepatol 62(1):198–207PubMedCrossRef
27.
Moeini A, Sia D, Zhang Z, Camprecios G, Stueck A, Dong H, Montal R, Torrens L, Martinez-Quetglas I, Fiel MI, Hao K, Villanueva A, Thung SN, Schwartz ME, Llovet JM (2017) Mixed hepatocellular cholangiocarcinoma tumors: Cholangiolocellular carcinoma is a distinct molecular entity. J Hepatol 66(5):952–961PubMedCrossRef
28.
Mertens JC, Rizvi S, Gores GJ (2018) Targeting cholangiocarcinoma. Biochim Biophys Acta 1864(4 Pt B):1454–1460CrossRef
29.
Aishima S, Oda Y (2015) Pathogenesis and classification of intrahepatic cholangiocarcinoma: different characters of perihilar large duct type versus peripheral small duct type. J Hepatobiliary Pancreat Sci 22(2):94–100PubMedCrossRef
30.
Carpino G, Cardinale V, Onori P, Franchitto A, Berloco PB, Rossi M, Wang Y, Semeraro R, Anceschi M, Brunelli R, Alvaro D, Reid LM, Gaudio E (2012) Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages. J Anat 220(2):186–199PubMedCrossRef
31.
Nakanuma Y, Crurado MP, Franceschi S, Gores GJ, Paradis V, Sripa B, Tsui WMS, Wee A (2010) Intrahepatic cholangiocarcinoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds) WHO classification of tumors of the digestive system, 4th edn. IARC, Lyon, pp 217–224
32.
Fernandez Moro C, Fernandez-Woodbridge A, Alistair D'souza M, Zhang Q, Bozoky B, Kandaswamy SV, Catalano P, Heuchel R, Shtembari S, Del Chiaro M, Danielsson O, Bjornstedt M, Lohr JM, Isaksson B, Verbeke C, Bozoky B (2016) Immunohistochemical typing of adenocarcinomas of the Pancreatobiliary system improves diagnosis and prognostic stratification. PLoS One 11(11):e0166067PubMedPubMedCentralCrossRef
33.
Lagana S, Hsiao S, Bao F, Sepulveda A, Moreira R, Lefkowitch J, Remotti H (2015) HepPar-1 and Arginase-1 immunohistochemistry in adenocarcinoma of the small intestine and Ampullary region. Arch Pathol Lab Med 139(6):791–795PubMedCrossRef
34.
Lodi C, Szabo E, Holczbauer A, Batmunkh E, Szijarto A, Kupcsulik P, Kovalszky I, Paku S, Illyes G, Kiss A, Schaff Z (2006) Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas. Mod Pathol 19(3):460–469PubMedCrossRef
35.
Borka K, Kaliszky P, Szabo E, Lotz G, Kupcsulik P, Schaff Z, Kiss A (2007) Claudin expression in pancreatic endocrine tumors as compared with ductal adenocarcinomas. Virchows Arch 450(5):549–557PubMedCrossRef
36.
Kloppel G, Adsay V, Konukiewitz B, Kleeff J, Schlitter AM, Esposito I (2013) Precancerous lesions of the biliary tree. Best Pract Res Clin Gastroenterol 27(2):285–297PubMedCrossRef
37.
Sato Y, Sasaki M, Harada K, Aishima S, Fukusato T, Ojima H, Kanai Y, Kage M, Nakanuma Y, Tsubouchi H, Hepatolithiasis Subdivision of Intractable Hepatobiliary Diseases Study Group of J (2014) Pathological diagnosis of flat epithelial lesions of the biliary tract with emphasis on biliary intraepithelial neoplasia. J Gastroenterol 49(1):64–72PubMedCrossRef
38.
Sato Y, Harada K, Sasaki M, Nakanuma Y (2013) Histological characteristics of biliary intraepithelial neoplasia-3 and intraepithelial spread of cholangiocarcinoma. Virchows Arch 462(4):421–427PubMedCrossRef
39.
Bosman FT, Carneiro F, Hruban RH, Theise ND (2010) WHO classification of tumors of the digestive system, 4th edn. IARC, Lyon
40.
Ohtsuka M, Shimizu H, Kato A, Yoshitomi H, Furukawa K, Tsuyuguchi T, Sakai Y, Yokosuka O, Miyazaki M (2014) Intraductal papillary neoplasms of the bile duct. Int J Hepatol 2014(459091):1–10CrossRef
41.
Nakanuma Y, Uesaka K, Miyayama S, Yamaguchi H, Ohtsuka M (2017) Intraductal neoplasms of the bile duct. A new challenge to biliary tract tumor pathology. Histol Histopathol 32(10):1001–1015PubMed
42.
Zen Y, Adsay NV, Bardadin K, Colombari R, Ferrell L, Haga H, Hong SM, Hytiroglou P, Kloppel G, Lauwers GY, van Leeuwen DJ, Notohara K, Oshima K, Quaglia A, Sasaki M, Sessa F, Suriawinata A, Tsui W, Atomi Y, Nakanuma Y (2007) Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria. Mod Pathol 20(6):701–709PubMedCrossRef
43.
Hajosi-Kalcakosz S, Dezso K, Bugyik E, Bodor C, Paku S, Pavai Z, Halasz J, Schlachter K, Schaff Z, Nagy P (2012) Enhancer of zeste homologue 2 (EZH2) is a reliable immunohistochemical marker to differentiate malignant and benign hepatic tumors. Diagn Pathol 7:86PubMedPubMedCentralCrossRef
44.
Sasaki M, Matsubara T, Kakuda Y, Sato Y, Nakanuma Y (2014) Immunostaining for polycomb group protein EZH2 and senescent marker p16INK4a may be useful to differentiate cholangiolocellular carcinoma from ductular reaction and bile duct adenoma. Am J Surg Pathol 38(3):364–369PubMedCrossRef
45.
Fukumura Y, Nakanuma Y, Kakuda Y, Takase M, Yao T (2017) Clinicopathological features of intraductal papillary neoplasms of the bile duct: a comparison with intraductal papillary mucinous neoplasm of the pancreas with reference to subtypes. Virchows Arch 471(1):65–76PubMedCrossRef
46.
Wan XS, Xu YY, Qian JY, Yang XB, Wang AQ, He L, Zhao HT, Sang XT (2013) Intraductal papillary neoplasm of the bile duct. World J Gastroenterol 19(46):8595–8604PubMedPubMedCentralCrossRef
47.
Nakanuma Y, Sato Y, Ojima H, Kanai Y, Aishima S, Yamamoto M, Ariizumi S, Furukawa T, Hayashi H, Unno M, Ohta T, Hepatolithiasis Subdivision of Intractable Hepatobiliary Diseases Study Group of J (2014) Clinicopathological characterization of so-called "cholangiocarcinoma with intraductal papillary growth" with respect to "intraductal papillary neoplasm of bile duct (IPNB)". Int J Clin Exp Pathol 7(6):3112–3122PubMedPubMedCentral
48.
Zen Y, Fujii T, Itatsu K, Nakamura K, Minato H, Kasashima S, Kurumaya H, Katayanagi K, Kawashima A, Masuda S, Niwa H, Mitsui T, Asada Y, Miura S, Ohta T, Nakanuma Y (2006) Biliary papillary tumors share pathological features with intraductal papillary mucinous neoplasm of the pancreas. Hepatology 44(5):1333–1343PubMedCrossRef
49.
Nakanuma Y, Kakuda Y, Uesaka K, Miyata T, Yamamoto Y, Fukumura Y, Sato Y, Sasaki M, Harada K, Takase M (2016) Characterization of intraductal papillary neoplasm of bile duct with respect to histopathologic similarities to pancreatic intraductal papillary mucinous neoplasm. Hum Pathol 51:103–113PubMedCrossRef
50.
Fujikura K, Fukumoto T, Ajiki T, Otani K, Kanzawa M, Akita M, Kido M, Ku Y, Itoh T, Zen Y (2016) Comparative clinicopathological study of biliary intraductal papillary neoplasms and papillary cholangiocarcinomas. Histopathology 69(6):950–961PubMedCrossRef
51.
Aishima S, Tanaka Y, Kubo Y, Shirabe K, Maehara Y, Oda Y (2014) Bile duct adenoma and von Meyenburg complex-like duct arising in hepatitis and cirrhosis: pathogenesis and histological characteristics. Pathol Int 64(11):551–559PubMedCrossRef
52.
Zimmermann A (2017) Tumors and tumor-like lesions of the hepatobiliary tract. General and surgical pathology. Vol. 1. Springer, SwitzerlandCrossRef
53.
Bertram S, Padden J, Kalsch J, Ahrens M, Pott L, Canbay A, Weber F, Fingas C, Hoffmann AC, Vietor A, Schlaak JF, Eisenacher M, Reis H, Sitek B, Baba HA (2016) Novel immunohistochemical markers differentiate intrahepatic cholangiocarcinoma from benign bile duct lesions. J Clin Pathol 69(7):619–626PubMedCrossRef
54.
Tsokos CG, Krings G, Yilmaz F, Ferrell LD, Gill RM (2016) Proliferative index facilitates distinction between benign biliary lesions and intrahepatic cholangiocarcinoma. Hum Pathol 57:61–67PubMedPubMedCentralCrossRef
55.
Song JS, Lee YJ, Kim KW, Huh J, Jang SJ, Yu E (2008) Cholangiocarcinoma arising in von Meyenburg complexes: report of four cases. Pathol Int 58(8):503–512PubMedCrossRef
56.
Orii T, Ohkohchi N, Sasaki K, Satomi S, Watanabe M, Moriya T (2003) Cholangiocarcinoma arising from preexisting biliary hamartoma of liver--report of a case. Hepatogastroenterology 50(50):333–336PubMed
57.
O'Dell MR, Huang JL, Whitney-Miller CL, Deshpande V, Rothberg P, Grose V, Rossi RM, Zhu AX, Land H, Bardeesy N, Hezel AF (2012) Kras(G12D) and p53 mutation cause primary intrahepatic cholangiocarcinoma. Cancer Res 72(6):1557–1567PubMedPubMedCentralCrossRef
58.
Sato Y, Harada K, Sasaki M, Nakanuma Y (2014) Cystic and micropapillary epithelial changes of peribiliary glands might represent a precursor lesion of biliary epithelial neoplasms. Virchows Arch 464(2):157–163PubMedCrossRef
59.
Cardinale V, Wang Y, Carpino G, Mendel G, Alpini G, Gaudio E, Reid LM, Alvaro D (2012) The biliary tree--a reservoir of multipotent stem cells. Nat Rev Gastroenterol Hepatol 9(4):231–240PubMedCrossRef
60.
Sutton ME, op den Dries S, Koster MH, Lisman T, Gouw AS, Porte RJ (2012) Regeneration of human extrahepatic biliary epithelium: the peribiliary glands as progenitor cell compartment. Liver Int 32(4):554–559PubMedCrossRef
61.
Gibiino G, Fabbri C, Fagiuoli S, Ianiro G, Fornelli A, Cennamo V (2017) Defining the biology of intrahepatic cholangiocarcinoma: molecular pathways and early detection of precursor lesions. Eur Rev Med Pharmacol Sci 21(4):730–741PubMed
62.
Walter D, Hartmann S, Waidmann O (2017) Update on cholangiocarcinoma: potential impact of genomic studies on clinical management. Z Gastroenterol 55(6):575–581PubMedCrossRef
63.
64.
Wise C, Pilanthananond M, Perry BF, Alpini G, McNeal M, Glaser SS (2008) Mechanisms of biliary carcinogenesis and growth. World J Gastroenterol 14(19):2986–2989PubMedPubMedCentralCrossRef
65.
Xie D, Ren Z, Fan J, Gao Q (2016) Genetic profiling of intrahepatic cholangiocarcinoma and its clinical implication in targeted therapy. Am J Cancer Res 6(3):577–586PubMedPubMedCentral
66.
Tshering G, Dorji PW, Chaijaroenkul W, Na-Bangchang K (2018) Biomarkers for the diagnosis of cholangiocarcinoma: a systematic review. Am J Trop Med Hyg 98(6):1788–1797PubMedPubMedCentralCrossRef
67.
Nakanuma Y, Sasaki M, Sato Y, Ren X, Ikeda H, Harada K (2009) Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts. World J Hepatol 1(1):35–42PubMedPubMedCentralCrossRef
68.
69.
Sasaki M, Matsubara T, Nitta T, Sato Y, Nakanuma Y (2013) GNAS and KRAS mutations are common in intraductal papillary neoplasms of the bile duct. PLoS One 8(12):e81706PubMedPubMedCentralCrossRef
70.
Hsu M, Sasaki M, Igarashi S, Sato Y, Nakanuma Y (2013) KRAS and GNAS mutations and p53 overexpression in biliary intraepithelial neoplasia and intrahepatic cholangiocarcinomas. Cancer 119(9):1669–1674PubMedCrossRef
71.
Churi CR, Shroff R, Wang Y, Rashid A, Kang HC, Weatherly J, Zuo M, Zinner R, Hong D, Meric-Bernstam F, Janku F, Crane CH, Mishra L, Vauthey JN, Wolff RA, Mills G, Javle M (2014) Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One 9(12):e115383PubMedPubMedCentralCrossRef
72.
Nakaoka T, Saito Y, Saito H (2017) Aberrant DNA methylation as a biomarker and a therapeutic target of cholangiocarcinoma. Int J Mol Sci 18(6):1111PubMedCentralCrossRef
73.
Udali S, Guarini P, Moruzzi S, Ruzzenente A, Tammen SA, Guglielmi A, Conci S, Pattini P, Olivieri O, Corrocher R, Choi SW, Friso S (2015) Global DNA methylation and hydroxymethylation differ in hepatocellular carcinoma and cholangiocarcinoma and relate to survival rate. Hepatology 62(2):496–504PubMedCrossRef
74.
Chiang NJ, Shan YS, Hung WC, Chen LT (2015) Epigenetic regulation in the carcinogenesis of cholangiocarcinoma. Int J Biochem Cell Biol 67:110–114PubMedCrossRef
75.
Lee H, Wang K, Johnson A, Jones DM, Ali SM, Elvin JA, Yelensky R, Lipson D, Miller VA, Stephens PJ, Javle M, Ross JS (2016) Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets. J Clin Pathol 69(5):403–408PubMedCrossRef
76.
Yoo KH, Kim NK, Kwon WI, Lee C, Kim SY, Jang J, Ahn J, Kang M, Jang H, Kim ST, Ahn S, Jang KT, Park YS, Park WY, Lee J, Heo JS, Park JO (2016) Genomic alterations in biliary tract Cancer using targeted sequencing. Transl Oncol 9(3):173–178PubMedPubMedCentralCrossRef
77.
Simbolo M, Fassan M, Ruzzenente A, Mafficini A, Wood LD, Corbo V, Melisi D, Malleo G, Vicentini C, Malpeli G, Antonello D, Sperandio N, Capelli P, Tomezzoli A, Iacono C, Lawlor RT, Bassi C, Hruban RH, Guglielmi A, Tortora G, de Braud F, Scarpa A (2014) Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups. Oncotarget 5(9):2839–2852PubMedPubMedCentralCrossRef
78.
Ross JS, Wang K, Gay L, Al-Rohil R, Rand JV, Jones DM, Lee HJ, Sheehan CE, Otto GA, Palmer G, Yelensky R, Lipson D, Morosini D, Hawryluk M, Catenacci DV, Miller VA, Churi C, Ali S, Stephens PJ (2014) New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist 19(3):235–242PubMedPubMedCentralCrossRef
79.
Ruzzenente A, Fassan M, Conci S, Simbolo M, Lawlor RT, Pedrazzani C, Capelli P, D'Onofrio M, Iacono C, Scarpa A, Guglielmi A (2016) Cholangiocarcinoma heterogeneity revealed by multigene mutational profiling: clinical and prognostic relevance in surgically resected patients. Ann Surg Oncol 23(5):1699–1707PubMedCrossRef
80.
Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J (2017) Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep 18(11):2780–2794PubMedPubMedCentralCrossRef
81.
Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM (2013) Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 45(12):1470–1473PubMedPubMedCentralCrossRef
82.
Putra J, de Abreu FB, Peterson JD, Pipas JM, Mody K (2015) Molecular profiling of intrahepatic and extrahepatic cholangiocarcinoma using next generation sequencing. Exp Mol Pathol 99(2):240–244PubMedPubMedCentralCrossRef
83.
Zou S, Li J, Zhou H, Frech C, Jiang X (2014) Mutational landscape of intrahepatic cholangiocarcinoma. Nat Commun 5:5696PubMedCrossRef
84.
Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, Hama N, Hosoda F, Urushidate T, Ohashi S, Hiraoka N, Ojima H, Shimada K, Okusaka T, Kosuge T, Miyagawa S, Shibata T (2015) Genomic spectra of biliary tract cancer. Nat Genet 47(9):1003–1010PubMedCrossRef
85.
Sia D, Losic B, Moeini A, Cabellos L, Hao K (2015) Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nat Commun 6:6087PubMedCrossRef
86.
Fujimoto A, Furuta M, Shiraishi Y, Gotoh K, Kawakami Y (2015) Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity. Nat Commun 6:6120PubMedCrossRef
87.
88.
Lee H, Ross JS (2017) The potential role of comprehensive genomic profiling to guide targeted therapy for patients with biliary cancer. Ther Adv Gastroenterol 10(6):507–520CrossRef
89.
Moeini A, Sia D, Bardeesy N, Mazzaferro V, Llovet JM (2016) Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma. Clin Cancer Res 22(2):291–300PubMedCrossRef
90.
Chong DQ, Zhu AX (2016) The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets. Oncotarget 7(29):46750–46767PubMedPubMedCentralCrossRef
91.
Maroni L, Pierantonelli I, Banales JM, Benedetti A, Marzioni M (2013) The significance of genetics for cholangiocarcinoma development. Ann Transl Med 1(3):28PubMedPubMedCentral
92.
Dalmasso C, Carpentier W, Guettier C, Camilleri-Broet S, Borelli WV, Campos Dos Santos CR, Castaing D, Duclos-Vallee JC, Broet P (2015) Patterns of chromosomal copy-number alterations in intrahepatic cholangiocarcinoma. BMC Cancer 15:126PubMedPubMedCentralCrossRef
93.
Arnold A, Bahra M, Lenze D, Bradtmoller M, Guse K, Gehlhaar C, Blaker H, Heppner FL, Koch A (2015) Genome wide DNA copy number analysis in cholangiocarcinoma using high resolution molecular inversion probe single nucleotide polymorphism assay. Exp Mol Pathol 99(2):344–353PubMedCrossRef
94.
Oliveira IS, Kilcoyne A, Everett JM, Mino-Kenudson M, Harisinghani MG, Ganesan K (2017) Cholangiocarcinoma: classification, diagnosis, staging, imaging features, and management. Abdom Radiol (NY) 42(6):1637–1649CrossRef
95.
Andersen JB, Spee B, Blechacz BR, Avital I, Komuta M, Barbour A, Conner EA, Gillen MC, Roskams T, Roberts LR, Factor VM, Thorgeirsson SS (2012) Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 142(4):1021–1031 e1015PubMedCrossRef
96.
Sia D, Hoshida Y, Villanueva A, Roayaie S, Ferrer J, Tabak B, Peix J, Sole M, Tovar V, Alsinet C, Cornella H, Klotzle B, Fan JB, Cotsoglou C, Thung SN, Fuster J, Waxman S, Garcia-Valdecasas JC, Bruix J, Schwartz ME, Beroukhim R, Mazzaferro V, Llovet JM (2013) Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 144(4):829–840PubMedCrossRef
97.
Guest RV, Boulter L, Kendall TJ, Minnis-Lyons SE, Walker R, Wigmore SJ, Sansom OJ, Forbes SJ (2014) Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma. Cancer Res 74(4):1005–1010PubMedCrossRef
98.
Kongpetch S, Jusakul A, Ong CK, Lim WK, Rozen SG, Tan P, Teh BT (2015) Pathogenesis of cholangiocarcinoma: from genetics to signalling pathways. Best Pract Res Clin Gastroenterol 29(2):233–244PubMedCrossRef
99.
Oikawa T (2016) Cancer stem cells and their cellular origins in primary liver and biliary tract cancers. Hepatology 64(2):645–651PubMedCrossRef
100.
101.
Terada M, Horisawa K, Miura S, Takashima Y, Ohkawa Y, Sekiya S, Matsuda-Ito K, Suzuki A (2016) Kupffer cells induce notch-mediated hepatocyte conversion in a common mouse model of intrahepatic cholangiocarcinoma. Sci Rep 6:34691PubMedPubMedCentralCrossRef
102.
Shibata M, Shen MM (2013) The roots of cancer: stem cells and the basis for tumor heterogeneity. Bioessays 35(3):253–260PubMedCrossRef
103.
Brandi G, Farioli A, Astolfi A, Biasco G, Tavolari S (2015) Genetic heterogeneity in cholangiocarcinoma: a major challenge for targeted therapies. Oncotarget 6(17):14744–14753PubMedPubMedCentralCrossRef
104.
Walter D, Doring C, Feldhahn M, Battke F, Hartmann S, Winkelmann R, Schneider M, Bankov K, Schnitzbauer A, Zeuzem S, Hansmann ML, Peveling-Oberhag J (2017) Intratumoral heterogeneity of intrahepatic cholangiocarcinoma. Oncotarget 8(9):14957–14968PubMedPubMedCentralCrossRef
105.
Chan-On W, Nairismagi ML, Ong CK, Lim WK, Dima S, Pairojkul C, Lim KH, McPherson JR, Cutcutache I, Heng HL, Ooi L, Chung A, Chow P, Cheow PC, Lee SY, Choo SP, Tan IB, Duda D, Nastase A, Myint SS, Wong BH, Gan A, Rajasegaran V, Ng CC, Nagarajan S, Jusakul A, Zhang S, Vohra P, Yu W, Huang D, Sithithaworn P, Yongvanit P, Wongkham S, Khuntikeo N, Bhudhisawasdi V, Popescu I, Rozen SG, Tan P, Teh BT (2013) Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet 45(12):1474–1478PubMedCrossRef
106.
Cardinale V, Carpino G, Reid L, Gaudio E, Alvaro D (2012) Multiple cells of origin in cholangiocarcinoma underlie biological, epidemiological and clinical heterogeneity. World J Gastrointest Oncol 4(5):94–102PubMedPubMedCentralCrossRef
107.
Li Z, Shen J, Chan MT, Wu WK (2017) The role of microRNAs in intrahepatic cholangiocarcinoma. J Cell Mol Med 21(1):177–184PubMedCrossRef
108.
Wang N, Xia S, Chen K, Xiang X, Zhu A (2015) Genetic alteration regulated by microRNAs in biliary tract cancers. Crit Rev Oncol Hematol 96(2):262–273PubMedCrossRef
109.
Esparza-Baquer A, Labiano I, Bujanda L, Perugorria MJ, Banales JM (2016) MicroRNAs in cholangiopathies: potential diagnostic and therapeutic tools. Clin Res Hepatol Gastroenterol 40(1):15–27PubMedCrossRef
110.
Olaizola P, Lee-Law PY, Arbelaiz A, Lapitz A, Perugorria MJ, Bujanda L, Banales JM (2018) MicroRNAs and extracellular vesicles in cholangiopathies. Biochim Biophys Acta 1864(4 Pt B):1293–1307CrossRef
111.
112.
Mazzocca A, Ferraro G, Misciagna G, Carr BI (2016) A systemic evolutionary approach to cancer: Hepatocarcinogenesis as a paradigm. Med Hypotheses 93:132–137PubMedCrossRef
Metadata
Title
Cholangiocarcinoma: Classification, Histopathology and Molecular Carcinogenesis
Authors
Gábor Lendvai
Tímea Szekerczés
Idikó Illyés
Réka Dóra
Endre Kontsek
Alíz Gógl
András Kiss
Klára Werling
Ilona Kovalszky
Zsuzsa Schaff
Katalin Borka
Publication date
01-01-2020
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 1/2020
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-018-0491-8

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