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Cholangiocarcinoma: Classification, Histopathology and Molecular Carcinogenesis

  • Gábor Lendvai
  • Tímea Szekerczés
  • Idikó Illyés
  • Réka Dóra
  • Endre Kontsek
  • Alíz Gógl
  • András Kiss
  • Klára Werling
  • Ilona Kovalszky
  • Zsuzsa SchaffEmail author
  • Katalin Borka
Review

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.

Keywords

Cholangiocarcinoma Liver cancer Biliary markers Stem cells MicroRNA 

Notes

Funding

This work was supported by grant #OTKA 108548 by the Hungarian National Research Foundation and grant #NVKP_16_1–2016-0004 by the Hungarian National Research, Development and Innovation Office.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest with respect to the research, authorship, and/or publication of this article.

Supplementary material

12253_2018_491_MOESM1_ESM.docx (150 kb)
ESM 1 (DOCX 150 kb)

References

  1. 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):1268–1289PubMedCrossRefGoogle Scholar
  2. 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 e734PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Rizvi S, Gores GJ (2013) Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 145(6):1215–1229PubMedCrossRefPubMedCentralGoogle Scholar
  4. 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):3838–3847PubMedCrossRefPubMedCentralGoogle Scholar
  5. 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):419–427PubMedPubMedCentralCrossRefGoogle Scholar
  6. 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 2014:805973PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Maemura K, Natsugoe S, Takao S (2014) Molecular mechanism of cholangiocarcinoma carcinogenesis. J Hepatobiliary Pancreat Sci 21(10):754–760PubMedCrossRefPubMedCentralGoogle Scholar
  8. 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):92–102PubMedCrossRefPubMedCentralGoogle Scholar
  9. 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):61PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Razumilava N, Gores GJ (2014) Cholangiocarcinoma. Lancet 383(9935):2168–2179PubMedPubMedCentralCrossRefGoogle Scholar
  11. 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):1–10PubMedGoogle Scholar
  12. 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) 21:707–718CrossRefGoogle Scholar
  13. 13.
    Serafini FM, Radvinsky D (2016) The pathways of genetic transformation in cholangiocarcinogenesis. Cancer Genet 209(12):554–558PubMedCrossRefGoogle Scholar
  14. 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):58CrossRefGoogle Scholar
  15. 15.
    Edge SB, Byrd DR, Compton CC (2010) AJCC Cancer staging manual, 7th edn. Springer, New YorkGoogle Scholar
  16. 16.
    Sobin LH, Gospodarowicz MK, Wittekind C (2009) TNM classification of malignant tumors, 7th edn. Wiley-Blackwell, OxfordGoogle Scholar
  17. 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):811–821PubMedCrossRefPubMedCentralGoogle Scholar
  18. 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):533–539PubMedCrossRefPubMedCentralGoogle Scholar
  19. 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):113–121PubMedPubMedCentralCrossRefGoogle Scholar
  20. 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 12:289PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Hu J, Yin B (2016) Advances in biomarkers of biliary tract cancers. Biomed Pharmacother 81:128–135PubMedCrossRefGoogle Scholar
  22. 22.
    Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ (2018) Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol 15(2):95–111PubMedCrossRefGoogle Scholar
  23. 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):89–98PubMedCrossRefGoogle Scholar
  24. 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):69–76PubMedPubMedCentralCrossRefGoogle Scholar
  25. 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):253–261PubMedCrossRefGoogle Scholar
  26. 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):198–207PubMedCrossRefGoogle Scholar
  27. 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):952–961PubMedCrossRefGoogle Scholar
  28. 28.
    Mertens JC, Rizvi S, Gores GJ (2018) Targeting cholangiocarcinoma. Biochim Biophys Acta 1864(4 Pt B):1454–1460CrossRefGoogle Scholar
  29. 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):94–100PubMedCrossRefGoogle Scholar
  30. 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):186–199PubMedCrossRefGoogle Scholar
  31. 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 217–224Google Scholar
  32. 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):e0166067PubMedPubMedCentralCrossRefGoogle Scholar
  33. 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):791–795PubMedCrossRefGoogle Scholar
  34. 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):460–469PubMedCrossRefGoogle Scholar
  35. 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):549–557PubMedCrossRefGoogle Scholar
  36. 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):285–297PubMedCrossRefGoogle Scholar
  37. 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):64–72PubMedCrossRefGoogle Scholar
  38. 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):421–427PubMedCrossRefGoogle Scholar
  39. 39.
    Bosman FT, Carneiro F, Hruban RH, Theise ND (2010) WHO classification of tumors of the digestive system, 4th edn. IARC, LyonGoogle Scholar
  40. 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):1–10CrossRefGoogle Scholar
  41. 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):1001–1015PubMedGoogle Scholar
  42. 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):701–709PubMedCrossRefGoogle Scholar
  43. 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 7:86PubMedPubMedCentralCrossRefGoogle Scholar
  44. 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):364–369PubMedCrossRefGoogle Scholar
  45. 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):65–76PubMedCrossRefGoogle Scholar
  46. 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):8595–8604PubMedPubMedCentralCrossRefGoogle Scholar
  47. 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):3112–3122PubMedPubMedCentralGoogle Scholar
  48. 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):1333–1343PubMedCrossRefGoogle Scholar
  49. 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 51:103–113PubMedCrossRefGoogle Scholar
  50. 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):950–961PubMedCrossRefGoogle Scholar
  51. 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):551–559PubMedCrossRefGoogle Scholar
  52. 52.
    Zimmermann A (2017) Tumors and tumor-like lesions of the hepatobiliary tract. General and surgical pathology. Vol. 1. Springer, SwitzerlandCrossRefGoogle Scholar
  53. 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):619–626PubMedCrossRefGoogle Scholar
  54. 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 57:61–67PubMedPubMedCentralCrossRefGoogle Scholar
  55. 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):503–512PubMedCrossRefGoogle Scholar
  56. 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):333–336PubMedGoogle Scholar
  57. 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):1557–1567PubMedPubMedCentralCrossRefGoogle Scholar
  58. 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):157–163PubMedCrossRefGoogle Scholar
  59. 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):231–240PubMedCrossRefGoogle Scholar
  60. 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):554–559PubMedCrossRefPubMedCentralGoogle Scholar
  61. 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):730–741PubMedGoogle Scholar
  62. 62.
    Walter D, Hartmann S, Waidmann O (2017) Update on cholangiocarcinoma: potential impact of genomic studies on clinical management. Z Gastroenterol 55(6):575–581PubMedCrossRefGoogle Scholar
  63. 63.
    Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX (2017) New horizons for precision medicine in biliary tract cancers. Cancer Discov 7(9):943–962PubMedPubMedCentralCrossRefGoogle Scholar
  64. 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):2986–2989PubMedPubMedCentralCrossRefGoogle Scholar
  65. 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):577–586PubMedPubMedCentralGoogle Scholar
  66. 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):1788–1797PubMedCrossRefGoogle Scholar
  67. 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):35–42PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Marks EI, Yee NS (2016) Molecular genetics and targeted therapeutics in biliary tract carcinoma. World J Gastroenterol 22(4):1335–1347PubMedPubMedCentralCrossRefGoogle Scholar
  69. 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):e81706PubMedPubMedCentralCrossRefGoogle Scholar
  70. 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):1669–1674PubMedCrossRefPubMedCentralGoogle Scholar
  71. 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):e115383PubMedPubMedCentralCrossRefGoogle Scholar
  72. 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):1111PubMedCentralCrossRefPubMedGoogle Scholar
  73. 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):496–504PubMedCrossRefGoogle Scholar
  74. 74.
    Chiang NJ, Shan YS, Hung WC, Chen LT (2015) Epigenetic regulation in the carcinogenesis of cholangiocarcinoma. Int J Biochem Cell Biol 67:110–114PubMedCrossRefGoogle Scholar
  75. 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):403–408PubMedCrossRefGoogle Scholar
  76. 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):173–178PubMedPubMedCentralCrossRefGoogle Scholar
  77. 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):2839–2852PubMedPubMedCentralCrossRefGoogle Scholar
  78. 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):235–242PubMedPubMedCentralCrossRefGoogle Scholar
  79. 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):1699–1707PubMedCrossRefPubMedCentralGoogle Scholar
  80. 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):2780–2794PubMedPubMedCentralCrossRefGoogle Scholar
  81. 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):1470–1473PubMedPubMedCentralCrossRefGoogle Scholar
  82. 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):240–244PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Zou S, Li J, Zhou H, Frech C, Jiang X (2014) Mutational landscape of intrahepatic cholangiocarcinoma. Nat Commun 5:5696PubMedCrossRefPubMedCentralGoogle Scholar
  84. 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):1003–1010PubMedCrossRefPubMedCentralGoogle Scholar
  85. 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 6:6087PubMedCrossRefPubMedCentralGoogle Scholar
  86. 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 6:6120PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Rizvi S, Gores GJ (2017) Emerging molecular therapeutic targets for cholangiocarcinoma. J Hepatol 67(3):632–644PubMedPubMedCentralCrossRefGoogle Scholar
  88. 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):507–520CrossRefGoogle Scholar
  89. 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):291–300PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Chong DQ, Zhu AX (2016) The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets. Oncotarget 7(29):46750–46767PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Maroni L, Pierantonelli I, Banales JM, Benedetti A, Marzioni M (2013) The significance of genetics for cholangiocarcinoma development. Ann Transl Med 1(3):28PubMedPubMedCentralGoogle Scholar
  92. 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 15:126PubMedPubMedCentralCrossRefGoogle Scholar
  93. 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):344–353PubMedCrossRefGoogle Scholar
  94. 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):1637–1649CrossRefGoogle Scholar
  95. 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 e1015PubMedCrossRefGoogle Scholar
  96. 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):829–840PubMedPubMedCentralCrossRefGoogle Scholar
  97. 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):1005–1010PubMedCrossRefGoogle Scholar
  98. 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):233–244PubMedCrossRefGoogle Scholar
  99. 99.
    Oikawa T (2016) Cancer stem cells and their cellular origins in primary liver and biliary tract cancers. Hepatology 64(2):645–651PubMedCrossRefGoogle Scholar
  100. 100.
    Vijgen S, Terris B, Rubbia-Brandt L (2017) Pathology of intrahepatic cholangiocarcinoma. Hepatobiliary Surg Nutr 6(1):22–34PubMedPubMedCentralCrossRefGoogle Scholar
  101. 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 6:34691PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Shibata M, Shen MM (2013) The roots of cancer: stem cells and the basis for tumor heterogeneity. Bioessays 35(3):253–260CrossRefGoogle Scholar
  103. 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):14744–14753PubMedPubMedCentralCrossRefGoogle Scholar
  104. 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):14957–14968PubMedPubMedCentralCrossRefGoogle Scholar
  105. 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):1474–1478PubMedCrossRefGoogle Scholar
  106. 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):94–102PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Li Z, Shen J, Chan MT, Wu WK (2017) The role of microRNAs in intrahepatic cholangiocarcinoma. J Cell Mol Med 21(1):177–184PubMedCrossRefGoogle Scholar
  108. 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):262–273PubMedCrossRefGoogle Scholar
  109. 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):15–27PubMedCrossRefGoogle Scholar
  110. 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):1293–1307CrossRefGoogle Scholar
  111. 111.
    Loosen SH, Schueller F, Trautwein C, Roy S, Roderburg C (2017) Role of circulating microRNAs in liver diseases. World J Hepatol 9(12):586–594PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Mazzocca A, Ferraro G, Misciagna G, Carr BI (2016) A systemic evolutionary approach to cancer: Hepatocarcinogenesis as a paradigm. Med Hypotheses 93:132–137PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2018

Authors and Affiliations

  • Gábor Lendvai
    • 1
  • Tímea Szekerczés
    • 1
  • Idikó Illyés
    • 1
  • Réka Dóra
    • 1
  • Endre Kontsek
    • 1
  • Alíz Gógl
    • 1
  • András Kiss
    • 1
  • Klára Werling
    • 2
  • Ilona Kovalszky
    • 3
  • Zsuzsa Schaff
    • 1
    Email author
  • Katalin Borka
    • 1
  1. 1.2nd Department of PathologySemmelweis UniversityBudapestHungary
  2. 2.2nd Department of Internal MedicineSemmelweis UniversityBudapestHungary
  3. 3.1st Department of Pathology and Experimental Cancer ResearchSemmelweis UniversityBudapestHungary

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