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Epidemiology, pathogenesis, and classification of cholangiocarcinoma

Authors
Robert C Lowe, MD
Nezam H Afdhal, MD, FRCPI
Christopher D Anderson, MD, FACS
Section Editor
Kenneth K Tanabe, MD
Deputy Editors
Diane MF Savarese, MD
Anne C Travis, MD, MSc, FACG, AGAF

INTRODUCTION

Cholangiocarcinomas (bile duct cancers) arise from the epithelial cells of the intrahepatic and extrahepatic bile ducts. Although these cancers are rare in the United States, they are highly lethal because most are locally advanced at presentation.

The epidemiology, pathology, pathogenesis, and classification of cholangiocarcinoma will be discussed here. Clinical manifestations, diagnosis, and treatment are reviewed separately. (See "Clinical manifestations and diagnosis of cholangiocarcinoma" and "Treatment of localized cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis" and "Treatment options for locally advanced cholangiocarcinoma" and "Systemic therapy for advanced cholangiocarcinoma".)

Cancers of the gallbladder and ampulla of Vater are discussed as separate disease processes, although these structures are part of the biliary drainage system. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis" and "Ampullary carcinoma: Epidemiology, clinical manifestations, diagnosis and staging".)

ANATOMY, TUMOR CLASSIFICATION, AND STAGING

Biliary tract cancers were traditionally divided into cancers of the gallbladder, the extrahepatic ducts, and the ampulla of Vater, while intrahepatic tumors of the bile system were classified as primary liver cancers. More recently, the term cholangiocarcinoma has been used to refer to bile duct cancers arising in the intrahepatic, perihilar, or distal (extrahepatic) biliary tree, exclusive of the gallbladder or ampulla of Vater (figure 1).

Intrahepatic cholangiocarcinomas originate from small intrahepatic ductules (termed peripheral cholangiocarcinomas) or large intrahepatic ducts proximal to the bifurcation of the right and left hepatic ducts. The extrahepatic bile ducts are divided into perihilar (including the confluence itself) and distal segments, with the transition occurring at the point where the common bile duct lies posterior to the duodenum distal to the insertion of the cystic duct into the common bile duct [1].

                           

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References
Top
  1. de Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med 1999; 341:1368.
  2. DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007; 245:755.
  3. Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 1992; 215:31.
  4. American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.201.
  5. Farges O, Fuks D, Le Treut YP, et al. AJCC 7th edition of TNM staging accurately discriminates outcomes of patients with resectable intrahepatic cholangiocarcinoma: By the AFC-IHCC-2009 study group. Cancer 2011; 117:2170.
  6. Zervos EE, Osborne D, Goldin SB, et al. Stage does not predict survival after resection of hilar cholangiocarcinomas promoting an aggressive operative approach. Am J Surg 2005; 190:810.
  7. Hong SM, Pawlik TM, Cho H, et al. Depth of tumor invasion better predicts prognosis than the current American Joint Committee on Cancer T classification for distal bile duct carcinoma. Surgery 2009; 146:250.
  8. American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.219.
  9. American Joint Committee on Cancer Staging Manual, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.227.
  10. Okabayashi T, Yamamoto J, Kosuge T, et al. A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables. Cancer 2001; 92:2374.
  11. Deoliveira ML, Schulick RD, Nimura Y, et al. New staging system and a registry for perihilar cholangiocarcinoma. Hepatology 2011; 53:1363.
  12. Vauthey JN, Blumgart LH. Recent advances in the management of cholangiocarcinomas. Semin Liver Dis 1994; 14:109.
  13. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66:7.
  14. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 2001; 33:1353.
  15. Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol 2004; 40:472.
  16. Jepsen P, Vilstrup H, Tarone RE, et al. Incidence rates of intra- and extrahepatic cholangiocarcinomas in Denmark from 1978 through 2002. J Natl Cancer Inst 2007; 99:895.
  17. West J, Wood H, Logan RF, et al. Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971-2001. Br J Cancer 2006; 94:1751.
  18. Rajagopalan V, Daines WP, Grossbard ML, Kozuch P. Gallbladder and biliary tract carcinoma: A comprehensive update, Part 1. Oncology (Williston Park) 2004; 18:889.
  19. Khan SA, Taylor-Robinson SD, Toledano MB, et al. Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol 2002; 37:806.
  20. Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2002; 2:10.
  21. Welzel TM, McGlynn KA, Hsing AW, et al. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst 2006; 98:873.
  22. Khan SA, Emadossadaty S, Ladep NG, et al. Rising trends in cholangiocarcinoma: is the ICD classification system misleading us? J Hepatol 2012; 56:848.
  23. Jarnagin WR. Cholangiocarcinoma of the extrahepatic bile ducts. Semin Surg Oncol 2000; 19:156.
  24. Shaib YH, El-Serag HB, Davila JA, et al. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 2005; 128:620.
  25. Broomé U, Olsson R, Lööf L, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996; 38:610.
  26. Henson DE, Albores-Saavedra J, Corle D. Carcinoma of the extrahepatic bile ducts. Histologic types, stage of disease, grade, and survival rates. Cancer 1992; 70:1498.
  27. Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol 1999; 10 Suppl 4:308.
  28. Tung BY, Brentnall T, Kowdley KV, et al. Diagnosis and prevalence of ulcerative colitis in patients with primary sclerosing cholangitis (abstract). Hepatology 1996; 24:169A.
  29. Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002; 36:321.
  30. Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med 1995; 332:924.
  31. Bergquist A, Glaumann H, Persson B, Broomé U. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. Hepatology 1998; 27:311.
  32. de Groen PC. Cholangiocarcinoma in primary sclerosing cholangitis: who is at risk and how do we screen? Hepatology 2000; 31:247.
  33. Burak K, Angulo P, Pasha TM, et al. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol 2004; 99:523.
  34. Claessen MM, Vleggaar FP, Tytgat KM, et al. High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol 2009; 50:158.
  35. Chapman MH, Webster GJ, Bannoo S, et al. Cholangiocarcinoma and dominant strictures in patients with primary sclerosing cholangitis: a 25-year single-centre experience. Eur J Gastroenterol Hepatol 2012; 24:1051.
  36. Rosen CB, Nagorney DM, Wiesner RH, et al. Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg 1991; 213:21.
  37. LaRusso NF, Wiesner RH, Ludwig J, MacCarty RL. Current concepts. Primary sclerosing cholangitis. N Engl J Med 1984; 310:899.
  38. Boonstra K, Weersma RK, van Erpecum KJ, et al. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology 2013; 58:2045.
  39. Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology 2000; 31:7.
  40. Melum E, Karlsen TH, Schrumpf E, et al. Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms. Hepatology 2008; 47:90.
  41. Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet 2005; 366:1303.
  42. Scott J, Shousha S, Thomas HC, Sherlock S. Bile duct carcinoma: a late complication of congenital hepatic fibrosis. Case report and review of literature. Am J Gastroenterol 1980; 73:113.
  43. Lipsett PA, Pitt HA, Colombani PM, et al. Choledochal cyst disease. A changing pattern of presentation. Ann Surg 1994; 220:644.
  44. Dayton MT, Longmire WP Jr, Tompkins RK. Caroli's Disease: a premalignant condition? Am J Surg 1983; 145:41.
  45. Watanapa P. Cholangiocarcinoma in patients with opisthorchiasis. Br J Surg 1996; 83:1062.
  46. Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg 2002; 89:962.
  47. Shin HR, Lee CU, Park HJ, et al. Hepatitis B and C virus, Clonorchis sinensis for the risk of liver cancer: a case-control study in Pusan, Korea. Int J Epidemiol 1996; 25:933.
  48. Honjo S, Srivatanakul P, Sriplung H, et al. Genetic and environmental determinants of risk for cholangiocarcinoma via Opisthorchis viverrini in a densely infested area in Nakhon Phanom, northeast Thailand. Int J Cancer 2005; 117:854.
  49. Zhang GW, Lin JH, Qian JP, Zhou J. Identification of risk and prognostic factors for patients with clonorchiasis-associated intrahepatic cholangiocarcinoma. Ann Surg Oncol 2014; 21:3628.
  50. Hsing AW, Gao YT, Han TQ, et al. Gallstones and the risk of biliary tract cancer: a population-based study in China. Br J Cancer 2007; 97:1577.
  51. Ahrens W, Timmer A, Vyberg M, et al. Risk factors for extrahepatic biliary tract carcinoma in men: medical conditions and lifestyle: results from a European multicentre case-control study. Eur J Gastroenterol Hepatol 2007; 19:623.
  52. Welzel TM, Mellemkjaer L, Gloria G, et al. Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: a nationwide case-control study. Int J Cancer 2007; 120:638.
  53. Lee PC, Hu YW, Hu LY, et al. Risk of cancer in patients with cholecystitis: a nationwide population-based study. Am J Med 2015; 128:185.
  54. Chijiiwa K, Yamashita H, Yoshida J, et al. Current management and long-term prognosis of hepatolithiasis. Arch Surg 1995; 130:194.
  55. Lee CC, Wu CY, Chen GH. What is the impact of coexistence of hepatolithiasis on cholangiocarcinoma? J Gastroenterol Hepatol 2002; 17:1015.
  56. Chen MF. Peripheral cholangiocarcinoma (cholangiocellular carcinoma): clinical features, diagnosis and treatment. J Gastroenterol Hepatol 1999; 14:1144.
  57. Su CH, Shyr YM, Lui WY, P'Eng FK. Hepatolithiasis associated with cholangiocarcinoma. Br J Surg 1997; 84:969.
  58. Kinami Y, Noto H, Miyazaki I, et al. A study of hepatolithiasis associated with cholangiocarcinoma. Acta Hepatol Jpn 1978; 19:573.
  59. Yamamoto K, Tsuchiya R, Ito I, et al. A study of cholangiocarcinoma coexisting with hepatolithiasis. Jpn J Gastroenterol Surg 1984; 17:601.
  60. Okuda K, Kubo Y, Okazaki N, et al. Clinical aspects of intrahepatic bile duct carcinoma including hilar carcinoma: a study of 57 autopsy-proven cases. Cancer 1977; 39:232.
  61. Donato F, Gelatti U, Tagger A, et al. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes Control 2001; 12:959.
  62. Kim YT, Byun JS, Kim J, et al. Factors predicting concurrent cholangiocarcinomas associated with hepatolithiasis. Hepatogastroenterology 2003; 50:8.
  63. Sahani D, Prasad SR, Tannabe KK, et al. Thorotrast-induced cholangiocarcinoma: case report. Abdom Imaging 2003; 28:72.
  64. Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin Gastroenterol Hepatol 2007; 5:1221.
  65. Zhou YM, Yin ZF, Yang JM, et al. Risk factors for intrahepatic cholangiocarcinoma: a case-control study in China. World J Gastroenterol 2008; 14:632.
  66. Shaib YH, El-Serag HB, Nooka AK, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based case-control study. Am J Gastroenterol 2007; 102:1016.
  67. Grainge MJ, West J, Solaymani-Dodaran M, et al. The antecedents of biliary cancer: a primary care case-control study in the United Kingdom. Br J Cancer 2009; 100:178.
  68. Kobayashi M, Ikeda K, Saitoh S, et al. Incidence of primary cholangiocellular carcinoma of the liver in japanese patients with hepatitis C virus-related cirrhosis. Cancer 2000; 88:2471.
  69. Sorensen HT, Friis S, Olsen JH, et al. Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology 1998; 28:921.
  70. Nagaoka T, Ohkawa S, Ito Y, et al. [A case of minute cholangiocellular carcinoma which was found in the follow-up periods of liver cirrhosis and was indistinguishable from hepatocellular carcinoma on hepatic angiography]. Nihon Shokakibyo Gakkai Zasshi 1991; 88:1369.
  71. Hsing AW, Zhang M, Rashid A, et al. Hepatitis B and C virus infection and the risk of biliary tract cancer: a population-based study in China. Int J Cancer 2008; 122:1849.
  72. Yamamoto S, Kubo S, Hai S, et al. Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma. Cancer Sci 2004; 95:592.
  73. Liu XF, Zou SQ, Qiu FZ. Pathogenesis of cholangiocarcinoma in the porta hepatis and infection of hepatitis virus. Hepatobiliary Pancreat Dis Int 2003; 2:285.
  74. Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: recent progress. Part 1: epidemiology and etiology. J Gastroenterol Hepatol 2002; 17:1049.
  75. Lu H, Ye MQ, Thung SN, et al. Detection of hepatitis C virus RNA sequences in cholangiocarcinomas in Chinese and American patients. Chin Med J (Engl) 2000; 113:1138.
  76. Chang JS, Tsai CR, Chen LT. Medical risk factors associated with cholangiocarcinoma in Taiwan: a population-based case-control study. PLoS One 2013; 8:e69981.
  77. Nakanuma Y, Xu J, Harada K, et al. Pathological spectrum of intrahepatic cholangiocarcinoma arising in non-biliary chronic advanced liver diseases. Pathol Int 2011; 61:298.
  78. Suriawinata A, Thung SN. Hepatitis C virus and malignancy. Hepatol Res 2007; 37:397.
  79. El-Serag HB, Engels EA, Landgren O, et al. Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: A population-based study of U.S. veterans. Hepatology 2009; 49:116.
  80. Lee CH, Chang CJ, Lin YJ, et al. Viral hepatitis-associated intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma. Br J Cancer 2009; 100:1765.
  81. Peng NF, Li LQ, Qin X, et al. Evaluation of risk factors and clinicopathologic features for intrahepatic cholangiocarcinoma in Southern China: a possible role of hepatitis B virus. Ann Surg Oncol 2011; 18:1258.
  82. Kinoshita M, Kubo S, Tanaka S, et al. The association between non-alcoholic steatohepatitis and intrahepatic cholangiocarcinoma: A hospital based case-control study. J Surg Oncol 2016; 113:779.
  83. Lee SS, Kim MH, Lee SK, et al. Clinicopathologic review of 58 patients with biliary papillomatosis. Cancer 2004; 100:783.
  84. Taguchi J, Yasunaga M, Kojiro M, et al. Intrahepatic and extrahepatic biliary papillomatosis. Arch Pathol Lab Med 1993; 117:944.
  85. Yeung YP, AhChong K, Chung CK, Chun AY. Biliary papillomatosis: report of seven cases and review of English literature. J Hepatobiliary Pancreat Surg 2003; 10:390.
  86. Jing W, Jin G, Zhou X, et al. Diabetes mellitus and increased risk of cholangiocarcinoma: a meta-analysis. Eur J Cancer Prev 2012; 21:24.
  87. Larsson SC, Giovannucci EL, Wolk A. Sweetened Beverage Consumption and Risk of Biliary Tract and Gallbladder Cancer in a Prospective Study. J Natl Cancer Inst 2016; 108.
  88. Welzel TM, Graubard BI, Zeuzem S, et al. Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology 2011; 54:463.
  89. Bulajic M, Maisonneuve P, Schneider-Brachert W, et al. Helicobacter pylori and the risk of benign and malignant biliary tract disease. Cancer 2002; 95:1946.
  90. Pandey M, Shukla M. Helicobacter species are associated with possible increase in risk of hepatobiliary tract cancers. Surg Oncol 2009; 18:51.
  91. Boonyanugomol W, Chomvarin C, Sripa B, et al. Helicobacter pylori in Thai patients with cholangiocarcinoma and its association with biliary inflammation and proliferation. HPB (Oxford) 2012; 14:177.
  92. Murphy G, Michel A, Taylor PR, et al. Association of seropositivity to Helicobacter species and biliary tract cancer in the ATBC study. Hepatology 2014; 60:1963.
  93. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224:463.
  94. Jarnagin WR, Bowne W, Klimstra DS, et al. Papillary phenotype confers improved survival after resection of hilar cholangiocarcinoma. Ann Surg 2005; 241:703.
  95. Martin RC, Klimstra DS, Schwartz L, et al. Hepatic intraductal oncocytic papillary carcinoma. Cancer 2002; 95:2180.
  96. Nakanuma Y, Harada K, Ishikawa A, et al. Anatomic and molecular pathology of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2003; 10:265.
  97. Nakanuma Y, Sato Y, Harada K, et al. Pathological classification of intrahepatic cholangiocarcinoma based on a new concept. World J Hepatol 2010; 2:419.
  98. Theise ND, Nakashima O, Park YN, Nakanuma Y.. Combined hepatocellular-cholangiocarcinoma. In: WHO Classification of Tumours of the Digestive System, 4th, Bosman FT, Carneiro F, Hruban RH, Theise ND.. (Eds), IARC, Lyon 2010. p.225.
  99. Akiba J, Nakashima O, Hattori S, et al. Clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification. Am J Surg Pathol 2013; 37:496.
  100. Alison MR. Liver stem cells: implications for hepatocarcinogenesis. Stem Cell Rev 2005; 1:253.
  101. Wu XZ, Chen D. Origin of hepatocellular carcinoma: role of stem cells. J Gastroenterol Hepatol 2006; 21:1093.
  102. Yano H, Iemura A, Haramaki M, et al. A human combined hepatocellular and cholangiocarcinoma cell line (KMCH-2) that shows the features of hepatocellular carcinoma or cholangiocarcinoma under different growth conditions. J Hepatol 1996; 24:413.
  103. Fujii H, Zhu XG, Matsumoto T, et al. Genetic classification of combined hepatocellular-cholangiocarcinoma. Hum Pathol 2000; 31:1011.
  104. Coulouarn C, Cavard C, Rubbia-Brandt L, et al. Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFβ signaling pathways. Carcinogenesis 2012; 33:1791.
  105. Lee CH, Hsieh SY, Chang CJ, Lin YJ. Comparison of clinical characteristics of combined hepatocellular-cholangiocarcinoma and other primary liver cancers. J Gastroenterol Hepatol 2013; 28:122.
  106. Kassahun WT, Hauss J. Management of combined hepatocellular and cholangiocarcinoma. Int J Clin Pract 2008; 62:1271.
  107. Yap AQ, Chen CL, Yong CC, et al. Clinicopathological factors impact the survival outcome following the resection of combined hepatocellular carcinoma and cholangiocarcinoma. Surg Oncol 2013; 22:55.
  108. Yin X, Zhang BH, Qiu SJ, et al. Combined hepatocellular carcinoma and cholangiocarcinoma: clinical features, treatment modalities, and prognosis. Ann Surg Oncol 2012; 19:2869.
  109. Garancini M, Goffredo P, Pagni F, et al. Combined hepatocellular-cholangiocarcinoma: a population-level analysis of an uncommon primary liver tumor. Liver Transpl 2014; 20:952.
  110. Hezel AF, Deshpande V, Zhu AX. Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol 2010; 28:3531.
  111. Zabron A, Edwards RJ, Khan SA. The challenge of cholangiocarcinoma: dissecting the molecular mechanisms of an insidious cancer. Dis Model Mech 2013; 6:281.
  112. Zen Y, Adsay NV, Bardadin K, et al. Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria. Mod Pathol 2007; 20:701.
  113. Klöppel G, Kosmahl M. Is the intraductal papillary mucinous neoplasia of the biliary tract a counterpart of pancreatic papillary mucinous neoplasm? J Hepatol 2006; 44:249.
  114. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014; 383:2168.
  115. Schlitter AM, Born D, Bettstetter M, et al. Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways. Mod Pathol 2014; 27:73.
  116. Nakanishi Y, Zen Y, Kondo S, et al. Expression of cell cycle-related molecules in biliary premalignant lesions: biliary intraepithelial neoplasia and biliary intraductal papillary neoplasm. Hum Pathol 2008; 39:1153.
  117. Hoang MP, Murakata LA, Katabi N, et al. Invasive papillary carcinomas of the extrahepatic bile ducts: a clinicopathologic and immunohistochemical study of 13 cases. Mod Pathol 2002; 15:1251.
  118. Isa T, Tomita S, Nakachi A, et al. Analysis of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahepatic cholangiocarcinoma. Hepatogastroenterology 2002; 49:604.
  119. Nehls O, Gregor M, Klump B. Serum and bile markers for cholangiocarcinoma. Semin Liver Dis 2004; 24:139.
  120. Taniai M, Higuchi H, Burgart LJ, Gores GJ. p16INK4a promoter mutations are frequent in primary sclerosing cholangitis (PSC) and PSC-associated cholangiocarcinoma. Gastroenterology 2002; 123:1090.
  121. Tannapfel A, Benicke M, Katalinic A, et al. Frequency of p16(INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut 2000; 47:721.
  122. Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 2012; 17:72.
  123. Andersen JB, Spee B, Blechacz BR, et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 2012; 142:1021.