Frontiers of Medicine in China

, Volume 4, Issue 4, pp 371–377 | Cite as

Hilar cholangiocarcinoma: Pathology and tumor biology

  • Dong Kuang
  • Guo-Ping WangEmail author


Hilar cholangiocarcinoma, first described by Klatskin in 1965, is a relatively rare tumor arising from the bile ducts. The histomorphological features of hilar cholangiocarcinoma are identical with other extra- and intra-hepatic bile duct carcinomas. The most common disease associated with cholangiocarcinoma is primary sclerosing cholangitis. The development of cholangiocarcinoma is a multistep process associated with several mutations in oncogenes and tumor-suppressor genes. Based on macroscopic appearance, three distinct subtypes have been described: sclerosing, nodular, and papillary. Microscopically, more than 95% of tumors are adenocarcinomas. Hilar cholangiocarcinoma is a slowly growing tumor and tends to spread longitudinally along the bile ducts with neural, perineural, and subepithelial extension. Lymph node invasion can be found in 30%–50% patients at the time of diagnosis, but blood-born metastases are rare and usually occur at late stages.


hilar cholangiocarcinoma morphology primary sclerosing cholangitis metastasis growth 


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  1. 1.
    Blechacz B, Gores G J. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology, 2008, 48(1): 308–321CrossRefPubMedGoogle Scholar
  2. 2.
    Welzel T M, McGlynn K A, Hsing AW, O’Brien T R, Pfeiffer R M. Impact of classication of hila rcholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst, 2006, 98(12): 873–875CrossRefPubMedGoogle Scholar
  3. 3.
    Ustundag Y, Bayraktar Y. Cholangiocarcinoma: a compact review of the literature. World J Gastroenterol, 2008, 14(42): 6458–6466CrossRefPubMedGoogle Scholar
  4. 4.
    Mosconi S, Beretta G D, Labianca R, Zampino M G, Gatta G, Heinemann V. Cholangiocarcinoma. Crit Rev Oncol Hematol, 2009, 69(3): 259–270CrossRefPubMedGoogle Scholar
  5. 5.
    Khan S A, Thomas H C, Davidson B R, Taylor-Robinson S D. Cholangiocarcinoma. Lancet, 2005, 366(9493): 1303–1314CrossRefPubMedGoogle Scholar
  6. 6.
    Yachimski P, Pratt D S. Cholangiocarcinoma: natural history, treatment, and strategies for surveillance in high-risk patients. J Clin Gastroenterol, 2008, 42(2): 178–190CrossRefPubMedGoogle Scholar
  7. 7.
    Klatskin G. Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatis. Am J Med, 1965, 38: 241–256CrossRefPubMedGoogle Scholar
  8. 8.
    Khan S A, Miras A, Pelling M, Taylor-Robinson S D. Cholangiocarcinoma and its management. Gut, 2007, 56(12): 1755–1756CrossRefPubMedGoogle Scholar
  9. 9.
    Yang J, Yan L N. Current status of intrahepatic cholangiocarcinoma. World J Gastroenterol, 2008, 14(41): 6289–6297CrossRefPubMedGoogle Scholar
  10. 10.
    Hammill C W, Wong L L. Intrahepatic cholangiocarcinoma: a malignancy of increasing importance. J Am Coll Surg, 2008, 207(4): 594–603CrossRefPubMedGoogle Scholar
  11. 11.
    Aljiffry M, Walsh M J, Molinari M. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990–2009. World J Gastroenterol, 2009, 15(34): 4240–4262CrossRefPubMedGoogle Scholar
  12. 12.
    McLean L, Patel T. Racial and ethnic variations in the epidemiology of intrahepatic cholangiocarcinoma in the United States. Liver Int, 2006, 26(9): 1047–1053CrossRefPubMedGoogle Scholar
  13. 13.
    Abbas G, Lindor K D. Cholangiocarcinoma in primary sclerosing cholangitis. J Gastrointest Cancer, 2009, 40(1–2): 19–25CrossRefPubMedGoogle Scholar
  14. 14.
    Burak K, Angulo P, Pasha T M, Egan K, Petz J, Lindor K D. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol, 2004, 99(3): 523–526CrossRefPubMedGoogle Scholar
  15. 15.
    Boberg K M, Bergquist A, Mitchell S, Pares A, Rosina F, Broomé U, Chapman R, Fausa O, Egeland T, Rocca G, Schrumpf E. Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol, 2002, 37(10): 1205–1211CrossRefPubMedGoogle Scholar
  16. 16.
    Lazaridis K N, Gores G J. Primary sclerosing cholangitis and cholangiocarcinoma. Semin Liver Dis, 2006, 26(1): 42–51CrossRefPubMedGoogle Scholar
  17. 17.
    Charatcharoenwitthaya P, Enders F B, Halling K C, Lindor K D. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology, 2008, 48(4): 1106–1117CrossRefPubMedGoogle Scholar
  18. 18.
    de Vries J S, de Vries S, Aronson D C, Bosman D K, Rauws E A, Bosma A, Heij H A, Gouma D J, van Gulik TM. Choledochal cysts: age of presentation, symptoms, and late complications related to Todani’s classification. J Pediatr Surg, 2002, 37(11): 1568–1573CrossRefPubMedGoogle Scholar
  19. 19.
    Ishiguro S, Inoue M, Kurahashi N, Iwasaki M, Sasazuki S, Tsugane S. Risk factors of biliary tract cancer in a large-scale population-based cohort study in Japan (JPHC study); with special focus on cholelithiasis, body mass index, and their effect modification. Cancer Causes Control, 2008, 19(1): 33–41CrossRefPubMedGoogle Scholar
  20. 20.
    Miyazaki M, Takada T, Miyakawa S, Tsukada K, Nagino M, Kondo S, Furuse J, Saito H, Tsuyuguchi T, Chijiiwa K, Kimura F, Yoshitomi H, Nozawa S, Yoshida M, Wada K, Amano H, Miura F. Risk factors for biliary tract and ampullary carcinomas and prophylactic surgery for these factors. J Hepatobiliary Pancreat Surg, 2008, 15(1): 15–24CrossRefPubMedGoogle Scholar
  21. 21.
    Strömberg C, Luo J, Enochsson L, Arnelo U, Nilsson M. Endoscopic sphincterotomy and risk of malignancy in the bile ducts, liver, and pancreas. Clin Gastroenterol Hepatol, 2008, 6(9): 1049–1053CrossRefPubMedGoogle Scholar
  22. 22.
    Mortensen F V, Jepsen P, Tarone R E, Funch-Jensen P, Jensen L S, Sørensen H T. Endoscopic sphincterotomy and long-term risk of cholangiocarcinoma: a population-based follow-up study. J Natl Cancer Inst, 2008, 100(10): 745–750CrossRefPubMedGoogle Scholar
  23. 23.
    Kim H G, Han J, Kim M H, Cho K H, Shin I H, Kim G H, Kim J S, Kim J B, Kim T N, Kim T H, Kim T H, Kim J W, Ryu J K, Moon Y S, Moon J H, Park S J, Park C G, Bang S J, Yang C H, Yoo K S, Yoo B M, Lee K T, Lee D K, Lee B S, Lee S S, Lee S O, Lee WJ, Cho C M, Joo Y E, Cheon G J, Choi YW, Chung J B, Yoon Y B. Prevalence of clonorchiasis in patients with gastrointestinal disease: a Korean nationwide multicenter survey. World J Gastroenterol, 2009, 15(1): 86–94CrossRefPubMedGoogle Scholar
  24. 24.
    Poomphakwaen K, Promthet S, Kamsa-Ard S, Vatanasapt P, Chaveepojnkamjorn W, Klaewkla J, Sujirarat D, Pichainarong N. Risk factors for cholangiocarcinoma in Khon Kaen, Thailand: a nested case-control study. Asian Pac J Cancer Prev, 2009, 10(2): 251–258PubMedGoogle Scholar
  25. 25.
    Andoh H, Yasui O, Kurokawa T, Sato T. Cholangiocarcinoma coincident with schistosomiasis japonica. J Gastroenterol, 2004, 39(1): 64–68CrossRefPubMedGoogle Scholar
  26. 26.
    Sahani D, Prasad S R, Tannabe K K, Hahn P F, Mueller P R, Saini S. Thorotrast-induced cholangiocarcinoma: case report. Abdom Imaging, 2003, 28(1): 72–74CrossRefPubMedGoogle Scholar
  27. 27.
    Lipshutz G S, Brennan T V, Warren R S. Thorotrast-induced liver neoplasia: a collective review. J Am Coll Surg, 2002, 195(5): 713–718CrossRefPubMedGoogle Scholar
  28. 28.
    Lazaridis K N, Gores G J. Cholangiocarcinoma. Gastroenterology, 2005, 128(6): 1655–1667CrossRefPubMedGoogle Scholar
  29. 29.
    Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: recent progress. Part 1: epidemiology and etiology. J Gastroenterol Hepatol, 2002, 17(10): 1049–1055CrossRefPubMedGoogle Scholar
  30. 30.
    Wu T T, Levy M, Correa A M, Rosen C B, Abraham S C. Biliary intraepithelial neoplasia in patients without chronic biliary disease: analysis of liver explants with alcoholic cirrhosis, hepatitis C infection, and noncirrhotic liver diseases. Cancer, 2009, 115(19): 4564–4575CrossRefPubMedGoogle Scholar
  31. 31.
    Ben-Menachem T. Risk factors for cholangiocarcinoma. Eur J Gastroenterol Hepatol, 2007, 19(8): 615–617CrossRefPubMedGoogle Scholar
  32. 32.
    Chuang S C, La Vecchia C, Boffetta P. Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection. Cancer Lett, 2009, 286(1): 9–14CrossRefPubMedGoogle Scholar
  33. 33.
    Lee C H, Chang C J, Lin Y J, Yeh C N, Chen M F, Hsieh S Y. Viral hepatitis-associated intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma. Br J Cancer, 2009, 100(11): 1765–1770CrossRefPubMedGoogle Scholar
  34. 34.
    Kobayashi M, Ikeda K, Saitoh S, Suzuki F, Tsubota A, Suzuki Y, Arase Y, Murashima N, Chayama K, Kumada H. Incidence of primary cholangiocellular carcinoma of the liver in japanese patients with hepatitis C virus-related cirrhosis. Cancer, 2000, 88(11): 2471–2477CrossRefPubMedGoogle Scholar
  35. 35.
    Zhou YM, Yin Z F, Yang JM, Li B, Shao WY, Xu F, Wang Y L, Li D Q. Risk factors for intrahepatic cholangiocarcinoma: a casecontrol study in China.World J Gastroenterol, 2008, 14(4): 632–635CrossRefPubMedGoogle Scholar
  36. 36.
    El-Serag H B, Engels E A, Landgren O, Chiao E, Henderson L, Amaratunge H C, Giordano T P. Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: A population-based study of U.S. veterans. Hepatology, 2009, 49(1): 116–123CrossRefPubMedGoogle Scholar
  37. 37.
    Jaiswal M, LaRusso N F, Burgart L J, Gores G J. Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res, 2000, 60(1): 184–190PubMedGoogle Scholar
  38. 38.
    Jaiswal M, LaRusso N F, Gores G J. Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis. Am J Physiol Gastrointest Liver Physiol, 2001, 281(3): G626–G634PubMedGoogle Scholar
  39. 39.
    Schottenfeld D, Beebe-Dimmer J. Chronic inflammation: a common and important factor in the pathogenesis of neoplasia. CA Cancer J Clin, 2006, 56(2): 69–83CrossRefPubMedGoogle Scholar
  40. 40.
    Wise C, Pilanthananond M, Perry B F, Alpini G, McNeal M, Glaser S S. Mechanisms of biliary carcinogenesis and growth. World J Gastroenterol, 2008, 14(19): 2986–2989CrossRefPubMedGoogle Scholar
  41. 41.
    Prawan A, Buranrat B, Kukongviriyapan U, Sripa B, Kukongviriyapan V. Inflammatory cytokines suppress NAD(P)H:quinone oxidoreductase-1 and induce oxidative stress in cholangiocarcinoma cells. J Cancer Res Clin Oncol, 2009, 135(4): 515–522CrossRefPubMedGoogle Scholar
  42. 42.
    Mon N N, Kokuryo T, Hamaguchi M. Inflammation and tumor progression: a lesson from TNF-alpha-dependent FAK signaling in cholangiocarcinoma. Methods Mol Biol, 2009, 512: 279–293CrossRefPubMedGoogle Scholar
  43. 43.
    Han C, Wu T. Cyclooxygenase-2-derived prostaglandin E2 promotes human cholangiocarcinoma cell growth and invasion through EP1 receptor-mediated activation of the epidermal growth factor receptor and Akt. J Biol Chem, 2005, 280(25): 24053–24063CrossRefPubMedGoogle Scholar
  44. 44.
    Sirica A E. Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma. World J Gastroenterol, 2008, 14(46): 7033–7058CrossRefPubMedGoogle Scholar
  45. 45.
    Fava G, Marzioni M, Benedetti A, Glaser S, DeMorrow S, Francis H, Alpini G. Molecular pathology of biliary tract cancers. Cancer Lett, 2007, 250(2): 155–167CrossRefPubMedGoogle Scholar
  46. 46.
    Lai G H, Zhang Z, Shen X N, Ward D J, Dewitt J L, Holt S E, Rozich R A, Hixson D C, Sirica A E. erbB-2/neu transformed rat cholangiocytes recapitulate key cellular and molecular features of human bile duct cancer. Gastroenterology, 2005, 129(6): 2047–2057CrossRefPubMedGoogle Scholar
  47. 47.
    Aishima S I, Taguchi K I, Sugimachi K, Shimada M, Sugimachi K, Tsuneyoshi M. c-erbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma. Histopathology, 2002, 40(3): 269–278CrossRefPubMedGoogle Scholar
  48. 48.
    Yoon J H, Gwak G Y, Lee H S, Bronk S F, Werneburg N W, Gores G J. Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells. J Hepatol, 2004, 41(5): 808–814CrossRefPubMedGoogle Scholar
  49. 49.
    Choi H J, Kim H J, Choi J H. Expression of c-erbB-2 and cyclooxygenase-2 in intrahepatic cholangiocarcinoma. Hepatogastroenterology, 2009, 56(91–92): 606–609PubMedGoogle Scholar
  50. 50.
    Batheja N, Suriawinata A, Saxena R, Ionescu G, Schwartz M, Thung S N. Expression of p53 and PCNA in cholangiocarcinoma and primary sclerosing cholangitis. Mod Pathol, 2000, 13(12): 1265–1268CrossRefPubMedGoogle Scholar
  51. 51.
    Greene F L, Page D L, Fleming I D. AJCC(AmericanJoint Committee on Cancer), cancer staging manual. 6th ed. New York: Springer-Verlag, 2002Google Scholar
  52. 52.
    Nathan H, Aloia T A, Vauthey J N, Abdalla E K, Zhu A X, Schulick R D, Choti M A, Pawlik T M. A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol, 2009, 16(1): 14–22CrossRefPubMedGoogle Scholar
  53. 53.
    Ito F, Agni R, Rettammel R J, Been M J, Cho C S, Mahvi D M, Rikkers L F, Weber S M. Resection of hilar cholangiocarcinoma: concomitant liver resection decreases hepatic recurrence. Ann Surg, 2008, 248(2): 273–279CrossRefPubMedGoogle Scholar
  54. 54.
    Anderson C D, Rice M H, Pinson C W, Chapman W C, Chari R S, Delbeke D. Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma. J Gastrointest Surg, 2004, 8(1): 90–97CrossRefPubMedGoogle Scholar
  55. 55.
    Jarnagin W R, Bowne W, Klimstra D S, Ben-Porat L, Roggin K, Cymes K, Fong Y, DeMatteo R P, D’Angelica M, Koea J, Blumgart L H. Papillary phenotype confers improved survival after resection of hilar cholangiocarcinoma. Ann Surg, 2005, 241(5): 703–712, discussion 712–714CrossRefPubMedGoogle Scholar
  56. 56.
    Boonmars T, Wu Z, Boonjaruspinyo S, Pinlaor S, Nagano I, Takahashi Y, Kaewsamut B, Yongvanit P. Alterations of gene expression of RB pathway in Opisthorchis viverrini infectioninduced cholangiocarcinoma. Parasitol Res, 2009, 105(5): 1273–1281CrossRefPubMedGoogle Scholar
  57. 57.
    Songserm N, Prasongwattana J, Sithithaworn P, Sripa B, Pipitkool V. Cholangiocarcinoma in experimental hamsters with longstanding Opisthorchis viverrini infection. Asian Pac J Cancer Prev, 2009, 10(2): 299–302PubMedGoogle Scholar
  58. 58.
    Loilome W, Yongvanit P, Wongkham C, Tepsiri N, Sripa B, Sithithaworn P, Hanai S, Miwa M. Altered gene expression in Opisthorchis viverrini-associated cholangiocarcinoma in hamster model. Mol Carcinog, 2006, 45(5): 279–287CrossRefPubMedGoogle Scholar
  59. 59.
    Yeh C N, Maitra A, Lee K F, Jan Y Y, Chen M F. Thioacetamide-induced intestinal-type cholangiocarcinoma in rat: an animal model recapitulating the multi-stage progression of human cholangiocarcinoma. Carcinogenesis, 2004, 25(4): 631–636CrossRefPubMedGoogle Scholar

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© Higher Education Press and Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Institute of Pathology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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