Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2010, Vol. 4 Issue (4) : 371-377     DOI: 10.1007/s11684-010-0130-6
Research articles |
Hilar cholangiocarcinoma: Pathology and tumor biology
Dong KUANG,Guo-Ping WANG,
Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
Download: PDF(133 KB)  
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract  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.
Keywords hilar cholangiocarcinoma      morphology      primary sclerosing cholangitis      metastasis      growth      
Issue Date: 05 December 2010
URL:     OR
Blechacz B, Gores G J. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment.Hepatology, 2008, 48(1): 308–321
PMID: 18536057
Welzel T M, McGlynn K A, Hsing A W, O'Brien TR, Pfeiffer R M. Impact of classi?cation of hila rcholangiocarcinomas(Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinomain the United States.J Natl Cancer Inst, 2006, 98(12): 873–875
PMID: 16788161
Ustundag Y, Bayraktar Y. Cholangiocarcinoma: a compact review of the literature.World J Gastroenterol, 2008, 14(42): 6458–6466
PMID: 19030196
Mosconi S, Beretta G D, Labianca R, Zampino M G, Gatta G, Heinemann V. Cholangiocarcinoma.Crit Rev Oncol Hematol, 2009, 69(3): 259–270
PMID: 18977670
Khan S A, Thomas H C, Davidson B R, Taylor-Robinson S D. Cholangiocarcinoma.Lancet, 2005, 366(9493): 1303–1314
PMID: 16214602
Yachimski P, Pratt D S. Cholangiocarcinoma: natural history, treatment, and strategies for surveillance in high-riskpatients.J Clin Gastroenterol, 2008, 42(2): 178–190
PMID: 18209589
Klatskin G. Adenocarcinoma of the hepatic duct at its bifurcationwithin the porta hepatis.Am J Med, 1965, 38: 241–256
PMID: 14256720
Khan S A, Miras A, Pelling M, Taylor-Robinson S D. Cholangiocarcinoma and its management.Gut, 2007, 56(12): 1755–1756
PMID: 17998326
Yang J, Yan L N. Current status of intrahepatic cholangiocarcinoma.World J Gastroenterol, 2008, 14(41): 6289–6297
PMID: 19009641
Hammill C W, Wong L L. Intrahepatic cholangiocarcinoma: a malignancy of increasing importance.J Am Coll Surg, 2008, 207(4): 594–603
PMID: 18926465
Aljiffry M, Walsh M J, Molinari M. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990―2009.World J Gastroenterol, 2009, 15(34): 4240–4262
PMID: 19750567
McLean L, Patel T. Racial and ethnic variations in the epidemiology of intrahepatic cholangiocarcinomain the United States.Liver Int, 2006, 26(9): 1047–1053
PMID: 17032404
Abbas G, Lindor K D. Cholangiocarcinoma in primary sclerosing cholangitis.J Gastrointest Cancer, 2009, 40(1―2): 19–25
PMID: 19705300
Burak K, Angulo P, Pasha T M, Egan K, Petz J, Lindor K D. Incidence and risk factors for cholangiocarcinoma inprimary sclerosing cholangitis.Am J Gastroenterol, 2004, 99(3): 523–526
PMID: 15056096
Boberg K M, Bergquist A, Mitchell S, Pares A, Rosina F, BroomBroomé U, Chapman R, Fausa O, Egeland T, Rocca G, Schrumpf E. Cholangiocarcinoma in primarysclerosing cholangitis: risk factors and clinical presentation.Scand J Gastroenterol, 2002, 37(10): 1205–1211
PMID: 12408527
Lazaridis K N, Gores G J. Primary sclerosing cholangitis and cholangiocarcinoma.Semin Liver Dis, 2006, 26(1): 42–51
PMID: 16496232
Charatcharoenwitthaya P, Enders F B, Halling K C, Lindor K D. Utility of serum tumor markers,imaging, and biliary cytology for detecting cholangiocarcinoma inprimary sclerosing cholangitis.Hepatology, 2008, 48(4): 1106–1117
PMID: 18785620
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 T M. Choledochal cysts: age of presentation, symptoms, andlate complications related to Todani's classification.J Pediatr Surg, 2002, 37(11): 1568–1573
PMID: 12407541
Ishiguro S, Inoue M, Kurahashi N, Iwasaki M, Sasazuki S, Tsugane S. Risk factors of biliary tract cancer in a large-scalepopulation-based cohort study in Japan (JPHC study); with specialfocus on cholelithiasis, body mass index, and their effect modification.Cancer Causes Control, 2008, 19(1): 33–41
PMID: 17906958
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 prophylacticsurgery for these factors.J Hepatobiliary Pancreat Surg, 2008, 15(1): 15–24
PMID: 18274840
Str?mberg C, Luo J, Enochsson L, Arnelo U, Nilsson M. Endoscopic sphincterotomy and risk of malignancy in the bile ducts,liver, and pancreas.Clin GastroenterolHepatol, 2008, 6(9): 1049–1053
PMID: 18585972
Mortensen F V, Jepsen P, Tarone R E, Funch-Jensen P, Jensen L S, S?rensen H T. Endoscopic sphincterotomy and long-termrisk of cholangiocarcinoma: a population-based follow-up study.J Natl Cancer Inst, 2008, 100(10): 745–750
PMID: 18477806
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 W J, Cho C M, Joo Y E, Cheon G J, Choi Y W, Chung J B, Yoon Y B. Prevalence of clonorchiasis in patientswith gastrointestinal disease: a Korean nationwide multicenter survey.World J Gastroenterol, 2009, 15(1): 86–94
PMID: 19115472
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 nestedcase-control study.Asian Pac J Cancer Prev, 2009, 10(2): 251–258
PMID: 19537893
Andoh H, Yasui O, Kurokawa T, Sato T. Cholangiocarcinoma coincident with schistosomiasis japonica.J Gastroenterol, 2004, 39(1): 64–68
PMID: 14767737
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): 72–74
PMID: 12483389
Lipshutz G S, Brennan T V, Warren R S. Thorotrast-induced liver neoplasia: a collective review.J Am Coll Surg, 2002, 195(5): 713–718
PMID: 12437262
Lazaridis K N, Gores G J. Cholangiocarcinoma.Gastroenterology, 2005, 128(6): 1655–1667
PMID: 15887157
Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: recentprogress. Part 1: epidemiology and etiology.J Gastroenterol Hepatol, 2002, 17(10): 1049–1055
PMID: 12201863
Wu T T, Levy M, Correa A M, Rosen C B, Abraham S C. Biliary intraepithelial neoplasiain patients without chronic biliary disease: analysis of liver explantswith alcoholic cirrhosis, hepatitis C infection, and noncirrhoticliver diseases.Cancer, 2009, 115(19): 4564–4575
PMID: 19670455
Ben-Menachem T. Risk factors for cholangiocarcinoma.Eur J Gastroenterol Hepatol, 2007, 19(8): 615–617
PMID: 17625428
Chuang S C, La Vecchia C, Boffetta P. Liver cancer: descriptiveepidemiology and risk factors other than HBV and HCV infection.Cancer Lett, 2009, 286(1): 9–14
PMID: 19091458
Lee C H, Chang C J, Lin Y J, Yeh C N, Chen M F, Hsieh S Y. Viral hepatitis-associated intrahepatic cholangiocarcinomashares common disease processes with hepatocellular carcinoma.Br J Cancer, 2009, 100(11): 1765–1770
PMID: 19436294
Kobayashi M, Ikeda K, Saitoh S, Suzuki F, Tsubota A, Suzuki Y, Arase Y, Murashima N, Chayama K, Kumada H. Incidence of primary cholangiocellularcarcinoma of the liver in japanese patients with hepatitis C virus-relatedcirrhosis.Cancer, 2000, 88(11): 2471–2477
PMID: 10861422
Zhou Y M, Yin Z F, Yang J M, Li B, Shao W Y, Xu F, Wang Y L, Li D Q. Risk factors for intrahepatic cholangiocarcinoma:a case-control study in China.World J Gastroenterol, 2008, 14(4): 632–635
PMID: 18203300
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 virusinfection: A population-based study of U.S. veterans.Hepatology, 2009, 49(1): 116–123
PMID: 19085911
Jaiswal M, LaRusso N F, Burgart L J, Gores G J. Inflammatory cytokines induce DNA damage and inhibitDNA repair in cholangiocarcinoma cells by a nitric oxide-dependentmechanism.Cancer Res, 2000, 60(1): 184–190
PMID: 10646872
Jaiswal M, LaRusso N F, Gores G J. Nitric oxide in gastrointestinalepithelial cell carcinogenesis: linking inflammation to oncogenesis.Am J Physiol Gastrointest Liver Physiol, 2001, 281(3): G626–G634
PMID: 11518674
Schottenfeld D, Beebe-Dimmer J. Chronic inflammation: a common and important factor in the pathogenesisof neoplasia.CA Cancer J Clin, 2006, 56(2): 69–83
PMID: 16514135
Wise C, Pilanthananond M, Perry B F, Alpini G, McNeal M, Glaser S S. Mechanisms of biliary carcinogenesisand growth.World J Gastroenterol, 2008, 14(19): 2986–2989
PMID: 18494047
Prawan A, Buranrat B, Kukongviriyapan U, Sripa B, Kukongviriyapan V. Inflammatory cytokines suppress NAD(P)H:quinone oxidoreductase-1and induce oxidative stress in cholangiocarcinoma cells.J Cancer Res Clin Oncol, 2009, 135(4): 515–522
PMID: 18820947
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: 279–293
PMID: 19347283
Han C, Wu T. Cyclooxygenase-2-derived prostaglandin E2 promotes human cholangiocarcinoma cell growth andinvasion through EP1 receptor-mediated activation of the epidermalgrowth factor receptor and Akt.J Biol Chem, 2005, 280(25): 24053–24063
PMID: 15855163
Sirica A E. Role of ErbB family receptor tyrosine kinases in intrahepaticcholangiocarcinoma.World J Gastroenterol, 2008, 14(46): 7033–7058
PMID: 19084911
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): 155–167
PMID: 17069969
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 cellularand molecular features of human bile duct cancer.Gastroenterology, 2005, 129(6): 2047–2057
PMID: 16344070
Aishima S I, Taguchi K I, Sugimachi K, Shimada M, Sugimachi K, Tsuneyoshi M. c-erbB-2 and c-Met expressionrelates to cholangiocarcinogenesis and progression of intrahepaticcholangiocarcinoma.Histopathology, 2002, 40(3): 269–278
PMID: 11895493
Yoon J H, Gwak G Y, Lee H S, Bronk S F, Werneburg N W, Gores G J. Enhanced epidermal growth factor receptor activationin human cholangiocarcinoma cells.J Hepatol, 2004, 41(5): 808–814
PMID: 15519654
Choi H J, Kim H J, Choi J H. Expression of c-erbB-2 and cyclooxygenase-2in intrahepatic cholangiocarcinoma.Hepatogastroenterology, 2009, 56(91-92): 606–609
PMID: 19621664
Batheja N, Suriawinata A, Saxena R, Ionescu G, Schwartz M, Thung S N. Expression of p53 and PCNAin cholangiocarcinoma and primary sclerosing cholangitis.Mod Pathol, 2000, 13(12): 1265–1268
PMID: 11144921
Greene F L, Page D L, Fleming I D. AJCC(AmericanJoint Committee on Cancer),cancer staging manual. 6th ed. New York: Springer-Verlag, 2002
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 intrahepaticcholangiocarcinoma.Ann Surg Oncol, 2009, 16(1): 14–22
PMID: 18987916
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): 273–279
PMID: 18650638
Anderson C D, Rice M H, Pinson C W, Chapman W C, Chari R S, Delbeke D. Fluorodeoxyglucose PET imaging in the evaluation of gallbladdercarcinoma and cholangiocarcinoma.J Gastrointest Surg, 2004, 8(1): 90–97
PMID: 14746840
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 confersimproved survival after resection of hilar cholangiocarcinoma.Ann Surg, 2005, 241(5): 703–712, discussion 712―714
PMID: 15849506
Boonmars T, Wu Z, Boonjaruspinyo S, Pinlaor S, Nagano I, Takahashi Y, Kaewsamut B, Yongvanit P. Alterations of gene expressionof RB pathway in Opisthorchis viverrini infection-induced cholangiocarcinoma.Parasitol Res, 2009, 105(5): 1273–1281
PMID: 19582476
Songserm N, Prasongwattana J, Sithithaworn P, Sripa B, Pipitkool V. Cholangiocarcinoma in experimental hamsters with long-standing Opisthorchisviverrini infection.Asian Pac J CancerPrev, 2009, 10(2): 299–302
PMID: 19537899
Loilome W, Yongvanit P, Wongkham C, Tepsiri N, Sripa B, Sithithaworn P, Hanai S, Miwa M. Altered gene expression in Opisthorchis viverrini-associated cholangiocarcinomain hamster model.Mol Carcinog, 2006, 45(5): 279–287
PMID: 16550611
Yeh C N, Maitra A, Lee K F, Jan Y Y, Chen M F. Thioacetamide-inducedintestinal-type cholangiocarcinoma in rat: an animal model recapitulatingthe multi-stage progression of human cholangiocarcinoma.Carcinogenesis, 2004, 25(4): 631–636
PMID: 14656942
[1] Chunxiao Li,Haijuan Wang,Feng Lin,Hui Li,Tao Wen,Haili Qian,Qimin Zhan. Bioinformatic exploration of MTA1-regulated gene networks in colon cancer[J]. Front. Med., 2016, 10(2): 178-182.
[2] Jiangnan Liu,Bin Yi,Zhe Zhang,Yi Cao. CD176 single-chain variable antibody fragment inhibits the adhesion of cancer cells to endothelial cells and hepatocytes[J]. Front. Med., 2016, 10(2): 204-211.
[3] Felice Ho-Ching Tsang,Sandy Leung-Kuen Au,Lai Wei,Dorothy Ngo-Yin Fan,Joyce Man-Fong Lee,Carmen Chak-Lui Wong,Irene Oi-Lin Ng,Chun-Ming Wong. MicroRNA-142-3p and microRNA-142-5p are downregulated in hepatocellular carcinoma and exhibit synergistic effects on cell motility[J]. Front. Med., 2015, 9(3): 331-343.
[4] Carmen Chak-Lui Wong, Alan Ka-Lun Kai, Irene Oi-Lin Ng. The impact of hypoxia in hepatocellular carcinoma metastasis[J]. Front Med, 2014, 8(1): 33-41.
[5] Lunxiu Qin. Osteopontin is a promoter for hepatocellular carcinoma metastasis: a summary of 10 years of studies[J]. Front Med, 2014, 8(1): 24-32.
[6] Tian Wang, Yan Li, Abidan Tuerhanjiang, Wenwen Wang, Zhangying Wu, Ming Yuan, Shixuan Wang. Correlation of Twist upregulation and senescence bypass during the progression and metastasis of cervical cancer[J]. Front Med, 2014, 8(1): 106-112.
[7] Eryuan Liao. FGF23 associated bone diseases[J]. Front Med, 2013, 7(1): 65-80.
[8] Ling XU MM, Feng WANG MM, Xuan-Fu XU MD, Wen-Hui MO BM, Rong WAN MD, Chuan-Yong GUO MD, Xing-Peng WANG MD, . Data mining of microarray for differentially expressed genes in liver metastasis from gastric cancer[J]. Front. Med., 2010, 4(2): 247-253.
[9] Guocheng LIU MD, Shouhua YANG MD, Zehua WANG MD, . The relationship between platelet-derived growth factor expression and angiogenesis/lymphangiogenesis in cervical cancer[J]. Front. Med., 2009, 3(4): 447-451.
[10] Liu LIU MD, PhD, Yaogui NING MM, Chen CHEN MD, Daowen WANG MD, PhD, . Effect of atorvastatin on tumor growth and metastasis in a breast cancer cell xenograft model and its mechanism[J]. Front. Med., 2009, 3(4): 443-446.
[11] Haiping SONG MD, Lan SHI MD, Chunping LIU MD, Tao HUANG MD, . Expression of PC-cell-derived growth factor in breast cancer[J]. Front. Med., 2009, 3(4): 426-430.
[12] Yumei DING BM , Lili CHEN MD , Bo CHENG PhD , Handong ZHANG MM , . Relative expression of PTTG and bFGF in oral squamous cell carcinoma and Tca8113[J]. Front. Med., 2009, 3(3): 357-362.
[13] Qigong LIU M D , Yan ZENG , Jiani LIU , Shan YE , Yongdong LI , Zaiying LU M D , . Role of nitric oxide in biological effects of vascular endothelial growth factor[J]. Front. Med., 2009, 3(3): 284-286.
[14] Qigong LIU, Honglian ZHOU, Yan ZENG, Shan YE, Jiani LIU, Zaiying LU. Mechanism of vascular endothelial growth factor on the prevention of restenosis after angioplasty[J]. Front Med Chin, 2009, 3(2): 177-180.
[15] Ling HOU, Xiaoping LUO, Minlian DU, Huamei MA, Chunxiu GONG, Yuchuan LI, Shuixian SHEN, Zhuhui ZHAO, Li LIANG, Guanping DONG, Chaoying YAN, Hongwei DU. Clinical evaluation of recombinant human growth hormone injection in children with growth hormone deficiency[J]. Front Med Chin, 2009, 3(2): 171-176.
Full text