Overview of Cholangiocarcinoma and Evidence for a Primary Liver Carcinoma Spectrum

  • Joe W. Grisham
  • Xin Wei Wang
  • Snorri S. Thorgeirsson
Chapter
Part of the Cancer Genetics book series (CANGENETICS)

Abstract

Intrahepatic cholangiocarcinoma, second in incidence to hepatocellular carcinoma among the primary liver carcinomas, has an even more dismal prognosis. Intrahepatic cholangiocarcinoma is difficult to diagnose at an early stage of development and advances aggressively, with widespread metastases. Molecular genetic features of intrahepatic cholangiocarcinoma have been partially elucidated, although the specific genetic lesions and molecular processes that drive its development, progression, and metastasis are still obscure. Evidence has accumulated from many sources suggesting that cholangiocarcinoma and hepatocellular carcinoma are components of a spectrum of primary liver carcinomas, including poorly and aberrantly differentiated varieties. Primary liver carcinomas arise from cells in different stages of development that encompass the entire lineage of liver epithelial cells generated from hepatoblasts and/or adult liver stem cells, and share critical genomic aberrations and phenotypes with these progenitor cells.

Keywords

Primary liver cancer Hepatocellular carcinoma Intrahepatic cholangiocarcinoma Overlap of primary liver cancers 

References

  1. Adamek HE, Spiethoff A, Kaufmann V et al (1998) Primary clear cell carcinoma of the noncirrhotic liver. Immunohistochemical discrimination or hepatocellular or cholangiocellular origin. Dig Dis Sci 41:33–38CrossRefGoogle Scholar
  2. Aishima S, Kuroda Y, Asayama Y (2006) Prognostic impact of cholangiocellular and sarcomatous elements in combined hepatocellular and cholangiocarcinoma. Hum Pathol 37:283–291CrossRefPubMedGoogle Scholar
  3. Aishima S, Nishihara Y, Kuroda Y et al (2007) Histologic characteristics and prognostic significance in small hepatocellular carcinoma with biliary differentiation. Subdivision and comparison with ordinary hepatocellular carcinoma. Am J Surg Pathol 31:785–791Google Scholar
  4. Allen RA, Lisa JR (1949) Combined liver cell and bile duct carcinoma. Am J Pathol 23:647–655Google Scholar
  5. Berthiaume EP, Wands J (2004) The molecular pathogenesis of cholangiocarcinoma. Semin Liver Dis 24:127–137CrossRefPubMedGoogle Scholar
  6. Blechacz B, Gores GJ (2008) Cholangiocarcinoma. Clin Liver Dis 12:131–150CrossRefGoogle Scholar
  7. Bosch FX, Ribes J, Díaz M et al (2004) Primary liver cancer: worldwide incidence and trends. Gastroenterology 127:S5–S16CrossRefPubMedGoogle Scholar
  8. Bosch FX, Ribes J, Cléries R et al (2005) Epidemiology of hepatocellular carcinoma. Clin Liver Dis 9:191–211CrossRefPubMedGoogle Scholar
  9. Cazals-Hatem D, Rebouissou S, Bioulac-Sage P et al (2004) Clinical and molecular analysis of combined hepatocellular-cholangiocarcinomas. J Hepatol 41:292–298CrossRefPubMedGoogle Scholar
  10. Chantajitr S, Wilasrusmee C, Lertsitchai P et al (2006) Combined hepatocellular and cholangiocarcinoma: clinical features and prognostic study in a thai population. J Hepatobiliary Pancreat Surg 13:537–542CrossRefPubMedGoogle Scholar
  11. Coleman WB, Smith GJ, Grisham JW (1994) Development of dexamethasone-inducible tyrosine aminotransferase activity in WB-F344 rat liver epithelial cells in the presence of sodium butyrate. J Cell Physiol 161:463–469CrossRefPubMedGoogle Scholar
  12. Coleman WB, McCullough KD, Esch GL et al (1997) Evaluation of differentiation potential of WB-F344 rat liver epithelial stem-like cells in vivo. Differentiation to hepatocytes after transplantation into dipeptidylpeptidase-IV-deficient rat liver. Am J Pathol 151:353–359PubMedGoogle Scholar
  13. Couchie D, Holic N, Chobert MN et al (2002) In vitro differentiation of WB-F344 rat liver epithelial cells into the biliary lineage. Differentiation 69:209–215CrossRefPubMedGoogle Scholar
  14. D’Errico A, Baccarini P, Fiorintino M et al (1996) Histogenesis of primary liver carcinomas: strengths and weaknesses of cytokeratin profile and albumin RNA detection. Hum Pathol 27:599–604CrossRefPubMedGoogle Scholar
  15. Durnez A, Verslype C, Nevens F et al (2006) The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin. Histopathology 49:138–151CrossRefPubMedGoogle Scholar
  16. Edamoto Y, Tani M, Kurata T et al (1996) Hepatitis C and B virus infections in hepatocellular carcinoma. Analysis of direct detection of viral genomes in paraffin embedded tissues. Cancer 77:1787–1791CrossRefPubMedGoogle Scholar
  17. Edmondson HA, Steiner PE (1954) Primary carcinoma of the liver. A study of 100 cases among 48,900 necropsies. Cancer 7:462–503CrossRefPubMedGoogle Scholar
  18. Fausto N, Campbell JS (2003) The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev 120:117–130CrossRefPubMedGoogle Scholar
  19. Fava G, Marzioni M, Benedetti A et al (2007) Molecular pathology of biliary tract cacers. Cancer Letters 250:155–167CrossRefPubMedGoogle Scholar
  20. Fujii H, Zhu XG, Matsumoto T et al (2000) Genetic classification of combined hepatocellular-cholangiocarcinoma. Hum Pathol 31:1011–10177CrossRefPubMedGoogle Scholar
  21. Gil-Benso R, Martinez-Lorente A, Pellin-Perez A et al (2001) Characterization of a new rat cell line established from 2’AAF-induced combined hepatocellular cholangiocellular carcinoma. In Vitro Cell Dev Biol Anim 37:17–25CrossRefPubMedGoogle Scholar
  22. Goodman ZD (2007) Neoplasms of the liver. Mod Pathol 20:549–560CrossRefGoogle Scholar
  23. Goodman ZD, Ishak KG, Langloss JM et al (1985) Combined hepatocellular-cholangiocellular carcinoma. A histologic and immunohistochemical study. Cancer 55:124–135CrossRefPubMedGoogle Scholar
  24. Grisham JW (2009) Organizational principles of the liver. In: Arias IW, Alter H, Shafritz D et al (eds) The Liver: Biology and Pathobiology, 5th edn. Wiley, LondonGoogle Scholar
  25. Hai S, Kubo S, Yamamoto S. (2005) Clinicopathologic characteristics of hepatitis C virus-associated intrahepatic cholangiocarcinoma. Dig Surg 22:432–439CrossRefPubMedGoogle Scholar
  26. Hashizume H, Sato K, Takagi H (2007) Primary liver cancers with nonalcoholic steatohepatitis. Eur J Gastroenterol Hepatol 19:827–834CrossRefPubMedGoogle Scholar
  27. Henson DE, Albores-Saavedra J, Corle D (1992) Carcinoma of the extrahepatic bile ducts: histologic types, stage of disease, grade, and survival rates. Cancer 70:1498–1501CrossRefPubMedGoogle Scholar
  28. Horie Y, Suzuki A, Kataoka E et al (2004) Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 113:1774–1783PubMedGoogle Scholar
  29. Ichikawa T, Yanagi K, Motoyoshi Y (2006) Two cases of non-alcoholic steatohepatitis with development of hepatocellular carcinoma without cirrhosis. J Gastroenterol Hepatol 21:1865–1868CrossRefPubMedGoogle Scholar
  30. Imai Y, Oda H, Arai M et al (1996) Mutational analysis of the p53 and K-ras genes and allelotype study of the Rb-1 gene for investigating the pathogenesis of combined hepatocellular-cholangiocellular carcinomas. Jpn J Cancer Res 87:1056–1062PubMedGoogle Scholar
  31. Jang F, Huang X, Yi T et al (2007) Spontaneous development of liver tumors in the absence of the bile acid transporter farsenoid X receptor. Cancer Res 67:863–867CrossRefGoogle Scholar
  32. Jarnigan WR, Weber S, Tickoo SK et al (2001) Combined hepatocellular and cholangiocarcinoma. Demographic, clinical, and prognostic features. Cancer 94:2040–2046CrossRefGoogle Scholar
  33. Kim H, Park C, Han K (2004) Primary liver carcinoma of intermediate (hepatocyte-cholangiocyte) phenotype. J Hepatol 40:298–304CrossRefPubMedGoogle Scholar
  34. Kim I, Morimura K, Shah Y et al (2007) Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28:940–946CrossRefPubMedGoogle Scholar
  35. Koh KC, Lee H, Choi MS et al (2005) Clinicopathologic features and prognosis of combined hepatocellular cholangiocarcinoma. Am J Surg 189:120–123CrossRefPubMedGoogle Scholar
  36. Komuta M, Spee B, Borght SV et al (2008) Clinicopathological study of cholangiolocellular carcinoma suggesting hepatic progenitor cell origin. Hepathology 47:1544–1556CrossRefGoogle Scholar
  37. Koo SH, Ihm CH, Kwon KC et al (2001) Genetic alterations in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Cancer Genet Cytogenet 130:22–28CrossRefPubMedGoogle Scholar
  38. Kuwahara R, Kofman AV, Landis CS et al (2008) The hepatic stem cell niche: identification by label-retaining assay. Hepatology 47:1994–2002CrossRefPubMedGoogle Scholar
  39. Lee J, Park Y, Uhm K et al (2004) Genetic alterations in intrahepatic cholangiocarcinoma as revealed by degenerate oligonucleotide primed PCR-comparative genomic hybridization. J Korean Med Soc 19:682–687CrossRefGoogle Scholar
  40. Lee JS, Chu IS, Heo J et al (2004a) Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 40:667–676CrossRefPubMedGoogle Scholar
  41. Lee JS, Chu IS, Mikaelyan A et al (2004b) Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet 16:1306–1311CrossRefGoogle Scholar
  42. Lee JS, Heo J, Libbrecht L et al (2006) A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 12:410–416CrossRefPubMedGoogle Scholar
  43. Lee W, Lee K, Heo J et al (2006) Comparison of combined hepatocellular and cholangiocarcinoma with hepatocellular carcinoma and cholangiocarcinoma. Surg Today 36:892–897CrossRefPubMedGoogle Scholar
  44. Lemaigre F, Zaret KS (2004) Liver development update: new embryo models, cell lineage control, and morphogenesis. Current Opinion Genet Dev 14:582–590CrossRefGoogle Scholar
  45. Lin YZ, Brunt EM, Bowling W (1995) Ras-transduced dimethylnitrosamine-treated hepatocytes develop into cancers of mixed phenotype in vivo. Cancer Res 55:5242–5250PubMedGoogle Scholar
  46. Liu D, Wada I, Tateno H et al (2004) Allelotyping of thorotrast-induced intrahepatic cholangiocarcinoma: comparison to liver cancers not associated with thorotrast. Radiat Res 161:235–243CrossRefPubMedGoogle Scholar
  47. Maeda T, Adachi E, Kajiyama K et al (1995) Combined hepatocellular and cholangiocarcinoma: proposed criteria according to cytokeratin expression and analysis of clinicopathologic features. Hum Pathol 26:956–964CrossRefPubMedGoogle Scholar
  48. McGlynn KA, Tarone RA, El-Serag HB (2006) A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States. Cancer Epidemiol Biomarkers Prev 15:1198–1203CrossRefPubMedGoogle Scholar
  49. Moinzadeh P, Breuhahn K, Stützer H et al (2005) Chromosome alterations in human hepatocellular carcinomas correlate with aetiology and histological grade – results of an explorative CGH meta-analysis. Brit J Cancer 92:935–941CrossRefPubMedGoogle Scholar
  50. Moll R, Franke WW, Schiller DL et al (1982) The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31:11–14CrossRefPubMedGoogle Scholar
  51. Momoi H, Okabe H, Kamikawa T et al (2001) Comprehensive allelotyping of human intrahepatic cholangiocarcinoma. Clin Cancer Res 7:2648–2655PubMedGoogle Scholar
  52. Morcos M, Dubois S, Bralet M-P (2001) Primary Liver carcinoma in genetic hemochromatosis reveals a broad histologic spectrum. Am J Clin Pathol 116:738–743CrossRefPubMedGoogle Scholar
  53. Murakami T, Yano H, Maruiwa M et al (1987) Establishment and characterization of a human combined hepatocholangiocarcinoma cell line and its heterologous transplantantion in nude mice. Hepatology 7:551–556CrossRefPubMedGoogle Scholar
  54. Murata M, Miyoshi Y, Iwao K et al (2001) Combined hepatocellular/ cholangiocellular carcinoma with sarcamatoid features: genetic analysis for histogenesis. Hepatol Res 23:220–227CrossRefGoogle Scholar
  55. Nakanuma Y, Harada K, Ishikawa A et al (2003) Anatomic and molecular pathology of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 10:265–281CrossRefPubMedGoogle Scholar
  56. National Toxicology Program (1980–2009) Nat’l Toxicol Prog Tech Rep Ser. VariousGoogle Scholar
  57. Obama K, Ura K, Li M et al (2005) Genome-wide analysis of gene expression in human intrahepatic cholangiocarcinoma. Hepatology 41:1339–1348CrossRefPubMedGoogle Scholar
  58. Olivera AM, Erickson LA, Burgart LJ et al (2000) Differentiation of primary and metastatic clear cell tumors of the liver by in situ hybridization for albumin messenger RNA. Am J Surg Pathol 24:177–182CrossRefGoogle Scholar
  59. Parent R, Marioon M, Furio L et al (2004) Origin and characterization of a human bipotent progenitor cell line. Gastroenterology 126:1147–1156CrossRefPubMedGoogle Scholar
  60. Perumal V, Wang J, Thuluvath P et al (2006) Hepatitis C and hepatitis B nucleic acids are present in intrahepatic cholangiocarcinomas from the United States. Hum Pathol 37:1211–1216CrossRefPubMedGoogle Scholar
  61. Ponomarev AB, Kosminkova EN, Geralova ST (1994) Diffuse cholangiocarcinoma in the context of multilobular cirrhosis as a manifestation of Wilson-Konalov disease. (In Russian) Arkh Pathol 56:74–77Google Scholar
  62. Robrechts C, De Vos R, Vanden Huevel M (1998) Primary liver tumor of intermediate (hepatocyte-bile duct cell) phenotype: a progenitor cell tumor? Liver 18:288–293PubMedGoogle Scholar
  63. Schurr R, Stöbel U, Schuppan D et al (2006) Zunahme des hepatozellulären und des intrhepatischen cholangiozellulären Karzinoms im Nordosten Deutschlands. Dtsch Med Wochenschr 131:1649–1655CrossRefPubMedGoogle Scholar
  64. Seeff LB, Hoofnagle JH (2006) Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity. Oncogene 25:3771–3777CrossRefPubMedGoogle Scholar
  65. Sell S, Dunsford HA (1989) Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma. Am J Pathol 134:1347–1363PubMedGoogle Scholar
  66. Shaib Y, El-Serag HB (2004) The epidemiology of cholangiocarcinoma. Seminars Liver Dis 24:115–125CrossRefGoogle Scholar
  67. Shaib YH, El-Serag HB, Davila JA et al (2005) Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 128:620–626CrossRefPubMedGoogle Scholar
  68. Sharp GB (2002) The relationship between internally deposited alpha-particle radiation and subsite-specific liver cancer and liver cirrhosis: an analysis of published data. J Radiol Res 43:371–380CrossRefGoogle Scholar
  69. Sirica AE (2006) Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy. Hepatology 41:5–15CrossRefGoogle Scholar
  70. Suto T, Habano W, Sugai T et al (2000) Aberrations of the K-ras, p53, and APC genes in extrahepatic bile duct cancer. J Surg Oncol 73:158–163CrossRefPubMedGoogle Scholar
  71. Steiner PE, Higginson J (1959) Cholangiolocellular carcinoma of the liver. Cancer 12:753–759CrossRefPubMedGoogle Scholar
  72. Tanaka K, Hanna T, KitanaY (2005) Combined fibrolamellar carcinoma and cholangiocarcinoma exhibiting biphenotype antigen expression: a case report. J Clin Pathol 58:884–887CrossRefPubMedGoogle Scholar
  73. Tang D, Nagano H, Nakamura M et al (2006) Clinical and pathological features of Allen’s type C classification of resected combined hepatocellular and cholangiocarcinoma: a comparative study with hepatocellular carcinoma and cholangiocellular carcinoma. J Gastrointestinal Surg 10:987–998CrossRefGoogle Scholar
  74. Theise ND, Yao JL, Harada K (2003) Hepatic “stem cell” malignancies in adults: four cases. Histopathology 43:263–271CrossRefPubMedGoogle Scholar
  75. Tickoo SK, Zee SY, Obiekwe S et al (2002) Combined hepatocellular-cholangioma. A histopathologic, immunohistochemical, and in situ hybridization study. Am J Surg Pathol 26:989–997CrossRefPubMedGoogle Scholar
  76. Tihan T, Blumgart L, Klimstra DS (1998) Clear cell papillary carcinoma of the liver: an unusual variant of peripheral cholangiocarcinoma. Human Pathol 29:196–200CrossRefGoogle Scholar
  77. Tsao MS, Smith JD, Nelson KD (1984) A diploid epithelial cell line from normal adult rat liver with phenotypic properties of “oval” cells. Exp Cell Res 154:38–52CrossRefPubMedGoogle Scholar
  78. Tsao MS, Grisham JW (1987) Hepatocarcinomas, cholangiocarcinomas, and hepatoblastomas produced by chemically transformed rat liver epithelial cells. A light- and electron-microscopic study. Am J Pathol 127:168–181PubMedGoogle Scholar
  79. Uhm K, Park Y, Lee J et al (2005) Chromosomal imbalances in Korean intrahepatic cholangiocarcinomas by comparative genomic hybridization. Cancer Genet Cytogenet 157:37–41CrossRefPubMedGoogle Scholar
  80. Vatanasapt V, Martin N, Sriplung H et al (1995) Cancer incidence in Thailand, 1988–1991. Cancer Epidemiol Biomarkers Prev 4:475–483PubMedGoogle Scholar
  81. Walshe JM, Waldenstrom H, Westermark K (2003) Abdominal malignancies in patients with Wilson’s disease. Quart J Med 96:657–662Google Scholar
  82. Weinberg RA (2006) The biology of cancer. Taylor and Francis, New York, NYGoogle Scholar
  83. Wells HG (1903) Primary carcinoma of the liver. Am J Med Sci 126:403–417CrossRefGoogle Scholar
  84. Welzel TM, Millemkjaer L, Gloria G (2006) Risk factors for intrahepatic cholangiocarcinoma in a low risk population: a nationwide case-control study. Int J Cancer 120:638–641CrossRefGoogle Scholar
  85. West J, Wood H, Logan RFA et al (2006) Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971–2001. Brit J Cancer 94:1751–1728CrossRefPubMedGoogle Scholar
  86. Wong N, Li L, Tsang K et al (2002) Frequent loss of chromosome 3p and hypermethylation of RASSF1A in cholangiocarcinoma. J Hepatol 37:633–639CrossRefPubMedGoogle Scholar
  87. Woo HG, Lee J-H, Yoon J-H et al (2010) Cholangiocarcinoma-like gene expression traits in hepatocellular carcinoma. Cancer Res 70:3034–3041Google Scholar
  88. Wu PC, Fang JW, Lau VK (1996) Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers, clinical and biological implications. Am J Pathol 149:1167–1175PubMedGoogle Scholar
  89. Xu X, Kobayashi S, Qiao W (2006) Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. J Clin Invest 116:1843–1852CrossRefPubMedGoogle Scholar
  90. Yamamoto S, Kubo S, Hai S (2004) Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma. Cancer Sci 95:592–595CrossRefPubMedGoogle Scholar
  91. Yano H, Iemura A, Haramaki M et al (1996) 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 24:413–422CrossRefPubMedGoogle Scholar
  92. Yano Y, Yamamoto J, Kosuge T et al (2003) Combined hepatocellular and cholangiocarcinoma: a clinicopathologic study of 26 resected cases. Jpn J Oncol 33:283–287CrossRefGoogle Scholar
  93. Zaret KS, Grompe M (2008) Generation and regeneration of cells of the liver and pancreas. Science 322:1490–1501CrossRefPubMedGoogle Scholar
  94. Zhao R, Duncan SA (2005) Embryonic development of the liver. Hepatology 41:956–967CrossRefPubMedGoogle Scholar
  95. Zimmermann A (2003) Hepatoblastoma with cholaangioblastic features (“cholangioblastic hepatoblastoma”) and other liver tumors with bimodal differentiation in young patients. Med Pediatr Oncol 39:487–491CrossRefGoogle Scholar
  96. Zuo H, Yan L, Zeng Y et al (2007) Clinicopathological characteristics of 15 patients with combined hepatocellular carcinoma and cholangiocarcinoma. Hepatobiliary Pancreatic Dis Int 6:161–165Google Scholar

Copyright information

© Springer New York 2010

Authors and Affiliations

  • Joe W. Grisham
    • 1
  • Xin Wei Wang
    • 2
  • Snorri S. Thorgeirsson
    • 3
  1. 1.University of North Carolina at Chapel HillChapel HillUSA
  2. 2.Liver Carcinogenesis Section, Laboratory of Human CarcinogenesisNational Cancer Institute, NIHBethesdaUSA
  3. 3.Laboratory of Experimental CarcinogenesisCenter for Cancer Research, National Cancer Institute, NIHBethesdaUSA

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