Skip to main content

Advertisement

SpringerLink
Log in

Cholangiocarcinoma in Primary Sclerosing Cholangitis

  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

Introduction

Cholangiocarcinoma (CCA) is an aggressive and nearly always fatal tumor of the biliary tract.

Purpose

This review explores risk factors, epidemiology, current diagnostic approaches, and treatment of CCA arising in patients with primary sclerosing cholangitis (PSC).

Methods

We review latest recommendations about screening strategies to enable the early detection of CCA in PSC, using CA 19-9 and ultrasound imaging, as well as fluorescent in situ hybridization techniques to enhance the accuracy of biliary cytology. We also review the emerging role of liver transplantation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CCA:

Cholangiocarcinoma

PSC:

Primary sclerosing cholangitis

PPV:

Positive predictive value

NPV:

Negative predictive value

US:

Ultrasonography

CT:

Computed tomography

MRI:

Magnetic resonance imagining

ERCP:

Endoscopic retrograde cholangiopancreaticography

MRCP:

Magnetic resonance cholangiopancreaticography

OLT:

Orthotopic liver transplantation

FDG-PET:

2-Fluoro-2-deoxy-d-glucose-positron emission tomography

EUS:

Endoscopic ultrasound

References

  1. Khan SA, Taylor-Robinson SD, Toledano MB, et al. Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol. 2002;37:806–13.

    Article  PubMed  Google Scholar 

  2. Shaib Y, El Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis. 2004;24(2):115–25.

    Article  PubMed  Google Scholar 

  3. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin. 2005;55:10–30.

    Article  PubMed  Google Scholar 

  4. Broome U, Olsson R, Loof L, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut. 1996;38:610–15.

    Article  PubMed  CAS  Google Scholar 

  5. Pitt HA, Nakeeb A, Abrams RA, et al. Perihilar cholangiocarcinoma: postoperative radiotherapy does not improve survival. Ann Surg. 1995;221:788–98.

    Article  PubMed  CAS  Google Scholar 

  6. Bergquist A, Glumann H, Persson B, et al. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case–control study. Hepatology. 1998;27:311–16.

    Article  PubMed  CAS  Google Scholar 

  7. Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case–control study. Hepatology. 2000;31:7–11.

    Article  PubMed  CAS  Google Scholar 

  8. Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer. 2002;2:10.

    Article  PubMed  Google Scholar 

  9. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 2001;33:1353–57.

    Article  PubMed  CAS  Google Scholar 

  10. Watanapa P, Watanapa WB. Liver fluke associated cholangiocarcinoma. Br J Surg. 2002;89:962–70.

    Article  PubMed  CAS  Google Scholar 

  11. Kubo S, Kinoshita H, Hirohashi K, et al. Hepatolithiasis associated with cholangiocarcinoma. World J Surg. 1995;19:637–41.

    Article  PubMed  CAS  Google Scholar 

  12. Walker NJ, Crockett PW, Nyska A, et al. Dose-additive carcinogenicity of a defined mixture of “dioxin-like compounds”. Environ Health Perspect. 2005;113:43–8.

    PubMed  CAS  Google Scholar 

  13. Bond GG, McLaren EA, Sabel FL, et al. Liver and biliary tract cancer among chemical workers. Am J Int Med. 1990;18:19–24.

    CAS  Google Scholar 

  14. Oh SW, Yoon YS, Shin SA. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J Clin Oncol. 2005;23:4742–54.

    Article  PubMed  Google Scholar 

  15. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. a spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463–73.

    Article  PubMed  CAS  Google Scholar 

  16. Tsuzuki T, Ogata Y, Iida S, et al. Carcinoma of the bifurcation of the hepatic ducts. Arch Surg. 1983;118:1147–51.

    PubMed  CAS  Google Scholar 

  17. Weinbren K, Mutum SS. Pathological aspects of cholangiocarcinoma. J Pathol. 1983;139:217–38.

    Article  PubMed  CAS  Google Scholar 

  18. Lim JH. Cholangiocarcinoma: morphological classification according to growth pattern and imagining findings. Am J Roentgenol. 2003;181(3):819–27.

    Google Scholar 

  19. 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;98:873–5.

    Article  PubMed  Google Scholar 

  20. Berthiaume EP, Wands J. The molecular pathogenesis of cholangiocarcinoma. Semin Liver Dis. 2004;24:127–37.

    Article  PubMed  CAS  Google Scholar 

  21. Mosconi S, Beretta GD, Labianca R, et al. Cholangiocarcinoma. Crit Rev Oncol Hematol. 2009;69(3):259–70.

    Article  PubMed  Google Scholar 

  22. 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;49:604–8.

    PubMed  CAS  Google Scholar 

  23. Swierczynski SL, Maitra A, Abraham SC, et al. Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue microarrays. Hum Pathol. 2004;35:357–66.

    Article  PubMed  CAS  Google Scholar 

  24. American Joint Committee on Cancer. AJCC cancer staging manual. 6th ed. New York: Springer; 2002.

    Google Scholar 

  25. Blechacz BR, Sanchez W, Gores GJ, et al. A conceptual proposal for staging ductal cholangiocarcinoma. Curr Opin Gastroenterol. 2009;25(3):238–9.

    Article  PubMed  Google Scholar 

  26. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002;51(Suppl 6):VI1–9.

    Article  PubMed  Google Scholar 

  27. Deshpande V, Sainani NI, Chung RT, et al. IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis on liver biopsy material. Mod Pathol. 2009. doi:10.1038/modpathol.2009.94.

  28. Charatcharoenwitthaya P, Enders FB, Halling KC, et al. Utility of serum tumor markers, imagining and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology. 2008;48(4):1106–17.

    Article  PubMed  CAS  Google Scholar 

  29. Campbell WL, Ferris JV, Holbert BL, et al. Biliary tract carcinoma complicating primary sclerosing cholangitis: evaluation with CT, cholangiography, US, and MR imaging. Radiology. 1998;207:41–50.

    PubMed  CAS  Google Scholar 

  30. Rosen CB, Nagorney DM, Wiesner RH, et al. Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg. 1991;213(1):21–5.

    Article  PubMed  CAS  Google Scholar 

  31. Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD. The value of serum CA 19-9 in predicting cholangiocarcinoma in patients with primary sclerosing cholangitis. Dig Dis Sci. 2005;50:1734–40.

    Article  PubMed  CAS  Google Scholar 

  32. Baron TH, Harewood GC, Rumalla A, et al. A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures. Clin Gastroenterol Hepatol. 2004;2:214–19.

    Article  PubMed  Google Scholar 

  33. Kipp BR, Stadheim LM, Halling SA, et al. A comparison of routine cytology and fluorescence in situ hybridization for the detection of malignant bile duct strictures. Am J Gastroenterol. 2004;99:1675–81.

    Article  PubMed  Google Scholar 

  34. Cheon YK, Cho YD, Moon JH, et al. Diagnostic utility of interleukin-6 (IL-6) for primary bile duct cancer and changes in serum IL-6 levels following photodynamic therapy. Am J Gastroenterol. 2007;102:2164–70.

    Article  PubMed  CAS  Google Scholar 

  35. Smith RA, Ghaneh P, Sutton R, et al. Prognosis of resected ampullary adenocarcinoma by preoperative serum CA19-9 levels and platelet-lymphocyte ratio. J Gastrointest Surg. 2008;12:1422–28.

    Article  PubMed  Google Scholar 

  36. Smith RA, Bosonnet L, Ghaneh P, et al. The platelet-lymphocyte ratio improves the predictive value of serum CA19–9 levels in determining patient selection for staging laparoscopy in suspected periampullary cancer. Surgery. 2008;143:658–66.

    Article  PubMed  Google Scholar 

  37. Lempinen M, Isoniemi H, Mäkisalo H, et al. Enhanced detection of cholangiocarcinoma with serum trypsinogen-2 in patients with severe bile duct strictures. J Hepatol. 2007;47:677–83.

    Article  PubMed  CAS  Google Scholar 

  38. Duraisamy S, Ramasamy S, Kharbanda S, et al. Distinct evolution of the human carcinoma-associated transmembrane mucins, MUC1, MUC4 and MUC16. Gene. 2006;373:28–34.

    Article  PubMed  CAS  Google Scholar 

  39. Bamrungphon W, Prempracha N, Bunchu N, et al. A new mucin antibody/enzyme-linked lectin-sandwich assay of serum MUC5AC mucin for the diagnosis of cholangiocarcinoma. Cancer Lett. 2007;247:301–08.

    Article  PubMed  CAS  Google Scholar 

  40. Matull WR, Andreola F, Loh A, et al. MUC4 and MUC5AC are highly specific tumor-associated mucins in biliary tract cancer. Br J Cancer. 2008;98:1675–81.

    Article  PubMed  CAS  Google Scholar 

  41. Uenishi T, Yamazaki O, Tanaka H, et al. Serum cytokeratin 19 fragment (CYFRA21-1) as a prognostic factor in intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2008;15:583–89.

    Article  PubMed  Google Scholar 

  42. Alvaro D, Barbaro B, Franchitto A, et al. Estrogens and insulin-like growth factor 1 modulate neoplastic cell growth in human cholangiocarcinoma. Am J Pathol. 2006;169:877–88.

    Article  PubMed  CAS  Google Scholar 

  43. Alvaro D, Macarri G, Mancino MG, et al. Serum and biliary insulin-like growth factor I and vascular endothelial growth factor in determining the cause of obstructive cholestasis. Ann Intern Med. 2007;2:451–59.

    Google Scholar 

  44. Nishino R, Honda M, Yamashita T, et al. Identification of novel candidate tumor marker genes for intrahepatic cholangiocarcinoma. J Hepatol. 2008;49:207–16.

    Article  PubMed  CAS  Google Scholar 

  45. Chen CY, Tsai WL, Wu HC, et al. Diagnostic role of biliary pancreatic elastase for cholangiocarcinoma in patients with cholestasis. Clin Chim Acta. 2008;390:82–9.

    Article  PubMed  CAS  Google Scholar 

  46. Ayaru L, Stoeber K, Webster GJ, et al. Diagnosis of pancreaticobiliary malignancy by detection of mini chromosome maintenance protein 5 in bile aspirates. Br J Cancer. 2008;6:1548–54.

    Article  CAS  Google Scholar 

  47. Cherqui D, Benoist S, Malassagne B, et al. Major liver resection for carcinoma in jaundiced patients without preoperative biliary drainage. Arch Surg. 2002;135:302–8.

    Google Scholar 

  48. Kluge R, Schmidt F, Caca K, et al. Positron emission tomography with [(18)F] fluoro-2-deoxy-D-glucose for diagnosis and staging of bile duct cancer. Hepatology. 2001;33(5):1029–35.

    Article  PubMed  CAS  Google Scholar 

  49. Fritscher-Ravens A, Bohuslavizki KH, Broering DC, et al. FDG PET in the diagnosis of hilar cholangiocarcinoma. Nucl Med Commun. 2001;22:1277–85.

    Article  PubMed  CAS  Google Scholar 

  50. Fritscher-Ravens A, Broering DC, Sriram PV, et al. EUS guided fine needle aspiration cytodiagnosis of hilar cholangiocarcinoma; a case series. Gastrointest Endosc. 2000;52(4):534–40.

    Article  PubMed  CAS  Google Scholar 

  51. Weber SM, DeMatteo RP, Fong Y, et al. Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients. Ann Surg. 2002;235(3):392–9.

    Article  PubMed  Google Scholar 

  52. Vollmer CM, Drebin JA, Middleton WD, et al. Utility of staging laparoscopy in subsets of peripancreatic and biliary malignancies. Ann Surg. 2002;235(1):1–7.

    Article  PubMed  Google Scholar 

  53. Small AJ, Baron TH. Novel endoscopic approaches for assessing biliary tract diseases. Curr Opin Gastroenterol. 2008;24(3):357–62.

    Article  PubMed  Google Scholar 

  54. Takada T, Kato H, Matsushiro T, et al. Comparison of 5-fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic-biliary carcinomas. Oncology. 1994;51:396–400.

    Article  PubMed  CAS  Google Scholar 

  55. Choi CW, Choi IK, Seo JH, et al. Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas. Am J Clin Oncol. 2000;23:425–28.

    Article  PubMed  CAS  Google Scholar 

  56. Patt YZ, Jones DV Jr, Hoque A, et al. Phase II trial of intravenous flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer. J Clin Oncol. 1996;14:2311–15.

    PubMed  CAS  Google Scholar 

  57. Patt YZ, Hassan MM, Lozano RD, et al. Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and 5-fluorouracil for biliary tract cancer. Clin Cancer Res. 2001;7:3375–80.

    PubMed  CAS  Google Scholar 

  58. Ducreux M, Rougier P, Fandi A, et al. Effective treatment of advanced biliary tract carcinoma using 5-fluorouracil continuous infusion with cisplatin. Ann Oncol. 1998;9:653–56.

    Article  PubMed  CAS  Google Scholar 

  59. Lee MA, Woo IS, Kang JH, et al. Epirubicin, cisplatin, and protracted infusion of 5- FU (ECF) in advanced intrahepatic cholangiocarcinoma. J Cancer Res Clin Oncol. 2004;130:346–50.

    Article  PubMed  CAS  Google Scholar 

  60. Taieb J, Mitry E, Boige V, et al. Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma. Ann Oncol. 2002;13:1192–96.

    Article  PubMed  CAS  Google Scholar 

  61. Raderer M, Hejna MH, Valencak JB, et al. Twoconsecutive phase II studies of 5- fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer. Oncology. 1999;56:177–80.

    Article  PubMed  CAS  Google Scholar 

  62. Jones DV Jr, Lozano R, Hoque A, et al. Phase II study of paclitaxel therapy for unresectable biliary tree carcinomas. J Clin Oncol. 1996;14:2306–10.

    PubMed  CAS  Google Scholar 

  63. Kiba T, Nishimura T, Matsumoto S, et al. Single-agent gemcitabine for biliary tract cancers. Study outcomes and systematic review of the literature. Oncology. 2006;70:358–65.

    Article  PubMed  CAS  Google Scholar 

  64. Scheithauer W. Review of gemcitabine in biliary tract carcinoma. Semin Oncol. 2002;29:40–5.

    PubMed  CAS  Google Scholar 

  65. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001;234:507–17.

    Article  PubMed  CAS  Google Scholar 

  66. Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. 2005;242(3):451–8.

    PubMed  Google Scholar 

  67. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation. 2000;69:1633–7.

    Article  PubMed  CAS  Google Scholar 

  68. Brandsaeter B, Isoniemi H, Broome U, et al. Liver transplantation for primary sclerosing cholangitis: predictors and consequences of hepatobiliary malignancy. J Hepatol. 2004;40:815–22.

    Article  PubMed  CAS  Google Scholar 

  69. Foo ML, Gunderson LL, Bender CE, Buskirk SJ. External radiation therapy and transcatheter iridium in the treatment of extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys. 1997;39:929–35.

    PubMed  CAS  Google Scholar 

  70. Rosen CB, Heimbach JK, Gores GJ. Surgery for cholangiocarcinoma: the role of liver transplantation. HPB (Oxford). 2008;10(3):186–9.

    CAS  Google Scholar 

  71. Heimbach JK, Gores GJ, Haddock MG, et al. Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma. Transplantation. 2006;82:1703–7.

    Article  PubMed  CAS  Google Scholar 

  72. Smith AC, Dowsett JF, Russell RC, et al. Randomized trials of endoscopic stenting versus surgical bypass in malignant low bile duct obstruction. Lancet. 1994;344:1655–60.

    Article  PubMed  CAS  Google Scholar 

  73. Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology. 2003;125(5):1355–63.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Mayo Clinic, 20 First Street, SW, Rochester, MN, 55905, USA

    Ghulam Abbas & Keith D. Lindor

Authors
  1. Ghulam Abbas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keith D. Lindor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keith D. Lindor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abbas, G., Lindor, K.D. Cholangiocarcinoma in Primary Sclerosing Cholangitis. J Gastrointest Canc 40, 19–25 (2009). https://doi.org/10.1007/s12029-009-9085-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-009-9085-8

Keywords

Search

Navigation