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Cholangiocarcinoma: From Mechanisms to Management

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Liver Cancers

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Abstract

Cholangiocarcinoma represents a spectrum of biliary tract adenocarcinoma, including intrahepatic and extrahepatic disease. A rare malignancy with recognized risk factors, the genomic spectra of the disease, is still being defined. Symptomatically silent in the early stages, cholangiocarcinoma manifests a very poor prognosis with many patients having advanced disease at presentation. Surgery represents the only curative approach. Unfortunately, only a minority of patients have resectable disease. Both resected and non-resected patients are offered a variety of chemotherapy regimens with randomized clinical trials having recently reported. Preoperative (neoadjuvant) chemotherapy and orthotopic liver transplantation are not standard treatment protocol at the current time. We conclude this chapter with a discussion of ongoing and future research.

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References

  1. Nagorney DM, Pawlik TM, Chun YS, et al. Perihilar bile ducts. In: Amin MB, editor. AJCC cancer staging manual. 8th ed. Chicago: AJCC; 2017. p. 312.

    Google Scholar 

  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(5):755.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg. 1992;215(1):31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Edge SB, Byrd DR, Compton CC, et al., editors. American Joint Committee on Cancer staging manual. 7th ed. New York: Springer; 2010. p. 201.

    Google Scholar 

  5. Janargin WR, Fong Y, DeMatteo RP, et al. Staging, resectability and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001;234(4):507–17.

    Article  Google Scholar 

  6. Vauthey JN, Blumgart LH. Recent advances in the management of cholangiocarcinomas. Semin Liver Dis. 1994;14(2):109.

    Article  CAS  PubMed  Google Scholar 

  7. Shaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology. 2005;128(3):620.

    Article  PubMed  Google Scholar 

  8. 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(6):1498.

    Article  CAS  PubMed  Google Scholar 

  9. Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol. 1999;10(Suppl 4):308.

    Article  PubMed  Google Scholar 

  10. Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol. 2002;36(3):321.

    Article  PubMed  Google Scholar 

  11. Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL. Choledochal cyst disease. A changing pattern of presentation. Ann Surg. 1994;220(5):644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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(11):1577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mahale P, Torres HA, Kramer JR, Hwang LY, Li R, Brown EL, Engels EA. Hepatitis C virus infection and the risk of cancer among elderly US adults: a registry-based case-control study. Cancer. 2017;123(7):1202. Epub 2017 Jan 24.

    Article  PubMed  Google Scholar 

  14. Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg. 2002;89(8):962.

    Article  CAS  PubMed  Google Scholar 

  15. Cardinale V, Carpino G, Reid L, Gaudio E, Alvaro D. Multiple cells of origin in cholangiocarcinoma underlie biological, epidemiological and clinical heterogeneity. World J Gastrointest Oncol. 2012;4:94–102.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Cardinale V, et al. Profiles of cancer stem cell subpopulations in cholangiocarcinomas. Am J Pathol. 2015;185:1724–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nakanishi Y, Zen Y, Kondo S, Itoh T, Itatsu K, Nakanuma Y. Expression of cell cycle-related molecules in biliary premalignant lesions: biliary intraepithelial neoplasia and biliary intraductal papillary neoplasm. Hum Pathol. 2008;39(8):1153.

    Article  CAS  PubMed  Google Scholar 

  18. Isa T, Tomita S, Nakachi A, Miyazato H, Shimoji H, Kusano T, Muto Y, Furukawa M. Analysis of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahepatic cholangiocarcinoma. Hepatogastroenterology. 2002;49(45):604.

    CAS  PubMed  Google Scholar 

  19. Arai Y, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology. 2014;59:1427–34.

    Article  CAS  PubMed  Google Scholar 

  20. 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(1):72–9. Epub 2011 Dec 16.

    Article  CAS  PubMed  Google Scholar 

  21. Yoshikawa D, et al. Clinicopathological and prognostic significance of EGFR, VEGF and HER2 expression in cholangiocarcinoma. Br J Cancer. 2008;98:418–25.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Webhe H, Henson R, Meng F, Mize-Berge J, Patel T. Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res. 2006;66:10517–24.

    Article  Google Scholar 

  24. Sato Y, et al. Epithelial-mesenchymal transition induced by transforming growth factor B-1/Snail activation aggravates invasive growth of cholangiocarcinoma. Am J Pathol. 2010;177:141–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Boulter L, et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J Clin Invest. 2015;125:1269–85.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224(4):463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Malaguarnera G, Paladina I, Giordano M, Malaguarnera M, Bertino G, Berretta M. Serum markers of intrahepatic cholangiocarcinoma. Dis Markers. 2013;34(4):219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kim HJ, Kim MH, Myung SJ, et al. A new strategy for the application of CA19-9 in the differentiation of pancreaticobiliary cancer: analysis using a receiver operating characteristic curve. Am J Gastroenterol. 1999;94(7):1941.

    Article  CAS  PubMed  Google Scholar 

  29. Patel AH, Harnois DM, Klee GG, LaRusso NF, Gores GJ. The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol. 2000;95(1):204.

    Article  CAS  PubMed  Google Scholar 

  30. Siqueira E, Schoen RE, Silverman W, et al. Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. Gastrointest Endosc. 2002;56(1):40.

    Article  PubMed  Google Scholar 

  31. Maeda T, Adachi E, Kajiyama K, Sugimachi K, Tsuneyoshi M. Combined hepatocellular and cholangiocarcinoma: proposed criteria according to cytokeratin expression and analysis of clinicopathologic features. Hum Pathol. 1995 Sep;26(9):956–64.

    Article  CAS  PubMed  Google Scholar 

  32. Saini S. Imaging of the hepatobiliary tract. N Engl J Med. 1997;336(26):1889.

    Article  CAS  PubMed  Google Scholar 

  33. Choi SH, Han JK, Lee JM, et al. Differentiating malignant from benign common bile duct stricture with multiphasic helical CT. Radiology. 2005;236(1):178. Epub 2005 Jun 13.

    Article  PubMed  Google Scholar 

  34. Iavarone M, Piscaglia F, Vavassori S, et al. Contrast enhanced CT-scan to diagnose intrahepatic cholangiocarcinoma in patients with cirrhosis. J Hepatol. 2013;58(6):1188–93. Epub 2013 Feb 26.

    Article  PubMed  Google Scholar 

  35. Adachi T, Eguchi S, Beppu T, et al. Prognostic impact of preoperative lymph node enlargement in intrahepatic cholangiocarcinoma: a multi-institutional study by the Kyushu Study Group of Liver Surgery. Ann Surg Oncol. 2015;22(7):2269–78. Epub 2015 Jan 13.

    Article  PubMed  Google Scholar 

  36. Tillich M, Mischinger HJ, Preisegger KH, Rabl H, Szolar DH. Multiphasic helical CT in diagnosis and staging of hilar cholangiocarcinoma. AJR Am J Roentgenol. 1998;171(3):651.

    Article  CAS  PubMed  Google Scholar 

  37. Manfredi R, Barbaro B, Masselli G, Vecchioli A, Marano P. Magnetic resonance imaging of cholangiocarcinoma. Semin Liver Dis. 2004;24(2):155.

    Article  PubMed  Google Scholar 

  38. Pelsang RE, Johlin FC. A percutaneous biopsy technique for patients with suspected biliary or pancreatic cancer without a radiographic mass. Abdom Imaging. 1997;22(3):307.

    Article  CAS  PubMed  Google Scholar 

  39. Corvera CU, Blumgart LH, Akhurst T, et al. 18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg. 2008;206(1):57. Epub 2007 Oct 1.

    Article  PubMed  Google Scholar 

  40. Weber SM, RP DM, Fong Y, Blumgart LH, Jarnagin WR. Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients. Ann Surg. 2002;235(3):392.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Su CH, Tsay SH, Wu CC, et al. Factors influencing postoperative morbidity, mortality, and survival after resection for hilar cholangiocarcinoma. Ann Surg. 1996;223(4):384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Khan SA, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut. 2012;61:1657–69.

    Article  CAS  PubMed  Google Scholar 

  43. Liberato MJ, Canena JM. Endoscopic stenting for hilar cholangiocarcinoma: efficacy of unilateral and bilateral placement of plastic and metal stents in a retrospective review of 480 patients. BMC Gastroenterol. 2012;12:103.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Tsao JI, Nimura Y, Kamiya J, et al. Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience. Ann Surg. 2000;232(2):166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Edge SB, Byrd DR, Compton CC, et al., editors. American Joint Committee on Cancer staging manual. 7th ed. New York: Springer; 2010. p. 219.

    Google Scholar 

  46. Panjala C, Nguyen JH, Al-Hajjaj AN, et al. Impact of neoadjuvant chemoradiation on the tumor burden before liver transplantation for unresectable cholangiocarcinoma. Liver Transpl. 2012;18(5):594.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Croome KP, Rosen CB, Heimbach JK, Nagorney DM. Is liver transplantation appropriate for patients with potentially resectable De Novo hilar cholangiocarcinoma? J Am Coll Surg. 2015;221(1):130–9. Epub 2015 Mar 11.

    Article  PubMed  Google Scholar 

  49. Rea DJ, Heimback JK, Rosen CB, et al. Ann Surg. 2005;242(3):451–8.

    PubMed  PubMed Central  Google Scholar 

  50. Eckel F, Brunner T, Jelic S, ESMO Guidelines Working Group. Biliary cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22(Suppl 6):vi40–4.

    PubMed  Google Scholar 

  51. Neoptolemos JP, Moore MJ, Cox TF, et al. European Study Group for Pancreatic Cancer. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA. 2012;308(2):147.

    Google Scholar 

  52. Primrose JN, Fox R, Palmer DH, et al. Adjuvant capecitabine for biliary tract cancer: the BILCAP randomized study (abstract). J Clin Oncol. 2017; 35 (suppl; abstr 4006).

    Article  Google Scholar 

  53. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273.

    Article  CAS  PubMed  Google Scholar 

  54. André T, Tournigand C, Rosmorduc O, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol. 2004;15(9):1339.

    Article  PubMed  Google Scholar 

  55. Knox JJ, Hedley D, Oza A, et al. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol. 2005;23(10):2332.

    Article  CAS  PubMed  Google Scholar 

  56. Novarino AM, Satolli MA, Chiappino I, et al. FOLFOX-4 regimen or single-agent gemcitabine as first-line chemotherapy in advanced biliary tract cancer. Am J Clin Oncol. 2013;36(5):466–71.

    Article  CAS  PubMed  Google Scholar 

  57. Nehls O, Oettle H, Hartmann JT, et al. Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial. Br J Cancer. 2008;98(2):309. Epub 2008 Jan 8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhu AX, Meyerhardt JA, Blaszkowsky LS, et al. Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol. 2010;11(1):48–54. Epub 2009 Nov 20.

    Article  CAS  PubMed  Google Scholar 

  59. Guion-Dusserre JF, Lorgis V, Vincent J, Bengrine L, Ghiringhelli F. FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma. World J Gastroenterol. 2015;21(7):2096–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Philip PA, Mahoney MR, Allmer C, et al. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol. 2006;24(19):3069.

    Article  CAS  PubMed  Google Scholar 

  61. Lubner SJ, Mahoney MR, Kolesar JL, et al. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol. 2010;28(21):3491. Epub 2010 Jun 7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. McMasters KM, Tuttle TM, Leach SD, et al. Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. Am J Surg. 1997;174(6):605.

    Article  CAS  PubMed  Google Scholar 

  63. Nelson JW, Ghafoori AP, Willett CG, et al. Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 2009;73(1):148. Epub 2008 Sep 19.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Hepatobiliary Surgery, Digestive Diseases Unit, Aintree University Hospital, Liverpool, UK

    Leonard M. Quinn, Nicholas Bird & David Vass

  2. Department of Liver Surgery, Aintree University Hospital NHS Foundation Trust, Liverpool, UK

    Robert Jones & Hassan Malik

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  1. Leonard M. Quinn
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  2. Nicholas Bird
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  3. Robert Jones
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  4. David Vass
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  5. Hassan Malik
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Correspondence to Hassan Malik .

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Editors and Affiliations

  1. Royal Liverpool University Hospital, Liverpool, Merseyside, UK

    Tim Cross

  2. University of Liverpool, Liverpool Early Drug Development Unit, Liverpool, UK

    Daniel H. Palmer

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Quinn, L.M., Bird, N., Jones, R., Vass, D., Malik, H. (2019). Cholangiocarcinoma: From Mechanisms to Management. In: Cross, T., Palmer, D. (eds) Liver Cancers. Springer, Cham. https://doi.org/10.1007/978-3-319-92216-4_16

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  • DOI: https://doi.org/10.1007/978-3-319-92216-4_16

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