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Malignancy and Primary Sclerosing Cholangitis: Cholangiocarcinoma, Hepatocellular Carcinoma, and Gallbladder Carcinoma

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Primary Sclerosing Cholangitis

Abstract

Primary sclerosing cholangitis is associated with an increased risk of malignancy. The chronic inflammation of the intra- and extrahepatic biliary tract predisposes to the development of cholangiocarcinoma and gallbladder carcinoma. In those who progress to cirrhosis, there is risk for development of hepatocellular carcinoma. Cholangiocarcinoma complicates primary sclerosing cholangitis in 10–15 % of individuals and often presents a diagnostic challenge. Diagnosis is largely guided by high clinical suspicion with laboratory testing, imaging, and biliary tissue sampling. Definitive therapy is surgical. Liver transplantation can be considered in highly selected individuals with hilar tumors who are not surgical resection candidates. Similarly, for hepatocellular carcinoma, curative therapy is also surgical. Liver transplantation is almost always required given it develops almost exclusively in patients with cirrhosis. Gallbladder carcinoma, while a less common malignancy, is more prevalent in primary sclerosing cholangitis. Gallbladder carcinoma is diagnosed with imaging, most commonly ultrasound, and again treatment is surgical with cholecystectomy/resection.

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Abbreviations

AASLD:

American Association for the Study of Liver Diseases

AFP:

Alpha-fetoprotein

AJCC:

American Joint Committee on Cancer

BCLC:

Barcelona Clinic Liver Cancer

CCA:

Cholangiocarcinoma

CLIP:

Cancer of the Liver Italian Program

CT:

Computerized tomography

CTP:

Child-Turcotte-Pugh

DDLT:

Deceased donor liver transplantation

ERCP:

Endoscopic retrograde cholangiopancreatography

EUS:

Endoscopic ultrasound

FISH:

Fluorescence in situ hybridization

FNA:

Fine needle aspiration

GBC:

Gallbladder carcinoma

HCC:

Hepatocellular carcinoma

LDLT:

Living donor liver transplantation

MELD:

Model for end-stage liver disease

MRCP:

Magnetic resonance cholangiopan-creatography

MRI:

Magnetic resonance imaging

NCCN:

National Comprehensive Cancer Network

OLT:

Orthotopic liver transplantation

PDT:

Photodynamic therapy

PIVKA II:

Prothrombin induced by vitamin K absence II

PSC:

Primary sclerosing cholangitis

RFA:

Radiofrequency ablation

TACE:

Transarterial chemoembolization

TNM:

Tumor, node, metastasis

UCSF:

University of California, San Francisco

UNOS:

United Network for Organ Sharing

US:

Ultrasound

Y-90:

Yttrium-90

References

  1. Abu-elmagd KM, Malinchoc M, Dickson ER, et al. Efficacy of hepatic transplantation in patients with primary sclerosing cholangitis. Surg Gynecol Obstet. 1993;177(4):335–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. AJCC Cancer Staging Manual. 6th ed. New York: Springer; 2002.

    Google Scholar 

  3. Bangarulingam SY, Bjornsson E, Enders F, Barr Fritcher EG, Gores G, Halling KC, Lindor KD. Long-term outcomes of positive fluorescence in situ hybridization tests in primary sclerosing cholangitis. Hepatology. 2010;51:174–80.

    Article  CAS  PubMed  Google Scholar 

  4. Barr Fritcher EG, Kipp BR, Voss JS, et al. Primary sclerosing cholangitis patients with serial polysomy fluorescence in situ hybridization results are at increased risk of cholangiocarcinoma. Am J Gastroenterol. 2011;106(11):2023–8.

    Article  PubMed  Google Scholar 

  5. Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol. 2002;36(3):321–7.

    Article  PubMed  Google Scholar 

  6. Bergquist A, Glaumann H, Persson B, Broomé U. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case–control study. Hepatology. 1998;27(2):311–6.

    Article  CAS  PubMed  Google Scholar 

  7. Bhangui P, Vibert E, Majno P, et al. Intention-to-treat analysis of liver transplantation for hepatocellular carcinoma: living versus deceased donor transplantation. Hepatology. 2011;53(5):1570–9.

    Article  PubMed  Google Scholar 

  8. Bialecki ES, Di Bisceglie AM. Diagnosis of hepatocellular carcinoma. HPB (Oxford). 2005;7(1):26–34.

    Article  Google Scholar 

  9. Björnsson E, Olsson R. Dominant strictures in patients with primary sclerosing cholangitis-revisited. Am J Gastroenterol. 2004;99(11):2281.

    Article  PubMed  Google Scholar 

  10. Boberg KM, Lind GE. Primary sclerosing cholangitis and malignancy. Best Pract Res Clin Gastroenterol. 2011;25(6):753–64.

    Article  PubMed  Google Scholar 

  11. Bolondi L, Sofia S, Siringo SE, et al. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma; a cost effectiveness analysis. Gut. 2001;48:251–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Broome U, Olsson R, Loof L, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut. 1996;38:610–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2010;53(3):1020–2.

    Article  Google Scholar 

  14. Buckles D, Lindor K, et al. In primary sclerosing cholangitis, gallbladder polyps are frequently malignant. Am J Gastroenterol. 2002;97:5.

    Article  Google Scholar 

  15. Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2004;99:523–6.

    Article  PubMed  Google Scholar 

  16. Cardinale V, et al. 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 

  17. Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case–control study. Hepatology. 2000;31(1):7–11.

    Article  CAS  PubMed  Google Scholar 

  18. Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51:660–78.

    Article  CAS  PubMed  Google Scholar 

  19. Charatcharoenwitthaya P, Enders FB, Halling KC, Lindor KD. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology. 2008;48:1106–17.

    Article  CAS  PubMed  Google Scholar 

  20. Chen YK, Pleskow DK. SpyGlass single-operator peroral cholangiopancreatoscopy system for the diagnosis and therapy of bile-duct disorders: a clinical feasibility study (with video). Gastrointest Endosc. 2007;65(6):832–41.

    Article  PubMed  Google Scholar 

  21. Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. 2012;143(1):88–98.e3.

    Article  PubMed  Google Scholar 

  22. Darwish Murad S, Kim WR, Therneau T, et al. Predictors of pretransplant dropout and posttransplant recurrence in patients with perihilar cholangiocarcinoma. Hepatology. 2012;56(3):972–81.

    Article  PubMed  Google Scholar 

  23. De Vreede I, Steers JL, Burch PA, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl. 2000;6:309–16.

    Article  PubMed  Google Scholar 

  24. Eaton JE, Barr Fritcher EG, Gores CJ, et al. Biliary multifocal chromosomal polysomy and cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2015;110:299–309.

    Article  PubMed  PubMed Central  Google Scholar 

  25. El-serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118–27.

    Article  CAS  PubMed  Google Scholar 

  26. Farazi PA, Depinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6(9):674–87.

    Article  CAS  PubMed  Google Scholar 

  27. Farrant JM, Hayllar KM, Wilkinson ML, et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology. 1991;100(6):1710–7.

    CAS  PubMed  Google Scholar 

  28. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35–50.

    Article  PubMed  Google Scholar 

  29. Fevery J, Verslype C, Lai G, Aerts R, Van Steenbergen W. Incidence, diagnosis, and therapy of cholangiocarcinoma in patients with primary sclerosing cholangitis. Dig Dis Sci. 2007;52:3123–35.

    Article  CAS  PubMed  Google Scholar 

  30. Gollin SM. Mechanisms leading to chromosomal instability. Semin Cancer Biol. 2005;15(1):33–42.

    Article  CAS  PubMed  Google Scholar 

  31. Harnois DM, Gores GJ, Ludwig J, Steers JL, Larusso NF, Wiesner RH. Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer? J Hepatol. 1997;27(3):512–6.

    Article  CAS  PubMed  Google Scholar 

  32. Heimbach JK, Sanchez W, Rosen CB, Gores GJ. Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination. HPB Off J Int Hepato Pancreato Biliary Assoc. 2011;13(5):356–60. doi:10.1111/j.1477-2574.2011.00298.

    Article  Google Scholar 

  33. Hong JC, Jones CM, Duffy JP, et al. Comparative analysis of resection and liver transplantation for intrahepatic and hilar cholangiocarcinoma: a 24-year experience in a single center. Arch Surg. 2011;146(6):683–9. Kozarek RA. Single-operator cholangioscopes in the diagnosis of cholangiocarcinoma: seeing is believing. Is belief enough to allow treatment? Gastrointest Endosc. 2015;82(4):615–7.

    Google Scholar 

  34. Ismail T, Angrisani L, Powell JE, et al. Primary sclerosing cholangitis: surgical options, prognostic variables and outcome. Br J Surg. 1991;78(5):564–7.

    Article  CAS  PubMed  Google Scholar 

  35. Jaiswal M, Larusso NF, Burgart LJ, Gores GJ. Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res. 2000;60(1):184–90.

    CAS  PubMed  Google Scholar 

  36. Kahaleh M, Mishra R, Shami VM, et al. Unresectable cholangiocarcinoma: comparison of survival in biliary stenting alone versus stenting with photodynamic therapy. Clin Gastroenterol Hepatol. 2008;6(3):290–7.

    Article  PubMed  Google Scholar 

  37. Kozarek RA. Single-operator cholangioscopes in the diagnosis of cholangiocarcinoma: seeing is believing. Is belief enough to allow treatment? Gastrointest Endosc. 2015;82(4):615–7.

    Article  PubMed  Google Scholar 

  38. Kronfeld D, Ekbon A, Ihre T. Survival and risk of CCA in patient with primary sclerosing cholangitis. Scand J Gastroenterol. 1997;32:1042–5.

    Article  Google Scholar 

  39. Leung UC, Wong PY, et al. Gallbladder polyps in sclerosing cholangitis: does the 1-cm rule apply? ANZ J Surg. 2001;77(5):355–7.

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham SC. Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: evidence for a metaplasia-dysplasia-carcinoma sequence. Am J Surg Pathol. 2007;31(6):907–13.

    Article  PubMed  Google Scholar 

  42. Linderg B, Arneio U, Bergquist A, et al. Diagnosis of biliary strictures in conjunction with endoscopic retrograde cholangiopancreatography, with special reference to patients with primary sclerosing cholangitis. Endoscopy. 2002;34:909–16.

    Article  Google Scholar 

  43. Lindor KD, Kowdley KV, Harrison ME. ACG clinical guideline: primary sclerosing cholangitis. Am J Gastroenterol. 2015;110:646–59.

    Article  CAS  PubMed  Google Scholar 

  44. Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66(24):11851–8.

    Article  CAS  PubMed  Google Scholar 

  45. Livraghi T, Goldberg SN, Lazzaroni S, et al. Hepatocellular carcinoma: radio-frequency ablation of medium and large lesions. Radiology. 2000;214(3):761–8.

    Article  CAS  PubMed  Google Scholar 

  46. Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19(3):329–38. Llovet JM, Bruix J. Prospective validation of the Cancer of the Liver Italian Program (CLIP) score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology. 2000;32(3):679–80.

    Google Scholar 

  47. Llovet JM, Real MI, Montaña X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359(9319):1734–9.

    Article  PubMed  Google Scholar 

  48. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.

    Article  CAS  PubMed  Google Scholar 

  49. Marsh JW, Iwatsuki S, Makowka L, et al. Orthotopic liver transplantation for primary sclerosing cholangitis. Ann Surg. 1988;207(1):21–5.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinoma in patients with cirrhosis. N Engl J Med. 1996;334(11):693.

    Article  CAS  PubMed  Google Scholar 

  51. Mcgahan JP, Brock JM, Tesluk H, Gu WZ, Schneider P, Browning PD. Hepatic ablation with use of radio-frequency electrocautery in the animal model. J Vasc Interv Radiol. 1992;3(2):291–7.

    Article  CAS  PubMed  Google Scholar 

  52. Okuda K, Ohtuiki T, Obata H, et al. Cancer. 1985;56:918.

    Article  CAS  PubMed  Google Scholar 

  53. Nashan B, Schlitt HJ, Tusch G, et al. Biliary malignancies in primary sclerosing cholangitis: timing for liver transplantation. Hepatology. 1996;23(5):1105–11.

    Article  CAS  PubMed  Google Scholar 

  54. www.nccn.org/professionals/physicians/f_guidelines.asp.

  55. Petrowsky H, Hong JC. Current surgical management of hilar and intrahepatic cholangiocarcinoma: the role of resection and orthotopic liver transplantation. Transplant Proc. 2009;41(10):4023–35.

    Article  CAS  PubMed  Google Scholar 

  56. 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  PubMed Central  Google Scholar 

  57. Said K, Glaumann H, Bergquist A. Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol. 2008;48(4):598–605.

    Article  PubMed  Google Scholar 

  58. Salgia RJ, Singal AG, Fu S, Pelletier S, Marrero JA. Improved post-transplant survival in the United States for patients with cholangiocarcinoma after 2000. Dig Dis Sci. 2014;59(5):1048–54.

    Article  PubMed  Google Scholar 

  59. Schwartz LH, Black J, Fong Y, et al. Gallbladder carcinoma: findings at MR imaging with MR cholangiopancreatography. J Comput Assist Tomogr. 2002;26(3):405–10.

    Article  PubMed  Google Scholar 

  60. Shah RJ, Langer DA, Antillon MR, Chen YK. Cholangioscopy and cholangioscopic forceps biopsy in patients with indeterminate pancreaticobiliary pathology. Clin Gastroenterol Hepatol. 2006;4(2):219–25.

    Article  PubMed  Google Scholar 

  61. Shin H-R, Oh J-K, Masuyer E, Curado M-P, Bouvard V, Fang Y-Y, Wiangnon S, Sripa B, Hong S-T. Epidemiology of cholangiocarcinoma: an update focusing on risk factors. Cancer Sci. 2010;101:579–85.

    Article  CAS  PubMed  Google Scholar 

  62. Silva MA, Hegab B, Hypde C, Guo B, Buckels JA, Mirza DF. Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut. 2008;57(11):159.

    Article  Google Scholar 

  63. Sumera R, Eaton JE, Gores GJ. Primary sclerosing cholangitis as a premalignant biliary tract disease: surveillance and management. Clin Gastroenterol Hepatol. 2015;13(12):2152–65.

    Article  Google Scholar 

  64. Timmer MR, Beuers U, Fockens P, et al. Genetic and epigenetic abnormalities in primary sclerosing cholangitis-associated cholangiocarcinoma. Inflamm Bowel Dis. 2013;19(8):1789–97.

    Article  PubMed  Google Scholar 

  65. Vijayakumar A, Vijayakumar A, Patil V, Mallikarjuna MN, Shivaswamy BS. Early diagnosis of gallbladder carcinoma: an algorithm approach. ISRN Radiol. 2013;2013:239424.

    PubMed  Google Scholar 

  66. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33(6):1394–403.

    Article  CAS  PubMed  Google Scholar 

  67. Yao FY, Mehta N, Flemming J, et al. Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria. Hepatology. 2015;61(6):1968–77.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Yoshimitsu K, Honda H, Kaneko K, et al. Dynamic MRI of the gallbladder lesions: differentiation of benign from malignant. J Magn Reson Imaging. 1997;7(4):696–701.

    Article  CAS  PubMed  Google Scholar 

  69. Zenouzi R, Weismüller TJ, Hübener P, et al. Low risk of hepatocellular carcinoma in patients with primary sclerosing cholangitis with cirrhosis. Clin Gastroenterol Hepatol. 2014;12(10):1733–8.

    Article  PubMed  Google Scholar 

  70. Zhu A, Theodore H, et al. Current management of gallbladder carcinoma. Oncologist. 2010;15(2):168–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. University of Colorado Hospital, Anschutz Outpatient Pavilion, 7th Floor, Transplant Center, 1635 Aurora Court, B154, Aurora, CO, 80045, USA

    Larissa Muething & James R. Burton Jr.

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  1. Larissa Muething
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  2. James R. Burton Jr.
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Editors and Affiliations

  1. Department of Gastroenterology-Hepatology, University of Colorado, Aurora, Colorado, USA

    Lisa M. Forman

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Muething, L., Burton, J.R. (2017). Malignancy and Primary Sclerosing Cholangitis: Cholangiocarcinoma, Hepatocellular Carcinoma, and Gallbladder Carcinoma. In: Forman, L. (eds) Primary Sclerosing Cholangitis. Springer, Cham. https://doi.org/10.1007/978-3-319-40908-5_2

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  • DOI: https://doi.org/10.1007/978-3-319-40908-5_2

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