Cholangiocarcinoma overview

Overview
Cholangiocarcinoma is a cancer of the bile ducts, which drain bile from the liver into the small intestine. It is a relatively rare cancer, with an annual incidence of 1–2 cases per 100,000 in the Western world, but rates of cholangiocarcinoma have been rising worldwide over the past several decades. Risk factors for cholangiocarcinoma include primary sclerosing cholangitis (an inflammatory disease of the bile ducts), congenital liver malformations, infection with the parasitic liver flukes Opisthorchis viverrini or Clonorchis sinensis, and exposure to Thorotrast (thorium dioxide), a chemical previously used in medical imaging. The symptoms of cholangiocarcinoma include jaundice, weight loss, and sometimes generalized itching. The disease is diagnosed through a combination of blood tests, imaging, endoscopy, and sometimes surgical exploration.

Surgery is the only potentially curative treatment, but most patients have advanced and inoperable disease at the time of diagnosis. After surgery, adjuvant chemotherapy or radiation therapy may be given to increase the chances of cure. Patients with advanced and inoperable cholangiocarcinoma are generally treated with chemotherapy and palliative care measures. Areas of ongoing medical research in cholangiocarcinoma include the use of newer targeted therapies (such as erlotinib) and the use of photodynamic therapy.

Diagnosis
Cholangiocarcinoma is definitively diagnosed from tissue, i.e. it is proven by biopsy or examination of the tissue excised at surgery. It may be suspected in a patient with obstructive jaundice. Considering it as the working-diagnosis may be challenging in patients with primary sclerosing cholangitis (PSC); such patients are at high risk of developing cholangiocarcinoma, but the symptoms may be difficult to distinguish from those of PSC. Furthermore, in patients with PSC, such diagnostic clues as a visible mass on imaging or biliary ductal dilatation may not be evident.

Treatment
Cholangiocarcinoma is considered curable only by surgical removal. Without surgery, it is a rapidly fatal disease with 5-year survival rates of less than 5%. Often, the operability of the tumor can only be assessed at the time of surgery; therefore, most patients undergo exploratory surgery unless there is a clear-cut indication that the tumor is inoperable.

Adjuvant therapy followed by liver transplantation may have a role in treatment of certain unresectable cases.

Additional Reading
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2. Patel T. "Worldwide trends in mortality from biliary tract malignancies". BMC Cancer 2: 10. PMID 11991810.

3. Nagorney D, Donohue J, Farnell M, Schleck C, Ilstrup D (1993). "Outcomes after curative resections of cholangiocarcinoma". Arch Surg 128 (8): 871–7; discussion 877-9. PMID 8393652.

4. Nakeeb A, Pitt H, Sohn T, Coleman J, Abrams R, Piantadosi S, Hruban R, Lillemoe K, Yeo C, Cameron J (1996). "Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors". Ann Surg 224 (4): 463–73; discussion 473-5. PMID 8857851.

5.Feldman, pp. 1493–1496.

6. Khan S, Taylor-Robinson S, Toledano M, Beck A, Elliott P, Thomas H (2002). "Changing international trends in mortality rates for liver, biliary and pancreatic tumours". J Hepatol 37 (6): 806-13. PMID 12445422.

7. Vauthey J, Blumgart L (1994). "Recent advances in the management of cholangiocarcinomas". Semin Liver Dis 14 (2): 109-14. PMID 8047893.

8.Henson D, Albores-Saavedra J, Corle D (1992). "Carcinoma of the extrahepatic bile ducts. Histologic types, stage of disease, grade, and survival rates". Cancer 70 (6): 1498-501. PMID 1516001.

9. Rosen C, Nagorney D, Wiesner R, Coffey R, LaRusso N (1991). "Cholangiocarcinoma complicating primary sclerosing cholangitis". Ann Surg 213 (1): 21-5. PMID 1845927.

10. Multiple independent studies have documented a steady increase in the worldwide incidence of cholangiocarcinoma. Some relevant journal articles include:
 * Patel T. "Worldwide trends in mortality from biliary tract malignancies". BMC Cancer 2: 10. PMID 11991810.
 * Patel T (2001). "Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States". Hepatology 33 (6): 1353–7. PMID 11391522.
 * Shaib Y, Davila J, McGlynn K, El-Serag H (2004). "Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase?". J Hepatol 40 (3): 472-7. PMID 15123362.
 * West J, Wood H, Logan R, Quinn M, Aithal G (2006). "Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971–2001". Br J Cancer 94 (11): 1751–8. PMID 16736026.
 * Khan S, Taylor-Robinson S, Toledano M, Beck A, Elliott P, Thomas H (2002). "Changing international trends in mortality rates for liver, biliary and pancreatic tumours". J Hepatol 37 (6): 806-13. PMID 12445422.
 * Welzel T, McGlynn K, Hsing A, O'Brien T, Pfeiffer R (2006). "Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States". J Natl Cancer Inst 98 (12): 873-5. PMID 16788161.

11. Shaib Y, El-Serag H, Davila J, Morgan R, McGlynn K (2005). "Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study". Gastroenterology 128 (3): 620-6. PMID 15765398.

12.Chapman R. "Risk factors for biliary tract carcinogenesis". Ann Oncol 10 Suppl 4: 308-11. PMID 10436847.

13.Epidemiologic studies which have addressed the incidence of cholangiocarcinoma in people with primary sclerosing cholangitis include the following:
 * Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Lööf L, Danielsson A, Hultcrantz R, Lindgren S, Prytz H, Sandberg-Gertzén H, Almer S, Granath F, Broomé U (2002). "Hepatic and extrahepatic malignancies in primary sclerosing cholangitis". J Hepatol 36 (3): 321-7. PMID 11867174.
 * Bergquist A, Glaumann H, Persson B, Broomé U (1998). "Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study". Hepatology 27 (2): 311-6. PMID 9462625.
 * Burak K, Angulo P, Pasha T, Egan K, Petz J, Lindor K (2004). "Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis". Am J Gastroenterol 99 (3): 523-6. PMID 15056096.

14.Watanapa P (1996). "Cholangiocarcinoma in patients with opisthorchiasis". Br J Surg 83 (8): 1062–64. PMID 8869303.

15.Watanapa P, Watanapa W (2002). "Liver fluke-associated cholangiocarcinoma". Br J Surg 89 (8): 962-70. PMID 12153620.

16.Shin H, Lee C, Park H, Seol S, Chung J, Choi H, Ahn Y, Shigemastu T (1996). "Hepatitis B and C virus, Clonorchis sinensis for the risk of liver cancer: a case-control study in Pusan, Korea". Int J Epidemiol 25 (5): 933-40. PMID 8921477.

17.Kobayashi M, Ikeda K, Saitoh S, Suzuki F, Tsubota A, Suzuki Y, Arase Y, Murashima N, Chayama K, Kumada H (2000). "Incidence of primary cholangiocellular carcinoma of the liver in Japanese patients with hepatitis C virus-related cirrhosis". Cancer 88 (11): 2471–7. PMID 10861422.

18. Yamamoto S, Kubo S, Hai S, Uenishi T, Yamamoto T, Shuto T, Takemura S, Tanaka H, Yamazaki O, Hirohashi K, Tanaka T (2004). "Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma". Cancer Sci 95 (7): 592-5. PMID 15245596.

19.Lu H, Ye M, Thung S, Dash S, Gerber M (2000). "Detection of hepatitis C virus RNA sequences in cholangiocarcinomas in Chinese and American patients". Chin Med J (Engl) 113 (12): 1138–41. PMID 11776153.

20. Sorensen H, Friis S, Olsen J, Thulstrup A, Mellemkjaer L, Linet M, Trichopoulos D, Vilstrup H, Olsen J (1998). "Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark". Hepatology 28 (4): 921-5. PMID 9755226.

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23. Mecklin J, Järvinen H, Virolainen M (1992). "The association between cholangiocarcinoma and hereditary nonpolyposis colorectal carcinoma". Cancer 69 (5): 1112–4. PMID 1310886.

24.Lee S, Kim M, Lee S, Jang S, Song M, Kim K, Kim H, Seo D, Song D, Yu E, Lee S, Min Y (2004). "Clinicopathologic review of 58 patients with biliary papillomatosis". Cancer 100 (4): 783-93. PMID 14770435.

25.Lee C, Wu C, Chen G (2002). "What is the impact of coexistence of hepatolithiasis on cholangiocarcinoma?". J Gastroenterol Hepatol 17 (9): 1015–20. PMID 12167124.

26. Su C, Shyr Y, Lui W, P'Eng F (1997). "Hepatolithiasis associated with cholangiocarcinoma". Br J Surg 84 (7): 969-73. PMID 9240138.

27. Donato F, Gelatti U, Tagger A, Favret M, Ribero M, Callea F, Martelli C, Savio A, Trevisi P, Nardi G (2001). "Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy". Cancer Causes Control 12 (10): 959-64. PMID 11808716.

28.Sahani D, Prasad S, Tannabe K, Hahn P, Mueller P, Saini S. "Thorotrast-induced cholangiocarcinoma: case report". Abdom Imaging 28 (1): 72-4. PMID 12483389.

29. Zhu A, Lauwers G, Tanabe K (2004). "Cholangiocarcinoma in association with Thorotrast exposure". J Hepatobiliary Pancreat Surg 11 (6): 430-3. PMID 15619021.

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31. Roskams T (2006). "Liver stem cells and their implication in hepatocellular and cholangiocarcinoma". Oncogene 25 (27): 3818–22. PMID 16799623.

32.Liu C, Wang J, Ou Q (2004). "Possible stem cell origin of human cholangiocarcinoma". World J Gastroenterol 10 (22): 3374–6. PMID 15484322.

33. Sell S, Dunsford H (1989). "Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma". Am J Pathol 134 (6): 1347–63. PMID 2474256.

34. Sirica A (2005). "Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy". Hepatology 41 (1): 5–15. PMID 15690474.

35. Holzinger F, Z'graggen K, Büchler M. "Mechanisms of biliary carcinogenesis: a pathogenetic multi-stage cascade towards cholangiocarcinoma". Ann Oncol 10 Suppl 4: 122-6. PMID 10436802.

36.Gores G (2003). "Cholangiocarcinoma: current concepts and insights". Hepatology 37 (5): 961-9. PMID 12717374.

37. de Groen P, Gores G, LaRusso N, Gunderson L, Nagorney D (1999). "Biliary tract cancers". N Engl J Med 341 (18): 1368–78. PMID 10536130.

38. Henson D, Albores-Saavedra J, Corle D (1992). "Carcinoma of the extrahepatic bile ducts. Histologic types, stage of disease, grade, and survival rates". Cancer 70 (6): 1498-501. PMID 1516001.

39. Studies of the performance of serum markers for cholangiocarcinoma (such as carcinoembryonic antigen and CA19-9) in patients with and without primary sclerosing cholangitis include the following:
 * Nehls O, Gregor M, Klump B (2004). "Serum and bile markers for cholangiocarcinoma". Semin Liver Dis 24 (2): 139-54. PMID 15192787.
 * Siqueira E, Schoen R, Silverman W, Martin J, Rabinovitz M, Weissfeld J, Abu-Elmaagd K, Madariaga J, Slivka A, Martini J (2002). "Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis". Gastrointest Endosc 56 (1): 40-7. PMID 12085033.
 * Levy C, Lymp J, Angulo P, Gores G, Larusso N, Lindor K (2005). "The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis". Dig Dis Sci 50 (9): 1734–40. PMID 16133981.
 * Patel A, Harnois D, Klee G, LaRusso N, Gores G (2000). "The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis". Am J Gastroenterol 95 (1): 204-7. PMID 10638584.

40.Saini S (1997). "Imaging of the hepatobiliary tract". N Engl J Med 336 (26): 1889–94. PMID 9197218.

41.Sharma M, Ahuja V. "Aetiological spectrum of obstructive jaundice and diagnostic ability of ultrasonography: a clinician's perspective". Trop Gastroenterol 20 (4): 167-9. PMID 10769604.

42.Bloom C, Langer B, Wilson S. "Role of US in the detection, characterization, and staging of cholangiocarcinoma". Radiographics 19 (5): 1199-218. PMID 10489176.

43.Valls C, Gumà A, Puig I, Sanchez A, Andía E, Serrano T, Figueras J. "Intrahepatic peripheral cholangiocarcinoma: CT evaluation". Abdom Imaging 25 (5): 490-6. PMID 10931983.

44.Tillich M, Mischinger H, Preisegger K, Rabl H, Szolar D (1998). "Multiphasic helical CT in diagnosis and staging of hilar cholangiocarcinoma". AJR Am J Roentgenol 171 (3): 651-8. PMID 9725291.

45.Zhang Y, Uchida M, Abe T, Nishimura H, Hayabuchi N, Nakashima Y. "Intrahepatic peripheral cholangiocarcinoma: comparison of dynamic CT and dynamic MRI". J Comput Assist Tomogr 23 (5): 670-7. PMID 10524843.

46. Sugiyama M, Hagi H, Atomi Y, Saito M. "Diagnosis of portal venous invasion by pancreatobiliary carcinoma: value of endoscopic ultrasonography". Abdom Imaging 22 (4): 434-8. PMID 9157867.

47.Schwartz L, Coakley F, Sun Y, Blumgart L, Fong Y, Panicek D (1998). "Neoplastic pancreaticobiliary duct obstruction: evaluation with breath-hold MR cholangiopancreatography". AJR Am J Roentgenol 170 (6): 1491–5. PMID 9609160.

48.Zidi S, Prat F, Le Guen O, Rondeau Y, Pelletier G (2000). "Performance characteristics of magnetic resonance cholangiography in the staging of malignant hilar strictures". Gut 46 (1): 103-6. PMID 10601064.

49.Lee M, Park K, Shin Y, Yoon H, Sung K, Kim M, Lee S, Kang E (2003). "Preoperative evaluation of hilar cholangiocarcinoma with contrast-enhanced three-dimensional fast imaging with steady-state precession magnetic resonance angiography: comparison with intraarterial digital subtraction angiography". World J Surg 27 (3): 278-83. PMID 12607051.

50.Yeh T, Jan Y, Tseng J, Chiu C, Chen T, Hwang T, Chen M (2000). "Malignant perihilar biliary obstruction: magnetic resonance cholangiopancreatographic findings". Am J Gastroenterol 95 (2): 432-40. PMID 10685746.

51.Freeman M, Sielaff T (2003). "A modern approach to malignant hilar biliary obstruction". Rev Gastroenterol Disord 3 (4): 187–201. PMID 14668691.

52.Szklaruk J, Tamm E, Charnsangavej C (2002). "Preoperative imaging of biliary tract cancers". Surg Oncol Clin N Am 11 (4): 865-76. PMID 12607576.

53. Weber S, DeMatteo R, Fong Y, Blumgart L, Jarnagin W (2002). "Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients". Ann Surg 235 (3): 392-9. PMID 11882761.

54. Callery M, Strasberg S, Doherty G, Soper N, Norton J (1997). "Staging laparoscopy with laparoscopic ultrasonography: optimizing resectability in hepatobiliary and pancreatic malignancy". J Am Coll Surg 185 (1): 33-9. PMID 9208958.

55.Länger F, von Wasielewski R, Kreipe HH (2006). "[The importance of immunohistochemistry for the diagnosis of cholangiocarcinomas]" (in German). Pathologe 27 (4): 244-50. PMID 16758167.

56. Darwin PE, Kennedy A. Cholangiocarcinoma. eMedicine.com. URL: http://www.emedicine.com/med/topic343.htm. Accessed on: May 5, 2007.

57. Zervos E, Osborne D, Goldin S, Villadolid D, Thometz D, Durkin A, Carey L, Rosemurgy A (2005). "Stage does not predict survival after resection of hilar cholangiocarcinomas promoting an aggressive operative approach". Am J Surg 190 (5): 810-5. PMID 16226963.

58.Tsao J, Nimura Y, Kamiya J, Hayakawa N, Kondo S, Nagino M, Miyachi M, Kanai M, Uesaka K, Oda K, Rossi R, Braasch J, Dugan J (2000). "Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience". Ann Surg 232 (2): 166-74. PMID 10903592.

59. Rajagopalan V, Daines W, Grossbard M, Kozuch P (2004). "Gallbladder and biliary tract carcinoma: A comprehensive update, Part 1". Oncology (Williston Park) 18 (7): 889-96. PMID 15255172.

60.Studies of surgical outcomes in distal cholangiocarcinoma include:
 * Nakeeb A, Pitt H, Sohn T, Coleman J, Abrams R, Piantadosi S, Hruban R, Lillemoe K, Yeo C, Cameron J (1996). "Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors". Ann Surg 224 (4): 463–73; discussion 473-5. PMID 8857851.
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61.Studies of outcome in intrahepatic cholangiocarcinoma include:
 * Nakeeb A, Pitt H, Sohn T, Coleman J, Abrams R, Piantadosi S, Hruban R, Lillemoe K, Yeo C, Cameron J (1996). "Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors". Ann Surg 224 (4): 463–73; discussion 473-5. PMID 8857851.
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62.Estimates of survival after surgery for perihilar cholangiocarcinoma include:
 * Burke E, Jarnagin W, Hochwald S, Pisters P, Fong Y, Blumgart L (1998). "Hilar Cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system". Ann Surg 228 (3): 385-94. PMID 9742921.
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