Cholangiocarcinoma

Cholangiocarcinoma

Micrograph of an intrahepatic cholangiocarcinoma (right of image) adjacent to benign hepatocytes (left of image). H&E stain.
Classification and external resources
Specialty Oncology
ICD-10 C22.1
ICD-9 155.1, 156.1
ICD-O M8160/3
DiseasesDB 2505
MedlinePlus 000291
eMedicine med/343 radio/153
Patient UK Cholangiocarcinoma
MeSH D018281
Digestive system diagram showing bile duct location.

Cholangiocarcinoma is a form of cancer that is composed of mutated epithelial cells (or cells showing characteristics of epithelial differentiation) that originate in the bile ducts which drain bile from the liver into the small intestine. Other biliary tract cancers include pancreatic cancer, gallbladder cancer, and cancer of the ampulla of Vater.

Cholangiocarcinoma is a relatively rare neoplasm that is classified as an adenocarcinoma (a cancer that forms glands or secretes significant amounts of mucins). It has an annual incidence rate of 1–2 cases per 100,000 in the Western world,[1] but rates of cholangiocarcinoma have been rising worldwide over the past several decades.[2]

Prominent signs and symptoms of cholangiocarcinoma include abnormal liver function tests, abdominal pain, jaundice, and weight loss. Other symptoms such as generalized itching, fever, and changes in color of stool or urine may also occur. The disease is diagnosed through a combination of blood tests, imaging, endoscopy, and sometimes surgical exploration, with confirmation obtained after a pathologist examines cells from the tumor under a microscope. Known 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 formerly used in medical imaging. However, most patients with cholangiocarcinoma have no identifiable specific risk factors.

Cholangiocarcinoma is considered to be an incurable and rapidly lethal malignancy unless both the primary tumor and any metastases can be fully resected (removed surgically). No potentially curative treatment yet exists except surgery, but most patients have advanced stage disease at presentation and are inoperable at the time of diagnosis. Patients with cholangiocarcinoma are generally managed - though never cured - with chemotherapy, radiation therapy, and other palliative care measures. These are also used as adjuvant therapies (i.e. post-surgically) in cases where resection has apparently been successful (or nearly so).

Signs and symptoms

Yellowing of the skin (jaundice) and eyes (scleral icterus)

The most common physical indications of cholangiocarcinoma are abnormal liver function tests, jaundice (yellowing of the eyes and skin occurring when bile ducts are blocked by tumor), abdominal pain (30%–50%), generalized itching (66%), weight loss (30%–50%), fever (up to 20%), and changes in stool or urine color.[3][4] To some extent, the symptoms depend upon the location of the tumor: patients with cholangiocarcinoma in the extrahepatic bile ducts (outside the liver) are more likely to have jaundice, while those with tumors of the bile ducts within the liver more often have pain without jaundice.[5]

Blood tests of liver function in patients with cholangiocarcinoma often reveal a so-called "obstructive picture," with elevated bilirubin, alkaline phosphatase, and gamma glutamyl transferase levels, and relatively normal transaminase levels. Such laboratory findings suggest obstruction of the bile ducts, rather than inflammation or infection of the liver parenchyma, as the primary cause of the jaundice.[6] CA19-9 is elevated in most cases of cholangiocarcinoma.

Risk factors

Life cycle of Clonorchis sinensis, a liver fluke associated with cholangiocarcinoma

Although most patients present without any known risk factors evident, a number of risk factors for the development of cholangiocarcinoma have been described. In the Western world, the most common of these is primary sclerosing cholangitis (PSC), an inflammatory disease of the bile ducts which is itself closely associated with ulcerative colitis (UC).[7] Epidemiologic studies have suggested that the lifetime risk of developing cholangiocarcinoma for a person with PSC is on the order of 10%–15%,[8] although autopsy series have found rates as high as 30% in this population.[9] The mechanism by which PSC increases the risk of cholangiocarcinoma is not well understood.

Certain parasitic liver diseases may be risk factors as well. Colonization with the liver flukes Opisthorchis viverrini (found in Thailand, Laos PDR, and Vietnam)[10][11][12] or Clonorchis sinensis (found in China, Taiwan, eastern Russia, Korea, and Vietnam)[13][14] has been associated with the development of cholangiocarcinoma. Patients with chronic liver disease, whether in the form of viral hepatitis (e.g. hepatitis B or hepatitis C),[15][16][17] alcoholic liver disease, or cirrhosis of the liver due to other causes, are at significantly increased risk of cholangiocarcinoma.[18][19] HIV infection was also identified in one study as a potential risk factor for cholangiocarcinoma, although it was unclear whether HIV itself or other correlated and confounding factors (e.g. hepatitis C infection) were responsible for the association.[18]

Infection with the bacteria Helicobacter bilis and Helicobacter hepaticus species can cause biliary cancer.[20]

Congenital liver abnormalities, such as Caroli's syndrome or choledochal cysts, have been associated with an approximately 15% lifetime risk of developing cholangiocarcinoma.[21][22] The rare inherited disorders Lynch syndrome II and biliary papillomatosis have also been found to be associated with cholangiocarcinoma.[23][24] The presence of gallstones (cholelithiasis) is not clearly associated with cholangiocarcinoma. However, intrahepatic stones (called hepatolithiasis), which are rare in the West but common in parts of Asia, have been strongly associated with cholangiocarcinoma.[25][26][27] Exposure to Thorotrast, a form of thorium dioxide which was used as a radiologic contrast medium, has been linked to the development of cholangiocarcinoma as late as 30–40 years after exposure; Thorotrast was banned in the United States in the 1950s due to its carcinogenicity.[28][29]

Pathophysiology

Cholangiocarcinoma can affect any area of the bile ducts, either within or outside the liver. Tumors occurring in the bile ducts within the liver are referred to as intrahepatic, those occurring in the ducts outside the liver are extrahepatic, and tumors occurring at the site where the bile ducts exit the liver may be referred to as perihilar. A cholangiocarcinoma occurring at the junction where the left and right hepatic ducts meet to form the common hepatic duct may be referred to eponymously as a Klatskin tumor.[30]

Although cholangiocarcinoma is known to have the histological and molecular features of an adenocarcinoma of epithelial cells lining the biliary tract, the actual cell of origin is unknown. Recent evidence has suggested that the initial transformed cell that generates the primary tumor may arise from a pluripotent hepatic stem cell.[31][32][33] Cholangiocarcinoma is thought to develop through a series of stages - from early hyperplasia and metaplasia, through dysplasia, to the development of frank carcinoma - in a process similar to that seen in the development of colon cancer.[34] Chronic inflammation and obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in this progression.[34][35][36]

Histologically, cholangiocarcinomas may vary from undifferentiated to well-differentiated. They are often surrounded by a brisk fibrotic or desmoplastic tissue response; in the presence of extensive fibrosis, it can be difficult to distinguish well-differentiated cholangiocarcinoma from normal reactive epithelium. There is no entirely specific immunohistochemical stain that can distinguish malignant from benign biliary ductal tissue, although staining for cytokeratins, carcinoembryonic antigen, and mucins may aid in diagnosis.[37] Most tumors (>90%) are adenocarcinomas.[38]

Diagnosis

Micrograph of an intrahepatic, i.e. in the liver, cholangiocarcinoma (right of image); benign hepatocytes are seen (left of image). Histologically, this is a cholangiocarcinoma as (1) atypical bile duct-like cells (left of image) extend from the tumor in an interlobular septum (the normal anatomical location of bile ducts), and (2) the tumor has the abundant desmoplastic stroma often seen in cholangiocarcinomas. A portal triad (upper-left of image) has a histologically normal bile duct. H&E stain.

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.

Blood tests

There are no specific blood tests that can diagnose cholangiocarcinoma by themselves. Serum levels of carcinoembryonic antigen (CEA) and CA19-9 are often elevated, but are not sensitive or specific enough to be used as a general screening tool. However, they may be useful in conjunction with imaging methods in supporting a suspected diagnosis of cholangiocarcinoma.[39]

Abdominal imaging

CT scan showing cholangiocarcinoma

Ultrasound of the liver and biliary tree is often used as the initial imaging modality in patients with suspected obstructive jaundice.[40][41] Ultrasound can identify obstruction and ductal dilatation and, in some cases, may be sufficient to diagnose cholangiocarcinoma.[42] Computed tomography (CT) scanning may also play an important role in the diagnosis of cholangiocarcinoma.[43][44][45]

Imaging of the biliary tree

ERCP image of cholangiocarcinoma, showing common bile duct stricture and dilation of the proximal common bile duct

While abdominal imaging can be useful in the diagnosis of cholangiocarcinoma, direct imaging of the bile ducts is often necessary. Endoscopic retrograde cholangiopancreatography (ERCP), an endoscopic procedure performed by a gastroenterologist or specially trained surgeon, has been widely used for this purpose. Although ERCP is an invasive procedure with attendant risks, its advantages include the ability to obtain biopsies and to place stents or perform other interventions to relieve biliary obstruction.[6] Endoscopic ultrasound can also be performed at the time of ERCP and may increase the accuracy of the biopsy and yield information on lymph node invasion and operability.[46] As an alternative to ERCP, percutaneous transhepatic cholangiography (PTC) may be utilized. Magnetic resonance cholangiopancreatography (MRCP) is a non-invasive alternative to ERCP.[47][48][49] Some authors have suggested that MRCP should supplant ERCP in the diagnosis of biliary cancers, as it may more accurately define the tumor and avoids the risks of ERCP.[50][51][52]

Surgery

Photograph of cholangiocarcinoma in human liver.

Surgical exploration may be necessary to obtain a suitable biopsy and to accurately stage a patient with cholangiocarcinoma. Laparoscopy can be used for staging purposes and may avoid the need for a more invasive surgical procedure, such as laparotomy, in some patients.[53][54] Surgery is also the only curative option for cholangiocarcinoma, although it is limited to patients with early-stage disease.

Pathology

Histologically, cholangiocarcinomas are classically well to moderately differentiated adenocarcinomas. Immunohistochemistry is useful in the diagnosis and may be used to help differentiate a cholangiocarcinoma from, hepatocellular carcinoma and metastasis of other gastrointestinal tumors.[55] Cytological scrapings are often nondiagnostic,[56] as these tumors typically have a desmoplastic stroma and, therefore, do not release diagnostic tumor cells with scrapings.

Staging

Although there are at least three staging systems for cholangiocarcinoma (e.g. those of Bismuth, Blumgart, and the American Joint Committee on Cancer), none have been shown to be useful in predicting survival.[57] The most important staging issue is whether the tumor can be surgically removed, or whether it is too advanced for surgical treatment to be successful. Often, this determination can only be made at the time of surgery.[6]

General guidelines for operability include:[58][59]

Treatment

Cholangiocarcinoma is considered to be an incurable and rapidly lethal disease unless all the tumors can be fully resected (that is, cut out surgically). Since the operability of the tumor can only be assessed during surgery in most cases,[60] a majority of patients undergo exploratory surgery unless there is already a clear indication that the tumor is inoperable.[6] However, the Mayo Clinic has reported significant success treating early bile duct cancer with liver transplantation using a protocolized approach and strict selection criteria.[61]

Adjuvant therapy followed by liver transplantation may have a role in treatment of certain unresectable cases.[62]

Adjuvant chemotherapy and radiation therapy

If the tumor can be removed surgically, patients may receive adjuvant chemotherapy or radiation therapy after the operation to improve the chances of cure. If the tissue margins are negative (i.e. the tumor has been totally excised), adjuvant therapy is of uncertain benefit. Both positive[63][64] and negative[5][65][66] results have been reported with adjuvant radiation therapy in this setting, and no prospective randomized controlled trials have been conducted as of March 2007. Adjuvant chemotherapy appears to be ineffective in patients with completely resected tumors.[67] The role of combined chemoradiotherapy in this setting is unclear. However, if the tumor tissue margins are positive, indicating that the tumor was not completely removed via surgery, then adjuvant therapy with radiation and possibly chemotherapy is generally recommended based on the available data.[68]

Treatment of advanced disease

The majority of cases of cholangiocarcinoma present as inoperable (unresectable) disease[69] in which case patients are generally treated with palliative chemotherapy, with or without radiotherapy. Chemotherapy has been shown in a randomized controlled trial to improve quality of life and extend survival in patients with inoperable cholangiocarcinoma.[70] There is no single chemotherapy regimen which is universally used, and enrollment in clinical trials is often recommended when possible.[68] Chemotherapy agents used to treat cholangiocarcinoma include 5-fluorouracil with leucovorin,[71] gemcitabine as a single agent,[72] or gemcitabine plus cisplatin,[73] irinotecan,[74] or capecitabine.[75] A small pilot study suggested possible benefit from the tyrosine kinase inhibitor erlotinib in patients with advanced cholangiocarcinoma.[76]

Prognosis

Surgical resection offers the only potential chance of cure in cholangiocarcinoma. For non-resectable cases, the 5-year survival rate is 0% where the disease is inoperable because distal lymph nodes show metastases,[77] and less than 5% in general.[78] Overall median duration of survival is less than 6 months[79] in inoperable, untreated, otherwise healthy patients with tumors involving the liver by way of the intrahepatic bile ducts and hepatic portal vein.

For surgical cases, the odds of cure vary depending on the tumor location and whether the tumor can be completely, or only partially, removed. Distal cholangiocarcinomas (those arising from the common bile duct) are generally treated surgically with a Whipple procedure; long-term survival rates range from 15%–25%, although one series reported a five-year survival of 54% for patients with no involvement of the lymph nodes.[80] Intrahepatic cholangiocarcinomas (those arising from the bile ducts within the liver) are usually treated with partial hepatectomy. Various series have reported survival estimates after surgery ranging from 22%–66%; the outcome may depend on involvement of lymph nodes and completeness of the surgery.[81] Perihilar cholangiocarcinomas (those occurring near where the bile ducts exit the liver) are least likely to be operable. When surgery is possible, they are generally treated with an aggressive approach often including removal of the gallbladder and potentially part of the liver. In patients with operable perihilar tumors, reported 5-year survival rates range from 20%–50%.[82]

The prognosis may be worse for patients with primary sclerosing cholangitis who develop cholangiocarcinoma, likely because the cancer is not detected until it is advanced.[9][83] Some evidence suggests that outcomes may be improving with more aggressive surgical approaches and adjuvant therapy.[84]

Epidemiology

Age-standardized mortality rates from intrahepatic (IC) and extrahepatic (EC) cholangiocarcinoma for men and women, by country. Source: Khan et al., 2002.[85]
Country IC (men/women) EC (men/women)
U.S.A. 0.60 / 0.43 0.70 / 0.87
Japan 0.23 / 0.10 5.87 / 5.20
Australia 0.70 / 0.53 0.90 / 1.23
England/Wales 0.83 / 0.63 0.43 / 0.60
Scotland 1.17 / 1.00 0.60 / 0.73
France 0.27 / 0.20 1.20 / 1.37
Italy 0.13 / 0.13 2.10 / 2.60

Cholangiocarcinoma is a relatively rare form of cancer; each year, approximately 2,000 to 3,000 new cases are diagnosed in the United States, translating into an annual incidence of 1–2 cases per 100,000 people.[1] Autopsy series have reported a prevalence of 0.01% to 0.46%.[86][87] There is a higher prevalence of cholangiocarcinoma in Asia, which has been attributed to endemic chronic parasitic infestation. The incidence of cholangiocarcinoma increases with age, and the disease is slightly more common in men than in women (possibly due to the higher rate of primary sclerosing cholangitis, a major risk factor, in men).[38] The prevalence of cholangiocarcinoma in patients with primary sclerosing cholangitis may be as high as 30%, based on autopsy studies.[9]

Multiple studies have documented a steady increase in the incidence of intrahepatic cholangiocarcinoma over the past several decades; increases have been seen in North America, Europe, Asia, and Australia.[88] The reasons for the increasing occurrence of cholangiocarcinoma are unclear; improved diagnostic methods may be partially responsible, but the prevalence of potential risk factors for cholangiocarcinoma, such as HIV infection, has also been increasing during this time frame.[18]

Research

Some areas of ongoing medical research in cholangiocarcinoma include the use of newer targeted therapies, (such as erlotinib) or photodynamic therapy for treatment, and the techniques to measure the concentration of byproducts of cancer stromal cell formation in the blood for diagnostic purposes.

Notable cases

Fred Kavli was a philanthropist, physicist, entrepreneur, and business leader. He established The Kavli Foundation in 2000 and the Kavli Prize in 2005 to advance science for the benefit of humanity and passed away on November 21, 2013, at the age of 86.

Notes

  1. ↑ 1.0 1.1 Landis S, Murray T, Bolden S, Wingo P (1998). "Cancer statistics, 1998". CA Cancer J Clin 48 (1): 6–29. doi:10.3322/canjclin.48.1.6. PMID 9449931.
  2. ↑ Patel T (2002). "Worldwide trends in mortality from biliary tract malignancies". BMC Cancer 2: 10. doi:10.1186/1471-2407-2-10. PMC 113759. 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. doi:10.1001/archsurg.1993.01420200045008. PMID 8393652.
  4. ↑ Bile duct cancer: cause and treatment
  5. ↑ 5.0 5.1 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. doi:10.1097/00000658-199610000-00005. PMC 1235406. PMID 8857851.
  6. ↑ 6.0 6.1 6.2 6.3 Mark Feldman, Lawrence S. Friedman, Lawrence J. Brandt, ed. (21 July 2006). Sleisenger and Fordtran's Gastrointestinal and Liver Disease (8th ed.). Saunders. pp. 1493–6. ISBN 978-1-4160-0245-1.
  7. ↑ Chapman R (1999). "Risk factors for biliary tract carcinogenesis". Ann Oncol 10 (Suppl 4): 308–11. doi:10.1023/A:1008313809752. PMID 10436847.
  8. ↑ 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. doi:10.1016/S0168-8278(01)00288-4. 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. doi:10.1002/hep.510270201. 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. doi:10.1111/j.1572-0241.2004.04067.x. PMID 15056096.
  9. ↑ 9.0 9.1 9.2 Rosen C, Nagorney D, Wiesner R, Coffey R, LaRusso N (1991). "Cholangiocarcinoma complicating primary sclerosing cholangitis". Ann Surg 213 (1): 21–5. doi:10.1097/00000658-199101000-00004. PMC 1358305. PMID 1845927.
  10. ↑ Watanapa P, Watanapa W (2002). "Liver fluke-associated cholangiocarcinoma". Br J Surg 89 (8): 962–70. doi:10.1046/j.1365-2168.2002.02143.x. PMID 12153620.
  11. ↑ Sripa B, Kaewkes S, Sithithaworn P, Mairiang E, Laha T, Smout M, Pairojkul C, Bhudhisawasdi V, Tesana S, Thinkamrop B, Bethony JM, Loukas A, Brindley PJ (2007). "Liver fluke induces cholangiocarcinoma". PLoS Medicine 4 (7): 1148–1155. doi:10.1371/journal.pmed.0040201. PMC 1913093. PMID 17622191.
  12. ↑ Sripa B, Kaewkes S, Intapan PM, Maleewong W, Brindley PJ (2010). "Food-borne trematodiases in Southeast Asia epidemiology, pathology, clinical manifestation and control". Adv Parasitol 72: 305–350. doi:10.1016/S0065-308X(10)72011-X. PMID 20624536.
  13. ↑ Rustagi T, Dasanu CA (2012). "Risk Factors for Gallbladder Cancer and Cholangiocarcinoma: Similarities, Differences and Updates". J Gastrointest Cancer 43 (2): 137–147. doi:10.1007/s12029-011-9284-y. PMID 21597894.
  14. ↑ Hong ST, Fang Y (2012). "Clonorchis sinensis and clonorchiasis, an update". Parasitol Int 61 (1): 17–24. doi:10.1016/j.parint.2011.06.007. PMID 21741496.
  15. ↑ 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. doi:10.1002/1097-0142(20000601)88:11<2471::AID-CNCR7>3.0.CO;2-T. PMID 10861422.
  16. ↑ 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. doi:10.1111/j.1349-7006.2004.tb02492.x. PMID 15245596.
  17. ↑ 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.
  18. ↑ 18.0 18.1 18.2 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. doi:10.1053/j.gastro.2004.12.048. PMID 15765398.
  19. ↑ 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. doi:10.1002/hep.510280404. PMID 9755226.
  20. ↑ Chang, A. H.; Parsonnet, J. (2010). "Role of Bacteria in Oncogenesis". Clinical Microbiology Reviews 23 (4): 837–857. doi:10.1128/CMR.00012-10. ISSN 0893-8512.
  21. ↑ Lipsett P, Pitt H, Colombani P, Boitnott J, Cameron J (1994). "Choledochal cyst disease. A changing pattern of presentation". Ann Surg 220 (5): 644–52. doi:10.1097/00000658-199411000-00007. PMC 1234452. PMID 7979612.
  22. ↑ Dayton M, Longmire W, Tompkins R (1983). "Caroli's Disease: a premalignant condition?". Am J Surg 145 (1): 41–8. doi:10.1016/0002-9610(83)90164-2. PMID 6295196.
  23. ↑ Mecklin J, Järvinen H, Virolainen M (1992). "The association between cholangiocarcinoma and hereditary nonpolyposis colorectal carcinoma". Cancer 69 (5): 1112–4. doi:10.1002/cncr.2820690508. 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. doi:10.1002/cncr.20031. 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. doi:10.1046/j.1440-1746.2002.02779.x. PMID 12167124.
  26. ↑ Su C, Shyr Y, Lui W, P'Eng F (1997). "Hepatolithiasis associated with cholangiocarcinoma". Br J Surg 84 (7): 969–73. doi:10.1002/bjs.1800840717. 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. doi:10.1023/A:1013747228572. PMID 11808716.
  28. ↑ Sahani D, Prasad S, Tannabe K, Hahn P, Mueller P, Saini S (2003). "Thorotrast-induced cholangiocarcinoma: case report". Abdom Imaging 28 (1): 72–4. doi:10.1007/s00261-001-0148-y. PMID 12483389.
  29. ↑ Zhu A, Lauwers G, Tanabe K (2004). "Cholangiocarcinoma in association with Thorotrast exposure". J Hepatobiliary Pancreat Surg 11 (6): 430–3. doi:10.1007/s00534-004-0924-5. PMID 15619021.
  30. ↑ Klatskin G (1965). "Adenocarcinoma Of The Hepatic Duct At Its Bifurcation Within The Porta Hepatis. An Unusual Tumor With Distinctive Clinical And Pathological Features". Am J Med 38 (2): 241–56. doi:10.1016/0002-9343(65)90178-6. PMID 14256720.
  31. ↑ Roskams T (2006). "Liver stem cells and their implication in hepatocellular and cholangiocarcinoma". Oncogene 25 (27): 3818–22. doi:10.1038/sj.onc.1209558. 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. PMC 1879951. PMID 2474256.
  34. ↑ 34.0 34.1 Sirica A (2005). "Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy". Hepatology 41 (1): 5–15. doi:10.1002/hep.20537. PMID 15690474.
  35. ↑ Holzinger F, Z'graggen K, Büchler M (1999). "Mechanisms of biliary carcinogenesis: a pathogenetic multi-stage cascade towards cholangiocarcinoma". Ann Oncol 10 (Suppl 4): 122–6. doi:10.1023/A:1008321710719. PMID 10436802.
  36. ↑ Gores G (2003). "Cholangiocarcinoma: current concepts and insights". Hepatology 37 (5): 961–9. doi:10.1053/jhep.2003.50200. 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. doi:10.1056/NEJM199910283411807. PMID 10536130.
  38. ↑ 38.0 38.1 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. doi:10.1002/1097-0142(19920915)70:6<1498::AID-CNCR2820700609>3.0.CO;2-C. 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. doi:10.1055/s-2004-828891. 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. doi:10.1067/mge.2002.125105. 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. doi:10.1007/s10620-005-2927-8. 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. doi:10.1111/j.1572-0241.2000.01685.x. PMID 10638584.
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  80. ↑ Studies of surgical outcomes in distal cholangiocarcinoma include:
  81. ↑ Studies of outcome in intrahepatic cholangiocarcinoma include:
  82. ↑ Estimates of survival after surgery for perihilar cholangiocarcinoma include:
  83. ↑ Kaya M, de Groen P, Angulo P, Nagorney D, Gunderson L, Gores G, Haddock M, Lindor K (2001). "Treatment of cholangiocarcinoma complicating primary sclerosing cholangitis: the Mayo Clinic experience". Am J Gastroenterol 96 (4): 1164–9. doi:10.1111/j.1572-0241.2001.03696.x. PMID 11316165.
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  86. ↑ Vauthey J, Blumgart L (1994). "Recent advances in the management of cholangiocarcinomas". Semin Liver Dis 14 (2): 109–14. doi:10.1055/s-2007-1007302. PMID 8047893.
  87. ↑ Cancer Statistics Home Page — National Cancer Institute
  88. ↑ Multiple independent studies have documented a steady increase in the worldwide incidence of cholangiocarcinoma. Some relevant journal articles include:

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