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, but rates of cholangiocarcinoma have been rising worldwide over the past several decades.
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). 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.
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. 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.
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. 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.
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). Epidemiologic studies have suggested that the lifetime risk of developing cholangiocarcinoma for a person with PSC is on the order of 10%–15%, although autopsy series have found rates as high as 30% in this population. The mechanism by which PSC increases the risk of cholangiocarcinoma is not well understood.
Congenital liver abnormalities, such as Caroli's syndrome or choledochal cysts, have been associated with an approximately 15% lifetime risk of developing cholangiocarcinoma. The rare inherited disorders Lynch syndrome II and biliary papillomatosis have also been found to be associated with cholangiocarcinoma. 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. 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.
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.
Although cholangiocarcinoma is known 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. 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.Chronic inflammation and obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in this progression.
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.
Ultrasound of the liver and biliary tree is often used as the initial imaging modality in patients with suspected obstructive jaundice. Ultrasound can identify obstruction and ductal dilatation and, in some cases, may be sufficient to diagnose cholangiocarcinoma.Computed tomography (CT) scanning may also play an important role in the diagnosis of cholangiocarcinoma.
Imaging of the biliary tree
ERCP image of cholangiocarcinoma, showing common bile duct stricture and dilation of the proximal common bile duct
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. Surgery is also the only curative option for cholangiocarcinoma, although it is limited to patients with early-stage disease.
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, a majority of patients undergo exploratory surgery unless there is already a clear indication that the tumor is inoperable. However, the Mayo Clinic has reported significant success treating early bile duct cancer with liver transplantation using a protocolized approach and strict selection criteria.
If the tumor can be removed surgically, patients may receive adjuvantchemotherapy 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 and negative 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. 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.
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, and less than 5% in general. Overall median duration of survival is less than 6 months 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. 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. 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%.
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. Some evidence suggests that outcomes may be improving with more aggressive surgical approaches and adjuvant therapy.
Cholangiocarcinoma is an adenocarcinoma of the biliary tract, along with pancreatic cancer (which occurs about 20 times more frequently),gall bladder cancer (which occurs twice as often), and cancer of the ampulla of Vater. Treatments and clinical trials for pancreatic cancer, being far more prevalent, are often taken as a starting point for managing cholangiocarcinoma, even though the biologies are different enough that chemotherapies can put pancreatic cancer into permanent remission whereas there are no reports in the literature of long-term survival due to chemotherapy or radiation applied to an inoperable cholangiocarcinoma case.
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.Autopsy series have reported a prevalence of 0.01% to 0.46%. 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). The prevalence of cholangiocarcinoma in patients with primary sclerosing cholangitis may be as high as 30%, based on autopsy studies.
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. 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.
^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 Surg190 (5): 810–5. doi:10.1016/j.amjsurg.2005.07.025. PMID16226963.
^ abcdMark 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. ISBN978-1-4160-0245-1.
^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 Hepatol36 (3): 321–7. doi:10.1016/S0168-8278(01)00288-4. PMID11867174.
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". Hepatology27 (2): 311–6. doi:10.1002/hep.510270201. PMID9462625.
^Rustagi T, Dasanu CA (2012). "Risk Factors for Gallbladder Cancer and Cholangiocarcinoma: Similarities, Differences and Updates". J Gastrointest Cancer43 (2): 137–147. doi:10.1007/s12029-011-9284-y. PMID21597894.
^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 Sci95 (7): 592–5. doi:10.1111/j.1349-7006.2004.tb02492.x. PMID15245596.
^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. PMID11776153.
^ abcShaib Y, El-Serag H, Davila J, Morgan R, McGlynn K (2005). "Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study". Gastroenterology128 (3): 620–6. doi:10.1053/j.gastro.2004.12.048. PMID15765398.
^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". Hepatology28 (4): 921–5. doi:10.1002/hep.510280404. PMID9755226.
^Mecklin J, Järvinen H, Virolainen M (1992). "The association between cholangiocarcinoma and hereditary nonpolyposis colorectal carcinoma". Cancer69 (5): 1112–4. doi:10.1002/cncr.2820690508. PMID1310886.
^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". Cancer100 (4): 783–93. doi:10.1002/cncr.20031. PMID14770435.
^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 Control12 (10): 959–64. doi:10.1023/A:1013747228572. PMID11808716.
^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 Med38 (2): 241–56. doi:10.1016/0002-9343(65)90178-6. PMID14256720.
^Holzinger F, Z'graggen K, Büchler M (1999). "Mechanisms of biliary carcinogenesis: a pathogenetic multi-stage cascade towards cholangiocarcinoma". Ann Oncol10 (Suppl 4): 122–6. doi:10.1023/A:1008321710719. PMID10436802.
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 Endosc56 (1): 40–7. doi:10.1067/mge.2002.125105. PMID12085033.
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 Sci50 (9): 1734–40. doi:10.1007/s10620-005-2927-8. PMID16133981.
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 Gastroenterol95 (1): 204–7. doi:10.1111/j.1572-0241.2000.01685.x. PMID10638584.
^Valls C, Gumà A, Puig I, Sanchez A, Andía E, Serrano T, Figueras J (2000). "Intrahepatic peripheral cholangiocarcinoma: CT evaluation". Abdom Imaging25 (5): 490–6. doi:10.1007/s002610000079. PMID10931983.
^Tillich M, Mischinger H, Preisegger K, Rabl H, Szolar D (1998). "Multiphasic helical CT in diagnosis and staging of hilar cholangiocarcinoma". AJR Am J Roentgenol171 (3): 651–8. doi:10.2214/ajr.171.3.9725291. PMID9725291.
^Zhang Y, Uchida M, Abe T, Nishimura H, Hayabuchi N, Nakashima Y (1999). "Intrahepatic peripheral cholangiocarcinoma: comparison of dynamic CT and dynamic MRI". J Comput Assist Tomogr23 (5): 670–7. doi:10.1097/00004728-199909000-00004. PMID10524843.
^Sugiyama M, Hagi H, Atomi Y, Saito M (1997). "Diagnosis of portal venous invasion by pancreatobiliary carcinoma: value of endoscopic ultrasonography". Abdom Imaging22 (4): 434–8. doi:10.1007/s002619900227. PMID9157867.
^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 Roentgenol170 (6): 1491–5. doi:10.2214/ajr.170.6.9609160. PMID9609160.
^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 Surg27 (3): 278–83. doi:10.1007/s00268-002-6701-1. PMID12607051.
^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 Gastroenterol95 (2): 432–40. doi:10.1111/j.1572-0241.2000.01763.x. PMID10685746.
^Freeman M, Sielaff T (2003). "A modern approach to malignant hilar biliary obstruction". Rev Gastroenterol Disord3 (4): 187–201. PMID14668691.
^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 Surg185 (1): 33–9. doi:10.1016/s1072-7515(97)00003-3. PMID9208958.
^Länger F, von Wasielewski R, Kreipe HH (2006). "[The importance of immunohistochemistry for the diagnosis of cholangiocarcinomas]". Pathologe (in German) 27 (4): 244–50. doi:10.1007/s00292-006-0836-z. PMID16758167.
^Todoroki T, Ohara K, Kawamoto T, Koike N, Yoshida S, Kashiwagi H, Otsuka M, Fukao K (2000). "Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma". Int J Radiat Oncol Biol Phys46 (3): 581–7. doi:10.1016/S0360-3016(99)00472-1. PMID10701737.
^Alden M, Mohiuddin M (1994). "The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer". Int J Radiat Oncol Biol Phys28 (4): 945–51. doi:10.1016/0360-3016(94)90115-5. PMID8138448.
^González González D, Gouma D, Rauws E, van Gulik T, Bosma A, Koedooder C (1999). "Role of radiotherapy, in particular intraluminal brachytherapy, in the treatment of proximal bile duct carcinoma". Ann Oncol10 (Suppl 4): 215–20. doi:10.1023/A:1008339709327. PMID10436826.
^Glimelius B, Hoffman K, Sjödén P, Jacobsson G, Sellström H, Enander L, Linné T, Svensson C (1996). "Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer". Ann Oncol7 (6): 593–600. doi:10.1093/oxfordjournals.annonc.a010676. PMID8879373.
^Choi C, Choi I, Seo J, Kim B, Kim J, Kim C, Um S, Kim J, Kim Y (2000). "Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas". Am J Clin Oncol23 (4): 425–8. doi:10.1097/00000421-200008000-00023. PMID10955877.
^Park J, Oh S, Kim S, Kwon H, Kim J, Jin-Kim H, Kim Y (2005). "Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study". Jpn J Clin Oncol35 (2): 68–73. doi:10.1093/jjco/hyi021. PMID15709089.
^Giuliani F, Gebbia V, Maiello E, Borsellino N, Bajardi E, Colucci G (2006). "Gemcitabine and cisplatin for inoperable and/or metastatic biliary tree carcinomas: a multicenter phase II study of the Gruppo Oncologico dell'Italia Meridionale (GOIM)". Ann Oncol17 (Suppl 7): vii73–7. doi:10.1093/annonc/mdl956. PMID16760299.
^Bhargava P, Jani C, Savarese D, O'Donnell J, Stuart K, Rocha Lima C (2003). "Gemcitabine and irinotecan in locally advanced or metastatic biliary cancer: preliminary report". Oncology (Williston Park)17 (9 Suppl 8): 23–6. PMID14569844.
^Knox J, Hedley D, Oza A, Feld R, Siu L, Chen E, Nematollahi M, Pond G, Zhang J, Moore M (2005). "Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial". J Clin Oncol23 (10): 2332–8. doi:10.1200/JCO.2005.51.008. PMID15800324.
^Philip P, Mahoney M, Allmer C, Thomas J, Pitot H, Kim G, Donehower R, Fitch T, Picus J, Erlichman C (2006). "Phase II study of erlotinib in patients with advanced biliary cancer". J Clin Oncol24 (19): 3069–74. doi:10.1200/JCO.2005.05.3579. PMID16809731.
^Ortner M, Caca K, Berr F, Liebetruth J, Mansmann U, Huster D, Voderholzer W, Schachschal G, Mössner J, Lochs H (2003). "Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study". Gastroenterology125 (5): 1355–63. doi:10.1016/j.gastro.2003.07.015. PMID14598251.
^Yamamoto M, Takasaki K, Yoshikawa T (1999). "Lymph Node Metastasis in Intrahepatic Cholangiocarcinoma". Japanese Journal of Clinical Oncology29 (3): 147–150. doi:10.1093/jjco/29.3.147. PMID10225697.
^Farley D, Weaver A, Nagorney D (1995). ""Natural history" of unresected cholangiocarcinoma: patient outcome after noncurative intervention". Mayo Clin Proc70 (5): 425–9. doi:10.4065/70.5.425. PMID7537346.
Bortolasi L, Burgart L, Tsiotos G, Luque-De León E, Sarr M (2000). "Adenocarcinoma of the distal bile duct. A clinicopathologic outcome analysis after curative resection". Dig Surg17 (1): 36–41. doi:10.1159/000018798. PMID10720830.
Lieser M, Barry M, Rowland C, Ilstrup D, Nagorney D (1998). "Surgical management of intrahepatic cholangiocarcinoma: a 31-year experience". J Hepatobiliary Pancreat Surg5 (1): 41–7. doi:10.1007/PL00009949. PMID9683753.
Valverde A, Bonhomme N, Farges O, Sauvanet A, Flejou J, Belghiti J (1999). "Resection of intrahepatic cholangiocarcinoma: a Western experience". J Hepatobiliary Pancreat Surg6 (2): 122–7. doi:10.1007/s005340050094. PMID10398898.
Nakagohri T, Asano T, Kinoshita H, Kenmochi T, Urashima T, Miura F, Ochiai T (2003). "Aggressive surgical resection for hilar-invasive and peripheral intrahepatic cholangiocarcinoma". World J Surg27 (3): 289–93. doi:10.1007/s00268-002-6696-7. PMID12607053.
Weber S, Jarnagin W, Klimstra D, DeMatteo R, Fong Y, Blumgart L (2001). "Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes". J Am Coll Surg193 (4): 384–91. doi:10.1016/S1072-7515(01)01016-X. PMID11584966.
^Estimates of survival after surgery for perihilar cholangiocarcinoma include:
Nagino M, Nimura Y, Kamiya J, Kanai M, Uesaka K, Hayakawa N, Yamamoto H, Kondo S, Nishio H (1998). "Segmental liver resections for hilar cholangiocarcinoma". Hepatogastroenterology45 (19): 7–13. PMID9496478.
Rea D, Munoz-Juarez M, Farnell M, Donohue J, Que F, Crownhart B, Larson D, Nagorney D (2004). "Major hepatic resection for hilar cholangiocarcinoma: analysis of 46 patients". Arch Surg139 (5): 514–23; discussion 523–5. doi:10.1001/archsurg.139.5.514. PMID15136352.
Launois B, Reding R, Lebeau G, Buard J (2000). "Surgery for hilar cholangiocarcinoma: French experience in a collective survey of 552 extrahepatic bile duct cancers". J Hepatobiliary Pancreat Surg7 (2): 128–34. doi:10.1007/s005340050166. PMID10982604.
^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 Gastroenterol96 (4): 1164–9. doi:10.1111/j.1572-0241.2001.03696.x. PMID11316165.
^Nakeeb A, Tran K, Black M, Erickson B, Ritch P, Quebbeman E, Wilson S, Demeure M, Rilling W, Dua K, Pitt H (2002). "Improved survival in resected biliary malignancies". Surgery132 (4): 555–63; discission 563–4. doi:10.1067/msy.2002.127555. PMID12407338.
^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 Hepatol37 (6): 806–13. doi:10.1016/S0168-8278(02)00297-0. PMID12445422.
Shaib Y, Davila J, McGlynn K, El-Serag H (2004). "Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase?". J Hepatol40 (3): 472–7. doi:10.1016/j.jhep.2003.11.030. PMID15123362.
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 Hepatol37 (6): 806–13. doi:10.1016/S0168-8278(02)00297-0. PMID12445422.
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 Inst98 (12): 873–5. doi:10.1093/jnci/djj234. PMID16788161.