Cholangiocarcinoma 968777 223818793 2008-07-05T23:37:40Z Kyle the bot 3115531 robot Adding: [[ja:胆管癌]] Modifying: [[pl:Rak przewodów żółciowych]] {{Infobox_Disease | Name = Cholangiocarcinoma | Image = Digestive system showing bile duct.png | Caption = Digestive system diagram showing bile duct location | DiseasesDB = 2505 | ICD10 = {{ICD10|C|22|1|c|15}} | ICD9 = {{ICD9|155.1}}, {{ICD9|156.1}} | ICDO = 8160/3 | OMIM = | MedlinePlus = 000291 | eMedicineSubj = med | eMedicineTopic = 343 | eMedicine_mult = {{eMedicine2|radio|153}} | MeshID = D018281 }} '''Cholangiocarcinoma''' is a [[cancer]] of the [[bile duct]]s, which drain [[bile]] from the [[liver]] into the [[small intestine]]. Other [[biliary tract]] cancers include [[pancreatic cancer]], [[gall bladder]] cancer, and cancer of the [[ampulla of Vater]]. Cholangiocarcinoma is a relatively rare [[adenocarcinoma]], with an annual [[incidence (epidemiology)|incidence]] of 1&ndash;2 cases per 100,000 in the Western world,<ref name="Landis">{{cite journal |author=Landis S, Murray T, Bolden S, Wingo P |title=Cancer statistics, 1998 |journal=CA Cancer J Clin |volume=48 |issue=1 |pages=6–29 |year= 1998|pmid=9449931 |doi=10.3322/canjclin.48.1.6}}</ref> but rates of cholangiocarcinoma have been rising worldwide over the past several decades.<ref name="rising">{{cite journal |author=Patel T |title=Worldwide trends in mortality from biliary tract malignancies |journal=BMC Cancer |volume=2 |issue= |pages=10 |year= 2002|pmid=11991810 |doi=10.1186/1471-2407-2-10}}</ref> Prominent symptoms of cholangiocarcinoma include abnormal [[liver function]] tests, [[abdominal pain]], [[jaundice]], [[weight loss]], and sometimes [[pruritis|generalized itching]], [[fever]], or changes in [[human feces|stool]] or [[urine]] color. The disease is diagnosed through a combination of [[blood test]]s, imaging, [[endoscopy]], and sometimes surgical exploration, though it commonly presents at [[cancer staging|Stage III or IV]]: too late to be resected surgically. Though most patients present without any risk factors evident, known risk factors for cholangiocarcinoma include [[primary sclerosing cholangitis]] (an inflammatory disease of the bile ducts), congenital liver malformations, infection with the parasitic [[liver fluke]]s ''[[Opisthorchis viverrini]]'' or ''[[Clonorchis sinensis]]'', and exposure to [[Thorotrast]] ([[thorium dioxide]]), a chemical formerly used in [[medical imaging]]. Cholangiocarcinoma is considered to be an incurable and rapidly lethal disease unless all of its tumors can be fully [[resection|resected]] (that is, cut out surgically). There is no potentially curative treatment except surgery, but unfortunately most patients have advanced and inoperable disease at the time of diagnosis. Patients with cholangiocarcinoma are generally managed, though never cured, with [[chemotherapy]] or [[radiation therapy]] as well as [[palliative care]] measures, and these are also used as [[adjuvant#oncology|adjuvant]] therapies post-surgically in cases where resection has been successful. Some areas of ongoing [[medical research]] in cholangiocarcinoma include the use of newer [[targeted therapy|targeted therapies]] (such as [[erlotinib]]) or [[photodynamic therapy]] for treatment, and the concentration of byproducts of cancer [[stromal cell]] formation in the blood for [[diagnosis]]. ==Symptoms== [[Image:PHIL 2860 lores.jpg|thumb|left|Yellowing of the skin and eyes (jaundice)]] The most common physical indications of cholangiocarcinoma are abnormal [[liver function tests]], [[jaundice]] (yellowing of the eyes and skin), which occurs only when bile ducts are blocked by the tumor, [[abdominal pain]] (30%&ndash;50%), [[pruritis|generalized itching]] (66%), [[weight loss]] (30%&ndash;50%), [[fever]] (up to 20%), or changes in [[human feces|stool]] or [[urine]] color.<ref>{{cite journal |author=Nagorney D, Donohue J, Farnell M, Schleck C, Ilstrup D |title=Outcomes after curative resections of cholangiocarcinoma |journal=Arch Surg |volume=128 |issue=8 |pages=871–7; discussion 877–9 |year=1993 |pmid=8393652}}</ref><ref>[http://www.surgery.usc.edu/divisions/tumor/pancreasdiseases/web%20pages/BILIARY%20SYSTEM/cholangiocarcinoma.html]</ref> 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 often have pain without jaundice.<ref name="nakeeb">{{cite journal |author=Nakeeb A, Pitt H, Sohn T, Coleman J, Abrams R, Piantadosi S, Hruban R, Lillemoe K, Yeo C, Cameron J |title=Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors |journal=Ann Surg |volume=224 |issue=4 |pages=463–73; discussion 473–5 |year=1996 |pmid=8857851 |doi=10.1097/00000658-199610000-00005}}</ref> [[Liver function tests|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, as the primary cause of the jaundice.<ref name="feldman">{{cite book |editor=Mark Feldman, Lawrence S. Friedman, Lawrence J. Brandt |title=Sleisenger and Fordtran's Gastrointestinal and Liver Disease |accessdate=May 5, 2008 |edition=8th edition |date=July 21, 2006 |publisher=Saunders, an imprint of Elsevier |isbn=978-1416002451 |pages=pp. 1493&ndash;1496 }}</ref> [[CA19-9]] is elevated in most cases. ==Epidemiology== Cholangiocarcinoma is an [[adenocarcinoma]] of the [[biliary tract]],<ref>[http://training.seer.cancer.gov/ss_module13_biliary_tract/unit01_sec01_intro.html]</ref> along with [[pancreatic cancer]] (which occurs about 20 times more frequently) <ref>[ http://seer.cancer.gov/csr/1975_2005/results_single/sect_01_table.01.pdf]</ref>, [[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. {| style="width: 50%; border-collapse: collapse; margin: 0.2em;" border="2" align="right" |+ align="bottom" | ''[[Age Standardized Mortality Rates|Age-standardized mortality rates]] from intrahepatic (IC) and extrahepatic (EC) cholangiocarcinoma for men and women, by country. Source: Khan et al, 2002.<ref>{{cite journal |author=Khan S, Taylor-Robinson S, Toledano M, Beck A, Elliott P, Thomas H |title=Changing international trends in mortality rates for liver, biliary and pancreatic tumours |journal=J Hepatol |volume=37 |issue=6 |pages=806–13 |year=2002 |pmid=12445422 |doi=10.1016/S0168-8278(02)00297-0}}</ref>'' |- ! ''Country'' ! ''IC (men/women)'' ! ''EC (men/women)'' |- ! U.S.A. | align="center" | 0.60 / 0.43 | align="center" | 0.70 / 0.87 |- ! Japan | align="center" | 0.23 / 0.10 | align="center" | 5.87 / 5.20 |- ! Australia | align="center" | 0.70 / 0.53 | align="center" | 0.90 / 1.23 |- ! England/Wales | align="center" | 0.83 / 0.63 | align="center" | 0.43 / 0.60 |- ! Scotland | align="center" | 1.17 / 1.00 | align="center" | 0.60 / 0.73 |- ! France | align="center" | 0.27 / 0.20 | align="center" | 1.20 / 1.37 |- ! Italy | align="center" | 0.13 / 0.13 | align="center" | 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 (epidemiology)|incidence]] of 1&ndash;2 cases per 100,000 people.<ref name="Landis"/> [[Autopsy]] series have reported a [[prevalence]] of 0.01% to 0.46%.<ref>{{cite journal |author=Vauthey J, Blumgart L |title=Recent advances in the management of cholangiocarcinomas |journal=Semin Liver Dis |volume=14 |issue=2 |pages=109–14 |year=1994 |pmid=8047893}}</ref><ref>[http://www.cancer.gov/statistics/]</ref> 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).<ref>{{cite journal |author=Henson D, Albores-Saavedra J, Corle D |title=Carcinoma of the extrahepatic bile ducts. Histologic types, stage of disease, grade, and survival rates |journal=Cancer |volume=70 |issue=6 |pages=1498–501 |year=1992 |pmid=1516001 |doi=10.1002/1097-0142(19920915)70:6<1498::AID-CNCR2820700609>3.0.CO;2-C}}</ref> The prevalence of cholangiocarcinoma in patients with primary sclerosing cholangitis may be as high as 30%, based on autopsy studies.<ref name="autopsy">{{cite journal |author=Rosen C, Nagorney D, Wiesner R, Coffey R, LaRusso N |title=Cholangiocarcinoma complicating primary sclerosing cholangitis |journal=Ann Surg |volume=213 |issue=1 |pages=21–5 |year=1991 |pmid=1845927 |doi=10.1097/00000658-199101000-00004}}</ref> 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]].<ref>Multiple independent studies have documented a steady increase in the worldwide incidence of cholangiocarcinoma. Some relevant journal articles include: *{{cite journal |author=Patel T |title=Worldwide trends in mortality from biliary tract malignancies |journal=BMC Cancer |volume=2 |issue= |pages=10 |year= 2002|pmid=11991810 |doi=10.1186/1471-2407-2-10}} *{{cite journal |author=Patel T |title=Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States |journal=Hepatology |volume=33 |issue=6 |pages=1353–7 |year=2001 |pmid=11391522 |doi=10.1053/jhep.2001.25087}} *{{cite journal |author=Shaib Y, Davila J, McGlynn K, El-Serag H |title=Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? |journal=J Hepatol |volume=40 |issue=3 |pages=472–7 |year=2004 |pmid=15123362 |doi=10.1016/j.jhep.2003.11.030}} *{{cite journal |author=West J, Wood H, Logan R, Quinn M, Aithal G |title=Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971–2001 |journal=Br J Cancer |volume=94 |issue=11 |pages=1751–8 |year=2006 |pmid=16736026 |doi=10.1038/sj.bjc.6603127}} *{{cite journal |author=Khan S, Taylor-Robinson S, Toledano M, Beck A, Elliott P, Thomas H |title=Changing international trends in mortality rates for liver, biliary and pancreatic tumours |journal=J Hepatol |volume=37 |issue=6 |pages=806–13 |year=2002 |pmid=12445422 |doi=10.1016/S0168-8278(02)00297-0}} *{{cite journal |author=Welzel T, McGlynn K, Hsing A, O'Brien T, Pfeiffer R |title=Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States |journal=J Natl Cancer Inst |volume=98 |issue=12 |pages=873–5 |year=2006 |pmid=16788161}}</ref> 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|HIV infection]], has also been increasing during this time frame.<ref name="riskfactors">{{cite journal |author=Shaib Y, El-Serag H, Davila J, Morgan R, McGlynn K |title=Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study |journal=Gastroenterology |volume=128 |issue=3 |pages=620–6 |year=2005 |pmid=15765398 |doi=10.1053/j.gastro.2004.12.048}}</ref> ==Risk factors== [[Image:Clonorchis sinensis LifeCycle.gif|thumb|right|350px|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 factor]]s 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 in turn closely associated with [[ulcerative colitis]] (UC).<ref>{{cite journal |author=Chapman R |title=Risk factors for biliary tract carcinogenesis |journal=Ann Oncol |volume=10 Suppl 4 |issue= |pages=308–11 |year= |pmid=10436847}}</ref> Epidemiologic studies have suggested that the lifetime risk of developing cholangiocarcinoma for a person with PSC is 10%&ndash;15%,<ref>Epidemiologic studies which have addressed the incidence of cholangiocarcinoma in people with primary sclerosing cholangitis include the following: *{{cite journal |author=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 |title=Hepatic and extrahepatic malignancies in primary sclerosing cholangitis |journal=J Hepatol |volume=36 |issue=3 |pages=321–7 |year=2002 |pmid=11867174 |doi=10.1016/S0168-8278(01)00288-4}} *{{cite journal |author=Bergquist A, Glaumann H, Persson B, Broomé U |title=Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study |journal=Hepatology |volume=27 |issue=2 |pages=311–6 |year=1998 |pmid=9462625 |doi=10.1002/hep.510270201}} *{{cite journal |author=Burak K, Angulo P, Pasha T, Egan K, Petz J, Lindor K |title=Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis |journal=Am J Gastroenterol |volume=99 |issue=3 |pages=523–6 |year=2004 |pmid=15056096 |doi=10.1111/j.1572-0241.2004.04067.x}}</ref> although autopsy series have found rates as high as 30% in this population.<ref name="autopsy"/> The mechanism by which PSC increases the risk of cholangiocarcinoma is not well-understood. Certain [[parasitic disease|parasitic liver diseases]] may be risk factors as well. Colonization with the [[liver fluke]]s ''[[Opisthorchis viverrini]]'' (found in [[Thailand]], [[Laos]], and [[Malaysia]]) or ''[[Clonorchis sinensis]]'' (found in [[Japan]], [[Korea]], and [[Vietnam]]) has been associated with the development of cholangiocarcinoma.<ref>{{cite journal |author=Watanapa P |title=Cholangiocarcinoma in patients with opisthorchiasis |journal=Br J Surg |volume=83 |issue=8 |pages=1062–64 |year=1996 |pmid=8869303 |doi=10.1002/bjs.1800830809}}</ref><ref>{{cite journal |author=Watanapa P, Watanapa W |title=Liver fluke-associated cholangiocarcinoma |journal=Br J Surg |volume=89 |issue=8 |pages=962–70 |year=2002 |pmid=12153620 |doi=10.1046/j.1365-2168.2002.02143.x}}</ref><ref>{{cite journal |author=Shin H, Lee C, Park H, Seol S, Chung J, Choi H, Ahn Y, Shigemastu T |title=Hepatitis B and C virus, Clonorchis sinensis for the risk of liver cancer: a case-control study in Pusan, Korea |journal=Int J Epidemiol |volume=25 |issue=5 |pages=933–40 |year=1996 |pmid=8921477 |doi=10.1093/ije/25.5.933}}</ref> Patients with chronic liver disease, whether in the form of viral hepatitis (e.g. [[hepatitis B]] or [[hepatitis C|C]]),<ref>{{cite journal |author=Kobayashi M, Ikeda K, Saitoh S, Suzuki F, Tsubota A, Suzuki Y, Arase Y, Murashima N, Chayama K, Kumada H |title=Incidence of primary cholangiocellular carcinoma of the liver in Japanese patients with hepatitis C virus-related cirrhosis |journal=Cancer |volume=88 |issue=11 |pages=2471–7 |year=2000 |pmid=10861422 |doi=10.1002/1097-0142(20000601)88:11<2471::AID-CNCR7>3.0.CO;2-T}}</ref><ref>{{cite journal |author=Yamamoto S, Kubo S, Hai S, Uenishi T, Yamamoto T, Shuto T, Takemura S, Tanaka H, Yamazaki O, Hirohashi K, Tanaka T |title=Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma |journal=Cancer Sci |volume=95 |issue=7 |pages=592–5 |year=2004 |pmid=15245596 |doi=10.1111/j.1349-7006.2004.tb02492.x}}</ref><ref>{{cite journal |author=Lu H, Ye M, Thung S, Dash S, Gerber M |title=Detection of hepatitis C virus RNA sequences in cholangiocarcinomas in Chinese and American patients |journal=Chin Med J (Engl) |volume=113 |issue=12 |pages=1138–41 |year=2000 |pmid=11776153}}</ref> [[alcoholic liver disease]], or [[cirrhosis]] from other causes, are at increased risk of cholangiocarcinoma.<ref name="riskfactors"/><ref>{{cite journal |author=Sorensen H, Friis S, Olsen J, Thulstrup A, Mellemkjaer L, Linet M, Trichopoulos D, Vilstrup H, Olsen J |title=Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark |journal=Hepatology |volume=28 |issue=4 |pages=921–5 |year=1998 |pmid=9755226 |doi=10.1002/hep.510280404}}</ref> HIV infection was also identified in one study as a potential risk factor for cholangiocarcinoma, although it was unclear whether [[HIV]] itself or correlated factors (e.g. hepatitis C infection) were responsible for the association.<ref name="riskfactors"/> [[Congenital disorder|Congenital]] liver abnormalities, such as [[Caroli's syndrome]] or choledochal cysts, have been associated with an approximately 15% lifetime risk of developing cholangiocarcinoma.<ref>{{cite journal |author=Lipsett P, Pitt H, Colombani P, Boitnott J, Cameron J |title=Choledochal cyst disease. A changing pattern of presentation |journal=Ann Surg |volume=220 |issue=5 |pages=644–52 |year=1994 |pmid=7979612 |doi=10.1097/00000658-199411000-00007}}</ref><ref>{{cite journal |author=Dayton M, Longmire W, Tompkins R |title=Caroli's Disease: a premalignant condition? |journal=Am J Surg |volume=145 |issue=1 |pages=41–8 |year=1983 |pmid=6295196 |doi=10.1016/0002-9610(83)90164-2}}</ref> The rare inherited disorders [[Lynch syndrome|Lynch syndrome II]] and biliary papillomatosis are associated with cholangiocarcinoma.<ref>{{cite journal |author=Mecklin J, Järvinen H, Virolainen M |title=The association between cholangiocarcinoma and hereditary nonpolyposis colorectal carcinoma |journal=Cancer |volume=69 |issue=5 |pages=1112–4 |year=1992 |pmid=1310886}}</ref><ref>{{cite journal |author=Lee S, Kim M, Lee S, Jang S, Song M, Kim K, Kim H, Seo D, Song D, Yu E, Lee S, Min Y |title=Clinicopathologic review of 58 patients with biliary papillomatosis |journal=Cancer |volume=100 |issue=4 |pages=783–93 |year=2004 |pmid=14770435 |doi=10.1002/cncr.20031}}</ref> The presence of gallstones ([[cholelithiasis]]) is not clearly associated with cholangiocarcinoma. However, intrahepatic stones (so-called hepatolithiasis), which are rare in the West but common in parts of Asia, have been strongly associated with cholangiocarcinoma.<ref>{{cite journal |author=Lee C, Wu C, Chen G |title=What is the impact of coexistence of hepatolithiasis on cholangiocarcinoma? |journal=J Gastroenterol Hepatol |volume=17 |issue=9 |pages=1015–20 |year=2002 |pmid=12167124 |doi=10.1046/j.1440-1746.2002.02779.x}}</ref><ref>{{cite journal |author=Su C, Shyr Y, Lui W, P'Eng F |title=Hepatolithiasis associated with cholangiocarcinoma |journal=Br J Surg |volume=84 |issue=7 |pages=969–73 |year=1997 |pmid=9240138 |doi=10.1002/bjs.1800840717}}</ref><ref>{{cite journal |author=Donato F, Gelatti U, Tagger A, Favret M, Ribero M, Callea F, Martelli C, Savio A, Trevisi P, Nardi G |title=Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy |journal=Cancer Causes Control |volume=12 |issue=10 |pages=959–64 |year=2001 |pmid=11808716 |doi=10.1023/A:1013747228572}}</ref> Exposure to [[Thorotrast]], a form of [[thorium dioxide]] which was used as a [[radiocontrast|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]].<ref>{{cite journal |author=Sahani D, Prasad S, Tannabe K, Hahn P, Mueller P, Saini S |title=Thorotrast-induced cholangiocarcinoma: case report |journal=Abdom Imaging |volume=28 |issue=1 |pages=72–4 |year= 2003|pmid=12483389 |doi=10.1007/s00261-001-0148-y}}</ref><ref>{{cite journal |author=Zhu A, Lauwers G, Tanabe K |title=Cholangiocarcinoma in association with Thorotrast exposure |journal=J Hepatobiliary Pancreat Surg |volume=11 |issue=6 |pages=430–3 |year=2004 |pmid=15619021 |doi=10.1007/s00534-004-0924-5}}</ref> ==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 bile duct]] may be referred to [[eponym]]ously as a [[Klatskin tumor]].<ref>{{cite journal |author=KLATSKIN G |title=Adenocarcinoma Of The Hepatic Duct At Its Bifurcation Within The Porta Hepatis. An Unusual Tumor With Distinctive Clinical And Pathological Features |journal=Am J Med |volume=38 |issue= |pages=241–56 |year= 1965|pmid=14256720 |doi=10.1016/0002-9343(65)90178-6}}</ref> Although cholangiocarcinoma is known to be an [[adenocarcinoma]] of the epithelial cells lining the biliary tract, the actual cell of origin is unknown, although recent evidence has suggested that it may arise from a [[pluripotent]] hepatic [[adult stem cell|stem cell]].<ref>{{cite journal |author=Roskams T |title=Liver stem cells and their implication in hepatocellular and cholangiocarcinoma |journal=Oncogene |volume=25 |issue=27 |pages=3818–22 |year=2006 |pmid=16799623 |doi=10.1038/sj.onc.1209558}}</ref><ref>{{cite journal |author=Liu C, Wang J, Ou Q |title=Possible stem cell origin of human cholangiocarcinoma |journal=World J Gastroenterol |volume=10 |issue=22 |pages=3374–6 |year=2004 |pmid=15484322}}</ref><ref>{{cite journal |author=Sell S, Dunsford H |title=Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma |journal=Am J Pathol |volume=134 |issue=6 |pages=1347–63 |year=1989 |pmid=2474256}}</ref> Cholangiocarcinoma is thought to develop through a series of stages &mdash; from early [[hyperplasia]] and [[metaplasia]], through [[dysplasia]], to the development of frank [[carcinoma]] &mdash; in a process similar to that seen in the development of [[colon cancer]].<ref name="targeting">{{cite journal |author=Sirica A |title=Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy |journal=Hepatology |volume=41 |issue=1 |pages=5–15 |year=2005 |pmid=15690474 |doi=10.1002/hep.20537}}</ref> [[inflammation|Chronic inflammation]] and obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in this progression.<ref name="targeting"/><ref>{{cite journal |author=Holzinger F, Z'graggen K, Büchler M |title=Mechanisms of biliary carcinogenesis: a pathogenetic multi-stage cascade towards cholangiocarcinoma |journal=Ann Oncol |volume=10 Suppl 4 |issue= |pages=122–6 |year= |pmid=10436802}}</ref><ref>{{cite journal |author=Gores G |title=Cholangiocarcinoma: current concepts and insights |journal=Hepatology |volume=37 |issue=5 |pages=961–9 |year=2003 |pmid=12717374 |doi=10.1053/jhep.2003.50200}}</ref> [[Histology|Histologically]], cholangiocarcinomas may vary from [[cellular differentiation|undifferentiated to well-differentiated]]. They are often surrounded by a brisk [[fibrosis|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 [[immunohistochemistry|immunohistochemical]] stain that can distinguish [[malignant]] from [[benign]] biliary ductal tissue, although staining for [[cytokeratin]]s, [[carcinoembryonic antigen]], and [[mucin]]s may aid in diagnosis.<ref name="nejm">{{cite journal |author=de Groen P, Gores G, LaRusso N, Gunderson L, Nagorney D |title=Biliary tract cancers |journal=N Engl J Med |volume=341 |issue=18 |pages=1368–78 |year=1999 |pmid=10536130 |doi=10.1056/NEJM199910283411807}}</ref> Most tumors (>90%) are [[adenocarcinoma]]s.<ref>{{cite journal |author=Henson D, Albores-Saavedra J, Corle D |title=Carcinoma of the extrahepatic bile ducts. Histologic types, stage of disease, grade, and survival rates |journal=Cancer |volume=70 |issue=6 |pages=1498–501 |year=1992 |pmid=1516001 |doi=10.1002/1097-0142(19920915)70:6<1498::AID-CNCR2820700609>3.0.CO;2-C}}</ref> ==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 [[jaundice#post-hepatic|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 test]]s that can diagnose cholangiocarcinoma by themselves. Serum levels of [[carcinoembryonic antigen]] (CEA) and CA19-9 are often elevated, but are not [[sensitivity (tests)|sensitive]] or [[specificity (tests)|specific]] enough to be used as a general [[screening (medicine)|screening]] tool. However, they may be useful in conjunction with [[medical imaging|imaging methods]] in supporting a suspected diagnosis of cholangiocarcinoma.<ref>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: *{{cite journal |author=Nehls O, Gregor M, Klump B |title=Serum and bile markers for cholangiocarcinoma |journal=Semin Liver Dis |volume=24 |issue=2 |pages=139–54 |year=2004 |pmid=15192787 |doi=10.1055/s-2004-828891}} *{{cite journal |author=Siqueira E, Schoen R, Silverman W, Martin J, Rabinovitz M, Weissfeld J, Abu-Elmaagd K, Madariaga J, Slivka A, Martini J |title=Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis |journal=Gastrointest Endosc |volume=56 |issue=1 |pages=40–7 |year=2002 |pmid=12085033 |doi=10.1067/mge.2002.125105}} *{{cite journal |author=Levy C, Lymp J, Angulo P, Gores G, Larusso N, Lindor K |title=The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis |journal=Dig Dis Sci |volume=50 |issue=9 |pages=1734–40 |year=2005 |pmid=16133981 |doi=10.1007/s10620-005-2927-8}} *{{cite journal |author=Patel A, Harnois D, Klee G, LaRusso N, Gores G |title=The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis |journal=Am J Gastroenterol |volume=95 |issue=1 |pages=204–7 |year=2000 |pmid=10638584 |doi=10.1111/j.1572-0241.2000.01685.x}}</ref> ===Abdominal imaging=== [[Image:CT cholangioca.jpg|right|thumb|[[Computed tomography|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.<ref>{{cite journal |author=Saini S |title=Imaging of the hepatobiliary tract |journal=N Engl J Med |volume=336 |issue=26 |pages=1889–94 |year=1997 |pmid=9197218 |doi=10.1056/NEJM199706263362607}}</ref><ref>{{cite journal |author=Sharma M, Ahuja V |title=Aetiological spectrum of obstructive jaundice and diagnostic ability of ultrasonography: a clinician's perspective |journal=Trop Gastroenterol |volume=20 |issue=4 |pages=167–9 |year= |pmid=10769604}}</ref> Ultrasound can identify obstruction and ductal dilatation and, in some cases, may be sufficient to diagnose cholangiocarcinoma.<ref>{{cite journal |author=Bloom C, Langer B, Wilson S |title=Role of US in the detection, characterization, and staging of cholangiocarcinoma |journal=Radiographics |volume=19 |issue=5 |pages=1199–218 |year= |pmid=10489176}}</ref> [[Computed tomography]] (CT) scanning may also play an important role in the diagnosis of cholangiocarcinoma.<ref>{{cite journal |author=Valls C, Gumà A, Puig I, Sanchez A, Andía E, Serrano T, Figueras J |title=Intrahepatic peripheral cholangiocarcinoma: CT evaluation |journal=Abdom Imaging |volume=25 |issue=5 |pages=490–6 |year= 2000|pmid=10931983 |doi=10.1007/s002610000079}}</ref><ref>{{cite journal |author=Tillich M, Mischinger H, Preisegger K, Rabl H, Szolar D |title=Multiphasic helical CT in diagnosis and staging of hilar cholangiocarcinoma |journal=AJR Am J Roentgenol |volume=171 |issue=3 |pages=651–8 |year=1998 |pmid=9725291}}</ref><ref>{{cite journal |author=Zhang Y, Uchida M, Abe T, Nishimura H, Hayabuchi N, Nakashima Y |title=Intrahepatic peripheral cholangiocarcinoma: comparison of dynamic CT and dynamic MRI |journal=J Comput Assist Tomogr |volume=23 |issue=5 |pages=670–7 |year= 1999|pmid=10524843 |doi=10.1097/00004728-199909000-00004}}</ref> ===Imaging of the biliary tree=== [[Image:ERCP cholangioca.jpg|thumb|right|[[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 duct]]s is often necessary. [[Endoscopic retrograde cholangiopancreatography]] (ERCP), an [[endoscopy|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 [[biopsy|biopsies]] and to place [[stent]]s or perform other interventions to relieve biliary obstruction.<ref name="feldman"/> [[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.<ref>{{cite journal |author=Sugiyama M, Hagi H, Atomi Y, Saito M |title=Diagnosis of portal venous invasion by pancreatobiliary carcinoma: value of endoscopic ultrasonography |journal=Abdom Imaging |volume=22 |issue=4 |pages=434–8 |year= 1997|pmid=9157867 |doi=10.1007/s002619900227}}</ref> As an alternative to ERCP, [[percutaneous transhepatic cholangiography]] (PTC) may be utilized. [[Magnetic resonance cholangiopancreatography]] (MRCP) is a [[non-invasive]] alternative to ERCP.<ref>{{cite journal |author=Schwartz L, Coakley F, Sun Y, Blumgart L, Fong Y, Panicek D |title=Neoplastic pancreaticobiliary duct obstruction: evaluation with breath-hold MR cholangiopancreatography |journal=AJR Am J Roentgenol |volume=170 |issue=6 |pages=1491–5 |year=1998 |pmid=9609160}}</ref><ref>{{cite journal |author=Zidi S, Prat F, Le Guen O, Rondeau Y, Pelletier G |title=Performance characteristics of magnetic resonance cholangiography in the staging of malignant hilar strictures |journal=Gut |volume=46 |issue=1 |pages=103–6 |year=2000 |pmid=10601064 |doi=10.1136/gut.46.1.103}}</ref><ref>{{cite journal |author=Lee M, Park K, Shin Y, Yoon H, Sung K, Kim M, Lee S, Kang E |title=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 |journal=World J Surg |volume=27 |issue=3 |pages=278–83 |year=2003 |pmid=12607051 |doi=10.1007/s00268-002-6701-1}}</ref> 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.<ref>{{cite journal |author=Yeh T, Jan Y, Tseng J, Chiu C, Chen T, Hwang T, Chen M |title=Malignant perihilar biliary obstruction: magnetic resonance cholangiopancreatographic findings |journal=Am J Gastroenterol |volume=95 |issue=2 |pages=432–40 |year=2000 |pmid=10685746 |doi=10.1111/j.1572-0241.2000.01763.x}}</ref><ref>{{cite journal |author=Freeman M, Sielaff T |title=A modern approach to malignant hilar biliary obstruction |journal=Rev Gastroenterol Disord |volume=3 |issue=4 |pages=187–201 |year=2003 |pmid=14668691}}</ref><ref>{{cite journal |author=Szklaruk J, Tamm E, Charnsangavej C |title=Preoperative imaging of biliary tract cancers |journal=Surg Oncol Clin N Am |volume=11 |issue=4 |pages=865–76 |year=2002 |pmid=12607576 |doi=10.1016/S1055-3207(02)00032-7}}</ref> ===Surgery=== [[Surgery|Surgical exploration]] may be necessary to obtain a suitable [[biopsy]] and to accurately [[cancer staging|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.<ref>{{cite journal |author=Weber S, DeMatteo R, Fong Y, Blumgart L, Jarnagin W |title=Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients |journal=Ann Surg |volume=235 |issue=3 |pages=392–9 |year=2002 |pmid=11882761 |doi=10.1097/00000658-200203000-00011}}</ref><ref>{{cite journal |author=Callery M, Strasberg S, Doherty G, Soper N, Norton J |title=Staging laparoscopy with laparoscopic ultrasonography: optimizing resectability in hepatobiliary and pancreatic malignancy |journal=J Am Coll Surg |volume=185 |issue=1 |pages=33–9 |year=1997 |pmid=9208958}}</ref> Surgery is also the only curative option for cholangiocarcinoma, although it is limited to patients with early-stage disease (see below). ===Pathology=== Histologically, cholangiocarcinomas are classically well to moderately differentiated. [[Immunohistochemistry]] is useful in the diagnosis and can be used to differentiate a cholangiocarcinoma primary tumour from metastasis of most other gastrointestinal tumours.<ref>{{cite journal |author=Länger F, von Wasielewski R, Kreipe HH |title=[The importance of immunohistochemistry for the diagnosis of cholangiocarcinomas] |language=German |journal=Pathologe |volume=27 |issue=4 |pages=244–50 |year=2006 |pmid=16758167 |doi=10.1007/s00292-006-0836-z}}</ref> Cytological scrappings are often non-diagnostic.<ref>Darwin PE, Kennedy A. Cholangiocarcinoma. eMedicine.com. URL: [http://www.emedicine.com/med/topic343.htm http://www.emedicine.com/med/topic343.htm]. Accessed on: May 5, 2007.</ref> ==Staging== Although there are at least 3 [[cancer staging|staging systems]] for cholangiocarcinoma (e.g. Bismuth, Blumgart, [[American Joint Committee on Cancer]]) none have been shown to be useful in predicting survival.<ref>{{cite journal |author=Zervos E, Osborne D, Goldin S, Villadolid D, Thometz D, Durkin A, Carey L, Rosemurgy A |title=Stage does not predict survival after resection of hilar cholangiocarcinomas promoting an aggressive operative approach |journal=Am J Surg |volume=190 |issue=5 |pages=810–5 |year=2005 |pmid=16226963 |doi=10.1016/j.amjsurg.2005.07.025}}</ref> The most important staging issue is whether the tumor can be [[resection|surgically removed]], or whether it is too advanced or invasive for surgical treatment. Often, this determination can only be made at the time of surgery.<ref name="feldman"/> General guidelines for operability include:<ref>{{cite journal |author=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 |title=Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience |journal=Ann Surg |volume=232 |issue=2 |pages=166–74 |year=2000 |pmid=10903592 |doi=10.1097/00000658-200008000-00003}}</ref><ref>{{cite journal |author=Rajagopalan V, Daines W, Grossbard M, Kozuch P |title=Gallbladder and biliary tract carcinoma: A comprehensive update, Part 1 |journal=Oncology (Williston Park) |volume=18 |issue=7 |pages=889–96 |year=2004 |pmid=15255172}}</ref> *Absence of [[lymph node]] or liver [[metastasis|metastases]] *Absence of involvement of the [[hepatic portal vein|portal vein]] *Absence of direct invasion of adjacent organs *Absence of widespread metastatic disease ==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<ref>{{cite journal |author=Yamamoto M, Takasaki K, Yoshikawa T |title="Lymph Node Metastasis in Intrahepatic Cholangiocarcinoma |journal=Japanese Journal of Clinical Oncology |volume=29 |issue=3 |pages=147–150 |year=1999 |doi=10.1093/jjco/29.3.147 |pmid=10225697}}</ref>, and less than 5% in general<ref>{{cite journal |author=Farley D, Weaver A, Nagorney D |title="Natural history" of unresected cholangiocarcinoma: patient outcome after noncurative intervention |journal=Mayo Clin Proc |volume=70 |issue=5 |pages=425–9 |year=1995 |pmid=7537346}}</ref>. Overall median duration of survival is less than 6 months<ref>{{cite journal |author= Grove MK, Hermann RE, Vogt DP, Broughan TA |title="Role of radiation after operative palliation in cancer of the proximal bile ducts" |journal=Am J Surg |volume=161 pages=454-458 |year=1991}}</ref> 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%&ndash;25%, although one series reported a [[five year survival rate|five year survival]] of 54% for patients with no involvement of the [[lymph node]]s.<ref>Studies of surgical outcomes in distal cholangiocarcinoma include: *{{cite journal |author=Nakeeb A, Pitt H, Sohn T, Coleman J, Abrams R, Piantadosi S, Hruban R, Lillemoe K, Yeo C, Cameron J |title=Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors |journal=Ann Surg |volume=224 |issue=4 |pages=463–73; discussion 473–5 |year=1996 |pmid=8857851 |doi=10.1097/00000658-199610000-00005}} *{{cite journal |author=Nagorney D, Donohue J, Farnell M, Schleck C, Ilstrup D |title=Outcomes after curative resections of cholangiocarcinoma |journal=Arch Surg |volume=128 |issue=8 |pages=871–7; discussion 877–9 |year=1993 |pmid=8393652}} *{{cite journal |author=Jang J, Kim S, Park D, Ahn Y, Yoon Y, Choi M, Suh K, Lee K, Park Y |title=Actual long-term outcome of extrahepatic bile duct cancer after surgical resection |journal=Ann Surg |volume=241 |issue=1 |pages=77–84 |year=2005 |pmid=15621994}} *{{cite journal |author=Bortolasi L, Burgart L, Tsiotos G, Luque-De León E, Sarr M |title=Adenocarcinoma of the distal bile duct. A clinicopathologic outcome analysis after curative resection |journal=Dig Surg |volume=17 |issue=1 |pages=36–41 |year=2000 |pmid=10720830 |doi=10.1159/000018798}} *{{cite journal |author=Fong Y, Blumgart L, Lin E, Fortner J, Brennan M |title=Outcome of treatment for distal bile duct cancer |journal=Br J Surg |volume=83 |issue=12 |pages=1712–5 |year=1996 |pmid=9038548 |doi=10.1002/bjs.1800831217}}</ref> Intrahepatic cholangiocarcinomas (those arising from the bile ducts within the [[liver]]) are usually treated with [[hepatectomy|partial hepatectomy]]. Various series have reported survival estimates after surgery ranging from 22%&ndash;66%; the outcome may depend on involvement of lymph nodes and completeness of the surgery.<ref>Studies of outcome in intrahepatic cholangiocarcinoma include: *{{cite journal |author=Nakeeb A, Pitt H, Sohn T, Coleman J, Abrams R, Piantadosi S, Hruban R, Lillemoe K, Yeo C, Cameron J |title=Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors |journal=Ann Surg |volume=224 |issue=4 |pages=463–73; discussion 473–5 |year=1996 |pmid=8857851 |doi=10.1097/00000658-199610000-00005}} *{{cite journal |author=Lieser M, Barry M, Rowland C, Ilstrup D, Nagorney D |title=Surgical management of intrahepatic cholangiocarcinoma: a 31-year experience |journal=J Hepatobiliary Pancreat Surg |volume=5 |issue=1 |pages=41–7 |year=1998 |pmid=9683753 |doi=10.1007/PL00009949}} *{{cite journal |author=Valverde A, Bonhomme N, Farges O, Sauvanet A, Flejou J, Belghiti J |title=Resection of intrahepatic cholangiocarcinoma: a Western experience |journal=J Hepatobiliary Pancreat Surg |volume=6 |issue=2 |pages=122–7 |year=1999 |pmid=10398898 |doi=10.1007/s005340050094}} *{{cite journal |author=Nakagohri T, Asano T, Kinoshita H, Kenmochi T, Urashima T, Miura F, Ochiai T |title=Aggressive surgical resection for hilar-invasive and peripheral intrahepatic cholangiocarcinoma |journal=World J Surg |volume=27 |issue=3 |pages=289–93 |year=2003 |pmid=12607053 |doi=10.1007/s00268-002-6696-7}} *{{cite journal |author=Weber S, Jarnagin W, Klimstra D, DeMatteo R, Fong Y, Blumgart L |title=Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes |journal=J Am Coll Surg |volume=193 |issue=4 |pages=384–91 |year=2001 |pmid=11584966 |doi=10.1016/S1072-7515(01)01016-X}}</ref> 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 [[cholecystectomy|removal of the gallbladder]] and potentially part of the liver. In patients with operable perihilar tumors, reported 5-year survival rates range from 20%&ndash;50%.<ref>Estimates of survival after surgery for perihilar cholangiocarcinoma include: *{{cite journal |author=Burke E, Jarnagin W, Hochwald S, Pisters P, Fong Y, Blumgart L |title=Hilar Cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system |journal=Ann Surg |volume=228 |issue=3 |pages=385–94 |year=1998 |pmid=9742921 |doi=10.1097/00000658-199809000-00011}} *{{cite journal |author=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 |title=Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience |journal=Ann Surg |volume=232 |issue=2 |pages=166–74 |year=2000 |pmid=10903592 |doi=10.1097/00000658-200008000-00003}} *{{cite journal |author=Chamberlain R, Blumgart L |title=Hilar cholangiocarcinoma: a review and commentary |journal=Ann Surg Oncol |volume=7 |issue=1 |pages=55–66 |year= 2000|pmid=10674450 |doi=10.1007/s10434-000-0055-4}} *{{cite journal |author=Washburn W, Lewis W, Jenkins R |title=Aggressive surgical resection for cholangiocarcinoma |journal=Arch Surg |volume=130 |issue=3 |pages=270–6 |year=1995 |pmid=7534059}} *{{cite journal |author=Nagino M, Nimura Y, Kamiya J, Kanai M, Uesaka K, Hayakawa N, Yamamoto H, Kondo S, Nishio H |title=Segmental liver resections for hilar cholangiocarcinoma |journal=Hepatogastroenterology |volume=45 |issue=19 |pages=7–13 |year= |pmid=9496478}} *{{cite journal |author=Rea D, Munoz-Juarez M, Farnell M, Donohue J, Que F, Crownhart B, Larson D, Nagorney D |title=Major hepatic resection for hilar cholangiocarcinoma: analysis of 46 patients |journal=Arch Surg |volume=139 |issue=5 |pages=514–23; discussion 523–5 |year=2004 |pmid=15136352 |doi=10.1001/archsurg.139.5.514}} *{{cite journal |author=Launois B, Reding R, Lebeau G, Buard J |title=Surgery for hilar cholangiocarcinoma: French experience in a collective survey of 552 extrahepatic bile duct cancers |journal=J Hepatobiliary Pancreat Surg |volume=7 |issue=2 |pages=128–34 |year=2000 |pmid=10982604 |doi=10.1007/s005340050166}}</ref> 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.<ref name="autopsy"/><ref>{{cite journal |author=Kaya M, de Groen P, Angulo P, Nagorney D, Gunderson L, Gores G, Haddock M, Lindor K |title=Treatment of cholangiocarcinoma complicating primary sclerosing cholangitis: the Mayo Clinic experience |journal=Am J Gastroenterol |volume=96 |issue=4 |pages=1164–9 |year=2001 |pmid=11316165 |doi=10.1111/j.1572-0241.2001.03696.x}}</ref> Some evidence suggests that outcomes may be improving with more aggressive surgical approaches and [[adjuvant#oncology|adjuvant therapy]].<ref>{{cite journal |author=Nakeeb A, Tran K, Black M, Erickson B, Ritch P, Quebbeman E, Wilson S, Demeure M, Rilling W, Dua K, Pitt H |title=Improved survival in resected biliary malignancies |journal=Surgery |volume=132 |issue=4 |pages=555–63; discission 563–4 |year=2002 |pmid=12407338 |doi=10.1067/msy.2002.127555}}</ref> ==Treatment== Cholangiocarcinoma is considered to be an incurable and rapidly lethal disease unless all the tumors can be fully [[resection|resected]] (that is, cut out surgically). Since the operability of the tumor can only be assessed during surgery in most cases,<ref>{{cite journal |author=Su C, Tsay S, Wu C, Shyr Y, King K, Lee C, Lui W, Liu T, P'eng F |title=Factors influencing postoperative morbidity, mortality, and survival after resection for hilar cholangiocarcinoma |journal=Ann Surg |volume=223 |issue=4 |pages=384–94 |year=1996 |pmid=8633917 |doi=10.1097/00000658-199604000-00007}}</ref> a majority of patients undergo exploratory surgery unless there is already a clear-cut indication that the tumor is inoperable.<ref name="feldman"/> Adjuvant therapy followed by [[liver transplantation]] may have a role in treatment of certain unresectable cases.<ref> Heimbach JK, Gores GJ, Haddock MG, et al, Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma, Transplantation. 2006 Dec 27;82(12):1703-7.</ref> ===Adjuvant chemotherapy and radiation therapy=== If the tumor can be removed surgically, patients may receive [[adjuvant#oncology|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 [[excision|excised]]), adjuvant therapy is of uncertain benefit. Both positive<ref>{{cite journal |author=Todoroki T, Ohara K, Kawamoto T, Koike N, Yoshida S, Kashiwagi H, Otsuka M, Fukao K |title=Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma |journal=Int J Radiat Oncol Biol Phys |volume=46 |issue=3 |pages=581–7 |year=2000 |pmid=10701737}}</ref><ref>{{cite journal |author=Alden M, Mohiuddin M |title=The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer |journal=Int J Radiat Oncol Biol Phys |volume=28 |issue=4 |pages=945–51 |year=1994 |pmid=8138448}}</ref> and negative<ref name="nakeeb"/><ref>{{cite journal |author=González González D, Gouma D, Rauws E, van Gulik T, Bosma A, Koedooder C |title=Role of radiotherapy, in particular intraluminal brachytherapy, in the treatment of proximal bile duct carcinoma |journal=Ann Oncol |volume=10 Suppl 4 |issue= |pages=215–20 |year= |pmid=10436826}}</ref><ref>{{cite journal |author=Pitt H, Nakeeb A, Abrams R, Coleman J, Piantadosi S, Yeo C, Lillemore K, Cameron J |title=Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival |journal=Ann Surg |volume=221 |issue=6 |pages=788–97; discussion 797–8 |year=1995 |pmid=7794082 |doi=10.1097/00000658-199506000-00017}}</ref> results have been reported with adjuvant radiation therapy in this setting, and no prospective [[randomized controlled trial]]s have been conducted as of March 2007. Adjuvant chemotherapy appears to be ineffective in patients with completely resected tumors.<ref>{{cite journal |author=Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, Nagakawa T, Nakayama T |title=Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma |journal=Cancer |volume=95 |issue=8 |pages=1685–95 |year=2002 |pmid=12365016 |doi=10.1002/cncr.10831}}</ref> 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.<ref name="nccn">{{PDFlink|[http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf National Comprehensive Cancer Network (NCCN) guidelines on evaluation and treatment of hepatobiliary malignancies]|216&nbsp;KB}}. Accessed [[March 13]] [[2007]].</ref> ===Treatment of advanced disease=== The majority of cases of cholangiocarcinoma present as inoperable (unresectable) disease<ref>{{cite journal |author=Vauthey J, Blumgart L |title=Recent advances in the management of cholangiocarcinomas |journal=Semin. Liver Dis. |volume=14 |issue=2 |pages=109–14 |year=1994 |pmid=8047893}}</ref> in which case patients are generally treated with [[palliation|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.<ref>{{cite journal |author=Glimelius B, Hoffman K, Sjödén P, Jacobsson G, Sellström H, Enander L, Linné T, Svensson C |title=Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer |journal=Ann Oncol |volume=7 |issue=6 |pages=593–600 |year=1996 |pmid=8879373}}</ref> There is no single chemotherapy regimen which is universally used, and enrollment in [[clinical trial]]s is often recommended when possible.<ref name="nccn"/> Chemotherapy agents used to treat cholangiocarcinoma include [[5-fluorouracil]] with [[leucovorin]],<ref>{{cite journal |author=Choi C, Choi I, Seo J, Kim B, Kim J, Kim C, Um S, Kim J, Kim Y |title=Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas |journal=Am J Clin Oncol |volume=23 |issue=4 |pages=425–8 |year=2000 |pmid=10955877 |doi=10.1097/00000421-200008000-00023}}</ref> [[gemcitabine]] as a single agent,<ref>{{cite journal |author=Park J, Oh S, Kim S, Kwon H, Kim J, Jin-Kim H, Kim Y |title=Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study |journal=Jpn J Clin Oncol |volume=35 |issue=2 |pages=68–73 |year=2005 |pmid=15709089 |doi=10.1093/jjco/hyi021}}</ref> or gemcitabine plus [[cisplatin]],<ref>{{cite journal |author=Giuliani F, Gebbia V, Maiello E, Borsellino N, Bajardi E, Colucci G |title=Gemcitabine and cisplatin for inoperable and/or metastatic biliary tree carcinomas: a multicenter phase II study of the Gruppo Oncologico dell'Italia Meridionale (GOIM) |journal=Ann Oncol |volume=17 Suppl 7 |issue= |pages=vii73-vii77 |year= |pmid=16760299}}</ref> [[irinotecan]],<ref>{{cite journal |author=Bhargava P, Jani C, Savarese D, O'Donnell J, Stuart K, Rocha Lima C |title=Gemcitabine and irinotecan in locally advanced or metastatic biliary cancer: preliminary report |journal=Oncology (Williston Park) |volume=17 |issue=9 Suppl 8 |pages=23–6 |year=2003 |pmid=14569844}}</ref> or [[capecitabine]].<ref>{{cite journal |author=Knox J, Hedley D, Oza A, Feld R, Siu L, Chen E, Nematollahi M, Pond G, Zhang J, Moore M |title=Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial |journal=J Clin Oncol |volume=23 |issue=10 |pages=2332–8 |year=2005 |pmid=15800324 |doi=10.1200/JCO.2005.51.008}}</ref> A small pilot study suggested possible benefit from the [[tyrosine kinase]] inhibitor [[erlotinib]] in patients with advanced cholangiocarcinoma.<ref>{{cite journal |author=Philip P, Mahoney M, Allmer C, Thomas J, Pitot H, Kim G, Donehower R, Fitch T, Picus J, Erlichman C |title=Phase II study of erlotinib in patients with advanced biliary cancer |journal=J Clin Oncol |volume=24 |issue=19 |pages=3069–74 |year=2006 |pmid=16809731 |doi=10.1200/JCO.2005.05.3579}}</ref> [[Photodynamic therapy]], an experimental approach in which patients are injected with a light-sensitizing agent and light is then applied [[endoscopy|endoscopically]] directly to the tumor, has shown promising results compared to supportive care in two small [[randomized controlled trial]]s. However, its ultimate role in the management of cholangiocarcinoma is unclear at present.<ref>{{cite journal |author=Ortner M, Caca K, Berr F, Liebetruth J, Mansmann U, Huster D, Voderholzer W, Schachschal G, Mössner J, Lochs H |title=Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study |journal=Gastroenterology |volume=125 |issue=5 |pages=1355–63 |year=2003 |pmid=14598251 |doi=10.1016/j.gastro.2003.07.015}}</ref><ref>{{cite journal |author=Zoepf T, Jakobs R, Arnold J, Apel D, Riemann J |title=Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy |journal=Am J Gastroenterol |volume=100 |issue=11 |pages=2426–30 |year=2005 |pmid=16279895 |doi=10.1111/j.1572-0241.2005.00318.x}}</ref> ==Notes== {{reflist|2}} ==External links== * [http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=69 American Cancer Society Detailed Guide to Bile Duct Cancer]. * [http://www.cancer.gov/cancertopics/pdq/treatment/bileduct/Patient/ Patient information on extrahepatic bile duct tumors], from the [[National Cancer Institute]]. * [http://www.cholangiocarcinoma.org/ The Cholangiocarcinoma Foundation]: a resource for patients, friends, caregivers and loved ones. {{Digestive system neoplasia}} {{Tumor morphology}} {{Featured article}} [[Category:Hepatology]] [[Category:Oncology]] [[Category:Types of cancer]] [[Category:Rare cancers]] [[Category:Rare diseases]] [[Category:Gastroenterology]] [[de:Gallengangskarzinom]] [[es:Colangiocarcinoma]] [[fr:Cholangiocarcinome]] [[ja:胆管癌]] [[pl:Rak przewodów żółciowych]]