Cholangiocarcinoma Explained

Cholangiocarcinoma
Synonyms:Bile duct cancer, cancer of the bile duct
Field:Oncology
Symptoms:Abdominal pain, yellowish skin, weight loss, generalized itching, fever
Onset:70 years old
Types:Intrahepatic, perihilar, distal
Risks:Primary sclerosing cholangitis, ulcerative colitis, infection with certain liver flukes, some congenital liver malformations
Diagnosis:Confirmed by examination of the tumor under a microscope
Treatment:Surgical resection, chemotherapy, radiation therapy, stenting procedures, liver transplantation
Prognosis:Generally poor
Frequency:1–2 people per 100,000 per year (Western world)

Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts.[1] Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever.[2] Light colored stool or dark urine may also occur. Other biliary tract cancers include gallbladder cancer and cancer of the ampulla of Vater.[3]

Risk factors for cholangiocarcinoma include primary sclerosing cholangitis (an inflammatory disease of the bile ducts), ulcerative colitis, cirrhosis, hepatitis C, hepatitis B, infection with certain liver flukes, and some congenital liver malformations.[2] [4] However, most people have no identifiable risk factors. The diagnosis is suspected based on a combination of blood tests, medical imaging, endoscopy, and sometimes surgical exploration. The disease is confirmed by examination of cells from the tumor under a microscope.[5] It is typically an adenocarcinoma (a cancer that forms glands or secretes mucin).

Cholangiocarcinoma is typically incurable at diagnosis which is why early detection is ideal.[6] [2] In these cases palliative treatments may include surgical resection, chemotherapy, radiation therapy, and stenting procedures.[2] In about a third of cases involving the common bile duct and less commonly with other locations the tumor can be completely removed by surgery offering a chance of a cure.[2] Even when surgical removal is successful chemotherapy and radiation therapy are generally recommended.[2] In certain cases surgery may include a liver transplantation.[7] Even when surgery is successful the 5-year survival is typically less than 50%.

Cholangiocarcinoma is rare in the Western world, with estimates of it occurring in 0.5–2 people per 100,000 per year.[2] Rates are higher in Southeast Asia where liver flukes are common.[8] Rates in parts of Thailand are 60 per 100,000 per year.[8] It typically occurs in people in their 70s; however, in those with primary sclerosing cholangitis it often occurs in the 40s.[7] Rates of cholangiocarcinoma within the liver in the Western world have increased.[9]

Signs and symptoms

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 the color of stool or urine.[10] To some extent, the symptoms depend upon the location of the tumor: people 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.[11]

Blood tests of liver function in people 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.[12]

Risk factors

Although most people 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 closely associated with ulcerative colitis (UC).[13] Epidemiologic studies have suggested that the lifetime risk of developing cholangiocarcinoma for a person with PSC is on the order of 10–15%,[14] although autopsy series have found rates as high as 30% in this population. For inflammatory bowel disease patients with altered DNA repair functions, the progression from PSC to cholangiocarcinoma may be a consequence of DNA damage resulting from biliary inflammation and bile acids.[15]

Certain parasitic liver diseases may be risk factors as well. Colonization with the liver flukes Opisthorchis viverrini (found in Thailand, Laos PDR, and Vietnam)[16] [17] [18] or Clonorchis sinensis (found in China, Taiwan, eastern Russia, Korea, and Vietnam)[19] [20] has been associated with the development of cholangiocarcinoma. Control programs (Integrated Opisthorchiasis Control Program) aimed at discouraging the consumption of raw and undercooked food have been successful at reducing the incidence of cholangiocarcinoma in some countries.[21] People with chronic liver disease, whether in the form of viral hepatitis (e.g. hepatitis B or hepatitis C),[22] [23] [24] alcoholic liver disease, or cirrhosis of the liver due to other causes, are at significantly increased risk of cholangiocarcinoma.[25] 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.

Infection with the bacteria Helicobacter bilis and Helicobacter hepaticus species can cause biliary cancer.[26]

Congenital liver abnormalities, such as Caroli disease (a specific type of five recognized choledochal cysts), have been associated with an approximately 15% lifetime risk of developing cholangiocarcinoma.[27] [28] The rare inherited disorders Lynch syndrome II and biliary papillomatosis have also been found to be associated with cholangiocarcinoma.[29] [30] 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.[31] [32] [33] 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.[34] [35] [36]

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.[37]

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.[38] [39] [40] 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.[41] Chronic inflammation and obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in this progression.[42] [43]

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.[44] Most tumors (>90%) are adenocarcinomas.

Diagnosis

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.[45]

Abdominal imaging

Ultrasound of the liver and biliary tree is often used as the initial imaging modality in people with suspected obstructive jaundice.[46] [47] Ultrasound can identify obstruction and ductal dilatation and, in some cases, may be sufficient to diagnose cholangiocarcinoma.[48] Computed tomography (CT) scanning may also play an important role in the diagnosis of cholangiocarcinoma.[49] [50] [51]

Imaging of the biliary tree

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.[12] 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.[52] As an alternative to ERCP, percutaneous transhepatic cholangiography (PTC) may be utilized. Magnetic resonance cholangiopancreatography (MRCP) is a non-invasive alternative to ERCP.[53] [54] [55] 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.[56] [57] [58]

Surgery

Surgical exploration may be necessary to obtain a suitable biopsy and to accurately stage a person 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 people.[59] [60]

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.[61] Cytological scrapings are often nondiagnostic,[62] 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.[63] 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.[12]

General guidelines for operability include:[64] [65]

Treatment

Cholangiocarcinoma is considered to be an incurable and rapidly lethal disease unless all the tumors can be fully resected (cut out surgically). Since the operability of the tumor can only be assessed during surgery in most cases,[66] a majority of people undergo exploratory surgery unless there is already a clear indication that the tumor is inoperable.[12] However, the Mayo Clinic has reported significant success treating early bile duct cancer with liver transplantation using a protocolized approach and strict selection criteria.[67]

Adjuvant therapy followed by liver transplantation may have a role in treatment of certain unresectable cases.[68] Locoregional therapies including transarterial chemoembolization (TACE), transarterial radioembolization (TARE) and ablation therapies have a role in intrahepatic variants of cholangiocarcinoma to provide palliation or potential cure in people who are not surgical candidates.[69]

Adjuvant chemotherapy and radiation therapy

If the tumor can be removed surgically, people 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[70] [71] and negative[11] [72] [73] 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 people with completely resected tumors.[74] [75] 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.[76] [77]

Treatment of advanced disease

The majority of cases of cholangiocarcinoma present as inoperable (unresectable) disease[78] in which case people 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 people with inoperable cholangiocarcinoma.[79] There is no single chemotherapy regimen which is universally used, and enrollment in clinical trials is often recommended when possible.[77] Chemotherapy agents used to treat cholangiocarcinoma include 5-fluorouracil with leucovorin,[80] gemcitabine as a single agent,[81] or gemcitabine plus cisplatin,[82] irinotecan,[83] or capecitabine.[84] A small pilot study suggested possible benefit from the tyrosine kinase inhibitor erlotinib in people with advanced cholangiocarcinoma.[85] Radiation therapy appears to prolong survival in people with resected extrahepatic cholangiocarcinoma,[86] and the few reports of its use in unresectable cholangiocarcinoma appear to show improved survival, but numbers are small.

Infigratinib (Truseltiq) is a tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR) that was approved for medical use in the United States in May 2021.[87] It is indicated for the treatment of people with previously treated locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or rearrangement.

Pemigatinib (Pemazyre) is a kinase inhibitor of fibroblast growth factor receptor 2 (FGFR2) that was approved for medical use in the United States in April 2020.[88] It is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

Ivodesinib (Tibsovo) is a small molecule inhibitor of isocitrate dehydrogenase 1. The FDA approved ivosidenib in August 2021 for adults with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.[89]

Durvalumab, (Imfinzi) is an immune checkpoint inhibitor that blocks the PD-L1 protein on the surface of immune cells, thereby allowing the immune system to recognize and attack tumor cells. In Phase III clinical trials, durvalumab, in combination with standard-of-care chemotherapy, demonstrated a statistically significant and clinically meaningful improvement in overall survival and progression-free survival versus chemotherapy alone as a 1st-line treatment for patients with advanced biliary tract cancer.[90]

Futibatinib (Lytgobi) was approved for medical use in the United States in September 2022.[91]

Prognosis

Surgical resection offers the only potential chance of cure in cholangiocarcinoma. For non-resectable cases, the five-year survival rate is 0% where the disease is inoperable because distal lymph nodes show metastases,[92] and less than 5% in general.[93] Overall mean duration of survival is less than 6 months in people with metastatic disease.[94]

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 to 25%, although one series reported a five-year survival of 54% for people with no involvement of the lymph nodes.[95] 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 to 66%; the outcome may depend on involvement of lymph nodes and completeness of the surgery.[96] 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 to 50%.[97]

The prognosis may be worse for people with primary sclerosing cholangitis who develop cholangiocarcinoma, likely because the cancer is not detected until it is advanced.[98] Some evidence suggests that outcomes may be improving with more aggressive surgical approaches and adjuvant therapy.[99]

Epidemiology

Age-standardized mortality rates from intrahepatic (IC) and extrahepatic (EC) cholangiocarcinoma for men and women, by country[100]
CountryIC (men/women)EC (men/women)
U.S.A.0.60/0.430.70/0.87
Japan0.23/0.105.87/5.20
Australia0.70/0.530.90/1.23
England/Wales0.83/0.630.43/0.60
Scotland1.17/1.000.60/0.73
France0.27/0.201.20/1.37
Italy0.13/0.132.10/2.60

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.[101] Autopsy series have reported a prevalence of 0.01% to 0.46%.[78] [102] 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).[103] The prevalence of cholangiocarcinoma in people with primary sclerosing cholangitis may be as high as 30%, based on autopsy studies.[104]

Multiple studies have documented a steady increase in the incidence of intrahepatic cholangiocarcinoma; increases have been seen in North America, Europe, Asia, and Australia.[105] 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.[106]

External links

Notes and References

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  19. Rustagi T, Dasanu CA . Risk factors for gallbladder cancer and cholangiocarcinoma: similarities, differences and updates . Journal of Gastrointestinal Cancer . 43 . 2 . 137–47 . June 2012 . 21597894 . 10.1007/s12029-011-9284-y . 31590872 .
  20. Hong ST, Fang Y . Clonorchis sinensis and clonorchiasis, an update . Parasitology International . 61 . 1 . 17–24 . March 2012 . 21741496 . 10.1016/j.parint.2011.06.007 .
  21. Sripa B, Tangkawattana S, Sangnikul T . The Lawa model: A sustainable, integrated opisthorchiasis control program using the EcoHealth approach in the Lawa Lake region of Thailand . Parasitology International . 66 . 4 . 346–354 . August 2017 . 27890720 . 5443708 . 10.1016/j.parint.2016.11.013 .
  22. Kobayashi M, Ikeda K, Saitoh S, Suzuki F, Tsubota A, Suzuki Y, Arase Y, Murashima N, Chayama K, Kumada H . 6 . Incidence of primary cholangiocellular carcinoma of the liver in Japanese patients with hepatitis C virus-related cirrhosis . Cancer . 88 . 11 . 2471–7 . June 2000 . 10861422 . 10.1002/1097-0142(20000601)88:11<2471::AID-CNCR7>3.0.CO;2-T . 22206944 . free .
  23. Yamamoto S, Kubo S, Hai S, Uenishi T, Yamamoto T, Shuto T, Takemura S, Tanaka H, Yamazaki O, Hirohashi K, Tanaka T . 6 . Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma . Cancer Science . 95 . 7 . 592–5 . July 2004 . 15245596 . 10.1111/j.1349-7006.2004.tb02492.x . free . 11158843 .
  24. Lu H, Ye MQ, Thung SN, Dash S, Gerber MA . Detection of hepatitis C virus RNA sequences in cholangiocarcinomas in Chinese and American patients . Chinese Medical Journal . 113 . 12 . 1138–41 . December 2000 . 11776153 .
  25. Sorensen HT, Friis S, Olsen JH, Thulstrup AM, Mellemkjaer L, Linet M, Trichopoulos D, Vilstrup H, Olsen J . 6 . Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark . Hepatology . 28 . 4 . 921–5 . October 1998 . 9755226 . 10.1002/hep.510280404 . 72842845 .
  26. Chang AH, Parsonnet J . Julie Parsonnet . Role of bacteria in oncogenesis . Clinical Microbiology Reviews . 23 . 4 . 837–57 . October 2010 . 20930075 . 2952975 . 10.1128/CMR.00012-10 . free . doi .
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  28. Dayton MT, Longmire WP, Tompkins RK . Caroli's Disease: a premalignant condition? . American Journal of Surgery . 145 . 1 . 41–8 . January 1983 . 6295196 . 10.1016/0002-9610(83)90164-2 .
  29. Mecklin JP, Järvinen HJ, Virolainen M . The association between cholangiocarcinoma and hereditary nonpolyposis colorectal carcinoma . Cancer . 69 . 5 . 1112–4 . March 1992 . 1310886 . 10.1002/cncr.2820690508 . 23468163 .
  30. Lee SS, Kim MH, Lee SK, Jang SJ, Song MH, Kim KP, Kim HJ, Seo DW, Song DE, Yu E, Lee SG, Min YI . 6 . Clinicopathologic review of 58 patients with biliary papillomatosis . Cancer . 100 . 4 . 783–93 . February 2004 . 14770435 . 10.1002/cncr.20031 . free .
  31. Lee CC, Wu CY, Chen GH . What is the impact of coexistence of hepatolithiasis on cholangiocarcinoma? . Journal of Gastroenterology and Hepatology . 17 . 9 . 1015–20 . September 2002 . 12167124 . 10.1046/j.1440-1746.2002.02779.x . 25753564 .
  32. Su CH, Shyr YM, Lui WY, P'Eng FK . Hepatolithiasis associated with cholangiocarcinoma . British Journal of Surgery . 84 . 7 . 969–73 . July 1997 . 9240138 . 10.1002/bjs.1800840717 . 29475282 . free .
  33. Donato F, Gelatti U, Tagger A, Favret M, Ribero ML, Callea F, Martelli C, Savio A, Trevisi P, Nardi G . 6 . 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 . December 2001 . 11808716 . 10.1023/A:1013747228572 . 12117363 .
  34. Sahani D, Prasad SR, Tannabe KK, Hahn PF, Mueller PR, Saini S . Thorotrast-induced cholangiocarcinoma: case report . Abdominal Imaging . 28 . 1 . 72–4 . 2003 . 12483389 . 10.1007/s00261-001-0148-y . 23531547 .
  35. Zhu AX, Lauwers GY, Tanabe KK . Cholangiocarcinoma in association with Thorotrast exposure . Journal of Hepato-Biliary-Pancreatic Surgery . 11 . 6 . 430–3 . 2004 . 15619021 . 10.1007/s00534-004-0924-5 .
  36. Lipshutz GS, Brennan TV, Warren RS . Thorotrast-induced liver neoplasia: a collective review . Journal of the American College of Surgeons . 195 . 5 . 713–8 . November 2002 . 12437262 . 10.1016/S1072-7515(02)01287-5 .
  37. Klatskin G . Adenocarcinoma of the Hepatic Duct at Its Bifurcation Within The Porta Hepatis. An Unusual Tumor With Distinctive Clinical And Pathological Features . American Journal of Medicine . 38 . 2 . 241–56 . February 1965 . 14256720 . 10.1016/0002-9343(65)90178-6 .
  38. Roskams T . Liver stem cells and their implication in hepatocellular and cholangiocarcinoma . Oncogene . 25 . 27 . 3818–22 . June 2006 . 16799623 . 10.1038/sj.onc.1209558 . free .
  39. Liu C, Wang J, Ou QJ . Possible stem cell origin of human cholangiocarcinoma . World Journal of Gastroenterology . 10 . 22 . 3374–6 . November 2004 . 15484322 . 4572317 . 10.3748/wjg.v10.i22.3374 . free .
  40. Sell S, Dunsford HA . Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma . American Journal of Pathology . 134 . 6 . 1347–63 . June 1989 . 2474256 . 1879951 .
  41. Sirica AE . Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy . Hepatology . 41 . 1 . 5–15 . January 2005 . 15690474 . 10.1002/hep.20537 . 10903371 . free .
  42. Holzinger F, Z'graggen K, Büchler MW . Mechanisms of biliary carcinogenesis: a pathogenetic multi-stage cascade towards cholangiocarcinoma . Annals of Oncology . 10 . Suppl 4 . 122–6 . 1999 . 10436802 . 10.1023/A:1008321710719 .
  43. Gores GJ . Cholangiocarcinoma: current concepts and insights . Hepatology . 37 . 5 . 961–9 . May 2003 . 12717374 . 10.1053/jhep.2003.50200 . 5441766 .
  44. de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM . Biliary tract cancers . New England Journal of Medicine . 341 . 18 . 1368–78 . October 1999 . 10536130 . 10.1056/NEJM199910283411807 .
  45. 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 . Serum and bile markers for cholangiocarcinoma . Seminars in Liver Disease . 24 . 2 . 139–54 . May 2004 . 15192787 . 10.1055/s-2004-828891 . 260316851 .
    • Siqueira E, Schoen RE, Silverman W, Martin J, Rabinovitz M, Weissfeld JL, Abu-Elmaagd K, Madariaga JR, Slivka A, Martini J . 6 . Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis . Gastrointestinal Endoscopy . 56 . 1 . 40–7 . July 2002 . 12085033 . 10.1067/mge.2002.125105 .
    • Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD . The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis . Digestive Diseases and Sciences . 50 . 9 . 1734–40 . September 2005 . 16133981 . 10.1007/s10620-005-2927-8 . 24744509 .
    • Patel AH, Harnois DM, Klee GG, LaRusso NF, Gores GJ . The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis . American Journal of Gastroenterology . 95 . 1 . 204–7 . January 2000 . 10.1111/j.1572-0241.2000.01685.x . 10638584 . 11325616 .
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  48. Bloom CM, Langer B, Wilson SR . Role of US in the detection, characterization, and staging of cholangiocarcinoma . Radiographics . 19 . 5 . 1199–218 . 1999 . 10489176 . 10.1148/radiographics.19.5.g99se081199 . free .
  49. Valls C, Gumà A, Puig I, Sanchez A, Andía E, Serrano T, Figueras J . 6 . Intrahepatic peripheral cholangiocarcinoma: CT evaluation . Abdominal Imaging . 25 . 5 . 490–6 . 2000 . 10931983 . 10.1007/s002610000079 . 12010522 .
  50. Tillich M, Mischinger HJ, Preisegger KH, Rabl H, Szolar DH . Multiphasic helical CT in diagnosis and staging of hilar cholangiocarcinoma . AJR. American Journal of Roentgenology . 171 . 3 . 651–8 . September 1998 . 9725291 . 10.2214/ajr.171.3.9725291 .
  51. Zhang Y, Uchida M, Abe T, Nishimura H, Hayabuchi N, Nakashima Y . Intrahepatic peripheral cholangiocarcinoma: comparison of dynamic CT and dynamic MRI . Journal of Computer Assisted Tomography . 23 . 5 . 670–7 . 1999 . 10524843 . 10.1097/00004728-199909000-00004 .
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  53. Schwartz LH, Coakley FV, Sun Y, Blumgart LH, Fong Y, Panicek DM . Neoplastic pancreaticobiliary duct obstruction: evaluation with breath-hold MR cholangiopancreatography . AJR. American Journal of Roentgenology . 170 . 6 . 1491–5 . June 1998 . 9609160 . 10.2214/ajr.170.6.9609160 . free .
  54. Zidi SH, Prat F, Le Guen O, Rondeau Y, Pelletier G . Performance characteristics of magnetic resonance cholangiography in the staging of malignant hilar strictures . Gut . 46 . 1 . 103–6 . January 2000 . 10601064 . 1727781 . 10.1136/gut.46.1.103 .
  55. Lee MG, Park KB, Shin YM, Yoon HK, Sung KB, Kim MH, Lee SG, Kang EM . 6 . 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 Journal of Surgery . 27 . 3 . 278–83 . March 2003 . 12607051 . 10.1007/s00268-002-6701-1 . 25092608 .
  56. Yeh TS, Jan YY, Tseng JH, Chiu CT, Chen TC, Hwang TL, Chen MF . 6 . Malignant perihilar biliary obstruction: magnetic resonance cholangiopancreatographic findings . American Journal of Gastroenterology . 95 . 2 . 432–40 . February 2000 . 10.1111/j.1572-0241.2000.01763.x . 10685746 . 25350361 .
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  64. Tsao JI, Nimura Y, Kamiya J, Hayakawa N, Kondo S, Nagino M, Miyachi M, Kanai M, Uesaka K, Oda K, Rossi RL, Braasch JW, Dugan JM . 6 . Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience . Annals of Surgery . 232 . 2 . 166–74 . August 2000 . 10903592 . 1421125 . 10.1097/00000658-200008000-00003 .
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  80. Choi CW, Choi IK, Seo JH, Kim BS, Kim JS, Kim CD, Um SH, Kim JS, Kim YH . 6 . Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas . American Journal of Clinical Oncology . 23 . 4 . 425–8 . August 2000 . 10955877 . 10.1097/00000421-200008000-00023 .
  81. Park JS, Oh SY, Kim SH, Kwon HC, Kim JS, Jin-Kim H, Kim YH . 6 . Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study . Japanese Journal of Clinical Oncology . 35 . 2 . 68–73 . February 2005 . 15709089 . 10.1093/jjco/hyi021 . free .
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  85. Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, Donehower RC, Fitch T, Picus J, Erlichman C . 6 . Phase II study of erlotinib in patients with advanced biliary cancer . Journal of Clinical Oncology . 24 . 19 . 3069–74 . July 2006 . 16809731 . 10.1200/JCO.2005.05.3579 .
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  87. BridgeBio Pharma's Affiliate QED Therapeutics and Partner Helsinn Group Announce FDA Approval of Truseltiq (infigratinib) for Patients with Cholangiocarcinoma . BridgeBio Pharma . GlobeNewswire . 28 May 2021 . 28 May 2021.
  88. Web site: 2020 . Pemazyre Prescribing Information . live . 5 March 2022 . Food and Drug Administration. https://web.archive.org/web/20200720125745/https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213736s000lbl.pdf . 20 July 2020 .
  89. Research . Center for Drug Evaluation and . 2022-02-01 . FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma . FDA . en.
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  91. FDA Approves Taiho's Lytgobi (futibatinib) Tablets for Previously Treated, Unresectable, Locally Advanced or Metastatic Intrahepatic Cholangiocarcinoma . Taiho Oncology . PR Newswire . 30 September 2022 . 4 October 2022.
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  95. Studies of surgical outcomes in distal cholangiocarcinoma include:
    • Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S, Hruban RH, Lillemoe KD, Yeo CJ, Cameron JL . 6 . Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors . Annals of Surgery . 224 . 4 . 463–73; discussion 473–5 . October 1996 . 8857851 . 1235406 . 10.1097/00000658-199610000-00005 .
    • Jang JY, Kim SW, Park DJ, Ahn YJ, Yoon YS, Choi MG, Suh KS, Lee KU, Park YH . 6 . Actual long-term outcome of extrahepatic bile duct cancer after surgical resection . Annals of Surgery . 241 . 1 . 77–84 . January 2005 . 15621994 . 1356849 . 10.1097/01.sla.0000150166.94732.88 .
    • Bortolasi L, Burgart LJ, Tsiotos GG, Luque-De León E, Sarr MG . Adenocarcinoma of the distal bile duct. A clinicopathologic outcome analysis after curative resection . Digestive Surgery . 17 . 1 . 36–41 . 2000 . 10720830 . 10.1159/000018798 . 23190342 .
    • Fong Y, Blumgart LH, Lin E, Fortner JG, Brennan MF . Outcome of treatment for distal bile duct cancer . British Journal of Surgery . 83 . 12 . 1712–5 . December 1996 . 9038548 . 10.1002/bjs.1800831217 . 30172073 .
  96. Studies of outcome in intrahepatic cholangiocarcinoma include:
    • Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S, Hruban RH, Lillemoe KD, Yeo CJ, Cameron JL . 6 . Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors . Annals of Surgery . 224 . 4 . 463–73; discussion 473–5 . October 1996 . 8857851 . 1235406 . 10.1097/00000658-199610000-00005 .
    • Lieser MJ, Barry MK, Rowland C, Ilstrup DM, Nagorney DM . Surgical management of intrahepatic cholangiocarcinoma: a 31-year experience . Journal of Hepato-Biliary-Pancreatic Surgery . 5 . 1 . 41–7 . 1998 . 9683753 . 10.1007/PL00009949 .
    • Valverde A, Bonhomme N, Farges O, Sauvanet A, Flejou JF, Belghiti J . Resection of intrahepatic cholangiocarcinoma: a Western experience . Journal of Hepato-Biliary-Pancreatic Surgery . 6 . 2 . 122–7 . 1999 . 10398898 . 10.1007/s005340050094 .
    • Nakagohri T, Asano T, Kinoshita H, Kenmochi T, Urashima T, Miura F, Ochiai T . 6 . Aggressive surgical resection for hilar-invasive and peripheral intrahepatic cholangiocarcinoma . World Journal of Surgery . 27 . 3 . 289–93 . March 2003 . 12607053 . 10.1007/s00268-002-6696-7 . 25358444 .
    • Weber SM, Jarnagin WR, Klimstra D, DeMatteo RP, Fong Y, Blumgart LH . Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes . Journal of the American College of Surgeons . 193 . 4 . 384–91 . October 2001 . 11584966 . 10.1016/S1072-7515(01)01016-X .
  97. Estimates of survival after surgery for perihilar cholangiocarcinoma include:
    • Burke EC, Jarnagin WR, Hochwald SN, Pisters PW, Fong Y, Blumgart LH . Hilar Cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system . Annals of Surgery . 228 . 3 . 385–94 . September 1998 . 9742921 . 1191497 . 10.1097/00000658-199809000-00011 .
    • Tsao JI, Nimura Y, Kamiya J, Hayakawa N, Kondo S, Nagino M, Miyachi M, Kanai M, Uesaka K, Oda K, Rossi RL, Braasch JW, Dugan JM . 6 . Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience . Annals of Surgery . 232 . 2 . 166–74 . August 2000 . 10903592 . 1421125 . 10.1097/00000658-200008000-00003 .
    • Chamberlain RS, Blumgart LH . Hilar cholangiocarcinoma: a review and commentary . Annals of Surgical Oncology . 7 . 1 . 55–66 . 2000 . 10674450 . 10.1007/s10434-000-0055-4 . 19569428 .
    • Washburn WK, Lewis WD, Jenkins RL . Aggressive surgical resection for cholangiocarcinoma . Archives of Surgery . 130 . 3 . 270–6 . March 1995 . 7534059 . 10.1001/archsurg.1995.01430030040006 .
    • Nagino M, Nimura Y, Kamiya J, Kanai M, Uesaka K, Hayakawa N, Yamamoto H, Kondo S, Nishio H . 6 . Segmental liver resections for hilar cholangiocarcinoma . Hepato-Gastroenterology . 45 . 19 . 7–13 . 1998 . 9496478 .
    • Rea DJ, Munoz-Juarez M, Farnell MB, Donohue JH, Que FG, Crownhart B, Larson D, Nagorney DM . 6 . Major hepatic resection for hilar cholangiocarcinoma: analysis of 46 patients . Archives of Surgery . 139 . 5 . 514–23; discussion 523–5 . May 2004 . 15136352 . 10.1001/archsurg.139.5.514 . free .
    • Launois B, Reding R, Lebeau G, Buard JL . Surgery for hilar cholangiocarcinoma: French experience in a collective survey of 552 extrahepatic bile duct cancers . Journal of Hepato-Biliary-Pancreatic Surgery . 7 . 2 . 128–34 . 2000 . 10982604 . 10.1007/s005340050166 .
  98. Kaya M, de Groen PC, Angulo P, Nagorney DM, Gunderson LL, Gores GJ, Haddock MG, Lindor KD . 6 . Treatment of cholangiocarcinoma complicating primary sclerosing cholangitis: the Mayo Clinic experience . American Journal of Gastroenterology . 96 . 4 . 1164–9 . April 2001 . 10.1111/j.1572-0241.2001.03696.x . 11316165 . 295347 .
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  100. Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC . Changing international trends in mortality rates for liver, biliary and pancreatic tumours . Journal of Hepatology . 37 . 6 . 806–13 . December 2002 . 12445422 . 10.1016/S0168-8278(02)00297-0 .
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  105. Multiple independent studies have documented a steady increase in the worldwide incidence of cholangiocarcinoma. Some relevant journal articles include:
    • Patel T . Worldwide trends in mortality from biliary tract malignancies . BMC Cancer . 2 . 10 . May 2002 . 11991810 . 113759 . 10.1186/1471-2407-2-10 . free .
    • Patel T . Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States . Hepatology . 33 . 6 . 1353–7 . June 2001 . 11391522 . 10.1053/jhep.2001.25087 . 23115927 .
    • Shaib YH, Davila JA, McGlynn K, El-Serag HB . Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? . Journal of Hepatology . 40 . 3 . 472–7 . March 2004 . 15123362 . 10.1016/j.jhep.2003.11.030 .
    • West J, Wood H, Logan RF, Quinn M, Aithal GP . Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971-2001 . British Journal of Cancer . 94 . 11 . 1751–8 . June 2006 . 16736026 . 2361300 . 10.1038/sj.bjc.6603127 .
    • Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC . Changing international trends in mortality rates for liver, biliary and pancreatic tumours . Journal of Hepatology . 37 . 6 . 806–13 . December 2002 . 12445422 . 10.1016/S0168-8278(02)00297-0 .
    • Welzel TM, McGlynn KA, Hsing AW, O'Brien TR, Pfeiffer RM . Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States . Journal of the National Cancer Institute . 98 . 12 . 873–5 . June 2006 . 16788161 . 10.1093/jnci/djj234 . free .
  106. Shaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA . Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study . Gastroenterology . 128 . 3 . 620–6 . March 2005 . 15765398 . 10.1053/j.gastro.2004.12.048 .

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