Introduction
Background
Cholangiocarcinoma is a slow-growing malignancy of the bile duct. It is the second most common primary hepatic tumor after hepatoma. The cause of bile duct cancer is unclear. Results of some epidemiologic studies have implicated bacteria-induced carcinogens derived from bile salts (eg, lithocholate) as a causative factor in the pathogenesis of cholangiocarcinomas. Biliary ductal calculi occur in 20-50% of patients with cholangiocarcinoma; however, the association of gallstones with cholangiocarcinoma is less marked than it is with carcinoma of the gallbladder. The most common cause of malignant biliary obstruction is pancreatic adenocarcinoma. Gallbladder carcinoma is 9 times more common than bile duct malignancy.
High-risk groups for cholangiocarcinomas include patients with the following:
- Parasitic diseases of the biliary tract with either Clonorchis sinensis or Opisthorchis viverrini infestation (C sinensis infestation is the most common cause worldwide.)
- Congenital choledochal cysts
- Inflammatory bowel disease (The risk increases 10 times. The incidence of cholangiocarcinomas in patients with ulcerative colitis is 0.4-1.4%, with a latent period of 15 y.)
- Primary sclerosing cholangitis (10% of cases)
- History of other malignancy (10% of cases)
- Previous surgery for choledochal cyst or biliary atresia
- Alpha1-antitrypsin deficiency
- Autosomal dominant polycystic kidney disease
- Gallstones (20-50% of cases, probably coincidental)
- Papillomatosis of the bile ducts
- Thorotrast exposure
- Chronic typhoid carrier status
Recent studies
According to Singal et al, the incidence of cholangiocarcinoma is rising and accurate predictors of survival at diagnosis are not well defined. The authors therefore reviewed the records of 136 patients with cholangiocarcinoma (79 intrahepatic and 57 extrahepatic) to help clarify the clinical presentation and prognostic factors in these patients. In their study, the median survival was 27.3-25.8 months for intrahepatic cholangiocarcinoma and 30.3 months for extrahepatic cholangiocarcinoma. Independent predictors of mortality at presentation were elevated bilirubin level, CA 19-9 levels greater than 100 U/mL, and the stage of disease. Surgical therapy was associated with improved survival for both tumors, but survival was generally poor, with no significant difference in outcomes between intrahepatic and extrahepatic cholangiocarcinoma.1
Guglielmi et al evaluated the surgical outcomes of 95 patients with intrahepatic (33 patients) and extrahepatic (62 patients) cholangiocarcinoma and found that overall median survival was 24 months, with a 3-year survival rate of 45% and a 5-year survival rate of 23%. Prognostic factors for survival were macroscopic types of the tumor, the resection of extrahepatic bile duct, radical resection, lymph node metastases, and macrovascular invasion. The 5-year survival rate for intrahepatic cholangiocarcinoma was 26% and for extrahepatic cholangiocarcinoma 13%. Patients with extrahepatic cholangiocarcinoma had a higher frequency of negative clinicopathologic factors, such as nonradical resection, perineural infiltration, and macrovascular invasion.2
Pathophysiology
Origin
Most of the tumors are adenocarcinomas originating from the biliary epithelium. The tumors can be nodular or diffuse (sclerosing scirrhous tumor). All cholangiocarcinomas grow slowly, infiltrate locally, and metastasize late in the course of the disease.
Classification
The tumors are classified as extrahepatic tumors (87-92%) or intrahepatic tumors (8-13%).3
Extrahepatic tumors are divided into proximal, middle, and distal ductal tumors. Tumors located at the confluence of the right and left hepatic ducts with the proximal common hepatic duct are called Klatskin tumors.
Intrahepatic tumors arise from the small ducts and are often diffuse and multicentric; satellite nodules occur in about 65% of patients. Solitary well-demarcated tumors are difficult to differentiate from primary hepatocellular carcinomas (HCCs). The diffuse sclerosing or scirrhous types are densely fibrotic and have annular long strictures. Compared with other tumors, they are less cellular and have relatively few well-differentiated carcinoma cells in a dense connective tissue stroma. They are generally confined to the proximal ducts. The nodular variety is also called the papillary type. The tumors are nodular on the intraluminal and extraluminal surfaces, and they form irregular strictures. They are most common in the distal duct and in the periampullary region. The papillary tumors are friable and vascular and tend to bleed easily, causing hemobilia.
Intrahepatic tumors have a special predilection for perineural spread. Hematogenous spread to the liver, peritoneum, or lung is extremely rare. Lymphatic spread is common and occurs in the cystic and common bile duct (CBD) nodes in about 32% of extrahepatic tumors and 15% of intrahepatic tumors. Extrahepatic tumors also spread to the celiac nodes in about 16% of cases and to the peripancreatic and superior mesenteric nodes. Infiltration of adjacent liver occurs in 23% of cases, and peritoneal seeding occurs in 9%.
Frequency
United States
Primary cancers of the liver and intrahepatic bile ducts account for only 1.5% of all cancers in the United States. Five-year survival rates are low in the United States, usually less than 10%. About 20% of liver cancers involve cholangiocarcinoma arising from the intrahepatic branches of the ductal system.
International
Cholangiocarcinoma is associated with C sinensis infestation, which is by far the most common cause worldwide. The prevalence of biliary tract and gallbladder cancer in England and Wales is 2.8 cases per 100,000 in females and 2.0 cases per 100,000 in males.
Mortality/Morbidity
Less than 20% of intrahepatic tumors are resectable. Distal and periampullary extrahepatic tumors are resectable, with a 5-year survival rate of 39%. The reported 5-year survival rate in patients with resected proximal tumors is 5-15%.
- Most patients die within a year of diagnosis.
- Recurrence of cholangiocarcinoma after liver transplantation is common.
Race
No specific race-related increase in prevalence exists, although the incidence in the Far Eastern countries is increased. This difference is related to dietary habits, notably the consumption of improperly cooked seafood contaminated with parasites.
Sex
In contrast to gallbladder carcinoma, cholangiocarcinoma has a male preponderance, with a male-to-female ratio of 3:2.
Age
The patient's age at presentation may vary, but the incidence peaks in those in the 50s.
- Intrahepatic cholangiocarcinoma occurs in those aged 50-60 years.
- Extrahepatic cholangiocarcinoma occurs in those aged 60-70 years.
Anatomy
The right and left hepatic ducts merge to form the common hepatic duct. The right and left hepatic ducts drain bile from their respective lobes of liver. The cystic duct insertion point marks the end of the common hepatic duct. The duct below the level of the cystic duct is referred to as CBD. The vaterian segment includes the distal 2.5-3.0 cm of the CBD, along with the distal part of the pancreatic duct and the ampulla.
Tumor involves only the left or right hepatic duct in 8-13% of cases, whereas tumor involves the confluence of the ducts (Klatskin tumor) in 10-26%. Tumor involves the common hepatic duct in 14-37% of cases. Cholangiocarcinoma involves the proximal CBD in 15-30% of cases and the distal CBD in 30-50%. Cystic duct cholangiocarcinoma occurs in 6% of cases.
Presentation
Intrahepatic tumors may cause abdominal pain, palpable masses, weight loss, and painless jaundice. Abdominal pain is the most common symptom; it is a feature in 47% of cases, whereas painless jaundice occurs in only 12%. Obstructive jaundice occurs in 90% of cholangiocarcinomas and is progressive with pruritus and anorexia. The duration of symptoms is usually short (ie, months). Some patients may have cholangitis or acute cholecystitis.
Patients may have chronic blood loss due to papillary tumors and resultant anemia. Physical examination reveals hepatomegaly, and a mass is palpable in about 18% of patients. The gallbladder may be palpable in patients with distal tumors.
Preferred Examination
The first-line investigation in a patient with jaundice or right upper quadrant pain is ultrasonography (US). Biliary ductal dilatation is easily demonstrated with US, but the tumor mass is seldom localized with it.4,5
CT may demonstrate the tumor if the malignancy is nodular and masslike, but tumors of the diffuse sclerosing variety are difficult to detect.
Compared with the other techniques, endoscopic retrograde cholangiopancreatography (ERCP) is a more definitive investigation that can depict the periampullary tumor. However, with the advent of magnetic resonance cholangiopancreatography (MRCP), easy demonstration of stricture-causing tumors is possible. The disadvantages of MRCP are its inability to distend the duct and the equivocal findings due to long segments and minimal narrowing in diffuse sclerosing tumors. Celiac-axis arteriography is required to assess the vascular supply and the potential for resectability.
MR angiography has shown some promising results, with a sensitivity similar to that of conventional angiography in demonstrating the mesenteric circulation.
The role of endoscopic and intraductal US in the management of these tumors is yet to be defined. Furthermore, determination of the preferred examination is complex in the presence of a predisposing condition such as primary sclerosing cholangitis (PSC). Recent findings have demonstrated the potential role of positron emission tomography (PET), which improves the depiction of cholangiocarcinoma superimposed on PSC.
Differential Diagnoses
| Biliary Tract, Percutaneous Intervention | Hepatic Adenoma |
| Cavernous Hemangioma, Liver | Hepatocellular Carcinoma |
| Cholangitis, Primary Sclerosing | |
| Cholangitis, Recurrent Pyogenic | |
| Focal Nodular Hyperplasia |
Other Problems to Be Considered
Infections involving the bile ducts (eg, tuberculosis) are rare, but they may cause strictures with portal lymphadenopathy that simulates findings in cholangiocarcinoma.
More on Cholangiocarcinoma |
 Overview: Cholangiocarcinoma |
| Imaging: Cholangiocarcinoma |
| Follow-up: Cholangiocarcinoma |
| References |
| Further Reading |
| Next Page » |
References
Singal AG, Rakoski MO, Salgia R, Pelletier S, Welling TH, Fontana RJ, et al. The clinical presentation and prognostic factors for intrahepatic and extrahepatic cholangiocarcinoma in a tertiary care centre. Aliment Pharmacol Ther. Mar 2010;31(6):625-33. [Medline].
Guglielmi A, Ruzzenente A, Campagnaro T, Pachera S, Valdegamberi A, Capelli P, et al. Does intrahepatic cholangiocarcinoma have better prognosis compared to perihilar cholangiocarcinoma?. J Surg Oncol. Feb 1 2010;101(2):111-5. [Medline].
Nathan H, Pawlik TM. Staging of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol. Feb 22 2010;[Medline].
Gakhal MS, Gheyi VK, Brock RE, Andrews GS. Multimodality imaging of biliary malignancies. Surg Oncol Clin N Am. Apr 2009;18(2):225-39. [Medline].
Ariff B, Lloyd CR, Khan S, Shariff M, Thillainayagam AV, Bansi DS, et al. Imaging of liver cancer. World J Gastroenterol. Mar 21 2009;15(11):1289-300. [Medline].
Senda Y, Nishio H, Oda K, Yokoyama Y, Ebata T, Igami T, et al. Value of Multidetector Row CT in the Assessment of Longitudinal Extension of Cholangiocarcinoma-Correlation Between MDCT and Microscopic Findings. World J Surg. Apr 19 2009;[Medline].
Keiding S, Hansen SB, Rasmussen HH. Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography. Hepatology. Sep 1998;28(3):700-6. [Medline].
Singal A, Welling TH, Marrero JA. Role of liver transplantation in the treatment of cholangiocarcinoma. Expert Rev Anticancer Ther. Apr 2009;9(4):491-502. [Medline].
Rea DJ, Rosen CB, Nagorney DM, Heimbach JK, Gores GJ. Transplantation for cholangiocarcinoma: when and for whom?. Surg Oncol Clin N Am. Apr 2009;18(2):325-37. [Medline].
Speer AG, Cotton PB, Russell RC. Randomised trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice. Lancet. Jul 11 1987;2(8550):57-62.
Bloom CM, Langer B, Wilson SR. Role of US in the detection, characterization, and staging of cholangiocarcinoma. Radiographics. Sep-Oct 1999;19(5):1199-218. [Medline].
Davids PH, Groen AK, Rauws EA. Randomised trial of self-expanding metal stents versus polyethylene stents for distal malignant biliary obstruction. Lancet. Dec 19-26 1992;340(8834-8835):1488-92. [Medline].
Dick BW, Gordon RL, LaBerge JM. Percutaneous transhepatic placement of biliary endoprostheses: results in 100 consecutive patients. J Vasc Interv Radiol. Nov 1990;1(1):97-100. [Medline].
Ferrucci JT. MRI and MRCP in pancreaticobiliary malignancy. Ann Oncol. 1999;10 Suppl 4:18-9. [Medline].
Gordon RL, Ring EJ, LaBerge JM. Malignant biliary obstruction: treatment with expandable metallic stents--follow-up of 50 consecutive patients. Radiology. Mar 1992;182(3):697-701. [Medline].
Herbener T, Zajko AB, Koneru B. Recurrent cholangiocarcinoma in the biliary tree after liver transplantation. Radiology. Dec 1988;169(3):641-2. [Medline].
Loyer EM, Chin H, DuBrow RA. Hepatocellular carcinoma and intrahepatic peripheral cholangiocarcinoma: enhancement patterns with quadruple phase helical CT--a comparative study. Radiology. Sep 1999;212(3):866-75. [Medline].
Miller BA, Kolonel LN, Bernstein L, et al. Racial/Ethnic Patterns of Cancer in the United States 1988-1992. NIH publications 96-4104. Bethesda, Md: National Cancer Institute;1996.
Shapiro MJ. Management of malignant biliary obstruction: nonoperative and palliative techniques. Oncology (Huntingt). Jun 1995;9(6):493-6, 499; discussion 499-500, 503. [Medline].
Smits NJ, Reeders JW. Imaging and staging of biliopancreatic malignancy: role of ultrasound. Ann Oncol. 1999;10 Suppl 4:20-4. [Medline].
Tamada K, Tomiyama T, Ohashi A. Preoperative assessment of extrahepatic bile duct carcinoma using three- dimensional intraductal US. Gastrointest Endosc. Oct 1999;50(4):548-54. [Medline].
Vilgrain V, Van Beers BE, Flejou JF. Intrahepatic cholangiocarcinoma: MRI and pathologic correlation in 14 patients. J Comput Assist Tomogr. Jan-Feb 1997;21(1):59-65. [Medline].
Further Reading
Related eMedicine topics
Cholangiocarcinoma (from Oncology)
Bile Duct Tumors
Gallbladder Tumors
Gallbladder, Carcinoma
Hepatic Carcinoma, Primary
Clinical guidelines
The Role of Gemcitabine in the Treatment of Cholangiocarcinoma and Gallbladder Cancer
Role of Endoscopy in the Evaluation and Treatment of Patients With Pancreaticobiliary Malignancy
Clinical trials
S-1 and Photodynamic Therapy in Cholangiocarcinoma
Liver Transplantation for Cholangiocarcinoma: An Effective Therapy
Keywords
cholangiocarcinoma, malignant bile duct tumors, biliary malignancy, primary hepatic tumors, bile duct cancer, intrahepatic tumors, extrahepatic tumors, Klatskin tumors, liver cancer, Clonorchis sinensis, C sinensis, Opisthorchis viverrini, Opisthorchis viverrini
