Cholangiocarcinomas (bile duct cancers) are malignant epithelial tumors arising from the biliary tree, excluding the gallbladder or ampulla of Vater. Cholangiocarcinoma is the second most common primary hepatobiliary malignancy after hepatocellular carcinoma (HCC). They tend to have a poor prognosis and high morbidity.
Although overall cholangiocarcinoma is rare, there are significant regional variations in incidence with much higher rates seen in south-east Asia and the Middle East 2. The incidence ranges from 0.3 to 6 per 100,000 inhabitants per year 14.
They usually present in the elderly, with a mean age of 65 years 7. There may be a slight male predilection.
Cholangiocarcinomas correspond to ~15% of all primary liver tumors and to ~3% of all gastrointestinal malignancies 14.
A number of risk factors for cholangiocarcinoma have been identified, and bile stasis and chronic inflammation of the biliary epithelium are identified as common features among many of them 1,2,9,14:
- Caroli disease / choledochal cysts: lifetime risk of 10-15% 2
- choledocholithiasis more than cholelithiasis 10,11
- primary sclerosing cholangitis, especially in Western countries
- recurrent pyogenic cholangitis (hepatolithiasis), especially in Southeast Asia
- cirrhosis 14
- toxins (eg, thorotrast, dioxin, polyvinylchloride, heavy alcohol use
- viral infections (eg, HIV, hepatitis B, hepatitis C, EBV)
Typically, the presentation is with painless jaundice.
Cholangiocarcinomas may be classified anatomically as follows 16:
- intrahepatic (10% of cases)
- perihilar (70%): also known as Klatskin tumor, involving the confluence of the bile duct and proximal to the cystic duct insertion
- distal (20%): distal to the cystic duct insertion
Note that there is variability in nomenclature in the literature, as perihilar cancers often span the vague and variable boundary between intrahepatic and extrahepatic bile ducts. For example, intrahepatic cholangiocarcinomas are sometimes subclassified into peripheral and hilar types 16.
Perihilar cholangiocarcinomas are commonly subclassified by their anatomic extent according to the Bismuth-Corlette classification (described separately).
Prognostic staging uses the TNM system, depending on location:
- intrahepatic cholangiocarcinoma (staging)
- perihilar cholangiocarcinoma (staging)
- distal cholangiocarcinoma (staging)
The previously mentioned Bismuth-Corlette anatomic classification is used for operative planning but is limited in predicting prognosis 16.
Cholangiocarcinomas are typically sclerotic masses without hemorrhage or macroscopic necrosis 2. In general, the active tumor is at the periphery, with the central portions having been replaced by fibrosis, accounting for the capsular retraction that may be seen in intrahepatic tumors.
The macroscopic appearance is further described according to the Liver Cancer Study Group of Japan classification 15,16:
- mass-forming: definite mass in the liver parenchyma
- periductal-infiltrating: extends longitudinally along the bile duct, often causing peripheral bile duct dilation
- intraductal growth: proliferates in the lumen of the bile duct like a papilla or tumor thrombus
Intrahepatic exophytic nodular (peripheral) tumors are most commonly of the mass-forming type 3. They demonstrate variable amounts of central fibrosis, usually marked.
Periductal infiltrating intrahepatic tumors are most common at the hilum (comprise over 70% of hilar-perihilar cholangiocarcinomas), where they are known as Klatskin tumors 3, but can also be seen in combination with mass-forming tumors within the liver. Growth along the walls of the duct may narrow or dilate the duct.
Intraductal tumors comprise 8-18% of resected cholangiocarcinomas 3 and a much smaller number of all cholangiocarcinomas (as most are inoperable). They are characterized by alterations in duct caliber, usually duct ectasia with or without a visible mass. If a mass is visible it may be mural or polypoid in shape 2. The duct dilatation is thought to be due to abundant mucin production. This entity is thought to be similar to the pancreatic intraductal papillary mucinous neoplasms (IPMN).
Histologically, cholangiocarcinomas are divided into well, moderately and poorly differentiated adenocarcinomas 2. In specimens of bile ducts from patients with hepatolithiasis, biliary intraepithelial neoplasia (BilIN) is a common finding and is considered to be a precursor lesion of cholangiocarcinoma. It is typically a microscopic lesion with a flat or micropapillary dysplastic epithelium. It is synonymous with carcinoma in situ 2.
The appearance will vary according to the growth pattern.
Mass-forming intrahepatic: tumors will be a homogeneous mass of intermediate echogenicity with a peripheral hypoechoic halo of compressed liver parenchyma. They tend to be well delineated but irregular in outline and are often associated with capsular retraction 2 which, if present, is helpful in distinguishing cholangiocarcinomas from other hepatic tumors.
Periductal infiltrating intrahepatic: tumors typically are associated with altered caliber bile duct (narrowed or dilated) without a well-defined mass.
Intraductal: tumors are characterized by alterations in duct caliber, usually duct ectasia with or without a visible mass. If a polypoid mass is seen, it is usually hyperechoic compared to surrounding liver 2.
Contrast-enhanced ultrasound may aid with the diagnosis of cholangiocarcinoma 8:
- arterial phase
- peripheral irregular rim-like enhancement
- heterogeneous central hypoenhancement
- portal venous phase / delayed phase
- decreased echogenicity relative to background liver ("wash out")
Mass-forming cholangiocarcinomas: these are typically homogeneously low in attenuation on non-contrast scans, and demonstrate heterogeneous minor peripheral enhancement with gradual centripetal enhancement 2,3. The rate and extent of enhancement depend on the degree of central fibrosis 2. Again, capsular retraction may be evident. The bile ducts distal to the mass are typically dilated.
Although narrowing of the portal veins - or less frequently, hepatic veins - is seen, unlike HCC, cholangiocarcinoma only rarely forms a tumor thrombus 2.
Lobar or segmental hepatic atrophy is usually associated with vascular invasion 6.
Periductal infiltrating: intrahepatic tumors appear as regions of duct wall thickening or of the periductal parenchyma, with altered caliber of the involved duct (usually narrowed). These are most common at the hepatic hilum. They tend to be longer than benign strictures (i.e. approximately 20 mm in length) and show contrast enhancement. There is usually some proximal (i.e. peripheral) dilatation of the biliary tree.
Intraductal tumors: these are characterized by alterations in duct caliber, usually duct ectasia with or without a visible mass. If a polypoid mass is seen it is hypoattenuating on pre-contrast imaging and demonstrates enhancement 2.
MRI is the imaging modality of choice as it can best visualize all three of the tumor mass, the biliary ducts, and the blood vessels - all of which are essential for determining resectability (see below). Appearances on MR are similar to those described above for CT, except that MR is more sensitive to contrast enhancement 3 and bile duct visualization.
- DWI/ADC: a peripherally hyperintense "target" appearance on DWI favors cholangiocarcinoma over hepatocellular carcinoma
Direct cholangiography is a blanket term for any imaging obtained with intra-biliary tree contrast and includes:
All these modalities not only allow evaluation of the biliary tree but are invaluable in planning treatment as assessing for resectability.
The following reporting checklist pertains to hilar/perihilar cholangiocarcinoma, as it is anatomically close to the large bile ducts and blood vessels, crucial to the determination of resectability:
- bile ducts (see Bismuth-Corlette classification)
- tumor confined to the common or hepatic bile duct?
- extension to right or left hepatic duct or both?
- does tumor involve second-order radicles and on which side?
- portal vein: does tumor abut/encase main/right/left portal vein and to what extent?
- hepatic artery
- lymph nodes: enlarged regional (N1) or distant (N2) lymph nodes?
- assess for distal metastases
Treatment and prognosis
The most important factor in prognosis is whether or not the tumor can be resected. Unfortunately, when discovered, most cases are too advanced for curative resection. Even with resection, the prognosis is poor with a five-year survival of only 10-44% 4, with prognosis favoring extrahepatic tumors (around 30% five-year survival vs. 15% for intrahepatic tumors).
The pattern of metastatic spread includes 1:
- intrahepatic vascular involvement with numerous local metastases
- regional lymph nodes (50% at autopsy)
- hematogenous (50% at autopsy)
- bones, especially vertebrae
An increase in margin-negative resection rates and survival can be achieved by resection of the ipsilateral hepatic lobe. In the interest of leaving the patient with a large enough contralateral lobe, portal vein branch embolization of the lobe intended for resection 4-6 weeks before surgery can induce hypertrophy of the contralateral lobe. It should be noted that when attempting resection, tumor size in itself is unimportant.
A hilar-perihilar tumor is considered unresectable in the following cases 12:
- Bismuth type IV: bilateral secondary biliary radicle involvement
- main portal vein encasement/occlusion
- atrophy of a liver lobe with contralateral portal vein or hepatic artery encasement
- atrophy of a liver lobe with contralateral secondary biliary radicle involvement
- involvement of both hepatic arteries
Differential diagnosis depends on whether the tumor is intrahepatic or extrahepatic and on the growth pattern.
For an intrahepatic mass-forming cholangiocarcinoma consider:
- central necrosis (high T2 signal) is more common
hepatocellular carcinoma (HCC)
- tumor thrombus more common
- capsular retraction uncommon
- may appear very similar
- other primary liver tumors
- hepatic abscess
For a periductal infiltrating cholangiocarcinoma consider:
- usually short-segment
- regular margin, but there are exceptions to this
- symmetric narrowing
- no ductal enhancement
- no lymph node enlargement
- no periductal soft-tissue mass
- periportal lymphangitic metastasis 2
For an intraductal cholangiocarcinoma consider:
- 1. Kumar V, Abbas AK, Fausto N et-al. Robbins and Cotran pathologic basis of disease. W B Saunders Co. (2005) ISBN:0721601871. Read it at Google Books - Find it at Amazon
- 2. Chung YE, Kim MJ, Park YN et-al. Varying appearances of cholangiocarcinoma: radiologic-pathologic correlation. Radiographics. 29 (3): 683-700. doi:10.1148/rg.293085729 - Pubmed citation
- 3. Han JK, Choi BI, Kim AY et-al. Cholangiocarcinoma: pictorial essay of CT and cholangiographic findings. Radiographics. 22 (1): 173-87. Radiographics (full text) - Pubmed citation
- 4. Fischer JE, Bland KI. Mastery of surgery. Lippincott Williams & Wilkins. (2007) ISBN:078177165X. Read it at Google Books - Find it at Amazon
- 5. Johnson CD, Taylor I. Recent Advances in Surgery. RSM Press. (2004) ISBN:1853155713. Read it at Google Books - Find it at Amazon
- 6. Vilgrain V. Staging cholangiocarcinoma by imaging studies. HPB (Oxford). 2008;10 (2): 106-9. doi:10.1080/13651820801992617 - Free text at pubmed - Pubmed citation
- 7. Sainani NI, Catalano OA, Holalkere NS et-al. Cholangiocarcinoma: current and novel imaging techniques. Radiographics. 28 (5): 1263-87. doi:10.1148/rg.285075183 - Pubmed citation
- 8. Malhi H, Grant EG, Duddalwar V. Contrast-Enhanced Ultrasound of the Liver and Kidney. Radiol. Clin. North Am. 2014;52 (6): 1177-1190. doi:10.1016/j.rcl.2014.07.005 - Pubmed citation
- 9. Welzel TM, Graubard BI, El-Serag HB et-al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin. Gastroenterol. Hepatol. 2007;5 (10): 1221-8. doi:10.1016/j.cgh.2007.05.020 - Free text at pubmed - Pubmed citation
- 10. Nordenstedt H, Mattsson F, El-Serag H et-al. Gallstones and cholecystectomy in relation to risk of intra- and extrahepatic cholangiocarcinoma. British journal of cancer. 106 (5): 1011-5. doi:10.1038/bjc.2011.607 - Pubmed
- 11. Cai H, Kong WT, Chen CB et-al. Cholelithiasis and the risk of intrahepatic cholangiocarcinoma: a meta-analysis of observational studies. BMC cancer. 15: 831. doi:10.1186/s12885-015-1870-0 - Pubmed
- 12. Caserta MP, Sakala M, Shen P et-al. Presurgical planning for hepatobiliary malignancies: clinical and imaging considerations. (2014) Magnetic resonance imaging clinics of North America. 22 (3): 447-65. doi:10.1016/j.mric.2014.04.003 - Pubmed
- 13. Itri JN, de Lange EE. Extrahepatic Cholangiocarcinoma: What the Surgeon Needs to Know RadioGraphics Fundamentals | Online Presentation. (2018) Radiographics : a review publication of the Radiological Society of North America, Inc. 38 (7): 2019-2020. doi:10.1148/rg.2018180067 - Pubmed
- 14. Jesus M. Banales, Jose J. G. Marin, Angela Lamarca et-al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. (2020) Nature Reviews Gastroenterology & Hepatology. 17 (9): 557. doi:10.1038/s41575-020-0310-z - Pubmed
- 15. Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. (2003) Journal of hepato-biliary-pancreatic surgery. 10 (4): 288-91. doi:10.1007/s00534-002-0732-8 - Pubmed
- 16. Joo I, Lee JM, Yoon JH. Imaging Diagnosis of Intrahepatic and Perihilar Cholangiocarcinoma: Recent Advances and Challenges. (2018) Radiology. 288 (1): 7-13. doi:10.1148/radiol.2018171187 - Pubmed
Related Radiopaedia articles
- depositional disorders
- infection and inflammation
- liver abscess
- hepatic hydatid infection
- liver and intrahepatic bile duct tumors
- benign epithelial tumors
- hepatocellular hyperplasia
- hepatocellular adenoma
- hepatic/biliary cysts
- benign nonepithelial tumors
- primary malignant epithelial tumors
- hepatocellular carcinoma
- hepatocellular carcinoma variants
- biliary cystadenocarcinoma
- combined hepatocellular and cholangiocarcinoma
- undifferentiated carcinoma
- primary malignant nonepithelial tumors
- hematopoietic and lymphoid tumors
- secondary tumors
- adrenal rest tumors
- hepatic carcinosarcoma
- hepatic fibroma
- hepatic Kaposi sarcoma
- hepatic lipoma
- hepatic mesenchymal hamartoma
- hepatic myxoma
- hepatic rhabdoid tumor
- hepatic solitary fibrous tumor
- hepatic teratoma
- hepatic yolk sac tumor
- inflammatory myofibroblastic tumor (inflammatory pseudotumor)
- nodular regenerative hyperplasia
- pancreatic rest tumors
- primary hepatic carcinoid
- benign epithelial tumors
- liver and intrahepatic bile duct tumors
vascular and perfusion disorders
portal vein related
- portal vein thrombosis (acute and chronic)
- extra-hepatic portal vein obstruction
- portal hypertension
- portal venous aneurysm
- portal venous gas
- congenital portosystemic shunts
- transjugular intrahepatic portosystemic shunt (TIPS)
- porto-portal shunt
- hepatic artery related
- hepatic veins related
- inferior vena cava related
- third inflow
- liver thrombotic angiitis
- infra diaphragmatic total anomalous pulmonary venous return (TAPVR)
- hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease)
- portal vein related