Cholangiocarcinoma is a malignant tumour arising from cholangiocytes in the biliary tree. It tends to have a poor prognosis and high morbidity. It is the second most common primary hepatic tumour, with intrahepatic cholangiocarcinomas (ICCs) accounting for 10-20% of primary liver tumours.
Although overall cholangiocarcinoma is rare, there are significant regional variations in incidence with much higher rates seen in south-east Asia 2.
Incidence is usually in the elderly (7th decade) 7. There may be a slight male predilection.
A number of risk factors for cholangiocarcinoma have been identified including 1-2,9:
primary sclerosing cholangitis (PSC)
- major risk factor in western countries
recurrent pyogenic cholangitis (hepatolithiasis)
- major risk factor in endemic areas
- choledocholithiasis more than cholelithiasis 10,11
- Asian liver flukes
- Opisthorchis viverrini
- Clonorchis sinensis (clonorchiasis)
Caroli disease / choledochal cysts
- lifetime risk of 10-15% 2
- polyvinyl chloride
- heavy alcohol use
- viral infection(s)
- hepatitis B and hepatitis C
Typically the presentation is with painless jaundice.
Macroscopically cholangiocarcinomas have a number of different growth patterns (see below), and their macroscopic appearance will reflect this. In general, they are sclerotic masses without haemorrhage or macroscopic necrosis 2.
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 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.
In general, the active tumour is at the periphery, with the central portions having been replaced by fibrosis, accounting for the capsular retraction which may be seen in intrahepatic tumours.
Cholangiocarcinomas can be either intra or extrahepatic. They are also classified according to macroscopic growth pattern 2:
Intrahepatic exophytic nodular (peripheral) tumours are most commonly of the mass-forming type 3. They demonstrate variable amounts of central fibrosis, usually marked.
Periductal infiltrating intrahepatic tumours are most common at the hilum, where they are known as Klatskin tumours 3, but can be seen in combination with mass forming tumours within the liver. Growth along the walls of the duct may narrow or dilate the duct.
Intraductal tumours make up 8-18% of resected cholangiocarcinomas 3 and a much smaller number of all cholangiocarcinomas (as most are inoperable). They are characterised by alterations in duct calibre, 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 IPMN.
There is much confusion in the literature as to the definition of extrahepatic cholangiocarcinomas, and there is thus some overlap.
Regarding the distribution of large duct (hilar and extrahepatic) tumours 3:
- intrahepatic large ducts: 15%
- hilum/proximal third of CBD: 50%
- middle third CBD: 17%
- distal third CBD: 18%
These tumours are most commonly infiltrating, although both exophytic (mass-forming) and polypoid (intraductal) types are identified. They have similar appearances to their intrahepatic counterparts 3.
Staging depends on the growth pattern/type of cholangiocarcinoma.
The appearance will vary according to the growth pattern.
Mass-forming intrahepatic: tumours will be a homogeneous mass of intermediate echogenicity with a peripheral hypoechoic halo of compressed liver. 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 tumours.
Periductal infiltrating intrahepatic: tumours typically are associated with altered calibre bile duct (narrowed or dilated) without a well-defined mass.
Intraductal: tumours are characterised by alterations in duct calibre, 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: are typically homogeneously low in attenuation on noncontrast scans, and demonstrate heterogeneous minor peripheral enhancement with gradual enhancement centrally 2-3. The rate and extent of enhancement depends 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 tumour thrombus 2.
Lobar or segmental hepatic atrophy is usually associated with vascular invasion 6.
Periductal infiltrating: intra-hepatic tumours appear as regions of thickening of the periductal parenchyma with altered calibre of the involved duct (narrowed or dilated). These are most common at the hepatic hilum. There is usually some distal dilatation of the biliary tree.
Intraductal tumours: are characterised by alterations in duct calibre, 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.
Appearances on MR are similar to those described above on CT, except that MR is more sensitive to contrast enhancement 3.
- DWI/ADC: a peripherally hyperintense "target" appearance on DWI favours cholangiocarcinoma over hepatocellular carcinoma
Direct cholangiography is a blanket term for any imaging obtained with intra-biliary tree contrast and includes:
- CT IVC
All these modalities not only allow evaluation of the biliary tree but are invaluable in planning treatment as assessing for resectability.
Treatment and prognosis
The most important factor in prognosis is whether or not the tumour can be resected. Even with resection, the prognosis is poor with five year survival of only 10-44% 4.
The pattern of metastatic spread includes 1:
- intrahepatic vascular involvement with numerous local metastases.
- regional lymph nodes (50% at autopsy)
- haematogenous (50% at autopsy)
- bones, especially vertebrae
Differential diagnosis is different according to whether the tumour is intra or extrahepatic and depending on the growth pattern.
For an intrahepatic mass-forming cholangiocarcinoma consider:
- central necrosis (high T2 signal) is more common
hepatocellular carcinoma (HCC)
- tumour thrombus more common
- capsular retraction uncommon
- may appear very similar
- other primary liver tumours
- hepatic abscess
For a periductal infiltrating cholangiocarcinoma consider:
- usually short-segment
- regular margin
- symmetric narrowing
- no ductal enhancement
- no lymph node enlargement
- no periductal soft-tissue mass
- periportal lymphangitic metastasis 2
For an intraductal cholangiocarcinoma consider:
- intraductal invasion by an HCC
- extraductal mass
- no enhancement
- higher attenuation
biliary cystadenoma or cystadenocarcinoma
- intratumoural cysts do not communicate with the biliary tree
- benign stricture
- depositional disorders
- infection and inflammation
- liver abscess
- hepatic hydatid infection
- liver and intrahepatic bile duct tumours
- benign epithelial tumours
- hepatic regenerative nodule
- focal nodular hyperplasia
- hepatocellular adenoma
- hepatic/biliary cysts
- hepatocellular hyperplasia
- benign nonepithelial tumours
- primary malignant epithelial tumours
- primary malignant nonepithelial tumours
- hematopoeietic and lymphoid tumours
- secondary tumours
- adrenal rest tumours
- hepatic carcinosarcoma
- hepatic fibroma
- hepatic Kaposi sarcoma
- hepatic lipoma
- hepatic mesenchymal hamartoma
- hepatic myxoma
- hepatic rhabdoid tumour
- hepatic solitary fibrous tumour
- hepatic teratoma
- hepatic yolk sac tumour
- inflammatory myofibroblastic tumor (inflammatory pseudotumor)
- nodular regenerative hyperplasia
- pancreatic rest tumours
- primary hepatic carcinoid
- benign epithelial tumours
- extrahepatic bile duct tumours
- liver and intrahepatic bile duct tumours
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