Cholangiocarcinoma

Cholangiocarcinomas are malignant tumors arising from cholangiocytes in the biliary tree and are the second most common primary hepatic malignancy after hepatocellular carcinoma (HCC). They tend to have a poor prognosis and high morbidity. 

Epidemiology

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. 

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. 

Risk factors

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 ¹⁴. Described risk factors include ^1,2,9,14:

• Caroli disease / choledochal cysts
  • lifetime risk of 10-15% ²
• choledocholithiasis more than cholelithiasis ^10,11
• primary sclerosing cholangitis (PSC)
  • a major risk factor in western countries
• recurrent pyogenic cholangitis (hepatolithiasis)
  • a major risk factor in endemic areas
  • Asian liver flukes
    • Opisthorchis viverrini
    • Clonorchis sinensis (clonorchiasis)
• cirrhosis ¹⁴
• toxins
  • thorotrast
  • dioxin
  • polyvinylchloride
  • heavy alcohol use
• viral infection(s)
  • HIV
  • hepatitis B
  • hepatitis C
  • EBV

Clinical presentation

Typically the presentation is with painless jaundice.

Pathology

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 hemorrhage 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 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.

In general, the active tumor is at the periphery, with the central portions having been replaced by fibrosis, accounting for the capsular retraction which may be seen in intrahepatic tumors.

Growth patterns/types

Cholangiocarcinomas can be either intrahepatic or extrahepatic. They are also classified according to macroscopic growth pattern ²:

• intrahepatic (20% of diagnosed cases)
• extrahepatic (80%)

Mass-forming

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

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

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).

Extrahepatic/large duct

There is much confusion in the literature as to the definition of extrahepatic cholangiocarcinomas, and there is thus some overlap.

The distribution of large duct (hilar and extrahepatic) tumors ³ is as follows:

• intrahepatic large ducts: 15%
• hilum/proximal third of CBD: 50%
• middle third CBD: 17%
• distal third CBD: 18%

These tumors 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

Staging depends on the growth pattern/type of cholangiocarcinoma.

See: Cholangiocarcinoma staging

Radiographic features

Ultrasound

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")

CT

Mass-forming cholangiocarcinomas: are typically homogeneously low in attenuation on noncontrast 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: 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/MRCP

MRI is the imaging modality of choice, as it can best visualize all three the tumor itself, 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

Direct cholangiography is a blanket term for any imaging obtained with intra-biliary tree contrast and includes:

• PTC
• ERCP
• CT IVC
• MRCP

All these modalities not only allow evaluation of the biliary tree but are invaluable in planning treatment as assessing for resectability.

Radiology report

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
  • common hepatic artery/hepatic artery proper involved and to what extent?
  • right/left hepatic artery involved and to what extent?
  • variant arterial anatomy, if any
• 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)
• haematogenous (50% at autopsy)
  • lungs
  • bones, especially vertebrae
  • adrenals
  • brain

Surgical resectability

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

Differential diagnosis depends on whether the tumor is intrahepatic or extrahepatic and on the growth pattern.

For an intrahepatic mass-forming cholangiocarcinoma consider:

• liver metastases
  • 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:

• benign stricture
  • 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:

• intraductal invasion by hepatocellular carcinoma (HCC)
  • extraductal mass
• hepatolithiasis
  • no enhancement
  • higher attenuation
• biliary cystadenoma or cystadenocarcinoma
  • intratumoral cysts do not communicate with the biliary tree
• benign stricture