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.
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
Gallstones (20-50% of cases, probably coincidental)
Papillomatosis of the bile ducts
Chronic typhoid carrier status
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. [2, 3]
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.
The tumors are classified as extrahepatic tumors (87-92%) or intrahepatic tumors (8-13%). 
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%.
See the image below.
Criteria for assessing unresectability by imaging
Imaging is an important link in the decision-making process at multidisciplinary meetings while determining resectability. Surgical colleagues depend vastly on imaging in case selection.
The major determinants of resectability are the following:
The extent of tumor within the biliary tree,
The amount of hepatic parenchyma involved
Hepatic lobar atrophy
Determination of resectability is most challenging in patients with Klatskin tumors. About half of patients with Klatskin tumors that are determined to be resectable preoperatively have unresectable disease intraoperatively.
See the image below.
The radiologic criteria defining unresectability in patients with hilar tumors is shown below  :
Local tumor invasion
See the list below:
Bilateral hepatic duct involvement up to secondary biliary radicles
Encasement or occlusion of the main portal vein
Unilateral tumor extension to secondary biliary radicles with contralateral portal vein or hepatic artery encasement or occlusion
Hepatic lobar atrophy with contralateral portal vein or hepatic artery encasement or occlusion
Hepatic lobar atrophy with contralateral tumor extension to secondary biliary radicles
Insufficient predicted hepatic reserve following extended hepatectomy
See the list below:
Lymph node metastases beyond the hepatoduodenal ligament (N2 lymph nodes) (peripancreatic, periduodenal, periportal, celiac, or superior mesenteric lymph nodes)
Distant metastasis (eg, lung, liver, peritoneal)
For more information on this topic, see Cholangiocarcinoma.
Plain radiographs usually have no diagnostic value. Calcifications occur in 18% of intrahepatic cholangiocarcinomas. They may appear on plain radiographs when they are large, nodular, and located in the right upper quadrant. Extrahepatic tumors may cause an extrinsic impression, with indentation or infiltration of the stomach or duodenum on an upper gastrointestinal barium series.
Intrahepatic cholangiocarcinomas cannot easily be depicted with cross-sectional imaging. The mass is predominantly hypoattenuating, with irregular margins, and the tumors may be 5-20 cm in size at the time of presentation. The mass is rounded or oval, and images may demonstrate segmental biliary ductal dilatation because of obstruction. With the intravenous administration of iodinated contrast material, the mass may demonstrate a variable enhancement pattern. No enhancement, minimal peripheral enhancement, or central enhancement may be depicted. [7, 8]
Delayed enhancement with increasing attenuation may be seen on images in as many as 74% of patients. This pattern of enhancement may be useful in differentiating HCC from cholangiocarcinomas. Hepatocellular carcinoma (HCC) shows an early peak increase in attenuation with a progressive decrease. The overlying liver capsule may be retracted when the lesions are peripheral. A central scar is present in about 30% of patients. Occasionally, peripheral cholangiocarcinomas are resectable when they do not involve the inferior vena cava or the caudate lobe.
The biliary ducts may show intense enhancement in the early phase owing to associated chronic bile duct inflammation. Satellite nodules of masses are seen in 65% of patients with intrahepatic tumors. Regional metastatic lymphadenopathy may be present in about 15% of cases involving intrahepatic tumors.
Extrahepatic disease is characterized by dilatation of intrahepatic ducts without extrahepatic ductal dilatation. The mass in or surrounding the ducts is visible on CT scans in about 40% of cases. The confluence of the right and left ducts may be obliterated with the loss of sharp distinction. The infiltrating tumors, which grow along the duct, and the intraluminal polypoidal tumors are difficult to detect with CT and may be defined in only 22-25% of cases. Infiltrating tumors are seen as high-attenuating lesions in 22% of cases. Exophytic tumors are larger, and with thin-section imaging, the mass is demonstrable in 100% of cases as a low-attenuating lesion with lobulation. Morphologic changes may occur late in the disease process, with atrophy of the left lobe of the liver compared with the right lobe. The left-sided ducts may be more dilated than the right-sided ducts.
Differentiating the tumor from HCC, especially the fibrolamellar type of HCC, may be difficult because the alpha-fetoprotein (AFP) level is not increased with either tumor.
Differentiating solitary intrahepatic cholangiocarcinoma from HCC is difficult with CT. The presence of satellite nodules suggests cholangiocarcinomas.
Magnetic Resonance Imaging
The intrahepatic mass is seen as a hypointense lesion relative to normal liver on T1-weighted images. T2-weighted images show predominant isointensity or slight hyperintensity relative to the liver parenchyma in about 64% of cases and marked hyperintensity in 36% of cases. These alterations in signal intensity are seen in the periphery of the tumor mass, with a hypointense area in the center of the mass. [9, 10, 11]
Pathologic correlation with MR appearances reveal that the isointense or slightly hyperintense areas on T2-weighted images are due to the abundant fibrous content of these tumors and that the hyperintense areas on T2-weighted images are due to mucous secretion within the lesion. The intravenous administration of gadolinium-based contrast material results in concentric contrast enhancement. 
Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans.
NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory.
MRI demonstrates vascular encasement, focal liver atrophy, or dilatation of intrahepatic ducts in about 70% of cases. Although MR features are well correlated with the pathologic changes, the appearances are nonspecific for a definitive diagnosis.
Conventional MRI, MRCP (MR cholangiopancreatography), and MR angiography have been applied to evaluate malignant biliary obstruction. These techniques can demonstrate the features of cholangiocarcinoma. The clinical application of the data and expertise with the use of MR imaging alone, compared with the application and use of helical CT and endoscopic US, are still evolving.
MRCP images may show a variety of artifacts and normal variants that mimic cholangiocarcinoma-like lesions. An experienced radiologist should be able to recognize such pitfalls.
Depending on the tumor type, the sensitivity of ultrasonography (US) in depicting cholangiocarcinomas is variable. Recently, a more definitive role in demonstrating cholangiocarcinomas with US has been defined. Dilatation of the intrahepatic bile ducts is the most common abnormality in patients with ductal cholangiocarcinoma. [13, 14, 15]
With intrahepatic tumors, the mass can be a predominantly homogeneous or heterogeneous lesion, and it is usually hyperechoic in 75% of cases. The mass may be isoechoic (about 10% of cases) or hypoechoic (15% of cases) with irregular borders and satellite nodules. Peripheral tumors are usually hypoechogenic when they are smaller than 3 cm, but they are hyperechoic when larger. Peripheral cholangiocarcinoma may be either infiltrating or nodular. The infiltrating form may be manifested as a simple diffuse abnormality of the liver echotexture. With the nodular type, the mass predominates and appears as a solitary mass with a distinct predilection for the right lobe.
With extrahepatic tumors, nearly 100% of cases with polypoidal intraluminal tumors are depicted at US, whereas US demonstrates the primary sign of the mass in only 13% of cases involving sclerosing tumors and in only 29% of those involving exophytic masses. Klatskin tumors classically manifest as segmental dilatation and nonunion of the right and left ducts at the porta hepatis.
Newer developments include extension of US techniques with endoscopic routes. Intraportal endovascular US has been used to assess vascular invasion by bile duct tumors. The use of 3-dimensional intraductal US has been investigated for the staging of bile duct cancer. In a group of 8 patients in Japan, this technique enabled the accurate assessment of tumoral invasion of the arteries in 88% of patients and of portal vein and pancreatic parenchymal invasion in 100%.
In capable hands, modern high-resolution color Doppler US is highly sensitive in depicting, characterizing, and determining the resectability of a cholangiocarcinoma.
In more than 90% of cases, US is sufficient for adequate imaging and staging. Diffuse tumors may be difficult to demonstrate with US. Benign tumors of the bile duct and cholangitis may simulate cholangiocarcinomas. Strictures caused by cholangitis may cause false-positive results. Sclerosing lesions may result in false-negative results.
Technetium-99m (99m Tc) sulfur colloid and99m Tc acetanilide iminodiacetic acid analogues may be used to demonstrate cholangiocarcinomas.
Approximately 85% of the volume of intravenously injected99m Tc sulfur colloid accumulates in the liver because of hepatocyte uptake. Intrahepatic cholangiocarcinomas are seen as cold liver lesions. The appearances on the scan do not suggest a primary diagnosis of cholangiocarcinoma. Cold lesions due to benign disease, trauma, and abscesses may be present. The technique helps in localizing the lesions when they are larger than 2 cm.
99m Tc diisopropyl iminodiacetic acid (DISIDA) is excreted into the biliary ducts and may reveal the site of biliary obstruction. After injection, the CBD and cystic duct are usually visualized within 15 minutes. The ducts might not be visualized, even in healthy patients.
Positron emission tomography (PET) is a noninvasive imaging technique that can be used to assess metabolism with the administration of positron-emitting radiolabeled tracers. Fluorodeoxyglucose is one such tracer that has been used in evaluating malignancies. Keiding et al used PET to improve the detection of intrahepatic cholangiocarcinoma in patients with superimposed PSC; their data are promising. The study group comprised 20 patients.  Larger prospective studies are required to further assess this technique.
In an Italian study, fluorine-18-fluorodeoxyclucose ([18)F-FDG) and PET or PET/CT were demonstrated to be accurate diagnostic imaging methods for primary tumor evaluation in patients with cholangiocarcinoma. These tools were found to have a better diagnostic accuracy in patients with intrahepatic cholangiocarcinoma than in patients with extrahepatic cholangiocarcinoma. 
Focal defects on sulfur colloid scans are nonspecific. The point of obstruction demonstrated on the DISIDA scan may be due to tumor or benign causes.
The appearances on the sulfur colloid and iminodiacetic acid (IDA) scans are nonspecific. The techniques probably are sensitive for larger lesions and may demonstrate the level of obstruction. False-positive findings on sulfur colloid scans may occur because of benign tumors and other malignant tumors. False-negative findings occur when the tumors are smaller than 2 cm and central in location. False-positive findings on IDA scans may occur because of benign biliary tumors and ductal stones complicated by infection.
Angiographic features of cholangiocarcinoma include arterial encasement, obstruction, and neovascularity and focal encasement of the portal vein. Angiographic findings alone are poor in confirming a diagnosis of cholangiocarcinoma because the features may occur in both hepatocellular and pancreatic malignancies.