You are in: eMedicine Specialties > Radiology > GASTROINTESTINAL CholangiocarcinomaArticle Last Updated: Apr 4, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Mahesh Kumar Neelala Anand, MBBS, DNB, FRCR, Clinical Director, Consultant Radiologist, Department of Radiology, Pennine Acute Hospitals NHS Trust, Manchester, UK Mahesh Kumar Neelala Anand is a member of the following medical societies: British Medical Association, Radiological Society of North America, and Royal College of Radiologists Coauthor(s): David Andrew Nicholson, BM, BS, FRCR, Honorary Lecturer, Department of Radiology, University of Manchester; Consultant Gastrointestinal Radiologist, Department of Radiology, Hope Hospital, Salford Royal Hospital NHS Trust Editors: Zahir Amin, MBBS, MRCP, MD, FRCR, Consulting Staff, Department of Imaging, The Middlesex Hospital, University College London Hospitals Trust; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Paul M Silverman, MD, Professor, Chief of Body Imaging, Chair in Diagnostic Imaging, Department of Radiology, University of Texas MD Anderson Cancer Center; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; John Karani, MBBS, FRCR, Consulting Staff, Department of Radiology, King's College Hospital, London Author and Editor Disclosure Synonyms and related keywords: 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 INTRODUCTIONSection 2 of 11
  BackgroundCholangiocarcinoma 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:
PathophysiologyOrigin 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%). 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%. FrequencyUnited StatesPrimary 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. InternationalCholangiocarcinoma 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/MorbidityLess 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%.
RaceNo 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. SexIn contrast to gallbladder carcinoma, cholangiocarcinoma has a male preponderance, with a male-to-female ratio of 3:2. AgeThe patient's age at presentation may vary, but the incidence peaks in those in the 50s.
AnatomyThe 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. Clinical DetailsIntrahepatic 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 ExaminationThe 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. 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. DIFFERENTIALSSection 3 of 11
Biliary Tract, Percutaneous Intervention Cavernous Hemangioma, Liver Cholangitis, Primary Sclerosing Cholangitis, Recurrent Pyogenic Focal Nodular Hyperplasia Hepatic Adenoma Hepatocellular Carcinoma Other Problems to Be ConsideredInfections involving the bile ducts (eg, tuberculosis) are rare, but they may cause strictures with portal lymphadenopathy that simulates findings in cholangiocarcinoma. RADIOGRAPHSection 4 of 11
FindingsPlain 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. Degree of ConfidenceWith plain radiographs, no diagnostic features suggest or confirm the diagnosis of cholangiocarcinoma. CT SCANSection 5 of 11
FindingsIntrahepatic 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. 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. 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. Degree of ConfidenceDifferentiating 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. False Positives/NegativesDifferentiating solitary intrahepatic cholangiocarcinoma from HCC is difficult with CT. The presence of satellite nodules suggests cholangiocarcinomas. MRISection 6 of 11
FindingsThe 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. 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 recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine 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. As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. 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 movingor 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 or Medscape. 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. Degree of ConfidenceConventional MRI, MRCP, 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. False Positives/NegativesMRCP 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. ULTRASOUNDSection 7 of 11
FindingsDepending on the tumor type, the sensitivity of 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. 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%. Degree of ConfidenceIn capable hands, modern high-resolution color Doppler US is highly sensitive in depicting, characterizing, and determining the resectability of a cholangiocarcinoma. False Positives/NegativesIn 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. NUCLEAR MEDICINESection 8 of 11
FindingsTechnetium-99m (99mTc) sulfur colloid and 99mTc acetanilide iminodiacetic acid analogues may be used to demonstrate cholangiocarcinomas. Approximately 85% of the volume of intravenously injected 99mTc 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. 99mTc 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. 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.1 Larger prospective studies are required to further assess this technique. Degree of ConfidenceFocal defects on sulfur colloid scans are nonspecific. The point of obstruction demonstrated on the DISIDA scan may be due to tumor or benign causes. False Positives/NegativesThe 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. ANGIOGRAPHYSection 9 of 11
FindingsAngiographic features of cholangiocarcinoma include arterial encasement, obstruction, and neovascularity and focal encasement of the portal vein. Degree of ConfidenceAngiographic findings alone are poor in confirming a diagnosis of cholangiocarcinoma because the features may occur in both hepatocellular and pancreatic malignancies. INTERVENTIONSection 10 of 11
Nonsurgical intervention of the biliary tract to provide palliation of malignant biliary obstruction is now recognized and well established. Biliary tract intervention for cholangiocarcinomas can be performed by means of endoscopic or percutaneous approaches. Direct comparison of the 2 methods is difficult because of wide variability in techniques, patient selection, operator preferences for equipment, and definitions of specific complications. The preferred treatment for biliary obstruction caused by a lesion at the distal CBD is endoscopic biliary drainage. High obstruction and tumor at the confluence may be beyond the reach of the endoscopists. Endoscopic versus percutaneous techniques In a study of 70 patients, Speer et al demonstrated that the success rate of endoscopic stents in relieving obstruction (endoscopic vs percutaneous, 81% vs 61%) and the complication rate (19% vs 67%) were significantly different and favored the endoscopic approach.2 The 30-day mortality rate in the endoscopic and percutaneous groups were 15% and 33%, respectively; this result also supported endoscopic palliation. Indications for drainage The general indications for biliary tract drainage in cholangiocarcinomas are jaundice associated with cholangitis, sepsis, pruritus, and nausea and vomiting resulting in dehydration and malnutrition. Not all patients need drainage. Only patients in whom further local, regional, or systemic therapies are planned should undergo drainage procedures. The patient's expected survival should be taken into account. Drainage techniques Drainage techniques may involve the use of internal-external drains, internal endoprostheses, metallic stents, radiation therapy with intervention, and metallic stents with brachytherapy. Internal-external drains are the standard devices for biliary drainage. They lie across the biliary stricture, with side holes both above and below the level of obstruction. Their placement facilitates drainage of bile into the duodenum through the distal side holes and also allows bile to externally drain through the proximal side holes from the proximally dilated ducts. Internal drainage of bile into the duodenum is important to prevent metabolic complications caused by electrolyte imbalance and malnutrition. The transhepatic catheters are usually changed every 2 months even if they do not seem to be causing any problems. Internal-external drains are a potential source of infection. When fever, leakage, or obstruction develops, the drain is exchanged for a new one. Regarding internal endoprostheses, Carey-Coons and Miller stents are well recognized as sole internally draining devices. The Miller stent, a double-mushroom stent, is suitable for use in cases of more proximal disease. An internal-external drainage procedure may be necessary as first-line treatment, and the drain may be exchanged for an internal endoprosthesis later. The expected patency of synthetic stents is about 4-6 months. Teflon catheters have no advantage over other synthetic stents in preventing encrustation and obstruction of the stents caused by sludge and bacteria. Metallic stents can be introduced into the biliary tract to relieve obstruction with a sheath the same size as a biliary drainage catheter. Metallic stents have the advantage of a larger-diameter lumen, because they self-expand to a size of 10 mm (30F). The metallic stent becomes incorporated into the wall of the bile duct over several weeks. Stent patency remains a problem because of tumor ingrowth through the struts and tumor overgrowth over the ends of the stent. The zigzag Gianturco Z stent has wide struts and may be more susceptible to tumor ingrowth than other stents. To prevent overgrowth, placement of the stent across a longer segment is recommended, but this may not be ideal for all stricture locations. Inspissated bile also may cause stent obstruction without tumor ingrowth or overgrowth. The long-term patency of metallic stents alone is a little longer than 6-8 months. Cholangiocarcinoma is very responsive to local radiation therapy. Intracavitary therapy, or brachytherapy, involves the administration of radiation through an internal-external catheter. This treatment provides high doses of radiation directly to the tumor while preventing excessive irradiation of the surrounding viscera. In a study performed at the Thomas Jefferson University hospital, patients treated with radiation had a 30% 2-year survival rate, compared with a 17% rate for patients not treated with radiation. Also, the dose is critical to patient survival. A total dose greater than 55 Gy resulted in an extended survival rate of 48%, compared with 0% with a total dose of less than 55 Gy. Metallic stents combined with brachytherapy and external-beam radiation appear to have better results in terms of stent patency and survival, especially in patients with cholangiocarcinoma. The biliary obstruction is first treated with an internal-external drain. A wire implanted with iridium seeds is passed through the internal-external catheter for local irradiation. After brachytherapy is completed, a metallic stent is placed, and the external catheters are removed. External-beam radiation is provided on an outpatient basis. Medical/Legal Pitfalls
REFERENCESSection 11 of 11
Article Last Updated: Apr 4, 2007 |
