Etiology
The exact pathogenesis of bile duct carcinoma has not been described, but predisposing factors include long-standing inflammation, parasitic infestation, toxin and drug exposures, and genetic abnormalities. It is believed that repeated inflammation leads to chronic bile duct injury with formation of premalignant lesions. DNA alterations secondary to genetic mutations, bile salt exposure, or other carcinogens can predispose to biliary epithelial proliferation and subsequent tumorigenesis. Intrahepatic cholangiocarcinoma and hepatocellular carcinoma likely arise from a common progenitor cell based on experiments in patients with chronic liver disease.
Prevalence and Epidemiology
Intrahepatic cholangiocarcinoma is the second most common primary hepatic cancer after hepatocellular carcinoma. Patients are older (50 to 60 years), with a male preponderance. Survival rates are initially high (50% at 1 year), but because of early metastasis, decline quickly (5% to 15% at 5 years). Established risk factors for the development of bile duct cancer include a family history of hepatic fibrosis, choledochal cysts, parasitic infestation (e.g., Clonorchis sinensis ), biliary stones, cholangitis, inflammatory bowel disease, chronic pancreatitis, thorium dioxide [Thorotrast] exposure, and certain medications. Factors that predispose specifically to intrahepatic cholangiocarcinoma include chronic hepatitis C virus infection, nonalcoholic liver disease, smoking, and obesity.
Prevalence and Epidemiology
Intrahepatic cholangiocarcinoma is the second most common primary hepatic cancer after hepatocellular carcinoma. Patients are older (50 to 60 years), with a male preponderance. Survival rates are initially high (50% at 1 year), but because of early metastasis, decline quickly (5% to 15% at 5 years). Established risk factors for the development of bile duct cancer include a family history of hepatic fibrosis, choledochal cysts, parasitic infestation (e.g., Clonorchis sinensis ), biliary stones, cholangitis, inflammatory bowel disease, chronic pancreatitis, thorium dioxide [Thorotrast] exposure, and certain medications. Factors that predispose specifically to intrahepatic cholangiocarcinoma include chronic hepatitis C virus infection, nonalcoholic liver disease, smoking, and obesity.
Clinical Presentation
Symptoms of cholangiocarcinoma result from biliary obstruction. Thus, intrahepatic tumors manifest late in the course of disease. Patients develop jaundice and pruritus and may also complain of acholic stools and bilirubinuria. Other symptoms resulting from liver dysfunction also may be the presenting symptom.
Prolonged biliary obstruction is associated with cholangitis, cirrhosis, renal dysfunction, and progressive malnutrition.
Intrahepatic cholangiocarcinoma metastasizes early, with a poor prognosis, and early surgical resection is the only chance for curative treatment.
Pathophysiology
The liver consists of bile-secreting hepatocytes draining into bile canaliculi, which merge into hepatic ductules to form the intrahepatic main right and left hepatic ducts. These converge just outside the liver to form the common hepatic duct ( Figure 54-1 ).
Bile duct tumors are classified as extrahepatic (87% to 92%) or intrahepatic (8% to 13%). Intrahepatic tumors develop in the small ductal branches within the liver. Morphologically, intrahepatic cholangiocarcinomas may exhibit mass-forming (most common), intraductal-growing, periductal-infiltrating, or combined growth patterns.
The majority of intrahepatic cholangiocarcinomas are solitary, well-circumscribed tumors. Tumors may be peripherally or centrally located. A single hepatic duct is involved in 8% to 13% of cases. Satellite nodules surrounding the main tumor occur in approximately 65% of patients. Ten percent of tumors have a diffuse multicentric distribution with no dominant mass.
Cholangiocarcinomas most commonly disseminate via perineural invasion and lymphatics with involvement of the cystic and common bile duct nodes in 15% of patients. Hematogenous spread is extremely rare. Tumors also can directly infiltrate adjacent liver or cause peritoneal seeding.
Staging of intrahepatic cholangiocarcinoma is performed using the American Joint Committee on Cancer Staging Tumor, Node, Metastasis (TNM) system of classification ( Table 54-1 ).
| TNM Definition | Tumor Location |
|---|---|
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| Tis | Intramucosal carcinoma (intraductal tumor) |
| T1 | Solitary tumor without vascular invasion |
| T2a | Solitary tumor with vascular invasion |
| T2b | Multiple tumors, with or without vascular invasion |
| T3 | Tumor perforating the visceral peritoneum or involving the local extrahepatic structures by direct invasion |
| T4 | Tumor with periductal invasion |
| NX | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis present |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
Pathology
Benign biliary tumors such as adenomas, hamartomas, cystadenomas, and papillomas are extremely rare compared with malignant cholangiocarcinomas.
Histologically, the majority (95%) of malignant cancers are mucin-secreting adenocarcinomas with varying levels of differentiation. Pathologic subtypes include scirrhous, nodular, and papillary cancers. The scirrhous type creates fibrotic annular thickenings with low cellularity and is generally seen in the proximal ducts and hilum.
Microscopic findings of anisonucleosis and distended intracytoplasmic lumina support the diagnosis of bile duct cancer. Immunohistochemical staining for carcinoembryonic antigen (CEA), carbohydrate antigens (CA 50 and CA 19-9), and mucins may facilitate diagnosis. The pathologic findings of cholangiocarcinoma and metastatic adenocarcinoma of unknown origin can be especially difficult to differentiate. Cytokeratin (CK) 7 suggests a gastric or colorectal primary, and CK-20 suggests cholangiocarcinoma. Mutations in the KRAS oncogene are seen in intrahepatic and perihilar tumors. Studies have also identified mutations in the TP53 tumor suppressor gene, c-erb oncogene, chromosomes 5 and 17, epidermal growth factors, and nuclear antigens.
Imaging
Bile duct tumors are variable in location and morphology and may require multiple modalities for complete characterization. In general, intrahepatic tumors are larger than their extrahepatic counterparts and more conspicuous on imaging. Imaging is also used to evaluate vascular and ductal anatomy, secondary signs of obstruction, and metastatic disease.
Radiography
Conventional radiography has a limited role in the evaluation of bile duct carcinoma. Intrahepatic tumors may contain calcifications or produce pneumobilia. Digital subtraction angiography (DSA) is infrequently used for assessment of the hepatic vasculature. Cholangiography allows for evaluation of biliary disease and can be performed via transhepatic or endoscopic approaches. Endoscopic retrograde cholangiopancreatography (ERCP) is used for assessment of distal tumors, whereas percutaneous transhepatic cholangiography is used to assess proximal lesions ( Figure 54-2 ).
Computed Tomography
Large exophytic tumors are easily seen with computed tomography (CT), whereas small or diffuse tumors may be difficult to visualize. Intraluminal polypoid tumors and exophytic tumors appear as lobulated, hypoattenuating masses with variable enhancement. Infiltrating tumors may be high attenuating and distributed throughout the bile ducts. Peripheral biliary dilatation may be seen, secondary to intrahepatic obstruction. Capsular retraction of the liver and intra-abdominal lymphadenopathy also can be evaluated. CT angiography (CTA) is useful for assessment of the hepatic vasculature ( Figure 54-3 ).
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) evaluates intrahepatic and periductal tumors more accurately than CT. Tumors appear isointense to hypointense on T1-weighted images. Continuous rim enhancement and progressive centripetal enhancement can be seen. Lesions are often hyperintense on T2-weighted imaging, with central hypointensity and delayed enhancement reflective of fibrosis ( Figure 54-4 ). Multiphase three-dimensional postcontrast imaging can accurately demonstrate the tumor extent and vascular involvement. Magnetic resonance cholangiopancreatography (MRCP) is useful in the detection of intrahepatic biliary ductal dilation resulting from the primary mass and ductal thickening. Benign ductal thickening appears circumferential and smooth, whereas malignant lesions tend to be eccentric and nodular ( Figure 54-5 ). MRI can be helpful in differentiating intrahepatic cholangiocarcinoma from metastatic adenocarcinomas of unknown primary.
