Blechacz B, Gores GJ (2008) Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology, 48(1):308-321
Introduction
Cholangiocarcinoma (CCA) is an epithelial cancer originating from the bile ducts with features of cholangiocyte differentiation.1 CCA is the second most common primary hepatic malignancy, and epidemiologic studies suggest its incidence is increasing in Western countries. 2 Advanced CCA has a devastating prognosis, with a median survival of <24 months.3 Three different growth patterns of extrahepatic CCA can be observed: (1) periductal infiltrating, (2) papillary or intraductal, and (3) mass forming.4 Intrahepatic CCA typically presents as an intrahepatic mass. An additional goal is to stimulate further interest in this disease with the hope of improving outcomes for this still highly lethal malignancy.
Epidemiology of CCA
Hepatobiliary malignancies account for 13% of the 7.6 million annual cancer-related deaths worldwide and for 3% of the 560,000 annual cancer-related deaths in the United States. CCA accounts for 10% to 20% of the deaths from hepatobiliary malignancies. The prevalence of CCA shows a wide geographic variability, with the highest rates in Asia and the lowest in Australia.5 In the United States, the incidence of CCA has been reported to be 0.95/100,000 for intrahepatic forms and 0.82/100,000 for extrahepatic forms of the disease.5 Its prevalence in different racial and ethnic groups is heterogeneously distributed, with the highest age adjusted prevalence in Hispanics (1.22/100,000) and the lowest in African Americans (0.17-0.5/100,000).6 In the last 4 decades, United States incidence rates of intrahepatic CCA have increased by 165%, whereas the extrahepatic CCA incidence has remained stable.7,8 The significant increase in age-adjusted incidence of intrahepatic CCA was confirmed after correction for a prior misclassification of hilar CCA as intrahepatic CCA.2 Similarly, increasing incidence rates of intrahepatic CCA have also been reported in Western Europe and Japan.9,10 The cause for the increasing incidence has not been identified. We speculate that increased lipid mediators such as oxysterols may contribute to the current increased incidence in Western societies.11
Etiology of CCA
Etiologic and experimental evidence implicates inflammation and cholestasis as key factors in the pathogenesis of CCA. Table 1
Pathogenesis of CCA
Table 2. The majority of these genetic changes were described in intrahepatic CCA.
Diagnosis of CCA
Intrahepatic mass-forming CCA presents with symptoms typical for hepatic masses, including abdominal pain, malaise, night sweats, and cachexia. Ultrasound and computed tomography (CT) are only of limited value for detection of intrahepatic and extrahepatic CCA due to their low sensitivity and specificity, as well as their low accuracy in estimating tumor extent of intrahepatic and extrahepatic CCA. 78,89–91
MRCP/magnetic resonance imaging (MRI) provides information about intrahepatic location and tumor dimensions of intrahepatic CCA, ductal as well as periductal tumor extent of extrahepatic CCA, vascular involvement, and metastases (Fig. 2).
In indeterminate cases, establishment of a diagnosis can be attempted with positron emission tomography (PET) with [18F]-2-deoxy-glucose.78,90 Sensitivity and specificity of integrated PET/CT in the identification of primary lesions has been reported as 93% and 80% for intrahepatic CCA and 55% and 33% for extrahepatic CCA.97
The introduction of digital image analysis (DIA) and fluorescence in situ hybridization (FISH) have significantly increased the diagnostic yield of brush cytology. Both techniques depend on the identification of aneuploidy.
Staging of CCA
This classification is a pathologic staging system and therefore often requires surgical acquisition of the tissue. An optimal staging system should provide detailed information about disease extent, vascular involvement, and metastases without subjecting the patient to surgical treatment. It should also take into account treatment options, performance status, and age and correlate with meaningful clinical outcomes. There is an urgent need for such a validated staging system in hilar CCA. Without a staging system, stratification of patients for clinical trials is currently hampered. Table 3
Surgical Therapy of CCA
Results of liver transplantation for intrahepatic CCA are discouraging with 5-year survival rates of 0% to 18%, and therefore cannot be recommended.108,129–132
New In Vivo Models of CCA
Liver-specific combined deletion of the tumor suppressor genes Smad4 plus PTEN results in formation of CCA in mice.195 Another model of intrahepatic mass-forming CCA is achieved by treating p53-deficient mice with carbon tetrachloride (CCl4).205 Sirica and colleagues developed two models of CCA in which malignant transformation of explanted rat cholangiocytes followed by direct biliary inoculation of these cells resulted in CCA formation in 56% to 100% of animals.73,206 In summary, new models of CCA have been developed that resemble human CCA in many aspects. The majority of these models represent intrahepatic CCA, however, and genetic models of hilar CCA still need to be developed.
Introduction
Cholangiocarcinoma (CCA) is an epithelial cancer originating from the bile ducts with features of cholangiocyte differentiation.1 CCA is the second most common primary hepatic malignancy, and epidemiologic studies suggest its incidence is increasing in Western countries. 2 Advanced CCA has a devastating prognosis, with a median survival of <24 months.3 Three different growth patterns of extrahepatic CCA can be observed: (1) periductal infiltrating, (2) papillary or intraductal, and (3) mass forming.4 Intrahepatic CCA typically presents as an intrahepatic mass. An additional goal is to stimulate further interest in this disease with the hope of improving outcomes for this still highly lethal malignancy.
Epidemiology of CCA
Hepatobiliary malignancies account for 13% of the 7.6 million annual cancer-related deaths worldwide and for 3% of the 560,000 annual cancer-related deaths in the United States. CCA accounts for 10% to 20% of the deaths from hepatobiliary malignancies. The prevalence of CCA shows a wide geographic variability, with the highest rates in Asia and the lowest in Australia.5 In the United States, the incidence of CCA has been reported to be 0.95/100,000 for intrahepatic forms and 0.82/100,000 for extrahepatic forms of the disease.5 Its prevalence in different racial and ethnic groups is heterogeneously distributed, with the highest age adjusted prevalence in Hispanics (1.22/100,000) and the lowest in African Americans (0.17-0.5/100,000).6 In the last 4 decades, United States incidence rates of intrahepatic CCA have increased by 165%, whereas the extrahepatic CCA incidence has remained stable.7,8 The significant increase in age-adjusted incidence of intrahepatic CCA was confirmed after correction for a prior misclassification of hilar CCA as intrahepatic CCA.2 Similarly, increasing incidence rates of intrahepatic CCA have also been reported in Western Europe and Japan.9,10 The cause for the increasing incidence has not been identified. We speculate that increased lipid mediators such as oxysterols may contribute to the current increased incidence in Western societies.11
Etiology of CCA
Etiologic and experimental evidence implicates inflammation and cholestasis as key factors in the pathogenesis of CCA. Table 1
Pathogenesis of CCA
Table 2. The majority of these genetic changes were described in intrahepatic CCA.
Diagnosis of CCA
Intrahepatic mass-forming CCA presents with symptoms typical for hepatic masses, including abdominal pain, malaise, night sweats, and cachexia. Ultrasound and computed tomography (CT) are only of limited value for detection of intrahepatic and extrahepatic CCA due to their low sensitivity and specificity, as well as their low accuracy in estimating tumor extent of intrahepatic and extrahepatic CCA. 78,89–91
MRCP/magnetic resonance imaging (MRI) provides information about intrahepatic location and tumor dimensions of intrahepatic CCA, ductal as well as periductal tumor extent of extrahepatic CCA, vascular involvement, and metastases (Fig. 2).
In indeterminate cases, establishment of a diagnosis can be attempted with positron emission tomography (PET) with [18F]-2-deoxy-glucose.78,90 Sensitivity and specificity of integrated PET/CT in the identification of primary lesions has been reported as 93% and 80% for intrahepatic CCA and 55% and 33% for extrahepatic CCA.97
The introduction of digital image analysis (DIA) and fluorescence in situ hybridization (FISH) have significantly increased the diagnostic yield of brush cytology. Both techniques depend on the identification of aneuploidy.
Staging of CCA
This classification is a pathologic staging system and therefore often requires surgical acquisition of the tissue. An optimal staging system should provide detailed information about disease extent, vascular involvement, and metastases without subjecting the patient to surgical treatment. It should also take into account treatment options, performance status, and age and correlate with meaningful clinical outcomes. There is an urgent need for such a validated staging system in hilar CCA. Without a staging system, stratification of patients for clinical trials is currently hampered. Table 3
Surgical Therapy of CCA
Results of liver transplantation for intrahepatic CCA are discouraging with 5-year survival rates of 0% to 18%, and therefore cannot be recommended.108,129–132
New In Vivo Models of CCA
Liver-specific combined deletion of the tumor suppressor genes Smad4 plus PTEN results in formation of CCA in mice.195 Another model of intrahepatic mass-forming CCA is achieved by treating p53-deficient mice with carbon tetrachloride (CCl4).205 Sirica and colleagues developed two models of CCA in which malignant transformation of explanted rat cholangiocytes followed by direct biliary inoculation of these cells resulted in CCA formation in 56% to 100% of animals.73,206 In summary, new models of CCA have been developed that resemble human CCA in many aspects. The majority of these models represent intrahepatic CCA, however, and genetic models of hilar CCA still need to be developed.
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