Malhi H, Gores GJ (2006) Cholangiocarcinoma: modern advances in understanding a deadly old disease. J Hepatol, 45(6):856-867
Introduction
Most cholangiocarcinomas arise in the absence of any known predisposition (5)
Classification
Cholangiocarcinomas can be classified into 3 distinct categories by anatomic location. These are intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma and distal extrahepatic bile duct cancers (Fig. 1 v Imp).
Hilar cancers, also known as Klatskin tumors, occur at the confluence of the right and left hepatic ducts, are the most frequent (50-60%) and can involve the liver by direct extension (6). Because of the proximity of hilar and left and right branch tumors to the liver, they are included in intrahepatic cholangiocarcinomas in the SEER (Surveillance Epidemiology and End Results) database frequently used for epidemiologic studies. This practice is confusing and should be avoided. In this review intrahepatic cholangiocarcinoma refers only to tumors that originate within the hepatic parenchyma. Of the non-hilar tumors, 10% are intrahepatic and 20-30% are extrahepatic distal bile duct tumors. Further classification of both intrahepatic and extrahepatic tumors is based on gross tumor morphology. Three categories of cholangiocarcinoma have been identified based on their growth pattern: massforming, periductal-infiltrating, or intraductal-growing cholangiocarcinomas (7).
Risk Factors
Chronic hepatitis C virus (HCV) infection was reported as a risk factor for intrahepatic cholangiocarcinoma initially in the East (9). Subsequently, it was identified as a risk factor even in the United States. HCV core protein has been detected in patient samples of cholangiocarcinoma (10).
Inflammation and Carcinogenesis
Molecular perturbations that lead to emergence of a cancerous phenotype involve the following pathways: growth autonomy, escape from senescence, unlimited replication, blockade of growth inhibitory signals, altered microenvironment and evasion of cell death. In chronically inflamed biliary epithelium several changes culminate in the upregulation of growth and prevention of cell death (Fig. 3).
Diagnosis
In summary, there are multiple parallel diagnostic algorithms to confirm cancer in suspicious cases. Cancer should be carefully sought and confirmed or excluded in patients with high grade strictures, elevated CA 19-9 and suspicious masses. Though histologic diagnosis is the gold standard, per-cutaneous or trans-luminal approach is not recommended because of the risk of tumor seeding. Ideally, biliary tissue should be obtained by ERCP. Non-diagnostic biopsy or cytology should not exclude the diagnosis of cholangiocarcinoma. Screening biliary instrumentation in stable, asymptomatic PSC patients is not recommended due to the concurrent risk of pancreatitis (>7% in patients with PSC, Dr. K. Lindor, personal communication), however, when clinically indicated advanced testing should be utilized to diagnose early cancers in PSC patients. Asymptomatic high risk patients maybe surveyed noninvasively, such as with a serum CA 19-9 value and MRCP annually to achieve early cancer detection, although there are no outcome studies or cost-effectiveness information to advocate this approach.
Staging
There is no unified single staging system for all cholangiocarcinomas, reflecting the different patho-biology of intrahepatic and extrahepatic tumors. The staging of Cholangiocarcinoma has also been dynamic. There have been several modifications and alternatives proposed, with the objective of improving the prognostic and therapeutic predictions for each cancer stage. For staging intrahepatic cholangiocarcinoma the proposed system correlates with survival after hepatic resection (59). Stage I disease is a solitary tumor without vascular involvement, Stage II disease is a solitary tumor with vascular encasement/invasion, Stage IIIA disease is multiple tumors with or without vascular involvement, Stage IIIB disease is any tumor with regional lymph node metastasis, and Stage IV disease is any tumor with distant metastases.
THERAPY
Curative Surgical Resection
Surgical resection is indicated in patients with cholangiocarcinoma in the absence of underlying liver or biliary tract disease. Solitary intrahepatic cholangiocarcinoma lesions are amenable to surgical resection. A partial hepatectomy with removal of the involved bile ducts is performed. Five year patient survival ranges from approximately 20-43%, the higher survival stems from careful patient selection (61-64). In the remainder, recurrent disease is the norm. Strategies to prolong disease free survival using neoadjuvant therapy or adjuvant therapy with radiation or chemotherapy are not effective. The best predictors of survival are the absence of lymph node involvement, negative tumor margins up to 1cm, solitary lesions, and lack of microscopic vascular invasion. Perineural involvement and tumor site do not affect survival. Liver transplantation is contraindicated in these patients due to the universal recurrence rates and lack of effective neoadjuvant or adjuvant therapy.
Tumor Palliation
Initial trials of chemotherapy were 5-fluorouracil (5FU) based. The response rates with 5FU alone were 10% at best. Several 5FU based combinations, including doxorubicin, mitomycin C, methyl-CCNU, streptozotocin, and cisplatin + epirubicin were of no added benefit(88,89). This led to the use of gemcitabine, which has become the mainstay of chemotherapy(90-92). Response rates ranging from 16% to 36% have been reported, based on different drug administration protocols. However, even with an initial 36% response rate, median survival was poor (6.5 months). It has also been tried in combination with other agents such as cisplatin, and 5-fluorouracil, and the of Gemcitabine ± Cisplatin is now in Phase III trials. Several other agents are in Phase I/II trials.
Introduction
Most cholangiocarcinomas arise in the absence of any known predisposition (5)
Classification
Cholangiocarcinomas can be classified into 3 distinct categories by anatomic location. These are intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma and distal extrahepatic bile duct cancers (Fig. 1 v Imp).
Hilar cancers, also known as Klatskin tumors, occur at the confluence of the right and left hepatic ducts, are the most frequent (50-60%) and can involve the liver by direct extension (6). Because of the proximity of hilar and left and right branch tumors to the liver, they are included in intrahepatic cholangiocarcinomas in the SEER (Surveillance Epidemiology and End Results) database frequently used for epidemiologic studies. This practice is confusing and should be avoided. In this review intrahepatic cholangiocarcinoma refers only to tumors that originate within the hepatic parenchyma. Of the non-hilar tumors, 10% are intrahepatic and 20-30% are extrahepatic distal bile duct tumors. Further classification of both intrahepatic and extrahepatic tumors is based on gross tumor morphology. Three categories of cholangiocarcinoma have been identified based on their growth pattern: massforming, periductal-infiltrating, or intraductal-growing cholangiocarcinomas (7).
Risk Factors
Chronic hepatitis C virus (HCV) infection was reported as a risk factor for intrahepatic cholangiocarcinoma initially in the East (9). Subsequently, it was identified as a risk factor even in the United States. HCV core protein has been detected in patient samples of cholangiocarcinoma (10).
Inflammation and Carcinogenesis
Molecular perturbations that lead to emergence of a cancerous phenotype involve the following pathways: growth autonomy, escape from senescence, unlimited replication, blockade of growth inhibitory signals, altered microenvironment and evasion of cell death. In chronically inflamed biliary epithelium several changes culminate in the upregulation of growth and prevention of cell death (Fig. 3).
Diagnosis
In summary, there are multiple parallel diagnostic algorithms to confirm cancer in suspicious cases. Cancer should be carefully sought and confirmed or excluded in patients with high grade strictures, elevated CA 19-9 and suspicious masses. Though histologic diagnosis is the gold standard, per-cutaneous or trans-luminal approach is not recommended because of the risk of tumor seeding. Ideally, biliary tissue should be obtained by ERCP. Non-diagnostic biopsy or cytology should not exclude the diagnosis of cholangiocarcinoma. Screening biliary instrumentation in stable, asymptomatic PSC patients is not recommended due to the concurrent risk of pancreatitis (>7% in patients with PSC, Dr. K. Lindor, personal communication), however, when clinically indicated advanced testing should be utilized to diagnose early cancers in PSC patients. Asymptomatic high risk patients maybe surveyed noninvasively, such as with a serum CA 19-9 value and MRCP annually to achieve early cancer detection, although there are no outcome studies or cost-effectiveness information to advocate this approach.
Staging
There is no unified single staging system for all cholangiocarcinomas, reflecting the different patho-biology of intrahepatic and extrahepatic tumors. The staging of Cholangiocarcinoma has also been dynamic. There have been several modifications and alternatives proposed, with the objective of improving the prognostic and therapeutic predictions for each cancer stage. For staging intrahepatic cholangiocarcinoma the proposed system correlates with survival after hepatic resection (59). Stage I disease is a solitary tumor without vascular involvement, Stage II disease is a solitary tumor with vascular encasement/invasion, Stage IIIA disease is multiple tumors with or without vascular involvement, Stage IIIB disease is any tumor with regional lymph node metastasis, and Stage IV disease is any tumor with distant metastases.
THERAPY
Curative Surgical Resection
Surgical resection is indicated in patients with cholangiocarcinoma in the absence of underlying liver or biliary tract disease. Solitary intrahepatic cholangiocarcinoma lesions are amenable to surgical resection. A partial hepatectomy with removal of the involved bile ducts is performed. Five year patient survival ranges from approximately 20-43%, the higher survival stems from careful patient selection (61-64). In the remainder, recurrent disease is the norm. Strategies to prolong disease free survival using neoadjuvant therapy or adjuvant therapy with radiation or chemotherapy are not effective. The best predictors of survival are the absence of lymph node involvement, negative tumor margins up to 1cm, solitary lesions, and lack of microscopic vascular invasion. Perineural involvement and tumor site do not affect survival. Liver transplantation is contraindicated in these patients due to the universal recurrence rates and lack of effective neoadjuvant or adjuvant therapy.
Tumor Palliation
Initial trials of chemotherapy were 5-fluorouracil (5FU) based. The response rates with 5FU alone were 10% at best. Several 5FU based combinations, including doxorubicin, mitomycin C, methyl-CCNU, streptozotocin, and cisplatin + epirubicin were of no added benefit(88,89). This led to the use of gemcitabine, which has become the mainstay of chemotherapy(90-92). Response rates ranging from 16% to 36% have been reported, based on different drug administration protocols. However, even with an initial 36% response rate, median survival was poor (6.5 months). It has also been tried in combination with other agents such as cisplatin, and 5-fluorouracil, and the of Gemcitabine ± Cisplatin is now in Phase III trials. Several other agents are in Phase I/II trials.
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