Tumors of the biliary tract are uncommon but serious problems. The spectrum of lesions ranges from benign tumors, such as adenomas, to malignant lesions, such as adenocarcinomas. This discussion excludes tumors of the gallbladder, which are discussed separately.
Bile duct tumors have been recognized for over a century. Musser first reported 18 cases of primary extrahepatic biliary cancer. Sako and colleagues found 570 cases of extrahepatic bile duct cancer when reviewing literature from 1935 through 1954. Malignancy of the intrahepatic bile ducts was described in 1957 by Altmeir; Klatskin described cancer of the hepatic duct bifurcation in 1965.
Tumors of the bile duct constitute about 2% of all cancers found at autopsy. Benign adenomas or papillomas are exceedingly rare compared with malignant tumors. Even benign tumors tend to recur after excision and have been reported to undergo malignant change. Patients usually present with jaundice. Occult gastrointestinal (GI) hemorrhage may occur.
Cholangiocarcinomas, the most important primary tumors of the bile ducts, may involve either the intrahepatic or the extrahepatic biliary ducts. The former variety is the second most common primary hepatic malignancy, after hepatocellular carcinoma. Patients with intrahepatic cholangiocarcinoma (cholangiocellular carcinoma) have a poor prognosis, and the tumor metastasizes early. This tumor has been associated with thorium dioxide (Thorotrast, an intravenous contrast medium used many years ago), ulcerative colitis, and sclerosing cholangitis; surgery is the only chance of treatment.
Bile duct cancer differs from gallbladder cancer in that it is distributed more evenly between males and females, and the course is more prolonged. All cholangiocarcinomas are slow-growing and locally infiltrative, and they metastasize late.
Most patients with bile duct tumors present with jaundice due to obstruction of the biliary tree by the tumor. Because the tumors are generally small, standard imaging studies, such as ultrasonography  and computed tomography (CT), may fail to show the lesion. These techniques may, however, provide a clue to the level of the obstruction and help exclude metastatic disease.
Cholangiography via a transhepatic or endoscopic approach is required to define the biliary anatomy and extent of the lesion. Magnetic resonance cholangiography is a noninvasive alternative available in an increasing number of centers.
The anticipated course of most cases of bile duct tumors includes recurrent biliary obstruction with infectious complications, local spread, and death in 6-12 months. Treatment depends on the site and extent of the lesion, and surgical resection improves survival and prognosis.
The liver is an epithelial-mesenchymal outgrowth of the caudal part of the foregut, with which it retains its continuity by the biliary tree. Hepatocytes in the liver are arranged in anatomic plates called hepatic laminae, which are lined by endothelium and separated from each other by hepatic sinusoids. Bile secreted by hepatocytes is collected in a network of canaliculi, which drain into hepatic ductules. In turn, the hepatic ductules join other ductules, forming the biliary tree.
The main right and left hepatic ducts from the liver unite near the right end of the porta hepatis as the common hepatic duct (CHD), which descends for about 2.5 cm before being joined by the cystic duct to form the common bile duct (CBD). The CHD lies to the right of the hepatic artery and anterior to the portal vein.
The CBD is 7.5 cm long and consists of three parts. The upper third lies in the free border of the lesser omentum anterior to the portal vein and to the right of the hepatic artery. The middle third lies behind the first part of the duodenum and slopes down to the right, eventually lying on the inferior vena cava. The lower third slopes down to the right behind the head of the pancreas, lying in a deep groove on the posterior surface of this organ. It opens, in common with the pancreatic duct, into the ampulla of Vater, which is situated in the second part of the duodenum.
The hepatic ducts and the upper and middle portions of the CBD are supplied with blood primarily by rami from the cystic artery. In addition, the middle portion of the CBD is supplied by rami from the right hepatic and posterior superior pancreaticoduodenal arteries. The latter also supplies blood to the lower portion of the CBD. Veins from the upper portion of the biliary tree enter the liver, and those from the lower portion drain into the portal vein.
With regard to lymphatic drainage, the upper portion of the biliary tree drains into the hepatic nodes, whereas the lower portion drains into the inferior hepatic and upper pancreaticosplenic nodes. Metastases from bile duct tumors can occur in lymph nodes lying along the common hepatic artery and the celiac axis and from distal lesions in the retropancreatic and superior mesenteric nodes.
Anatomically, the upper third of the biliary tree extends from the confluence of the hepatic ducts to the level of the cystic duct, the middle third extends from the cystic duct to the upper part of the duodenum, and the lower third extends from that level to the papilla of Vater.
The reported distribution of bile duct tumors is 55% in the upper third, 15% in the middle third, and 10% in the lower third. Of these tumors, 10% are diffuse.
Tumors of the bifurcation of the hepatic ducts are classified by the Bismuth classification, as follows:
Type I - Involvement of the CHD
Type II - Involvement of the bifurcation without involvement of the secondary intrahepatic ducts
Type IIIa - Extends into the right secondary intrahepatic duct
Type IIIb - Extends into the left secondary intrahepatic duct
Type IV - Involvement of the secondary intrahepatic ducts on both sides
Bile duct tumors cause bile duct obstruction with biliary stasis and a consequent alteration of liver function test results. Prolonged biliary obstruction causes hepatocellular dysfunction,  progressive malnutrition, coagulopathy, pruritus, renal dysfunction, and cholangitis.
Longstanding inflammation with the development of chronic injury is the final common pathway for tumorigenesis in the bile ducts in patients with preexisting inflammatory conditions.
Parasitic organisms induce DNA changes and mutations through the production of carcinogens and free radicals and the stimulation of cellular proliferation of the biliary epithelium, which is thought to cause cancer.
Bacterially induced, endogenous, carcinogen-derived bile salts, such as lithocholate, also have been implicated in the pathogenesis. These implications are supported by the findings of some epidemiologic studies and in the higher incidence in typhoid carriers.
Point mutations in codon 12 of the K-ras oncogene are found in cholangiocarcinoma.  Aneuploidy is found in hilar cholangiocarcinoma and is associated with neural invasion and shorter survival. P53 protein is particularly expressed in high-grade midduct and distal duct cholangiocarcinomas.  Cholangiocarcinoma cells contain somatostatin-receptor RNA, and cell lines have specific receptors. Cell growth is inhibited by somatostatin analogues. Cholangiocarcinomas have been detected using radionuclide scanning with a labeled somatostatin analogue. Unique preinvasive lesions appear to precede different types of cholangiocarcinoma (ie, intrahepatic, perihilar, and distal). 
Family history of congenital fibrosis or cysts
Gallstones and hepatolithiasis
Ulcerative colitis, with or without PSC
In the Far East (ie, China, Hong Kong, Korea, Japan), where Clonorchis sinensis (a liver fluke) is prevalent, intrahepatic cholangiocarcinoma accounts for 20% of primary liver tumors.  Opisthorchis viverrini is found in Thailand, Laos, and West Malaysia.
The risk of extrahepatic bile duct cancer is significantly decreased 10 years or more after cholecystectomy, thus suggesting a link between bile duct cancer and gallstones. The risk is much less than that of carcinoma of the gallbladder, which is itself quite rare.
Among patients undergoing liver transplantation for PSC, 10-30% are found to have unsuspected cholangiocarcinoma in the hepatectomy specimen. Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 have, in combination, a sensitivity of 66% and a specificity of 100% in diagnosing cholangiocarcinoma in patients with PSC.
The majority of patients with PSC who develop cholangiocarcinoma have ulcerative colitis. The incidence of cholangiocarcinoma in patients with ulcerative colitis and PSC is further increased if they have associated colorectal malignancy. Patients with PSC who develop a rapid deterioration in clinical status with worsening jaundice, weight loss, and abdominal discomfort and who have evidence of intrahepatic biliary dilatation on ultrasonography  of the abdomen are suspected of having cholangiocarcinoma.
Toxic materials associated with an increased risk of bile duct cancer include thorium dioxide (Thorotrast), radionuclides, and carcinogens (eg, arsenic, dioxin, nitrosamines, polychlorinated biphenyls).
Drugs associated with an increased risk of bile duct cancer include oral contraceptives, methyldopa, and isoniazid.
Chronic typhoid carriers appear to have a greater incidence of hepatobiliary cancer, including cholangiocarcinoma.
Bile duct cancers are also associated with biliary cirrhosis.
The annual incidence of bile duct cancer in the United States is approximately 1 case per 100,000 people. In autopsy studies, the incidence ranges from 0.01% to 0.46%. Patients with bile duct tumors are typically elderly; the average age is 60-65 years. In contrast to carcinoma of the gallbladder, only a minor sex difference in incidence exists, with a very slight male preponderance.
Bile duct cancer is more common in Israel and Japan and in American Indians than it is in the general US population. The prevalence of carcinoma of the gallbladder and bile ducts in England and Wales is 2.8 cases per 100,000 females and 2 cases per 100,000 males.
In patients with bile duct tumors, the choice of treatment and the prognosis are influenced greatly by the location of the tumor. The prognosis is better for distal bile duct tumors, histologically differentiated, and polypoidal tumors. Factors that suggest poor prognosis include involvement of lymph nodes, vascular invasion, advanced T stage, positive tumor margins of the resected specimen, and the presence of mutations of the P53 gene. 
With hilar cholangiocarcinoma, the overall resection rate in most series is in the range of 40-60%. The mean survival rate for patients undergoing curative resection is 67-80% at 1 year and 11-21% at 5 years. Local resection has a lower operative mortality (8%) than does major hepatic resection (15%), with a mean survival of 21 months compared with 24 months for major hepatic resection. No clear indication exists that survival is improved significantly by major hepatic resection as compared with local bile duct resection, though some studies suggest that hepatic resection is associated with a greater incidence of tumor-free margins and, consequently, survival.
In distal bile duct cancers, the resection rate is higher than 60%, and the prognosis is better than for hilar tumors, the mean survival being 39 months. The survival rate is 50-70% at 1 year and 17-39% at 3 years.
In a study of 188 consecutive patients who underwent resection of intrahepatic cholangiocarcinoma, Doussot et al reported estimated survival rates of 59% at 3 years and 45% at 5 years.  The investigators found both the Wang nomogram and the Hyder nomogram to provide accurate estimates of prognosis after liver resection for intrahepatic cholangiocarcinoma. Diffuse intrahepatic tumors have a dismal prognosis; most patients with these tumors die within 1 year of diagnosis.
If left untreated, 50% of patients with bile duct cancer may survive for 1 year, 20% may survive for 2 years, and 10% may survive for 3 years.
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