Excerpt from Cholangiocarcinoma

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Background

Cholangiocarcinoma 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:

• Parasitic diseases of the biliary tract with either Clonorchis sinensis or Opisthorchis viverrini infestation (C sinensis infestation is the most common cause worldwide.)

• Congenital choledochal cysts

• Inflammatory bowel disease (The risk increases 10 times. The incidence of cholangiocarcinomas in patients with ulcerative colitis is 0.4-1.4%, with a latent period of 15 y.)

• Primary sclerosing cholangitis (10% of cases)

• History of other malignancy (10% of cases)

• Previous surgery for choledochal cyst or biliary atresia

• Alpha1-antitrypsin deficiency

• Autosomal dominant polycystic kidney disease

• Gallstones (20-50% of cases, probably coincidental)

• Papillomatosis of the bile ducts

• Thorotrast exposure

• Chronic typhoid carrier status

Pathophysiology

Origin

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%.

Frequency

United States

Primary 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.

International

Cholangiocarcinoma 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/Morbidity

Less 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%.

• Most patients die within a year of diagnosis.
• Recurrence of cholangiocarcinoma after liver transplantation is common.

Race

No 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.

Sex

In contrast to gallbladder carcinoma, cholangiocarcinoma has a male preponderance, with a male-to-female ratio of 3:2.

Age

The patient's age at presentation may vary, but the incidence peaks in those in the 50s.

• Intrahepatic cholangiocarcinoma occurs in those aged 50-60 years.
• Extrahepatic cholangiocarcinoma occurs in those aged 60-70 years.

Anatomy

The 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 Details

Intrahepatic 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 Examination

The 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.

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