Cholangiocarcinoma

Cholangiocarcinoma is a cancer of the bile ducts, which drain bile from the liver into the small intestine. It is a relatively rare cancer, with an annual incidence of 1–2 cases per 100,000 in the Western world, but rates of cholangiocarcinoma have been rising worldwide over the past several decades. Risk factors for cholangiocarcinoma include primary sclerosing cholangitis (an inflammatory disease of the bile ducts), congenital liver malformations, infection with the parasitic liver flukes Opisthorchis viverrini or Clonorchis sinensis, and exposure to Thorotrast (thorium dioxide), a chemical previously used in medical imaging. The symptoms of cholangiocarcinoma include jaundice, weight loss, and sometimes generalized itching. The disease is diagnosed through a combination of blood tests, imaging, endoscopy, and sometimes surgical exploration. 

Surgery is the only potentially curative treatment, but most patients have advanced and inoperable disease at the time of diagnosis. After surgery, adjuvant chemotherapy or radiation therapy may be given to increase the chances of cure. Patients with advanced and inoperable cholangiocarcinoma are generally treated with chemotherapy and palliative care measures. Areas of ongoing medical research in cholangiocarcinoma include the use of newer targeted therapies (such as erlotinib) and the use of photodynamic therapy.

 The most common symptom of cholangiocarcinoma is jaundice (yellowing of the eyes and skin), which occurs when bile ducts are blocked by the tumor. Other common symptoms include, in order of frequency: generalized itching (66%), abdominal pain (30%–50%), weight loss (30%–50%), and fever (up to 20%). To some extent, the symptoms depend upon the location of the tumor; patients with cholangiocarcinoma in the extrahepatic bile ducts (outside the liver) are more likely to have jaundice, while those with tumors of the bile ducts within the liver often have pain without jaundice.

 Blood tests of liver function in patients with cholangiocarcinoma often reveal a so-called "obstructive picture", with elevated bilirubin, alkaline phosphatase, and gamma glutamyl transferase levels and relatively normal transaminase levels. Such laboratory findings suggest obstruction of the bile ducts, rather than inflammation or infection of the liver, as the primary cause of the jaundice.

Epidemiology

Cholangiocarcinoma is a relatively rare form of cancer; each year, approximately 2,000 to 3,000 new cases are diagnosed in the United States, translating into an annual incidence of 1–2 cases per 100,000 people. Autopsy series have reported a prevalence of 0.01% to 0.46%. There is a higher prevalence of cholangiocarcinoma in Asia, which has been attributed to endemic chronic parasitic infestation. The incidence of cholangiocarcinoma increases with age, and the disease is slightly more common in men than in women (possibly due to the higher rate of primary sclerosing cholangitis, a major risk factor, in men). The prevalence of cholangiocarcinoma in patients with primary sclerosing cholangitis may be as high as 30%, based on autopsy studies. 

Multiple studies have documented a steady increase in the incidence of intrahepatic cholangiocarcinoma over the past several decades; increases have been seen in North America, Europe, Asia, and Australia. The reasons for the increasing occurrence of cholangiocarcinoma are unclear; improved diagnostic methods may be partially responsible, but the prevalence of potential risk factors for cholangiocarcinoma, such as HIV infection, has also been increasing during this time frame. 

Risk factors

A number of risk factors for the development of cholangiocarcinoma have been described; in the Western world, the most common of these is primary sclerosing cholangitis (PSC), an inflammatory disease of the bile ducts which is in turn closely associated with ulcerative colitis (UC). Epidemiologic studies have suggested that the lifetime risk of developing cholangiocarcinoma for a person with PSC is 10%–15%, although autopsy series have found rates as high as 30% in this population. The mechanism by which PSC increases the risk of cholangiocarcinoma is not well-understood.

 Certain parasitic liver diseases may be risk factors as well. Colonization with the liver flukes Opisthorchis viverrini (found in Thailand, Laos, and Malaysia) or Clonorchis sinensis (found in Japan, Korea, and Vietnam) has been associated with the development of cholangiocarcinoma. Patients with chronic liver disease, whether in the form of viral hepatitis (e.g. hepatitis B or C) alcoholic liver disease, or cirrhosis from other causes, are at increased risk of cholangiocarcinoma. HIV infection was also identified in one study as a potential risk factor for cholangiocarcinoma, although it was unclear whether HIV itself or correlated factors (e.g. hepatitis C infection) were responsible for the association.

 Congenital liver abnormalities, such as Caroli's syndrome or choledochal cysts, have been associated with an approximately 15% lifetime risk of developing cholangiocarcinoma. The rare inherited disorders Lynch syndrome II and biliary papillomatosis are associated with cholangiocarcinoma. The presence of gallstones (cholelithiasis) is not clearly associated with cholangiocarcinoma. However, intrahepatic stones (so-called hepatolithiasis), which are rare in the West but common in parts of Asia, have been strongly associated with cholangiocarcinoma. Exposure to Thorotrast, a form of thorium dioxide which was used as a radiologic contrast medium, has been linked to the development of cholangiocarcinoma as late as 30–40 years after exposure; Thorotrast was banned in the United States in the 1950s due to its carcinogenicity.

Pathophysiology

 Cholangiocarcinoma can affect any area of the bile ducts, either within or outside the liver. Tumors occurring in the bile ducts within the liver are referred to as intrahepatic; those occurring in the ducts outside the liver are extrahepatic, and tumors occurring at the site where the bile ducts exit the liver may be referred to as perihilar. A cholangiocarcinoma occurring at the junction where the left and right hepatic ducts meet to form the common bile duct may be referred to eponymously as a Klatskin tumor.

 The cell of origin of cholangiocarcinoma is unknown, although recent evidence has suggested that it may arise from a pluripotent hepatic stem cell. Cholangiocarcinoma is thought to develop through a series of stages — from early hyperplasia and metaplasia, through dysplasia, to the development of frank carcinoma — in a process similar to that seen in the development of colon cancer. Chronic inflammation and obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in this progression.

 Histologically, cholangiocarcinomas may vary from undifferentiated to well-differentiated. They are often surrounded by a brisk fibrotic or desmoplastic tissue response; in the presence of extensive fibrosis, it can be difficult to distinguish well-differentiated cholangiocarcinoma from normal reactive epithelium. There is no entirely specific immunohistochemical stain that can distinguish malignant from benign biliary ductal tissue, although staining for cytokeratins, carcinoembryonic antigen, and mucins may aid in diagnosis. Most tumors (>90%) are adenocarcinomas.

Diagnosis

 Cholangiocarcinoma is definitively diagnosed from tissue, i.e. it is proven by biopsy or examination of the tissue excised at surgery. It may be suspected in a patient with obstructive jaundice. Considering