Cholangiocarcinoma


Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever. Light colored stool or dark urine may also occur. Other biliary tract cancers include gallbladder cancer and cancer of the ampulla of Vater.
Risk factors for cholangiocarcinoma include primary sclerosing cholangitis, ulcerative colitis, cirrhosis, hepatitis C, hepatitis B, infection with certain liver flukes, and some congenital liver malformations. Most people have no identifiable risk factors. The diagnosis is suspected based on a combination of blood tests, medical imaging, endoscopy, and sometimes surgical exploration. The disease is confirmed by examination of cells from the tumor under a microscope. It is typically an adenocarcinoma.
Cholangiocarcinoma is typically incurable at diagnosis, which is why early detection is ideal. In these cases palliative treatments may include surgical resection, chemotherapy, radiation therapy, and stenting procedures. In about a third of cases involving the common bile duct and, less commonly, with other locations, the tumor can be completely removed by surgery, offering a chance of a cure. Even when surgical removal is successful, chemotherapy and radiation therapy are generally recommended. In some instances, surgery may include a liver transplantation. Even when surgery is successful, the 5-year survival probability is typically less than 50%.
Cholangiocarcinoma is rare in the Western world, with estimates of it occurring in 0.5–2 people per 100,000 per year. Rates are higher in Southeast Asia where liver flukes are common. Rates in parts of Thailand are 60 per 100,000 per year. It typically occurs in people in their 70s, and in the 40s for those with primary sclerosing cholangitis. Rates of cholangiocarcinoma within the liver in the Western world have increased.

Signs and symptoms

The most common physical indications of cholangiocarcinoma are abnormal liver function tests, jaundice, abdominal pain, generalized itching, weight loss, fever, and changes in the color of stool or urine. To some extent, the symptoms depend upon the location of the tumor: people with cholangiocarcinoma in the extrahepatic bile ducts are more likely to have jaundice, while those with tumors of the bile ducts within the liver more often have pain without jaundice.
Blood tests of liver function in people 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 parenchyma, as the primary cause of the jaundice.

Risk factors

Although most people present without any known risk factors evident, 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, an inflammatory disease of the bile ducts which is closely associated with ulcerative colitis. Epidemiologic studies have suggested that the lifetime risk of developing cholangiocarcinoma for a person with PSC is on the order of 10–15%, although autopsy series have found rates as high as 30% in this population. For inflammatory bowel disease patients with altered DNA repair functions, the progression from PSC to cholangiocarcinoma may be a consequence of DNA damage resulting from biliary inflammation and bile acids. The gut microbiota and bile acid activity are intricately linked and likely play crucial roles in cholangiocarcinoma development.
Certain parasitic liver diseases may be risk factors as well. Colonization with the liver flukes Opisthorchis viverrini or Clonorchis sinensis has been associated with the development of cholangiocarcinoma. Control programs aimed at discouraging the consumption of raw and undercooked food have been successful at reducing the incidence of cholangiocarcinoma in some countries. People with chronic liver disease, whether in the form of viral hepatitis, alcoholic liver disease, or cirrhosis of the liver due to other causes, are at significantly 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 other correlated and confounding factors were responsible for the association.
Infection with the bacteria Helicobacter bilis and Helicobacter hepaticus species can cause biliary cancer.
Congenital liver abnormalities, such as Caroli disease, have been associated with an approximately 15% lifetime risk of developing cholangiocarcinoma. The rare inherited disorders Lynch syndrome II and biliary papillomatosis have also been found to be associated with cholangiocarcinoma. The presence of gallstones is not clearly associated with cholangiocarcinoma. Intrahepatic stones, 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 hepatic duct may be referred to eponymously as a Klatskin tumor.
Although cholangiocarcinoma is known to have the histological and molecular features of an adenocarcinoma of epithelial cells lining the biliary tract, the actual cell of origin is unknown. Recent evidence has suggested that the initial transformed cell that generates the primary tumor 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 are adenocarcinomas.

Diagnosis

Blood tests

There are no specific blood tests that can diagnose cholangiocarcinoma by themselves. Serum levels of carcinoembryonic antigen and CA19-9 are often elevated, but are not sensitive or specific enough to be used as a general screening tool. They may be useful in conjunction with imaging methods in supporting a suspected diagnosis of cholangiocarcinoma.

Abdominal imaging

of the liver and biliary tree is often used as the initial imaging modality in people with suspected obstructive jaundice. Ultrasound can identify obstruction and ductal dilatation and, in some cases, may be sufficient to diagnose cholangiocarcinoma. Computed tomography scanning may also play an important role in the diagnosis of cholangiocarcinoma.

Imaging of the biliary tree

While abdominal imaging can be useful in the diagnosis of cholangiocarcinoma, direct imaging of the bile ducts is often necessary. Endoscopic retrograde cholangiopancreatography, an endoscopic procedure performed by a gastroenterologist or specially trained surgeon, has been widely used for this purpose. Although ERCP is an invasive procedure with attendant risks, its advantages include the ability to obtain biopsies and to place stents or perform other interventions to relieve biliary obstruction. Endoscopic ultrasound can also be performed at the time of ERCP and may increase the accuracy of the biopsy and yield information on lymph node invasion and operability. As an alternative to ERCP, percutaneous transhepatic cholangiography may be utilized. Magnetic resonance cholangiopancreatography is a non-invasive alternative to ERCP. Some authors have suggested that MRCP should supplant ERCP in the diagnosis of biliary cancers, as it may more accurately define the tumor and avoids the risks of ERCP.

Surgery

may be necessary to obtain a suitable biopsy and to accurately stage a person with cholangiocarcinoma. Laparoscopy can be used for staging purposes and may avoid the need for a more invasive surgical procedure, such as laparotomy, in some people.

Pathology

Histologically, cholangiocarcinomas are classically well to moderately differentiated adenocarcinomas. Immunohistochemistry is useful in the diagnosis and may be used to help differentiate a cholangiocarcinoma from hepatocellular carcinoma and metastasis of other gastrointestinal tumors. Cytological scrapings are often nondiagnostic, as these tumors typically have a desmoplastic stroma and, therefore, do not release diagnostic tumor cells with scrapings.

Staging

Although there are at least three staging systems for cholangiocarcinoma, none have been shown to be useful in predicting survival. The most important staging issue is whether the tumor can be surgically removed, or whether it is too advanced for surgical treatment to be successful. Often, this determination can only be made at the time of surgery.
General guidelines for operability include:
  • Absence of lymph node or liver metastases
  • Absence of involvement of the portal vein
  • Absence of direct invasion of adjacent organs
  • Absence of widespread metastatic disease