All About Cholangiocarcinoma

OncoLink Team
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 13, 2014

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What is cholangiocarcinoma?

Cholangiocarcinoma is cancer of the bile duct. A bile duct carries bile from the liver to the small intestine. About 95% of cholangiocarcinomas are classified histologically (what type of tumor cells are seen when the tumor is examined under a microscope) as adenocarcinomas. Cholangiocarcinoma develops in the epithelial cells which line the bile ducts. In general, cholangiocarcinomas occur in the bile ducts within the liver (intrahepatic), the bile ducts just outside of the liver (perihilar) and distal bile ducts. The majority of cholangiocarcinomas (about 60-70%) appear in the perihilar region. About 25% arise from the distal ductal system and 5-10% from the intrahepatic ductal system. Cholangiocarcinomas do not include cancers that arise from the Ampulla of Vater or the gallbladder. Cholangiocarcinomas that involve the area where the right and left ducts meet to form the common bile duct have a special name (Klatskin tumors).

Cholangiocarcinomas are rare tumors. It is estimated that approximately 2000-3000 people in the United States will be diagnosed with cholangiocarcinoma annually. Approximately 2% of all cancer diagnoses in the United States will originate in the liver or bile ducts, with a diagnosis incidence of about 7.9 per 100,000 individuals. There is a higher prevalence of cholangiocarcinoma in the Middle East and Asia due to a higher prevalence of liver flukes, a common parasitic infection, and an increased incidence of biliary stones. Cholangiocarcinoma tends to occur in older persons. It is estimated that two out of every three people diagnosed are over the age of 65. There is data that suggests that the incidence of cholangiocarcinoma and liver cancer is slowing rising.

What is bile and the biliary system?

Bile is a greenish substance made in the liver, and stored in the gall bladder. Bile assists in the digestion of fats by breaking them down into amino acids, fat soluble vitamins (vitamins A, D,E and K) as well as disposed of hemoglobin from old red blood cells which are no longer functional.

The network of ducts which transport the bile is known as the biliary system. This system can be broken down into several sections:

  1. The ducts which are inside of the liver (intrahepatic)
    Small bile ductules in the liver combine with each other to form larger ducts known as intrahepatic bile ducts. The liver can be grossly divided into two lobes, the left and the right. As the intrahepatic ducts combine with each other they form two large ducts known as the right and left hepatic ducts. The left and right hepatic ducts come together to form the common hepatic duct.
  2. The ducts immediately outside of the liver (perihilar)
    The gallbladder sits just below the liver and the cystic duct delivers bile into and out of the gallbladder. As the common hepatic duct exits the liver it connects with the cystic duct to form the common bile duct.
  3. The distal biliary tree
    The common bile duct enters the pancreas. It combines with the pancreatic duct. Secretions from both the pancreas and the common bile duct exit into the duodenum through the Ampulla of Vater.

Risk factors and prevention

Risk factors associated with cholangiocarcinoma include increased age, obesity, hepatitis and a family history. There are also certain medical conditions that can increase your risk for cholangiocarcinoma including primary sclerosing cholangitis (PSC), ulcerative colitis, cholechochal cysts and biliary infections (like those that occur in typhoid carriers). There is also a possible link between exposure to certain chemicals, nitrosamines, dioxin, asbestos and polychlorinated biphenyls and cholangiocarcinoma.

There are few recommendations for prevention of cholangiocarcinoma. Experts recommend decreasing exposure to the previously mentioned chemicals. Hepatitis vaccinations may decrease risk of cholangiocarcinoma. It is also important to be sure to eat well, exercise regularly, quit smoking (or don't start!) and see your primary care physician annually for a routine physical exam and lab tests.

What screening tests are available?

At this time, there are no tests that have been shown to be effective in screening for or detecting cholangiocarcinoma. However, there are several blood tests that can be used to help monitor treatment efficacy in cholangiocarcinoma. These tests include the Carcinoembryonic Antigen (CEA) and the Cancer Antigen 19-9 (CA 19-9).

CEA screens for a protein that is usually associated with fetal development, but has also been shown to be elevated in people with certain types of cancer; most often colon cancer. CEA can also be elevated in some lung, breast, pancreas, ovarian cancers, and cholangiocarcinomas. A CEA screening is not a full proof test, as several non-cancerous medical conditions, including cirrhosis, infection, pancreatitis and inflammatory bowel disease, can cause an elevated CEA. Smoking is also known to increase blood levels of CEA.

Studies have investigated the use of CA 19-9 in detecting cholangiocarcinoma. Elevated levels of CA 19-9 are most commonly found in people with pancreatic cancer, though it can also be elevated in colon and stomach cancers and cholangiocarcinoma. Several non-cancerous medical conditions, including cirrhosis, pancreatitis, cholangitis, and gallstones, can also cause an elevated CA 19-9.

There have been several challenges in the application of CA 19-9 to cholangiocarcinoma, including the difficulty in determining how high a CA 19-9 needs to be in order to indicate if a cancer is present. Currently, the best use for CA 19-9 may not be as a screening test for cholangiocarcinoma, but rather as a way to check if the disease is responding to treatments. There are also studies underway to use the results from both the CEA and the CA 19-9 tests to screen people at high risk for cholangiocarcinoma, such as those with PSC.

Imaging studies (x-rays, CT scans, MRI's) that are used when the diagnosis of cholangiocarcinoma is suspected have not been found to be effective screening tools.

What are the signs and symptoms of cholangiocarcinoma?

Most symptoms associated with cholangiocarcinoma result from the obstruction of the biliary tree by the tumor. Symptoms include painless jaundice (the presence of too much bilirubin which results in a yellowing of the skin and whites of the eyes), itchy skin, weight loss, fever (in conjunction with biliary tree infection), gray/clay colored stool and dark urine.

During physical examination, your physician may detect an enlargement of the liver (hepatomegaly) or may feel a mass in the upper right part of the abdomen. Infrequently, the gallbladder may be enlarged and can also be felt during physical exam.

How is cholangiocarcinoma diagnosed?

If cholangiocarcinoma is suspected, several imaging studies can be used to identify the tumor. An endoscopic or laparoscopic ultrasound uses sound waves to image the biliary tree and check for abnormalities. An endoscopic ultrasound is performed by inserting a camera through the mouth and into the small intestine where is can be placed closed to the tumor. The ultrasound can then determine the size of the tumor and the depth to which the tumor has invaded into the surrounding tissue. A laparoscopic ultrasound is performed during a surgical procedure, where a camera is inserted through a small incision in the abdomen. Again, the ultrasound is placed near the tumor and used to determine tumor size and depth. During both of these types of ultrasound procedures, instruments can be used to take a small sample of tissue (biopsy), which is sent to a pathologist to determine the tumor type.

Another specialized endoscopic technique known as an endoscopic retrograde cholangiopancreatography (ERCP) can be used to find blockages or compressions in the bile ducts which may be related to cholangiocarcinoma. An ERCP is similar to a regular endoscopy procedure in that a small camera on a tube is inserted through the mouth and slowly advanced to the Ampulla of Vater, where the bile drains into the small intestine. Then dye is injected. The dye is observed via x-ray and reveals areas in the biliary tree that are blocked or narrowed. During ERCP, small samples of the bile duct cells are taken using a small brush to gather cells inside the ducts. Brushings can detect cells associated with cholangiocarcinoma 35-70% of the time. During ERCP, the physician can also place a stent to relieve the blockage.

Cholangiography is another method to visualize the biliary tree. During this procedure, enlarged biliary ducts are identified using ultrasound. A needle is then inserted through the skin into the biliary duct and an x-ray visible dye is injected. The dye identifies obstructions in the biliary ducts that may be cause by cholangiocarcinoma.

Another method is cholangioscopy. In this procedure, an endoscope is used to identify the Ampulla of Vater. Then a smaller scope is fed through the larger scope and passed into the Ampulla of Vater and then the biliary tree. The smaller scope can visualize obstructions and allow for biopsy samples to be taken.

Staging

Identifying how much tissue the tumor has invaded, and if it has spread to other organs, assists your treatment team in determining the stage of the cholangiocarcinoma. This information helps your team determine the best course of treatment for you.

There are several imaging studies that help your treatment team visualize the size of the tumor, as well as check for possible metastasis, or spread to other organs. A CT (computerized tomography) scan of the chest, abdomen and pelvis is typically ordered. During the CT scan, x-ray views are taken from different angles. Then a computer processes the pictures and creates cross sectional images of the bones, organs and tissues in your body. CT scans can also be used to determine if the cancer has spread to the lymph nodes. Contrast dye is often given prior to the study, either by mouth or IV (intravenous) to help clarify the pictures of specific areas imaged by the CT scan.

MRI (magnetic resonance imaging) is a test that uses a large magnetic field and pulses of radio wave energy to take images of parts of the body. MRI can also help determine the size of the tumor and if it has spread. As with CT scans, IV dye may also be used to produce better images. MRIs have some advantages compared with CT scans for imaging of the biliary tree, as they may produce clearer images and do not utilize radiation as CT scan does. However, some patients cannot tolerate MRI due to claustrophobia. A special type of MRI called an MRI MRCP can be performed to visualize the biliary tree and identify tumors.

PET (positron emission tomography) scan is an imaging test that uses a radioactive substance, called a tracer, to detect disease in the body. Whereas a CT or MRI scan will show organ structure and blood flow, a PET scan shows us how organs and tissues are working or not working. PET scans also help your healthcare team identify benign versus cancerous masses. 

After imaging and lab testing are completed, your healthcare team will assign a stage to your tumor.

Stage 0: In this stage, the cholangiocarcinoma only involves the lining of the bile ducts and has not spread to lymph nodes or other organs.

Stage IA: Cholangiocarcinomas that invade the bile duct.

Stage IIB: Cholangiocarcinomas that have penetrated through the bile duct to the surrounding fat tissue or liver, but have not spread to lymph nodes or other organs.

Stage IIIA: Cholangiocarcinomas that have invaded into adjacent organs, such as the liver, or surrounding fat, or if the tumor has invaded a branch of the portal vein or hepatic (liver) artery.

Stage IIIB: Cholangiocarinomas that have invaded into adjacent organs, such as the liver and surrounding fat, or if the tumor has invaded a branch of the portal vein or hepatic (liver) artery and lymph nodes are involved.

Stage IV: Cholangiocarcinomas that have spread to other distant organs.

See Appendix A [CV1] below for further information regarding TNM staging guidelines that your team may use to help describe your tumor as well as to determine treatment plans. The TNM results are compiled to come up with the stages above.

Treatment of cholangiocarcinoma

Treatments are generally based on the stage of the disease. For people with stage 0 or Stage 1 disease, surgery alone is generally recommended. However, people rarely present with early stage disease because they often do not have symptoms until the tumor has progressed further. Generally, for higher stage cholangiocarcinomas, the ability to resect the disease becomes the most important predictor of survival. Surgery is recommended if imaging studies suggest that the disease is resectable and there is no evidence of cancer spread. After resection, if visible portions of tumor have been left behind, chemotherapy and radiation are generally recommended. In unresectable disease, chemotherapy and radiation may be used, as well as surgery or stent placement to bypass obstructions in the bile duct and relieve symptoms.

Surgery

Surgical removal of the tumor is the only curative treatment for cholangiocarcinoma. The goal of surgery is to remove as much of the tumor as possible and achieve tumor-free surgical margins. The larger the percentage of tumor left behind, the higher the risk for cancer recurrence. Intrahepatic (tumors within the liver) and perihilar tumors (tumors near the liver) are difficult to resect completely, with tumor free surgical margins obtained in only 20 to 40% of surgeries.

Not all individuals with cholangiocarcinoma can have surgery. Generally, surgery is not possible if the large blood vessels which travel next to the common bile duct, the hepatic artery and the portal vein, are surrounded by tumor, and/or if the tumor has grown into the liver or has metastasized to the liver, lymph nodes or abdominal cavity.

The location of the tumor greatly influences the extent of surgical resection necessary, however all are extensive procedures, which require an experienced surgical care team and significant recuperation time. Due to the complexity of these interventions, serious post-surgical complication rates can be as high as 25-45%.

Intrahepatic (in the liver) tumors are generally treated with resection of the tumor, which can require the removal of an entire lobe of the liver. Perihilar (near the liver) tumors often require resection of a portion of the liver, bile duct, and gallbladder. Additionally, the removal of part of the pancreas and small intestine may also be indicated. Distal tumors (those located further from the liver) can generally be treated with resection of a portion of the small bowel or pancreas.

If the tumor is found to be unresectable, the surgical team may perform a surgical bypass of the blocked portion of the biliary ducts. The procedure involves connecting the portion of the bile duct before the obstruction with a portion of the bile duct beyond the obstruction. This type of procedure allows drainage of the bile alleviating the symptoms of jaundice. However this procedure can have a high incidence of post-surgical complications and studies have suggested that biliary stenting is as effective as surgical bypass in providing relief from obstructive jaundice. Thus, in most cases where imaging studies, such as CT scans, suggest inoperable (unresectable) disease, stent placement is preferred. Up to 50-90% of people with cholangiocarcinomas have tumors which are unresectable when they are diagnosed. In these patients, the primary treatment goal is preventing further blockage of the biliary tree and symptom relief.

A stent can be placed in 70-90% of these cases. A stent is a small flexible plastic or metal tube that is inserted into the bile duct and allows bile to flow again into the small intestine. Stent placement is typically not an invasive procedure and can often be done during ERCP. Metal stents are preferred because they are able to keep ducts open longer, but plastic stents are easier to adjust. Stent placement is a palliative measure, it does not cure the underlying cancer diagnosis, but provides symptom management. A stent is not always a permanent solution to biliary blockage. The tumor can grow into the stent and cause another blockage in the bile ducts. Sometimes radiation is used to prevent this from happening.

Some treatment centers may consider liver transplantation in combination with chemotherapy and radiation for treatment of intrahepatic cholangiocarcinoma. However, this is a controversial procedure that yields minimal favorable outcomes and does not appear to impact overall survival rates significantly.

Radiation

The goal of radiation treatment after surgery is to decrease the chances of tumor recurrence, particularly if there are positive margins. However, radiation's role as an additional treatment in tumors which have been completely resected is unclear, with studies indicating that it is beneficial and others suggesting that it may be harmful. Radiation for cholangiocarcinoma can be given externally using a machine called a linear accelerator or internally using a technique known as brachytherapy.

External beam radiation delivers radiation similar to that used in X-ray machines. However, the energy of the radiation used in linear accelerators is much higher. There are also side effects associated with external beam radiation including skin irritation, nausea and fatigue.

In brachytherapy, a catheter, (flexible tube) is placed in the area where the tumor was. A radioactive source then travels through the catheter to the area where the tumor was/is and delivers radiation directly to that specific area. In inoperable cholangiocarcinoma after stent placement, brachytherapy has been shown to increase the length of time that previously placed stents remain functional (patent) by preventing tumor cells from growing into the stent and blocking the flow of bile. However, there are potentially serious side effects from brachytherapy including cholangitis (infection of the bile ducts), stricture formation (scarring of the bile duct leading to obstruction), and ulcer formation in the intestine.

Chemotherapy

Chemotherapy can be used alone or in combination with surgery and radiation. There are several different chemotherapy options for cholangiocarcinoma. These treatment options are not curative, but offer palliation (symptom management/relief) and control of further tumor progression. Various combinations of chemotherapeutic agents are used in the treatment of cholangiocarcinoma, including 5-FU, mitomycin-C, gemcitabine, oxaliplatin, cisplatin and doxorubicin. Chemotherapy side effects vary based on how the medication is administered (IV vs oral) as well on the types of chemotherapy agents utilized.

Transcatheter arterial chemoembolization (TACE) delivers chemotherapy to a targeted tumor area, while preserving the health of surrounding tissues and organs. This procedure is most commonly used in intrahepatic (inside the liver) cholangiocarcinomas. During TACE, the tumor is targeted in two ways. First, a very high concentration of chemotherapy is delivered directly into the tumor. Second, the blood supply to the tumor is then cut off, entrapping the anti-cancer drugs within the targeted site. The tumor is then denied oxygen and other nutrients it needs to continue to grow. This procedure is performed by an interventional radiologist, in conjunction with your primary oncology team.

Follow up

For patients who have had surgical resection, further treatment options may include radiation therapy and chemotherapy. For all patients, surveillance imaging is considered every 6 months for 2 years post resections if clinically indicated.

Future Directions

Research into the treatment of cholangiocarcinomas continues to develop and evolve. Some options being studied include the use of targeted chemotherapeutic agents including Nexavar, Tarceva, Avastin and Erbitux. These drugs block certain mechanisms that contribute to tumor growth.

Photodynamic therapy (PDT) is also being studied to treat cholangiocarcinoma. With this type of treatment, a medication known as a photosensitizer, is utilized. When the photosensitizer absorbs light it creates oxygen free radicals which are toxic to the tumor and can destroy the tumor cells and structure. PDT has been studied in unresectable cholangiocarcinoma and has been shown to be effective in maintaining the function (patency) of stents. Additionally, several small studies have shown an improvement in bilirubin levels (better drainage of the bile ducts), quality of life, and survival with the use of PDT.

Resources for Further Reading & Support

The Cholangiocarcinoma Foundation

AMMF, The Cholangiocarcinoma Charity of the UK

 

Appendix

[CV1]

Primary Tumor (T)

Regional Lymph Nodes (N)

Distant Metastasis(M)

TX Primary tumor cannot be assesed

NX Regional lymph nodes cannot be assessed

M0 No distant metastasis

T0 No evidence of primary tumor

N0 No regional lymph nodes metastasis

M1 Distant present

T1s Caricnoma in situ (intraductal tumor)

N1 Regional lymph node metastasis present

 

T2a Solitary tumor with vascular invasion

   

T2b Multiple tumors, with or without vascular invasion

   

T3 Tumor perforating the visceral peritoneum or involving the local extra hepatic structure by direct invasion

   

T4 Tumor with periductal invasion

   

Perihilar Bile Duct Tumors

Primary Tumor (T)

Regional Lymph Nodes (N)

Distant Metastasis(M)

TX Primary tumor cannot be assessed

NX Regional lymph nodes cannot be assessed

M0 No distant metastasis

T0 No evidence of primary tumor

N0 No regional lymph node metastasis

M1 Distant metastasis

T1s Carcinoma in situ

N1 Regional lymph node metastasis (including nodes along the cystic duct, common bile duct, hepatic artery, and portal vein)

 

T1 Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue

N2 Metastasis to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes

 

T2a Tumor invades beyond the wall of the bile duct to surrounding adipose tumor

   

T2b Tumor invades adjacent hepatic parenchyma

   

T3 Tumor invades unilateral branches of the portal vein or hepatic artery

   

T4 Tumor invades main portal vein or its branches bilaterally; or the common hepatic artery; or the second order biliary radicals bilaterally; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement

   

Distal Bile Ducts Tumors

Primary Tumor (T)

Regional Lymph Nodes (N)         

Distant Metastasis(M)

TX Primary tumor cannot be assessed

N0 No regional lymph node metastasis

M0 No distant metastasis

T0 No evidence of primary tumor

Regional lymph node metastasis

M1 Distant metastasis

T1s Carcinoma in situ

   

T1 Tumor confined to the bile duct histologically

   

T2 Tumor invades beyond the wall of the bile duct

   

T3 Tumor invades the gallbladder, pancreas, duodenum, or other adjacent organs without involvement of the celiac axis, or the superior mesenteric artery

   

T4 Tumor involved the celiac axis, or the superior mesenteric artery

   

References

American Cancer Society http://www.cancer.org/cancer/bileductcancer/detailedguide/

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Lad, N., & Kooby, D.A. (2014). Distal cholangiocarcinoma. Surgical Oncology Clinics of North America 23(2), 265-287.

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National Comprehensive Cancer Institute http://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf, retrieved 10 October 2014

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Shindoh, J., & Vauthey, J.N. (2014). Staging of biliary tract and primary liver tumors. Surgical Oncology Clinics of North America 23(2), 313-322.

Sithithaworn, P., Yongvanit, P., Duenngai, K., Kiatsopit, N., & Pairojkul, C. (2014). Roles of liver fluke infection as risk factor for cholangiocarcinoma. Journal of Hepato-Biliary-Pancreatic Sciences 21(5), 301-308.

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