Cholangiocarcinoma: The Basics

Eric T. Shinohara, MD, MSCI
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: January 9, 2009

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What is bile and what is the biliary system?

Bile is a greenish substance produced by the cells of the liver (hepatocytes) which aids in the digestion of fats. It emulsifies fats, causing the fats to accumulate into droplets which can be easily absorbed in the small intestine. It also aids in the absorption of so call fat soluble vitamins, vitamins A, D, E and K. Bile is also the way the body disposes of hemoglobin from old red blood cells which are no longer functional. This is what makes bile green and stool brown. Once hepatocytes have made bile it is transported to the duodenum, the segment of small intestine right after the stomach, where it is secreted through a small hole known as the Ampulla of Vater. It can then form droplets with fat exiting the stomach. The bile also goes to the gallbladder where it can be stored.

The network of ducts which transport the bile is known as the biliary system. This system can be broken down into several sections. The first section is comprised of the ducts which are inside of the liver, also known as the intrahepatic ducts. 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.

The segment of ducts immediately outside of the liver is known as the perihilar ducts. The gallbladder sits on the underside of 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. The common bile duct enters the pancreas and combines with the pancreatic duct and secretions from both the pancreas and the common bile duct exit into the duodenum through the ampulla of Vater. These areas of ductal system are known as the distal biliary tree.

What is cholangiocarcinoma?

Cholangiocarcinoma is the name given to cancers of the bile duct.  They arise from the epithelial cells which line the bile ducts. Generally, cholangiocarcinomas arise from the intrahepatic (within the liver), perhilar (just outside of the liver) and distal bile ducts. Cholangiocarcinomas excludes cancers which arise from the Ampulla of Vater and the gallbladder. The majority of tumors arise from the perihilar region, which represent 60 to 70% of all cholangiocarcinomas. About 25% arise from the distal ductal system and 5-10% from the intrahepatic ductal system.  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. They occur in about one to two people per 100,000 and represent approximately 3% of all gastrointestinal cancers. It is estimated that approximately 18,500 primary liver cancers were diagnosed in the US in 2006 and of these; approximately 15% of them were intrahepatic cholangiocarcinomas. There are approximately 2000-3000 cases of extrahepatic cholangiocarcinoma a year. However, there is data that suggests that the incidence of cholangiocarcinomas is slowing rising. Cholangiocarcinoma can be further classified histologically (What type of tumor cells are seen when the tumor is examined microscopically). Adenocarcinomas arise from glandular tissue and are the most common type of cholangiocarcinoma, making up 95% of cholangiocarcinomas.  

Am I at Risk for Cholangiocarcinoma?

As with most cancers, increasing age has been linked with cholangiocarcinoma. Additionally, obesity, hepatitis and people with a family history of the disease may be at increased risk. Medical conditions which have been linked to cholangiocarcinoma include primary sclerosing cholangitis, ulcerative colitis, choledochal cysts and biliary infections, such as in typhoid carriers. Chemical exposures to nitrosamines, dioxin, asbestos and polychlorinated biphenyls have also been linked to cholangiocarcinoma.

There are not any guidelines on how to prevent cholangiocarcinomas. However, decreasing exposure to the above mentioned chemicals and getting vaccinated against viruses which cause hepatitis, such as the Hepatitis B virus may help prevent cholangiocarcinoma.  

What Screening Tests are Available?

Screening tests are used to detect diseases in patients without symptoms. Currently, there are no tests which have been shown to be effective in screening for cholangiocarcinoma. There is not a specific blood test which can detect cholangiocarcinoma. However, there are blood tests which can be used to help detect several different types of cancer and their use in detecting cholangiocarcinomas is currently being tested. One such blood test detects a protein known as Carcinoembryonic Antigen (CEA). This protein 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, but it has also be found to be elevated in some lung, breast, pancreas and ovarian cancers. However, other non-cancer medical conditions such as cirrhosis, infection, pancreatitis and inflammatory bowel disease can also cause a positive result. Smoking is also known to increase blood levels of CEA. A normal CEA varies from laboratory to laboratory, but in a non-smoker 3 ng/ml is generally normal and in a smoker 5 ng/ml is generally normal. Recent studies in people with primary sclerosing cholangitis (PSC) found that CEA could be used to help detect cholangiocarcinoma but was not highly accurate. It was able to detect 68% percent of cases of cholangiocarcinoma in people with PSC but it also detected cholangiocarcinoma in 18% of people with PSC who did not actually have cholangiocarcinoma.

Another blood test, Cancer Antigen 19-9 (CA 19-9), has also been studied. 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. Other non-cancer medical conditions, such as cirrhosis, pancreatitis, cholangitis, and gallstones can also cause an elevated CA 19-9. Studies have investigated the use of CA 19-9 in detecting cholangiocarcinoma however there have been several problems. It has been difficult to determine how high a CA 19-9 needs to be in order to indicate if a cancer is present. Part of what causes this difficulty is that cholangitis, which is infection of the bile ducts, and biliary stasis, which is caused by blockage of the bile ducts, can be associated with both benign medical conditions and cholangiocarcinoma. Hence, in studies people who do not have active cholangitis or biliary stasis, a cut off of 37 U/ml has been used. However, in people with active cholangitis or biliary stasis a cutoff of 300-400 U/ml has been used. 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 in people with PSC.

There are several imaging studies used once the diagnosis of cholangiocarcinoma is suspected, however none of these imagining studies has been found to be an effective screening tool.

What are the Signs of Cholangiocarcinoma?

The majority of the symptoms from cholangiocarcinoma arise from obstruction of the biliary tree by the tumor. Symptoms include painless jaundice and abdominal pain, particularly in the right upper portion of the abdomen. Pruritis, or itching, commonly occurs with jaundice as well as weight loss. Fever can also be a presenting sign due to infection of the biliary tree (cholangitis). People may also notice that their stool appears gray or clay colored and that their urine appears darker.

Other signs that may be found during physical examination include enlargement of the liver, also known as hepatomegaly. Less commonly, a mass can be felt in the right upper part of the abdomen in the area of the liver. Rarely, because the tumor can block the bile ducts, the gallbladder can be enlarged and felt during examination.

How is Cholangiocarcinoma Diagnosed?

Generally, cholangiocarcinomas are not detected until people become symptomatic from them. The signs of cholangiocarcinoma are described above and most are caused by the tumor obstructing the biliary tree.    

If cholangiocarcinoma is suspected, several imaging studies can be used to identify the tumor. Ultrasound imaging can be used to detect the tumor. Ultrasound use sound waves to imaging the biliary tree and see if there are any abnormalities. Ultrasound technology can also be combined with a flexible camera, known as an endoscope. Endoscopic ultrasound is performed with the camera entering through the mouth and going into the small intestine where it can be placed close to the tumor. The ultrasound can then be used to determine the size of the tumor and depth to which the tumor has invaded into tissue. Ultrasounds can also be used with a laparoscope, which is a camera that can be inserted into the abdominal cavity through a small hole in the abdomen. The ultrasound is placed near the tumor and is used to determine tumor size and depth. During an endoscopy or laparoscopy, instruments can be used to take a sample of tissue which can be used to confirm that the tumor is cholangiocarcinoma.

A special endoscopic technique, known as endoscopic retrograde cholangiopancreatography (ERCP) can be used to find blockages in the bile ducts, which may be related to cholangiocarcinomas compressing the ducts. Similar to a normal endoscopy, a small camera on a tube is inserted through the mouth and moved to the point where it reached where bile drains into the small intestine (The Ampulla of Vater). A small tube is placed in the Ampulla of Vater, where the bile duct drains in the intestine, and dye is injected into the biliary tree. This dye is visible on X-ray and can reveal areas which are blocked. During ERCP a small brush can be inserted into the bile ducts and used to brush the inside of the ducts. Cells from this brushing are collected and can be used to identify cells from cholangiocarcinoma. Brushings can detect cholangiocarcinomas between 35-70% of the time.

Another way to visualize the biliary tree is through the use of a cholangiography. In this study, enlarged biliary ducts are found using ultrasound. A needle is inserted through the skin into the dilated biliary duct. A dye which will show up on X-ray is injected and allows the location of obstructions that may be caused by cholangiocarcinoma.

There are several modalities which can be used to image the main tumor and to check for possible spreads to other organs (metastasis). These imaging modalities allow the physician to see the extent of the disease and determine its stage, which aids the physician in determining the best course of treatment. CT scans uses X-rays to take multiple images along the length of a person, then puts the slices together again to make a 3D image. CT’s can also be used to determine if cancer has spread to lymph nodes as well as to guide biopsies. Oral contrast, which is a liquid, is often given prior to the study to improve imaging of the intestine. To better visualize blood vessels and the tumor IV contrast may also be given.

MRI’s can also be used to create 3D images of the body to determine the size of the tumor and if it has spread. IV dye can also be used to allow better imaging of the blood vessels and tumor. MRI’s have some advantages compared with CT scans for imaging of the biliary tree. A special type of MRI, an MRI cholangiogram, can be performed to visualize the biliary tree. This study provides information similar to what a cholangiogram can provide in a non-invasive fashion.

PET scans can also be used to detect if disease has spread. PET can also sometimes be used as a means to differentiate a benign mass from one that is cancerous. Because cancers tend to grow rapidly and use more energy, they tend to take up more sugar (glucose). By radioactively labeling glucose and injecting it into the person being scanning, areas of high glucose uptake on can identified, which are suspicious for tumor spread.

A more recent technique, cholangioscopy, takes advantage of the further miniaturization of cameras. An endoscope is used to find the Ampulla of Vater. A smaller scope is then fed through the larger scope and passed into the Ampulla of Vater and into the biliary tree. Through this smaller scope obstructions can be visualized and biopsies can be taken.

Staging

By determining how much tissue the tumor has invaded and if it has spread to other organs allows the physician to determine the stage of the cholangiocarcinoma. This information is important in determining which treatments are necessary to optimally treat the tumor.

Stage 0: Stage 0 cholangiocarcinomas only involve the lining of the bile ducts and have not spread to lymph nodes or other organs.

Stage I: Cholangiocarcinomas which invade the bile duct (stage Ia) or which have penetrated through the bile duct (stage Ib), but have not spread to lymph nodes or other organs.

Stage II: The tumor has invaded into adjacent organs, such as the liver, gallbladder or pancreas or if the tumor has invaded a branch of the portal vein or hepatic (liver) artery. Additionally, people who have disease which involve lymph nodes near the bile ducts are considered to have Stage II disease.

Stage III: Tumor which has invaded adjacent organs, such as the colon, stomach, duodenum or abdominal wall.  Disease which invades the main portal vein, both branches of the main portal vein or the main common hepatic artery are also considered stage III disease.

Stage IV: Tumor which has spread to other distant organs.

Treatment of Cholangiocarcinoma

Surgery: The only curative treatment for cholangiocarcinoma is surgery. However, there are several restrictions on which people are eligible for surgery. There are several large blood vessels which travel next to the common bile duct, namely the hepatic artery and portal vein. Generally, if these vessels are surrounded by tumor, surgery is not possible, though at some centers surgery will be attempted with reconstruction of the removed blood vessels. If the tumor has grown into the liver or metastasis form in the liver, surgery is generally not considered. If tumor has spread to the lymph nodes or to the abdominal cavity, surgery is also contraindicated. 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. Tumors that develop further from the liver have slightly higher rates of complete resection with about a 50% rate of tumor free margins. Margins involved with tumor indicate that a portion of tumor has been left behind and increases the risk of a recurrence of the cancer. Often, prior to the operation, it is not completely clear whether the tumor is resectable or not, even with thorough tumor imaging, and the surgeon will decide whether or not to proceed with the tumor resection during the surgery. Alternatively the surgeon may perform a laparoscopic examination using a small camera to look inside the abdominal cavity to determine if surgery is possible.

Intrahepatic (tumors with the liver) tumors are generally treated with resection of the tumor, which can require the removal of an entire lobe of the liver. Perihilar (tumors 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 are also sometimes required. Due to the complexity of this surgery, serious complication rates can be as high as 25-45%. Distal tumors (those located further from the liver) can generally be treated with resection of a portion of the small bowel or pancreas. All three of these operations are extensive and require an experienced team of surgeons to perform.

Unresectable Cholangiocarcinoma: Up to 50-90% of people with cholangiocarcinomas will have tumors which are unresectable when they are diagnosed. Cholangiocarcinomas grow along the various sections of the biliary tree and can prevent the bile from draining properly from the liver and gallbladder. In people who are unable to undergo surgical resection of the tumor, the primary goal of treatment is preventing blockage of the biliary tree. When the biliary tree is blocked people can develop jaundice, which occurs when the bile is unable to drain properly and builds up in the blood. This can cause the skin and eyes to turn yellow, severe itching, and pain. A stent can be placed in 70-90% of cases. Metal stents are preferred because they are able to keep ducts open longer, but plastic stents are easier to adjust. Stents are usually placed using an endoscopic scope. An endoscopic scope is a camera at the end of a long tube that can be maneuvered into the duodenum, the first portion of the small intestine. Small tools can then be used to insert a small stent, made of metal or plastic, into the ampulla of Vater . The stent can then be moved up the bile duct to where the blockage is. Alternatively, a small hole can be made in the skin and into the liver. Small instruments can then be inserted into the blocked hepatic duct and a stent can be maneuvered into the proper location. A problem which can occur is when tumor grows into the stent causing another blockage at the same spot in the bile duct. Radiation can be used to prevent this from occurring. Surgical bypass of the blocked portion of the biliary ducts can also be done during an exploratory surgery when the tumor is found to be unresectable to prevent jaundice. This 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. Studies have suggested that biliary stenting is as effective as surgical bypass in providing relief from obstructive jaundice 6. Therefore, in most cases where imaging studies, such as CT scans show unresectable disease, stent placement with an endoscopic scope is preferred.

Liver Transplantation: Liver transplantation for the treatment of cholangiocarcinoma is being performed at a few major cancer centers at present. This involves the complete removal of the liver and bile ducts with transplantation of a donor liver. The best results have been published in a recent study of people with relatively well localized cholangiocarcinomas (Ones that have not spread). Prior to transplantation all patients were treated with radiation and chemotherapy. Ultimately only about half of patients in this study were able to undergo transplantation. This study had extremely good results with survival rates of 88% at one year and 82% at 5 years. However, other studies have shown worse results with transplantation and this remains an area of treatment which requires further study.

Radiation: After surgery several treatments can be given to decrease the chances of a tumor recurrence. If the surgeon suspects that there are positive tumor margins, radiation treatments can be used. Radiation’s role as an additional treatment in tumors which have been completely resected is unclear, with studies indicating that it is beneficial and other suggesting that it may be harmful. Radiation can be given externally using a machine called a linear accelerator or internally using a technique known as brachytherapy. External beam radiation delivers radiation uses radiation which is similar to that used in X-ray machines used for a chest X-rays and various other diagnostic studies. However, the energy of the radiation used in linear accelerators is higher. In brachytherapy, a catheter, which is a flexible tube placed in the area where the tumor was, is used. A radioactive source can travel down the catheter to the area where the tumor was/is and treat that specific area with radiation. In inoperable cholangiocarcinoma after stent placement, brachytherapy has been shown to increase the length that stents remain patent. The radiation prevents tumor cells from growing into the stent and blocking it.

Side effects from external beam radiation include skin irritation with redness, nausea and fatigue. Side effects from brachytherapy are generally mild. Potentially serious side effects from brachytherapy include 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 broken down into two categories; systemic, meaning that dispersed throughout the body, and local therapy, where chemotherapy is delivered specifically to the area with cancer. Chemotherapy has been used in combination with surgery. Chemotherapeutics such as 5-FU and Mitomycin C have been used after surgery but they have not been shown to improve survival compared with having surgery alone. Chemotherapy combined with radiation has shown promise in some phase II trials, but there have not been large trials to prove its effectiveness. Other chemotherapies which have been used to treat cholangiocarcinoma include gemcitabine, oxaliplatin, cisplatin, and doxorubicin. Various combination of chemotherapy have also been used and there are ongoing studies to determine the best combination. Side effects from chemotherapy vary with the technique used to administer it (local versus systemic) and the type of chemotherapy used.

Localized chemotherapy is generally given through a thin tube that is fed into one of the arteries of the liver. The tube is fed into the arteries that supply the tumor and chemotherapy is administered through the artery to the tumor. This direct treatment can limit side effects from the chemotherapy.

Photodynamic Therapy: Photodynamic therapy (PDT) involves the use of a medication, known as a ÒphotosensitizerÓ which can cause tumor cells to become sensitive to light of a specific wavelength. This drug preferentially accumulates in tumor tissues, making them more sensitive to light than normal tissues. The drugs themselves have no affect on the cancer tissue until they are exposed to light. When the photosensitizer absorbs the light it creates oxygen free radicals which are toxic to the tumor and can destroy the tumor cells, the tumor vasculature, and stimulate the immune response. Currently, the most commonly used photosensitizer for PDT is Photofrin. Treatment is performed by giving the photosensitizer and after a set amount of time, usually 48 hours, an endoscope is used to direct the light source to the area of the tumor. The light is then turned on to activate the photosensitizer. However, after treatment people will continue to be photosensitive for four to six weeks. This can be inconvenient as people must avoid exposure to direct sunlight and wear long sleeve clothes and eye protection during this time. PDT has been studied in unresectable cholangiocarcinoma and has been shown to be effective in maintaining the 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.

Treatments are generally based on the stage of the disease. For people with stage 0 or Stage I disease surgery alone is generally recommended. Five year survival in people with Stage 0 and Stage 1 disease are 58% and 29%, respectively. 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 most important. Surgery is recommended if imaging studies suggest that the disease is resectable. After resection, if visible portions of tumor have been left behind, chemotherapy and radiation are generally recommended. People with Stage II or III disease have a five year survival of 22% and 8%, respectively. In unresectable disease chemotherapy and radiation can be used as well as surgeries or stent placement to bypass obstructions in the bile duct.  

Follow Up: Close follow up after the resection of cholangiocarcinoma is recommended. Repeat radiologic imaging is recommended every six months for two years to make sure that the cholangiocarcinoma has not recurred.

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