Bile Duct Cancer

Risk Factors for Bile Duct Cancer

The precise cause of most bile duct cancers (cholangiocarcinoma) is unknown and there is no proven way to prevent it. But there appears to be a link to certain conditions that irritate and inflame the bile ducts, such as bile duct stones or a parasitic infestation, possibly leading to gene mutations related to cancer growth. Therefore, chronic inflammation of the bile ducts has been identified as one of several risk factors that can increase the chance of a person getting bile duct cancer.

Having one or more risk factors does not mean you will get bile duct cancer, and some people get the disease without any known risk factors. Some risk factors are things you can control, while others are not.

These are among the most notable risk factorsfor bile duct cancer. In many cases, the degree of increased risk of cancer from many of these conditions is small.

Chronic inflammation of the bile ducts:This can be caused by various conditions of the liver or bile ducts, including:

• Primary sclerosing cholangitis (PSC), in which inflammation of the bile ducts (cholangitis) causes the formation of scar tissue (sclerosis).
• Bile duct stones, similar to gallstones but smaller. They can become lodged in the bile duct network, forming a blockage and causing inflammation.
• Choledochal cyst disease, a rare condition in which bile-filled sacs form along the bile ducts. Left untreated, this condition can cause inflammation.
• Liver fluke infection, caused by tiny parasitic worms consumed in raw or undercooked fish. The liver flukes live in the bile ducts, liver, and gallbladder. This form of parasitic infection is more common in parts of Asia and is rare in the United States, although people who travel to Asia can be affected.
• Bile duct reflux, caused by abnormalities where the bile duct and pancreatic duct normally meet, causing digestive juices from the pancreas to flow back into the bile ducts.
• Cirrhosis, scarring damage to the liver that can be caused by alcohol and hepatitis.
• Infection with hepatitis B virus or hepatitis C virus which increases the risk of intrahepatic bile duct cancers. This may be at least in part because long-term infections with these viruses can also lead to cirrhosis.

Age: Older people are more likely than younger people to get bile duct cancer. For intrahepatic bile duct cancer (inside the liver), the average age of diagnosis in the United States is 70. For extrahepatic bile duct cancer (outside the liver), it’s 72.

Ethnicity: Hispanic Americans are at a higher risk of bile duct cancer than the U.S. population as a whole.

Geography: Bile duct cancer is far more common in Southeast Asia and China than elsewhere, largely because of the higher rate of liver fluke infection.

Family history: A history of bile duct cancer in the family appears to be a risk factor, although most diagnoses of bile duct cancer do not involve people with a family history of the disease.

Obesity: Being overweight or obese is associated with a higher risk of cancers of the bile ducts and gallbladder.

Alcohol: It’s associated with a higher risk of intrahepatic bile duct cancer, particularly for people with liver problems caused by alcohol.

Non-alcoholic fatty liver disease: A build-up of extra fat in the liver cells that’s not caused by alcohol, which over time can cause swelling and scarring leading to cancer.

Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease.

Exposure to Thorotrast: A radioactive substance that was used as a contrast agent for X-rays before the 1950s. Exposure increases risk for bile duct cancer and some kinds of liver cancer.

Diabetes: A small increased risk of bile duct cancer is associated with type 1 or type 2 diabetes.

Potential risk factors: Some studies suggest other potential risk factors for bile duct cancer, including smoking, HIV infection, exposure to asbestos, exposure to radon, and exposure to certain chemicals such as dioxins.

Symptoms of Bile Duct Cancer

These are among the signs and symptoms associated with bile duct cancer. They may also be caused by other conditions. Check with your doctor if you experience any of these:

• Jaundice (yellowing of the skin or whites of the eyes).
• Dark urine.
• Clay colored stool.
• Pain in the abdomen, particularly the upper-right part.
• Fever.
• Itchy skin.
• Nausea and vomiting.
• Weight loss for an unknown reason.

Diagnosing Bile Duct Cancers

If you have any of the possible signs and symptoms listed under Risk Factors & Symptoms, particularly jaundice or pain in the upper-right part of the abdomen, have them examined by a doctor. Also, tell your doctor about any possible risk factors.

So far there are no routine screening tests to detect bile duct cancer (cholangiocarcinoma). The bile ducts are deep inside the body, so abnormalities are difficult to detect in a routine physical examination. Only a small number of these cancers are diagnosed before they have spread beyond the point where they can be removed surgically.

If bile duct cancer is suspected, based on symptoms or risk factors, your doctor will conduct a physical exam, checking your skin and eyes for jaundice, and your abdomen for signs of lumps, tenderness, or fluid build-up. The next step could be one or more specialized tests:

Blood tests: The doctor may order lab tests or your blood to determine levels of bilirubin, a chemical that causes jaundice, as well as albumin, liver enzymes, and other substances. High levels of these could signal problems in the bile ducts, gallbladder, or liver, possibly but not always including cancer. Tests might also look for tumor markers, which are substances made by cancer cells that sometimes are found in the blood.

Imaging and camera tests: One or more of these tests might be used to examine the interior of your body during diagnosis, perhaps to look for possible signs of cancer or to determine how far cancer has spread (its stage) in preparation for surgery. Imaging tests often can detect a bile duct blockage, but may not show if a blockage is caused by cancer. They can also be used to guide a biopsy in which a needle is inserted into the body to extract suspicious tissue for testing. Some of these tests might also be used after diagnosis to help find out if treatment is working or if cancer has returned after treatment. Imaging tests might include:

• Ultrasound, a test using sound waves that bounce off your body’s tissues to create images that can be viewed on a screen. A simple abdominal ultrasound test can be performed by a technician moving an instrument called a transducer over your abdomen. In some cases, an internal ultrasound might be performed, in which a transducer is inserted into your body to get it closer to the bile ducts. It might be on the end of a tube (endoscope) that’s inserted through your mouth and stomach and into the small intestine near the bile ducts (endoscopic ultrasound), or through a small surgical cut in the skin on the side of your body (laparoscopic ultrasound).
• Computed tomography (CT) scan, using X-rays to make images of a cross-section of your body. It can be used to look for signs of tumors, find out if cancer has spread, or help develop a plan for surgery.
• Magnetic resonance imaging (MRI) scan, using radio waves and magnetic waves to create images of your body’s tissues. Sometimes an intravenous contrast agent is injected into the blood stream as a sort of dye to make the images more detailed. An MRI may be better able than other tests to distinguish benign tumors from cancerous ones than other tests.
• Cholangiography, another imaging technology, typically using X-rays. In endoscopic retrograde cholangiopancreatography (ERCP), an endoscope tube is threaded down your throat and into the small intestine. From there, a tiny catheter is inserted into the common bile duct and inserts contrast dye to make the duct network stand out for X-ray imaging. During an ERCP, a thin fiber-optic tube with a tiny camera on the end might also be threaded down the endoscope tube to look for possible tumors (known as cholangioscopy). In percutaneous transhepatic cholangiography (PTC), instead of an endoscope, a doctor inserts a needle through your skin and into a bile duct inside your liver in order to inject a contrast dye. The bile ducts can then be X-rayed.
• Angiography, an X-ray test in which contrast dye is injected into the blood stream to make it easier to see blockages that might be caused by cancer. It also can help surgeons decide on whether a bile duct cancer can be removed surgically, and if so, how.
• Laparoscopy, a camera examination generally performed in the operating room while a patient is under general anesthesia. One or more small incisions is made in your belly, and a thin tube with a tiny camera on the end (laparoscope) is inserted into your abdomen so the doctor can look directly at your bile ducts and other tissues. This can help in planning surgery on the cancer.

Biopsy: Bile or bile duct tissue might be removed to help confirm a cancer diagnosis. This is often done using a needle inserted through the skin and into the tumor. A biopsy may be performed in conjunction with one of the imaging tests described above, especially a ERCP or PTC. Biopsy samples can then be examined for cancer cells or tested for biomarkers that might indicate whether certain targeted drugs might be suitable for a treatment.

Stages of Bile Duct Cancer

“Stage” means the extent of a cancer in the body. The stage is determined by several factors, including where the cancer formed and whether and how much it has spread. That information can aid in decisions on the best way to treat bile duct cancer.

There are two main staging systems used for bile duct cancer (cholangiocarcinoma). One – the American Joint Committee on Cancer’s TNM system -- is complex and varies depending on the location of the cancer’s start. The other – resectable vs. unresectable – is simpler and focuses on surgery options. Here’s a look at each.

American Joint Committee on Cancer / TNM system

This staging is based on three key factors, identified by letters:

• T (for tumor): How large has the tumor grown, and has it reached nearby structures or organs?
• N (for nodes): Has the cancer spread to nearby lymph nodes?
• M (for metastasis): Has the cancer spread (metastasis) to distant lymph nodes or distant organs such as the bones, lungs, or peritoneum (the lining of the abdomen)?

The AJCC’s TNM system is used to describe how far a bile duct cancer has spread and where, assigning a code (0, I, II, III, or IV) and several subdivisions of each code based on a cancer’s extent. Most bile duct cancers start in the innermost layer of a bile duct’s wall (the mucosa). Eventually they may grow through the bile duct wall. From there it can invade nearby blood vessels, organs, and other tissues. The cancer might also grow into nearby lymphatic or blood vessels, and from there spread to nearby lymph nodes or to other areas of the body.

Under the TNM system, three different classification hierarchies are used in describing the stage of bile duct cancer, depending on where the cancer starts: Intrahepatic bile duct cancers (those starting inside the liver), perihilar bile duct cancers (those starting in the area just outside the liver), and distal bile duct cancers (those starting farther down the bile duct system). Those three types are described in greater detail under Types of Bile Duct Cancer.

According to the National Cancer Institute, here are stages for the three types of bile duct cancer under the TNM system:

Intrahepatic bile duct cancer stages

• Stage 0: Abnormal cells are found in the innermost layer of tissue lining the intrahepatic bile duct. These abnormal cells are not actually cancer but may become cancer and spread into nearby normal tissue.
• Stage IA: Cancer has formed in an intrahepatic bile duct and the tumor is 5 centimeters or smaller and does not involve blood vessels.
• Stage IB: Cancer has formed in an intrahepatic bile duct and the tumor is larger than 5 centimeters and does not involve blood vessels.
• Stage II: Either of the following is found: The tumor has spread through the wall of an intrahepatic bile duct and into a blood vessel, or more than one tumor has formed in the intrahepatic bile duct and may have spread into a blood vessel.
• Stage IIIA: The tumor has spread through the capsule (outer lining) of the liver. 
• Stage IIIB: Cancer has spread to organs or tissues near the liver by direct invasion, such as the duodenum, colon, stomach, common bile duct,  diaphragm, or the part of the vena cava behind the liver, or the cancer has spread to nearby lymph nodes.  
•  Stage IV: Cancer has spread to other parts of the body, such as the bone, lungs, distant lymph nodes, or tissue lining the wall of the abdomen and most organs in the abdomen.

Perihilar bile duct cancer stages

• Stage 0: Abnormal cells are found in the innermost layer of tissue lining the perihilar bile duct. These abnormal cells are not actually cancer but may become cancer and spread into nearby normal tissue. Stage 0 is also called high-grade dysplasia.
•  Stage I:  Cancer has formed in the innermost layer of tissue lining the perihilar bile duct and has spread into the muscle layer or fibrous tissue layer of the perihilar bile duct wall.
•  Stage II: Cancer has spread through the wall of the perihilar bile duct to nearby fatty tissue or to liver tissue. 
• Stage IIIA: Cancer has spread to branches on one side of the hepatic artery or the portal vein. 
• Stage IIIB: Cancer has spread to one or more of the following:  The main part of the portal vein or its branches on both sides, the common hepatic artery, the right hepatic duct and the left branch of the hepatic artery or of the portal vein, or the left hepatic duct and the right branch of the hepatic artery or of the portal vein.
• Stage IIIC: Cancer has spread to one to three nearby lymph nodes.
• Stage IVA: Cancer has spread to four or more nearby lymph nodes.
• Stage IVB: Cancer has spread to other parts of the body, such as the liver, lung, bone, brain, skin, distant lymph nodes, or tissue lining the wall of the abdomen and most organs in the abdomen.

Distal bile duct cancer

• Stage 0: Abnormal cells are found in the innermost layer of tissue lining the distal bile duct. These abnormal cells are not actually cancer but may become cancer and spread into nearby normal tissue. Stage 0 is also called high-grade dysplasia.
• Stage I: Cancer has formed and spread fewer than 5 millimeters into the wall of the distal bile duct.
• Stage IIA: Cancer has spread fewer than 5 millimeters into the wall of the distal bile duct and has spread to 1 to 3 nearby lymph nodes; or cancer has spread 5 to 12 millimeters into the wall of the distal bile duct and no lymph nodes are involved.
• Stage IIB: Cancer has spread 5 millimeters or more into the wall of the distal bile duct. Cancer may have spread to 1 to 3 nearby lymph nodes.
• Stage IIIA: Cancer has spread into the wall of the distal bile duct and to 4 or more nearby lymph nodes.
• Stage IIIB: Cancer has spread to the large vessels that carry blood to the organs in the abdomen (celiac artery, superior mesenteric artery and/or common hepatic artery). Cancer may have spread to 1 or more nearby lymph nodes.
• Stage IV: Cancer has spread to other parts of the body, such as the liver, lungs, or tissue lining the wall of the abdomen and most organs in the abdomen.

Resectable / Unresectable classification

Often, for treatment purposes, doctors classify bile duct cancer based on whether the cancer can be surgically removed:

• Resectable cancers: Those that doctors believe can be removed completely by surgery.
• Unresectable cancers: Those that have spread too far or are in too difficult a place to be removed entirely by surgery.

Most stage 0, I, and II cancers and possibly some stage III cancers as classified under the TNM system are likely to be resectable, while most stage III and IV tumors are likely to be unresectable. However, there are other factors involved, such as the size and location of the cancer and whether a person is healthy enough for surgery.

Treatments for Bile Duct Cancer (Cholangiocarcinoma)

The treatment for bile duct cancer (cholangiocarcinoma) is customized to each patient and depends on the type, location, and extent of cancer; the stage at which the patient is diagnosed; whether the cancer is resectable (removable by surgery); likely side effects of treatment; the chances of curing the disease, extending life, or relieving symptoms; and the patient’s general health.

Treatments for bile duct cancer can include surgery, radiation, chemotherapy, targeted drug therapy, immunotherapy, and palliative therapy. Patients may receive one or more of these treatments in combination. Some patients may also be eligible to participate in clinical trials — doctor-led research studies of new or experimental procedures or treatments.

Surgery for Bile Duct Cancer

Surgery options for bile duct cancer depend on whether the cancer is considered to be resectable, or able to be completely removed. That determination can be made through imaging tests or a preliminary surgery, such as a laparoscopy. The American Cancer Society says surgical removal offers the best chance for a cure, but entirely removing the cancer is possible only in a minority of cases. It is a complex surgery requiring an experienced team, so consult with an advanced cancer center (such as the CU Cancer Center) to see if this kind of surgery is an option.

In the case of a resectable bile duct cancer, the type of surgery depends on the cancer’s location. If it’s intrahepatic bile duct cancer (in bile ducts inside the liver), the surgeon may remove a piece of the liver where the cancer is located (a partial hepatectomy), or an entire lobe of the liver (a hepatic lobectomy).

As for an extrahepatic bile duct cancer (outside the liver) that’s deemed resectable, depending on the cancer’s location, the surgeon may remove some sections of the bile duct network, the gallbladder, nearby lymph nodes, and sometimes part of the pancreas and small intestine. The remaining bile ducts are reconnected. Some versions of this kind of surgery are known as a Whipple procedure. Such operations are complex and require a highly skilled team.

In other cases, doctors may decide the cancer is unresectable, meaning it can’t be entirely removed. That may be because the cancer is too advanced, has spread too far, or is difficult to access because of its location. In such cases, surgery is less likely to be performed and would not be expected to cure the cancer. But palliative surgery might be performed to relieve a patient’s symptoms or to correct blockage of the bile ducts.

Risks of bile duct surgery vary based on the extent of the surgery and other factors, such as the patient’s overall health and liver function. They can include possible bile leakage into the abdomen, infections, and liver failure. Patients should understand the extent of possible risks and benefits of any surgery before agreeing to proceed.

Radiation Therapy for Bile Duct Cancer 

Radiation therapy usually involves a carefully focused beam of radiation to kill cancer cells. A doctor who specializes in radiation therapy to treat cancer is a radiation oncologist.

Radiation is not commonly used in treating bile duct cancer. Some doctors may use radiation before surgery to try to shrink the cancer to make it easier to remove (neoadjuvant therapy), or after surgery to kill whatever cancer cells might remain after surgery (adjuvant therapy).

In cases of bile duct cancers that can’t be removed surgically, radiation might be used to shrink tumors, sometimes along with chemotherapy. In such cases, radiation is not a means to a cure, but might help a patient to live longer or relieve pain.

Chemotherapy for Bile Duct Cancer 

Chemotherapy (or chemo) uses drugs to kill cancer cells. Drugs are either injected into a vein or taken orally. The drugs enter the bloodstream and are carried throughout the body, so chemo might be used in cases of bile duct cancer where the cancer has spread to organs beyond the bile duct network.

Some doctors may use chemo before surgery to try to shrink the cancer to make it easier to remove, or after surgery – possibly along with radiation therapy – to try to reduce the risk of the cancer returning.

If a liver transplant is planned as part of bile duct cancer treatment, chemo may be used to control the growth of bile duct cancer while a patient is waiting for a transplant.

In cases of bile duct cancers that can’t be removed surgically, chemo might be used to shrink tumors (sometimes along with radiation therapy). In such cases, chemo is not a means to a cure, but might help a patient to live longer or relieve pain.

Chemo is administered in cycles, with a period of treatment followed by a period of rest to allow time for the body to recover. Each cycle usually lasts for several weeks. Most chemo treatments are administered on an outpatient basis, but some involve a hospital stay.

Chemo can cause side effects because it can affect certain non-cancerous tissues in the body. Possible side effects of chemo, depending on drug type, dosage, and length of treatment, include:

• Hair loss.
• Mouth sores.
• Loss of appetite.
• Nausea and vomiting.
• Diarrhea or constipation.
• Nerve damage that can lead to numbness, tingling, and pain in the hands and feet.
• Increased chance of infection.
• Bleeding or bruising after minor cuts or injuries.
• Fatigue and shortness of breath.

Most side effects can be treated. Side effects usually go away after chemo treatment is concluded.

Targeted Drug Therapy for Bile Duct Cancer 

Targeted therapy focuses on the specific genes, proteins, or tissue environments that contribute to cancer, limiting damage to non-cancerous cells and tissues. They can cause various side effects depending on the drug, including fatigue, abdominal pain, diarrhea, nausea, and loss of appetite.

There are targeted drug therapies that might be used for advanced cases of bile duct cancer in patients who previously have received another form of treatment. Both are typically taken by mouth once a day.

FGFR2 inhibitors block an abnormal protein called FGFR2 that can cause cells to grow out of control and turn into bile duct cancer. Normally, FGFRs (fibroblast growth factor receptors) help cells grow and divide without becoming cancer, but some people with bile duct cancer in the liver have genetic changes that lead to abnormal FGFR2 proteins. FGFR2 inhibitors might be used if surgery isn’t possible. For the drug to work, a test must show that your cancer has an abnormal FGFR2 gene.

IDH1 inhibitors can slow down the progression of bile duct cancer by blocking an abnormal protein caused by a mutated IDH1 gene in the bile duct cancer cells of some people. The drug is for people with advanced cancer that has been previously treated by other means and whose cancer cells have a IDH1 mutation.

Immunotherapy for Bile Duct Cancer 

Sometimes the body’s immune system does not attack cancer because cancer cells produce proteins that help them hide from immune system cells. Immunotherapyis intended to boost the patient’s immune system to help it attack and destroy cancer cells.

Some immunotherapy drugs target “checkpoints” on immune cells that switch an immune response on or off. These drugs are called checkpoint inhibitors. 

In bile duct cancer, two types of checkpoint inhibitors can be used to shrink tumors or slow their growth, PD-L1 and PD-1. These drugs are administered as an intravenous infusion every few weeks. Checkpoint inhibitors usually are used only if the cancer cannot be removed surgically or if the cancer has spread through the body, and/or if cancer cells have certain genetic mutations or defects. Checkpoint inhibitors are most commonly used along with certain chemotherapy drugs. Side effects can include feeling tired or weak, fever, cough, nausea, itching, skin rash, loss of appetite, muscle or joint pain, shortness of breath, and constipation or diarrhea.

Palliative Care for Bile Duct Cancer 

This kind of treatment can help reduce or control various symptoms related to bile duct cancer, but not cure it. Palliative care might be used if the cancer has spread too far to be removed surgically. Possible forms of palliative therapy might include:

• Pain medications.
• Drugs to control nausea.
• A stent or catheter is inserted into a bile duct to keep it open and prevent jaundice, infection, and liver failure.
• Bypass surgery to create a path for bile around a blockage caused by cancer.
• An injection of alcohol into nerves near the bile ducts to relieve pain.

The University of Colorado (CU) Cancer Center partners with UCHealth, Children’s Hospital Colorado, and Rocky Mountain Regional VA to provide clinical care. Please make an appointment with one of our clinical partners to be seen by a CU Cancer Center doctor.

UCHealth:

UCHealth Cancer Care - Anschutz Medical Campus
1665 Aurora Court Anschutz Cancer Pavilion
Aurora, CO 80045
720-848-0300

UCHealth Cherry Creek Medical Center
100 Cook Street
Denver, CO 80206
720-848-0000

Rocky Mountain Regional VA Medical Center:
1700 North Wheeling Street
Aurora, CO 80045-7211
303-399-8020