Cholangiocarcinoma

bile duct cancer

Cholangiocarcinoma is a rare and aggressive cancer that begins in the bile ducts, the thin tubes that carry digestive fluid from the liver to the small intestine. Most people don’t experience symptoms until the disease has advanced, making early detection difficult and successful treatment challenging.

Table of contents

• What is cholangiocarcinoma?
• Types of bile duct cancer
• Associated anatomy
• Signs and symptoms
• Causes and risk factors
• How common is this condition?
• Diagnosis
• Staging
• Treatment options
• Outlook and prognosis

What is cholangiocarcinoma?

Cholangiocarcinoma is a type of cancer that forms in the bile ducts, which are slender tubes that carry bile from the liver and gallbladder to the small intestine^[1]. Bile is a fluid made by the liver that helps break down fats during digestion^[4].

This cancer develops when cells lining the bile ducts undergo abnormal gene changes that cause them to grow and divide without stopping. These cancer cells form tumors^[8]. More than 95% of cholangiocarcinomas are adenocarcinomas, a specific type of cancer that begins in glandular tissue^[3].

Cholangiocarcinoma is an aggressive cancer, which means it spreads quickly. Most people receive a diagnosis after the cancer has already spread outside of their bile ducts. At this point, bile duct cancer is difficult to treat, and the chance of recovery is usually poor^[2].

Types of bile duct cancer

Doctors divide cholangiocarcinoma into different types based on where the cancer occurs in the bile ducts^[1].

Intrahepatic cholangiocarcinoma forms in the bile ducts inside the liver. Only a small number of bile duct cancers are intrahepatic. This type is sometimes classified as a type of liver cancer^[1][4].

Perihilar cholangiocarcinoma (also called hilar cholangiocarcinoma) occurs in the bile ducts just outside of the liver. This happens in the area where the right and left bile ducts exit the liver and join to form a larger duct. It is the most common form of cholangiocarcinoma^[1][2]. Perihilar cholangiocarcinoma is also called a Klatskin tumor^[2][4].

Distal cholangiocarcinoma occurs in the portion of the bile duct nearest the small intestine. The common bile duct passes through the pancreas and ends in the small intestine^[1][4].

Perihilar cholangiocarcinoma and distal cholangiocarcinoma are together known as extrahepatic bile duct cancers because they form outside the liver rather than inside it^[2][4].

• Bile ducts
• Liver
• Gallbladder
• Small intestine
• Pancreas

Signs and symptoms

Cholangiocarcinoma symptoms don’t usually start until the cancer advances and blocks a bile duct^[2]. Most people with this cancer do not have symptoms until the disease becomes more advanced. For this reason, it is often difficult for healthcare providers to diagnose the disease early^[8].

Symptoms of bile duct cancer include^[2][4]:

• Yellowing of the skin or whites of the eyes (called jaundice)
• Itchy skin
• Dark urine
• Light-colored or greasy stools
• Abdominal pain
• Fever
• Fatigue
• Nausea and vomiting
• Unexplained weight loss

Cholangiocarcinoma isn’t usually painful in the early stages. But a large tumor can cause pain that may feel concentrated in the right side of the abdomen, underneath the ribs. For some people, the pain may shift to other regions in their abdomen or back^[2].

This type of pain is common in many conditions, not just bile duct cancer. It’s important to see a healthcare provider to determine what’s causing unusual abdominal pain^[2].

Causes and risk factors

Experts don’t know exactly what causes cholangiocarcinoma. But health conditions that cause chronic (long-term) inflammation in the bile ducts may play a role^[2]. Cholangiocarcinoma frequently arises in the absence of genetic predisposition and without a clear cause^[3].

Ongoing damage from inflammation can cause changes in cell DNA. DNA contains the instructions that tell cells how to behave. Damaged DNA can cause problems with how cells grow and divide, creating tumors that damage tissue^[2].

Risk factors for bile duct cancer include^[7]:

• Older age (the cancer is most common in people around age 70)^[2]
• Primary sclerosing cholangitis (a progressive disease in which the bile ducts become blocked by inflammation and scarring)
• Chronic ulcerative colitis
• Cysts in the bile ducts
• Chronic liver diseases such as hepatitis or cirrhosis
• Inflammatory bowel disease (ulcerative colitis and Crohn’s disease)
• Biliary stones or infections
• Having a family member with cholangiocarcinoma
• Weighing more than is healthy

How common is this condition?

Cholangiocarcinoma is rare. About 8,000 people in the United States develop this cancer each year^[2]. It occurs mostly in people older than age 50, though it can occur at any age^[1].

Worldwide, cholangiocarcinoma is more common in Southeast Asia. Bile duct cancer is a complication of clonorchiasis, a chronic infection associated with a Chinese liver fluke parasite^[2].

Diagnosis

Your healthcare team will do a full exam of your body and ask you questions about your health^[6]. Diagnosing cholangiocarcinoma can be difficult, particularly for tumors outside the liver. Available biopsy techniques lack diagnostic sensitivity, and surgical intervention may be indicated even without a confirmatory tissue diagnosis in the appropriate clinical setting^[3].

Tests that may be used include^[10]:

• Liver function tests: Blood tests to measure your liver function can give your doctor clues about what’s causing your signs and symptoms
• Tumor marker test: Checking the level of carbohydrate antigen (CA) 19-9 in your blood may give your doctor additional clues about your diagnosis. CA 19-9 is a protein that’s overproduced by bile duct cancer cells. However, a high level of CA 19-9 in your blood doesn’t always mean you have bile duct cancer, as this result can also occur in other bile duct diseases^[2]
• Endoscopic retrograde cholangiopancreatography (ERCP): A thin, flexible tube equipped with a camera goes through the throat and into the small intestine. A dye enters the ducts through a small hollow tube passed through the endoscope. This highlights the bile ducts on X-ray images
• Endoscopic ultrasound: An ultrasound device at the end of a tube emits sound waves that generate images of nearby tissues
• CT scan (computed tomography): A 3D image of your body generated by a machine that moves around you^[6]
• MRI (magnetic resonance imaging): Uses magnets, radio waves, and a computer to image your body’s soft tissues^[6]
• PET scan (positron emission tomography): An imaging test used to diagnose certain diseases^[6]

A biopsy is the only way to know for sure if you have cancer. A biopsy looks at a piece of the bile duct using a microscope and is used to find out the cancer type, how normal it is (grade), and if it has spread^[6].

After you are diagnosed, your doctor may order a test called next-generation sequencing (NGS), which is a type of molecular profiling or biomarker testing. This type of test can help determine if you have certain gene changes, such as an FGFR2 fusion, and could help direct how your disease is managed^[8].

Staging

To guide treatment, cholangiocarcinoma is “staged.” This stage is based on^[6]:

• Where and how big the tumor is
• If there are cancer cells in the lymph nodes
• If there are cancer cells in other parts of the body

Stages range from stage I (smallest tumors) to stage IV (tumors that have spread to other parts of the body, also called metastatic cancer)^[6]. The stage and type of cholangiocarcinoma will guide your treatment plan.

Almost 75% of patients have non-resectable (cannot be removed with surgery) or metastatic disease at presentation^[3]. All patients with suspected or confirmed cholangiocarcinoma should be evaluated for distant metastatic disease^[3].

Treatment options

Surgery is the only curative treatment for cholangiocarcinoma, though radiation and chemotherapy serve as adjuncts^[3]. Which treatments a person receives will depend on whether the cancer can be completely removed with surgery (resectable) or not (unresectable)^[11].

Surgery

The following types of surgery are used to treat bile duct cancer^[11]:

• Removal of the bile duct: This surgical procedure removes part of the bile duct if the tumor is small and is in the bile duct only. Lymph nodes are removed and tissue is examined under a microscope to see if there is cancer
• Partial hepatectomy: A surgical procedure to remove the part of the liver where cancer is found. The part removed may be a wedge of tissue, an entire lobe, or a larger part of the liver, along with some normal tissue around it
• Whipple procedure: During this surgical procedure the head of the pancreas, the gallbladder, part of the stomach, part of the small intestine, and the bile duct are removed. Enough of the pancreas is left to make digestive juices and insulin

After the doctor removes all the cancer that can be seen at the time of surgery, some people may receive chemotherapy or radiation therapy to kill any cancer cells that are left. Treatment given after surgery to lower the risk that the cancer will come back is called adjuvant therapy^[11].

Surgery to remove the whole tumor is the only way to cure this cancer. The type of surgery depends on how big and where the tumor is. Surgery may also be done to remove only part of the tumor. However, surgery may not be an option if the tumor takes up too much of the liver, or if the disease has spread to other parts of the body^[6][8].

Palliative surgery

Palliative surgery may be done to relieve symptoms caused by a blocked bile duct and improve quality of life. These procedures include^[11]:

• Biliary bypass: The doctor cuts the gallbladder or bile duct before the blockage and sews it to the part of the bile duct that is past the blockage or to the small intestine, creating a new pathway around the blocked area
• Endoscopic stent placement: Surgery to put in a stent (a thin, flexible tube) to drain bile that has built up in the area
• Percutaneous transhepatic biliary drainage: A thin needle is inserted through the skin below the ribs and into the liver. A stent may be left in the liver to drain bile

Radiation therapy

Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing^[11]. A machine outside the body sends radiation toward the area of the body with cancer. Radiation is given in a series of treatments to allow healthy cells to recover^[11]. Radiation can sometimes be used alone or with other treatments^[6].

Chemotherapy

Chemotherapy is the use of medication to treat cancer. It can be used alone or with surgery^[6]. Chemotherapy and radiation therapy also play an important role in slowing down disease progression^[12].

Targeted therapy and immunotherapy

Recent investigations into the molecular mechanisms underlying cholangiocarcinoma have yielded various targeted therapies that have improved outcomes^[3]. Targeted therapy and immunotherapy are changing rapidly and their combined effect may have great potential for the treatment of cholangiocarcinoma^[12].

Treatment usually involves a combination of surgery, chemotherapy or radiation therapy. Clinical trials to improve the outcomes of cholangiocarcinoma are ongoing^[2]. Experts are continually researching and developing new treatments that can slow cancer spread and improve the outlook associated with cholangiocarcinoma^[2].

Outlook and prognosis

The overall prognosis of cholangiocarcinoma is poor, given the aggressive nature of the tumor and the usually advanced stage at presentation^[3]. Cholangiocarcinoma is often diagnosed when it’s advanced, making successful treatment difficult to achieve^[1].

The overall five-year survival rate for cholangiocarcinoma is less than 10%. However, if doctors can establish clear margins with resection and the lymph nodes are not involved, the median survival is around 4 to 5 years. These patients have a 20% to 30% chance of a cure^[16].

Certain factors affect prognosis (chance of recovery) and treatment options, including the location and size of the tumor, whether it has spread to lymph nodes or other parts of the body, and the stage of the cancer^[6][7].