Cholangiocarcinoma

Cholangiocarcinoma is a rare and aggressive cancer that forms in the bile ducts, the thin tubes that carry digestive fluid from the liver to the small intestine. Most people don’t develop symptoms until the cancer has already advanced, making it difficult to treat and cure.

Table of contents

• What is Cholangiocarcinoma?
• Types of Bile Duct Cancer
• Who is Affected?
• Signs and Symptoms
• Causes and Risk Factors
• Diagnosis
• Treatment Options
• Outlook and Prognosis

bile duct cancer

• Bile ducts
• Liver
• Gallbladder
• Small intestine

What is Cholangiocarcinoma?

Cholangiocarcinoma is a type of cancer that starts in the bile ducts. Bile ducts are thin tubes that connect your liver to your gallbladder and to your small intestine^[1]. These tubes carry bile, a yellow-green fluid made by the liver that helps your body break down fats during digestion^[1].

This cancer is aggressive, which means it spreads fast^[2]. More than 95% of cholangiocarcinomas are adenocarcinomas, a type of cancer that begins in cells that make and release mucus and other fluids^[3]. When cancer starts in the bile ducts, the cells grow out of control and form a tumor^[6].

Most people receive a cholangiocarcinoma diagnosis after the cancer has already spread outside of their bile ducts^[2]. 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 classify cholangiocarcinoma into different types based on where the cancer occurs in the bile ducts^[1]. There are three main types:

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

Perihilar cholangiocarcinoma, also called hilar cholangiocarcinoma, occurs in the bile ducts just outside the liver^[1]. This cancer forms in the area where the smaller bile ducts from inside your liver merge to form a larger duct called the common hepatic duct^[2]. This is the most common form of cholangiocarcinoma^[2]. Another name for perihilar cholangiocarcinoma is a Klatskin tumor^[2].

Distal cholangiocarcinoma occurs in the portion of the bile duct nearest the small intestine^[1]. This type starts outside your liver, in the ducts closer to your small intestine^[2]. The common bile duct passes through the pancreas and ends in the small intestine^[4].

Perihilar cholangiocarcinoma and distal cholangiocarcinoma are also known as extrahepatic bile duct cancers because they form outside your liver instead of inside your liver^[2].

Who is Affected?

Cholangiocarcinoma is rare. About 8,000 people in the United States develop this cancer each year^[2]. The cancer occurs mostly in people older than age 50, though it can occur at any age^[1]. It is most common in people around age 70^[2].

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

Signs and Symptoms

Cholangiocarcinoma symptoms don’t usually start until the cancer advances and blocks a bile duct^[2]. Cholangiocarcinoma isn’t usually painful in the early stages^[2]. However, a large tumor can cause pain that may feel concentrated in the right side of your abdomen, underneath your ribs^[2]. For some people, the pain may shift to other regions in their abdomen or back^[2].

Signs and symptoms of cholangiocarcinoma include^[1][2][4]:

• Yellowing of the skin or whites of the eyes, called jaundice
• Itchy skin
• Dark urine
• Light-colored, clay-colored, or greasy stools
• Abdominal pain
• Fever
• Fatigue
• Nausea and vomiting
• Weight loss for an unknown reason
• Loss of appetite

These symptoms may be caused by bile duct cancer or by other conditions^[4]. It’s important to see a healthcare provider to determine what’s causing unusual symptoms^[2]. There are no routine screening tests to check for bile duct cancer before signs and symptoms occur^[4].

Causes and Risk Factors

Experts don’t know exactly what causes cholangiocarcinoma^[2]. Cholangiocarcinoma frequently arises without a clear cause^[3]. However, health conditions that cause chronic inflammation in your bile ducts may play a role^[2].

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

Several clinical conditions and premalignant lesions predispose to developing cholangiocarcinoma, and these risk factors vary with ethnicity and geography^[3]. Risk factors may include^[2][6]:

• Older age
• Weighing more than is healthy
• Having a family member with cholangiocarcinoma
• Hepatitis
• Cirrhosis, a condition where the liver becomes scarred
• Primary sclerosing cholangitis, a disease that causes scarring of the bile ducts
• Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease
• Choledochal cysts
• Biliary stones or infections
• Liver fluke infection, which is associated with cholangiocarcinoma in endemic regions due to chronic biliary tract inflammation^[9]

Diagnosis

Diagnosing cholangiocarcinoma can be difficult, particularly for extrahepatic lesions, as available biopsy techniques lack diagnostic sensitivity^[3]. Your healthcare team will do a full exam of your body and ask you questions about your health^[6].

Several tests may be used to diagnose cholangiocarcinoma:

Blood tests to measure your liver function can give your doctor clues about what’s causing your signs and symptoms^[10]. Checking the level of carbohydrate antigen (CA) 19-9 in your blood may give your doctor additional clues about your diagnosis^[10]. CA 19-9 is a protein that’s overproduced by bile duct cancer cells and is a tumor marker excreted by the biliary epithelium^[3]. 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, such as bile duct inflammation and obstruction^[10].

Imaging tests help doctors see the inside of your body. These can include^[6]:

• Endoscopic or laparoscopic ultrasound
• Endoscopic retrograde cholangiopancreatography (ERCP), a test that examines your bile duct with a small camera
• Cholangiography
• Computed tomography (CT) scans
• Magnetic resonance imaging (MRI)
• Positron emission tomography (PET) scans

During endoscopic ultrasound, your doctor inserts a long, flexible tube down your throat and into your abdomen. An ultrasound device at the end of the tube emits sound waves that generate images of nearby tissues^[10].

A biopsy is the only way to know for sure if you have cancer^[6]. 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, and if it has spread^[6]. A pathology report details these results and is sent to your healthcare provider, about 5 to 10 days after the biopsy^[6].

To guide treatment, cholangiocarcinoma is “staged”^[6]. This stage is based on where and how big the tumor is, if there are cancer cells in the lymph nodes, and if there are cancer cells in other parts of the body^[6]. 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]. Almost 75% of patients have nonresectable or metastatic disease at presentation^[3].

Treatment Options

Treatment usually involves a combination of surgery, chemotherapy, or radiation therapy^[2]. The type of treatment a person receives will depend on whether the cancer can be completely removed with surgery (resectable) or not (unresectable)^[11].

Surgery

Surgery is the only curative treatment modality for cholangiocarcinoma^[3]. Surgery that removes the whole tumor is the only way to cure this cancer^[6]. The type of surgery depends on how big and where the tumor is^[6].

Several types of surgery may be used^[11]:

• Removal of the bile duct: This surgical procedure is done to remove part of the bile duct if the tumor is small and is in the bile duct only
• Partial hepatectomy: This is a surgical procedure to remove the part of the liver where cancer is found
• 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

Surgery may also be done to remove only part of the tumor. Surgery can also be done with other treatments^[6]. Some people may receive chemotherapy or radiation therapy after surgery 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].

Some patients with cholangiocarcinoma are eligible for potentially curative surgical options, such as resection or liver transplantation^[9].

Palliative Surgery

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

• Biliary bypass: If cancer is blocking the bile duct and bile is building up in the gallbladder, a biliary bypass may be done to create a new pathway around the blocked area
• Endoscopic stent placement: If the tumor is blocking the bile duct, surgery may be done to put in a stent (a thin, flexible tube) to drain bile
• Percutaneous transhepatic biliary drainage: A thin needle is inserted through the skin below the ribs and into 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]. Radiation can be given in a series of treatments to allow healthy cells to recover and to make radiation more effective^[11]. It is not known whether external radiation therapy helps in the treatment of resectable bile duct cancer^[11].

Chemotherapy

Chemotherapy is the use of medication to treat cancer^[6]. It can be used alone or with other treatments^[6]. Radiation and chemotherapy serve as adjuncts to surgery^[3].

Targeted Therapy and Immunotherapy

Recent investigations into the molecular mechanisms underlying cholangiocarcinoma have yielded various targeted therapies that have improved outcomes^[3]. Genetic studies have provided new insights into the pathogenesis of cholangiocarcinoma, and certain genetic abnormalities can be therapeutically targeted^[9]. Targeting the tumor immune microenvironment might be a promising therapeutic approach^[9].

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

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

Most people receive a cholangiocarcinoma diagnosis after it’s already spread outside of their bile ducts. At this point, bile duct cancer is difficult to treat, and the prognosis is usually poor^[2]. Advanced bile duct cancer is cancer that has spread outside the bile ducts or has come back some time after treatment. Unfortunately, advanced bile duct cancer is unlikely to be cured^[17].

However, your doctor might suggest you have treatment to try to slow its growth and relieve symptoms^[17]. All patients with suspected or confirmed cholangiocarcinoma should be evaluated for distant metastatic disease^[3].

Cholangiocarcinoma remains a highly lethal disease and further scientific and clinical insights are needed to improve patient outcomes^[9].