What Is Cholangiocarcinoma?

Cholangiocarcinoma is the name given to a group of cancers that form in the bile ducts. The bile ducts are part of the digestive system and are small tubes that connect the liver to the gallbladder and small intestine. The liver has a number of roles including cleaning the blood to remove harmful substances and metabolizing proteins, fats, and carbohydrates so your body can use them. The liver also makes a fluid called bile that helps the body to break down fats from food. Bile can be stored in the gallbladder or can travel directly from the liver to the small intestine. Most of the digestive process takes place in the small intestine and it is here that nutrients and minerals from our food are absorbed into the blood.

Cholangiocarcinoma is divided into three types based on where the cancer develops in the bile ducts:

• Intrahepatic cholangiocarcinoma starts in parts of the bile ducts that are inside the liver (“intrahepatic” literally means “inside the liver”).
• The other two types of cholangiocarcinoma are extrahepatic (meaning that they start outside the liver). Hilar (also sometimes known as “perihilar”) cholangiocarcinoma starts just outside the liver, where the right and left bile ducts join to form the common hepatic duct (which is the area of bile duct before the gallbladder). Distal bile duct cholangiocarcinoma starts in the common bile duct, where the ducts from the liver and gallbladder join together, which passes through the pancreas and ends in the small intestine.

What Are the Signs and Symptoms of Cholangiocarcinoma?

Most people with cholangiocarcinoma don’t have any symptoms when the cancer first starts to develop, and only start to experience symptoms when the cancer is at an advanced stage and the flow of bile from the liver becomes blocked. It is when this happens and the bile starts to move back into the blood and body tissue that signs and symptoms start to develop. These can include jaundice (yellowing of the skin and the whites of your eyes), dark urine and/or white-colored stools, itchy skin, pain in the stomach area (usually in the upper right-hand side), loss of appetite, and non-specific symptoms such as fever, night sweats, fatigue, and losing weight without trying. These signs and symptoms can also be caused by other conditions so if you have any of them it is important that you consult a medical professional.

What Causes Cholangiocarcinoma?

Cholangiocarcinoma is rare. According to the National Cancer Institute it affects fewer than 6 in 10,000 people worldwide each year, although it is more common in some countries than others. It is not yet clear why some cholangiocarcinomas develop, but some factors that have been identified as increasing a person’s risk include having primary sclerosing cholangitis (a rare type of liver disease that causes long-term inflammation of the liver and hardening and scarring of the bile ducts) and liver cirrhosis (permanent scarring of the liver tissue caused by damage), bile duct problems that are present at birth (such as Caroli’s disease and choledochal cysts), liver fluke infection in areas of Southeast Asia, and biliary stones (these are similar to gallstones but form in the liver). Some DNA changes that cause inherited conditions, including Lynch syndrome and cystic fibrosis, are also associated with increased risk.

Cholangiocarcinoma is slightly more common in men than women and the risk of developing it increases with age. Although most people who are diagnosed with cholangiocarcinoma are over the age of 65, it can occur at any age. Cholangiocarcinoma does occur in children but is exceedingly rare, with some analyses concluding that fewer than 22 cases have been reported in the last 40 years, with the majority of the children who developed the cancer having a gastrointestinal disorder that is linked to its development. Because of its rarity, there is no standard treatment protocol for children diagnosed with cholangiocarcinoma.

What Did This Study Investigate?

The authors of this study describe the case of a 16-year-old girl who was diagnosed with advanced hilar cholangiocarcinoma. The authors used a “precision medicine” approach for her treatment plan, which aims to optimize the efficiency of treatment by using genetic analysis (such as DNA sequencing) or molecular profiling (laboratory analysis of tissue, blood, or fluid samples to check for certain genes, proteins, or other molecules). Specific information about a person’s cancer can then be used to help make a diagnosis, develop a targeted treatment plan, or find out how well a treatment is working.

Precision medicine is increasingly being used in the treatment of cholangiocarcinoma. A number of mutated genes have been identified in samples from cholangiocarcinomas that belong to a family of genes called “oncogenes”. Oncogenes are genes that are involved in normal cell growth and division, but can cause cancer if they become altered by changes that cause there to be too many copies of the gene or result in it being more active than normal.

The genetic changes in oncogenes that cause them to become activated result in the proteins that they code for being slightly different from the proteins that would be made if they had not become altered. These differences are being exploited by scientists to develop targeted treatments that only attack cancer cells. In this study, the authors describe how DNA sequencing of tissue from the patient’s tumor that was obtained from biopsy sampling during the diagnostic process showed that the tumor had a genetic change called an “oncogenic gene fusion”.

This means that part of the tumor cell DNA had become structurally rearranged, causing an area on chromosome 1 to become fused with chromosome 8 (humans have 23 pairs of chromosomes), producing a hybrid gene and leading to the activity of a gene called neuregulin-1 (NRG1) becoming dysregulated. NRG1 fusions have been found in a number of cancer types, including lung cancer, and have been estimated to occur in 0.8% of cholangiocarcinomas. They lead to NRG1 protein expressed at the cell surface binding to a protein called ERBB3 (its name is “erythroblastic oncogene B 3” and also known as human epidermal growth factor 3 or HER3).

This causes it to bind with ERBB2, which is also known as HER2 and is an oncogene that has been shown to play an important role in the development and progression of certain types of aggressive breast cancer, leading the two proteins to form dimers (a complex made up of two molecules linked together) that result in the activation of signaling pathways in cells that result in abnormal cell proliferation. This can contribute to the growth of a tumor.

Having identified that the patient’s tumor DNA had an NRG1 fusion, the authors were able to treat her with a combination of conventional chemotherapy and radiotherapy, followed by targeted treatment with a drug that specifically blocks signaling by members of the ERBB family of proteins. The treatment with the targeted drug was able to slow the growth of the tumor. In addition, the genetic changes that were identified in the patient’s tumor DNA meant that she was eligible to take part in a clinical trial, which she would not have been able to do if her tumor DNA had not been sequenced.

This case highlights how the increasing use of precision medicine approaches and targeted therapies can improve the quality of life of patients with rare cancers.