Cholangiocarcinoma (CCA) Facts

What is cholangiocarcinoma?

Cholangiocarcinoma is a rare cancer that occurs in the bile ducts. Bile is a yellow/green digestive fluid that is constantly made by liver cells. The bile ducts are a network of vessels that drain bile from the liver to the gall bladder, where it is stored, through to the small intestine, where it helps break down fats.¹

Cholangiocarcinoma is the second most common primary liver cancer in the world. It typically affects people over the age of 65 and unfortunately it has a poor prognosis.2 In general, the incidence and mortality rates of cholangiocarcinoma appear to be increasing globally and across all age groups, including younger people, but current data show this increase varies between the different subtypes.^1–5

There are three main subtypes of cholangiocarcinoma, which are defined by the location of the tumor. These are classified as below, with the estimated proportion of each type shown¹:

Intrahepatic cholangiocarcinoma occurs in the smaller bile ducts within the liver before they join into the left or right hepatic ducts, ~10–20%.
Perihilar/hilar cholangiocarcinoma occurs within the left or right hepatic ducts and the common hepatic duct, ~50–60%.
Distal or extrahepatic cholangiocarcinoma occurs outside the liver in the common bile duct after the cystic duct, ~20–30%.

What causes cholangiocarcinoma?

Most cases of cholangiocarcinoma happen without any known cause.

General risk factors include age (>65 years old)2, obesity, diabetes mellitus, and nonalcoholic fatty liver disease.¹

Some well-defined risk factors for cholangiocarcinoma have one thing in common—they all cause long-term chronic inflammation of the biliary tract. Established risk factors include the following^1,2,6,7:

Inflammatory diseases, such as primary sclerosing cholangitis (PSC), which causes inflammation of the bile ducts (cholangitis) that leads to the formation of scar tissue (sclerosis).
Congenital conditions and diseases that result in the bile ducts being wider than usual, such as biliary/choledochal cysts and Caroli disease, disrupt the flow of bile causing stone formation and scarring.
Bile duct stones or gallstones, which are deposits of bile caused by an infection or slow movement of the bile through the ducts that can irritate the lining of the ducts.
Viral infections, such as hepatitis B or C, can lead to scaring of the liver (also known as cirrhosis).
Drugs, chemicals, and toxins, such as asbestos, tobacco, and alcohol can also cause irritation and damage to the liver.
Parasitic infections with liver flukes (Opisthorchis viverrini and Clonorchis sinensis) occur mainly in Southeast Asia, particularly near the Mekong River. Infection is caused by eating raw fish that has been contaminated with the liver flukes. Once in the liver or bile ducts, the parasites cause inflammation and scarring. In Western countries these types of infection are almost non-existent.

Geographically, the incidence rates of cholangiocarcinoma vary. In Western countries, cholangiocarcinoma affects fewer than six people per 100,000 each year. However, in Southeast Asia, specifically Thailand, South Korea, and China, the incidence of cholangiocarcinoma is higher, affecting more than six people per 100,000 each year.2 This variation may be based on the exposure to the risk factors listed above, such as the high prevalence of carcinogenic liver flukes in Southeast Asia.^1,8

What are the symptoms?

During the early stages, cholangiocarcinoma is commonly asymptomatic, however there are some patients who do experience vague symptoms that develop as the disease progresses.^1,2 These include abdominal pain (usually on the right-hand side just below the ribs), weight loss, fever, and fatigue.^1,4

As the disease becomes more advanced, the clinical features that a patient presents with depend on the location of the tumor. In intrahepatic cholangiocarcinoma, patients generally present with abdominal pain described as a constant, dull ache.⁴ However, in perihilar and extrahepatic cases, patients often experience painless jaundice due to the tumor blocking the biliary ducts and preventing bile from flowing freely. Therefore, bile that is yellow in color builds up in the blood and body tissues and results in yellowing of the skin and whites of the eyes, pale stools, and dark urine. Stools may also be difficult to flush as they have a higher fat content because the fats are not broken down and absorbed as efficiently due to less bile reaching the small intestine. The buildup of bile in the skin can also cause the skin to become itchy.^1,4,9

How is it diagnosed?

It is crucial to diagnose cholangiocarcinoma as early as possible in order to optimize survival rates. Currently, the survival rate 5 years after diagnosis is between 7% and 20% globally.1 The symptoms described above are general and can be associated with more common, less serious, conditions; therefore, cholangiocarcinoma can be difficult to diagnose. Diagnosis often occurs at an advanced stage of disease and many cases (20–25% for intrahepatic cholangiocarcinoma) are detected incidentally when investigations and scans are conducted for other reasons.^1,2,9

Given that cholangiocarcinoma is difficult to diagnose, a combination of methods is required to accurately confirm a diagnosis. The methods used vary across different regions of the world and may include the following^{1,3,9,10–13}:

Observation of symptoms, with details of past medical history, and a physical examination to check for pain in the abdomen and enlargement of the liver or other organs.
Blood tests to assess liver function as well as proteins associated with some cancers such as cancer antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA). The blood may also be tested for a protein known as IgG4 to rule out autoimmune cholangitis.
General imaging of the bile ducts and surrounding organs using various methods, such as:
- Ultrasound/ultrasonography, which uses high frequency sound waves.
- Magnetic resonance imaging (MRI), which uses radio waves and strong magnets, and computerized tomography (CT) scans, which use a series of X-rays taken at different angles. These tests may also involve the use of a contrast agent (dye), which is usually ingested or injected into a vein, to help visualize the organs better.
- Positron emission tomography (PET), which requires injection of a radioactive chemical to identify cancer cells; it is often used together with CT or MRI scans.
More invasive imaging tests that are often carried out under sedation, including:
- Endoscopic retrograde cholangiopancreatography (ERCP), where a long tube with a camera attached is passed down the throat to the small intestine and into the common bile duct, a contrast agent is injected, then X-rays are taken to see any narrowing or blockage of the bile ducts.
- Endoscopic ultrasound scan (EUS), which uses a very similar process to ERCP, although the camera works differently by taking ultrasound pictures rather than X-rays.
- Percutaneous transhepatic cholangiography (PTC), where a long needle is inserted from the abdomen to the liver (guided by X-rays or ultrasound) in order to find the cause of the blockage and to alleviate it.
- An angiogram that is used to look at larger blood vessels in the liver. This involves the insertion of a very fine tube into the artery in the groin and injection of a dye that is absorbed by blood vessels so they can be seen by X-ray.
- A laparoscopy, which involves an incision in the abdomen, followed by the insertion of a tube with a camera attached. This allows the surgeon to examine the bile ducts and surrounding tissues for cancer.
Biopsies (small tissues samples) may be taken during any of the more invasive imaging tests and can be examined by histology (examination under a microscope).
Molecular profiling/testing may also be carried out on biopsy samples to look at specific genes that may be mutated in the cancer and make it more susceptible to targeted treatments. The most commonly occurring molecular alternations in patients with intrahepatic cholangiocarcinoma are in IDH1, which occur in ~20% of patients, and FGFR2, which occur in ~15% of patients.¹⁴

Other, more recently adopted technologies to diagnose cholangiocarcinoma include mutational analysis of cell-free DNA, detection of circulating tumor DNA, and analysis of microRNA (miRNA), which is responsible for the regulation of gene expression.³

Can it be treated?

Treatment options vary across different regions of the world depending on what is available and approved in each country. Currently, the only potentially curative treatment is surgery; however, this is only an option in approximately 25% of patients.¹ Surgery can be performed to remove the cancer or to relieve the symptoms the patient is experiencing. The location of the tumor can affect the surgical treatment, so it is critical that the patient is properly evaluated by a specialist to determine if surgery is an option.^1,3,4,9

Surgical treatment options include the following^11–13:

Removal of the affected bile ducts. This is usually only performed in early stages of the disease when only the bile ducts are affected. The remaining healthy ducts are reconnected to the small intestine.
Partial liver resection (removal) can be carried out at earlier stages if the cancer has only spread to certain parts of the liver and is removed with the affected bile ducts.
The Whipple procedure involves removal of the bile ducts, part of the stomach, part of the small intestine, the pancreas, gall bladder, and the surrounding lymph nodes, if affected.
Bypass of the blocked bile ducts to allow the flow of bile to the small intestine and relieve the symptoms of jaundice. This is usually carried out where removal of the tumor is not possible.
Stent insertion, where a tube is placed into the bile ducts to hold them open and prevent blockages.

For patients where surgery is not an option, chemotherapy with the anticancer drugs gemcitabine and cisplatin is the first treatment option. Second-line treatment for those in which the first-line treatments have not worked or the cancer has come back and is advanced or metastatic, include a combination of folinic acid, fluorouracil, and oxaliplatin (often referred to as FOLFOX).^1,13

These chemotherapeutic drugs are given intravenously and work together to destroy fast growing cells, such as cancer cells, by interfering with the process of cell replication. However, because other cells in the body also divide quickly, they can cause several side effects, including easy bruising/bleeding, anemia, fatigue, susceptibility to infections, sickness, diarrhea, mouth ulcers, suppressed appetite, changes in taste, hair loss, and changes to the skin and nails. Damage to the kidneys and liver may occur as the body tries to excrete these toxic agents.^11–13

Radiation therapy may be given to lower the risk of the cancer coming back after surgery or to relieve symptoms. It utilizes high-energy X-rays, gamma rays, or protons to kill cancer cells. The two main types of radiation therapy are:

Stereotactic body radiation therapy (SBRT) that directs radiation beams from many different positions around the body, which results in the cancer receiving high doses of radiation, but the surrounding tissues receiving only a low dose, thus lowering the risk of side effects.¹¹
Selective internal radiation therapy (SIRT), which uses small pellets of radioactive material that are inserted next to or into the tumor to minimize the risk of radiation to other organs and tissues. (Note: this is type of therapy is not approved in the UK).¹⁵

The side effects of radiation therapy are similar to chemotherapy and may also result in skin changes such as redness, blistering, and peeling, but usually only occur in the area being treated.¹⁵

More personalized/targeted therapies for patients with specific gene mutations are currently under investigation in clinical trials. One targeted therapy that has already been approved in the US, UK, and Europe is pemigatinib, which can be used for patients who have an FGFR2 fusion.^16–18

What is the future of cholangiocarcinoma?

Genetics

Genetic and molecular profiling is a fast expanding area of interest across all cancers. Molecular profiling looks at the mutations present within a patient’s cancerous cells. Currently, in cholangiocarcinoma, several genetic mutations/abnormalities have been identified, including^1,3,19:

IDH1/2
BRCA1/2
BAP1
ARID1A/B and ARID2
ELF3
PBRM1
PRKACA/B
CDKN2A/B
CCND1
FGFR1/2/3
MCL1
PD-L1
PBRM1
TP53
MYC
SMAD4
ERBB2

However, the mutations that cause cholangiocarcinoma vary from one person to the next. These mutations may also vary from one cancer cell to another within the same person. This represents a limitation to current therapies, as one treatment may not work for all patients with cholangiocarcinoma and may not work on all the cholangiocarcinoma cells, leading to treatment failure or the disease returning. The future of cholangiocarcinoma treatment relies on research into the genetic causes to allow for personalized targeted therapies and clinical trials that compare combinations of different therapies to maximize destruction of the cancer cells.¹

Clinical trials

When developing a new drug or treatment approach, it is important to prove that it is safe and effective in the patients who will be treated. Clinical trials aim to develop new treatments to improve survival rates or the quality of life for patients.

New treatments for cholangiocarcinoma that are currently being tested in clinical trials include liver transplantation, targeted therapies for patients with specific types of mutations, and immunotherapies, which are treatments that help the immune system find and attack cancer cells better.

Liver transplants may be beneficial for certain types of cholangiocarcinoma. Clinical trials have been undertaken in patients with perihilar cholangiocarcinoma that can and cannot be surgically removed. In these studies, patients were treated with a combination of chemotherapy and radiation therapy, followed by a liver transplant. These studies showed a benefit in some patients as they were free from disease after 5 years, however in some patients the cancer returned. Potential obstacles to this strategy include the limited availability of livers for transplantation and the need for life-long medication to suppress the immune system. Therefore, identifying factors that affect whether treatment will work well is vital to improving treatment options.¹

Targeted therapies require molecular testing to be carried out first to see if the cancer has a particular mutation/s that make it more likely to respond to specific agents. Agents that may be of benefit include^10,13:

Entrectinib or larotrectinib for those with NTRK gene fusions
Pemigatinib and infigratinib for those with FGFR2 fusions/rearrangements
Erdafitinib and futibatinib for those with FGFR mutations
Ivosidenib for those with IDH1 mutations
Dabrafenib and trametinib for those with BRAFV600E mutations
Zanidatamab for those with HER2 mutations

Immunotherapies such as pembrolizumab and nivolumab are being tested in clinical trials in combination with other agents. Pembrolizumab and nivolumab work by blocking a protein called PD 1, which is present on the surface of a type of immune cell known as the T cell. This blockade allows the T cells to remain active and destroy cancer cells.^1,10,13

Treatment approaches

It is recommended that patients with cholangiocarcinoma are seen in dedicated centers with multidisciplinary treatment teams, where diagnosis and management can be personalized. At-risk populations (such as those in areas where liver flukes are present) should also be identified, educated about the risk of eating raw fish, and followed up so that diagnosis occurs as early as possible.²

Why do cholangiocarcinoma incidence rates differ geographically?

South East Asia

In Southeast Asian countries, such as Thailand, cholangiocarcinoma is one of the top five causes of death,²⁰ which is associated with the higher prevalence of liver flukes in this region. Opisthorchis viverrine and Clonorchis sinensis have both been classified as Group 1 carcinogens (substances capable of causing cancer).⁷ These liver flukes infect ~90–95% of fish with scales in the Mekong River,⁷ putting an estimated 700 million people at risk of infection.²¹ Infection occurs from eating raw fish contaminated with the liver flukes, which can travel through the small intestine and into the bile ducts, where they cause inflammation and scaring.⁷

Liver fluke infection is both preventable and treatable. Mass drug administration and educational awareness programs have promising results in controlling the parasite, so it is believed that cholangiocarcinoma cases can be reduced through these methods.⁶

Western Countries

Since liver flukes are not found in Western countries, this population is not at risk.

Most cases of cholangiocarcinoma are sporadic and without a known cause. There are some established risk factors, but often the exact cause cannot be attributed to any of these. Therefore, more work is required to establish the risk factors of cholangiocarcinoma and improve patient outcomes.

Globally

Globally, it is important to increase awareness of cholangiocarcinoma and encourage early and accurate diagnosis. It is also crucial that research and treatment advances are shared to make treatment decisions and clinical trials as well informed and knowledgeable as possible.

References

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Banales JM, Cardinale V, Carpino G, et al. Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastro Hepat. 2016;13:261-280. DOI: 10.1038/nrgastro.2016.51
Rizvi S, Khan SA, Hallemeier CL, et al. Cholangiocarcinoma ‐ evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15(2):95-111. DOI: 1038/nrclinonc.2017.157
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NCCN Guidelines for Patients. Gallbladder and bile duct cancers 2021. https://www.nccn.org/patients/guidelines/content/PDF/gallandbile-hp-patient.pdf. Accessed Sep 14, 2021.
Cancer Research UK. Bile duct cancer. https://www.cancerresearchuk.org/about-cancer/bile-duct-cancer. Reviewed Sep 16, 2021. Accessed Oct 8, 2021.
Cholangiocarcinoma Foundation of Thailand. About CCA. http://cca.in.th/wpen/overview/. Accessed Oct 8, 2021.
AMMF The Cholangiocarcinoma Charity. Cholangiocarcinoma. https://ammf.org.uk/cholangiocarcinoma/. Accessed Oct 8, 2021.
OncologyPRO. FGFR2 fusions testing in intrahepatic cholangiocarcinoma: ESMO biomarker factsheet. https://oncologypro.esmo.org/education-library/factsheets-on-biomarkers/fgfr2-fusions-testing-in-intrahepatic-cholangiocarcinoma. Updated Apr 12, 2021. Accessed Oct 13, 2021.
American Cancer Society. Radiation therapy for bile duct cancer. https://www.cancer.org/cancer/bile-duct-cancer/treating/radiation.html. Accessed Sep 15, 2021.
U.S. Food and Drug Administration. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion. Published Apr 20, 2020. Accessed Oct 8, 2021.
European Medicines Agency. Pemazyre. https://www.ema.europa.eu/en/medicines/human/EPAR/pemazyre. Accessed Oct 8, 2021.
National Institute for Health and Care Excellence. Pemigatinib for treating relapsed or refractory advanced cholangiocarcinoma with FGFR2 fusion or rearrangement. https://www.nice.org.uk/guidance/ta722/chapter/1-Recommendations. Published Aug 25, 2021. Accessed Oct 8, 2021.
OncLive. Dr. Shroff discusses molecular profiling in cholangiocarcinoma. https://www.onclive.com/view/dr-shroff-discusses-molecular-profiling-in-cholangiocarcinoma?eKey=bWVsaW5kYS5iYWNoaW5pQGNob2xhbmdpb2NhcmNpbm9tYS5vcmc%3D&utm_medium=email&utm_campaign=ONCSS. Published Jan 18, 2019. Accessed Feb 1, 2019.
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Prueksapanich P, Piyachaturawat P, Aumpansub P, et al. Liver fluke-associated biliary tract cancer. Gut Liver. 2018;12(3):236-245. DOI: 10.5009/gnl17102

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