Cholangiocarcinoma (CCA) Facts

What is cholangiocarcinoma?

Cholangiocarcinoma, also known as bile duct cancer, is a rare cancer that occurs in the bile ducts within, or outside, the liver. It is the second most common primary liver cancer in the world.^1,2 It typically affects patients over the age of 65 and unfortunately has a poor prognosis.³ 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.^2-5

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 shown:¹

Intrahepatic (within the liver) ~20%
Perihilar (at the junction between the left and right bile ducts) ~50–60%
Distal extrahepatic (outside the liver) ~20%

What causes cholangiocarcinoma?

There are some well-defined risk factors for cholangiocarcinoma that have one thing in common—they all cause long-term chronic inflammation of the biliary tract. Established risk factors include⁵^-7:

Parasitic infections with liver flukes (Opisthorchis viverrini and Clonorchis sinensis) or infectious diseases, such as hepatitis B or hepatitis C
Inflammatory diseases, such as primary sclerosing cholangitis (PSC), chronic pancreatitis, or bile duct stones
Drugs, chemicals, and toxins, such as asbestos, tobacco, and alcohol
Congenital conditions and diseases, such as biliary cysts and Caroli disease
General risk factors include age (>65 years old), male gender, obesity, diabetes mellitus, and non-alcoholic fatty liver disease

Known risk factors, however, can only be attributed to less than 30% of cases, meaning most cases are sporadic and without a known cause.³ Therefore, it is likely that there is a genetic element to a patient’s predisposition to cholangiocarcinoma.^1,4

Geographically, the incidence rates of cholangiocarcinoma vary based on the exposure to the risk factors listed above. In South East Asian countries, such as Thailand, there are significantly higher incidence rates due to the prevalence of carcinogenic liver flukes.⁸ However, in Western countries, PSC is the most common known predisposing factor for cholangiocarcinoma, but most cases appear without known risk factors being present.¹

What are the symptoms?

During the early stages, cholangiocarcinoma is commonly asymptomatic, however there are some patients who do experience symptoms.⁵ Some common symptoms that develop as the disease progresses include: abdominal pain, weight loss, itching, fever, and fatigue.³ Since all of these are generic symptoms, diagnosis can prove difficult.

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.³ In perihilar and extrahepatic cases, however, patients often experience painless jaundice (the skin and whites of the eyes become yellow), their stools (bowel motions) become pale, and the urine becomes dark. These symptoms are due to the tumor blocking the biliary ducts and preventing bile from flowing freely.^1,3

How is it diagnosed?

It is crucial to diagnose cholangiocarcinoma as early as possible in order to optimize survival rates. The symptoms described above are general and can be associated with more common, less serious, conditions. Therefore, cholangiocarcinoma is a difficult condition to diagnose and diagnosis often occurs at an advanced stage of disease. Many cases (between 20–25% for intrahepatic) are detected incidentally when investigations and scans are conducted for other indications.^1,5

Given that cholangiocarcinoma is difficult to diagnose, a combination of methods are required to accurately confirm a diagnosis. The main methods used are^1,2:

Observation of symptoms
Imaging: contrast magnetic resonance imaging (MRI), high-resolution computerized tomography (CT) scans, endoscopic ultrasound, positron emission tomography (PET), and cholangiography
Blood tests to detect blood biomarkers, with cancer antigen 19–9 (CA 19–9) being the most relevant (though a blood test alone cannot diagnose cholangiocarcinoma)
Histology and cytology (examination of cancerous cells in a laboratory)
Molecular tumor profiling using fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) for chromosomal instability and gene aberrations (e.g. KRAS, TP53, and CDKN2A)

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), responsible for the regulation of gene expression.²

Can it be treated?

Currently, the only potentially curative treatment is surgery, however, this is only an option in approximately a third of patients.¹Surgery 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

Cholangiocarcinomas are highly chemoresistant, meaning drug-based treatments, like chemotherapy, are generally unsuccessful.⁵However, if surgery is not an option, chemotherapy is often offered to patients and radiotherapy may be considered, but in these cases the aim is usually to improve the patient’s quality of life by relieving their symptoms.³

Main treatment options include²:

Surgical resection—for patients with any type of early cholangiocarcinoma
Liver transplantation—for patients with early intrahepatic and unresectable perihilar cholangiocarcinoma
Locoregional therapies—for patients with unresectable intrahepatic and perihilar cholangiocarcinoma or before transplantation
- Transarterial chemoembolization (TACE)
- Radioembolization
- External-beam radiation therapy (EBRT)
Cytotoxic chemotherapy—for patients not suitable for resection or locoregional therapy
Targeted therapies—still in development but potentially useful for patients with specific mutations that could be targeted with inhibitors

What is the future of cholangiocarcinoma?

Genetics

Genetic and molecular profiling is a fast expanding area of interest across all cancers. Patients with the same type of cholangiocarcinoma will not have the same genetic mutations in their cancer cells, as no two tumors are the same. Molecular profiling looks at the mutations present within the patient’s cancerous cells and so far, in cholangiocarcinoma, several genetic mutations and other genetic abnormalities have been identified^2,9:

IDH1/2
BRACA1/2
BAP1
ARID1A/B and ARID2
ELF3
PBRM1
PRKACA/B
CDKN2A/B
CCND1
FGFR1/2/3
MCL1
PD-L1
PBRM1

Some mutations can be more common in certain subsets of cholangioncarcinoma than in others. Knowing the molecular profile of the tumor can help identify the optimal treatment because the specific mutation(s) affect how, and if, they will respond to treatment. There are some targeted therapies currently under investigation in cholangiocarcinoma and moving forwards it will become more important that patients are biopsied and screened at diagnosis to identify the best treatment approach as quickly as possible.⁹

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, ultimately, to develop new treatments to improve survival rates or quality of life for patients. There are many ongoing clinical trials in cholangiocarcinoma internationally. The main trials are currently looking at: chemotherapy regimens, targeted therapy (based on genetics), immunotherapy (using the immune system to fight cancer), radiation therapy, other novel treatments (new approaches), and second line treatments (when the first treatment has not worked).

Treatment Approaches

It is recommended that cholangiocarcinoma patients are seen in dedicated centres 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.⁵

Why do cholangiocarcinoma incidence rates differ geographically?

South East Asia

In South East Asian countries, such as Thailand, cholangiocarcinoma is one of the top five causes of death.¹⁰

The risk of developing cholangiocarcinoma is 14x higher when infected with the liver fluke Opisthorchis viverrini⁵, which is acquired by eating undercooked freshwater fish.⁴ There are other liver flukes in different regions that are also carcinogenic, with an estimated 700 million people at risk of infection.⁶

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

Khan S.A. et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut. 2012. DOI: 10.1136/gutjnl-2011-301748
Rizvi S. et al. Cholangiocarcinoma ‐ evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018; 15(2):95–111. DOI: 1038/nrclinonc.2017.157
Anderson C.D. et al. Diagnosis and treatment of cholangiocarcinoma. Oncologist. 2004 Feb; 9(1):43–57. DOI: 10.1634/theoncologist.9-1-43
Bridgewater J. et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014 Jun; 60(6):1268–1289. DOI: 10.1016/j.jhep.2014.01.021
Banales J.M. et al. Expert consensus document. Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastro Hepat. 2016 Apr 20; 13:261–280. DOI: 10.1038/nrgastro.2016.51
Suwannatrai A.T. et al. Bayesian spatial analysis of cholangiocarcinoma in Northeast Thailand. Sci Rep. 2019 Oct 03; 9:14263. DOI: 1038/s41598-019-50476-7
Khan S.A. et al. Cholangiocarcinoma: Epidemiology and risk factors. Liver Int. 2019 Mar 09; 39(S1):19–31. DOI: 1111/liv.14095
Sithithaworn P. et al. Roles of liver fluke infection as risk factor for cholangiocarcinoma. J Hepato-Bil-Pan Sci. 2014 Jan 10; 21(5):301–308. DOI: https://doi.org/10.1002/jhbp.62
OncLive. Expert Interview. Dr. Shroff discusses molecular profiling in cholangiocarcinoma. https://www.onclive.com/conference-coverage/gi-2019/dr-shroff-discusses-molecular-profiling-in-cholangiocarcinoma?eKey=bWVsaW5kYS5iYWNoaW5pQGNob2xhbmdpb2NhcmNpbm9tYS5vcmc=&utm_medium=email&utm_campaign=ONCSS Published; 2019 Jan 18. [Accessed 2019 Feb 01]
AMMF The cholangiocarcinoma charity. Specialist Viewpoint – or cholangiocarcinoma as they see it. http://ammf.org.uk/article-6-cc-in-thailand/ Published; 2014 May. [Accessed 2019 Jan 03]

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