All About Cholangiocarcinoma

Author: OncoLink Team
Last Reviewed:

What is bile and the biliary system?

Bile is a greenish substance made in the liver, and stored in the gall bladder. Bile assists in:

  • The digestion of fats by breaking them down into amino acids and fat soluble vitamins (vitamins A, D, E and K).
  • Disposal of hemoglobin from old red blood cells which are no longer functional.

A bile duct carries bile from the liver to the small intestine. The network of ducts which transport the bile is known as the biliary system. This system can be broken down into several sections:

  • The ducts which are inside of the liver (intrahepatic):
    Small bile ductules in the liver combine with each other to form larger ducts known as intrahepatic bile ducts. The liver can be grossly divided into two lobes, the left and the right. As the intrahepatic ducts combine with each other they form two large ducts known as the right and left hepatic ducts. The left and right hepatic ducts come together to form the common hepatic duct.
  • The ducts immediately outside of the liver (perihilar):
    The gallbladder sits just below the liver and the cystic duct delivers bile into and out of the gallbladder. As the common hepatic duct exits the liver it connects with the cystic duct to form the common bile duct.
  • The distal biliary tree:
    The common bile duct enters the pancreas. It combines with the pancreatic duct. Secretions from both the pancreas and the common bile duct exit into the duodenum through the Ampulla of Vater. Any reason you used numbers instead of bullets?

What is cholangiocarcinoma?

Cholangiocarcinoma is cancer of the bile duct. It is also called bile duct cancer. About 95% of cholangiocarcinomas are classified histologically (what type of tumor cells are seen when the tumor is examined under a microscope) as adenocarcinomas. Cholangiocarcinoma develops in the epithelial cells which line the bile ducts. The majority of cholangiocarcinomas (about 60-70%) appear in the perihilar region. About 25% arise from the distal ductal system and 5-10% from the intrahepatic ductal system. Cholangiocarcinomas do not include cancers that arise from the Ampulla of Vater or the gallbladder. Cholangiocarcinomas that involve the area where the right and left ducts meet to form the common bile duct are called Klatskin tumors.

What causes cholangiocarcinoma and am I at risk?

Cholangiocarcinomas are rare tumors. It is estimated that approximately 8000 people in the United States will be diagnosed with cholangiocarcinoma annually. There is a higher prevalence of cholangiocarcinoma in the Middle East and Asia due to a higher prevalence of liver flukes, a common parasitic infection, as well as an increased incidence of biliary stones. Cholangiocarcinoma tends to occur in older persons. Cholangiocarcinomas occur more frequently in people over the age of 65.

Risk factors associated with cholangiocarcinoma include increased age, obesity, hepatitis and a family history. There are also certain medical conditions that can increase your risk for cholangiocarcinoma including cirrhosis, diabetes, primary sclerosing cholangitis (PSC), ulcerative colitis, cholechochal cysts and biliary infections (like those that occur in typhoid carriers). There is also a possible link between exposure to certain chemicals, nitrosamines, dioxin, asbestos and polychlorinated biphenyls and cholangiocarcinoma.

How can I prevent cholangiocarcinoma?

There are few recommendations for prevention of cholangiocarcinoma. Experts recommend decreasing exposure to the previously mentioned chemicals. Hepatitis vaccinations may decrease risk of cholangiocarcinoma. It is also important to be sure to eat well, exercise regularly, quit smoking (or don't start!) and see your primary care provider annually for a routine physical exam and lab tests.

What screening tests are used for cholangiocarcinoma? 

Currently, there are no tests that have been shown to be effective in screening for or detecting cholangiocarcinoma. 

What are the signs of cholangiocarcinoma?

Most symptoms associated with cholangiocarcinoma result from the obstruction of the biliary tree by the tumor. Symptoms include: 

  • Painless jaundice: a yellowing of the skin and whites of the eyes.
  • Itchy skin.
  • Weight loss and loss of appetite.
  • Fever.
  • Gray/clay colored stool.
  • Abdominal pain
  • Dark urine.

During physical examination, your healthcare provider may detect an enlargement of the liver (hepatomegaly) or may feel a mass in the upper right part of the abdomen. Infrequently, the gallbladder may be enlarged and can also be felt during physical exam.

How is cholangiocarcinoma diagnosed?

If cholangiocarcinoma is suspected, several imaging studies can be used to identify the tumor. These tests include CT scans, MRI and PET/CT scans. There are also several specialized tests used to help diagnosis cholangiocarcinoma. An endoscopic or laparoscopic ultrasound uses sound waves to image the biliary tree and check for abnormalities. An endoscopic ultrasound is performed by inserting a camera through the mouth and into the small intestine where is can be placed closed to the tumor. The ultrasound can then determine the size of the tumor and the depth to which the tumor has invaded into the surrounding tissue. A laparoscopic ultrasound is performed during a surgical procedure, where a camera is inserted through a small incision in the abdomen. The ultrasound is placed near the tumor and used to determine tumor size and depth. During both of these types of ultrasound procedures, instruments can be used to take a small sample of tissue (biopsy), which is sent to a pathologist to determine the tumor type.

Another specialized endoscopic technique known as an endoscopic retrograde cholangiopancreatography (ERCP) can be used to find blockages or compressions in the bile ducts which may be related to cholangiocarcinoma. An ERCP is similar to a regular endoscopy procedure in that a small camera on a tube is inserted through the mouth and slowly advanced to the Ampulla of Vater, where the bile drains into the small intestine. Then dye is injected. The dye is observed via x-ray and reveals areas in the biliary tree that are blocked or narrowed. During ERCP, small samples of the bile duct cells are taken. This is done using a small brush that gathers cells inside the ducts. Brushings can detect cells associated with cholangiocarcinoma 35-70% of the time. During ERCP, the provider can also place a stent to relieve the blockage.

Cholangiography is another method used to visualize the biliary tree. During this procedure, enlarged biliary ducts are identified using ultrasound. A needle is then inserted through the skin into the biliary duct and an x-ray visible dye is injected. The dye identifies obstructions in the biliary ducts that may be caused by cholangiocarcinoma.

Another method is cholangioscopy. In this procedure, an endoscope is used to identify the Ampulla of Vater. Then a smaller scope is fed through the larger scope and passed into the Ampulla of Vater and then the biliary tree. The smaller scope can visualize obstructions and allow for biopsy samples to be taken.

Your provider may also order tumor marker blood tests such as AFP, CEA, CA125 and CA19-9 levels as part of your diagnostic work-up as well as during treatment. (will link to tumor marker article). 

How is cholangiocarcinoma staged?

With these tests, a stage is determined to help decide the treatment plan. The stage of cancer, or extent of disease, is based on information gathered through the various tests done as the diagnosis and work-up of the cancer is being performed. 

Cholangiocarcinoma is most commonly staged using the “TNM system.” The TNM system is used to describe many types of cancers. It has three components: T-describing the extent of the "primary" tumor (the tumor itself); N-describing if there is cancer in the lymph nodes; M-describing the spread to other organs (metastases). The staging system is very complex. The entire staging system is outlined at the end of this article. Though complicated, the staging system helps healthcare providers determine the extent of the cancer, and in turn, make treatment decisions for a patient's cancer. 

How is cholangiocarcinoma treated?

Surgery

Surgical removal of the tumor is the only curative treatment for cholangiocarcinoma. The goal of surgery is to remove as much of the tumor as possible and achieve tumor-free surgical margins. The larger the percentage of tumor left behind, the higher the risk for cancer recurrence. Intrahepatic (tumors within the liver) and perihilar tumors (tumors near the liver) are difficult to resect (remove) completely, with tumor free surgical margins obtained in only 20 to 40% of surgeries. A margin is defined as the border or edge of tissue that is removed during cancer treatment. A clean margin is when there are no cancer cells at the edge of the tissue removed. This would indicate that all of the tumor has been removed.

Intrahepatic (in the liver) tumors are generally treated with resection of the tumor, which can require the removal of an entire lobe of the liver. Perihilar (near the liver) tumors often require resection of a portion of the liver, bile duct, and gallbladder. Additionally, the removal of part of the pancreas and small intestine may also be indicated. Distal tumors (those located further from the liver) can generally be treated with resection of a portion of the small bowel or pancreas. The location of the tumor greatly influences the extent of surgical resection necessary, however all are extensive procedures, which require an experienced surgical care team and significant recuperation time. 

Not all individuals with cholangiocarcinoma can have surgery. Some 50-90% of people with cholangiocarcinomas have tumors which are unresectable when they are diagnosed. In these patients, the primary treatment goal is preventing further blockage of the biliary tree and symptom relief.

Generally, surgery is not possible if the large blood vessels which travel next to the common bile duct, the hepatic artery and the portal vein, are surrounded by tumor, and/or if the tumor has grown into the liver or has metastasized to the liver, lymph nodes or abdominal cavity.

If the tumor is found to be unresectable (not surgically removable), the surgical team may perform a surgical bypass of the blocked portion of the biliary ducts. However, this procedure can have a high incidence of post-surgical complications and studies have suggested that biliary stenting is as effective as surgical bypass in providing relief from obstructive jaundice. Thus, in most cases where imaging studies, such as CT scans, suggest inoperable (unresectable) disease, stent placement is preferred

A stent can be placed in many individuals with unresectable tumors. A stent is a small flexible plastic or metal tube that is inserted into the bile duct and allows bile to flow again into the small intestine. Stent placement is typically not an invasive procedure and can often be done during ERCP. Metal stents are preferred because they are able to keep ducts open longer, but plastic stents are easier to adjust. Stent placement is a palliative measure. It does not cure the underlying cancer diagnosis, but provides symptom management and improves quality of life. A stent is not always a permanent solution to biliary blockage. The tumor can grow into the stent and cause another blockage in the bile ducts. Sometimes radiation is used to prevent this from happening.

Some treatment centers may consider liver transplantation in combination with chemotherapy and radiation for treatment of intrahepatic cholangiocarcinoma. However, this is a controversial procedure that yields minimal favorable outcomes and does not appear to impact overall survival rates significantly.

Radiation

The goal of radiation treatment after surgery is to decrease the chances of tumor recurrence, particularly if there are positive margins. However, radiation's role as an additional treatment in tumors which have been completely resected is unclear, with studies indicating that it is beneficial and others suggesting that it may be harmful. Radiation for cholangiocarcinoma can be given externally using a machine called a linear accelerator or internally using a technique known as brachytherapy.

External beam radiation delivers radiation similar to that used in X-ray machines. However, the energy of the radiation used in linear accelerators is much higher. There are also side effects associated with external beam radiation including skin irritation, nausea and fatigue.

In brachytherapy, a catheter, (flexible tube) is placed in the area where the tumor was. A radioactive source then travels through the catheter to the area where the tumor was/is and delivers radiation directly to that specific area. In inoperable cholangiocarcinoma after stent placement, brachytherapy has been shown to increase the length of time that previously placed stents remain functional (patent) by preventing tumor cells from growing into the stent and blocking the flow of bile. However, there are potentially serious side effects from brachytherapy including cholangitis (infection of the bile ducts), stricture formation (scarring of the bile duct leading to obstruction), and ulcer formation in the intestine.

Chemotherapy

Chemotherapy can be used alone or in combination with surgery and radiation. There are several different chemotherapy options for cholangiocarcinoma. These treatment options are not curative, but offer palliation (symptom management/relief) and control of further tumor progression. Various combinations of chemotherapeutic agents are used in the treatment of cholangiocarcinoma, including 5-FUmitomycin-Cgemcitabinecapecitabineoxaliplatinalbumin bound paclitaxelcisplatin and doxorubicin. Your healthcare provider may also test your tumor for certain genetic markers that make it eligible for treatment with a targeted immunotherapy called pembrolizumab

Transcatheter arterial chemoembolization (TACE) delivers chemotherapy to a targeted tumor area, while preserving the health of surrounding tissues and organs. This procedure is most commonly used in intrahepatic (inside the liver) cholangiocarcinomas. During TACE, the tumor is targeted in two ways. First, a very high concentration of chemotherapy is delivered directly into the tumor. Second, the blood supply to the tumor is then cut off, entrapping the anti-cancer drugs within the targeted site. The tumor is then denied oxygen and other nutrients it needs to continue to grow. This procedure is performed by an interventional radiologist, in conjunction with your primary oncology team.

Clinical Trials

There are clinical research trials for most types of cancer, and every stage of the disease. Clinical trials are designed to determine the value of specific treatments. Trials are often designed to treat a certain stage of cancer, either as the first form of treatment offered, or as an option for treatment after other treatments have failed to work. They can be used to evaluate medications or treatments to prevent cancer, detect it earlier, or help manage side effects. Clinical trials are extremely important in furthering our knowledge of disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service.

Follow-Up Care and Survivorship

Regular follow-up visits with your healthcare provider are important. Be sure to report any new or worsening symptoms to your provider immediately. For patients who have had surgical resection, further treatment options may include radiation therapy and chemotherapy. For all patients, surveillance imaging is considered every 6 months for 2 years post resections if clinically indicated.

Fear of recurrence, relationships and sexual health, financial impact of cancer treatment, employment issues, and coping strategies are common emotional and practical issues experienced by cholangiocarcinoma survivors. Your healthcare team can identify resources for support and management of these challenges faced during and after cancer.

Cancer survivorship is a relatively new focus of oncology care. With some 15 million cancer survivors in the US alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your healthcare providers. Create a survivorship care plan today on OncoLink.

Resources for More Information

The Cholangiocarcinoma Foundation

Provides research support, disease specific education and increases public awareness about cholangiocarcinoma. Hosts discussion boards for patients and caregivers giving you the opportunity to connect and learn from each other.

AMMF, The Cholangiocarcinoma Charity of the UK

United Kingdom based organization focused on raising awareness about cholangiocarcinoma, providing educational information about the disease and supporting research.

Appendix: AJCC Complete Staging, Cholangiocarcinoma, 8thedition, 2017

Intrahepatic Bile Duct Tumors

T(Tumor)

Description

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1s

Carcinoma in situ (intraductal tumor)

T1

Solitary tumor without vascular invasions ≤ 5cm or > 5cm

  • T1a

Solitary tumor ≤5cm without vascular invasion

  • T1b

Solitary tumor >5cm without vascular invasion

T2

Solitary tumor with intrahepatic vascular invasion or multiple tumors, with or without vascular invasion

T3

Tumor perforating the visceral peritoneum

T4

Tumor involving local extrahepatic structures by direct invasion

N(Regional Lymph Nodes)

Description

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Regional lymph node metastasis present

 

M(Distant Metastasis)

Description

M0

No distant metastasis

M1

Distant metastasis

 

Stage Grouping

T

N

M

0

T1s

N0

M0

IA

T1a

N0

M0

IB

T1b

N0

M0

II

T2

N0

M0

IIIA

T3

N0

M0

IIIB

T4

Any T

N0

N1

M0

M0

IV

Any T

Any N

M1

 

Perihilar Bile Duct Tumors

T (Tumor)

Description

TX

Primary tumors cannot be assessed

T0

No evidence of primary tumor

T1s

Carcinoma in situ/high-grade dysplasia

T1 

Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue.

T2

Tumor invades beyond the wall of the bile duct to surrounding adipose tissues, or tumor invades adjacent hepatic parenchyma

  • T2a

Tumor invades beyond the wall of the bile duct to surrounding adipose tissue

  • T2b

Tumor invades adjacent hepatic parenchyma

T3

Tumor invades unilateral branches of the portal vein or hepatic artery

T4

Tumor invades main portal vein or its branches bilaterally, or the common hepatic artery; or unilateral second-order biliary radicals bilaterally with contralateral portal vein or hepatic artery involvement

 

N (Regional Lymph Nodes)

Description

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal, and portal vein lymph nodes

N2

Four of more positive lymph nodes from the sites described for N1

 

M(Distant Metastasis)

Description

M0

No distant metastasis

M1

Distant metastasis

 

Stage Grouping

T

N

M

I

T1s

N0

M0

II

T2a-b

N0

M0

IIIA

T3

N0

M0

IIIB

T4

N0

M0

IIIC

Any T

N1

M0

IVA

Any T

N2

M0

IVB

Any T

Any N

M1

Distal Bile Duct Tumors

T (Tumor)

Description

TX

Primary tumor cannot be assessed

T1s

Carcinoma in situ/high grade dysplasia

T1

Tumor invades the bile duct wall with a depth less than 5mm

T2

Tumor invades the bile duct wall with a depth of 5-12mm

T3

Tumor invades the bile duct wall with a depth greater than 12mm

T4

Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery

 

N (Regional Lymph Nodes

Description

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in one to three regional lymph nodes

N2

Metastasis in four or more regional lymph nodes

 

M(Distant Metastasis)

Description

M0

No distant metastasis

M1

Distant metastasis

 

Stage Grouping

T

N

M

0

T1s

N0

M0

I

T1

N0

M0

IIA

T1

T2

N1

N0

M0

M0

IIB

T2

T3

T3I

N1

N0

N1

M0

M0

M0

 

IIIA

T1

T2

T3

N2

N2

N2

M0

M0

M0

IIIB

T4

T4

T4

N0

N1

N2

M0

M0

M0

IV

Any T

Any N

M1

References

References

American Cancer Society, https://www.cancer.org/cancer/bile-duct-cancer.html

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Brown, K.M., et.al. (2014). Intrahepatic cholangiocarcinoma. Surgical Oncology Clinics of North America 23(2), 231-246.

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Gores, G. J. (2015). Liver transplantation for cholangiocarcinoma. Liver Transplantation21(S1).

He, C., Mao, Y., Wang, J., Song, Y., Huang, X., Lin, X., & Li, S. (2018). The Predictive Value of Staging Systems and Inflammation Scores for Patients with Combined Hepatocellular Cholangiocarcinoma After Surgical Resection: a Retrospective Study. Journal of Gastrointestinal Surgery, 1-12. 

Hong, M., Cheon, Y.K., Lee, E.J., Lee, T.Y., & Shim, C.S. (2014). Long-term outcome of photodynamic therapy with systemic chemotherapy compared to photodynamic therapy alone in patients with advanced hilar cholangiocarcinoma. Gut and Liver, 8(3), 318-323.

Jarnagin W.R, et al. (2001). Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Annals of Surgery 234, 507-19.

Kambakamba, P., & DeOliveira, M.L. (2014). Perihilar cholangiocarcinoma: paradigms of surgical management. American Journal of Surgery 208 (4)563 -570.

Kim, H.M. et. al. (2014). A pilot study of S-1-based concurrent chemoradiotherapy in patients with biliary tract cancer. Cancer Chemotherapy and Pharmacology (in press). Early view retrieved from http://download.springer.com/static/pdf/833/art%253A10.1007%252Fs00280-014-2565-y.pdf?auth66=1412173498_7b4ff02cdede6ac575ca6ec4a8e49141&ext=.pdf, 29 Sept 2014.

Lad, N., & Kooby, D.A. (2014). Distal cholangiocarcinoma. Surgical Oncology Clinics of North America 23(2), 265-287.

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Lee, T. Y., Cheon, Y. K., & Shim, C. S. (2013). Current Status of Photodynamic Therapy for Bile Duct Cancer. Clinical Endoscopy46(1), 38–44. http://doi.org/10.5946/ce.2013.46.1.38

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Moeini, A., Sia, D., Bardeesy, N., Mazzaferro, V., & Llovet, J. M. (2016). Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma. Clinical Cancer Research22(2), 291-300.

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Razumilava, N., & Gores, G. J. (2014). Cholangiocarcinoma. The Lancet383(9935), 2168-2179.

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Thanasuwan, S.,et.al. (2014). Suppression of aquaporin, a mediator of water channel control in the carcinogenic liver fluke, Opisthorchis viverrini. Parasites and Vectors 7(1), 224-233.

Thomas, M.B. (2014). Systemic and targeted therapy for biliary tract tumors and primary liver tumors. Surgical Oncology Clinics of North America 23(2), 369-381.

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Wagner, A., Wiedmann, M., Tannapfel, A., Mayr, C., Kiesslich, T., Wolkersdörfer, G. W., ... & Witzigmann, H. (2015). Neoadjuvant Down-Sizing of Hilar Cholangiocarcinoma with Photodynamic Therapy—Long-Term Outcome of a Phase II Pilot Study. International journal of molecular sciences16(11), 26619-26628.

Weiss, M.J., Cosgrove, D., et.al. (2014). Multimodal treatment strategies for advanced hilar cholangiocarcinoma. Langenbeck's Archives of Surgery 399(6), 679-692.

Wo, J.Y., Dawson, L.A., Zhu, A.X., & Hong, T.S. (2014). An emerging role for radiation therapy in the treatment of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Surgical Oncology Clinics of North America 23(2), 353-368.

Zaydfudim, V.M., Rosen, C.B., & Nagorney, D.M. (2014). Hilar cholangiocarcinoma. Surgical Oncology Clinics of North America 23(2), 247-263.

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