Cholangiocarcinoma - "Klatskin's" Tumors of the Bile Duct System

-edited
by Dr.C.H. Weaver M.D. updated 2/2020

What is Cholangiocarcinoma (bile duct cancer)?

Cholangiocarcinoma (CCA) is a cancer that starts in the bile duct, a thin tube, about 4 to 5 inches long, that reaches from the liver to the small intestine. The major function of the bile duct is to move a fluid called bile from the liver and gallbladder to the small intestine, where it helps digest the fats in food.

About 8,000 people in the United States develop cholangiocarcinoma each year. The average age at diagnosis is 71-72 and two thirds of all CCA’s are diagnosed in individuals over 65. Cholangiocarcinoma is much more common in Asia and the Middle East, mostly because of a common parasitic infection of the bile duct.

Different parts of the bile duct system have different names. In the liver it begins as many tiny tubes called ductules where bile collects from the liver cells. The ductules come together to form small ducts, which then merge into larger ducts and eventually the left and right hepatic ducts. The ducts within the liver are called intrahepatic bile ducts. These ducts exit from the liver and join to form the common hepatic duct at the hilum.

About one-third of the way along the length of the bile duct, the gallbladder is attached via the cystic duct together forming the common bile duct. The common bile duct passes through part of the pancreas before it empties into the first part of the small intestine next to where the pancreatic duct also enters the small intestine.

A cancer can develop in any part of the bile duct and, based on its location the cancer is classified into 3 types:

Intrahepatic Cholangiocarcinoma (ICCA)

Intrahepatic Cholangiocarcinoma occurs inside the liver where cancer develops in the hepatic bile ducts or the smaller intrahepatic biliary ducts and accounts for about 10% of CCA.

Perihilar or “Klatskin” Cholangiocarcinoma

Perihilar Cholangiocarcinoma’s begin where the right and left hepatic ducts have joined and are leaving the liver and is the most common type of CCA accounts for more than half of all bile duct cancers.

Extrahepatic Cholangiocarcinoma (ECCA)

Distal or ECC occurs outside the liver after the right and left hepatic bile ducts have joined to form the common bile duct. This type of cancer is found where the common bile duct passes through the pancreas and into the small intestine and accounts for approximately 25% of bile duct cancers. (1)

Signs & Symptoms of Cholangiocarcinoma

Cholangiocarcinoma often causes no symptoms during its early stages. Symptoms that can occur as the cancer grows include the following: (1)

  • Pain in the upper abdomen on the right side; the pain may extend to the back and shoulder
  • Swollen abdomen (bloating)
  • Weight loss
  • Loss of appetite and feelings of fullness
  • Weakness or feeling very tired
  • Nausea and vomiting
  • Yellow skin and eyes, and dark urine from jaundice
  • Fever

These signs and symptoms can be caused by conditions other than CCA and do not necessarily mean that an individual has cancer – they should however be brought to the attention a physician.

Cause of Cholangiocarcinoma

A Cholangiocarcinoma begins when healthy cells acquire a genetic change (mutation) that causes them to turn into abnormal cells. Hereditary conditions, chronic viral infection of the liver and heavy alcohol use all contribute to the development of liver cancers. (2)

Risk Factors for Developing Cholangiocarcinoma

Primary Sclerosing Cholangitis; Cholangitis (inflammation of the bile duct) leads to the formation of scar tissue (sclerosis) and increases the risk of developing CCA. The cause of the inflammation is not usually known. But is often associated with ulcerative colitis.

Liver Fluke Infections; Liver fluke infections occur in some Asian countries when people eat raw, pickled, fermented or poorly cooked fish that are infected with tiny parasitic worms. Ten percent of chronically infected patients with these parasites will develop CCA.

Cirrhosis; Cirrhosis of the liver which can result from long term alcohol consumption and hepatitis results in the replacement of normal liver tissue by scar tissue slowly over months or years.

Choledochal cysts are bile-filled sacs that are connected to the bile duct. The cells lining the sac often have areas of pre-cancerous growth, which can increase the risk for developing cholangiocarcinoma.

Inflammatory Bowel Disease; People with IBD are around 3 times more likely develop intrahepatic CCA and 2 times more likely to develop extrahepatic CCA.

Diagnosis & Test for Cholangiocarcinoma

When CCA is suspected, imaging tests such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) play an important role in confirming the diagnosis. Blood levels of a protein known alpha-fetoprotein (AFP) may also be assessed. Elevated levels of AFP in combination with a liver mass is a common indication of liver cancer. When a liver mass is present, but AFP levels are normal, additional imaging procedures may be used to help confirm or exclude the diagnosis of the cancer. A biopsy is often required to evaluate liver cancer and obtain genomic information essential for determining if precision cancer medicines can be used to treat the cancer. (3) Although more invasive than fine-needle aspiration, core-needle biopsy provides important pathological details about the tumor and typically yields enough tissue to allow for comprehensive molecular profiling.

Evaluation of Cholangiocarcinoma

The following tests may be used to evaluate a suspected CCA and determine the extent of spread of the cancer.

  • Computed Tomography (CT) Scan: A CT scan is a technique for imaging body tissues and organs, during which X-ray transmissions are converted to detailed images, using a computer to synthesize X-ray data. A CT scan is conducted with a large machine positioned outside the body that can rotate to capture detailed images of the organs and tissues inside the body. This method is more sensitive and precise than an X-ray.
  • Magnetic Resonance Imaging (MRI): MRI uses a magnetic field rather than X-rays and can often distinguish more accurately between healthy and diseased tissue. MRI gives better pictures of tumors located near bone than CT, does not use radiation as CT does, and provides pictures from various angles that enable doctors to construct a three-dimensional image of the tumor.
  • Positron emission tomography (PET): Positron emission tomography scanning is an advanced technique for imaging body tissues and organs. One characteristic of living tissue is the metabolism of sugar. Prior to a PET scan, a substance containing a type of sugar attached to a radioactive isotope (a molecule that emits radiation) is injected into the patient’s vein. The cancer cells “take up” the sugar and attached isotope, which emits positively charged, low energy radiation (positrons) that create the production of gamma rays that can be detected by the PET machine to produce a picture. If no gamma rays are detected in the scanned area, it is unlikely that the mass in question contains living cancer cells.
  • Endoscopic Retrograde Cholangiopancreatography (ERCP): ERCP is a procedure that enables your physician to examine the pancreatic and bile ducts. A bendable, lighted tube (endoscope) about the thickness of your index finger is inserted into your mouth and passed into your stomach and first part of the small intestine. In the small intestine a small opening is identified (ampulla) and a small plastic tube (cannula) is passed through the endoscope and into this opening. Dye (contrast material) is injected and X-rays are taken to study the ducts of the pancreas and liver. ERCP can be used to obtain a sample (biopsy) of any suspicious lesions in the area or place a stent to relieve blockage of the ducts.
  • Endosonography: Endosonography refers to an ultrasound test performed through an endoscope. Ultrasound tests utilize sound waves to detect different densities of tissue, including cancer. Endoscopic ultrasound may be used to determine the size of the cancer and whether surrounding lymph nodes may be enlarged.
  • Laparoscopy: Laparoscopy is a procedure that involves the insertion of an endoscope through a small incision in the abdomen. Laparoscopy is an important tool for staging and has proven to be more reliable than CT scanning in detecting spread of cancer to the liver and the lining of the abdomen (peritoneum).

Genetic Mutations

Not all cancer cells are alike. They may differ from one another based on what genes have mutations. Molecular testing can be performed to identify cancer causing genetic mutations or the proteins they produce. Once a genetic abnormality is identified, a precision cancer medicine can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.

By testing an individual’s cancer for specific unique biomarkers doctors can offer the most personalized treatment approach utilizing precision cancer medicines. All individuals with CCA or other liver cancers should discuss the role of genomic testing for the management of their cancer with their doctor. A blood biopsy can often be performed to identify cancer driving mutations if liver tissue is not available

Treatment Options for Cholangiocarcinoma

Treatment of CCA may consist of surgery, precision cancer medicines, chemotherapy, radiation therapy and or other liver directed therapies. The specific treatment depends on the stage and genomic profile of the cancer. Optimal treatment will often require more than one therapeutic approach and is likely to involve several different types of physicians. These physicians may include a gastroenterologist, a surgeon, a medical oncologist, a radiation oncologist, or other specialists. Care must be carefully coordinated between the various treating physicians.

Potentially curative surgery is the treatment of choice for cancers that can be surgically removed. Surgery is considered when the staging evaluation indicates a good chance that the surgeon may be able to remove all of the cancer. The type of surgery depends on the specific cancer location.

  • Intrahepatic CCA are in the bile ducts within the liver. To treat these cancers, a surgeon performs a partial hepatectomy which removes the part of the liver containing the cancer. When a whole lobe of the liver must be removed it is called a hepatic lobectomy.
  • Perihilar CCA begins where the branches of the bile duct first leave the liver. Surgery typically removes part of the liver, along with the bile duct, gallbladder, nearby lymph nodes, and sometimes part of the pancreas and small intestine. Then the surgeon connects the remaining ducts to the small intestine.
  • Distal CCA requires the removal of the bile duct, nearby lymph nodes, and in most cases part of the pancreas and small intestine. This operation is called a Whipple procedure.

If the amount of liver tissue removed is not too great, the liver will function normally because it has the ability to regenerate.

Liver transplantation

For selected patients who have cancer that is confined to the liver but cannot be surgically resected, liver transplantation may be an option. In some situations, treatment with systemic therapy and or radiation prior to the transplant can make a transplant more feasible.

A benefit of liver transplantation is that it treats not only the cancer but also any underlying liver disease. Because the number of donor livers is limited, however, liver transplantation is generally reserved for those patients who are expected to have the best survival and the lowest risk of recurrence after transplantation. According to the commonly used “Milan criteria,” for example, transplant candidates should have a single liver nodule that measures no more than 5 cm or two or three nodules that measure no more than 3 cm each. These criteria are fairly restrictive, and the question of whether and how to expand the criteria to include more patients is currently being evaluated. A living donor transplant where a close relative gives a part of their liver for transplant is another treatment option. (4)

For some people with early stage unresectable intrahepatic or perihilar cancers, removing the liver and bile ducts and then transplanting a donor liver may be an effective and potentially curative treatment option. Patients should be evaluated at a major cancer center with a liver transplant team of physicians that has significant experience in performing the procedure.

Systemic Therapy

Systemic treatment is any substance that travels through the bloodstream, reaching and affecting cells all over the body. Systemic therapy is used in 3 settings.

  • Adjuvant systemic therapy is used after curative surgery for early stage cancers to reduce the risk of recurrence. (6)
  • Neoadjuvant systemic therapy can be used to “shrink” the cancer prior to surgery to increase the likelihood of successful surgery or liver transplantation. (14)
  • Systemic therapy is used to control symptoms and prolong survival in individuals unable to undergo surgical removal of their cancer.

Traditionally systemic treatment consisted mainly of chemotherapy with Gemzar (gemcitabine) and cisplatin but increasingly consists of precision cancer medicines and immunotherapy administered alone or in combinations to target specific cancer driving genetic mutations. (5,6) Systemic treatment is the standard of care for individuals with advanced stage or recurrent CCA.

Precision Cancer Medicines for CCA

Precision cancer medicines are increasingly replacing chemotherapy as a preferred systemic treatment. Clinically significant cancer driving genomic alterations have been identified in approximately 50% of ICCA patients, several of which can be targeted with a precision medicine. (7,8) The most common clinically significant genomic alterations include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH) mutations. (8) Patients should discuss genomic testing for the following mutations all of which have precision medicines available for treatment or in development.

  • FGFR: Fibroblast growth factor receptor (FGFR) genetic alterations include point mutations, gene amplifications, and chromosomal rearrangements that may result in fusion proteins, including FGFR2 fusions. FGFR2 fusions or rearrangements occur almost exclusively in ICCA, where they are observed in 10-16 percent of patients and play an important role in cancer cell growth and survival by enhancing migration and the formation of new blood vessels known as angiogenesis. Pemigatininb is a novel precision cancer medicine that binds to and inhibits FGFRs which prevents the growth and proliferation of FGFR over expressing cancer cells. (10-12)
  • IDH 20% - 25%
  • KRAS
  • BRAF
  • MSI-High
  • NTRK
  • EGFR

Non-surgical Liver Directed Therapy

Even when the cancer is confined to the liver, not all patients will be candidates for surgery. There are several non-surgical treatments available for the management of ICCA and liver cancers.

Palliative surgery may be performed to relieve symptoms or treat (or even prevent) complications, such as blockage of the bile ducts. This type of surgery is performed when the tumor is too widespread to be completely removed. Two palliative surgeries used to help relieve symptoms and prolong survival are the biliary bypass and biliary stent insertion.

  • Biliary bypass: The surgeon creates a bypass around the cancer blocking the bile duct by connecting part of the bile duct before the blockage with a part of the duct that lies past the blockage. Often, the gallbladder is used to provide some of the bypass.
  • Biliary stent or biliary catheter: If cancer is blocking the bile duct, the doctor may insert a small tube or “stent” into the duct to help keep the duct open. Stent insertion can be done during percutaneous transhepatic cholangiography (PTC) or endoscopic retrograde cholangio-pancreatography (ERCP) or during surgery. A stent opens the duct to allow the bile to drain into the small intestine, while a catheter drains into a bag outside the body that can be emptied when needed. The stent or catheter may need to be replaced every few months if it becomes clogged and to reduce the risk of infection and gallbladder inflammation.

Hepatic Arterial Infusion Plus Systemic Chemotherapy Active in Unresectable ICCA

In a clinical trial of patients with unresectable intrahepatic cholangiocarcinoma (ICCA), combining hepatic arterial infusion (HAI) floxuridine with systemic chemotherapy was shown to be clinically active.

Thirty-eight patients at the Memorial Sloan Kettering Cancer Center were treated with the combination of HAI and chemotherapy between May 20, 2013, and 90% survived 1 year or greater following the treatment. Patients with IDH1/2-mutation had a 2-year overall survival rate of 90% suggesting that HAI plus systemic chemotherapy is highly active in patients with unresectable ICCA. (13)

References:

  1. https://cholangiocarcinoma.org/defined/
  2. https://www.cancer.org/cancer/bile-duct-cancer/causes-risks-prevention/risk-factors.html
  3. Lancet. 2017;389;10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.
  4. Mazzaferro V, Llovet JM, Miceli R et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncology. 2009;10:35-43.
  5. https://www.nejm.org/doi/pdf/10.1056/nejmoa0908721
  6. https://jnccn.org/view/journals/jnccn/15/5/article-p563.xml
  7. Shibata T, Arai Y, Totoki Y. Cancer Sci. 2018;109(5):1282-1291.
  8. Arai Y, Totoki Y, Hosoda F, et al. Hepatology. 2014;59(4):1427-1434.
  9. Graham RP, et al. Hum Pathol. 2014;45:1630‒1638.
  10. Farshidfar F, et al. Cell Rep. 2017;18(11):2780–2794.
  11. Ross JS et al. The Oncologist. 2014;19:235–242.
  12. JAMA Oncol. 2019 Oct 31. Epub ahead of print.
  13. https://jamanetwork.com/journals/jamasurgery/article-abstract/407501
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