by Jason Wasserman MD PhD FRCPC and Catherine Forse MD FRCPC
September 5, 2023
Intrahepatic and extrahepatic cholangiocarcinoma are very similar types of cancer. The main difference is that intrahepatic cholangiocarcinoma starts from one of the small bile ducts found inside the liver while extrahepatic cholangiocarcinoma starts from one of the larger bile ducts found outside the liver. A Klatskin tumor (also known as hilar cholangiocarcinoma) is a special type of extrahepatic cholangiocarcinoma that arises at the junction of the right and left hepatic bile ducts.
Pathologists divide cholangiocarcinoma into two histologic types – small duct and large duct. Small duct cholangiocarcinoma is typically found near the periphery (outside) of the liver. In contrast, large duct cholangiocarcinoma typically involves one of the large bile ducts near the hilum (middle) of the liver.
The most common symptoms of cholangiocarcinoma are abdominal pain, weight loss, and weakness. Extrahepatic cholangiocarcinoma frequently causes jaundice (yellowing of the eyes and skin).
The causes associated with cholangiocarcinoma vary by type. Small duct cholangiocarcinoma is caused by chronic viral infections of the liver (e.g., hepatitis B and hepatitis C) and excessive alcohol consumption, both of which are associated with cirrhosis. Large duct cholangiocarcinoma is caused by primary sclerosing cholangitis, hepatolithiasis (gallstones in the large bile ducts), and liver fluke infection.
Metastatic cholangiocarcinoma means that tumour cells have spread from the bile duct to another part of the body such as a lymph node or the lungs.
The diagnosis of cholangiocarcinoma can be made after tissue is examined under the microscope by a pathologist. Additional information such as the results of abdominal imaging (e.g., CT scan, MRI, or ultrasound), blood tests, and direct examination of the bile ducts during a procedure called an endoscopy also aid in the diagnosis.
When examined under the microscope, cholangiocarcinoma is made up of medium to large-sized tumour cells that connect together to form gland-like structures that are often described as tubules or ducts. The tumour cells often produce a substance called mucin which may be intracellular (inside the cells) or extracellular (outside of the cells).
Pathologists use the term differentiated to divide cholangiocarcinoma into three grades – well-differentiated, moderately differentiated, and poorly differentiated. The grade is based on the percentage of the tumour forming round gland-like structures. The grade is important because less differentiated tumours (for example, poorly differentiated tumours) behave in a more aggressive manner and are more likely to spread to other parts of the body.
Biliary intraepithelial neoplasia (BiIN) is a precancerous condition that can turn into cholangiocarcinoma over time. For this reason, it is not unusual for a pathologist to see BiIN inside the bile ducts surrounding the tumour. When BiIN is seen, it is divided into two grades – low grade BiIN and high grade BiIN. The risk of developing bile duct cancer is greater when high grade BiIN is present.
One or more tumours may be found when the tissue is examined. If there is only one tumour, it will be described in your report as solitary. If more than one tumour is found, your report will describe the size and location of each tumour. More than one tumour increases the tumour stage (pT) for intrahepatic cholangiocarcinoma and is associated with a worse prognosis.
Pathologists use the term tumour extension to describe how far the tumour cells in intrahepatic cholangiocarcinoma have spread through the bile ducts and liver. Tumour extension is also used to describe tumour cells that have spread outside the liver and have entered a nearby organ or tissue (for example, the pancreas or small bowel). The spread of tumour cells outside of the bile ducts and into a nearby organ or tissue is called invasion.
Tumour extension is important because tumours that have grown outside the bile ducts and into other organs or tissues are more likely to regrow in the same area after treatment or to metastasize (spread) to another part of the body.
Pathologists describe intrahepatic cholangiocarcinoma tumour extension in the following ways:
Lymphatic and blood vessels are found throughout your body. These vessels are used for blood cells, immune cells, and other substances to travel from one location to another. Lymphatic invasion means that cancer cells were found inside of a lymphatic vessel while vascular invasion means that cancer cells were found inside of a blood vessel.
Vascular invasion is important because it increases the pathologic tumour stage (pT) for intrahepatic cholangiocarcinoma (it does not change the tumour stage for extrahepatic cholangiocarcinoma). Tumours with vascular invasion are also more likely to spread to other parts of the body including the liver. Lymphatic invasion does not change the pathologic tumour stage (pT) but lymphatic invasion does increase the risk that the tumour cells will spread to lymph nodes.
Depth of invasion is a measurement that describes the distance the tumour cells have travelled from the bile duct into the surrounding tissue. The depth of invasion is only measured for extrahepatic cholangiocarcinoma. The depth of invasion is important because it is used to determine the pathologic tumour stage (pT) and because tumours with a greater depth of invasion are associated with worse overall prognosis.
When surgery is performed to remove a cholangiocarcinoma, the surgeon will have to cut through normal tissue in order to remove the tumour from your body. A margin is the cut edge of the tissue that was removed. It represents the line that separates the tissue that was removed from the tissue left in your body.
For intrahepatic cholangiocarcinoma, the surgeon will need to cut out a portion of your liver (because the tumour is inside the liver). The surgeon will also need to cut through parts of the bile duct that are outside of the liver. These two margins will be described in your report as the hepatic parenchymal margin (liver margin) and the bile duct margin.
For extrahepatic cholangiocarcinoma, the surgeon may need to remove parts of the pancreas, stomach, small intestine, liver, and bile ducts outside of the liver. All of these margins will be described separately in your report.
The margin will be described as negative if no cancer cells are seen at the cut edge of the tissue. A margin is considered positive when there are cancer cells near the cut edge of the tissue. A positive margin is associated with a higher risk that the tumour will re-grow in the same site again after treatment.
Nerves are located throughout all parts of your body. When cancer cells come in contact with nerves and wrap around them it is called perineural invasion. When cancer cells invade nerves, they can then travel along the nerve to areas far from the original location of the tumour. When perineural invasion is seen, there is a higher risk that the tumour will re-grow at the same site or spread to a distant site away from the liver.
Lymph nodes are small organs attached to lymphatic vessels. They contain cells from the immune system which help to defend our body from infections. Cancer cells that enter a lymphatic vessel can spread to a nearby lymph node. This process is called lymph node metastasis. Once cancer cells have entered a lymph node there is a higher risk that cancer cells will spread to other areas throughout your body. All lymph nodes sent to pathology will be carefully examined to see if any contain cancer cells. Your pathology report will describe the total number of lymph nodes seen and if any contained cancer cells.
If you were diagnosed with cholangiocarcinoma in Canada, please visit www.cholangio.ca, the official website of the Canadian Cholangiocarcinoma Collaborative (C3). Starting October 2023, the website can provide you with information on how to (1) sign up for the patient registry, (2) receive a welcome kit, (3) speak to a Research Navigator, and (4) learn more about biliary tract cancer and molecular testing options.