Intrahepatic cholangiocarcinoma

by Stephanie Reid, MD FRCPC
May 20, 2022

What is intrahepatic cholangiocarcioma?

Intrahepatic cholangiocarcinoma is a type of bile duct cancer. It is called ‘intrahepatic’ because the tumour starts from a bile duct located inside the liver.

What are the symptoms of cholangiocarcinoma?

Unfortunately, most patients with cholangiocarcinoma experience very few symptoms until the tumour reaches an advanced stage and blocks the drainage of the bile ducts. At this point, patients may experience pain, weight loss, pale-coloured stool, itching, pain in the abdomen or back, and yellowing of the skin.

How do pathologists make the diagnosis of intrahepatic cholangiocarcinoma?

The diagnosis of cholangiocarcinoma is made after a doctor takes a small sample of tissue from the bile ducts and sends it to a pathologist for examination. The sample can be taken by brushing the inside of the duct or by performing a biopsy with a needle. The diagnosis may also only be made after the entire tumour is removed.

How do pathologists grade intrahepatic cholangiocarcinoma?

Grade is a word that pathologists use to describe how abnormal the cancer cells look compared to the normal, healthy cells found in the same location of the body. For cholangiocarcinoma, the tumour cells are compared to the normal epithelial cells that line the inside of the bile ducts.

Because the normal cells connect together to form tubes, the grade also depends on the amount of tube-like structures seen in the tumour. Pathologists call these tube-like structures glands and cholangiocarcinoma is divided into three different grades based on the amount of cancer cells that are forming glands.

• Grade 1 (well differentiated) – More than 95% of the tumour is made up of glands.
• Grade 2 (moderately differentiated) – 50 to 95% of the tumour is made up of glands.
• Grade 3 (poorly differentiated) – Less than 50% of the tumour is made up of glands.

Higher grade (grade 2 and 3) tumours grow faster and are more likely to spread to other parts of the body.

Number of tumours

One or more tumours may be found inside the liver. 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 (see Pathologic stage below) and is associated with a worse prognosis.

Tumour pattern of growth

When examined under the microscope, intrahepatic cholangiocarcinoma can show several different patterns of growth. Some tumours grow as a round group of cells and the tumour is relatively easy to see during surgery and radiological tests. This pattern of growth is called mass-forming. In contrast, some tumours are hard to see because they do not form a single large group. Instead, the cancer cells grow along the inside of the bile ducts. This pattern of growth is called periductal or infiltrating. Finally, some tumours show both a mass-forming and periductal/infiltrating pattern of growth.

What does tumour extension mean and why is it important?​

Pathologists use the term tumour extension to describe how far the tumour cells 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 spread to another part of the body.

Pathologists describe intrahepatic cholangiocarcinoma tumour extension in the following ways:

• Tumour confined to the intrahepatic bile ducts – The tumour cells are only seen inside the small bile ducts within the liver.
• Tumour confined to liver parenchyma – The tumour cells have spread outside of the bile ducts and into the surrounding normal liver cells.
• Tumour involving the peritoneal surface – The tumour cells have broken through the thin layer of tissue that surrounds the liver and are seen within the abdominal cavity.
• Tumour directly invades the gallbladder – The tumour cells have spread outside of the bile ducts and into the gallbladder.
• Tumour invades nearby organs (other than the gallbladder) – The tumour cells have spread outside of the bile ducts and into a nearby organ such as the pancreas, small bowel, or colon.

What does lymphatic and vascular invasion mean?

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.

Cancer cells found inside a lymphatic vessel is called lymphatic invasion while cancer cells found inside a blood vessel is called vascular invasion.

Tumours with vascular invasion are given a higher tumour stage (pT) than tumours without vascular invasion (see Pathologic stage below). Tumours with vascular invasion are also more likely to spread to other parts of the body including the liver.

What is a margin?

When surgery is performed to remove an intrahepatic 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.

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.

What does perineural invasion mean?

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.

What are lymph nodes?

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 travel 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 travel 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.

How do pathologists determine the pathologic stage (pTNM) for intrahepatic cholangiocarcinoma?

​The pathologic stage for intrahepatic cholangiocarcinoma is based on the TNM staging system, an internationally recognized system originally created by the American Joint Committee on Cancer. This system uses information about the primary tumour (T), lymph nodes (N), and distant metastatic disease (M)  to determine the complete pathologic stage (pTNM). Your pathologist will examine the tissue submitted and give each part a number. In general, a higher number means more advanced disease and a worse prognosis.

Tumour stage (pT) for intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma is given a tumour stage of either Tis, 1, 2, 3, or 4. The tumour stage is based on the tumour extension, the number of tumours present, and if vascular invasion is identified (see above sections for more details).

• Tis – Tumour cells are only seen inside the bile ducts
• T1 – Only a single tumour is seen and there is no vascular invasion. This stage is divided into T1a for tumours that are less than or equal to 5 cm and T1b stage for tumours that are larger than 5 cm.
• T2 – One tumour is found with vascular invasion within the liver OR multiple tumours are found with or without vascular invasion.
• T3 – The tumour cells have broken through the capsule on the liver surface (visceral peritoneum)
• T4 – Tumour cells are seen in organs or tissues outside of the liver.

Nodal stage (pN) for intrahepatic cholangiocarcinoma

Cholangiocarcinoma is given a nodal stage between 0 and 1. If no tumour cells are seen in any of the lymph nodes examined, the stage is pN0. If tumour cells are found in any lymph nodes, the stage is pN1. If no lymph nodes are sent for pathologic examination, the nodal stage cannot be determined and is listed as pNX.

Metastatic stage (pM) for intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma is given a metastatic stage of 1 if there are tumour cells at a distant site in the body. The metastatic stage can only be determined if tissue from a distant site is submitted for pathological examination. If no tissue from a distant site has been sent for pathologic examination, the metastatic stage cannot be determined and is listed as pMX.