This article focuses on intrahepatic cholangiocarcinoma, meaning the cancer arises in the bile ducts within the liver (for information on extrahepatic cholangiocarcinoma, see this article).
Intrahepatic cholangiocarcinoma is an aggressive cancer, but its behaviour and prognosis can vary depending on factors such as tumour type, stage, and whether surgery is possible.
Where does intrahepatic cholangiocarcinoma develop?
Intrahepatic cholangiocarcinoma develops within the liver, in bile ducts located away from the main bile ducts outside the liver. It tends to arise either:
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Near the larger bile ducts, closer to the liver hilum (the area where major ducts and vessels enter the liver).
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In the peripheral parts of the liver, farther from the main ducts.
These two locations correspond to different tumour subtypes that behave somewhat differently.
What are the symptoms of intrahepatic cholangiocarcinoma?
Common symptoms of intrahepatic cholangiocarcinoma include general fatigue, abdominal discomfort or pain, and unintentional weight loss. Because the tumour grows within the liver, early symptoms may be subtle. Tumours arising near larger bile ducts can block bile flow and cause cholestasis, which may lead to jaundice, dark urine, pale stools, itching, or episodes of bile duct infection (cholangitis).
Tumours arising in the outer parts of the liver often grow silently and may not cause symptoms until they become relatively large.
How common is intrahepatic cholangiocarcinoma?
Intrahepatic cholangiocarcinoma is the second most common primary liver cancer, after hepatocellular carcinoma. It accounts for approximately 10–15% of primary liver cancers worldwide.
The incidence varies significantly by region. It is particularly common in parts of south-eastern Asia, while it remains relatively uncommon in Europe and North America. In many areas, the incidence has been increasing over time.
What causes intrahepatic cholangiocarcinoma?
The cause of intrahepatic cholangiocarcinoma is not always clear, but several risk factors have been identified.
Tumours arising in the small bile ducts share many risk factors with hepatocellular carcinoma, including chronic viral hepatitis and liver cirrhosis, not related to bile duct disease.
Tumours arising in the large bile ducts share risk factors with extrahepatic and perihilar cholangiocarcinoma. These include primary sclerosing cholangitis, liver fluke infection in certain parts of the world, and other conditions that cause long-standing bile duct inflammation.
Despite these known associations, many patients have no identifiable risk factor.
Types of intrahepatic cholangiocarcinoma
Pathologists recognize two main types based on where the tumour arises and how it grows.
Large-duct intrahepatic cholangiocarcinoma develops near the larger bile ducts, closer to the liver hilum. It tends to grow along bile ducts and spread into surrounding liver tissue. This type closely resembles extrahepatic cholangiocarcinoma.
Small duct intrahepatic cholangiocarcinoma arises in the peripheral parts of the liver. It usually forms a distinct mass within the liver tissue. Some specific subtypes, such as cholangiolocarcinoma, fall into this category.
These two types differ in risk factors, microscopic appearance, molecular changes, and prognosis.
How is the diagnosis made?
The diagnosis is made using a combination of imaging studies, tissue examination, and sometimes molecular testing.
Imaging
Imaging studies such as ultrasound, CT, MRI, and PET scans are used to detect the tumour, assess its size and location, and look for spread to other organs. Small duct tumours usually appear as a mass in the liver, while large duct tumours may show bile duct narrowing or thickening with upstream duct dilation.
Microscopic (pathologic) features
Under the microscope, intrahepatic cholangiocarcinoma is almost always an adenocarcinoma, meaning it forms abnormal gland-like structures. The glands can be round, tubular, or cord-like and are often surrounded by a dense scar-like tissue called desmoplastic stroma.
The tumour cells are typically cuboidal or columnar and may vary in appearance. Mucus production is common in large duct tumours but is usually absent in small duct tumours. These cancers frequently invade nearby portal tracts and may grow into lymphatic channels or small blood vessels.
Large duct intrahepatic cholangiocarcinoma closely resembles extrahepatic cholangiocarcinoma under the microscope and often shows perineural invasion, meaning the tumour grows along nerves. Small duct intrahepatic cholangiocarcinoma more often exhibits a replacement growth pattern, in which tumour cells gradually replace normal liver cells.
Pathologists also look for precancerous changes in nearby bile ducts. A common precursor lesion is biliary intraepithelial neoplasia, which consists of abnormal cells confined to the bile duct lining and supports the idea that the cancer developed gradually over time.
Cytology
In some cases, tumour cells are sampled using fine-needle aspiration or bile duct brushings. Abnormal features such as enlarged nuclei, prominent nucleoli, and disorganized cell clusters suggest malignancy, although sensitivity is limited.
Molecular testing
Molecular testing is not required for diagnosis, but it is increasingly used because it can identify genetic changes that may guide treatment.
Common genetic alterations include mutations in KRAS, TP53, IDH1/2, ARID1A, and BAP1, as well as gene fusions involving FGFR2, particularly in small duct tumours. Results are usually reported by naming the gene and mutation or fusion detected and stating whether it is present or not detected.
Tumour grade
Intrahepatic cholangiocarcinoma is graded based on the extent to which the tumour forms well-organized glands.
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Well-differentiated tumours closely resemble normal bile ducts and tend to grow more slowly.
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Moderately differentiated tumours show a mix of gland-forming and less organized areas.
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Poorly differentiated tumours form a few glands and behave more aggressively.
Tumour grade helps predict how the cancer is likely to behave.
What does tumour extension mean and why is it important?
Tumour extension describes how far the cancer cells have spread from where they started in the bile ducts. Pathologists use this term to explain whether the tumour is limited to the bile ducts, has grown into the surrounding liver tissue, or has spread beyond the liver into nearby structures.
When cancer cells spread outside the bile ducts and into surrounding tissues or organs, this is called invasion. Tumour extension is necessary because cancers that invade nearby tissues are more likely to recur after treatment or spread to other parts of the body.
For intrahepatic cholangiocarcinoma, tumour extension may be described in the pathology report in one of the following ways:
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Tumour confined to the intrahepatic bile ducts: The cancer cells are limited to the small bile ducts inside the liver.
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Tumour confined to liver parenchyma: The cancer cells have spread outside the bile ducts and into the surrounding normal liver tissue.
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Tumour involving the peritoneal surface: The cancer cells have grown through the liver’s thin outer lining and are exposed to the abdominal cavity.
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The tumour directly invades the gallbladder: The cancer has spread from the bile ducts into the gallbladder.
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Tumour invades nearby organs (other than the gallbladder): The cancer cells have spread into nearby organs such as the pancreas, small bowel, or colon.
The extent of tumour extension helps determine the tumour stage and guides treatment planning.
What does lymphatic and vascular invasion mean?
Lymphatic vessels and blood vessels are part of the body’s circulation system. They allow blood cells, immune cells, and other substances to travel throughout the body.
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Lymphatic invasion means cancer cells are found inside lymphatic vessels.
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Vascular invasion means cancer cells are found inside blood vessels.
Vascular invasion is significant because it increases the pathological tumour stage (pT) and indicates a higher risk that the cancer could spread to other parts of the body, including different areas of the liver.
Lymphatic invasion does not directly change the tumour stage, but it increases the risk of spread to nearby lymph nodes, which can affect overall staging and prognosis.
What are margins, and why are they important?
A margin is the cut edge of tissue removed during surgery. It represents the boundary between the tissue taken out and the tissue left behind in the body. After surgery, a pathologist examines the margins to see whether cancer cells are present.
For intrahepatic cholangiocarcinoma, margins commonly include:
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The hepatic parenchymal margin, which is the cut edge of the liver tissue.
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The bile duct margin, which is the cut edge of the bile duct outside the liver.
Margins are described as:
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Negative if no cancer cells are seen at the cut edge. This suggests the tumour was removed entirely.
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Positive if cancer cells are present at or very near the cut edge. This means some cancer cells may remain in the body.
A positive margin is associated with a higher risk that the tumour will regrow in the same area after treatment and may influence decisions about additional therapy or closer follow-up.
What is the pathologic stage for intrahepatic cholangiocarcinoma?
Pathologists determine the pathologic stage of intrahepatic cholangiocarcinoma using the TNM staging system, an internationally recognized system developed by the American Joint Committee on Cancer. This system combines information about:
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T (tumour) – How large the tumour is and how far it has spread locally.
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N (nodes) – Whether cancer cells are found in nearby lymph nodes.
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M (metastasis) – Whether the cancer has spread to distant organs.
Each component is given a number. In general, higher numbers mean more advanced disease and a worse prognosis.
Tumour stage (pT)
The tumour stage is based on tumour extension, the number of tumours, and the presence of vascular invasion.
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Tis (tumour in situ): Cancer cells are confined to the bile duct lining and have not invaded surrounding tissue.
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T1: A single tumour is present, and no vascular invasion is seen.
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T1a: Tumour is 5 cm or smaller.
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T1b: Tumour is larger than 5 cm.
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T2: Either a single tumour with vascular invasion is present, or multiple tumours are found, with or without vascular invasion.
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T3: The tumour has grown through the outer surface of the liver (the visceral peritoneum).
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T4: The tumour has spread into nearby organs or tissues outside the liver, such as the stomach, intestine, or diaphragm.
Nodal stage (pN)
The nodal stage describes whether cancer cells have spread to nearby lymph nodes.
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pN0: No cancer cells are found in any lymph nodes examined.
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pN1: Cancer cells are found in one or more lymph nodes.
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pNX: No lymph nodes were submitted for examination, so the nodal stage cannot be determined.
Lymph node involvement is an important prognostic factor and often influences treatment decisions.
What is the prognosis for a person with intrahepatic cholangiocarcinoma?
Overall, intrahepatic cholangiocarcinoma has a poor prognosis, mainly because many patients are diagnosed at an advanced stage. Surgical removal offers the best chance for long-term survival, but only a minority of patients are candidates for surgery.
Tumours of the small duct type generally have a better outcome than large duct tumours. Features such as vascular invasion, perineural invasion, positive surgical margins, and advanced stage are associated with a higher risk of recurrence and worse survival.
What happens after the diagnosis?
After intrahepatic cholangiocarcinoma is diagnosed, your healthcare team will focus on determining the stage of the cancer and planning treatment. This usually involves reviewing imaging studies, pathology findings, and blood tests together to understand how advanced the tumour is and whether it has spread.
If surgery has already been performed, the pathology report provides critical information about tumour size, tumour extension, vascular invasion, lymph node involvement, and margin status. These findings help determine whether additional treatment, such as chemotherapy or radiation therapy, may be recommended.
If surgery has not yet been performed, additional imaging or biopsies may be needed to decide whether the tumour can be removed safely. Unfortunately, not all intrahepatic cholangiocarcinomas are resectable at diagnosis.
After treatment, regular follow-up is important. This typically includes imaging studies and blood tests to monitor for recurrence or progression. Your care team will also address symptoms related to bile flow, liver function, and overall health.
Questions to ask your doctor
- What type of intrahepatic cholangiocarcinoma do I have?
- Can the tumour be surgically removed?
- What stage is my cancer?
- Were any high-risk features seen on pathology?
- Was molecular testing performed, and could it affect treatment?
- What follow-up or additional treatment will I need?
