Your pathology report for hepatocellular carcinoma (HCC)

by Ipshita Kak MD FRCPC
December 21, 2025

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Hepatocellular carcinoma is the most common type of liver cancer. It starts from liver cells called hepatocytes, which are the main cells responsible for normal liver function. Hepatocellular carcinoma most often develops in a liver that has already been damaged by long-standing disease, such as cirrhosis, although in a small number of people it can arise in a liver that is otherwise close to normal.

What are the symptoms of hepatocellular carcinoma?

The symptoms of hepatocelluar carcinoma may come from the tumour itself or from worsening of underlying liver disease.

Early hepatocellular carcinoma often causes no symptoms and is frequently detected during routine imaging performed to monitor people with cirrhosis. When symptoms do occur, they usually indicate more advanced disease.

People may experience pain or discomfort in the right upper abdomen, unintentional weight loss, or a sudden decline in their general health. Common physical findings include enlargement of the liver or spleen, yellowing of the skin or eyes (jaundice), and rapid accumulation of fluid in the abdomen (ascites).

Tumours that cause noticeable symptoms are usually advanced and tend to have a poorer prognosis. For this reason, regular imaging surveillance in people with chronic liver disease is critical to detect hepatocellular carcinoma at an earlier, more treatable stage.

What causes hepatocellular carcinoma?

In more than 90% of cases, hepatocellular carcinoma develops in the setting of a known underlying liver disease. The most common causes include chronic hepatitis B infection, chronic hepatitis C infection, and steatohepatitis related to alcohol use or metabolic conditions such as obesity and type 2 diabetes.

Inherited metabolic diseases affecting the liver, such as hereditary hemochromatosis, Wilson disease, glycogen storage diseases, and hereditary tyrosinaemia, also increase the risk. In some regions of the world, exposure to aflatoxin, a toxin produced by certain fungi that contaminate food, is an important cause.

Rarely, hepatocellular carcinoma can develop from a benign liver tumour called a hepatocellular adenoma. In most people, however, cancer develops after years of repeated liver injury, inflammation, and regeneration. This cycle increases the chance that genetic changes will accumulate in liver cells, eventually leading to cancer.

How is hepatocellular carcinoma diagnosed?

Hepatocellular carcinoma is diagnosed using a combination of imaging, clinical information, and pathology, depending on the situation.

Imaging

Imaging plays a central role. Contrast-enhanced ultrasound, CT, or MRI is used to detect and stage tumours. A typical imaging pattern shows the tumour becoming brighter than the surrounding liver during the arterial phase of contrast injection and darker during the venous phase. This pattern reflects the abnormal blood supply of hepatocellular carcinoma.

Detecting very small tumours (less than 2 cm) can be challenging. Some early tumours do not show the classic enhancement pattern, which is why close surveillance and expert interpretation are important.

Liver biopsy

A biopsy may be performed when imaging is inconclusive or when tissue confirmation is required. Under the microscope, the pathologist looks for features showing that the tumour cells resemble hepatocytes but grow in an abnormal, malignant way.

Microscopic features

When hepatocellular carcinoma is examined under the microscope, the tumour cells show features that confirm they come from hepatocytes, the normal cells of the liver. However, unlike healthy liver tissue, these cells grow in a disorganized, invasive manner.

One of the key findings is loss of normal liver architecture. In a healthy liver, hepatocytes are arranged around structures called portal tracts, and the supporting framework of the liver (called the reticulin framework) is evenly spaced. In hepatocellular carcinoma, portal tracts are usually absent within the tumour, and the reticulin framework is reduced or completely lost. This loss of structure is an important clue that the lesion is malignant.

Hepatocellular carcinomas also show changes in blood supply. Normal liver tissue receives blood from both veins and arteries, but tumour tissue becomes increasingly supplied by arteries alone. Under the microscope, this appears as abnormally small arteries within the tumour and changes called sinusoidal capillarization, where normal liver sinusoids begin to resemble capillaries. These vascular changes help explain why hepatocellular carcinoma shows characteristic enhancement patterns on imaging studies.

The tumour cells themselves can range from looking only slightly abnormal to very abnormal. This variation is called cytologic atypia. In more aggressive tumours, cells divide more rapidly, reflected by an increased number of mitotic figures (dividing cells).

Growth patterns

Hepatocellular carcinoma can grow in several recognizable patterns under the microscope. The four main patterns are:

• Trabecular, where tumour cells form thickened plates or cords.

• Solid (compact), where sheets of tumour cells grow without obvious spaces.

• Pseudoglandular (pseudoacinar), where tumour cells form gland-like spaces that may contain bile.

• Macrotrabecular, where the cell plates are very thick, often ten or more cells across.

About half of hepatocellular carcinomas show a mixture of patterns. The macrotrabecular pattern has been associated with more aggressive behaviour, but in general, the growth pattern alone does not determine treatment and does not always need to be listed in the pathology report.

Cellular changes and inclusions

Some hepatocellular carcinomas show additional cellular features that help pathologists recognize the tumour:

• Bile production, seen as green or yellow pigment within tumour cells.

• Fat accumulation, similar to fatty liver disease.

• Clear-cell change, where cells appear pale due to stored glycogen.

• Lipofuscin, a brown pigment related to cell aging or injury.

Tumour cells may also contain inclusions such as hyaline bodies, Mallory–Denk bodies, or pale bodies. Pale bodies are often seen in fibrolamellar carcinoma, but are not unique to that subtype.

Changes in the tumour blood spaces may include peliosis-like areas (blood-filled spaces) and small clusters of immune cells called macrophages.

Nodule-in-nodule growth

Some hepatocellular carcinomas show areas with different appearances within the same tumour. This often represents tumour progression, in which a more aggressive, poorly differentiated area develops within a previously less aggressive tumour. This pattern, called nodule-in-nodule growth, supports the diagnosis of hepatocellular carcinoma.

Immunohistochemistry (IHC)

Immunohistochemistry is a laboratory tes that uses special stains to detect proteins made by tumour cells. In hepatocellular carcinoma, IHC is used to confirm hepatocellular differentiation, especially when the diagnosis is uncertain or when the tumour is poorly differentiated.

The most commonly used markers include:

• Arginase-1 (ARG1): This stain highlights the cytoplasm and nucleus of hepatocellular carcinoma cells. It is positive in many cases and performs particularly well in poorly differentiated tumours, where other markers may be negative. However, it can occasionally be negative in well-differentiated tumours.

• Hep Par-1: This stain highlights the cytoplasm of tumour cells and is especially useful in well-differentiated hepatocellular carcinoma. It may be less reliable in poorly differentiated tumours.

• Polyclonal CEA and CD10: These stains can show a distinctive canalicular pattern, reflecting bile canaliculi between tumour cells. While supportive of hepatocellular carcinoma, they are used less often because more sensitive markers are available.

• Alpha-fetoprotein (AFP): AFP stains the cytoplasm of tumour cells in a minority of cases. It is frequently negative in well-differentiated tumours, so a negative result does not exclude hepatocellular carcinoma.

No single stain is perfect. The results of immunohistochemistry must always be interpreted together with the microscopic appearance on routine stains and the clinical and imaging findings. A diagnosis of hepatocellular carcinoma requires both compatible tumour morphology and, when needed, supportive immunohistochemical findings.

Tumour grade

Tumour grade describes how abnormal the cancer cells look compared with normal hepatocytes. Hepatocellular carcinoma is generally classified as well-differentiated, moderately differentiated, or poorly differentiated.

Well-differentiated tumours resemble normal liver cells and usually grow more slowly. Poorly differentiated tumours show marked abnormalities, grow more aggressively, and are more likely to spread.

Some tumours contain areas of different grades. In these cases, the highest (worst) grade present is most important because it best predicts behaviour and outcome.

Early hepatocellular carcinoma

Early hepatocellular carcinoma is usually small (2 cm or less) and well differentiated, meaning the tumour cells still look quite similar to normal liver cells. These tumours often have ill-defined borders and lack a capsule. They may invade the surrounding supportive tissue, but typically do not show blood vessel invasion.

Early tumours can be difficult to distinguish from high-grade dysplastic nodules, which are precancerous lesions. Subtle features such as invasion of surrounding tissue and specific immunohistochemical staining patterns help confirm the diagnosis.

Small progressed hepatocellular carcinoma

Small progressed hepatocellular carcinoma is also 2 cm or less but shows more advanced features. These tumours usually have sharper borders, often form a capsule, and grow in a more aggressive pattern. Blood vessel invasion is more common, and the tumour’s blood supply is more abnormal.

Overall, small, progressed tumours behave more like larger hepatocellular carcinomas and carry a higher risk of spread than early tumours.

Histologic subtypes of hepatocellular carcinoma

Hepatocellular carcinoma includes several histologic subtypes, some of which have distinctive clinical or molecular features.

Commonly described subtypes include:

• Fibrolamellar carcinoma, which occurs in younger patients and typically arises in a non-cirrhotic liver.

• Clear cell carcinoma, in which tumour cells appear pale due to stored glycogen or fat.

• Scirrhous carcinoma, which contains abundant scar tissue.

• Steatohepatitic carcinoma, which resembles fatty liver disease under the microscope.

• Macrotrabecular massive carcinoma, associated with more aggressive behaviour.

• Lymphocyte-rich or neutrophil-rich carcinomas, which show prominent inflammatory cells.

Recognizing these subtypes can provide additional information about tumour behaviour and, in some cases, prognosis.

Vascular invasion

Vascular invasion means that tumour cells are found inside blood vessels within or near the tumour. This is an important finding because it indicates a higher risk that cancer cells can spread within the liver or to other organs.

Vascular invasion is associated with a greater chance of recurrence after treatment and a worse overall prognosis.

Margins

Margins refer to the edges of the tissue removed during surgery. A negative margin means no tumour cells are seen at the cut edge of the specimen, suggesting the tumour was completely removed. A positive margin means tumour cells are present at the edge, which increases the risk that cancer remains in the liver.

Margin status is an important part of the pathology report because it helps guide further treatment and follow-up.

How is hepatocelluar carcinoma staged?

Hepatocellular carcinoma is staged using the American Joint Committee on Cancer (AJCC) TNM system. The stage is based on the size and number of tumours, whether blood vessels are invaded, and whether the cancer has spread to lymph nodes or other organs.

T category (tumour)

• T0: No tumour is found.

• T1a: A single tumour that is 2 cm or smaller and no vascular invasion.

• T1b: A single tumour larger than 2 cm without vascular invasion.

• T2: A single tumour larger than 2 cm with vascular invasion, or multiple tumours, none larger than 5 cm.

• T3: Multiple tumours, with at least one larger than 5 cm.

• T4: A single tumour or multiple tumours of any size that grow into a major branch of the portal vein or hepatic vein, or into nearby organs (other than the gallbladder), or that break through the outer surface of the liver.

N category (lymph nodes)

• N0: No cancer is found in regional lymph nodes.

• N1: Cancer is found in at least one regional lymph node.

What is the prognosis for a person with hepatocellular carcinoma?

The prognosis for a person diagnosed with hepatocelluar carcinoma depends on tumour size, stage, grade, vascular invasion, underlying liver function, and available treatment options.

Small tumours detected early may be cured with surgery, liver transplantation, or local treatments such as radiofrequency ablation. Advanced hepatocellular carcinoma has a poorer prognosis, with limited long-term survival.

Because of this, early detection through surveillance in people with cirrhosis or chronic liver disease is critical.

Questions to ask your doctor

• Is my tumour early or progressed hepatocellular carcinoma?
• What is the size and grade of my tumour?
• Is there evidence of vascular invasion?
• Were the surgical margins clear?
• How does my underlying liver disease affect treatment options?
• Am I a candidate for surgery, transplantation, or local therapy?
• What follow-up imaging or blood tests will I need?