Hepatocellular Carcinoma: Understanding Your Pathology Report

by Ipshita Kak MD FRCPC
April 22, 2026

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.

This article will help you understand the findings in your pathology report — what each term means and why it matters for your care.

What causes hepatocellular carcinoma?

In more than 90% of cases, hepatocellular carcinoma develops in a liver that has already been damaged by long-standing disease. The most common underlying causes are chronic hepatitis B infection, chronic hepatitis C infection, and steatohepatitis related to alcohol use or to metabolic conditions such as obesity and type 2 diabetes.

Years of repeated liver injury, inflammation, and attempts at repair gradually damage the DNA inside liver cells. Over time, genetic changes accumulate, and a small group of cells eventually begins to grow uncontrolled. This is the process that turns a damaged liver into one at risk for cancer.

Inherited metabolic diseases that affect the liver — including hereditary hemochromatosis, Wilson disease, glycogen storage diseases, and hereditary tyrosinemia — also increase risk. In some parts of the world, food contaminated with aflatoxin (a toxin made by certain molds that grow on grains and peanuts) is an important cause. Rarely, hepatocellular carcinoma arises from a benign liver tumor called a hepatocellular adenoma.

What are the symptoms of hepatocellular carcinoma?

Early hepatocellular carcinoma often causes no symptoms. Many tumors are found during routine imaging performed to monitor people with cirrhosis or chronic liver disease. When symptoms do occur, they usually indicate more advanced disease.

Possible symptoms include pain or discomfort in the right upper abdomen, unintentional weight loss, loss of appetite, and a general decline in health. Physical findings may include an enlarged liver or spleen, yellowing of the skin or eyes (jaundice), and rapid build-up of fluid in the abdomen (ascites). Tumors that cause noticeable symptoms tend to be advanced and are associated with a poorer outcome, which is why regular imaging surveillance in people with chronic liver disease is critical.

How is the diagnosis made?

The diagnosis of hepatocellular carcinoma is usually made using a combination of imaging and, when needed, a tissue sample examined under the microscope by a pathologist. In people with cirrhosis, a liver tumor that shows a very specific pattern on contrast-enhanced CT or MRI — bright on the arterial phase and dark on the venous phase — can be diagnosed as hepatocellular carcinoma based on imaging alone, without a biopsy. When imaging is inconclusive, a sample of the tumor is obtained via biopsy, typically a needle biopsy performed through the skin with ultrasound or CT guidance.

Under the microscope, the pathologist looks for cells that resemble hepatocytes but exhibit a disorganized, invasive growth pattern. In a healthy liver, hepatocytes are arranged in orderly plates around structures called portal tracts, which contain a small artery, vein, and bile duct. In hepatocellular carcinoma, portal tracts are usually absent within the tumor, and the supportive framework that holds liver cells in place (the reticulin framework) is reduced or lost. The tumor also develops an abnormal blood supply that relies almost entirely on arteries rather than the normal mix of veins and arteries — this change produces the characteristic enhancement pattern on imaging.

When the appearance under the microscope is not clear-cut, the pathologist may order immunohistochemistry to confirm that the tumor cells are hepatocytes. Stains commonly used for this purpose include arginase-1 (Arg-1), HepPar-1, and glypican-3 (GPC3). These stains help confirm hepatocellular origin but do not change treatment and are not biomarkers in the treatment-decision sense.

Once the diagnosis is made, imaging — usually contrast-enhanced CT or MRI of the abdomen and chest — is used to determine the size and number of tumors, whether blood vessels are involved, and whether the cancer has spread outside the liver.

Histologic grade

Histologic grade describes how abnormal the tumor cells look compared with normal hepatocytes. The grade helps predict how quickly the tumor is likely to grow and spread and is one of several factors used to guide treatment planning.

• Well differentiated — The tumor cells closely resemble normal hepatocytes and tend to grow more slowly. Well differentiated tumors are generally associated with a better outcome.
• Moderately differentiated — The cells show clear abnormalities but still retain some features of normal liver cells. This is the most common grade.
• Poorly differentiated — The cells look very abnormal and bear little resemblance to normal hepatocytes. Poorly differentiated tumors grow more aggressively and are more likely to spread.

Some tumors contain a mix of grades. When this happens, the highest (worst) grade present is reported, because it best predicts how the tumor will behave.

Early and small progressed hepatocellular carcinoma

Two categories of small hepatocellular carcinoma (2 cm or less) are recognized because they behave differently and can sometimes be hard to tell apart from each other or from precancerous changes.

• Early hepatocellular carcinoma — A small, well differentiated tumor with ill-defined borders and no capsule. These tumors may invade the surrounding supportive tissue, but typically do not invade blood vessels. They can be difficult to distinguish from high-grade dysplastic nodules (precancerous lesions), and special stains are sometimes needed to confirm the diagnosis.
• Small progressed hepatocellular carcinoma — A tumor that is still 2 cm or less but already shows more aggressive features, including a sharper border or capsule, a disorganized growth pattern, and sometimes blood vessel invasion. Small progressed tumors behave more like larger hepatocellular carcinomas and carry a higher risk of spread than early tumors.

Histologic subtypes

Most hepatocellular carcinomas fall into a single general category. A smaller number belong to recognized subtypes with distinctive features under the microscope, and some of these subtypes behave differently from typical hepatocellular carcinoma.

• Fibrolamellar carcinoma — Occurs in younger patients, typically arises in a liver that is not cirrhotic, and is driven by a specific gene fusion called DNAJB1–PRKACA. It tends to have a somewhat better outcome than typical hepatocellular carcinoma when diagnosed early.
• Clear cell hepatocellular carcinoma — Tumor cells appear pale because they store large amounts of glycogen or fat. Behavior is usually similar to that of typical hepatocellular carcinoma.
• Scirrhous hepatocellular carcinoma — Contains abundant scar tissue. Because the cells can look unusual, it is sometimes mistaken for other tumors on biopsy.
• Steatohepatitic hepatocellular carcinoma — Contains features that resemble fatty liver disease, including fat droplets, swollen liver cells, and inflammation. It is seen more often in people with metabolic liver disease.
• Macrotrabecular massive hepatocellular carcinoma — Tumor cells grow in very thick plates. This pattern is associated with more aggressive behavior and a higher risk of recurrence.
• Lymphocyte-rich hepatocellular carcinoma — Contains large numbers of immune cells within the tumor. This subtype may have a somewhat better outcome and may be more responsive to immunotherapy.

Lymphovascular (vascular) invasion

Lymphovascular invasion, often called vascular invasion in hepatocellular carcinoma, means that tumor cells are found inside blood vessels within or at the edge of the tumor. Because hepatocellular carcinoma spreads primarily through the bloodstream, vascular invasion is one of the most important findings in the pathology report. Two forms are distinguished:

• Microvascular invasion — Cancer cells are seen inside small blood vessels under the microscope. This finding increases the risk of recurrence after surgery or transplantation and is used to guide follow-up and, in some cases, additional treatment.
• Macrovascular invasion — The tumor has grown into a large blood vessel such as the portal vein or a hepatic vein, usually visible on imaging. This is a marker of advanced disease, raises the pathologic stage to pT4, and generally excludes surgery or liver transplantation as curative options.

Surgical margins

A margin is the edge of the tissue that the surgeon cuts through to remove the tumor. Pathologists examine the margins under the microscope to determine whether any tumor cells reach the cut edge.

• Negative margin — No tumor cells are seen at the cut edge. This suggests that the tumor was completely removed and is associated with a lower risk of recurrence in the liver.
• Close margin — Tumor cells are within a few millimeters of the cut edge but do not reach it. The clinical meaning of a close margin varies, and your surgeon will consider it alongside other features of the tumor.
• Positive margin — Tumor cells are present at the cut edge. A positive margin raises the risk that cancer remains in the liver and may prompt consideration of further treatment.

Lymph nodes

Hepatocellular carcinoma rarely spreads to lymph nodes — most cancers instead spread through the bloodstream to other parts of the liver, to the lungs, or to bone. When lymph nodes are removed during surgery, the pathologist examines each one for tumor cells. The report will state the total number of lymph nodes examined and the number that contain cancer. The presence of cancer in any regional lymph node corresponds to nodal stage pN1 and is associated with a worse outcome.

Biomarker and molecular testing

Biomarker testing plays a less central role in hepatocellular carcinoma than in many other cancers, because most currently available treatments for advanced hepatocellular carcinoma are selected based on liver function and disease stage rather than on molecular features of the tumor. However, a small number of tests may be relevant in specific situations.

Alpha-fetoprotein (AFP)

Alpha-fetoprotein is a protein produced by some hepatocellular carcinomas and released into the bloodstream, where it can be measured by a blood test. AFP is used for surveillance in people with cirrhosis, to support the diagnosis when imaging is uncertain, and to monitor for recurrence after treatment. Not all hepatocellular carcinomas produce AFP — a normal AFP level does not rule out the disease — and some benign liver conditions can also raise AFP. For treatments such as ramucirumab, a markedly elevated AFP level is used to identify patients who are most likely to benefit.

PD-L1

PD-L1 is a protein on tumor cells that can help cancer hide from the immune system. In many cancers, PD-L1 testing by immunohistochemistry is used to decide whether a patient is likely to benefit from immunotherapy. In hepatocellular carcinoma, PD-L1 testing is not required to start immunotherapy — approved combinations such as atezolizumab plus bevacizumab and durvalumab plus tremelimumab are given based on clinical factors rather than on PD-L1 status — and PD-L1 has only limited ability to predict who will respond.

Mismatch repair (MMR) and microsatellite instability (MSI)

The mismatch repair system is a group of proteins that corrects small errors made during DNA replication. When this system does not work properly, many small mutations accumulate in the tumor, a state called mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H). Mismatch repair deficiency is uncommon in hepatocellular carcinoma, but when present, it makes the tumor eligible for the immunotherapy drug pembrolizumab under a tumor-agnostic approval that applies across cancer types. A dMMR or MSI-H result may also indicate Lynch syndrome, an inherited condition that increases the risk of several cancers, and should prompt referral for genetic counseling.

Tumor mutational burden (TMB)

Tumor mutational burden measures the total number of mutations in the tumor’s DNA. A very high TMB (generally defined as 10 or more mutations per megabase) makes the tumor eligible for pembrolizumab under another tumor-agnostic approval. High TMB is uncommon in hepatocellular carcinoma but may occasionally be identified when broad molecular testing is performed.

For more information about these and other biomarkers, visit the Biomarkers section.

Pathologic stage (pTNM)

Hepatocellular carcinoma is staged using the American Joint Committee on Cancer (AJCC) 8th edition TNM system, which combines information on tumor size and number (T), whether regional lymph nodes are involved (N), and whether the cancer has spread to distant sites (M). The M category is almost always determined by imaging rather than by pathology.

Tumor stage (pT)

• pT1a — A single tumor 2 cm or smaller, with or without vascular invasion.
• pT1b — A single tumor larger than 2 cm without vascular invasion.
• pT2 — A single tumor larger than 2 cm with vascular invasion, or multiple tumors, none larger than 5 cm.
• pT3 — Multiple tumors, at least one larger than 5 cm.
• pT4 — A single tumor or multiple tumors of any size involving a major branch of the portal vein or hepatic vein, or with direct invasion of nearby organs other than the gallbladder, or perforating the outer surface of the liver (the visceral peritoneum).

Nodal stage (pN)

• pN0 — No cancer is found in regional lymph nodes.
• pN1 — Cancer is found in one or more regional lymph nodes.

What is the prognosis?

The outlook for a person with hepatocellular carcinoma depends on the size and number of tumors, the presence of vascular invasion, the grade of the tumor, the health of the rest of the liver, and whether curative treatment is possible. Because liver function strongly influences which treatments can be used, the same tumor may carry a very different outlook in a person with well-preserved liver function than in someone with advanced cirrhosis.

In broad terms, hepatocellular carcinoma detected at an early stage — a single small tumor in a person with good liver function — can often be cured, with five-year survival rates of 60 to 70% or higher after surgery, liver transplantation, or local ablation. For intermediate-stage disease treated with regional therapies such as transarterial chemoembolization, median survival is generally two to three years. Advanced hepatocellular carcinoma treated with modern systemic therapy (such as atezolizumab plus bevacizumab) has a median survival of approximately 19 months, with some patients living considerably longer. Overall, five-year survival across all stages combined is approximately 20%, largely because many cases are diagnosed after the cancer has become advanced.

Pathologic features associated with a worse outcome include:

• Vascular invasion — Especially macrovascular invasion into the portal or hepatic vein, which is the single strongest pathologic predictor of recurrence and death.
• Large tumor size — Tumors larger than 5 cm have a higher risk of recurrence and spread.
• Multiple tumors — The presence of more than one tumor often reflects spread within the liver and carries a worse outlook than a single tumor.
• High histologic grade — Poorly differentiated tumors tend to behave more aggressively.
• Positive surgical margins — Tumor cells at the cut edge raise the risk of recurrence in the liver.
• Macrotrabecular massive subtype — Associated with a higher risk of recurrence after surgery.
• High AFP level — Very high pre-treatment AFP levels are associated with more aggressive disease.
• Poor underlying liver function — Advanced cirrhosis limits treatment options and independently affects survival.

What happens after the diagnosis?

After a diagnosis of hepatocellular carcinoma, care is usually coordinated by a multidisciplinary team that typically includes a hepatologist, a surgical oncologist or transplant surgeon, an interventional radiologist, a medical oncologist, and a radiation oncologist. Decisions about treatment depend on the size and number of tumors, whether blood vessels or other organs are involved, whether the cancer has spread, and how well the rest of the liver is functioning.

Curative options for early disease include surgical removal of the tumor (partial hepatectomy), liver transplantation, and local ablation techniques such as radiofrequency or microwave ablation. For intermediate-stage disease that cannot be removed surgically, regional treatments delivered through the blood vessels — transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) — can control tumor growth. Advanced disease is treated with systemic therapy, most often a combination of immunotherapy and a drug that blocks blood vessel growth (atezolizumab plus bevacizumab, or durvalumab plus tremelimumab), or with targeted oral drugs such as lenvatinib or sorafenib.

Treatment of the underlying liver disease — for example, antiviral therapy for hepatitis B or C, abstinence from alcohol, or management of metabolic liver disease — remains important throughout, because ongoing liver injury increases the risk of new tumors. After treatment, follow-up typically includes regular imaging and AFP blood tests to watch for recurrence, along with ongoing care for cirrhosis when present.

Questions to ask your doctor

• What is the size of my tumor, and is there more than one tumor in my liver?
• What is the histologic grade of my tumor, and does it belong to a specific subtype?
• Is there evidence of microvascular or macrovascular invasion in my pathology report?
• What is the pathologic stage (pTNM) of my cancer?
• If I had surgery, were the surgical margins negative, close, or positive?
• Were any lymph nodes examined, and did any contain cancer?
• What does the rest of my liver look like — is there cirrhosis or another underlying liver disease?
• How well is my liver functioning, and how does this affect my treatment options?
• Am I a candidate for surgery, liver transplantation, or local ablation?
• If surgery is not an option, could regional treatments such as TACE or TARE be used?
• Is my tumor advanced enough that systemic therapy (immunotherapy or targeted therapy) should be considered?
• Was any biomarker or molecular testing performed on my tumor, and did it change my treatment options?
• What is my AFP level, and how will it be used to monitor my disease?
• What is the plan for follow-up imaging and blood tests after treatment?
• Are there steps I can take to protect my remaining liver and reduce the risk of new tumors?