Hepatocellular adenoma: what it means and when it needs treatment

A hepatocellular adenoma, also called a hepatic adenoma, is a benign tumor that begins in liver cells. It is not a metastasis and is not the same as liver cancer. However, it should not be confused with other benign lesions that rarely cause problems, because some adenomas may grow, bleed and, much less often, become malignant.

Management depends on more than confirming that an adenoma is present. Its size, growth over time, the person’s sex, hormone exposure and, in some cases, the tumor subtype all matter. Many small adenomas can be monitored with imaging, while others require treatment.

In recent years, I have been seeing these lesions more often in clinical practice. We do not know whether this means that their true frequency has increased. One likely explanation is that ultrasound, CT and MRI are now used more often for many different reasons, revealing lesions that previously went unnoticed. Another may be the increasing prevalence of overweight, obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), which are particularly associated with a subtype called inflammatory hepatocellular adenoma. Both changes probably contribute.

What causes a hepatocellular adenoma?

Hepatocellular adenoma is uncommon and may occur in women or men, although it has traditionally been diagnosed most often in young women. The main associated factors are:

• Estrogen-containing contraceptives. Risk increases with prolonged exposure, although modern formulations contain less estrogen than contraceptives used decades ago.
• Anabolic steroids and androgens. These may promote adenomas in both men and women.
• Overweight, obesity and metabolic syndrome. These are particularly associated with inflammatory adenomas and fatty liver.
• Pregnancy. Pregnancy hormones do not usually cause a new adenoma during those months, but they may stimulate the growth of one that is already present.
• Certain rare diseases. These include some glycogen storage diseases and specific genetic conditions.

Having obesity or MASLD does not mean that a person will develop an adenoma. Most people never do. The association helps place the lesion in context and makes weight and metabolic health relevant to its management.

What are the different types of hepatocellular adenoma?

We now know that not all adenomas are alike. Molecular classification identifies groups with different risk factors, imaging appearances and behavior. It also explains why one small lesion may require treatment while another, larger lesion may initially be observed.

• Inflammatory hepatocellular adenoma. This accounts for approximately 35% to 45% of cases. It is associated with obesity, metabolic syndrome, hepatic steatosis, heavy alcohol use and certain glycogen storage diseases. On MRI it is often markedly bright on T2-weighted images, may show the so-called atoll sign and may retain enhancement after the arterial phase. The tissue expresses C-reactive protein (CRP) and serum amyloid A (SAA). Its malignant potential is low unless the beta-catenin pathway is also activated.
• HNF1A-inactivated hepatocellular adenoma. This accounts for about 35% to 40% of cases and occurs almost exclusively in women. It often contains abundant intratumoral fat, producing a characteristic signal drop on opposed-phase MRI. Immunohistochemistry shows loss of liver fatty acid-binding protein (LFABP) expression. This is one of the subtypes with the lowest risks of bleeding and malignant transformation.
• Beta-catenin-activated hepatocellular adenoma. This is associated with male sex, androgen or anabolic steroid exposure and glycogen storage disease. It may occur alone or overlap with an inflammatory adenoma. Exon 3 mutations in the CTNNB1 gene are the most clinically relevant because they increase the risk of transformation into hepatocellular carcinoma. Exon 7 and 8 mutations do not appear to carry the same risk. MRI cannot reliably distinguish these groups.
• Sonic hedgehog hepatocellular adenoma. This uncommon subtype accounts for fewer than 5% of cases and has been associated with obesity and hormonal exposure. Its main significance is a greater risk of bleeding. It has no sufficiently specific imaging pattern and is usually identified by examining the surgical specimen or, exceptionally, a biopsy.
• Unclassified hepatocellular adenoma. Approximately 5% to 10% do not fit the other groups with the available tests. This is a diagnosis of exclusion, and management depends on size, growth, sex and histologic features.

How is the diagnosis made, and when can MRI identify the subtype without biopsy?

The first examination should be multiphase contrast-enhanced MRI, or multiphase CT when MRI cannot be performed. Ultrasound detects the nodule but rarely distinguishes an adenoma from focal nodular hyperplasia or a malignant tumor.

Clinical context combined with MRI can diagnose many inflammatory and HNF1A-inactivated adenomas with reasonable confidence. Imaging cannot reliably identify beta-catenin activation, sonic hedgehog adenomas or unclassified adenomas. There is also no blood test that establishes the subtype. An elevated CRP level, for example, does not replace imaging or tissue analysis.

The assessment should also review contraceptives, hormone therapy, anabolic steroids, pregnancy history, weight changes, liver tests and the presence of fatty liver. When the imaging and clinical context do not provide a coherent answer, the case should be discussed by a team that includes hepatology, radiology, surgery and pathology.

When the imaging appearance is typical and observation would be recommended regardless, a molecular label is not required for every adenoma. The key question is whether any feature would change the person’s risk assessment or treatment.

Is a biopsy needed?

In practice, we almost never biopsy a suspected hepatocellular adenoma. If MRI is characteristic and the plan is observation, biopsy adds little. If an important diagnostic uncertainty remains and the lesion can be removed with reasonable operative risk, we generally prefer complete resection rather than taking a small tissue sample.

Resection allows the pathologist to examine the entire lesion, reduces the risk that a biopsy will miss a different area or a small focus of malignant transformation and treats the problem at the same time. This approach is particularly reasonable in a man, in a growing or larger tumor, or when imaging raises concern for hepatocellular carcinoma.

A core needle biopsy is reserved for exceptional situations discussed with radiology, surgery and a multidisciplinary liver tumor team. It may be considered when the lesion is not resectable, the operative risk is disproportionate or diagnostic confirmation is required before ablation or embolization. It may also help in highly selected patients with multiple lesions when the result would truly alter the overall strategy.

Biopsy is not harmless. It carries a small but real risk of bleeding and, more importantly, a limited sample may not represent an entire heterogeneous lesion. When substantial uncertainty remains in a resectable tumor, examining the complete lesion generally provides a more reliable answer than sampling one part of it.

When should beta-catenin be assessed, and what is it used for?

Beta-catenin is assessed in tissue, not with a blood test. In our practice, that tissue almost always comes from the surgical specimen and only exceptionally from a biopsy. The pathologist may use a panel that includes LFABP, CRP, SAA, glutamine synthetase and beta-catenin. Nuclear beta-catenin staining and diffuse glutamine synthetase expression suggest activation of this pathway, but neither stain is perfect.

When tissue is available, beta-catenin activation should be investigated particularly in a tumor from a man, with anabolic steroid exposure or glycogen storage disease, in an inflammatory adenoma with suspicious features, or when changes raise concern for hepatocellular carcinoma. We do not perform a biopsy solely to determine beta-catenin status when the lesion is resectable and the diagnostic uncertainty already justifies surgery. Testing is performed on the complete specimen.

When immunohistochemistry is equivocal or discordant and the decision depends on the result, molecular analysis of CTNNB1 may be appropriate. The report should distinguish an exon 3 mutation from an exon 7 or 8 alteration because they do not carry the same implications. Confirmation of a high-risk exon 3 mutation favors resection even when the adenoma is smaller than 5 cm. It also prompts careful assessment for any focus of malignant transformation.

The purpose of beta-catenin testing is not simply to provide a more sophisticated label. It identifies the small group of adenomas with greater malignant potential and prevents an apparently quiet lesion from being left under surveillance when treatment would be safer.

Does it cause symptoms?

Most hepatocellular adenomas cause no symptoms. They are commonly found by chance on an ultrasound, CT scan or MRI performed for abdominal pain, a routine examination or another reason.

Some large adenomas may cause persistent discomfort in the right upper abdomen. Bleeding is uncommon but may present as sudden, severe abdominal pain, sometimes with dizziness, weakness or fainting. The risk rises with tumor size and certain lesion characteristics.

Malignant transformation is uncommon. Risk is higher in men, in large or continuously growing tumors and in some beta-catenin-activated subtypes. This is why the same recommendation should not be applied to every adenoma.

When is observation enough?

For a woman with a well-characterized adenoma smaller than 5 cm and no high-risk features, conservative management is often appropriate. This usually includes:

• Reviewing and, when appropriate, stopping estrogen-containing contraceptives or other hormones under medical guidance.
• Stopping anabolic steroids.
• Addressing excess weight, diabetes, high blood pressure and other features of metabolic syndrome.
• Repeating MRI or another imaging study to determine whether the adenoma shrinks, remains stable or grows.

The first reassessment is often performed after about six months. If the lesion remains smaller than 5 cm and is stable or smaller, imaging can continue at intervals tailored to the individual. Weight loss may help some obesity-associated adenomas regress, but it does not replace imaging follow-up.

When is treatment recommended?

Active treatment is generally considered when:

• The adenoma is 5 cm or larger and does not shrink after hormonal and metabolic risk factors have been addressed.
• The lesion continues to grow.
• Bleeding occurs or symptoms are clearly attributable to the adenoma.
• There is reasonable concern for a malignant tumor or a high-risk subtype is identified.
• The adenoma occurs in a man, because the risk of malignant transformation is higher even in small lesions.

Surgical resection is the usual treatment for higher-risk lesions and can often be performed using a minimally invasive approach. Arterial embolization can control a bleeding adenoma and may also be used as an alternative to surgery in selected cases. Ablation is another option for specific lesions. The choice depends on the tumor’s size, location and number, as well as the person’s overall health.

What about contraception and pregnancy?

When an adenoma is confirmed, contraception should be reviewed with the treating team. Estrogen-containing contraceptives are usually discontinued, but the change should be planned so that effective contraception is maintained. Decisions about progestin-only methods are individualized.

An adenoma smaller than 5 cm does not automatically rule out pregnancy. Before conception, the diagnosis should be secure and the lesion carefully measured. Closer ultrasound monitoring is used during pregnancy because about one-quarter of small adenomas may grow, although serious complications were uncommon in prospective studies. If an adenoma is 5 cm or larger, treatment before pregnancy is generally preferred.

When should someone seek urgent care?

A person with a known adenoma should seek emergency care for sudden, severe abdominal pain, especially in the right upper abdomen, or pain accompanied by pallor, cold sweats, dizziness, fainting, marked weakness or a feeling of low blood pressure. These symptoms may indicate bleeding and should not wait until the next scheduled visit.

For most people, the adenoma is detected before a complication occurs. An accurate diagnosis, careful measurement and a clear follow-up plan help avoid both undertreatment and unnecessary surgery.

See also

• Focal nodular hyperplasia of the liver
• Liver hemangioma
• Fatty liver disease (MASLD)
• Liver biopsy
• Hepatocellular carcinoma