Hepatic Adenoma

Description

Hepatic adenomas (pleural: adenomata) are rare benign tumours of the liver predominantly composed of hepatocytes. The incidence is highly related to the use of oral contraceptives and anabolic steroids. It’s important to note that despite their benign status, hepatic adenomas hold a potential risk for malignant transformation and complications, including haemorrhage.

Pathogenesis

Hepatic adenomas originate from hepatocytes, the main cell type in the liver. Although the precise mechanism of adenoma formation is not fully understood, the overuse of oral contraceptives or anabolic steroids, metabolic syndrome and glycogen storage diseases have been implicated as key contributing factors.

Subtypes

There are four main subtypes of hepatic adenoma, identified by their histopathological and genetic features:

• Inflammatory hepatic adenomas (IHAs): The most common subtype (50% of all cases). IHAs often have systemic manifestations such as fever and leukocytosis. Associated with non-alcoholic fatty liver disease. Small risk of malignancy. Found both in men and women.
• Hepatocyte nuclear factor 1 alpha (HNF1A) inactivated hepatic adenomas: Approximately 35-40% of all hepatic adenomas. They are associated with adenomatosis and usually occur in female patients with oral contraceptive use. Very low to no risk of malignant transformation.
• Beta-catenin-activated hepatic adenomas: They make up about 10-15% of all hepatic adenomas and have a higher risk of malignant transformation to hepatocellular carcinoma. Associated with OCP and anabolic steroid use in both men and women.
• Unclassified hepatic adenomas: These account for about 10% of all cases and have no specific clinical, radiologic or genetic features that allow classification into the other three subtypes.

Epidemiology, Risk Factors & Associations

• Hepatic adenomas are more common in women than men, especially in those of childbearing age (20-44 years) [1.8 per 100,000 women vs 0.2 per 100,000 men].
• Oral contraceptive use: Hepatic adenomas are 3-4 times more likely in women who have used oral contraceptives for more than two years. Particularly associated with HNF1A and Beta-catenin subtypes.
• Anabolic steroids: Bodybuilders and others who use anabolic steroids are also at higher risk. Particularly associated with the Beta-catenin subtype.
• Glycogen storage diseases: People with glycogen storage diseases, such as type I (Von Gierke disease), have a higher risk of developing multiple hepatic adenomas.
• Non-alcoholic fatty liver disease. Particularly associated with the inflammatory subtype.

Clinical Features

Hepatic adenomas are typically asymptomatic and are often found incidentally. In cases where they do cause symptoms, patients may experience:

• Right upper quadrant abdominal pain
• Palpable mass in the abdomen
• Rarely, they can present with acute abdomen due to tumour rupture and intra-abdominal haemorrhage

They may enlarge with:

• OCP use (decreases on cessation)
• Pregnancy

Complications

• Haemorrhage: This can occur if the adenoma ruptures, leading to internal bleeding. Adenomas larger than 5 cm are at increased risk of haemorrhage and maybe resected. Ruptured hepatic adenomas are clinical emergencies.
• Malignant transformation: There is a small risk that hepatic adenomas may transform into hepatocellular carcinoma, particularly in the Beta-catenin-activated subtype.

Pathological Features

Morphology

Hepatic adenomas appear as solitary, well-circumscribed lesions that can be several centimetres in diameter. They typically lack a fibrous capsule. The cut surface is often soft and pale yellow with occasional areas of haemorrhage or necrosis.

Histopathology

Histologically, hepatic adenomas are composed of plates of hepatocytes with no portal tracts or bile ducts. There can be a variable amount of fat and inflammatory cells. The hepatocytes are generally uniform with abundant eosinophilic cytoplasm.

Genetics

Molecularly, different subtypes of hepatic adenomas show different genetic alterations. For example, HNF1α-inactivated HAs are associated with inactivating mutations of the TCF1 gene, which encodes HNF1α. β-catenin-activated HAs are associated with mutations in the CTNNB1 gene, which encodes β-catenin.

Radiological Features

General Features

• Typically solitary lesions that may be located anywhere within the liver, but are found in the subcapsular region of the right lobe in 75% of cases.
• They usually appear as well-defined, hypervascular homogeneous masses.
• May contain foci of fat or haemorrhage. Focal calcification is uncommon (5%).
• Subtype:
  • IHA – Can demonstrate heterogeneity due to areas of inflammatory infiltration and haemorrhage.
  • HNF1A – Usually homogeneous and smaller than other subtypes.
  • Beta-catenin – May appear heterogeneous due to areas of haemorrhage or necrosis.
• Adenomatosis is the term used to describe 10 or more adenomata.

US

• May be indeterminate on ultrasound alone and requires further imaging.
• B-mode: Well-defined, round, heterogenous mass. Heterogenity may reflect haemorrhage, intralesional fat, necrosis and calcification. May have a hypoechoic halo of compressed parenchyma.
• Colour Doppler: Variable internal vascularity. Large peripheral vessels

CT

• Non-contrast: Usually isodense or slightly hypodense compared to the surrounding liver parenchyma.
• Arterial phase: The adenoma shows intense homogeneous enhancement.
• Portal venous and delayed phases: The lesion becomes isointense or slightly hypointense to liver.

MRI

• T1: Adenomas are typically isointense to slightly hypointense. Increased signal intensity may represent recent haemorrhage or fat.
• T2: Usually slightly hyperintense. The atoll sign describes IHAs which demonstrate peripheral rim of high T2 signal with central isointensity to background parenchyma.
• In-phase and Out-of-phase: Hepatic adenomas with intratumoral fat will demonstrate signal loss on out-of-phase images
• DWI/ADC: Adenomas may demonstrate diffusion restriction due to their cellular nature.
• SWI: Hyperintense signal on SWI can indicate recent or old haemorrhage.
• Post-Gadovist:
  • Arterial phase: Intense enhancement.
  • Portal venous phase: Isointense compared to the liver parenchyma.
  • Delayed phase: Isointense compared to liver parenchyma.
• Post-Primovist:
  • Arterial phase: Intense enhancement.
  • Portal venous phase: Hypointense compared to the liver.
  • Hepatobiliary phase: Hypointense compared to liver parenchyma, as adenomas do not have functioning hepatocytes and therefore, do not take up the contrast agent.

Differential Diagnosis

• Focal Nodular Hyperplasia (FNH): FNH is typically characterised by a central scar visible on CT and MRI imaging, which shows delayed enhancement due to the fibrotic nature of the scar tissue. On the hepatobiliary phase of MRI (20 min delay), FNH will typically show intense, homogeneous enhancement, unlike hepatic adenomas. The presence of functioning Kupffer cells in FNH can be detected by increased uptake of technetium-99m sulfur colloid on nuclear medicine scans, which helps to distinguish it from hepatic adenoma.
• Hepatocellular Carcinoma (HCC): HCC is usually associated with underlying chronic liver disease or cirrhosis, unlike hepatic adenomas. On imaging, HCC lesions typically demonstrate arterial phase enhancement and washout in the venous phase. Additionally, HCC may present with more aggressive features such as vascular invasion or distant metastasis, which are not seen with hepatic adenomas.
• Metastatic Disease: Metastatic liver disease will usually present as multiple lesions, whereas hepatic adenomas are typically solitary. The primary cancer site can often provide useful clues for differentiation, as the imaging characteristics of liver metastases can vary greatly depending on the primary cancer type. For example, metastases from colorectal cancer typically show a rim-like, or “ring”, enhancement after contrast administration on CT or MRI, unlike the homogeneous enhancement seen in hepatic adenomas.
• Intrahepatic Cholangiocarcinoma: This is generally hypointense on T1-weighted MRI images and hyperintense on T2-weighted images, similar to hepatic adenoma. However, cholangiocarcinoma typically shows peripheral irregular rim-like enhancement in the arterial phase with progressive centripetal fill-in on delayed phases, contrasting with the homogeneous enhancement pattern of hepatic adenomas.
• Haemangioma: Hepatic haemangiomas usually present as well-defined, hyperechoic lesions on ultrasound, which show characteristic peripheral nodular enhancement on contrast-enhanced CT or MRI. This “filling in” phenomenon, with enhancement progressing from the periphery to the centre, helps distinguish haemangiomas from hepatic adenomas.

Management

• The management of hepatic adenomas often involves a multi-disciplinary team including hepatologists, radiologists and surgeons.
• Regression may occur following cessation of OCP.
• Genetic counseling for hepatic adenomatosis, family history of adenomas or MODY3 type diabetes may be considered.
• The decision to intervene usually depends on the size of the adenoma, the presence of symptoms and the potential for complications.
  • For small, asymptomatic adenomas, conservative management with regular monitoring may be adopted.
  • For larger adenomas (>5 cm), or those causing symptoms or complications, surgical resection is generally recommended.
• In cases where surgery is not possible or the risk of surgery is high, other techniques such as radiofrequency ablation may be considered.
• Rupture hepatic adenomas are clinical emergencies
  • Transarterial embolisation
  • Laparoscopic resection