Hepatic adenomas, or hepatocellular adenomas (HCA), are benign, generally hormone-induced liver tumours. They are usually solitary but can be multiple. Most adenomas have a predilection for haemorrhage, and they must be differentiated from other focal liver lesions due to the risk of HCC transformation.

Epidemiology

The incidence of hepatic adenomas is unknown, with studies showing migration from the classically described female predominance related to the use of oral contraceptives, to an increased prevalence in men, particularly recognising that obesity and metabolic syndrome are emerging risk factors for adenomas ¹⁸. 

Hepatic adenoma is traditionally considered the most frequent hepatic tumour in young women on the oral contraceptive pill.

Associations

Hepatic adenomas are associated with ³:

• oral contraceptive use (especially the first generation pills which have a high concentration of oestrogens)

• anabolic steroids: typically young men

• glycogen storage diseases:

  • type I (von Gierke disease)

  • type III (Cori or Forbes disease)

• obesity

• metabolic syndrome ¹⁸

• diabetes mellitus ¹⁹

Clinical presentation

The lesions usually remain asymptomatic until they spontaneously rupture, resulting in abdominal pain. Occasionally rapid bleeding into the peritoneal cavity can lead to massive exsanguination and death.

Pathology

Hepatic adenomas are usually solitary (70-80% of cases ¹⁰) and large at the time of diagnosis (5-15 cm) ^3,13. They are most frequently seen at a subcapsular location in the right lobe of the liver and are often round, well-defined pseudo-encapsulated masses. Occasional dystrophic calcification may be present. 

When multiple, usually >10 adenomas ⁹, the term hepatic adenomatosis is used which has been described in all subtypes ²¹. Multiple lesions are frequently observed in patients with type I glycogen storage disease.

Macroscopic appearance

The lesion is well-circumscribed, often subcapsular with yellow colouration on account of frequently abundant fat and lack of bile. Haemorrhagic change is frequent. The tumour may be surrounded by a fibrous pseudocapsule ¹⁵.

Microscopic appearance

Histologically, hepatic adenomas are characterised by proliferation of pleomorphic hepatocytes without normal lobular architecture. These cells frequently have abundant glycogen (thus the link with von Gierke disease) ⁵. They are traditionally described as devoid of bile ducts and Kupffer cells, although this has been shown not to be the case, with a diminished number of Kupffer cells found in many cases ^1,3,4. This has an important implication for Tc-99m sulfur colloid scans (see below).

Molecular classifications

The original 2006 Bordeaux classification, described four subtypes of hepatic adenomas ¹⁷. The second major update in 2017 added four additional groups ²¹.

The current classification contains eight groups as follows:

• inflammatory

  • ​​most common subtype

  • linked with obesity and alcohol use

  • mainly occur in women

• HNF 1 alpha mutated

  • ​​second most common subtype

  • mainly occur in women, typically on oral contraceptives

• beta catenin mutated exon 3

  • higher risk in men on anabolic steroids

  • highest risk of HCC transformation (47%)

• mixed inflammatory and beta catenin mutated exon 3

  • primarily inflammatory histologically (mutation second genetic event)

  • more common in females

• beta catenin mutated exon 7/8

  • negligible risk of HCC transformation

  • high risk of bleeding

  • exclusively found in female patients

  • linked with glycogen storage disease 

• mixed inflammatory and beta catenin mutated exon 7/8

  • primarily inflammatory histologically (mutation second genetic event)

  • linked with obesity and alcohol use

• Sonic hedgehog

  • highest risk of bleeding

  • linked with longer term oral contraceptive usage

  • strongest association with liver steatosis

• unclassified

  • 5-10% of adenomas do not show distinctive pathogenic or molecular features

Radiographic features

Ultrasound

A hepatic adenoma usually presents as a solitary, well-demarcated, heterogeneous mass. Echogenicity is variable ³:

• hypoechoic: 20-40%

• hyperechoic: ≤30%, often due to fat ^3,8

A hypoechoic halo of focal fatty sparing is also frequently seen.

• colour Doppler: may show perilesional sinusoids

• contrast-enhanced ultrasound ¹⁶:

  • arterial phase: 

    • hypervascular: similar to focal nodular hyperplasia (FNH), although adenomas usually enhance to a lesser degree

  • portal venous and delayed phases: 

    • ​centripetal filling: opposite of focal nodular hyperplasia, which shows centrifugal filling

CT

The attenuation of these tumours is variable, depending on ⁸:

• fresh haemorrhage: may be hyperattenuating

• fat content: may render the mass hypoattenuating

In general, they are well-marginated and isoattenuating to the liver. On contrast administration, they demonstrate transient, relatively homogeneous enhancement, returning to near isodensity on portal venous and delayed phase images ^8,10.

If the rest of the liver shows diffuse fatty infiltration, they will appear hyperattenuating.

Calcification may be seen in areas of old haemorrhage (5-10% of cases ¹⁰).

MRI

In non-haemorrhagic adenomas, they typically appear as:

• T1: variable and can range from being hyper-, iso-, to hypointense (hyperintense in 35-77% of cases ⁸)

• T2: mildly hyperintense (in 47-74% of cases ^2,8)

• IP/OP: the presence of fat typically leads to signal drop out on out-of-phase imaging

• T1 C+ (Gd)

  • some reports suggest that the enhancement becomes isointense to the rest of the liver by 1 minute ⁶

  • on the dynamic post-contrast sequence, adenomas show early arterial enhancement and become nearly isointense about liver on delayed images ¹⁰

• T1 C+ (Eovist/Primovist): 

  • usually appears hypointense on hepatobiliary phase (20 mins after injection) due to reduced uptake of Eovist ¹⁴ (whereas focal nodular hyperplasia appears iso- to hyperintense)

  • >80% of beta catenin mutated exon 3 HCA are iso or hyperintense during the hepatobilary phase due to increased OATP expression²². This imaging feature can be used in risk stratification.

If haemorrhagic, blood products may cause significant heterogeneity in signal on all sequences.

Nuclear medicine

Although classically described as a focal photopenic lesion with a surrounding rim of increased uptake on Tc-99m sulfur colloid scans, uptake may be seen in up to 23% of cases ¹. This is accounted for by the presence of Kupffer cells in many adenomas, though they may be reduced in number.

Usually has increased activity on a HIDA scan, but does not take up gallium on a gallium scan.

Treatment and prognosis

Management is usually determined by a number of factors including; patient sex, tumour size, location and any complications ²³.

Much of the management has been developed from the management of oestrogen-related HCAs.

In women, the initial step is cessation of exogenous hormones. The liver is then re-imaged with MRI in 6 months to reassess, looking for regression. If the lesion is <5cm, shows typical features of a HNF1A adenoma or regresses, then this is generally followed up with 6 monthly MRI for 12-24 months. If stable, patients may have annual or biennial follow-up.

If a lesion is > 5cm, is exophytic or shows interval growth, surgical excision or biopsy is recommended. If proven beta catenin mutated or Sonic hedgehog on biopsy, then surgical excision is recommended. Other subtypes can be resected or followed up depending on other patient specific factors.

In men, due to risk of malignant transformation, surgical resection is recommended for all HCAs ²³.

Given the importance of the latest molecular classification with regards to the risk of HCC transformation, biopsy of hepatic adenomas appears to have an increasing role in management ²³.

In inoperable cases hepatic arterial embolisation may have a role ⁷. Embolisation is the treatment of choice for an acutely bleeding HCA.

Complications

• spontaneous rupture/bleeding

• malignant transformation into hepatocellular carcinomas (HCC) ⁸: rare, higher risk in men and certain sub-types (see above)

Differential diagnosis

General imaging differential considerations include:

• hepatocellular carcinoma (HCC)

  • washout tends to render the lesion hypointense to the liver

  • rim enhancement of the pseudocapsule may persist on the delayed scan

  • different demographics

  • may be difficult to distinguish from an adenoma if well-differentiated ⁷

• fibrolamellar hepatocellular carcinoma

  • radiating/central scar

  • calcification more common ⁸

  • lymph node enlargement common

• focal nodular hyperplasia (FNH)

  • T2: bright central scar that has late enhancement

  • retains hepatocyte-specific contrast material (e.g. Eovist) on delayed phase MRI

• hepatic metastases (hypervascular) 

  • usually hypointense on T1 and moderately hyperintense on T2

  • fat and haemorrhage are less common

• hepatic haemangioma

  • typical haemangioma: discontinuous peripheral nodular enhancement, with gradual centripetal fill-in

  • flash-filling haemangioma: isodense/isointense to blood pool on all phases