Hepatic adenoma

Hepatic adenomas, also referred to as hepatocellular adenomas, are benign, generally hormone-induced, liver tumors. The tumors are usually solitary, have a predilection for hemorrhage, and must be differentiated from other focal liver lesions.

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 recognizing that obesity and metabolic syndrome are emerging risk factors for adenomas ¹⁸. 

Hepatic adenoma is traditionally considered the most frequent hepatic tumor 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 estrogens)

• 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. Multiple lesions are frequently observed in patients with type I glycogen storage disease.

Macroscopic appearance

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

Microscopic appearance

Histologically, hepatic adenomas are characterized 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 being 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

According to the original 2006 Bordeaux classification, there are four subtypes of hepatic adenomas ¹⁷:

1. inflammatory

   • ​​most common subtype

   • highest bleed rate

2. HNF 1 alpha mutated

   • ​​second most common subtype

   • only occur in women, typically on oral contraceptives

   • often multiple

3. beta catenin mutated

   • ​​least common subtype

   • higher risk in men on anabolic steroids and patients with glycogen storage disease or familial adenomatous polyposis 

4. unclassified

Since this classification, another molecular subtype, sonic hedgehog-activated hepatocellular adenoma (sh-HCA), has emerged ²⁰.

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.

• color 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 tumors is variable, depending on ⁸:

• fresh hemorrhage: 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 hemorrhage (5-10% of cases ¹⁰).

MRI

In non-hemorrhagic 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)

If hemorrhagic, 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

In general, and if feasible, adenomas are resected, both to eliminate the risk of spontaneous rupture and to conclusively confirm the diagnosis ⁷. In cases where the lesion is small, not subcapsular, and has a typical appearance, monitoring with imaging and serum alpha-fetoprotein (AFP) levels is performed. Oral contraceptives are also ceased, and in such instances, the adenoma may regress. In inoperable cases, hepatic arterial embolization may have a role ⁷.

Complications

• spontaneous rupture

• malignant transformation into hepatocellular carcinomas (HCC) ⁸: rare, higher risk in men

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 hemorrhage are less common

• hepatic hemangioma

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

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