Hepatocellular Adenoma

Hepatic adenoma (HA).

The differential diagnosis for imaging findings suggesting HA in children includes hemangioma, focal nodular hyperplasia (FNH), hepatocellular carcinoma (HCC), fibrolamellar carcinoma, and metastatic tumors.^1,2

HA is a rare, benign epithelial hepatic neoplasm that is extremely rare during childhood, with few published reported cases and series.^1,2 Liver tumors as a whole are very rare in children and account for 1-4% of all pediatric tumors, and benign tumors account for 30-40% of these.^1,2 Benign liver tumors include hemangiomas, which occur most commonly in infancy, as well as HAs and FNH. Of these, HA itself has been reported to comprise between 0% and 21% of the pediatric benign liver tumors, with rates varying likely due to recruitment criteria.^1,2

HA may occur sporadically but is more frequently associated with predisposing factors, such as glycogen storage disease types 1 and 3, androgenic steroid treatments with or without Fanconi anemia, congenital or surgical portosystemic shunt (CPSS), germline mutation of the HNF1-α gene, and familial adenomatosis polyposis, in addition to Hurler syndrome, Turcot syndrome, Lynch syndrome, immunodeficiency, tyrosinemia, galactosemia, and Glanzmann thrombasthenia treated with progestin therapy.^1,2 HAs are highly associated with oral contraceptive pills in adults or adolescents.¹

A 2024 systematic review of 316 children with HA, who had a mean age of 11.5 and predominantly girls (59.5%), found that most HAs (83.6%) occurred in children with predisposing diseases, most commonly glycogen storage disease, followed by portosystemic shunts and maturity-onset diabetes of the young type 3 (MODY3).^1,3 Other associated conditions included right-sided cardiopathies, endogenous or exogenous hormone exposure, and other rare conditions such as familial adenomatous polyposis, constitutional mismatch repair deficiency syndrome, and Wolf-Hirschhorn syndrome (4p partial deletion).

In this same review, clinical features included a mean and median lesion size of 7.4 and 6.7 cm, respectively, and symptoms of abdominal pain (26.6%) leading to HA diagnosis, in addition to increased liver enzyme levels and/or cholestasis in 53.2% and 38% of patients, respectively, at the time of the first assessment. Alpha-fetoprotein (AFP) levels were increased in 3% of patients, of which 66.6% had imaging and/or histology confirming malignant transformation of HA.³

Adult guidelines continue to be relied upon to classify and manage HAs in pediatric patients, which is less than optimal because presentation, physiopathology, predisposing factors, frequency of complications, and management of HA in children differ from adults.³

HCA has been extensively investigated in adults and has been found to carry an overall incidence rate of approximately 3-4/100,000 overall.⁴ Women are more prone to developing HAs (female-to-male ratio 8:1), with oral contraceptives being the most frequent risk factor. HA has an overall incidence of approximately 3 per 100,000. Adult HAs are classified into 8 molecular types, based on their genotypes and phenotypes.^5,6 HA type has an impact on patient management and is the major determinant of the risk of malignant transformation or hemorrhage.

HAs are currently categorized into various distinct subtypes: inflammatory (I-HCA); biallelic hepatocyte-nuclear-factor-1-alpha or HNF-1α-mutated (H-HCA); β-catenin-mutated (B-HCA), sonic hedgehog-activated hepatocellular adenoma (Sh-HCA), and mixed lesions. Unclassified HAs (U-HCA) share no characteristics with the aforementioned types.³ Each subtype has a unique pathogenesis, clinical presentation, typical imaging appearance, and outcome.

In adults and the general population, the most common type is H-HCA, which involves biallelic mutations of the T-cell factor-1 gene that encodes the HNF-1α transcription factor that is involved in hepatocyte differentiation, liver development, and glucose and lipid metabolism. This represents 34% of lesions, affects primarily women (average age 37 by one estimate),⁴ and demonstrates immunohistochemical (IHC) staining characterized by marked steatosis and reduced expression of liver fatty acid binding protein. The mutation is also often associated with mature-onset diabetes of the young (MODY3).¹

I-HCAs are associated with chronic alcohol consumption and obesity as well as systemic inflammatory syndrome, GSD type 1, and primary sclerosing cholangitis. These represent 40-50% of all HAs and present at an average age of 40 potentially with fever, leukocytosis, and elevated C-reactive protein (CRP), gamma-glutamyl transferase, alkaline phosphatase, and amyloid-associated proteins, in addition to positive IHC staining for serum amyloid A and CRP. They are associated with activating somatic mutations in the JAK/STAT pathway and the IL-6 inflammatory pathway. I-HCA can manifest with dystrophic vessels with pleiosis, telangiectasia, inflammatory infiltrates (predominantly lymphocytes and histiocytes, admixed with plasma cells and neutrophils), and ductular reactions and have the highest risk of hemorrhage among HAs.^1,3,4

B-HCA, which represents 15-20% of all HA cases, commonly presents as a single lesion in young adults (average age 27.5-28.5⁴) and has a high risk of malignant transformation (the highest risk among HAs) if the mutation occurs in exon 3 (B^ex3-HCAs). [1.3]. B^ex3-HCAs demonstrate diffuse and strong expression of glutamine synthetase (GS) on IHC and aberrant, nuclear positivity for beta-catenin [1.4], while B^ex7,8 HCAs are characterized by perivenular and heterogeneous GS staining without nuclear beta-catenin expression. [1.5] A female predominance is described, though with a higher proportion of males affected than in other subtypes, and an association with androgen therapy.⁴

Sh-HCAs are caused by chromosomal translocation with fusion of the INHBE gene promoter with the GLI1 gene, activating the sonic hedgehog pathway that is involved in liver regeneration and lipid metabolism, with the INHBE-GLI1 fusion serving as a molecular marker for sh-HCA. B-HCA is often associated with androgen exposure, glycogenesis, and familial adenomatous polyposis and manifests with hepatic cellular architectural abnormalities with an acinar, pseudoglandular pattern. Sh-HCA tends to cause bleeding and commonly occurs in obese patients, with strong female predominance and average age at diagnosis of 43 and tends to cause bleeding.^1,3,4

Finally, unclassified HA (U-HCA) represents 7-10% of cases and is negative for CRP, SAA, β-catenin, and glutamine synthetase but positive for LFABP staining.^1,3 These have a female predominance and an average age at presentation of 38 years⁴

Pediatric HA is more rare than in adults and occurs in approximately one per million children.⁷ HA most commonly presents with an incidental imaging finding or with vague or nonspecific abdominal pain that can be related to bleeding, rupture, and/or peritonitis and may seem nonpositional, have no specific modifying factors, and can spontaneously increase or decrease in severity.⁷ HA occurs equally in prepubertal girls vs boys, but is higher in girls after puberty. In children, a 2024 review demonstrated 43.2% of HA lesions to be H-HCAs, 25.9% B-HCAs, 21% I-HCAs, 9.9% HAs with combined inflammatory and β-catenin features (B^{ex3 or ex7-8}I-HCA), and 3.7% U-HCAs, while 7.6% of children had mixed or combined lesions of different subtypes in the liver (H- and B-HCA, n = 5; and I- and B-HCA, n = 1) in the liver. The more recently described Sh-HCA has not yet been identified in children.³

In diagnosing HA, US of the right upper quadrant with or without Doppler is the most common initial imaging test used in evaluation in cases of pediatric HA, which typically presents on US as a heterogeneous, round, well-demarcated vessel-containing solid nodule that is hypoechoic compared with steatosis surrounding the liver parenchyma, though small isoechoic nodules can be missed particularly in the setting of steatosis.² Contrast-enhanced US can help differentiate HA from FNH based on centripetal arterial flow in HA and may potentially yield similar specificity to contrast-enhanced MRI or be used as an adjunct to improve differentiation of HA from other liver masses.⁹

Repeat US every 3 months can be used to monitor cases of HA, and CT or MRI with IV contrast is done if the nodules increase in size or develop features suggesting malignant transformation. MRI may be used in place of US for this purpose as well.¹⁰

MRI, preferably with a hepatocyte-specific contrast agent such as gadobenate dimeglumine that is mainly excreted via the biliary system, is considered the gold standard in imaging for HA, which typically appears as heterogeneous on T1- and T2-weighted imaging, with a high signal on T2-weighted imaging. Appearance on MRI depends on the amount of fat, vascularity, hemorrhage, and necrosis within the mass. Acute intratumoral hemorrhage will demonstrate high signal on T1-weighted imaging, while chronic hemorrhages show low T1 and T2 signaling. MR imaging features of the various subtypes are well described, including H-HCA, β-HCA, I-HCA, and U-HCA.

Nearly 78% of H-HCAs exhibit diffuse signal loss on out-of-phase imaging because of intratumoral fat deposition, with a specificity of 100%.^7,11,12 H-HCAs can have variable signal with slight hyperintensity on T2-weighted imaging and show moderate enhancement in the arterial phase with no retention of hepatocyte-specific contrast on delayed phase imaging. The background liver often is diffusely steatotic.¹¹

I-HCAs typically show heterogeneous T2 hyperintensity most prominently peripherally (“atoll sign,” which is present in 43%) related to dilated sinusoids.^11,12 I-HCAs exhibit avid arterial phase enhancement that persists on the portal venous and delayed phase images, also related to dilated sinusoids.¹¹ Intratumoral steatosis is rare, and when present, is usually heterogeneous and focal or patchy rather than diffuse, and the background liver may be steatotic. I-HCAs have a 30% incidence of hemorrhage.

β-HCAs do not have specific imaging features but can show intense arterial phase enhancement with subsequent washout, like HCC.¹² They usually lack intratumoral steatosis.¹¹

U-HCA demonstrates no specific MRI features, with no steatosis expected, and 60% with hemorrhagic components.¹²

While FNHs can be difficult to differentiate from HCAs on MRI, HCAs usually lack the central scar that is characteristic for FNH.^9,12 It is also important to monitor the progression of these tumors as early washout with arterial enhancement is characteristic of malignant transformation.^9,12

While US and MRI are the currently recommended imaging modalities for detection and monitoring of pediatric HCA, CT may be used in situations where there is a lack of other imaging tools.⁷ The downside with CT is the high radiation dose, especially with multiphase CT imaging, and multifocal tumor burden may be hard to assess given the poor soft tissue contrast resolution, especially with a single post-contrast phase.⁷ On CT, HCA appears without central scar and can show a heterogeneous appearance. Dynamic CT may show peripheral enhancement of the tumors during the early phase, transitioning to centripetal flow in the later portal venous phase.¹

The prognosis of hepatic adenomas is not well-established but relates primarily to risks of hemorrhage and malignant transformation, which are the 2 major risks with HA.^3,13,14 Malignant transformation usually does not occur in pediatric patients, and the exceptional cases that have been reported were mainly associated with GSD, FA with steroid therapy, and CPSS.² Hemorrhage is one of the most important complications, with risks of bleeding and rupture estimated at 27.2 and 17.5 percent of patients in one study.¹⁵ This can involve either internal hemorrhage, usually with necrotic changes and in tumors larger than 4  cm, or spontaneous rupture potentially with subcapsular hematoma and/or hemoperitoneum. Intraperitoneal or intratumoral hemorrhage can be associated with severe abdominal pain and hemodynamic instability. Hemorrhage has been reported in FA even after discontinuation of the predisposing factor of androgen therapy.^16,17 Fatality has been reported in familial adenomatosis related to HNF1-α mutation and in FA.

Management is guided by the presence of symptoms, size, number, subtype classification, and surgical risk, and may include cessation of hormone therapy, serial imaging surveillance, screening for malignancy using alpha-fetoprotein to identify HCC, and/or surgical resection. Monitoring with imaging and serum AFP levels may be recommended in cases where the lesion is small and not subcapsular or atypical in appearance. Serial imaging is appropriate for confirmed lesions of less than 5 cm. Individuals with cirrhosis require surveillance US to monitor stability due to increased risk of HCC. Elective resection is often recommended in males with adenomas regardless of size and in females with adenomas greater than 5 cm and HAs greater than 7 cm require close monitoring or resection as they are particularly prone to bleeding due to hypervascularization and fragile sinusoids. Embolization of the hepatic artery may be used to control acute hemorrhage. Liver transplantation may also be considered in cases of adenomatosis, due to increased malignant potential.^13,14

HA is a benign liver tumor that is rare, particularly in pediatric patients, where it is encountered most frequently in association with genetic conditions such as glycogen storage disease and has associated risks of hemorrhage, rupture, and malignant transformation. Lesions are often asymptomatic until rupture or hemorrhage and are detected by imaging, with MRI (or less favorably, multiphase contrast-enhanced CT) helpful to distinguish HA from other hepatic tumors with no potential for malignant transformation. A definitive diagnosis is with image-guided core needle biopsy. Management may include cessation of hormone therapy if applicable, serial imaging surveillance, screening for malignancy, and/or surgical resection, as well as transplantation in cases of adenomatosis, and embolization to control acute hemorrhage.