Magnetic Resonance Imaging of Hepatic Adenoma Subtypes

Abbreviations

β‐HCA

β‐catenin‐mutated hepatocellular adenoma

HCA

hepatocellular adenoma

HCC

hepatocellular carcinoma

H‐HCA

hepatocyte nuclear factor‐1‐alpha–mutated hepatocellular adenoma

HNF‐1α

hepatocyte nuclear factor‐1‐alpha

I‐HCA

inflammatory hepatocellular adenoma

L‐FABP

liver fatty acid binding protein

MRI

magnetic resonance imaging

OATP1B3

organic anion transporting polypeptide 1B3

U‐HCA

unclassified hepatocellular adenoma

Hepatocellular adenomas (HCAs) are uncommon benign liver tumors that occur more often in female patients of reproductive age. There is a strong association with oral contraceptive (OCP) use. Other risk factors include anabolic steroid use, glycogen storage diseases, familial adenomatous polyposis, and obesity.

Recent insights into the genetic and molecular biology of HCA have helped classify adenomas into four subtypes: hepatocyte nuclear factor‐1‐alpha (HNF‐1α)‐mutated HCA (H‐HCA), β‐catenin‐mutated HCA (β‐HCA), inflammatory HCA (I‐HCA), and unclassified HCA (U‐HCA).

The genetic‐phenotype classification system has important clinical and management implications because of each subtype’s unique propensity toward hemorrhage and malignant degeneration.

Subtypes

I‐HCAs are the most common subtype, representing approximately 40% to 50% of adenomas. ¹ They occur most often in women and are associated with obesity, diabetes, and hepatic steatosis. ² Overactivation of the JAK‐STAT pathway, either from interleukin‐6 signal transducer gene mutations or glycoprotein‐130 overexpression, results in proliferation of acute‐phase reactants, such as C‐reactive protein and serum amyloid A, ³ and inflammatory cell infiltration within the tumor. ⁴ In addition to inflammation, I‐HCAs are characterized by sinusoidal dilation, peliosis, and thickened arteries. These vascular characteristics result in I‐HCAs having the highest risk for hemorrhage among all adenoma subtypes, with hemorrhage seen in approximately 30%. A subset of I‐HCAs also expresses β‐catenin mutations (10%) and is at a higher risk for malignant transformation when compared with typical I‐HCAs. ⁵

H‐HCAs are the second most common subtype, representing 30% to 40% of adenomas, and are seen predominantly in women who use OCPs. ¹ , ⁶ The HNF‐1α gene helps control the trafficking of fatty acids through its effect on liver fatty acid binding proteins (L‐FABP). HNF‐1α gene mutations induce lipogenesis by promoting fatty acid synthesis and down‐regulating L‐FABP, resulting in intratumoral fat accumulation. ⁴ Histologically, H‐HCAs show marked steatosis and bland hepatocyte cytology. ³ H‐HCAs are the least aggressive of the subtypes with low risk for hemorrhage and minimal to no risk for malignant transformation when measuring less than 5 cm. ⁷

β‐HCAs represent approximately 10% to 20% of adenomas, ¹ are more common in men, and are associated with glycogen storage diseases, androgen administration, and familial adenomatous polyposis. ⁵ Normally, activation of the β‐catenin/Wnt pathway causes accumulation of β‐catenin within the nucleus to induce gene transcription, playing an important role in hepatocellular function, including cell proliferation. Mutations involving the catenin β1 gene (CTNNB1) cause overaccumulation of β‐catenin, leading to autonomous hepatocyte proliferation. β‐Catenin mutations are observed in 30% to 40% of patients with hepatocellular carcinoma (HCC), explaining the highest risk for malignant transformation of β‐HCAs into HCC among the HCA subtypes. HCC has been found in 46% of HCAs with β‐catenin mutations (β‐HCA and I‐HCA with coexisting β‐catenin mutations). ⁸ β‐HCAs and well‐differentiated HCCs can be difficult to distinguish pathologically. ⁴

U‐HCAs represent 5% to 10% of adenomas and are poorly understood. They lack any specific genetic abnormality or phenotypic features. ¹

Imaging

Magnetic resonance imaging (MRI) is the modality of choice for evaluating HCAs and can characterize H‐HCAs when they contain intratumoral fat and I‐HCAs based on the dilated sinusoids (Table 1).

TABLE 1.

MRI Findings and Clinical Features of HCA Subtypes

MRI Sequences and Clinical Features	I‐HCA	H‐HCA	β‐HCA	U‐HCA
T1 weighted imaging	Isointense to mildly hyperintense	Isointense to hyperintense	Isointense to hyperintense 7 , 9	No known specific findings
T2 weighted imaging	Markedly T2 hyperintense	Isointense to mildly hyperintense	Poorly demarcated T2‐hyperintense scar 9
	Atoll sign: incomplete T2 hyperintense rim
Post‐contrast imaging	Arterial enhancement that persists on later phases	Variable arterial enhancement that does not persist on later phases	May mimic HCC with arterial enhancement with washout 7
			Poorly demarcated scar that enhances in the portal venous phase 9
			Isointense or hyperintense on hepatobiliary phase 6
In‐phase and out‐of‐phase imaging	May have focal mild signal loss	Diffuse signal loss on out‐of‐phase images	Commonly, no signal loss 9 , 10
Prevalence rate	40%‐50% of cases	30%‐40% of cases	15%‐20% of cases	10%
Risk for malignant transformation 13	11% 13	No to low risk 8 , 13	Up to 46% 8	14% 13
Hemorrhage	16%‐30% 12 , 13	9% 12 , 13	14% 12	14%‐33% 8 , 12
Management considerations 1 , 12	Conservative management if <5 cm and stable	Conservative management if <5 cm and stable	Resection regardless of size	Conservative management if <5 cm and stable

H‐HCAs exhibit diffuse signal loss on out‐of‐phase images in up to 78% of cases ⁹ because of intracellular fat content (Fig. 1) with a sensitivity of 87% and specificity of 100%. ¹⁰ Up to 17% of I‐HCAs can also show intratumoral fat, ⁹ although the fat is typically mild‐to‐moderate in amount and more focally distributed (Fig. 2), rather than the large amount of diffusely distributed fat typically seen in H‐HCA. ⁹ H‐HCAs more commonly appear isointense to slightly hyperintense on T₁‐weighted images and isointense to slightly hyperintense on T₂‐weighted images, and show moderate enhancement in the arterial phase with no persistent enhancement on the portal venous and delayed phases. ⁷

FIG 1.

H‐HCA. Diffuse signal loss is seen on the out‐of‐phase image (B) when compared with the in‐phase image (A) of this pathologically proved adenoma, in keeping with H‐HCA. Mild heterogeneous arterial enhancement can be seen (C) with contrast that does not persist on the portal venous phase (D).

FIG 2.

I‐HCA. Pathologically proved inflammatory adenoma shows diffuse hyperintensity on T₂‐weighted imaging (A). A focus of signal loss (arrow) can be seen between the in‐phase (B) and out‐of‐phase images (C) denoting a small amount of fat. Postcontrast images show arterial enhancement (D) that persists on later phases (E and F).

I‐HCAs are commonly hyperintense on T₂‐weighted imaging, either diffusely (Fig. 2) or peripherally (atoll sign, Fig. 3) due to dilated sinusoids. ⁹ T₂ hyperintensity is seen in 83% to 100% of I‐HCA, whereas the atoll sign is seen in 43% to 81%. ⁹ , ¹⁰ After contrast administration, they typically demonstrate intense arterial enhancement that persists on the venous and delayed phases. The combination of T₂ hyperintensity and persistent enhancement on delayed phase has a sensitivity of 85% to 88% and specificity of 88% to 100%. ¹⁰ The areas of sinusoidal dilation enhance during the venous phase, whereas the remaining tumor enhances in the arterial phase. ⁹

FIG 3.

I‐HCA. Pathologically proved inflammatory adenoma shows an incomplete rim of hyperintensity (arrows) on T₂‐weighted imaging (A), referred to as the “atoll sign.” Arterial enhancement is seen (B), which persists on the portal venous phase (C). The lesion is hypointense on 20‐minute delayed hepatobiliary phase image (D) because of the lack of normal functioning hepatocytes.

β‐HCAs are without specific imaging features but commonly show arterial enhancement. They may mimic HCC with washout on the portal venous or delayed phase. ⁷ In one study of five β‐HCAs, two adenomas showed arterial enhancement with washout. ¹⁰ The other three showed inflammation on histology and had similar enhancement to I‐HCAs. ¹⁰ In another study of four β‐HCAs, 75% showed poorly demarcated T₂‐hyperintense scars that enhance on portal venous phase. ⁹ β‐HCA can also show isointensity/hyperintensity on hepatobiliary phase. Organic anion transporting polypeptide 1B3 (OATP1B3), which transports gadolinium‐based hepatobiliary MRI contrast agents into hepatocytes during the hepatobiliary phase, is a downstream target of the Wnt/B‐catenin signaling pathway. β‐HCAs overexpress OATP1B3 and thus can show enhancement on hepatobiliary phase without known specific imaging findings. ⁶

U‐HCAs are also without no known specific imaging findings.

Management

Historically, HCAs were managed primarily based on size with size cutoff of 5 cm because of the higher risk for hemorrhage and malignant transformation. ¹¹

Further risk stratification is possible when using size and phenotype to help guide management (Fig. 4). One suggested practice guideline was published by the European Association for the Study of the Liver in 2016. ¹ All presumed HCAs in women should undergo contrast‐enhanced MRI after 6 months. For I‐HCA and H‐HCA in women, conservative management is recommended, including discontinuation of OCPs and weight loss. On follow‐up imaging, resection is considered for masses that remain >5 cm or show significant growth. Masses that measure <5 cm or have decreased in size on follow‐up imaging can undergo annual surveillance with MRI or ultrasound. Lesions that are stable or smaller after 5 years can be considered for follow‐up imaging every 2 years.

FIG 4.

Management of HCA.

Resection is recommended for β‐HCA because of the high risk for malignant transformation. Resection is recommended for HCA in male patients, regardless of size, because of the higher likelihood of β‐HCA being present. ¹

Biopsy may be considered for those adenomas that cannot be confidently classified as H‐HCA or I‐HCA and are thus indeterminate by MRI. ¹²

For HCA requiring resection, nonsurgical treatments, such as thermal ablation, may be considered if the patient is a poor surgical candidate. ¹ If nonsurgical treatment is pursued, biopsy is recommended prior to therapy. ¹

Foci of hemorrhage within HCA are not an indication for intervention. ¹ Clinically significant hemorrhage can be managed based on severity, with management considerations ranging from observation to transfusion and embolization. ¹

Conclusion

Understanding the unique biology of HCA subtypes can allow for a more individualized approach in their management because of their varied risk for hemorrhage and malignant transformation. MRI is able to identify two subtypes, I‐HCA and H‐HCA, which can be conservatively managed. More research is needed to identify specific imaging features of the two remaining subtypes, β‐HCA and U‐HCA.