INTRODUCTION

Hepatocellular adenomas (HCAs), a heterogeneous group of benign monoclonal liver tumors derived from mature hepatocytes, have undergone significant reclassification over the past few decades. Initially considered a singular entity when first described in the 1970s,¹ HCAs now encompass multiple subtypes, with distinct molecular pathways, risk factors, and prognoses. Insights into the molecular and immunohistological mechanisms in HCAs have led to the establishment of a genotype-phenotype classification system, reflected in the 2019 World Health Organization (WHO) classification of digestive system tumors.²

The first major molecular insights emerged in 2006 with the identification of four HCA subtypes: inflammatory HCA (IHCA), hepatocyte nuclear factor 1α-inactivated HCA (HHCA), β-catenin-activated HCA (βHCA), and unclassified HCA (UHCA).^3,4 Subsequent advancements have led to further refinement of this classification, with additional subtypes of β-cateninmutated exon 3 HCA (βHCA^exon3), β-catenin-mutated exon 7/8 HCA (βHCA^exon7/8), mixed types of β-catenin-activated and inflammatory subtypes HCA (βIHCA), and sonic hedgehog HCA (shHCA) being added to the classification system (Table 1).^5,6 These updates enhance our understanding of HCAs through the lens of molecular diversity. Subtyping of HCAs is clinically important because the rates of malignant transformation and symptomatic bleeding, the two major complications of HCA, vary greatly on the subtypes (Table 1).^7,8 However, expensive genomic sequencing, not widely available in routine clinical practices (especially for benign tumors such as HCAs), must be performed to facilitate this sophisticated molecular subtyping. Some studies suggested that findings on immunohistochemical staining can be used as surrogate markers for molecular characterization of HCAs (Table 1).

Advanced imaging techniques, particularly magnetic resonance imaging (MRI) with hepatobiliary contrast agents, hold the potential for facilitating the non-invasive differentiation of HCA subtypes.^9-13 The integration of imaging findings with clinical and molecular insights enables accurate subtype identification and risk stratification, thereby guiding clinical decisionmaking and potentially suggesting additional immunohistochemical staining for further characterization of HCAs.¹⁴

HCAs have been mainly reported in Western countries such as France and the United States. Although traditionally considered rare, the incidence of HCAs is increasing globally, owing to a combination of improved imaging techniques, rising obesity rates, and heightened awareness.^15-17 Recent studies conducted in Asian population have also reported an increase in the incidence of HCA.^9,18,19 Notably, differences in HCA epidemiology and subtype distribution have been observed between Asian and Western populations. This review discusses the molecular classification of HCAs based on the 2019 WHO classification and highlights geographic variations in epidemiology and subtype distribution. Furthermore, it examines the clinical characteristics and imaging features of each HCA subtype, presenting their implications for diagnostic and management strategies with a particular focus on the risk of hepatocellular carcinoma (HCC).

EPIDEMIOLOGY AND CLINICAL CHARACTERISTICS OF HCAS IN ASIA

Most reports of HCA originate in Western population. However, several cases from Asian population have been reported in recent years (Table 2). HCAs occur in women of childbearing age in Western population. Prolonged use of oral contraceptives is a significant risk factor, increasing the incidence by 30-40-fold. Other risk factors include anabolic steroid use, obesity, alcohol consumption, and certain genetic conditions (i.e., MODY 3 diabetes, glycogenosis). In contrast, HCAs in Asian populations exhibit distinct demographic and clinical characteristics (Table 3). The age distribution is similar (mean age of 35-39 years); however, 39-70% of patients are males in Asia,^9,18-22 compared with 0-16% in Western population.^5,8,11,23 This disparity may be attributed to the differences in the underlying risk factors, such as hormonal exposure and metabolic profiles. Obesity rates among patients with HCA in Asia range from 14-50%, slightly higher than 16-34% in Western population.^9,18-21 However, the use of oral contraceptives is notably lower (0-29%) compared to Western population (70-87%).^9,18-22 These findings suggest an expanded role for non-hormonal metabolic factors, such as obesity, in the pathogenesis of HCAs in Asia.

The distribution of the molecular subtypes of HCAs further emphasizes the differences. HHCAs and IHCAs are the two most common subtypes in Western population (accounting for 30-45% of cases each), followed by βHCAs (10-12%).^5,24 In contrast, IHCA, accounting for 38-50% of cases, is the most prevalent subtype in Asian population, followed by βHCAs, which account for 9-26% of cases.^9,18,20,21 HHCAs are far less prevalent in Asian population, representing only 7-16% of cases. To the best of our knowledge, no previous report has evaluated shHCAs in Asian population, likely because molecular biology is required to accurately identify this subgroup (inhibin β E gene with glioma-associated oncogene 1 [INHBE-GLI1] fusion), but it is not routinely performed in clinical practice. These differences in the subtype distribution may be attributed to the lower prevalence of oral contraceptive use in Asia,^9,18,20,21 coupled with the influence of metabolic factors more strongly associated with IHCAs and βHCAs.^5,9 For instance, a male predominance was particularly evident in terms of IHCAs (59%) and βHCAs (46%)^5,9 in Asian populations. These distinct epidemiological and clinical characteristics must be considered when diagnosing and treating these tumors in clinical practice in Asian population.

CLINICOPATHOLOGIC AND IMAGING FEATURES OF HCA MOLECULAR SUBTYPES

HNF1-α inactivated subtype

HHCAs, which represent 7-16% of HCAs in Asian populations,^9,18,20,21 are caused by an inactivating mutation of the hepatocyte nuclear factor 1α (HNF1A) gene. HNF-1α, a tumor suppressor and key hepatocyte transcription factor, regulates liver fatty acid-binding protein (L-FABP) and organic anion transporter proteins.^25,26 L-FABP facilitates fatty acid trafficking, and its downregulation leads to intracellular fat accumulation. Histologically, HHCAs are characterized by the presence of macrovesicular fat in the tumor cells on hematoxylin-eosin (H&E) staining, and loss of L-FABP staining on immunohistochemistry (Table 1).^25,27

This subtype is associated with a low risk of malignant transformation or bleeding. It is least associated with obesity but shows a stronger link to oral contraceptive use. This subtype is also most frequently associated with adenomatosis, with the presence of >10 concomitant adenomas.²⁸

HHCAs are typically well-defined, homogeneous tumors of <5 cm (90%) that predominantly affect females (88-90%) in Asian and Western populations.^5,9,11,29 Homogeneous intra-tumoral fat, the hallmark imaging feature of this subtype observed in 78-100% of cases, manifests as a diffuse signal drop on the out-of-phase sequence compared with that on the in-phase MRI sequences (Fig. 1).^{9-11,20,29-33} These tumors often exhibit iso- or hypo-intensity on fat-suppressed sequences, such as fat-suppressed T2-weighted imaging (T2WI) and diffusion-weighted imaging. Dynamic contrast-enhanced imaging also reveals characteristic patterns. For instance, an arterial phase high signal intensity (SI) compared to the surrounding liver (50%) is less frequent than other subtypes (84-94%), and most tumors exhibit a lower SI relative to the liver on the portal venous phase (96%), a sharp contrast to other subtypes (12-16%).⁹ These unique imaging patterns with diffuse and homogenous intra-tumoral fat help differentiate HHCAs from other subtypes, with intra-tumoral fat (4-19% of cases) rarely exhibiting a diffuse, homogeneous distribution. HHCAs are the most common subtype to exhibit metabolic uptake on 18F-fluorodeoxyglucose positron emission tomography (88% of cases).⁹ This uptake may be attributed to the overexpression of glucose transporter type 1 rather than actual hypermetabolic activity.^34-36

Inflammatory subtype

IHCAs account for 38-50% of all HCAs in Asia.^9,18,20,21 IHCAs are characterized by sustained activation of the interleukin-6/Janus kinase/signal transducer and activator of transcription (IL-6/JAK/STAT) pathway owing to somatic gain-of-function mutations (Table 1).^5,37 On H&E staining, sinusoidal dilatation and congestions of variable degrees are shown, with pseudoportal tracts with inflammation, large arteries, and ductular reaction.⁶ Immunohistochemistry has revealed that the serum amyloid A and C reactive protein, two proteins of acute phase inflammation, are overexpressed in the hepatocyte cytoplasm of the tumor.³⁸

IHCAs are associated with a low risk of malignant transformation or bleeding, except for βIHCAs that have a high risk of malignant transformation. IHCAs are observed more frequently among male patients in Asia, with obesity being a significant risk factor.⁹ Additionally, patients with IHCAs exhibit higher rates of at-risk drinking, smoking, diabetes, and hypertension,⁹ suggesting a potential link to metabolic risk factors. In contrast, in Western populations, this subtype shows a female predominance and is strongly associated with oral contraceptive use.³⁹

In addition to the general characteristics of IHCA, a subset of IHCAs have a mutation in the cadherin-associated protein β1 (CTNNB1) gene at exon 3 or exon 7/8, a characteristic feature of βHCAs, yielding βIHCA. These represent approximately 8% (exon 3) and 5% (exon 7/8) of all HCAs.⁷ βIHCAs with exon 3 mutations (βIHCA^exon3) share a high risk of malignant transformation with pure βHCAsexon3. Therefore, additional immunohistochemical staining of all IHCAs is necessary to exclude coexisting CTNNB1 mutations.

IHCAs present as well-defined tumors in the background of the steatotic liver (55%) (Fig. 2).⁹ Most IHCAs (94%) demonstrate arterial phase hyperenhancement, with persistent hyper-or isointensisty on delayed phase images (88%).^9,30,33 Reports on the frequency of hepatobiliary phase (HBP) iso or high SI in IHCAs are inconsistent, with some studies reporting frequencies of 26-57%.^32,40,41 However, these studies did not differentiate IHCAs from βIHCAs. Studies that specifically subcategorized βIHCAs have reported a lower incidence of HBP iso or high SI in IHCAs (9-10%).^9,11 Thus, iso- or hyperintensity during HBP may not be considered a characteristic feature of IHCAs but rather a feature of βHCAs. βIHCAs exhibit a combination of the imaging features of IHCAs and βHCAs, thereby hindering their differentiation (Fig. 3). Similar to pure βHCAs, βIHCA lesions exhibit iso- or hyperintensity during the HBP phase (71%) according to their β-catenin activation status. Furthermore, they also exhibit substantial background liver steatosis (57%).⁹ The atoll sign, characterized by marked hyper SI on T2WI in the peripheral portion of the lesions -owing to sinusoidal dilatation- has been observed in 81%³⁰ and 58%¹¹ of IHCAs in two studies. However, other studies have reported that this feature occurs in 12-38% of cases.^9,20,32,33

β-catenin-activated subtype

βHCAs accounts for 9-26% of cases of HCAs in Asia.^9,18,20,21 βHCAs are a distinct molecular subtype of HCAs, with activating mutations in the CTNNB1 gene at exon 3 or exon 7/8 (Table 1). These mutations lead to variable activation of the Wnt/β-catenin signaling pathway, thereby playing a central role in liver zonation, embryogenesis, regeneration, and amino acid metabolism.^42,43 The specific mutation site (exon 3 vs. exon 7/8) has significant clinical and pathological implications. βHCA^exon3 strongly activates the Wnt/β-catenin pathway, whereas βHCA^exon7/8 induces mild activation of the Wnt/β-catenin pathway.^3,4,44 Common features on H&E staining include cytological atypias, pseudoglandular/acinar architecture, small-cell liver change and cholestasis.⁶ βHCA^exon3 is characterized by nuclear translocation of β-catenin and overexpression of glutamine synthase (GS) on immunohistochemistry. βHCA^exon7/8 exhibits no nuclear translocation of β-catenin and yields only a slight increase in GS expression,⁴⁵ thereby limiting definite diagnosis without DNA/RNA sequencing.^45,46

βHCA^exon3 is are associated with the highest risk of malignant transformation among HCAs, with rates reaching 40%,⁴ in contrast, βHCA^exon7/8 has a negligible risk of malignant transformation.^8,47 βHCA^exon7/8 have been reported to be associated with microscopic bleeding without symptoms, though the extent of this association remains a topic of discussion in the literature. These mutations are linked to androgenic steroid use, vascular liver diseases, and male sex, with 30-40% of cases occurring in men.⁵

βHCAs exhibit distinct characteristics on gadoxetate disodium-enhanced MRI that can aid in their identification (Fig. 4). The iso- or hyperintensity on the HBP, observed in >80% of cases,^9,11,13 is a key distinguishing feature associated with increased organic anion transporting polypeptide 1B3 (OATP1B3) expression, driven by the activation of Wnt/β-catenin pathway.^48,49 They are also larger in size than other subtypes and exhibit substantial tumor heterogeneity (84%) attributable to common intra-tumoral necrosis or hemorrhage.⁹ Vaguely defined central scars, which appear as T2-hyperintense central lines enhancing in the late venous phase, are observed in 16-71% of tumors.^9,31

Imaging features to differentiate βHCA^exon3 from βHCA^exon7/8 have not been identified; however, strong nuclear β-catenin expression can be a possible substitute for DNA/RNA sequencing to identify βHCA^exon3. Studies from France and Korea^9,13,50 have reported that high SI on HBP can serve as a biomarker for marked β-catenin activation in HCAs, which is suggestive of a higher risk for malignant transformation.

Sonic hedgehog subtype

shHCAs, the most recently identified subtype of HCAs, represent approximately 4% of HCAs in Western population.⁵ However, they have not been reported in Asian population, probably due to the fact that DNA/RNA sequencing is not widely performed in clinical practice. shHCAs are characterized by the activation of the sonic hedgehog pathway through focal deletions that fuse the promoter of the INHBE-GLI1 (Table 1).⁵ No specific microscopic features on H&E staining have been described. On immunohistochemical staining, shHCA may express argininosuccinate synthase 1 or prostaglandin D2 synthase; however, their reliability as robust markers for identifying this subgroup has yet to be validated.⁵¹

Surgical resection of shHCAs is recommended as they carry a very high risk of symptomatic hemorrhage (71-91%).^5,52 These tumors predominantly affect females, with oral contraceptive use and obesity being primary risk factors.

Only one study has described the imaging features of shHCAs. Ducatel et al.⁵² evaluated 35 cases and identified fluid-filled cavities on T2-weighted MRI sequences in 46% of shHCAs (Fig. 5). Hemorrhage or necrosis (71%) and background liver steatosis (66%) are other commonly observed imaging features.⁵²

Unclassified subtype

UHCAs account for 4-27% of HCAs in Asian population.^9,18,20,21 UHCAs are those that cannot be classified as any of the established subtypes based on histological, molecular or immunohistochemical findings (Table 1). The clinical and imaging characteristics of UHCAs are poorly understood. Previous studies may have been confounded by incomplete subtyping, with a significant portion likely representing shHCAs or βHCA^exon7/8 before the reclassification. UHCAs exhibit female predominance in Asian and Western populations.^5,9

UHCAs demonstrate a notably higher prevalence of ill-defined margins (40%) than other subtypes (0.0-4.1%), which are predominantly well-defined (Fig. 6).⁹ A large proportion of these tumors exhibit slightly hypointense SI on HBP (76.0%), defined as intensity lower than that of the surrounding liver but higher than that of the vessels.⁹

NON-INVASIVE IMAGING-BASED MODELS FOR DIFFERENTIATING THE HCA SUBTYPES AND HCC RISK PREDICTION

HCAs differ in terms of their risk of complications based on subtypes. Some subtypes require immediate resection owing to a higher risk of malignant transformation (e.g., βHCA^exon3 and βIHCA^exon3) or bleeding (e.g., shHCAs), whereas others are more suitable for follow-up.⁵³ Determining the subtypes of HCA currently requires pathologic specimens obtained through invasive procedures and expensive DNA/RNA sequencing. Thus, there is a pressing need for non-invasive methods to subtype HCAs accurately. Previous studies have explored imaging-based approaches to differentiate βHCA and βIHCA from the other subtypes as they carry a high risk for developing HCC, mainly based on MRI using either extracellular contrast agent or hepatobiliary contrast agent.^{9,11,13,30,31,50}

Tse et al.¹¹ proposed a stepwise imaging-based algorithm for determining HCA subtypes using gadoxetate disodium-enhanced MRI with an accuracy of 95%. This approach involves considering lesions exhibiting hyper-intensity on the HBP as βHCA or βIHCA after excluding HHCA and IHCA. However, this algorithm was developed using a single cohort and has not been validated. Furthermore, DNA/RNA sequencing was not performed to differentiate specific exon subtypes.

A simple 3-tier scoring system using gadoxetate disodium-enhanced MRI to predict βHCA or βIHCA was proposed by a group of Korean researchers.⁹ The scoring system assigns one point for each of the following imaging features: heterogeneous SI of the tumor, defined as two of more varying SI areas each constituting more than 20% of the tumor on T2WI or HBP image, and iso- or high SI of the tumor on HBP compared to the background liver parenchyma. The total score ranges from 0 to 2, with higher scores increasing the likelihood of βHCA or βIHCA. Based on their analysis, tumors with scores of 2, 1, and 0 have an 81.5%, 19.8%, 1.4% probability of being classified as βHCA or βIHCA, respectively. External validation of this scoring system demonstrated excellent performance (area under the curve, 0.91-0.92). SI on HBP imaging is correlated with histologically determined β-catenin activity, which can be considered as a surrogate marker for exon 3 mutations, consistent with the findings of studies in France.^13,50 Thus, high SI on HBP imaging of gadoxetic acid-enhanced MRI can serve as a biomarker to predict high HCC risks for HCAs.

CURRENT LIMITATIONS AND FUTURE DIRECTIONS

Several critical gaps remain in literature and clinical practice despite the significant advancements in the understanding of HCAs. Current guidelines and classification systems are predominantly based on DNA/RNA sequencing and data from Western populations.^8,54 Western guidelines recommend surgery for all male patients with HCAs, while in female patients, surgery is advised for HCAs >5 cm if they do not regress after discontinuation of oral contraceptives.^55,56 This approach may be appropriate in Western population, where HCAs are much less common in males, and male gender is independently associated with an increased risk of malignant transformation regardless of molecular subgroup. However, in Asia, approximately 60% of HCA cases occur in males, and a substantial number of HCAs with a lower risk of complications -such as pure IHCAs without CTNNB1 mutations- are unnecessarily subjected to surgery under Western guidelines. This discrepancy underscores the necessity for region-specific research and tailored management strategies. Furthermore, the role of environmental and lifestyle factors in the development of distinct HCA subtypes, particularly in Asia, warrants in-depth exploration.

DNA/RNA sequencing can overcome the limitations of traditional immunohistochemistry and improve the accuracy of subtype identification;^45,51 however, it has not been widely applied to benign tumors. DNA/RNA sequencing may be necessary to determine appropriate treatment plans for HCA after receiving pathological confirmation. Furthermore, imaging-based models must be validated and optimized for subtype differentiation combined with DNA/RNA sequencing data.

CONCLUSION

HCAs exhibit unique epidemiological characteristics and subtype distribution in Asia, setting them apart from those observed in Western population, and underscoring the requirement for region-specific diagnostic and management strategies. Recent advances in genomic characterization of HCAs have revealed distinct subtypes of HCAs with varying risks of complications such as malignant transformation. The βHCA^exon3 and βIHCA^exon3 subtypes are associated with high risks for HCC development. Thus, identifying these subtypes should be a primary focus when HCA is suspected clinically. When DNA/RNA sequencing is unavailable, additional immunohistochemical staining such as GS or analysis of β-catenin-stained nuclei staining should be performed to distinguish these high-risk subtypes. High SI on HBP imaging of gadoxetic enhanced MRI may serve as a surrogate marker for βHCA^exon3 and βIHCA^exon3. Current guidelines and classification systems based on Western data may not fully capture the clinical realities in Asia. Future studies must prioritize region-specific evaluations, further validation of imaging-based models, and integration of DNA/RNA sequencing to enhance diagnostic precision and patient care to develop management strategies that optimize outcomes of HCAs in Asia.

Article information

Conflicts of Interest

The authors have no conflicts to disclose.

Ethics Statement

This review article is fully based on articles which have already been published and did not involve additional patient participants. Therefore, IRB approval is not necessary.

Funding Statement

None.

Data Availability

Not applicable.

Author Contributions

Conceptualization: SH, SYK

Formal analysis: SH

Project administration: SYK

Resources: SH, IHS, ER, HYK, SHC, SYK

Supervision; MR, JCN, SYK

Validation; MR, JCN, SYK

Visualization: SH, ER, SYK

Writing - original draft: SH

Writing - review & editing: IHS, ER, MR, JCN, HYK, SHC, SYK

Figure 1.

Representative case of HNF1-α inactivated subtype of hepatocellular adenoma. Gadoxetic acid-enhanced liver MR images of a 39-year-old female revealed a 3 cm mass in liver segment 8 (white arrow). The tumor exhibits a homogeneous signal drop on the opposedphase image (A) compared with that of the in-phase image (B), suggesting diffuse fat deposition. On dynamic phases of liver MR imaging, compared with that of the background liver, the lesion shows lower signal intensity on pre-contrast image (C), similar signal intensity on arterial phase (D), and lower signal intensity on portal venous phase (E), and hepatobiliary phase (F). Over ten other sub-centimeter-sized hepatic lesions with similar characteristics are detected (arrowheads), suggesting adenomatosis. HNF1-α, hepatocyte nuclear factor 1α; MR, magnetic resonance.

Figure 2.

Representative case of an inflammatory subtype of hepatocellular adenoma. Gadoxetic acid-enhanced liver MR images of a 40-year-old male revealed a 2.8 cm mass (white arrow) in liver segment 6. The background liver shows signal drop on opposed-phase image (A) compared with that on the in-phase (B), suggesting background hepatic steatosis. The tumor exhibits higher signal intensity compared with that of the background liver on T2 weighted image (C) and pre-contrast T1 weighted image (D), strong arterial phase hyperenhancement (E), and maintains a higher signal intensity than that of the liver on portal venous phase (F). MR, magnetic resonance.

Figure 3.

Representative case of a β-catenin-activated inflammatory subtype of hepatocellular adenoma. Gadoxetic acid-enhanced liver MR images of a 21-year-old female revealed a 4.3 cm-sized mass in liver segment 1 (white arrow). The background liver shows signal drop on opposed-phase image (A) compared with that on the in-phase image (B), suggesting background hepatic steatosis. The tumor exhibits no evidence of an internal fat component. The tumor shows higher signal intensity compared with that of the background liver on T2 weighted image (C), demonstrates strong arterial phase hyperenhancement (D), and maintains a higher signal intensity than that of the liver on portal venous phase (E) and hepatobiliary phase (F). MR, magnetic resonance.

Figure 4.

Representative case of a β-catenin-activated subtype of hepatocellular adenoma. Gadoxetic acid-enhanced liver MR images of a 25-year-old female revealed a 15 cm-sized mass in the right hemi-liver (white arrow). The tumor exhibits heterogeneous iso to high signal intensity on T2-weighted image (A). The tumor contains internal bright signal intensity foci (white arrowhead) on the pre-contrast T1 weighted image (B) suggestive of hemorrhage. The solid portion of the tumor demonstrates arterial hyperenhancement compared with that of the background liver (C), no washout on portal venous phase (D) and transitional phase (E), and shows higher signal intensity than that of the liver on hepatobiliary phase (F). MR, magnetic resonance.

Figure 5.

Representative case of a sonic hedgehog subtype of hepatocellular adenoma. Extracellular fluid agent-enhanced liver MR images of a 46-year-old female/male revealed a 8.5 cm-sized mass in liver segment 3 (white arrow). The background liver shows signal drop on opposed-phase image (A) compared with that on the in-phase image (B), suggesting background hepatic steatosis. The tumor exhibits fluidfilled cavities (arrowhead) on the T2 weighted image (C), which does not show enhancement on portal venous phase image (D). MR, magnetic resonance.

Figure 6.

Representative case of an unclassified subtype of hepatocellular adenoma. Gadoxetic acid-enhanced liver MR images of a 32-year-old female revealed a 3.8 cm mass (white arrow) in liver segment 6. The tumor exhibits slightly high signal intensity on the T2 weighted image (A). The tumor shows iso-signal intensity on the pre-contrast T1 weighted image (B), faint arterial hyper-enhancement (C), iso-signal intensity on the portal venous (D) and transitional (E) phases, and slightly low signal intensity on the hepatobiliary phase image (F), defined as a signal intensity lower than that of the liver but higher than that of the vessels. The tumor exhibits ill-defined margins across all MR imaging sequences. MR, magnetic resonance.

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