Hepatocellular adenomas (HCAs) are rare benign tumors. This single entity has been split into 3 subtypes corresponding to specific mutations: HNF1α-inactivated HCA; inflammatory HCA related to different mutations, all leading to activation of STAT3 pathway; and β-catenin–activated HCA related to CTNNB1 mutations. The risk of malignant transformation depends on the level of β-catenin activation, reported mainly for exon 3, including S45. It is possible using specific immunohistochemical markers to identify the 3 different HCA subtypes and the level of β-catenin activation. Fewer than 10% of HCAs remain unclassified.
Key points
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Hepatocellular adenoma (HCA) is a global entity encompassing several subtypes identified by specific mutations.
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Immunomarkers, liver-type fatty acid binding protein (LFABP) and C-reactive protein (CRP), allow the identification of the 2 major subtypes, hepatocyte nuclear factor (HNF) 1α-inactivated HCA (H-HCA) and inflammatory HCA (IHCA).
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Glutamine synthetase (GS) is a surrogate marker to identify β-catenin–activated HCA (β-HCA): homogeneous and diffuse for exon 3 mutation (outside S45) and heterogeneous and diffuse for exon 3 S45, both linked to potential malignancy.
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IHCA can be β-catenin mutated.
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β-Catenin mutation alone is not sufficient to induce malignancy. A second hit is necessary, such as telemorase reverse transcriptase promoter mutation.
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HCA classification using immunomarkers may require expertise, particularly on liver biopsy, and, if necessary, molecular confirmation.
HCAs are rare benign monoclonal liver tumors, described for the first time by Edmondson in 1953. HCAs have since been linked to the use of oral contraceptives by Baum and colleagues in 1973. The understanding of HCA was completely renewed when the 2 first underlying gene mutations were discovered in 2002, soon followed by others. These mutations are the basis of the genotype/phenotype classification of HCA discussed in this article.
Hepatocellular adenomas: genomics—the genotype classification
The first mutations responsible for the development of HCA were described in 2002, in Taiwan and in France. The first one is an activating mutation of CTNNB1 gene coding for β-catenin and the second corresponds to a biallelic inactivating mutation of HNF1A . Consequently, HCAs are classified today into 3 main categories : (1) HNF1A -mutated HCA [H-HCA] (35%–40%); (2) IHCA (40%–50%), with multiple mutated genes identified, mainly IL6 ; and (3) β-catenin–mutated HCA (β-HCA) (15%–20%). An additional important leap forward was made recently, in 2014 and 2016, when β-HCA was subdivided into several subgroups according to the degree of activation of β-catenin. β-Catenin mutation is also found in 10% of IHCA (β-IHCA). So far, fewer than 10% of HCAs remain unclassified HCAs (UHCAs).
HCAs, mainly β-HCA (discussed later), have a malignant potential and can evolve into hepatocellular carcinoma (HCC). The transformation depends on the occurrence of additional mutations. Telomerase reverse transcriptase (TERT) promoter mutations have been identified as responsible for this complication in half of the β-HCAs (mainly those showing mutations in exon 3). In HCC derived from HCA, the observed number of genetic alterations is much lower than in classic HCC.
The different mutated genes in HCA identified to date, in 2016, are presented in Box 1 .
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