New Insights in the Management of Hepatocellular Adenoma

Anne J. Klompenhouwer; Robert A. de Man; Marco Dioguardi Burgio; Valerie Vilgrain; Jessica Zucman-Rossi; Jan N. M. Ijzermans


Liver International. 2020;40(7):1529-1537. 

In This Article


HCA results from a monoclonal benign proliferation of hepatocytes. Usually, tumour hepatocytes in HCA look similar to normal hepatocytes. During the last 20 years, genomics analyses of large series of hepatocellular adenomas enabled to progressively identify six major molecular subgroups and additional mixed subtypes of HCA. Each of these molecular subgroups are defined by specific gene mutations and pathway activations. They are all related to specific risk factors and show a various biological behaviour.

HNF1A Inactivated HCA (H-HCA)

The first molecular subgroup accounts for 30% to 40% of adenomas and is defined by a mutation inactivating HNF1A, a gene coding for Hepatocyte Nuclear Factor 1 Alpha. This is a transcription factor essential for the differentiation of hepatocytes.[16] HNF1A inactivation in hepatocytes leads to several metabolic alterations with an activation of lipogenesis.[17,18] As a result, HNF1A inactivated adenomas accumulate lipids in tumour hepatocytes leading to a characteristic homogeneous steatotic phenotype at histology, without inflammatory infiltrates. Multiple H-HCA is frequent in patients, and it is often referred to liver adenomatosis when more than 10 H-HCA are identified in the liver. In rare cases, familial liver adenomatosis has been described related to a Maturity Onset Diabetes type 3 (MODY3) with a transmitted HNF1A germline mutation.[7,19]

Inflammatory HCA (I-HCA)

I-HCA is the most frequent subtype (40%-50% of the cases), defined by the activation of STAT3, a major transcription factor of inflammation. In I-HCA, an activating mutation of one the factors of the IL6/STAT3 signalling pathway is identified targeting either IL6ST, FRK, STAT3, JAK1, GNAS1 or ROS1.[20–22] Each of these gene activations leads to the overexpression of the proteins of the acute inflammatory phase including SAA (serum amyloid protein) and CRP (C-reactive protein), by tumour hepatocytes. At histology, I-HCAs show marked inflammatory infiltrates together with a high vascularization combining small arteries and telangiectasia. Immunohistochemistry shows a typical staining of tumour hepatocytes using antibodies against SAA or CRP. I-HCA is frequently identified in obese patients and can be associated with alcohol intake. They are also frequent in patients with vascular liver diseases and finally multiple I-HCA and liver I-HCA adenomatosis are described.[19,21]

Beta-catenin Activated HCA (b-HCA)

ß-catenin is an important oncogene in the liver. Two types of mutations in the CTNNB1 gene have been identified in HCA, leading to an activation of ß-catenin.

Mutations or deletions at exon 3 of CTNNB1 are identified in 10 to 15% of HCA (bex3HCA). These alterations are well-known oncogenic mutations, that lead, in the vast majority of the cases, to a high activation of the WNT/ß-catenin pathway.[23,24] The histological phenotype of the tumour usually combines tumour cholestasis, cytological atypia and tumour dysplasia. Using immunohistochemistry, a homogeneous overexpression of GS (glutamine synthetase) is detected with a nuclear accumulation of ß-catenin in some cases. This subtype is frequently associated with a malignant transformation to hepatocellular carcinoma, particularly in males.[21,23]

Around 7 to 10% of HCA show atypical hotspot mutation at exon 7 or 8 of CTNNB1 (bex7,8HCA).[25] These mutations lead to a faint ß-catenin activation, and immunohistochemistry show only a heterogeneous and weak expression of glutamine synthetase without nuclear ß-catenin. Interestingly, malignant transformation to hepatocellular carcinoma has been described far less in CTNNB1 mutations in exon 7 or 8 as compared to exon 3.[26] Overall, b-HCA is not steatotic and do not show inflammatory infiltrates.[21,25]

Sonic Hedgehog Activated HCA (sh-HCA)

In 5% of all hepatocellular adenomas, an activation of GLI1, a major transcription factor of the sonic hedgehog pathway, is observed. As a consequence, sh-HCA shows an overexpression of specific genes such as PTGDS (Prostaglandin D2 Synthase) that can be demonstrated by immunohistochemistry.[21] Sh-HCA is frequently identified in obese patients and they are associated with a higher risk of bleeding. However, currently no other specific histological features are associated with this subtype.

Mixed Beta-catenin-inflammatory Adenoma (b-IHCA)

Mixed molecular subclasses showing both inflammatory and ß-catenin activation and resulting in bex3IHCA or b-ex7,8IHCA are observed in around 10% of the cases. Their histological pattern results from the combination of each subtype. In contrast, H-HCA or sh-HCA is almost never mixed with another molecular subtype.[21]

Unclassified HCA (U-HCA)

Overall, in less than 7%, HCA remain unclassified. They do not show specific histological features. An overview of all molecular subtypes, risk factors and biological behaviour is given in Figure 1.

Figure 1.

Overview of HCA subtypes