Hepatocellular adenoma classification

The hepatocellular adenomas are classified on the basis of molecular patterns called phenotypic–genotypic classification into 4 major groups, including HNF1-alpha inactivated adenoma, beta-catenin activated adenoma, inflammatory hepatic adenoma and unclassified type adenoma.

• In 2007, Bioulac-Sage and associates from Bordeaux, classified the hepatocellular adenomas based on molecular patterns called phenotypic–genotypic classification. They classified hepatocellular adenomas into 4 main groups.^[1][2][3][4]

HNF-1 Alpha Inactivated Hepatocellular Adenoma (35 – 40%)

• This group of hepatocellular adenomas is defined by the somatic inactivation of HNF1A (hepatocyte nuclear factor 1 A) gene by a mutational mechanism in tumor cells.^[5]
• HNF1A is a transcription factor controlling hepatocyte metabolism.^[6]
• Most of these variants show macrovesicular steatosis of variable extent and no atypical hepatocytes and are associated with metabolic syndrome.
• This type occurs mostly in women and is often associated with maturity onset diabetes of young (MODY3).
• Expression of liver fatty acid binding protein (LFABP) involved in lipid trafficking, usually expressed in normal liver, is specifically down-regulated in these cases as a consequence of HNF1A mutation.

Inflammatory Hepatocellular Adenoma (40 – 50%)

• The most important feature of these tumors is activation of JAK/STAT pathway.^[7]
• Inflammatory hepatocellular adenoma also exhibits over expression of serum amyloid alpha (SAA) and C-reactive protein (CRP) induced by STAT3.
• They show greater morphological pleomorphism as they may show pseudo portal tracts, sinusoidal dilatation, dystrophic arteries, hemorrhage, and inflammatory infiltrate.
• Inflammatory syndrome, obesity, and alcohol consumption are reported in these patients.
• Five different molecular drivers, IL6 signal transducer, FRK, STAT3, GNAS, and JAK1 have been reported.^[8]

Beta-catenin Mutated Hepatocellular Adenoma (10 – 15%)

• These are frequently associated with exposure to male hormones, glycogenolysis, and familial adenomatous polyposis.^[9]
• This group has a higher risk of malignant potential.^[10]
• Morphologically, these tumors have cytological and architectural atypical features of tumoral hepatocytes as well as that of cholestasis.
• On immunohistochemical staining, these adenomas tend to stain for glutamine synthetase rather than beta catenin, which stains patchily.

Unclassified Hepatocellular Adenoma (10%)

• By definition, they lack characteristics of other sub-types and their identification relies on a silent phenotype and by exclusion of criteria featuring other sub-types.
• The exact underlying pathogenesis is not completely understood.
• These adenomas do not stain for the C-reactive protein (CRP), beta-catenin, or glutamine synthetase.^[11]

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