Subtype classification of hepatocellular adenoma.

Area of Science:

• Hepatobiliary pathology
• Tumorigenesis
• Molecular classification of liver tumors

Background:

• Hepatocellular adenomas (HCA) are rare benign liver tumors primarily affecting women using oral contraceptives.
• HCAs can bleed and rarely transform into hepatocellular carcinoma.
• Genetic mutations and genotype/phenotype correlations form the basis for HCA classification.

Purpose of the Study:

• To present a pathomolecular classification of HCA subgroups.
• To correlate genetic mutations with specific immunohistochemical markers and clinical features.
• To highlight the clinical and prognostic significance of HCA phenotyping.

Main Methods:

• Identification of recurrent gene mutations in HCA (HNF1A, beta-catenin).
• Immunohistochemical analysis for specific markers (L-FABP, glutamine synthetase, beta-catenin).
• Assessment of inflammatory markers (serum amyloid A, C-reactive protein) and histological features.

Main Results:

• HNF1A-mutated HCA (35-40%) show biallelic inactivating mutations, steatosis, and downregulated L-FABP.
• Beta-catenin-mutated HCA (10-15%) exhibit Wnt/beta-catenin pathway activation, glutamine synthetase overexpression, and increased malignant transformation risk.
• Inflammatory HCA (50%) are characterized by inflammatory infiltrates, IL-6 pathway alterations, and overexpression of inflammatory proteins; associated with higher BMI and potential beta-catenin mutations.

Conclusions:

• HCA classification into HNF1A-mutated, beta-catenin-mutated, and inflammatory subtypes is supported by distinct molecular and phenotypic features.
• Beta-catenin-activated HCA carry a higher risk of malignant transformation and can mimic well-differentiated HCC.
• Phenotyping HCA based on these subgroups is essential for guiding clinical management and prognosis.