Can the molecular subtype of a benign liver tumor help indicate its risk of becoming cancerous?

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Hepatocellular adenomas (HCA) are rare benign tumors occurring mainly in women taking oral contraceptives. HCA bleed frequently but rarely transform into hepatocellular carcinoma (HCC).

This overview describes a pathomolecular classification based on the identification of recurrently mutated genes and good correlations between genotype and phenotype, with HCA subgroups characterized using immunohistochemical markers. The abstract does not specify a particular study design.

HNF1A-mutated HCA: Inactivating mutations affecting both alleles of HNF1A are identified in 35–40% of HCA. HNF1alpha-inactivated HCA have characteristic pathological features, including marked steatosis. Expression of FABP1, a target gene of HNF1A, is downregulated; absence of L-FABP expression identifies this subgroup.

Beta-catenin-mutated HCA: Mutations in beta-catenin that activate the Wnt/beta-catenin pathway account for 10–15% of HCA. These tumors show overexpression of glutamine synthetase and abnormal nuclear beta-catenin staining. Beta-catenin-activated HCA have a greater risk of malignant transformation and are difficult to distinguish from well-differentiated HCC.

Inflammatory HCA account for 50% of HCA and are defined by inflammatory infiltrates, sinusoidal dilatation, and thick-walled arteries. Small in-frame deletions targeting the IL-6 binding site on gp130 have been reported in 60% of inflammatory HCA. The inflammatory proteins serum amyloid A and C-reactive protein are overexpressed in tumor hepatocytes at both the mRNA and protein levels. Inflammatory HCA occur more frequently in patients with high body mass index; they can also carry beta-catenin mutations and therefore are probably at risk of HCC.

Unclassified HCA: Less than 10% of HCA express none of the phenotypic markers described above.

Because HCA subgroups differ noticeably in their clinical and prognostic features, phenotyping may become an important tool for planning HCA management.