Hepatocellular adenoma classification: a comparative evaluation of immunohistochemistry and targeted mutational analysis

Elizabeth Margolskee, Fei Bao, Anne Koehne de Gonzalez, Roger K. Moreira, Stephen Lagana, Anthony N. Sireci, Antonia R. Sepulveda, Helen Remotti, Jay H. Lefkowitch, Marcela Salomao

Four subtypes of hepatocellular adenomas (HCA) are recognized: hepatocyte-nuclear-factor-1α mutated (H-HCA), β-catenin-mutated type with upregulation of glutamine synthetase (b-HCA), inflammatory type (IHCA) with serum-amyloid-A overexpression, and unclassified type. Subtyping may be useful since b-HCA appear to have higher risk of malignant transformation. We sought to apply subtype analysis and assess histological atypia, correlating these with next-generation sequencing analysis. Twenty-six HCA were stained with serum amyloid A (SAA), liver fatty acid-binding protein (LFABP), glutamine synthetase (GS), and β-catenin IHC, followed by analysis with a targeted multiplex sequencing panel. By IHC, 4 HCA (15.4 %) were classified as b-HCA, 11 (42.3 %) as IHCA, 9 (34.6 %) as H-HCA, and two (7.7 %) unclassifiable. Eight HCA (30.8 %) showed atypia (3 b-HCA, 4 IHCA and 1 H-HCA). Targeted sequencing confirmed HNF1A mutations in all H-HCA, confirming reliability of LFABP IHC in identifying these lesions. CTNNB1 mutations were detected in 1 of 4 (25 %) of GS/β-catenin-positive cases, suggesting that positive GS stain does not always correlate with CTNNB1 mutations. Immunohistochemistry does not consistently identify b-HCA. Mutational analysis improves the diagnostic accuracy of β-catenin-mutated HCA and is an important tool to assess risk of malignancy in HCA.