title: Hepatocellular adenoma classification: a comparative evaluation of immunohistochemistry and targeted mutational analysis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th Street, VC14-238, New York, NY, 10032, USA. bethmargolskee@gmail.com.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Margolskee
authors.affiliation: Department of Pathology, Scripps Clinic, La Jolla, CA, USA. fbao03@gmail.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Bao
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th Street, VC14-238, New York, NY, 10032, USA. ak3304@cumc.columbia.edu.
authors.forename: Anne Koehne
authors.initials: AK
authors.lastname: de Gonzalez
authors.affiliation: Department of Pathology, Mayo Clinic, Rochester, MN, USA. Moreira.roger@mayo.edu.
authors.forename: Roger K
authors.initials: RK
authors.lastname: Moreira
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th Street, VC14-238, New York, NY, 10032, USA. sml2179@cumc.columbia.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lagana
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th Street, VC14-238, New York, NY, 10032, USA. ans2133@cumc.columbia.edu.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Sireci
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th Street, VC14-238, New York, NY, 10032, USA. as4400@cumc.columbia.edu.
authors.forename: Antonia R
authors.initials: AR
authors.lastname: Sepulveda
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th Street, VC14-238, New York, NY, 10032, USA. her2007@cumc.columbia.edu.
authors.forename: Helen
authors.initials: H
authors.lastname: Remotti
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th Street, VC14-238, New York, NY, 10032, USA. jhl3@cumc.columbia.edu.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lefkowitch
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th Street, VC14-238, New York, NY, 10032, USA. marcelafa@hotmail.com.
authors.forename: Marcela
authors.initials: M
authors.lastname: Salomao
mesh_terms: D018248:Adenoma, Liver Cell / Q000737:chemistry / Q000145:classification / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D050556:Fatty Acid-Binding Proteins / Q000032:analysis; D005260:Female; D005974:Glutamate-Ammonia Ligase / Q000032:analysis; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000737:chemistry / Q000145:classification / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012189:Retrospective Studies; D000685:Serum Amyloid A Protein / Q000032:analysis; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C493319:FABP1 protein, human; D050556:Fatty Acid-Binding Proteins; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D000685:Serum Amyloid A Protein; D051176:beta Catenin; D005974:Glutamate-Ammonia Ligase