title: Hepatic adenomas with synchronous or metachronous fibrolamellar carcinomas: both are characterized by LFABP loss.
abstract: Rare hepatic adenomas are associated with synchronous or metachronous fibrolamellar carcinomas. The morphology of these adenomas has not been well described and they have not been subclassifed using the current molecular classification schema. We examined four hepatic adenomas co-occurring with or preceding a diagnosis of fibrolamellar carcinoma in three patients. On histological examination, three of the adenomas showed the typical morphology of HNF1-α inactivated adenomas, whereas one showed a myxoid adenoma morphology. All of the adenomas were negative for PRKACA rearrangements by Fluorescence in situ Hybridization (FISH) analysis. All four of the adenomas showed complete loss or significant reduction of liver fatty acid binding protein (LFABP) expression by immunohistochemistry. Interestingly, the fibrolamellar carcinomas in each case also showed loss of LFABP by immunohistochemistry. One of the fibrolamellar carcinomas was negative for PRKACA rearrangements by FISH, whereas the others were positive. To investigate if LFBAP loss is typical of fibrolamellar carcinomas in general, an additional cohort of tumors was studied (n=19). All 19 fibrolamellar carcinomas showed the expected PRKACA rearrangements and immunostains showed loss of LFABP in each case, consistent with HNF1-α inactivation. To validate this observation, mass spectrometry-based proteomics was performed on tumor-normal pairs of six fibrolamellar carcinomas and showed an average 10-fold reduction in LFABP protein levels, compared with matched normal liver tissue. In conclusion, hepatic adenomas co-occurring with fibrolamellar carcinomas show LFABP loss and are negative for PRKACA rearrangements, indicating they are genetically distinct lesions. These data also demonstrate that LFABP loss, which characterizes HNF1-α inactivation, is a consistent feature of fibrolamellar carcinoma, indicating HNF1-α inactivation is an important event in fibrolamellar carcinoma pathogenesis.
authors.affiliation: Division of Anatomic Pathology, Department of Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Rondell P
authors.identifier: 0000-0002-8686-4867
authors.initials: RP
authors.lastname: Graham
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Terracciano
authors.affiliation: Department of Dermatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meves
authors.affiliation: Proteomics Core, Medical Genome Facility, Mayo Clinic, Rochester, MN, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Vanderboom
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Surendra
authors.initials: S
authors.lastname: Dasari
authors.affiliation: Department of Anatomic Pathology, University of Washington Medical Center, Seattle, WA, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.affiliation: Division of Anatomic Pathology, Department of Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Torbenson
authors.affiliation: Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Cruise
mesh_terms: D000236:Adenoma / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis*; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics; D015536:Down-Regulation; D050556:Fatty Acid-Binding Proteins / Q000032:analysis*; D005260:Female; D050939:Gene Fusion; D015321:Gene Rearrangement; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008113:Liver Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D009378:Neoplasms, Multiple Primary / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000737:chemistry* / Q000235:genetics / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C494647:DNAJB1 protein, human; C493319:FABP1 protein, human; D050556:Fatty Acid-Binding Proteins; C496487:HNF1A protein, human; D050956:HSP40 Heat-Shock Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human