title: Inflammatory hepatocellular adenomas developed in the setting of chronic liver disease and cirrhosis.
abstract: Hepatocellular adenoma is considered to occur exclusively in non-fibrotic livers. It is a heterogeneous entity and a molecular classification is now widely accepted. The most frequent hepatocellular adenoma subtype, namely inflammatory adenoma, harbor somatic activating mutations of genes involved in the interleukin-6 pathway that lead to high C-reactive protein and serum amyloid A expression. The aim of our study was to investigate a series of benign hepatocellular neoplasms developed on cirrhotic livers and characterized by an unequivocal histological diagnosis. We performed a clinical, pathological, and molecular study of 10 benign hepatocellular neoplasms developed in three patients with cirrhosis. Markers allowing hepatocellular adenoma classification were assessed by quantitative real-time PCR and immunohistochemistry. Samples were sequenced for CTNNB1, HNF1A, IL6ST, GNAS, STAT3, and TERT (promoter) mutations. A control series of 32 classical macronodules developed in cirrhosis related to various etiologies was screened by immunohistochemistry and gene sequencing. The three patients had cirrhosis related to metabolic syndrome and/or alcohol intake; two had a single tumor, while the third developed more than 30 lesions. Microscopic examination showed well-differentiated neoplasms sharing features with inflammatory adenoma including inflammatory infiltrates, sinusoidal dilatation, and dystrophic vessels. Sequencing revealed classical hotspot somatic mutations (IL6ST, n=8; STAT3, n=1; and GNAS, n=1) known to be responsible for IL-6/JAK/STAT pathway activation. Two classical high-grade macronodules demonstrated high serum amyloid A and/or C-reactive protein expression, without gene mutations. Altogether, our findings support the existence of rare inflammatory adenoma developed in cirrhosis.
authors.affiliation: Département de Pathologie, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.|Université Paris Est Créteil, Créteil, France.|Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.affiliation: Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Paris, France.|Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.|Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie humaine, Bobigny, France.|Liver Unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance Publique-Hôpitaux de Paris, Bondy, France.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Nault
authors.affiliation: Inserm, UMR-1053, Université Bordeaux Segalen, Bordeaux, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.affiliation: Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Paris, France.|Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.affiliation: Department of Pathology, CHU Pasteur, Nice, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Saint-Paul
authors.affiliation: Department of Digestive and Hepatobiliary Surgery, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Azoulay
authors.affiliation: Département de Pathologie, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.
authors.forename: Dalila
authors.initials: D
authors.lastname: Mehdaoui
authors.affiliation: Department of Medical Imaging, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Luciani
authors.affiliation: Département de Pathologie, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.
authors.forename: Elie S
authors.initials: ES
authors.lastname: Zafrani
authors.affiliation: Inserm, UMR-1053, Université Bordeaux Segalen, Bordeaux, France.|Department of Pathology, Pellegrin Hospital, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.affiliation: Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Paris, France.|Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Jessica
authors.identifier: http://orcid.org/0000-0002-5687-0334
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D018248:Adenoma, Liver Cell / Q000150:complications / Q000235:genetics / Q000473:pathology*; D000328:Adult; D002864:Chromogranins; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D058625:End Stage Liver Disease / Q000150:complications / Q000235:genetics / Q000473:pathology*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000150:complications / Q000235:genetics / Q000473:pathology*; D008113:Liver Neoplasms / Q000150:complications / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D002864:Chromogranins; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C494199:IL6ST protein, human; D050796:STAT3 Transcription Factor; D051176:beta Catenin; D050822:Cytokine Receptor gp130; C509186:TERT protein, human; D019098:Telomerase; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs