ASS1 Overexpression: A Hallmark of Sonic Hedgehog Hepatocellular Adenomas; Recommendations for Clinical Practice

Margaux Sala, Delphine Gonzales, Thierry Leste-Lasserre, Nathalie Dugot-Senant, Valerie Paradis, Sylvaine Di Tommaso, Jean-William Dupuy, Vincent Pitard, Cyril Dourthe, Amedeo Sciarra, Christine Sempoux, Linda D. Ferrell, Andrew D. Clouston, Gregory Miller, Mathew M. Yeh, Swan Thung, Annette S. H. Gouw, Alberto Quaglia, Jing Han, Ji HuanCathy Fan, James Crawford, Yasuni Nakanuma, Kenichi Harada, Brigitte le Bail, Claire Castain, Nora Frulio, Herve Trillaud, Laurent Possenti, Jean-Frederic Blanc, Laurence Chiche, Christophe Laurent, Charles Balabaud, Paulette Bioulac-Sage, Anne Aurelie Raymond, Frederic Saltel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Until recently, 10% of hepatocellular adenomas (HCAs) remained unclassified (UHCA). Among the UHCAs, the sonic hedgehog HCA (shHCA) was defined by focal deletions that fuse the promoter of Inhibin beta E chain with GLI1. Prostaglandin D2 synthase was proposed as immunomarker. In parallel, our previous work using proteomic analysis showed that most UHCAs constitute a homogeneous subtype associated with overexpression of argininosuccinate synthase (ASS1). To clarify the use of ASS1 in the HCA classification and avoid misinterpretations of the immunohistochemical staining, the aims of this work were to study (1) the link between shHCA and ASS1 overexpression and (2) the clinical relevance of ASS1 overexpression for diagnosis. Molecular, proteomic, and immunohistochemical analyses were performed in UHCA cases of the Bordeaux series. The clinico-pathological features, including ASS1 immunohistochemical labeling, were analyzed on a large international series of 67 cases. ASS1 overexpression and the shHCA subgroup were superimposed in 15 cases studied by molecular analysis, establishing ASS1 overexpression as a hallmark of shHCA. Moreover, the ASS1 immunomarker was better than prostaglandin D2 synthase and only found positive in 7 of 22 shHCAs. Of the 67 UHCA cases, 58 (85.3%) overexpressed ASS1, four cases were ASS1 negative, and in five cases ASS1 was noncontributory. Proteomic analysis performed in the case of doubtful interpretation of ASS1 overexpression, especially on biopsies, can be a support to interpret such cases. ASS1 overexpression is a specific hallmark of shHCA known to be at high risk of bleeding. Therefore, ASS1 is an additional tool for HCA classification and clinical diagnosis.

Original languageEnglish
Pages (from-to)809-824
Number of pages16
JournalHepatology communications
Issue number6
Publication statusPublished - Jun-2020


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