Sala Margaux, Gonzales Delphine, Leste-Lasserre Thierry, Dugot-Senant Nathalie, Paradis Valérie, Di Tommaso Sylvaine, Dupuy Jean-William, Pitard Vincent, Dourthe Cyril, Sciarra Amedeo, Sempoux Christine, Ferrell Linda D, Clouston Andrew D, Miller Gregory, Yeh Mathew M, Thung Swan, Gouw Annette S H, Quaglia Alberto, Han Jing, Huan Ji, Fan Cathy, Crawford James, Nakanuma Yasuni, Harada Kenichi, le Bail Brigitte, Castain Claire, Frulio Nora, Trillaud Hervé, Possenti Laurent, Blanc Jean-Frédéric, Chiche Laurence, Laurent Christophe, Balabaud Charles, Bioulac-Sage Paulette, Raymond Anne Aurélie, Saltel Frédéric
BaRITOn Bordeaux Research in Translational Oncology University of Bordeaux INSERM UMR1053 Bordeaux France.
Neurocentre Magendie INSERM U1215 Bordeaux France.
Hepatol Commun. 2020 Apr 11;4(6):809-824. doi: 10.1002/hep4.1514. eCollection 2020 Jun.
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.
直到最近，10%的肝细胞腺瘤（HCA）仍未分类（未分类HCA，UHCA）。在未分类HCA中，音猬因子HCA（shHCA）由InhibinβE链启动子与GLI1融合的局灶性缺失所定义。前列腺素D2合酶被提议作为免疫标志物。同时，我们之前利用蛋白质组学分析的工作表明，大多数未分类HCA构成一种与精氨酸琥珀酸合酶（ASS1）过表达相关的同质亚型。为了阐明ASS1在HCA分类中的应用并避免对免疫组织化学染色的误解，本研究的目的是探讨（1）shHCA与ASS1过表达之间的联系，以及（2）ASS1过表达在诊断方面的临床相关性。对波尔多系列的未分类HCA病例进行了分子、蛋白质组学和免疫组织化学分析。对一个包含67例病例的大型国际系列进行了临床病理特征分析，包括ASS1免疫组织化学标记。在通过分子分析研究的15例病例中，ASS1过表达与shHCA亚组重叠，确立了ASS1过表达为shHCA的一个标志。此外，ASS1免疫标志物优于前列腺素D2合酶，且在22例shHCA中仅7例呈阳性。在67例未分类HCA病例中，58例（85.3%）ASS1过表达，4例ASS1阴性，5例ASS1无意义。在ASS1过表达解释存疑的情况下，尤其是在活检中进行的蛋白质组学分析，可为解释此类病例提供支持。ASS1过表达是已知有高出血风险的shHCA的一个特异性标志。因此，ASS1是HCA分类和临床诊断的一个额外工具。
