Hepatocellular adenomas (HCAs) are rare benign tumors divided into three main subgroups defined by pathomolecular features, HNF1A (H-HCA), mutated β-catenin (b-HCA), and inflammatory (IHCA). In the case of unclassified HCAs (UHCAs), which are currently identified by default, a high risk of bleeding remains a clinical issue. The objective of this study was to explore UHCA proteome with the aim to identify specific biomarkers. Following dissection of the tumoral (T) and nontumoral (NT) tissue on formalin-fixed, paraffin-embedded HCA tissue sections using laser capture methodology, we performed mass spectrometry analysis to compare T and NT protein expression levels in H-HCA, IHCA, b-HCA, UHCA, and focal nodular hyperplasia. Using this methodology, we searched for proteins which are specifically deregulated in UHCA. We demonstrate that proteomic profiles allow for discriminating known HCA subtypes through identification of classical biomarkers in each HCA subgroup. We observed specific up-regulation of the arginine synthesis pathway associated with overexpression of argininosuccinate synthase (ASS1) and arginosuccinate lyase in UHCA. ASS1 immunohistochemistry identified all the UHCA, of which 64.7% presented clinical bleeding manifestations. Interestingly, we demonstrated that the significance of ASS1 was not restricted to UHCA, but also encompassed certain hemorrhagic cases in other HCA subtypes, particularly IHCA. Conclusion: ASS1 + HCA combined with a typical hematoxylin and eosin stain aspect defined a new HCA subgroup at a high risk of bleeding. (Hepatology 2017;66:2016–2028)

中文翻译：

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精氨酸琥珀酸合酶1（ASS1）：未分类的肝细胞腺瘤和高出血风险的标志

肝细胞腺瘤（HCA）是罕见的良性肿瘤，分为由病理分子特征定义的三个主要亚组：HNF1A（H-HCA），突变的β-catenin（b-HCA）和炎性（IHCA）。对于当前默认识别的未分类HCA（UHCA），出血的高风险仍然是临床问题。这项研究的目的是探索UHCA蛋白质组，以鉴定特定的生物标记。使用激光捕获方法在福尔马林固定，石蜡包埋的HCA组织切片上解剖肿瘤（T）和非肿瘤（NT）组织后，我们进行了质谱分析，比较了H-HCA，IHCA， b-HCA，UHCA和局灶性结节性增生。使用这种方法，我们搜索了UHCA中特异调节的蛋白质。我们证明蛋白质组学概况允许通过识别每个HCA亚组中的经典生物标志物来区分已知的HCA亚型。我们观察到与UHCA中精氨酸琥珀酸合酶（ASS1）和精氨酸琥珀酸裂合酶过表达相关的精氨酸合成途径的特异性上调。ASS1免疫组织化学鉴定了所有UHCA，其中64.7％表现为临床出血表现。有趣的是，我们证明了ASS1的意义不仅限于UHCA，还包括其他HCA亚型，尤其是IHCA的某些出血病例。我们在UHCA中观察到与精氨酸琥珀酸合酶（ASS1）和精氨酸琥珀酸裂合酶过表达相关的精氨酸合成途径的特异性上调。ASS1免疫组织化学鉴定了所有UHCA，其中64.7％表现为临床出血表现。有趣的是，我们证明了ASS1的意义不仅限于UHCA，还包括其他HCA亚型，尤其是IHCA的某些出血病例。我们在UHCA中观察到与精氨酸琥珀酸合酶（ASS1）和精氨酸琥珀酸裂合酶过表达相关的精氨酸合成途径的特异性上调。ASS1免疫组织化学鉴定了所有UHCA，其中64.7％表现为临床出血表现。有趣的是，我们证明了ASS1的意义不仅限于UHCA，还包括其他HCA亚型，尤其是IHCA的某些出血病例。结论： ASS1 + HCA与典型的苏木精和曙红染色相结合，定义了一个新的HCA亚组，具有较高的出血风险。（《肝病学》 2017年； 66：2016- 2028年）