当前位置: X-MOL 学术Liver Int. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Hepatocellular adenoma in men: Is it time for a precision approach?
Liver International ( IF 6.7 ) Pub Date : 2021-09-21 , DOI: 10.1111/liv.15050
Ezequiel Mauro 1 , Alejandro Forner 1, 2
Affiliation  

Although hepatocellular adenoma (HCA) is a very infrequent liver tumour, with a reported incidence of 0.07 per 100.000 inhabitants/year,1 it has gained great interest in the scientific community during the last 2 decades. The recent increase in HCA prevalence is markedly associated with the rising prevalence of obesity and the metabolic syndrome,2 and the widespread use of imaging techniques. In addition, based on genomic analysis, several molecular subtypes, all of them related to different risk factors, morphology and biological behaviour, have been described and have markedly contributed to the understanding of the oncogenic pathways involved in liver tumorigenesis.2 Contrary to other liver benign tumours, HCA may evolve to hepatocellular carcinoma (HCC), and this risk guides management. Size is closely correlated with the risk of complications—both haemorrhage and HCC development. Several studies have proved that in women, lifestyle changes, including cessation of oral contraceptives and control of body weight, are associated with tumour size regression.3, 4 Related to the sensitivity of HCA to hormones, most HCAs regress after menopause, and the risk of complications in post-menopausal women is negligible.5 More interestingly, molecular subtyping is highly associated with the risk of malignant transformation into HCC. Among the different subgroups, beta-catenin-activated HCA (β-HCA), with mutations or deletions at exon 3 of the CTNNB1 gene, exhibits the highest risk for malignancy, including those with mixed β-catenin and inflammatory activation.1, 6 Regrettably, methods for the molecular analysis of HCA are not currently sensitive enough for widespread application, and whether the risk of malignant transformation attributed to β-catenin activation is independent of clinical risk factors such as size, pattern of growth, or even the presence of underlying chronic liver disease (for instance, metabolic (dysfunction) associated fatty liver disease [MAFLD] associated with obesity), is currently undetermined.

HCA is rarely diagnosed in males, with a reported female:male ratio of 10:1.6 Remarkably, the incidence of HCA in males is increasing, probably due to the use of anabolic substances to increase muscle mass.6 HCA diagnosed in men have a higher risk of malignant transformation than in women (estimated as 50% in men compared with 5% in women),7 and this different course could be explained by the higher proportion of β-HCA in men. The higher incidence of malignant transformation in men, based on a very limited number of patients with associated clinical risk factors, is the main argument for recommending tumour resection, irrespective of size, for all HCA diagnosed in men.6, 8

In this issue of Liver International, van Rosmalen and collaborators provide a nationwide overview of diagnosis and management of HCA in men in the Netherlands with the aim of correlating histopathological, immunohistochemical and molecular findings with the clinical course of the disease.9 A total of 66 patients from 26 centres across a period of 20 years were included. The diagnosis made in the primary centre was classified as HCA, uncertain HCA/HCC or preferential HCC (these tumours were eventually diagnosed as HCC but HCA was suspected at some point in the workup). Based on expert revision of morphology, additional immunohistochemistry, and (eventually) next generation sequencing (NGS) targeting genes that were selected based on their suggested relevance in HCA and HCC development, the final diagnoses were formulated in 33 of the 66 patients. The final diagnoses after central review were: 20 HCA (30%), 26 uncertain HCA/HCC (39%) and 20 HCC (30%). After immunohistochemistry and NGS, 7 out of 20 HCA had dual β-catenin-activated and inflammatory adenoma (β-IHCA), 3 of them with CTNNB1 exon 3 mutation (βex3-IHCA) and 4 with CTNNB1 exon 8 mutation (βex8-IHCA). Remarkably, 4 out of the 7 β-catenin-activated HCA were identified by NGS, which were not yet identified by immunohistochemistry (homogeneous overexpression of glutamine synthetase, with a nuclear accumulation of β-catenin in some cases) and expert revision. Clinical data were available for 41/66 patients (62%); in 18 cases, an underlying liver disease was present and in only 2 patients the use of anabolic substances was reported.

Despite some evident limitations related to the retrospective study design, the lack of availability of clinical data in a relevant proportion of cases and the limited amount of tissue from biopsies that impeded from conducting full assessments, particularly NGS, this study provides one of the largest series of HCA in men to date and clearly reflects the difficulties in managing this rare disease in real clinical practice. Remarkably, after expert pathological revision with additional relevant stainings and genetic evaluation by NGS, the final diagnoses were modified in 50% of the patients. However, even after this further step in 26 out of 66 patients (39%), HCC could not be distinguished from HCA with certainty. Accordingly, HCA should be managed in large volume, highly experienced centres and in the setting of multidisciplinary teams. Another relevant finding is the unexpected low proportion of β-HCA after a meticulous investigation. Thus, the previously reported high risk of malignant degeneration of HCA in male patients might be explained by other associated risk factors such as the presence of underlying liver disease (particularly MAFLD and alcohol intake) or even because the lesion was already an HCC misdiagnosed as HCA. An open question that cannot been addressed by van Rosmalen et al is whether the management of HCA should be different in men. The retrospective study design and the small proportion of patients with ‘pure’ HCA impede any robust analysis and conclusion. Because most HCA were resected or transplanted, the natural history could not be assessed. On the basis of the results by van Rosmalen et al, we could advocate for an adequate stratification of patients through expert revision, including immunohistochemistry and NGS, and reserve resection for those patients with nodules bearing β-catenin mutations or uncertain HCA/HCC. This may provide a starting point to apply a more conservative approach including lifestyle change and close surveillance in confirmed HCA in male patients (Figure 1). Further prospective studies exploring this à le carte approach are needed, and they should come from international collaboration of highly experienced centres.

image
FIGURE 1
Open in figure viewerPowerPoint
Suggested management of a presumed hepatocellular adenoma (HCA) in men. MRI is the preferred imaging technique for HCA diagnosis and characterization. Referral patient to an expert centre should be mandatory. *Histomorphology revised by an expert liver pathologist. Consider additional stainings to eventually support the differentiation of HCA from HCC (glutamine synthetase, heat-shock protein 70 and glypican-3) and stainings to subtype HCA (for instance, glutamine synthetase, β-catenin, serum amyloid A, C-reactive protein and liver fatty acid binding protein). In doubtful cases, consider conducting NGS aimed at identifying β-catenin and occasionally hTERT mutations


中文翻译:

男性肝细胞腺瘤:是时候采用精确方法了吗?

虽然肝细胞腺瘤(HCA)是一种非常罕见的肝肿瘤,据称其每0.07居民100.000 /年,发病率1已经在过去的20年里获得了科学界的极大兴趣。最近 HCA 患病率的增加与肥胖和代谢综合征的患病率上升2以及成像技术的广泛使用显着相关。此外,基于基因组分析,已经描述了几种分子亚型,所有这些亚型都与不同的危险因素、形态和生物学行为有关,并且显着有助于了解参与肝脏肿瘤发生的致癌途径。2与其他肝脏良性肿瘤相反,HCA 可能演变为肝细胞癌 (HCC),这种风险指导管理。大小与并发症的风险密切相关——出血和 HCC 的发展。几项研究证明,在女性中,生活方式的改变,包括停止口服避孕药和控制体重,与肿瘤大小消退有关。3, 4与 HCA 对激素的敏感性有关,大多数 HCA 在绝经后会消退,绝经后妇女出现并发症的风险可以忽略不计。5更有趣的是,分子亚型与恶性转化为 HCC 的风险高度相关。在不同的亚组中,β-连环蛋白激活的 HCA (β-HCA) 的外显子 3 有突变或缺失。CTNNB1基因表现出最高的恶性肿瘤风险,包括那些具有混合 β-连环蛋白和炎症激活的基因。1, 6遗憾的是,HCA 的分子分析方法目前还不够灵敏,无法广泛应用,β-catenin 激活引起的恶变风险是否独立于临床风险因素,如大小、生长模式,甚至目前尚未确定是否存在潜在的慢性肝病(例如,与肥胖相关的代谢(功能障碍)相关脂肪肝 [MAFLD])。

HCA 很少在男性中被诊断出来,据报道女性与男性的比例为 10:1。6值得注意的是,男性 HCA 的发病率正在增加,这可能是由于使用合成代谢物质来增加肌肉质量。6男性诊断出的 HCA 比女性具有更高的恶变风险(估计男性为 50%,女性为 5%),7这种不同的过程可以用男性中较高的 β-HCA 比例来解释。基于非常有限数量的具有相关临床危险因素的患者,男性恶性转化的发生率较高,这是推荐对所有男性 HCA 诊断的肿瘤切除术的主要论据,无论大小。6、8

在本期Liver International 中,van Rosmalen 及其合作者提供了荷兰男性 HCA 诊断和管理的全国性概述,目的是将组织病理学、免疫组织化学和分子学发现与疾病的临床过程相关联。9共纳入 20 年期间来自 26 个中心的 66 名患者。初级中心的诊断被归类为 HCA、不确定的 HCA/HCC 或优先 HCC(这些肿瘤最终被诊断为 HCC,但在检查的某个时间点怀疑 HCA)。基于对形态学、额外免疫组织化学和(最终)下一代测序 (NGS) 靶向基因的专家修订,这些基因是根据它们在 HCA 和 HCC 发展中的建议相关性选择的,最终诊断是在 66 名患者中的 33 名中制定的。中央审查后的最终诊断为:20 例 HCA(30%)、26 例不确定的 HCA/HCC(39%)和 20 例 HCC(30%)。在免疫组织化学和 NGS 后,20 个 HCA 中有 7 个具有双重 β-连环蛋白激活和炎症性腺瘤 (β-IHCA),其中 3 个具有CTNNB1外显子 3 突变 (β ex3 -IHCA) 和具有CTNNB1外显子 8 突变的 4 (β ex8 -IHCA)。值得注意的是,7 种 β-连环蛋白激活的 HCA 中有 4 种是通过 NGS 鉴定的,它们尚未通过免疫组织化学(谷氨酰胺合成酶的均质过表达,在某些情况下具有 β-连环蛋白的核积累)和专家修订鉴定。41/66 名患者 (62%) 的临床数据可用;在 18 例中,存在潜在的肝病,只有 2 例报告了使用合成代谢物质。

尽管与回顾性研究设计相关的一些明显局限性、相关病例比例的临床数据缺乏可用性以及活检组织的数量有限阻碍了进行全面评估,特别是 NGS,但这项研究提供了最大的系列之一迄今为止,男性 HCA 的发病率并清楚地反映了在实际临床实践中管理这种罕见疾病的困难。值得注意的是,经过专家病理学修正、额外的相关染色和 NGS 遗传评估后,50% 的患者的最终诊断得到了修改。然而,即使在 66 名患者中的 26 名 (39%) 中进行了进一步的步骤之后,也无法确定地将 HCC 与 HCA 区分开来。因此,HCA 应该在大量、经验丰富的中心和多学科团队的环境中进行管理。另一个相关发现是经过细致调查后出乎意料的低比例β-HCA。因此,先前报道的男性患者 HCA 恶性变性的高风险可能是由其他相关的危险因素来解释的,例如存在潜在的肝脏疾病(特别是 MAFLD 和酒精摄入),或者甚至因为病变已经是 HCC 被误诊为 HCA . van Rosmalen 等人无法解决的一个悬而未决的问题是 HCA 的管理是否应该在男性中有所不同。回顾性研究设计和“纯”HCA 患者比例小阻碍了任何稳健的分析和结论。由于大多数 HCA 被切除或移植,因此无法评估自然病程。根据 van Rosmalen 等人的结果,我们可以提倡通过专家修订对患者进行充分分层,包括免疫组化和 NGS,并为那些带有 β-catenin 突变或不确定的 HCA/HCC 结节的患者保留切除术。这可能为应用更保守的方法提供一个起点,包括改变生活方式和密切监测男性患者确诊的 HCA(图 1)。需要进一步探索这种点菜方法的前瞻性研究,它们应该来自经验丰富的中心的国际合作。这可能为应用更保守的方法提供一个起点,包括改变生活方式和密切监测男性患者确诊的 HCA(图 1)。需要进一步探索这种点菜方法的前瞻性研究,它们应该来自经验丰富的中心的国际合作。这可能为应用更保守的方法提供一个起点,包括改变生活方式和密切监测男性患者确诊的 HCA(图 1)。需要进一步探索这种点菜方法的前瞻性研究,它们应该来自经验丰富的中心的国际合作。

图片
图1
在图形查看器中打开微软幻灯片软件
男性推定肝细胞腺瘤 (HCA) 的建议管理。MRI 是 HCA 诊断和表征的首选成像技术。将患者转诊到专家中心应该是强制性的。*组织形态学由专家肝脏病理学家修订。考虑额外的染色以最终支持 HCA 与 HCC(谷氨酰胺合成酶、热休克蛋白 70 和 glypican-3)的区分和 HCA 亚型的染色(例如,谷氨酰胺合成酶、β-连环蛋白、血清淀粉样蛋白 A、C 反应蛋白和肝脏脂肪酸结合蛋白)。在有疑问的情况下,考虑进行旨在识别 β-连环蛋白和偶尔 hTERT 突变的 NGS
更新日期:2021-09-22
down
wechat
bug