Fischer Anne Kristin, Semaan Alexander, Wulf Anna-Lena, Vokuhl Christian, Goltz Diane, Fischer Hans-Peter
Institute of Pathology, University of Cologne, Kerpener Str. 62 50937, Germany.
Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Venusberg Campus 1, 53127 Bonn, Germany.
Int J Hepatol. 2023 Aug 9;2023:4313504. doi: 10.1155/2023/4313504. eCollection 2023.
The promoter mutation represents a common and early event in hepatocarcinogenesis, but its linkage to the morphological status of the underlying liver tissue is poorly understood. We analyzed the connection between the histopathological changes in tumor-bearing liver tissue and the occurrence of the promoter mutation in hepatocellular carcinoma (HCC), correlated with clinical data.
The study cohort comprised 160 histologically confirmed HCC in patients with or without cirrhosis that were investigated for the promoter mutation. We evaluated the frequency of the promoter mutation in patients with HCC with or without cirrhosis and correlated it with potential clinical and histopathological drivers. In particular, we examined tumor-bearing noncirrhotic liver tissue regarding inflammation; the modified histological activity index (mHAI), fibrosis, and steatosis; and its correlation with the frequency of the promoter mutation in HCC. We evaluated overall survival with multivariate Cox regression. Furthermore, we compared hTERT antibody immunohistochemistry and molecular promoter mutation analysis of both HCC and background liver tissue.
The promoter mutation was especially related to HCC in cirrhotic compared with noncirrhotic liver ( < 0.001) and independently of cirrhosis in patients ≥ 60 years ( = 0.005). Furthermore, the promoter mutation was associated with cirrhosis caused by alcohol toxicity and hepatitis C virus infection. In noncirrhotic liver tissue, the frequency of -promoter-mutated HCC increased with the degree of inflammation and fibrosis. Nevertheless, 25% of the -promoter-mutated HCC developed in normal liver tissue without HCC risk factors. Multivariate Cox regression analysis did not reveal an influence of the promoter mutation in HCC on overall survival at 3, 5, and 16 years. Immunohistochemical analysis with the hTERT antibodies LS-B95 and 2D8 in -promoter-mutated HCC and -wildtype HCC showed a mildly stronger immunoreaction compared with the tumor-bearing liver tissue (LS-B95: < 0.01, 2D8: < 0.01).
Our study reveals a connection between pathological changes in tumor-bearing liver tissue and the promoter mutation in most HCC, even in noncirrhotic liver tissue. Immunohistochemical hTERT antibodies do not discriminate between -promoter-mutated and wildtype HCC.
启动子突变是肝癌发生过程中常见的早期事件，但其与肝脏组织形态学状态的联系尚不清楚。我们分析了荷瘤肝组织的组织病理学变化与肝细胞癌（HCC）启动子突变发生之间的关联，并与临床数据进行了相关性分析。
研究队列包括160例经组织学确诊的HCC患者，有或无肝硬化，均对启动子突变进行了检测。我们评估了有或无肝硬化的HCC患者中启动子突变的频率，并将其与潜在的临床和组织病理学驱动因素进行相关性分析。特别是，我们检查了荷瘤非肝硬化肝组织的炎症情况、改良组织学活动指数（mHAI）、纤维化和脂肪变性情况，以及其与HCC中启动子突变频率的相关性。我们用多变量Cox回归评估总生存期。此外，我们比较了HCC及背景肝组织的hTERT抗体免疫组化和分子启动子突变分析。
与非肝硬化肝脏相比，启动子突变在肝硬化肝脏的HCC中更为常见（P<0.001），且在≥60岁患者中与肝硬化无关（P = 0.005）。此外，启动子突变与酒精性毒性和丙型肝炎病毒感染所致肝硬化有关。在非肝硬化肝组织中，启动子突变的HCC频率随炎症和纤维化程度增加而升高。然而，25%启动子突变的HCC发生于无HCC危险因素的正常肝组织中。多变量Cox回归分析未显示HCC中启动子突变对3年、5年和16年总生存期有影响。在启动子突变的HCC和野生型HCC中，用hTERT抗体LS-B95和2D8进行免疫组化分析显示，与荷瘤肝组织相比，免疫反应略强（LS-B95：P<0.01，2D8：P<0.01）。
我们的研究揭示了荷瘤肝组织的病理变化与大多数HCC（即使在非肝硬化肝组织中）启动子突变之间的联系。免疫组化hTERT抗体无法区分启动子突变的HCC和野生型HCC。
