Zhang Q Y, Chen L L, Gao F, Sujie Akesu, Hou Y Y, Huang X W, Huang C, Sun H C, Zhou J, Ji Y
Department of Pathology, Zhongshan Hospital of Fudan University, Shanghai 200032, China.
Department of Liver Surgery, Zhongshan Hospital of Fudan University, Shanghai 200032, China.
Zhonghua Bing Li Xue Za Zhi. 2020 Apr 8;49(4):329-335. doi: 10.3760/cma.j.cn112151-20190720-00403.
To compare the histologic features of immune-mediated hepatitis (IMH) due to immune checkpoint inhibitors (ICIs) monotherapy and combined ICIs anti-angiogenesis tyrosine kinases (TKIs) targeted therapy. Twenty-one IMH patients who had liver biopsy during ICIs treatment in Zhongshan Hospital of Fudan University from 2015 to 2019 were included. Among them, ten were treated with ICIs monotherapy, and 11 were treated with combined ICIs and anti-angiogenesis targeted therapy. The histologic features of IMH were assessed by HE staining and PD-L1/2 was evaluated by immunohistochemical staining. Patients treated with monotherapy ICIs presented with different levels of lobular hepatitis and portal inflammation. Besides, there were also cholangitis, endothelialitis, Kupffer cells activation and peliosisi hepatitis. Eight cases (8/10) showed mild and two cases (2/10) showed moderate hepatic injury. As for patients receiving combined ICIs and TKIs therapy, the extent of IMH was more severe, with four cases (4/11) showing moderate-severe liver injury, with confluent or bridging necrosis, portal inflammation, cholangitis, interface hepatitis. Among these, one patient developed acute severe hepatitis with massive hepatocyte necrosis and died of multisystem dysfunction. In those cases with severe liver injury, many CD8 positive lymphocytes aggregated in the portal area and hepatic sinusoid, and PD-L1 was expressed in many endothelial cells. There were both 2 cases of death in ICIs monotherapy and combination therapy group. Among the latter group, 1 patient developed acute severe hepatitis with massive hepatocyte necrosis and died of multisystem dysfunction. Compared with ICIs monotherapy, combined ICIs and anti-angiogenesis targeted TKIs therapy may cause overlapping hepatic injury, leading to severe IMH.
比较免疫检查点抑制剂（ICI）单药治疗与ICI联合抗血管生成酪氨酸激酶（TKI）靶向治疗所致免疫介导性肝炎（IMH）的组织学特征。纳入2015年至2019年在复旦大学附属中山医院接受ICI治疗期间进行肝脏活检的21例IMH患者。其中，10例接受ICI单药治疗，11例接受ICI联合抗血管生成靶向治疗。通过HE染色评估IMH的组织学特征，通过免疫组化染色评估PD-L1/2。接受ICI单药治疗的患者表现出不同程度的小叶性肝炎和门管区炎症。此外，还存在胆管炎、内皮细胞炎、库普弗细胞活化和紫癜性肝炎。8例（8/10）表现为轻度肝损伤，2例（2/10）表现为中度肝损伤。对于接受ICI联合TKI治疗的患者，IMH程度更严重，4例（4/11）表现为中重度肝损伤，伴有融合性或桥接坏死、门管区炎症、胆管炎、界面性肝炎。其中，1例患者发生急性重型肝炎，伴有大量肝细胞坏死，死于多系统功能障碍。在那些肝损伤严重的病例中，许多CD8阳性淋巴细胞聚集在门管区和肝血窦，且许多内皮细胞表达PD-L1。ICI单药治疗组和联合治疗组均有2例死亡。在联合治疗组中，1例患者发生急性重型肝炎，伴有大量肝细胞坏死，死于多系统功能障碍。与ICI单药治疗相比，ICI联合抗血管生成靶向TKI治疗可能导致重叠性肝损伤，引发严重的IMH。
