免疫检查点抑制剂治疗后肝功能异常的组织病理学分析

目的:探讨单独使用免疫检查点阻断剂(immune checkpoint inhibitors,ICI)、ICI与靶向抗血管生成的酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)联合使用两种情况下,免疫反应介导性肝炎(immune-mediated hepatitis,IMH)的组织学表现差异。方法:收集2015至2019年在复旦大学附属中山医院接受抗ICI治疗发生肝功能异常且获得肝组织标本的病例21例。其中10例使用单药ICI,另11例使用ICI及靶向抗血管TKI联合治疗,观察组织病理形态,使用免疫组织化学方法检测程序性死亡配体1、2(programmed cell death-ligand 1,PD-L1/2)表达情况。结果:单药ICI治疗的IMH表现为程度不等、均匀分布于肝小叶及汇管区的炎性病变,并可出现小胆管炎、静脉内皮炎、Kupffer细胞活化及紫癜样变。8例(8/10)出现轻度肝损伤,2例(2/10)出现轻-中度肝损伤。在使用ICI及抗血管TKI联合治疗的患者中,肝损伤往往较为严重,其中4例(4/11)出现中-重度肝损伤,肝细胞桥接坏死、大片坏死,汇管区中-重度炎性病变,部分小胆管上皮变性,伴显著界面性肝炎。在较严重IMH的病例中,较多CD8+的T淋巴细胞聚集在汇管区及肝窦内,且有部分肝窦内皮细胞表达PD-L1。单药治疗、联合治疗中各有2例发生死亡,其中联合治疗组中有1例发生急性多发性肝炎,肝组织大片凝固性坏死,肝功能不可逆损伤,最终患者因多系统免疫失调,多器官衰竭而死亡。结论:与单用ICI相比,联合使用ICI及抗血管TKI有可能造成肝细胞的叠加损伤,引起严重IMH的可能性更高。

Pathological features of immune-mediated hepatitis due to immune checkpoint inhibitors and anti-angiogenesis targeted therapy

Objective 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.Methods 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.Results 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.Conclusion Compared with ICIs monotherapy,combined ICIs and anti-angiogenesis targeted TKIs therapy may cause overlapping hepatic injury,leading to severe IMH.