From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
Arch Pathol Lab Med. 2021 Feb 1;145(2):191-200. doi: 10.5858/arpa.2019-0700-OA.
CONTEXT.—: Immune checkpoint inhibitor (CPI) therapies are associated with multi-organ immune-related adverse events. Although colonic mucosal changes have been described, inflammatory changes incited by CPIs in the upper gastrointestinal tract have not been well characterized.
OBJECTIVE.—: To investigate morphologic and immunologic changes incited by CPI therapy in the upper gastrointestinal tract.
DESIGN.—: We compared the morphology and immune cell phenotype of gastric and duodenal biopsies from patients treated with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or anti-programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) antibodies with biopsies from patients with Helicobacter pylori gastritis, patients with celiac disease, and normal controls.
RESULTS.—: Gastric biopsies from patients on CPIs showed chronic gastritis mimicking H pylori gastritis. However, CPI gastritis demonstrated greater numbers of CD8+ intraepithelial lymphocytes, less lamina propria inflammation, fewer plasma cells and CD20+ B cells, fewer lymphoid aggregates, and reduced CD4:CD8 ratio in both the lamina propria and the epithelial layer. There were no differences between anti-CTLA-4 and anti-PD-1/PD-L1 gastritis, except for more lymphoid aggregates in anti-PD-1/PD-L1 gastritis. Duodenal biopsies from patients on CPIs revealed chronic duodenitis with villous blunting, mimicking celiac disease. Compared with celiac disease, CPI duodenitis demonstrated higher prevalence of neutrophilic infiltrates and erosions, increased lamina propria CD3 and CD8 T cells, and reduced CD4:CD8 ratio. Upper gastrointestinal biopsies were more inflamed than concomitant colonic biopsies in the majority of patients.
CONCLUSIONS.—: The morphologic and immunophenotypic distinctions between CPI-associated upper gastrointestinal injuries and common infectious and autoimmune diseases may provide useful discriminators when clinicians are confronted with gastric and duodenal inflammatory changes in patients receiving CPI therapy.
免疫检查点抑制剂（CPI）治疗与多器官免疫相关的不良反应有关。尽管已经描述了结肠黏膜的变化，但 CPI 在上消化道引起的炎症变化尚未得到很好的描述。
研究 CPI 治疗在上消化道引起的形态和免疫变化。
我们比较了接受抗细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）或抗程序性死亡受体 1/程序性死亡配体 1（PD-1/PD-L1）抗体治疗的患者与幽门螺杆菌胃炎、乳糜泻和正常对照患者的胃和十二指肠活检的形态和免疫细胞表型。
接受 CPI 治疗的患者的胃活检显示出类似于 H pylori 胃炎的慢性胃炎。然而，CPI 胃炎表现出更多的 CD8+上皮内淋巴细胞，固有层炎症较少，浆细胞和 CD20+B 细胞较少，淋巴样聚集较少，固有层和上皮层的 CD4:CD8 比值降低。抗 CTLA-4 和抗 PD-1/PD-L1 胃炎之间没有差异，除了抗 PD-1/PD-L1 胃炎中淋巴样聚集更多。接受 CPI 治疗的患者的十二指肠活检显示出绒毛变钝的慢性十二指肠炎，类似于乳糜泻。与乳糜泻相比，CPI 十二指肠炎表现出更高的中性粒细胞浸润和糜烂的发生率，固有层 CD3 和 CD8 T 细胞增加，CD4:CD8 比值降低。在大多数患者中，上消化道活检比同时进行的结肠活检更具炎症性。
CPI 相关上消化道损伤与常见感染和自身免疫性疾病之间的形态和免疫表型差异可能为临床医生在接受 CPI 治疗的患者出现胃和十二指肠炎症变化时提供有用的鉴别诊断。
