Maccio Umberto, Wicki Andreas, Ruschitzka Frank, Beuschlein Felix, Wolleb Sibylle, Varga Zsuzsanna, Moch Holger
Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland.
Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland.
Mod Pathol. 2025 Apr;38(4):100683. doi: 10.1016/j.modpat.2024.100683. Epub 2024 Dec 14.
Although immune checkpoint inhibitors (ICIs) have revolutionized modern oncology, they are also associated with immune-related adverse events (irAEs). Previous histopathologic descriptions of organ-related inflammatory changes do not consider systemic effects of ICIs, because of the absence of comprehensive autopsy studies. We performed a retrospective study on 42 whole-body autopsies of patients treated with ICIs from January 2011 to March 2024 to determine the frequency, organ distribution, and morphology of ICI-associated inflammatory changes as well as their clinical relevance. Twenty-three of 42 (54.8%) patients presented irAEs with inflammatory changes in at least one organ. Most frequent irAEs were ICI-related hypophysitis (N = 12; 28.6%), myocarditis (N = 8; 19.0%), pneumonitis (N = 5; 11.9%), hepatitis (N = 6; 14.3%), and adrenalitis (N = 5; 11.9%). ICI-related inflammation was mainly characterized by lymphohistiocytic and macrophage-rich tissue infiltrates, whereas a granulomatous "sarcoid-like" reaction was observed in 1 patient. Cause of death was attributable to ICI therapy in 7 (16.7%) patients, with ICI-associated myocarditis as the most common cause of death (N = 5; 71.4%). Clinically, irAEs were unsuspected in 5 of 7 ICI-related deaths (71.4%). Among irAEs, myocarditis has been clinically undiagnosed in 5 out of 8 cases (62.5%). Encephalitis was identified only at autopsy in all cases (N = 2). Hypophysitis was clinically unsuspected in 8 of 12 (66.7%) cases. Patients who died from irAEs developed more frequently a complete tumor regression than patients who died from other causes (P = .018). Of note, ICI-related myocarditis and pneumonitis were both associated with a systemic occurrence irAEs. Our study demonstrates that some irAEs, especially myocarditis, hypophysitis, and encephalitis, are clinically underdiagnosed. Autopsy remains a valuable tool to monitor diagnostic accuracy and therapeutic side effects in patients who died under ICI therapy.
尽管免疫检查点抑制剂（ICIs）彻底改变了现代肿瘤学，但它们也与免疫相关不良事件（irAEs）有关。由于缺乏全面的尸检研究，先前关于器官相关炎症变化的组织病理学描述并未考虑ICIs的全身影响。我们对2011年1月至2024年3月接受ICIs治疗的42例患者进行了全身尸检的回顾性研究，以确定ICI相关炎症变化的频率、器官分布、形态及其临床相关性。42例患者中有23例（54.8%）出现了irAEs，至少一个器官有炎症变化。最常见的irAEs是ICI相关的垂体炎（N = 12；28.6%）、心肌炎（N = 8；19.0%）、肺炎（N = 5；11.9%）、肝炎（N = 6；14.3%）和肾上腺炎（N = 5；11.9%）。ICI相关炎症主要表现为淋巴细胞和巨噬细胞丰富的组织浸润，而1例患者观察到肉芽肿性“类肉瘤样”反应。7例（16.7%）患者的死亡归因于ICI治疗，其中ICI相关心肌炎是最常见的死亡原因（N = 5；71.4%）。临床上，7例与ICI相关的死亡中有5例（71.4%）未怀疑有irAEs。在irAEs中，8例心肌炎中有5例（62.5%）临床上未被诊断。所有病例（N = 2）的脑炎仅在尸检时发现。12例垂体炎中有8例（66.7%）临床上未被怀疑。死于irAEs的患者比死于其他原因的患者更频繁地出现完全肿瘤消退（P = 0.018）。值得注意的是，ICI相关的心肌炎和肺炎均与全身性irAEs的发生有关。我们的研究表明，一些irAEs，尤其是心肌炎、垂体炎和脑炎，在临床上未得到充分诊断。尸检仍然是监测接受ICI治疗死亡患者诊断准确性和治疗副作用的有价值工具。
