Frequency and consequences of immune checkpoint inhibitor-associated inflammatory changes in different organs: an autopsy study over 13-years.

Abstract

While immune checkpoint inhibitors (ICIs) have revolutionized modern oncology, they are also associated with immune-related adverse events (irAEs). Previous histopathological descriptions of organ-related inflammatory changes do not consider systemic effects of ICIs, because of an 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 frequency, organ distribution and morphology of ICIs-associated inflammatory changes as well as their clinical relevance. Twenty-three of 42 patients (54.8%) presented irAEs with inflammatory changes in at least one organ. Most frequent irAEs were ICIs-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%). ICIs-related inflammation was mainly characterized by lympho-histiocytic and macrophage-rich tissue infiltrates, whereas a granulomatous "sarcoid-like" reaction was observed in one patient. Cause of death was attributable to ICIs-therapy in 7 patients (16.7%), with ICIs-associated myocarditis as the most common cause of death (N=5, 71.4%). Clinically, irAEs were unsuspected in 5 of 7 ICIs-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 cases (66.7%). Patients who died from irAEs developed more frequently a complete tumor regression than patients who died from other causes (P=0.018). Of note, ICIs-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 ICIs-therapy.