Metachronous severe multisystem immune-related adverse events during tremelimumab plus durvalumab therapy for hepatocellular carcinoma: a clinicopathological autopsy case report.

Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced hepatocellular carcinoma (HCC), but severe multisystem immune-related adverse events (irAEs) remain a major clinical challenge. We report an autopsy-confirmed case of advanced HCC treated with tremelimumab plus durvalumab that developed severe metachronous multisystem irAEs characterized by sequential pancreatitis, laryngeal edema with sialadenitis, and myocarditis. Twelve days after treatment initiation, the patient presented with fever and abdominal distension, and computed tomography showed CTCAE grade 3 pancreatitis. On hospital day 6, he developed life-threatening laryngeal edema requiring intubation and steroid pulse therapy. Although the airway edema improved, complete atrioventricular block developed on day 23. Cardiac troponin I increased to 42,006 pg/mL, and endomyocardial biopsy demonstrated CD8-predominant myocarditis consistent with CTCAE grade 4 irAE. Cardiac conduction recovered after additional corticosteroid therapy, but the patient subsequently died of septic shock. Autopsy revealed CD8-positive lymphocytic infiltration not only in clinically recognized irAE-affected organs, including the pancreas, salivary glands, pharynx/larynx, and heart, but also in clinically silent organs, including the kidneys and intestine, indicating widespread subclinical immune-mediated injury. Multiplex immunofluorescence analysis demonstrated CD3-positive T-cell infiltration enriched for CD8-positive T cells, with variable or focal Granzyme B expression across affected tissues. In contrast, CD68-positive macrophages and CD66b-positive neutrophils were not the dominant inflammatory populations. This clinicopathological autopsy case supports the concept that clinically apparent irAEs may represent only the visible portion of systemic CD8-positive T-cell-dominant immune-mediated injury. Severe irAEs after tremelimumab plus durvalumab therapy may progress metachronously and involve clinically silent organs beyond those recognized during life, highlighting the need for continued multisystem monitoring after the onset of severe irAEs.