Novel insights into the histopathological characteristics of immune checkpoint inhibitor-related myocarditis

BACKGROUND AND AIMS: Pathological examination is commonly used to diagnose immune checkpoint inhibitor (ICI)-related myocarditis. However, well-organized clinicopathological evidence remains limited. In this study, we aimed to investigate the pathological and clinical characteristics of myocarditis to enhance understanding. METHODS: This multicentre retrospective observational study included 38 patients diagnosed with or suspected of having ICI-related myocarditis. Patients were stratified using the pathological grading system proposed by Palaskas et al. Lymphocyte infiltration was assessed using both global and hot-spot (hotspot) methods. Immunohistochemistry was performed for lymphocytes, macrophages, and inflammatory markers, including human leucocyte antigen-DR isotype (HLA-DR), programmed death-ligand 1 (PD-L1), granzyme B, and tenascin C. RESULTS: An increased infiltration of CD3, CD4, CD8-positive T cells, and CD68 and CD163-positive macrophages was observed with higher pathological grades. HLA-DR and tenascin C (clone 4F10) were sensitive markers of inflammation, whereas PD-L1 and tenascin C (clone 4C8) were more specific for high-grade inflammation. Global assessment more accurately predicted myocarditis-related mortality than hotspot assessment, although both methods similarly predicted fulminant myocarditis and major adverse cardiac events. Two patients presented with suspected ICI-mediated non-inflammatory left ventricular dysfunction (NILVD), with minimal myocardial inflammation. CONCLUSIONS: Pathological grading using both global and hotspot assessment is valuable for the diagnosis and risk stratification of ICI-related myocarditis. As low-grade inflammation is not uncommon, supplementary markers such as HLA-DR, granzyme B, tenascin C, and PD-L1 may aid diagnosis. Furthermore, ICI-mediated NILVD may encompass cases of low-grade myocarditis.