A 17-year-old male with no previous medical history was admitted 2 days before his death to a local hospital after mild dyspnea. Electrocardiography, chest radiography, and blood analysis revealed no abnormalities. Blood oxygen saturation was 99%, and SARS-CoV-2 nasopharyngeal swabs tested negative; thus, he was discharged without prescriptions. After 2 days, the subject died suddenly during a pool party. Forensic autopsy was performed analyzing all anatomical districts. Cardiac causes were fully excluded after deep macroscopic and microscopic evaluation; lung and brain analyses showed no macroscopic pathology. Finally, a large subglottic solid mass was detected. The whitish neoplasm showed an aggressive invasion pattern to the thyroid and adjacent deep soft tissues and occluded the trachea. High-power microscopy showed sheets of small, uniform cells with scant cytoplasm; round nuclei; and small, punctate nucleoli, with immunohistochemical expression of CK8-18, AE1/AE3, and CD99. Using FISH analysis, the break-apart molecular probes (EWSR1 (22q12) Break – XL, Leica Biosystem, Nussloch, Germany) showed distinct broken red and green fluorochromes, diagnostic of Ewing sarcoma. The neoplasm was characterized as adamantinoma-like Ewing sarcoma, and the mechanism of death was identified as airway obstruction. The rarity of the case resides in the circumstances of death, which pointed to the possibility of sudden unexpected death due to heart disease, but an oncological cause and the underlying mechanism were finally diagnosed. The best method to perform autopsies is still complete, extensive, and systematic macroscopic sampling of organs and districts followed by histopathological analysis, in addition to immunohistochemical and molecular investigations in those cases in which they are necessary. In fact, when neoplasms are detected, the application of advanced techniques such as immunohistochemistry and molecular diagnostics is fundamental to accurately certify death.
Immune checkpoint inhibitors (ICIs) represent a major advance in cancer treatment. The lowered immune tolerance induced by ICIs brought to light a series of immune-related adverse events (irAEs). Pembrolizumab belongs to the ICI class and is a humanized IgG4 anti-PD-1 antibody that blocks the interaction between PD-1 and PD-L1. The ICI-related irAEs involving various organ systems and myocarditis are uncommon (incidence of 0.04% to 1.14%), but they are associated with a high reported mortality. Unlike idiopathic inflammatory myositis, ICI-related myositis has been reported to frequently co-occur with myocarditis. The triad of myasthenia, myositis, and myocarditis must not be underestimated as they can rapidly deteriorate, leading to death. Herein we report a case of a patient with metastatic melanoma who fatally developed myasthenia gravis, myocarditis, and myositis, after a single cycle of pembrolizumab. Considering evidence from the literature review, autopsy, histological, and immunohistochemical investigations on heart and skeletal muscle are presented and discussed, also from a medical–legal perspective.
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