Pembrolizumab-Induced Fatal Myasthenia, Myocarditis, and Myositis in a Patient with Metastatic Melanoma: Autopsy, Histological, and Immunohistochemical Findings-A Case Report and Literature Review

Abstract

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.

Keywords: autopsy; immunohistochemistry; myasthenia; myocarditis; myositis; pembrolizumab.

Figure 1

Severe lympho-histiocytic myocarditis (hematoxylin and eosin). Areas of damaged myocardium were diffuse and involved both ventricles and the septum ((A) 4 HPF). In those zones, necrosis (blue star) and contraction bands (blue arrow) were well represented ((B) 40 HPF).

Figure 2

Immunohistochemistry of lympho-histiocytic myocarditis. Abundance of TCD3+ lymphocytes ((A) 20 HPF) and CD68 PGM1+ macrophages ((B) 20 HPF).

Figure 3

Immunohistochemical characterization of the lymphocytic inflammatory response in myocarditis. TCD4+ cells ((A) 10 HPF) were rare compared with TCD8+ ((B) 10 HPF), but there was a cross reaction with macrophages, and the darker brown cells were lymphocytes. TCD8+ cytotoxic cells were Tia-1+ ((C) 40 HPF) and PD-1+ ((D) 40 HPF), but Granzyme B negative ((E) 40 HPF). TCD25+ regulatory T cells were abundant ((F) 10 HPF), intermixed with rare BCD20+ lymphocytes ((G) 10 HPF). Scale bar: 200 μm.

Figure 4

PD-L1 expression in the damaged areas was focally expressed in the cytoplasmic membrane of myocardiocytes (40 HPF).

Figure 5

Necrotizing myositis (hematoxylin and eosin). Sample from iliopsoas muscle with abundant inflammatory infiltrate surrounding necrotic myofibers (20 HPF).

Figure 6

Immunohistochemical features of necrotizing myositis. Abundance of TCD3+ lymphocytes ((A) 10 HPF) and CD68 PGM1+ macrophages ((B) 20 HPF).

Figure 7

Immunohistochemical characterization of the lymphocytic inflammatory response in necrotizing myositis. TCD4+ cells ((A) 20 HPF) presented a cross reaction with macrophages, and lymphocytes were the darker brown. TCD4+ cells and TCD8+ ((B) 20 HPF) were in a similar ratio. TCD8+ cytotoxic cells were Tia-1+ ((C) 40 HPF) and PD-1+ ((D) 40 HPF), but Granzyme B negative ((E) 40 HPF). TCD25+ regulatory T cells were almost absent ((F) 40 HPF), associated with abundant BCD20+ lymphocytes ((G) 20 HPF). Scale bar: 200 μm.

Figure 8

PD-L1 expression in necrotizing myositis. Focal positivity in the injured myocytes and within the macrophages (40 HPF).