Fatal Pericarditis and Cardiac Tamponade During Selumetinib Treatment for Pericardial Neurofibroma.
Selumetinib has recently become available for the treatment of inoperable and symptomatic plexiform neurofibroma (NF) [1] with neurofibromatosis 1 (NF1). Here, we report a fatal case of aseptic pericarditis, massive pericardial effusion, and cardiopulmonary failure during 3 years of selumetinib treatment. A 19-year-old man with NF1 had plexiform neurofibromas in the left cervical region, pericardiac region, left side of the vertebral body, left back muscles, and left shoulder, along with severe scoliosis and thoracic cage deformity. Since there was a risk of serious functional impairment due to the future growth of plexiform neurofibromas particularly in the left cervical and pericardial regions, he had been treated with oral selumetinib (50 mg/day) for 3 years. Given a report of selumetinib-associated left ventricular dysfunction [2], the patient underwent routine surveillance echocardiography every 6 months. Echocardiographic findings were unremarkable until 1 month before admission, when a small, asymptomatic pericardial effusion was detected and managed conservatively. Several days before admission, he developed decreased responsiveness. At an outpatient visit, profound hypoxemia was noted, and he was emergently hospitalized. Contrast-enhanced computed tomography demonstrated a large pericardial effusion, and cardiac tamponade was diagnosed. Emergency pericardial drainage yielded exudative fluid; cytology showed reactive changes, and microbiological cultures were negative. Despite drainage, the effusion rapidly recurred, and his respiratory status progressively deteriorated. FDG positron emission tomography demonstrated an FDG-avid mass adjacent to the heart (Figure 1a). Although the maximal diameter was largely unchanged compared with imaging obtained 2 years earlier (29.6 to 30.9 mm), the mildly increased FDG uptake raised concern for malignant transformation at our institution. A pericardial window procedure was considered; however, it was deemed too high risk because intubation and positive-pressure ventilation were expected to further compromise his restricted cardiopulmonary function. His chronic type II respiratory failure worsened, and he died on hospital day 34. Autopsy revealed a well-circumscribed nodular mass extending from the outer surface into the parietal pericardium (Figure 1b). Histologically, the tumor consisted of wavy spindle cells without significant atypia (Figure 1c). The tumor cells were positive for S100 and SOX10, retained H3K27me3 expression, and showed a low Ki-67 index (~1%), consistent with a benign pericardial neurofibroma. A lymphocyte-predominant inflammatory infiltrate was observed in the surrounding pericardium, suggesting tumor-associated aseptic pericarditis (Figure 1d). We concluded that persistent exudative pericardial effusion secondary to aseptic pericarditis led to cardiac tamponade and progressive cardiorespiratory failure, which was exacerbated by NF1-related skeletal deformities and limited respiratory reserve. MEK inhibitors have been shown to induce activated CD8+ T cells [3] and to facilitate T-cell trafficking via fibroblast modulation [4], suggesting a potential to trigger inflammation in predisposed patients. In addition, the contribution of selumetinib to the acceleration of left ventricular dysfunction, particularly during cardiac tamponade, cannot be excluded in the present case. Clinicians should be particularly cautious when using selumetinib in patients who, as in the present case, are thought to have pulmonary congestion related to scoliosis, as selumetinib may accelerate the deterioration of left ventricular function. In addition, patients with multiple comorbidities require strict, multidisciplinary monitoring involving relevant specialties. This work was supported by Japan Society for the Promotion of Science (Grants 22K18392 and 23K15267) and Ministry of Health, Labour and Welfare Grant-in-Aid for Scientific Research (Grant 23FC1037a). The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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