Immune-Related Fulminant Myocarditis Revealed Using Myocardial Histopathology at Autopsy in the Treatment of Advanced Renal Cell Carcinoma: A Case Report Open Access

We encountered a case in which immune checkpoint inhibitor (ICI)-associated myocarditis was diagnosed based on an autopsy. In this case report, we consider the pathology, diagnosis, and treatment of this disease and review the collaboration between urologists and cardiologists.

A 78-year-old man who was referred to our department because of a left renal tumor invading the inferior vena cava was found at a hospital where he was examined for hematuria. Contrast-enhanced computed tomography (CT) revealed a 13-cm-diameter tumor extending into the inferior vena cava at the upper pole of the left kidney, left adrenal gland invasion, portal vein involvement in the liver metastasis, and a right pulmonary nodule (Fig. 1). The cancer was determined to be unresectable, and systemic therapy was administered. Based on the imaging findings and the results of the tumor biopsy, the diagnosis was clear cell renal cell carcinoma (cT4N0M1) and poor risk according to the International mRCC Database Consortium classification. The patient had a history of hypertension and atrial fibrillation and had been taking antihypertensive and antiarrhythmic drugs. Combination therapy with pembrolizumab and axitinib was initiated, and in the first cycle, a reduction in the primary and metastatic lesions was observed on CT. In the second cycle, axitinib was suspended because of suspected drug-induced kidney injury; however, as the patient’s condition improved with conservative treatment, it was restarted at a reduced dose.

One month later, grade 3 or higher anorexia, dizziness, and fatigue appeared, and emergency hospitalization was performed because of the possibility of adverse events from the systemic therapy. Blood biochemistry tests showed no abnormalities in the endocrinological data except for an increase in brain‐type natriuretic peptide levels. Chest radiography and electrocardiography were performed; however, no findings were suggestive of heart failure. Additionally, there were no significant findings on planar CT other than the further reduction of the existing lesion. The cause of the anorexia and fatigue could not be identified, and the patient’s general condition did not improve. On the 6th day of hospitalization, sudden hypotension and loss of consciousness were observed, and the Cardiology Department was consulted. We thought the possibility of drug-induced myocarditis due to pembrolizumab, but there were no significant changes in the myocardial deviation enzymes in the blood biochemistry test, nor no findings other than atrial fibrillation AF in the electrocardiogram, and the cardiac function (left ventricular ejection function 50%) was maintained in the echocardiogram. However, the next day, tachycardia appeared (140 bpm), and a repeat echocardiogram showed a marked decrease in cardiac function (left ventricular ejection function 25%) (Fig. 2). β-Blockers and diuretics were started for heart failure. The next morning, he was transferred to the cardiac high-care unit for specialized management. Immediately after that, a fatal arrhythmia that repeatedly caused cardiac arrest for more than 10 s appeared. Cardiopulmonary resuscitation and temporary pacemaker placement were performed to maintain the heart rate and hemodynamics; however, the patient continued to have poor blood pressure control (systolic blood pressure <80 mm Hg). Owing to poor hemodynamics, ICI-induced fulminant myocarditis was strongly suspected at that time, and the cardiologist skipped the cardiac biopsy and administered steroid pulse therapy; however, cardiac function had already improved. As systemic therapy for renal cell carcinoma was successful, and the disease was well controlled, we recommended that the patient be treated for myocarditis using mechanical support; however, the patient did not want invasive treatment and died on the same day. A pathological autopsy was performed with the family’s consent to determine the cause of death. The pathological results were consistent with ICI-induced myocarditis, showing necrotic changes in the myocardium, detachment of myocardial cells, and severe lymphocyte infiltration.

The incidence of ICI-associated myocarditis is relatively low, ranging from 0.27% to 1.14% [1]; however, the mortality rate is high, estimated about 25% [2]. The period from the first dose to onset is approximately 3 months [3, 4]; in this case, the onset of symptoms occurred 3 months after starting the treatment. Risk factors for ICI-associated myocarditis include arrhythmia, history of heart failure, and metastasis [5]. The initial symptoms of ICI-associated myocarditis are not uniform and include chest symptoms, fever, general malaise, cold-like symptoms, such as coughing, and gastrointestinal symptoms, such as nausea and vomiting [6].

During the clinical course, many patients who develop ICI-associated myocarditis show abnormal findings such as elevated troponin T levels and ST changes on electrocardiograms early on [7]. In addition to the pathological diagnosis, a definitive diagnosis may be made clinically based on troponin T levels, magnetic resonance imaging findings, clinical findings, etc. [5]. Measurement of troponin T levels is considered useful, and there are reports recommending that troponin be measured in addition to a baseline electrocardiogram before the use of ICIs and that if there are signs such as chest symptoms suggestive of myocarditis, troponin T should be compared promptly [8]. Treatment of ICI-associated myocarditis involves prompt discontinuation of the drug in question, administration of steroids, immunoglobulin therapy, or plasma exchange in cases of refractory disease [9‒11]. Delaying the start of treatment is considered a risk factor for poor prognosis, and it has been reported that administering high-dose steroids within 24 h of disease onset contributes to more favorable outcomes [11]. In the case of fulminant myocarditis, most deaths occur during the acute phase; therefore, a natural recovery is expected if the patient can overcome the peak phase [12]. Therefore, it is important to manage the acute phase quickly and accurately to prevent hemodynamic compromise. If the therapeutic effect and patient performance status are good, the introduction of circulatory support devices such as venoarterial extracorporeal membrane oxygenation might be considered while carefully taking into account the prognosis of advanced cancer [13].

Histopathologically, the disease is characterized by the infiltration of CD8-positive T cells and macrophages into the myocardial tissue. The autopsy revealed necrotic changes in the myocardium, loss of myocardial cells, and severe lymphocyte infiltration, consistent with myocarditis caused by ICIs (Fig. 3). Most renal cancer lesions had become necrotic, and treatment would have been effective; therefore, it is regrettable that the patient’s life could not be saved.

There was a discrepancy in the clinical course of this case. We are concerned that the patient’s overall poor condition, of unknown cause, might be due to ICI-induced myocardial damage. However, there were no new ST changes on the electrocardiogram or echocardiogram until the end, and renal function was maintained. These physiological test findings may have led to a lack of awareness regarding the urgency of treating immune-related adverse events, which may have resulted in the measurement of troponin T levels and other tests not being performed. Consequently, the diagnosis and treatment of ICI-induced myocarditis may have been delayed.

In conclusion, we report a case of pembrolizumab-associated fulminant myocarditis confirmed by autopsy. Although disease control of renal cancer was good, the patient died of treatment-related disease 3 months after the start of systemic therapy. In cases where patients complain of nonspecific symptoms within 3 months of starting ICI therapy, measuring troponin T levels is useful for early diagnosis. Sharing information about myocarditis as an immune-related adverse event with cardiologists is essential for early therapeutic interventions.

This case report was supported in part by many medical staffs in Tohoku University Hospital, Sieryo-Machi, 1-1 Aobaku, Sendai, Japan.

Because the patient died, informed consent was obtained from the patient’s family, and this case report was reviewed and approved by the Ethics Committee of Tohoku University Hospital (Approval No.: 38220). Written informed consent was obtained from the patient’s family for the publication of this case report and accompanying images.

The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546288).

The authors have no conflicts of interest to declare.

No funding was received for the present work.

Yuka Hayashi and Yoshihide Kawasaki contributed to the writing of the manuscript. Hiromichi Katayama, Rie Sakagami, Takuro Goto, Tomonori Sato, Yohei Satake, Takuma Sato, Naoki Kawamorita, Shinichi Yamashita, and Akihiro Ito served as attending physicians for the presented patient. Hiryoyuki Takahama was a cardiologist who was involved in that patient’s intensive care. Satoko Sato was in charge of the autopsy pathology. All authors agree to be accountable for all aspects of this study.

All data generated or analyzed during this study are included in this article. Data supporting the findings of this study are available from Yoshihide Kawasaki upon request.