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Histopathological Characteristics in Autoimmune Myocarditis Associated with Pembrolizumab: A Case Report and Literature Review

Introduction: Immune checkpoint inhibitors (ICIs) are revolutionizing cancer therapy and have significantly improved the clinical outcome of multiple tumor types. ICIs-induced myocarditis is a rare, but potential fatal side effect that requires prompt treatment. The histopathological features of ICIs-induced myocarditis are not well characterized due to limited number of cardiac biopsy or autopsy performed. Case presentation: Here we reported an autopsy finding from a 70-year-old white male with severe myocarditis induced by pembrolizumab administered during the treatment for high grade urothelial carcinoma. He initially presented with left eye ptosis, diplopia, fatigue, and shortness of breath for four days, followed by quickly developed brachycardia and complete heart block. He was treated with high-dose glucocorticoids, but his condition continued to deteriorate. He experienced two cardiopulmonary arrests and died on the fifth day of admission. Sections from heart show extensive myocarditis with dense mixed inflammatory infiltration and patchy myocyte necrosis. Focal endothelitis associated with scattered micro-hemorrhages are also identified. Discussion and conclusion: We reviewed the published case reports or case series from 2015 to 2018 and identified 13 cases of ICIs-induced myocarditis with available histopathologic description. We summarized the finding of these 14 patients including our own case in this paper. Although lymphocytic myocarditis was present in all cases, some histopathologic features are not consistently observed. Better characterization of histopathologic features of ICIs-induced myocarditis will help us understand the mechanism of this fatal toxicity and lead to potentially more specific treatment. Citation: Hou T, Sheub T, Campbellc MT, Subudhic SK, Gaoc J, et al. (2019) Histopathological Characteristics in Autoimmune Myocarditis Associated with Pembrolizumab: A Case Report and Literature Review. J Cancer Sci Ther 11: 198-202. J Cancer Sci Ther, an open access journal ISSN: 1948-5956 Volume 11(6) 198-202 (2019) 199 A detailed discussion about the next treatment options was undertaken and the patient decided to begin treatment with pembrolizumab. He received a standard, 200 mg, intravenous dose. Fifteen days after the initial dose, he presented to the emergency department with left eye ptosis, diplopia, fatigue, and shortness of breath over a 4-day duration. An initial electrocardiogram (ECG) revealed sinus bradycardia at 51 beats per minute with profound prolongation of the PR interval to 480 msec and slight widening of the QRS complexes, but no ischemic changes. An ECG 4 months prior had revealed a PR interval of 166 msec. On laboratory analysis, the patient had an elevated level of troponin T (2,740 ng/L; reference range, ≤ 18 ng/L), creatine kinase (CK) (12,706 U/L; reference range, 20-200 U/L), CK muscle/brain (CK-MB) (272.3 ng/mL; reference range, ≤ 104 ng/mL), and serum creatinine (1.95 mg/dL; baseline for patient, 1.5 mg/dL). He also had elevated liver transaminases: his alanine transaminase level was 240 U/L (reference range, <41 U/L) and his aspartate transaminase level was 591 U/L (reference range, ≤ 40 U/L). The patient’s complete blood count was notable for mild leukocytosis. He had a white blood cell count of 13.8 K/uL with left shift and an absolute neutrophil count of 12.1 K/uL, and he had lymphopenia with an absolute lymphocyte count of 0.88 K/uL. Serum studies for human immunodeficiency virus, hepatitis B, and hepatitis C were all negative. A cytomegalovirus (CMV) Ab IgG test was positive. The patient’s blood culture was negative for microorganisms, but his urine culture was positive for Klebsiella oxytoca and Pseudomonas aeruginosa. The patient was admitted to the intensive care unit and given broad-spectrum antibiotics and methylprednisolone (1 mg/kg every 12 hours) for suspected immunotherapy-mediated myositis. About 7 hours after admission, the patient’s heart rate dropped to 30-40 beats per minute and a second ECG showed intermittent third-degree heart block. A temporary pacemaker was inserted immediately and the patient was also intubated. An initial echocardiogram revealed normal left ventricular systolic function with a left ventricular ejection fraction (LVEF) of 68% and normal wall motion. The patient received one cycle of plasmapheresis, but the treatment was discontinued due to severe hypotension. He rapidly developed severe lactic acidosis, acute kidney injury, and worsening acute hepatic injury. He was started on continuous veno-venous hemofiltration and required vasopressor support. Two days after admission, a repeat echocardiogram showed mildly to moderately depressed left ventricular systolic function with an LVEF of 43% and global hypokinesis. In addition, the repeat echocardiogram showed a minimal pericardial effusion that had not been present on the initial echocardiogram. Given the severity of his condition, the patient did not undergo an endomyocardium biopsy and instead underwent a muscle biopsy of his right quadriceps on day 3 of admission. The biopsy revealed focal muscle fiber necrosis and mild lymphocyte infiltration. On day 4 of admission, a T-SPOT. TB test was negative for tuberculosis and the patient was given a dose of infliximab. Over the 5 days that the patient was hospitalized, his CK level dropped (admission day 0, 12,706 U/L; day 1, 4,204 U/L; day 2, 1,941 U/L; day 3, 1,077 U/L; day 4, 872 U/L; and day 5, 584 U/L), but his troponin T level climbed (admission day 0, 2,740 ng/L; day 1, 3,694 ng/L; day 2, 4,076 ng/L; day 3, 6,495 ng/L; day 4, 7,008 ng/L; and day 5, 11,070 ng/L). The patient’s condition continued to deteriorate on day 5. He experienced two cardiopulmonary arrests and died. A broad panel of immune-related antibody tests were ordered during admission. The pertinent positive findings included an elevated acetylcholine receptor binding antibody (Ab) level of 1.2 nmol/L (reference range, ≤ 0.02 nmol/L), an antinuclear antibody homogenous pattern (titer, 1:320), and a positive finding of smooth muscle Ab (titer, 1:20). A cytokine 12 send-out panel did not reveal any grossly elevated cytokines. Characteristics No. (N=14) Age, years 23 to 80 (average, 64.7) Sex