Eosinophillic Myocarditis Secondary to Metastatic Melanoma

Abstract

Eosinophilic myocarditis is a rare form of myocarditis that may manifest from cancer-mediated inflammation. A case of eosinophilic myocarditis secondary to metastatic melanoma is described; metastatic melanoma can cause a T helper type 2 lymphocyte–mediated increase in circulating levels of interleukin-5, which is known to stimulate eosinophil proliferation resulting in myocardial inflammation and fibrosis. Cardiac imaging with transesophageal echocardiography revealed a large immobile left ventricular apical thrombus. Cardiac MRI was then performed and revealed enhancing fibrosis along the endocardial surface.

© RSNA, 2019

Supplemental material is available for this article.

Summary

In the presence of hypereosinophilia and findings consistent with myocarditis at transesophageal echocardiography and cardiac MRI, a diagnosis of eosinophilic myocarditis secondary to metastatic melanoma was made.

Key Points

• ■ Hypereosinophilia can develop into eosinophilic myocarditis due to eosinophil-mediated cardiac damage, which can result in myocardial necrosis, intracardiac thrombus formation, and fibrosis.

• ■ Transesophageal echocardiographic results showed thickening of the left ventricular apex and cardiac MRI results showed early and late enhancement indicating fibrosis along the endocardial surface in a case of eosinophilic myocarditis secondary to metastatic melanoma.

Introduction

Hypereosinophilia is defined as an absolute eosinophil count greater than 1.5 × 10⁹/L (or >1500 cells per microliter) on two occasions separated by 1 month and/or the presence of eosinophilic deposition in tissues (1). Hypereosinophilic syndrome (HES) is diagnosed once hypereosinophilia is associated with end-organ damage and/or dysfunction and is a diagnosis of exclusion (1). Approximately 50% of patients with HES will develop eosinophilic myocarditis due to eosinophil-mediated cardiac damage resulting in myocardial necrosis, intracardiac thrombus formation, and fibrosis (2). Myocardial necrosis occurs secondary to eosinophil and lymphocyte infiltration and release of toxic cationic proteins (3). Left untreated, the later stages ensue with thrombus formation over damaged myocardium, which is eventually replaced by fibrosis (4). The condition may not be evident until chronic fibrosis results in a restrictive cardiomyopathy with impaired ventricular function, a condition known as Löffler endomyocarditis (5). Clinicians may suspect the diagnosis based on laboratory and imaging findings. However, the reference standard for diagnosis is cardiac biopsy (3); echocardiography and cardiac MRI have emerged as useful noninvasive diagnostic tools.

Case Report

A 61-year-old white man presented with a 3-month history of low-grade fevers, myalgias, and a 7-kg weight loss. He denied chest pain, palpitations, dyspnea, or symptoms on exertion. He had two transient ischemic attacks prior to presentation; one presenting with confusion and global amnesia, the other presenting with transient left eye blindness. CT and MRI of the head and brain showed negative results for hemorrhage or ischemia at the time.

He was subsequently hospitalized with abdominal pain and diarrhea secondary to nontyphoid Salmonella. A CT scan of the abdomen showed multiple discrete hepatosplenic lesions. The patient’s low-grade fevers persisted despite completing 3 weeks of ciprofloxacin for treatment of Salmonella which prompted a splenic biopsy, the results of which were consistent with metastatic melanoma. Peripheral blood flow cytology results were normal. No malignant skin lesions were found at full skin examination, which included multiple cutaneous biopsies. However, the patient was noted to have splinter hemorrhages. Other than lower extremity pitting edema, the cardiopulmonary examination results were unremarkable. Laboratory findings included a leukocytosis (22.1 × 10⁹/L [normal range, 3.5–10.5 × 10⁹/L]) with eosinophilia (absolute eosinophil count of 4.55 × 10⁹/L [normal range, 0.05–0.5 × 10⁹/L], 20% eosinophils on peripheral smear). Investigations for parasitic infection were negative. Hemoglobin level, platelet count, serum creatinine level, and electrolyte level were normal. Brain MRI results showed multiple small ischemic infarctions.

Transesophageal echocardiography was performed to rule out infective endocarditis in light of highly suspicious findings of fevers, splinter hemorrhages, and a history of transient ischemic attacks. Transesophageal echocardiography revealed thickening of the left ventricular apex, which was a large immobile thrombus at the left ventricular apex measuring 3.4 × 2.6 cm (Fig 1; Movies 1 and 2 [supplement]). His estimated ejection fraction was 55%. Cardiac MRI was performed and revealed early and late enhancement indicating fibrosis along the endocardial surface of the left ventricular apex surrounding a large apical thrombus (Fig 2). Additionally, T2-weighted short tau inversion-recovery images showed the apex as brighter than other areas of the myocardium, a finding consistent with edema. Due to no primary source for cutaneous melanoma, a repeat fine-needle aspiration biopsy of a liver lesion was performed and confirmed the splenic findings of metastatic melanoma. The patient was given a diagnosis of eosinophilic myocarditis likely secondary to underlying metastatic melanoma. He was given nivolumab (anti–programmed cell death 1 [PD-1] monoclonal antibody) and was prescribed warfarin for anticoagulation (goal international normalized ratio, 2.0–3.0). The patient was referred to a hospital close to his hometown where he could be followed by a local oncologist and cardiologist. However, 6 months after discharge from our institution, the patient died of complications secondary to the extensive burden of metastatic disease.

Figure 1:

A, Transesophageal echocardiogram shows long-axis view of the left ventricle. The ventricular apex appears thickened with concern for apical thrombus (arrow). B, Intravenous contrast material–enhanced echocardiographic image shows the filling defect at the ventricular apex confirming the concern for apical thrombus (arrow).

Figure 2:

Cardiac MR images. A, Axial balanced steady-state free precession (SSFP) end-diastolic four-chamber view shows the thickened left ventricular apex (arrow). B, Sagittal balanced SSFP end-diastolic two-chamber view shows the apical thrombus (arrow) and apical wall thickening. C, Phase-sensitive inversion-recovery (PSIR) late gadolinium enhanced (LGE) image shows enhancement consistent with endomyocardial fibrosis (arrows) obtained in diastole. D, PSIR LGE short-axis image of the left ventricle in diastole. Apical thrombus appears dark in the center of the ventricle due to the lack of contrast enhancement (arrow).

Movie 1:

Download video file ^{(3.4MB, mp4)}

Transesophageal echocardiographic long-axis view without contrast shows left ventricular apical thrombus.

Movie 2:

Download video file ^{(1.5MB, mp4)}

Transesophageal echocardiographic long-axis view with contrast enhancement showing left ventricular apical thrombus.

Discussion

Eosinophilic myocarditis is an inflammatory disease of the heart due to eosinophilic infiltration (6). The majority of cases are associated with hypereosinophilia and can be classified into one of three forms of HES: (a) primary HES due to clonal expansion from an underlying stem cell, myeloid, or eosinophilic neoplasm, (b) secondary HES due to overproduction of eosinophilic cytokines commonly seen with parasitic infections, certain solid tumors, and T-cell lymphomas, and (c) idiopathic HES from hypereosinophilia of unknown causes. Less common causes of eosinophilic myocarditis are due to drug hypersensitivity, eosinophilic granulomatosis with polyangiitis, systemic atopy, or drug-related eosinophilic systemic syndrome (5).

Eosinophilic myocarditis presents with three stages of cardiac disease. The acute necrotic stage occurs early in the course of disease, after approximately 5 weeks of hypereosinophilia, and is characterized by myocardial necrosis due to eosinophil degranulation and release of toxic cationic proteins (3,7). The thrombotic stage occurs after approximately 10 months of eosinophilia as a result of ventricular wall vascular damage and exposure of von Willebrand factor, collagen, and tissue factor which serve as a nidus for fibrin thrombus formation (4). After approximately 2 years of exposure to eosinophilia, the late-fibrosing stage occurs where thrombus is replaced by fibrosis (4,8). Over time, fibrosis results in a restrictive cardiomyopathy; this is known as Löffler endomyocardial fibrosis (5).

Clinical manifestations of eosinophilic myocarditis vary based on the stage of involvement. During the acute necrotic stage, patients may remain asymptomatic with little evidence of cardiac involvement at echocardiography. Later, more significant signs of cardiac involvement present with symptoms of heart failure, intracardiac thrombus, myocardial ischemia, arrhythmia, and, rarely, pericarditis (9).

Diagnosing eosinophilic myocarditis is a challenge early in the course of illness as cardiac symptoms and evidence of cardiac involvement and dysfunction at echocardiography are often absent (4). During the later stages, noninvasive imaging with echocardiography and cardiac MRI may show evidence of endomyocardial thickening, right and left ventricular apical thrombus formation, and posterior mitral leaflet involvement which should raise concern for the diagnosis, particularly with concurrent eosinophilia (2). Noninvasive imaging may also differentiate progressive disease based on restrictive filling patterns with regurgitation of the atrioventricular valves due to subvalvular damage (10). The use of cardiac MRI over echocardiography is arguably the preferred noninvasive imaging modality due to the higher sensitivity and specificity for depicting ventricular thrombi in comparison to transthoracic or transesophageal echocardiography (11). Of added benefit, cardiac MRI with delayed enhancement can help identify right and/or left ventricular myocardial abnormalities such as fibrosis and/or edema. Differentiating fibrosis from edema may be made with T2-weighted imaging with areas of edema showing increased signal intensity (11). Ultimately, the reference standard for diagnosing eosinophilic myocarditis is with endomyocardial biopsy performed in the right ventricle. However, prior to biopsy, imaging should be performed to exclude the presence of thrombus as this can lead to thromboembolic complications (5).

Treatment of eosinophilic myocarditis includes immunosuppression with early high-dose glucocorticoid therapy to mitigate myocardial damage and fibrosis. In addition, identification and management of the underlying etiology of eosinophilia is necessary. Standard heart failure therapy and anticoagulation with warfarin should also be applied in situations with coexisting heart failure and thrombi, respectively. Additional treatment considerations include surgical intervention for valvular dysfunction and heart transplant once peripheral eosinophilia is well controlled.

Our patient’s eosinophilic myocarditis was a result of malignancy; therefore, treatment was targeted toward his metastatic melanoma. Treatment with dual therapy including ipilimumab (anti-cytotoxic T-lymphocyte antigen-4 [CTLA-4] antibody) and nivolumab (anti-PD-1 monoclonal antibody) were both considered. However, use of anti-CTLA-4 and anti-PD-1 monoclonal antibodies have been associated with manifestations of autoimmune myocarditis despite survival benefit in metastatic melanoma (12). Due to the patient’s diagnosis of myocarditis, treatment with single therapy nivolumab was initiated.

Alternatively, treatment with an interleukin (IL)-5 antibody was also considered. However, application of this therapy in treating eosinophilic myocarditis has not yet been approved (13). The rationale behind this approach is related to T helper type 2–mediated inflammation, which is predominant in melanoma and the likely cause for eosinophilia in our patient. Elevations in T helper type 2 leads to increased circulating levels of IL-4, IL-5, IL-10, and IL-13 (14). IL-5 is known to stimulate eosinophil proliferation. Therefore, targeted therapy with an IL-5 antibody may decrease eosinophil counts. Additionally, empirical treatment with corticosteroids was held in the setting of immunotherapy initiation.

Conclusion

To our knowledge, this is the first case of untreated metastatic melanoma presenting with eosinophilic myocarditis. In the presence of hypereosinophilia and findings consistent with myocarditis at transesophageal echocardiography and cardiac MRI, eosinophilic myocarditis was logically suspected. Treatment was directed toward metastatic melanoma as this was the likely culprit for hypereosinophilia. The choice of immunotherapy regimen was modified to a single agent due to associations of immunotherapy agents and autoimmune myocarditis.