In this article, we present a case of a rare neoplasm with an uncommon therapy side effect, along with its timely management and treatment. Extra-osseous Ewing’s sarcoma/primitive neuroectodermal tumor (ES/PNET), which belongs to the Ewing sarcoma family of tumors (ESFTs), is a rare small round cell carcinoma. PNETs are most common in children and adolescents, with no significant gender predisposition. The incidence rates range from 0.15 per 100,000 in those younger than 5 years old, decreasing to 0.03 per 100,000 in young adolescents up to 19 years old [2,3,4].

The first-line treatment regimen for Ewing sarcoma is VAC/IE [5], which includes Vincristine, Doxorubicin, Cyclophosphamide, Ifosfamide, and Etoposide.

The combination of negative viral, bacterial, and rheumatologic tests, along with the absence of a history of herbal drugs, substances, and recent vaccinations, leads us to suspect cancer therapy-related myocarditis, especially considering the patient’s previous exposure to these drugs.

Vinca alkaloids, such as vincristine, are microtubule destabilizing agents, mostly prescribed in hematologic malignancies, brain neoplasms, and solid tumors [6, 7]. Their cardiotoxic effects mainly present as myocardial ischemia and infarction, occurring during or shortly after treatment, and are mainly attributed to cellular hypoxia and subsequent coronary artery vasospasm caused by the drug [8].

Doxorubicin, an anthracycline commonly used and highly effective for treating hematological malignancies and solid tumors, including Ewing sarcoma, can lead to cardiotoxicity. The cardiotoxicity is primarily dose-dependent but may also occur early during treatment. Anthracycline-induced cardiotoxicity primarily results from topoisomerase-II inhibition and oxidative stress induced by reactive oxygen species. cardiotoxicity manifests in three distinct forms: immediate myo-pericarditis, occurring within the initial month of treatment or following a single dose which is rare; early-onset chronic progressive congestive heart failure (CHF); and late-onset cardiotoxicity, emerging several years after treatment. While the cardiotoxic effects of anthracyclines are well-known, myocarditis is considered a rare manifestation [9,10,11,12,13].

Cyclophosphamide, a nitrogen mustard alkylating agent with potent anti-neoplastic, immunosuppressive, and immunomodulatory properties, can cause a spectrum of cardiotoxic effects, mostly manifesting as tachyarrhythmias, hypotension, heart failure, myocarditis, and pericardial disease, typically presenting within 2–10 days of drug administration. These cardiotoxic effects mostly occur due to increased oxidative stress and direct endothelial injury caused by cyclophosphamide metabolites, leading to extravasation of plasma proteins, erythrocytes, and toxic metabolites [14,15,16].

Ifosfamide is another alkylating agent that presents its cardiac side effects mainly as heart failure and arrhythmia [17].

Etoposide’s cardiotoxic effects mainly presents as hypotension, or less frequently as myocardial ischemia and MI. Concurrent chemotherapy with other agents or a previous history of chemotherapy or mediastinal irradiation are known risk factors that predispose patients to etoposide-induced MI [18, 19].

Doxorubicin and Cyclophosphamide are the drugs reported to cause myocarditis as a cardiotoxic effect, each acting through different pathways and highly suspected as the cause of myocarditis in this case.

Myocarditis exhibits a range of clinical presentations, from asymptomatic cases to those posing a life-threatening condition [20]. Based on the 2022 ESC Guidelines on cardio-oncology, the diagnosis of myocarditis involves a new or significant elevation of cTn plus 1 major criterion or 2 minor criteria. In this case, the patient’s CMR was diagnostic for myocarditis based on the updated Lake Louise criteria, serving as a major criterion. Additionally, the patient exhibited the clinical syndrome of myocarditis and a decline in LV systolic function, fulfilling 2 minor criteria. Consequently, the cTn elevation with 1 major and 2 minor criteria led to the clinical diagnosis of Myocarditis, and the patient is in the recovery phase. This patient experienced symptomatic severe CTRCD, requiring hospitalization [21, 22].

The treatment for myocarditis typically involves diuretics, vasodilators, and remodeling therapy, such as ACE inhibitors or angiotensin II receptor blockers, beta-blockers, and aldosterone antagonists. Regular follow-up using echocardiography and cardiac magnetic resonance imaging is also essential. In this patient,  all these treatments were administered. However, the absence of a positive response led us to consider intravenous immunoglobulin (IVIG), which has shown favorable results in pediatric cases [23] Additionally, a meta-analysis by Huang et al. demonstrated that IVIG therapy improves in-hospital survival and left ventricular function recovery in acute myocarditis patients. It also enhances survival rates in those with acute fulminant myocarditis, providing further support for its efficacy [24].