What is the role of endomyocardial biopsy (EMB) versus cardiac Magnetic Resonance Imaging (MRI) in diagnosing immune checkpoint inhibitor (ICI) myocarditis?

Endomyocardial Biopsy vs Cardiac MRI for Immune Checkpoint Inhibitor Myocarditis

Endomyocardial biopsy (EMB) remains the gold standard for definitive diagnosis of immune checkpoint inhibitor (ICI) myocarditis, while cardiac MRI serves as a valuable non-invasive alternative with limitations in sensitivity that may lead to false negatives. 1, 2

Diagnostic Approach for ICI Myocarditis

Initial Evaluation

• Suspect ICI myocarditis in patients receiving immune checkpoint inhibitors who present with:
  • New cardiac symptoms (chest pain, dyspnea, palpitations)
  • Elevated cardiac biomarkers (troponin, BNP)
  • ECG abnormalities (conduction disorders, arrhythmias)
  • Symptoms typically appear within first 4 cycles of treatment 1

Cardiac MRI (CMR) Role

• CMR provides non-invasive assessment using the updated Lake Louise Criteria:
  • T1-based criteria: increased myocardial T1, extracellular volume, or late gadolinium enhancement
  • T2-based criteria: increased T2 relaxation time or signal intensity in T2-weighted images 1
• Advantages:
  • Non-invasive approach
  • Can identify myocardial inflammation patterns (typically epicardial or midwall)
  • Useful for monitoring treatment response 3
• Limitations:
  • May yield false-negative results in ICI myocarditis
  • Limited sensitivity in early disease
  • Normal CMR does not exclude ICI myocarditis 2

Endomyocardial Biopsy Role

• Remains the definitive diagnostic test for ICI myocarditis
• Critical when:
  • CMR is normal but clinical suspicion remains high
  • Patient is hemodynamically unstable
  • Diagnosis remains uncertain despite other testing
  • Treatment decisions depend on definitive diagnosis 2, 4
• Provides:
  • Histopathologic confirmation of inflammatory infiltrates
  • Characterization of T-cell subsets involved (CD3+, CD4+, CD8+)
  • Assessment of disease severity through grading systems 4, 5

Diagnostic Algorithm

1. Initial Assessment:

   • Obtain ECG, troponin, and BNP in all patients with suspected ICI myocarditis
   • Admit to monitored setting if clinical suspicion is high 1

2. First-Line Imaging:

   • Perform echocardiogram to assess ventricular function
   • Proceed to CMR with T1/T2 mapping when available 1, 3

3. Decision Point:

   • If CMR confirms myocarditis → Initiate treatment
   • If CMR is negative but clinical suspicion remains high → Proceed to EMB 2
   • If patient is unstable → Consider immediate EMB without waiting for CMR 1

4. EMB Considerations:

   • Perform immunohistochemical staining (anti-CD3, anti-CD68, anti-HLA antigens)
   • Consider grading system based on inflammatory infiltrate severity 4
   • Use findings to guide immunosuppression intensity and ICI rechallenge decisions

Treatment Implications

• Treatment should begin promptly when clinical suspicion is high, even before confirmatory testing
• Severity of histological findings on EMB may guide immunosuppression strategy:
  • High-grade inflammation: High-dose corticosteroids ± additional immunosuppression
  • Low-grade inflammation: Some patients may continue ICI therapy with close monitoring 4
• EMB findings may help identify patients who can safely resume ICI therapy after recovery

Important Caveats

• CMR sensitivity for ICI myocarditis varies; native T1 mapping appears more sensitive than T2 mapping 3
• Troponin elevation may persist despite clinical improvement, making CMR useful for monitoring treatment response 3
• EMB remains essential when CMR is normal but clinical suspicion is high 2
• Consider concurrent ICI-induced myositis and myasthenia gravis, which frequently co-occur with myocarditis 1

In summary, while CMR offers a valuable non-invasive approach to diagnosing ICI myocarditis, EMB provides definitive diagnosis and should be pursued when CMR is negative but clinical suspicion remains high, or when the patient is unstable and rapid diagnosis is critical.