Is a specific type of biopsy order needed to diagnose immune complex inhibitor myocarditis or will a generic biopsy suffice?

Endomyocardial Biopsy Requirements for Immune Checkpoint Inhibitor Myocarditis

For diagnosing immune checkpoint inhibitor (ICI) myocarditis, a specific endomyocardial biopsy (EMB) is required rather than a generic biopsy, as it needs specialized histological, immunohistochemical, and molecular analysis. 1

Biopsy Requirements and Processing

Specimen Collection

• At least 3-4 EMB fragments, each 1-2 mm in size, should be obtained 2
• Additional sampling is recommended for suspected focal myocardial lesions
• Proper tissue handling is critical:
  • Some fragments should be immediately fixed in 10% buffered formalin at room temperature for light microscopy
  • 1-2 specimens should be snap-frozen in liquid nitrogen and stored at -80°C or preserved in RNA-later for molecular testing 2
  • A parallel blood sample (5-10 ml in EDTA or citrate) should be collected at the time of biopsy for comparative molecular testing 2

Specialized Analysis Required

• Histological examination: To identify inflammatory infiltrates with necrotic myocytes
• Immunohistochemical staining: Essential to improve sensitivity - looks for >14 leukocytes/mm² with >7 T-lymphocytes/mm² 2
• Molecular biological techniques: PCR or nested-PCR to detect viral genomes or other specific etiologies 2

Diagnostic Algorithm for ICI Myocarditis

1. Initial Suspicion: When patients on ICI therapy develop new CV symptoms, arrhythmias, conduction abnormalities, or LVSD 1

2. First-line Testing:

   • ECG
   • Troponin (elevated in most cases)
   • BNP or NT-pro-BNP
   • C-reactive protein
   • Viral titers
   • Echocardiogram with global longitudinal strain 1

3. Second-line Testing:

   • Cardiac MRI with inflammatory sequences (T2STIR, T1, LGE) 1
   • If CMR unavailable/contraindicated: Consider cardiac PET-CT (preferably with 68Ga-DOTATOC) 1

4. Endomyocardial Biopsy: Indicated when:

   • Diagnosis remains uncertain after non-invasive testing 1
   • Life-threatening clinical presentation 3
   • Suspected giant cell myocarditis 1
   • Deterioration despite supportive treatment 3

Interpretation of Biopsy Results

The EMB should be analyzed according to:

• Dallas criteria: Inflammatory infiltrate with necrosis/degeneration of adjacent myocytes 2
• Immunohistochemical criteria: >14 leukocytes/mm² with >7 T-lymphocytes/mm² 2
• Molecular analysis: PCR for viral genomes and other specific etiologies 2

Management Implications Based on Biopsy Results

• Positive EMB for ICI myocarditis: ICI therapy should be permanently discontinued 1
• Treatment: High-dose corticosteroids (methylprednisolone 1000 mg/day followed by oral prednisone 1 mg/kg/day) 1
• Steroid-refractory cases: Consider additional immunosuppressive therapies (antithymocyte globulin, infliximab, mycophenolate mofetil, or abatacept) 1

Important Considerations

• A generic biopsy without proper processing and specialized analysis will likely miss the diagnosis
• EMB remains the gold standard for definitive diagnosis despite advances in non-invasive imaging 3
• The combination of clinical suspicion, cardiac biomarkers, and cardiac imaging is often needed alongside biopsy to support the diagnosis 4
• Half of confirmed cases of ICI-myocarditis have normal left ventricular ejection fraction at presentation 1

Remember that proper specimen collection, handling, and specialized analysis are essential for accurate diagnosis of ICI myocarditis. A standard or generic biopsy without these specific procedures will not provide adequate diagnostic information.