What are the histopathological findings of a muscle biopsy in immune-mediated necrotizing myositis?

Histopathological Findings of Muscle Biopsy in Immune-Mediated Necrotizing Myopathy

The defining histopathological feature of immune-mediated necrotizing myopathy (IMNM) is prominent muscle fiber necrosis and regeneration with minimal or absent inflammatory infiltrates, accompanied by macrophages surrounding necrotic fibers. 1

Primary Histopathological Features

Muscle Fiber Necrosis and Regeneration

• Prominent necrotic muscle fibers are present in 93% of cases, representing the most consistent finding in IMNM 2
• Necrotic fibers are randomly distributed throughout the muscle tissue rather than in a perifascicular pattern 3, 4
• Regenerating muscle fibers with basophilic cytoplasm and enlarged nuclei are abundant 1, 2
• Atrophic fibers are present alongside necrotic and regenerating fibers 1

Inflammatory Infiltrate Characteristics

• Inflammatory infiltrates are minimal or absent, which distinguishes IMNM from polymyositis and dermatomyositis 1, 2
• When present, inflammatory cells are scattered and isolated (65% of cases) rather than forming dense aggregates 2
• Macrophages (CD68+) predominate (68% of cases) and surround necrotic muscle fibers 1, 2
• T lymphocytes (CD3+) may be present around necrotic and regenerating fibers but do not invade non-necrotic fibers 1, 2
• CD8+ T cells do not surround or invade non-necrotic muscle fibers, unlike in polymyositis 2, 4

Immunohistochemical Findings

MHC Class I Expression

• MHC class I expression on non-necrotic muscle fibers is variable (56% of cases) and typically less prominent than in polymyositis 2, 5
• Expression may be faint or absent, which helps differentiate IMNM from other inflammatory myopathies 2

Complement Deposition

• Sarcolemmal C5b-9 (membrane attack complex) deposition occurs in only 42% of cases overall 2
• C5b-9 deposition is significantly different between subtypes: only 18% in anti-SRP IMNM versus 56% in anti-HMGCR IMNM (p=0.0001) 2
• When present, complement deposition is typically less extensive than in dermatomyositis 5

Additional Immunohistochemical Markers

• Sarcoplasmic p62 expression is constant and serves as a useful diagnostic marker 2
• Type 1 interferon-induced protein MxA is typically absent, helping distinguish IMNM from dermatomyositis 2

Distinguishing Features Between IMNM Subtypes

Anti-SRP IMNM

• More severe necrosis and regeneration compared to anti-HMGCR IMNM (p=0.01) 2
• Very low sarcolemmal C5b-9 deposition (18%) 2
• Less frequent inflammatory infiltrates 2

Anti-HMGCR IMNM

• More frequent inflammatory infiltrates (p=0.007) with perivascular localization (p=0.01) 2
• Clustered expression of MHC class I (p=0.007) 2
• Higher frequency of C5b-9 deposition (56%) 2

Immune Profile Characteristics

Cellular Immune Response

• Strong Th1/M1 polarized immune response with classically activated macrophages as the primary effector cells 1, 6
• Elevated interferon-γ, tumor necrosis factor-α, IL-12, and STAT1 levels in muscle tissue 6
• B cells and high CXCL13 expression may be present in patients with defined autoantibodies 6

Critical Differential Diagnostic Considerations

Features Absent in IMNM

• No perifascicular atrophy, which is characteristic of dermatomyositis 3, 2, 4
• No rimmed vacuoles, which are pathognomonic for inclusion body myositis 3, 7
• No endomysial infiltrates invading non-necrotic fibers, which characterizes polymyositis 2, 4
• No significant microangiopathy or vasculopathy 4

Common Pitfalls

• Non-immune necrotizing myopathies (toxic, critical illness myopathy) can mimic IMNM histologically but lack MHC class I overexpression and C5b-9 deposition 2, 5
• Muscular dystrophies with secondary inflammation may show necrosis but typically demonstrate increased connective tissue and fiber size variability 2
• Muscle biopsy findings must always be interpreted in clinical context including autoantibody profile (anti-SRP, anti-HMGCR), creatine kinase levels, and clinical presentation to avoid misdiagnosis 2, 5