What are the differential diagnoses for an elderly female patient with pseudoepitheliomatous hyperplasia, subglottic mucosal thickening, and MPO (myeloperoxidase)-ANCA (anti-neutrophil cytoplasmic antibody) positivity?

Differential Diagnoses for Pseudoepitheliomatous Hyperplasia with MPO-ANCA Positivity and Subglottic Involvement

In an elderly female with pseudoepitheliomatous hyperplasia, subglottic mucosal thickening, and MPO-ANCA positivity, the primary differential diagnosis is MPO-ANCA-positive granulomatosis with polyangiitis (GPA), which represents a distinct clinical subset characterized by limited disease, frequent subglottic stenosis, and predominance in females. 1

Primary Vasculitic Differentials

MPO-ANCA-Positive Granulomatosis with Polyangiitis (GPA)

• This is the most likely diagnosis given the clinical triad of subglottic involvement, MPO-ANCA positivity, and female sex 1
• MPO-ANCA-positive GPA patients frequently present with limited disease without severe organ involvement and have a high prevalence of subglottic stenosis 1
• This subset is predominantly female and younger than typical microscopic polyangiitis patients, with significantly lower relapse rates compared to PR3-ANCA-positive GPA 1
• Pseudoepitheliomatous hyperplasia can occur as a reactive epithelial response to the chronic inflammation and granulomatous process 2
• Testing for both PR3-ANCA and MPO-ANCA using high-quality antigen-specific assays is essential, as 84-85% of GPA patients are PR3-ANCA positive, but MPO-ANCA positivity occurs in a distinct subset 3

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

• MPO-directed p-ANCA is found in 35% of EGPA patients 4
• EGPA typically presents with adult-onset asthma, chronic rhinosinusitis with eosinophilic nasal polyps, and marked peripheral eosinophilia (>1500 cells/μL or >10%) 4
• Subglottic involvement can occur but is less characteristic than in GPA 4
• The absence of asthma, nasal polyposis, and peripheral eosinophilia would argue strongly against EGPA 4
• EGPA rarely presents with PR3-ANCA positivity and has a different clinical phenotype from GPA 3

Microscopic Polyangiitis (MPA)

• MPO-ANCA positivity occurs in 20-40% of MPA cases 4
• MPA typically presents with renal involvement (necrotizing crescentic glomerulonephritis) and pulmonary capillaritis rather than granulomatous upper airway disease 1
• Subglottic stenosis is not a characteristic feature of MPA, making this diagnosis less likely in this clinical context 1

Non-Vasculitic Differentials for Pseudoepitheliomatous Hyperplasia

Chronic Infection

• Prolonged inflammation and chronic infection can cause pseudoepitheliomatous hyperplasia that mimics squamous cell carcinoma histologically 2
• Fungal infections, mycobacterial infections, and other chronic granulomatous infections should be excluded with appropriate stains and cultures 2

Chronic Inflammatory Conditions

• Lye-induced or caustic injury can cause chronic inflammation leading to pseudoepitheliomatous hyperplasia 5
• Chronic laryngeal inflammation from reflux, smoking, or other irritants can produce reactive epithelial proliferation 6

Neoplastic Conditions

• Well-differentiated squamous cell carcinoma must be definitively excluded, as pseudoepitheliomatous hyperplasia closely simulates malignancy histologically 2
• Careful morphological and immunophenotypical study is required to distinguish benign reactive hyperplasia from true malignancy 6

Diagnostic Algorithm

Initial Workup

• Complete ANCA testing with both PR3-ANCA and MPO-ANCA using high-quality antigen-specific assays 3
• CT chest to evaluate for pulmonary nodules, infiltrates, or cavitating lesions characteristic of GPA 3
• Sinus CT scan to assess upper respiratory tract involvement 3
• Complete blood count with differential to assess for eosinophilia (which would suggest EGPA over GPA) 4
• Renal function tests and urinalysis to evaluate for glomerulonephritis 3

Tissue Diagnosis

• Biopsy of affected tissue is essential, with careful endoscopically directed sampling after cleaning and decongesting the area 7
• Look for the three key histopathological findings of GPA: granulomatous inflammation, necrosis, and vasculitis affecting small to medium vessels 7
• Bronchial biopsies have lower sensitivity (only 12% positive) compared to lung or kidney biopsies, so consider open lung biopsy if bronchial samples are non-diagnostic 7
• Special stains and cultures must be performed to exclude fungal, mycobacterial, or other infectious etiologies 2

Additional Testing to Exclude EGPA

• Serum total IgE and specific IgE/IgG for Aspergillus species 4
• Serologic testing for toxocariasis and other parasitic infections 4
• Pulmonary function tests to assess for asthma 4

Critical Pitfalls to Avoid

• Do not mistake pseudoepitheliomatous hyperplasia for squamous cell carcinoma—this is a self-limited benign condition that requires immunophenotypical confirmation before considering invasive treatment 5, 6
• Do not assume all MPO-ANCA-positive vasculitis is microscopic polyangiitis—MPO-ANCA-positive GPA is a distinct entity with different clinical features, prognosis, and treatment requirements 1
• Do not rely solely on ANCA testing—a negative ANCA does not rule out GPA, particularly in limited disease, and tissue diagnosis remains essential 4, 3
• Nasal and bronchial biopsies often fail to show the classic triad of GPA features, so "consistent with" rather than definitive diagnoses are common and should prompt consideration of additional biopsy sites 7