What are the differential diagnoses for an elderly female patient with hoarseness of voice, mucosal thickening in the subglottis, pseudoepitheliomatous hyperplasia on biopsy, Myeloperoxidase (MPO) Anti-Neutrophil Cytoplasmic Antibodies (ANCA) positivity, and non-Fluorodeoxyglucose (FDG) avid calcified nodules in the bilateral apex and lingula on Positron Emission Tomography (PET) Computed Tomography (CT) scan, without systemic signs of vasculitis?

Differential Diagnoses for Elderly Female with Subglottic Involvement and MPO-ANCA Positivity

The primary differential diagnosis is localized granulomatosis with polyangiitis (GPA) affecting the subglottis, despite MPO-ANCA positivity, given the pseudoepitheliomatous hyperplasia, subglottic mucosal thickening, and absence of systemic vasculitis. 1

Primary Consideration: Localized Granulomatosis with Polyangiitis (GPA)

Subglottic stenosis with pseudoepitheliomatous hyperplasia is highly characteristic of GPA, even when MPO-ANCA positive rather than the typical PR3-ANCA. 1

• Subglottic involvement occurs in GPA and can present as an isolated finding without systemic disease 1
• While 10-20% of GPA patients show MPO-ANCA (P-ANCA) rather than the classic PR3-ANCA (C-ANCA), this does not exclude the diagnosis 2
• Pseudoepitheliomatous hyperplasia on biopsy is consistent with chronic granulomatous inflammation seen in GPA 1
• The calcified apical lung nodules suggest old granulomatous disease, compatible with either healed GPA or prior tuberculosis exposure 1
• Critical pitfall: Nasal/laryngeal biopsies in GPA often show only "consistent with" rather than definitive findings, as all three criteria (necrosis, granulomatous inflammation, and vasculitis) may not be present in mucosal samples 1

Secondary Differential: Microscopic Polyangiitis (MPA) with Upper Airway Involvement

MPO-ANCA positivity is most commonly associated with MPA (35-40% of cases), though upper airway involvement is less typical. 3, 2

• MPA patients are predominantly MPO-ANCA positive 1, 3
• However, isolated subglottic involvement without renal or pulmonary vasculitis manifestations makes MPA less likely 1, 4
• The absence of microscopic hematuria, dysmorphic red blood cells, red cell casts, or declining renal function argues strongly against active MPA 4, 5

Tertiary Differential: Eosinophilic Granulomatosis with Polyangiitis (EGPA)

EGPA should be considered given MPO-ANCA positivity (present in 35-77% of EGPA cases), though the absence of asthma and eosinophilia makes this unlikely. 1

• MPO-ANCA positive EGPA patients frequently manifest upper airway involvement and neuropathy 1
• However, EGPA requires asthma and marked peripheral eosinophilia (>1500 cells/μL or >10%) for diagnosis 1
• The absence of these cardinal features essentially excludes EGPA 1

Alternative Granulomatous Conditions to Exclude

Sarcoidosis

Sarcoidosis can present with laryngeal involvement and non-caseating granulomas, with calcified lung nodules on imaging. 1

• Laryngeal sarcoid shows nodular hypertrophy and can affect the supraglottis and subglottis 1
• Non-FDG avid calcified apical nodules are compatible with chronic sarcoid 1
• However, sarcoid is ANCA-negative, making this diagnosis less likely given the MPO-ANCA positivity 1
• Serum angiotensin-converting enzyme (SACE) testing and tissue biopsy showing non-caseating granulomas would support sarcoidosis 1

Tuberculosis

Old tuberculosis can cause calcified apical lung nodules and laryngeal involvement, but would not explain MPO-ANCA positivity. 1

• The bilateral apical calcified nodules are classic for healed tuberculosis 1
• Active laryngeal tuberculosis would show FDG avidity on PET-CT, which is absent here 1
• Special stains for acid-fast bacilli should be negative on biopsy to exclude this 1

Rhinoscleroma

Rhinoscleroma causes upper airway granulomatous inflammation but is an infectious process incompatible with ANCA positivity. 1

Diagnostic Algorithm

Immediate next steps should prioritize:

1. Urinalysis with microscopy looking specifically for dysmorphic RBCs, red cell casts, and proteinuria to assess for occult renal involvement 4, 5
2. Renal function testing (serum creatinine, GFR) to exclude subclinical glomerulonephritis 4, 5
3. Inflammatory markers (ESR, CRP) which are typically elevated in active vasculitis 1, 4
4. Repeat ANCA testing with high-quality antigen-specific ELISA for both MPO-ANCA and PR3-ANCA to confirm specificity 4, 5
5. Chest CT to better characterize the lung nodules and assess for active pulmonary vasculitis features (infiltrates, cavitation, ground-glass opacities) 1
6. Consider deeper laryngeal biopsy after decongestion to increase diagnostic yield for definitive GPA features 1

Critical management point: If urinalysis shows active sediment or renal function is declining, do not delay immunosuppressive therapy while awaiting additional biopsies, as this represents organ-threatening disease requiring immediate treatment with glucocorticoids plus rituximab or cyclophosphamide. 4, 5

Key Clinical Pitfalls

• Do not dismiss GPA based solely on MPO-ANCA positivity: 10-20% of GPA patients are MPO-ANCA positive rather than PR3-ANCA positive 2
• Do not assume absence of systemic disease means no treatment needed: Localized GPA can progress to systemic disease and subglottic stenosis itself is organ-threatening 1
• Do not overlook occult renal involvement: Up to 10% of AAV patients may have normal inflammatory markers, and renal disease can be asymptomatic initially 4
• Pseudoepitheliomatous hyperplasia can mimic malignancy: Ensure adequate sampling ruled out NK/T cell lymphoma or squamous cell carcinoma 1