How is pulmonary amyloidosis diagnosed?

Diagnosing Pulmonary Amyloidosis

Pulmonary amyloidosis diagnosis requires tissue biopsy demonstrating Congo red-positive deposits with apple-green birefringence under polarized light, followed by amyloid typing via mass spectrometry to determine the protein subtype and guide treatment. 1, 2

Initial Clinical Suspicion

Suspect pulmonary amyloidosis when patients present with:

• Chronic cough, wheezing (often misdiagnosed as asthma), or hemoptysis in middle-aged to older adults (average diagnosis age ~55 years) 3
• Unexplained dyspnea or respiratory symptoms with CT chest findings of nodular lesions, diffuse interstitial infiltrates, or tracheobronchial thickening 4, 5
• Constitutional symptoms including weight loss and fatigue, particularly if systemic involvement is suspected 1

Diagnostic Algorithm

Step 1: Imaging Evaluation

• CT chest is typically the first modality to identify pulmonary amyloid patterns 4
• Look for three distinct patterns: nodular, diffuse alveolar-septal (most common), or tracheobronchial involvement 5

Step 2: Tissue Biopsy (Essential for Diagnosis)

Bronchoscopic approaches:

• Transbronchial lung cryobiopsy (TBLC) provides larger specimens than forceps biopsy with lower mortality than surgical lung biopsy 6
• Bronchoscopy with biopsy for tracheobronchial disease showing diffuse submucosal infiltration (nodular, tumor-like, or polypoid appearance) 3

Surgical lung biopsy remains standard but carries higher procedural mortality, particularly in elderly patients with comorbidities 6

Step 3: Histopathological Confirmation

Required findings:

• Congo red staining showing red deposits under normal light 2
• Apple-green birefringence under polarized light - this is pathognomonic and the gold standard for diagnosis 1, 2
• Eosinophilic (pink) hyaline material on routine H&E staining 2

Step 4: Amyloid Typing (Critical for Treatment)

Mass spectrometry is the gold standard (88% sensitivity, 96% specificity) to identify the protein subtype 2

Alternative methods include immunohistochemistry, immunofluorescence, or immunogold electron microscopy 1

Step 5: Distinguish Localized vs. Systemic Disease

For localized pulmonary amyloidosis:

• Abdominal fat pad biopsy to rule out systemic involvement 7
• Bone marrow biopsy to exclude plasma cell disorders or lymphoproliferative disease 7
• Localized tracheobronchial amyloidosis typically does not progress to systemic disease 3

For systemic AL amyloidosis workup:

• Serum and urine immunofixation to detect monoclonal protein 1
• Serum free light chain (FLC) assay with abnormal kappa/lambda ratio (reference 0.26-1.65 for normal renal function) 1
• Cardiac biomarkers: NT-proBNP (>332 ng/L has >99% sensitivity for cardiac involvement) and troponin T for staging 1
• Echocardiography or cardiac MRI if cardiac involvement suspected 1
• 24-hour urine protein and eGFR for renal assessment 1
• Consider fat aspirate or bone marrow biopsy with Congo red staining as accessible alternative sites 1

Critical Pitfalls to Avoid

• Never rely on imaging alone - tissue diagnosis with Congo red staining and polarized light microscopy is mandatory 2
• Always perform amyloid typing - AL amyloidosis requires chemotherapy while TTR amyloidosis requires targeted therapy like tafamidis; treatment differs fundamentally 1
• Do not assume localized disease without systemic workup - perform fat pad and bone marrow biopsies to exclude occult systemic involvement 7
• Recognize that pulmonary amyloidosis is frequently asymptomatic - diagnosis is often made incidentally or in the setting of known systemic disease 5
• Consider TBLC over surgical biopsy when feasible to reduce procedural mortality while obtaining adequate tissue 6