What is the recommended algorithm for evaluating and managing a suspected malignant pleural effusion in an adult patient?

Algorithmic Approach to Malignant Pleural Effusion

Begin with thoracic ultrasound and diagnostic thoracentesis for any unilateral pleural effusion, send fluid for cytology with immunocytochemistry, and if two cytology specimens are negative proceed directly to pleural biopsy rather than repeating cytology a third time. 1, 2

Step 1: Initial Clinical Assessment

Obtain specific historical details that point toward malignancy:

• Document occupational asbestos exposure, as this is essential for diagnosing mesothelioma and has legal implications 1
• Review medications including tyrosine-kinase inhibitors, amiodarone, nitrofurantoin, and methotrexate, which cause exudative effusions 1, 3
• Identify known metastatic cancer, as this is the most common cause of malignant effusion 1
• Note weight loss, fever, and night sweats, which suggest malignancy or tuberculosis 1
• Assess for symptoms persisting for months, indicating chronic processes like malignancy 1

Physical examination findings that support malignancy:

• Unilateral reduced chest expansion, dullness to percussion, and diminished breath sounds 1
• Cachexia and lymphadenopathy raise suspicion for malignant effusion 1
• Oxygen saturation <92% indicates severe disease requiring urgent intervention 1

Step 2: Imaging Strategy

Perform chest radiography first to confirm the effusion and determine laterality 4, 1

• PA and lateral chest radiographs detect effusions ≥200 mL on PA view and ≥50 mL on lateral view 4

Thoracic ultrasound is mandatory before any pleural procedure 1, 3

• Ultrasound identifies diaphragmatic or parietal pleural nodularity, which strongly suggests malignancy 1
• Complex septated, complex non-septated, or homogeneously echogenic patterns on ultrasound indicate exudates 4
• Ultrasound guidance is required for all thoracentesis procedures to maximize safety 4, 1

Obtain contrast-enhanced CT of the chest (venous phase) when:

• Malignancy is suspected based on clinical features 1
• Initial thoracentesis is non-diagnostic 1
• CT should be performed while fluid is still present to visualize pleural abnormalities 1

Step 3: Diagnostic Thoracentesis

Indications for thoracentesis:

• Any unilateral pleural effusion 1, 3
• Bilateral effusions with normal cardiac silhouette 3
• Suspected malignancy regardless of bilaterality 1

Do NOT perform thoracentesis if:

• Bilateral effusions with clear clinical evidence of heart failure, cirrhosis, or hypoalbuminemia, unless atypical features are present or the effusion fails to respond to treatment 1, 3

Technique:

• Use ultrasound guidance with a 21-gauge needle attached to a 50 mL syringe 1, 3
• Limit initial fluid removal to 1.5 L maximum to prevent re-expansion pulmonary edema 3
• Place samples in both sterile containers and blood culture bottles 1

Essential pleural fluid tests:

• Visual appearance and odor 1
• Protein and LDH to apply Light's criteria 1
• pH measurement (prognostic: pH <7.3 predicts median survival of ~2 months vs ~10 months for pH >7.3) 2
• Glucose (values <3.3 mmol/L suggest malignancy) 2
• Cell count with differential 1
• Gram stain and aerobic/anaerobic cultures 1
• Acid-fast bacilli stain and tuberculosis culture 1
• Cytology on 25-50 mL of fluid 3

Step 4: Cytology Interpretation and Next Steps

First cytology specimen:

• Cytology detects only ~60% of malignant effusions overall 4, 2, 5
• The first specimen yields diagnosis in 65% of ultimately positive cases 2
• Prepare both cell blocks and fluid smears; if fluid has clotted, fix and section as histologic tissue 4, 2

Apply immunocytochemistry to all cytology specimens:

• Use epithelial membrane antigen (EMA) to confirm epithelial malignancy 4, 2
• Apply a panel including CEA, B72.3, Leu-M1, calretinin, and cytokeratin 5/6 to distinguish adenocarcinoma from mesothelioma 4, 2

If first cytology is negative or shows only atypical cells:

• Obtain a second cytology specimen immediately, as this adds diagnostic yield in 27% of ultimately positive cases 2

If two cytology specimens are negative:

• Proceed directly to pleural biopsy rather than obtaining a third cytology specimen, as the third cytology adds only ~5% diagnostic yield 2
• Pleural biopsy is especially critical for mesothelioma, squamous cell carcinoma, lymphoma, and sarcoma, which have lower cytologic detection rates than adenocarcinoma 4, 2

Step 5: Pleural Biopsy Strategy

Image-guided biopsy:

• If CT shows pleural thickening, nodules, or masses, perform ultrasound- or CT-guided pleural biopsy 3, 2
• For small or loculated effusions, ultrasound-guided biopsy ensures adequate tissue sampling 2

Closed (Abrams) pleural biopsy:

• Combined with cytology, closed biopsy yields diagnosis in 80-90% of cases 3
• Complications include pneumothorax (3-15%, with only ~1% requiring chest tube) and site pain (1-15%) 3
• Closed biopsy has lower diagnostic yield for malignancy compared with thoracoscopy 3

Thoracoscopy (medical or surgical):

• Provides diagnostic sensitivity of ~95% for malignant pleural disease 3
• Identifies malignancy in approximately two-thirds of patients whose prior closed biopsy was non-diagnostic 3
• Allows therapeutic interventions including fluid evacuation and talc pleurodesis 3
• Complications are uncommon: subcutaneous emphysema (6.9%) and cardiac dysrhythmia (0.35%) 3

Step 6: Role of Bronchoscopy

Do NOT perform routine bronchoscopy for isolated pleural effusion 3

Bronchoscopy is indicated only when:

• Hemoptysis is present 3
• Radiographic evidence shows bronchial obstruction or mass 3
• Large effusion without contralateral mediastinal shift suggests endobronchial obstruction 3
• In isolated pleural effusions without these features, bronchoscopy yields <5% diagnostic rate versus 61% from pleural-focused investigations 3

Step 7: Special Considerations for Hemorrhagic Effusions

Hemorrhagic effusions (RBC count >100,000/mm³) suggest:

• Malignancy (most commonly lung cancer, breast carcinoma, or mesothelioma in descending order) 3, 2
• Pulmonary infarction 2
• Traumatic injury 2

For suspected mesothelioma:

• Minimize the number of invasive pleural procedures, as ~40% of needle-track biopsies become infiltrated by tumor 3

Critical Pitfalls to Avoid

• Do not accept a single negative cytology as definitive—40% of malignant effusions are missed on first cytology, and a second specimen adds 27% diagnostic yield 2
• Do not obtain a third cytology specimen—proceed to pleural biopsy after two negative cytologies, as the third adds only ~5% yield 2
• Do not delay pleural biopsy when clinical suspicion remains high, particularly for mesothelioma, lymphoma, and sarcoma, which are poorly detected by cytology alone 4, 2
• Do not perform bronchoscopy routinely—it yields <5% in isolated pleural effusions without pulmonary abnormalities or hemoptysis 3
• Always use ultrasound guidance for thoracentesis to significantly reduce complication rates 4, 1