Does a negative cytology (cell examination) on an adequate sample of pleural (relating to the lungs) fluid more than 10 mL rule out malignancy (cancer) as the cause of effusion (fluid buildup)?

Negative Cytology on Pleural Fluid Does Not Definitively Rule Out Malignancy

A negative cytology result on an adequate pleural fluid sample (>10 mL) does not definitively rule out malignancy as the cause of pleural effusion, as pleural fluid cytology has a sensitivity of only about 60-72% for detecting malignant cells. 1

Diagnostic Yield of Pleural Fluid Cytology

Sensitivity Limitations

• Pleural fluid cytology has a mean sensitivity of approximately 60-72% for detecting malignancy 1
• Sensitivity varies by tumor type:
  • Higher for adenocarcinoma (especially lung and breast cancer)
  • Lower for mesothelioma (33%), squamous cell carcinoma, lymphoma, and sarcoma 2
• False negative results are more common when pleural thickening is present on CT scan 2

Volume Considerations

• The British Thoracic Society recommends:
  • At least 25 mL, and ideally 50 mL, of pleural fluid should be sent for cytological examination 1
  • If volumes <25 mL cannot be achieved, smaller volumes should be sent, but with awareness of reduced sensitivity 1
• Research studies have demonstrated:
  • 10 mL samples have significantly lower sensitivity than larger volumes 3
  • Volumes between 25-50 mL are required for adequate assessment 4
  • Volumes >50 mL may not significantly improve diagnostic yield 4

Diagnostic Algorithm for Suspected Malignant Pleural Effusion

Initial Evaluation

1. Thoracentesis with collection of at least 25-50 mL for cytology
2. Process samples with both direct smear and cell block preparation 1
3. Note appearance of fluid (cloudy or yellow/gold appearance may increase likelihood of positive cytology) 2

If Initial Cytology is Negative

1. Consider a second thoracentesis

   • Second specimen may yield diagnosis in approximately 25-28% of malignant cases 1
   • Third specimen has minimal additional yield (only ~5%) 1

2. Consider additional diagnostic procedures:

   • Thoracoscopic or image-guided pleural biopsy 1
   • CT scan to evaluate for pleural thickening or nodularity 5
   • Thoracic ultrasound to identify diaphragmatic or pleural thickening and nodularity 5

Important Caveats and Pitfalls

• False negative risk factors: Pleural thickening on CT scan increases risk of false negative cytology 2
• Tumor-specific considerations: Mesothelioma has particularly low cytology sensitivity (33%) 2
• Sample preparation matters: Both cell blocks and smears should be prepared to increase diagnostic yield 1
• Immunocytochemistry: Can help distinguish benign from malignant mesothelial cells and mesothelioma from adenocarcinoma 1
• Diagnostic persistence: A negative cytology result should lead to consideration of further investigation if clinical suspicion remains high 1

In conclusion, while pleural fluid cytology is a valuable initial diagnostic test for suspected malignant pleural effusion, its limited sensitivity means that a negative result cannot definitively exclude malignancy. Further diagnostic procedures should be considered when clinical suspicion remains high despite negative cytology.