What is the clinical significance of mesothelial cells in pleural fluid?

Clinical Significance of Mesothelial Cells in Pleural Fluid

The presence of mesothelial cells in pleural fluid is clinically significant primarily as a normal finding that helps distinguish benign from malignant effusions, though their absence does not rule out benign disease and their presence—even when atypical—does not reliably diagnose malignancy, particularly mesothelioma.

Diagnostic Utility and Limitations

Normal Presence and Benign Conditions

• Mesothelial cells are specialized epithelial cells that normally line the pleural cavity and are commonly shed into pleural fluid during any pleural irritation or inflammation 1
• Their presence in pleural fluid is expected in most benign effusions and does not indicate pathology 2
• DNA-synthesizing mesothelial cells appear as single, small-sized cells with basophilic cytoplasm that exfoliate from the pleural surface during normal cellular turnover 2

Critical Limitation in Malignancy Detection

Cytologic examination of pleural fluid containing mesothelial cells is insufficient for diagnosing mesothelioma and should never be relied upon as a definitive diagnostic test 3. The American Society of Clinical Oncology guidelines provide strong evidence-based recommendations that:

• Pleural fluid cytology can serve only as an initial screening test for mesothelioma, not a diagnostic confirmation 3
• The major limitation is the extreme difficulty in differentiating malignant mesothelioma cells from reactive benign mesothelial cells 3
• When definitive diagnosis is needed, tissue biopsy via thoracoscopy (>95% diagnostic yield) or CT-guided core biopsy must be performed 3

Sensitivity for Malignancy

The British Thoracic Society guidelines demonstrate that pleural fluid cytology has approximately 60% sensitivity for detecting malignant effusions overall 3:

• First specimen detects 65% of malignancies when positive 3
• Second specimen adds another 27% 3
• Third specimen contributes only 5% additional yield 3

The diagnostic yield is particularly poor for mesothelioma compared to adenocarcinoma 3, with less than one-third of mesotheliomas diagnosed accurately on pleural fluid cytology 3.

Atypical Mesothelial Cells: A Diagnostic Pitfall

When Atypia Occurs

Atypical mesothelial hyperplasia can be encountered in several benign conditions and creates significant diagnostic confusion 4:

• Bronchogenic carcinoma in the subjacent lung can cause reactive atypical mesothelial hyperplasia that mimics mesothelioma 4
• Congestive heart failure, liver cirrhosis, and uremia can produce abnormal mesothelial cell labeling patterns 2
• The presence of atypical mesothelial cells should not be interpreted as mesothelioma without tissue confirmation 4

Immunohistochemical Limitations

• Standard immunohistochemical studies have limited value in differentiating benign reactive mesothelial cells from malignant mesothelioma cells 3
• Newer markers (BAP1 loss, p16 deletion) show promise for distinguishing mesothelioma from reactive mesothelial cells 3, 5
• However, immunocytochemistry on pleural fluid is useful for distinguishing mesothelioma from adenocarcinoma using markers like Claudin-4 (positive in adenocarcinoma, negative in mesothelioma), CEA, calretinin, and cytokeratin 5/6 3

Clinical Algorithm for Mesothelial Cell Interpretation

When Mesothelial Cells Are Present:

1. If morphologically benign: Consistent with benign effusion; correlate with clinical context and Light's criteria
2. If atypical or suspicious: Do not diagnose mesothelioma; proceed directly to tissue biopsy 3
3. If overtly malignant-appearing: Consider mesothelioma in situ (rare) but still require tissue confirmation with BAP1 immunohistochemistry 5

When Malignancy Is Suspected:

• Perform thoracoscopy with multiple pleural biopsies from different locations (diagnostic yield >95%) 3
• If thoracoscopy contraindicated: CT-guided core needle biopsy of pleural nodules 3
• Ensure biopsies are of sufficient depth to assess for invasion, which distinguishes malignant mesothelioma from benign mesothelial proliferation 3

Important Caveats

• Absence of mesothelial cells in pleural fluid may suggest malignant effusion (particularly with extensive pleural involvement), but this is not diagnostic
• Multinucleated giant mesothelial cells with emperipolesis (lymphocytes within mesothelial cell cytoplasm) can occur in lymphomas and should not be confused with malignancy of the mesothelial cells themselves 6
• Sarcomatoid and biphasic mesothelioma are rarely detected in pleural fluid specimens, even when malignant mesothelial cells are present 3