What is the clinical significance and management of mitotic cells in pleural fluid?

Clinical Significance and Management of Mitotic Cells in Pleural Fluid

The presence of mitotic cells in pleural fluid strongly suggests malignancy and warrants prompt diagnostic evaluation with pleural biopsy, as cytology alone has limited sensitivity (58.2%) for definitive diagnosis of malignant pleural effusions. 1

Diagnostic Significance of Mitotic Cells

• Mitotic cells in pleural fluid are highly suspicious for malignancy, particularly when accompanied by nuclear atypia, which correlates with prognosis in epithelioid mesothelioma 2

• The diagnostic sensitivity of pleural fluid cytology varies significantly by cancer type:

  • High sensitivity for lung adenocarcinoma (83.6%) and ovarian cancer (85.2%) 1
  • Moderate sensitivity for breast cancer (65.3%) 1
  • Low sensitivity for lung squamous cell carcinoma (24.2%) and mesothelioma (28.9%) 1, 3

• Atypical mesothelial cells with mitotic activity may represent either malignant mesothelioma or reactive mesothelial hyperplasia associated with underlying bronchogenic carcinoma 4

Diagnostic Approach

• Initial cytological evaluation should identify cells as benign/reactive or malignant based on morphological and immunohistochemical parameters 2

• When malignant cells are detected, immunohistochemical markers help determine the origin (primary pleural versus metastatic disease) 2

• For optimal diagnostic yield:

  • Submit up to 150 mL of pleural fluid when using both direct smear/cytospin and cellblock preparations 2
  • Use combined cytological methods (direct smear plus cellblock) which offer additional diagnostic value compared to smear slides alone 2

• Flow cytometry may be useful for lymphoma diagnosis but has variable sensitivity (50-94%) for non-lymphoma malignant pleural effusions 2

Limitations of Cytology

• Despite widespread use, the overall sensitivity of pleural fluid cytology for malignancy is only 58.2% (range 20.5-86.0%) 1, 3
• Cytology has particularly poor sensitivity for mesothelioma (as low as 6% in some studies) 3
• In asbestos-exposed males with exudative effusions, the risk of malignant pleural effusion is 60%, but cytological sensitivity is only 11% 3
• The pauci-cellular nature of pleural fluid often results in insufficient cells for necessary diagnostic tests 2

Role of Pleural Biopsy

• Pleural biopsy is the gold standard for diagnosing pleural malignancy, with sensitivity >92% for malignancy 2
• Thoracoscopic pleural biopsies consistently outperform cytological examination, even when cell block preparation is performed 2
• The International Mesothelioma Interest Group recommends that mesothelioma diagnosis should always be based on biopsy rather than cytology alone 2
• Pleural biopsy provides:
  • More definitive diagnosis 2
  • Prognostic information (nuclear atypia and mitotic index correlate with prognosis) 2
  • Sufficient tissue for molecular profiling to guide targeted therapies 2

Management Considerations

• When mitotic cells are identified in pleural fluid, further investigation with pleural biopsy is usually necessary 2
• In patients with clinical suspicion of mesothelioma, more definitive investigations should be performed sooner due to low cytological sensitivity 3
• Even with negative initial biopsies, up to 15% of patients with nonspecific pleuritis are subsequently diagnosed with pleural malignancy 2
• Long-term radiological monitoring is recommended when initial investigations are inconclusive but clinical suspicion remains high 2

Emerging Diagnostic Approaches

• Newer molecular profiling technologies such as high-throughput, next-generation and Sanger sequencing show promise in detecting genetic mutations in malignant pleural effusion cell blocks 2
• "Liquid biopsy" methods can identify circulating cell-free tumor DNA, tumor RNA, and circulating tumor cells from blood samples 2
• These newer approaches require further investigation before widespread clinical adoption 2