What are the possible causes of a lymphocyte‑predominant, loculated pleural effusion?

Differential Diagnosis of Lymphocytic Loculated Pleural Effusion

The primary causes of a lymphocytic, loculated pleural effusion are tuberculosis and malignancy, with tuberculosis being the most common infectious etiology and malignancy accounting for 42-77% of all exudative effusions. 1

Major Etiologies

Malignancy (Most Common Overall)

• Lung carcinoma accounts for approximately one-third of all malignant effusions and is the leading malignant cause, particularly adenocarcinoma. 1
• Breast carcinoma is the second most common malignancy causing lymphocytic effusions. 1
• Lymphomas (both Hodgkin's and non-Hodgkin's) represent approximately 10% of malignant pleural effusions and characteristically present with lymphocyte-predominant exudates. 2, 1
  • In Hodgkin's disease, obstruction of lymphatic drainage by enlarged mediastinal lymph nodes is the main mechanism. 2
  • In non-Hodgkin's lymphoma, direct tumor infiltration of the parietal or visceral pleura predominates. 2
  • Effusions may be serous, hemorrhagic, or chylous, with non-Hodgkin's lymphoma being the most common cause of chylothorax. 2
• Multiple myeloma causes effusions in approximately 6% of cases with characteristically high pleural protein values (8-9 g/L). 2, 1

Tuberculosis (Most Common Infectious Cause)

• Tuberculous pleural effusion is generally characterized by lymphocytic exudative effusion and can present as either free-flowing or loculated. 3
• Neutrophilic loculated tuberculous effusion occurs in approximately 30% of neutrophilic tuberculous cases (10% of all tuberculous effusions), representing an important diagnostic pitfall. 3
• Lymphocytes predominate overwhelmingly (>80% of all leukocytes) in 29 of 31 effusions with verified or probable tuberculous etiology. 4
• High mycobacterial burden may be observed in the pleural fluid, and favorable outcomes are achieved with antituberculosis drug administration alone. 3

Systemic Lupus Erythematosus

• SLE affects up to 50% of patients during disease course and produces lymphocytic exudates. 1

Diagnostic Algorithm

Initial Characterization

• Apply Light's criteria first to confirm exudative nature (sensitivity 98%, specificity 72%). 1
• Perform thoracic ultrasound on every patient to assess safety of diagnostic aspiration, effusion size, character, and look for nodularity of the diaphragm and parietal pleura (highly suggestive of malignancy). 1
• Obtain detailed occupational history, including asbestos exposure, as this should raise suspicion for mesothelioma. 1

Pleural Fluid Analysis

• Cytology achieves approximately 80% diagnostic yield in malignancy but only 31-55% in lymphoma, with the lowest yield in Hodgkin's disease. 2, 1
• Adenosine deaminase (ADA) levels are independent discriminators of tuberculous effusion from complicated parapneumonic effusion. 3
• Pleural fluid pH and glucose correlate with prognosis but have poor predictive value for pleurodesis success. 2
• VEGF levels are significantly higher in malignant effusions (2,091.47 ± 1,624.80 pg/mL) compared to tuberculous effusions (1,291.05 ± 1,100.53 pg/mL), with area under the curve of 0.73. 5

Advanced Diagnostic Procedures

• Thoracoscopy has superior diagnostic yield, particularly for lymphoma (85% sensitivity with chromosome analysis) and when malignancy is suspected after routine tests fail. 2, 1
• Flow cytometry can demonstrate clonality and should be performed when lymphoma is suspected. 2, 6
• CT chest/abdomen/pelvis should be obtained if malignancy is suspected, with diagnostic yield of approximately 80%. 1

Specific Diagnostic Features

• Nodular parenchymal lesions on imaging are independent discriminators of neutrophilic loculated tuberculous effusion from complicated parapneumonic effusion. 3
• Absence of mediastinal shift in massive effusions may indicate mediastinal fixation by tumor, mainstem bronchus occlusion, or extensive pleural involvement, particularly in mesothelioma. 7
• Eosinophilia (>10%) of pleural fluid was not present in any patient with proven tuberculosis and in only one patient with malignant effusion, indicating nontuberculous, nonmalignant etiology. 4

Critical Pitfalls to Avoid

• Do not exclude tuberculosis based on neutrophilic predominance alone, as neutrophilic loculated tuberculous effusion occurs in 30% of neutrophilic tuberculous cases and requires differentiation from complicated parapneumonic effusion. 3
• Do not rely on pleural fluid ANA testing for diagnosing SLE, as it merely mirrors serum levels. 1
• Reconsider pulmonary embolism and tuberculosis in persistent undiagnosed effusions, as both are amenable to specific treatment. 1
• Empirical anti-tuberculous therapy may be justified with positive tuberculin skin test and exudative lymphocytic effusion in appropriate clinical context. 1
• Malignant effusions can be bilateral, and should not be excluded based on bilaterality alone. 7
• Review medication history carefully, as tyrosine kinase inhibitors are now the most common drugs causing exudative pleural effusions. 1