Can non-small cell lung cancer (NSCLC) cause fever and leukocytosis?

Non-Small Cell Lung Cancer as a Cause of Fever and Leukocytosis

Non-small cell lung cancer (NSCLC) can directly cause fever and leukocytosis as a paraneoplastic phenomenon, particularly in cases with necrotic tumor tissue or rapidly progressive metastatic disease.

Mechanisms of Fever and Leukocytosis in NSCLC

• NSCLC can cause fever through paraneoplastic mechanisms, with tumor fever being a well-described phenomenon that may occur at both initial diagnosis and disease relapse 1
• Necrotic tumor tissue, particularly liver metastases, can trigger systemic inflammation leading to fever and leukocytosis 2
• Some lung cancers can produce granulocyte colony-stimulating factor (G-CSF), resulting in paraneoplastic leukocytosis even in the absence of infection 2
• Malignancy-related fever is more commonly encountered in metastatic disease but can occur in non-metastatic NSCLC as well 1

Differential Diagnosis

• Bacterial infections remain the most common cause of neutrophilic leukocytosis with fever in cancer patients and must be excluded first 3, 4
• Healthcare-associated infections, particularly catheter-related infections, are important considerations in cancer patients with fever 4
• Venous thromboembolic disease is another potential cause of fever in cancer patients 4
• Treatment-related fever (chemotherapy, immunotherapy, radiation) should be considered in patients receiving active cancer treatment 4
• Opportunistic infections, though less common in solid tumors than hematologic malignancies, should be considered, particularly systemic candidiasis and Pneumocystis jiroveci pneumonia 4

Diagnostic Approach

• When a cancer patient presents with fever, extensive diagnostic studies are needed to differentiate neoplastic fever from infectious causes 5
• Laboratory markers suggesting bacterial infection include:
  • Neutrophil percentage >90% (likelihood ratio 7.5 for bacterial infection) 3
  • Band neutrophils >16% (likelihood ratio 4.7 for bacterial infection) 3
  • Elevated total band count >1500 cells/mm³ (high likelihood for bacterial infection) 3
• The naproxen test (resolution of fever within 24 hours after naproxen administration) can help differentiate neoplastic fever from infectious causes 5
• Imaging studies to identify necrotic tumor tissue, particularly liver metastases, may support the diagnosis of tumor-related fever 2

Management Considerations

• Treatment of the underlying NSCLC is the definitive approach for managing paraneoplastic fever 1
• Non-steroidal anti-inflammatory drugs (NSAIDs), particularly naproxen, can effectively manage neoplastic fever when specific cancer treatment is not immediately possible 5
• Corticosteroids may be considered as an alternative for symptomatic management of tumor-related fever 1
• Patients with NSCLC presenting with fever and leukocytosis have often been found to have rapidly progressive disease and limited survival, making prompt diagnosis and treatment crucial 2

Important Caveats

• Neoplastic fever should be considered a diagnosis of exclusion after ruling out infectious causes, as missing an infection could lead to significant morbidity and mortality 5
• The presence of fever and leukocytosis in NSCLC patients may indicate a more aggressive disease course and should prompt consideration of appropriate staging and treatment planning 2
• While NSCLC can cause fever and leukocytosis directly, patients with cancer remain at increased risk for infections, and the threshold for initiating empiric antibiotics should be low while diagnostic workup is ongoing 4