What is the differential diagnosis of hyperleucocytosis in a patient presenting with a high white blood cell count?

Differential Diagnosis of Hyperleukocytosis

The differential diagnosis of hyperleukocytosis (WBC >100,000/μL) must distinguish between malignant and reactive causes, with acute leukemias—particularly acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)—representing the most life-threatening etiologies requiring immediate intervention. 1

Malignant Causes (Primary Considerations)

Acute Leukemias

• Acute Myeloid Leukemia (AML): Particularly monocytic/myelomonocytic subtypes (FAB M4/M5) carry significantly higher early mortality (23% vs 5% in ALL) due to intracerebral hemorrhage and pulmonary leukostasis 2
• Acute Lymphoblastic Leukemia (ALL): T-cell ALL is a specific high-risk subtype for hyperleukocytosis 3
• Acute Promyelocytic Leukemia (APL): The microgranular variant presents with hyperleukocytosis and requires special consideration—leukapheresis is absolutely contraindicated due to catastrophic hemorrhage risk 4

Chronic Leukemias

• Chronic Myeloid Leukemia (CML): Can present with hyperleukocytosis but carries lower risk of leukostasis complications compared to acute leukemias 5
• Chronic Lymphocytic Leukemia (CLL): Less commonly presents with extreme leukocytosis but should be considered in older adults 5

Reactive/Non-Malignant Causes

Infectious Etiologies

• Severe bacterial infections: Far more common than malignancy and must never be assumed absent without peripheral smear review 4
• Sepsis with leukemoid reaction: Can produce WBC counts >50,000/μL but rarely exceeds 100,000/μL 4

Other Reactive Causes

• Leukemoid reaction: Secondary to severe infection, inflammation, or malignancy (non-hematologic) 4
• Medication-induced: Growth factor administration (G-CSF, GM-CSF) can cause marked leukocytosis 6

Critical Diagnostic Distinctions

Peripheral blood smear review is mandatory and must be performed immediately—never assume malignancy without direct visualization of blast cells, as reactive leukocytosis from infection is far more common. 4

Key Differentiating Features:

• Presence of blasts: Acute leukemia shows >20% blasts in peripheral blood or bone marrow 1
• Cell morphology: Monocytic features (M4/M5 AML) indicate highest risk for leukostasis 2
• Associated cytopenias: Anemia and thrombocytopenia suggest malignancy over reactive process 4
• Clinical presentation: Leukostasis symptoms (pulmonary infiltrates, altered mental status, retinal hemorrhages) indicate acute leukemia emergency 1

Immediate Diagnostic Workup Required

• Complete blood count with differential: Evaluate all cell lines for cytopenias 4
• Peripheral blood smear: Immediate review for blast morphology 4
• Bone marrow aspiration and biopsy: Obtain immediately if acute leukemia suspected 4
• Tumor lysis syndrome markers: Uric acid, LDH, potassium, phosphate, calcium, renal function 2, 4
• Coagulation studies: Detect DIC, particularly in APL 1
• Blood cultures: Before antibiotics if infection suspected 6, 4

Common Pitfalls to Avoid

• Never delay hydration and cytoreduction while awaiting definitive diagnosis if hyperleukocytosis is present—early death from complications occurs before diagnosis is confirmed 4
• Never perform leukapheresis in APL without excluding this diagnosis first, as it causes fatal hemorrhage 4
• Never assume infection is absent in patients with fever and hyperleukocytosis—obtain cultures before starting chemotherapy 4
• Never transfuse red blood cells excessively until WBC is reduced, as this increases blood viscosity and worsens leukostasis 1