What are the causes of chronic leukocytosis?

Causes of Chronic Leukocytosis

Chronic leukocytosis is most commonly caused by hematologic malignancies, particularly chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and other myeloproliferative neoplasms, with non-hematologic causes accounting for only approximately 3% of cases and typically associated with advanced solid tumors in a paraneoplastic context. 1

Primary Hematologic Causes (97% of chronic cases)

Chronic Lymphocytic Leukemia (CLL)

• Most frequent adult leukemia (25% of all leukemias) and the leading cause of chronic lymphocytosis 2, 3
• Defined by sustained peripheral blood lymphocytes ≥5 × 10⁹/L with characteristic immunophenotype: CD5+, CD19+, CD20+ (low), CD23+, surface Ig low 2, 3
• Incidence: 3-5/100,000/year, increasing to 50/100,000/year after age 70 2
• Presents with small, morphologically mature lymphocytes on blood smear 3

Chronic Myeloid Leukemia (CML)

• Characterized by excessive granulocytosis with left shift of granulopoiesis 4
• Caused by BCR-ABL1 fusion from t(9;22) Philadelphia chromosome translocation 4
• Incidence: 10-15 cases/million/year, median age 60-65 years 4
• Diagnosis confirmed by Philadelphia chromosome or BCR-ABL1 transcripts on peripheral blood 4

Other Myeloproliferative Neoplasms

• Chronic myelomonocytic leukemia (CMML): Accounts for 10% of myelodysplastic syndromes, presents with monocytosis and variable clinical phenotypes 5
• Atypical CML: Characterized by neutrophilic leukocytosis ≥13 × 10⁹/L with circulating immature myeloid cells ≥10%, dysgranulopoiesis, and absence of BCR-ABL1 fusion 6

Secondary Non-Hematologic Causes (3% of chronic cases)

Paraneoplastic Syndromes

• Advanced solid tumors are the predominant non-hematologic cause in chronic cases 1
• These represent paraneoplastic phenomena rather than direct tumor infiltration
• Critical finding: Isolated infection-related chronic leukocytosis was NOT observed in large cohort studies 1

Chronic Inflammatory Conditions

• Autoimmune diseases
• Chronic infections (though not typically causing sustained marked elevations)
• Allergic conditions (typically eosinophilia) 7, 8

Other Benign Causes

• Medications
• Asplenia
• Smoking
• Obesity 8

Diagnostic Approach Algorithm

When encountering chronic leukocytosis:

1. Immediate peripheral blood smear review to assess:

   • Cell morphology and maturity
   • Presence of immature cells or blasts
   • Toxic granulations
   • Uniformity of white blood cells 8

2. Determine predominant cell line:

   • Lymphocytosis: Pursue CLL workup with flow cytometry (CD5, CD19, CD20, CD23) 3
   • Neutrophilia with left shift: Evaluate for CML with BCR-ABL1 testing 4
   • Monocytosis: Consider CMML 5

3. Red flags requiring immediate hematology referral 8:

   • Constitutional symptoms (fever, weight loss, night sweats)
   • Unexplained bruising or bleeding
   • Fatigue disproportionate to anemia
   • Abnormal peripheral smear with immature cells
   • WBC >100,000/µL (hyperleukocytosis) 9

4. If malignancy excluded: Consider secondary causes only after thorough hematologic evaluation, as these represent <3% of chronic cases 1

Critical Clinical Pitfalls

• Do not attribute chronic leukocytosis to infection alone: No cases of isolated infection-related chronic leukocytosis were identified in comprehensive cohort analysis 1
• Do not delay hematology consultation: 97% of chronic leukocytosis cases have underlying hematologic malignancy 1
• Hyperleukocytosis (WBC >100,000/µL) demands urgent intervention: Risk of leukostasis, DIC, and tumor lysis syndrome requires immediate cytoreduction with hydroxyurea and definitive diagnosis 10, 9
• Age-appropriate reference ranges are essential: Normal WBC counts vary by age and pregnancy status 8