What laboratory tests should be ordered for a patient presenting with chronic leukocytosis (elevated white blood cell count)?

Laboratory Evaluation for Chronic Leukocytosis

For a patient with chronic leukocytosis, you should order a complete blood count with differential (including manual differential to assess bands and immature forms), peripheral blood smear review, comprehensive metabolic panel, lactate dehydrogenase, and proceed to bone marrow aspiration and biopsy with flow cytometry and cytogenetic analysis (including FISH for del(13q), del(11q), del(17p), trisomy 12) if a hematologic malignancy is suspected. 1, 2

Initial Essential Laboratory Tests

Complete Blood Count and Differential

• Obtain CBC with manual differential to assess absolute lymphocyte count, presence of immature forms (bands, metamyelocytes), and identify cytopenias 2, 1
• An elevated WBC count ≥14,000 cells/mm³ or left shift (band neutrophils ≥6% or total band count ≥1,500 cells/mm³) warrants careful assessment for bacterial infection or hematologic malignancy 2
• Document both percentage and absolute number of lymphocytes and prolymphocytes 2

Peripheral Blood Smear

• Manual review of peripheral smear is critical to identify abnormal cells, assess cell morphology, and detect features suggestive of hematologic malignancy 1, 2
• Look specifically for blasts, immature cells, atypical lymphocytes, or uniformity suggesting clonal proliferation 3, 4

Chemistry and Metabolic Panel

• Comprehensive metabolic panel including creatinine, bilirubin, liver transaminases, and alkaline phosphatase 2, 1
• Lactate dehydrogenase (LDH) as a marker for hemolysis, tissue damage, or malignancy 1, 2
• Serum protein electrophoresis if paraproteinemia is suspected 1, 2

Immunophenotyping and Flow Cytometry

When Lymphocytosis is Present

• Flow cytometry of peripheral blood is essential if lymphoproliferative disorder is suspected 1, 2
• For chronic lymphocytic leukemia evaluation, look for the composite immunophenotype: CD5+, CD19+, CD20+ (low), CD23+, surface immunoglobulin low, CD79b low, FMC7- 2
• Sustained lymphocytosis ≥5 × 10⁹ cells/L with appropriate immunophenotype establishes CLL diagnosis 2

Additional Immunologic Studies

• Quantitative immunoglobulins and immunoelectrophoresis 2
• Direct antiglobulin test (Coombs test) to evaluate for autoimmune hemolysis 2, 1

Bone Marrow Evaluation

Indications for Bone Marrow Biopsy

• Perform unilateral bone marrow aspirate and biopsy if abnormal cells are found in peripheral blood, unexplained cytopenias exist, or when hematologic malignancy is suspected 1, 2
• Bone marrow is not needed for CLL diagnosis if peripheral blood shows characteristic findings, but is recommended before initiating therapy to evaluate unclear cytopenias 2
• Include morphology assessment, immunohistochemistry, flow cytometry, and cytogenetic analysis 2

Cytogenetic and Molecular Testing

• FISH analysis for del(13q), del(11q), del(17p), trisomy 12, and del(6q) in peripheral blood lymphocytes for CLL evaluation 2
• Karyotyping and molecular analyses to identify recurrent chromosomal abnormalities 2
• For acute leukemia concerns, assess for Philadelphia chromosome t(9;22), MLL translocations, and other prognostic markers 2

Infectious Disease Workup

When Infection is Suspected

• Bacterial cultures if infection is clinically suspected 1, 2
• Viral studies including EBV, CMV, HIV, and hepatitis testing when clinically indicated 1
• Tuberculosis testing (PPD or interferon-gamma release assay) if granulomatous disease is suspected 1
• HIV testing should not be overlooked in patients with unexplained lymphadenopathy or leukocytosis 1, 2

Imaging Studies

Anatomic Assessment

• CT scan of chest, abdomen, and pelvis with contrast to document organomegaly and extent of lymphadenopathy if hematologic malignancy is suspected 1, 2
• Chest radiograph at minimum 2
• PET/CT if transformation to aggressive lymphoma is suspected 1

Common Pitfalls to Avoid

• Do not delay bone marrow evaluation when peripheral blood shows concerning findings such as blasts, immature cells, or unexplained cytopenias 1
• Avoid assuming all leukocytosis is infectious—consider paraneoplastic syndromes, particularly with extreme elevations (WBC >40,000/μL) without infection 5, 6
• Do not overlook nonmalignant causes including medications, smoking, obesity, chronic inflammatory conditions, and physiologic stress responses 3, 7
• Remember that leukocytosis in hospitalized patients may represent persistent inflammation-immunosuppression and catabolism syndrome (PICS) rather than active infection, potentially avoiding unnecessary prolonged antibiotics 6
• Exclude myeloproliferative neoplasms by appropriate testing including BCR-ABL for chronic myeloid leukemia if neutrophilia predominates 5, 7