What are the diagnostic criteria for lymphocytosis?

Diagnostic Criteria for Lymphocytosis

Lymphocytosis is defined as an absolute lymphocyte count (ALC) >4,000/μL in adults, though the threshold for diagnosing chronic lymphocytic leukemia specifically requires >5,000/μL of mature-appearing lymphocytes. 1, 2

Defining Thresholds

• General lymphocytosis: ALC >4,000/μL (normal range 1,000-4,800/μL in adults) 2, 3
• CLL-specific threshold: ALC >5,000/μL of mature-appearing lymphocytes required for diagnosis 1, 2
• Monoclonal B-cell lymphocytosis (MBL): Monoclonal B-cells <5,000/μL without lymphadenopathy, organomegaly, cytopenias, or constitutional symptoms 4

Essential Diagnostic Workup

Initial Laboratory Assessment

• Complete blood count with differential to confirm absolute lymphocyte count 2
• Peripheral blood smear examination to assess lymphocyte morphology (mature vs. atypical/abnormal cells) 1, 2
• Flow cytometry immunophenotyping is mandatory and should include:
  • Pan-B markers: CD19, CD20, CD23 1, 2
  • Pan-T markers: CD3, CD4, CD8 2
  • CD5 antigen 1, 2
  • Surface immunoglobulin light chain restriction (kappa/lambda) to assess clonality 1, 2

Critical pitfall: Do not rely solely on absolute lymphocyte count for CLL diagnosis—immunophenotyping is essential to distinguish CLL from other lymphoproliferative disorders and reactive processes. 2

Morphologic Features for CLL

• Lymphocytes must appear mature on peripheral blood smear 1
• Up to 55% prolymphocytes is still consistent with CLL diagnosis 1, 2
• >55% prolymphocytes and/or >15,000/μL prolymphocytes establishes prolymphocytic leukemia (PLL), not CLL 1

Immunophenotypic Criteria for B-CLL

The diagnosis requires three main phenotypic features: 1

1. CD5+ with B-cell markers (CD19+, CD20+, CD23+) in absence of other pan-T-cell markers 1, 2
2. Monoclonal B-cells with either kappa or lambda light chain restriction 1, 2
3. Low-density surface immunoglobulin expression 1

Additional Testing When Monoclonal Population Detected

• Quantitative immunoglobulins (IgG, IgA, IgM) and beta-2 microglobulin 2
• Comprehensive metabolic panel and LDH 2
• Hepatitis B testing (HBsAg and HBcAb) and hepatitis C in high-risk patients 2
• CT scan of chest/abdomen/pelvis with contrast if treatment is being considered or concerning symptoms present 2

When Bone Marrow Evaluation Is Needed

Bone marrow biopsy is not routinely required for CLL diagnosis if peripheral blood flow cytometry confirms the diagnosis. 2

However, consider bone marrow evaluation when: 2

• Treatment is being considered for a confirmed lymphoproliferative disorder
• Evaluating unexplained cytopenias in the setting of lymphocytosis
• Assessing early-stage disease requiring further characterization

Duration Considerations

• Historical requirement: Original 1996 guidelines required lymphocytosis duration of at least 4 weeks 1
• Current practice: Only rare patients with questionable or indolent/smoldering CLL require reassessment of lymphocyte count after 24 weeks, as clinical features, histology, and phenotypic characteristics are sufficient for accurate diagnosis in the majority 1

Key Diagnostic Distinctions

Monoclonal B-cell lymphocytosis (MBL) is diagnosed when monoclonal B-cells are <5,000/μL without lymphadenopathy, organomegaly, cytopenias, or constitutional symptoms. 4 These patients require observation only, with monitoring every 3-12 months depending on B-cell count. 4

Reactive lymphocytosis typically shows polyclonal T-cell expansion rather than monoclonal B-cell population, and often resolves with treatment of underlying condition (infection, inflammation). 5