Workup for Lymphocytosis
The workup for a patient with lymphocytosis should begin with a complete blood count (CBC), peripheral blood smear examination, and flow cytometry immunophenotyping to determine if the lymphocytosis is monoclonal or reactive in nature. 1, 2
Initial Evaluation
- Complete blood count (CBC) with differential to confirm absolute lymphocyte count >4000/μL 2
- Peripheral blood smear examination to assess lymphocyte morphology (mature vs. atypical/abnormal cells) 1
- Flow cytometry immunophenotyping of peripheral blood with minimum panel including:
- Pan-B markers (CD19, CD20, CD23)
- Pan-T markers (CD3, CD4, CD8)
- CD5 (to identify potential CLL)
- Surface immunoglobulin light chain restriction (kappa/lambda) to assess clonality 1
- Comprehensive metabolic panel 1
- Lactate dehydrogenase (LDH) level 1
- Hepatitis B testing (HBsAg and HBcAb) 1
- Hepatitis C testing in high-risk patients 1
Additional Testing Based on Initial Results
If Monoclonal B-Cell Population Detected:
- Quantitative immunoglobulins (IgG, IgA, IgM) 1
- Beta-2 microglobulin 1
- CT scan of chest/abdomen/pelvis with contrast (if treatment is being considered or if there are concerning symptoms) 1
- Bone marrow biopsy with aspirate if:
- Treatment is being considered
- Evaluating for early-stage disease (stage I or II)
- Assessing cytopenias 1
If Monoclonal T-Cell Population Detected:
- HTLV-I serology (especially if from endemic areas) 1
- T-cell receptor gene rearrangement studies 1
- CT scan of chest/abdomen/pelvis 1
- Bone marrow aspirate and biopsy 1
If Reactive Lymphocytosis Suspected:
- Viral studies (EBV, CMV, HIV) 3
- Assessment for other infectious causes 4
- Evaluation for autoimmune disorders if clinically indicated 4
Special Considerations
- For lymphocyte count >10,000/μL, the likelihood of chronic lymphocytic leukemia (CLL) increases significantly 5
- For CLL diagnosis, absolute lymphocyte count must exceed 5,000/μL with specific immunophenotypic features (CD5+, CD19+, CD20+ dim, CD23+, with light chain restriction) 1, 2
- Monoclonal B-cell lymphocytosis (MBL) is diagnosed when monoclonal B-cells are <5,000/μL without other features of lymphoproliferative disorder 1
- Consider hemophagocytic lymphohistiocytosis (HLH) if lymphocytosis is accompanied by fever, splenomegaly, cytopenias, hyperferritinemia, and elevated triglycerides 1
When to Consider Bone Marrow Evaluation
- When treatment is being considered for a confirmed lymphoproliferative disorder 1
- To evaluate unexplained cytopenias in the setting of lymphocytosis 1
- For staging of potential early-stage lymphoma 1
- Not routinely needed for CLL diagnosis if peripheral blood flow cytometry confirms the diagnosis 1
Pitfalls to Avoid
- Do not rely solely on absolute lymphocyte count for diagnosis of CLL; immunophenotyping is essential 1, 2
- Do not mistake transient lymphocytosis (e.g., post-trauma, stress, or infection) for a lymphoproliferative disorder 6
- Avoid overinterpreting isolated lymphocytosis without clinical context 2
- Remember that up to 55% prolymphocytes can still be consistent with CLL diagnosis; >55% suggests prolymphocytic leukemia 1
Following this systematic approach will help determine whether lymphocytosis represents a benign reactive process or a lymphoproliferative disorder requiring further management.