What is the next step in evaluating an adult patient with leukopenia, small lymphadenopathy, and normal differential counts, with all other blood profiles being normal?

Next Step in Evaluating Leukopenia with Small Lymphadenopathy and Normal Differential

Perform flow cytometry immunophenotyping on peripheral blood to assess for monoclonal B-cell lymphocytosis or early chronic lymphocytic leukemia, as this is the cornerstone diagnostic test for suspected lymphoproliferative disorders. 1, 2

Rationale for Flow Cytometry as First-Line Test

Flow cytometry is essential because it can detect clonal B-cell populations even when the absolute lymphocyte count appears normal and the differential is unremarkable. 3 The test specifically evaluates:

• Clonality confirmation through surface immunoglobulin light chain restriction (kappa or lambda expression) 1, 2
• Characteristic immunophenotype for CLL/lymphoma: CD5+, CD19+, CD20 (dim), CD23+, with low surface immunoglobulin expression 1, 2
• Exclusion of other lymphoproliferative disorders such as mantle cell lymphoma (which typically lacks CD23 expression) 1

Clinical Context Supporting This Approach

The combination of leukopenia with small lymphadenopathy raises concern for:

• Monoclonal B-cell lymphocytosis (MBL): defined as <5 × 10^9/L clonal B-cells without lymphadenopathy, organomegaly, or cytopenias 4
• Early CLL/SLL: requires ≥5 × 10^9/L monoclonal B lymphocytes, though lymphadenopathy may be present 1
• Other low-grade lymphomas: which frequently show circulating malignant cells detectable by flow cytometry 5, 3

Specific Testing Algorithm

Step 1: Order peripheral blood flow cytometry panel including CD19, CD5, CD20, CD23, surface immunoglobulin (kappa/lambda), CD10, and CD43 2, 3

Step 2: If flow cytometry demonstrates monoclonal B-cells:

• Confirm characteristic CLL immunophenotype (CD5+, CD23+, CD20 dim) 1, 2
• If CD23 negative or atypical, perform cyclin D1 staining or FISH for t(11;14) to exclude mantle cell lymphoma 1, 2
• Obtain complete blood count to calculate absolute lymphocyte count 1

Step 3: If flow cytometry is negative but clinical suspicion persists:

• Consider lymph node biopsy for histopathologic evaluation, particularly if nodes are >1.5 cm, hard, or matted 6
• Evaluate for non-lymphoproliferative causes of leukopenia and lymphadenopathy 6

Important Caveats

Flow cytometry has very low yield in isolated neutropenia or mature neutrophilia (4.4-12.5% positive rate), but shows 93% positive rate in absolute lymphocytosis. 7 However, in your case with lymphadenopathy present, the pretest probability is higher and justifies testing even with normal differential counts. 5, 3

Peripheral blood smear morphology should be reviewed for smudge cells, monotonous lymphocyte appearance, or atypical lymphocytes, which can provide early diagnostic clues. 5 However, morphology alone is insufficient and must be confirmed by flow cytometry. 5, 3

Avoid empiric antibiotics or corticosteroids before establishing a diagnosis, as corticosteroids can mask histologic features of lymphoma. 6

Additional Baseline Studies

While flow cytometry is being processed, obtain:

• Complete metabolic panel including LDH (elevated in lymphoproliferative disorders) 1
• Serum immunoglobulin levels and direct antiglobulin test (DAT) 1
• Hepatitis B, C, and HIV testing if lymphoproliferative disorder is confirmed and treatment is anticipated 1