In an overweight adult female with a hematocrit of 46.6 % (upper limit of normal) and an absolute lymphocyte count of 5,034 cells/µL (lymphocytosis), what is the recommended diagnostic work‑up and management?

Diagnostic Work-Up for Lymphocytosis in an Overweight Female with Borderline-Elevated Hematocrit

Immediate Assessment

Order a complete blood count with differential, peripheral blood smear review, and flow cytometry immunophenotyping to evaluate the lymphocytosis, as an absolute lymphocyte count of 5,034 cells/µL in an adult warrants investigation for a lymphoproliferative disorder. 1, 2, 3

The hematocrit of 46.6% falls within the normal range for women (38–46%) and does not meet criteria for erythrocytosis (>48–49% in women). 4, 5 However, the lymphocytosis requires systematic evaluation.

Lymphocytosis Evaluation Algorithm

Initial Laboratory Testing

• Peripheral blood smear morphology is essential to differentiate reactive from malignant lymphocytes, though "reactive" morphology has high predictive value (negative predictive value 0.58) while "malignant" morphology is a poor predictor of lymphoproliferative disorders (positive predictive value 0.60). 2

• Flow cytometry immunophenotyping should be performed immediately, as monoclonal B-cell populations are found in 19.1% of patients ≥50 years old with absolute lymphocyte counts ≥4.0 × 10⁹/L. 3

• The optimal threshold for triggering flow cytometry in adults with new-onset lymphocytosis is approximately 7.0 × 10⁹/L, though this patient's count of 5.0 × 10⁹/L still warrants evaluation given the established diagnostic threshold for chronic lymphocytic leukemia. 2, 1

Specific Immunophenotyping Panel

• Test for monoclonal surface immunoglobulin (SIg), CD5, CD19, CD20, CD22, and CD2 to identify B-cell chronic lymphocytic leukemia, which can present with absolute lymphocyte counts as low as 1.5–4.9 × 10⁹/L when accompanied by relative lymphocytosis ≥50%. 6, 7

• Evaluate for large granular lymphocyte proliferations and T-cell lymphocytosis, as these represent important differential diagnoses in chronic lymphocytosis. 7

Chronic Lymphocytic Leukemia Diagnostic Criteria

When to Initiate CLL Treatment

This patient does NOT require treatment at present, as CLL treatment is indicated only when active disease criteria are met, not based on lymphocyte count alone. 1

Treatment indications require at least one of the following: 1

• Progressive marrow failure (worsening anemia/thrombocytopenia)
• Massive splenomegaly (≥6 cm below left costal margin) or progressive/symptomatic splenomegaly
• Massive lymphadenopathy (≥10 cm longest diameter) or progressive/symptomatic adenopathy
• Progressive lymphocytosis with >50% increase over 2 months or lymphocyte doubling time <6 months (only if initial count >30 × 10⁹/L)
• Autoimmune cytopenias poorly responsive to corticosteroids
• Constitutional symptoms: ≥10% unintentional weight loss in 6 months, significant fatigue (ECOG PS ≥2), fevers >38°C for ≥2 weeks without infection, or night sweats >1 month without infection

Critical Caveat

• Absolute lymphocyte count alone should NOT be used as the sole indicator for treatment in CLL, as symptoms of leukostasis rarely occur even with markedly elevated counts. 1

Hematocrit Considerations

Confirming Normal vs. Elevated Status

• The hematocrit of 46.6% is at the upper limit of normal for women but does not meet WHO criteria for erythrocytosis (>48–49% in women). 4, 5

• Repeat hemoglobin and hematocrit measurements to confirm stability, as single measurements are unreliable for establishing diagnoses. 4

• If values remain stable and <48%, no further erythrocytosis work-up is needed. 4, 5

If Hematocrit Were Truly Elevated

• Evaluate for relative polycythemia due to dehydration or plasma volume depletion before pursuing extensive work-up. 4

• Check serum ferritin and transferrin saturation, as iron deficiency can coexist with or mask erythrocytosis. 4

• JAK2 mutation testing (exon 14 V617F and exon 12) would be indicated only if hemoglobin >16.5 g/dL or hematocrit >48% in women. 4, 8, 5

Common Pitfalls to Avoid

• Do not dismiss lymphocytosis based solely on the absence of lymphadenopathy or splenomegaly, as early CLL can present with isolated lymphocytosis. 6

• Do not perform therapeutic phlebotomy for this hematocrit level (46.6%), as it is indicated only when hemoglobin >20 g/dL and hematocrit >65% with hyperviscosity symptoms. 4

• Do not overlook monoclonal B-cell lymphocytosis (MBL), which can be detected in up to 19% of older adults with modest lymphocytosis and may progress to CLL. 3

• Do not initiate CLL treatment based on lymphocyte count alone without meeting active disease criteria, as early intervention does not improve survival and may increase toxicity. 1

Recommended Follow-Up

• If flow cytometry confirms monoclonal B-cell population consistent with CLL or MBL, monitor with serial complete blood counts every 3–6 months without treatment unless active disease criteria develop. 1

• If flow cytometry shows reactive/polyclonal lymphocytosis, investigate for underlying infections, autoimmune conditions, or other reactive causes. 7

• Bone marrow biopsy is NOT indicated at this stage unless flow cytometry suggests a lymphoproliferative disorder requiring further characterization or if cytopenias develop. 1