Should I order a peripheral smear for a patient with isolated elevated lymphocytes (lymphocytosis)?

Should You Order a Peripheral Blood Smear for Isolated Lymphocytosis?

Yes, you should order a peripheral blood smear for patients with isolated elevated lymphocytes, particularly when the absolute lymphocyte count (ALC) exceeds specific age-adjusted thresholds or when the differential lymphocyte percentage is persistently elevated above 50% in older adults.

Age-Adjusted ALC Thresholds for Smear Review

The decision to order a peripheral blood smear depends critically on both the absolute lymphocyte count and patient age:

For Patients Under 75 Years Old

• Order a peripheral blood smear when ALC ≥ 4.4 × 10⁹/L 1
• Below this threshold in younger patients, monoclonal B-cell populations are rarely identified 1
• The traditional threshold of 5 × 10⁹/L can be safely lowered to 4.4 × 10⁹/L without missing significant pathology 2

For Patients 75 Years and Older

• Order a peripheral blood smear when ALC ≥ 4.0 × 10⁹/L 1
• Older patients have higher incidence of monoclonal B-cell populations even at lower ALCs 1
• Age itself becomes a critical discriminator, with 93% sensitivity for detecting neoplastic cases when reviewing patients >50 years with ALCs between 5-10 × 10⁹/L 2

Alternative Indication: Persistent Relative Lymphocytosis

Even with normal absolute counts, order a smear if the differential lymphocyte percentage is ≥50% persistently in patients over 50 years old 3. This is crucial because:

• Cases of chronic lymphocytic leukemia with low lymphocyte count (CLL-LLC) constitute approximately 6% of B-CLL cases 3
• These patients would be missed if only absolute lymphocytosis triggers investigation 3
• The diagnostic value of differential lymphocyte counts is often underemphasized but clinically significant 3

What to Look for on the Smear

When examining the peripheral blood smear, systematically evaluate 4:

• Lymphocyte morphology: Look for small, mature-appearing lymphocytes characteristic of B-CLL 5
• Atypical features: Identify "flower cells" with polylobated nuclei (suggesting adult T-cell leukemia/lymphoma) 5, binucleated lymphocytes (may indicate benign persistent polyclonal lymphocytosis) 6, or large granular lymphocytes 7
• Perform differential count of at least 100-200 white blood cells 4

Critical Next Steps After Smear Review

If the smear shows abnormal or suspicious lymphocytes:

Immediate Follow-up Testing

• Flow cytometry is mandatory to confirm clonality and establish immunophenotype 5, 8
• For B-CLL diagnosis, look for the characteristic pattern: CD5+, CD19+, CD20+ (dim), CD23+, surface immunoglobulin (dim) 5, 3
• The Matutes score helps distinguish B-CLL from other CD5+ B-cell lymphomas 5

Additional Workup

• LDH and β2-microglobulin for prognostic stratification 5, 8
• Direct antiglobulin test (Coombs test) to assess for autoimmune hemolysis 5, 8
• FISH cytogenetics for risk stratification in younger patients with confirmed CLL 5, 8

High-Risk Scenarios Requiring Urgent Evaluation

Order a peripheral blood smear immediately regardless of ALC threshold when:

• ALC >10 × 10⁹/L (90% specificity for neoplastic process) 2
• Presence of B-symptoms, cytopenias, or organomegaly 5
• Rapid lymphocyte doubling time <12 months 5
• Associated lymphadenopathy or splenomegaly 8

Common Pitfalls to Avoid

• Don't wait for ALC >5 × 10⁹/L in older patients – this traditional threshold misses significant pathology in patients ≥75 years 1
• Don't ignore persistent relative lymphocytosis – absolute counts can be misleadingly normal in early CLL 3
• Don't assume all lymphocytosis is reactive – morphologic examination combined with immunophenotyping identifies early leukemia or clonal proliferative disorders that appear benign clinically 7
• Don't overlook benign mimics – persistent polyclonal lymphocytosis with binucleated B lymphocytes (associated with HLA-DR7, elevated IgM, predominantly in women) can mimic malignancy but is benign 6

Efficiency Considerations

Applying these age-adjusted thresholds can reduce laboratory workload by approximately 50% while maintaining diagnostic sensitivity 2. The key is using ALC >10 × 10⁹/L for all ages and age >50 years for ALCs between 5-10 × 10⁹/L as your decision points 2.