Peripheral Blood Smear Findings: Atypical Lymphocytes, Burr Cells, and Ovalocytes
The combination of atypical lymphocytes, burr cells (echinocytes), and ovalocytes on a peripheral blood smear suggests a mixed picture requiring systematic evaluation for viral infection (particularly EBV/CMV), renal dysfunction, and hereditary red cell disorders or myelofibrosis, respectively.
Understanding Each Cell Type
Atypical Lymphocytes
Atypical lymphocytes represent activated, enlarged lymphocytes with increased DNA synthesis that indicate a polyclonal immune response to antigenic stimulation 1. These cells appear in:
- Viral infections (infectious mononucleosis, CMV, EBV, COVID-19)
- Drug reactions
- Autoimmune disorders
- Post-transplant immune reactions
- Malignancies (though less common)
Critical distinction: While atypical lymphocytes can appear in both benign reactive conditions and malignancies like Sézary syndrome or adult T-cell leukemia/lymphoma, the presence of >5% atypical lymphocytes with specific immunophenotyping is required for malignant diagnoses 2. Recent evidence shows COVID-19 patients demonstrate atypical lymphocytes in 52.5% of cases 3.
Burr Cells (Echinocytes)
These spiculated red cells with evenly distributed projections primarily indicate:
- Renal failure (uremia)
- Liver disease
- Pyruvate kinase deficiency
- Artifact from blood storage
Ovalocytes (Elliptocytes)
Elongated red cells suggest 4:
- Hereditary elliptocytosis (when predominant)
- Myelofibrosis or myeloproliferative disorders
- Iron deficiency anemia
- Megaloblastic anemia
- Thalassemia
Initial Workup Algorithm
Step 1: Complete Blood Count with Differential
- Absolute lymphocyte count
- Platelet count
- Hemoglobin/hematocrit
- White blood cell count with manual differential
Step 2: Targeted Laboratory Testing
For atypical lymphocytes:
- EBV serology (VCA-IgM, VCA-IgG, EBNA)
- CMV serology (IgM, IgG)
- HIV testing
- COVID-19 testing if clinically indicated
- Flow cytometry if lymphocyte count >5 × 10⁹/L to rule out lymphoproliferative disorders 5
For burr cells:
- Renal function panel (BUN, creatinine)
- Liver function tests (AST, ALT, bilirubin)
- Electrolytes
For ovalocytes:
- Reticulocyte count
- Iron studies (ferritin, TIBC, serum iron)
- LDH (elevated in hemolysis or myeloproliferative disorders)
- Peripheral blood smear review for teardrop cells (suggesting myelofibrosis)
Step 3: Advanced Testing Based on Initial Results
If lymphocytosis with atypical cells:
- Flow cytometry panel: CD3, CD4, CD7, CD8, CD25 for T-cell disorders 2
- For B-cell evaluation: CD5, CD19, CD20, CD23 5
- Consider bone marrow biopsy if flow cytometry suggests malignancy
If ovalocytes predominate (>25% of RBCs):
- Osmotic fragility testing for hereditary elliptocytosis
- Bone marrow biopsy if myelofibrosis suspected (presence of teardrop cells, elevated LDH, splenomegaly)
Common Pitfalls to Avoid
Misidentifying malignant cells: Large atypical lymphocytes at the feathered edge of smears can represent CMV-infected endothelial cells in immunocompromised patients, not malignancy 6. These cells are 50-60 microns with granular eosinophilic cytoplasmic inclusions.
Assuming all atypical lymphocytes indicate malignancy: The vast majority represent benign reactive processes 1. Malignancy requires sustained lymphocytosis >5 × 10⁹/L with specific immunophenotyping 5.
Ignoring clinical context: A patient with acute viral symptoms and atypical lymphocytes requires different workup than an asymptomatic patient with chronic lymphocytosis.
Overlooking artifact: Burr cells can result from prolonged blood storage or improper smear preparation 7.
Risk Stratification for Urgent Evaluation
Immediate hematology consultation if:
- Absolute lymphocyte count >5 × 10⁹/L sustained over weeks
- Presence of blasts or immature cells
- Severe anemia (Hgb <8 g/dL) with ovalocytes and teardrop cells
- Thrombocytopenia with atypical lymphocytes (consider TTP, HLH, or malignancy)
- Immunocompromised patient with large atypical cells (rule out CMV viremia) 6
Routine follow-up appropriate if:
- Mild atypical lymphocytosis with viral symptoms
- Isolated burr cells with known renal disease
- Mild ovalocytosis (<10%) without anemia