What are atypical lymphocytes?

What Are Atypical Lymphocytes?

Atypical lymphocytes are abnormal-appearing lymphocytes seen on peripheral blood smear, characterized by enlarged size, increased cytoplasm, and irregular nuclear features—they represent reactive immune responses in most cases but can also indicate malignancy. 1

Morphologic Characteristics

Atypical lymphocytes display distinctive features on blood smear examination:

• Enlarged cells with abundant basophilic (blue-staining) cytoplasm 1
• Irregular nuclear contours including polylobated or hyperconvoluted nuclei 2
• Condensed chromatin pattern with small or absent nucleoli 2
• "Flower cell" appearance in certain malignant conditions, particularly adult T-cell leukemia/lymphoma 2, 1

The morphologic assessment remains subjective with high interobserver variability, making it an imperfect diagnostic tool 2.

Common Causes

Benign/Reactive Causes

Viral infections are the most frequent cause of atypical lymphocytosis:

• Epstein-Barr virus (EBV) causing infectious mononucleosis—the classic association 3, 4
• Cytomegalovirus (CMV) infection 1, 5
• Human herpesvirus 6 (HHV6) 1
• Parvovirus 1

Important clinical caveat: Atypical lymphocytes in children without the classic triad of splenomegaly, pharyngitis, and adenopathy do NOT reliably indicate infectious mononucleosis 4. These cells can appear in healthy individuals and various benign conditions 2.

Malignant Causes

• Adult T-cell leukemia/lymphoma (HTLV-1 associated) with characteristic "flower cells" 2, 1
• Sézary syndrome and mycosis fungoides with cerebriform nuclei 2
• Richter's transformation (transformation of indolent lymphomas) 1
• Chronic lymphocytic leukemia (CLL) may show larger atypical cells or prolymphocytes, though these must not exceed 55% 2

Diagnostic Approach

Initial Laboratory Assessment

When atypical lymphocytes are identified, perform:

• Complete blood count with manual differential to quantify the percentage of atypical lymphocytes 1
• Peripheral blood smear examination to confirm morphology and assess for specific features 1
• Absolute lymphocyte count assessment: lymphocytosis ≥2.375 × 10⁹/L has 68% sensitivity and 83% specificity for predicting atypical lymphocytes 6

Distinguishing Reactive from Malignant

Flow cytometry is essential for differentiating benign from neoplastic causes by assessing clonality and immunophenotype 1:

Reactive (Viral) Patterns:

• Marked increase in activated CD8+ T cells (most prominent feature) 3, 5
• Moderate increase in NK cells (CD3-/CD16/56+) 3
• No increase in CD4+ T cells or B cells 3
• Polyclonal population without light chain restriction 3

In EBV-positive mononucleosis specifically, expect increased CD57-negative CD8 T cells and gamma-delta T cells 3. In CMV mononucleosis, approximately 69% of atypical lymphocytes are CD8+ (cytotoxic/suppressor phenotype) 5.

Malignant Patterns:

• Monoclonal B-cell population in CLL: CD5+, CD19+, CD20+ (dim), CD23+ with kappa or lambda light chain restriction 2
• Loss of CD7 and CD26 in Sézary syndrome 2
• CD4+, CD25+ expression in adult T-cell leukemia/lymphoma 2

Further Workup Based on Clinical Context

For suspected viral etiology:

• EBV serology (heterophil antibody, EBV-specific antibodies) 4
• CMV, HHV6, parvovirus testing if EBV negative 1

For suspected hematologic malignancy:

• Flow cytometry to assess clonality, CD5, CD19, CD20, CD23 expression, and light chain restriction 2, 1
• Cytogenetic studies (FISH) for del(17p), del(13q), and other abnormalities if lymphoproliferative disorder suspected 2, 1
• HTLV-1 serology if adult T-cell leukemia/lymphoma considered 2
• Bone marrow biopsy for persistent unexplained atypical lymphocytosis or associated cytopenias 1

Critical Clinical Pitfalls

Atypical lymphocytes are NOT specific for any single condition and can appear in healthy individuals 2. The presence of atypical lymphocytes alone, particularly in children without classic mononucleosis symptoms, does not confirm infectious mononucleosis 4.

During CAR T-cell therapy, atypical lymphocytes resembling leukemic blasts are common at peak CAR-T expansion and should not be misinterpreted as disease progression 2.

Persistent atypical lymphocytosis warrants monitoring with serial CBCs and consideration of bone marrow evaluation if cytopenias develop 1.

Management Implications

• Transient atypical lymphocytosis in the setting of acute viral illness typically resolves without intervention 3, 4
• Persistent or progressive atypical lymphocytosis requires hematology referral and comprehensive workup including flow cytometry 1
• Immunocompromised patients may develop atypical lymphocytosis from opportunistic infections requiring specific antimicrobial therapy 1
• Malignant causes require disease-specific treatment protocols per appropriate guidelines 2