Atypical Lymphocytes in CBC with Differential

Definition and Appearance

Atypical lymphocytes appear on peripheral blood smear as lymphocytes with polylobated nuclei, condensed chromatin, and basophilic cytoplasm, sometimes described as "flower cells", according to the National Comprehensive Cancer Network 1

Cytomegalovirus (CMV), human herpesvirus 6 (HHV6), and parvovirus are other viral causes of atypical lymphocytosis, as reported in the Journal of Clinical Oncology 2
Adult T-cell leukemia/lymphoma (HTLV-1 associated) is a cause of atypical lymphocytosis, according to the National Comprehensive Cancer Network 1
Transformation of indolent lymphomas (Richter's transformation) is a cause of atypical lymphocytosis, as reported in the National Comprehensive Cancer Network 3

Flow cytometry can differentiate reactive from neoplastic causes by assessing clonality, according to the National Comprehensive Cancer Network 3

Complete blood count with manual differential to quantify atypical lymphocytes is recommended, as reported in the Journal of Clinical Oncology 2
Peripheral blood smear examination to confirm morphology is essential, according to the National Comprehensive Cancer Network 4

For suspected viral etiology, consider testing for CMV, HHV6, parvovirus if EBV negative, as reported in the Journal of Clinical Oncology 2
For suspected hematologic malignancy, flow cytometry to assess clonality and immunophenotype is recommended, according to the National Comprehensive Cancer Network 3
If CLL is suspected, evaluate for CD5, CD19, CD20, CD23 expression and light chain restriction, as reported in Annals of Oncology 5 and 6
Cytogenetic studies (FISH) if lymphoproliferative disorder is suspected, according to the National Comprehensive Cancer Network 3
Bone marrow biopsy may be indicated in cases with persistent unexplained atypical lymphocytosis, as reported in Clinical Cancer Research 7

Persistent atypical lymphocytosis warrants monitoring with serial CBCs, according to Clinical Cancer Research 7
In cases with associated cytopenias, consider bone marrow evaluation, as reported in the Journal of Clinical Oncology 2

Immunocompromised patients may have atypical lymphocytes due to opportunistic infections, as reported in MMWR Recommendations and Reports 8

The National Comprehensive Cancer Network recommends a comprehensive metabolic panel, including lactate dehydrogenase (LDH), which may be elevated in lymphoproliferative disorders 9
Liver function tests are essential to assess for hepatic involvement, as recommended by the Annals of Oncology 10

The Journal of the National Comprehensive Cancer Network and the Journal of Clinical Oncology suggest evaluating T-cell markers, including CD2, CD3, CD4, CD5, CD7, and CD8, to assess for antigen loss patterns 9, 11, 12
CD30 expression should be evaluated to assess for anaplastic large cell lymphoma or CD30+ lymphoproliferative disorders, as recommended by Blood and the Journal of Clinical Oncology 12, 13

The Journal of the National Comprehensive Cancer Network recommends cytogenetic studies (FISH) for recurrent chromosomal abnormalities, including t(9;22) BCR-ABL1, t(12;21) TEL-AML1, MLL rearrangements, and hyperdiploidy/hypodiploidy 9
T-cell receptor (TCR) gene rearrangement is necessary to demonstrate clonality in suspected T-cell lymphoproliferative disorders, as suggested by the Journal of the American Academy of Dermatology 11

The Annals of Oncology notes that atypical lymphocytes resembling leukemic blasts are not uncommon at peak CAR-T expansion in patients receiving cellular therapy, highlighting the importance of clinical context 10
The Journal of Clinical Oncology recommends considering reactive T cells rather than lymphoma when CD30+ cells are present on flow cytometry, particularly if small CD30+ cells with preserved T-cell antigens (CD2, CD3, CD5, CD7) are indicated 12

The Centers for Disease Control and Prevention, as reported in MMWR Recommendations and Reports, suggests considering recent tick bites, sick contacts, or immunocompromised status when assessing exposure history in patients with atypical lymphocytes 14
The presence of B-symptoms (fever, night sweats, weight loss) without identified viral etiology is an indication for flow cytometry, as recommended by MMWR Recommendations and Reports 14

The Blood journal recommends using B-cell markers (CD19, CD20, CD23, surface immunoglobulin light chains) and T-cell markers (CD2, CD3, CD4, CD5, CD7, CD8) in flow cytometry panels to evaluate for CLL and T-cell lymphoproliferative disorders 15