What additional testing should be ordered for a patient with chronic elevation of White Blood Cell (WBC) count and lymphocytes?

Additional Testing for Chronic Leukocytosis and Lymphocytosis

For a patient with chronic elevation of White Blood Cell (WBC) count and lymphocytosis, a comprehensive hematologic workup should be performed to evaluate for potential lymphoproliferative disorders, particularly chronic lymphocytic leukemia (CLL).

Initial Laboratory Evaluation

• Complete blood count with manual differential to assess for other cytopenias, abnormal cell populations, and to confirm lymphocytosis 1, 2
• Peripheral blood smear review to identify morphology of lymphocytes and other abnormal cells 1, 2
• Comprehensive metabolic panel including liver and renal function tests 2
• Lactate dehydrogenase (LDH) as a marker for potential malignancy 1, 2
• Serum immunoglobulin levels and direct antiglobulin test (DAT) 1

Specialized Testing for Lymphoproliferative Disorders

• Flow cytometry of peripheral blood for immunophenotyping to identify clonal B-cell populations (particularly important to evaluate for CLL which typically shows CD5+, CD19+, CD20+, CD23+ expression with dim surface immunoglobulin) 1
• FISH analysis for detection of cytogenetic abnormalities, particularly deletion 17p [del(17p)] and deletion 11q [del(11q)], which have prognostic and therapeutic implications 1
• Molecular analysis for TP53 mutations, which has strong prognostic and predictive relevance 1
• Immunoglobulin heavy chain variable (IGHV) mutational status testing, which has strong prognostic value 1

Bone Marrow Evaluation

• Bone marrow aspiration and biopsy with immunohistochemistry if a lymphoproliferative disorder is suspected based on peripheral blood findings 1
• Conventional cytogenetics on bone marrow sample to detect complex karyotype and other chromosomal abnormalities 1
• For CLL specifically, bone marrow examination is not required for diagnosis but is recommended for evaluation of unclear cytopenias 1

Imaging Studies

• CT scan of chest, abdomen, and pelvis with contrast if lymphoproliferative disorder is suspected to document extent of lymphadenopathy and organomegaly 1
• Ultrasound may be considered as an alternative for initial evaluation of superficial lymphadenopathy in elderly patients 1, 2

Additional Testing Based on Clinical Suspicion

• Serology testing for viral infections (HBV, HCV, CMV, HIV) that may be associated with reactive lymphocytosis or that need to be evaluated prior to potential treatment 1
• Serum protein electrophoresis and immunofixation if paraproteinemia is suspected (particularly for Waldenström macroglobulinemia) 1, 2
• Beta-2 microglobulin level, which is an important prognostic marker in CLL and other lymphoproliferative disorders 1

Special Considerations

• For persistent unexplained lymphocytosis without clear evidence of CLL, consider testing for MYD88 L265P mutation which is strongly associated with Waldenström macroglobulinemia 1, 2
• If eosinophilia is present alongside lymphocytosis, consider testing for TK fusion gene rearrangements 1
• In cases where hemophagocytic lymphohistiocytosis (HLH) is suspected, additional testing including ferritin, triglycerides, and soluble IL-2 receptor levels should be considered 1

Common Pitfalls to Avoid

• Failure to exclude common causes of reactive lymphocytosis (viral infections, stress, medications) before pursuing extensive workup 3, 4
• Overlooking the need for flow cytometry, which is essential for distinguishing between reactive and neoplastic causes of lymphocytosis 1, 5
• Not considering smoking status, which can cause mild leukocytosis but typically affects neutrophils more than lymphocytes 6, 7
• Delaying bone marrow evaluation in patients with concerning peripheral blood findings 2