What is the appropriate workup for a patient with a white‑blood‑cell count suggestive of lymphoma?

Workup for White Blood Cell Count Suggestive of Lymphoma

When a patient presents with a WBC count suggestive of lymphoma, immediately obtain a complete blood count with differential including absolute lymphocyte counts, peripheral blood smear examination, and flow cytometry immunophenotyping to distinguish between reactive lymphocytosis and lymphoproliferative neoplasm. 1

Initial Laboratory Evaluation

Essential Blood Tests

• Complete blood count with differential including white blood cell count, hemoglobin, hematocrit, platelet count, and absolute lymphocyte/prolymphocyte counts 1, 2
• Peripheral blood smear review to assess lymphocyte morphology—monomorphic populations suggest malignancy while polymorphic populations indicate reactive processes 3
• Comprehensive metabolic panel including blood urea nitrogen, creatinine, electrolytes, albumin, calcium, and liver function tests 1
• Lactate dehydrogenase (LDH) for prognostic information 4
• Beta-2 microglobulin provides useful prognostic data 1

Immunophenotyping Requirements

• Flow cytometry on peripheral blood is mandatory when monomorphic lymphocytosis is present 1, 3
• For suspected CLL/SLL: Look for sIgM+, CD19+, CD20+, CD22+, typically CD5+, CD10-, CD23- pattern 1
• For suspected Waldenström macroglobulinemia/LPL: Confirm sIgM+, CD19+, CD20+, CD22+ with approximately 10-20% expressing CD5, CD10, or CD23 1
• Quantitative immunoglobulins are informative in patients with recurrent infections 1

Critical Thresholds for Malignancy Risk

Age-Stratified Lymphocyte Count Cutoffs

• Patients >67 years: Absolute lymphocyte count ≥4 × 10⁹/L has high sensitivity for abnormal immunophenotype 5
• Patients 50-67 years: Absolute lymphocyte count >6.7 × 10⁹/L indicates high likelihood of lymphoproliferative disorder 5
• Monoclonal B-cell lymphocytosis (MBL): Defined as <0.5 × 10⁹/L monoclonal B-lymphocytes without lymphadenopathy, organomegaly, or cytopenias 1

Distinguishing CLL from MBL

• High-count MBL: 0.5-5 × 10⁹/L monoclonal B-cells, progresses to CLL requiring treatment at 1-2% per year 1
• Rai 0 CLL: Monoclonal B-cell count ≥5 × 10⁹/L distinguishes from high-count MBL 1

Additional Diagnostic Studies

Specialized Testing

• Reticulocyte count and direct Coombs test in patients with anemia to evaluate for hemolysis or pure red cell aplasia 1
• Serum protein electrophoresis, quantitative immunoglobulins, and immunofixation when IgM monoclonal protein is suspected (Waldenström macroglobulinemia) 1
• MYD88 (L265P) mutation testing on bone marrow aspirate—present in >90% of Waldenström macroglobulinemia cases, helps differentiate from IgM myeloma or marginal zone lymphoma 1

Bone Marrow Evaluation

• Bone marrow biopsy is NOT routinely required for CLL diagnosis given reliable prognostic markers from peripheral blood (IGHV mutation status, FISH cytogenetics) 1
• Bone marrow aspirate and biopsy ARE required for Waldenström macroglobulinemia to document clonal lymphoplasmacytic infiltration confirmed by immunohistochemistry/flow cytometry 1
• Consider bone marrow biopsy for CLL only when evaluating immune-mediated or disease-related cytopenias before treatment initiation 1

Imaging Studies

When to Image

• CT scans are useful for evaluating symptoms, bulky disease, monitoring progression with new symptoms when peripheral adenopathy absent, or assessing tumor lysis syndrome risk before venetoclax 1
• Serial CT scans are NOT recommended for asymptomatic patients 1
• Contrast-enhanced CT scan (chest, abdomen, pelvis) with or without PET is indicated for suspected primary cutaneous anaplastic large-cell lymphoma 1
• PET scan is generally not useful in CLL but assists in directing nodal biopsy if Richter's transformation suspected 1

Lymph Node Biopsy Indications

• Perform lymph node biopsy if enlarged nodes >1.5 cm in greatest transverse diameter are palpable or detected on imaging 1
• Lymphoma as a trigger may be difficult to detect—use PET-guided imaging, repetitive tissue sampling, and lymphoma reference pathologist consultation 1

Common Pitfalls to Avoid

• Do not delay treatment decisions waiting for genetic testing results in suspected primary HLH—pending results must not delay clinical decision to treat 1
• Do not use absolute lymphocyte count alone as sole indicator for treatment in CLL; include lymphocyte doubling time and total clinical picture 1
• Do not overlook atypical presentations—certain lymphoma subtypes (Hodgkin, diffuse large B-cell, NK/T-cell, angioimmunoblastic T-cell, anaplastic large cell) are more strongly associated with hemophagocytic lymphohistiocytosis 1
• Recognize that hyperleukocytosis (>100 × 10⁹/L) in CLL rarely causes leukostasis, but when present with acute pulmonary symptoms, this is a medical emergency requiring ICU admission, cytoreduction, and possible leukapheresis 6