What is the initial diagnostic test for an older adult suspected of having Chronic Lymphocytic Leukemia (CLL)?

Initial Diagnostic Test for Chronic Lymphocytic Leukemia (CLL)

The initial diagnostic test for an older adult suspected of having CLL is a complete blood count (CBC) with differential, followed immediately by flow cytometry immunophenotyping of peripheral blood lymphocytes to confirm the characteristic CD5+, CD19+, CD20+ (low), CD23+, sIg low, CD79b low, FMC7– immunophenotype. 1, 2

Diagnostic Algorithm

Step 1: Complete Blood Count with Differential

• Order a CBC with differential showing sustained lymphocytosis ≥5×10^9 cells/L (≥5,000 lymphocytes/μL) that persists for at least 3 months and cannot be explained by other clinical disorders 1, 2
• The absolute lymphocyte count must include both percentage and absolute number of lymphocytes 1
• Document reticulocyte count to assess for hemolytic anemia 1

Step 2: Peripheral Blood Smear Examination

• Examine the blood smear for predominance of small, morphologically mature lymphocytes with narrow cytoplasm borders and dense nuclei lacking discernible nucleoli 1, 2
• Note the proportion of prolymphocytes if present (should be minimal in CLL) 1

Step 3: Flow Cytometry Immunophenotyping (Essential for Diagnosis)

• Flow cytometry of peripheral blood is mandatory to establish the diagnosis and confirm B-cell clonality 1, 2, 3, 4
• The diagnostic immunophenotype must show: CD5+, CD19+, CD20+ (low expression), CD23+, surface immunoglobulin (sIg) low, CD79b low, and FMC7 negative 1, 2
• This composite immunophenotype distinguishes CLL from other CD5+ B-cell lymphomas, particularly mantle cell lymphoma 1

What You Do NOT Need Initially

Bone Marrow Biopsy

• Bone marrow biopsy is NOT required for diagnosis 1
• Reserve bone marrow aspirate and biopsy for before initiating therapy to evaluate unclear cytopenias 1

Lymph Node Biopsy

• Lymph node biopsy is only recommended if the immunophenotypic diagnosis is not clear-cut and an enlarged peripheral lymph node is accessible 1

Additional Initial Evaluation Tests

Once diagnosis is confirmed, perform these tests before any treatment decisions:

Physical Examination

• Carefully palpate all lymph node areas (cervical, axillary, supraclavicular, inguinal, femoral) and record bidimensional diameters of the largest nodes 1, 2
• Assess liver and spleen size by palpation 1, 2

Laboratory Studies

• LDH, bilirubin, serum protein electrophoresis, and direct antiglobulin test (Coombs test) 1, 2
• Serum chemistry including creatinine, transaminases, and alkaline phosphatase 1

Imaging

• Chest X-ray is recommended as part of initial evaluation 1

Prognostic Testing (Desirable but Not Required for Diagnosis)

• FISH analysis for cytogenetic abnormalities (del(17p), del(11q), del(13q), trisomy 12) has prognostic value and should be performed during initial evaluation, particularly in younger patients 1, 2
• CD38, ZAP70 expression, and IGHV mutational status may predict time to progression but should not be used as treatment indications outside clinical trials 1, 2

Critical Diagnostic Pitfall

The most common pitfall is failing to perform flow cytometry immunophenotyping. A lymphocyte count ≥5×10^9 cells/L alone is insufficient for diagnosis—you must confirm the characteristic CLL immunophenotype to distinguish it from other lymphoproliferative disorders, particularly mantle cell lymphoma which can have devastating consequences if treated as CLL 1, 2.