What is the diagnostic approach for Chronic Lymphocytic Leukemia (CLL)?

Diagnostic Approach for Chronic Lymphocytic Leukemia (CLL)

The diagnosis of CLL requires a sustained increase of peripheral blood lymphocytes ≥5×10^9 cells/L with characteristic immunophenotype (CD5+, CD19+, CD20+ low, CD23+, sIg low, CD79b low, FMC7–) confirmed by flow cytometry. 1

Essential Diagnostic Criteria

• Sustained increase of peripheral blood lymphocytes ≥5×10^9 cells/L for at least 3 months, not explained by other clinical disorders 1
• Predominance of small, morphologically mature lymphocytes in the blood smear 1
• Characteristic immunophenotype by flow cytometry showing CD5+, CD19+, CD20+ (low), CD23+, sIg low, CD79b low, FMC7– expression pattern 1

Diagnostic Algorithm

Step 1: Initial Blood Tests

• Complete blood count with differential showing lymphocytosis ≥5×10^9 cells/L 1, 2
• Peripheral blood smear examination showing small, mature lymphocytes with narrow cytoplasm borders and dense nuclei lacking discernible nucleoli 3
• Presence of smudge cells (nuclear shadows or cell debris from ruptured lymphocytes) is characteristic but not diagnostic 3

Step 2: Confirmatory Testing

• Flow cytometry of peripheral blood to confirm B-cell clonality and characteristic CLL immunophenotype 1, 4
• The composite immunophenotype (CD5+, CD19+, CD20+ low, CD23+, sIg low, CD79b low, FMC7–) distinguishes CLL from other CD5+ B-cell lymphomas 1, 5

Step 3: Differential Diagnosis

• Distinguish from other B-cell disorders such as:
  • Mantle cell lymphoma (MCL): Evaluate using CD23 expression, RT-PCR for cyclin D1 overexpression, FISH for t(11;14) translocation, and CD200 expression 1
  • Marginal zone lymphoma (MZL): Typically negative or low CD43 expression and high CD180 expression 1
  • Small lymphocytic lymphoma (SLL): Same entity as CLL but with <5×10^9/L B lymphocytes in peripheral blood with lymphadenopathy/splenomegaly 1

Step 4: Additional Evaluation

• Physical examination with careful palpation of all lymph node areas, spleen, and liver 1
• Laboratory tests: LDH, bilirubin, serum protein electrophoresis, direct antiglobulin test (DAT) 1
• Chest X-ray 1
• FISH analysis for cytogenetic abnormalities (particularly del(17p), del(11q)) for prognostic value 1

Special Considerations

• Bone marrow biopsy is not required for diagnosis but recommended before initiating therapy to evaluate unclear cytopenias 1
• If B lymphocytes in peripheral blood are <5×10^9/L but lymphadenopathy/splenomegaly is present, SLL should be diagnosed instead of CLL 1
• In the absence of lymphadenopathy, organomegaly, cytopenia, and clinical symptoms, <5×10^9/L monoclonal B lymphocytes defines "monoclonal B lymphocytosis" (MBL), which progresses to CLL in 1-2% of cases per year 1

Prognostic Assessment

• Cytogenetic abnormalities by FISH (particularly del(17p) and del(11q)) 1, 6
• Expression of CD38, ZAP70, and immunoglobulin mutational status (IgVH mutation) may predict time to progression 1, 5
• Staging using either Binet or Rai staging systems 1

Common Pitfalls

• Failing to distinguish CLL from other B-cell disorders with similar presentations 4
• Not performing flow cytometry to confirm the characteristic immunophenotype 5
• Missing the diagnosis in patients with atypical morphological features 4
• Relying solely on lymphocyte count without immunophenotypic confirmation 1