What are the diagnostic criteria for Chronic Lymphocytic Leukemia (CLL)?

Diagnostic Criteria for Chronic Lymphocytic Leukemia (CLL)

The diagnosis of CLL requires the presence of ≥5000 monoclonal B lymphocytes/µl in peripheral blood for at least 3 months with a characteristic immunophenotype (CD5+, CD19+, CD20+ low, CD23+, surface immunoglobulin low, CD79b low) confirmed by flow cytometry. 1

Essential Diagnostic Criteria

Peripheral Blood Findings

• Lymphocytosis: ≥5000 monoclonal B lymphocytes/µl persisting for at least 3 months 1
• Morphology: Small, mature-appearing lymphocytes with:
  • Narrow border of cytoplasm
  • Dense nucleus lacking discernible nucleoli
  • Partially aggregated chromatin
  • Atypical lymphocytes or prolymphocytes may be present but must not exceed 55% 1

Immunophenotyping (Critical for Diagnosis)

• Required markers: CD5+, CD19+, CD20+ (low), CD23+
• Additional features:
  • Surface immunoglobulin (sIg) low
  • CD79b low
  • Restricted expression of either kappa or lambda light chains
  • FMC7 typically negative 1

Differential Diagnosis

Distinguishing CLL from other B-cell lymphoproliferative disorders is crucial:

• Mantle cell lymphoma: Typically CD23-, with t(11;14) translocation and cyclin D1 expression
  • For CD23+ cases, cyclin D1 staining or FISH for t(11;14) is recommended 1
• Small lymphocytic lymphoma (SLL): Same disease as CLL but with lymph node involvement and <5000 circulating monoclonal B lymphocytes/µl 2

Recommended Initial Evaluation

Required Tests

1. Complete blood count with differential
2. Peripheral blood flow cytometry
3. Peripheral blood smear examination
4. Serum chemistry including LDH, bilirubin, serum immunoglobulin
5. Direct antiglobulin test (DAT/Coombs test)

Recommended Additional Tests

1. Cytogenetic analysis by FISH: Particularly for del(17p), del(11q), del(13q), and trisomy 12 1
2. TP53 mutation analysis: Critical for treatment planning 2
3. IGHV mutational status: Important prognostic marker 2

Staging Systems

Binet Staging System (European standard)

• Stage A: Hb ≥10.0 g/dl, platelets ≥100×10⁹/l, <3 lymph node regions
• Stage B: Hb ≥10.0 g/dl, platelets ≥100×10⁹/l, ≥3 lymph node regions
• Stage C: Hb <10.0 g/dl and/or platelets <100×10⁹/l 1

Rai Staging System (US standard)

• Stage 0: Lymphocytosis only
• Stage I: Lymphocytosis + lymphadenopathy
• Stage II: Lymphocytosis + hepatomegaly/splenomegaly ± lymphadenopathy
• Stage III: Lymphocytosis + anemia (Hb <11.0 g/dl)
• Stage IV: Lymphocytosis + thrombocytopenia (platelets <100×10⁹/l) 1

Common Pitfalls in CLL Diagnosis

1. Failure to confirm clonality: Always verify by flow cytometry
2. Misdiagnosis of other CD5+ B-cell disorders: Particularly mantle cell lymphoma
3. Relying solely on lymphocyte count: The immunophenotype is essential
4. Premature diagnosis: Ensure persistence of lymphocytosis for at least 3 months
5. Missing prognostic markers: FISH and molecular testing are important for treatment planning

Key Points to Remember

• Bone marrow biopsy is not required for diagnosis but may be needed to evaluate unexplained cytopenias or before starting myelosuppressive therapy 1
• CLL and SLL are considered the same disease with different presentations 2
• Prognostic markers (FISH, IGHV, TP53) should be assessed before initiating treatment 2
• CT scans are not routinely required for diagnosis but may be used for baseline assessment in clinical trials 1

By following these diagnostic criteria and recommended evaluations, clinicians can accurately diagnose CLL and appropriately stratify patients for treatment decisions.