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

Diagnostic Approach 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 confirmed by flow cytometry. 1

Essential Diagnostic Criteria

Laboratory Testing

1. Complete Blood Count (CBC)

   • Absolute lymphocyte count ≥5000/µL persisting for at least 3 months 2, 1
   • Examination of peripheral blood smear showing small, mature lymphocytes with:
     • Narrow border of cytoplasm
     • Dense nucleus lacking discernible nucleoli
     • Partially aggregated chromatin 2, 1

2. Flow Cytometry (most critical diagnostic test)

   • Required markers for CLL diagnosis: 1

     • CD5+ (co-expression of T-cell antigen)
     • CD19+ (B-cell marker)
     • CD20+ (dim expression)
     • CD23+ (distinguishes from mantle cell lymphoma)

   • Additional characteristic features: 2, 1

     • Surface immunoglobulin (sIg) dim
     • CD79b dim/low
     • Restricted expression of either kappa or lambda light chains
     • CD43+ (in most cases)
     • FMC7 typically negative
     • CD200+ (helps distinguish from mantle cell lymphoma)

Differential Diagnosis

• Mantle Cell Lymphoma (MCL): Typically CD23-, with t(11;14) translocation and cyclin D1 expression 2, 1
  • If CD23+, perform cyclin D1 staining or FISH for t(11;14) to rule out MCL 1
• Marginal Zone Lymphoma: Typically CD5-
• Other B-cell lymphomas: Distinguished by different immunophenotypic patterns 3

Additional Testing for Prognosis and Treatment Planning

Cytogenetic Analysis

• FISH analysis recommended before starting therapy for: 2, 1
  • del(17p) - poor prognosis, affects treatment choice
  • del(11q) - poor prognosis
  • del(13q) - favorable prognosis
  • trisomy 12 - intermediate prognosis

Molecular Testing

• IGHV mutation status: Important prognostic factor 2, 1
  • Mutated IGHV: Better prognosis
  • Unmutated IGHV: Worse prognosis
• TP53 mutations: Associated with poor prognosis and treatment resistance 1, 4

Staging Evaluation

• Physical examination: Careful palpation of all lymph node regions 2
• Laboratory tests: LDH, bilirubin, serum protein electrophoresis, and Coombs test 2
• Imaging:
  • Chest X-ray recommended 2
  • CT scans not routinely required outside clinical trials 2

Bone Marrow Assessment

• Not required for initial diagnosis 2, 1
• Recommended before initiating myelosuppressive therapies 2
• Useful for evaluating unexplained cytopenias 2, 1

Staging Systems

Binet Staging System (European)

Stage	Definition	Median Survival
A	Hb ≥10.0 g/dL, platelets ≥100×10⁹/L, <3 lymph node regions	>10 years
B	Hb ≥10.0 g/dL, platelets ≥100×10⁹/L, ≥3 lymph node regions	7 years
C	Hb <10.0 g/dL and/or platelets <100×10⁹/L	1.5-2.5 years

Rai Staging System (American)

Stage	Characteristics	Median Survival
0	Lymphocytosis only	>10 years
I	Lymphocytosis + lymphadenopathy	7-9 years
II	Lymphocytosis + hepatomegaly/splenomegaly ± lymphadenopathy	7-9 years
III	Lymphocytosis + anemia	1.5-3 years
IV	Lymphocytosis + thrombocytopenia	1.5-3 years

Common Pitfalls and Caveats

1. Distinguishing CLL from Monoclonal B Lymphocytosis (MBL):

   • MBL: <5000 B cells/µL with CLL phenotype 2
   • MBL has approximately 1.1% annual risk of progression to CLL 2

2. Distinguishing CLL from Small Lymphocytic Lymphoma (SLL):

   • SLL: <5000 B lymphocytes/µL with lymphadenopathy/splenomegaly 2
   • Same disease with different presentations; treated similarly 4
   • SLL diagnosis requires lymph node biopsy showing effacement of architecture 2

3. Atypical CLL presentations:

   • Prolymphocytes should not exceed 55% of lymphoid cells 1
   • Atypical morphology may require additional testing to exclude other lymphomas 5

4. CLL Scoring System:

   • Scores of 4-5 points highly suggestive of CLL (97% specificity) 3
   • Scores of 0-3 points more likely to be other B-cell neoplasms 3

By following this systematic diagnostic approach, CLL can be accurately diagnosed and distinguished from other lymphoproliferative disorders, allowing for appropriate prognostication and treatment planning.