Chronic Lymphocytic Leukemia (CLL) Differential Diagnoses

Updated: Jan 30, 2023
  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Diagnostic Considerations

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease; SLL is diagnosed when the disease is mainly nodal, and CLL is diagnosed when the disease is seen in the blood and bone marrow. CLL is diagnosed when >5000 monoclonal lymphocytes/mm3 are present for longer than 3 months. The diagnosis of SLL requires the presence of lymphadenopathy and absence of cytopenias that are attributable to bone marrow infiltration of the monoclonal lymphocytes. [2] The B-lymphocyte count cannot exceed 5000/mm3. The diagnosis should be confirmed by a lymph node biopsy.

Monoclonal B-lymphocytosis (MBL) is a precursor form of CLL that is defined by the following [2] :

  • < 5000 monoclonal lymphocytes/mm 3
  • Absence of lymphadenopathy or organomegaly
  • Absence of cytopenias

The differential diagnosis of CLL includes several other entities, such as the following:

  • Hairy cell leukemia, which is moderately positive for surface membrane immunoglobulins of multiple heavy-chain classes and is typically negative for CD5 and CD21.
  • Prolymphocytic leukemia (B-cell PLL) has a typical phenotype that is positive for CD19, CD20, and surface membrane immunoglobulin; one-half will be negative for CD5.
  • Large granular lymphocytic leukemia has a natural killer (NK) cell phenotype (CD2, CD16, and CD56) or a T-cell immunotype (CD2, CD3, and CD8).
  • Splenic lymphoma with villous lymphocytes is strongly positive for surface immunoglobulin and positive for FMC-7, CD22, CD79b, and DBA-44.
  • Follicular lymphoma is also strongly positive for surface immunoglobulin, positive for FMC-7, CD22, CD10, CD79b, and weakly positive for CD23.
  • Mantle cell lymphoma (MCL) can have a clinical presentation very similar to that of CLL, but MCL is more aggressive. Like CLL, MCL expresses CD5, CD19, and CD20; however, MCL does not express CD23, which is expressed in CLL. MCL typically expresses the B-cell antigen FMC-7. Importantly, expression of CD20 is bright in MCL, whereas it is dim in CLL.

Anemia secondary to bone marrow involvement with CLL, splenic sequestration of red blood cells, and autoimmune hemolytic anemia associated with a positive Coombs test are included in the differential diagnosis of a patient with anemia who has CLL. Autoimmune hemolytic anemia or thrombocytopenia should be distinguished from bone marrow suppression in the staging of CLL.

Transient lymphocytosis can also be observed in viral infections. However, this is often not sustained for longer than 3 months. In addition, infectious lymphocytosis would not be clonal, would not involve the bone marrow, and would not have a typical CLL immunophenotype. 

Differential Diagnoses