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

Workup

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Media Gallery

Peripheral smear from a patient with chronic lymphocytic leukemia, small lymphocytic variety.
Peripheral smear from a patient with chronic lymphocytic leukemia, large lymphocytic variety. Smudge cells are also observed; smudge cells are the artifacts produced by the lymphocytes damaged during the slide preparation.

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Table 2. CLL-IPI prognostic index^[33]

Table 2. CLL-IPI prognostic index ^[33]

CLL-IPI category	Overall Survival at 5 years	Treatment Recommendation
Low risk	93.2%	Do not treat
Intermediate risk	79.3%	Treat only if symptomatic
High risk	63.3%	Treatment indicated; however, can consider no treatment if asymptomatic
Very high risk	23.3%	If treatment needed, do not use chemotherapy; instead, use targeted agent or clinical trial

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Author

Mohammad Muhsin Chisti, MD, FACP Associate Professor of Medicine (Hematology and Oncology), Oakland University William Beaumont School of Medicine; Medical Director of Research, Karmanos Cancer Institute

Mohammad Muhsin Chisti, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Medical Society of the State of New York

Disclosure: Nothing to disclose.

Coauthor(s)

Bilal M Ali, BS MD Candidate, Oakland University William Beaumont School of Medicine

Disclosure: Nothing to disclose.

Emma L Herrman, MD Resident Physician, Department of Internal Medicine, Beaumont Hospital

Emma L Herrman, MD is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American College of Physicians

Disclosure: Nothing to disclose.

Mariam Aoun, MD Resident Physician, Department of Internal Medicine, Beaumont Hospital – Royal Oak

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.

Haleem J Rasool, MD, FACP Chair, Department of Oncology, Mayo Clinic Health System, La Crosse, WI

Haleem J Rasool, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Delong Liu, MD, PhD Professor of Medicine, Division of Oncology/Hematology, New York Medical College; Chief of Hematology, Phelps Memorial Hospital Center; Director of Non-ablative Allogeneic Stem Cell Transplantation Program, Westchester Medical Center; Editor-in-Chief, Journal of Hematology and Oncology

Delong Liu, MD, PhD is a member of the following medical societies: American Society of Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Samir C Patel, MD Fellow, Department of Hematology and Medical Oncology, Metropolitan Hospital, New York Medical College

Disclosure: Nothing to disclose.

Muhammad A Mir, MD, FACP Assistant Professor of Medicine (Hematology, Blood/Marrow Transplant) Milton S Hershey Medical Center, Pennsylvania State University College of Medicine

Muhammad A Mir, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Hematology, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Acknowledgements

Michael Perry, MD, MS, MACP† Former Nellie B Smith Chair of Oncology Emeritus, Former Director, Division of Hematology and Medical Oncology, Former Deputy Director, Ellis Fischel Cancer Center, University of Missouri-Columbia School of Medicine

Clarence Sarkodee-Adoo, MD Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program

Disclosure: Takeda Millenium Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment