Lymphoma & related disorders

Mature B cell neoplasms

Small B cell lymphomas with a circulating component


Editorial Board Member: Patricia Tsang, M.D., M.B.A.
Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.
Béla Kajtár, M.D., Ph.D.

Last author update: 6 July 2021
Last staff update: 8 August 2022

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PubMed Search: CLL SLL

Béla Kajtár, M.D., Ph.D.
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Cite this page: Kajtár B. CLL / SLL. website. Accessed April 14th, 2024.
Definition / general
  • Indolent mature B cell lymphoma
  • Clonal proliferation of B cells with characteristic phenotype
Essential features
  • Indolent mature B cell lymphoma
  • Most common adult leukemia in the Western world
  • Characteristic immunophenotype with CD19, CD5, CD20, CD23, CD200 positivity
  • 2 types with distinct biological behavior based on mutation status of rearranged IGH gene
  • Chronic lymphocytic leukemia (CLL): neoplasm of mature B cells with characteristic immunophenotype showing peripheral lymphocytosis (≥ 5 x 109/L) with or without nodal or extranodal manifestation (Blood 2016;127:2375)
  • Monoclonal B cell lymphocytosis: clonal B cells with or without CLL-like immunophenotype in peripheral blood < 5 x 109/L and without nodal manifestation (see B cell monoclonal lymphocytosis)
  • Small lymphocytic lymphoma (SLL): < 5 x 109/L CLL-like cells in peripheral blood with nodal or extranodal manifestation, usually with bone marrow involvement
ICD coding
  • ICD-O: 9823/3 - Chronic lymphocytic leukemia / small lymphocytic lymphoma
  • ICD-10: C91.1 - Chronic lymphocytic leukemia
  • Related codes:
    • ICD-O: 9823/1 - Monoclonal B cell lymphocytosis, CLL type (or atypical CLL type)
    • ICD-O: 9591/1 - Monoclonal B cell lymphocytosis, non-CLL type
    • ICD-10: D72.8 - Lymphocytosis - for monoclonal B cell lymphocytosis
  • Most common adult leukemia in the Western world (Future Oncol 2017;13:1873)
  • Median age is between sixth and seventh decade, practically nonexistent in children
  • Male preponderance (M:F = 1.5 - 2:1)
  • Incidence is low in Asian countries (Int J Oncol 2013;43:561)
  • Lymph nodes, bone marrow, spleen and peripheral blood
  • Usually widespread disease, clinical staging system is used
  • Clonal restriction of specific B cell populations with reduced competition of remaining B cell clones due to aging
  • B cell receptors show evidence of selection by antigens, B cell receptor signaling is crucial in survival of CLL cells (Front Oncol 2020;10:592205)
  • Evidence for autoreactivity of B cell receptors (antigens recognized by studies are related to normal tissue maintenance, apoptosis, atherosclerosis, common infections, etc.) (Front Oncol 2020;10:592205)
  • Some evidence indicating self stimulation by B cell receptors (Cell Res 2013;23:182)
  • 30% of cases show stereotyped B cell receptors with identical or nearly identical structure (Leukemia 2019;33:287)
  • 2 types of CLL that do not show conversion during disease course:
    • CLL-UM (unmutated): few mutations in the IGH gene (≥ 98% homology with germline sequence), associated with more proliferation, more aggressive disease course
    • CLL-MUT (mutated): many mutations in the IGH gene (< 98% homology), associated with less proliferation, better prognosis
  • Gradual accumulation of genetic alterations, however, no clear malignant transformation event recognizable
  • Incidence is not increased following radioactive incidents
  • Familial predisposition in 5 - 10% cases
Clinical features
  • Frequently no symptoms
  • Lymphadenopathy, splenomegaly are common
  • Anemia, thrombocytopenia and neutropenia related symptoms frequently occur
  • Autoimmune hemolytic anemia is common (Best Pract Res Clin Haematol 2010;23:47)
  • Extramedullary involvement may occur; liver, skin, GI mucosa, kidneys are most commonly involved
  • Laboratory diagnosis of lymphocytosis
  • Detection of generalized adenopathy or splenomegaly
  • CT scans are helpful to detect lymph node enlargement
  • Immunophenotyping is essential: flow cytometry of peripheral blood or bone marrow or immunohistochemistry of biopsy material
  • Lymph node biopsy is not generally required, unless to establish diagnosis of Richter transformation (Blood 2018;131:2745)
  • Lymphocytosis
  • Anemia, thrombocytopenia are common
  • Monoclonal gammopathy may occur
  • Hypogammaglobulinemia commonly occurs (Blood 2015;126:573)
Radiology images

Images hosted on other servers:
CT scan

CT scan

Prognostic factors
  • Clinical stage (based on physical manifestations and blood parameters): Rai and Binet systems
  • Beta-2 microglobulin: high levels associated with high tumor burden and adverse prognosis
  • TP53 mutation / 17p deletion is adverse, is associated with poor response to traditional chemotherapeutic regimens; patients may respond to newer agents (J Oncol Pract 2017;13:371)
  • Unmutated IGH gene is adverse
  • Complex karyotype (10 - 15%, 3 or more unrelated abnormalities) is adverse (Blood 2019;133:1205)
  • 13q deletion is favorable, 11q deletion is unfavorable, trisomy 12 is associated with intermediate prognosis
  • CD38 (> 30% positive in CLL cells by flow cytometry) is adverse, ZAP70 expression (> 20%) is adverse
  • CD49d (> 30% positive in CLL cells) has been associated with progression (Blood 2020;135:1244)
  • Large, confluent proliferation centers (adverse) (Blood 2016;127:2375)
  • Methylation profile, various gene mutations may correlate with epigenetic maturation status, response to therapy or prognosis but are not currently used in clinical practice (Nat Genet 2016;48:253)
  • Pattern of bone marrow infiltration is no longer considered important
Case reports
  • Treatment is tailored based on clinical progression (progressive bone marrow failure, progressive or bulky lymphadenopathy, short lymphocyte doubling time, etc.), biological fitness of patient, presence of TP53 mutation / 17p deletion and IGH mutation status (Curr Oncol Rep 2020;22:36)
  • Cytostatic agents: chlorambucil, fludarabine, bendamustine, cyclophosphamide, etc.
  • Monoclonal antibodies: rituximab, obinutuzumab (anti-CD20), alemtuzumab (anti-CD52)
  • Kinase inhibitors: ibrutinib, acalabrutinib (Btk inhibitors), idelalisib (PI3K inhibitor)
  • BCL2 inhibitors: venetoclax
  • Lenalidomide
Gross description
  • Lymph node: enlarged lymph node with homogeneous, fleshy cut surface
  • Spleen: often miliary pattern of white pulp expansion, homogeneous infiltration with massive splenomegaly also occurs (Am J Clin Pathol 2003;120:335)
Gross images

Contributed by Béla Kajtár, M.D., Ph.D.
Paraaortic lymph nodes

Paraaortic lymph nodes

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Splenic involvement

Splenic involvement

Frozen section description
  • Diffuse infiltrate of small, mature lymphocytes with inconspicuous nuclei and scant cytoplasm
  • Immunophenotyping is necessary for diagnosis
Microscopic (histologic) description
  • Diffuse effacement of parenchyma by small, mature lymphocytes
  • Round nucleus, clumped chromatin with only small nucleoli and scant cytoplasm
  • Ill defined, pale proliferation centers (pseudofollicles) are common, composed of prolymphocytes and paraimmunoblasts
  • Bone marrow: nodular or diffuse infiltration; paratrabecular aggregates are not common

  • Occasionally extensive plasmacytoid differentiation
  • Partial lymph node infiltration is possible with perifollicular or interfollicular infiltration (Haematologica 2011;96:1144)
  • Prolymphocyte: small to medium sized mature lymphocyte with clumped chromatin, somewhat larger central nucleolus
  • Paraimmunoblast: large cell with round nucleus, dispersed chromatin and central, enlarged nucleolus, often with basophilic cytoplasm
  • No grading system is used, prolymphocytic transformation is defined based on peripheral blood
  • Histologically aggressive CLL: confluent or very large proliferation center or > 40% Ki67 index; not the equivalent of Richter transformation (Blood 2018;131:2761)
  • Richter transformation: usually high grade B cell lymphoma (DLBCL) appearing in the context of CLL; confluent areas of large cells are required for diagnosis
  • Hodgkin transformation: rare form of Richter transformation, usually clonally unrelated and EBV positive, requires classical Hodgkin lymphoma pattern; scattered Reed-Sternberg cells may be present in CLL (Blood 2018;131:2761)
  • Prolymphocytic transformation: ratio of prolymphocytic cells in peripheral blood increases (< 55%), transformation into B cell prolymphocytic leukemia does not occur, by definition
Microscopic (histologic) images

Contributed by Béla Kajtár, M.D., Ph.D.
Proliferation centers

Proliferation centers

Diffuse lymphocytic infiltrate

Diffuse lymphocytic infiltrate

Proliferation center

Proliferation center





Bone marrow involvement

Bone marrow involvement

Virtual slides

Images hosted on other servers:


Cytology description
  • Small, mature lymphocytes with round nucleus, clumped chromatin and only small nucleoli
Cytology images

Contributed by Béla Kajtár, M.D., Ph.D.
Touch prep SLL

Touch prep SLL

Peripheral smear description
  • Lymphocytosis composed of small, mature lymphocytes with round nucleus, clumped chromatin and only small nucleoli
  • Smudged cells (Gumprecht cells) commonly seen representing mechanically damaged cells (J Clin Oncol 2009;27:1844)
  • Prolymphocytes usually < 15%; 15 - 55% in case of atypical CLL; > 55% defines B cell prolymphocytic leukemia (see Prolymphocytic leukemia)
Peripheral smear images

Contributed by Béla Kajtár, M.D., Ph.D.

CLL in peripheral blood

Positive stains
Negative stains
Flow cytometry description
Flow cytometry images

Contributed by Béla Kajtár, M.D., Ph.D.
CLL, scatter plot

CLL, scatter plot

Molecular / cytogenetics description
  • Unmutated IGH (sequencing) (40 - 60% of cases), testing is necessary before treatment
  • TP53 mutations (sequencing) 10% at diagnosis, 30% at relapse, testing is necessary before treatment (Hematology Am Soc Hematol Educ Program 2016;2016:149)
  • 17p deletion (5 - 30%) may be independent from TP53 mutation, testing is necessary before treatment
  • 13q deletion (50 - 55%), 11q23 deletion (5 - 20%), 12 trisomy (10 - 20%), 6q deletion by FISH is recommended (Biomed Res Int 2014;2014:435983, Blood 2018;131:2745)
  • Karyotyping to show complex karyotype is recommended in clinical studies, not generally indicated in routine clinical practice (Blood 2018;131:2745)
  • IGH translocations rarely occur, IGH-BCL2+ CLL does exist (2 - 5%) (Am J Hematol 2019;94:338)
Molecular / cytogenetics images

Contributed by Béla Kajtár, M.D., Ph.D.
FISH images

FISH images



Sample pathology report
  • Bone marrow, left posterior iliac crest, core biopsy, clot section, aspirate smears and peripheral blood smears:
    • Hypercellular bone marrow with maturing hematopoietic activity and 85% diffuse lymphocytic infiltrate with immunophenotype consistent with chronic lymphocytic leukemia (CLL) (see comment)
    • Comment:
      • Flow cytometric analysis of bone marrow demonstrates 62% lymphocytes with CD19+, CD5+, CD10-, CD43+, CD23+, CD200+, CD38-, CD20(dim)+, sIgL-kappa(dim)+ immunophenotype consistent with CLL. Peripheral blood smears indicate > 5 x 109/L CLL cells.
      • FISH showed biallelic 13q14 deletion in 58%, 11q23 monoallelic deletion in 32% of cells, no 12 trisomy or 17p deletion was noted (see details in separate cytogenetic report).
      • Additional molecular studies (TP53 and IGH sequencing) are in progress and will be reported separately.
    • Peripheral smear: Manual review of the peripheral blood shows unremarkable platelets, no morphological alteration of red blood cells and lymphocytosis with few smudged cells. 12% of lymphocytes show enlarged nuclei and nucleoli (prolymphocytes). A manual 500 cell differential count reveals 87% lymphocytes, 2% monocytes, 10% neutrophils and 1% eosinophils.
    • Bone marrow biopsy: Quality: adequate. Cellularity: 80%. Hematopoiesis: trilineage maturation is present but diminished without dysplastic features or increased blasts. Megakaryopoiesis: normal, cell number is reduced. Granulopoiesis: normal, no blast increase. Erythropoiesis: normal. Infiltrate: 85% diffuse lymphocytic infiltrate composed of mature lymphocytes, approximately 15% are prolymphocytes. Special stains: Reticulin: loose network of reticulin without significant intersections (minimal reticulin fibrosis). Trichrome: negative for collagen deposition.
    • Bone marrow clot section: Quality: adequate. Cellularity: 80% morphologic features are similar to those observed in the core biopsy.
    • Bone marrow aspirate: Quality: adequate. Granulocytes: decreased; normal maturation; no dysplastic features. Erythrocytes: decreased, normal maturation, no dysplastic features, no ringed sideroblasts. Megakaryocytes: significantly decreased; no dysplastic features. Blasts: less than 1% of nucleated cells. Infiltrate: diffuse lymphocytic infiltrate (78%) consisting of small, mature lymphocytes as well as 13% prolymphocytes. A manual 500 cell differential count reveals 23% erythroblasts, 1% myelocytes, 7% metamyelocytes, 2% neutrophils, 1% eosinophils and 66% lymphocytes (of which 13% are prolymphocytes).
Differential diagnosis
Board review style question #1

Which of the following is necessary for diagnosis of CLL?

  1. Immunophenotyping
  2. Sequencing of IGH genes
  3. Sequencing of TP53 gene
  4. Testing for BCL2 rearrangement
  5. Testing for CCND1 rearrangement
Board review style answer #1
A. Immunophenotyping

Comment Here

Reference: CLL / SLL
Board review style question #2
Which of the following constitutes Richter transformation?

  1. Appearance of complex karyotype as part of progression of CLL
  2. Appearance of TP53 mutation as part of progression of CLL
  3. Diffuse large B cell lymphoma appearing as progression of CLL
  4. Nodal CD5+ diffuse large B cell lymphoma
  5. Unmutated CLL turning into mutated CLL
Board review style answer #2
C. Diffuse large B cell lymphoma appearing as progression of CLL

Comment Here

Reference: CLL / SLL
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