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    • Surgical Pathology Criteria
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    Small Lymphocytic Lymphoma / Chronic Lymphocytic Leukemia

    Definition

    • Neoplasm composed primarily of small round B lymphocytes that can range from solid (small lymphocytic lymphoma) to leukemic (chronic lymphocytic leukemia)

    Alternate/Historical Names

    • Mu heavy chain disease (variant)
    • Well differentiated lymphocytic lymphoma

    Diagnostic Criteria

    • Small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) are histologically indistinguishable
      • CLL defined as having circulating B lymphocytes > 4000/mm3
    • Architecture effaced by sheets of small B lymphocytes
      • Predominant population similar to cells of primary follicles
      • Clumped chromatin, small or inconspicuous nucleoli
      • Plasmacytoid differentiation may be prominent
        • Vacuolated plasma cells present on bone marrow biopsy in Mu heavy chain variant
      • Frequent extracapsular extension
      • Occasional more limited patterns: perifollicular, interfollicular or marginal zone
      • May involve extranodal sites, especially if leukemic
    • Pseudofollicular proliferation centers frequent
      • Pale, vague nodules containing larger prolymphocytes and paraimmunoblasts
      • Mitotic figures may be frequent in proliferation centers
      • Prolymphocytes
        • Slightly larger nucleus than typical small lymphocytes
          • Less condensed chromatin
          • Small but distnct nucleoli
        • Slightly more cytoplasm
      • Paraimmunoblasts
        • Intermediate to large cells
        • Partially vesicular nucleus, prominent central nucleolus
        • Delicate nuclear membrane
    • Transformation to diffuse large B cell lymphoma (Richter syndrome) in 10-20% of cases
      • May show immunoblastic features
      • Generally retains same phenotype
      • Genetic study may show different clone in up to 40% of cases
      • Clinically abrupt worsening of symptoms or tumor growth
    • Transformation to Hodgkin lymphoma rare (0.5-2%)
      • May be all types of classical Hodgkin lymphoma
        • Usual Hodgkin phenotype
        • Most cases EBV RNA positive by in situ hybridization
      • Rare cases of nodular lymphocyte predominant Hodgkin lymphoma reported
        • Both cases CD20 negative, one with discordant light chain
      • Most but not all show same clone
    • Prolymphocytic transformation
      • CLL with increased prolymphocytes
        • 11-55% circulating prolymphocytes
        • May be refractory to treatment and have worse prognosis
      • CLL with prolymphocytic transformation
        • Over 55% circulating prolymphocytes
        • May be refractory to treatment and have worse prognosis
    • Peripheral T cell lymphoma has been described associated with SLL/CLL
    • Paraimmunoblastic variant
      • Diffuse population of paraimmunoblasts with interspersed prolymphocytes and small lymphocytes
      • Mitotic rate 15-50%
        • May have starry sky macrophages
      • Half of cases leukemic but circulating prolymphocytes always <10%
      • Same clinical behavior as usual SLL/CLL
      • Reported incidence 2% of SLL/CLL
    • Separation from other small B cell lymphomas requires immunologic study

    Yasodha Natkunam MD PhD
    Dita Gratzinger MD PhD
    Robert V Rouse MD
    Department of Pathology
    Stanford University School of Medicine
    Stanford CA 94305-5342

    Original posting:: May 1, 2006

    Supplemental studies

    Immunohistology and Flow Cytometry

    B lineage 100%
    Immunoglobulin Variably detectable
    CD23 85%
    CD5 80%
    bcl2 95%
    CD43 80%
    bcl1 2%
    CD10 Negative
    CD38 33%
    ZAP70 36%
    FMC7 Negative
    • Cases with transformation to diffuse large cell lymphoma show the same phenotype as SLL/CLL
    • CD38 and ZAP70 reactivity may predict behavior (Hus 2006)

    Laboratory Studies

    • Serum or urine electrophoresis, immunofixation, light chain quantification
      • Small M component (serum monoclonal immunoglobulin) may be present
    • Mu heavy chain disease variant
      • Serum protein electrophoresis reveals Mu polymers
      • Urine protein electrophoresis: 50% show monoclonal free light chain (Bence Jones protein)
        • Usually kappa

    Differential Diagnosis

    Small B Cell Lymphomas
      SLL/CLL Mantle Marginal Zone Lymphoplasmacytic Follicular
    CD23 85% 2% 8% 0-30% on immunohistology but up to 60% weak positive on flow 0-25%
    CD5 80% 80% 0% 5% 0%
    bcl1 2% 85% 0% 0% 0%
    CD10 0% 2% 2% 3% 85%
    CD43 80% 85% 35% 10-30% 7%
    bcl2 95% 95% 65-90% >50% 90%
    • CD23 staining refers to lymphoid staining
      • Follicular dendritic cells stain in many processes
    • bcl1
      • Blastic mantle cell lymphoma 100%
      • Hairy cell leukemia 41%
    • CD43 stains only 2% of splenic marginal zone lymphoma

     

    Mantle Cell Lymphoma SLL/CLL
    Irregular nuclear membranes Round nuclei
    Residual germinal centers may be prominent Proliferation centers present
    Expanded mantle zone around germinal centers variably present No mantle zone pattern
    Scattered histiocytes Histiocytes not prominent
    bcl1 85% bcl1 2%
    CD23 2% CD23 85%
    Blastic transformation Large cell transformation
    Some mantle cell lymphomas have been reported to have proliferation centers; these are better considered as SLL/CLL

     

    Lymphoplasmacytic Lymphoma / Immunocytoma SLL/CLL
    Proliferation centers absent Proliferation centers frequent
    Plasmacytoid differentiation marked Plasmacytoid differentiation variable
    CD5 5% CD5 80%
    CD23 0-30% on immunohistology but up to 60% weak positive on flow CD23 85%

     

    Nodal, Extranodal and Splenic Marginal Zone Lymphoma SLL/CLL
    Enlarged marginal zone Diffuse effacement
    Pale monocytoid cells Small round lymphocytes
    May have residual germinal centers Proliferation centers frequent
    CD23 8% CD23 85%
    CD5 negative CD5 80%
    CD43 35% (Splenic 2%) CD43 80%
    Both may involve the GI tract and other mucosal sites

     

    Follicular Lymphoma SLL/CLL
    Distinct nodular pattern Vague proliferation centers
    Nodules composed of cleaved cells Nodules composed of prolymphocytes and paraimmunoblasts
    Interfollicular cleaved cells common Background sheets of regular small lymphocytes
    CD23 0-38% CD23 85%
    CD5 negative CD5 80%
    CD43 7% CD43 80%
    CD10 85% CD10 0%
    bcl2 stains over 90% of both

     

    Lymphocyte Predominant Hodgkin Lymphoma SLL/CLL
    Wide age range Rare under 30 years
    Limited number of large nodules Scattered small proliferation centers
    Large atypical cells scattered in and around nodules Large cells confined to proliferation centers
    CD23 negative CD23 85%
    CD5 negative on B cells CD5 80%
    CD43 negative on B cells CD43 80%
    Large cells may be EMA positive EMA negative
    Light chains polytypic or negative Light chains monotypic or negative
    CD57+ small cells surrounding large cells No CD57 ringing pattern

     

    Sporadic Diffuse Large B Cell Lymphoma SLL/CLL with Large Cell Transformation
    No history of SLL/CLL History or concurrent SLL/CLL
    CD23 negative CD23 85%
    CD5 negative CD5 80%
    CD43 rare CD43 60-80%

     

    Diffuse Large B Cell Lymphoma Paraimmunoblastic SLL/CLL
    Nuclear shape variable Nuclei round, uniform
    Nucleoli frequently multiple Nucleoli single
    Cytoplasm may be basophilic Cytoplasm pale
    Node capsule frequently destroyed Node capsule preserved even if overrun
    CD5 rare CD5 80%

     

    Immunoblastic Large B Cell Lymphoma Paraimmunoblastic SLL/CLL
    Very large cell size Moderate to large cell size
    Very vesicular nuclei Partially vesicular nuclei
    Very large nucleoli Intermediate size nucleoli
    Basophilic cytoplasm Pale cytoplasm
    CD5 rare CD5 80%

     
    Burkitt Lymphoma Prolymphocytic SLL/CLL
    Starry sky macrophages present Starry sky macrophages variable
    Uniform population Admixed prolymphocytes and small cells
    Cytoplasm amphophilic or basophilic Cytoplasm pale
    Multiple nucleoli Single nucleolus
    Ki67 nearly 100% Ki67 moderately high
    CD23 negative CD23 85%
    Translocation involving myc gene No myc translocation

    Nodal Involvement by Prolymphocytic Leukemia Paraimmunoblastic SLL/CLL
    Many circulating prolymphocytes <10% circulating prolymphocytes
    Pure prolymphocytic infiltrate Predominantly paraimmunoblasts
    Splenomegaly present Splenomegaly variable
    Lymphadenopathy minimal Lymphadenopathy prominent

    Chronic Inflammation SLL/CLL
    Germinal centers may be present Proliferation centers indistinct
    Mixed population Uniform small cells (except proliferation centers)
    CD23 negative (follicular dendritic cells positive) CD23 85% positive on lymphocytes
    No coexpression Coexpression of CD5 or CD43 75-100%
    B and T zones Sheets of B cells
    No light chain monotypia Light chain monotypia variably demonstrable
    Clonal immunoglobulin rearrangements absent Clonal immunoglobulin rearrangements present
    Capsular fibrosis infrequent Capsular fibrosis frequent
    Plasmacytosis infrequent Plasmacytosis frequent

    Clinical

    • Mean age 60 years, rare before 30
    • Median survival after transformation is 5-8 months
    • Mu heavy chain disease variant
      • Rare variant with prominent hepatosplenomegaly in the absence of lymphadenopathy

    Grading/Staging/Report

    • While staging is linked to prognosis, it does not generally determine therapy
      • Therapy generally determined by clinical signs and symptoms
    • Pathologic staging is usually limited to bone marrow biopsy and biopsies of other sites to confirm clinical evidence of involvement
    • 80% present as stage IV, generally bone marrow

    Ann Arbor Staging System

    • Stage I
      • I if involvement of a single lymph node region
      • IE if involvement of a single extralymphatic organ or site
    • Stage II
      • II if two or more lymph node regions on same side of diaphragm
      • IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm
    • Stage III
      • III if Involvement of lymph node regions on both sides of the diphragm
      • IIIS if spleen involved
      • IIIE if extralymphatic site involved
    • Stage IV
      • Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement
    • Systemic Symptoms in 6 months preceding admission
      • Fever, night sweats, 10% weight loss
      • A = absent
      • B = present
    • Extranodal sites are also designated
      • M+ = marrow
      • L+ = lung
      • H+ = liver
      • P+ = pleura
      • O+ = bone
      • D+ = skin and subcutaneous tissue
    • Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas.

    The pathology report should contain the following information:

    • Diagnosis in the World Health Organization (WHO) classification
      • Equivalent diagnosis in other classifications used by relevant clinicians
    • Pathology report should explain that SLL and CLL are separable only based on peripheral blood findings
      • Comment on peripheral blood findings if available
    • Results of supplementary studies if performed
    • Relationship to other specimens from the same patient
    • Information relevant to staging if available

     

     

    Lists

    Types of small B cell lymphoma

    Bibliography

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    • Jaffe ES, Harris NL Stein H, Vardiman JW . Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2001
    • Pugh WC, Manning JT, Butler JJ. Paraimmunoblastic variant of small lymphocytic lymphoma/leukemia. Am J Surg Pathol. 1988 Dec;12(12):907-17.
    • Gupta D, Lim MS, Medeiros LJ, Elenitoba-Johnson KS. Small lymphocytic lymphoma with perifollicular, marginal zone, or interfollicular distribution. Mod Pathol. 2000 Nov;13(11):1161-6.
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    • Giles FJ, O'Brien SM, Keating MJ. Chronic lymphocytic leukemia in (Richter's) transformation. Semin Oncol. 1998 Feb;25(1):117-25. Review.
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    • Weisenberg E, Anastasi J, Adeyanju M, Variakojis D, Vardiman JW. Hodgkin's disease associated with chronic lymphocytic leukemia. Eight additional cases, including two of the nodular lymphocyte predominant type. Am J Clin Pathol. 1995 Apr;103(4):479-84.
    • Kroft SH, Dawson DB, McKenna RW. Large cell lymphoma transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma. A flow cytometric analysis of seven cases. Am J Clin Pathol. 2001 Mar;115(3):385-95.
    • Dunphy CH, Wheaton SE, Perkins SL. CD23 expression in transformed small lymphocytic lymphomas/chronic lymphocytic leukemias and blastic transformations of mantle cell lymphoma. Mod Pathol. 1997 Aug;10(8):818-22.
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    • Hus I, Podhorecka M, Bojarska-Junak A, Rolinski J, Schmitt M, Sieklucka M, Wasik-Szczepanek E, Dmoszynska A. The clinical significance of ZAP-70 and CD38 expression in B-cell chronic lymphocytic leukaemia. Ann Oncol. 2006 Apr;17(4):683-90.
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