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  • Surgical Pathology Criteria

    Splenic Marginal Zone B Cell Lymphoma


    • B cell neoplasm composed of small and medium sized cells that involves the mantle and marginal zones of splenic follicles and the splenic red pulp

    Alternate/Historical Names

    • Monocytoid lymphoma
    • Splenic lymphoma with circulating villous lymphocytes
    • Splenic lymphoma with villous lymphocytes

    Diagnostic Criteria

    • Polymorphous population with mantle and marginal zone distribution
      • Small round lymphocytes surround and replace follicles (follicular colonization)
        • Results in micronodular pattern
      • Medium sized cells with clear cytoplasm in surrounding marginal zone
        • Scattered large blasts may be intermixed
      • Occasional features
        • Plasmacytoid differentiation
        • Epithelioid histiocytes
    • Red pulp infiltrated by small nodules of mixed sized cells
      • Small cells invade sinuses
    • Marginal zone type lymphocytes may be numerous
      • Small cells with clear cytoplasm
    • Peripheral blood may show villous lymphocytes
      • Lymphoid cells with short polar villi
      • Plasmacytoid differentiation may be seen
      • Not all cases or cells show villi
      • 65% of cases have some kind of circulating lymphocytes
    • Marrow involved in 95% of cases
    • Splenic hilar nodes frequently involved
      • May not show distinct marginal zone distribution
      • More mixing of small and medium sized cells
    • Lacks specific markers of other small cell lymphomas
      • Negative to infrequent for CD23, bcl1, CD5, CD10
      • Positive for B lineage markers and bcl2
      • No specific positive immunologic marker
        • Immunologically, a diagnosis of exclusion
    • Lacks features of nodal or extranodal marginal zone lymphomas
      • No peripheral node involvement
      • No extranodal tissue involvement
    • Transformation reported in 13% of cases
      • Large B cell lymphoma

    Yasodha Natkunam 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 light and heavy chains variably detectable
      • More frequently detectable in plasmacytoid cases
      • IgM and IgD positive
    • CD23 8%
    • CD5 negative
    • CD43 2%
    • bcl1 negative
    • CD10 2%
    • bcl2 65-90%
    • bcl6 negative
    • Cases with transformation to diffuse large cell lymphoma maintain CD5 and CD10 negativity
    • CD138 can be extensive if plasmacytoid differentiation is prominent

    Genetic Study

    • Microarray analysis supports a single molecular entity
    • 7q31-32 allelic loss is found in 45% of cases
      • Associated with aggressive disease
      • Not specific as may be found in other B cell lymphomas

    Clinical Laboratory

    • 30-50% have small monoclonal protein spike


    Differential Diagnosis


    Extranodal vs. Nodal vs. Splenic Marginal Zone Lymphomas

    • Extranodal involvement takes precedence in separation of the three types
      • Mixed types are designated as extranodal with nodal or splenic involvement
    • Nodal type must lack extranodal involvement
    • Splenic type must lack both extranodal and peripheral nodal involvement
      • Splenic hilar nodes may be involved
    • Genetic abnormalities are incompletely studied but support the above separation
      Extranodal Nodal Splenic
    7q21-32 loss rare rare 40%
    trisomy 3 60% rare 17%
    t(11;18) 25-50% rare 0%


    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


    Splenic Marginal Zone Lymphoma SLL/CLL
    Nodular pattern with prominent marginal zone Diffuse effacement
    Polymorphous cell population Uniform small round lymphocytes
    May have residual germinal centers Proliferation centers frequent
    May have circulating villous lymphocytes No villi on circulating cells
    CD23 8% CD23 85%
    CD5 negative CD5 80%
    CD43 2% CD43 80%


    Nodal, Extranodal and Splenic Marginal Zone Lymphoma Lymphoplasmacytic Lymphoma
    Enlarged marginal zone Diffuse effacement
    Pale monocytoid cells No monocytoid population
    • No useful distinguishing immunologic markers
    • Marginal zone lymphomas are frequently plasmacytoid; this combined with the lack of a definitive marker can make this distinction difficult
    • The distinction is sometimes suggested by the propensity to involve mucosal sites by extranodal marginal zone lymphoma


    Nodal, Extranodal and Splenic Marginal Zone Lymphoma Mantle Cell Lymphoma
    Enlarged marginal and mantle zones Enlarged mantle zone frequent
    Polymorphous population Uniform small lymphocytes
    bcl1 negative bcl1 85%
    CD25 negative CD25 30%
    CD5 negative CD5 80%
    CD43 35% (Splenic 2%) CD43 85%
    • Both may involve the GI tract and other mucosal sites in extranodal cases.
    • Enlarged marginal and mantle zones may be hard to distinguish


    Splenic Marginal Zone Lymphoma Follicular Lymphoma
    Polymorphous population Uniform population of atypical small lymphocytes
    Centers of nodules may contain bcl2 negative residual germinal centers Centers of nodules composed of bcl2 positive small atypical lymphocytes
    Plasmacytoid differentiation frequent Plasmacytoid differentiation rare
    CD10 2% CD10 85%
    No peripheral adenopathy May have peripheral adenopathy
    May have circulating villous lymphocytes May have circulating prolymphocytes
    • Both usually express bcl2 in the neoplastic cells
    • Both may have prominent marginal zones
    • Cases with combined features are occasionally seen


    Nodal, Extranodal and Splenic Marginal Zone Lymphoma Mast Cell Disease
    B lineage markers positive B lineage markers negative
    Toluidine blue, Giemsa stains negative Toluidine blue, Giemsa stains positive
    CD117, tryptase immuno stains negative CD117, tryptase immuno stains positive
    Pale marginal zone cells may simulate mast cells


    Nodal, Extranodal and Splenic Marginal Zone Lymphoma Marginal Zone Hyperplasia
    Monocytoid cells may be prominent No monocytoid population
    Light chain monotypia variably demonstrable No monotypia
    Clonal Ig gene rearrangement No clonal rearrangement
    Coexpression of CD43 by B cells 35% No CD43 coexpression
    Sheets of B cells Distinct B and T cell zones


    Nodal, Extranodal and Splenic Marginal Zone Lymphoma with Large Cell Transformation Sporadic Diffuse Large B Cell Lymphoma
    Prior or concurrent specimen with typical marginal zone lymphoma No evidence of typical marginal zone lymphoma
    CD5 negative CD5 10%
    CD10 2% CD10 25-50%
    bcl6 negative bcl6 60%
    Both may involve the GI tract and other mucosal sites


    Plasmacytoma / Myeloma Lymphoplasmacytic Lymphoma and Nodal, Extranodal and Splenic Marginal Zone Lymphomas
    Plasma cells may be pleomorphic or plasmablastic Plasma cell component usually not markedly atypical
    Uniform plasma cell morphology Plasma cells mixed with small lymphocytes
    IgG or IgA M component most common IgM or IgG M component most common
    CD20 often negative CD20 80%
    Uniformly CD138 positive Scattered CD138 positive cells
    Often CD56+, CD19-, CD45- CD56-, CD19+, CD45+

    Splenic Marginal Zone Lymphoma Hairy Cell Leukemia
    DBA44 negative DBA44 positive
    Tartrate resistant acid phosphatase negative Tartrate resistant acid phosphatase positive
    Biphasic cell sizes Uniform cells with small nuclei and abundant cytoplasm
    Villi if present are polar Hairy projections circumferential
    Nodular pattern of white pulp involvement White pulp atrophic
    Peripheral nodes only rarely involved Peripheral nodes may be involved
    Both typically involve the spleen and may have circulating cells with cytoplasmic processes/villi


    • Mean age 60's, rare before 30
    • Involves spleen, splenic hilar nodes, bone marrow
      • May involve peripheral blood
      • May involve liver
      • Peripheral node involvement rare
    • Autoimmune associations
      • Hemolytic anemia
      • Thrombocytopenia
    • Frequent Hepatitis C reported in Italian cases
    • 70% 5 year survival
      • No worsening of prognosis with marrow involvement
      • Splenectomy may relieve hematologic abnormalities
      • Worse prognosis following transformation
    • Incidence
      • Approximately 1-3% of lymphomas

    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

    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
    • Results of supplementary studies if performed
    • Relationship to other specimens from the same patient
    • Information relevant to staging if available
    • If present, comment on transformation
    • Comment on the possiblity or presence of peripheral blood involvement



    Types of small B cell lymphoma


    • Warnke RA, Weiss LM, Chan JKC, Cleary ML, Dorfman RF . Tumors of the Lymph Nodes and Spleen, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 14, 1995
    • Jaffe ES, Harris NL Stein H, Vardiman JW eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2001
    • Ruiz-Ballesteros E, Mollejo M, Rodriguez A, Camacho FI, Algara P, Martinez N, Pollan M, Sanchez-Aguilera A, Menarguez J, Campo E, Martinez P, Mateo M, Piris MA. Splenic marginal zone lymphoma. Proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis. Blood. 2005 May 24;
    • Iannitto E, Ambrosetti A, Ammatuna E, Colosio M, Florena AM, Tripodo C, Minardi V, Calvaruso G, Mitra ME, Pizzolo G, Menestrina F, Franco V. Splenic marginal zone lymphoma with or without villous lymphocytes. Hematologic findings and outcomes in a series of 57 patients. Cancer. 2004 Nov 1;101(9):2050-7.
    • Arcaini L, Paulli M, Boveri E, Vallisa D, Bernuzzi P, Orlandi E, Incardona P, Brusamolino E, Passamonti F, Burcheri S, Schena C, Pascutto C, Cavanna L, Magrini U, Lazzarino M. Splenic and nodal marginal zone lymphomas are indolent disorders at high hepatitis C virus seroprevalence with distinct presenting features but similar morphologic and phenotypic profiles. Cancer. 2004 Jan 1;100(1):107-15.
    • Kansal R, Ross CW, Singleton TP, Finn WG, Schnitzer B. Histopathologic features of splenic small B-cell lymphomas. A study of 42 cases with a definitive diagnosis by the World Health Organization classification. Am J Clin Pathol. 2003 Sep;120(3):335-47.
    • Dogan A, Isaacson PG. Splenic marginal zone lymphoma. Semin Diagn Pathol. 2003 May;20(2):121-7.
    • Thieblemont C, Felman P, Callet-Bauchu E, Traverse-Glehen A, Salles G, Berger F, Coiffier B. Splenic marginal-zone lymphoma: a distinct clinical and pathological entity. Lancet Oncol. 2003 Feb;4(2):95-103.
    • Chacon JI, Mollejo M, Munoz E, Algara P, Mateo M, Lopez L, Andrade J, Carbonero IG, Martinez B, Piris MA, Cruz MA. Splenic marginal zone lymphoma: clinical characteristics and prognostic factors in a series of 60 patients. Blood. 2002 Sep 1;100(5):1648-54.
    • Camacho FI, Mollejo M, Mateo MS, Algara P, Navas C, Hernandez JM, Santoja C, Sole F, Sanchez-Beato M, Piris MA. Progression to large B-cell lymphoma in splenic marginal zone lymphoma: a description of a series of 12 cases. Am J Surg Pathol. 2001 Oct;25(10):1268-76.
    • Mateo M, Mollejo M, Villuendas R, Algara P, Sanchez-Beato M, Martinez P, Piris MA. 7q31-32 allelic loss is a frequent finding in splenic marginal zone lymphoma. Am J Pathol. 1999 May;154(5):1583-9.
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