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  • Surgical Pathology Criteria

    Lymphoplasmacytic Lymphoma


    • Neoplasm composed primarily of small round B lymphocytes with prominent plasmacytoid differentiation, lacking defining features of other types of small B cell lymphomas

    Alternate/Historical Names

    • Gamma heavy chain disease (variant)
    • Immunocytoma
    • Lymphoplasmacytoid lymphoma
    • Small lymphocytic lymphoma with plasmacytoid features
    • Waldenstrom macroglobulinemia

    Diagnostic Criteria

    • Monomorphic lymphoplasmacytoid population with interfollicular, sinusoidal or diffuse pattern
      • Residual germinal centers may be atretic or hyperplastic
      • Epithelioid histiocytes may be numerous, may form granulomas
      • Hemosiderosis frequently associated with autoimmune hemolytic anemia
      • Amyloid may be present
      • Three clusters of patterns described by Andriko et al.
        • Atretic germinal centers, dlated sinuses, hemosiderosis, no histiocytes
        • Interfollicular with normal or hyperplastic germinal centers and epithelioid histoctyes
        • Complete effacement of architecture with clusters of epithelioid histocytes
    • Nuclear features are those of small round lymphocytes
      • Similar to cells of primary follicles
      • Clumped chromatin with small or inconspicuous nucleoli
    • Cytoplasm shows plasmacytoid features
      • Amphophilic staining
      • Russell bodies (cytoplasmic inclusions)
      • Dutcher bodies (intranuclear inclusions)
      • Crystals may be seen in lymphocytes or histocytes
    • Most cases secrete IgM with resultant hyperviscosity (Waldenstrom hypergammaglobulinemia)
      • Variant secreting truncated gamma heavy chain without light chains termed "gamma heavy chain disease"
    • Must lack specific features of other small lymphocytic lymphomas:
      • Proliferation centers, mantle pattern, marginal zone pattern, follcular pattern
      • CD5 (5%), CD10 (3%), bcl1
      • CD23 0-30% in immunohistochemistry
        • Up to 60% positive by flow, but weak
    • Polymorphous type with 10-40% large transformed cells, immunoblasts and small cleaved cells
      • No monomorphous sheets of large cells
      • Increased mitotic figures (30/10 hpf vs. 4/10 hpf)
      • Occasional Reed-Sternberg like cells
      • Reported in 25% of cases
      • Worse survival than typical cases

    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%
    • Light chain monotypia and heavy chains reliably detectable in plasmacytoid cells
      • IgM 67%
      • IgG 33%
      • IgA very rare
    • Immunoglobulin light and heavy chains variably detectable in small cells
    • bcl2 >50%
    • CD43 10-30%
    • Lacks specific markers of other lymphoma types
      • CD5 5%
      • bcl1 negative
      • CD10 3%
    • CD23
      • 0-30% by immunohistology
      • Flow results reported up to 60% but weak
    • CD138 100%
    • FMC7 38%

    Clinical Laboratory

    • IgM monoclonal spike (>3 gm/dl) in 100%

    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


    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%


    Lymphoplasmacytic Lymphoma / Immunocytoma Mantle Cell Lymphoma
    Round nuclear membranes Variably irregular nuclear membranes
    bcl1 negative bcl1 85%
    CD5 5% CD5 80%
    Large cell transformation Blastic transformation
    Plasmacytoid diffrentiation may be prominent in mantle cell lymphoma


    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


    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+


    Castleman disease Lymphoplasmacytic Lymphoma
    Small burned out follicles Residual follicles infrequent
    No intranuclear inclusions Intranuclear inclusions present
    30% of cases monotypic 100% monotypic
    IgG or IgA IgM or IgG


    Reactive Plasmacytosis Lymphoplasmacytic Lymphoma
    Polytypic Monotypic
    No intranuclear inclusions Intranuclear inclusions present
    Generally a problem only with small samples or LLI with an interfollicular pattern


    • Mean age 60 years, rare before 30
    • 100% have monoclonal serum or urine IgM
      • Typically exhibit findings of Waldenstrom macroglobulinemia
        • Hyperviscosity
        • Autoimmune hemolytic anemia and thrombocytopenia
        • Cryoglobulinemia
        • Neuropathy
      • Rare cases make a defective, non-secreted IgM
      • Rare gamma heavy chain variant
      • Very rare alpha heavy chain production
    • More frequent extranodal disease than SLL/CLL
    • Increased circulating lymphocytes variably reported from 0-30%
    • 50% 4 year survival
    • May be associated with Hepatitis C
      • 30% incidence of Hepatitis C reported
      • So far, only reported from Italy

    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


    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 . Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2001
    • Andriko JA, Swerdlow SH, Aguilera NI, Abbondanzo SL. Is lymphoplasmacytic lymphoma/immunocytoma a distinct entity? A clinicopathologic study of 20 cases. Am J Surg Pathol. 2001 Jun;25(6):742-51.
    • Berger F, Felman P, Sonet A, Salles G, Bastion Y, Bryon PA, Coiffier B. Nonfollicular small B-cell lymphomas: a heterogeneous group of patients with distinct clinical features and outcome. Blood. 1994 May 15;83(10):2829-35.
    • Silvestri F, Sperotto A, Fanin R. Hepatitis C and lymphoma. Curr Oncol Rep. 2000 Mar;2(2):172-5.
    • Konoplev S, Medeiros LJ, Bueso-Ramos CE, Jorgensen JL, Lin P. Immunophenotypic profile of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. Am J Clin Pathol. 2005 Sep;124(3):414-20.
    • Owen RG, Barrans SL, Richards SJ, O'Connor SJ, Child JA, Parapia LA, Morgan GJ, Jack AS. Waldenstrom macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors. Am J Clin Pathol. 2001 Sep;116(3):420-8.
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