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    Diffuse Large B Cell Lymphoma

    Definition

    • B lineage lymphoma composed of large cells with a diffuse pattern of growth

    Alternate/Historical Names

    • Diffuse histiocytic lymphoma
    • Diffuse mixed lymphocytic and histioctyic lymphoma
    • Centroblastic lymphoma
    • Large cleaved follicular center cell lymphoma
    • Large noncleaved follicular center cell lymphoma

    Diagnostic Criteria

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

    Original posting:: September 30, 2007

    Variant: ALK Positive Large B Cell Lymphoma

    • Amongst lymphomas, ALK is nearly restricted to primary systemic large cell lymphoma (T lineage)
    • A rare set of large B cell lymphomas express ALK
      • Large cells with immunoblastic features
        • Round nuclei with single large nucleolus
        • Binucleate cells common
        • One case reported with mixture of large and small cells
        • Basophilic cytoplasm, frequently with paranuclear hof
        • Frequently sinusoidal
      • B lineage based on immunoglobulin expression
        • IgA 5/7 cases
        • Light chain restriction 6/7
          • Based on stains or in situ hybridization
        • B lineage markers negative (CD20, CD79a)
        • ALK membrane positive, cytoplasm +/-
          • Rare cases with clathrin-ALK t(2;17) reported
          • t(2;5) not identified
        • EMA positive 7/7
        • CD30 negative 0/7
        • CD45RB weak to moderate positive
        • T lineage negative (CD3, CD43, CD45RO)
        • CD68 negative
        • CD57 positive 5/7
      • Aggressive course in 6/7 reported cases
      • Note that these are distinct from anaplastic variant of large B cell lymphoma, which is ALK negative

    Variant: Anaplastic Variant of Diffuse Large B Cell Lymphoma

    • Previously included in Anaplastic Large Cell Lymphoma (ALCL)
      • ALCL is now restricted to T lineage (by phenotype or genotype) lymphomas
    • May share several featuares of ALCL
      • Very large cells with markedly pleomorphic nuclei
        • May resemble Reed-Sternberg cell
      • Sinusoidal pattern of growth
      • CD30 expression variable
      • EMA 7/22 positive
    • Distinguishing features from ALCL
      • B lineage
      • Lack of ALK staining
      • Age median 54 years more like large B cell lymphoma than ALCL
    • Behavior same as diffuse large B cell lymphoma
    • Note that these are distinct from ALK positive large B cell lymphoma

    Variant: Immunoblastic Large B Cell Lymphoma

    • Abundant amphophilic cytoplasm and prominent central nucleolus
    • Currently thought to have same behavior as usual diffuse large B cell lymphoma
      • Originally thought to have high grade behavior
    • May be confused with plasmablastic lymphoma, especially in the setting of an oral cavity mass in an HIV+ patient

    Variant: Microvillous Large B Cell Lymphoma

    • Alternate names
      • Anemone cell lymphoma
      • Villiform cell lymphoma
      • Porcupine cell lymphoma
      • Filiform cell lymphoma
    • Numerous microvilli seen by electron microscopy
      • No desmosomes as seen in carcinoma or mesothelioma
    • No distinctive histologic pattern
      • Some are sinusoidal or have fibrillar matrix
      • Rosettes seen in some lymphomas are composed of long cytoplasmic processes
        • Could be considered related to this variant
    • Same clinical behavior as usual diffuse large B cell lymphoma

    Variant: T Cell Rich B Cell Lymphoma / Histiocyte Rich B Cell Lymphoma

    • Can be considered as a spectrum
    • Large atypical cells make up less than 10% of population
      • May have any features of usual large B cell lymphoma
      • May resemble Reed-Sternberg cells
      • B lineage
        • Neoplastic cells may be missed on flow analysis
        • CD30 0-8%
        • CD15 0-15%
        • EMA 0-60%
    • Reactive T cells predominante
      • Small to medium sized
      • Nuclei may be round or irregular
      • No increase in CD57 positive cells
    • Histiocytes may be numerous
    • May be associated with conventional large B cell lymphoma pattern
      • May be concurrent or metachronous
    • Same behavior as conventional diffuse large B cell lymphoma, stage for stage
      • Over half present as stage III or IV
     

    Supplemental studies

    Immunohistology and Flow

    • B lineage (CD20 or CD79a) positive
    • Immunoglobulin variably demonstrable
      • More frequent in immunoblastic variant
    CD5 10%
    bcl2 30-50%
    CD10 25-50%
    CD43 variable
    CD30 variable
    Ki67 usually >40%
    • T cell / histiocyte rich variant
      • Large cells may be missed on flow
      • CD30 0-8%
      • CD15 0-15%
      • EMA 0-60%
      • No increase in CD57+ small cell population

    Genetic Study

    • Gene expression profiling has demonstrated subtypes:
      • Germinal center B-like DLBCL
        • Better prognosis
      • Activated B-like DLBCL
      • Burkitt-like including c-myc
        • Some DLBCL with this signature show better response to aggressive chemotherapy targeting Burkitt lymphoma rather than standard DLBCL therapy
      • No reliable immunologic panel exists to make these distinctions
     

    Differential Diagnosis

    Reactive immunoblastic processes may simulate DLBCL

    • Most common causes are mononucleosis, other viruses, vaccination and drug reaction
    • Any of the following favor a reactive process
      • History or clincal evidence of any of the above causes
      • Age under 20 years
      • Polymorphous infiltrate with immunoblastic large cells
      • Partial node involvement
      • Mixed B and T phenotype of large cells
      • Light chain polytypia in large cells
    • CD30 may be seen in both neoplastic and reactive processes
    • EBV is rare in DLBCL except in immunosuppressed patients
      • Its presence suggests mononucleosis or other reactive conditions
    • Immunoglobulin gene rearrangement study may be neccesary in difficult cases

     

    Kikuchi lymphadenitis may simulate DLBCL

    • Patchy pale foci composed of histocytes and karyorrhectic debris
    • Atypical activated large lymphocytes predominantly peripheral
      • Most large cells T lineage
      • Plasmacytoid dendritic cells (plasmacytoid monocytes) may be present
    • No sheets of large B cells on CD20 stain
    • Extracapsular extension rare

     

    Burkitt Lymphoma Diffuse Large B Cell Lymphoma
    Starry sky macrophages present Starry sky pattern infrequent
    Fine chromatin Vesicular chromatin
    Multiple small nucleoli Few, prominent nucleoli
    Uniform cells Heterogeneous cells
    Ki67 nearly 100% Ki67 moderately high
    Translocation involving myc gene 15% of cases have myc translocation
    Generally only a problem if cytologic detail is obscured by processing related artifacts

     

    Lymphoblastic Lymphoma, B or T DLBCL
    Median age 17-20 years Median age 60 years
    90% T lineage, 10% B lineage B lineage
    Starry sky macrophages present Starry sky pattern infrequent
    Fine chromatin Vesicular chromatin
    None or small nucleoli May have prominent nucleoli
    Uniform cells Heterogeneous cells
    Generally only a problem in suboptimally processed specimens

     

    Diffuse Mixed Lymphoma DLBCL
    50-75% of cells are small atypical B cells Over 50% large atypical B cells
    No confluent foci of large cells Confluent foci of large cells
    In T cell rich B cell lymphoma, the background small cells are T lineage

     

    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%

     

    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%

     

    Plasmablastic Lymphoma Immunoblastic DLBCL
    Typically oral cavity mass in HIV+ patient Wide variety of presentations, including HIV
    LCA negative or minimal + LCA >90%
    CD20 minimal to negative, CD79a positive Both CD20 and CD79a >90%
    Ki67 >95% Ki67 moderately high, variable
    EBV in situ 50% EBV in situ rare in de novo cases; frequent in immunodeficiency cases
    CD138 positive CD138 negative
    Amphophilic cytoplasm and pleomorphic nuclei with prominent nucleoli may cause difficulty with distinction of plasmablastic lymphoma from immunoblastic large B cell lymphoma

     

    Both may partially replace the node and be negative or minimally reactive for CD20 and CD45RB
    Diffuse Large B Cell Lymphoma KSHV-associated Germinotropic Lymphoproliferative Disorder
    Typically effaced architecture Overall nodal architecture preserved
    Typically sheets of large atypical cells Follicular pattern
    HHV8 and EBV negative except in immunosuppressed patients HHV8 and EBV positive

     

    Diffuse Large B Cell Lymphoma True Histiocytic Lymphoma
    Variable cytoplasm Abundant cytoplasm with erythrophagocytosis
    Most over 30 years of age Most under 30 years
    CD20, CD79a positive CD20, CD79a negative
    CD68, CD15, CD163, Lysozyme, CD138 negative or rare CD138+ or at least two of: CD68, CD15, CD163, Lysozyme

     

    Classical Hodgkin Lymphoma Diffuse Large B Cell Lymphoma
    CD45RB, CD20 and CD79a 10-20% CD45RB, CD20 and CD79a >90%
    CD15 80% CD15 5%
    CD30 90% CD30 30%
    Light chains polytypic or negative Light chains monotypic or negative
    Reed-Sternberg cells are frequently positive for both kappa and lambda, apparently due to nonspecific uptake of serum immunoglobulin

     

    Lymphocyte Predominant Hodgkin Lymphoma Diffuse Large B Cell Lymphoma, T Cell Rich B Cell Variant
    Background small cells B lineage Background small cells T lineage
    CD57+ small cells increased No increase in CD57+ small cells
    CD57+ rosettes around large cells No CD57+ rosettes
    Large cells EMA 50% Large cells EMA negative
    • One report questions this clear distinction describing a subset of TCRBCL that had bcl6 positive large cells with increased numbers of CD57+ small cells and rosette formation (EMA not tested). In this same report, some LPHL cases showed 50% of small cells to be T lineage. (Kraus et al.)
    • Some consider cases reported as diffuse LPHL to fall in the spectrum of TCRBCL as the background population in diffuse LPHL is enriched for T cells

     

    Primary Systemic Anaplastic Large Cell Lymphoma Anaplastic Variant Large B Cell Lymphoma ALK Positive Large B Cell Lymphoma
    Marked anaplasia Marked anaplasia Monomorphic with round nuclei
    Frequently sinusoidal Frequently sinusoidal Frequently sinusoidal
    CD30 >90% CD30 variable CD30 negative
    EMA 60% EMA 33% EMA positive
    T lineage B lineage B lineage
    ALK immunohistology 60-85% positive ALK immunohistology negative ALK immunohistology 100% positive
    Majority of ALK positive cases show ALK translocation such as t(2;5) or t(1:2) Lack ALK translocation Rare cases reported with clathrin-ALK t(2:17) gene rearrangement
    ALCL may lack T markers and require genetic analysis to determine lineage  

    Clinical

    • Approximately 30% of lymphomas
    • Median age 60 years
      • May occur at any age
    • 40% present in extranodal sites
      • Most commonly in GI tract
      • May involve any site
     

    Grading/Staging/Report

    • Diffuse large B cell lymphomas not currently graded
      • Previously, the immunoblastic variant was considered high grade
        • Subsequent studies have shown no difference in prognosis
      • Adverse prognostic factors reported include
        • High prolferation rate measured by Ki67 staining
        • bcl2 expression
        • p53 overexpression

    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
     

    Classification/Lists

    Types and variants of large B cell lymphoma

     

    Bibliography

    • 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
    • Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000 Feb 3;403(6769):503-11.
    • Delsol G, Lamant L, Mariame B, Pulford K, Dastugue N, Brousset P, Rigal-Huguet F, al Saati T, Cerretti DP, Morris SW, Mason DY. A new subtype of large B-cell lymphoma expressing the ALK kinase and lacking the 2; 5 translocation. Blood. 1997 Mar 1;89(5):1483-90.
    • Haralambieva E, Pulford KA, Lamant L, Pileri S, Roncador G, Gatter KC, Delsol G, Mason DY. Anaplastic large-cell lymphomas of B-cell phenotype are anaplastic lymphoma kinase (ALK) negative and belong to the spectrum of diffuse large B-cell lymphomas. Br J Haematol. 2000 Jun;109(3):584-91.
    • Hammer RD, Vnencak-Jones CL, Manning SS, Glick AD, Kinney MC. Microvillous lymphomas are B-cell neoplasms that frequently express CD56. Mod Pathol. 1998 Mar;11(3):239-46.
    • Greer JP, Macon WR, Lamar RE, Wolff SN, Stein RS, Flexner JM, Collins RD, Cousar JB. T-cell-rich B-cell lymphomas: diagnosis and response to therapy of 44 patients. J Clin Oncol. 1995 Jul;13(7):1742-50.