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    • Surgical Pathology Criteria
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    Burkitt Lymphoma

    Definition

    • Highly aggressive B lineage lymphoma frequently presenting in extranodal sites or as a leukemia, characterized by monomorphic medium sized cells with a very high proliferation rate

    Alternate/Historical Names

    • Small non-cleaved lymphoma

    Diagnostic Criteria

    • Three types:
      • Endemic in equatorial Africa and Papua New Guinea
      • Sporadic cases world wide
      • Immunodeficiency associated cases
    • Uniform, round, medium sized nuclei
      • Intermediate in size between small and large lymphoma cells
      • Nucleoli multiple, central
      • Coarse chromatin
      • Plasmacytoid and atypical variants may show more nuclear pleomorphism
    • Thin but distinct rim of cytoplasm
      • Typically appears to be "squared off" in tissue sections
      • Amphophilic to basophilic
        • Velveteen and basophilic on Giemsa stain
      • Small numbers of vacuoles on touch preps
      • Plasmacytoid variant has eccentric basophilic cytoplasm
    • Very high mitotic rate
      • Ki67 nearly 100%
      • Many tingible body macrophages ("starry sky")
    • Diffse pattern of growth
      • May preferentially involve germinal centers
    • Always B lineage
    • Frequent extranodal involvement
      • GI tract, ovary, breast, kidney, central nervous system, peripheral blood
      • Half of endemic cases involve facial bones
      • HIV related cases frequently involve nodes or marrow
    • Variants

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

    Original posting:: Oct 11, 2007

    Variant: Burkitt Lymphoma with Plasmacytoid Differentiation

    • Abundant eccentric basophilic cytoplasm
      • Stains for immunoglobulin
    • Nuclei may be more pleomorphic than classical type
      • Frequently with single prominent nucleolus
    • Makes up about 20% of HIV associated non-Hodgkin lymphomas
    • May also occur in children
    • EBV positive by FISH in >50%

    Variant: Atypical Burkitt / Burkitt-like Lymphoma

    • Mild to moderate nuclear pleomorphism
    • Nucleoli fewer, more prominent
    • Ki67 nearly 100%
    • t(8;14) translocation must be demonstrated to distinguish from other lymphomas
    • Cases lacking nearly 100% Ki67 or translocation designated diffuse large B cell lymphoma with high growth fraction

    Variant: Burkitt Cell Leukemia

    • Rare, presents purely as acute leukemia
    • Mature B phenotype
    • CD34 negative
    • tdt negative
    • Distinguish from leukemic phase occasionally seen in cases with bulky disease

    Supplemental studies

    Immunohistology and Flow

    • Always B lineage
      • CD20, CD79a 100%
      • Light chain monotypic, variably demonstrable in paraffin
    Ki67 100 %
    bcl6 100%
    CD10 99%
    CD43 73%
    bcl1 negative
    CD5 negative
    CD23 negative
    CD25 negative
    CD30 negative
    CD34 negative
    CD99 negative
    ALK negative
    TdT negative
    bcl2 0-25%

    Genetic analysis

    • EBV EBER identifiable by FISH
      • Endemic cases nearly 100%
      • Middle East, North Africa, South America 60-80% of cases
      • 34% of immunodeficiency cases
      • Sporadic cases <30%
    • Three major translocations involving myc gene and various Ig genes
      • t(8;14)(q23;q21)
        • Approximately 80% of cases
        • Same translocation present in up to 15% of diffuse large B cell lymphoma
      • t(8;22)
      • t(2;8)
    • Ig heavy and light chains clonally rearranged in all cases
    • Gene expression profiling shows a Burkitt signature involving c-myc
      • Some diffuse large B cell lymphomas with this signature show better response to aggressive chemotherapy targeting Burkitt lymphoma rather than standard DLBCL therapy (CHOP or R-CHOP)

    Differential Diagnosis

    Burkitt Lymphoma Lymphoblastic Lymphoma, T and B
    Median age 30 years Median age 17-20 years
    B lineage markers positive 90% T, 10% B
    Multiple nucleoli Inconspicuous nucleoli
    Coarse chromatin Fine chromatin
    Thin rim of cytoplasm Scant cytoplasm
    Frequently GI or ovary T frequently mediastinal, B frequently cutaneous
    TdT negative TdT virtually always positive
    Translocation involving myc gene No myc translocation
    Both have extremely high mitotic rates and starry sky macrophages although Burkitt lymphoma typically has a higher mitotic rate and the starry sky pattern is more uniform

    Burkitt Lymphoma Blastic Mantle Cell Lymphoma
    Median age 30 years Rare under 30 years
    Histiocytes infrequent (tingible body macrophages frequent) Scattered histiocytes in most cases
    No prior diagnosis of mantle zone lymphoma May have prior diagnosis of mantle zone lymphoma
    bcl1 negative bcl1 100%
    CD5 negative CD5 80%
    CD10 99% CD10 negative
    Translocation involving myc gene No myc translocation

    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

    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

    Clinical

    • Sporadic
      • Median age 30 years
      • 30-50% of childhood lymphomas
      • <30% associated with EBV
      • Most cases extranodal
        • GI tract, ovary, breast, kidney, central nervous system
    • Immunodeficiency associated
      • 25-40% EBV positive
      • Frequent HIV associated lymphoma
      • More commonly involves nodes and marrow
    • Endemic Burkitt lymphoma has a markedly different complex of clinical features
      • Endemic zone includes equatorial Africa and Papua New Guinea
        • Areas of high incidence correspond with areas of endemic malaria
        • Most common pediatric neoplasm in this zone
      • 95% of cases associated with EBV
      • Peak incidence 4-7 years
      • Most cases extranodal
        • Half of cases involve facial bones
        • GI tract, ovary, breast, kidney, central nervous system

    Grading/Staging

    • Definitionally high grade

    Special Staging System for Burkitt Lymphoma

    Stage I

    A single extranodal tumor or single anatomic nodal area, except mediastinum or abdomen

    Stage II

    A single extranodal tumor with regional node involvement

    Two or more nodal areas on the same side of the diaphragm

    Two single extranodal tumors with or without regional node involvement ond the same side of the diaphragm

    Primary GI tumor, with or without involvement of associated mesenteric nodes only

    Stage IIR

    Completely resected abdominal disease

    Stage III

    Two single extranodal tumors above and below the diaphragm

    Two or more nodal areas above and below the diaphragm

    All primary intrathoracic tumors

    All extensive primary intra-abdominal disease

    Stage IIIA

    Localized but non-resectable abdominal disease

    Stage IIIB

    Widespread multiorgan abdominal disease
    Stage IV

    Any of above with initial CNS and/or bone marrow involvement (25%)

    Diebold et al. in Jaffe et al. eds, WHO Classification of Tumours 2001

    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

    Lists

    Types and variants of B cell lymphoma

    Blastic lymphomas

    Gastrointestinal tract lymphomas

    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
    • Prevot S, Hamilton-Dutoit S, Audouin J, Walter P, Pallesen G, Diebold J. Analysis of African Burkitt's and high-grade B cell non-Burkitt's lymphoma for Epstein-Barr virus genomes using in situ hybridization. Br J Haematol 1992 Jan;80(1):27-32
    • Hamilton-Dutoit SJ, Raphael M, Audouin J, Diebold J, Lisse I, Pedersen C, Oksenhendler E, Marelle L, Pallesen G. In situ demonstration of Epstein-Barr virus small RNAs (EBER 1) in acquired immunodeficiency syndrome-related lymphomas: correlation with tumor morphology and primary site. Blood 1993 Jul 15;82(2):619-24
    • Chan JK, Tsang WY, Ng CS, Wong CS, Lo ES. A study of the association of Epstein-Barr virus with Burkitt's lymphoma occurring in a Chinese population. Histopathology 1995 Mar;26(3):239-45
    • Davi F, Delecluse HJ, Guiet P, Gabarre J, Fayon A, Gentilhomme O, Felman P, Bayle C, Berger F, Audouin J, Bryon PA, Diebold J, Raphael M. Burkitt-like lymphomas in AIDS patients: characterization within a series of 103 human immunodeficiency virus-associated non-Hodgkin's lymphomas. Burkitt's Lymphoma Study Group. J Clin Oncol 1998 Dec;16(12):3788-95
    • Diebold J, Raphael M, Prevot S, Audouin J. Lymphomas associated with HIV infection. Cancer Surv. 1997;30:263-93. Review.
    • Carbone A, Gloghini A, Gaidano G, Cilia AM, Bassi P, Polito P, Vaccher E, Saglio G, Tirelli U. AIDS-related Burkitt's lymphoma. Morphologic and immunophenotypic study of biopsy specimens. Am J Clin Pathol. 1995 May;103(5):561-7.
    • Raphael MM, Audouin J, Lamine M, Delecluse HJ, Vuillaume M, Lenoir GM, Gisselbrecht C, Lennert K, Diebold J. Immunophenotypic and genotypic analysis of acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas. Correlation with histologic features in 36 cases. French Study Group of Pathology for HIV-Associated Tumors. Am J Clin Pathol. 1994 Jun;101(6):773-82.
    • Dave SS, Fu K, Wright GW, Lam LT, Kluin P, Boerma EJ, Greiner TC, Weisenburger DD, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Delabie J, Rimsza LM, Braziel RM, Grogan TM, Campo E, Jaffe ES, Dave BJ, Sanger W, Bast M, Vose JM, Armitage JO, Connors JM, Smeland EB, Kvaloy S, Holte H, Fisher RI, Miller TP, Montserrat E, Wilson WH, Bahl M, Zhao H, Yang L, Powell J, Simon R, Chan WC, Staudt LM; Lymphoma/Leukemia Molecular Profiling Project. Molecular diagnosis of Burkitt's lymphoma. N Engl J Med. 2006 Jun 8;354(23):2431-42.
    • Hummel M, Bentink S, Berger H, Klapper W, Wessendorf S, Barth TF, Bernd HW, Cogliatti SB, Dierlamm J, Feller AC, Hansmann ML, Haralambieva E, Harder L, Hasenclever D, Kuhn M, Lenze D, Lichter P, Martin-Subero JI, Moller P, Muller-Hermelink HK, Ott G, Parwaresch RM, Pott C, Rosenwald A, Rosolowski M, Schwaenen C, Sturzenhofecker B, Szczepanowski M, Trautmann H, Wacker HH, Spang R, Loeffler M, Trumper L, Stein H, Siebert R; Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe. A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. N Engl J Med. 2006 Jun 8;354(23):2419-30.
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