HOMO SAPIENS DISEASES - BURKITT'S LYMPHOMA (BL) / AFRICAN LYMPHOMA (highly aggressive, high grade malignancy)

Table of contents :


  • Epidemiology
  • Aetiology
  • Pathogenesis
  • Symptoms & signs
  • Laboratory examinations
  • Therapy
  • Web resources

  • Epidemiology : in 1958, Dennis Burkitt first described a disorder associated with jaw tumours in African childrenref. In 1961, the neoplasm was identified as a form of malignant lymphoma, and what had initially emerged as a clinical syndrome became a pathological entity called Burkitt’s lymphoma (BL)ref. It is the most frequent tumor in children aged 5 to 9 years in equatorial Sub-Saharan Africa, South America, and Papua New Guinea. The overall incidence of BL in the USA was 1.4 per million for white males and 0.4 per million for white females during 1973-1981ref. BL accounts for 30 to 50% of lymphomas in children but only 1 to 2% of lymphomas in adultsref
    Aetiology :

    Pathogenesis of HHV-4 / EBV+ BL appears to involve the combined actions of virus-induced B cell proliferation and
  • a chromosomal translocation in a single B cell which leads c-myc protooncogene under the control of ...
  • Ig H chains promoter : t(8;14)(q32;q21) (80%)
  • l chain promoter : t(8;22)(q21;q11)
  • k chain promoter : t(2;8)(p11-12;q21)
  • => overexpression have been identified in endemic and sporadic BL. However, some not very strict associations between JH and DH recombination have been identified at 14q32, with distant 5‘ c-myc recombination in endemic cases of BL, whereas in sporadic cases Sµ and S recombination was identifiedref at 14q32, with near 5‘ or intronic c-myc recombination at 8q24. These differences between endemic and sporadic BL do not mean that each of these subtypes of lymphoma represents a perfectly homogeneous entityref. Instead, it seems probable that BL is composed of a mixture of molecular types and that the incidence of each subtype might depend upon environmental factorsref1, ref2. Yet, the sporadic form of BL can also occur in endemic areasref, as reported in the table below, which summarises the distribution of BL collected from endemic areas of Kenya according to the age of patients, the clinical pathological characteristics, and the EBV and HIV status. These observations emphasise the importance of precise disease definition for biological and epidemiological studies.
    BL age under 16 years (range 2–16; median 6)
    BL age over 16 years (range, 17–58; median 29)
    Total cases
    23
    16
    Male/Female
    14/9
    10/6
    Site jaw
    16
    2
    nodal
    3
    7
    ileum
    2
    5
    other
    2
    2
    HIV
    0
    8
    EBV
    21
    12
    The necessary cytogenetics for the diagnosis of BL should be the presence of the t(8;14) (q24;q32) translocation and its variants, or c-myc rearrangement. If cytogenetic or Southern blot cannot be applied to solid tumours the most reasonable surrogate for c-myc rearrangement is probably the proliferation fraction. Therefore, cases in which cytogenetic analysis is not available should not be diagnosed as BL or BL-like without a Ki-67 fraction close to 100%Pathology and genetics: tumors of haematopoietic and lymphoid tissues. The World Health Organisation classification of tumors. Jaffe ES, Harris NL, Stein H, et al, eds. Lyon: IARC Press, 2001. The morphological similarity between BLs probably results from the fact that they all have a common translocation, t(8;14), and consequent c-myc rearrangement and overexpression. However, it is also true that BLs account for only 30% of lymphomas bearing a c-myc translocation at presentationGaulard Ph, Delsol G, Callat MP, et al. Cytogenetic and clinicopathologic features of B-cell lymphomas associated with the Burkitt translocation t(8;14) (q24;q32) or its variants. J Clin Pathol 2002; 55(suppl 1):A22. Furthermore, the c-myc translocation is not the only genetic lesion found in BLref, and myc transformed cells are usually characterised by the loss of expression of several genesref. Cooperating alterations of cell cycle associated genes probably contribute to the pathogenesis of BLref1, ref2. The c-Myc oncoprotein promotes proliferation and apoptosis, such that mutations that disable apoptotic programmes often cooperate with MYC during tumorigenesis : 2 common mutant MYC alleles derived from human BL uncouple proliferation from apoptosis and, as a result, are more effective than wild-type MYC at promoting B cell lymphomagenesis in mice. Mutant MYC proteins retain their ability to stimulate proliferation and activate p53, but are defective at promoting apoptosis due to a failure to induce the BH3-only protein Bim (a member of the Bcl2 family) and effectively inhibit Bcl2. Disruption of apoptosis through enforced expression of Bcl2, or loss of either Bim or p53 function, enables wild-type MYC to produce lymphomas as efficiently as mutant MYC. These data show how parallel apoptotic pathways act together to suppress MYC-induced transformation, and how mutant MYC proteins, by selectively disabling a p53-independent pathway, enable tumour cells to evade p53 action during lymphomagenesisref.
  • p53 mutations have been found in 30–40% of BL samplesref, and most lymphomas with wild-type p53 might have lesions in other growth suppressor genesref
  • recently, mutations of the nuclear localisation signal of the RBL2 / p130 tumour suppressor gene have also been detected in BL cell lines and primary tumoursref. The pRb2/p130 tumour suppressor gene belongs to the retinoblastoma (Rb) gene family, along with Rb and p107. Although they have similar functional properties, Rb family members are not functionally redundant and each protein has a different temporal profile of interaction with different E2F membersref1, ref2, ref3. Whereas Rb is found in both quiescent and proliferating cells, the expression of Rb2/p130 and p107 is related to the cell cycleref. In an ideally controlled proliferating cell population with identical cell cycle and cycle phase times, during which a given protein can be detected in the nucleus by the corresponding antibody, the percentages of cells expressing pRb2/p130 and p107 should be inversely correlatedref. Although such a pattern of Rb2/p130 and p107 expression has been demonstrated in different types of non-Hodgkin’s lymphomas, this is not the case in BLsref. The Rb2/p130 gene is mutated in most cases of endemic BL and to a lesser extent in sporadic BL. In contrast, in AIDS related BL, the wild-type pRb2/p130 gene is highly expressedref1, ref2. In those tumours in which the Rb2/p130 gene is mutated, the interaction between individual proteins and E2F family members and the timing of formation of particular protein–E2F complexes during the cell cycle can be deregulated.25 In addition to mutations of the gene, interaction with viral oncoproteins is another important mechanism of pRb2/p130 inactivationref1, ref2. pRb2/p130 shares, with all members of the retinoblastoma gene family, the ability to interact physically with certain DNA virus oncoproteins; by this mechanism, pRb2/p130 is inactivated yet maintained in its underphosphorylated formref1, ref2, ref3, ref4, ref5. Thus, the absence of mutations in the Rb2/p130 gene and the unusually high expression of pRb2/p130 in tumours with high proliferative activity, such as AIDS related BL, may suggest a physical interaction of pRb2/p130 with viral products. Although HIV-1 has long been recognised as the aetiological agent of AIDS, the role of HIV-1 as an oncogenic virus has not yet been well established. Data exist that clearly suggest that the HIV gene product Tat can contribute to the growth and oncogenesis of human and animal cellsref. Soluble Tat can function as a biologically active extracellular protein released by infected cells and readily taken up by uninfected cells.36,37 This has also been shown to occur in AIDS related B cell lymphomas, by the diffuse and nuclear staining seen in tissue sections immunostained with anti-Tat monoclonal antibodyref. In addition, there is experimental evidence that extracellular Tat acts directly on B cellsref. In particular, germinal centre B cell proliferation was enhanced by the addition of Tat at the initiation of the culture, suggesting that Tat acts on the early stage of B cell activation, probably before the G1 to S phase transitionref. This is in line with new data indicating that the well established function of Rb2/p130 in the control of the G0/G1 transition can be inactivated by physical interaction with the Tat protein of HIV-1. In fact, the results of an in vitro and in vivo binding assay suggest that the Tat protein of HIV-1 is one of those viral oncoproteins that interact with the Rb family. In particular, they revealed that the Tat protein of HIV-1 interacts specifically with the pocket region of the Rb2/p130 proteinref. This can result in the inactivation of Rb2/p130 oncosuppressive properties and the induction of genes needed to proceed through the cell cycle including p107, cyclin A, and cyclin Bref. Consequently, some B cell clones among a virus induced B cell proliferation might have an uninterrupted cell cycle and a growth advantage, thus favouring the incidence of B cell malignancies in lymphoid organs of HIV-1 positive patients. Increased cell proliferation has been shown to account almost entirely for tumour prevalence in immunocompromised patientsref. Spontaneous regression of HIV-1 associated lymphoproliferative disorders has been reported after highly active antiretroviral therapyref1, ref2, ref3.  In quiescent G0 cells, the nuclear E2F–pRb2/p130 complex is responsible for the active repression of several cellular promoters. After its release into the cell cycle, pRb2/p130 is phosphorylated by G1 cyclin dependent kinases (cdks) and subsequently degraded through a proteosome dependent mechanism, resulting in the derepression of a variety of genes, including p107. The accumulated p107 protein is then able to interact with E2F4 and E2F5, which have been released from pRb2/p130, and associate with cyclin A (cyc A)/cdk2.

  • Expression of the TCL-1 oncogene in EBV+ BL tumour cells is dependent on the presence of EBV. This finding suggests that the ability of EBV to induce TCL-1 would circumvent the need for the additional genetic or epigenetic changes that lead to the constitutive expression of this oncogene in EBV-negative BL tumoursref.

    Differential diagnosis : the distinction between BL and diffuse large-B-cell lymphoma is not reliably reproducible with the use of the current criteria of morphology, immunophenotype, and genetic abnormalities : the characteristic t(8;14) translocation of Burkitt's lymphoma also occurs in 5-10% of cases of DLBCLref. Because DLBCL is > 20 times as common as BLref, a lymphoma with a t(8;14) translocation can present a diagnostic problem. Agreement among expert hematopathologists on the pathological diagnosis of classic Burkitt's lymphoma, atypical Burkitt's lymphoma, and diffuse large-B-cell lymphomas is only 53%ref (Magrath I, Jaffe ES, Bhatia K. Burkitt's lymphoma. In: Knowles DM, ed. Neoplastic hematopathology. Philadelphia: Lippincott Williams & Wilkins, 2001:953-86). The Burkitt's translocation or its variants, which juxtapose the locus of the myc oncogene and one of the three immunoglobulin (IG) loci, are present in almost all Burkitt's lymphomasref1, ref2. Nevertheless, myc translocations are not specific for BL since they also occur in other lymphomas, including DLBCL. In the latter, chromosomal breakpoints at the myc locus are recurrently associated with non-IG partner loci and complex chromosomal alterationsref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8. The imprecise distinction between BL and DLBCL on diagnosis may lead to the inadequate treatment of some patients with a mature aggressive B-cell lymphoma. A molecular signature consisting of 58 genes, including several target genes of the nuclear factor-B pathway (i.e., BCL2A1, FLIP, CD44, NFKBIA, BCL3, and STAT3) that are known to distinguish ABC–like or GCB-cell–like lymphomasref1, ref2, allows differentiation of BL (mBL) and DLBCLref. The mBL signature extends the WHO definition of Burkitt's lymphoma to cases with the morphologic characteristics of DLBCL and expression of BCL2. Yet not all cases with morphologic or immunophenotypical features of BL were classified as mBL.
    It is notable that these genes were expressed at lower levels in mBL cases than in cases of GCB-cell–like DLBCL. 3 main cytogenetic groups can be distinguished within the mature aggressive B-cell lymphomas :

    The mBL group predominantly consisted of myc-simple lymphomas; the non-mBL group predominantly consisted of myc-negative lymphomas. In contrast, the intermediate group contained most of the myc-complex cases but also occasional myc-simple and several myc-negative cases. Hierarchical clustering revealed four prominent clusters of coordinately expressed genes, which we term gene-expression "signatures," because they reflect specific biologic processesref : The third and fourth signatures were expressed at lower levels in BL than in DLBCLref.
    The microarray method seems to outperform the expert pathologists: 17%ref and 34%ref of cases with the gene-expression signature of Burkitt's lymphoma had been called DLBCL or unclassifiable high-grade B-cell lymphoma; 0.4%ref and 4%ref of cases without the Burkitt's signature had been called classic or atypical BL; and 3%ref and 8%ref of cases diagnosed as DLBCL or unclassifiable high-grade B-cell lymphoma had a BL.

    Though BL and GCB-cell–like DLBCL both originate from GC B cellsref1, ref2, the expression of a subgroup of GC B-cell genes distinguished BL from DLBCL. NF-kB target genes were expressed at lower levels in BL than in any of the DLBCL subgroups; it is unclear whether this is due to differences in the malignant cells or in the tumor-infiltrating immune cells. BL tumors expressed MHC class I genes at very low levels as compared with tumors of DLBCL. Previous studies have documented the loss of MHC class I molecules in some cell lines derived from BL (Voltz R, Jilg W, Wolf H. Modification of HLA expression as a possible factor in the pathogenesis of Burkitt's lymphoma. Hamatol Bluttransfus 1989;32:289-292), but the mechanism underlying this down-modulation is unclear. Cases with both the t(8;14) and t(14;18) translocations are very aggressive and associated with a poor prognosisref.

    Laboratory examinations :

  • immunophenotype : CD5-10 / CALLA+19+20+22+23-45+79a+, sIgM+
  • cytomorphology : Burkitt’s tumours are composed of monomorphic, medium sized cells (smaller than the cells of most DLBCL) with round nuclei, multiple nucleoli, and relatively abundant basophilic cytoplasm, which may give the cells a "cohesive appearance". Typical morphological pattern of Burkitt’s lymphoma (Giemsa stained; original magnification, x375).


  • These tumours have an extremely high rate of proliferation, in addition to a high rate of apoptosis. A "starry sky" pattern is usually present, imparted by numerous benign macrophages that have ingested apoptotic tumour cells. These features are distinctive, but they overlap with morphologic and genetic attributes of DLBCL. BL may have an admixture of large lymphoid cells, and DLBCL may have medium-sized cells, a high proliferation fraction, a starry-sky pattern, and even a c-myc rearrangement.
    Based on Ig gene rearrangement studies, the cell of origin of BL is currently thought to be a germinal centre B cellref, although several studies of IgHV genes in BLs suggest that they may derive from memory B cells rather than germinal centre B cellsref. However, most of these studies rely on cell lines or a small series of cases. Endemic and AIDS-related forms showed a considerably higher VH mutation rate than the sporadic form (5.1%, 5.4% and 1.5% respectively). The mutations in eBL and AIDS-related BL also showed signs of antigen selection, while no signs of antigen selection were found in sBL. Finally, after subcloning the amplificates, sequence analysis revealed no signs of ongoing mutations in any of the cases analyzed. Since one of the main differences between eBL and AIDS related BL on the one hand and sBL on the other hand is the association with EBV, we compared EBV-positive and EBV-negative BL, independently of their geographical origin and HIV status. The differences in the number of somatic mutations and antigen selection were even more evident when this approach was used. EBV+ and EBV- BL may originate from 2 distinct subsets of B cells, pointing to a particular role for the GC reaction in the pathogenesis of these tumors. The different types of C-MYC translocation reported in BL may also be related to the different stages of B-cell maturationref.
    What are the immediate implications of these studies for clinical practice? RNA extraction and microarray analysis are laborious and expensive and are therefore not ready for real-time diagnosis in clinical practice, but other tools that are currently available to pathologists can be used to identify some of the distinguishing features of cases with the molecular signature of BL :
    morphologic features
    proliferation fraction (Ki-67) (%)
    translocation
    immunophenotype
    myc
    other
    standard
    future
    features suggestive of BL medium-sized cells > 95% Ig-myc none CD10+
    BCL6+
    BCL2-
    CD44-
    MUM1-
    TCL1+
    HLA-I-
    CD23-
    cyclin H-
    features not suggestive of BL large cells < 90% myc-negative
    non-IG-MYC
    BCL2
    BCL6
    CD10-
    BCL6-
    BCL2+
    CD44+
    MUM1+
    TCL1-
    HLA-I+
    CD23+
    cyclin H+
    Both the gene-expression signatureref and the immunophenotyperef of lymphomas with the Burkitt's signature reflect the germinal-center stage of B-cell differentiation. Markers of germinal-center and non–germinal-center B cells can be detected by routine immunohistochemical analysis. IGH, IGL, myc, BCL2, and BCL6 rearrangements can be detected by FISH in paraffin sections. New markers could be used in practice: down-regulation of class I HLA antigens and CD44 and up-regulation of TCL1 in Burkitt's lymphoma; other immunophenotypic markers have been suggested recently as wellref1, ref2, ref3, ref4
    Therapy : Web resources : Burkitt's lymphoma at LymhomaInfo

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