Burkitts lymphoma (BL)

2018-01-01   Luis Miguel Juárez Salcedo , Luis Miguel Juárez Salcedo , Luis Miguel Juárez Salcedo 

1.Principe de Asturias University Hospital, Madrid, Spain (LMJS); Clinic Valladolid University Hospital, Valladolid, Spain (ACM); Oncology and Hematology, Mercy Clinic Joplin, Joplin, MO, USA sdalia@gmail.com (SD).
2.Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy

Abstract

Review on Burkitts lymphoma, with data on clinics, and the genes involved.

Clinics and Pathology

Note


Phenotype stem cell origin

Pan-B antigens positive (CD19, CD20, CD21, CD22 and CD79a); co-expression of CD10 and Bcl-6. TdT-, CD5-, CD23-, Bcl-2- and CD138-; sIgM+. The cell of origin is a peripheral IgM+ memory B-cell (presence of somatic hypermutation of the Ig gene). Ki67 expression is close to 100% of neoplastic cells.

Etiology

Burkitt lymphoma (BL) originates from germinal or post-germinal center B cells. The three clinical subtypes are: endemic, sporadic and immunodeficiency-related. All of these likely arise from B cells at different stages of development.
The development of BL is dependent upon the constitutive expression of the MYC proto-oncogene located at chromosome 8q24. The transcription of MYC protein modulates the expression of target genes that regulate many cell processes including cell growth, division, metabolism and apoptosis.
Chronic Epstein-Barr virus (EVB) infection appears to play a role in all cases of endemic BL and minority of sporadic and immunodeficiency-associated BL (Klapproth and Wirth, 2010).

Epidemiology

Most common in children (1/3 of lymphomas). Endemic BL is mainly confined to equatorial Africa where it accounts for 30-50% of all childhood cancers diagnosed each year (3-6 cases per 100.000 children).
Sporadic variant is mostly seen in the US and Western Europe. 30% of pediatric lymphomas and <1% of adult NHL.
3 distinct peaks at around age 10, 40 and in the elderly. In all groups, most patients are male with a 3:1 or 4:1 male to female ratio (Magrath, 2012).

Clinics

  • African endemic variant usually develops in children with a jaw or facial bone tumor; initial involvement of the abdomen is less common.
    The primary tumor can spread to mesentery, ovary, testis, kidney, breast, and meninges, spreading to lymph nodes, mediastinum, and spleen less frequently.
  • The non-endemic variant may be associated with immunodeficiency states and usually presents with abdominal involvement (distal ileum, ciecum, mesentery). Presenting symptoms can be related to bowel obstruction or gastrointestinal bleeding, mimicking acute appendicitis or intussusception. Lymphadenopathy is generally localized.
    The disease is very aggressive and requires prompt treatment with appropriate regimens.
  • Cytology

    The blast cells in the peripheral blood and bone marrow display a basophilic cytoplasm with characteristic vacuolization, a picture indisinguishable from acute lymphoblastic leukemia (ALL) L3 of the FAB classification, which represents the leukemic counterpart of BL.
    WHO recognize three different types of Burkitt Lymphoma:
  • Classic Burkitt lymphoma: Characterized for the monomorphic medium-size blast proliferation, with lax chromatin, multiple nucleolis and intense basophilic cytoplasm.
  • Plasmablastic Burkitt Lymphoma and Atypical Burkitt lymphoma: Cells with nuclear pleomorphism and nucleoli of big size but in inferior number to the observed in the classic form.
    The three variants, blastic cells can be associated with plenty mitotic images.
  • Pathology

    The tumor mass demonstrate complete effacement of the normal architecture by sheets of atypical lymphoid cells.

    Treatment

    Aggressive regimens specifically designed for this lymphoma must be used.
    Multiple intensive regimens demonstrate excellent activity in BL and are composed of doxorubicin, alkylators, vincristine, and etoposide combined with therapy directed at the eradication and/or prevention of central nervous system disease.
    In patients younger than 60 years of age, including those with well-controlled HIV, and those up to 70 years of age with good baseline functional status, CODOX-M is recommended.
    Patients with extensive disease and elevated LDH, 2 cycles each of R-CODOX-M and R-IVAC can be used.
    For patients with low-risk disease (a single site of disease and normal LDH) 3 cycles of R-CODOX-M.
    For patients with preexisting organ dysfunction, or significant comorbidities and patients older than 60 years of age with low-risk disease, DA-REPOCH could be considering a great option associated with IT therapy or systemic methotrexate upon the completion of cycle 6.
    The addition of rituximab to hyper-CVAD may improve outcome in adult BL or B-ALL, particularly in elderly patients (Castillo et al., 2013; Jacobson and LaCasce, 2014; Dozzo et al., 2016).

    Evolution

    Apart from the occasional refractory case, a few responsive BL patients will relapse soon after treatment completion and generally within the first 6 months of follow-up.
    Results in refractory/relapsed BL are extremely poor, and new options are urgently needed.
    Relapse and progression frequency varies according to first-line treatment used.
    In chemoresistant disease cases, experimental therapies, due to the globally poor results of traditional salvage programs, should be considered in all refractory or relapsed cases.

    Prognosis

    If treated promptly with appropriate regimens the majority of patients can be cured.

    Cytogenetics

    Cytogenetics morphological

    The molecular hallmark of BL is the translocation of the MYC proto-oncogene to the Ig heavy or 1 light chain genes, leading to constitutive MYC activation. In classic BL, either endemic type or sporadic type, 90-95% of Ig loci are involved, 85% for t(8:14)/ IgH-MYC, 10% for t(8;22)(q24;q11) /Ig-lambda /MYC and approximately 5% for t(2;8)(p12;q24) /Ig-kappa/MYC.
  • In the Burkitt-like form there are at least 3 cytogenetic categories: one with an 8q24/MYC translocation, one with an 8q24 and 18q21/ BCL2 translocation and another with "miscellaneous" rearrangements, frequently including an 18q21 break (Bellan et al., 2005).
  • Additional anomalies

    Recurrent chromosome aberrations associated with the 8q24 translocations include 1q21-25 duplications, deletions of 6q11-14, 17p deletions and trisomy 12, +7, +8 and +18.

    Genes Involved and Proteins

    Gene name
    Location
    8q24.21
    Protein description
    MYC functions as a transcriptional regulator. MYC binds to MAX that is an obligate heterodimeric partner for MYC in mediating its functions. The MYC-MAX complex is a potent activator of transcription. Thousands of MYC target genes have been identified. Genes targeted by MYC include mediators of metabolism, biosynthesis, and cell cycle progression (Mohamed 2017).
    Gene name
    Location
    14q32.33
    Note
    Alternatively: IGK, located in 2p11.2 or IGL, located in 22q11.22

    Result of the Chromosomal Anomaly

    Oncogenesis

    Constitutive expression of MYC is crucial for the pathogenesis of BL, this protein being a key transcriptional regulator, controlling cell proliferation, differentiation and death. The deregulated expression of MYC, caused by the 8q24 translocations, is achieved through multiple mechanisms: a) juxtaposition to regulatory elements of the Ig loci, b) mutations in the MYC 5 regulatory regions and, c) aminoacid substitutions occurring in exon 2, making the MYC transactivation domain less susceptible to modulation (Hecht and Aster, 2000).
    Additional gene alterations include the following: truncating mutations of ARID1A and amplification of MCL1; point mutations of LRP6; truncating alterations of LRP1B, PTPRD, PTEN, NOTCH1, and ATM; amplifications of RAF1, MDM4, MDM2, KRAS, IKBKE, and CDK6; deletion of CDKN2A; overexpression ofMIR17HG; activating mutations of TCF3 and/or inactivating mutations of its negative regulator ID3; and CCND3 activating mutations (Havelange et al., 2016).

    Bibliography

    Pubmed IDLast YearTitleAuthors
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    239135752013Population-based prognostic factors for survival in patients with Burkitt lymphoma: an analysis from the Surveillance, Epidemiology, and End Results database.Castillo JJ et al
    28096691989The present and future medicolegal importance of record keeping in anesthesia and intensive care: the case for automation.Gibbs RF et al
    105778571999World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.Harris NL et al
    268877762016Genetic differences between paediatric and adult Burkitt lymphomas.Havelange V et al
    110544442000Molecular biology of Burkitt's lymphoma.Hecht JL et al
    252583442014How I treat Burkitt lymphoma in adults.Jacobson C et al
    203460132010Advances in the understanding of MYC-induced lymphomagenesis.Klapproth K et al
    18692431991Chromosomal abnormalities in adult non-endemic Burkitt's lymphoma and leukemia: 22 new reports and a review of 148 cases from the literature.Kornblau SM et al
    103345441999Small noncleaved, non-Burkitt's (Burkit-Like) lymphoma: cytogenetics predict outcome and reflect clinical presentation.Macpherson N et al
    77299491995High frequency of EBV association with non-random abnormalities of the chromosome region 1q21-25 in AIDS-related Burkitt's lymphoma-derived cell lines.Polito P et al
    105561971999Clinicopathogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell lymphoma. Kiel-Wien-Lymphoma Study Group.Schlegelberger B et al
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    Citation

    Luis Miguel Juárez Salcedo ; Luis Miguel Juárez Salcedo ; Luis Miguel Juárez Salcedo

    Burkitts lymphoma (BL)

    Atlas Genet Cytogenet Oncol Haematol. 2018-01-01

    Online version: http://atlasgeneticsoncology.org/haematological/2077/burkitts-lymphoma-(bl)

    Historical Card

    2001-03-01 Burkitts lymphoma (BL) by  Gianluigi Castoldi,Antonio Cuneo 

    Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy

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