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|Written||2001-03||Antonio Cuneo, Gianluigi Castoldi|
|Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy|
|Updated||2018-01||Luis Miguel Juárez Salcedo, Ana Corazón Monzón, Samir Dalia|
|Principe de Asturias University Hospital, Madrid, Spain (LMJS); Clinic Valladolid University Hospital, Valladolid, Spain (ACM); Oncology and Hematology, Mercy Clinic Joplin, Joplin, MO, USA firstname.lastname@example.org (SD).|
|Abstract||Review on Burkitt's lymphoma, with data on clinics, and the genes involved.|
|Keywords||Burkitt's lymphoma; MYC; IGH; IGK; IGL|
(Note : for Links provided by Atlas : click)
|ICD-Topo||C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS|
|ICD-Morpho||9687/3 Burkitt lymphoma|
|Other names||Burkitt's tumor|
|Malignant lymphoma Burkitt's type|
2. Clinics and Pathology
|Phenotype / cell stem 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 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).
The primary tumor can spread to mesentery, ovary, testis, kidney, breast, and meninges, spreading to lymph nodes, mediastinum, and spleen less frequently.
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:
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. |
The related form 'Burkitt-like' lymphoma shows intermediate features between diffuse large cell lymphoma and BL and probably includes different disease entities. It was suggested by the WHO panel that only those cases with MYC rearrangement and/or a >99% proliferation fraction as demonstrated by Ki-67 positivity should be classified as Burkitt-like lymphoma.
|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 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. |
|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.|
4. Genes involved and Proteins
|Protein||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).|
|Note||Alternatively: IGK, located in 2p11.2 or IGL, located in 22q11.22|
5. 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).
|Immunoglobulin gene analysis reveals 2 distinct cells of origin for EBV-positive and EBV-negative Burkitt lymphomas|
|Bellan C, Lazzi S, Hummel M, Palummo N, de Santi M, Amato T, Nyagol J, Sabattini E, Lazure T, Pileri SA, Raphael M, Stein H, Tosi P, Leoncini L|
|Blood 2005 Aug 1;106(3):1031-6|
|Population-based prognostic factors for survival in patients with Burkitt lymphoma: an analysis from the Surveillance, Epidemiology, and End Results database|
|Castillo JJ, Winer ES, Olszewski AJ|
|Cancer 2013 Oct 15;119(20):3672-9|
|Molecular genetics of malignant lymphoma. In: Fo R (ed): Reviews in clinical and experimental hematology.|
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|Br J Haematol 2016 Apr;173(1):137-44|
|Molecular biology of Burkitt's lymphoma|
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|How I treat Burkitt lymphoma in adults|
|Jacobson C, LaCasce A|
|Blood 2014 Nov 6;124(19):2913-20|
|Advances in the understanding of MYC-induced lymphomagenesis|
|Klapproth K, Wirth T|
|Br J Haematol 2010 May;149(4):484-97|
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|MYC (MYC proto-oncogene, bHLH transcription factor)|
|Atlas Genet Cytogenet Oncol Haematol. in press. On line version : http://atlasgeneticsoncology.usal.es/classic/Genes/MYCID27.html|
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|This paper should be referenced as such :|
|Juárez Salcedo LM, Corazón Monzón A, Dalia S|
|Burkitt's lymphoma (BL);|
|Atlas Genet Cytogenet Oncol Haematol. in press|
|On line version : http://atlasgeneticsoncology.usal.es/classic/Anomalies/BurkittID2077.html|
|History of this paper:|
|Cuneo, A ; Castoldi, GL. Burkitt's lymphoma (BL). Atlas Genet Cytogenet Oncol Haematol. 2001;5(2):121-122.|
8. External links
|COSMIC||Histo = - Site = haematopoietic_and_lymphoid_tissue (COSMIC)|
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