Burkitt Lymphoma: beyond discoveries
© Mbulaiteye; licensee BioMed Central Ltd. 2013
Received: 7 June 2013
Accepted: 17 September 2013
Published: 30 September 2013
First described in 1958 in Uganda, Burkitt lymphoma (BL) attracted interest worldwide following reports of its uneven geographic distribution and rapidly fatal clinical course. Both suggested infectious etiology and curability. Seminal discoveries followed in quick succession. Viral etiology – due to Epstein-Barr virus (EBV) – was confirmed. Chromosomal translocations, involving cellular MYC, a protooncogene, were discovered, shown to be a hallmark of BL, and central to the genetic basis of cancer. Cure of BL using combination chemotherapy was demonstrated. Unfortunately, civil disturbance in Africa disrupted BL research and blunted its impact on education and oncology care in Africa. Important questions went unanswered. The risk of BL due to malaria or EBV was not quantified. Efforts to answer whether BL could be prevented – by preventing malaria or early EBV infection – were abandoned. The mechanism of malaria in BL is unknown. In Africa, BL remains mostly fatal and diagnosis is still made clinically. Unprecedented advances in molecular, genomics and proteomic technologies, promising to unlock mysteries of cancers, have re-awakened interest in BL. With return of stability to Africa, the unanswered questions about BL are re-attracting global interest. This interest now includes exploiting the knowledge gained about genetics, proteomics, and bioinformatics to enable the development of targeted less toxic treatment for BL; and simpler methods to diagnose BL with high accuracy and sensitivity. The articles in the Burkitt Lymphoma (BL): Beyond Discoveries in Infectious Agents and Cancer highlight BL as priority. Authors explore etiology, pathology, pathogenesis of BL, and whether knowledge gained in the studies of BL can catalyze sustainable cancer services in one of the world’s poorest served regions.
Burkitt lymphoma: beyond discoveries
Infectious Agents and Cancer is pleased to present a thematic series entitled Burkitt Lymphoma (BL): Beyond Discoveries. BL is an aggressive non-Hodgkin lymphoma (NHL) that was first described in African children by Dennis Burkitt. Within less than 10 years, Burkitt’s report of an obscure tumor in Africa had a dramatic impact on epidemiology, virology, immunology and oncology, spawning over 10,000 publications within a few decades of it’s description in 1958. Originally considered peculiar to Africa, characterization of histochemical and cytological properties of BL[1, 4, 5] led to recognition of cases worldwide and realization that the discovery had a universal relevance. Notable geographic differences in BL incidence were apparent and suggested etiology by a vectored virus. They also suggested an intuitive classification of the types of BL as “endemic BL “when occurring at a high incidence and “sporadic BL” when occurring at low incidence.
Many questions about BL remain unanswered. For example, the definition of BL and its subtypes remains a matter of debate. Dennis Burkitt described a purely clinical entity in Africa. In 1969, a consensus conference organized by the World Health Organization (WHO) in Washington D.C. reviewed tumor tissues from patients with clinical BL and reached a consensus definition that BL was a distinct patho-biological entity characterized by specific histological features or properties. This pathologic definition has changed over the years as pathology techniques have evolved. Refinements in histochemical stains, morphological, cytogenetic, immunophenotypic and, molecular techniques have led to description of classical cases, variously referred to typical or classical BL, and variant cases referred to as atypical BL or BL-like. The pathology properties noted above are unrelated to the intuitive clinico-epidemiological classification of BL as endemic, sporadic, and immunodeficiency associated BL.
The infectious etiology of BL was recognized immediately. Despite this, until the advent of the HIV epidemic and application of organ transplant technologies, which necessitated immunosuppressive therapy to prevent organ rejection, no clear evidence linking immunosuppression in individuals to the risk of BL was adduced. Other provocative questions went unanswered. These include why jaw tumors occur significantly more commonly in males than females, particularly in prepubescent children. Because BL is endemic in Africa, it has always been assumed that basal risk for BL is higher in Blacks even in areas where BL is sporadic. However, data from the U.S., where many Blacks live and BL is sporadic suggest that the risk of BL may be lower in Blacks than Whites[20, 21]. Why? Blacks in the U.S. are more likely to be of a lower socioeconomic status and therefore more likely to be exposed to EBV at a younger age. Assuming EBV conveys an independent risk of BL risk, one would predict that the risk of BL would be higher in Blacks than in Whites. Yet the opposite has been repeatedly observed, even in the setting of immunosuppression[23, 24]. If EBV is relevant, then is early exposure to EBV in the absence of malaria protective for BL? If EBV is irrelevant, then do Blacks have a lower basal genetic risk of BL? Or are there other local exposures in Africa that are the culprit? Likewise, the higher risk of BL in young males compared to females, observed in endemic, sporadic, and immunodeficiency BL is an unsolved puzzle. Answers to these questions could provide new clues about lymphoma biology. The endemicity of BL maps quite well with holo-endemic malaria, in and outside of Africa (example, Papua New Guinea). But if early acquisition of EBV and malaria together increase risk for BL, why is BL not endemic in other malarial regions, such as in India and Burma? Are there differences in risk posed by P. falciparum and P. vivax? Are differences in clinical presentations and EBV association of endemic and sporadic BL indicative of truly different clinical entities? Are EBV positive jaw tumors seen in 'non endemic” settings like Turkey similar to disease in Africa?
Through the articles in Burkitt Lymphoma (BL): Beyond Discoveries, Infectious Agents and Cancer aims to highlight BL as a priority, which allows unique opportunities for scientists, policy makers, program managers in countries where BL is endemic to collaborate. Their challenge will be to answer to what extent the discoveries made about BL will impact the life of a child with or at risk of BL in Africa. Can knowledge gained in the studies of BL, conducted both in African countries solely outside Africa, be translated into affordable implementable programs that introduce or catalyze sustainable cancer services in one of the world’s poorest served regions. Some of these questions are not be new, but there are new toolboxes in the present genomic era to answer new and old questions. These issues and others, not explicitly touched, will be discussed in the various papers collected in the thematic issue introduced here.
- Wright DH: Cytology and histochemistry of the Burkitt lymphoma. British J Cancer. 1963, 17: 50-55. 10.1038/bjc.1963.7.View ArticleGoogle Scholar
- Burkitt D: A sarcoma involving the jaws in African children. Br J Surg. 1958, 46 (197): 218-223. 10.1002/bjs.18004619704.PubMedView ArticleGoogle Scholar
- Klein G: Burkitt lymphoma–a stalking horse for cancer research?. Semin Cancer Biol. 2009, 19 (6): 347-350. 10.1016/j.semcancer.2009.07.001.PubMedView ArticleGoogle Scholar
- O’Conor GT, Davies JN: Malignant tumors in African children. With special reference to malignant lymphoma. J Pediatr. 1960, 56: 526-535. 10.1016/S0022-3476(60)80369-1.PubMedView ArticleGoogle Scholar
- Burkitt D, O’Conor GT: Malignant lymphoma in African children I. A clinical syndrome. Cancer. 1961, 14: 258-269. 10.1002/1097-0142(196103/04)14:2<258::AID-CNCR2820140206>3.0.CO;2-7.PubMedView ArticleGoogle Scholar
- Burkitt D: Burkitt’s lymphoma outside the known endemic areas of Africa and New Guinea. IntJ Cancer J Int du Cancer. 1967, 2 (6): 562-565. 10.1002/ijc.2910020603.View ArticleGoogle Scholar
- Burkitt D: A children’s cancer dependent on climatic factors. Nature. 1962, 194: 232-234. 10.1038/194232a0.PubMedView ArticleGoogle Scholar
- Epstein MA, Achong BG, Barr YM: Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet. 1964, 1 (7335): 702-703.PubMedView ArticleGoogle Scholar
- Ziegler JL, Deisseroth AB, Applebaum FR, Graw RG: Burkitt’s lymphoma–a model for intensive chemotherapy. Seminars Oncol. 1977, 4 (3): 317-323.Google Scholar
- Ziegler JL, DeVita VT, Graw RG, Herzig G, Leventhal BG, Levine AS, Pomeroy TC: Combined modality treatment of American Burkitt’s lymphoma. Cancer. 1976, 38 (6): 2225-2231. 10.1002/1097-0142(197612)38:6<2225::AID-CNCR2820380606>3.0.CO;2-F.PubMedView ArticleGoogle Scholar
- Manolov G, Manolova Y: Marker band in one chromosome 14 from Burkitt lymphomas. Nature. 1972, 237 (5349): 33-34. 10.1038/237033a0.PubMedView ArticleGoogle Scholar
- Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC, Croce CM: Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci USA. 1982, 79 (24): 7824-7827. 10.1073/pnas.79.24.7824.PubMedPubMed CentralView ArticleGoogle Scholar
- Henle G, Henle W, Clifford P, Diehl V, Kafuko GW, Kirya BG, Klein G, Morrow RH, Munube GM, Pike P, et al.: Antibodies to Epstein-Barr virus in Burkitt’s lymphoma and control groups. J Nat Cancer Insti. 1969, 43 (5): 1147-1157.Google Scholar
- Burkitt DP: Etiology of Burkitt’s lymphoma–an alternative hypothesis to a vectored virus. J Nat Cancer Insti. 1969, 42 (1): 19-28.Google Scholar
- Rochford R, Cannon MJ, Moormann AM: Endemic Burkitt’s lymphoma: a polymicrobial disease?. Nat Rev Microbiol. 2005, 3 (2): 182-187. 10.1038/nrmicro1089.PubMedView ArticleGoogle Scholar
- Wright DH: What is Burkitt’s lymphoma and when is it endemic?. Blood. 1999, 93 (2): 758-PubMedGoogle Scholar
- Carbone PP, Berard CW, Bennett JM, Ziegler JL, Cohen MH, Gerber P: NIH clinical staff conference. Burkitt’s tumor. Annals Int Med. 1969, 70 (4): 817-832. 10.7326/0003-4819-70-4-817.View ArticleGoogle Scholar
- Ziegler JL, Cohen MH, Morrow RH, Kyalwazi SK, Carbone PP: Immunologic studies in Burkitt’s lymphoma. Cancer. 1970, 25 (3): 734-739. 10.1002/1097-0142(197003)25:3<734::AID-CNCR2820250335>3.0.CO;2-1.PubMedView ArticleGoogle Scholar
- Burkitt D, Wright D: Geographical and tribal distribution of the African lymphoma in Uganda. British med J. 1966, 1 (5487): 569-573. 10.1136/bmj.1.5487.569.View ArticleGoogle Scholar
- Levine PH, Connelly RR, McKay FW: Burkitt’s lymphoma in the USA: cases reported to the American Burkitt Lymphoma Registry compared with population-based incidence and mortality data. IARC Sci Publ. 1985, 60: 217-224.PubMedGoogle Scholar
- Mbulaiteye SM, Biggar RJ, Bhatia K, Linet MS, Devesa SS: Sporadic childhood Burkitt lymphoma incidence in the United States during 1992–2005. Pediatric Blood Cancer. 2009, 53 (3): 366-370. 10.1002/pbc.22047.PubMedPubMed CentralView ArticleGoogle Scholar
- Brodsky AL, Heath CW: Infectious mononucleosis: epidemiologic patterns at United States colleges and universities. Am J Epidemiol. 1972, 96 (2): 87-93.PubMedGoogle Scholar
- Guech-Ongey M, Simard EP, Anderson WF, Engels EA, Bhatia K, Devesa SS, Mbulaiteye SM: AIDS-related Burkitt lymphoma in the United States: what do age and CD4 lymphocyte patterns tell us about etiology and/or biology?. Blood. 2010, 116 (25): 5600-5604. 10.1182/blood-2010-03-275917.PubMedPubMed CentralView ArticleGoogle Scholar
- Mbulaiteye SM, Clarke CA, Morton LM, Gibson TM, Pawlish K, Weisenburger DD, Lynch CF, Goodman MT, Engels EA: Burkitt lymphoma risk in U.S. solid organ transplant recipients. Am J Hematol. 2013, 88 (4): 245-250. 10.1002/ajh.23385.PubMedPubMed CentralView ArticleGoogle Scholar
- Celkan TT, Baris S, Ozdemir N, Ozkan A, Apak H, Dogru O, Karaman S, Canbolat A, Ozdil M, Aki H, et al.: Treatment of pediatric Burkitt lymphoma in Turkey. J Pediatric Hematol Oncol. 2010, 32 (7): e279-e284. 10.1097/MPH.0b013e3181e90017.View ArticleGoogle Scholar
- Ziegler JL: Treatment results of 54 American patients with Burkitt’s lymphoma are similar to the African experience. N Engl J Med. 1977, 297 (2): 75-80. 10.1056/NEJM197707142970202.PubMedView ArticleGoogle Scholar
- Patte C, Auperin A, Michon J, Behrendt H, Leverger G, Frappaz D, Lutz P, Coze C, Perel Y, Raphael M, et al.: The societe francaise d’Oncologie pediatrique LMB89 protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood. 2001, 97 (11): 3370-3379. 10.1182/blood.V97.11.3370.PubMedView ArticleGoogle Scholar
- Mbulaiteye SM, Talisuna AO, Ogwang MD, McKenzie FE, Ziegler JL, Parkin DM: African Burkitt’s lymphoma: could collaboration with HIV-1 and malaria programmes reduce the high mortality rate?. Lancet. 2010, 375 (9726): 1661-1663. 10.1016/S0140-6736(10)60134-1.PubMedView ArticleGoogle Scholar
- Phillips JA: Is Burkitt’s lymphoma sexy enough?. Lancet. 2006, 368 (9554): 2251-2252. 10.1016/S0140-6736(06)69898-X.PubMedView ArticleGoogle Scholar
- Baik S, Mbaziira M, Williams M, Ogwang MD, Kinyera T, Emmanuel B, Ziegler JL, Reynolds SJ, Mbulaiteye SM: A case–control study of Burkitt lymphoma in East Africa: are local health facilities an appropriate source of representative controls?. Infect Agents Cancer. 2012, 7 (1): 5-10.1186/1750-9378-7-5.PubMedPubMed CentralView ArticleGoogle Scholar
- Molyneux EM, Rochford R, Griffin B, Newton R, Jackson G, Menon G, Harrison CJ, Israels T, Bailey S: Burkitt’s lymphoma. Lancet. 2012, 379 (9822): 1234-1244. 10.1016/S0140-6736(11)61177-X.PubMedView ArticleGoogle Scholar
- Schmitz R, Young RM, Ceribelli M, Jhavar S, Xiao W, Zhang M, Wright G, Shaffer AL, Hodson DJ, Buras E, et al.: Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature. 2012, 490 (7418): 116-120. 10.1038/nature11378.PubMedPubMed CentralView ArticleGoogle Scholar
- Bornkamm GW: Epstein-Barr virus and its role in the pathogenesis of Burkitt’s lymphoma: an unresolved issue. Semin Cancer Biol. 2009, 19 (6): 351-365. 10.1016/j.semcancer.2009.07.002.PubMedView ArticleGoogle Scholar
- Mbulaiteye SM, Pullarkat ST, Nathwani BN, Weiss LM, Nagesh R, Emmanuel B, Lynch CF, Hernandez B, Neppalli V, Hawes D, et al.: Epstein-Barr virus patterns in US Burkitt lymphoma tumors from the SEER residual tissue repository during 1979–2009. APMIS: Acta pathol microbiol et immunol Scand. 2013, doi:10.1111/apm.12078. Epub ahead of printGoogle Scholar
- Muller JR, Janz S, Goedert JJ, Potter M, Rabkin CS: Persistence of immunoglobulin heavy chain/c-myc recombination-positive lymphocyte clones in the blood of human immunodeficiency virus-infected homosexual men. Proc Natl Acad Sci USA. 1995, 92 (14): 6577-6581. 10.1073/pnas.92.14.6577.PubMedPubMed CentralView ArticleGoogle Scholar
- de-The G, Geser A, Day NE, Tukei PM, Williams EH, Beri DP, Smith PG, Dean AG, Bronkamm GW, Feorino P, et al.: Epidemiological evidence for causal relationship between Epstein-Barr virus and Burkitt’s lymphoma from Ugandan prospective study. Nature. 1978, 274 (5673): 756-761. 10.1038/274756a0.PubMedView ArticleGoogle Scholar
- Lingwood RJ, Boyle P, Milburn A, Ngoma T, Arbuthnott J, McCaffrey R, Kerr SH, Kerr DJ: The challenge of cancer control in Africa. Nat Rev Cancer. 2008, 8 (5): 398-403. 10.1038/nrc2372.PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.