3 is Endemic Burkitt’s Lynphoma an Alliance Beween Three Infeccions and a Tumour Prometer

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Malaria and Epstein-Barr virus (EBV), recognisedcofactors for endemic Burkitt’s lymphoma, areubiquitous within the lymphoma belt of Africa, and,unless other cofactors are involved, the tumour shouldbe much more common than it is. Malaria and EBV alonecannot account for the occasional shifting foci andspace-time case clusters of endemic Burkitt’s lymphoma.Arboviruses and plant tumour promoters are otherpossible local cofactors that could explain suchcharacteristics. The geographical and age distributionsof endemic Burkitt’s lymphoma parallel those ofpotentially oncogenic, mosquito-borne arboviruses.Arboviruses seem to be associated with case clusters ofendemic Burkitt’s lymphoma, and symptoms compatiblewith arbovirus infection have been seen immediatelybefore the onset of the tumour. RNA and DNA viruses,including EBV, are promoted by extracts of a commonlyused plant, Euphorbia tirucalli, the distribution of whichcoincides with the boundaries of the lymphoma belt.Extracts of E tirucalli are tumour promoters and caninduce the characteristic 8;14 translocation of endemicBurkitt’s lymphoma in EBV-infected cell-lines. They alsoactivate latent EBV in infected cells, enhance EBV-mediated cell transformation, and modulate EBV-specificimmunity.

Lancet Oncol 2004; 5: 738–46

Burkitt’s lymphoma (figure 1) has been called the Rosettastone of oncology and is a model of human cancer.1 It is ahigh-grade non-Hodgkin lymphoma that occurssporadically worldwide, but is endemic in Papua NewGuinea and in the lymphoma belt of Africa (figure 2). Thisbelt stretches from about 10º north to 10º south of theequator. Within these latitudes, the lymphoma is found inregions where the mean minimum temperature exceeds15·5ºC and the rainfall is higher than 50 mL per year.2 It ismore common in damp, humid regions, and is absent inarid regions. Within the lymphoma belt, endemic Burkitt’slymphoma accounts for up to 74% of childhood malignantdisorders. Incidence rates of Burkitt’s lymphoma vary fromlow in industrialised countries such as the USA and inwestern Europe, through intermediate rates in countriessuch as Algeria, up to high rates such a 4–10 per 100 000 inchildren aged younger than 15 years who live in thelymphoma belt.3 Rates of Burkitt’s lymphoma haveincreased in low-incidence countries since the 1980s,preceding the advent of HIV/AIDS, which has alsocontributed to the rise in non-Hodgkin lymphomas.4 Cases

of Burkitt’s lymphoma peaked in the late 1980s in low-incidence countries, whereas in the lymphoma belt, theyhave tripled and continue to increase.5

Endemic Burkitt’s lymphoma most commonly presentsas a facial tumour (figure 1), but it can also present in otherways, such as abdominal tumours (figure 3). In sporadicBurkitt’s lymphoma, including countries with intermediaterates, abdominal tumours are commonest. In addition tothe two main forms of Burkitt’s lymphoma, HIV-associated Burkitt’s lymphoma has been recognised, whichtends to present similarly to sporadic Burkitt’s lymphomaoutside the lymphoma belt. Within the lymphoma belt, itoccurs mainly in adults, presents atypically, and accountsfor up to two-thirds of Burkitt’s lymphoma.5

Personal view Endemic Burkitt’s lymphoma

CAvdB is Consultant in Communicable Disease Control, SurreyHealth Protection Unit, Health Protection Agency and HonoraryClinical Lecturer at the Wolfson Institute of Preventive Medicine,Barts and the London Queen Mary’s School of Medicine andDentistry, London, UK.

Correspondence: Dr C van den Bosch, Surrey Health ProtectionUnit, Century House, 26 Bridge Street, Leatherhead, KT22 8BZ UK. Tel: + 41 (0)1372 869 625. Fax: +41 (0)1372 869884. Email: [email protected]

Is endemic Burkitt’s lymphoma an alliancebetween three infections and a tumourpromoter?

C A van den Bosch

Oncology Vol 5 December 2004 http://oncology.thelancet.com

Figure 1. African child with facial lesions of Burkitt's lymphoma.

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A combination of malaria and EBV seems to boost theincidence of endemic Burkitt’s lymphoma in the lymphomabelt by a factor of 100–150.1 The EBV genome isincorporated into 96% of endemic Burkitt’s lymphomas,but in only 10–15% of sporadic cases in France and in 80%in Algeria.1,6 A gradient exists for the tumour subtype, thenumber of patients who have EBV positivity and the type oftranslocation, strongly suggesting that other environmentalfactors are involved.7 The presence of EBV in Burkitt’slymphoma probably reflects the prevailing socioeconomicstatus and age at seroconversion of each population ofpatients.

Despite the HIV epidemic in sub-Saharan Africa, EBV isstill present in 94% of cases of endemic Burkitt’s lymphomain children aged younger than 15 years in whom it is notassociated with HIV.8 HIV has been associated with somecases of sporadic Burkitt’s lymphoma: HIV-associatedBurkitt’s lymphoma has increased worldwide, where30–50% of cases are EBV-positive,9 and within thelymphoma belt, where it has increased three-fold, especiallyin adults, with atypical presentations,5 but mostly EBV-positive tumours, attributable to the HIV epidemic.8

Burkitt’s lymphoma is a B-cell lymphoma with a highreplication rate. Almost all the cells are in cycle and have adoubling time of 24–48 h,10 which is consistent with therapid clinical progression of the tumour. Cells in bothendemic and sporadic forms of Burkitt’s lymphoma areB lymphocytes that have rearranged Ig genes and containone of three translocations6 involving the long arm of chro-mosome 8, of which 8;14 is the commonest. Thetranslocation occurs at the site of the MYC oncogene onchromosome 8 and the Ig heavy-chain genes on chromo-some 14. Less common translocations occur betweenchromosome 8 and chromosome 2 (site of � light-chain

gene) or chromosome 22 (site of light-chain gene). Endemicand sporadic forms of Burkitt’s lymphoma have differentbreakpoints within both the MYC locus on chromosome 8and the Ig heavy-chain locus on chromosome 14.7

EBV1 and holoendemic malaria1,6,7,11 are recognised asimportant cofactors of endemic Burkitt’s lymphoma, yetthis disease can occur in the absence of both of theseinfections. Both infections are ubiquitous in the lymphomabelt and, if early EBV infection and malaria were the onlyprerequisites for endemic Burkitt’s lymphoma, then thetumour should be much commoner than it is. In thisPersonal view, I discuss the epidemiological evidence for thepathogenesis of endemic Burkitt’s lymphoma and proposethat malaria and early EBV infection precede thetranslocation that occurs as the result of an interactionbetween EBV and a plant tumour promoter, and that thesefinal stages of tumourigenesis are enhanced by acutearboviral infection. The pathogenesis of sporadic and HIV-associated Burkitt’s lymphoma are not discussed becausethe geographical gradient for the clinical, molecular, andcytological differences and the varying degrees of EBVpositivity and different chromosomal breakpoint sitesbetween the different types of Burkitt’s lymphoma suggestthat, outside the lymphoma belt, other, unrecognised,environmental factors are important in the pathogenesis ofthis tumour, and these factors probably differ throughoutthe world.

PathogenesisKlein12 proposed a multistep hypothesis for the pathogenesisof endemic Burkitt’s lymphoma with early, heavy infectionwith EBV in children as the first stage, resulting in theimmortalisation of B lymphocytes and some immunetolerance, permitting proliferation of infected cells. Heavymalarial infection would stimulate expansion of the B-cellpool and suppress T cells involved in EBV control. The finalstage of tumorigenesis would be the development of thetranslocation leading to deregulation of MYC and thedevelopment of a malignant clone.

Personal viewEndemic Burkitt’s lymphoma


Figure 2. The lymphoma belt: Burkitt’s lymphoma is endemic in regionswith mean minimum temperatures that exceed 15·5ºC and yearly rainfallof higher than 50 mL, which stretch from about 10º north to 10º south ofthe equator.

Figure 3. Abdominal and facial tumours from Burkitt’s lymphoma.

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Bornkamm and colleagues13 thought that the Burkitt’slymphoma translocation occurred when B cells wererearranging their chromosomes, as suggested by the constantinvolvement of one of the Ig loci. Intense immunologicalstimulation from holoendemic malaria would give rise to alarge pool of B cells, which would increase the risk ofdeveloping translocations. They argued that once thetranslocation involving MYC had arisen, the third stepwould be infection and immortalisation by EBV of a cell thathad already rearranged its Ig genes.

Klein’s theory seems more probable than that ofBornkamm and colleagues because EBV infection occurs ininfants in Africa.1 The rapid growth rate of Burkitt’slymphoma cells could be an immediate consequence of thetranslocation, which juxtaposes a gene involved in IgGproduction with MYC—an oncogene involved in cellularproliferation—which becomes deregulated.

Arboviral infection was proposed as a cofactor byHaddow in 1964.14 Some arboviruses have been shown tohave oncogenic properties,15,16 and some plant extracts canact as tumour promoters.17 Immunotypic data and molecularevidence suggest that the translocation occurs in a B cell thatis actively arranging its Ig genes, and that somedifferentiation of the cell then occurs as it acquires thecharacteristics of malignant disease. I suggest that therearrangement of the Ig genes18 involved in the Burkitt’slymphoma translocation takes place during the arboviralinfection and that the action of the two potentially oncogenicviruses—ie, the arbovirus and EBV—are potentiated by aplant tumour promoter. Epidemics of arboviruses couldexplain the occurrence of space-time case-clusters ofendemic Burkitt’s lymphoma.3

Role of EBVEBV is a DNA herpesvirus that occurs worldwide, infectingmore than 90% of the population. Infection is mostlyasymptomatic when it occurs at an early age, but, if the age ofonset is delayed, it gives rise to infectious mononucleosis.Infection in Africa occurs at a very young age,1 andconsequently, immune tolerance to the virus usuallydevelops. EBV infects and immortalises B lymphocytes invivo and in vitro, resulting in polyclonal activation andproliferation, which are usually controlled by inhibitoryimmunological mechanisms, with EBV-specific cytotoxicT cells playing a crucial part.19 Primary EBV infection isusually followed by latency, but in immunodeficiency, theproliferation of cells can proceed unchecked, and cellssometimes evolve from a polyclonal reactive process to amonoclonal malignant lymphoma.20 In fatal infectiousmononucleosis, moreover, multiple distinct clones, some ofwhich involve MYC rearrangement, have been detectedwithin a few days of primary EBV infection.21

EBV could act as a cofactor by increasing the size of theB-cell pool and by transforming lymphocytes, therebyincreasing the chances of a translocation occurring, or itcould have a more direct role in tumorigenesis, actingtogether with the changes induced by the MYCtranslocation.6,7,18 Endemic Burkitt’s lymphoma seems to beassociated with raised concentrations of some EBV

antibodies, suggesting that EBV is not merely a passenger inthis disease. Compared with matched controls, patients withendemic Burkitt’s lymphoma were shown to havesignificantly higher titres of IgG antibody to EBV viral capsidantigen (VCA) up to 6 years before the onset of thelymphoma.1 However, the VCA antibody titres did not riseafter the onset of endemic Burkitt’s lymphoma, suggestingthat chronic rather than acute infection with EBV wasrelevant to tumorigenesis. No other EBV antibody showedsignificant differences between pre-endemic Burkitt’slymphoma cases and controls. EBV early antigenconcentrations rise as the disease develops, and decline aftertreatment.22 The amount of cellular cytotoxicity mediated byEBV-specific antibodies seems to be important in theoutlook for patients with endemic Burkitt’s lymphoma,further confirming the relation between this disease andEBV.23

EBV can exist in several different types of latency.Latency 1 has been identified in biopsy samples frompatients with Burkitt’s lymphoma and in early-passageBurkitt’s lymphoma lines, in which many EBV-encodedRNA (EBER) transcripts are found, and EBNA1 is usuallyexpressed in the absence of other EBV proteins.24 EBNA1, anEBV antigen that is indispensable for B-cell transformation,seems to maintain the EBV episome in latent infected cells.25

EBNA1 can bind both RNA and DNA, which could affect theexpression of viral or cellular genes,26 upregulate therecombinase activating genes that mediate variable diversityjoining (VDJ) recombination, which are usually expressedonly in immature lymphoid cells,27 and can enhance B-cellimmortalisation by several thousand times.28 In transgenicmice, EBNA1 and Myc, the mouse analogue of the humanoncogene MYC, cooperate in the development oflymphomas, suggesting that the same process could occur inhumans.29 However, EBNA1 does not seem to be oncogenicon its own, since it is consistently expressed in cells infectedwith EBV, including latently infected cells, and the EBERtranscripts seem to be needed for a malignant phenotype andresistance to apoptosis.30 EBER1 and EBER2 are small, non-polyadenylated nuclear RNAs. They upregulate BCL2, toinhibit apoptosis by binding to protein kinase, blocking thesignalling of interferon �, and inducing colony growth ofcells in agar.31 Furthermore, a binding site for MYC has beenfound in the promoter for EBER1, suggesting that itcooperates with MYC, and that EBV has a role in thedevelopment of lymphomas.31

Role of malariaHoloendemic malaria undoubtedly has a majorimmunomodulatory role in endemic Burkitt’s lymphoma inthe lymphoma belt. It contributes to the greatly increasednumbers of EBV-positive Burkitt’s lymphoma in this regionand might facilitate the transformation of cells. A malarialmitogen32 that produces a polyclonal expansion of B lymphocytes, and, in acute attacks of malaria, the numberof circulating EBV-positive lymphocytes is increased byabout five times.33 Hyperendemic malaria also inhibits EBV-specific suppressor T cells, thus expanding the pool of EBV-positive lymphocytes in two ways. Spontaneous



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transformation has also been noted in cell cultures frompeople living in hyperendemic malaria regions.34 Malarialinfection in holoendemic regions is common from infancythroughout childhood, until some immunity and tolerance isacquired by the age of puberty.35

The reduced incidence of endemic Burkitt’s lymphomain people with the sickle-cell trait36 and in regions wheremalaria has been eradicated,11 together with the delayed ageof onset of endemic Burkitt’s lymphoma in immigrants fromhigher, malaria-free altitudes, to lower malarial regions,11

have been regarded as evidence in favour of malaria acting asa cofactor in Burkitt’s lymphoma. Malaria-eradicationprogrammes in Italy have also been linked with reduction inthe number of cases of another herpesvirus-associatedmalignant disease—Kaposi’s sarcoma37—showing that thetumour-suppressor effect of malaria eradication is notconfined to endemic Burkitt’s lymphoma. However, malariacould be both an amplifier and a confounder in endemicBurkitt’s lymphoma because, apart from the inverseassociation with the sickle-cell trait, which is controversial,these associations could also be the result of effects ofmosquito-borne arboviruses acting as cofactors.

A malaria-prophylaxis programme in Tanzaniacoincided with a reduction in the number of cases ofendemic Burkitt’s lymphoma, but the reduction actuallyantedated the malaria suppression programme and was alsoseen in the adjoining district where there had been nointervention, suggesting that other factors might be active. Alag period before the incidence of endemic Burkitt’slymphoma returned to its former level was seen afterparasitaemia levels returned to normal and suppression hadbeen stopped.38 These findings cannot be explained by areduction in malaria from prophylaxis, because thereduction antedated the programme, but they could be theresult of cyclical changes in other cofactors. In holoendemicregions, malaria occurs more or less throughout the year andis seasonal, but not cyclical, in regions where transmission isless intense. Outbreaks attributed to malaria are confined toregions where malaria is not usually seen, or where malarialactivity increases unusually as a result of ecological changes.35

Cyclical changes are also not a feature of EBV infection inAfrica, but are typical of mosquito-borne arboviruses;epidemics with arboviruses such as chikungunya or yellowfever occur regularly at variable intervals of 3–20 years.

Age and acquisition of antibodiesIn the lymphoma belt, endemic Burkitt’s lymphoma is adisease of childhood with a peak around 5–8 years of age. Nocase has been recorded in children younger than 1 year andmost patients are younger than 10 years of age. Burkitt’slymphoma in children younger than 4 years or older than20 years are rare in endemic regions. Endemic Burkitt’slymphoma is seen in adults who have been brought up inhighland regions when they move into lower areas. This agedistribution does not accord with the pattern of acquisitionof antibodies to EBV. Infection with EBV occurs at a youngage in sub-Saharan Africa, usually within the first year oflife,1 in regions conforming to the climatic requirements ofthe lymphoma belt, and in higher, colder, and dryer regions.

Most children in tropical Africa have acquired antibodies toEBV by their second birthday. The age distribution ofendemic Burkitt’s lymphoma is similar to the pattern ofacquisition to immunity to malaria.34,35 Malaria in thelymphoma belt is rare in children younger than 3 months,although congenital malaria can occur and is commonthroughout childhood, with the main adverse effect onhealth being in children younger than 6 years. Sometolerance and immunity is established by 8–14 years of age,depending on the amount of malarial endemnicity.However, the age distribution of acquisition of antibodies toarboviruses mimics the age distribution of endemic Burkitt’slymphoma almost exactly.14,39 Neither endemic Burkitt’s lym-phoma nor arbovirus infections are seen in children youngerthan 2 years, these infections peak at the age of 5–8 years,and, in the absence of HIV, are rarely seen in individualsolder than 20 years, except in those who originated fromhigher altitudes.11 The age distribution of endemic Burkitt’slymphoma and rates of acquisition of antibodies toarboviruses coincide up to the age of 10 years, after which thefit is less good, but this finding could be attributed to thepattern of age estimation seen in the teenage years in ruralAfrican hospitals.39 The age distribution of endemic Burkitt’slymphoma thus accords best with the pattern of acquisitionof antibodies to arboviruses, rather than with EBV ormalaria.39

Arboviruses and herbal remediesArboviruses, with their cycles of activity every 3–20 years,could, if acting as cofactors, provide an explanation for thevariation in incidence of endemic Burkitt’s lymphoma seenbefore, during, and after the Tanzanian malaria prophylaxisprogramme.38 Because mosquito-borne arboviruses andmalaria share the same insect vector, both would be reducedby programmes of malarial or mosquito eradication, butarboviruses would not be affected by malarial prophylaxisprogrammes. Arboviruses as cofactors, with their cyclicalactivity, could equally explain, either wholly or in part, notonly the reduction in the number of cases of endemicBurkitt’s lymphoma seen after malarial eradicationprogrammes, but also the case clusters and shifting foci ofcases of endemic Burkitt’s lymphoma within the lymphomabelt3 and the older age of onset of endemic Burkitt’slymphoma in cases emigrating from highlands that are freeof malaria and arboviruses.11 Both endemic Burkitt’slymphoma and yellow fever, a flavivirus and arbovirus, sharethe same temperature-determined altitude barrier2 of 1524 min eastern Africa, whereas malaria epidemics have beenrecorded at 2438 m.

Arbovirus infectionsArboviruses are RNA viruses transmitted by insect vectorssuch as mosquitoes and are found in both temperate andtropical regions. Arboviruses belong to several differentfamilies such as alphaviruses, flaviviruses, and Bwambaviruses. Arbovirus epidemics occur regularly in Africa,causing febrile illnesses with varied symptoms, includingrashes, joint pains, encephalitis, jaundice, haemorrhagicmanifestations, and, more rarely, shock syndrome.



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Subclinical cases are common in the flavivirus yellow fever,in which the ratio of subclinical to clinical cases is seven to one.

Case clusters during an arboviral epidemicChikungunya fever, an alphavirus40 and arbovirus, has cyclesof activity every 5–10 years. An increased number of cases ofendemic Burkitt’s lymphoma, most of which were positivefor the arbovirus chikungunya, and a southerly drift of fociof cases, were seen in 1987–88 in Malawi,3 when an epidemicof chikungunya fever spread from north to south. Clusters ofcases of endemic Burkitt’s lymphoma, which were closertogether in time and space than would occur from chance,were seen in children older than 7 years in Uganda41–43 in1961–65 and 1972–73 and in Malawi in 1987–89.3 69% of theMalawian patients seen during the chikungunya feverepidemic, including some in clusters, who were tested forantibodies were seropositive for chikungunya virus IgM orIgG at high titres on admission, or seroconverted to IgGduring their first admission for endemic Burkitt’slymphoma, suggesting that they had recently acquired theinfection.44 The case clusters described in Uganda in1961–6541,43 occurred at times of o’nyong-nyong virusactivity,45 and in 1972–73 during times of Bwamba virusactivity.46

Antibodies to several arboviruses were much morecommon in patients with endemic Burkitt’s lymphoma andtheir families than in controls, but no one arboviruspredominated.10,45 This finding would fit with severalarboviruses having the ability to act as a cofactors.10,45 Thefact that seroconversion occurred in Malawi44 during the firstadmission for endemic Burkitt’s lymphoma could be becausethe time between the arboviral infection and the onset of thetumour was very short, which is consistent with the reportsof typical arboviral symptoms with means of 8–19 daysbefore the onset of the tumour (see table),44,47 the tumour’srapid growth rate,3 and the abnormal Ig response seen inendemic Burkitt’s lymphoma.44,48

Signs and symptoms of arbovirus infectionIt is possible that the case clusters of endemic Burkitt’slymphoma are the result of arboviruses acting as cofactors,precipitating the final stages of the pathogenesis of thetumour, and that they are seen only during arbovirus

epidemics. Signs and symptoms compatiblewith arbovirus infection, including rashes, jointpains and fever, were reported in patients withendemic Burkitt’s lymphoma shortly before theonset of the lymphoma, both in Uganda47 andin Malawi.44 88 of 108 proven cases of endemicBurkitt’s lymphoma had signs and symptomsconsistent with arboviral illness, 51 patientshad typical signs and symptoms, and only tenpatients could not recall any signs of symptomsin the 3 months preceding the onset of thetumour (see table).44 Early studies in Uganda48

showed that patients with endemic Burkitt’slymphoma and their relatives were more likelyto be seropositive for some arboviruses,

including chikungunya virus, than were controls, but inMalawi, the number of patients seropositive forchikungunya IgG was significantly greater than in age-matched controls—both local and hospital. 44 The late onsetof seroconversion seen in some patients with a history ofarbovirus-like signs and symptoms in the 2 months beforetumour manifestation could be attributed to the abnormalimmune function described in endemic Burkitt’slymphoma,48 consistent with three patients remainingseropositive for chikungunya IgM and seronegative for IgGover many months.44 Acute infection with an arbovirus couldthus explain why the B cells are rearranging their genes whenthe translocation in endemic Burkitt’s lymphoma occurs.

Chikungunya, an alpha virus, and yellow fever, aflavivirus, have the potential to be oncogenic; they cantransform mouse brain cells16 and are tumorigenic in nudemice.15 Hepatitis C, a flavivirus, is independently associatedwith hepatocellular carcinoma in humans, and can actsynergistically with hepatitis B, a DNA virus.49 Thereplication of hepatitis C has also been shown to beenhanced in the presence of EBNA1.50 In endemic Burkitt’slymphoma, an arbovirus, many of which are flaviviruses,could act synergistically with the DNA virus EBV, and itsreplication be enhanced by EBNA1. Several researchers51,52

have shown that hepatitis B, C, and G (another flavivirus),occur more commonly in patients with B-celllymphoproliferative disorders than in controls, and it hasbeen tentatively proposed that the possibility of these viruseshaving a role in development of lymphomas is stronger forhepatitis C and G than for hepatitis B. Although neitherhepatitis C nor G are, by definition, arboviruses, both areflaviviruses, like many important arboviruses, and, if a rolein the development of lymphomas is confirmed, theargument for arboviruses acting as cofactors in endemicBurkitt’s lymphoma would be strengthened. Theepidemiology of hepatitis B does not resemble that ofendemic Burkitt’s lymphoma and the epidemiology of theother two viruses has not been fully elucidated.

Chikungunya virus is commonly found in southeast Asiain regions where Burkitt’s lymphoma is found, but is notendemic. The lesser incidence of Burkitt’s lymphoma in thisregion could possibly be accounted for by genetic, cultural,or socioeconomic differences, or could relate to differingepidemiology of falciparum malaria or arboviruses, or a later



Characteristic arboviral signs and symptoms in patients with endemicBurkitt’s lymphoma immediately before development of lymphoma*

Sign or Patients Time before Burkitt’s Chikungunya Chikungunyasymptom (%) lymphoma† IgG, IgMseroconversionRash 9 (8) 8 (2–14) 5 5

Sore eyes 16 (18) 19 (7–28) 10 9

Joint pains 32 (37) 14 (2–28) 16 7

Mouth ulcers 14 (16) 13 (3–21) 10 8

Fever 27 (31) 16 (1–56) 19 9

Bleeding 14 (16) 19 (14–28) 6 3

*Data taken from ref 44. †Data are median (range) in days.

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age of infection with EBV, since Burkitt’s lymphoma is seenin people of all ethnic origins in the lymphoma belt inapparently representative proportions. Standards of living inrural Africa and India are much the same.

Chapin’s zonesThe geographic distribution of endemic Burkitt’s lymphomain Africa coincides with one of Chapin’s zones whichcircumscribe a region where some insects and plants arelocated because of the environmental conditions which theyrequire.53 A common plant within the lymphoma belt, whichhas a similar distribution, is Euphorbia tirucalli (figure 4).54

Use of tumour-promoting herbal remediesE tirucalli, a herbal remedy commonly used in Africa, growssignificantly more frequently at the homes of patients withendemic Burkitt’s lymphoma than in those of peoplewithout this disease.54–56 It contains a substance closely relatedto the tumour-promoter TPA (12-O-tetradecanoylphorbol-13-acetate), which is derived from another euphorbia,Croton tiglium. E tirucalli is used medicinally and as hedging,and its rubbery latex is played with by children.57 It producesEBV-promoting substances, present in plant parts, andsecreted into the soil around the plant in active form.56 Inaddition to activating the latent EBV in infected cells, thesesubstances can also enhance EBV-mediated cell trans-formation,56 modulate EBV-specific T-cell activity andcellular immunity,58,59 and induce chromosomal transloca-

tions in B cells,59 thus suggesting that these substances have arole in development of lymphomas associated with EBV andwith endemic Burkitt’s lymphoma.54,55,57

Action of plant tumour-promoter on EBV in vitroCell lines of human lymphocytes immortalised by EBV afterprotracted culture develop chromosomal abnormalities thathave some concordance with those seen in B-cellneoplasms.60 A very small number of aneuploid lympho-blastoid cell lines are tumorigenic in immunocompromisedanimals.60 Although the characteristic 8;14 chromosomaltranslocation of Burkitt’s lymphoma has not been seen toarise spontaneously in lymphoblastoid cell lines, when anextract of E tirucalli was added, continuous mitoses ensuedin the lymphoblastoid cell lines, with chromosomalabnormalities in 10% of the mitoses seen over the course of1 year.61 About 10% of these abnormalities weretranslocations involving the long arm of chromosome 8 withactivation of the oncogene MYC. Cells with theseabnormalities were tumorigenic in nude mice.61 Thus,E tirucalli, which is commonly used in the lymphoma belt asa toy, hedge, and a herbal remedy for paediatric complaints,including signs and symptoms of arbovirus infections,54,55,57

can produce translocations of the type seen in endemicBurkitt’s lymphoma in human lymphocytes in vitro whenthey are infected with EBV, and might also be able to do so in vivo.

Effect of plant tumour promoter on arbovirusesTanaka62 showed the potentiation of a carcinogen by theapplication of TPA to a nude mouse during infection withthe arbovirus West Nile virus. The synergy between virusand carcinogen has been shown in many other models,including the interaction between hepatitis B and thecarcinogen aflatoxin.63 TPA can also enhance production ofcomplete virions of several viruses—both DNA viruses likeEBV64 and RNA viruses such as retroviruses orarboviruses—and can amplify the expression of oncogenessuch as MYC, known to be implicated in the pathogenesis ofBurkitt’s lymphoma.65 The extracts of E tirucalli, which aretumour promoters, could possibly act synergistically witharboviruses, which are potentially oncogenic,15,16 and, inaddition to their clastogenic effect on chromosomes andpredilection for chromosome 8,61 could potentiate anyoncogenic activity of EBV and the arbovirus. Other plantsused medicinally in Africa also contain substances that canactivate EBV in latently infected cells64 and could possiblyhave at least some of the other properties of the extracts of E tirucalli.

Chikungunya virus and probably other arbovirusescould be cofactors in the pathogenesis of endemic Burkitt’slymphoma, as suggested by Haddow,2,14,39 and a tumourpromoter such as E tirucalli could be the final stage in theinduction of endemic Burkitt’s lymphoma. Thiscombination of cofactors could act with a short latentperiod, which would fit with both the history of arboviral-like illnesses immediately preceding the onset of the tumourseen in Uganda47 and Malawi,44 and with the rapid doublingtime of the tumour—66 h in one study.10 Cloning of



Figure 4. The Euphorbia tirucalli plant is a commonly used herbal remedyin Africa.

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translocation breakpoints from several endemic cases hasshown involvement of VDJ recombinase in the genesis ofthe translocations,18 suggesting that endemic Burkitt’slymphoma arises in a B cell that is in the process of activelyarranging its IgG genes. However, other evidence suggeststhat the pattern of deletions and insertions seen in Ig VH DJH

mutations occurs as the result of an antigen-drivenselection process, and that the MYC/Ig translocation takesplace as a result of hypermutation in B cells entering ortransiting germinal centres.66–68 Such changes could occur inresponse to arboviral infection.

The germinal centres of individuals who are undergoinggerminal-centre hyperstimulation, as in hyperendemicmalarial regions, are rich in EBER-positive cells, which areusually absent from the germinal centre. Niller31 haspostulated that when an EBER-positive cell undergoes atranslocation associated with Burkitt’s lymphoma in thegerminal centre, MYC helps to open and upregulate theantiapoptotic EBER transcription units, and the balancebetween apoptosis and anti-apoptosis is thus permanentlyshifted in favour of cell survival. The cell will then have timeto accumulate additional tumorigenic mutations, if theseare necessary, or if it is already a Burkitt’s lymphoma cell,can expand under an appropriate growth stimulus. Thistheory would also fit with the action of the plant tumourpromoter to induce the translocation and promote theEBV, and an acute infection with an arbovirus, as suggestedhere, could stimulate B-cell expansion.

Possible mechanisms of viral oncogenesis A mechanism for arboviral oncogenesis could be virus-induced immunosuppression, but interaction orpotentiation of the two viruses, EBV and the arbovirus, ismore likely because the increase in Burkitt’s lymphoma inendemic areas is all related to EBV. The arbovirus might act

by driving cell growth and hypermutation, enhancing theMYC deregulation so that any genetic errors induced byEBV and the tumour promoter would be fixed before DNArepair could be affected, or by increasing the tendency tochromosomal breakages, as seen in EBV-positive cell linescultured for long periods,60 or in some other way, such asthe enhancement of hepatitis-C replication by EBNA1.50 Anuclear phase of yellow fever and other arboviruses hasbeen reported,69 so that interaction between the two virusesand the host’s chromosomes could occur in the nucleus.Single-stranded RNA viruses such as alphaviruses have beensuggested to function as mRNA and as catalysts, andflaviviruses can form recombinants.70 In the new era of mix-and-match designer virology, alphaviruses71 andflaviviruses72 are being developed both as vaccine vectors intheir own right and to enhance the effectiveness of DNAvaccines.73 If arboviruses have a nuclear phase, there is alsothe possibility that they have an action similar to that ofretroviruses, where the viral genome is integrated into thegenome at the nuclear stage and can act to produceinsertional oncogenesis. Arboviruses could also provide theexplanation for the retroviral-like sequences that have beendescribed in patients with Burkitt’s lymphoma and in theirhealthy parents,74 postulated to be silent in the parents, butactive in an oncogenic capacity in young people. Suchinsertions of oncogenic viruses, along with translocations,amplification of proto-oncogenes, and deletion of tumour-suppressor genes occur preferentially in certain fragile sitesof genomic DNA that are prone to breakage.75

The burden of proof Because the case-clusters described in Uganda41,43 coincidedwith widespread o’nyongnyong virus,45 and localisedBwamba virus, activity,45,46 and the Malawian case-clustersoccurred during a chikungunya epidemic,3 thesearboviruses would seem to be likely candidates for cofactorsacting at the final stage of endemic Burkitt’s lymphomatumorigenesis. If serum samples are still available frompatients who were part of the clusters or from theprospective study undertaken in Uganda,1 they could betested for evidence of recent infection by a range ofarboviruses at the onset of the lymphoma. If high titres ofantibodies, or seroconversion early in the course of thetumour were detected in cases significantly more often thanin controls, this finding would argue in favour of thearbovirus-cofactor hypothesis. Prospective case-control



Search strategy and selection criteriaThe initial hypothesis was derived from background reading ofwork on endemic Burkitt’s lymphoma from 1958 onwards,augmented by searches of MEDLINE Plus, from 1966 to 2004,and PubMed databases for primary references. Search termsused were “Burkitt’s lymphoma” or “endemic Burkittslymphoma”, in combination with “viruses”, “oncogenicviruses”, “Epstein-Barr virus”, “alphaviruses”, and“flaviviruses”. Secondary searches were done after a review ofthe published work derived from primary searches, includingrelated articles and search terms.

Further reading1 Burkitt DP. An alternative hypothesis to a vectored virus. In:

Burkitt DP, Wright DH (eds). Burkitt’s lymphoma. Edinburgh:Churchill Livingstone, 1970: 211.

2 De The G. Epstein-Barr virus and Burkitt’s lymphoma worldwide:the casual relationship revisited. In: Lenoir G, O’Conor G,Olweny CLM (eds). A human cancer model, Burkitt’s lymphoma.Lyon: IARC Scientific Publication, 1985; 60: 165–75.

3 Haluska FG, Tsujimoto Y, Croce CM. The molecular genetics ofnon-Hodgkin’s lymphomas. In: Magrath IT (ed). The non-Hodgkin’s lymphomas. Philadelphia: Edward Arnold, 1990:97–102.

4 Ito Y. Vegetable activators of the viral genome and the causationof Burkitt’s lymphoma and nasopharyngeal carcinoma. In:Epstein MA, Achong, BG (eds). The Epstein-Barr Virus: recentadvances. London: Heinnemann Medical Books, 1985: 209–34.

5 Monath TP, Flavividae: flaviviruses(yellow fever, dengue, denguehaemorrhagic fever, Japanese encephalitis, St Louis encephalitis,tick-borne encephalitis) In: Mandell GL, Bennett JE, Dolin R(eds). Principles and practice of infectious diseases. 4th edn. New York. Churchill Livingstone, 1995: 1465–74.

6 Morrow RH. Epidemiological evidence for the role of Falciparummalaria in the pathogenesis of Burkitt’s Lymphoma. In: Lenoir G,O’Conor G, Olweny CLM (eds). A human cancer model, Burkitt’slymphoma. Eds. Lyons: IARC Scientific Publications No 60, 1985:177–84.

7 Rickinson AB, Gregory CD. Burkitt’s lymphoma. Trans R SocTrop Med Hyg 1988; 82: 657–59.

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studies are also needed. The arbovirus cofactor hasconsistency, temporality, and biological plausibility in itsfavour.

If subsequent work elucidates the possible role for botharboviruses and plant extracts as final cofactors in thepathogenesis of endemic Burkitt’s lymphoma, which workin conjunction with EBV, and, to a lesser extent, withmalaria, appropriate health education could be instituted.Measures advocated would include destruction of mosquitobreeding sites, early treatment of malaria, early recognitionand treatment of endemic Burkitt’s lymphoma and adviceto traditional healers on the dangers of certain remedies.The new EBV vaccine, if deployed widely in the lymphomabelt, would be expected to reduce the incidence of EBV-related endemic Burkitt’s lymphoma, but not EBV-negative HIV-associated Burkitt’s lymphoma. However,most of the Burkitt’s lymphoma in the lymphoma belt remains EBV positive.5,8 It is important that furtherresearch into this disease should be done because it nowoccurs even more commonly in Africa than previously, andbecause elucidation of the pathogenesis of this rapidlygrowing tumour offers an unparalleled opportunity tounravel the mechanisms of carcinogenesis.

Conflict of interestI declare no conflicts of interest.

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3 is Endemic Burkitt’s Lynphoma an Alliance Beween Three Infeccions and a Tumour Prometer

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