DOI: 10.1054/ bjoc.1999.1049, vilble online t http://www.idelibrry.com on Risk fctors for HodgkinÕs disese by Epstein-Brr virus (EBV) sttus: prior infection by EBV nd other gents FE Alexnder 1, RF Jrrett 2, D Lwrence 3, AA Armstrong 2, J Freelnd 2, DA Gokhle 4, E Kne 5, GM Tylor 4, DH Wright 6 nd RA Crtwright 5 1 Deprtment of Public Helth Science, University of Edinburgh, Medicl School, Teviot Plce, Edinburgh EH8 9AG, UK; 2 Leukemi Reserch Fund Virus Centre, Deprtment of Veterinry Pthology, Bersden Rod, Glsgow G61 1QH, UK; 3 Clinicl Tril nd Sttistics Unit, Institute of Cncer Reserch, Block D, 15 Cotswold Rod, Sutton, Surrey SM2 5NG, UK; 4 North West Immunogenetics Lbortory, St Mry s Hospitl, Hthersge Rod, Mnchester M13 0JH, UK; 5 Leukemi Reserch Fund, Centre for Clinicl Epidemiology, UMV Leeds, 17 Springfield Mount, Leeds LS2 9NG, UK; 6 Deprtment of Pthology, University of Southmpton, Level E, South Block, Southmpton Generl Hospitl, Southmpton, UK Summry A UK popultion-bsed cse control study of Hodgkin s disese (HD) in young dults (16 24 yers) included 118 cses nd 237 controls mtched on yer of birth, gender nd county of residence. The mjority (103) of the cses were clssified by Epstein Brr virus (EBV) sttus (EBV present in Reed Stenberg cells), with 19 being EBV-positive. Anlyses using conditionl logistic regression re presented of subject reports of prior infectious disese (infectious mononucleosis (IM), chicken pox, mesles, mumps, pertussis nd rubell). In these nlyses HD cses re compred with mtched controls, EBV-positive cses nd EBV-negtive cses re compred seprtely with their controls nd forml tests of differences of ssocition by EBV sttus re pplied. A prior history of IM ws positively ssocited with HD (odds rtio (OR) = 2.43, 95% confidence intervl (CI) = 1.10 5.33) nd with EBV-positive HD (OR = 9.16, 95% CI = 1.07 78.31) nd the difference between EBV-positive nd EBV-negtive HD ws sttisticlly significnt (P = 0.013). The remining infectious illnesses (combined) were negtively ssocited with HD, EBV-positive HD nd EBV-negtive HD (in the totl series, for 2 episodes compred with 1, OR = 0.45, 95% CI = 0.25 0.83). These results support previous evidence tht erly exposure to infection protects ginst HD nd tht IM increses subsequent risk; the comprisons of EBV-positive nd EBV-negtive HD re new nd generte hypotheses for further study. 2000 Cncer Reserch Cmpign Keywords: Hodgkin s disese; Epstein Brr virus; etiology; lte host exposure model; infectious gents The ge-incidence curve for Hodgkin s disese (HD) in developed countries includes striking pek mongst young dults (ged 16 34 yers) which, in 1966, led to the hypothesis tht there re three distinct HD entities corresponding to childhood, young dult nd older ge-t-onset (McMhon, 1966) with n infectious etiology for young dult HD. Considerble support hs mssed for the lte host response model (Gutensohn nd Cole, 1980) of HD in young dults under which the disese is (rre) sequell to lte first infection by one or more unknown infectious gents. The evidence includes ecologicl, cse control nd cohort studies showing positive ssocitions between HD in young dults nd proxies for risk of lte exposure to infections or bsence of erly exposure to mrker gents (reviewed in Mueller nd Gruffermn, 1999). Further support hs come from reports (Miller nd Beebe, 1973; Connelly nd Christine, 1974; Rosdhl et l, 1974; Crter et l, 1977; Munoz et l, 1978; Kvle et l, 1979) tht incidence of HD is high in cohorts of subjects who hve hd infectious mononucleosis (IM); these studies involve nerly 42 000 young dults with serologiclly confirmed IM nd, overll, show risk elevted round threefold. IM is cused by lte first infection with the Epstein Brr virus (EBV) nd its ge-incidence curve prllels tht of HD in young dults. Received 6 My 1999 Revised 18 October 1999 Accepted 19 October 1999 Correspondence to: FE Alexnder The demonstrtion tht EBV genomes were present nd expressed in the HD tumour cells (Reed Sternberg cells) of proportion of cses provided n importnt new understnding of the biology of the disese (Weiss et l, 1987; Pllesen et l, 1991). It is now known tht EBV is present in round 40% of ll cses of HD (Jrrett et l, 1996) nd its role is generlly greed to be cusl lthough detils of the reltionship remin poorly understood (Michels, 1995; Mueller, 1996). Subclssifiction of cses of HD by presence (EBV-positive) or bsence (EBV-negtive) of EBV in Reed Stenberg cells provides biologicl clssifiction which is lterntive to the histologicl grouping by Rye type nd hs the potentil to identify etiologicl subgroups but only one study ( cse-series) hs compred epidemiologicl risk fctors by EBV sttus (Sleckmn et l, 1998). The objective of the present study ws to investigte the lte host response model for HD in young dults (16 24 yers) nd determine whether it pplied differently to EBV-positive nd EBV-negtive disese. The present report focuses on self-reported history of IM nd other specific infectious illness. A subsequent pper will report HLA-DP type of cses by EBV sttus. METHODS Cses All cses of HD newly dignosed between 1 October 1991 nd 31 My 1995 in the Yorkshire, Wessex nd South West FHSA res 1117
1118 FE Alexnder et l nd in Cumbri nd Lncshire (prt), nd ged 16 24 yers t dignosis were eligible for inclusion. These res re tken from the Leukemi Reserch Fund (LRF) Dt Collection Study (DCS) re nd methods of scertinment were those of the DCS (Crtwright et l, 1990). This ensures high qulity scertinment free of geogrphicl bis. Altogether 129 cses were eligible nd 118 consented to prticipte. Controls Controls (two per cse) were rndomly selected from people registered with generl prctitioners in the study re mtched for sex, yer of birth nd dministrtive re (FHSA) of residence. This rndom selection from computerized generl prctitioner (GP) lists will hve included n unknown number of people who were no longer living t the registered ddress (or even in the FHSA); such people were not eligible for the study. Controls were pproched by letter fter their GPs hd given consent; second letters were sent to those who did not respond nd further ttempts to mke contct included telephone clls nd home visits. Controls who did not give consent or who could not be trced were replced with further rndom selection bsed on the sme mtching criteri nd using the sme methods of pproch. Socio-economic sttus The ddress of residence hs been used to give the Crstir s index (Jrmn et l, 1991) of re of residence s n indictor t five levels of socio-economic sttus using dt derived from the 1991 census. Interview dt Fce-to-fce interviews were conducted by trined interviewers using questionnires developed from others in use by the LRF Centre for Clinicl Epidemiology in Leeds (Crtwright et l, 1990). The period covered ws from birth up to reference dte, which ws dte of dignosis of the cse for members of ech mtched set. Informtion ws elicited on proxies for exposure to infection (not reported here), pst history of infectious illness, pst medicl history of index nd fmily, nd limited history of infectious illness in friends nd household members. Ech subject ws sked Hve you ever suffered from glndulr fever? nd the response ws recorded s Yes, No, It ws suspected or Not known. Self-reported IM (glndulr fever) hs been nlysed in two wys tking suspected s Yes nd s No ; tking suspected s missing led to too much exclusion of dt under the mtched design. Since symptoms of IM cn rise s preliminry indiction of HD, nlyses for both totl IM before reference dte nd IM up to 1 yer before reference dte re reported. Reported history of childhood infectious illness (mesles, rubell, mumps, chicken pox nd pertussis) ws vilble for lmost ll subjects. A blind ssessment of the distribution of frequencies of childhood infections led to sensible strt for the number of episodes for nlyses. The nlyses reported here in detil re ll bsed on dichotomies in which the lowest level (usully none) is tken s reference group nd ll others combined. A decision ws tken prior to inspection of the dt tht childhood infections should be considered t ll ges nd in 5-yer ge groups. Since few infectious illnesses occurred in children over 10 yers, some nlyses hve tken 5 s single ge group. EBV sttus clssifiction nd histopthology Prffin-embedded biopsy mteril ws retrieved from cses nd histopthologicl review ws performed by DHW. Sections were exmined for the presence of EBV using EBV EBER in situ hybridiztion nd lso, in the mjority of cses, LMP-1 immunohistochemistry. The in situ hybridiztion ssy utilized biotinylted oligonucleotide probe complementry to the EBER-1 RNA which hs been described previously (Armstrong et l, 1992). Hybridiztion ws detected using vidin biotin complexes, nd nitroblue tetrzolium ws used s the chromogenic substrte (Dko, High Wycombe, UK). Expression of the LMP-1 protein ws investigted using the CS1 4 cocktil of monoclonl ntibodies s previously described (Armstrong et l, 1992). Sections from known cses of EBV-positive ssocited HD were used s positive controls in both ssys. Cses re described s EBV-positive if the Reed Sternberg cells scored positive in either ssy. EBV sttus is vilble for 103 nd histologicl review for 105 of the cses, including ll but one of those with EBV sttus known. All but four cses hve been given specific Rye type but those with type given s lymphocyte predominnt (LP) hve been excluded from some nlyses becuse they re not now considered clssicl HD. Sttisticl nlysis Almost ll sttisticl nlyses hve pplied conditionl logistic regression to the mtched set dt to compre risk fctors for cses nd controls with results reported s odds rtios (OR) nd 95% confidence intervls (CI). These hve been implemented in the softwre pckges SAS nd EGRET. Multivrite conditionl logistic regression hs permitted djustment for confounding vribles nd for Crstir s index of ddress of residence. Anlyses hve been pplied to the following subgroups: ll subjects ll sets where cse EBV sttus is known, with testing for interction by EBV sttus of the cse. Where the conditionl logistic model could not be fitted (0 subjects in one cell) exct nlyses (with mtching retined) hve been conducted in EGRET. All testing of sttisticl significnce for conditionl logistic regression modelling hs exmined the devince difference ginst its symptotic chi-squre distribution under the null hypothesis (Clyton nd Hills, 1993). Min effects were mostly tested ginst χ 2 distribution with one degree of freedom; for heterogeneity of risk by cse EBV-sttus subgroups the χ 2 for the interction hd further 1 degree of freedom. The hierrchy of hypotheses considered here is: no ssocition, ssocition common to both cse subgroups, ssocition different by cse subgroup. RESULTS The mjority (90%) of cses scertined in the geogrphic re during the study period were recruited into the study. Cses (Tble 1) were predominntly of NS type nd predominntly EBV-negtive. Overll, there ws very slight excess of mles but the EBVpositive cses showed substntil mle excess (14 mles, five femles).
Risk fctors for HD by EBV sttus 1119 Tble 1 Numbers of cses for nlysis with selected chrcteristics Chrcteristics N (%) Gender Mle 62 (52.5) Femle 56 (47.5) Rye type NS 81 (68.6) MC 14 (11.9) LD 1 (0.8) LP 14 (11.9) NOS 4 (3.4) EBV sttus Positive 19 (16.1) Negtive 84 (71.2) % of ll cses; where dt re missing %s do not dd up to 100. NS, Nodulr sclerosing MC, Mixed cellulrity LD, Lymphocyte depleted LP, Lymphocyte predominnt NOS Not otherwise specified Childhood infectious illnesses were significntly protective for the totl cse series nd for EBV-positive HD nd EBV-negtive HD nlysed seprtely (Tble 3). Infections t ges 5 9 yers were significntly protective for EBV-negtive HD but ppered to increse risk of EBV-positive HD nd the interction with cse EBV sttus chieved forml sttisticl significnce (P = 0.02). Mesles (but not ny other of the individul illnesses) ws significntly protective for the totl series. Further exmintion of combined infections t ges 5 9 yers ws pproprite becuse of the significnt interction with EBV sttus. Scrutiny of the dt reveled tht the (non-significnt) excess risk of EBV-positive HD ssocited with infections t ges 5 9 yers ws focused in the IM-positive subjects. The interction of IM with combined infection t this ge ws tested in the totl series nd found to be sttisticlly significnt (Tble 4). Thus, the dt suggest tht people with IM who hve lso hd school-ge Tble 2 Assocition of reported IM with HD cse sttus Definition of Totl series EBV-positive cses EBV-negtive cses exposed % Positive OR b P % Positive OR b P % Positive OR 2 P C Ct (95% CI) C Ct (95% CI) C Ct (95% CI) Definite prior IM 16.1 9.0 2.43 0.027 31.6 8.1 9.16 + 0.043 13.1 9.0 1.60 0.32 (1.10 5.33) (1.07 78.31) (0.63 4.07) Definite or suspected 21.2 13.7 1.87 0.07 31.6 8.1 9.16 + 0.043 19.0 13.3 1.50 0.32 prior IM (0.95 3.66) (1.07 78.31) (0.68 3.33) Definite IM > 1 yer 13.6 8.2 1.93 0.11 31.6 5.4 c 0.011 c 9.5 8.4 1.09 0.87 before dignosis (0.87 4.28) (1.66 ) (0.40 2.97) Definite or suspected IM > 1 yer 17.8 12.9 1.46 0.29 31.6 5.4 c 0.011 c 14.3 12.7 1.00 1.00 before dignosis (0.72 2.94) (1.66 ) (0.42 2.41) % reporting positive of those with results vilble for the present nlysis. b Adjusted for Crstirs index (except where this leves 0 cses or 0 controls exposed for one exposure ctegory (+) where undjusted results re reported). c Exct tests performed mintining the mtching. Recruitment of controls proved difficult in this ge group. The percentge of first choice controls recruited ws 36.5%; 39% of femles but just 31% of mles who were pproched consented to prticipte. Approximtely hlf of the non-prticipnts were eligible but refused consent. We hd no wy of verifying the eligibility of the reminder. Our recorded response rtes my therefore be rtefctully low. Control response ws ssocited with Crstir s index with 45% of those pproched in the two lest deprived groups consenting compred with 25% in the most deprived group. Subsequent nlyses therefore hve been djusted for Crstir s index whenever possible; since the index could not be clculted from the recorded ddresses of 20 cses nd 38 controls this hs led to the exclusion of smll mount of dt. When frequencies of reported IM in cses nd controls were compred (Tble 2) there ws significnt cse excess in the totl series when suspected ws interpreted s no. The mgnitude of the OR nd the level of sttisticl significnce ws reduced if suspected ws tken s yes nd/or IM in the lst yer before reference dte ws ignored. The OR re much higher when the EBV-positive cses re compred with their controls nd no comprisons chieve sttisticl significnce when nlyses re restricted to the EBV-negtive cses. Sttisticl testing of the interction confirms heterogeneity of the OR by cse EBV-sttus (P = 0.013 for definite nd 0.009 for definite or suspected IM prior to dignosis). history of other infectious illness re t specil risk of HD (prticulrly EBV-positive). Numbers of EBV-positive cses were too smll to permit these nlyses for EBV-positive cses lone; we did, however, confirm tht the effect of IM in the EBV-positive subjects persisted fter djustment for infections t ges 5 9 yers (minor reduction in OR in both the conditionl logistic model nd exct nlyses). The five childhood infectious illnesses were considered individully in two ge groups (younger: < 5 yers, older: 5 yers). When ll these were included in multivrite nlysis of the totl series older mesles ws significntly protective (OR = 0.32; 95% CI = 0.14 0.74, djusting for younger mesles nd the other infections in two ge groups). No other comprisons pproched sttisticl significnce. When similr nlysis ws conducted for the EBV-negtive cses (nd their controls) the results for mesles were similr but older chicken pox ws now protective to similr extent (OR = 0.39, 95% CI 0.17 0.93). The numbers of EBVpositive cses were too smll for the multivrite nlysis to be pplied. Addition of IM to the two full models (i.e. those contining terms for five infections ech t two ges) mde some improvement for the totl series (OR = 1.86, 95% CI = 0.71 4.84, P = 0.20) but hd very smll effect for the EBV-negtive series (OR = 1.18, 95% CI = 0.39 3.52, P = 0.77) so tht IM hs virtully no independent effect on risk of EBV-negtive HD.
1120 FE Alexnder et l Tble 3 Assocition of selected reported infections with HD cse sttus Definition of Totl series EBV-positive cses EBV-negtive cses exposed % positive OR b P % positive OR b P % positive OR 2 P C Ct (95% CI) C Ct (95% CI) C Ct (95% CI) Totl n infections 2 (see Tble 2) 68.6 81.8 0.45 0.010 63.2 86.5 0.18 0.043 66.7 81.7 0.43 0.017 (0.25 0.83) (0.03 0.95) (0.21 0.86) Totl n infections < 5 yers 1 37.3 40.7 0.89 0.66 26.3 43.2 0.32 0.15 40.5 39.6 1.01 0.97 (0.54 1.49) (0.07 1.49) (0.55 1.88) Totl n infections 5 9 yers 1 72.9 78.5 0.82 0.48 84.2 70.3 4.70 0.16 66.7 81.1 0.51 0.042 (0.47 1.42) (0.55 40.22) (0.27 0.98) Totl n infections 10 yers 1 16.9 20.3 0.85 0.62 31.6 21.6 2.31 0.24 15.5 21.9 0.62 0.24 (0.44 1.63) (0.57 9.37) (0.27 1.39) Mesles ever 37.8 53.3 0.53 0.018 47.4 58.3 0.48 0.28 34.6 51.9 0.49 0.020 (0.32 0.90) (0.13 1.81) (0.27 0.90) % reporting positive of those with results vilble for the present nlysis. b Adjusted for Crstirs index (except where this leves 0 cses or 0 controls exposed for one exposure ctegory (+) where undjusted results re reported). Tble 4 Interction of reported IM nd totl infections t ges 5 9 yers (using totl series) Exposure (term in model) OR 95% CI Reported IM 0.47 0.09 2.52 (suspected = No) Totl n infections (s in Tble 2) 1 ges 5 9 yers 0.64 0.37 1.10 Interction (reported IM nd 1 infection 5 9 yers) 5.84 0.99 34.59 P-vlue for sttisticl interction: 0.035. DISCUSSION The study possesses unique strengths; these include the cses being popultion-bsed census of ll those rising in nrrow ge rnge nd the systemtic scertinment of Rye-type nd EBV-sttus of cses. No previous epidemiologicl cse control study of HD hs included ll of these clssifictions. The results present the first evidence of n ssocition between prior IM nd EBV-positive HD. Our study, however, hs two importnt limittions. First, it is bsed on smll numbers, especilly of EBV-positive cses. Secondly, lrge number of first-choice controls could not be recruited; this my hve led to bis between prticipting controls nd controls selected so tht the former re not representtive of the popultion from which the cses derive. We hve evidence tht, in prticulr, controls recruited re of higher socio-economic sttus. Whilst cknowledging these limittions we emphsize tht, in regrd to the first point, this study provides preliminry conclusions for subsequent testing. With regrd to control recruitment we note tht djustment for Crstir s index will reduce the problem but, criticlly, the bis cnnot ffect comprisons by biologicl subgroups of cses. A further potentil wekness is bsence of medicl cse-note or serologicl verifiction of IM. A recent lrge cse control of severl cncers including HD hs found ORs for self-reported IM which were similr to those from the cohort studies, nd show disese specificity nd time-period specificity which were consistent with the literture (Levine et l, 1998). This suggests tht recll bis is of limited importnce. Also, it is cler tht ny such effects cnnot pply to comprisons of the EBV subgroups of HD. There re three seprte strnds of evidence relting EBV to HD: pst history of IM in HD cses; serologicl studies compring EBV ntibody titres in HD cses nd controls; moleculr biologicl studies which hve demonstrted presence nd expression of EBV in HD tumour cells for round 40% of cses (Jrrett et l, 1996). The bove three strnds hve not been criticlly compred with ech other. Previous IM is ssocited with young dult HD, wheres EBV positivity is rre in this ge group (Glser et l, 1997). The evidence ssociting prior IM with HD is open to two interprettions which re not mutully exclusive: EBV infection my hve cusl role in the subsequent HD or lte first infection by EBV (resulting in IM) my indicte lifestyle in which first infection by brod rnge of gents is delyed to young dulthood. Limited dt hve been published for EBV sttus of HD cses with prior IM (Mck et l, 1995; Sleckmn et l, 1998) but EBV-negtive cses certinly occur in people with history of IM. The first study to hve compred risk fctors in EBV-positive nd -negtive HD cses ws cse-series (Sleckmn et l, 1998) which found no ssocition between prior IM nd EBV sttus; this study hd similr numbers of cses to our own but included much broder rnge of ges t dignosis (16 55 yers). Our most importnt results re evidence tht reported IM (i) is sttisticlly significntly ssocited with HD, (ii) is focused in EBV-positive cses, nd (iii) hs sttisticlly significnt interction with EBV sttus of cses. Our results suggest specific cusl ssocition of recent EBV exposure with EBV-positive HD which my be superimposed on n dditionl risk relted to lifestyle conducive to lte first exposure to infection. Our dt re consistent with either n bsence of ssocition of EBV-negtive HD with prior IM or wek positive ssocition; the ltter could be interpreted in terms of lifestyles nd environments predisposing to lte first exposures to EBV nd other gents with similr trnsmission routes. It is lso importnt to note tht our dt document for the first time the high frequency of reported IM in young dults in the UK (nd similr countries) tody. This could in itself explin the necdotl reports of prior IM in EBVnegtive HD. Evidence for protective role for (erly exposure to) nonspecific infectious gents in the etiology of HD comes lrgely from proxy dt (see Introduction), lthough one cohort study with bseline dt being detiled history of prior infectious illness reported by 1st yer university students, reched similr conclusions (Pffenbrger et l, 1977). Mesles nd/or combined child-
Risk fctors for HD by EBV sttus 1121 hood infections re protective for HD in our dt; biologicl considertions nd the HD epidemiologicl profile suggest tht this is due to their being mrkers of reduced risk of lte first exposure to etiologicl gents. The present dt cnnot distinguish between mesles nd totl infections but re consistent with specific protective effect of mesles in school ge children. Although, in generl, infection is protective ginst both EBVpositive nd EBV-negtive HD there is evidence tht the relevnce of childhood infectious illnesses t specific ges differs by EBV sttus. Totl infectious illness in children ged 5 9 yers hs negtive ssocition with EBV-negtive HD but positive one with EBV-positive disese (these results being driven by chicken pox). The elevted OR nd the sttisticlly significnt interction between EBV-positive HD nd EBV-negtive HD my be (i) due to chnce or (ii) indictive of genuine ssocition, possibly involving n underlying synergism with IM. The ltter is supported by the sttisticlly significnt interction in which risk of HD is concentrted in individuls who reported both IM nd childhood infectious illness (5 9 yers). The present study genertes hypotheses for testing in lrger series. Severl of us re collborting in much lrger study of HD in subjects 16 74 yers. The sme risk fctor nd biologicl dt re vilble in this lrger study nd nlyses will begin shortly. The results point to the importnce of recent exposure to EBV in the development of EBV-positive HD in young dults. REFERENCES Armstrong AA, Weiss LM, Gllgher A, Jones DB, Krjewski AS, Angus B, Brown G, Jck AS, Wilkins BS nd Onions DE (1992) Criteri for the definition of Epstein Brr virus ssocition in Hodgkin s disese. Leukemi 6: 869 874 Crter CD, Brown TM Jn, Herbert JT nd Heth CW (1977) Cncer incidence following infectious mononucleosis. Am J Epidemiol 105: 30 Crtwright RA, Alexnder FE, McKinney PA, Ricketts TJ, Hyhoe FGJ nd Clyton DGC (1990) Leukemi nd Lymphom: An Atls of Distribution Within Ares of Englnd nd Wles, 1984 88. Leukemi Reserch Fund: London Clyton D nd Hills M (eds) (1993) Sttisticl Methods in Epidemiology. Oxford University Press: New York Connelly RR nd Christine BW (1974) A cohort study of cncer following infectious mononucleosis. Cncer Res 34: 1172 Glser SL, Lin RJ, Stewrt SL, Ambinder RF, Jrrett RF, Brousset P, Pllesen G, Gulley ML, Khn G, OGrdy J, Hummel M, Precido MV, Knecht H, Chn JKC nd Clviez A (1997) Epstein Brr virus-ssocited Hodgkin s disese: epidemiologic chrcteristics in interntionl dt. Int J Cncer 70: 375 382 Gutensohn N nd Cole P (1980) Epidemiology of Hodgkin s disese. Semin Oncol 7: 92 Jrmn B, Townsend P nd Crstirs V (1991) Deprivtion indices. Br J Med 303: 523 Jrrett RF, Armstrong AA nd Alexnder FE (1996) Epidemiology of EBV nd Hodgkin s lymphom. Ann Oncol 7: S5 S10 Kvle G, Hoiby EA nd Pedersen E (1979) Hodgkin s disese in ptients with previous infectious mononucleosis. Int J Cncer 23: 593 Levine R, Zhu KM, Gu Y, Brnn E, Hll I, Cpln L nd Bum M (1998) Selfreported infectious mononucleosis nd 6 cncers. A popultion bsed cse control study. Scnd J Inf Dis 30: 211 214 Mck TM, Cozen W, Shibt DK, Weiss LM, Nthwni BN, Hernndez AM, Tylor CR, Hmilton AS, Depen DM nd Rppport EB (1995) Concordnce for Hodgkin s disese in identicl twins suggesting genetic susceptibility to the young dult form of the disese. N Engl J Med 332: 413 418 McMhon M (1966) Epidemiology of Hodgkin s disese. Cncer Res 26: 1189 Miller RW nd Beebe GW (1973) Infectious mononucleosis nd the empiricl risk of cncer. J Ntl Cncer Inst 50: 315 Michels KB (1995) The origins of Hodgkin s disese. Eur J Cncer Prev 4: 379 388 Mueller NE (1996) Hodgkin s disese. In: Cncer Epidemiology nd Prevention, 2nd edn, Schottenfield D nd Frumeni JF Jr (eds). Oxford University Press: New York Mueller NE nd Gruffermn S (1999) Epidemiology. In: Hodgkin s Disese, Much P, Armitge J, Diehl V, Hoppe R nd Weiss L (eds) Rven Press: New York (in press) Munoz N, Dvidson RJL, Witthoff B, Ericsson JE nd De-The G (1978) Infectious mononucleosis nd Hodgkin s disese. Int J Cncer 22: 10 Pffenbrger RS Jn, Wing AL nd Hyde RT (1977) Chrcteristics in youth indictive of dult-onset Hodgkin s disese. J Ntl Cncer Inst 58: 1489 Pllesen G, Hmilton-Dutoit SJ, Rowe M nd Young LS (1991) Expression of Epstein Brr virus ltent gene products in tumour cells of Hodgkin s disese. Lncet 337: 320 322 Rosdhl N, Lrsen SO nd Clemmenson J (1974) Hodgkin s disese in ptients with infectious mononucleosis: 30 yers experience. Br Med J 2: 253 Sleckmn BG, Much PM, Ambinder RF, Mnn R, Pinkus GS, Kdin ME, Sherburne B, PerezAtyde A, Thior I nd Mueller N (1998) Correltion between EBV-sttus nd risk fctor profile in Hodgkin s disese. Cncer Epidemiol Biomrk Prev 7: 1117 1121 Weiss LM, Strickler JG, Wrnke RA, Purtilo DT nd Sklr J (1987) Epstein Brr virl DNA in tissues of Hodgkin s disese. Am J Pthol 129: 86 91