Risk factors for testicular germ cell tumours by histological tumour type

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1 Article no. bjoc Risk fctors for testiculr germ cell tumours by histologicl tumour type CAC Couplnd 1, CED Chilvers 1, G Dvey 2, MC Pike 3, RTD Oliver 4 nd D Formn 2 on behlf of the United Kingdom Testiculr Cncer Study Group* 1 Division of Public Helth Medicine nd Epidemiology, School of Community Helth Sciences, University of Nottinghm Medicl School, Nottinghm NG7 2UH, UK; 2 ICRF Cncer Epidemiology Unit, Rdcliffe Infirmry, Oxford OX2 6HE, UK; 3 Deprtment of Preventive Medicine, University of Southern Cliforni School of Medicine, Los Angeles, Cliforni , USA; 4 Deprtment of Medicl Oncology, The Royl London Hospitl, London ECIA 7BE, UK Summry There re two min histologicl groups of testiculr germ cell tumours, which my hve different risk fctors. Some uthors hve nlysed potentil risk fctors by histologicl group but few consistent differences hve been identified. In this pper we exmine risk fctors for pure seminom nd other tumours using dt from the United Kingdom cse control study of testiculr cncer. Seven hundred nd ninetyfour cses were included in the study, ech with mtched control; 400 cses hd pure seminom tumours, nd 394 hd other testiculr tumours. The risk of seminom ssocited with undescended testis ws slightly higher thn tht for other tumours (odds rtio of 5.3 compred with 3.0). When split t the medin ge t dignosis, this difference ws greter in men ged 32 nd over (odds rtio of 11.9 compred with 5.1) thn in the younger men (3.0 compred with 2.5). Risks ssocited with testiculr or groin injuries were higher in the non-seminom group, s ws the risk for history of sexully trnsmitted disese. The protective effect of lte puberty ws more mrked for tumours of other histologies. Some differences were lso detected for prticiption in sports. Whilst some of the differences detected my hve risen by chnce, the stronger ssocition between undescended testis nd pure seminom hs been identified by number of other studies nd my reflect genuine difference in etiology. Keywords: cse-control study; histology; risk fctors; seminom; testiculr cncer The United Kingdom Testiculr Cncer Cse-control Study is one of the lrgest studies of the etiology of testiculr germ cell tumours crried out to dte. The min ssocitions with testiculr tumour risk previously reported from this study were for history of undescended testis or inguinl herni, n erly ge t puberty nd lck of exercise (UK Testiculr Cncer Study Group, 1994) in ddition to testiculr trum nd history of sexully trnsmitted disese (UK Testiculr Cncer Study Group, 1994b). These results combined the two histologicl groups of testiculr tumours, nmely pure seminom nd other tumours. The different geprofiles t dignosis for these two groups s well s some findings from other studies suggest possible differences in the etiology of these tumour types. A preliminry nlysis of differences by histologicl tumour type using dt from the United Kingdom Testiculr Cncer Csecontrol Study suggested some fctors where risks differed significntly by tumour type (Couplnd et l, 1998). These findings were derived using mtched nlyses whereby ech histologicl group of tumour cses ws compred with its own mtched set of controls. In these nlyses we found significnt differences in the distribution of certin vribles between the two control groups, which mde ny differences between the histologicl groups hrd Received 22 October 1998 Revised 22 Februry 1999 Accepted 23 Februry 1999 Correspondence to: CAC Couplnd to interpret. Further nlysis ws therefore necessry, nd the finl results of this nlysis re reported here. MATERIALS AND METHODS The study ws crried out in nine helth regions within the UK. Full detils of the study design hve been previously published (UK Testiculr Cncer Study Group, 1994). In brief, geogrphicl re ws defined in ech region. All men dignosed with testiculr germ cell tumour between 1 Jnury 1984 nd 30 September 1986 (with some regionl vrition), ged yers t dignosis nd resident in the study res were included. The min sources for identifiction of cses were mjor tretment centres nd regionl cncer registries. The study ws restricted to white men with no previous mlignncy or severe mentl disbility. One control ws interviewed for ech cse, selected from the list of the generl prctitioner (GP) with whom the cse ws registered nd mtched by dte of birth to within 1 yer. Ech mtched pir ws seen by the sme interviewer. The interview included questions on medicl history, sexul development nd mritl history, personl lifestyle including prticiption in sports nd exercise, nd occuptionl history. Most questions referred to events hppening up to 1 yer before the dignosis of the cse or the equivlent dte for their ge-mtched control. The reference ge ws defined s the ge of the cse nd *Remining members re given t the end of the rticle Current ddress: Centre for Cncer Reserch, University of Leeds, Cookridge Hospitl, Leeds LS16 6QB, UK

2 1860 CAC Couplnd et l mtched control 1 yer before the dignosis dte, or the equivlent dte for the control. After the interview nd with the subjects consent, further dt on medicl history were bstrcted from their generl prctitioner notes, permission ws lso sought to send postl questionnires to the subjects mothers to collect informtion on their sons helth s child. Both the generl prctitioner notes nd the mothers questionnires were used to confirm history of undescended testis, inguinl herni nd testiculr trum. Detils of the tumours of the cses were bstrcted from their hospitl notes nd copies of their pthology reports were obtined. These reports were reviewed centrlly to determine the histologicl type of tumour. Tumours were clssified s pure seminom or other histologicl type, the ltter group including tumours with mixed histologies. The preliminry nlyses by histologicl group used conditionl logistic regression for mtched studies to estimte odds rtios for the two histologicl groups of cses nd their mtched controls seprtely. There were, however, considerble differences in the distribution of certin vribles between the group of controls mtched to the pure seminom cses nd the group mtched to cses with other histologicl tumours (Couplnd et l, 1998), the prevlence of undescended testis, for exmple, ws higher in controls mtched to cses of other histologies (3.6%) compred with controls mtched to seminom cses (0.8%), difference which remined sttisticlly significnt fter djustment for ge group, study re nd socil clss (P = 0.03). There were lso differences in the distribution of testiculr trum-relted vribles between the two control groups. In order tht differences between the histologicl groups could be estimted without being unduly influenced by differences between the control groups, the nlyses reported here used unconditionl logistic regression, which broke the mtching nd compred ech histologicl group of cses with ll the controls. The odds rtios (OR) nd 95% confidence intervls (CI) clculted were djusted for ge (t dignosis or equivlent, in 5-yer ge bnds), study re nd socil clss (ctegorized into seven groups). Adjustment ws lso crried out where stted for history of undescended testis nd inguinl herni (before ge 15). Significnce tests (tests of heterogeneity) were lso clculted bsed on direct comprison of the two groups of cses, djusted for the vribles listed bove in order to identify risks which differed significntly by tumour type using the likelihood rtio test in n unconditionl logistic regression. The significnce vlues reported re two-sided. Anlyses were performed only for vribles either previously found to be significnt for ll tumours combined (UK Testiculr Cncer Study Group, 1994, 1994b), or identified by other uthors to hve different ssocitions by histologicl group. This strtegy ws chosen to reduce the chnce of detecting flse-positive ssocitions. RESULTS A totl of 863 eligible cses were identified nd 794 of these (92.0%) were interviewed, s were 609 (76.7%) of the 794 firstselected controls nd 185 replcement controls (UK Testiculr Cncer Study Group, 1994). There were 400 cses with tumours described s pure seminom nd 394 with tumours of other germ cell histologicl types (including 77 of mixed histology). The medin ge t dignosis ws 35 for pure seminom, 28 for non-seminom nd 32 for ll tumours. As previously reported (UK Testiculr Cncer Study Group, 1994) the odds rtio ssocited with history of undescended testis for ll testiculr cncer cses ws 3.82 (95% CI = ). Using n unmtched nlysis, the djusted OR for pure seminom ssocited with undescended testis of 5.30 (95% CI = ), did not differ significntly from the OR of 3.00 (95% CI = ) for other histologies (Tble 1). The djusted OR ssocited with undescended testis in the 77 mixed tumour cses ws 5.15 (95% CI = ), nd in the remining non-seminom cses it ws 2.46 (95% CI = ). In cses with history of undescended testis, there ws significntly higher proportion of bilterl undescended testis in pure seminom cses (39.5%) thn in the other cses (14.8%), mong which 12.5% of the mixed tumour cses hd bilterl undescended testis. In ddition, in cses with unilterl undescended testis, higher proportion of pure seminom cses hd lte corrected (15 or older) or uncorrected testis (47.8% compred with 26.1% in ll other tumours) lthough this difference ws not sttisticlly significnt. The overll risk of testiculr cncer ssocited with history of undescended testis when split t the medin ge t dignosis (32 yers) ws higher in the older (OR = 8.25) thn the younger men (OR = 2.46) (UK Testiculr Cncer Study Group, 1994). In men ged younger thn 32 the OR ssocited with undescended testis were 3.03 for pure seminom tumours nd 2.46 for ll other tumours, wheres in the older men they were nd 5.10 respectively, the ltter difference being of borderline Tble 1 Odds rtios for undescended testis by ge-group nd histologicl tumour type Pure seminom Other histologies All controls Significnce Undescended Cses Odds rtio Cses Odds rtio test,b testis n (%) (95% CI) n (%) (95% CI) n (%) All men No 362 (90.5) (93.1) (97.9) P = 0.16 Yes 38 (9.5) 5.30 ( ) 27 (6.9) 3.00 ( ) 17 (2.1) Men ged <32 No 121 (91.0) (92.4) (96.7) P = 0.76 Yes 12 (9.0) 3.03 ( ) 20 (7.6) 2.46 ( ) 13 (3.3) Men ged 32+ No 241 (90.3) (94.7) (99.0) P = Yes 26 (9.7) ( ) 7 (5.3) 5.10 ( ) 4 (1.0) Odds rtios, 95% confidence intervls (CI) nd significnce tests djusted for ge-group, study re nd socil clss. b Significnce test clculted using likelihood rtio test in comprison of two groups of cses.

3 Risk fctors for testiculr cncer by tumour type 1861 Tble 2 Odds rtios for inguinl herni, testiculr trum nd sexully trnsmitted disese by histologicl tumour type Vrible Response Pure seminom Other histologies Cses Odds rtio Cses Odds rtio All controls Significnce test,b n (%) (95% CI) n (%) (95% CI) n (%) Inguinl herni c No 340 (93.9) (94.3) (96.8) P = 0.59 Yes 22 (6.1) 1.60 ( ) 21 (5.7) 2.39 ( ) 25 (3.2) Inguinl herni <15 yers 17 (4.7) 3.12 ( ) 12 (3.3) 2.49 ( ) 11 (1.4) P = d Age t dignosis c 15+ yers 5 (1.4) 0.56 ( ) 9 (2.5) 2.28 ( ) 14 (1.8) Testis or groin injury for which () Took t lest 1 dy No 388 (97.0) (94.2) (97.6) P = off work or school Yes 12 (3.0) 1.39 ( ) 23 (5.8) 2.66 ( ) 19 (2.4) (b) Consulted GP No 390 (97.5) (95.2) (97.0) P = Yes 10 (2.5) 0.89 ( ) 19 (4.8) 1.67 ( ) 24 (3.0) (c) Went to hospitl No 392 (98.0) (95.7) (98.1) P = Yes 8 (2.0) 1.19 ( ) 17 (4.3) 2.45 ( ) 15 (1.9) Ever hd ny sexully No 367 (92.2) (88.5) (95.1) P = trnsmitted disese Yes 31 (7.8) 1.55 ( ) 45 (11.5) 2.93 ( ) 39 (4.9) Odds rtios, 95% confidence intervls (CI) nd significnce tests djusted for ge-group, study re nd socil clss nd undescended testis or inguinl herni dignosed < 15 yers (but see note c). b Significnce test clculted using likelihood rtio test in comprison of two groups of cses. c Adjusted for ge-group, study re nd socil clss, ll men with undescended testis excluded from nlysis. d Significnce test using 3 ctegories of response: no herni, dignosed t <15 yers, nd dignosed t 15+ yers. Tble 3 Odds rtios for sexul development nd sports prticiption by histologicl tumour type Vrible Response Pure seminom Other histologies Significnce Cses Odds rtio Cses Odds rtio All controls test,b n (%) (95% CI) n (%) (95% CI) n (%) Age t first <13 46 (13.7) (16.8) (13.5) P = c nocturnl (16.7) 1.07 ( ) 62 (19.6) 0.98 ( ) 103 (16.4) emissions (24.4) 1.24 ( ) 70 (22.2) 0.80 ( ) 130 (20.7) (yers) (13.1) 0.90 ( ) 38 (12.0) 0.62 ( ) 100 (15.9) 16+ or never 108 (32.1) 1.04 ( ) 93 (29.4) 0.67 ( ) 210 (33.4) Age voice <13 45 (16.4) (19.5) (14.5) P = c broke (yers) (26.5) 0.93 ( ) 89 (32.1) 1.00 ( ) 137 (24.9) (35.3) 1.02 ( ) 78 (28.2) 0.66 ( ) 177 (32.2) (13.5) 0.80 ( ) 38 (13.7) 0.68 ( ) 85 (15.5) 16+ or not yet 23 (8.4) 0.61 ( ) 18 (6.5) 0.34 ( ) 71 (12.9) Prticiption in sports At ge 16: Athletics 65 (16.3) 0.74 ( ) 89 (22.8) 1.20 ( ) 155 (19.7) P = Contct sports 241 (60.4) 1.02 ( ) 244 (62.6) 1.03 ( ) 482 (61.3) P = 0.88 Rcquet sports 60 (15.0) 0.96 ( ) 77 (19.7) 1.07 ( ) 132 (16.8) P = 0.70 At ge 20: Athletics 30 (7.7) 0.74 ( ) 37 (10.9) 1.10 ( ) 71 (9.7) P = 0.11 Contct sports 133 (33.9) 0.71 ( ) 134 (39.5) 0.91 ( ) 306 (41.9) P = Rcquet sports 56 (14.3) 0.87 ( ) 72 (21.2) 1.27 ( ) 123 (16.8) P = At reference ge: Athletics 25 (6.4) 0.54 ( ) 49 (12.5) 0.95 ( ) 101 (12.9) P = Contct sports 41 (10.4) 0.52 ( ) 83 (21.2) 0.87 ( ) 158 (20.1) P = Rcquet sports 85 (21.6) 1.08 ( ) 103 (26.3) 1.53 ( ) 160 (20.4) P = Odds rtios, 95% confidence intervls (CI) nd significnce tests djusted for ge group, study re, socil clss nd undescended testis or inguinl herni dignosed < 15 yers. b Significnce test clculted using likelihood rtio test in comprison of two groups of cses. c Trend test cross ctegories s shown in Tble. sttisticl significnce (Tble 1). For the mixed tumours the OR were 2.98 nd for younger nd older men respectively. The OR for inguinl herni were similr for pure seminom nd other tumours (Tble 2); however, when subdivided by ge t dignosis of herni the risk ssocited with hernis dignosed fter the ge of 15 ws higher for non-seminom tumours thn for pure seminom. The OR for the only other medicl fctors which differed significntly by tumour type re lso shown in Tble 2. The risks ssocited with testiculr trum were greter for histologies other thn pure seminom, this being so for injuries requiring t lest 1 dy s bsence from work or school nd those requiring generl prctitioner consulttion or hospitliztion (ll P < 0.05). There ws n incresed risk of non-seminom (OR = 2.93) compred with pure seminom (OR = 1.55) ssocited with ever hving hd sexully trnsmitted disese (P = 0.018). The OR for the sexul development nd lifestyle vribles which differed by histologicl group re shown in Tble 3. The protective effect of lter puberty identified for ll testiculr tumours (UK Testiculr Cncer Study Group, 1994) ws

4 1862 CAC Couplnd et l mrginlly stronger for non-seminom tumours for the ge t first nocturnl emissions nd the ge t which the voice broke. Prticiption in contct sports t ge 20 nd t the reference ge ws more protective for pure seminom tumours thn for nonseminom tumours nd there were differences of borderline significnce for prticiption in rcquet sports nd thletics t some ges. There were, however, no significnt differences in risk between the two histologicl groups ssocited with time spent prticipting in exercise per week or spent sitting down ech dy (dt not shown) which were significnt overll both t ge 20 nd t the reference ge (UK Testiculr Cncer Study Group, 1994). There were no significnt differences in risk by histologicl group ccording to employment for 5 or more yers in ny of 16 stndrd occuptionl groups. DISCUSSION Most studies of testiculr tumours hve considered tumours of ll histologicl types s single group in their nlyses, s we did in our previous reports on the United Kingdom Testiculr Cncer Cse-control Study (UK Testiculr Cncer Study Group, 1994, 1994b). There re, however, some indictions tht the risk fctor profiles my differ by histologicl group since severl uthors hve found some differing risk fctors for the histologicl groups, lthough few used forml sttisticl tests to identify significnt histologicl differences. It is unlikely, however, tht differences in etiology would be lrge since both groups show similr trends in incidence (Møller, 1993). In our nlyses, s in other studies, number of vribles were explored, so there is n incresed risk of identifying spurious differences by chnce lone. Therefore, in the interprettion of our results we ttch more importnce to findings consistent with those from other studies. We found stronger, but not sttisticlly significnt, ssocition between history of undescended testis nd pure seminom thn non-seminom tumours, lthough there ws lrger difference in risk, of borderline sttisticl significnce, in n nlysis restricted to older men (OR of 11.9 nd 5.1). Among the uthors who hve exmined risks seprtely, Morrison (1976), Stone et l (1991) nd Prener et l (1996) found significntly stronger ssocition with seminom, Morrison (1976) for exmple reported OR of 15.6 for pure seminom compred with 5.3 for non-seminom, nd Prener et l (1996) reported OR of 7.3 nd 3.6 respectively. Henderson et l (1979), Moss et l (1986), Swerdlow et l (1987), Strder et l (1988), Hughey et l (1989), Gllgher et l (1995) nd Møller et l (1996) reported similr risks ssocited with undescended testis in the two histologicl groups, lthough where seprte OR were presented, they were consistently higher for seminoms thn other tumours (Moss et l, 1986; Swerdlow et l, 1987; Strder et l, 1988; Møller et l, 1996). In cse-control study only of pure seminom tumours (Coldmn et l, 1982) the OR ssocited with undescended testis ws These studies used vrious definitions of undescended testis including self-report nd physicin ssessment. Our definition required either evidence of orchidopexy or lck of descent t the reference ge nd so ws not susceptible to recll bis. The overll consistency in the pttern of risk from ll these reports for undescended testis implies genuine difference with higher risk for pure seminom. Our finding of n excess of bilterl undescended tests in seminom cses dds further support to this being rel effect. It is of interest tht the risk ssocited with undescended testis in men with mixed tumours ws similr to tht for pure seminom, lthough conventionlly these tumours re grouped with non-seminom tumours. This would suggest considering this group seprtely where numbers re sufficient, s proposed by Oliver et l (1995). Two other studies (Swerdlow et l, 1987; Stone et l, 1991) hve found, s we did tendency for lte corrected or uncorrected undescended testis to predispose to pure seminom, the consistency of these findings, lbeit in rther smll subgroup, gin suggests rel effect. The risks ssocited with inguinl herni were similr in the two histologicl groups overll in our nlyses. An exmintion ccording to the ge t dignosis of the herni, however, reveled differing ptterns of risk. Risks were rised, nd of similr mgnitude, for hernis dignosed before the ge of 15, whilst for hernis dignosed lter thn this the risk ws incresed for non-seminom tumours (OR = 2.3), but reduced for pure seminoms (OR = 0.6). In the study by Swerdlow et l (1987) n incresed odds rtio for seminom (OR = 3.8) ws ssocited with childhood herniorrhphy before ge 15, wheres no ssocition ws found with nonseminom tumours. Similrly, Prener et l (1996) reported n OR for hernis dignosed before 15 yers of ge of 2.3 for pure seminom compred with 1.2 for other tumours. Morrison (1976), Hughey et l (1989) nd Gllgher et l (1995) found no difference in risk. There is no cler nd consistent pttern in these results, nd lthough there is n indiction tht hernis dignosed in childhood my be more strongly ssocited with seminom ny true difference in risk is unlikely to be lrge. For three vribles exmining the effect of testiculr trum we found risks were significntly incresed for non-seminom tumours, compred with pure seminom tumours. This remined so when nlyses were restricted to men either bove or below the medin ge. In order to reduce recll bis for testiculr trum, mother s questionnires nd GP notes were used to verify these reports. Only two other studies to our knowledge hve investigted the role of trum by histologicl group, the study by Stone et l (1991) found, like us, incresed levels of trum in non-seminom cses, wheres Hughey et l (1989) reported no difference. We hve previously reported n incresed risk ssocited with history of sexully trnsmitted disese for ll testiculr tumours (UK Testiculr Cncer Study Group, 1994b), but considered tht reporting bis ws possible explntion for this finding due to the sensitive nture of the question. In comprison of cses lone, reporting bis should be reduced, nd here we found tht more cses with non-seminom tumours thn pure seminom reported sexully trnsmitted disese. This finding ws consistent for genitl herpes, gonorrhoe nd other sexully trnsmitted diseses considered seprtely nd lso in younger nd older men, lthough the sttisticl significnce ws reduced due to smller numbers. No other studies to our knowledge hve investigted such n effect by histologicl group. Our finding of stronger protective effect of lte puberty for non-seminom thn pure seminom is consistent with two other reports. Moss et l (1986) found similr difference using question bout ge t ppernce of pubic hir, s did Møller nd Skkkebek (1996) where boys were sked to compre their ge t puberty to tht of their clssmtes. These findings for rnge of relted questions imply genuine, though smll, difference. Overll, exercise hd protective effect of similr mgnitude in the two histologicl groups. Prticiption in specific sporting ctivities such s contct sports nd thletics tended to hve stronger protective effect for seminom compred with other tumours. As number of different ctivities were exmined in

5 Risk fctors for testiculr cncer by tumour type 1863 these nlyses this my be chnce finding. Other uthors hve not presented results from similr nlyses. Some uthors hve explored occuptionl differences by tumour type. Hyes et l (1990) found n incresed risk of non-seminom for production workers, Knight et l (1996) reported incresed risks of non-seminom for miners nd employees in food production, utilities nd the lether industry, wheres Hughey et l (1989), like us, found no occuptionl differences by tumour type. Due to the number of occuptions being exmined, these nlyses gin re susceptible to the detection of spurious ssocitions. None of the differences in risk identified by us nd supported by other studies were very lrge, nd would not in their own right be deserving of mjor considertion. There is, however, incresing evidence tht testiculr germ cell cncer my rise by clonl evolution with seminom being seen s n intermedite stge between crcinom in situ nd non-seminom (Oliver et l, 1995). Cytogenetic studies provide support for this s they demonstrte tht the step from seminom to non-seminom is ssocited with loss of chromosomes 12 nd 15 (Looijeng et l, 1993). With evidence for n ssocition of declining sperm counts with rising testis cncer rtes (Crlsen et l, 1995) nd trophy induced incresed gondotrophin drive s the finl common pthwy (Oliver, 1990), it is possible to understnd how n trophogenic insult such s testiculr trum could be ssocited with ccelerted progression nd chromosome loss. The observtion tht seminom ws more frequent in the older cryptorchid ptients who hd lower incidence of surgicl correction would lso fit with this observtion s uncorrected cryptorchidism would be less trumtic. There is evidence from Swerdlow et l (1997) tht the trum of biopsy t orchidopexy is ssocited with n incresed risk of tumour. In conclusion, we hve identified, in lrge study of testiculr tumours, severl fctors where the risks of pure seminom nd tumours of other histologies differ. We hve found ptterns of risk, consistent with other published studies which indicte tht undescended testis is ssocited more strongly with pure seminom tumours thn other tumours, nd tht the protective effect of lte puberty is more mrked for non-seminom tumours. Our finding of differences for testiculr trum, sexully trnsmitted disese nd sporting ctivities my hve risen by chnce, nd require confirmtion in other studies. Although the differences identified tended to be smll, they my indicte fctors which ct s selection pressures nd contribute to the clonl evolution of these tumours. Members of the United Kingdom Testiculr Cncer Study Group Study coordintors: K Bker, S Dwson. Regionl collbortors: J Birch, RA Crtwright, PC Elwood, C Tyrell. Interviewing stff: R Brett, T Bush, V Isbell, A Cornwell, R Steer, S Thistlethwite, H Gellmn, J Hughes, M Llewellyn, A Ardern-Jones, A Allen, E Hilton, B Lloyd, S McVeigh, M Thorne, P Trowbridge, S Reid. ACKNOWLEDGEMENTS This study ws funded by Imperil Cncer Reserch Fund, the Cncer Reserch Cmpign nd the Medicl Reserch Council. Further nlysis ws supported by the Cncer Reserch Cmpign. We wish to thnk those who helped with cse finding, the fmily prctitioner committees (now FHSAs) who helped with control selection, the consultnts nd generl prctitioners who llowed us to interview their ptients nd the ptients nd control men who helped with the study. REFERENCES Crlsen E, Giwercmn A, Keiding N nd Skkkebek NE (1995) Declining semen qulity nd incresing incidence of testiculr cncer: is there common cuse? Environ Helth Perspect 103: Coldmn AJ, Elwood JM nd Gllgher RP (1982) Sports ctivities nd risk of testiculr cncer. Br J Cncer 46: Couplnd CAC, Chilvers CED, Pike MC, Dvey G nd Formn D (1998) Differences in the etiology of testiculr cncer by histologicl tumour type. 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