Int. J.
Cancer: 124, 687–689 (2009)
' 2008 Wiley-Liss, Inc.
Risk of contralateral testicular cancer among men with unilaterally
undescended testis: A meta analysis
Olof Akre1,2*, Andreas Pettersson2 and Lorenzo Richiardi1
1
Cancer Epidemiology Unit, CeRMS and CPO-Piemonte, University of Turin, Turin 10126, Italy
2
Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden
The association between undescended testis (cryptorchidism) and
testicular cancer is established, but it is not known whether the
risk of testicular cancer among men with unilateral maldescent is
increased in both testes, or only on the undescended side. This is a
meta-analysis of 11 case-control studies and 1 cohort study that all
assessed the risk of testicular cancer separately for the unde-
scended and descended testis. We used fixed-effects meta-analysis
to calculate pooled estimates and 95% confidence intervals (CIs)
for the relative risk. Of 199 tumors in men with unilateral cryp-
torchidism, 158 (79%) were on the ipsilateral side and 41 (21%)
on the contralateral side. The pooled relative risks for testicular
cancer in the ipsilateral and contralateral testis were 6.33 (95%
CI, 4.30 to 9.31) and 1.74 (95% CI, 1.01 to 2.98), respectively. We
conclude that in 1-sided undescended testis, the risk of testicular
cancer may be increased in both testes, although to a much greater
extent on the ipsilateral side.
' 2008 Wiley-Liss, Inc.
Key words: testicular neoplasms; undescended testis; cryptorchidism;
risk; meta-analysis
The mechanism behind the well-established association
between undescended testis, or cryptorchidism, and testicular can-
cer is not known. Two models, not mutually exclusive, may
explain the association:
1. The ectopic position of the testis directly or indirectly
increases the risk of testicular cancer.
2. Cryptorchidism and testicular cancer share intrauterine and/
or genetic causes.
We reported recently that surgical treatment of undescended
testis before puberty decreases the risk of testicular cancer among
cryptorchid men from 5-fold to 2-fold.1 Although challenged by a
similar analysis of Danish data,2 our results suggested that the ec-
topic position of the testis at puberty is a factor in the development
of testicular cancer. A further clue to the role of cryptorchidism in
testicular carcinogenesis may be found by studying whether the
increased risk among cryptorchid men is confined to the unde-
scended testis, or if the contralateral descended testis is also at
increased risk of cancer development. Similar risks in the 2 testes
would strongly argue in favor of a major role of shared risk factors
between testicular cancer and cryptorchidism. In this meta-analy-
sis, we pooled the data from previous studies on unilateral cryp-
torchidism, to evaluate the risk of testicular cancer separately in
the ipsilateral and the contralateral testis. To our knowledge, no
such analysis has been undertaken before.
Material and methods
We searched the literature for all analytical studies reporting on
the association between cryptorchidism and testicular cancer with
specific information for the ipsilateral and contralateral testis.
First, we used specific search terms to identify relevant articles,
but no study presenting data on this issue was focusing primarily
on laterality, and the separate studies all had few exposed subjects
to compare. Data on laterality of maldescent and tumor are rarely
presented as main results in the abstracts, and some studies pro-
vide merely the absolute number of subjects with ipsilateral and
contralateral tumor unaccompanied by a relative risk (RR). There-
fore, a structured search gave much poorer results than did manual
Publication of the International Union Against Cancer
scrutiny of a general search of all articles on risk factors for testic-
ular cancer. To increase the sensitivity of the search, we also
checked all studies that were cited in the relevant articles we
found. Eventually, we identified 12 studies, 11 case-controls stud-
ies3–13 and 1 cohort study,14 with data on laterality of both the
maldescent and the tumor (Table I). Two other studies were
excluded: the study by Stone et al.15 because of lack of control
group and that of Swerdlow et al.16 because of lacking informa-
tion about the number of bilaterally undescended testes among
controls.
Only a few of the included studies provided a laterality-specific
RR estimate, and we therefore calculated a crude odds ratio (OR)
with 95% confidence interval (CI) for all case-control studies. To
do so, we extracted the number of cases and controls with unilat-
eral cryptorchidism, and the number of ipsilateral and contralateral
tumors among the cases. Since risk has to be estimated per testis
rather than per subject, the controls with undescended testis were
divided into 2 equally sized groups for the separate calculation of
risk in the ipsilateral and contralateral testis. Our estimated crude
ORs were essentially the same as the adjusted estimates given in
the articles that presented such estimates. We calculated pooled
estimates and 95% CIs for the RRs using fixed-effects meta-analy-
sis implemented in the STATA1 software. We provisionally cal-
culated separate pooled estimates for studies that used prospective
exposure data either as the primary source of information or to
validate questionnaire information,3,9,11,13,14 and those that relied
exclusively on questionnaire data.4–8,10,12 Heterogeneity was
assessed through the i2 statistics.17 Statistical significance was set
at the 5% level. All reported p values are 2-tailed.
Results
The total number of cases with unilateral cryptorchidism and
known laterality of both the maldescent and the tumor was 199, of
which 158 (79%) had an ipsilateral, and 41 (21%) a contralateral
tumor (Table I). The pooled RRs for testicular cancer in the ipsi-
lateral and contralateral testis were 6.33 (95% CI, 4.30 to 9.31)
and 1.74 (95% CI, 1.01 to 2.98), respectively (Fig. 1 and 2). The i2
was close to 0% in both analyses, indicating a lack of heterogene-
ity between studies. None of the studies provided information
about the specific distribution of histologic types of cancers occur-
ring ipsilaterally or contralaterally.
To assess the importance of the reliability of exposure data, we
dichotomized the studies into those with prospective and nonpro-
spective exposure information and ran stratified analysis. We
found no heterogeneity between the 2 groups of studies in those
analyses; the pooled ORs for ipsilateral cancer were 6.10 and 6.56
(p for homogeneity, 0.94) for studies with prospective and nonpro-
spective data, respectively. In the analysis of contralateral tumors,
Grant sponsor: UICC Yamagiwa-Yoshida Memorial International Can-
cer Study Grant.
*Correspondence to: Servizio di Epidemiologia dei Tumori, V Santena
7, Torino 10126, Italy. Fax: 139-011-633-4664. E-mail: olof.akre@ki.se
Received 19 June 2008; Accepted after revision 6 August 2008
DOI 10.1002/ijc.23936
Published online 30 October 2008 in Wiley InterScience (www.interscience.
wiley.com).
688 AKRE ET AL.

TABLE I – PRESENTATION OF THE STUDIES INCLUDED IN THE META-ANALYSIS. THE DATA IS RESTRICTED
TO CASES AND CONTROLS WITH UNILATERALLY UNDESCENDED TESTIS

Study Year Country Ipsilateral cases Contralateral cases Noncryptorchid Cryptorchid Noncryptorchid
cases controls controls

Case-control studies
Morrison3 1976 USA 12 2 579 2 600
Henderson et al.4 1979 USA 8 1 70 2 77
Schottenfeld et al.5 1980 USA 15 4 135 12 266
Coldman et al.6 1982 Canada 11 1 81 0 90
Pottern et al.7 1985 USA 13 2 246 7 252
Strader et al.8 1988 USA 22 5 286 10 658
UK TC study group9 1994 UK 34 12 729 17 777
Møller et al.10 1996 Denmark 14 7 401 6 599
Prener et al.11 1996 Denmark 6 5 155 10 335
Stang et al.12 2001 Germany 8 0 216 8 741
Herrinton et al.13 2003 USA 11 1 171 8 543
Cohort study Observed/expected Observed/expected
Swerdlow et al.14 1997 UK 4/0.47 1/0.48

FIGURE 1 – Forest plot of the relative risk of testicular cancer in the FIGURE 2 – Forest plot of the relative risk of testicular cancer in the
ipsilateral testis among men with unilaterally undescended testis. contralateral testis among men with unilaterally undescended testis.

the corresponding ORs were 1.80 and 1.68 (p for homogeneity,
0.74), respectively.
Discussion
The combined data suggest that in unilateral cryptorchidism,
the risk of testicular cancer is highest in the undescended testis,
but also significantly elevated in the contralateral testis. Our inter-
pretation is that the mechanism behind the association between
cryptorchidism and testicular cancer is mediated through both a
local effect on the ectopic testis, and a systemic effect affecting
both sides may be either prenatal or postnatal.
At least 3 biases exist in these data. First, 7 of the 12 studies
collected exposure data from questionnaires, thus relying on the
knowledge and memory of the study subjects. Among case
patients afflicted by testicular cancer, it might be hard to remember
on which side they were treated for cryptorchidism, and possibly
cancer patients may be prone to believe that the undescended testis
was on the same side as the tumor, thus causing a bias that inflates
the association for the ipsilateral testis and dilutes the one on the
contralateral side. However, we found no difference in the esti-
mates when we stratified the analysis by quality of exposure data.
Second, while right-sided germ-cell tumors are slightly more
common than left-sided (53% vs. 47%),15 maldescent occurs more
often on the left side.14 This correlation between sidedness of the
2 conditions should introduce some confounding by laterality that
bias the estimates toward a stronger positive association on the
contralateral side. However, the differences in prevalences of
tumor and maldescent between the 2 testes are small, and there-
fore the confounding potential of laterality is limited.
Third, we calculated crude estimates for the RRs using data
from some matched case-control studies, thus potentially using bi-
ased crude estimates for the pooled analyses. For the individual
studies that provided an adjusted estimate, we found reassuring
similarities with our estimates, but for those who did not, we had
no other choice than using potentially biased estimates. The bias
is, however, likely to be minor, and should make cases and con-
trols more equal and thus cause bias toward the null.
The 74% increased risk in the contralateral testis was borderline
significant and even a weak bias could affect the estimate enough to
change the interpretation to a possible null finding. However, the
more than 6-fold increase on the ipsilateral side is robust and highly
unlikely explained by bias. It could then also be concluded that the
difference between the sides is robust as well, suggesting a carcino-
genic effect related to the ectopic location of the testis per se.
We conclude from this systematic review that in unilateral cryp-
torchidism, the risk of testicular cancer may be increased on both
sides, although to a much greater extent on the ipsilateral side.
The results indicate that both the ectopic position of the testis and
shared risk factors are involved in the mechanism behind the asso-
ciation between cryptorchidism and testicular cancer.
Acknowledgements
Mr. Olof Akre is supported by the Stockholm County Council
and Karolinska Institutet, Stockholm. Mr. Lorenzo Richard is
 RISK OF CONTRALATERAL TESTICULAR CANCER
supported by the Italian Association for Cancer Research
(AIRC) and the Compagnia San Paolo/Fondazione Internazio-
nale in Medicina Sperimentale (FIRMS). The funding bodies
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