[CANCER
RESEARCH
45, 5145-5150,
October 1985]
Lesions of the Rete Testis in Mice Exposed Prenatally to Diethylstilbestrol
Retha R. Newbold,1 Bill C. Bullock, and John A. McLachlan
Developmental Endocrinology and Pharmacology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute ol Environmental Health Sciences,
NIH, Research Triangle Park, North Carolina 27709 [Fi. R. N., J. A. M.], and Bowman Gray School of Medicine, Wake Forest University, Winston-Salem,
North Carolina 27103 [B. C. B.¡
ABSTRACT
Adenocarcinoma of the rete testis is an exceptionally rare and
malignant testicular neoplasm. Although treatment of pregnant
women with diethylstilbestrol (DES) results in reproductive tract
abnormalities in their male offspring, increased incidence of
testicular tumors has not been verified. However, recently three
cases of seminoma have been described in men prenatally
exposed to DES, suggesting an association of prenatal DES
treatment and the subsequent development of testicular tumors.
This report describes the treatment of outbred pregnant CD-1
mice with DES (100 M9/kg) on Days 9 through 16 of gestation
and its effects on their male offspring. In addition to nonmalignant
abnormalities such as retained testes which have been reported
in men exposed prenatally to DES, lesions resembling adenocarcinoma of the rete testis were seen in prenatally DES-treated
mice at 10 to 18 mo of age (11 of 233; 5%). No comparable
lesions were seen in 96 age-matched control male mice. These
results suggest an association of prenatal DES exposure and
the subsequent development of testicular lesions in the rete
testis of mice.
INTRODUCTION
Work in our laboratory has established that the mesonephric
duct, as well as the Müllerianduct, is a target for DES2 (1, 2). In
fact, in adult female mice (2) and humans3 exposed prenatally to
DES, hyperplastic mesonephric remnants are a common feature.
The relationship of these dysmorphogenic mesonephric struc
tures to the pathogenesis of hyperplastic or neoplastic disease
in the female is under study. These findings raise the possibility
that structures derived from the mesonephric ducts or tubules
may also be dysplastic in male offspring. Although the embryol
ogy of the rete testis is still controversial, Byskov (3,4) attributes
the rete system to mesonephric tubular origin. Thus, the rete
testis, a clearly definable adult structure apparently derived from
mesonephric tubules, was evaluated for hyperplastic or neoplas
tic changes in male CD-1 mice exposed prenatally to DES.
Adenocarcinoma of the rete testis is a rare form of neoplasia
arising from the lining cells of the channels connecting the
seminiferous tubules of the testis and the epididymis. The first
report of a rete testis tumor in humans was made by Curling in
1853 (5). In a review of the subject, Schoen and Rush in 1959
(6) found only 12 cases described in the literature to which they
added one of their own. A more recent summary of the entire
clinical literature estimates 21 adenocarcinomas of the rete testis
1To whom requests for reprints should be addressed.
2The abbreviation used is: DES, diethylstilbestrol.
3A. F. Haney, R. R. Newbold, B. F. Fetter, and J. A. McLachlan. Hyperplastic
paraovarian cysts associated with prenatal diethylstilbestrol
for publication.
Received 1/15/85; revised 6/25/85; accepted 6/27/85.
exposure, submitted
occurring in humans (7).
In animals, spontaneous adenocarcinoma of the rete testis is
also extremely rare; one case was reported in a ram (8), and
another in the rodent, Mastomys (9). In a recent report of
spontaneous tumors of the mouse testis, Yoshitomi and Morii
(7) described one case of rete testis adenocarcinoma in 500
aged mice examined.
Previous studies from this laboratory and others have de
scribed some testicular tumors, mainly interstitial cell tumors, in
prenatally DES-exposed male mice (1, 10, 11). Likewise, a few
recent case reports have appeared, suggesting an association
between prenatal DES exposure and the subsequent develop
ment of testicular seminoma in men (12, 13). In this paper, we
describe a high prevalence of lesions in the rete testis of mice
exposed prenatally to DES.
MATERIALS AND METHODS
Animals and Treatment Schedule. Outbred CD-1 mice were obtained
from Charles River Breeding Laboratories, Inc., Wilmington, MA, and
were bred to male mice of the same strain in the animal facility at the
National Institute of Environmental Health Sciences. The time of vaginal
plug detection was considered Day 0 of pregnancy. Pregnant mice were
housed separately in a room with controlled temperature (21-22°C) and
lighting (14-h light and 10-h dark periods) and were provided with
hardwood chip bedding, fresh water, and NIH 31 laboratory mouse chow
ad libitum.
Pregnant female mice were untreated or given s.c. injections of DES
(Sigma Chemical Co., St. Louis, MO) dissolved in corn oil on Days 9 to
16 of gestation. The daily dose of DES was 100 Mg/kg body weight, and
the total volume of corn oil administered was 0.01 ml/g maternal body
weight. The offspring of these animals are referred to as DES-100 or
controls in this study. Purity of the DES was checked by thin-layer
chromatography, high-pressure liquid chromatography, and gas chromatography-mass spectrometry and exceeded 99%.
Pregnant mice delivered their young on Day 19 of gestation, and all
litter sizes were randomly standardized to 8. At 25 days of age, offspring
were weaned, segregated by gender, and housed in groups of 5/cage.
At 10 to 18 mo of age, 122 control and 277 DES-100 male offspring
were sacrificed by cervical dislocation. The abdominal cavity was quickly
opened, and gross structural abnormalities in the reproductive tract
including location of testes were observed. Testes and epididymis were
removed, fixed in 10% neutral buffered formalin, and embedded in
paraffin, and 20 serial 6-nm sections of each testis were made. Sections
were stained with hematoxylin and eosin and evaluated. In some cases,
paraffin sections were stained by the periodic acid-Schiff reaction. This
paper describes only the animals in which the rete testis could be
evaluated which are as follows: 10 mo (4 control and 31 DES-100); 11
mo (11 DES-100); 12 mo (9 DES-100); 13 mo (18 controls and 21 DES100); 14 mo (8 controls and 49 DES-100); 15 mo (23 controls and 52
DES-100) 16 mo (14 controls and 18 DES-100); 17 mo (12 controls and
8 DES-100); and 18 mo (17 controls and 34 DES-100). The results were
analyzed statistically using the Fisher exact test, and the limit of signifi
cance was set at 5%.
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LESIONS OF THE RETE TESTIS
RESULTS
Histology of the Normal Rete TestÃ-s.The excretory ducts of
the testis in mice include the rete testis, efferent ducts, epididymis, and ductus deferens. Near the hilus of the testis within the
tunica, the seminiferous tubules become straight and are gath
ered into a network of anastomosing canals, the rete. The rete
testis is lined with a simple low cuboidal or flat epithelium resting
on a basement membrane (Fig. 1). The network of irregular,
broad-lumened canals of the rete opens into a single lacuna
which, outside the tunica albugÃ-nea,branches into the efferent
ducts. Spermatozoa and secretions are transported from the
seminiferous tubules to the rete and then the efferent ducts
which, in turn, carry the secretions toward the head of the
epididymis. In this study, the rete testis of 10- to 18-mo-old
Table 1
flefe fesf/s lesions in male mice exposed prenatally to diethylstilbestrol
Males were 10- to 18-mo-old offspring of CD-1 mice treated with DES (100 ^g/
kg s.c.) on Days 9-16 of gestation. Since there was not a statistically significant
difference in prevalence of lesions with age, rete testis hyperplasia and lesions
resembling adenocarcinoma in each age group have been combined.
Hyperplasia
Adenocardnoma-like
lesion
Control
23/96(24)"
DES-100
130/233(56)"
0/96(0)
11/233(5)c
Numbers in parentheses, percentages.
" Statistical significance of DES-exposed animals to corresponding age-matched
controls by the Fisher exact test: P < 0.0001.
CP<0.05.
A more severe lesion was also observed in these mice after in
utero exposure to DES. This lesion, resembling adenocarcinoma,
was not found in any controls but was found in 5% of the
prenatally exposed DES-100 mice (Table 1; 0 of 96 versus 11 of
233, P < 0.05). Although distant métastases could not be
documented, the lesions often infiltrated into the seminiferous
tubules or into the ductuli efferentes; the histological pattern was
suggestive of either papillary adenocarcinoma (Fig. 4) or tubolopapillary adenocarcinoma (Fig. 5a). The lesion in Fig. 5a occupied
approximately 10% of the section surface of the testis, and there
was an area of local invasion (Fig. 5b). There was increased
cellularity of the epithelium, and there were papillary or floridly
folded regions in the epithelium. The epithelial cells were mainly
cuboidal and appeared to be enlarged. There was considerable
pleomorphism of nuclei (Fig. 5c); mitotic figures were not numer
ous, but they were abnormal (Fig. 5d).
The incidence of this lesion of the rete testis which resembled
adenocarcinoma in the DES-100 males was: 1 of 31 (3%), 10
animals appeared to be normal in 75% (72 of 96) controls and
14% (32 of 233) DES-100 animals.
The abnormalities in control animals were consistent with usual
age-related changes, whereas the changes in the DES-100
animals were not.
Histology of the Rete Testis of Prenatally DES-exposed
Mice. Prenatal exposure to DES resulted in numerous changes
in the testes of all the males examined at 10 to 18 mo of age.
Ninety-one % (252 of 277 total number sacrificed) had cryptorchid testes ranging from a location directly under and firmly
attached to the kidney, to the region of the inguinal canal. The
retained testes were hypoplastic and sometimes fibrotic with
multinucleated cells in the seminiferous tubules. In some cases,
the testes were necrotic with just scar tissue remaining. Abnor
malities including tumors of the corpus testis are described in
another report.4
mo; 1 of 21 (8%), 13 mo; 4 of 49 (8%), 14 mo; 1 of 52 (2%), 15
mo; 1 of 18 (6%), 16 mo; and 3 of 34 (9%), 18 mo. The median
age of this lesion was 14 mo. Data on rete testis hyperplasia
and the more severe lesions have been combined among ages
in Table 1.
This paper concerns only the animals in which the rete could
be evaluated (96 controls and 233 DES-100). In this group,
inflammatory changes in the rete testis were observed in one
14-mo control (1%) and 5 DES-100 animals (2%) at 10 mo and
15 mo of age (1 of 96 versus 5 of 233, not significantly different).
Dilated rete was seen in one 18-mo control (1%) and 5 DES-100
(2%) at 15 and 18 mo of age (1 of 96 versus 5 of 233, not
significantly different). Two of the five DES-100 animals with
DISCUSSION
dilated rete also had inflammation.
The rete testis of a control 10-mo-old male mouse is repre
Adenocarcinoma of the rete testis in humans and experimental
animals is so rare that it is difficult to estimate how many
authentic cases exist. Moreover, investigators disagree on di
agnostic criteria, site of origin, and the designation that should
be applied to the tumors. Criteria were first formulated in 1945
by Feek and Hunter (14) and later by others (6,15-17) and have
sented in Fig. 1. Tubules of the rete are lined by cuboidal or flat
epithelium. Mild focal hyperplasia of the rete testis was seen in
23 of 96 (24%) control males in this study.
Various degrees of hyperplasia of the rete testis were found
among 130 of 233 (56%) DES-100 animals (23 of 96 versus 130
of 233, P < 0.0001) (Table 1). The simplest form of this DESinduced lesion consisted of knob-like proliferation of cuboidal
epithelium (Fig. 2) and diffuse hyperplasia of the epithelium (Fig.
3). In other animals, these proliferative overgrowths formed
papillary structures consisting of small cuboidal cells with in
creased hyperchromatism and vacuolated cells over a vascular
core. The distribution of rete testis hyperplasia between ages in
the DES-100 males was as follows: 21 of 31 (68%), 10 mo; 9 of
11 (82%), 11 mo; 9 of 9 (100%), 12 mo; 12 of 21 (57%), 13 mo;
22 of 49 (45%), 14 mo; 22 of 52 (42%), 15 mo; 11 of 18 (61%),
16 mo; 6 of 8 (75%), 17 mo; and 18 of 34 (53%), 18 mo. Papillary
proliferation was not observed in any control animals.
been accepted by most investigators as the basis for identifying
this neoplasm. Shillitoe (16) emphasized that these criteria were
not absolute, but they formed significant guidelines in making
the diagnosis. In summary, the diagnostic criteria of tumor of the
rete testis were: (a) involvement centering on the mediastinum
testis rather than the testis proper; (b) lack of direct extension
through the parietal tunica; (c) transition from normal epithelial
structures to neoplastic structures in the rete testis; (d) no
evidence of teratoma; and (e) lack of any other primary tumor.
In the affected mice described in this paper, lesions were seen
in the area of the mediastinum testis. There was maximum
involvement of the rete but minimal involvement of the corpus.
Cells also appeared to be transformed from the normal epithelial
structures of the rete testis to abnormal areas. Although certain
strains of mice frequently show teratomatous changes (18) and
4 R. R. Newbold, B. C. Bullock, and J. A. McLachlan. Testicular tumors in mice
exposed in utero to diethylstilbestrol,
submitted for publication.
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LESIONS OF THE RETE TESTIS
for higher prevalence of rete abnormalities, since 4 of the 11
mice with the lesion had spermatogenesis occurring in the same
testis.
To date, there have been no reports of rete hyperplasia or
adenocarcinoma in men that have been attributed to prenatal
exposure to DES, but three cases of seminoma have been
described in prenatal DES-exposed men, suggesting an associ
ation of such treatment and the subsequent development of
testicular tumors (12, 13). Since Yoshitomi and Morii (7) report
that rete adenocarcinoma can be misdiagnosed as seminoma
and since established criteria state seminoma must be ruled out
before a diagnosis of rete adenocarcinoma can be made, caution
should be taken when examining the testicular lesions associated
with prenatal DES exposure.
Although animal studies must be considered thoughtfully if
extrapolation to humans is to follow, the prenatal mouse model
has provided some interesting comparisons to similarly DES-
since Ewing (19) believed that teratocarcinomas originated in the
rete testis, we examined all of the tumors for evidence of
teratocarcinoma, but no neural elements, muscle, cartilage,
bone, or other components of teratomas were found. Thus, the
tumors described in this paper conform closely to the criteria
established for rete adenocarcinoma.
The demonstration of an extremely rare lesion described in
this paper is unique in its prevalence alone, since it appears in
5% of the prenatal DES animals. Recently, Yoshitomi and Morii
(7) have reported the spontaneous occurrence of a rete adeno
carcinoma in a 23-mo-old mouse from a colony of 500 mice
(0.2% incidence). Therefore, our data suggest prenatal exposure
to DES results in at least a 20-fold increase in prevalence of
adenocarcinoma-like lesions. In fact, if these prenatal DES males
were allowed to age past 18 mo, they might have a higher
incidence of abnormalities of the rete.
The embryology of the rete testis is still controversial. In
addition to a mesonephric tubular origin (3, 4), the coelomic
epithelium has also been suggested as a precursor for the
gonadal rete system (20, 21). This is important because coelmic
epithelium also gives rise to the uterus which is also a target for
DES dysmorphogenesis and carcinogenesis. Results such as
lesions of the rete testis described in this paper may help
determine the embryological origin of this poorly understood
tissue compartment.
Since 1943 (22), the induction of interstitial cell tumors in adult
mice with DES has been well studied; however, no studies of
estrogen-treated adult mice (23) have reported abnormalities of
the rete. The increased incidence of lesions in the rete testis
reported in this paper thus suggests this lesion may be associ
ated with developmental exposure to DES. In addition, early
exposure in development may be important, since no reports of
this lesion have been made in other rodent models treated
neonatally with DES or other estrogenic substances (24-27). An
exposed women such as reduced reproductive capacity (34),
uterine structural malformations (35), malformed oviduct (2, 36),
and salpingitis isthmica nodosa of the oviduct (2, 37). Moreover,
in our earlier report on DES-exposed male mice, we suggested
cryptorchid testes and epididymal cysts might be a common
finding in exposed humans (10). Therefore, experimental results
can be informative and predictive. Hence, continued close sur
veillance would seem prudent, especially in view of the young
age of the exposed men and the high incidence of cryptorchidism
and hydrocele in the DES-exposed patients.
ACKNOWLEDGMENTS
The authors wish to thank James Mangum, Pat Monahan. Iris Wagman, Glen
Ballard,and Curtis Woods for technicalassistance;the NIEHSHistologyLaboratory
for their assistance in preparing slides; and Anna Lee Howard for typing the
manuscript.Also the authors are indebtedto Dr. Beth Gladenfor statistical analysis.
increased prevalence of a rare tumor, vaginal adenocarcinoma,
called attention to the adverse effects on female offspring of
women given DES while pregnant. The occurrence of rete testis
tumors in male offspring of mice given DES during pregnancy
suggests this may be an analogous situation, as naturally occur
ring rete testis lesions are extremely rare among mice.
Among men, there does not appear to be a strong age-related
factor associated with carcinoma of the rete testis, the reported
age range being 20 to 80 yr, and tumors were reported almost
equally divided between right and left side with one patient having
bilateral tumors (28). Likewise, in the present study, there was
no association between ages 10 to 18 mo of the male mouse
and prevalence of rete testis lesions. In humans, the tumors
usually were present as a testicular mass often associated with
a hydrocele (29). It is of special interest that, in the group of
human cases that have been reported, there are at least three
tumors in maldescended testes (30-32), one of which had been
placed in the scrotum by orchiopexy 10 yr previously. Cryptorchidism has been implicated as a predisposing factor for testic
ular neoplasms (33). The high incidence of retained testes in
mice (92%) following prenatal DES exposure in the present study
and the occurrence of this specific rare form of testicular abnor
mality, rete tumors, also raise the possibility of an association
between cryptorchidism, prenatal DES exposure, and rete testis
cancer. Although cryptorchidism results in decreased or lack of
spermatogenesis in male mice, inactivity cannot solely account
CANCER
RESEARCH
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Fig. 1. Normal rete testis, 10-mo-old control CD-1 mouse. Irregular tubules of the rete (R) are located at the mediastinum of the testis. The channels of the rete are
lined by cuboidal or flat epithelium. H & E, x 25.
Fig. 2. Focal hyperplasia of the epithelium of rete testis (fl) from a 15-mo-old prenatally DES-exposed mouse. There is simple knob-like proliferation of cuboidal cells
that have a tendency to pile up. H & E, x 25.
Fig. 3. Diffuse hyperplasia of the epithelium of the rete testis from a 14-mo-old prenatally DES-exposed mouse. The rete joins the efferent ducts at the fop of the
photomicrograph. H & E, x 25.
Fig. 4. Lesion resembling papillary adenocarcinoma from a 13-mo-old prenatally DES-treated mouse. The rete is largely filled by papillary projections covered by
pleomorphic epithelium. H & E, x 25.
Fig. 5. a, lesion of the rete testis from a 16-mo-old prenatally DES-treated mouse. While the papillary pattern is focally apparent, the majority of the tumor has a
tubular arrangement of pleomorphic epithelial cells. Rete epithelium in channels at the bottom of the photomicrograph is hyperplastic. This tumor occupies approximately
10% of the section surface of the testis. H & E, x 25. b, higher magnification of the lesion, suggestive of tubulopapillary adenocarcinoma in Fig. 5a; there is an area of
local invasion (arrow). H & E, x 60. c, higher magnification of the lesion in Fig. 5a; marked pleomorphism with bizarre nuclei (arrow). H & E, x 60. d, higher magnification
of the lesion in Fig. 5a; mitotic figures are not numerous, but they are abnormal (arrow). H & E, x 60.
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LESIONS OF THE RETE TESTIS
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1985
5150
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1985 American Association for Cancer Research.
Lesions of the Rete Testis in Mice Exposed Prenatally to
Diethylstilbestrol
Retha R. Newbold, Bill C. Bullock and John A. McLachlan
Cancer Res 1985;45:5145-5150.
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Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1985 American Association for Cancer Research.