[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 andmalignant testicular neoplasm. Although treatment of pregnantwomen with diethylstilbestrol (DES) results in reproductive tractabnormalities in their male offspring, increased incidence oftesticular tumors has not been verified. However, recently threecases of seminoma have been described in men prenatallyexposed to DES, suggesting an association of prenatal DEStreatment 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 gestationand its effects on their male offspring. In addition to nonmalignantabnormalities such as retained testes which have been reportedin men exposed prenatally to DES, lesions resembling adeno-carcinoma of the rete testis were seen in prenatally DES-treated

mice at 10 to 18 mo of age (11 of 233; 5%). No comparablelesions were seen in 96 age-matched control male mice. These

results suggest an association of prenatal DES exposure andthe subsequent development of testicular lesions in the retetestis of mice.

INTRODUCTION

Work in our laboratory has established that the mesonephricduct, as well as the Müllerianduct, is a target for DES2 (1, 2). Infact, in adult female mice (2) and humans3 exposed prenatally to

DES, hyperplastic mesonephric remnants are a common feature.The relationship of these dysmorphogenic mesonephric structures to the pathogenesis of hyperplastic or neoplastic diseasein the female is under study. These findings raise the possibilitythat structures derived from the mesonephric ducts or tubulesmay also be dysplastic in male offspring. Although the embryology of the rete testis is still controversial, Byskov (3,4) attributesthe rete system to mesonephric tubular origin. Thus, the retetestis, a clearly definable adult structure apparently derived frommesonephric tubules, was evaluated for hyperplastic or neoplastic changes in male CD-1 mice exposed prenatally to DES.

Adenocarcinoma of the rete testis is a rare form of neoplasiaarising from the lining cells of the channels connecting theseminiferous tubules of the testis and the epididymis. The firstreport of a rete testis tumor in humans was made by Curling in1853 (5). In a review of the subject, Schoen and Rush in 1959(6) found only 12 cases described in the literature to which theyadded one of their own. A more recent summary of the entireclinical 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 exposure, submittedfor publication.

Received 1/15/85; revised 6/25/85; accepted 6/27/85.

occurring in humans (7).In animals, spontaneous adenocarcinoma of the rete testis is

also extremely rare; one case was reported in a ram (8), andanother in the rodent, Mastomys (9). In a recent report ofspontaneous tumors of the mouse testis, Yoshitomi and Morii(7) described one case of rete testis adenocarcinoma in 500aged mice examined.

Previous studies from this laboratory and others have described some testicular tumors, mainly interstitial cell tumors, inprenatally DES-exposed male mice (1, 10, 11). Likewise, a few

recent case reports have appeared, suggesting an associationbetween prenatal DES exposure and the subsequent development of testicular seminoma in men (12, 13). In this paper, wedescribe a high prevalence of lesions in the rete testis of miceexposed prenatally to DES.

MATERIALS AND METHODS

Animals and Treatment Schedule. Outbred CD-1 mice were obtained

from Charles River Breeding Laboratories, Inc., Wilmington, MA, andwere bred to male mice of the same strain in the animal facility at theNational Institute of Environmental Health Sciences. The time of vaginalplug detection was considered Day 0 of pregnancy. Pregnant mice werehoused 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 chowad 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 to16 of gestation. The daily dose of DES was 100 Mg/kg body weight, andthe total volume of corn oil administered was 0.01 ml/g maternal bodyweight. The offspring of these animals are referred to as DES-100 orcontrols in this study. Purity of the DES was checked by thin-layerchromatography, high-pressure liquid chromatography, and gas chro-matography-mass spectrometry and exceeded 99%.

Pregnant mice delivered their young on Day 19 of gestation, and alllitter sizes were randomly standardized to 8. At 25 days of age, offspringwere 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 quicklyopened, and gross structural abnormalities in the reproductive tractincluding location of testes were observed. Testes and epididymis wereremoved, fixed in 10% neutral buffered formalin, and embedded inparaffin, 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 beevaluated which are as follows: 10 mo (4 control and 31 DES-100); 11mo (11 DES-100); 12 mo (9 DES-100); 13 mo (18 controls and 21 DES-100); 14 mo (8 controls and 49 DES-100); 15 mo (23 controls and 52DES-100) 16 mo (14 controls and 18 DES-100); 17 mo (12 controls and8 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 significance was set at 5%.

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RESULTS

Histology of the Normal Rete Testís.The excretory ducts ofthe testis in mice include the rete testis, efferent ducts, epididy-

mis, and ductus deferens. Near the hilus of the testis within thetunica, the seminiferous tubules become straight and are gathered into a network of anastomosing canals, the rete. The retetestis is lined with a simple low cuboidal or flat epithelium restingon a basement membrane (Fig. 1). The network of irregular,broad-lumened canals of the rete opens into a single lacuna

which, outside the tunica albugínea,branches into the efferentducts. Spermatozoa and secretions are transported from theseminiferous tubules to the rete and then the efferent ductswhich, in turn, carry the secretions toward the head of theepididymis. In this study, the rete testis of 10- to 18-mo-old

animals appeared to be normal in 75% (72 of 96) controls and14% (32 of 233) DES-100 animals.

The abnormalities in control animals were consistent with usualage-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 changesin the testes of all the males examined at 10 to 18 mo of age.Ninety-one % (252 of 277 total number sacrificed) had cryptor-

chid testes ranging from a location directly under and firmlyattached to the kidney, to the region of the inguinal canal. Theretained testes were hypoplastic and sometimes fibrotic withmultinucleated cells in the seminiferous tubules. In some cases,the testes were necrotic with just scar tissue remaining. Abnormalities including tumors of the corpus testis are described inanother report.4

This paper concerns only the animals in which the rete couldbe evaluated (96 controls and 233 DES-100). In this group,

inflammatory changes in the rete testis were observed in one14-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, notsignificantly different). Two of the five DES-100 animals with

dilated rete also had inflammation.The rete testis of a control 10-mo-old male mouse is repre

sented in Fig. 1. Tubules of the rete are lined by cuboidal or flatepithelium. Mild focal hyperplasia of the rete testis was seen in23 of 96 (24%) control males in this study.

Various degrees of hyperplasia of the rete testis were foundamong 130 of 233 (56%) DES-100 animals (23 of 96 versus 130of 233, P < 0.0001) (Table 1). The simplest form of this DES-induced 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 formedpapillary structures consisting of small cuboidal cells with increased hyperchromatism and vacuolated cells over a vascularcore. The distribution of rete testis hyperplasia between ages inthe DES-100 males was as follows: 21 of 31 (68%), 10 mo; 9 of11 (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. Papillaryproliferation was not observed in any control animals.

4R. R. Newbold, B. C. Bullock, and J. A. McLachlan. Testicular tumors in mice

exposed in utero to diethylstilbestrol, submitted for publication.

Table 1

flefe fesf/s lesions in male mice exposed prenatally to diethylstilbestrolMales 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 significantdifference in prevalence of lesions with age, rete testis hyperplasia and lesionsresembling adenocarcinoma in each age group have been combined.

Control DES-100

Hyperplasia

Adenocardnoma-like lesion

23/96(24)" 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 inutero exposure to DES. This lesion, resembling adenocarcinoma,was not found in any controls but was found in 5% of theprenatally exposed DES-100 mice (Table 1; 0 of 96 versus 11 of

233, P < 0.05). Although distant métastases could not bedocumented, the lesions often infiltrated into the seminiferoustubules or into the ductuli efferentes; the histological pattern wassuggestive of either papillary adenocarcinoma (Fig. 4) or tubolo-papillary adenocarcinoma (Fig. 5a). The lesion in Fig. 5a occupiedapproximately 10% of the section surface of the testis, and therewas an area of local invasion (Fig. 5b). There was increasedcellularity of the epithelium, and there were papillary or floridlyfolded regions in the epithelium. The epithelial cells were mainlycuboidal and appeared to be enlarged. There was considerablepleomorphism of nuclei (Fig. 5c); mitotic figures were not numerous, but they were abnormal (Fig. 5d).

The incidence of this lesion of the rete testis which resembledadenocarcinoma in the DES-100 males was: 1 of 31 (3%), 10

mo; 1 of 21 (8%), 13 mo; 4 of 49 (8%), 14 mo; 1 of 52 (2%), 15mo; 1 of 18 (6%), 16 mo; and 3 of 34 (9%), 18 mo. The medianage of this lesion was 14 mo. Data on rete testis hyperplasiaand the more severe lesions have been combined among agesin Table 1.

DISCUSSION

Adenocarcinoma of the rete testis in humans and experimentalanimals is so rare that it is difficult to estimate how manyauthentic cases exist. Moreover, investigators disagree on diagnostic criteria, site of origin, and the designation that shouldbe applied to the tumors. Criteria were first formulated in 1945by Feek and Hunter (14) and later by others (6,15-17) and have

been accepted by most investigators as the basis for identifyingthis neoplasm. Shillitoe (16) emphasized that these criteria werenot absolute, but they formed significant guidelines in makingthe diagnosis. In summary, the diagnostic criteria of tumor of therete testis were: (a) involvement centering on the mediastinumtestis rather than the testis proper; (b) lack of direct extensionthrough the parietal tunica; (c) transition from normal epithelialstructures to neoplastic structures in the rete testis; (d) noevidence of teratoma; and (e) lack of any other primary tumor.

In the affected mice described in this paper, lesions were seenin the area of the mediastinum testis. There was maximuminvolvement of the rete but minimal involvement of the corpus.Cells also appeared to be transformed from the normal epithelialstructures of the rete testis to abnormal areas. Although certainstrains of mice frequently show teratomatous changes (18) and

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since Ewing (19) believed that teratocarcinomas originated in therete testis, we examined all of the tumors for evidence ofteratocarcinoma, but no neural elements, muscle, cartilage,bone, or other components of teratomas were found. Thus, thetumors described in this paper conform closely to the criteriaestablished for rete adenocarcinoma.

The demonstration of an extremely rare lesion described inthis paper is unique in its prevalence alone, since it appears in5% of the prenatal DES animals. Recently, Yoshitomi and Morii(7) have reported the spontaneous occurrence of a rete adenocarcinoma in a 23-mo-old mouse from a colony of 500 mice

(0.2% incidence). Therefore, our data suggest prenatal exposureto DES results in at least a 20-fold increase in prevalence ofadenocarcinoma-like lesions. In fact, if these prenatal DES males

were allowed to age past 18 mo, they might have a higherincidence of abnormalities of the rete.

The embryology of the rete testis is still controversial. Inaddition to a mesonephric tubular origin (3, 4), the coelomicepithelium has also been suggested as a precursor for thegonadal rete system (20, 21). This is important because coelmicepithelium also gives rise to the uterus which is also a target forDES dysmorphogenesis and carcinogenesis. Results such aslesions of the rete testis described in this paper may helpdetermine the embryological origin of this poorly understoodtissue compartment.

Since 1943 (22), the induction of interstitial cell tumors in adultmice with DES has been well studied; however, no studies ofestrogen-treated adult mice (23) have reported abnormalities of

the rete. The increased incidence of lesions in the rete testisreported in this paper thus suggests this lesion may be associated with developmental exposure to DES. In addition, earlyexposure in development may be important, since no reports ofthis lesion have been made in other rodent models treatedneonatally with DES or other estrogenic substances (24-27). An

increased prevalence of a rare tumor, vaginal adenocarcinoma,called attention to the adverse effects on female offspring ofwomen given DES while pregnant. The occurrence of rete testistumors in male offspring of mice given DES during pregnancysuggests this may be an analogous situation, as naturally occurring 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 reportedage range being 20 to 80 yr, and tumors were reported almostequally divided between right and left side with one patient havingbilateral tumors (28). Likewise, in the present study, there wasno association between ages 10 to 18 mo of the male mouseand prevalence of rete testis lesions. In humans, the tumorsusually were present as a testicular mass often associated witha hydrocele (29). It is of special interest that, in the group ofhuman cases that have been reported, there are at least threetumors in maldescended testes (30-32), one of which had beenplaced in the scrotum by orchiopexy 10 yr previously. Cryptor-

chidism has been implicated as a predisposing factor for testicular neoplasms (33). The high incidence of retained testes inmice (92%) following prenatal DES exposure in the present studyand the occurrence of this specific rare form of testicular abnormality, rete tumors, also raise the possibility of an associationbetween cryptorchidism, prenatal DES exposure, and rete testiscancer. Although cryptorchidism results in decreased or lack ofspermatogenesis in male mice, inactivity cannot solely account

for higher prevalence of rete abnormalities, since 4 of the 11mice with the lesion had spermatogenesis occurring in the sametestis.

To date, there have been no reports of rete hyperplasia oradenocarcinoma in men that have been attributed to prenatalexposure to DES, but three cases of seminoma have beendescribed in prenatal DES-exposed men, suggesting an associ

ation of such treatment and the subsequent development oftesticular tumors (12, 13). Since Yoshitomi and Morii (7) reportthat rete adenocarcinoma can be misdiagnosed as seminomaand since established criteria state seminoma must be ruled outbefore a diagnosis of rete adenocarcinoma can be made, cautionshould be taken when examining the testicular lesions associatedwith prenatal DES exposure.

Although animal studies must be considered thoughtfully ifextrapolation to humans is to follow, the prenatal mouse modelhas provided some interesting comparisons to similarly DES-

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 commonfinding in exposed humans (10). Therefore, experimental resultscan be informative and predictive. Hence, continued close surveillance would seem prudent, especially in view of the youngage of the exposed men and the high incidence of cryptorchidismand hydrocele in the DES-exposed patients.

ACKNOWLEDGMENTS

The authors wish to thank James Mangum, Pat Monahan. Iris Wagman, GlenBallard,andCurtis Woods for technicalassistance;the NIEHSHistologyLaboratoryfor their assistance in preparing slides; and Anna Lee Howard for typing themanuscript.Also the authorsare indebtedto Dr. Beth Gladenfor statistical analysis.

REFERENCES

1. McLachlan, J. A. Rodent models for perinatal exposure to diethylstilbestroland their relation to human disease in the male. In: A. L. Herbst and H. A.Bern (eds.), Developmental Effects of Diethylstilbestrol (DES) in Pregnancy,pp. 148-157. New York: Thieme-Stratton, 1981.

2. Newbold, R. R., Bullock, B. C., and McLachlan, J. A. Exposure to diethylstilbestrol during pregnancypermanentlyalters the ovary and oviduct. Biol. Rep.,28:735-744,1983.

3. Byskov, A. G. The anatomy and ultrastructure of the rete system in the fetalmouse ovary. Biol. Rep., ?9: 720-735,1978.

4. Byskov, A. G. Gonadalsex and germ cell differentiation. In: C. R. Austin andR. G. Edwards (eds.), Mechanismsof Sex Differentiationin Animalsand Man,pp. 145-164. New York: Academic Press, 1981.

5. Curling,T. B. Observationson cystic diseaseof the testicle. Med.-Chir.Trans.,36:449-457,1853.

6. Schoen,S. S., and Rush, B. F., Jr. Adenocarcinomaof the rete testes. J. Uro!.,82:356-363,1959.

7. Yoshitomi, K., and Morii, S. Benignand malignantepithelial tumors of the retetestis in mice. Vet. Pathol., 21: 300-303,1984.

8. Searson,J. E. Testicular adenocarcinomain a ram. Vet. Pathol., 17:391-393,1980.

9. Snell, K. C., and Hollander,C. F. Tumors of the testes and seminalvesicle inPraomys(Mastomys)natalensis.J. Nati. Cancer Inst., 49: 1381-1393,1972.

10. McLachlan,J. A., Newbold, R. R., and Bullock, B. C. Reproductivetract lesionsin malemiceexposed prenatallyto diethylstilbestrol.Science(Wash.DC), 190:991-992,1975.

11. Suzuki, Y., Lamb,J. C., IV,andMcLachlan,J. A. Age-dependentmorphologicalchanges in the seminal cdliculus in male mice. Anat. Embryo!., 158: 1-12,1979.

12. Contey, G. R., Sant, G. R., Ucci, A. A., and Mitcheson, H. D. Seminoma andepididymal cysts in a young man with known diethylstilbestrol exposure inutero. J. Am. Med. Assoc., 249:1325-1326,1983.

13. Gill,W. B., Schumacher,G. F. B., Bibbo, M., Straus, F. H., Ill, and Schoenberg,H. W. Association of diethylstilbestrol exposure in utero with cryptorchidism,

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testicular hypoplasia, and semen abnormalities. J. Urol., 722: 36-39,1979.14. Peek, J. D., and Hunter, W. C. Papillary carcinoma arising from rete testis.

Arch. Pathol., 40: 399-402, 1945.15. Mostofi, F. K., and Price, E. B., Jr. Tumors of the male genital system. In:

Atlas of Tumor Pathology, Second Ser., Fascicle 8, pp. 127-130. Washington,DC: Armed Forces Institute of Pathology, 1973.

16. Shillitoe, A. J. Carcinoma of the rete testes. J. Pathol. Bacteriol., 64:650-651,1952.

17. Teilum, G. Special Tumors of Ovaries and Testes and Related Extra GonadalLesions: Comparative Pathology and Histological Identification, p. 407. Philadelphia: J. B. Lippincott Co., 1971.

18. Meiser, H., Mayers, D. D., Fox, R. R., and Laird, C. W. Occurrence, pathologicalfeatures, and propagation of gonadal teratomas in inbred mice and in rabbits.Cancer Res., 30: 30-34, 1970.

19. Ewing, J. Neoplastic Diseases, pp. 863-883. Philadelphia: W. B. SaundersCompany, 1940.

20. Arey, L. B. The genital system. In: Developmental Anatomy, pp. 312-339.Philadelphia: W. B. Saunders Company, 1954.

21. Tuchmann-Duplessis, H., and Haegel, P. Illustrated Human Embryology. Organogénesis,Vol. 2, pp. 72-103. New York: Springer-Verlag, 1972.

22. Gardner, W. U. Spontaneous testicular tumors in mice. Cancer Res., 3: 757-761, 1943.

23. Huseby, R. A. Demonstration of a direct carcinogenic effect of estradici onLeydig cells of the mouse. Cancer Res., 40:1006-1013,1980.

24. Arai, Y., Mori, T., Suzuki, Y., and Bem, H. Long-tenu effects of perinatalexposure to sex steroids and diethylstilbestrol on the reproductive system ofmale mammals. Int. Rev. Cytol., 84: 235-268, 1983.

25. Boylan, E. S. Morphological and functional consequences of prenatal exposureto diethylstilbestrol in the rat. Biol. Rep., Õ9:854-863,1978.

26. Jones, L. A. Long term effects of neonatal administration of estrogen and

progesterone, alone or in combination, on male BALB/c and BALB/cf C3Hmice. Proc. Soc. Exp. Biol. Med., 765:117-122,1980.

27. Takasugi, N. Testicular damages in neonatally estrogenized adult mice. Endocrino). Jpn., 77: 277-281, 1970.

28. Schapira, H. E., and Engel, M. Adenocarcinoma of the rete testis. NY State J.Med., 72: 1283-1285, 1972.

29. Gisser, S. D., Nayak, S., Kaneko, M., and Tchertkoff, V. Adenocarcinoma ofthe rete testis: a review of the literature and presentations of a case withassociated asbestosis. Hum. Pathol., 8: 219-224,1977.

30. Dundon, C. Carcinoma of the rete testis occurring ten years after orchidopexy.Br. J. Urol., 24: 58-63, 1952.

31. Jacobellis, U., Ricco, R., and Ruotdo, G. Adenocarcinoma of the rete testis21 years after orchiopexy: case report and review of the literature. J. Urol.,725:429-431,1981.

32. Laird, R. M. Adenocarcinoma of the excretory ducts of the testicle. J. Urol.,72: 904-907,1954.

33. Henderson, B. E., Benton, B., Jing, J., Yu, M. C., and Pike, M. C. Risk factorsfor cancer of the testis in young men. Int. J. Cancer, 23: 598-602,1979.

34. McLachlan, J. A., Newbold, R. R., Shah, H. C., Hogan, M. D., and Dixon, R.L. Reduced fertility in female mice exposed transplacentally to diethylstilbestrol(DES). Fértil.Steril., 38: 364-371,1982.

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36. Newbold, R. R., Tyrey, S., Haney, A. F., and McLachlan, J. A. Developmentallyarrested oviduct: a structural and functional defect in mice following prenatalexposure to diethylstilbestrol. Teratology, 27: 417-426, 1983.

37. Newbold, R. R., Bullock, B. C., and McLachlan, J. A. Diverticulosis andsalpingite isthmica nodosa (SIN) of the fallopian tube. Estrogen-induced di-verticulosis and SIN of the mouse oviduct. Am. J. Patho)., 777: 333-335,1984.

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 arelined 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 cellsthat 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 thephotomicrograph. 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 bypleomorphic 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 atubular arrangement of pleomorphic epithelial cells. Rete epithelium in channels at the bottom of the photomicrograph is hyperplastic. This tumor occupies approximately10% 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 oflocal 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 magnificationof the lesion in Fig. 5a; mitotic figures are not numerous, but they are abnormal (arrow). H & E, x 60.

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1985;45:5145-5150. Cancer Res   Retha R. Newbold, Bill C. Bullock and John A. McLachlan  DiethylstilbestrolLesions of the Rete Testis in Mice Exposed Prenatally to

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