Induction of Urogenital Neoplasia and Abnormalities from Prenatal Exposure to Diethylstilbestrol

Transcription

1 ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 9, No. 4 Copyright 1979, Institute for Clinical Science, Inc. Induction of Urogenital Neoplasia and Abnormalities from Prenatal Exposure to Diethylstilbestrol M ICHAEL L. N ETZLO FF, M.D. Department o f Pediatrics, Division o f Genetics, University o f Florida College o f Medicine, Gainesville, FL ABSTRACT The occurrence of vaginal clear cell adenocarcinoma in young women follow ing exposure in utero to diethylstilbestrol (DES) is now w ell docum ented. In addition to this carcinogenic potential, DES has been shown to be teratogenic. In females, the D ES-related malformations include vaginal adenosis, transverse ridges of the vagina or cervix and uterine abnormalities. Although no neoplasms have been observed in DES-exposed males, malformations of the epididym is, testes and phallus are relatively common and may result in infertility. The carcinogenic mechanism of DES may be either a direct induction of m alignant potential in vaginal cells or a teratogenic effect causing ectopic M iillerian epithelium which could be exposed later to mutagenic agents in the vagina. The absence of malignancy in DES-exposed males may favor the latter hypothesis since male M iillerian rem nants are internal structures and thus w ould not be exposed to surface carcinogens. In the early 1970 s, reports of vaginal tumors in young women exposed in utero to diethylstilbestrol (DES) docum ented the carcinogenic potential of this com pound.11,16 Subsequent studies in both m ales and fem ales have show n nonneoplastic changes,2,8 7,12 some of which are congenital, suggesting that DES is also teratogenic. This paper will review both effects of DES on exposed offspring. D ES, a nonsteroidal estrogenic su b stance,' was sy n th esized in 1938 and Reprint requests to: Michael L. Netzloff, M.D., Department of Pediatrics, Division of Genetics, Box J-296, JHM Health Center, University of Florida College of Medicine, Gainesville, FL gained rapid acceptance because of its novel characteristics. It was effective when given orally and its synthesis was both simple and inexpensive.16 Following a study by Smith et al,20 it was widely prescribed to prevent threatened abortion and other com plications of pregnancy during the 1940 s and I950 s. D uring this time, DES was used in approximately 7 percent of all pregnancies at the Mayo C linic, and g eneral estim ates o f th e num ber of wom en who received DES som etim e during their gestation range from 500,000 to perhaps as many as two million.16 Subsequent studies questioned the therapeutic value of the drug in pre /79/ $00.90 Institute for Clinical Science, Inc.

2 264 NETZLOFF venting threatened abortion, and its popularity for this use decreased quickly after I960.8 In 1971, following the reports of H erbst et al11 describing clear cell adenocarcinom a in association w ith in utero exposure to DES, the Food and Drug A dm inistration banned its use during pregnancy. Results of Exposure to DES In Utero in Fem ale Offspring C l e a r C e l l A d e n o c a r c i n o m a Clear cell adenocarcinoma (CCA) had been reported almost exclusively in older w om en18 until 1966, when Fawcett et al4 showed that this was the most common tumor of the cervix in the pediatric age range. In 1971, H erbst et al11 reported the o ccu rren ce of CCA in se v en young females at M assachusetts General Hospital betw een 1966 and A search for a common denom inator in th eir m edical histories showed a high incidence of in utero exposure to DES. These observations led to the establishm ent in 1971 of the Registry of C lear C ell A denocarcinoma o f the G enital Tract in Young Females. Over 300 cases were thus ascertained and showed: (1) an average age of 17 years at the time of diagnosis, w ith an overall range of 7 to 28 years,18 and a peak incidence at age 19 years which thereafter dropped precipitously;10 (2) that the diagnosis of most cases was made in a narrow age range of 10 years (14-23 years) which makes D E S-related adenocarcinom a unusual;10 (3) a m arked increase in the frequency of these cancers after age 14 years, suggesting a relationship to the events of puberty;18 (4) a docum ented exposure to DES always prior to the 18th week of gestation in approximately two-thirds of the patients in whom maternal histories were available;18 (5) that as little as 1.5 mg of DES adm inistered throughout pregnancy was associated with the development of cancer in female offspring;1 (6) that w om en born in 1951 to 1953 had higher incidence rates than those born in the previous or subsequent three-year periods, possibly indicating an increased exposure during the early 1950 s;10 and (7) that the estim ated risk o f developing adenocarcinoma of the vagina through age 24 following DES exposure in utero was 0.14 to 1.4 per thousand.10 In two-thirds of cases the tumors have been confined to the vagina while m ost of the rem ainder involve the vaginal portion of the cervix.18 Those which can be accurately localized almost always arise from the anterior wall, suggesting a M ullerian (param esonephric) rather than a m esonephric origin, since the Wolffian rem nants commonly are lateral in position.3 T he tum ors, usually polypoid and nodular, range in size from 3 mm to more than 10 cm and exfoliate cells which allow for cytologic d e te c tio n. C ervical-vaginal smears, however, are negative in about one-fourth of patients, usually because of technical reasons and only rarely due to confinem ent of the tumor to the lamina propria w ith com plete covering by the norm al squam ous e p ith e liu m.18 T he tumors are radiosensitive, and radiation therapy or radical surgery have been used effectively to treat them; lim ited followup has prevented a decision concerning the superiority of eith er therapeutic modality. Alm ost all patients w ith small, asymptomatic CCA are curable. Larger tum ors, associated w ith lym ph nodes m etastases and recurrences in approximately one-fourth of patients, are usually lethal.18 S q u a m o u s C e l l D y s p l a s i a a n d C a r c i n o m a O ther related conditions which may rarely occur in DES-exposed women are squamous cell dysplasia and carcinoma in situ The incidence ofvaginal rather than cervical dysplasia appears slightly increased,17 b u t alm ost all biopsy specim ens show squamous metaplasia, which occasionally may be m isin te rp re te d as

3 PRENATAL EXPOSURE TO DIETHYLSTILBESTROL 265 dysplasia.18 A few reports of invasive squamous cell carcinoma have appeared in the literature, but the possible progression from dysplasia to invasive carcinoma and increased risk of the latter following DES exposure rem ain unproved.18,21 N o n - N e o p l a s t i c A b n o r m a l i t i e s Vaginal adenosis may be an antecedent condition in the developm ent of CCA. It has been reported to occur in over 90 percent of wom en exposed to DES in utero1 and consists of heterotopic glandular e p i thelium w ithout the normal squamous cell covering. Ultrastructural studies by Fenoglio et al5 have id entified endom etrial-type cells which may be the cell of origin for CCA. The relative rarity of these endom etrial-type cells may be an important explanation for the infrequency of these cancers. G landular epithelium located in the vaginal portion of the cervix, or cervical ectropion, is found in nearly all DESexposed females and is usually extensive. This abnorm ality may be distinct from vaginal adenosis, as indicated by subtle histo lo g ic d ifferen ces, b u t cytologic smears in both conditions are sim ilar.18 Transverse ridges, called hoods, cockscom b cervix, rim s, collars or p seu d o polyps, are other anomalies found in the upper vagina or cervix in about 25 percent of D E S-exposed fem ales.1,2,18,21 H ypoplasia of the cervix also occurs and can result in functional changes, such as cervical incom petency.7 In addition to the abnorm alities of the lower structures, changes of the upper genital tract associated with exposure in utero to D ES have b een reported recently. Kaufman et al,12 using hysterosalpingograms, found that 40 of 60 DESexposed women had abnormal uteri while none of 23 controls showed comparable changes. These abnorm alities included a w idening of the interstitial and isthmic portions of the oviducts, giving the uterus a T -sh ap e d ap p e ara n ce, c o n stric tio n bands, narrow ing or w id enin g of the low er two-thirds o f the uterus and shortening of the uterine cavity. N inety p ercent of patients with changes noted in the uterus had gross anatomic changes of the cervix. The functional significance of these uterine abnorm alities for reproduction has not yet been established, but infertility, m enstrual irreg u larities and prem ature deliveries may result.12,13 Results of Exposure to DES In Utero in Males The developm ent of cancer in human males has not been reported following prenatal exposure to DES.2,6,16,18 H ow ever, several abnormalities have been described despite the small num ber of m en examined. Bibbo et al2 reported a significantly higher incidence of epididym al cysts, hypotrophic testes and capsular induration in 163 DES-exposed males compared to 168 unexposed controls. They also found that 64 percent of the DESexposed group had a pathologic semen with a reduced ejaculate volum e and lower num bers and mobility of sperm. Tw o-thirds of these subjects had abnormal genital findings, including four with microphallus. As a consequence of these abnorm alities, 30 percent of the DESexposed group were estim ated to be subfertile.19 H enderson et al,9 reporting the results of a questionnaire survey, found an increased incidence of difficulties in m icturition and urethral stenosis or hypospadius am ong D E S -ex p o sed m ales. T hese observations aw ait clinical confirmation. Teratogenesis and Pathogenesis Several observations support the suggestion by numerous authors that DES has teratogenic effect.3,11,13,15,18,21 In the first place, the gross and m icroscopic anomalies are detected only w hen exposure occurs during the first 18 weeks of pregnancy, w hich includes the period of

4 266 N ETZLO FF organogenesis for the vagina, cervix and other urogenital structures.22 F u rth e r more, the chance of teratogenic effects p ro g ressiv ely d e c re a ses as em bryogenesis and differentiation advance to completion.18 Normally, during the period of approximately the 4th to 18th week of developm ent, the M ullerian ducts of the embryo extend caudally and fuse to form a solid structure. Squamous cells arising in the epithelium of the urogenital sinus invade from below and replace completely the M ullerian mucosa up to the level of the external cervical os. That DES can have a teratogenic effect on this orderly process is indicated by the finding of congenital vaginal adenosis in hum an fetuses and new borns.18 W hether DES stimulates the persistence of M ullerian epithelium or inhibits its replacem ent by squamous epithelium in the vagina is uncertain at this time, but the latter seems embryologically m ore likely. O ther m alform a tions associated with adenosis, such as ridges, strictures and pseudopolyps, are true m orphologic aberrations w hich probably result from an effect of DES on the m esodermal stroma from which derive the fibrous and muscular coats o f the vagina, cervix and uterus.23 T he p reced in g observations substantiate the teratogenicity of DES, but the question of w hether it is also a carcinogen in hum ans rem ains unansw ered. The fin d in g s of D E S -re la ted m alignancy satisfy the prem ise that exposure to a cancer-causing agent may have ceased long before disease occurs.3 It is possible that DES, in addition to being a teratogen, is an extrem ely weak carcinogen, inducing latent neoplastic changes in utero which are delayed in their manifestation or require stim ulation by other agents at the tim e of puberty for their expression. This w ould suggest that cancer may d e velop from adenosis18 and, in fact, almost every cancer is found in the presence of benign adenosis. However, no instance also showing a transitional lesion has ever b een reported.18,21 An alternative explanation is that DES is only a teratogen, which does not itself produce a precancerous condition. In this hypothesis, DES would only cause ectopy of normal M ullerian epithelium, which co u ld be ex p o sed at a la te r age to m utagenic stim uli in the vagina. Evidence indicates th at this may be the mechanism for induction of squamous cell carcinoma in situ following transplacental DES exposure.15 T he risk for this carcinom a in situ is in creased in those women with an extensive transformation zone (glandular epithelium undergoing squam ous m etaplasia), such as is frequently caused by DES. T hese observations suggest the presence of vaginal carcinogens, the effect of which would be significantly greater w hen the transform a tion zone is extensive. This postulate could also be true for D ES-related adenocarcinom a, but data on this point are lacking. The low carcinogenicity of DES and the small num ber of DES-exposed males who have been studied may explain the failure to demonstrate urogenital tumors in men. Another explanation may be the different hormonal responses of males and females at puberty. Alternatively, these tumors may not occur because, unlike the vaginal adenosis in fem ales, the M ullerian rem nants in the male (prostatic utricle and appendices of the testes) are strictly in ternal structures and would not be exposed to surface carcinogens. Cysts occur in the efferent ductules and superior epididymis in D ES-exposed m ales6 and may represent teratogenic abnorm alities of M ullerian duct rem nants. From this review, it is obvious that DES, a nonsteroidal estrogen, can cause abnormal M ullerian developm ent. These effects correlate with exposure not only to DES and chemically related estrogenic compounds but may also be related to the use o f steroidal estrogens. Changes sim i lar to those caused by DES, including cancer, have been reported following exposure to natural estrogens and proges

5 PRENATAL EXPOSURE TO DIETHYLSTILBESTROL 267 terone and to progesterone alone.18 These types of hormones are widely used by w om en as contraceptives, som etim es even during early, unrecognized pregnancies. Such observations indicate the need to examine closely these offspring for disorders sim ilar to those caused by prenatal exposure to DES. References 1. Ad a m, E., D e c k er, D. G., H e r b s t, A. L., N oller, K. L., Tillary, B. C., and Tow n se n d, D. E.: Vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones. Cancer Res. 37: , B ib b o, M., G i l l, W. B., F r e id o o n, A., Blo u g h, R., F a n g, V. S., Ro se n fie l d, R. L., Schum ach er, G. F. B., Sleeper, K., Sonek, M. G., and Wie d, G. L.: Follow -up study of m ale and fem ale offspring o f D E S-exposed mothers. Obstet. G ynec. 49:1-8, Bis h u n, N. P., Sm ith, N. S., William s, D. C., and Ra v en, R. W.: Carcinogenic and possible mutagenic effects of stilbestrol in offspring exposed in utero. J. Surg. Oncol. 9: , F a w c e t t, K. J., D o c k e r t y, M. B., and H u n t, A. B.: Mesonephric carcinomas and adenocarcinomas of the cervix in children. J. Pediat. 69: , F e n o g l i o, C. M., F e r e n c z y, A., R ic h a r t, R. M., and T o w n s e n d, D.: Scanning and transmission electron microscopic studies of vaginal adenosis and the cervical transformation zone in progeny exposed in utero to diethylstilbestrol. Amer. J. Obstet. Gynec. 226: , Gil l, W. B., S c h u m a c h e r, G. F. B., and Bib b o, M.: Structural and functional abnormalities in the sex organs of male offspring of mothers treated with diethylstilbestrol (DES). J. Reprod. Med. 16: , Go l d s t e in, D. P.: Incom petent cervix in offspring exposed to diethylstilbestrol in utero. Obstet. Gynecol. 52(1) Supplment: 73-75, H e i n o n e n, O. P.: D ieth ylstilb estrol in pregnancy: frequency of exposure and usage patterns. Cancer 31: , H e n d e r s o n, B. E., Be n t o n, B. B., C o s grove, M., Baptista, J., Aldrich, J., T ow n send, D., Hart, W., and Mack, T. M.: Urogenital tract abnormalities in sons of women treated with dieth ylstilb estrol. Pediatrics 58: , H e r b s t, A. L., C o l e, P., C o l t o n, T., R ob- BOY, S. J., and SCULLY, R. E.: Age-incidence and risk of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix. Amer. J. Obstet. Gynec. 228:43-50, H e r b s t, A. L., U l f e l d e r, H., and P o s - k a n z e r, D. C.: Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. N. Eng. J. Med. 284: , K a u fm a n, R. H., B in d e r, G. L., G r a y, Jr., P. M., and A d a m, E.: Upper genital tract changes associated with exposure in utero to diethylstilbestrol. Amer. J. Obstet. Gynec. 228:51-59, K a u fm a n, R. H., B in d e r, G. L., G r a y, Jr., P. M., and A d a, E.: Upper genital tract changes associated with exposure in utero to diethylstilbestrol. Surv. Obstet. Gynec. 32: , Lam b, E. J.: Invasive squamous cell carcinoma of the cervix in a diethylstilbestrol-exposed offspring. Amer. J. Obstet. Gynec. 129: , M a t t i n g l y, R. F. and S t a f l, A.: Cancer risk in diethylstilbestrol-exposed offspring. Amer. J. Obstet. Gynec. 226: , N o l l e r, K. L.: DES and pregnancy: lower reproductive tract changes in offspring. Bioscience 26: , R o b b o y, S. J., P r a t, J., W e l c h, W. R., and B a r n e s, A. B.: Squamous cell neoplasia controversy in the female exposed to diethylstilbestrol. Human Path. 8: , R o b b o y, S. J., S c u l l y, R. D., W e l c h, W. R., and H e r b s t, A. L.: Intrauterine diethylstilbestrol exposure and its consequences. Arch. Path. Lab. Med. 101 :l-5, R o s e n f i e l d, R. L., G i l l, W. B., and B ib b o, M.: DES effect on males. Pediatrics 62: , S m ith, O. W., S m ith, G. V. S., and H u r w it z, D.: Increased excretion of pregnanediol in pregnancy from diethylstilbestrol with special reference to the prevention of late pregnancy accidents. Amer. J. Obstet. Gynec. 52: , U l f e l d e r, H.: DES-transplacental teratogenand possibly also carcinogen. Teratology 23: , U l f e l d e r, H. and R o b b o y, S. J.: The embryologic development of the human vagina. Amer. J. Obstet. Gynecol. 126: , V e r i d i a n o, N. P., T a n c e r, M. L., and W e in e r, E. A.: Squamous cell carcinoma in situ of the vagina and cervix after intrauterine DES exposure. Obstet. Gynec. 52 Supplement:30-33, 1978.