The vaginal and cervical cellular changes encountered in 575 postpubertal females exposed prenatally to diethylstilbestrol (DES) were compared with those of an unexposed population with particular reference to the role of cytology in the detection of vaginal adenosis and cervical ectropion (erosion).
Several methods of obtaining specimens were utilized, the most effcacious of which was scraping of the vagina, especially the fornices, and the portio vaginalis of the cervix. With this technic, columnar cells of the mucinous type and metaplastic squamous cells were observed in 34% of the vaginal scrapes and 54% of the scrapes of the cervical portio. A higher incidence was apparent among those patients in whom iodine staining of the vaginal mucosa was abnormal or vaginal adenosis was proven by biopsy. Moderate to severe dysplasia of the squamous cells or atypical glandular cells were found in 1% of the exposed subjects.
This study indicates that the presence of mucinous columnar or metaplastic squamous cells in vaginal scrapes is suggestive of vaginal adenosis but that vaginal cytology cannot be considered a uniformly reliable screening technique for detecting the presence of this disorder.
Sources and more information
Cytology of 575 young women with prenatal exposure to diethylstilbestrol, Robboy SJ, Friedlander LM, Welch WR, Keh PC, Taft PD, Barnes AB, Scully RE, Herbst AL., Obstet Gynecol. 1976 Nov;48(5):511-5. NCBI PMID: 980279.
Prevalence rate of the anomalies lower among subjects who had been pregnant, and higher among those with later age at menarche
1984 Study Abstract
Among women exposed in utero to diethylstilbestrol (DES) and enrolled in the Diethylstilbestrol Adenosis (DESAD) Project, structural anomalies of the cervix or vagina were found in 25% of the 1,655 subjects identified by review of prenatal records, 43% of the 800 who themselves requested entry into the project, and 49% of the 1,089 referred by physicians but in only 2% of the 963 control subjects. Among the 367 cases found by record review to have complete information on the DES exposure, multivariate analysis indicated close association of the anomalies with the gestational week of first exposure and the total dose. Also, the prevalence rate of the anomalies was lower among subjects who had been pregnant and higher among those with later age at menarche.
Sources and more information
Structural anomalies of the cervix and vagina in women enrolled in the Diethylstilbestrol Adenosis (DESAD) Project, Am J Obstet Gynecol, NCBI PMID: 6691382, 1984 Jan 1;148(1):59-66.
Cancer risk in diethylstilbestrol-exposed offspring, 1976 findings
1976 Study Abstract
The occurrence of columnar epithelium in the vagina (vaginal adenosis) in young women with intrauterine exposure to diethylstilbestrol (DES) during the first trimester of pregnancy was observed in 231 patients (82 per cent of 280 cases who underwent colposcopic study). Extension of columnar epithelium onto the portio of the cervix was present in the remaining 18 per cent of the cases. Abnormal colposcopic findings were present in the transformation zone in 96 per cent of the patients with vaginal adenosis. Directed biopsy revealed four cases of vaginal and/or cervical squamous carcinoma in situ (CIS), two cases of severe dysplasia, five cases of moderate, and 29 cases of mild dysplasia. The prevalence of CIS in DES-exposed girls (1.4 per cent) was nearly five times the prevalence rate of CIS in a control group of 5,808 DES-unexposed women (0.44 per cent). This finding correlates well with the hypothesis that the genesis of squamous intraepithelial neoplasia is specifically related to the extent and surface area of the vaginal transformation zone. An unusual case of invasive squamous carcinoma in a DES-exposed young girl is presented, which represents the initial observation of this association to date.
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Cancer risk in diethylstilbestrol-exposed offspring, Mattingly RF, Stafl A., NCBI PMID: 984124, Am J Obstet Gynecol. 1976 Nov 1;126(5):543-8.
The prevalence rate of abnormal cytologic findings in the study group was 9%.
In half of these patients a low-grade intraepithelial neoplasia of the cervix and vagina was found.
It was concluded that colposcopy in diethylstilbestrol-exposed offspring in inexperienced hands can result in many unnecessary biopsies. Therefore colposcopic examination should be performed by expert colposcopists in referral diethylstilbestrol centers.
Sources and more information
Colposcopic findings and intraepithelial neoplasia in diethylstilbestrol-exposed offspring. The Dutch experience, NCBI PubMed PMID: 2589438, Am J Obstet Gynecol. 1989 Nov;161(5):1191-4.
During the 6 years from the initial survey, 830 young women exposed to DES in utero were periodically screened.
1979 Study Abstract
The physician population delivering obstetric care in Philadelphia between 1950 and 1970 was contacted to ascertain their use of diethylstilbestrol (DES) during pregnancy. Of the 31.8% of the physicians who responded to the questionnaire, 71.8% used DES during pregnancy and 12.7% desired assistance in review of their records.
During the 6 years from the initial survey, 830 young women exposed to DES in utero were periodically screened for cervicovaginal abnormalities and clear cell adenocarcinoma. Of these 830 patients 61.7% were found to have cervicovaginal abnormalities, and 65.9% of the patients showed either adenosis or evidence of the prior existence of vaginal adenosis. Eight patients were treated for clear cell adenocarcinoma. Two cases were detected while asymptomatic. Seven of the patients are living with no evidence of cancer, and two of these have survived over 5 years.
Sources and more information
Six years’ experience with screening of a diethylstilbestrol-exposed population, NCBI PMID: 463989, Am J Obstet Gynecol. 1979 Aug 15;134(8):860-5.
All cases of adenosis should be followed by colposcopy
1978 Study Abstract
Two patients exposed in utero to maternal diethylstilbestrol DES ingestion presented with adenosis. Each developed intraepithelial neoplasia in an area of active metaplastic change.
The question is raised whether a continuum exists beginning with DES exposure and proceeding through the occurrence of adenosis and active squamous metaplasia to dysplastic alteration and finally squamous neoplasia.
Since the cytologic smear is negative in 50% of cases during the dysplastic phase, it is recommened that all cases of adenosis be followed by colposcopy.
Sources and more information
Squamous cell carcinoma in situ of the vagina and cervix after intrauterine DES exposure, NCBI PMID: 683639, Obstet Gynecol. 1978 Jul;52(1 Suppl):30S-33S.
DiEthylStilbestrol usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced
This report presents the cytologic findings and the rates of dysplasia for 4,589 young women enrolled in the National Cooperative Diethylstilbestrol-Adenosis (DESAD) Project. Mucinous columnar cells and/or metaplastic squamous cells with or without mucinous droplets were encountered in 22% of vaginal scrape smears from all diethylstilbestrol (DES)-exposed participants identified by review of prenatal records and in 43% of women in whom vaginal epithelial changes (VEC) were observed by colposcopy or by iodine staining. The frequency of cellular findings in the vaginal scrape smears was closely related to the timing of the administration of the DES to the mother. With increasing age of the daughters, the overall frequencies of both the mucinous and metaplastic cells decreased; relative to each other, an increasing proportion was metaplastic squamous cells. These data suggest that, as the women grow older, vaginal adenosis regresses by the process of squamous metaplasia. Endometrial type cells were found in 2% of vaginal scrape smears. Their cyclical occurrence during the menstrual cycle and lack of correlation with the presence of VEC indicated an origin from the uterine corpus rather than the tuboendometrial type of adenosis. Squamous cell dysplasia of the vagina and cervix was detected by biopsy or scrape smear specimens in 1.8% of DES-exposed women in the record review group. The rate of unexposed women was twice as high. In general, the rates of dysplasia were higher in the cervix than vagina, and the more severe degrees of dysplasia were encountered only in those women who were referred to the DESAD Project or who themselves requested entry. Four patients who were referred or who themselves requested entry were found to have clear cell adenocarcinoma of the vagina. The vaginal smear provided the first clue to the presence of an abnormality in three of them.
Dysplasia and cytologic findings in 4,589 young women enrolled in diethylstilbestrol-adenosis (DESAD) project, NCBI, PMID: 7195652, Am J Obstet Gynecol. 1981 Jul 1;140(5):579-86.
The stage of cellular differentiation at the time of DES exposure may be critical in the final expression of these abnormalities
The association of intrauterine exposure to diethylstilbestrol (DES) and the subsequent development of reproductive tract abnormalities in young women has been well documented. Although the incidence of vaginal adenocarcinoma was low in the exposed population, vaginal adenosis, a nonmalignant abnormality, was quite common. In order to study the pathogenesis of adenocarcinoma and to determine the frequency of adenosis following prenatal exposure to DES, timed pregnant CD-1 mice were treated s.c. with DES (dose range, 5 to 100 micrograms/kg/day) on Days 9 though 16 of gestation. This period corresponds to major organogenesis of the reproductive tract in the mouse. Female offspring were sacrificed between 1 and 18 months of age. In addition to nonmalignant abnormalities, some of which have been described in women exposed prenatally to DES, two cases of vaginal adenocarcinoma (2%) were observed in 91 prenatally DES-treated animals. No comparable epithelial lesions were seen in 158 control female mice. One other case of adenocarcinoma of the vagina was reported previously by this laboratory using the prenatally exposed animal model. In another series of mice treated prenatally with DES, 100 micrograms/kg/day, 3 of 20 (15%) 1-month-old animals and one of 10 (10%) 18-month-old treated offspring had glandular epithelium abnormally located in the vaginal fornices (adenosis). Other cervicovaginal abnormalities observed after prenatal DES exposure included structural alterations, cervical enlargement, squamous metaplasia in the endocervical canal, excess keratinization of the ectocervix and vagina, transverse folds and basal cell hyperplasia in the upper vagina, and prominent Wolffian duct remnants. Thus, vaginal adenosis in the mouse does not appear to be a common abnormality following treatment with DES in utero. Neonatal exposure to DES on Days 1 to 5, on the other hand, resulted in six of eight (75%) animals with adenosis at 35 days of age. Since perinatal mouse studies have reported high incidences of vaginal adenosis, but, to our knowledge, no cases of vaginal adenocarcinoma, the results presented in this report suggest that the stage of cellular differentiation at the time of DES exposure may be critical in the final expression of these abnormalities.
Women pre-natally exposed to DES develop abnormalities that can lead to cancer
Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed with DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenosis are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Müllerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces adenosis lesions in the cervix and vagina. This review describes mouse models can be used to study the development of DES-induced anomalies, focusing on cervicovaginal adenoses, and discusses its molecular pathogenesis.
NCBI, PMC3443265, Oct 2012 The Development of Cervical and Vaginal Adenosis as a Result of Diethylstilbestrol Exposure In Utero.
Women exposed to DES in utero develop abnormalities, including cervicovaginal adenosis that can lead to cancer
Women exposed to diethylstilbestrol (DES) in utero develop abnormalities, including cervicovaginal adenosis that can lead to cancer. We report that transient disruption of developmental signals by DES permanently changes expression of p63, thereby altering the developmental fate of Müllerian duct epithelium. The cell fate of Müllerian epithelium to be columnar (uterine) or squamous (cervicovaginal) is determined by mesenchymal induction during the perinatal period. Cervicovaginal mesenchyme induced p63 in Müllerian duct epithelium and subsequent squamous differentiation. In p63(-/-) mice, cervicovaginal epithelium differentiated into uterine epithelium. Thus, p63 is an identity switch for Müllerian duct epithelium to be cervicovaginal versus uterine. P63 was also essential for uterine squamous metaplasia induced by DES-exposure. DES-exposure from postnatal day 1 to 5 inhibited induction of p63 in cervicovaginal epithelium via epithelial ERalpha. The inhibitory effect of DES was transient, and most cervicovaginal epithelial cells recovered expression of p63 by 2 days after discontinuation of DES-treatment. However, some cervicovaginal epithelial cells failed to express p63, remained columnar and persisted into adulthood as adenosis.
NCBI, PMID: 14998922, Apr 2004 – Full article The Company of Biologists Limited131/7/1639 15 Dec 2003.