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.
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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.
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.
Incidence of squamous neoplasia of the cervix and vagina in DES-exposed
1978 Study Abstract (1)
Two hundred and fifty patients were examined because of a history of in utero exposure to diethylstilbestrol (DES) or because of the presence of physical findings suggesting such exposure. One thousand biopsies were examined for the presence of neoplasia and then compared to the colposcopic findings. There were no cases of glandular or squamous cell carcinoma. Fifteen (6 per cent) of the patients had squamous cell dysplasia. The degree of dysplasia was mild in 11 and moderate in only 4 (1.6 per cent) of the women. The majority of the cases of dysplasia involved the cervix, whereas the vagina was involved in only four cases, with simultaneous cervical dysplasia in three of these. Patients with cervical mosaic and white epithelium had dysplasia on biopsy much more frequently as compared with patients with similar colposcopic appearances in the vagina. Our results suggest a low incidence of significant squamous precancerous change in the DES-exposed population and provide evidence that colposcopic data concerning dysplasia pertinent to the cervix cannot be applied without modification to the evaluation of dysplasia in vaginal adenosis.
1978 Study Abstract (2)
Among 199 women from 12 to 30 years of age who had been exposed to DES in utero, the colposcopic evaluation of the vagina and cervix was considered normal for only 13.6%. The incidence of colposcopically detected lesions was not related to the trimester of DES exposure, the patient’s age, use of oral contraceptives, or presenting symptoms. Areas of punctation, mosaic patterns, white epithelium, and keratosis were not considered areas of adenosis. Cervical bands, hoods, cock’s combs, etc., were considered as part of the cervix. Under this definition adenosis of the vagina was diagnosed in only 14.1% of the patients. Eight (4.0%) women were found to have cervical intraepithelial neoplasia (CIN), Grade 3 lesions, and an additional 36 (14.1%) women were found to have CIN, Grade 1 lesions based on the light microscopy evaluation of directed biopsies. There were no cases of clear cell adenocarcinoma. It appears that women with in utero DES exposure may be at a higher risk of developing squamous neoplasia compared with non-DES-exposed women.
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In utero exposure to DES. Evaluation and followup of 199 women,
NCBI PMID: 662229, Obstet Gynecol. 1978 Apr;51(4):459-63.
Vaginal and cervical squamous cell dysplasia in women exposed to diethylstilbestrol in utero,
NCBI PMID: 717453, Am J Obstet Gynecol. 1978 Nov 1;132(5):537-44.
Squamous cell abnormalities of the vagina and cervix were evaluated in 1424 women exposed to diethylstilbestrol (DES) in utero
1978 Study Abstract
Squamous cell abnormalities of the vagina and cervix were evaluated in 1424 women exposed to diethylstilbestrol (DES) in utero. The prevalence of dysplasia was 2.1% and the incidence 0.85/100 person-years of followup. The dysplastic epithelial changes were almost always mild in women with no prior history of dysplasia and was slightly more frequent in the cervix than the vagina. Severe dysplasia and carcinoma in situ (CIS) were encountered only in those subjects specifically referred because of those abnormalities. The most common problem in the diagnosis of these squamous cell changes was the misinterpretation of mature and immature metaplastic cells for dysplastic squamous cells. Discordance between biopsy and cytology was common-place in the detection and followup of dysplasia, especially when it was mild. There were no instances in the study where cytology and biopsy samples from the vagina were both abnormal concurrently. Colposcopically directed biopsies did not increase the frequency of confirmation of cytologic findings. These data suggest that both cytology and biopsy of abnormal segments of the vagina and cervix remain an integral part of the examination of the DES-exposed female during long-term follow-up studies.
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Squamous cell dysplasia and carcinoma in situ of the cervix and vagina after prenatal exposure to diethylstilbestrol,
NCBI PMID: 652199, Obstet Gynecol. 1978 May;51(5):528-35.
A DES Experience of the National Collaborative Diethylstilbestrol Adenosis Project.
1984 Study Abstract
The incidence rates of dysplasia and carcinoma in situ (CIS) of the cervix and vagina were determined in 3,980 young women exposed prenatally to diethylstilbestrol. Strict criteria were developed to minimize selection bias among the subset of 744 pairs of matched exposed and unexposed (control) cohort participants, all of whom were identified through review of prenatal obstetrical records. A high degree of compliance was achieved throughout the seven-year study period since in each group about 90% of the women remained as active participants, kept 77% of the annual anniversary examinations, and had separate Papanicolaou smears of the cervix and vagina performed in 99% of the anniversary examinations. The incidence rate for dysplasia and CIS was significantly higher in the women exposed to diethylstilbestrol than in those not exposed in the matched cohort (15.7 v 7.9 cases per 1,000 person-years of follow-up). The rates were higher in the exposed women if squamous metaplasia extended to the outer half of the cervix or onto the vagina. In other respects, the matched cohorts were strikingly similar.
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Increased incidence of cervical and vaginal dysplasia in 3,980 diethylstilbestrol-exposed young women. Experience of the National Collaborative Diethylstilbestrol Adenosis Project, NCBI PMID: 6502858, JAMA. 1984 Dec 7;252(21):2979-83.
The higher risk group of DES-exposed women need early detection of cervical and vaginal adenocarcinomas
2015 Study Abstract
Women in the 1940s-1960s were prescribed Diethylstilbestrol (DES), a nonsteroidal estrogen, to prevent miscarriages, but the practice was terminated after it was discovered that the daughters so exposed in utero were at increased risk for developing clear cell adenocarcinoma (CCA) of the vagina or cervix at early ages. Pap smear screening is one of the principal methods used to identify tumor development and is necessary in this group of women to maintain their health. Currently, little is known about the factors associated with nonutilization of this screening tool in this high-risk population of women.
National cohort data from the National Cancer Institute (NCI) DES Combined Cohort Follow-up Study during 1994, 1997, 2001, and 2006 were used to determine which factors were associated with Pap smear screening nonutilization in 2006 among DES-exposed and unexposed women. Self-reported questionnaire data from 2,861 DES-exposed and 1,027 unexposed women were analyzed using binary logistic regression models.
DES exposure, not having a previous gynecologic dysplasia diagnosis, lack of insurance, originating cohort, increasing age, and previous screening behavior were all factors associated with not reporting a Pap smear examination in the 2006 questionnaire, although college education reduced nonutilization.
Understanding which factors are associated with not acquiring a screening exam can help clinicians better identify which DES-exposed women are at risk for nonutilization and possibly tailor their standard of care to aid in the early detection of cervical and vaginal adenocarcinomas in this high-risk group.
Factors associated with a lack of pap smear utilization in women exposed in utero to diethylstilbestrol, NCBI PMID: 25768943, J Womens Health (Larchmt). 2015 Apr;24(4):308-15. doi: 10.1089/jwh.2014.4930. Epub 2015 Mar 13.
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.
Some experimental evidence points to the possibility of a transgenerational carcinogenic effect after prenatal exposure to Diethylstilbestrol
Diethylstilboestrol (DES) exerts several toxic effects in experimental animals, by mechanisms which are still unclear. The genotoxicity of the drug has been attributed to a quinone metabolite and is mainly clastogenic, including sister chromatid exchange, unscheduled DNA synthesis, chromosomal aberrations, disruption of mitotic spindle and aneuploidy. There is evidence that genotoxic effects may occur also transplacentally. Intrauterine and early postnatal exposure to DES can cause a variety of dysplasias. In the offspring of female mice exposed to DES during pregnancy, histological changes are observed in the vaginal and cervical epithelium, the endometrium, the ovary, the testis and the epididymis. Prenatal exposure of rats to DES led to decreased litter size and to urethrovaginal cloaca, penile and testicular hypoplasia, and cryptorchidism. Vaginal ridging, vaginal adenosis, testicular hypoplasia and cryptorchidism have been observed in rhesus monkeys following prenatal exposure. There is sufficient evidence that diethylstilboestrol is carcinogenic in experimental animals, after either prenatal or postnatal exposure. Mice show a similar type of carcinogenicity to that observed in humans, target organs being vagina, cervix, uterus, ovary, mammary gland and testis. In rats, prenatal exposure to DES produces mostly mammary and pituitary tumours, but also some tumours of the vagina. Hamsters develop tumours of vagina, cervix, endometrium, epididymis, testis, liver and kidney. DES induces ovarian papillary carcinomas in dogs, and malignant uterine mesotheliomas in squirrel monkeys. Some experimental evidence points to the possibility of a transgenerational carcinogenic effect, since prenatal treatment of mice with DES is followed by an increased incidence of uterine and ovarian carcinomas in the second-generation descendants. Experimental results could have been used to predict the adverse effects of DES observed in humans in the early 1970s: DES had been reported to be carcinogenic in mice in the 1930s, while experiments in the 1960s had provided evidence that exposure during pregnancy could result in an increased cancer risk in the progeny.
Diethylstilboestrol: II, pharmacology, toxicology and carcinogenicity in experimental animals, NCBI, PMD: 1445734, Eur J Cancer. 1992;29A(1):149-55.