The higher risk group of DES-exposed women need early detection of cervical and vaginal adenocarcinomas
2015 Study Abstract
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
OBJECTIVE: We examined long-term risk of cancer in women exposed to diethylstilbestrol (DES) in utero.
METHODS: A total of 12,091 DES-exposed women in the Netherlands were followed prospectively from December 1992 till June 2008. Cancer incidence was assessed through linkage with the Dutch pathology database (PALGA) and the Netherlands Cancer Registry and compared with the Dutch female population.
RESULTS: A total of 348 medically verified cancers occurred; median age at end of follow-up was 44.0 years. No overall increased risk of cancer was found (standardized incidence ratio [SIR] = 1.01; 95% confidence interval [CI] = 0.91, 1.13). The risk of clear cell adenocarcinoma of the vagina and cervix (CCA) was statistically significantly increased (SIR = 24.23; 95% CI = 8.89, 52.74); the elevated risk persisted above 40 years of age. The risk of melanoma diagnosed before age 40 was increased (SIR = 1.59; 95% CI = 1.08, 2.26). No excess risks were found for other sites, including breast cancer.
CONCLUSIONS: The results of our study are generally reassuring except for CCA, with a risk increase persisting at older ages. The slightly elevated risk of melanoma before age 40 is remarkable, but needs to be confirmed by other studies. We did not confirm the increased risk of breast cancer at older ages, as suggested in the NCI DES Follow-up study. Since most DES daughters in our cohort are still relatively young (44.0 years), longer follow-up is warranted to examine cancer risks at ages when cancer occurs more frequently.
Association between in utero DES exposure and high-grade squamous neoplasia
2000 Study Abstract
PURPOSE: Women exposed to diethylstibestrol (DES) in utero are known to have an excess risk of clear cell adenocarcinoma of the vagina and cervix, in addition to vaginal epithelial changes, but the effect on the incidence of squamous neoplasia is uncertain. This study evaluated the long-term risk of developing high-grade squamous neoplasia of the genital tract among women exposed prenatally to diethylstilbestrol.
METHODS: A cohort comprising 3899 DES-exposed and 1374 unexposed daughters was followed for thirteen years (1982-1995) for pathology-confirmed diagnoses of high-grade squamous neoplasia. A pathologist blinded to exposure status reviewed seventy-seven percent of cases. Poisson regression analysis was used to compute relative risks (RR) and 95% confidence intervals (CI) controlling for age, calendar year, screening history and other covariates.
RESULTS: The RR (95% CI) among DES-exposed versus unexposed, based on 111 cases of high-grade disease, was 2.12 (1.19-3.77). Adjustment for screening history had little effect, but when the analysis was restricted to a group highly screened before 1982, the risk was reduced. Risk estimates were higher among women exposed earlier in gestation; the RR (95% CI) for exposure within 7 weeks of the last menstrual period was 2.82 (1.43-5.53).
CONCLUSIONS: The findings support an association between in utero DES exposure and high-grade squamous neoplasia, although a role for more intensive screening among DES-exposed women in the production of this excess could not be completely ruled out..
Incidence of squamous neoplasia of the cervix and vagina in des-exposed daughters, NCBI, PMID: 11018391, Ann Epidemiol. 2000 Oct 1;10(7):467. Full text link.
DES daughters in France: experts’ points of view on the various genital, uterine and obstetric pathologies, and in utero DES exposure
Background Compensation of diethylstilbestrol exposure depends on the judicial system. In France, girls having been exposed to diethylstilbestrol are currently being compensated, and each exposure victim is being evaluated. Fifty-nine expert evaluations were studied to determine the causal relation between exposure to diethylstilbestrol and the pathologies attributable to diethylstilbestrol.
Methods The following were taken into consideration: age at the first signs of the pathology; age of the sufferer at the time of evaluation; the pathologies grouped into five categories: fertility disorders – cancers – mishaps during pregnancy – psychosomatic complaints – pathologies of “3rd generation DES victims”; submission of proof of DES exposure; the degree of causality determined (direct, indirect, ruled out).
61% of the cases related to fertility disorders,
28.8% to cancer pathologies (clear-cell adenocarcinoma),
18.6% to mishaps during pregnancy,
8.5% to disorders resulting from preterm delivery,
and 3.4% to psychosomatic disorders.
Some cases involved a combination of two types of complaints. Indirect causality was determined in 47.1% of the cases involving primary sterility, in 66.7% involving secondary sterility, and in 5 out of 6 cases of total sterility. There is direct causality between in utero diethylstilbestrol exposure and vaginal or cervical clear cell adenocarcinoma. Causality is indirect in the case of disorders linked to prematurity in third generation victims.
Conclusion Causality was determined by the experts on the basis of scientific criteria which attribute the presenting pathologies to diethylstilbestrol exposure. When other risk factors come into play, or when exposure is indirect (third generation), this causality is diminished.
Sources DES daughters in France: experts’ points of view on the various genital, uterine and obstetric pathologies, and in utero DES exposure, Med Sci Law, PMID: PubMed 24534146, 2014 Feb 17.
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 authors describe a 15-year-old girl with small cell carcinoma of the ovary whose maternal grandmother had been taking DES while she was pregnant with the patient’s mother.
This case, while anecdotal, suggests that a transgenerational history of DES exposure should be noted, and that granddaughters with persistent abdominal pain even during childhood may need evaluation for genital tract abnormalities.
Ovarian carcinoma in an adolescent with transgenerational exposure to diethylstilbestrol, NCBI, PMID: 12902917, 2003 Aug;25(8):635-6.
Full text – Clinical and Laboratory Observations Volume 25 – Issue 8, Lippincott Williams & Wilkins, pp 635-636 2003.
Full text – A case of small cell carcinoma of the ovary hypercalcemic variant in a teenager, ScienceDirect, S2211338X12000622 2012.
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.
Developmental exposure to DES alters uterine gene expression that may be associated with uterine neoplasia later in life
Previously, we described a mouse model where the well-known reproductive carcinogen with estrogenic activity, diethylstilbestrol (DES), caused uterine adenocarcinoma following neonatal treatment. Tumor incidence was dose-dependent reaching >90% by 18 mo following neonatal treatment with 1000 μg/kg/d of DES. These tumors followed the initiation/promotion model of hormonal carcinogenesis with developmental exposure as initiator, and exposure to ovarian hormones at puberty as the promoter. To identify molecular pathways involved in DES-initiation events, uterine gene expression profiles were examined in prepubertal mice exposed to DES (1, 10, or 1000 μg/kg/d) on days 1–5 and compared to controls. Of more than 20 000 transcripts, approximately 3% were differentially expressed in at least one DES treatment group compared to controls; some transcripts demonstrated dose–responsiveness. Assessment of gene ontology annotation revealed alterations in genes associated with cell growth, differentiation, and adhesion. When expression profiles were compared to published studies of uteri from 5-d-old DES-treated mice, or adult mice treated with 17β estradiol, similarities were seen suggesting persistent differential expression of estrogen responsive genes following developmental diethylstilbestrol exposure. Moreover, several altered genes were identified in human uterine adenocarcinomas. Four altered genes [lactotransferrin (Ltf), transforming growth factor beta inducible (Tgfb1), cyclin D1 (Ccnd1), and secreted frizzled-related protein 4 (Sfrp4)], selected for real-time RT-PCR analysis, correlated well with the directionality of the microarray data. These data suggested altered gene expression profiles observed 2 wk after treatment ceased, were established at the time of developmental exposure and maybe related to the initiation events resulting in carcinogenesis.
NCBI, Dr Retha Newbold, PMCID: PMC2254327 25 Feb 2008 – Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life.