Late cervical and vaginal clear cell adenocarcinoma in women exposed in utero to diethylstilbestrol: Evaluation and screening.

OBJECTIVES: We aimed to evaluate the risk of cervical and vaginal clear cell adenocarcinoma (CCA) in women, aged 50 years or more, exposed in utero to diethylstilbestrol (DES) and contribute to a reevaluation of the recommendations for cervical and vaginal cancer and pre-cancer screening for these women. METHODS: We carried out a retrospective review for patients received in a cancer institute. Two cohorts were consecutively studied, the first from 1970 to 2003 and the second from 2004 to 2021, and then linked. RESULTS: During the first period, we observed 61 CCA cases, with a mean age at diagnosis of 23 years (7-42), 36 (59%) following DES exposure in utero. During the second period, we found 27 cases, with one case of DES exposure (4%) for a women diagnosed at the age of 40 years. The mean age of the second cohort was 38 years (14-79). For the seven women aged 50 years or more at the time of CCA diagnosis, DES exposure was excluded for five and considered unlikely for the other two. CONCLUSION: In total, 88 cases of cervical or vaginal CCA were observed over a period of 51 years in a cancer center. The 37 cases associated with DES exposure represented approximatively one third of the CCA related to DES expected in France. DES exposure was improbable for the seven cases of CCA for women aged 50 years or more. These results do not support the hypothesis of late cervical or vaginal CCA in women exposed to DES in utero and indicate the need for larger multicentric studies. For the present, we propose specific screening for women exposed to DES in utero in terms of : 1) methods: association of cytology and hrHPV testing, with cervical and vaginal sampling, 2) timing : annual, or without exceeding a three-year interval, continuing after 65 years of age and after hysterectomy.

Neonatal administration of synthetic estrogen, diethylstilbestrol to mice up-regulates inflammatory Cxclchemokines located in the 5qE1 region in the vaginal epithelium.

A synthetic estrogen, diethylstilbestrol (DES), is known to cause adult vaginal carcinoma by neonatal administration of DES to mice. However, the carcinogenic process remains unclear. By Cap Analysis of Gene Expression method, we found that neonatal DES exposure up-regulated inflammatory Cxcl chemokines 2, 3, 5, and 7 located in the 5qE1 region in the vaginal epithelium of mice 70 days after birth. When we examined the gene expressions of these genes much earlier stages, we found that neonatal DES exposure increased these Cxcl chemokine genes expression even after 17 days after birth. It implies the DES-mediated persistent activation of inflammatory genes. Intriguingly, we also detected DES-induced non-coding RNAs from a region approximately 100 kb far from the Cxcl5 gene. The non-coding RNA up-regulation by DES exposure was confirmed on the 17-day vagina and continued throughout life, which may responsible for the activation of Cxcl chemokines located in the same region, 5qE1. This study shows that neonatal administration of DES to mice causes long-lasting up-regulation of inflammatory Cxcl chemokines in the vaginal epithelium. DES-mediated inflammation may be associated with the carcinogenic process.

Risk of clear-cell adenocarcinoma of the vagina and cervix among US women with potential exposure to diethylstilbestrol in utero.

PURPOSE: Women exposed to diethylstilbestrol (DES) in utero were at elevated risk of clear-cell adenocarcinoma of the vagina and cervix (CCA) as young women. Previous research suggested that this elevated risk of CCA may persist into adulthood. We extended a published analysis to measure CCA risk as these women aged. METHODS: Standardized incidence ratios (SIR) compared CCA risk among women born from 1947 through 1971 (the DES-era) to CCA risk among the comparison group of women born prior to 1947, using registry data that covered the US population. RESULTS: Incidence rates of CCA among both cohorts increased with age. Among the DES-era birth cohort, higher rates of CCA were observed across all age groups except 55-59 years. SIR estimates had wide confidence intervals that often included the null value. CONCLUSIONS: Results are consistent with prior research and suggest an elevated risk of CCA in midlife and at older ages among women exposed in utero to DES. These results highlight unresolved issues regarding cancer risk among aging DES daughters and appropriate screening guidance. The examination of population-based cancer surveillance data may be a useful tool for monitoring trends in the incidence of other rare cancers over time among specific birth cohorts.

New frontiers of developmental endocrinology opened by researchers connecting irreversible effects of sex hormones on developing organs.

In the early 1960's, at Professor Bern's laboratory, University of California, Berkeley) in the US, Takasugi discovered ovary-independent, persistent vaginal changes in mice exposed neonatally to estrogen, which resulted in vaginal cancer later in life. Reproductive abnormalities in rodents were reported as a result of perinatal exposure to various estrogenic chemicals. Ten years later, vaginal cancers were reported in young women exposed in utero to the synthetic estrogen diethylstilbestrol (DES) and this has been called the "DES syndrome". The developing organism is particularly sensitive to developmental exposure to estrogens inducing long-term changes in various organs including the reproductive organs. The molecular mechanism underlying the persistent vaginal changes induced by perinatal estrogen exposure was partly demonstrated. Persistent phosphorylation and sustained expression of EGF-like growth factors, lead to estrogen receptor α (ESR1) activation, and then persistent vaginal epithelial cell proliferation. Agents which are weakly estrogenic by postnatal criteria may have major developmental effects, especially during a critical perinatal period. The present review outlines various studies conducted by four generations of investigators all under the influence of Prof. Bern. The studies include reports of persistent changes induced by neonatal androgen exposure, analyses of estrogen responsive genes, factors determining epithelial differentiation in the Müllerian duct, ESR and growth factor signaling, and polyovular follicles in mammals. This review is then expanded to the studies on the effects of environmental estrogens on wildlife and endocrine disruption in Daphnids.

KLK5, a novel potential suppressor of vaginal carcinogenesis.

Vaginal cancer is rare and largely unexplored. We found here that kallikrein-related peptidase 5 (KLK5) is coordinately expressed along with other KLKs in all stratified epithelia, including vagina, pointing to potential role(s) in differentiation. Further, we propose that KLK5 could be implicated in vaginal cancer development based on the fact that Klk5-/- mice are prone to develop vaginal tumors when exposed to 7,12-dimethylbenz[a]anthracene. Nf-κb activation is markedly enhanced in Klk5-/-, leading to increased resistance to apoptosis of mutated vaginal cells. This explains the higher tumor numbers observed in Klk5-/- compared to wildtype. Thus, KLK5 may represent a putative suppressor of vaginal cancer.

Factors associated with a lack of pap smear utilization in women exposed in utero to diethylstilbestrol.

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.

[Diethylstilbestrol story]. / Histoire du diéthylstilbestrol.

This story, that has been going on for 75 years begins with an infatuation for a "miraculous" drug supposed to, according to a theory and without scientific proof of effectiveness, reduce the pregnancy complications, especially the number of miscarriages. The next steps are painful with the discovery during the seventies, for the in utero exposed daughters, of particular cancers (clear cells adenocarcinoma) of the uterus cervix or the vagina, then during the eighties infertility and pregnancy accidents. This story is exemplary because it involves the different society actors whose roles will be analysed: health professionals, health authorities, patients associations, media and pharmaceutical companies. We will propose lessons for the future.

Primary non-clear-cell adenocarcinoma of the vagina in a diethylstilbestrol exposed woman.

A 54-year-old woman with a history of in-utero diethylstilbestrol (DES) exposure, who had a prior hysterectomy for symptomatic leiomyomata and dysmenorrhea, presented for vaginal bleeding. Vaginal biopsies showed a non-clear-cell adenocarcinoma, and the patient was subsequently treated with radiation therapy. We present a case of primary vaginal non-clear-cell adenocarcinoma in a patient with in-utero DES exposure. Continued monitoring of older DES-exposed women for vaginal lesions is warranted because of reported cases of non-clear-cell adenocarcinoma and persistent risk of clear cell adenocarcinoma.

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). RESULTS: 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.

The development of cervical and vaginal adenosis as a result of diethylstilbestrol exposure in utero.

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 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 adenoses 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 that can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses their molecular pathogenesis.

Diethylstilboestrol--a long-term legacy.

Diethylstilboestrol (DES) is an endocrine disrupter which causes cancer in rodents. It was prescribed in large amounts to treat women with gynaecological problems; some of the daughters of these women subsequently developed a rare cancer (vaginal clear cell adenocarcinoma) while genital abnormalities were found in some of the sons. It was used for decades in livestock feed and this may have contaminated the food chain leading to the exposure of the more general population. DES appears to cause epigenetic effects in animals and there is some evidence that this also occurs in man. The mechanisms of carcinogenesis are complex and the effects are difficult to prove due to the background of dietary and environmental phyto- and xenooestrogens. It has been suggested that, like other endocrine disrupters, DES may have acted as an obesogen in the human population.

Cancer risk in DES daughters.

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: Except for an elevated risk of CCA, persisting at older ages, and an increased risk of melanoma at young ages, we found no increased risk of cancer. Longer follow-up is warranted to examine cancer risk at ages when cancer occurs more frequently.

[Vaginal and cervical cancer due to diethylstilbestrol (DES); end epidemic]. / Vagina- en cervixcarcinoom door diëthylstilbestrol (des). Einde epidemie.

OBJECTIVE: To determine the current situation regarding the epidemic of clear cell adenocarcinoma of the vagina and the uterine cervix (CCAC) in relation to the exposure in utero to diethylstilbestrol (DES). DESIGN: Descriptive. METHODS: Patients with CCAC of the uterine cervix or vagina born after 1946 and diagnosed in the period 1969-2005, were identified through the Nationwide network and registry of histo- and cytopathology in the Netherlands and from 2003 onwards through the Netherlands Cancer Registry. Exposure data and clinical data were obtained by means of questionnaires and medical records. The histology slides of tumours were reviewed. For the patients who did not provide consent, only the date of diagnosis and age at diagnosis were known (n = 10). RESULTS: Up to 2005, 144 CCAC patients were registered. Age at diagnosis varied from 8-54 years (mean: 28 years). In the years 1981-2000, the number of new diagnoses in 4 successive 5-year periods was fairly stable (n=26-30) but it was considerably lower in 2001-2005 (n=13). Of the patients whose history of intrauterine exposure to DES was known, 62% had been exposed (76/122). The mean age at diagnosis was 24 years for exposed patients compared to 32 years for non-exposed patients. The 10-year survival rate was 78% (95% CI: 68-87) for exposed and 69% (95% CI: 56-82) for non-exposed patients. CONCLUSION: Since 2000, the incidence of CCAC of the vagina and cervix has decreased markedly compared to the situation in the 1980s and 1990 s. In particular, the number of patients with CCAC exposed in utero to DES has decreased. Whether this decrease shall continue over the coming years remains to be seen.

Cytodiagnostic problems in cervicovaginal smears from symptomatic breast cancer patients on tamoxifen therapy.

OBJECTIVE: To evaluate the effect of tamoxifen on cervicovaginal epithelium, identify tamoxifen-related changes that mimic cancer and detennine the morphologic features differentiating the 2 changes. STUDY DESIGN: Cervicovaginal smears from 153 conventionally treated primary breast cancer patients presenting with gynecologic symptoms were studied. RESULTS: All 153 patients presented with menorrhagia or irregular periods. Of 4 patients with a cytodiagnosis of atypical glandular changes, 2 had negative histology; 1 each had a uterine leiomyoma and endometrial hyperplasia. Of the 6 cases reported as adenocarcinoma, 3 were histologically confirmed, and the others were false positives. Conversely, 1 false negative case histologically was an endometrioid carcinoma. CONCLUSION: Our study revealed that reactive glandular cells are a cause of false positive diagnoses. Tamoxifen-associated cellular changes can mimic morphologic features of cancer. To avoid diagnostic errors, cervicovaginal smears should be repeated after discontinuing tamoxifen treatment. Clinical correlation is mandatory. Regular follow-up with cervicovaginal smears from patients on tamoxifen treatment is recommended.

Antenatal exposure to DES: lessons learned...future concerns.

The short- and long-term effects of the widespread use of diethylstilbestrol (DES) over 3 decades have become a distant memory for many clinicians. Others are too young to remember the flurry of activity in the early 1970s on the part of many medical centers to identify the offspring of women who were prescribed DES during their pregnancies. This medication was given in an attempt to prevent multiple pregnancy-related problems such as miscarriage, premature birth, and abnormal bleeding. The recognition of the association of DES with an increased incidence of cervical and vaginal cancers in very young women led the Food and Drug Administration to ban its use during pregnancy in 1971. Other pregnancy-related problems for the daughters and genitourinary tract changes in the sons did not become apparent until years later. Ongoing follow-up of these offspring has raised concerns for their future as well as their mothers' future. Clinicians need to be up-to-date with current knowledge regarding risks for cancer and other health-related issues.