Diane Anderson

The Association between In Utero Cigarette Smoke Exposure and Age at Menopause

Menopause onset, on average, occurs earlier among women who smoke cigarettes than among women who do not smoke. Prenatal smoke exposure may also influence age at menopause through possible effects on follicle production in utero. Smoking information was obtained from the mothers of 4,025 participants in the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project, a US study begun in 1975 to examine the health effects of prenatal diethylstilbestrol exposure. Between 1994 and 2001, participants provided information on menopausal status. Cox proportional hazards modeling compared the probability of menopause among participants who were and were not prenatally exposed to maternal cigarette smoke. Participants prenatally exposed to maternal cigarette smoke were more likely than those unexposed to be postmenopause (hazard ratio = 1.21, 95% confidence interval: 1.02, 1.43). The association was present among only those participants who themselves had never smoked cigarettes (hazard ratio = 1.38, 95% confidence interval: 1.10, 1.74) and was absent among active smokers (hazard ratio = 1.03, 95% confidence interval: 0.81, 1.31). In this cohort of participants predominantly exposed to diethylstilbestrol, results suggest that prenatal exposure to maternal cigarette smoke may play a role in programming age at menopause. The possibility that active cigarette smoking modifies this effect is also suggested.

Local therapy in stage I clear cell adenocarcinoma of the vagina

Of the 219 cases of Stage I vaginal clear cell adenocarcinoma reviewed, 176 had conventional therapy and 43 underwent local therapy. The two groups appear to be similar with respect to symptoms, stage, location of the lesion in the vagina, greatest tumor diameter, surface area, depth of invasion, predominant histologic pattern, grade, and number of mitoses; nonetheless, firm conclusions cannot be drawn because of missing data. Actuarial survival rates at 5 and 10 years for the local therapy group (92% and 88%, respectively) were essentially equivalent to those for the conventional therapy group (92% and 90%, respectively), however, the recurrence experience after local therapy was less favorable. Local therapy consisted of vaginectomy in nine cases, local excision alone in 17 cases, and local irradiation (with or without local excision) in 17 cases. The subgroup of patients receiving local irradiation had a recurrence experience as favorable as that of the conventional therapy group and more favorable than that of either the subgroup treated with vaginectomy or local excision alone. The data suggest that when employed, local therapy should include local irradiation.

Preterm birth, fetal growth, and age at menarche among women exposed prenatally to diethylstilbestrol (DES).

Diethylstilbestrol (DES), a synthetic estrogen used in pregnancy during the 1950s and 1960s, provides a model for potential health effects of endocrine disrupting compounds in the environment. We evaluated prenatal exposure to DES, based on medical record review, in relation to gestational length, fetal growth, and age at menarche in 4429 exposed and 1427 unexposed daughters. DES exposure was associated with an increase in preterm birth (odds ratio (OR)=2.97; 95% CI=2.27, 3.87), and a higher risk of small for gestational age (SGA) (OR=1.61; 95% CI=1.31, 1.98). The association between DES exposure and early menarche was borderline, with stronger effects when early menarche was defined as ≤ 10 years (OR=1.41 95% CI=0.97, 2.03) than defined as ≤ 11 years (OR=1.16; 95% CI=0.97, 1.39). This study provides evidence that prenatal DES exposure was associated with fetal growth and gestational length, which may mediate associations between DES and health outcomes in later life.

Clear cell adenocarcinoma (CCA) of the vagina and cervix in association with pregnancy

The effect of pregnancy on patients with CCA of the vagina and cervix was evaluated based upon a review of 503 cases. Eighty-five had been pregnant (24 at diagnosis), 408 had never been pregnant, and the pregnancy history was unavailable in 10 cases. All of the 24 patients pregnant at diagnosis were over 16 years of age; 14 were in the first trimester, 6 in the second, and 4 in the third trimester. By FIGO criteria, 15 were stage I, 7 stage II, and 2 were stage III. The 24 pregnant and 408 never pregnant (age corrected) cases were compared with regard to maternal hormone history, symptoms, stage, location, predominant histologic or cell type, greatest tumor diameter, surface area, depth of invasion, grade, and number of mitoses. No significant differences were detected. Twelve of the 24 pregnant patients had radical hysterectomy with or without irradiation (9 stage I, 3 stage II); of the 7 treated by local therapy (5 stage I, 2 stage II), 3 required additional therapy due to persistent disease; 4 had radiotherapy alone (1 stage I, 2 stage II, and 1 stage III); one had teletherapy followed by exenteration (stage III). Six of the 24 died 2 to 12 years after diagnosis (1 stage I, 3 stage II, 2 stage III). Eighteen are alive at 1 to 17 years. The overall 5 and 10 year actuarial survival rates (age adjusted) for the group pregnant at diagnosis (86 and 68%) do not differ significantly from the never pregnant group. Pregnancy does not seem to adversely affect the outcome of CCA. Guidelines are presented to treat pregnant patients with CCA.

Risk factors for diethylstilbestrol-associated clear cell adenocarcinoma☆

Objective To assess the influence of postnatal factors on the development of clear cell adenocarcinoma in women exposed to diethylstilbesterol (DES), particularly factors related to exogenous or endogenous hormone exposures, and to reassess the relation of season of birth. Methods For the analysis of postnatal factors, 244 cases were compared with 244 age-matched DES-exposed women. Information was obtained from telephone interviews, with questions asked in reference to an index age, the age at which clear cell adenocarcinoma was diagnosed. For the analysis of season of birth, 604 cases, living or deceased, were compared with 1749 DES-exposed women. Results Neither oral contraceptive (OC) use nor pregnancy was associated with risk of clear cell adenocarcinoma: the odds ratios (OR) were 1.1 (95% confidence interval [CI] 0.7, 1.8) for OC use and 1.3 (95% CI 0.7, 2.3) for pregnancy. The OR for fall season of birth relative to all other seasons was 1.2 (95% CI 0.9, 1.4). Conclusion Pregnancy and OCs do not increase risk of DES-associated clear cell adenocarcinoma. In addition, season of birth does not appear to be a material factor; the previous finding of an increased risk for fall season of birth is most likely not valid and probably a chance finding due to small sample size.

Clear cell adenocarcinoma of the lower genital tract: Correlation of mother's recall of diethylstilbestrol history with obstetrical records

The written obstetric records of maternal exposure to diethylstilbestrol (DES) were used as a criterion standard and compared with the DES exposure history recalled by mothers of women with vaginal, cervical, or indeterminable vaginal/exocervical clear cell adenocarcinoma. Among cervical cases, the sensitivity of maternal recall was 50% (N = 2), and its specificity was 100%. Among vaginal and vaginal/exocervical cases, this sensitivity was 72%; specificity was 60%; and the majority of these mothers who said they did not take DES were DES positive by written records. Thus investigators should avoid using maternal recall alone to measure DES exposure. Among subjects for whom written maternal obstetric records were available, 88% of vaginal cases and 46% of cervical cases were DES positive. the authors conclude that few cases of vaginal clear cell adenocarcinoma should occur in young women as the cohort of women exposed in utero to DES continues to age, whereas cases of cervical origin may continue to occur.

Incidence rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix: Update after 40-year follow-up

OBJECTIVE Women exposed to diethylstilbestrol (DES) in utero are at increased risk for the development of vaginal and cervical clear cell adenocarcinoma (CCA) at younger age. It is unknown if a second peak will occur in later life, the ages when CCA developed spontaneously in the pre-DES era. The complete epidemiologic curve of CCA has not been reported, yet. METHODS We reviewed 720 cases of CCA from the CCA registry at the University of Chicago through 2014. Incidence rates and cumulative risks for CCA were calculated based on white women born in the U.S. from 1948 through 1971. RESULTS In 420 CCA cases there was documented evidence of prenatal DES exposure. 80% were among those between ages 15 and 31 but some occurred as late as age 55. A small second peak occurred around age 42. The risk of DES-related CCA was highest in the 1951-1956 birth cohort and this birth cohort effect closely correlated with DES prescriptions over time in the U.S. (r=0.98, P=0.005). By age 50, the cumulative risk of CCA was 1 per 750 exposed women. CCA cases without evidence of DES exposure had similar ages, year of diagnosis, and birth cohort patterns as the documented DES-exposed cases, suggesting that some negative cases were exposed. Their inclusion raises the cumulative risk of CCA to 1 per 520. CONCLUSION With the largest data available, our results confirmed the association between prenatal DES exposure and clear cell adenocarcinoma. The study also refines the risks of DES-related CCA.

Diethylstilbestrol (DES) Pregnancy Treatment: A Promising Widely Used Therapy with Unintended Adverse Consequences

Diethylstilbestrol (DES) was widely used in the 1940s to 1960s to prevent pregnancy loss but was later found to be associated with adverse health effects in exposed offspring, underscoring the need for careful evaluation of new therapies.

Follow-up of Patients with Clear-Cell Adenocarcinoma of the Vagina and Cervix

Clear-Cell Adenocarcinoma and DES Exposure Among 695 women with clear-cell carcinoma of the vagina and cervix who were followed for a median of nearly 23 years, 5-year survival was 86% among women with documented diethylstilbestrol exposure and 81% among those without such exposure.

Abstract 709: Incidence and mortality of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix: 40 years of long-term follow-up

Objective: Women exposed to diethylstilbestrol (DES) in utero are at increased risk for the development of vaginal and cervical clear cell adenocarcinoma (CCA), and possibly of breast cancer, diabetes, and cardiovascular diseases as well. A peak in the age-incidence curve in DES- related CCA has been documented at ages 19 to 24. It is unknown if a second peak will occur in later life, the ages when CCA developed spontaneously in the pre-DES era. In addition, the long-term prognosis and health impact for adolescents and young adults who have DES-related CCA are unknown. Methods: 720 cases of CCA were reviewed from the CCA Registry at the University of Chicago through 2014. Rates and cumulative risks for CCA were calculated based on white women born in the U.S. from 1948 through 1971. Kaplan-Meier method was used to estimate survival probability among women with CCA. Cox models were used to identify independent prognostic factors. To gauge the relative impact of young-onset clear-cell adenocarcinoma on mortality, we compared their mortality hazards with mortality hazards of the U.S. female population, and calculated standardized mortality ratio (SMR). Results: In 420 CCA cases there was documented evidence of prenatal DES exposure. 80% patients had a CCA between ages 15 and 31 but some occurred as late as age 55. A small second peak occurred around age 40. The risk of U.S. born, white DES-related CCA was highest in the 1951-1956 birth cohort, and this birth cohort effect correlated with DES use in the U.S. By age 50, the cumulative risk of CCA was 1 per 750 exposed women. A total of 695 CCA patients were included in the survival analysis. After a median follow-up of 22.7 years (interquartile range: 10.8-35.1 years), 219 patients died. The 5-year, 10-year, and 20-year survival probabilities were 83%, 75%, and 69%, respectively. As expected, tumor stage was a strong prognostic factor for survival among DES-related CCA cases. Tubular-cystic histology was associated with better survival compared with papillary, solid, or a combination of these histological patterns. Adolescent patients ( Conclusion: Our study drew a relatively complete epidemic curve of DES-related CCA. There existed late-onset CCA among women with prenatal exposure of DES. DES-related CCA increased mortality not only during early life among exposed women, but also impacted life after age 50. These results suggest continued close health follow-up of this population. Citation Format: Dezheng Huo, Diane Anderson, Arthur L. Herbst. Incidence and mortality of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix: 40 years of long-term follow-up [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 709. doi:10.1158/1538-7445.AM2017-709