Arthur L. Herbst

Adenocarcinoma of the Vagina

Although cancer of the vagina is rare and occurs principally in women over age 50 in the form of epidermoid carcinoma 8 girls (15-22) between 1966 and 1969 with adenocarcinoma of the vagina (clear-cell or endometrial) were seen at 2 Boston hospitals. The 4 controls (female) for each case were born within 5 days of the patient and on the same type of service (ward or private). The association between treatment of the mothers (7 or 8) with estrogen diethylstilbestrol during the pregnancies and the development of adenocarcinoma of the vagina in the girls is highly significant (p less than 0.00001). All 7 mothers began therapy in the first trimester and received either a constant dose administered to term or a continually increasing dose given almost to term. Other factors with lower levels of significance are maternal bleeding in the study pregnancy (p less than 0.05) and any prior pregnancy loss (p less than 0.01). Non-significant factors include maternal age at time of birth smoking in parents intrauterine x-ray exposure and breast feeding.

Adenocarcinoma of the vagina in adolescence. A report of 7 cases including 6 clear-cell carcinomas (so-called mesonephromas)

Seven cases of adenocarcinoma of the vagina occurring in young women 15 to 22 years of age are reported. Six sought medical advice because of abnormal bleeding, which was assumed to be due to anovulation. Hormonal therapy delayed the correct diagnosis, which was not made until vaginal examination was performed. Vaginal smears contained rare suspicious or malignant cells in 3 cases but were negative in 3 others, indicating that cytologic examination is unreliable as a diagnostic aid. Six of the tumors were clear‐cell carcinomas, or so‐called mesonephromas, and one was an endometrioid carcinoma. The frequent presence of vaginal adenosis and other evidence suggested that the clear‐cell carcinomas were of müllerian and not mesonephric origin. Although the follow‐up has not been long, radical surgery with vaginal replacement and ovarian conservation appears to have been a safe and effective method of therapy.

Prenatal Diethylstilbestrol Exposure and Risk of Breast Cancer

It has been hypothesized that breast cancer risk is influenced by prenatal hormone levels. Diethylstilbestrol (DES), a synthetic estrogen, was widely used by pregnant women in the 1950s and 1960s. Women who took the drug have an increased risk of breast cancer, but whether risk is also increased in the daughters who were exposed in utero is less clear. We assessed the relation of prenatal DES exposure to risk of breast cancer in a cohort of DES-exposed and unexposed women followed since the 1970s by mailed questionnaires. Eighty percent of both exposed and unexposed women completed the most recent questionnaire. Self-reports of breast cancer were confirmed by pathology reports. Cox proportional hazards regression was used to compute incidence rate ratios (IRR) for prenatal DES exposure relative to no exposure. During follow-up, 102 incident cases of invasive breast cancer occurred, with 76 among DES-exposed women (98,591 person-years) and 26 among unexposed women (35,046 person-years). The overall age-adjusted IRR was 1.40 [95% confidence interval (95% CI), 0.89-2.22]. For breast cancer occurring at ages ≥40 years, the IRR was 1.91 (95% CI, 1.09-3.33) and for cancers occurring at ages ≥50 years, it was 3.00 (95% CI, 1.01-8.98). Control for calendar year, parity, age at first birth, and other factors did not alter the results. These results, from the first prospective study on the subject, suggest that women with prenatal exposure to DES have an increased risk of breast cancer after age 40 years. The findings support the hypothesis that prenatal hormone levels influence breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1509–14)

Prenatal exposure to stilbestrol. A prospective comparison of exposed female offspring with unexposed controls.

Abstract The effects of prenatal exposure to diethylstilbestrol were studied by a prospective cohort investigation of 110 exposed and 82 unexposed females. The general health characteristics of mothers and daughters in both groups were similar. Among the exposed, there were striking benign alterations of the genital tract, which included transverse ridges (22 per cent), abnormal vaginal mucosa (56 per cent), and biopsy-proved adenosis (35 per cent). Among the unexposed there were no ridges and one case of vaginal mucosal abnormality including adenosis (p < 0.0001). Abnormal cervical epithelium occurred in almost all exposed subjects but in only half the unexposed (p < 0.0001). The incidence of vaginal adenosis was highest when diethylstilbestrol was begun in early pregnancy. It was not detected when treatment was initiated in the 18th week or later. Oral contraceptive use and prior pregnancy were associated with less adenosis and erosion, respectively (p <0.05). No cases of cancer were observed. (N Engl J...

Fertility in men exposed prenatally to diethylstilbestrol.

Background Prenatal exposure to diethylstilbestrol causes infertility in male mice and has been associated with malformations of the genital tract in men. However, little is known about the fertility of men who have been exposed prenatally to diethylstilbestrol. Methods In 1950 through 1952, 1646 pregnant women were enrolled in a randomized, placebo-controlled clinical trial of diethylstilbestrol at Chicago Lying-in Hospital. We interviewed men who were born to the women during that study about their fertility. Results Four decades after their birth, we were able to trace 548 of the surviving sons (68 percent). Ninety percent consented to be interviewed (253 who had been exposed to diethylstilbestrol in utero and 241 who had not been exposed). Congenital malformations of the genitalia were reported three times as often by the diethylstilbestrol-exposed men as by the sons of the women in the placebo group. Within the exposed group, malformations were reported twice as often among those exposed to diethylst...

Adverse Health Outcomes in Women Exposed In Utero to Diethylstilbestrol

BACKGROUND Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood. METHODS We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero. RESULTS Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75); spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88); preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86); loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54); ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38); preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89); stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54); early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27); and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18). For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes. CONCLUSIONS In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute.).

Age-incidence and risk of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix.

This study was based on cases accessioned in the Registry of Clear Cell Adenocarcinoma of the Genital Tract in Young Females to ascertain the incidence of diethylstilbestrol (DES)-related cancers by age and year of birth. For accuracy in estimating the size of the reference population for the incidence rates, calculations were restricted to 127 white residents of the United States who were exposed prenatally to DES or other nonsteroidal synthetic estrogens. The disease is exceedingly rare prior to age 14 when the incidence rate begins to rise rapidly. The incidence peaks at age 19 (median 19.2 years) and then drops precipitately. Thus, DES-related clear cell adenocarcinoma is unusual in that nearly all cancers have been diagnosed in a narrow age range of 10 years (14 to 23 years). Women born in 1951 to 1953 have higher incidence rates than those born in the previous or subsequent three-year period. This suggests that the prevalence of pregnancy-related use of DES was at a peak in the early 1950s. The cumulative risk of this type of genital cancer, through age 24, for DES-exposed female subjects is estimated to be in the range of 0.14 to 1.4 per thousand. The wide limits are due to the fact that the number of young women exposed is not known precisly. The low risk of disease and the narrow age range of the cases, relative to the long latency period, suggest that DES is an incomplete carcinogen. Other factors, possibly related to puberty, may be involved in the causation of this disease.

Clear-cell adenocarcinoma of the vagina and cervix in girls: Analysis of 170 Registry cases ☆

Abstract One hundred cases of vaginal and 70 cervical adenocarcinomas from the Registry of Clear-Cell Adenocarcinoma of the Genital Tract in Young Females have been analyzed. The age range of the patients was 7 to 29 years, and the frequent association with prenatal exposure to diethylstilbestrol and similar nonsteroidal estrogens was confirmed. The hormone administration began prior to the eighteenth week of pregnancy and was continued for periods ranging from 1 week to almost the entire length of the pregnancy. The total dosages ranged from 300 to 18,200 mg. Although most patients had vaginal bleeding or discharge, 16 per cent were asymptomatic. Abnormal cytology was the first clue to the diagnosis of cancer in 11 patients, but 21 per cent of the smears were negative. The larger and more deeply invasive tumors were often complicated by lymph node metastases, but these were also encountered in 1 case in which the tumor had an area of only 3 sq. cm. and with another tumor that invaded less than 3 mm. These findings suggest that local treatment of the primary tumor alone may be inadequate in some cases. Recurrences developed in 37 of the patients and 24 of them died, although the follow-up in one third of the cases has been less than 2 years. The recurrences frequently involved the lungs and supraclavicular lymph nodes as well as the pelvis. The very common association of vaginal adenosis and the occasional coexistence of transverse vaginal or cervical ridges provide morphologic evidence of a stilbestrol-related disturbance in the development of the lower Mullerian tract. The results of intravenous pyelography suggest that the development of the urinary tract is not affected. The fact that all the asymptomatic patients with carcinoma have been successfully treated thus far underscores the importance of screening exposed asymptomatic patients in search of early cases. The rarity (9 per cent) of these cancers prior to the age of 12 years suggests that the inclusion of a large population of girls in this age group in a screening program would uncover very few cases. However, such individuals should certainly be examined at any time abnormal vaginal bleeding or discharge develops.

Risk of breast cancer in women exposed to diethylstilbestrol in utero: preliminary results (United States)

BACKGROUND: A synthetic estrogen, diethylstilbestrol (DES), was widely prescribed to pregnant women during the 1950s and 1960s but was later discovered to be associated with an increased risk of clear-cell carcinoma of the vagina and cervix in female offspring. DES has not been linked to other cancers in female offspring, but studies of other prenatal factors such as twin gestation and pre-eclampsia have indicated that in-utero estrogen levels may influence breast cancer risk. We evaluated the relation of in-utero DES exposure to the risk of adult breast cancer.METHODS: A cohort of 4821 exposed women and 2095 unexposed women, most of whom were first identified in the mid-1970s, were followed by mailed questionnaires for an average of 19 years. Reported cancer outcomes were validated by medical record review. Breast cancer incidence in DES-exposed daughters was compared with cancer incidence in unexposed daughters with use of Poisson regression analysis, adjusting for year of birth, age at menarche, age at first birth, and number of births.FINDINGS: The rate ratio for incidence of invasive breast cancer in exposed versus unexposed women was 1.4 (95% confidence interval (CI) = 0.7–2.6). DES exposure was not associated with an increased risk of breast cancer in women under 40 years, but among women aged 40 and older the rate ratio was 2.5 (95% CI = 1.0–6.3). The rate ratio for the association of DES exposure with estrogen receptor-positive tumors was 1.9 (95% CI = 0.8–4.5).INTERPRETATION: While not statistically significant, the overall 40% excess risk, arising exclusively from the subset of estrogen receptor-positive cases, raises a concern calling for continued investigation.

Avoiding serious infections associated with abdominal hysterectomy: A meta-analysis of antibiotic prophylaxis

OBJECTIVE Our objective was to determine whether the use of preoperative antibiotics prevents serious infections associated with total abdominal hysterectomy. STUDY DESIGN We identified 25 randomized controlled trials of antibiotic prophylaxis that used rigorous protocols. We performed meta-analysis and cumulative meta-analyses for all of the trials, and then we performed separate meta-analysis for cefazolin, metronidazole, and tinidazole. RESULTS Overall, 21.1% (373 of 1768) of the patients who did not receive antibiotic prophylaxis had serious infections after abdominal hysterectomy. Among patients who received any antibiotics, we found that 9.0% (166/1836) had serious postoperative infections; among those who received cefazolin, metronidazole, or tinidazole, 11.4% (70 of 615), 6.3% (17 of 269), and 5.0% (5 of 101), respectively, had serious postoperative morbidity. The differences in the prevalence of infection between women who received prophylaxis and women who did not receive prophylaxis were statistically significant (any antibiotics, p = 0.00001; cefazolin, p = 0.00021; metronidazole, p = 0.015; and tinidazole, p = 0.034). CONCLUSION Because preoperative antibiotics are highly effective in the prevention of serious infections associated with total abdominal hysterectomy, we believe they should be used routinely. In addition, we believe that the use of controls who receive no treatment is no longer justified in trials of antibiotic prophylaxis for total abdominal hysterectomy.