Diethylstilbestrol-associated vaginal adenosis followed by clear cell adenocarcinoma

A young woman was examined because of a history of in utero exposure to diethylstilbestrol and was identified as having vaginal adenosis. Fourteen months later, on routine follow-up, a small vaginal clear cell adenocarcinoma was recognized. She refused any therapy other than wide local excision. She was seen intermittently for several years with no recurrence. Five and one-half years after initial diagnosis she was found to have multiple sites of clear cell adenocarcinoma in the upper third of the lateral and anterior vaginal walls. Cases of vaginal adenosis followed later by the development of clear cell adenocarcinoma (metachronous cases) are distinctly unusual. The authors have collected the other recorded cases in the literature or in the Registry for Research on Hormonal Transplacental Carcinogenesis and have attempted to compare these cases with the larger group of patients who present with clear cell adenocarcinoma and have associated vaginal adenosis (synchronous cases). The authors have found few differences between the two groups. Most of the differences can be accounted for by the close follow-up of patients with known vaginal adenosis. However, it has been noted that the location of the clear cell adenocarcinoma is apparently different in the two groups. The reasons for this apparent difference are briefly discussed.     

Pathology of the vagina.

This review summarizes key articles published in 1990 relevant to abnormalities of the vagina. The subjects covered include vaginal squamous neoplasia, including epidemiologic characteristics, vaginal intraepithelial neoplasia, superficially invasive carcinoma of the vagina, and the expression of epidermal growth factor and HER-2neu in normal and neoplastic epithelium. Clear cell adenocarcinoma is discussed, and recent epidemiologic factors distinguishing vaginal from cervical clear cell adenocarcinoma, as they are related to in utero diethylstilbestrol exposure, are presented. Small cell neuroendocrine carcinoma of the Bartholin's gland, presenting as a vaginal mass, is documented in a reviewed case report. A series of primary malignant melanomas of the vagina are presented and clinical and pathologic features, as well as survival data and factors influencing survival are presented. Three studies on vaginal fibroepithelial polyps, clinical and pathologic evaluations, as well as differential diagnosis and concepts of origin, are reviewed. These findings provide new insights into the understanding of the properties of the subepithelial stroma of the lower female genital tract and its capacity to change in pregnancy and the postpartum state.     

Vaginal adenosis in stillborns and neonates exposed to diethylstilbestrol and steroidal estrogens and progestins.

A histologic study was conducted of sagittal sections of the genital tracts of 281 autopsied female stillborns and neonates. The prevalence of vaginal adenosis among 43 offspring exposed in utero to diethylstilbestrol (DES) was 70%, a frequency 18 times greater than the 4% prevalence among 159 unexposed offspring. The relationship of the prevalence of vaginal adenosis to the gestational age at initial exposure was highly significant: 81% of those first exposed during the period of vaginogenesis had adenosis, whereas none exposed after 21 weeks' gestation had adenosis (P1 = 1 X 10(-4)). The relationship of the prevalence of vaginal adenosis to the total dose of DES prior to 22 weeks' gestation also was significant (P1 = 0.02), and this relationship was independent of gestational age at first exposure (P1 =0.01). In contrast, the prevalence of adenosis among 23 offspring exposed to steroidal estrogens and progestins was about the same as that among the unexposed offspring. Vaginal adenosis was unrelated to the complications of pregnancy for which the hormones were given, the calendar year of birth, and the gestational age at delivery.     

Findings in female offspring of women exposed in utero to diethylstilbestrol

OBJECTIVE: To examine a group of women (third-generation daughters) whose mothers were exposed in utero to diethylstilbestrol (DES) and compare their findings on pelvic examination with those noted in their mothers. METHODS: Letters were mailed to women documented to have been exposed in utero to DES who had given birth to a female offspring, inviting them to have their daughters come in for a detailed history and pelvic examination. Records of the mothers whose daughters appeared for examination were reviewed, and findings noted at the time of their initial examination were recorded. Detailed pelvic examination of the third-generation daughters included colposcopic examination and iodine staining of the vagina and cervix and Papanicolaou smear. The findings observed in these women were compared with those noted in their mothers at the time of their mothers' first examination. RESULTS: Twenty-eight third-generation daughters were examined. Three of the daughters were delivered from one mother. Review of the mothers' records indicated that 16 (61.5%) of the mothers exposed to DES during their pregnancy demonstrated structural changes of the cervix, upper vagina, or vaginal epithelial changes consisting of adenosis, nonstaining vaginal epithelium after application of iodine solution, or white epithelium within the vagina. None of the daughters were found to have changes usually associated with DES exposure. CONCLUSION: The absence of abnormalities in the lower genital tract in third-generation women compared with the high frequency of these abnormalities in their mothers suggests that third-generation carryover effects of in utero DES exposure are unlikely.     

Upper genital tract abnormalities and pregnancy outcome in diethylstilbestrol-exposed progeny

Previous studies have suggested that there is an association between genital tract abnormalities and pregnancy outcome in women exposed to diethylstilbestrol (DES) in utero. In a collaborative study, 676 DES-exposed women had hysterosalpingographic examinations, and the findings were related to the outcome of pregnancy in 327 of these women. The findings revealed that (1) there is a considerable variation of frequency of different types of upper genital tract anomalies in women from different sources and with different motivations for enrollment in the study, (2) the presence of structural cervical changes and vaginal epithelial changes are markers for the likelihood of abnormalities in the uterine fundus, (3) women with upper genital tract abnormalities have increased odds for poor pregnancy outcome as compared to women with normal hysterosalpingographic findings, and (4) although some abnormalities were most often or consistently associated with poor pregnancy outcome, no specific changes could be related to specific types of pregnancy outcomes.     

Clear cell adenocarcinoma of the vagina: a second primary in a diethylstilbestrol-exposed woman?

A clear cell adenocarcinoma of the vaginal remnant in a diethylstilbestrol (DES)-exposed woman developed 20 years after anterior exenteration for a histologically similar stage II vaginal cancer. Arguments favoring a new primary cancer over a late recurrence are presented. This case probably represents the first report of a second primary vaginal clear cell cancer after DES exposure in utero. The implications of a second vaginal primary and the need for long-term surveillance in DES-exposed women are discussed.     

Six years' experience with screening of a diethylstilbestrol-exposed population.

The physician population delivering obstetric care in Philadelphia between 1950 and 1970 was contacted to ascertain their use of diethylstilbesterol (DES) during pregnancy. Of the 31.8% of the physicians who responded to the questionnaire, 71.8% used DES during pregnancy and 12.7% desired assistance in review of their records. During the 6 years from the initial survey, 830 young women exposed to DES in utero were periodically screened for cervicovaginal abnormalities and clear cell adenocarcinoma. Of these 830 patients 61.7% were found to have cervicovaginal abnormalities, and 65.9% of the patients showed either adenosis or evidence of the prior existence of vaginal adenosis. Eight patients were treated for clear cell adenocarcinoma. Two cases were detected while asymptomatic. Seven of the patients are living with no evidence of cancer, and two of these have survived over 5 years.     

Vaginal adenosis in a non-diethylstilbestrol-exposed 6-year-old patient.

Vaginal adenosis is rare, and it is defined as the presence of metaplastic cervical or endometrial epithelium within the vaginal wall. It is associated with in utero exposition to diethylstilbestrol and a high risk of vaginal carcinomas. A case of vaginal adenosis arising in a non-diethylstilbestrol-exposed 6-year-old patient is presented. Few cases have been described in children and adolescents, and since the withdrawal of diethylstilbestrol from the market, this condition is rarely described in the medical literature. However, it should be considered as a possible diagnosis in girls with persistent vaginal discharge.     

Phenotypic differences in upper genital tract abnormalities and reproductive history in dizygotic twins exposed to diethylstilbestrol in utero. A case report

Major phenotypic variations in reproductive function and upper genital tract abnormalities were found between 30-year-old dizygotic twins exposed in utero to diethylstilbestrol (DES). The women were exposed to maternal DES doses of 12.5-50.0 mg daily starting from the 12th gestational week as documented in the original antepartum obstetric office records. Twin A had primary involuntary infertility of over four years' duration associated with a severe DES uterine deformity on hysterosalpingography (HSG). A complete evaluation demonstrated all other infertility investigations to be normal. Twin B had two term pregnancies but a significant history of reproductive loss, including three miscarriages and one ectopic pregnancy. HSG demonstrated mild DES-induced changes. Cervical adenosis was observed only in the more severely affected twin.     

Concurrent primaries of vaginal clear cell adenocarcinoma and endometrial adenocarcinoma in a 39-year old woman with in utero diethylstilbestrol exposure

Abstract. Keller C, Nanda R, Shannon RL, Amit A, Kaplan AL. Concurrent primaries of vaginal clear cell adenocarcinoma and endometrial adenocarcinoma in a 39-year-old woman with in utero diethylstibestrol exposure.
Diethylstilbestrol (DES) was used widely in the late 1940s in an attempt to prevent adverse pregnancy outcomes. In 1971 the US Food and Drug Administration proscribed its use for pregnancy support secondary to its association with clear cell adenocarcinoma of the vagina. Several studies in animal models demonstrated an association with endometrial cancer among offspring following in utero DES exposure. To date, there is only one case report of endometrial cancer in women exposed to DES in utero . We present the first case, to our knowledge, of a woman exposed to DES in utero who presented with double primaries of clear cell cancer of the vagina concomitant with endometrial cancer.     

Diethylstilbestrol (DES)-induced clear cell adenocarcinoma of the vagina metastasizing to the brain

BACKGROUND: Primary vaginal clear cell adenocarcinoma (CCA) is a rare gynecological malignancy occurring predominantly in young females with a history of diethylstilbestrol exposure in utero. Vaginal CCA commonly metastasizes to the lungs and the supraclavicular lymph nodes; however we present a rare case of diethylstilbestrol-induced vaginal CCA with cerebral metastases. CASE DESCRIPTION: A 43-year-old woman with prenatal diethylstilbestrol exposure and history of vaginal CCA treatment 8 years prior to current presentation noted new onset headache and dizziness. MRI showed an enhancing mass in the right frontal lobe. Histopathology was consistent with CCA. CONCLUSIONS: This case report highlights the necessity of close extended follow-up in patients with a history of vaginal CCA and demonstrates the potential for spread of primary vaginal CCA to the brain.     

Symposium on scanning electron microscopy of fertility and infertility, Eighth Congress of Fertility and Sterility, Buenos Aires, Argentina, November 1974. Human vaginal adenosis and adenocarcinoma.

Samples of vaginal tissue were obtained from patients with a recorded history of exposure to nonsteroidal estrogens such as diethylstilbestrol (DES) in utero as well as from patients not exposed to DES but undergoing vaginal operations for other reasons. The tissue was removed from various sites within the vagina and divided into 2 segments, 1 fixed in 10% formalin and the other in 3.5% glutaraldehyde. The formalin series received routine histological analysis. The glutaraldehyde series was further prepared for scanning electron microscopy. As a result of exposure to DES several cervico-vaginal aberrations were noted, the most striking of which were those seen histologically. These have been classified into 5 groups: 1) complete epidermidization - complete replacement by metaplasia; 2) surface epidermidization - residual glands beneath and surface; 3) incomplete epidermidization - mixture of columnar epithelium on surface including crypts and glandlike elements; in-situ or invasive: and 5) squamous cell dysplasia. The differentiation of the early embryonic vaginal epithelium to that of the mature squamous epithelium of the newborn seems to be interfered with by the in utero exposure to nonsteroidal estrogens. It is not known whether this is due to inhibition with steroid estrogens or to some other enzymatic process. As a result of this exposure, vaginal adenosis develops. There is a natural tendency of the body to convert this adenosis to normal squamous epithelium through the process of metaplasia and the 5 states observed represent all phases of this process. In the group of patients in which the metaplastic process is incomplete or in a state of transition both columnar cells and squamous cells exist adjacent to each other and between them cells with variable degrees of metaplastic change. In a few patients these abnormal embryonic cell nests lead to the development of a malignancy, usually a mesonephromal clear-cell adenocarcinoma. Furthermore, within the areas of metaplastically converted squamous epithelium, anaplastic and dysplastic cellular changes also occur, with the potential danger of developing intraepithelial and possibly invasive squamous cell carcinomas of athe vagina.     

Colposcopic aspects of management of vaginal adenosis in DES children

This report presents evidence from clinical experience of the etiological role of in utero exposure to diethylstilbestrol (DES) in vaginal adenosis of children and adolescents. Figures depict the histological pattern of adenosis lesions, and a brief history of research and serendipity leading to the causal hypothesis is reviewed. This research included 2 retrospective studies of pediatric vaginal carcinoma (circa 1927 and 1963) as well as current studies. The study summarized here was prompted by the author's extensive use of DES for high-risk pregnancy management and his resultant attempt to locate patients exposed in utero during his practice. Office records since 1948 were reviewed, comprising 10,051 charts. Using colposcopy, 20 respondents to a questionnaire have been examined, and 17 had varying degrees of vaginal or cervical abnormalities. The mothers of all cases with severe adenosis (n=9) received more than 100 mg daily during the first trimester of pregnancy. All 20 mothers had received from 15-600 mg daily. In the 3 patients without adenosis, 1 mother was treated daily with 15 mg, starting Day 78; the second was treated with 15-25 mg daily, starting on Day 28; and the third was treated with 100 mg daily for only 5 days on Day 67-72 of gestation. 2 case reports are published. The treatment method recommended is to remove all abnormal epithelium from the top of the vagina under colposcopic guidance in the operating room under general anesthesia or in the office with local anesthesia; a small Eppendorfer biopsy instrument should be used to "weed the garden."     

Primitive Clear Cell Carcinoma of the Vagina Treated Conservatively

BackgroundClear cell adenocarcinoma of the vagina is rare tumour that is usually treated aggressively. We report a case of clear cell adenocarcinoma in which conservative treatment using new technology was successfully completed.CaseA 19-year-old woman with a biopsy proven clear cell adenocarcinoma of the vagina was referred to our clinic. There was no history of in utero diethylstilbestrol exposure. Colposcopic examination and pelvic MRI confirmed a superficial vaginal lesion. Fertility-sparing surgery, comprising radical local vaginal excision, laparoscopy, sentinel node mapping, pelvic node dissection, and omentectomy, was planned. A staging surgical procedure including a unilateral sentinel lymph node was negative.ConclusionConservative surgery can be offered to a young woman presenting with this rare tumour in order to preserve fertility. Sentinel node mapping is an adjunct to the conservative surgery.     

Synchronous clear cell adenocarcinoma of the cervix and endometrioid carcinoma of the endometrium

Synchronous primary malignant neoplasms of uterus are uncommon. Patients with synchronous cervical and endometrial cancers are even rarer. We describe a case of cervical clear cell carcinoma and endometrial adenocarcinoma occurring simultaneously in a 54-year-old woman presenting with intermittent vaginal bleeding. The concept of synchronous primary malignancies of the genital tract is also reviewed in this report.     

Cervical-vaginal adenosis after in utero exposure to synthetic estrogens

A study to determine the incidence of adenosis and/or adenocarcinoma of the vagina in 528 females between 13 and 25 years who were exposed to diethlstilbesterol in utero and to define the clinical and microscopic changes in their vaginas was undertaken, using primary physicians records as a source for patient identification. Lugol's staining was evaluated and was found to be a simple technique for identifying the lesion of adenosis. Of the young women with documented exposure to diethylstilbesterol or dienestrol, over 90% had adenosis of the vagina. In almost all cases the drug treatment began before the twelfth gestational week. In some patients, the appearance of the cervix was unusual. Of the 188 patients who underwent excisional biopsy, 2 showed a small focus of clear cell adenocarcinoma which was not detected clinically. A causal relationship between in utero exposure to diethylstilbesterol or dienestrol is suggested. It is also suggested that the lesion is developmental since it has been found in prepubertal girls.     

Value of screening procedures for the detection of vaginal adenosis.

This study describes the use of routine vaginal iodine staining and other screening procedures for the detection of vaginal adenosis in 3871 postpubertal female patients. Iodine staining identified 65 patients with nonstaining areas in the vagina. Colposcopy verified the presence of vaginal adenosis in 11 of the 65 patients. Directed biopsies confirmed the diagnosis in 10 patients. The iodine staining procedure detected vaginal adenosis in only 1 patient who did not have a positive history of DES exposure or coexisting physical findings. Iodine staining of the vagina has little value as a screening procedure for the detection of vaginal adenosis. Based on these findings, a careful medical history and vaginal examination are recommended as the most productive routine screening procedures for vaginal adenosis. Evaluation and followup of those patients with a history of DES exposure in utero or physical findings suggestive of vaginal adenosis should include vaginal Papanicolaou smears supplemented by colposcopy at 6-month to 1-year intervals. Colposcopically directed biopsies of all abnormal areas should be obtained.     

The effects of prenatal diethylstilbestrol (DES) exposure on the genitalia of pubertal Macaca mulatta. I. Female offspring.

Nineteen pregnant female rhesus monkeys (Macaca mulatta) received 1 mg/day diethylstilbestrol (DES) over three time periods during gestation: day 21 to delivery (group I), day 100 to delivery (group II) and day 130 to delivery (group III). Seven females and five males of a total of 20 offspring are presently alive at 5 1/2 years of age; one female died at 5 years of age. No deaths have been shown to be treatment related. In female offspring, menstruation began at about 2 1/2 years of age, was irregular for approximately one and one-half to two years and then became regular. Vaginal ridging and/or cervical hooding have been observed in seven of the eight DES-exposed females, and three had histologically demonstrable vaginal adenosis. None of the anomalies was related to a specific treatment period, for they appeared in all treatment groups, nor did they occur in the age-matched controls. Furthermore, none of the animals, either treated or control, showed any evidence of adenocarcinoma. Therefore, exposure of Macaca mulatta females to DES in utero appears to be teratogenic, but thus far no carcinogenicity has been observed. Reports in humans indicate that adenocarcinoma is an additional manifestation of prenatal exposure to DES; also, treatment effects appear to be more commonly observed in individuals exposed during the early stages of gestation. From this viewpoint, the rhesus monkey is a potentially valuable model for the study of vaginocervical anomalies and adenosis, but it is premature to consider it a suitable model for the study of adenocarcinoma.     

Colposcopic findings and intraepithelial neoplasia in diethylstilbestrol-exposed offspring. The Dutch experience

Data from two regional diethylstilbestrol clinics for colposcopic evaluation of young women with a history of diethylstilbestrol exposure in utero are presented: A total of 224 subjects with a well-documented history were enrolled in this study. Structural anomalies of the cervix and vagina were found in 30%. Vaginal epithelial changes were colposcopically observed in 65%, including vaginal adenosis in 22%. The prevalence rate of abnormal cytologic findings in the study group was 9%. In half of these patients a low-grade intraepithelial neoplasia of the cervix and vagina was found. It was concluded that colposcopy in diethylstilbestrol-exposed offspring in inexperienced hands can result in many unnecessary biopsies. Therefore colposcopic examination should be performed by expert colposcopists in referral diethylstilbestrol centers.     

Vaginal adenosis with adenocarcinoma in situ in a woman with no recognised antecedent factors

We present a case of vaginal adenosis with adenocarcinoma in situ in a woman with no recognised antecedent factors. This case demonstrates the importance of continuing thorough colposcopic assessment of the entire lower genital tract with repeated biopsies of all abnormal epithelium in women with persistent or recurrent cervical cytology abnormalities. Successful management requires accurate definition of the vaginal lesion.