Colposcopic evaluation of DES-exposed progeny at two large medical centers: the squamous neoplasia problem

The squamous neoplasia problem, Southern medical journal, 1978

Colposcopy-Unit
Cases of vaginal adenosis in young women should be investigated and screened appropriately, and preferably referred to centres where colposcopic expertise is available.

1978 Study Abstract

Two hundred eight patients with confirmed or suspected diethylstilbestrol exposure were examined colposcopically at two separate medical centers.

  • Cervicovaginal ridges were present in 90 (43.3%)
  • and ectopy was found in 188 (90.4%) of the patients.
  • Evidence of vaginal adenosis was present in 122 (58.6%) of the cases.

Seventy-four percent of the patients had abnormal colposcopic findings:

  • 15.4% having columnar epithelium on the surface of the vagina
  • and 66% having abnormal transformation zones (white epithelium, punctation, mosaic).
  • Twenty patients (9.6%) were initially identified histologically as having squamous dysplasia. Subsequent review of the histologic material in these cases could document only two cases of significant squamous dysplasia, both severe, the remainder having immature, atypical metaplasia or possibly very mild dysplasia.

This finding emphasizes the problems encountered in histologically differentiating squamous neoplasia from the peculiar metaplasia found in these patients, thereby making it difficult to establish whether these patients are at increased risk for the development of squamous neoplasia..

Sources and more information
  • Colposcopic evaluation of DES-exposed progeny at two large medical centers: the squamous neoplasia problem, Southern medical journal, NCBI PMID: 663728, 1978 Jul.
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1985 Swiss case of vaginal adenocarcinoma after uterine exposure to diethylstilbestrol

Schweizerische medizinische Wochenschrift, NCBI pubmed 3841230 2;115(44):1555-61, Nov 1985.

CCAC
Following reports on a few cases in other countries, this 1985 report was the first in a Swiss female, aged 23, with stage III DES-induced adenocarcinoma of the vagina.

1985 Study Abstract

From 1946 to 1971, diethylstilbestrol, a nonsteroid synthetic estrogen, came in for widespread use in the USA, and in other countries only occasional use, for the treatment of high-risk pregnancies.

In 1971 a retrospective epidemiologic study showed a close association of this therapy with occurrence of vaginal and cervical adenocarcinoma in young women (mean age 19 years). Up to 1981 63% of 429 clear cell carcinomas of the vagina and cervix were related to DES exposure in utero in the USA.

Following reports on a few cases in other countries, the present report is the first in a Swiss female, aged 23, with stage III DES-induced adenocarcinoma of the vagina.

The risk of DES-related adenocarcinoma is estimated at about 1%, but benign teratogenic lesions are present in over 50% of patients. Vaginal adenosis is the most frequent finding, but other malformations of vagina (septa), cervix, uterus and fallopian tube may be found. Malformations of the genital tract have also been described in DES-exposed male offspring.

Sources and more information
  • A case of vaginal adenocarcinoma after uterine exposure to diethylstilbestrol, Schweizerische medizinische Wochenschrift, NCBI pubmed 3841230  2;115(44):1555-61, Nov 1985.
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Epidemiology of vaginal adenosis and adenocarcinoma associated with exposure to stilbestrol in utero

US National Library of Medicine National Institutes of Health, 1977

image of woman thinking
While the risk of developing adenocarcinoma appears to be very low, a majority of exposed females do have other abnormalities of the lower genital tract. Almost sad – m00by by M.E. Aguila.

1977 Study Abstract

Following the observation that maternal ingestion of diethylstilbestrol was associated with the development of adenocarcinoma of the vagina in young women, analysis of 170 cases of the disease, collected over a two-year period, was undertaken. Details of history of non-steroidal estrogenic intake during pregnancy, its dosage and duration of intake and prevalence of concomitant abnormalities of the vagina and cervix were recorded.

This analysis disclosed that dosage and duration of intake do not appear to be vital factors in contributing to the development of carcinoma. A controlled, prospective investigation of prenatal exposure to stilbestrol was also carried out. Vaginal and cervical abnormalities were common among 110 young women exposed to stilbestrol in utero. Biopsy-proved vaginal adenosis was present in 35% of the exposed population as compared with only 1% of the control subjects. Fibrous ridges of the vagina and cervix and failure of the vaginal mucosa and portions of the cervix to stain with iodine were also more frequently observed in the exposed population.

While the risk of developing adenocarcinoma appears to be very low, a majority of exposed females do have other abnormalities of the lower genital tract. While some investigators believe that adenosis is a premalignant lesion, at present there is no clear-cut evidence of transition from adenosis to adenocarcinoma.

Sources and more information
  • Epidemiology of vaginal adenosis and adenocarcinoma associated with exposure to stilbestrol in utero, Cancer. ;39(4 Suppl):1892-5., Poskanzer DC, Herbst AL., NCBI PMID: 856457, 1977 Apr.
  • Full study, Volume 39, Issue Supplement S4, PDF, Article first published online: 27 JUN 2006
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Refocusing on the gynecological and obstetrical consequences of intrauterine exposure to DES

Full examination of the DES-exposed pregnant patients is advised, including colposcopy and hysterosalpingography

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 for consumption

1991 Study Abstract

The oncological and obstetrical follow-up is described of 321 patients who presented between 1981 and 1988 in the St Radboud Hospital with a history of intrauterine diethylstilbestrol(DES) exposure.

In 45 out of 321 cases cytological abnormalities were found including 20 cases of cervical intraepithelial neoplasia (CIN). No relation could be established between CIN and the extension of the cervical adenosis.

  • 22% of 87 evaluable pregnancies terminated in spontaneous abortion,
  • 13% of the patients delivered immaturely
  • and 27% prematurely.

These percentages were significantly higher than in the rest of the hospital population. The consequences of intrauterine exposure to DES are discussed.

Full examination of the patients is advised, including colposcopy and hysterosalpingography. If abnormalities are present it is advised to offer a timely cerclage in case of pregnancy.

Sources and more information
  • Refocusing on the gynecological and obstetrical consequences of intrauterine exposure to diethylstilbestrol (DES)., Nederlands tijdschrift voor geneeskunde, 1991 Jan 19;135(3):89-93., NCBI PMID: 1996166.
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The effects in the human of DiEthylStilbestrol (DES) use during pregnancy

US National Library of Medicine National Institutes of Health, 1987

Diethylstilbestrol advert image
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 for consumption.

1987 Study Abstract

Intrauterine diethylstilbestrol (DES) exposure is associated with an increased risk for the development of clear cell adenocarcinoma (CCA) of the vagina and cervix.

The age of the patients at diagnosis has varied from 7-35 years with the highest frequency from 14-22 years. The risk among the exposed, however, is small and is of the order of 1 per 1,000.

Almost all of the cases occur in postmenarchal females. Other factors that may increase the risk are maternal history of prior miscarriage, exposure to DES in early gestation, a fall season of birth and prematurity.

The occurrence of CCA has paralleled the sales of DES for pregnancy support in the U.S. Both vaginal adenosis (benign glands in the vagina) and CCA are more frequent among those whose mothers began DES in early pregnancy.

An increased risk of squamous cell neoplasia has been hypothesized but not proven. The changes that occur in the female genital tract of the DES exposed appear to result from alterations in the development of the mullerian ducts.

Currently there is not definitive evidence for an elevated risk of cancer among DES mothers or DES sons but studies have suggested a possible increase of breast cancer in the former group and testicular cancer in the latter group; a valid association has not been established in either.

Sources and more information
  • The effects in the human of diethylstilbestrol (DES) use during pregnancy, Princess Takamatsu Symposia 1987;18:67-75., NCBI PMID: 3506546.
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Cervical intraepithelial neoplasia associated with exposure to diethylstilbestrol in utero

Obstetical Gynecology, Clinical and Pathologic Study 1981

intraepithelial-neoplasia image
Orr JW Jr, Shingleton HM, Gore H, Austin JM Jr, Hatch KD, Soong SJ., Obstetrics and Gynecology 1981.

1981 Study Abstract

The anatomic, colposcopic, cytologic, and histologic findings of the cervix in 300 women exposed to diethylstilbestrol (DES) in utero are reported.

Structural cervical abnormalities were found in 51.7% of these patients and an abnormal colposcopic examination was present in 50.6%. The initial interpretation of the pathologic specimens revealed that 26.6% of patients had cytologic or histologic evidence of cervical dysplasia. A uniform pathologic review demonstrated that 10.8% of the cytologic specimens and 37.5% of the histologic specimens had been overread by the initial pathologist. A correlation of the review cytology and histology revealed that the Papanicolaou smear sensitivity for the prediction of abnormal histology was 83.9% and specificity was 86.3%. The probability of an atypical cytologic finding predicting an abnormal histologic pattern was highly significant (P less than .00001). Colposcopic and structural cervical abnormalities were not predictive of an abnormal histologic diagnosis. Of the 18 patients (6%) with histologic evidence of mild-moderate dysplasia, 12 have been followed with no treatment, and cytologic and colposcopic examination has been normal. Marked dysplasia-carcinoma in situ was found in 14 patients (4.7%). Their therapy is summarized.

These data strongly suggest that women exposed to DES may be followed safely with Papanicolaou smears and colposcopic examinations provided that both cytopathologists and colposcopists are cognizant of the metaplastic changes in the DES progeny that distinguish them from patients with cervical intraepithelial neoplasia (CIN) who were not exposed to DES. Biopsy should be performed only if indicated by cytologic atypia, colposcopic evidence of advanced CIN, or the presence of an invasive lesion.

Sources and more information
  • Cervical intraepithelial neoplasia associated with exposure to diethylstilbestrol in utero: a clinical and pathologic study, Obstet Gynecol. 1981 Jul;58(1):75-82, NCBI PMID: 7195532.
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Vaginal adenosis and diethylstilboestrol

The size of the problem in the UK is small, but clinicians should be aware that it exists

Colposcopy-unit
Cases of vaginal adenosis in young women should be investigated and screened appropriately, and preferably referred to centres where colposcopic expertise is available.

1984 Study Abstract

Unlike the effects of Thalidomide on the developing child, those of DES are not readily apparent at birth. The administration of diethylstilbestrol DES and its sequelae are in this respect a unique medical experience. Fortunately, with the realization that late sequelae occur, the use of the drug in pregnancy has been discontinued and the problems are likely to be self-limiting.

The link between DES and particularly the benign changes in the vagina and cervix (adenosis) seems well established. The association between this drug and the development of genital malignancies is less clear, and the very low incidence in the prospective studies in the USA supports this concept.

The size of the problem in the UK is small, but clinicians should be aware that it exists. Cases of vaginal adenosis in young women should be investigated and screened appropriately, and preferably referred to centres where colposcopic expertise is available. Treatment of simple vaginal adenosis should be avoided.

Sources and more information
  • Vaginal adenosis and diethylstilboestrol, British journal of hospital medicine 1984 Jan;31(1):42-8, NCBI PMID: 6697040.
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A clinicopathologic study of vagina and cervix in DES-exposed progeny

Involution of vaginal adenosis – following DES exposure – occurs with increasing age

worried-girl image
The 1980 study findings suggest that involution of vaginal adenosis – following DES exposure – occurs with increasing age

1980 Study Abstract

In this survey of 210 women with a history and/or gross changes of the cervix and vagina characteristic of diethylstilbestrol (DES) exposure, changes related to vaginal adenosis were correlated with age. The mean age of women with columnar epithelium alone was 18.5 +/- 3.2 years, columnar epithelium with squamous metaplasia was 20.2 +/- 3.4 years, and squamous metaplasia alone was 23.0 +/- 2.7 years. These findings suggest that involution of vaginal adenosis occurs with increasing age. Involution of glands in the superficial stroma in most cases occurred concurrently with that of surface columnar epithelium. However, those deeply seated and complex glands in the stroma might lag in the metaplastic process and might persist. The pitfalls of misinterpretation of squamous cell changes in histologic samples were discussed. The lack of correlation between the colposcopic findings of mosaicism and/or punctuation and squamous cell neoplasia was confirmed in this study.

Sources and more information
  • A clinicopathologic study of vagina and cervix in DES-exposed progeny, Diagn Gynecol Obstet. 1980 Winter;2(4):245-56, NCBI PMID: 7215109.
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Atypical vaginal adenosis and cervical ectropion, Association with CCAC in DES-exposed offspring

Atypical vaginal adenosis and atypical cervical ectropion of the tuboendometrial type are precursors of clear cell adenocarcinoma

Cervical-Ectropion-Analysis image
The frequency with which atypical tuboendometrial glands in the vagina and cervix were associated with the carcinomas and the proximity of the former to the latter provide strong evidence that atypical vaginal adenosis and atypical cervical ectropion of the tuboendometrial type are precursors of clear cell adenocarcinoma.

1984 Study Abstract

Knowledge of the evolution of clear cell adenocarcinomas of the vagina and cervix in diethylstilbestrol-exposed progeny has remained elusive despite the known topographical association of these tumors with the tuboendometrial form of vaginal adenosis and cervical ectropion.

Twenty radical hysterectomy or radical hysterectomy and vaginectomy specimens of clear cell adenocarcinoma of the vagina or cervix were serially blocked in toto;

  • tuboendometrial epithelium was found in the vagina in 19 (95%) of the cases, usually in greatest concentration at the margin of the tumor, particularly inferiorly.
  • Foci of atypical tuboendometrial epithelium were identified in 16 (80%) of the cases, almost always immediately adjacent to the tumor.

Twenty-five of a second group of 47 specimens in which only substantial portions of the vagina or cervix adjacent to a clear cell adenocarcinoma were available for examination also had foci of atypical tuboendometrial epithelium.

The frequency with which atypical tuboendometrial glands in the vagina and cervix were associated with the carcinomas and the proximity of the former to the latter provide strong evidence that atypical vaginal adenosis and atypical cervical ectropion of the tuboendometrial type are precursors of clear cell adenocarcinoma.

Sources and more information
  • Atypical vaginal adenosis and cervical ectropion. Association with clear cell adenocarcinoma in diethylstilbestrol-exposed offspring, Cancer. 1984, Sep 1, ;54(5):869-75. Robboy SJ, Young RH, Welch WR, Truslow GY, Prat J, Herbst AL, Scully RE, NCBI PMID: 6537153.
  • Full paper: Cancer Volume 54, Issue 5, Article first published online: 29 JUN 2006, PDF.
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Prenatal diethylstilbestrol exposure and human genital tract abnormalities

Herbst AL, Scully RE, Robboy SJ, DES research 1979

foetus image
Nonneoplastic abnormalities including vaginal adenosis, cervical eversion (ectropion), and transverse cervical and vaginal ridges are frequent in the DES-exposed population, particularly if the drug was administered early in pregnancy.

1979 Study Abstract

The incidence of clear cell adenocarcinoma of the vagina and cervix associated with intrauterine exposure to diethylstilbestrol DES and similar compounds during the first half of pregnancy has increased. Ninety percent of these cancers have occurred in patients 14 years of age or older.

Although these carcinomas are exceedingly rare, nonneoplastic abnormalities including vaginal adenosis, cervical eversion (ectropion), and transverse cervical and vaginal ridges are frequent in the exposed population, particularly if the drug was administered early in pregnancy. Current evidence favors a disturbance in development of the müllerian duct as the explanation of these changes.

Whether DES is only a teratogen or also a carcinogencerviccervi is unknown, as is the possible role of other factors in the development of cancer. An increased incidence of cancer among exposed males has not been documented.

Sources and more information
  • Prenatal diethylstilbestrol exposure and human genital tract abnormalities, Herbst AL, Scully RE, Robboy SJ. 1979 May;(51):25-35. NCBI PMID: 481577.
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