Prenatal DES exposure and high-grade squamous cell neoplasia of the lower genital tract

Whether neoplasia risk remains elevated among DES-exposed women as they age, American Journal of Obstetrics and Gynecology, 2016

Abstract

BACKGROUND
Prenatal diethylstilbestrol (DES) exposure is associated with an excess risk of clear-cell adenocarcinoma of the vagina and cervix, and of high-grade squamous neoplasia.

OBJECTIVE
We explored whether neoplasia risk remains elevated among DES-exposed women as they age.

STUDY DESIGN
In all, 4062 DES-exposed and 1837 unexposed daughters were followed for approximately 30 years (1982 through 2013) for pathology-confirmed diagnoses of cervical intraepithelial neoplasia grade ≥2 (CIN2+) of the lower genital tract (n = 178). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated adjusting for birth year and individual study cohort.

RESULTS
The cumulative incidence of CIN2+ in the DES-exposed group was 5.3% (95% CI, 4.1-6.5%) and in the unexposed group was 2.6% (95% CI, 1.5-3.7%). The HR for DES and CIN2+ was 1.98 (95% CI, 1.33-2.94), and was similar with further adjustment for frequency of cervical cancer screening (HR, 1.97; 95% CI, 1.33-2.93). The HR was 2.10 (95% CI, 1.41-3.13) with additional adjustment for other potential confounders. The HR for DES exposure was elevated through age 44 years (age 15th week (HR, 1.14; 95% CI, 0.59-2.20).

Prenatal diethylstilbestrol exposure and high-grade squamous cell neoplasia of the lower genital tract, American journal of obstetrics and gynecology, NCBI PMID: 26979629, 2016 Mar 12.
Full study ajog.

CONCLUSION
CIN2+ incidence was higher among the DES exposed, particularly those with early gestational exposure and VEC. The HR for DES and CIN2+ remained positive and significant until the mid-40s, confirming that the recommendation of annual cytological screening among these women is appropriate. Whether those ≥45 years of age continue to require increased screening is unclear, and would require a careful weighing of possible risks and benefits.

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Management of females exposed to DES-type drugs ; 1977 recommendations

Vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones

woman-at-hospital
1977 study and recommendations about vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones. all you’ve been through.

1977 Study Abstract

All asymptomatic girls who wore exposed to diethylstilbestrol in utero should receive a thorough pelvic examination at menarche or if they have reached 14 years of age. Younger girls should be examined if they develop abnormal bleeding or discharge. Whenever prenatal exposure is probable and theme are symptoms of discharge, further investigation is imperative, regardless of the patient’s age. This investigation should not be concluded until it is certain that no lesion is present.

Before the examination is undertaken, the entire procedure should be thoroughly discussed with the patient (and her mother on father if she is a minor).

The examination should include inspection and palpation, Papanicolaou smear (cervix and vagina), and an iodine staining test of the entire cervix and vagina. Abnormal areas, including those that do not stain with iodine, should be biopsied.  This procedure can be performed in the physician’s office with small biopsy instruments and without significant discomfort.

For the very young patient who has symptoms that require investigation, anesthesia may occasionally be required be fore an examination. A small speculum permits adequate visualization of the vagina without undue discomfort in younger patients.

With asymptomatic females, if adequate examination is not possible at the initial visit, vaginal tampons should be used for a few months to allow an adequate examination later without discomfort. Colposcopy is a useful adjunct to this examination, but it is not essential. Utilizing its low power magnification to examine the vagina and cervix, the physician can identify areas of glandular tissue (adenosis) in the vagina on on the cervix. This identification permits directed rather than “blind” biopsies. When used in con junction with the iodine staining test and selected biopsy, colposcopy permits precise recording of observed abnormalities and their appraisal at fixed intervals.

The patient exposed to DES-type drugs should be followed on a regular basis. After a normal initial examination, annual pelvic examinations with cervical and vaginal cytology and iodine staining are probably adequate. If any abnormalities are noted during the initial evaluation, more frequent follow-up examinations are suggested (every 3 to 6 months, depending on the severity of the findings).

Locally destructive measures such as cauterization, cryosurgery, or excision can be utilized if atypical changes such as marked squamous dysplasia on carcinoma in situ of the vagina or cervix are found on biopsy.

Sources and more information
  • Vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones, Cancer Research, 1977 Apr.
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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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Identification and management of DES-exposed women

Emphasis has been placed on screening for clear cell adenocarcinoma rather than squamous cell carcinoma and reproductive alterations

identification-lab image
Greater effort must be made by practitioners to identify and screen for DES exposure in their practices, as well as to educate the public regarding the health risks posed by DES exposure so that affected women may be reached and receive care.

1988 Study Abstract

Diethylstilbestrol (DES), a synthetic estrogen compound, was prescribed to many women with history of miscarriage between the years 1940 and 1971.

As a result of prolonged use of DES in gynecological practice, an estimated 1 million to 1.5 million women were exposed prenatally, resulting in multiple upper and lower genital tract abnormalities. These anomalies may affect reproductive function and place women at greater risk for developing clear cell adenocarcinoma (peak incidence at age 19) and squamous cell carcinoma of the vagina and cervix (peak incidence at ages 35 to 40).

Emphasis has been placed on screening for clear cell adenocarcinoma rather than squamous cell carcinoma and reproductive alterations. Despite the previous emphasis during the 1970s and a subsequent decline in public and practitioner awareness, women are at risk for the known effects of DES exposure until the year 2010. Greater effort must be made by practitioners to identify and screen for DES exposure in their practices, as well as to educate the public regarding the health risks posed by DES exposure so that affected women may be reached and receive care.

Sources and more information
  • Identification and management of DES-exposed women, The Nurse practitioner, 1988 Nov;13(11):15-6, 19-20, 22 passim, NCBI PMID: 3231355.
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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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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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Squamous cell carcinoma in situ of the vagina and cervix after intrauterine DES exposure

All cases of adenosis should be followed by colposcopy

young-woman
This 1978 study recommended that all cases of adenosis be followed by colposcopy.
I think I will just image by Mary.

1978 Study Abstract

Two patients exposed in utero to maternal diethylstilbestrol DES ingestion presented with adenosis. Each developed intraepithelial neoplasia in an area of active metaplastic change.

The question is raised whether a continuum exists beginning with DES exposure and proceeding through the occurrence of adenosis and active squamous metaplasia to dysplastic alteration and finally squamous neoplasia.

Since the cytologic smear is negative in 50% of cases during the dysplastic phase, it is recommened that all cases of adenosis be followed by colposcopy.

Sources and more information
  • Squamous cell carcinoma in situ of the vagina and cervix after intrauterine DES exposure, NCBI PMID: 683639, Obstet Gynecol. 1978 Jul;52(1 Suppl):30S-33S.
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In-Utero DES Exposure associated with a Higher Rate of Herpes and HPV infections

Development of cervical and vaginal squamous cell neoplasia as a late consequence of in utero exposure to diethylstilbestrol

herpes-simplex-virus
In 1984, the DES-Adenosis (DESAD) Project found that DES-exposed daughters are associated with a higher rate of herpes simplex virus and human papillomavirus infections.

1988 Study Abstract

During the last 14 years, several articles have given contradictory reports on prevalence rates of squamous cell neoplasia of the cervix and vagina in diethylstilbestrol (DES)-exposed progeny.

In 1984, the DES-Adenosis (DESAD) Project found that the incidence of cervical and vaginal intraepithelial neoplasia in DES-exposed daughters was twice as high as in a comparison group of unexposed women.

This was also associated with a higher rate of herpes simplex virus and human papillomavirus infections. Possible hypotheses on the etiology of the increased incidence of squamous neoplasia are discussed.

Sources and more information
  • Development of cervical and vaginal squamous cell neoplasia as a late consequence of in utero exposure to diethylstilbestrol,
    NCBI PMID: 2829071, Obstet Gynecol Surv. 1988 Jan;43(1):15-21.
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Higher risk of developing squamous neoplasia following prenatal Diethylstilbestrol exposure

Incidence of squamous neoplasia of the cervix and vagina in DES-exposed

High-Grade-Squamous-Intraep
In this 1978 study, it appeared that women with in utero DES exposure may be at a higher risk of developing squamous neoplasia compared with non-DES-exposed women.

1978 Study Abstract (1)

Two hundred and fifty patients were examined because of a history of in utero exposure to diethylstilbestrol (DES) or because of the presence of physical findings suggesting such exposure. One thousand biopsies were examined for the presence of neoplasia and then compared to the colposcopic findings. There were no cases of glandular or squamous cell carcinoma. Fifteen (6 per cent) of the patients had squamous cell dysplasia. The degree of dysplasia was mild in 11 and moderate in only 4 (1.6 per cent) of the women. The majority of the cases of dysplasia involved the cervix, whereas the vagina was involved in only four cases, with simultaneous cervical dysplasia in three of these. Patients with cervical mosaic and white epithelium had dysplasia on biopsy much more frequently as compared with patients with similar colposcopic appearances in the vagina. Our results suggest a low incidence of significant squamous precancerous change in the DES-exposed population and provide evidence that colposcopic data concerning dysplasia pertinent to the cervix cannot be applied without modification to the evaluation of dysplasia in vaginal adenosis.

1978 Study Abstract (2)

Among 199 women from 12 to 30 years of age who had been exposed to DES in utero, the colposcopic evaluation of the vagina and cervix was considered normal for only 13.6%. The incidence of colposcopically detected lesions was not related to the trimester of DES exposure, the patient’s age, use of oral contraceptives, or presenting symptoms. Areas of punctation, mosaic patterns, white epithelium, and keratosis were not considered areas of adenosis. Cervical bands, hoods, cock’s combs, etc., were considered as part of the cervix. Under this definition adenosis of the vagina was diagnosed in only 14.1% of the patients. Eight (4.0%) women were found to have cervical intraepithelial neoplasia (CIN), Grade 3 lesions, and an additional 36 (14.1%) women were found to have CIN, Grade 1 lesions based on the light microscopy evaluation of directed biopsies. There were no cases of clear cell adenocarcinoma. It appears that women with in utero DES exposure may be at a higher risk of developing squamous neoplasia compared with non-DES-exposed women.

Sources and more information
  • In utero exposure to DES. Evaluation and followup of 199 women,
    NCBI PMID: 662229, Obstet Gynecol. 1978 Apr;51(4):459-63.
  • Vaginal and cervical squamous cell dysplasia in women exposed to diethylstilbestrol in utero,
    NCBI PMID: 717453, Am J Obstet Gynecol. 1978 Nov 1;132(5):537-44.
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