Clear Cell Adenocarcinoma of the Ovary Associated with In Utero DES Exposure

A 45-year-old white woman was referred to an outpatient clinic with a self-discovered lump in the left lower abdominal quadrant

Abstract

Background
To our knowledge, this patient is the first clinical case featuring clear cell adenocarcinoma of the ovary that may be linked to diethylstilbestrol exposure in utero. We would like to emphasize that clear cell adenocarcinoma of the vagina and cervix, not the ovary, were previously shown to be sites for tumors in female offspring exposed prenatally to DES.

Case
A 45-year-old woman presented with a self-discovered lump in the lower abdominal quadrant. She underwent surgery and staging that revealed clear cell adenocarcinoma confined to the left ovary. Foci of high-grade squamous neoplastic proliferation, inflammation, and a paratubal cyst were also present on the pathology specimen. Medical records established unequivocally that the patient’s mother received diethylstilbestrol therapy throughout the pregnancy. since clear cell cancers can develop, not infrequently, in foci of endometriosis, our patient’s pathology specimen was carefully inspected for endometriosis and none was found. Moreover, evidence linking prenatal DES exposure with chronic ovarian inflammation, paraovarian cysts, and high-grade squamous neoplastic proliferation in the genital tract has been accumulating. Although our patient is older than most patients in the Herbst cohort and a sporadic case of clear cell carcinoma cannot be excluded with certainty, all of the above changes were present in our patient’s pathology specimen. This further enhances our degree of suspicion on the causality between in utero DES exposure and the clear cell adenocarcinoma of the ovary in our patient.

Clear Cell Adenocarcinoma of the Ovary Associated With In Utero Diethylstilbestrol Exposure: Case Report and Clinical Overview, Medscape J Medv.11(1); 2009PMC2654676, 2009 Jan 7.

Conclusion
Our case is consistent with clear cell adenocarcinoma, probably related to diethylstilbestrol exposure in utero. Our case of probable DES-induced transplacental carcinogenesis more than 4 four decades after exposure reinforces the need for continued vigilance and routine gynecologic examinations in individuals prenatally exposed to this drug.

More DES DiEthylStilbestrol Resources

Genital clear cell adenocarcinoma

A carefully structured screening program of the DES exposed is needed

painting of CCAC
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.

1983 Study Abstract

Genital clear cell adenocarcinoma is a rare cancer in young women related to prenatal exposure to diethylstilbestrol (DES).

From the Diethylstilbestrol Registry, an analysis of 57 cases of genital clear cell adenocarcinoma is presented from the state of California, the most populous state in the United States. Approximately two-thirds of these patients have positive histories of prenatal diethylstilbestrol exposure.

The majority of patients had early-stage genital cancer. Generally, early-stage clear cell cancer is successfully treated with radical pelvic surgery. A carefully structured screening program of the DES exposed patient is advised.

Sources and more information
  • International surgery, Johnston GA Jr, Jones HA., 1983 Jul-Sep;68(3):257-61, NCBI PMID: 6662641.
More DES DiEthylStilbestrol Resources

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

Necessity of close extended follow-up in the DES-exposed

metastasizing-to-the-brain
This 2007 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.

2007 Study Abstract

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.

Sources and more information
  • Diethylstilbestrol (DES)-induced clear cell adenocarcinoma of the vagina metastasizing to the brain, Gynecologic oncology, NCBI pubmed 17292458, 105(1):273-6. Epub 2007 Feb 8.
More DES DiEthylStilbestrol Resources

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.
More DES DiEthylStilbestrol Resources

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
More DES DiEthylStilbestrol Resources

Primary Vaginal Mucinous Adenocarcinoma of Intestinal Type in a DES-Exposed Woman

American journal of clinical pathology, 2015

Intestinal-metaplasia
Recognition of primary vaginal mucinous adenocarcinoma of intestinal type, extremely rare malignancy, is important, particularly to avoid the pitfall of misdiagnosing metastatic disease.

2015 Study Abstract

OBJECTIVES:
Primary mucinous vaginal adenocarcinoma of intestinal type is an extremely rare malignancy of uncertain histogenesis, which makes for a diagnostic challenge. We report a case and describe the histopathologic features and the unusual immunoprofile of this rare entity.

METHODS:
We report a case of vaginal mucinous adenocarcinoma of intestinal type in a diethylstilbestrol-exposed woman in which intestinal metaplasia of the Skene duct was found at the time of recurrence.

RESULTS:
As the histogenesis of primary vaginal intestinaltype adenocarcinomas remains uncertain, the finding of Skene duct metaplasia in association with invasive adenocarcinoma lends support to the origin of vaginal mucinous adenocarcinomas of intestinal type to be metaplasia, at least in some cases. Such an origin accounts for the unusual immunohistochemical profile, which raises concern for a metastatic adenocarcinoma of gastrointestinal origin.

CONCLUSIONS:
Recognition of this rare entity is important, particularly to avoid the pitfall of misdiagnosing metastatic disease.

Sources and more information
  • Primary Vaginal Mucinous Adenocarcinoma of Intestinal Type, Associated With Intestinal Metaplasia of Skene Ducts in a Diethylstilbestrol-Exposed Woman, American journal of clinical pathology, 2015 Nov;144(5):790-5. doi: 10.1309/AJCPVZ0QNLUO7OFE., NCBI PMID: 26486744.
More DES DiEthylStilbestrol Resources

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.
More DES DiEthylStilbestrol Resources

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.
More DES DiEthylStilbestrol Resources

Epidemiologic aspects and factors related to survival in DES-associated cases of CCAC cancer

American Journal of Obstetrics and Gynecology, 1979

CCAC painting
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.

1979 Study Abstract

Three hundred and eighty-four cases of clear cell adenocarcinoma of the vagina and cervix accessioned in the Registry as of December 31, 1978, have been analyzed.

The annual incidence of these tumors has been found to correspond closely to the estimated usage of diethylstilbestrol (DES) for pregnancy support in the United States. The annual incidence of the DES-associated cases appears to have dropped in the United States in the past 2 years in comparison to 1973 to 1975.

The risk of tumor development appears to be higher in young women exposed to DES early in intrauterine life than in those exposed later. The carcinomas are rare before the age of 14 years and an irregular peak in the age-incidence curve appears between 17 and 21 years followed by a decline.

The 5-year survival rate is better for women over the age of 19 years than for younger patients, and a higher frequency oral contraceptive usage did not appear to influence the behavior of the tumor and the improved survival in those using this medication appears to be related to greater medical surveillance.

Sources and more information
  • Epidemiologic aspects and factors related to survival in 384 Registry cases of clear cell adenocarcinoma of the vagina and cervix, American Journal of Obstetrics and Gynecology 1979 Dec 1;135(7):876-86, NCBI PMID: 507130.
More DES DiEthylStilbestrol Resources

Development of DES-associated clear-cell carcinoma: the importance of regular screening

Regular and frequent PAP smears are needed for DES-affected women

pap-smear image
This 1979 study underscores the necessity for frequent vaginal cytologic smears and pelvic examinations at intervals no greater than 6 months for the DES-affected women.

1979 Study Abstract

Because the rate of malignancies in young women exposed in utero to diethylstilbestrol (DES) is low, appropriate population screening methods have not been established. A case is presented that is believed to represent the first reported instance of a DES-exposed daughter who developed clear cell adenocarcinoma of the vagina after initially negative examinations. The patient was followed with Papanicolaou smears, pelvic examinations, and colposcopy every 6 months for 2 years prior to the discovery of malignancy. Initially negative, Papanicolaou smears successfully predicted the presence of an early adenocarcinoma. Palpation aided by colposcopy allowed directed biopsy of the small asymptomatic lesion.

This case underscores the necessity for frequent vaginal cytologic smears and pelvic examinations at intervals no greater than 6 months. Colposcopy is indicated to direct biopsies when an abnormal cytologic smears is reported or when abnormal bleeding or discharge occurs. Biopsy of any palpable lesion is mandatory.

Sources and more information
  • Development of DES-associated clear-cell carcinoma: the importance of regular screening, Obstetrics and Gynecology 1979 Mar;53(3):293-9, NCBI PMID: 424100.
More DES DiEthylStilbestrol Resources