Tag: CCAC

POLE-mutated clear cell cervical cancer associated with in-utero diethylstilbestrol exposure

Gynecologic Oncology Reports, Volume 28, Pages 15-17, May 2019

2019 Study Highlights

  • We report a POLE-mutated clear cell cervical cancer associated with in-utero DES.
  • Tumor exhibited increased tumor infiltrating lymphocytes and PD-L1 expression.
  • Patient remains in remission for ≥4 years after standard therapy.
  • POLE mutation confers a phenotype of higher immunogenicity and improved outcome.

Abstract

We report an extraordinary case of a woman, exposed to diethylstilbestrol in utero, who developed clear cell adenocarcinoma of the cervix with a concurrent polymerase-Ɛ (POLE) somatic mutation. The tumor exhibited the classic phenotypic characteristics of POLE-mutated tumors originating from other organs (e.g. the uterus or the colon) including increased tumor infiltrating lymphocytes and high PD-L1 expression and has remained in remission since completion of primary therapy for >4 years. This case highlights the importance of next generation sequencing in unraveling the biology of rare tumors and supports that the presence of a POLE mutation and the associated ultramutated state confers a unique phenotype of higher immunogenicity and possibly improved prognosis in a tissue-agnostic manner, i.e. regardless of the type of cancer where the POLE mutation is present. Image credit bioinfo.

DES DiEthylStilbestrol Resources

Follow-up of Patients with Clear-Cell Adenocarcinoma of the Vagina and Cervix

New England Journal of Medicine, May 3, 2018 – Supported by the National Cancer Institute, National Institutes of Health, through a cooperative agreement

A new report on the risks of exposure during pregnancy to a supplement, diethylstilbestrol (DES), that is linked to a rare cancer. The study found that DES-exposed patients with clear-cell adenocarcinoma had ‘increased mortality across their life span.’ For women aged 10 to 34 with DES-related clear-cell adenocarcinoma, the risk of death was 27 times higher than for other US women in that age group.

Women who had prenatal exposure to diethylstilbestrol (DES) are at increased risk for clear-cell adenocarcinoma of the vagina and cervix early in life. Previous studies have investigated the clinical features of this disease and survival among these patients, but data on their long-term survival are lacking. Women with DES-related clear-cell adenocarcinoma are aging into their 50s and 60s, but the effect of this condition during their overall life span has not been well established.

A total of 695 patients with clear-cell adenocarcinoma in the Registry for Research on Hormonal Transplacental Carcinogenesis were followed through 2014 (see the Methods section of the Supplementary Appendix, available with the full text of this letter at NEJM.org). The mean year of birth was 1955. The mean age at diagnosis of clear-cell adenocarcinoma was 22 years, and 80% of the patients received the diagnosis between the ages of 15 and 30 years. In 415 patients, evidence of prenatal DES exposure was documented.

During a median follow-up of 22.7 years, 219 patients died, yielding a probability of 20-year survival of 69%. The 5-year probability of survival differed between the patients with prenatal DES exposure (86.1%) and patients without documentation of DES exposure (81.2%), but the 20-year probability of survival was similar between the two groups. After adjustment for tumor stage, histologic type, and age, the difference in probability of survival between patients with DES exposure and those without DES exposure was significant only in the first 5 years (P=0.025).

Since the epidemiologic curve was similar between the two groups, some of the patients with clear-cell adenocarcinoma for whom there was no documentation of DES exposure may have actually been exposed to DES in utero, and thus the true survival difference between women with DES exposure and those with idiopathic clear-cell adenocarcinoma would be larger without potential misclassification. This differential effect of DES according to time suggests that clear-cell adenocarcinoma associated with DES exposure and idiopathic clear-cell adenocarcinoma may have different tumor biologic features. Idiopathic clear-cell adenocarcinoma may be more likely to progress quickly or recur earlier, whereas clear-cell adenocarcinoma associated with DES exposure may be more likely to recur later. This interesting phenomenon has also been observed in other estrogen-associated cancers, including breast and endometrial cancers. During the first 5 to 7 years after diagnosis, patients with estrogen receptor (ER)–negative breast cancer have a worse survival than patients with ER-positive breast cancer, but the survival rates between the two groups become similar thereafter. Data from molecular studies of germline genetic mutations, tumor genomic changes, and epigenetic alterations to elucidate the underlying mechanisms for this improved behavior of estrogen-associated cancers are lacking.

We found that patients with clear-cell adenocarcinoma had increased mortality across their life span. The risk of death among women with DES-related clear-cell adenocarcinoma was 27 times higher than that in the general U.S. population of women between 10 and 34 years of age, 5 times higher between 35 and 49 years of age, and 2 times higher between 50 and 65 years of age. The excess mortality risk between the ages of 35 and 49 years is mainly due to late recurrences, whereas the excess mortality risk after 50 years of age may be due to other life-threatening health conditions in the population of women who were exposed to DES. It is therefore important to continue the surveillance of this unique cohort of patients with DES-related clear-cell adenocarcinoma to examine their health conditions late in life.

Press Releases

  • ‘DES daughters’ with rare cancer continue to face higher death rates, reuters, MAY 2, 2018.
  • The DES saga: Death risk high for young women exposed in utero, sciencedaily, May 2, 2018.
  • The pill that gave a generation deadly rare cancers: Mothers-to-be took DES to avoid the pain of a miscarriage – now their daughters are paying the price, DailyMail, 3 May 2018.
  • Mortality Risk Persists for Cancer Tied to Prenatal DES Exposure, empr, May 04, 2018.
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

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

Clear cell adenocarcinoma of the vagina and cervix, twin age incidence peaks

An update of the central Netherlands registry, 1997

CCAC image
Despite the fact that DES has not been prescribed to pregnant women in the Netherlands in the last 20 years, CCAC is still relevant in our times. It is important to stay alert and periodically to update and evaluate the data of this registry, including data on women born outside the DES exposure period.

1997 Study Abstract

BACKGROUND:
The objective of this study was to update the registry of women in the Netherlands with clear cell adenocarcinoma (CCAC) of the cervix or vagina with or without intrauterine exposure to diethylstilbestrol (DES).

METHODS:
From a nationwide search in PALGA, the automated pathology registry in the Netherlands, data were gathered on women with CCAC born after 1947. Information obtained from the clinical files of the patients included reported exposure to DES, patterns of complaints previous to diagnosis, the current status of the patients, and the results of cytopathologic examinations previous to histopathologic diagnosis. After review of the histopathologic slides, the specific pathologic characteristics of CCAC were determined. The age distribution of women born after 1947 was compared with that of women born before 1947.

RESULTS:
Information about possible exposure to DES during pregnancy was available for 73 of 88 women with CCAC born after 1947. Exposure to DES was reported for 47 (64%) of these women. The DES medication was most often reported as having started before the 18th week of pregnancy. Cytopathologic examination was informative in 81% of the cases of CCAC of the cervix, but only in 41% of the cases of CCAC of the vagina. Most patients had Stage I or II tumors at diagnosis. Tumor Stage III and IV and a high grade of nuclear atypia were related to unfavorable outcome. The age distribution of all patients with CCAC showed two distinct peaks; one at young age, (a mean age of 26 years), and one at older age (a mean age of 71 years). This bimodal age distribution still applied when the cases in which DES exposure was reported had been excluded.

CONCLUSIONS:
Despite the fact that DES has not been prescribed to pregnant women in the Netherlands in the last 20 years, CCAC is still relevant in our times. It is important to stay alert and periodically to update and evaluate the data of this registry, including data on women born outside the DES exposure period. The bimodal age distribution in this study of women without intrauterine exposure to DES suggests a carcinogenesis-promoting role of menarche and menopause and/ or the existence of a subpopulation with genetic risk factors or exogenous risk factors other than exposure to DES. Postmenopausal observation of women exposed to DES must be encouraged for clinical reasons and may help facilitate differentiation between these two hypotheses. If these risk factors of CCAC were better documented and their interrelationships better defined, CCAC could become an important model of multistep carcinogenesis in tissues sensitive to sex hormones.

Sources and more information
  • Clear cell adenocarcinoma of the vagina and cervix. An update of the central Netherlands registry showing twin age incidence peaks, Cancer. 1997 Jun 1;79(11):2229-36., NCBI PMID: 9179071.
More DES DiEthylStilbestrol Resources

Vaginal and cervical cancer due to diethylstilbestrol DES; end epidemic?

The current situation regarding the epidemic of clear cell adenocarcinoma of the vagina and the uterine cervix in the DES-exposed population

CCAC painting
Since 2000, the incidence of CCAC of the vagina and cervix has decreased markedly compared to the situation in the 1980s and 1990 s. In particular, the number of patients with CCAC exposed in utero to DES has decreased.

2009 Study Abstract

OBJECTIVE:
To determine the current situation regarding the epidemic of clear cell adenocarcinoma of the vagina and the uterine cervix (CCAC) in relation to the exposure in utero to diethylstilbestrol (DES).

DESIGN:
Descriptive.

METHODS:
Patients with CCAC of the uterine cervix or vagina born after 1946 and diagnosed in the period 1969-2005, were identified through the Nationwide network and registry of histo- and cytopathology in the Netherlands and from 2003 onwards through the Netherlands Cancer Registry. Exposure data and clinical data were obtained by means of questionnaires and medical records. The histology slides of tumours were reviewed. For the patients who did not provide consent, only the date of diagnosis and age at diagnosis were known (n = 10).

RESULTS:
Up to 2005, 144 CCAC patients were registered. Age at diagnosis varied from 8-54 years (mean: 28 years). In the years 1981-2000, the number of new diagnoses in 4 successive 5-year periods was fairly stable (n=26-30) but it was considerably lower in 2001-2005 (n=13). Of the patients whose history of intrauterine exposure to DES was known, 62% had been exposed (76/122). The mean age at diagnosis was 24 years for exposed patients compared to 32 years for non-exposed patients. The 10-year survival rate was 78% (95% CI: 68-87) for exposed and 69% (95% CI: 56-82) for non-exposed patients.

CONCLUSION:
Since 2000, the incidence of CCAC of the vagina and cervix has decreased markedly compared to the situation in the 1980s and 1990 s. In particular, the number of patients with CCAC exposed in utero to DES has decreased. Whether this decrease shall continue over the coming years remains to be seen.

Sources and more information
  • Vaginal and cervical cancer due to diethylstilbestrol (DES); end epidemic, Ned Tijdschr Geneeskd. 2009;153:A366. NCBI PMID: 19857300.
More DES DiEthylStilbestrol Resources

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.
More DES DiEthylStilbestrol Resources

Clear cell adenocarcinoma of the vagina and cervix secondary to intrauterine diethylstilbestrol exposure

Recurrent CCA has been observed as long as 20 years after primary therapy

image of CCAC
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. Recurrent CCA has been observed as long as 20 years after primary therapy emphasizing the importance of prolonged follow-up..

1990 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 DES-exposed patients has varied from 7 to 34 years with the highest frequency from 14 to 22 years. The risk among the exposed is small and is on the order of 1 per 1,000.

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. Pregnancy does not appear to influence adversely the tumor characteristics or prognosis of patients who have developed these malignancies.

Criteria for appropriate local therapy of small clear cell adenocarcinomas of the vagina are presented. Recurrent CCA has been observed as long as 20 years after primary therapy emphasizing the importance of prolonged follow-up..

Sources and more information
  • Clear cell adenocarcinoma of the vagina and cervix secondary to intrauterine exposure to diethylstilbestrol, Herbst AL, Anderson D, Semin Surg Oncol. 1990;6(6):343-6. NCBI PMID: 2263810.
More DES DiEthylStilbestrol Resources