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

Very late recurrence of DES-related clear cell carcinoma of the cervix

Long term surveillance of DES exposed women is a must

image of clear-cell-carcinoma-of-the-cervix
This 2015 case demonstrates the need and the importance for continued and frequent follow-up examination in individuals prenatally exposed to diethylstilbestrol.

2015 Study Abstract

Clear cell adenocarcinoma of the cervix is a rare tumor of the lower genital tract. It has been described in young women with a history of intra uterine exposure to diethylstilbestrol. This tumor is characterized by a greater tendency for late recurrences. In this article, we report the case of one exposed-patient who developed recurrence as liver metastases, 24 years after the initial treatment. This case demonstrates the need and the importance for continued follow-up in individuals prenatally exposed to diethylstilbestrol.

2015 Study Conclusions

To summarize, this case represents the longest reported disease-free interval till recurrence and the first description of metastatic liver disease of DES related clear cell adenocarcinoma of the cervix. It reemphasizes the necessity of long term surveillance of DES exposed women and confirms previous reports recommending the importance of frequent follow-up examination not only of the pelvis but also of all distant potential sites of metastasis. It also shows that treatment with paclitaxel, carboplatin and bevacizumab can be an effective and safe therapeutic option for treating recurrence of this rare tumor.

Sources and more information
  • Very late recurrence of Diethylstilbestrol – related clear cell carcinoma of the cervix: case report,Ablavi Adani-Ifè, Emma Goldschmidt, Pasquale Innominato, Ayhan Ulusakarya, Hassan Errihani, Philippe Bertheau and Jean François Morère, Gynecologic Oncology Research and Practice 2015, $article.volume.volumeNumber:3 doi:10.1186/s40661-015-0010-5, gynoncrp.com/content/2/1/3, 17 July 2015.
  • Gynecologic Oncology Research and Practice PDF case report.
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Clear cell carcinoma of the cervix: a multi-institutional review in the post-DES era

Patients with low risk early stage CCCC may be managed with radical surgery alone

Cervix Normal Squamocolumnar Junction
This 2008 study results suggest that patients with low risk early stage CCCC may be managed with radical surgery alone, without the need for adjuvant chemotherapy or radiation.
Cervix: Normal Squamocolumnar Junction image by Ed Uthman.

2008 Study Abstract

Objective
To conduct an outcome analysis of patients with cervical clear cell carcinoma (CCCC) in the post-DES era.

Methods
A retrospective review was conducted at 3 major gynecologic cancer centers of all primary CCCC between 1982 and 2004.

Results
CCCC was confirmed in 34 patients. Median age was 53 years. DES exposure was confirmed in 2 (6%) patients. A history of smoking was elicited in 22%, and of abnormal Pap smear 18% patients. Primary surgical resection was performed in all stage I or IIA patients (n=26); they displayed superior 3-year overall survival (OS) compared to advanced stage (n=8) patients (91% vs. 22%, p<0.001). Pelvic lymph node involvement was noted in 25%; all patients with positive para-aortic nodes (20% of patients sampled) had positive pelvic nodes. All node positive patients were treated with adjuvant radiation, but nevertheless displayed reduced progression free (31% vs 92%, p<0.001) and overall survival (80% vs. 100%, p=0.02). Adjuvant radiotherapy did not appear to impact OS in patients with negative lymph nodes.

Discussion
This series provides insight into the management of early stage CCCC in the post-DES era. Although these patients may be at slightly higher risk of nodal spread, clear cell histology by itself does not appear to portend a worse prognosis than squamous cell carcinoma of the cervix in the absence of traditional risk factors. Our data suggest that patients with low risk early stage CCCC may be managed with radical surgery alone, without the need for adjuvant chemotherapy or radiation.

Sources and more information
  • Clear cell carcinoma of the cervix: A multi-institutional review in the post-DES era, M. Bijoy Thomas, Jason D. Wright, Aliza L. Leiser, Dennis S. Chi, David G. Mutch, Karl C. Podratz, and Sean C. Dowdya,, Gynecol Oncol. 10.1016/j.ygyno.2008.02.007, NCBI PMC3667392, 2008 Apr 3.
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Doctors and antenatal exposure to DES: lessons learned and future concerns…

Are today’s doctors DES-aware?

doctor-and-patient image
Communication can be difficult between doctors and the DES-affected. This 2007 publication confirms it…

2007 Publication Abstract

The short- and long-term effects of the widespread use of diethylstilbestrol (DES) over 3 decades have become a distant memory for many clinicians. Others are too young to remember the flurry of activity in the early 1970s on the part of many medical centers to identify the offspring of women who were prescribed DES during their pregnancies. This medication was given in an attempt to prevent multiple pregnancy-related problems such as miscarriage, premature birth, and abnormal bleeding. The recognition of the association of DES with an increased incidence of cervical and vaginal cancers in very young women led the Food and Drug Administration to ban its use during pregnancy in 1971. Other pregnancy-related problems for the daughters and genitourinary tract changes in the sons did not become apparent until years later. Ongoing follow-up of these offspring has raised concerns for their future as well as their mothers’ future. Clinicians need to be up-to-date with current knowledge regarding risks for cancer and other health-related issues.

Sources
  • Antenatal exposure to DES: lessons learned…future concerns, Obstet Gynecol Surv, 62(8):548-55, NCBI PMID: 17634156, 2007 Aug.
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Long-term risk of cancer in women exposed to Diethylstilbestrol in utero

Cancer risk in DES Daughters, 2010 cohort study

woman-on-a-bench
In this 2010 cohort study, most DES daughters are still relatively young (44 years), Image by Nicholas Erwin.

2010 Study Abstract

OBJECTIVE:
We examined long-term risk of cancer in women exposed to diethylstilbestrol (DES) in utero.

METHODS:
A total of 12,091 DES-exposed women in the Netherlands were followed prospectively from December 1992 till June 2008. Cancer incidence was assessed through linkage with the Dutch pathology database (PALGA) and the Netherlands Cancer Registry and compared with the Dutch female population.

RESULTS:
A total of 348 medically verified cancers occurred; median age at end of follow-up was 44.0 years. No overall increased risk of cancer was found (standardized incidence ratio [SIR] = 1.01; 95% confidence interval [CI] = 0.91, 1.13). The risk of clear cell adenocarcinoma of the vagina and cervix (CCA) was statistically significantly increased (SIR = 24.23; 95% CI = 8.89, 52.74); the elevated risk persisted above 40 years of age. The risk of melanoma diagnosed before age 40 was increased (SIR = 1.59; 95% CI = 1.08, 2.26). No excess risks were found for other sites, including breast cancer.

CONCLUSIONS:
The results of our study are generally reassuring except for CCA, with a risk increase persisting at older ages. The slightly elevated risk of melanoma before age 40 is remarkable, but needs to be confirmed by other studies. We did not confirm the increased risk of breast cancer at older ages, as suggested in the NCI DES Follow-up study. Since most DES daughters in our cohort are still relatively young (44.0 years), longer follow-up is warranted to examine cancer risks at ages when cancer occurs more frequently.

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

Association between in utero DES exposure and high-grade squamous neoplasia

2000 Study Abstract

image of PubMed NCBI The Endocrine Society logo
The 2000 study findings support an association between in utero DES exposure and high-grade squamous neoplasia

PURPOSE:
Women exposed to diethylstibestrol (DES) in utero are known to have an excess risk of clear cell adenocarcinoma of the vagina and cervix, in addition to vaginal epithelial changes, but the effect on the incidence of squamous neoplasia is uncertain. This study evaluated the long-term risk of developing high-grade squamous neoplasia of the genital tract among women exposed prenatally to diethylstilbestrol.

METHODS:
A cohort comprising 3899 DES-exposed and 1374 unexposed daughters was followed for thirteen years (1982-1995) for pathology-confirmed diagnoses of high-grade squamous neoplasia. A pathologist blinded to exposure status reviewed seventy-seven percent of cases. Poisson regression analysis was used to compute relative risks (RR) and 95% confidence intervals (CI) controlling for age, calendar year, screening history and other covariates.

RESULTS:
The RR (95% CI) among DES-exposed versus unexposed, based on 111 cases of high-grade disease, was 2.12 (1.19-3.77). Adjustment for screening history had little effect, but when the analysis was restricted to a group highly screened before 1982, the risk was reduced. Risk estimates were higher among women exposed earlier in gestation; the RR (95% CI) for exposure within 7 weeks of the last menstrual period was 2.82 (1.43-5.53).

CONCLUSIONS:
The findings support an association between in utero DES exposure and high-grade squamous neoplasia, although a role for more intensive screening among DES-exposed women in the production of this excess could not be completely ruled out..

Sources

  • Incidence of squamous neoplasia of the cervix and vagina in des-exposed daughters, NCBI, PMID: 11018391, Ann Epidemiol. 2000 Oct 1;10(7):467. Full text link.
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Ovarian Carcinoma in an Adolescent with TransGenerational Exposure to DiEthylStilbestrol

More transgenerational health risks posed by DES exposure

Abstract

image of PubMed NCBI The Endocrine Society logo
DES granddaughters with persistent abdominal pain even during childhood may need evaluation for genital tract abnormalities.

Small cell carcinoma of the ovary is rare in adolescence. The etiology of such tumors is unknown. Several reports suggest that transgenerational exposure to Diethylstilbestrol (DES) may have deleterious effects on the genitourinary tract.

The authors describe a 15-year-old girl with small cell carcinoma of the ovary whose maternal grandmother had been taking DES while she was pregnant with the patient’s mother.

This case, while anecdotal, suggests that a transgenerational history of DES exposure should be noted, and that granddaughters with persistent abdominal pain even during childhood may need evaluation for genital tract abnormalities.

Sources:
  • Ovarian carcinoma in an adolescent with transgenerational exposure to diethylstilbestrol, NCBI, PMID: 12902917, 2003 Aug;25(8):635-6.
  • Full text – Clinical and Laboratory Observations Volume 25 – Issue 8, Lippincott Williams & Wilkins, pp 635-636 2003.
  • Full text – A case of small cell carcinoma of the ovary hypercalcemic variant in a teenager, ScienceDirect, S2211338X12000622 2012.
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Significant Alterations in Uterine Gene Expression following NeoNatal DiEthylStilbestrol Treatment

Developmental exposure to DES alters uterine gene expression that may be associated with uterine neoplasia later in life

Abstract:

PubMed logo
Significant Alterations in Uterine Gene Expression following NeoNatal DiEthylStilbestrol Treatment

Previously, we described a mouse model where the well-known reproductive carcinogen with estrogenic activity, diethylstilbestrol (DES), caused uterine adenocarcinoma following neonatal treatment. Tumor incidence was dose-dependent reaching >90% by 18 mo following neonatal treatment with 1000 μg/kg/d of DES. These tumors followed the initiation/promotion model of hormonal carcinogenesis with developmental exposure as initiator, and exposure to ovarian hormones at puberty as the promoter. To identify molecular pathways involved in DES-initiation events, uterine gene expression profiles were examined in prepubertal mice exposed to DES (1, 10, or 1000 μg/kg/d) on days 1–5 and compared to controls. Of more than 20 000 transcripts, approximately 3% were differentially expressed in at least one DES treatment group compared to controls; some transcripts demonstrated dose–responsiveness. Assessment of gene ontology annotation revealed alterations in genes associated with cell growth, differentiation, and adhesion. When expression profiles were compared to published studies of uteri from 5-d-old DES-treated mice, or adult mice treated with 17β estradiol, similarities were seen suggesting persistent differential expression of estrogen responsive genes following developmental diethylstilbestrol exposure. Moreover, several altered genes were identified in human uterine adenocarcinomas. Four altered genes [lactotransferrin (Ltf), transforming growth factor beta inducible (Tgfb1), cyclin D1 (Ccnd1), and secreted frizzled-related protein 4 (Sfrp4)], selected for real-time RT-PCR analysis, correlated well with the directionality of the microarray data. These data suggested altered gene expression profiles observed 2 wk after treatment ceased, were established at the time of developmental exposure and maybe related to the initiation events resulting in carcinogenesis.

Sources:

NCBIDr Retha Newbold, PMCID: PMC2254327 25 Feb 2008 – Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life.

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Gynaecological Cancers Information Leaflet

About five cancers that start in the female reproductive system

gynaecological cancers
Referring to five cancers that start in a woman’s reproductive system

The term gynaecological cancer refers to the five cancers that start in the female reproductive system:

Download The Eve Appeal Gynaecological Cancer Information Leaflet
By The Eve Appeal gynaecology cancer research fund, London UK – find them on Facebook and Twitter.

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Cancer Risk in Women exposed to DiEthylStilbestrol in Utero

DES-exposed daughters need continued surveillance to determine whether any increases in cancer risk occur during the menopausal years

1998 Study Abstract

TheEndocrineSociety logo
DES-exposed daughters showed no increased cancer risk, except for CCA. Nevertheless, because exposed daughters included in the 1998 study were, on average, only 38 years old at last follow-up, continued surveillance is warranted to determine whether any increases in cancer risk occur during the menopausal years.

CONTEXT:
The association between in utero exposure to diethylstilbestrol (DES) and clear cell adenocarcinoma (CCA) of the vagina and cervix is well known, yet there has been no systematic study of DES-exposed daughters to determine whether they have an increased risk of other cancers. As many as 3 million women in the United States may have been exposed to DES in utero.

OBJECTIVE:
To determine whether women exposed to DES in utero have a higher risk of cancer after an average of 16 years of follow-up.

DESIGN:
A cohort study with mailed questionnaires and medical record review of reported cancer outcomes.

PARTICIPANTS:
A cohort of 4536 DES-exposed daughters (of whom 81% responded) and 1544 unexposed daughters (of whom 79% responded) who were first identified in the mid-1970s.

MAIN OUTCOME MEASURES:
Cancer incidence in DES-exposed daughters compared with population-based rates and compared with cancer incidence in unexposed daughters.

RESULTS:
To date, DES-exposed daughters have not experienced an increased risk for all cancers (rate ratio, 0.96; 95% confidence interval [CI], 0.58-1.56) or for individual cancer sites, except for CCA. Three cases of vaginal CCA occurred among the exposed daughters, resulting in a standardized incidence ratio of 40.7 (95% CI, 13.1-126.2) in comparison with population-based incidence rates. The rate ratio for breast cancer was 1.18 (95% CI, 0.56-2.49); adjustment for known risk factors did not alter this result.

CONCLUSIONS:
Thus far, DES-exposed daughters show no increased cancer risk, except for CCA. Nevertheless, because exposed daughters included in our study were, on average, only 38 years old at last follow-up, continued surveillance is warranted to determine whether any increases in cancer risk occur during the menopausal years.

Sources

  • Cancer risk in women prenatally exposed to diethylstilbestrolNCBI, PMID: 9718055, 1998 Aug 19;280(7):630-4.
  • Full text JAMA. 1998;280(7):630-634. doi:10.1001/jama.280.7.630. link.
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