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.
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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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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.
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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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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.
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Rates and risks of DES-related clear-cell adenocarcinoma of the vagina and cervix

CCAC update, Dr Arthur Herbst, 1987

clear_cell_carcinoma 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

We reviewed 519 cases of clear-cell adenocarcinoma of the vagina and cervix identified by the Registry for Research on Hormonal Transplacental Carcinogenesis of the University of Chicago through June 30, 1985. In 60 percent of all cases the patient’s mother had received diethylstilbestrol during pregnancy. An additional 12 percent of all mothers had been treated with another hormone or with an unidentified medication. Ninety-one percent of the cases in diethylstilbestrol-exposed women were diagnosed when the patient was between the ages of 15 and 27. The median age at diagnosis was 19.0 years. The risk that clear-cell adenocarcinoma will develop in an exposed female from birth through age 34 is 1 case per 1000 women. The temporal pattern of occurrence of clear-cell adenocarcinoma corresponds closely with that of the use of diethylstilbestrol for pregnancy support in the United States. The rarity of this tumor among exposed women suggests that diethylstilbestrol is not a complete carcinogen and that some other factor is also involved in the pathogenesis of clear-cell adenocarcinoma of the vagina and cervix.

Sources and more information
  • Rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix. An update., Melnick S, Cole P, Anderson D, Herbst A., N Engl J Med. 1987 Feb 26;316(9):514-6, NCBI Pubmed PMID: 3807995.
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Clear cell adenocarcinoma of the vagina and cervix: incidence, undetected disease, and DES

DES 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

Cervical-cancer
The finding of stable (or rising) incidence rates for clear cell adenocarcinoma occurring nearly 30 years after the marked decrease in diethylstilbestrol sales emphasizes the need for continued clinical and epidemiologic studies of the etiology and clinical course of CCAC.

1988 Study Abstract

We conducted an incidence study to determine the occurrence rates of clear cell adenocarcinoma (CCAC) of the vagina and cervix in young women (born in 1940 and thereafter), and a case-series analysis, focusing on the maternal history of pregnancy and delivery and in-utero exposure to diethylstilbestrol (DES).

Overall, 10 cases of CCAC had been listed in the files of the Connecticut State Tumor Registry prior to the study, and each of the 10 cases were confirmed as valid. In addition, another 10 cases, all previously undetected, were found after the tissue slides of young women listed as having other cancers of the vagina and cervix were reviewed by expert pathologists, suggesting that prior estimates of the incidence rate for CCAC must be misleading unless special efforts are taken to identify undetected cases. The incidence rates of vaginal CCAC (11 cases total) were highest in 1975-1979, and decreased slightly during 1980-1982. In the cervix (nine cases total), the rate increased consistently since 1970. History of in-utero exposure to diethylstilbestrol was obtained for five of eight vaginal cases and four of eight cervical cases of CCAC. In all nine cases, exposure to diethylstilbestrol was associated with a history of bleeding during the pregnancy or prior miscarriage.

We conclude that the finding of stable (or rising) incidence rates for CCAC occurring nearly 30 years after the marked decrease in diethylstilbestrol sales emphasizes the need for continued clinical and epidemiologic studies of the etiology and clinical course of CCAC.

Sources and more information
  • Clear cell adenocarcinoma of the vagina and cervix: incidence, undetected disease, and diethylstilbestrol, NCBI PMID: 3385459, J Clin Epidemiol. 1988;41(6):593-7.
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Vaginal cancer: six years’ experience with screening of a diethylstilbestrol-exposed population

During the 6 years from the initial survey, 830 young women exposed to DES in utero were periodically screened.

Of these 830 patients who responded to the questionnaire,in 1979, 61.7% were found to have cervicovaginal abnormalities, and 65.9% of the patients showed either adenosis or evidence of the prior existence of vaginal adenosis. Screening survey image via SelectScience.

1979 Study Abstract

The physician population delivering obstetric care in Philadelphia between 1950 and 1970 was contacted to ascertain their use of diethylstilbestrol (DES) during pregnancy. Of the 31.8% of the physicians who responded to the questionnaire, 71.8% used DES during pregnancy and 12.7% desired assistance in review of their records.

During the 6 years from the initial survey, 830 young women exposed to DES in utero were periodically screened for cervicovaginal abnormalities and clear cell adenocarcinoma. Of these 830 patients 61.7% were found to have cervicovaginal abnormalities, and 65.9% of the patients showed either adenosis or evidence of the prior existence of vaginal adenosis. Eight patients were treated for clear cell adenocarcinoma. Two cases were detected while asymptomatic. Seven of the patients are living with no evidence of cancer, and two of these have survived over 5 years.

Sources and more information
  • Six years’ experience with screening of a diethylstilbestrol-exposed population, NCBI PMID: 463989, Am J Obstet Gynecol. 1979 Aug 15;134(8):860-5.
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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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