Colposcopy of DES Daughters

E.J. Mayeaux, Jr., M.D.
Associate Professor of Family Medicine
Clinical Associate Professor of Obstetrics and Gynecology
Louisiana State University Medical Center - Shreveport, Louisiana

History

A. Diethylstilbestrol (DES), a nonsteroidal estrogen, was first synthesized in 1938. 1
1. From the 1940s through the early 1970s -- prescribed to pregnant women for complications of pregnancy such as bleeding, threatened miscarriage, or diabetes.
2. Regularly given as a prophylactic measure to mitigate pregnancy complications.
3. Prospective and confirmative data demonstrating its efficacy was totally lacking.
B. In 1971, Herbst and co-workers reported a link between the maternal administration of DES and subsequent occurrence of clear-cell adenocarcinoma of the vagina in the female offspring exposed to the drug in utero. 1, 1a
1. The FDA withdrew approval of the drug for the prevention of adverse pregnancy outcomes the same year.
2. The same group in 1972 reported an association of vaginal adenosis and other developmental abnormalities of the cervix and vagina in the female offspring.
3. Therapy during the first 18-20 weeks of gestation is associated with most of the benign structural and epithelial changes and the subsequent development of malignancy.
C. In 1974 the National DES and Adenosis (DESAD) project began as an inquiry into the effect of in-utero exposure to DES on female offspring.
D. An estimated 5 to 10 million Americans received DES during pregnancy or were exposed to the drug in utero. 2 There are approximately 2 million live births that have had DES exposure. Estimated cancer risks from the Registry for Research on Hormonal Transplacental Carcinogenosis number 0.14 to 1.4 per 1000.

Cancer in DES-Exposed Females

A. Clear-cell adenocarcinoma (CCA) of the vagina and cervix. 1a
1. Peak of the epidemic occurred in 1975, when 33 cases were reported.
2. To date, 522 confirmed DES cases have been reported.
3. Although the majority of the cases occurred in the 1970s and 1980s, approximately 18 new cases occur each year in the United States.
4. 91% of cases have been diagnosed in daughters between the age of 7 and 31 years of age, and the mean age of diagnosis is 20 years.
5. Lifetime risk of clear-cell cervico-vaginal cancer in DES daughters numbers 1/1000 to 1/10,000. 2
6. The tumor has been diagnosed in women up to the age of 42.
7. The incidence rate of adenocarcinoma for DES offspring over 40 years of age is currently unknown, since women are just entering this age range.
8. Why certain women develop the cancer is unknown, but the age-incidence curve suggests that increase endogenous secretion of hormones at puberty may act as a promoter. DES may merely act as the initiator of carcinogenesis.
B. Squamous Dysplasias and Cancers 1a
1. There has as yet not been an increased incidence of squamous cell cancer of the cervix in DES daughters. 1
2. The DESAD data has shown the prevalence of dysplasia to be about 2% in DES-exposed women -- slightly less than that of matched controls.
3. Squamous VAIN lesions have been rarely reported in DES exposed women.
C. Other Cancers
1. An increased incidence of breast cancer in DES-exposed daughters or their mothers has been reported but a recent well designed study refutes this finding. 1

Nonmalignant Conditions in DES-Exposed Daughters

A. Benign cervical and vaginal changes are much more common than cancer. There is no indication for treatment to prevent cancer, but close follow-up is warranted. 1a
B. Structural Variations 1a, 4
1. Cockscomb
2. Cervical collar
3. Pseudopolyps
4. Septae
5. Multiple sulci
6. T- shaped uterus
7. Vaginal constriction ring
8. Forniceal obliteration
9. Stromal hyperplasia
C. Epithelial Variations 4
1. Adenosis –- will develop in 90% of daughters exposed in utero.
2. Wide transformation zone (extensive cervical ectropion)
3. Increased squamous metaplasia

Examination of DES-Exposed Daughters

A. Screening Examinations –- every 6 months. 1a
1. Begin with careful digital palpation of the cervix and vagina to identify areas of irregularity and nodularity.
2. The entire cervix and vagina should be carefully visually examined to look particularly for reddened or raised areas. Areas of nodularity identified with the initial palpitation should be carefully examined with colposcopy.
3. Cervical cytology -- All areas of the cervix that show glandular change or suspected of having metaplasia should be carefully sampled. Endocervical and vaginal fornices samples should also be obtained. Metaplasia on the vaginal smear requires further investigation.
B. Colposcopy 1a
1. Initial examination -– at menarche or age 14 years.
2. Follow-up -– every 2 years for women with no obvious abnormalities and more frequently for women with vaginal epithelial changes.
3. Evaluation of abnormal smears, bleeding, or abnormal discharge.
C. Colposcopic Examination
1. The standard colposcopic examination is used with particular care taken to examine the cervix and vagina.
2. Identify areas that have atypical vessels. This is the most likely area to be involved in neoplasia.
3. Iodine staining is useful (but nonspecific) and allows the colposcopist to confirm the boundaries of epithelial changes.
Follow-up of DES Daughters
A. Repap and pelvic examination q 6-12 months.
B. Baseline colposcopic examination (then prn) according to maturation of T-Zone.
C. Breast self-examination and mammography according to ACS Guidelines.
D. Be alert for signs of early pregnancy.
1. Establish that it is an intrauterine pregnancy.
2. Follow pregnancies carefully, being alert for early dilatation, premature labor, and premature rupture of membranes.

Treatment

A. Surgery has most often been the treatment of choice.
1. Radical hysterectomy with partial or complete vaginectomy, pelvic lymphadenectomy, and replacement of vagina with split thickness skin grafts has been the most common surgical procedure.
B. Local irradiation of the cancer and the immediately adjacent tissues has been found to be adequate treatment in some localized vaginal tumors.
C. Both local and distant metastases have been reported.
D. About 90% of recurrent disease occurs within 7 years of initial diagnosis and treatment.
E. Clear-cell adenocarcinoma most commonly metastasizes to the lungs or the supraclavicular nodes.
F. Since distant metastases have been found 20 years after initial diagnosis, meticulous follow-up is essential.
G. Use of estrogen replacement therapy or oral contraceptives does not appear to affect the survival of DES daughters.

Other Problems

A. DES sons 3
1. They have not experienced cancer as a result of their in-utero exposure to the drug.
2. They have shown abnormalities such as cryptorchidism, testicular hypoplasia, more frequent epididymal cysts, and abnormal semen analysis.
3. Follow-up is prudent, emphasizing self-testicular examination.
4. The association between DES exposure and testicular cancer in DES sons remains controversial. 2
B. Adverse pregnancy outcome 1a, 3
1. Includes ectopic pregnancy, first and second trimester pregnancy loss, preterm labor, and premature rupture of membranes.
2. Hysterosalpingograms are not recommended, but vaginal ultrasound to confirm intrauterine pregnancy can be useful.
3. Digital examination of the cervix for premature dilatation is recommended, and cerclage is selectively used.
C. Other Problems
1. Exposure to DES has been linked to reproductive tract abnormalities in DES sons and daughters that consist of immune system disorders and psychosexual effects. 2
2. Reports have been published indicating a link between DES exposure and alterations in the immune system. 4 Definitive data is still lacking.

References

1. Hatch EE, Palmer JR, Titus-Ernstoff, Noller KL, Kaufman RH, Mittendorf R, et al.  Cancer risk in women exposed to diethylstilbestrol in utero.  JAMA 1998; 280:630-4.
1a. Giuntoli R, Atkinson B, Ernst C, Rubin M, Egan V.  Atkinson's Correlative Atlas of Colposcopy, Cytology, and Histopathology. Philadelphia: J. B. Lippincott Company 1987.
2. Giusti RM. Iwamoto K. Hatch EE. Diethylstilbestrol revisited: A review of the long-term health effects. Annals of Internal Medicine. 122(10):778-88, 1995.
3.  Mittendorf R. Teratogen update: Carcinogenesis and teratogenesis associated with exposure to diethylstilbestrol (DES) in utero. Teratology. 51(6):435-45, 1995.
4.  Anderson MC, Jordan JA, Morse AR, Sharp F, Stafl A.  Intergrated colposcopy for colposcopists, histopathologists, and cytologists. Second Edition Chapman and Hall Medical  New York, NY  1996.

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