17. Screening in DES-exposed women

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Background

Diethylstilbestrol (DESDiethylstilbestrol) is a synthetic oestrogen, transplacental carcinogen and an endocrine disrupting compound.[1] It was prescribed from the 1940s until the early 1970s, predominantly to pregnant women in the first trimester, to prevent miscarriages by stimulating the synthesis of oestrogen and progesterone in the placenta.[1] It has been estimated that 15,000 Australian women used the drug during pregnancy.[2] DESDiethylstilbestrol is no longer registered for human use in Australia.

The first study to provide conclusive evidence of an association between in utero exposure to DESDiethylstilbestrol and clear cell adenocarcinoma (CCA) was reported in 1970 by Herbst and Scully, who found vaginal CCA in seven women aged 15–22 years.[3] Subsequent studies have consistently confirmed this finding, and the most recent review of human carcinogens by the International Agency for Research on Cancer (2012) states that there is substantial evidence indicating that women exposed in utero to DESDiethylstilbestrol have a markedly increased risk of clear cell carcinoma of the vagina and cervix.[1]

Vaginal adenosis is a known precursor of CCA that affects between 34–88% of DESDiethylstilbestrol-exposed women and less than 4% of unexposed women.[1]

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Evidence

Systematic review evidence

A systematic review was conducted to identify studies that evaluated the safety and effectiveness of screening women who were exposed to DESDiethylstilbestrol in utero and their daughters, using screening strategies other than those recommended for the general population, compared with those recommended for the general population. The search strategy and inclusion and exclusion criteria used are described in detail in the Technical report. No relevant randomised controlled trials or paired diagnostic performance studies were found.

General literature review evidence

In the absence of any direct evidence from the systematic review, three separate general reviews of the literature were performed to ascertain:

  1. whether clear cell carcinomas are HPV positiveWomen with a positive HPV test result of any oncogenic HPV types detected using HPV testing platforms in a pathology laboratory.
  2. the risks of cervical and vaginal squamous cell carcinomas overall or high-grade cervical intraepithelial neoplasia (CINCervical Intraepithelial NeoplasiaRefers to abnormal changes in the cells on the surface of the cervix that are seen using a microscope (i.e. histologically-confirmed).CIN 1 – Mild dysplasiaCIN 2 – Moderate dysplasiaCIN 3 – Severe dysplasia to carcinoma in situ(The term CIN 2+ refers to CIN 2, 3, or invasive cervical cancer; CIN3+ refers to CIN 3 or invasive cervical cancer)CIN 2/3 refers to CIN 2 or CIN 3.) or high-grade vaginal intraepithelial neoplasia (VAINVaginal intra-epithelial neoplasia) in women exposed to DESDiethylstilbestrol in utero, compared with women who were not exposed to DESDiethylstilbestrol
  3. the risks of cervical and vaginal carcinomas or dysplasia in daughters of women who were exposed to DESDiethylstilbestrol in utero, compared with daughters of women who were not exposed.

Clear cell carcinomas

Nineteen studies were identified that tested for the presence of HPV DNA in samples of clear cell carcinoma of the cervix or vagina. Overall, about a third of 158 samples of clear cell carcinoma of the cervix were found to be HPV positiveWomen with a positive HPV test result of any oncogenic HPV types detected using HPV testing platforms in a pathology laboratory.. The findings are summarised in the Technical report.

Squamous cell carcinomas in women exposed in utero

A Dutch study reported no excess risk for combined cervical and vaginal squamous cell carcinoma in a cohort of over 12,000 women exposed to DESDiethylstilbestrol in utero (standard incidence ratio 0.64; 95%CI 0.31–1.17].[4] In this study, women were recruited in 1992 and were followed prospectively until 2008.

In another analysis, data was combined from three studies initiated in the 1970s with long-term follow-up on 4653 women exposed to DESDiethylstilbestrol and 1927 unexposed controls. The cumulative risk of CIN2/CIN2+ in women exposed to DESDiethylstilbestrol in utero was 6.9% versus 3.4% in women who were not exposed to DESDiethylstilbestrol (hazard ratio 2.28; 95%CI 1.59–3.27).[5]

Squamous cell carcinomas in daughters of women exposed in utero

A recent study reported data, confirmed from medical notes, from 463 daughters of women exposed to DESDiethylstilbestrol in utero and 330 unexposed women. No significant increased risk of cervical dysplasia was found in the daughters:[6]

  • relative risk (RR) of any cervical lesion 1.45 (95%CI: 0.69–3.05)
  • RR of moderate/severe cervical lesions 0.93 (95%CI: 0.29–2.94)].

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Recommendations

Consensus-based recommendationQuestion mark transparent.png

REC17.1: Screening in DESDiethylstilbestrol-exposed women
Women exposed to DESDiethylstilbestrol in utero should be offered an annual co-testHPV test and LBC both requested and performed on a cervical sample. and colposcopic examination of both the cervix and vagina indefinitely.

Consensus-based recommendation*Question mark transparent.png

REC17.2: ColposcopyThe examination of the cervix and vagina with a magnifying instrument called a colposcope, to check for abnormalities. referral for abnormalities in DESDiethylstilbestrol-exposed women
Women exposed to DESDiethylstilbestrol in utero who have a screen-detected abnormality should be managed by an experienced colposcopist.

Practice pointQuestion mark transparent.png

REC17.3: Daughters of women exposed to DESDiethylstilbestrol
These women should be screened in accordance with the NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears. policy (5-yearly HPV testing). Evidence of an adverse effect on the daughters of women exposed to DESDiethylstilbestrol in utero has not been found.

However, if these women have concerns, testing similar to that recommended for their DESDiethylstilbestrol-exposed mothers could be considered on an individual basis. Self-collection for HPV testing is not recommended.

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Benefits and harms

On the basis of the evidence summarised above, we have proposed that HPV testing be added to the previous recommendations for annual cytological testing as part of screening offered to women exposed to DESDiethylstilbestrol in utero. The addition of HPV testing is expected to increase the detection of CCA in DESDiethylstilbestrol-exposed women. It is important, however, that clinicians are aware that not all CCA are HPV positiveWomen with a positive HPV test result of any oncogenic HPV types detected using HPV testing platforms in a pathology laboratory. and that co-testingHPV test and LBC both requested and performed on a cervical sample. with cytology is necessary for early detection.

There is very little evidence available on the risk of cervical cancer or CIN in the daughters of women exposed in utero to DESDiethylstilbestrol. Due to the lack of evidence, the possibility that the risk of cancer in the daughters of women exposed in utero to DESDiethylstilbestrol is different to the risk in the general female population cannot be excluded, but is considered unlikely. If requested, annual co testing (HPV and LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory.) can be offered by clinicians to these women to provide reassurance.

See Chapter 5. Benefits, harms and cost-effectiveness of cervical screening in the renewed National Cervical Screening Program (NCSP).

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Health system implications of these recommendations

Clinical practice

These recommendations are consistent with present clinical practice.

Frequent follow-up of this cohort of women will enable the timely observation and early treatment of any DESDiethylstilbestrol-associated changes.

Resourcing

No material changes to costs are anticipated.

Barriers to implementation

There are no barriers to implementation.

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Discussion

Unresolved issues

There remains uncertainty as to whether daughters of women who were exposed to DESDiethylstilbestrol in utero experience a higher risk of clear cell carcinoma of the vagina or of other cervical or vaginal neoplasms than women without this maternal history.

Future research priorities

Where it is possible to do so, efforts should be made to follow-up additional cohorts of daughters of women who were exposed to DESDiethylstilbestrol in utero to ascertain whether or not they have a greater risk of cervical or vaginal neoplasms than women in the same populations without this maternal history.

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References

  1. 1.01.11.21.3 International Agency for Research on Cancer. Pharmaceuticals. Volume 100 A: A review of human carcinogens. IARC monographs on the evaluation of carcinogenic risks to humans. Lyon France: World Health Organization; 2012 Available from: http://monographs.iarc.fr/ENG/Monographs/vol100A/mono100A.pdf.
  2. Fickling D. Australia recognises cancer risk for "DES daughters". Lancet 2004 Jun 19;363(9426):2059 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15209080.
  3. Herbst AL, Scully RE. Adenocarcinoma of the vagina in adolescence. A report of 7 cases including 6 clear-cell carcinomas (so-called mesonephromas). Cancer 1970 Apr;25(4):745-57 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/5443099.
  4. Verloop J, van Leeuwen FE, Helmerhorst TJ, van Boven HH, Rookus MA. Cancer risk in DES daughters. Cancer Causes Control 2010 Jul;21(7):999-1007 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20204493.
  5. Hoover RN, Hyer M, Pfeiffer RM, Adam E, Bond B, Cheville AL, et al. Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med 2011 Oct 6;365(14):1304-14 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21991952.
  6. Titus-Ernstoff L, Troisi R, Hatch EE, Hyer M, Wise LA, Palmer JR, et al. Offspring of women exposed in utero to diethylstilbestrol (DES): a preliminary report of benign and malignant pathology in the third generation. Epidemiology 2008 Mar;19(2):251-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18223485.
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Appendices

Jutta's magnifying glass icon.pngPICO question 11 View Systematic review report q 11View Systematic review report question 11 View General evidence summary table q 11View General evidence summary table question 11
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