Kenneth L. Noller

Interim guidance for the use of human papillomavirus DNA testing as an adjunct to Cervical cytology for screening

Human papillomavirus (HPV) DNA testing was recently approved by the Food and Drug Administration for use as an adjunct to cytology for cervical cancer screening. To help provide guidance to clinicians and patients when using HPV DNA testing as an adjunct to cervical cytology for screening, a workshop was cosponsored by the National Institutes of Health–National Cancer Institute, American Society of Colposcopy and Cervical Pathology (ASCCP), and American Cancer Society. Consensus was reached based on a literature review, expert opinion, and unpublished results from large ongoing screening studies. The conclusions of the workshop were that HPV DNA testing may be added to cervical cytology for screening in women aged 30 years or more. Women whose results are negative by both HPV DNA testing and cytology should not be rescreened before 3 years. Women whose results are negative by cytology, but are high-risk HPV DNA positive, are at a relatively low risk of having high-grade cervical neoplasia, and colposcopy should not be performed routinely in this setting. Instead, HPV DNA testing along with cervical cytology should be repeated in these women at 6 to 12 months. If test results of either are abnormal, colposcopy should then be performed. This guidance should assist clinicians in utilizing HPV DNA testing in an effective manner, while minimizing unnecessary evaluations and treatments.

American Cancer Society Guideline for Human Papillomavirus (HPV) Vaccine Use to Prevent Cervical Cancer and Its Precursors

The American Cancer Society (ACS) has developed guidelines for the use of the prophylactic human papillomavirus (HPV) vaccine for the prevention of cervical intraepithelial neoplasia and cervical cancer. These recommendations are based on a formal review of the available evidence. They address the use of prophylactic HPV vaccines, including who should be vaccinated and at what age, as well as a summary of policy and implementation issues. Implications for screening are also discussed.

Long-term cancer risk in women given diethylstilbestrol (DES) during pregnancy.

From 1940 through the 1960s, diethylstilbestrol (DES), a synthetic oestrogen, was given to pregnant women to prevent pregnancy complications and losses. Subsequent studies showed increased risks of reproductive tract abnormalities, particularly vaginal adenocarcinoma, in exposed daughters. An increased risk of breast cancer in the DES-exposed mothers was also found in some studies. In this report, we present further follow-up and a combined analysis of two cohorts of women who were exposed to DES during pregnancy. The purpose of our study was to evaluate maternal DES exposure in relation to risk of cancer, particularly tumours with a hormonal aetiology. DES exposure status was determined by a review of medical records of the Mothers Study cohort or clinical trial records of the Dieckmann Study. Poisson regression analyses were used to estimate relative risks (RR) and 95% confidence intervals (CI) for the relationship between DES and cancer occurrence. The study results demonstrated a modest association between DES exposure and breast cancer risk, RR = 1.27 (95% CI = 1.07–1.52). The increased risk was not exacerbated by a family history of breast cancer, or by use of oral contraceptives or hormone replacement therapy. We found no evidence that DES was associated with risk of ovarian, endometrial or other cancer.

Cervical cytology screening practices among obstetrician-gynecologists

OBJECTIVE To estimate the current cervical cytology screening practices of American College of Obstetricians and Gynecologists (ACOG) Fellows, to establish a baseline for tracking future changes in practice. METHODS Questionnaires were mailed to a random sample of ACOG Fellows (n = 599) and to a group of Fellows who have regularly participated in past ACOG surveys (n = 409). The questionnaires asked about current cytology screening and evaluation practices and presented clinical practice vignettes with additional questions. Descriptive statistical methods were used to evaluate the responses. RESULTS Questionnaires were returned by 651 physicians (64.6%); 624 were complete. More than 94% of the respondents start cytology testing at age 18 years. Almost three fourths (74.2%) continue screening indefinitely. More than 80% use a liquid-based method of collection. Almost two thirds (65.1%) order human papillomavirus testing occasionally, usually (81.9%) for reports of atypical squamous cells of undetermined significance (ASCUS). Most Fellows in the sample perform colposcopy for an ASCUS result. Reports of atypical glandular cells resulted in variable approaches to further evaluation. Patient age and history were important variables for all test reports. Legal concerns were mentioned as important determinants of practice patterns. CONCLUSION In this sample of ACOG Fellows, most perform cervical cytology and evaluate abnormal results in accord with guidelines in place before the recommended changes in screening and evaluation were published in 2003.

The Management of ASCUS Cervical Cytologic Abnormalities and HPV Testing: A Cautionary Note

A recently published study of the management of low-grade cytologic smears compared immediate colposcopy to human papillomavirus (HPV) triage and entry cytology smears (conservative management) as three triage techniques for managing atypical squamous cells of undetermined significance (ASCUS) smears (Atypical Squamous Cells of Undetermined Significance/Low-grade Squamous Intraepithelial Lesion Triage Study [ALTS]). The study reported a high sensitivity (96.3%) for HPV testing using hybrid capture 2 to detect cervical intraepithelial neoplasia (CIN) III. The authors concluded that HPV testing is a viable option for managing ASCUS smears. We have reviewed the published data from the ALTS trial and have found a large excess of colposcopies and biopsies in the HPV arm in comparison with the conservative management (cytology) arm. In addition, the ALTS trial quality control and pathology review results raise doubts about the diagnostic validity of the study to establish standards of clinical practice. Furthermore, until the 2-year follow-up analysis of the conservative management arm is completed to detect CIN III, a valid comparison between HPV triage and conservative management is not possible. We conclude that, based on published data, HPV testing for routine clinical management of low-grade cytologic abnormalities (ASCUS smears) is not warranted, and that HPV testing is currently an investigational tool.

Breast cancer incidence in women prenatally exposed to maternal cigarette smoke.

Background: Clinical studies show that maternal cigarette smoking reduces pregnancy estrogen levels. Women prenatally exposed to maternal cigarette smoke may, therefore, have a lower breast cancer risk because the fetal mammary glands exposure to maternal estrogen is decreased. Associations between prenatal maternal cigarette smoke exposure and breast cancer, however, have not been observed in previous case–control studies that relied on exposure assessment after the onset of cancer. At the start of this study, cigarette smoking history was obtained directly from the mother. Methods: The National Cooperative DES Adenosis project was a follow-up study of health outcomes in women prenatally exposed to diethylstilbestrol (DES). At the start of the study, womens mothers provided information about cigarette smoking habits during the time they were pregnant with the study participant. In the current study, the breast cancer rates are compared among 4031 women who were or were not prenatally exposed to maternal cigarette smoke. The resultant relative rate (RR) is adjusted for potential confounding by other breast cancer risk factors using Poisson regression modeling. Results: Fetal exposure to maternal cigarette smoke appeared to be inversely associated with breast cancer incidence (RR = 0.49; 95% confidence interval [CI] = 0.24–1.03). The inverse association was more apparent among women whose mothers smoked 15 cigarettes or fewer per day than among daughters of heavier smokers. There were, however, too few cases to precisely estimate a possible dose-response relationship. Conclusion: These results support the hypothesis that in utero exposure to maternal cigarette smoke reduces breast cancer incidence.

Preparing digitized cervigrams for colposcopy research and education: determination of optimal resolution and compression parameters.

Objective Visual assessment of digitized cervigrams through the Internet needs to be optimized. The National Cancer Institute and National Library of Medicine are involved in a large effort to improve colposcopic assessment and, in preparation, are conducting methodologic research. Materials and Methods We selected 50 cervigrams with diagnoses ranging from normal to cervical intraepithelial neoplasia 3 or invasive cancer. Those pictures were scanned at 5 resolution levels from 1,550 to 4,000 dots per inch (dpi) and were presented to 4 expert colposcopists to assess image quality. After the ideal resolution level was determined, pictures were compressed at 7 compression ratios from 20:1 to 80:1 to determine the optimal level of compression that permitted full assessment of key visual details. Results There were no statistically significant differences between the 3,000 and 4,000 dpi pictures. At 2,000 dpi resolution, only one colposcopist found a slightly statistically significant difference (p = 0.02) compared with the gold standard. There was a clear loss of quality of the pictures at 1,660 dpi. At compression ratio 60:1, 3 of 4 evaluators found statistically significant differences when comparing against the gold standard. Conclusions Our results suggest that 2,000 dpi is the optimal level for digitizing cervigrams, and the optimal compression ratio is 50:1 using a novel wavelet-based technology. At these parameters, pictures have no significant differences with the gold standard.

Age at Natural Menopause in Women Exposed to Diethylstilbestrol in Utero

Age at natural menopause is related to several health outcomes, including cardiovascular disease and overall mortality. Age at menopause may be influenced by the number of follicles formed during gestation, suggesting that prenatal factors could influence menopausal age. Diethylstilbestrol (DES), a nonsteroidal estrogen widely prescribed during the 1950s and 1960s, is related to reproductive tract abnormalities, infertility, and vaginal cancer in prenatally exposed daughters but has not been studied in relation to age at menopause. The authors used survival analyses to estimate the risk of natural menopause in 4,210 DES-exposed versus 1,829 unexposed US women based on responses to questionnaires mailed in 1994, 1997, and 2001. DES-exposed women were 50% more likely to experience natural menopause at any given age (hazard ratio = 1.49, 95% confidence interval: 1.28, 1.74). Among women for whom dose information was complete, there were dose-response effects, with a greater than twofold risk for those exposed to >10,000 mg. The causal mechanism for earlier menopause may be related to a smaller follicle pool, more rapid follicle depletion, or changes in hormone synthesis and metabolism in DES-exposed daughters. Age at menopause has been related, albeit inconsistently, to several exposures, but, to the authors knowledge, this is the first study to suggest that a prenatal exposure may influence reproductive lifespan.