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Background: Prenatal diethylstilbestrol (DES) exposure is associated with an excess risk of clear-cell adenocarcinoma of the vagina and cervix, and of high-grade squamous neoplasia., Objective: We explored whether neoplasia risk remains elevated among DES-exposed women as they age., Study Design: In all, 4062 DES-exposed and 1837 unexposed daughters were followed for approximately 30 years (1982 through 2013) for pathology-confirmed diagnoses of cervical intraepithelial neoplasia grade ≥2 (CIN2+) of the lower genital tract (n = 178). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated adjusting for birth year and individual study cohort., Results: The cumulative incidence of CIN2+ in the DES-exposed group was 5.3% (95% CI, 4.1-6.5%) and in the unexposed group was 2.6% (95% CI, 1.5-3.7%). The HR for DES and CIN2+ was 1.98 (95% CI, 1.33-2.94), and was similar with further adjustment for frequency of cervical cancer screening (HR, 1.97; 95% CI, 1.33-2.93). The HR was 2.10 (95% CI, 1.41-3.13) with additional adjustment for other potential confounders. The HR for DES exposure was elevated through age 44 years (age <45 years HR, 2.47; 95% CI, 1.55-3.94), but not in women age ≥45 years (HR, 0.91; 95% CI, 0.39-2.10). In exposed women, HRs for DES were 1.74 (95% CI, 1.09-2.79) among those who had earlier evidence of vaginal epithelial changes (VEC), presumably reflecting glandular epithelium undergoing transformation to normal, adult-type squamous epithelium, and 1.24 (95% CI, 0.75-2.06) among those without VEC, compared with unexposed women. The HRs for DES and CIN2+ were higher among women with earlier intrauterine exposure (HR, 2.64; 95% CI, 1.64-4.25 for <8 weeks' gestation and HR, 1.41; 0.88-2.25 for ≥8 weeks' gestation), and lowest when exposure began >15th week (HR, 1.14; 95% CI, 0.59-2.20)., Conclusion: CIN2+ incidence was higher among the DES exposed, particularly those with early gestational exposure and VEC. The HR for DES and CIN2+ remained positive and significant until the mid-40s, confirming that the recommendation of annual cytological screening among these women is appropriate. Whether those ≥45 years of age continue to require increased screening is unclear, and would require a careful weighing of possible risks and benefits., Competing Interests: The authors report no conflicts of interest., (Published by Elsevier Inc.)

Objective: This study was undertaken to assess the effect of the time interval between referral cytology and the outcome of colposcopically directed biopsy in relation to human papillomavirus (HPV) DNA detected by polymerase chain reaction in women referred after abnormal Papanicolaou (Pap) smears., Study Design: The study enrolled 453 women who were referred for colposcopic examination after two Pap smears were reported as atypical squamous cells of undetermined significance (ASCUS) or low-grade intraepithelial lesions (LSIL) and 553 women who were referred with a single smear reported as high-grade squamous intraepithelial lesions (HSIL)., Results: The results in both patient groups were evaluated in time intervals of 60 days or more, 61 to 120 days, and more than 120 days between referral and colposcopy. A higher proportion of white women than African American women and Hispanic women were seen within 60 days after referral in both referral groups. Women of all race/ethnic backgrounds referred with HSIL were seen within 60 days in a significantly larger proportion than women referred with ASCUS/LSIL. Women referred with ASCUS/LSIL had an increasing frequency of negative HPV findings with the prolonged time intervals. In women referred with a single smear of HSIL, there was a significantly decreasing trend over time in detection of low-risk and unidentified types of HPV and an increasing trend of HPV DNA negative results., Conclusion: The frequency of high-risk HPV DNA was similar in patients referred with ASCUS/LSIL or HSIL. In both referral groups, there was a time-dependent increase of negative biopsy results and a decreased frequency of low-risk HPV or of unidentified HPV types. This suggests that the initial abnormality on the Pap smear associated with other than high-risk HPV types may regress over time. The presence of high-risk HPV DNA does not predict the actual histologically verifiable tissue changes but indicates a lower probability of negative biopsy results in all time intervals between referral and biopsy.

Objective: This study was undertaken to assess the association between detection of high-risk types of human papillomavirus and various demographic and behavioral characteristics and to further relate this association to cervical histopathologic findings., Study Design: A total of 1007 patients with a Papanicolaou test result reported as high-grade squamous intraepithelial lesion or with 2 results reported as atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion were referred from city and county clinics to a colposcopic clinic. All women had a cervical smear obtained, underwent colposcopically directed biopsy and endocervical curettage, and had a specimen taken for human papillomavirus deoxyribonucleic acid detection by polymerase chain reaction. Demographic information was obtained from each patient., Results: Human papillomavirus deoxyribonucleic acid was identified in 655 (66%) of the specimens. High-risk human papillomavirus types (16, 18, 31, 33, and 35) were detected in 463 (70.7%) of these specimens. The prevalence of evidence of human papillomavirus (koilocytosis) and grade 1 cervical intraepithelial neoplasia in the biopsy specimen decreased significantly with age, whereas the prevalence of grade 2 or 3 cervical intraepithelial neoplasia in the biopsy specimen increased with age. There was a significant age-dependent decreasing trend in detection of high-risk human papillomavirus deoxyribonucleic acid among women who had human papillomavirus-associated changes, grade 1 cervical intraepithelial neoplasia, and grade 2 or 3 cervical intraepithelial neoplasia in the biopsy specimen. The prevalences of high-risk human papillomavirus among patients with grade 1 cervical intraepithelial neoplasia and grade 2 or 3 cervical intraepithelial neoplasia were similar, and both were significantly higher than among women with no evidence of cervical intraepithelial neoplasia or koilocytosis in the biopsy specimen. Risk factors associated with grade 2 or 3 cervical intraepithelial neoplasia were different from those associated with human papillomavirus-associated changes and with grade 1 cervical intraepithelial neoplasia., Conclusion: The detection of high-risk human papillomavirus was age-dependent for all histologic categories. Patients with grade 2 or 3 cervical intraepithelial neoplasia had a prevalence of high-risk human papillomavirus that was similar to that among women with grade 1 cervical intraepithelial neoplasia but significantly higher than that among women whose biopsy specimens appeared normal or demonstrated only the presence of human papillomavirus-induced changes (koilocytosis). This suggests that separation of human papillomavirus-associated changes only from grade 1 cervical intraepithelial neoplasia may be of significance in tissue diagnosis.

The objective of this review was to evaluate the current status of human papillomavirus testing in predicting the presence of high-grade or invasive disease in the cervix in women with Papanicolaou smears reported as atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion. This is a review of many of the studies already published evaluating the utility of human papillomavirus testing as part of the triage for patients whose Papanicolaou smears were reported as ASCUS or low-grade squamous intraepithelial lesion. Two triage approaches for follow-up of such patients are presented, and recommendations are made as to which is most cost-effective and safe. Data related to human papillomavirus testing were obtained with both currently available commercial kits for detection of high-risk human papillomavirus and the polymerase chain reaction. There was variation in results reported, possibly related to populations studied. The approach to management by cytologic screening and colposcopy, when indicated, appeared over the long term to be equal to human papillomavirus testing. In our opinion current human papillomavirus testing is of little clinical use to the practitioner. Its use should be limited to appropriately designed and implemented research studies.

Objective: Our purpose was to assess the usefulness of the polymerase chain reaction assay for detection of human papillomavirus infection for prognostic value in the triage strategies for high-grade (grade 2 or 3) cervical intraepithelial neoplasia in women referred for colposcopy after abnormal Papanicolaou smears., Study Design: A total of 1007 women referred to a colposcopic clinic providing care for an indigent population were studied. Four hundred fifty-four women were referred after two Papanicolaou smears reported as atypical squamous cells of undetermined significance or low grade-squamous cervical intraepithelial lesion, and 553 were referred after a single smear reported as high-grade squamous intraepithelial lesion. All women had a cervical smear, colposcopy-directed biopsy, and endocervical curettage performed. A sample for human papillomavirus deoxyribonucleic acid detection by polymerase chain reaction was obtained., Results: High-risk human papillomavirus types were detected in 463 (46%) of 1007 women studied. There was a significant increase of the frequency of high-risk human papillomavirus by the increasing severity of biopsy findings ranging from 32.7% in women without cervical intraepithelial neoplasia on biopsy to 60% in women having grade 2 or 3 on the biopsy specimen. Women having a negative Papanicolaou smear found to have high-risk human papillomavirus deoxyribonucleic acid at the time of colposcopy had a significantly higher rate of grade 2 or 3 cervical intraepithelial neoplasia on the biopsy specimen than did women without high-risk human papillomavirus. There was no such difference observed in women with a cytologic finding of low- or high-grade squamous intraepithelial lesions at the time of colposcopy. The polymerase chain reaction assay appears to be more sensitive than the commercial human papillomavirus profile test. The positive predictive value for grade 2 or 3 cervical intraepithelial neoplasia of both tests was similar (21.7% and 22.8%, respectively)., Conclusion: The human papillomavirus is associated with high-grade cervical intraepithelial neoplasia, but the screening for human papillomavirus deoxyribonucleic acid does not have prognostic value in women reported as having atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions on two precolposcopy Papanicolaou smears.

Objective: Our purpose was to evaluate the cost-effectiveness of the use of a Food and Drug Administration-approved human papillomavirus test in triaging patients with Papanicolaou smears showing atypical squamous cells of undetermined significance or a low-grade squamous intraepithelial lesion for colposcopy compared with an algorithm that used cytologic follow-up., Study Design: Four hundred sixty-two women referred to our Colposcopy Clinic with a Papanicolaou smear report of atypical squamous cells of undetermined significance or a low-grade squamous intraepithelial lesion underwent repeat Papanicolaou smear, cervical colposcopy, directed cervical biopsy, and endocervical curettage. In addition, human papillomavirus testing by the Food and Drug Administration-approved HPV Profile (Digene Diagnostics, Silver Spring, Md.) test was done. A comparison of sensitivity, specificity, and cost-effectiveness of an algorithm determining the need for colposcopy on the basis of repeat cytologic testing versus an algorithm that incorporated repeat cytologic testing and human papillomavirus screening was done. The cost-effectiveness of both of these triage algorithms was also compared., Results: As expected, high-risk human papillomavirus deoxyribonucleic acid was detected with greater frequency in relation to increasing severity of cervical intraepithelial neoplasia. In 268 women, the follow-up smear obtained in our clinic was reported as negative. High-risk human papillomavirus types were found in 23.5% of these women. In the human papillomavirus-negative women, 5.9% had grade 2 or 3 cervical intraepithelial neoplasia confirmed on cervical biopsy. In comparison, 20.6% of those with a positive result of the human papillomavirus test had grade 2 or 3 cervical intraepithelial neoplasia on biopsy (p < 0.001). Despite this difference, the sensitivity of a positive result of a high-risk human papillomavirus test in predicting the presence of grade 2 or 3 cervical intraepithelial neoplasia was only 52%. Among the women for whom a follow-up clinic Papanicolaou smear was reported as showing atypical squamous cells of undetermined significance or a low-grade squamous intraepithelial lesion, there was no difference in the frequency of biopsy-proved grade 2 or 3 cervical intraepithelial neoplasia between those women with a positive human papillomavirus test result and those with a negative test result. Colposcopy would have been recommended for 194 women because of a repeat clinic smear revealing atypical squamous cells of undetermined significance, a low-grade squamous intraepithelial lesion, or a high-grade squamous intraepithelial lesion, and in 21.6% of these grade 2 or 3 cervical intraepithelial neoplasia was shown on biopsy (sensitivity 63%, specificity 62%). Colposcopy would have been recommended for 180 women because high-risk human papillomavirus or a high-grade squamous intraepithelial lesion was detected at the clinic visit, and in 25% of this group grade 2 or 3 cervical intraepithelial neoplasia was shown on biopsy (sensitivity 67%, specificity 66%). Sensitivity and specificity were virtually identical for the two algorithms, but the cost of human papillomavirus testing was nearly double that of triage based on repeat cytologic testing alone ($692 vs $1246 per case)., Conclusion: The Food and Drug Administration-approved HPV Profile test is not a cost-effective triage for patients referred with Papanicolaou smears reported as showing atypical squamous cells of undetermined significance or low-grade squamous lesions.

Objective: To evaluate the utility of human papillomavirus detection in identifying women with abnormal Papanicolaou smears who can be safely followed up with cytologic study only, we conducted a study to determine the sensitivity, specificity, and negative and positive predictive values of a Food and Drug Administration-approved human papillomavirus test kit for detection of cervical intraepithelial neoplasia in colposcopically directed biopsy specimens., Study Design: We enrolled women with abnormal Papanicolaou smears referred to a colposcopy clinic serving indigent patients. All 1128 women had a referral Papanicolaou smear, a clinic Papanicolaou smear, and a sample for human papillomavirus deoxyribonucleic acid test; 1075 underwent colposcopically directed biopsies and endocervical curettage. We used the HPV Profile kit for human papillomavirus testing., Results: Of 486 women with low-grade squamous intraepithelial lesions on Papanicolaou smear, 35.4% had high-risk human papillomavirus deoxyribonucleic acid detected, and of 592 with high-grade lesions, 44.4% had high-risk human papillomavirus detected. Among 527 women with biopsy specimens showing cervical intraepithelial neoplasia and in 267 with cervical intraepithelial neoplasia grades 2 or 3, 38.7% and 56.2% had high-risk human papillomavirus deoxyribonucleic acid detected. However, the sensitivity of human papillomavirus deoxyribonucleic acid detection to identify biopsy-confirmed cervical intraepithelial neoplasia grades 2 or 3 was 55.7%, and the positive predictive value of the test was only 34.9%., Conclusion: Human papillomavirus appears to be causally associated with cervical cancer but human papillomavirus screening does not appear to be of value to identify women with abnormal Papanicolaou smears who can be safely followed up with cytologic study alone.

Samples of cervical and vaginal secretions obtained daily from five women were studied for the presence of active virus and/or viral antigens. In women with a history of recurrent genital herpes, either infectious virus or viral antigen in exfoliated cells was repeatedly detected in the absence of overt clinical symptoms. The epidemiologic and obstetric importance of the observations is discussed.

Human papillomavirus deoxyribonucleic acid were detected in tissue specimens from 38 to 46 patients (83%) with squamous cell carcinoma in situ of the vulva. Herpes simplex virus type 2--related antigen ICSP 34/35 was demonstrated in 23 of the lesions (50%), and antibodies to herpes simplex virus types 1 and 2 were found in 74% and 65% of the serum samples tested, respectively. Both human papillomavirus deoxyribonucleic acid and herpes simplex virus type 2 antigen were detected in 19 cases (41%). Correlation of human papillomavirus type to the ages of the patients revealed that types 16, 18, and 31 are most often seen in older patients, although the frequencies do not differ significantly. No relationship between the presence or absence of herpes simplex virus type 2--related antigen to age of the patient was observed.

A possible relationship of upper genital tract abnormalities in the diethylstilbestrol-exposed woman and infertility was studied. Six hundred thirty-two women had roentgenography performed. Three hundred sixty-seven of these women were not using contraception and were actively trying to become pregnant. One hundred thirty-four (36%) of these women reported difficulties conceiving for a period of 1 or more years. Seventy-three percent of these women had abnormal hysterosalpingograms. The frequency of abnormal x-ray films in the women who did conceive within 1 year was essentially the same (74%). Furthermore, a similar number of women with normal x-ray films (37%) had difficulty conceiving as did women with abnormal x-ray films (36%). When specific hysterosalpingographic abnormalities were related to the presence or absence of infertility, it was observed that the presence of a constriction of the upper uterine cavity resulted in a 2.26-times greater likelihood that a woman would not be able to conceive. If a T-shaped uterus was found in association with constriction of the upper uterine cavity, the odds ratio for inability to conceive was found to be 2.63.

A seroepidemiologic study was conducted to determine the incidence of antibodies to herpes simplex virus in a population of middle-class Caucasian women. In utero exposure to diethylstilbestrol did not influence the frequency of herpes simplex virus infection. The frequency of infection increased with age and number of sex partners and a 50% increase in incidence of herpes simplex virus type 2 infection was noted during the 4-year period of the study. Subclinical herpes simplex virus type 2 infections apparently occurred in some women without preexisting antibodies to herpes simplex virus type 1.

A double-blind randomized study to evaluate the effect of proflavine in the treatment of genital herpesvirus infection was conducted. One hundred fifty-seven women were studied, of whom 75 were treated with proflavine (treated women) and 82 were treated with placebo (control group). There were 62 women with primary disease and 95 with recurrent infection. Under the conditions by which this study was conducted, there was no apparent difference in the time of healing of lesions, development of recurrences, or virus isolation following treatment in the proflavine-treated and control groups.

Hysterosalpingograms of 60 young women exposed in utero to diethystilbestrol were obtained. In 46 instances, documentation of this exposure was obtained from the mother's chart review or confirmed by the attending physician. In 14 instances, the patients' mothers were sure they had received stilbestrol, but documentation could not be specifically confirmed. Hysterosalpingograms of 23 women being investigated for infertility during the same period that the current study was conducted were also reviewed. In 40 women exposed to stilbestrol, changes in the uterus which differed significantly from those seen in the past in nonexposed individuals were noted. These changes consisted of a 'T-shaped appearance of the uterus,' constricting bands in the uterine cavity, a hypoplastic uterus, and less frequently, intrauterine polypoid defects, synechiae, and in one instance a unicornuate uterus. In 36 of the 40 women gross defects were also noted in the cervix. By comparison, in none of the control subjects were defects noted which could be considered comparable with those seen in the DES-exposed patient.

Hysterosalpingography (HSG) was performed on 267 diethylstilbestrol (DES)-exposed women. One hundred eighty-five (69%) of these women demonstrated an abnormality and 82 women had normal findings. A relationship between abnormal x-ray findings and structural abnormalities of the cervix and vaginal epithelial changes was noted. Ninety-three women on whom roentgenography was performed had a total of 144 pregnancies. The pregnancy outcome in this group of women was significantly worse than that found in a control population of 87 women who had 147 pregnancies. In addition, women with abnormal x-ray films were found to have a poorer pregnancy outcome than the group of women with normal findings. The women with abnormal x-ray films had more ectopic pregnancies, spontaneous abortions, and premature deliveries than women with normal x-ray films although these differences were not statistically significant. Significantly fewer women with abnormal findings than women with normal x-rays were delivered of term infants.

Previous studies have suggested that there is an association between genital tract abnormalities and pregnancy outcome in women exposed to diethylstilbestrol (DES) in utero. In a collaborative study, 676 DES-exposed women had hysterosalpingographic examinations, and the findings were related to the outcome of pregnancy in 327 of these women. The findings revealed that (1) there is a considerable variation of frequency of different types of upper genital tract anomalies in women from different sources and with different motivations for enrollment in the study, (2) the presence of structural cervical changes and vaginal epithelial changes are markers for the likelihood of abnormalities in the uterine fundus, (3) women with upper genital tract abnormalities have increased odds for poor pregnancy outcome as compared to women with normal hysterosalpingographic findings, and (4) although some abnormalities were most often or consistently associated with poor pregnancy outcome, no specific changes could be related to specific types of pregnancy outcomes.