Background Human papillomavirus vaccines prevent human papillomavirus infection and cervical precancers. The impact of vaccinating women with a current infection or after treatment for an human ...papillomavirus-associated lesion is not fully understood. Objectives To determine whether human papillomavirus-16/18 vaccination influences the outcome of infections present at vaccination and the rate of infection and disease after treatment of lesions. Study Design We included 1711 women (18−25 years) with carcinogenic human papillomavirus infection and 311 women of similar age who underwent treatment for cervical precancer and who participated in a community-based trial of the AS04-adjuvanted human papillomavirus-16/18 virus-like particle vaccine. Participants were randomized (human papillomavirus or hepatitis A vaccine) and offered 3 vaccinations over 6 months. Follow-up included annual visits (more frequently if clinically indicated), referral to colposcopy of high-grade and persistent low-grade lesions, treatment by loop electrosurgical excisional procedure when clinically indicated, and cytologic and virologic follow-up after treatment. Among women with human papillomavirus infection at the time of vaccination, we considered type-specific viral clearance, and development of cytologic (squamous intraepithelial lesions) and histologic (cervical intraepithelial neoplasia) lesions. Among treated women, we considered single-time and persistent human papillomavirus infection, squamous intraepithelial lesions, and cervical intraepithelial neoplasia 2 or greater. Outcomes associated with infections absent before treatment also were evaluated. Infection-level analyses were performed and vaccine efficacy estimated. Results Median follow-up was 56.7 months (women with human papillomavirus infection) and 27.3 months (treated women). There was no evidence of vaccine efficacy to increase clearance of human papillomavirus infections or decrease incidence of cytologic/histologic abnormalities associated with human papillomavirus types present at enrollment. Vaccine efficacy for human papillomavirus 16/18 clearance and against human papillomavirus 16/18 progression from infection to cervical intraepithelial neoplasia 2 or greater were −5.4% (95% confidence interval −19,10) and 0.3% (95% confidence interval −69,41), respectively. Among treated women, 34.1% had oncogenic infection and 1.6% had cervical intraepithelial neoplasia 2 or greater detected after treatment, respectively, and of these 69.8% and 20.0% were the result of new infections. We observed no significant effect of vaccination on rates of infection/lesions after treatment. Vaccine efficacy estimates for human papillomavirus 16/18 associated persistent infection and cervical intraepithelial neoplasia 2 or greater after treatment were 34.7% (95% confidence interval −131, 82) and −211% (95% confidence interval −2901, 68), respectively. We observed evidence for a partial and nonsignificant protective effect of vaccination against new infections absent before treatment. For incident human papillomavirus 16/18, human papillomavirus 31/33/45, and oncogenic human papillomavirus infections post-treatment, vaccine efficacy estimates were 57.9% (95% confidence interval −43, 88), 72.9% (95% confidence interval 29, 90), and 36.7% (95% confidence interval 1.5, 59), respectively. Conclusion We find no evidence for a vaccine effect on the fate of detectable human papillomavirus infections. We show that vaccination does not protect against infections/lesions after treatment. Evaluation of vaccine protection against new infections after treatment and resultant lesions warrants further consideration in future studies.
Summary Whole slide imaging is increasingly used for primary and consultative diagnoses, teaching, telepathology, slide sharing, and archiving. We compared pathologist evaluations of glass slides and ...corresponding digitized images within the context of a statewide surveillance effort. Cervical specimens collected by the New Mexico HPV Pap Registry research program targeted cases diagnosed between 2006 and 2010. Two samples of 250 slides each were digitized with the ScanScope XT (Aperio, Vista, CA) microscope and reviewed with Aperio ImageScope reader. (1) A “random set” had a distribution of community diagnoses: 70% from cases of cervical intraepithelial neoplasia grade 2 or higher, 20% from cases of cervical intraepithelial neoplasia grade 1 and 10% from negative cases. (2) A “discrepant set” was represented by difficult cases where 2 study pathologists initially disagreed. Within the regular workflow of the New Mexico HPV Pap Registry, 3 pathologists read the slides 2 to 3 times each without knowledge of clinical history, previous readings or sampling scheme. Pathologists also read each corresponding image twice. For within- and between-reader comparisons we calculated unweighted κ statistics and asymmetry χ2 tests. Across all comparisons, slides and images yielded similar results. For the random set, almost all within-reader and between-reader Kappa values ranged between 0.7 and 0.8 and 0.6 and 0.7, respectively. For the discrepant set, most within- and between-reader κ values were 0.4 to 0.6. As cervical intraepithelial neoplasia diagnostic terminology changes, pathologists may need to re-read histopathology slides to compare disease trends over time, eg, before/after introduction of human papillomavirus vaccination. Diagnosis of cervical intraepithelial neoplasia differed little between slides and corresponding digitized images.
Summary Background Anal cancer remains rare (incidence of about 1·5 per 100 000 women yearly), but rates are increasing in many countries. Human papillomavirus (HPV) 16 and 18 infections cause most ...cases of anal cancer. We assessed efficacy of an AS04-adjuvanted HPV 16 and HPV 18 vaccine against anal infection with HPV 16, HPV 18, or both (HPV 16/18). Methods Women from Costa Rica were registered between June 28, 2004, and Dec 21, 2005, in a randomised double-blind controlled trial that was designed to assess vaccine efficacy against persistent cervical HPV 16/18 infections and associated precancerous lesions. Eligible women were residents of Guanacaste and selected areas of Puntarenas, Costa Rica, age 18–25 years, in good general health, willing to provide informed consent, and were not pregnant or breastfeeding. Participants were randomly assigned (1:1) to receive an HPV vaccine (Cervarix, GlaxoSmithKline, Rixensart, Belgium) or a control hepatitis A vaccine (modified preparation of Havrix, GlaxoSmithKline, Rixensart, Belgium). Vaccines were administered in three 0·5 mL doses at enrolment, 1 month, and 6 months. Women, selected at the final blinded study visit 4 years after vaccination, provided anal specimens for assessment of vaccine efficacy against anal HPV 16/18 infection. Prevalence of anal HPV 16/18 infections, reported as vaccine efficacy, was the primary endpoint of the study described here. Vaccine efficacy against cervical HPV 16/18 infection in the same women at the 4-year visit was used as a comparator. Analyses were done in a restricted cohort of women who were negative for both cervical HPV 16 and HPV 18 DNA and who were HPV 16 and HPV 18 seronegative before enrolment (HPV naive), and also in the full cohort of women who provided an anal specimen. Investigators were masked to group assignment. This study is registered at ClinicalTrials.gov , number NCT00128661. Findings All women who attended the final blinded study visit and consented to anal specimen collection were included in the analysis (4210 of 6352 eligible women). In the full cohort, vaccine efficacy against prevalent HPV 16/18 infection measured one-time, 4 years post vaccination was lower at the anus (62·0%, 95% CI 47·1–73·1) compared with the cervix (76·4%, 67·0–83·5; p for interaction by anatomical site 0·031). In the restricted cohort, vaccine efficacy against anal HPV 16/18 infection was 83·6% (66·7–92·8), which was similar to vaccine efficacy against cervical HPV 16/18 infection (87·9%, 77·4–94·0). Safety issues were not addressed in the current analysis. Additional safety data will be published later in a separate article. Interpretation The AS04-adjuvanted vaccine affords strong protection against anal HPV infection, particularly among women more likely to be HPV naive at enrolment. Funding National Cancer Institute with contributions from the National Institutes of Health Office of Research on Women's Health. Vaccine was provided by GlaxoSmithKline Biologicals.
Advances in screening and diagnosis make it increasingly possible to prevent cervical cancer. However, if misused or poorly understood, these new tools will only increase costs and potentially harm ...patients without benefit. As a framework for standardized care that maximizes patient safety and well-being, we propose that a risk model be adopted to guide clinical management now and in the future. The model would use thresholds of increasing risk for cervical precancer and treatable cancer to guide clinical decision making for screening intensity, diagnostic evaluation, or treatment. Experts would decide on these risk thresholds and stratum based on the patient risk to benefit, independent of current (eg, cytology, carcinogenic HPV testing, and colposcopy) and future methods of measuring risk. A risk management model for cervical cancer prevention, based on appropriate clinical actions that correspond to risk stratum, can result in better allocation of resources to and increased safety for women at the greatest risk and increased well-being for women at the lowest risk.
Objective Infection with carcinogenic human papillomaviruses (HPVs) is necessary for cervical precancer and cancer, but the effects of type-specific HPV infection on cervical appearance are poorly ...understood. Study Design Twenty expert colposcopists evaluated a total of 939 digitized cervigrams that were obtained during the ASCUS (atypical squamous cells of undetermined significance)-LSIL (low-grade squamous intraepithelial lesion) Triage study after the application of 5% acetic acid. Each reviewer rated the number and severity of lesions in 112 pictures that were matched on histologic diagnoses and HPV typing results so that ≥2 reviewers rated each image. We used standard tests of association and correlation to relate HPV type and visual appearance. Results Pairs of reviewers were significantly ( P < .05) more likely to agree that a definite lesion was present when HPV DNA was found, particularly HPV16, regardless of histologic diagnosis. However, the link between infection status and visual appearance was weak for each individual reviewer. Interestingly, many women with multiple HPV infections had no visible lesions and vice versa. Conclusion HPV16 causes more definite visual abnormalities than other HPV types, regardless of eventual histologic diagnosis. Otherwise, the associations between HPV infection and lesion recognition are weak.
Introduction Successful cervical cancer screening has led to decreasing numbers of malignant Papanicolaou tests in most laboratories. A previous study demonstrated a greater trend to unsatisfactory ...Papanicolaou tests in women with squamous carcinoma when compared with adenocarcinoma cases. However, adenocarcinomas were less frequently recognized as malignant. Materials and methods In an effort to elucidate differences in Papanicolaou tests from these tumor types, the relative distribution of cells was blindly and semi-quantitatively assessed in ThinPrep Papanicolaou slides from 332 women with biopsy-proven squamous carcinoma (237 cases), adenocarcinoma (45), and noninvasive lesions (50). Results Significant differences ( P < 0.0001) among the three categories were observed in total cellularity, amount of blood and diathesis, normal endocervical cells, and normal squamous cells. When slides from squamous carcinomas and adenocarcinomas were compared, the amount of blood ( P < 0.4) and presence of diathesis ( P > 0.004) were more prominent in squamous carcinomas. The number of endocervical cells ( P < 0.0001) was greater in adenocarcinomas, but adenocarcinomas were less likely to be recognized as malignant. Conclusions This systematic evaluation reinforces earlier suggestions that the presence of blood and tumor diathesis allow easier recognition of squamous carcinoma. A more detailed analysis of adenocarcinoma's cellular characteristics in Papanicolaou tests is needed to understand the reasons for undercalls in this tumor type.
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