Strategies for Endocervical Canal Investigation in Women With Abnormal Screening Cytology and Negative Colposcopy

Dual staining for p16/Ki‐67 to detect high‐grade cervical lesions: Results from the Screening Triage Ascertaining Intraepithelial Neoplasia by Immunostain Testing study

AbstractWe compared clinical performance of p16/Ki‐67 dual‐stained cytology and human papillomavirus (HPV) genotyping, via different algorithms—alone, or in combination with cytology—to identify cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+) in women referred to as colposcopy. We included 492 cervical specimens (134 normal, 130 CIN1, 99 CIN2, 121 CIN3, 8 cancers) randomly selected from 1158 specimens with valid conventional cytology, HPV (cobas 4800 HPV test) and biopsy results. Dual‐stained cytology was retrospectively performed (CINtec PLUS assay) on PreservCyt material; slides were read by a cytologist and confirmed by two pathologists, blinded to cytology, biopsy and genotyping results. Sensitivity and specificity (95% confidence intervals in parentheses) of dual‐stained cytology to detect CIN2+ and CIN3+ were compared to other screening tests available for the same women. Positivity rate for dual‐stained cytology increased with histological severity: 30.6% in normal, 41.5% in CIN1, 72.7% in CIN2, 86.8% in CIN3 and 87.5% in cancer. Dual‐stained cytology alone had lower sensitivity than HPV testing for CIN2+ [80.7% (75.0‐85.6) vs 89.9% (85.3‐93.5)] and CIN3+ [86.8% (79.7‐92.1) vs 92.3% (86.2‐96.2)]. However, corresponding specificity values were higher [64.0% (57.9‐69.8) vs 56.1% (49.8‐62.1) for CIN2+; 54.0% (48.7‐59.2) vs 44.4% (39.2‐49.6) for CIN3+]. Combining dual‐stained cytology with an ASC‐US abnormality threshold decreased specificity to 31.4% (25.9‐37.4) for CIN2+ and 24.2% (19.9‐29.0) for CIN3+. The corresponding values considering low squamous intraepithelial lesion threshold values were 42.8% (36.8‐49.0) and 35.0% (30.1‐40.1). Dual‐stained cytology and HPV testing exhibited similar performance, although the former improved the specificity by 7.9% and 9.6% for CIN2+ and CIN3+, respectively.

HPV Vaccination and the Risk of Invasive Cervical Cancer

The efficacy and effectiveness of the quadrivalent human papillomavirus (HPV) vaccine in preventing high-grade cervical lesions have been shown. However, data to inform the relationship between quadrivalent HPV vaccination and the subsequent risk of invasive cervical cancer are lacking. We used nationwide Swedish demographic and health registers to follow an open population of 1,672,983 girls and women who were 10 to 30 years of age from 2006 through 2017. We assessed the association between HPV vaccination and the risk of invasive cervical cancer, controlling for age at follow-up, calendar year, county of residence, and parental characteristics, including education, household income, mother's country of birth, and maternal disease history. During the study period, we evaluated girls and women for cervical cancer until their 31st birthday. Cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. The cumulative incidence of cervical cancer was 47 cases per 100,000 persons among women who had been vaccinated and 94 cases per 100,000 persons among those who had not been vaccinated. After adjustment for age at follow-up, the incidence rate ratio for the comparison of the vaccinated population with the unvaccinated population was 0.51 (95% confidence interval [CI], 0.32 to 0.82). After additional adjustment for other covariates, the incidence rate ratio was 0.37 (95% CI, 0.21 to 0.57). After adjustment for all covariates, the incidence rate ratio was 0.12 (95% CI, 0.00 to 0.34) among women who had been vaccinated before the age of 17 years and 0.47 (95% CI, 0.27 to 0.75) among women who had been vaccinated at the age of 17 to 30 years. Among Swedish girls and women 10 to 30 years old, quadrivalent HPV vaccination was associated with a substantially reduced risk of invasive cervical cancer at the population level. (Funded by the Swedish Foundation for Strategic Research and others.).

Eduardo L. Franco

Professor Eduardo Franco is a Distinguished James McGill Professor in the Departments of Oncology and Epidemiology & Biostatistics at McGill University. He served as Director of the Division of Cancer Epidemiology (1995–2024) and Chair of the Department of Oncology (2011–23). Earlier, he was on the faculty of Université du Québec and Head of the Epidemiology Unit at the Ludwig Institute for Cancer Research in São Paulo, Brazil. He holds biology degrees from the Universidade de Campinas and MPH and DrPH degrees from the University of North Carolina at Chapel Hill. His early training included fellowships at the U.S. Centers for Disease Control, the International Agency for Research on Cancer, the U.S. National Cancer Institute, and Louisiana State University. Since 1985, his research has contributed to understanding and preventing cervical cancer and HPV‑related diseases, and to studies of upper aerodigestive tract, prostate, endometrial, and childhood cancers. His work spans cancer screening evaluation, measurement error, and factors influencing cancer survival. He has led international collaborations in the Americas, Europe, Africa, and through IARC. His research has been funded by CIHR, NIH, the National Cancer Institute of Canada, the Canadian Cancer Society, FRSQ, and the Cancer Research Society. As of March 2026, he had published more than 600 scientific papers (Google Scholar link: https://scholar.google.com/citations?user=9GDejd4AAAAJ&hl=en). His work has appeared in The Lancet, JAMA, NEJM, JNCI, BMJ, and PLOS Medicine. He is Editor‑in‑Chief of the Journal of the National Cancer Institute and JNCI Monographs, and Editor‑in‑Chief Emeritus of Preventive Medicine and Preventive Medicine Reports. He has served on more than a dozen major editorial boards, on scientific and grant‑review panels internationally, and twice advised the U.S. President’s Cancer Panel. Professor Franco has mentored 101 graduate students, 36 postdoctoral fellows, and 41 undergraduate trainees, and has taught widely in North America, Latin America, Europe, Asia, and the Middle East. He has held leadership roles in 68 conference committees, chaired the 16th World Congress of Epidemiology, and served as Vice-President and President of the Canadian Society for Epidemiology and Biostatistics. He is President‑Elect of the International Epidemiological Association (2024–27). His honours include major lifetime achievement awards from McGill and international organizations, and national distinctions such as Officer of the Order of Canada, Fellow of the Royal Society of Canada, the Canadian Academy of Health Sciences, and Foreign Fellow of the Brazilian Academy of Sciences.

Jiayao Lei

Karin Sundström

Mariam El-Zein