Paolo Giorgi Rossi

Italian guidelines for cervical cancer screening. Multisocietal recommendations on the use of biomarkers in HPV screening with risk-based approach and GRADE methodology

The European Council recommends adopting risk-based screening when relevant. In triaging HPV-positive women, it can be an effective strategy to reduce overtreatment and referral to colposcopy. HPV genotyping and p16/ki67 expression may allow a better risk stratification than cytology. In Italy, recommendations on their use (alone or combined) in screening were developed by a multi-professional (nine scientific societies) and multidisciplinary working group (including patients and decision makers). Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence to Decision frameworks were used. Data from large clinical trials on screening populations with long follow-up instructed the biomarkers' evaluation. The working group defined the CIN3+ risk thresholds (a surrogate marker of cancer risk) to guide decisions on management: immediate colposcopy, referral to 1-year and 3-year retesting. The risk-based approach allowed to reduce the number of possible strategies to be compared to five specific healthcare questions framed as PICOs. The prioritised outcomes were risk of cancer and of CIN3+ in HPV+/triage-negative women, number of colposcopies, number of samples to be taken, and number of unneeded treatments. The combination of morphological markers (cytology or p16/ki67) and extended HPV genotyping was the only strategy with a conditional recommendation in favour when compared with cytology.

Conservative Management of CIN2 Within Primary HPV Cervical Cancer Screening Programme: A Cohort Study

Objectives: To quantify the probabilities of becoming HPV-negative, or receiving delayed treatment within 24 months in women with CIN2 managed conservatively; describing the determinants of the decision for conservative management, losses to follow-up and outcomes. Methods: This prospective cohort included biopsy-confirmed CIN2 from HPV-based pilot screening in Valcamonica, Italy. Women aged 45 and under, with no glandular lesion, and assessed as low-risk by gynecologists were offered conservative management instead of treatment; those who accepted were followed with HPV testing, cytology, and colposcopy at 6, 12, and 24 months; then, if the lesion persisted, treatment was recommended; a few women without inclusion criteria entered the conservative management protocol. Competing-risk models were built to investigate the determinants of testing negative and log-binomial models for the determinants of decision for conservative management and loss to follow-up. Results: In all, 180 out of 352 women with CIN2 choose conservative management. Within 24 months, 25 women were lost to follow-up. Of the remaining, 40.6% (95% CI: 32.8%-48.8%) tested HPV-negative, 43.9% (95% CI: 35.9%-52.1%) underwent delayed treatment, and 15.5% (95% CI: 10.2%-22.2%) remained HPV-positive. Younger age, immediate colposcopy referral, low-grade cytological and grade I colposcopy were associated with the conservative management decision. Women who had attended prior screening testing HPV-negative were more likely to become HPV-negative [SHR 1.93 (95% CI: 1.06-3.49)] and had better adherence to follow-up tests. Two cases of invasive carcinoma were identified in treated women. Conclusions: After 24 months, 40% of the women avoided treatment. Women diagnosed at the second HPV screening round are more suitable candidates for conservative management.

Challenges and Opportunities for Global Cervical Cancer Elimination: How Can We Build a Model for Other Cancers?

Cervical cancer remains a leading cause of cancer-related death among women globally, despite the availability of effective prevention through human papillomavirus (HPV) vaccination and HPV-based screening. This review explores the state-of-the-art technologies for cervical cancer prevention, examining their efficacy, implementation challenges, and global disparities in access. Prophylactic HPV vaccination and HPV DNA testing have demonstrated high efficacy in reducing cervical cancer incidence, yet their uptake remains uneven—especially in low- and middle-income countries (LMICs), where the disease burden is greatest. Barriers include infrastructure limitations, workforce shortages, sociocultural obstacles, and competing health priorities. Strategies such as single-dose vaccination, early childhood immunization, self-sampling, and screen-and-treat approaches offer promising pathways to expand access. In high-income countries (HICs), where HPV vaccine uptake is higher and screening systems are more established, the reduced risk of infection and high negative predictive value of HPV testing support a shift toward screening deintensification. Precision prevention frameworks—leveraging biomarkers, genotyping, and artificial intelligence—offer further opportunities to enhance accuracy and efficiency. The review also underscores the importance of health system strengthening, international collaboration, and policy support to achieve the WHO's 90-70-90 targets for cervical cancer elimination. Moreover, innovations developed for cervical cancer prevention—such as decentralized screening, mobile health platforms, and task-shifting—offer a valuable model for improving strategies for primary and secondary prevention of other cancers.

HPV screening performance indicators in women who previously tested HPV-negative: The second round of Vallecamonica screening programme, Northern Italy

Objective To present performance indicators from the second round of the Vallecamonica-Sebino HPV screening programme in women who had tested negative about four years earlier (mean 45 months). Methods From 2010 to 2012, the target female population (aged 25–64) was invited to the first HPV screening round. In 2013–2017, women were rescreened for the second round. HPV-negative women at the first round were initially rescreened after three years. The interval was gradually increased to five years. HPV-positive women underwent cytology triage: positives were referred to colposcopy and negatives to repeat testing after one year. If HPV was persistently positive, women were referred to colposcopy, if negative, to normal interval rescreening. Results In the second round, of 13,824 previously HPV-negative women, 598 were HPV-positive (4.3%), of whom 297 were positive at cytology triage. Of those referred to one-year HPV test, 291 complied (98.0%), 133 (50.2%) of whom were persistently positive. Total referral was 3.1% compared with 6.6% in the first round (age-adjusted relative referral 0.59, 95% CI: 0.53–0.65). There were 24 cervical intraepithelial neoplasia 2+ (three cervical intraepithelial neoplasia 3+). Detection was 0.17%, compared with 0.9% in the first round. Age-adjusted relative detections were 0.25 (95% CI: 0.16–0.39) and 0.18 (95% CI: 0.05–0.61) for cervical intraepithelial neoplasia 2+ and cervical intraepithelial neoplasia 3+, respectively. Positive predictive value was 5.7%, compared with 14.6% in the first round. Conclusions At second round, referral was half that at first round, while cervical intraepithelial neoplasia 2+ detection decreased nine-fold. Consequently, positive predictive value decreased dramatically. Rescreening four years after an HPV-negative test makes the process inefficient due to the low prevalence of lesions.

Changes in the incidence of cervical tumours by disease stage in a cytology-based screening programme

Objectives To report changes in incidence of cervical tumours by disease stage, following the introduction of an organized cytology-based screening programme. Methods An intention-to-screen study of a cytology-based screening programme targeting 1,219,000 women aged 25–64 in northern Italy was carried out. Based on the previously reported trend in total incidence of cervical cancer, the study period 1995–2014 was divided into 1995–1996 (pre-screening, or reference, years), 1997–1998 (screening implementation phase), 1999–2006 (transition phase, when incidence decreased), and 2007–2014 (steady-state phase, when incidence stabilized again). Tumour stage was categorized as preinvasive (cervical intraepithelial neoplasia grade 3 (CIN3) and adenocarcinoma in situ), early (pT1a), advanced (pT1b or greater, ypT), and unknown (pT1 not otherwise specified, pTx, missing information). Average annual incidence rates observed in each phase were compared with the expected (reference) rates, using the incidence rate ratio, calculated with a Poisson regression model. Results In the steady-state phase, incidence rate ratios were: CIN3, 1.55 (95% confidence interval, 1.41–1.70); early-stage squamous carcinoma, 0.49 (0.36–0.67); advanced-stage squamous carcinoma, 0.44 (0.33–0.57); unknown-stage squamous carcinoma, 0.69 (0.48–0.99); adenocarcinoma in situ, 1.44 (0.72–2.88); early-stage adenocarcinoma, 2.65 (0.82–8.53); advanced-stage adenocarcinoma, 1.03 (0.56–1.91); and unknown-stage adenocarcinoma, 0.46 (0.23–0.92). Conclusions After stabilization, changes in incidence by tumour stage included a 55% increase for CIN3 and a 50–55% decrease both for early- and advanced-stage squamous carcinoma, but no significant changes for glandular tumours. These data will serve to quantify the incremental impact of the implementation of human papillomavirus-based screening, introduced in 2015.

Accuracy of different triage strategies for human papillomavirus positivity in an Italian screening population

AbstractHow to manage human papillomavirus (HPV)‐positive women in cervical cancer screening remains debated. Our study compared different strategies to triage HPV positivity in a large cohort of women participating in a population HPV‐based screening program. Women were tested for HPV (Cobas 4800; Roche), and those positive were triaged with cytology; cytology‐positives were referred to colposcopy, while negatives were referred to 1‐year HPV retesting. All HPV‐positive women were also evaluated with p16/ki67 dual staining (Roche). All lesions found within 24 months of follow‐up were included in the analyses. Of the 70 146 women tested, 4757 (6.8%) were HPV‐positive. Of these, 1090 were cytology‐positive and were referred to colposcopy. Of the 2958 HPV‐positive/cytology‐negative women who presented at 1‐year retesting, 1752 (59.9%) still tested positive. Cumulatively, 532 CIN2+ (including 294 CIN3+) were found. The sensitivity of cytology, HPV16/18 and p16/ki67 as triage test for CIN3+ was 67.9%, 56.0% and 85.0%, respectively. The positive predictive value (PPV) for immediate colposcopy referral was 21.0%, 15.8% and 22.9%, respectively. Combining cytology with typing increased sensitivity to 83.9% and lowered PPV to 14.8%, while combining p16/ki67 and typing increased sensitivity to 91.1%, lowering the PPV to 15.9%. Women negative to p16/ki67 triage presented a cumulative 1‐year CIN3+ risk of about 1%. In conclusion, when triaging HPV positivity, p16/ki67 performed better than cytology with or without HPV16/18 genotyping. The strategies that included dual staining achieved sensitivity and low 1‐year risk for CIN3+ sufficiently high enough to permit considering extending the surveillance interval to 2 to 3 years for HPV‐positive/triage‐negative women.

Impact of a Human Papillomavirus Vaccination Program within Organized Cervical Cancer Screening: Cohort Study

Abstract Background: We assessed the effectiveness of an HPV (human papillomavirus) vaccination program in lowering cervical abnormality risk, and conferring herd protection. Methods: Retrospective cohort study using linked screening and vaccination administrative health data of the general population of Ancona Province, Italy. We included all female residents born in 1990–1993, eligible for catch-up HPV vaccination up to age 25 years, and adhering to organized screening in 2015–2020 (n = 4,665). Cervical abnormalities rates were compared between: Vaccinated and unvaccinated women, and cohorts with high and low vaccination uptake. Analyses were adjusted for age, country of birth, screening tests number, laboratory, and municipality average income. Main outcomes were ASC-US+ or LSIL+ Pap smears, and CIN1+ or CIN2+ histology. Results: Mean screening age was 26.6±1.5 years, and 1,118 screened women (24.0%) were vaccinated (mean vaccination age 19.2±1.5 years). The diagnosed cervical abnormalities were: 107 LSIL+ (2.3%), 70 CIN1+ (1.5%), and 35 CIN2+ (0.8%). The adjusted odds ratios of LSIL+, CIN1+, and CIN2+ among vaccinated versus unvaccinated women were, respectively: 0.55 [(95% confidence interval (CI), 0.33–0.91)], 0.43 (95% CI, 0.22–0.86), and 0.31 (95% CI, 0.11–0.91). Among the unvaccinated, those in the highest-uptake (45.3%) 1993 cohort, versus the last pre-vaccination 1990 cohort, showed AORs of LSIL+ and CIN1+ of 0.23 (95% CI, 0.10–0.50), and 0.22 (95% CI, 0.07–0.69), respectively. Conclusions: In the first evaluation from Central Italy, catch-up HPV vaccination considerably reduced the risk of all cervical abnormalities diagnosed within organized screening, and conferred an elevated degree of herd protection among unvaccinated women. Impact: The high protection conferred by HPV vaccination suggests the need to update cervical screening.

Extended HPV genotyping by the BD Onclarity assay: concordance with screening HPV-DNA assays, triage biomarkers, and histopathology in women from the NTCC2 study

ABSTRACT The use of clinically validated human papillomavirus (HPV) assays is recommended in cervical cancer screening, and extended genotyping is getting attention as a triage biomarker because of the different oncogenic risk of the high-risk HPV genotypes. We compared the results of the Becton & Dickinson (BD) Onclarity HPV assay, on the residual baseline cervico-vaginal specimens of the NTCC2 trial, to those of the screening HPV-DNA assay (Cobas 4800 or HC2) and to cytology, p16/ki67 and E6/E7 mRNA triage results. We genotyped virtually all HPV-positive women and a consecutive sample of HPV-negatives. Among the 3,129 baseline-positives, 75.5% ( k = 0.368) were BD-positive, as were 5 of the 333 baseline-negatives (1.5%). The concordance between BD and HPV-DNA screening test was 87% for Cobas (1,250/1,436) and 65.9% for HC2 (1,115/1,693). A higher than the recommended positivity threshold for Onclarity would increase the agreement but would not improve concordance in the overall screening population. Among the baseline-positive cases, we observed an increasing trend of BD positivity with cytology severity (from 71.6% in negative for intraepithelial lesion of malignancy to 95.1% in ASC-H+ samples), with histologically confirmed CIN3 (96.9%), with p16/ki67 dual staining positivity (90.9% among the positive and 69.6% among the negative specimens), and with E6/E7 mRNA positivity (93.4% in the mRNA-positive cases vs 39.7% among the mRNA-negatives). Our findings confirm some disagreement among different HPV assays used for screening. Nevertheless, the agreement is substantial for women with high-grade cytology, histologically confirmed CIN3, and p16/ki67 or mRNA positivity at triage, thus confirming a good clinical performance of all the tests used. The NTCC2 trial is registered as Clinicaltrials.gov identifier NCT01837693 . IMPORTANCE Large randomized clinical trials have demonstrated that human papillomavirus (HPV) testing for high-risk types is more effective than cytology in detecting pre-cancerous lesions and preventing cervical cancer. Its use is being implemented in cervical cancer screening in several countries. The most recent guidelines recommend a risk-based management. It is therefore important to assess the individual risk of having/developing high-grade lesions of women testing high-risk HPV-positive. A crucial viral factor influencing the risk is the HPV genotype since different types are associated to different carcinogenetic risks. Understanding the degree of concordance among different assays targeting either HPV presence/type(s) or cellular morphology and proteins’ expression provides knowledge useful to better define how these tests can be used in screening protocols for an effective triage and to anticipate the possible implementation issues. Our study shows that the concordance between tests is higher when the infections have a higher probability of producing a clinically relevant lesion.

What are the barriers towards cervical cancer screening for vulnerable women? A qualitative comparative analysis of stakeholder perspectives in seven European countries

Objectives The aim of this study was to map and compare stakeholders’ perceptions of barriers towards cervical cancer screening for vulnerable women in seven European countries. Design In Collaborative User Boards, stakeholders were invited to participate to identify barriers towards participation in cervical cancer screening. Setting The study is nested in the European Union-funded project CBIG-SCREEN which aims to tackle inequity in cervical cancer screening for vulnerable women ( www.cbig-screen.eu ). Data collection took place in Bulgaria, Denmark, Estonia, France, Italy, Portugal and Romania. Participants Participants represented micro-level stakeholders covering representatives of users, that is, vulnerable women, meso-level stakeholders covering healthcare professionals and social workers, and macro-level stakeholders covering programme managers and decision-makers. Methods Across the seven countries, 25 meetings in Collaborative User Boards with a duration of 2 hours took place between October 2021 and June 2022. The meetings were video recorded or audio recorded, transcribed and translated into English for a qualitative framework analysis. Results 120 participants took part in the Collaborative User Boards. Context-specific barriers were related to different healthcare systems and characteristics of vulnerable populations. In Romania and Bulgaria, the lack of a continuous screening effort and lack of ways to identify eligible women were identified as barriers for all women rather than being specific for women in vulnerable situations. The participants in Denmark, Estonia, France, Italy and Portugal identified providers’ lack of cultural and social sensitivity towards vulnerable women as barriers. In all countries, vulnerable women’s fear, shame and lack of priority to preventive healthcare were identified as psychological barriers. Conclusion The study provides an overview of stakeholders’ perceived barriers towards vulnerable women’s cervical cancer screening participation in seven European countries. The organisation of healthcare systems and the maturity of screening programmes differ between countries, while vulnerable women’s psychological barriers had several similarities.