European guidelines on cervical cancer screening and diagnosis

These recommendations concern birth cohorts vaccinated against human papillomavirus (HPV), as they reach screening age. HPV-vaccinated birth cohorts have varying background HPV prevalence, which is linked to the HPV vaccination coverage achieved, and include a mixed population of individuals vaccinated and unvaccinated against HPV. The recommendations take into account the substantial epidemiological heterogeneity across European populations. 

These recommendations refer specifically to cervical screening with HPV detection tests in the context of an organised, population-based screening programme in European Union Member States. However, they may also be relevant for individuals being screened opportunistically, and in settings outside the European Union. 

What is the optimal age to start HPV-based cervical screening and the appropriate screening interval for HPV-vaccinated birth cohorts? 

The EC-CvC Working Group (WG) suggests the following start age and screening interval for birth cohorts vaccinated against human papillomavirus (HPV), comprising individuals with a cervix, according to their risk of cervical cancer (defined by vaccination coverage [<50%, 50–75% and >75%] and pre-vaccination HPV prevalence: high [6% and above] and low [less than 6%]). 

For birth cohorts receiving HPV vaccination before the age of 15 and reaching screening age:

   - If HPV vaccination coverage in the birth cohort is at least 75%, irrespective of the pre-vaccination HPV16 prevalence in the population, start screening with HPV detection test at age 30 with an interval of 10 years between negative HPV tests.

   - If HPV vaccination coverage in the birth cohort is between 50% and 74% and the pre-vaccination HPV16 prevalence in the population is low, start screening with HPV detection test at age 30 with an interval of 10 years between negative HPV tests.

   - If HPV vaccination coverage in the birth cohort is between 50% and 74% and the pre-vaccination HPV16 prevalence in the population is high, start screening with HPV detection test at age 25 with an interval of 10 years between negative HPV tests. 

  - If HPV vaccination coverage in the birth cohort is less than 50%, irrespective of the pre-vaccination HPV16 prevalence in the population, please refer to recommendations for general population. 

Remark: This conditional recommendation applies to all HPV-vaccinated birth cohorts, as defined in the Definitions. However, in settings where populations received a 9-valent vaccine in a gender-neutral programme, with successive vaccinated cohorts (e.g. the first to the tenth vaccinated birth cohort), >75% vaccination coverage and low pre-vaccination HPV16 prevalence (<6%), the recommendation to start screening at age 30 years with a 10-year interval is considered strong, despite low-certainty evidence, because of the expected large reduction in undesirable effects (fewer colposcopies, overtreatments and preterm births) and improved cost-effectiveness.

The scenario of birth cohorts with >75% vaccination coverage before age 15 may be considered for vaccinated individuals with a cervix in contexts where individual-level vaccination status is available and can be reliably verified.

When HPV16 prevalence is not available, recommendations should follow approaches developed for high-prevalence settings.
Starting screening at age 25 requires the adoption of effective triage strategies for HPV-positive individuals.

The WG highlight that individuals who are not vaccinated and do not attend screening continue to represent a high-risk subpopulation for invasive carcinoma. Individuals who are eligible for screening but do not attend should be systematically tracked and recalled for screening to ensure overall effectiveness of the screening programme, irrespective of vaccination status.

The EC-CvC WG based these recommendations on the balance of desirable and undesirable effects, resource use and cost implications, and the equity, feasibility and acceptability of reducing screening intensity in HPV-vaccinated birth cohorts.  

As HPV vaccination substantially lowers the risk of cervical cancer and precancer, maintaining pre-vaccination screening intensity offers diminishing desirable effects, and increases potential undesirable effects and use of resources associated with unnecessary colposcopies, overtreatment and preterm births. De-intensification is justified when the balance of effects supports a safe reduction in screening. 

1. Birth cohorts with ≥75% vaccination coverage before age 15 (or vaccinated individuals with individually assessed vaccine status): High coverage provides strong direct and indirect (herd) protection, regardless of pre-vaccination HPV16 prevalence. Cervical cancer incidence and mortality projected through modelling with 10-year intervals as compared with 5-year intervals were very similar (a negligible difference in effect – ‘trivial’), while undesirable effects and resource use are substantially reduced. Screening starting at age 30 with an HPV detection test with a 10-year interval offers a favourable balance of desirable and undesirable effects while also being most cost-effective. This strategy may be considered for vaccinated individuals with a cervix in contexts where individual-level vaccination status is available and can be reliably verified.  

2. Birth cohorts with 50–75% vaccination coverage and low pre-vaccination prevalence of HPV16: In settings with already low HPV16 prevalence, moderate coverage of 50–75% still yields very low cancer risks. Increases in cervical cancer incidence and mortality as observed through modelling with 10-year intervals as compared with 5-year intervals remain trivial to small. The desirable effects in terms of reduction in colposcopies, treatments and preterm births are moderate. Screening starting at age 30 years with HPV detection test with a 10-year interval offers a favourable balance of desirable and undesirable effects in these cohorts while also being most cost-effective.  

3. Birth cohorts with 50–75% vaccination coverage and high pre-vaccination prevalence of oncogenic HPV: In such settings, the underlying risk remains somewhat higher in cohorts vaccinated early. Although 10-yearly screening with HPV test starting at the age of 30 is effective, models show a narrower margin between desirable and undesirable effects. Screening starting at age 25 with an HPV detection test with a 10-year interval improves early cancer prevention with minimal additional undesirable effects.  

4. Birth cohorts with <50% vaccination coverage: With low coverage, herd immunity is limited, and underlying risk is comparable to that in unvaccinated cohorts. Screening remains critical, and de-intensification would raise cancer risk (and not meet WHO’s targets for cervical cancer elimination). The recommended screening strategy for general populations should be implemented. 

Certainty of evidence is currently low, as it relies mainly on modelling projections validated against empirical vaccine effectiveness for individuals aged under 30. Although effect sizes are uncertain, the direction of effect, substantially reduced risk and potential for safe de-intensification of screening were considered robust. Implementation will require clear communication to support acceptability and equitable uptake. 

Overall, the EC-CvC WG judged that screening strategies must adapt to post-vaccination epidemiology, maintaining cancer prevention while minimising undesirable effects and resource use. 

HPV detection test: Assays that detect at least 12 oncogenic HPV genotypes established as causal for cervical cancer, as defined in IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Human Papillomaviruses. These genotypes are HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59.1 The test should be validated for cervical screening.

HPV-vaccinated birth cohort: A group of people born in the same time period for whom HPV vaccination before age 15 was part of the immunisation programme. Within the immunisation programme, individuals were vaccinated against HPV before the age of 15, using bivalent, quadrivalent or 9-valent vaccines licensed by the European Medicines Agency, through either girls-only or gender-neutral programmes. Individuals in this birth cohort will have completed the recommended vaccination schedule and have now reached the age of eligibility for cervical screening. These cohorts typically include both vaccinated and unvaccinated individuals, depending on the coverage achieved.

Pre-vaccination HPV prevalence: HPV16 prevalence in unvaccinated individuals aged 25–29 years with normal cytology (pre-vaccination) as an indicator of underlying cervical cancer risk. The pre-vaccination period is defined as the years preceding the introduction of the HPV vaccine in the national immunisation programme. The European Union Member States were grouped into two categories based on HPV16 prevalence:  

• High prevalence: HPV16 prevalence was ≥6% among unvaccinated individuals aged 25–29 years with normal cytology during the pre-vaccination period, i.e. the years preceding the introduction of HPV vaccination in the national immunisation programme. 
• Low prevalence: HPV16 prevalence was lower than 6% in individuals aged 25–29 years with normal cytology during the pre-vaccination period, i.e. the years preceding the introduction of the HPV vaccination programme.  

Vaccination coverage: An incremental increase of 5% in vaccination coverage was considered in the modelling, starting at 50% coverage and ending at 100%. Coverage below 50% was not considered, as the impact of vaccination at the population level would not be sufficient to justify a change in screening protocols.