Published 28 July 2009, doi:10.1136/bmj.b3005
Cite this as: BMJ 2009;339:b3005

Editorials

Cervical screening according to age and HPV status

Cytological screening under age 25 has very low effectiveness; after that HPV genotyping helps to stratify risk

Strong evidence is now available that testing for human papillomavirus (HPV) infection is more sensitive than cytology in detecting high grade cervical intraepithelial neoplasia, and some randomised controlled trials showed that HPV testing is able to detect, earlier than cytology, persistent and therefore clinically relevant neoplasia.^{1 2} However, HPV testing is less specific than cytology.³ The best management of HPV positive women is therefore of major concern.

In one of two linked articles (doi:10.1136/bmj.b2569),⁴ Castle and colleagues show that the risk of developing high grade cervical intraepithelial neoplasia in the next three to five years is much higher in women with HPV infection that has persisted for at least one year than in those in whom the infection cleared. This suggests that HPV positive women need repeat testing, with differential management of those with or without persistent infection. Randomised trials have shown that if only HPV positive women with cytological abnormalities or persistent infection are referred for colposcopy, the positive predictive value for colposcopy referral is similar to that for cytological screening.^{1 2}

Castle and colleagues found that the same HPV type is usually involved in women who are persistently positive for high risk HPV, especially those aged 30 or more, so that persistent positivity for high risk HPV (using a general high risk HPV assay) entails almost the same risk as persistent positivity for the same type. However, persistent infection by HPV types 16 and 18 predicts a much higher future risk of high grade cervical intraepithelial neoplasia than persistent infection by other high risk types. Such risk stratification is important for clinical management. For example, HPV positive women who clear the infection after one year have a low risk of high grade cervical intraepithelial neoplasia for many years (a cumulative risk of 1.17% at three years and of 1.58% at five years) and can therefore be recalled for screening at long intervals. Also, the probability of having cervical intraepithelial neoplasia grade II+ detected at the time of a second positive test is more than 30% in persistently HPV 16 positive women aged under 30, and this suggests that these women need immediate colposcopy after that second test. However, the same probability is well below 5%, regardless of the HPV type carried, in women aged 30 and over; these women need intensive follow-up because they are at high future risk but probably do not need immediate referral to colposcopy.

It is still unclear whether triage of women positive for high risk HPV after just one test that uses biomarkers, such as p16 overexpression, could provide the same predictive value as two repeated HPV tests.⁵

In a second linked article (doi:10.1136/bmj.b2968),⁶ Sasieni and colleagues evaluate the age specific effectiveness of cytology based screening in England. They show that effectiveness in preventing cancers in the five years after screening is limited below age 25, and that screening is fully effective only from age 35. The large sample size allowed analysis of the cancers by stage: the same pattern was seen for microinvasive (stage IA) and fully invasive cancers and was even more marked for advanced (stage II+) cancers.

In developed countries, the prevalence of HPV infection is high at young ages in relation to the start of sexual activity.⁷ At these ages, most infections are transient, possibly because they are recently acquired.⁸ Nevertheless, several studies have shown a high incidence of high grade cervical intraepithelial neoplasia in young women shortly after HPV infection.⁹ The sensitivity of cytology is low at younger ages, however, with values around 50%.³ One plausible reason is the young age of such lesions, which need time to reach sufficient size to be cytologically detectable. In younger women, cytological screening results in large numbers of detected abnormalities, but with only a small fraction being progressive, whereas an important fraction (though small in absolute number) of lesions that will progress to invasive cancer in the next five years may be missed.

The question is whether to screen younger women, and if so, how? In many developed countries the low incidence of invasive cervical cancer and the lack of effectiveness of screening in young women indicate that screening should not start before the age of 25. For women aged 25-34, screening with HPV testing alone is much more sensitive than screening with cytology, but it is also less specific.³

Looking at persistence of infection could identify women at low risk and limit excessive referral to colposcopy, as Castle and colleagues’ study suggests. In the New Technology in Cervical Cancer (NTCC) study, referral to colposcopy only of HPV positive women aged 25-34 who showed cytological abnormalities or persistent infection for one year increased sensitivity by around 50% compared with cytology, with only a minor loss in positive predictive value.¹⁰ In another phase of the same study, direct referral to colposcopy of all HPV positive women aged 25-34 resulted in a much larger (about 3.5 times) increase in sensitivity compared with cytology,¹¹ suggesting that some of the additional high grade lesions detected might represent overdiagnosis. At younger ages, the main challenge is to find the progressive lesions and to avoid treating the remaining lesions, given that treatment may be harmful to future reproductive health.¹² Follow-up data from the NTCC trial, unlike the Sweenscreen and POBASCAM trials,^{1 2} will provide information on the effectiveness of different strategies to detect persistent lesions in younger women and on overdiagnosis.

Cite this as: BMJ 2009;339:b3005

¹ Unit of Cancer Epidemiology, Centre for Cancer Prevention, Via San Francesco da Paola 31, 10123 Turin, Italy, ² Unit of Cancer Epidemiology, Scientific Institute of Public Health, Brussels, Belgium

Research, doi:10.1136/bmj.b2569; Research, doi:10.1136/bmj.b2968

---

Competing interests. GR and MA participated in an advisory board workshop organised by GenProbe S.Diego (CA), USA, expenses for which were covered. This relationship ceased in spring 2008.

Provenance and peer review: Commissioned; not externally peer reviewed.

References

1. Bulkmans NWJ, Berkhof J, Rozendall L, van Kemenade F, Boeke A, Bulk S, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 2007;370:1764-72.[CrossRef][Web of Science][Medline]
2. Naucler P, Ryd W, Törnberg S, Strand A, Wadell G, Elfgren K, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med 2007;357:1589-97.[Abstract/Free Full Text]
3. Cuzick J, Arbyn M, Sankaranarayanan R, Tsu V, Mayrand M-H, Dillner J, et al. Overview of human papillomavirus-based and other novel options for cervical cancer screening in developed and developing countries. Vaccine 2008;26S:K29-41.
4. Castle PE, Rodrìguez AC, Burk RD, Herrero R, Wacholder S, Alfaro M, et al. Short term persistence of human papillomavirus and risk of cervical precancer and cancer: population based cohort study. BMJ 2009;339:b2569.[Abstract/Free Full Text]
5. Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, Gillio-Tos A, De Marco L, et al. Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 2008;9:937-45.[CrossRef][Web of Science][Medline]
6. Sasieni P, Castanòn A, Cuzick J. Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data. BMJ 2009;339:b2968.[Abstract/Free Full Text]
7. Franceschi S, Herrero R, Clifford G, Snijders PJ, Arslan A, Anh PT, et al. Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int J Cancer 2006;119:2677-84.[CrossRef][Web of Science][Medline]
8. Castle PE, Schiffman M, Herrero R, Hildesheim A, Rodriguez A C, Bratti MC, et al. A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste, Costa Rica. J Infect Dis 2005;191:1808-16.[CrossRef][Web of Science][Medline]
9. Woodman CI, Collins S, Winter H, Bailey A, Ellis J, Prior P, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal study. Lancet 2001;357:1831-6.[CrossRef][Web of Science][Medline]
10. Ronco G, Giorgi-Rossi P, Carozzi F, Dalla Palma P, Del Mistro A, De Marco L, et al. Human papillomavirus testing and liquid-based cytology in primary screening of women younger than 35 years: results at recruitment for a randomised controlled trial. Lancet Oncol 2006;7:547-55.[CrossRef][Web of Science][Medline]
11. Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, et al. Results at recruitment from a randomised controlled trial comparing human papillomavirus testing alone with conventional cytology as a primary cervical cancer screening test. J Natl Cancer Inst 2008;100:492-501.[Abstract/Free Full Text]
12. Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, Martin-Hirsch P, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ 2008;337:a1284.[Abstract/Free Full Text]

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Rapid Responses:

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Cervical cytology in under 25 year olds? We have all the evidence, so why don’t we base some medicine on it ?

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