1. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals PRIMARY HPV SCREENING A view from colposcopy John Tidy Consultant Gynaecological Oncologist Chair National Colposcopy PAG Member HPV primary screening group

2. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Why are we considering HPV primary screening? The arrival of the first cohort of women who have offered prophylactic HPV vaccination –60 – 70% reduction in high grade CIN rates –Cytology, given it’s relatively poor sensitivity will not be a viable screening test in this population –Primary HPV screening while very sensitive may still lack specificity

3. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Why start now in the non vaccinated population? There will be a mixed screening population for many years –i.e. non HPV vaccinated women and HPV vaccinated women Separating these populations will be a challenge A single screening strategy will be more efficient and more reliable

4. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals HPV Primary Screening Pilot Colposcopy Management Recommendations Index test HR-HPV +ve/cytology ≤low grade <40yrs Colposcopy Examination Inadequate Abnormal Normal and adequate No biopsy or biopsy <CIN1 ≥CIN2CIN1 Negative biopsy Abnormal Biopsy CIN1+ Discussion at MDT within 2m Treat † Recall in 12m Index test HR-HPV +ve/ cytology ≤low grade Index test HR-HPV +ve/cytology ≥high grade Discussion at MDT within 2m Discharge to 3y recall HR-HPV -veHR-HPV +ve † Option of colposcopy at clinicians discretion Version 1 May 2012 Reflex cytology and/or 12m follow up Index HR-HPV +ve/cytology ≥high grade or ≥40yrs Repeat colposcopy in 12m LLETZ

5. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Issues for colposcopy Caseload Return of women with HR-HPV who are have a normal colposcopy to routine recall The management of low grade CIN The performance of colposcopy particularly in the vaccinated population

6. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals HPV Primary Screening Pilot Colposcopy Management Recommendations Index test HR-HPV +ve/cytology ≤low grade <40yrs Colposcopy Examination Inadequate Abnormal Normal and adequate No biopsy or biopsy <CIN1 ≥CIN2CIN1 Negative biopsy Abnormal Biopsy CIN1+ Discussion at MDT within 2m Treat † Recall in 12m Index test HR-HPV +ve/ cytology ≤low grade Index test HR-HPV +ve/cytology ≥high grade Discussion at MDT within 2m Discharge to 3y recall HR-HPV -veHR-HPV +ve † Option of colposcopy at clinicians discretion Version 1 May 2012 Reflex cytology and/or 12m follow up Index HR-HPV +ve/cytology ≥high grade or ≥40yrs Repeat colposcopy in 12m LLETZ

7. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Colposcopy referrals at STH HPV triage and TOC

8. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Caseload The unknowns –Baseline HPV positivity rate

9. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Women eligible for screening HPV high risk positive Women with abnormal smears High grade CIN HPV Screening - The Dilemma

10. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals ARTISTIC Primary HPV testing –HC2 Ages 20-64 Prevalence of HR-HPV –15.6% –Ages 25-64 – 12.7% –Ages 25-30 – 27.9% –Ages 30-34 – 18.5% –Ages 55-64 – 6.0%

11. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals ARTISTIC HR-HPV rates in abnormal cytology –Borderline 31% –Mild 70% HR-HPV rates in abnormal cytology –HPV sentinel site study –Borderline 40% increase compared with ARTISTIC –Mild 17% increase compared with ARTISTIC

12. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Sentinel sites HPV +ve (%) rates by cytology and age BorderlineMildTotal Age group N=6507N=3544N=10051 25-34 N=5324 68.6%89.2%77.2% 35-49 N=3912 41.9%77.0%52.0% 50-64 N=815 31.0%66.5%40.2% Total N=10051 53.7%83.9%64.4%

13. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Baseline HPV rate Every UK study testing for HPV has found a higher rate of infection compared with other international studies and prior UK based studies Will the primary HPV screening study produce a similar result –i.e. a higher rate of HPV+ve women

14. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Performance of reflex cytology Only you can tell me how cytology might perform within this new strategy However we know that there is variation in practice between laboratories as indicated by the sentinel site study

15. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Sentinel sites HPV +ve (%) rates by laboratory and cytology SiteBorderlineMildTotal A57.7%88.6%68.4% B34.8%73.4%52.1% C43.4%81.8%57.7% D61.2%89.8%74.3% E68.6%91.6%74.1% F73.3%87.2%75.9% Thinprep58.2%87.7%68.7% Surepath52.6%78.5%61.7%

16. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals PPV of HPV for detecting CIN by site and referral cytology BorderlineMildTotal Site PPV CIN2+ PPV CIN3+ PPV CIN2+ PPV CIN3+ PPV CIN2+ PPV CIN3+ A16.5%7.4%21.8%7.6%18.97.5% B11.2%6.2%9.1%3.5%9.9%4.4% C11.6%5.0%15.9%4.8%13.9%4.9% D9.3%2.5%10.9%2.5%10.2%2.5% E21.5%7.8%25.4%7.1%22.7%7.6% F20.9%11.5%30.0%15.2%23.4%12.3%

17. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals HPV positivity in borderline cytology and PPV for high grade CIN Percentage Study site Av. CIN3 6.7%

18. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals HPV positivity in mild cytology and PPV for high grade CIN Percentage Study site Av. CIN3 5.4%

19. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals How might we reduce high referral rates? Only some PCTs will convert to primary HPV screening so only some of the caseload of a colposcopy clinic will be affected Should we start at age 30 –Women aged 25 to 30 would have primary cytology screening Could other tests reduce the referral rates –HPV genotyping –p16/Ki67 staining

20. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals HPV Genotyping Only offer reflex cytology for HPV16/18+ve women Repeat HPV testing in 2 years for non 16/18+ve Refer HPV16/18 women without bothering with reflex cytology

21. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Safety of new colposcopy management pathways What is the risk of a woman who is HR HPV positive and has a normal colposcopic examination developing CIN2+ over the next 3 years?

22. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Safety of new colposcopy management pathways What is the risk of missing CIN2+ in women with a low grade cytology smear who has a normal colposcopic examination The risk of CIN3 developing over the next three plus years is reported to be between 3 and 10%. The negative predictive value for colposcopy to exclude high-grade CIN, when colposcopy is described as normal, is reported as 98-99%. NHSCSP No 20 Bellinson et al 2001 Cantor et al 2008

23. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Risk of developing CIN3+ based on HPV type Recent prospective population based study Risk at 12 years HPV 1626.7% HPV 1819.1% HPV 3114.3% HPV 3314.9% Other high risk HPV6.0% HC2+ negative3.0% The risk of developing CIN 3+ at 3 years appears to be 5% for HPV16 and <3% for other high risk types. Kjaer et al 2010

24. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Detection of CIN2+ in women referred in pilot triage study 360 women attended colposcopy 72.2% had a negative colposcopy Rates of CIN2+ 4.4%, CIN3 2.4% at 3 years were reported for those women with a negative colposcopy at entry In the normal UK screened population; in 2007-08 there were 39,456 cases of CIN2+ among 3,670,846 women screened, a rate of 1.2% Kelly et al 2011

25. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Long term outcome for women with normal colposcopy after referral with low grade cytology 622 women 2292 years of follow up 96% had negative or low grade cytology in the future 3.3% had CIN2+ in the future Cumulative rate of CIN2+ at 5 years if negative colposcopy and non-dyskaryotic cytology at first visit –1.3% borderline –8.5% mild Smith et al 2006

26. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Summary The risk of developing CIN2+ over three years based only HR HPV infection alone is low – 3-5% Colposcopy has a high NPV to exclude high grade CIN when colposcopy is normal – 98- 99% In the pilot sites the rate of CIN2+ in the women with low grade cytology, HP HPV + with normal colposcopy was low – 4.4%, similar to previous follow up strategies

27. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Management of CIN1 Should we consider CIN1 a manifestation of transient HPV infection? Does CIN1 ever need to be treated –Highest TOC failure rates for LLETZ are associated with treatment of CIN1 Can we safely increase the interval between colposcopic examinations? Should all women with CIN be returned to community based follow-up

28. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Management of CIN1 What should the re-call interval be –12 months What should the re-call test be –HPV + reflex cytology alone is suggested in current algorithm –If this is done in colposcopy then we have the same situation as we had with TOC i.e. a diagnostic test is performed and then a screening result becomes available a few days later

29. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Management of CIN1 Could the re-call interval be –36 months Tombola study –166 women with CIN1 followed for 3 years –76 (46%) HR-HPV positive –16% HPV 16, 10% HPV 18 –12 (20%) women developed HG-CIN –Only predictor of developing HG-CIN was HPV16 or HPV18. OR 4.3. Could we use genotyping?

30. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Performance of colposcopy in post vaccination screening population Technique not changed since 1920s Rely on tissue changes i.e. whiteness and vascular patterns associated with application of acetic acid Only measure of performance in NHSCSP No. 20 is PPV >65% to correctly identify HG- CIN based on colposcopic impression PPV is dependent on disease prevalence

31. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Performance of colposcopy in post vaccination screening population Some recent studies suggest that HPV16 and 18 are associated with significant aceto-white change Other HR-HPVs may produce more subtle changes Subtle aceto-white change is associated with LG-CIN and metaplasia Will colposcopy become more dependent on directed biopsies? Will we have to use random biopsies?

32. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Challenges to management involving HPV testing Almost 100% of cervical cancers are associated with HR-HPV IARC has stated that HR-HPVs are cancer causing viruses Nobel prize awarded to Prof H zur Hausen for his work linking HPV to cervical cancer Prophylactic vaccination programme against HR-HPV

33. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Challenges to management involving HPV testing HPV infection is ubiquitous 80% of sexually active people will be infected at some stage Duration of infection is 13 months HPV alone cannot cause a cancerous growth in the laboratory setting The risk of developing CIN3+ after 12 years exposure is 27% The duration between HPV infection and CIN3 is 7-8 years

34. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Challenges to management involving HPV testing The development of CIN3 is not a failure of the cervical screening programme Treating CIN3 is associated with a lower test of cure failure rate than treating CIN1 The development of invasive cervical cancer is We should not place the same emphasis on the development of CIN3 compared with the development of cervical cancer CIN3 will progress to cancer at the rate of –10yrs – 18%, 20yrs – 36%, 30yrs – 54%

35. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals Summary HPV is a common infection associated with intimate contact The duration of infection is long but most people will eradicate the infection Low grade changes are a manifestation of HPV infection once high grade CIN has been excluded The risk of HPV infection leading to HG-CIN is low and occurs over a long time period The development of CIN3 is not a failure of the screening programme as it is easily treated without increased risk of recurrence, without any increase in morbidity when compared with low grade CIN

36. Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals