Sheffield Gynaecological Cancer CentreSheffield Teaching Hospitals PRIMARY HPV SCREENING A view from...

Sheffield Gynaecological Cancer Centre Sheffield Teaching Hospitals

PRIMARY HPV SCREENING

A view from colposcopy

John TidyConsultant Gynaecological Oncologist

Chair National Colposcopy PAG

Member HPV primary screening group


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


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


HPV Primary Screening Pilot

Colposcopy Management Recommendations

Index test HR-HPV +ve/cytology ≤low

grade <40yrs

Colposcopy Examination

Inadequate AbnormalNormal and adequate

No biopsy or biopsy <CIN1 ≥CIN2CIN1 Negative

biopsy

Abnormal Biopsy CIN1+

Discussion at MDT within

2m

Treat†Recall in 12mIndex 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 -ve HR-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


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


HPV Primary Screening Pilot

Colposcopy Management Recommendations

Index test HR-HPV +ve/cytology ≤low

grade <40yrs

Colposcopy Examination

Inadequate AbnormalNormal and adequate

No biopsy or biopsy <CIN1 ≥CIN2CIN1 Negative

biopsy

Abnormal Biopsy CIN1+

Discussion at MDT within

2m

Treat†Recall in 12mIndex test HR-HPV +ve/ cytology ≤low

grade

Index test HR-HPV +ve/cytology ≥high

grade

Discussion at MDT within 2m



HR-HPV -ve HR-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


Colposcopy referrals at STH

HPV triage and TOC


Caseload

• The unknowns– Baseline HPV positivity rate


Women eligible for screening

HPV high risk positive

Women with abnormal smears

High grade CIN

HPV Screening - The Dilemma


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%


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


Sentinel sites HPV +ve (%) rates by cytology and ageBorderline Mild Total

Age group N=6507 N=3544 N=10051

25-34N=5324

68.6% 89.2% 77.2%

35-49N=3912

41.9% 77.0% 52.0%

50-64N=815

31.0% 66.5% 40.2%

TotalN=10051

53.7% 83.9% 64.4%


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


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


Sentinel sites HPV +ve (%) rates by laboratory and cytology

Site Borderline Mild Total

A 57.7% 88.6% 68.4%

B 34.8% 73.4% 52.1%

C 43.4% 81.8% 57.7%

D 61.2% 89.8% 74.3%

E 68.6% 91.6% 74.1%

F 73.3% 87.2% 75.9%

Thinprep 58.2% 87.7% 68.7%

Surepath 52.6% 78.5% 61.7%


PPV of HPV for detecting CIN by site and referral cytology

Borderline Mild Total

Site PPV

CIN2+

PPV

CIN3+

PPV

CIN2+

PPV

CIN3+

PPV

CIN2+

PPV

CIN3+

A 16.5% 7.4% 21.8% 7.6% 18.9 7.5%

B 11.2% 6.2% 9.1% 3.5% 9.9% 4.4%

C 11.6% 5.0% 15.9% 4.8% 13.9% 4.9%

D 9.3% 2.5% 10.9% 2.5% 10.2% 2.5%

E 21.5% 7.8% 25.4% 7.1% 22.7% 7.6%

F 20.9% 11.5% 30.0% 15.2% 23.4% 12.3%


HPV positivity in borderline cytology and PPV for high grade CIN

0

10

20

30

40

50

60

70

80

A B C D E F

Borderline HPV%

Borderline PPVCIN2+

Borderline PPVCIN3+P

erce

nta

ge

Study site

Av. CIN3 6.7%


HPV positivity in mild cytology and PPV for high grade CIN

0102030405060708090

100

A B C D E F

Mild HPV%

Mild PPV CIN2+

Mild PPV CIN3+

Per

cen

tag

e

Study site

Av. CIN3 5.4%


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


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


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?


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 2001Cantor et al 2008


Risk of developing CIN3+ based on HPV type

• Recent prospective population based studyRisk at 12 years

• HPV 16 26.7%• HPV 18 19.1%• HPV 31 14.3%• HPV 33 14.9%• Other high risk HPV 6.0%• HC2+ negative 3.0%

• 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


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


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


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


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


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


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?


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


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?


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



• 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



• 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%


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


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