Download Tidy_HPV_Primary_BAC_2012

PRIMARY HPV SCREENING
A view from colposcopy
John Tidy
Consultant Gynaecological Oncologist
Chair National Colposcopy PAG
Member HPV primary screening group
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield Teaching Hospitals
HPV Primary Screening Pilot
Colposcopy Management Recommendations
Colposcopy Examination
Inadequate
Index test HR-HPV
+ve/cytology ≤low
grade <40yrs
Repeat colposcopy in
12m
Normal and adequate
Index HR-HPV
+ve/cytology ≥high
grade
or ≥40yrs
LLETZ
No biopsy or biopsy
<CIN1
Index test HR-HPV
+ve/ cytology ≤low
grade
Discharge to 3y
recall
†Option
of colposcopy at clinicians discretion
Version 1 May 2012
Abnormal Biopsy
CIN1+
Index test HR-HPV
+ve/cytology ≥high
grade
Discussion at MDT
within 2m
Sheffield Gynaecological Cancer Centre
Abnormal
†Recall
HR-HPV -ve
Discharge to 3y
recall
CIN1
≥CIN2
Negative
biopsy
in 12m
Treat
Discussion at
MDT within
2m
HR-HPV +ve
Reflex cytology
and/or 12m
follow up
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield Teaching Hospitals
HPV Primary Screening Pilot
Colposcopy Management Recommendations
Colposcopy Examination
Inadequate
Index test HR-HPV
+ve/cytology ≤low
grade <40yrs
Repeat colposcopy in
12m
Normal and adequate
Index HR-HPV
+ve/cytology ≥high
grade
or ≥40yrs
LLETZ
No biopsy or biopsy
<CIN1
Index test HR-HPV
+ve/ cytology ≤low
grade
Discharge to 3y
recall
†Option
of colposcopy at clinicians discretion
Version 1 May 2012
Abnormal Biopsy
CIN1+
Index test HR-HPV
+ve/cytology ≥high
grade
Discussion at MDT
within 2m
Sheffield Gynaecological Cancer Centre
Abnormal
†Recall
HR-HPV -ve
Discharge to 3y
recall
CIN1
≥CIN2
Negative
biopsy
in 12m
Treat
Discussion at
MDT within
2m
HR-HPV +ve
Reflex cytology
and/or 12m
follow up
Sheffield Teaching Hospitals
Colposcopy referrals at STH
HPV triage and TOC
Sheffield Gynaecological Cancer Centre
Sheffield Teaching Hospitals
Caseload
• The unknowns
– Baseline HPV positivity rate
Sheffield Gynaecological Cancer Centre
Sheffield Teaching Hospitals
HPV Screening - The Dilemma
Women eligible for screening
HPV high risk positive
Women with abnormal smears
High grade CIN
Sheffield Gynaecological Cancer Centre
Sheffield 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%
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield Teaching Hospitals
Sentinel sites HPV +ve (%) rates by
cytology and age
Borderline
Mild
Total
Age group
N=6507
N=3544
N=10051
25-34
68.6%
89.2%
77.2%
41.9%
77.0%
52.0%
31.0%
66.5%
40.2%
53.7%
83.9%
64.4%
N=5324
35-49
N=3912
50-64
N=815
Total
N=10051
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield Teaching Hospitals
Sentinel sites HPV +ve (%) rates by
laboratory and cytology
Site
A
B
C
Borderline
57.7%
34.8%
43.4%
Mild
88.6%
73.4%
81.8%
Total
68.4%
52.1%
57.7%
D
E
F
61.2%
68.6%
73.3%
89.8%
91.6%
87.2%
74.3%
74.1%
75.9%
Thinprep
Surepath
58.2%
52.6%
87.7%
78.5%
68.7%
61.7%
Sheffield Gynaecological Cancer Centre
Sheffield Teaching Hospitals
PPV of HPV for detecting CIN by site
and referral cytology
Borderline
Site
PPV
CIN2+
A
PPV
CIN3+
Mild
PPV
CIN3+
PPV
CIN2+
PPV
CIN3+
16.5% 7.4%
21.8% 7.6%
18.9
7.5%
B
11.2% 6.2%
9.1%
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%
Sheffield Gynaecological Cancer Centre
PPV
CIN2+
Total
3.5%
Sheffield Teaching Hospitals
HPV positivity in borderline cytology
and PPV for high grade CIN
80
70
Borderline HPV%
Percentage
60
50
Borderline PPV
CIN2+
40
Borderline PPV
CIN3+
30
20
10
Av. CIN3 6.7%
0
A
B
C
D
E
F
Study site
Sheffield Gynaecological Cancer Centre
Sheffield Teaching Hospitals
Percentage
HPV positivity in mild cytology and
PPV for high grade CIN
100
90
80
70
60
50
40
30
20
10
0
Mild HPV%
Mild PPV CIN2+
Mild PPV CIN3+
Av. CIN3 5.4%
A
B
C
D
E
F
Study site
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield 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?
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield Teaching Hospitals
Risk of developing CIN3+ based on
HPV type
• Recent prospective population based study
Risk at 12 years
•
•
•
•
•
•
HPV 16
HPV 18
HPV 31
HPV 33
Other high risk HPV
HC2+ negative
26.7%
19.1%
14.3%
14.9%
6.0%
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
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Smith et al 2006
Sheffield 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 – 9899%
• 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
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield 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?
Sheffield Gynaecological Cancer Centre
Sheffield 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 HGCIN based on colposcopic impression
• PPV is dependent on disease prevalence
Sheffield Gynaecological Cancer Centre
Sheffield 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?
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield 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%
Sheffield Gynaecological Cancer Centre
Sheffield 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
Sheffield Gynaecological Cancer Centre
Sheffield Teaching Hospitals
Sheffield Gynaecological Cancer Centre
Sheffield Teaching Hospitals