1. Cervical Cancer Screening
Jeddah Colposcopy Course Jan 2014
James Bentley
Professor Dept. Obstetrics and Gynnecology Dalhousie
University, Halifax, NS, Canada
Secretary General IFCPC

2. Cervical Cancer Prevention
Normal
Cervix
HPV
Infection
Cervical
Dysplasia
Cervical
Cancer
Primary
Prevention:
Vaccination
Secondary
Prevention:
Screening

3. WHO Criteria for a screening test 1968
1. Condition an important health problem
2. There should be a treatment
3. Facilities for diagnosis and treatment should be available
4. There should be a latent stage of the disease
5. There should be a test or exam for the condition
6. The test should be acceptable to the population
7. The natural history should be adequately understood
8. There should be an agreed policy on whom to treat
9. The total cost of finding a case should be economically
balanced in comparison to whole medical expenditure
10. Case-finding should be a continuous process, not just a
“once and for all project”

4. Modified WHO criteria:
• The screening programme should respond to a recognized need. •
The objectives of screening should be defined at the outset. • There
should be a defined target population. • There should be scientific
evidence of screening programme effectiveness. • The programme
should integrate education, testing, clinical services and programme
management. • There should be quality assurance, with mechanisms
to minimize potential risks of screening. • The programme should
ensure informed choice, confidentiality and respect for autonomy. •
The programme should promote equity and access to screening for the
entire target population. • Programme evaluation should be planned
from the outset. • The overall benefits of screening should outweigh
the harm.
WHO Bulletin: Vol 86:2008, 4, 241-320

5. Screening Options
• Visual Inspection with acetic acid/ Lugols (VIA,
VILI)
• Cervical Cytology:
– Conventional
– Liquid based
• HPV testing
• When to start?
• when to end?
• how often?

6. Visual Inspection
with Acetic Acid (VIA)

7. VIA Classification
• Negative
• Positive
• Cancer

8. Test Qualities of VIA in Primary Healthcare Setting
(Phase 2)
TEST
SENSITIVITY
(%)
SPECIFICITY
(%)*
POSITIVE
PREDICTIVE
VALUE (%)*
NEGATIVE
PREDICTIVE
VALUE (%)*
VIA
(n = 2,130)
77
(70–82)
64
(62–66) 19 96
Pap smear
(n = 2,092)
44
(35–51)
91
(37–51) 33 94
95% Confidence Interval
University of Zimbabwe/JHPIEGOCervical Cancer Project 1999.

9. Cryotherapy post VIA
• Risk of overtreatment
– Unlikely to be associated
with adverse pregnancy
outcome
• Risk of undertreatment
• Missing small cancers as
biopsy was not done

10. Pap smear
• MD/RN to collect
• Supplies-low cost
• Cytotech to process and read
• Pathologist to confirm
• Oversight of the lab – Quality
control due to this subjective test
• Weeks to report
• Notify woman
• Counsel woman
• Possible other assessments or
treatment
• Expensive Sherris J. Intn Persp Sex Reprod Health 2009;35,3:147

11. Cervical Cytology
Where does it fail?
Due to mediocre sensitivity, there
are false negative cases so the test
needs to be repeated frequently to
identify all cases of high grade
disease
Compliance: Patient has to come
back for results, for repeat tests or
colposcopy - case based system

12. How to screen?
• In Canada we have a long
history of cytology based
screening
• Effective in reducing the
burden of cervical cancer
• In the UK really became
effective in the late 1980’s
early 1990’s
• BUT….
• Very labor intensive
• Needs repeat testing
• Needs a organized program
to be truly effective

13. Where are we starting from?
No progress until we understand the limitations
 Cytology is irreproducible (Sherman et al, ALTS)
 Sensitivity of screening cytology for any grade of dysplasia is
~50% (Fahey et al, Nanda et al)
 Sensitivity of optimized LBC for detection of CIN2/3+ diagnosed
at a single colposcopy is ~75% (ASCCP, Ronco et al)
 Sensitivity of colposcopy for detection of CIN2/3+ is at most 56-
76% (Belinson et al, ALTS)
 Credentials of the colposcopist don’t matter (ALTS), but number
of biopsies does (Belinson et al, ALTS)
 Histology <CIN3+ is irreproducible (ALTS)
 Loss to followup is huge (all refs)

14. Possible qualitative changes in
Pap cytology performance
• Sensitivity will be negatively affected:
– Today’s typical case load: approximately 10% of all
smears contain abnormalities that are serious enough
to merit slide review
– Reduction in lesion prevalence  fatigue will set in
given expectation that abnormalities will be rare 
smears may not be read as thoroughly  more false
negatives
– End result: further decline in the PPV of cytology
– (some of the lowest estimates of Pap sensitivity are in
frequently screened, low risk populations of developed
countries)
Franco et al., Vaccine 2006

15. Cryotherapy post VIA
• Risk of overtreatment
– Unlikely to be associated
with adverse pregnancy
outcome
• Risk of undertreatment
• Missing small cancers as
biopsy was not done

16. Pap smear
• MD/RN to collect
• Supplies-low cost
• Cytotech to process and read
• Pathologist to confirm
• Oversight of the lab – Quality
control due to this subjective test
• Weeks to report
• Notify woman
• Counsel woman
• Possible other assessments or
treatment
• Expensive Sherris J. Intn Persp Sex Reprod Health 2009;35,3:147

17. Cervical Cytology
Where does it fail?
Due to mediocre sensitivity, there
are false negative cases so the test
needs to be repeated frequently to
identify all cases of high grade
disease
Compliance: Patient has to come
back for results, for repeat tests or
colposcopy - case based system

18. How to screen?
• In many countries we have
a long history of cytology
based screening
• Effective in reducing the
burden of cervical cancer
• In the UK really became
effective in the late 1980’s
early 1990’s
• BUT….
• Very labor intensive
• Needs repeat testing
• Needs a organized program
to be truly effective

19. Where are we starting from?
No progress until we understand the limitations
 Cytology is irreproducible (Sherman et al, ALTS)
 Sensitivity of screening cytology for any grade of dysplasia is
~50% (Fahey et al, Nanda et al)
 Sensitivity of optimized LBC for detection of CIN2/3+ diagnosed
at a single colposcopy is ~75% (ASCCP, Ronco et al)
 Sensitivity of colposcopy for detection of CIN2/3+ is at most 56-
76% (Belinson et al, ALTS)
 Credentials of the colposcopist don’t matter (ALTS), but number
of biopsies does (Belinson et al, ALTS)
 Histology <CIN3+ is irreproducible (ALTS)
 Loss to followup is huge (all refs)

20. Possible qualitative changes in
Pap cytology performance
• Sensitivity will be negatively affected:
– Today’s typical case load: approximately 10% of all
smears contain abnormalities that are serious enough
to merit slide review
– Reduction in lesion prevalence  fatigue will set in
given expectation that abnormalities will be rare 
smears may not be read as thoroughly  more false
negatives
– End result: further decline in the PPV of cytology
– (some of the lowest estimates of Pap sensitivity are in
frequently screened, low risk populations of developed
countries)
Franco et al., Vaccine 2006

21. Possible qualitative changes in
Pap cytology performance
• But specificity may suffer as well…
– Decrease in signal-to-noise ratio of cytology  due to
rarity of squamous abnormalities and koilocytotic atypias
(the signal) inflammatory changes or reactive atypias
(the noise) may be overcalled
– Could be aggravated by cytotechnician’s fear that
relevant abnormalities will be missed
– Heightened awareness of the potential for false-negative
diagnoses may lead to more false-positive reports 
loss in specificity
– End result: further decline in the PPV of cytology
Franco et al., Vaccine 2006

22. Women who have sex
with HPV-infected men
HR-HPV infection
(within weeks to months
some will develop)
Persistent HR-HPV
infection
(within months some will
develop)
HG cervical lesions
(within months to years
some will develop)
Cervical cancer
(within months to years
some will develop)
Detected
with
moderate
sensitivity
Detected
with low
sensitivity
Pap
Cytology
Detected
with high
sensitivity
Detected
with high
sensitivity
HPV
Testing
Perceived
as cause
of low
specificity

23. HPV testing in cervical cancer screening
 Approaches already implemented or being examined:
• Serial: Cytology screening followed by HPV testing to triage
ASC-US (USA, Nfld)
• Parallel: Cytology and HPV cotesting (approved in USA,
implemented in California(Kaiser),Quebec)
• Serial: HPV testing followed by cytologic triage (being
examined in the Finnish trial, BC RCT, a.k.a., HPV FOCAL
Study, Ronco etc)

25. Kyrgiou et al Lancet 2006: 367; 489-498

26. Effects of treatment
• Treatment for CIN by
excisional methods and
potentially by ablation
has an increased
incidence of preterm
delivery in subsequent
pregnancy in most
studies
• CIN itself may increase
risk of preterm delivery
• Perhaps knowledge of
the risks has facilitated
safer treatment??

27. Cervical Screening Guidelines
• Canada:
– Start age 21, q 3 years, end age 70
– Cytology
• USA:
– Start age 21, q 3 years till 30, then q 5 yrs till 70
– Cytology q 3 yrs or combined cytology/HPV q 5 yrs
• UK
– Start age 25, q 3 yrs then q 5 yrs
– Cytology
• Women who have had a hysterectomy and no history of
CIN/Cancer do not need screening

28. Role of HPV testing
•Triage equivocal or low grade cytology smears (ALTS
trial)
•FUP of women with abnormal cytology but normal
colposcopy
•Predict outcome after treatment of high grade
disease
•Primary Screening
Cuzick J. Vaccine 2008

29. Sankarnaryanan
52 clusters

30. HPV
• High Sensitivity for CIN 2 +
• 89.7% (95%CI 86.4-93%)
• You identify all the cases of high grade disease
• Lengthen the screening interval
• Lower Specificity
• 87.8% (95% CI 8.5-90%)
• You get a high number of false positive tests which need a
second test
• Colposcopy or Pap test
Arbyn M. Vaccine 24S3 (2006)S3/78-S3-89

31. HPV Testing
ADVANTAGES
• Objective result
• Very sensitive
• Better quality control
• Decreases the number of
cytologists needed
• Avoids the situation of HPV
negative ASC/LSIL
• Increase screening interval
which decreases cost and
improves convenience
DISADVANTAGES
• Need a second test due
to lower specificity

32. HPV +
Cytology for ASC + to detect CIN 2 +
• Sensitivity 99.2% (95% CI 97.4-100%)
• Specificity 87.3% (95% CI 84.2-90.4%)
• 14.5% had a positive test
• This sensitivity is 45% higher rate of CIN 2, 39% higher rate
of CIN 3 over cytology with specificity of 7% lower
Arbyn M. Vaccine 24S3 (2006)S3/78-S3-89

33. Issues to work out
Second test
• HPV 16 or HPV 18 testing
• mRNA E6, or E7 oncoprotein
test to rule out infection
• Age – use only in 30 year and
above
Cuzick J. Vaccine 2008

34. Digene Hybrid Capture 2
(existing test)
Gaithersburg, MD
Digene FASThpv Arbor Vita E6 strip test
Sunnyvale, CA
Test format Batch Rapid-batch Rapid-strip
Time 7 hours Less than 2 hours Less than 20 minutes
Detects HPV-DNA HPV-DNA E6 protein
Setting Lab
Refrigeration needed
Static or mobile clinic
No refrigeration needed
Near patient testing
No refrigeration needed
Number of samples 96 well batch 24 or 48 well batch One at a time
Number of oncogenic
HPV types
13 At least 13 To be determined
Target price per
specimen
Substantially more than US$5 Less than US$5 Less than US$5

35. FastHPV Kit and reagents
© 2006, Digene Corporation. All rights reserved

36. Self sampling for HPV
• May be a way to sample for HPV when women
are reluctant to have a gynecological exam
• Methods used:
– Pad
– Tampon
– Vaginal brush
– Vaginal swab
– Lavage
– Urine specimen

37. Self sampling for HPV
• All had > 90% satisfactory samples
• Most methods acceptable to women
– Decreases sensitivity the further from the cervix
• About 70% sensitivity compared to biopsy
• Specificity ~80% compared to biopsy
• Reasonable concordance with physician
sampling
• Vagina swab may be best compromise
Stewart et al. JOGC 2007

39. Ronco et al. Lancet Nov 2013
• 176000 women from 4 studies
• Cancer as end point
• invasive cancer reduced by 60-70% over 6.5
years in HPV group compared with cytology
• No real change in first 2.5 yrs post test
• Supports screening with HPV at age 30, with a
5 year interval

40. Efficient, low-cost solutions for screening of cervical
cancer in low-resource settings
• In order to be effective, screening techniques need to be tailored to the
contexts of low resources countries.
• The “screen and treat” single-visit programs are essential for remote, low-
resource regions where women often travel long distances to receive
healthcare services and where communication related to follow-up is difficult.
• The World Health Organization (WHO) estimates that a one-time screening
among women around the age of 40 could reduce the chance of fatality due to
cervical cancer by 25-30% if adequately followed up.
• The most recommended and accessible method of screening for cervical
cancer in low resource settings is Visual Inspection with Acetic acid (VIA).

41. Optimal Screening Now
HPV test at
age 35
Reflex Pap
test
Positive refer
for
colposcopy
Negative
repeat pap in
6-12 months
Negative
? Rescreen at
age 45