Cervical Cancer Screening
Jeddah Colposcopy Course Jan 2014
James Bentley
Professor Dept. Obstetrics and Gynnecology Dalho...
Cervical Cancer Prevention
Normal
Cervix
HPV
Infection
Cervical
Dysplasia
Cervical
Cancer
Primary
Prevention:
Vaccination
...
WHO Criteria for a screening test 1968
1. Condition an important health problem
2. There should be a treatment
3. Faciliti...
Modified WHO criteria:
• The screening programme should respond to a recognized need.
•
The objectives of screening should...
Screening Options
• Visual Inspection with acetic acid/ Lugols (VIA,
VILI)
• Cervical Cytology:
– Conventional
– Liquid ba...
Visual Inspection
with Acetic Acid (VIA)
VIA Classification
• Negative
• Positive
• Cancer
Test Qualities of VIA in Primary Healthcare Setting
(Phase 2)
TEST
SENSITIVITY
(%)
SPECIFICITY
(%)*
POSITIVE
PREDICTIVE
VA...
Cryotherapy post VIA
• Risk of overtreatment
– Unlikely to be associated
with adverse pregnancy
outcome
• Risk of undertre...
Pap smear
• MD/RN to collect
• Supplies-low cost
• Cytotech to process and read
• Pathologist to confirm
• Oversight of th...
Cervical Cytology
Where does it fail?
Due to mediocre sensitivity, there
are false negative cases so the test
needs to be...
How to screen?
• In Canada we have a long
history of cytology based
screening
• Effective in reducing the
burden of cervic...
Where are we starting from?
No progress until we understand the limitations
 Cytology is irreproducible (Sherman et al, A...
Possible qualitative changes in
Pap cytology performance
• Sensitivity will be negatively affected:
– Today’s typical case...
Cryotherapy post VIA
• Risk of overtreatment
– Unlikely to be associated
with adverse pregnancy
outcome
• Risk of undertre...
Pap smear
• MD/RN to collect
• Supplies-low cost
• Cytotech to process and read
• Pathologist to confirm
• Oversight of th...
Cervical Cytology
Where does it fail?
Due to mediocre sensitivity, there
are false negative cases so the test
needs to be...
How to screen?
• In many countries we have
a long history of cytology
based screening
• Effective in reducing the
burden o...
Where are we starting from?
No progress until we understand the limitations
 Cytology is irreproducible (Sherman et al, A...
Possible qualitative changes in
Pap cytology performance
• Sensitivity will be negatively affected:
– Today’s typical case...
Possible qualitative changes in
Pap cytology performance
• But specificity may suffer as well…
– Decrease in signal-to-noi...
Women who have sex
with HPV-infected men
HR-HPV infection
(within weeks to months
some will develop)
Persistent HR-HPV
inf...
HPV testing in cervical cancer screening
 Approaches already implemented or being examined:
• Serial: Cytology screening ...
Kyrgiou et al Lancet 2006: 367; 489-498
Effects of treatment
• Treatment for CIN by
excisional methods and
potentially by ablation
has an increased
incidence of p...
Cervical Screening Guidelines
• Canada:
– Start age 21, q 3 years, end age 70
– Cytology
• USA:
– Start age 21, q 3 years ...
Role of HPV testing
•Triage equivocal or low grade cytology smears (ALTS
trial)
•FUP of women with abnormal cytology but n...
Sankarnaryanan
52 clusters
HPV
• High Sensitivity for CIN 2 +
• 89.7% (95%CI 86.4-93%)
• You identify all the cases of high grade disease
• Lengthen ...
HPV Testing
ADVANTAGES
• Objective result
• Very sensitive
• Better quality control
• Decreases the number of
cytologists ...
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%)
...
Issues to work out
Second test
• HPV 16 or HPV 18 testing
• mRNA E6, or E7 oncoprotein
test to rule out infection
• Age – ...
Digene Hybrid Capture 2
(existing test)
Gaithersburg, MD
Digene FASThpv Arbor Vita E6 strip test
Sunnyvale, CA
Test format...
FastHPV Kit and reagents
© 2006, Digene Corporation. All rights reserved
Self sampling for HPV
• May be a way to sample for HPV when women
are reluctant to have a gynecological exam
• Methods use...
Self sampling for HPV
• All had > 90% satisfactory samples
• Most methods acceptable to women
– Decreases sensitivity the ...
Ronco et al. Lancet Nov 2013
• 176000 women from 4 studies
• Cancer as end point
• invasive cancer reduced by 60-70% over ...
Efficient, low-cost solutions for screening of cervical
cancer in low-resource settings
• In order to be effective, screen...
Optimal Screening Now
HPV test at
age 35
Reflex Pap
test
Positive refer
for
colposcopy
Negative
repeat pap in
6-12 months
...
1  prof james bently cervical cancer screening 2014
1  prof james bently cervical cancer screening 2014
1  prof james bently cervical cancer screening 2014
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1 prof james bently cervical cancer screening 2014

  1. 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. 2. Cervical Cancer Prevention Normal Cervix HPV Infection Cervical Dysplasia Cervical Cancer Primary Prevention: Vaccination Secondary Prevention: Screening
  3. 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. 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. 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. 6. Visual Inspection with Acetic Acid (VIA)
  7. 7. VIA Classification • Negative • Positive • Cancer
  8. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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)
  24. 24. Kyrgiou et al Lancet 2006: 367; 489-498
  25. 25. 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??
  26. 26. 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
  27. 27. 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
  28. 28. Sankarnaryanan 52 clusters
  29. 29. 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
  30. 30. 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
  31. 31. 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
  32. 32. 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
  33. 33. 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
  34. 34. FastHPV Kit and reagents © 2006, Digene Corporation. All rights reserved
  35. 35. 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
  36. 36. 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
  37. 37. 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
  38. 38. 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).
  39. 39. 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

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