Cervical Cancer Screening

Jeddah Colposcopy Course Jan 2014James Bentley

Professor Dept. Obstetrics and Gynnecology Dalhousie University, Halifax, NS, Canada

Secretary General IFCPC

Cervical Cancer Prevention

Normal Cervix

HPV Infection

Cervical Dysplasia

Cervical Cancer

Primary Prevention:Vaccination

Secondary Prevention:Screening

WHO Criteria for a screening test 1968

1. Condition an important health problem2. There should be a treatment3. Facilities for diagnosis and treatment should be available4. There should be a latent stage of the disease5. There should be a test or exam for the condition6. The test should be acceptable to the population7. The natural history should be adequately understood8. There should be an agreed policy on whom to treat9. The total cost of finding a case should be economically

balanced in comparison to whole medical expenditure10. Case-finding should be a continuous process, not just a

“once and for all project”

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 programmeshould integrate education, testing, clinical services and programmemanagement. • 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

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?

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

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 IntervalUniversity of Zimbabwe/JHPIEGO Cervical Cancer Project 1999.

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

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

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

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

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)

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

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

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

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

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

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)

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

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

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

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)

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 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??

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

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

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 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 testArbyn M. Vaccine 24S3 (2006)S3/78-S3-89

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

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

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

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

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 used:

– Pad

– Tampon

– Vaginal brush

– Vaginal swab

– Lavage

– Urine specimen

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

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

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).

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