Faculty Disclosures: Cervical Cancer Prevention in Teresa ...…Changing Paradigms… Teresa M....
Transcript of Faculty Disclosures: Cervical Cancer Prevention in Teresa ...…Changing Paradigms… Teresa M....
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Cervical Cancer Prevention in the 21st Century
…Changing Paradigms…
Teresa M. Darragh, MD
UCSF
Departments of Pathology and
Obstetrics, Gynecology & Reproductive Sciences
Faculty Disclosures: Teresa M. Darragh, MD• Hologic: Research supplies for anal cytology• OncoHealth: Advisory Board (Ended August 2014)• Roche: Advisory Board (October 2013)
– Honorarium paid to UCSF• Roche-Ventana: Advisory Board (August 2014)
– Honorarium paid to UCSF• TheVax: Advisory Board (August 2014)
– Honorarium paid to UCSF
Objectives• Bethesda 2015: Updates, in brief• Cervical cancer screening in the US
– Current recommendations– Current screening options
• Changing Paradigms: Risk assessment approach to cervical cancer screening
• The future of cervical cancer screening?
The Bethesda System: Atlases
TBS 1: 1991 TBS 2: 2001
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Bethesda 3• Publication: July 2015
– Print & online
• New content includes:– 30% greater page content– Updated recommendations– Increased background
• Literature review• Data in support• Biological descriptions
– Management issues for each entity
Why a 3rd Edition?• Significant changes in practice of gynecologic cytology
– Primary HPV screening with Pap as “diagnostic” triage– New screening and management guidelines– Changes in histopathology terminology– Increasing uptake of HPV vaccination
• New data and technology– Additional experience with LBP over last 10 yrs– Endometrial cells, Anal cytology, Biomarkers, Automation, Risk
assessment– Still a need for Pap testing in low resource areas and for
standardization of terminology for trials and research
TBS: Possible Confusion?• Bethesda 3 � Additional Guidance / Clarification
• Specimen adequacy• LSIL + possible HSIL: how to report?• Benign endometrial cells
– Significance on Pap– Reporting issues
Specimen adequacy• Clarified cellularity criteria for vaginal / post
radiation samples• Added data on lubricant / blood interference• HPV testing on unsatisfactory specimens
• Negative Pap: Absent t-zone components– Addressed in updated ASCCP Management
Guidelines– Affirmed in Bethesda 3
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The Bethesda System: T-zone• Definition of “adequate” endocervical cells
or transformation zone component• 10 well preserved cells
– Endocervical or squamous metaplastic– Single cells or in clusters
• With atrophy– May not be able to tell atrophic T-zone from
parabasal cells– TBS: “No identifiable t-zone component in an
atrophic pattern sample”• Quality indicator ≠ Unsa sfactory Pap
Quality Indicator: No t-zone on Pap• No T-zone on approximately 10-20% of Paps• More frequent in pregnant & older women
• Recent meta-analysis: Negative Pap �– Regardless +/- t-zone– Good specificity and NPV
• HPV test result independent of t-zone sampling
Elumir-Tanner L. CMAJ 2011; 183:563-8.Zhao C. Gynecol Oncol 2007;107:231-5.
Bethesda 3: No t-zone• TBS still recommends reporting the presence or
absence of EC/TZ component as a quality indicator.
• Absence of an EC/TZ component should not lead to early repeat screening.
• Provides feedback to clinician.
• May provide valuable information in women with a history of atypical glandular cells, early adenocarcinoma, trachelectomy for early-stage cancer, or other high-risk processes.
Negative Pap, No t-zone
No early repeat needed* *Unless HPV+
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Bethesda 3: LSIL + ASC-H• LSIL with some cells suggestive
of HSIL• Some labs report modified TBS
– LSIL, cannot exclude HSIL– LSIL-H
• Risk for HSIL on biopsy intermediate between:– LSIL and HSIL on cytology– Risk similar to ASC-H
• No new category!– Management guidelines based
on LSIL, ASC-H, HSIL• Report as ASC-H + LSIL
– Should be relatively uncommon interpretationLSIL with some cells
suggestive of concurrent HSIL
Bethesda: Benign Endometrial cells• In post-menopausal women, exfoliated endometrial
cells are abnormal.– Raise possibility of endometrial neoplasia
• TBS 1: Report benign EMs in post-menopause.– In US, average age is 51 years (but large variation)
• TBS 2: Report in all women ≥ 40 years– Status often unclear, inaccurate, or unknown to lab– Clinician to determine if further evaluation needed…
• Confusion, especially among non-gynecologists• Led to unnecessary endometrial sampling in some women
Consequence of 2001 Bethesda• Increased reporting of benign-appearing EMs
– 0.17% to 0.49% of Paps (↑3x)– Decreased predictive value for hyperplasia and
cancer with Bethesda 2
Risk Associated with Benign-appearing Endometrial cells on PapPre-2001 Post-2001
Hyperplasia 12% 2%Cancer 6% 1%
Bethesda 3: ReportingBenign Endometrial cells on Pap
• Endometrial cells are present in a woman ≥ 45 years of age.
• Negative for squamous intraepithelial lesion.
Note: Endometrial cells in women 45 years and older may be associated with benign endometrium, hormonal alterations and less commonly, endometrial or uterine abnormalities. Endometrial evaluation is recommended in postmenopausal women.
Images: The Bethesda Atlas
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Objectives• Bethesda 2015: Updates, if brief• Cervical cancer screening in the US
– Current recommendations– Current screening options
• Changing Paradigms: Risk assessment approach to cervical cancer screening
• The future of cervical cancer screening?
Cervical Cancer Screening in U.S.• Pap test
– Best cancer screening test in medicine in 20th century• In U.S.
– Opportunistic screening– No national screening registry– Single state screening registry
• The New Mexico HPV Pap Registry• Screening rate ~83%• Adherence to guidelines � poor
Cervical Cancer Screening is U.S.• Cervical cancer was the #1 cancer killer for U.S. women• Between 1955 and 1992, the number of cervical cancer
deaths in the U.S. dropped ~ 75%
• In 2016:• 12,990 cases in U.S.• 4,120 deaths in U.S.• 6-7 per 100,000 women per year
• Screening has increased:• Detection/treatment of precursor lesions• Detection/treatment of early stage CA’s
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Siegel, R. L., Miller, K. D. and Jemal, A. (2016), Cancer statistics, 2016. CA: A Cancer Journal for Clinicians, 66: 7–30.
Cervical Cancer: Screening Failures
~12,000 Cervical cancers diagnosed/year– 60%: Failure to screen
• Never had a Pap• No Pap within the last 3 years
– 30%: Errors in sampling/evaluation• 20 - 25%: Sampling error• 5 - 10%: Laboratory error
– 10%: System Failure
Sawaya Obstet Gynecol 1999
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Cervical Cancer: Screening Failures
~12,000 Cervical cancers diagnosed/year– 60%: Failure to screen
• Never had a Pap• No Pap within the last 3 years
– 30%: Errors in sampling/evaluation• 20 - 25%: Sampling error• 5 - 10%: Laboratory error
– 10%: System Failure
Sawaya Obstet Gynecol 1999
Developments: Cervical Cancer Screening
• Since the early 1990’s
• Liquid-based cytology• Computer assisted screening• HPV testing• HPV typing
What are the current US standards?USPSTF ACS/ASCCP/ASCP
When to start? 21 yo 21 yo
How often? Q3yInsufficient data on HPV tests < 30 yrsbut recs co-testing > 30 years q 5 yrs
Q3y Paps ages 21-29Q5y co-testing ages 30-65Q3y Paps remain an option
When to stop? 65 if adequate prior screens
Age 65 if 3 negative Paps or 2 negative co-tests in previous 10 years
Rationale for Beginning Screening at Age 21Cervical Cancer Incidence by Age Group
USCS*, 1998-2002
Age Rate per 100,0000-19 0.120-29 4.530-39 13.940-49 16.550-64 15.465+ 14.6All ages 9.4
*United States Cancer Statistics includes data from CDC’s National Program of Cancer Registries and NCI’s
Surveillance, Epidemiology and End Results Program.
Saraiya M et al. Obstet Gynecol 2007;109:360-70
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What are the current US standards?USPSFTF ACS/ASCCP/ASCP
AFTER HYSTERECTOMY
Recommends against screening in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (ie, CIN 2 or 3) or cervical cancer.
Women of any age following a hysterectomy with removal of the cervix who have no history of CIN2+ should not be screened for vaginal cancer. Evidence of adequate negative prior screening is not required. Screening should not be resumed for any reason, including if a woman reports having a new sexual partner
HPV VACCINATED Women who have been vaccinated should continue to be screened.
Recommended screening practices should not change on the basis of HPV vaccination status
Rationale for Stopping after Hysterectomy
• Vaginal cancer rate: 7 per million/year• 663 vaginal cuff Paps needed to find one VaIN• 2066 women followed after hysterectomy for
average 89 months– 3% had VaIN, 0 had cancer
• Risk of Pap abnormality after hysterectomy = 1%.• Comparable to risk of breast cancer in men for
which screening is not recommendedPearce KF et al. NEJM 1996;335:1559-62
Piscitelli JT et al. AmJOG 1995;173:424-30
Percentage of women who had a Pap test within 3 years of hysterectomy
MMWR 2013;61(51):1043-1047Compliance with guidelines: Poor!
Cervical Cancer: Screening Failures
~12,000 Cervical cancers diagnosed/year– 60%: Failure to screen
• Never had a Pap• No Pap within the last 3 years
– 30%: Errors in sampling/evaluation• 20 - 25%: Sampling error• 5 - 10%: Laboratory error
– 10%: System Failure
Sawaya Obstet Gynecol 1999
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System Failures
Women do notcome in for screening
Health care providersdo not screen women
at visits
No Colposcopy for abnormal
screen
Patient does not getappropriate therapy
Courtesy of Connie Trimble, MD, Johns Hopkins University School of Medicine, Baltimore, MD
Patient gets cervical cancer
www.cdc.gov
HPV-Associated Cervical Cancer Rates
3-dose HPV vaccination coverage among girls (aged 13 to 17 years), 2010
Ahmedin Jemal et al. JNCI J Natl Cancer Inst 2013;jnci.djs491© The Author 2013. Published by Oxford University Press.
The Bottom Line• “The biggest gain in reducing cervical cancer
incidence and mortality would be achieved by increasing screening rates among women who have not been screened or who have not been screened regularly. . .
• ~50% of women with cervical cancer are never screened
• Improvement in mortality from cervical cancer can only be obtained by – Screening everyone (when appropriate)–HPV vaccination!!!
Spence AR Prev Med 2007
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Objectives• Bethesda 2015: Updates, if brief• Cervical cancer screening in the US
– Current recommendations– Current screening options
• Changing Paradigms: Risk assessment approach to cervical cancer screening
• The future of cervical cancer screening?
Cervical Cancer Screening in US: Options
• Cytology alone• Pap test
– ASC-US triage: Reflex HPV testing
• Co-testing = Pap test + HPV testing
• Primary HPV testing (one HPV test FDA-approved for this
indication, April 2014)
NB: HPV testing = high-risk HPV testing with FDA-approved method
Concept of Risk Assessment /Stratification in Cancer Screening
• Rapid evolution of cervical cancer screening options
• Advantage of screening and management recommendations based on risk thresholds
• Current U.S. cervical cancer screening and management guidelines are based on risk thresholds and balancing benefits and potential harms
Underlying Principle Screening test: Risk stratification
DifferentManagement
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Underlying Principle
Treatment
Colposcopy
Increased surveillance
Repeat screen
Similar Management for Similar RiskPap Test as Benchmark:
Similar Management for Similar Risk
Pap Test as Benchmark:Similar Management for Similar Risk
Pap Test as Benchmark:Similar Management for Similar Risk
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Pap Test as Benchmark:Similar Management for Similar Risk
Management options
• Repeat screen at regular intervals
• Increased surveillance– Shorter screening interval
• Colposcopy• Treatment
How to incorporate new technologies?
*“Lesser abnormalities” include ASC-US or LSIL Cytology, HPV 16+ or 18+, and persistent HPV∞ Management options may vary if the
woman is pregnant or ages 21-24+Cytology if age <30 years, cotesting if
age ≥30 years† Either ablative or excisional methods.
Excision preferred if colposcopy inadequate, positive ECC, or previously treated.
Management of Women with No Lesion or Biopsy-confir med Cervical Intraepithelial Neoplasia - Grade 1 (CIN1) Preceded by “Lesser Abnormalities”* ∞
Manage perASCCP Guideline
Follow-up without Treatment
Cotesting at 12 months > ASC or HPV (+)
HPV (-)and
Cytology Negative
Colposcopy
Age appropriate* retesting 3 years later
No CIN CIN2,3 CIN1
If persists forat least 2 years
© Copyright, 2013, American Society for Colposcopy and Cervical Pathology. All rights reserved.
Follow-up orTreatment †
Cytology negative+/-
HPV (-)
Routine screening
1 of 19 different algorithms
Management of Women with No Lesion or Biopsy-confir med Cervical Intraepithelial Neoplasia - Grade 1 (CIN1) Preceded by ASC-H or HSIL Cytology
Cotesting at 12 and 24 months*
Age-specificRetestingin 3 years+
Colposcopy
HPV(+) or Any cytology
abnormality except HSIL
*Only if colposcopy was adequate and endocervical sampling negative^ Except in special populations (may include pregnant women and those ages 21-24)+ Cytology if age <30; cotesting if age ≥30 years
© Copyright, 2013, American Society for Colposcopy and Cervical Pathology. All rights reserved.
HPV(-)and
Cytology Negativeat both visits
HSILat either visit
Diagnostic Excision
Procedure ^
OrReview of cytological,
histological, and colposcopic findings
Or
Manage perASCCP Guideline
for revised diagnosis
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Cervical Cancer Screening & Management
• ASCCP app: Risk assessment tool bar update
Cervical Cancer Screening: Current Options
Cytology with HPV Testing as Triage
HPV test
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HPV testing with Cytology as Triage
Screening & Triage• Sensitivity and specificity are characteristics of the test.
– The population does not affect the results.• Positive and negative predictive values are influenced
by the prevalence of disease in the population that is being tested.
• Screen with the more sensitive test– HPV testing
• Triage with more specific test– Pap test– HPV 16 & 18 genotyping– ? Dual staining– ? Others
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E.L. Franco et al. / Vaccine 24S3 (2006) S3/171–S3/177
Effect on PPV with changes in sensitivity, specificity, and lesion prevalence
Specificity estimates (dashed line: 95%; solid line: 85%; dotted line: 75%)
No VaccinationPrevalence = 10%
After VaccinationPap as ScreeningPrevalence = 1%
After VaccinationPap as Triage
Prevalence = 50%
HPV + Vaccination Rates in US• ≥1 HPV vaccine dose
– Females: 56.7% to 60.0%– Males: 33.6% to 41.7%
CDC Weekly:July 31, 2015 / 64(29);784-792
Markowitz LE, Hariri S, Lin C, Dunne EF, Steinau M, McQuillan G, et al. J Infect Dis 2013;208(3):385–93.
Human Papillomavirus — Cervicovaginal Prevalence of Types 6, 11, 16 and 18
Objectives• Bethesda 2015: Updates, if brief• Cervical cancer screening in the US
– Current recommendations– Current screening options
• Changing Paradigms: Risk assessment approach to cervical cancer screening
• The future of cervical cancer screening?
20th CenturyMorphologyModel - Cytology
21st centuryHybrid modelHPV + Pap
21st centuryMolecular modelHPV only
Cervical Cancer Screening
U.S.
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Cervical Cancer Screening Options• Rapid Evolution
• Advantage of screening and management recommendations based on risk thresholds:
• New assays can be integrated into current recommendations more easily based on risk equivalence studies
Evolving risk-based guidelines• Guidelines set risk levels, not algorithms for
specific assays/ combinations• Agree on management options and associated
risk levels– (Exit)– Regular screening interval– Accelerated return (increased surveillance)– Colposcopy– Treatment
Cutting out the complexityScreening test(s)
Type 16 Positive 12 other hrHPV +Negative
Cytology
Increased SurveillanceRoutine Screening Colposcopy
Black box
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Cervical Cancer Prevention• Primary Prevention: HPV vaccination
• Secondary Prevention:– Screen all women, as appropriate– Improve screening test sensitivity– Improve triage test specificity– Reduce system failures
Future?• Primary prevention: HPV vaccination!!!
– 9-valent vaccine is now available– Vaccinate boys � increase herd immunity– Other HPV-associated cancers
• Secondary prevention:– HPV screening
• Reflex with cytology? Biomarkers? Other?• Self-collection?
– HPV treatment vaccines
• We have the tools to eliminate cervical cancer!
Dear Pap Smear……It’s over
…Thank you…