faculty disclosures: cervical cancer prevention in teresa ...…changing paradigms… teresa m....

5/26/2016

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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




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

0

2

4

6

8

10

50-5

455

-59

60-6

465-

6970-

7475-

7980

-84

85-8

990

-94

95-9

900-

04

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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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!







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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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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


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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





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…

faculty disclosures: cervical cancer prevention in teresa ...…changing paradigms… teresa m....

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