Cervical Cancer Prevention in the 21 st Century Changing Paradigms

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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

1 Cervical Cancer Prevention in the 21 st 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 The Bethesda System: Atlases 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? TBS 1: 1991 TBS 2:

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

2 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 2

The Bethesda System: T-zone Definition of adequate endocervical cells or transformation zone component 10 well preserved cells Endocervical or

t-zone component in an atrophic pattern sample Quality indicator Unsa sfactory Pap Quality Indicator: No t-zone on Pap No T-zone on

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.

Absence of an EC/TZ component should not lead to early repeat screening. Provides feedback to clinician.

3 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: Zhao C. Gynecol Oncol 2007;107: Bethesda 3: No t-zone Negative Pap, 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. No early repeat needed* *Unless HPV+ 3

Bethesda 3: LSIL + ASC-H LSIL with some cells suggestive of concurrent HSIL LSIL with some cells suggestive of HSIL Some labs report modified TBS LSIL, cannot exclude HSIL LSIL-H Risk for HSIL on

Management guidelines based on LSIL, ASC-H, HSIL Report as ASC-H + LSIL Should be relatively uncommon interpretation Bethesda: Benign Endometrial cells In post-menopausal women, exfoliated

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

4 Bethesda 3: LSIL + ASC-H LSIL with some cells suggestive of concurrent HSIL 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 interpretation 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 Bethesda 3: Reporting Benign Endometrial cells on Pap 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 Pap Pre-2001 Post-2001 Hyperplasia 12% 2% Cancer 6% 1% Images: The Bethesda Atlas 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. 4

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

5 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 20 th 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 Siegel, R. L., Miller, K. D. and Jemal, A. (2016), Cancer statistics, CA: A Cancer Journal for Clinicians, 66: 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

6 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 Developments: Cervical Cancer Screening Since the early 1990 s Liquid-based cytology Computer assisted screening HPV testing HPV typing Sawaya Obstet Gynecol 1999 What are the current US standards? When to start? 21 yo How often? When to stop? USPSTF Q3y Insufficient data on HPV tests < 30 yrs but recs co-testing > 30 years q 5 yrs 65 if adequate prior screens 21 yo ACS/ASCCP/ASCP Q3y Paps ages Q5y co-testing ages Q3y Paps remain an option Age 65 if 3 negative Paps or 2 negative co-tests in previous 10 years Rationale for Beginning Screening at Age 21 Cervical Cancer Incidence by Age Group USCS*, Age Rate per 100, All 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:

7 What are the current US standards? Rationale for Stopping after Hysterectomy USPSFTF ACS/ASCCP/ASCP AFTER HYSTERECTOMY HPV VACCINATED 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 who have been vaccinated should continue to be screened. 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 Recommended screening practices should not change on the basis of HPV vaccination status 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 recommended Pearce KF et al. NEJM 1996;335: Piscitelli JT et al. AmJOG 1995;173: Percentage of women who had a Pap test within 3 years of hysterectomy 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 Compliance with guidelines: Poor! MMWR 2013;61(51): Sawaya Obstet Gynecol

System Failures HPV-Associated Cervical Cancer Rates Patient does not get appropriate therapy Health care providers do not screen women at visits Patient gets cervical cancer No Colposcopy for

gov 3-dose HPV vaccination coverage among girls (aged 13 to 17 years), 2010 The Bottom Line Ahmedin Jemal et al. JNCI J Natl Cancer Inst 2013;jnci.djs491 The Author 2013.

8 System Failures HPV-Associated Cervical Cancer Rates Patient does not get appropriate therapy Health care providers do not screen women at visits Patient gets cervical cancer No Colposcopy for abnormal screen Women do not come in for screening Courtesy of Connie Trimble, MD, Johns Hopkins University School of Medicine, Baltimore, MD 3-dose HPV vaccination coverage among girls (aged 13 to 17 years), 2010 The Bottom Line Ahmedin Jemal et al. JNCI J Natl Cancer Inst 2013;jnci.djs491 The Author Published by Oxford University Press. 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

9 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 Underlying Principle Screening test: Risk stratification 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 Different Management 9

10 Underlying Principle Similar Management for Similar Risk Pap Test as Benchmark: Similar Management for Similar Risk Treatment Colposcopy Increased surveillance Repeat screen Pap Test as Benchmark: Similar Management for Similar Risk Pap Test as Benchmark: Similar Management for Similar Risk 10

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

Management of Women with No Lesion or Biopsy-confirmed Cervical Intraepithelial Neoplasia - Grade 1 (CIN1) Preceded by Lesser Abnormalities * Management of Women with No Lesion or Biopsy-confirmed

11 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? Management of Women with No Lesion or Biopsy-confirmed Cervical Intraepithelial Neoplasia - Grade 1 (CIN1) Preceded by Lesser Abnormalities * Management of Women with No Lesion or Biopsy-confirmed Cervical Intraepithelial Neoplasia - Grade 1 (CIN1) Preceded by ASC-H or HSIL Cytology Follow-up without Treatment Cotesting at 12 months > ASC or HPV (+) HPV (-) and Cytology Negative Age appropriate* retesting 3 years later Cytology negative +/- HPV (-) Manage per ASCCP Guideline Colposcopy No CIN CIN2,3 CIN1 If persists for at least 2 years * 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 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. Follow-up or Treatment Cotesting at 12 and 24 months* HPV(-) and Cytology Negative at both visits Age-specific Retesting in 3 years + HPV(+) or Any cytology abnormality except HSIL Colposcopy Or HSIL at either visit Diagnostic Excision Procedure ^ *Only if colposcopy was adequate and endocervical sampling negative Or ^ Except in special populations (may include pregnant women and those ages 21-24) + Cytology if age <30; cotesting if age 30 years Review of cytological, histological, and colposcopic findings Manage per ASCCP Guideline for revised diagnosis Routine screening 1 of 19 different algorithms Copyright, 2013, American Society for Colposcopy and Cervical Pathology. All rights reserved. Copyright, 2013, American Society for Colposcopy and Cervical Pathology. All rights reserved. 11

12 Cervical Cancer Screening & Management Cervical Cancer Screening: Current Options ASCCP app: Risk assessment tool bar update Cytology with HPV Testing as Triage HPV test 12

Positive and negative predictive values are influenced by the prevalence of disease in the population

13 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 13

Effect on PPV with changes in sensitivity, specificity, and lesion prevalence HPV + Vaccination Rates in US After Vaccination Pap as Triage Prevalence = 50% After Vaccination Pap as Screening

14 Effect on PPV with changes in sensitivity, specificity, and lesion prevalence HPV + Vaccination Rates in US After Vaccination Pap as Triage Prevalence = 50% After Vaccination Pap as Screening Prevalence = 1% No Vaccination Prevalence = 10% 1 HPV vaccine dose Females: 56.7% to 60.0% Males: 33.6% to 41.7% CDC Weekly: July 31, 2015 / 64(29); Human Papillomavirus Cervicovaginal Prevalence of Types 6, 11, 16 and 18 Specificity estimates (dashed line: 95%; solid line: 85%; dotted line: 75%) E.L. Franco et al. / Vaccine 24S3 (2006) S3/171 S3/177 Markowitz LE, Hariri S, Lin C, Dunne EF, Steinau M, McQuillan G, et al. J Infect Dis 2013;208(3): Objectives Cervical Cancer Screening 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? 20 th Century Morphology Model - Cytology 21 st century Hybrid model HPV + Pap U.S. 21 st century Molecular model HPV only 14

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

15 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 Cutting out the complexity 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 Negative Routine Screening Screening test(s) 12 other hrhpv + Black box Cytology Increased Surveillance Type 16 Positive Colposcopy 15

Cervical Cancer Prevention Primary Prevention:

all women, as appropriate Improve screening

specificity Reduce system failures Future?

!! 9-valent vaccine is now available Vaccinate

HPV-associated cancers Secondary prevention:

16 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 16

Over-diagnoses in Cytopathology: Is histology the gold standard?

Over-diagnoses in Cytopathology: Is histology the gold standard? Teresa M. Darragh, MD UCSF Departments of Pathology and Obstetrics, Gynecology & Reproductive Sciences Faculty Disclosures: Teresa M. Darragh,