5/26/2016 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 • 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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Faculty Disclosures: Cervical Cancer Prevention in Teresa ...…Changing Paradigms… Teresa M. Darragh, MD UCSF Departments of Pathology and Obstetrics, Gynecology & Reproductive
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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
• 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
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
0
2
4
6
8
10
50-5
455
-59
60-6
465-
6970-
7475-
7980
-84
85-8
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95-9
900-
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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
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
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
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