Current guidelines for Cervical Cancer Screening Rachael Chambers, DO May 29, 2015

Objectives Review current cervical cancer screening guidelines Discuss role of HPV testing in cervical cancer screening Discuss role of primary HPV testing in cervical cancer screening

Background Initial Bethesda system classification revised in 2001 ASCCP consensus conference 2006 Updated guidelines in 2008 Not from a national consensus conference 2012 follow up consensus conference Data from KPNC, NCI, ALTS Screening decreases incidence and mortality of cervical squamous cell cancer and increases cure rate of cervical cancer

2012 Consensus Conference 47 experts 23 professional societies Goal to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia and adenocarcinoma in-situ Literature review and data from ~1.4 million women in the Kaiser Permanente Northern California Medical Care Plan Most prior guidelines were reaffirmed

Major changes 2012 guidelines ECC showing CIN 1 manage as CIN 1 Repeat unsatisfactory cytology Even when HPV results are known Negative cytology with absent or insufficient endocervical cells can be managed without early repeat

Major changes 2012 guidelines Genotyping triages HR HPV positive women to colposcopy earlier after negative cytology Colposcopy indicated for ASCUS +HPV regardless of genotyping HPV negative ASCUS Follow up at 3 years with co-testing Not sufficient for exiting women from screening at age 65

Major changes 2012 guidelines CIN 2+ follow up is more clearly defined with incorporation of co-testing Women age 21-24 Conservative management Pap only Co-test in certain circumstances Incorporate co-testing post colposcopy

Guidelines Available at: www.asccp.org/Portals/9/docs/ASCCP%20Management%20Guidelines_August%202014.pdf App available for iPad, iPhone and Android

Routine Screening Cytology every 3 years Co-testing every 5 years Women age 30-64 only Multi-year intervals ok only if risk of developing CIN 3+ is low 2006 routine screening not defined and shorter screening intervals recommended. 2006 guidelines recommended return to “routine screening” 2012

Case 1 55 year old G2P2 Menopause at age 52 No history of abnormal pap testing Pap test with physical shows: Insufficient cellularity. HPV co-testing is negative. Now what?

Unsatisfactory Cytology 1% or less across all preparations Decreased with use of liquid based pap Most cases now due to insufficient squamous cells Most studies find higher risk in women that had unsatisfactory cytology employed by conventional pap test May be unsatisfactory due to blood, inflammation or other processes Some HPV testing does not have a control for epithelial cellularity so negative HPV can not be relied on

Repeat cytology in 2-4 months Consider treatment to resolve atrophy (vaginal estrogens) or obscuring inflammation if infection is present Colposcopy is acceptable alternative to repeat pap testing if HPV is positive.

Case 2 Same patient as in Case 1 Now pap test shows normal results, but no EC/TZ HPV remains negative Now what?

Cytology NILM but EC/TZ Absent/Insufficient Suggests squamocolumnar junction may not have been adequately sampled Reported rates 10-20% More prevalent in older women Good specificity and negative predictive value HPV testing is independent of TZ sampling Adds margin of safety when co-testing is performed. Personal bias: Cervical broom may not be adequate when dealing with stenotic cervix Previously recommended to repeat cytology early. Women with absent EC/TZ have fewer concurrent cytologic abnormalities and do not have a higher risk for CIN 3+ over time compared to women with adequate EC/TZ. Appears to be due to older population with this finding which goes with lower CIN 3+ risk. Absent EC/TZ component is NOT associated with increased incidence of cervical disease after treatment of CIN 2+

Management Age 21-29: routine screening Age 30-64 HPV negative: Routine screening HPV unknown: Test for HPV or repeat cytology in 3 years HPV positive: Cytology +HPV in 1 year or HPV genotyping Category of evidence BIII Genotyping for type 16/18. If present proceed to colposcopy, if negative repeat co-testing in 12 months.

Case 3 32 year old G1P0 No previous pap testing available Here for initial prenatal care How do we screen her?

Case 3 continued Pap test normal HPV co-test is positive Now what?

Management Negative Cytology, HPV positive Due to increased risk for CIN 3+ if hrHPV positive guidelines balance risk of observation vs intervention Return for earlier retesting HPV genotyping Higher risk of CIN 3+ with type 16/18 Colposcopy if 1 year follow up is ASC or HPV + or immediately if HPV 16/18 are positive Co-testing is the preferred screening strategy ages 30-64 HPV+ women higher risk for CIN 3+ especially if HPV persistent infection HPV type 16 high risk, but type 18 is higher risk for cervical adenocarcinoma which is less efficiently detected by cytology

Case 4 30 year old referred to you for management of ASCUS pap What else do you want to know? Was she HPV co-tested?

Atypical Squamous Cells of Undetermined Significance Most common cytologic abnormality Lowest risk of CIN 3+ 2/3 are NOT HPV associated Women >60 years have higher risk for cervical cancer even if HPV negative compared to women with negative co-testing. ALTS trial= ASCUS-LSIL triage study Conducted before 2001 Bathesda system update ALTS separated ASC-H from ASCUS With the separation of ASCH and ASCUS in 2001 and the observed 3% risk of CIN 3+ in women age 30+of Kaiser Permanente Northern California annual cytology was recommended wit update. Women >60 years have higher risk for cervical cancer even if HPV negative compared to women with negative co-testing.

ASC-US Reflex HPV testing preferred HPV negative HPV positive Type 16/18 positive women have twice the risk of CIN 3+ compared to other hrHPV positive women HPV negative Repeat cotesting in 3 years HPV positive Colposcopy If no CIN co-test at 12 months Recommend endocervical sampling for colposcopy if no lesions are seen or if inadequate colposcopy LEEP is not an acceptable treatment unless CIN 2+ is identified.

ASC-US Cytology only Repeat cytology in 1 year Colposcopy if > ASC Routine screening if normal Routine screening is 3 year cytology follow up

ASC-US in Special Populations Postmenopausal Manage the same as general population Women age 65 and older Repeat screening in 1 year when considering exit from screening Cytology Co-testing (preferred)

ASC-US in Special Populations Pregnant women Identical to nonpregnant women Acceptable to defer colposcopy until 6 weeks postpartum ECC is unacceptable If no suspected CIN 2+ at initial colposcopy, follow up postpartum

Case 5 21 year old, G0 No previous pap test Seen for complete physical Pap test shows LSIL. What next?

Young Women No screening before age 21 Routine screening with initial normal pap test is every 3 years Cervical CA risk is low through age 25 HPV is common Most lesions will regress Less intensive management Encourage HPV vaccination, smoking cessation Risk of cervical cancer for weomen age 21-24 is 1.4/100,000 and almost 55,000 cytology tests must be obtained for each cancer diagnosis

Young women ASCUS/LSIL Cytology every 12 months preferred HPV reflex is acceptable Follow up is repeat cytology if positive Routine screening if negative Colposcopy only if ASC-H, AGC, HSIL at follow up Colposcopy is not recommended for ASCUS or LSIL

Low-grade Squamous Intraepithelial Lesions ALTS Trial showed natural history to be similar to ASC-US HPV+ Women 21-24 have lower risk CIN 3+ Estimated 77% of LSIL are HPV positive High positive rate does not allow for HPV testing to select efficiently for colposcopy

LSIL Management Colposcopy (recommended) Manage based on colposcopic findings If co-test is negative, repeat co-test in 1 year If cytology negative and HPV negative Repeat co-testing in 3 years If >ASC or HPV positive Colposcopy

LSIL Management Pregnant women: Colposcopy preferred ECC unacceptable Acceptable to defer until 6 weeks postpartum If no CIN 2+, follow up post partum

LSIL Management Postmenopausal Obtain HPV test Repeat cytology at 6 and 12 months Colposcopy Repeat cytology in 12 months if HPV negative or no CIN on colposcopy If HPV+ or ASC-US or greater on repeat cytology perform colposcopy Routine screening after 2 negative cytology

Atypical Squamous Cells, Cannot Exclude High-Grade Squamous Intraepithelial Lesion Higher risk of CIN 3+ compared to ASC-US or LSIL Risk also elevated for women age 21-24, but overall CIN 3+ risk remains lower than older women

ASC-H Management Colposcopy for all women High rate of HPV + makes reflex testing unsuitable 5 year cancer risk among ASC-H, HPV negative is 2% 2% risk is too high to justify observation

High-Grade Squamous Intraepithelial Lesion CIN 2+ identified in 60% of women at colposcopy Consider immediate excision of transformation zone Cervical cancer found in 2% at colposcopy Risk rises with age Risk modifies with HPV result HPV result from co-test may help inform choice Substantial risk Immediate excision justified for women due to high risk, especially for women at risk for loss to Follow-up or who have completed childbearing 5 year Cervical cancer risk 8% in women 30+ HPV negative 5 year risk for Cin 3+ 29%, while 7% will develop cancer In KPNC cohort women 30+, HPV + SIL 5 year CIN 3+ risk was 50%, cancer risk 7% Choice of immediate excision vs colposcopy and between diagnostic excision and cytology and colposcopic surveillance if no CIN 2+ identified.

Management HSIL Immediate LEEP Colposcopy Diagnostic excisional procedure recommneded for inadequate colposcopy Except if pregnant Triage with repeat cytology or reflex HPV testing is unacceptable

HSIL in Young Women Colposcopy If no CIN 2+ observe with colposcopy and cytology at 6 month intervals for 24 months. If CIN 2/3 present manage with colposcopy and biopsy or treat See and treat (Immediate treatment) is unacceptable Colposcopy must be adequate and ECC negative or CIN 1 to continue observation

Atypical Glandular Cells Interpretation is poorly reproducible and uncommon Associated with Polyps Metaplasia Neoplasia Adenocarcinomas Endometrium, cervix, ovary, fallopian tube and other sites

AGC Risk of neoplasia higher if reported as AGC favor neoplasia or AIS Cancer risk is lower in women <35, but risk of CIN 2+ is higher Commonly associated with squamous lesions including CIN 1 In KPNC women 9% rate of Cin 3+ in womein30+ with cancer in 3%

AGC Management Colposcopy with ECC Do not use HPV testing to triage Endometrial sampling is recommended in women 35+ Also for women <35 if clinical indictors suggesting risk for endometrial neoplasia. If no CIN 2+ co-test at 12 and 24 months and routine screening if both are negative. Risks for endometrial neoplasia: unexplained vaginal bleeding, conditions suggesting chronic anovulation Same management for women 21-24 No ECC/endometrial biopsy in pregnant women

What’s next? Primary HPV Screening

Primary hrHPV screening Rate of hrHPV is common in sexually active population Most infections are transient FDA previously approved hrHPV testing For triage of ASCUS Adjunct to cytology for women age 30+ April 2014 FDA approved labeling of hrHPV assay to include primary hrHPV screening in women 25+ Some women will develop persistent hrHPV infection and are at risk for cervical cancer and its precursors Triage of hr HPV subtypes also FDA approved in select settings Consider 70% of cervical cancer is associated with type 16/18

Primary hrHPV screening Highly sensitive Specificity depends on subsequent evaluation strategies and screening frequencies FDA approval does not include specific recommendations for applying hrHPV screening in the US Clinical practice guidelines do not yet exist

2011 guidelines American Cancer Society, American Society for Colposcopy and Cervical Pathology and American Society for Clinical Pathology “in most clinical settings, women age 30-65 should not be screened with HPV testing alone as an alternative to co-testing at 5 year intervals or cytology alone at 3 year intervals” Guidelines did not suggest settings that are appropriate, despite stating “most” Recommendation primarily based on concerns about specificity of screening and potential harms such as excess colposcopy and treatment of non-neoplastic HPV lesions. Additional concerns: lack of well-defined and evaluated strategy to manage hrHPV+ women, inadequate information to define appropriate screening intervals, for hrHPV – women, lack of data on testing errors due to specimen inadequacy, cost-effectiveness, and adherence to implementation within the current US opportunistic screening setting At the time of the guideline update several screening studies had reported on only a single round of screening, limiting the evaluation of hrHPV screening Several large studies have since been published including new primary screening data and updates on subsequent rounds of data from previously published trials All concerns from 2011 screening guidelines are not fully addressed but the evidence strengthens the support of primary hrHPV screenign

Consensus panel Met via conference call and face to face Invited to scientific summary presentation by Roche Diagnostics of the Addressing the Need for Advanced HPV Diagnostics (ATHENA) trial MEDLINE database review 11 papers reviewed in addition to significant papers published prior to November 2011 Co-sponsored by: Society of Gynecologic Oncology and American Society for Colposcopy and Cervical pathology Included 13 experts representing SGO, ASCCP, ACOG, ACS, American Society of Cytopathology, College of American Pathologists, American Society of Clinical Pathology Observers invited from Centers for Disease Control and Prevention and the US Food and Drug Administration ATHENA trial data and findings related to the hrHPV screening components. Panel members were able to submit questions before and after the discussion. Roche Diagnostic’s staff and experts participation limited to presentation of ATHEN data including answering of specific questions regarding trial data from panel members Articles reviewed by at least 3 members of the panel and members commented on relevance of article to clinical update and how article should be considered in the guidance document

Consensus panel: Primary question Is hrHPV testing for primary screening as safe and effective as cytology-based screening? Negative hrHPV provides greater reassurance of low CIN3+ risk than negative cytology. Several large trials have evaluated this Gage studied Kaiser permanent Northern California: >1 million women Wright ATHENA 42, 209 Ronco analyzed follow up data from 4 previously published trials from Europe 176,464 Dillner Combined follow up data from 7 European screening trials to compare risk of Cin 3+ 24,295

Consensus panel: Primary question Can primary hrHPV screening be considered as an alternative to current US cervical cancer screening methods? hrHPV can be considered as an alternative to current cytology-based screening because of equivalent of superior effectiveness. Cytology alone and co-testing remain the screening recommended in major guidelines

Additional questions How Should Positive hrHPV be managed? Combination of triage of genotyping and reflex cytology appears to be a reasonable approach Based on data from ATHENA and other studies What is the Optimal Screening interval? No sooner than every 3 years Limited data available Ronco et al reported hrHPV screening interval of every 5 years is safer than cytology every 3 years, but 3 of 4 studies analyzed screened at 3 year intervals. ATHENA follow up data restricted to 3 years, but CIN3+ cumulative incidence less than 1% Rate unlikely to sharply increase after 3 years, but due to limited data there is insufficient prospective data to recommend screening interval beyond 3 years.

Additional questions At What Age Should One initiate primary HPV screening? Not before age 25 ATHENA trial shows 30% of CIN3+ in women 25-29 (more than half had normal cytology), 37% in Women 30-39 Primary screening at age 25 doubled number of colposcopies, but resulted in 54% greater detection rate of CIN3+ when compared to the same strategy at age 30 Panel concerned with risks due to increased number of colposcopies. Unclear if this will translate to a meaningful reduction in cervical cancer

Additional questions How does the performance of primary hrHPV screening compare to co-testing? Most reassurance from co-test comes from the HPV component. Data shows the 3 year risk following HPV negative test is less than the 5 year risk following co-testing. Primary hrHPV test every 3 years is at least as effective as 5 year co-testing.

Currently only 1 hrHPV test is FDA-approved for primary screening. Comparative effectiveness studies are needed Look for future updates

Summary Cervical cancer screening continues to evolve. Trend is toward less invasive methods of screening and managing. hrHPV screening may become the primary screening tool in the future.

References Massad, et al. 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors. Journal of Lower Genital Tract Disease, Volume 17, Number 5, 2013, S1-S27. Huh , et al. Use of Primary High-Risk Human Papillomavirus Testing for Cervical Cancer Screening: Interim Clinical Guidance. Journal of Lower Genital Tract Disease, Volume 19, Number 2, 2015, 91-96. Partridge et al. Cervical Cancer Screening: Featured Updates. Journal of the National Comprehensive Cancer Network. Volume 12, number 3, march 2014, 333-341. ACOG Practice Bulletin. Management of Abnormal Cervical Cancer Screening Test Results and Cervical Cancer Precursors. Number 140, Volume 122, No. 6, December 2013, 1338-1367 Saraiya, et al. Evolution of cervical cancer screening and prevention in United States and Canada: Implications for public health practitioners and clinicians. Preventive Medicine, Volume 57, 2013, 426-433. Dinkelspiel and Kinney. State of the Science: Cervical cancer screening in transition. Gynecologic Oncology, 133, 2014, 389-393. Cannistra and Niolff. Cancer of the Uterine Cervix. The New England Journal of Medicine. Volume 334, number 16, 1996, 1030-1038.