10/31/2017. Disclosures. I. Background: History 1,4. Cervical Cancer Screening and HPV

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Clemence Jefferson
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Current Recommendations for III. Workup of Cytologic Abnormalities IV. V. Subsequent Management of CIN/Follow-up After VI. Vaccination VII.Pearls I. Background: History 1,4 I.

1 Cervical Cancer and Disclosures I have no conflicts of interest to disclose Slides courtesy of : Dr. Sarah Morgan Sukhpreet S. Multani, MD St. Vincent Women s Clinical Assistant Professor, Marian University COM Volunteer Clinical Faculty, Indiana University SOM Indianapolis, IN 2 Cervical Cancer and I. Background II. Current Recommendations for III. Workup of Cytologic Abnormalities IV. V. Subsequent Management of CIN/Follow-up After VI. Vaccination VII.Pearls I. Background: History 1,4 I. Background: History 1,4 The Pap test was developed by George Papanicolaou as a research method in understanding the menstrual cycle. Papanicolaou soon recognized its potential for finding cervical cancer early and presented his findings in 1923 American Cancer Society (ACS) promoted the Pap test during the early 1960s and it became widely used 4 1

women The mortality rate from cervical cancer has declined by 70% since routine Pap screening

1925 1943 1960 1978 1995 US Death Rate from Cervical Cancer, per 100,000 5 I.

Background: Current Disease Burden in the US: In 2017 approximately 12,820 women will be

never screened is the major contributing factor to most cervical cancer deaths in the US today.

2 I. Background: Cervical Cancer 1,4 I. Background: Cervical Cancer 1 Cervical cancer historically was a leading cause of death in US women The mortality rate from cervical cancer has declined by 70% since routine Pap screening was implemented US Death Rate from Cervical Cancer, per 100,000 5 I. Background: Cervical Cancer 1 I. Background: Current Disease Burden in the US: In 2017 approximately 12,820 women will be diagnosed with cervical cancer Approximately 4,210 will die from the disease Being rarely or never screened is the major contributing factor to most cervical cancer deaths in the US today. 12,109 new cases of cervical cancer deaths in ,000 new cases of high-grade cervical dysplasia (CIN 2/3) million new cases of low-grade cervical dysplasia (CIN 1) 9 1 million new cases of genital warts 9 I. Background: Cervical Cancer 1 I. Background: Cervical Cancer 1 2

deaths in women 80% of cervical cancer deaths occur In developing countries I.

39, 45, 51, 52, 58 *** 16 (54%) and 18 (13%) account for the majority of cervical cancers***

with external anogenital warts*** Human Papilloma Virus (): Non-enveloped DS DNA virus 6 I.

Half of women within 3 yrs of starting sex 31% get 16 20% get 18 80% of women by age 25 Nearly

Background: 11,18 1. Infection of the host cell. 2. Virus DNA is released within the nucleus 3.

(LCR), starting transcription of the two transforming early genes (E6 and E7). 4.

3 I. Background: Cervical Cancer 2 I. Background: Cervical Cancer 2 Worldwide, cervical cancer is the 4 th leading cause of cancer deaths in women 80% of cervical cancer deaths occur In developing countries I. Background: >100 types identified anogenital Oncogenic types include: 16, 18, 31, 33, 35, 39, 45, 51, 52, 58 *** 16 (54%) and 18 (13%) account for the majority of cervical cancers*** Non-oncogenic types include: 6, 11, 40, 42, 43, 44, 54 *** 6 and 11 are most often associated with external anogenital warts*** Human Papilloma Virus (): Non-enveloped DS DNA virus 6 I. Background: Who gets? Half of women within 3 yrs of starting sex 31% get 16 20% get 18 80% of women by age 25 Nearly 100% of women with > 5 lifetime partners 90% of infections clear by 1 year I. Background: I. Background: 11,18 1. Infection of the host cell. 2. Virus DNA is released within the nucleus 3. Numerous cellular transcription factors interact with the non-coding viral regulatory region (LCR), starting transcription of the two transforming early genes (E6 and E7). 4. The transforming proteins interact with the cellular anti-oncogenic regulator p53 disrupting the cell cycle. 16 Genome 11 Lower 1/3 of epithelium CIN1 CIN2 CIN3 Cervical Cancer LSIL HSIL HSIL Invasive Carcinoma Mildly atypical cellular changes Lower 2/3 of epithelium Moderately atypical cellular changes Preservation of epithelial maturation >2/3 to full thickness of epithelium Severely atypical cellular changes p16 p16 positive p16 positive Invasive Severely atypical cellular changes 3

I. Background: I. Background: 12 3-6 Months 4-5 Years 9-15 Years Initial Infection Persistent Infection CIN 1 CIN 2/3 Cervical Cancer Cofactors: Viral, host, environmental 27.

4 I. Background: I. Background: Months 4-5 Years 9-15 Years Initial Infection Persistent Infection CIN 1 CIN 2/3 Cervical Cancer Cofactors: Viral, host, environmental 27.2% Cleared Infection Cervical cancer is typically the culmination of a years-long process that begins with an infection with a carcinogenic type 36 month cumulative incidence of CIN2-3 among women with -16 or -18 infection I. Background: 19 II. Current Recommendations for 13 The guidelines are based on a systematic evidence review, Baseline Result Frequency (%) in women YO 5 year CIN3+ risk (%) HSIL HSIL AGC AGC ASC-H ASC-H LSIL LSIL ASCUS ASCUS Pap Pap contributions from six working groups, and a recent symposium co-sponsored by the ACS, American Society for and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP), which was attended by 25 organizations. The guidelines generally advise a reduction in the number of tests women get over their lifetime to better ensure that they receive the benefits of testing while minimizing the harms II. Recommendations for : Caveats These recommendations apply to women who have a cervix, regardless of sexual history. They do NOT apply to women who have received a diagnosis of a high-grade, precancerous cervical lesion or cervical cancer. They do NOT apply to women with in-utero diethylstilbesterol (DES) exposure They do NOT apply to women who are immunocompromised II. Recommendations for A. Pap B. hr 4

5 II. A. Pap 13 II. A. Pap 13 Age Group <21 No screening Recommendation screening every 3 years testing/cotesting should not be used for screening in this age group with co-testing every 5 years Acceptable: cytology every 3 years >65 No screening IF adequate prior screening Starting Recommend screening starting at 21 YO regardless of sexual activity Stopping Women with history of CIN2 or a more severe diagnosis should continue screening for at least 20 years Women who have had hysterectomy do not need screening if they do not have a cervix and do not have a history of CIN2 or a more severe diagnosis Women over 65 YO may discontinue screening if they have an adequate prior screening history II.B. hr 14 II.B. hr 14 Because of equivalent or superior effectiveness, primary hr screening can be considered as an alternative to current US cytology-based cervical cancer screening methods. alone and cotesting remain the screening options specifically recommended in major guidelines. Primary hr screening should not be initiated prior to 25 years of age Rescreening after a primary hr screen should occur no sooner than every 3 years A hr test provides greater reassurance of low CIN3+ risk than a cytology result II.B. hr 14-16/18 positive II.B. hr : USPSTF Draft The USPSTF recommends: Primary Other hr positive NILM for cervical cancer every 3 years with cervical cytology alone in women ages 21 to 29 years. Either screening every 3 years with cervical cytology alone or every 5 years with high-risk human papillomavirus (hr) testing alone in women ages 30 to 65 years Negative FU 12 months

II.B. hr 29 II.B. hr 15 ACOG and the American Society for and Cervical Pathology issued a joint statement reaffirming their support for testing for both every five years, or screening with a Pap

6 II.B. hr 29 II.B. hr 15 ACOG and the American Society for and Cervical Pathology issued a joint statement reaffirming their support for testing for both every five years, or screening with a Pap alone every three years. A prospective cluster randomized study in rural India showed an approximate 50% reduction in cervical cancer mortality and late-stage disease with a single lifetime DNA screening test compared with controls Cultural obstacles to successful cytology screening in the U.S. Affiliated Pacific Islands potentially could be overcome with testing of selfcollected specimens. Self-collected specimens have similar detection rates as those collected by clinicians. The sensitivity of testing on selfcollected specimens has been shown to be comparable with cytology and almost as high as physician-collected specimens III. Workup of Cytologic Abnormalities 13 A. Unsatisfactory cytology B. Absent endocervical cells C. +hr with normal cytology D. ASCUS E. LSIL F. ASC-H G. HSIL H. AGC I. Special populations i YO ii. iii. iv. Pregnancy Menopausal women Adolescents III. Workup of Cytologic Abnormalities 17 A group of 47 experts representing 23 professional societies, national and international health organizations, and federal agencies met in Bethesda, MD, September 14-15, 2012, to revise the 2006 American Society for and Cervical Pathology Consensus s. III.A. Unsatisfactory III.B. Absent Endocervical Cells (NILM) unknown (any age) ( 30) positive ( 30) YO 30 YO unknown 2-4mos 3 yrs testing **preferred** positive Abnormal: Follow Negative: (Cotesting 1 yr if +) Unsatisfactory 6

7 III.C. +hr with cytology **Women 30 YO** III.D. ASCUS ASCUS Options vary if patient is pregnant or is YO Cotesting 1 year +hr DNA Typing Negative 1 year Positive testing **preferred** Negative +hr -16 or -18 positive -16 and -18 Cotesting 3 years Cotesting 1 year 3 years (routine screening) Co-testing 3 years III. E. LSIL Options vary if patient is pregnant or is YO III. F. ASC-H Options vary if patient is YO Negative Unknown Positive Positive Negative preferred acceptable Negative Negative Cotesting 1 year Co-testing 3 years +hr Negative Pap and III. G. HSIL Options vary if patient is pregnant or is YO III. H. AGC Atypical Endometrial Cells Immediate Excisional Biopsy (LEEP) Practical tip: Colpo with ECC EMB with few exceptions Endometrial Pathology Endometrial Endocervical Sampling No Endometrial Pathology 7

8 III. H. AGC All other categories/nos III.I.i. Special Populations: YO ASCUS or LSIL ASCUS or LSIL * ** endometrial sampling IF 35YO risk factors for endometrial hyperplasia** Negative/ ASCUS/LSIL at ASC-H /HSIL/AGC Positive Reflex testing (ASCUS only) Negative Practical tip: Colpo with ECC EMB with few exceptions at Negative x2 Colpo III.I.i. Special Populations: YO ASC-H or HSIL 2 Consecutive Neg +No HR findings on colpo No CIN2-3 on Biopsy Observation: Colpo+ cytology Q6 mos x2yrs Other Results HSIL x24 mos without CIN2-3 No lesion on colpo HSIL or Highgrade lesion on colpo PERSISTS >1yr Diagnostic Excision CIN2-3 on Biopsy III.I.ii. Special Populations: Pregnant Women LSIL Pregnant Woman LSIL No CIN 2-3 FU Postpartum preferred CIN 2-3 Defer Colpo to 6 weeks PP III.I.iii. Special Populations: Postmenopausal Women LSIL Negative Cotesting Positive LSIL Postmenopausal 6+ Negative Return to Normal No CIN CIN III.I.iv. Special Populations: Adolescents WHY ARE YOU DOING A PAP?? cytology If <HSIL continue to follow qx2 If persistent LSIL at 24 mos colposcopy If HSIL colposcopy Do NOT do cotesting; because of high prevalence it is not clinically significant Ignore status if you happen to know it WHY ARE YOU DOING A PAP?? 8

IV. : ASCCP Standards 20 Component Pre-colposcopy Evaluation Minimum Practice Evaluate and document at least the following: Indication for colposcopy Pregnancy status Menopausal/menstrual status

9 IV. : ASCCP Standards 20 Component Pre-colposcopy Evaluation Minimum Practice Evaluate and document at least the following: Indication for colposcopy Pregnancy status Menopausal/menstrual status Hysterectomy status Examination Obtain informed consent Examine vulva and vagina grossly Examine cervix with magnification after application of 3-5% acetic acid Documentation Document findings at least in text format: Document SCJ Document Colposcopic findings (AWE Y/N, Lesions Y/N) Document Impression (Normal/LSIL/HSIL/Cancer) Biopsy If indicated, take biopsies at SCJ Document whether or not endocervical sampling performed Post-procedure Make arrangements to notify patient of results IV. : ASCCP Standards 21 Assessment of Adequacy Assessment Cervix Visibility SCJ Visibility Abnormal Findings Description Fully/Not Fully Visible Fully/Not Fully Visible Low-grade features High-grade features IV. : ASCCP Standards 21,26 Features Low-Grade Abnormal Colposcopic Findings Findings Acetowhite Epithelium (AWE) Thin/translucent Rapidly fading Vascular Patterns Fine mosaic Fine punctation Margins/Border Irregular/geographic contour Condylomatous/raised/papillary Flat IV. : ASCCP Standards 21,26 Features High-Grade Abnormal Colposcopic Findings Findings Acetowhite Epithelium (AWE) Thick/dense Rapidly appearing/slowly fading Cuffed gland openings Varegated red and white Vascular Patterns Coarse mosaic Coarse punctation Margins/Border Sharp border Inner border sign (internal margin) Ridge sign Peeling edges Contour flat Fused papillae IV. : ASCCP Standards 21,26 Features Suspicious for Invasive Cancer Abnormal Colposcopic Findings Findings Atypical Vessels Irregular Surface Exophytic lesion Necrosis IV. : ASCCP Standards 22 General Guidance Multiple biopsies targeting all areas with abnormalities Number of Biopsies At least 2, and up to 4 biopsies Biopsies Reasoning A single biopsy, targeting the worst appearing lesion may miss up to 1/3 of prevalent precancers Evidence Britain 2016 Canada 2012 Gage et al Stoler et al Pretorius et al Wentzensen et al 9

10 V. Subsequent management of CIN A. CIN1 or No Lesion preceded by lesser abnormalities ( LSIL) B. CIN1 preceded by ASC-H or HSIL C. CIN 2 or 3 D. CIN1 in Women YO E. CIN 2 or 3 in Young Women F. AIS G. AGC V.A. Subsequent Management: CIN1 or No Lesion preceded by lesser abnormalities Pap/Cotesting at Age-appropriate re-test 3 yrs Follow-up Without Treatment + No CIN CIN 2/3 CIN 1 If persistent 2 years: Testing Treatment V.B. Subsequent Management: CIN1 preceded by ASC-H or HSIL Pap/Cotesting at 12 and 24 mos Diagnostic Excisional Procedure Pathology Review V.C. Subsequent Management: CIN 2 or 3 Adequate Colpo Excision or Ablation of T-zone Inadequate Colpo Recurrent CIN 2/3 Diagnostic Excisional Procedure X2 Age-specific retest in 3 years + Any Cytologic Abnormality except HSIL + HSIL on either FU Based on Review X2 Pap/ Cotesting 3 years Pap/Cotesting at 12 and 24 mos Any abnormal cytology or + V.D. Subsequent Management: CIN1 in after ASCUS/LSIL Women YO V.D. Subsequent Management: CIN1 in after HSIL/ASC-H Women YO Inadequate Adequate <ASC-H or HSIL ASC-H or HSIL Diagnostic Excisional Procedure Colpo and Q6 months x1 year Pathology Review Negative 6 or Negative x2 Other Results Follow per 10

V. E. Subsequent Management: CIN 2 or 3 in Young Women Negative Normal Colpo x2 Pap and Cotest 12 months Negative Pap neg Cotest 3 years Negative Pap neg Observation: Colpo+ at 6 and

Subsequent Management: AIS Hysterectomy preferred Excision Recommended Margins positive ECC positive Fertility Sparing Conservative Management Reevaluation 6 months*

Cancer Pap and Cotest at 12 and 24 mos + Initial AGC NOS CIN 2/3 BUT no Glandular Neoplasia Both VI. Vaccine VI.

11 V. E. Subsequent Management: CIN 2 or 3 in Young Women Negative Normal Colpo x2 Pap and Cotest 12 months Negative Pap neg Cotest 3 years Negative Pap neg Observation: Colpo+ at 6 and Worsening Colpo HSIL on cytology Colpo impression=hsil x1 year ASC + Colpo and Biopsy Treatment using Excision or Ablation of T- zone Progression to CIN3 persistent CIN 2/3 at 24 mos V.F. Subsequent Management: AIS Hysterectomy preferred Excision Recommended Margins positive ECC positive Fertility Sparing Conservative Management Reevaluation 6 months* *Reevaluation/Follow-up with combination of: Cotesting+Colpo+ECC Margins and ECC Long-term follow-up* V.G. Subsequent Management: AGC V.G. Subsequent Management: AGC Practical Tip: CKC with ECC and D+C Initial Favor neoplasia AIS No Neoplasia Diagnostic Excisional Procedure With Endocervical Sampling Both Pap and Cotest 3 years No CIN2/3, AIS, or Cancer Pap and Cotest at 12 and 24 mos + Initial AGC NOS CIN 2/3 BUT no Glandular Neoplasia Both VI. Vaccine VI. Vaccine: Formulations in US 23 Cervarix Gardasil Gardasil 9 Type Bivalent Quadrivalent 9-Valent Manufacturer GlaxoSmithKline Merck Merck types 16, 18 6, 11, 16, 18 6, 11, 16, 18, 31, 33, 45, 52, 58 Licensing October Females Contraindications Dosing Schedule Hypersensitivity to latex 3-dose series: 0, 1, 6 months June Females October Males Hypersensitivity to yeast 3-dose series: 0, 2, 6 months December 2014 Females and Males Hypersensitivity to yeast 3-dose series: 0, 2, 6 months 11

20-24 YO CIN 3 IV. Vaccine: Adverse Reactions 25 IV.

12 VI. Vaccine: ACIP Recommendations 24 VI. Vaccine: Trends in CIN 3 VI. Vaccine: CIN 1 CIN Following Vaccine Implementation: Significant reduction in all CIN 1-3 for women 15-19YO Significant reduction in CIN 2 for women 20-24YO Downtrend in CIN1 in women YO CIN 3 IV. Vaccine: Adverse Reactions 25 IV. Vaccine: Adverse Reactions 25 Vaccine/ Reaction Type Quadrivalent Local/Mild Injection site reaction Erythema and swelling Reaction Local/Severe Injection site erythema and/or swelling > 2 inches in size and pain severe Systemic/Mild Pyrexia Urticaria Headache Myalgia Arthalgia Gastrointestinal disorders Systemic/ Severe Rate/doses 83 per per per per per per per per per 100 Anaphylaxis per 10 6 Vaccine/ Reaction Type Bivalent Local/Mild Injection site pain Swelling Redness Reaction Systemic/Mild Fatigue Headache Myalgia Itching Arthalgia Gastrointestinal symptoms Fever Rash Urticaria Rate/doses 78 per per per per per per per per per per per per 100 IV. Vaccine VII. Pearls: Principles of Clinicians should not screen average risk women younger than age 21 for cervical cancer 5. Clinicians should not perform testing in average risk women younger than 30 years Summary of Recommendations: It is crucial that OB/GYNs & other providers educate parents and patients on the benefits and safety of vaccination CDC and ACOG recommend routine vaccination with vaccine for girls and boys. The target age for vaccination is year for girls and boys. The 9-valent vaccine has been added to the ACIP recommendations for girls and boys. 2. Clinicians should start screening average risk women for cervical cancer at age 21 ONCE every 3 years with cytology alone 3. Clinicians should not screen average risk women for cervical cancer with cytology more often than ONCE every 3 years. 4. Clinicians may use combination of cytology and testing once every 5 years in average risk women aged >30 who prefer screening less often than every 3 years 6. Clinicians should stop screening average risk women older than 65 for cervical cancer if they have had 3 consecutive cytology results or 2 consecutive cytology results plus within 10 years with the most recent test performed within 5 years 7. Clinicians should not screen average risk women of any age for cervical cancer if they have had a hysterectomy with removal of the cervix 12

VII. Pearls: Resources References 1. www.cancerstatisticscenter.cancer.org/#!/cancer-site/cervix. Accessed 10/7/17. 2.

Benard et al. Cervical Carcinoma Rates Among Young Females in the United States. Obstet Gynecol. 2012 November ; 120(5): 1117 1123. 4. https://www.roche.

13 VII. Pearls: Resources References 1. Accessed 10/7/ Cervical cancer, human papillomavirus (), and vaccines Key points for policy-makers and health professionals. Accessed 10/7/17 3. Benard et al. Cervical Carcinoma Rates Among Young Females in the United States. Obstet Gynecol November ; 120(5): Accessed 10/7/17 5. Wingo et al. Long-Term Trends in Cancer Mortality in the United States, CANCER Supplement June 15, 2003 / Volume 97 / Number Kirby, T. FDA approves new upgraded Gardasil 9. Vol16 February CDC website. US Cancer Statistics Incidence and Mortality Report 8. US Cancer Statistics Working Group, 2010 ACOG App ASCCP App 9. Fleischer AB, Parrish CA, Glenn R, Feldman SR. Condylomata acuminata (genital warts):patient demographics and treating physicians. Sex Transm Dis. 2001;28: The web site of the National Cancer Institute ( Accessed 10/7/17 ACOG By Fountainhead Mobile Solutions ASCCP Mobile By ASCCP 11. Doobar et al. The Biology and Life-Cycle of Human Papillomaviruses. Vaccine 30S (2012) F55 F Winer et al. Development and Duration of Human Papillomavirus Lesions, after Initial Infection J Infect Dis. 2005;191(5): Saslow et al. American Cancer Society,American Society for and Cervical Pathology, andamerican Society for ClinicalPathology s forthe Prevention and Early Detectionof Cervical Cancer Journal of Lower Genital Tract Disease, Volume 16, Number 3, 2012, 00Y00 References 14. Huh et al. Use of Primary High-Risk Human Papillomavirus Testing for Cervical Cancer : Interim Clinical Guidance. J Lower Gen Tract Dis 2015;19: ACOG Committee Opinion 624. Cervical cancer screening in low-resource settings. February Reaffirmed Sawaya et al. Cervical Cancer in Average Risk Women: Best Practice Advice From the Clinical s Committee of the America College of PhysiciansAnn Intern Med 2015; 162: Massad et al Updated Consensus s for the Management of Abnormal Cervical Cancer Tests and Cancer Precursors. Journal of Lower Genital Tract Disease, Volume 17, Number 5, 2013, S1YS Waxman et al/ Revised Terminology for Cervical Histopathology and Its Implications for Management of High-Grade Squamous Intraepithelial Lesions of the CervixObstet Gynecol Dec; 120(6): Katki et al. Benchmarking CIN 3+ Risk as the Basis for Incorporating and Pap Cotesting into Cervical and Management s. Journal of Lower Genital Tract Disease, Volume 17, Number 5, 2013, S28YS Wentzensen et al. Evidence-Based Consensus Recommendations for Practice for Cervical Cancer Prevention in the United States Journal of Lower Genital Tract Disease Volume 21, Number 4, October Khan et al. ASCCP Standards: Role of, Benefits, Potential Harms, and Terminology for Colposcopic Practice. JournalofLowerGenitalTractDisease Volume21,Number4,October Mayeaux et al. ASCCP Standards: Quality Improvement Recommendations for the United States. Journal of Lower Genital Tract Disease Volume 21, Number 4, October Accessed 10/9/ Accessed 10/9/ Accessed 10/9/ Accessed 10/9/ Accessed 10/9/ Accessed 10/12/ Haelle, Tara. Could Making Cancer Simpler Increase Women's Risk? Npr.com. Accessed 10/12/17 13

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