1. VETERANS HEALTH ADMINISTRATION The Pelvic Exam including Cervical Cancer Screening

2. Learning Objectives Discuss the epidemiology and etiology of cervical cancerReview latest screening guidelinesDescribe how results are reportedExplain how to manage abnormal resultsDiscuss indications and benefits of the HPV vaccine 2

3. VETERANS HEALTH ADMINISTRATION Why Screen for Cervical Cancer? 12,000 cases/year 11 th cause of cancer death 85% death reduction due to screening 50% of cases are in women who have never been screened 10% of cases are in women with no screening in 5 years Photo courtesy of peir.net 3

4. VETERANS HEALTH ADMINISTRATION Risk Factors for Cervical Cancer Chronic HPV infection At-risk for contracting HPV −Hx of multiple sexual partners −HIV/immunosuppression −Early age of first intercourse (<17) −Multiple pregnancies −Long-term oral contraceptive use Risks for not clearing HPV −Smoking −HIV/Immunosuppression In utero exposure to diethylstilbestrol (DES) Screening issues −Low socioeconomic status −Immigration from a country where screening is not the norm 4

5. High-Risk Types 16 & 18 Low-Risk Types 6 & 11 HPV Group of >150 related viruses Causes 100% of cervical cancers Two high-risk types (16 and 18) cause 70% of cervical cancers Persistent infection is necessary to develop cancer Low-risk subtypes (6 and 11) cause genital warts or mild cervical dysplastic changes that do not usually progress to cancer 70% of new HPV infections spontaneously clear within one year; up to 91% clear within two years. Patient may remain immune to that subtype for up to 3 years 5

6. VETERANS HEALTH ADMINISTRATION Incidence of 6/11/16/18 HPV New infection is less likely with older age Older women are less likely to clear infection Age groupIncidence/100 person years 24-297.4 (5.9 – 9.2) 30-343.6 (2.4 – 5.1) 35-392.4 (1.5 – 3.6) 40-451.9 (1.2 – 3) 6

7. VETERANS HEALTH ADMINISTRATION Screening Guidelines

8. VETERANS HEALTH ADMINISTRATION Things to keep in mind with cervical cancer screening guidelines… Natural time course is long HPV will often clear on its own Guidelines do not always fit Do no harm

9. VETERANS HEALTH ADMINISTRATION 1.Invasive cervical cancer is very rare in women under 21 (<0.1%). 2.Although the rate of HPV infection is high among sexually active adolescents, the immune system in most of these women clears the HPV infection in 1-2 years. 3.Adolescents have a higher incidence of HPV-related precancerous dysplasia because the cervix is immature, but most lesions resolve without treatment. 4.Women treated with excisional procedures for dysplasia have more premature births. Adolescents have most of their childbearing years ahead of them; thus it's important to avoid unnecessary procedures that negatively affect the cervix. Start Screening at Age 21. Why? 9

10. VETERANS HEALTH ADMINISTRATION How Frequently Should We Screen? Women Ages 21-29 Screen at 3-year intervals with cytology USPSTF, ACS, ASCCP Not necessary to test for HPV; it is often present and most likely will resolve Compared to annual screening… No significant differences found in lifetime risk of cancer Annual screening resulted in twice the colposcopy rate 10

11. VETERANS HEALTH ADMINISTRATION How Frequently Should We Screen? Women Ages 30-65 Option 1 Co-testing… Cytology + HPV at 5-year intervals Option 2 Cytology at 3-year intervals if HPV co-testing is not available 11 Provide similar benefits

12. When to Stop Screening? Discontinue at 65 with adequate recent screens AND no hx of high grade dysplasia or worse Do not resume screening once stopped History of high-grade lesion or cancer, screen routinely for 20 years after diagnosis Adequate screening = 3 consecutive negative Paps or 2 consecutive negative Paps with negative HPV results in the 10 yrs prior to screening cessation with most recent test in the last 5 yrs 12

13. VETERANS HEALTH ADMINISTRATION Special Considerations High-Risk Conditions – History of high grade cervical lesion, DES exposure in utero, transplant, or immunocompromised patient Screen more frequently After Hysterectomy – No screening if cervix was removed and no previous high grade lesions or cancer – If a cervix is present, screen! Woman may not know if her cervix was removed. Provider may have to look. 13

14. VETERANS HEALTH ADMINISTRATION If the exam of the cervix was abnormal, do not be reassured by a normal Pap report… REFER! Dear Dr. GYN: Help! 14

15. Pap Smear Collection Supplies Photograph courtesy of Michael Crawford / Bpac NZ Endocervical brush and spatula used together ─Brush samples endocervix) ─Spatula samples ectocervix Broom-like device may be used alone ─Longer bristles are inserted in cervical opening to sample endocervical canal ─Shorter bristles sample ectocervix 15

16. VETERANS HEALTH ADMINISTRATION Pap Collection Processes Slide Preparation Method Liquid Cytology Method 16

17. VETERANS HEALTH ADMINISTRATION Assisting During a Pelvic Exam Slide Preparation Method

18. VETERANS HEALTH ADMINISTRATION Liquid Cytology Method

19. Conventional Pap smear slide ThinPrep® (one liquid-based cytology brand) VS Images provided courtesy of HOLOGIC, Inc. and affiliates Liquid-based cytology provides: 1.Ability to do reflex HPV testing 2.No differences in detection of high grade lesions 3.Better detection of glandular abnormalities 4.Ability to perform Pap smears during menstruation 19

20. Bethesda Reporting System Specimen Adequacy (satisfactory, unsatisfactory) Descriptive Diagnosis (conventional slide vs. ThinPrep) General Categories Negative for intraepithelial lesion or malignancy (“normal”) Epithelial cell abnormality (will also indicate if it is glandular or squamous) 20

21. VETERANS HEALTH ADMINISTRATION Specimen Reports 21 Unsatisfactory for interpretation (not enough cells) Repeat Pap in 2-4 months Satisfactory but no endocervical cells/transformation zone (EC/TZ) identified or partially obscured Follow usual screening guideline

22. Normal ASC-US Low-Grade High-GradeCancer Microscopic Appearance (P hotos by Dianne Solomon, MD)

23. Abnormal Pap Smear Terminology

24. Pap reports may also mention… OrganismsTrichomonas (treat) Candida Garnerella (bacterial vaginosis). Not normally treated if seen on Pap smear, especially if exam was normal. Actinomyces (typically found in women with an IUD; does not need treatment) Changes seen with herpes (will be described as “multinucleated giant cells”) Reactive Changes Inflammation related to infection or irritation (organism is not usually identified). Repeat Pap in 6 mos if patient is HIV positive or immunocompromised. IUD-related Atrophy Benign endometrial cells (investigate for endometrial cancer in women over 40)

25. VETERANS HEALTH ADMINISTRATION Epithelial Cell Abnormalities (7% of women receiving Paps each year) Squamous Cell Abnormalities − ASC-US, including ASC-H (2-3 million; 3% of smears) − LGSIL (1.25 million) − HGSIL (300,000) − Squamous cell carcinoma (12,800; 90% of cervical cancers) Glandular Cell Abnormalities − Atypical glandular cells (AGC) − Endocervical adenocarcinoma in situ − Adenocarcinoma (10% of cervical cancers) 25

26. VETERANS HEALTH ADMINISTRATION Biopsy Findings by Pap/HPV Result Pap resultCIN1CIN2/3Cancer Normal Papup to 10%<1%0.25% ASC-US, HPV neg<10%<1.5%<0.01% Normal Pap, HPV+<1.1%<0.08% ASC-US, HPV+50-60%7-18%<0.1% LGSIL50-60%2-19%0.16% HGSIL20%up to 70%7% 26

27. VETERANS HEALTH ADMINISTRATION HPV Testing Alone HPV has increased sensitivity to detect CIN2/3 Increased negative predictive value Concerns about inadequate sampling, lack of a standard, and providing false assurance due to false negative results Problem with the positive predictive value -- no defined management strategies Potential harms from increased colposcopies More data is needed and not recommended 27

28. VETERANS HEALTH ADMINISTRATION When is HPV Testing Useful? HPV testing has higher sensitivity and lower specificity than Pap with less variability 1.Triage inconclusive ASC-US Pap results ─If liquid-based cytology is used, residual cells from the vial can be tested for high-risk HPV (reflex testing) ─If your facility still uses slides for Pap collection, ASC-US results can be triaged with a repeat Pap, colposcopy referral, or ordering an HPV test 2.After colposcopy, if no CIN2,3 is found—will show if persistent HPV is present 3.Can stratify postmenopausal women or women age <25 with LSIL 4.Co-testing for women ages 30-65 28

29. VETERANS HEALTH ADMINISTRATION When is HPV Testing Not Useful? Females <30 unless ASC-US Pap result (HPV is more likely to be present in this age group) Prescreening for HPV vaccination STI screening Women >25 years of age with ASC-H, LSIL, HSIL results (refer for colposcopy regardless of HPV status) 29

30. VETERANS HEALTH ADMINISTRATION When HPV is +, but cytology is normal… Women ages 30-65 At one year, risk is high enough to warrant repeat co-testing in one year but not high enough for an immediate colposcopy CIN3 riskCancer risk 1 year<1% - 4.1%0.08% 3 years2.2% - 7.0% 5 years5.9% - 9.3% >10 years16% - 21.2% 30

31. VETERANS HEALTH ADMINISTRATION When HPV is +, but cytology is normal… Women ages 30-65 (cont’d) Repeat co-testing in 1 year − If HPV+, refer for colposcopy (persistent infection) − If HPV- with cytology of LSIL or more, refer to colposcopy (high risk of CIN2+) − If HPV- and cytology is ASC-US or less, screen with co-testing in 3 years (not 5 years) or Test for HPV 16/18 with genotype testing − If HPV 16/18 positive, refer to colposcopy (most cancers occur with these types) − If HPV 16/18 negative, repeat co-testing in 1 year 31

32. 32 Managing Abnormal Cytology Results VETERANS HEALTH ADMINISTRATION

33. ASC-US Three ways to evaluate… 1. Triage by HPV testing (helps determine risk of CIN2+) Standard in >95% of labs if liquid-based cytology is used to collect Pap smear If high-risk HPV+, refer for colposcopy as CIN2+ risk is >15% 2. Repeat Pap Repeat Pap in 12 months If Pap is ASC-US or worse, refer for colposcopy 3. Colposcopy (in selected circumstances) 33

34. VETERANS HEALTH ADMINISTRATION ASC-H Risk of CIN 2 or worse is 50% HPV triage is not indicated Refer for colposcopy 34

35. LGSIL and HGSIL Risk of CIN2+ is high For <25, risk of CIN3+ with LSIL is less than for older women No role for HPV testing Exception: postmenopausal women with LSIL can be triaged with HPV testing and managed in the same manner as ASC-US LSIL: Women >25, refer for colposcopy Women 21-25, repeat Pap in 1 year −If normal, repeat Pap in 1 year. Negative x 2, return to routine screening. −If ASC-US or LSIL, repeat Pap in 1 year. Refer to colposcopy if still abnormal. −If ASC-H, HSIL, or AGC, refer to colposcopy HSIL: All ages, refer for colposcopy 35

36. VETERANS HEALTH ADMINISTRATION Glandular Cell Abnormalities Atypical Glandular Cells (AGC) More likely to be associated with both squamous and glandular abnormalities High rates of CIN2+ with this abnormality Pap smears are less sensitive for detecting glandular dysplasia and malignancy Refer for colposcopy and do an endometrial biopsy CIN2/3Cancer AGC-NOS9-41%1-9% AGC27-96%5% 36

37. VETERANS HEALTH ADMINISTRATION Summary: Who Needs a Referral for Colposcopy? HPV(+) on one-year repeat co-testing HPV subtypes 16/18 genotyped after HPV(+) ASC-US with HPV(+) (over age 25 or repeated <25) ASC-US x 2 if no reflex HPV testing done ASC-H LGSIL (if post-menopausal, HPV triage may be useful) −Ages 21-25 repeat 1 year only. If persistent +, refer HGSIL AGC American Society for Colposcopy and Cervical Pathology Guidelines 37

38. VETERANS HEALTH ADMINISTRATION HPV Vaccines 38

39. HPV Vaccine Facts More effective if no prior HPV exposure Protects at least 7-10 yr; doesn’t replace regular screening Well tolerated Don’t test for HPV before vaccination $125 per does, $375 for full series Don’t restart series for missed dose Gardasil on VA national formulary Continue to screen as indicated 39

40. Quadrivalent vaccine for subtypes 6/11/16/18 Women and men ages 9-26 Three 0.5-mL doses IM at 0, 2 mos, 6 mos Prevents CIN2 and 3 cancer, genital warts, anal and vulvar cancers and precursors Gardasil® Bivalent vaccine for subtypes 16/18 Women ages 9-26 Three 0.5-mL doses IM at 0, 1 mo, 6 mos Indicated to prevent CIN 2 and 3 cancer Less protection for genital warts Cervarix® Two HPV vaccines 40

41. VETERANS HEALTH ADMINISTRATION Why is the vaccine recommended only for younger women? Age group Incidence of high-risk subtypes per 100 person years 24-297.4 (5.9 – 9.2) 30-343.6 (2.4 – 5.1) 35-392.4 (1.5 – 3.6) 40-451.9 (1.2 – 3) Higher in younger women Less likely in older age groups 41

42. VETERANS HEALTH ADMINISTRATION Efficacy of HPV Vaccines % Decrease in CIN 2 or worse in vaccine group (vs. placebo) Women negative for all vaccine HPV types and per protocol >99% Women positive for at least 1 viral type OR off protocol (missed or late doses) 40 – 60% Nearly identical for bivalent and quadrivalent vaccines. Efficacy thus far indicates duration of at least 7-10 years; studies are ongoing. 42

43. HPV Vaccine Contraindications and Risks Not for women with Pregnancy Moderate to severe acute illness Yeast allergy Adverse events Fainting in adolescents likely due to injection process (keep in area for 15-20 mins) 43

44. http://www.asccp.org/ConsensusGuidelines/tabid/7436/Default.aspx The ASCCP has released the updated Consensus Guidelines on the Management of Women with Abnormal Cervical Cancer Screening Tests and Cancer Precursors © 2013. 44

45. ASCCP APP

46. VETERANS HEALTH ADMINISTRATION Helpful References and Resources American Cancer Society. Human Papilloma Virus (HPV), Cancer, HPV Testing, and HPV Vaccines: Frequently Asked Questions. http://www.cancer.org/docroot/CRI/content/CRI_2_6x_FAQ_HPV_Vaccines.a sp http://www.cancer.org/docroot/CRI/content/CRI_2_6x_FAQ_HPV_Vaccines.a sp American Society for Colposcopy and Cervical Pathology (ASCCP). Algorithms: Updated Consensus Guidelines for Managing Abnormal Cervical Cancer Screening Tests and Cancer Precursors. c2013. http://www.asccp.org/ConsensusGuidelines/tabid/7436/Default.aspx http://www.asccp.org/ConsensusGuidelines/tabid/7436/Default.aspx CDC. HPV Vaccination. 02/07/13. http://www.cdc.gov/vaccines/vpd- vac/hpv/default.htm#edhttp://www.cdc.gov/vaccines/vpd- vac/hpv/default.htm#ed Massad et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121(4):829-46. USPSTF recommendation on cervical cancer screening, March 2012: http://www.uspreventiveservicestaskforce.org/uspstf/uspscerv.htm http://www.uspreventiveservicestaskforce.org/uspstf/uspscerv.htm 46

47. VETERANS HEALTH ADMINISTRATION Authors Primary: Catherine Staropoli, MD VA Maryland Healthcare System Kathleen McIntyre-Seltman, MD VA Pittsburgh Healthcare System Contributors: Linda Baier Manwell, MS Division of General Internal Medicine, University of Wisconsin-Madison Molly Carnes, MD, MS University of Wisconsin-Madison Center for Women’s Health Research 47