1. C ERVICAL C ANCER S CREENING U PDATE Based on the 2012 Recommendations (ASCCP) Sarah Lamanuzzi, MD, FAAFP

2. D ISCLOSURES I have no disclosures other than: the ASCCP gave permission for use of their slide content. The American Society for Colposcopy and Cervical Pathology. “Cervical Cancer Screening Recommendations, 2012” http://www.asccp.org/Guidelines/Screening- Guidelines. http://www.asccp.org/Guidelines/Screening- Guidelines

3. O BJECTIVES Highlight changes in the guidelines for cervical cancer screening and comparison of guidelines between agencies Explain some of the reasoning behind the changes Take-home points for cervical cancer screening

4. W HAT ARE THE B ENEFITS IN SCREENING FOR CERVICAL CANCER ?

5. W HAT IS THE IMPORTANCE OF CERVICAL CANCER SCREENING ? Highest risk for developing Cervical Cancer: being rarely or never screened. Least likely to be screened: Minorities Low socioeconomic status/uninsured Recent immigration (<10 yrs in US) No usual source of health care The American Society for Colposcopy and Cervical Pathology. “Cervical Cancer Screening Recommendations, 2012.” NB: Kaiser study of women with cervical cancer noted that 56% had not ever had a pap smear. 81% of those had seen a provider in the KP system Leyden MA, Manos M, Kinney W et al. J Natl Cancer Inst. 2005; 97:67583.

6. W HAT ARE THE H ARMS OF C ERVICAL C ANCER S CREENING ? ASCCP: Uses colposcopy as marker of harm. Anxiety associated with false positive cancer screening test Potential stigmatization from diagnosis of STI Discomfort &/or bleeding from additional diagnostic & treatment procedures Increased risk of pregnancy complications due to treatment ACOG: harms not stated in the 2012 guidelines USPSTF: False positive results leading to frequent testing & invasive procedures & the harms of those (bleeding, pain, infection, failure to dx; anxiety, distress, concern about health) Adverse pregnancy outcomes Over-diagnosis (many lesions regress spontaneously)/ overtreatment National Guideline Clearinghouse. “Guideline Synthesis: Screening for Cervical Cancer in Women at Average Risk.” http://www.guideline.gov/syntheses/synthesis.aspx?id=43606.http://www.guideline.gov/syntheses/synthesis.aspx?id=43606

7. H OW DID THEY DECIDE TO CHANGE EVERYTHING ? Team from ASCCP, ACS, and ASCP Literature review from 1995 – 2011 (graded evidence) Consensus when reviewing literature: We can’t prevent every case of cervical cancer CIN3 is a reliable surrogate for cervical cancer Risk of developing invasive cancer before next screen should be unlikely # of colposcopies ~ marker for harm 6 topics of interest: Optimal screening interval Screening age 30+ Impact of HPV vaccination on screening Potential for HPV testing alone (no pap) Exiting women from screening Managing discordant cytology & HPV results

8. T WO AREAS THAT NEED MORE STUDY : Impact of HPV vaccination: “Recommended screening practices should not change on the basis of HPV vaccination.” Paavonen J et al. Lancet 2009; 374: 301-314. Decreases CIN3 and colposcopy but no reliable way to confirm full vaccination series. HPV testing alone: Strong negative predictive value, so it may replace co-testing in the future BUT: Test specificity is lacking Appropriate follow-up is not yet known Knowledge of HPV status affects interpretation of cytology It is NOT recommended to test with HPV alone.

9. W HAT ARE THE MAJOR CHANGES IN CERVICAL CANCER SCREENING ? Do not start cervical cancer screening until age 21 regardless of sexual activity status. (Does not apply to special populations: DES exposure, immune compromised, history of cervical cancer) Screening in ages 21-29 should be: Cytology every 3 years Not co-testing (or HPV alone) Screening in ages 30-65 should be: Co-testing (cytology+HPV) every 5 years (preferred) Cytology alone every 3 years (acceptable) Discordant cytology (pap) & HPV management recommendations

10. W HAT ARE THE MAJOR CHANGES IN THE UPDATED GUIDELINES ? ( CONT.) Stop screening at age 65 if acceptable prior negative testing Stop screening after hysterectomy for benign causes if no CIN2 or above within 20 yrs. Continue screening after age 65 if within 20 years of CIN2+ diagnosis.

11. D O NOT START CERVICAL CANCER SCREENING UNTIL AGE 21 REGARDLESS OF SEXUAL ACTIVITY STATUS. W HY ? Cervical Cancer Incidence by Age Group (USCS), 1998-2002 AgeIncidence per 100,000 0-190.1 20-294.5 30-3913.9 40-4916.5 50-6415.4 65+14.6 All ages9.4 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.

12. D O NOT START CERVICAL CANCER SCREENING UNTIL AGE 21 REGARDLESS OF SEXUAL ACTIVITY STATUS. T REATMENT OF A DOLESCENTS STI screening as recommended (urine) Contraceptive management No pap tests No speculum exams for asymptomatic women

13. S CREENING IN A GES 21-29: Q3 YEARS W HY ? Sensitivity of single pap test: 50-70% Cancer risk 18 mo after 3 neg paps: 1.5/100,000 Cancer risk 36 mo after 3 neg paps: 4.7/100,000 99,997 screened unnecessarily to help 3 Risk of HSIL/cancer < 3 years after neg pap not significantly higher than after 1 year Sawaya GF et al. Acta Cytol 2005: 49: 391-7. There is also a much decreased incidence of lifetime-risk of colposcopy from 2000 per 1000 women (with annual screening) to 760 per 1000 women (with q3 year screening). Stout NK et al. Arch Intern Med 2008; 168:181. Kulasingam S et al. 2011. AHRQ Publication No. 11-05157-EF-1.

14. S CREENING IN A GES 21-29: REFLEX HPV W HY ? Co-testing NOT recommended b/c: Carcinogenic (high-risk) HPV incidence nearly 20% in teens and early 20s & most resolve w/o tx. Reflex HPV testing (with ASCUS or LSIL) allows for differentiating management of the abnormal cytology. Weighted Prevalence of High-Risk HPV among US Women, 2007-2010 (NHANES) AgeWeighted Prevalence 14-19~25% 20-24~45% 25-29~30% Adapted from: Hariri S et al. J Infect Dis 2011; 204:566-573.

15. S CREENING AGES 30-65: C O - TESTING Q5 YRS. W HY ? Co-testing = cytology plus testing for HR-HPV Equivalent risk of CIN3 as q1-3 year cytology alone Increases detection of CIN3 and AIS Decreased incidence of CIN3 in subsequent screening Minimizes the number of colposcopies Histological progression in this age group: < 10% progress over 30 months ~70% clear completely over 30 months Rodriguez AC et al. J Natl Cancer Inst. 2008; 100: 513-517.

16. S CREENING AGES 30-65: OPTION Q 3 YR W HY ? Financial and / or logistical barriers to HR-HPV co-testing Cytology is still effective (q3 yrs) acknowledging that there are: Increased frequency of visits Increased number of colposcopies for equivocal cytology results

17. D ISCORDANT C O - TESTING R ESULTS : N EGATIVE C YTOLOGY /(+) HR-HPV Normal pap smear with (+) HR-HPV has 2 options for follow-up: Repeat co-testing in 12 months If abnormal, colposcopy. If normal, routine screening Immediate genotyping (16/18) of HR-HPV If (+)16 or 18, colposcopy. If normal, repeat co-testing 12 mo If repeat co-testing abnormal, colpo. If rpt co-test nl, routine * Direct referral to colposcopy is not indicated.

18. D ISCORDANT C O - TESTING R ESULTS : ASCUS PAP / (-) HR-HPV These women can co-test again in 3 years. (Routine screening would be Q5 yrs >30 yrs of age) (This applies to ages 21-29 as well, which is routine screening for them) The risk of CIN3 in women in this situation is less than 2% (lower than threshold for colposcopy).

19. S TOP SCREENING AT AGE 65 IF NORMAL PRIOR. W HY ? Stop screening at age 65 if acceptable prior negative testing no history of CIN2 or above within last 20 yrs 3 consecutive (-) pap or 2 consecutive (-) co-test w/in 10 yrs Screening “should not resume for any reason, even if a woman reports having a new sexual partner” CIN2+ is rare after age 65 HPV risk still 5-10% but unlikely to lead to cancer within remaining lifetime Colposcopy more difficult (increases harm) Chen HC et al. J Natl Cancer Inst. 2011; 103: 1387-1396. Rodriguez AC et al. J Natl Cancer Inst. 2009; 101: 721-728.

20. S TOP SCREENING AFTER HYSTERECTOMY FOR BENIGN REASONS. W HY ? Stop screening after hysterectomy (including cervix) and no history of CIN2+. No evidence of prior negative screening required. Over 600 vaginal cuff paps required to find 1 VAIN (another study – over 2000 women followed >5 y: no vaginal cancer, 3% VAIN) Similar to risk of breast cancer in men, in which regular screening is not recommended. Pearce KF et al. NEJM 1996; 335: 1559-1562. Piscitelli JT et al. AJOG 1995; 173: 424-430.

21. C ONTINUE SCREENING AFTER AGE 65 IF H / O CIN2+ WITHIN 20 YRS. W HY ? If history of CIN2, CIN3, or AIS within the last 20 years, even if it extends screening past age 65. Women treated for CIN2+ within 20 yrs still have a 5 to 10-fold higher risk for cervical cancer than the general population. Testing is “routine” for ages 30-65 unless abnormal results are obtained.

22. S UMMARY OF SCREENING UPDATES : Do not start cervical cancer screening until age 21 regardless of sexual activity status. Screen Q3 yrs (pap) in ages 21-29. Co-test Q5 yrs in ages 30-65 (or pap Q3 yrs). ASCUS with (-) HR-HPV: routine screening Pap (-) with (+) HR-HPV: Repeat co-testing in 12 months OR Immediate genotyping (16/18) with colpo if (+) Stop screening at 65 or after hysterectomy Continue screening after 65 or after hysterectomy only if (+) CIN2+ w/in 20 yrs

23. Summary of 2012 Cervical Cancer Screening Recommendations USPSTFASCCPACOG When to start?Age 21 How often?Age 21-29: q3 y Age 30-65: -q5 y co-testing -q3 y cytology Age 21-29: q3 y Age 30-65: -q5 y co-testing -q3 y cytology Age 21-29: q3 y Age 30-65: -q5 y co-testing -q3 y cytology When to stop?Age 65 yrs if adequate negative OR Hysterectomy if no h/o of CIN 2+ Age 65 yrs if 3 consecutive (-) pap or 2 consecutive (-) co- test w/in 10 yrs OR Hysterectomy if no h/o of CIN 2+ Age 65 yrs if 3 consecutive (-) pap or 2 consecutive (-) co- test w/in 10 yrs OR Hysterectomy if no h/o of CIN 2+

24. M ANAGEMENT OF A BNORMAL P AP S MEAR (C YTOLOGY ): 2012 recommendations for management of abnormal pap smears are more complex than previous, and they differ by cytology, by age, and by HR-HPV status. ASCCP has free printable PDF of tx algorithms (can buy in pamphlet form).

25. W HERE CAN WE FIND THESE UPDATES ? P RIMARY R EFERENCES Saslow, Solomon, Lawson et al. “American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer.” (online March 2012) JLGTD 2012; 16(3): 00-29. http://www.asccp.org/Guidelines/Screening- Guidelines http://www.asccp.org/Guidelines/Screening- Guidelines Massad et al. “2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors.” JLGTD 2013; 17(5): S1-S27. http://www.asccp.org/Guidelines-2/Management- Guidelines-2 http://www.asccp.org/Guidelines-2/Management- Guidelines-2

26. R EFERENCES ( CONT.) National Guideline Clearinghouse. “Guideline Synthesis: Screening for Cervical Cancer in Women at Average Risk.” http://www.guideline.gov/syntheses/synthesis.aspx?id=43606. http://www.guideline.gov/syntheses/synthesis.aspx?id=43606

27. Q UESTIONS ? Contact information: Sarah Lamanuzzi, MD slamanuzzi@kodfp.org @sarahlamanuzzi