SESSION J4. What's Next? Managing Abnormal PAPs in 2014

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1 37th Annual Advanced Practice in Primary and Acute Care Conference: October 9-11, :45 SESSION J4 What's Next? Managing Abnormal PAPs in 2014 Session Description: Linda Eckert, MD Review current guidelines for cervical cancer screening, and learn about recent updates for management. S E S S I O N J4 Learning Objectives: Following my presentation, participants will be able to: 1. Review current 2012 cervical cancer screening guidelines. 2. Discuss recent update cytology management guidelines. 3. Screen for oral or anal HPV related disease.

Overview New Pap Guidelines: Case Studies Linda O Eckert, MD Professor, Department of Ob/Gyn Adjunct Professor, Department of Global Health University of Washington 1) Review current 2012 cervical

Benefits of More Screening Decrease cancer rates Increase detection precursor lesions Reduce anxiety of false negative tests Harms Cost Too many procedures Overtreatment pregnancy risks Increased

2 Overview New Pap Guidelines: Case Studies Linda O Eckert, MD Professor, Department of Ob/Gyn Adjunct Professor, Department of Global Health University of Washington 1) Review current 2012 cervical cancer screening guidelines 2) Recent updates cytology management guidelines 3) Screening for oral or anal HPV related disease Acknowledgement: Connie Mao, MD for her slides Benefits Risks and Benefits of More Screening Decrease cancer rates Increase detection precursor lesions Reduce anxiety of false negative tests Harms Cost Too many procedures Overtreatment pregnancy risks Increased anxiety, pain 2012 Screening Guidelines ASCCP/ACS Q3 years age Recommend cotesting age 30 and older with 5 year interval or Pap every 3 years. USPSTF NOTE: NO PAPS <21 years of age Q3 year screening for ages May use HPV cotesting to extend interval of screening to 5 years 30 and older Who gets Annual Screening? HPV <age 30 HIV positive/immuno-suppressed Hx DES exposure in utero Not necessarily women with history tobacco, STDs, OCPs, high risk behavior No longer women who have been treated for high grade cervical disease 1

3 Liquid versus Conventional Cytology Dutch trial 89,784 women, no difference in performance liquid versus conventional pap. Liquid cytology fewer unsatisfactory and more costly. Siebers Jama 2009; 302 (16): Italian study, 45,307 women randomized. Equal sensitivity for CIN2+ but lower PPV for liquid pap. Detects more CIN1+ lesions. Also found lower rate of unsat paps. Ronco BMJ 2007 Should you co-test? 4 randomized trials, 2 rounds of screening compared co-testing to Pap. Little to no reduction cervical CA incidence. Increased CIN3 first round with co-testing, colpo numbers not reported. Decreased cancer second round No cost analysis, general increase colpo RONCO trial, Lancet 2010;11:249 Co-testing extends interval Pooled data 24, 295 subjects. Risk of CIN3 or Cancer Co-test 6 year interval 0.28% HPV only 6 year interval 0.27% Pap only 6 year interval 0.97% CASE 1: 69 yo TAH for fibroids with LSIL Pap, negative hx A) HPV testing B) Treatment with estrogen, repeat Pap C) Colposcopy Pap only 3 year interval 0.51% CASE 1: 64 yo TAH for fibroids with LSIL Pap, negative hx A) HPV testing B) Treatment with estrogen, repeat Pap C) Colposcopy Post Hysterectomy Pap smears Vaginal cancers are rare 7/1,000,000 women, Pap with low PPV Combined 19 studies of 6543 women Reason for Hyst Abnormal Pap VAIN Benign 1.8% 0.12% 0 Cancer CIN3 14.7% 1.7% 1 case HPV testing can help with older women age 45 and greater Treatment: estrogen and repeat Lonky, Am J Obstet Gynecol

Percentage of Women with recent Pap by Hysterectomy status and Age Post Hysterectomy Vaginal cancers rare. No screening except with history symptoms or lesions.

4 Percentage of Women with recent Pap by Hysterectomy status and Age Post Hysterectomy Vaginal cancers rare. No screening except with history symptoms or lesions. If treated for high grade dysplasia, risk of cancer increased 2-3 times for next 20 years. After two normals can stop screening this group MMWR Jan 2013 Vol 61 No 51& 52 Pap screening in pregnancy Only diagnosis that may change management is invasive cancer: route and timing of delivery. Management of ASCUS and LSIL same as non pregnant but can defer until postpartum. Therefore HPV triage not necessary. Do refer HSIL or AGC pap smears for colposcopy in pregnancy 2006 ASCCP Consensus Conference Updates* Published in Obstetrics and Gynecology March 2013 Algorithms in Journal of Lower Genital Tract Disease Release March 22, *Why new guidelines? Data from ALTS based on LSIL/ASCUS enrollment. New data from Kaiser Permanente N. California with all pap results and age stratification. Recommendation Criteria Follow-up 5 Year Risk CIN3 Colposcopy >5% 6-12 Months 2-5% 5 years 0.1% What to do with abnormal cytology and histology results? Co-test HPV positive/pap negative Unsatisfactory Paps LSIL HPV negative Change to ASCUS management Women less than 25 years Follow-up after colpo and LEEP These are the thresholds used to design follow-up recommendations 3

5 CASE 2: 35yo with Neg Paps. Co-testing performed Pap Neg HPV Pos CASE 2: 35yo with Neg Paps. Co-testing performed Pap Neg HPV Pos A) Pap and HPV test one year B) HPV typing C) Refer to colposcopy A) Pap and HPV test one year B) HPV typing C) Refer to colposcopy HPV positive/pap negative >30 No colposcopy: CIN % 12 months Repeat testing current recommendation with colposcopy for persistent positive HPV weak evidence. HPV genotyping for 16/18 with immediate colposcopy if 16/18 positive based on observational studies and one industry sponsored trial. Wright, Am J Clin Path (4): Athena Study 32,260 Women >30years Negative cytology 6.7% HPV positive 1.5% were 16/18 positive CIN2+ Absolute risk CIN3+ HPV 16/ % Wright, Am J Clinic Pathol 2011;136:578 Other HPV + 4.6% HPV Neg 0.8% 9.8% 2.4% 0.3% Value of Type specific testing Cumulative incidence of CIN3 over a 10 year period, as a function of a single HPV test results at enrollment. Khan, JNCI2005;97: HPV Type Specific Testing New FDA approved test- Cervista 16,18 specific Triage of women with normal cytology but positive HPV test- 4% of women tested, Ranges from 11% 30 to 34 years to 2.6% age 60 to 65 years May triage with type specific testing or repeat HPV and Pap in one year. 4

6 Case #3 45 yo with Unsat PAP A) Repeat pap 2-4 months Case #3 45 yo with Unsat PAP A) Repeat pap 2-4 months B) Treat specific infections to resolve inflammation if present B) Treat specific infections to resolve inflammation if present C) HPV test, if positive then may genotype, if 16/18 positive to Colpo, if not 16/18 then repeat pap. C) HPV test, if positive then may genotype, if 16/18 positive to Colpo, if not 16/18 then repeat pap. Unsat pap: too few cells too much blood or inflammation may affect HPV test HPV Negative Absent EC/TZ Pooled data 24, 295 subjects. Interval Risk of CIN3 or Cancer Co-test 6 year 0.28% HPV only 6 year 0.27% Pap only 6 year 0.97% Age Pap every 3 years Age 30 or over Repeat pap 3 years is fine HPV negative routine screen 5 years if HPV positive then either Pap with HPV one year or immediate genotyping 16/18 Pap only 3 year 0.51% Absent EC/TZ Age Pap every 3 years Age 30 or over Repeat pap 3 years is fine HPV negative routine screen 5 years if HPV positive then either Pap with HPV one year or immediate genotyping 16/18 In this case no effect of absent TZ zone on HPV screen, so negative test is valid. Case #4 32 yo with LSIL HPV Neg A) Colposcopy B) Repeat Pap 1 yr C) Repeat Co-test 1 yr 5

7 Case #4 32 yo with LSIL HPV Neg A) Colposcopy B) Repeat Pap 1 yr Abnormal Pap (LSIL) HPV negative LSIL with HPV negative, repeat cotesting 1 year preferred. If co-test is negative negative then repeat at 3 years. Colpo if any other result. C) Repeat Co-test 1 yr For AGC, ASCH, AIS or HSIL, Colpo no matter what HPV status. Abnormal Pap (ASCUS) HPV negative ASCUS HPV Neg risk CIN3 0.3% 1 year ASCUS HPV Pos risk CIN3 14.4% (Wright, Am J Clin Path (4):578-86) 5 year cumulative risk CIN3 0.85% (Katki, Lancet Oncol 2011; 12 (7): ) Case #5 26 yo ASCUS pap smear A) Immediate Colpo B) HPV Triage C) Repeat Pap 6 mo D) Repeat Pap 1 year REPEAT PAP 3 YEARS Case #5 26 yo ASCUS pap smear A) Immediate Colpo B) HPV Triage C) Repeat Pap 6 mo D) Repeat Pap 1 year* ASCUS If ASCUS repeat 1 year, if ASCUS again then Colpo. If normal then cytology 3 years Preferred- use HPV triage unless under 25 years. *If no HPV test available 6

End of Screening Screening Exit HPV Neg ASCUS Pap is considered an abnormal result, repeat screen in one year before exiting screening age 65 Case #6 28 yo with LSIL Colpo biopsy CIN1 A) HPV test 1

months, may begin routine screening 3 years if both negative Pap at 12,24 months equivalent Pap only should be done for less than age 25 CIN1/Neg results after HSIL or ASC-H Co-test 12 and 24 mo, if

8 End of Screening Screening Exit HPV Neg ASCUS Pap is considered an abnormal result, repeat screen in one year before exiting screening age 65 Case #6 28 yo with LSIL Colpo biopsy CIN1 A) HPV test 1 year B) Pap 12, 24, 36 mo C) Co-testing 12 mo Case #6 28 yo with LSIL Colpo biopsy CIN1 A) HPV test 1 year B) Pap 12, 24, 36 mo C) Co-testing 12 mo CIN1/Neg result after LSIL or ASCUS Co-test 12 months, may begin routine screening 3 years if both negative Pap at 12,24 months equivalent Pap only should be done for less than age 25 CIN1/Neg results after HSIL or ASC-H Co-test 12 and 24 mo, if both negative routine screening in 3 years. Refer to colposcopy if HPV positive or ASCUS or worse Also women with CIN1 on ECC can be followed similarly Following Treatment CIN2,3 Co-test 12, 24 mo if both negative then co-test 3 years then return to routine screening intervals at least 20 years 7

4/100,000 False Positive Pap 55,000/ cancer USPTF report 2012 NO IMMEDIATE COLPO Negative Pap x 2 return to routine screening TRYING TO AVOID OVER TREATMENT IN THESE YOUNG WOMEN who often have

9 False positive Paps <25 Paps < Age 25 US ASCUS or LSIL, annual Pap recommended. After 24 months then ASCUS or greater referred to Colpo. HPV REFLEX NOT RECOMMENDED Even if HPV positive then repeat cytology at 12 months. Cancer cases 1.4/100,000 False Positive Pap 55,000/ cancer USPTF report 2012 NO IMMEDIATE COLPO Negative Pap x 2 return to routine screening TRYING TO AVOID OVER TREATMENT IN THESE YOUNG WOMEN who often have transient HPV infections CIN1 biopsy < Age 25 CIN2-3 biopsy < Age 25 Annual Pap for follow-up At 12 mo repeat Colpo only if HSIL or ASH At 24 mo repeat Colpo for ASCUS or greater Observation is preferred. Treatment acceptable. Treatment recommended for CIN3, Colpo unsatisfactory or ECC positive Treatment CIN1 in young women unacceptable! Untreated CIN2/CIN3 Young Women Pap and colposcopy every 6 months x 2 Cotest after colpo neg x2 then routine screen 3 years HEALTH New York Times F.D.A. Panel Recommends Replacement for the Pap Test (Roche Cobas) By Andres Pollack MARCH 12, 2014 In the News Untreated CIN2/3 in women <25 is only time Q 6 month pap and colposcopy is recommended 8

10 Cumulative detection of invasive cervical carcinoma Proposed HPV primary screening algorithm. The Lancet, Volume 383, Issue 9916, 2014, Strategy Performance of Screening Strategies in Women No. of CIN3 Detected Aged 25 Years Total At Baseline Years 1-3 Total Missed CIN3 No. of Screening Tests No. of Colpos Colpos per CIN3 Cytology , Cotesting , HPV with genotyping and reflex cytology , Estimate Cancer rates US Site Average #/yr % HPV related Range Cervix Vulva Vagina Anus-female Anus-male Oral-female Oral-male Gillison, Cancer 2008; 113: Total CIN3 cases = 347 Wright, Stoler, et al submitted Screening with Anal Paps? Who would we screen HIV positive women CIN3 Vulvar Cancer Regular Anal intercourse? Screening risks May not prevent cancer Treatment premalignant lesions is morbid Natural history poorly understood Risk of progression 10% in 5-10 years primarily limited to immune compromised. Average age 60 compared to 48 for cervical cancer. Screening should start with anoscopy at time of colonoscopy age 50 9

11 Proposed HPV primary screening algorithm

Oral HPV HPV linked to oropharyngeal squamous cell carcinomas (OSCCs) (~90% due to HPV16) 1 Incidence of OSCCs is increasing and expected to surpass that of cervical cancer by 2020 2 Risk factors for

J Clin Oncol 2011;29(32):4294-301 Autoinnoculation In a small study of 25 heterosexual couples, the rate of autoinnoculation (between genitals, anus, hands) in men was comparable to the rate of

12 Oral HPV HPV linked to oropharyngeal squamous cell carcinomas (OSCCs) (~90% due to HPV16) 1 Incidence of OSCCs is increasing and expected to surpass that of cervical cancer by Risk factors for Oral Cancer Tobacco Alcohol HPV Immune compromise 1 D Souza et al. N Engl J Med 2007;356(19): Chaturvedi et al. J Clin Oncol 2011;29(32): Autoinnoculation In a small study of 25 heterosexual couples, the rate of autoinnoculation (between genitals, anus, hands) in men was comparable to the rate of female-to-male transmission. 1 In female university students, vaginal HPV infections tended to precede cervical infections. 2 1 Hernandez et al. Emerging Infectious Diseases 2008;14: Take Home Lessons HPV testing NOT recommended in young women, no HPV triage less than age 25 No immediate colposcopy for ASCUS or LSIL pap less than age 25 Post colposcopy and treatment follow-up co-test annual x1 if low grade, x2 for all others Only two indications for HPV genotyping, HPV + Pap negative (or Pap Unsat or EC/TZ lacking) 2 Winer et al. AJE 2003;157:

Goals. In the News. Primary HPV Screening 3/9/2015. Your PAP and HPV Update Primary HPV Testing- Screening Intervals- HPV Vaccine Updates-

Goals. In the News. Primary HPV Screening 3/9/2015. Your PAP and HPV Update Primary HPV Testing- Screening Intervals- HPV Vaccine Updates- Your PAP and HPV Update 2015 Connie Mao, MD University of Washington Goals Primary HPV Testing- Is it time to stop doing pap smears? Screening Intervals- Should patients have a choice? HPV Vaccine Updates-