1. Pap Smears, Dysplasia, and HPV Nicholas Montalto Jr, MD, FACOG Albany Gynecology and Fertility CNY Fertility Centers Division of Minimally Invasive Surgery www.albanygyn.com

2. 2 History of the Conventional Pap Smear Developed by Dr. George N. Papanicolaou in 1940’s Most common cancer screening test Critical aspect of annual gynecologic examination Ferris et al. Modern Colposcopy. 2004: 2-4, 49. Photo accessed from http://www.cytology-iac.org/Cytopaths/1998/cytoFall98.htm

3. 3 Collection Devices Broom Device Spatula & Endocervical Brush Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27. All pictures accessed from http://www.clinilab.fr/cytopathologie.html

4. Transformation Zone of the Cervix  ~ 99% of HPV-related genital cancers arise within the transformation zone of the cervix. 1 1. Castle PE. J Low Genit Tract Dis. 2004;8:224-230. 2. Kahn JA. Curr Opin Pediatr. 2001;13:303–309. 3. Rager KM et al. Curr Women Health Rep. 2002;2:468–475.

5. 5 Thin-Layer Preparations Reduce Sampling Errors –Virtually all of the sample is collected into the vial –Randomized, representative sample Reduce Screening Errors –Thin, uniform layer of cells –“Satisfactory, but limited” specimens greatly reduced –Screening errors reduced by 50% Linder J. et al. Arch Pathol Lab Med. 1998; 122: 139-144.

6. 6 Cervical Cytology Terminology Atypical squamous cells (ASC) 4 –Atypical squamous cells of undetermined significance (ASC-US) –Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions (ASC-H) Squamous intraepithelial lesions (SIL) 4 –Low-grade SIL (LSIL): Mild dysplasia, cervical intraepithelial neoplasia 1 (CIN 1) –High-grade SIL (HSIL): Moderate and severe dysplasia (CIN 2/3) carcinoma in situ (CIS) Atypical glandular cells (AGC) 4 1. Spitzer M, Johnson C. Philadelphia, Pa: WB Saunders Co; 2002:41–72. Reprinted with the permission of Elsevier. 2. Apgar BS, Zoschnick L. Am Fam Physician. 2003;68:1992–1998. Reprinted with the permission of the AAFP. 3. Cannistra SA, Niloff JM. N Engl J Med. 1996;334:1030–1038. Images reproduced courtesy of Dr. Graziella Abu-Jawdeh. 4. Solomon D, Davey D, Kurman R, et al, for the Forum Group Members and the Bethesda 2001 Workshop. JAMA. 2002;287:2114–2119. Normal 1 ASCUS 2 LSIL 3 HSIL 3

7. 7 Cervical Cancer Screening Guidelines From ACS, USPSTF, and ACOG Account for technologic innovations in cervical cancer screening Thin-layer liquid-based cytology Thin-layer liquid-based cytology HPV DNA testing HPV DNA testing Specifies screening intervals, start and stop rules Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.

8. 8 Comparison of Guidelines ACS 2 (2002) USPSTF 1 (2003) ACOG 3 (2003) Method of screening Bothconventional and liquid based cytology acceptable; HPV DNA test with cytology  30 years also acceptableCannot recommend for or against new technologies Same as ACS First Screen Approximately 3 years after initiation of intercourse or by age 21 or by age 21 Up to Age 30 Annually with conventional pap or every 2 years with liquid-based Every 3 years after 3 consecutive normal results Annually

9. 9 Comparison of Guidelines ACS 2 (2002) USPSTF 1 (2003) ACOG 3 (2003) Age  30 years Screen every 2-3 years Every 3 years Same as ACS Age to Stop Age 70, after 3 negative tests in 10 years for non-high risk women Age 65, after consistentnegativetests No upper age limit Hysterectomy Discontinue if for benign reason Same as ACS 1. USPSTF. 2003. Available at http://www.ahrq.gov/clinic/uspstf/uspscerv.htm. 2. Saslow D et al. CA Cancer J Clin. 2002;52:342-362. 3. Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.

10. 10 High-Risk HPV Testing ACOG Guidelines Two Indications: Primary screening after age 30 –If both Pap and HPV test negative Re-screen no more frequently than every 3 years Triage of minimally abnormal Paps –ASC-US Only need to do colposcopy if HPV + Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.

11. 11 Women Under 30 years of age Cytology Negative HPV not done Liquid based Cytology Annually There is no role for the use of “routine” HPV screening in women of this age group. Women 30 years and older Cytology Negative HPV done: negative x3 consecutive screens No previous history of: CIN 2 or 3, HIV immunosuppression,or DES exposure in utero yesyes yesyes Women 30 years and older Cytology negative HPV positive Repeat both liquid based cytology & HPV testing in 6-12 months Cytology HPV Both Negative Cytology ASC-US HPV negative ALGORITHM: PAP & HPV GUIDELINES Routine rescreening in 2-3 years Rescreen with liquid based cytology & HPV @ 12 months and yesyes Women any age Cytology ASC-US HPV negative Repeat Liquid based Cytology & HPV @ 12 months Cytology ASC-US or Greater HPV negative Any Cytology Positive HPV Colposcopy Liquid based Cytology every 2-3 yrs Cytology Negative HPV Negative Repeat Cytology @ 12 months yes Women any age Cytology ASC-US HPV Positive result yes yesyes result yes Colposcopy yes Cytology negative HPV positive Colposcopy yes result

12. 12 Human Papillomavirus (HPV) Over 100 types identified 2 –30–40 anogenital 2,3 –15-20 oncogenic types 2,3 –30-35 types sexually transmitted Disease Burden –20,000,000 current cases in US 6 –6,200,000 new annual cases 5 –80% of women will have acquired HPV infection by age 50 5 –50% of college students are infected 4 1. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology. 4 th ed. Philadelphia, Pa: Lippincott-Raven; 2001:2197–2229. Picture reprinted with the permission of Lippincott-Raven. 2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4. Winer RL et al. Am J Epidemiol. 2003; 157:218-226. 5. Centers for Disease Control and Prevention. Rockville, Md: CDC National Prevention Information Network; 2004. 6. Cates W Jr, and the American Social Health Association Panel. Sex Transm Dis. 1999;26(suppl):S2–S7.

13. 13 HPV & Cervical Cancer HPV is the Underlying Cause of Cervical Cancer NIH Consensus Conference on Cervical Cancer, 1996 World Health Organization/European Research Organization on Genital Infection and Neoplasia, 1996 Journal of the National Cancer Institute –Schiffman et al., 1993 –Franco et al., 1995 –Bosch et al., 1995

14. Cancer Types, Other Than Cervical Cancer, Attributable to HPV Estimated percentage of cancer cases attributable to HPV González Intxaurraga MA et al. Acta Dermatovenerol. 2002;11:1–8. Cancer Type

15. 15 Common HPV Types Associated With Benign and Malignant Disease HPV TypesManifestations Low-Risk High-Risk, HPV 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81 HPV 16, 18, -31, -33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82 Benign low-grade cervical changes Condylomata acuminata (Genital warts) Low-grade cervical changes High-grade cervical changes Cervical cancer Anogenital and other cancers 1. Cox. Baillière’s Clin Obstet Gynaecol. 1995;9:1. 2. Munoz et al. N Engl J Med. 2003;348:518.

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21. 21 NCI Portland: HPV persistence amongst 61 initially Pap normal / HPV 16 positive women 0 9152127 20 40 60 80 100 Elapsed time in months % Persistence 0 Schiffman M ASCCP 2002 Biennial Orlando, Fl. Most HPV infections are transient 23%

22. 22 HPV Prevalence and Cervical Cancer - Incidence by Age 1,2 1. Sellors et al. CMAJ. 2000;163:503. 2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000. Age (Years) HPV Prevalence (%) 40-4415-1920-2425-2930-3435-3945-4950-54 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Cancer incidence per 100,000

23. 23 HPV Infections: Summary Most will acquire HPV at some time Most will clear HPV, but some do not Persistence of low-risk HPV can lead to anogenital warts Persistence of high-risk HPV can lead to pre-cancer CIN 3 Long persistence of high risk HPV is necessary for the accumulation of mutations that lead to cancer

24. 24 HPV Vaccine Gardasil ® (Merck) Quadrivalent vaccine against types 16, 18, 6, 11 FDA approved for use in females 9-26 years of age Prophylactic, not therapeutic Virus-like particles (VLP) Highly effective Safe, few serious adverse side effects Requires 3 injections Expensive ($360 + administrative fees) Smith, RA et al. Cancer. 2003;53(1): 27-43.

25. 25 HPV L1 Virus-Like-Particle (VLP) Vaccine Synthesis Eukaryotic Cell L1 gene of HPV DNA L1 gene is inserted into a plasmid, which is inserted in the nucleus of a cell mRNA Transcription Translation Capsid proteins Empty viral capsid (VLP) Elicits immune response in host HPV Inside HPV HPV

26. 26 Vaccine Specifics Dosage Schedule –3 separate 0.5-mL doses at 0, 2 months, 6 months –Evidence suggests adequate immune response if all 3 doses given within 12 months Ordering –Through Merck www.MerckVaccines.com1-877-VAX-MERCK Vaccine Patient Assistance Program –Vaccines for Children Program http://www.cdc.gov/nip/vfc/provider/provider_home.htmStorage –Refrigerated at 2-8°C (36-46°F) Consent –Currently in NYS, minors need parental consent Adverse event reporting –http://vaers.hhs.gov/ Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.

27. Recommendations ACIP 1,a ACOG 2,b AAFP 3,c AAP 4,d Routine vaccination in females 11– 12 years old and catch-up vaccination in 13- to 26-year-olds Females 9–10 years old can be vaccinated Vaccinate regardless of previous HPV infection or abnormal Pap test results Continue Pap testing after vaccination Summary of US Vaccine Recommendations a ACIP = Advisory Committee on Immunization Practices. b ACOG = American College of Obstetricians and Gynecologists. c c AAFP = American Academy of Family Physicians. d AAP = American Academy of Pediatrics. ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 1. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2007;56(RR-2):1–24. 2. American College of Obstetricians and Gynecologists (ACOG). Obstet Gynecol. 2006;108(3):699–705. 3. Department of Health and Human Services, Centers for Disease Control and Prevention. Recommended immunization schedule for persons aged 7–18 years, United States, 2008. http://www.cispimmunize.org/IZSchedule_ Adolescent.pdf. Accessed July 14, 2008. 4. Committee on Infectious Diseases. Pediatrics. 2007;120(3);666–668.

28. 100 80 60 40 20 Suggests minimal 9 to 11 exposure to HPV at 9 to 11 years of age 12–13 14–1516–17 <11 The Most Effective Time to Vaccinate Is Before Exposure 1 1. Centers for Disease Control and Prevention. MMWR. 2002;51(RR-6):1–80. 2. Hoff T et al. National Survey of Adolescents and Young Adults: Sexual Health Knowledge, Attitudes and Experiences. Henry J. Kaiser Family Foundation;2003:14. Cohorts that have had intercourse, % Age at first intercourse, Years Behavior Reported in an Independent Study These data suggest minimal risk of exposure to HPV in 9- to 11-year-olds. In an analysis of 1,552 adolescents and young adults, the subset (n=1,014) featured in this chart reported having engaged in sexual intercourse. 2

29. Exposure to HPV at a Young Age Increases the Risk of Cervical Lesions and Cancer in Women *Mantle-Haenszel estimates adjusted for age only. La Vecchia C et al. Cancer. 1986;58:935–941. Relative risks for CIN and invasive cancer increase with decreasing age of first sexual intercourse. Age at first intercourse, Years (n=206)(n=327) Reference population: First intercourse  23 years of age or never

30. 30 Total HPV 6, 11,16, & 18 IgG Antibody Titers from the Quadrivalent and Natural Infection Titers

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36. 36 HPV Vaccine ACOG Recommendations Continued screening with Pap tests is mandatory VACCINATE Females 9-26 years old, regardless of sexual activity –Potential benefit diminishes with age & increasing number of sexual partners Special populations Previous CIN, abnormal cervical cytology or genital warts –Vaccine may be less effective Immunocompromised Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.

37. 37 Continued screening with Pap tests is mandatory NOT CURRENTLY RECOMMENDED (Awaiting more evidence) Women over age 26 Pregnant women (Category B) –If pregnancy diagnosed during the vaccine schedule, give remaining vaccine post-partum Men HPV Vaccine ACOG Recommendations Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.

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39. HPV Vaccination: Monitoring Short- and Long- Term Impact

40. 40 Select Surveillance Studies of HPV Vaccine Several surveillance studies of GARDASIL ® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] are being conducted by Merck & Co., Inc., on behalf of or by the Centers for Disease Control and Prevention (CDC). These studies are designed to evaluate the short- and long-term efficacy and safety of the vaccine and the impact of the human papillomavirus (HPV) vaccine in the population.

41. 41 Monitoring Short- and Long-Term Impact of HPV Vaccination Patient Population Study Objectives Nordic Registry and Long-Term Follow-Up 5496 females 16 to 23 yrs in Nordic Countries  Duration of effectiveness of HPV vaccine  Rates of HPV disease in a population  Monitor long-term safety Postlicensure Safety Study Primary : 44,000 9 to 26 year old females  Safety events (emergency room & hospitalizations)  Pregnancy outcomes  Autoimmune conditions VIP Observational population based in Nordic countries  Monitor HPV vaccination in a population  Trend of disease burden  Vaccine exposure in pregnancy  Potential for type replacement  Behavioral surveys CDCHVIMP Women aged 18+ at sites in 4 US states  Develop comprehensive approach to monitoring HPV types– specific CIN 2/3 and AIS – Determine vaccine history among subset of CIN 2/3 cases CDC SSuN Patients with genital warts  Develop standardized methodology for genital wart surveillance in STD clinics CDC VSD 11- to 30- year-old females and 11- to 30- year-old males  Assess HPV-associated outcomes at baseline before (2000–2005) and after HPV vaccine implementation to measure vaccine impact

42. Quadrivalent HPV Vaccine Rapid Cycle Analysis Study Objective: identify associations between HPV vaccine and a prespecified list of adverse outcomes in females aged 9 to 26 years 7 participating VSD sites Females 9 to 26 yrs –Youth: 9 to 17 yrs –Adults: 18 to 26 yrs Data from August 20, 2006 to July 20, 2008 –Allow for late-arriving data Monitor until: –Youth: 350,000 doses –Adults: 150,000 doses Gee J. Vaccine Safety Datalink Project: Monitoring the Safety of Quadrivalent Human Papillomavirus Vaccine (HPV4). Presented at Advisory Committee on Immunization Practices Meeting, October 22, 2008.

43. Preliminary CDC Findings and Next Steps (October 2008) With >375,000 doses administered, VSD active surveillance did not find statistically significant risk for any of the prespecified adverse events (Guillain-Barré syndrome [GBS], seizures, syncope, appendicitis, stroke, venous thromboembolism [VTE], allergic reactions) after vaccination for either age group. –GBS, seizures, syncope, appendicitis, VTE, and allergic reactions are listed as adverse reactions in the prescribing information. No major increase in rate of anaphylaxis following HPV4 as compared to previous studies (no formal comparison made) Gee J. Vaccine Safety Datalink Project: Monitoring the Safety of Quadrivalent Human Papillomavirus Vaccine (HPV4). Presented at Advisory Committee on Immunization Practices Meeting, October 22, 2008.

44. Preliminary CDC Findings and Next Steps (October 2008) Continue to monitor outcomes until reach upper limits for adverse events or until reach dose limit (500,000) 1 Continue to monitor rare adverse events 1 –GBS, VTE, stroke (limited power at this time to rule out risk of GBS) CDC also noted that syncope following vaccination could lead to serious outcomes; preventive measures are criticial 2 1.Gee J. Vaccine Safety Datalink Project: Monitoring the Safety of Quadrivalent Human Papillomavirus Vaccine (HPV4). Presented at Advisory Committee on Immunization Practices Meeting, October 22, 2008. 2.Calugar A. Quadrivalent human papillomavirus vaccine (HPV4): post-licensure safety update, Vaccine Adverse Event Reporting System (VAERS), United States. Presented at Advisory Committee on Immunization Practices Meeting, October 22, 2008.

45. Thank You Questions? Nicholas Montalto Jr, MD, FACOG Albany Gynecology and Fertility CNY Fertility Centers Division of Minimally Invasive Surgery www.albanygyn.com