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What causes cervical cancer ?
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  1. What causes cervical cancer? What is HPV?

  2. >100 types identified2 30–40 anogenital2,3 15–20 oncogenic*,2,3 types (16, 18, 31, 33, 35, 39, 45, 51, 52, 584) HPV 16 (54%)/HPV 18 (13%) account majority of cervical cancers5 Nononcogenic† types (6, 11, 40, 42, 43, 44, 54)4 HPV 6/11 are most often associated with external genital warts.3 *High risk; †Low risk HPV Non-enveloped double-stranded DNA virus1 1.Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 1996:2045–2076.2. 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. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527. 5.Clifford GM, Smith JS, Aguado T, Franceschi S. Br J Cancer. 2003:89;101–105.

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

  4. Cervical Cancer: Etiology • Caused by high-risk HPV, most frequently HPV16 • Low-risk HPV is responsible for genital warts • HPV common sexually transmitted infection • 75-85% lifetime risk of infection • HPV infection may be latent for many years(?) • Persistent infection, most common in women over the age of 30, necessary for cancer and precursors

  5. US HPV Statistics • Lifetime risk for sexually active men/women is > 50%1 • By 50 yoa, >80% of women acquired genital HPV infection1 • Estimated incidence: 6.2 m/ year1 • Estimated prevalence: 20 m2 • In sexually active individuals 15–24 years of age, ~9.2 m currently infected.3 • 74% new HPV infections in this age group.3 • Among women <25, prevalence rates ranged from 28% to 46%.4,5 1. Centers for Disease Control and Prevention. Rockville, Md: CDC National Prevention Information Network; 2004. 2. Cates W Jr, and the American Social Health Association Panel. Sex Transm Dis. 1999;26(suppl):S2–S7. 3. Weinstock H, Berman S, Cates W Jr. Perspect Sex Reprod Health. 2004;36:6–10. 4. Burk RD, Ho GYF, Beardsley L, Lempa M, Peters M, Bierman R. J Infect Dis. 1996;174:679–689. 5.Bauer HM, Ting Y, Greer CE, et al. JAMA. 1991;265:472–477.

  6. Global HPV Statistics Worldwide prevalence of HPV infection estimated between 9-13% or ~630 million infected individuals1 13.3%2Ontario, Canada 15.3%5Reims, France 18%*,7Shanxi Province, China 14.5%3Morelos State, Mexico 40.2%–41.6%6Harare, Zimbabwe 16.6%4Concordia, Argentina *Among women 30–45 years of age 1.World Health Organization; 2001. Available at: http://www.who.int/vaccines/en/hpvrd/shtml. Accessed July 12, 2004. 2. Sellors JW, Mahony JB, Kaczorowski J, et al. CMAJ. 2000;163:503–508. 3.Lazcano-Ponce E, Herrero R, Muñoz N, et al. Int J Cancer. 2001;91:412–420. 4. Matos E, Loria D, Amestoy GM, et al. Sex Transm Dis. 2003;30:593–599. 5.Clavel C, Masure M, Bory JP, et al. Br J Cancer. 2001;84:1616–1623. 6. Blumenthal PD, Gaffikin L, Chirenje ZM, McGrath J, Womack S, Shah K. Int J Gynecol Obstet. 2001;72:47–53. 7. Belinson J, Qiao YL, Pretorius R, et al. Gynecol Oncol. 2001;83:439–444.

  7. HPV Infection & Cervical Cancer1 0–1 Year 0–5 Years 1–20 Years Invasive Cervical Cancer InitialHPV Infection ContinuingInfection CIN 2/3 CIN 1 Cleared HPV Infection 1. Pinto AP, Crum CP. Clin Obstet Gynecol. 2000;43:352–362.

  8. HPV and Cancer1 Cancer % Associated With Certain HPV Types Cervical* ≥95% Vaginal* 50% Vulvar* >50% Penile 50% Anal >70% Oropharyngeal 20% Nonmelanoma skin/cutaneous squamous cell 90%† *Includes cancer and intraepithelial neoplasia †Immunocompromised patients 1. Gonzalez Intxaurraga MA, Stankovic R, Sorli R, Trevisan G. Acta Dermatovenerol. 2002;11:1–8.

  9. How do you get HPV? • Sexual contact • Sexual intercourse1 • Genital–genital, manual–genital, oral–genital2–4 • Genital HPV infection in “virgins” rare, may result from nonpenetrative sexual contact2 • Condom use may reduce risk, but not fully protective2 • Nonsexual routes • Mother to newborn (vertical transmission; rare)5 • Fomites, theoretical (undergarments, surgical gloves, medical instruments)6,7 1. Kjaer SK, Chackerian B, van den Brule AJC, et al. Cancer Epidemiol Biomarkers Prev. 2001;10:101–106. 2. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Am J Epidemiol. 2003;157:218–226. 3. Fairley CK, Gay NJ, Forbes A, Abramson M, Garland SM. Epidemiol Infect. 1995;115:169–176. 4. Herrero R, Castellsague X, Pawlita M, et al. J Natl Cancer Inst. 2003;95:1772–1783.5. Smith EM, Ritchie JM, Yankowitz J, et al. Sex Transm Dis. 2004;31:57–62. 6. Ferenczy A, Bergeron C, Richart RM. Obstet Gynecol. 1989;74:950–954. 7. Roden RBS, Lowy DR, Schiller JT. J Infect Dis. 1997;176:1076–1079.

  10. Women Young age (peak age group 20–24 years of age)1 Lifetime number of sex partners2 Early age of first sexual intercourse3 Male partner sexual behavior3 Smoking4 Oral contraceptive use4 Uncircumcised male partners5 Men Young age (peak age group 25–29 years of age)1 Lifetime number of sex partners6 Being uncircumcised6 Risk Factors for HPV Infection 1.Insinga RP, Dasbach EF, Myers ER. Clin Infect Dis. 2003;36:1397–1403. 2. Burk RD, Ho GYF, Beardsley L, Lempa M, Peters M, Bierman R. J Infect Dis. 1996;174:679–689. 3. Murthy NS, Mathew A. Eur J Cancer Prev. 2000;9:5–14. 4. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Am J Epidemiol. 2003;157:218–226. 5. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 6. Svare EI, Kjaer SK, Worm AM, Osterlind A, Meijer CJLM, van den Brule AJ. Sex Transm Infect. 2002;78:215–218.

  11. Cumulative Incidence of HPV Infection Months Since First Intercourse Infection From Time of First Intercourse Study of female college students (N=603) From Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218–226, by permission of Oxford University Press.

  12. Most HPV infections are transient NCI Portland: HPV persistence amongst 61 initially Pap normal/ HPV 16 positive women 100 80 60 % Persistence 40 23% 20 0 0 9 15 21 27 Elapsed time in months Schiffman M ASCCP 2002 Biennial Orlando, Fl.

  13. Natural history of cervical cancer CIN 1,2 Avg. 6-24 mo Avg. 10 yrs HPV infection CIN 2,3 Invasive CA Avg. 6-9 mo. HPV disappearance Ho GY, et al. New England Journal of Medicine. 1998,338:423-428. Bory JP, et al. Int J Cancer, 2002;102:519-525. Nobbenhuis MAE, et al. Lancet. 1999;354:20-25.

  14. Most will get HPV at some time • Most will clear high-risk HPV, some do not • Persistence high-risk HPV leads to pre-cancer Cancer • Long persistence of HPV & CIN3 necessary for cancer CIN 3