Cervical cancer hpv-feb07
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This document provides an overview of cervical cancer and HPV. It discusses that HPV is the underlying cause of cervical cancer and describes the natural history of HPV infection. HPV is very common and usually clears without symptoms, but sometimes causes pre-cancerous cervical changes that can develop into invasive cancer if left untreated. Screening guidelines and new HPV vaccines are aimed at preventing cervical cancer by detecting and treating pre-cancerous cells or protecting against HPV infection. Regular Pap screening allows most pre-cancer to be detected and treated before it develops into invasive cancer.
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Cervical cancer hpv-feb07
- 1. 1 Cervical Cancer & HPV
- 2. 2 Presentation Overview • Cervical cancer 101 – Cause: Human Papilloma Virus (HPV) – “Natural history” – Treatment • Preventing cervical cancer – Avoiding exposure to HPV – Current screening guidelines – The new HPV vaccines
- 3. 3 Cervical Cancer 101 • Abnormal cell growth on cervix (lowest part of the uterus) • Caused by HPV infection, especially during the first years after puberty • Pre-cancerous changes long before invasive cancer develops • Rarely fatal in this country • A major cause of death worldwide
- 4. 4 Human Papillomavirus (HPV) • Long known to cause warts • Found in many cancers too • Over 100 types identified • Most benign, but 15-20 can cause cancers • Very common – 20,000,000 current cases in US – 6,200,000 new cases annually – 80% of women have HPV by age 50 – 50% of college students are infected
- 5. 5 HPV & Cervical Cancer • HPV recognized as the underlying cause ofHPV recognized as the underlying cause of cervical cancer since 1996cervical cancer since 1996 – NIH Consensus Conference on Cervical Cancer, 1996 – World Health Organization/European Research Organization on Genital Infection and Neoplasia, 1996
- 6. 6 Common HPV Types and their effects HPV Types Lead to: 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 cervical changes Genital warts Precancer cervical changes Cervical cancer Anal and other cancers 1. Cox. Baillière’s Clin Obstet Gynaecol. 1995;9:1. 2. Munoz et al. N Engl J Med. 2003;348:518.
- 7. 7 Human Papillomavirus Cancer of cervix 100% Cancer of esophagus . Cancer of skin . Cancer of X,Y,Z…. . Cancer of mouth 3% Cancer of throat 12% Cancer of penis 40% Cancer of vulva, vagina 40% Cancer of anus 90% Parkin DM et al. CA Cancer J Clin 2005; 55:74-108.
- 8. 8 Natural History of HPV Infections • Sexually transmitted • Usually no symptoms • No treatment for HPV infection before symptoms • Immune system clears most cases; some persist • HPV present in >99% of cervical cancers • High risk types (16, 18) associated with cancer • Low risk types (6, 11) are associated with genital warts • All can cause abnormal Pap tests Human Papillomavirus. ACOG Practice Bulletin No. 61. 2005; 105: 905-18.
- 9. 9 Co-factors for HPV Infection •Smoking •HIV infection •Other immune system defect •Pregnancy •Oral contraceptive use Ferris et al. Modern Colposcopy. 2004.
- 10. 10 HPV and Cervical Cancer Rates by Age 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) HPVPrevalence(%) 40-4415-19 20-24 25-29 30-34 35-39 45-49 50-54 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Cancerincidenceper100,000
- 11. 11 HPV Infections: Summary • Most people are infected by HPV at some time • Immune system usually clears HPV, but not always • Persistent low-risk HPV can lead to genital warts • Persistent high-risk HPV can lead to pre-cancer HPV Long persistence of HPV can lead to cancer
- 12. 12 Preventing Cervical Cancer • Screening for precancerous changes (and treatment if problems found) • Vaccination against HPV
- 13. 13 History of the Conventional Pap Smear • Developed by Dr. George N. Papanicolaou in 1940’s • Most common cancer screening test • Key part of annual gynecologic examination • Has greatly reduced cervical cancer mortality in U.S. Ferris et al. Modern Colposcopy. 2004: 2-4, 49. Photo accessed from http://www.cytology-iac.org/Cytopaths/1998/cytoFall98.htm
- 14. 14 Screening with the Conventional Pap Smear • Widely available • Inexpensive • But not perfect – Screening test – not diagnostic – 7-10% of women need further evaluation – Low sensitivity – need regular repeats Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.
- 15. 15 New Liquid Pap Tests • More accurate test – Thin, uniform layer of cells – Screening errors reduced by half • Screening needed less often • Can test for HPV with same specimen if abnormal cells found • Expensive Linder J. et al. Arch Pathol Lab Med. 1998; 122: 139-144.
- 16. 16 Cervical Cancer Screening Guidelines • First screen 3 years after first intercourse or by age 21 • Screen annually with regular Paps or every 2 years with liquid-based tests • After three normal tests, can go to every three years • Stop at 65-70 years with history of negative tests • Still need annual check-ups Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.
- 17. 17 NEW! The HPV Vaccine Gardasil ® (Merck) • Protects against types 16, 18, 6, 11 • FDA approved for use in females 9-26 years of age • Prevents HPV infection; doesn’t treat existing infection • 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.
- 18. 18 HPV Vaccine ACOG Recommendations VACCINATE allVACCINATE all females 9-26 years old, regardless of sexual activity • Less potential benefit with increasing age & number of sexual partners Special populations – vaccine less effective • Previous abnormal Pap tests or genital warts • Immunocompromised Continue screening with Pap tests!Continue screening with Pap tests! Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.
- 19. 19 NOT CURRENTLY RECOMMENDEDNOT CURRENTLY RECOMMENDED (Awaiting more evidence)(Awaiting more evidence) Continue screening with Pap tests!Continue screening with Pap tests! • Women over age 26 • Pregnant women – If vaccine started before pregnancy, give remaining dose(s) post-partum • Breastfeeding women • Men HPV Vaccine ACOG Recommendations Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.
- 20. 20 HPV Vaccine Important Considerations Continue screening with Pap tests!Continue screening with Pap tests! • Vaccine is most effective before first sexual intercourse – less effective in sexually active women • HPV testing before vaccine not recommended • Vaccine is not a treatment for current HPV infection, genital warts, or pre-cancer Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.
- 21. 21 HPV Vaccine FAQ • Vaccine will not cause HPV – Virus-like particle vaccine (not live virus) • HPV vaccines appear to be very safe – Few major adverse events, but limited data • Most side effects are minor – Injection site reaction • Potentially effective in preventing cervical cancer (and other HPV-related cancers) – BUT not all cancer-causing HPV types are covered by the vaccine Continue screening with Pap tests!Continue screening with Pap tests! Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.
- 22. 22 References Advisory Committee on Immunization Practices. ACIP provisional recommendations for the use of quadrivalent HPV vaccine. August 14, 2006. Accessed from http://www.cdc.gov/nip/recs/provisional_recs/hpv.pdf. American Cancer Society. Cancer facts and figures 2003. Atlanta (GA): ACS 2003. Available at http://www.cancer.org/downloads/STT/CAFF2003PWSecured.pdf. Apgar BS, et al. “The 2001 Bethesda System Terminology.” Am Fam Physician. 2003;68:1992–1998. Cannistra SA, Niloff JM. “Cancer of the Uterine Cervix.” N Engl J Med. 1996;334:1030–1038. Cates W Jr, and the American Social Health Association Panel. “Estimates of the incidence and prevalence of sexually transmitted diseases in the United States.” Sex Transm Dis. 1999;26(suppl):S2–S7. Centers for Disease Control and Prevention. Rockville, Md: CDC National Prevention Information Network; 2004. Cervical Cytology Screening. ACOG Practice Bulletin No. 45. American College of Obstetricians and Gynecologists. Obstet Gynecol 2003; 102:417-27. Cox. Baillière’s Clin Obstet Gynaecol. 1995;9:1. Ferris et al. Modern Colposcopy: Textbook and Atlas. 2nd ed. Dubuque, Iowa: Kendall/Hunt; 2004: 2-4, 49, 78-82. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology. 4th ed. Philadelphia, Pa: Lippincott-Raven; 2001:2197–2229. Human Papillomavirus. ACOG Practice Bulletin No. 61. American College of Obstetricians and Gynecologists. Obstet Gynecol 2005; 105: 905-18. Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006; 108: 699-705. Hutchinson ML. et al. “Homogeneous sampling accounts for the increased diagnostic accuracy using the ThinPrep Processor.” Am J Clin Pathol. 1994; 101:215-219. Jansen KU, Shaw AR. ”Human Papillomavirus Vaccines and prevention of cervical cancer.” Annu Rev Med. 2004;55:319– 331. Kodner CM, Nasraty S. “Management of genital warts.” Am Fam Physician. 2004;70:2335–2342. Lacey CJN. “Therapy for genital human papillomavirus-related disease.” J Clin Virol. 2005;32(suppl):S82–S90. Linder J. et al. “ThinPrep Papanicolaou testing to reduce false-negative cervical cytology.”Arch Pathol Lab Med. 1998; 122: 139-144. Management of Abnormal Cervical Cytology and Histology. ACOG Practice Bulletin No. 66. American College of Obstetricians and Gynecologists. Obstet Gynecol 2005; 106: 645-64. Maw RD, Reitano M, Roy M. “An international survey of patients with genital warts: perceptions regarding treatment and impact on lifestyle.” Int J STD AIDS. 1998;9:571–578.
- 23. 23 References (Cont.) McCrory DC, Matchar DB, Bastian L, et al. Evaluation of Cervical Cytology. Evidence Report/Technology Assessment No. 5. AHCPR Publication No. 99-E010. Rockville, MD: Agency for Health Care Policy and Research. February 1999. Moscicki, A.B. et al. “Updating the natural history of HPV and anogenital cancer.” Vaccine. 2006; 24S3; 42-51. Munoz et al. “Epidemiologic classification of human papillomavirus types associated with cervical cancer.” N Engl J Med. 2003;348:518. Ostor, AG. “Natural history of cervical intraepithelial neoplasia: a critical review.” Int J Gynecol Pathol 1993; 12(2): 186- 92. Parkin DM, Bray F, Ferlay J, Pisani P. “Global cancer statistics 2002.” CA Cancer J Clin 2005; 55:74-108. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000. Saslow D et al. “American Cancer Society Guideline for the Early Detection of Cervical Neoplasia and Cancer.” CA Cancer J Clin. 2002;52:342-362. Schiffman M, Castle PE. “Human papillomavirus: Epidemiology and public health.” Arch Pathol Lab Med. 2003;127:930–934. Schiffman M ASCCP 2002 Biennial Orlando, Fl. Sellors et al. “Prevalence and predictors of human papillomavirus infection in women in Ontario, Canada.” CMAJ. 2000;163:503-8. Smith, RA et al. “American Cancer Society Guidelines for the Early Detection of Cancer, 2003.” Cancer. 2003;53(1): 27-43. Solomon D, Davey D, Kurman R, et al, for the Forum Group Members and the Bethesda 2001 Workshop. JAMA. 2002;287:2114–2119. Soper DE. In: Berek JS, ed. Novak’s Gynecology. 13th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002:453– 470. Spitzer M, Johnson C. Philadelphia, Pa: WB Saunders Co; 2002:41–72. Wiley DJ, Douglas J, Beutner K, et al “External genital warts: diagnosis, treatment and prevention.” Clin Infect Dis. 2002;35(suppl 2):S210–S224. Winer RL et al. “Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students.” Am J Epidemiol. 2003; 157:218-226. Wright, T.C. et al. “2001 Consensus Guidelines for the Management of Women with Cervical Cytological Abnormalities.” JAMA. 2002; 287: 2120-2129. USPSTF. 2003. Available at http://www.ahrq.gov/clinic/uspstf/uspscerv.htm.
- 24. 24 Questions? Program sponsored by Middle Earth Slide set developed with help from Dr. Kim Noyes Preventive Medicine Resident, School of Public Health Information provided by the New York State Department of Health, Cancer Services Program Please take a few momentsPlease take a few moments to complete the evaluation!to complete the evaluation!
Editor's Notes
- Key Point There are many different types of HPV; of the 15–20 oncogenic types, HPV 16 and HPV 18 account for the majority of cervical cancers. The disease burden is large. HPV is very prevalent, especially among young sexually active teens and adults. Background Papillomaviruses such as HPV are nonenveloped, double-stranded DNA viruses. More than 100 HPV types have been detected, with >80 types sequenced and classified. Approximately 30–40 types of HPV are anogenital, of which 15–20 types are oncogenic. HPV Types 16 and 18 are oncogenic and account for about two thirds of all cervical cancers. HPV Types 6 and 11 are nononcogenic and are associated with external anogenital warts and RRP. References 1. Schiffman M, Castle PE. Human papillomavirus: Epidemiology and public health. Arch Pathol Lab Med. 2003;127:930–934. 2. Wiley DJ, Douglas J, Beutner K, et al. External genital warts: Diagnosis, treatment, and prevention. Clin Infect Dis. 2002;35(suppl 2):S210–S224.
- The causal role of human papillomavirus in all cancers of the cervix has been firmly established biologically and epidemiologically. Reference: Munoz, N. et al. “HPV in the etiology of human cancer.” Vaccine 24S3 2006;24S3: 1-10.
- Low-risk HPV types, such as types 6 and 11, most commonly cause benign low-grade cervical changes and genital warts. Types 16 and 18 and other “high-risk” HPV types are the most common cause of low-grade cervical cell abnormalities, and almost exclusively cause high-grade cervical cell abnormalities that are precursors to invasive cervical cancer and other lower genital tract malignancies including vulvar, vaginal, penile and anal cancer. The large IARC study of cervical cancers around the world demonstrated that over 90% of all of cervical cancers were associated with high-risk types of HPV Irrespective of geographical area 43% to 65% of the cancers were associated with HPV 16 8% to 31% were associated with HPV 18. Taken together, HPV 16 and 18 accounted for approximately two-thirds of all invasive cancers from all geographic areas. References: 1. Cox. Baillière’s Clin Obstet Gynaecol. 1995;9:1.2. Munoz et al. N Engl J Med. 2003;348:518.
- HPV is implicated as the cause of cervical cancer and many other ano-genital cancers. Reference: Parkin DM, Bray F, Ferlay J, Pisani P. “Global cancer statistics 2002.” CA Cancer J Clin 2005; 55:74-108.
- Genital HPV is transmitted sexually. Transmission occurs through contact with infected genital skin, mucous membranes, or body fluids from a partner with either overt or subclinical HPV infection. Other modes include oro-genital, manual-genital, and nonpenetrative genital-genital contact. Covering infected areas with a latex condom provides theoretical protection from infection. Areas not covered by condom can transmit HPV infection. Infrequently transmitted in the neonatal period, although published studies are conflicting. Most HPV infections are transient and are cleared by the immune system 70-90% will clear within 1-2 years Persistent HPV viral infections may lead to cancer and its precursors No treatment for HPV infection but cervical changes and warts CAN be treated Reference: Human Papillomavirus. ACOG Practice Bulletin No. 61. American College of Obstetricians and Gynecologists. Obstet Gynecol 2005; 105: 905-18.
- Co-factors to HPV in cervical carcinogenesis may act in at least 3 ways: By influencing the acquisition of HPV infection (OCPs, multiparity) By increasing the risk of HPV persistence (HIV, immunosuppresion) By increasing the risk of progression from HPV infection to CIN 2,3 and cancer (smoking, multiparity) Cigarette smoking is a significant and independent risk factor for the development of CIN3 and SCC of cervix, increasing RR 2-5 fold. Risk increases with increased intensity and duration of smoking. Mechanism is likely that tobacco containing carcinogens promote neoplastic progression in HPV infected cells. HIV and other immunosupression cause an inability to clear HPV, increasing susceptibility to HPV and oncogenicity. Multiparity has been found to be associated with both cervical cancer and CIN3 with risk rising with increased number of pregnancies. Effect is independent of sexual behavior and socioeconomic variables. Pregnancy-induced alterations in nutritional status, the effects of hormones on the cervix or on HPV expression, increased susceptibility to potential mutagens or effect of trauma at delivery are proposed mechanisms. OCP use conveys a measurable increase in risk for SCC. The strongest evidence comes from an IARC multicenter case-control study demonstrating only a moderate association with cancer risk. Mechanism appears to be the physiologic effects such as eversion of the columnar epithelium, thus activating HPV-vulnerable immature squamous metaplasia. Reference: Ferris et al. Modern Colposcopy. 2004: 2-4, 78-82..
- This graph shows HPV prevalence and cervical cancer incidence as a function of a woman’s age. Key observations In younger women, there is a high prevalence of HPV infection but that cervical cancer is very rare. As women age, the prevalence of HPV declines and the incidence of cancer increases. Women over 30 years of age have a greater risk for developing high-grade lesions and cancer. Women with persistent high-risk HPV infections are the population most at-risk for having or developing cervical cancer. References: 1. Sellors et al. CMAJ. 2000;163:503. 2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000. **Note: Data from the CMAJ study was collected from women aged 15-49, whereas the SEER data reported cancer incidence in all age-segments of the population.
- In summary Most will get HPV at some time during their lifetime Most, even with high-risk HPV, will clear or permanently suppress the virus. However, some do not. It is persistence of high-risk HPV that can lead to true pre-cancer Long persistence of high-risk HPV and HPV-induced CIN3 are necessary for the accumulation of random mutations that lead to cancer.
- Primary cervical cancer screening essentially began with the introduction of the Pap Smear. Introduced in the 1940’s, by Dr. George N. Papanicolaou, the pap smear eventually became the standard screening test for cervical cancer and pre-malignant lesions. The Pap test is based on a relatively simple principle. Cells from squamous epithelium exfoliate over time. Thus, the cells removed for cytologic examination represent epithelial cells, normal or abnormal, found at the surface. Widespread use of the pap smear has decreased cervical cancer deaths by 70%. Reference: Ferris et al. Modern Colposcopy. 2004: 2-4, 49.
- Cervical cytology screening is, in many respects, the ideal screening test. Cervical cancer has a defined premalignant phase of many years, which allows repeated tests to significantly reduce the impact of individual false-negative test results. Cervical cytology is inexpensive and is readily accepted among American women. However, cervical cytology, is not a diagnostic test. The sensitivity of the pap smear is low (ranges from 47-85%) and the specificity is high (95-98%). Reference: Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.
- In 1996, the FDA approved the first of two currently available liquid-based thin-layer cytology preparations for cervical screening. Liquid-based thin-layer cervical cytology was introduced to help reduce the potential sampling errors. The Thin-Prep method appears to have increased sensitivity for detecting cancer precursor lesions over the conventional method, but the degree to which sensitivity is increased is unknown. The reported increase in sensitivity may make this method especially useful in women who are screened infrequently (fewer false negatives). The difference in specificity between the liquid-based and conventional tests has not been determined. Although an increase in sensitivity will permit earlier detection of cancer precursor lesions, any decrease in specificity can result in increased cost and morbidity from false-positive diagnoses. Both the conventional test and the liquid-based thin-layer test can be effective in population screening. Providers selecting a cervical cytology method should consider the screening history of their patient, the cost of the test, and the possible effects of false-negative or false-positive results. Reference: ACOG Practice Bulletin. Cervical Cytology Screening. 2003; 45:1-11.
- The next several slides will review the newest guidelines for cervical cancer screening from the American Cancer Society, the United States Preventive Services Task Force and the American College of Obstetricians and Gynecologists. These guidelines specifically state how often screening should be done, when to initiate screening and when screening can be discontinued. Reference: Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.
- Key points: The only currently available, FDA approved HPV vaccine is Gardasil, manufactured by Merck. It is a quadrivalent vaccine, effective against 4 HPV types: 6, 11, 16, and 18. Highly efficacious Only approved for use in females 9-26 years old. $120/dose plus cost of administering/physician charge, etc. Reference: Cancer 2003;53(1): 27-43.
- Important points: Vaccination recommended for all females 9-26 years old. Vaccine is most effective if administered before sexual activity ACOG supports vaccination at 13-15 years of age during first visit to GYN The vaccine can be given to women with previous CIN, abnormal cytology or genital warts, but it is not intended to treat these patients. Patients with these conditions should undergo the appropriate evaluation and treatment. Women with suppressed immune systems can be vaccinated, although protection may be less than that of women with normal immune function. Pap screening recommendations remain the same. The vaccine is a preventive tool and is not a substitute for cancer screening. Reference: Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.
- Important Points: Vaccination of women over age 26 and of males is not currently recommended. Pregnant women should not be vaccinated. The FDA classifies it as pregnancy category B. Although its use in pregnancy is not recommended, no teratogenic effects have been reported in animal studies. In clinical studies, the proportion of pregnancies with an adverse outcome were comparable in women who received the quadrivalent HPV vaccine and in women who received a placebo. If a woman discovers she is pregnant during the vaccine schedule, she should delay finishing the series until after she gives birth. The manufacturer’s pregnancy registry should be contacted if pregnancy is detected during the vaccination schedule. It is unclear whether vaccine can be provided to women who are breastfeeding because inactivated vaccines do not affect the safety of breastfeeding for mothers or infants. It is not known whether vaccine antigens or antibodies found in the quadrivalent vaccine are excreted in human milk. ACOG and ACIP state that lactating women can receive the vaccine. Reference: Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.
- The Advisory Council on Immunization Practices has recommended the initial vaccination target of females aged 11 or 12. This is part of the “adolescent platform” that supports a routine well-child check at age 11-12 that would include discussion of HPV vaccine and other recommended immunizations (DTaP and Meningitis). In summary The earlier the vaccine is given, the better Continue cervical cytology screening Vaccine is prophylactic, not treatment Reference: Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.
- Health care providers are encouraged to discuss with their patients the benefits and limitations of the quadrivalent HPV vaccine and the need for continued routine cervical cytology screening. Reference: Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.