Cancer Screening and Prevention:: Eliminating Deaths From Cervical Cancer
Cancer Screening and Prevention:: Eliminating Deaths From Cervical Cancer
Cancer Screening and Prevention:: Eliminating Deaths From Cervical Cancer
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Learning Objectives
• Participant will understand the evolution of
cervical cytology screening as well as current
evidence-based guidelines
• Participant will gain knowledge about HPV, its
relationship to cervical cancer, and
indications for HPV testing
• Participant will be introduced to the HPV
vaccine, including current recommendations
for its use
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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
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Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.
Sources of Error with the
Conventional Pap Smear
• Sampling / preparation errors1
– Cells not collected on sampling device 2/3 of false
– Collected cells not transferred to slide negatives
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Linder J. et al. Arch Pathol Lab Med. 1998; 122: 139-144.
Collection Devices
Spatula & Broom Device
Endocervical Brush
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Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.
All pictures accessed from http://www.clinilab.fr/cytopathologie.html
Cervical Cytology Terminology
Normal1 ASCUS2 LSIL3 HSIL3
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Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.
Cervical Cancer Screening Guidelines
Summary
How often
• Adults
– Annually with conventional paps and every 2 years with liquid-based
cytology
– ≥30 with 3 consecutive negatives may change to every 2-3 years
• GUIDANCE BY HPV STATUS!!
• Adolescents
– First screen 3 years after onset of sexual intercourse or at age 21
– Those who do not need screening should still get appropriate contraceptive
services, STD screening and other preventive health care
• Exclusions:
• DES exposure
• Immunocompromised
• HIV
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Cervical Cytology Screening. ACOG Practice Bulletin No. 45. 2003; 102:417-27.
Cervical Cancer Screening Guidelines
Summary
When To Stop
• Women >70 years with:
– At least 3 consecutive documented, satisfactory negative smears1
– No abnormal/positive cytology within past ten years1
• After hysterectomy
– If hysterectomy performed for benign disease and cervix was removed2
– Negative history of abnormal paps2
• Exclusions2:
– History of cervical cancer
– DES exposure
– Immunocompromised
– Positive HPV DNA test
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Human Papillomavirus (HPV)
• Over 100 types identified2
– 30–40 anogenital2,3
– 15-20 oncogenic types2,3
– 30-35 types sexually transmitted
• Disease Burden
– 20,000,000 current cases in US6
– 6,200,000 new annual cases5
– 80% of women will have acquired HPV
infection by age 505
– 50% of college students are infected4
1. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology. 4th 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. 14
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.
Common HPV Types Associated With
Benign and Malignant Disease
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1. Cox. Baillière’s Clin Obstet Gynaecol. 1995;9:1.
2. Munoz et al. N Engl J Med. 2003;348:518.
Human Papillomavirus
Cancer of cervix uteri 100%
Cancer of anus (squamous cell) 90%
Cancer of vulva, vagina 40%
Cancer of skin .
Cancer of X,Y,Z…. .
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Parkin DM et al. CA Cancer J Clin 2005; 55:74-108.
Natural History of HPV Infections
• HPV is sexually transmitted
• Asymptomatic
• No treatment for HPV infection
• Cervical changes and warts CAN be treated
• Transient or persistent
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Human Papillomavirus. ACOG Practice Bulletin No. 61. 2005; 105: 905-18.
Biology of HPV Infection: Low-Grade Lesions
Normal HPV Infection
Cervix (CIN* 1/Condyloma)
New infectious Viral Perinuclear Clearing
Infectious Viral Particles (Koilocytosis)
Particles Episome
Episome
•Smoking
•HIV infection and other host immune factors
•Parity
•Oral contraceptive use
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Ferris et al. Modern Colposcopy. 2004.
HPV Prevalence and Cervical Cancer -
1,2
Incidence by Age
25 25
20 20
15 15
10 10
5 5
0 0
15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54
Age (Years)
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1. Sellors et al. CMAJ. 2000;163:503.
2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000.
Most HPV infections are transient
NCI Portland: HPV persistence
100 amongst 61 initially Pap normal /
HPV 16 positive women
80
% Persistence
60
40
23%
20
0
0 9 15 21 27
Elapsed time in months 21
Schiffman M ASCCP 2002 Biennial Orlando, Fl.
HPV and Anogenital Warts
• HPV 6 and 11 responsible for over
90% of anogenital warts1
• Infectivity upon exposure is over
75%2
• Spontaneous regression can occur in
up to 30% women within 4 months3
• Treatment can be painful and
embarrassing4
– Topical and surgical therapies5
• Recurrence rates vary greatly5
– As low as 5% with podofilox or laser
treatment
Images top left and top right: Reprinted with permission – As high as 65% with other treatments
from NZ DermNet (www.dermnetnz.org).
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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)
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Smith, RA et al. Cancer. 2003;53(1): 27-43.
HPV L1 Virus-Like-Particle (VLP)
Vaccine Synthesis
HPV
L1
gene Inside Empty viral
of HPV HPV capsid (VLP)
DNA
Elicits
immune
response
in host
Transcription
L1 gene is Capsid proteins
inserted into a mRNA
plasmid, which
Translation
is inserted in the
nucleus of a cell
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Eukaryotic Cell
Characteristics of Women who Participated in
the Phase III Quadrivalent HPV Vaccine Trials
Asia Latin North
Total Pacific Europe America America
Day 1 Characteristics (N=20887) (N=748) (N=9181) (N = 5666) (N=5292)
Percent of total 100% 4% 44% 27% 25%
Mean Age 20 21 20 21 20
Non-virgin 94% 96% 92% 99% 93%
Mean Age at Sexual Debut (y) 17 18 17 17 17
Med. Lifetime # of Sex Partners 2 2 2 2 2
Past Pregnancy 23% 25% 7% 51% 16%
Using Hormonal Contraception 58% 50% 68% 46% 55%
Chlamydia (+) 4% 3% 3% 7% 3%
LSIL or HSIL 6% 5% 6% 7% 7%
HPV 6, 11, 16, or 18 (+) 27% 16% 25% 32% 25%
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Prevention of HPV16/18-Related Precancerous
Cervical Lesions (CIN2/3) in a
Susceptible Population
HPV16 and/or HPV18 negative at enrollment
Mean 25 months of follow-up (starting 1 month postdose 1)
† Subjects are counted once per row. Subjects may be counted in >1 row.
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Prevention of HPV6/11/16/18-Related Genital Warts,
and Precancers of the Vagina and Vulva in a
Susceptible Population
HPV6, 11, 16 and/or HPV18 negative at enrollment
Mean 26 months of follow-up (starting 1 month postdose 1)
Placebo
Vaccine Cases† Cases† Vaccine Efficacy
Endpoint (N = 2620) (N = 2628) (95% CI)
HPV 6/11/16/18- Lesions of the 3 59 95% (84, 99)
Vagina and Vulva
Genital warts and other minor 3 53 94%
lesions of the vagina and vulva
Precancer of the vagina or vulva 0 9 100%
(VIN 2/3 or VaIN 2/3)
† Subjects are counted once per row. Subjects may be counted in more than one row.
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Total HPV 6, 11,16, & 18 IgG
Antibody Titers from the Quadrivalent
and Natural Infection Titers
HPV 6 HPV 11
100,000 100,000
Naturally Infected
10,000 Vaccinated 10,000
1,000 1,000
100 100
10 10
0 5 10 15 20 25 30 35 40 45 50 55 0 5 10 15 20 25 30 35 40 45 50 55
10,000 10,000
1,000 1,000
100 100
10 10
0 5 10 15 20 25 30 35 40 45 50 55 0 5 10 15 20 25 30 35 40 45 50 55
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HPV VACCINE: ADVERSE
EVENTS (CDC/ACIP-6/07)
• 5 million doses distributed, 3/07
• 87% in HPV alone; 70% ages 9-26
• Vomitting/syncope/fever/nausea/pain at
injection site
• 1763 adverse events 33/100k reported
94 SAEs – 1.8/100k: 4 deaths, 13 GBS
RECOMMEND: OBSERVE X 15 MIN.
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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
– Vaccine may be less effective
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Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.
HPV Vaccine
ACOG Recommendations
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
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Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.
HPV Vaccine
Important Considerations
Continued screening with Pap tests is mandatory
• Vaccine is most effective if administered
before sexual debut
– Vaccine may be less effective in sexually active
women
• HPV testing prior to initiating vaccine is not
recommended
• Vaccine is not a treatment for current HPV
infection, genital warts, or CIN
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Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.
HPV Vaccine Counseling Points
• Vaccine administration will not cause HPV
– Virus-like particle vaccine (not a live virus)
• HPV vaccines appear to be safe in the vast majority
– Few major adverse events but limited data
• Most side effects are minor
– Injection site reaction
• HPV vaccines are potentially effective in preventing cervical and
other HPV-related cancers
– Sexually active women may still contract HPV genotypes not
covered by the vaccine
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Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.
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.com
• 1-877-VAX-MERCK
• Vaccine Patient Assistance Program
– Vaccines for Children Program
• http://www.cdc.gov/nip/vfc/provider/provider_home.htm
• Storage
– Refrigerated at 2-8°C (36-46°F)
• Consent
– Currently in NYS, minors need parental consent
• Adverse event reporting
– http://vaers.hhs.gov/
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Human Papillomavirus Vaccination. ACOG Committee Opinion No. 344. 2006; 108: 699-705.
2006 ASCCP GUIDELINES
AJOG, OCTOBER, 2007
• Last consensus report – 2001
• Why now?
– 90% use of Liquid based cytology
– Increased use of LEEP as office-based modality
– ALTS trial results and clinical adoption
– Widespread use of Hybrid Capture II HPV
– FDA approval of “HPV-DNA Pap” for >30
– Need for modification in special populations
– Adolescents; Postmenopausal; Pregnant
– Cytologic results have different risks for CIN2/3
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2006 ASCCP GUIDELINES
• SPECIAL POPULATIONS: <20 YO
– Have more minor cytology abns, higher
rate of HPV (+); low risk for invasive cancer
– Most HPV infections clear in 2 years
– DON’T do reflex HPV testing in <20 for
ASCUS or LSIL Paps
– “See and treat” LEEPs are acceptable for
HSIL but not in adolescents
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2006 ASCCP GUIDELINES
• SPECIAL POPULATION: PREGNANT
– Treatment only for invasive cancer
– No Endocervical curettage
– Colposcopic referral to those experienced
with pregnancy evaluations
• SPECIAL POPULATION: POSTMENO.
– Because both HPV (+) and CIN 2/3 decline
with age in women with LSIL, reflex HPV
acceptable after LSIL Pap in PM women
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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. 39
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.
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Questions?
Program sponsored by
The American College of Obstetricians and Gynecologists District II/NY
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Case # 1
28 yr old female with post coital bleeding
• Pelvic exam reveals normal appearing cervix
• Pap smear results LSIL
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Case # 2
45 year old female
• Asymptomatic
• Routine pap results ASC-US
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Case # 2, continued
• Repeat pap at 12 months reveals ASC-US
• Do you perform an HPV test again?
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Case # 3
35 year old female
• Asymptomatic
• Pap reveals AGC
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