Pap Smears, Dysplasia, and HPV

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
History of the Conventional Pap Smear

• Developed by Dr. George N. Papanicolaou in 1940s
• 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.or
g/Cytopaths/1998/cytoFall98.htm
3
Collection Devices

• Broom Device

• Spatula
• Endocervical Brush

Cervical Cytology Screening. ACOG Practice
Bulletin No. 45. 2003 102417-27. All pictures
accessed from http//www.clinilab.fr/cytopathologi
e.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.
20048224-230. 2. Kahn JA. Curr Opin Pediatr.
200113303309. 3. Rager KM et al. Curr Women
Health Rep. 20022468475.
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
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 20024172. Reprinted with the
permission of Elsevier. 2. Apgar BS, Zoschnick
L. Am Fam Physician. 20036819921998. Reprinted
with the permission of the AAFP. 3. Cannistra
SA, Niloff JM. N Engl J Med. 199633410301038.
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. 200228721142119.
7
Cervical Cancer Screening Guidelines

• From ACS, USPSTF, and ACOG
• Account for technologic innovations in cervical
  cancer screening
• Thin-layer liquid-based cytology
• HPV DNA testing
• Specifies screening intervals, start and stop
  rules

Cervical Cytology Screening. ACOG Practice
Bulletin No. 45. 2003 102417-27.
8
Comparison of Guidelines
9
Comparison of Guidelines
1. USPSTF. 2003. Available at http//www.ahrq.gov/
clinic/uspstf/uspscerv.htm. 2. Saslow D et al.
CA Cancer J Clin. 200252342-362. 3. Cervical
Cytology Screening. ACOG Practice Bulletin No.
45. 2003 102417-27.
10
High-Risk HPV TestingACOG 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 102417-27.
11
ALGORITHM PAP HPV GUIDELINES
Women Under 30 years of age Cytology
Negative HPV not done
Women 30 years and older Cytology Negative HPV
done negative x3 consecutive screens
Women 30 years and older Cytology negative HPV
positive
Women any age Cytology ASC-US HPV negative
Women any age Cytology ASC-US HPV Positive
yes
yes
yes
yes
and
Colposcopy
No previous history of CIN 2 or 3,
HIV immunosuppression,or DES exposure in utero
Repeat both liquid based cytology HPV
testing in 6-12 months
Repeat Liquid based Cytology HPV _at_ 12 months
Liquid based Cytology Annually
yes
result
result
result
result
result
There is no role for the use of routine HPV
screening in women of this age group.
Cytology HPV Both Negative
Cytology ASC-US HPV negative
Cytology negative HPV positive
result
Cytology ASC-US or Greater HPV negative
Liquid based Cytology every 2-3 yrs
Cytology Negative HPV Negative
Any Cytology Positive HPV
yes
yes
yes
yes
yes
Routine rescreening in 2-3 years
Rescreen with liquid based cytology HPV _at_ 12
months
Colposcopy
Colposcopy
Repeat Cytology _at_ 12 months
12
Human Papillomavirus (HPV)

• Over 100 types identified2
• 3040 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 200121972229. Picture
reprinted with the permission of
Lippincott-Raven. 2. Schiffman M, Castle PE.
Arch Pathol Lab Med. 2003127930934. 3. Wiley
DJ, Douglas J, Beutner K, et al. Clin Infect Dis.
200235(suppl 2)S210S224. 4. Winer RL et al. Am
J Epidemiol. 2003 157218-226. 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.
199926(suppl)S2S7.
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
Cancer Type
González Intxaurraga MA et al. Acta
Dermatovenerol. 20021118.
15
Common HPV Types Associated With Benign and
Malignant Disease
HPV Types
Manifestations
HPV 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81
Benign low-grade cervical changes Condylomata
acuminata (Genital warts)
Low-Risk



Low-grade cervical changes High-grade cervical
changes Cervical cancer Anogenital and other
cancers
High-Risk
HPV 16, 18,-31, -33, 35, 39, 45, 51, 52, 56, 58,
59, 68, 73, 82
1. Cox. Baillières Clin Obstet Gynaecol.
199591.2. Munoz et al. N Engl J Med.
2003348518.
16
(No Transcript)
17
(No Transcript)
18
(No Transcript)
19
(No Transcript)
20
(No Transcript)
21
NCI Portland HPV persistence amongst 61
initially Pap normal / HPV 16 positive women
Most HPV infections are transient
100
80
60
Persistence
40
23
20
0
9
15
21
27
0
Elapsed time in months
Schiffman M ASCCP 2002 Biennial Orlando, Fl.
22
HPV Prevalence and Cervical Cancer - Incidence by
Age 1,2
Cancer incidence per 100,000
HPV Prevalence ()
Age (Years)
1. Sellors et al. CMAJ. 2000163503. 2. Ries et
al. Surveillance, Epidemiology and End Results
(SEER) Cancer Stats NCI, 1973-1997. 2000.
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

Long persistence of high risk HPV is necessary
for the accumulation of mutations that lead to
cancer
Cancer
CIN 3
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. 200353(1) 27-43.
25
HPV L1 Virus-Like-Particle (VLP) Vaccine
Synthesis
HPV
L1 gene of HPV DNA
Empty viral capsid (VLP)
Inside HPV
Elicits immune response in host
Transcription
Capsid proteins
L1 gene is inserted into a plasmid, which is
inserted in the nucleus of a cell
mRNA
Translation
Eukaryotic Cell
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.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 2-8C (36-46F)
• 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
Summary of US Vaccine Recommendations
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
aACIP Advisory Committee on Immunization
Practices. bACOG American College of
Obstetricians and Gynecologists. cAAFP American
Academy of Family Physicians. dAAP
American Academy of Pediatrics.
1. Centers for Disease Control and Prevention.
MMWR Morb Mortal Wkly Rep. 200756(RR-2)124. 2.
American College of Obstetricians and
Gynecologists (ACOG). Obstet Gynecol.
2006108(3)699705. 3. Department of Health and
Human Services, Centers for Disease Control and
Prevention. Recommended immunization schedule for
persons aged 718 years, United States, 2008.
http//www.cispimmunize.org/IZSchedule_
Adolescent.pdf. Accessed July 14, 2008.
4. Committee on Infectious Diseases.
Pediatrics. 2007120(3)666668.
28
The Most Effective Time to Vaccinate Is Before
Exposure1
Behavior Reported in an Independent Study
100
Suggests minimal exposureto HPV at9 to 11years
of age
80
60
Cohorts that have had intercourse,
40
20
1415
1617
1213
lt11
Age at first intercourse, Years
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 (n1,014) featured in this
chart reported having engaged in sexual
intercourse.2
1. Centers for Disease Control and Prevention.
MMWR. 200251(RR-6)180. 2. Hoff T et al.
National Survey of Adolescents and Young Adults
Sexual Health Knowledge, Attitudes and
Experiences. Henry J. Kaiser Family
Foundation200314.
29
Exposure to HPV at a Young Age Increases the Risk
of Cervical Lesions and Cancer in Women
Relative risks for CIN and invasive cancer
increase with decreasing age of first sexual
intercourse.
Age at first intercourse, Years
Reference population First intercourse ?23
years of age or never
(n206)
(n327)
Mantle-Haenszel estimates adjusted for age
only.La Vecchia C et al. Cancer.
198658935941.
30
Total HPV 6, 11,16, 18 IgG Antibody Titers from
the Quadrivalent and Natural Infection Titers
31
(No Transcript)
32
(No Transcript)
33
(No Transcript)
34
(No Transcript)
35
(No Transcript)
36
HPV VaccineACOG 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

Human Papillomavirus Vaccination. ACOG Committee
Opinion No. 344. 2006 108 699-705.
37
HPV VaccineACOG 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

Human Papillomavirus Vaccination. ACOG Committee
Opinion No. 344. 2006 108 699-705.
38
(No Transcript)
39
HPV Vaccination Monitoring Short- and Long-Term
Impact
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.

40
41
Monitoring Short- and Long-Term Impact of HPV
Vaccination
41
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 gt375,000 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 events1
• 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 criticial2

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 YouQuestions?

• Nicholas Montalto Jr, MD, FACOG
• Albany Gynecology and Fertility
• CNY Fertility Centers
• Division of Minimally Invasive Surgery
• www.albanygyn.com