Pap Smear, HPV and HPV Vaccine







Peggy JB Scurry, MD, Ph.D. FACOG, FACS
Assistant Professor & Chief of Gynecology
Howard University
Department of Obstetrics & Gynecology
http://pscurrymd.scurtek.net
National Medical Association Annual Conference
August 2007
Objectives

After completing the lecture, participants should be able to:

Identify the risks of acquiring HPV infection
Describe the role of HPV in low-and high grade cervical lesions,
cervical cancer and genital warts
Understand the appropriate clinical triage of patients with
abnormal Pap smear results based on the Bethesda 2001 System
and ACOG guidelines
Understand the efficacy of HPV DNA testing as an adjunct to
conventional screening methods
Understand conservative management of abnormal pap smears
for adolescents and menopausal women
Evaluate the new HPV Vaccine and counsel patients





What are Common patient
questions about HPV?








What is the difference between a Pap smear and an
HPV test?
How do you get HPV?
How can I reduce the risk of getting HPV?
If I’m treated, can my partner reinfect me?
Does the diagnosis of HPV mean that my partner
cheated?
Will I always have HPV?
How often should I be tested?
Is there a vaccine for HPV?
Pap Smear Facts






More than 50 million Pap smears are performed on
American women every year
With the use of Pap Smear screening programs, the
incidence of cervical cancer has been reduced by
75%
False-negative reports are as high as 40%
One half of women who are diagnosed with cervical
cancer have never had a Pap smear
An estimated 5 to 10% of Pap smears are interpreted
as abnormal
ASCUS & LGSIL reports constitute over 95% of
abnormal Pap smears
Impact of the Bethesda System
2005
Natural History of the Minimally
Abnormal Pap Smear
ASCUS
LGSIL
53.8%
78.3%
46.2%
Regress
Persist
Progress
18.2%
3.4%
Comparison of
Classification
Bethesda System
Classic System
Modified Pap
Normal
I
Inflammatory
atypia
(organism)
II
Within Normal Limits
Infection
organism should
be specified
Reactive &
reparative
changes
Comparison of Classification
Squamus Cell Abnormalities
Bethesda System
Classic System
Atypical squamus cells of
undetermined significance
ASCU- H
ASCU- G
Squamus atypia of
uncertain significance
Low-grade squamus
intraepithelial lesion (LGSIL)
HPV Atypia
Mild dysplasia
High-grade squamus
intraepithelial lesion(HGSIL)
Moderate dysplasia
Severe dysplasia
Carcinoma in situ
Squamus cell cancer
Squamus cell ca
Modified PAP
IIR
CIN 1
IIR
III
CIN 2
CIN 3
III
IV
V
Liquid Base Cytology





detection of cervical disease
Fewer cases of “obscuring features” and
unsatisfactory test
More amenable to automation
Allows for reflex testing of residual fluid for
High Risk HPV testing
Allows for chlamydia and GC testing from the
liquid
Why test for HPV?

It helps to clarify ambiguous cytology results and
identifies persistent infection in women over 30

HPV Testing, when combined with the Pap test, is
more sensitive in determining the presence of disease
than a pap test alone
Manos MM. et al. JAMA. 1999:281:1605-1610.
Clavel C. et al. Brit J Cancer. 2001:89:1616-1623.
HPV




Nonenveloped double-stranded cicular DNA virus
Only effect epithelial cell
100 types identified – species specific
30-40 anogenital
–
–


15-20 oncogenic types, including 16, 18, 31, 33, 35, 39,
45,51,52, 58
HPV 16 (54%) and HPV 18 (13%) account for the majority of
worldwide cervical cancers
Nononcogenic types include 6,11,40,42,43,44,
HPV 6 and 11 are most often associated with
external anogenital warts
HPV & Cervical Cancer, Merk Vaccine Div.,2005
Education about HPV







HPV causes cervical cancer
70% of women get HPV infections
Transmitted by skin to skin contact
HPV can remain dormant for years
Most HPV infections are usually transient &
assymptomatic
HPV is not a disease, it is only a virus that may cause
disease manifestations seen as CIN
While HPV is common, cancer is rare
Education about HPV
About 70% of women of all ages will clear an HPV
infection within 1 year
 90% of women will clear the infection within 2 yrs.
 However, in adolescents (14-17yrs old)
they required a longer time to clear, i.e. 12 mos and 3
yrs when compared to adults
 This study found that only 3% of LGSIL progressed to
high grade lesions by 36 mos.

Lancet 2004:364:1678-83.
HPV




Epidemiology
HPV DNA has been found in 99.7% of cases of highgrade CIN and invasive cervical cancer
HPV detection is associated with a minimum 250X
increased risk of HGSIL
HPV 16 is the most common cancer-associated HPV
type:other types 18,31,33,35,39,51,52,56,58
Persistent HPV infection produces chronic cervical
dysplasia
Pathogenesis of Cervical Cancer
HPV Infection
Persistent
HPV Infection
Immunologic
Factors
Cellular
Dysregulation
High-Grade CIN
Invasive Cancer
Co- carcinogens
HPV Mode of Transmission








Sexual Intercourse
Non-penetrative Sexual activities
Perinatal transmission
Transmission through fomites
Early age of first intercourse
Multiple sex partners or partner with Msp
Smoke cigarettes
Oral Contraceptives
Impact of Persistence of Oncogenic
HPV Types


Persistent infection with high-risk HPV types is
necessary for the development of CIN 3
There is a strong relationship between persistent highrisk HPV infections (particularly with HPV 16 and `18)
and SIL/HSIL incidence
–
–
–
Infections with high-risk types are more likely to persist than
infections with low-risk types
A study of HPV persistence reported that HPV 16 infections
persist longer than infections with other types
The persistence of high-risk types of HPV infections
increases the risk of HSIL and is necessary for the
development of CIN 3
Why test only women 30 and older
for HPV



HPV testing in women less than 30 is not effective due
to high prevalence and transient infections
HPV prevalence decreases in women age 30 and older
Cervical cancer incidence increases for women age 30
and older
Saslow D. et al. CANCER 52(6)342-362.
Meikert PW. Et al. Int J Cancer. 1993.53.919-923.
FDA Approval for HPV Testing

Two FDA- approved indications

Reflex testing ASCUS triage for women of any
age with inconclusive Pap results
Primary adjunctive screening with a Pap test
for women age 30 and older to detect the
presence or absence of High-risk HPV

HPV DNA Detection

Hybrid Capture 2 High-risk HPV Test
–
–
–
–
–
–
The Digene HPV Test
Commercially available, FDA approved
Two Probe mixing
High Risk – 16,18,31,33,35,39,45,51,52,56,58
Low Risk – 6,11,42,43,44
Sensitivity is about 5,000 copies of HPV-DNA
Reflex HPV DNA Test Advantages






No need for patient to RTO for additional testing
Immediately inform patient of their risk status reassurance if negative
Cost effective compared to other managements
More sensitive than cytology
More reproducible than cytology
Very high negative predictive value
HPV FACTS




Most women will have HPV at some point, but very few
will develop cervical cancer
Most HPV infections are temporary and go away on
their own
Only HPV infections that do not go away over many
years can lead to cervical cancer
While regular Pap tests have been successful in
preventing many cervical cancers by finding cell
changes early, some women at risk may be missed
Management of Minimally
Abnormal Pap



PAP nl cytology & (-) HPV = RS at 2- 3 yrs
PAP nl cytology & (+) HPV= Repeat 6-12 m
Risk of cervical cancer associated with extending the
interval between cervical cancer screening (Women
30-64 yr)
LESS Than 3 in 100,000
Excess risk of cervical cancer
Management of Screen Positives


ASCUS may be managed by referral to
immediate colposcopy, by repeat Pap smear,
or by HPV testing.
Reflex HPV testing when ASCUS is derived
from liquid based cytology has advantage
–
–
ASCUS (+) & HPV +
ASCUS (+) & HPV -
Colposcopy
Repeat Pap @ 12 mos
Management of Screen Positives


Initial management of all other Pap
abnormalities is by immediate referral to
colposcopy
finding of atypical squamous cells cannot rule
out high-grade (ASC-H), atypical glandular
cells (AGC), LGSIL, and high-grade
intraepithelial lesions (HGSIL)
Adolescents & LGSIL



Best to be less aggressive with treatment
A large percentage of lesion regress
spontaneously
Intervention treatment leads to:
–
–
–
–
*Increase risk of Preterm Labor
*Low birth weight infants
*Cervical Incompetence
*Detrimental to future fertility
Management of Screen Positives


CIN 2/3 should usually be treated, both
guidelines say.
The only exception is the adolescent with CIN
2, who may be followed with repeat cytology
and colposcopy at 4 to 6 months if she is
deemed reliable for follow-up, the colposcopy
is adequate, and the endocervical sampling
negative
Management of Screen Positives


Women treated for CIN 2/3 can be monitored
after treatment by cytology screening at 6
month intervals 3 or 4 times or by a single HPV
test at 6 month, before returning to annual
screening.
Any repeat abnormal Pap at the threshold of
ASCUS or more advanced abnormality or a
positive HPV test requires colposcopic
evaluation
Management of Screen Positives


An excisional procedure is required for abnormal
findings, or an unsatisfactory colposcopy in non
pregnant women referred for atypical glandular cells
“favor neoplasia” (AGC-H), or adenocarcinoma in situ
(AIS), or repeat atypical glandular cell “not otherwise
specified: (AGC-NOS), or HGSIL.
The only exception is an adolescent with HGSIL
cytology and a satisfactory and normal colposcopy and
biopsy, who may be followed closely
Genital Warts - Diagnosis




Diagnosis of genital warts are made by visual
inspection
The use of HPV tests is not indicated for the routine
diagnosis or management of visible genital warts
A genital warts diagnosis may be confirmed by biopsy,
although biopsy is needed only in certain
circumstances
HPV 6 and 11 are most often associated with
nononcogenic types of external anogenital warts
Genital Warts - Treatment




If left untreated, genital warts may resolve on their own,
remain unchanged or increase in size or number
The primary goal of treating visible genital warts is
removal for cosmetic reasons
In most patients, treatment can remove warts however,
recurrences are frequent
Some patients may forego treatment as genital warts
may resolve on their own
Genital Warts - Treatment
Regimens



A number of treatment options are available for visible
genital warts
Factors which may influence the selection of treatment
include patient preference, available resources,
provider experience, the size, number, anatomic site,
and morphology of warts and the cost, convenience,
and adverse effects of treatment
Providers should have at least one patient-applied and
one provider applied treatment
Genital Warts - Recommended
Treatment Regimens

Patient-Applied
Treatments




Podofilox 0.5% solution
or gel
Imiquimod 5% cream



Provider-Applied
Treatments
Cryotherapy
Podophyllin resin
Trichloroacetic Acid or
Bichloroacetic Acid 80%90%
Surgical Removal by
electrosurgery
HPV Vaccines



HPV Vaccines will stop CIN 2/3 and cancer
The HPV 16 vaccine provided 100% protection
against development of HPV 16 related CIN
2/3 during an average of 3.5 yrs of follow-up
Although the target is children, many women
will want HPV vaccination – creating a “catchup challenge for doctors
The Digene HPV Test



Test for a panel of the 13 most common HPV
types known to cause cervical cancer, but does
not report of individual types
Digene is nearly ready to launch a 16, 18, 45
type-specific “reflex” test (to a positive Hybrid
Capture 2 HPV panel)
Roche is preparing to get its type-specific
Linear Array HPV test approved
Quadrivalent 6,11,16,18 trial
AKA Gardasil



The study reached an average of 3.5 years of
follow-up
CIN 2/3 developed in 12 of the 750 women
receiving placebo, in contrast to none of the
755 vaccine recipients
It may be that if an immune response has not
been mounted, the vaccine may still have a
positive effect for women already HPV 16
infected
Quadrivalent HPV Vaccine





Protects against four HPV types (6,11,16,18)
These HPV types are responsible for 70% of cervical
cancers & 90% of genital warts
The vaccine is admin thru a series of injections over a
six month period (at 1,2 and 6 months)
Current studies indicate the vaccine is effective for at
least five years (with 5 yr follow-up)
The private sector list price of the vaccine is $120 per
dose (about $360 for the full series)
Quadrivalent HPV Vaccine







Testing for HPV is currently not recommended before
vaccination
Testing for HPV DNA would not identify past HPV
infections, only current HPV infections
The vaccine is a preventive tool and is not a substitute
for cancer screening
The quad HPV vaccine has been classified by the FDA
as pregnancy category B
Its use in pregnancy is not recommended
Lactating women can receive the vaccine
It is not known whether vaccine Ag or Ab found in the
vaccine are excreted in human milk
Quadrivalent HPV Vaccine




Vaccination of women older than 26 yrs and males is
currently under way.
The presence of immunosuppression is not a
contraindication to the vaccine
However, the immune response may be smaller than in
the immunocompetent patient
Women with previous HPV infection will benefit from
protection against disease caused by the HPV vaccine
genotypes with which they have not been infected
Quadrivalent HPV Vaccine


Genital infection with low-risk types of HPV is
associated with genital warts in men
Infection with high-risk types of HPV is
associated preinvasive squamous lesions of
the penis (penile intraepithelial neoplasm or
PIN) and with penile cancer and anal
intraepithelial neoplasia or AIN and with anal
cancer
Who will be vaccinated?


The primary target group for the HPV vaccine
is young people from 9-26 yrs old & before
sexual encounter
Many women already sexually active will likely
want to be vaccinated
Quadrivalent vaccine 100% 99.7% effective!


The trial became center stage in the world
media in early Oct. 2005, with headlines such
as first anti-cancer vaccine 100% effective.
The results were truly astounding, as there
were no CIN 2/3 cases in the Per Protocol
group, among the 5,301 women vaccinated, in
contrast to 21 cases in the 5,258 women who
received the placebo
Table
Gardasil and Cervarix vaccines


Now the challenge will be in getting the
population vaccinated. Merck has its Gardasil
Quadrivalent vaccine on the market
GlaxoSmithKline expects to put cervarix
Bivalent HPV 16,18 vaccine on the market in
late 2007
How HPV vaccine will and won’t
change practice




We will continue screening long after the
advent of multivalent HPV vaccines
To prevent the 30% of cancers linked to highrisk HPV types that are not in the vaccine
To protect the unvaccinated
To protect the previously HPV infected pt
Cervical screening will continue,
but will be more accurate and more
efficient


We are on the verge of reducing the risk of
cervical cancer to close to zero, but it will take
decades
Vaccinating young girls will not significantly
reduce cervical cancer rates until these girls
reach the median ages of microinvasive and
invasive cervical cancer
Cervical cancer rates will depend
on these factors




The extent of vaccination coverage
The number of high-risk HPV types in the
vaccine
Whether vaccination provides multidecade
protection or falls off with time
Whether the medical community and the public
continue to diligently follow recommended
screening guidelines
Fewer abnormal Paps
The vaccine will likely steadily decrease the rate
of abnormal paps that are important, as an
increasing proportion of women are vaccinated
against the 2 most common types in highgrade CIN
Colposcopies and cervical treatment will decline
in number with the proportion of the populated
vaccinated
Specific testing

Finding women with significant abnormalities
may more and more be accomplished with the
accuracy afforded by testing for specific HPV
types known to be most at risk for CIN 3
Improving folate status protects
against HPV



Improving folate status in women at risk of
getting infected or already infected with highrisk HPV may help prevent cervical cancer.
It is reasonable to advise women with HPV that
folate supplements may be helpful
Women with higher folate status were
significantly less likely to be repeatedly HPV
positive over a 2 year follow-up
Questions
1. The development of cervical cancer is thought to require which of
the following?

–
–
–
–
a. Infection with any human papillomavirus
b. Persistent infection with select HPV types
c. Sustained immune deficiency
d. Prolonged use of oral contraceptives
Questions

2. The 2001 Consensus Guidelines for women
with cervical abnormality recommends which
modality as the preferred approach to manage
patients with an ASCUS Pap result?
–
A.
– B.
– C.
– D.
Repeating the pap test times 2
Testing for high-risk types of HPV
Immediate coloposcopy
Follow closely
Questions

3. The CDC estimates what percent of
sexually active women will be infected with
HPV by the age of 50.
–
A.
– B.
– C.
– D.
50%
60
70%
80%
Questions

4. Which of the following were associated with
HPV vaccine acceptance among young
women.
–
A. Knowledge about HPV and the vaccine
– B. Belief that others would approve of vaccination
– C. Perceived support from health care providers, partners
and parents
--D. All of the above.
Questions

5. Ms. Smith claims she has been in a monogamous
relationship for several years. She cannot understand
why she has recently developed an uncomfortable
cauliflower like lesion on the labia majora. She is
concerned that her sex partner has been unfaithful
recently. She believes that a positive HPV infection
is an indication of infidelity. Ms. Smith’s belief is likely
to be correct.
A. True
B. False
Questions

6. Among women, risk of acquiring HPV
infection is most strongly associated with which
of the following?
A.
B.
C.
D.
Smoking
Number of full-term pregnancies
Number of life time sexual partners
Immunosupression
Questions

7. Most HPV infections resolve spontaneously
and cause no symptoms.
A. True
B. False
Questions

8. HPV 16 and 18 together cause what
proportion of cervical cancers?
A.
B.
C.
D.
40%
50%
60%
70%
Questions

9. What two HPV types are responsible for
nearly 97% of genital warts?
A.
B.
C.
D.
HPV 6 and 11
HPV 31 and 35
HPV 45 and 51
HPV 16 and 18
Questions

10. Sexually active young adults are known to
be at the highest risk of contracting HPV
infection. Prevalence is particularly high
among 15 – 26 year old women. Therefore, all
young women should be tested for the HPV
infection.
A. True
B. False
Answers to Questions





1.
2.
3.
4.
5.
B
B
C
D
B
6. C
7. A
8. D
9. A
10. B
Answer these commonly asked
questions for your patients








What is the difference between a Pap smear and HPV Test?
How do you get HPV?
How can I reduce the risk of getting HPV?
If I'm treated, can my partner reinfect me?
Does the diagnosis of HPV mean that my partner cheated?
Will I always have HPV?
How often should I be treated?
Is there a vaccine for HPV?
New Pap Smear Classification and HPV Diagnosis
and Rx
References

ACOG Practice Bulletin, Number 61. Human papillomavirus.
Washington, DC: American College of OB/GYN: April 2005.

ACOG Practice Bulletin, Number 45. Cervical cytology screening.
Washington, DC: American College of OB/GYN;2003

ACOG Committee Opinion, Number 330.Evaluation and
Management of Abnormal Cervical Cytology and Histology in the
Adolescent.American College of OB?GYN;Obstet Gynecol
2006;107:963-8.
New Pap Smear Classification and HPV Diagnosis
and Rx
References

REFERENCES

APGO Educational Series, Advances in the Screening, Diagnosis, and
treatment of Cervical Cancer:Assoc. of Professors of Gynecology and
Obstetrics:20002

Clavel C, Masure M, Bory JP, et al. Human papillomavirus testing in
primal screening for the detection of high-grade cervical lesions: a study
of 793 women. Br J Cancer. 2001;89:1616-1623.

Cuzick J, Szarewski A, Cuble H, et al. Management of women who test
positive for high –risk types of human papillomavirus: the HART study.
Lan 2003;362:1871-1876.
New Pap Smear Classification and HPV Diagnosis &
Rx
References

Brown DR, Shew ML,Qadadri B, et al. Alongitudinal study of genital
human pappillonavirus infections in a cohort of closely followed
adolescent women. J Infect Dis.2005;191:182-92.

Franco, El, Harper DM. Vaccination against human papillomavirus
infection: a new paradigm in cervical cancer control.
Vaccine.2005;23:2388-2394
New Pap Smear Classification HPV Diagnosis Rx
References

Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10 year risk of
cervical precancer and cancer in women with HPV type 16 or 18 and the
possible utility of type-specific HPV testing in clinical practice. J Nat'l
Cancer Inst. 2005;97:1072-1079.

Plyathilake CJ, Henao OL, Macaluso Mm et al. Folate is associated with
the natural history of high risk human papillomaviruses Caner Res.
2004;64:8788-8793.
New Pap Smear Classification and HPV Diagnosis
and Rx
References

Saslow D, Runowicz CD, Solomon D, et al. American Cancer Society
guide for the early detection of cervical neoplasia and cancer. AC Cancer
J. Clin. 2002;52:342-362.

Wright TC, Jr., Cox JT, Massad LS, Carlson J, Twiggs LB, Wilkinson EJ.
2003 consensus guidelines for the management of of women with
cervical intraepithelial neoplasia. Am. J Obstet Gynecol. 2003;189:295304.
New Pap Smear Classification and HPV Diagnosis
and Rx
References

Wright TC, Jr., Schiffman M, Solomon D, et al. Interim guidance of the
use of human papillomavirus DNA testing as an adjunct to cervical
cytology for screening. Obstet Gynecol. 2004;103:304-309.

Wright, TC Jr, Schiffman M, Solomon D,et al. Interim guidance for the use
of human papillomavirus DNA testing as an adjunct to cervical cytology
for screening. Obstet Gynecol. 2004;103:304-309