KrisEmily McCrory, MD
Objectives:
 Review cervical cancer epidemiology and
pathophysiology
 Identify the role of the Human Papilloma Virus in
cervical cancer
 Explain the use of HPV testing in cervical cancer
screening
 Describe current recommendations for cervical cancer
screening
EPIDEMIOLOGY
Incidence of cervical cancer worldwide:
 530,000 cases annually
 275,000 deaths annually
 Mortality of 52%
Incidence of cervical cancer in the United States:
 12,170 cases of invasive cancer annually
 4220 deaths from cervical cancer
Screening programs in the United States have
significantly reduced the mortality of cervical cancer
in this country.
Since development of the PAP smear, the rate of
cervical cancer in the United States has declined by
75% in the past 50 years.
In the United States:
 50% of cervical cancers are diagnosed in women who
were NEVER screened.
 10% are diagnosed in women who were NOT screened
in previous five years.
 10% are diagnosed in women in lacking adequate
follow up of an abnormal PAP.
Risk factors for cervical cancer:
 Multiple sexual partners
 Early age of sexual initiation
 Multiparity (>3)
 Immunodeficiency
 Smoking
 Early onset parity (<20 yo)
 h/o STDs
 Low socioeconomic status
 Non white race
HUMAN PAPILLOMA VIRUS
(HPV)
HPV: Most common sexually transmitted infection
Precursor to 99.7% of all cervical cancers
Also implicated in:




Common warts
Plantar warts
Genital warts
Bowen’s disease
HPV oncogenic subtypes:
 HPV 16 associated with 50-60% of cervical cancers
 HPV 18 associated with 10-15% of cervical cancers
 Ten other HPV strains associated with remaining 25-35%
of cervical cancers
HPV prevalence
 64% of urban adolescent females
 40% of women aged 18-40
Lifetime risk for women is 80%
Most common in teenagers and young adults
In one study, 43% of college aged women who initially
tested negative proceeded to test positive within three
years.
HPV transmission
 Primarily through sexual contact



Oral sex
Vaginal intercourse
Anal intercourse
 Also through genital skin to skin contact
Condoms reduce but do not eliminate the risk!
HPV link in cervical cancer
Infection with HPV is virtually required for the
development of cervical cancer, but most HPV
infections do NOT go onto to develop clinically
significant cervical abnormalities.
Transient nature of HPV
90% of infections are transient and are undetectable in
1-2 years.
It is that 10% of infections that persist that we need to
worry about. These have a 20-30%
chance of becoming CIN3 within
the following five years.
PATHOPHYSIOLOGY
SCREENING
When done correctly screening has the potential to
reduce rates of cervical cancer by 60-90% within three
years.
Things to consider when developing cervical cancer
screening guidelines:
 Cannot prevent 100% of cervical cancers as no
screening test is capable of finding all cancers
 Need to define the benefits and harms clearly to
compare different screening techniques
Defining Benefits:
Compare the new techniques to the prior technique.
Screening that is able to achieve the same or better
reduction in incidence of or mortality from cervical
cancer may be a better choice.
In development of the new guidelines the
organizations looked at detection of CIN3 as a
measure of sensitivity of the screening technique.
Benchmark for cervical cancer screening at time of the
development of these guidelines was cytology alone
every 2-3 years.
Benefits:
Earlier identification of cancer causing lesions


Untreated, CIN3 has 30% risk of invasive cancer
Treated, CIN3 has only 1% risk of invasive cancer
Decrease in the incidence of CIN3/cervical cancer
Decrease in mortality from cervical cancer
Defining Harms:
Identify harms in current screening as well as potential
harms in new screening technique.
Harms:
Detection/treatment of lesions that would have
regressed on their own (false positive) leading to:
 More frequent testing
 More frequent invasive diagnostic procedures
 Colposcopy
 Cervical biopsy
 Anxiety/Distress
 Unnecessary treatment of benign lesions
 Cold knife conization
 Loop excision
Harms:
Coloposcopy is used as
marker of harms because it is
associated with physical
discomfort, psychological
stress, and is a pre-requisite
for invasive treatment.
Tools for cervical cancer screening:
 Cytological screening
 HPV testing
Cytology (PAP smear)
Two types available:
 Conventional
 Liquid based (ThinPrep)
No group has found a clinically significant difference
between the two.
Benefit of ThinPrep is ability to do HPV co-testing,
gonorrhea, and chlamydia.
HPV testing
Tests for 13 high-risk subtypes of HPV
Sensitivity for HPV is 88-100%
Greater reproducibility compared to cytology
HPV testing has a greater negative predictive value for
CIN3+ compared to cytology
HPV testing
Increased sensitivity (>90%) for CIN2/CIN3 compared to
cytology alone but a lower specificity so more potential
false positives.
Increased false positives leads to a potential for
increased harms when utilizing HPV test alone
Appropriate use of HPV in cervical cancer screening:
 Use for triaging ASCUS cytology in any age group:
Most ASCUS (56.5%) is associate with normal
histology.
HPV neg/ASCUS has a very low risk of
precancerous lesions (<2%)
 Co testing in women between 30-65
The ultimate goal is to utilize PAP and HPV testing
in such a way that maximizes good patient
outcomes and minimizes risk.
In one study, only 22% of clinicians (including FPs,
OBGYNs, and IMs) were able to correctly identify:
Who to screen
 When to screen
 When to stop screening

Organizations:
American Society for Colpscopy and Cervical Pathology
(ASCCP)
United States Preventive Task Force (USPTF)
American College of Obstetricians-Gynecologists
(ACOG)
Guidelines
1.
2.
3.
4.
5.
When to start screening for cervical cancer?
How often to screen for cervical cancer?
When is HPV testing appropriate?
When to discontinue testing?
Does cervical cancer vaccination alter screening for
cervical cancer?
When to start screening?
Considerations:
 Cervical cancer is rare in adolescents
 0.1% of all cervical cancers
 1-2/1,000,000 women aged 15-19
 HPV in this population is almost always transient and
resolves spontaneously
 Dysplasia in this age group usually regresses without
treatment
Dysplasia in adolescents:
 Women aged 18-22 with LSIL
 61% were negative by one year
 91% were negative by three years

Only 3% progressed to CIN3
 Women aged 18-22 with CIN2
 65% negative by eighteen months
 75% negative by three years
Lack of benefits to screening adolescents:
 Despite screening in this age group over four decades, there
has been NO improvement in incidence of cervical cancer
in adolescents.
 Cervical cancers in the age group are often more aggressive
and don’t seem to be preventable by current screening
abilities.
 There is no difference in mortality/incidence of cervical
cancer if screening delayed until 21 years of age.
Harms associated with screening adolescents:
 High potential for harm from diagnosing/treating
precancerous lesions with a high probability of selfresolution.
 Anxiety associated with a positive cancer screen
 Potential stigmatization from diagnosis with STD
 Additional discomfort from further
diagnostic/treatment procedures
 Increased risk of preterm delivery following treatment
Overall screening adolescents is associated with
minimal benefit and great potential for harm.
All three groups recommend waiting to screen until
age 21 regardless of sexual history.
Already screened your adolescent patient and got
abnormal results?
Cytology: Only need to proceed to colposcopy if HSIL
HPV: Positive results should not determine managment
How often to screen?
Annual screening:
Associated with $7.5 billion in health care costs
Little to no evidence to support annual screening at any age
by any modality
Annual screening has never been shown to be cost effective
Ultimately screening should be determined by age and
clinical history.
Age-specific guidelines recognizes that women of different
ages have different trade-of between harms and benefits.
Ages 21-29
Incidence of cancers in 21-29 yo with varying screening
intervals:
Annual screening: 3 cancers/1000 women
Biennial screening: 4-6 cancers/1000 women
Triennial screening: 5-8 cancers/1000 women
Predicted lifetime risk of death secondary to cervical
cancer in women aged 21-29 with varying screening
intervals:
Annual screening: 0.03 deaths/1000 women
Biennial screening: 0.05 deaths/1000 women
Triennial screening: 0.05 deaths/1000 women
Lifetime risk of colposcopy based on varying screening
intervals:
Annual screening: 2000 colposcopies/1000 women
Biennial screening: 1040 colposcopies/1000 women
Triennial screening: 760 colposcopies/1000 women
Screening every three years has an approximately
equal risk of death from cervical cancer compared to
annual screening but decreases the harm from
colposcopy (and the potential for further intervention)
by 40%.
ASCCP recommends screening with cytology alone every
three years
USPTF recommends screening with cytology alone every
three years
ACOG recommends screening with cytology alone every
two years
HPV co-testing in the age group is not recommended by
any of the three organizations.
 High prevalence of HPV in this age group increases the
risk of identification of benign lesions
 Higher likelihood of regression of precancerous lesions
 Low incidence of cervical cancer at this age
Ages 30-65
HPV has 37% greater sensitivity for CIN3+ compared to cytology
alone.
Review of four RCTs compared cytology to co-testing:
Two rounds of screening:
First round: Co-testing found more CIN3+
compared to cytology
Second round: Decreased incidence of
CIN3+
Overall diagnosis of CIN3 comparable but most
diagnosed in first round with co-testing
Six year risks of CIN3+ following:
Negative cytology 0.97%
Negative HPV 0.27%
Negative co-test 0.28%
HPV and co-testing has a greater negative predictive
value compared to cytology.
 Co-testing diagnoses more CIN3 than cytology alone.
 Co-testing at the same interval as cytology also
increases the number a false positives, colposcopies,
and other potential harms.
 Lifetime cancer risk:
Cytology every 3 years: 0.69%
Co-testing every 5 years: 0.61%
 Five year incidence of cervical cancer:
Negative cytology: 7.5/100,000
Negative co-testing: 5.2/100,000
Three year risk of CIN3:
Following negative cytology: 0.17%
Five year risk of CIN3+:
Following negative HPV: 0.16%
Following negative co-testing: 0.17%
Three year risk of CIN3/cancer following negative
cytology is virtually identical to the five year risk
following a negative co-test.
In a cohort of 100 women receiving co-testing every
five years had fewer lifetime colposcopies compared to
cytology alone every three years :
Co-testing every five years: 575 colposcopies
Cytology every three years: 758 colposcopies
Earlier diagnosis of high grade lesions with co-testing
is beneficial and by lengthening the screening interval
the harms of solo HPV testing are mitigated.
ASCCP
Preferred: Cytology with HPV co-testing every five years
Acceptable: Cytology alone every three years
USPTF
Cytology with HPV co-testing every five years with a note
that similar benefits of cytology alone every three years
ACOG
Cytology every three years if there have been three
consecutive negative cytologies
Further benefits of HPV testing: Adenocarcinoma
Cytology provides only modest protection against
adenocarcinoma

HPV detects 93% of adenocarcinomas

63% of adencarcinomas diagnosed in a five year period had an
HPV+/cytology negative co-test
HPV+/Cytology Negative Co-test
Prevalence in women over 30: 3.4-8.5%
12 month risk of CIN3: 0.8-4%
12 month risk of cancer: 0.08%
HPV+/cytology negative co-test:
Management Options:
 Repeat co-testing in 12 months
 Most infection that are transient will clear in that time
 At time of repeat co-testing
 Positive on either HPV/cytology refer to colposcopy
 Negative on both return to routine screening
 Immediate HPV genotype specific testing for HPV 16 or
16/18


Positive for either HPV 16 or 16/18 refer to colposcopy
Negative for both then co-test in 12 months
When to stop screening?
Considerations:
Age of CIN development peaks in mid-productive years and
declines in the fourth decade.
Most cervical cancer diagnoses occur between the ages of 3555.
Cervical cancer is less aggressive in older women compared
to younger women.
Transformation zone of older women is smaller and less
accessible than in younger women.
Benefits of continued screening in women over 65 who
have been adequately screened:
 Prevention of 1.6 cancer cases per 1000 women
 Prevention of 0.5 cancer deaths per 1000 women
 Increases life expectancy by no more than one year
Harms of continued screening in women over 65 who
have been adequately screened:
 58 false positives/1000 women
 127 extra colpscopies/1000 women
 13 extra CIN2/CIN3 treatment/1000 women
Adequate screening defined:
 Three consecutive negative cytologies
 Two consecutive negative HPV within 10 years
 Most recent test within 10 years
When properly screened, a 55 year old woman with
two negative HPV tests has only a 0.08% chance of
developing CIN3/cancer.
The risks associated with overtreatment in the elderly
population outweigh the benefits of screening.
ASCCP recommends stopping cervical cancer screening
at age 65 if adequate prior negative screening and no
history of CIN2 in prior 20 years.
USPTF recommends stopping cervical cancer screening
at age 65 if there has been adequate prior negative
screening
ACOG recommends stopping cervical cancer screening
between 65-70 if there are been three consecutive
cytologies and no abnormal tests in prior 10 years.
History of CIN2+ in prior 20 years increases risk for
cervical cancer by 5-10 fold.
ASCCP recommends routine screening for twenty years
following regression/treatment of lesion even if this
extends screening beyond age 65.
ACOG recommends routine screening for ten years
following regression/treatment of lesion even if this
extends screening beyond age 65.
Women over 65 without adequate screening:
 Screen every 2-5 years with co-testing
 Discontinue testing at ages70-75
Potentially reduce mortality by 74%
Reinitiating cervical cancer screening
USPTF/ASCCP recommend that once screening has
been discontinued it should NOT be reinitiated even if
patient has a new sexual partner.
ACOG recommends that as older patients with multiple
partners still have a theoretical risk for acquiring HPV
and risk factors they need to be assessed to determine
if reinitiating screening is appropriate.
Do you screen women who
has had a hysterectomy for
benign reasons?
Vaginal malignancy is uncommon.
 0.18/100,000 in situ
 0.69/100,000 invasive
Positive predictive value of vaginal cuff cytology for detection of
vaginal cancer is zero.
10, 000 PAPs in women status post hysterectomy:


104 abnormal PAPs
4 high grade lesions
 3 VIN
 1 squamous carcinoma of vagina
*042 high grade lesions/1000 PAP
ASSCP-Do not screen women with hysterectomy for
benign indications and no history of CIN2+.
USPTF-Do not screen women with hysterectomy for
benign indications and no history of CIN2+.
ACOG-Do not screen women with total hysterectomy for
benign indications and no prior history of high grade
lesion.
Hysterectomy for cervical cancer
All three organizations recommend continued
screening for women who have had a hysterectomy for
cervical cancer.
Women in this category may be at an increased risk of
vaginal cancer, but no good data exists to support or
refute discontinuing screening in this population.
Does HPV vaccination alter
screening?
 30% of oncogenic subtypes of HPV are not covered by
the first generation vaccines.
 Many women are vaccinated after exposure which
decreases efficacy.
 Not enough of the population is vaccinated:
 Only 32% of eligible women have received all doses of
vaccine.
 Initiation of Gardisil in ages 13-17 has increased from
25% in 2007 to 48% in 2010.
 Number of insured females aged 13-17 completing the
series dropped from 50% in 2006 to 20% in 2009.
 Only 1/3 of females complete the series.
 In one study, FPs were the least successful specialty in
getting their female patients to complete the series
 Once vaccination is widely implemented it takes 15-20
years to realize a reduction in cervical cancer.
 It is possible that vaccination will alter screening in the
future, but for now all three organizations’ guidelines
recommend that we screen vaccinated and
unvaccinated patients identically.
ACOG (2009)
ASCCP (2012)
USPFT (2012)
Under 21
No screening
No screening
No screening
30-64
May space
screening to q 3
years if has three
consecutive
negative
screenings
Preferred: Screen
with cytology and
HPV testing q 5
years
Preferred: Screen
with cytology and
HPV testing q 5
years
Alt: Screen with
cytology alone q3
years
Alt: Screen with
cytology alone q3
years
May cease
screening between
65-70 if has three
consecutive prior
screenings and no
abnl results in past
ten years.
May cease
screening at 65 if
no CIN2+ in past
twenty years.
Otherwise screen
for 20 yrs after
lesion.
May cease
screening at 65 if
no CIN2+ in past
twenty years.
Otherwise screen
for 20 yrs after
lesion.
>65
Bringing it back to the office
 Screen your patients at appropriate intervals using




HPV as recommended
Make your population aged 9-26 is fully vaccinated
Know when to stop screening
Know who doesn’t need screening
Reach out to your female population that hasn’t been
screened. This is where we can make an impact on
cervical cancer mortality.
References
 Robbins Pathologic Basis Of Disease 7th Ed. (1999)
 Diag cytopathol 2011 Apr; 39 (4): 258-63
 J Women’s Health 2011 Oct; 20 (10): 1479-1484
 Contraception 72 (3): 179-181
 Lancet Oncology 2012 Jan; 13: 78-88
 J of Lower Genital Tract Disease 2012; 16 (3)
 Annals of Internal Medicine 2012, March
 Obstetrics & Gynecology 2009 Dec; 114 (6): 1409-1420
 Up To Date:




Cervical Intraepithelial Neoplasia: Reproductive Effects of Treatment
Cervical Intrepithelial Neoplasia: Procedure For Cervical Conization
Invasive Cervical Cancer: Epidemiology, Risk Factors, Clinical Manifestations and Diagnosis
Screening for Cervical Cancer: Rationale and Recommendations