Expert Reviews ajog.

org

GYNECOLOGY
Cervical cancer screening: evidence behind
the guidelines
Brittany F. Lees, MD; Britt K. Erickson, MD; Warner K. Huh, MD

hrHPV types. HPV 16 and 18 remain the

Cervical cancer screening involves a complex process of cytology, human papillomavirus most prevalent types, and are associated
(HPV) testing, colposcopy, and a multitude of algorithms for the identification of pre- with approximately 70% of all cervical
invasive disease and prevention of invasive disease. High-risk HPV is a prerequisite for cancers.4
the development of almost all types of cervical cancer; therefore, a test for high-risk HPV Not every woman who becomes
has become an integral part of new screening strategies. Major changes to screening infected with HPV develops a precan-
guidelines in the last decade include initiation of screening at age 21 years, conservative cerous lesion or cancer. The majority
management of young women with abnormal cytology, extended screening intervals for of young women are able to clear the
women age
30 years, and cessation of screening in low-risk women at age 65 years. HPV virus. As evidenced by negative
This review will focus on the evidence that has led to the current evidence-based follow-up hrHPV DNA testing,
guidelines. Evidence regarding primary HPV testing as well as postvaccine-based approximately 90% of HPV infections
screening strategies will also be reviewed. are cleared within 1-2 years.5-7
Although it is possible that the HPV
Key words: cervical cancer screening, colposcopy, cytology, human papillomavirus virus could remain dormant at unde-
testing, human papillomavirus vaccine tectable levels,8 it is most likely that
women make anti-HPV antibodies
that confer long-term protection

C ervical cancer screening was once

a simple annual Pap smear. This
has since evolved into a more sophisti-
cated, albeit complex, process of
cytology, high-risk human papilloma-
virus (hrHPV) testing, colposcopy, and a
multitude of algorithms for the preven-
tion of cervical cancer. As new evidence
emerges regarding the natural history of
human papillomavirus (HPV) and the
optimal screening strategies, primary
care providers as well as obstetrician-
gynecologists have had to continually
adapt to the ever-changing guidelines
from the American Cancer Society
From the Department of Obstetrics and
Gynecology (Dr Lees), Division of Gynecologic
Oncology (Dr Huh), University of Alabama at
Birmingham, Birmingham, AL; and Division of
Gynecologic Oncology, University of Minnesota,
Minneapolis, MN (Dr Erickson).
Received Aug. 11, 2015; revised Oct. 17, 2015;
accepted Oct. 22, 2015.
Disclosure: Dr Huh is a consultant for Merck and
THEVAX.
Corresponding author: Brittany F. Lees, MD.
blees@uabmc.edu
0002-9378/$36.00
ª 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2015.10.147
(ACS), American Society for Colposcopy
and Cervical Pathology (ASCCP),
American Society for Clinical Pathology
(ASCP), and US Preventive Services Task
Force (USPSTF). The objective of this
review is to discuss the evidence behind
the major changes in current cervical
cancer screening guidelines including
initiation of screening at age 21 years,
conservative management of young
women with abnormal cytology,
extended screening intervals for women
age
30 years, and cessation of screening
in low-risk women at age 65 years
(Table 1). Evidence regarding primary
HPV testing as well as postvaccination
screening strategies will also be reviewed.
HPV and cervical cancer
Cervical cancer develops from hrHPV-
infected cells that typically originate in
the squamocolumnar junction, an area
of high cell turnover. Through viral
proteins E6 and E7, HPV causes reduced
cell apoptosis and unregulated cell
growth.1,2 The causal link between HPV
infection and the development of cervi-
cal cancer was first identified in 1984 by
Dr Harald zur Hausen, who won the
Nobel Prize for isolating HPV types 16
and 18.3 Further study has identified 14
against subtype-specific infection. HPV
infections that persist are at much
greater risk of progression to a precan-
cerous lesion or cervical cancer. When
these lesions are detected, cervical
excisional procedures are highly effica-
cious (90-95%) in eliminating pre-
invasive disease.9
History of cervical cancer screening
In the 1920s, Dr George Papanicolaou
began work on the cervicovaginal smear
at Weill Medical College in New York
City, which was first published with his
partner Dr Herbert Traut in 1941. This
test would later become known as the
“Pap smear.”10,11 No large randomized
control trials have confirmed its efficacy
and as such, cervical cytology was never
formally evaluated before being imple-
mented as a screening test. However,
global epidemiologic studies have
convincingly demonstrated its efficacy as
a cancer prevention strategy. In areas
where cervical cytology was imple-
mented, the mortality and morbidity
from cervical cancer has been greatly
reduced.12-14 In the United States, rates
declined from 36.3 per 100,000 women
in the 1930s to 7.2 per 100,000 women in
the 1990s. The greatest decline was

438 American Journal of Obstetrics & Gynecology APRIL 2016

ajog.org Gynecology Expert Reviews

TABLE
Review of recent cervical screening guidelines
Important
Recommendation Rationale references
9,23,24
Initiate screening at age 21 y - Low incidence of invasive cervical cancer
- Higher rates of HPVþ, but lower rates of HPV persistence
- Minimize no. of colposcopies performed
5,42
Screening ends at age 65 y in low-risk women - Smaller transformation zone decreases rate of transmission
- Modeling studies show rates of cervical cancer deaths minimally affected
by prolongation of screening
- Minimizes no. of colposcopies
5,26,27,29
Cytology every 3 y at age 21-29 y - Modeling studies demonstrate similar cervical cancer death rate compared
to screening every 2 y
- Minimizes no. of colposcopies
Cotesting every 5 y at age
30 y - Addition of hrHPV testing increases sensitivity 5,29,37,38

- A negative result indicates 5-y cumulative CIN3þ incidence rate low

Repeat cytology at 12 mo with ASCUS/HPVþ - Lower risk of progression to CIN3þ compared to >30 y 5,31

or LSIL age 21-25 y - Minimizes no. of colposcopies

Primary HPV testing age
25 y - Increases sensitivity of CIN3þ 20,22

- Minimizes no. of screening tests performed

ASCUS, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; hrHPV, high-risk human papillomavirus; LSIL, low-grade squamous
intraepithelial lesion.
Lees. Cervical screening reviewed. Am J Obstet Gynecol 2016.

from 1950 through 1970, with a decline traditional screening. Approved by the patients to colposcopy.19 In 2004, the
of 3% per year, which correlates with the Food and Drug Administration (FDA) National Institute of Health National
adoption of routine cervical cancer in 1999, hrHPV testing was first rec- Cancer Institute, ASCCP, and ACS
screening programs in the United States ommended for reflex testing of atypical convened and agreed on interim
(Figure 1).15 squamous cells of undetermined sig- guidelines to expand the use of hrHPV
Traditional cytology has been shown nificance (ASCUS) cytology to triage to cotesting women age
30 years given
to have a sensitivity of only 51%
(30-87%) and specificity of 98%
(86-100%).16 Additionally, due to the FIGURE
subjective nature of the screening test, Cervical cancer screening timeline
there is significant interobserver vari-
ability in the interpretation of cytology,
which further contributes to its variable
sensitivity and specificity rates.17 Annual
screening has been able to overcome this
low sensitivity (ie, false-negative rate) of
cervical cytology. A metaanalysis by
Spence et al18 sought to understand how
women develop cervical cancer despite
availability of widespread screening
programs. In this study, which examined
42 studies from 1950 through 2007,
the authors concluded that an estimated
29% (95% confidence interval,
21e40%) of failures to prevent invasive
cervical cancer can be attributed to false-
negative cytology. Brief overview of screening practice changes and related discoveries.
Given the inherent deficiencies of FDA, Food and Drug Administration; HPV, human papillomavirus.
cytology screening, hrHPV testing Lees. Cervical screening reviewed. Am J Obstet Gynecol 2016.
developed initially as an adjunct to

APRIL 2016 American Journal of Obstetrics & Gynecology 439

Expert Reviews Gynecology
data that demonstrated high sensitivity
and specificity in this age group.20,21
Many clinical trials have now been
performed that have increased our
understanding of the performance of
hrHPV testing. The data have consis-
tently shown HPV testing to have a
higher sensitivity and reproducibility
with increased negative predictive
values compared to cytology, thus
leading to a scientific and clinical
interest in primary HPV testing
as a method for cervical cancer
screening.22
Delayed screening start until age 21
years
In 2009, experts convened and reviewed
the available literature and recom-
mended screening start at age 21 years.23
The rationale for this decision is based
on the following primary concept:
although the rates of HPV infection in
the age group is high, the incidence
of cervical cancer in this age group
is exceedingly low. The Surveillance,
Epidemiology, and End Results (SEER)
data from 1998 through 2003 (and again
in 2007 through 2011) estimated there
was an average of 14 invasive cervical
cancers diagnosed in US females <20
years old, with an incidence of 0.1 per
100,000 women.24 To prevent 1 case of
cervical cancer, 1 million young women
would need to be screened. This
would lead to thousands of unnecessary
colposcopies, biopsies, and excisional
procedures. The costs and morbidities
associated with this far outweigh the
benefits in this population. To further
emphasize the ineffectiveness of
screening in this age group, an expert
group compared SEER data from the
1970s to data from the present era, and
noted that since the initiation of wide-
spread screening programs in the United
States, the incidence rate of invasive
disease is largely unchanged in this
age group9 indicating that screening in
this population has had no effect on
incidence.
Although the incidence of cervical
cancer in young women is very low,
many young women harbor both
low-risk HPV and hrHPV infections.
According to the 2003 through 2006
440 American Journal of Obstetrics & Gynecology APRIL 2016
National Health and Nutrition Exami-
nation Survey, the US HPV prevalence in
those <20 years of age is estimated at
32.9% with hrHPV prevalence estimated
at 28.3%. Women age 20-24 years have
slightly higher rates of hrHPV infection
at 43.4%.25 From these new screening
guidelines, one should not assume that
women age <21 years do not acquire a
persistent HPV infection or go on to
develop a high-grade preinvasive lesion.
Instead, because time to progression
from preinvasive to invasive disease is
long (years to decades), screening at
age >21 years can still prevent the
development of invasive disease.
Screening in the 20s and
conservative management of
low-grade cytology
Once screening has been initiated, one
goal is to detect the majority of precan-
cerous lesions while limiting morbidity
associated with detection and treatment.
The appropriate screening intervals and
treatment guidelines in young women
age 21-29 years slowly evolved
throughout the early 2000s. Initially, the
ACS, USPSTF, and American Congress
of Obstetricians and Gynecologists
(ACOG) wrote separate opinions
throughout this time period with vary-
ing recommendations. In 2012, the ACS/
ASCCP/ACS, USPSTF, and ACOG all
aligned their recommendations to
change the cytology screening interval to
every 3 years.5,26,27 This increase in the
screening interval was based on concepts
similar to those that guided initiation of
screening at age 21 years. Although this
age group has a high rate of HPV infec-
tion (46.8-53.8%),25 rates of cervical
cancer remain exceedingly low, at 1.2-1.4
per 100,000 in women age 21-24 years
and 5.1 per 100,000 in women age 25-29
years.24,28 The appropriate screening
interval should be set long enough to
minimize harms, while still maximizing
detection of abnormal lesions prior to
progression. It should be noted that
there is limited prospective data evalu-
ating the appropriate screening interval
in this young age group. A decision
analysis by Kulasingam et al29 showed
that the predicted death rate from cer-
vical cancer with screening every 3 years
ajog.org
was 0.05 per 1000 women. When this
was compared to screening every 2 years,
the predicted death rate was equivocal,
but there was a 40% increase in the
number of colposcopies performed.5
As to whether to extend the interval
>3 years, a large Scandinavian study
reviewed the screening history of women
with cervical intraepithelial neoplasia
(CIN)3. This study found that women
with
3 years since their last negative
cervical cytology screen were at an
increased risk of having CIN3 compared
to women who had screening intervals
<3 years with an age-adjusted incidence
rate of 12.2 vs 1.5 and a relative risk of 1.3
(95% confidence interval, 0.6e3.2).30
Overall, the current 3-year guideline is
based on limited data that are not spe-
cific to this age group, but to most pro-
viders, a 3-year interval appears to align
with current acceptable risk-benefit
parameters.
The most recent ASCCP guidelines
recommend women age 21-24 years with
ASCUS/HPVþ or low-grade squamous
intraepithelial lesion (LSIL) cytology
results have repeat cytology at 12 months
instead of colposcopy, which has been a
past recommendation.9 The rationale for
these changes is based primarily on the
ASCUS-LSIL Triage Study indicating
similar low risk of progression to cervical
cancer with either LSIL or ASCUS/
HPVþ cytology in young women.31
Women age
30 years with LSIL
cytology have a 5-year cumulative risk of
CIN3þ of 5.2%, which is high enough to
necessitate colposcopy examination.32
However, in women age <25 years, the
risk is substantially lower at 3.0%.33
Although HPV prevalence is high in
this age group, HPV clearance is also
high and therefore delaying colposcopy
until a woman has proven HPV persis-
tence (with consecutive abnormal
cytology) can be considered in younger
women. However, given the possibility
of persistence, these individuals
should have closer follow-up to ensure
clearance.5,34-36
Extended screening interval in the
30s
According to SEER data from 2007
through 2011, compared to young
ajog.org
women age <30 years, cervical cancer
incidence is significantly higher in
women ages 30-39 years at 24.0 per
100,000 women.24 The increased inci-
dence necessitates a screening program
that has a high sensitivity for early
detection in this age group. It is also
important to minimize testing of women
at low risk of developing CIN3þ.
Compared to younger women, women
age
30 years are less likely to clear a new
HPV infection and more likely to have
HPV persistence. Therefore, the focus of
screening is to detect persistent HPV
infections and extend the screening in-
terval testing for those who are HPV
negative (and thus low risk).
In the most recent guidelines, women
age
30 years can continue with
cytology alone every 3 years.5 Notably,
simply adding hrHPV cotesting to a 3-
year screening interval would increase
the detection rate of HPV, but would
simultaneously lead to an increase in
colposcopy examinations. As demon-
strated in the model by Kulasingam
et al,29 this would translate to an in-
crease from 3-15 incremental colpos-
copies per life-year. However, studies
have shown the safety and cost-
effectiveness of extending the
screening interval in this age group to
every 5 years with a negative HPV cot-
est. A European study of 330,000
women demonstrated that women with
negative cytology had a risk of CIN3þ of
0.17% at 3 years. When women were
HPV negative, either via primary HPV
test or with a cotest, the rate of CIN3þ at
5 years was similar at 0.17% and 0.16%,
respectively, indicating comparable risk
to screening with cytology every 3
years.37 Katki et al38 used the large
database of HPV cotests collected by
Kaiser Permanente Northern California
to demonstrate that the 5-year cumu-
lative incidence rate of CIN3þ in
women age
30 years with negative
cytology screening is 7.1 per 100,000,
but with a concurrent negative HPV
cotest that rate was reduced by >50% to
3.2 per 100,000. Thus, given acceptable
reductions in risk with minimal impact
on the harms, the ACS/ASCCP/ASCP
Consensus guidelines recommended
cytology with HPV cotesting for women
age
30 years at 5-year intervals.5 As
Kinney et al39 recently argued, the safety
of extension to a 5-year interval was
based on comparison to 3-year
screening intervals and not to annual
screening cytology. This indicates a
potentially higher risk of a subsequent
cervical cancer diagnosis long-term
compared to the gold standard of
annual cytology. Moving forward, the
risk of cervical cancer and potential
death (not just CIN3) should be
considered in future modeling studies.
Another important benefit of HPV
cotesting is the diagnosis of cervical
adenocarcinoma and adenocarcinoma
in situ. Due to its endocervical location,
traditional cytology often fails to di-
agnose these lesions. In a large pooled
analysis of almost 200,000 women
enrolling in various HPV screening tri-
als, HPV testing (compared to tradi-
tional cytology) showed improved
detection of adenocarcinoma compared
to squamous cell carcinoma.40 Adeno-
carcinoma incidence is increasing and
accounts for 15-25% of invasive cervical
cancers,41 further supporting the addi-
tion of HPV testing in screening
algorithms.
Why stop at age 65 years?
To determine the appropriate age to stop
cervical cancer screening, guidelines
must take into account a combination of
screening history, known pathophysi-
ology of HPV in the older age groups,
and the potential risk of developing
clinically significant disease. The ASCCP
guidelines recommend cessation at
age 65 years only in women with previ-
ous adequate negative screening. The
ASCCP defines adequate negative
screening as 3 consecutive negative cer-
vical cytology results or 2 consecutive
negative HPV tests within the past 10
years prior to screening cessation with
the most recent screen not <5 years ago.
Women with a history of CIN2þ should
continue screening until 20 years
following their diagnosis of CIN2þ given
their increased risk of developing pre-
invasive or invasive disease.42 Alterna-
tively, women in this age group with a
negative screening history are at very low
risk of developing persistent HPV
APRIL 2016 American Journal of Obstetrics & Gynecology
Gynecology Expert Reviews
infection that will become cervical
cancer.
Women age >65 years have a smaller
and less accessible transformation zone,
which makes the acquisition and pro-
gression of HPV infections less likely.5
While there are no clinical trials to
confirm the exact incidence of invasive
cervical cancer in this age group,
mathematical models demonstrated
that continuing screening until age
90 years only prevented 0.5 cervical
cancer deaths per 1000 women, but at
the cost of 127 additional colpos-
copies.29 The decision to exit cervical
screening requires knowledge of the
patient’s cytology screening history and
appropriate counseling about potential
risks.
Primary HPV screening
HPV is found in the vast majority of
cervical cancers.4 HPV’s role in cervical
cancer carcinogenesis as well the low
sensitivity and poor reproducibility of
cervical cytology has led to investigations
regarding HPV testing as a primary
screening strategy. Multiple studies have
demonstrated that HPV testing increases
the sensitivity for detecting new CIN2þ
lesions, but at the cost of decreased
specificity and therefore increased
cost.22,40,43-47 For these reasons, the FDA
initially approved its use in the setting of
cotesting in women age
30 years.
However, there are now data that clearly
show the efficacy of hrHPV testing alone
as a primary screening strategy.
The Addressing the Need for
Advanced HPV Diagnostics Trial was the
first US-based prospective cohort study
to evaluate hrHPV testing as an upfront
screening trial. Over 40,000 women age

25 years were enrolled and had both
cervical cytology and HPV testing.
Abnormal testing was referred for col-
poscopy and subsequent follow-up
as appropriate. All women had repeat
colposcopy with biopsy at a 3-year
follow-up. The objective of this study
was to evaluate various screening stra-
tegies. Endpoints included detection of
CIN2þ, number of screening tests
required, and number of colposcopies
required.48 Cytology alone (with HPV
testing only for ASCUS triage) had the
441
Expert Reviews Gynecology
lowest sensitivity for detecting CIN2þ.
Primary HPV testing with triage to
colposcopy based on HPV typing (that
is, immediate colposcopy if HPV 16þ or
18þ and follow-up HPV testing if other
hrHPVþ) had the highest sensitivity to
CIN2þ detection (80%) but required
more colposcopy exams. Cotesting with
both upfront cytology and hrHPV
testing had similar sensitivity, but
required many more screening tests.49
These data support a potential primary
HPV screening (with colposcopy triage
based on HPV subtype analysis) for
women age >25 years.22
Post-HPV vaccination screening
There are currently 3 FDA-approved
HPV vaccines: a bivalent (Cervarix,
GlaxoSmithKline, Brentford, England),
a quadrivalent (Gardasil, Merck & Co.,
Inc., Kenilworth, New Jersey), and the
new 9-valent (Gardasil 9, Merck & Co.,
Inc). Prior to starting vaccination pro-
grams, there were concerns regarding
their potential impact on screening
methods. The positive predictive value
(PPV) of any screening test is highly
dependent on the prevalence of the dis-
ease (in this case CIN2þ). The intention
of the vaccine is to greatly decrease the
prevalence of HPV, and consequently
CIN2þ and cancer, in the vaccinated
population. Following the introduction
of Cervarix, the prevalence of HPV 16 or
18 in women age 16-24 years decreased
from 19.1-6.5% in one study in En-
gland.50 Additional data released from
Gertig et al51 following the school- and
community-based vaccination program
in Australia demonstrated a significant
reduction in high-grade cytology in the
vaccinated women compared to unvac-
cinated women (15.3 vs 11.9/1000
person-years). Although these results are
encouraging, a decrease in overall inci-
dence of HPV infection will further
lower the PPV of current screening tests.
One mathematical model shows a
decrease in the PPV of cytology from
the current 50-70% to 10-20% in a
vaccinated cohort will lead to more
false-positive results and unnecessary
interventions.52 Thus, primary HPV
testing may be a better screening test as
its higher sensitivity would allow it to
442 American Journal of Obstetrics & Gynecology APRIL 2016
maintain a higher PPV despite a
decreasing prevalence. The additional
challenge in the post-HPV vaccination
era is whether we can make specific
screening recommendations in women
who have been previously vaccinated.
Given the low rate of HPV vaccination in
the United States, it is unclear whether
this will be possible in the near future.
Conclusion
Despite the profound impact of cervical
cancer screening programs, in 2015 an
estimated 12,900 women will be diag-
nosed with cervical cancer with 4199
women dying from the disease.53 While
many of these women may never have
been screened (or were underscreened),
it is still imperative that the cervical
cancer screening algorithms be effective
at detecting precancerous changes while
minimizing harm. The initial screening
algorithm of annual cytology proved to
be effective in decreasing the incidence
of cervical cancer. However, with a
clearer understanding of disease patho-
genesis and natural history with an
emphasis on cost-effective screening
strategies and a reduction on morbidity,
screening algorithms have undergone
substantial changes. Unfortunately, the
complexity of cervical screening guide-
lines has been challenging for many
health care professionals, which in some
cases has caused delay in adoption of
new guidelines. With a better under-
standing of the data behind these
evidence-based guidelines, practitioners
can ensure that they are screening their
patients appropriately while minimizing
unnecessary harms. - routinely collected statistics. BMJ 1999;318:
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