RECOMMENDED CERVICAL CANCER SCREENING MODALITIES
Recommended Cervical Cancer Screening Modalities
Anna Lee
School of Nursing, University of Minnesota
NURS 7600: Nursing Research and Evidence Based Practice
Dr. Nataya Stroud
April 1st, 2024
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RECOMMENDED CERVICAL CANCER SCREENING MODALITIES
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Recommended Cervical Cancer Screening Modalities
Today there are several screening options available for cervical cancer. These include a
primary human papilloma virus (HPV) test, papanicolaou (pap) test which may include liquid
based cytology (LBC), or a co-test (American Cancer Society, n.d.). Organizations such as the
Center for Disease Control (CDC), American Cancer Society (ACS), American College of
Obstetricians and Gynecologists (ACOG), and the American Society for Colposcopy and
Cervical Pathology (ASCCP) currently have differing screening recommendations in terms of
which test to perform and how often for specific age ranges of women (Center for Disease
Control and Prevention, 2023; Swid & Monaco, 2022). This raises the questions of whether one
screening modality is superior to the others and if organizations should move to a more
standardized approach across the board.
A search of the literature reveals each screening modality has its strength and
weaknesses. Several large studies have been conducted to compare the screening modalities such
as the HPV Focal Trial and the Addressing the Need for Advanced HPV Diagnostics (ATHENA)
Study (Ogilvie et al., 2018; Wright et al., 2015). HPV tests have been shown to have greater
sensitivity while pap cytology provides greater specificity (Swid & Monaco, 2022). Providers
can use this evidence to make an informed decision with their patient based on resources
available to them.
Pico Question
The PICO question is in women aged 21-65, how do pap and liquid based cytology tests
compared to HPV tests affect detection of cervical cancer? The components included target
RECOMMENDED CERVICAL CANCER SCREENING MODALITIES
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population: women aged 21-65 years, intervention: pap and liquid based cytology, comparison:
HPV test, and outcome: detection of cervical cancer.
Search Methodology
The OVID Medline and CINAHL databases were searched for studies related to the
PICO question. In OVID Medline, the key words used were “pap test,” “hpv test,” “cervical
cancer,” and “early detection of cancer.” Search headings were used for pap test which changed
to Papanicolaou test and cervical cancer which changed to uterine/cervical neoplasms. The subheadings of diagnosis and prevention and control were used under uterine/cervical neoplasms.
The search was limited to those published within the past 10 years (2014-current), the English
language and study type of randomized control trial (RCT) and comparative/observational study.
The key words were first searched individually and then those searches were combined with the
Boolean operator “AND.” This search resulted in a total of 34 studies. In CINAHL, the key
words used included “Papanicolaou test,” “HPV test,” and “cervical cancer.” Based on these key
words, the subject major headings of “cervical neoplasms” and “cancer screenings” were
selected. The same limitations as applied in OVID Medline were applied here. The Boolean
operator “AND” was used to do one search with all three key words after which the subject
headings were used to further narrow the results. This search resulted in 25 studies.
Of the abstracts reviewed, a total of 10 studies were found to be relevant to the PICO
question. The level of evidence, sample size, and definitiveness of findings were all considered
when selecting studies. 7 studies were eliminated due to their small or narrow sample sizes, or
having inconclusive results related to participants dropping out. The three studies selected
provided large and broad sample sizes of women as well as compared multiple screening
RECOMMENDED CERVICAL CANCER SCREENING MODALITIES
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modalities as stand-alone options or co-tests (Liang et al, 2021, Ogilvie et al., 2018; Wright et al.,
2015).
Results: Narrative Summary
The three selected studies are presented in a matrix format in the Appendix. The study by
Liang et al (2021) was a randomized prospective cohort study comparing the clinical test
accuracy of pap tests, LBC, and HPV tests as both stand-alone screening options and co-tests.
The findings showed HPV tests outperformed all co-tests and pap tests had the high rate of false
positive screenings (Liang et al, 2021). Ogilvie et al (2018) performed a RCT looking to
determine the detection of cervical intraepithelial neoplasia stage 3 or worse (CIN3+) by primary
HPV testing versus LBC within a 48 month period. The findings showed HPV testing better
detected cervical intraepithelial neoplasia stage 2 or worse (CIN2+) and CIN3+ than LBC and an
initial negative HPV test was predictive of reduced risk at 48 months (Ogilvie et al, 2018). The
study by Wright et al (2015) was a prospective cohort study with both cross-sectional and
longitudinal components that aimed to evaluate HPV testing as a primary screening for cervical
cancer in the US and to evaluate triage options for HPV positive women. The findings showed
HPV testing as a primary screening with genotyping and cytology for triage increases detection
of CIN3+ over cytology alone as well as cytology alone missed approximately 50% of cases of
CIN3+ in women in aged 25-29 (Wright et al, 2015).
Results: Critique of Studies
Liang et al (2021) provides a thorough literature review of the current research citing
several RCTS and observational studies including the ATHENA trial which led to the approval of
HPV testing as a stand-alone screening modality in the United States (US). The authors bring to
attention the lack of studies comparing co-testing strategies using pap tests and LBC with HPV
RECOMMENDED CERVICAL CANCER SCREENING MODALITIES
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tests to HPV tests as a stand-alone option (Liang et al, 2021). Methodological strengths include
the authors use of a prospective cohort design which aligned with their study purpose of
comparison between screening modalities (Liang et al 2021). The sample size was also
population-based and randomized into two study arms for recruitment allowing for more
generalizable results (Liang et al, 2021). The results provided a direct comparison between
cytology and HPV test modalities within the same study population which had previously not
been reported (Liang et al, 2021). Limitations were addressed in the discussion section and
included the lack of longitudinal outcomes such as cumulative risk incidence due to the studies
cross-sectional design (Liang et al, 2021). The attendance for follow-up colposcopy was also
poor among those who screening positive or randomly selected for it (Liang et al, 2021).
The study by Ogilvie et al, (2018) had multiple methodological strengths. Its study design
as a RCT and large sample size contribute to the high level of evidence it presents. It used a wellestablished cervical screening program to guide its methods and all testing was done at one
certified laboratory by experienced staff which minimized interobserver bias (Ogilvie et al,
2018). Histopathologists were blinded to screening results and colposcopy procedures were
standardized which reduced bias and variability within study groups (Ogilvie et al, 2018). The
authors asked a clear research question and gave rationale for why the research was necessary.
The independent and dependent variables were explicitly defined and consistent materials were
used for the measuring of both the intervention and outcome. Limitations were described in the
discussion section. The exit intervention differed from the initial intervention due to authors
wanting to provide a comprehensive census of events at 48 months (Ogilvie et al, 2018). There
also may have been some selection bias due to the cohort being highly educated and primarily
from two specific geographic regions within British Columbia potentially underrepresenting
RECOMMENDED CERVICAL CANCER SCREENING MODALITIES
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under-screened women from rural and remote areas who may be at a higher risk of cervical
cancer (Ogilvie et al, 2018).
The study by Wright et al (2015) provides a thorough literature review, citing studies that
have led to guidelines in Europe recommending HPV stand-alone testing as a primary screening
modality for cervical cancer (Wright et al, 2015). This study sought to conduct a comparable
study in US to provide support for similar guideline changes to be made here (Wright et al,
2015). Methodological strengths include the use of both cross-sectional and longitudinal
components with their prospective cohort study design as well as the vast and broad sample size
(Wright et al, 2015). The authors also used verification bias adjustment when calculating the risk
of CIN2+ and CIN3+ and cumulative risk over 3 years (Wright et al, 2015). Limitations were
presented in the discussion section and included the high rate of loss to follow up during the
longitudinal phase of the study and the use of organized follow-up which cannot be used to
predict performance of opportunistic screening in the US (Wright et al, 2015). Additionally, only
one type of HPV test was evaluated (Wright et al, 2015).
Discussion and Synthesis
Several themes emerged from the three studies selected including the comprehensive
literature reviews, methodological strengths such as sample size, blinding and study design, and
less than ideal follow-up participation.
All three articles provided a thorough review of the current state of research regarding
cervical cancer screening modalities and established why their study’s research question/purpose
was necessary. The ATHENA study used in this critical review was even cited as a reference by
Liang et al (2021) to provide evidence and rationale for their study.
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All the studies had similar methodological strengths. Sample sizes ranged from 5,275 to
47,208, included a broad scope of ages, and were population based though the study from
Ogilvie et al (2018) may have suffered from selection bias (Liang et al, 2021, Wright et al, 2015).
Two of the studies used blinding with their original histopathologists when reviewing colposcopy
results while Liang et al (2021) only blinded their second, independent histopathologist which
they used to verify colposcopy results (Ogilvie et al, 2018, Wright et al, 2015). Additionally, two
studies used a prospective cohort study design providing cross-sectional results (Liang et al,
2021, Wright et al, 2015).
A limitation discussed by two of the studies was the loss of participants during follow-up.
Liang et al (2021) discussed how participants who were referred to follow up with colposcopy
after a positive screening was poor while Wright et al (2015) reported high loss to follow up
during the longitudinal phase of their study. Ogilvie at al (2018) does discuss statistical methods
to account for loss to follow up in their methods sections but does not mention it as a limitation
to the study.
All the collected studies had similar findings. The HPV test appears to be a superior
screening modality for detecting cervical cancer, especially CIN3+ (Liang et al, 2021, Ogilvie et
al, 2018, Wright et al 2015). Additionally, the studies suggest negative HPV testing lowers the
risk and incidence of cervical cancer over time (Ogilvie et al, 2018, Wright et al 2015). These
studies provide evidence for implementing stand-alone HPV testing or as a co-test with cytology
as a primary screening in primary care today. Future research is necessary to determine economic
impact of HPV testing as a primary screening modality as well as determine resources needed to
disseminate the practice and make it more accessible in areas where it may be unavailable
(Ogilvie et al, 2018).
RECOMMENDED CERVICAL CANCER SCREENING MODALITIES
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References
American Cancer Society. (n.d.). Cervical Cancer Overview | Guide To Cervical Cancer.
American Cancer Society. Retrieved November 27, 2023, from
https://www.cancer.org/cancer/types/cervical-cancer.html
Center for Disease Control and Prevention. (2023, June 6). Cervical Cancer. Centers for Disease
Control and Prevention. https://www.cdc.gov/cancer/cervical/statistics/index.htm
Liang, L. A., Einzmann, T., Franzen, A., Schwarzer, K., Schauberger, G., Schriefer, D., Radde,
K., Zeissig, S. R., Ikenberg, H., Meijer, C. J. L. M., Kirkpatrick, C. J., Kölbl, H., Blettner,
M., & Klug, S. J. (2021). Cervical Cancer Screening: Comparison of Conventional Pap
Smear Test, Liquid-Based Cytology, and Human Papillomavirus Testing as Stand-alone or
Cotesting Strategies. Cancer Epidemiology, Biomarkers & Prevention, 30(3), 474–484.
https://doi.org/10.1158/1055-9965.EPI-20-1003
Ogilvie, G. S., van Niekerk, D., Krajden, M., Smith, L. W., Cook, D., Gondara, L., Ceballos, K.,
Quinlan, D., Lee, M., Martin, R. E., Gentile, L., Peacock, S., Stuart, G. C. E., Franco, E. L.,
& Coldman, A. J. (2018). Effect of Screening With Primary Cervical HPV Testing vs
Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 Months: The HPV
FOCAL Randomized Clinical Trial. JAMA, 320(1), 43–52.
https://doi.org/10.1001/jama.2018.7464
Swid, M. A., & Monaco, S. E. (2022). Should screening for cervical cancer go to primary human
papillomavirus testing and eliminate cytology? Modern Pathology, 35(7), 858–864.
https://doi.org/10.1038/s41379-022-01052-4
Wright, T. C., Stoler, M. H., Behrens, C. M., Sharma, A., Zhang, G., & Wright, T. L. (2015).
Primary cervical cancer screening with human papillomavirus: End of study results from the
RECOMMENDED CERVICAL CANCER SCREENING MODALITIES
ATHENA study using HPV as the first-line screening test. Gynecologic Oncology, 136(2),
189–197. https://doi.org/10.1016/j.ygyno.2014.11.076
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RECOMMENDED CERVICAL CANCER SCREENING MODALITIES
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Appendix
Matrix for Literature Review
PICO Question: In women aged 21-65, how do pap and liquid based cytology tests compared to HPV tests affect
detection of cervical cancer?
Author/Title/
Purpose/Problem/ Study Design
Sample
Data Collection/
Analysis
Comments
Journal/Year
Objective/Aims
(Setting)
Measures
Outcomes
Published
Liang, L.,
Einzmann, T.,
Franzen, A., et
al
Cervical
Cancer
Screening:
Comparison of
Conventional
Pap Smear
Test, LiquidBased
Cytology, and
Human
Papillomavirus
Testing as
Stand-alone or
Cotesting
Strategies
Cancer
Epidemiology,
Biomarkers
and Prevention
2021
To compare
clinical test
accuracy of pap
tests, LBC, and
HPV tests in both
stand alone and
co-testing
formats
Randomized
prospective
cohort study,
crosssectional
comparative
study
5275 women
eligible aged
30 in
Germany
selected from
population
registries
IV: screening
tests: HPV
test, pap test,
LBC
Previous
history of
cervical
cancer,
hysterectomy,
and
pregnancy
were
exclusion
criteria
DV:
incidence of
CIN2+
Positive
screenings
and 5%
random
sample of
negative
screening
invited for
colposcopy
More f
n=2,627 who
attended
screening
Pap: n=2,558
LBC:
n=2,624
HPV test:
n=2,622
Colposcopy:
n=203
Pelvic
examination
with collection
of cervical
specimen
Bootstrap
sampling
method used
to calculate
CI
Pap: specimen
sent to lab for
assessment as is
Comparisons
conducted
using
McNemar’s
paired
sample test
Cytology:
specimen placed
in PreservCyt
vial (Thinprep,
Hologic Inc.)
HPV test:
specimen tested
using Hybrid
Capture 2 High
Risk DNA test
and PCR
(processed post
hoc)
Colposcopy:
conducted by
certified
colposcopists
according to
IFCPC
guidelines,
biopsies taken
and reviewed by
two
histopathologists
(one of which
was
independent)
Analysis
conducted
with SAS
9.4
HC2 had
highest
sensitivity as
both stand
alone and
co-test
Strengths: used
random,
population based
sample, first
study to compare
cytology cotesting to stand
alone HPV test,
used
independent
histopathologist
to verify
colposcopy
samples
Weaknesses:
colposcopy
attendance was
poor, reported
cross-sectional
results,
colposcopist and
first
histopathologist
not blinded
Cytology
(both pap
and LBC)
had higher
specificity as
stand alone
Similar accuracy
between stand
alone HPV test
and LBC co-test
Specificity
lower with
co-tests
False positive
test results
associated most
with pap cotesting
HC2 stand
alone and
co-tests
detected
twice as
many CIN2+
lesions
LBC co-testing
favorable over
pap co-testing
No co-test
outperformed
stand alone HPV
test
RECOMMENDED CERVICAL CANCER SCREENING MODALITIES
Ogilvie, G. S.,
van Niekerk,
D., Krajden,
M., et al
Effect of
Screening With
Primary
Cervical HPV
Testing vs
Cytology
Testing on
High-grade
Cervical
Intraepithelial
Neoplasia at 48
Months: The
HPV FOCAL
Randomized
Clinical Trial.
JAMA
To determine
incidence of
CIN3+ detected
within 48 months
by primary HPV
testing vs LBC
RCT
IV: type of
screening –
HPV test
(intervention)
vs LBC
(control)
DV:
detection of
CIN3+
Secondary
outcome:
detection of
CIN2+
19,009
women aged
25-65 with
no history of
CIN2 in the
past 5 years
from 224
collaborating
clinicians in
BC between
January 2008
and May
2012 with
follow-up
through
December
2016
Intervention:
n=9552
Control:
n=9457
11
Pelvic
examination
with collection
of cervical
specimen placed
in Thinprep vial
(Hologic Inc) at
baseline, 12, 24,
36, and 48
months
Multiple
imputation
set at 25
based on
logistic
regression
HPV test:
specimen tested
using Hybrid
Capture 2 High
Risk HPV DNA
test, positive
tests verified
with in-house
beta-globin
polymerase
chain reaction
test
Round 1 RR
1.61 (95%
CI 1.092.37) in
intervention
group
2018
LBC: specimen
prepared in
Thinprep 2000,
abnormal results
referred to
cytopathologist
for
interpretation
Analysis
done using
SAS or R
Exit round
RR 0.42
(95% CI
0.25-0.69)
At 48
months,
rates of
CIN2+ and
CIN3+ were
significantly
higher in
control
group
compared to
intervention
group across
all ages
Strengths:
population had
well established
screening
program, all
cytology testing
done at 1 lab,
histopathological
assessment
blinded to HPV
and LBC results,
standardized
colposcopy
procedures
Weaknesses: exit
intervention not
the same as
baseline
intervention
(both groups
received co-test),
potential for
selection bias –
participants
highly educated
and primarily
from 2 areas in
BC, lack of
representation
from rural
populations
HPV testing
better detected
CIN2+ and
CIN3+ than
LBC at initial
test and reduced
incidence at 48
months
Further research
needed to assess
economic impact
of implementing
HPV testing as a
primary
screening
RECOMMENDED CERVICAL CANCER SCREENING MODALITIES
Wright, T.,
Stoler, M.,
Behrens, C., et
al
Primary
cervical cancer
screening with
human
papillomavirus:
End of study
results from the
ATHENA
study using
HPV as the
first-line
screening test
Gynecologic
Oncology
2015
To evaluate HPV
testing as a
primary
screening for
cervical cancer in
the US and to
evaluate triage
options for HPV
positive women
Prospective
cohort study,
crosssectional and
longitudinal
(3 years)
phases
IV: HPV test,
cytology test
DV:
incidence of
CIN2+ and
CIN3+
Positive
screenings
and a random
sample of
negative
screenings
underwent
colposcopy
during
baseline
phase
Negative
screenings
and negative
colposcopy
eligible for
follow-up
phase
47,208
women aged
21
presenting
for routine
cervical
screening
from 61
clinical sites
across 23
states
between May
2008-August
2009
Pelvic
examination
with collection
of cervical
specimen at
baseline, then
yearly for 3
years
Longitudinal
follow up:
n=41,955
women aged
25
HPV test:
specimen tested
using Cobas
HPV test (Roche
Molecular
Systems), also
tested with
AMPLICO and
LINEAR
ARRAY HPV
Genotyping test
(Roche
Molecular
Systems)
Cytology:
specimen placed
in PreservCyt
vial (Thinprep,
Hologic Inc.)
Cytology and
HPV testing
done at 4
clinical labs in
US, HPV tests
additionally
done at Roche
Molecular
Systems
Colposcopy:
results reviewed
by 3
pathologists
12
Post hoc
analysis
done of
screening
performance
over the full
3 year study
VBA risk of
CIN2+ and
CIN3+
obtained
Cumulative
risk over 3
years
obtained
using
Kaplan-Meir
method and
VBA
CI obtained
using
bootstrap
method
Positive
HPV test at
baseline was
predictive
for CIN2+
and CIN3+
HPV testing
had highest
sensitivity
(95% CI:
70.3–81.8%)
Cytology
testing has
highest
specificity
(95% CI:
96.9–97.2%)
Strengths:
Colposcopists
and patients
blinded to
screening
results,
Pathologists
blinded to
patient
information and
screening
results, large
sample size,
VBA
Weaknesses:
high loss during
follow-up,
screening in
follow-up was
scheduled, not
opportunistic,
only one type of
HPV test
evaluated
HPV testing as a
primary
screening with
genotyping and
cytology for
triage increases
detection of
CIN3+ over
cytology alone
Cytology did not
detect CIN3+ in
about 50% of
women aged 2529
At baseline, a
negative HPV
test predicts half
the risk of
CIN3+ over 3
years compared
to negative
cytology
Legend: ATHENA- Addressing the Need for Advanced HPV Diagnostics, BC- British Columbia, CIN2+- cervical
intraepithelial neoplasia stage 2, CIN3+- cervical intraepithelial neoplasia stage 3 or worse, CI- confidence interval,
DV- dependent variable, HC2- Hybrid Capture 2, HPV FOCAL- human papillomavirus for cervical cancer, HPVhuman papillomavirus, IFCPC- International Federation of Cervical Pathology and Colposcopy, IV- independent
variable, LBC- liquid-based cytology, n-sample size, RR- risk ratio, RCT- randomized control trial, VBAverification bias adjusted