Cancer is one of the leading causes of death in the world. Among women, cervical cancer) is one of the
deadly cancers in the world. Invasive cervical cancer is AIDS-defining since its presence means that the
patient has AIDS. Hetero-sexual activity is a risk factor of cervical cancer. As all cancers are, cervical cancer
is progressive and so can be prevented if detected in its early stages of development. Several laboratorybased diagnostic tests for screening women for cervical cancer exist. While these tests may be useful,
different tests may be preferred in different localities depending on the availability of resources. Given several
diagnostic tests, before any screening method is recommended for use, it is necessary to compare several
screening methods in order to identify a method which is cost-effective. In this work an attempt is made to
review several laboratory-based diagnostic methods and to explain the procedures for designing an
experiment for identifying a cost-effective method.
[Afr J Health Sci. 2014; 27(4):356-369
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Evaluation of methods for cervical cancer screening
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African Journal of Health Sciences, Volume 27, Number 4, October-December 2014
Evaluation of methods for cervical cancer screening
Misiri H1, 2
1. Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
2. Department of Community Health, College of Medicine, Private Bag 360, Chichiri. Blantyre 3.Malawi.
Correspondence: Email: hmisiri@gmail.com/humphrey.misiri@medisin.uio.no
Key words: cancer, Malawi, neoplasm
SUMMARY
Cancer is one of the leading causes of death in the world. Among women, cervical cancer) is one of the
deadly cancers in the world. Invasive cervical cancer is AIDS-defining since its presence means that the
patient has AIDS. Hetero-sexual activity is a risk factor of cervical cancer. As all cancers are, cervical cancer
is progressive and so can be prevented if detected in its early stages of development. Several laboratory-
based diagnostic tests for screening women for cervical cancer exist. While these tests may be useful,
different tests may be preferred in different localities depending on the availability of resources. Given several
diagnostic tests, before any screening method is recommended for use, it is necessary to compare several
screening methods in order to identify a method which is cost-effective. In this work an attempt is made to
review several laboratory-based diagnostic methods and to explain the procedures for designing an
experiment for identifying a cost-effective method.
[Afr J Health Sci. 2014; 27(4):356-366]
Introduction
Cervical cancer is cancer of the uterine cervix. It is a
common gynaecological cancer which occurs world-
wide. The risk factors for the disease are related to
sexual promiscuity. Consequently, cancer is rare
among women who are not sexually active. The
burden of cancer reflects the level of screening and
exposure to the risk factors. In Malawi, cervical cancer
is the leading among women[1].
There are two main types of cancer of the cervix the
commonest of which is squamous cancer of the cervix.
Like all other cancers, cervical cancer is progressive
and so can be prevented if detected early. Most
premalignant and malignant changes of the uterine
cervix take place at the squamo-columnar junction.
This is the transitional zone. The cells involved are
the ectocervical squamous cells, squamous metaplastic
cells and endocervical columnar cells. Invasive
squamous cervical cancer is usually preceded by an
asymptotic preinvasive stage of the disease where the
precancerous cells are confined to the epithelium of
the cervix. This precancerous stage is called cervical
intraepithelial neoplasia (CIN). If precancerous lesions
are diagnosed and treated, there is strong evidence
that invasive cancer can be prevented by identifying
and treating the preinvasive stages. Evidence exists of
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African Journal of Health Sciences, Volume 27, Number 4, October-December 2014
the benefits of screening in reducing the cervical
cancer [2-4]. Invasive cervical cancer is AIDS-
defining since its presence means that the patient has
AIDS. Cervical cancer is caused by the human
papilloma virus (HPV). More than 230 types of HPV
have been discovered because of advances in DNA
testing[5]. However, not all the HPV varieties cause
cancer.
There are several tests which are used for screening
women for cervical cancer. This report attempts to
explain the procedures for designing an experiment
with the sole objective of choosing a screening test
which is cost-effective and the method of choice for a
particular place or region.
There is always some uncertainty associated with the
use of a screening test in a particular area. In fact,
screening tests with 100% specificity or sensitivity are
always rare or nonexistent. The setting where
screening is done is one of the factors which can
affect the choice and performance of screening tests.
For instance, availability of well-trained personnel to
conduct a screening test, the equipment or devices or
reagents used in performing the tests, and the
condition or quality of available devices or reagents
used in screening may vary from place to place.
Different tests may also be preferred in different
localities depending on different reasons. Therefore,
before a recommending a screening test as a method
of choice in a particular area, it is advisable to conduct
an evaluation study comparing the performance of
several screening methods. The method which is cost-
effective and performs better in that particular location
should be adopted for use as the method of choice.
Screening methods
There are several methods for screening women for
cervical cancer. These are cytology tests,
cervicography, HPV DNA tests, visual inspection with
acetic acid or Lugol’s solution (VIA or VIL),
colposcopic and Biopsy.
Cytology tests
These are cytology procedures in which a sample of
cells is taken from the woman’s cervix by either a
doctor or a nurse. There are two such procedures for
screening women namely the Pap smear test and the
liquid-based cytology test.
Pap smear test
The smear taker takes a sample of cells from the
cervix of a woman, smears these cells on to a glass
slide and then preserves them. At the laboratory, the
cells are stained. A cytologist then manually searches
across the slide for abnormal cells using a
conventional light microscope.
Results of the Pap smear test
The results of Pap smear tests are classified in
different ways depending on the classification system
used. The two most commonly used classification
system are the cervical intraepithelial neoplasia (CIN)
grading and the Bethesda classification system. The
table below (Table 1) contains the description of
results of the Pap smear test, the CIN grading and the
corresponding Bethesda classification [6].
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Table 1: Description of results from a Pap smear test and classification of squamous cell abnormalities
Description CIN Grading Bethesda System
Normal Normal Normal
Atypia, Reactive or Neoplastic Atypia ASCUS
HPV HPV Low-grade SIL
Atypia with HPV Atypia,"condylatomatous", atypia and "koilocytic" atypia Low-grade SIL
Mild Dysplasia CIN I Low-grade SIL
Moderate Dysplasia CIN II High grade -SIL
Severe dysplasia CIN III High grade -SIL
Carcinoma in situ CIS High grade -SIL
Invasive cancer Invasive cancer Invasive cancer
Source: http://www.oncolink.org/types/article1.cfm?id=6028.
Interpretation of Pap smear results
The surface of the cervix from which cells are sampled
for a Pap smear test is a layer of cells called the
intraepithelial layer. The sample of cells from this
region of the cervix is what is smeared on a slide. A
cytologists looks for cell changes which would make
the cells on the slide look different from what a normal
cell looks like. If no changes are found on the slide,
the results are said to be normal. If the results are
unclear, the test result is ASCUS. In such cases of
unclear results, another test is needed to establish a
definitive diagnosis[2]. Early changes in shape and
size of the intraepithelial cells are called low-grade
squamous intraepithelial lesions (LSILs)[2]. These are
regarded as mild cell abnormalities. These changes
can also be classified as CIN-1. In some cases, there
are evident changes in the intraepithelial cells such
that the abnormalities of the cells are severe. The
changes in shape and size of the intraepithelial cells
are so great that the cells look completely different
from normal cells. These lesions are called high-grade
squamous intraepithelial lesions (HSILs)[2]. These
precancerous lesions have a very high likelihood of
progressing to cancer if they are not treated. HSILs
can be CIN-I, CIN-II, CIN-II depending on whether
the lesions exhibit signs of moderate or severe
dysplasia and carcinoma in situ (CIS). When test
results are not normal, other tests like the HPV test
and colposcopic examination can also be used as
follow-up procedures. The gold standard for cervical
screening methods is a biopsy. The routine use of
follow-up tests like the colposcopic examination is
advisable only if there are suspicions of cervical cancer
otherwise this may lead to increased costs if screening
is conducted on a massive scale [7].
A second cytology test is called the liquid-based
cytology test (LBC). To perform this test, the person
who takes the sample of cervical cells places the cells
into a liquid solution which acts as a preservative. A
laboratory machine removes excess blood, mucous
and inflammatory cells and produces a thin layer of
cells on a glass slide. The cells are stained and
examined under the microscope by a cytologist using a
conventional light microscope. Automated technology
can also used to read a slide[8], but the sensitivity of
such automatic procedures is inferior to the sensitivity
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of manual examination. The grading or classification of
results from a LBC test is similar to that described for
the Pap smear. The LBC is deemed convenient by
laboratory staff and personnel who take smear
samples because it is easy and there is no need for
those taking the sample of cells to prepare a slide.
The quality of the sample is improved the slides are
often clearer leading to accurate assessments of the
slides.
A colposcopy is a type of microscope with low power
which is used to examine a woman's cervix in order to
assess the extent and severity of any problem and to
determine appropriate treatment. A colposcopic
examination is conducted as a follow up test when the
result of a Pap smear or LBC test is abnormal. To
enable the person conducting the examination to see
the abnormal areas of the cervix clearly, acetic acid or
Lugol’s solution is applied on the birth canal or cervix
using a swab.
Visual aided inspection of the cervix
The practice of looking at a cervix in order to detect
cervical cancer disease in its early stages is called
down-staging or unaided visual inspection (VI). Before
1987, this was one of the methods for detecting
disease in women[9]. From 1987 to date, dilute acetic
acid (3-5%) or Lugol’s iodone is applied to the cervix
to help in inspection. When acetic acid is used the
method is called aided Visual Inspection with Acetic
Acid(VIA) or Visual Inspection with Lugol’s
solution(VILI) depending on which of the two
liquids(acetic acid or Lugol’s solution ) were used in
examination. The reference standard for assessing the
performance of VIA is colposcopy with directed biopsy.
In some cases, a handheld device like a magnifying
glass is used in VIA. VIA or VILI is somehow
subjective as the performance of VIA depends on
training of personnel and type of light source used in
the examination. The results of VIA or VILI are
classified as in the table below (Table 2)
Table 2: Classification of results of visual inspection with acetic acid
Description Possible thresholds Characteristics
A B C
Normal
Negative
Negative
Negative
Normal looking cervix: no white lesion,smooth,uniform,featureless
atypical cervix:ectopion,polyp,cervicitis,inflammation,Nabothian cysts
Indeterminate
Positive
Severe inflammation or cervicitis so that cervix cannot be adequately
assessed for aceto white lesion
Ill-defined lesion
Positive
Pale white lesion(aceto white lesion),poorly circumscribed and faintly
acetowhite
Focal,small punctuated areas of aceto whitening usually involving
the transformation zone
Definite lesion
Positive
Dense white lesion with sharp border; one border abutting the
squamo-columnar junction
Suspicious cancer
Cervical ulcer or growth cauliflower-like growth or ulcer
fungation mass
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Source: IARC.2005
A more detailed classification of the results is in the table (Table 3) below.
Table 3: Classification of results of visual inspection with acetic acid
Classification Appearance of the cervix
Normal Smooth, pink
Clear mucoid secretion
Central hole-'external os'
Nulliparours-round
Multiparous-slit or criciate
Cervix in postmenopausal women is atrophic
Abnormal Hypertrophy
Redness or congestion
Irregular surface
Distortion
Simple erosions (do not bleed on touch)
Cervical polyps (with smooth surface)
Abnormal discharge: foul smelling, dirty/greenish, cheesy white, blood
stained
Nabothian follicles
Prolapsed uterus
Suspicious of
malignancy Erosion that bleeds on touch or friable
growth, with an irregular surface or friable
Cervicography
This method was invented in 1981[10].To perform
cervicography, acetic acid(5%) is applied to the cervix
and a specialised camera with a fixed focal length and
internal light source is used to take pictures of the
cervix. The photographs are called cervigrams. These
pictures are similar to what is seen during colposcopy.
The photographs are projected on a screen at a fixed
distance and interpreted by specially trained people.
The results of cervicography are classified depending
on whether colposcopy was the reference standard or
not. When colposcopy is not used as the reference
standard the classification of a cervigram is shown in
the table below (Table 4).
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Table 4: Classification of results of visual inspection with acetic acid
Classification Description
Negative No definite lesion is visible
Atypical1(A1)
A lesion inside the transformation zone is visible; based
on the lesion’s site and morphology, the lesion is
presently considered to be of doubtful significance
Atypical2(A2):
A lesion outside the transformation zone is visible;
Based on the lesion’s site and morphology, the lesion is
presently considered to be of doubtful significance
Technically
defective
The cervigram slide is not adequate for evaluation "koilocytic"
atypia
Source: IARC,2005
The HPV test
This method is used to detect the presence of DNA or
RNA from HPV types 16 and 18 in cervical cells
extracted from a woman. There are two main
approaches for detecting HPV from a sample of cells
from the cervix namely the polymerase chain reaction
method (PCR) and the hybrid capture method(HC) [5].
Many DNA-based HPV tests are variations of the PCR
or HC tests. Examples of HPV tests are digene HCII
assay [11], the Hybrid Capture II (HCII), careHPV test
[12], Hybrid Capture ((R)) 2 (HC2)[13], Cervista HPV
test and Roche AMPLICOR[14]. The HPV test is
deemed effective [15].
Through DNA analysis, more than 200 types of HPV
have been discovered [5]. These HPV types are
classified as low or high risk according to whether they
are associated with low or high grade lesions
respectively [5]. Research has documented a spectrum
of HPV types with known proportion of cervical cancers
they cause [16]. The table below (Table 5) shows
some HPV types and corresponding attributable
fractions.
Table 5: Proportion of cervical cancers caused by the carcinogenic HPV types
HPV Type Percentage of cervical cancers caused Cumulative total
HPV16 54.6 54.6
HPV18 15.8 70.4
HPV33 4.4 74.8
HPV45 3.7 78.5
HPV31 3.5 82
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HPV Type Percentage of cervical cancers caused Cumulative total
HPV58 3.4 85.4
HPV52 2.5 87.9
HPV35 1.8 89.7
HPV59 1.1 90.8
HPV56 0.8 92.2
HPV51 0.7 92.9
HPV39 0.7 93.6
HPV73 0.5 94.1
HPV68 0.5 94.6
HPV82 0.2 94.8
No type identified 5.2 100
Source: Schiffman et al(2007)
Comparison of screening tests
Pap smear tests, VIA or VILI and LBC tests are two
stage procedures. At the first stage, a doctor or a
paramedic takes a sample of cells. At the second
stage, slides are prepared from the sampled cervical
cells. The person who reads a slide is called a rater.
Two people reading the same slide can arrive at two
different conclusions. Consequently, therefore is some
degree of subjectivity associated with the Pap smear
and LBC tests. Methods where for example pre-
cancerous lesions are to be detected by assessing a
picture of the cervix or by looking at a cervix smeared
with acetic acid are also prone to subjectivity because
different people looking at the same picture or stained
cervix may see different things. Some of the reasons
[17] of the subjectivity which may contribute to
uncertainty when screening for cervical cancer are lack
of adequate experience on the part of the rater, poor
training of the rater, differences in the scales of rating
used, poor quality of fixation of slides (in Pap smears),
imprecise classification rules, an over-elaborate
classification scale, rater misunderstanding of the
classification rules. These factors differ according to
setting.
Uncertainty in screening leads to false positives and
false negatives. These are inevitable. Follow up tests
are recommended if the result is that the woman has
abnormal results. The recommended gold standard for
cervical cancer screening is a biopsy which is invasive.
Other tests like the HPV test may also be prescribed
as confirmatory tests. If the false positive rate is high,
many normal women will be referred to such an
invasive procedure as the biopsy. The rationale is to
use a method with a low positive rate but with a higher
sensitivity.
There is no consensus on which of the two cytology
tests (Pap smear and LBC) is more sensitive or
specific than the other. A meta-analysis of prospective
studies[18] comparing cytologic diagnosis and sample
adequacy of liquid-based cervical cytologic smear
study and conventional Papanicolaou smears found
that The ThinPrep test had improved sample adequacy
and improved diagnosis of low-grade and high-grade
squamous intraepithelial lesions. The same study
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African Journal of Health Sciences, Volume 27, Number 4, October-December 2014
found that there was no difference in the rate of
atypical cells of undetermined significance diagnosis
between ThinPrep and conventional smear groups.
Another study[4] compared a liquid-based (ThinPrep)
cytology test and a conventional Pap smear as method
for the detection of CIN I-CIN II lesions found
conflicting results. Liquid-based cytology test had
better sensitivity than a Pap smear test. Besides, the
agreement between the diagnosis of the liquid-based
test and histology was higher for the liquid-based test
than the Pap smear test. Other studies reported that
the liquid based cytology test showed no significant
difference in sensitivity to conventional cytology [4,
19]. Over all, the liquid-based test is convenient
because a HPV DNA test can also be conducted using
the same sample. Besides, LBC produces clear slides
which can be easily read and so the proportion of
ASCUS is lower than for the Pap smear test.
There is evidence to suggest that VIA has a higher
sensitivity in detecting CINII or worse lesions than a
Pap smear test. A Brazilian study [20] found that VIA
had the best performance in detecting CINII or worse
lesions, HC II had the highest sensitivity and the Pap
smear was the most specific test.
Although cervicography had poor performance when it
was first used in 1981, it performs marginally better
that LBC for the detection of invasive cervical cancer
but is not recommended for post-menopausal women
[21]. It has a moderately higher sensitivity and a very
high specificity in the special case of high-grade
squamous intraepithelial lesions (HSILs).Cervicography
is in general of slightly high performance than the Pap
smear [22]. The overall performance of cervicography
is poor when compared to HPV tests.
The HPV test can be performed on a sample of
cervical cells collected by a physician (Physician HPV
test) or by the woman herself (Self-HPV test). In
general, HPV tests perform better than cytology-based
tests [23, 24] and VIA. However, a study found that
the sensitivity of Self-HPV testing compared
favourably with that of LBC and was superior to the
sensitivity of VIA [25]. The physician HPV test
performs better than the Self-HPV test although the
margin is narrow. VIA and VILI are slightly more
sensitive but less specific than Pap [26].
Designing an evaluation study
There are several aspects of a diagnostic test which
can be assessed such as sensitivity, specificity and
predictive value, false positive rate and false negative
rate. However, for screening purposes, the sample
size should be based on the comparison of the
sensitivity of the screening tests. For each possible
pair wise comparison we compute a sample size using
the following formula:
( ) ( )
( )
c
pp
pppp
n
ji
jjii
s .
11
2
-
-+-
=
where
ns is the sample size for comparing test i and test j
pi is the sensitivity of test i
pj is the sensitivity of test j
c is a quantity depending on choice of power and
signicance level. Possible values of c are given in the
below (Table 5).
Table 5: Values of c for different values of power and
significance level
Significance
level(Two-sided)
Power
0.8 0.9 0.95
0.10 6.2 8.6 10.8
0.05 7.9 10.5 13.0
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African Journal of Health Sciences, Volume 27, Number 4, October-December 2014
0.01 11.7 14.9 17.8
Source: Laake et al(2007)
The effective sample size for an evaluation study will
be the sample given by the
formula: { }snnnn ,...,,max 21= . In other words, all
the sample sizes for the 10 potential comparisons will
be compared and the biggest sample size will be
chosen as the sample size for the evaluation study.
Before women are screened, consent should be
obtained. Pregnant women shouldn’t be included in
screening activities. Before women are screened, they
should be advised that a day before screening they
musn’t :
i) Use a tampon
ii) Have sex
iii) Use a birth control foam, jelly or cream
iv) Use any medicine in the birth canal.
Conducting the evaluation study
Screening for cervical cancer is a procedure which can
be interpreted as a violation of sexual modesty as the
subject to be screened has to be partially undressed in
which case the genital region is exposed. Because of
this, before screening is done, women have to be
counselled and assured that confidentiality will be
maintained. The reasons for screening have to be
politely and clearly explained in order to achieve
maximum participation in screening activities. The
benefits of screening should also be explained before
a woman undergoes a screening test. The immediate
benefit of participation should be the possible follow up
of abnormal screening results for further testing and if
appropriate, treatment.
The five screening tests namely the Pap cytology test,
VIA, LBC, Cervicography and HPV test can all be
conducted on the same woman. For this to be feasible
these tests must be conducted following a proper
sequence in stages, one at a time. On the first stage,
the Pap smear or LBC can be conducted. From the
LBC sample an HPV test can also be conducted.
Cervicography depends on how clear the cervigram is.
The clearest picture of the cervix can be taken as soon
as acetic acid is applied. Therefore, VIA must follow
cervicography because in that case one is assured of
taking a good picture. If the aim is to compare all 5
tests, there are 10 possible pair wise comparisons
which can be made among the screening tests.
The true disease status of each woman should be
established by performing a biopsy. The number of
positives, sensitivity, specificity, false positive rate,
false negative rate and predictive values of each test
should be computed with corresponding
( )%1100 a- confidence intervals. The performance of
the tests can then be compared based on these
statistics. The cost-effectiveness of each screening
test should also be assessed and results for all tests
should be compared. A method should be selected
based its performance and cost-effectiveness. A
combination of screening tests can also be adopted if
the methods are cost-effective and of high
performance.
Acknowledgements
I am thankful to NUFU who provided funding during
the late 2013 when I started working on this paper.
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