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Methods of Detecting Cervical Cancer

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Advances in Biological Research 5 (4): 226-232, 2011
ISSN 1992-0067
© IDOSI Publications, 2011

Methods of Detecting Cervical Cancer

Krishnakumar Duraisamy, K.S. Jaganathan and Jagathesh Chandra Bose

Shantha Biotechnics, Hyderabad, India

Abstract: Cervical cancer is the second most common cancer in women worldwide, with more than half a million
new cases diagnosed in 2010. The disease disproportionately affects the poorest regions—more than 80% of
cases are found in developing nations, mainly in Latin America, sub-Saharan Africa and the Indian
subcontinent. Cervical cancer is an important cause of early loss of life as it affects relatively young women.
Important advances have taken place in the diagnosis and treatment of this cancer in recent years. Surgery or
chemo radiotherapy can cure 80-95% of women with early stage disease (stages I and II) and 60% with stage
III disease. An ideal screening test is one that is minimally invasive, easy to perform, acceptable to the subject,
cost-effective and efficacious in diagnosing the disease process in its preinvasive or early invasive state when
the disease process is more easily treatable and curable. A variety of screening tests have therefore been
developed in an attempt to overcome the innate limitations of conventional cytology. Screening techniques for
cervical cancer include Conventional exfoliative cervicovaginal cytology i.e. the cervical (Pap) smear, Fluid
sampling techniques with automated thin layer preparation (liquid based cytology), Automated cervical
screening techniques, Neuromedical systems, HPV testing, Polar probe, Laser induced fluorescence, Visual
inspection of cervix after applying Lugol’s iodine (VILI) or acetic acid (VIA), Speculoscopy, Cervicography.
The screening strategies mentioned above though applicable to the developed world may not be cost effective
enough for widespread application in the third world countries. Currently, cervical cytology is widely regarded
as the gold standard for cervical cancer screening in all developed countries. It is however not feasible to
implement a systematic cytology based screening programme in a country like India. This is mainly due to
severe restrictions on the availability of infrastructure, resources and funding. There is therefore a need to
develop low cost screening strategies for cervical cancer. This will necessarily involve the use of a very simple
technique that can be easily taught to and practiced by paramedical personnel in the rural areas. Such
techniques will need to be cost effective while retaining adequate sensitivity and specificity to perform as
practical screening techniques.

Key words: Cervical Cancer HPV Pap Test Cytology

INTRODUCTION between the columnar epithelium of the endocervix and

squamous epithelium of the ectocervix where there is
Cervical cancer is one of the most common types of continuous metaplastic change. Since maximum
cancer among women worldwide. The good news is that metaplastic activity occurs at puberty and first pregnancy
92% of the cases can be detected (Table 1) and treated if between 18-30 yrs of age, hence detected during active
a woman undergoes regular pelvic exams and Pap tests sexual life. All women are at risk of developing the
[1]. Many methods currently exist to detect cervical disease, but several factors can increase the risk. The
cancer. Cancer of the uterine cervix is a leading cause of risk factors for cervical cancer are viral infections
mortality and morbidity among women worldwide. In India (HPV, HIV, HSV), multiparity, early initiation of sexual
cervical cancer is still the most common cancer and activity, multiple sex partners, smoking, low
occupies the top rank among cancers in women in socioeconomic status, diet low in antioxidants, long term
most developing countries, constituting 34% of all use of oral contraceptives and poor hygiene etc.Since
women’s cancers. Most cervical cancers arise at the early detection predicts better prognosis, one of the most
squamo-columnar junction and transformation zone effective ways of preventing and controlling cervical

Corresponding Author: Krishnakumar Duraisamy, Shantha Biotechnics,

Hyderabad, India. E-mail: [email protected].
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 Advan. Biol. Res., 5 (4): 226-232, 2011

Table 1: Key Statistics on India

Population
Women at risk for cervical cancer (Female population aged >=15 yrs) 366.58 millions
Burden of cervical cancer and other HPV-related cancers
Annual number of cervical cancer cases 134420
Annual number of cervical cancer deaths 72825
Projected number of new cervical cancer cases in 2025* 203757
Projected number of cervical cancer deaths in 2025* 115171
WHO Cervical cancer summary report update. September 15, 2010

S.No Screening methods

1 Conventional exfoliative cervicovaginal cytology i.e. the cervical (Pap) smear
2 Pelvic Examination
3 Colposcopy
4 Liquid based cytology
5 Automated cervical screening techniques
6 Neuromedical systems
7 HPV testing
8 Polar probe
9 Laser induced fluorescence
10 Visual inspection of cervix after applying Lugol’s iodine (VILI) or acetic acid (VIA)
11 Speculoscopy
12 Cervicography

cancer is regular screening and early diagnosis. vaginal intercourse is initiated and no later than the
Despite the fact that more than 80% of cervical cancer age of 21 [2]. For most women, the test is recommended
cases are in developing countries, only 5% of women every one to three years, depending upon the woman's
there have ever been screened for cervical abnormalities age and history of abnormal results. For women who
(WHO 2006). Cervical screening is a way of checking have a past history of an abnormal screening test or who
women regularly for changes in the cells in the cervix. have risk factors for cervical cancer, testing is
Invasive cervical cancer is largely preventable if recommended once per year (Picture 1). The
precancerous lesions are detected by effective screening Papanicolaou (Pap) smear is the most common screening
and then adequately treated. Several screening modalities method used to detect precancerous changes for
are now available for early detection of cervical cancer squamous cervical cancer. However, other methods, i.e
and its precursor lesions. It is normally recommended that liquid based cytology and HPV testing are now the most
cervical cancer screening should begin three years after advocated tests.

PAP TEST

NORMAL ABNORMAL

BORDERLINE CLEARLY
ABNORMAL ABNORMAL

LIQUID BASED
CYTOLOGY
TEST
ROUTINE SCREENING FURTHER STEPS
EVERY 3 YEARS POSITIVE &TREATMENT

Picture 1: Frequency of PAP test

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 Advan. Biol. Res., 5 (4): 226-232, 2011

Papanicolaou (Pap) Smear Test: The most common form white. The doctor can then view the cells using the
of diagnosis for detecting cervical cancer in its early high-powered microscope to detect any abnormal
stages is a procedure called a Papanicolaou test or Pap cancerous cells [7]. It is used not as a screening test, but
smear. This test is painless, normally takes less than 5 as a diagnostic test.Conization or Cone Biopsy,
minutes to complete and can be performed in a doctor´s Edocervical Curettage, LLETZ/LEEP and imaging
office. Women who are 18 or older or who are sexually procedures are further techniques which may be applied
active are recommended to undergo annual Pap smear when diagnosing cervical cancer.
tests [3]. The procedure is performed while a woman is
lying on her back on a table. The doctor will insert an Liquid-Based Cytology (LBC): All currently available
instrument called a speculum inside her vagina before cytology technologies rely on the visual analysis of
removing some cells from the cervix using a cotton swab exfoliated cells from the uterine cervix. Improvement of
or small brush. The cells are then sent to a laboratory conventional cytological screening has been proposed by
where they are studied under a microscope to determine the introduction of molecular-based markers applied to
if any precancerous or cancerous cells exist. If the tests liquid based cytology (LBC). It was developed to address
show any abnormalities, the patient will be asked to return the limitation of Pap smear and represents the first major
to the doctor so an additional test can be performed. If the change in preparation method for cervical screening
test results are negative, women can schedule an annual samples. Instead of cells being smeared onto a glass slide,
appointment (Picture 1) [4]. they are washed into a vial of liquid and filtered and a
The value of the Pap test in cervical carcinoma random sample is presented in a thin layer on a glass
screening is undisputed. Routine cytological screening by slide. DNA methylation changes occur very early in
this method has resulted in a reduction in the cervical carcinogenesis and identification of appropriate DNA
carcinoma mortality rate of close to 60% in women aged 30 methylation markers in such samples should be able to
and older. However, several limitations of conventional distinguish high-grade squamous intraepithelial lesions
Pap smear were identified; sensitivity to detect cervical (HSIL) from nonspecific cytology changes and the normal
cancer precursors is less than 50%, inadequate transfer of cervix [8] The liquid based cytology (LBC) corresponds to
cells to slide, in homogenous distribution of abnormal a sampling where cells are put in suspension in a
cells, presence of obscuring blood, inflammation or thick conversation liquid. For the clinician, the sample is
areas of overlapping epithelial cells. The occurrence of made the same manner as that of the conventional
false-negative and unsatisfactory Pap smears has smear by using a plastic brush, which can take the
prompted the development of LBC and automated squamo-columnar junction and the endocervix, or by
screening devices [5]. combining the use of a spatula and an endocervical brush.
The taken material is then immediately rinsed in the bottle,
Pelvic Examination: A pelvic examination is also an which contains a fixative allowing transport to the
important method of detecting cervical cancer. The exam laboratory. A part of the sizable brush can be left in the
is very similar to the Pap smear. A woman lies on her back bottle. The clinician does not have to deal with any
while a doctor inserts a speculum into her vagina. A spreading, which is done at the laboratory. Currently, two
doctor will then examine a woman´s vagina and technical methods, which use automats, were validated by
surrounding organs both visually and manually. He will Food and Drug Administration (FDA) and are used
insert gloved fingers and gently feel the cervix and frequently [9].
surrounding organs with his fingers, while his other hand One is proceeding by filtration and collecting cells
presses gently on the patient´s stomach [6]. vacuum-packed on a membrane with transferring cells on
a glass (ThinPrep®, Cytyc®). The other is proceeding by
Colposcopy: Colposcopy is magnified visual examination centrifugation and sedimentation through a gradient of
of the ectocervix, SCJ and endocervical canal using a density (Surepath®, Tripath Imaging®). Cytoscreen
special instrument called a colposcope.It may be System® (SEROA®), Turbitec® (Labonord®), CellSlide®
accompanied by a biopsy of any abnormal-looking tissue (Menarini®) and Papspin® (Shandon®) technics are
is very similar to a Pap smear. A woman will lie on her centrifugation and sedimentation manual techniques,
back while a doctor inserts a speculum into her vagina. He which do not use automate and do not require a FDA
will also apply a local anesthetic to her cervix as well as a agreement [10].
special solution that will stain any abnormal cells Current methods that use LBC technology include:

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 Advan. Biol. Res., 5 (4): 226-232, 2011

SurePath (formerly AutoCytePREP or CytoRich LBC): of LBC due to the reduction of recalls for a new sample.
The SurePath method requires that the collection device The advantage of LBC includes improved sensitivity and
be retained in the proprietary SurePath collection vial, specificity since fixation is better and nuclear details are
which contains transport fluid, so that all cervical cells well preserved. There is, therefore, lower rate of
collected are sent to the laboratory. Vials are vortexed and unsatisfactory cervical samples. Another major advantage
centrifuged by laboratory personnel; all subsequent of LBC is that the residual specimen can be used for
preparation of the sample and slide is automated using ancillary testing like Immunocytochemistry and detection
the Prepstain machine, which processes 48 samples at a of HPV DNA [15].
time [11].
Automated Screening Technology: The effectiveness of
Cytoscreen: Cytoscreen is a manual method of sample any cervical cancer screening program that relies on
preparation using a proprietary sample collection device cervical cytology is the quality control of the cytological
(CYTOPREP) and transport fluid (CYTeasy). Samples are review of Pap smears. This is essential for reducing the
vortexed and a photometric reading taken to estimate the false positives and false negatives that invariably result
cellularity of the sample. An aliquot of the sample is from inter- and intra- observer variation [16] Automated
centrifuged onto a glass slide that is then stained using screening techniques have recently been developed that
normal laboratory procedures [12]. can not only perform this quality control rescreening but
also can be used for primary screening of cervical smears.
Labonard Easy Prep: Labonard Easy Prep is a manual The Autopap300 (TriPath Imaging, Burlington NC) and
method of sample preparation that uses a proprietary PAPNET (Neuromedical systems) are the two automated
sample collection device (CYTOPREP brush) and fixative screening techniques that rely largely on neural network
(CYTOscreen). An aliquot of sample fluid is placed in a technology and are based on the computerized imaging
separation chamber attached to a glass slide containing and identification of abnormal cervical cells. Among this
absorbent paper. only the Autopap300 is approved by the USFDA for
Cervical cells sediment onto the slide in a thin layer primary and secondary cervical screening while the
and slides are stained using normal laboratory PAPNET is only approved for secondary screening [17].
procedures [13].
Hpv-Dna Testing: The etiopathological role of HPV in the
Thin Prep: ThinPrep provides a semi-automated (T2000) development of cervical cancer has been proved beyond
or fully automated (T3000) method of sample preparation. doubt. HPV 16, 18, 31, 33, 35, 39 45, 51, 52, 56, 59 and 68
Cervical samples are rinsed with proprietary PreservCyt are known to be frequently associated with HSIL and
transport medium into a vial, which is then processed by invasive cancers of the cervix [18]. Testing for the
the ThinPrep method using the T2000 or T3000 machine. presence of HPV-DNA in the cervical cells is thus a
The T2000 machine processes slides individually, while potentially useful screening method, which could be
the T3000 machine is a fully automated device that can incorporated in cervical cancer screening programs. There
batch process up to 80 specimens per cycle. Subsequent are various techniques available for HPV-DNA testing of
staining and microscopic evaluation of the slides is which Southern Blot hybridization is regarded as a
conducted in a similar manner to a conventional smear laboratory gold standard. This is however unsuitable for
test [14]. clinical use as it is laborious, tedious and requires fresh
The quality of the evaluation of the performance of tissue. The specimen for HPV-DNA testing can be
these technologies often was poor and rarely on the basis obtained in two ways, either by using a cell suspension
of histologically defined outcomes using randomised from liquid based cytology or by using the endocervical
study designs. In general, the proportion of cytobrush [19].
unsatisfactory samples is lower in LBC compared with
conventional cytology and the interpretation of LBC Visual Inspection of the Cervix with Acetic Acid (VIA):
requires less time. The cost of an individual LBC test is The technique is very simple and consists of an
considerably higher, but ancillary molecular testing, such examination of the cervix after acetic acid application.
as high-risk HPV testing in the case of atypical squamous After obtaining the clinical history and performing a
cells of undetermined significance (ASC-US), can be general examination, the cervix is exposed using a bivalve
carried out on the same sample. The economic advantage speculum. A 4% dilute solution of acetic acid is then

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 Advan. Biol. Res., 5 (4): 226-232, 2011

applied to the cervix and any excess liquid is aspirated Laser Induced Fluorescence: Various investigators have
from the posterior vaginal fornix. The cervix is inspected shown that low powered laser illumination can induce
after two minutes. Lesions which stain acetowhite are endogenous tissue fluorescence. This depends upon the
regarded as positive for VIA. Those with dull white chemical and morphological composition of individual
plaques and faint borders are considered low grade VIA tissues. The spectroscopic difference if detectable can be
while those with sharp borders are considered high grade used to differentiate normal and diseased tissues [22].
VIA. The test is regarded as being negative if no
acetowhite lesions are detected [20]. Studies have shown Computer Imaging: The diagnosis of precancerous
that VIA is a reliable, sensitive and cost effective changes is primarily a task of visual discrimination and
alternative to conventional Pap smear testing, particularly sorting of graphical information. Recently there has been
in low resource settings. VIA is better than Pap smear for a lot of focus on the use of computers to assist this
identifying CIN—especially if a woman is tested only process. This is very similar to cervicographic technics
once in her life.VIA is simple to perform and provides an except that a computer replaces the colposcopy expert.
immediate result without expensive equipment. However a lot of research needs to be done to critically
evaluate this technology before it can be incorporated
Visual Inspection with Lugol’s Iodine (VILI): VILI is also into a screening program.
promising as a visual method to screen for cervical
cancer.After the woman’s cervix is examined using VIA, Comparison of Visual Inspection with Acetic Acid and
the cervix is painted with Lugol’s iodine solution and Cervical Cytology to Detect High-Grade Cervical
examined again with the naked eye. The small high-grade Neoplasia: As a point-of-care clinical test, VIA is easy
lesion is easier to see within the larger low-grade area. and inexpensive to perform, can be taught to non
Normal squamous epithelial cells have substantial stores physician health workers and can link screening and
of glycogen. diagnostic or treatment interventions in the same clinic
Glycogen stains mahogany-brown with iodine visit. On the other hand, there are significant real-world
solution. Abnormal areas of squamous epithelium challenges in implementing cytology- based screening in
(CIN or inflammation) do not contain glycogen to the resource-limited settings. Adequacy of samples is
same extent and do not stain brown [21]. VILI is more hampered by challenges in sample collection and slide
accurate and more reproducible than VIA and better than preparation. Even in the hands of highly qualified
a Pap smear for identifying CIN. VILI is simple to perform pathologists, cytological interpretation is precariously
and provides an immediate result without expensive modest in its detection rate and sensitivity. Besides, the
equipment. costs and inconvenience of multiple clinic visits and the
resulting poor compliance in cytology-based screening
Speculoscopy: Speculoscopy involves inspection of the programs are significant barriers to successful cervical
cervix following the application of 5% acetic acid with cancer control for most resource-limited settings.
chemiluminiscent light and a low power magnification.
Conventional Pap Smear and Liquid Based Cytology for
Cervicography: Cervicography involves taking Cervical Cancer Screening: Cervical cytology was
photographs of the cervix using a special camera introduced by George Papanicolaou into clinical practice
following the application of 5% acetic acid during a in 1940. In 1945, the Papanicolaou smear received the
routine pelvic examination and Pap smear collection. The endorsement of the American cancer society as an
photographs are then developed and the slide is effective method for the prevention of cervical cancer.
projected on a 2x2 meter screen and read by an expert in Center of cytology in Vancouver, British Columbia
colposcopy. published data which confirmed that cytologic screening
leads to a reduction in the rate of invasive cancer of the
Polar Probe: This technology is based upon the fact that uterine cervix. Park et al. established that the sensitivity
the tissue impedance to electrical stimulation differs of the conventional Pap smears for the detection of
between normal and abnormal tissues. Investigators cervical cancer precursors was less than 50%. Several
have tried to utilize spectral and electrical stimulation of limitations of conventional smear were identified including
the cervical tissues as an adjunct to conventional Pap inadequate transfer of cells to slide, in homogenous
smear testing. distribution of abnormal cells, presence of obscuring

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 Advan. Biol. Res., 5 (4): 226-232, 2011

blood, inflammation or thick areas of overlapping vaccines will reduce the efficiency of screening by
epithelial cells. Liquid based, thin layer technology was any method, while introduction of HPV testing is likely
developed to address the limitation of Pap smear. More to lead to increased screening sensitivity that should
than 5,00,000 subjects have been studied with a permit lengthened screening intervals. It is not yet clear
preponderance of data indicating a significant benefit of how to optimally combine prevention and screening
liquid-based, thin layer technology in the detection of options. The further evolution of screening practices
cervical cancer precursor lesions and in the improvement should follow high-quality data on comparative
of specimen adequacy. effectiveness.
The Pap smear has been utilized for cervical cancer
screening for more than 50 years. Despite being credited CONCLUSIONS
with a 70% reduction in mortality for cervical cancer, the
false negative rate is still a cause for concern. It is widely Over the past few years, in most industrialised
acknowledged that two third of the overall false negative countries women with cervical cancer have benefited
rate can be attributed to sampling errors. Liquid based from improved imaging techniques, better treatments
cytology has been developed to address the sampling (including chemoradiotherapy) and more conservative
problems of conventional Pap smear. The present work surgical approaches. In low resource settings-where
was done to evaluate the liquid based cytology and to facilities for radiology, chemoradiotherapy and supportive
compare the sensitivity of the same with conventional Pap care are limited or unavailable-it is important to identify
smear.Liquid based cytology is strongly advocated in the which resources fill healthcare needs most effectively and
best interest of public health, by improving the quality of to consider alternative approaches.
the sample and reducing the likelihood of false negative
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