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Cancer Therapy Vol 3, page 231
Cancer Therapy Vol 3, 231-236, 2005
Cervical cancer screening
Review Article
Malihe Hasanzadeh and Nadereh Behtash*
Gynecology Oncology Department, Vali –Asr Hospital, Tehran University of Medical Sciences, Keshavarz Blvd., Tehran
14194, Iran
__________________________________________________________________________________
*Correspondence: Nadereh Behtash, Associate Professor, Gynecologist Oncologist, Tehran University of Medical Sciences.
Gynecology Oncology Department, Vali-e-Asr Hospital, Imam Khomeini Hospital Complex, Keshavarz Blvd., Tehran 14194, Iran.
Phone: #98-21-6939320, Fax: #98-21-6937321, E-mail: [email protected], [email protected]
Key words: Cervical cancer screening, cervical cytology, Pap smear, Human papilloma virus, Cervicography, Speculoscopy, Truscan
(Polarprobe), Visual inspection with acetic acid (VIA)
Abbreviations: cervical intraepithelial neoplasi,a (CIN); human papilomavirus, (HPV); Papilloma viruses, (PV); Visual inspection with
acetic acid, (VIA)
Received: 28 February 2005; Accepted: 8 March 2005; electronically published: April 2005
Summary
Cervical cancer is the second most common cancer in women throughout the world and it is the leading cause of
cancer death among the women in underdeveloped countries. Regarding the known etiology, availability of the
organ, the possibility of proper screening test and the long latency between the precancerous lesion and the full
blown clinical cancer, screening programs have been able to drastically curtail the incidence and fatality rate of the
disease. The extent of the reduction in mortality achieved is related directly to the proportion of the population that
has been screened. In this article, we discuss about different screening methods for cervical cancer.
beginning of a screening program in a previous unscreened population, by detecting prevalent cases of
invasive cancer in earlier stages. Although it has not been
proved in a prospective randomized study, all investigators
credit screening as a major contributor to this reduction in
death rate.
In contrast to the industrialized world, cancer of the
cervix remains the primary cancer killer in women in
third-world countries (Disia and Cresman, 2002). During
the last decade there has been increasing emphasis on
cervical cancer screening in both governmental health
services and private medical practitioners in our country
(Annual report of Tehran university of medical sciences,
district cancer registry (TUMS- DCR), 1997; Behtash et
al, 2003).
Cancer deaths may also be prevented by detecting
disease at a stage when it is more curable. To be
successful, a screening program must be directed at a
suitable disease with a suitable screening test (Cole and
Morrison, 1980).
A suitable disease must be one that has serious
consequences, as most cancers do. Treatment must be
available so that when such therapy is applied to screendetected (preclinical) disease, it will be more effective
than when applied after symptoms of the disease have
appeared. Also, the preclinical phase of the disease must
I. Introduction
Invasive squamous cell carcinoma of the cervix is the
end stage of a process beginning with atypical
transformation
of
cervical
epithelium
at
the
squamocolumnar
junction,
leading
to
cervical
intraepithelial neoplasia (CIN) of advancing grades and
eventual invasive disease (Berek et al, 2000). Cervical
cancer is the second most common cancer in women
throughout the world and it is the leading cause of cancer
death among women in underdeveloped countries (Solar et
al, 2000; Cohn de and Herzog, 2001; Naud et al, 2001).
There is convincing evidence that
cytologic
screening programs are effective in reducing mortality
from carcinoma of the cervix. The extent of the reduction
in mortality achieved is related directly to the proportion
of the population that has been screened. In fact all studies
worldwide show that screening for cancer not only
decreases mortality but also probably does so by
decreasing the incidence.
Numerous paper and lengthy discussions have
focused on the optimal screening interval, unfortunately
numerous recommendations during the last decade and a
half have resulted in a confused public and dissatisfied
professionals.
Screening decreases cervical cancer mortality by
detecting pre-invasive disease and, specially at the
231
Hasanzadeh and Behtash: Cervical cancer screening
be long enough that the chances are good that a person
will be screened.
There must also be a suitable screening test as
defined by simplicity, acceptability to patients, low cost,
and high validity (Berek et al, 2000).
The sample is unrolled onto the slide in the opposite
direction from which it was collected by twirling the
handle of the brush.
Based on a meta- analysis of 84 appropriately
designed and conducted studies, the Agency for Health
Care Policy and Research reported that conventional
cytology has a specificity of 98% and a sensitivity of 51%.
It has become clear the sensitivity of conventional
cytology is even lower that traditionally recognized
(Apgar et al, 2002).
However, even with this limited sensitivity, if three
consecutive tests are negative, there is less than a 1%
chance that the patient will have a cervical
abnormality(Rock and Jones, 2003).
A false- negative Papanicolaou smear may result
from either screening or interpretation problems.
Screening problems include lesions that do not shed cells
or that are not sampled by the clinician, or, sometimes, the
diagnostic cells are not transferred from the spatula or
collection device to the glass slide(Rock and Jones, 2003),
Rarely, the slide preparation or staining is unsatisfactory.
In other patients, problems with interpretation include
failure to identify abnormal cells or misinterpretation of
cells that are diagnosed as reactive or metaplastic when a
dysplastic lesion exists. Various studies have shown the
women who are diagnosed with invasive cervical cancer
after a reportedly "negative" Papanicolaou smear, most
often have abnormal cells on review of their slides. The
diagnostic cells may be few in number or obscured by
blood or inflammatory changes (Rock and Jones, 2003).
II. Terminology in cervical cytology
George Papanicolaou devised the first system of
reporting cervical cytology results and based the
classification on the degree of certainty that malignant
cells were present (Davey et al, 1992).
The current cytologic terminology, the Bethesda
system was the result of the work of an expert panel which
convened in 1988 under the auspices of the National
Cancer Institute. It was revised in 1991 and again in 2001
(National Cancer Institute Workshop, 1989).
III. The cervical cytology
After the introduction of cervical cytology for cancer
screening more than 50 years ago, multiple screening
programs from all parts of the world have reported
decreased rates of invasive cervical cancer and decreased
death rates from a malignancy that had previously been the
number one worldwide cause of cancer death in
women(Disia and Cresman, 2002).
Despite the effectiveness of cervical cytology
screening programs, there are several limitations of
Papaniclaou smear screening.
A single Pap smear has a sensitivity of only about
51% (Apgar et al, 2002).
The cytologic sample should not be collected during
the menstrual period. The patient should avoid vaginal
medications, vaginal contraceptive or duches during the 48
hours before the appointment and intercourse is not
recommended on the night before or the day of the
examination(Apgar et al, 2002). From the standpoint of
obtaining ideal cytology, postpartum Pap smears should
not be performed until at least 6 or even 8 weeks after
delivery, by which time the cervix has undergone
reparative changes (Rarick and Tchabo, 1994).
If the woman is postmenopausal and previous smears
have lacked endocervical cells or have demonstrated
atrophy with inflammation, the cervix may be primed with
3 weeks of treatment with intravaginal estrogen cream
followed by repeat cytologic sampling use of a
combination of the Ayre spatula for sampling the
ectocervix and a brush for sampling the endocervix has
been shown to be superior to other techniques for
obtaining a conventional Pap smear (Toffler et al, 1993).
The quality of the smear can be improved by using
the spatula first, followed by the endocervical brush,
because fewer smears will be obscured by blood
(Eisenberger et al, 1997). The spatula is first placed at the
cervical os, using the end the best conforms to the cervical
anatomy. It is rotated 360 degrees about the circumference
of the maintaining contact with the ectocervix. The sample
smeared on the slide must be fixed immediately. Both
slides of the spatula should be smeared on the slide. The
brush is then inserted in to the os and rotated 180 degrees
similarly.
IV. Liquid-based, thin–layer cytology
To decrease the false- negative rate of cervical
cytology, attempts have been made to improve both
specimen collection and quality and to reduce errors of
interpretation. Over the past several years, several liquidbased techniques have been approved by Food and Drug
Administration in United States. Those techniques differ
from the conventional method of Papaniclaou smear, once
the clinician obtain a scraping of the squamo columnar
junction and transformation zone, the spatula and brush
are dipped and agitated in a small bottle of fixation
solution to elute the cell rather than being smeared on a
glass slide. Once in the lab, a machine prepares a slide
containing about 40,000 representative epithelial cells in a
thin layer. The slide is the stained and reviewed by the
cytologist (Rock and Jones, 2003).
Liquid- based, thin -layer technology was developed
to address the five major limitation posed by conventional
Pap smear: failure to capture the entire specimen,
inadequate fixation, random distribution of abnormal cells,
obscuring elements, and technical variability in the quality
of the smear.
Despite the limitations of the current data, more than
500,000 subjects have been studied, with a preponderance
of data indicating a significant benefit of liquid- based,
thin- layer technology in the detection of cervical cancer
precancer lesions and in the improvement of specimen
adequacy (Apgar et al, 2002).
Only one published study to date failed to find more
squamous intraepithelial lesion in the liquid- based slides
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Cancer Therapy Vol 3, page 233
than in the conventional Pap smear, showing a
nonsignificant 3% decrease in the detection of squamous
intraepithelial lesions (Takahashi and Naito, 1997).
Liquid-based cytology has been shown to aid in
reducing the proportion of ASCUS diagnoses, probably
based on improvements in both the fixation and the quality
of the slide. Also Ashfaq et al reported a signigicant
improvement in the detection of adenocarcinoma of the
cervix, with a 65% decrease in the false negative rate for
the diagnosis of adenocarcinoma by Thin-prep over the
conventional Pap smear, as well as 64% increase in the
specificity of a diagnosis of AGUS or adenocarcinoma
(Ashfaq et al, 1999).
Re-training of cytotechnologists on liquid-based
cytology is needed because the characteristics of the cells
differ from conventional cytology.
hybridization and quantification by chemiluminescence
reaction to identify the presence of any of 13 different,
oncogenic types HPV.
Because HPV is difficult to culture one or more of
three nucleic acid- based tests have been used for detecting
and typing HPV in specimens: the Polymerase Chain
Reaction, the Hybrid Capture II System and In Situ
Hybridization (Apgar et al, 2002). Nevertheless, HPV
testing is easy to perform and is a relatively inexpensive
test that can be automated in the laboratory and requires
no interpretation (a problem with the Papanicolaou test).
HPV testing has been shown to be 15% to 20% more
sensitive than the conventional Pap smear and at least 10%
more sensitive than liquid- based Pap smears while
exhibiting an equivalent specificity in the relevant defined
subgroups of women (Cuzick et al, 1999; Krumholz, 2000;
Wright et al, 2000).
The most compelling data for clinical utility of HPV
DNA testing in patient management relates to women with
ASCUS Pap smears. Based on data, the immediate HPVbased triage of ASCUS would result in a sensitivity of
90% to 96% compared with 75% to 85% for the repeat
Pap smear (Kuperman et al, 2000).
The Pap smear was slightly more specific than HPV
DNA testing for the presence of high grade cervical
disease (Apgar et al, 2002).
HPV testing does not appear to be beneficial in
young women, who are known to have predominantly
transient HPV infection. Thus, most HPV screening
strategies call for HPV DNA testing in women older than
30 years (Clavel et al, 1999). HPV testing combined with
cytology is a reasonable approach in elderly women in
order to increase the screening interval to 3-5 years (Fehr
and Welti, 2004).
V. Computer-assisted diagnosis
These techniques have been used mostly for quality
control to identify slides that have been read as normal by
cytotechnology screeners but that have cellular
characteristics recognized by the computer as suspicious
(Duggan, 2000).
There is good evidence to suggest that computerassisted diagnosis is even better when liquid- based, thinlayer slides are used because the background is much
cleaner and there are fewer cell clumps with diagnostic
cells obscuring another. Although the initial cost of a
computer- based system is large, considerable saving
should be realized by the around- the-clock work reduced
need for cytotechnologists who could concentrate on the
diagnostic evaluation of high- risk slides identified by the
computer on primary screening (de Villiers, 1997). More
clinical experience with these computer techniques is
needed but results are promising.
VII. Adjunctive testing
A. Cervicography
VI. Human papilloma virus typing
Cervicography has been proposed as a adjunctive
test that would increase the sensitivity and specificity of
the Pap test in detecting precancerous and invasive
cervical disease. Cervicography is not promoted as an
independent or stand – alone test. In 1980, Adolf Stafl,
invented a diagnostic methods, he called cervicography
using an apparatus he called the cervicograph.
The procedure uses the cerviscope camera to take a
color picture of the cervix after 5% acetic acid has been
applied to it. The film is developed in to 35mm slides, and
the resulting slide image is projected on to a screen and
evaluated by an expert colposcopist. Cervigram are
reported in one of four categories: negative, atypical,
positive, and technically defective.
Early studies of cervicography reported a sensitivity
the ranged from 89% to 92% for the detection of highgrade lesions or invasive disease, but the specificity was
low. Changes on the cervigram report form have resulted
in increased specificity, but at the expense of a decreased
sensitivity as low as 49.2% in one study (Stafl, 1981;
Tawa et al, 1988).
In several studies, cervicography has detected
cervical cancer when the cervical cytology was
normal(Apgar et al, 2002).
Papilloma
viruses
(PV)
are
ubiquitous
microorganisms that cause productive and/ or latent
infections in a wide variety of species and tissues. To date,
more than 90 types of human papilomavirus (HPV) have
been detected (de Villiers, 1997).
Many of the newly discovered HPV types in the male
and female anogenital tract were associated with cervical
cancer and cancer precursors. The most prevalent
anogenital HPV can be divided in to three groups: low,
intermediate and high oncogenic risk.
Emerging technologies such as HPV vaccines
(Kulasingam and Myers, 2003), HPV tests (Mandelblatt et
al, 2002) and enhanced pap screening methods are leading
policy markers to evaluate new guidelines for
incorporating these technologies into current care
practices, and to consider changes to the frequency of
cervical cancer screening and management of cervical
HPV- related disease (Insinga et al, 2004).
HPV testing in the past has been inaccurate and the
complex laboratory techniques are not conductive to large
volume clinical work. However, with the newer secondgeneration Hybrid Capture techniques, these problems
seem to have been resolved. Current technology uses DNA
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Hasanzadeh and Behtash: Cervical cancer screening
In addition to being as an adjunctive test,
cervicography has been used as a valuable research tool,
for chart documentation, for teaching colposcopy
recognition skills, and in the testing and monitoring of
colposcopic skills (Apgar et al, 2002).
approach in underdeveloped countries (Ghaemmaghami et
al, 2004; Millogo et al, 2004).
The major concern about VIA test is its low
specificity (a high false- positive rate), which means that
many subjects must be recalled for colposcopy
(Sankaranarayanan et al, 1997).
Advantages
of
VIA
are
easy
learning,
inexpensiveness, and immediate availability to assess
results. Thus, VIA is likely to assume a feasible method of
screening in cervical cancer in many parts of the world,
especially in poorly resourced locations, where largescale Papanicolaou smear screening is not available and
establishing and maintaining the quality of screening
program based on cytology is difficult. However, there is
much to be learned concerning the most effective
techniques for training provides (both medical and
paramedical) to detect acetowhite lesions with the naked
eye (Ghaemmaghami et al, 2004).
VIA decreased the number of patients lost at followup (Jeronimo et al, 2005)
B. Visual methods
1. Speculoscopy
The performance of colposcopy involves significant
clinician time and financial expenditures. Colposcopy
requires special training, is expensive, and is not available
in the majority of clinical setting. Therefore, it has not
been used during routine screening. Colposcopy is a
diagnostic test, however, visual test may also be used as
screening tools. The false- positive rate of a visual
screening tool may appear higher if the gold standard
(colposcopically directed biopsy) misses some disease
(Buxton et al, 1991; Massad et al, 1996).
The appearance of intravaginal structures is
improved using chemiluminescent light energy,compared
with using bright room light. Visualization of the cervix
and lower genital tract with speculoscopy is indicated
whenever a patient is having a pap smear for cervical
cancer screening. Speculoscopy is no longer used.
Speculoscopy visualizes the cervix with blue white
chemiluminescent illumination and low power, portable
magnification following the application of dilute acetic
acid.
According to published data screening with
chemiluminescence, as opposed to other light sources,
imparts the overcall rate. Colposcopy is a more sensitive
test than speculoscopy for very small lesions (Wertlake et
al, 1997).
Speculoscopy can be effectively performed by all
clinicians currently performing Pap smears, including
nurse practitiones, with an improvement in screening
sensitivity of 200% to 300% (Edwards et al, 1997;
Wertlake et al, 1997).
The negative predictive value of the combined
speculoscopy and Pap smear (Pap Sure) is more than 99%
and provides that option of widened screening intervals in
women who test negative.
A study comparing the conventional Pap test
performed usually with Pap Sure performed biannually
showed Pap Sure to be cost- effective while reducing the
cervical cancer prevalence and death rate using a Markov
prediction model (Taylor et al, 2000).
3. Truscan (Polarprobe)
The Truscan device employs a real time approach to
the detection of tissue abnormalities. The device includes a
pen- shaped handpiece that is connected by a cable to a
console containing a microprocessor control module and a
digital signal processor. The handpiece makes contact with
the cervix, emitting low- level electrical pulses and optical
signals. The probe alerts the operator through the array of
lights on the probe handle if proper contact is being made
between the probe on the cervix. When an electrical
voltage is applied to tissue and a bruptly turned off, the
tissue behaves like a decaying battery, lasting for a
fraction of a second. Because both the decay time and the
waveform will differ among different types of tissue, the
voltage decay waveform can provide a dynamic signature
of the tissue that can assist in its classification.
Truscan also uses the transmission and scattering
properties of electromagnetic radiation in tissue, in a
process called diffuse reflectance.
By combining the electrical decay and spectroscopic
information from a particular area on the cervix, Truscan
is able, by means of a classification algorithm, to
categorize the tissue.
Seventeen tissue types have been programmed in to
the system and divided to three categories: normal, lowgrade abnormality, and cancer or high grade abnormality.
Truscan has a significantly better sensitivity and a lower
false- positive rate than does repeat cytology
(Wundermann et al, 1995; Singer, 1997; Quek, 1999).
Women experienced less anxiety, less pain and fewer
after effects like bleeding and discomfort with Truscan
than with the Pap smear (Campion et al, 1988).
This method have been conducted or are being
conducted in several centers in different countries for data
collection refine the tissue classification algorithm. A
smaller- diameter handpiece is being developed to enable
tissue measurements within the endocervical canal. In
addition, the technology is potentially applicable to other
sites in the body.
2. Visual inspection with acetic acid (VIA)
Papanicolaou smear has been the norm for cervical
cancer screening for many years in developed countries.
However, in most underdeveloped countries, screening
program are not routinely available (Wesley et al, 1997;
Bulmenthal et al, 2001).
VIA meets most generally agreed criteria of a good
screening test (Bulmenthal et al, 2001).
In this method, at first, 3-5% acetic acid applicate on
the cervix. The cervix was examined often 60 (second)
under adequate light (100 w lamp).
Several studies have shown the potential value of
visual inspection with acetic acid (VIA) as a screening
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Cancer Therapy Vol 3, page 235
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