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Principles and Practice of
Cancer Prevention and Control
Edited by
OMICD Group eBooks
Ibrahim Hashim
Redhwan Ahmed Al-Naggar
001
Cervical Cancer: Prevention
and Control
Redhwan Ahmed Al-Naggar*
Population Health and Preventive Medicine Department, Faculty of
Medicine, Universiti Teknologi MARA (UiTM), Malaysia
*Corresponding author: Redhwan Ahmed Al-Naggar, Population
Health and Preventive Medicine Department, Faculty of Medicine,
Universiti Teknologi MARA (UiTM), Malaysia
Background
Cervical cancer is one of the leading causes of morbidity and mortality amongst the gynaecological cancers worldwide
[1]. Cervical cancer is primarily a disease found in low income countries [2]. There are a multitude of risk factors for
cervical cancer worldwide [3]. Virtually all cases of cervical cancer are attributable to persistent infection by certain
strains of Human Papilloma Virus (HPV) especially HPV-16 and HPV-18. Cervical cancer is highly preventable when
precursor lesions are detected and treated before they develop into cancer. Cervical cancer is potentially preventable,
and effective screening programs can lead to a significant reduction in the morbidity and mortality associated with this
cancer [4]. The prevention of cervical cancer includes primary, secondary and tertiary prevention. Primary prevention
is avoiding exposure to risk factors and vaccination; secondary prevention means detecting the precancerous disease
through screening, and providing treatment. Tertiary prevention includes measures to reduce recurrence or progression
of an invasive disease, or palliative measures.
Prevalence and Incidence
Worldwide, cervical cancer is the second most common malignancy in women worldwide after breast cancer. It is
the leading cancer causes of death of women in the developing world [5]. Eighty-three percent of new cases and 85% of
deaths from cervical cancer reported in developing countries. The world pattern of cervical cancer indicates that this is
predominantly a problem of low resource setting countries. The main reason is limited access to screening and treatment
facilities [6].
The highest incidence was reported in developing countries including the sub-Saharan Africa [7]. In sub-Saharan Africa,
the majority of cancers (over 80%) are detected in late stages, predominantly due to lack of information about cervical
cancer and prevention services [8]. This high incidence is attributed to the unawareness of the disease and inadequacy
of screening programs in less developed countries [7]. Cervical cancer is a key reproductive health problem for women
particularly in the developing countries where screening services are lacking or inaccessible for the majority [9]. In South
East Asia, the age-standardized incidence ranges from about 10 per 100,000 women in Hong Kong and Singapore to about
20 per 100,000 women in Malaysia, the Philippines, Thailand, and Vietnam [10]. In China, the incidence rate of cervical
cancer ranged from 2.4 per 100,000 women in Jiashan to 4.6 per 100,000 women in Guangzhou. However, specific areas
have notably high incidences of cervical cancer, such as Yangcheng, Shanxi, with an age-adjusted estimated incidence rate
of 81 per 100,000 women between 1998 and 2002 [11].
In developing countries, the prevention of cervical cancer is mainly challenging. About 5% of eligible women undergo
cytology-based screening in a 5-year period [13]. This may be due to availability of very few skilled and trained professionals
to implement such a program effectively. Furthermore, healthcare funds are not available to sustain such a program [14].
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In Europe, the incidence rates of cervical cancer are not proportionate throughout the whole continent though in
general the incidence rate is 10.6 per 100,000. In Western Europe, the incidence rate is lower than in central and Eastern
Europe. The low rate in Western Europe is due to the development of the prevention programs. It is also due to the human
papillomavirus (HPV) vaccines provided in Western Europe; such vaccination programs have not been implemented in
the high-incidence countries. To control the problem of cervical cancer in Europe is based on providing public health
care programs [12].
In developing countries, many problems stand opposed to cytology services. One of such problems is the improper
distribution of the services where only teaching hospitals or private laboratories receive them. Another problem is the
delay in reporting cytology results, where the concerned patients may not get their results, receive treatment, or follow-up 002
[15].
Risk Factors of Cervical Cancer
Human papilloma virus
HPV is the primary risk factor of cervical cancer. The risk for HPV acquisition markedly increases with the number
of sexual partners [16,17]. Additional risk factors for cervical cancer include history of smoking, younger age at first
intercourse and at first pregnancy, high parity, and long-term use of oral contraceptives [17-21]. Women previously
treated for any CIN [22] or for CIN3 [23] have a 2-to 3-fold increased risk for future cervical cancer, but may not have
an increased risk for death from cervical cancer [24]. Infection with HPV at early age of first sexual intercourse, multiple
sexual partners and smoking are the risks for developing cervical cancer [25].
Sexual activity
According to Mitra [26], low age at first sexual intercourse exposed the young subjects to semen which is a potential
carcinogen. Biswas et al. [27], highlighted that cervical epithelium is more susceptible to carcinogenic agents during
adolescence. Early age at marriage indicated an early exposure to sexual activities and early pregnancy, which are well
known etiological factors for cancer cervix. Bayo et al. [28], in their study also found that reusing home-made sanitary
napkins is a risk factor for cervical cancer.
Smoking
Chen et al. [29] correlated oral non malignant lesions with HPV infection, betel leaf chewing and cigarette smoking.
Smoking appears to be strongly associated with the development of precancerous cervical lesions and cancer [30,31].
Smoking is among the most consistently identified environmental cofactors likely to influence the risk of cervical
cancer; studies show at least a twofold risk for current smokers compared to non-smokers [30,32]. sFactors associated with
HPV persistence include cigarette smoking, immune suppression, early age of first sexual intercourse, multiparity, longterm use of hormonal contraceptives, and infection with sexually transmitted diseases [20,33-39]. It has been shown that
ever and current smoking increases the risk of cervical cancer among HPV-positive women. Among cases of squamous
cell carcinoma, an excess risk was observed for current smokers and ex-smokers [35].
Obesity
Obese subjects have not only increased risk of developing cancer [36], but their mortality is also increased with
increasing body mass index (BMI). Obesity has been identified as a risk factor for several cancers including endometrial
cancer and breast cancer, colon and rectal, oesophageal, kidney, pancreatic, biliary, ovarian, cervical and liver cancer
[36,37].
High parity
Several studies on cervical cancer found a positive relationship between high parity and cervical cancer [38,39]
compared to women who had never given birth, those with three or four full-term pregnancies had 2.6 times the risk of
developing cervical cancer; women with seven or more births had 3.8 times the risk [36]. Furthermore, women infected
with HPV had seven or more full-term pregnancies have approximately four times the risk of squamous cell cancer
compared with nulliparous women, and two to three times the risk compared with women who had one or two full-term
pregnancies [36].
Long-term use of oral contraceptives
Several studies on patients with cervical cancer reported that long-term use of oral contraceptives could increase
the risk of cervical cancer [40]. A multicentre case-control study showed that among HPV-infected women, those who
used oral contraceptives for 5 to 9 years have approximately three times the incidence of invasive cancer, and those who
used them for 10 years or longer have approximately four times the risk [20]. Therefore, lifestyle modifications, such as,
stopping smoking and reducing the number of sexual partners, can help reduce the risk of cervical cancer.
Co-infection
Low socio-economic status
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Women infected with HIV are more readily infected with high risk HPV types and are more likely to develop
precancerous lesions than HIV-negative women in the same age category [41-43]. Women who are co-infected with HPV
and another sexually transmitted agent, such as Chlamydia trachomatis or herpes simplex virus-2 (HSV-2), are more
likely to develop cervical cancer. Several studies examining the effect of HSV-2 infection with increased risk of cervical
cancer found that among HPV DNA-positive women [33].
Low socio-economic status is also recognized as a risk factor for many health problems, including cervical cancer,
particularly in low-resource settings. This May due to restricted access to health care services, limited income, poor
nutrition, and a low level of awareness about health issues and preventive behavior. All of these factors can make them
more vulnerable to illness and preventable diseases such as cervical cancer [44]. Studies reported that poor hygienic
practices or conditions may increase risk of HPV infection or cervical cancer while there is no consistent evidence to
003
support this assertion [45].
Cervical Cancer Prevention
Primary prevention
Reducing exposure to risk factors associated with HPV infection: The very strong association between HPV infection
of the cervix and cervical cancer is now regarded as causal [46]. There are many implications for this to the prevention
of cervical cancer. Considering the above assertion true, the cervical cancer can be eliminated by preventing the HPV
infection. There are many ways for transmitting the HPV infection; some are the sexual route and the autoinoculation. In
fact, there is lack of understanding for the way of the interaction within the HPV virus between the major structural protein
L1 and major caspid protein L2, on the one hand, and the doubled-stranded DNA genome bound to cellular histones. Yet,
blocking the HPV infection is possible via antibodies to L1 and L2 [47]. In the episomal state in the host cell, the HPV
genome expresses proteins coded for by the E1 and E2 regions as well as E6 and E7 [48].
In productive infections, HPV remains in the episomal state, but in cancers, the HPV genome becomes integrated into
the host genome. Integration into the host genome leads to changes in the gene expression that result in the upregulation of
E6 and E7 genes and their proteins. These oncoproteins appear to be necessary to the oncogenic transformation of infected
cells. Animal and human studies of papilloma virus infection have provided good evidence that neutralising antibodies to
these proteins can block new infections with HPV [49,50].
HPV vaccine: For prophylactic vaccines, empty viral capsids called virus-like particles (VLPs) are synthesized from
microbial or cellular expression systems. Early studies of HPV 16 L1 VLP vaccines showed that they were well tolerated and
generated high levels of antibodies against HPV 16 [51].
The most prevalent HPV types associated with cervical cancer are HPV-16 and HPV-18, which account for more than
70% of cervical cancer. Two HPV vaccines have shown promise in protecting against HPV16 and HPV-18 persistent
infection and their associated cervical cancer precursor, and cervical cancer. The bivalent vaccine protects against infection
with the two most common cancer-causing types of HPV, types 16 and 18, while the quadrivalent vaccine prevents infection
with high-risk HPV types 16 and 18 and protects against two low-risk HPV types 6 and 11, which cause about 90% of genital
warts. Both vaccines are given in a series of three 0.5 mL injections over 6 months. The vaccine has now been approved in
more than 100 countries and has become part of the national immunization program in the United Kingdom and Australia.
It was initially approved for use in females aged 9–26 years, but in some countries, the age range has now been extended to
45.
Studies showed that both vaccines are at least 95% effective in preventing HPV-16 or-18 persistent infection and 100%
effective in preventing type-specific cervical lesions when given to girls prior to sexual activity or to women without prior
infection with these HPV types [52,53]. Vaccine protection appears to be long-lasting. So far, the vaccines are found to be
effective for at least 6.5 years.
HPV vaccination programs have been implemented in numerous affluent countries worldwide, but penetration is poor
in the developing world–where the need is greatest–due to the high cost of the vaccine. Currently, two HPV vaccines are
available: a bivalent (Cervarix®, GSK) and a quadrivalent (Gardasil®, Merck) vaccine. In the US, the quadrivalent HPV
vaccine is recommended for routine vaccination of girls aged 11 and 12 years, with catch-up vaccination recommended
through to age 26 years [54]. Ongoing vaccination monitoring programs will provide data on vaccination coverage and the
population-level impact of HPV vaccination. Since April 2007, Australia has a nationwide vaccination program that provides
the recombinant HPV quadrivalent vaccine to schoolgirls between 12 and 18 years of age. Since July 2007, vaccination has
also been provided to women younger than 26 years. In Australia, the coverage rate for HPV vaccination is 65–75% [55].
The best example to study the effectiveness of the HPV vaccine; in the UK, HPV vaccination was introduced into the
national immunization program in September 2008 for girls aged 12 to13 years, and more than 1.4 million doses have been
given since the vaccination program started. A 3-year catch-up campaign was initiated in the autumn of 2009 to vaccinate all
girls up to 18 years of age. This program, consisting of 3 injections given over a 6-month period, is largely delivered through
secondary schools (Department of Health 2009). With 80% coverage in women aged 12–13 years, this study projected a
63% reduction of invasive cancer, a 51% reduction of CIN3, and a 27% reduction of cytological abnormalities before age 30
years, though this is not to be expected until the next decade [56].
Reducing HPV infection is one of the most important preventive measures in reducing cervical cancer. Reducing
exposure to or vaccinating against the virus is the best preventive method. HPV infection is mainly transmitted by sexual
contact; therefore, abstinence from sexual activity or mutual monogamy will reduce the risk of exposure to the virus.
Condoms can provide about 70% protection against HPV when used at all times [57].
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Condom: Mitra [26], observed that use of condoms may not be very effective in preventing HPV infection. This is
because the papilloma virus lives in the skin covering the pubic area as well as the cells lining the vagina and cervix in
women and urethra and anus in both sexes. Condoms do not block contact with pubic skin and hence unable to give
protection from HPV.
Circumcision: Studies have suggested that circumcision may reduce the risk of penile cancer, urinary tract infections,
and common sexually transmitted diseases, including human immunodeficiency virus (HIV) infection [58-61]. Little is
known, however, about the effect of male circumcision on the risk of acquiring HPV. HPV causes genital warts in men
and women, and it has been linked to cancers of the cervix, vulva, vagina, anus, and penis [62,63]. About 99 percent of all 004
cervical cancer cases may be attributed to infection by oncogenic HPV genotypes [46,64]. Therefore, factors that reduce the
probability of acquiring or transmitting HPV among men or women may reduce the risk of disease associated with these
infections.
Tomato: A study in The Netherlands [65] found women who consumed tomatoes three or more times a week to have
a 40% reduction in risk of cervical dysplasia relative to nonconsumers.
Secondary prevention
Screening, diagnosis and treatment: There have been to evaluate the impact of cervical cancer screening on cervical
cancer incidence and mortality and all data on the effect of screening has come from cohort and case–controlled studies.
Finally, there is increasing recognition of the limitations inherent in cytology screening. The screening test should be a low
technology test and one that provides either an immediate result (as is possible with simple visual screening methods such
as direct visual inspection or DVI) or a rapid turnaround of results (as is possible with HPV DNA testing), particularly in
settings where transport and communication technologies (even postal services) are lacking. This article will talk in detail
of the most three methods which useful in worldwide, visual inspection, cervical cytology, and HPV testing.
Direct visual inspection: Because of the problems intrinsic to cytological based screening protocols, considerable
attention is being paid to developing alternative screening methods, such as visual inspection methods and HPV testing,
as well as alternative management protocols for the prevention of cervical cancer in low resource settings. Ideally, for low
resource settings, screening should be performed at a primary health care level, using trained nurses or paramedical staff,
whether in an urban or rural setting. Linking screening to treatment and eliminating the intermediate steps of colposcopy
and histological sampling may not only reduce the costs and infra-structural requirements of screening, but may increase
women’s compliance with screening protocols.
Methodologically, screening the cervix has undergone many attempts. The first method was the visual inspection
of the cervix, which was introduced by Schiller in 1930s. Schiller used the Lugot’s iodine to ‘increase the number of
clinically diagnosed leucoplakias by making visible the lesions which would otherwise escape the naked eye’. This method
was replaced by the cytology when Schiller’s test was found to be of very poor specificity. Studies evaluating the visual
inspection of the cervix were resumed. A number of large clinical trials have evaluated the DVI. At some trials, the DVI was
evaluated alone; at some others, it was compared to the performance of cytology and HPV DNA testing. In such studies,
there were many definitions as well as training techniques. Because of the fact that such studies were cross-sectional in
nature, verification bias constrained such studies; in such studies, the ‘gold stranded’ was only used to positive tests. This
prevented the diagnosis of disease in women. In such case, high grade cervical cancer precursors and/or cancer were used
as outcome measures.
Details of some of these studies are given below [66-71]. Sanakarayanana et al. [69] published data on 3000 women who
were screened by paramedical personnel using DVI and cytology.
Using DVI and cytology, 10, 934 women were screened by the University of Zimbabwe/JHPIEGO Cervical Cancer
Project. Such screening was carried out in two phases: in phase one 8731 women screened and in phase two, 2203 women.
Based on a positive DVI or Pap smear, 18.1% of women had colposcopy in phase one. In phase two, irrespective of the
results of DVI or cytology, 97.5% of 2203 women underwent colposcopy. Similarity to cytology was detected for CIN by
DVI. In phase two, the DVI sensitivity for HSIL (77%) was higher than that of cytology (44%). 64% was recorded for the
specificity of DVI for HSIL while it was 91% for cytology. 2944 women (aged 35-65) having had no previous screening
were screened using cytology, HPV DNA testing, DVI and cervicography [71]. 18% of the cases recorded positive DVI
indentifying 67% of all cases with high grade cervical disease while 8% of the women had a positive CIN1 or LSIL test
identifying 78% of the case with high grade disease. Statistically, there was no difference.
Visual Inspection with acetic acid: Visual inspection with acetic acid (VIA), cervicoscopy, the acetic acid test and
the vinegar test are some of the names that DVI is also known by. Such test requires a certain procedure to be followed: a
patient lies in the lithotomy or supine position; and to visualize the cervix, speculum is passed. Then the cervix needs to be
washed with a dilute solution (3-5%) of acetic acid for nearly 1-2 minutes. After that using the naked eye or with a handheld magnifying device and an adequate light, the cervix is examined. Here, ‘whitening’ (or acetowhitening) of epithelial
cells is caused by the acetic acid; this has a high nuclear-cytoplasmic ratio. After the use of the acetic acid epithelial changes
become acetowhite; these have immature squamous metaplasia-that is, cervix infection with HPV and true cervical cancer
precursors. DVI is different from colposcopy; while the latter examines the cervix in greater details, the former determines
the availability or otherwise of an acetowhite lesion in the transformation zone of the cervix. Grading the acetowhite lesion
positive or otherwise depends on the detection of any distinct acetowhite area. The DVI and cytology were almost similar in
their specificities of positive cases. DVI was positive in 9.8% of women while it was 10.2% with positive cytology. Moreover,
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The natural history of cervical cancer is well understood. Studies have demonstrated that invasive cervical cancer arises
as a consequence of progression from mild dysplasia through severe dysplasia to carcinoma in situ. Some of the preinvasive lesions (cervical intraepithelial neoplasia [CIN]) will regress to normal, but a significant proportion will progress
to cervical cancer in 10–15 years’ time. High grade cervical cancer precursors are also known as CIN grades 2 and 3 or high
grade squamous intraepithelial lesions (HSIL), which encompasses the diagnoses of CIN 2 or 3,with a long precancerous
stage, an effective screening program can potentially diagnose most of the precancerous lesions, which can be treated
before progression to cancer. In the last decades, this strategy has greatly contributed to the decreased cervical cancer
morbidity in developed countries.
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while DVI identified 90.1% of the true cases, cytology spotted 86.2% of the true positive cases. Cytology and DVI were
somehow equivalent screening tests.
Recent studies have demonstrated that visual inspection with acetic acid (VIA) is an alternative sensitive screening
method [72,73]. It is cheap and non invasive, and can be done in a low level health facility like a health centre [74]. More
importantly, VIA provides instant results, and those eligible for treatment can receive treatment of the precancerous lesions
using cryotherapy on the same day and in the same health facility. This “see and treat” method ensures adherence to
treatment soon after diagnosis, hence stemming the problem of failing to honour patient referrals [75-77].
In developing countries, widespread screenings by Pap smear and HPV DNA test are still too expensive to achieve.
Screen treatment by visual inspection with acetic acid (VIA) and cryotherapy may be the optimal screening strategy in
these countries. VIA involves applying 3% to 5% acetic acid (vinegar) to the cervix using a spray or a cotton swab and
observing the cervix with the naked eye after 1 minute. If characteristic, well-defined acetowhite areas are seen adjacent to
the transformation zone, the test is considered positive for precancerous cell changes or early invasive cancer. VIA does
not require laboratory staff training. The results are immediately available, allowing treatment during a single visit and thus
reducing loss to patient follow-up.
The sensitivity of VIA is equivalent to or better than that of a Pap smear, although its specificity is lower [78,79].
In a cluster randomized trial in the Dindigul district in India, of the 49,311 eligible women aged 30–59 years in the
VIA group, 31,343 (63.6%) were screened during 2000–2003; 30,958 women in the control group received routine care.
A significant 25% reduction in cervical cancer incidence and 35% reduction in mortality were reported 7 years after the
beginning of screening in this study [73].
Like the Pap smear, visual inspection is subjective, and supervision is needed for quality control of visual inspection
methods. VIA might not work as well in postmenopausal women, because the transformation zone recedes into the cervical
canal at menopause [79]. A study has shown that VIA also can be used in follow-up post cryotherapy with a negative
predictive value of 99.7% and an accuracy of 93.7%, which is comparable to those of Pap smear.
In low-resource countries, transportation, time and other access issues make follow-up visits difficult. Through screenand-treat programmes, the women are less likely to be lost to follow-up before being treated. Screen-and-treat programs
have been evaluated in Thailand, Bangladesh, India, South Africa and Ghana with good results. The data show that VIA
and cryotherapy, in one or two clinical visits, without an intermediary colposcopic diagnostic step, is one of the most costeffective alternatives to conventional multi visit strategies [80-82].
Visual inspection with Lugol’s iodine: Visual inspection with Lugol’s iodine (VILI) is similar to VIA, but uses Lugol’s
iodine to map the cervix, followed by an examination for mustard-yellow areas. The screening and treatment also can be
done in a single visit. A multicentre study in India and Africa showed that the sensitivity and specificity of VILI to detect
high-grade CIN were 92% and 85%, respectively.41 In contrast, in a Latin American study, VILI was found to have a
sensitivity of 53% and a specificity of 78% in detecting high-grade CIN. Therefore, further studies of the accuracy of VILI
are warranted.
Cytology screening: For decades, the Papanicolaou (Pap) smear has been used throughout the world to identify
precancerous cervical lesions for treatment and follow-up. In developed countries, routine Pap smear screening has
contributed to a 70–80% reduction of cervical cancer [83]. However, a single cervical cytology result is relatively insensitive
for the detection of cervical precancer and cancer. The sensitivity to detect CIN 2/3 lesions ranges from 47% to 62% and
the specificity from 60% to 95% [84]. Recent meta-analyses have suggested that a single conventional cervical smear
misses between 40% and 50% of biopsy confirmed high grade SIL and cervical cancers [18,84]. Pap smear failure can be
a consequence of sampling technique or the monotony of subjectively processing many samples. Efforts to improve Pap
smears in the last decade include the development of liquid-based cytology (LBC), which uses a small amount of fluid to
preserve cells collected from the cervix, and automation of the process of preparing smears.
The second technological development of significance in cytology is automation, in which computer technology using
algorithms of recognition can identify the most abnormal areas of an entire slide and present them for the purpose of
reading [87]. Automation and LBC have the potential to improve the efficiency of cervical cytology testing; however, they
increase the cost of screening, which means that they may not be well suited for use in low-resource settings [79].
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Liquid-based cytology has greater laboratory efficiency and reduces a number of problems such as poor fixation, uneven
thickness of the cell spread, debris, and air-drying artifacts [85]. This method improves sample adequacy and sensitivity
but reduces specificity compared with conventional Pap smear. A population-based study of more than 8,000 women in
Costa Rica showed that significantly more women were referred to colposcopy of which the threshold for referral was
atypical squamous cells of undetermined significance (ASC-US) (12.7% vs 6.7% in LBC group and conventional smear
group, respectively). However, LBC was more sensitive at detecting high-grade squamous intraepithelial lesions (HSIL)
and cancer. LBC detected 92.9% of HSIL and 100% of carcinoma, whereas conventional smears detected 77.8% of HSIL
and 90.9% of carcinomas [86].
Early diagnosis and treatment have proven to be effective ways of preventing cervical cancer. In countries where
organized screening programs are available, incidence rates are in decrease. This is because pre-cancerous lesions have been
prevented to develop to cancer by using repeated Pap Smear screening and treatment. Such screening helps reduce the risk 006
of cervical cancer up to 80% [88,89].
Many countries have significant reduction in cervical cancer morbidity and mortality through cervical cancer screening
and early treatment. The success of developed countries is largely due to the widespread and systematic use of Pap smear.
In the United States, Pap Smear has been responsible for 90% decrease in cervical cancer deaths. Although, Pap Smear
has been introduced in the United States and was as effective as such, half of the American women have not had a Pap
Smear and were diagnosed with invasive cervical cancer. Moreover, there were 10% of the American women who have
not had Pap Smears in the last five years. Australia has decreased cervical cancer to almost 2.8% a year with introducing
the National Cercial Cancer Screening Program in 1991. 85% of Australian women who do not take regular Pap Smear die
and 50% have never had a Pap Smear at all. The world Health Organization recommends that screening for cervical cancer
should begin on women aged 30 or more; and while screening is not necessary for women aged 65 years and more, a 3-year
interval is considered suitable for women aged between 25 and 49 years. Pap testing is suggested to be carried out yearly by
other studies for it has helped reduce the cervical cancer in the past 40 years. Other studies suggest Pap Smear for women
every 3 years after consecutive normal Pap Smear results. Such suggestions were based on many studies which employed
many cervical cancer screening programs with more than 1.8 million women. Such studies indicated that reduction rate of
the cumulative incidence of invasive cervical cancer was 64% when the interval between screening tests was 10 years. The
reduction rate when interval was 5 years was 83.6%; and 90.8% at 3 years; 92.5% at 2 years and 93.5% at 1 year.
The World Health Organization recommendations on target ages and frequency of cervical cancer screening state
that screening should start on women aged 30 years or more, a 3-year interval can be considered in the age group 2549 years, and screening is not necessary for women over 65 years [90]. Other studies recommend annual Pap testing,
because this practice might have contributed to the declining incidence of invasive cervical cancer during the past 40 years
[91]. However some other recognized bodies suggest that low-risk women need Pap smears only every 3 years after 3
consecutive normal Pap smear results [92]. These recommendations are based upon data from 8 cervical cancer screening
programs with more than 1.8 million women which showed that the cumulative incidence of invasive cervical cancer was
reduced 64.1% when the interval between Pap tests was 10 years, 83.6% at 5 years, 90.8% at 3 years, 92.5% at 2 years, and
93.5% at 1 year [93].
HPV testing: It has been well established that cervical neoplasia is caused by persistent infection with certain oncogenic
types of HPV. This knowledge has led to the evaluation of HPV testing as a screening tool. The hybrid capture (HC) assay
is currently the most widely used and the only US Food and Drug Administration HPV test approved for clinical use.
The HC2 test can detect 13 types of high-risk HPV. Other HPV DNA testing formats based on polymerase chain reaction
permit identifying infection with individual oncogenic types. One advantage of HPV DNA testing is that it is not as
subjective as cytology screening. Its other advantage is that in addition to identifying those who are at increased risk for
developing cervical disease, HPV DNA testing can identify women who already have the disease [94].
HPV infections are very common in young, sexually active populations. Fortunately, most HPV infections in young
women are transient, and only a small proportion of women would become persistently infected with high-risk HPV
types [95]. However, in women aged 30 years or older, the HPV DNA positivity rate drops and transient HPV infection
is much less common. HPV DNA testing is particularly valuable in detecting high-grade precancerous lesions in women
older than 30 years, with average sensitivity and specificity at 89% and 90%, respectively [96]. A randomized controlled
trial was designed to compare HPV testing (HC2) and the Pap smear in parallel as stand-alone primary screening tests to
identify CIN 2+ in 10,154 women aged 30–69 years presenting for routine screening. The outcome showed that compared
with Pap smear, HPV testing has greater sensitivity for the detection of CIN [97]. In addition, testing for high-risk types
of HPV DNA has a very high negative predictive value, that is, the likelihood of having no disease if the HPV DNA test is
negative [98].
Recently, a population-based randomized trial indicated that using HPV DNA testing as the primary screening followed by cytological triage and repeat HPV DNA testing of women with normal cytology who are HPV DNA positive
after at least 1 year is a feasible strategy for incorporating HPV testing in primary cervical cancer screening, because it
improves sensitivity and maintains a high positive predictive value, thus minimizing unnecessary referrals [101]. A few
large, randomized, controlled trials of HPV testing in primary cervical cancer screening are currently ongoing in the
Netherlands, the United Kingdom, Sweden, Finland, Italy, Canada, and India [78,85,102-106].
However, HPV DNA testing is expensive and presents some of the same challenges as cytology screening in lowresource areas. For example, the test requires laboratory facilities, special equipment, and trained personnel; takes 6 to 8
hours for results; and requires follow-up visits for results and treatment. Fortunately, easier-to-use and less expensive HPV
DNA tests are being developed and may revolutionize cervical cancer screening around the globe [107].
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A meta-analysis assessed the accuracy of HPV testing as an alternative to repeat cytology in women who had equivocal
results on a previous Pap smear and found that HPV testing has better accuracy (higher sensitivity, similar specificity)
than the repeat Pap smear [99]. Another meta-analysis showed that after treatment of cervical lesions, HPV testing more
easily detects (with higher sensitivity without lowering the specificity) residual or recurrent CIN than follow-up cytology.
Furthermore, compared with cytology with cut-offs at ASC-US or low-grade squamous intraepithelial lesion, primary
screening with HC2 generally detects 23% more CIN 2/3 or cancer, but is 6% less specific. In comparison with isolated HC2
screening, using combined HPV and cytology screening can identify another 4% more CIN 3 lesions, but after incurring
a 7% loss in specificity [100].
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As has been pointed out, it is now widely accepted that persistent infection of the cervix with high risk types of HPV is
necessary for the development of cervical cancer [46].
Such information has important implications for screening programmes; for it indicates that one can use HPV DNA
testing instead of cytological screening. Low resource settings need such alternative. There are important factors that need
to be considered before implementing the HPV DNA testing for primary screening in low resource settings. These are the
cost and the natural history of HPV infections. In most developing countries, a cost of US$30 per test poses a difficulty
for patients. As regards the natural history of HPV infections, they are prevalent among young sexually active populations
[108].
In some studies, up to 70% of college-aged women are found to be HPV DNA positive [108-110]. Fortunately, the
majority of HPV infections in young women are transient, and only a minority of HPV infectedwomen develop persistent
infections [110-113].
Such women who become persistently infected and who are at risk of CIN 2, 3 or cervical cancer are small in number. It
is these women who need to be screened instead of screening large number of women with temporary infections. Women
over the age of 30 year are not likely to develop temporary HPV infections compared to younger women, for after the age of
30, the HPV DNA positivity rate drops considerably [110]. Therefore, one of the easiest ways not to identify large numbers
of transiently infected women is to restrict screening to women 30 years of age and older. This is not a disadvantage
for most developing countries that lack the resources to screen young women. Numerous cost-effectiveness studies have
clearly shown that in settings where only one to three screens can be performed in a woman’s lifetime, screening should
not be initiated before the age of 30–35 years.
Self-testing for high risk types of HPV DNA: One way in which HPV DNA testing could be utilized to screen large
numbers of women without access to speculum examinations is through the use of self-collected vaginal samples. Previously
we published data on supervised self-testing for high risk types HPV DNA in our cohort of South African women [114]. It
is found that 66% (95% CI: 52-78%) was the sensitivity of HPV DNA testing of a self-collected vaginal sample for CIN 2, 3
or cancer. This was found to be equivalent to that of the conventional cervical smear when LSIL or greater was defined as
a positive test (61%; 95% CI: 47-73%, p¼ 0.58). Contrastively, it is also found that the sensitivity of HPV DNA testing of a
clinically obtained sample was 84% (95% CI: 71-92%). Such sensitivity was significantly greater than that of a conventional
cervical cancer smear and of a self-collected sample for HPV DNA testing. Such information indicates that self-collected
HPV DNA testing could replace the cytology screening for identifying old women at risk for cervical cancer when cytology
screening not available. However, such testing has its limitations: lower sensitivity for high grade lesions. Regardless of
such limitation, the self-collected samples provide chances to large numbers of unscreened women who do not have proper
access to health care facilities.
Summary
Studies suggest that even if a woman were screened for cervical cancer only once in her lifetime between the ages of 30 and 40, her
risk of cancer would be reduced by 25-36% [115]. Cervical cancer can be prevented by identifying pre-cancerous lesions early using Pap
smear screening and treating these lesions before they progress to cancer [116]. Prevention, early diagnosis and treatment have been
shown to reduce mortality due to cervical cancer in many countries [117] and HPV vaccine has high efficacy for prevention of HPV vaccine
types and related outcomes [118].
There is supporting evidence that direct visualization with acetic acid (VIA) may be a valuable alternative to Pap smears in areas
where access to healthcare is a limitation [119]. However, more recent studies have shown that a single round of HPV testing might have
a greater impact on the reduction of advanced cervical cancer cases and associated mortality than VIA or cytology [120]. With adequate
infrastructure, HPV testing could be an attractive alternative to previously used screening methods, as it also requires fewer hospital visits,
and could even be conducted by patients themselves.
Furthermore, it has additional advantages, including the facts that it is affordable; there is no need for complicated equipment (although
a supply of electricity is needed); and it can be done by less specialized personnel and thus can be implemented in a primary health-care
(PHC) setting [121].
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