Best Practice & Research Clinical Obstetrics and Gynaecology

Vol. 19, No. 4, pp. 517–529, 2005

doi:10.1016/j.bpobgyn.2005.02.005
available online at http://www.sciencedirect.com

Screening for cervical cancer in the developing

world

H.S. Cronjé* MMed (OetG), FCOG (SA), MD

Head of Department of Obstetrics and Gynaecology
Department of Obstetrics and Gynaecology, University of the Free State, P.O. Box 339, Bloemfontein 9300,
South Africa

Cervical cancer remains the most common malignancy amongst females in countries of low
income, mainly due to a lack of screening. Responsible factors are centred around inadequacies of
the Pap smear: high cost; low sensitivity; the need of a laboratory with high human expertise; and
a demanding logistic system for mass screening. No alternative screening method seems to be
clearly advantageous. Although combinations of tests have higher sensitivities, they are complex,
costly and associated with low specificities. Adding the problem of effective treatment, it seems
that mass screening with adequate coverage of the population is an unreachable goal for many
developing countries. The most promising development in the control of cervical cancer seems to
be vaccination against the human papillomavirus, either as a preventative measure or for
stimulating immunity in infected women.

Key words: cervix; cancer; neoplasia; screening; developing countries.

Cancer of the cervix is the most common malignancy in women of developing countries1
and second only to breast cancer worldwide.2 According to the South African National
Cancer Registry, the lifetime risk for a woman to develop cancer of the cervix is one in
26.3 In the author’s department, cervical cancer cases comprise 82% of all gynaecological
malignancies.4 Furthermore, evidence exists that cancer in African countries, particularly
in certain regions, occurs at a younger age and is more aggressive in nature.1 This could be
partly attributed to the human immunodeficiency virus (HIV) pandemic.
Developed countries have been successful in controlling the incidence of invasive
carcinoma of the cervix, whereas low-income countries have failed dismally in this
respect. The success of developed countries is largely attributed to the widespread and
systematic use of the Papanicolaou (Pap) smear.5 In Sweden, for example, more than
80% of women are regularly screened. In contrast, less than 1% of women have ever

* Tel.: C27 51 405 3444; Fax: C27 51 444 2660.

E-mail address: gnoghsc.md@mail.uovs.ac.za.

1521-6934/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
518 H. S. Cronjé

been screened in the Free State Province of South Africa.6 Since this survey was done in
the early 1980s, the situation has not improved.
South Africa, with at least 35 cytological laboratories (private and state owned) and
adequate treatment facilities, is the country in Africa that is most favourably positioned
for an effective population-based screening programme. However, this country’s
performance is similar to most developing countries throughout the world. A
reasonable conclusion is that developing countries are unable to utilize the Pap smear
as an efficient screening tool. In this chapter, the reasons for this inability will be
examined, and suggestions will be given for the future control of cervical cancer.

NATURAL HISTORY OF CERVICAL NEOPLASIA

Cervical cancer develops over a period of two to three decades, providing sufficient
time for the screening for precursors (Figure 1).7 During adolescence, lesions are
usually low grade and the majority will regress back to normal spontaneously. A small
proportion will continue to develop into true cancer precursors, known as cervical
intra-epithelial neoplasia (CIN), which is divided into grades 1, 2 and 3. The median ages
of patients with these different precursor grades are 25, 29 and 34 years, respectively.8
At least two-thirds of CIN 1 lesions, half of CIN 2 lesions and one-third of CIN 3 lesions
will regress back to normal. Ultimately, a small proportion will develop into infiltrating
cancer, usually from the age of 45 years onwards. On admission, the mean age of
patients with cancer of the cervix is 54 years.5 In South Africa, only 8% of patients with
cervical cancer are less than 30 years old.3
By the age of 30 years, the majority of minor lesions (koilocytes, atypia and CIN 1)
will have regressed, leaving behind a larger proportion of CIN 2 and 3 (high-grade
precursors) and a few cases of infiltrating cancer.4 Therefore, in settings where the
number of Pap smears per lifetime has to be reduced due to funding restraints, this age
seems to be an ideal time for screening. However, as will be discussed, screening for the
high-risk human papillomavirus (HPV) subtypes may change this assumption.

Age (years)
20 30 40 50

Atypia CIN Infiltrating

Koilocytes I II III cancer

Regression

CIN, cervical intra-epithelial neoplasia.

Reproduced from reference 4 with permission.

Figure 1. Natural history of cervical neoplasia.

 Screening for cervical cancer in the developing world 519

Table 1. Prevalence of cervical neoplasia based on cytology from South African studies.

Study CIN 2 and 3 (%) Infiltrating cancer (%)

9
Cronjé et al (2001) 1.0 0.3
Cronjé et al (2003)10 4.7 1.0
Michelow et al (1999)55 2.4 0.9
Fonn et al (2002)56 1.8 0.5
Denny et al (2000)41 2.2 0.1
Wright et al (2000)57 3.0 0.3

CIN, cervical intra-epithelial neoplasia. Reproduced from reference 4 with permission.

PREVALENCE OF DISEASE

Based on cytological reports, the prevalence of CIN 2 and 3 in South Africa was 2.5%
(range 1.0–4.7%) and the prevalence of infiltrating cancer was 0.5% (0.1–1.0%) (Table 1).
However, in two studies where histological biopsies were performed on all patients,
the prevalence of CIN 2 and 3 was 8%, compared with 0.8% for infiltrating cancer.9,10
Using these results as a gold standard, cytologically the Pap smear could only identify
31% of CIN 2 and 3 cases and 63% of infiltrating cancer cases (Table 1). These findings
bring the Pap smear’s sensitivity into question.

SENSITIVITY AND SPECIFICITY OF SCREENING TESTS

The calculation of the sensitivity and specificity of a screening test is based on the 2!2
table (Figure 2).
Sensitivity is calculated by a/aCc and specificity by b/bCd. An important
prerequisite is that the gold standard should be determined on both the screening
positives and the screening negatives; otherwise, the sensitivity and specificity will be
biased.11–13

Golden standard
+ -
Test + a b a+b
- c d c+d
a+c b+d N

Sensitivity=a/a+c
Specificity=d/b+d
Figure 2. The 2!2 table for calculating sensitivity and specificity.
520 H. S. Cronjé

SENSITIVITY AND SPECIFICITY OF THE PAP SMEAR

The Pap smear’s sensitivity is an issue of debate. Most studies have shown a sensitivity of
70% or more.14,15 In these studies, only positive Pap smears were submitted to the gold
standard (histology). In practice, patients with positive Pap smears were referred to
colposcopy clinics, where a repeat smear was usually taken. Only these repeat smears’
results were used for the calculation of sensitivity (with biopsies or colposcopy on all of
these patients). This resulted in inadequate numbers in the c cell of the 2!2 table and,
hence, an inflated sensitivity.
Fahey et al11, McCrory et al12 and Nanda et al13 clearly showed that when the gold
standard was applied to all the negative screens, or at least a representative
proportion thereof, the sensitivity was lower. In all three of these studies, a sensitivity
of around 50% was documented, which can be regarded as the true sensitivity of the
Pap smear.
The abovementioned results were based on studies performed in the developed
world. In our population, using the methodology advocated by the abovementioned
authors11–13, the sensitivity was 53% using CIN 2 as a threshold and 23% when CIN 1
was used as a threshold.9,10 In a study from India where colposcopy on all patients was
used as the gold standard (with or without biopsy), the sensitivity of the Pap smear was
29.5%.14 This figure correlates with a perceived sensitivity of 31% based on Table 1.
Therefore, the sensitivity of the Pap smear is probably lower in the developing world,
around 30%, but slightly higher for CIN 2 and 3 only.
New technologies and computerized screening and rescreening have been
associated with higher sensitivities, reaching the 70% level.12,13 Unfortunately, these
techniques are not generally available in developing countries.

SPECIFICITY OF THE PAP SMEAR

The specificity of the Pap smear has consistently been found to be high, over 92%.9–13,16
This included developing countries.

OTHER CHARACTERISTICS OF THE PAP SMEAR

Advantages

The Pap smear is a simple test, acceptable to both the general population and the
medical profession. Although certain countries do not have any cytologists or
cytological laboratories, Pap smears are available in a very large proportion of the
world’s countries.

Disadvantages

Disadvantages attributed to the Pap smear include the following4:

† the need for repetitive smears (due to the low sensitivity);

† the recall of patients for their results;
† the need for a laboratory with high human expertise;
 Screening for cervical cancer in the developing world 521

† the need for a colposcopy clinic for evaluation and treatment of positive cases; and
† the high cost of a cytological screening programme (see below).

In developing countries, at least one-third of the patients are lost to follow-up,

resulting in non-treatment of cases who screened positive.6,9,10 Furthermore, there are
insufficiently trained cytologists and colposcopists to meet the needs for mass
screening in these countries.

COST OF SCREENING

Population-based screening is expensive. However, little research has been done on the
affordability of screening in developing countries. In 1983, Aucamp from the South
African Department of Health examined the problem.17 At that time, an ideal screening
programme was valued at R33 million/year, while the Government allocated only R400
000 (1.2% of the required amount) for cervical cancer in the preceding year (US$1.00Z
R7.00). Presently, at R50/patient, it will cost R40 million to screen each woman aged
30–50 years just once in the Free State Province of South Africa.4 In Thailand, the
discounted costs per year of life saved ranged from US$121 to US$6720 depending on
the extent and cost of screening.18 No further evidence is needed to realize that
population-based screening is expensive, and beyond the reach of most developing
countries.

COVERAGE

The coverage of all eligible women for screening is, together with the cost of
screening, the most important barrier to effective mass screening. Unless the
screening programme reaches 70–80% of women, the decrease in the incidence of
infiltrating cancer will be insignificant.19 In developing countries, with limited
communication and other forms of infrastructure, coverage of 70% or more will be
extremely difficult to achieve. Women less likely to be reached by a screening
programme are those that are older, poorer, less educated and unemployed (or
working in the informal sector). They tend to live in non-permanent dwellings without
a partner, are ignorant about cervical screening, and are generally irresponsible about
their own health.20 These women are not only difficult to reach, but at high risk for
developing cancer of the cervix.
A common approach in developing countries is to attempt cervical screening
through primary healthcare clinics. The proportion of women ever attending such
clinics will be less than the desired coverage target, and will probably be
approximately 60%.4 Furthermore, primary care nurses, burdened by large patient
numbers, are often reluctant to perform Pap smears.4 Taking all these factors into
account, screening through primary healthcare clinics will not yield ideal coverage of
a population. A dedicated screening programme, performed by a dedicated team, is
more likely to succeed, even though only a section of the population will be
reached.4
522 H. S. Cronjé

SCREENING PROGRAMMES

Current internationally accepted screening programmes are based on a perceived

sensitivity of 80% for the Pap smear.21 In the USA, three annual smears are
recommended after first sexual intercourse, followed by triennial smears in low-risk
women and annual smears in high-risk women.22 This means anything between 12 and
31 smears over a period of 30 years, which is not feasible in developing countries.
The World Health Organization reviewed this problem and suggested one smear
per woman between the ages of 35 and 40 years in countries of low income.23 It has
been estimated that this policy will reduce invasive cervical cancer by 65%. However,
with a Pap smear sensitivity of 30–50%, a loss to follow-up of 33% and coverage of say
60%, a maximum reduction of 20% can be expected using this approach.
The South African Government has adopted a policy of three smears per woman at
the ages of 30, 40 and 50 years, respectively. It has been suggested that this policy may
reduce the incidence of cancer by 87%.4 These long intervals, however, will limit this
perceived reduction.24 Adding the factors mentioned above, the reduction in cancer
would not exceed 35%.

KNOWLEDGE OF CERVICAL SCREENING WITHIN THE POPULATION

The compliance of women is of extreme importance in population-based screening

programmes. In order to co-operate, women need basic knowledge about screening.
Such knowledge will vary considerably amongst different regions and populations.
A recent study in a remote area amongst South African rural women attending
primary healthcare clinics revealed that 64% of 538 women had ever heard of a Pap
smear. Of those that had heard of the test, 83% knew it was for the detection or
prevention of cancer of the cervix, but only 56% had ever been tested.25 In a Kenyan
study, 32% of women admitted to hospital knew about Pap smear testing.26 Information
and motivation of women on a broad scale, therefore, need to accompany any attempt
at population-based screening.

TREATMENT OF CANCER PRECURSORS

Treatment methods for cancer precursors include the following27:

† cold knife cone biopsy;

† laser vaporization;
† large loop excision of the transformation zone (LLETZ) (also known as loop excision
by electrosurgical procedure, LEEP); and
† cryotherapy (freezing of the transformation zone).

All these methods require pretreatment colposcopy with the necessary human
expertise. Furthermore, except for cryotherapy, all these methods are expensive.
Cryotherapy, although the least expensive and easiest to apply, still needs a continuous
supply of N2O. In rural populations of low income, this is often not possible.
The success of all these treatment methods is dependent on human expertise, both
at pretreatment colposcopic evaluation and the treatment itself. The less the expertise,
 Screening for cervical cancer in the developing world 523

the higher the failure rate. In developing countries, a high degree of human expertise is
often lacking, and funding for treatment fall short of the needs. These two factors make
it unlikely that any of these methods will be utilized on a large scale in the foreseeable
future in developing countries.4

TREATMENT OF INFILTRATING CANCER

In contrast to mass screening, it might be more cost effective for developing countries
to wait for infiltrating cancer to develop, which is then detected and treated at an early
stage. This approach was evaluated in India, unfortunately without success.28
Furthermore, many developing countries do not have sufficient facilities for treating
cervical cancer.4
Although South Africa has an adequate number of facilities for irradiation (more than
the rest of Africa), the results are not encouraging. Of 770 patients who were
irradiated, 50% were lost to follow-up and of those that were followed, only 38% were
alive after 6 years.4

ALTERNATIVE METHODS OF SCREENING

In view of the Pap smear’s disadvantages, alternative screening methods have been
considered. Recognized alternatives included cervicography, the acetic acid test (AAT,
with or without magnification) and HPV identification. An opto-electronic device has
also been tested, but not yet made available for general use29, while colposcopy is not a
recognized screening method.

Cervicography

Cervicography involves photography of the cervix with a special camera known as a

Cerviscopew (National Testing Laboratories Worldwide, St Louis, MO, USA), following
the application of diluted acetic acid.30 A certified evaluator evaluates the slides. In our
experience, its sensitivity and specificity are 50 and 88%, respectively.9 A recent
attempt at improving the sensitivity with an ‘arbitrated cervigram’ revealed a sensitivity
of 64% and a specificity of 94%.31 It seemed to be more sensitive for low-grade lesions
compared with high-grade lesions.9 Its main disadvantages include:

† advanced technology (camera, film, development of colour slides);

† cost; and
† necessary recall of patients.

Acetic acid test

The AAT, also known as visual inspection using acetic acid or direct visual inspection, is
a simple, inexpensive test where the cervix is examined with the naked eye following
the application of diluted acetic acid (3–5%).32 The presence of a visible acetowhite area
on the cervix (usually around the external os) signifies a positive result.
A meta-analysis on the AAT revealed a sensitivity of 66–96% (most approximately
70%) and a specificity of 64–98% (most approximately 70%).33 However, studies
524 H. S. Cronjé

applying the gold standard (histology or colposcopy) to all cases (i.e. those who screen
positive and negative) revealed lower sensitivities (37–79%) with specificities of
49–91%.9,10,16,34
Important advantages of the AAT include its simplicity, extremely low cost and the
provision of an immediate result. Its main disadvantages are a degree of overdiagnosis
and wide interobserver variation.
Magnification was also used to improve the sensitivity and specificity of the AAT, but
this was not found to be advantageous.10,35,36

HPV DNA identification

Since cancer of the cervix is caused (at least partially) by HPV, it makes sense to identify
HPV DNA as a marker for the presence of cervical neoplasia.2 The types of HPV
associated with cervical cancer (high-risk types) include 16, 18, 31, 33, 35, 39, 45,51, 52,
56, 58, 59, 68, 73 and 82, of which 16, 18, 31, 33, 35, 45, 52 and 58 are the most
common.37 Diagnostic testing for the presence of HPV usually identifies some of the
common high-risk types (usually 16, 18, 31 and 33).
The sensitivity of the HPV DNA test ranges from 70 to 83% and the specificity
ranges from 63 to 73% when colposcopy is performed.38,39 The results are improved
when selective colposcopy and biopsy are performed.
Unfortunately, this test is expensive and involves high technology, putting it beyond
the reach of most developing countries. New developments are aimed at providing a
test with an on-site result at low cost. Currently, however, HPV DNA testing is used in
combination with other screening tests (such as cytology) to improve the diagnostic
accuracy. Unnecessary colposcopy is thereby decreased, particularly in patients with
borderline or mildly abnormal Pap smear results.40
If a patient tests positive for a high-risk type of HPV, she is at risk of developing
cervical neoplasia, irrespective of her age. Where the thirties are probably the best
years for screening with other tests, HPV identification can be utilized at any age.
However, the presence of a high-risk type of HPV does not imply that the woman has a
CIN lesion or cancer; she is only at risk of developing it.

COMBINATION OF TESTS

Any combination of screening tests significantly improves sensitivity.9,10,41 The

disadvantages of this approach, however, include decreased specificity42 and an
increase in the direct cost of screening. A combination of tests can by applied at one
stage (e.g. cytology with cervicography or HPV DNA testing) or in sequential stages
(e.g. the AAT followed by HPV DNA testing, provided the AAT was positive).9,10,41
Although the principle of combining tests is promising, insufficient research has been
done to identify the ideal combination.

COLPOSCOPY

Colposcopy is used for the identification and localization of lesions on the cervix. In
experienced hands, both its sensitivity and specificity are over 90%.43 However, results
such as these are dependent on high human expertise, a rare commodity in developing
 Screening for cervical cancer in the developing world 525

countries. Nurse colposcopists have been proposed for these countries, but this concept
has not been met with great enthusiasm, nor has it been thoroughly investigated.

HUMAN IMMUNODEFICIENCY VIRUS

HIV infection, which occurs predominantly in developing countries, is associated with

an increased incidence of HPV infection and cervical neoplasia.44–46 The recurrence
rate of CIN after treatment varies from 20 to 60% depending on the degree of
immunosuppression.46 Subsequently, the cost-effectiveness of screening for cervical
neoplasia in HIV-infected women has been questioned.46,47 However, not to screen
HIV-infected women may be seen as discriminatory.

VACCINATION AGAINST HPV

Much research has recently been devoted to possible vaccination against HPV
infection.48 Vaccination can be aimed at either preventing neoplasia or stimulating
immunity in individuals already infected with HPV or cervical neoplasia.49
In the first report on vaccination against HPV type 16, a vaccine efficacy of 100% was
achieved.50 The postulation that followed this study was that such a vaccine might
prevent cancer formation dependent on HPV-16. In the future, vaccines against more
than one HPV type will be tested and reported. Since future vaccines will not cover all
high-risk HPV types, cancer of the cervix will not be completely eradicated, but these
vaccines have the potential to decrease the incidence of cervical cancer significantly.51

DISCUSSION

The main elements of a population-based screening programme include the following:

† information and education of the population;

† coverage;
† the screening process;
† treatment of the screening-positive patients; and
† funding.

In developing countries, the first element is possible. Coverage, however, is difficult

in view of poor infrastructures and funding restraints. Since a high degree of coverage is
essential for decreasing the incidence of cervical cancer19, it is advisable to start
screening with a dedicated team on a small scale with something like a door-to-door
approach.52 If such an effort is successful, it can be expanded gradually.
The recommended method and timing of screening is another difficult issue.
Cytology as a screening method for poor countries is probably unattainable.53
Currently, the AAT is receiving a great deal of attention. However, the main problems
with this test are its overdiagnosis and, hence, overtreatment as well as high
interobserver variability. The HPV DNA test holds promise if it can be simplified and
provided at low cost. Combinations of tests also hold promise, but have not been
sufficiently investigated.
526 H. S. Cronjé

Vaccination against HPV probably holds more promise for the control of cervical
cancer in developing countries than screening.53 Pubescent girls will also be more
reachable (through schools) compared with women in the community. However,
vaccination as a preventative measure is a long way from becoming common practise.53
Therefore, research into improved screening and screening practices should continue.
The ideal screening method for a developing country should:

† be inexpensive and simple to apply;

† be acceptable to both the public and healthcare workers;
† have a high sensitivity and specificity (both over 70%);
† be reproducible; and
† provide an immediate result.

Treating positive cases is also difficult. For CIN lesions, the LLETZ (LEEP) method is
probably too technically advanced and expensive. Cryotherapy is more acceptable, but
only successful if performed by experts, which is a problem in developing countries.
The recommendation of an AATwith immediate cryotherapy of positive cases (without
colposcopy) has not been investigated adequately and cannot be supported at the
present time
Standard treatment of cervical cancer is beyond the ability of many developing
countries. New methods of treatment should be investigated, such as vaccination49 or
even viral treatment.54
The most important aspect of any screening programme is funding. Cervical
neoplasia prevention programmes have to compete with other conditions and diseases
(e.g. malnutrition, sanitation, housing, clean water supply, tuberculosis and HIV) for
funding; subsequently, they often do not receive priority. Therefore, whatever method
is used for the control of cervical cancer, it has to be affordable.
In conclusion, conventional screening for cervical cancer is not practical for the
developing world. The most promising future control method of this cancer is
immunization against HPV. In the meanwhile, new avenues of screening and treatments
should be investigated.

SUMMARY

Screening for cervical neoplasia has failed in the developing world, resulting in an
extremely high incidence of cervical cancer. The main reasons are funding restraints,

Table 2. Essential elements for a screening programme.

Element Proposition for the developing world

Information and education of the Possible
population
Coverage of O70% Impossible; start on small scale
Screening for cervical neoplasia Impossible by Pap smear; consider other methods
Treatment of those who screen On-site identification and immediate treatment is essential.
positive Simpler, less-expensive treatment methods should be developed
Funding The current costs are too high
 Screening for cervical cancer in the developing world 527

problems with Pap-smear-based screening and inadequate coverage. A need exists

for a simple, inexpensive, on-site screening test with a high sensitivity and specificity.
Although no alternative test complies with these prerequisites, the AAT and the HPV
DNA test merit more research and development. Treatment methods also need
refinement in order to be more cost effective for developing countries (Table 2).
Taking all these difficulties into account, a new vaccine against high-risk HPV types
holds more promise. A vaccine has the potential to significantly decrease the
incidence of cervical cancer, but this will take a number of years to develop. In the
meantime, small-scale screening programmes run by dedicated teams should be
implemented.

Practice points

† screening for cervical neoplasia in developing countries has been largely

unsuccessful and, therefore, provides a challenge for healthcare workers and
health administrators
† the Pap smear is not suited for countries of low income; alternative screening
methods should be considered, e.g. the AAT
† before any attempt at screening is made, the treatment facilities should be in
place
† adequate coverage of a population (O70%) is mandatory for a successful
screening programme
† any attempt at screening a population should be met with the co-operation of
all concerned: community leaders, health administrators, the public and
healthcare workers
† all screening programmes in developing countries should be closely monitored
in order to determine the success
† a dedicated team is probably the best approach, starting with a small
proportion of the population

Research agenda

† cervical neoplasia in developing countries provides important challenges for

research, particularly in view of the high incidence of disease and failure at
successful screening
† interventional studies on the improvement, awareness and utilization of
cervical screening by communities
† improving the AAT with respect to overdiagnosis and interobserver variation
† development of a low-cost, on-site HPV DNA test
† evaluation of different combinations of screening tests
† new, inexpensive, uncomplicated methods of treatment of CIN lesions and
even cancer
† new insights into HIV infection and cervical neoplasia interaction
† further development of HPV vaccines
† studies on the interaction between HIV infection and HPV vaccines
 528 H. S. Cronjé

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