Cervical Cancer Screening in Developing Countries

Cervical cancer is the second most common cancer among women worldwide,
with almost half a million new cases each year. Almost 80% of the women
Cervical
aff ected are in the developing world. However, many of these cases could be
prevented from progressing to invasive disease, and potentially death. More
so than any other cancer, cervical cancer is a disease which lends itself to early
detection and treatment. Th e eff ectiveness of cytology screening as a method
C
e
Cancer
to reduce the number of invasive cases and deaths resulting from cervical
r
v
cancer in developed countries has already been demonstrated. Alternative
i
c
a
screening tests, such as Visual Inspection with Acetic acid (VIA) and Human
l C
Papilloma Virus (HPV) are currently being examined and may prove feasible
a
n
in the near future.
Screening
c
e
r S
Policy makers and clinicians are faced with the responsibility of establishing
c
and reviewing screening programmes that have the potential to save the lives
r
e
of many millions of women each year.
e
n
in Developing
i
n
Th is report off ers a summary of the evidence on which to base important decisions.
g i
It focuses particularly on the situation in low and middle income countries
n D
— countries in which cervical cytology screening may not be feasible or cost-
ev
eff ective. It documents the current state of evidence concerning alternative
Countries
e
tests — VIA and HPV testing. It reviews trials that are currently being undertaken,
l
o
and gives policy makers an indication of developments that are likely to emerge
p
i
in the near future. However, it also emphasizes that the effi
cient and eff ective
n
g C
functioning of the system in its entirety is central to the success of any screening
o
programme, irrespective of the screening method chosen.
u
n
t
Th is publication is the product of a comprehensive consultation undertaken
r
i
e
by WHO in 2001 and subsequent discussions which continued for several
s
Report of a WHO consultation
months after the meeting, involving leading experts in the fi elds of cancer
epidemiology, screening and treatment. It is part of WHO’s commitment to
provide evidence-based guidelines to decision makers and highlights the
priority that should be given to cervical cancer screening and treatment
as an essential component of any comprehensive National Cancer Control
Programme.
ISBN 92 4 154572 0
W
H
O
Published collaboratively by
WORLD HEALTH ORGANIZATION
Programme on Cancer Control,
GENEVA
Department of Reproductive
Health and Research
World Health Organization

---

CERVICAL CANCER SCREENING
IN DEVELOPING COUNTRIES
REPORT OF A WHO CONSULTATION
W O R L D H E A L T H O R G A N I Z AT I O N
G E N E VA

---

WHO Library Cataloguing-in-Publication Data
Cervical cancer screening in developing countries : report of a WHO consultation.

1.Cervix neoplasms – diagnosis 2.Diagnostic techniques, Obstetrical and gynaecological – utilization
3.National health programmes – organization and administration 4.Guidelines 5.Developing countries
ISBN 92 4 154572 0


(NLM/LC classification: WP 480)
© World Health Organization 2002
All rights reserved. Publications of the World Health Organization can be obtained from Marketing and
Dissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791
2476; fax: +41 22 791 4857; email: bookorders@who.int). Requests for permission to reproduce or translate WHO
publications – whether for sale or for noncommercial distribution – should be addressed to Publications, at the
above address (fax: +41 22 791 4806; email: permissions@who.int).
The designations employed and the presentation of the material in this publication do not imply the expres-
sion of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any
country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed
or recommended by the World Health Organization in preference to others of a similar nature that are not men-
tioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
The World Health Organization does not warrant that the information contained in this publication is complete
and correct and shall not be liable for any damages incurred as a result of its use.
Edited and designed by Inís – www.inis.ie
Printed in France

---

TABLE OF CONTENTS


Preface v

Executive Summary vii

Introduction 1
1 Epidemiological Status Of Cervical Cancer 3
2 Programme Organization 5
The essential elements for successful cervical screening 5
Fundamental components essentialfor an organized programme 11
3 Cytology Screening in Middle-income Countries 13
Cervical cytology as an effective screening test 13
The validity of cervical cytology as a screening test 13
The essential elements for successful cytology screening programmes 14
Elements that interfere with the development of successful cervical screening
programmes 20
The strengths of the conventional cervical cytology test 21
The implications of different methods of sampling 22
The implications of different methods of smear reading 23
The circumstances when cervical screening programmes should be recommended 23
Research issues on cervical screening programmes in developing countries 24
Research issues on cervical cytology in developing countries 24
4 Visual Inspection with Acetic Acid Application (VIA) as an
Alternative Approach to Cytology Screening in Low-Income Countries 25
Test characteristics and current level of evidence for VIA as an alternative screening
approach 26
Definition and reporting of test outcomes 30
Diagnostic evaluation and management of lesions detected by VIA 31
Training issues 33
Advantages and limitations of VIA 34
Research issues 36
Conclusion on VIA 36

---

5 HPV Tests in Cervical Screening Programmes;
Possible Role in Middle-Income Countries 39
Introduction 39
Rationale for using HPV testing in cervical screening 40
HPV testing systems: current methods for screening 41
Tests available and results to date 42
Sample preparation / handling 44
HPV testing systems: developments for the near future 45
Uses of HPV testing in screening 46
Natural history studies and case control studies 47
HPV tests in primary screening programmes 49
HR-HPV testing and HPV type-specific testing performance in screening 49
Impact of HIV status and age on performance of HPV DNA 50
HPV tests in the triage of minimal cervical abnormalities 50
The Kaiser Permanente study 52
The ALTS trial 52
Opportunities for self-sampling in screening and triage 54
HPV in quality control of cytology-based screening programmes 54
Recommendations on the designs of studies on HPV testing for cervical screening 56
Advantages and disadvantages of HPV tests in screening 58
Conclusions on HPV testing 58
6 Overall Conclusion 61

Appendix 1: Epidemiological Issues in the Evaluation of
Alternative Screening Tests 63
Tests used in the diagnosis and management of minimal cervical abnormalities 63
Investigations of tests in primary screening 63

Appendix 2: List of participants 65

References 69

---

PREFACE
C ERVICAL CANCER is an important area of action for any cancer control
programme because of the burden of disease, and the potential for effective
prevention via screening.
It is the second most common cancer among women worldwide. In 2000,
there were over 471 000 new cases diagnosed, and 288 000 deaths from
cervical cancer worldwide. Approximately 80% of these deaths occurred in
developing countries.
Cervical cancer is preventable, but most women in poorer countries do
not have access to effective screening programmes.
This report documents the discussions and findings of an expert consulta-
tion called by WHO in 2001. The objectives of the meeting were:
• To develop a position paper on cytology screening in middle-income
countries with specific recommendations for improving efficacy and effec-
tiveness of programmes in this type of setting.
• To develop a status report on VIA and HPV screening for cervical cancer
which analyzes level of evidence of their efficacy and effectiveness in dif-
ferent resource settings and highlights research issues that still need to be
addressed for adequate policy development.
• To identify priority areas to be addressed by WHO with its partners.
The meeting was organized in three modules, and a chairperson was
appointed for each. Dr Anthony Miller chaired the module on cytology
screening, Dr Rengaswamy Sankaranarayanan the module on visual inspec-
tion with acetic acid application (VIA) and Dr Xavier Bosch the module on
human papilloma virus (HPV) screening. I am extremely grateful to each
of these distinguished scientists for contributing so much of their time and
expertise.
For each module, key participants were chosen on the basis of their rec-
ognized expertise in the subject matter. These participants contributed
actively to the considerations of their specialized subject matter, but were
also able to attend the meetings of the other modules if they chose to do
so. At the conclusion of the discussions on each topic the main conclusions
were reported and discussed jointly by all meeting participants during the
final session of the consultation. Subsequent discussions which continued
for several months after the consultation helped to clarify critical issues in
v

---

Preface
each module. Again, my thanks to each of the participants in the meeting
whose names are listed in Appendix 2.
The resulting report of this consultation aims to provide policy makers
with the evidence base upon which to found decisions about the establish-
ment or modification of existing cervical cancer screening programmes. It
also gives insight into types of screening for which there is currently insuffi-
cient evidence on which to base a screening programme. It signals to policy
makers areas that will be of importance in the future, including potentially
promising screening tests such as VIA, which are the subject of current trials.
If these trials yield positive results, these tests may provide effective alterna-
tives to current screening systems.
Cervical cancer is an important public health problem, and a priority con-
cern for the WHO Programme on Cancer Control. In its recent publication
on National Cancer Control Programmes (WHO, 2002) WHO recom-
mends early detection policies for countries with various levels of resources.
Special emphasis is given to the need to develop programmes that have a
systemic approach, are well integrated into the existing health system and
take into account the social, cultural and economic context.
WHO will continue to monitor progress in the area of cervical cancer
screening and make evidence-based recommendations about screening tests.
However, the underlying truth is that irrespective of how good a screening
test is, it will have no impact unless introduced as part of a well planned
and implemented screening programme. It will always remain important
for WHO and its Member States to work together to ensure that these sys-
tems function effectively so that the life-saving potential of cervical cancer
screening can benefit women and their families in all parts of the world.
vi

---

EXECUTIVE SUMMARY
W ORLDWIDE, cervical cancer comprises approximately 12% of all can-
cers in women. It is the second most common cancer in women worldwide
but the commonest in developing countries. Cervical screening is acknowl-
edged as currently the most effective approach for cervical cancer control.
However, in many countries, including most middle-income developing
countries, the existing programmes are failing to achieve a major impact.
PROGRAMME ORGANIZATION
Central to the success of any screening programme is the functioning of
that programme in its entirety. The requirements include the ability of a pro-
gramme to ensure high levels of coverage of the target population, to offer
high quality, caring services, to develop and monitor good referral systems
that ensure good patient follow-up and to ensure that the patients receive
appropriate, acceptable and caring treatment in the context of informed
consent.
Cervical screening should be planned within the context of national plan-
ning for cancer control. In many countries some form of screening exists,
but will have to be reorganized to achieve success. There needs to be the
political will to proceed, with support and funding from the Ministry of
Health. Screening has to be based on an adequate health infrastructure.
There must be a defined target population, and means to identify, invite,
screen and follow-up that population. The women in this population will
have to be educated about screening for cervical cancer, and the health pro-
fessionals who serve them may need education and retraining. A defined
referral system for women with an abnormality and a mechanism to ensure
women with an abnormality attend for diagnosis and treatment must be put
in place. Systems to manage the abnormalities and follow-up those treated
will also be required, while the programme will require monitoring and eval-
uation. Leadership, management skills, attention to linkages at all levels of
the programme, and budgeting skills are essential.
vii

---

Executive
CYTOLOGY SCREENING IN MIDDLE-INCOME COUNTRIES
Summary
It is generally agreed that cytology screening for cancer of the cervix has
been effective in reducing the incidence and mortality from the disease in
many developed countries. It is the organised programmes that have shown
the greatest effect, while using less resources than the unorganised pro-
grammes. There is general agreement that high quality cytology is a highly
specific screening test, with estimates of the order of 98-99%. There is less
agreement on the sensitivity of the test, cross-sectional studies have sug-
gested sensitivity in the order of 50% in some circumstances. However,
studies that have been able to assess sensitivity longitudinally have produced
estimates that approximate to 75%.
The essential elements for successful cytology screening include:
• training of the relevant health care professionals, including smear takers,
smear readers (cytotechnologists), cytopathologists, colposcopists and
programme managers,
• an agreed decision on the priority age group to be screened (initially
35–54),
• adequately taken and fixed smears,
• efficient and high quality laboratory services, that should preferably be
centralized,
• quality control of cytology reading,
• a means to rapidly transport smears to the laboratory,
• a mechanism to inform the women screened of the results of the test in an
understandable form,
• a mechanism to ensure that women with an abnormal test result attend
for management and treatment,
• an accepted definition of an abnormality to be treated, i.e. high grade
lesions,
• a mechanism to follow-up treated women,
• a decision on the frequency of subsequent screens,
• a mechanism to invite women with negative smears for subsequent
smears.
Elements that interfere with the development of successful cytology
screening programmes include over-reliance upon maternal and child
health services for screening, as women in their target group are generally
too young, opportunistic rather than organised screening, and low coverage
of the target group. Setting too low a threshold for referral for colposcopy,
i.e. over-treating non-progressive disease, will lead to reduced cost-effec-
tiveness.
The major advantages of cytology screening are the considerable experi-
viii

---

ence accrued worldwide in its use, and that it is so far the only established
Executive
screening test for cervical cancer precursors that has been shown to reduce
Summary
the incidence and mortality of the disease. However, cytology has limita-
tions, it is incompatible with some women’s beliefs, and it is impossible
to abolish the disease with screening. It is important that women are not
coerced into screening, nor given an overoptimistic view of its potential.
New developments in cytology, such as liquid-based cytology and auto-
mated reading have advantages, but are currently out of reach of most
programmes.
Research into means to improve programme efficiency in middle-income
countries is a high priority.
VISUAL INSPECTION WITH ACETIC ACID (VIA) AS AN
ALTERNATIVE APPROACH TO CYTOLOGY SCREENING
IN LOW-INCOME COUNTRIES
The technical and financial constraints of implementing cytology-based
screening programmes in developing countries have led to the investigation
of screening tests based on visual examination of the uterine cervix. Among
these tests, visual inspection with 3–5% acetic acid (VIA) appears to fulfil the
basic criteria of a satisfactory screening test. VIA involves non-magnified vis-
ualization of uterine cervix soaked with 3–5% acetic acid.
The results of test accuracy in cross-sectional study settings indicate that
the sensitivity of VIA to detect high-grade precancerous lesions ranges from
66–96 % (median 84%); the specificity varied from 64–98% (median 82%);
the positive predictive value ranged from 10–20% and the negative predic-
tive value ranged from 92–97%. However, all reported studies, except two,
suffered from verification bias. Despite different study settings, providers,