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Worldwide, cervical cancer comprises approximately 12% of all cancers in women.1 It is the second most common cancer in women worldwide but still the commonest in many developing countries. Cervical screening is acknowledged as currently the most effective approach for cervical cancer control. However, in many countries, including some middle-income developing countries, the existing programmes are failing to achieve a major impact.2

The World Health Organization has recently released a comprehensive report on Cervical Screening in Developing Countries.2 The purpose of our review is to place this report in the context of what we know of the effectiveness of cervical screening and the ongoing research endeavours designed to evaluate new tests for cervical cancer precursors, and major efforts in many countries to improve programme organisation.

CYTOLOGY SCREENING

  1. Top of page
  2. CYTOLOGY SCREENING
  3. VISUAL INSPECTION WITH ACETIC ACID (VIA)
  4. HPV TESTS IN CERVICAL CANCER SCREENING PROGRAMMES
  5. PROGRAMME ORGANISATION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

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.3, 4 The organised programmes have shown the greatest effect, while using less resources than the unorganised (opportunistic) programmes.4 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 suggested sensitivity of the order of 50% in some circumstances.5, 6, 7 However, studies that have been able to assess sensitivity longitudinally have produced estimates of approximately 75%.8, 9

There are several essential elements for successful cytology screening.2 Critical is training of the relevant health care professionals, including smear takers (e.g., physicians, nurses, midwives), smear readers (cytotechnologists), cytopathologists, licensed colposcopists and programme managers, to ensure adequate quality in the administration and assessment of the smear. This should ensure adequately taken and fixed smears, though checks to make sure that adequate quality is obtained should be built into the system, and retraining conducted for those who have a high proportion of unsatisfactory smears (>10%).10 Funding should be such as to provide efficient and high-quality laboratory services. These should preferably be centralised to ensure adequate throughput through the laboratory and staff that can ensure quality control of cytology reading. Communications should be exemplary, starting with a means to rapidly transport smears to the laboratory and building in a mechanism to inform the women screened of the results of the test in an understandable form, coupled with a mechanism to ensure that women with an abnormal test result attend for management and treatment and a mechanism to follow up treated women.

Guidelines should be agreed upon regarding a number of policy issues. These include a decision on the priority age group to be screened, which in an unscreened population should initially be women ages 35–54 years to ensure maximum impact.11 However, in many countries, it will often be found that previous policies have resulted in a concentration on screening younger women, often in association with family planning and maternal and child health services, resulting in a diversion of resources from those who need to be screened and very little impact on disease in the population.2 Correcting such imbalances will be difficult and will require many consultations and professional education on the natural history of the disease. For those women with abnormalities, the guidelines should include an accepted definition of an abnormality to be treated, i.e., high-grade lesions, because of the substantial tendency of low-grade lesions to regress spontaneously.12, 13 It will also be crucial to make a decision on the frequency of subsequent screens and develop a mechanism to invite women with negative smears for subsequent smears, as this has a major impact on costs for the health system.14, 15

It follows that elements that interfere with the development of successful cytology screening programmes include over-reliance upon maternal and child health services for screening, opportunistic rather than organised screening and low coverage of the target group.4, 11 Setting too low a threshold for referral for colposcopy, i.e., overtreating nonprogressive disease, will lead to reduced cost-effectiveness.15

The major advantages of cytology screening are the considerable experience accrued worldwide in its use and that it is so far the only established screening test for cervical cancer precursors that has been shown to reduce the incidence and mortality of the disease.3, 4 However, cytology has limitations, and it is incompatible with some women's beliefs. It is important that women are not coerced into screening, nor given an overoptimistic view of its potential, as it is impossible to abolish mortality from the disease with screening.15

New developments in cytology, such as liquid-based cytology and automated reading, have advantages but are currently out of reach of most programmes in developing countries.2

Research into means to improve programme efficiency in middle-income countries is a high priority.

VISUAL INSPECTION WITH ACETIC ACID (VIA)

  1. Top of page
  2. CYTOLOGY SCREENING
  3. VISUAL INSPECTION WITH ACETIC ACID (VIA)
  4. HPV TESTS IN CERVICAL CANCER SCREENING PROGRAMMES
  5. PROGRAMME ORGANISATION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

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) seems to fulfill the basic criteria of a satisfactory screening test.2 VIA involves nonmagnified visualization of uterine cervix soaked with 3–5% acetic acid.

The results of assessments of test accuracy in cross-sectional study settings indicate that the sensitivity of VIA to detect high-grade precancerous lesions ranged from 66–96% (median 84%); the specificity varied from 64–98% (median 82%); the positive predictive value ranged from 10–20% and the negative predictive value ranged from 92–97%.16, 17, 18, 19, 20, 21, 22 However, all reported studies, except 2, suffered from verification bias.23 Despite different study settings, providers, study protocols and definitions of positive tests, the estimates of sensitivity of VIA have tended to cluster around a mean of 76%. In most of the studies where cytology and VIA have been provided under the same conditions, the sensitivity of VIA was found to be similar to that of cytology, whereas the specificity was consistently lower.2

A wide range of personnel ranging from doctors, nurses and other allied health workers to nonmedical personnel have been involved in the administration and reporting of results of VIA. The most common form of reporting involved negative and positive categories. The emerging consensus is that well-defined, demarcated, densely opaque acetowhite lesions located in the transformation zone (TZ) close to the squamocolumnar junction should define a positive VIA test. The criteria for a negative test included one or more of the following: no acetowhite lesions, faint ill-defined translucent acetowhite lesions, endocervical polyps, nabothian cysts, dot-like acetowhite lesions and prominent squamocolumnar junction.2

The investigation of women with a positive VIA initially followed similar principles to those of cytology-positive women. Now, in various settings, 5 options may be considered for women testing positive on VIA:

  • Colposcopy with histologic sampling and treatment based on the histologic finding;

  • Colposcopy with histologic sampling and treatment given on the basis of the colposcopic diagnosis (with retrospective access to histologic diagnosis);

  • Colposcopy and treatment on the basis of the colposcopic diagnosis;

  • Magnified visual inspection (VIAM) with histologic sampling and immediate treatment with cryotherapy;

  • Immediate treatment with cryotherapy with diagnostic referral (for colposcopy or biopsy) restricted to cases ineligible for immediate treatment.

All of the above approaches are still being evaluated in terms of safety, acceptability to women, feasibility and effectiveness in eradicating pre-invasive cervical disease.

In most of the reported study settings, training in the administration and reporting of VIA has been carried out in sessions lasting 3 days to 2 weeks, accompanied by written manuals. A learning period has been recognised after the training sessions. In the reported and unreported studies, the screen-positive rate among newly trained screeners has ranged from 25–35%, which later decreased to 10–18% in most instances.2

The major limitations of VIA include: low specificity (generally <85%), which can lead to overinvestigation and overtreatment of screen-positive women, and lack of standardised methods of quality control, training and competency evaluation. It is limited in its ability to detect endocervical disease. The major strengths of VIA include its simplicity and low cost, real-time availability of results and potential for immediate linkage with investigations/treatment, consistent estimates of accuracy, feasibility to be offered in low-resource settings and the possibility of rapid training of providers. In recent model-based evaluations of the cost-effectiveness of VIA compared to cytology and HPV DNA testing, a major advantage of VIA has been the possibility of treatment (cryotherapy) in the same session as an abnormality is detected, this obviating the need to bring women back for diagnosis and treatment, with the associated costs and risk of failure to attend.24, 25

Further research in addressing methods for improving specificity, quality control, tests to be used to follow up women who have been treated and competency and evaluation of skills of screeners and other health personnel involved in screening programs is essential. The efficacy and cost-effectiveness of VIA-based population-screening programmes in reducing the incidence of and mortality from cervical cancer is not known and remains to be established, as do the long-term complications and safety of overtreatment in the context of a VIA screening programme.2

Further information from ongoing studies regarding VIA's longitudinal (programme) sensitivity, efficacy in reducing incidence/mortality from cervical cancer, its cost-effectiveness and safety will be useful in formulating public health policies to guide the organisation of VIA-based, mass population-based screening programmes in developing countries and to reorganise programmes in countries with currently ongoing inefficient cytology screening programmes.

HPV TESTS IN CERVICAL CANCER SCREENING PROGRAMMES

  1. Top of page
  2. CYTOLOGY SCREENING
  3. VISUAL INSPECTION WITH ACETIC ACID (VIA)
  4. HPV TESTS IN CERVICAL CANCER SCREENING PROGRAMMES
  5. PROGRAMME ORGANISATION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

Molecular and epidemiologic studies have unequivocally shown that the vast majority of cervical cancer cases worldwide are caused by persistent infections with some high-risk types of the Human Papillomavirus family.26 From the point of view of defining preventive strategies, the HPV-attributable fraction should be considered to be 100%.27

Current HPV-testing systems are able to detect the presence of viral markers (HPV-DNA in exfoliated cervical cells) in close to 100% of invasive cervical cancer specimens, 75–90% of precursor lesions (LSIL/CIN1, CIN2/3, HSIL) and in some 50% of borderline cytology lesions (ASCUS).28, 29

Commercially available, FDA approved testing systems can be transferred to settings with some level of sophisticated technology. Such laboratories can be found in all developed and many middle-income countries.

In triage studies (investigations of the minor abnormalities detected by cytology) and in screening studies when both cytology and HPV tests are jointly performed, the cross-sectional sensitivity of the HPV test to detect HSIL or more advanced lesions is at least as good as cytology.30, 31 In most studies, the reported sensitivity of the HPV test is some 10% higher than cytology.

Triage studies, including large, randomised controlled trials, have shown that reduction in the number of visits and referrals to colposcopy/biopsy can be achieved with HPV tests.32, 33

One of the strongest gains of the combination of HPV tests and cytology lies in the very high negative predictive value (i.e., >97%). Major savings to the health systems may derive from substantially increasing the duration of the interval between screens without losses in sensitivity for high-grade intraepithelial lesions.2

The advantages of HPV tests compared to cytology are:

  • The objectivity of the test, resulting in very low inter- and intra-observer variability;

  • The possibility of almost complete automation of the process. This should ensure high throughput at a standard level of quality;

  • Built-in quality-control procedures;

  • Opportunities for self-sampling for HPV DNA in some populations with limitations in health care facilities and manpower, albeit with some loss of sensitivity;

  • The high sensitivity of the HPV DNA test to identify HSIL in women ages ≥30 years;

  • Gains in effectiveness could be achieved by increasing the length of the interval between screens and reducing the total number of lifetime screens required.

The disadvantages of HPV DNA testing are:

  • Its relatively high costs compared to cytology and VIA;

  • Dependence on reagents currently produced by only a single commercial manufacturer;

  • The requirement for a molecular diagnostic laboratory;

  • Its low specificity in younger women and populations with significant rates of HIV seropositivity;

  • Further, since HPV DNA testing, like cytology, is not a test that provides results at the time of the visit or soon afterwards, many of the traditional barriers to cytologic screening have not been eliminated.

Cost-benefit analyses are underway. Modelling based upon results from South Africa suggests that VIA or HPV DNA tests may offer attractive alternatives to cytology-based screening programmes.24

In countries with established cytology-based screening programmes, HPV tests are an alternative to repeat cytology in the presence of abnormal cytology. Women who are HPV-negative need not be rescreened for at least 5 years and possibly 10 years. In countries without established cytology-based screening programmes, but with the necessary laboratory facilities, HPV tests could be evaluated for primary screening. Appropriate trials are strongly encouraged and are now underway in India.2

New tests for HPV are being developed to overcome the disadvantages of both conventional cervical cytology and current HPV DNA tests. Ideal would be a test that indicates that an oncogenic HPV virus has already enhanced genetic instability and rendered infected cells susceptible to transformation, thereby facilitating the development of cancer. An example is based upon the fact that continuous expression of viral oncogenes E6 and E7 interferes with normal cell cycle control by targeting p53 and pRB. This phenomenon is a general event in persistent high-risk HPV infections but seems not to be induced by low-risk types. The functional loss of pRB by binding of E7 protein in turn leads to an increase in cell cycle regulating p16INK4a, possibly as a negative feedback loop. Therefore, it should be possible to use the detection of overexpression of this cell cycle regulatory protein as a surrogate marker for essential steps in early cervical carcinogenesis.34 A simple immunohistochemistry assay has been developed that detects p16 expression in both cell smears and tissue sections and is under evaluation. Detection systems using microarray technology are also under investigation. Alternative targets to HPV such as telomerase gene expression and other host genetic targets alone or in combination with HPV testing are being considered.2

PROGRAMME ORGANISATION

  1. Top of page
  2. CYTOLOGY SCREENING
  3. VISUAL INSPECTION WITH ACETIC ACID (VIA)
  4. HPV TESTS IN CERVICAL CANCER SCREENING PROGRAMMES
  5. PROGRAMME ORGANISATION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

Central to the success of any screening programme is the functioning of that programme in its entirety. This is true whatever test is chosen for screening. The requirements include the ability of a programme 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.15

WHO recommends that cervical screening should be planned within the context of national planning for cancer control.35 In many countries some form of screening exists but will have to be reorganised to achieve success. There needs to be the political will to proceed, with support and funding from the Ministry of Health.2, 15 Screening has to be based on an adequate health infrastructure. There must be a defined target population and means to identify and recruit into screening that population.15 The women in this population will have to be educated about screening for cervical cancer, and the health professionals who serve them may need educating and retraining. As indicated above for cytology but applicable for all tests, 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 evaluation. Leadership, management skills, attention to linkages at all levels of the programme and budgeting skills are essential.35 In many developing countries, lack of information systems constitutes an important barrier to the effective control of cervical cancer. A framework for creating such systems in developing countries has recently been described.36

In the long term, vaccination programmes against the relevant oncogenic HPV types could become the mainstay of cervical cancer control. However, development of these vaccines, though proceeding apace, has to be followed by careful evaluation of their safety and efficacy under field conditions. Some univalent candidate vaccines are already under evaluation,37 but until they can be established as effective and replaced by vaccines incorporating the large majority of the prevalent oncogenic HPV types in each region, they cannot substitute for screening. Further, if the hope that therapeutic as distinct for prophylactic vaccines proves unfounded, it will take more than one generation before screening, directed to those infected before vaccines became available, can be withdrawn. So it seems probable that effective screening programmes for cervical cancer will be needed for many decades.

CONCLUSIONS

  1. Top of page
  2. CYTOLOGY SCREENING
  3. VISUAL INSPECTION WITH ACETIC ACID (VIA)
  4. HPV TESTS IN CERVICAL CANCER SCREENING PROGRAMMES
  5. PROGRAMME ORGANISATION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

Cytology screening remains the standard for application in middle-income resource settings. However, VIA holds substantial promise, and provided this is confirmed in the ongoing studies and the difficulties associated with its lower specificity overcome, it may replace cytology in lower-income settings. Tests for HPV DNA have shown efficacy in the triage of equivocal diagnosis (ASCUS in the Bethesda system) and, if their cost and the required technology are made affordable, could eventually become the preferred approach for screening in middle-income settings. All tests, however, have to be applied within an organised setting, preferably as a component of a National Cancer Control Programme.35

Acknowledgements

  1. Top of page
  2. CYTOLOGY SCREENING
  3. VISUAL INSPECTION WITH ACETIC ACID (VIA)
  4. HPV TESTS IN CERVICAL CANCER SCREENING PROGRAMMES
  5. PROGRAMME ORGANISATION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

This article is dedicated to Prof. Dr. Harald zur Hausen on the occasion of his retirement as head of Deutsches Krebsforschungszentrum, with gratitude and appreciation for 20 years of leadership and for his support of research into cervical cancer. We thank all those who contributed to the discussions during the WHO consultation on Cervical Cancer Screening in Developing Countries in March 2001 and others who have provided input from the World Health Organization, on which this review is based.

REFERENCES

  1. Top of page
  2. CYTOLOGY SCREENING
  3. VISUAL INSPECTION WITH ACETIC ACID (VIA)
  4. HPV TESTS IN CERVICAL CANCER SCREENING PROGRAMMES
  5. PROGRAMME ORGANISATION
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES
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