Screening for cervical cancer is well established in resourced countries, but in resource-constrained countries, it is almost non-existent at national level. In resourced countries, the Pap test forms the hallmark of screening, with the human papillomavirus DNA test a recent adjunct. In many resourced countries, however, screening for cervical cancer is still far from ideal. A coverage around 50% prevails in some countries, and few have reached the target of 80% or more. Furthermore, the human papillomavirus test and newly developed biomarkers may lead to the development of a ‘super test’, which could be applied less frequently compared with present-day cytological screening. In resource-constrained countries, the movement is towards a ‘screen and treat’ approach. The main screening methods under investigation are the visual inspection after diluted acetic acid application test and the human papillomavirus test. Cryotherapy and large loop excision of the transformation zone have been used most often as treatment methods. The ideal seems to be the human papillomavirus test with large loop excision of the transformation zone, provided a low-cost human papillomavirus test becomes available. Coverage is even a greater problem in resource-constrained countries, a problem in need of urgent attention. Resource-constrained countries, however, must curtail the high incidence of cervical cancer, which is often a lower priority than other pressing healthcare needs.
Introduction
Cancer of the cervix remains a major healthcare problem worldwide. In resource-constrained countries, the high incidence of invasive cervical cancer (often the most prevalent cancer in women) is a major problem, whereas, in resourced countries of the world, the emphasis falls on the most appropriate method of screening and how to achieve adequate coverage. For example, although over 80% of women in the USA have had a Pap smear within the past 3 years, most of those who get squamous cell cervical cancer have not been well screened.
Traditionally, screening for cervical neoplasia was synonomous with the Pap test. This test, however, has certain inadequacies that make it a less than ideal test for screening. These inadequacies are the following : (1) a relatively low sensitivity of around 50% (lower in resource constrained countries), even though liquid-based cytology has a higher sensitivity of up to 70%; (2) as a result of the above, a need for repetitive smears exists; (3) the recall of women for their results; (4) the need for a laboratory with high human expertise; (5) the need for a colposcopy clinic for evaluation and treatment of positive cases; and (6) the high cost of a cytological screening programme.
As a result, several alternative methods of screening have been investigated, including visual inspection of the cervix after acetic acid application (VIA) or Lugol’s iodine application (VILI), colposcopy, cervicography, human papillomavirus DNA testing (HPV test), spectroscopy and newer biomarkers.
Although none of these have managed to replace the Pap test, the HPV test, and to a lesser extent VIA, have received a great deal of attention in the recent past. This raises the question: are we approaching a new era of screening for cervical neoplasia with only one or a few screening events per woman per lifetime? This review will take a closer look at these possibilities.
Principles of screening
Screening involves either primary or secondary prevention of disease.
Primary prevention
In primary prevention, screening is aimed at the identification of risk factors present in individuals without disease. By eliminating the risk factors, the incidence of disease will decrease. In the case of cervical cancer, primary prevention will be aimed at sexual education and monogamy to prevent the spread of the HPV. Screening will focus on women with a lifestyle that includes risk factors for the development of cervical cancer. These women will then be informed and motivated to change their lifestyle.
Secondary prevention
In secondary prevention, the progression of disease to a fatal outcome is halted by means of screening of seemingly healthy individuals, the identification of early stage disease and the treatment thereof. The Pap test is a classical example of screening, with the aim of secondary prevention. Cancer precursors are identified and, by eliminating them, cancer formation is prevented.
Principles of screening
Screening involves either primary or secondary prevention of disease.
Primary prevention
In primary prevention, screening is aimed at the identification of risk factors present in individuals without disease. By eliminating the risk factors, the incidence of disease will decrease. In the case of cervical cancer, primary prevention will be aimed at sexual education and monogamy to prevent the spread of the HPV. Screening will focus on women with a lifestyle that includes risk factors for the development of cervical cancer. These women will then be informed and motivated to change their lifestyle.
Secondary prevention
In secondary prevention, the progression of disease to a fatal outcome is halted by means of screening of seemingly healthy individuals, the identification of early stage disease and the treatment thereof. The Pap test is a classical example of screening, with the aim of secondary prevention. Cancer precursors are identified and, by eliminating them, cancer formation is prevented.
Principles of a screening programme
A number of factors must be considered before initiating a screening programme :
The sensitivity and specificity of the tests or procedures used for screening
In Fig. 1 , a high sensitivity will increase the true positives identified by the test (cell a in the 2 × 2 table), whereas a low sensitivity will increase the false negatives (cell c). Conversely, a high specificity will increase the true negatives (cell d) and a low specificity will increase the false positives (cell b). The Pap test has a moderate sensitivity and a high specificity. Therefore, true negatives will be increased.
Predictive value of a positive test
This is the proportion of women with a positive test who actually have the disease (a/a + b in Fig. 1 ). It declines only slightly as test sensitivity (a/a + c in Fig. 1 ) decreases, but declines markedly as test specificity (d/b + d in Fig. 1 ) declines. In addition, the predictive value of a positive test declines as the prevalence of disease decreases. For example, if we have a test with a high sensitivity (e.g. 95%) and a high specificity (e.g. 98%), and if the prevalence of a cancer is low (e.g. 1 per 1000), then only 4.6% of the individuals with a positive test will actually be found to have the disease on further examination. The rest will have false–positive test results. In resourced-constrained countries, the positive predictive value of the Pap test should be higher compared with resourced countries owing to the increased incidence of cervical cancer.
The target population
Women at highest risk for the disease should be identified, and special efforts should be made to screen such people. Women at highest risk for cervical cancer are often difficult to reach.
The prevalence of disease in the target population
For any test of given sensitivity and specificity, numbers of false–positive and false–negative tests are functions of the prevalence of the disease in the target population. More false–negative tests occur if the disease is common and more false positives if the disease is rare. The latter is of particular importance in screening for cancer.
The consequence of false–positive tests
A false–positive test is a false alarm, with serious consequences in the case of cancer — economically, medically and psychologically. This accounts for cervical cancer as well.
Consequenses of a false–negative test
A false–negative test gives the screened person a false sense of security, and the neoplasm may then progress to a non-curable stage and kill the patient. This could have medico-legal implications.
Applicability of the test
Can the test be used on the people in the target population? Are special equipment and special resources needed (e.g. electrical power, water, a mobile van, transportation for potential screenees)? Can the test be done rapidly? The infrastructure for screening for cervical cancer with the Pap test is quite comprehensive, something to be taken in account in resource-constrained countries.
Acceptability of the test
Will the healthcare providers and the target population accept the test? Are there cultural or ethnic barriers? Is the cost to those being screened acceptably low? Generally, the Pap test is well accepted.
Adverse consequences of the test
Is there a possibility that the test will do harm? An example is the possible harm caused by irradiation during multiple mammography tests. In the case of the Pap test, possible harm is not an issue.
Life expectancy
Is the woman’s life expectancy longer than the time gained by early screening of asymptomatic individuals? A controversial issue is screening men over age 75 years for prostate cancer, as many of them will die of other causes before the prostate cancer becomes fatal. Women with cervical neoplasia are much younger, making screening a meaningful issue.
The evaluability of the programme
Every screening programme should be evaluated. Too often, the evaluation process is delayed for too long, after vast amounts of money and energy have been spent. The time to begin programme evaluation is when the programme is being planned.
Application of these principles in resourced countries
In resourced countries, the main method of cervical screening is Pap-test screening. In recent years, however, HPV testing has gained popularity owing to its higher sensitivity and being directed at detecting the main cause of cervical cancer.
Different countries have different guidelines. The guidelines of a selected group of resourced countries are presented in Table 1 . The guidelines from European countries are similar and slightly more conservative than those from the USA. All the countries, however, agree that high-risk women (including those with a previous abnormal Pap test result) should be screened annually until a high age (usually for life). Although screening is not recommended after a hysterectomy, women with a history of cervical neoplasia, or with neoplasia present in the hysterectomy specimen, should continue with screening.
| Country | First smear (age, years) | Follow-up Smears | Termination of screening (age, years) |
|---|---|---|---|
| USA | 21 | Every 2 years until 29 years, then every 3 years in low-risk women | 70 in low-risk women |
| England | By 25 | Every 3 years from 25–49 years; thereafter every 5 years | 65 in low-risk women |
| Wales | 20 | Every 3 years | 65 in low-risk women |
| North-Ireland | 20 | Every 5 years | 65 in low-risk women |
| Scotland | 20 | Every 3 years | 60 in low-risk women |
The American College of Obstetrics and Gynecology guidelines (2009) are used as an example, and the guidelines are evaluated against the above mentioned principles of screening for cancer in Table 2 .
| Principles | Conventional cytology | Liquid-based cytology | Human papillomavirus test alone | Human papillomavirus test plus cytology |
|---|---|---|---|---|
| Sensitivity | Low to moderate (± 50%) | Moderate to high (± 70%) | High (± 95%) | Very high (97–100%) |
| Positive predictive value | High | High | Very high | Very high |
| Target population | High-risk cases difficult to trace | High-risk cases difficult to trace | High-risk cases difficult to trace | High-risk cases difficult to trace |
| Prevalence of disease | Low | Low | Low | Low |
| Consequences of a false negative result | Serious | Serious | Serious | Serious |
| Applicability | Good | Reasonably good | Moderate | Moderate |
| Acceptability | Good | Reasonably good | Good | Good |
| Adverse effects | Very low | Very low | Very low | Very low |
| Life expectancy after testing | Good | Good | Good | Good |
| Evaluability | Good | Good | Good | Good |
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