The screening of the cervical cancer. The classical and the new.

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 synonymous 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 program.

As a result, several alternative methods of screening have been investigated, including visual inspection of the cervix after acetic acid application (VIA)4 or Lugol’s iodine application (VILI), colposcopy, cervicography,4 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 there of. The Pap test is a classic example of screening, with the aim of secondary prevention. Cancer precursors are identified and, by eliminating them, cancer formation is prevented.

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 from European countries are similar and slightly moreconservative 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.

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. The sensitivity of the HPV test is higher than that of cytology, resulting in more false–positives for the HPV test. A woman with a high-risk HPV type virus and negative cytology (even negative colposcopy), however, cannot be ignored and should be followed carefully.

The extremely high sensitivity of the HPV test (with or without cytology) promises a very high positive predictive value, but this is dependent on the specificity of the test, which is lower than the 95%- plus for cytology. However, the specificity is sufficient (60–90%) to ensure a high positive predictive value.

Women at high risk for cervical cancer are difficult to trace irrespective of the screening test used. In the USA, for example, 50% of women in whom cervical cancer is diagnosed each year have never had cytological testing. Therefore, in resourced countries, a special effort should be made to increase screening rates among women who currently are not screened or who are screened infrequently. The coverage in many resourced countries is low, around 50%. Examples include 48% for the Czech Republic and 47% for Belgium (Limburg province). The Nordic countries, however, are known for their efficient national screening programmes, with a high coverage of 90% or more.

The prevalence of cervical cancer is estimated at 6.5 per 100,000 women in the USA (2006) and 6.9 per 100,000 women in The Netherlands. The prevalence of CIN 2 and 3 on cytology varies from 1.1– 2.8%. In a study from South Africa, however, where histology was obtained from all women (n Ό 1286) attending a primary healthcare clinic (mean age 34 years), the prevalence of CIN 2 and 3 together was 7.4%. Therefore, the prevalence of pre-invasive disease is not low and, subsequently, false–positives will not be a significant problem.

The consequenses of a false–negative test result can be serious in the case of cervical neoplasia. As this is a well-known problem of the Pap test, the addition of the HPV test makes sense, particularly in women aged 30 years or more. In resourced countries, the applicability of the Pap test is excellent, as adequate facilities exist in virtually all these countries. Even for the HPV test, the applicability is good, although it is a much more expensive test. The acceptability of both the Pap test and the HPV test is good both within medicine and the general population. Adverse effects are not a problem in cervical screening with either the Pap test or the HPV test. As women are screened mostly between 20 and 50 years of age, the life expectancy after screening is substantial. This adds to the cost effectiveness of cervical screening. Pap smear screening has been evaluated adequately in resourced countries. In the USA for example, the incidence of cervical cancer has decreased more than 50% in the past 30 years.

Resourced countries have therefore done well with screening for cervical cancer. Certain limitations, however, have been identified:

(1) the Pap test is notideal, mainly owing to its restricted sensitivity, and (2) the coverage in many countries is well below 80%, whereby the control of cervical cancer and cancer-related deaths is limited.
The HPV test should be used more in screening programmes owing to its high sensitivity, and the best option seems to be in conjunction with cervical cytology in women over 30 years. Furthermore, every resourced country with opportunistic screening should institute a systematic nationally controlled screening programme with the aim of reaching coverage of greater than 80%.

Humanpapillomavirus test

This test is directed at identifying high-risk HPV DNA strains that are strongly associated with the development of cervical neoplasia. The rate of positive tests will vary markedly according to the woman’s age and the number of strains tested for. Its sensitivity varies from 82.8% to 100%and specificity from 62.5% to 99.3%.A low positive predictive value was documented (8.9%) with a high negative predictive value (99.7%).22 The use of this test resulted in a 73% reduction in CIN 2 or more. Unfortunately, this test is expensive, requiring high technology to perform. Subsequently, it is out of reach for most low-resource countries. A low-cost HPV test, however, which can be applied easily is in the process of development. Advantages of HPV tests compared with cytology are as follows29: (1) the objectivity of the test resulting in low inter- and intra-observer variability; (2) the possibility of almost complete automation of the process; (3) built-in quality-control procedures; (4) opportunities for self-sampling for HPV DNA in some populations with limitations in healthcare facilities and manpower (abeit with some loss in sensitivity); and (5) a higher sensitivity for detecting high-grade squamous intraepithelial lesion in women aged 30 years and over.
Gains in effectiveness could be achieved by increasing the length of the interval between screens and reducing the number of lifetime screens required.