Cytologic Screening Programs

Cervical Cancer Incidence and Mortality Worldwide

Currently, cervical cancer is potentially curable, but still continues to be the second most frequent cause of death by neoplasia in women and the survival rate at 5 years varies from 44% to 66%.

The highest incidence occurs in Latin America, the Caribbean, Africa (tropical sub-Sahara), and South and South East Asia ( Fig. 3-1 ). More than 85% of the cases occur in developing countries. Socioeconomic and cultural aspects are a factor in the unequal distribution of this neoplasia around the world. However, a preponderant factor in the areas of low incidence is the level of information from the feminine population regarding the disease and the continual screening of this population. On the other hand, in developing countries, the low level of awareness of the problem, the lack of interest of the sanitary authorities, and the use of opportunist screening favors the continuance of this unfavorable situation and indicates the urgent need for the public health authorities to find a solution.

An important number of risk factors for cervical carcinoma have been identified and can therefore be controlled, avoiding the progress of pre-neoplastic lesions. These factors are: early start to sexual activity, multiple partners, the number of partners a man has, infection by oncogenic HPV, precarious genital hygiene, and smoking.

Histologically, the largest number of cases is of squamous cell carcinoma; however, the incidence of cervical adenocarcinoma has gradually increased over the past decades, particularly in young women, where it has doubled. A larger number of adenocarcinomas are being identified, either by control of cervical cancer in developed countries or by association with HPV infection, above all, type 18.

Programs applied in Scandinavian countries and in Canada demonstrate that, with continuous screening, it is possible to reduce mortality from cervical cancer by almost 75%. However, the reduction of the mortality rate is related to the real efforts by doctors and the population; the frequency and quality of the specimen collection; the examination and diagnostic analysis; adequate communication between the specialists; and the efficacy of the system for management of the patients.

Efficacy of Screening

The efficacy of cytological screening for cervical cancer depends on the possibility of modifying the course of the disease through identification of women with high-degree precursor lesions and invasive initial lesions. With this identification, it is possible to distinguish the woman apparently not affected from the woman who could have the disease.

Even though the efficacy of cytology screening has never been proven through randomized trials, it is generally agreed that the marked reduction in the incidence and mortality from cervical cancer before and after the introduction of screening programs in a variety of developed countries has been interpreted as strong non-experimental support for organized cervical cancer screening programs.

The best known studies are those that compared incidence and mortality in Iceland and in the four Nordic countries. Before screening was installed in Iceland, mortality had been on the increase but fell 50% in the period of 10 years from introducing screening. In the Nordic countries, the decline in cumulative incidence rates over a 15-year period, between 1966–1970 and 1981–1985, was related to the coverage and extent of the organized programs. In Norway, where only 5% of the population had been screened opportunistically, the incidence rates fell by 20% in comparison to Finland, with a national population-based program, where incidence fell by 65%.

In a study of invasive cervical cancer in British Columbia, approximately half of the new cases diagnosed had no previous cytology or the last examination had been made more than 5 years previously.

Two important parameters traditionally used to measure the validity of screening tests are sensitivity and the specificity. The sensitivity means the percentage of positive cases reported as being positive. It relates to the ability to detect disease and can be calculated using the formula:

The specificity means the percentage of negative cases reported as being negative. It relates to the ability to exclude disease and can be calculated using the formula:

A third criterion is the positive predictive value that measures the probability of the disease being present in those patients whose test was reported as positive, and it can be calculated using the formula:

Glandular lesions are much less frequent than those originating from squamous epithelium and the diagnosis of the intraepithelial forms is the principal objective of the screening programs. In relation to the prevention of cervical adenocarcinoma, the Pap test is potentially a powerful weapon, but, in comparison to the diagnosis of squamous lesions, the diagnosis of cervical adenocarcinoma in situ has shown a significantly higher rate of false-negatives, not being so effective in the prevention of invasive glandular lesions.

In 2004, a working group at the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) met to evaluate the efficacy of prevention of cervical cancer in reducing mortality caused by the disease. It concluded that the programs of prevention based on the Pap test continue to be the mainstay for prevention of this type of cancer throughout the world, there being sufficient evidence that screening of cervical cancer diminishes mortality caused by the disease.

Despite the knowledge of the efficacy of cytopathological tests in contributing to the reduction of cervical cancer through organized programs by their characteristics of simplicity, acceptability, and low cost, studies have shown major variations in the estimates of sensitivity and specificity of the test. A meta-analysis to estimate the accuracy of the Pap test in which data from 59 studies were combined reported estimates of sensitivity and specificity ranging from 11% to 99% and from 14% to 97%, respectively. A systematic review reported sensitivity and specificity ranging from 30% to 87% and from 86% to 100%, respectively.

Sensitivity and specificity are important parameters for the evaluation of the accuracy of the screening test. However, it is important to bear in mind that the efficacy of screening is not restricted to the performance of the test used. Special emphasis must be given to the need to develop organized programs that have a systemic approach, that are well integrated into the existing health system, and that consider social, cultural, and economic aspects. A meta-analysis of social inequality and the risk of cervical cancer in 57 studies revealed that both cervical infection with HPV and a lack of access to adequate cervical cancer screening and treatment services are likely to be important in explaining the large cervical cancer incidence rates observed in different socioeconomic groups. An estimated 100% increased risk of invasive cervical cancer was found for women in low social class categories when compared with women in high social class categories.

In an analogous way, this difference occurs in developing countries and in those developed countries where the inequality in access is the consequence of the inequality in the quality of services. Past failures of cervical screening in developing countries are attributable to failures in program quality, rather than to technological limitations of the screening test.

It is very important to evaluate the efficacy of programs in reducing disease, and also whether the screening approach chosen is cost-effective, before considering extending implementation to large populations. A screening program is justified if a prior diagnosis that permits a cost-effective and measurable reduction of the disease is made.

Design of Screening Programs

Cervical cancer can be avoided when there is an early diagnosis of the precursor lesions, without local or systemic compromise. The implementation of a systematic program of prevention of gynecological cancer among women in British Columbia in 1949 reduced both the incidence and the mortality caused by this neoplasia. Among the methods available for early detection of cervical cancer, exfoliative cytology, or the Pap test, is recommended worldwide for mass screening, because the efficacy in the detection of premalignant lesions, associated with the social role of the method, permits minimization of costs with curative medicine.

From that stated above, a routine of procedures essential to the success of a program of prevention may be obtained. The basic integrated actions include: (1) care with collection; (2) processing of the smears; (3) screening and interpretation of the specimens; (4) follow-up of the patients; and (5) quality control.

• 1.

  Care with collection . The majority of false-negatives arise from problems with collection of specimens, and, for this reason, this stage should be systemized and there should be training and recycling of the personnel responsible for taking the samples. The smears must be well identified, slim, uniform, and without contaminants, and contain samples from the transformation zone, where, in the majority of cases, the cervical cancer develops. There should be a minimum of blood, mucus, or other obscuring material such as lubricating gel. It is also important at this moment to adequately fix the material so as not to compromise subsequent stages.

• 2.

  Processing the smears . In general, prevention programs cover a large number of tests, so laboratories should have guidance regarding the systemizing of the processing and the recording of a large volume of specimens. One of the characteristics of the Pap test is that it consists of various stages. Each stage should be monitored so as to minimize the possibility of error. The condition on arrival of the slides, and the number of slides per case, must be verified. Special care should be taken with the flow of the tests, with adequate numbering and balanced coloration with control of the number of cases colored in each set. The end-product of this stage will be fundamental to a good result with the rest.

• 3.

  Screening and interpretation of the specimens . The screening should be done in as little time as possible, depending on the basic requirements of each program, by trained and qualified personnel. Care should also be taken with excess workloads for cytopathologists and cytotechnicians, and also with refresher courses and recycling. The report on the tests should be systemized and use a unique nomenclature, of which all involved in the preparation and interpretation of the results should be fully aware.

• 4.

  Follow-up of patients . The prevention program should include reference, contra-reference, and active search services. The mere detection of the lesions will not determine the impact on the natural history of the disease. For this reason, the treatment of lesions in a pre-invasive stage is fundamental. Outpatient treatment centers for the more simple cases, and others for more complex cases, should be integrated into a service network for the program. Mechanisms for finding and managing patients who did not return after the initial test and who show alterations are fundamental for a prevention program to function well.

• 5.

  Quality control . Quality is fundamental in gynecological cytopathology. One of the greatest problems in mass cytology is the false-negative cases. Cytopathology laboratories must have mechanisms for internal quality control, with the objective of avoiding false-negative and false-positive tests. These mechanisms should include measures relating to the screening and interpretation of the specimens, a review of 10% of the cases seen by the cytotechnician, and grouping the technicians according to hierarchy. External quality control must be included in the design of the prevention program, conducted by an accredited entity and with interlaboratory action, with the objective of guaranteeing the homogeneity and quality of the laboratory procedures. It should also function as a detector of eventual problems and could indicate a need for redirectioning continuous education efforts within the program. For additional information on quality assurance in cytopathology, see Chapter 4 .

Cancer screening may be offered to a population either as an organized program or opportunistically, or as some combination of the two. Opportunistic screening is spontaneous and initiated either by the individual or by the healthcare provider during routine healthcare encounters. It is often associated with low coverage of people at high risk and excessive repetition of procedures at frequent intervals, high costs, and a small benefit at the population level. Systematic or organized screening programs refer to planned and concerted public health application of early detection and treatment in defined populations, operating under precise protocols and guidelines.

Some countries with organized screening programs can reduce the incidence of cervical cancer by up to around 80% in areas with high-quality screening, good coverage, and a reliable follow-up. Organized programs with systematic call-up, recall, follow-up, and vigilant systems have shown more expressive effects with less resources than less organized programs. Various alternative screening strategies are being researched for developing countries, although the challenge in less-developed countries is surpassed by the complex array of problems that go far beyond the introduction of simplified technology.

Features of Successful Screening Programs

The success of cervical cancer screening is shown by its ability to reduce the incidence of cervical cancer and the resulting mortality, in a cost-effective way. To be successful, it is fundamental that the program is organized and broad-based, developing along the line of care for cervical cancer. All the stages involved in the finding of the women, the collection of material for the cytological test, transport and processing of the slides, identification of lesions, and finally the delivery of results, treatment, and follow-up of the women with alterations should happen in sequence, synchronized and with the highest quality. Any failure in one of these stages can compromise the impact of the screening on the health of the population. The following are some aspects of successful screening programs:

• Government policy . Planning within a governmental policy and national planning for cancer control. This includes the definition of the age range of the population to be prioritized and the frequency (interval) of screening, apart from production of instructions to guide the process, including recommendations regarding nomenclature and the therapeutic action for the lesions identified.

• Coverage . Measures to guarantee good coverage, with special attention to identification of women in the target population. Education of these women regarding cervical cancer screening can contribute to increased attendance and confidence in the procedure, apart from facilitating understanding of the results of the cytological test.

• Integrated system . The different levels of healthcare in the program should be integrated like a network, with the capacity to ensure continuity of the care within the different levels.

• Health professionals . Good results can be achieved by educating and training the health professionals, improving the attention given to the women, the quality of samples collected, the quality of the screening and the results of the tests, and also the research and follow-up of the patients with lesions needing treatment.

• Quality of the diagnosis . Efficient and high-quality laboratory service, which should preferably be centralized; quality control of cytology reading.

• Infrastructure of health services . Adapting the services to give the treatment needed, with the capacity for attending to the planned demand, in relation both to equipment, installations, and material and to the human resources available. It is of fundamental importance to guarantee the supply and the accessibility of the health services.

• Information system . An integrated information system linking the different elements of the program, permitting identification of each woman and the exchange of management information, and monitoring and referring women with results showing alterations to the respective health services, with a view to ensuring that these patients receive appropriate diagnosis and treatment, should be achieved.

• Indicators . Monitoring and evaluating cervical cancer prevention programs is essential for effective, efficient planning and service organization, as well as for patient management. Indicators created to evaluate performance at the different stages of the program should be monitored regularly, using information generated preferably through the routine information system.

• Leadership . Leadership, management skills, attention to linkages at all levels of the program, and budgeting skills are essential.