Gynecologic Cytopathology: Past, Present and Future
Moderator: Annabelle Farnsworth
Section 5 -
Screening in Developing Nations
Stephen S. Raab
University of Pittsburgh School of Medicine
Department of Pathology
Pittsburgh , PA USA
Cervical cancer is the leading cause of cancer-related death among women in developing nations, where
more than 80% of new cases of cancer occur. The impact of this disease is likely to increase over time.
On a global scale, cervical cancer is probably the most preventable form of cancer related deaths in
women. In 1947, prior ot the widespread introduction of Pap test screening, the incidence rate of
invasive cervical cancer in the United States was 44 per 100,000, which is similar to cervical cancer
incidence rates reported for many developing nations today. By 1996 in the United States , the incidence
rates of invasive cervical cancer had declined to 7.5 per 100,000. Similar remarkable reductions have
been achieved in other industrialized nations. However, it is estimated that fewer than 5% of women in
developing nations have ever received a Pap test. Hakama et al and Womack et al reported that the
disproportionate burden of cervical cancer in developing nations is due largely to the absence of
well-organized screening programs.
In many developing nations, health care resources for cytologic screening programs compete for funding
with other healthcare problems. Alternatives to Pap testing also are advocated and include visual
screening, human papillomavirus testing (HPV) DNA testing, and HPV vaccines. Suba et al and Miller
argued that past failures of Pap testing screening in developing nations were most likely secondary to
failures in achieving adequate quality in programmatic components rather than technological failures.
Sociopolitical obstacles limit effective screening practices. Currently, using Pap test screening in
developing nations is controversial and debate frequently centers on data derived from theoretical cost
Alternative to Pap testing:
- Visual screening . Visual screening of
the cervix after application of acetic acid (referred to as direct visual inspection (DVI)) coupled with
immediate cryosurgical treatment has been advocated as a point-of-care strategy in low resource
settings. The single visit DVI eliminates the need for return visits and future colposcopy. The Royal
Thai College of Obstetrics and Gynecology adopted the single visit DVI as a safe and acceptable policy
and the single-visit DVI was recommended for immediate introduction to 54 districts in India.
- HPV vaccine . Infection with specific
types of HPV DNA appears to be an essential step in the development of cervical cancer and its precursor
lesion, squamous intraepithelial lesion (SIL). HPV DNA can be identified in more than 96% of invasive
cervical cancers. Studies support the promise of effective vaccination for selected high-risk types of
HPV DNA. Goldie et al reported that first generation vaccines will target young adolescents and it will
take several decades to determine the effect of these vaccines on cervical cancer mortality rates. As
some of the currently available vaccines target only several types of oncogenic HPV, a combination of
screening and vaccination will be required. Mahoney and Maynard reported that even if vaccines are
available, it could take up to 20 to 30 years for individuals in developing nations to have access to the
vaccine. Suba et al and Kulasingam and Myers reported that the use of vaccines could result in more,
rather than less, cervical cancer screening. However, many individuals believe that the future
prevention of cervical cancer depends on the rapid and effective development of HPV vaccines.
- HPV DNA testing . Highly sensitive HPV
DNA tests offer the potential replacement of conventional cytologic screening in settings where the
cytologic screening programs have not been successful or have not been fully introduced. There are
several methods of HPV testing. These methods include Hybrid Capture II, in situ hybridization, ligase
chain reaction, Southern blot hybridization, and polymerase chain reaction. Each method has its
advantages and disadvantages. Studies in developing nations has mainly focused on the use of Hybrid
Capture II although labs in developing nations have the technology to develop polymerase chain reaction
tests. These tests will have variable quality control and subsequent performance characterizes in HPV
DNA detection and cervical cancer prevention.
Analyses of cervical screening practices.
Studies examining the introduction of cervical cancer screening services generally have examined
practices in specific developing nations and it must be remembered that there are wide differences of
cultures, infrastructures, and practices that effect adoption, success, and dissemination. Thus, cost
effectiveness studies performed in one developing nation may not be applicable to other nations.
Suba et al reported on the establishment and cost effectiveness of Pap test screening in the Socialist
Republic of Viet Nam. The authors obtained their data from time motion studies based on actual personnel
costs in Viet Nam. Suba et al argued that the cost per woman screened to establish cervical cancer
prevention services was less than $0.53 USD. Suba et al argued that the assumed costs in other cost
effectiveness studies comparing the costs of Pap test screening to other methods of screening (HPV DNA
testing or DVI) artificially assumed high Pap testing costs that biased those studies against
conventional Pap testing. For example, Mandleblatt et al assumed the reported Pap test cost of $7.50 USD
for establishing services in Thailand although the mean country specific income was $1,970 USD. In
contrast, the mean country specific income in Viet Nam was $410 USD. Similarly, Robyr et al reported
that the cost of a Pap test in Cameroon was $13 and the mean country specific income was $570 USD.
In the analysis of establishing Pap test services, Suba et al categorized costs with regard to
personnel salaries, disposable supplies, equipment, space and overhead. Clearly, sensitivity analyses
would indicate that if the cost of the Pap test were considerably higher, then the cost per women of
cervical cancer prevention would escalate.
Difficulties in establishing Pap test screening services depend on establishing a cytologic
infrastructure including the creation of labs that could handle testing services. Suba et al argued for
centralized lab processes in which all Pap tests would be sent to regional labs. A second challenge was
in establishing return visit services following interpretation of Pap test results. Some authors have
argued that return visits are impractical in some low resource settings and in some cultures.
In studying a South African population, Denny et al argued that DVI approaches were safe and resulted
in a lower prevalence of high grade cancer precursor lesions compared with delayed evaluation. Goldie et
al reported that DVI or HPV DNA testing in one or two visits were a cost effective alternative to
conventional three-visit cytology based screening programs in low resource settings. In the study by
Goldie et al, HPV DNA testing was performed using Hybrid Capture II (Digene); the authors also considered
a combined strategy in which visual inspection was followed a positive HPV DNA test. The authors
considered that a three-visit strategy consisted of an initial screening test, colposcopy and biopsy in
the case of positive results, and treatment of cervical intraepithelial neoplasia. A two-visit strategy
consisted of initial screening followed by treatment, without colposcopic evaluation, of all women with
positive screening results. One-day screening incorporated same-day screening and treatment with
positive screening results. Goldie et al reported that screening women once in a lifetime, at the age of
35 years, with one or two visit strategies, reduced the lifetime risk of cervical cancer by 25 to 36
percent and cost less than $500 per year of life saved.
These studies clearly indicate that experts disagree on the most cost effective method of reducing
cervical cancer in the developing world and some studies indicate that gynecologic cytologic services
should not be further developed. Other studies conclude the opposite. The choice of cervical cancer
screening depends only partly on these cost effective studies and also is affected by global public
policies and resource allocation.
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