Cervical Cancer in Developing Countries
Ralph M. Richart, M.D.
Professor of Pathology, Columbia University College of Physicians
and Surgeons, and Director,
Division of Ob/Gyn Pathology and Cytology,
The Sloane Hospital for Women
New York, New York
Squamous cell cancer of the cervix is frequently the leading cause of death from cancer among women in the less developed countries. There are about half a million new cases of cancer of the cervix per year and 77 percent of these are in less developed countries. In many areas of the world, at least 3 to 5 percent of adult female deaths are due to this cancer. Unlike the West where cervical cancers peak in the 50 and 60 year age groups, in LDCs the peak seems to be in the 30 and 40 year age groups.
Virtually all of the epithelial neoplasms of the male and female lower anogenital tract are causally related to infection with human papillomaviruses (HPV). Approximately 60 HPV types have been identified, of which approximately 22 produce lesions of the genital tract. These viruses are generally divided into three groups - those of low oncogenic risk, medium oncogenic risk, and high oncogenic risk. The principal viral types of low oncogenic risk are types 6 and 11, those of high oncogenic type principally 16 and 18, and those of intermediate oncogenic risk principally HPV types 31, 33, 35, 51, 52, and 56. Although genital tract HPVs are sometimes transmitted by non-sexual means, the overwhelming majority of these infections appears to be sexually related.
The epidemiology of lower tract epithelial neoplasia parallels that of other sexually transmitted diseases. Cervical cancers are extremely rare in virginal women or in women who are in mutually monogamous relationships. In contrast, the principal co-variable which identifies a woman or group of women as being at high risk is the history of multiple male sexual partners or a male partner or partners who have had multiple partners. Relative risk of six-fold and greater are associated with having had partners in excess of six, and data suggest that a woman who smokes will suffer from an independently increased relative risk of lower genital tract cancer on the basis of her smoking behavior.
In those countries in which early sexual intercourse, multiple sexual partners, either in women or their male sexual partners, and prevalent cigarette smoking are the rule, lower genital tract cancers - particularly cervical cancers - would be expected to be, and in fact are, highly prevalent. It has been reported that in much of the developing world cervical cancer is either the leading cause or the second leading cause of death from cancer among women, and in some parts of the world penile cancer has been reported to be a leading cause of death from cancer among men.
Virtually all of the cancers of the epithelia of the lower genital tract have well studied and well defined precursor stages. It has been reported by a number of authors and convincingly substantiated in a number of statistical studies that the detection and eradication of precursor stages will lead to a substantial fall in the risk of developing lower genital tract cancers - particularly cervical cancer - and to a substantial decline in deaths from cervical cancer as well. Most of the precursor lesions in women are detected using the Papanicolaou smear which, in much of North America and Europe, is available as a routine procedure to virtually the entire population. In these highly developed and industrialized areas of the world, it is principally the poor, the elderly, and the uneducated who fail to avail themselves of Papanicolaou smear screening, and it is these populations in which invasive cervical cancer still persists at a high rate. In the remainder of the population, cervical cancer has fallen to an extremely low level which has been sustained for a number of years. Even those invasive cancers which are discovered tend to be low-stage cancers with higher survival rates than in the pre-Papanicolaou era when late-stage cancers were the rule and survival was relatively uncommon.
One of the principal advantages of Papanicolaou smears for screening is the cost effectiveness of this approach. Even a single smear in the patient's lifetime will reduce the death rate from cervical cancer by about 50 percent, with each additional smear reducing the death rate by a decreasing increment. However, as the mean transit time from the precursor stage to invasion is approximately 10 years, the screening intervals can be spaced fairly widely and still allow the program to be highly effective in reducing the cervical cancer risk. The appropriate time to begin screening and the appropriate screening interval can be chosen by each health authority to maximize the yield consistent with available monetary and other resources. At least one of the smears should be timed to coincide with the peak prevalence of the high-grade precursor lesions in countries in which resources are limited.
It is important to note that in previously unscreened populations in which there is a high prevalence of disease, the initial several screens will detect a very large number of invasive cancers and their precursors. The health care system must be prepared for this large influx of new cases of neoplasia. In a country with a poorly developed medical infrastructure, the output of a screening program can easily overwhelm the gynecological, surgical, and radiotherapy services.
Papanicolaou smear screening requires a well organized general and medical infrastructure, well organized and well equipped laboratories, and cadres of trained cytotechnologists and pathologists to screen and interpret the collected slides. In addition, it requires that effective means of following patients with abnormal smears be in place before the program is established and that trained gynecologists, adequate clinics, and treatment facilities be available to deal with the relatively large number of women who are detected as having abnormalities during the course of the screening campaign. All these tasks require a significant investment in facilities and personnel and a continuing high level of monetary investment to maintain these services.
Because of the perceived, and probably very real, difficulties in initiating and maintaining a population-based Papanicolaou smear screening program, various authors have suggested alternatives to Pap smears in developing a cervical cancer control program. One of these, referred to as "downstaging," proposes that women's cervices be examined visually during a speculum examination in an effort to detect invasive cancers at an early stage when they are potentially more curable. Even this relatively simple approach requires the availability of a well organized medical infrastructure, laboratories, and pathologists capable of processing and interpreting the biopsies, and, most importantly, a follow-up mechanism to identify and recall patients with cervical cancer and its precursors and to treat those patients. Because of the extremely high prevalence of cervical cancer in developing countries, it would be anticipated that, even in a downstaging detection program, very large numbers of cancer cases would be discovered in the initial and in subsequent screens and that a very significant investment in radical surgery and radiotherapy units would have to be made to accommodate the treatment of the large numbers of detected cases. One of the principal disadvantages of this approach to downstaging is that the lesions will be detected principally at the invasive stages when major therapeutic responses are required, rather than at the intraepithelial stage when treatment can be much less radical and hence less costly.
There is great interest in newer molecular approaches to the detection of women potentially at risk for developing cervical neoplasia, particularly since the development of new tests to detect HPV DNA using relatively simple hybridization procedures. Although these detection technologies are expensive at the present time, there is little question that new technology will be developed which will allow the mass application of HPV DNA detection at a substantially reduced cost. Such tests, which will be automated or semi-automated for processing and interpretation, offer the potential for screening for HPV-related neoplasms in less developed countries without the necessity of training large numbers of cytotechnologists and organizing screening laboratories. This opens the possibility that prescreening programs using HPV DNA detection could be initiated in large population bases to be followed by conventional Pap smears in those patients in whom positive results are obtained. Those women whose smears are positive could be assessed by colposcopic examination, biopsies, and endocervical curettage and appropriate follow-up diagnostic and therapeutic procedures. However, it is important to emphasize that even with the newest high technology detection modalities the problems relating to follow-up, diagnosis, and treatment will remain and that this part of the intervention equation should not be ignored when consideration of a screening program is being made.
It is likely that a better understanding of patient treatment modalities, coupled with simpler and cheaper detection techniques, will make it possible in the relatively near future to be able, realistically, to consider programs which may lead to meaningful cervical cancer detection and treatment programs in the less developed world.
References
1. R. Lunt, "Worldwide Early Detection of Cervical Cancer," Obstetrics and Gynecology 63 : 708-713, 1984.2. R.M. Richart, "Causes and Management of Cervical Intraepithelial Neoplasia," Supplement to Cancer 60: 1951-9, 1987.
3. T.C. Wright and R.M. Richart, "Role of Human Papillomavirus in the Pathogensis of Genital Tract Warts and Cancer: A Review," Gynecology and Oncology - in press.
4. C. Bergeron, A. Ferenczy, and R.M. Richart, "Underwear: Contamination by Human Papillomaviruses," American Journal of Obstetrics and Gynecology - in press.
5. B. Winkler and R.M. Richart (M. Baggish, series editor), "Human Papillomavirus Infections," Clinical Practice of Gynecology, Volume 1 (New York: Elsevier Science Publishers, 1989).
6. M.E. Boon, I. Susanti, M.J. Tasche, et al., "Human Papillomavirus (HPV)-associated Male and Female Genital Carcinomas in a Hindu Population: The Male as Vector and Victim," Cancer 64 : 559-65, 1989.
7. Canadian Task Force, The Walton Committee, "Cervical Cancer Screening Programs," Summary of the 1982 Canadian Task Force Report. Canadian Medical Association Journal 127 : 581-9, 1982.
8. B.A. Barron, M.C. Cahill, and R.M. Richart, "A Statistical Model of the Natural History of Cervical Neoplastic Disease: The Duration of Carcinoma-in-situ." Gynecology and Oncology 6 : 196-205, 1978.
9. J. Stjernsward, et al. "Plotting a New Course for Cervical Cancer Screening in Developing Countries," World Health Forum 8 : 42-5, 1987.
10. A.T. Lorincz, "Detection of Human Papillomavirus Infection by Nucleic Acid Hybridization," Obstet. Gynecol. Clin. N. Am. 14 : 451-69, 1987.
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