ReviewThe viral etiology of cervical cancer
Introduction
Research in relation to the etiology of cervical cancer has made substantial progress in the last two decades both in scientific and operational terms. For decades, the epidemiological profile of women with cervical cancer was recognized as suggestive of a sexually transmitted process and several infectious agents were proposed over the years including syphilis, gonorrhea, Chlamydia Trachomatis and type 2 Herpes Simplex Virus. The development of technology to test for the presence of Human Papillomavirus (HPV)-DNA in cellular specimens in the early 1980s made possible the establishment of a definite etiological role for HPV in cervical cancer (Bosch et al., 2002). Evidence is also accumulating for HPV involvement in a considerable proportion of the cancers of the vulva, vagina, anal canal, perianal skin and penis. On going research is investigating the role of HPV in skin cancer, oral cavity cancers and other cancers of the upper aerodigestive tract. The association of HPV with cervical cancer has provided the background and the scientific justification for improving screening programs and for developing HPV vaccines.
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Estimates of the health burden related to HPV infections
Table 1, Table 2 show current estimates of the prevalence of sub clinical HPV infections and of the burden of disease linked to HPV. In many countries, HPV is considered the most common sexually transmitted infection (STI) and cervical cancer remains the second most common cancer among women worldwide. In countries where screening is not implemented, cervical cancer is still a major health problem and a frequent cause of death.
HPV DNA in cervical cancer. The impact of the HPV testing system
Case-control studies, case-series and prevalence surveys have unequivocally shown that, with currently available technology, HPV-DNA can be recovered from adequate specimens of cervical cancer virtually in 80–99% of the cases. This compares to a prevalence of some 5–15% from cervical specimens of women identified as epidemiological controls.
Historically, the prevalence of HPV-DNA has dramatically increased with technology. In the early 1980s, the use of Southern Blot tests identified HPV in
Risk estimates by HPV-DNA status in age groups
The strength of the association between HPV-DNA and cervical cancer is usually expressed and evaluated by the magnitude of the relative risk (RR) in prospective studies, or the odds ratio (OR), which is the estimate of the relative risk in case control studies. Fig. 1 summarizes the results of some of the best recent studies, including the results of the large international program conducted by the International Agency for research on Cancer (IARC). The figure shows that the ORs related to
Other environmental factors
In addition to HPV-DNA, other environmental risk factors have been shown to be associated to cervical cancer. Because of the universal presence of the viral DNA, these factors should be considered co-factors in the sense that their independent effect on cervical carcinogenesis in the absence of HPV cannot be observed. The factors that are currently accepted as co-factors to HPV are high parity (i.e. seven or more pregnancies), long term use of oral Contraceptives (OC) (i.e. 5 or more years) and
Parity
In the IARC's Multicenter study, HPV positive women who reported seven or more full term pregnancies had a three to six-fold increased risk of cervical cancer as compared with similar HPV positive women that were nulliparous (OR: 3.8, 95% CI 2.7–5.5). There was still a 2-fold increased risk when women reporting seven or more pregnancies were compared with HPV positive women who reported one to two full term pregnancies (Muñoz et al., 2002). Similar results were obtained in Costa Rica (
Smoking
Smoking has been related to cervical cancer since the late 1970s based upon the correlations observed between cervical cancer incidence and the incidence of other tobacco related cancers (Winkelstein, 1977). An extensive review of the relation between smoking and cervical cancer was published in 1998 including eight cohort and 44 case-control studies. The report concluded that the association was largely consistent in studies that adjusted for HPV-DNA or restricted analyses to HPV positive
Oral contraceptives
The IARC's Multicenter study included 1768 cases and 262 controls that were positive for HPV-DNA. Ever OC use was associated with a significant increase in risk (OR=1.47[1.02–2.12]) restricted to men for at least 5 years. Use of OCs for <5 years was not related to cervical cancer (OR=0.77[0.46–1.29]). Risk increased for 5–9 years of use (OR=2.72[1.36–5.46]) and for 10+ years (OR=4.48[2.24–9.36]) (Moreno et al., 2002).
The evidence for an association of cervical cancer with the use of oral or
Relative contribution of selected risk factors to cervical cancer
Table 4 shows the distribution of some 2000 cases of invasive cervical cancer from the IARC studies according to their exposure to the established risk factors. The table shows that for close to one quarter of the cases, HPV DNA was the only risk factor identified. Close to three quarters of the cases showed the presence of HPV-DNA and one or more of the additional risk factors. The table also shows that, under optimal testing conditions, the fraction of cases that were unexposed to HPV falls
Conclusion
At the current level of knowledge, the causal role of persistent HPV infections in the development of cervical cancer and its precursors has been proven beyond reasonable doubt. A large number of human studies have been conducted following standard criteria that reasonably excluded bias, chance and confounding in the estimation of the risk. The evidence available at this time is consistent with the established criteria of causality. The association of HPV with cervical cancer has been proposed
Acknowledgements
The statistical contribution of Mireia Diaz in extracting and elaborating cancer statistics and of Cristina Rajo in the preparation of the manuscript are deeply recognized. Partial support has been received from the Fondo de Investigaciones Sanitarias (FIS 2001/1237—Principal Investigator: Dr. F. Xavier Bosch).
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