The viral etiology of cervical cancer

doi:10.1016/S0168-1702(02)00187-9

Virus Research

Volume 89, Issue 2, November 2002, Pages 183-190

https://doi.org/10.1016/S0168-1702(02)00187-9 Get rights and content

Abstract

Epidemiological studies supported by molecular technology have provided sufficient evidence on the causal role of some Human Papillomavirus (HPV) infections in the development of cervical cancer. This association has been evaluated under all proposed sets of causality criteria and endorsed by the scientific community and major review institutes. HPV has been proposed as the first-ever identified, necessary cause of a human cancer. In practical terms, the concept of a necessary cause implies that cervical cancer does not and will not develop in the absence of the persistent presence of HPV-deoxyribonucleic acid (DNA). This important advancement has two practical implications in prevention. Firstly, screening programs can be enhanced if HPV testing is judiciously incorporated into solving the fraction of ambiguous cytology readings. In some populations HPV screening as a primary test may prove to be the strategy of choice. Secondly, like in the hepatitis B disease model, intense efforts are currently being put into the development and testing of vaccines that may prevent the relevant HPV infections, and presumably, cervical cancer. At this stage of development, regulatory agencies are requested to evaluate the scientific evidence and weigh its implications in relation to costs, public health investments and policy. This is a subjective evaluation that could be guided by a careful description of the most relevant studies and findings.

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.

Section snippets

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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ReviewThe viral etiology of cervical cancer

Abstract

Introduction

Section snippets

Estimates of the health burden related to HPV infections

HPV DNA in cervical cancer. The impact of the HPV testing system

Risk estimates by HPV-DNA status in age groups

Other environmental factors

Parity

Smoking

Oral contraceptives

Relative contribution of selected risk factors to cervical cancer

Conclusion

Acknowledgements

Lancet

Med. Clin. (Barc)

Lancet

Lancet

Lancet

Lancet

Prevalence of human papillomavirus in cervical cancer: a worldwide perspective

J. Natl. Cancer Inst.

The causal relation between human papillomavirus and cervical cancer

J. Clin. Pathol.

Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN3 among those infected: a case-control study nested within the Manchester cohort

Br. J. Cancer

Co-factors related to the causal relationship between human papillomavirus and invasive cervical cancer in Honduras

Int. J. Epidemiol.

Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica

J. Natl. Cancer Inst.

HPV co-factors related to the development of cervical cancer: results from a population-based study in Costa Rica

Br. J. Cancer

Review
The viral etiology of cervical cancer