Epidemiologic evidence and human papillomavirus infection as a necessary cause of cervical cancer.


As with other malignant neoplasms, epidemiologic and laboratory studies conducted during the past 20 years have shown cervical cancer to be a disease with multifactorial causes and long latency. Unlike most other cancers, however, in which multiple environmental, biologic, and lifestyle determinants contribute independently or jointly to carcinogenesis, cervical cancer has been shown to have a central causal agent, human papillomavirus (HPV) infection (1–3), whose contribution to the risk of the disease is much greater than that of any other recognized determinant (4). On the basis of recent evidence from an international collaborative study (5) of more than 1000 cervical cancer specimens that used a highly sensitive polymerase chain reaction (PCR) protocol, researchers found that the prevalence of HPV DNA in cervical tumors was 93%. This is a higher estimate than had been observed previously in studies that used less meticulous methods for sample collection, preservation, and testing [reviewed in (4)]. Reanalysis of specimens that remained HPV negative revealed that HPV DNA could be detected in other portions of the same specimen or by use of PCR with different primers, thereby raising the prevalence to higher than 95% (5). Similar strategies have also been used to show the presence of HPV DNA in virtually all cases of cervical intraepithelial neoplasia (CIN) (6). Walboomers and Meijer (7) questioned the existence of HPVnegative cervical carcinomas and have argued that the use of the most recent generation of consensus–PCR protocols, which are highly sensitive, allows the identification of a wide spectrum of mucosotropic HPV types, thereby increasing the detection rate to virtually 100%. They proposed (7) that the occurrence of cervical cancer “without involvement of specific HPVs is exceptional or impossible.” Continuous expression of the viral E6 and E7 genes seems to be necessary for cervical carcinogenesis, with additional genetic changes being required to maintain the malignant phenotype (8). Of the known causes and determinants of cancer, none is considered necessary or sufficient. The suggestion that HPV infection may be the first cause of a human cancer that has been shown to be necessary has obvious implications for primary and secondary prevention of this disease (9). Walboomers and Meijer (7) suggested that the answer to whether or not an HPVindependent causal pathway exists in cervical cancer may be provided by epidemiology. In this commentary, we analyze the pitfalls of traditional epidemiologic approaches to distinguishing necessary from nonnecessary causes of cancer, using as a specific example the role of HPV infection in cervical cancer. We argue that, in traditional epidemiologic designs, misclassification of cumulative exposure to HPV may make it impossible to use the magnitude of the relative risk (RR) estimates for the association between HPV and cervical cancer to differentiate between the necessaryand non-necessary-cause assumptions.

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@article{Franco1999EpidemiologicEA, title={Epidemiologic evidence and human papillomavirus infection as a necessary cause of cervical cancer.}, author={Eduardo L Franco and Thomas E. Rohan and Luisa L. Villa}, journal={Journal of the National Cancer Institute}, year={1999}, volume={91 6}, pages={506-11} }