Etiological studies: human papillomavirus and cervical cancer

Abstract

Since zur Hausen (1976) drew attention to papilomavirus as a possible agent for genital cancer, impressive experimental data have been accumulated supporting an etiological role for human papillomavirus (HPV) in the pathogenesis of cervical cancer. Early epidemiological studies investigating the relation between HPV and cervical neoplasia found strong associations. These studies, however, presented important methodogical problems such as small sample size, biased selection of study subjects, different cervical sampling methods for cases and controls, and little or no control for confounding. Unexpcted findings reported from carefully designed studies were attributed to the use of filter in situ hybridization (FISH), now regarded as a technique with low accuracy. A reliable and sensitive HPV detection strategy based on polymerase chain reaction (PCR), recently developed, is now considered the technique of choice for epidemiological studies.. In developing countries cancer of the cervix is the leading cancer even when sites common to both sexes are combined. A hospital-based case-control study was undertaken to examine the etiological role of HPV in the development of invasive cervical cancer in Sao Paulo, Brazil, using PCR.Women with a diagnosis of invasive cervical cancer and women selected as controls were recruited from seven hospitalsofSaoPaulocity, between June 1990 and June 1991. The cases were women less than 80 years old, with diagnosis confirmed by biopsy and who had had no previous treatment for the disease. Controls enrolled from hospitals were the cases we recruited were age-frequency. matched to the cases. Patients admitted for treatment of a gynecological condition or who had had a hysterectomy corisation were inelegible as controls as were those with diseases associated with known risk factors for cervical neoplasia. Evidence of a gynecological or cytological abnormality detected on examination after recruitment was not a criterion for exclusion.Two hundred and six women with invasive cervical caneel' and 238 controls were eligible for investigation; 199 (96.6%) and 225 (94.5%), respectively, were interviewed. The controls were selected from a wide range of diagnostic categories. Study subjects were interviewed privately in the hospital using a standardized questionnaire. All study had a pelvic examination performed by a gynacologist when exfoliated cells for cytological examination and for HPV analysis were collected. One control (0.5%) had cytologcal evidence of low-grade squamous intraepithelial lesion; she was retained in the study. A PCR technique was used to analyse HPV DNA in cervical speciments collected with spatula and brush. During sample preparation care was taken to avoid contamination; the equipament used was disposable. When the study was completed, the material was sent to the Department of Pathology, Free University Hospital, Amsterdam. HPV detection was performed directly on crude cell suspensions without knowledge of the case/control status.To estimate the risk of cervical cancer...