A prospective study of association of herpes simplex virus and human papillomavirus infection with cervical neoplasia in women exposed to diethylstilbestrol in utero

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Abstract
One thousand one hundred thirty-four women, enrolled in a prospective study of the development of cervical neoplasia in women exposed to diethylstilbestrol (DES) in utero, were examined at least once a year. Twenty-three women developed cervical intraepithelial neoplasia (CIN) of different degrees during the 7-year follow-up period and were matched with women who did not develop CIN during the study period. Serum samples were obtained at the time of entry into the study and at the time of diagnosis of neoplasia. In the control group, a second serum sample was obtained close to the time when CIN was diagnosed in the other group of women. The sera were studied for antibodies to both types of herpes simplex virus (HSV) by microneutralization assay and by a radioimmunoassay using, as antigens, glycoproteins VPI23 for HSV type I and VPII9 for HSV type 2. Women who developed CIN had, in the enrolment specimen which preceded the neoplasia, a higher rate of antibodies to HSV-1 than did the matched controls (22%), while the two groups did not differ in frequency of antibodies to HSV-2 (9%). Similar differences were observed in the samples drawn at the time of diagnosis of CIN. Women who later developed CIN and had, at the time of entry into the study, cervical epithelial changes associated with DES exposure, were infected with HSV-1 at a higher rate than women who remained free of neoplasia or women with CIN but without DES-associated cervical epithelial changes. Morphologic evidence of associated papillomavirus (HPV) infection was observed in 74% of CIN cases and no such observation was made in biopsy specimens taken prior to development of CIN. Morphologic evidence of HPV infection was found in a woman of the control group having squamous metaplasia. HPV structural antigens were found in 3 of 10 CIN I and CIN II cases, and none in the CIN III specimens. The possible role of the HSV and HPV infection in the pathogenesis of cervical neoplasia is discussed.