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To evaluate the clinical significance of HPV genotyping for the prediction of progressive cervical intraepithelial neoplasia (CIN) in women with cytomorphologically abnormal smears, a prospective, blind, non-intervention study was performed. A total of 342 patients screened with cytomorphologically abnormal cervical smears were monitored every 3-4 months by cervical cytology, colposcopy and HPV testing using PCR. Women with progressive CIN disease were defined as patients developing lesions with a colposcopic impression of CIN III over more than 2 quadrants or resulting in a cytological smear equivalent to Pap 5. These patients were subsequently treated according to standard procedures. If any doubt arose about the true status of the patients (n = 75) these patients were censored and biopsied. The mean follow-up time was 16.5 months (range 3-36 months). Nineteen women showed progressive CIN disease and all appeared to be continuously HPV-positive from the start of the study. At biopsy, all these patients were histologically classified as CIN III. Seventeen of these women were positive for high-risk HPV types. Two cases were classified as still unidentified HPV. No progression was seen in the absence of HPV DNA or in the presence of low-risk HPV types. In life-table analysis the cumulative rate of progressive, histologically verified CIN disease was 17% after 36 months. Further analyses showed that other risk factors such as age, sexarche, number of sexual partners or smoking hardly influenced the effect of HPV on progression. The results show that the continuous presence of high-risk HPV types in women with cytomorphologically abnormal smears is a strong marker for progressive CIN disease.

We assessed a possible role for high-risk human papillomavirus (HPV) testing in the policy after treatment for cervical intraepithelial neoplasia (CIN) 2 or 3 (moderate to severe dysplasia). According to the Dutch guidelines follow-up after treatment consists of cervical cytology at 6, 12 and 24 months. Colposcopy is only performed in case of abnormal cervical cytology. In this observational study 184 women treated for CIN 2 or 3 were prospectively monitored by cervical cytology and high-risk HPV testing 3, 6, 9, 12 and 24 months after treatment. Post-treatment CIN 2/3 was present in 29 women (15.8%). A positive high-risk HPV test 6 months after treatment was more predictive for post-treatment CIN 2/3 than abnormal cervical cytology (sensitivity 90% and 62% respectively, with similar specificity). At 6 months the negative predictive value of a high-risk HPV negative, normal smear, was 99%. Largely overlapping, partly different groups of women with post-treatment CIN 2/3 were identified by HPV testing and cervical cytology. Based on these results we advocate to include high-risk HPV testing in monitoring women initially treated for CIN 2/3. In case of a high-risk HPV positive test or abnormal cervical cytology, colposcopy is indicated. All women should be tested at 6 and 24 months after treatment and only referred to the population-based cervical cancer screening programme when the tests are negative on both visits. © 2001 Cancer Research Campaign http://www.bjcancer.com

Adenocarcinoma in situ (ACIS) and adenocarcinoma (AdCA) of the cervix are frequently missed in population-based screening programmes. Adding high-risk HPV (hrHPV) testing to cervical cancer screening might improve the detection rate of ACIS and AdCA. Since the exact proportion of AdCAs of the cervix that can be attributed to hrHPV infection is still a matter of debate, a comprehensive study was performed of hrHPV presence in ACIS and AdCA of the cervix. Archival formalin-fixed specimens of indisputable ACIS (n=65) and AdCA (n=77) of the cervix were tested for hrHPV DNA by GP5+/6+ PCR-enzyme immunoassay (EIA) and type-specific E7 PCR for 14 hrHPV types. Further immunostaining for p16INK4A and p53 was performed to assess alternative pathways of carcinogenesis potentially unrelated to HPV. hrHPV DNA was found in all (100%) ACISs and 72 (94%) cervical AdCAs, whereas none of 20 endometrial AdCAs scored hrHPV-positive. HPV 18 was most prevalent and found as single or multiple infection in 68% of ACISs and 55% of cervical AdCAs. Diffuse immunostaining for p16INK4a, a potential marker of hrHPV E7 function, was significantly more frequent in hrHPV-positive cervical AdCAs (19/20; 95%) than in those without hrHPV (1/5; 20%; p<0.001). Immunostaining for p53, pointing to stabilized wild-type or mutant p53 protein, was significantly more frequent in hrHPV cervical AdCAs negative for hrHPV (p=0.01). No difference in p16INK4a and p53 immunostaining was found between hrHPV-negative cervical AdCAs and endometrial AdCAs. Hence, only a minority of cervical AdCAs displayed absence of HPV DNA and immunostaining profiles suggestive of an aetiology independent of HPV. Since all ACISs and nearly all cervical AdCAs were hrHPV-positive, the incorporation of hrHPV testing in cervical cancer screening programmes is likely to decrease markedly the incidence of cervical AdCA.

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