According to the current guidelines in most western countries, women treated for cervical intraepithelial neoplasia grade 3 (CIN 3) are followed for at least 2 years after treatment by cytology.High-risk human papillomavirus (hrHPV) infections are necessary for the development and maintenance of CIN 3. HrHPV testing could be used to improve monitoring of women treated for CIN 3. This has prompted numerous studies for the implementation of hrHPV testing in monitoring of women treated for CIN 3. Included in this review are 20 studies, published between 1996 and 2003, comparing hrHPV testing with either resection margins or cervical cytology to predict recurrent/residual disease, and 11 of them could be used in a meta-analysis. In the meta-analysis of the 11 studies, the negative predictive value (NPV) for recurrent/residual disease of hrHPV testing was 98% (95% CI 97-99%), that of resection margins 91% (95% CI 87-94%), and that of cervical cytology 93% (95% CI 90-95%). When hrHPV testing was performed in conjunction with cytology, the sensitivity was 96% (95% CI 89-99%), specificity was 81% (95% CI 77-84%), the associated positive predictive value (PPV) was 46% (95% CI 38-54%), and the NPV was 99% (95% CI 98-100%). Combined hrHPV and cytology testing yielded the best test characteristics. We propose to include hrHPV testing in conjunction with cytology for monitoring women treated for CIN 3. Some follow-up visits for women testing negative for both hrHPV and cytology can be skipped. In western countries, this could mean that for women double negative at 6 months, retesting at 12 months should be skipped while keeping the 24-month follow-up visit.

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.

We present the type-distribution of high-risk human papillomavirus (HPV) types in women with normal cytology (n ¼ 1467), adenocarcinoma in situ (ACIS) (n ¼ 61), adenocarcinoma (n ¼ 70), and squamous cell carcinoma (SCC) (n ¼ 83). Cervical adenocarcinoma and ACIS were significantly more frequently associated with HPV18 (OR MH 15.0; 95% CI 8.6 -26.1 and 21.8; 95% CI 11.9 -39.8, respectively) than normal cytology. Human papillomavirus16 was only associated with adenocarcinoma and ACIS after exclusion of HPV18-positive cases (OR MH 6.6; 95% CI 2.8 -16.0 and 9.4; 95% CI 2.8 -31.2, respectively). For SCC, HPV16 prevalence was elevated (OR MH 7.0; 95% CI 3.9 -12.4) compared to cases with normal cytology, and HPV18 prevalence was only increased after exclusion of HPV16-positive cases (OR MH 4.3; 95% CI 1.6 -11.6). These results suggest that HPV18 is mainly a risk factor for the development of adenocarcinoma whereas HPV16 is associated with both SCC and adenocarcinoma. (Walboomers et al, 1999). Testing for hrHPV types combined with cervical cytology becomes increasingly attractive as data accumulate that a combined test increases the efficacy of cervical screening programmes and triage policies for women with both equivocal and normal cervical smears (Cuzick et al, 2003;Khan et al, 2005). Possibly, even more efficient screening strategies can be developed by selecting hrHPV types conferring a preferential risk for the development of cervical cancer, and treat these infections more aggressively. In order to assess the preferential risk for cervical cancer and its precursors, typespecific prevalence of hrHPV types in cancer cases should be compared to type-specific prevalence in women without cancer. In a meta-analysis of cervical squamous cell carcinomas (SCCs) compared to high-grade squamous intraepithelial lesions, HPV16, HPV18 and HPV45 appeared to display an elevated prevalence in cervical cancer (Clifford et al, 2003a). A second meta-analysis revealed that HPV16 and HPV18 are more prevalent in SCC than in low-grade SIL (Clifford et al, 2005). However, a comparison with hrHPV prevalence in women with normal cytology was not made, hampering the translation of these findings to implementation of type-specific hrHPV testing in population-based screening.Recently in a cross-sectional study, we have demonstrated that among the hrHPV types, HPV16 and HPV33 were significantly more common in women with cervical intraepithelial neoplasia grade 2 or more (XCIN2) than in women with normal cytology. However in that study, cases of XCIN2 were retrieved from population-based screening, and consequently, the prevalence of invasive carcinomas as well as adenocarcinoma in situ (ACIS) was low.In order to obtain a more comprehensive view on the change in distribution from hrHPV infections without cytological abnormalities to hrHPV prevalence in cervical cancer, we compared crosssectional screening data of women with normal cytology to retrospectively collected cases of SCC, adenocarcinoma (AdCx) and ACIS. MATERIALS AND METHODS Women wi...

In a retrospective case–control study, we investigated high-risk HPV DNA presence by general primer GP5+/6+ PCR in the last normal cervical smear in the patient archives (i.e. baseline smear) of 57 women who later developed cervical cancer. Also, normal cervical smears of 114 age-matched control women were analysed. High-risk HPV DNA was detected in 37 of the 57 (65%) baseline smears of the case women, and 7 (6%) of 114 smears of the control women (OR 28, 95% Cl 11–72). The HPV positive subsequent smears and cervical cancer biopsies of the case women contained the same HPV type as was detected in the baseline smear. After cytological revision, the baseline smears of 48 case women (84%) were reclassified as abnormal, 33 (69%) of which scored high-risk HPV DNA positive. Ultimately, an undisputable normal baseline smear was found in only 10 case women. In 7 (70%) of them this smear was HPV positive, whereas only 7 (7%) of 104 revised, undisputable normal smears of control women were high-risk HPV positive (OR 32, 95% Cl 6.8–153). The results showed that (1) high-risk HPV presence precedes abnormal cytology in women who develop cervical cancer, and (2) high-risk HPV testing signals false-negative smears of women at risk of cervical cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com

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