Two cocktails of digoxigenin-labeled human papillomavirus (HPV) type-specific oligonucleotide probes and an enzyme immunoassay (EIA) were used as a basis to develop a group-specific detection method for 14 high-risk (

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.

Summary In previous studies we have shown down-regulation of class I major histocompatibility complex (MHC) expression in a significant proportion of primary cervical carcinomas, which was found to be strongly correlated with loss of expression of the transporter associated with antigen presentation (TAP). By contrast, class II MHC expression was frequently up-regulated on neoplastic keratinocytes in these malignancies. In order to investigate whether these changes are associated with biological behaviour of the tumours, 20 cervical carcinomas were analysed for MHC (HLA-A, HLA-B/C, HLA-DR) and TAP-1 expression in the primary tumours and in lymph node metastases by immunohistochemistry. The results showed a significant increase in the prevalence of HLA-A and HLA-B/C down-regulation in metastasised neoplastic cells as compared with the primary tumour (P = 0.01). In all cases this was accompanied by loss of TAP-I expression. Up-regulated HLA-DR expression was found exclusively in primary tumours and was absent in the corresponding metastases (P= 0.002). These data are consistent with the hypothesis that loss of TAP-1 and the consequent down-regulation of class I MHC expression provides a selective advantage for neoplastic cervical cells during metastasis. Furthermore, the lack of class II MHC expression in metastasised cells either reflects a different local lymphokine production or indicates that these cells may have escaped CD4+ cytotoxic T-lymphocyte (CTL)-mediated killing.

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Summary Cervical intraepithelial neoplasia (CIN) grades I to III lesions (n = 94) and squamous cell carcinomas of the uterine cervix (n = 27) were analysed for MHC class I and II expression and presence of HPV genotypes.MHC class I and II expression was studied by immunohistochemistry and HPV typing was performed by general primer-and type-specific primer mediated PCR (GP/TS PCR). Both A central role in the antigen-specific immune response is played by the major histocompatibility complex (MHC), which are cell surface proteins that act as restricting elements in the recognition of antigen by T-cells. MHC class I (MHC-I) present endogenous antigen to cytotoxic T-lymphocytes (CTLs). Low levels or lack of MHC-I surface expression can consequently render aberrant cells non-immunogenic to CTLs, and may provide a way for cells to escape immune surveillance. MHC-1 alterations have been described in human cancer of different sites of the body (see review RuizCabello et al., 1991).Generally, MHC class II (MHC-II) surface expression is restricted to specialised antigen presenting cells (APCs), that present mainly opsonised exogenous antigen to T-helper cells. Recognition leads to activated T-cells, which can stimulate B-cell, CTL proliferation and MHC non-restricted killing by natural killer (NK) cells or activated macrophages. Occasionally, other cells like neoplastic epithelial cells have been described to express MHC-II, which could assist in the onset of the cellular immune response (Ostrand-Rosenberg et al., 1991).Infections with specific human papillomavirus (HPV) types are strongly associated with the development of cervical cancer, with HPV types 16 and 18 as the most predominant types (Zur Hausen, 1989 (Connor & Stern, 1990;Glew et al., 1992), suggesting that changes in the presentation of viral tumour antigens to the cellular immune system can occur. However, to get insight whether altered MHC-I and -II expression is related to the development of cervical cancer from its premalignant lesions, it is necessary to study dysplastic cervical lesions (CIN) for the MHC-I and -II status.Tumour virus based mechanisms have been described that specifically influence MHC-I cell surface expression (Signas et al., 1982;Schrier et al., 1983). Similar mechanisms could exist for HPV affecting antigen presentation of the infected cells. However, little is known about MHC alterations in CIN lesions in relation to the presence of different HPV genotypes.Therefore in this study expression of MHC-I and -II was investigated in CIN lesions of different grades and cervical carcinomas. HPV typing was carried out by a combined general primer-mediated (GP-) and type-specific (TS-) polymerase chain reaction (PCR) strategy (van den Brule et al., 1991;Walboomers et al., 1992). In addition, HPV RNA in situ hybridisation (RISH) was applied to some HPV 16 PCR positive lesions, in order to localise cells containing transcriptionally active HPV 16 in relation to altered MHC expression. The results indicate that MHC-I and -II alterations are also...