The use of host cell DNA methylation analysis in the detection and management of women with advanced cervical intraepithelial neoplasia: a review.

This paper briefly reviews the role of hypermethylation of host cell genes in cervical carcinogenesis and discusses potential clinical applications of methylation analysis in the management of high-risk HPV (hrHPV) -positive women. We argue that methylation assays can be used: 1. for primary triage of hrHPV-positive women to detect cervical cancer and advanced cervical intraepithelial neoplasia (CIN); 2. as secondary triage for women with minor cytological abnormalities to identify those with the highest risk of CIN3 or worse; 3. as exit test for women leaving the screening programme to identify cervical cancer and advanced CIN; and 4. to support management of CIN. TWEETABLE ABSTRACT: This paper discusses potential clinical applications of DNA methylation analysis in the management of women with a high-risk HPV infection.

Dynamic spectral imaging colposcopy: higher sensitivity for detection of premalignant cervical lesions.

OBJECTIVE: to validate the dynamic spectral imaging (DSI) colposcope's colour-coded map in discriminating high- from low-grade cervical lesions and non-neoplastic tissue. DESIGN: prospective, comparative, multicentre clinical trial. SETTING: the colposcopy clinics of three Dutch hospitals. POPULATION: women of 18 years or over with an intact cervix, referred for colposcopy. METHODS: during a 3-minute image acquisition phase, the DSI colposcope was used as a regular video colposcope: the colposcopist located and graded potential lesions based on conventional colposcopic criteria. Subsequently, a colour-coded map was calculated and displayed, representing localisation and severity of the cervical lesion. Biopsies were collected from all atypical sites, as identified by digital mapping and/or conventional colposcopy. Furthermore, one additional biopsy was taken. MAIN OUTCOME MEASURES: histologically confirmed high-grade cervical disease (CIN2+). RESULTS: in total 275 women were included in the study: 183 women were analysed in the 'according-to-protocol' (ATP) cohort and 239 women in the 'intention-to-treat' (ITT) cohort. In the ATP cohort, the sensitivity of DSI colposcopy to identify women with high-grade (CIN2+) lesions was 79% (95% CI 70-88) and the sensitivity of conventional colposcopy was 55% (95% CI 44-65) (P = 0.0006, asymptotic McNemar test). When the DSI colour-coded map was combined with conventional colposcopy, the sensitivity was 88% (95% CI 82-95). CONCLUSIONS: DSI colposcopy has a significantly higher sensitivity to detect cervical lesions than conventional colposcopy. If the colour-coded map is combined with conventional colposcopic examination, the sensitivity increases further.

Lack of granzyme expression in T lymphocytes indicates poor cytotoxic T lymphocyte activation in human papillomavirus-associated cervical carcinomas.

Changes in major histocompatibility complex (MHC) class I expression in neoplastic cells are frequently observed in human papillomavirus type 16 (HPV16)-associated cervical carcinomas. In order to investigate whether this affects cytotoxic T-cell (CTL) activation, 20 HPV16-positive cervical carcinomas with variable MHC expression were analyzed immunohistochemically for the expression of granzyme B and interleukin-2 receptor (IL-2R). The results revealed that most carcinomas show strong CD3+ T-lymphocyte infiltrates. In nine of these cases CD8+ cells outnumbered the CD4+ cells, whereas in the remaining cases equal amounts of CD4+ and CD8+ cells were found. Double staining revealed that CD3+ granzyme B+ cells were not detected in 19 out of 20 cervical lesions, whereas in one carcinoma an occasional cluster of granzyme B+ T cells was observed. Positive controls, including genital warts and renal allograft rejections, showed granzyme B+ T cells. In agreement with this observation was the extremely low frequency of IL-2R+ T cells in the carcinomas tested, while warts contained IL-2R+ lymphocytes. The data indicate that cytotoxic (CD8+) T cells in cervical carcinomas are not activated, as demonstrated by the lack of granzyme B and IL-2R expression in the T cells.