Cigarette smoking is an independent risk factor for cervical intraepithelial neoplasia in young women: a longitudinal study.

Repeated measurements of smoking, cervical human papillomavirus (HPV) status and sexual behaviour were used to measure the risk of high-grade cervical intraepithelial neoplasia (CIN) in relation to changes in smoking and cervical HPV status, and to explore the impact of smoking on the acquisition and duration of incident cervical HPV infection. Included in this longitudinal analysis are 1485 women aged 15-19 years: 1075 were HPV-negative and cytologically normal at recruitment; 410 were HPV-positive, cytologically abnormal or both, at this time. Women re-attended every 6 months, when samples were taken for cytological and virological examination. Current smoking intensity was associated with an increased risk of high-grade CIN, after controlling for cervical HPV status (compared to non-smokers, hazards ratio (HR) for 10 or more cigarettes per day=2.21, 95% confidence interval (CI) 1.19-4.12, p-trend=0.008). In women who were HPV-negative and cytologically normal at recruitment, current smoking was not significantly associated with the risk of acquiring a cervical HPV infection, after controlling for life-time number of partners and age of oldest partner (HR=1.13, 95% CI 0.90-1.41); nor did it prolong the length of time during which HPV could be detected (HR=1.03, 95% CI 0.78-1.34). Current smoking intensity is an independent risk factor for high-grade CIN in young women, after controlling for cervical HPV infection.

Proximity of first intercourse to menarche and the risk of human papillomavirus infection: a longitudinal study.

Cross-sectional studies have suggested that compared with women who delay the start of their sexual career, those who first have intercourse soon after menarche are more susceptible to cervical human papillomavirus (HPV) infection and thus have a greater risk of cervical neoplasia. We describe, using longitudinal observations, how the risk of infection with HPV varies with the interval between menarche and first intercourse in 474 women aged 15-19 recruited within 12 months of first intercourse and before the acquisition of a second sexual partner. One hundred forty-five women became HPV-positive; the cumulative risk of HPV infection 3 years after first intercourse was 45.0% (95% CI = 37.9-51.2). In univariate analyses, the hazards ratio (HR) of HPV infection increased significantly with age at first intercourse (HR = 1.212 per year; 95% CI = 1.050-1.398), partner age (HR = 1.084 per year; 95% CI = 1.045-1.125) and when women reported a sexually experienced partner (HR = 2.794; 95% CI = 1.804-4.326); the interval between menarche and first intercourse was a significant predictor of infection, with an increase in the HR of 12.9% for every year of increase in this interval (95% CI = 2.1%-24.9%). In a multivariate analysis, compared with women who first had intercourse within 3 years of menarche, those who postponed first intercourse beyond this time had a greater risk of infection (HR = 1.581; 95% CI = 1.113-2.245) after controlling for age and sexual experience of partner.

Human papillomavirus type 18 and rapidly progressing cervical intraepithelial neoplasia.

BACKGROUND: Human papillomavirus type 18 (HPV-18) is the second most frequent of the HPV types detected when squamous-cell cancer is diagnosed and the type most strongly associated with adenocarcinoma of the cervix. However, in cross-sectional studies, HPV-18 is rarely detected at the time of diagnosis of high-grade cervical intraepithelial neoplasia (CIN). We used a longitudinal study design to describe the occurrence of cytological abnormality after incident HPV-18 and HPV-16 infections. METHODS: The analysis was based on 1075 women aged 15-19 years, who had normal cytology and were negative for HPV at recruitment from a single family-planning clinic, and who had further follow-up. The women reattended every 6 months, and samples were taken for cytological and virological examination. FINDINGS: The relative risk of a cytological diagnosis of borderline nuclear abnormality after exposure to HPV-18 was 2.06 (95% CI 1.24-3.43) and that after exposure to HPV-16 was 1.99 (1.32-3.01). The relative risks of mild dyskaryosis were 3.11 (1.86-5.18) and 4.76 (3.15-7.18), and the relative risks of moderate or severe dyskaryosis were 0.80 (0.24-2.65) and 2.85 (1.36-5.97). Time to acquisition of cytological abnormality was unrelated to the infecting type (p=0.88). INTERPRETATION: Our findings do not support the long-held view that the reason why HPV-18 infection is under-represented at the time of diagnosis of high-grade CIN is because HPV-18-associated disease rapidly progresses through the preinvasive stages of neoplasia. We suggest that the cytological changes detected after HPV-18 infection might understate the severity of underlying disease. This feature could compromise the effectiveness of screening programmes in reducing the frequency of HPV-18-associated cancers.

Changes in expression of the human homologue of the Drosophila discs large tumour suppressor protein in high-grade premalignant cervical neoplasias.

The Drosophila tumour suppressor discs large (Dlg) is a cell-junction localized protein that is required for the maintenance of epithelial cyto-architecture and the negative control of cell proliferation. The mammalian homologue is likely to have a similar mode of action, and therefore functional perturbation of this protein may be linked to the development of epithelial-derived cancers. The finding that several unrelated viral oncoproteins, including the E6 protein of oncogenic human papillomaviruses, bind to the human homologue of Dlg (hDlg) supports this proposition. Employing immunohistochemistry, we show that in uterine cervical squamous epithelia, prominent localization of hDlg at sites of intercellular contact occurs in cells that have left the proliferating basal cell layers and begun maturation. The presence of hDlg at sites of cell:cell contact diminishes, whilst intracellular cytoplasmic levels increase significantly in high-grade, but not low-grade, cervical neoplasias. In invasive squamous cell carcinomas, total cellular hDlg levels are greatly reduced. Our data suggest that loss of hDlg at sites of intercellular contact may be an important step in the development of epithelial cancers.