Cervical HPV infection and neoplasia in a large population-based prospective study: the Manchester cohort

Abstract

Cytology and histology records and cervical samples for HPV assay were obtained from a prospective cohort of 49 655 women attending clinics for routine cervical cytology in or near Manchester between 1988 and 1993. The women were followed up for cytological abnormality and neoplasia through the cytology laboratory's records. HPV at entry was assayed in an age-and periodstratified random sample of 7278 women and in prevalent and incident CIN3 cases. The prevalence of newly diagnosed CIN3 increased with time since last normal smear, indicating that most cases persist for several years. CIN3 prevalence did not increase further for screening intervals exceeding 5 years, however, suggesting that CIN3 eventually regresses cytologically. CIN2 prevalence increased less steeply with screening interval, while the prevalence of lesser abnormality was almost independent of screening interval. The prevalence of oncogenic HPV at entry declined from 19% among women aged under 25 to less than 3% at age 40 or above. Oncogenic HPV infection was strongly predictive of subsequent CIN3 (OR 17.2, 95% CI 10.4 -28.4), but only weakly related to CIN2 (OR 2.3, 95% CI 0.5 -10.7) and lesser abnormality (OR 1.4, 95% CI 0.8 -2.5). At current incidence rates, the lifetime risk of developing CIN3 will be 9% in this population. The cumulative risk of CIN3 diagnosis among cytologically normal women with oncogenic HPV detected at entry was 28% (CI 18 -43%) after 14 years. Persistence of oncogenic HPV may be more sensitive and specific than cytology for early detection of CIN3 and invasive cancer. Population-based prospective data on cervical neoplasia rates in relation to age, screening interval and history of type-specific HPV infection are still limited. Few cohorts are representative of regularly screened women in the general population, and those using the Bethesda system under which the high-grade category (HSIL) includes both CIN2 and CIN3 (Solomon et al, 2002) have often not analysed CIN2 and CIN3 separately. There is a strong and consistent association of genital HPV infection with cervical intraepithelial neoplasia (CIN) and cancer. CIN3 is almost always preceded by persistently detectable oncogenic HPV (Nobbenhuis et al, 1999), and HPV DNA was present in virtually all (99.7%) of a large sample of cervical cancers obtained from populations worldwide . Uninfected women, including those with abnormal cytology, are thus at negligible risk of invasive cancer. Follow-up studies indicate that most HPV infections are transient (Hildesheim et al, 1994;Remmink et al, 1995;Ho et al, 1998;Liaw et al, 1999;Nobbenhuis et al, 1999), but women with persistent HPV are at high risk of developing CIN3 (Nobbenhuis et al, 1999(Nobbenhuis et al, , 2001. HPV testing could thus be superior to cytology in routine cervical screening (Nobbenhuis et al, 1999;Cuzick et al, 2003).This report describes the relationship between HPV detection at entry and cytological and histological follow-up based on routine laboratory records in a prospective population-based cohort...

Human papillomavirus testing in cervical cancer screening

“…Follow-up studies of women with negative cytology, according to HPV status, are therefore important. In this issue, Bulkmans et al (2005) and Grainge et al (2005), using two different study designs, provide further evidence of the value of adding HPV testing to cervical cytology in screening programmes.In their 5-year cohort study in The Netherlands of 2810 women aged 30 -60 years with normal cytology, Bulkmans et al (2005) show that, in agreement with previous findings from the US (Sherman et al, 2003), France (Clavel et al, 2004) and the UK (Cuzick et al, 2003;Peto et al, 2004), HR HPV testing combined with cytology has higher sensitivity and higher negative predictive value for cervical intraepithelial neoplasia (CIN) 3 and cancer than cytology alone. Specificity was, however, slightly lower for HPV testing and cytology (93%) than cytology alone (95%).…”

“…In their 5-year cohort study in The Netherlands of 2810 women aged 30 -60 years with normal cytology, Bulkmans et al (2005) show that, in agreement with previous findings from the US (Sherman et al, 2003), France (Clavel et al, 2004) and the UK (Cuzick et al, 2003;Peto et al, 2004), HR HPV testing combined with cytology has higher sensitivity and higher negative predictive value for cervical intraepithelial neoplasia (CIN) 3 and cancer than cytology alone. Specificity was, however, slightly lower for HPV testing and cytology (93%) than cytology alone (95%).…”

Papillomavirus infection in rural women in southern India

“…All-age HPV prevalence in Dindigul District is similar to that found in high-risk areas for cervical cancer in Latin America (Molano et al, 2002;Matos et al, 2003), although lower than in some parts of sub-Saharan Africa (Thomas et al, 2004). No clear peak in HPV prevalence was found in young women in Dindigul District, whereas in most countries studied so far the prevalence of HPV below age 25 is X2-fold higher than at 45 or above (Molano et al, 2002;Peto et al, 2004). However, a constant prevalence of HPV across age groups has been recently reported in Nigeria (Thomas et al, 2004), suggesting that in some poor countries the risk of HPV infection is similar in different generations of women in contrast to the markedly higher HPV prevalence among younger women in many developed countries (Peto et al, 2004).…”

“…No clear peak in HPV prevalence was found in young women in Dindigul District, whereas in most countries studied so far the prevalence of HPV below age 25 is X2-fold higher than at 45 or above (Molano et al, 2002;Peto et al, 2004). However, a constant prevalence of HPV across age groups has been recently reported in Nigeria (Thomas et al, 2004), suggesting that in some poor countries the risk of HPV infection is similar in different generations of women in contrast to the markedly higher HPV prevalence among younger women in many developed countries (Peto et al, 2004). Low rates of HPV clearance and frequent HPV reinfections may also contribute to the steady age pattern observed in Dindigul District and Nigeria (Thomas et al, 2004).…”

“…HPV prevalence shows different patterns of infection by age in different populations. Much higher HPV prevalences were generally found below age 25 (Molano et al, 2002;Shin et al, 2003;Peto et al, 2004) or 35 years (Ronco et al, 2005) than above these ages, but in a very high HPVprevalence area (Ibadan, Nigeria), the proportion of HPV-positive women was similar in all 10-year age groups between 15 and 65 years or more (Thomas et al, 2004).…”