Elsevier

The Lancet Oncology

Volume 8, Issue 4, April 2007, Pages 311-316
The Lancet Oncology

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Risk of anogenital cancer after diagnosis of cervical intraepithelial neoplasia: a prospective population-based study

https://doi.org/10.1016/S1470-2045(07)70043-8Get rights and content

Summary

Background

The first vaccine against human papillomavirus (HPV)-related disease is now available. Although it has been designed and tested mainly to protect against cervical lesions, it is also expected to be effective against other anogenital cancers. Associations between HPV and vaginal, vulvar, and anal cancers are well established, but the full extent in terms of age and time since diagnosis of these associations is not well known.

Methods

We established a cohort of all women in Sweden who were aged 18–50 years at some timepoint from 1968 to 2004. Using national registration numbers, we linked this cohort to nationwide population, migration, cancer, and death registers. The incidence rate ratios (IRRs) of vaginal, vulvar, anal, and rectal cancer in women with a history of a cervical intraepithelial neoplasm (CIN), grade 3, compared with women with no such history were estimated by use of multivariate Poisson regression.

Findings

Women with a history of grade 3 CIN had increased risks of cancer of the vagina (6·74 [95% CI 5·24–8·56]), vulva (2·22 [1·79–2·73]), and anus (IRR 4·68 [3·87–5·62]). No excess risk was found for rectal cancer. For all four anatomical sites, the IRRs varied substantially with the amount of time that had elapsed since the date of first diagnosis of grade 3 CIN. Analyses stratified by attained age during follow-up showed that the risk of cancer conferred by a history of diagnosis of grade 3 CIN was highly age dependent. The observed increased risks were not explained by smoking or socioeconomic status.

Interpretation

This study confirms the known association between history of CIN, presumed HPV infection, and increased risk of cancers of the vagina, vulva, and anus by use of large and complete databases, but also shows that this risk varies both by the time from initial diagnosis of grade 3 CIN and by the age of the individual. Further studies are needed to clarify the type of HPV associated with this increase in risk to determine the clinical applicability of the new HPV vaccines.

Introduction

Women with a history of a cervical intraepithelial neoplasia (CIN) are well known to be at increased risk of vaginal, vulvar, and anal cancer,1, 2, 3, 4, 5 presumably due to human papillomavirus (HPV) infection. Specifically, HPV infection has been associated with anal cancer, non-keratinising vulvar cancer,6, 7, 8, 9, 10 and to some extent with vaginal cancer.11 The risks of developing these cancers associated with HPV infection is lower than that reported for grade 3 CINs, or for invasive cervical cancer.12 However, the extent of these associations remains poorly characterised.

Although the incidence of anal and vulvar cancer is rapidly increasing,13, 14, 15 cancers of the vagina, vulva, and anus are still rare.14, 15, 16 In certain subpopulations, such as among men who have sex with men, anal cancer is comparably common.17, 18, 19 The first vaccine against HPV-related disease is now available.20, 21, 22 Although this vaccine, and another soon to be released, have been developed and tested to prevent CIN and invasive cervical cancer, they are also expected to prevent other anogenital cancers and genital condylomas.20 Results from clinical trials of HPV vaccination have been extremely encouraging.20, 21, 22, 23

Almost 100% of tissue samples from grade 3 CINs are infected with HPV.24 Therefore, estimation of the risk of anogenital cancer after diagnosis of grade 3 CIN could potentially further our understanding of the relation between HPV infection and anogenital cancer. Since such data can be used to predict the potential effect of HPV vaccines, which is essential for the planning of health care and vaccination programmes, we did a population-based cohort study to assess the risks of vaginal, vulvar, anal, and rectal cancer in women with a history of a grade 3 CIN diagnosis.

Section snippets

Participants and procedures

Since 1947, all residents of Sweden have been assigned a unique national registration number. This number is routinely used in everyday life, in contact with authorities and health-care providers, and as a unique personal identifier in national population and health databases. From the Swedish National Population Register, we extracted the national registration number, date of birth, and date of death for all women who were born between 1918 and 1986 (ie, aged 18–50 years at some point during

Results

From the register of the Swedish population, we identified 3 747 698 women who were eligible for analysis. The women were on average quite young; almost 50% of the risk time included in the study was contributed by women aged less than 40 years. Risk time was relatively evenly distributed across the study period, with a slight excess in the later decades. The study population is described in more detail in table 1. During a median follow-up of 27 years (range 0–37 years), 91 229 349

Discussion

In this large population-based cohort study in more than 3·7 million women over a period of 37 years, we have shown a strong and consistent association between a history of grade 3 CIN and cancers of the vagina, vulva, and anus. The IRRs of these three cancers were substantially increased for more than 10 years after the first recorded cervical lesion. As was expected, we have found no evidence of such an association with cancer of the rectum.

Since HPV infection is present in almost all

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