Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
This summer, the much-discussed human papilloma virus (HPV) vaccine entered a new phase of utilisation across the UK. In response to a report by the Joint Committee on Vaccination and Immunisation,1 Public Health England has initiated a pilot in which 42 genitourinary medicine and HIV clinics will provide the Gardasil vaccine to men who have sex with men (MSM). This pilot is supported by the evidence: MSM have a higher incidence of HPV than heterosexual men2 and the virus is linked to around 85% of anal cancers.3 Among the general population, however, it is also important to remember the burden of anal cancer among women. Not only is there a higher incidence of anal cancer among women than among men in the UK (2.6 per 100 000 compared with 1.3 per 100 000), the last 10 years have also seen a higher rate of increase within the female population (a 46% increase, compared with almost no increase in men).4 With these figures in mind, eliminating women from the discussion around anal cancer prevention seems somewhat short sighted. Although efforts towards vaccinating teenage girls against HPV are likely to have a significant effect on future prevalence of anal cancer, there remains a subgroup of unvaccinated women who are currently at risk. This discussion becomes even more vital when looking at anal cancer on a global scale. It has long been known that women who are living with HIV are more susceptible to HPV-related cancers, and with oncology services being scarce in many parts of the world, a greater understanding of cost-effective prevention strategies is vital.
The first step towards improved anal cancer prevention involves identifying those women who are most likely to be affected. Given the strong association between HPV and anal cancer, it seems reasonable to investigate the prevalence of anal cancer among women with confirmed infection, particularly those with existing neoplasia. A 2016 cross-sectional study examined samples taken from 311 Mexican women with abnormal cervical cytology. Anal samples (38%) from the study group were infected with high-risk HPV (16, 18, 58 and/or 45), and 82% of positive samples had E2 gene disruption implying HPV integration and malignancy risk.5 Similarly, a recent subgroup analysis of the British ‘Million Women’ study looking at 517 incidences of anal cancer over a 13-year period found that a history of cervical intraepithelial neoplasia grade 3 (CIN 3) significantly increased the likelihood of developing anal cancer (RR=4.03; 95% CI 2.59 to 6.28).6 In 2015, the International Anal Neoplasia Society conducted a systematic review that aimed to support guidelines on the necessity and feasibility of anal cancer screening in women. The review found there to be strong evidence for an increased risk of anal cancer in women with a history of in situ and invasive cancers of the lower genital tract and made recommendations for screening in these women.7
Having identified that women who have a history of genital high-grade neoplasia are at increased risk of developing anal cancer, the next step is to explore the economic and practical feasibility of various prevention methods within this group. One option would be to embark on some form of screening programme; however, even within the subpopulations who are most at risk, it is difficult to fit anal cancer into the Wilson criteria. The current gold standard for identification of early anal malignancy is high-resolution anoscopy-guided biopsy—something which is too expensive to be used as a primary screening method, even in high-income countries.7 Anal cytology has a variable sensitivity and specificity, meaning that repeat screening would be necessary; something which is unlikely to be feasible for most groups—particularly given the relatively low prevalence of anal cancer.7 Crucially, in many parts of the world, the lack of treatment options for anal cancer and the relative lack of data on management of precancerous anal lesions would render screening futile.
The most effective method of prevention in adult women is therefore the same as for MSM—vaccination against HPV. Adult women are currently excluded from most vaccination programmes, on the grounds that they have already been exposed to the virus, despite mounting evidence of the benefits that vaccination may present to those who are not HPV naive. An extension of the Costa Rica HPV vaccine trial, examining the efficacy of the bivalent Cervarix vaccine (HPV 16 and 18) against persistent HPV infection, found that women who were seropositive for HPV 16 and/or 18 who had negative cervical samples still displayed vaccine efficacy of 57.8% (CI 34.4% to 73.4%), compared with 83.5% efficacy in women who had not been infected with HPV.8 This is particularly relevant in the management of women after treatment for HPV-related malignancy. A 2016 study of 737 women who had received loop electrosurgical excision procedure (LEEP) as treatment for CIN 2 or 3 found a recurrence rate of 2.5% among those randomised to receive the quadrivalent vaccine (HPV 6, 11, 16 and 18) after the procedure, compared with 7.2% in those who had not been vaccinated.9 A retrospective analysis of the international FUTURE I and FUTURE II trials examined this phenomenon on a larger scale, examining the progression of 2054 women across 24 countries who had undergone cervical surgery or been diagnosed with genital warts, vulvar intraepithelial neoplasia or vaginal intraepithelial neoplasia. Women who had been randomised to receive the quadrivalent HPV vaccine after treatment were 35.1% less likely (CI 13.8% to 51.8%) to subsequently develop HPV-related disease.10 Although little data currently exists on the effect of post-treatment vaccination on the development of anal cancer, it is clear that this is a prevention method that deserves further exploration. A 2016 study of over 500 precancerous and cancerous anal lesions from 24 countries found that 84.3% of the samples were associated with either HPV 16 or 18, with 16 being the most prevalent. As the Cervarix vaccine is active against HPV 16 and 18 and Gardasil prevents HPV 6, 11, 16 and 18, the authors postulated that widespread use of currently available HPV vaccines could prevent up to 84.3% of anal cancers.11
Data arising from a multitude of studies continue to indicate that anal cancer is a malignancy that poses a significant risk to women, especially those who have previously experienced anogenital neoplasia. It is therefore vital that clinicians, particularly gynaecologists and sexual health physicians, are aware of these risks and that they appropriately counsel their patients who have been treated for HPV-related neoplasia on the warning symptoms of anal malignancy. Given the demonstrable effectiveness of postsurgical HPV vaccination, there is also a public health argument for proactively vaccinating women who have CIN 2/3 or worse at the time of treatment. Limiting vaccine programs to teenage girls and high-risk men, when it is clear that post-LEEP vaccination of older women could also have a significant impact on anal cancer prevalence, is discriminatory, and it is time for the medical community to consider the clinical and economic impact that HPV vaccination may have when used to combat this increasingly prevalent malignancy in women.
Twitter Follow Danielle Solomon at @df_solomon
Contributors The overarching concepts of this article were developed collaboratively by all authors (DS, MS, AR). First draft of the manuscript was written by DS. All authors contributed to manuscript revisions.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.