Sexual Practices and Anal Squamous Cell Carcinoma

When I first started my research into Anal SCC, I was told by multiple clinicians that the rise in incidence of ASCC in England is due to the relaxation of social stereotypes and the rise of sexual freedom. In particular in women, who were within the first generation to benefit from oral contraceptives and the rise of feminism.  

To put bluntly; women were more able to have sexual relationships and therefore were more likely to be exposed to different strains of HPV from different partners.  

Their evidence for this was that this patient subgroup are associated with the highest incidence increase worldwide and that patients in England are more likely to be female Caucasians in their 60’s and 70’s. 

However the more I read about Anal SCC the more I think that it cannot be so simple. 

Firstly, this generation would have been within the first cohorts of cervical screening, although the risk of cervical cancer is increasing over the last few years (in particular in younger women who did not participate in screening) there is a net reduction in cervical cancer incidence by 24% in the UK since the 1990’s. However, geographical areas with high incidence rates of cervical cancer are not necessarily associated with high incidence rates of Anal SCC.  

Secondly, as the highest risk of ASCC is actually associated with being an HIV positive MSM, is the risk actually associated with receptive anal intercourse? 

In demographic areas where HIV prevalence is high, the majority of patients seen with Anal SCC  and AIN are HIV positive MSM.  There is less of an association with HIV negative MSM.  

There are some papers in the literature that demonstrate a higher risk of AIN in women and men who practice receptive anal intercourse, however there are also papers that also show that there is no difference identified between sexual practices and risk.

I think this theory is difficult to prove, firstly due to recall bias, sexual practices change over time, just because you practiced receptive anal intercourse with one partner does not mean that you regularly do so. Nor does it mean that interaction was the time you were exposed to an oncogenic HPV. Patients can also be, understandably sensitive about their sexual practices and not wish to disclose them. In particular the paper I refer to above which did not show a different with sexual practices and risk, the group denying receptive anal intercourse were statistically older. It’s possible that this group were less likely to disclose due to social stigma.  

Like cervical cancer, Anal SCC has been associated with promiscuity and a higher number of sexual partners. There are some interesting papers that suggest patients with sexually transmitted infections are more likely to have High Grade AIN. I also think that this is not the most simple answer as being exposed to sexually transmitted infections also increases your risk of HIV which is known to be a much greater risk factor in AIN and Anal SCC.  

Unfortunately, at the moment the data we have is limited by the clinical data we have access to. From talking to female patients, in particular, after a diagnosis with Anal SCC, they do report concerns about social stigma that Anal SCC is a cancer associated with promiscuity and sexual practices.  

I think that this is unfair as although, in theory, promiscuity increases your likelihood of eventually becoming infected with an oncogenic HPV, you do not need to have multiple HPV exposures before unfortunately becoming infected with a high risk one.  

Histology and Cytology – What should we use?

The Papanikolaou (Pap) smear or cytology screening has long been used for cervical screening with reliable results. This can be used for screening of patients with or at risk of AIN.  

However, its reliability in the use in AIN is controversial. Many papers report that cytological testing often under-reports AIN grade. Unlike the cervix, which is a fixed structure, taking a cytological sample of the anus can be technically difficult.  

In fact the American Guidelines (ASCRS) for the treatment of Anal SCC do not recommend its use.  

In European countries, the use of anal cytology is more widespread and although its limitations are accepted it is often used with High Resolution Anoscopy and Histology of concerning lesions to form a complete clinical picture.  

In Anal SCC there is not sufficient evidence that cytology alone could be a suitable screening technique.  

It is accepted practice that before considering the treatment of an area diagnosed with AIN that a biopsy should be taken for formal histopathology.  

HIV and Anal Squamous Cell Carcinoma

Human Immunodeficiency Virus (HIV) has long been associated with Anal Squamous Cell Carcinoma. It is the 3rd most common cancer in patients with HIV.  

Patients at the highest risk of Anal Squamous Cell Carcinoma are men with HIV and a concurrent oncogenic HPV infection who are also men who have sex with other men (MSM). Their risk of Anal SCC is higher than the risk of an average person getting a common cancer.  

There is also noted to be an increase in incidence worldwide of Anal SCC . This is likely in part due to HIV prevalence increasing as advanced antiretrovirals are now able to give patients with well controlled HIV a near to normal life expectancy. However, these patients are then at risk of developing the long term sequelae of an immunocompromised state.  

HIV positive MSM are at 5x higher risk of ASCC than HIV negative MSM and HIV positive MSM, on screening, have up to 86% prevalence of Anal Intraepithelial Neoplasia (AIN), the dysplastic precursor to Anal SCC.  

There are many reports of HIV positive MSM having a high prevalence of High Grade AIN with some papers reporting up to a third of HIV positive MSM having High Grade AIN detected on anoscopy. Although HIV negative MSM do also have a risk of AIN, their risk is frequently reported as lower than HIV positive MSM.  

Due to their high risk profile, HIV positive MSM are regularly within screening programmes such as High Resolution Anoscopy, therefore this patient group’s AIN prevalence is widely reported in the literature. As they have the most contact with anoscopists, most studies assessing the treatment of AIN are involving HIV positive MSM. Consistently the treatment studies show that HIV positive patients are more likely to relapse after successful treatment of AIN and are more likely to have multifocal disease.  

The persistence of a immunocompromised state is likely to prevent the clearance of HPV, however, the treatment of HIV with antiretrovirals does not reduce the risk of developing Anal SCC, just having the virus itself is all it takes. Although it is possible that this will not always be the case, as more and more patients are receiving treatment and are successfully being classified as having an undetectable viral load.   

Previous viral loads and HIV treatment outcomes have been included in the mASCARA dataset, we hope that mASCARA will be able to answer some of the unanswered questions.  

High Resolution Anoscopy

High Resolution Anoscopy (HRA) is seen as the gold diagnostic standard for the diagnosis and surveillance of AIN. 

It is a reliable and well tolerated procedure that can be performed in the outpatient setting.   

It’s problems lie in that the best operator outcomes are from experienced anoscopists and as the transformation rate of AIN to Anal SCC is low. In the hospital I am currently working at, which has one of the highest HIV prevalence rates in the country, 116 anoscopies needed to take place to diagnose one high risk patient with Anal SCC. (3% of anoscopies performed) 

In areas with less high risk patients the yield is likely to be much lower, as such High Resolution Anoscopy has been downgraded in the American (ASCRS) guidelines to only take place if they high risk patient and an experienced anoscopists is available. In the UK, there is equipoise whether to undertake HRA, as in theory it should be beneficial but currently there is insufficient evidence to support it.  

The low yield also has an effect on whether HRA is cost effective leading to some clinical centres abandoning the practice in all but the highest risk patients.  

There are clinical societies such as the International Anal Intraepithelial Neoplasia Society that provide standardised HRA training and support for clinicians wishing to undertake HRA as part of their clinical practice.  

Anal Intraepithelial Neoplasia

Anal intraepithelial Neoplasia (AIN) is thought to be the dysplastic precursor to Anal Squamous Cell Carcinoma. The rationale for this is that disease progression is similar to other HPV related dysplasias like cervical or vulval intraepithelial neoplasia and that there is often a dysplastic field changes around Anal Squamous Cell Carcinomas. Anal Squamous Cell carcinomas often arise from the same sites as previous AIN.  

Classifying AIN can be contentious, in the UK, we regularly use the terms AIN1, AIN2 and AIN3 where AIN1 is the lowest grade of dysplasia and AIN3 is the highest grade of dysplasia. Using this terminology, what we determine as “high grade dysplasia” for clinical research can be confusing. Classically, AIN3 is seen to be high grade as this is the grade that is most often reported to have a risk of direct progression to malignancy. However, the use of p16 staining as a marker for grade of AIN means that there are also some AIN2 patients who would meet the criteria for high grade but are not classified as AIN3.  

In other countries, in particular  in the USA guidelines , they use a more simplified approach where AIN is divided into low grade (typically AIN1) and high grade (AIN2 and AIN3). They use the nomenclature LGAIN (Low Grade Anal Intraepithelial Neoplasia) and HGAIN (High Grade Anal Intraepithelial Neoplasia) 

P16 is a CDK inhibitor, its overexpression is associated with Human Papillomavirus expressing E7 proteins that deactivate retinoblastoma protein. Therefore its overexpression on staining is seen as an adjunct of ongoing HPV oncogenic activity. Interestingly, there are some papers investigating the use of treatment of AIN that show that the successful treatment of AIN is associated with a reduction of p16 overexpression.  

The Lower Anogenital Squamous Terminology (LAST) guidelines recommend the two tier approach with the use of p16 staining by histopathologists to determine equivocal lesions. The guidelines are very detailed and worth reading if you are interested in the classification of AIN. 

The differences in nomenclature have a significant impact on the generalisability of clinical research. In particular, limiting the comparability of different small studies on the efficacy of treatments for AIN as comparative clinical centres often classify AIN differently.  

Team mASCARA at ESCP

The mASCARA study team from Imperial College London and Chelsea and Westminster Hospital NHS Foundation Trust had a great time at ESCP this year. Great Collaborations made. Looking forward to working together on this project!.

Dinner out with Colleagues

Anal cancer and Human Papillomavirus

Anal SCC is related to HPV virus exposure with up to 95% of patients with Anal SCC having a concurrent high risk HPV infection.   

HPV is a non-enveloped double stranded DNA virus and is the most frequent sexually transmitted infection. Most infections clear spontaneously, however, some can persist leading to dysplasias. There are over 30 different genotypes and not all are oncogenic. HPV produces oncogenic proteins that inhibit the function of p53 and retinoblastoma proteins. 

It’s thought that immunosuppressive states such as HIV or the long term use of steroids (inflammatory bowel disease) can prevent HPV clearance and lead to a higher risk of dysplasias and squamous cell carcinomas.  

Up to 90% of patients with Anal SCC have HPV 16, making it, by far the most common high risk HPV infection in this patient population. It is also possible to have coinfections with several oncogenic HPV virus genotypes; HPV16/18 being often observed. We don’t know whether a co-infection can affect progression to anal SCC or have an impact on relapse/recurrence of ASCC.   

This is one of the questions we are hoping to answer with mASCARA.  

Team mASCARA in Nice

Our mASCARA study team will be at the European Society of Coloprotoctology Conference next month in Nice. It would be great to catch up with other like minded Colorectal Units with an interest in Anal Squamous Cell Carcinoma.

mASCARA

After discussions with study members at Imperial College London and our primary clinical site Chelsea and Westminster Hospital NHS Foundation Trust we have agreed that our study name should be:

Multinational Anal Squamous Cell Carcinoma Registry and Audit.

Aerial View of Imperial College London South Kensington Campus

We are now in the process of getting Ethics approval and consulting with GDPR experts at Imperial College London.

GDPR

EU General Data Protection Regulation is coming into force today. Thanks to Imperial College London for their help in setting up what will be the first GDPR compliant cancer registry at Imperial.