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.  

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.