New Treatments for Anal Cancer. Part 2.
Just to try and sort out the pathology, we have the uncommon tumors which we are not really going to talk about, and then we have the anal cancers. They essentially are squamous cell cancers, or derived from squamous cell cancers. The anal skin cancers are keratinizing just like any kind of a skin cancer, a squamous carcinoma of the skin. Then you have the non-keratinizing anal cancers of the anal canal. These are really non-keratinizing squamous cancers, sometimes called basilo-squamous. And there is this transition zone from adenomatous to squamous. Sometimes they are called basaloid, sometimes the more poorly differentiated are cloacogenic. But they all derive from the epithelium of the anal canal, which essentially is a non-keratinizing squamous epithelium.
It appears that there is a strong association with human papilloma virus in anal cancers. There are several factors that are important here; genital warts are strongly associated with the risk of anal cancer and if you look at anal cancers, a large percentage of them are positive for the human papilloma virus genome. The types of human papilloma viruses that cause anal cancer are similar to the types that are associated with cervical cancer. Just like there is a high grade, a carcinoma … a CIN in the cervix or cervical intraepithelial neoplasm, a premalignant condition associated with type 16. There are other types associated with lower grade AIN’s and with condylomas. But human papilloma virus continues to be an important factor.
How might human papilloma virus be associated with the development of a neoplasm? Well, this is really very interesting and again it tells us something about viral carcinogenesis. The human papilloma virus gets incorporated into the genome and produces a couple of proteins; one from the E-7 gene and one from the E-6 gene. These proteins are really very interesting in what they do. Basically they bind the gene product of P-53 and of the RB, the retinoblastoma gene. As you know, P-53 is the tumor suppresser gene and the retinoblastoma gene is also a tumor suppresser gene. So essentially what happens is that this virus co-opts this cell into moving towards a malignant phenotype by binding post-transcriptionally the product of tumor suppresser genes. And obviously P-53, as you know, the normal function of P-53 is to prevent cells with damaged DNA from dividing and also to promote apoptosis. So what happens when you block P-53 – you either mutate or bind the gene product – is that you take off those controls and you are more likely to get a malignant phenotype. And that certainly appears to be the case with anal cancer. This is just an example of anal tumor staining actually, for human papilloma viruses with an immuno-histochemical stain. I think it was for type 16.