If you look at the etiology and how people might get anal cancer, certainly in males there is a very strong correlation with anal receptive intercourse. There doesn’t appear to be the correlation in females. This is from Cancer Medicine, Brenda Shank in 1994. There also is a strong correlation with HPV virus. Presumably the HPV virus is transmitted in male homosexual populations as a sexually transmitted disease. If you look at other associations, just like cervical cancer, there is a mild association with herpes virus type II. Immunosuppression is actually important. If you work in an institution where there is a lot of solid organ transplant - for example, liver and heart transplant - where patients are on cyclosporine for long periods of time - years - you’ll see an increased risk of anal cancer. And these are in patients who previously had HPV infection, and as I’ll show you, immunosuppression appears to facilitate or decrease the period of time for viral carcinogenesis in people with previous HPV infection. It’s interesting that what cyclosporine as an immunosuppressive does is that it doesn’t change CD-4 numbers but what it does is it freezes CD-4 cells so that they cannot divide, they cannot function. So in effect you are getting a very similar defect to what you get with HIV which of course decreases CD-4 numbers. Smoking has some increased relative risk. And HIV alone is not necessarily associated with anal cancer. It’s HIV in patients who have had a previous papilloma virus infection.
These are very interesting, very recent, data suggesting or giving you an insight in to what may be happening with concomitant HIV infection, or for that matter immunosuppression, and the presence of patients who have a history of anal cancers. This was presented at the Digestive Diseases Week a couple of months ago in Florida from a group in Paris. Essentially what they did is they took patients who were HIV positive and HIV negative, all of them had anal condylomata. Because genital warts are not terribly uncommon and people can get them without being immunosuppressed. They treated the genital warts as you would, resected them, froze them or did whatever was necessary to make them go away. Then they looked at recurrence and they found that within a year about 75% of the HIV positive patients recurred versus only 8% of the HIV negative patients. There was a ten-fold increase in dysplasia. So again suggesting that what happens here is that when you have HIV infection, what you are doing - because of the immune dis-modulation of HIV infection - you are accelerating the rate with which viral neoplasia, in this case benign viral neoplasias or perhaps pre-malignant viral neoplasia, can occur.
What about treatment and prognosis with anal cancer? There are a couple of things that are important. One is the size of the tumor and another is the differentiation of the tumor and obviously the metastatic dissemination of the tumor, if it has disseminated. Although the vast majority of the times, anal cancers - because of their location -are picked up fairly early. The patients have symptoms very early of bleeding and pain in the anal canal. These are older data from Bruce Bowman, who is now at Jefferson actually but was at the Mayo Clinic at the time, looking at the experience with anal cancer at the Mayo Clinic. And pointing out that if you looked at patients with very small, grade I to II, good risk, small primary tumors that could be locally resected - which is an unusual group - there was essentially a high cure rate with surgical resection. If you looked at the squamous-basaloid group that were at higher grade tumors, there was a recurrence rate that was very high with local resection. So you can’t treat these. Occasionally the small cell patients you can get small cell carcinoma much like a non-pulmonary small cell cancer, and those patients do very badly with local therapy.
Сontinued at Cancer treatment blog
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.
Tumors of the anus and rectum are uncommon because these are tumors really of the anal canal. I am going to talk about the squamous, the basaloid, cloacogenic tumors of the anus. Basically anal canal tumors fall into this squamous, basaloid or cloacogenic category. Above the pectinate line there is a zone of transition here from an adenomatous epithelium of the rectum and the large bowel, down to a non-keratinizing squamous epithelium of the anal canal. Then out here in the perianal skin you have typical skin cancers, which would be keratinizing squamous carcinomas. There is a big difference, biologically, in the treatment orientation between a tumor that occurs here and a tumor that occurs there in the rectum proper. A rectal cancer drains to the internal hemorrhoidal nodes and the ileac nodes. The anal carcinomas drain to the superficial ileac nodes. If you look at the tumors that drain to the ileac nodes, aside from local skin cancers in the ileac area, you have - in females - you have labial cancer, which of course is a cancer of older … it tends to be a cancer of older females. You have anal canal cancers. You have penile cancers in men, which are quite an uncommon cancer in this country, and anal cancers are the main ones that will drain to the inguinal nodes and not drain internally.
If you look at the epidemiology of anal cancer you’ll see that it represents a relatively small percentage of the large bowel cancers. Of course, the anus is only about an inch, inch-and-a-quarter, long. If you look, there has been a difference in the occurrence of this tumor. For most of this century it was more common in people above the age of 55, it was about twice as common in women as men, was associated with people that had previous anal-rectal pathology; hemorrhoids, fissures, perhaps anal warts. And in the recent past it has increased significantly in men below the age of 45 and tends now to be more common in men. So there is really a bimodal peak. You still see the older patients but you do see younger patients. Why this occurred is of considerable interest and is telling us something about viral carcinogenesis, actually.