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New Treatments for Colon Cancer and Rectal Cancer

Colon cancer is by far the most important GI cancer in the United States. The number of new cases has actually gone down a little bit since that slide, 132,000 per year, 56,000 deaths colon cancer and rectal cancer. Far ahead of all of the others and definitely different than in the world where it is only second and is surpassed by gastric cancer. Again, to illustrate that this is a disease of the developed world, the darkness represents the relative incidence of colorectal cancer, a disease of North America, Europe, Australia and only in the last 20 years or so, as the Japanese have developed more Western eating habits.

Predisposing factors; inflammatory bowel disease, particularly ulcerative colitis, the various polyposis syndromes, hereditary non-polyposis colorectal cancer, and I think you have to consider anyone who has a strong family history or personal history of prior colon cancer to be at a substantially increased risk for colorectal cancer. Of the inflammatory bowel diseases, ulcerative colitis is by far the most important. There is some increased risk with Crohn’s disease but not nearly as much so as with ulcerative colitis. In ulcerative colitis, the risk is much higher with pan-colitis rather than with simple proctitis.

These patients are best followed by random biopsies and dysplasia. When dysplasia is seen - and it can be seen on random biopsy - the risk of colon cancer developing in the next year or two is very high and those patients should undergo a total colectomy.

Familial adenomatous polyposis is a very important risk factor for colon cancer, even though it accounts for only about 1% of colon cancer in the United States. It is important because virtually all patients who have this entity will develop colon cancer before they are 40 unless they undergo a total colectomy. This is a germ-line mutation of the APC gene.

The formation of these polyps for some reason does not begin until around the time of puberty and it can begin substantially later than that. So patients with a family history of that should begin having surveillance colonoscopies before puberty, and that should continue even if they are negative at least through age 25 or so. It’s important to remember that spontaneous mutations of the APC gene are very common. In fact, more than 50% of the cases of familial adenomatous polyposis that you’ll see are not familial at all.

Related effects of these mutations; depending upon where the mutation occurs, where the truncation occurs, you can have extra-colonic tumors, you can have chronic hypertrophy of the retinal pigment epithelium - which I’ll show you an example of in just a minute - and this is a photograph of a surgical specimen in a patient who underwent a total colectomy for familial adenomatous polyposis. These patients develop hundreds or thousands of adenomatous polyps.

The other important well-characterized genetic entity predisposing to colorectal cancer is HNPCC, hereditary non-polyposis colon cancer, formerly known as Lynch syndrome. In these patients, in contrast to FAP, these patients don’t develop a particularly high number of polyps but when they do develop a polyp it’s much more likely to progress into a cancer. This defect is a defect in the ability of the cells to repair mismatched errors. Again, it’s a germ line mutation. There are four genes that have been identified which are important in this entity. Patients who have germ line mutation in these genes develop an RER-positive genotype, which makes them much more likely to develop additional mutations, once they have a polyp which is growing rapidly. So polyps which do develop become malignant early. Mutation of these genes responsible for HNPCC as well as of the APC gene are also seen in sporadic cancers.

This is more or less the distribution of colon cancers in the United States. About 1% will turn out to be familial adenomatous polyposis. Maybe another 5% HNPCC and maybe another 15% or so other as yet uncharacterized genetic factors, but patients with a striking family history, so you know there must be something there somewhere. But that leaves about 80% of the cancers in the United States sporadic. Now the sporadic cancers also have been fairly well characterized in terms of the genetic events that occur in their development. Development of sporadic colon cancer is a progressive, step-wise event. First an adenomatous polyp, then dysplasia develops in the polyp and eventually frank malignancy. In this progression - and these events don’t have to occur in this order, but this just lists some of the genetic events that occur - early events include hypo-methylation. Methylation helps to promote chromosomal stability and when methylation is lost there is a greater possibility of mutations then occurring because of the lack of organization of the chromosome. APC, we’ve previously discussed. This is frequently mutated in sporadic colon cancers. K-ras is a very important gene. K-ras is activated in many colon cancers and then promotes more rapid turnover of the cell cycle. These are the mismatched repair genes. Late events are the DCC gene on chromosome 18 and P-53 on chromosome 17. DCC has a role in cellular adhesion and migration and as you might expect, because of that, patients who have a DCC mutation are at greater risk of metastasis.

The very wide range of incidence of colorectal cancer between different countries, different populations is largely dietary. In the United States we consume a lot of calories, a lot of animal fat, a lot of protein. These all tend to increase the risk of colorectal cancer. Whereas fiber, calcium and a number of micronutrients tend to decrease it. There is an interaction between the diet and the bacterial flora which leads to the conversion of bile acids.

Now screening for colorectal cancer is very important for primary care physicians to understand that this is the standard of care. I get called all the time to defend physicians who are being sued for failure to detect colon cancer. I tell them that, "If you didn’t do guaiac screening on this patient you might as well settle the case." There are now a number of studies in the literature that show a substantial reduction in disease-specific mortality in patients who just have the simple screening modality of checking annually or twice annually for occult blood in the stool. These are two of them.

Clinical presentation of colorectal cancer depends on the site. Blood on or around the stool certainly is a presentation that you can see. Changes in bowel habits are more common with left-sided lesions, where the fecal stream is more solid and where the histology, where the tumors tend to be more infiltrative and firm. These changes can consist of changes in the caliber or frequency of stools, and either constipation or diarrhea. Abdominal pain can occur. With right-sided lesions a common presentation is anemia or microscopic blood loss. This is particularly true for cecal carcinomas on the right side of the colon. The diameter of the colon is larger, the stool is liquid and the lesions tend more to be exophytic rather than infiltrative.

The preferred modality for diagnosis is colonoscopy. The air-contrast barium enema is almost as good in terms of sensitivity; not quite but fairly sensitive. But the factor that recommends the colonoscopy is; you see the lesion, you biopsy it, and you immediately have the diagnosis. Sometimes it’s not possible to pass the colonoscope beyond the lesion. You should remember that before you send a patient to surgery you want to know the status of the entire bowel. Because synchronous

Here’s what the colonoscopist sees, here’s a pedunculated adenomatous polyp. The reddish coloration is pretty typical. This polyp can just be simply snared. That will eliminate the lesion. Basically the reason that screening is effective for colon cancer is that colon cancers exist in this stage for long periods of time, in a premalignant stage where they can actually be removed via the colonoscope and prevent the development of cancer. Here’s a sessile polyp, a villous adenoma.

Pathology of colon carcinoma; grossly, the can be either exophytic which is more common on the right, or infiltrating which tend to infiltrate circumferentially first and then longitudinally second, leading to your classic "napkin ring" lesion. Microscopically, virtually all colon carcinomas are adenocarcinoma. About 10% of them are mucinous, meaning that in your biopsy specimen you will see just lakes of mucin with islands of carcinoma cells. About 1% will retain the characteristic of producing mucin but will no longer be able to transport it to the outside world, so they will develop a big blob of mucin in the middle, giving rise to the characteristic "signet ring" cell.