Now, let’s talk about the predictable pathway from a polyp to a cancer. This is called appropriately
the polyp-cancer sequence. Here’s a slide that demonstrates a mutation from normal epithelium on the left
side of the screen to full-on carcinoma. Through this process, there are predictable sides to genetic mutation
that allows hyper-proliferation forming a polyp eventually degrading to a carcinoma. Let’s look at some of this
in detail. First mutation that occurs is an APC tumor suppressor gene. This allows tumor initiation.
Now remember, tumor suppressor genes which we have a lot of, its main job is to suppress overgrowth.
Next, K-Ras is a proto-oncogene. K-Ras proto-oncogene mutation alone only causes hyperplastic syndrome.
But if it follows APC in this predictable line of mutations, it leads to colon cancer. Scientists are still
working on why the K-Ras in this context leads to colon cancer versus the mutation alone
that only leads to hyperplastic polyps. This then progress to a deleted in colorectal cancer
which is yet another tumor suppressor gene, and finally the p53 which leads to apoptosis.
Mutations of p53 then allow a cancer phenotype. Let’s review for a second, another question.
What’s the difference between Lynch syndromes 1 and 2? I’ll give you a second to think about this.
That’s right. Lynch syndrome 1 again is a familial colon cancer without extracolonic manifestations
versus Lynch syndrome 2, it’s associated with other cancers particularly of the GI and reproductive tumors.
Amsterdam criteria is an important set of criteria for the diagnosis of Lynch syndrome or hereditary
nonpolyposis. This is the classic definition. Three relatives with colon cancer over two generations.
At least one of which was diagnosed at a fairly young age. There have been subsequent iterations
of this diagnosis. But the bottom line is fairly similar in that we want to see multiple young people
diagnosed with colon cancer in a family over multiple generations suggestive of number 1, a genetic mutation,
and 2, potentially an autosomal dominance. Here’s Amsterdam criteria II. Amsterdam criteria II
liberalized the definitions a little bit. Here, the requirements that there should be at least three relatives
with any Lynch syndrome-associated cancer, be it colorectal, cancer of the endometrium, small bowel,
ureter, or renal pelvis. One should be a first-degree relative of the other two; at least two
successive generations much like the original definition; and at least one should be diagnosed before the
age of 50, again very familiar to you. Remember that FAP should be excluded in colorectal cancer cases
if any tumors should be verified by pathologic examination. Yet, another criteria, they call the Bethesda
criteria is also used for Lynch syndromes. In the Bethesda criteria, colorectal cancer diagnosed in a
patient who is less than 50 years of age, there has to be a presence of synchronous or metachronous
colorectal, synchronous or metachronous meaning at the same time or at different times, or other
nonpolyposis-associated tumors regardless of age. That the colorectal cancer with a gene repair mutation
and histology diagnosed in a patient who’s less than 60 years of age. The colorectal cancer diagnosed in
a patient with one or more first-degree relatives in a nonpolyposis-related tumor. And lastly,
that the colon cancer is diagnosed in a patient with two or more first or second-degree relatives.
Basically different spins on the same criteria of multiple relatives, multiple generations, and diagnosis
early on. What are some physical findings on colorectal cancer? Unfortunately, the vast majority of
patients do not have a classic profile of physical findings that will allow us, clinicians, to detect it early on.
That’s why screening is so important. Usually, there’s no pain. Maybe there’s bleeding, maybe a large bowel
obstruction. That’s why due to colonoscopy, early detection is the most important thing that we can offer
to our patient. By the time you wait for classic physical findings of bleeding and obstruction, it's likely
that the colorectal cancer has already progressed into late stages. We now consider colon surgery
preventable due to screening and because of the predictable deterioration from a polyp to cancer
in the polyp-cancer sequence. Again, no set of routine labs is indicative of colorectal cancer.
One may find a drop in the hemoglobin, hematocrit due to a slow bleed. We oftentimes get a CEA
or carcinoembryonic antigen both before and after surgery. We don’t use that as a screening tool however.
But it is very useful as a follow-up after treatment for detection of recurrences.