Polyp-Cancer Sequence

00:01 Now, let's talk about the predictable pathway from a polyp to a cancer.

00:05 This is called appropriately the polyp-cancer sequence.

00:11 Here's a slide that demonstrates a mutation from normal epithelium on the left side of the screen to a full long carcinoma.

00:19 Through this process, there are predictable sides of genetic mutation that allows hyperproliferation, forming a polyp, eventually degrading to a carcinoma.

00:32 Let's look at some of this in detail.

00:34 First mutation that occurs is an APC-tumor suppressor gene.

00:39 This allows tumor initiation.

00:41 Now, remember, tumor suppressor genes, which we have a lot of its main job is to suppress overgrowth.

00:51 K-Ras is a proto-oncogene.

00:52 K-Ras is a proto-oncogene mutation only causes hyperplastic syndrome.

00:56 But if it follows APC in this predictable line of mutations, it leads to adenoma.

01:01 Scientists are still working on why the K-Ras in this context leads to adenoma versus the mutation alone, that only leads to hyperplastic polyps.

01:10 This then progress to a deleted in colorectal cancer, which is yet another tumor suppressor gene.

01:16 And finally, the p53, which leads to apoptosis.

01:21 Mutations of p53, then allows a cancer phenotype.

01:27 Let's review for a second, another question.

01:30 What's the difference between Lynch Syndromes 1 and 2? I'll give you a second to think about this.

01:40 That's right.

01:40 Lynch syndrome 1, again, is a familial colon cancer without extracolonic manifestations versus Lynch syndrome 2, its associated with other cancers, particularly of the GI and reproductive tumors.

01:56 Amsterdam criteria is an important set of criteria for the diagnosis of Lynch syndrome or hereditary nonpolyposis.

02:04 This is the classic definition of three relatives with colon cancer over two generations, at least one of which was diagnosed at a fairly young age.

02:14 There have been subsequent iterations of this diagnosis.

02:17 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 one, a genetic mutation and two, potentially an autosomal dominance.

02:32 Here's Amsterdam criteria II.

02:35 Amsterdam criteria II liberalize the definitions a little bit.

02:40 Here, the requirements that there should be at least three relatives with any Lynch syndrome associated cancer, be a colorectal, cancer of the endometrium, small bowel, ureter, or renal pelvis.

02:52 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 diagnosed before the age of 50.

03:02 Again, very familiar to you.

03:04 Remember that FAP should be excluded in colorectal cancer cases.

03:08 Tumors should be verified by pathologic examination.

03:15 The another criteria that called the Bethesda criteria is also used for Lynch syndromes.

03:21 In the Bethesda criteria, colorectal cancer diagnosed in a patient who is less than 50 years of age.

03:27 There has to be presence of synchronous or metachronous colorectal.

03:31 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 the histology diagnosing a patient who is less than 60 years of age.

03:51 The colorectal cancer diagnosing a patient with one or more first degree relatives in a nonpolyposis related tumor.

03:59 And lastly, that the colon cancer is diagnosed in a patient with two or more first or second degree relatives.

04:05 Basically different spins on the same criteria of multiple relatives, multiple generations, and diagnosis early on.

04:15 What are some physical findings in 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.

04:27 That's why screening is so important.

04:29 Usually, there is no pain.

04:31 Maybe there is bleeding, maybe a large bowel obstruction.

04:36 That's why due to colonoscopy, early detection is the most important thing that we can offer to our patient.

04:42 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.

04:52 We now consider colon surgery preventable due to screening.

04:56 And because of the predictable deterioration from a polyp to cancer in the polyp-cancer sequence.

05:04 At this point, it's worth mentioning the difference between left-sided lesions and right-sided lesions.

05:08 Left-sided lesions are more likely to present with symptoms of obstruction, such as constipation or decreased stool caliber.

05:15 On the other hand, right sided lesions are more commonly present with bleeding, macroscopic or microscopic, or iron deficiency anemia.

05:22 The reason that right-sided lesions do not cause obstruction is that the diameter of the right colon is greater than the left, and the stools have increased water content.

05:32 Again, no set of routine labs is indicative of colorectal cancer.

05:38 We may find a drop in the hemoglobin, hematocrit due to a slow bleed.

05:44 We oftentimes get a CEA or Carcinoembryonic Antigen, both before and after surgery.

05:52 We don't use that as a screening tool, however, but it is very useful as a follow up after treatment for detection or recurrences.