Good afternoon, my name is Jennifer Murat, and today I'll be discussing several aspects of colorectal cancer, including screening, surveillance guidelines, as well as reviewing polyposis and nonpolyposis syndromes. I have no disclosures to report. Here are the three objectives we'll be covering in the next 30 minutes, so let's jump right into the first one, which is to recognize trends in colorectal cancer. Colorectal cancer is the third most common cause of cancer among men and women. It's the second most common cause of cancer-related deaths in the United States. As you can see in this figure on the bottom, incidence and mortality for those 50 years of age and older have been declining for the last several decades, primarily due to the fact that we implemented screening in the early 1990s. In contrast, we've seen a rise in the early onset of colorectal cancers. It is also the third most common cancer and second leading cause of cancer-related deaths among men and women under the age of 50 in the U.S. Between 2006 and 2015, on average, we saw a 1.1% annual increase in early onset colorectal cancers. Interestingly, the incidence rates for those who are 45 to 49-year-olds are similar to those seen among individuals over the age of 50 before we started screening in the early 1990s. This has informed the recent shift to start screening at the age of 45 instead of 50. When we think about the causes of colorectal cancer, as we can see in this figure, the majority, or up to 65%, are sporadic. Another 25% are familial, meaning there may be a relative in the family who's had colorectal cancer, but there's no identifiable genetic mutation that has been associated in the family. Another 5% and up to really 10% are related to hereditary colorectal cancer syndromes. Here are the three main colorectal carcinogenesis pathways. The first one is chromosomal instability, which comprises about 65% to 70% of all sporadic colorectal cancers. In this pathway, we see non-hypermutated tumors with defects in chromosomal separation. The initial hit is thought to be the APC mutation, followed by a series of mutations in genes, including KRAS and p53. The serrated pathway accounts for about 25% to 30% of colorectal cancers, and the initial mutation is in the BRAF oncogene, followed by a series of other mutations. The microsatellite instability pathway comprises a smaller proportion, up to 5% of colorectal cancers. Here we see defective DNA mismatch repair in hypermutated tumors with the commonly known Lynch syndrome, which is in this pathway. There have been several risk factors associated with colorectal cancer, including both non-modifiable and modifiable risk factors. One of the strongest is age, along with sex, race, personal medical history of colorectal cancer or inflammatory bowel disease, or a family history of advanced neoplasia, including colorectal cancer. Modifiable risk factors include obesity, smoking, alcohol use, sedentary lifestyle, and diet. Now we'll get to our second objective, which is to review colorectal cancer screening and surveillance recommendations based on the most recent updated guidelines. I'd like to start with a question. So a 35-year-old white woman presents to clinic to discuss screening colonoscopy. She is otherwise healthy and denies any gastrointestinal symptoms. Her mother was diagnosed with colon cancer at the age of 53. Other than her mother's age, she denies any family history of colon cancer or other malignancies. She's interested in learning when she should undergo a screening colonoscopy. According to the current guidelines, when should this patient undergo a colonoscopy? A, now, B, at the age of 40, C, at the age of 43, or D, at the age of 45. The correct answer here is age 40. So if we look at this table, we see the high-risk category. So in this question, the patient was 35 and had a single first-degree relative with colorectal cancer diagnosed at an age less than 60. The recommendation is to start screening 10 years younger than the age at which the first-degree relative was affected, which in our question would be at the age of 43, or when the patient is 40 years of age, whichever is earlier. So the right answer was to start screening her at the age of 40. Now, if there's two first-degree relatives with colorectal cancer or advanced adenoma diagnosed at any age, the recommendation is the same, 10 years younger than the age at which the youngest relative was diagnosed, or when the patient is 40, whichever is earlier. If, on the other hand, there's a single first-degree relative with colorectal cancer or advanced adenoma diagnosed at 60 years of age or older, then the recommendation is to start at 40. As I mentioned earlier, all average-risk patients should start screening for colorectal cancer starting at the age of 45 now, not 50. Here's a table from the most recent U.S. Multi-Society Task Force Guidelines in 2020 that highlights the post-polypectomy surveillance intervals for adenomas. I've highlighted in red the recent changes based on prior guidelines, which include one to two tubular adenomas, each less than 10 millimeters in size, for which a surveillance interval of seven to 10 years is recommended now, whereas previously it was five to 10 years. Three to four tubular adenomas that are all less than 10 millimeters in size should have a surveillance interval of three to five years. Five to 10 tubular adenomas all less than 10 millimeters in size should have a surveillance interval of three years. Large adenomas that are at least 10 millimeters or greater in size should have a surveillance interval of three years. And then 10 or more adenomas found during a single exam should prompt a surveillance of one year. Based on high-risk features such as villus or tubular villus histology or adenomas that have high-grade dysplasia, the surveillance interval should be three years. The next two tables highlight post-polypectomy surveillance intervals for serrated polyps. So one to two SSPs that are each less than 10 millimeters in size should have a surveillance interval of five to 10 years. Three to four SSPs less than 10 millimeters in size should have a surveillance interval of three to five years. And five to 10 SSPs less than 10 millimeters in size should have a surveillance interval of three years. If a patient has less than 20 hyperplastic polyps that are all small in size, the surveillance interval is still 10 years. But in contrast, if there's any hyperplastic polyp that is 10 millimeters in size or greater, then the surveillance is much shorter of three to five years. SSPs with dysplasia or traditional serrated adenomas are considered high-risk and the surveillance interval for each of these would be three years. Let's go to question two. So a 65-year-old woman undergoes screening colonoscopy. During the exam, you remove a 12-millimeter flat lesion in the right colon. The lesion was partially covered with yellow mucuses below. What is the pathological diagnosis and which of the following is the most appropriate recommendation for this patient? A, hyperplastic polyp, repeat colonoscopy in 10 years. B, Cis-cell serrated polyp, repeat colonoscopy in five years. C, Cis-cell serrated polyp, repeat colonoscopy in three years. Or D, traditional serrated polyp, The correct answer here is C. The histology here, at least looking endoscopically, is a Sessile serrated polyp, and the recommendation based on size of 12 millimeters would be to repeat colonoscopy in three years. Now we'll move to our last objective and spend the remaining time discussing hereditary colorectal polyposis and non-polyposis syndromes. So I mentioned this previously, but familial colorectal cancers comprise 25% of all CRCs, up to 10% have an identifiable genetic mutation, and there's a lifetime risk of colorectal cancer in these hereditary syndromes that can approach 70 to 100% if preventative or prophylactic measures are not taken. Why these are so important is because there's also a high risk of extra intestinal malignancies as you'll see. This table highlights many of the identifiable genetic mutations that we can detect for both polyposis and non-polyposis syndromes. I've highlighted in red the ones we'll be discussing today and the ones you're most likely to see on the boards. So we'll start with Lynch syndrome. Lynch syndrome is or was previously known as hereditary non-polyposis colorectal cancer or HNPCC. It comprises approximately 3% of all colorectal cancers. It is the most common hereditary syndrome affecting 1 in 279 individuals. It's inherited in an autosomal dominant pattern caused by pathogenic germline variants and DNA mismatch repair genes including MLH1, MSH2, MSH6, PMS2, and deletions in EpCAM. We see errors in replication of repetitive DNA nucleotide sequences in Lynch syndrome. It should be highly suspected in colorectal tumors that show microsatellite instability or those with immunohistochemistry showing loss of mismatched repair proteins. One of the most common criteria that we can apply clinically is the Amsterdam criteria, also known as 3-2-1 rule. These criteria include at least three relatives diagnosed with histologically confirmed Lynch syndrome-associated cancer, one of whom is a first-degree relative of the other two. At least two generations should be affected by the Lynch syndrome-associated cancer and at least one relative is diagnosed with a Lynch syndrome- associated cancer under the age of 50. If a patient meets all three of these criteria, your suspicion for Lynch syndrome should be very high and the patient should be referred for genetic counseling and testing for germline variants. The Lynch syndrome-associated cancers that the Amsterdam criteria intended to cover were colorectal, endometrial, small bowel, urinary tract, and renal. So the strong recommendations for Lynch syndrome include screening colonoscopy as well as endometrial biopsy and a baseline of burndoscopy. First, screening colonoscopy should be started at the age of 20 to 25 and repeated every one to two years. I've indicated here that based on the NCCN 2021 guidelines, there are gene-specific recommendations. So of the pathogenic germline variants we can see in Lynch syndrome, MSH6 and PMS2 patients typically present with later onset of colorectal cancer. So unless there's a strong family history of colorectal cancer at a young age, patients with MSH6 and PMS2 variants could be considered to start screening colonoscopy a little bit old at a later age of 30 to 35. Endometrial biopsy should be started at the age of 30 to 35 and continued every one to two years. A pelvic and transvaginal ultrasound should also be considered. I always recommend early referral for gynecology for women who have Lynch syndrome just so that they can discuss family planning early on. And then finally, baseline upper endoscopy is recommended to be done with gastric biopsies to rule out H. pylori. If the upper endoscopy is normal, it can be repeated every three to five years. So there's two big recommendations I wanted to highlight as far as management goes to prevent or in the case of colorectal neoplasia to manage Lynch syndrome associated malignancies. So as I mentioned previously, colorectal and endometrial cancer are the two leading or the two most strongly associated with Lynch syndrome. So if there's colorectal neoplasia that is not amenable to endoscopic therapy, colectomy with ilioverctal anastomosis is recommended. In addition, prophylactic hysterectomy plus or minus bilateral salpingio oophorectomy should be offered to women who are either done with childbearing age or by the time that they're 40 to 45 years of age. There's many different chemoprevention trials underway for Lynch syndrome. I wanted to highlight aspirin. Byrne and colleagues in the United Kingdom performed the CAP2 RCT, which showed that the long-term effect of aspirin taken at 600 milligrams for at least an average of 55 months showed a reduced incidence of colorectal cancer in these men and women. Now for 600 milligrams is a fairly high dose and not always tolerated by all patients, and there is ongoing work to determine the optimal dose or duration of aspirin in Lynch syndrome. However, I do recommend starting patients or at least considering starting them on daily aspirin if there's no contraindication. Now we'll move on to familial adenomatous polyposis or FAP. This is also an autosomal dominant condition caused by an APC germline variant in chromosome 5, which leads to loss of tumor suppressor activity. Up to a third of patients with FAP have no family history and they represent de novo mutations. There's two forms of FAP. There's classic FAP and attenuated FAP. The classic form, patients with the classic form present with over 100 colorectal adenomas and the mean age of adenoma development is at the age of 16, and the mean age of colorectal cancer development is by age 40 if preventative or prophylactic colectomy is not performed. For patients that have attenuated FAP, they typically present with less than 100 colorectal adenomas, which form later than the classic form, more so in the third or fourth decade of life. There's several extracolonic manifestations of patients with FAP, including gastric and duodenal adenomas and carcinoma, pancreatic obiliary malignancies, desmoids, thyroid cancer, hepatoblastomas, and medulloblastomas. There's three strong recommendations for patients who have FAP, including annual colonoscopy starting at the age of 10 to 12 years, as well as an annual EGD to look for gastric and duodenal neoplasia, and then finally an annual thyroid ultrasound. Similar to Lynch syndrome, if the colon follicle burden is not amenable to be managed endoscopically or dysplasia is present, total colectomy is recommended for FAP patients. If they do have a rectal cuff that remains intact, the recommendation is for annual surveillance of the rectal cuff and ilium post-op. If they have an ileostomy after surgery, surveillance is recommended of the stoma and ilium every two years. I wanted to highlight Solandac for chemoprevention and FAP. So the way Solandac works is that in FAP there's loss of tumor suppressor activity with APC mutations, which leads to an increase in COX-2 expression. Solandac inhibits COX-2 impression and reduces colorectal adenoma formation. Solandac is also being studied for duodenal adenomas, and there's several other agents that are under investigation for chemoprevention for FAP, showing promise, including erlotinib and afluorinathine. Now we'll end with a discussion of three hamartomatous syndromes and then serrated polyposis syndrome. So the first of the hamartomatous syndromes is Putz-Jager syndrome, which is also inherited in an autosomal dominant fashion, caused by the pathogenic variant in a tumor suppressor gene STK11. The polyps can be anywhere in the GI tract, and the histology will involve the epithelium as a part of the GI tract where the polyps are formed, which is most commonly in the small bowel. Up to 96% will be the small bowel, followed by colon, rectum, and stomach. These polyps can vary in size, but sometimes they tend to be large and bulky. So if you hear about a patient in the second or third decade of life who's presenting either with bleeding or iron deficiency anemia or abdominal pain due to small bowel obstruction or intussusception, think Putz-Jager syndrome. The criteria for testing are listed here on the bottom of the slide, so anyone who has two or more hamartomas in the GI tract or mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, or fingers in the setting of family history of Putz-Jagers, or there's a first degree relative with Putz-Jagers, these patients should be referred for genetic counseling and testing. There's several screening recommendations for patients with Putz-Jagers, including testicular cancer to start anywhere ranging from the birth to teen years, depending on which guidelines you see. Certainly by the age of 10, this should be started. For polyps and gastrointestinal cancers, there are several recommendations, including performing an upper endoscopy, colonoscopy, as well as small bowel imaging by way of either video capsule endoscopy or MRN choreography, starting at the age of 8 to 10. If polyps are found, then these modalities should be repeated every two to three years. However, if no polyps are found, then EGD colonoscopy and small bowel imaging can be repeated at 18 years of age, and then every three years. Women with Putz-Jagers syndrome should also undergo cervical ovarian and breast cancer screening, as I've listed here, with cervical and ovarian cancer screening starting between the ages of 18 and 25, and breast cancer screening starting at the age of 25. Pancreatic cancer should also be done with an annual EUS or MRI MRCP starting at the age of 30 to 35. Next, we'll go on to juvenile polyposis syndrome, again in autosomal dominant condition. This is caused by mutations in tumor suppressant genes SMAD4 or BMPR1A. The polyps involved here primarily are found in the colorectum up to 98%, followed by the stomach and small bowel. Juvenile polyps are mostly pedunculated. They're often multilobulated, and you'll see a white exudate on them. The most common clinical presentation you may see here on the boards would be somebody around the age of 18 who's presenting with rectal bleeding or iron deficiency anemia. The criteria for testing include at least five juvenile polyps in the colorectum, or at least two or more juvenile polyps in other areas of the GI tract, or finally, any number of juvenile polyps anywhere in the GI tract in an individual with a first-degree relative of juvenile polyposis. The screening recommendations for juvenile polyposis include colonoscopy and upper endoscopy starting between the ages of 12 and 15. If polyps are present, these should be repeated every one to three years. If there's no polyps, then we can repeat colonoscopy and EGD at 18 and then continue onwards. If a patient with juvenile polyposis has a SMAD4 mutation, they should also be screened for hereditary hemorrhagic telangiectasia. Finally, the last hammertoma syndrome we'll talk about is P10 caused by the tumor suppressor gene P10. There are two, there are several variants of this, including Cowden syndrome and benign Reilly-Ruvalcaba syndrome, or BRRS. They may not ask you to differentiate between these two on the boards, but if you see a patient with GI tract polyps, with skin tags, or papillomatous papules as you can see in the picture on this slide right around the lips, or macrocephaly developmental delay, any of these features you should think P10 hammertoma syndrome. The criteria for testing include multiple GI hammertomas or ganglion neuromas. Screening for a patient with P10 hammertoma syndrome should include an annual thyroid ultrasound starting at the age of seven, melanoma screening starting at the age of 18, colonoscopy and EGD starting at the age of 35, and then repeated every three to five years, and then breast cancer screening as well as an endometrial biopsy or transvaginal ultrasound both starting between the ages of 30 to 35. Renal, renal ultrasounds should start around the age of 40. And then the last syndrome we'll discuss is serrated polyposis syndrome. This is due to an unclear genetic etiology thus far. Both RNF43 and MutYH have been hypothesized as being associated with SPS. I wanted to highlight the most recent WHO 2019 criteria, which if a patient has either of these two, they should be suspected to have serrated polyposis syndrome. So either at least five serrated polyps proximal to the rectum, all five millimeters in size, including two which are at least 10 millimeters or greater, or 20 serrated polyps of any size in any part of the colon with five proximal to the rectum. Screening and surveillance should start at by age 40 at the latest or earlier based on family history of colorectal cancer, and then continue every one to three years based on findings. So we have two questions left. The first is question three. A 55-year-old woman undergoes first screening colonoscopy. She reports that her father has had many colon polyps. She has five cecil polyps ranging in size from 8 to 13 millimeters in the ascending and transverse colon, which are found to be serrated polyps on pathology. Which of the following is the most appropriate recommendation for this patient? Is it A, to obtain genetic testing, B, repeat colonoscopy in six months and then extend the interval as appropriate, C, repeat colonoscopy in one year, or D, refer to a colorectal surgeon for extended right hemicolectomy due to increased cancer risk? So the correct answer here is to repeat colonoscopy in one year. So A could be considered, but as I mentioned, there isn't a clear genetic association with serrated polyposis syndrome, which is what they're trying to get you to recognize here. A repeat colonoscopy in six months is a bit too soon for the size of the lesions. Referring to a colorectal surgeon would be preemptive for a right hemicolectomy because these polyps are endoscopically manageable at this time. So the fourth question, the last question we'll cover is the following. You're seeing a 30-year-old woman with a strong family history of colon cancer. Her father was diagnosed at the age of 40, her paternal grandfather at the age of 46, and paternal uncle at the age of 40. In addition, one of her paternal aunts had endometrial cancer and another aunt had ovarian cancer. Which of the following is the most appropriate recommendation? Colonoscopy every five years starting now, colonoscopy every three years starting at the age of 40, colonoscopy every three years starting now, or colonoscopy every one year starting now? The correct answer is choice D, colonoscopy every one year starting now. So if we break this down, this is a patient who has three relatives diagnosed with colorectal cancer of which at least two generations or span includes a first degree relative and then also includes a relative diagnosed at an age less than 50. So she meets all three Amsterdam criteria for Lynch syndrome. For patients with Lynch syndrome as I discussed earlier, you should start screening at the age of 20 to 25 or between 30 and 35 for PMS2 and MSH6 variants. We don't know which variant she would have but the correct answer or the best answer choice here is D, colonoscopy every one year starting now. She should in addition of course also be referred for genetic testing for pathogenic germline variants for Lynch syndrome. I wanted to thank you all for your time. I'd also like to thank the course directors and moderators for giving me the opportunity to speak on this topic today. I'm sorry I could not join you all in Texas. I wish you the best of luck on your upcoming boards. I've listed several hopefully helpful references and resources that I used to put this talk together that may be helpful as you review for the boards. If you have any questions please feel free to email me at the email address listed here on this slide. Thank you.

colorectal cancer

screening

surveillance guidelines

polyposis

nonpolyposis syndromes

carcinogenesis pathways