During this 20-25 minute pre-recorded lecture, Dr. Steven Itzkowitz discusses the topic of colon cancer syndromes. This in-depth review will provide an update on this topic for your clinical practice as well as supplement your learning for the ABIM Gastroenterology and Hepatology boards. CME pre-requiste of live Q & A webinar, 8th Annual Mount Sinai Intensive Board Review in Gastroenterology & Hepatology on Oct 6.
My name is doctor steven. It's quits and I'll be discussing the hereditary colorectal cancer syndromes. Yeah if you look at all colorectal cancers that occur every year they can be thought of as sporadic familial or hereditary. Two thirds of cases every year occur as erratic cancers, meaning there's no familial or hereditary component. But if you take a family history, about 2025% of the time you'll find some degree of a family history, maybe one relative to relatives that's referred to as familial colorectal cancer. But we're going to be discussing the hereditary colorectal cancer syndromes that account for about three to as much as 5% of colon cancer is every year. The colorectal cancer syndromes can be thought of as either Peloponnesus syndromes or non Peloponnesus syndromes. The Peloponnesus syndromes are always classified according to the predominant type of polyp that is seen histological E so if the predominant genotype is at an ominous polyps, you're looking at either familial adenomas, polyp Asus or F. A. P. That's caused by a pc gene mutations or M. A. P. Which stands for multiple adenomas polyp Asus and that can be caused by either N. Y. H mutations also known as mud yh mutations And a newly described gene called NOT L. one. If most of the polyps are hematomas then you may be dealing with either puts Yeager syndrome, juvenile Peloponnesus syndrome Cowden syndrome or serrated Peloponnesus. If there are many cancers, many colon cancers in the family but not many people who have polyp Asus or multiple polyps, then you're dealing with a non polyp Asus familial colorectal cancer syndrome and those can be thought of as either lynch syndrome where there is a hereditary DNA mismatch repair deficiency. A mutation in one of those jeans or a syndrome called familial colorectal cancer type X where there are multiple colon cancers in a family. But when you do gene testing, there's no gene mutation. Yes, Let's start with lynch syndrome. First Lynch Syndrome is an autism, all dominant condition that accounts for as much as 3-4% of all colorectal cancers. Every year, There's a 40-70% lifetime risk of developing colorectal cancer and colorectal cancers occur at much younger ages than in the general population. In addition, adenomas can progress to carcinomas very rapidly, sometimes within a year or even two years, Which justifies doing surveillance, colonoscopy every 1-2 years in these people. There's an excess number of synchronous and manta Cronus colorectal cancers and many times we see colon cancer is predominantly in the proximal colon histological e these cancers are typically micro satellite unstable and such tumors often have a mutinous or signet ring cell phenotype and with lynch syndrome, there's often an inflammatory reaction which is due to tumor infiltrating lymphocytes and it looks much like Crohn's disease, which is why it's sometimes referred to as a Crohn's like reaction. At the molecular level. These tumors have micro satellite instability and lots of mutations. So they're called hyper mutable mhm. With respect to treating lynch syndrome, colon cancers. in general, micro satellite unstable Cancell do not benefit from. five few based chemotherapy. However, they're highly responsive to PD L. One and P. D. One inhibitors, the so called immunotherapy because they express neo antigens on the tumor cells that are recognized by the immune system. The prognosis of lynch syndrome. Colon cancer is ironically enough, is better stage for stage than sporadic colorectal cancer. So even though these individuals are more likely to develop colorectal cancer once they have colorectal cancer, their prognosis tends to be better than microsatellites stable colon cancers that are seen in the sporadic population. The extra colonic features are shown here and the thing we worry perhaps the most about our gynecological cancers because after colorectal cancer, uterine cancer is the second most common type of cancer. But we also see cancers in the ovary, the breast throughout the gi tract stomach, small bowel, pancreas, gall, bladder bile ducts in the G. U tract, renal pelvis, ureter bladder prostate. All of these cancers are higher than the general population in the brain you may find on rare occasion glioblastoma is. And then the syndrome is often referred to as Turco syndrome, which is something that they like to ask about on the boards. And the other thing they like to ask about is muir Tory syndrome, which is lynch syndrome where there are sebaceous adenomas or sebaceous adrenal carcinomas. That occurs in about maybe 4-5% of patients with Lynch syndrome with respect to genetic features, Lynch syndrome is due to a germline mutation in one of the DNA mismatch repair genes. The names of those genes are M. S. H. Two ml H one p.m. S. one p.m. S two, M. S. H. six or F. Cam. The colon cancer show micro satellite instability. And if you do immuno hist o chemical staining of the colon cancer tissue for the expression of the mismatch repair proteins, you will find in the case of lynch syndrome, that there will be loss of mismatch repair proteins. Now it's important that With L. H. one if that particular protein is lost, it might mean that the patient has Lynn syndrome but it could also be seen in sporadic colorectal cancer. If it's Lynn syndrome, that's due to a mutation of the BRCA one gene and in that situation, if one were to test for the b ralf gene, it would be wild type. Whereas if it's a sporadic colorectal cancer, That loss of Emil H one is due to methylation, not mutation and in that situation be wrath will be mutated. So performing the raft mutation analysis can often be complementary to the imminent history chemical staining. If L. H. One is lost, there's a rare syndrome called Bilek or constitutional mismatch repair deficiency. So what happens in this syndrome is that two individuals with lynch syndrome. Uh huh have a child who inherits the mismatch repair deficient gene from each parent. So they have a biologic or constitutional mismatch repair problem, whereas most people with lynch syndrome only have one parent and the other parent is wild type. So they have mono a lalique mismatch repair deficiency. Fortunately this is a very rare condition. But the thing to be concerned about is that we see very young people developing colorectal adenomas and cancers. Even Children younger than age 10 might develop a colorectal cancer. You see small bowel adenocarcinoma is brain tumors, leukemias, lymphomas, cafe ole spots. And the key here is that if you do staining for the mismatch repair proteins, you'll not only see loss of expression in the tumor, but you'll also find loss of expression in the normal tissue because there's constitutional loss of the mismatch repair protein. You may have heard about a syndrome called tumor lynch syndrome. What happens in these individuals is that they do not have a germline mutation of DNA, but in the tumor tissue itself, there are two somatic mutations of a DNA mismatch repair proteins. So this is not a heredity able type of situation. There's no germline defect in the DNA, the tumor tissue itself has developed to somatic mutations of a mismatch repair protein and that's why it's referred to as tumor lynch syndrome. Now with regular limb syndrome. One way to recognize a family with lynch syndrome as the Amsterdam criteria. Sometimes referred to as the 3 to 1 rule, which refers to three or more people with lynch associated cancers two or more generations, one person affected by age 50. And we used to rely heavily on this uh genotype, but more often now what's done clinically is that if a patient has colorectal cancer, it's stained for immuno history, chemical staining for the expression of the various mismatch repair proteins. Now if the mismatch repair proteins are retained, if they're intact then that's not likely to be lynch syndrome, that's much more likely to be a sporadic cancer. Um So you do do not really have to refer these individuals for genetic testing unless it's a very young patient or there's a positive family history with loss of M. L. H. One N. P. M. S. Two. Then you might consider that this patient has lynch syndrome. But as I said earlier in this situation, you might want to look at either the L. H. One promoter methylation or be raft testing. If the promoter is methylated or this be raft mutation, then that's likely to be a sporadic colon cancer and the patient does not have to be referred to a genetics counselor. But if there is no promoter methylation and the B raft mutation is absent, meaning the B. Raph is wild type. Those individuals should be referred for genetic counseling, a genetic testing with all of the other mismatch repair proteins, loss of any of them. M. S. H. Two. M. S. H. six p.m. S. Two is much more indicative of lynch syndrome over sporadic. So if if any of those other proteins are lost in the tissue then the patient really should be referred directly for genetic counseling and genetic testing. So let's take a case. A healthy 30 year old woman presents with new onset of Cramp E. Right, lower quadrant pain and iron deficiency anemia. Her menses are regular. She's planning to start raising a family in the coming year. On colonoscopy she has a mass in the ascending colon biopsy show a moderately differentiated adenocarcinoma with tumor infiltrating lymphocytes I. H. C. Standing for DNA mismatch repair protein shows a loss of M. L. H. One expression. The next slide shows her family history. So here's our patient who had colon cancer has colon cancer at age 30 it's in the right colon with loss of M. L. H. One. Her mother died at age 45 of uterine cancer. Her father at the age of 55 had two tubular adenomas but one tubular villas adenoma that was 1.5 centimeters and his father died at age 72 of colorectal cancer. This is the I. H. C. Steyn and on the left you see retained expression of M. S. H. Two but loss of M. L. H. One on a serial section. So question number one which of the following is the most correct A. She has lynch syndrome because her mother had uterine cancer at a young age B. She has lynch syndrome because she's the third generation on her father's side with Kalanick neo pleasure. See she has lynch syndrome because she has a proximal colon cancer with tumor infiltrating lymphocytes and loss of M. L. H. One protein D. She has lynch syndrome because she's younger than age 50 or e she may not have lynch syndrome. The answer is e she may not have lynch syndrome. Mhm strictly speaking, her family history does not fulfil Amsterdam criteria. She is the third generation with colon neo pleasure but her father only had adenoma is not colon cancer. It's debatable whether adenomas even advanced adenomas are qualifying lesions although they usually are considered as such. She has lynch cancers on both sides of the family. Her mother's uterine cancer of course, does not count towards the 3-1 rule on the father's side. But note her mother's side rather than the father's side might be the source of her lynch syndrome. Although her colon cancer has features of micro satellite instability is right sided as loss of M. L. H. One. Remember most colon cancers that RMS I positive are sporadic colon cancers, That means they're due to epigenetic methylation, not germline mutation of the H1 gene in that case you can do be raft mutation testing on the tumor. And if it's mutated, it's sporadic it's wild type. It's lynch question number two. She does undergo gene testing and is found to have a germline mutation of M. L. H. One, how would you treat her colon cancer? A A right hemi collected me because our prognosis is poor due to lynch syndrome. Be a sub total collecting me with Ilya rectal anastomosis. C total proctor collecting me with elio anal j pouch, anastomosis, D. A. Th bso with her colon cancer surgery or e preoperative chemo radiation followed by surgical resection. The correct answer is B sub total collecting me with ilya rectal anastomosis. The risk of developing a new primary colon cancer in Lynch syndrome after the reception of the first colon cancer is as high as 16% at 10 years. Therefore at the time of the first colon cancer resection, it's important to think about removing as much colon as possible. And in this patient's case because the lesion was in the right colon instead of a right hemi collected me. A sub total collect to me is really preferred because you're removing more colon that can be at risk of subsequently developing cancer. And although total practical, practical ectomy is certainly the ultimate protection against colon cancer. Most patients with lynch syndrome are young and the quality of life is better is if you can spare the rectum or the rectal sigmoid and it's important to remember that if a j pouch is constructed um women who have that anatomy will have decreased fecundity and this is a young woman who would like to raise a family. The survival of patients with lynch syndrome colon cancer is better stage for stage than those without lynch syndrome. And we think this is due to better immune recognition of cancer cells. And a th th bso should be offered to women with no lynch syndrome mutation. Once they finished childbearing, there's no role for neo adjuvant therapy for right side of colon cancers. Let's turn to familial adenomas polyp Asus. This is an order some more dominant condition due to a mutation of the A. P. C. Gene. But importantly, about a third of patients have no family history of either F. A. P. Or colon cancer in the Gi tract. The colon has hundreds or thousands of adenomas in the stomach. There are multiple fund a gland polyps, usually in the proximal stomach, the Antrim is spared and most many times I would say 30 to 50% of the time these funding planned polyps will often have low grade dysplasia. So that's a very common occurrence with F. A. P. In the duodenum. You may find adenomas especially around the ambulatory region. And you can also find adenomas in the june um or the ilium although that's less common outside of the Gi tract. Uh It's common to find benign soft tissue tumors called Desmarais tumors. Those are often in the abdomen epidermal cysts in the eye. You can see a congenital hypertrophy of the retinal pigment epithelium a lesion called chirpy. These are usually small pigmented spots, bilateral in the in the retina. They do not interfere with vision in the bones. You find askyoo maze of the long bones, the skull, the mandible. You can even find extra teeth malignancies outside of the Gi tract are rare. Uh If you do find them in F. A. P. They will occur in the brain, in which case it's a medal. A blast oma in contradistinction to the glioblastoma is that you see with lynch syndrome, you may find thyroid papillary carcinoma and on very rare occasion you may find a paddle blast oma in Children as young as one or two years old. The most important thing to think about outside of the colon rectum is the Duodenum. Because the lifetime risk of developing duodenal adenocarcinoma is as high as 4-12%. So once people have had a collective me or um sub total or total collected me, you really have to still maintain vigilance on their duodenum. Attenuated F. A. P. Is a condition that looks very much like F. A. P. Except there are fewer polyps. There's usually more right sided than left sided lesions. It's later onset. Usually there's no chirpy lesions, but upper GI lesions are still present, just like we saw with F. A. P funded gland polyps. You can even find duodenal adenomas and that's because this is a condition that still caused by mutations of the A. P. C. Gene. Although it's on the five prime or three prime. And the gene. Now a condition that looks very much like attenuated F. A. P. Is M. A. P. It's also referred to as multiple adenomas, polyp Asus or mutt. Yh associated Peloponnesus. This is the only one of all of the syndromes we're talking about that. It's also more recessive. But yh Peloponnesus is caused by a biologic inactivation of the mud. Yh jean. If there's monetarily look inactivation, those individuals may be prone to colorectal cancer but they don't have as many adenomas. And what you find in the colon is what's called Allah gopal apotheosis like between five and 100 adenomas polyps. You can also find hyper plastic and cecil serrated polyps scattered throughout the average age is 45 to 60 years old. And just like we saw with F. A. P. You can find duodenal adenomas. Gastric cancer is osteo Mazz and chirpy lesions. So case number two, A 55 year old man complains of GERD, he's been self medicating with um appraisal 20 mg a day for three months but does not feel better. He comes to you for an E. G. D. He has not yet had a colonoscopy. So you do an E. G. With screening colonoscopy, There's no family history of colon cancer. But he thinks his brother age 51 may have had several polyps. On colonoscopy. He's found to have about 20 diminutive adenomas less than five each mostly in the proximal colon and the rectum is spared on E. G. D. The gastric fund is is carpeted with funder gland polyps. Some of them have low grade dysplasia. The Antrim is spared. And in the Duodenum he's found to have about 10 Dominion of adenomas but his ample a. Is normal. So question number one, what would you conclude about his condition? A he should have a total practical ectomy be His funding and polyps are from PPE use see he should undergo a whipple procedure because of the gastro duodenal polyps. D. He should undergo partial gastrectomy because of the low grade dysplasia. E. He should be tested for an A. P. C. Or M. Y. H. G. Mutation. The answer is C. So this patient has attenuated F. A. P. Which is usually caused by either in a pc or a mutt Y. H. G. Mutation. But many cases have no known gene mutation. Uh The N. Th L one gene was recently described but it's still quite rare. Procter collectively is usually not necessary because the rectum is often spared and easily managed. Endoscopic lee and cox two inhibitors can be used in this situation because they can reduce rectal adenoma size and number but it's important to remember that the effect is reversible. So stopping the use of a cox two inhibitor, these pattern arms will come back and it also does not prevent the development of rectal cancer. If the rectum is still in place, a whipple is indicated only for dense duodenal Peloponnesus or an ambulance with worrisome dysplasia such as high grade dysplasia or villas adenoma, fortunately gastric cancer is rare in this country and F. A. P. Despite the numerous fund gland polyps, even those containing low grade dysplasia. So gastrectomy is rarely warranted. But we still survey the stomach carefully. And dysplasia in funding planned polyps is very common in F. A. P. But only rare in the setting of PP. I use pucci eager syndrome is another syndrome that will discuss. This is again, or decimal dominant. It's caused by a genetic mutation of the STK 11 or L. K. B. One gene and about half of individuals have no family history of pucci anger syndrome. These individuals often have mucous cutaneous pigmentation martoma is manifest as gi tract polyps and this gi and non gi cancers. The mucus cutaneous pigmentation can be seen as freckles on the soles of the feet, the palms of the hand, the lips and the buccal mucosa. And it's interesting if you look at your palms or your soles of your feet. It's very very rare to have freckles in those areas. So if you see freckles, think put Sjogren's syndrome in the gi tract, you can find polyps virtually anywhere in the Luminal gi tract, except for perhaps the esophagus. But interestingly it's the small bowel that's much more prone to developing polyps much more so than the colon rectum or stomach and the small bowel is of concern because these polyps can often predisposed to intussusception. What's very concerning about Puccio syndrome is the very high lifetime cancer risk. So these individuals have a 93% chance of developing a cancer uh at some point in their life. And these cancers are actually very commonly breast cancer, Pancreatic cancer, ovarian cancer as well as colon stomach, small bowel. But notice that breast cancer is even more common than Gi tract cancers in these individuals. So they really have to be advised to make sure that they are compliant with breast cancer screening. Pancreas is also of concern. There are occasionally rare tumors of the cervix and the testes that have to be looked for as well. Mhm. And then finally juvenile Peloponnesus syndrome is also on a single dominant caused by Smart four or B. M. P. R. One a jeans. The diagnosis is made if there's at least five juvenile polyps of the colon rectum or if they're a juvenile polyps throughout the Gi track or any number of juvenile polyps in the Gi tract with a family history of juvenile paul opposes syndrome. Cancers are seen in the colon and in the stomach. And there are other anomalies such as microcephaly, hydrocephalus congenital heart disease and a variety of guiyu abnormalities. So case three is a 22 year old college student who presents with symptoms of small bowel obstruction. She had a colonoscopy three years ago for mild rectal bleeding that showed several small polyps on physical exam. She had a distended abdomen. There were several freckles on her lips, buccal mucosa and the soles of her feet. Family history reveals that her mother died of breast cancer, but there were no geologic cancers or polyps. Mhm. A cat scan showed intussusception. So she underwent emergency laparotomy which revealed the long segment of gangrenous june. Um The reception specimen shows several large polyps, including one at the leading edge of the interception. And the histology of the polyps showed branching bands of smooth muscle which of the following statements is not true about this patient. A She has a hammer toe minutes paul opposes syndrome. B. She may have a mutation of the SDK 11 L. K. B. One gene. See she may have a mutation of this Mad four jean de she is at high risk of pancreatic and breast cancer. Or any her Children have a 50 50 chance of inheriting her disorder. The correct answer is c um This is Putin bigger syndrome and that's due to the SDK 11 gene, not the SAT for genius. Mad for gene is seen with juvenile Peloponnesus syndrome. Yeah, So I've included some supplementary material for conditions that I don't have time to discuss. And you'll see these include the p. 10 syndromes. Sorry, did paul opposes syndrome and chronic on catena syndrome. And I've also included for your interest suggested reading list. Thank you very much for your attention