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Check out the show notes for the application link. All applications are due May 25th. Okay, welcome back everybody from the colorectal surgery team from Montreal. In today's topic... we'll be discussing Lynch syndrome. It's quite a complicated topic, but we'll try to make it as clear as possible. We'll guide you through the epidemiology. the manifestation, the challenges of the diagnosis itself, and also we'll discuss management and follow-up associated with Lynch syndrome.
So for this clinical challenging episode, we're going to review two different cases that we actually treated here in our institution. So let's start now with our first case. So Maer, our resident, you're in my office and you have a young 32 year old patient with a referral for erectile cancer. The biopsy showed adenocarcinoma. He had a colonoscopy and he had no other abnormalities on colonoscopy.
When you do the rectal exam, he has a rectal mass and it is located at around 6 centimeters. And in fact, it's quite fixed on the sacrum. You have the CEA level, which is normal. The distant metastasis workup for secondary lesion is negative. And the MRI of the pelvis reveals a T4N0 posterior rectal cancer with involvement of the distal sacrum. What are the elements in this case that would...
possibly make you suspect a Lynch syndrome or hereditary colorectal cancer? In this situation, we're faced with a 32-year-old patient, so I'd say the age... of the patient is very important and it could lead us towards some form of hereditary disease. And a positive family history for colorectal cancer could also indicate such a thing. but one should also search for advanced colitis or other malignancies such as in the uterus ovaries stomach pancreas small bowel brain etc in the family obviously
as these could be linked to Lynch syndrome or HNPCC. Okay, so in other words, you'd want to have the family history associated with this patient? Yeah. And what you're saying is that you don't... Only look for colon cancer. Exactly. But there are other cancers that we'll discuss later on. Exactly. Okay. So, in fact, this patient's father had two colon cancers. One... around the age of 40 and the second when he was 60. Of course, in this case, we would suspect Lynch syndrome.
What is exactly Lynch syndrome? It's a very good question. Actually, Lynch syndrome is the most common cause of inherited colorectal. It accounts for about 3% of all colon and rectal cancer. And it is an autosomal dominant disorder. with a variable penetrance, which is caused by a germline mutation in one of the DNA mismatch repair genes, commonly referred as to MMR.
It can also be linked to the loss of expression of a gene due to deletion in the Epcam gene, which is less common though. So there are four common... mismatch repair genes that are mutated or that we know that can be associated with Lynch syndrome, which are MLH1, MSH2. MSH6, and PMS2. And out of these, the MLH1 and MSH2 confers the highest risk of colorectal cancer.
Basically, what happens is that these genes usually maintain genomic integrity by correcting any mismatches when the DNA is replicated. And when you have a germline mutation in one of these genes, basically you have more errors during the replication, which leads to some form of cancer. Okay, so when would you suspect Lynch syndrome, Mahal?
So there are the Amsterdam 2 criteria that could be used when questioning a patient, and they could be remembered with the 3-2-1 rule. So Amsterdam criteria go as follows. First of all, three or more relatives with an associated cancer, whether it's colorectal cancer or cancer of the endometrium, small intestine ureter, or renal pelvis. And one of them should be a first degree relative of the other two. And then one needs to have two or more successive generations that are affected.
And third of all, one or more relatives diagnosed before the age of 50. FAP should be excluded in cases of colorectal carcinoma, and tumors should be verified by pathologic examination whenever possible. That is correct, but you have to keep in mind that the sensitivity of the Amsterdam 2 criteria is only 22%, while the specificity is around 98% for the diagnosis of Lynch syndrome.
Obviously, with the new generations with smaller families, these criterias have become a little bit less popular now because a lot of people don't have many siblings. So these criterias are not always rich. And we are now also usually screening pretty much every colon cancer for the mismatch preparer genes or the satellite microcyclic instability. But it's important to keep in mind that these criteria still can be used to distinguish families who don't have Lynch syndrome.
but might have other strong hereditary risks. In fact, Lynch syndrome is commonly referred to as HNPCC, which is hereditary nonpolyposis colon cancer. But HNPCC refers to patients who fulfill the Amsterdam criteria. But a portion of these... we will call Lynch syndrome and this refers to patients. where a germline mutation in one of the DNA mismatch repair genes or EP-CAM genes is found. There are also... the Bethesda criteria that were first published in 1997 and later updated in 2004.
So they were originally developed to identify patients with colorectal cancer who should undergo tumor testing for MSI or microsatellite instability. They were not meant to diagnose Lynch syndrome, but they are commonly used to suspect Lynch syndrome upon initial evaluation or trigger some form of genetic evaluation. The revised Bethesda criteria go as follows.
Tumors from individuals should be tested for MSI in the following situations. 1. Colorectal cancer is diagnosed in a patient who is less than 50 years of age. presence of synchronous, metachronous, colorectal, or other HNPCC-associated tumors, regardless of age. 3. Colorectal cancer with the MSI high histology diagnosed in a patient who is less than 60 years of age.
colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under the age of 50. And lastly, colorectal cancer diagnosed in two or more first or second degree relatives with HNPCC-related tumors, regardless of age? Okay. In these criteria that you just mentioned, you say that they should be tested for MSI. So what's the difference between testing MSI and immunohistochemistry?
So IHC staining usually is performed for the proteins. And MSI refers more to the genetic testing. So patients who do not stain for certain proteins that are coded by the genes then necessitate genetic testing. But one must keep in mind that just because a protein is missing doesn't mean there is necessarily a microsatellite instability and a genetic mutation linked to Lynch syndrome.
Okay, so we'll come back to our case. Our patient had a rectal cancer. He was 32 years old. So we treated the rectal cancer, and that was about 10 years ago. He had neoadjuvant chemorad. And he required an APR with a partial sacrectomy. And he recovered well from his surgery. And his PATH report came back with a YPT4N0 with negative margin on the sacrum. So we were quite happy about that. So in his follow-up, he required...
annual colonoscopy because he was lynched, because his dad actually had two colon cancer. So he had annual colonoscopy. And after eight years post treatment of his rectal cancer, we found kind of a small polyp that was one or 1.5 centimeter in the left colon And this was removed. So Matt, are there differences in polyp behavior in normal patients versus Lynch syndrome patients?
Yeah, so from what I understand from your question, I believe you're referring to the adenoma carcinoma sequence, which is the classical sequence we see for most polyps, sporadic polyps to be precise. But in patients with Lynch syndrome, they tend to present with polyps with an accelerated sequence. And the adenomas are usually found to be larger, flatter, and with a higher chance of high-grade dysplasia or villus pathology.
There's also an increased risk for synchronous and metachronous colorectal cancers. And 7% of patients with Lynch syndrome have more than one cancer at the time of diagnosis. Of their initial cancer. Exactly. This is a good example of why frequent colonoscopy evaluation of the colon is important in patients with Lynch, as significant polyps can develop in a short interval.
The pathology report of this patient, which had the polyps eight years after his initial treatment, showed high-grade villisadenoma. with in fact microfoci of intramucosal adenocarcinoma. The lesion was in contact with the cauterized margin. He then underwent a chromoendoscopy. It demonstrated a few other small small adenoma in the sigmoid and one had in fact high-grade dysplasia. With the initial path
Was it indicated to do another promoendoscopy? Well, the patient had an intramucosal adenocarcinoma with his first colonoscopy, which is basically a cancer in situ. And considering this, I think the patient could have underwent colectomy. after obviously discussing the benefits and the risks associated with the procedure. But a chromoendoscopy could also help establish a better diagnosis and find other lesions which could
be missed on a standard colonoscopy and which could orient us to a better surgical planning. So I think this test was complementary but not necessary. Absolutely. So the patient was recommended to undergo a colectomy. So we did a formal total colectomy with an N-ileostomy. And PATH report confirmed actually a T2N0 invasive adenocarcinoma of the left colon. And again, immunohistochemistry analysis was performed on the specimen and showed absence of expression of MLH1 and PMS2.
At this stage, can we confirm that this patient has Lynch? That's a great question, actually. And a lot of people get mixed up with this situation, actually. Basically, what the IHC staining refers to is that you test for the expression of the MMR proteins in the tumor to see if... the proteins are expressed normally or if they are not expressed normally. You can also test it on normal cells.
to see if it's expressed or not expressed. So if all the proteins are expressed, it usually means there is no germline mutation. But if one or two of the proteins are not expressed, it does not necessarily mean that there's a germline mutation. So especially with the MLH1 or PMS2, you have to go and look if there's a BRAF mutation or you can also check for the MLH1 hyperventilation.
In most centers, they will do one or the other. They're pretty equivalent to find out. But if you have one of these two specific characteristics, most likely that cancer is sporadic. It's not caused by a germline mutation. If you don't have a BRAF mutation or if you don't have hypermethylation, then you have to do a germline mutation testing, a blood test for the patient to see if his...
if there's a germline mutation in one of those genes. And if there's a germline mutation, then you can say the patient has Lynch syndrome. That's pretty complicated, but to summarize from what I understand, and I think I tried to answer that question before. I'm just going to repeat it again. IHC is staining for proteins. If a protein is missing...
then one should further push the search for a germline mutation. But it doesn't mean there is a genetic mutation from when the patient is born. Okay, so let's say this patient has an IHC. testing which is normal but you still have a high high suspicion level for Lynch syndrome what would you do So if I have a high clinical suspicion for Lynch syndrome, despite normal pathology, it doesn't mean that the patient does not have Lynch syndrome.
As we know, many patients who fall under the Amsterdam criteria that I mentioned previously, in other words, that are considered HNPCC, will have negative IHC staining. but one should consider genetic evaluation and testing for these patients. That just places more emphasis on clinical suspicion. Exactly. Exactly. And they will usually do... broad genetic testing because these patients with strong family history, sometimes they can have attenuated FAP or MYH mutations. So it's not only the...
the Lynch syndrome that they check. And to add on that also, nowadays, most centers will do what we call universal screening. So for all... colorectal, or endometrial cancer, the pathology should report on the MMR status or the MSI status. That way you can identify about one in four cases of Lynch syndrome that would not be diagnosed only with the clinical criteria. That's basically what we do at the institution here for quite some time now.
Yeah, we've been doing it for at least 15 years. So what is the usual recommended screening for patients with Lynch syndrome or HNPCC? For patients with HNPCC, meaning those fulfilling Amsterdam criteria, or those that are actually affected with Lynch syndrome, Colonoscopy has to be performed every year or two, beginning at the age of 20 to 25. or two to five years before the youngest age of diagnosis of colorectal cancer in the family, if obviously the cancer occurred before the age of 25.
An annual colonoscopy should be performed after resection of colon cancer in these patients. Coming back to my patient, he has twins. And his twins are now 13 years old. How do you handle this twin situation? So now that we know the patient has a confirmed germline mutation of MLH1 and PMS2, his children can be tested specifically for this mutation.
And obviously such genetic testing needs counseling before and after testing. So referral to a specialist in medical genetics is strongly recommended. If they are found to be carriers... meaning the children, they should be screened according to the Lynch syndrome follow-up routine that I mentioned earlier. If they don't have the mutation, they're...
Risk of lifetime colorectal cancer is comparable to the general population, and they can be screened according to those normal guidelines, as we know. I think it's also important to mention that this... like when you compare this to fap which occur even earlier you can wait you can delay a little bit this genetic testing until the patients can actually decide and understand the implication of genetic testing. So we would generally wait until like 18 years old or something. If there's no earlier.
cancer than 25. So usually it's at the end of the teenage years that patients will be referred for genetic counseling and then... Possibly genetic testing. Yeah. So are there any special consideration for patients with Lynch syndrome and rectal cancer? Well... Obviously, these patients have a higher risk of developing a cancer if we leave some of the colon in situ, but it's not as...
drastic as it can be with FEP, which is 100%. Usually, we will just treat the rectal cancer according to standard treatment. I mean, nowadays, there may be more TNT. than just chemo rads but still it's a good option of treatment and We will generally not recommend a total proctocolectomy with or without an ill pouch unless they have multiple lesions.
that mandate some form of bigger resection but if there's only a rectal cancer we would treat it standard with standard resection obviously the follow-up afterwards will be different But the treatment of the rectal cancer will be according to standard practice. So Maya, if you had a patient, say, with a rectal cancer and he's 28, Is there a place for a total proctocolectomy in a pouch? Not necessarily. Why not? Because having a total proctocolectomy is more of a major...
and could have impact on the functional outcome of the patient. Because there are functional issues where quality of life with a pouch is quite different from... a proctectomy, okay, a standard proctectomy. And we'll see a bit later on. But the message here is just to say that usually, In Lynch syndrome, there's no indication of doing a prophylactic or even with a cancer to do a pouch. And also, not only the functional results, but...
the morbidities associated with doing such a surgery. Let's stop there. Being a soldier, it's exciting. You already know that. What you want to know is, what's in it for me? I wanted to learn leadership skills from the experts. I wanted to get paid to earn qualifications. I wanted more confidence. And now, look, I'm on the radio.
That's what was in it for me. Get skills, get qualified, get confident. Army. Recruiting now. Search Army jobs. All right. I think that's a good take-home message for Lynch syndrome and rectal cancer. So let's jump to our second case now. So you see in your office a 30-year-old female. In your office, you mean.
Yeah, I see in my office a 30-year-old female with actually a recently diagnosed Lynch syndrome on her mother's side. And so she went for a screening colonoscopy, which was the first one in her. in her history and they actually diagnosed a small ulcer-like lesion in the right colon which really did not seem like much
But they did biopsy it, which was a great thing because that biopsy revealed an invasive adenocarcinoma. So she had a full extension workup, which was negative. And actually the CT scan... It doesn't even show colonic mass. They can't even say that there's something on imaging. CA levels are normal. This is actually a good example of easily missed invasive cancers in Lynch syndrome. So when doing a screening colonoscopy, you have to make sure that first of all, the bowel prep is excellent.
And that you have to be extra vigilant in looking. for, I mean, minimal abnormalities. And if you do see anything that's abnormal, it requires biopsies because in these patients, you can easily miss. small lesions that are in fact already cancers. And typically there are flat polyps, small ulcers, and it's very important to be very... meticulous in doing these colonoscopies. Well, in fact, you have to be meticulous for all colonoscopies. But extra. That's it. All right. That's very important.
Take-home point message here. So how would you treat this patient, Maya? In terms of what would you recommend for the surgical treatment of her cancer, her right colon cancer? Yeah.
So standard surgical treatment of colon cancers associated with Lynch syndrome would be total abdominal colectomy with an ileo-rectal anastomosis. If a patient is suspected to have Lynch syndrome, Tumor testing on the suspected specimen should be performed on preoperative biopsy specimens, if possible, to make surgical planning easier, although it's not necessary.
This is specifically true for patients who would rather go with a segmental colectomy, and then after which a biopsy confirms Lynch syndrome, so one would switch surgical planning to. Total colectomy. But, but, but, but, wait a minute. Because if, like, if your patient is 30 years old and has a right colon cancer, I would say that independent of your biopsy, I mean, for sure, you've got adenocarcinoma proven. But wouldn't you say, Francois, that any patient...
who's 30 years old, you would recommend anyways a total collectible? You definitely have to consider that and you have to speak thoroughly with your patient. Because they, whether they are Lynch syndrome or not, they are at high risk of developing. Another cancer in their next 30 years. But obviously sometimes if there is like a proven genetic defect that can motivate them.
to uh undergo it could bring more to your uh to your discussion in in trying to convince them but some patients will not necessarily want a total colectomy. But my argument to this patient is in terms of functional outcome, there's not that much of a difference between a right colectomy. and a subtotal collective. And there's not also a higher risk of complication between the two procedures. So I would tend to push in any patients that...
is younger than 40 to undergo a total colectomy. Yeah, especially that their risk of developing a second cancer down the line is... up to like 40-45% if you leave the rest of the colon and it goes down to about 10% if you only leave the rectum in place. And that's a good argument for patients as well. Yeah, it's true.
I don't know, in your practice, say you end up diagnosing a patient who is a little bit older than the standard 30, 40-year-old patient, and they would ask for a segmental colectomy. say they're 60 years old, I don't know if that happens in your practice, would you still recommend a total abdominal colectomy or would you go with a limited colectomy with follow-up after surgery?
Meaning if that patient is 60 and has developed at age 60 a cancer. That ends up being confirmed Lynch syndrome. Prior to. Yeah. Probably that I would recommend a subtotal. Total colectomy? Yeah, probably. If they have some... If they have a... If they don't have any functional issues, you know, you have to make sure that you have a good sphincter. And, you know, you probably go on to doing an ileo-sig anastomosis and maybe not a true ileo-rectal.
Because it's mainly to decrease the length of remaining colon. So if you keep a little bit of sigmoid in these patients, they definitely get a better function out of it. Exactly. Okay, so back to our case. Actually, I had that discussion with the patient for about like, I would say a good 45 minutes and she was completely...
closing her mind and stubborn. She really only wanted to have a right colectomy. So I said, OK, think about it for a week or two. Call back. And when you have the decisions and she stick with it. So, I mean, you still have to respect their decision. Absolutely. You did your job. You showed her the arguments in favor at her direction. And then, I mean, you can't force her. And you have to respect the patient's decision. So she underwent a laparoscopic right colectomy.
She was discharged on post-op day three. Everything went well. And her final pathology report was a PT1N1B with two involved lymph nodes, actually. even with that small cancer. So the MLH1 and PMS2 were absent on IHC staining. And actually on further evaluation, she had a germinal mutation of MLH1 gene. So Dr. Richard. What would you recommend in terms of adjuvant therapy for this young patient with stage 3 colon cancer? Well, the discussion is interesting. We know that patient...
with Lynch usually have a better prognostic than patient with sporadic colorectal cancer stage by stage. And in fact... You know how usually in stage two traditional colon cancer, if we have high-riskers... we probably will suggest a form of adjuvant chemotherapy. But in fact, when we're dealing with Lynch syndrome and their stage 2 disease, independent...
of the risk factors, we usually will not recommend adjuvant chemotherapy in stage two. However, in patients with stage three, As in this case, a given chemotherapy will be recommended and should be given to lower the chances of getting further metastases over time. Okay, and what about immunotherapy? Well, you know, we're in the era of immunotherapy, and it's currently only indicated in patients with known Lynch.
or MSI high tumors that are metastasic. So we're not yet there in terms of adjuvant treatment with immunotherapy. There are agents as Pembrolizumables who are now approved as first-line therapy, but again in metastatic disease. Or a second line after failed chemo. So in this setting, the achievement therapy, there is no data to adding immunotherapy. Not yet.
Yeah, there's a randomized control study that is underway actually right now, combining Folfox and Pembrolizumab, but then we will only have the results of this in it. A few years. Right, exactly. And we know that usually Linz syndrome will not respond as well to the traditional chemo, especially with the oxaliplatin. All right. So, Maya, is there anything else in this particular patient that you want to consider? Yeah. So, in this female patient, considering that she's a female...
and has a confirmed MLH1 Lynch syndrome, I would obviously think of her risk of getting endometrial and ovarian cancer. So first, I would suggest a consultation with gynecology. Because her risk of developing endometrial cancer varies from 34 up to 54% at an estimated average age of 49. Sorry, was she seen? She was C. They did a biopsy. It was negative. Obviously, she's 34 and she wants to have kids, so we didn't...
Okay, go ahead. So, yeah, so I was saying the risk could go up to 54% according to the NCCN guidelines. as opposed to a standard person from the general population who at the age of around 49 would have only a 3.1 cumulative risk for diagnosis of endometrial cancer.
There's also the ovarian cancer to keep in mind, but that risk is a little bit lower and could go up to 20%. And since she will be undergoing surgery, preoperative endometrial biopsy should be performed as it was performed in this patient. And hysterectomy should be completed at the time of surgery if a cancer is proven on biopsy. Okay.
So in fact, women should be educated regarding the importance of prompt reporting and evaluation of any abnormal uterine bleeding or postmenopausal bleeding in Lynch syndrome. And as mentioned, this patient starting the age between 30 and 35 should in fact... be followed by a gyne team and get yearly or every two years an endometrial biopsy. And also ovarian cancer screening. be recommended by ultrasound, again starting at age 30 and 35.
Now, as for prophylactic total hysterectomy and ophorectomy, it's been shown to reduce the incidence naturally of such cancer. But when you look at the overall data, it doesn't kind of reduce the overall mortality rate in these patients. However, it should be discussed. And usually how it goes is that if Patient, like your young patient, has, of course, is not menopause and has not finished having her family.
will not go on to discussing a prophylactic hysterectomy. Usually this occurs when either you have a patient... a female patient that has finished having her family and in that case then prophylactic hysterectomy can be considered and should in fact be discussed. And in terms of the ovaries, usually we'll recommend to remove the ovaries, especially in
postmenopausal because you wouldn't want to induce a menopause. Exactly. So you have to be careful about these recommendations. And if they have a colon cancer and they are... operated for their colon cancer and they're done with their family, if they still have their uterus, you should remove it at the same time. Yes. Okay. So, I mean, in female patient with Lynch syndrome, I think it's... important to mention that endometrial cancer is at least
as important in terms of risk reduction than colon cancer. Absolutely. Especially in the patient with MSH6. That's it. Depending on the gene. deletion certainly will have a higher chance of having endometrial cancer than the colon cancer itself. Okay, so we talked about colon cancer. We talked about also endometrial and ovarian cancers. But, Francois, give us kind of an uptake. on other type of cancers that can be associated with Lynch. So basically, although less prevalent, gastric cancer...
can be associated with Lynch. And it's recommended that the patient undergo at least a baseline gastroscopy. And in terms of follow-up... There's no clear recommendation if they should have follow-up gastroscopies unless they have a family member that had a gastric cancer. In this case, they should be followed also with... upper GI scope. The other cancer that can be associated with Lynch syndrome is the renal cancer.
These as well, there's now strong recommendation in terms of follow-up for these patients, unless they have a family member who was affected by such a cancer. And if screening is deemed necessary, then they could have annual hearing analysis or renal scan that can be performed every one or two years. Okay. So really, it shows how complicated Lynch can be, but it also makes it such that as surgeons, we really have to be aware.
of all these particularities associated with Lynch because often will be the first. to diagnose and encounter these patients and we'll have to counsel them as such. All right. And one last point, Maire. What do you think about using aspirin? in terms of prevention for cancer in these patients. Do you really have a thought on that? Well, I do have a thought on that, but it's not necessarily a firm thought, if I may say.
Individuals with Lynch syndrome, they are at risk of having a future colorectal cancer. I believe taking aspirin should be considered to reduce their future risk of colorectal cancer. I won't get into the... the details of why and how, but according to the ASCRS guidelines, for example,
aspirin intake is recommended, although one has to keep in mind that there is no standard dosage that is recommended to patients. And a recent trial from JAMA demonstrated that patients taking up to 600 milligrams per day have a lower risk of cancer, but... 600 milligrams is still a considerable dose, and for patients, this could be a lot, especially with their risk of bleeding. So there is some data. It is part of the guidelines, but this has to be discussed, and the dose is not very clear.
Okay, so these two cases really highlight the complexity of managing patients with colorectal cancer associated with Lynch syndrome. Hopefully we've cleared that up. A little bit. So you have a few take-home messages. Yeah. For our listeners out there. Microsatellite instability is not specific for Lynch syndrome. 15% of sporadic colorectal cancers. And 5 to 10% of metastatic colorectal cancers demonstrate microsatellite instability because of hypermethylation of MLH1.
That's number one. Number two, germline sequencing of the mismatch repair genes. remains the gold standard for confirming the diagnosis of Lynch syndrome. Number three, universal screening of colorectal cancer specimens should be performed and is recommended according to many guidelines. Four, colorectal with iliorectal anastemosis is the primary treatment for colon cancer associated with Lynch syndrome.
Screening colonoscopy should be routinely performed every year or two starting at the age of 20 to 25 for patients with known Lynch syndrome or a family history of Lynch syndrome.
and no genetic screening available, while post-colectomy annual colonoscopies should be performed in patients that already developed colorectal cancer. And lastly, the most common extracolonic manifestation of Lynch syndrome is endometrial cancer and appropriate gynecologic counseling is required so from all of us to you
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