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Okay. Hello everyone. Good afternoon. Uh My name is Caron Mutassim, um, a consultant pathologist at University Hospital Southampton. And over the next 45 to 50 minutes or so, we'll talk a little bit about uh pathology and specifically cancer pathology, but also more specifically to make it more clinically relevant to everyone. Uh We will use example of colorectal or bowel cancer uh as the main disease type that we will be going through. So, the learning outcomes for this session are that you will hopefully be able to describe the presenting clinical symptoms of colorectal cancer in patient's and then explain how those symptoms relate to the pathology of the disease. To describe the macroscopic appearances as in what you see with your naked eye, as well as the microscopic features and what we see when we look down the microscope of colorectal cancer and to relate those to the typical symptoms and signs that patient's will present with. And also, uh you should be able to describe the adenoma carcinoma sequence, which is one of the classical examples of cancer progression um in tumor's. Uh so the adenoma to carcinoma progression sequence in bowel cancer, you should be able to hopefully describe that at the end of this lecture. So to begin with bowel cancer or colorectal cancer is common, is the third most common cancer worldwide. And it's actually the second leading cause of cancer death in Western societies. Uh The incidence of bowel cancer varies globally across the world. Um Now, traditionally, when I was in university, we were taught that bowel cancer was linked very closely to the Western diet. So, effectively processed food, white bread, red meat, high saturated animal fats. But now we know that this is changing uh because there is really no such thing as a pure Western diet anymore. Uh We live in more globalized world diets and food and fast food. Can you can get access to that everywhere in the world. Uh So that's beginning to change. And also colorectal cancers we are starting to recognize are a group of molecularly heterogeneous diseases. So that means that not every patient with bowel cancer will have the same genomic or mutational changes in their tumor. Uh And that's important because it means that different patient's uh disease might behave differently, but also different patient's might respond to different sorts of of cancer treatment. So it's not a one size fits all anymore. So to understand those molecular pathways and the genomic changes in colorectal cancer will facilitate the implementation of what we describe as personalized therapies for colorectal cancer patient. So we have our usual or classical way of treatment, surgery, chemotherapy, radiotherapy, but actually, increasingly what we are trying to, to look for are more personalized treatments that target specific mutational changes, uh, that are present in the, in each individual's tumor. So again, when I was in university, we were always taught that bowel cancer is a disease of older people. Uh, usually people who are in their sixties or maybe seventies. Uh But again, what I'd like to emphasize when I give this lecture to, to our students here is that actually this is changing and there is a large cohort now of bowel cancer patient's who are young. And when we say young patient with bowel cancer, we mean normally patient's under the age of 50 that's considered young bowel cancer patient's. So these are some famous celebrities that you might know. So Chadwick Boseman on the top left was an American actor. He was diagnosed with stage three bowel cancer when he was 40 years old. And then he progressed to stage four and unfortunately passed away of the disease three years later. Uh Then on the bottom left hand side, we have a uh Dame Deborah James who was diagnosed with bowel cancer when she was in her thirties, she was diagnosed with stage four bowel cancer uh with a very aggressive form. And she did a lot of work with a lot of charities and on social media uh to increase awareness about bowel cancer and younger patient's. Um and unfortunately, she, she passed away last year, but she was actually alive with bowel cancer for five years. Stage four, bowel cancer, which is quite remarkable. And then on the bottom, left hand, side, bottom, right hand side, sorry, we have Adele Roberts who is a British radio one DJ. And she's also in her thirties and she's recently been diagnosed with bowel cancer and she, you can see the picture of her there with the stoma. She's recently just completed her surgery and her chemotherapy treatment. So these are all very visible, um, and, um, well known, uh, younger people who are diagnosed with bowel cancer. And this has meant that there's more active research in trying to understand the differences perhaps or the similarities between bowel cancer in younger patient's and bowel cancer in your more traditional age group of people in their sixties and seventies. And this is an area of active research. Um, and again, we must remember, as I said that bowel cancer is the second most common cause of death worldwide from cancer. But if you look at cancer types within the age group of 20 to 49 so younger patient's, we find that bowel cancer is the number one cause of death in, in men and it's the third cause of cancer, death in women. So it's, it's, um, it's killing a lot of young people as well. Okay. So where does bowel cancer or colorectal cancer develop? So, if you look at our anatomy and revise our right side and left sided colon. Um a large proportion of tumor's arise on the. Um Hopefully, you can see my mouse which is the pointer. Um a, a large proportion of them will arise on the left side of the colon. So, sigmoid, rectal, sigmoid and rectum, um and then a second larger proportion or right sided colon. So, cecum and ascending colon and that's important to know because the symptoms that the patient's will present with uh will often be quite different between a left sided tumor and the right side of tumor. And when we say sporadic colorectal cancer, what we mean, our patient's who developed colorectal cancer as a result of uh somatic mutations and they don't have a germline mutation or a tumor syndrome. So, this is sporadic rather than genetically inherited. Now, one way of trying to reduce the overall number of patient's who are diagnosed with bowel cancer and to reduce the burden and improve the survival is obviously to try and diagnose it early. And uh one such method of trying to diagnose bowel cancer early is to have a screening program. So, uh the UK has had a screening program for bowel cancer for about uh 16 years now. Uh It started in 2006 and this was, this is part of the NHS screening. And um up until recently, uh the age cut off for that was patient's over the age of 16. But to recognize now, as we said, just earlier, that bowel cancer is also becoming more and more increasingly diagnosed in younger patient's. The age for bowel cancer screening has now dropped to 50 years old. So when a patient turns 15 in the UK, they will get a letter in the post within that letter, there will be uh what we describe as a fit kit, which is uh the fecal immunochemical test for. Um So this is a very noninvasive kit. You can see it over here. Uh The patient will provide a fecal sample into that provided uh container, they will write their own details back and it goes back, pops gets popped back into this envelope and sent off. And if that fit test is positive, what that means is that there is uh fecal immunochemical protein, which is effectively means there's blood from the blood fragments from the hemoglobin uh that's positive. So if that's positive and then that means that there's some kind of occult bleeding from the bowel and then that will trigger the patient to be referred and to have an endoscopy uh and then further investigations. So how do patient's present with bowel cancer? So the patient might present with what we call either primary or secondary tumor symptoms. So primary tumor symptoms as the name implies, relates specifically to the tumor itself. So the patient might present with an abdominal mass or abdominal swelling. They might present with abdominal obstruction or bowel obstruction. So, if the tumor is growing within, as you know, the bowel is a, is a hollow viscous, it's aluminum. So if the tumor grows into the lumen of the bowel, it might obstruct the bowel. So that could either be partial or complete obstruction. And depending on that, the patient will present with different symptoms, they might present with their preparations. If the tumor again, we've got the hollow viscous. If the tumor perforates through the serosal and the peritoneum, then they might present with perforation or a fistula. Um, they might present with what they describe as change in bowel habits and that's partly because of potential partial obstruction. So their usual bowel habit will change and they might say that they're going to the toilet now far more often or they're not going at all or not so much at all. And they might say that the quality or the type of stool that's coming out is different from their usual bowel habit. They might present with anemia. So they could present with symptoms of anemia, breathlessness, tiredness, nous, or they could, or it could be picked up in a blood test for anemia for another reason. Um, they could present with pr perect and bleeding and mucus and that's quite important. So the blood, so they will say that there's blood in the stools, this could be bright red or dark. Um, and there might be mucus that is add mixed with the blood as well. Um And they will also often present with abdominal pain. So that could be an acute abdomen or it could be nonspecific or chronic type abdominal pain. Um And the question here is whether this is different between the right and the left side of the colon. And if so why, um and the answer is that yes, it is different between the left and the right side. So as we said earlier in the lecture, the left sided colon, uh when we is, when we're talking about the sigmoid rectal sigmoid and the rectum. And at that end of the bowel, the left side, the lumen of the bowel is narrower. Um and the feces are more formed. So the feces will be more solid. So because the luminous narrower and the feces are more solid, the patient will tend to present with more obstructive type symptoms. Um And they will present more with change in bowel habit and abdominal pain. Whereas on the right hand side of the colon, the lumen is larger and the fecal content at that point is more liquid because we haven't had all the re absorption of the fluids as as the feces makes its way through the, through the large bowel. So because of that, the tumor may grow to quite a large size without uh without presenting with obstructive symptoms. Um In fact, it may even be a symptomatic. Um And because of that, the patient might also have what we describe as chronic bleeding rather than acute or bright red blood bleeding, which you might see more on the left handed side. So those symptoms are different. And that also means that the tumor staging a diagnosis might be different. So because the right sided colon, the tumor's may grow to a large size without obstruction. Then these t staging in the terms of the tumor size might be at a higher level uh before it actually produces any kind of symptoms for the patient. So we talked about primary tumor symptoms as to how patient's will present. And we said it could be abdominal obstruction or bleeding or abdominal pain or fistula, etcetera. But then apart from the primary tumor itself, there are also some general features of malignancy in general when patient's have cancer. So they might present with loss of appetite or anorexia, they might present with weight loss. And in very extreme cases of the tumor is very advanced and has spread to different sites in the body. They might present to what we describe as cachexia, which is um wasting do and loss of muscle mass due to cancer. They might present with fatigue, tired, they will say they feel tired, breathless because of the anemia, et cetera. And then in addition to that in bowel cancer, we can, there are certain markers that can be used in the blood that could be helpful to say if a patient may or may not have bowel cancer or if they are on bowel cancer treatment, if they're responding to treatment or not. And that is uh carcinoembryonic antigen. So C E A, um it is a tumor marker. They can be measured in the blood in the serum and the normal levels should be between zero and up to about three. Um And if a patient has a raised C E A before diagnosis, then that could indicate that they have cancer. Uh it could be raised in bowel cancer. It can be also raised in a couple of other types of cancer, like breast and ovarian cancer as well. Um And then if a patient has uh is on treatment for bowel cancer and their C E A was raised before treatment, then normally they get monitored during their cycles of chemotherapy. And C E A is taken every few weeks to see if it's going down or if it's staying steady or if it's going up because that might indicate that they're not responding to treatment. Um Now, one thing to keep in mind is that C E A is not a specific tumor marker for bowel cancer, I can be raised in other conditions. In fact, smokers can generally have slightly higher levels of C E A than nonsmokers. Um And what is increasingly becoming more um uh research intensive is to look at what we call circulating tumor D N A. So we know that tumor cells will have mutations within them and those DNA mutations can sometimes be detected in the peripheral blood. Uh So there is a lot of research into that and there are a few tests now for bowel cancer were circulating tumor DNA can be detected and these are available. Um They're not quite mainstream yet in terms of uh worldwide to being part of patient management. So in the UK, they're not yet in the USA, they are. Um so that is a better way of assessing whether there is actually circulating tumor D N A in the patient's circulation than C E A. And it can work with CIA together. And the advantage of that is if we get these tests working very well, then you might have the, then you might be able to do with giving the patient's fewer scans uh during their interval for monitoring and spare the patient's radiation. But also a simple blood test from uh from a healthcare efficiency point of view is certainly a lot more um efficient and cheaper than getting patient's to have lots and lots of scans. So watch this space. It's not quite there yet. But circulating tumor D N A is, is another test to look up. So we talked about primary tumor symptoms, we talked about generalized tumor symptoms. And then the next thing is uh symptoms of metastasis. So patient's can also present with symptoms directly to related to metastatic deposits. So we have here a CT image where we have a brain metastasis deposit from a bowel tumor. So, the patient in this case will present with neurological symptoms. On the right side, we have a femoral head. Uh So this is the head of the femur and this is the shaft. And what we have here is this deposit of hemorrhagic and necrotic tumor. So, the patient in this case presented with a pathological fracture of the neck of femur. Uh And on scanning, we found that there is this mass and on histology, the pathologists examined this took some sections and what we saw was uh bowel cancer. Uh Next thing here is we have the liver and what we can see on the surface of the liver are multiple metastatic deposits of bowel cancer. So the patient could present with symptoms related to liver function, deranged liver function. And in fact, we know that uh liver metastases is generally speaking, the most uh ominous and the most common cause of death due to cancer in bowel cancer patient's. So what does bowel cancer or colorectal cancer look like macroscopically as in with the naked eye? So the patient's will often have surgery, uh plus minus chemo and radiotherapy depending on when the cancer is. If the tumor is located really low down in the rectum, the patient will often have radiotherapy externally plus some chemotherapy to shrink the tumor first and then they'll have a resection. But if the tumor is elsewhere, if it's right side and left sided. Then they might have uh, surgery straightaway. And that surgery could either be open abdominal surgery or increasingly and more commonly laproscopic keyhole surgery. So the surgeon will go in laparoscopically if it's not an emergency admission, um, and remove a segment of bowel. And then that segment of bowel can either be attached together in surgery or if that is not possible, then a stoma will be created and then down the line, the patient might have that stoma reversed. Um, so this here is a cecal uh tumor. So, right sided. And we can see here, you have got your exophytic tumor and in the background, you have got a polyp as well. And then this is the rest of the normal bowel. This is a rectal tumor which is ulcerated and bleeding. So, uh, in opposite to the top tumor where you have an exophytic tumor that's growing into the lumen that might produce obstruction. Uh, this tumor is growing more an ulcerated way and it's pushing through the wall of the bowel. This is a sigmoid uh tumor. And you can see on the cross section that the tumor is actually push has invaded through the wall of the bowel and it's actually going into the fat into the serosal surface. And then here there's this round little no nodule here which looks quite suspicious for a metastatic lymph node that is possibly involved by colorectal cancer. But the way to find that out is that the pathologists will take samples from these and examine them down the microscope. And what do we see when we look at bowel cancer down the microscope? So, on this image here on the left, we have normal large bowel mucosa on the life on the left and we have your muscular Aris, uh propria. And then on the right hand side, we can see you've got these islands and nests of invasive adenocarcinoma are pushing and infiltrating into the skeletal, into the muscularis propria. And then what the pathologist does next. After we say that, yes, this looks like bowel cancer, we then grade it. So grading means how much the tumor looks like normal cells. And then we graded from 1 to 31 is well differentiated, two is moderate in the middle and three is poorly differentiated. And the importance of that is that generally speaking, as the tumor becomes higher grade than the prognosis for the patient tends to be worse. So well to moderate differentiated is in this example here, you can see they are malignant glands are back to back and invading, but they still form glands and they still look like glandular structures. Whereas the bottom right hand image, you can see these solid sheets and nests of um cells with very, very little if any glandular formation. So this is poorly differentiated and sometimes we may even need to do additional tests to confirm whether this is actually coming from uh the colon or not. Another important pathological parameter for staging bowel cancer is what we call extramural venous invasion. So, what we are referring here to here are the large extramural vessels that are located in the serosa here, um which normally should be patent. And then you can see here on the left, on the top left hand side, you've got the bowel cancer, it's invading through the muscularis propria. And then these three structures here, these are large extramural veins which basically contain tumour, mbali. So if we see that, then we have to comment on it in the pathology report because extramural venous invasion correlates with distant metastases and specifically metastases to the liver. So if a patient has a stage two or three tumour, but we find extramural invasion at the start and it hasn't spread yet to deliver, then that's a sign that it might spread to deliver. So the patient will get adjuvant chemotherapy or any other treatments needed in order to prevent that likelihood of metastases. The next thing we look at which is quite important are lymph node metastases. So when a bowel, when a segment of bowel is removed, there will be associated lymph nodes in the vicinity of that segment of bowel. So the pathologist will examine all those lymph nodes and then we will have to generate a report where we say how many lymph nodes are involved by metastatic adenocarcinoma of the bowel um and that's important in staging. Uh So the higher the number of involved nodes, the higher the end parameter of TMM staging. And that will stratify the patient's and put them in a category in terms of their prognosis. And whether or not they will need to have chemotherapy after surgery. And then we also have the concept of the apical lymph node. So when we have a segment of bowel that's removed, you will have one lymph node that is the furthest away from the segment of bowel. And that we call the apical lymph node. And it's important for the pathologist to say whether that apical lymph node has tumor in it or not because if there's tumor in the apical node, which is the furthest away from the tumor that also has a poor prognosis and it means that the tumor might spread more distantly. So in a way, if you have three lymph nodes that are involved, they are all very close to the tumour. It's actually better, so to speak than having one lymph node involved that's really far away from the tumor. So how do we stage uh colorectal cancer? We stage it using the TNM system. So tumor note and metastases, but we also used to use Dukes staging an awful lot in the UK and in the US, gradually, we are using it less and less. So Duke's stage A was traditionally considered to be a tumor that is either T one or t to. So, t one tumor goes into the muscularis new cozy, but it doesn't go into the muscularis propria. Whereas A T two tumor goes into the muscularis, appropriate. Uh but neither of these tumor's have lymph node metastases yet. Um So that's your duke stage. A, your duke stage. Uh B has some lymph node metastases to close nodes, but it's uh not going through uh to the serosa. Your duke stage, see, sorry, this should be P T three and two. Here has more involved lymph nodes. So generally speaking, in terms of survival uh for bowel cancer, patient's about 80% of patient's um in the UK or in England at least will survive for one year or more. Uh And about 60% will survive for five years or more. And then the 10 year survival overall is just over 55%. So this has improved. Uh This is as of 2019. This has improved uh due to largely due to advances in bowel cancer screening. So, early diagnosis, early section, advances in surgery, advances in chemotherapy and also advances in molecular stratification of tumor's and targeted therapy. But there's still a lot more work to do. So, pathogenesis of colorectal cancer. So what causes colorectal cancer? And this is where we talked about the adenoma carcinoma sequence. So, adenomas are pre malignant lesions in the bowel, their little polyps that have dysplastic changes or pre malignant changes in them. And we population studies have shown that populations that have higher prevalence of adenomas in their bowels tend to have a higher prevalence of colorectal cancer. So that's one level of evidence. The other level of evidence shows that the distribution of adenoma is comparable to that of colorectal cancer. So at the start of the lecture, when we said that most of the tumor's arise at these sites in the bowel, these tend to be the sites also where you have the most adenomas. So that is another level of evidence that shows that adenomas are pre malignant. Um and then the peak incidence of the number of polyps and two dates, the peak of colorectal cancer by a number of years. So that also shows you that the number of polyps will peak and then at some point, they will then start acquiring more mutational changes and damage, which will potentially then lead to invasive cancer. And then normally, as we saw in that other image just over here, when you have a bowel cancer tumor, you'll normally find one or two polyps kind of right next door to it as well. And finally, we know that in patient's who have certain syndromes, uh that they have a very high likelihood, in fact, almost 100% certainty of developing cancer. So the cancer risk is directly related to the number of adenoma or polyps. So the more polyps or adenoma as a patient has the they're more likely they will develop bowel cancer. And that is why there is a virtual certainty of patient's developing colorectal cancer who have the familial polyposis syndrome or familial adenomatous polyposis syndrome. Jeane F A P. So what is F A P F A P? Uh is an autosomal dominant dominant disorder where patient's will have mutations in the APC gene as an A metis polyposis coli which is a tumor suppressor gene that is located on the long arm of chromosome five. So patient's will have multiple colorectal polyps. As you can see in this image, it's basically the entire bowel is carpeted, as we say, bye, numerous innumerable, hundreds thousands of polyps. Um And at some 0.1 of these will definitely progress to cancer because 100% of all patient's with F A P will develop bowel cancer by the age of 50 unless they have a prophylactic removal of the entire colon. So how, how, how does that translate on a cellular or molecular level? So APC or the adenomatous polyposis coli gene is involved in quite important in regulation of micro tubules but also in cell motility. So, migration and adhesion. So if you look at this image, which is a little bit busy, but you can hopefully see a PC right here. What APC tends to do is that it will bind to be Ticotin in which is a protein and uh part of the wind signaling pathway. So that will activate the wind signaling pathway. Be Ticotin in as a protein is a transcription, excuse me, is a transcription factor. So once a PC binds to it, Byetta Kettunen will move into the nucleus and then it will bind to the D N A and it will facilitate the transcription of downstream signals like cyclin D one fibronectin. And see, Mick and all of these genes are important in cell motility, proliferation and survival. And normally what you have is beta carotene in is normally complex with like a deer in which is an important protein in maintaining that epithelial phenotype and apical basil of polarity. And basically the cells sticking together and forming that nice epithelial membrane. But if you have a mutation in APC, this beta carotene an EKG in complex will get disrupted and be Ticotin in will as a result of its activation and binding with be with A P C will then trans locate and it will move uh into the nucleus and facilitate tumera genesis. So that was F A P, uh which is one mode of hereditary bowel cancer due to a mutation in the APC gene. The other uh mode through which you can have bowel cancer, hereditary bowel cancer in families is what we call HNPCC, which is hereditary nonpolyposis, colorectal cancer. So these patient's will not do, don't, they do not have tons and tons of polyps like F A P patient's do. Um, and this is called Lynch Syndrome. So, Lynch syndrome or HNPCC is autosomal dominant as well and it results in germline mutations in mismatch repair genes. So, mismatch repair is important during DNA replication. These are four genes that are effectively proof reading or editing the D N A as it gets replicated. And if you have a mutation in those genes, then that normal proof reading or editing function is lost, which means that you will have more mutations which then could lead to development of cancer. So, there are four genes which we call the mmr genes or mismatch repair genes. And these are MSH two ML H 1 p.m. S one and PMS too, which are normally paired. Um and then some cells and some organs are susceptible to a second somatic mutation. So the patient, because they have a germline mutation, they're already born with one mutational hit and then they might get a second mutational hit. And these cells are normally in the colon, stomach, bladder and endometrium. So, patient's will not just be susceptible to bowel cancer, but they also have a harsh susceptibility of developing uh stomach, bladder and endometrial cancer. Patient's with HNPCC or Lynch Syndrome tend to have right sided tumor's. They tend to be under the age of 50 as we said. And morphology is normally either Mucinex or signet ring. So when we say Mucinex or signet ring, what that means is that this is what the tumor cells look like down the microscope. Mucinous means that you have these nests of tumor that are swimming in pools of mucin signet ring means that, uh, that the cell looks like a signet ring, which is, I don't have a signet ring. But if you have a ring and you've got that signature at the edge of it, so the nucleus is kind of pushed to the edge because of a blob of mucin in the middle. Why is that important? Because both mucinous signet ring adenocarcinomas tend to have uh more aggressive or, or higher um uh or a poor prognosis. Um Important things to keep in mind here is that you can have patient's who have sporadic bowel cancer, who don't have Lynch syndrome, who have mutations in the Mmr genes about 10 to 15% so that they don't have Lynch Syndrome, but they have Mmr gene mutation. That's number one. Number two is that uh the patient's that we talked about at the start of the lecture when we said you have a large increasing number. Now of patient's with bowel cancer who are under the age of 50 those are not Lynch syndrome. Patient's none of those patient's are, none of them are. So we're not seeing more bowel cancer in younger people because we are seeing more Lynch Syndrome. That that's a different group. Okay. Oh What happens in the adenoma carcinoma uh sequence? Morphologically when you look at the tissue. So if we look at the adenoma carcinoma sequence, it might be, that patient has a normal co along, but they were born with F A P gene, right. So, if they have an F A P gene mutation, they've already got one germline inherited hit. So they've got that first hit of APC gene. Then as they progress, they might have an activation of other tumor suppressor genes or methylation abnormalities. Uh So then they've got their second mutation, once they get their second mutation, then they form that adenoma. And that's when you have proto-oncogene mutations. So then you have additional mutations, loss of cancer suppressor genes, expression of other genes like TP 53 um loss of heterozygosity. So effectively, ultimately, what will happen is that you get these accumulation of genetic mutations and events that ultimately means that you go from a normal colon to a mucosa that's at risk to an adenoma with the polyp with dysplasia in it. And finally, once it, once it tips the balance, you've got far more mutational changes and gross chromosomal abnormalities, then the patient will develop that invasive malignancy. Now, in the mismatch repair side of things, it's different because they don't have the polyps, they don't have the adenomas. Uh they have a different kind of adenoma called cis ulcerated adenomatosis, ulcerative lesion. But also the genes that are involved are different because as we said, in Lynch Syndrome or mismatch repair pathway, uh it's the mmr genes. So again, if a patient has Lynch syndrome, they will be born with one mutation already. Uh and then they might acquire a second mutation, somatic lee or if they're not, they might just accumulate more and more mutations. And then similarly, they have this microsatellite instability. Uh they will develop this is ulcerated adenoma. The gene mutations will accumulate more proliferation, less apoptosis, more cell division, more motility. And then finally, it will turn into an invasive malignancy. So the the reason why this is quite important is because as we said earlier, a lot of these genes that were mentioning, we're not just mentioning the amount of interest were mentioning them because they have a direct effect on the patient's treatment. So for example, the care as gene in bowel cancer, which is important in the E G F R epidermal growth factor receptor signaling pathway is mutated in about 20 to 40% of all bowel cancers. Why is that important? Well, because there is a drug called cetuximab, which is a monoclonal antibody that inhibits the E G F R pathway. And that drug is normally given as a first line treatment to patient's with metastatic bowel cancer to the liver particularly. But if the patient's tumor has a K ras mutation, then they will not respond to sit oximeter because that pathways already constitutive lee activated. So there's no point giving the patient that drug because a it won't do anything for their cancer, it won't shrink it, it won't treat it. But also all you're going to be giving the patient will be more side effects from chemo from that drug. So that's why we nowadays, you know, 20 years ago, we used to have the biopsy or resection and we just looked down the microscope and say yeah, colorectal cancer. But nowadays, we do, we sequence the tumor's. We look at all the genomic changes, we can identify not just to understand the pathway and to give some kind of idea of prognosis. But also because uh they're predictive of how the tumor's might respond to certain kinds of treatment. Another mutation that we talked about with the B raf gene. Uh And as we said, one of the earlier patient's, one of the younger patient with bowel cancer had a beer after gene mutation and that tends to also have a prognostic effect. So be raft mutated tumor's tend to be right sided and they tend to behave more aggressively. Um and they tend not to respond to certain kinds of treatment. Um And then finally, when we talk about the Mmr genes, the Mmr genes are important because you have this, as we said, DNA mismatch repair um changes and microsatellite and stability. But what that means is that these tumors tend to have a high mutation burden and tumors that have a high mutation burden are tend to be the tumors that are more responsive to immunotherapy. So, immunotherapy is the most recent and most exciting change in cancer therapy. So it's not chemo and it's not radiotherapy, immunotherapy. The principle of that is that we stimulate is the stimulation of the immune response by the patient themselves so that the immune system can destroy the cancer cells. But not every patient with cancer, uh will respond to immunotherapy and not even every patient with bowel cancer will have a suitable tumor that is responsive to immunotherapy. So, actually, what we are now increasingly finding in research studies and clinical trials is that in bowel cancer, you can pretty much divide them into two groups, what we call immune hot tumor's and immune cold tumor's. So immune hot tumor's are the ones where they have a hyper mutated uh phenotype. So they will have a lot of uh inflammation, they will have a lot of uh they have mutations in the mmr genes. They might have be wrapped mutations, but they might not. This is somewhat of an area of, of, of, of um of research. But those patients' then you could potentially prescribe immunotherapy. Um The on the other side, you have tumors that we call uh immune cold. So these tend to be the tumor's that have care as mutations and activations of the wind signaling pathway and the MC gene, those tumors tend not to respond very well immunotherapy. And that shows you again why it's important when we diagnose patient's with bowel cancer, that we have a look at the um the immune uh micro environment in the tumor and also the genomic landscape and sequencing of the tumor. So it's not just the mutations and the genes that are important, which is the tumor cells themselves. But it's also the tumor micro environment, which is effectively those normal cells are surrounding the tumor, like lymphocytes like stromal fibroblasts. And these also have a very, very important role in tumor progression and pathogenesis, but also increasingly in the management of of patient's with cancer. So I think that brings us now just to the end of these 45 minutes lecture. So hopefully you found it useful if you have any access to textbooks, I would recommend Underwood's Pathology or Robins basic pathology um for the pathology side of things and Kumar and Clark for basic medicine, there was a really, really good paper. It's a bit old now, nearly 10 years old, but still uh really, really good in the land set. Uh Just an overall review of colorectal cancer uh If you wanted to look at that as well. So that brings me to the end of the lecture. Uh Thank you very much for listening. I can see there have been some questions in the chat. So I'm just going to go through them. So we've got a question um from Dr Addy. Can you do a non radiating uh M R uh should a patient not want an uncomfortable invasive scope nor wish to risk CD radiation and has Crohn's disease? That may preclude wireless camera capsule, endoscopy. Okay. Well, that's a very good question. Um It's a bit of a difficult one for me because it's more to do with um with imaging. The problem with M R would be that you can do an MRI, which is great because they don't have uh radiation exposure, but you will not be able to get all the good planes and seeing areas of med static deposits potentially. So, and the scoping, you can, you can also the scoping is important because it kind of localizes to you where the tumor is exactly. Now with Crohn's disease, um you, you could still have an endoscopy via a camera um without, without, without a capsule. So they could still get an endoscopy if needed the CT stages. So, normally, at least in the UK, the standard for staging colorectal cancer is ct staging chest abdomen and pelvis. Um But I'm sure that if there are contra indications and other modalities like M R would, would be, would be used another question in an elderly hypertensive with vasculopathy who has chronic abdominal purpose of bilateral lower limb pain has been discharged by gastro, would you consider vascular, it's and polar arteries and the dosa? Uh you probably would, but I think it would be difficult for me to answer this question without looking at the entire clinical history of the patient and all the investigations if C E A is normal, but symptoms persist what should you do? So, yeah, generally if it's so, as we said, at the start, not every bowel cancer will have raised pee and not every tumor that has raised DEA is a bowel cancer. So C E A can be helpful, but it's not the be all in there. So if a patient is suspected of having bowel cancer and their C E A is normal, they might still have bowel cancer. So we need to scope do blood tests, do CT scans, do biopsies, do everything else we talked about even if the C E A is normal because they might have a tumor that's not psa creating. See a okay. I think the other two are for feedback link. So I'm not going to click on those. So um if this is it for questions, uh do you have any more questions? If not? Hello. Uh Do you mind if you could just go back to the initial slide where you're showing the moderately differentiated and poorly differentiated? Yes. You just briefly explain that once more, please if you have time. Yes, of course. We are expected to get questions similar to this in Indian clearance exams. Really? Okay. So this is um so on the left hand side, when you have the large image, you've got an image of the bowel on the left side of it, you have normal bowel. So you this is where the normal bowel mucosa is. And then underneath that is the, is the muscularis propria. So you have mucosa, submucosa muscularis mucosy and you have muscular is appropriate. Now, this big mass that is going and invading, um through the muscularis is the tumor. So this is the tumor on low power. And where the arrow is, are these infiltrative nests of tumor going in. So, what you should normally have is this flat base of the mucosa. Whereas what you have here is this kind of infiltrative time, lungs and nests are pushing down and that's not normal. So first of all, you look at that on the low power and you're like, well, this is malignant, it's adenocarcinoma. The next thing you do is when you go to higher power and you try to grade it. So as you say, grading is well moderate or poor and well differentiated is grade one, moderate is great too and poor is grade three. Uh So, well, sometimes you say well to moderate, which is basically between one and two. So the top left, right hand side, one is a well to moderately differentiated tumor. So you can see here you've still got these invasive glands and they're kind of sitting back to back to each other. Um But you can tell they're glands because they've got these ducts, these lumina, yeah, with these rounded structures. So you can look at that sorry, uh medication, no meta metaplasia is different. So, metaplasia is when a cell type changes from one cell to another, displaced, displaced from. It's, yeah. And then dysplasia is what we see in the polyps. So, dysplasia is, you might see this sort of thing at the top, but it hasn't invaded yet. So, once it's invaded, it's not displaced anymore, it's an invasive carcinoma. But dysplasia is what you see in the adenoma and the polyps, but they just haven't breached that basement membrane yet. But once they've gone through that, which is here, then it's invasive and it's carcinoma. So, dysplasia is like a precursor step. So here you still got these invested invasive nests, but they look like glands. They've got doctor structures. Um, so you can still call this well to moderately differentiated. But grading I have to say is very subjective and it changes and different pathologists will not always great things in the same way. So, although we teach it, it's not 100% all the time. And the bottom one is what we call poorly differentiated because basically what you have got, um, if you compare it to the top one is you've just got lots and lots and more of these malignant glands that are back to back, back to back there, there's not any space between them. And if you're trying to look for these ductile structures that you found here, you're not really seeing them. I mean, you might find the odd one here or there, but you're not really seeing that much positive evidence of glandular differentiation. So that means it's poorly differentiated because it's gone a bit further down the line and it's more histologically aggressive. So just to go back to metaplasia, for example. So one example of metaplasia is when respiratory epithelium in the lung changes from pseudostratified Columbia to stratified squamous in patient's who smoke. So normally normal lung, epithelium is respiratory type with goblet cells because it's therefore I on gas exchange. But when patient smoke, smoking is harsh for the lungs. So the the the epithelium has to change and reinvent itself somehow. So what it does is it changes from one type to another. So that doesn't mean it's cancer and it doesn't mean it's pre cancerous. It just means it's changed from respiratory to squamous, for example. Okay. Um Yes, no problem. You're welcome. Ok. So I think that brings us to the end. I'm going to stop share ng. Um In fact, I'm not sure how to sorry. I'm not a zoom. Oh, there is uh stop video. Know that. Stop video, not stop sharing. Paul's share. Okay. Okay. So uh yeah, that brings us to the end of the lecture. Um Thank you all very much for um attending um handed. Would you like me to stop the recording?