This on-demand teaching session is an opportunity for medical professionals to learn key concepts relevant to the MRCS examinations in pathology. In part one, Dr John Griffin’s prerecorded slides will provide an introduction to key concepts in urological pathology.
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Learning objectives

1. Explain the key differences between Gleason pattern 3 and 4 in prostate cancer. 2. Analyse various scenarios and be able to group them with the Gleason score and grade group approach. 3. Discuss the ways in which histological grading is used to diagnose prostate cancer. 4. Describe the commonalities and differences between biopsy, TURP, and radical prostatectomy specimens. 5. Explain the concept of Cambridge prognostic groups and their role in clinical decision-making.
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The following transcript was generated automatically from the content and has not been checked or corrected manually.

Good evening everyone. Thank you for joining us tonight. This will be part one of the asset essential pathology for surgeons. Um We are joined this evening by members of the Pathological Society who kindly agreed to give up their time to teach us key concepts in pathology, which will be particularly relevant for the MRCS examinations. And tonight, we'll be joined by Dr John Griffin, who will be giving us his prerecorded slides on key concepts in urology will then be followed by Doctor Amanda Hilton. He'll be running through some cardiothoracic pathology. And alongside this, we also have Doctor Ali uh visit India who will be facilitating the questions. So if people have questions throughout the talk, feel free to pop in the chat box, we'll try to get to as many of the questions as you can throughout the evening. If there's any questions that we can answer throughout the talks, we can either answer them at the end or you might be provided with an email link to them to email us your questions. And the first talk will be about 15 minutes before we move on to the second part of the series. And at the end of the talk or rather at the end of the three days, you'll be given a link for feedback. And once that feedback is completed, we can give you a certificate for your portfolio. And thank you in advance to sue for Medal who's given up her time this evening as well to help ensure the smooth running of the talk. And without further do, I'll hand over to Doctor John Griffin's prerecorded slides and I hope that you find this evening useful. Good evening. My name's John Griffin unless T four in his day pathology. And I'm going to be talking about your a pathology for mrcs. I did the MRCS exam about 10 years ago before moving across the pathology. I have some idea of the sorts of topics that turn up and the sorts of questions that get asked. Um I'm aiming to cover the four common types of cancers that we see in neuropathology. Um And for each of these cancer types, I'm going to introduce things like staging and grading talk about some of the common entities that we see and also some of the less common entities so that you have things that you can go away and read about in your own time if you want to. So we'll dive straight in with prostate cancer. Um This is the second commonest cause of male cancer death according to cancer research UK statistics, the key molecular event to be aware of here is that Andrew in signaling is the main driver of prostate cancer. And that applies both in the initiation of prostate cancer and also in the setting of treatment resistance when patients become resistant to things like cancer and decoration therapy. Um Andrian signaling pathways are actually upregulated in medical school. We were taught that prostate cancer is this range of disease. Um from being very indolent cancer, that patient's die with a rapidly progressive metastatic cancer. So, cancer, the patient's die of and that's backed up by large autopsy studies that show that roughly 50% of men um in their seventies and eighties. Um if they have an autopsy, clinically indolent prostate cancer can be found. Um and this may not have been anything that was known about in life. So what's really important is that we have a way of picking those patients who are going to benefit the most from therapy and follow up without overtreating people. Um Gleason grading is really central to all of that. So why should we bother with Gleason grading? Well, what we've got here is a Kaplan Meier plot. I'm going to just talk you through it. So the side here, we have the risk of recurrence free progression after prostatectomy. And then along the bottom here, the years since surgery and what we done here is patient's are grouped by their grade group and I'm going to explain what that means a bit more in a moment, but essentially grade group one is very low grade cancer. And grade group five down here is very high grade cancer. And you can see how this histological grouping of patient's gives you really good splits between these groups as being able to predict which patient's are going to do well and which you're going to do poorly after surgery. And this is based on a really large, really large cohort. You can have a look at the numbers that risk down here. Um And that shows that we've got really good statistical power here to show that Gleason grading and this um more recently described grade group approach is really important. I'm going to go into a bit more detail now about what Gleason grading is. So it's a histopathological grade. So it's great that I as a pathologist can give looking down the microscope, usually at prostate core biopsies in the first instance, but also at prostatectomy specimens. And it's based on the architectural pattern, tumor growth. And what that means is it's the sort of structures that the normal or the sorry, the near plastic prostate glands are forming. Um So the first thing that we look at is these different architectural patterns and we can assign those patterns a number. And this is based on the original system that was developed by Donald Gleason in 1962. And I'd recommend reading about the history in the development of this just to see what a successful Histological biomarker looks like. Um So these days, we only assigned pattern 34 or 52, Toomer's and then we take the two most common patterns and add them together. And that gives us a Gleason score. So three plus four equals seven is different from four plus three equals seven. Even though there's the same final number at the end here, in this first case, here were implying that the patient has um a higher proportion of low grade cancer and then a smaller proportion of higher grade cancer. This comes together in a score of seven. Whereas the reverse is true. Um in this second score here, now, it was recognized that this can be confusing for patients and clinicians, particularly as this is apparently a score that's out of 10 from patient's were saying, well, I've got a score that's already seven out of 10. Isn't that pretty bad when actually, that's probably at the lower risk end of the spectrum. And also that seven out of 10 can mean two different things because these two um types of prostate cancer, three plus four versus four plus three can be treated quite differently. So recently, we've started grouping those scores into grade groups and this relates to the slide that I was showing before. So we have great group one all the way down to grade group five. And depending on what combination of Gleason patterns are seen and how they come together in a Gleason score that those are then grouped into grade groups which are then used to guide treatment and follow up decisions. Now, I'm going to talk a bit more about architectural patterns and what that means. Another way of thinking about this is how well does the tumor that we're seeing down the microscope form glands? The prostate is normally a glandular organ. And so the tumor is that arise from it are typically glandular tumors or adenocarcinoma. These are all examples of Gleason pattern three tumors. So the things that characterize that are having these well formed glands that are easy to identify as glandular spaces. They're medium sized, they have this open lumen. So that's this white area in the middle here and you can still see the intervening stroma around the outside. And that's the pink stuff that's in between the glands here and here. The other thing to notice here is that these all look roughly similar one compared to the other moving on to gleason pattern floor. And these are four examples of what that looks like. This is characterized by these poorly formed glands. So this team is still trying to form glands. We can see these white spaces here in this example at the top, but it's not nearly as well defined as gleason pattern. Three. Um So poorly form glands is the kind of hallmark of this pattern glands that are fused together. So that's what we're seeing on the bottom right here as well. Where lots of these tumor glands have just kind of started to merge into one another. And then over on the left hand side here, some of these are forming little aggregates of cells, but they're not doing a very good job of having a glandular space in the middle. And then the final pattern for Gleason pattern for is this cribriform or civil like architecture, which is what we're seeing up from the top right here where malignant glands have fused together as they've grown. And finally, this is Gleason pattern five. And we can see here that these cells are just sheets that have permeated their way through the prostate gland and not making any attempts at forming normal glands at all. So this idea of sheets of cells and also single cells that are wandering off on their own into the stroma are all hallmarks of gleason pattern. Five. The final thing to mention here is that collections of malignant cells like this with necrosis also makes these um gleason pattern five. So that's another feature that we can see down the microscope and that's this pink stuff in the middle here. Um is the middle of these collections of neoplastic cells that have died and that's the crosis and the great groups and Gleason grading all get brought together um as a core part of clinical decision making. So I'd very much recommend reading um this guideline from the National Institute for Health and Care Excellence it's available freely online. Um And it's got those of really good information about how clinical decisions are made in prostate cancer based on various risk factors. Um The key takeaway from this for me is this idea of the Cambridge prognostic groups, which groups patient's the prostate cancer into one of five groups and then suggests various different management pathways according to that, the Gleason score and the Gleason score based grade groups are one of the core elements of that together with imaging such as MRI um prostate specific antigen levels. But this last part of the prostate cancer section, I just want to move away from Gleason grading a little bit and talk about radical prostatectomies. So we typically see prostate specimens in one of three forms in pathology. We see biopsies. Um we see transurethral resection of prostate um specimens and we see radical prostatectomy specimens. So in a radical prostatectomy, there are lots of different bits of pathology data that we're looking for. But the three main pieces are firstly looking to confirm the grade of cancer and there certainly are some cancers that are upgraded when we look at all of the chamber in the radical prostatectomy because obviously, the biopsy is only looking at a sample of that tumor. Uh Secondly, we're looking for evidence of extraprostatic extension of the tumor and that would upstage a otherwise confined tumor to P T three A R P T three B. And that's what this picture on the right shows. So the black dotted line here represents the boundary where the normal prostate ends. And then this white area over here, this is um fat and then the pink bits in between the muscle fibers. And this represents the uh external tissue to the prostate. So these malignant glands here representative of invasion of fat and extraprostatic extension. This will be graded as P T three A. Um The final thing that we look at with prostatectomy specimens is whether or not the margin, so the surgical margin is involved or not. And there's, there's different rules for doing that uh depending on where the margin involvement is. And if you want to know more about that, I'd recommend looking at the Royal College of Pathologists data set for prostate specimens. So, what I didn't mention at the beginning is that after each of these four subsections, I've got a couple of practice questions which I've tried to write in the style of the MRCS. Um So this is the first one for prostate. Um And the question is what histological feature is used in Gleason grading of, of prostate cancer. Um So we have a nuclear pleomorphic is um which means variation in nuclear shape and size, be invasion of paraprosthetic fact, see stromal cellularity d the pattern and planned formation or e number of mitosis. Gonna wait just a few seconds for everyone to have a quick think about that. Think what you would could. And the answer is the pattern of gland formation. So they've asked about Gleason grading specifically here. All of these features can be important when we're talking about prostate cancer from a histological point of view. But the key feature for grading is the pattern of gland formation. So well, then if you got that right, and we'll move on to the next question. And this time we have a question about staging. Um So which histological feature indicates PT three, a prostate cancer. Um And we've got five options. A two e invasion of paraprosthetic fat, invasion of the bladder metastases to local or regional lymph nodes, metastases to the liver or a Gleason score of four plus five equals nine, which would be a great group, five tumor. So very high grade prostate cancer and the answer to this one is invasion of peri prosthetic fat. Um In terms of the other options, invasion of the bladder is taken into account in prostate cancer staging, but that councils an adjacent organs. So that would be P T four. Um Metastases, obviously part of the tumor node metastases classification, but they don't affect the T stage. And the Gleason score itself isn't used for staging, but these high grade cancers often do have a higher stage than the lower grade cancers. Next, we're going to move on to bladder cancer. So the majority of bladder cancer is your ethereal cell carcinoma. This was previously known as transitional cell carcinoma and you might still see that no mentality used in some textbooks. Um And broadly, we divide bladder cancer into two clinical and histological groups. So, non muscle invasive bladder cancer and muscle invasive bladder cancer. First of all, I'm going to talk about non muscle invasive bladder cancer. This represents about 80% of bladder cancer cases. Um So it's by far the more common one of the two clinical types. Um and it's a very expensive malignancy to treat. And the reason for that because this is characterized by cancer recurrence and repeated need for surveillance and treatments such as transurethral resection of that tumor and introvert cycle B C G. Um Now, as invasive bladder cancer often has a papillary growth pattern. And I'm going to show you some slides in a second as to what that looks like. Blood cancer is a bit odd in the way that it's staged because it has this PT A stage. And what that means is that the cancer hasn't invaded at all into the layers below the epithelium. And it's just involving the epithelium itself yet. It's still assigned a stage. Um Non muscle invasive bladder cancer can either be superficial and have this PT A stage or it can invade the lamina propria, which is the layer just below the epithelium. At which point we call it P T one separate from staging. Um We can grade muscle invasive bladder cancer as either being low grade or high grade as well. And the key molecular event to be aware of here is that a lot of non muscle invasive bladder cancer is associated mutations in the F G F R three gene on this side. I'm just trying to explain the difference between P T A and PT one bladder cancer. So, the neoplastic cells of this purple line running on the top here and you can see how improv pillory tumor's. The epithelium is kind of heaped up into these finger like projections. And there are blood vessels running up the middle of these projections in a PT A tumor, neoplastic cells are just confined to the epithelium here. Um You can see in a PT one tumor here, you have these neoplastic cells. It's looks papillary, but then there are these little blobs of tumor that's starting to invade the lamb inappropriate. And if they're invading that area there, they've then got access to the blood vessels and the blood supply. So this is a higher stage tumor. So here's what that looks like on a histological slide. So each of these here is one of those papillary finger like projections that I was talking about. And this correlates quite nicely with what you see at cystoscopy because often these things are described as being frowned like. Um so running up the middle here, that's a blood vessel. We've got the same here, the same over here. And then the urethral carcinoma cells are all of these sitting on the outside of this. Um The reason this happens is because these have grown faster than the surrounding epithelium. And so they all kind of move upwards and it forms them into these, these papillary projections. Um all of this pink area that we can see under here, this is lamb inappropriate um and zooming in a little bit more over here, this gives you an idea as to how we grade um tumor's like this. And we're looking at things like the thickness of the epithelium away from where the papillary court is. And also looking at the variation in the shape and size of the nuclear. And you can see here, there are some of these nuclei that look quite large and dark like these ones here, compare those to the nuclear over here, which are a bit smaller. This is nuclear, clear, more phys. Um And that's one of the features of a higher grade tumor. We'll move on to talk about muscle invasive bladder cancer now. Um so muscle invasive bladder cancer either arises from carcinoma in psyche. And I'm going to go into that in a bit more detail and the two slides after this one um or it can occur from non muscle invasive bladder cancer that's progressed. Um So in non muscle invasive bladder cancer, there's somewhere between five and 20% chance of progression and things like a higher grade or higher stage tumour or a patient who has multiple tumours, um is at a higher risk of that non muscle invasive bladder cancer becoming muscle invasive. But the thing to take away from this is the majority of Muslim base of bladder cancer doesn't actually have non muscle invasive bladder cancer before it it arises from carcinoma insight to instead. And that's one of the reasons that we tend to think of these two things as separate diseases. Um As soon as the cancer has invaded into the detrusor muscle, um that's PT to at least by definition, that's the definition of PT too. Um And this has a far worse prognosis than Muslim basic bladder cancer. Um and is prone to uh lymphatic spread and early recurrence even with uh cystectomy and quite aggressive treatment. So, what we can see in the slide on this side is that we've got these pink muscle bundles, that's what these are here. And then in between uh the cells that are malignant and they're kind of permeating their way between the muscle bundles and these are urethral carcinoma cells that are just spreading through the bladder wall. So now let's talk a little bit about C I S. So that stands for carcinoma in psyche. And the key thing with C I S is that it is a flat lesion. So, cystoscopically, this doesn't tend to form those front like papillary structures. Um Sometimes you may not see anything at all. Cystoscopically, sometimes you can see kind of velvety appearance to the inside of the bladder, which gives a hint that this is hit. The next thing to know about CVS is that it's a high grade lesion. So there isn't a low grade and high grade C I S. If we see sightsee I s by definition, that's high grade. Um on its own, it's not muscle invasive, but it is thought to be the main precursor for Muslim base of bladder cancer in the cystectomy. Um if we find some muscle invasive bladder cancer, often nearby and elsewhere in the bladder, we will find C I S. And if you just sample areas of C I S and look at the gene expression profile or their mutational changes, those are often the same or very similar to the corresponding Muslim basic bladder cancer in that patient. And this is what it looks like morphologically. So over on the right here, we have normal urothelium. Um this area at the bottom islam inappropriate. And then this area here is the epithelium and we can see that the normal urothelium is very organized. It has an organized structure. There are these basal cells all lined up along the bottom here with the nuclei pointing upwards towards the lumen of the bladder, which is up here and then these gradually mature until we get these much larger cells over the top, which are called umbrella cells. And they cover numerous smaller cells underneath them. And that's so as the bladder expands and contracts you can maintain an impermeable barrier. Now, if you look over on the left here for cast member, insight you or C I S, these are just two examples. You can see that, that normal relationship between the cells is lost on the top. Here, you can see how there's no real difference in how the cells look between the top and the bottom there quite jumbled up. They're a lot darker there, nucleus is a lot larger. Um And the chromosome pattern within the nucleus itself looks more disorganized and these are all features of sis and then down at the bottom here, we see just a slightly different pattern of that where it looks like we've got fewer cells, there's maybe just one or two layers of cells hanging on here, but each of those cells is very dark, we call that hyperchromasia. Um And the nuclei themselves are much larger in comparison as a kind of proportion of the whole cell. Often in this sort of situation, the next bit of epithelium along may well have nothing attached to it at all. And that's because these cells are quite fragile and fall off easily. Um And it's these cells that we're looking for often when we do urine cytology, looking to follow up cases of bladder cancer. The final thing that I'm going to cover in this bladder section is squamous cell carcinoma. Um So this is separate from your a thelial sell cast namer. We see about 5% of our cases um S CCS. Um but that's a lot higher in areas with endemic schistosomiasis. So, about 30% of bladder cancer in those areas is squamous cell carcinoma. And, and this is the kind of classic risk factor um for this cancer. Other risk factors include things like um chronic inflammation, a bladder that's chronically irritated by stones, a neurogenic bladder. So one that isn't emptying properly and also smoking is a risk factor for cancer in general. And the other thing to say here is that confusingly, your ethereal cell carcinoma can differentiate and look like squamous cell carcinoma under the microscope. So for us to give a diagnosis of squamous cell carcinoma in the bladder, it has to be purely that cancer type and us not see any urethra viel type. This is what squamous cell carcinoma looks like under the microscope. So hopefully, you can see that this looks different from the um you're a thelial cancers we were looking at before. There's no real papillary formations here. It's just got these large islands of cells which invades deeply into the bladder wall. Um This looks a lot pink in than what we were seeing before. And that's because each of these cells here is making keratin. So they're keratinized, which is one of the features of squamous cell carcinoma. And the other thing to mention here is that this is often widely invasive at presentation and has a poorer prognosis than your thelial sold cast amendment. So we move on to our practice questions. Um This is what we've just covered. So which infection is commonly associated with squamous cell carcinoma of the bladder? We've got five options. H pylori HPV Justice mice is human herpes virus, eight, an Epstein Barr virus. And the answer is schistosomiasis. All of these five options here are viruses or infections that can cause cancer in humans. Um So if you haven't come across the cancers that are related to all of those, that is worth a look. And then our next question is this one. So if pathology report describes a papillary, urethral carcinoma confined to the epithelium brackets pt A know carcinoma in situ A see which gene is most likely to be mutated. We've got again, five options. P 53 Smarck be one C, Mike M D M one and FGFR three. And our answer is E so this is describing papillary. You see, see um as we know FGFR three is more likely to be mutated in those cancers in muscle invasive bladder cancer, coming from A C I S type pathway. P 53 is more likely to be mutated. And the other genes that here, Smarck be one C, Mike and M D M one are all associated with other human tumour. So again, things for you to go away and look up if you want to. So that's everything I'm going to talk about for bladder cancer and now we're going to move on to kidney cancer. So, from a pathologist point of view, kidney cancer can be quite challenging. And one of the reasons for that is because there are more than 30 distinct histological tumor types um that are defined in the kidney. Um, now, somewhere between two thirds and three quarters of these are clear cell renal cell carcinoma. So that's by far and away, the commonest tumor that we see in the kidney. Um Then these two papillary renal cell carcinoma, and chromophobe renal cell carcinoma take up quite a lot of the rest. And then about 10 to 15% are rare tumor types. So these can be difficult to diagnose. Um Some of them are defined by certain mutations or transportations. Um And every year, there are more of these described as we get better at drilling down into what tumor types there are. Now, I'm going to only talk about clear cell renal cell carcinoma today. Um There's a lot of good basic science to do with this tumor. And the key molecular event in clear cell RCC is this loss of the von Hippel Lindau gene which some chromosome three p. So normally you have, hey, if one alpha here. So that's hypoxic inducible factor, one alpha. Um And this is normally kept in check by this or degradation reaction. So it's here in the cytoplasm. It has an O H group added to it by this phd enzyme that then um brings VHL or the von Hippel lindau gene on which as ubiquity into this gene. And that targets it for a breakdown of that protein by the protease own. And that's the main way that the cell keeps the levels of hip on alpha in check. Now, obviously, if there's hypoxia, then hip on alpha moves to the nucleus taxes to chroma seen and it transcribes lots of these hypoxia inducible genes, things like veg F E P O transforming growth factor alpha. And these are all things that help normal tissues grow or repair themselves after hypoxia. Now, in Von Hippel Lindau syndrome and also in lots of sporadic clear cell RCC, there's this loss of the gene or the area of the chromosome has that gene on it. So VHL is lost this bit here doesn't happen. So you end up with a build up of hip on alpha in the size plasm and more of that's going to move into the nucleus by chance and then you then have transcription of these genes but in the absence of hypoxia. So in normal csic conditions, and that's what then allows these cells to transform to grow without an appropriate stimulus and also to recruit things like blood vessels through veg F and under the microscope. This is what clear cell renal cell carcinoma looks like. So these cells here are the neo plastic ones and you can see where this gets its name from because these cells are optically clear. So the cytoplasm looks white, the nuclear iron in the middle here. And they're quite sort of largely describe them as political type cells and their groups into these little aggregates and surrounding these aggregates is this very delicate and a fiber vascular network. Now, in the middle here, you can see some red blood cells inside this vessel here, there's one here but each of these aggregates is surrounded by blood vessels. And that makes sense from the previous slide. So if these cells here have lost their Von Hippel Lindau gene, there's more hip on alpha, they're going to be recruiting um blood vessel formation through things like veg F. And that's one of the ways that this tumor adapts and survives. So this is a very vascular tumor that's obvious on CT and obviously, and sometimes this tumor can be hemorrhagic when we cut into it. A sampling it. And aside from deciding that tumor is clear cell renal cell carcinoma. One of the important things we do is pathologists is grade this tumor and are grading is based on some rules or a grading system um set out by the World Health Organization and the International Society for Urological Pathology. So that's what I said stands for up here. I'm not going to go into the money share of what each grade means, but it's a grading system from 1 to 4 with one being the lowest grade for being the highest grade. And the main factor that we use is it's based on how easy it is to see the nuclear lists in those cells. So the nucleolus is where these cells are transcribing ribosome all RNA. So it's a kind of surrogate marker as to how many rivers owns this cell needs. And higher grade cells are going to be turning over more proteins, they're going to be more ribosomes. And that's why we see a larger nucleolus. We can see on this example, over on the left, this is a great one tumor. It's quite hard to see the new clothes inside the cells here. The chromatin all looks quite even. And over here where I put these red arrows, hopefully you can see there's a little dot inside each of these nuclei. It's one down here as well. And that's the prominent nucleolus of a grade two or grade three type tumor. I'm going to briefly touch on staging here. Um So staging is based on a number of different factors. The size of the tumor, whether or not the vessels in the highland, the kidney are invaded by tumor, whether or not the renal sinus and the fat surrounding that is invaded, whether or not the fat around the outside of the kidneys, the perinephric fats invaded and also whether or not the tumor involves the adrenal planned. Um There's a really good explanation of this in the Royal College data set for renal cell carcinoma. Um So I'd recommend looking that up. And finally, I'm just going to mention how we use this histological information and how clinicians use it. Um So this can be combined. So the stage, the grade and also whether or not we've seen necrosis in that tumor under the microscope, these can be combined using something called the mayo clinic score. Um and this group's renal cell carcinoma patient's into low medium and high risk. And then that's used amongst other things to guide the frequency of surveillance CT after radical nephrectomy. Um renal cell carcinoma is one of these cancers that can have a very late recurrences. So patient's followed up for a long time and it's maybe not uncommon to see a recurrence five or 10 years after an initial curative operation. So let's move on to our practice questions. So our first one, which histological feature is used to grade clear cell renal cell carcinoma. And we've got five options here. Mitotic counts, the presence of necrosis, the proportion of tumor with papillary morphology, clear cell renal cell carcinoma is always low grade or the size of the nuclear lists. And the right answer is option. E um So it's predominantly the size of the nuclear list that we use to grade clear cell renal cell carcinoma. Um Some of these others are important in other tumors. Things like mitotic county is important in Melanoma. The presence of necrosis is important in um renal cell carcinoma, but it doesn't affect the grading. Um And option D is just clearly wrong. There can be um any many different grades of clear. So renal cell carcinoma and that's the reason why doing this accurately is important. And our next question uh in clear. So, renal cell carcinoma and the VHL gene is commonly lost through deletion of chromosome three P. What's the consequence of this genetic event? Um This is one of these questions where they're expecting you to do part of the answer in your head. Um And the answer is a so expression of growth factors such as veg F and transforming growth factor A. Um And this is going back to that first slide that I showed of the molecular biology behind BHL loss. Um and then the translocation to the nucleus and the expression of these factors. Um The rest of these answers are obviously all wrong. As far as I'm aware, the morphology isn't determined specifically by the underlying molecular alterations. Um And regardless of that clear cell renal cell carcinoma doesn't tend to have papillary morphology. Um It's a decrease in ubiquity nation of Heffron alpha. That's the underlying problem here. Uh Sarcomatoid morphology is something that we look for in clear cell renal cell carcinoma. But again, it's not really related to the underlying loss of the V H L G. Um And again, as far as I'm aware, there isn't an association between VHL G and lost an increased, likely the late metastasis. This is just something that is common to renal cell carcinoma as a disease entity. And now we're going to move on to our final topic, which is testes cancer. There are lots of different types of testes tumor's. Um And the way to classify them is how I've laid it out on the slide here and this is related to which cells they arise from. So you have testes, tumor's that arise arise from germ cells. And the germ cells are these cirrhotics sites which mature into spermatozoa and eventually um spermicides and this gives rise to two subgroups. So of the germ cells, humans, you have those that are related to germ cell near plays a insight G or G C N I S. Um And that's tumors, things like seminoma embryonal cast member and the others in this list here. And then there are tumors that are not related to G C N I S. And the main one that I'm going to talk about here is spermatid citic tumor. So that's the group of germ cell tumors. There's then tumors that can arise from the supporting cells. So, the supporting cells are called sex cord stromal tumors. Um And two of the communist of these are Leydig cell tumors which arise from the Leydig cells which sit in the interstitium here. Um And they are a sight of androgen synthesis um or so Tony cells which sit here in the tubules which sort of support the psoriasis sites as they mature into sperm. It, it's, and then within the testes, there's a lot of other tumors that can happen as well. Um, lymphoma can affect the testes. There can be um sarcoma that involves the testes. Uh and it's a site that cancers can metastasize to as well. So for most of this topic, I'm just going to talk about germ cell tumors. So germ cell tumor is the commonest cancer in young men, say men from 15 to 45 years. Uh but in spite of that, they have a high cure rate. So approximately 90% um these tumors typically, if they do metastasize metastasize to para-aortic nodes. And that's a common anatomy embryology type question. And, and the reason for that is because the test is normally develop next to where the paraglottic nodes are and then traveled down um into the scrotum by the gubernaculum. Uh There are some risk factors for germ cell tumor. So, cryptorchidism a previous germ cell tumor predisposes you to another germ cell tumor. There is um some association with family history and there's some evidence out there that testicular trauma, may them predispose you to germ cell tumor development. So to start with, I'm going to talk about this group of germ cell tumors that arise from germ cell neoplasia in psyche. So, this slide that we've got here shows two different populations of um tubules within the testes Now, the tubules that looks like this and this and this, hopefully, they look similar to the uh normal tubules that I was showing before where we've got this kind of maturation of Sparta sites and then spermatid in the lumen of the tubal here. But then next to these, we have these other tubules that have this thicker kind of pink connective tissue around the outside and then the cells inside look very different. So we don't have any of this maturation much bigger. And the nuclei are kind of larger and more hipaa chromatic, more variable cell to cell. So this is germ cell neoplasia in psyche. These are um these are germ cells that have acquired certain mutations to then give them the potential to become a germ cell tumor. Um And these are the five common types of tumors that arise from G C and I S. Um seminoma, probably the most common um teratoma yolk sac Touma embryo know carcinoma and Corio cast namer. The thing to say is that often a germ cell tumor is a mixture of one or more sorry, two or more of these different tumor types. Um The key molecular event to remember here is that germ cell tumor is defined by an ice A chromosome 12 P. Um So that's a duplication of the short arm of uh chromosome 12. So you end up with the chromosome 12, too short arms essentially. Um And we can use this diagnostically when we're not sure if we have any germ cell tumor is in a particular tumor that we're seeing. Um for whatever reason we can then use presence in situ hybridization to detect if we have ice a creams M 12 P. And if we do that can be a really useful marker for sending us down the right path in diagnosing these tumors. This is what seminoma looks like under the microscope. You can see that the neoplastic cells here, which are these, these cells here over here look a lot like what we were seeing inside that germ cell neoplasia in psyche. Um And that's because it's the same stuff, it's just become invasive into the rest of the testes. Um So these cells have clear cytoplasm, they've got these quite kind of bland nuclei and the nuclei and the cells don't tend to overlap that much, which seems like a really small detail, but it'll be important when we come to talk about the next tumor. They also have this vascular network that separates out individual aggregates of cells. And then within this and actually through the tumor itself are these darker smaller cells that we can see these here and these are lymphocytes. And that's one of the kind of key features of seminoma. And as a contrast, this is what embryo nulle cast number looks like. So this is another germ cell tumor that arises from germ cell neoplasia in psyche, but it looks a lot different from the seminoma case that we saw on the slide before. And so the first thing to note here is that there's this large area of necrosis over here that's quite common in embryo carcinoma. And then the cells are much more pleomorphic. So for a start, there's not so much of this clear size plasm, we're seeing mitosis. So this is a mitotic figure up here. That's the cell that's dividing and then the nuclei are much more pleomorphic than what we were seeing before. There's much more variability, quite a lot darker and in places these cells emerging into each other and overlapping. Um Now, all of the germ cell tumor can form different sorts of patterns, embryonal carcinoma can form things that look like glands, which is what we're seeing here and can also form solid areas where the tumor cells merge into one another. Next, I'm going to talk about germ cell tumors don't arise from germ cell neoplasia in psyche. Uh The only one I'm going to talk about is spermatid citic Touma. So, in some older textbooks, you'll see this called Spermatid Citic Seminoma. Uh that's a misnomer. It's not called that anymore. And the reason that was changed is to reflect the fact that this doesn't come from the same lineage that seminoma comes from it or it doesn't come about by the same process. So it's normocytic Jima, it's different clinically. So it occurs more commonly in older men. Um has a very indolent disease course, you're not going to find germs only a phaser insight you in the background of these tumors. Um And reflecting that we're not going to see isochromosome 12 P and it shows some similarities with seminoma. So you can see that there are some clear cells in here. But the kind of classic pathological feature of this is that there are three cell types, um small, medium and large sized cells. Um and the large size cells like these cells down here have this kind of dottie chromatin pattern, which is called Spiriva um Chrome A tin. Um You could see how if you had one of these tumors and it was composed mostly of these clear cells, maybe it would be um confused with seminoma. Um And there's various techniques we can use to help us out with that in history. Chemistry is one and for essence, in such a hybridization for this isochromosome 12 P is another and this is how we stage germ cell tumors. Um So invasion of vascular spaces around where the tumor is that bumps us up to a PT to tumor. And also knowing the different layers of protesters is really important for staging these because the invasion into the tunica vaginally is another pt to feature. We also focus quite heavily on where the ricci testes is and where the testes joins this dramatic cord. Because invasion in that sort of region makes actually quite a high stage tumor because there's more access to blood vessels there. And lymphatics are a greater chance of, of spread. Um And then the final two interesting things about staging germ cell tumors. The first is that direct extension into the cirrhotic cord is staged under the T part of the TNM classification. But if we find separate tumor further up the spermatic cord, that's discontinuous with the main tumor that actually counts for the metastasis. And so that's going to be an overall cancer stage, which is a lot higher. And the last thing to mention is that this is one of or maybe the only staging system where serum markers are used as part of the staging as well. So, serum markers like A L D H HCG and AFP are usually measured in these patient's um and different types of the germ cell tumors secrete different of these markers. And those are used as part of the staging to help inform follow up and treatment decisions. At the start of this section, I mentioned sex cord stromal tumors as a separate category of Chima. I'm just going to talk about one of them here, which is the commonest type, which is a Lady XL Chima. Um So, Leydig cells are normally responsible for screening hormones, particularly androgens like testosterone. Um and the presence of a Lady XL tumor can manifest in lots of different ways because Leydig cell tumors can also secrete things like estrogen. These can present things like kind of dumb ass to decrease spermatid genesis. Um These are usually benign uh and removing them by architect Ammi is curative. So this slide that we've got down here shows Leydig cells. So these are quite large political pink cells and normally you see one or two or very small aggregates of these dotted around in between the seminiferous tubules. But what happens in a Leydig cell tumor is that you get a much larger aggregate of these cells growing, moving on to our final practice questions. I've tried to phrase this one. Like some of the MRCS questions are phrased where there's a clinical scenario. So you performed an orchidectomy on a 77 year old man. The pathology report states that the mass is a spermatocyte eczema. What is the relationship between this tumor and germ cell neoplasia in psyche GCN I S? So I'll give you a second just to read the options and the answer for this one is a so, soma statistics um does not arise from G C N I S as for the other options. Uh This second one about some a specific GM A arising um only in the presence of ice cream 12 P as incorrect ice creams. Um 12 P is the defining event for G C N I S. Um GCMS isn't any sort of precursor to spot acidic tumor for option D. Um cryptorchid testes are a uh risk factor for um germ cell tumors. But the present evidence of GCN ice doesn't make a difference. And this last one is about serum alpha feta protein levels. And those are typically raised in yolk sac tumor, which is one of the G C N I S related tumor's. And our final practice question is this one which lymph node basin does some innate that most commonly metastasized to common iliac obturator para-aortic axillary or E seminary does not metastasize. Um Certainly Seminoma can metastasize. And you remember from embryology and that's me that the test is developing the para-aortic regions and that's where they're draining lymph nodes are. So this is where we commonly see, ok, options see, we commonly see um metastasis of lots of these tumors from the testes. And that's the end of my talk. Thanks for listening, apologies that I couldn't deliver this live and that I can't answer questions afterwards. Um As for general pathology resources, Robbins pathologic basis of disease is pretty much the standard textbook for this. Um I'd recommend looking at things like the European Association of Urology and nice guidelines. And also the Royal College of Pathologists has data sets which inform how we as pathologists um look at and report all of the specimens that I've spoken about today. And indeed, in other cancer types, in terms of some online resources, pathology outlines and web pathology are both really good for kind of snapshots of information about pathology and also um some slides with annotations. And for anyone that's more interested in histopathology training or wanting to get into his to pathology, I'd recommend this website, the bottom histopathology training dot org about the career pathway and seeing as I've got a few minutes left, I just wanted to add some general advice about making the best use of histopathology. This isn't necessarily going to come up in the exam, but it could be useful on a day to day basis. Um So the main thing I would say is that we really like clinical information, give us lots of clinical information. There's a big difference between being told on a form safer and anterior resection, rectal chima versus rectal gemma. And the patient had a previous diagnosis of lymphoma or something else. That's a bit unusual. We're going to tailor what we do with that specimen according to what you tell us. Uh likewise theme towards this session. Um There's a very big difference between saying the patient has your ethereal cell carcinoma and you did a cystectomy versus your s ethereal cell carcinoma where it was the fact that they've had previous treatment. And that all we've seen before is carcinoma in sight. You um and that this patient failed B C G therapy. This is going to change how we sample that specimen and also how we then look at it and what the tests we might do on there. So generally try to ask us a specific question if you can tell us what you think it is clinically. Um, tell us about any previous treatments. There are lots of things that modify pathology like neo adjuvant chemotherapy or radiotherapy. Um And also be wondering if it could be something odd like metastasis, if they've had cancer in the distant past or they've got some other inflammatory disease. Um, also don't be afraid to talk to us, reach out, send an email, um, asked to come to your local pathology department. Look at things that you may be involved in that operation, you want to see the slides afterwards. Um And lastly, if you're doing any sort of tissue based research, need to involve a pathologist early because we have lots of experience with dealing with human tissue, uh and all of the regulatory side of that. Um So just leads me to say, thank you very much for taking the time and listening. I hope this was useful and I wish you the best of luck with your exam.