 Thank you. With that, I'd like to introduce Sunny Kau. And one of the important things in kidney cancer really is to get your diagnosis right. Like I showed you the picture of the kidney, is that kidney cancer? Are there different types within kidney cancer? Is it a urinary type of cancer? We are really fortunate to have a dedicated GU pathologist. And after a lot of search, we had Sunny Kau come to us from, she did a training in Indiana and then went to MGH and we've really been fortunate to have her be part of our team. Not many institutions have this dedicated GU pathologist. It's really what you look under the microscope to be able to tell you what your disease is. So Sunny is going to cover just the pathology from a pathologist's point of view. How can they help in making a diagnosis and touch a little bit about prognosis and what each different type of kidney cancer really means to us as clinicians in taking care of patients with kidney cancer. So thanks so much for agreeing to be part of our day-to-day Sunny. Thank you, Sandy, for that introduction. And I just wanted to say welcome and thanks for coming. Like Sandy said, I joined Stanford last year after finishing fellowship training at Mass General Hospital and GU pathology, which includes kidney cancer, is a big part of my passion and it's what I'm really enthusiastic about and I would love to share that passion with you guys as far as the pathology end. So the topic is diagnosis and prognostic factors of kidney cancer for today. And unfortunately, you can't say the whole day, but Sandy has my contact information and if you guys would like me to talk about a different topic another time or focus on something different, please give me feedback. I would love again to tailor this talk to whatever it is you guys are most interested in learning about pathology. All right, so goals and objectives for today is understand the role of pathologists in your care because what we do a lot of times is we do behind the scenes stuff. So the surgeons take out your specimen and it sort of goes into this vague black box and out spits a diagnosis and you get a pathology report, but actually a lot happens in that black box area and I wanted to do a brief overview of what it is that we do behind the scenes and how we are participating in your care even though you don't really see us face to face for the most part, okay. And then of course, a little bit is left to understand the important prognostic factors of kidney cancer, what it is that is most important information that you should get out of your pathology report that helps your oncologist or your clinician in determining the best care management that is tailored to you based on your cancer, okay. So that's the goals and objectives for today. So the first things pathologists, when we get our specimen is we do a gross examination, right. So the surgeon hands us the specimen, we fix the specimen. So fixing means then we dump it in a solution, it hardens the actual organ that allows us to process it in a very efficient manner rather than just cutting it fresh. So cutting it fresh means, imagine you have a piece of tofu. It's like wiggly and it's very hard to cut, right. But once we put it into a formula and this special solution actually firms it, so it allows us to make very smooth and accurate cuts to best help us determine how far the kidney cancer has involved. Rather than wiggly, remember it's very hard to cut and things might not be as accurate. So that's the first process, we get your specimen, we fix it and then we start to cut it, right. So this is just an example of someone's tumor and remember everyone's tumor looks different, okay. So patient A's tumor is not gonna look exactly the same as patient B. Okay, so this is an example of what one, excuse me, what one patient's specimen looks like and as you can see down here, so let's see. So this end is actually the kidney and this cystic part is the tumor. So when we describe terms we use solid and cystic, that's one of the major descriptions in pathology and each, again, cystic tumors has different types of tumors can look cystic and again, different types of tumors can look solid. So the first time we, as pathologists evaluate is what is the consistency? What does it look like grossly? Because that helps in our mind because we have different differentials for different types of tumors that we see macroscopically. So this is a examination on the macroscopic levels that we can see using our bare eyes without any instrumentation. So we evaluate what does it look like and a very important part of a gross examination other than consistency is the size of the tumor, right? Because Sandy briefly listed the TNM staging of the tumor and part of that is determined based on the actual size of the tumor and that can be measured macroscopically. So you can see a ruler above and this tumor is roughly about 10 centimeters large. And here's another example of someone else's tumor. So as you can see, this tumor looks a little bit differently because rather than a cystic component, you see the tumor down here is more of this golden yellow with areas of hemorrhage right here. So the consistency is different, right? So this tumor is more of a solid consistency and with its golden yellow color, it's actually very characteristic of a clear cell, renal cell carcinoma. So again, gross examination is very important for us because it helps us formulate a differential diagnosis and in this case, the top of the differential diagnosis is clear cell, renal cell carcinoma, okay? So gross examination is very important. Again, the size is a very important determination of stage and this one is a smaller than the tumor that you've seen before. Again, the color is different. So in addition to that, we evaluate for the extent of involvement, right? Again, that plays into the stage. So what does the actual tumor involve? In this case, the tumor is, again, down here, this golden yellow stuff and you can see that it is within the cortex that Sandy talked about, this brown area and sometimes not this particular case, but sometimes the tumor can actually go into the adjacent fat down here that you see in the blue so that's a higher stage, right? So extent ties into the stage and we can see that for the most part pretty accurately doing a gross examination. So sometimes tumor would go down here in the perinephric fat. Sometimes it would go into the hyalur fat, renal hyalur fat that's at the central portion of the kidney. Again, that's a higher stage. That's a locally advanced disease and then sometimes we would get lymph node specimens that we would dissect and again process. This is a very brief overview of how we handle the gross specimen, what are we looking for when we do a gross examination. So that's only the first part, we're not done yet. All right, see it's very complicated, right? This black box outspits the diagnosis but a lot happens in between. So after we do the gross examination, we have to do a histologic examination. So gross examination, we're doing that using our bare eyes without any instrumentation but how do we arrive in an actual diagnosis? We have to use a microscope to confirm our gross findings and also to subtype the tumor. Okay, so after we sample the actual kidney specimen, again a lot happens in between and then what happens is that we turn them into actual, these are called glass slides, right? So when we're talking about slides and pathology, this is what they look like. Each of them are labeled with the patient's name, labeled with the number and then, again, every patient's tumor is different so each patient is gonna have a different number of slides depending on the complexity of the actual tumor. So if it's a bigger tumor, we sample more sections. If it's a smaller tumor, it's a smaller number of sampling and then we turn them into glass slides and these are the things that we actually look under the microscope, okay? All right, so this is actually what it looks like under the microscope for this particular patient's tumor and you kind of see that it vaguely corresponds to what we're seeing on a gross examination, right? So gross examination, it looks very cystic, it's fibrous, there's a lot of spaces in between the tumor and you can see that reflected on an actual histologic examination. So this one correlates pretty well, okay? Now here, yes? So that, I would say, is about maybe a hundred times magnification, so if you imagine this is one, one X, one magnification, well no magnification at all and then that would be a hundred, okay? And we can go even further than a hundred. So this is again a 100, same magnification as before but you can see that it looks different, right? And that corresponds to a more solid tumor growth. So most of the times what we see on gross examination would correlate to what we see under the microscope, okay? So this is what, this is how we as pathologists look under the microscope and how it went from that large specimen to that small cellular level that we see, so that's how it translates into it, okay? So this is about a 200 to 400 magnification. So in addition to seeing things on a macroscopic level, we can see things on a cellular or a microscopic level and this is really an important part of the process where we determine, number one, the tumor type. So if you remember, a lot of the tumors can have the same look grossly. It's really when we look under the microscope that we can tell which exact subtype is that tumor. So this is an important process. Another thing that we do is we grade the tumor, right? So how does the grading come from? How do we grade it? And we grade it based on a cellular level. We look at the actual cell and a cell is composed of a nucleus that contains all the DNA material that you see here. So here's one nucleus. If you can see my arrow moving there. Here's another nucleus. This is another nucleus, right? So we grade kidney cancers based on the look of the nucleus and the nucleoli, which is the dot within the nucleus, what it looks like. So in layman's terms, it's how ugly does it look? Does it look like a really ugly tumor or does it look like a very small and very uniform tumor? So grade is determined by the look of the tumor. Does it look to be a higher grade tumor? And we grade it as such. And of course, there's different complicated criterias that we use, but the uglier it looks, the higher grade it is. The more, but now the more lower grade looking, it's gonna be assigned a lower grade number, which is gonna be a one or two. Okay, so that's how we arrive at that. So you would get a pathology report, right? Lots of words. What is it? What does it mean? And for the most part, it's separated into these four sections. Of course, the most important part is gonna be the diagnosis, right? So the diagnosis, it's gonna be, which I'll talk about a little bit later, sorry. And then there's gonna be a common section and clinical history and gross description. So these are the four major parts of your pathology report. I'm gonna talk about what they mean for you. Okay, all right. So diagnosis is gonna be the bottom line results. Okay, so this is gonna be a baseline. What is the type of your tumor? What is the size? And what is the extent of involvement? Okay, this is gonna contain the most important part of your report is gonna be in the diagnosis line, bottom line, what is your tumor? Okay, the next section is gonna be a common section. So this is an area where we describe what the tumor looks like on a microscopic level. It's called an H and E description. So that's maybe not so important to you. And then we also document if there's any stains we use. So pathology isn't as simple as I've described it to be and it might not even be as simple as it sounds. But sometimes we would need to perform some special stains to help us determine the subtype of tumor. And we would document that if any is used. And the most important part of this comment section is probably gonna be the synoptic table that we use. And I'm gonna go into the synoptic table in a little bit more detail later. Clinical history, this is usually provided by your surgeon, tells us the patient presents with blood in the urine, presents with back pain, things like that. And gross description, in my opinion, is probably the second or if not the most important part of the pathology report because it reflects how your tumor, how your specimen has been handled. So I have been a patient myself of some other sort of disease but and I've had specimens done before and the first thing I look right after the diagnosis is the gross description because I wanna know how the pathology department did as a job of sampling my tumor. Because like I said, it's usually, we determine the tumor type based on using microscopes, right? So we can't diagnose what we don't see on a microscope. We can't diagnose what's not been sampled. So for me, as a patient, I would always read the gross description. How was my specimen handled? Is it handled in an accurate way? Does it reflect the disease extent? So for instance, if it's a 10 centimeter tumor, the standard of practice is one, you sample one area of the tumor per centimeter. So if you have a 10 centimeter tumor, you would expect to see that 10 sections have been taken for your tumor, right? Because you want it to be, again, sampled in a fashion where we would be able to make a diagnosis. So that is a very important thing and we at Stanford make sure we do that. So that is adequately sampled is very important. So that's something that I would recommend that when you receive your pathology report, look at the diagnosis, but also read the gross description because that is a summary of what your specimen looks like, right? Again, everyone's is different. I would be curious to know what my tumor looks like and the information would be in the gross description. So that's a very important part. All right, so this is a synoptic table. So after looking at your tissue, after looking at the slides generated from your specimen, we would be able to come up with a list of information. So this is called a synoptic table and if for every single patient with kidney cancer, when we review the pathology specimen, we would always generate a summary table that is pertaining to your specimen, pertaining to your cancer, okay? The site, some people would have left kidney, right? Some people would have right kidney specimen type. There are two, it's called partial. So if we only take out a portion of your kidney, that's a partial nephrectomy. If we took out the entire kidney, that would be a radical nephrectomy. So on and so forth, right? And then we have the tumor type. Is it a clear cell renal cell carcinoma? Is it a papillary renal cell carcinoma? What exactly is the subtype of the tumor? That would be listed here. So it's now grade one through four. One and two are the lower grades, three and four are the higher grades. And that is very important in prognostic information. So basically this table contains a lot of the information that your clinician and your oncologist is using to determine your prognosis, okay? So again, this is a very important table and it's a summary. So you can see it clearly listed here. It talks about whether or not your tumor shows lymphatic invasion, lymphovascular invasion. Is it in the bloodstream? Does it involve your lymph nodes? What is your margin status? Did the surgeon take out the entire tumor, right? It would be listed here. And at the bottom, you can see that there's a TNM stage. And that is the most important information in determining your prognosis is based on the TNM stage. And that is called a pathologic stage that is incorporated into your imaging findings. Sometimes you serum tumor markers in determining the clinical stage, okay? So this again is a very important table that pertains information to each and individual patients with kidney cancer. So last but not least, prognosis. So like Sandy and I have said, prognosis really depends on number one, your tumor type. Some types of tumors behave better than other types of tumors. And then when you're comparing the same tumor type, how else are you gonna come up with prognostic information is based on the stage, right? So when you're comparing stage, you really are comparing tumors within the same tumor type and what is the extent. So I think of stage as the extent of your cancer. So how extensive is it? Is it confined to the kidney? Does it involve associated vascular tumor like renal vein? Does it involve the lymph nodes? Is it metastatic already? That information is your stage, okay? So again, I think of stage N is an extent of your cancer involvement. And that goes into determining your prognosis. Further prognostic markers are, again, tumor grade. So higher tumor grades tend to behave worse if you have tumor necrosis. So tumor necrosis is something that we see on this slide and it reflects tumor death. So is tumor proliferating at such a rate that it's dying quickly? Is there degeneration of the tumor that's a bad prognostic factor? So if you have that in your tumor, it means that it likely is going to behave in a worse fashion than comparing to someone's tumor without tumor necrosis. Same thing goes for sarcomatoid differentiation and also rabdoid differentiation. So these are all features that we can see under the microscope at a microscopic level. These things, unfortunately, for the most part cannot be seen at a macroscopic level at the gross examination. So that's why it's very important to do a good gross examination, sample adequate areas of your tumor and then making an accurate diagnosis using the help of a microscope. So all of that comes together and that's a pretty long and gruesome process and that's why sometimes pathology reports can take a while, I know, but just be patient with us because we're doing our due diligence and making sure that every single patient receive the most accurate information that pertains to that particular patient. And again, everyone's tumor is different, so we wanna make sure that we evaluate each individual factors accurately, okay? All right, last but not least, after all of that pathology is how do we help the clinicians manage your disease, right? So what can we do on our pathology end that can help your urologists or your clinicians assess for exactly how the tumor is gonna behave and help assess whether or not the tumor will respond to other additional treatment modalities like drugs or chemotherapy. And unfortunately, currently, there is nothing on pathologist end, no specific stains that we can do or no molecular biomarkers that's done as a standard practice. Again, we do them still and we do them actually in a lot of them, but those are lumped under research. So they aren't really clinically validated as of yet, but hopefully that will be done soon in the future and then when that happens, pathologists will play a very important role in working with the oncologist and urologist in formulating a plan that is tailored to individual patients. But unfortunately, as of right now, there's not that much that's been validated as of yet, but everything is up and coming and a lot of research and resources are being spent on this area to help with that. So that ends my presentation and hopefully that hasn't gone too fast or and hopefully that helps you understand what we do behind the scenes. And again, if you have any questions or any feedback, you wanna know some more about a particular type of tumor, I can go into that in more detail next time. So thank you. Thank you. Any questions? Yes. Chemical, yes. No, I use that term as a special stain. So that doesn't, sometimes it correlates, but most of the times it does not. Yeah. The drug that we have today in the Voluma, it targets a protein called PD1 or PDL1. So when this drug initially came about, it was our hope that we could take an individual tumor, stain it for this PDL1 on the tumor cells or on the immune cells and have that help predict if somebody's going to respond to immunotherapy. Today it's been a little confusing and disappointing because as we show you in our immunotherapy slides, patients who test completely negative, they have a response as to people who stain positive as well. So there's something beyond just this staining that helps predict whether somebody's going to respond. So today till we understand more, we don't want patients to be excluded if they are going to benefit from it. So right now that's not being used as a marker and there are a lot of groups working on it because there are different immunotherapy drugs and every company has its own antibody and there's no harmonization between these various staining. So today it's not being used, but suddenly it's being looked at and there may be things beyond just PDL1 or PD1 that helps us pick up patient for a given time. My naive understanding of cancer is that often, especially during metastasis, the tumor itself involves and as a result of that might go to different sites and the different sites who may have a different histology. That is true, yes. So as a result of that, if you lined up, for example, just sampling a little bit like your idea of doing it at least one centimeter so that you can go on and get an adequate sample. Correct. And your point is that sampling is really important. If it's metastasized and if it's evolved, you want to go on and actually look for targeting and stuff, seems to me that present a problem. How do you deal with that kind of an issue where people that have metastatic treatments? Right, so in our experience is that we would get a biopsy at least to take a look at the morphology of the tumor that has already moved on from the kidney. And by that, we would be able to see how it looks like, what it looks like, whether or not it's the same tumor. Again, sometimes it might be different tumors from other sites. And then we would be able to hopefully correspond that with just confirming that it is metastatic tumor and what it looks like. And of course, in that, so sampling is a very, that's a very, very interesting aspect of it is because when we do, so taking out the whole tumor and sampling at one section per centimeter, it's totally different than having, let's say a three centimeter mass located somewhere that you can't take it out entirely, right? So that's a biopsy specimen. So biopsy is different than the resection specimens that I've shown you. Biopsy is usually someone taking a needle, poking it into a tumor and sucking a portion of that out. Will align with your sampling concern. That is correct. That is a very, very, very good concern. And the short answer to that is no, because we can't, because once every time the needle goes in, there's a risk of bleeding, right? So being poked 10 times have a higher risk of bleeding than being poked one or two times. So we just use our best judgment and we trust our clinicians to sample the best areas. A lot of times when they do the biopsy, they're doing it with a help of ultrasound. They're doing it with a help of a CT scan. So that helps us determining where is the best area to poke that needle once or twice, right? But you're absolutely right. That is one of our biggest concerns is do we have adequate sampling on a biopsy sample, which can be very, very limited. I believe that's mutated. You aren't going to know how effective it is if you haven't checked everything. Well, you know, I mean, there was a very elegant paper that came out several years ago where four patients with kidney cancer that had spread to the lung and multiple areas. The investigators went in and did a biopsy sample of every one of those, I mean, so it's a lot for a patient to go through, but it gave us remarkable insight into this disease where let's say a patient had two spots in the lung. Both of those spots were sampled and when they actually looked at it at a genomic level, they were completely different. So you can imagine clinically this happens a lot where we see patients who have a spot in their lung and the lymph nodes, we give them a drug, it works dramatically for the lung, but that pesky lymph node continues to grow bigger. So we now know that there is some difference in what they look like at a genomic level that they are not the same. And this is classic in lung cancer. We hope to be able to get that to kidney cancer one day where we can biopsy an individual tumor and show that it's now changed to a different type and that we would have a different drug for that patient. That's where biomarkers come in and individual mutations. So in kidney cancer, unfortunately despite having all of these drugs, we haven't come to that level yet, but that's where we hope to be able to get to where pathology and genomics is going to help us select patients for a given treatment, not just at the first time, but as the disease changed. So does drug therapy evolve and make your tumor look different that we would need to biopsy at every single time? And to that point, rather than just biopsying, there's a lot of effort now at just getting blood test. Can you just do a blood test and get circulating cell-free DNA from the tumor? So tumors are shed and we now have the ability to take a blood test and detect tumor DNA in the blood and that to be able to give us some insight. So that's the hope and that's where we hope to be able to get to where we can get in a less invasive way rather than put patients through an individual biopsy every single time. Yes. I understand that when we're diagnosed or given a treatment, that it's a good idea to get a second opinion. My question is, is it also a good idea to get a second opinion on the slides of our tumor? That is an excellent question. Do we have access to our slides to take to you or to some other specialist to make sure that the diagnosis of our type of cancer was correct? That is an excellent, excellent question and we do that on a regular basis. So for instance, if you're seen at hospital A and you're referred in to see Dr. Sandy here at Stanford, so when that happens we will acquire your slides that was seen at hospital A, we will take a look at that here at Stanford before your appointment with, say, Dr. Sandy. So yes, we will confirm your pathology that was diagnosed at an outside institution. Yes, so we absolutely would take a second look, confirm that the diagnosis is indeed accurate and that we agree. Yes, so absolutely. That is the standard practice for every single one. Yes. So it's actually Stanford's institutional policy that we don't just take somebody else's word and that we have that pathology confirmed. So that's part of the practice that's here, but I also wanted Sandy to briefly touch on what happens to people's tumors and how pathology saves them, because that's always a question that comes up. What happens, I mean, can we do stuff from a kidney that was removed five years ago? Oh yes, so pathology specimens, yes. So when we do the gross examination, we take areas that we think are pertinent to evaluating the extent of your tumor. And so the parts that we sample are what we think are the most important parts and we read the slides under the microscope to confirm that. And if we think there are additional areas that need to be sampled, we will go back, pull out the specimen and take some more. But after the whole process is completed, we've issued a pathology report, the specimen or the residual tissue that is left over will be kept for maybe two to three weeks and that will be discarded. Because the most important part is already preserved in what we call a paraffin block that is the tissue saved where we cut the glass slides from. And again, those are the most important sampled areas and those blocks are usually kept for at least 10 years or so. And remember, we have multiple for each patient. So we've saved a number of the most important tissue blocks from your specimen and that's kept for at least 10 years. Sometimes we keep it for 20 years if we have space but if we don't, it's being kept for at least 10 years and it's fixed in the way that the tissue will survive for a multitude of testings. Molecular testings, we can use the blocks for that. We can use special staining testing. So for instance, the blocks we saved today, we will be able to perform testing on that, say five years later, if there is a special molecular test or special stain that we can do to help manage your cancer or help deciding whether or not the drug will work for you, that tissue is still going to be there for at least 10 years. Just related to that, is that best practice or standard practice across the country? That is standard practice for at least 10 years. Yes, so for any accredited lab, that is standard practice. Yeah, but as far as keeping it longer than a certain number of years, then that is institutional based. So there's a minimum requirement of the length that the blocks need to be kept. Same thing for your slides too. So your slides are, I think, don't quote me on that, but maybe at least 20 years. So the slides are usually kept for like forever. We have slides back in 1990s still in our warehouse, so. But yes, there is at least a minimum number that those samples need to be kept. Yes. Has the pathology practice changed enough over like the last 10 years that if you have slides that are 10 years old, that there would be any reason to ask for a new report from those slides? Wow, the answer is very complicated and that's tumor dependent. So yes, you're absolutely right. A lot has changed in the diagnosis of kidney cancer and I would say the last five years. So now with the help of a lot of the molecular tests, different staining available to us to help in the diagnosis of kidney cancer, some of the kidney cancers that was diagnosed as unclassified before, meaning that we don't know what the cancer is, now we actually have names for them because of the advancement in pathology and the molecular studies. So, but that's only true for a limited number of cases for, like I said, the unclassified types. So if you had a tumor that was diagnosed as clear cell renal cell carcinoma five years ago, it's still going to be a clear cell renal cell carcinoma five years later. It's only in that very limited area where we couldn't classify it before, but now we maybe can based on the new advancements. But the clear cut tumor types, papillary will remain is still papillary, clear cell is still clear cell. So yes and no. Okay. Any other questions for Sunny? The subtypes have changed, however, significantly? Well, we've added more subtypes. So before the classic kidney cancers are clear cell, papillary, chromophobe, and probably, you know, some other random types, oncocytoma, but now it's bloomed to where we've added maybe five or 10 more subtypes that we can now recognize that we couldn't before based on molecular tests, the new molecular tests and also new stains that we have now. So I would say the subtypes have expanded, yes, but as far as what's most important, which is the stage, again, that's the extent of your tumor involvement, that hasn't changed much. My surgery was 12 years ago. And it was papillary. Mm-hmm. I had the pathology run twice. Mm-hmm. It was run once at the hospital where it was done, was we're in a second time at Cal Pacific. Mm-hmm. But the subtype of the papillary was diagnosed differently both times. What do you mean? And there was only one sample out of a 12 centimeter tumor as far as I'm given to understand. Okay. One sample, like one tissue block? As far as I understood it, yes. Okay. Well, I can't speak to the practice done at another institution, but like I said, the standard practice that we do nowadays is at least one sample per centimeter of the mass. So I can't say anything much else to how it was done 12 years ago, unfortunately. Well, thank you, Sonny. Thank you so much. Thanks for all the questions. Thanks.