 One of the one of the people behind the scenes that's critical to your care is the pathologist Oftentimes the pathologist is often a different part of the hospital evaluating tissue and and helping the clinician figure out exactly what The path out what the tissue looks like It's become as as young mentioned as we start to think about personalized approaches to kidney cancer The relationship between the pathologist the surgeon and the clinician has become ever more important So Dan Luthringer is the head of our gender urinary pathology Section here at Cedars-Sinai Medical Center and a professor and he'll talk to us about How the pathology report and how what he does is important to how we then decide how to approach treatment Dan Thanks, thanks Bob and thanks for the invitation to come and participate in this conference today Again, I'm the guy behind the scenes who really is responsible at least at this institution for of doing most of the histologic microscopic analysis of the genitourinary malignancies specifically the renal cell primarily the renal cell carcinomas All right, there's really two main categories of specimens that we receive one is as our Samples from the renal tumor itself. These can either be biopsies or resections as dr. Kim alluded to and Or samples from a metastatic site or recurrence or a metastatic site the most common specimens that we see are Nefrectomy's resections of the tumors and they're either the partial nefrectomies or a complete nefrectomy and these are Examples of some of these a partial nefrectomy is as dr. Kim suggested our Smaller sections partial resection of the entire tumor which include a little bit of the nephric fat And a little bit of the perinephric tissue as well The goal is to try to get the entire tumor out with a negative margin of resection when the tumors are bigger Generally or infiltrative we tend to get the entire kidney and this is an example of an nefrectomy with perinephric fat the Sinus fat drainage area down in here Maybe an adrenal gland up top and this would be an example of a tumor that's been completely resected occasionally we will we will get biopsies from metastatic sites or Unusually from the primary renal tumor will get a core biopsy usually which is really a much smaller sample of the the tumor mass Usually, it's about a millimeter or two in diameter. It's a core Maybe up to several millimeters or a centimeter in length, but generally it's just a small sample of a much larger tumor A little bit about the specimen handling generally within a few minutes of having the tissue removed It comes up to the pathology laboratory and we're able to do some initial assessment on it We have workstations Where they will come and a pathology team will assess let's assume it's an nephrectomy specimen We'll look at it measure it cut it open We'll procure some of the tissue if there's some tissue that needs to be taken Fresh for potentially for a biobank to be stored away or maybe some tissue needs to be taken for immediate Diagnosis or a margin or something like that will do that or if there's a the if the if you're enrolled in a study Where some fresh tissue needs to be taken and sent off to a particular institution or reference laboratory for analysis We'll procure that as well and make arrangements to send that off on an immediate basis and then at that point We will do photography tissue fixation and over the next few hours. We will dissect the specimen Analyze it do a lot of important Evaluation with our eyes and ears and whatever it takes and then we will take what are called representative sections of that tumor or the Specimen put them into these little take sections of the tissue Put them into these little capsules called cassettes and then we process them overnight in these tissue processors These are pretty standard from institution to institution The next morning the tissue is taken out of the processors and it's manually placed into these other sort of Tissue cassettes which are filled with paraffin wax essentially and they're embedded in Into these wax molds and then the blocks and then very thin sections fortified microns are cut with these special Microtomes they're picked up on glass slides. They're again processed stained cover slip and then ultimately we get as a Sample of glass slides from that tumor that's been removed on an average partial or complete nephrectomy We'll do anywhere from five to ten paraffin blocks Therefore equating to five to ten glass slides This takes about a day or two to complete this and then the initial report and the slides are delivered to the pathologist Who will begin the process of doing the microscopic analysis using obviously as microscope and whatever other tools he needs Looking at that set of slides and it usually will be the sections from the kidney Maybe some lymph nodes margins adrenal gland things like that that were provided by the surgical resection The whole process usually takes about two to three days to complete. So there is a bit of a time lag Because of mostly the technical processing that's involved The elements of the report once we generate the report and becomes available. There really are sort of three Categories of information which are really relevant to to the to the Not just the diagnosis, but the future care of the patient The first thing really is is the diagnosis. What is the diagnosis? Is it renal cell carcinoma or some other unusual type of renal cancer and I'll talk more about that and then Aspects related to cancer stage the tumor size local infiltration has a metastasizer spread and then other features that dr. Kim sort of alluded to resection margins grade vascular invasions We'll talk about each of these just briefly The first aspect is diagnosis the important thing is to remember and again I think everyone in this room is a little bit beyond this, but just remember that at the initial phase tumors are resected and it's oftentimes it's not known whether it's a renal cell carcinoma often times It's not even known if it's even a neoplasma at all not all oops Not all tumor masses are neoplastic or even malignant. I'm sorry. That's fine and so Examples of non-tumorous masses would be things like cysts a lot of renal cysts like this or areas where the Collecting system is dilated called hydronephrosis or multiple cysts can present and look just like a renal cell carcinoma And they're resected as if they're renal cell carcinomas, but in fact, they're not they're benign There are other types of tumors besides renal cell carcinomas Angiomyelopomas are very common tumors. They could be big big like this one. Here's a kidney Here's a big one. They could be multiple here's two They can be small one or two centimeters like this, but they all look like fatty tumor They're not renal cell carcinomas different types of tumors like fibromas Acocytomas can be very big and aggressive looking, but in fact, they're not they're not malignant at all there are other types of Malignancies true malignancies of the kidney which are not renal cell carcinomas Eurythiolial cancers those tumors that are derived at the lining of the kidney That it can extend into the kidney and be derived to the kidney These are examples of some of these here and they these were resected thinking that these are probably renal cell carcinomas but in fact they proved to be Eurythiol not renal cell carcinomas different types of Tumors like sarcomas can to be derived to the kidney or around the kidney other types of tumors can metastasize To the kidney or near the kidney adrenal tumors lymphomas There's a whole host of malignancies that can mimic renal cell carcinomas But what we're really talking about today here obviously is renal cell carcinomas which represent probably 90% or more of all true malignancies of The kidney and these are the tumors that are derived at the renal tubular epithelial cells those little ducks that that are Line the the epithelium of the kidney the diagnosis of renal cell carcinoma Really depends it's it's contingent on microscopic analysis You can't make the diagnosis any other way the pathologist needs to look at the growth take his sections look at the microscopic And then there are a spectrum a range of features that that will ensure the diagnosis or put it into a diagnostic Category of renal cell carcinoma Sometimes it's not so simple sometimes we need to employ special testing through the use of antibody Immune histochemical studies or even as dr. Young Kim alluded to sometimes we need to refer to some molecular Analysis to put it into a diagnostic category of renal cell carcinoma Once we've done that the next phase is to determine the subtype There are different many different sub types of renal cell carcinomas Really based primarily on the appearance of the tumor cells and their architectural growth patterns and that sometimes we need to again Rely on immune histochemical some of the molecular properties or the genetic profiles that To put us in the proper subtype category now the sub classification of renal cell carcinomas You probably all know this because you're all familiar with renal cell carcinomas. It's not so simple It's an evolving sort of complex and and ever-changing Categorization in fact the overall category categorization of subtypes just changed just a few months ago We like to think about renal cell carcinoma subtypes really in sort of developmental Pathways there's a sporadic type those that just happen to occur Just because they just happen to occur which is probably the type of cancers that most people in this room have and those are our typical Typical clear cell Chromophobe papillary renal cell carcinomas and maybe a few of the other rare variants There are those which tend to be familiar and these represent probably 90 plus percent of all of all renal cell carcinomas The familial patterns which again are associated. They're pretty rare. They're associated with In families multiple tumors Different family members can have these and we'll talk a little bit more about these and then there's actually going to be a talk a little bit later In the afternoon or in the morning about genetic based or familial based renal cell carcinomas there are those rare really associated with treatment of other types of cancers and then there's an unusual Category when you have scarred or damaged kidneys those kidneys are at risk for developing renal cell carcinomas So let's move through this a little bit once we've made the the the diagnosis of renal cell carcinoma. We've subcategorized it I know it seems complex, but there really are only three or four main Subtypes that we really need to talk about especially in the context of a setting like this the most common subtype is The clear cell type this represents about the vast majority of all sporadic type renal cell carcinomas Then there are the papillary and chromophobe renal cell carcinomas. These are really the usual types The the much less common type is collecting type collecting duck carcinoma, which is more like a urethanil cancer It behaves more like like that. It's a little bit more of an aggressive type of renal cell carcinoma These are really the main four that we need to be concerned about They're each unique based on their gross appearance and these are all partial nephrectomies This is a complete nephrectomy down here But partial nephrectomies and look at the gross appearance. They're very unique Look at their microscopic appearance the clear cells of the clear cell the papillary architectural growth pattern of a papillary tumor These chromophobe this unusual eosinophilic cytoplasm of the tumor cells probably doesn't mean much to you But it means a lot to us and also some of the clinicians So they have very characteristic gross Microscopic and also they're very unique biochemical and as dr. Kim alluded to very specific Molecular and genetic profiles as well. This is all really evolving as we speak They also And this is a small graph, but we all know that that the different subtypes behave differently some behave better than others So it's really important that we subclassify these renal cell carcinomas Based on there on the appearance all the appearances that we talked about And the other thing that dr. Kim alluded to and I think we're going to talk about this a little bit later And I won't get into detail on this, but just to point out that the subclassification subcategories are They respond differently to the different armament area that we have in terms of treatment modalities And so it's very important for the pathologist to specifically subclassify Subclassify the type of renal cell carcinoma. So on any Standard pathology report you're going to see the diagnosis renal cell carcinoma That's what it is and then the subtype somewhere buried in the report will say clear cell type Papillary type chromophobic type or something like that. So that's an important one important aspect of it to diagnosis The next important aspect is really the cancer stage And the cancer stage is dictated Really by the size of the cancer and it's local the local growth Is it extending sustained confined to the kidney is extending outside the kidney into the local fat Is it going to any regional lymph nodes that that might have been removed or is it extending into the the adrenal gland? Which might have been removed as well And so we analyze each case based on what we have and what we see This is a typical example of a partial nephrectomy specimen of a clear cell renal cell carcinoma With a margin that's out here here measures about 2.1 centimeters the margins negative This is a very small tumor of clear cell carcinoma. This is a stage out as a t1a a pretty low stage tumor This would have a pretty good prognosis based on that on that Staging profile now compare that to this particular tumor Which is a complete nephrectomy specimen showing the kidney a lot of perinephric fat Here's the sinus of the kidney and here is the tumor out here much bigger about 9 centimeters It's growing into the fat. It's growing into the sinus fat. It's demonstrating more aggressive local growth This would stage out. This is a microscopic showing it extending into fat We would stage this out as a t3a tumor because it's obviously more its larger and more infiltrative a Different example would be a same thing a renal cell carcinoma clear cell type This is a full nephrectomy specimen. Here's the kidney. Notice though the tumor is extending into the renal vein This is another feature that we analyze to look for we look for it grossly and microscopically and look for tumor extension Into that vein because we know that this will upstage The tumor the overall tumor stage and this is associated with generally adverse outcome It's telling us this tumors behaving more aggressively with its local growth in a case like this We might have received a lymph node. This is a lymph node with metastatic clear cell renal cell carcinoma again another aspect We would analyze both microscopically and under the microscope or Grossly and microscopically so we take all these features once we've analyzed the the tumor and we apply a grading system the American Joint Counsel on cancer staging the AJCC and we apply the pathologic stage Why because it's dr. Kim alluded to and we all know that? Cancer staging and it's true for any type of cancer the higher the cancer stage The more aggressive that that tumor will likely behave and therefore the therapy needs to be tailored to that particular stage Okay, and the report will clearly should clearly dictate. What is the tumor stage? And that's part of the standard reporting of any good cancer report Cancer the final cancer features are going to talk about a resection margin the grade Vascular invasion the presence of necrosis and then this unusual Circumitri to rabdoid differentiation. These are elements which go beyond cancer staging and the diagnosis Here's two exam. Let's talk about resection margins. These are indirectly related to or they indicate The local aggressiveness of a tumor if it's growing to a margin. It's ideally It's ideal that when a partial nephrectomy or a complete nephrectomy is that we have here is performed the surgeon always Tries to get the whole thing out. So we achieve negative margins. That's optimal sometimes It's not possible especially when we have a high stage renal cell carcinoma like this Which is extending into fat? Sometimes it's impossible to get a clear margin. This might again pretend some additional therapy When it comes to therapeutic Time for therapy with a smaller resection Sometimes it's impossible to get a negative margin or the surgeon needs to go back and take a cleaner margin That's interpreted for frozen section analysis Whatever to try and clear out that margin again because optimally went we want to try to achieve a negative resection margin The next factor is vascular invasion Vascular invasion when the tumor invades either into those lymphatics that dr. Kim talked about its surgery They have a propensity then to go to lymph nodes or they can go into veins or even sometimes arteries And then they have unfortunately the capacity to go to the lung or bone or other sites Those confer an adverse prognostic indicator Those are an indicator that this tumor might behave in a more aggressive manner So if we see it Microscopically we included in the report also if there's tumor cell degeneration undercrosis that is usually associated with aggressive gross growth of the tumor and We too will report that because sometimes that Will dictate how the next round of therapy will be undertaken dr. Kim already talked about tumor grade We apply the pathologist applies the tumor grade The Furman grade is the one that's used for renal cell carcinomas and it's a grading system from one to four Really it delineates the degree of differentiation grade ones are well differentiated tumor grade four are poorly differentiated and In any type of tumor it doesn't matter if it's breast colon renal cell carcinoma Generally well differentiated tumors behave better than poorly differentiated tumors So we assess the tumor under the microscope and we assign a a grade based on our observation And then finally sarcomatoid or rabdoid differentiation Most tumors will have just one type of differentiation. This is an example of a renal cell carcinoma The vast majority of it was this typical clear cell type renal cell carcinoma Sorry the conventional type But in it there were some pockets where the tumor cells Sort of had this unusual morphology under the microscope called sarcomatoid differentiation Or over here with a heat we had this rabdoid differentiates. You can see it looks very different than clear cell These for whatever reason are associated with tumor aggressiveness. So when we see this we need to report it We need to quantitate it and we put it in the report because these mandate some additional therapy independent of stage because they are really associated with aggressive tumors and All of these last category of features that I talked about once we've observed them We include them in the report and again usually enter any standard RCC report will have these features indicated in them Because they will potentially impact on the therapy Two quick categories and then I'll be I'll be done here I was asked to see a couple words about hereditary genetic syndromes associated with renal cell carcinomas and Again, this is taken out of that that long list that I presented a few slides back We all know that they're well known well-defined syndromes Genetic syndromes are familial syndromes that are associated with increased risk of developing different types of neoplasms including renal cell carcinomas notably von Hippel-Lindau Tuber sclerosis Burt hog debate these sorts of things The bottom line is as a pathologist I can't look at most of these tumors and say this is a clear cell carcinoma It's clearly von Hippel-Lindau tuber sclerosis or whatever all I can say is that it's clear cell carcinoma There are a few types of tumors that I can look at and if they have unusual Morphology like this tumor up here or this tumor up here I could say they don't comfortably fit into the typical types of renal cell carcinomas Maybe it is a syndromic type of carcinoma Very very rare less than 1% that we would ever suggest that to a clinician that maybe is this a syndromic but what we can do when we get samples like a renal like a renal resection like these three different cases where there are multiple tumors here We have multiple tumors or multiple cysts with here We have maybe 20 or 30 different tumors in this particular kidney or here's a younger patient with one two three separate tumors Then we can suggest that there's something odd about this because we do usually don't see this in sporadic type tumors Maybe it's associated with a genetic syndrome So multiple tumors cysts a young age presentation at a renal cell carcinoma or unusual histology Well, we will suggest to your treat treatment team that maybe this is a genetic or syndromic pattern of renal cell Carcinoma there's going to be more on this this after or later this morning on this topic the final topic for one minute I was asked to talk a little bit about the performance of secondary slide reviews. It's kind of important It's really important when you come to an institution for your definitive therapy It's always good to have that team and we do this all the time Review the outside slides to ensure that you have an expert team who works with their treating physicians And we work as a team through tumor board reviews and discussions of each almost every single individual case to ensure that We have the correct diagnosis. We've had the critical elements included in that report. We've under we've that these the specific Special testings have been performed and we have accurate diagnosis and staging and things like that what you need to do to provide is is when you come here is to provide the Copy of the report and a set of the glass slides the so-called recuts we sometimes call on the recuts That's really all we need to provide that incoming secondary review The other scenario is when you go off you might need to go off somewhere else for For some additional testing or some additional therapy and in that situation You might need to take or you should take a set of slides with you off to that institution Because they will probably want to do the same thing and review to ensure that we're all talking about the same disease process Remember that your slides and blocks when you're treated here or whatever institution generally those tissue blocks are stored in an incredible Huge file either in the basement of the hospital right below us here or in a warehouse as we have down in torrents They're basically saved forever So when you need to go somewhere in five or ten or fifteen or twenty years God forbid that there's a recurrence and you need to get some additional testing we can pull those blocks out of Torrents create a second set of recuts or a third set or four set And we can send it off to wherever it needs to go for some additional testing or evaluation And what you need to do is fill out this authorization form here at Cedars if you're if you're being treated here at Cedars And all you need to do is check off get a copy of the pathology report and please provide a set of recuts It'll take a few days two or three days We'll get that for you we can send it to where it needs to go or we can give it to you directly And you can just carry it with you to that next institution or wherever you need to go All right on that note. I thank you for your attention and I'll take any questions either now or during the break I know I think I'm a little bit over Thank you So in our efforts to try and stay on time Dan's available for a few minutes and let's take a coffee break and come back in 15