 then we take care of you. So we're very fortunate to have Dan Luthringer, who's a kidney cancer pathology expert, talk to us and we had to drag him off of the tennis court, but we thank him for coming. No tennis. Thank you. I appreciate the invitation to come and participate. Again, Dan Luthringer, I'm one of, we have four genital urinary pathologists here at Cedars. I'm just one of the team. I tended to see most of the cases, but we have a team of well-trained people that really do spend a significant amount of their time diagnosing genital urinary type malignancies and pathologies, and the renal sulcarcinomas are a big part of that. So I'm just going to take a few minutes and go through a more in-depth explanation of some of the pathology that, some of the things about the pathology that have been alluded to through the earlier presentations, and which will be talked about a little bit later in some of the upcoming presentations as well, hopefully to clarify some of the issues. So as was mentioned, there are a number of different types of specimens that we would typically see related to renal cell tumors. Specimens related to the actual tumor itself, either a core biopsy or a resection. Core biopsies can either be an actual core biopsy of the renal lesion or an aspiration cytology, or a resection, either a complete resection where the kidney is removed with the tumor and the tissue around it, or a partial infractomy where only the tumor is removed with a little bit of the renal prankoma, maybe some fat around it as we see here. And then we also would commonly would see samples from metastatic sites, either core biopsies or a cytology aspiration, and these are done through these needle core biopsies, tiny little samples of tissue, or sometimes we get a resection of a larger metastatic focus like from a lung nodule. And so I wanted to go through a little bit of the sort of the background of how these specimens are handled because a lot of people don't fully understand what goes on in the laboratory. It's a big mystery to even some of the doctors what actually happens. So once these specimens are removed, usually through the operating room or through an imaging suite, they're sent up to the pathology lab, which is on the eighth floor directly above this room. And it would be handled in an area like this where the specimen would come in. There would be an initial evaluation even while the patient is in the operating suite. And we might be asked, well, what kind of tumor is this, or can you tell us, at least preliminarily, a little bit of information about that particular tumor. And we would look at it, observe it, cut it with some scalpels, open it up, do some photography, maybe do a rapid microscopic evaluation to perhaps guide the surgeon and say, well, yes, this is some sort of tumor, or it's clearly a renal cell carcinoma, or it's clearly invading the vein. Some things that could impact the intraoperative care at that point in time. And then what happens is that specimen would be fixed, informal unusually, and for a number of hours, sometimes overnight. And then in greater detail, the pathology team would evaluate that specimen, measure the size of the tumor, look at the size and shape of it where it's infiltrating. And then eventually, the pathology team would take what we call representative sections. We look at the tumor and the adjacent tissue, and we cut out little pieces of tissue and we put them in these little plastic cassettes. And this is a blown-up photograph of one of those cassettes. They're about the size of a quarter. And we put pieces of that tumor in that cassette and then those go on tissue processors up in the laboratory, which run overnight. And the tissue processors dehydrate that tissue and they impregnate it with a wax-like material. And then the next day or so, the tissue is embedded in paraffin blocks and subjected to very thin cutting on a microtome. And these little pieces of very thin, four micron-thick sections of tissue or the tumor are picked up on glass slides. Those glass slides are processed in tissue processors, stained, put cover slips on, and then they're put onto a tray like this and after they're stained up with the H&E stain, hematoxiline, eosin stain. And that's what the pathologist would use to look at under the microscope. The typical nephrectomy or partial nephrectomy sample would be anywhere from, would generate five to maybe 20 glass slides that the pathology team would then look at. So the next day, this takes two or three days for all this to happen, the glass slides with a preliminary report are delivered to the pathologist who looks at things under, looks at the glass slides under the microscope. He does an initial review, might order some additional testing. He might discuss the case with the treating physicians, the surgeons or the oncologist or whatever generate a report and there would be a final report generated and available on the, on an electronic system for the treating physicians to review and then even available for you if you wanted to copy the report, they're available for you to review as well. And this whole process generally takes about two to three days because it's a little bit labor-intensive. And so in terms of the pathology report, there are some elements which when you get a copy of that report and I would encourage you to look at those reports because there's a lot of important information in that, in there, in each report. The diagnosis is really key and we'll talk about the different types of tumors that we see but we're focusing primarily on the renal cell carcinomas. The stage that that cancer was alluded to, I'll talk more about that, explain some of the features. And then other features which are related specifically to the appearance of that tumor underneath the, underneath the microscope. The diagnosis, remember, a lot of things, masses in the kidney are removed and a lot of those masses are not necessarily renal cell carcinomas. A lot of the masses are actually not even neoplastic and some are really not even tumors at all and we'll talk about that. So for instance, these are examples of complete nephrectomies which are abnormal because they have these dilated collecting systems and it's called hydrophrosis and it can mimic a mass, a tumor mass or down here where we have a kidney that's been virtually replaced by all kinds of cysts or these are partial nephrectomies of masses that have been removed that prove to be simple cysts. Again, the treating physicians up front before we have this out, the tissue in our hands, we don't know whether that might be a renal cell carcinoma or some other type of cancer or a benign cyst or hydrophrosis as in these examples. Benign tumors, we have things like angiomyelipomas. These are partial nephrectomies or complete nephrectomy. This is the kidney with a very large tumor next to it and the assumption was these are renal cell carcinomas but in fact once we examined these tumors under the microscope they proved to be these very indolent actually non-neoplastic proliferations and then there are other non-neoplastic or non-malignant tumors fibromas, oncocytomas, things that would mimic renal cell carcinomas or other malignancies which are not renal cell carcinomas. We get different types of malignancies, tumors that involve the collecting system, urethylial cancers like what we get in the bladder or the ureter, you can also get those in the kidneys very commonly. These are examples of resections done for those types of tumors. Sarcomas, different types of sarcomas in the kidney. These are all different types again not renal cell carcinomas. Sometimes tumors from other sites from the lung, from the breast, from almost anywhere in the body can metastasize to the kidney and present as a solitary renal mass where the differential would be is this a renal cell carcinoma. The only way to really know is to do that core biopsy or a partial or complete nephrectomy. That happens pretty commonly. So once we've determined under the microscope that we're dealing with a renal cell carcinoma these constitute probably about 90% of all masses besides cystic non-neoplastic cysts. They constitute about 90% of all masses that are removed for true neoplasms. These are tumors that are derived probably of the tubular epithelial cells of the renal cortex as Dr. Hoffman suggested. The diagnosis is really predicated on the gross appearance and the microscopic features that we see underneath the microscope. Sometimes we need to do some additional special testing which can help us better stratify the type of tumor or the subtype of renal cell carcinoma. And it's all again there are sub types of renal cell carcinoma which I'll talk about in a minute based on the appearance and the architectural growth pattern and sometimes on some additional studies that have to be done either by these immunohistochemical analyses or sometimes even genetic analyses to better stratify the subtype of renal cell carcinoma. As was alluded to renal cell carcinoma the subtypes are really there it's a really heterogeneous population of different tumors and it's really the current classification system is really quite complex it's still evolving and it's going to evolve is going to change. If you look at the most common types of renal cell carcinomas they're just what we consider the sporadic type and the most common two or three would be the clear cell chromophobe and the papillary types and then there are the RCCs can then fall into any of these other types of either sporadic or special types of RCCs that arise in special settings and then rarely we get these what are called familial cancers those that have more of a genetic or hereditary component and this is the area that's really evolving because we're recognizing more and more that there's a genetic basis for many of these types of tumors and probably a lot of these sporadic those tumors that we currently classify as just sporadic sort of run-of-the-mill RCCs probably do have more of a genetic component and we'll know more on that probably in the next clearly in the next few years and decades as information progresses. The two or three or four main subtypes the clear cell type is the one that we really are really talking about and it's very characteristic gross appearance and a very characteristic appearance under the microscope the papillary subtype again maybe five or so percent of all RCCs of the papillary and then the chromophobe is the other big subtype and again they had very characters to gross appearance to us the pathologist and then under the microscope they have very particular appearances by the way that they grow and as has been suggested all along it's important to really substratify carcinomas based on RCC is it RCC and then what particular subtype is it because we know that this different subtypes look and act and actually behave very differently and they respond to therapies very differently and then there's this whole the whole issue of the the molecular or the genetic basis of these tumors it's clearly evolving that there are different molecular pathways that give rise to these probably give rise to most of these particular subtypes and the important thing again has been alluded to is that there are now these targeted therapies which can potentially hit some of the pathways that actually drive these subtypes of renal cell carcinomas it's important that we continue to work on deriving or figuring out what these subtypes are and then the pathways that give rise to these to these different subtypes and so that's work in progress and it's probably again going to continue to evolve over the next few years so each pathology report will clearly state what the specimen is but most importantly what type of cancer it is renal cell carcinoma and this this is just one of our typical reports but any report wherever your pathology would have been done really should and will should clearly dictate that it's a renal cell carcinoma so look for that when you read the report the cancer stage is an important predictor of how the tumor is going to behave cancer stage is it incorporates things such as the tumor size the local extent of the tumor and the distant growth of tumor has it spread to lymph nodes maybe to adjacent structures structures like the adrenal gland or metastasized to other places like lungs and bone and this is an example of a partial nephrectomy which is it shows a renal cell carcinoma clear cell type which measured 2.1 centimeter here's a negative margin here and in a report it should clearly state that the primary tumor based on the AJCC that we talked about earlier would be a PT1 a low-stage tumor so look for that in your report it's important as tumors get bigger here's an example of a renal cell carcinoma that measures 9 centimeters this is the kidney by the way here's the normal this cancer is eroded into the renal sinus and out into the fat it's a big tumor since it's extended locally into the fat it now is classified as a t3a tumor it might not mean much to you but the important thing is when we get to I'll show you one more slide in a minute which I'll come back to here's a here's yet a different renal cell carcinoma again a clear cell type which is clearly invaded the renal vein so it's invading it's showing it local growth into the vein and it also metastasize to a regional lymph node so when we have these sorts of aggressive spread of tumor cells we know that as the stage increases over time the survival of patients is actually decreased dependent on the clinical stage so when you get your report look at the clinical stage all this information it should be reported in the pathology report what the actual stage is is it locally invasive is it invading into fat is it invading into the the blood vessels or metastatic to regional lymph nodes or adrenal gland things of that nature it all should be clearly delineated in your report some other features which are important that might dictate how you might be treated following a surgical approach looking at resection margins are the positive or negative the grade of the tumor is their vascular space invasion under the microscope not just into the renal vein is their tumor cell necrosis is there unusual unusual histology for instance a sarcomatoid or rabdoid component which I will talk about for a moment resection margins here's a partial nephrectomy where the tumor has actually stented to the renal parenchymal margin of resection here's an nephrectomy where there's a very large clear cell type RCC which is extended to multiple margins of resection these features are really an indicator of aggressive disease of that tumor and if there is a positive margin it's not ideal there might have to be additional therapy undertaken to deal with that particular issue or a fund of the microscope we see blood vessels or lymphatics where there is tumor spread as we see here or if we find tumor associated necrosis studies have shown that these microscopic features portend to worse in part a worse outcome or more aggressive growth of that particular tumor or the grade of the tumor we have a grading system called the firming grading system one through four one is a more indolent grade four is a higher grade and again studies have shown that depending on the the grade of that tumor that over time the higher grade tumors tend to behave more aggressively with poor outcomes than the lower grade tumors so that's an important feature that we have to evaluate and then finally this issue of sarcomatoid orabdoid differentiation in some renal cell carcinomas this happens to be a typical clear cell carcinoma but sometimes we'll find areas where the cells look like this and have this what is called a sarcomatoid or rabdoid differentiation and studies have shown that this sort of morphology under the microscope imparts a rather aggressive growth to that particular otherwise typical clear cell renal cell carcinoma and in the pathology report all of these features that I mentioned should be clearly delineated and again it's important that your treating physician look at those components and he will look at those components and decide how that information will dictate the modalities of therapy under which you will be treated. I'm going to finish up with just a brief comment about secondary slide reviews it's important Nancy brings us up all the time I get emails all the time about doing secondary reviews when you come to an institution like here at Cedars for or doesn't matter UCLA USC for treatment it's really good to get a second review not only just to get a second set of eyes of a good pathologist to look at the case because sometimes there's differences of opinion and different features which might be interpreted slightly differently but also if you come to an institution where you're going to be undergoing a particular trial for instance it's really good to have that particular institution review the slides to ensure that the diagnosis is correct the staging is correct the sub typing is correct the histologic features are all there the report is actually accurate or if there's any misinformation that it might be properly interpreted to do that all you need to do is request from wherever your pathology was done to have a get a copy of the report and a set of recuts a set of glass slides either bring those along when you come to see Dr. Figlin or whoever you come to see Dr. Kim or whoever bring bring those slides and the in the pathology report with you and they'll get shuffled up to the pathology department and get reviewed by me and sometimes we need to get some additional slides or some additional studies and we can we can get that taken care of it's a very easy process all you need to do is fill out a request either here at Cedars or back with your original treating team back at that particular hospital and they'll release that they'll generate that material and you can pick it up or they can send it directly to us it's a very simple process a second sort of secondary review is when you leave Cedars if your pathology was done here and you want to set a slide either sent out for that second opinion or if you're going to New York or somewhere else you move you go to for a clinical trial somewhere else you should really have a set of slides and a report taken with you or sent ahead so that that institution can also have the benefit of seeing and verifying what they're dealing with it's a very easy process we have a form that I'll show you in just a second you fill it out you give it to Nancy or your treating physicians it's very you could send it to me or anybody we could generate all we need is your authorization will generate a set of slides from that set of tissue blocks remember that set of tissue blocks goes into an archive which is stored basically forever we maintain those blocks forever we have decades and decades of tissue blocks down some downstairs right below here and some had a very big warehouse down in Torrance from the 1930s and 40s if you can believe that and we can have multiple sets of glass slides cut and sent off on a few days notice to wherever you go for your particular therapy so it's very easy to do all you need to do is fill out this form and then shuffle it along and we will take it from there and send it off for secondary review don't we're in that we are never offended the pathologists are never offended when someone said yeah I'd just like to have somebody at UCLA or USC or somebody at Memorial Sloan Kettering review your case it's it's it's not a problem we do this all the time if it were me and I actually have like to have somebody else take a look at it because one never knows it's always good to have a second set of eyes so on that note that's all I wanted to say and I'll be available for questions as necessary thank you Dan