Category Archives: Newly Diagnosed

“Got It All!” or “Gotcha!” The Guessing Game…

No one wants to look for extra trouble after having been diagnosed with kidney cancer, even if the tumor is small.  Horrified already by the cancer, it is more horrifying to realize that there are no guarantees, even when told by a reassuring surgeon that he “got it all”.  The reality is that even small masses can have sent out cells to other sites, in the rest of the kidney, should it have remained, or to distant sites.  (In cancer, ‘distant’ is never as distant as it should be, as that means there is cancer in some area away from the primary tumor.  Could be lungs, bones or brain, sorry to say.) So now what do you do?  And what can you do?

With the more sensitive imaging techniques, x ray, ultrasound, CT scans, and MRIs, more smaller tumors are being found.  The hope is that finding and removing them will be completely curative, and there are plenty of papers to say that is the case.  But is it really true?  Unfortunately, finding tumors sooner also means that they may need to be “followed” or monitored longer than has been done in the past.

Consider the situation where a tumor about 2 inches in size is found, and scheduled to be monitored for five years.  Though with no symptoms, the patient gets that “last” scan, only to find a newly visible met. Not visible at the year four scan, it may have been slowly growing , unseen for 2-3 years  There may be further monitoring, and perhaps a surgery to remove it or one of the newer drugs is given, in hopes of downsizing or stabilizing the met. Happily the five year plan worked to catch this one.

Had that same tumor been found two years earlier, maybe just 1 inch in size, and monitored for five years, no further met would have been found.  The monitoring may well stop at five years, while the slow-growing met continues to grow, still not visible to the scan. It may only be symptoms at year 7 or 8 which brings the patient back to the doctor, and this time with larger and perhaps more mets, not visible at the year five.

Older monitoring schedules were based on the low and grim expectations for kidney cancer patients. There was little thought to tracking patients for more than five years. After five years there weren’t that many patients!

With earlier detection, and more treatment options, now is the time to review monitoring to capture recurrent disease, which we patient call, “It came back.”

We do look to the five year mark, thrilled to have made it, especially so if we have been cancer-free. Not quite like graduation, but more like the beginning of summer vacation.  But we (and our doctors) must be reminded to keep checking back in with the school principal/CT scan. We need to be sure no leftover bunch of cancer cells have become a measurable metastasis.

Let’s talk about size, as it really matters.  So does the attitude–aggressive or indolent–of the cells of  even the tiniest tumors.  Some may well have sent out their own colonists, looking for areas to set up housekeeping.  Clear cell RCC most often goes to the lungs, so lungs deserve close attention. X-rays can only see a pea-sized met, about 1 centimeter in size, so a CT scan, with and without contrast is best to find new mets.

What are the chances of finding mets, either sooner or later, with a small renal mass?  Lots of stats and some terminology here, so take notes as needed. Better yet,  grab your own post-surgery report, or the imaging reports so you know where you stand.

Measuring Small Renal Masses

Primary kidney tumors are measured on a T (for primary Tumor) scale that runs from TX–no primary tumor found, to T4, which is any tumor 10cm or larger(There are 2.54cm to the inch, so that is 10cm/2.54cm=3.9 inches.  Think four inches, and remember that it can be shaped like a potato, not a ball or a pancake. They can be measured  at a different spots in different scans. That is why measurements can vary from report to report.

T1 tumors are divided into T1a and T1b, and are limited to the kidney.  T1a tumors can be up to 4cm in size, using the largest dimension. Officially this is the small renal mass. Volume counts in the real world, but a 4cm x  2cm will be described as the same size as a 4cm x 4cm tumor.

Tumors which are named at T1b size are still limited to the tumor, but can be up to 7cm in the longest dimension, so about 2 3/4 inches long. The officially small renal masses   No longer described as small, it SOUNDS small by the name.  Assuming that there is no other evidence of cancer outside these masses, this is Stage I cancer. Given the grade of the biopsied tumor, it may be considered to be low or high grade, which is a measure of the aggressive nature of the tumor.

Tumors in the T2 range are also divided into T2a and T2b.  These are still limited to the kidney, with the division at the 7cm mark. T2a tumors are over 7 centimeters (think 3+ inches), and up to  10 centimeters, nearly 4 inches









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Filed under Guidelines, RCC Basics

Into the Abyss: Becoming a Patient

My first foray into the world of “patient” began the day I was diagnosed with kidney cancer.  All my other visits with the doctor, my hospitalizations to have children, and even the odd time I received IVs of blood never had turned me into a patient.  To be deemed a patient was for other people, for those who were sick, or chronically ill.

That was never me until a wish for cosmetic eye surgery led me to get a blood test and the report of extremely low red blood cell count, a hemoglobin measure.   Mostly aggravated that low reading would hinder my plans to have new eyelids, I assumed my approaching menopause  had shifted things a bit for me.  Get “re-calibrated” with some blood, be a bit smarter about eating other than M&Ms for lunch, and all would be well.

Well didn’t happen that way.  Being told by my GP to go to the ER to be admitted to test for my low red blood cell count was more an annoyance, and bewildering.  The GP told me to be careful driving, as I could “bleed out”,  were I in an accident.  Had I taken him seriously, I might have been better off, but who wants to become a patient?

Three pints of blood, a colonoscopy, an endoscopy and a doctor assigned to me by the hospital later, I was sent home with a packet of iron pills, and reminder to eat very well, especially protein.  More liver pate and red meat, and fewer M&Ms, and an improved diet would fix it all, I was told.

Months and more tests later, looking less and less healthy, losing weight, being polite to the doctor, being on time and starting to fade away, I did not know that I was dying.  As I could later determine from the doctor’s notes, he thought I was an alcoholic in need of a liver biopsy to “confirm the cirrhosis”.  That biopsy required an ultrasound, and the race was on.

The ultrasound tech was chatty and friendly, until a sweep of her wand across my lower right belly. She turned herself and her screen away from me and stopped talking.  Knowing the liver was on the left, and her wand was on the right, I had a pretty good idea that the kidney was the new problem area.  Of course, my questions went unanswered, but was told that I would have a CT scan later than day.  But still no answers.

Still in the flimsy hospital gown, I discussed with my husband what was likely my new kidney cancer diagnosis, and figured I would just get a neat little incision, where they could take out the neat little tumor and I would get on with my neat little life.  Off to the CT scan, with more techs discussing me, carefully out of earshot, ignoring my pleas to explain what had been found.  “You doctor will talk to you” was the non-response.

But he was pretty non-responsive as well, waiting until late in the evening before telling me what I already knew, that I had a mass on my kidney.  Masses don’t belong there, so it must be cancer, but he was unwilling to affirm that.  He would find me a urologist the following day, he promised.

That recommendation given without further info, and in light of the frantic internet search, I was not enthusiastic about his recommendations, and especially when the urologist failed to mention any expertise with kidney cancer on his website.  Ain’t a good sign, says I, so plan B was to get to the Mayo Clinic.

I had grown up in western North Dakota and had learned that fancy health problems spurred a trip to Rochester, Minnesota.  Within a few days, I was in the Mayo Clinic, going through a series of new tests and imaging with the urologist appointment at the end of the day.  Try to coordinate that in less than 24 hours, and you will appreciate the miracle of Mayo.

At that appointment, my neat little tumor was now described as a malignant mass, about the size of a softball.  It had pushed the kidney up toward the liver, and thus caught the attention of the US technician.  Bad enough, I thought, but the subsequent CT had also shown my lower lungs to be full of tiny mets.  Mayo’s more thorough CT showed my entire lungs to be filled with tiny white metastases.  Not only did I have a huge tumor, my lungs were essentially a tumor colony.

Stunned, and nearly deafened by this news, I struggled to hear the doctor say, “I have a plan for you.”  With that hope and that plan, I began to breathe again.  And have been doing so for the last 10 1/2 years.

Thanks to so many people at Mayo, including Dr. Brad Leibowich, his staff, the angel nurses, and the Mayo brothers who created this wonderful place.

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Filed under About Peggy, Newly Diagnosed, Patient Resources, Your Role

My Radiologist or New Best Friend

In our kidney cancer world, it is unusual even to know the name of the radiologist, and most patients rely on his report, as given to the doctor. Many kidney cancers are “incidental findings” on CTs given with another diagnosis anticipated, broken rib, for example. Thus, it is the radiologist who recognizes the cancer long before either the doctor or patient. It may be a metastases that is found, with the primary tumor not yet imaged, or vice versa. If the tumor is relatively small, and no mets are seen in that initial scan, most patients are assumed to have localized disease. Often there are sudden plans for surgery, but not necessarily to search for other distant mets. The patient may be told, “I got it all.”

Of course, that is the best news, and the only news we want to hear.  But we are wrong, as what we NEED to know, even before the surgery, is whether or not there has been a spread of the cancer.  Treating kidney cancer is already a guessing game, and without knowing the whole game and all its rules, the patient is too often the loser. (Look for a longer, somewhat geeky post on small primary tumors and their potential to metastasize, both quickly and years later.  Ain’t a pretty picture.)

Any good radiologist will know that even small primary tumors can have already produced distant mets. That radiologist likely knows  that additional imaging should be done in such cases. The GP or even the urologist without RCC experience may NOT know that.

Too often small, overlooked mets in the lungs or on a bone can go unnoticed for months or years. Only the radiologist can provide a complete understanding of the extent of the cancer, and only with imaging outside the area of the “incidental finding”. He is the first line of defense, and often the first real expert in determining the extent of the disease. Thanks to those unsung heroes!


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Filed under Ablation & Radiation, RCC Basics

Pathology and Why It is So Damn Important!


How Does the Pathology Report Help Direct my Treatment Options?

Lecture by Dr. Daniel Luthringer of Cedars Sinai Medical Center of Los Angeles at Kidney Cancer Association meeting December 2013.   (Follow via YouTube)

I have transcribed the lecture edited for readability, included the slides, to make it easier to follow.  If you have not seen your own pathology, GET THAT REPORT now. Important to read!

A terrific introduction by Dr. Robert Figlin reminds us of the work of those people we never meet, but who care for us. “One of the people behind the scenes is the pathologist at this and other institutions. Often times the pathologist is in a different part of the hospital evaluating tissue, and helping the clinician figure out what the tissue looks like. It’s become, as Hyung (Dr. Kim) mentioned, time to start to think about personalized approaches to kidney cancer, and the relationship between the pathologist, the surgeon, and the clinician becomes ever more important. Dr. Daniel Luthringer is Professor of Pathology and Section Chief of the Genitourinary Pathology. He will talk to us about how the pathology report and how what he does– is important to then what we decide how to go forward with treatment.”

Dr. Luthringer begins:

“Thank you, Bob, for this introduction and the ability to speak at this conference. I am the guy behind the scenes, at least at this institution responsible for doing the histologic/microscopic analysis of genitourinary malignancies, primarily renal cell carcinomas. (RCC)

1 PATH 1 PathReportTypesThere are really two main categories of specimens we receive, samples from the real tumor itself, which can either be biopsies or resections, as Dr. Kim alluded to, or samples from a metastatic site, a recurrence or a metastatic site. The most common specimens that we see are nephrectomies, resections of the tumor, andeither partial nephrectomy or complete nephrectomy.

2Path 2 Types of Spec These are examples. A partial nephrectomy, as per Dr. Kim, are smaller resections or partial resections of the entire tumor.They include a bit of nephric fat and a little bit of the perinephretic fat as well. The goal is to get the entire tumor out, with a negative margin of resection. With tumors that are bigger generally, or infiltrative, we tend to get the entire kidney. This is an example of a nephrectomy with perinephric fat, the sinus fat, drainage area down here, maybe an adrenal gland up top and this would be an example of tumor that is completely resected.

Occasionally we will get tumors from metastatic sites or—unusually from the primary tumor—and will get a core biopsy, which is really a small smaller sample of the tumor mass. Usually it is about a millimeter or two in diameter; it’s a core, maybe up to several millimeters up to a centimeter in length. Generally, it is just a small sample of a much larger tumor .

Path 3 Speci Handling3  A bit about the specimen handling: within a few minutes of having the tissue removed, it comes to the pathology lab. We do some initial assessment on it.  We have work stations where they will come and the pathology team will assess it. Assume it is a nephrology specimen.  We look at it and measure it, cut it open, procure some of the tissue.  If there is some tissue that needs to be taken fresh, potentially for a biobank to be stored away, or if some tissue needs to be taken for immediate diagnosis or margins or something like that, we will do that.

If you’re enrolled in a study where there some fresh tissue is needed, sent to a particular institution or a reference laboratory for an analysis, we will procure that as well and make arrangements to send it off on an immediate basis. At that point we do photography, tissue fixation and over the next few hours we will dissect the specimen, will analyze it, do a lot important evaluation with our eyes and ears, whatever it takes. Then we will take what are called representative sections of that tumor or specimen, put them. We 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.

Path 3a Specimen Handling3a The next morning the tissue is taken out of the processors and is manually placed in these other tissue cassettes which are filled with paraffin wax essentially. They are embedded into these wax molds, and then the blocks. Then very thin sections of 4 to 5 microns are cut with these special microtomes and they are picked up on the glass slides. They are again processed, stained, and cover slipped. Ultimately we get a sample of glass slides from that tumor that has been removed.  On an average partial or complete nephrectomy, we will go anywhere from 5-10 paraffin blocks, equating to 5 -10 glass slides.

Path 4 Speci Handling2This takes about a day or two to complete this. Then the initial slides are delivered to the pathologist, who will begin the process of microscopic analysis. He uses obviously his microscope and whatever tools he needs.

He’ll be looking at those sections from the slides, and it will usually be the sections from the kidney, maybe some lymph nodes, margins, adrenal glands, things that were provided by the surgical resection. The whole process usually takes 2-3 days to complete. There is a bit of a time lag, due to the technical processing involved.

Path 4a Import element of report4a The Elements of the Report. Once we generate the report, and it becomes available, there are really three categories of information that are really relevant– not just the diagnosis, but the future care of the patient. The first is the diagnosis. What is the diagnosis? Is it really renal cell carcinoma or is it some other unusual type of renal cell cancer? I will talk more about that. Then: aspects related to cancer stage–tumor size, local infiltration. Has it metastasized or spread? Last, the other features that Dr. Kim alluded to in his talk—resection margins, grade, vascular invasions. We will talk to about these just briefly.

Path 4b Not all masses4bThe first aspect is diagnosis. The important thing to remember, and I think everyone in the room is a little bit beyond this, but remember that at the initial phase, tumors are resected and often times it is not know if it is a RCC. Often times it isn’t even know if it is a neoplasm at all. Not all tumor masses are neoplastic or malignancies.

Path 5 Exp of non cancer tumors 5 Examples of non-tumor masses would be like cysts, a lot of cysts. A lot like this or areas where the collecting system is dilated called hydronephrosis or multiple cysts can present or look just like a RCC. They are resected as if they were RCCs. But in fact they are not—they are benign

There are other types of tumors besides kRCCs. Angiomylipomas are a very common tumor. They could be very big like this one. Here’s a kidney. Here’s a big one. They could be multiple. Here’d two. They could be small one or 2 cm like this, but they all look like fatty tumors, but not all RCCs. Different types of tumor like fibroma or oncocytoma can be very big and aggressive-looking, but in fact, they’re not malignant at all.

Path 6 ex of cancer not RCC6 There are other types of malignancies, true malignancies of the kidney which are not real carcinomas. Urothelial tumors, those that are derived from the lining of the kidney that can extend into the kidney, be derived of the kidney. These are examples of some of these here. They were resected, thinking that these are probably RCCs, but in fact they turned to be urothelial, not RCCs.

Different types of tumors like sarcoma can be derived of the kidney or around the kidney. Other types of tumors can metastasize to the kidney or near the kidney. Adrenal tumors, lymphomas—there is a whole host of malignancies which can mimic RCC.

Path 7 RCC7 What were really talking about today here obviously is renal cell carcinomas which represent probably 90% of more of all true malignancies of the kidney. These are the tumors which are derived from the renal tubular epithelian cells, those little ducts that line the epithelium of the kidney. The diagnosis of RCC really is contingent upon microscopic analysis. You can’t make the diagnosis any other way.

The pathologist needs to look at the gross, take a section, look under the microscopic, and then there’s a spectrum, a range of features that will ensure the diagnosis or put it into a diagnostic category of RCC. Sometimes is not so simple. We need special testing–the use of antibodies, immunohistochemical 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 RCC.

Path 7a RCC Subtypes7a Once we’ve done that, the next phrase is to determine the subtype. There are many different subtypes of RCCs really based primarily on the appearance of the tumor cells and their architectural growth patterns. Sometimes they can rely on immunohistochemical, some of the molecular properties or genetic profiles that put it in the proper subtype category.

Now the subclassification of RCCs and probably this is familiar. You’re familiar with RCCs and it is not so simple. It’s an evolving, sort of complex and ever-changing categorization. In fact, the overall categorization of subtypes just changed a few months ago. We like to think about RCC and subtypes in a sort of developmental pathway.

There is a sporadic type– that which just happened to occur–which is probably the type of cancer that most people in this room happen to have. Those are our typical clear cell, chromophobe, papillary renal cell carcinomas or maybe a few of the other rare variants.

There are those which tend to be familiar; these represent 90+ percent of all RCCs. The familial patterns–again what is associated—they are pretty rare. They are associated with and in families, multiple tumors. Different family members can have these, and we will talk a little bit more about these. There is actually going to be a talk about later in the afternoon or the morning about genetic-based or familial-based RCCs.

There are those rare—really associated with treatment of other types of cancers, and there is unusual category when you have scarred or damaged kidneys. Those kidneys are at risk for developing RCC.

Let’s move through this little bit. Once we have made the diagnosis of RCC, we’ve sub categorized it. I know it seems complex, but there are really only three or four main subtypes that we really need to talk about, especially in the context of a setting like this.

Path 8 RCC Most types8 The most common subtype is the clear cell type. This represents about the vast majority of all sporadic types of renal cell carcinoma. Then there are the papillary and chromophobe renal cell carcinomas. Since these are really the usual types. The much less common type is collecting duct carcinoma which is really more like a urothelial cancer, it behaves like a urothelial cancer, it’s a more aggressive type of RCC.

These are really the main four that we need to be concerned about. They are each unique based on their gross appearance and these are all partial nephrectomies (this is complete down here). Look at their gross appearance. They are very unique under the microscope. Look at their microscopic appearance.

The clear cell is clear, the papillary, very architectural pattern of a papillary tumor. These are chromophobe. This unusual eosinophilic cytoplasm are the tumor cells. Probably doesn’t mean a lot to you, but it means a lot to us, also to some other clinicians. So they have very characteristic gross, microscopic and they are 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.

And we all know—this is small graph—that these also behave differently, Some behave better than others, so it is really important that we subclassify these RCCs based on their appearance—all the appearances that we talked about.

Path 9 Potential Therap Implic9 The other thing that Dr. Kim alluded to, and I think we are going to talk about this a little later, and I won’t get into detail on this, but just to point out that the sub-classifications, the sub-categories, they respond differently to the different armamentaria that we have in terms of treatment modalities. So it’s very important for the pathologist to sub classify the type of RCC.

Path 10 typ report10 So on any standard pathology report, you are going to see the diagnosis, RCC, then the subtype, buried somewhere in the report; It will say, clear cell type, papillary type, chromophobe. That’s a very important part of the report.




Path 11 Imp Elements of path11 After diagnosis, the next important aspect is the cancer stage; The cancer stage is really defined by the size of the tumor and its local growth. Is it extending, is it staying confined to the kidney, outside the kidney to the local fat, is it going into any regional lymph nodes that might have been removed during surgery, or was it extending into the adrenal gland, which might have been removed as well? So we analyze each case on what we have and what we see.

This is a typical example of a partial nephrectomy specimen of clear cell carcinoma with a margin that’s out here. Here it measures about 2.1 centimeters the margin is negative. This is a very small tumor of clear cell RCC. This would stage out at T1a, pretty low stage tumor. This would have a pretty good prognosis based on that staging profile.

Path 12 Imp elements of Path 212 Now compare that with this tumor which is a complete nephrectomy specimen, shown the kidney, a lot of nephritic fat. Here’s the sinus of the kidney and here’s the tumor out here. Much bigger, about 9 centimeters and it is growing into the fat. It’s growing into the sinus fat; it is demonstrating more aggressive local growth. This would stage out—this is a microscopic showing it extending into fat. We would stage this out at T3a tumor, as it is obviously larger and more infiltrative.

Path 13 Imp Elements313 A different example would be the same thing. A RCC clear cell type; this is a full nephrectomy specimen. Here’s the kidney. Notice that the tumor is extending into the renal vein. This is another feature that we analyze and look for. We look for it grossly and microscopically and look for tumor extension into that vein, because that will upstage the tumor, overall tumor stage, and this is associated with generally adverse outcome. It is telling us this tumor is behaving more aggressively with local growth. We might see a lymph node, with metastatic clear cell RCC. Again, another aspect we would examine grossly and microscopically.

Path 15 Import elemts 515 So we take all these features, once we have analyzed the tumor and we apply the grading system created by the Joint Council on Cancer Staging, the AJCC and we apply the pathologic stage. Why? Because as Dr. Kim alluded to, we all know, that cancer staging, and it is true for any type of cancer, the higher the stage, the more aggressive that tumor will likely behave therefore the therapy needs to be tailored to their particular stage. And the report should indicate clearly dictate the tumor stage. And that’s part of the standard reporting. Any good cancer report.

Path 14 Impor Elements 414 The final cancer features I’m going to talk about we’re talking about are; resection margin, the grade, vascular invasion, tumor necrosis and this this unusual rhabdoid or sarcomatoid differentiation. These are elements which go beyond cancer staging and the diagnosis. Here’s two examples.

Path 16 impor eleme616 Let us talk about resection margins. These are indirectly related to or they indicate the local aggressiveness of a tumor, if they are growing to a margin. It’s ideal when a partial nephrectomy or a complete nephrectomy is performed, as we have here, the surgeons always try to get the whole thing out so we achieve negative margins . That is optimal. Sometimes it’s not possible, especially if we have a high stage RCC like this one which is extending into fat. Sometimes it’s impossible to get a clear margin. This might get portend some additional therapy when it comes to therapeutic– time for a therapy . With a smaller resection sometimes it’s impossible to get a negative margin or the surgeon needs to go back and take cleaner margins. That interpreted for frozen section analysis, and clear out that margin, again because optimally, we want to achieve a negative resection margin.

Path 17 Imp elements 717 The next factor is vascular invasion. When the tumor invades into those lymphatics that Dr. Kim talked about in surgery. They have a propensity for them to go to the lymph node or they can go into veins or even sometimes arteries and then they have unfortunately, the capacity to go to the lungs or bones 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 include it in the report. Also if there’s tumor cell degeneration and necrosis, that is usually associated aggressive growth in the tumor and we will report that, too. Sometimes that will dictate how the next round of therapy will be undertaken.

Path 18 Imp elem 818 Dr. Kim already talked about tumor grade. We apply–the pathologist applies the tumor grade. The Fuhrman grade is the one that is used for RCC, and it a grading system for 1 to 4. Really, it delineates the degree of differentiation. Grade 1s are well-differentiated tumor, grade 4 are poorly differentiated and in any type of tumor–doesn’t matter if it’s breast, color, renal cell carcinoma–generally well-differentiated tumors behave better than poorly-differentiated tumors.And we assign a grade based on our observations.

Path 19 Imp Ele of report19  Finally, sarcomatoid or rhabdoid differentiation. Most tumors will have just one type of differentiation. This is an example of RCC. The vast majority are RCCclear cell, the conventional type. But in it, there were some pockets where the tumor cells had this unusual morphology under the microscope, called sarcomatoid differentiation, or over here, with we had this rhabdoid differentiation. You can see it that it’s 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

All these last category features that I talked about, once we have observed them, we include them in the report. Again, usually any standard RCC report will have these features included in them because they will really impact upon therapy. *See slide10

Path 20 Hereditary20 Two quick categories and I will be done here.I was say a couple of words about hereditary genetic syndromes associated with RCC. This is taken out there that long list that I presented a few slides back. We all know that there are well-known, well-defined syndromes–genetic syndromes or familial syndromes that put you at increased risk from dying from other neoplasms, including RCC, notably Von Hippel Lindau, tuberous sclerosis, Birt-Hogg Dube, these sorts of things. The bottom line: 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, tubersclerosis, or whatever.” All I can say is that it is clear cell carcinoma.

Path 21 Hereditary Genetic21 There are a few types of tumors that I can look at and say, if they have unusual morphology, like this tumor up here, or this tumor up here (references images) , they don’t comfortably fit into the typical types of RCC. Maybe it is a syndromic-type of carcinoma. Very, very rare, less than one percent that we would ever suggest to a clinician that maybe this is syndromic. What we can do is when we get samples like a renal resection like these three different cases, where there are multiple tumors. Here we have multiple tumors or multiple cysts—here we have maybe 20 or 30 different tumors in the particular kidney—or here’s a younger patient with one, two, three separate tumors. Then we can suggest that there is something odd about this, as we usually don’t see this in sporadic type tumors. Maybe it is associated with a genetic syndrome. So; multiple tumors, cysts, a young age, presentation of a renal cell carcinoma of unusual histology, we will suggest to your treatment team that maybe this is a genetic or syndromic pattern of RCC. There’s going to be more on this topic later this morning.

Path 22 Secondary Reviews22 The final topic I was asked to talk about the performance of secondary slide reviews. It’s kind of important. It’s really important when you come to an institution for definitive therapy, it’s always good to have that team—and we do this all the time—review the outside slides to be sure that you have an expert team who works with your treating physicians. We work as a team through tumor board reviews and discussions, and almost every discussions–.                                                                                                                                                       Almost every single individual case, to ensure that we have the correct diagnosis. We have the critical elements included in that report. The specific special testings have been performed, and we have accurate diagnosis and staging and things like that. What you need to do is provide, when you come here, is a copy of the reports, a set of the glass slides, sometimes we call them the recuts. That is all we need to provide an incoming secondary review.

The other scenario when you go off, you might need to off somewhere else for some additional testing for some additional therapy. In that situation, you might need to take, or you should take a set of slides with you to that institution because they will probably want to the same thing and review to ensure that we are all talking about the same disease process.

Remember that your slides or blocks, when you are 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 done down in Torrance. T. They are basically saved forever. So when you need to go somewhere in five or ten or fifteen or twenty years, God forbid that there is a recurrence, and you need to get some additional testing, we can pull those blocks out from Torrance (CA) and create a second set of recuts, or a third or fourth set. We can send it off wherever it needs to go for some additional testing or evaluation.

Path 23 Authorizat23 What you need to do is fill out this authorization form here at Cedars if you are being treated here at Cedars. All you need to do is check off “Get a copy of the pathology report” and please provide a set or recut. It’ll take a few days, three days. We’ll get that for you, send it 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.”

With that Dr. Luthringer thanks the KCA, the audience and Dr. Figlin for the chance to speak.  And with that, I agree remind you to get a copy of your own pathology report, and know where your slides are stored. If there is any questions as to your own pathology, if the tumor seems to be unusual, or of an especially high grade, do yourself and your family a big favor, and discuss whether a review of your slides is in order!

With this rare disease, and the complexity of doing the kind of analysis you see here, do not be afraid to get that second opinion.  Go back and see so that pathology may affect the treatment options given–very important!










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Filed under Genomics & Genes, RCC Basics

Adaptive Immunity in Cancer Immunology & Therapeutics–My Summary

I was dying ten years ago. My kidney cancer had moved into my lungs, threatening to choke me to death.The tumor and kidney were gone, but 100s of tiny lung metastases were growing. Lucky to get an FDA-approved immune therapy, high dose interleukin 2, my own immune system was revved up so as to destroy the cancer. Thus, I am intrigued by all things about the immune system and cancer research. “Adaptive immunity in cancer immunology and therapeutics”is one of the most comprehensive explanation of the tumor cell/immune system interactions–that I can somewhat(!) understand.

My summary is below, a more patient-friendly version. Don’t hesitate to take on the original, via the link! It is just the kind of article to take to your doctor to discuss immune response meds/treatments. It begins with the “abstract”, a summary of the information to follow.

Abstract: The vast genetic alterations characteristic of tumours produce a number of tumour antigens that enable the immune system to differentiate tumour cells from normal cells. Counter to this, tumour cells have developed mechanisms by which to evade host immunity in their constant quest for growth and survival. Tumour-associated antigens (TAAs) are one of the fundamental triggers of the immune response. They are important because they activate, via major histocompatibility complex (MHC), the T cell response, an important line of defense against tumourigenesis. However, the persistence of tumours despite host immunity implies that tumour cells develop immune avoidance. An example of this is the up-regulation of inhibitory immune monoclonal antibodies in clinical practice have been developed to target tumour-specific antigens. More recently there has been research in the down-regulation of immune checkpoint proteins as a way of increasing anti-tumour immunity.”

Immune Responses in Tumors—A Quick Summary by Peg

Since cancer cells are genetically different from normal cells, they also produce different substances—antigens—which can make them more noticeable to the immune system. Any antigen will generate a response from the immune system—think how the body reacts to an infection, an insect sting or a splinter.
Antigens trigger the immune system into action, keeping abnormal cells from taking over the system—most of the time. To grow, tumor cells develop inhibitory responses to limit or down-regulate those immune responses. An over-active immune response can be problem, well-known to those with severe allergies or auto-immune diseases like lupus. Keeping the proper balance is the norm for the immune system, despite ongoing external and internal changes

Using knowledge of these interactions to support the immune system, researchers have develop agent/medications. These are intended to strengthen the beneficial responses, and to prevent the tumors from suppressing or down-regulating those desired responses. Some monoclonal antibodies can effectively target these tumor-specific antigens and trigger tumor death or inhibit such growth. Some of these new agents include bevacizumab (Avastin), rituximab (Rituxin), alemtuzumab (Campath or Lemtrada), bortezomib (Velcade), denosumab (Xgeva) and trastuzumab (Herceptin), among many others, and for a variety of cancers.

Be aware that these agents may be called by the brand name, as Sutent, or the scientific name, as sunitinib, and may have several brand names for different cancers. Just another new challenge to all of us newbies.

Tumors exist with a system of structures, various types of cells and with a chemical signaling process. These shifts away from the normal cells and organs produce tumor antigens. The immune system notices the antigens and works to destroy the foreign cells. Then the tumors shift to counter the immune response in an endless signaling battle. It is a dynamic “fail-safe” system, with multiple checks and balances, work-around pathways, evasive signaling, and constant testing to maintain itself. When this system does fail, a tumor can be established and move to different sites.

Solid tumors have a tumor core, a margin that is invading into a healthy structure–blood vessels or layers of an organ–and lymphoid components. This can vary patient to patient, despite the seeming similarity of tumors, and vary from one metastatic tumor site to another. Inside the tumor will be the immune-cell types–macrophages, dendritic cells, natural killer (NK) cells, mast cells, B cell, and T cells. Different immune cells can be found in different parts of the tumor, and the variation and the density of these cells may play a role in clinical response. It may be that this reflects the robust nature of the natural response to the tumor invasion, or reflect that the system is being overwhelmed by the tumor. Others think that the infiltration of immune cells can be utilized the support of the treatments given to the patient.
The linked journal article goes into detail as to the various types of responses, including adaptive immunity, immune editing and immune evasion. In summary, there are numerous approaches to limit tumor growth within the complex system of antigens and immune responses.
As immune cells infiltrate a tumor, that infiltration can be measured. What is the meaning of a higher or lower level of immune cell infiltration? The following paragraph sums up the challenge of using tumor infiltration as a marker of prognosis or treatment response.
It is a commonly held belief that infiltration of immune cells into tumor tissues and direct physical contact between tumor cells and infiltrated immune cells is associated with physical destruction of the tumor cells. That can reduce the tumor burden, and improve prognosis. An increasing number of studies, however, have suggested that aberrant infiltration of immune cells into tumor or normal tissues may promote tumor progression, invasion, and metastasis. Neither the primary reason for these contradictory observations, nor the mechanism for the reported diverse impact of tumor-infiltrating immune cells has been elucidated, making it difficult to judge the clinical implications of infiltration of immune cells within tumor tissues. J Cancer 2013; 4(1):84-95. doi:10.7150/jca.5482

Tumor Infiltrating Immune Cells—a Good Sign or Not?

If the immune system is at work, immune cells infiltrate the tumor to work directly against the tumor cells, is the tumor destroyed? Does the body naturally destroy the tumor? Does the patient benefit from medical treatments which support the immune system? Unfortunately, the presence of the tumor-infiltrating cells can mean very different things, with a better prognosis in one type of cancer, and a poorer prognosis in another.

Monoclonal antibodies can target antigens in blood cancers and solid tumors. In blood cancers, antibodies counter several cluster of differentiation (CD) markers, and in solid tumors, growth factors such as EGFR (epidermal growth factor receptor) or angiogenesis factors, such as vascular endothelial growth factor (VEGF). The mechanisms of action can lead to direct cell death, or simply impede its growth or inhibit checks on the immune response.

Normal cells are naturally programmed to die, but cancer cells do not “follow the program”. When certain proteins on the surface of cells bind with one another, the expected immune response is inhibited. These anti-PD-1 (anti-Programmed Death-1) proteins bind with other proteins, the binders or ligands, PD-L1 and PD-L2. Studies indicated these agents can help the immune system, with some disease stabilization or tumor shrinkage. Recent trials show some response by 20-25% of patients, some of whom had failed previous treatments. Some responses lasted more than a year. In a few cases, some responses were lasted for a period after stopping the medications. Newer trials will likely combine several of these therapies. This is not without risk, as some had severe side effects, and several patients  died from such side effects.

Nevertheless, the earlier successes with this approach and the increased knowledge of the various immune responses to be targeted will continue, especially in combination studies. This work will have impact on existing immune therapies, as does the more integrated approach to cancer treatment.

I welcome any comments and corrections, and remind you that I am a patient, and am not a medical professional. My goal is to help educate other patients to receive the best understanding of their illness and best possible treatment.

Peggy Zuckerman

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Gene Sequencing? What is it? Does it Matter? (* *YES***)

We hear about gene sequencing and personalized medicine, and yet few of us really understand what that means. All of this, despite the hype! We also hear about targeted therapy. As a minimum that should mean that doctors are targeting the tumor for destruction, but is not that easy.  As usual.

The University of North Carolina researchers have done critical reviews of clear cell kidney cancer. They questioned why there is such wide variation in the aggressiveness of clear cell RCC (ccRCC). Almost all ccRCC looks alike under the microscope, the usual “pathology” report, but tumors don’t behave the same. Some are shockingly aggressive in their growth, even the small ones.  They metastasize quickly, and break the surgeon’s “got it all” prediction.  The overall survival (OS–the longer, the better!) is wildly different, despite the similarity.

If this is the same kind of cancer, why does it behave so differently?

The obvious answer is that these tumors are not really the same biologically. That can be shown by an inside look at the tumor’s DNA and patient’s normal kidney DNA. This is what gene sequencing can do, i.e., help define what differences exist in the tumor cell. This is essential in “targeting” the treatment to the tumor. You have to see the recognize what IS the target to hit it with the right treatment.

This linked YouTube lecture below helps explain these new terms. It gives me appreciation for the challenge faced by researchers, clinicians and patients in getting proper treatment.  And nobody cares as much as we patients!

Dr. Kimryn Rathmell and colleagues at U of NC created a test which can differentiate the more aggressive form of clear cell kidney cancer from a less aggressive form.  Should one monitor a smallish tumor, monitor a patient more closely after surgery, or just assume everything is fine and dandy?  These tests help in that decision.  (PS Don’t forget that a “small” Stage 1 kidney cancer tumor can be the size of a golf ball.  “Regular” size Stage 1 tumor can be the size of a nice tomato.  Small, indeed.)

We’ve learned it isn’t just “cancer”. It’s not just “kidney cancer”. It’s not even just just “clear cell” or “papillary” or “chromophobe”! Instead it is a molecularly defined cancer which has taken up residence in one’s kidney. Different drivers, some more aggressive than others–big surprise.  Different strokes for different folks, and different targets for different testy genes in our tumors! A transcription can be found in “Genetic Sequencing for Dummies and Me”


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Treatments for Metastatic RCC? Does Timing Matter? Who Is On First?

“Now what?” may be the first coherent question a newly diagnosed cancer patient asks.  Maybe the smarter version of that is “What–when and why?” And your doctor had better have a good answer, as to the treatment, the when and the why.

We cancer patients usually get surgery “first”, even when the disease has spread.  Primary surgical strike and then a clean-up operation, in the ‘war on cancer’ parlance, we think–when we can think. “But which is the best and first clean-up approach?” we must ask. “What works the best? What can I take with my other health problems? Where does surgery or radiation fit in this scheme? What does the doctor favor and why? Where do I get this treatment? And then what?”

Treatments and their sequence are often chosen with little reliance or clarity as to the data. But some light was shed today at ASCO (American Society of Clinical Oncology). It released a comparison of the sequencing of High Dose Interleukin2 (HD IL2) and of targeted therapies for metastatic RCC.  Which should come first?

It shouldn’t be a high-stakes  gamble to choose a medication, as no one can guarantee any results–with any of the meds. You take a chance with any drug, so which do you start wi We may be closer to a logical approach in sequencing these drugs. Sequencing of these highly different medications has measurable effect on overall survival (OS)—and to patients’ lives.  That sequencing is critical and certainly can extend life, even when treatments fail, as they so often do.

A retrospective study  of 97 US patients who received HD IL2, before or after a targeted therapy was just presented at ASCO. These patients were followed for a median duration 37 months–half more than 37 months, half fewer than 37 months. Of that group, 22% had either a partial (14%) or complete (8%) response to HD IL2. (No specifics as to what was a “partial” response, perhaps a 30% shrinkage of the total tumor burden). In addition, another 24% of patients had Stable Disease(SD). Thus, nearly half of these patients benefited from having had HD IL2.

Stable disease is better than progressive disease, as any patient knows, though it was rarely measured in older trials. Though we patients really want a cure, we do want to be around for the next treatment, to have a surgery or ablation to remove the “stable” tumor, or to try another medication.

Of these 97 patients, 82 received HD IL2 before any targeted therapy. Another 15 patients had HD IL2 following a TKI therapy. That timing made an important difference. HD IL2 followed by the TKI, showed a median Overall Survival (OS) of 61.8 months. The OS of those with the TKI before the HD IL2 was 48 months.  A median, not an average, so half lived longer, half lived shorter than the quoted medians.

A pre-2006 NCI (National Cancer Institute) series showed a 19 month median survival for HD IL2 alone, and a similar 19 months for the use of targeted therapy alone. Using the two in sequence dramatically improved OS, especially when HD IL2 was first line of treatment.  Obviously things have improved, though it can be very difficult to compare older trial data, as so many variables are different–including the type of RCC the patients had as they entered the trials.

Several points can be made from this study. First, no therapy should be examined only as to Complete or Partial Response. Stable Disease also adds to Overall Stability.  To stop the tumor from growing, even if for a period of time, is valuable to patients and can prep them for the next anticipated treatment.  Sure beats tumor growth!

Second, therapies should be chosen to maximize their impact on the overall survival of the patient. Some patients will naturally be precluded (or delayed) from surgery, or taking one drug due to existing co-morbidities, due to heart disease or liver damage. For those post-op patients, likely to tolerate the side effects of HD IL2, it should be given in a first-line setting.

The most critical variables that impact patients are the recommendations and expectations of the physician. Most patients are not even told about HD IL2 treatment, or it is dismissed casually as “not for you”.  Others are told to wait until more mets emerge, with some weird theory that waiting for more trouble is a good thing!  Many nephrectomy patients are not monitored post-operatively, despite the risk of mets. This is surely an indicator of the lack of knowledge by urologists. Still others are told that the disease has spread, and that nothing can be done–also untrue.

The rarity of RCC and its variants leaves most physicians unaware of all options in the field, and how to any one might suit for a particular patient.  Most oncologists to whom patients are referred, have little or no experience treatmenting for RCC, or may not access to academic centers for support until it is too late. Even the pathology of the primary tumor and later metastases may be questionable, adding to the challenge of care.

With the dramatic changes in the RCC field, this is to be expected—but not tolerated. The patient may have to provide his physician with the data that can extend or save his life, which is a sad but realistic commentary on the field today.


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Molecular Marker for RCC/ Papillary RCC. Molecular

One of the many challenges in fighting kidney cancer is knowing where it all got started.  This research indicates that a gene gone astray, the MET gene, is part of the problem from some patients.  It is this type of study that will change the treatment for us, as there will be greater clarity as to the “target” to be reached by “agents of change”.  (Nothing political intended, but seems to work here!)  Especially of interest to patients who have the variant of papillary RCC, about 10% of us.

 MET Variant as a Prognostic Marker in Clear Cell Renal Cell Carcinoma

 Dr. Ari Hakimi of Memorial Sloan-Kettering Cancer Ctr.,New York USA

ASCO GU Congress 2014

eCancer reporter Peter Goodwin’s questions are in italics. Where I was not certain of the lecture, I added a (?) to show that. Link below to the actual lecture.

Ari, you have been looking at prognosis or prognostic features, or actually, molecular features of renal cell carcinoma. Can you tell me what you were doing in the study you’ve just been talking about?

There was a great paper that was published by the people at Harvard and Lancet (?) Oncology last year. It found for the first time a prognostic marker that was associated with poor survival in kidney cancer, a molecular marker. This was a variant, a normal variant in the gene, the MET gene. In that study they had several hypotheses they generated from that study, but they didn’t really have enough genetic data to try to figure out what was going on here with this variant in the genes. So what we did was, we took that same concept, that same variant, in the Cancer Genome Atlas Study, which has both patient information and then a host of genomic information. We tried to validate their finding and explore the biology of that marker.

It sounds like a needle in the haystack but you’ve but you become quite familiar with this variant called RS11762213. What you know about it so far?

 We know about that it is a variant in the MET oncogene, a very important gene in a lots of different cancers, particularly in papillary renal cell cancer. It’s a gene not thought to be very important in clear cell renal cell carcinoma, but we found that it is, and we explored the variant in an exonic region of the gene–meaning the coding region of the gene.  Because the variant is in a coding region of the gene, we thought it might be more than just a prognostic marker. It might also have some biological implications.

Biological implications?  What sort of biological implications?

 We think the marker may be; we figured out through computational methods, exploring the TCGene data(?) that it might be in the region of enhancement,  meaning the variant leads to higher activation of the MET oncogene.  In turn, this might explain why these patients have a poorer outcome.  It might also have potential therapeutic implications.

So what have you found so far then, about the level of additional risk if you happen to have this variant gene?

Great question.  We took about 270 patients from the cohort who had available information.  We genotyped them, meaning we determined what percentage of these patients had the risk variant, which is about 10 %, consistent with prior studies.  We showed that when these patients had that risk, in addition to the current prognostic features, they had about a 3-4 fold increased risk of cancer-specific death, or tumor recurrence after surgery.

That’s really quite powerful!  Am I right that there wasn’t any clear kind of molecular feature to give you some help in the past?

Until this study, which was published last year, there were really only tumor features and patient features that were associated with poor survival in kidney cancer. This is the first study that really showed, that they published last year, to show in two different cohorts that had a molecular feature that added to the prognostic models.  We showed, augmented their findings, that if you took the best current prognostic models and stratified patients, added to that model, meaning it improved the predictive accuracy of even the best post-surgical models that are out there.

You are looking actually disease mechanisms–mechanisms of cancer production. You established prognosis, but what about predicting response to therapy?

That’s a great question. Our goal now– that we’ve established that this is a valid biomarker, truly multiple cohorts now showing this marker can stratify patients for aggressive behavior, we can now explore—hopefully–whether this has therapeutic implications because it is in a gene that is a known cancer gene.  Because there are multiple drugs that target this gene, and because we think that this variant that is activating this gene, it stands to reason that an inhibitor for these patients with this variant might work. These patients might have another option.

So theoretically a new drug which is an inhibitor for this variant might work.  What about existing cancer drugs? Do you have any ideas about if any these do influence that variant?

We don’t know yet. We are trying to find it in cell lines, meaning cell lines that are derived from tumors that are used in the lab, to see MET inhibitors that currently exist and are in phase I or II trials in kidney cancer could potentially be used against patients against this variant. That could be a very powerful tool, and a kind of the precision medicine that were looking for.

This is an amazing achievement, actually going through the Cancer Genome Atlas to find information like this, information about expression. In the realm of the everyday cancer doctor with patients to treat today, tomorrow, what you think the doctor should take home from this development?

The exciting thing about this is to genotype the patient, that is to determine that this patient carries this risk variant, is something you can detect from the patient’s blood or even a swab from the cheek. It’s a very inexpensive. It costs about $10-$70 to get this information for a patient. You can have what is called a liquid biopsy, meaning you need any tissue. You can get it from their own normal cells, because this is germline variant. You can find out this information very affordably and very quickly to determine risk for these patients. Obviously, if we are able to show that it has implications for therapy, that as a whole opens a whole new avenue.

How much hope to have that this it will be possible to manipulate this gene expression by using this kind of drug to target this?

I think that the data there is quite strong for other types of cancers. We know that other genes that are overexpressed or mutated in activated fashion respond quite well to inhibitors. This exists in multiple cancer types, lung cancer, breast cancer, for example. It stands to reason that this would work as well in kidney cancer, and the hope would be that this variant would be actually an activating factor and that we could use that also.

We’re also hearing, and especially at this GU meeting here in San Francisco, about the heterogeneity of the tumors. In fact, you may have tracked down one particular cause of cancer, but there’s another five going to rear their ugly heads at the same time. What you make of that?

 Well, that’s definitely a major factor, particularly in kidney cancer, where heterogeneity was really first described in the clinical setting two years ago in the New England Journal. What the nice thing is about this variant is, is that it is germline. It exists in every cell. Thus heterogeneity does not exist in this situation. The variant is present in all cells, including the tumor cells. So if our data does hold up, and it is a therapeutic target, it will not be affected by tumor heterogeneity.

Give me a message to take home for the community cancer doctor very briefly..

The messages that we have truly validated this important finding that was published last year and we truly believe that this is a new prognostic marker and adds to the existing prognostic markers.  Time will tell if it will actually help guide treatment of metastatic disease and really change the paradigm for kidney cancer.

Thank you very much.



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Uniting the Genome & Clinic to Advance Care of Renal Cell Carcinoma: ccA & ccB –Lecture by Rathmell, MD, PhD

Why should you care about genomic research?  Simple; it could save your life! Want to know EXACTLY which type of cancer you have, and how to choose the best treatment?  New hope comes from this research which really examines the nature of the cells that make up your cancer.  Pretty important stuff.

  Genomic research is bringing improvements to care, and points up the need to be aware of this new knowledge–and if your own doctor is keeping up with that type of data. At a 2012 Conference sponsored by the The Oncology Journal, Dr. Kimrym Rathmell spoke in regard the genomic knowledge that is leading to improved care for kidney cancer patients. Maybe the most critical lecture of late.

Dr. Rathmell begins after introductory remarks; Complete access on YouTube via this link:

First, kidney cancer, like pancreatic cancer, has been on the rise. This is a somewhat dated slide, dating back to the 70s. We have seen a steady increase in this cancer. Although it was originally characterized as a rare tumor type, it is not really anymore.This talk will focus on one subtype of kidney cancer, that is, clear cell histology renal cell carcinoma. This is a histology slide showing why it is called clear cytoplasm

  1 Incidence of and Mortality of Kidney2 Focus on clear cell RCC

This tumor is characterized by particular mutation. That is the Von Hippel Landau gene, coordinate the loss of 3p, (a chromosome) where VHL is housed. We see these in mutations and loss of 3p which house other tumor suppressors as well, in up to 90% of these tumors. Based on this strong correlation between clear cell renal cell carcinoma and the VHL mutation, a tumor type. is a very distinct paradigm in which VHL loss causes upregulation of hypoxia inducible factors (HIF). These tumors are characterized by loss of high loss of these HIF factors. These are transcription factors that normally allow cells to respond to low levels of oxygen by turning on a repertoire of genes that allow them to bring in new blood vessels, to shift their metabolic properties, to migrate away, to promote survival, and to de-differentiate. That is a perfect storm for kidney cancer, in some respects.

3 Pathways of action Low o 2 VHL mutation4 Pathways with related agents                                               Targeted Agents in Use

Because this cancer has highly nonresponsive to typical chemotherapy, there’s much effort in recent years to develop targeted agents. These targeted agents to date all focus on this well-known pathway in clear cell type renal cell carcinoma. Most of the agents focus far down on this pathway, including that of receptors of VEGF and PDGF. They are tyrosine kinase inhibitors, effective at reducing the tumor angiogenic profile and can be quite effective at reducing the bulk of these diseases. Other drugs similarly target this pathway, for example, targeting features of the tumor that enable HIF to be stabilized such as that in the mTOR pathways.  Temsirolimus and Everolimus are approved for use. There are in-developments drugs for targeting MET, which is another mutation that can occur in this cancer, similarly increases HIF levels.

5 the reality of treating RCcBut the reality of treating kidney cancer is that the available drugs that we have do not produce complete responses. We only work in the arena of minimal response and partial response. The extent of response that a patient gets is unpredictable. The duration is also unpredictable and the toxicity is also unpredictable. For drugs we expect them to be effective on average 1 to 2 years, this is chronic therapy, very expensive, and it’s dominated by effects that are substantially detrimental to quality-of-life—fatigue, rash, diarrhea, as well as laboratory abnormalities that indicate damage to the liver or elevations of glucose and cholesterol.

PART I: Clear Cell Renal Cell Carcinoma, Molecular and Genetic Contributions to

INTER–Tumoral Heterogeneity.6 Renal Cell Carcinoma

With that, I will talk about various molecular probes that we use to understand some of the diversity or the heterogeneity of these tumors across the clear cell renal cell carcinoma spectrum. Before I really dive into clear cell  renal cell carcinoma, I need to point out that there are other histologies with this tumor as well. So when we say kidney cancer, we’re talking about a big spectrum. Clear cell renal cell carcinoma, we are talking about those tied to Von Hippel Lindau disease and loss of 3p and it is about 70% of all cases we encounter in cancers of the kidney. But there are also other types. Papillary type renal carcinoma, chromophobe, benign tumor—oncocytoma, a translocation form and some very rare. With these types of tumors we have very little in terms of knowledge of how to treat these patients.  Their genetics are highly distinct from clear cell renal cell carcinoma. So someday in the future, we will understand not only how to treat not only our clear cell carcinoma patients, but how to use effective molecular information to target these cancers as well.

7 ccRCc is well known to be molecuallry heteroge

Clear cell carcinoma is well know to be molecularly heterogeneous for some time. This is  a gene expression profile. We’ve already seen heat maps from several of these other talks, looking at gene expression profiles. And as you can see the gene expression profiles across a large selection of tumors here, suggests there are great areas of variability–at least two and as many as five groups, based upon gene expression purely.

8 Expression-directed pattern recognition Concensus cluster

                                                                        Pattern Recognition Profile to Find Subtypes

Our group undertook at the time developing a pattern recognition profile which is now fairly routine use. To try to see with a more robust computational strategy what subtypes we could really identify, that we could really pen down and understand with genetic profiles. 8aWe found two. For lack of better knowledge, we are calling clear cell A and clear cell B, ccA and ccB. These are very distinct biologically, and when we look at these tumors in terms of their outcome, they also have significant prognostic relevance–with the ccA tumors in this original cohort having a median survival of 103 months, compared to the 24 months for  ccB tumors.

9 Cancer Specific SurvivalThe TCGA which is been discussed here in many of the previous talks is a great source of validation. We assigned these tumors to clear cell A and cc B groups subtypes, validating our previous results with the clear cell A tumors having much better survival profile than those ccB tumors.

10 TCGA Validation, confrims prognostic valueThis classification scheme, which is based 120-130 gene signatures classified robust subdivisions of clear cell type renal cell can be applied with a small number of genes on individual tumors and is independently associated disease-specific overall survival, making it a valuable prognostic biomarker.

11 ccA, ccB RCc Classification

PART II: Rare Variant Groups12 Rare variant groups

We use these profile tools to understand the rare variants. This is still in the clear cell renal cell carcinoma arena, but when we took a very large group of compiled tumors; this was a meta-analysis of 500 tumors, all histologically defined as clear cell type renal cell carcinoma, and we applied our expression pattern recognition algorithm. We asked for two groups and we found two and they correlated with our ccA and ccB, but when we ask for three groups, we can find a small group that now filters out. Now that we have power in numbers to identify what we called Cluster 3.  What is in Cluster 3?

Cluster 3, as we’ve said, is histologically defined as clear cell renal cell carcinomas. But we look to the genetic expression profiles, it’s very different, particularly with regard to metabolic properties. We see upregulation of genes that are involved in mitochondrial regulation and oxidative phosphorylation, suggesting a striking difference in the way these tumors likely regulate metabolism.


13 What is in Cluster 3

14 Cluster 3 tumor display

In addition, and now these are tumors that we can not go back and genotype for VHL mutation, for loss of chromosome 3p, but the loss VHL regulation leads to  characteristic changes in the gene expression profile. So when we use the gene expression changes to predict whether these tumors have an intact VHL or a mutant type VHL. The wild type VHLS signature shown here is shown in  purple. You can see that these purple tumors, the wild type VHL tumors all tightly cluster with Cluster 3. These are probably not clear cell renal cell carcinomas although many, pathologists call them that. So we pulled them all out so, asking, “DO they look a little bit different?”  My graduate student, who did this work, came right away and said “There’s something funky about these clear cell tumors that we call Cluster 3.”

16 a New Paradims of subtypes for clinical stratificaiton15 Transcriptional segregation coincides with distinct morphology

As you can see, these are clear cell A and a clear cell B tumors, but they all have the clear cytoplasm and really, what we are seeing, is that they are not distinct histologically, although they are very different molecularly. And as I have shown, they have a very different prognostic outcome. The Cluster 3 tumors; although the cells themselves might have clear cell cytoplasm that gave them the clear cell histology designation, they have a very different pattern of organization—with a papillary type of feature. So what we think it would be identified as is a new rare variant of clear cell renal cell carcinoma.

Simultaneously another group of pathologists identified, that the pathologists call clear cell papillary carcinoma. That suggests that we need to take a very great care as we treat these patients.  What we have is clear cell type renal cell carcinoma, most of which are VHL-mutated, and we do have clear cell A and clear cell B. These are the tumors we should be treating with the drugs with identified, based on the effect of the pathway that is activated by loss of VHL.  But clear cell papillary renal cell carcinomas probably won’t react very well, as they are VHL-wild type.  Just like papillary renal cell carcinomas don’t react well either.

16a summaryRC types

To summarize this section, clear cell renal carcinoma can be separated into ccA and ccB groups, based on transcript profiling, but further clustering can identify highly biologically dissimilar subtypes within the clear cell group, and that subtyping can convey a biological distinction which is a valuable tool for prognostic evaluation, and a likely cause of poor responses to some therapy.

Part III; Using Clinical Trials to Understand Biological Relationships to Response to Therapy

As my title indicated,  we also refer to clinical trials to help us understand renal cell carcinoma a bit more. A clinical trial we completed some years ago, LCCC0603, was in neoadjuvant trial that looked at the treatment of renal tumors with sorafenib. Patients were identified as having renal tumor and underwent CT scans for basic size, description and PET scan, and then were treated with sorafenib. It is the first generation VEGF receptor tyrosine kinase inhibitor for 4 to 8 weeks, and then underwent post treatment CT scan, PET scan and a nephrectomy. We are going to look at radiographic indicators of response, rather than molecular indicators.17 LCCC0603- A Pilot Study of Radiogrph

18 Response to sorafenib

Waterfall Graph with Response at 30% as goal

First standard RECIST criteria do show that we do see partial responses.  Again, there were no complete responses. Many had subpartial or minimal or some partial responses. Their tumors shrank, but most did not meet the standard criteria of 30% decrease in one longest size. Some tumors actually grew.

Now what we realized as we looked at these tumors, is that we probably need new ways to describe response. The standard RECIST criterion response is just based on longest diameter and measuring this in comparison, after treatment..

I will use this patient is an example. (References I and J, in the lowest row). Here is a pretreatment; we have a very large renal tumor. Post treatment, the tumor was still large, but it measures slightly larger than it had been before.  But if you look at this tumor, it is very different. The central area of this tumor is now very dark, indicating necrosis—is what we think. But we took these tumors out, we could confirm that these dark areas were indeed necrotic. So we developed a new way to try to quantify the area of the tumor that is actually killed in response with this treatment.

14a Metabolic

19 new Ways to Measure Response

Similarly we were doing PET scans on these patients, and we were doing this because we’re trying to understand how the metabolic properties of these tumors might indicate how these tumors were likely to respond to this treatment. We see, and have known, that are some tumors which are very dim on FTG PET. This is a tumor; (Smallest of upper images) you can see that here is very visible on the PET scan. It doesn’t take up any FTG. So this tumor has the metabolic profile that is not dependent upon uptake of glucose. Others; this tumor (Smallest of lower picture), for example, have regional areas that are can be very high in terms of FTG uptake. When we looked at these tumors, we discovered first that non-clear histology tumors were much more likely to have high levels of FTG uptake. So, metabolically active tumors more likely in the (correction) non-clear cell group, probably the papillary, the chromophobes and the papillary clear cell types, than the clear cell group. Secondly. we discovered that the correlation between FTG uptake and response looked somewhat different than we might have expected. We might have expected the most metabolically active tumors would be those that would response better to anti-angiogenic agent. But the opposite was true. The best are those that had very low levels of uptake FTG uptake. We are still trying to understand exactly what that means. Certainly that means that those clear cell tumors are the ones more like to respond, activity, what we have known, but those are the ones with the lower level FTG activity.  But we continue to try the metabolic properties of the tumors that make theme different more likely to respond.

21 LCCC1028That leads to our next clinical trial. This is now ongoing. This is LCCC1028. It is a neoadjuvent clinical trial using the newest generation—well, they are  coming out so fast that it’s the not the newest, but the next to newest VEGF receptor tyrosine kinase inhibitor. They are now getting PET scans and a biopsy to confirm in fact that they would be clear cell renal cell carcinoma, and also to allow us to do molecular studies that directly measure their metabolic activity and other effects. They’re being treated for eight weeks with another CT scan, undergoing nephrectomy. We will then be able to look at clear cell variant histology. They will all be clear cell going in, but there may be variants included–as well as looking at their VHL mutation and their other mutational status, their transcript profile,  in particular  the clear cell A and clear cell B group and other protein expression signatures.

23 Genetic Intratumoral Heterogeneity22 What lies beneath the variatble historoloyg of human tumors-

This, of course, is known for all tumors, but if you sample in multiple different places, the histology will look different and in effect,  the grade can look different depending on where you are sample.

What does that mean molecularly? Well, a group at the Sanger Center published on a small number of tumors. When they sequenced these tumors, they found while there are some mutations that are ubiquitous, meaning the mutation is found in all samples across the primary tumor and the metastatic tumors, that there are mutations that are private.  There are mutations that are common only among the primary tumors and there are mutations that are common only in the metastases, and there are a lot mutations that are unique to the individual sample. This makes a whole new level of complication as we moved toward personalized therapy, in particular therapy that is based on biopsy metrics.24 Expression profiling in a heterogeneous tumor

This group also looked at our clear cell A and B subtypes. And what they saw, when they looked at six samples from the primary tumors, was  that in five of those samples, the gene signature indicated that these would be clear cell B type tumors. So depending  on  your glass half-full/glass half empty: The glass half full version of this, that  five out of six times, they would pick that the patient would have poor outcomes. This patient has metastatic disease, so it fact, that is true. The glass half empty would be that one out of six times, he would pick wrong. This patient would have been  indicated to have clear cell type A tumor, and you might have predicted that this patient would do well, when in fact that would be wrong. So what helps us understand the limitation of this test.  It also gives us the opportunity to understand a little bit more about these tumors.

25 Future- Uniting imaging

(Footnote reads: BRIC Funded Grants LCCC1213) So for the future, a trial (LCCC1213) that we have really just initiated is uniting some of these imaging observations we have made with genetics.

We are taking in patients. This is patient number one. Patient number two just has his MRI last week. and doing an MR in coordination with the PET scan so we can get the detailed look at these patients’ tissue perfusions, vascularity and the density of these tumors, as well as  regional areas at the FTG uptake and sample according to the map that is created by the imaging, as well as samples that are collected, based on what we see grossly in the tumor. Here  you can see a sample that we collected from a tumor region that is highly distinct from the  mostly more pale yellow regions of tumor.

This is just begun, so I cannot tell how well were going to get to correlate the gene expression and genetic underpinnings, and what we see in the tumor and what we see in the MR / PET.  But it will help us to move forward.

To summarize are multiple ways for RCC to diverge.  The subsets can enrich tumor sets for clinical and genetic features, and a multiplatform approach that with genetics, molecular biology and imaging techniques will give us man ways to tackle a surprisingly very heterogeneous disease.

26 SummaryQED

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What IS Cancer, Anyway? And Why Is It So Damned Hard to Cure?!

Once a patient can stop asking why cancer happened to him/her, the next question is the fundamental version of the many questions that the researchers ask– “What is cancer really? and “Why can’t they just stop it?”.

The scary part of cancer is that it seems so insidious.  Cut it out. Burn it out. Zap or freeze it out.  Why doesn’t that work, at least for the solid tumors?  Getting rid of the blood cancers, like leukemia and lymphomas seem more difficult, less obvious, but it was really the cases of leukemia which first responded to treatments.

Without going into volumes of discussion about cell and molecular biology (you are safe from that with me), just understand that cells go wild, left to their own with the family checkbook, an endless liquor cabinet, permanent pizza delivery, car keys, disguises, blind neighbors, a fancy cloning machine, and the police on strike.  You get the picture.  Now a more formal explanation.

Cells are supposed to do their respective duties and then die.  That process is called apoptosis.  You know that your scabs don’t keeping growing, but cancer cells lose the “time to die” signal.

Foreign bodies are supposed to be cleared by the immune system, and what is more foreign that cancer?  However, cancer cells manage to evade immune destruction.   And while doing that, they can also evade the growth suppressors, the immune brakes which would otherwise slow and prevent excess growth.

While cutting the brake lines to growth, they can also change the regulating signals for growth (think scars and healing), so those signals all left in permanent “ON” position.  No brakes and an open throttle with a very full tank of fuel.  To top that, they reprogram the nutrition or energy metabolism to keep the fuel of growth alive.

Liking the growth, the cancer cells override signals that naturally limit the times a cell can divide, creating endless replication instead. With the endless replication, the chances for mistakes, or genetic mutations increase, which can mean changes from the original cancer cells.  Sheesh, not only alien cells, but aliens cells making alien-er cells!

To keep tumors growing, cancer cells send out signals to create blood vessels or angiogenesis when tumors outgrowth the local nutrient sources. Running out of room for all these many cells, billions and billions, the cells break down the lining of blood vessels and the lymphatic system to search out new locations, spreading and metastasizing away from the original cancer.  Quite naturally, they also provide support to those tumors through inflammation-related factors, mimicking the way that the immune system responds to any injury.

Since a healthy being grows, fights off infections, responds to an allergy or heals after an injury, usually with little support, those healthy responses are amazingly efficient and interactive.  Complex cellular, molecular and chemical actions are occurring all the time, and with aging, some genetic dispositions, the harmful things we ingest or do to ourselves, it is no wonder that a few things go on without our noticing it.  But when those few things are not noticed by the immune system, slipping into a growth phase, a cancer can begin.

Estimates of the numbers of cells in the human body are calculated from 10 trillion to 100 trillion, so if the occasional cell goes rogue, what’s the problem?  When all things are working well, there will be no problem. But when the tiniest cancer is visible with a CT scan, perhaps 1/8 inch, it will have millions of cells.  Not all tiny cancer tumors are dangerous. Not all become aggressive.  Digging around to cut out a tiny tumor creates plenty of opportunity for infection, for expense and emotional anguish.  But does that mean that a “Cancer!” has been prevented.  Or would the person and his natural immune system have lived in complete tranquility with his cancer until the end of his days?

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