I always wonder if I'm up to date on the current management of pediatric solid tumors. And so in this audio chapter, Doctor Peter Ehrlich from the University of Michigan goes over everything we need to know on the current management of Wilm's tumor. I want to thank Doctor Abdul Raoof Lamoshi for editing this audio chapter. Stay Current is a multimedia publication designed to keep healthcare professionals up to date with standards of care and new emerging ideas. This chapter is created and edited by Todd Ponsky, Ian Glenn, Sophia Abdulhai, and Abdul Raoof Lamoshi and is recorded and produced at Akron Children's Hospital in Akron, Ohio. This is Todd Ponsky from Akron Children's Hospital. And today with Stay Current, we're gonna be talking about Wilm's tumor. This is certainly something that uh I find to be ever-changing. And with us today, we have a great expert who's definitely knows the field, uh, Doctor Peter Ehrlich, who is professor of pediatric surgery at the University of Michigan, CS Mott Children's Hospital. And he's also vice chair of surgery in the renal tumor section of the Children's Oncology Group. And he's gonna help us sort of sift through what we need to know about Wilm's tumor. Peter, thanks for joining us today. Great. You're welcome. Thanks for having me. So, let's dig right in and uh give you sort of the typical case that we get. So, Peter, let's say a 3 year old boy presents with a uh left abdominal mass. He gets a CAT scan which shows a left renal mass. Tell me how you approach this patient. What is your differential diagnosis, and then let's talk about what kind of tests you might get. Sure, so the first thing that I would think of looking at the CT scan is the characteristics of the mass. Is it a large mass of a kidney because there's a benign or a blockage somewhere down along the way and the child has a benign lesion like hydronephrosis or maybe an underlying process. Genital duplication of the cyst in the kidney that makes it look larger or does it just a simple renal cyst? Those are the common, more common benign lesions. And then I start to think about the differential diagnosis of children with more neoplastic lesions, one of them being Wilm's tumor, another one being clear cell sarcoma of the kidney. Or rhabdoid tumor of the kidney, or it could be depending on the age or any congenital problems, a renal cell carcinoma or some of the rare tumors like AMLs or sarcomas, and depending on the age of the child, in this case he's a little old for it, but if we're younger, it could be a mesoblastic nephroma. I will also look for things. Is it completely solid? Is it cystic? And those things would point the potential to things like a cystic nephroma or if it's solid, most commonly it's at this age it is going to be a nephroblastoma or a Wilms tumor. OK, so what is it on the CAT scan that might look more like a Wilms tumor? So, so Wilms tumors tend to, uh, oh, Todd, I forgot to also mention that one of the differentials could be a neuroblastoma, uh, which I forgot to mention. Or a metastatic tumor such as lymphoma to the kidney. The features on the CAT scan that make it look like a Wilms tumor, it's the classic feature is something called a sign where you have the kidney. The normal kidney being displaced into a horseshoe pattern and fitting inside that horseshoe pattern is a tumor and so it looks like the normal kidney is grabbing the mass that's coming out of it. Wilm's tumor also tends to push things out of the way rather than growing into it, whereas a neuroblastoma, you look for things that would tend to grow out and around structures like blood vessels. Wilm's tumor tends to push things out of the way. Even look radiographically like it has a capsule and is quite distinct features, whereas other tumors are less so distinct. You may even see some calcifications on it, but they're not specific per se to Wilm's tumor. OK, so let's say you've got the CAT scan. It has the classic claw sign. Now what do you do? So the next thing that you would want to do is start to think about what other imaging studies you would need for a patient who has a renal tumor where you're thinking most likely a Wilms tumor, and also some routine lab work that may help you make some decisions about how you would approach the kidney. So the other. Imaging studies that you would want to obtain would be scan or imaging cross section limit of the lungs where CAT scan is the best. The current versions of CAT scans will also be able to tell you quite nicely the assessment of the vasculature because Wilms tumors, they spread sometimes by growing out of the kidney and into the renal. Vein in the IVC. CAT scans are very good at that. Some people will prefer to get a Doppler ultrasound of the kidney as a secondary study, then routine lab work, including CBC, coagulation, PT, PTT, and some basic renal studies such as ferritin, electrolytes, etc. OK, so let's say you get all that work up and the lab work comes back normal and uh you don't see any evidence of vascular invasion and there does not appear to be any lung lesions or any other metastases. Now what? So in North America we believe and prefer that the next step in the treatment of children with renal tumors is to go ahead and perform surgery. That surgery is Called total nephrectomy and uteectomy, taking part of the ureter down to the level of the bladder and doing lymph node sampling in the regions that drain the kidney. That is our recommendation for the majority of. Of tumors that present in children, there are exceptions to that. Sometimes these tumors can be exceedingly large in such a way that it compromises the respiratory status of the child and that the child may not make a good operative candidate. In that situation, we would recommend a biopsy and then giving Pre-surgical chemotherapy, other situations that we would recommend doing chemotherapy up front based on the children's oncology group philosophy would be if the tumor extended into the inferior vena cava and beyond the intrahepatic vena cava. So if the tumor went up and started to go behind the liver of the vena cava or up to the atrium. That that would tumor most likely would benefit from undergoing preoperative chemotherapy. Some of these tumors are just massive and fill the whole abdomen where you are worried about having to take out other organs or doing resections of large parts of the liver or the bowel again. Those aren't warranted if the tumor is that large because the majority of them will respond to some degree to chemotherapy. And then finally, if it turns out that the child only has one functioning kidney, we don't want to take that kidney out and we would try and give them preoperative chemotherapy. Other situations that we would do that if there happened to be tumors in both kidneys we would not do a primary kidney tumor or if a child had a certain genetic or predisposition to developing. A tumor in the other side in those situations we would take a different approach. Some examples of that include children with Wegar syndrome, Danny Draft syndrome, Beck with Weedman syndrome, or children who have tumors in multiple positions throughout the kidney, multicentric tumors. OK, so what you just said was so critical and probably the most important thing about what we're going to talk about. So I want to make sure. I got it right, um, so, and, and, and actually you alluded to something, and so I'm just gonna, uh, mention that so Peter, probably more than half of the people, uh. That subscribe to stay current are are not from the United States, so it's interesting that probably half of the people listening will do something different. I know that there are different protocols for CG in the United States and SIO in Europe, so you're going to go into more detail about that in a minute, but I want you first in North America. That in a in an isolated Wilms tumor looking uh on the CAT scan you're going to do go straight for resection if there's no invasion. OK, so if it goes above the infrahepatic cava cava. Then you would not do a primary resection. Consider not doing a primary resection. And in that patient, would you do a biopsy or just start chemotherapy? We would do a biopsy. OK. Avi has a question. So Peter, I was wondering, um, if preoperative imaging seems to indicate that it's invading a small section of intestine. Would that change your management at all? Which way would it sway you? So in general, if you think that you have to take out part of the colon, which is usually the part that it's in that situation, I would biopsy the patient because we do know first of all that you probably will respond, and secondly, the complication rates have been shown to be higher if you have to take out liver or bowel at the same time as taking out the kidney. So there's no reason to do that and and overall the consequence in that case of of upstaging, where does that so it's not really upstaging it's so this goes to the question of there are different types of staging systems that people use depending on whether you do pre-nephrectomy chemotherapy or whether you do a primary nephrectomy and then treat or difference between the children's oncology group staging and the. Uh CIO or based protocols which also includes the UK and some other countries, and if we leave gross tumor behind or just biopsy, it has always been and it continued, we've always felt that this should be treated as a stage 3 abdominal tumor. And those tumors will get 3 drug chemotherapy plus flank radiation. Now if you feel that the tumor has invaded into the to such an extent that you'd have to do a major liver resection or a bowel resection. Then that's going to be a stage 3 tumor anyways. What you're really doing in that situation is say I don't want to, it's not valuable to take out the descending left colon or ascending right colon or do a right hepatectomy because we know that if we give chemotherapy those will almost always respond. And you're not going to change things. So that's how I look at it now. If you just often Wilmston which will push up to the liver and some people will take a little rim of that just to make sure they have a clear margin, that's completely different. So again, I want to go back to these, this list you gave. The first thing, uh, one of the things you want to make sure of when you look at the CAT scan is that there's no other lesions in the other kidney. Uh, and once you're satisfied that the second thing that you want to look at is whether the tumor in the abdomen has extended anywhere. Is the disease in the liver? Has the Wilms tumor itself extended out through the renal vein and into the inferior vena cava and to the extent of that. And then you want to get cross sectional imaging of the chest because those things that will help with the what's called the final stage of the disease. At that point in time, there are two prevailing treatment strategies. The first treatment strategy, the Children's oncology group, primarily a North American strategy, has been to, if the tumor is resectable, that we would do a nephrouterectomy with lymph node sampling. In the children's oncology group strategy, the criteria that we use for patients who are, we would not recommend that for include the following one, a tumor that is so big that it impairs the child's respiratory status and that they're not a good surgical candidate. Second, if you look and you find out there's only one kidney or that there's there's only one functioning kidney because the other kidney had some underlying congenital problem, again, we would not recommend doing that up front to do that. The third is if the tumor extends out the renal vein and beyond the infrahepatic vena cava, that there is a higher risk of complications. Uh, 4, if you feel that you would have to do a major liver or bowel resection at the same time, that is a situation in which we would not recommend doing a primary nephrectomy. And 5, if you feel the tumor just based on the size would be so difficult and generally the size, the evidence suggests that your tumor, you get into trouble when tumors start to get between. 1314, and 15 centimeters or bigger, that there is a higher risk of rupture that you might want to consider not doing a primary nephrectomy. What about crossing midline? Is that so those tumors tend to fall into that in some of those larger tumors, they are very mobile and it's actually an easy resection. In other tumors, they are very fixed and you might. not want to do it. It's really a judgment call and sometimes you make the judgment at the time when you do an operation and you feel around and see how mobile the tumor is, but that is a judgment call that the surgeon will have to make. The evidence suggests that you should be more cautious as you get somewhere around 1314, 15 centimeters with the tumor size, and all of those will cross the abdomen and children. And is it fair to say that in those, and I'm trying to remember if one of the ones you mentioned was that they had a lung lesion on. No, I did not. OK, so let's take the ones that you said. Um, you're, is it fair to say that for all of those you would proceed with a biopsy of the lesion? OK, we proceed with the biopsy because, um, there's really, uh, uh, no way of knowing exactly what type of, of tumor, uh, you're dealing with without the pathology, and the pathology really directs the. The treatment, for example, although the majority of them will be Wilm's tumor, Wilms tumor has two groups one of what's called unfavorable anaplastic histology. The other one is favorable histology. The chemotherapy is different for each one, and the prognosis is significantly different for each one. There's also something called a rhabdoid tumor of the kidney which has a very different prognosis and also has very different chemotherapy and clear cell sarcoma of the kidney. All of those would be very different. And while you can get a better idea whether it's a malignant tumor versus one of. The nonmalignant types, there is no imaging study available that'll be able to tell you the difference between a rhabdoid tumor and clear cell sarcoma and a Wilms tumor or even whether it's favorable or nonfavorable histology. So we think that biopsying and getting it is very important. And tell me how you would do your biopsy. So there are really two options we have for a long time recommended that you do an open biopsy to get a large section of tissue versus needle or other biopsies. Recent interventional technology with a large core sampling has in several series proven to be. Be accurate. It hasn't been tested, but a lot of people are doing that. Um, one of the things that we would recommend that whatever approach that they use, if they do an open that they place the central venous catheter or port at the same time to avoid multiple anesthetics and if they're going to do a core one that. Take at least 10 cores and the data suggests that between 10 and 20 you increase the accuracy. We would not suggest doing fine needle aspiration or just doing a simple pass of a true cut needle biopsy as they, you cannot diagnose anaplasia based on those biopsies and in fact in If you're not sure that it's a Wilms tumor or something called a rest, you can't diagnose those based on those core biopsies. That's great. So putting in a port or a brviac at the time of biopsy, is there any possibility that a biopsy would come back of something that you wouldn't end up needing chemotherapy? It's always possible. Some of the children. Or 6 months of age it may come back as being a benign lesion, but it's unlikely itself would be those lesions, mesoblastic nephromas never get to the size, never extend out through the inferior vena cava or where it would change it, so it'd be an exceedingly rare event that that would happen if you have made the. Decision to do a biopsy at that stage and it's pretty much OK to put in a single lumen at this point. They're not going to need a double lumen, right? No, most chemotherapy protocols, it's, it's a single lumen port is preferred because of infection risk. However, in the younger kids, as we know, we don't have small enough ports, so it's a single lumen roviac-like catheter. So can you go over the staging of Wilm's tumor? I know that you talk about disease stage and abdominal stage. Can you go over that with us? Sure. So in the children's oncology group staging system, we treatment is determined based on two factors. One is called the local abdominal stage, and the second is the disease stage. Stage one. Is the tumor that is limited to the kidney. It's completely resected. There is no invasion through the renal capsule. The tumor was not ruptured or biopsied prior to removal, and the vessels of the renal sinus are not involved. There's no evidence of tumor beyond the margins of resection, and the regional lymph nodes are negative. Stage two is the tumor is completely resected and there's no evidence of tumor beyond the margins, but the tumor can extend beyond the kidney in a few. There can be regional extension of the tumor such as. Penetration of the renal capsule or invasion of the soft tissue of the renal sinus. Blood vessels within the nephrectomy specimen that are kind of outside of the primary kidney, if they contain tumor cells, that is considered stage 2. Stage 3 is when the tumor comes is either biopsied and there's gross tumor remaining. That there are lymph nodes that are positive within the tumor. The tumor has penetrated through the peritoneal surface where you find tumor implants, where you have positive margins on the tumor, or that there's microscopic residual either from an intraoperative spill, OK, or you couldn't completely resect the tumor. tumor is considered stage 3 or if the patient was biopsied, got chemotherapy, that is considered stage 3, or if in to get the tumor out you have to take it out in pieces. Or for example, if the tumor extended into the renal vein and you divided the renal vein with tumor, that is also considered stage 3. Stage 4 for a tumor is considered when you have hemato metastasis to the lung. Or liver, which are the two most common places, or bone or brain, and then stage 5 is bilateral renal tumor involvement. So what are all these stages and how do you put it together in treatment? Well, for example, you could have a tumor that is in the abdomen, a stage 1, but. The patient would then could have a lung lesion, and that is not uncommon, particularly stage 2 tumors, and that would mean that the child would get different chemotherapy and if it was stage 1 in the abdomen, the child would not get abdominal radiation, whereas if the child had a stage 3 tumor in the abdomen. And lung metastasis, the child would get chemotherapy plus abdominal radiation and then in some instances may require lung radiation also. So every stage is going to get chemotherapy. It's just a matter of what chemotherapy they get, is that right? Well, so if a patient is stage 2 in the abdomen or stage 1 in the abdomen. And they do not have any disease in the lungs, those patients only get two drug chemotherapy. They get it for a shorter duration. The chemotherapy is not as toxic, and the risk of late effects is significantly lower than adding the third drug, which is doxorubicin, and or adding the abdominal radiation. When you look at the late effects, and by late effects the main ones are renal failure, you're looking at the Development of second malignancies and you look at or problems for the females in pregnancy or hypertension, cardiovascular disease, the two main factors that contribute to that are radiation and doxorubicin, which are the two main drugs. So there's a big difference between using those and doing it. So if a child has Stage 1 or 2 in the abdomen, they would not require abdominal radiation, and that's a really good long term thing to avoid. So if you said one of the things that is somewhat confusing to both the oncologist and the surgeon is just because they have a lung lesion doesn't mean that you shouldn't take out the primary tumor and So if you have a lung lesion and a 5 centimeter tumor and you biopsy that tumor, that in the children's oncology group treatment paradigm would mean that the child would automatically be considered a stage 3 because of residual gross tumor, and you would, the child would get the 3 drug chemotherapy but would also get abdominal radiation. And if you had gone ahead and removed the tumor. The child and the lymph nodes were negative, you would not necessarily have gotten abdominal radiation. That's a great point. And so now that we understand that, that the abdomen is separate from mets and the treatment, abdominal treatment could not necessarily require the radiation, tell me then what you do. Preoperatively in a patient that has what looks like to be, even though you don't know because you haven't done surgery yet, but looks like to be a probable stage 1 or stage 2 with a lung lesion, how do you proceed with that patient? My approach to that patient is I take out the renal tumor. And I leave the lung lesion alone. There's two reasons to do that. One is that you want to know what the pathology is. So if it's favorable tology Wilms tumor and I do my lymph node sampling, lymph nodes are negative, it's stage 1 or stage 2, this child avoids abdominal radiation. The second thing that is important that the Children's Oncology group recently finished. A trial to see if all kids needed pulmonary radiation. Pulmonary radiation has been the gold standard for treatment for pulmonary disease, and it's very effective. The problem is that of its late effects, and 15% of the girls who get pulmonary radiation from Wilms tumor end up getting breast cancer, which is significant. There's also problems with pneumonitis, long term restrictive lung disease. Based on some psyop data and some children's oncology group data, it suggested that there is a section, a group of patients who respond very quickly by 6 weeks to chemotherapy, and those patients may not need pulmonary radiation. So a recent study, the Children's Oncology Group, addressed that where children who have pulmonary Disease underwent 6 weeks of chemotherapy and got a repeat CT scan and then those that were complete responders, and there was about 40% of the patients, they were not given pulmonary radiation and looking at that group at this point in time looking at relapses, there was about 80% to 85% that did not relapse. So those kids completely avoided pulmonary radiation and the Toxicity without any effect on either their event free or overall survival. The people that did recur, all but one of them have survived, and they did get pulmonary radiation. The one patient who did not survive actually died of a non-oncologic cause of death. So just to clarify then, you have the patient, you go in, you've done your nephrectomy, they have a lung lesion. You're just going to start chemotherapy based on the pathology from the kidney tumor. You're not even going to get tissue from the lung lesion. Now there's no reason at this point in time in the primary dude to get lung tissue. Now there are situations where you might want to consider doing a lung tissue biopsy at the 6 week evaluation. So again, And in North America what we do is we would treat and see about the response. Now if you happen to have a lesion that was there and did not respond to chemotherapy or a single lesion left that you're not sure what the etiology of, then it would be reasonable to go in and do a thoracoscopic biopsy because about 50 to 60% of the time those lesions may not turn out to be cancer. They could be scarred. They could be a variety of things. And in those situations those patients would not need pulmonary radiation. If you had this patient again with the lung lesion, you do your nephrectomy and it comes back as favorable histology stage 1. Wilms tumor and they have a lesion in the lung, do you give them two drug chemo? So if I was convinced, assuming that the lesion in the lung was a malignant lesion, OK, now if you're at all uncertain about that, then you would resect that lesion to find out. But, how can you ever be certain without resecting it? Well, the radiologists have criteria that they Use and they're they're pretty comfortable at deciding it and if I said hey we're not really sure this is a you know a 1 centimeter lesion that looks more like a scar, I would definitely resect it because that would change things with the chemotherapy but those situations are not that common but there's something that you should do but routinely if you have like a 1 centimeter lesion. In the, you know, upper lobe that's peripheral, that's classic for a metastatic lesion, then there's no reason to biopsy it. And now if you are treating the lung lesion and you're treating it assume it's metastatic disease, you would start with 3 drug chemotherapy and all patients with lung lesions to do that from that standpoint. So Peter, we've been talking about cog. Can you tell me where psyop is different? Sure, so the psyop protocols and the countries, and those are mainly Western European countries have taken a different approach to patients with Wilms tumor where they will start with chemotherapy. All patients, they don't go to operation. In some situations, the majority of them, they don't biopsy it, but they will give two. Drug chemotherapy in very different doses. OK, that is, they use a lot higher doses of the two common drugs that we use and then they will give evaluate the patient at 4 and 8 weeks looking for a response. And after the and then go on to chemotherapy, then go on to resection based on they do the same operation then based on the pathology. And they know the status afterwards. They have a post chemotherapy, post nephrectomy classification that goes into patients that are low risk, intermediate risk, and high risk patients. So Peter, what are their criteria for abdominal radiation? Sure, so they give abdominal radiation to their high risk patients who are, whether they're lymph node positive or negative, they're intermediate risk patients who are lymph node positive. So their low risk patients are patients who have complete necrosis. Their intermediate risk patients are for Wilm's tumor our patient is based on the percentage of what is called blastem. Components and their high risk patients are if their blastema component what is called a predominantly blastoma or if they're anaplasia and in that situation if they're high risk patients they get 3 drug or possibly more drugs in chemotherapy plus abdominal radiation in the patients who are low risk, they only get 2 drug chemotherapy. Intermediate risk, it's a moving target sometimes. I just don't know what drugs they give particularly, OK, but if we go into in the COG protocols and if we look at the patients that are all in stage 3, are there any differences between a patient who underwent empiric biopsy versus an outcomes difference in a patient who ended up getting spillage in the operating room when trying to undergo a complete nephrectomy? No, no, there's no difference. One of the things that there is, there's no difference in that group. The main factor that predicts outcome in stage 3 is whether they're lymph node positive or not. That's one of, and then whether they have certain genetic changes that we've validated prospectively called loss of heterozygosity and a genetic change that we've validated. On retrospective data that's called 1Q gain. So what you're saying basically also is that if you're looking at a CAT scan preoperatively and it's unclear whether this tumor is completely resectable, then technically giving it a try or attempting a resection wouldn't relegate the patient to a poor prognosis if a bailout had to be performed and only and stay with the biopsy. No, no. At all, and I think it's reasonable to think about it in that way. If you sometimes you just can't tell or you go in and you find out that the tumor is fixed and you'd have to do a major bowel resection, then backing out is reasonable. Our European colleagues might say, Well, why are you doing that? Why don't you just treat them because the majority are going to respond to some degree. And that's also a reason. When when you look at the outcomes for stage 1 and stage 2 patients between the children's oncology group and the psyop groups, they're basically identical. Let's say, going back to this patient that has what looks like a resectable Wilms tumor with no reasons to to biopsy, but actually looks like a good resective candidate. Talk to me about how you prepare the patient for surgery. What do you tell the parents and then talk about technical pearls and potential pitfalls during this procedure? Sure, so my preparation for the kid includes, you know, making sure that I have, um, I know the lab work going in to make sure that nothing's out of whack. The things I do is make sure I know what the hemoglobin is. Some of these patients present because the tumor ruptures inside itself and they start with a low hemoglobin. Very rare cases they can be bleeding as the case starts, but those are pretty rare to do that. I also will want to know the COAG status, particularly the PT and PTT. There is something called acquired von Willebrand's disease which these patients get. In the majority of cases it is meaningless, but there have been reports in a few case series where these patients may bleed a lot. During surgery until the tumor is out and in one or two cases that has been significant and some people have recently suggested that a bleeding time should be obtained on all patients with Wilm's tumor. The majority of us are not convinced of the value of that, but it's something that we should look at and patient surgeons should be aware of and to do that. And then just routine electrolytes. I then, I don't Routinely bowel prep the patients unless I have a particular concern about that, and then I will talk with the family. In general, I talk with the family, with the oncologist, talking to them about what we're going to do during the operation in terms of taking out the kidney, taking out the ureter, and then taking lymph nodes. I will talk to them about the presence or absence of what the imaging has told us about vascular extension. And then I will talk to them about, you know, complications based on the location and size of the tumor from, you know, routine things like infections and postoperative fevers to areas where you have to be a little careful about right-sided tumors that can sometimes the adrenal vein can cause problems or they can be quite close to the duodenum and you have to be careful. So there's been duodenal injuries reported. There's been Superior mesenteric artery injuries that because everything is distorted to do that, particularly right sided tumors can sometimes distort the IVC and you know when I think about it, I make sure that the IVC is clear and that so I tell the family about potential IVC injuries. So once you're in the operating room, how do you position the patient and how do you make your incision? So I typically position the patient is slightly elevated on the side of the tumor. I tend to either make a kind of modified subcostal incision or a transverse incision depending on the age and the shape of the child, going to the midline to do that. I don't make a medium incision and I don't make a retroperitoneal incision that they might use routinely in adults to do that, but I make a transverse. Abdominal-like incision over where I feel the hyland may be tend to make it more subcostal on the right side and less so on the left. And then upon entering the abdomen you look around and make sure that there's no other, there's no peritoneal seating. I will look at the liver to make sure the liver doesn't have anything. And if I can easily do it, I may palpate. The IVC or renal, the appropriate renal vein to feel for tumor and that itself is often can be difficult. These tumors tend to be large and although ideally you would like to identify the renal artery and the renal vein, it's been well recognized. It's even back in Gross's book that these, if you can't do that, then you shouldn't try and do it up front. Then I'll start by immobilizing everything off the kidney and then mobilizing the kidney either starting at the inferior or superior pull and slowly go around the kidney until I get it on a pedicle. Once I've identified the ureter, I will put a vessel loop on it and I will follow the ureter down as far as I can to where it. It goes into the bladder and I may divide it and then I will identify the vasculature within the hilum getting around the main renal artery and the main renal vein. Once I've identified the main renal artery and the kidney is usually pretty mobile at that time, I'll divide those structures and usually at that point in time the tumor can come out. If it's easy, I will take. Adrenal off the superior pole of the kidney, but it's not necessary. There's really been no reports of adrenal insufficiency and presence or absence of tumor in the adrenal vein has no correlation with outcomes. Sometimes there can be, sometimes there can't be dependent on the specimen to do that. So and then once the tumor is out, I then will look in the renal. Hilum paraaortically or paracavially for lymph nodes and I will try and sample. I will sample it, you know, at least try and sample at least 5 or 6. At this point in time we don't have any evidence that that makes a difference, but there's some secondary evidence to suggest that those, that number, more than 1 may be better, OK, and. Does it make a difference if you get the artery or the vein first, or you just take what it gives you? In general, it has not made a difference. By principles, it's always better to get the artery first. It's not always possible. Some of these tumors are quite big, and if you may get yourself in trouble to do that, often the artery sits below a large vein, so. It can be difficult to do that, so I take it when it comes to me. If I can see the artery first, I will divide the artery first, but it doesn't always happen that way, OK? And then do you need to place metal clips? So we used to recommend that we still do to some degree with the good imaging available. The radiation oncologists don't find that to be as helpful, but I generally will put a few clips on superiorly and inferiorly for the radiation oncologists, but it's not as important in their in their treatment marking because the 3D volumetric CD scans, they're able to match up with the patient. OK, so let's say you've resected the tumor and it goes to histology. What are the significance of surgical margins in these patients? So the surgical margin will tell you whether the patient is a stage 2 or a stage 3. So, if the surgical margins are positive, that automatically means the patient is a stage 3. Now sometimes the tumor can extend and kind of microscopically rupture, and you can't tell that until they look under the microscope and there's nothing you can do about it. That's a stage 3 tumor. There's very good data to support that from both our North American studies and SIOP studies to do that. Sometimes you come across You say, oh, this tumor ruptured. That makes a difference. Other times you come across and the tumors are very soft and you handle it and it ruptures and there's just nothing you can do about it. If the margins are negative, then that means the patient could be a stage 1 or stage 2 if it met all the pathological criteria for that. Has there ever been any role for frozen section, uh, for this evaluation, or once you've already cut through theoretically? So if you've divided the tumor by accident, that automatically makes you a stage 3. There are a few technical points, but sometimes these tumors, it's not unusual that they get, they cause a lot of reaction and become very adherent to the diaphragm, and taking a piece of diaphragm so that you don't violate the tumor is recommended and will not, in that case, if you haven't divided the tumor, that will not upstage. Your tumor. Sometimes the tumors, they tend to come up to and then directly get attached to the liver, but there's, it's not really an invasion, it's an inflammatory action. So taking a part of the liver, particularly the right or left lobe, just a tiny bit, is done to preserve to make sure that you don't accidentally get into the tumor. In the majority of those cases, the tumor hasn't extended. It's just that in some cases these tumors cause an intense inflammation reaction that makes it seem like it's invaded, but it actually hasn't, and other times it has invaded and you deal with that. Peter, is there any patient that can be treated with surgery alone? Yes, this is something that's sort of unique to the children's oncology group and really was based on observations by Dr. Bob Shamberger, based on the review of kids from the predecessor of the. Oncology group, which is the National Wilms Tumor Study Group, and they ran 5 studies, and the 1st 4 looked at a variety of different questions, but it was noted that there was a group of patients that no matter what you did, whether you treated them with surgery, whether you added 1 drug of chemotherapy, 2 drugs of chemotherapy, 3 drugs, radiation, that they had excellent overall survival, and these patients that were originally treated with Surgery and no matter what else they did they couldn't improve and their survival overall survival was greater than 95% and the characteristics of these patients at the time were patients who had tumors that were less than 550 g, that they were stage 1 tumors, and that the child happened to be less than 2. They had and favorable histology. So based on that there was a small series of 10 patients that were treated that way. had excellent overall survival and then two studies that were done, one on NWTS Study 5 and one on the recent Children's oncology group that looked and validated that these children, about 90-95% of them, can be treated without chemotherapy. Now what is the value of that? Well, the complications from chemotherapy, particularly in these younger patients, tend to be more severe. Then there's the late effects of Chemotherapy that can do that and it turns out that if these kids met this criteria that about 90% of them can avoid any chemotherapy and those that do relapse, we have 100% survival in them. We've done some secondary aim studies to look at some of the biological predictors because what if the child is 2 years and 1 day or what if the child is 556 g? Are there any features that Would make them OK not to be treated by chemotherapy alone, or are there any in the in the 10% or so that relapse, are there any common features, biological markers that, hey, maybe these are kids that should get chemotherapy to improve their survival? I want to talk about cable extension for a little bit. OK, so let's first take the situation that the patient had intrahepatic cable extension. So you went. To do upfront surgery, tell me your strategies on how you resect that caval extension thrombus. When you look at the outcomes of patients with tumor that extends into the cava or even up to the atrium, that's not a negative prognostic factor, OK? And if you're looking purely at oncologic outcomes, if you have loss of heterozygosity or anaplastic histology or rhabdoid tumor, those are much worse than. Cable extension and in fact in many instances if it extends into the renal vein it's not adherent to anything and if it comes out kind of in one piece it's considered stage 2. So when I go in and when I think about it, a tumor like this, I will come in and I will assess the extent of the tumor extension and if I'm concerned and can't 100% palpate things I will use intraoperative ultrasound. Down and then I will assess how far it goes up and if I can get proximal and distal control of the cava safely to get it out. Ideally what is described is that you mobilize the kidney completely, tie off the renal artery and any accessory veins, and then slide, make a small nick in the renal vein and slide the whole tumor and thrombus out in one piece. In reality it doesn't always come as easy as that, and you sometimes have to open. Put a side clamp on the cava and open the cava to make sure that you get it all out at that time. When it starts to get above that, what's really been shown is that the major complication rate in patients goes up. Those include mortalities, number of blood transfusions, ICU stay, complications go up, and it's been shown that in those cases, if I say, hey, this tumor goes up to the atrium or goes up to the paddock veins and. Belief even though it's short, if it goes above the infrahepatic cava that I think that it's the better part of valor is to treat it with upfront with preoperative chemotherapy. Now that the kidney will almost always respond to some degree. The tumor itself doesn't always completely go away in those situations. In a lot of situations it'll shrink and in some, and not in significant amount, it will completely disappear. But you still may end up. In a situation where you may need to have bypass or vascular occlusion to get out the tumor, there have been some who claim that after chemotherapy, the tumor thrombus is oftentimes even harder to resect because of the reaction from the chemo. You can, but a lot of times those are necrotic tumors, and to do that, there's no doubt it can be difficult, but in the largest series that we have, there was no mortality in those patients, and, and there was a 26 to 30%. Major morbidity and complication rates in patients who were operated up front with tumors that extended beyond the infrahepatic cava, inferior hepatic veins, and the atrium. There still was need for bypass, but the complication rates tended to be lower. There's no doubt about that. Peter, can you tell me in more detail if I'm going in and I have a known tumor thrombus up to still below the liver. I go in, I do my mobilization of the kidney. Talk to me in more detail about technically the step of taking out that that tumor thrombus. What I do is I approach it, I say, I know I'm going in there. I will try and without doing too much to the primary kidney if I'm not 100% sure I can get it out, mobilize the bowel off, do whatever maneuver I need to do to expose the cava, and then I will use intraoperative ultrasound. To make sure I know how high this tumor thrombus goes and then I, I'm asking myself, well, can I partially occlude the cava or do I have to totally occlude the cava to get this out and if my, if I say my first decision is boy this actually goes up much higher than it looked like on imaging, then I will, you know, back out and biopsy or hey, you know what, it really only extends slightly. into the inferior vena cava I can get a clamp on it. I can do a resection of the inferior vena cava and then repair that a partial of that, and I get all the tumor out. That's great, you know, I'll just take it all out of the block if if it's filling the cava to do that, uh, you know, that is so it's harder, then I'll make sure I get use good vascular principles. I will then mobilize the whole kidney. I will then tie. The renal artery and make sure that really the whole kidney is based on the and the thrombus is based on on that and then I will occlude the cava. I will do an anterior venotomy and pull the tumor out. Now does it always come out in one piece? No, but a lot of times it does. Sometimes you have to do an extensive anterior venotomy to really just make sure you get it all. Those are not common because. If it really does occlude the whole cava, often you get clot that goes all the way up, and these kids present in extremists. So Todd, I, I've read 6000 operative notes, OK. The amount of time that somebody actually had it go all the way up there like that and stop at the infrapatic cava, I don't even recall reading a case where that happened. There is what people say you're supposed to do, and then there's. The reality and you know, after reading 6000 and not seeing that, I'm not sure that some of these things that are described from historically actually occurred, OK? And I don't know what yours and Avi's experience has been, but you know when it really fills it up, it tends to go up and in some of those situations after treating it, the cava, there's collaterals. Three months ago I had to take out a kit, and they had all collaterals and the easiest thing I did, I Took out the whole cava because he wasn't using it and it then got a margin just proximal to where all the hepatic veins came in and that's not the first time that that's happened because and it turned out there was no tumor in there. It was just it had just been not used so it had clotted up. Let's, can we go over briefly some of the different pathologic results you may get and how you treat those? Sure, the first thing the pathologist looks for is in. In North America is they wanted to find out whether there is what's favorable histology, and there's the favorable histology has epithelial components, stromal components, and mesonchymal components. So the glomerular and the amount of stroma, and it's called a triphasic tumor, those are the classic features of Wilm's tumor. Excuse me, there's blastomo component, stromal component, and epithelial component. And most of them have some degree of all three. Some just have two components, and they're all considered favorable. And in the children's oncology group protocols, the amount of blastoma has never correlated with outcome. Alternatively, the treatment strategy used by the psyop group, if you have predominantly. STEMO after preoperative chemotherapy that is considered to be a negative prognostic factor. It doesn't seem to play a role in the primary nephrectomy chemotherapy patients. If the tumor pathology is favorable histology, then the next decision is what stage is it. Is the lymph nodes positive? Is it stage 1 or stage 2? And that's considered the abdominal staging. And then finally look for lung metastasis. If it's negative and it's stage 2, they are then there's well described, well tested standard treatment includes chemotherapy, what's called two drug chemotherapy, which is vincristine and dactinomycin. And it's usually about 19 weeks of therapy. If it turns out that it's stage 3, then they add doxorubicin. The regimen's called DD4A, and that regimen is for 25 weeks. If it's favorable histology or any of them, they'll do a secondary test looking for the presence or absence of loss of heterozygosity, and loss of heterozygosity is when you lose certain genetic material on certain. In chromosomes and this has been noted in cancers of a variety of cancers and particularly for renal tumors 1, 16 and 11P chromosomes that had loss of heterozygosity associated with it and it turned out that in our treatment paradigm if you have both loss of 1% and 16q that your outcomes regardless. Of stage were significantly worse, and on the most recent children's oncology group studies we did lots of heterozygosity testing and if it turned out that you have both of them, which is between 5 and about 7% of the patients, your treatment was increased. So if you were stage 1 and 2, where you would normally get a vincristine and dactinomycin 2 drug therapy, you would add a second drug because The patients who were stage 1 or stage 2 who had loss of heterozygosity of 1% and 16q had about a 10% less overall survival than patients who didn't have it. For stage 3 and stage 4, it was significantly more. It was about 18%. And those patients, if they were stage 3 or stage 4, they got what's called regimen M, which was 5 drugs for chemotherapy. Now you asked about Then the other thing, the other thing about pathology, once if it's not favorable, then it falls into a classification of unfavorable histology, and unfavorable histology is broken into two groups with the pathology determines whether they have what's called diffuse anaplastic or focal anaplastic, and the pathology, if it's the number of high powered fields you see anaplasia, I think it may be 20, but I'm not sure. So diffuse, if the patient has focal amiplasia or diffuse, there are different treatments depending on that or whether they have those features. They go from just having 3 drug chemotherapy all the way up to 5 drug chemotherapy plus or minus radiation therapy if they need it. What other surprises we might get when looking at that we talked about these, alluded to these earlier that it may not have even been Wilm's tumor, right? Yes, so the other things that you, the second most common tumor in children that we will come across is a renal cell carcinoma, which we don't have really good therapy for. Well, we actually don't have any good therapy for, particularly for metastatic disease, but then we also have two other renal tumors that were originally thought to be variants of women's tumor but are really distinct entities. One is called clear. Cell sarcoma of the kidney which we have pretty reasonable treatment for, particularly for the low stages, and then rhabdoid tumors which we really have failed to treat very well. The only outcomes that we have reasonable outcomes are stage 1, but beyond that, and most of them present at stage 3 or stage 4, the rhabnoid tumors, the outcomes are terrible. So I want to talk about the bilateral Wilms. So what is the treatment plan for a patient with bilateral Wilms tumor? So bilateral Wilms tumors, around 8 to 10% of all children who present with Wilms tumors, and As opposed to unilateral tumors where you want to and you take out the whole kidney, bilateral wombs tumors, you don't want to force the child to go undergo dialysis because you took out both the kidneys. So the strategy is to treat them up front with chemotherapy in order to try and shrink the tumors enough so that at least one of them could undergo a partial nephrectomy or hopefully two. Undergo a partial nephrectomy. Bilateral Williams tumors had never until recently really been formally studied. There was a number of different treatments that people had reported. They were all different. Some of them, they treated these patients for 50 or 60 months of chemotherapy without really any effect. Other times where they operated up front and the outcomes, when you look at the overall outcomes in patients with bilateral Wilms tumors, they're significantly poorer. Event and overall survival, for example, the event free and overall survival for unilateral Wilms tumors, if you took all comers was about 88% eventfree survival and 95% overall survival, whereas event-free survival for patients on NWTS-5 with bilateral Wilms tumor was 61% and overall survival was only 80%. And so we've recently, and it's been recently closed, did a study to look at that to to try and fix. Those things and the strategy that we used was using an induction regimen of chemotherapy called VAD, which includes different doses of vincristine, Adriamycin, and doxorubicin, and then doing evaluations, cross sectional imaging at 6 and 12 weeks. And the reason those were chosen were based on prior studies which shows that the maximum response of most children with Wilmstrom. is 12 weeks and the early response in most cases will predict late response. So after 6 weeks, which is 2 doses of the chemotherapy, if you were going to have a response you would get it and then we use response based criteria depending on whether you do the partial nephrectomies. If they didn't respond, you should biopsy both kidneys and look for features that either say this isn't your typical Wilms tumor or this is a. It's already differentiated. It's not going to respond and then move on. And if they did respond, then give another 12 weeks and then go on to do your definitive surgery. Is there ever a role for biopsy in any of these patients? There's not a hard and fast rule. When you look at children who present in the typical age under, you know, 36 months with bilateral renal tumors, it is almost universally Wilm's tumor and The purpose of a biopsy in children with Wilm's tumor is to determine whether you have unfavorable histology or favorable histology, and when you look at the data on biopsying, doing open biopsies to determine that, it's not very accurate initially. So based on that fact and on the long history of not biopsying from the psyop group plus the improved imaging, we did not. or mandate that the patients to get on this study with Wilm's tumor had to have a biopsy to start, and there were 250 patients who were enrolled and one patient who met the criteria to be enrolled turned out to have a rhabdoid tumor. Now the interesting thing about that patient was that there was one big lesion and then a lesion of 2 centimeters on the other side. The lesion in 2 cm. Meters went away and the patient turned out to have rhabdoid. There was also one report of bilateral clear cell sarcoma from Asia during the course of this study, but the rest of them who fit the recommendations of not biopsying all had Wilms tumor diagnosed. If a patient presents with bilateral renal tumors and his older patients, such as, you know, 89, or 10, or has a syndrome such as von Hippel-Lndau where they may likely end up having Renal cell carcinoma or it's atypical feature, then in those cases we have recommended biopsy. I think there's a very important role for it. There's no negative to do, but if you're going to biopsy, you should biopsy both kidneys because there's a discordant pathology in up to about 20% of patients to do that. But the initial chemotherapy. we used was not going to be different based on the pathology in the 1st 6 weeks. Would a biopsy in that situation mandate postoperative radiation for this study? We did not do that to do that because we did not want to commit people to biopsying and then having to do radiation therapy. We're going to look at that as to whether the patients who were biopsied had any impact on it because there is some controversy in general surrounding some biopsy work when you're giving pre-nephrectomy chemotherapy, but we did not mandate that and and in reality, the vast majority who enrolled enrolled without a biopsy. Well, Peter, this is certainly a very difficult topic to try to tackle in a short period of time. This is, as I said before, something that. Many of us don't have near the amount of information that you do about this, so this has been very enlightening for us and I'm sure it will be to everyone listening to this. I, uh, I want to thank you for taking a lot of time out of your day to enlighten us, and we may have to do part two because there's so much to discuss with this. So, so Peter, thank you very much for taking the time and hopefully we'll talk to you again soon. OK, thanks, Todd, and thanks Avi and all the best to everybody. Thank you. All right. We hope you enjoyed this episode of Stay Current in Pediatric Surgery. You can listen, watch, or read all content by downloading the Stay Current in Surgery app. Please send questions or comments to us attacurrent podcast@gmail.com. We'll see you next time.
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