Dr. Peter Ehrlich is a professor of pediatrics surgery at the University of Michigan C.S. Mott Children’s Hospital who is also a vice chair of surgery and renal tumor section of the children oncology group, he is going to help us sift through what we need to know about Wilms tumor.
A three-year-old boy presents with a left abdominal mass; CT scan shows a left renal mass. How do you approach this patient? and what is your differential diagnosis? what kind of tests you might get?
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 the kidney because: there is a blockage somewhere down along the way, the child has a benign lesion like hydronephrosis, maybe an underlying process of a congenital duplication of the kidney that makes it look large, or it is just a simple renal cyst? Those are the more common benign lesions.
The differential diagnosis of children with more neoblastic lesions: Wilms tumor, clear-cell sarcoma or rhabdoid tumor of the kidney. Depending on the age or any congenital problems, it can be renal cell carcinoma or some of the rare tumor’s; like AMLs or sarcomas. If the patient was younger it could be a mesoblastic nephroma. We would also look if it’s completely solid or cystic; those would point to it if it’s a cystic nephroma, or if it is solid at this age it would be nephroblastoma or Wilm’s tumor. Also, one of the differentials is neuroblastoma or a metastatic tumor; such as lymphoma to the kidney.
What is it on the CT scan that might look like a Wilms tumor?
The classic sign is claw signwhere you have the normal kidney being displaced into a horseshoe patternand sitting inside that horseshoe pattern is a tumor. So, it seems like the normal kidney is grabbing the mass coming out of it. Wilms tumor tends to push things out-of-the-way rather than growing into it. Whereas the neuroblastoma tends to grow out and around things like blood vessels. Also, Wilm’s tumor, by pushing the structures including the blood vessels, radiologically, it looks like as if it has a capsule which is a distinctive feature, whereas other tumors are less distinct. It may also have some calcifications on it but they are not specific to Wilm’s tumor.
After CT Scan
What after getting a CT scan with classic Claw sign?
We might need some other imaging studies and lab work for a patient that has a renal tumor where you are thinking mostly Wilms tumor. The other imaging studies that you would want to obtain it would be a scan or image cross-section at the lungs, whereCT scan is the best. The current versions of CT scan would also be able to tell you quite nicely the assessment of the vasculature because Wilm’s tumors can spread by growing out of the kidney and into the renal vein and the IVC. CT scan are really good at that. Some people would prefer to get a doppler ultrasound of the kidney as a secondary study. Then, a routine lab work including CBC, coagulation, PT, PTT , and some basic renal studies such as creatinine, electrolytes , etc.
No Metastatic Approach
In case of normal lab work up and no evidence of vascular invasion or metastatic lesions, what comes next?
Nephrectomy and ureterectomy.In North America, we believe and prefer to be the next step in treatment of children with renal tumor is to go ahead and perform surgery. That surgery is called total nephrectomy and ureterectomy, taking part of the ureter down to the level of the bladder and doing a lymph node sampling in the regions that trail the kidney, that is our recommendations for the majority of the tumors that present in children. There are some exceptionsto that sometimes these tumors can be exceptionally large in such a way that compromises the respiratory status of the child and 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 we would recommend doing chemotherapy upfront based on the children’s oncology group. The philosophy would be if the tumor extended into the inferior vena cava and beyond the infra-hepatic 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 tumor 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 and bowel. Again, those are not warranted if the tumor is that large because the majority of them will respond to some degree to chemotherapy. Finally, if the child has only one functioning kidney, we don’t want to take that kidney out and we would try 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 if the child has certain genetic or predisposition to developing tumor in the other side, in those situations we will take a different approach.
Some of the samples of that include children with Wagr syndrome, Denys-Drash syndrome, Beckwith-Wiedemann syndrome, or children who have tumors in multiple positions throughout the kidney; multi centric tumors.
Above the infra hepatic cava:
If tumor goes above the infra hepatic cava then would you do a biopsy or just start chemotherapy?
We would do a biopsy
Intestinal invasion management:
If the preoperative imaging seems to indicate that it is invading a small section of the intestines would that change the management?
In general, if you think that you would have to take out part of the colon, which usually the part that is invaded, then in that situation I would biopsy the patient because we do know, first of all, probably they will respond and the complication rate is showing to be higher if you have to take out the liver or bowel at the same time you’re taking out the kidney, so there’s no reason to do that.
Over all, is there a consequence in that case of upstaging?
It’s not really upstaging. This goes to the question if there are different types of staging systems that people use depending on whether you do pre-nephrectomy chemotherapy, or whether you do primary nephrectomy and then treat, or the difference between the children's oncology group staging and the SIOP base protocols, which are offered in the UK and some other countries. If we leave gross tumors behind or just biopsy it, has always been it should be treated as stage III abdominal tumor and those tumors will get three drug chemotherapy plus flank radiation. Now that if you feel that the tumor has invaded into such an extent that you have to do a major liver resection or bowel resection, then that is going to be a stage III tumor anyways. What you are really doing in that situation is that you’re saying it’s not valuable to take out the descending left colon or ascending right colon or do a right hepatectomy because we know if we give chemotherapy those will almost always respond and you’re not going to change things. Often Wilm’s tumors will push up to the liver and some people will take a little rim of that, just to make sure that clear margin that’s completely different.
Different therapeutic approaches:
How you would tailor the therapeutic approach based on the imaging finding?
The first thing you should make sure when you’re looking at the kidney at the CT that there are no other lesions in the other kidney.
Once you’re satisfied, the secondthing that you would want to look at is whether the tumor in the abdomen has extended anywhere. Is the disease of the liver having the Wilm’s 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 a cross-section sectional imaging of the chest; because those things will help with what’s called final stage of the disease.
At that point in time there are two prevailing treatment strategies. The first treatment strategy, in the children’s oncology group, primarily in North America strategy, has been if the tumor is resectable that we would do nephron-ureterectomy with lymph node sampling.
In the children’s oncology group strategy, the criteria that we use for patients who would not recommend that for include the following:
- A tumor that's so big that it impairs the child's respiratory status and that they are not a good surgical candidate
- If there’s only one kidney or that there’s only one functioning kidney and the other kidney has some underlying continental problems, again we would not recommend doing that upfront
- If the tumor extends out the renal vein and beyond the infra-hepatic vena cava that there is high risk of complications
- If you feel that you would have to do major liver or bowel resection at the same time, that is a situation in which we do not recommend doing the primary nephrectomy
- If the tumor, just based on the size, would be so difficult and generally the evidence suggests that you get into trouble with the tumor start to get in between 13, 14, and 15 cm and bigger, but there is a higher risk of rupture and you might want to consider not doing a primary nephrectomy.
Crossing the midline:
What about crossing midline?
Those tumors tend to fall into that categoryand some of those larger tumors they are very mobile and easily resected, and other tumors are very fixed and you might not really do it; it’s really a judgment call. Sometimes you make the judgment when you do the operation; you feel around and see how mobile the tumors are. So that is a judgment call the evidence says that you have to be more cautious as you get some more closer to 13, 14, 15 cm from the tumor size and all of those would cross the abdomen in children.
In case there is a lung lesion
Should we proceed with the biopsy of the lesion first?
Yes, because there’s really no way of knowing exactly what type of tumor you are dealing with without the pathology and the pathology really directs the treatment. For example, although the majority of them will be Wilm’s tumor, has two groups: one is called unfavorable anaplastic histology and 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 the rhabdoid tumor of the kidney, which has a very different prognosis and has very different chemotherapy, and clear cell sarcoma of the kidney. All of those would be very different and you can get a better idea whether it’s a malignant tumor versus one of the non-malignant types, there is no imaging study available that would be able to tell you the difference between a rhabdoid tumor, clear cell sarcoma, and Wilm’s tumor or even whether it’s favorable or non-favorable histology. So, we think that biopsying is very important.
How would you do the biopsy?
There are really two options, we 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 technologies with large core sampling has for several series is proven to be accurate but it hasn’t been tested but a lot of people are doing that. One of the things that we would recommend that wherever approach they use if they do it 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 then they take at least 10 cores and the data suggest that between 10 and 20 they increase the accuracy. We would not suggest by needle aspiration or just doing a simple pass of a true-cut needle biopsy as we cannot diagnose anaplasia based on those biopsies and in fact if you are not sure if it’s Wilms tumor or something called a RAS you can diagnose those based on the core biopsies.
Need for chemotherapy:
Is there any possibility that the biopsy would come back with something that you would not need chemotherapy?
It’s always possible, some of the children under six months of age may come back as a benign lesion, but it’s unlikely. Those lesions such as mesoblastic nephromas never extend out to the inferior vena cava or where it would change it would be an exceedingly rare event if that happened to do a biopsy at that stage.
Type of CVC needed:
What is the type of the CVC you place?
Most chemotherapy protocols require a single lumen port, it’s preferred because of the infection risk, however and younger kids as we know we don’t have enough small ports so it’s a single lumen Broviac like catheter
What is Wilm’s tumor staging?
In the children’s oncology group staging system, the treatment is determined based on two factors.
- The local abdominal stage
- The disease stage
The tumor that is limited to the kidney, it's completely resected and there is no invasion through the renal capture
The tumor was not ruptured or biopsied prior to removal, and the vessels of the renal sinus are not involved
There is no evidence if tumor beyond the margins of resection and the regional lymph nodes are negative
It is completely resected
There’s no evidence of the tumor beyond the margins
The tumor can extend beyond the kidney, can be regional extension of the tumors such as penetrations after the renal capsule
Or invasion of the soft tissue of the renal sinus. Blood vessels within nephrectomy specimens are kinder outside of the primary kidney if they contain tumor cells that is considered stage II
The tumor is either biopsied and there is a gross tumor remaining, there are lymph nodes that are positive within the tumor.
The tumor has penetrated through the peritoneal surface where you find two or more implants where you have positive margins on the tumor or there is microscopic residual either from intraoperative spell or you couldn’t completely resect the tumor.
Or if the patient is biopsied and got chemotherapy
If you have to take the tumor out in pieces or if the tumor extended into the renal vein and you divided the renal vein with tumor
Hematogenous metastasis to the lung or liver, which are the most common places, or bone or brain
Bilateral renal tumor involvement
Treatment based on stage:
Treatment approach: You could have a tumor in the abdomen at stage I but the patient could have a lung lesion. That is not uncommon, particularly stage II tumors, and that would mean that the child would get different chemotherapy and it was stage I in the abdomen and the child would not get abdominal radiation. Whereas if the child had stage III tumor in the abdomen and lung metastasis, the child would get chemotherapy plus abdominal radiation, and in some instances, may require lung radiation also.
Need for Chemotherapy:
Is every stage would get chemotherapy? it’s just a matter of what chemotherapy they’re going to get, is that right?
Correct. If the patient has stage I or II Wilm’s tumor in the abdomen and no lung metastasis, the patient will only get two drug chemotherapy for short term duration and that chemotherapy regimen is not toxic and the risk of late effects are significantly lower than adding a third drug, which are doxorubicin or adding the abdominal radiation.
The main late effects are renal failure, development of second malignancies, and problems with female 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 is a significant difference between using those and not using them. if a child has stage I or II in the abdomen, they would not require abdominal radiation that’s a really a good long-term thing to avoid.
There is something that is confusing to the oncologist and the surgeon which is the presence of the lung lesion. The rule is because there is a lung lesion it doesn’t mean that you shouldn’t take out the primary tumor. So, if there is a lung lesion and a 5 cm tumor and you need to biopsy that tumor, that in the children’s oncology group treatment paradigm would mean the child is automatically considered a stage III because of the risk residual gross tumor and the child will get the three drug chemotherapy and also get the abdominal radiation. If you go on ahead and remove the tumor and the child and the lymph nodes were negative, you would not necessarily have gotten abdominal radiation.
Stage I and II approach:
How to approach stage I or stage II tumor with the lung lesion?
My approach to that patient is to take out the renal tumor and leave the long lesion alone. There are two reasons to do that.
- You want to know what the pathology is. so if it’s a favorable histology Wilm’s tumor, I do my lymph nodes sampling. if lymph nodes are negative, it’s stage I or stage II; this child avoids abdominal radiation
- The children’s oncology group has recently finished a trial to see if all kids need the pulmonary radiation. Pulmonary radiation has been the gold standard for treatment for this disease and the problem is of late effects and 15% of girls who get pulmonary radiation for Wilm’s tumor end up having breast cancer which is significant. There’s also a problem with pneumonitis and long term restrictive lung disease. Based on some SIOP data and children’s oncology group data suggests that there is a section of a group of patients who respond very quickly by six weeks to chemotherapy and those patients may not need pulmonary radiation.
- So, a recent study at the children’s oncology group addressed that there where children who had pulmonary disease, underwent six weeks of chemotherapy, and got a repeat CT scan. And that those who were complete responders, and that was about 40% of the patients, they were not given pulmonary radiation and looking back to that group, at this point of time looking at relapses, there were 80% to 85% who did not relapse so those kids completely avoided pulmonary radiation and the toxicity without any effect on being event free or their overall survival. Of the people who did recur, all but one of them have survived and they did get pulmonary radiation, and the one patient who did not survive actually died of non-oncological cause.
Need for lung lesion biopsy:
When you had the patient, you have done your nephrectomy, they have a lung lesion, and you’re just going to start chemotherapy based on the pathology from the kidney tumor, you’re not going to even going to get tissue from the lung lesion?
Yes, no there is no reason at this point in time to get the lung tissue, there are situation where you might want to consider long tissue biopsy at the six-week evaluation. Again, in North America what we do is we would treat and see the response. If you happen and have a lesion that was there and did not respond to chemotherapy or a single lesion left that you are not sure what the etiology of, then it would be reasonable to go in and do thoracoscopic biopsy. Because about 50 to 60% of the time those lesions may not turn out to be cancer; they could be scar, could be a variety of things, in those situations those patients would not need pulmonary radiation.
Chemotherapy for stage I:
If you had this patient again with a lung lesion, after nephrectomy, comes back with favorable histology stage I Wilms tumor and they have a lung lesion, do you give them two drug chemotherapy?
Yes, if I was convinced, assuming that the lesion in the lung was a malignant lesion, or if I am uncertain about that, then I will resect that lesion to find out.
How can you ever be a certain without resecting it?
The radiologists have criteria that they useand they are pretty comfortable at deciding it. If I am not sure and have a 1 cm lesion that looks like a scar, I will resect it because that will change the chemotherapy plan, but those situations are not the common. Routinely, if I have a 1 cm lesion in the upper lobe that’s peripheral, which is classic for a metastatic lesion, then there is no reason to biopsy it. Now if you are treating the lung lesion assuming that it’s a metastatic disease, you would start with three drug chemotherapy with lung lesion from that stand point.
Differences between COG and SIOP:
What are the differences between COG and SIOP approaches?
the SIOP protocol used mainly by western European countries have taken a different approach to patients with Wilms tumor:
- They will start chemotherapy with all patients, they don’t to go to operation and the majority of situations are not biopsied.
- They will give two drug chemotherapy in very different doses; a lot higher doses of the two common drugs that we use
- They will evaluate the patient at four weeks looking for a response
- Then they go on to resection
- Then based on the pathology and nodal status afterwards they have a post chemotherapy post-nephrectomy classification that goes into patients who are low risk, intermediate risk and high-risk patients.
What are those criteria for abdominal radiation?
They give abdominal radiation to their high-risk patients whether their lymph nodes are positive or negative, and to their intermediate risk patients who are lymph node positive.
SIOP classification of Wilms tumor:
- Low-risk patients, patients who have complete necrosis.
- Intermediate-risk patients, is based on the percentage of what is called blastemo components.
- High-risk patients, they have high blastemal components, it is called predominantly blastema or if there is anaplasia.
SIOP therapeutic approach:
- For high-risk patients, three drugs or more in chemotherapy plus abdominal radiation.
- For low-risk patients, two drug chemotherapy.
- For intermediate-risk patients, it’s a moving target sometime so I am not sure what drugs they give particularly.
Based on COG protocol, if we look at the patients who are all at stage III, are there any differences between the patient who underwent empiric biopsy versus the outcomes difference in the patient who in ended up getting spillage at the operating room when trying to undergo complete the nephrectomy?
No.there is no difference in that group. The main factor that predicts outcome in stage III is whether they are lymph node positive or not and then whether they have certain genetic changes that we validated prospectively, that we call loss of heterozygosity, and a genetic change, that we validated on retrospective data that is called 1q gain.
Advanced stages approach:
If you’re looking at a CT scan pre-operative and it’s unclear whether the tumor is resectable then technically giving it a try or attempting to resection wouldn’t really get the patient to poor prognosis if the bailout is only to be performed at the time of the biopsy?
No not at all. I think it’s reasonable to think about it in that way. If you sometimes just can’t tell and you go and find out that the tumor is fixed and you have to do a major bowel resection, then backing out is reasonable. Our European colleagues might say well while you’re doing that why don’t you just treat them, because the majority of them would respond to some degree, and that’s also reasonable. When you look at the outcomes for stage I and stage II patients between the children’s oncology group and SIOP groups, they are basically identical.
Talking to family:
For a respectable Wilms tumor with no reason to biopsy but seems like a good resection candidate, how do you prepare the patient for surgery, what do you tell the parents and talk about technical pearls and potential pitfalls during this procedure?
Making sure I know the lab work going in and make sure that nothing is out of whack. For example, make sure what is the hemoglobin level, because some of these patients present because the tumor is ruptured inside itself and start with very low hemoglobin and in very rare cases they might bleed as the case starts, but those are very rare.
knowing coagulation statusparticularly the PT and PTT, there is something called acquired Von Willebrand disease which these patients get. In the majority of cases it’s minimal but there have been reports of few Key series where these patients may bleed a lot during surgery and until the tumor is out. One or two cases, these have been significant. Some people have recently suggested that bleeding time should be obtained for all patients with Wilms tumor, the majority of us are not convinced of the value of that but it’s something that we should look at and surgeons should be aware of, and then just routine electrolytes.
I don’t routinely bowl prep the patient unless I have a particular concern about that.
Discussion with the family, I will talk with the family,in general, with the oncologist. I talk to them about what we are going to do during the operation in terms of taking out the kidney, the ureter and taking lymph nodes. I will talk to them about the presence and absence, about what the imaging telling us about the vascular extension, and then I will talk to them about complications based on the location and size of the tumor from routine things; like infection and postoperative fever to areas where you have to be really careful about right-sided tumors where sometimes the adrenal vein can cause problems or can be really quite close to the duodenum. Because there have been duodenal injuries reported and superior mesenteric artery injuries, because everything can be distorted. Particularly, right-sided tumors can also sometimes distort IVC, so I tell the family about potential IVC injuries.
Position and incision:
In the operating room, how do you position the patient, and how you do your incision?
I typically position the patient slightly elevated on the side of the tumor and I tend to make a modified subcostal incision or transverse incision depending on their age and shape of the child going to the midline. To do that, I don’t make a paramedian incision and I don’t make a retroperitoneal incision that we might use routinely in adults. To do that, I make a transverse abdominal-like incision over where I feel the hilum maybe and tend to make it subcostal on the right side and less so to the left.
Then upon entry to the abdomen, I look around and make sure that there’s no other peritoneal seeding. I will look at the liver to make sure that the liver doesn’t have anything, and if I can easily do it, I may palpate the IVC or the appropriate renal vein to look for the tumor. Sometimes that is often difficult; these tumors tend to be large and although ideally you would like to identify the renal artery and the renal vein, if you can’t do that, you shouldn’t try to do it upfront.
Then I will start by mobilizing everything off the kidney and mobilizing the kidney either starting at the inferior or superior pool and slowly go around the kidney until I get it on a pedicle. once I have identified ureter, I will put a vessel loop on it and I will follow the ureter down as far as I can to where it goes into the bladder and then I divide it. if I don’t, then I will identify the vasculature within the hilum getting around the main renal artery and the main renal vein. once I have identified the main renal artery and the kidney is usually pretty mobile about time, I will divide those structures. Usually at that point in time the tumor can come out. if it’s easy, I will take the adrenal off the superior part of the kidney. But it’s not necessary; there is been no reports of adrenal insufficiency’s, and presence or absence of tumor into adrenal vein has no correlation with outcomes. Sometimes there can be and sometimes there can’t be; depending on the specimen to do that.
So once the tumor is out, I then willlook into the renal hilum para-aortically or para-cavally for lymph nodesand I will try to sample at least 5 or 6. At this point in time I don’t have any evidence that makes a difference, but there’s some secondary evidence that suggests that more than one may be better
Artery vs vein:
Does it make a difference if you get the artery or the vein first?
In general, it has not made a difference. By principle, it’s always better to get the artery first but it’s not always possible. Some of these tumors are quite big and you may get yourself in trouble if you do that. often the artery sets below large vein and it may be difficult to do that, so I take what it comes to me. If I see the artery first, I will divide the artery first but that doesn’t always happen that way.
Do you need to place metal clips?
We used to recommend that. We still, due to some degree to that good imaging available the radiation oncologist doesn’t find that to be as helpful, but generally I will put few clips on superiorly and inferiorly for the radiation oncologist. But it’s not as important in their treatment marking because the 3-D volumetric CT scans are able to match up the patient.
what is the significance of surgical margins in these patients?
Surgical margins will tell you whether the patient is at a stage II or III. If the surgical margins are positive then that automatically means the patient is at stage III. Know sometimes the tumor can extend and microscopically rupture, you can’t tell that until they look under the microscope and there’s nothing you can do about it. That’s at stage III tumors. There’s very good data to support that from both our North American studies and SIOP studies. To do that, sometimes you come across and you say this to my ruptured that makes a difference other times you come across and the tumors are very soft and you handle it and rupture and there’s just nothing you can do about it. If the margins are negative, then that means the patient could be at stage I or stage II has met all the pathological criteria for that.
Has there been any rule for frozen section for the evaluation or once you have already cut through it theoretically?
So, if you have already cut through the tumor by accident then that makes you at stage III. There are a few technical points, sometimes these tumors are not unusual that they cause a lot of reactions and be very adherent to the diaphragm. Taking a piece of the diaphragm so you do not violate the tumor is recommended, and if you haven’t divided the tumor then that will not upstairs your tumor. Sometimes the tumors tend to come up and directly get attached to the liver, but not really an invasion or an inflammatory reaction. So, taking a part of the liver, particularly the right or the left lobe’s just a tiny bit, is done to make sure that you don’t accidentally get into the tumor. The majority of those cases, the tumor has extended, and in some cases these tumors cause intense inflammatory reaction. That makes it seem like they have invaded but actually it hasn’t, and other times it has invaded and you deal with that.
Is there any patients that can’t be treated with surgery alone?
Yes, this is unique to the Children’s oncology group and was really based on observations by Dr. Bob Shamburger based on the review of kids pre-assed from children’s oncology group, which is the National Wilms tumor Study Group. They run five studies; the first four looked at the variety of different questions but it was known that there is a group of patients that no matter what you did treat them with, surgery your ad one drug of chemotherapy, two drugs of chemotherapy, three drugs, or radiation, they had excellent overall survival and these patients were treated with just surgery and no matter what else to do they couldn’t improve, their survival was greater than 95% and the characteristics of these patients at the time where patients who had tumors that were: less than 550 g, stage I tumor, less than 2 years of age, and had favorable histology
Based on that, there was a small series of 10 patients who were treated that way and had excellent overall survival, and then, two studies that were done one on NWTS study five 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. However, what is the value of that? Well, complications from chemotherapy particularly can be more severe then there is a late effects of chemotherapy that could do that and it turns out if these kids met these criteria, then about 90% of them can avoid any chemotherapy and those who do relapse we have 100% survival.
Now we have gone through a few other secondary aim studies looking at the biological predictors because what if the child is two years and one day and what if the child is 556 g, are there any other features that would make them OK not to be treated with chemotherapy alone? are there any in the 10% or so to relapse? are there any other common features, biological markers, that these kids maybe should get chemotherapy to improve their survival.
Regarding caval extension that needs upfront surgery, what is your strategy and how you would do resect that caval extension?
When you look at the outcomes of patients with the tumor that extend into the cava, or even up to the atrium, that is not a negative prognostic factor if you are looking purely at oncological outcomes. Actually, loss of heterozygosity or anaplastic histology or rhabdoid tumor, those are much worse than caval extension. In fact, in many instances, if it extends into the renal vein, it’s not insert into anything and it comes out in one piece, it’s considered stage II.
So, when I go in, I will assess the extent of the tumor extension and if I am concerned and can’t 100% palpate it, I will use an intra-operative ultrasound. I will assess how far it goes up and if I 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, then make a small nick in the renal vein and you slide the whole tumor and thrombose in one piece. In reality, it doesn’t always, you sometimes have to open or put a side clamp on the cava and open the cava to make sure you get it all out at that time. When it starts to get above, what’s really been shown is that the major complication rate in patients goes up and those include more mortalities, number of blood transfusions, ICU stay, and complications go up. So, for those cases, it’s been shown that it would be better if you treat it upfront with the preoperative chemotherapy. To that, the kidney will always respond to some degree. The tumor itself doesn’t always completely go away in those situations but in a lot of times it will shrink and in some, not a significant amount, it will completely disappear. But you may still end up in situations where you may need to have bypass or vascular occlusion to take out the tumor.
Chemotherapy and tumor consistency:
Does chemotherapy make the tumor harder to resect because of the reactions to the chemotherapy?
That can be right, but in a lot of times those are necrotic tumors and there’s no doubt it can be difficult. But in the larger series that we have there was no mortality in those patients and there was a significant 26 to 30% major morbidity and complication rates were operated upfront with tumors that extended beyond the infra hepatic cava and inferior hepatic veins and the atrium. There is still a need for a bypass, but the complication rates tended to be lower. There is no doubt about that.
Technical steps for thrombus:
For a known tumor thrombus below the liver, what are the detailed technical steps of taking out that tumor thrombus?
If I know that I am getting in thereI try and without doing too much to the primary kidney, if I’m not 100% sure, I can get it out. I mobilize the bowel and I 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. Then I ask myself can I partially occlude the cava or do I have to totally occlude it to take this out.If I find that it goes much higher than it appears during imaging, then I will back out and biopsy it, but if it’s slightly extends into the inferior veina cava, I can get a clamp on it and then I can do resection of the inferior cava and then repair that; I get all the tumor out in a block.
If it’s filling the cava, then I have to do vascular principles and then mobilize the whole kidney, I will then tie the renal arteryand make sure that the whole kidney and the thrombus is based on that. Then I will occlude the cava and do that anterior veinotomy and pull the tumor out.
Now, does it always come out in one piece, no but in a lot of times yes; sometimes you will have to do an extensive anterior veinotomy to really just make sure you get it all. But those are not common becaus truly does it oclude the whole cava often you get clogged, it goes all the way up and present an extremist. I read 6000 operative notes; the amount of time somebody actually had to go all the way up there and stop at the infra hepatic cava, I’ve not even recalled reading a case where that happened.
There is what people say you are supposed to do and there is the reality. After reading 6000 and not seeing that I’m not sure some of these things that are described historically actually occurred and I don’t know what yours’ experiences have been. When it fills it up, it tends to go up and in some of those situations after treatment the kidney there’s collaterals.
Few months ago, I had to take out the kidney that’s all collaterals and the easy thing to do was to take out the whole cava, he wasn’t using it. And then I got a margin just where all the proximal veins came in. It turned out that there’s no tumor in there and it was just not used so it quadded up.
What are the different pathological results and how you treat those?
The main categories are favorable and unfavorable. The first thing, the pathologists just looks for in North America is to find out whether there is a favorable histology which has epithelial components, stromal components and blastemal components. The glomerular and amount of stroma it’s called a triphasal tumor. There are the classic features off wilms tumor and most of them have some degree of all three, some have only two and all considered favorable.
The children’s oncology group protocols, the amount of blastema has never correlated with outcome. Alternatively, the treatments that are used by the SIOP group if you have pre-dominantly blastemal preoperative chemo therapy, that’s considered to be a negative prognostic factor. It doesn't seem to play a role in the primary-nephrectomy chemotherapy patients.
That to my pathology is a favorable histology, then the next decision is what stage is it. Is the lymph nodes positive, is at stage I or stage II, and that’s considered the abdominal staging.
Finally, we look for lung metastasis. If it’s negative, then it’s stage II. Then there’s a well described tested standard treatment that includes chemotherapy, which is called two drug chemotherapy. Which is vincristine and actinomycin and it’s usually about 19 weeks of therapy.
If it turns out it is at stage III, then dab doxorubicin treatment that’s called DD4A and that regimen is for 25 weeks.
If it’s favorable histology,or any of them, we do a secondary test looking for the presence or absence of loss of heterozygosity, which is when you lose certain genetic material on certain chromosomes. This has been noted in variety of cancers and in particular renal tumors the 1p 16 Q and 11T were chromosomes that had loss of heterozygosity associated with it.
And it turned out that in this particular paradigm if you have 1P and 16 Q, that were outcomes regardless of stage were significantly worse. In the most recent children’s oncology group studies we did loss of heterozygosity testing and it turned out if you have both of them, which is about 5- 7% of the patients, your treatment will increase. If you’re at stage I or II where you would normally get vincristine and actinomycin two drug therapy, you will add a second drug because the patients who were at stage I or II who had lost of heterozygosity where normally get vincristine and actinomycin two drug therapy you will add a second drug because the patients who were at stage one or two who had lost of heterozygosity at 1P and 16Q had about a 10% less overall survival then patients who didn’t have it.
For stage III and stage IV, it was significantly more- about 14% - and those patients if they were at stage three or four they got what's called regimen M which is 5 drugs for chemotherapy
The other thing about pathology if it’s not favorable, then it falls into a classification of unfavorable histology which is broken into two groups diffuse anaplastic or focal anaplastic.
If the patient has the diffuse or focal anaplasia, there are two treatments depending on that and they go from having just three drug chemotherapy all the way to five drug chemotherapy plus or minus radiation therapy, if they need it.
What other surprises we might get, you alluded to earlier?
Renal cell carcinoma, clear cell sarcoma, and rhabdoid tumors. The second most popular tumor in children that we will come across is renal cell carcinoma. Which we don’t really have good therapy for, actually we don’t have any good therapy for any metastatic disease. Also, we have two other renal tumors that were urgently thought of as variations of Wilms tumor but there are two distinct identities one of them is called clear cell sarcoma of the kidney which we have a pretty reasonable treatment for particularly low status and rhabdoid tumors which we have failed to treat very well the only outcome that we have reached is for stage I and the most of them present at stage III or IV and for those tumors the outcomes are terrible.
Bilateral Wilms Tumor:
What is the treatment plan for a patient with bilateral Williams tumor?
Bilateral Wilm’s tumors are about 8 to 10% of all children’s present with Wilms tumor’s and as opposed to unilateral tumors where you want to take out the whole kidney, for bilateral Wilms tumor’s you do not want to force the child to undergo dialysis because you got out of both kidneys. So, the strategy is to treat them upfront with chemotherapy in order to shrink the tumor’s enough so that at least one of them could undergo a partial nephrectomy or hopefully the two will undergo partial nephrectomy.
Bilateral Wilms tumors haven’t before, till recently, been formally studied. There is a number of different treatments that people have reported they were all different, some of them treated these patients for 50 or 60 months of chemotherapy without any effect and other times they were operated upfront and the outcomes when you look at the overall outcomes of these patients, they significantly poor event overall survival. For example, the survival for a unilateral Wlims tumor is about 88% event free survival, and 95% overall survival whereas for patients with bilateral Wilms tumor is 61% event free, and overall survival is 80%.
We recently have done a study to look at that and try and fix those things and the strategy that we used was using an induction regimen of chemotherapy called VAD which include different doses of vincristine, adrinomycin, and doxorubicin been doing evaluations cross-sectional imaging at 6 and 12 weeks and the reason those were chosen were based on prior Studies which showed that the maximum response of most children with Wilms tumor is 12 weeks and the early response in most cases will predict the late response, after six weeks which is two doses of chemotherapy if you are going to get response you will get it. Then we use response base criteriais based on whether they respond to chemotherapy or not. If they didn’t respond, you should biopsy both kidneys and look for features that either say this is your typical Wilm’s tumor or this is already differentiated and it’s not going to respond and move on. If they do respond we get another 12 weeks and go on to do definitive surgery.
Role of biopsy:
What is the role of biopsy in any of these patients?
There is no hard and fast rule. when you look at children who present in the typical age under 36 months with bilateral renal tumors it’s almost universally Wilm’s tumors. The purpose of a biopsy for children with Wilm’s tumor is to determine whether you can determine if you have favorable histology or unfavorable. When you look at the data of the biopsy it’s not very accurate initially, so based on that fact the long history of not biopsying for the SIOP group plus the improved imaging we do not recommend that the patient depending on the study he had to have a biopsy start. There are 250 patients who are enrolled and one patient who met the criteria turned out to have a rhabdoid tumor. The interesting thing about that patient that there was one big lesion and a lesion of 2 cm at the other side, and the lesion of 2 cm went away and the patient turned out to have rhabdoid a tumor.
There’s 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 biopsy all had Wilms tumor diagnosed
Patient presents with bilateral renal tumors - older patients such as 8, 9 or 10 who has a syndrome such as Van Hippo Lindo, they may likely end up having renal cell carcinoma or it is atypical feature and in those cases, we recommend a biopsy and it’s a really important role for it.
There is no negative to do, but if you are going to biopsy you need to biopsy both kidneys because there is a discordant pathology and up to 20% of patients to do that but the initial chemotherapy that we use is not going to be different based on the pathology in the first six weeks
Biopsy and post-op radiation:
Would a biopsy in that situation mandate a post-operative radiation?
For this study, we did not dothat because we didn’t want to commit people to biopsy and then having to do radiation therapy. We are going to look at whether the patients who had been biopsied had any impact on it. There's some controversy in general surrounding some biopsy work when you give pre-nephrectomy chemotherapy, but we did not mandate that. In reality, the fast majority who enrolled, enrolled without a biopsy.
this is certainly a very difficult topic to tackle in a short period of time. This is something, as I said before, 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 am sure for everybody who is listening to this.
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. So, Peter thank you very much for taking the time and hopefully we will talk to you again soon.