So thank you very much, Stacey. It's a real pleasure to be here and welcome everyone. It's been, maybe a couple of years since I had the opportunity to do one of these webinars and it sounds like, the webinar that's really grown quite substantially since then and it's a real credit to the organisation.
So again, thank you very much for attending. I'm gonna talk again primarily today about mass cell tumours. And there's a few reasons why I really, really enjoy talking about this particular topic.
One of the reasons is, again, anyone who's in, who's in a private practise certainly knows that this is a tumour that we see a lot of. So it's actually a very common tumour, one of the most common tumours that we see. And the other thing that's really nice and the thing that again we in sort of the academic community sometimes forget is that the vast majority of these tumours are tumours that can be dealt with quite effectively in first opinion practise.
You know, we in, in tertiary care tend to see the bad ones. We see the ones that can't be resected or that have grown back or that have spread all over the place. And I think sometimes new graduates get a really sort of biassed opinion about what mast cell tumours are all about because of, the tumour types, or the tumours that they've actually seen here at the university.
But again, the good news is 2/3 or more of all the mast cell tumours that are encountered in practise are, you know, quite manageable, often just with surgery alone. . Final reason why I think this is a really good topic is also because it's a great example of what we call multi-modality therapy.
So depending on the circumstance, we'll do surgery, we'll do radiation therapy. There are drugs that we can use, and then there are again some, some novel and quite interesting, new forms of therapy that can be effective for some mast cell tumours as well. So it's a really good opportunity to at least touch on all of sort of the pillars of oncology that we talk about, you know, for therapies.
So again, as I mentioned, the good news about mast cell tumours is that about 2/3 to 3/4 of them are what we would call lower intermediate grade tumours, which means they're generally local problems only. And if you're able to get sufficiently aggressive with your local treatment, those dogs have the potential to do incredibly well, for the long term. Again, very common, and we do see some dogs that appear to be more likely to develop mast cell tumours than other breeds.
Classically, the, the breeds that tend to get the most depressed in this arena are the brachycephalic breeds, or, what I like to say the smushy face breeds, the Bostons, the bulldogs, the pugs, etc. This is just one day, the picture here is one day on the oncology clinic, back at University of Wisconsin where we had 3 Bostons all on the same day. A little dirty secret is that actually none of these dogs happen to have mast cell tumour, but it does make for a cute picture.
The good news about, about the Bostons and the, and the other brachiocephalics is that, that although they do tend to get a lot of mass cell tumours, statistically, the mass cell tumours that they do get tend to be a bit more on the benign side. So that's not a hard and fast rule, and it doesn't mean that the tumours that you see on these breeds don't need to be submitted for histopathology or that they can be ignored. But again, as a group, these brachycephalic breeds do tend to get generally better behaved mast cell tumours.
So This is a paper that came out just a couple of years ago looking at the breed-related incidence of mast cell tumours in dogs. And you can see that there are a variety of breeds, not only brachycephalics that do seem to be predisposed. These are the ones we talked about already, the brachycephalic breeds and they're indicated in red here with the boxer being sort of far above all the others.
So all of these dogs with one exception, are actually genetically related. So the one kind of outlier here is actually the pug, despite the fact that they look quite a bit like these other brachycephalic breeds. I've been told that genetically they're actually kind of distinct.
This is not the only group of related dogs that also has an increased risk of mast cell tumour. So the ones in blue here are some retriever breeds. So, you've got Rhodesian Ridgeback, you've got Hungarian Vila, and you've got Weimaranner.
So again, these are dogs that can often, at least I don't think of as being as predisposed, but certainly the literature does support that. And again, very closely related genetically, which is quite interesting and really does suggest that there's a genetic or potentially heritable component to mast cell tumour development. At least in certain dogs.
So, there's one other breed that I always want to point out very carefully that's predisposed to these tumours, and that's the Chinese Shar Pei. And the reason for that is, is, not only because again they're at increased risk for development of these tumours, but, contrary to what we see with the, the brachycephalic breeds, these, sharpei tend to get awful mast cell tumours. So again, the brachycephalics as a group tend to get better behaved mast cell tumours.
The majority of Shar Pei get actually very aggressive tumours. We have some unpublished data from here at Colorado State that suggests that about 70% of mast cell tumours in Shar Pei dogs are high grade. Again, compared to 20 to 25% of all the other breeds put together.
So if I see a mast cell tumour in a shar pei, I am going to assume that it is bad and, and until I see the histopathology report. So a little important tidbit there. One of the other things that can be tricky about mast cell tumours in general is they are one of those tumours that are sometimes referred to as the great pretender.
So they can look like anything, they can feel like anything. They can be erythematous or not firm, soft, painful, not painful, itchy, not itchy. Haired hairless, ulcerated, not ulcerated, cutaneous, subcutaneous.
Really, it can be very difficult to say what's a mast cell tumour and what's not purely based on its appearance. And that's why we really sort of try to drum into the student's head the idea that really any lump or bump should be aspirated because of its possibility of being a mass cell tumour and not The lipoma that it looks like, etc. Etc.
The other thing that we know can be a problem related to mast cell disease is the fact that, in addition to, to the local problems that we can see with the space occupying mass, in addition to the potential for metastasis that some of these tumours have, there is the potential for effects related to substances that the mass cell tumours can release. And again, the classic one, the one that tends to get the most press is histamine, which is one of the components of those little classic purply blue granules you see in the mast cell tumours. And histamine can cause local problems like swelling and erythema, as you see here, but it can also cause systemic problems, and again, the one that we're most familiar with with high plasma histamine levels is a high potential for gastrointestinal ulceration.
So this is another thing that we need to concern ourselves with in those dogs who have very heavy disease burdens. And in those dogs where for reasons of necessity, the tumours are going to be treated in situ, and there's a high risk of killing a lot of tumours all at the same time. So one again helpful hint that I'll mention is that this, this concept of GI ulceration is something that I virtually never see associated with a solitary mast cell tumour.
So if I see a dog that has a, a small mass cell tumour and concurrently has signs that could be consistent with GI ulceration, my index of suspicion and that that, that, that we're going to find dissemination is gonna be much higher. Or alternatively, the dog have something else going on that may be completely unrelated to the mast cell tumour, but that you'd want to get sorted before bothering to deal with that mast cell tumour. We think of mass cell tumours being primarily a cutaneous disease, but we can see forms of mast cell tumour that occur everywhere else.
So, again, mast cells are one of the white blood cells. So as a result, they really have access to the to the entire body. We can see primary visceral forms of mast cell disease like liver, spleen, and intestines.
These are more common in cats than they are in dogs, but we can see them in dogs. We can see primary bone marrow infiltration with mass cell disease, which would be a mass cell leukaemia. In general, the visceral forms of disease in dogs have a very, very high likelihood of already being metastatic at presentation and generally they're associated with a very poor prognosis.
These dogs are often usually quite sick at presentation. We can also occasionally see dogs with what appears to be primary mast cell tumour of the lymph node. So again, a solitary lymph node that appears to be enlarged, you aspirate it, you get lots of mast cells out of it, and you go over the dog with a fine tooth comb.
It can't find anything that appears to be a primary mast cell tumour. So that's another thing that we occasionally see that seems seems kind of confusing, but, kind of makes sense when you realise that mass cells can live in normal lymph nodes and there's no reason that one of those particular mass cells can transform. As I mentioned, the good news is about 2/3 or 3/4 of mast cell tumours that we see are pretty well behaved.
It's identifying that 1/3 that may be more aggressive and more problematic that can sometimes be an issue and be a bit troubling. So there's a large variety of different things that have been looked at for prognostic value in dog mass cell tumours. But the ones that you see here in blue are the ones that have kind of been shown over and over and over again in multiple studies to carry the most prognostic significant.
So grade, clinical stage. So is this a localised tumour or has it spread beyond the local site location? And again, by location, I'm usually talking about tumours that arise from a mucous membrane tend to be more aggressive.
We'll talk about that more in a second. And then proliferation rate, so how quickly these tumours are growing. So again, histologic grade really is the gold standard and remains probably the most important determinant of biologic behaviour.
As I mentioned earlier, the majority of tumours that we see fall into this histologically low or intermediate grade category, which are associated with the low risk of metastasis, maybe only about 5%. But they do have the potential to invade tissue very locally and as a result, appropriately large surgery needs to be performed, in order to prevent local recurrence. High grade tumours, which can constitute somewhere between 1/3 to 20%, have just as much or higher likelihood of causing local problems if they're incompletely resected, but in addition, also have a pretty high likelihood of eventual spread.
So in those cases, these are the ones where surgery or local therapy alone is probably not enough. And we really do think that adding some systemic therapy has the potential to be beneficial. So this is a little summary that actually comes out of the the Withrow and McEwan book chapter that I wrote about mast cell tumours that kind of summarises the postoperative outcome in a bunch of dogs with mast cell tumours based on histologic grade.
And you'll notice a really interesting sort of distinction here between the three studies that are at the top and the 2 studies that are below. So if, if one takes a look at sort of the outcomes. That are observed in these studies.
I think you'd be quite surprised, you'd say, whoa, only 37% of dogs with intermediate grade mast cell tumours are alive at 7 months. That doesn't seem right. Only 45% of dogs make it to 4 years with an intermediate grade mast cell tumour, also, Really just doesn't seem, doesn't seem like what at least I would, would expect with surgery alone.
But then these two studies down here actually have numbers that I think jive more with kind of what I expect and what I see in my clinical practise. So 90% of dogs with an intermediate grade mast cell tumour make it to 12 months. You know, in this case, 70% of dogs with an intermediate grade mast cell tumour make it to 20 months.
So what's the difference between the studies on the top and the studies on the bottom? So one of the things is temporal, so the studies on the top are quite old. The studies in the, on the bottom are more contemporary.
And the big thing that I think has changed between the top studies and the lower studies is surgical dose. So those tumours or those studies that are reported on the bottom of this chart, were really tumours where I think there's a much higher likelihood that an appropriately large surgery was performed. So what you're seeing in those bottom studies probably represents metastatic behaviour.
Whereas in the top studies, often very small, very conservative surgeries were performed, and I think a lot of the recurrences and deaths that were observed in those studies were actually due to insufficient surgical dose and a very high likelihood of local recurrence, which again hammers home the point that, you know, appropriately large surgery is an incredibly important component of management of mass cell tumours. Recently, in the past few years, I think many of us have been aware of an alternate grading schema for mast cell tumours. So most of us who've been in practise for a while, grew up with a 123 grading scheme where one was really good and 3 was really bad.
But a few years ago, a large group of pathologists from all over the world actually collaborated on, a study to look at a two-tier grading schema where instead of again 3 different grades, tumours were divided into high grade or low grade, and the primary reason that this change was made was to try and reduce the amount of inter pathologist variability between reading different mass cell tumours. So with the three-tier system, there's an awful lot of subjectivity and an awful lot of variability that really causes different pathologists to often classify these tumours into different grades. When this simplified two-tier schema was employed, actually, there was much less variability between pathologists.
And as you can see from the Kala-Myer curve on the right here, I'm still an incredibly, important, incredibly prognostic, finding. So this two-tier system is still incredibly good at being able to distinguish between quote unquote good acting mast cell tumours and bad acting mast cell tumours. And just for reference, these are all dogs that were treated only with surgery.
So many times now, you will see this two-tier also sometimes called the Kupel histologic grade reported. This is new enough and hasn't been validated in enough studies yet that I'm 100% comfortable relying only solely on this two-tier schema. So in a perfect world, I actually like to get both grading schemas reported on my pathology report.
So both the old three-tier schema, which is often called the patneck scheme. And the new two-tier schema as well. So when possible, that's what I requested my pathologist.
Location, we talked about a bit before and again, some of the locations that are statistically associated with the higher likelihood of aggressive behaviour are any of the mucous membranes. So the oral cavity, the, the, nail bed. So technically the nail bed is mucous membrane.
The prep use, the perineal region. All of these, irrespective of what the tumour looks like under the microscope, the risk of eventual metastasis is considerably higher, and I'm generally inclined to treat these dogs as if they have, a high grade mast cell tumour, when I see a tumour that's arising from the mucous membrane. The one potential exception to this rule, is the conjunctiva.
So those tumours that arise from the conjunctiva in general tend to actually have a fairly favourable outcome. And one theoretical reason for this may have to do with the fact that these tumours in the conjunctive are generally caught when they're very, very small, compared to many of the other sites. Here's a little Kaplan-Myer curve from a study that we did looking at a combination of surgery and chemotherapy for dogs with mast cell tumours.
And when all other things were thrown aside, you can see that the outcome in dogs, with a tumour that arose from a mucous membrane was substantially worse than those that had a tumour arising from haired skin. So again, the mucous membrane tumours tend to be more aggressive. Some of the other things that we talked about very briefly, clinical stage.
So that poor, bulldog that I showed you previously with the giant ulcerated mast cell tumour on his foot also has an enormous pre-scapular lymph node and certainly, we are concerned that if we see disease that's gone to a node, it has a much higher potential than average of showing up elsewhere as well. Rapid growth, as we mentioned, so, some people think that tumour ulceration may be a surrogate for rapid growth. And again, there's fairly sophisticated ways to evaluate this histologically and with some special immuno histochemical stains.
But ultimately, often what I'll do is simply ask the owner, Hey, how, how long has the tumour been there, Mrs. Smith, and how quickly is it changing? And I'll be much more concerned about the tumour where the owner says, I swear this thing wasn't here two weeks ago and now it's the size of my fist.
Compared to the one where the owner says, well, it's been there around 6 months or so and it hasn't really changed, but time for my yearly exam, I thought maybe you ought to take a look at it. So something as simple as just quizzing the owner can sometimes really help to increase or decrease my index of suspicion for a bad acting mast cell tumour. Some studies have suggested that local recurrence, so tumours that have grown back after incomplete excision, may be more aggressive, and I'm going to be a bit more concerned with how these tumours are as well.
And clinical signs we mentioned before, again, dogs with localised mast cell tumours almost never have clinical signs. So that's either a sign that there's a much higher likelihood of of spread, or the dog's got another problem that should get sorted first. So back to the issue of proliferation.
There's one very simple thing that can now be done that can give you a more scientific assessment of, of tumour proliferation, and that's what's called the mitotic index. And that's actually a very simple test that the pathologist can do. They simply count the number of mitotic figures that they see just on their plain old H&E slide that they're using to report their histopathology, and they report that to you.
It's generally reported as the number of mitotic figures observed in 10. High power fields. And again, I think at this point, if you get a pathology report back that does not include a mitotic index for a mass cell tumour, I would phone up the pathologist and ask them for it.
If they refuse to give it to you, I'd find yourself another pathologist. So as you'd expect, the, the mitotic index increases with increasing grade. So low grade tumours have a very low mitotic index.
Intermediate grade tumours, some of them are a little bit higher, and then high grade tumours. Most of them are a little bit higher. And when you put all of these patients together, and again, these are patients undergoing surgery only, you can see that those tumours with a high mitotic index and generally are cut off for bad behaviour is about 5 mitosis for high power field, have a significantly worse outcome than those dogs, whose tumours have a low mitotic index.
And again, you might look at this graph and say, well, that's intuitive, right? Because high grade tumours have higher mitotic indices. So, is this just a fancier way to do tumour grade?
So the people who did this paper are smart, they actually look specifically at the grade 2 tumours. So these ones where most of them do fine, but there's this subset that are a little funny and a little bit more aggressive. And when they broke out the mitotic index just in the grade 2 tumours, they actually saw a profound difference in outcome.
Between the grade 2 tumours with a high mitotic index and the grade 2 tumours with a low mitotic index. So again, this really helps us to sort of stratify those problematic grade 2 tumours into the ones that 10% or so that have the potential to behave badly versus all the rest. When they did the same act activity with the grade 3 tumours.
So look at the low mitotic grade 3, there was a whopping 3 cases here. Those dogs tended to have a great outcome. Now, again, with an NF 3 in a study that's never been repeated, I am not comfortable saying, ah, it's got a low mitotic index, even though it's a grade 3, so don't worry about it.
So those I still do treat aggressively, but I do sort of treat my high mitotic grade 2s as if they have the potential for very bad behaviour. So it certainly does change how I choose to treat. There are more sophisticated ways to measure proliferation, and one of the places that offers these tests is actually right here at Colorado State University.
I very rarely find the need for these added, sophisticated, expensive. Special tests to, to measure proliferation. Because again, I'm not convinced from the data that's out there that they're necessarily any better than just counting mitotic figures, which is free.
The one situation in which I will use these is as a tiebreaker. If we've got one of these rare cases where the mitotic index is borderline. So, again, I mentioned that the cutoff for bad behaviour that we use is generally 5 mitosis per high power field.
If I've got a tumour where it's kind of in that sort of 3 to 7-ish range, I often will actually do one of these panels, as a tiebreaker to say, well, you know, counting mitosis isn't the most scientific thing. Maybe one of these slightly more sensitive methods could help us sort of refine that. Is it really gonna be one of these good doers or one of these bad doers.
Otherwise, I generally do not find the need to do these tests. So, how are we gonna approach clinically a dog with a mast cell tumour that walks into our clinic. So, obviously, a good physical examination is gonna be, you know, really the, the cornerstone to this.
So is the, how big is the tumour? Is it fixed to underlying tissues? Does it seem like the kind of tumour that we're going to be able to get good margins around without having to do something heroic?
Fortunately, this is the kind of tumour, as most of us know, that's fairly readily diagnosed by simple cytology in, in practise. So about 90% of mass cell tumours can be diagnosed very readily just with the standard in-house cytologic stains, like diffuk that you have available. There are about 10% or so where actually the granules do not stain particularly well with diffquik.
A few of these. The granules will show up much better with the cytologic stains that your referral pathology lab has, the so-called regemsa stains. But there's still probably 5 to 7% that simply do not have granules, and those often will require a biopsy and sometimes even some special stains in order to be able to definitively diagnose.
After I sort of go into a room and aspirate a mass and come back with a diagnosis of mass cell tumour, the very next thing that I will do is go back into the room and try my best to aspirate the regional lymph node, whether it is enlarged or not. There are plenty of dogs that can have mass cell tumours in their regional lymph nodes where that mass that lymph node is not necessarily enlarged. So if I can feel it at all, I will go in and try to aspirate that lymph node as the, at the very next thing that I do during the exact same visit.
Because what I find in that lymph node does have the potential to influence what else I do subsequently. And then again, I may or may not consider doing some additional diagnostics. I don't feel like absolutely complete thorough staging is necessary in every single dog with a mast cell tumour.
It's never wrong, of course. And you know, the likelihood of finding bad things with the additional staging is not zero, but it's generally very low. What I like to try to do is see if I can use the information that I already have to really calm down on the number of dogs I think that really ought to be staged before surgery.
So, here are the criteria that I generally use to try and figure out if I think a dog with a mast health tumour ought to be staged before surgery. So, can I aspirate the lymph node in, and if so, is that lymph node OK? So if the lymph nodes OK, my index of suspicion about bad behaviour is gonna be lower.
There are no other negative prognostic factors. So it's not arising from a mucous membrane. It's not a locally recurrent tumour.
It hasn't grown like a weed. It's not ulcerated, the dog's not sick, and the dog's not a sharppe. .
Then the third one is, again, that an appropriately large surgery is possible and it's not going to require an incredibly aggressive or expensive procedure in order to do. So you're not gonna have to take a leg off or do a major body wall reconstruction or something else like that. So in the case of the top two, the reason that I'd want to take a step back and do some additional staging is cause something about this dog makes me think I'm, there's a higher likelihood than average of finding something.
Again, if there are no negative prognostic factors, I'll generally tell the owner that the likelihood of finding something with additional staging is about 5%. Again, if any of these things are, are there, then that likelihood potentially jumps up. In this case, the reason that I'm contemplating doing some additional staging is not necessarily because the risk of spread is higher, but it's more as an insurance policy.
So if I'm taking off a leg, if I'm taking off a piece of a jaw, if I'm again, doing a major thoracic wall resection. I want this additional information as an insurance policy. You know, there might only be a 5% chance that we're gonna find something, but wouldn't I feel terrible if I didn't take the extra time and effort to make absolutely certain that that this dog didn't fall into that 5%.
So that's kind of my logic for that. So it's money well spent if you have to do something truly heroic. Otherwise, again, I'm, I'm gonna push the staging a little bit harder in those cases where something about the way this dog is presenting has me concerned that there's a higher than average likelihood I'm going to find something.
So what additional things am I gonna do for staging? So again, here in the ivory tower, if we have an old dog that needs surgery, we'll always do sort of baseline blood work. There's generally nothing very pathonomonic that you're going to see on blood work in a dog with a mast cell tumour.
You can see a bit of a peripheral ES. Op hi li a and it's actually of no clinical significance, but it is something that's noteworthy. Generally, we're looking for other things.
Does the dog have a non-regenerative anaemia? Does the dog have biochemical evidence that might be consistent with subclinical GI ulceration, so highUN, low albumin, etc. Are the dog's liver enzymes elevated, which could be an indicator of liver metastasis?
So, you know, all those things, again, are generally mostly a safety check, a pre-anesthetic safety check, but could increase or decrease my index of suspicion that maybe we do have a called metastasis. Again, to be complete, we'll generally recommend chest X-rays. But this is one tumour where actually pulmonary parenchimal involvement is incredibly rare.
I can't say it never happens, but again, I've seen it probably 3 times in my career. I've probably seen 2000 mast cell tumours. So very, very rare.
There are other structures in the thorax, however, that are worthy of, of looking at carefully, and those are primarily the lymph nodes. So if I have a tumour on the cranial half of the dog, sometimes the regional lymph node could actually be inside the thorax, the sternal node, the mediastinal node, etc. So taking chest X-rays for that reason, probably a little bit more important with the tumour on the cranial part of the dog than on the caudal part.
Again, lymph node, we talked about already. Ultrasound is actually a far more useful test for the average mast cell tumour than chest films are. And we usually will pay special attention.
To the liver, the spleen, and the sublumbar lymph nodes, which again could be the regional lymph nodes for some of the tumours on the caudal half of the dog. Tumour biopsy is very much optional. The primary reason why, when I will consider a tumour biopsy is if the results would change how an owner chooses to proceed.
So, for example, if I have to take a leg off, because I have a huge, you know, tumour wrapped around some part of the distal forelimb. And there's really no other way to even do a conservative resection. Some owners might be more inclined to pursue a procedure like that.
If the tumour is, again, low risk, low grade, low mitotic index, than an owner would if that tumour is high grade, where the likelihood of permanent cure is not nearly as high. So if one of those situations is the case, then I certainly won't hesitate to perform a tumour biopsy if the information gained is going to change how we proceed. In the vast majority of cases, I don't find it necessary.
So, tests not to do for mass cell tumours. So there are, is an old test called a buffy coat smear, which used to be very popular for the staging of dogs with mass cell disease. If you look at some of the older papers or some of the older textbooks, you will see it listed.
And this is a test that actually allows the clinical pathologist to concentrate 20 or 30 slides worth of white blood cells onto a single slide. That can then be scanned for abnormalities. And the bottom line is, you can see the occasional mass cell in the buffy coat smear of normal dogs, dogs with inflammatory disease, dogs with a variety of conditions, and it's of no prognostic significance.
So it's an uninterpretable test and not one that's worth doing. This is one that's the subject of a bit more debate, so there are some oncologists that will routinely aspirate normal looking livers and spleens on ultrasound looking for mass cell disease. At our practise, we generally don't do that.
Well, generally only aspirate structural abnormalities in the liver and spleen. But again, now in the age where these ultrasounds are getting so incredibly sensitive, probably 95% of the dogs that we do an ultrasound now and have some little nodule in their liver or spleen that we end up aspirating. So we practically aspirate all of them anyway just by default.
But I generally don't aspirate a normal looking liver or spleen, although again, other folks do, and I can't say that that's 100% wrong. Again, in the older literature, you will see bone marrow aspirs as listed as part of the complete staging for a dog with a mast cell tumour. It was on, when I was coming through my residency in the late 90s, every single dog with a mast cell tumour got a bone marrow aspirt.
And you know, from a training perspective, it was outstanding. I got to be incredibly good at doing bone marrow aspirates. But after we went back and looked at 40 or 500 dogs' worth of bone marrow aspirates, and we never found anything, we said we really ought to stop doing this and and really, do not do these bone marrow aspirates anymore unless we see something very odd and very unexpected on our on our hemogram.
So, you know, multilineage, cytopenia, etc. Otherwise, it's just not helpful. So here's the money shot about treatment of mast cell tumours.
So for the vast majority of mass cell tumours, surgical excision is the treatment of choice, assuming it's solitary. That may not be the end of the end of all treatment, but it's the place to start. Radiation therapy is an incredibly efficacious postoperative therapy for incompletely resected lower intermediate grade mass cell tumours.
And chemotherapy is something that we generally think about employing for those tumours that we think are at high risk of spread postoperatively, or in those tumours where radiation therapy or surgery is not possible. Then again, ancillary therapy. So we will use antihistamines for those tumours where an incisional biopsy is going to be performed for those tumours that are being treated in situ.
So if we have an unresectable tumour that we're doing chemotherapy on radi radiation on, we'll certainly use it to prevent some of the effects associated with degranulation. Perioperative H1 and H2 blockers are fine, but these drugs have no anti-tumor effect whatsoever. So if we have a dog with a solitary mass cell tumour, there's no rationale for postoperative use of these drugs.
These are purely for the management of clinical signs. So again, surgical excision is the, the treatment of choice for the majority of mass cell tumours. And we do know that aggressive surgery is generally necessary.
So the party line has been for a long time that 3 centimetre margins in all directions in one fascial plane deep should be obtained whenever possible. And I still stand by that recommendation. But recently, an alternative approach was, was published, and this is what's now come to be called the proportional margins approach, and it's actually very simple to explain.
So basically, you take a margin that's equivalent to the maximal diameter of the tumour. So if you have a 1 centimetre mast cell tumour, you go for 1 centimetre margins. If you have a 2 centimetre mast cell tumour, you go for 2 centimetre margins.
Anything 3 centimetres or larger, you stop at 3 centimetre margins. So in this one retrospective study that looked at this approach, about 85% of mast cell tumours were completely excised. Using this proportional margins approach, and none of the tumours grew back.
But one of the huge caveats about this particular retrospective study is that the vast majority of the tumours that were studied were lower intermediate grade tumours, and you're much more likely to be able to get away with skimpy margins in the lower intermediate grade tumour than you are with a high grade tumour. And unfortunately, we don't have this information until after the fact. So for this reason, again, my recommendation stays, if you can get 3 centimetres, get 3 centimetres.
But what I do say is, if you can't get 3 centimetres, it doesn't mean you shouldn't do surgery. It just generally means from my perspective that I'm gonna forewarn the owner, the likelihood of incomplete excision might be a little bit higher, but there's a fair number of these tumours where you certainly can get away with smaller margins. Again, when the tumours are smaller, if you have to.
So again, 3 is great if you can get it. If you can't get 3, take 2. If you can't get 2, take 1, but just forewarn the owners about the potential risk.
So we do know that incomplete resected mast cell tumours have a significantly higher risk of local recurrence. So in this particular study, again, dogs with incompletely resected mast cell tumours, about 70% of those tumours eventually grew back with an average time to recurrence of about 10 months or so. Completely excised tumours, the likelihood of death from mast cell tumour is only about 10%, so big difference there.
One of the most common questions I'm asked is, so what is the outcome with a completely excised low risk canine mast cell tumour? Should I be doing additional therapy, etc. So what I teach the students now is what's called the 55-10 rule.
So about 5% of these are going to grow back even though they look like they've been completely excised. About 5% will spread, usually to the regional lymph node first, and about 10% of dogs have the potential to develop another, presumably unrelated cutaneous mass cell tumour sometime in their life. One of the other sort of controversial issues that has come up recently is the use of neoadjuvant prednisone before surgery.
So in other words, giving some systemic prednisone to try and shrink up a mast cell tumour before doing surgery in order to potentially reduce the size of the margins that are necessary. And this approach has also been looked at in one recent publication. And I have a big problem with this approach too for all but the biggest and most aggressive mass cell tumours, and I hope I can explain it based on this diagram.
So we know that the part of the tumour that we can see and feel is merely the tip of the iceberg, and these kinds of tumours are notorious for being able to extend little fingers into the surrounding tissue. If you give, so let's suppose we're planning to do a surgery that incorporates these margins of at least 1.5 centimetres.
If we give a bunch of prednisone, we may shrink the primary tumour some. We may reduce the number of tumour cells in these these fingers as well, but the length of the fingers does not change. So as a result, if we're planning our new surgical margins based on the size of the new mass, there's a very high likelihood that we could actually be skimping on those margins.
And again, in this particular paper, 17.5% of completely excised mass cell tumours experienced local recurrence. Compared with 5% where you use no prednisones.
But for this reason, again, unless we need the prednisone in order to even be able to do small surgery, we do not recommend the routine use of neoadjuvant prednisone before surgery. So, as far as the need for postoperative therapy, it's pretty easy actually to summarise what we do for what tumours based on this very simple chart, which will knock off 95% of the tumours that you see. So if I have a completely excised low-risk mast cell tumour, no additional therapy is necessary.
I'll usually do quarterly rechecks on those dogs. If I have an incompletely excised low or intermediate grade mass cell tumour, my fear is that we're gonna see local recurrence. And in those patients recut or radiation therapy can be very effective.
For high grade mass cell tumours, or again, high-risk mass cell tumours as defined otherwise, that are completely excised, the risk of local recurrence is quite low, but the risk of spread is very high. And these are the dogs that can benefit from chemotherapy. Then we have the incompletely excised high-risk mast cell tumour, the worst of both worlds, unfortunately.
And these are the dogs where additional local therapy and additional chemotherapy has the potential to be the most beneficial. If I have to pick one or the other, but I can't pick both, I will generally pick the medical therapy. Why do I do that?
Cause I'm a medical oncologist. That's what I do for a living. Seriously, that's not the case.
My logic is that if I'm doing medical therapy, I'm doing something to address both problems. So these drugs have the potential to work all over the body, and they may be killing some tumour cells that are left over at the local site as well as any little microscopic tumour cells that might be present elsewhere. Whereas if I do more local therapy, I can be doing a great job at preventing local recurrence, but I won't be doing anything to address the potential for spread.
This is an example of a recut that takes place after an incomplete excision. And again, in a perfect world, we'll go for 3 centimetre margins around the prior surgical scar, and another fascial plane deep, but we're starting to learn that even smaller surgeries can be very beneficial if that tissue is resected, submitted for histopathology, and those margins are clean. So take what you can get again.
RT, as I mentioned, incredibly useful treatment for postoperative, incompletely excised mast cell tumours. We can expect 90% local control rates for 2 years or longer after radiation therapy is done. It doesn't work nearly as well for for gross unresectable mass cell disease but sort of can certainly be part of the plan.
So chemotherapy. Again, the indications for chemotherapy are postoperative therapy for those high-risk tumours, the ones where our risk of metastasis is very high, or those tumours where surgery or radiation therapy are either declined or not feasible. A large number of different agents and protocols have been looked at over the years to try and shrink big mass cell tumours.
If you look at all these studies and put them together, what I will generally tell owners and other veterinarians is that the likelihood of seeing meaningful tumour shrinkage is probably a little bit less than 50/50, probably in the neighbourhood of about 40%. And the average amount of time that this shrinkage will persist is in the neighbourhood of 2 to 5 months. So, some longer, some not that long.
So it's certainly better than no treatment, but it really hammers home the point that if you can do surgery first and then follow up with chemotherapy, the potential outcome is much better. The treatment that we generally start with is a combination of prednisone and viblastin. Prednisone is incredibly well tolerated and cheap as everyone knows.
Venlastine is also incredibly cheap, and very, very well tolerated. And again, there are a couple of papers that sort of describe the protocol that's used for treating these that you can see here. Very few side effects are observed.
Asymptomatic neutropenia is the most common one that we see, and less than 5% of dogs will require hospitalisation or a significant dosage adjustment. It's just very well tolerated. In the gross disease setting, a little bit less than half of dogs will experience significant tumour shrinkage and again, and the average duration of that shrinkage is about 5 months.
This again hammers home the point that when we're able to at least get down to microscopic disease, so these are dogs with microscopic disease in the red here, their outcome is substantially better than those dogs where we're trying to treat a big unresectable tumour. So even if all we can do is marginal excision and then follow up with chemotherapy, that outcome is far better than if we're trying to use chemotherapy alone. So just sort of look here at the grade 3 dogs.
So these are grade 3 dogs that are treated with a combination of surgery and prednisone and blasting chemotherapy. Their median survival time is about 3 years, and again, that compares very favourably to the reported median survival time of about 8 months with a combination or with just surgery. So now we have 3 different studies that have been reported that really strongly suggest that postoperative chemotherapy does significantly improve the outcome in those dogs with high-risk mast cell tumours.
I'm gonna skip this in the interest of time, but just say treat it as aggressively as possible, as early as possible because locally recurrent tumours do have the potential for worse behaviour. Some dogs may be able to tolerate doses of blastin higher than 2 milligrammes per metre squared. So we generally start at 2.5 milligrammes per metre squared in our patients and still quite, quite a, the majority of dogs don't require any dosage adjustments and don't get sick.
There's no difference in outcome between a dog that has a single mass cell tumour and up to 6 cutaneous mass cell tumours. We do see this happen in a few of our patients, and the same things are prognostic, grade margins and mitotic index. So appropriately large surgery can be an incredibly effective treatment for these dogs with multiple cutaneous mast cell tumours.
And one of the things that I do forewarn owners about, however, is that almost half of these dogs will continue to get more mass cell tumours in the future. So it is important to be very vigorous and rechecking these dogs, have the owners point out any new lumps or bumps as soon as they're observed. So again, surgery can be performed when the tumours are nice and small.
We don't know whether this represents some odd form of spread or whether there are some dogs that just seem to be genetically programmed to make mast cell tumours. Either way, it really does appear that the long-term outcome of these dogs can be very good. So, just in the last few minutes, I want to talk about kind of the newest thing that's really come to the forefront in mast cell tumour therapy, and that's targeted therapy directed against a protein on the surface of canine mast cell tumours called CIT.
And CIT is the receptor for a growth factor that's called a stem cell factor. Which is expressed on both normal and malignant mass cell tumours. And we do see more kid expression in high grade mast cell tumours.
But the interesting thing beyond that is about a third of all canine mast cell tumours actually have a mutation in the gene that codes for this kit protein that makes it on all the time. So, in a normal kit protein, it usually just sits on the surface of the cell and does nothing until a little bit of growth factor floats by and then that sends some signals into the cells to it, telling it to do things. But again, about a third, slightly less of canine mast cell tumours actually have this mutation in the gene that makes it on always.
And it's always telling the cell to divide, selling, telling the cell to grow, telling the cell to survive under conditions when it might normally die. All these things obviously have the potential to contribute to more aggressive behaviour, and that is in fact the case. So, mast cell tumours with a kid mutation are much more likely to be high grade and to result in the death of the patient.
So this is a Kaplan-Myer curve that actually demonstrates the outcome compared, so these are dogs with wild type kit, these are dogs with mutant kit, profound difference in their post-surgical outcome. I'm gonna skip this in the interest of time. So what you saw there was post-surgical outcome.
We've actually looked at the same, criteria looking at a combination of surgery and conventional chemotherapy. And again, dogs with kid mutations have a significantly worse outcome than dogs whose tumours do not have kid mutations. So, the good news is that there are actually drugs available, 2 of them that are specifically for the veterinary market that actually work by inhibiting signalling through thisIt protein.
And the two that most of us are most familiar with are Toerinib, which is also called palladia and meitinib, which, in the EU is called Massive vet. Over here in the states, it's not available anymore, but it was called Kyavet. Iatinib is a human drug that actually is approved for some other kinds of cancer, but also targets and has been used a little bit primarily in Japan.
So, this little graph just shows that if you dump, in this case toceraib into a petri dish, with canine mast cell tumour cells, you can make them not grow. And gee, that's very exciting, but I can do the same thing with table salt or a molten lava in a petri dish and kill cancer cells just great. So this particular drug has been investigated in dogs with mass cell disease.
And again, the initial studies that were done, about 50% of dogs with mast cell tumours experienced meaningful tumour shrinkage. And the average duration of that shrinkage again was in the 4 month range or so. But the interesting thing is that the likelihood of seeing tumour shrinkage was twice as high in dogs whose tumours had a kit mutation than in those tumours that were wild types.
So here's a drug that appears that it might work better against the worst mass cell tumours. I'm gonna again skip this in the interest of time. There was a randomised placebo controlled trial that was performed, basically running to sarinib against placebo, and actually, the response rates were obviously much higher, about 40% in the taserinib arm versus only about 8% in the placebo arm.
And again, the average dog was on study for about 18 weeks. These are not necessarily benign drugs even though there are, there are pills. So both, so these are oral therapies that can be given at home by the owners, but actually, we do see a fair bit of side effects from them.
And the most common side effect that we see is gastrointestinal disturbance. Diarrhoea and loss of appetite are most common, but we can sometimes see vomiting as well. You can see a laundry list of other signs that we can sometimes see neutropenia, protein losing, nephropathy, or others that we watch for fairly carefully.
So, we do need owners who are really pretty willing to be vigilant, who are watching their dogs very carefully, who are willing to bring them in for multiple, recheck examinations in order to make sure that these drugs are being tolerated. If these adverse events that can sometimes occur are caught early, they can usually be dealt with quite simply, but if they're allowed to progress, they can become extremely serious. And one of the good take-home messages that the company is actually not allowed to tell you.
Is that the label dose for palladia is higher than the dose that most of us oncologists feel comfortable using. So the label dose is 3.25 milligrammes per kilo every other day.
Most of us will not use a dose that's this high. Most of us will use a dose of between 2.4 and 2.75 milligrammes per kilo, either every other day or 3 days per week.
And in our hands, it appears that this dose is better tolerated and just as efficacious. So a nice little tidbit of information, then again, unfortunately, Zoetas is not able to share with you for legal reasons. So how do we monitor these dogs?
So again, this is a typical monitoring schema for how to monitor a dog that's receiving palladia, and I would do the same thing for Massive vet as well. So, baseline, good physical examination, weight, CBC chemistry, urinalysis, blood pressure, and urine protein creatinine ratio. Then I'll generally see them every 2 weeks until we get to the 6-week mark just for a physical exam and a CBC.
At that 6-week mark, and then every 6 weeks thereafter, if things are going well, I repeat this whole battery of tests. Certainly, in between these visits, if the owners are noticing GI signs or other problems, I'll unequivocally tell them to report those to us and bring the dogs in if possible. So again, fairly careful monitoring is necessary and you really need the right owners in order to use these drugs safely.
So unanswered questions about palladia and other drugs like this. So one is, we know that they work very differently from chemotherapy and radiation. Can they be used together?
The answer is yeah. So there's actually a number of studies that have been reported looking at a combination of palladia with either conventional chemotherapy, with NSAIDs. With metronomic chemotherapy, and the answer is, yeah, in most cases, it appears that they can be given together pretty safely.
With other cytotoxics, however, like viblastin and Lomustine, you do need to do a fairly substantial dose reduction of the cytotoxic agent, and that needs to be kept in mind pretty carefully. And the dose limiting toxicity with these combinations is generally severe neutropenia. So again, if that's something that you're considering, take a look at these papers very carefully so that you can get appropriate dosing information.
How about radiation therapy? This combination actually works incredibly well. So with palliative or once weekly, very conservative, all outpatient radiation therapy, we see a response rate of about 75%, to a combination of palladia and radiation, and the average duration of those responses is about 10.5 months.
So this has become our standard of care. For the treatment of locally advanced unresectable canine mass cell tumours. It's incredibly effective and there is actually no enhanced toxicity from the radiation when this combination is used.
This is just one particular dog that had a huge, obviously unresectable mass cell tumour, in the periocular region that had actually a complete response to the combination of palladia and palliative radiation therapy. I think you certainly could see a very similar result if you combined massive with with palliative radiation therapy. All that although that study hasn't been done systematically.
What about postoperative use? This is really the, the kind of the last little point here and this remains an issue of, of significant controversy. So there are no studies that have yet been performed that demonstrate that post-operative kinase inhibitors.
Improve the outcome after surgery, either in high-risk cases where the risk of metastasis is very good or in cases of incomplete excision. I think there's a lot of reasons to think that it could be useful, but we simply don't have that data. Also, we don't know how long to give it for.
So in my practise, again, we stick with the conventional cytotoxics, the drugs like prednisone and then blastin. Because we only use them for a total of 8 injections, and there are several studies that prove that the outcome is improved in those dogs who get those medications. I generally tend to save drugs like paladia and massive vet for use in the relapse setting to keep more tools in my toolbox for relapse rather than using them in the postoperative setting.
Can't say that it's wrong to use them postoperatively, but all I can say is we don't know if they work or how well they work or how long to use them for as things stand today. And I'm very eager to see some data potentially generated in the future that helps to answer to this particular question a bit more thoroughly. And with that, I'm actually more than happy to answer any questions that anyone might have.
Thank you very much, Doug. That was a thoroughly informative presentation. I thought it was absolutely brilliant, and I really enjoyed it.
Just while people are thinking about questions and typing out questions, I'm going to launch that feedback poll that I spoke about in the introduction. So I've just launched that now. But actually, Doug, we've got a couple of questions already.
The first question is from Greg, and Greg says, if you are aspirating the spleen or liver, do you run a COA screen first? Great question. So, the answer is generally no.
So it's absolutely true that one of the other compounds that can be hidden in mast cell tumour granules is heparin. And obviously, we do know that heparin has the potential to increase the risk of bleeding. This is usually manifested just by a little bit of extra local oozing, sort of in the intraoperative period that could sort of catch you unawares and cause problems, but it's rarely life-threatening.
And again, the likelihood of any type of systemic coagulopathy in a dog with a mast cell tumour, even a dog with fairly diffuse mast cell disease is vanishingly small. So the risk of aspiration, you know, even of a mass cell tumour, you know, even if the spleen that's loaded with mass cell tumour remains actually quite low, and I don't feel like it's necessary to do coagulation analysis before aspiration. Great question.
Thank you very much. Another question here from Gordon. Would your clean or dirty margins in a grade 3 influence your choice of chemo needed, especially if a client would not consider radiotherapy?
Yeah, so, good, great question again. So with clean margins in a grade 3 tumour, I think the likelihood of local recurrence is quite low and I generally wouldn't be pushing radiation therapy or a second surgery. Those are the tumours where I'd feel comfortable pursuing just chemotherapy by itself.
In those cases where again, we have dirty margins, with a grade 3 tumour, I think there's equal likelihood that we're gonna run into problems related to local recurrence or metastasis. And again, if I have an owner who, who's willing to take no prisoners and do absolutely everything there is to be done, I certainly would not hesitate to recommend a combination, you know, of more local therapy, so another surgery or radiation. And chemotherapy.
But again, that's the situation where if I have to pick one or the other, I'll certainly lean more forcefully towards the systemic therapy if I have to pick. And I hope that clarifies things. Thank you very much again.
We've had a 3rd question from Katie. Do you test for the mutated C kit on all histologies? Ah, another great question.
So, as, as things stand right now, the way I treat postoperatively, most mass cell tumours is not influenced by, the presence or absence of a kit mutation. So again, until I have information to the contrary. Again, my recommendation, for all high-risk mast cell tumours is a combination of surgery and conventional chemotherapy.
It's unequivocally true that testing for the CIT mutation can give an owner additional information potentially about what to expect. So we do know that statistically, the outcome is far worse than those dogs whose tumours do express a CI mutation. So if the owner wants that additional information for prognostic value, it's unequivocally useful information to have.
But again, as things stand today, it generally does not influence the way I choose to treat those patients. So, I, it's, it's something that I feel comfortable offering. If the owner wants to do it, that's great.
I certainly don't feel that it's mandatory. A situation in which I will consider doing it though is in that situation where I am faced with treating a large mass cell tumour in situ. So, we have a big unresectable tumour or a tumour where we already have spread.
So we're really faced with using medical therapy by itself. And in that situation, we're really faced with two distinct options. So we could consider a kinase inhibitor like palladia or massive, or we can consider a cytotoxic drug like enlastine or Lomustine.
And we do know that the likelihood of seeing improvement is higher with palladia or Massy that in those dogs that have a kid mutation. So, if I have the opportunity, I might consider testing a patient like that for the presence or absence of the mutation. And if in fact the mutation is present, I might be more inclined to lean towards trying a chinase inhibitor first, versus again, if a dog is wild type and all other things are the same, I'm much more likely to reach for a conventional cytotoxic drug first.
Similarly, if I don't know the mutation status, I'll also generally think about reaching for a cytotoxic first, primarily because in my hands, these cytotoxic drugs are considerably better tolerated than the kinase inhibitors are. So we're much less likely to run into side effects from chemotherapy than we are from these little pills that are being that are being marketed these days. Not to say they're not useful.
But statistically, just as likely to help and better tolerate it. Thank you. I think that's a really interesting development.
So, yeah, interesting to see how that goes. A question from Catherine. Do you pre-medicate with a H1 antagonist for FNA or surgery?
And if so, which drugs specifically and what time frames? Yeah, another outstanding question. So, you know, often when we're doing a fine needle aspirate of a, of a mass, we don't know if it's a mass cell tumour or not, and I certainly don't think it's practical to premedicate all dogs, before any mass is ever aspirated.
So we do not routinely pre-medicate before a fine needle aspirate, and the likelihood of seeing a serious degranulation reaction is vanishingly small. Again, in my career, I think I've seen, you know, less than a dozen, you know, very serious. Degranulation reactions following a fine needle aspirate, which puts it at the, you know, at less than 0.5% kind of range.
So very, very small. So no, I don't routinely premedicate them. I don't routinely go back and actually post-medicate them after I look at my slide and say, oh, it's a mast cell tumour.
The issue of pre-medicating before surgery is actually a, a different one. And you know, technically, if your surgery is being done correctly, you shouldn't touch the tumour because you're doing nice wide margins around the tumour. And as a result, the risk of serious degranulation intraoperatively should be very low.
However, These drugs are very cheap. They're very well tolerated. And if it makes the surgeon and or the anaesthetist feel better to have these drugs on board, there's absolutely no contraindication to having them on board.
As far as choice of H1 and H2 blockers, that's totally at the discretion of the of the doctors. So statistically, there's no difference whether you use Diphenhydramine or chlorophenamine or something else for your H1 blocker. There's no difference if you use, you know, cytidine versus ranitidine versus some other H2 blocker.
Really, the outcome should be exactly the same, just a matter of what's on your shelf and what you feel comfortable with. But yeah, again, here at our institution, there are many of our surgeons who don't routinely premedicate these dogs before surgery, but again, there's absolutely no harm in doing so if it sort of increases your comfort level. That's great.
Thank you very much, Doug. And in the interest of time, I think this will be the last question. And Pat asks if a client refuses surgery, will Preds and vivasin give very much better results than Preds on their own?
Yeah, so great question there also. So, there are no head to head studies comparing Pre alone to a combination of Pred and blastine, but we do have several retrospective studies that have looked at both questions. And what the, the apparent outcome with prednisone alone is in the neighbourhood about a 20% likelihood of seeing meaningful improvement in tumour size, which will generally persist for something like a month or two.
If you contrast that with a combination of prednisone and blasting, you're looking at about a 45% response rate and the average response duration is in the neighbourhood of about 5 months. So you're about twice as likely to see meaningful tumour shrinkage, and that meaningful tumour shrinkage is likely to last 2 to 3 times longer if finblastin is added to prednisone alone. So don't get me wrong, prednisone by itself it certainly has the potential to be better than no treatment, but it's unfortunately, it's, it's efficacy is generally pretty transient, and we certainly would prepare the owner for a relatively short period of improvement.
That's great. Thank you, Doug. Have you got time to squeeze in just one more?
Absolutely. Yeah, great. If you are getting incomplete excision after biopsy, is feeding a problem?
Hmm. So, not entirely sure what the, you know, what the questionnaire is asking. So, we do know that incomplete excision is associated with about a 70% likelihood of eventual tumour recurrence across all the different grades.
And the average amount of time it takes until recurrence occurs is about 10 months. Again, statistically recurrent tumours have the potential for worse behaviour. So we do try to be as aggressive as possible with those tumours right away, right when we know that the tumour has been completely resected rather than sort of adopting one of these sort of wait and see philosophies.
If the question has to do with does incomplete resection, change the likelihood of eventual spread and seeding to distant organs, the answer to that appears to be no. So incompletely resected, you know, lower intermediate grade. Tumours, for example, still have a very, very low risk of spread, even though their risk of recurrence is quite high.
What we do know again as I brought up earlier, is if those tumours are allowed to grow back, those tumours that have grown back do have the potential to be higher grade, to have a higher mitotic index. And then have the potential for a higher risk of eventual dissemination, which is why we really try and caution owners against taking that wait and see approach versus again doing as much as possible as early as possible. And I hope that answers the question.
That's great. Thank you very much, Doug. We've had thank yous and positive comments.
So on behalf of our members, I'd like to thank Doug for being a fantastic speaker this evening and for Wendy and her technical support.