OK, welcome everyone. So, the, the lecture that we're going to do this hour is about, as you can see from the slide, some of the less common hematopoietic cancers, specifically plasma cell tumours and histiocytic tumours. And I think many of us will go to continuing education conferences and hear people speak about what's new with lymphoma and how do I treat dogs with mast cell tumours.
But I think it's, it's less frequent that we'll actually get information about some of these tumour types that are seen, but, maybe a little bit less frequently encountered. So I thought that spending an hour on this particular topic might be very worthwhile. Obviously, this is a, an on-demand lecture, not one that's being done live, so we don't have the opportunity to interact, and I don't have the opportunity to answer any questions at the end of this lecture in real time.
However, you can see that I've provided my email address. On the bottom of the slide here. And I would certainly encourage all of you to reach out and use that email address.
If you do have any questions about the content of this lecture, I am more than happy to answer any questions that anyone has by email at any time. So again, thanks very much for your, for your attention. And again, please don't hesitate to reach out if you'd like for additional information.
So, we're gonna start by talking about hisytic tumours. And one of the things that's actually quite tricky and complicated about this particular constellation of diseases is the fact that there are multiple, multiple, multiple different diseases that appear to be caused by different sort of subsets of these monocyte macrophage, type. Of white blood cells.
And these different diseases have different presentations and different treatments and different outcomes. And it's really only been in the last few years that there have been tools that at our disposal to actually allow us to more carefully and extensively characterise which of these different diseases are, are responsible for, for certain, kinds of, of situations. So, One of the things that I'll say is that unfortunately, not all of these antibodies, not all of these additional special stains will work on routine formalin fixed tissues.
Some of them require frozen tissues and things like that, but it is becoming a bit easier to characterise these tumour types even with formalin tissues. Unfortunately, it does generally require some additional special stains which will be offered at an additional cost. But they can be very useful in trying to get things sorted out here.
And again, another thing that can be quite confusing about this group of tumours is the fact that the nomenclature is actually quite confusing as well. And there are a number of different disease processes, as I mentioned, that can really sort of all fall into this category of technically being histiocytic diseases. And again, here are some of the ones.
They are the benign histiocytomas, which I think we're all familiar with. Transmissible venereal tumour, not a disease that's seen in the UK very often, but it certainly is seen at some of the lower latitudes. We're not gonna talk, a lot about that today.
Then there are these, sort of, Reactive or hyperplastic histiocytic conditions that can occur like Langerhans cell histiocytosis and either systemic or cutaneous histiocytosis. And then we have these true neoplastic diseases like fibrohistocytic nodules and and what used to be called malignant histiocytosis and is now called histiocytic sarcoma. So for this section, these are really the two disease processes that we're gonna focus on, because again, this is an oncology lecture and we're here to sort of talk about malignant disease.
Oh, let's very, very briefly, talk about splenic fibrohsteocytic nodule. So this is actually one of the less common, splenic tumours that we can encounter in practise. And again, some dogs with other types of splenic disease, these dogs may present for the typical signs of, you know, being a little off, not eating particularly well, being lethargic, etc.
We can often palpate an enlarged spleen on these animals. And again, this is a disease process where they, it can be associated with hemoabdomen as well. So not every dog with hemoabdomen and a splenic mass is going to have hemangiosarcoma.
There certainly are other tumour types that can occur in the spleen that can result in rupture and haemorrhage, and this is one of them. . On ultrasound examination, which is gonna be our most sensitive test generally, we can see multifocal hypoechoic nodules with very well-defined borders.
So again, we tend to not see quite as commonly that cavitated, sort of heteroechoic kind of appearance that we can see sometimes with the vascular tumours. Like hemangioma and hemangiosarcoma. At the time this ultrasound is performed, we really do want to make sure that the rest of the abdomen is evaluated very carefully because these histiocytic tumours do have a penchant for evaluating other abdominal organs like the liver and the visceral lymph nodes.
And again, similarly, we Also want to take thoracic radiographs. And again, for these histiocytic type tumours, in addition to the possibility of seeing pulmonary parental involvement, we also want to take a careful look at the lymph nodes that live in the thorax because again, lymphadenopathy is a, is a really key component of these histcytic diseases. So splenectomy is the treatment of choice for these dogs who have a disease that's localised to the spleen.
And there actually is a grading scheme for these splenic fibrohistocytic nodules. And essentially what the grade grading scheme primarily looks at is what's called the lymphoid to fibrohistocytic ratio. So, you know, for every, for every fibrohistocytic cell, which is effectively the tumour cells, how many lymphocytes are there, that kind of thing.
And again, the more lymphocyte rich the tumour is, actually, the better the outcome is. So again, if you've got a very, very lymphocyte rich tumour, that would be called grade 1. If you've got a lymphocyte-poor tumour where less than 40% of the cells are lymphoid, then you're gonna have a grade 3 tumour.
And again, why do we bother doing this grading scheme because it actually has quite a bit. Of, statistical value in predicting outcome. So dogs with grade 1 or 2 fibrohistytic nodules, most of those dogs are gonna do fine with surgery alone.
These grade 3 fibrohsteocytic nodules. There's a much higher likelihood of death, as a result of tumour, than, we see with the grade 1 and 2 tumours. And so for these dogs that have high grade splenic fibrohistocytic nodules, we do think that following, following up these dogs with chemotherapy, which we'll talk about a little later, is probably something that's worth considering.
So, moving on to the more common form of the diseases that we see. So this histiocytic sarcoma slash malignant histiocytosis, constellation of tumours that we see. One of the interesting things about this group of tumours is there's a very profound breed predilection for this kind of tumour.
And again, as most of you probably are aware, the two breeds that we really see far at the top of the list here are the Bernese Mountain dog. And the flat-coated retriever. So the incidence of, of histocytic tumours is quite, quite high in these breeds, but we can also see them at increased frequency in Rottweilers and golden retrievers.
There is some evidence that, the miniature schnauzer may be predisposed as well. And unquestionably, we can see, see sporadic cases of, these, these kinds of histiocytic sarcomas in any breed of dog. So you can't completely rule out the possibility of a histiocytic tumour, just because the dog doesn't fall into one of these four breeds.
So coning down into the Bernese mountain dog, a little bit. Again, it appears that from some surveys that have been done that 25% of all the tumours that occur in Bernese mountain dogs are actually histiocytic tumours. And again, based on this early data, it appears that almost 25% of all Bernese mountain dogs will get one of these tumours if they have a parent with one of them.
So there does appear to be a fairly profound heritable component to this disease in this breed. Again, the literature that we have suggested about 60% of Berne's mountain dogs will die from some kind of neoplasia. So, the incidence of neoplasia is extremely high, and within the neoplasms, the incidence of hisytic disease is also extremely high.
So, here's a little pedigree that comes out of a paper that was done about 10 years ago that really does suggest that there is a heritable component to this disease. And at the time, they were able to sort of say that this appears to, there appears to have an oligogenic mode of transmission. So it's not a single gene.
That appears to be responsible for the risk for this disease, but it's also probably not 50 genes. So a relatively small number of genes are suspected to be implicated. And again, in one study, they were actually able to cone down on on one particular locus or one particular gene that appeared to confer some of the susceptibility to to this disease in Bernie's mountain dogs, and that's a gene called CDKN2A.
So this is what's called a cyclin dependent kinase. And this group of genes actually regulates cell division. So if you're going to sort of pick a gene that you could sort of envision having a role in cancer, boy, a gene that helps to regulate cell division makes a lot of sense.
So intuitively, this made a lot of sense. And I believe that there may be a group in France offering a commercial test for this gene and as well as a couple of other genes specifically to predict histocytic sarcoma risk in Bernese Mountain dogs. So, what's different between the Bernese Mountain dog and the flat-coated retriever as far as the incidence, the development, the the characteristics of their histiocytic sarcomas.
So one of the things that's interesting is that it does appear that the Bernie's mountain dogs tend to have an an an average incidence that's about 2 years younger than the average flat-coated retriever. So a median of 7 to 8 years versus a median of 9 to 10 years, or actually, these are modes, so a modal time of 9 to 10 years for the flat-coated retriever. And also, if you look Get the anatomic distribution, it's actually quite different as well.
So a full half of the Bernese mountain dogs are gonna present with a disseminated form of the disease, so multifocal tumours in multiple places of the body. Whereas only about 25% of the dogs, in, in the flat-coated retriever group are actually gonna have this disseminated histocytic sarcoma form. And if you flip that around, another interesting thing is about 40% of flat-coated retrievers are actually going to have histocytic sarcoma on the limb.
And this is primarily what's called the peri-articular histeocytic sarcoma variety, the version that actually occurs around the joint. Whereas only about 3% of of Bernie's mountain dogs will present with a peri-articular form. So, this is actually a plot looking at areas of loss or gain of chromosome numbers in tumour tissue between the breeds.
And you can see there's actually at the level of cytogenetics. So at the at the level of chromosomal gain and loss, there's actually a lot of similarity between the flat-coated retrievers, and, the Bernice's mountain dog. So we can see a loss of, of, some DNA here on chromosome 2.
We can see a conserved loss on chromosome 11, which happens to be where the CDKN2A gene is. We can see a loss here in both, in both breeds in chromosome 22 and another one in 31. That again, do tend to correlate with each other.
And then there's this one, which is actually very, very profound that in this particular study was not characterised. So we don't know what that guy is. But again, the take home message is cytogenetically, it actually appears that there's a lot of similarities between the disease that the Bernie's Mountain dogs get and the disease that the flat coats get, despite the fact that their sort of clinical presentations are actually quite different.
One of the interesting things that was looked at, in a, in a group of dogs from the Netherlands primarily, although I, I think they were, they actually solicited cases from other places in Europe as well, was whether there was an association between the development of these perarticular hisocytic sarcomas in Bernese mountain dogs and joint disease. And there actually did seem to be a pretty profound association in that about 6% Of Bernie's mountain dogs with joint disease, developed a peri-articular histiocytic sarcoma versus only about 1% of Berne's mountain dogs without joint disease. So again, it, it lends credence to the concept that maybe chronic inflammation and things like that that can be associated with diseases like osteoarthritis, or cruciate rupture or things like that could be a predisposing factor for this disease, at least in the Bernese Mountain dog.
Again, clinical presentation, we certainly can see solitary versions of this disease occur and often again, those are, are gonna be termed now solitary histocytic sarcomas or focal histocytic sarcomas. And we can see these occur in the subcutaneous space. We can see them occur in the spleen.
Again, some of those are gonna be also referred to as your high grade fibrohteocytic nodule, like we talked about previously. We can see primary lung histocytic sarcoma and as I mentioned previously, you can certainly see primary periarticular histocytic sarcoma as well. And then we also have a systemic version of this disease.
And again, in the older literature, you'll see this referred to as malignant histiocytosis. More, more often these days, we'll use terms like systemic histocytic sarcoma. Or multifocal histiocytic sarcoma.
And again, in dogs with this kind of clinical presentation, we can see multifocal lung involvement, we can see liver involvement and spleen involvement, involvement of lymph nodes anywhere in the body. We can see plus or minus skin involvement, subcutaneous involvement, even bone marrow involvement from this disease. So, again, this is the disease again, and, and this really sort of hammers home the fact that very thorough staging is a really critical component of, of workup of these dogs to determine is this truly solitary, in which case we know that surgery has the potential to be a very important component of our therapy, or is there disease beyond that local site, in which case, really surgery has the potential to be of much less benefit.
Oh, how's a dog with a histocytic sarcoma likely to show up? Well, it will often depend on the site of disease, obviously. So for primary pulmonary lesions or dogs who have a lot of pulmonary involvement, we certainly can see things like cough, exercise intolerance, dyspnea, tachypnea, for dogs with peri-articular involvement, we can see lameness.
We can sometimes see a subcutaneous mass, etc. Occasionally, hypercalcemia can be reported from this disease. So polyurea lydipsia secondary to that would be another possibility as well.
I think a more common presentation, especially for dogs with the disseminated form of the disease, is again, these sort of vague non-specific clinical signs like lethargy, hyperexia, fever, weakness, etc. And one of the very good reasons for this is that this particular kind of cell, these tumour cells that are derived from monocytes and macrophages. Are very adept at secreting a variety of different kinds of cytokines, pro-inflammatory cytokines that can cause things like lethargy and hyperexia and feeling poorly and fever, much the way they can in normal situations.
So these are the cells that secrete cytokines that give you a fever when you have the flu. And if those same cells become deregulated in a tumorous situation, it's quite common for those same sorts of quote unquote, flu-like symptoms to manifest. And that's how I usually explain it to owners.
There's one special variant of this disease that's worth mentioning too, and that's a disease called hemohagocytic histiocytic sarcoma. And these are dogs that generally will present for the same kinds of clinical signs. So lethargy, weakness, anorexia, fever, etc.
But actually, while you're doing your workup, you'll see some profound changes on your complete blood count. So it's quite common for these dogs to have a Coombs negative regenerative anaemia. Again, as you can see, the mean hematocrit in these dogs is about 23%.
It's quite common for them to be variably thrombocy. Penic, although usually not severely thrombocytopenic. And these dogs will always have involvement of their spleen.
But again, extensive staging is actually very, very important because many of these dogs will have at least microscopic give them all the involvement of the liver, lung, and bone marrow. And the outcome in these dogs is almost uniformly dismal. So the median survival time post treatment is about 7 weeks.
So again, a really important disease process to be able to identify. Sometimes this is a disease that can be diagnosed pre-surgically from cytology. So again, if you have a dog who presents like this, especially if it's an at-risk breed, and it actually does have diffuse splenomegaly.
Again, a fine needle aspirt of that spleen can sometimes make a diagnosis, at least of histeocytic sarcoma, and sometimes they'll even see the very characteristic features, which are again, this, this hemohagocytic component, which is actually the tumour cells. Cells chewing up other blood cells, whether they were red blood cells, white blood cells, platelets, etc. So sometimes this is a diagnosis that can be made pre-surgically and again, the owner appropriately advised as to the likely outcome with surgery.
So again, as I just mentioned, needle aspiration, cytology can be performed of accessible lesions and quite often, actually cytology alone may be sufficient to achieve a diagnosis or at least a tentative diagnosis of this disease. It's quite common for us to aspirate organs under ultrasound guidance if we have internal disease in the thorax or abdomen. But again, for a definitive diagnosis, histopathology may be necessary, and again, sometimes, especially for relatively poorly differentiated tumours, some special stains may actually be necessary in order to confirm the hisocytic origin of the tumour, and primarily to separate it from other kind of anaplastic or poorly differentiated round cell tumours.
So, in those dogs who appear to have solitary disease, we do like to obtain finelarates of the regional lymph nodes in all the cases where we can feel it at all. It doesn't have to be enlarged. If we can feel the regional lymph node at all, we do like to try to sample it because it's not at all uncommon for dogs with normal feeling lymph nodes to have occult metastatic disease.
And again, that's important because if that's the only site of disease beyond the local site, we would want to remove that at the time of surgery. And as we mentioned previously, thoracic and abdominal imaging, again, even here, even here at Colorado State University where we have all kinds of, you know, really sophisticated imaging tools like, like CT scan, MR, even PET CT, we tend to rely on the, on the old favourites of just plain old thoracic radiographs and abdominal ultrasound for workup of these dogs. And again, the main reason for that is that if we have a dog who has disease beyond that regional lymph node in more than one place, surgery is rarely going to be of benefit unless it's necessary to palliate some kind of clinical sign like pain or ulceration.
So, again, as we mentioned with previously, surgery is really the mainstay of treatment for this disease to start with. And again, the kind of surgery that's necessary will obviously depend on the, the site of presentation of the disease. So that could be limb amputation.
It could be mass, just a, a lumpectomy or a, or a mass resection for a subcutaneous mass. It could be splenectomy, it could be a lung lobectomy, etc. I mean, all those really we wanna sort of utilise the same sorts of surgical oncologic principles that we would use for a typical soft tissue sarcoma, which I discussed in a separate lecture.
So wide margin excision, try to not only remove the tumour itself, but the microscopic fingers that extend out from that tumour to minimise the likelihood of local recurrence. So, as I mentioned, there are several situations in which sometimes light microscopy alone will not be sufficient in order to confirm a diagnosis. Of histiocytic sarcoma.
Sometimes these tumours will have a very sort of undifferentiated look and the pathologist will come back and just say, oh, it looks like an undifferentiated round cell tumour, and we need special stains to be able to sort that out. And a specific case is made for doing some special stains on these synovial tumours because really we do see two distinct kinds of synovial tumours. One of them is a true synovial cell sarcoma.
So this is a tumour that actually arises from the connective tissues in the joint. And then the other is again what's referred to as peri-articular hisocytic sarcoma. And this is a tumour that actually is derived from the monocytes and macrophages that live in the joint space.
And the reason that this distinction is actually quite important is because there's quite a difference in outcome and what kind of postoperative treatment we recommend between these two distinct entities. So if we have a tumour that's positive for markers of histiocytic disease and CD 18 is sort of one of the classic ones that's been around for a long time. Another one that many of the labs are starting to offer now is, is another marker called CD204, which you, you may see recommended to you as an alternative by your pathologist and that one works very well too.
So these tumours are peri-articular histocytic sarcomas, which are generally associated with actually quite a poor outcome. Versus our CD 18 or CD204 negative tumours, which are true synovial cell sarcomas, may have quite a good outcome, if these are lower intermediate grade tumours, much like other soft tissue sarcomas. But again, the choice of postoperative treatment that we would reach for would be very different for our CD 18 negative synovial cell tumour than it would be for our histocytic tumour.
Again, for a routine synovial cell sarcoma, we'll generally follow with doxorubicin. If this is a histiocytic tumour, we're more likely to want to follow with Lomatine. And again, we'll talk more about that in a few slides.
But again, as you can see, here's, here's really the reason why we think that this additional refinement of the diagnosis carries a lot of value because again, dogs who have a, a true synovial tumour, either synovial cell sarcoma, or synovial myxoma, actually have a relatively good outcome with surgery alone. So again, you're looking at median survival times in the excess of 5 years with surgery. Versus again a dog with a peri-articular his acidic sarcoma, those that are CD18 positive in this particular study, in which case, these dogs were primarily treated with surgery only, the median survival time was only about 5 months.
So it really does carry a lot of prognostic significance. So, what about chemotherapy for this disease? So the two treatments that have been looked at for the management of bulky, bulky, unresectable or multifocal disease are Lomustine and doxorubicin, either alone or in combination.
So, two different studies have evaluated Lomustine as a single agent, for the treatment of unresectable or gross metastatic, histiocytic disease. And again, standard dose and schedule that you would find in your formularies, and we're looking at an overall response rate between about 1/3 and 5, with again, unfortunately, the majority of these responses being partial responses, not complete responses. And the median response duration is about 3 months or so.
So again, this is not a maximum or minimum. This is a halfway point, so half the dogs will respond for longer than that and half the dogs will not respond for that long. Layin is oral.
It's only given once every few weeks. It's generally quite well tolerated. So again, it definitely is a beneficial therapy, but again, it's not the kind of thing that we're gonna associate with long term cure when we're trying to use it to manage a big, bulky or unresectable tumour.
A very, very recent study just came out a year or two ago actually looked at a combination of alternating Lomaine and doxorubicin, and either one or the other was given every other week. And in this one study, the overall response rate was more like 60%, so almost twice as high, and the average response duration was about 6 months. It's almost twice as long.
So for the management of gross or unresectable or metastatic histcytic sarcomas, I do tend to reach for this protocol of alternating lousine and doxorubicin right now based on the, on the data that's been published. So what about post-operative therapy? So we really think that the large majority of these tumours has the potential to eventually metastasize.
So even if our staging really doesn't reveal any obvious evidence of metastatic disease at the time of surgery, the majority of these dogs will have microscopic metastatic disease that's going to catch up with them. So again, the metastatic rate that's been reported, the surgery alone is in the 70 to 90% range. And again, in some cases, the survival times have been as short as a month after surgery alone.
So really, it behoves us to do what we can to try and delay or prevent metastasis. And generally in the post-operative setting, I tend to be a fan of just lousine by itself. Again, it's cheap, it's well tolerated.
It's only once every 3 to 4 weeks. And again, if things go well, I plan to do 5 of those treatments. And then restage at the time of the 5th treatment.
So another set of chest X-rays, another abdominal ultrasound. And if everything isn't looking good, I give them sort of my blessing and I say, OK, let's just go to quarterly rechecks after this point and see how things go. So, here's a paper from a few years ago that actually looked at a combination of surgery and Lomasinein for localised histocytic sarcoma of a bunch of different locations.
And again, we can see our median disease for interval is about 8 months and our median overall survival time was about a year and a half, which certainly compares very favourably with much of the data that's been reported looking at surgery alone. So I do feel that I can look at an owner and say, yeah, I really do think that, that your dog has the potential to do better with this postoperative lousine than your dog does if postoperative lousine is not employed. Here's another study that looks specifically at, at primarily perarticular histocytic sarcomas and flat-coated retrievers.
And again, those dogs that received chemotherapy did about 6 times better than those dogs that did not. So we're still looking, unfortunately, at relatively short survival times in this particular study. But again, the outcome was relatively better.
However, it's important to note that not all of these dogs with the perarticular hisocytic sarcomas were treated with amputation, and some of these dogs actually succumbed as a result of local recurrence and not metastasis. So I would expect the outcome to be better in a dog who has appropriately treated local disease than a dog who we're treating, again, a, a visible tumour or a tumour that was treated with marginal excision. Again, another example, here, these are dogs with, with, either perarticular or non-perarticular, hisocytic sarcoma, where, again, the peri-articular hisocytic sarcoma dogs that got chemotherapy.
Again, we're looking at a median survival time of about 500 days. The non-particular hisocytic sarcoma dogs, median survival time of about 400 days. So again, it does appear to be considerably better than with surgery alone.
In this particular study, one of the interesting things was that the use of prednisone or, or, corticosteroids was associated with an inferior outcome. And really what I think that this represents is not that the steroid use itself is the culprit, but steroids are much more likely to be used in dogs that come in feeling sick. And those dogs that come in feeling sick are more likely to have extensive disease burdens and as a result, are either less likely to respond to therapy or more likely to have clinical signs catch up with them and become quality of life limiting sooner.
So again, I don't think that the use of prednisone by itself is bad. I think that it's a surrogate for a dog that comes into our clinic from the beginning, not feeling great where prednisone is necessary for palliation. And certainly I'm a big fan who says if, if prednisone is necessary, by all means, I think it's, it's very, very fine to use it.
Again, I try to, not use it unless necessary. If I have a happy dog who's not having any trouble, I certainly don't feel like it's necessary, but if it's necessary for, controlling clinical signs, I won't hesitate to recommend it. So, we have one little slide about histocytic disease in cats.
Unfortunately, these are considerably less common in cats and we have considerably less information on all the different spectrums of diseases that we can see and what those look like. Malignant histiocytosis, or again, sort of disseminated hisytic sarcoma has been reported very rarely in cats. And when it's seen, it does have that seem to have a similar anatomic distribution and presentation.
So we can see the same sort of visceral organs involved, lymph node involvement, similar sort of non-specific, not feeling so great, vague clinical presentation. And then again, there's one specific disease process which is not a a malignant disease but actually a hyperplastic disease called feline progressiveytic sorry, feline progressive histiocytosis, which generally often occurs primarily in the cutaneous location and that can then slowly disseminate over time. And unlike in the dogs, this is a disease where really treatment has not been well described.
So, if I actually saw a cat with a, honest to God, histiocytic sarcoma or disseminated hisocytic, tumour, I would treat it as if it was a dog with a combination of surgery, Lomotine, potentially doxorubicin. These are certainly drugs that we know we can administer safely to cats. So we're gonna change gears now and actually start talking about another tumour entity, another one of these hematopoietic tumours, and I'm gonna start with a little case.
So this is a doggie named Trixie. And Trixie actually is a mixed breed dog who presented for lameness and what her regular veterinarian was suspicious might be a possible osteosarcoma of the right humerus. So, Trixie is an 18 kg dog who does have quite a bit of lameness on the right front limb, but really has no other significant physical examination abnormalities.
And here we can see Trixie's radiograph. So, It's quite obvious, especially from the AP view here, that we do have some evidence of a disease process in the proximal humerus here. And I can certainly understand why the veterinarian might have osteosarcoma quite high on the list based on this clinical presentation.
So what are some things that would make us think about osteosarcoma? What are some things that might make us think, well, maybe this could be something else. So certainly the proximal humerus is a location that we associate with his aid, I'm sorry, with with osteosarcoma.
Often these dogs will only present with lameness. In this particular case, there was no history of travel to areas where fungal disease would be a concern. And the fact that we don't have any evidence of a penetrating wound or a draining tract made of bacterial osteomyelitis also less likely.
But there's some things that also make us a little bit less, convinced about osteosarcoma. And one is the fact that, again, this is a dog that only weighs 18 kg, so it's a little on the small side for a typical osteosarcoma dog. And again, the the lesion is very, very lytic on radiographs, almost purely lytic rather than sort of having that mixed lytic and proliferative appearance that will often associate with osteosarcoma.
So then there are some other things that we put on our differential list. So other primary bone tumours. That are not osteosarcoma.
And then metastatic disease as well could be a consideration. So we do see, for example, some carcinomas that will metastasize to bone, not infrequently. The location is not classic for this.
Usually, you will see mid diaphysele lesions that are associated with metastatic disease and often they can have more of a blastic type appearance than a purely lytic appearance like this, but it would definitely be on the list. So, we explored this dog a little bit more thoroughly with some additional tests and actually found a 3+ protonuria on a urine dipstick. The dog had mild anaemia and thrombocytopenia.
On chemistry profile, we saw mild hypercalcemia and actually, a quite high total protein, that was primarily associated with a significant hyperglobular anaemia. And seeing this type of pattern actually did sort of raise our suspicion, for a different disease process than osteosarcoma because we don't usually see these changes in osteosarcoma dogs. So our biggest differential now became multiple myeloma.
Because of the, the radiographic appearance of the lesion. And again, these other sort of constellation of signs that are quite consistent. So our hyperglobular anaemia, or hypercalcemia, etc.
So, we can sometimes see solitary lymphomas of bone that can be associated with hyperglobular anaemia and hypercalcemia. And as a result, we do think that some kind of interrogation of the, of the diseased bone is really indicated in order to confirm the diagnosis. And this is actually what we saw in the case of Trixie's bones.
So we can see this population of round cells with sort of central nuclei, very deeply basophilic cytoplasm. But what you can see on the blow up here, are these, are these quite pronounced what we call perin-nuclear clear zones. So these little areas around the nuclei where the cytoplasm is much less intensely staining.
And these are actually the Golgi apparatus of the, of the cells that are really ramped up. Here's another little example down here that are really ramped up because these cells are making immunoglobulin, and they're actually pumping out so much immunoglobulin that they're crowding those Golgi apparatus with protein, in this case, specifically globulins, and actually causing those perinnuclear clear zones to occur. So this is a fairly classic appearance for a plasma cell tumour or in this case, multiple myeloma in a dog.
So, again, multiple myeloma is fairly rare, which is why you don't hear as many lectures about it as we do mast cell tumours or lymphoma. It's only about 8% of the hematopoietic tumours that we see in the dog, and it's actually quite rare in the cat. Generally, we think about this as a middle aged to older dog disease and really we don't have any good idea about why it occurs.
So, it's very, very common, as the name implies for this actually to be a disease that affects multiple bones and not just a single bone. Actually, if we are very, very thorough in looking for disease elsewhere and really cannot find any evidence of the disease elsewhere, we don't The term multiple myeloma and we would use a different term which is called solitary osseous plasma cytoma. And that difference is actually noteworthy because those dogs who have a solitary osseous plasma cytoma can have a quite good outcome with surgery alone or local therapy alone.
So again, one of the hallmarks of multiple myeloma is their ability to cause this hyperglobular anaemia. So these tumours are producing so much immunoglobulin that it actually raises total globulin levels. And again, when we interrogate that a little bit further, this is associated with what we call a monoclonal gammopathy.
So all of these tumours are making the same kind of globulin. And it's relatively equally distributed between Being an IgG, isotype and an IGA isotype of globulin. Occasionally, blonal gammopathies have been reported where a tumour can be making both IgG and IGA for example, and rarely, we can actually see odd things like non-secretory myelomas.
So bone marrows that are full of plasma cells that are definitely malignant, but there's no gammopathy associated with it at all. And rarely we can also see an IGM. A gammopathy, and then we use a term called Waldenstrom's macroglobu anaemia to describe this disease process, but it is essentially just another variant of multiple myeloma.
So, most of the clinical signs that we see are associated with one of two things. They're either associated with the fact that there's bone missing. So, actually, so pain, bone weakness, pathologic fracture, and actually the hypercalcemia may be due to diffuse, bone destruction as well.
So the local or diffuse destruction of bone. And then the other is actually due to the presence of large amounts of protein in the blood. And the presence of these large amounts of protein in the blood can cause quite a different, a range of constellations of different kinds of adverse effects.
So we can see coagulation disorders, primarily having to do with abnormal platelet function. We can see what's called a hyperviscosity syndrome, where actually the blood literally becomes thicker and as a result, it is harder for the heart to pump around. So we can see cardiac failure as a result of this.
And again, we can also see CNS and ocular complications, so dilated, tortuous, swollen blood vessels that may or may not be associated with bleeding. So we can see primary CNS signs, we can see primary ocular signs. Again, about 20% of dogs with multiple myeloma can be hypercalcemic.
And then this large amount of paraprotein circulating around in the blood can also increase susceptibility to infection. And this may seem counterintuitive if you say, oh, wow, this is a dog that's making, you know, an excess of antibodies. Wouldn't that actually make them more able to fight off infection?
Well, the important thing is that they're only making one antibody. They're just making tonnes and tonnes of only one antibody. And actually, that can often be at the expense of all the other antibodies that that a patient needs to prevent against infection.
So we can see infection as a sequel. And we can also see renal disease as a sequel in these dogs. So, these dogs who have chronic hyperglobular anaemia can actually run into problems with glomerullo sclerosis and as a result, we can see protein loss, normal protein loss in the urine, and in some cases that can actually translate either as a primary renal disease or as a secondary complication of hypercalcemia to renal tubular disease as well.
So a large number of different body systems that can actually be adversely affected as a result of multiple myeloma. Again, one of the hallmarks of this disease is are these multiple lytic lesions and different long bones. Again, it's quite common for them to have what we call this sort of punched out, purely lytic kind of appearance rather than that sort of mixed lytic and proliferative appearance like we might see with fungal disease or osteosarcoma or metastatic disease.
So again, not a hard and fast rule, but a generalisation. And again, here's a dog who has that same kind of things occurring actually, within the, the cervical spine. You can see a big old chunk of bone missing right there.
So how are we gonna make a diagnosis of this disease in dogs? So ultimately, what we really wanna see is some organ that has too many plasma cells in it. So again, if we have a lesion that we can aspirate, a bone lesion that we can aspirate and suck pla plasma cells out of, that's great.
If we have a dog who's might have very, very subtle lesions or maybe even have no bony lesions, but has the other criteria of multiple myeloma, so hypercalcemia, hyperglobular anaemia, etc. Etc. a bone marrow aspirate of any random bone can actually quite often be diagnosed, diagnostic as well.
Again, part of the, of the, diagnostic criteria are the presence of a gammopathy. And again, one of the interesting things is occasionally we can have a dog who has a normal total globulin level. So if you actually just measure your total globulins from your chemistry profile, it'll appear normal.
But actually, if you then sort of cone down and ask for a serum protein electrophoresis. You'll find that it's a monoclonal gammopathy. So don't not do a serum alphesis if you have other evidence that might be consistent with multiple myeloma just because the dog has a normal total globulin.
So again, some of the other things we want to consider, a fundic exam can be very, very useful. Again, we do like to look and often these dogs may have dilated or tortuous retinal vessels, retinal haemorrhages can be seen as well. We do want our minimum database because again, we can see varying kinds of cytopenias.
We can see different degrees of azotemia and things like that as well. And quite often, a skeletal survey of of looking for evidence of bony lytic disease can be useful in a dog who may not present with those signs, to help us confirm our diagnosis. So, here's an example of a serum protein electrophoresis are actually several different serum, serum protein electrophoresis.
So this actually takes the serum in the blood, and runs it out by by size and charge, to look at different fractions that are occurring in the blood. And again, here's a little handwritten one. Here's our albumin, which is one of the most common proteins in the blood, obviously.
And then we've got alpha 1, alpha 2 globulin, beta 1 beta 2 globulin, and gamma globulin. So, just to, give you an idea about what these look like, so this top one would be what a monoclonal gammopathy would look like. So a huge, huge peak in the peak in the gamma region here.
So that would be something that would be consistent with the multiple myeloma. This middle one is a polyclonal gammopathy cause, so you can see actually a variety of different kinds of gamma globulins in that gamma fraction that appear to be increased. And this is actually what a normal one would look like.
So here's our albumin spike. Then again, our globulins are a lot less than that. So this is more what you'd expect to see if you just took anybody's blood and and did a serum protein electrophoresis on it.
Oh, how are we gonna treat this disease? So, thankfully, this is a pretty rewarding disease to treat. So, the mainstay of treatment is actually two pills that the owner can get at home.
One of them is prednisone or prednisolone, and the other is melphalan, which is an oral alkylating agent. And again, you can see the, the doses that are here. I'm not going to, to read them out to you.
You can see them just fine. Generally, we do start the prednisone at a relatively high dose and then taper that down over time. I tend to be a fan of actually maintaining dogs.
On a low every other day dose of prednisone long term rather than completely eliminating it after a couple of months. That's just a personal preference thing. I can't quote you any statistics that say that that results in a superior outcome to completely discontinuing the prednisone.
It just happens to be how I was trained to treat it. And then malalan, there are actually two different dosing schemas that have been reported for malalan. So one of them is this sort of low dose daily approach.
So you start at a sorry, 1/10 of g per kg daily for 10 days, then go down to half of that, so 0.05 mg per kg daily after that. And there's also what's called a pulse dosing schedule for mealan that has been described as well, where, again, you give 7 milligrammes per metre squared actually daily for 5 days.
So this slide is incorrect, please make a note of that. So this is 7 milligrammes per metre square daily for 5 days, not divided over 5 days. So the total dose is 35 milligrammes per metre squared.
And then that dose is repeated every 3 weeks. So, you know, for for simple purposes, I kind of like the daily or every other day dosing schema, that's sort of continuous dosing. But if you happen to have a patient who is really hard to pill, for example, it might certainly be preferable to give them only, these pills for a short number of days every 3 weeks.
There's a recent paper that just came out that really suggests that these two different dosing schemes are equivalent in terms of outcomes. So you can really pick the one that appears to be the most convenient for you or your owner. Some other things that we'll do for supportive care.
So, I do tend to sometimes empirically culture the urine of these dogs. I think there's a fair number of these dogs that actually may have sort of smouldering occult urinary tract infections, and they are gonna be on chronic corticosteroid therapy. So occasional empiric urine culture, I think is not the worst idea in the world.
Some of these dogs, if they're, if they come in with significant cytopenias at presentation, those can take some time to resolve. So as a result, blood product support may be necessary while we're sort of seeing how the disease is going to respond. And then there are some dogs who may be able to benefit from bisphosphonate drugs as well too.
So bisphosphonates are a class of drug. That actually work by inhibiting the function of osteoclasts in the bone, and as a result, they can limit or inhibit bone resorption. So in those dogs that present very symptomatic for bone pain, Those dogs who have significant hypercalcemia or those dogs who appear to have quite a bit of bone lysis on skeletal survey radiographs, I think there's a rationale for, adding bisphosphonate therapy to the other therapy that we're doing for the These dogs.
So this is something that is done fairly routinely in humans with different kinds of destructive neoplastic bone disease. And it does appear that the prophylactic use of bisphosphonates can help to delay skeletal events, so pathologic fracture, worsening pain, things like that. So I do tend to be a fan again in those dogs who are very symptomatic for their bone lesions or who have extensive bolytic disease of adding bisphosphonate therapy as well.
And the two drugs that are used most commonly, one is a drug called Pamironate. The other is a drug that I don't have on the slide that is called zoledronate. Both of these are injectables.
They're only given once every month. The advantage, in our practise, at least to zoledronate is that, it's given as a 15 minute treatment and pomironate has to be given as a 2-hour infusion. So, in our hands, despite the fact that Zeggenase a little more expensive, the drug itself, the costs out the door for the owner is actually less because we charge considerably more for a two-hour infusion than we do for a 15 minute bolas.
So something to consider again for those dogs with extensive skeletal involvement or significant bone pain. Radiation therapy can actually be very, very useful for the treatment of symptomatic lesions, in these dogs again. So if we find that we have a dog who either presents with sign of localised bone pain, or we have a dog that's somewhere along the course of their therapy actually develops significant bone pain and it's not related with pathologic fracture, radiation therapy can actually be very, very useful.
In those dogs who have that disease process that I described called solitary, Osseous plasma cytoma. Radiation therapy by itself can effectively be curative, so it can actually work very, very well. So definitely something to consider for the management of symptomatic bony disease.
How well does treatment work for this disease? So again, with this combination of prednisone and melphalan, the overall response rate is about 85%. So 85% of dogs will have their, globulins decrease by at least 5, and almost all of those dogs are gonna have really quite significant improvement in their, in their, quality of life and clinical signs.
And the median survival time is about 18 months or so. So again, that is not a maximum, it's not a minimum, that's technically the halfway point. Dogs that are hypercalcemic at presentation and those dogs that have very extensive bony lysis tend to fall on the short side of the average mark.
Doesn't mean we don't treat them, doesn't mean that it's a lost cause. But again, if I have to look at a dog like that and, and pick a side of the average mark, I think they're likely to fall. It's likely to be the short side.
About cats. So cats do get multiple myeloma as well. And one of the interesting things about cats is that it's much more likely to hide in the liver and spleen of cats than it is to hide in the bones.
So, if I have a dog with a You know, hyperglobular anaemia where we can't find another cause for it and I'm trying to rule in or rule out multiple myeloma, I will try and look in the bone marrow. In a cat, faced with that same situation, so if I have a cat with a hypoglobular anaemia, we can't find another cause for it. It doesn't look like it's feline infectious peritonitis or another one of those kinds of disease processes.
I'll tend to look in the abdomen and I like to sample organs like the liver and spleen because we will often find plasma cell neoplasia hiding in those organs in cats more often than we will in dogs. Another thing that is sort of reported in some cats is that they may not tolerate malalan as well as dogs do, as a result of GI signs and potentially an enhanced risk of mild suppression. So, in those dogs, or in those cats, we often reach for a cyclophosphamide instead of malalan.
And again, that can be delivered in a pulse fashion, once every other week, for example. Responses are less predictable, so it doesn't seem like they're quite as high as that 85% mark. And the reported median survival times are more in the 8 to 12 month range, so.
Far better than no treatment. And again, these are still oral medications that tend to be quite well tolerated, so definitely a disease that's worth treatment, treating, but maybe not quite as optimistic in this outcome as what we might see with dogs. So how do we monitor these dogs and cats for that matter?
So generally, I like to, get a, a complete blood count and look at immunoglobulins about 2 weeks after they start treatments and then then again at the 6-week mark. And assuming that dogs are doing well, and cats are doing well at those rechecks, then I'll generally just do a recheck every 6 to 8 weeks. Weeks thereafter.
So I personally really like to quantify the specific immunoglobulin that's abnormal in these patients rather than following total globulins. But I think it's, it's not necessarily wrong to make treatment decisions based on total globulins if a patient presents initially with very significant hyperglobular anaemia. We can often see clinical signs and bone pain and calcium improve relatively rapidly within a week or two of treatment.
During that period of time, again, some other kinds of symptomatic treatments may be necessary, bisphosphonate drugs, radiation therapy, other kinds of analgesics, etc. But it may take several weeks or many, many weeks before we see a maximal decline in paraprotein. So in other words, if the globulins are going to normalise, it may take a few months for that to occur.
And you, it may take months and months for skeletal lesions to change radiographically. So if you take an X-ray of a dog 6 weeks after they start malfain and say, oh, it doesn't look like the lesion is any different. It doesn't mean the treatment's not working.
So you may have killed every tumour cell in that lesion, but the bone just takes a very long time to remodel. So don't be disheartened if the lesions don't look any better even if the dog is otherwise doing better. One thing that we always forewarn owners about, and we wanna watch for it very carefully with melphalan is that it can be associated with a cumulative thrombocytopenia.
So it's not something that we generally see after a month or 2 months or 3 months, but 68, 1012. 15 to 18 months of treatment, we can see a very slow, gradual, cumulative decrease in their platelet count, and this is incredibly important to monitor for because if it occurs, it can be irreversible. It, those platelets may never come back.
So as a result, again, continuous monitoring of these patients is really, really critical to make sure, well, A, that our treatment is still working, and B, that we're not getting into one of those scenarios where we have dangerous levels of thrombocytopenia. So that's why again, I will keep those, those 6 to 8 week rechecks up indefinitely in these patients, mostly for safety reasons, but also to make sure that our treatment is working. So, Almost every single dog and cat with multiple myeloma will eventually relapse.
There are virtually no cures from this disease. And we really don't have as much information as we would like about effective options for rescue therapy for these patients. So there's a little bit of information out there about the efficacy of some second line therapy, but not nearly as much as we would like.
So some of the things that we would consider reaching for either based on anecdote or based on human experience or based on a little bit of canine data would be things like VAD, which is Vincristine, doxorubicin, and dexamethasone. Single agent doxorubicin would be another thing to consider. An alternate oral medication, another alkylating agent like Lomustine or cyclophosphamide could be considered and that appears to work in some patients.
There are isolated individual like single case reports. Of dogs with multiple myeloma potentially benefiting at least in the short term from Tocerinib therapy, which is the kind of inhibitor that's approved for treatment of mast cell tumours. And then there's a, a small case series of dogs treated with rabi phosidine, that's been reported in the literature too, and I will just show you a little bit of that data.
So in 11 dogs that were valuable, almost all the dogs had almost all of their different clinical signs or clinical pathologic abnormalities either resolve or improve following treatment with rabiphosidine. The only one that didn't improve at all was azotemia. So those dogs who came in azotemic, those dogs tended to stay azotemic after treatment, probably due to permanent damage to their kidneys as a result of either the hyperglobular anaemia or the hypercalcemia.
So this is just a little graph that shows 3 of the dogs that were treated with rabiphozidine in the study that was published. So all three of these dogs had, happened to have IGA myelomas and they all had profound reductions in their pararoteins. All three of these dogs started out mildly hypercalcemic, and their calcium went into the normal ranges.
And again, in two of these dogs, they bounced back, and the third dog, it stayed low for quite a while. Total white counts improved, total hematocrits improved. You might wonder what the deal is with this dog whose hematocrit actually got into the 60s.
This was actually a, a greyhound. So, their PCDs are supposed to be high like this. So this is actually a dog who's who's hematocrit normalised.
And then finally, this is just kind of a really neat example. One particular dog, this was a dog named Seamus, who actually had multiple, I'm sorry, a meal and refractory myeloma, who had what we call a stringent complete response to rabi phosidine. So the marrow went from being mostly plasma cells to being less than 5% plasma cells after treatment.
And we actually did a technique that's usually used for lymphoma called PCR for antigen receptor rearrangement. That actually demonstrated the presence of a clonal expansion of neoplastic B cells or in this case, plasma cells in the bone marrow before treatment. And after treatment, we actually saw a normal distribution of of different B cells in the marrow.
So this would be what's considered a molecular complete response. And this is a dog that actually was in remission for 3 years, died of an anal sac tumour, at that 3-year mark and had no evidence of multiple myeloma at the time of postmortem examination. So important things to know is that, although I do think that it is possible to get rabbiphozidine in the UK, on a compassionate basis.
This drug is not approved by the US Food and Drug Administration for the treatment of multiple myeloma, and at least in the United States, it's use for multiple myeloma would be a label violation and as a result of violation of federal law. So in the US this drug cannot be used for the treatment of multiple myeloma until it has a full approval by the FDA. Oh, we can see plasma cytomas occur in other locations as well.
So we, it's actually a fairly common skin tumour that we can see in dogs and the vast majority of cutaneous plasma cytomas that we see in dogs are benign. So marginal excision is curative. I already mentioned we can see solitary osteo plasma cytomas, and then we can also see mucocutaneous plasma cytomas that can occur in organs like the oral cavity and, the gastrointestinal tract.
So in these dogs, we really do want to be as thorough as possible in our staging to convince ourselves that the disease is truly solitary. And again, these bone and mucuscutaneous lesions can invade aggressively, so aggressive local treatment in the form of, of wider margin surgery or radiation therapy may be necessary, but the silver lining is that local therapy alone can result in really excellent outcomes in these patients. We will consider chemotherapy as per myeloma if surgery or radiation therapy is not possible due to owner preference, or location, for example.
So a couple of, of slides that we have about this. So here's a very small study that actually looked at oral extramedullary plasma cytosis plasma cytoma. So it's a small case series of maybe 14 animals.
So dogs that were treated with just debulking surgery had a very short time to recurrence, only about 2 months. But those dogs that had aggressive local therapy actually had a median survival time pushing 15 to 18 months, and most of the deaths were not due to a tumour. They were due to other things.
So again, if we can convince ourselves that the disease is solitary, it appears that, you know, appropriately aggressive local therapy can actually be associated with a quite good outcome in these patients. There's another very small case series of colorectal, plasma cytomas. And again, all of these, when they were solitary at presentation that were treated with surgical resection, had a fairly good outcome and again we're looking at a median survival time of around 15 months of these patients.
So, again, take home message is that these, these plasma cell neoplasms for the most part are very treatable. When we see our classic multiple myeloma, oral medical therapy can be associated with a very high response rate, and comparatively long survival times. What to do at the time when those drugs stop working.
As a matter of, of a lot of personal opinion and not a lot of data, but there are several different things that we can try. The outcome is not as good in cats, but it still definitely appears to be a disease that's worth treating in cats as well. And again, when we do see these solitary plasma cytomas of different locations in the body.
If we can convince ourselves that they are truly solitary, actually, the long term outcome can be very good with appropriate really aggressive local therapy. So again, I hope that a discussion of these two sort of less common hematopoietic tumours, was of use to you guys and as I said at the very, very beginning, please do not hesitate to reach out by email, if you have any questions about any of the stuff that was covered for this hour or anything else having to do with oncology. And again, I thank you very much for your attention.