So thank you very much to the webinar vet for inviting me to do this webinar with you today. I'm going to be talking about paraoplastic syndromes in equine medicine. So just a tiny bit of background about myself.

I have a particular interest in oncology, and I've been working entirely in the field of equine oncology at the Animal Health Trust for several years now, and I also have a master's in clinical Oncology. So just a little reminder briefly about what neoplasia actually is. It can be.

Said to be a silent disorder of cell growth or differentiation, which results in a nodule or a mass. There is a notable exception to this, where hematopoietic tumours such as leukaemia do not have an actual mass, so you're not gonna find a mass on that patient. The diagnosis of neoplasia is generally done via clinical assessments, so the classical tumour, nodule, and metastasis.

But it may also be diagnosed via clinical pathology, via histopathology, or in some cases, via recognition of a perineoplastic syndrome. So paraneoplastic syndromes are signs or symptoms that happen before or during a neoplastic process. They arise as a direct consequence of a neoplastic process.

But then to the physical presence of the tumour in question. So the best way to think about that is if a horse is coughing secondary to a bronchial neoplasm, that is not a perineoplastic syndrome because it's due to the physical presence of the tumour. But if that same animal has anaemia that arises secondary to that very same tumour, that is a perineoplastic syndrome because it's not because of the physical presence of the tumour in its location.

Paineoplastic syndromes are often completely unrelated to the normal physiological activities of the mature tissue from which the neoplasm originated. They are non-metastatic but systemic effects of neoplasia, and as I've mentioned, they are an indirect effect of the process. They are pathophysiological rather than physical processes and may be caused by hormones or cytokines produced by neoplastic cells from depletion of essential substances such as iron.

From an immune response to the tumour. But in most cases, the actual cause of the perineoplastic syndrome is completely unknown. It's interesting to note that any neoplasm can lead to development of any paraineoplastic syndrome.

Some paraineoplastic syndromes are certainly more commonly seen with certain tumour types, but frustratingly from a diagnostic point of view, there is not one single paraoplastic syndrome that is only seen with one single form of neoplasia, and conversely, there is no one form of neoplasia that will consistently produce only one paraoplastic syndrome. One thing to note is that the immune effects in particular of perineoplastic syndromes can be absolutely devastating because immunosuppression can lead to secondary infections and can even lead to progression of the primary neoplasm itself. They can also lead to the development of autoimmune diseases, which can be incredibly debilitating.

Paineoplastic syndromes will generally affect tissues or systems that are distant from the tumour itself, and as already mentioned, they're often more debilitating than the neoplasia. The severity of the clinical signs associated with the perineoplastic syndrome can preclude effective treatment of the primary neoplasm. And certainly, treatment of any meta metabolic abnormalities can be essential for case management.

Successful treatment of the primary neoplastic process will usually lead to resolution of the paraoplastic syndrome. But there are some abnormalities such as renal failure that may never resolve, even if you can successfully treat the neoplastic process. Paineoplastic syndromes are actually relatively commonly diagnosed prior to the primary neoplastic process.

So recognition of a weird clinical sign as a paraineoplastic syndrome can be an early indicator of neoplasia. They can be particularly challenging because the lack of recognition of a syndrome as being paraneoplastic could lead to missing that neoplastic cause, which could be potentially devastating because we all know that if you can pick up a tumour quite early, a lot of the time the prognosis is much, much better than later on in the disease. As I've already mentioned, they may occur early in the disease process.

And interestingly, in some cases, the severity can correlate to the tumour load, which can make them really, really useful to monitor response to treatment of that tumour. In humans, there are lots of common neoplas paraneoplastic syndromes, and the most commonly reported ones are fatigue, pain, dyspnea, nausea, vomiting, and anorexia, delirium and weight loss despite adequate food intake. A lot of these are obviously going to be quite difficult to recognise in our horses.

But these are caused by substances released by neoplastic cells, such as those hormones, peptides, growth factors, and cytokines. Other paraineoplastic phenomena are usually classified according to the organ or the system affected. So you've got this big group of miscellaneous or non-specific signs, and then more specifically, rheumatological, renal, gastrointestinal, haematological, cutaneous, endocrine, or neuromuscular.

And we'll go through each of these in turn. In veterinary medicine, paraineoplastic syndromes are very poorly recognised and poorly understood, but they are likely to be just as common in our veterinary species as they are in humans. They're a real clinical challenge because the vast majority of the syndromes have far more common non-neoplastic causes.

But I think that any clinical sign of or collection of signs with no obvious cause should trigger a much more thorough investigation to rule in or rule out neoplasia as a potential link. So looking firstly at the various miscellaneous syndromes. Probably the most significant of these is cancer cachexia.

I'm sure everybody's fairly familiar with this idea, but it's a profound state of malnutrition and wasting in the face of adequate nutritional intake. What I think's particularly interesting is that certainly in people, the syndrome biochemically and metabolically occurs before any clinical evidence of the cancer cachexia is seen. So way before the weight loss is recognised.

And it's actually one of the most common perineoplastic signs signs in humans, with between 45 and 87% of hospitalised human cancer patients displaying cancer cachexia. So it's a really significant issue. Humans that have cancer cachexia will have a decreased quality of life compared to those that do not, even with the same neoplasia, a decreased response to treatment regardless of what else you do, a shorter survival time, and this means that it's got really significant prognostic value, and we know that the degree of cancer cachexia may more accurately predict a person's survival time than whether or not that person is actually treated at all.

So it's really quite a scary phenomenon that's very, very significant in people with cancer. It's got a complex aetiology, and there are lots of factors that might tie into this. Anorexia is an obvious one, but actually the degree of anorexia shown by most cancer patients is not that bad.

However, we know they have impaired digestion, increased nutritional requirements because of the neoplastic process, impaired muscle synthesis, a loss of nutrients, some inflammation will often be present, and they often have metabolic and endocrine derangements. We know that cancer cachexia leads to alterations in carbohydrate, lipid and protein metabolism, which leads to a net energy gain by the tumour and a net energy loss by the patient. Interestingly, they also have significantly altered carbohydrate metabolism, which can lead to glucose intolerance in cancer patients.

We also see increased fat lysis, increased free fatty acids, and increased plasma lipoproteins in human cancer patients with cancer cachexia. As well as the obvious, it's associated with impaired wound healing, increased infections and impaired immune function. So it has some really significant side effects other than being very thin and potentially very weak as a, as a result of the muscle loss.

It's important to note that appropriate nutritional support is not associated with increased tumour growth in humans undergoing treatment for cancer cachexia. So keeping an adequate plan of nutrition is not gonna make their cancer any worse. Horses that display cancer cachexia are likely to have a worse prognosis, although we don't know this for sure.

But it doesn't preclude palliative care and ensuring an adequate plan of nutrition if palliative care is to be pursued. The next significantyineoplastic syndrome that's very well recognised is pyrexia. It's particularly commonly found with lymphoma, but it can be found with any kind of cancer.

And in general, pyrexia that's pyoplastic in origin will be non-specific, intermittent or remittent. The pathogenesis, like many things with paraineoplastic syndromes, is very poorly understood. But it's believed that interleukin 1, interleukin 6, tumour necrosis factor, and prostaglandin E2 in the vascular endothelial cells in the hypothalamus lead to changes in temperature regulating neurons, which then lead to the subsequent pyrexia.

Why this is often waxing and waning is completely unclear. The incidence of pyrexia associated with neoplasia in horses is unknown, but what I think is really interesting is that in humans, up to 40% of pyrexia of unknown origin is actually caused by undiagnosed neoplasia. So we're probably missing this in quite a lot of our pyrexia of unknown origin cases.

While you're chasing down the source of the fever, or even just as palliative care, you can treat the pyrexia symptomatically using combinations of non-steroidals, corticosteroids, and potentially paracetamol even in our patients. Successful treatment of the primary cause will result in resolution of the pyrexia, and that should always be the aim where possible. One very bizarre paraineoplastic syndrome is that of tumour lysis syndrome.

It's incredibly rare, but it's a genuine oncological emergency because it leads to severe metabolic derangements and subsequent issues. In humans, it's more commonly seen in patients that have lymphoma or leukaemia, who are undergoing active treatment and that might be chemotherapy or radiotherapy. But it can be seen in the absence of treatment and with other forms of neoplasia.

There are some very well characterised risk factors in people of a high tumour burden, a high tumour growth fraction, and pre-existing renal disease. So these are certainly quite significant factors. The syndrome is believed to be because of rapid tumour cell turnover or tumour cell death, which is why it's associated with active treatment.

This leads to the release of intracellular ions and metabolic byproducts. Which leads to increased potassium, uric acid, and phosphate in the blood, and often will result in acute renal failure. Although it's extremely rare, it should certainly be considered as a possibility in any horse with signs of both renal failure and neoplasia.

And what I think is particularly interesting is that this can lead to cardiac arrhythmia and even sudden death because of the electrolyte arrangements. So if you do see a horse with signs of both renal failure and neoplasia, it should be taken extremely seriously. Amyloidosis is another thing that we see as a paraineoplastic syndrome from time to time.

I will fess up and say that these images are all taken from Google. So we have cutaneous amyloidosis on the left and then two examples of nasal amyloidosis in the middle and on the right. This may be a perineoplastic manifestation of plasma cell tumours, especially multiple myeloma.

In any species, but in horses, it's been reported with multiple myeloma, with plasma cytoma, lymphoma and adenoma. And as I mentioned, both in the nasal cavity and generalised cutaneous amyloidosis have been reported in association with neoplasia in horses. Certainly any unexplained case of reactive amyloidosis should prompt a full investigation, but the primary neoplasia can sometimes be really difficult to locate.

Moving on to the rheumatological syndromes. The most significant and most commonly observed is certainly hypertrophic osteopathy, which is often known as Mary's disease. This is a symmetrical proliferation of connective tissue and subperiosteal bone, which affects the diaphysis and metaphysis of appendicular bones.

It most commonly leads to swelling in all four limbs, but occasionally also affects the maxilla, mandible, and nasal bones. In humans, only 25% of cases report pain associated with the disease. So you often don't get much of a pain response if you're squeezing the swollen areas in horses.

Here are just a couple of examples on the left of Mary's disease in a relatively young animal, and on the right here you can see the more obvious swelling of the limbs. And this again is taken off a case report and the link is on there, on the slide. You can see that really diffuse swollen area that looks very, very different from your classic cellulitis lesion.

So hypertrophic osteopathy will lead to impaired limb circulation and distal limb edoema. The horses are very lame and they're stiff and reluctant to move. You may also see reduced joint mobility and synovial effusions.

It's quite interesting in people, they tend to get these bony lesions actually within the joints. And in horses, we don't really see actual joint lesions, but they still show this reduced joint mobility and effusions, which is probably just all part of the distal limb edoema and impaired limb circulation. Classically, the radiographic changes are described as palisade like new bone formation perpendicular to the cortex, and we'll see a couple of examples of that shortly.

In the vast majority of human cases, hypertrophic osteopathy is secondary to intrathoracic neoplasia. But interestingly, in horses, they may be secondary to neoplastic or inflammatory intrathoracic disease, or even occasionally associated with extra thoracic disease, which may be neoplastic or non neoplastic. But in both humans and horses, you can sometimes have no obvious inciting call.

Reported neoplastic diseases that have been associated with hypertrophic osteopathy in horses include squamous cell carcinomas, gra granular cell tumours and thymic lymphomas, and non neoplastic diseases that have been associated with hypertrophic osteopathy in horses include various granulomatous inflammatory diseases, especially of the lungs and pulmonary abscessation. The pathophysiology of the disease is very unclear. There are several theories.

One is that it may be secondary to toxic products from the intrathoracic disease. And we know that there's round cell inflammation in the periosteum prior to new bone deposition, which may go along with the toxic theory. More commonly, it's thought that it may be secondary to increased vascular endothelial growth factor.

And this could certainly explain how such diverse diseases, including extra thoracic diseases lead to the condition. It might occur secondary to shunting of pulmonary vasculature also affecting this edger. It's interesting to note that in other species, surgical removal of a lung lesion with lobectomy and rib resection can lead to resolution of the clinical signs.

And there's a case report of a dog where avagotomy led to resolution of the disease, which has led to speculation that it could be a result of a nervous reflex condition. Again, some sort of nervous reflex could explain how extra thoracic diseases lead to the condition without chanting of the pulmonary vasculature that has also been suggested. So this is just an example of a horse that had hypertrophic osteopathy.

This is a thoracic radiographs and you can see this very, very large abscess here on the left of the view of the film. And here are some radiographs of a horse with hypertrophic osteopathy, so you can see that very bizarre new bone formation there perpendicular to the cortex of the bone. So it's relatively straightforward to diagnose, at least in theory, because you have this very classic proliferative monolayer changes of long bones with or without involvement of the nasal, mandibular and maxillary bones.

However, it's really, really important to establish the primary condition because in the vast majority of cases there will be a reason for this. It's very unusual that there's no inciting cause. The prognosis will depend entirely on that primary condition and whether or not the primary condition is treatable.

If the inciting causes neoplastic, the feasibility of removing the primary condition will absolutely determine the prognosis. Unfortunately in our horses, the vast majority of inthoracic neoplastic disease is not going to be treatable. However, if it's not neoplastic, the prognosis may be better if the primary cause is treatable.

So if you've got something like an inthoracic abscess or extra thoracic disease that may have a treatable cause, then potentially the prognosis is not nearly so bad. Because the non neoplastic causes of hypertrophic osteopathy are so common in horses compared to the neoplastic causes, it's really important to establish that primary inciting event before you condemn the patient. Moving on to some of the renal syndromes that you may see.

Renal syndromes in particular can be very, very debilitating, probably secondary only to the cancer cachexia syndrome we already discussed. Early recognition and treatment of renal syndromes will markedly improve the quality of life of the animal, even if this is only performed whilst you're investigating the disease. The compromised tubular and glomerular function may lead to or be a result of electrolyte disturbances such as hypercalcemia, and we'll discuss that in a little bit more detail.

It may be a result of hormone producing tumours affecting the kidneys, such as renin producing tumours, the syndrome of inappropriate anti-diuretic hormone secretion, and diabetes incipidus. And it can also occur as a secondary effect of other paraineoplastic problems. We've already mentioned tumour lysis syndrome as being one of those.

So very briefly looking at renin producing tumours, this will lead to severe hypertension, polyurea and polydipsia, and edoema. You'll see hypokalemia due to increased aldosterone, which occurs as a result of the increase in renin. And this hypokalemia may lead to weakness and paralysis.

I'm not aware of this ever being observed in the horse, but it's certainly something to consider. Syndrome of inappropriate anti-diuretic hormone secretion, it's a nice big mouthful. This is where you have release of anti-diuretic hormone or related peptides from the tumour, leading to water retention by the kidneys.

This leads to hypo osmolarity of the osmolarity of the blood. Peripheral edoema initially results, but as this progresses, you'll get intracellular edoema, and the hyponatremia that results from the hypoosmolarity of the blood can lead to cerebral edoema, which can lead to a range of neurological signs, including head pressing such as this horse on the slide, seizure, coma, and in severe cases, even death. We know that syndrome of inappropriate anti-diuretic hormone secretion has been associated with carcinomas, lymphoma and sarcomas, and should certainly be considered if you've got a horse that has a bizarre collection of signs which may include a very low sodium with no obvious reason.

The diagnostic criteria for this syndrome are hypo osmolarity and hyponatremia, dilute urine, and a sustained renal excretion of sodium in the face of normal renal and adrenal function. I'm not aware of anybody that's attempted to treat this in horses or what the treatment might be, but certainly, addressing the primary neoplastic process should lead to resolution of the disease if that is a treatable neoplasm. Diabetes incipidus is effectively the opposite, so it's a decreased amount of vasopressin, which is also known as anti-diuretic hormone, where water is not reabsorbed by the kidneys.

The primary clinical sign is polyurea and polydipsia, and it can lead to dehydration and seizures if water is restricted, so the horse isn't able to keep itself hydrated. Very briefly discussing gastrointestinal syndromes. The major perineoplastic gastrointestinal syndrome that's been reported in humans is watery diarrhoea, which tends to be associated with electrolytes arrangements which can be quite severe, exhaustion and confusion.

I'm not sure that we're gonna notice that our horses are exhausted and confused, but you may well notice watery diarrhoea with electrolyte arrangements. And these have been reported in humans in association with a variety of different neoplasms, including thyroid tumours, melanoma, myeloma, ovarian tumours, and metastatic lung disease. It's believed to be mediated by prostaglandins, although this is still uncertain, and it's certainly accompanied by malabsorption and malnutrition which can worsen any weight loss.

Of course there are many more common causes of watery diarrhoea in horses than neoplasia, but it's certainly something to consider in cases of unremittent diarrhoea. And don't forget this doesn't have to be intestinal neoplasia, it could be neoplasia absolutely anywhere within the horse. So the more common things that we see, haematological syndromes.

One of the most interesting ones, or at least I find it the most interesting, is absolute erythrocytosis, which is sometimes known as polycythemia. This is an increase in the total circulating red cell mass, and your pack cell volume in these cases is often very high, well over 55%. This may be due to erythropoietin secretion by the tumour itself, or an analogue which is a substance with the same effect that's secreted by the tumour, or potentially prostaglandin production by the tumour which leads to erythropoietin secretion.

This syndrome has been reported in horses, particularly in association with hepatoblastoma and other hepatic tumours, but also with renal tumours and lymphoma. Interestingly, in the literature, there is a report of palliative treatment with hydroxyurea. However, you're much more likely to be successful if you treat the primary issue.

Just a quick side note on polycythemia vera, which may be due to a myeloroliferative disorder due to clonal proliferation of red blood cell precursors, and that is not a perineoplastic syndrome. It's a syndrome that occurs directly because of that myeloroliferative disorder. Thrombocytosis is very commonly observed in cancer patients, and it's certainly associated with worse prognosis in many different types of neoplasia.

It's interesting that this occurs, and it's probably because they actually plateletslets themselves will actually promote tumour growth and progression, and they regulate and maintain angiogenesis, so maintain that blood supply to the tumour. The tumour cells may secrete humeral factors that lead to thrombocytosis through increased synthesis of platelets and increased platelet activation. But this syndrome is actually only very rarely reported in horses.

However, thrombocytosis would trigger me to wonder whether there was something strange like this going on. Thrombocytopenia is another thing that we see, and it's actually reported in 35% of horses that are diagnosed with lymphoma. So it's actually quite common in those cases.

Thrombocytopenia may occur because of increased platelet consumption, decreased production, sequestration of blood, or immune-mediated platelet destruction, and in those horses with lymphoma, it's believed to be due to bone marrow suppression because of cytokines produced by the neoplasia. It's also been reported alongside hemangiosarcoma. Older horses were disseminated forms of the disease.

It's important to remember when assessing platelet counts in horses that you really need to collect the blood in a citrate tube to make that more accurate because platelet clumping's a huge problem in our equine species and is much more likely in EDTA blood. If you're confident that thrombocytopenia is present, a bone marrow biopsy may be required to assist with the differential diagnosis of this disorder, and the treatment could be with corticosteroids and or azathioprine because it's effectively most likely to be an immune-mediated issue. But as ever, as with all of these syndromes, you should try and treat the primary neoplasm first where possible.

Anaemia is also extremely common as a perineoplastic syndrome, and there are various different forms that we'll go through. This may occur because of disorders of iron metabolism and storage, because of reduced bone marrow er erythroid progenitor cells and reduced bone marrow response. A relative erythropoietin insufficiency due to increased inflammatory cytokines, or a reduced erythrocyte lifespan.

Anaemia is very commonly seen in lymphoma and also a lot of other tumour types in humans, and it's associated with a worse prognosis. Everybody's probably familiar with the concept of anaemia of chronic disease, and that can be a perineoplastic syndrome too. This is a normocytic normochromic anaemia.

With normal bone marrow cellularity associated with it. It's likely to be due to reduced iron metabolism, to reticular endothelial iron sequestration. And it can also become secondary to malignancy associated inflammation due to the reduction of bone marrow suppressing cytokines.

Specifically, interleukins 1 and 6, and interferon gamma and growth factor beta will suppress iron uptake and metabolism, and tumour necrosis factor alpha will antagonise any effects of the erythropoietin on the bone marrow. One particularly interesting form of anaemia is microangiopathic hemolytic anaemia, which is very rare and it is fatal. Generally, this is associated only with neoplasia in humans.

And it presents as anaemia with thrombocytopenia, renal failure and pyrexia. It's mostly seen in patients with very advanced cancer, and the prevalence in veterinary cancer patients is unknown. It's a distinct syndrome, but the pathophysiology is not really understood.

It may be because of hemolysis in the arterial circulation, or possibly due to fibrin deposition or damage to the arterioar endothelium. Immune-mediated hemolytic anaemia is occasionally recognised in other species as a perineoplastic syndrome, and it might be underreported in the horse. Immune mechanisms triggered by the neoplasia lead to destruction of the red blood cells, and you see a non-regenerative anaemia and spherocytosis.

For palliative purposes, corticosteroids and azathioprine may be useful, but as ever, treating the primary cause is much more successful. Leukocytosis is an interesting one that's common in all species with a huge variety of tumour types, and the mechanism for this is completely unclear. It's probably secondary to a hematopoietic growth factor that's produced by the tumour, but it's not clear why this would be.

It could also result from tissue necrosis and granulocyte breakdown with a subsequent positive feedback loop, leading to increased neutrophil production. And the significance is unclear other than it may confuse the diagnostic picture. Eosinophilia is rarely reported in veterinary medicine and is probably more commonly seen in dogs than horses with neoplasia.

It's certainly caused by an imbalance of eosinophil production in the bone marrow, and the prevalence in horses with neoplasia is unknown. However, neoplasia should be a differential diagnosis for absolute eosinophilia in the horse and should trigger a more thorough investigation. Disseminated intravascular coagulation is also occasionally seen as a rare complication of neoplasia, and it's been reported as a paraoplastic syndrome in human cancer patients.

Because it tends to be rapidly fatal, it's very hard to diagnose the primary cause without a postmortem examination. So most likely it's underreported in our veterinary patients. Hyperfibrinogenemia can also be associated with neoplasia, and this can confuse the picture sometimes because intrinsically you assume that there's an infectious or inflammatory process, but your mind doesn't necessarily go to neoplasia.

Tumours, however, may produce interleukin 6, which leads to increased production of acute phase proteins by the liver. And if the primary neoplasia is successfully treated, that hyperfibrinogenemia will resolve. To confuse the picture further, it can also be associated with inflammatory side effects of the tumour or secondary infections.

For example, intestinal lymphoma could lead to ulceration and subsequent inflammatory responses, which leads to hyperfibrinogenemia which is not perineoplastic. Another thing that most people are familiar with the concept of is monoclonal gammopathy. This is secondary to multiple myeloma and is due to an excessive production of proteins from a monoclonal line of immunoglobulin producing cells.

These are usually plasma cells, but very occasionally they're lymphocytes. And this syndrome has been reported in horses in association with multiple myeloma. Generally, the gammopathy is IgG, but sometimes it's IGA and sometimes the other immunoglobulins have also been implicated.

If you see a hypoglobular anaemia in a horse, serum protein electrophoresis will identify if it's monoclonal or polyclonal, and if it's polyclonal, it's much more likely to be inflammatory in origin. It's important to notice that in contrast to other species, in horses, you rarely see Ben Jones proteins in their urine when they've got multiple myeloma or a monoclonal gammopathy. Interestingly, this may present just as a bleeding disorder such as epitaxis because the increased blood proteins may interfere with platelet function.

An extreme hypoglobulin anaemia can lead to increased blood viscosity, which has all manner of weird and wonderful side effects. Reported things associated with increased blood viscosity include retinopathies, ataxia, neurological signs such as seizures and coma, cardiac compromise and poor circulation, renal decompensation and renal amyloidosis. So a real variety of clinical signs that can be traced back to this gammopathy.

In other species, melanan is used to treat the multiple myeloma, often alongside prednisolone. And supportive palliative care is important, such as intravenous fluids and possibly antimicrobials, because myeloma cells can secrete an immunosuppressive substance that reduces macrophage and lymphocyte function. How relevant this is in the horse is questionable, whether or not you're gonna try malfanan treatments, but certainly prednisolone and palliative care is worth a go.

Just a side note on lymphoma, because that's so commonly associated with haematological alterations, and these are often very specific ones. So you'll often see lymphoma alongside anaemia, lymphocytosis, neutrophilia, leukocytosis, leukopenia, or thrombocytopenia. So it can be basically whatever combination you want.

However, the combination of anaemia with lymphocytosis should be an indication for bone marrow biopsy unless there's a very obvious alternative cause. Hypercuremia is a really interesting one, so increased copper and ceruloplasmin concentrations are reported in a lot of human cancer patients and can be used for early diagnosis and also for prognostication in these. In particular, ocular copper deposition is associated with lymphoma and multiple myeloma in humans, so it's a really interesting way to end up with a cancer diagnosis.

It's been reported in horses associated with renal carcinoma, but because we rarely measure copper or ceruloplasmin in routine clinical practise, we're probably missing a lot of these. And it might be something worth thinking about if you've got a pyrexia of unknown origin or other strange clinical sign that you can't quite tie down. Just have a look at those copper and ceruloplasmin concentrations and see whether that might lead you to have neoplasia higher up on your differential diagnosis list.

Moving on to the various endocrine syndromes. So as we've already mentioned, tumours can release hormones, cytokines, peptides and amines, which can lead to metabolic disorders and behavioural changes. Just as a side note, probably the most commonly recognised hormonal syndrome in the horse is virulism associated with ovarian granulosa cell tumours.

And this really is a perineoplastic syndrome. However, other things to think about, hypercalcemia is really, really commonly associated with neoplasia in all species and especially commonly seen with lymphoma. Interestingly, 30% of humans with lymphoma will develop the syndrome at some point in their disease course.

It's also one of the most commonly reported perineoplastic syndromes in the horse, with 25% of horses with gastric squamous cell carcinoma having hypercalcemia as well. It's also been reported in horses in association with multiple myeloma, with carcinoma, amyeloblastoma, and lymphoma. There are lots of potential mechanisms and probably the most likely is ectopic synthesis of parathyroid hormone related protein or parathyroid hormone itself, which leads to bone resorption and an increase in the blood calcium concentration.

Other potential mechanisms include the production of prostaglandin E1 and E2 or other prostaglandins. The tumour may produce osteoclast activating factors. And more unlikely, but certainly possible, you can get extensive bone lysis from metastasis or bone destruction secondary to a primary bony neoplasm, which would be very unusual in a horse.

You may also get an abnormal form or an induced abnormal function of vitamin D, which goes along with hypercalcemia. Clinical signs of hypercalcemia may relate to the gastrointestinal tract, the cardiovascular system, the neuromuscular syndrome system, or the urogenitals system. You may see anorexia and constipation associated with decreased gastrointestinal motility.

You can see weakness and syncope associated with decreased myocardial contractility, polyurea and polydipsia because of some renal compromise, and acute renal failure may result because of the toxic effects of calcium on the renal tubules. Specifically looking at hypercalcemia and the kidneys, hypercalcemia itself leads to an inability to concentrate urine. Because it decreases the sensitivity of distal convoluted tubule and the collecting ducts to pH changes.

It also leads to vasoconstriction, decreasing renal blood flow and glomerular filtration rate. And the renal epithelium can undergo degenerative changes, necrosis and calcification, worsening the renal function. Just to complicate matters even more, chronic renal failure itself will lead to hypercalcemia, and that can be an additive effect.

So it almost becomes a positive feedback loop, where the hypercalcemia gets worse and so the renal function gets worse. It's important to remember that there are lots of other causes of hypercalcemia that are probably much more common than neoplasia. The number one is probably just laboratory error, but certainly in horses, chronic renal failure is a major cause as well.

You may also occasionally see things like iatrogenic hypervitaminosis D. Or hyperparathyroidism, which has been reported in horses as well, and certainly toxic exposure to certain plants can lead to hypercalcemia. Treatment of this hypercalcemia can improve the quality of life in horses with neoplasia where it's successful.

And you want to concentrate on trying to increase renal calcium excretion, inhibit bone resorption, promote calcium deposition in the soft tissues and or promote external loss of calcium. So some practical ways you can do this, firstly, would be to do intravenous fluids, which will just increase the glominrular filtration rate and renal blood flow, and also hopefully dilute that hypercalcemia slightly. In other species, frozamide is known to inhibit calcium absorption, although it's not believed to be particularly effective at doing that in the horse, but it might be worth the go.

And certainly prednisolone, our good old friend prednisolone, will inhibit osteoclast activating factor, inhibit prostaglandins, inhibit vitamin D, and inhibits intestinal calcium absorption. So lots of different ways in which it can be helpful in horses with hypercalcemia. Moving on to hypoglycemia, this has been associated with both carcinomas and mesothelioma, and true paraineoplastic hypoglycemia is often associated with production of an insulin-like growth factor by the tumour.

However, it can also be associated with failure of compensatory mechanisms with hepatic compromise, increased tumour nephrosis factor alpha, hyperinsulinemia, and increased metabolic rate. Hypoglycemia is rarely recognised in mature horses, but it could lead to weakness, tachycardia, parsis, and seizures. However, laboratory error is much more likely, so pseudo hypoglycemia because of inappropriate sample handling is much more common, and you should certainly rule this out before hanging your hat on this being a perineoplastic issue for the horse.

Moving on to the cutaneous syndromes that you may see as a perineoplastic syndrome, these are particularly interesting. So apparently a plastic pruritus is really horrible because it can lead to a huge amount of self trauma by the horse, as is demonstrated quite nicely by this poor guy. It's a relatively common perineoplastic syndrome in horses, and it's been reported in association with lymphoma and with renal carcinoma.

Sometimes pruritus may be an early indicator of the presence of a tumour. And it could be accompanied by primary alopecia, which is perineoplastic, or secondary alopecia due to the self trauma associated with the pruritus. Certainly if you have pruritus with no obvious inciting cause, I would start wondering whether there was some sort of neoplastic process going on in that horse.

The most likely cause of perineoplastic pruritus is T cell destruction, secondary to cytokines produced by the tumour. However, there are various non-perineoplastic causes of psoriasis in the horses with tumours. So it could be secondary to nerve compression by a tumour, er, tumour growth itself, or bile duct compression with cholestasis.

Generally this pruritus will resolve with effective treatment of the primary cause, but for palliative purposes, we may go back yet again to corticosteroids for these cases. You may also come across paraneoplastic pemphigus, and certainly I would want to rule out a paraneoplastic phenomenon in any horse with Penthagus. So just a couple of examples of what this can look like, cause it can look pretty different in different horses.

You can see this guy's got some degree of self trauma as well, over his thorax and over his hind quarters where he's been itching it himself. Here we've got Penhagus which is more focused on the limbs of this horse. And again, a less sore looking version of Pemphigus in this young horse.

So pemphigus itself is an autoimmune disease caused by autoantibo production todesin 1 and 2, bullus pemphigoid antigen, and possibly some other antigens. It's very rarely seen in association with neoplasia, and in humans, it's been associated with renal carcinoma most commonly. It's also been reported in association with neoplasia in the horse, so it should be ruled in or out.

You're most likely to come across pemphigus foliaceous as a perineoplastic phenomenon, but the other forms of pemphigus, so pemphigus vulgaris and Bulos pemphigus, are also sometimes seen. Rather unhelpfully, the characteristic hist histopathological changes of pemphigus are the same as in non-neoplastic disease, but there is one particular combination which can suggest a neoplastic cause, which is where there is suprabasal achanthylisis and dykeratotic harriinized sites throughout the epidermis. And this is a very unusual combination of things seen in Penhagus that should trigger an investigation into a neoplastic cause.

Ulcerative coronitis has also been reported in horses associated with neoplasia, where you see severe swelling and ulceration of the coronary bands with or without effects around the edges of the ergots and chestnuts, and they have been reported in association with neoplasia in the horse, usually with lymphoma, but other types of neoplasia are also a possibility. It's often a primary presenting sign of neoplasia, and it's likely to be immune mediated, although the exact underlying mechanism is completely unknown. Stomatitis is another very rare autoimmune condition, which has been associated with neoplasia in both humans and horses.

So it's been reported associated with hemangiosarcoma in the horse. And you just see oral blisters that don't respond to treatment, and this should certainly prompt a diagnostic investigation to rule out a primary neoplastic disorder, which again could be very distant from the mouth of the horse. Looking at some of the neuromuscular syndromes.

It's quite interesting to note that 6% of human cancer patients will develop neuromuscular perineoplastic syndromes, and it's especially common in ovarian and pulmonary cancers in people. To my knowledge, we haven't had any reports of neuromuscular perineoplastic syndromes in the horse. It's possible that they just haven't been recognised, or maybe because we don't tend to see the really horrible aggressive ovarian and pulmonary cancers in horses that you do see in people, and maybe that's why.

However, it's certainly something that should be considered if you're presented with an inexplicable neuromuscular disorder in the horse. There's a huge variety of neuromuscular syndromes that have been reported in people, including myasthenia gravis, encephalitis, encephalomyelitis, cerebellar degeneration, and sensory neuropathies. So really, any neuromuscular sign could hypothetically be associated with neoplasia.

So to sum up, a whistle stop tour of perineoplastic syndrome in the horse. Any type of tumour can lead to the development of a paraineoplastic syndrome, and paraineoplastic syndromes represent a hugely variable collection of clinical signs and laboratory abnormalities. It's important to remember that no one form of neoplasia is exclusively associated with any one paraneoplastic syndrome.

But we should certainly be considering neoplasia as a possible reason for any sign or clinical signs for which the cause is not evident. Where it's possible to treat the primary neoplasm, you're likely to have resolution of the paraneoplastic syndrome, and that should always be the goal. Although palliative management of these is often also possible.

Thank you very much for your attention.