Ferrets (Laboratory) - Pathology

Introduction

Ferrets (Mustela putorius furo) are thought to have been dometicated for over 2000 years and are descended from the wild European Polecat. Despite being domesticated for such a long period, ferrets were only recognised as important in medical research in the 20th century and were only beginning to be used in the 1960s as an important animal model. Ferrets are often utilised in a laboratory setting as they are known to share many anatomical, metabolic and physiological features with humans. Therefore ferrets are often utilised in studies covering a broad subject matter including toxicology, bacteriological and virological studies. Ferrets have also been used as a model for studies into ischemia and ion exchange in the heart, influenza, neurological injury and gastric infections. Ferrets are particularly important in influenza studies as they can be infected with type A and B influenza viruses. According to the US Department of Agriculture Animal Care Report, approximately 17,000 ferrets per year are used in laboratory studies.

As ferrets are a social, curious and intelligent species, they often require a higher level of husbandry than other species such as hamsters or mice. Laboratory ferrets will require a complex and stimulating environment with enrichments that include tubes and boxes that are able to simulate a burrow. Ferrets have a strong drive to explore and therefore they will investigate all aspects of their enclosure. Enclosures therefore need to be well designed and strong as ferrets will exploit any opportunity to escape.

Strains and Stocks

Most ferrets utilised for laboratory studies are males due to oestrous related health problems associated with females (see Reproductive disease section below). Female ferrets are induced ovulators and can develop severe hyperoestrous if not mated. Laboratory ferrets are often purchased pre-castrated and 'de-scented' (i.e. anal gland sacculectomy).

Due to the small number of laboratory ferrets compared to species such as mice, there are no specific strains/stocks commonly used. Researchers often request natural wild-type colour patterns (called sable or fitch) which is often in contrast to the various coat colour variations found in domestic populations. Some studies have also utilised albino ferrets due to their specific genetic properties.

Physiology

Most physiological data for ferrets is very similar to that of the domestic cat. Ferrets are obligate carnivores that typically have a total length of ~50cm (with a ~13cm tail) and weight between 0.7 - 2kg. Ferrets have a natural life span of between 7 - 10 years and males are substantially larger than females, with males up to 2kg and females up to 1.2kg. Ferrets become sexually mature at around 4-6 months, usually occurring in the first spring after birth.

Ferret gestation is 42 days and litters usually contain between 3-7 young. The litter are usually weaned between 3 - 6 weeks and are totally independant of the parents at 3 months. Females can have up to 3 litters annually.

Ferrets are crepuscular and therefore they spend between 14-18hrs per day asleep and are most active around dawn and dusk. Ferrets have scent glands near their anus which are used for scent marking. Ferrets have also been shown to use urine marking.

Anatomy

This section has been included to allow familiarisation with the peculiarities of ferret anatomy to provide a context for some of the disease and pathological headings found below. Therefore only anatomical areas with specific features warranting emphasis have been included below;

Digestive System

As ferrets are obligate carnivores, they require a diet containing high levels of fat and protein. High quality cat food or kitten food is commonly used. Adult ferrets also have comparatively large spleens which is often caused by extramedullary haematopoiesis, although this is non-pathogenic.

Diseases

For ease of use, the diseases of ferrets listed below are by body system, or where this is not appropriate in an “Other” category displayed after the body system sections. Those diseases listed below are not exhaustive but rather highlight common diseases encountered with laboratory ferrets.

Nervous System

Canine Distemper
This morbillivirus is essentially 100% fatal in ferrets and disease progression can range from 12 to 42 days. This disease is immunosuppressive and animals die from neurologic dysfunction. Treatment is not recommended. There is one approved distemper vaccine in the US (Fervac-D) which is commercially produced. The presence of suppurative bronchopneumonia in young ferrets is suggestive of this disease.

Gross lesions will be similar to those found in canines. Animals will suffer photophobia (excessive sensitivity to light). Gross lesions will include oculonasal discharge, hyperkaratosis of the planum nasale and footpads, papular rashs around the chin and bronchopneumonia. Microscopic lesions will include brightly eosinophilic intracytoplasmic and intranuclear inclusions often in epithelial cells, neurons, WBCs and megakaryocytes. (Studies have shown that the biliary epithelium, urinary bladder and renal pelvis are the most productive places to look for these inclusions. A non-suppurative encephalitis with de-mylination may also be seen.

Rabies
Although the incidence of rabies in ferrets is low, rabies still represents a risk for ferrets, often causing hind limb paralysis. In the US there is currently a commercially available rabies vaccine (Imrab).

There are no gross lesions associated with rabies. Microscopic lesions will include intracytoplasmic eosinophilic viral inclusions, called Negri bodies. These can be demonstrated on HE stains or via standard fluorescent antibody tests.

Neural Tube Defects
NTDs are the most common birth defect in ferrets ranging from cranioschisis (external opening of the skull) to spina bifida. Many variations in defects can be seen.

Gross lesions can include agenesis of the skin and musculature overlaying various areas of the skull and/or the spinal cord. There is also often a degree of nerual tissue loss associated with these lesions. Microscopic lesions can include fusion or deformation of the vertebrae.

Endocrine System

Islet Cell Tumors
Islet cell tumors are the most common form of neoplasia in ferrets and generally result in hypoglycemia as a result of inappropriate insulin secretion. Clinical signs will include lethargy, stupor, ataxia, coma and eventually death. Non-functional islet cell tumors are usually seen in older animals at necropsy. These tumors are all potentially malignant but few are metastatic, which is in contrast to islet cell tumors in canines and felines.

Gross lesions will include reddish-brown islet cell tumors that have well defined nodules ranging in size from 2mm to 1cm. Tumors will be firmer than surrounding pancreatic tissue and they can be multiple. Islet cell tumors must be differentiated grossly from the foci of pancreatic exocrine hyperplasia which is also a common benign age-related finding in ferrets. (Foci of pancreatic exocrine hyperplasia are generally the same colour and consistency as surrounding tissue whereas tumors are noticeably different from surrounding tissues). Microscopic lesions will include an unencapsulated tumor and often greatly enlarged islets of Langerhans. Identical foci may be present on surrounding mesentery.

Adrenal-Associated Endocrinopathy
AAE is a common disorder of middle aged and older ferrets and is a result of proliferative lesions in the adrenal cortex which secrete excess amounts of estrogenic hormones. This causes ferrets to exhibit a range of cutaneous, behavioural and reproductive signs and is technically a form of hyperadrenocorticism (although should not be confused with Cushing's disease). Only rarely are cortisol levels elevated. Metastasis can occur extremely late in the course of the disease resulting in adrenocorticol carcinoma. This is in contrast to the usual progression of the disease in dogs and cats.

Gross lesions will include bilaterally symmetrical alopecia beginning over the tailhead and progressing cranially over the flanks and abdomen. The presence of an enlarged vulva in a spayed female is also strongly suggestive of AAE. The normal length of ferret adrenal glands is 3-5mm. Glands exceeding 5mm will often contain proliferative lesions. Approximately 45% of these will be carcinomas, 45% will be hyperplasia and 10% adenomas. Diameters exceeding 1cm is highly suggestive of adrenocortical carcinoma. In cases of adrenal malignancy, metastasis often occurs late in the course of the disease and ferrets are more likely to die from vascular haemorrhage as a result of tumor necrosis in a large adrenal malignancy rather than as a result of metastatic disease. Microscopic lesions will include proliferative lesions within the adrenal cortex that can be catagorised into three stages; hyperplasia, adenoma and carcinoma. The presence of necrosis, cellular atypia and a high mitotic rate are suggestive of malignancy. The presence of a single nodule within the adrenal cortex without any other factors associated with cancer may indicate adenoma. The presence of multiple nodules without any other factors associated with cancer may indicate cortical hyperplasia.

Diabetes Mellitus
Diabetes mellitus is an uncommon disease in ferrets. Affected animals can have blood glucose levels ranging from 500-725g/dl. Polydipsia, polyuria, glucosuria and loss of body condition are suggestive clinical symptoms.

There are no gross lesions associated with diabetes mellitus. Microscopic lesions may include glycogenic vacuolation of the islets of Langerhans and this is the most indicative lesion for diabetes mellitus. Glycogen accumulation may also be seen in renal tubular epithelium. It has also been noted in some cases that ferrets may have lenticular (cloudy) cataracts.

Hematolymphatic System

Splenomegally
This finding is extremely common in ferrets, although the causes are unknown. It is most common in middle to old age ferrets but has been reported in animals from six months old. The incidence of neoplasia in splenomegally is less than 10%. However, marked enlargement of the spleen increases the spleen's phagocytic capability resulting in increased RBC breakdown. In chronic cases, anemia may occur.

Gross lesions will include enlarged spleens ranging up to 10cm in length. Most spleens will be diffusely enlarged whilst a small number will contain single or multiple discrete nodules which are likely to represent splenic neoplasms. Microscopic lesions include a combination of marked congestion and extramedullary haematopoiesis from erythrocytic, leukocytic and megakaryocytic cell lines in 95% of cases. There may also be large areas of coagulative necrosis which is often bordered by a combination of viable and degenerate neutrophils and various levels of granulation tissue. Enlarged spleens are prone to rupture and therefore there may be various signs of splenic trauma including haematoma, siderotic plaques and large areas of parenchymal fibrosis.

Lymphosarcoma
Lymphosarcoma is the most common form of malignancy in ferrets. These neoplasms usually arise spontaneously, although recently some degree of horizontal transmission has been suggested. There are several variants of lymphoma in ferrets. The most common form is where the neoplastic cell is a mature, well-differentiated lymphocyte primarily resulting in peripheral lymphadenopathy with visceral spread and a subsequent organ failure. This form usually occurs in older ferrets. A second form of lymphoma that usually occurs in younger ferrets is where the neoplastic cell is a large blastic lymphocyte characterised by early visceral neoplasms and is almost always concurrent with the production of a large thymic mass. A third uncommon form is characterised by combinations of peripheral lymphadenopathy, visceral neoplasms and numerous bizarre lymphoblasts. This third form is known as the immunoblastic polymorphous variant.

Gross lesions in the adult (lymphocytic) form include a diffuse lymphadenopathy. The splenic white pulp may be enlarged and visible grossly on a cut section. During later stages, firm white nodules may be seen within visceral organs including the liver and kidneys. The spleen may also be diffuse and enlarged. Gross lesions in the juvenile (lymphoblastic) form include the presence of a thymic mass. There may also be hepatosplenomegaly due to the infiltration of these organs by neoplastic cells. Neoplastic cells can be found in any organ including bone marrow.

Microscopic lesions in the adult form (lymphocytic) can be seen by undertaking biopsy of peripheral lymph nodes. These will reveal effacement of the normal lymph node architecture by an infiltrate of small non-cleaved lymphocytes which breach the capsule and reach into the surrounding tissue. There may also be "tingible" (found in lymph nodes) macrophages scattered throughout the node. Neoplastic infiltrates can also be found in the portal areas of the liver. In the juvenile form (lymphoblastic), the examination of visceral organs will reveal effacement of any normal architecture by a monomorphic population of large cleaved and non-cleaved lymphoblasts. In the liver neoplastic cells can often be seen as discrete nodules.

Aleutian Disease
Aleutian disease is caused by a parvovirus and results in hypergammaglobulinemia and in late stages glomerulonephritis, although the disease can take up to two years for this to occur. In the late stages of the disease, ferrets will be hyperproteinaemic with this being almost totally made up of gammaglobulins.

Gross lesions can only be seen in the late stages of the disease with splenomegaly and lymphadenopathy the most common signs. Enlarged brown-tan kidneys may also be present. Microscopic lesions can include prominent plasmacytic infiltrates seen in numerous organs but particularly in the renal interstitium, hepatic portal areas and in the splenic red pulp. In addition there may also be marked plasmacytosis of numerous lymph nodes and the bone marrow. In the majority of cases there will also be membranous glomerulonephritis. Vasculitis can also be seen in almost any organ.

Integument System

Neoplasia
Neoplasia is the most common skin problem in ferrets, where the incidence of neoplasia increases with age. There are a wide range of types of skin neoplasia found in ferrets with the two most common being sebaceous epithelioma and mast cell tumors. Dermal leiomyomas/leiomyosarcomas are also commonly seen in ferrets and commonly arise from smooth muscle associated with hair follicles (piloeimyomas). This condition most commonly affects the back and neck areas but can also be found anywhere on the body.

Gross lesions for sebaceous epitheliomas will appear as warty, verrucous lesions that can arise anywhere on the animal's body, but are most often seen on the head and neck. Microscopic lesions for sebaceous epitheliomas will include an unencapsulated neoplasm composed of basal cells of which a small percentage will exhibit sebaceous and or squamous differentiation. These cells are reported to have no features of malignancy or metastatic abilities. Gross lesions for mast cell tumors will appear as flat, alopecic, hyperkeratotic plaques which are variably pruritic. Microscopic lesions will include a well demarcated, unencapsulated neoplasm that is commonly confined to the superficial dermis and will be composed of well differentiated mast cells. Small numbers of eosinophils will be scattered throughout the neoplasm. Vasculitis and/or collagen are rarely seen. Gross lesions for leiomyomas are often well encapsulated but have no metastatic potential.

Dermatomycosis
This disease is uncommon in ferrets but may occur in either young, old or immunosuppressed animals kept in poor conditions. Microsporum canis and Trichophyton mentagrophytes have been reported as causative agents.

Gross lesions include areas of crusting alopecia with brittle hair and broken hair shafts. In immunosuppressed animals, any associated rashes can become generalised. Microscopic lesions from biopsies taken from affected sites will include a thick layer of keratin debris, degenerate neutrophils and fungal arthrospores with hyphae. There will be ulceration of the skin and hair follicles will often contain numerous fungal arthrospores which can occasionally invade the hair shaft. Many follicles will not contain a hair shaft at all and will contain only lamellar keratin debris. There may also be a generalised neutrophilic or lymphoplasmacytic dermal infiltrate in perivascular and periadnexal areas.

Ectoparasites
Ferrets are most commonly infected with two ectoparasites; ear mites (Otodectes cynotis) and fleas (Ctenocephalides sp.). Sarcoptic mange has also been reported in ferrets and comes in two forms; a very pruritic whole-body form and a variably pruritic form localised to the feet. Demodectic mange is also seen in ferrets, although mainly in older or immunosupressed ferrets.

Gross lesions regarding ear mites will include large amounts of a thick black-brown wax. Swabs should be examined microscopically for the presence of adult mites and/or their eggs. Gross lesions relating to sarcoptic mange are characterised by swollen feet, evidence of self-mutilation and nail loss. Microscopically, mange lesions will include marked ulceration and hyperkeratosis of the skin. There may also be some cross sections of mites in the epidermis or deep under the overlying crust. Skin scrapings may microscopically demonstrate demodectic mange via the presence of nymphs or adults. Skin biopsies should reveal moderate hyperkeratosis and the presence of mites (cigar shaped) within the hair follicles.

Pemphigus foliaceous
This disease in ferrets has similar symptoms to those in other species.

Gross lesions include generalised eruptions and vesicular lesions. These lesions are most commonly intracorneal pustules containing rafts of acantholytic (loss of cohesion), a thickened epidermis and prominent superficial lymphocytic and eosinophilic dermatitis.

Reproductive System

Oestrous-associated Aplastic Anemia
As ferrets are induced ovulators, intact females will remain in oestrous until mated or spayed. Half of un-mated jills will develop marked bone marrow suppression as a result of these high levels of oestrogen. Erythrocytes, leukocytes and megakaryocytes will all be affected. During the early stages, there will be mild thrombocytosis and leukocytosis but in cases that have progressed there will be a non-regenerative anaemia, leukopenia and thrombocytopenia. A liver-associated clotting abnormality has also been reported with oestrous-associated aplastic anemia.

Gross lesions will include a prominently swollen vulva. Associated signs of hyperoestrogenism will include pale mucus membranes, alopecia, thin watery blood, haemorrhages throughout the body, pyometra, bronchopneumonia and vaginitis. Microscopic lesions will include aplastic anemia (PCV <20%). Characteristic lesions will include hypocellularity of the bone marrow and some evidence of haemorrhage in lymph nodes and spleen. Supparative metritis or pneumonia may also be seen as a result of the leukopenia.

Mastitis
Mastitis is occasionally seen in pregnant jills during the first few weeks of lactation with haemolytic E. coli being the most commonly isolated causative organism. This usually results in gangrenous mastitis and if untreated jills can become septic and/or endotoxemic. Staphylococcus aureus has also been suggested as another potential causative agent, although this infection produces more of a supparative and less necrotic form of mastitis.

Gross lesions will include swelling in any affected teats that may also appear necrotic, black, firm and non-painful. If this causative agent is Staphylococcus aureus, the mammary glands will be hot, painful, reddish and purulent exudate may be expressed from the lactiferous ducts. Microscopic lesions associated with E. coli will include diffuse severe coagulative necrosis that often extends into the adjacent adipose tissue and muscle. There will be large pockets of haemorrhage and oedema together with numerous bacteria. Areas of infarction will be demarcated with a line of degenerate neutrophils and cellular debris. Vascular thrombosis may also be seen. Other microscopic signs of sepsis/endotoxaemia may be seen including margination of neutrophils in the pulmonary capillaries and hypertrophy of Kupfer cells with hepatic sinusoids. Microscopic lesions regarding Staphylococcus aureus infections may include less evidence of infarction, although a purulent galactophoritis and mastitis will be present along with numerous bacteria.

Urinary System

Bacterial Urinary Tract Infections
These infections are commonly seen in female ferrets and not in males. The common causative agents are E. coli and Staphylococcus aureus. Bladder infections are often sub-clinical in females and infections commonly ascend resulting in pyelonephritis. Renal failure can result from a severe pyelonephritis infection.

Gross lesions can include hydronephrosis and hydroureter in long-standing infections but there are often no lesions grossly. Microscopic infections include ulcerative cystitis and/or a supparative tubulointerstitial nephritis. Bacteria are rarely seen.

Prostatic Squamous Metaplasia
Squamous metaplasia of the prostate has only recently been recognised as a common cause of dysuria and urethral blockage in ferrets. The squamous change within the prostate is due to excess estrogens caused by proliferative adrenal lesions (see endocrine section). Accumulation of secretory material and lamellated keratin results in the formation of porstatic cysts. The impingement of these cysts upon the prostatic urethra results in dysuria and in some cases complete blockage. Surgery is commonly required.

Gross lesions include single to multiple fluctant cysts present near the bladder trigone. Cysts will be thick-walled and firm. Concurrent confirmation of enlarged adrenal glands or adrenal neoplasm is often possible. Microscopic lesions will include atrophic prostate glands around the periphery of the cysts. Cyst walls will consist of multiple layers of squamous epithelium surrounded by variable levels of fibrous connective tissue. The luminal contents of the cysts can contain material ranging from keratin debris to purulent inflammatory material.

Urolithiasis
Male ferrets are more likely to develop uroliths than females, although females can also develop uroliths. Cat food diets that are high in ash have been sighted as a major cause. Clinical signs will include licking of the genital area, dysuria, anuria and occasionally haematuria. In jills pregnancy may increase the risk of developing uroliths due to the effect of oestrogens on the metabolism of calcium and phosphorus.

Gross lesions may include single or multiple uroliths in the bladder or more rarely the renal pelvis. Struvite uroliths are the most commonly reported type.

Renal Cysts
Renal cysts are a common finding in ferrets, although they rarely have any affect on renal function. Polycystic kidneys are found in ferrets but very rarely. Polycystic kidneys are enlarged and often can be felt on external palpation. Polycystic kidneys can result in kidney failure.

Gross lesions may include single or multiple cysts present within the cortex of one or both kidneys. Cysts may range up to 1cm in diameter. Polycystic kidneys may be markedly enlarged and fill the posterior abdomen. Microscopic lesions can include thick walls of fibrous tissue surrounding cysts resulting in numerous atrophic glomeruli and tubules.

Chronic Interstitial Nephritis
Chronic interstitial nephritis is a common finding in ferrets and lesions can be seen as early as age two. Advanced cases may result in renal failure and can occur as early as age four. The progression of this disease is very similar to that found in older cats.

Gross lesions will include pitted kidneys with large focal depressions in the outer cortex, formed as a result of scar tissue. Removal of the renal capsule during necropsy is recommended. The size of the kidneys may also be asymmetric. Microscopic changes associated with this disease in ferrets are unique. At low magnifications there will be linear bands of fibrosis extending from the outer capsule towards the medulla. Where these fibrotic changes have occurred, tubule and glomerular changes will also be visible. There will be glomerularsclerosis within the periglomerular region. The intersititium of the kidney will also contain fibrotic tissue together with moderate numbers of lymphocytes and plasma cells. These microscopic findings are very similar to chronic infarction. Areas of fibrosis tend to coalesce into large areas on non-functional glomeruli and tubules.

Cardiovascular System

Cardiomyopathy
Several forms of this disease can be seen in ferrets; dilative, hypertrophic and a restrictive form where there is marked replacement of the myocardium with fibrous connective tissue. Signs of myocardiopathy can be seen as early as age one but are most common between age five and seven.

Gross lesions in sub-clinical cases may include a congested and occasionally nodular liver, the heart may be enlarged and the right ventricle may appear thin or flabby. In severe cases gross lesions may include an accumulation of serosanguinous ascitic transudate in the abdominal cavity and/or the pleural cavity. The lungs may also be atelectatic (lack of gas exchange within alveoli, due to alveolar collapse or fluid consolidation) and compressed by the heart. There may also be significant pleural effusion. Microscopic lesions in early cases will include an increase in fibrous connective tissue around myocardial vessels that may extend into the interstitium. In advanced cases there will be atrophy and loss of myocytes. Within focal areas of myocyte denegeration there may also be moderate numbers of macrophages, lymphocytes, plasma cells and rare neutrophils. Signs of liver congestion such as fibrosis will may also be present. In terminal cases there may be necrosis of centrilobular hepatocytes due to stasis and hypoxia.

Dirofilariasis
Although uncommon, ferrets are susceptible to heartworm infection. Due to the relatively small size of the ferret heart, as little as two worms may result in fatal cardiac insufficiency.

Gross lesions will include the presence of heartworms within the right ventricles and pulmonary artery and can be construed as the cause of death of any ferret in which they are found. Microscopic lesions will include normal signs expected with heart failure.

Respiratory System

Endogenous Lipid Pneumonia
This condition is also known as "foam cell foci" or "subpleural histiocytosis". This is often a common necropsy finding in mustelid species, although it is of no clinical significance. This condition is often mistaken by pathologists as a dissemination neoplasm. The cause of this condition and the origin of the lipid is unknown.

Gross lesions will include multiple foci that coalesce to form a white to yellow subpleural pulmonary parenchyma. This parenchyma is of a very superficial nature. Microscopic lesions will include an aggregation of lipid-laden macrophages in the alveoli immediately subjacent to the pleura. Larger lesions will include moderate numbers of lymphocytes and cholesterol clefts.

Aspiration Pneumonia
Aspiration pneumonia is the most common cause of pneumonia in ferrets and is caused by either oral drug administration or vomiting. This is particularly common when administering oral drugs to ferrets due to their tendancy to fight/wriggle during administration.

Gross lesions will include consolidation of the cranioventral lung lobes, either uni or bi-laterally. The severity of the lesions will be proportionate to the length of time since the aspiration occurred. In most cases minimal lesions will be visible but in severe and long-standing cases gangerenous, cavitated lesions may be seen within the pulmonary parenchyma. Microscopic findings may include primary lesions within the small airways. Bronchioles may contain a variable mixture of viable and degenerate neutrophils, sloughed epithelial cells and enosinophilic proteinaceous material (particularly if the aspirate is vomit based). There may also be a foamy accumulation of macrophages in surrounding alveoli. In long-standing cases there may be a pronounced granulomatous response with numerous foreign bodies. Where vomit has been aspirated there may also be extensive necrosis of the airways and surrounding alveoli with sloughing of the bronchiolar epithelium.

Influenza
Ferrets are the only domestic species that are susceptible to human influenza viruses which, as mentioned in the introduction, is why they are a key laboratory animal. As a result, infection from human to animal is possible. Clinical signs are similar to those in humans including photophobia, a catarrhal nasal discharge, sneezing, coughing, pyrexia, anorexia and malaise. The disease is rarely fatal.

Gross lesions are minimal but may include congestion and exudation of the nasal mucosa and mild reddening of the tracheal mucosa. Microscopic lesions may include a mild sub-acute inflammation and occasional necrosis of the nasal mucosa. A mild sub-acute interstitial pneumonia may also be present.

Digestive System

General GI

Dental Disease
The two most common dental diseases of ferrets are periodontal disease and fractured teeth (common in older ferrets), particularly the upper canines. In fractured teeth, if the tooth pulp is exposed, extraction or root canal procedures are required. Tooth root abscesses are common in ferrets as well as dental malformations including supernumerary teeth. Periodontal disease can present (rarely) in immunosuppressed animals such as those on long-term immunosuppressive drugs. Accumulation of dental calculi is also common in older animals.

Gross lesions for damaged teeth will include discolouration of broken teeth which suggests devitalisation.

Megaoesophagus
The cause of megaoesophagus in ferrets is currently unknown, although its clinical presentation is similar to that found in dogs and cats. In some cases a secondary infection with Candida sp. may been seen. This condition most commonly occurs in middle aged ferrets and any treatment is usually ineffective.

Gross lesions will include a marked dilation of the intrathoracic oesophagus together will ulcerations anywhere along it's length. Concurrent bronchopneumonia may also be present due to aspiration. Microscopic lesions are often inconclusive but can include muscle atrophy, hyperkeratosis of the epithelial lining and yeast within the mucosa resulting in a lymphocytic and neutrophilic inflammatory response.

Gastric Ulcers
Ferrets are very susceptible to stress-related gastric ulcers. These are often associated with Helicobacter mustelae infections, see bacterial GI section below. Large ulcers may result in sudden death due to erosion of sub-mucosal blood vessels.

There are two distinct types of gastric ulcer in ferrets. The most common is associated with the presence of digested blood in the lumen of the stomach. All types of ulcers will be pin point and difficult to see with the naked eye. They will be in highest numbers in the pylorus. Microscopic ulcer lesions will appear as full thickness areas of glandular necrosis and loss which are well demarcated from the surrounding tissue. Bleeding ulcers will be coated with a layer of brown haemoglobin pigment.

Inflammatory Bowel Disease
IBD is very common in middle to old age ferrets and generally falls into two categories; a lymphocytic/plasmacytic form and an eosinophilic form (also known as eosinophilic gastroenteritis). The causes of IBD are multifactorial and the nature of the disease is an uncontrolled inflammatory reaction in the intestine. Strong evidence exists that infections by helicobacter mustelae and ferret coronavirus may eventually result in this condition.

Gross lesions are not normally associated with IBD, aside from generally inflammed GI tract lining. Microscopic lesions will include small to moderate numbers of lymphocytes, plasma cells and eosinophils, mainly within the small intestine. Lymphocytic forms of IBD are associated with intramucosal lymphocytes and villi atrophy, blunting and fusion. Microscopic lesions associated with the eosinophilic form include eosinophilic infiltrates within the small intestine. Additionally, prominent eosinophilic infiltrates may be seen in the mesenteric lymph nodes, liver, pancreas or other abdominal organs.

GI Foreign Bodies
Foreign bodies are commonly seen in young or bored, cage-bound ferrets. They will commonly ingest latex, plastic, foam rubber, towels or other forms of bedding. Anorexia and passage of abnormal stools are common clinical signs.

Gross lesions will include a focal area of abdominal distention with or without haemorrhage. The wall of the intestines at the site of blockage may be thinner than that of the adjacent intestine due to continuous peristaltic movements at the site of blockage. In rare cases, intestinal perforation may be seen. Microscopic lesions may include ulceration, necrosis and thinning of the muscular layers at the site of blockage. In longstanding blockages there will be marked attenuation of villi and granulation tissue.

Neoplasia
The most common form of GI tract neoplasia is lymphosarcoma. The lymphoblastic form of lymphosarcoma is the most common for in the intestine.

Bacterial Infections

Helicobacter mustelae
This bacterial infection can cause disease in significant numbers of ferrets over the age of four via two gastri mechanisms. It can cause stimulation of the lymphoplasmacytic inflammatory response resulting in a loss of granular epithelium, mainly in the pylorus. Secondly this infection has the ability to increase the pH of the stomach. Helicobacter can also be found in the stomach and duodenum of almost all ferrets after weaning. If there are sufficient numbers, this infection can induce chronic, persistant gastritis, ulcer formation and in extreme circumstances gastric lymphoma can occur. Animals over three years of age will rarely show clinical symptoms with a Helicobacter infections.

There are often no gross lesions associated with uncomplicated cases of Helicobacter. Advanced cases may include gastric ulcers and where these occur the gastric mucosa is often lined by moderate amounts of digested blood. Microscopic lesions will include the presence of bacteria in the superficial mucus and in extracellular locations within the gastric glands. The pyloric stomach is the preferred biopsy site.

Proliferative Colitis
Proliferative colitis is uncommon in ferrets but is usually seen in male ferrets under the age of one. This disease can be sporadic and may be present in only one or two animals within a large colony. Clinical signs can include tenesmus and production of small, frequent bowel movements that will contain blood and mucus. Proliferative colitis is caused by a campylobacter-type organism resulting in asymmetrical proliferation of immature epithelium and thickening of the gut wall. This disease is also associated with stress and if untreated can be fatal.

Gross lesions will include noticeable thickening of the colonic wall which will be opaque, rather than being able to see fecal matter through the wall. The mucosa will be prominently "cobblestoned". Microscopic lesions will include a mucosa that is thickened by up to five times via a proliferation of immature epithelial cells with vesicular nuclei and basophilic cytoplasm. There will also be a marked decrease in goblet cells.

Clostridium perfringens
Clostridium perfringens type A has been reported in black-footed ferret kids.

Gross lesions will include gastric bloat and multifocal intestinal haemorrhage. Microscopic lesions will include marked coagulative necrosis of the intestinal mucosa with numerous adherent bacilli.

Mycobacterium avium
This is a rare infection in ferrets but is most commonly seen in the GI tract and mesenteric lymph nodes. Having said that, macrophages containing the infectious organism have been shown to be able to accumulate in any organ.

Gross lesions are mainly related with mesenteric lymphadenopathy. Microscopic lesions can include the presence of large foamy macrophages with a grayish granular cytoplasm and acid-fast stains may reveal numerous bacilli within these macrophages.

Viral Infections

Epizootic Catarrhal Enteritis
ECE is a coronavirus found in ferrets that can cause epizootics of high morbidity (up to 100%), but low mortality. This infection usually results in diarrhoea that is rapidly dehydrating and can cause mortality in older animals, especially with a concurrent illness. Clinical symptoms will include vomiting and dark green stools with abundant mucus.

There are generally no associated gross lesions although the intestine may be flaccid and contain watery ingesta. For examination of microscopic lesions, tissue samples should be taken from 3-4 different areas of the jejunum as well as other areas of the GI tract. Lesions will include vacuolar degeneration and necrosis of apical enterocytes with marked villi atrophy, fusion and blunting. In severe cases, there is a marked lymphocytic enteritis with large numbers of lymphocytes among mucosal epithelial cells.

Intestinal Parasites

Intestinal parasites are uncommon in ferrets with the exception of coccidia. Toxocara cati, Toxacaris leonina, Ancylostoma sp., Dipylidium caninum and Giardia sp. have all been reported in ferrets. Coccidial species reported in ferrets include Eimeria furo, Eimeria ictidea and Isospora laidlawii. Most coccidial infections will be sub-clinical. Lethal coccidial infections are mainly seen in young kids, although this is rare.

Gross lesions are generally not visible but may include the presence of digested blood in the GI tract of kids with severe infections. Microscopic lesions will include numbers of parasites ranging from low to extremely high depending on the severity of the infection. All stages of the parasite including micro and macrogamemetocytes can be seen. Coccidial infections have also been reportedly found in the hepatobiliary system.

Musculoskeletal System

Chordoma
Chordomas are the most common form of musculoskeletal neoplasm in ferrets and arise either in or adjacent to vertebra from remnants of the primitive notochord. These most commonly occur in the tip of the tail but have been reported in the cervical area. Chordomas are considered potentially malignant although metastasis has not been reported in neoplasms arising in the tail.

Gross lesions from chordomas are usually seen as club-like swellings at the tip of the tail, involving the last caudal vertebrae. Cervical chordomas often present as lytic neoplasms together with posterior paralysis. Microscopic lesions will manifest as locally aggressive neoplasms often infiltrating the vertebral bodies. The neoplasm itself will usually be composed of foamy "physaliferous cells" (having vaculoes) which are seperated by a moderate amount of myxomatous matrix (weakening of connective tissue). There may also be multifocal areas of well-differentiated cartilage and bone within the neoplasms.

Polymyositis Syndrome
This syndrome is a recent discovery in ferrets and usually affects ferrets of less than one year old. Clinical symptoms are non-descript but can include persistent high fever, leukocytosis, hindlimb weakness, paresthesia, occasional abscessation of one or more peripheral lymph nodes (usually in hind legs), wasting, difficulty swallowing and ultimately death. Morbidity associated with this syndrome is low whilst mortality is high. Research has currently failed to find a causative agent.

Gross lesions may include suppurative inflammation of the thorax with inflammation of the oesophagus the primary finding. Other gross lesions may be minimal in most cases but can include chronic wasting and associated muscle loss and mottling with multifocal oesophageal haemorrhage. More acute cases may have swelling of the peripheral lymph nodes, most commonly the popliteal lymph nodes. Microscopic lesions may histologically resemble a bacterial infection of the thorax with large numbers of neutrophils infiltrating the pleura, thoracic lymph nodes and oesophagus. Oesophageal lesions will include neutrophil infiltration into the serosal and muscular layers eventually resulting in widespread necrosis and loss of muscle tissue, dysphagia and death. In some cases, suppurative inflammation of the peripheral lymph nodes and surrounding muscle and fat may be seen.

Other

Cataracts
No definitive cause has been found for cataracts in ferrets and many cases are thought to be spontaneous. Cataractous changes may also be seen in diabetic animals but often due to the short life span of ferrets, grossly visible cataracts are not common.

Gross lesions will involve both the cortex and nucleus of the lens. Microscopic lesions will include the formation of balloon cells in the outer cortex initially, then progressing towards the nucleus of the lens.

Neoplasia (Other than described above)
Neoplasms represent approximately 60% of surgical biopsies in ferrets with the majority being islet cell tumors, adrenal neoplasms, chordomas and skin tumors, all mentioned in the relevant sections above. There are others that are worth mentioning here. Testicular neoplasms are usually interstitial cell tumors and are often a combination of two or more neoplasms. The removal of cryptorchid testicles is very important in ferrets as at least one one neoplasm will always be found on a retained testicle. Ovarian neoplasms are tumors of germ cells or stromal cells. The second most commonly seen neoplasms are Gastrointestinal neoplasms. These are usually tumors of smooth muscle origin. Low-grade leiomyosarcommas are most commonly seen although mesotheliomas are sometimes seen in the peritoneum and serosal surfaces of ferrets. These mesotheliomas are locally aggressive and will result in marked abdominal effusion and often have a poor prognosis. Pancreatic exocrine adenocarcinomas are also found and these are also locally aggressive neoplasms. Within the musculoskeletal system, Osteomas have also been reported, arising from flat bones. These are expansile neoplasms composed of trabecular, well-differentiated bone and lined by osteoblasts. Apocrine cysts are also a common finding within the integumentary system of ferrets. These most commonly occur around the head, neck, prepuce and vulva due to the large number of scent glands in these areas. Apocrine gland carcinomas are also not uncommon and have a similar distribution. Apocrine carcinomas are locally aggressive neoplasms with a moderate potential for metastasis.