Pathology of the Domestic Ferret
(Mustela putorius furo L.)
Bruce H. Williams, DVM, DACVP
Department of Veterinary Pathology
Armed Forces Institute of Pathology
Email: Williams@afip.mil
General References:
Nervous System
Synopsis: Canine distemper is the most serious disease in ferrets. Essentially 100% fatal, the morbillivirus that causes canine distemper results in an accelerated syndrome that closely mimics signs seen in canids and other susceptible species. Disease progression ranges from 12 days in ferret-adapted strains to approximately 42 in wild canine strains. The disease is profoundly immunosuppressive, with animals that survive this stage of the disease succumbing to neurologic dysfunction within several weeks. This disease in the U.S. is primarily seen in young kits from pet stores. Treatment is not recommended. Currently, there is one approved distemper vaccine for ferrets (Fervac-D, United Vaccines), however, many commercial modified live canine vaccines are used in ferrets.
Gross lesions: Similar to those seen in the dog. Photophobia, oculonasal discharge, hyperkeratosis of the planum nasale and footpads, a papular rash beginning on the chin and progressing to a generalized form, bronchopneumonia.
Microscopic lesions: Brightly eosinophilic, 2-5 um intracytoplasmic and intranuclear inclusions may be seen in a wide variety of epithelial cells, neurons, and occasionally in white blood cells and megakaryocytes. (The urinary bladder, renal pelvis, and biliary epithelium in my experience are the most productive places to look for inclusions.) Additionally, multinucleate cells may be found in any of these sites. A non-suppurative encephalitis with demyelination may be seen in animals with neurologic disease. The presence of suppurative bronchopneumonia in a young ferret is suggestive of this disease.
Additional references:
Synopsis: Ferrets are susceptible to rabies as are any other mammals. Ferrets, however, have a low recorded incidence of rabies, with less than 25 confirmed cases since 1954. The disease can result in both furious (less common) and dumb forms, and may present as a progressive hindlimb paralysis. Researchers have shown that ferrets inoculated IM with virulent rabies virus do not secrete the virus in their saliva. Currently, there is one approved killed rabies vaccine available for use in the ferret (Imrab, Rhone-Merieux).
Gross lesions: None.
Microscopic lesions: Intracytoplasmic eosinophilic viral inclusions (Negri bodies) may be demonstrated on HE stains or on standard fluorescent antibody tests.
Additional references:
Synopsis: NTD's are one of the most common birth defects in ferret kits. They may range from simple cranioschisis (external opening of the skull), to spina bifida, to craniorachischisis (opening of the skull and vertebral column with loss of cerebral tissue). Many variants are seen. Additionally, growth retardation and other birth defects (kidney defects appear commonly) may be seen in the fetus.
Gross lesions: Agenesis of skin and musculature overlying various segments of the skull and/or spinal cord, with variable loss of neural tissue.
Microscopic lesions: See Gross lesions. Additionally, there may be fusion or other deformation of the vertebrae. With cranioschisis or craniorachischisis, there is often agenesis of the cerebrum and cerebellum, with a rudimentary medulla (cerebrovasculosa) remaining.
Additional reference:
Gastrointestinal System
Synopsis: Broken teeth are common in older ferrets, most commonly affected are the upper canines. While few broken teeth result in clinical debility, exposure of the pulp requires extraction or root canal procedures. Accumulation of dental calculi is common in older ferrets on semi-moist or moist diets. Tooth root abscesses are occasionally seen in ferrets. Dental malformations, including supernumerary teeth or decreased numbers of adult teeth have also been documented.
Gross lesions: Discoloration of broken teeth suggests devitalization. Draining tracts may be seen, especially in the area of the zygomatic arch with tooth root abscesses.
Microscopic lesions: N/A
Additional references:
Synopsis: The cause of megaesophagus is currently unknown in the ferret. It presents similarly to megaesophagus in the dog and cat. Occasionally, secondary Candida infections may be seen. The condition occurs in middle-aged to older ferrets, and treatment is usually ineffective.
Gross lesions: Marked dilation of the intrathoracic esophagus. Ulcerations may be present anywhere along the length. Evidence of bronchopneumonia may be present due to aspiration.
Microscopic lesions: Often none. In chronic cases, there may be discernable atrophy of the muscular layers. In other cases, there may be hyperkeratosis of the lining epithelium, and the presence of numerous yeast within the mucosa, inciting a lymphocytic and neutrophilic inflammatory response.
Additional reference:
Synopsis: This bacterium, recently discovered by James Fox et al. at MIT, causes disease in significant numbers of ferrets over the age of four years. The bacterium causes gastric disease via two mechanisms - a) the stimulation of a marked lymphoplasmacytic inflammatory response, resulting in loss of glandular epithelium, most prominently in the pylorus, and b) the ability to increase the pH of the stomach. Animals over the age of 3 years rarely do not show evidence of Helicobacter infection.
Gastric ulcers are also commonly seen in animals with severe Helicobacter infection. (see below)
Gross lesions: There are often no gross lesions in uncomplicated cases of gastric Helicobacter. Advanced cases may be coupled with gastric ulcers. In these cases, the gastric mucosa is often lined by moderate amounts of digested blood; gastric ulcers are often fine bleeding points concentrated in the pylorus.
Microscopic lesions: Warthin-Starry 4.0 is the stain of choice to demonstrate the presence of the bacteria in the superficial mucus and in extracellular locations within the gastric glands. The pyloric stomach is the preferred biopsy site, although low numbers of bacilli may also be seen in the fundus and duodenum in severely infected animals.
Additional references:
Synopsis: Ferrets, like other mustelid, are extremely susceptible to stress-related gastric ulcers. This is a common finding in animals with other systemic diseases and often contributes to debility in older animals. Gastric ulcers are often seen in association with gastric Helicobacter mustelae infection, however, a definitive cause-and-effect relationship has not been proven in this species.
Gross lesions: Two distinct forms of gastric ulceration may be seen in the ferret. The most common form is the presence of digested blood within the stomach lumen. Ulcers are pinpoint, extremely difficult to see, and are present in the highest numbers in the pyloric region of the stomach. The second, less common form, is he presence of a single, focally extensive, ulcer in the pyloric stomach. These large ulcers may result in sudden death due to erosion into the submucosal blood vessels.
Microscopic lesions: Microscopically, ulcers appear as full-thickness areas of glandular necrosis and loss which are well-demarcated from the surrounding tissue. Bleeding ulcers may be covered with a layer of brown hemoglobin pigment.
Additional reference:
Synopsis: Eosinophilic enteritis was first described by James Fox et. al of MIT in 1992, but is not an uncommon disease. Although the etiology of this disease is unknown, presumed cases have been treated successfully with ivermectin, suggesting some form of parasitic origin. The wasting disease is most commonly seen in young male ferrets under 14 months of age. Peripheral eosinophilia may be seen in affected animals.
Gross lesions: None.
Microscopic lesions: Eosinophilic infiltrates may be seen in the small intestine - a diffuse mucosal infiltrate and an eosinophilic vasculitis may be present. Additionally, prominent eosinophilic infiltrates may be seen in the mesenteric lymph nodes, and rarely in the liver. Aggregates of Splendore- Hoeppli material may be seen within the lymph nodes and rarely in the liver in areas of accumulated eosinophils.
Additional references:
Synopsis: Proliferative colitis is an uncommon disease which is usually seen in male ferrets under one year of age. The disease is sporadic, with only one or two animals in a large colony being affected. Clinical signs include tenesmus and production of small, frequent bowel movements which often contain frank blood and mucus. The disease is caused by a campylobacter-like organism (recently reclassified as a species of Desulfovibrio) which results in asymmetrical proliferation of immature epithelium, causing marked thickening of the wall. This condition is subject to periodic periods of recrudescence, often during times of stress. If untreated, it may be fatal.
Gross lesions: There is noticeable thickening of the colonic wall, which becomes opaque (normally you can see fecal material through the colonic wall).. The mucosa is prominently "cobblestoned."
Microscopic lesions: The mucosa is multifocally thickened up to five times normal by a proliferation of immature epithelial cells with vesicular nuclei and a moderate amount of basophilic cytoplasm. Scattered islands of normal goblet cells may be present, but there is an overall marked decrease in goblet cells. Silver stains will demonstrate the presence of the bacteria in the apical cytoplasm of epithelial cells.
Additional references:
Synopsis: With the exception of coccidia, intestinal parasites are uncommon in ferrets. Toxocara cati, Toxascaris leonina, Ancylostoma sp., Dipylidium caninum, and Giardia sp. have all been reported in ferrets. Three species of coccidia have been seen in ferrets: Eimeria furo, Eimeria ictidea, and Isospora laidlawii. While most coccidial infections are subclinical, lethal coccidial infections are occasionally seen in young kits.
Gross lesions: Generally none, although digested blood may be present in the GI tract of several affected kits.
Microscopic lesions: Numbers of parasites range from very low to extremely high in severe infections where almost every enterocyte contains merozoites. All stages of the parasite, including micro- and macrogametocytes can be seen. Meronts contain up to 16 merozoites.
Additional reference:
Synopsis: ECE is a new diarrheal disease of ferrets which causes epizootics of high morbidity (up to 100%), but low mortality. The diarrhea is rapidly dehydrating and most mortalities occur in older animals with concurrent illness. Symptoms include vomiting and passage of a dark green stool with abundant mucus. During the recovery phase, stools assume a "birdseed" like appearance. The causative agent - presumed to be a virus - has not yet been identified.
Gross lesions: Generally none. The intestine may be flaccid with a moderate amount of watery ingesta.
Microscopic lesions: Sections should be taken from 3-4 different areas of the jejunum, as well as the remainder of the gastrointestinal tract. Early lesions include vacuolar degeneration and necrosis of apical enterocytes, with resultant marked villar atrophy, fusion and blunting. Later in the course of disease, there is a marked lymphocytic enteritis with large numbers of lymphocytes among mucosal epithelial cells.
Synopsis: Gastrointestinal foreign bodies are commonly seen in young or bored, cage-bound ferrets. Ferrets commonly ingest latex, plastic, and foam rubber. Ferrets may also ingest towels or other forms of bedding. Anorexia and passage of abnormal stools are common presenting signs; abdominal pain is not commonly seen.
Gross lesions: A focal area of intestinal distention with or without hemorrhage may be seen. In many cases, the wall of the intestine at the site of the blockage is thinner than that of the adjacent intestine due to continuous peristaltic movements at the site of blockage. Intestinal perforation may rarely be seen.
Microscopic lesions: Ulceration, necrosis and thinning of the muscular layers at the site of blockage. Marked attenuation of villi and granulation tissue may be seen in longstanding blockages.
Additional reference:
Synopsis: Clostridium perfringens type A has been reported in black- footed ferret kits.
Gross lesions: Gastric bloat, multifocal intestinal hemorrhage.
Microscopic lesions: Typical of clostridial infections. Marked coagulative necrosis of the intestinal mucosa with numerous adherent 2 X 6-8um bacilli.
Additional reference:
Synopsis: This is a rare condition in ferrets which is most commonly seen in the gastrointestinal tract and mesenteric lymph nodes, although accumulation of macrophages containing the organism may be seen in any organ.
Gross lesions: Mesenteric lymphadenopathy is the most common gross lesion.
Microscopic lesions: The presence of large foamy macrophages with a grayish granular cytoplasm are suggestive of this disease - acid-fast stains reveal numerous bacilli within macrophages.
Additional reference:
Synopsis: The most common gastrointestinal neoplasiam is, as in several other organ systems, lymphosarcoma. The lymphoblastic form of lymphosarcoma is the most common form in the intestine. (See hematolymphatic system for a more detailed description of this condition.)
Endocrine System
Islet cell neoplasms are the most common neoplasm of this species. These neoplasms generally result in hypoglycemia as a result of inappropriate secretion of insulin. Clinical signs include lethargy, stupor, ptyalism, and ataxia, and may progress to coma and death. Non-functional islet cell tumors are commonly seen in older animals at necropsy. While all islet cell tumors are potentially malignant, metastasis is rare, as opposed to islet cell neoplasms in the dog and cat.
Gross lesions: Islet cell tumors are reddish-brown, well-defined nodules which range in size from 2mm-1cm. They are firmer than the surrounding pancreatic tissue and may be multiple. These neoplasms must be differentiated grossly from foci of pancreatic exocrine hyperplasia, a common benign age-related finding. (Foci of exocrine hyperplasia are generally the same color and consistency of the surrounding tissue, and may be numerous). Small reddish brown nodules may also be present in the mesentery adjacent to the pancreas.
Microscopic lesions: Similar to islet cell neoplasms in other species. These tumors are most commonly unencapsulated, and resemble normal, albeit greatly enlarged islets of Langerhans. Identical foci may be present in the surrounding mesentery. Metastasis to visceral organs is rare. These neoplasms stain strongly for insulin with scattered glucagon staining.
Additional references:
Synopsis: AAE is a common endocrine disorder of middle aged to older ferrets. The syndrome is the result of proliferative lesions in the adrenal cortex which secrete excess amounts of estrogenic hormones. As a result of this excess estrogen, affected ferrets exhibit a range of cutaneous, behavioral, and reproductive signs. While technically a form of hyperadrenocorticism, AAE should not be confused with Cushing's disease, or hypercortisolism. Only rarely are cortisol levels elevated in these patients. Interestingly, unlike dogs and cats, metastasis occurs extremely late in the course of disease with adrenocortical carcinoma, and early removal of affected adrenals carries a fair prognosis.
Gross lesions: Bilaterally symmetrical alopecia beginning over the tailhead and progressing forwards over the flanks and abdomen is strongly suggestive of AAE. Additionally, the presence of an enlarged vulva in a spayed female also strongly suggests AAE. These clinical signs may be the result of any of the three types of proliferative adrenocortical lesions - hyperplasia, adenoma, or carcinoma. The normal length of the ferrets adrenal gland ranges from 3-5 mm; glands exceeding 5 mm often contain proliferative lesions. Diameters exceeding 1 cm are highly suggestive of adrenocortical carcinoma in the ferret.
Microscopic lesions: Proliferative lesions of the ferret adrenal cortex fall into three categories - hyperplasia, adenoma, and carcinoma. In a recent retrospective of 104 proliferative adrenocortical lesions archived at the AFIP, hyperplasia and carcinoma were present in 45% of cases each, while adenoma was present in 10%. The presence of necrosis, cellular atypia, and a mitotic rate greater than 1/10 hpf are strong indicators of malignancy. The presence of a single nodule in the adrenal cortex without factors associated with malignancy indicates adenoma, while the presence of multiple nodules is evidence of nodular cortical hyperplasia. Extracapsular extension of proliferative cortical tissue may be seen in all three lesions, and does not occur indicate one lesion over another.
Additional references:
Synopsis: Interestingly, thyroid disease has not been reported in the ferret. In the almost 2500 cases on archive in the Registry of Veterinary Pathology at the AFIP, not one thyroid lesion has been catalogued.
Synopsis: Diabetes mellitus, is a poorly-defined, uncommon disease which has been reported in both the domestic and the black-footed ferret. Blood glucose levels in affected ferrets generally range into the 500's, but levels as high as 725 g/dl have been reported. Polydipsia, polyuria, glucosuria, and loss of body condition have been reported in affected ferrets.
Gross lesions: None.
Microscopic lesions: Glycogenic vacuolation of the islets of Langerhans is the most consistent and noteworthy histologic lesion. Glycogen accumulation may also be seen in renal tubular epithelium. In several cases in the AFIP archive, lenticular cataracts have been noted.
Synopsis: The cause of this extremely common finding in ferrets is yet unknown; many theories abound. This condition is most commonly seen in middle-aged to older ferrets, but may be seen in ferrets as young as six months. As the incidence of neoplasia in enlarged spleens is somewhat less than 10%, this change most likely represents a response to chronic inflammatory disease (Bruce Williams, personal opinion). The previously reported syndrome of hypersplenism in a ferret is most likely not a distinct entity in this species. Marked enlargement of the spleen for any reason increases the spleen's phagocytic capability, resulting in increased RBC breakdown. Additionally, anemia of chronic disease may complicate many cases of splenomegaly.
Lymphosarcoma is by far the most common splenic neoplasm, with hemangiosarcoma being rarely seen.
Gross lesions: Enlarged spleens may range up to 10 cm. in length. While most spleens are diffusely enlarged, a small percentage of spleens will contain single or multiple discrete nodules, which are more likely to represent splenic neoplasms.
Microscopic lesions: 95% of cases consist of a combination of marked congestion and extramedullary hematopoiesis, representing erythrocytic, leukocytic, and megakaryocytic lines. Florid EMH may resemble lymphosarcoma in that a large percentage of the cells within the red pulp may have a markedly increased nuclear/cytoplasmic ratio and a high mitotic rate, but represent the immature forms of the various cell lines. The marked variation in cell size, and the presence of islands of erythrocytic precursors and megakaryocytes contrasts well with the monomorphic population of cells seen in most cases of lymphosarcoma.
Large areas of coagulative necrosis, often bordered by a combination of viable and degenerate neutrophils and various amounts of granulation tissue may be seen in grossly enlarged spleens. As enlarged spleens are prone to rupture, various signs of splenic trauma, including hematoma, siderotic plaques, and large areas of parenchymal fibrosis are commonly seen.
Additional references:
Synopsis: Lymphosarcoma is the most common malignancy in the domestic ferret. These neoplasms most commonly arise spontaneously, however, a recent article documents horizontal transmission of malignant lymphoma in ferrets using cell or cell-free inoculum. This finding, coupled with the occasional clustering of lymphomas in a single facility, has prompted speculation that lymphosarcoma in the ferret may be the result of a retroviral infection. A viral agent has not, as of yet, been isolated from cases of lymphosarcoma in the ferret.
Several variants of lymphoma exist in the ferret. The most commonly seen form, in which the neoplastic cell is a mature, well-differentiated lymphocyte occurs in older ferrets, primarily resulting in peripheral lymphadenopathy, with visceral spread and subsequent organ failure late in the course of disease. A second form occurs primarily in young ferrets less than two years of age. This form, in which the neoplastic cell is a large blastic lymphocyte, is characterized by early visceral neoplasms, often with the production of a large thymic mass. An enlarging thymic neoplasm often results in compression of the lung lobes, dyspnea, and pleural effusion, and may often be misdiagnosed as pneumonia or heart disease by veterinarians with little experience in this species. A third, uncommon form, in which combinations of peripheral lymphadenopathy and visceral neoplasms may be seen and in which the neoplastic cells is often a large, atypical lymphoblast is known as the immunoblastic polymorphous variant.
Gross lesions: Adult (lymphocytic) form - diffuse lymphadenopathy. Splenic white pulp may be greatly expanded and grossly visible on cut section. In later stages, firm white nodules may be seen in a number of visceral organs, including the liver and kidney, and the spleen may be diffuse and enlarged. Juvenile (lymphoblastic) form - The presence of a thymic mass is strongly suggestive of this condition. Diffuse hepatosplenomegaly is often seen due to massive infiltration of these organs also. Neoplastic cells may be seen in any organ, including the bone marrow.
Microscopic lesions: In the adult form, biopsy of peripheral lymph nodes reveals effacement of the normal architecture by an infiltrate of small non-cleaved lymphocytes which breach the capsule and extend into the surrounding tissue. (However, extension into surrounding tissue may also be seen in cortical hyperplasia of the mesenteric nodes due to the attenuated and occasionally absent capsule seen in these nodes.) The presence of tingible body macrophages scattered throughout the node ("starry-sky" effect) is commonly seen in this form. In the liver, neoplastic infiltrates are primarily seen extending from portal areas, while in the spleen, the earliest sign of lymphosarcoma is an expansion of the well-differentiated lymphocytes in the mantle of the periarteriolar lymphoid sheaths. Mitotic rates generally average 1-2/hpf.
In the juvenile form, examination of infiltrated organs often reveals effacement of normal architecture by a monomorphic population of large cleaved and non-cleaved lymphoblasts, which may be admixed with smaller, more well-differentiated cells. In the liver, neoplastic cells are more commonly seen as discrete nodules distending sinusoids and replacing hepatocytes, while in the spleen, the periarteriolar lymphoid sheath is totally replaced and expanded by a monomorphic lymphoblast population. Discrete nodules of blastic lymphocytes may be seen in any visceral organ; infiltration of lymph nodes is a late finding. The mitotic rate of the lymphoblastic cells is generally high, ranging up to 6/hpf.
Finally, the distribution of the immunoblastic polymorphous variant resembles that of the lymphocytic form. However, scattered through infiltrated nodes is a subpopulation of atypical large cleaved, often multinucleate lymphocytes which may range up to 50 or 60um in diameter. Occasionally, Reed-Sternberg-like cells may be present. Bizarre-looking lymphocytes in this condition may be misinterpreted as megakaryocytes, however, use of immunohistochemical techniques such as Factor VII antigen, CD3 and BLA-36 (a lymphocyte marker) may be used to distinguish between the two cell lines in the spleen and bone marrow. The mitotic index in this form of lymphoma is also high.
A common request for pathologists working with ferrets is evaluation of splenic aspirates from animals with enlarged spleens. This task is fraught with pitfalls. As a general rule: extramedullary hematopoiesis will be seen in the VAST majority of cases. Evidence of erythrocytic precursors and abundant peripheral blood should lead the prudent pathologist to a diagnosis of EMH. Cases of splenic lymphosarcoma may be identified on splenic cytology by the presence of a monomorphic population of cells with large nuclei, prominent nucleoli, an absence of erythrocytic precursors, and minimal blood elements. Additionally, mitotic figures should be present.
Additional references:
Synopsis: Aleutian disease is caused by the same parvovirus that causes Aleutian disease in mink, however, the disease is quite different between these two species. In mink, AD results in rapidly life-threatening immune-mediated glomerulonephritis, vasculitis, and hypergammaglobulinemia. In ferrets, there are notable similarities, including a hypergammaglobulinemia, and in late stages of the disease, an immune complex glomerulonephritis; however, the disease is much more insidious, with a progression of as long as 2 years. Ferrets in the late stages of disease will be hyperproteinemic (8-9 mg/dl, with >20% of this total being comprised of gammaglobulins. Serologic testing is available through United Vaccines (Madison, WI) or the Research Animal Diagnostic Laboratory in the Department of Comparative Medicine, Massachusetts Institute of Technology.
Gross lesions: Gross lesions are seen only late in the course of disease. Splenomegaly and lymphadenopathy are the most common gross lesions with this disease; splenic infarction as a result of marked splenomegaly may complicate the clinical and pathologic picture. Enlarged, brown-tan kidneys may be present. In terminal cases, clotting abnormalities resulting from vasculitis and the marked hypergammaglobulinemia may result in petechial hemorrhage and hematuria.
Microscopic lesions: Several characteristic microscopic findings are seen in ferret AD as well as in the mink disease. Prominent plasmacytic infiltrates are seen in numerous organs, most prominently in the renal interstitium, hepatic portal areas, and in the splenic red pulp, where an almost pure population of plasma cells expands the red pulp. Additionally, there may be marked plasmacytosis of numerous lymph nodes and the bone marrow. In most cases, there will be marked membranous glomerulonephritis and numerous ectatic protein-filled tubules as a result. (Note: Glomerulosclerosis is commonly seen in chronic interstitial nephritis in this species - but there is little evidence of tubular protein casts or plasmacytic infiltrate in uncomplicated CIN). Vasculitis may be seen in almost any organ.
Additional references:
Urinary System
Synopsis: Bacterial urinary tract infections are commonly seen in female ferrets, and uncommonly seen in male ferrets. The most common causative agent in the ferret is E. coli, with Staphylococcus aureus being isolated out of a significant number of cases. Bladder infections are often subclinical in female ferrets, and ascending infections resulting in pyelonephritis are not uncommon. Renal failure may result from severe pyelonephritis in this species.
Gross lesions: Often none. Hydronephrosis and hydroureter may be present in long-standing or resolved infections.
Microscopic lesions: Ulcerative cystitis and/or a suppurative tubulointerstitial nephritis. Bacteria are rarely seen.
Synopsis: Squamous metaplasia of the prostate has only recently been recognized as a common cause of dysuria and urethral blockage in the ferret. The squamous change in the prostate is the result of excess estrogens liberated from proliferative adrenal lesions (see adrenal-associated endocrinopathy, above). Accumulation of secretory material and lamellated keratin results in the formation of multiple prostatic cysts. Impingement of the prostatic cysts upon the prostatic urethra results in dysuria, and finally complete urinary blockage in male ferrets. The bladder of blocked ferrets may be manually expressed, but ferrets cannot void on their own. In earlier literature, due to the close association with the bladder, the condition was referred to as the "triple bladder syndrome". Surgery is directed toward removal of prostatic cysts and the affected adrenal.
Gross lesions: Single to multiple, variably-sized fluctuant cysts are present near the bladder trigone. The cysts are thick-walled, and firm on palpation. Identification of an enlarged adrenal gland or an adrenal neoplasm is often possible in these animals.
Microscopic lesions: Multiple cysts or fragments of cysts are often available for examination. Atrophic prostate glands (as a result of the effects of circulating estrogens) are often present at the periphery of the cysts, although in advanced cases, they may be lined by squamous, rather than glandular epithelium). The wall consists of multiple layers of squamous epithelium, surrounded by variable amounts of immature fibrous connective tissue. The lumenal contents of the cyst may vary from lamellated keratin and keratin debris, to abundant purulent inflammation (in which case there is often a combination of chronic-active inflammation and granulation tissue in the cyst wall and prostate (overeager manual expression of the bladder?).
Synopsis: Numerous references refer to the formation of struvite uroliths in ferrets; however, the actual incidence is probably overestimated, especially in light of recent findings of prostatic squamous metaplasia. Male ferret are more likely to develop uroliths than females; however, the syndrome has not been well characterized, and dietary influences have not been explored, although high ash cat foods are frequently blamed. Clinical signs include frequent licking of the genital area, dysuria, anuria, and occasionally, hematuria. Reportedly, pregnancy may increase the incidence of urolithiasis in pregnant jills due to the effects of estrogen on the ferret's handling of calcium and phosphorus. Cystine crystals have also been reported.
Gross lesions: Struvite uroliths often have a corrugated surface. Single or multiple uroliths may be present in the bladder, or rarely in the renal pelvis. Reports of struvite "sand" as may be seen in the feline urologic syndrome are anecdotal.
Microscopic lesions: Similar to that seen in urolithiasis in other animals.
Additional references:
Synopsis: Renal cysts are common incidental findings in the ferret. Although often submitted for histologic evaluation, they are of little clinical significance and have no effect on renal function. Rare cases of true polycystic disease may be seen in this species. Polycystic kidneys are enlarged, may be felt on external palpation, and may cause renal failure.
Gross lesions: Single or multiple cysts may be present in the cortex of one or both kidneys. When viewed from the capsular surface, they are thin, bulge slightly, and are fluid filled. Cysts may range up to 1 centimeter in diameter. Polycystic kidneys may be markedly enlarged and fill the posterior abdomen. They are composed of variable numbers of cysts with little intervening fibrous connective tissue.
Microscopic lesions: In benign cysts, there may be little or no fibrosis surrounding the cyst, or the cyst may have a thick wall of fibrous connective tissue throughout which are scattered numerous atrophic glomeruli and tubules. In a reported case of polycystic disease in a ferret, the kidney contained multiple fluid-filled cysts in both the cortex and medulla which were lined by cuboidal epithelium. The cysts were separated by abundant fibrous connective tissue which contained moderate numbers of lymphocytes.
Additional reference:
Synopsis: Chronic interstitial nephritis is a common finding in ferrets. Early lesions can be seen as early as 2 years, and advanced cases resulting in renal failure may occur as early as 4.5 years. The progression of the disease is most akin to that seen in older cats. Ferrets are generally maintained on a high protein diet with protein levels in excess of 34%. This is generally accomplished by feeding premium kitten chows or specially formulated ferret chows. Due to the prevalence of chronic interstitial nephritis in older ferrets, lowering of protein levels after three years of age is reached is generally advocated by most practitioners.
Gross lesions: Kidneys are generally pitted and large focal depressions may be seen in the outer cortex as a result of scarring. "Peeling" the renal capsule is recommended during the ferret necropsy. Severely affected kidneys may be asymmetric with respect to size.
Microscopic lesions: The pattern of microscopic changes associated with chronic interstitial nephritis in the ferret is unique. At low magnification, there are linear bands of fibrosis which extend from the capsule inward. Glomerular and tubular changes are most commonly seen in these areas of fibrosis. There are periglomerular and glomerular fibrosis resulting in glomerulosclerosis. The interstitium is expanded by fibrous connective tissue throughout which is scattered moderate numbers of lymphocytes and plasma cells. Tubules within these radiating streaks of fibrosis exhibit variable degrees of atrophy. Pathologists with little experience with ferret tissues may be tempted to diagnose chronic infarction. As the disease progresses, there is a diffuse glomerulosclerosis throughout the cortex, as glomeruli outside of the areas of interstitial fibrosis are affected. Areas of fibrosis tend to coalesce into large areas devoid of functional glomeruli and tubules.
Reproductive System
Synopsis: Ferrets are induced ovulators - intact females remain in estrus until mated, spayed, or are cycled out by injections of human chorionic gonadotropin. 50% of unmated jills will develop marked bone marrow suppression as a result of high levels of circulating estrogens. All three bone marrow cell lines are affected - erythrocytes, leukocytes, and megakaryocytes. Initially, there is a mild thrombocytosis and leukocytosis, but the condition soon progresses to a non-regenerative anemia, leukopenia, and thrombocytopenia. The anemia may remain non-regenerative anemia up to 4 months past ovariohysterectomy in affected animals. In addition to thrombocytopenia, a liver-associated clotting abnormality may also be present. Hemorrhage is reported to be the most common cause of death. Similar signs may be caused by exogenous estrogen administration, but are not seen in cases of adrenal-associated endocrinopathy.
Gross lesions: Female ferrets in estrus have prominently swollen vulvas. Signs of hyperestrogenism include pale mucus membranes, alopecia, melena, thin watery blood, hemorrhages throughout the body, hematuria, pyometra, bronchopneumonia, and vaginitis.
Microscopic lesions: Diagnosis of aplastic anemia is most commonly based on the presence of a low PCV (<20%) in an estrus jill. The most characteristic lesion in affected jills is hypocellularity of the bone marrow. There is also no evidence of splenic hematopoiesis; small amounts of EMH may be seen in the liver. There may be evidence of hemorrhage (hemosiderin-laden macrophages, erythrophagocytosis) in lymph nodes and the spleen. Suppurative metritis or pneumonia may be seen as a result of the marked leukopenia.
Additional references:
Synopsis: Mastitis is occasionally seen in pregnant jills in the first few weeks of lactation. Hemolytic E. coli is the most commonly isolated organism, and results in a syndrome of gangrenous mastitis. If untreated, jills rapidly become septic and/or endotoxemic. Staph aureus is occasionally cultured from cases of mastitis and produces a more suppurative, less necrotic form of mastitis.
Gross lesions: Affected teats are swollen, necrotic, black, firm, and non-painful. In Staph aureus mastitis, the mammary glands are hot, painful, and reddish in color; purulent exudate may be expressed from the lactiferous ducts.
Microscopic lesions: The primary lesion in E. coli mastitis is diffuse severe coagulative necrosis which extends into the adjacent adipose tissue and muscle. There are large pockets of hemorrhage and edema in the affected glands; numerous bacteria may be seen. Areas of infarctions are well-demarcated by a line of degenerate neutrophils and cellular debris, and vascular thrombosis may be seen. Other signs of sepsis, or endotoxemia, including margination of neutrophils in the pulmonary capillaries and hypertrophy of Kupffer cells in the hepatic sinusoids may be seen, as well as colonies of gram-negative bacilli in numerous tissues.
In staphyloccoccal mastitis, there is less evidence of infarction. A purulent galactophoritis and mastitis is present. Staphylococci are often prominent.
Additional reference:
Cardiovascular System
Synopsis:Cardiomyopathy is a common disease in the American lines of ferrets, which has a presumed genetic basis. Several forms of this condition may be seen - dilatative, hypertrophic, and a restrictive form in which there is marked replacement of myocardium by fibrous connective tissue, with minimal change in chamber area. Signs of cardiomyopathy may be seen as early as 1 year of age in severely affected animals, but are more common between 5 and 7 years of age.
Gross lesions: Gross lesions are similar to those seen in other domestic species. In subclinical cases, a congested, occasionally nodular liver may be the only gross lesion as a result of chronic passive congestion in this organ. The heart may appear enlarged, and the right ventricle may appear thin or flabby. With progressively severe cases, there is often an accumulation of a serosanguinous ascitic transudate in the abdominal cavity, the pleural cavity, or both. In severe cases, the lungs are atelectatic and compressed by the presence of a globose heart and abundant pleural effusion. In cases in which the heart is not enlarged, examination of the left ventricular free wall and the interventricular septum may reveal marked thickening and impingement upon the ventricular lumen. Rarely, the presence of fibrous connective tissue may be seen upon close inspection of the cardiac wall, and occasionally, due a previous ischemic event, a focally extensive area of the ventricular wall may be translucent and paper thin as a result of total loss of myocytes in this area and replacement by fibrous connective tissue.
Microscopic lesions: Early lesions consist of an increase in fibrous connective tissue around myocardial vessels which extends into the interstitium. As the condition progresses, there is atrophy and loss of myocytes. Focal areas of myocyte degeneration may be present, with an infiltrate of moderate numbers of macrophages, lymphocytes, plasma cells, and rare neutrophils. In some cases of cardiomyopathy, there may be marked focal malalignment of myocytes, suggesting orientation in several different planes.
Centrilobular fibrosis, edema, micronodular hemosiderosis, and loss of subcapsular hepatocytes with resulting fibrosis all attest to chronic hepatic congestion, which is a common finding in cardiac disease in the ferret. In contrast, the presence of chronic signs of left-sided heart failure are relatively uncommon. In terminal stages of the disease, there may be necrosis of centrilobular hepatocytes due to stasis and hypoxia. The presence of marked myocardial fibrosis with or without inflammation, and evidence of chronic systemic congestion are highly suggestive of cardiomyopathy in this species.
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Synopsis: Ferrets are also susceptible to heartworm infection, but due to the fact that most ferrets are kept indoors, cases are still uncommon. Ferrets in heartworm endemic areas are usually maintained on monthly ivermectin at approximately 0.2 mg/kg. (Note: in my experience, the vast majority of cases of dirofilariasis in ferrets are in Florida.) Due to the small size of the ferret heart, as few as two heartworms may result in fatal cardiac insufficiency. The small numbers of heartworms in these animals also necessitates the use of occult heartworm tests due to the low levels of circulating microfilaremia.
Gross lesions: Lesions of heartworm disease in the ferret are essentially the same as cardiomyopathy (see above), as infection commonly results in heart failure in this species. Aberrant cerebral heartworm migration has been noted in this species. The presence of heartworms within the right ventricles and pulmonary artery can be construed as the cause of death in any ferret in which it is observed.
Microscopic lesions: Microscopic lesions are as expected with heart failure (see above).
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Respiratory System
Synopsis: This condition, also known as "foam cell foci" or "subpleural histiocytosis" is a common incidental finding in mustelids at necropsy and is of no clinical significance. It is often mistaken at necropsy by practitioners as a dissemination neoplasm. The cause of this finding, and the origin of the lipid, is not known.
Gross lesions: Multiple to coalescing white to yellow foci are present within the subpleural pulmonary parenchyma. A transverse cut through one of these foci will reveal its superficial nature.
Microscopic lesions: The basic lesion is simply an aggregate of lipid-laden macrophages in the alveoli immediately subjacent to the pleura. As the lesion increases in size, it may include moderate numbers of lymphocytes and cholesterol clefts.
Synopsis: By far, the most common cause of pneumonia in the ferret is aspiration, either of orally administered medicants or of vomitus. Ferrets often resist liquid oral medication by fighting and squirming during administration, and often involuntarily inhale part of the medication.
Gross lesions: In cases of aspiration pneumonia, there may be consolidation of the cranioventral lung lobes, either unilaterally or bilaterally. The severity of lesions seen with aspiration of vomitus is proportionate to the length of time since the event. In most cases, aspiration occurs as a terminal event, so minimal gross lesions are seen. In long-standing cases, gangrenous, cavitated lesions may be seen in the pulmonary parenchyma.
Microscopic lesions: The primary lesion in aspiration pneumonia is in the small airways. Bronchioles contain a mixture of viable and degenerate neutrophils, sloughed epithelial cells, and variable amounts of eosinophilic proteinaceous material (which may be admixed with food particles when vomitus is aspirated). Often, there is an accumulation of foamy macrophages in the surrounding alveoli. In long-standing cases, there may be a pronounced granulomatous response, with numerous foreign body and multinucleate giant cells admixed with lymphocytes, plasma cells, and cholesterol clefts. Occasionally, you may find eosinophilic crystalline proteins within the cytoplasm of macrophages. In cases of aspiration of vomitus, the lesion is characterized by extensive necrosis of the airway and surrounding alveoli, with sloughing of the bronchiolar epithelium and coagulative necrosis of the adjacent alveolar septa. Colonies of gram- negative bacilli or mixed colonies may be seen in cases of aspiration of vomitus.
Synopsis: Ferrets are the only domestic animal species which is susceptible to the human influenza viruses. For this reason, they are a) often used as animal models in influenza research, and b) often infected by their human owners. The disease is quite similar to that in humans, with clinical signs being photophobia, a catarrhal nasal discharge, sneezing, coughing, pyrexia, anorexia, and malaise.
Gross lesions: Lesions are generally minimal, with congestion and exudation of the nasal mucosa and mild reddening of the tracheal mucosa.
Microscopic lesions: There is mild subacute inflammation and occasional necrosis of the nasal mucosa. A mild subacute interstitial pneumonia may be present. Because the disease is so rarely fatal, there is often little opportunity to examine tissues from infected animals.
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Musculoskeletal System
Synopsis: Chordomas are the most common neoplasm of the musculoskeletal system of the ferret. They arise in or adjacent to vertebra from remnants of primitive notochord, and are most commonly seen at the tip of the tail. Chordomas have also been documented in cervical spine. Early reports mischaracterized this neoplasm as a chondrosarcoma, and this mistake is still repeated by pathologists who are unfamiliar with ferret tissue. Chordomas are considered potentially malignant, however, metastasis has not been seen in neoplasms arising in the tail. Cutaneous metastasis was reported in one chordoma from the cervical spine.
Gross lesions: Chordomas are most commonly seen as club-like swellings at the tip of the tail which involve the last caudal vertebra. Cervical chordomas present as lytic neoplasms in the neck of animals with posterior paresis. Physical exam shows a markedly decreased range of motion and pain upon movement of the neck.
Microscopic lesions: Chordomas are locally aggressive neoplasms which often infiltrate vertebral bodies. The neoplasm is composed of foamy "physaliferous cells" which are separated by a moderate amount of myxomatous matrix. There are multifocal areas of well-differentiated cartilage and bone within these neoplasms.
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Integumentary System
Synopsis: By far, the most common skin problem in ferrets is neoplasia. The incidence of cutaneous neoplasia increases with age in this species. While there are a wide range of cutaneous neoplasms that have been documented in the ferret, the two most common types of neoplasms seen in the skin of the ferret are 1) sebaceous epithelioma and 2) mast cell tumor.
Sebaceous epitheliomas appear as warty, verrucous lesions which may arise anywhere on the animal's body, but have a predilection for the head and neck. Microscopic examination reveals an unencapsulated neoplasm composed of basal cells, of which a small percentage exhibit sebaceous and/or squamous differentiation. Although early reports referred to these neoplasms as "basosquamosebaceous carcinomas", they possess no features of malignancy, and evidence of metastasis has not been seen.
Mast cell tumors are also common skin tumors in ferrets. Gross, they most often appear as flat, alopecic, hyperkeratotic plaques which are variably pruritic. Microscopic examination reveals a well-demarcated, unencapsulated neoplasm which is generally confined to the superficial dermis, and is composed of well-differentiated mast cells. Low numbers of eosinophils are scattered through the neoplasm, but vasculitis and collagen degradation is hardly ever seen. Metachromatic stains such as toluidine blue or Giemsa reveal few cytoplasmic granules, so the diagnosis is primarily made (and rightly so) on the HE section.
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Synopsis: This is an uncommon disease in ferrets, but is occasionally seen in mink. Most cases occur either in very young animals kept in poor conditions, or in older, immunosuppressed animals. Both Microsporum canis and Trichophyton mentagrophytes have been seen in ferrets.
Gross lesions: Dermatophytosis is similar to that seen in other domestic species - animals have areas of crusting alopecia with brittle hair and numerous broken hair shafts. In immunosuppressed animals, the rash can become generalized (at which time it must be differentiated from that seen with canine distemper infection).
Microscopic lesions: Biopsies from affected sites are generally covered with a thick layer of keratin debris, degenerate neutrophils, and entrapped fungal arthrospores and hyphae. There is ulceration of the skin, and follicles often contain numerous fungal arthrospores which occasionally invade the hair shaft. Many follicles may not contain a hair shaft, only lamellar keratin debris. There is generally a neutrophilic or lymphoplasmacytic dermal infiltrate in perivascular and periadnexal areas.
Synopsis: Ferrets are commonly infected with two types of ectoparasites: ear mites (Otodectes cynotis) and fleas (Ctenocephalides sp.) Most young ferrets and many older ones have clinical cases of ear mite infection which require periodic treatment. Grossly, ferrets with ear mites have copious amounts of a thick brown-black wax. However, swabs from the ears should be examined microscopically for the presence of adult mites or their eggs, as ferrets without mites may also have large accumulations of wax due to neglectful owners.
Sarcoptic mange has been reported in ferrets. This disease comes in two distinct forms in ferrets - a very pruritic whole-body form, and a variably pruritic form localized to the feet. Grossly, this form is characterized by swollen feet, evident of self-mutilation, and nail loss. Histologically, the disease is similar to that in the dog, with marked ulceration and hyperkeratosis of the skin and a few cross sections of mites in the epidermis or deep under the overlying crust.
Demodectic mange is generally seen in older or immunosuppressed ferrets. Skin scrapings may demonstrate the presence of nymphs or adults. Skin biopsies reveal moderate hyperkeratosis and the presence of a few cigar-shaped mites within the hair follicles.
Special Senses
Synopsis: There are several reports of cataracts in individual animals and breeding colonies. While many causes have been postulated, no definitive cause has been isolated. Cases in individual animals are considered to be spontaneous. Cataractous change may also be seen in the lenses of diabetic animals, however, since the lifespan of diabetic ferrets is generally short, grossly visible cataracts generally have not formed.
Gross lesions: Cataracts in ferrets generally involve both the cortex and nucleus of the lens.
Microscopic lesions: The microscopic appearance of cataracts in ferrets is similar to that in other domestic species, with formation of balloon cells in the outer cortex, initially, progressing toward the nucleus. Morgagnian change has not been described in ferrets.
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Neoplasia (other than previously described)
Synopsis: Numerous neoplasms have been described in the ferret, most of which are similar both grossly and histologically to those seen in other animals. Neoplasms easily represent up to 60% of total surgical biopsies of ferrets, with the balance being islet cell tumors, adrenal neoplasms, chordomas, and the skin tumors already mentioned. While the following is by no means an exhaustive list of the remaining, it represents those which I, personally, feel are most commonly seen and most significant in this species.
Reproductive: Tumors of smooth muscle are the most common neoplasm of this system, and are also seen in the endocrine system (generally arising in the adrenal gland) and rarely in the gastrointestinal system and subcutaneous tissue. Low grade leiomyosarcomas, demonstrating an infiltrative nature, moderate atypia, and a moderate mitotic rate are more common than leiomyomas in this species. Additionally, leiomyosarcomas have been reported as occurring "free-floating" in the abdomen. As the majority of these tumors are attached to the adrenal gland, ovary, or testis, and are removed due to the organomegaly that they cause, the prognosis is generally good. Metastasis of leiomyosarcoma has not been seen.
Testicular neoplasms: Interstitial cell tumors are the most common neoplasm of the ferret testicle, but combinations of two or more neoplasms are not uncommon. (Indeed, one of my own ferrets, obtained as a 4-year-old cryptorchid had FOUR neoplasms in the same testicle - interstitial cell tumor, seminoma, Sertoli cell tumor, and a carcinoma of the rete testis). This illustrates the importance of removing cryptorchid testicles in this species - you can always find at least one neoplasm and often more in retained testicles.
Ovarian neoplasms: Tumors of germ cell or stromal cell origins are most commonly seen, epithelial neoplasms are rare. One teratoma has been reported. Gastrointestinal system: The second most commonly seen neoplasm of the gastrointestinal system (after lymphosarcoma) are tumors of smooth muscle origin, arising from the muscular layers of the GI tract. Low-grade leiomyosarcomas are most commonly seen. Mesotheliomas are occasionally seen in the peritoneum and serosal surfaces of ferrets. They are locally aggressive, result in marked abdominal effusion, and warrant a poor prognosis. Pancreatic exocrine adenocarcinomas are occasionally seen in the pancreas - these neoplasms are locally aggressive with a moderate metastatic potential, most commonly to the liver. Intestinal adenocarcinomas are rare locally aggressive neoplasms Gastric carcinoma has been experimentally reproduced in the presence of Helicobacter mustelae with a carcinogenic compound.
Musculoskeletal system: Osteomas are generally seen arising from flat bones. They are expansile neoplasms composed of trabecular of well-differentiated bone lined by osteoblasts and a few osteoclasts. The trabeculae are wide and there is little intervening space. Marrow is not seen. Interestingly, osteosarcoma has not been reported in the ferret.
Integumentary system: Apocrine cysts are a common finding in ferrets. They most commonly occur around the head, neck, prepuce, and vulva, due to the large numbers of scent glands in these regions. Apocrine gland cystadenomas and carcinomas are not uncommon and have a similar distribution. Apocrine gland carcinomas are locally aggressive neoplasms with a moderate potential for metastasis. Hemangiomas and low-grade hemangiosarcomas are occasionally seen; metastasis has not been reported. Squamous cell carcinoma has been reported several times in the ferret and has a predilection for the face, where it is locally destructive with a low metastatic potential.
Urinary system -Transitional cell carcinoma has been reported in the ferret.
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