Pathologyofdiseasesof Geriatricexoticmammals: Drury R. Reavill,, Denise M. Imai

Pathology of Diseases of
G e r i a t r i c E x o t i c Ma m m a l s
a,
Drury R. Reavill, DVM, DABVP (Avian and Reptile & Amphibian Practice), DACVP *,
b
Denise M. Imai, DVM, PhD, DACVP
KEYWORDS
Rodents Rabbit Ferret Geriatric Neoplasia Chronic respiratory disease
Chronic progressive nephropathy Atrial thrombosis
KEY POINTS
Neoplasia is the most prevalent geriatric disease of small companion rodents, guinea pigs,
rabbits, and ferrets.
Chronic respiratory disease complex, cardiomyopathy, and chronic progressive nephrop-
athy in aged rats.
Atrial thrombosis with congestive heart failure in aged hamsters.
Pododermatitis is not uncommon in older rats, mice, guinea pigs, and rabbits.
Some infections are more common in older animals such as mycoplasma in rats, myco-
bacteria in ferrets, cryptococcus in ferrets, cestode cysts in rabbits, and internal and
external parasites in rats and hamsters.
INTRODUCTION
Much of what we know about aging in small rodents (mice and rats) comes from
studies on inbred laboratory strains1–3 that are maintained under controlled condi-
tions. This is also true for laboratory ferrets, rabbits, and guinea pigs.4–6 With the inter-
est in understanding human aging and developing interventional therapeutics to slow
or reverse these aging processes, rodent, rabbit, and ferret models of aging are well
defined2,3 and the lesions of aging, both clinically significant and incidental, have
been well described.1,2,4–12 Only clinically significant and/or relatively prevalent dis-
ease processes are discussed here and include neoplastic diseases and respiratory,
cardiovascular, gastrointestinal, renal, vestibular, neurologic, hepatobiliary, endo-
crine, musculoskeletal, and infectious diseases. The resources listed in the references
a
ZNLabs Veterinary Diagnostics, 7647 Wachtel Way, Citrus Heights, CA 95610, USA;
b
Comparative Pathology Laboratory, University of California, 1000 Old Davis Road, Building
R1, Davis, CA 95616, USA
* Corresponding author.
E-mail address: Drury@vin.com
Vet Clin Exot Anim 23 (2020) 651–684

https://doi.org/10.1016/j.cvex.2020.06.002 vetexotic.theclinics.com
1094-9194/20/ª 2020 Elsevier Inc. All rights reserved.
652 Reavill & Imai
should be used to explore additional histopathologic lesions associated with aging in

small rodents, rabbits, and ferrets, if of interest.
Relative prevalence of disease processes for mice, rats, and hamsters was based
on a retrospective survey of pathology reports from the Veterinary Medical Teaching
Hospital and Comparative Pathology Laboratory at the University of California, Davis.
Prevalence of diseases does not directly correlate with cause-of-death assignation;
for example, a rat may have multiple benign tumors but may have died of respiratory
disease. The survey of rats and hamsters was collected from complete necropsy re-
ports spanning a 20-year period, from 2000 to early 2020. The survey of mice was
collected from complete necropsy reports spanning a 2-year period, from 2017 to
2018. The inclusion criteria for age varied by species; rats older than 1.5 years,
mice older than 15 months, and hamsters older than 12 months were included.
The disease conditions of elderly guinea pigs, rabbit, and ferrets were collected
from material in the literature, and the selected specific conditions were augmented
with data from Zoo/Exotic Pathology Service (1998–2019). Guinea pigs at 3 years
and rabbits and ferrets at 5 years and older were considered geriatric.
DISEASES BY ORGAN SYSTEM

Respiratory Disease
Respiratory disease was far more common in the aged rats surveyed than in the mice
or hamsters (Table 1). Among the aged rats with respiratory disease in this retrospec-
tive survey, the most common diagnosis was chronic respiratory disease (CRD) (45 of
88 rats, 51.1%). CRD is a pneumonic complex classically considered to be initiated by
an inhaled irritant (ammonia) or viral infection (Sendai virus) and promoted by infection
with either or both Mycoplasma pulmonis and cilia-associated respiratory (CAR) bacil-
lus.8 In many cases, M pulmonis can be the primary pathogen, and murine respiratory
mycoplasmosis has been used as a synonym for this respiratory disease complex.8
The classic lesion of CRD is suppurative bronchopneumonia with bronchiectasis
and abscessation. It is the bronchiectasia that gives the characteristic "cobblestone"
gross appearance to the lungs, and the lobar distribution of disease is often asym-
metric (Fig. 1). Histopathologically, respiratory mycoplasmosis incites a striking hy-
perplasia of the bronchial-associated lymphoid tissue. If there is a concurrent CAR
bacillus infection, filamentous bacteria will be present in parallel with respiratory cilia.
The prevalence of CRD in this study group is likely underrepresented as the diagnosis
of bronchopneumonia—etiology (unspecified) was reported in 23 rats (26.1%) and
probably represents unrecognized CRD. Pulmonic pseudotuberculosis due to Cory-
nebacterium kutscheri was identified in 6 (6.8%) of the 88 rats. The gross appearance
of pseudotuberculosis is distinct from CRD, manifesting as multiple foci of consolida-
tion and necrosis (Fig. 2) without the asymmetric distribution or bronchiectatic
appearance. The histopathologic pattern of neutrophilic inflammation with large col-
onies of amorphous bacteria is considered pathognomonic.8 Bordetellosis (Bordetella
bronchiseptica) and chronic passive pulmonary congestion (CPPC) due to cardiac
insufficiency was each identified in 2 of the 88 rats (2.3%).
In the aged mice surveyed, eosinophilic crystalline pneumonia (ECP) accounted for
most of the cases (5 of 6, 83.3%). ECP (alternatively called acidophilic macrophage
pneumonia) can be extensive and often occurs after other pulmonary diseases (pul-
monary adenomas, CPPC, and so forth).7,10 Grossly, the pattern is interstitial to alve-
olar with tan to brown discoloration and failure to collapse in a regional to lobar
distribution. Histologically, alveoli are filled with foamy macrophages and extracellular
and intracellular sharp acicular brightly eosinophilic crystals (Fig. 3). A neutrophilic
Table 1
Retrospective survey of diseases in pet and laboratory rodents
Otitis/Inner Degenerative
Pathology of Diseases of Geriatric Exotic Mammals

Total Age Average Respiratory Chronic Ear Neurologic Infectious
Species No. Range Age Tumors Disease Cardiomyopathy Nephropathy Infarction Disease Dermatitis Disease
Rats 195 1.5–4y 2.3 y 151 (77.4%) 88 (45.1%) 50 (25.6%) 62 (31.8%) 33 (16.9%) 15 (7.7%) 7 (3.6%) 82 (42.1%)
Micea 79 1.3–2.3 y 1.6 y 51 (64.6%) 6 (7.6%) 32 (40.5%) 30 (40.0%) 8 (10.1%) 2 (2.5%) 4 (5.1%) 0 (0.0%)**
Hamster 23 l–2.5 y 1.4 y 16 (69.6%) 6 (26.1%) 9 (39.1%) 10 (43.5%) 0 (0%) 0 (0%) 2 (8.7%) 3 (13.0%)
a
Three pet mice, 76 laboratory mice (strain C57BL/6J). ** 96.2% of the aged mouse population were housed in controlled specific pathogen free laboratory con-
ditions, therefore the prevalence of infectious disease does not correlate to the companion animal population.
Data collected from the Veterinary Medical Teaching Hospital (2000-early 2020) and Comparative Pathology Laboratory (2017-2018) at the University of Cali-
fornia, Davis.
653
654 Reavill & Imai
Fig. 1. Chronic respiratory disease in a rat, exhibiting the characteristic asymmetric "cobble-
stone" appearance caused by bronchiectatic abscessation. The causal agents include Myco-
plasma pulmonis and CAR bacillus, with or without underlying Sendai virus infection.
(Courtesy of C. M. Reilly, DVM, Davis, CA.)
Fig. 2. Pulmonic pseudotuberculosis in a rat, caused by Corynebacterium kutscheri. The dis-

tribution of the tan foci of necrosis and suppurative inflammation is multifocal to coa-
lescing. (Courtesy of J. Magnusson Wulcan, DVM, Davis, CA.)
Pathology of Diseases of Geriatric Exotic Mammals 655
Fig. 3. Eosinophilic crystalline pneumonia in a mouse. Prevalence increases with age and
with the existence of another pulmonary disease, such as a pulmonary adenoma or chronic
passive congestion. Hematoxylin and eosin stain. 400x magnification.
interstitial pneumonia, smooth muscle metaplasia, and occasionally papillary intra-

bronchial granulation tissue can accompany ECP. The composition of the crystals is
YM1 chitinase,7 derived from activated macrophages and is part of the systemic hya-
linosis seen as an incidental finding in the respiratory, biliary, and gastric epithelium of
aged mice.7,11 CPPC due to congestive left-sided heart failure was present in 2 of the
6 mice (33.3%) with respiratory disease and occurred simultaneously with ECP in one
mouse.
The most common respiratory disease in the aged hamsters was CPPC (4 of 6,
66.7%) due to heart failure. Grossly, CPPC presents with an interstitial pattern, where
the lung diffusely is pale pink to tan and fails to collapse. Histologically, in CPPC, alve-
olar spaces are filled with variable amounts of fluid and hemorrhage as well as foamy
macrophages that contain erythrocytes or hemosiderin pigment (heart failure cells).
The most common cause of CPPC in hamsters (and in mice) is left atrial thrombosis
(see cardiovascular section).9 One of 6 hamsters had gram-negative bacterial pneu-
monia (16.7%), and the last hamster had interstitial pneumonia (16.7%) with features
of sepsis and possibly, CPPC.
Cardiovascular Disease
Cardiovascular disease was less common in aged rats (54 of 195, 27.7%) than in mice
(34 of 79, 43.0%) or hamsters (10 of 23 hamsters, 43.5%) but can affect up to 80% of
the population in some rat strains.8 Most of the cardiovascular diagnoses was cardio-
myopathy (50 out of 54, 92.6%) with 25 rats having moderate-to-severe disease based
on histopathologic changes in the heart and/or indicators of fulminant left-sided heart
failure. Left ventricular hypertrophy (Fig. 4) with thickening of the ventricular wall and
stenosis of the lumen was the most frequent indicator of cardiomyopathy. Infectious
myocarditis (due to Streptococcus pneumoniae) was present in 1 of 54 (1.9%) rats.
Polyarteritis nodosa (PA) was present in 1 of 54 (1.9%) aged rats. PA is characterized
by chronic fibrinoid arteritis with mural dissections to saccular aneurysms, periarterial
fibrosis, and luminal thrombosis. Any medium-sized artery can be affected, except in
the lung.8 Six rats (11.1%) had arteriosclerosis, a nonspecific thickening of the arterial
wall.
In the aged mice, the 39 cases of cardiovascular disease were primarily cardiac.
Mild to marked left ventricular hypertrophy (32 of 39, 82.1%) was the most common
656 Reavill & Imai
Fig. 4. Left ventricular hypertrophy in a rat. The cross-section of the affected heart (right)
exhibits a thickened left ventricular wall and interventricular septum with collapse or steno-
sis of the lumen. A normal, unaffected heart on cross-section (left) is present for comparison.
diagnosis with a single case of dilative cardiomyopathy reported. Histopathologic

changes are characterized by cardiomyocyte hypertrophy, disarray, and karyomegaly
with variably mononuclear cell infiltration and fibrosis.1,7 Left-sided congestive heart
failure was documented in 2 of the 32 mice (6.3%). Chronic necrotizing arteritis
(CNA), the mouse equivalent of PA, was diagnosed in 7 of 39 (17.9%). CNA in the
mouse is typified by fibrinoid degeneration and necrosis of the tunica media with var-
iable cellular inflammation, fibrosis, and luminal stenosis.7 CNA differs from PA as it is
not associated with aneurysmal weakening of the vascular wall and thus lacks the
nodular component that defines PA. CNA tends to involve arteries in the head, heart,
kidneys, mesentery, tongue, and urogenital tract though involvement of the gastroin-
testinal system and pancreas also occurs.7,10 A single diagnosis of endocardiosis was
reported, the prevalence of which is likely underrepresented, as it is difficult to consis-
tently evaluate murine heart valves in section. Other age-related clinically significant
diseases that were not reported in these mice include left auricular thrombosis.
In the aged hamsters, atrial thrombosis (Fig. 5) was the most common diagnosis (6
of 10, 60%) and would seem grossly as a firm mass within the left atrium/auricle. If pre-
sent for some duration, the left side, and often the right, of the heart is hypertrophied.
Classically, the pathogenesis of atrial thrombosis has involved renal amyloidosis9 pre-
sumably due to loss of antithrombin III and has been thought to result in anasarca6;
however, in this survey, none of the hamsters with atrial thrombosis had either lesion.
Instead, the development of renal amyloidosis with subsequent anasarca (protein-
losing nephropathy) may occur simultaneously with atrial thrombosis, as both are dis-
eases of aging in hamsters.
Renal Disease
Chronic renal disease was similarly prevalent in these aged rats, mice, and hamsters
(see Table 1). Unsurprisingly, chronic progressive nephropathy (CPN) was the most
common diagnosis in the aged rats with renal disease (62 of 63, 98.4%). CPN is a ma-
jor life-limiting disease in rats and is considered multifactorial, associated with
advanced age, male sex, and high dietary protein.3,8 Prolactin, from hormonally pro-
ductive pituitary adenomas, has been associated with CPN but the association may
be indirect, as both CPN and pituitary adenomas are diseases of aged rats. In this
Fig. 5. Left atrial thrombosis in a hamster. (A) Externally, the left atrium is enlarged and
firm. (B) On cut section, the left atrial lumen is filled with a tan lamellar thrombus (T)
that is firmly adhered to the endocardial surface. (Courtesy of M. A. Highland, DVM, PhD,
Manhattan, KS.)
retrospective survey, there was no statistically significant relationship between the 2

(Fisher’s exact test, P 5 .07). The classic presentation of CPN is a light red to brown
kidney with a pitted to finely cystic cortical surface (Fig. 6). Histologic changes are
consistent with a chronic glomerulonephropathy with tubular degeneration and pro-
teinuria. Glomerular changes include mesangial thickening, basement membrane
thickening, synechiae formation, and sclerosis. Tubular changes include degeneration
and cystic dilation with protein casts. Interstitial fibrosis and lymphoplasmacytic
inflammation can accompany the glomerulonephropathy.8 One rat out of the 63 had
chronic cystitis with ureteral obstruction (1.6%).
Fig. 6. Chronic progressive nephropathy in a rat. Affected kidneys are shrunken and pale
tan to brown with a pitted to cystic surface. The small cortical cysts represented dilated, ec-
tatic tubules.
658 Reavill & Imai
Chronic nephropathy (CN) in the aged mouse resembles CPN in the rat and was
diagnosed in 30 out of 36 mice (83.3%) with renal disease. The gross and histopath-
ologic appearance of CN in the mouse is similar to the rat but is thought to begin with
tubular changes and progress to membranoproliferative glomerulonephritis.7,10,12 In
certain cases, glomerular mesangial or basement membrane thickening can be so
strikingly amorphous that it can be confused with amyloidosis1 and is called hyaline
glomerulopathy (HG) (Fig. 7).13 In general, HG is more common than glomerular
amyloidosis in the mouse (0 cases of amyloidosis in this survey), and there are histo-
pathologic features that can distinguish between the 2 diseases. In HG, in contrast to
glomerular amyloidosis, mesangial deposits can asymmetrically affect the glomerulus,
and glassy thrombi can be present in glomerular capillaries. In glomerular amyloidosis,
deposits are uniformly distributed within the glomerulus, and amyloid is present in at
least 1 other tissue.13 The prevalence of CN in C57BL/6 mice can approach 100% in
aged colonies.10 Pyelonephritis (3 of 36, 8.3%), unilateral hydronephrosis (2 of 36,
5.6%), and urolithiasis (1 of 36, 2.8%) comprise the remaining diagnoses of renal dis-
ease in the aged mice surveyed. Another common age-related renal disease not
observed in this population includes obstructive uropathy due to retrograde ejacula-
tion (mouse urologic syndrome).7,10,11
Renal disease was identified in 11 of 23 (47.8%) aged hamsters, with chronic ne-
phropathy similarly being the most common diagnosis (10 of 11, 90.9%). The last ham-
ster of the group had chronic pyelonephritis. Renal amyloidosis was not identified in
any of the hamsters in this survey but is a classic age-related disease of hamsters.9
Special Senses
Disorders of the special senses (ears and eyes) were observed in the rats and mice
surveyed but was not reported in the hamsters. Otitis media and interna (33 of 40,
82.5%) was the most common diagnoses and cataracts was the second and only
other diagnosis (11 of 40, 27.5%). Four rats had both otitis and cataracts. Mycoplas-
mosis was confirmed in the ear or lungs of 12 (36.4%) of the rats with otitis. In the aged
mice, labyrinthine infarction due to chronic necrotizing arteritis (6 of 10, 60%) was the
Fig. 7. Hyaline glomerulopathy in a mouse. The mesangium and basement membranes of

the glomeruli are thickened by hyaline amorphous material. Capillary thrombosis, character-
ized by round to oval aggregates of the hyaline material (arrows) within capillaries, is a
diagnostic feature that can be used to differentiate this entity from amyloidosis. Hematox-
ylin and eosin stain. 200x magnification.
most common diagnosis, followed by otitis media (2 of 10, 20%) and cataracts (2 of
10, 20%). CNA is incidental unless luminal stenosis or occlusion results in local tissue
infarction, as in the ear.10 One other age-related ocular condition of mice that was not
diagnosed in this retrospective survey is ulcerative keratitis due to lacrimal gland atro-
phy and suboptimal tear film quality or quantity (keratoconjunctivitis sicca).10
Neurologic Disease
Neurologic disease was present in 20 rats (10.3%), 2 mice (2.5%), and no hamsters. In
the rats, the majority (15 out of 20, 75%) had degenerative myelopathy/radiculoneur-
opathy, a syndrome of demyelination and axonal loss in the white matter of the spinal
cord and spinal nerve roots.8 The syndrome starts caudally, in the lumbar spinal cord
and cauda equina, and manifests as posterior paresis or paralysis. Luxol fast blue can
effectively highlight the extent of myelin loss as it progresses rostrally. Five of the 20
rats (25%) had a presumed bacterial meningoencephalitis or cerebellar abscess.
The 2 mice identified to have neurologic disease both had compressive myelopathies
subsequent to intervertebral disc degeneration (IVDD) and intraspinal canal protru-
sion/extrusion. IVDD is not unique to the mouse but also recognized as an age-
related and life-limiting disease in rats.8,11 IVDD, especially in the mouse, is easiest
to assess histopathologically in longitudinal sections through the decalcified vertebral
column. Spinal cord is best evaluated if left in situ for evaluation together with the
vertebral column.
Integumentary Disease
Nononcologic integumentary diseases was identified in 3% to 9% (see Table 1) of the
aged rat, mouse, and hamster population. In the rats, 7 of 7 (100%) diagnoses were for
ulcerative pododermatitis. The cause is likely a combination of husbandry conditions,
obesity in ad libitum–fed pets, and decreased grooming with general debilitation.11 In
the mice, ulcerative dermatitis (3 of 4, 75%) and pododermatitis (1 of 4, 25%) is a com-
mon disease attributed to many causes, from trichotillomania to a primary follicular
dystrophy, and are often exacerbated by opportunistic staphylococcal infection.7,10
In the hamsters, 2 cases of atrophic and fibrotic dermatopathies of unknown cause,
although potentially paraneoplastic, were reported.
Infectious Disease
Infectious agents were primarily identified in the pet rats surveyed and less so in the
hamsters. As the mice were laboratory animals raised in controlled conditions under
stringent health surveillance, the lack of infectious disease agents was an expected
finding. In the rats, agents of CRD (Mycoplasma sp. and CAR bacillus) were the
most commonly reported (45 of 82, 54.9%). Pneumocystis sp. was identified in 2 of
82 rats (%). Fourteen rats had metazoan endoparasites (cestodes, nematodes) and
8 had arthropod ectoparasites (lice, mites). In the hamsters, demodicosis, pinworm
infestation, and giardiasis was each diagnosed once, in 1 hamster.
Neoplastic Disease
The prevalence of neoplastic disease in the aged rats, mice, and hamsters ranges be-
tween 64.6% and 77.4%. Among the aged rats, 151 out of 195 rats had tumors and a
total of 214 tumors were diagnosed. Based on clinical presentation (Box 1), subcu-
taneous masses were most frequently identified (56 of 195 rats, 28.7%), of which 3
had multiple types of subcutaneous tumors. The next most common were intracranial
tumors in rats that presented with neurologic signs (49 of 195, 25.1%). Conversely, the
most prevalent tumor diagnosis was pituitary adenoma (19.2%) (Fig. 8) followed by
660 Reavill & Imai
Box 1
Retrospective survey of common neoplastic diseases in 196 older pet rats (1.5 years) by clinical
presentation (124 tumors)
Diagnoses (No./No in category)

Subcutaneous mass
Mammary fibroadenoma (36/59)
Mammary carcinoma/adenocarcinoma (7/59)
Mammary adenoma/cystadenoma (5/59)
Subcutaneous fibroma (4/59)
Intracranial mass/Neurologic signs
Pituitary adenoma (41/49)
Pituitary carcinoma (2/49)
Granular cell tumor (2/49)
Head/Neck/Oral mass
Squamous cell carcinoma, facial, buccal, glossal, or laryngeal (10/20)
Osteosarcoma, mandibular, or cranial (3/20)
Intrathoracic mass/Respiratory signs
Lymphoma, pulmonary, mediastinal, or hilar (11/18)a
Disseminated masses
T-cell lymphoma/leukemia (7/14)
Non-B-cell, non-T-cell lymphoma (3/14)
LGL lymphoma/leukemia (3/14)
Myeloid leukemia (1/14)
Endocrine signs
Islet cell adenoma/insulinoma (4/14)
Pheochromocytoma (3/14)b
Adrenocortical adenoma (3/14)
Reproductive mass
Ovarian granulosa theca cell tumor (2/13)
Endometrial adenocarcinoma (2/13)
Uterine stromal tumor (2/13)
Uterine leiomyosarcoma (2/13)
Hepatosplenic/Abdominal mass
Histiocytic sarcoma (6/10)c
Axial/appendicular mass
Fore/hindlimb soft tissue sarcoma (3/7)d
Abbreviation: LGL, large granular lymphocytic.a Eight were typed as B-cell origin by immuno-
histochemistry.b Two were bilateral.c Three were suspected.d Includes peripheral nerve sheath
tumor and fibrosarcoma.
Data collected from the Veterinary Medical Teaching Hospital, University of California, Davis
(2000-early 2020).
mammary fibroadenoma (16.8%) (Fig. 9). The actual prevalence of mammary fibroa-
denomas may be slightly higher, as a few rats had a history of subcutaneous tumor
removal without a biopsy diagnosis. An association between mammary fibroadeno-
mas and prolactin-producing pituitary adenomas has been suggested5 but remains
unsubstantiated. In this retrospective survey, there was no statistically significant rela-
tionship between the 2 (Fisher’s exact test, P 5 .3706). Mammary fibroadenoma
occurred with pituitary adenoma/carcinoma in 20 out of 43 rats (46.5%) with pituitary
tumors. Mammary fibroadenoma occurred without the presence of a pituitary tumor in
13 out of 36 rats (36.1%) with mammary fibroadenoma.
Fig. 8. Pituitary adenoma in a rat.
Other common tumor diagnoses in the aged rats included orofacial squamous cell
carcinoma (Fig. 10), intrathoracic lymphoma, disseminated lymphoma/leukemia, and
intraabdominal histiocytic sarcoma (see Box 1). Less common diagnoses (1–2 cases)
presenting as subcutaneous masses included lymph node hemangioma, preputial
squamous cell carcinoma, mammary myoepithelioma, peripheral nerve sheath tumor,
fibrosarcoma, and lipoma. Less common diagnoses presenting as intracranial disease
included a cerebral lymphoma and astrocytoma. Less common diagnoses presenting
as masses in the head, neck, and oral region include an anaplastic sarcoma, soft tis-
sue sarcoma, Harderian gland adenoma, B-cell lymphoma, and lip papilloma. Less
common diagnoses presenting as intrathoracic masses included thymoma, medias-
tinal hibernoma, pulmonary carcinoma, fibrosarcoma, and osteosarcoma. Less com-
mon diagnoses presenting as endocrine disease included thyroid/c cell adenoma,
thyroid carcinoma, and parathyroid adenoma. Less common diagnoses presenting
with reproductive disease included a prostatic carcinoma, Leydig cell tumor, uterine
histiocytic sarcoma, cervical leiomyoma, and uterine myxoma. Less common diagno-
ses presenting as a hepatosplenic or intraabdominal mass included an exocrine
Fig. 9. Mammary fibroadenoma in a rat. The red to brown staining around the eyes and on
the forelimbs is chromodacryorrhea. Other features of age-associated debilitation include
scruffiness of the hair coat and possible ectoparasitism.
662 Reavill & Imai
Fig. 10. Glossal squamous cell carcinoma in a rat. The mandible is transected along midline
with the tongue in situ. The black arrow indicates the tumor.
pancreatic carcinoma, splenic stromal sarcoma, splenic lymphoma, and biliary ade-
noma. Less common diagnoses presenting as an axial or appendicular mass included
a hindlimb leiomyosarcoma, hindlimb hemangiosarcoma, malignant chordoma, and
femoral osteosarcoma. Less common diagnoses presenting as an integumentary
mass included a trichofolliculoma, dermal fibroma, sebaceous cystadenoma, dermal
lipoma, and squamous cell carcinoma. Less common diagnoses presenting with
gastrointestinal disease included a pyloric adenocarcinoma, intestinal lymphoma,
colonic sarcoma, and colonic polyp.
In mice, the strain of mouse dictates the prevalence of and types of tumors that
occur with age.1,3,7,10–12 As these mice surveyed are mostly C57BL/6, the strain-
specific tumor prevalence (Box 2) is not directly translatable to pet mice but can be
used as a diagnostic guide. In this mouse strain, hematopoietic neoplasms are known
Box 2
Retrospective survey of common neoplastic diseases in 79 aged mice (15 monthsD) (68 total
tumors)
Diagnoses (No.)
Histiocytic sarcoma (15)
Lymphoma/Pleomorphic lymphoma (9)
Pulmonary adenoma (6)
Harderian gland adenoma (6)
Hemangiosarcoma, subcutaneous (4)
Cutaneous papilloma, lip, or muzzle (3)
Pituitary adenoma (3)
Keratoacanthoma (2)
Pulmonary carcinoma (2)
Hepatic adenoma (2)
Data collected from the Veterinary Medical Teaching Hospital (2000-early 2020) and Compara-
tive Pathology Laboratory (2017-20188) at the University of California, Davis.
to be very common.10 As expected, the most common tumors in this study were his-
tiocytic sarcoma (17 out of 51 mice with tumors, 33.3%) and lymphoma (9 of 51,
17.6%). Histiocytic sarcoma typically presents as abdominal distention due to hepa-
tosplenomegaly (Fig. 11) with variable hematogenous dissemination14 but can be
localized to an axial or appendicular region (2 of the 17 cases, 11.8%). Expected gross
findings with histiocytic sarcoma are an enlarged, light red to brown, variably mottled
liver and spleen. The reticular pattern can be enhanced or there can be multiple pale
tan foci that are nodular (representing neoplastic cellular infiltration) or depressed (rep-
resenting necrosis). The histopathologic pattern of histiocytic sarcoma in the mouse is
distinct; the neoplasm begins in the liver, in a sinusoid-dependent pattern that is
initially more expansile than obliterative. The neoplastic histiocytes are small, oval to
angular to plump spindle-shaped with modest amounts of cytoplasm and small but
pleomorphic and folded nuclei.14 Multinucleated cells are often present, and a charac-
teristic associated lesion is renal tubular epithelial hyalinosis.7,10,14 Immunohisto-
chemical markers for macrophage antigens can be used to confirm the diagnosis.
Most of the lymphomas were consistent with T-cell lymphoma (8 of 9 tumors), and
1 case was diagnosed as a follicular (pleomorphic) lymphoma. Most lymphomas in
C57BL/6 mice are composed of moderately sized (lymphoblastic) cells with a charac-
teristic "starry sky" appearance and aggressively disseminate to multiple sites.14
Follicular (pleomorphic) lymphoma arises in the splenic follicles, is composed of a
mixture of small and large blastic follicular center cells, and can include bi- or multinu-
cleated cells.12,14 These histopathologic features can be confused with histiocytic sar-
coma but is differentiated from histiocytic sarcoma by the primary splenic follicular
involvement and dissemination to lymphoid structures.14 Pulmonary adenomas are
typically incidental but can be clinically significant (causing dyspnea) if large enough
or if associated with ECP. Harderian gland adenomas typically present with unilateral
exophthalmos10 or facial asymmetry.7 Other common mouse tumors that are not
Fig. 11. Histiocytic sarcoma in a mouse. The liver (Liv) and spleen (Sp) are markedly enlarged
and mottled red to pale tan with nodular aggregates scattered throughout. In this aged
male mouse, the seminal vesicles (s) are also enlarged and the right seminal vesicle is orange
to pink in color. Distention and color change in the seminal vesicles is a common incidental
finding in aged male mice.
664 Reavill & Imai
represented in this study due to strain-bias include mammary or salivary gland myoe-
pitheliomas, rhabdomyosarcomas, and osteosarcomas.7
In the aged hamsters, 23 neoplastic diseases were diagnosed in 16 hamsters, of
which 5 hamsters had multiple types of tumors. Lymphoma was the most prevalent
tumor type (5 of 23, 21.7%). Three of the cases were disseminated T-cell lymphomas
and 2 were epitheliotropic T-cell lymphomas. Both types of tumors are recognized as
spontaneous tumors of hamsters and not necessarily associated with infection by
hamster polyomavirus.9 Epitheliotropic T-cell lymphoma presents characteristically
with patchy alopecia with erythroderma and ulceration (Fig. 12). Diagnostic findings
are characterized by monomorphic neoplastic lymphocytes aggregating within the
epidermis (Pautrier microabscesses). Adrenocortical tumors (an adenoma and a car-
cinoma) were identified in 2 hamsters, and biliary cystadenomas were identified in 2
hamsters. Other tumor diagnoses included sebaceous adenoma, hepatoma, heman-
giosarcoma, plasmacytoma, mucinous carcinoma, ovarian cystadenoma, pituitary
adenoma, renal adenoma and carcinoma, scrotal sarcoma, splenic sarcoma, uterine
leiomyoma, and dermal histiocytic sarcoma.
Other Clinically Significant Changes Associated with Aging

Foreign-body periodontitis,7,10,11 caused by the lodging of hair shafts in the gingival
sulcus with subsequent reactive inflammation and bony resorption, is an age-
related disease in mice that can result in dental attrition and inanition. Seminal ve-
sicular dilation is age related in male mice and although impressive and possibly
causing space-occupying disease, is largely an incidental finding.7,10,11 In ham-
sters, polycystic liver disease9 can result in hepatic dysfunction and visceral
compression.
Fig. 12. Epitheliotropic T-cell lymphoma (mycosis fungoides) in a hamster. The typical pre-
sentation, depicted here, is alopecia with thickening and ulceration (u) of the skin. (Cour-
tesy of K. D. Watson, DVM, PhD, DACVP, Davis, CA.)
GUINEA PIGS
Guinea pigs are vocal, interactive pets that will live up to 5 to 7 years. They are gener-
ally considered senior around 3 to 5 years. A select number of diseases specific to
guinea pigs are described based on submissions to Zoo/Exotic Pathology Service
from 1998 to late 2019. Additional entities are selected based on recent publications
that add more information about the disease/lesion.

Older males (boars) can accumulate large amounts of waxy, malodorous, sebaceous
material in the skin of the perianal region.15 This material is often mistaken for a fecal
impaction (Fig. 13). The circumanal region contains a large number of perineal seba-
ceous glands that in the male are used for scent marking. The sebaceous glands are
testosterone dependent; females have much smaller glands and in castrated males
the gland atrophy and are infiltrated with fat.16 Intact adult males also have a deeper
perineal sac than females and castrated males so the secretions tend to accumulate in
the folds of the circumanal and genital region.16
Musculoskeletal Disease
Guinea pigs are prone to pododermatitis, and this is a common finding in older ani-
mals.17 The lesion is a painful ulcerative and/or erosive inflammation of the footpads
that can become severe enough to affect the phalanges as an osteolysis (Fig. 14).
Secondary bacterial involvement, usually Staphylococcus aureus, can result in septi-
cemia.18 Typically the animals are overconditioned and housed on wire floors or on
Fig. 13. Male guinea pig with accumulation of brown to black, malodorous sebaceous ma-
terial around the perineum.
666 Reavill & Imai
Fig. 14. Mild to moderate pododermatitis with ulceration in guinea pig. Compare with the
foot in Fig. 16.
abrasive bedding.18 Overweight animals may not move around enough resulting in
them sitting for long periods of time on contaminated bedding with feces and urine.19
Reproductive Disease
Ovarian cysts are very common reproductive tract lesion, and the incidence increases
with advancing age.20 The primary cyst is a cystic rete ovarii, and these are commonly
bilateral (Fig. 15). The rete ovarii is considered to be the remnant of an embryonic
structure in adult animals. These cysts are usually located in the hilus of the ovary
or are limited to the mesovarium adjacent to the hilus. Cysts can also arise from Graa-
fian follicles that fail to ovulate, luteal bodies, and infolds of the surface epithelium;
however, these are rare in guinea pigs. A common associated lesion is bilateral non-
pruritic flank alopecia, which is suspected to be hormonally influenced although rete
ovarii are not documented to produce sex hormones.20 One guinea pig report with
a confirmed follicular ovarian cyst had elevated estrogen levels.21
Renal Disease
Renal disease is a common finding in older guinea pigs. The lesions of chronic fibros-
ing nephritis, interstitial nephritis, pyelonephritis, and renal cysts have been
Fig. 15. Cystic ovary in a guinea pig. Hematoxylin and eosin stain. 10x magnification.
reported.22,23 In inflammatory lesions the kidneys may be irregular grossly, and in py-
elonephritis the ureters may be dilated. Chronic nephrosclerosis (fibrosing interstitial
nephritis/nephrosis) is renal scarring of undetermined cause primarily due to the
chronic nature of the lesion. It may be the result of vascular disease, infection, or
immune-mediated disease. Grossly the renal cortex is irregularly pitted and histolog-
ically there is interstitial fibrosis, variable glomerulosclerosis, tubular dilatation, and
variable mononuclear inflammation. Most cases of acquired renal cysts are associ-
ated with chronic renal disease.
Infectious Disease
Cervical lymphadenitis, one differential diagnosis for thyroid tumors, is commonly
associated with Caviibacter abscessus (previously known as Streptococcus zooepide-
micus).24,25 Although this is not necessarily a lesion of older guinea pigs, it is an impor-
tant differential for both thyroid lesions and lymphoma. The infection generally results
in a chronic suppurative lesion, which frequently involves the cervical lymph nodes
(Figs. 16 and 17). It can become septicemic. In young animals it tends to progress
to a severe respiratory infection (fibrinopurulent pleuritis, pericarditis, and broncho-
pneumonia) that has a high mortality and morbidity.26
Neoplastic Disease
A review of neoplastic diseases diagnosed at Zoo/Exotic Pathology Service is tabu-
lated (Box 3). The most common tumors in geriatric guinea pigs (5 years or greater)
were mammary gland adenocarcinomas/carcinomas, lipomas, trichofolliculomas,
and thyroid gland carcinomas.
Thyroid tumors are a common tumor in guinea pigs (median age 4.3 years, range
2.5–6 years).27 The typical presentation is of a palpable mass on the ventral neck
with progressive weight loss. The differential based on physical examination includes
cervical lymphadenitis and lymphoma. Aspiration cytology is an easy, diagnostic
method to obtain a quick answer as to the cause of cervical swellings.28 The clinical
Fig. 16. A ventral cervical swelling in a guinea pig. This is similar in appearance as thyroid
lesions and lymphoma.
668 Reavill & Imai
Fig. 17. The swelling has been opened to demonstrate the pus of cervical lymphadenitis in
this older guinea pig.
signs in functional tumors are typical for most mammals: weight loss, increased activ-
ity, and tachycardia due to cardiomegaly. The tumors have been macrofollicular thy-
roid adenomas, thyroid cystadenoma, papillary thyroid adenoma, follicular thyroid
carcinoma, follicular-compact thyroid carcinoma, small-cell thyroid carcinoma, and
an ectopic thyroid carcinoma.27,29 Some of the tumors may develop foci of osseous
metaplasia, which may be identified by radiology (Fig. 18).27,29 In one study all neo-
plasms were positive for thyroid transcription factor 1 and thyroglobulin but negative
for parathyroid hormone and calcitonin.27
In guinea pigs, mammary tumors occur with equal frequency in female and male an-
imals.30 The age range is reported from 3 to 7.5 years.30 The tumor types encompass
papillary cystadenomas, adenomas, papillary adenocarcinoma, tubulopapillary carci-
nomas, adenocarcinoma, and mixed mammary.30,31 Bilateral tumors frequently occur;
however, they have a low potential for metastases. The lung is the common site for the
rare metastases.31 From one study it seems most tumors are arising from the mam-
mary ducts, and these are positive for alpha-estrogen and progesterone receptors
suggesting hormonal influence on tumor formation.30
Rabbit
A rabbit is considered older or senior from the age of 4 to 5 years.32,33 The maximum
age ranges from 8 to 13 years for domestic rabbits.33,34 Many of the diseases in rab-
bits are similar to other elderly mammals and only a select number of diseases specific
to rabbits are described based on submissions to Zoo/Exotic Pathology Service from
1998 to late 2019. Additional entities are selected based on recent publications that
add more information about the disease/lesion.

Aging New Zealand rabbits are commonly used as models of cardiac disease in
humans.35,36 With aging there is an incorporation of fat cells and connective tissue
(fibrosis) in ventricular tissue and atrioventricular nodes that affects conduction time
resulting in arrhythmias.35 Myocardial fibrosis is one of the consequences of aging,
and this affects the myocardial stiffness that impairs cardiac function. The causes
for myocardial disease include hypovitaminosis E,37 bacterial infection (salmonella,
Box 3
Retrospective survey of common neoplastic diseases in 341 older adult pet guinea pigs
(5.0 yearsD) by clinical presentation (223 total tumors)
Diagnoses (No./No. in category)

Subcutaneous mass
Mammary gland adenocarcinoma/carcinoma (45/145)
Lipoma (27/145)
Trichofolliculoma (25/145)
Mammary gland adenoma/cystadenoma (9/145)
Fibrolipoma (6/145)
Liposarcoma (5/145)
Soft tissue sarcoma (4/145)
Myxosarcoma (4/145)
Neurofibrosarcoma (3/145)
Epitheliotropic lymphosarcoma (3/145)
Squamous cell carcinoma (3/145)
Carcinoma, site not provided (2/145)
Extraskeletal osteosarcoma (2/145)
Lymphoma (1/145)
Malignant melanoma (1/145)
Fibrosarcoma (1/145)
Hemangioma (1/145)
Myxoma (1/145)
Trichoepithelioma (1/145)
Leiomyosarcoma (1/145)
Head/Neck/Oral mass
Lymphoma, lymph nodes (2/4)
Odontogenic tumor (1/4)
Sarcoma, poorly differentiated (1/4)
Intrathoracic mass/Respiratory signs
Pulmonary adenoma (5/5)
Disseminated masses
Lymphoma (8/8)
Endocrine signs
Thyroid gland carcinoma (10/12)
Thyroid gland adenoma (2/12)
Reproductive mass
Leiomyoma/fibroleiomyoma, uterus (6/18)
Endometrial adenocarcinoma/carcinoma, uterus (4/18)
Carcinoma, ovary (2/18)
Leiomyosarcoma, uterus (2/18)
Seminoma, testicle (1/18)
Endometrial adenoma, uterus (1/18)
Squamous cell carcinoma, uterus (1/18)
Deciduoma, uterus (1/18)
Hepatosplenic/Abdominal mass
Sarcoma (autolyzed or poorly differentiated) (5/24)
Hepatic biliary cystadenoma (4/24)
Leiomyosarcoma, intestine (3/24)
Neurofibrosarcoma, stomach/intestine (3/24)
Hemangiosarcoma, spleen (2/24)
Hemangiosarcoma, stomach (1/24)
Hemangioma, spleen (1/24)
Lymphoma, spleen (1/24)
Leiomyoma, cecum (1/24)
Leiomyoma, site not determined (1/24)
670 Reavill & Imai
Hepatic biliary carcinoma (1/24)

Fibrosarcoma, site not determined (1/24)
Urinary mass
Lymphoma (urinary bladder) (1/2)
Soft tissue sarcoma (urinary bladder) (1/2)
Skeletal mass
Osteosarcoma, limb (2/5)
Osteoma, vertebral column (1/5)
Fibrosarcoma, limb (1/5)
Carcinoma, limb (1/5)
pasteurella),38 and encephalitozoonosis.39,40 Rabbits that are fed a hyperlipemic diet

are models for myocardial fibrosis and coronary atherosclerosis in man.36
Digestive Tract Diseases

Dental disease in older rabbits includes malocclusion typically from the loss of an
opposing tooth, tooth root abnormalities, and abscesses.41 There are many complete
reviews and books written about rodent and rabbit dental disease, and the reader is
referred to the published literature.
Chronic abscesses especially associated with the oral cavity and dental diseases
are common in older rabbits.41 These pyogranulomatous abscesses can invade into
the mandibular or maxillary bones. Even with complete surgical removal and appro-
priate antibiotics these abscesses frequently recur.41 Abscesses can occur in many
organs when the causative bacteria go septic.41
The mucosal recto-anal papilloma is an uncommonly reported lesion in rabbits. It
has been described primarily in older rabbits and demonstrated to be nonviral in
origin.42,43 There is no sex predilection, and the age range is 1 to 11 years with a me-
dian age of 4.8 years.42 These are usually well-differentiated cauliflower-like growths
that arise from the anorectal junction, and they are reported to be benign (Fig. 19).
Complete surgical removal is recommended although too little information is avail-
able to determine if these undergo neoplastic transformation in other mammalian
species.
Fig. 18. Guinea pig thyroid gland carcinoma with osseous metaplasia (arrows). Hematoxylin
and eosin stain. 2x magnification.
Fig. 19. Rabbit rectoanal papilloma. Hematoxylin and eosin stain. 2x magnification.
Sebaceous adenitis is widely reported in rabbits. To date, this has been primarily in
older animals. It presents as a nonpruritic scaling dermatitis with patchy to coalescing
areas of alopecia. Biopsy is usually opted, as these will have little response to many
treatments, including antimicrobials and antiinflammatories. On histology, there will
be several changes that include hyperkeratosis, follicular interface dermatitis, and
reduction in the numbers of sebaceous glands with possible association of lympho-
cytic infiltrations. Perifollicular to diffuse dermal fibrosis is also noted. The differentials
should include dermatophytes as well as ectoparasitic infections. It seems that there is
an increasing association between these lesions in adult rabbits and thymomas.19
A common nontumorous skin mass is the collagen nevi (collagenous hamartoma).
The median age is 6 years. This nodular, raised, firm skin lesion has been described
primarily on males. In some animals these may be solitary masses and in others, mul-
tiple nodules may develop. The common locations are on the abdomen and thorax.44
The lesions are of haphazardly arranged collagen bundles thickening in the middermis
(Fig. 20).
Musculoskeletal Disease
Pododermatitis, commonly known as sore hocks, has a complex cause. This is
commonly identified in older overconditioned adults. Poor sanitation, inappropriate
caging such as wire-bottom cages, and bedding materials will contribute to this dis-
ease resulting in a lack of mobility.34 Coarse bedding materials with poor liquid and
ammonia binding such as straw, wood shavings, or course bark mulch are associated
with lesion development.45 These lesions develop on the plantar aspect of the meta-
tarsal bones and are usually circumscribed ulcerative foci that may be associated with
granulation tissue. Early in the lesions, there may be a purulent exudate. Staphylo-
coccus species is the most frequent isolate from these lesions.41
Aging rabbits can develop degenerative spinal disease. In one study the spondylotic
vertebral lesions were present in rabbits as early as 2 years. The lesions first develop in
672 Reavill & Imai
Fig. 20. Rabbit collagenous hamartoma thickening the skin in males. Hematoxylin and eosin
stain. 2x magnification.
the cervicothoracic region and then the lumbar spine. The study did not evaluate the
findings with clinical signs.32 Osteoarthritis of the lumbosacral areas and hindlimbs
have been noted to affect normal behavior of aging rabbits. It is not typical for the le-
sions to result in signs of pain or discomfort.33
Reproductive Disease
Endometrial hyperplasia, frequently cystic, is a common finding in rabbits.46,47 The
mean age is 4.5 years to 5.2 years,47 which is younger than rabbits that develop uter-
ine tumors (mean age 6.1 years).46,47 Endometrial adenocarcinoma is the most com-
mon neoplastic lesion.47 Frequently both conditions may be present; however, there is
no documented evidence that hyperplasia progresses to a neoplastic lesion.47,48 The
development of abnormal proliferative lesions in the endometrium is under hormonal
influence.49 The ovaries of mature rabbits generally support multiple maturing follicles
and corpora lutea that suggests the uterine tissue is exposed to both estrogens and
progesterones continuously.48
Respiratory Disease
Respiratory lesions in aging rabbits are uncommonly described. Spontaneous pulmo-
nary emphysema has been recognized in older rabbits. It was found to have minimal
clinical significance and no relationship with overdistension of alveoli during ventila-
tion.50 One review associates the development of the lesion with atrophy of pulmonary
tissue.51
Renal Disease
As with many mammals, aged rabbits can develop chronic renal disease (Fig. 21).
Depending on the severity of the lesions, there may be associated metastatic miner-
alization of the soft tissues, particularly of the aorta. It is believed that many cases may
be a lesion of chronic or previous infections of Encephalitozoon cuniculi.33 A recent
review of urinary tract disease covers chronic lesions as well as common neoplasms
of the urinary tract.52
Fig. 21. Histology of chronic interstitial fibrosing nephritis in a rabbit. Arrows point to
bands of fibrosis through the cortex. Hematoxylin and eosin stain. 2x magnification.
Infectious Disease
Cysticercosis is the infection of a host by the eggs of a parasitic tapeworm whose
larval form creates cysts in various tissues of the body. Rabbits and hares are often
the intermediate host for many cestodes, usually Taenia multiceps, Taenia pisiformis,
and Taenia serialis, whose primary host are canids and other carnivores.53,54 It is more
commonly reported in wild rabbits and hares and rarely in domestic rabbits.55,56 Infec-
tion rates in domestic pet rabbits are unknown but are assumed to be comparably low.
Published cases of cysticercosis in pet and other caged rabbits include 2 laboratory
animals that were believed to be infected via contaminated hay, but other cases do
not report possible means of infection.57,58 The parasitic cysts can be found on the
liver surface, peritoneal, diaphragmatic and intestinal serosa, and in subcuticular tis-
sues (Fig. 22).58,59 These are reported to be more commonly identified in older female
Fig. 22. Cestode cysts proliferating on the serosa of the stomach in a rabbit.
674 Reavill & Imai
rabbits,59 although one author (DRR) has cases evenly divided between the sexes. The
age range from one author (DRR) is 1 to 9 years with a medium of 4.1 years.
Neoplastic Disease
Although tumor development increases with age, only a few tumors will be discussed.
More comprehensive reviews of rabbit tumors are published.60,61
The reported age range for mammary gland tumor development is 8 months to
14 years; the mean age is between 4.9 and 5.5 years.62–65 It seems that most of the
invasive cancer cases develop through a stepwise progression from noninvasive
forms. For many, the mammary gland starts with simple cysts or lobar hyperplasia,
to benign intracystic tubulopapillary tumors, and finally to carcinomas with possible
metastasis.62–64 Both benign and malignant mammary gland lesions can occur
together.63,64 Most of the tumors reported are carcinomas and/or adenocarci-
nomas.63–65 From one study both cranial and caudal glands are equally affected.65
Unlike in human medicine, there is no standardization of tumor classification for rab-
bits, which complicates developing prognostic factors. The primary option for therapy
is surgical removal.66 Nearly all reported tumors are in females or neutered females
and most are carcinomas.66 These carcinomas are often negative for estrogen and
progesterone receptors. This suggests the tumor growth is independent to exposure
and/or progesterone. Therapy aimed at these receptors will unlikely be beneficial for
most rabbits.63 Secretory activity is commonly recognized on histology (lipid droplets
in tumor cells), which can suggest prolactin influence on tumor development.66 Tumor
recurrence has been reported with matrix-producing carcinomas and adenocarci-
nomas.64 Metastasis are difficult to determine in studies involving pet rabbits, as
many were not evaluated further after death although vascular invasion is noted in
some malignancies.65 The metastatic sites include regional lymph nodes, kidneys,
lungs, liver, pancreas, adrenal glands, ovary, and bone marrow, and rarely the eye
(uvea).61,67 In one study, 29% of the pet rabbits with mammary tumors had concurrent
uterine carcinomas.64
Uterine tumors are the most common lesion found in the reproductive tract of fe-
male rabbits.46 From a study with full necropsies, metastasis from endometrial adeno-
carcinomas was found in 44.2% of the rabbits, with the lung being the most common
site.46 Other sites include pleura and mediastinum, peritoneum and omentum, liver,
kidney, ovaries, diaphragm, spleen, lymph nodes, brain, bone marrow, and urinary
bladder.47 Endometrial adenocarcinomas will locally implant if they invade through
the uterine wall. The tumor can be found as masses in both uterine horns.47 The
mean age was 6.2 years.46 Uterine adenocarcinomas are the most common tumor
with lesser numbers of adenomas, leiomyosarcomas, leiomyomas, hemangiosar-
coma, and hemangioma.46 Endometrial adenocarcinomas can be subdivided into
papillary and tubular/solid, which have some differences in how aggressive they
invade through the myometrium. They also differ in hormonal expression. Most papil-
lary adenocarcinomas are both estrogen receptor-a (ER) and progesterone receptor
(PR) negative, whereas the more aggressive tubular/solid adenocarcinomas are pos-
itive for ER-a, PR, or both.48 This could suggest additional therapies for hormone sen-
sitive tumors.48 Survival after ovariohysterectomy (OVH) was 22 to 27 months from
one study. Unless metastasis can be identified, OVH should be recommended.47
Rabbit testicular tumors typically occur in elderly males. In a review the age range
for all tumors was from 2 years to 12 years.68 As described in sporadic case reports,
8 tumors were bilateral and 2 were metastatic in this review.68 Most of the tumors were
diagnosed as granular cell tumors (GCT), with a fewer number of seminomas, and Ser-
toli cell tumors.68,69 Granular cell tumors have been recently better characterized and
most tumors originally diagnosed as interstitial cell tumors have been reclassified as
GCTs.69 The age range for GCT is 2 to 11 years with a median of 7.3 years. Surgical
removal carries a good prognosis.
Trichoblastomas, which are tumors arising from basal-type cells, are one of the
most common skin tumors and typically occur in older rabbits (median age 5–
7 years).44,70 In general, trichoblastomas are solitary, well-circumscribed intradermal
masses. The common sites of tumor occurrence are the neck, head, axilla, thorax,
flank, and hindlimb.44,70 The malignant form is very uncommon.70
FERRET
The lifespan of ferrets is reported to be 8 to 10 years in European reports. In North

America, the average age is reported to be 5 to 7 years of age; many veterinarians
consider 3 years of age as old.71,72 The diseases and lesions commonly associated
with aging include neoplastic disease as well as changes in vision, musculoskeletal
degeneration, oral disease, cardiomyopathy, renal disease, and nonspecific gastroin-
testinal lesions. Long-term anorexia, particularly in older animals, and secondary to
any other disease conditions can lead to hepatic lipidosis, a very common finding.71

Both dilated and hypertrophic cardiomyopathies have been recognized. Valvular dis-
eases are less common, and heartworm disease is reported in areas with exposure to
the disease agents. Dilated cardiomyopathy is the most common heart lesion.
Changes in cardiac function are typically recognized antemortem using electrocardio-
grams, ultrasound, radiographs, and CT in order to make the definitive diagnosis.
Gross evaluation will also confirm generalized changes to the heart, including dilated
and hypertrophic hearts, as well as identification of lesions on the heart valves, and the
presence of heartworm within the chambers. Histologic evaluation can add in addi-
tional information such as evidence of fibrosis indicating damage to the heart or any
possible inflammatory lesion and less likely identification of disease agents that may
be present.71
Digestive Tract Diseases
As with many mammals, aging ferrets can also develop dental calculi and not uncom-
monly, fractured canines.73 Tooth fractures can occur with fighting and abnormal wear
from chewing on hard surfaces.74 Extruded canine teeth are also a common oral lesion
in older ferrets.75 With the development of dental calculi, it is not uncommon to see
gingivitis. Untreated and progressive gingivitis can lead to periodontal disease, which
can contribute to tooth mobility and loss.73 Dental caries and tooth resorption seem to
be very rare in ferrets, although diet may be an influencing factor.75 Although rare,
similar to domestic dogs and cats, ferrets have been reported to develop oronasal
fistulae.71,74
Gastrointestinal diseases are fairly common in older ferrets, with trichobezoars,
gastric ulcers, epizootic catarrhal enteritis, and inflammatory bowel disease (IBD) as
the most commonly reported causes. Gastrointestinal foreign bodies are typically
recognized in younger ferrets, with the exception of trichobezoars. From one study
the age of the animals ranged from 22 to 59 months, with a mean of 43.7 months
compared with an age mean of 22.4 months with other foreign bodies (sponges and
rubber items). Trichobezoar formation may be due to excessive grooming or the accu-
mulation of fur around a previously ingested nidus of material.76
676 Reavill & Imai
IBD is a common, idiopathic, chronic disorder of the gastrointestinal tract in ferrets

older than 1 year. The mean age for IBD is reported at 4.1 years77 and 3 years.78 The
disease presents with nonspecific clinical signs but related to the digestive tract:
nausea, anorexia, weight loss, diarrhea, melena, and rectal prolapse. The definitive
diagnosis requires full-thickness intestinal biopsies, in order to differentiate from intes-
tinal lymphoma.78 A histologic grading scheme that correlates with the severity of the
clinical signs has been developed in order to provide more consistent evaluation for
prognosis.78 Histologically, IBD is characterized by blunting of the intestinal villi and
by a lymphoplasmacytic inflammatory infiltrate of the mucosa. The cause of IBD is
yet undetermined. The treatment of IBD generally consists of suppression of the in-
flammatory response with azathioprine or corticosteroids.
Spleen
Nonspecific splenic enlargement is fairly common in older ferrets (Fig. 23). This can be
secondary to any number of disease conditions, including tumors, myeloid hyperpla-
sia, and chronic congestion such as from heart disease as well as nodular hyperplasia.
Extramedullary hematopoiesis is a very common cause for enlargement. The initiating
factor for this particular proliferation is unknown in ferrets.71
Renal Disease
It seems aging ferrets, particularly those older than 4 years, will have varying degrees
of chronic interstitial nephritis. This is typically a progressive change that may result in
dysfunction and possibly failure. Renal cysts are also not uncommon, which can occur
secondary to the lesions of interstitial nephritis with obstructive lesions of renal ducts
and/or renal tubules. There is a form of inherited polycystic disease with multiple cysts
identified both in the kidneys as well as occasionally in the liver of young ferrets.52
Infectious Disease
Mycobacterial infections are reported in pet ferrets, although uncommon. It is a more
significant disease with Mycobacterium bovis in feral ferrets of New Zealand.79 As
chronic infections, these are typically diagnosed in older ferrets (3–6 years). The mi-
crobes have been of a variety of species: Mycobacterium xenopi (probable aquarium
origin), Mycobacterium genavense, Mycobacterium avium subsp hominissuis, and
Mycobacterium celatum.80–86 The clinical signs are diverse and depends on the major
Fig. 23. Large spleen in a ferret, which is congested and supporting extramedullary
hematopoiesis.
organ system involved. Progressive weight loss is a consistent finding. Concurrent

diseases or immunosuppression are not always present.81,82,84 The histologic lesions
are of granulomatous inflammation with macrophages and multinucleated giant cells
with cytoplasmic acid-fast bacteria. Treatment has been attempted in some cases;
however, the infection recurred in most cases after discontinuation of
therapy.82,83,85,86
Cryptococcus infections are uncommon in ferrets but as mycobacteria, can be
chronic infections more commonly identified in older ferrets.87 The clinical signs are
related to the organ system involved and include lymphadenopathy, blindness,
rhinitis, dermatitis, pneumonia, and meningitis.88 Cryptococcus gattii seems to be
more virulent than Cryptococcus neoformans and will cause infection in immune-
competent hosts. The infection in ferrets is generally protracted as opposed to the
rapid dissemination to the central nervous system reported in other species.88
Cytology of the lesions reveals mixed inflammation (multinucleated giant cells, macro-
phages, and neutrophils) and generally large numbers of yeast with the characteristic
morphology of a thick, nonstaining capsule. The source of the infection is environ-
mental and typically associated with Eucalyptus trees.87,88
Neoplastic Disease
Although tumor development increases with age, only a few tumors are discussed.
More comprehensive reviews of ferret tumors are published covering more
details.60,89,90
Adrenal disease is a common hyperplastic to neoplastic lesion in aging ferrets
(Fig. 24). In reports the mean age is 4.4 years and the median age is 4.5 years.90 Tu-
mors of the adrenal gland are reported to be the most common tumor in ferrets.90 The
tumors are primarily cortical carcinomas and adenomas.90 Uncommonly, pheochro-
mocytomas and neuroblastomas arise in the medulla.90 Mesenchymal tumors are
also reported: leiomyosarcomas, leiomyomas, and spindle cell sarcomas.90 It has
been shown that there is correlation with the age of neutering to the development of
the very common proliferative and/or neoplastic adrenal cortical tumor of ferrets.91
The study was comparing ferrets in Europe, which are neutered much later than ferrets
in North America. European ferrets developed adrenal gland lesions at an older age.
The lesion does seem to be related to the act of neutering of the animal and removal
of those reproductive hormones. The sex of the animal had no association with
Fig. 24. Right adrenal gland tumor (arrow) and kidney buried in perirenal fat (arrow head)
in a ferret.
678 Reavill & Imai
development of adrenal gland lesions.91 In adrenal gland disease, it is not uncommon

for one or more of the sex steroids to elevate: estradiol, 17-hydroxyprogesterone, or
androstenedione. These hormones can lead to vulvar enlargement in female, squa-
mous metaplasia of the prostate in male ferrets and commonly progressive, symmet-
ric alopecia. The disease currently is less commonly identified, as surgical removal of
the adrenal glands has fallen out of favor compared with medical treatment with leu-
prolide acetate (Lupron). This is a gonadotropin-releasing hormone analogue. Lupron
does result in reduction of clinical signs but will not affect the size of affected adrenal
glands. With the advent of the common use of Lupron, adrenal gland tumors that are
surgically removed seem to occur in older ferrets and the tumors are more aggressive
(personal observation DRR).
Pancreatic islet cell tumors (insulinoma or pancreatic islet B-cell tumor) are also a
very common endocrine tumor in middle-aged to older ferrets and in some studies
the most common tumor in ferrets.92 In studies the age range is 2 years to 8 years (me-
dian 5 years).90 Some reports suggest there is a male sex predilection.72 Islet cell tu-
mors are most frequently beta cell tumors and are functional.92 These cells produce
insulin, which can result in hypoglycemia. The lesions range from hyperplasia to ade-
nomas and adenocarcinomas. The tumors have a high recurrence rate but are slow to
metastasize. The common sites of metastases are liver, spleen, and lymph nodes.72
Most of the pancreatic tumors arise from the isles of Langerhans. Fewer numbers of
exocrine tumors have been described. Exocrine pancreatic carcinomas are aggres-
sive tumors of older ferrets.93 The clinical signs are nonspecific, usually weight loss
and the development of ascites. The tumor typically widely metastasizes into organs
(liver, lung, intestines) and/or seeds the abdomen as carcinomatosis.93
Lymphoma is a common tumor identified in older animals. In studies the mean age
ranges from 5.2 years to 6.8 years.77,94 There is an apparent difference in the tumor
type based on the age of the ferret. Juvenile ferrets typically have more high-grade
lymphomas. Most of the lymphomas in adults have a slower progression and a
more chronic pattern than the juvenile form. Multicentric and gastrointestinal forms
are the more common presentations.95 Multicentric forms will involve superficial
lymph nodes, as well as the mesenteric lymph nodes, spleen, and liver.94,95 Gastroin-
testinal lymphoma develops nodular to diffuse lesions of the intestines, particularly the
small intestines, and the mesenteric lymph nodes.95 Gastric lymphoma in ferrets is re-
ported to be associated with Helicobacter mustelae infection (a B-cell lymphoma).96
Skeletal lymphoma has been described as aggressive lytic osseous lesions usually
involving the lumbar spine although the further evaluation is needed for this uncom-
mon presentation.94,97,98 Immunohistochemistry seems to be a factor in prognosis
with survival of 5 months with T-cell lymphomas and 8.4 months with B-cell lym-
phoma.99 The clinical signs will vary depending on the organ system affected but
does include generalized weakness, depression, anorexia, weight loss, vomiting,
and changes in the gastrointestinal functions.71,94 Nonregenerative anemia is a com-
mon finding on blood analysis.94,95,99 Hypercalcemia has also been reported as a par-
aneoplastic syndrome in ferrets. In these ferrets the parathyroid hormone–related
protein levels were elevated with suppressed intact parathyroid hormone as charac-
terized for humoral hypercalcemia of malignancy.98
Cutaneous epitheliotropic lymphoma typically presents as areas of a progressive,
pruritic dermatitis. The neoplastic lymphocytes infiltrate into the epidermis, outer
root sheaths of the follicles, and adnexa. These are T-cell lymphomas.100
Mast cell tumors are a common cutaneous tumor. These tend to arise in middle-
aged to older ferrets from 2 to 9 years (median 5 years). Surgical excision is generally
curable and these tumors do not metastasize. Multiple tumors can develop.101 The
tumors are small, round to plaquelike masses frequently with surface crusting. They
develop commonly on the extremities and the trunk. Histologically they are sheets
of infiltrative mast cells associated with eosinophils. The mast cell cytoplasmic gran-
ules stain poorly with hematoxylin and eosin stains.
A less common cutaneous tumor is a dermal leiomyosarcomas. The age range is 3-
to 6-year-old ferrets. They appear as single cutaneous nodules. These tumors are
discrete masses originating from smooth muscle of the arrector pili, with no site pref-
erence. Most are malignant tumors although with completer removal they do not
appear to recur or metastasize. Poorly differentiated tumors may require immunohis-
tochemistry to differentiate from fibrosarcomas and malignant peripheral nerve sheath
tumors. In one study there was a slight sex predilection in males.102 From the data-
base of ZEPS, this was also noted with 22 males (neutered and intact) and 8 females
(neutered and intact) with a median age 5.3 years (range 4–7 years).
DISCLOSURE
The authors have no commercial or financial conflicts of interest nor any funding
sources.
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Vet Clin Exot Anim 23 (2020) 651–684

should be used to explore additional histopathologic lesions associated with aging in

DISEASES BY ORGAN SYSTEM