AFIP Wednesday Slide Conference - No. 2
15 September 1999
- Conference Moderator:
COL Nancy Jaax, Diplomate, ACVP
U.S. Army Medical Research Institute of Infectious Disease
Ft. Detrick, Frederick, MD 21702-5011
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- Case I - 78536 (AFIP 2677920)
- Signalment: 6-month-old, female, athymic, nude mouse,
- History: Swollen, firm abdomen; no experimental manipulations
had been performed.
- Gross Pathology: Markedly enlarged liver and spleen;
bilaterally, kidneys have large (2cm) yellow, nodular masses
engulfing kidneys; masses are firm on cut section and core material
- Contributor's Diagnoses and Comments:
- 1. Kidney, nephritis, pyogranulomatous, multifocal and coalescing,
severe with intralesional coccoid bacteria and Splendore-Hoeppli
(botryomycosis), etiology consistent with Staphylococcus sp.
2. Kidney, nephritis, interstitial, chronic with tubular degeneration,
regeneration, peritubular and periglomerular sclerosis
Although bacterial culture of the kidney was not done, the diagnosis
is most likely renal botryomycosis cased by Staphylococcus. No
obvious route of entry for the organism was noted at necropsy.
Abscesses, furunculosis and similar histomorphologic lesions
are reported and are not uncommon on the face and mandibular
area in athymic nude mice. S. aureus is most commonly isolated.
Although reactive lymphocytic hyperplasia may be seen in regional
lymph nodes and spleen with these lesions, a literature search
did not reveal any reports of similar systemic or renal lesions.
- AFIP Diagnosis:
- 1. Kidney and mesenteric fibroadipose tissue: Abscesses,
chronic, multifocal and coalescing, with large colonies of cocci
surrounded by Splendore-Hoeppli material, athymic nude mouse
( Mus musculus), rodent.
- 2. Kidney: Nephritis, interstitial, chronic-active, multifocal,
- Conference Note: The term botryomycosis originates
from the characteristic histologic finding of granules in clusters
and the early belief that the cause was fungal. It usually follows
some form of trauma and typically involves the deep dermis, subcutis,
and occasionally extends to muscle, adjacent bone, and rarely
viscera. Splendore-Hoeppli material is not unique to botryomycosis
and is seen in other microbial infections and foreign body reactions.
It is thought to represent glycoprotein antigen-antibody complexes.
- Bacteria that may cause botryomycosis include: Staphylococcus,
Streptococcus, Pasteurella, Proteus, Pseudomonas, and Actinobacillus;
eumycotic and actinomycotic mycetomas may have a similar appearance.
The presence of cocci within the pyogranulomas shortens this
list to Staphylococcus sp. and Streptococcus sp. Staphylococcus
aureus is the most common cause of botryomycosis.
- Homozygous nude mice (nu/nu) have been shown to be more resistant
to experimental challenge with Staphylococcus aureus than heterozygous
controls (nu/+). The increased resistance is attributed to the
presence of naturally occurring activated macrophages in the
reticuloendothelial organs. The enhanced activation of macrophages
may be explained by the absence of T lymphocyte suppressor cells.
- Tissue Gram stains demonstrated that the bacteria are Gram
positive. Some sections do not have identifiable kidney.
- Contributor: FDA/CBER/VSS, HFM-22, 8800 Rockville
Pike, Bldg. 29A, rm. 1A17, Bethesda, MD 20892
1. Abe Y, Akiyama H, Arata J: Furuncle-like lesions in mouse
experimental skin infections with Staphylococcus aureus. Journ
Dermatology, 20:198-202, 1993
- 2. Biberstein EL, Jang SS, and Hirsch DC: Species distribution
of coagulase-positive staphylococci in animals. J Clin Microbiol
- 3. Bywater JEC: Furunculosis in a mouse. Vet Rec 101:385,
- 4. McBride DF, Stark DM, Walberg JA: An outbreak of staphylococcal
furunculosis in nude mice. Lab Anim Sci 31(3):270-72, 1981
- 5. Percy DH, Barthold SW: Staphylococcal Infections. In:
Pathology of Laboratory Rodents and Rabbits, pp. 35-36. Iowa
State University Press, Ames, IA, 1993
- Case II - 99-275X (AFIP 2679285)
- Signalment: One-year-old, male, ferret (Mustela putorius)
- History: This ferret was inoculated intranasally with
a type A avian influenza virus. The ferret became lethargic,
developed a serous nasal discharge, and began sneezing. In addition,
it became febrile. Three days after inoculation, the ferret was
- Gross Pathology: The right and left caudal dorsal
lung lobes and the caudal dorsal region of the right cranial
lung lobe were red. The abdomen contained serosanguinous fluid.
The stomach was filled with mucus and lacked food. The liver
was tan and had an enhanced lobular pattern.
- Laboratory Results: Influenza virus was isolated from
the nasal turbinates, lung, spleen, and nasal washes taken at
one and three days post-inoculation
- Contributor's Diagnoses and Comments: Interstitial
bronchopneumonia, subacute, diffuse, severe, with edema and bronchiolar
- Clinical signs of influenza infection in ferrets include
fever, sneezing, mucoid or mucopurulent nasal discharge, lethargy,
inappetance, ocular discharge, photophobia, and conjunctivitis.
It has a 7-14 day course, and is generally self-limiting. Neonates
may develop more serious disease than adults, and death may ensue.
Lower respiratory tract infection is less common, but when it
occurs it is usually confined to the bronchial epithelium. Limited
enteritis may occur and experimentally infected ferrets have
been reported with signs referable to hepatic and renal disease.
- Histologic findings included interstitial bronchopneumonia
with a mixed inflammatory reaction composed predominately of
lymphocytes. Pulmonary edema was multifocal and moderate. In
addition, the bronchiolar epithelium was hyperplastic.
- Differential diagnosis of pneumonia in ferrets includes viral
diseases caused by influenza virus, canine distemper virus and
respiratory syncytial virus. Streptococcus zooepidemicus, S.
pneumoniae, groups C and G streptococci, Escherichia coli, Klebsiella
pneumonia, Pseudomonas aeruginosa, Bordetella bronchiseptica,
and Listeria monocytogenes are the most common bacteria isolated
from ferrets with pneumonia. In addition Pneumocystis carinii
can also infect ferrets, resulting in pneumonia.
- The ferret is a common model for the study of influenza.
Infection generally results in clinical signs and lesions similar
to those seen in humans. As a result, ferrets are often used
for studies of potential vaccine candidates prior to clinical
trials in humans.
- AFIP Diagnosis: Lung: Pneumonia, bronchointerstitial,
serofibrinous, subacute, diffuse, severe, with bronchiolar epithelial
hyperplasia, ferret ( Mustela putorius furo), mustelid.
- Conference Note: Several influenza viruses are readily
transmitted to ferrets from humans and vice versa. The differential
diagnosis discussed at the conference included: influenza, canine
distemper (morbillivirus), and Aleutian mink disease (mink parvovirus).
The significant neutrophilic component suggests secondary bacterial
infection; however, tissue gram stains did not demonstrate bacteria.
- The bronchiolar pattern is strongly suggestive of nasal aerosol
exposure. Inhalation chamber exposure to the same pathogen would
generally produce a diffuse alveolar pattern. This variation
is associated with particle size. Particles of less than 5mm
diameter are required to produce an alveolar infection.
Contributor: Emory University, Div. Animal Resources,
G70 Rollins Bldg, 1510 Clifton Road, Atlanta, GA 30322
- 1. Collie MH, Rushton DI, Sweet C, Smith H: Studies of influenza
infection in newborn ferrets. J Med Microbiol 13:561-571, 1980
- 2. Hinshaw VS, Webster RG, Easterday BC, and Bean WJ: Replication
of avian influenza A viruses in mammals. Inf and Immun 34:354-361,
- 3. Renegar BR: Influenza virus infection and immunity: A
review of human and animal models. Lab Ani Sci 42(3):222-232,
- 4. Reuman PD, Keely S, and Schiff GM: Assessment of signs
of influenza illness in the ferret model. J of Viro Meth 24:27-34,
- 5. Rosenthal KL. Respiratory Diseases. In: Clinical medicine
and surgery. eds. Hillyer EV, and Quesenberry KE, pp. 79-81.
WB Saunders Co., Philadelphia, 1997
- 6. Smith, H, and Sweet, C: Lessons for human influenza from
pathogenicity studies with ferrets. Review of Infectious Diseases
- Case III - MT299 (AFIP 2675680)
- Signalment: The brains are from double knockout mice,
Mus musculus. The strain is 129 SvEv X C57Bl/6 Fn
History: These mice are the product of a mating to produce
double-knockout mice in which the genes coding for the VLDL and
ApoE2 lipoprotein receptors have been deleted. By day 10 after
birth (P10), failure to thrive became apparent in the double
knockout mice. By P13 to P15 neurological signs developed, characterized
by progressive ataxia, wide gait and tremor. The animals frequently
flipped onto their backs and had difficulty righting themselves.
By P20 the mice were distinctly smaller than their unaffected
littermates. Progressive hind-limb paralysis developed between
P16 and P20 and the animals died shortly thereafter.
- Gross Pathology: The brains were smaller than those
of the wild-type animals of the same age. This difference was
most dramatic for the cerebellum that in the double knockout
- Contributor's Diagnoses and Comments: Neocortical,
hippocampal and cerebellar dysgenesis, diffuse, marked, brain,
- The lesions in the brains of these mice are a consequence
of the deletion of two lipoprotein receptors, ApoER2 and VLDLR.
- The pyramidal cells in the CA 1 region of the hippocampus
are split, forming two layers rather than one, and the neurons
of the dentate gyrus are scattered, distorting the normal C-shaped
pattern characteristic of the dentate. The rudimentary cerebellum
completely lacks foliation and the Purkinje cells are aggregated
in the cerebellar peduncle. The granular cell layer is thin.
In the neocortex, the cortical laminations are indistinct. As
well, there are an increased number of neurons in the marginal
layer, which is normally free of cell bodies.
- The lesions are an exact phenocopy of those seen in two previously
described spontaneous mutant mice named Reeler and Scrambler
in which the genes for the extracellular protein "reelin"
and the intracellular protein "disabled" are mutated
- Reelin is involved in a molecular pathway that regulates
the migration of neurons along the radial glial fiber network
during development of the brain. In the cortex, this protein
is either associated with the extracellular matrix or with the
surface of Cajal-Retzius neurons that produce it in the outermost
layer just beneath the pial surface. The Cajal-Retzius neurons
are formed during the early stages of neural development. When
the gene encoding reelin is defective, migratory neurons apparently
do not receive a critical cue that informs them of their position
during their migration away from the ventricular zone, leading
to an inversion of the cortical layers. The cortical laminae
normally form from the inside out, with later-born neurons migrating
past old ones to form progressively more superficial, and thus
younger, layers of the neocortex. When reelin is defective, the
cortical laminae are inverted, i.e. the cortex is inside out.
In the cerebellum, reelin is required for the Purkinje cells
to migrate outward, where they form a well-defined cortical plate
through which postmitotic granule cells migrate inward to form
the internal granule layer. Both of these laminate structures
do not form normally in the reeler mouse.
- In 1991 at the Jackson Laboratory an exact phenocopy of Reeler
occurred and was found to be caused by a spontaneous mutation
in mDab1, the mouse homologue of the Drosophila disabled gene.
This mouse was named Scrambler. Mouse Dab1 is an intracytoplasmic
adapter protein, which is thought to interact with tyrosine kinases
of the Src and Abl families. Unlike reelin, mDab1 is expressed
in the neurons that manifest the Reeler phenotype suggesting
that it is a key element of the response to a reelin signal.
- The fact that the deletion of the ApoER2 and VLDLR results
in a phenocopy of Reeler and Scrambler mice suggests that VLDLR
and ApoER2 participate in transmitting the extracellular reelin
signal to an intracellular signaling cascade initiated by mDab1.
- AFIP Diagnosis: Brain: Dysgenesis, with marked cerebellar
hypoplasia, 129 SvEv X C57Bl/6 Fn mouse (Mus musculus), rodent.
Conference Note: The normal formation of the central nervous
system involves a precisely orchestrated series of waves of migration
of post-mitotic neurons from ventricular zones to their final
anatomic locations. In humans, neuronal migratory defects have
been associated with lissencephaly syndrome, Fukuyama type cerebromuscular
dystrophy, Norman-Roberts syndrome, Neu-Laxova syndrome, Joubert
syndrome, pediatric epilepsy, schizophrenia and others. Mice
models help elucidate the neuronal migration abnormalities.
Contributor: University of Texas Southwestern Medical
Center at Dallas, 5323 Harry Hines Blvd. Dallas, TX. 75235
- 1. Curran T, D'Arcangelo G: Role of reelin in the control
of brain development. Brain Res. Brain Res Rev. 26: 285-294,
- 2. D'Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI,
and Curran T: A protein related to extracellular matrix proteins
deleted in the mouse mutant reeler. Nature 374: 719-723, 1995
- 3. Falconer DS: Two new mutants "trembler" and
"reeler" with neurological actions in the house mouse.
J Genet. 50: 192-201, 1951
- 4. Gallagher E, Howell BW, Soriano P, Cooper JA, Hawkes R:
Cerebellar abnormalities in the disabled (mdab1-1) mouse. J Comp
Neurol. 402: 238-251 1998
- 5. Howell BW, Hawkes R, Soriano P, Cooper JA: Neuronal position
in the developing brain is regulated by mouse disabled-1. Nature
389: 733-737, 1997
- 6. Sweet HO, Bronson RT, Johnson KR, Cook SA, Davison MT:
Scrambler, a new neurological mutation of the mouse with abnormalities
of neuronal migration. Mamm. Genome 7: 798-802, 1996
- 7. Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger
W, Nimpf J, Hammer RE, Richardson JA, Herz J: Reeler/disabled-like
disruption of neuronal migration in knockout mice lacking the
VLDL receptor and ApoE receptor-2. Cell 97: 689-701, 1999
- Case IV- 96458/148-16, 16A, 16B, 16C (AFIP 2681373)
- Signalment: 10-month-old, CD-1, male mouse (Mus musculus).
- History: This animal was a control mouse (no experimental
manipulation) on a long-term study and was housed under conventional
Gross Pathology: At necropsy, the lungs appeared enlarged
due to failure to completely deflate. The lungs were diffusely
discolored red and white with a nodular surface. There were multiple,
firm, white, pleural nodules associated with the mediastinum.
- Laboratory Results: None
- Contributor's Diagnoses and Comments: Lung: Pulmonary
ossification with mineralization, diffuse, severe.
- Pulmonary osseous metaplasia is an uncommon incidental finding
in aged mice. The lesion is usually confined to a small focus.
This case was submitted because of its unusual severity.
- AFIP Diagnosis: Lung: Osseous metaplasia, diffuse,
CD-1 mouse (Mus musculus), rodent.
- Conference Note: Subpleural and centriacinar foci
of ossification are occasionally observed in laboratory mice.
These foci may contain osteoid with or without mineralization.
They must be differentiated from osteosarcoma. In this case,
the regular organization of the bony spicules, the lack of cellular
atypia, and a low mitotic rate support the diagnosis of osseous
- Pulmonary osseous metaplasia in mice and rats was originally
thought to result from inhalation of feed dust containing fishmeal.
However, the current theory is that osseous metaplasia arises
within the alveolar walls. The intra-alveolar appearance is an
artifact that results from herniation into the alveolar spaces
Contributor: Schering-Plough Research Institute 144 Route
94, P.O. Box 32, Lafayette, NJ 07871
- 1. Dixon D, Herbert RA, Sills RC, Boorman GA: Lungs, pleura
and mediastinum, miscellaneous lesions. In: Pathology of the
Mouse, reference and atlas, ed. Maronpot RR, pp. 320. Cashe River
Press, Vienna, IL, 1999
- 2. Dungworth DL, Ernst T, Mohr U: The respiratory system,
Nonneoplastic lesions in the lungs. In: Pathobiology of the aging
rat, Vol. 1, ed. Mohr U, Dungworth DL, Capen CC, pp. 157-158.
International Life Sciences Institute,. Washington, DC, 1992.
- J Scot Estep, DVM
Captain, VC, USA
Registry of Veterinary Pathology*
Department of Veterinary Pathology
Armed Forces Institute of Pathology
(202)782-2615; DSN: 662-2615
- * The American Veterinary Medical Association and the American
College of Veterinary Pathologists are co-sponsors of the Registry
of Veterinary Pathology. The C.L. Davis Foundation also provides
substantial support for the Registry.
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