AFIP Wednesday Slide Conference - No. 8
27 October 1999
- Conference Moderator:
Dr. Jerrold Ward
National Cancer Institute
Fairview 201, PO Box B
Frederick, MD 21702-1201
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- Case I 99-8172 (AFIP 2695446)
- Signalment: 18-week-old, C57BL/6L viable motheaten
male mouse (Mus musculus) (Hcph me-v/Hcph me-v = mev/mev = viable
- History: This mouse was from a mutant colony maintained
at the Jackson Laboratory.
- Gross Pathology: The lungs were mottled reddish-brown,
the spleen was enlarged and the feet had patchy areas of tan,
thickened exudative lesions. There was a generalized patchy loss
Contributor's Diagnosis and Comments: Acidophilic macrophage
The viable motheaten spontaneous autosomal recessive mutation
on chromosome 6 disrupts the hematopoietic cell phosphatase (Hcph)
gene. Hcph encodes the SHP-1 protein-tyrosine phosphatase, which
is primarily expressed in hematopoietic cells. SHP-1 is a critical
negative regulator in multiple signaling pathways in the hematopoietic
and immune systems.
- Viable motheaten mice develop systemic autoimmunity, anemia
and immunodeficiency. Pathology includes severe inflammatory
lesions in the skin and lungs. These lesions, comprised mainly
of macrophages and granulocytes, are not associated with infection
and occur even under specific pathogen-free husbandry conditions.
T- and B-lymphocytes are not required for the development of
these lesions as evidenced by the persistence of these inflammatory
lesions in mice doubly homozygous for viable motheaten and severe
combined immunodeficiency mutations.
- A number of signaling pathways in monomyeloid cells are regulated
through the phosphorylation of tyrosine residues in growth factor
receptors and other proteins, resulting in activation of the
pathway. The dephosphorylation of tyrosine residues and subsequent
deactivation of this pathway maintains normal homeostasis. In
viable motheaten mice, which are deficient in SHP-1, tyrosine
residues are not dephosphorylated, thus preventing down regulation
of the signaling pathway resulting in proliferation of monomyeloid
- Treatment of viable motheaten mice with anti-MAC-1-antibody
inhibits the development of inflammatory lesions, thus supporting
a role for monomyeloid cells in the pathogenesis of this disease.
Additionally, in-vitro studies have shown several hematopoietic
growth factors, including CSF-1, G-CSF and GM-CSF, to enhance
proliferation of bone marrow progenitor cells from viable motheaten
mice as compared to littermate controls.
- Trichrome staining of lung sections from viable motheaten
mice demonstrates increased intra-alveolar and interstitial collagen
deposition. The interstitial fibrosis noted in the lung lesions
has been associated with increased TNF-alpha in macrophages and
serum of viable motheaten mice. The relationship between elevated
TNF-alpha and macrophage dysfunction is unclear; however, TNF-alpha
has been shown to stimulate the proliferation of fibroblasts
and increase collagen synthesis.
- Eosinophilic amorphous and crystalline structures are seen
free in the alveoli and contained within macrophages in the lungs
of viable motheaten mice. Gormori's iron stain does reveal hemosiderin
within macrophages; however, the crystalline structures do not
stain for iron. These crystals do not fluoresce in ultraviolet
light and are not birefringent with polarized light. It is believed
that this eosinophilic material is a blood breakdown product
or it may result from defective macrophage catabolism of surfactant.
- The pulmonary pathology of viable motheaten mice is just
one manifestation of their disease. This mutant mouse is the
first animal model of a specific protein-tyrosine phosphatase
deficiency and provides the opportunity to elucidate the regulatory
mechanisms of the hematopoietic and immune systems.
- AFIP Diagnosis: Lung: Alveolitis, granulomatous, diffuse,
moderate, with abundant eosinophilic intrahistiocytic crystalline
material and brown granular intrahistiocytic pigment, C57BL/6L
viable motheaten mouse (Mus musculus), rodent.
- Conference Note: Participants agreed with the contributor's
interpretation of the lesion. Eosinophilic crystals may be found
in the lungs and alveolar macrophages of normal mice and in mice
with various diseases to include experimental oxygen toxicity
and Toxocara canis infection. Mice with Chediak-Higashi syndrome
may have crystals within granulocytes and monocytes. Alveolar
macrophage crystals are also reported in the lungs of human smokers.
In most cases of murine pneumonia with eosinophilic crystals,
the cause of crystal formation is unknown.
- Viable motheaten mice also commonly have lymphoid depletion/necrosis
of thymus from 3-10 weeks of age, absence of lymphoid follicles
in lymph nodes, depletion of white pulp in spleen, elevated erythropoiesis
in spleen, increased myelopoiesis in the bone marrow, glomerulonephritis,
focal abscesses in the skin, decreased Leydig cells and decreased
- Contributor: The Jackson Laboratory, 600 Main Street,
Bar Harbor, ME 04609-1500
- 1. Shultz L, Rajan T Greiner D: Severe defects in immunity
and hematopoiesis caused by SHP-1 protein-tyrosine-phosphatase
deficiency. Tibtech Vol. 15:302-307, 1997
- 2. Shultz L, Coman DR, Bailey CL, Beamer WG, Sidman CL: "Viable
Motheaten," a new allele at the motheaten locus. Am J Path
Vol.116 (2):179-192, 1984
- 3. Thrall R, Vogel S, Evans R, Shultz L: Role of tumor necrosis
factor-alpha in the spontaneous development of pulmonary fibrosis
in viable motheaten mutant mice. Am J Path 151(5):1303-1310,
- 4. Ward J: Pulmonary pathology of the motheaten mouse. Vet
Path 15:170-178, 1978
- 5. Yank YH, Campbell JS: Crystalline excrements in bronchitis
and cholecystitis of mice. Amer J Path 45: 337-345, 1964
- Case II 99-000068, 69-12, -12, 88-12, 89-12, 90-12 (AFIP
- Signalment: B6, 129 (C57BL/6 X 129) male mice, 20-23
months of age.
- History: Aging study, incidental findings.
- Contributor's Diagnosis and Comments: Dental dysplasia,
various degrees in different sections, unilateral or bilateral.
Other lesions in some slides include Harderian gland hyperplasia/adenomas
and inflammation. Dental dysplasia is a common lesion in many
strains of mice. It has not been noted in many studies. Up to
25% of 2-year-old Balb-C mice have unilateral or bilateral dental
- AFIP Diagnoses:
- 1. Teeth: Dental dysplasia, B6,129(C57/BL6 x 129) mouse,
- 2. Harderian gland: Papillary cystadenoma.
- 3. Harderian gland: Adenitis, lymphoplasmacytic, multifocal,
- 4. Auditory canal: Otitis externa, ulcerative and suppurative,
- Conference Note: Mice have one set of teeth that grow
and erupt continuously throughout life. The normal dentition
for a mouse is one incisor and three molars in each quadrant;
therefore, the dental formula is 2(I1/1, M3/3) = 16. The incisors
grow at a rate of 2-3mm/week under normal conditions and up to
9mm/week as an adaptive response.
Destruction and inflammation of the tooth pulp results in proliferation
of odontoblasts, cementoblasts and osteoblasts that produce disorganized
masses of dental material in an attempt to repair the tooth.
Factors that have been associated with development of dental
dysplasia are consumption of powered feeds, malocclusion, frequent
trimming, trauma, chronic inflammation and increased age. Maxillary
incisors are more prone to dysplasia than mandibular incisors
as they are seated in softer bone., Therefore, they are more
- Some sections contain significant inflammation in association
with the dental dysplasia. This may support the theory that dental
dysplasia develops in response to chronic inflammation. In addition,
some sections contain benign proliferative lesions of the Harderian
glands. One examined in conference contained a papillary cystadenoma.
Harderian gland neoplasms have been reported to occur in up to
75% of adult 129 black mice.
Contributor: National Cancer Institute, Fredrick, MD
- 1. Long PH, Leininger JR: Teeth. In: Pathology of the Mouse,
ed. Maronpot RR, Boorman GA, Gaul BW, pp.13-22. Cashe River Press,
Vienna, IL, 1999
2. Losco PE: Dental Dysplasia in rats and mice. Tox Patho, 23(6):677-688,
- Case III Case 1/160947-493/NIEHS (AFIP# 2677919)
- Signalment: Two-year-old female Fischer 344 rat.
- History: Tissue from a 2-year old female rat sacrificed
at the end of a 2-year toxicity/ carcinogencity study. Administration
of the chemical by gavage for 2 years resulted in a dose-related
increase in the incidence of hyperplasia and benign and malignant
neoplasms of the glandular stomach.
- Gross Pathology: The fundic region of the glandular
stomach was diffusely thickened and the mucosal surface appeared
rough and granular.
Contributor's Diagnoses and Comments: Glandular stomach
- Malignant neuroendocrine tumor (carcinoid).
- Extensive areas of the fundic mucosa of the glandular stomach
are thickened by a densely cellular neoplasm that has effaced
the glandular epithelium and multifocally has invaded through
the muscularis mucosa into the submucosa. The epithelium of the
gastric pits is not affected. The neoplasm is composed of 2 morphologically
distinct cell types. The larger population is composed of large
polygonal cells arranged in sheets, nodular aggregates, small
clusters, and well to poorly defined glandular structures. The
cells have finely granular, lightly eosinophilic, amphophilic
cytoplasm with pleomorphic nuclei and single nucleoli. The second
cell population occurs as focally extensive sheets or variably-sized
nodular aggregates of large polygonal cells characterized by
intensely eosinophilic granular cytoplasm and single round to
oval vesicular nuclei with 1 or 2 prominent nucleoli. Multifocally,
both cell types occlude submuscosal blood vessels and lymphatics.
The number of mitotic figures is low.
- The majority of the benign and malignant neoplasms in this
study were composed of cells that were morphologically consistent
with neuroendocrine or enterochromaffin-like cells, and frequently,
were accompanied by focal or multifocal proliferations (hyperplasia)
of similar cells in the deeper one-third of the fundic mucosa
extending toward the mucosal surface. Together the hyperplastic
lesions and neoplasms appeared to form a morphologic continuum
from preneoplasia to neoplasms. An additional consistent finding
in this study was marked atrophy of the fundic mucosal epithelium
due primarily to loss of parietal cells and chief cells to a
lesser extent. Parietal cell degeneration and necrosis were evident
in 90-day (subchronic) studies conducted earlier. Based on the
morphologic, histochemical (Sevier-Munger) and immunohistochemical
(neuron specific enolase and chromogranin-A) characteristics,
the lesions were diagnosed as neuroendocrine cell hyperplasia
and benign and malignant neuroendocrine tumors (carcinoids) of
the glandular stomach.
- As a group, spontaneous and chemically induced neuroendocrine
proliferative lesions of the stomach are extremely rare in commonly
used laboratory rodents. However, spontaneous malignant neuroendocrine
neoplasms develop with high frequency in the wild rodent Praomys
(Mastomys) natelensis, and this species has been used as a model
for neuroendocrine neoplasia.
- Neuroendocrine proliferative lesions arise from neuroendocrine
or enterochromaffin-like (ECL) cells that are sparsely dispersed
among the glandular epithelial (parietal and chief) cells in
the deepest third of fundic mucosa. The exact functional role
of ECL cells is not known; however, these cells are known to
synthesize, store and secrete histamine and may also function
in stimulating gastric acid secretion. ECL cells are specifically
immunoreactive for neuron specific enolase and chromaganin-A;
and are argyrophylic with the Sevier-Munger and Grimelius stains.
These stains are commonly used to identify neuroendocrine tumors
in the glandular stomach.
- Experimentally, neuroendocrine proliferative lesions have
been induced in the fundic stomach by the administration of antisecretagogues
that produced prolonged inhibition of gastric acid secretion
and achlorhydria. Such compounds include those that are proton
pump inhibitors and histamine H2 receptor antagonists.
- The proposed mechanism for the development of neuroendocrine
lesions is thought to be related to the regulatory effects of
circulating gastrin, which in addition to being a potent stimulator
of gastric acid secretion, has a generalized trophic effect on
the fundic glandular mucosa, in particular, the ECL cells. It
is thought that gastric neuroendocrine proliferative lesions
which develop in rats after prolonged inhibition of gastric secretion
do so through the secondary mechanism of hypergastrinemia. A
negative feedback control exists between gastric acidity and
gastrin secretion by G-cells in the pylorus. An increase in gastric
pH under the influence of potent inhibitors of gastric acid secretion
results in secretion of gastrin by antral G-cells leading to
hypergastrinemia, and subsequently, growth stimulation of ECL
cells. With prolonged acid inhibition and hypergastrinemia, there
is ECL cell hyperplasia which, when sustained, results in the
development of neuroendocrine neoplasms. Direct stimulation of
chief cells, or of a glandular epithelial stem cell population,
may explain the presence of other glandular epithelial cell populations
that are often components of these neoplasms.
- In this study, atrophy of the fundic mucosa due to profound
loss of parietal cells may have been the critical event leading
to the induction of neoplasia. Loss of parietal cell mass most
likely resulted in marked gastric hypochlorhydria, an increase
in intragastric pH, and consequently hypergastrinemia. The trophic
effect of prolonged hypergastrinemia on the fundic mucosa resulted
in sustained proliferation of ECL cells leading ultimately to
the development of proliferative neuroendocrine lesions. This
proposed mechanism was supported by the results of additional
90-day studies which were conducted to elucidate possible mechanism(s)
involved in the development of the neoplasms. We observed time
and dose-dependent increases in intragastric pH and circulating
gastrin levels in addition to morphologic evidence of progressive
parietal cell degeneration and necrosis, and mucosal atrophy.
- AFIP Diagnosis: Stomach: Neuroendocrine carcinoma
(malignant carcinoid), Fischer 344 rat, rodent.
- Conference Note: Based on histomorphology, conference
participants considered the differential diagnosis of gastric
carcinoma, metastatic pancreatic carcinoma and neuroendocrine
carcinoma (malignant carcinoid). The Churukian-Schenk method
was performed at the AFIP and demonstrated numerous argyrophilic
granules within neoplastic cells, supporting the diagnosis of
Contributor: National Institute of Environmental Health
Sciences, PO Box 12233, Research Triangle Park, NC 27709
1. Betton GR, Domer CS, Wells T, Pert P, Price CA, Buckley PP:
Gastric ECL-cell hyperplasia and carcinoids in rodents following
chronic administration of H2-antagonists SK&F 93479 and oxmetidine
and omeprazole. Tox Pathol 16(2):288-298, 1988
- 2. Ekmam L. Hansson E, Hau N. Carlsson E, Lundberg C: Toxicological
studies on omeprazole. Scand J Gastroenterol. 108(Suppl): 56-69,
- 3. Frantz JD, Betton G, Cartwright ME, Crissman JW, Macklin
AW, Maronpot RR: Proliferative lesions of the non-glandular and
glandular stomach in rats, GI-3. In: Guides for Toxicologic Pathology.
STP/ARP/AFIP, Washington, DC. 1991
4. Hard GC, Iatropoulos NJ, Thake DC, Wheeler D, Tatematsu M,
Hagiwara A, Williams GM, Wilson GE: Identity and pathogenesis
of stomach tumors in Sprague-Dawley rats associated with the
dietary administration of butachlor. Exp Toxic Pathol 47:95-105,
- 5. Hirth RS, Evans LD, Buroker RA, Oleson FB: Gastric enterochromaffin-like
cell hyperplasia and neoplasia in the rat: An indirect effect
on the histamine H2-recptor antagonist, BL-6341. Tox Pathol 16(2):273-287,
6. Thake DC, latropoulos NJ, Hard GC, Hotz KJ, Wang C-X, Williams
GM, Wilson A: A study of the mechanism of butachlor-associated
gastric neoplasms in Sprague-Dawley rats. Exp Toxic Pathol 47:
- Case IV - 99-000174-9c, 9b, 9c, 9d, 9e (AFIP# 2694795)
- Signalment: Two female B6,129 mice (C57BL/6 x 129)
(Mus musculus), with targeted mutation (gene name pending), 7
and 8 months old.
- History: Clinically normal in early phases, but eventually
sicken and die from renal disease.
- Gross Pathology: Kidneys are granular in appearance.
- Laboratory Results: Urinalysis, blood parameters and
ultrastructural studies are not available for these two mice.
Contributor's Diagnoses and Comments:
- 1. Acute proliferative glomerulonephritis in earliest stage.
2. Membranoproliferative glomerulonephritis in moderate stage.
3. Sclerosing glomerulonephritis at end stage.
4. Tubular casts.
- Etiology - specific gene inactivation.
- AFIP Diagnosis: Kidney: Glomerulonephritis, membranoproliferative,
global, chronic, diffuse, moderate, with multifocal lymphoplasmacytic
interstitial nephritis and tubular proteinosis, B6,129 (C57BL/6
x 129) (Mus musculus), mouse.
- Conference Note: The etiology of most spontaneous
cases of glomerulonephritis is unknown. Glomerular lesions are
generally uncommon in mice, although certain strains have a higher
incidence than others do. In particular, NZB x NZW F1 hybrid
mice have an autoimmune glomerulonephritis with a histologic
appearance that is very similar to the case presented in conference.
This lesion is characterized by mesangial proliferation, deposition
of PAS-positive material, and lymphoplasmacytic infiltrates.
The contributor (Dr. Ward, the moderator of the conference) noted
that this case represents a targeted genetic mutation whose effects
and nature are not completely understood. Affected mice develop
a fatal, progressive glomerulonephropathy. A unique fibrillar
material that is thought to be immunoglobulin is deposited in
the renal interstitium. Ninety percent of females and 40 percent
of males in this group of mice have circulating anti-DNA antibodies.
Contributor: National Cancer Institute, Frederick, MD
- Seely JC: Kindey. In: Pathology of the Mouse, eds. Maronpot
RR, Boorman GA, Gaul BW, pp221-213. Cashe Vally Press, Vienna,
- 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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