Microsoft word - 0607wsc21.doc

The Armed Forces Institute of Pathology
Department of Veterinary Pathology

Conference Moderator: Dr. Thomas Lipscomb, DVM, Diplomate ACVP

CASE I – C31715-04 4 (AFIP 2988635).

Signalment: 3-year-old, male, castrated, Cocker Spaniel, Canis domesticus, dog.
The dog was presented to the referring veterinarian with a 3 week history
of coughing. The dog was placed on Amoxil and prednisone. Two days later the
dog began vomiting. Thoracic radiographs were performed at this time and
revealed what was interpreted as peri-hilar pulmonary edema and right atrial
enlargement. The dog was then treated with furosemide. Prednisone was
discontinued after 4 days of treatment due to the development of polyuria and
polydipsia. The dog then began seizuring, became very dehydrated and was
referred to the Atlantic Veterinary College 6 days after initial presentation. On
arrival, the dog was lethargic, dehydrated and a freely moveable, mid-abdominal
mass was palpated. The dog was rehydrated with IV lactated ringers. Exploratory
laparotomy revealed a 5 cm long segment of proximal jejunum where the intestinal
wall was firm, pale yellow-tan and approximately 8-18 mm thick. There was a
poorly defined approximately 3 cm in greatest diameter, mottled tan and red, firm,
thickened area in the adjacent mesentery. The nearby Ileocecal lymph node was
moderately enlarged measuring 6 cm in greatest diameter. These tissues were
surgically excised and submitted for histopathology. The dog never completely
recovered from anesthesia and remained depressed with no papillary light reflex, no
menace response, and was unable to stand or walk. The owners elected
euthanasia 2 days later and the dog was submitted for necropsy.
Gross Pathology: The dog was in fair body condition with small visceral and
subcutaneous fat stores. The lungs were diffusely dark red, rubbery, failed to
collapse, and contained many scattered, poorly-defined, pale, whitish, firm foci.
There were two, 5 mm in greatest diameter, slightly raised, discrete, pale, yellow
nodules visible on the epicardial surface of the right atrium. The right ventricular
free wall was slightly thickened and measured 5 mm thick (compared to the left
which was 1 cm thick). The site of tissue resection and skin incisions were
unremarkable. Otherwise, the carcass, including the nasal passages, was grossly

Laboratory Results:
Fungal culture of lung tissue contained a heavy growth of
yeast identified as Cryptococcus neoformans.

Histopathologic Description:
The pulmonary parenchyma contains numerous,
multifocal to coalescing, nodular, interstitial aggregates of large, epithelioid
macrophages interspersed with fewer lymphocytes, plasma cells, rare
multinucleated foreign body type giant cells and large numbers of uninucleate
yeasts. The latter organisms have 2.5-8 µm, pale, eosinophilic to slightly blue-
grey, round to oval, thin-walled yeast bodies surrounded by a thick clear capsule.
Mucicarmine staining reveals a thick, intensely carminophilic capsule which often
has a slightly spiny outer surface surrounding the cell body of these organisms.
The thickened segment of small intestine is characterized by similar moderate
inflammatory infiltrates consisting largely of epithelioid macrophages and myriads
of the previously described yeasts. These foci extend in to the surrounding
mesentery and largely effaced the enlarged ileocecal lymph node. The
leptomeninges of the cerebrum, cerebellum and brain stem are multifocally, mildly
to moderately, thickened due to similar granulomatous infiltrates accompanied by
numerous yeasts. Within the cerebral cortex and the hippocampus there are
patchy, poorly-defined areas where the parenchyma is mildly hypercellular, mildly
vacuolated and sometimes congested. Blood vessels within these areas are often
lined by plump, reactive endothelial cells. Also in these areas, neuronal cell bodies
are frequently hypereosinophilic, angular, shrunken and often have pyknotic nuclei.
Multifocal, variably-sized nodular discrete granulomatous foci accompanied with
numerous yeasts are also present in sections of the pancreas, spleen, cortex of the
right kidney and the wall of the right atrium. In the liver, similar infiltrates often
moderately to markedly expand most portal areas and are frequently scattered
randomly throughout the lobules. Smaller granulomatous foci containing yeasts are
also scattered within the myocardium of the left and right ventricular free walls and
the thyroid glands.

Contributor’s Morphologic Diagnoses: 1. Granulomatous interstitial pneumonia,
multifocal, severe, with myriads of intralesional yeast
2. Granulomatous transmural enteritis and lymphadenitis, locally extensive, severe,
with many intralesional yeast
3. Granulomatous meningitis, multifocal, moderate, with intralesional yeasts
4. Neuronal necrosis, multifocal, moderate, acute, cerebral cortex and
5. Granulomatous splenitis, hepatitis, thyroiditis, pancreatitis, myocarditis and
nephritis, multifocal, mild to moderate, with numerous intralesional yeasts
Contributor’s Comment: The postmortem findings in this case are consistent with
widely disseminated cryptococcosis. Cryptococcus neoformans occurs worldwide
in temperate, as well as tropical climates.1 This opportunistic pathogen infects a
wide variety of wild and domestic animals (most commonly cats and dogs), as well
as humans. The organism is saprophytic in soil and is environmentally often
associated with avian habitats or areas heavily contaminated with pigeon
droppings.2 Infection occurs most commonly via inhalation of yeasts from the
environment and is not considered contagious. Nasal and/or pulmonary infection
may become disseminated via direct extension and/or hematogenous routes.3
Recovery or localization of infection is dependent on a good cell mediated immune
response. Most cases of disseminated human cryptococcosis are associated with
concurrent immunosuppressive disease processes (e.g. AIDS) or treatments (e.g.
chemotherapy or prolonged use of glucocorticoids).4 However, immunosuppression
has not been documented in most affected cats and dogs. There was no evidence
of an underlying immunosuppressive disease process nor was there a history of
prolonged steroid use in this case.
The cause of coughing (the initial presenting complaint) in this dog was severe,
fungal pneumonia. The right atrial enlargement noted by the referring veterinarian
and mild right ventricular hypertrophy found at necropsy were likely secondary to
pulmonary hypertension due to severe pneumonia. The initial seizure activity
described was due to fungal meningitis (C. neoformans is often referred to as
neurotropic). The lack of full recovery from anesthesia and postsurgical
neurological clinical signs which necessitated euthanasia were due to more acute
areas of neuronal necrosis in the cerebral cortex and hippocampus. This finding
may have been due to hypoxia secondary to prolonged seizure activity or possibly
was associated with poor oxygen exchange through the abnormal lung during

AFIP Diagnosis:
Lung: Pneumonia, granulomatous, multifocal to coalescing,
moderate, with edema and myriad intralesional yeasts, Cocker Spaniel (Canis
), canine.
Conference Comment:
Cryptococcus neoformans is a saprophytic fungus that
causes disease in a wide variety of animals, but most frequently in cats, dogs,
horses and humans. As pointed out by the contributor, immunosuppression has
not been documented in most affected cats and dogs. Lesions can occur in any
organ, but are most common in the nasal cavity and central nervous system,
followed by the integumentary system and eyes. Cryptococcus neoformans is a
cause of mastitis in cattle. Cryptococcosis is the most frequent systemic mycosis
in cats, and often begins in the nasal cavity. Dissemination to brain, eyes, skin,
subcutis, and lymph nodes is common. Pulmonary involvement is rare in cats.2,3,5,6

C. neoformans
is the species that most commonly causes disease and is
environmentally associated with avian habitats, especially pigeon droppings. C.
is also pathogenic, typically occurs in tropical and subtropical climates and is
generally associated with bark and leaf litter of certain eucalyptus trees. Following
an outbreak of cryptococcosis on Vancouver Island, British Columbia that affected
humans, dogs, Dall’s porpoises and other mammals, it was found that C. gattii was
the cause and was present on the bark of non-eucalypts in the area including alder,
bitter cherry, cedar, Douglas fir and Garry oak. Changing climatic conditions,
possibly caused by global warming, may have been involved in the spread of C.
to new ecological niches.6,7
Gross lesions of Cryptococcus neoformans are often gelatinous due to the yeast’s
mucopolysaccharide capsule. The capsule hinders phagocytosis and is a major
diagnostic feature of the organism. However, unencapsulated mutants do exist.
Histologically, the yeasts are round, 5-20 µm in diameter, reproduce by narrow-
based budding and are usually surrounded by a 2-8 µm mucopolysaccharide
capsule that stains with mucicarmine, PAS, and Alcian blue. Masses of organisms
surrounded by clear capsules have a “soap bubble” appearance. The immune
response varies from sparse to a prominent granulomatous depending on the
presence of a capsule and the host’s immune status.2,3,5,6,7
Other fungi that cause granulomatous pneumonia include Blastomyces dermatitidis,
Coccidioides immitis and Histoplasma capsulatum. Blastomyces, Coccidioides, and
Histoplasma are unencapsulated, unlike Cryptococcus. Blastomyces reproduces by
broad-based budding, while Cryptococcus and Histoplasma reproduce by narrow-
based budding. Coccidioides reproduces by endosporulation. Mature sporangia of
Coccidioides are 10-80um in diameter with a double-contoured highly refractile wall
and are filled with 2-5um diameter endospores. Histoplasma is much smaller (5-
6um diameter) than Cryptococcus and is located intracellularly within
Contributor: Atlantic Veterinary College, University of Prince Edward Island, 550
University Avenue, Charlottetown, PEI, Canada,
1. Chandler FW, Watts JC: Pathologic Diagnosis of Fungal Infections, pp. 161-
175. ASCP Press, Chicago, Illinois, 1987
2. Dungworth DL: The respiratory system. In: Pathology of Domestic Animals, eds.
Jubb KVF, Kennedy PC, Palmer N, 4th ed., vol. 2, pp. 667-668. Academic Press,
Inc., San Diego, California, 1993
3. Taboada J, Grooters AM: Systemic mycoses. In: Textbook of Veterinary
Internal Medicine Diseases of the Dog and Cat, eds. Ettinger SJ, Feldman EC, 6th
ed., vol. 1, pp. 671-685. Elsevier Saunders, St. Louis, Missouri, 2005
4. Jacobs GJ, Medleau L: Cryptococcosis. In: Infectious Diseases of the Dog and
Cat, ed. Greene CE, 2nd ed., pp. 383-390. W.B. Saunders Company, Philadelphia,
Pennsylvania, 1998
5. Lňpez A: Respiratory system. In: Pathologic Basis of Veterinary Disease, eds.
McGavin MD, Zachary JF, 4th ed., pp. 543-545, 548. Mosby Elsevier, St. Louis,
Missouri, 2007
6. Malik R, Krockenberger M, O’Brien CR, Martin P, Wigney D, Medleau L:
Cryptococcosis. In: Infectious Diseases of the Dog and Cat, ed. Greene CE, 3rd
ed., pp. 584-598. Saunders Elsevier, St. Louis, Missouri, 2006
7. Kidd SE, Hagen F, Tscharke RL, Huynh M, Bartlett KH, Fyfe M, MacDougall L,
Boekhout T, Kwon-Chung KJ, and Meyer W: A rare genotype of Cryptococcus
caused the cryptococcosis outbreak on Vancouver Island, (British Columbia,
Canada) Proc Natl Acad Sci USA 101:17258-17263, 2004
CASE II – P04-4470 (AFIP 2956312).
Signalment: 12-year-old, male neutered, Cocker Spaniel, Canis familiaris, pet dog.
History: 12-year-old neutered male Cocker Spaniel pet dog weighing 27.4 kg, with
signs of diabetes mellitus; hyperglycemia (16.8 mmol/l) and polyuria/polydipsia.
There was a firm mass in the caudal part of the pancreas. The dog was also
affected by an axillary and inguinal alopecic hyperkeratotic dermatosis. The
partially excised pancreas containing the nodular mass was sent in for histological
evaluation. No skin biopsies were available.

Gross Pathology
: Tissue section approximately 5 x 1 cm, pale, firm, multinodular
Histopathologic Description: Pancreas: The pancreatic parenchyma is partly
effaced by a multinodular non-encapsulated partially circumscribed focally
infiltrating hypercellular mass consisting of moderately pleomorphic neoplastic cells
arranged in small multi-layered trabeculae and islands separated and supported by
well vascularized delicate fibrous septa.
The polygonal tumor cells have round to oval vesicular nuclei, which vary
moderately in size with finely stippled chromatin containing a single central
conspicuous medium-sized nucleolus and regularly displaying mitotic figures
(ranging from 2-4 per HPF). Tumor cells have abundant pale basophilic, finely
granular cytoplasm with mainly indistinct cell borders.
Extensive tumorous vascular invasion can be observed within lymphatics and blood
vessels in the pre-existing pancreatic hilar stroma and in the extra-pancreatic
mesenteric adipose tissues.
Some portions of the tumor display a moderate amount of fibrovascular stroma
with extensive central tumorous necrosis and hemorrhage with the presence of iron
pigment and/or ceroid bearing macrophages.
The interlobular pancreatic septa are slightly edematous containing congested blood
vessels with moderate neutrophilic leucocytosis.
In the intact pancreatic parenchyma, there is diffuse prominent cytoplasmic medio-
to macro-vacuolation of the exocrine acinar cells and intercalated ductular cells,
and also to a lesser extent affecting the endocrine islet cells. Multifocally there are
poorly delineated areas in which the aforementioned cytoplasmic vacuolation is
more pronounced with a tendency of loss of acinar detail.
Immunohistochemistry: Tumor cells stain strongly positive for glucagon and show
no positivity for insulin, ACTH, gastrin or somatostatin. Pancreatic islets of
Langerhans stain slightly positive for insulin.
Contributor’s Morphologic Diagnoses: 1.
Pancreas: Well-differentiated pancreatic
glucagon-producing endocrine carcinoma, (Malignant pancreatic α-cell tumor,
malignant glucagonoma), with vascular invasion and dissemination, canine, Canis
familiaris, Cocker Spaniel.
2. Pancreas: Pancreatic endocrine and exocrine and ductular vacuolar fatty
degeneration consistent with paraneoplastic hyperglycemia and diabetes mellitus
type II, canine, Canis familiaris, Cocker Spaniel.
Contributor’s Comment: Several types of pancreatic endocrine tumors in animals
and man are recognized. In dogs they include insulinoma (β-cells), glucagonoma (α-
cells) and gastrinoma (gastrin-producing non-β-cell tumor). Some islet cell tumors
show mixed immunohistochemical reactivity, including somatostatin (δ-cells).
Additionally, in humans, VIPomas (which produce vasoactive intestinal peptide) are
seen. In this case, the tumor cells only showed immunohistochemical positivity for
glucagon. The preexisting pancreatic islets showed only faint positivity for insulin
(periphery of islets) when compared to the strongly staining positive control of a
normal dog. The preexisting pancreatic islets did not stain for glucagon.
This dog was also affected by an axillary and inguinal alopecic hyperkeratotic
dermatosis as can be seen in conjunction with liver disease and with pancreatic
disease; this is known as hepatocutaneous syndrome or superficial necrolytic
dermatitis (SND). SND in canids and in humans (necrolytic migratory erythema
(NME)) is a paraneoplastic syndrome associated with functional pancreatic
endocrine tumors that secrete glucagon (glucagonoma) resulting in hyperglycemia.
The pathogenesis of SND is still obscure. Persistent gluconeogenesis, due to
hyperglucagonemia, is associated with hypoaminoacidemia and seems to be a likely
pathogenic factor. In the cat, paraneoplastic flank alopecia is associated with
pancreatic neoplasms.

AFIP Diagnosis:
1. Pancreas: Islet cell carcinoma, Cocker Spaniel (Canis
), canine.
2. Pancreas, acini, islets, ducts: Vacuolation, cytoplasmic, multifocal, moderate.

Conference Comment: Almost all islet cell tumors in dogs are malignant and
generally microscopic metastasis has occurred by the time of surgical diagnosis.
Carcinomas of the pancreatic islets commonly occur in the duodenal (right) lobe of
the pancreas. Metastasis most commonly occurs to the liver, mesentery,
omentum, and regional lymph nodes. In contrast, islet cell tumors in humans and
ferrets are usually benign. Islet cell carcinomas tend to be larger than adenomas,
invade into and through the fibrous capsule of the pancreas, and are multilobular.
Mitotic figures are usually infrequent.12,13
Glucagonomas in humans cause the glucagonoma syndrome, which is
characterized by necrolytic migratory erythema, glossitis, stomatitis, anemia,
weight loss, mild diabetes mellitus, hypoaminoacidemia, deep vein thrombosis and
depression. In dogs, glucagonomas have been associated with superficial
necrolytic dermatitis, lethargy, anorexia, hyperglycemia and hypoaminoacidemia.
The large majority of cases of canine superficial necrolytic dermatitis are associated
with severe vacuolar hepatopathy rather than glucagonoma.13,14,15
Other neoplasms of islet cell origin which can be differentiated on the basis of
clinical signs and/or immunohistochemical stains include insulinoma and
gastrinoma. Typical clinical findings associated with insulinoma include marked
hypoglycemia, recurrent disorientation or seizures associated with exercise, stress
or fasting. Animals recover with administration of glucose. Gastrinomas secrete
excess gastrin producing Zollinger-Ellison syndrome, which is characterized by
gastric hypersecretion resulting in gastric hyperacidity and gastric and duodenal
ulceration.12, 15
The cytoplasmic vacuolation of multiple pancreatic cell types in this case was
probably caused by hyperglycemia. This finding suggested that the islet cell
carcinoma might be a glucagonoma.
Readers are encouraged to review WSC 20, Case 1, 2006-2007 for a summary of
superficial necrolytic dermatitis.
Contributor: University Medical Center Utrecht, Department of Veterinary
Pathology, Yaleaan 1, P.O. Box 80158, Utrecht, The Netherlands

1. Allenspach K, Arnold P, Glaus T, Hauser B, Wolff C, Eberle C, Komminoth P: Glucagon-
producing neuroendocrine tumour associated with hypoaminoacidaemia and skin lesions. J
Small Anim Pract 41:402-406, 2000
2. Byrne KP: Metabolic epidermal necrosis-hepatocutaneous syndrome. Vet Clin North Am
Small Anim Pract 29(6):1337-1355, 1999
3. Fukushima U, Sato M, Okano S, Aramaki Y, Ito H, Yoshioka K, Oyamada T, Uechi M: A
case of gastrinoma in a Shih-Tzu Dog. J Vet Med Sci 66:311-313, 2004
4. Gross TL, Song MD, Havel PJ, Ihrke PJ: Superficial necrolytic dermatitis (necrolytic
migratory erythema) in dogs. Vet Pathol 30:75-81, 1993
5. Hawkins KL, Summers BA, Kuhajda FP, Smith CA: Immunocytochemistry of normal
pancreatic islets and spontaneous islet cell tumors in dogs. Vet Pathol 24:170-179, 1987
6. Kasper CS, McMurry K: Necrolytic migratory erythema without glucagonoma versus
canine superficial necrolytic dermatitis: is hepatic impairment a clue to pathogenesis? J Am
Acad Dermatol 25:534-541, 1991
7. Turek MM: Invited review cutaneous paraneoplastic syndromes in dogs and cats: a
review of the literature. Vet Dermatol 14:279-296, 2003
8. Miller WH, Scott DW, Buerger RG, Shanley KJ, Paradis M, McMurdy MA,
Angarano DW: Necrolytic migratory erythema in dogs: a hepatocutaneous
syndrome. J Am Anim Hosp Assoc 26:573-581, 1990
9. Ramos-Vara JA, Miller MA, Preziosi D: Glucagonoma in a jaguar (Panthera onca) J Zoo
Wildl Med 31:563-565, 2000
10. Robben JH, Van Garderen E, Mol JA, Wolfswinkel J, Rijnberk A: Locally produced
growth hormone in canine insulinomas. Mol Cell Endocrinol 29:187-195, 2002
11. Solcia E, Klöppel G, Sobin LH: World Health Organization International Histological
Classification of Tumours Histological Typing of Endocrine Tumours, 2nd ed., pp. 48-56.
Springer-Verlag, Berlin, Germany, 2000
12. Capen CC: Tumors of the endocrine glands. In: Tumors of Domestic Animals, ed.
Meuten DJ, 4th ed., pp. 684-690. Iowa State Press, Ames, Iowa, 2002
13. La Perle KMD, Capen CC: Endocrine system. In: Pathologic Basis of Veterinary
Disease, eds. McGavin MD, Zachary JF, 4th ed., pp. 738-739. Mosby Elsevier, St.
Louis, Missouri, 2007
14. Jubb KVF: The pancreas. In: Pathology of Domestic Animals, eds. Jubb KVF, Kennedy
PC, Palmer N, 4th ed., vol. 2, pp. 423-424. Academic Press, Inc., San Diego, California,
15. Ward CR, Washabau RJ: Gastrointestinal endocrine disease. In: Textbook of
Veterinary Internal Medicine Diseases of the Dog and Cat, eds. Ettinger SJ,
Feldman EC, 6th ed., vol. 2, pp. 1627-1631. Elsevier Saunders, St. Louis,
Missouri, 2005

N05-238 (AFIP 2984014).

11-year-old, female spayed, domestic short-haired feline (Felis
History: The patient was an indoor cat which resided in a household of four cats.
All four cats began sneezing acutely. By the following evening, the patient was
coughing and began open mouth breathing with her neck extended. On the third
day, the patient was inappetant, lethargic, and was drooling excessively in addition
to the open mouth breathing. The patient was taken to the veterinarian where she
was sedated with telazol for radiographs. After sedation, the patient went into
extreme respiratory distress and was taken to NCSU-CVM Veterinary Teaching
Hospital for emergency treatment. The patient was placed in an oxygen cage for
observation and to decrease stress and was noted to be unable to expand her chest
(working clinical diagnosis of diaphragm paralysis secondary to the zolazepam).
Intubation and hand ventilation was initiated. The zolazepam portion of the telazol
was reversed with flumenzanil and the patient regained the ability to move her
chest; however, the severe dyspnea was still present. The patient was current on
rabies vaccination only. FeLV and FIV status are not known.
Gross Pathology:
Within the left cranial and caudal lung lobes and the right cranial
and middle lung lobes, there were multifocal, poorly demarcated, dark pink to
purple, slightly collapsed, semi-firm to rubbery regions, interpreted as pneumonia.
There was a moderate amount of yellow mucoid material within the trachea and
large airways. Cytology of the tracheal material revealed moderate numbers of
neutrophils and macrophages within a proteinaceous and mucinous background.
Involving approximately 50-60% of the mucosal surface of the esophagus, there
were numerous multifocal to coalescing, tan, 2-4 mm diameter, ulcers.
Histopathologic Description: There is diffuse acute interstitial pneumonia
characterized by alveolar septal necrosis and fragmentation, and mild expansion of
the septa with fibrin, edema, and small numbers of macrophages and neutrophils.
There is intra-alveolar accumulation of edema, fibrin with scattered hyaline
membrane formation, alveolar macrophages, small to moderate numbers of
neutrophils, and small amounts of hemorrhage. Throughout all sections of lung
examined, there are multifocal to coalescing regions of marked necrosis of the
bronchi and bronchioles with often complete loss of the epithelium and infiltration
of the surrounding alveoli and septa with moderate numbers of macrophages and
neutrophils. The bronchial and bronchiolar necrosis extends into the surrounding
tissue with necrosis of adjacent bronchial glands and pulmonary parenchyma.
Within remaining bronchiolar epithelial cells and bronchial glandular epithelial cells,
there are scattered eosinophilic intranuclear inclusions surrounded by a clear
nuclear halo and marginated chromatin (herpesviral inclusions).
ESOPHAGUS: Multifocally, there is ulceration of the esophageal mucosa with
necrosis of the underlying submucosa and infiltration by moderate numbers of
neutrophils. Within the epithelium adjacent to the regions of ulceration, there are
scattered eosinophilic intranuclear inclusions surrounded by a clear nuclear halo and
marginated chromatin (herpesviral inclusions).

Contributor’s Morphologic Diagnoses:
1. LUNGS, Multiple lobes:
a. Multifocal to coalescing, severe, acute necrotizing and suppurative bronchiolitis and bronchopneumonia with intraepithelial herpetic intranuclear inclusions. b. Diffuse, moderate to severe, acute interstitial pneumonia. 2. ESOPHAGUS: Multifocal to coalescing, marked, subacute, ulcerative and
neutrophilic esophagitis with intraepithelial herpetic intranuclear inclusions.
Contributor’s Comment: The primary lesion in this patient is a herpesvirus induced
severe necrotizing pneumonia, bronchitis and bronchiolitis with intraepithelial
intranuclear inclusions consistent with a fulminant fatal herpesviral infection.
Similar inclusions are identified within the esophageal mucosa adjacent to regions
of ulceration.
Feline viral rhinotracheitis caused by feline herpesvirus-1 (FHV-1) is primarily an
infection of the upper respiratory system in cats. Infected cats exhibit sneezing,
coughing, oral respiration, and salivation, similar to clinical signs identified in the
presented case. Infected cats usually recover in 7-14 days, although there can be
high mortality in kittens, debilitated, or immunosuppressed cats. Lesions are
typically limited to the upper respiratory tract including nasal cavity, pharynx, soft
palate, tonsils, and conjunctiva. Rare infections proceed to a fulminant fatal
pneumonia characterized by a severe necrotizing bronchitis and bronchiolitis with
an interstitial pneumonia.1
The ulcerative esophagitis in this patient is thought to be related to the herpesviral
infection due to the presence of intranuclear inclusions with a similar
histomorphology. Ulcerative esophagitis in cats is most commonly associated with
calicivirus infection. Esophageal ulcers are not specifically mentioned in association
with feline herpesviral infections, although oral ulcers and pharyngitis have been
Although FeLV and FIV status in this patient are not known, we suspect some
underlying cause of immunosuppression.
We did consider a possible severe fatal feline caliciviral infection in this case.
Feline caliciviral pneumonia is generally less severe than herpesviral pneumonia and
often requires a secondary bacterial infection to become significant. Also, the
presence of the typical herpesviral intranuclear inclusion bodies within both the
lungs and esophagus make a diagnosis of herpesviral pneumonia and esophagitis
most likely in this case.2 Virulent systemic feline calicivirus infection typically
includes cutaneous ulceration of the pinnae, footpads, nares, and skin, along with
subcutaneous edema, alopecia, and other systemic lesions such as
bronchopneumonia and hepatic necrosis.3 Cutaneous ulcerations and marked
subcutaneous edema were not identified in this patient.
AFIP Diagnoses: 1. Lung: Pneumonia, bronchointerstitial, necrotizing, diffuse,
severe, with fibrin, edema, syncytia, and epithelial intranuclear inclusion bodies,
etiology consistent with feline herpesvirus, domestic shorthair (Felis domesticus),
2. Esophagus: Esophagitis, necro-ulcerative, multifocal, marked, with fibrin,
edema, and intraepithelial inclusion bodies.

Conference Comment:
Feline herpesvirus 1 (FHV-1) is a double-stranded DNA
alpha-herpesvirus that causes feline viral rhinotracheitis. All species of felidae are
believed to be susceptible. Infection with FHV-1 is naturally acquired through oral,
nasal, or conjunctival routes by either direct contact or from aerosolized oronasal
secretions of virus-shedding infected cats. After an incubation of 24-48 hours, the
onset of typical clinical signs of serous to mucopurulent nasal and conjunctival
discharge occurs, accompanied by fever, sneezing, coughing, oral respiration,
profuse salivation and corneal ulcers. While oral ulceration may also be present in
FHV-1, this lesion is more typical of feline calicivirus infections. Skin ulcers and
dermatitis syndrome in domestic cats and cheetahs, and nervous signs have been
described, but are likely rare sequels to infection.1,4,5
Viral replication occurs primarily in the epithelium of the nasal cavity, oropharynx,
conjunctiva, tonsils, and, to a lesser extent, the trachea. Shedding of viral particles
may begin as early as 24 hours post infection and may last as long as one to three
weeks, though most active viral replication and cell necrosis occur between two to
seven days post infection. During this time, herpesviral intranuclear inclusions are
most often present in infected epithelial cells and occasionally within endothelial
cells. Inclusions are rarely detected beyond seven days after infection and cannot
be relied on for diagnosis. Because viral replication is normally restricted to areas
of lower body temperature, such as the upper respiratory passages, viremia is rare,
and resolution of disease normally takes about two to three weeks. FHV-1 remains
latent in carriers in the trigeminal ganglia.1,4,5
Uncommonly, generalized disease may follow initial upper respiratory tract infection
in debilitated or immunocompromised animals and in neonatal kittens. In these
cases, viremia may be present. Mortality due to FHV-1 is rare in domestic cats;
however, when fulminating cases of viral infection occur, there is often widespread
necrotizing bronchitis, bronchiolitis, and interstitial pneumonia with edema. Viral
infection may predispose to fatal secondary bacterial bronchopneumonia with
bacteria such as Pasteurella multocida, Bordetella bronchiseptica, Streptococcus
sp., and Mycoplasma felis.1,4,5
Contributor: North Carolina State University, College of Veterinary Medicine
Department of Population Health and Pathobiology,

1. Dungworth DL: The respiratory system. In: Pathology of Domestic Animals, eds.
Jubb KVF, Kennedy PC, Palmer N, 4th ed., vol. 2, pp. 558-559. Academic Press,
Inc., San Diego, California, 1993
2. Jones TC, Hunt RD, King NW: Veterinary Pathology, 6th ed., p. 274. Williams
& Wilkins, Baltimore, Maryland, 1997
3. Pesavento PA, MacLachlan NJ, Dillard-Telm L, Grant CK, Hurley KF: Pathologic,
immunohistochemical, and electron microscopic findings in naturally occurring
virulent systemic feline calicivirus infection in cats. Vet Pathol 41:257-263, 2004
4. Lňpez A: Respiratory system. In: Pathologic Basis of Veterinary Disease, eds.
McGavin MD, Zachary JF, 4th ed., p. 483. Mosby Elsevier, St. Louis, Missouri,
5. Gaskell RM, Dawson S, Radford A: Feline respiratory disease. In: Infectious
Diseases of the Dog and Cat, ed. Greene CE, 3rd ed., pp. 145-154. Saunders
Elsevier, St. Louis, Missouri, 2006

C30551-06 (AFIP 3034589).
Signalment: 1.5-year-old, male/neutered, Doberman Pinscher, canine.
History: The patient presented with a 3 month history of lethargy, shifting leg
lameness, and waxing and waning fever. The lameness was getting progressively
worse, and the dog was very depressed and anorexic at the time of referral.
Vaccinations were current. The dog was given a monthly heartworm preventative
and was routinely treated for the control of fleas and ticks.
Gross Pathology:
The dog was humanely killed. The dog had significant loss of
muscle mass and was emaciated, evidenced by minimal body fat stores. Peripheral
lymph nodes including mandibular, prescapular, axillary, cranial mediastinal, and
popliteal were moderately enlarged and soft. The liver was massively enlarged,
extending approximately 6 cm caudal to the costal arch, and had a pale reticulated
lobular pattern and friable consistency. The spleen was similarly massively
enlarged and had a meaty consistency exuding very little blood on the cut surface.
Numerous small thin-walled tortuous blood vessels extended from the portal vein to
the left renal vein and caudal vena cava, consistent with acquired portosystemic
shunts. Both kidneys had a slightly pitted capsular surface. Numerous
approximately 1 mm diameter red foci were scattered throughout the cortex. The
ribs folded rather than breaking. The femoral bone marrow had replacement of
marrow by firm white tissue that sank in formalin. This change was prevalent
throughout the diaphysis of the bone.
Laboratory Results: The CBC revealed a hyperproteinemia (8.3), a leukopenia (5.3)
characterized by a neutropenia (1007) and monocytopenia (106), and a profound
non-regenerative anemia (RBC 1.77, Hgb 3.8, HCT 11.4) with an increased number
of nucleated RBC (128). Abnormalities in the serum chemistry included a low
carbon dioxide (18.7), mild hypercalcemia (11.3), hypoalbuminemia (1.7),
hyperglobulinemia (4.8), low ALT (8), and high cholesterol (436). Evaluation of the
blood smear revealed variably sized blast cells that had round, centrally located
nuclei, indistinct nucleoli, and deeply basophilic cytoplasm. Several of the blast
cells had cytoplasmic projections or blebs. The morphologic features of these blast
cells were suggestive of a megakaryocytic lineage. The platelet count was within
the reference interval; however, several giant, atypical platelets
(macrothrombocytes) were observed. Bone marrow aspiration was performed but
was not diagnostic; only peripheral blood contamination was obtained.
Histopathologic Description: The bone marrow is diffusely filled with a population
of neoplastic cells interspersed with abundant fibrous tissue and intermittent bony
trabeculae with evidence of marked osteolysis. The neoplastic cells are
pleomorphic polygonal cells with prominent anisocytosis and anisokaryosis and
variable chromatin patterns and amounts of cytoplasm. Larger cells have large,
lobulated and sometimes ring-shaped nuclei or multiple small nuclei, often with
dense ropey chromatin, and abundant eosinophilic cytoplasm with distinct
cytoplasmic margins. Smaller blast-type cells also occur and blend with a
background of fibroblasts and intervening fibrillary collagen. Bony trabeculae are
often scalloped and marginated by osteoclasts in Howship's lacunae.
Similar large multi-nucleated cells resembling megakaryocytes, as well as smaller
blast type cells, fill some capsular and medullary sinuses and often efface the
architecture of lymph nodes. The spleen is similarly filled with neoplastic
megakaryocytes and immature precursors intermingled with small residual
populations of lymphocytes. Virtually no distinction of red and white pulp can be
seen. The sinusoids of the liver are diffusely filled with neoplastic megakaryocytes.
Atrophy of hepatic cords is often prominent in centrilobular regions. Alveolar
septal capillaries are prominently thickened by intraluminal neoplastic
megakaryocytes. Small numbers of similar cells occur in pulmonary vessels and
some pulmonary arteries have prominent medial hypertrophy and tortuosity.
Glomeruli throughout the kidney have global thickening of glomerular capillary loops
and moderate hypercellularity. This correlates with frequent intraluminal hyaline
casts in tubules.
Contributor’s Morphologic Diagnosis: Megakaryocytic leukemia with myelofibrosis
and metastatic sites in spleen, liver and lymph nodes

Contributor’s Comment:
Acute myeloid leukemias (AML) are neoplastic
myeloproliferative disorders (MPD) that arise from hematopoietic precursors,
including granulocytic, monocytic, erythrocytic, and megakaryocytic cell lines.1
Megakaryocytic leukemia is a rare subtype of AML, both in humans and animals,
and is designated as AML-M7. While chronic leukemias are characterized by
infiltration of the bone marrow with more mature neoplastic hematopoietic cells,
AMLs, in contrast, are characterized by large numbers ( >20%) of blast cells in the
bone marrow.2 Megakaryoblasts are pleomorphic, and can potentially resemble
lymphoblasts or myeloblasts. Thus, a diagnosis of AML-M7 based on morphology
alone can only be accomplished if the blasts demonstrate some degree of
differentiation. Cytoplasmic blebs or platelet shedding help identify
megakaryoblasts. When the megakaryoblasts are poorly differentiated, it is difficult
to distinguish AML- M7 from acute myeloid leukemia, acute lymphoid leukemias,
and pure erythroid leukemia simply from evaluation of blood smears or bone
marrow aspirates.2 Thus, cytochemical, ultrastructural, and immunophenotypic
features may be required for a definitive diagnosis. Immunophenotyping is a very
useful diagnostic tool for determination of cell origin in poorly differentiated
leukemias. In dogs with AML-M7, the blasts will be positive for CD41 (GPIIb/IIIa),
CD61 (GPIIIa), and factor VIII-related antigen.2
Myelofibrosis develops in some cases of AML-M7 in dogs, similar to human
patients with megakaryocytic leukemia.1 A critical role for megakaryocytes in the
pathogenesis of myelofibrosis has been recognized in human patients with
idiopathic myelofibrosis (IMF). IMF is a clonal hematopoietic disorder characterized
by atypical megakaryocytes, severe myelofibrosis, and splenic extramedullary
hematopoiesis.1 Megakaryocytic overproduction of fibrogenic cytokines, particularly
platelet derived growth factor (PDGF) and transforming growth factor-β (TGF-β), are
thought to be responsible for the myelofibrosis observed in IMF and other
disorders of the megakaryocytic lineage, including AML-M7 and MDS with
prominent dysmegakaryopoiesis.3 It has been demonstrated that the PDGF
contained within the platelet α granules are capable of inducing fibroblast
proliferation.3 The release of PDGF from megakaryocytes, however, is not thought
to be completely responsible for the observed myelofibrotic stroma observed in
megakaryocytic disorders. PDGF does not have angiogenic properties or the
capability of inducing gene transcription of laminin, fibronectin, or the collagens.
Thus, other growth factors must be involved; TGF-β is probably the most important
additional growth factor involved.3 TGF-β, also stored in platelet α granules,
regulates the synthesis of the extracellular matrix in myelofibrotic disorders.3 It
accomplishes this by increasing the expression of genes for fibronectin, collagens
type I, III, and IV production, in addition to chondroitin/dermatan sulphate
proteoglycans. TGF-β is also pro-angiogenic and decreases the production of
collegenase-like enzymes that are responsible for degrading extracellular matrices.
Ultimately, these properties of TGF-β result in an increase in extracellular matrix.

AFIP Diagnoses:
1. Bone marrow: Acute megakaryoblastic leukemia (AML M7)
with myelofibrosis, Doberman Pinscher (Canis familiaris), canine.
2. Lymph node and liver: Acute megakaryoblastic leukemia, metastatic.

Conference Comment: The contributor provides a thorough overview of
megakaryocytic leukemia, a rare subtype of acute myeloid leukemia. This condition
is designated acute megakaryoblastic leukemia (AML M7) in the WHO
classification. CD61 immunohistochemical staining performed at the AFIP revealed
multifocal cytoplasmic immunoreactivity of the neoplastic megakaryocytes
supporting the diagnosis of megakaryoblastic leukemia.5
Mississippi State University, College of Veterinary Medicine, Wise
Center, 1 Spring Street, Mississippi State, MS 39762
1. Blue JT: Myelodysplastic syndromes and myelofibrosis. In: Schalm’s Veterinary
Hematology, eds. Feldman BF, Zinkl JG, Jain NC, 5th ed., pp. 682-688. Lippincott
Williams & Wilkins, Baltimore, Maryland, 2000
2. Grindem CB: Acute myeloid leukemia. In: Schalm’s Veterinary Hematology, eds.
Feldman BF, Zinkl JG, Jain NC, 5th ed., pp. 717-726. Lippincott Williams &
Wilkins, Baltimore, Maryland, 2000
3. Ledieu D, Palazzi X, Marchal T, Fournel-Fleury C: Acute megakaryoblastic
leukemia with erythrophagocytosis and thrombosis in a dog. Vet Clin Pathol 34:52-
55, 2005
4. Reilly JT: Pathogenesis of idiopathic myelofibrosis: role of growth factors. J Clin
Pathol 45:461-464, 1992
5. Valli VE, Jacobs RM, Parodi AL, Vernau W, Moore PF: World Health
Organization Histological Classification of Hematopoietic Tumors of Domestic
Animals, Second Series, vol. VIII, p. 55. Armed Forces Institute of Pathology,
Washington, D.C., 2002

*Sponsored by the American Veterinary Medical Association, the American College of Veterinary Pathologists and the C. L. Davis Foundation.



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