Haemophagocytic syndrome in a dog

History: A 4 year old female spayed Border Collie mix had a 10 day history of refractory IMHA/ ITP with possible DIC.  She had abdominal effusion which was determined to be a modified transudate.

Gross Lesions:

Icterus of mucous membranes and mesentery. The abdominal cavity contained approximately 100-200 ml of bright orange clear fluid.

The spleen was diffusely enlarged with multifocal red to pink nodules.

The pancreas had a focal soft red nodule arising distal to the pyloric

junction.

Histopathology:

Lymph nodes:  Normal lymph node architecture is replace and effaced by a mass of pleomorphic neoplastic histiocytes forming sheets of polygonal to spindle cells with ample eosinophilic cytoplasm and indented nuclei with vesicular chromatin.  There are large clusters of multinucleated giant cells with up to 50-70 nuclei and large numbers of macrophages with intracytoplasmic erythrocytes (erythrophagocytosis),  and large numbers of hemosiderophages.  There is severe anisocytosis and anisokaryosis of the histiocytes and large numbers of bizarre nuclei.

Pancreatic lymph node: The lymph node is diffusely infiltrated by neoplastic histiocytic cells

Pancreatic lymph node: Numerous multinucleated neoplastic cells are present, with often bizarre shapes

Pancreatic lymph node: Multinucleated cells have nuclei too numerous to count, and often have bizarre mitotic figures

Pancreatic lymph node: There is prominent erythrophagocytosis by neoplastic histiocytic cells

Spleen:  There are multifocal areas of infarction and necrosis with intravascular fibrin thrombi in large arterioles.  There is diffuse extramedullary hematopoiesis with large numbers of megakaryocytes and erythroid and myeloid precursors.  Multifocal areas of the spleen are hypercellular.

Splenic artery: Occluding the lumen is a large fibrin thrombus

The liver and bone marrow contained small foci of neoplatic histiocytic cells.

Diagnosis:

1. Lymph nodes:  Histiocytic sarcoma with erythrophagocytosis

2. Spleen: Multifocal infarction and marked extra-medullary

hematopoiesis

3. Bone Marrow:  Multifocal histiocytic sarcoma, mild

4. Liver:  Diffuse vacuolar degeneration with extra-medullary

hematopoiesis.

Comment:

The erythrophagocytosis seen histologically can be due either to the

IMHA or the histiocytic sarcoma or both.  A hemophagocytic histiocytic

sarcoma has been described in dogs (Vet Pathol 43:632–645 (2006))

which is derived from splenic CD11d+ macrophages.  This disease is

distinct from disseminated histiocytic sarcoma (malignant histiocytosis)

which is believed to arise from CD11c+ (CD11d-) dendritic cells and have

significantly less erythrophagocytosis as well as presenting with discrete

focal splenic nodules instead of having diffuse splenic enlargement.  The

hemophagocytic syndrome mimics immune mediated hemolytic anemia

and thrombocytopenia but is Coombs negative.  It presents with diffuse

splenic enlargement and can involve the liver and bone marrow and

lungs.  But because they are similar in histological characteristics the best

way to differentiate the two diseases is with immunophenotyping on fresh

tissues.

Feline Infectious Peritonitis – neurotropic

History: A 7 month old female intact DSH kitten had neurologic signs and seizures in the past few months (Along with several others from a shelter).  This particular kitten presented for circling and ataxia.

Gross Findings:

Gross lesions were limited to multifocal petechiae  in the white matter of the cerebellum.

Histopathology:

Brain:  There are moderate numbers of lymphocytes, plasma cells, and histiocytes tightly surrounding blood vessels in the meninges,  superficial cerebral and brainstem blood vessels and expanding Virchow-Robbins space.  Similar cellular infiltrates surround blood vessels adjacent to the lateral ventricle and central canal.  There are lesser numbers of these cells located below the ependyma of the lateral ventricles and central canal.

A 7 month old female intact DSH kitten was presented for necropsy 12/8/08.  Several kittens at the

humane society have had neurologic signs and seizures in the past few months.  They are from

different litters and have been euthanized.  This particular kitten presented for circling, ataxia, and

possible seizures (none observed).  The primary concern is for a possible cause on a kennel-level,

and JCHS would like to prevent future deaths through the sacrifice of this kitten.

Brain, bordering the lateral ventricle: vasculitis, primarily lymphocytes, macrophages and plasma cells

Brain and meninges: Vasculitis and perivasculitis, lymphoplasmacytic and histiocytic

Brain: Lymphocytes, macrophages, and plasma cells surrounding and infiltrating a blood vessel

Brain: Inflammation often spreads into parenchyma

Morphologic Diagnosis:

Brain:  Multifocal granulomatous meningitis, perivasculitis and periventriculitis

Comment:

Further diagnostics were cost prohibitive in this case.  The character of the lesions were attributed to the dry form of FIP.  More typical lesions of the dry form include multifocal pyogranulomas on serosal surfaces of visceral organs.  In constrast, the wet form presents as profuse body cavity effusions that are protein rich.

The neurologic form of FIP is a recognized subset of the infection with the FIP mutation of feline enteric coronavirus.  A high CSF IgG titer to feline coronavirus is considered diagnostic.

References:

Foley JE, Lapointe JM, Koblik P, Poland A, Pedersen NC. Diagnostic features of clinical neurologic feline infectious peritonitis. J Vet Intern Med. 1998 Nov-Dec;12(6):415-23.

Niels C Pedersen. A synopsis of feline infectious peritonitis virus infection. http://www.vetmed.ucdavis.edu/ccah/documents/FIP_Synopsis_Jan13_09.pdf

Proventricular dilatation in a Cockatoo

History: A male adult Cockatoo had regurgitated.  His feed was changed but continued to regurgitate, and died within a few days.

Gross Pathology:

The bird was very thin with a very prominent keel bone and pectoral muscle atrophy.

The crop and proventriculus were markedly dilated and filled with soft oats. The proventriculus  filled 80% of the cranial coelom and displaced the liver dorsally and to the right. The ventriculus was displaced caudally and displaced the intestines dorsally. The intestines contained a small amount of brown liquid.

Histopathology:

Large artery: There is disruption of the internal elastic lamina and there is accumulation of pale basophilic mucinous material within the tunica muscularis of the artery.

Brain: In the cerebrum there are moderate numbers of small blood vessels surrounded by small numbers of lymphocytes and plasma cells in the grey and white matter.

Comment:

Causes of proventricular dilatation include Bornavirus, lead  intoxication,  foreign body obstruction, fungal infection, megabacterial infection or neoplasia. Bornavirus infection (proventricular dilatation disease) causes inflammation in the central and peripheral nervous systems.  We did not see any inflammation in the peripheral nerves, proventriculus,  ventriculus,  crop or esophagus.   In the absence of inflammation of in peripheral ganglia/nerves we could not definitively diagnose this case as a “proventricular dilatation disease”.  However, since no fungi, bacteria, neoplasia, obstruction or other evidence of lead toxicity, Bornavirus is the most likely  cause/agent of disease in this case.

A male adult Cockatoo was presented for necropsy on 12/29/08. The bird had regurgitated and been

switched from dyed to non-dyed foods. He regurgitated again and was fed oatmeal and died later

that night.

Amyloidosis and Diabetes in a dog

History: A twelve year old castrated male Miniature Schnauzer was presented with diabetic ketoacidosis and a 48 hour history of vomiting, polyuria, and polydypsia.   The dog also had a chronic history of urinary tract infection.  The dog died of cardiac arrest.

Gross Lesions: (no gross pictures)

Heart:  Endocardiosis

Lungs:  Diffuse congestion and edema

Eye:  Corneal inclusion cyst

Urinary bladder:  Cystitis

Liver:  Multifocal nodular regeneration

Gall Bladder:   Mucocoele

Histopathology:

Kidneys:  The glomerular tufts are hypocellular with increased mesangium and amyloid. Glomeruli were positive for amyloid by Congo Red stain showing an orange material that glows green with polarized light. Amyloid is present globally in some glomeruli and segmentally in others. In some cases amyloid is admixed with collagen in the same glomerulus.

Bowman’s capsules have thickend basement membranes (PAS positive) and the parietal epithelium of Bowman’s capsule is multifocally lined by cuboidal epithelium.  Occasional tubules contain eosinophilic granular casts.  There is increased amounts of fibrous tissue in the cortex and medulla.

Kidney: Glomerular tuft is thickened (segmentally) with eosinophilic material (amyloid)

Kidney: Glomerulus is completely thickened (globally) with eosinophilic material (amyloid)

Kidney: Glomerulus with Congo Red stain- orang/red = amyloid

Kidney: Multiple Glomeruli: Polarized light and Congo Red stain- Apple green bi-refringence = amyloid

Eye:  There is a small cyst lined by stratified squamous epithelium within the cornea.

Cornea: Epithelial inclusion cyst

Cornea: Interior lining of the cyst- lined by cuboidal epithelium

Liver:  Multifocally hepatocytes contain moderately sized clear lipid vacuoles, and scattered Kupffer cells contain hemosiderin.  There are numerous hepatocytes with yellow/brown cytoplasmic pigment (bile). There are multifocal coalescing areas of nodular hyperplasia with variably sized hepatic lobules.

Heart:  In the atria the arteriolar walls are thickened with an eosinophilic material resembling amyloid.  The smooth muscle cells of the tunica media are vacuolated and the lumen is narrowed in many arterioles.  The aortic valve is focally expanded by a pale basophilic matrix of mucinous material.  The base of the valve is replaced by chondrocytes within lacunae surrounded by basophilic cartilaginous matrix.

Spleen:  Small arterioles contain vacuolated and swollen smooth muscle cells with replacement by amyloid and mineralization.

Lung:  In multifocal areas the alveoli and small bronchi contain large numbers of degenerate and intact neutrophils with small amounts of fibrin.

Pancreas:  Diffusely there are fewer Islets than normal and the ones that are present are small, with few vacuolated cells.

Gall bladder:  The glands of the gall bladder mucosa are dilated and hypertrophied and filled with amphophilic material.  The mucosa is covered with a layer of amphophilic material approximately 10x the thickness of the gall bladder wall.

Diagnosis:

1. Kidneys:  Amyloidosis, multifocal, global and segmental

2. Eye, cornea: Epithelial inclusion cyst, focal

3. Heart and spleen:  Arteriolar medial degeneration and amyloidosis

4. Heart, aortic valve:  Endocardiosis, focal, severe

5. Lung: Bronchopneumonia, mild, multifocal

6. Pancreas:  Pancreatic Islet atrophy and degeneration

7. Gall bladder:  Mucocoele

Comment:

The most significant lesion (to the dog) is the loss of Islets of Langerhans in the pancreas.  This ultimately led (presumably) to the urinary tract infection, and to the acute crisis of diabetic ketoacidosis.  Uncontolled diabetes mellitus can explain the clinical signs noted in the history (Polyuria/polydypsia, vomiting).  The photomicrographs highlight the diagnosis of amyloidosis in the glomeruli using Congo Red and polarized light (apple green bi-refringence).  The amyloid is presumably AA type resulting from the chronic urinary tract infection.   In this case amyloid was found in the glomeruli and in the small arterioles of the heart and spleen.  The cause of the bronchopneumonia is unknown.   The rest of the lesions were considered incidental findings.

Amyloidosis can be subdivided into 2 common subtypes in domestic animals.  One is the AA type in which the amyloid fibrils are derived from serum amyloid A (SAA) – a positive acute phase protein.  IT is produced by the liver under the influence of acute inflmmatory cytokines IL-1, and IL-6.  The second type is AL, which is derived from the light chains of immunoglobulins (amyloid light-chain), which is produced by plasma cells in certain autoimmune disease, and multiple myelomas, or chronic activation of humoral immunity.

Other types of amyloid proteins (other than AA and AL) include:

AB (beta) amyloid- age related neurodegenerative change.

IAPP- Islet amyloid polypeptide- secreted by beta cells in the pancreas. Found in Islet amyloidosis.  This can lead to development of

AI- Apolipoprotein AI- Found in the pulmonary vasculature of aged dogs

Prion Diseases- CWD , Scrapie, BSE, Mink and feline spongioform encephalopathy.

References:

Snyder PW. Diseases of Immunity. Chaper 5 in Pathologic Basis of Veterinary Disease, 4th ed, eds McGavin DM, and Zachary JF.  Mosby, Inc, St Louis Missouri.  2007

patient was presented to the KSU VMTH on 12/07/08 with diabetic ketoacidosis and a 48 hour history

of vomiting, polyuria, and polydypsia.  He has been treated by the referrimg veterinarian for a urinary

tract infection and ear/skin infection for about a month.  At presentation to KSU CVM he was

depressed, dehydrated, febrile (105ºF), and leukopenic with diarrhea and abdominal pain.  He

became oliguric and arrested 12/08/08 at 1:00pm. A cosmetic necropsy was requested.PrionTh

Porcine Multisystemic Wasting Syndrome – PCV-2

Whats your diagnosis #3

Porcine Multisystemic Wasting Syndrome – PCV-2

See original post here

History: A feeder pig was found dead in the morning, it was thinner than its penmates.

Gross Necropsy: (no photos)

The lungs were loosely adhered to the thoracic body wall by multiple strands of fibrin. The lungs were diffusely edematous and firm.

The pericardium contained approximately 200 mls of fluid. The right ventricle was severely enlarged and the pulmonary trunk was dilated.

There was diffuse serous atrophy of fat.

Histopathology:

Lungs: Alveolar septa contain large numbers of lymphocytes, macrophages, plasma cells and lesser numbers of neutrophils and eosinophils. Small bronchioles and a few alveoli contain neutrophils. There are perivascular infiltrates of lymphocytes and macrophages. Within the walls of arterioles there are neutrohilic and lymphocytic infriltrates and there is vacuolar degeneration of the tunica media. There is proliferation of fibrous tissue which occludes the lumens of multifocal small arterioles and bronchioles.

Lung: Vasculitis and perivasculitis, proliferative, and bronchointerstitial pneumonia

Kidneys: The renal interstitium is infiltrated with large numbers of lymphocytes, macrophages, and plasma cells with lesser numbers of neutrophils and eosinophils. There are macrophages containing multiple basophilic round cytoplasmic inclusions.

Kidney: Interstitial nephritis, eosinophilic and granulomatous

Kidney, renal cortical tubule: Sloughed necrotic epithelial cells with basophilic cytoplasmic inclusions in epithelial cells and macrophages

Lymph nodes: There is diffuse lymphoid depletion characterized by loss of lymphoid follicles and germinal centers. There are moderate numbers of multinucleated giant cells in the medullary sinuses along with moderate numbers of lymphocytes, neutrophils, macrophages, and some eosinophils.

Lymph node: Granulomatous lymphadenitis- Macrophages and multinucleated giant macrophages replace normal architecture

Spleen: There is diffuse lymphoid depletion in the spleen similar to the lymph node.

Ileum: There is diffuse lymphoid depletion in the Peyer’s patches of the ileum, and there are large numbers of macrophages and lymphocytes infiltrating the submucosa along with small numbers of neutrophils.

Brain: There are a few foci of perivascular histiocytic and lymphocytic infiltrates in the brain stem.

Kidney, PCV-2 IHC: Strong immunoreactivity in tubular epithelial cells

Lung, PCV-2 IHC: Strong immunostaining in macrophages around blood vessels

Lymph node, PCV-2 IHC: The centers of follicles are devoid of lymphocytes and macrophages/ dendritic cells stain strongly with PCV-2 antigen

Diagnosis:

1. Lungs: Interstitial pneumonia, granulomatous, severe, diffuse, with arteritis, perivasculitis, and multifocal proliferation of vascular fibrous tissue

2. Kidneys: Interstitial nephritis, granulomatous, multifocal, moderate, with intrahistiocytic basophilic cytoplasmic inclusions.

3. Brain: Perivasculitis, granulomatous, mild, multifocal

4. Spleen/Lymph nodes/ Ileum: Diffuse lymphoid depletion

5. Lymph nodes: Granulomatous lymphadenitis, moderate, diffuse

6. Ileum : Granulomatous enteritis, mild, multifocal

A feeder pig was presented for necropsy 12/8/08. This pig is thinner than its pen mates. It was found

dead 12/08/08 in the morning. The farm has had APP and Strep on the premises.

Comment:

The gross and microscopic lesions are consistent with PMWS, and PCV- 2 was detected in pooled tissues by PCR. No significant bacterial agents were isolated from the lymph node or intestines, and no bacteria were isolated from the lung. The PCR test for PRRSV was negative. An ELISA for swine flu was negative as well.

This case demonstrates the usefulness of histopathology as a diagnostic tool.  The gross lesions alone suggest polyserositis such as would be caused by Streptococcus suis or Haemophilus parasuis.  The histopathologic lesions of granulomatous inflammation with multinucleated giant macrophages and intracytoplasmic basophilic inclusions are specific for PCV-2 associated disease.  Immunohistochemistry and PCR confirmed the presence of PCV-2 antigen in the affected tissues, and other viruses (PRRS and Influenza) were ruled out by PCR and ELISA tests.

A diagnosis of PMWS is made based on 1) clinical signs of failure to grow, weight loss, and pneumonia, 2) typical histologic lesions including granulomatous lymphadenitis/ lymphoid depletion, and 3) detection of the virus in tissues by IHC or ISH.  Affected pigs are 5-18 weeks old and may have gastric ulcers, pleural and perioneal effusions and diarrhea.

Due to the ubiquitous presence of PCV-2 in swine herds and the broad variety of diseases that can involve PCV-2 it is proposed to introduce the term Porcine Circovirus Associated Disease (PCVAD).   PCVAD  can  be  subclinical  or  include  one or more of the following:  multisystemic disease with weight loss,  respiratory  signs,  PDNS,  diarrhea, and reproductive disorders.

Other proposed systems of classification of  PCVAD   includes: systemic infection (such as PMWS),  PCV2-associated  pneumonia,  PCV2-associated enteritis,  PCV2-associated  reproductive  failure,  and PCV2-associated  PDNS.

References:

Opriessnig T,  Xiang-Jin M, Halbur  P G.  2007. Porcine circovirus type 2–associated disease: Update on current terminology, clinical manifestations, pathogenesis, diagnosis, and intervention strategies.  J Vet Diagn Invest 19:591–615.

Luteinizing follicular cyst in a dog

History: Tissue from an 11 month old female Great Dane.  The tissue was removed during a routine spay surgery and submitted for histopath due to abnormal appearance.

Ovary: Large corpus luteum at the top of the image and a smaller luteinizing follicle in the center

Ovary: Below the solid corpus luteum is a large cyst lined by granulosa cells with a focal area of luteinization (foamy vacuolated cells)

Ovary: Higher magnification of the luteinizing cells lining the cyst

Ovary:  In each section examined there are primary follicles present in a fibrovascular stroma.  There are two normal corpora lutea present consisting of a large solid mass ofpolygonal cells with large intracytoplasmic lipid vacuoles (luteinized cells). In addition there are two large cystic follicles partially lined by luteinized cells and partially lined by follicular epithelium.

Comment:

Luteinized ovarian cysts are derived from anovulatory Graffian follicles and can cause hyperestrogenemia in some cases and are associated with cystic endometrial hyperplasia and development of pyometra in dogs.

Tissue from an 11 month old female Great Dane was submitted for histopathology.  During the spay

surgery the submitting veterinarian noticed an abnormal anatomical arrangement of the reproductive

tract and requests identification of the submitted tissue to see if it is ovarian or lymphoid.

Whats Your Diagnosis #3

History: A feeder pig was found dead in the morning, it was thinner than its penmates.

Gross Necropsy: (no photos)

The lungs were loosely adhered to the thoracic body wall by multiple strands of fibrin. The lungs were diffusely edematous and firm.

The pericardium contained approximately 200 mls of fluid. The right ventricle was severely enlarged and the pulmonary trunk was dilated.

There was diffuse serous atrophy of fat.

Histopathology:

Lung:

Differential Diagnoses for interstitial pneumonia and vasculitis in a pig:

1. PRRS virus

2. Porcine Circovirus-2-

3. Classical Swine Fever (Pestivirus)

To Be Continued….

What other tissues would you examine?   What histologic lesions do you expect to find with each of the differentials above?

To see our diagnosis and discussion click here