AFIP Wednesday Slide Conference - No. 9
November 13 1996

Conference Moderator: Dr. Jerrold M. Ward
Diplomate, ACVP
National Cancer Institute
Frederick Research Center
Frederick, MD 21701

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Case I - 9710-95 (AFIP 2550133)

Signalment: Adult female pygmy African hedgehog.

History: Sudden onset of posterior paresis. Prolapsed disc diagnosed by CAT scan. Dexamethasone and antibiotic therapy resulted in dramatic improvement. Two weeks later, the animal went off feed and died.

Gross Pathology: The liver was stippled with barely visible 0.5 mm diameter, white, opaque foci.

Laboratory Results: Candida albicans isolated from lung. No bacterial growth from liver or spleen. Direct FA results: Canine and feline herpes -- negative; Bovine herpes 1 -- negative, pseudorabies -- positive (weak), equine herpes 1 -- positive (weak). Herpes simplex I -- positive (strong). Herpes simplex II -- negative.

Contributor's Diagnosis and Comments: Liver -- 1. Moderate multifocal and coalescing necrosis with intranuclear inclusion bodies, syncytial cells, and vascular necrosis. 2. Mild multifocal subacute pericholangitis. Etiology: Herpesvirus.

Herpesvirus infection has not been reported in the hedgehog. The fluorescent antibody results suggest that the virus from this animal may be herpes simplex type I. PCR studies are pending. Vascular necrosis is present in some but not all slides.

AFIP Diagnosis:

1. Liver: Necrosis, multifocal to coalescing, random, with eosinophilic intranuclear inclusion bodies and syncytia.
2. Liver: Vacuolar change (lipid type), diffuse, moderate.
3. Liver: Hepatitis, portal, subacute and eosinophilic, mild.
4. Liver, sinusoids: Extramedullary hematopoiesis, multifocal, small amount.

Conference Note: The hepatic necrosis associated with syncytia and eosinophilic intranuclear inclusion bodies is typical of herpesvirus infections. Although a number of diseases affecting hedgehogs have been documented, information concerning viral infections is limited. Infections with foot and mouth disease virus and a morbillivirus have been reported. We found one article that reported herpesviral hepatitis in a European hedgehog with lesions almost identical to those present in this case. The PCR results mentioned in the contributors comments became available by the time of the conference and were positive for Herpes simplex type I. Herpes simplex type I is known to infect humans, non-human primates and in SCID mice.

Contributor: C.E. Kord Animal Disease Laboratory, P.O. Box 40627, Melrose Station, Nashville, TN 37204

Stack MJ, Higgins RJ, Challoner DJ, Gregory MW: Herpesvirus in the liver of a hedgehog (Erinaceus europaeus) Veterinary Record 127:620-621, 1990.

International Veterinary Pathology Slide Bank: None


Case II - 96-0338 (AFIP 2550170)

Signalment: 10-year-old male crossbred dog.

History: This dog had shown progressive neurological signs over a period of a few months. The dog circled to the left, was blind and depressed.

Gross Pathology: At necropsy, cerebral leptomeninges were severely congested. There was a spherical hemorrhagic mass, 10 mm in diameter, in the left cerebral hemisphere.

Laboratory Results: None.

Contributor's Diagnosis and Comments: Angiotropic large-cell lymphoma.

There was a widespread proliferation of large neoplastic mononuclear cells under the endothelium and within the lumens of small and medium sized vessels of many organs (cerebral leptomeninges and hemispheres, irises and retinas of both eyes, kidneys, spleen, liver and adrenal glands). Vascular lesions ranged from the presence of small aggregates of neoplastic cells to a complete occlusion of the lumen. Some of the affected vessels were thrombosed, and vascular ectasia, sometimes severe, was common. Neoplastic cells were also observed in the interstitium of the renal and adrenal cortex and medulla. The bone marrow was not involved. Immunohistochemical studies of paraffin-embedded fixed brain tissue showed that the intravascular neoplastic cells were positive for kappa-lambda immunoglobulin light chains, but negative for muramidase and factor VIII-related antigen. This intravascular proliferation of neoplastic mononuclear cells is compatible with angiotropic large-cell lymphoma reported in humans and dogs. The term "malignant angioendotheliomatosis" had been used initially to describe this lesion which was supposed to have an endothelial origin. Recent reports indicate that these neoplastic cells are positive for the common leukocyte antigen, kappa or lambda light chains, IgM, IgG and other lymphocyte markers, which is suggestive of an unusual angiotropic manifestation of malignant lymphoma.

AFIP Diagnosis: Brain: Ectasia, vascular, multifocal, with thrombosis and atypical intravascular mononuclear cells, cross-breed, canine.

Conference Note: Most of the conference participants favored a diagnosis of vascular malformation due to the presence of numerous, cavernous blood vessels. The morphology of many of the cells within the lumens of these vessels could not be clearly seen. Without additional evidence as was given in the contributor's comments, specific diagnosis was not possible.

Angiotropic large-cell lymphoma has been reported in humans and dogs and is a rare, generally fatal disease characterized by massive proliferation of neoplastic lymphocytes within blood vessels, often in a subendothelial location. Although scattered extravascular nodules of neoplastic cells can be seen, this is a predominantly intravascular neoplasm. The neoplasm has a predilection for vessels of the skin and central nervous system, but any organ can be involved. Characteristic pathologic features are thrombosis and infarction.

The influences that largely limit the malignancy to vascular spaces are poorly understood, but may involve the tendency of lymphocytes to bind certain endothelial receptors or a lack of a receptor necessary for exocytosis.

Contributor: Department of Pathology and Microbiology, Faculty of Veterinary Medicine, University of Montreal, P.O. Box 5000, St. Hyacinthe, Quebec CANADA J2S 7C6.

1. Dargent FJ, et al: Neoplastic angioendotheliomatosis in a dog: An angiotropic lymphoma. Cornell Vet. 78:253-262, 1988.

2. Sheibani K, et al. Further evidence that "malignant angioendotheliomatosis" is an angiotropic large-cell lymphoma. New Engl J Med 134:943-948, 1986.

3. Kilrain CG, Saik JE, Jeglum KA: Malignant angioendotheliomatosis with retinal detachments in a dog. J Am Vet Med Assoc 204(6): 918-921, 1994.

4. Jubb KVF, Kennedy PC, Palmer N (eds): Pathology of Domestic Animals, Vol. 3, pg. 99, Academic Press, 1993.

International Veterinary Pathology Slide Bank: None.


Case III - 96-13546 (AFIP 2550624)

Signalment: Mouse c57BL x 129 Uteroglobin +/- (heterozygous for normal gene), 7-month-old female.

History: Clinically normal. Knockout has severe lesions, heterozygous mouse has mild lesions.

Gross Pathology: None

Laboratory Results: None

Contributor's Diagnosis and Comments: Kidney - focal glomerulosclerosis.

In many glomeruli one can see focal eosinophilia of the mesangium. Many other glomeruli appear normal. In knockouts for this gene, all glomeruli are severely affected, but in heterozygotes, only mild lesions are seen. The lesions contain fibronectin and collagen and some have immunoglobulin. On EM studies, no dense deposits are noted but much deposition of finely granular material and collagen fibrils in the mesangium can be seen.

AFIP Diagnosis: 1. Kidney, glomeruli: Eosinophilic mesangial deposits and hyalinization, segmental, multifocal, mild, mouse, rodent.
2. Kidney: Nephritis, interstitial, lymphoplasmacytic, multifocal, mild.

Conference Note: The lesions in this kidney section could be easily overlooked or considered an insignificant finding. The contributor and conference moderator, Dr. Jerrold Ward, demonstrated the severity and progressive nature of the glomerulosclerosis in uteroglobin gene knockout mice as compared to milder lesions in heterozygotes. A possible role of uteroglobin may be to bind fibronectin preventing deposition in the glomerulus. The results of this study are due to be published in the near future.

Uteroglobin is a small glandular protein, which was originally described in the uterine fluid of pregnant rabbits. Later, the protein was identified as a major product of the bronchiolar Clara cells. Binding of polychlorinated biphenyl metabolites has been discussed as a major function of uteroglobin in the lung. Uteroglobin is also expressed in lower levels in other secretory epithelia including those of the genital tract, stomach, and salivary gland.

Fibronectin is a large (400 kd) multifunctional glycoprotein associated with cell surfaces, basement membranes, and pericellular matrices. It is produced by fibroblasts, monocytes, endothelial cells, and other cells. Fibronectin binds extracellular matrix components (collagen, fibrin, heparin, and proteoglycan) via a specific tripeptide (arginine- glycine-aspartic acid) domain and to cells via integrin receptors to signal cell attachment, locomotion, and differentiation. The binding of fibronectin is also thought to sensitize cells to growth factors. In a recent article, fibronectin-derived peptides were suggested to be the major fibroblast chemoattractant produced by the renal cortex in anti-glomerular basement membrane disease.

Contributor: National Cancer Institute, NCI-FCRDC, Fairview 201, P.O. Box B, Frederick, MD 21702-1201.

1. Sandmoller A, et al: A transgenic mouse model for lung adenocarcinoma. Cell Growth & Diff, 6:97-103, 1995.

2. Peri A, et al: Tissue-specific Expression of the Gene Coding for Human Clara Cell 10 kd Protein, a Phospholipase A2-inhibitory Protein. J Clin Invest, 92:2099-2109, 1993.

3. Gharaee-Kermani M, et al: Fibronectin is the Major Fibroblast Chemoattractant in Rabbit Anti-Glomerular Basement Membrane Disease. Amer J Pathol, 148(3): 961-970, 1996.

International Veterinary Pathology Slide Bank: None.


Case IV - 95-15187 (AFIP 2550640)

Signalment: Mouse, double knockout gamma chain and zeta chain of the T cell receptor, 129 x C57BL, 4-months-old, male.

History: Progressive wasting, rectal prolapse.

Gross Pathology: Entire large bowel is white and thickened.

Laboratory Results: Culture and identification of Helicobacter hepaticus from the cecum.

Contributor's Diagnosis and Comments: Inflammatory large bowel disease, proliferative inflammatory large bowel disease, typhlitis, chronic, proliferative, atypical, possible etiology is H. hepaticus or H. bilus.

The double knockout mouse is deficient in some immune function tests. Enzootic helicobacter makes them more susceptible to large bowel disease. Large bowel disease due to helicobacter in mice may occur only in various types of immunodeficient mice.

AFIP Diagnosis: Colon: Colitis, proliferative, erosive, chronic-active, diffuse, moderate, with crypt dilatation and abscesses, mouse, rodent.

Conference Note: The discovery of Helicobacter hepaticus in the liver and gastrointestinal tracts of mice has raised questions regarding the use of these mice in biomedical research. Animals infected with these organisms may not be acceptable for research involving the liver and gastrointestinal tract.

Helicobacter hepaticus is a recently identified bacterium that has been associated with a chronic-active hepatitis in certain strains of inbred mice and has been linked to the development of hepatic adenomas and adenocarcinomas in A/JCr mice.

A high incidence of inflammatory bowel disease has been noted in nude and SCID mice and several immunocompromised target gene mutant mice including T-cell receptor, IL-2, IL-10, and common cytokine receptor mutants, infected with H. hepaticus. The lack of T and B lymphocytes or defective interaction of T lymphocytes with their receptors may result in an abnormal immune response to a normal antigenic stimulus. Infected immunocompetent mice do not develop inflammatory bowel disease.

As in this case, a clinical syndrome rectal prolapse associated with inflammatory bowel disease has been described in certain immunodeficient mice. Such mice were found to infected with Helicobacter hepaticus and all had varying degrees of chronic proliferative typhlitis, colitis, and proctitis, usually without concomitant hepatitis. In several mice, there was epithelial pseudo-invasion of the submucosa which might be mistaken for adenocarcinoma. Susceptibility to the development of hepatitis caused by H. hepaticusseems to be related to the ability to mount an antibody response, which these immunocompromised animals are usually unable to do.

The other bacterium noted by the contributor, Helicobacter bilus, was recently found to be associated with hepatitis but not colitis in immunocompetent mice. It has been isolated from bile, liver, and intestines of aged, inbred mice.

For more information about various Helicobacter species and diseases, visit the National Cancer Institute's website at:

Contributor: National Cancer Institute, NCI-FCRDC, Fairview 201 P.O. Box B, Frederick, MD 21702-1201.

1. Shores EW, et al: Role of TCR Chain in T Cell Development and Selection. Science 266:1047-1050, 1994.
2. Russel RJ, et al: Use of Antibiotics to Prevent Hepatitis and Typhlitis in Male scid Mice Spontaneously Infected with Helicobacter hepaticus. Lab An Sci 45(4): 373- 378, 1995.
3. Mombaerts P, et al: Spontaneous Development of Inflammatory Bowel Disease in T Cell Receptor Mutant Mice. Cell 75:275-282, 1993.
4. Fox JG, et al: Persistent Hepatitis and Enterocolitis in Germfree Mice Infected with Helicobacter hepaticus. Infect and Immun 64(9):3673-3681, 1996.
5. Sadlack B, et al: Ulcerative Colitis-like Disease in Mice with a Disrupted Interleukin-2 Gene. Cell 75:253-261, 1993.
6. Ward JM, et al: Inflammatory Large Bowel Disease in Immunodeficient Mice Naturally Infected with Helicobacter hepaticus. Lab An Sci 46(1):15-20, 1996.

International Veterinary Pathology Slide Bank: None.

Lance Batey
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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