AFIP Wednesday Slide Conference - No. 20
16 February 2000

Conference Moderator:
Dr. F. Yvonne Schulman
Diplomate, ACVP
Department of Veterinary Pathology
Armed Forces Institute of Pathology, Washington, DC 20306-6000
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Case I 405/98 (AFIP 2677385)
Signalment: Equine: Six-year-old, half-breed, bay gelding
History: Treated 6 months ago for conjunctivitis. More recently eye became cloudy, blood-shot and increased in size. Eyelids were also swollen. Ocular examination, including ultrasound, revealed the presence of an intraocular mass.
Case 20-1. Gross Eye. The globe is filled by a variegated tan mass.
Gross Pathology: The globe of the left eye was submitted for examination. Grossly it was enlarged and contained a nodular, soft tissue mass. This mass was white/pale gray in color, friable and contained small cystic foci. It expanded both the anterior and posterior chambers with minimal displacement of the lens. The mass appeared to be contained within the globe.
Laboratory Results: Routine hematology, including differentials, failed to reveal any significant abnormalities. Urea, creatinine and GGT were within normal concentrations.
Contributor's Diagnosis and Comments: Diagnosis: Medulloepithelioma
Microscopic examination reveals a poorly demarcated densely cellular mass partially bordered by ocular sclera and ocular muscle bundles. Remnants of choroid and retinal pigmented epithelium are also observed. The cells forming the mass are mononuclear containing oval or polygonal medium-sized nuclei (occasionally a large nucleus is observed). These nuclei are pale staining with a speckled chromatin pattern. Both single cell necrosis and cell mitosis are seen. Cell borders and cytoplasm are not discernible. Cells are arranged in loose sheets or aggregated into pseudostratified formations to resemble duct-like structures (neuroepithelial rosettes). Cells within these latter formations rest on thickened hyalinized membranes. Separating many of these neuroepithelial rosettes are dense bands of connective tissue. In addition, large expanses of necrotic tissue and regions of hemorrhage are also noted.
Follow-up: After surgery this animal returned home. Over a couple of months there was weight loss and a general deterioration in the animal's condition. No additional investigations were performed and the animal was euthanized. At death, the local veterinary surgeon sampled the submandibular lymph node, which appeared enlarged. This tissue was submitted for microscopic examination and revealed metastatic spread of the tumor.
In the horse intraocular primary or secondary neoplasms are very rare. Primary melanomas, astrocytomas, microgliomas, neuroepithelial tumors of the optic nerve, medulloepitheliomas and secondary lymphosarcomas have been reported (Davidson, 1991; Ueda et al., 1993). A medulloepithelioma is a ciliary body tumor arising from undifferentiated embryonal medullary epithelium of the forebrain and optic vesicles (Eagle et al., 1978; Davidson et al., 1981). They may be classified as teratoid medulloepitheliomas if they also contain undifferentiated mesenchyme, cartilage, striated muscle or tissue resembling brain (Collins & Moore, 1991).
Medulloepitheliomas are also observed in man where they usually manifest early in life (up to 5 years of age (cited in Ueda et al., 1993)). However, in the horse they have been reported in young and middle-aged animals (Bistner, 1974; Eagle et al., 1978; Ueda et al, 1993).
AFIP Diagnosis: Eye: Medulloepithelioma, breed not specified, equine.

Conference Note: Embryologic invagination of the optic cup results in a bilayered medullary epithelium with the inner layer forming the iridial pigmented epithelium, ciliary body non-pigmented epithelium and the neurosensory retina, while the outer layer forms the outer iridial pigmented epithelium, ocular ciliary pigmented epithelium, iridal dilator muscle, ciliary pigmented epithelium, and the retinal pigmented epithelium. Tumors arising from the undifferentiated embryonal medullary epithelium that form primitive neuroectodermal structures (retina, ciliary epithelium, vitreous, and neuroglia), as well as differentiated mesenchymal tissues (cartilage, skeletal muscle, brain, etc.) in some cases, are classified as medulloepitheliomas. Ciliary tumors developing from more differentiated cell types form adenomas or adenocarcinomas.

Contributor: Department of Veterinary Pathology, University College Dublin, Ballsbridge, Dublin 4, Ireland.
1. Bistner SI: Medulloepithelioma of the iris and ciliary body in a horse. Cornell Vet 64:588-595, 1974
2. Collins BK, Moore CP: Canine anterior uvea. In: Veterinary Ophthalmology, ed. Gelatt KN, 2nd ed., pp. 385-387. Lea and Febiger, Philadelphia, PA, 1991
3. Davidson MG: Equine ophthalmology. In: Veterinary Ophthalmology, ed. Gelatt KN, 2nd ed., p. 598. Lea and Febiger, Philadelphia, PA, 1991
4. Eagle RC, Font RL, Swerczek TW: Malignant medulloepithelioma of the optic nerve in a horse. Vet Pathol 15:488-494, 1978
5. Ueda Y, Senba H, Nishimura T, Usui T, Tanaka K, Inagaki S: Ocular medulloepithelioma in a thoroughbred. Eq Vet J 25:558-561, 1993
Case II - 990663.5 (AFIP 2694700)
Signalment: 8-year-old, male, Bernese mountain dog.
Case 20-2. CAT scans.
History: According to the owner, the dog exhibited three generalized tonic/clonic seizures and behavioral changes for ten days. The seizures occurred at various times of the day. Neurologic examination revealed that vision was normal in right eye and absent in the left eye. Pupillary light reflexes were lower for this eye. Computed tomography images obtained after administration of contrast media showed two lesions, one (7 mm diameter) in the left olfactory lobe and the second (25 mm diameter) in the right temporal area. Stereotactic biopsy was performed three days later. Histopathological features revealed an idiopathic granulomatous encephalitis. The dog was treated by immunosuppressive therapy. Generalized seizures occurred a few weeks later. Continued decline resulted in euthanasia.
Gross Pathology: Necropsy examination was normal except for the encephalon. Leptomeninges were thickened. The encephalon was fixed two days in buffered formaldehyde and cut in 0.5 mm thick sections. Two regular and uniform nodules, one of 6 mm diameter and the second of 8 mm diameter were respectively located in the left olfactory lobe and in the right parahippocampal gyrus.
Laboratory Results: Laboratory evaluations (glucose, alkaline phosphatase, serum urea nitrogen, alanine aminotransferase, calcium, and analysis of blood and urine) did not reveal any abnormalities.
Contributor's Diagnosis and Comments: Brain: Poorly differentiated large round cell tumor, Bernese mountain dog.
The meninges and subpial parenchyma are focally infiltrated by neoplastic cells. The neoplasm is composed of pleomorphic round cells. They also infiltrate Virchow--Robin spaces. They are characterized by distinct-cell borders. Their cytoplasm, abundant and eosinophilic, is occasionally vacuolated. Mitotic activity is high (8 per HPF). Large binucleated and multinucleated cells are seen in great number. Variations in nuclear size and shape are marked.
The silver stain for reticulin doesn't demonstrate characteristic pattern seen in primary lymphomas of the CNS. It is not associated with the angiocentric growth pattern.
Immunohistochemically, neoplastic cells in the tumor of this dog were negative for glial fibrillary acidic protein, S-100 protein, cytokeratin and CD3. Some scattered lymphocytes stained positively for CD3.
Lack of gross lesions in peripheral organs and of histological lesions in lymph nodes, spleen and liver ruled out the hypothesis of malignant histiocytosis. Although individual cell morphology is more atypical than usually observed in primary lymphomas of CNS, this hypothesis can't be discarded. Immunohistochemical staining to prove histiocytic or lymphoid origin might help in establishing the diagnosis.
AFIP Diagnosis: Brain: Histiocytic sarcoma, Bernese mountain dog, canine.

Conference Note: Based on the H&E slides, most conference participants diagnosed malignant round cell tumor and favored histiocytic sarcoma based on the cellular features including occasional phagocytosis by neoplastic cells; however, malignant plasma cell tumor, lymphoma and rhabdoid tumor were also included in the differential diagnosis.
By immunohistochemistry performed at the Armed Forces Institute of Pathology, neoplastic cells were strongly positive for lysozyme and did not stain for CD3 (a T lymphocyte marker) and CD79a (a B lymphocyte marker), with good staining of internal controls.
The Department of Hematopathology reviewed this case and favored a diagnosis of malignant histiocytic neoplasm. In humans, this rare and controversial condition is known as true histiocytic lymphoma.
Although histiocytic sarcoma is generally associated with disseminated disease (malignant histiocytosis), especially in the Bernese mountain dog, histiocytic malignancies can be localized. It is not known whether disseminated histiocytic sarcoma represents metastases of a localized sarcoma or multicentric malignancy developing simultaneously in different organs (Affolter VK and Moore PF1,2). There was a recent report of a case of primary malignant histiocytosis of the brain of a miniature schnauzer; some might argue that localized histocytic sarcoma would have been a more appropriate diagnosis.
Contributor: UP d'Anatomie-Pathologique, Ecole Nationale Veterinaire d'Alfort, 7 av. du General de Gaulle, 94704 Maisons-Alfort (France).
1. Affolter VK, Moore PF: Canine cutaneous and systemic histiocytosis: reactive histiocytosis of dermal dendritic cells. Am J Dermatopathol 22(1):40-48, 2000
2. Affolter VK, Moore PF: Canine histiocytic proliferative disease. Proceedings of 15th AAVD/ACVD, pp. 79-86. 1999
3. Chandra AMS, Ginn PE: Primary malignant histiocytosis of the brain of a dog. J Comp Path 121:77-82, 1999
4. Morgello S: Pathogenesis and classification of primary central nervous system lymphoma: an update. Brain Pathol 5:383-393, 1995
5. Vandevelde M, Fatzer R, Fankhauser R: Immunohistochemical studies on primary reticulosis of the canine brain. Vet Pathol 18:577-588, 1981
Case III 99-4036 (AFIP 2694682)
Signalment: 5-year-old female spayed standard poodle, canine
History: The dog had experienced a gastrointestinal upset with vomiting which progressed over a 1 week period to abnormal behavior with head pressing, circling, hypermetria, drooling and dementia.
Gross Pathology: There was a mass present on the ventral surface of the cerebellomedullary regions that extended around the optic chiasma. The mass was red/brown, friable and 5 cm in greatest dimension. There were few scattered grey/brown discolored areas throughout the parenchyma of the cerebrum.
Laboratory Results:

Routine CBC - Lymphopenia

Routine chemistry - no diagnostic abnormalities

CSF tap- wbcs 45/ul, rbcs 20/ul and TP 39 mg/dl. The cell population consisted of 80% mononuclear cells with 80% of these small and medium sized lymphoid cells. Sixty percent of the lymphoid cells were reactive with increased cytoplasmic basophilia. The remainder were macrophages, some of which exhibited erythrophagy. Twenty percent of the cells were nondegenerate polymorphonuclear cells. Intact erythrocytes were also present.

Contributor's Diagnosis and Comments: Granulomatous meningoencephalitis
The microscopic lesions with the typical vascular orientation were thought to be consistent with the descriptions of granulomatous meningoencephalitis. The lesions also resembled a neoplastic process, but immunohistochemistry distinguished 3 cell populations with a predominance of T cells, mixed with plasma cells and macrophages.
AFIP Diagnosis: Brain: Atypical angiocentric lymphohistiocytic infiltrates, favor malignant leukocyte neoplasm, standard poodle, canine.

Conference Note: This lesion was the subject of lively debate. The discussion centered on whether the lesion is inflammatory or neoplastic and what is the appropriate morphologic diagnosis. When first described, similar lesions were called reticulosis (inflammatory or neoplastic) due to the presence of reticulin fibers surrounding individual cells. Later, the milder variants of this lymphohistiocytic infiltrate were dubbed granulomatous meningoencephalitis (GME). Some maintain that these lesions represent a lymphoproliferative disorder that blends into frank neoplasia. Others prefer to separate them into GME (or inflammatory reticulosis) and non-B non-T leukocytic neoplasm (or malignant reticulosis). If they are distinct entities, there is clearly a grey zone between them. In this case, the density of the infiltrate, cytologic atypia and moderate numbers of mitotic figures suggest malignancy. The Department of Hematopathology reviewed the case and concurred with this assessment. They also mentioned similarities between this lesion and lymphomatoid granulomatous/angiocentric T cell lymphoma.
Contributor: Central Laboratory for Veterinarians c/o PMB 8O, 250 H Street. Blaine Washington, 98230.
1. Kipar A, Baumgartner W, Vogl C, Gaedke, Wellman M: Immunohistochemical characterization of inflammatory cells in brains of dogs with granulomatous meningoencephalitis. Vet Pathol 35:43-52, 1998
2. Koestner A, Bilzer T, Fatzer R, Schulman FY, Summers BA, Van Winkle TJ: Histological Classification of the Tumors of the Nervous System of Domestic Animals. In: World Health Organization, Histological Classification of Tumors of Domestic Animals, ed. Schulman FY, 2nd ed., vol. 5, pp. 31-32. The Armed Forces Institute of Pathology, Washington, DC, 1999
3. Munana KR, Luttgen PJ: Prognostic factors for dogs with granulomatous meningoencephalitis: 42 cases (1982-1996): JAVMA 212(12):1902-1906, 1998
4. Summers BA, Cummings JF, de Lahunta A: Veterinary Neuropathology, 99. 110-111. Mosby-Year Book, St. Louis, Missouri, 1995
Case IV - S-60006 (AFIP 2607937)
Signalment: Aged (originally wild-caught), female, cynomolgus macaque (Macaca fascicularis)
Case 20-4. Lateral and Dorsal Radiographs. The lateral view shows diffuse fluid density of the lung space (pulmonary edema). Both views demonstrate an enlarged cardiac silhouette.
History: This animal arrived at our facility in 1988. It underwent an ovariohysterectomy in 1993, and had subsequently been treated for periodontal disease. In June 1997, it was observed to have ascites when sedated for a routine health check. Abdominocentesis was performed and the fluid revealed to be a transudate. A CBC was normal and serum biochemistry profile revealed a mild increase of BUN and creatinine. Approximately 1 week later, the animal was noted to be weak and anorexic. It was again sedated and intravenous fluids were administered. On auscultation, this monkey was noted to have a gallop rhythm. Thoracic radiographs revealed an enlarged cardiac silhouette, compatible with generalized cardiomegaly. An ECG revealed increased P wave amplitude compatible with right atrial enlargement, and increased PR interval consistent with 1st degree heart block. A repeat serum biochemistry profile indicated a moderate increase of BUN, creatinine, and bilirubin. Several days later, this animal was noted to be increasingly weak and anorexic, and was euthanatized.
Case 20-4. Gross Heart. There is multifocal myocardial pallor.
Gross Pathology: Approximately 100 ml of ascitic fluid was present and the liver was firm. The heart appeared slightly enlarged and weighed 27.7 grams, which was 0.73% of this animal's body weight (~3.79 kg). [For comparison, the heart weight as a percent of body weight ranges from 0.35-0.65% in similarly sized (body weight) rhesus monkeys; our laboratory does not have similar historical data for cynomolgus macaques].
Laboratory Results: Serum biochemistry- mildly to moderately increased BUN, creatinine, and bilirubin.
Contributor's Diagnosis and Comments: Severe multifocal to coalescing myocardial fibrosis with myofiber atrophy and myofiber karyomegaly
Myocardial fibrosis has been previously reported in western lowland gorillas, orangutans, and chimpanzees. Generally, these animals are mature to aged (often in the 2nd and 3rd decades of life, occasionally older), they often have underlying cardiac dysfunction, and die during restraint or under anesthesia. [A review of our archives reveals no record of having ever diagnosed a similar lesion in any rhesus or cynomolgus monkey from our studies, though we do not generally use aged primates in safety studies nor maintain them on site for such a duration].
Myocardial fibrosis also occurs in humans, having been reported to be associated with hypertension, chemotherapy, and as a feature of chronic ischemic heart disease. Two types of fibrosis are noted, the first type being a scarring phenomenon, with the replacement of lost myocardium by fibrous tissue and having an apparent vascular relation (ie. anoxia/hypoxia). The second type is interstitial fibrosis, where a delicate network of collagen fibers encircle individual myofibers. This latter phenomenon represents an aging process and is not believed to be a disease-related alteration.
Specific etiologic agents or entities causing myocardial fibrosis are rarely identified, though potential etiologies would include viral infection (picornaviruses such as coxsackie B and encephalomyocarditis viruses), vitamin E/selenium deficit, hypertension, hypercholesterolemia, and heredity. Frequently, death results from congestive cardiac failure secondary to the myocardial fibrosis.
AFIP Diagnosis: Heart: Myocardial fibrosis, interstitial and replacement, multifocal to coalescing, moderate, with myofiber atrophy, karyomegaly, and mild multifocal lymphocytic inflammation, cynomolgus monkey (Macaca fascicularis), non-human primate.

Conference Note: The conference participants and the Department of Cardiovascular Pathology essentially agree with the contributor's diagnosis and comments. In additional to the myocardial fibrosis and myofiber atrophy, in many conference participants' slides there were small, scattered foci of lymphocytic inflammation. There was also some discussion about the amount of karyomegaly normally seen in aged macaques. Although the myocardial fibrosis and atrophy could lead to compensatory myocardial karyomegaly, without age-matched controls, it is difficult to assess the significance of this finding.
Contributor: Merck Research Laboratories, Departments of Safety Assessment and Laboratory Animal Resources, West Point, PA, 19486.
1. Callaway MP, Tyrrell CJ, Williams MP, Marshall AJ: Chemotherapy induced myocardial fibrosis. Clin Oncol 6:55-56, 1994
2. Hansen JF, Alford PL, Keeling ME: Diffuse myocardial fibrosis and congestive heart failure in an adult male chimpanzee. Vet Pathol 21:529-531, 1984
3. Klima M, Burns TR, Chopra A: Myocardial Fibrosis in the Elderly. Arch Pathol Lab Med 114:936-942, 1990
4. Munson L, Montali RJ: Pathology and diseases of great apes at the National Zoological Park. Zoo Biol 9:99-105, 1990
5. Schulman FY, Farb, A Virmani R, Montali RJ: Fibrosing cardiomyopathy in captive western lowland gorillas (Gorilla gorilla gorilla) in the United States: A retrospective study. J Zoo and Wild Med 26(1):43-51, 1995
J Scot Estep, DVM
Captain, United States Army
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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