AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

February 2017

N-N01

 

Signalment Slide A (JPC #1336140):  A military working dog

 

HISTORY:  This dog developed severe convulsions.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum (2 sections):  Expanding and infiltrating the neuropil and extending to the cut margins of the tissue is a 7mm diameter, unencapsulated, poorly circumscribed, densely cellular neoplasm composed of round to polygonal cells arranged in vague whorls which are interspersed by numerous small caliber blood vessels and areas of mild hemorrhage.  Neoplastic cells have indistinct borders, small to moderate amounts of eosinophilic, vacuolated, fibrillar cytoplasm, and irregularly round nuclei with finely stippled chromatin and one variably distinct nucleolus.  The mitotic rate is less than 1/10 HPF.  Multifocally the adjacent white matter and neuropil is mildly vacuolated (spongiosis) with few microglial cells (microgliosis) several foci of hemorrhage, and perivascular infiltrates of lymphocytes, fewer plasma cells and macrophages (perivascular cuffing).

 

MORPHOLOGIC DIAGNOSIS:  Brain, cerebrum:  Astrocytoma, fibrillary, breed unspecified, canine.

 

Signalment Slide B (420072): A cat

 

HISTORY: None

 

HISTOPATHOLOGIC DESCRIPTION: Spinal cord (3 sections): Affecting up to 80% of the sections, effacing both gray and white matter, surrounding and separating remaining neurons, and compressing the central canal, is an unencapsulated, poorly demarcated, poorly circumscribed, infiltrative, densely cellular neoplasm composed of polygonal to spindle to round cells arranged in short interlacing streams and bundles on a moderate fibrovascular stroma. Neoplastic cells have indistinct cell borders, a large amount of pale eosinophilic fibrillar cytoplasm, an oval to elongate nucleus with finely stippled chromatin and 1-3 variably distinct nucleoli. Anisocytosis and anisokaryosis are marked; mitoses average 2 per 10 HPF. There are multifocal multinucleated and binucleate cells. Within the neoplasm there are low numbers of dilated axon sheaths with swollen eosinophilic axons (spheroids) admixed with scattered neurons that are swollen with central chromatolysis (degenerate) or, rarely, shrunken, angular and hypereosinophilic neurons with pyknotic or karyolytic nuclei (necrotic). The remaining adjacent neuropil is mildly spongiotic with slightly increased numbers of glial cells (gliosis).

 

MORPHOLOGIC DIAGNOSIS: Spinal cord: Astrocytoma, anaplastic, breed unspecified, feline.

 

GENERAL DISCUSSION: 

·         Astrocytoma is the most common primary intracranial tumor of neuroepithelial origin; comprising approximately 25% of all canine primary CNS tumors

·         Diagnosis is based on the histomorphology of the predominant neuroepithelial cell type transformed

·         Increased incidence in the brachycephalic breeds, particularly the boxer and Boston terrier; usually dogs 6-11 years of age

 

PATHOGENESIS: 

·         Low-grade astrocytic tumors in dogs are reported to have mutations in the p53 gene, overexpress epithelial growth factor receptor genes (EGFR), and/or mutations of the MYC oncogene

·         Recent study found only 3 p53 mutations of 88 canine brain tumors

·         Low-grade astrocytic tumors in humans have mutations in the p53 gene and overexpress platelet derived growth factor-a (PDGF-a) and as astrocytic tumors increase in severity to high grade tumors there is additional disruption of tumor-suppressing gene, Rb and the p16 gene

 

TYPICAL CLINICAL FINDINGS: 

·         Mentation changes, seizures, vestibular disturbances, and vision loss

 

TYPICAL GROSS FINDINGS: 

·         Considerable variation with most being poorly defined

·         Slower growing tumors are usually poorly defined, firm and white to pink

·         Rapidly growing tumors are often well delineated, soft and mottled with hemorrhage and necrosis

·         Distortion of the sulci and gyri may occur with tumor expansion

·         Most common sites in dogs are the telencephalon and diencephalon

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

·         Tumor cells may palisade around vessels

·         Low grade (well differentiated types): Slow growing, uniform cell population, low mitotic rate

o   Fibrillary:  Stellate cells with abundant cytoplasm containing prominent neuroglial fibrils; most common form

o   Protoplasmic:  Stellate cells with abundant cytoplasm, few processes and often microcystic areas

o   Gemistocytic:  Large cells with abundant eosinophilic cytoplasm and a marginally located nucleus that resemble gemistocytic astrocytes

o   Pilocytic (spongioblastoma):  Interwoven bundles of elongated bipolar cells; recently described in dogs

·         Medium grade (anaplastic):

o   Same as glioblastoma multiforme without the necrosis and vascular proliferation

o   Very cellular, pleomorphic population of fusiform to polygonal to round cells

o   High mitotic rate with multinucleated giant cells

o   Hemorrhage, cysts and edema

·         High grade (glioblastoma, “glioblastoma multiforme”):

o   Similar to anaplastic but also characterized by necrosis and/or glomeruloid vascular proliferation; often pseudopallisading of tumor cells along foci of necrosis

 

ULTRASTRUCTURAL FINDINGS: 

·         Cytoplasmic glycogen granules

·         10 nm bundles of intermediate filaments

 

ADDITIONAL DIAGNOSTIC TESTS: 

·         GFAP (glial fibrillary acid protein) positive; some high grade tumors lose GFAP reactivity (Astrocytomas in rats are GFAP negative)

·         Vimentin positive

·         S-100 positive

·         AQP4 and p75NTR in one study discriminated between canine astrocytomas and oligodendrogliomas

 

DIFFERENTIAL DIAGNOSIS: 

Gross

·         Oligodendroglioma:  Usually well demarcated

·         Neuroblastoma:  Well circumscribed, pink-grey neoplasm with areas of hemorrhage, necrosis and calcification

·         Medulloblastoma:  Usually in cerebellum of puppies, calves and adult dogs

·         Primitive neuroectodermal tumor (PNET):  Soft, grey-pink tumors

·         Mixed glioma (oligoastrocytoma)

·         Inflammatory lesions

·         Metastatic brain tumors:  Less common than primary tumors

 

Microscopic

·         Oligodendroglioma:  Artifactual perinuclear halos, delicate branching vasculature

·         Primitive neuroectodermal tumors:  Closely packed round to polygonal cells in sheets and bands, often with Homer-Wright or Flexner-Wintersteiner rosettes

 

COMPARATIVE PATHOLOGY: 

·         Also reported in cats, pigs, baboon, mice, fowl and rats

·         Malignant astrocytoma was most frequent CNS tumor in a survey of Sprague-Dawley rats (8 cases from 670 rats); most are GFAP negative and positive for macrophage markers indicating they may be of monocytic origin

·         Oligoastrocytoma reported in a hooded crane

·         High grade astrocytoma (glioblastoma multiforme) reported in an Atlantic spotted dolphin

 

References: 

1.     Bertrand L, Mukaratirwa S, Bradley A. Incidence of spontaneous central nervous system tumors in CD-1 mice and Sprague-Dawley, Han-Wistar, and Wistar rats used in carcinogenicity studies. Toxicol Pathol. 2014;42(8):1168-73.

2.     Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:398-9.

3.     Fraser AR, Bacci B, le Chevoir MA, Long SN. Epidermal growth factor receptor and Ki-67 expression in canine gliomas. Vet Pathol. 2016; 53(6):1131-7.

4.     Diaz-Delgado J, Sacchini S, Suarez-Bonnet A, Sierra E, Arbelo M, Espinosa A, et al.  High grade astrocytoma (glioblastoma multiforme) in an Atlantic spotted dolphin (Stenella frontalis). J Comp Pathol. 2015; 152(2-3):278-82.

5.     Frosch MP, Anthony DC, De Girolami U. The central nervous system. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia, PA: Elsevier Saunders; 2015:1306-9.

6.     Higgins RJ, Bollen AW, Dickinson PJ, Sisó-Llonch S. Tumors of the nervous system. In: Meuten DJ, ed. Tumors in Domestic Animals. 5th ed. Ames, IA: Wiley Blackwell; 2017:838-44.

7.     Hostnik ET, Kube SA, Jortner B, Hager D, Garman RH. Pleomorphic xanthoastrocytoma within the medulla oblongata of a young dog. Vet Pathol.  2015; 52(1):178-80.

8.     Ide T, Miyoshi N, Ochiai K, Yasuda N. Oligoastrocytoma in the brain of a hooded crane (Grus monacha). Vet Pathol. 2009;46(2):309-312.

9.     Koestner A, Bilzer T, Fatzer R, Schulman FY, Summers BA, Van Winkle TJ: The Histological Classification of Tumors of the Nervous System of Domestic Animals. Washington, DC: Armed Forces Institute of Pathology; 1999:17-20. 

10.  Sisó S, Lorenzo V, Ferrer I, Villagrassa M, Pumarola M. An anaplastic astrocytoma (optic chiasmatic-hypothalamic glioma) in a dog. Vet Pathol. 2003;40(5):567-569.

11.  Spitzbarth I, Heinrich F, Herder V, Recker T, Wohlsein P, Baumgärtner W. Canine central nervous neoplasm phenotyping using tissue microarray technique. Vet Pathol. DOI: 10.1177/0300985816688745. [Epub ahead of print] Accessed February 10, 2017.

12.  Stoica G, Levine J, Wolff J, Murphy K. Canine astrocytic tumors: a comparative review. Vet Pathol. 2011;48(1):266-275.

13.  Summers BA, Cummings JF, de Lahunta A.Veterinary Neuropathology. St. Louis, MO: Mosby Yearbook; 1995:362-370.

14.  York D, Higgins RJ, LeCouteur RA, et. al. TP53 mutations in canine brain tumors. Vet Pathol. 2012;49(5):796-801.

 


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