JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

February 2026

N-N04

SIGNALMENT (JPC #1078510): 7-year-old spayed female boxer

HISTORY: This dog presented with progressive deterioration of the CNS. The animal was eventually unable to right itself.

HISTOPATHOLOGIC DESCRIPTION: Cerebrum: Expanding and replacing approximately 75% of the neuroparenchyma in section is a poorly circumscribed, unencapsulated, infiltrative neoplasm composed of spindle to round cells loosely arranged in indistinct interlacing streams or packed into dense, solidly cellular areas that blend into the surrounding neuroparenchyma. Neoplastic cells have variably distinct cell borders, a scant amount of wispy, eosinophilic, fibrillar cytoplasm, and an oval to elongate nucleus with finely stippled chromatin and 1 to 2 distinct nucleoli. Anisocytosis and anisokaryosis are moderate, and there are up to 4 mitotic figures per HPF. There are multiple large, serpiginous areas of abundant karyorrhectic and eosinophilic cellular debris (liquefactive necrosis) admixed with numerous degenerate neutrophils and erythrocytes, fewer gitter cells, fibrin, edema, and necrotic blood vessels, that are often lined by neoplastic cells oriented perpendicularly to the areas of necrosis (perinecrotic palisades). There are numerous vascular proliferations at the periphery, which often form glomeruloid-like structures lined by hypertrophied (reactive) endothelium that occasionally pile up to 3-4 cell layers thick. Multifocally, neoplastic cells invade or obliterate vessel walls, and there is mild to moderate hemorrhage extending into the surrounding neuropil. There is mild gliosis of the neuroparenchyma surrounding the neoplasm.

MORPHOLOGIC DIAGNOSIS: Cerebrum: Astrocytoma, diffusely infiltrative, high-grade, boxer, canine.

SYNONYMS: Glioblastoma, Glioblastoma multiforme (GBM)

GENERAL DISCUSSION:

• Astrocytoma is the most common intracranial primary tumor in dogs
• Most commonly occur in middle-aged or older dogs (17% of all primary nervous system tumors); also reported in cats, cattle, horses, pigs
  • Brachycephalic breeds are overrepresented
• Most commonly affected locations include cerebral hemispheres (particularly the temporal and pyriform lobes), thalamus, hypothalamus, and midbrain; less common locations include cerebellum, spinal cord, and retina
• The Comparative Brain Tumor Consortium recently published a revised diagnostic classification of canine gliomas (Koehler Jour Neuropathol Exp Neurol 2018)
  • In canines, high grade astrocytoma was previously known as glioblastoma or glioblastoma multiforme; this nomenclature is still in use for other species
• WHO classification system, currently utilized for all but canine gliomas; astrocytomas are morphologically classified based on differentiation of tumor cells:
  • Diffuse astrocytomas (well differentiated, low-grade; WHO grade I and II) [N-N01]
  • Anaplastic astrocytomas (medium-grade; WHO grade III) [N-N01]
  • Glioblastoma (high-grade; WHO grade IV) [N-N04]

PATHOGENESIS:

• Arise from astroglia and glial precursor cells
• Canine glioblastomas overexpress epidermal growth factor receptor (EGFR), platelet-derived growth factor-α (PDGFR-α), and insulin-like growth factor binding protein 2 (IGFBP-2)

TYPICAL CLINICAL FINDINGS:

• Specific nervous signs vary depending on site and size of the tumor
• Typically non-metastatic but highly locally invasive and diffusely disseminates into the brain parenchyma
• Case report of a Cane Corso dog with lung metastases from an epithelioid glioblastoma (Van de Weyer, 2024)
• Recent study correlated survival time in dogs with glial tumors to various putative markers of malignancy (MC, glomeruloid vascularization, necrosis) across glial tumors and grades (Merickel, 2021):
  • Dogs with astrocytic tumors had longer survival times than oligodendrogliomas and undefined gliomas
  • Mitotic count was the only histologic feature on biopsy that significantly correlated with survival
  • Analysis of the three features of malignancy showed that lower values on all three criteria were significantly correlated with survival

TYPICAL GROSS FINDINGS:

• Astrocytomas exhibit varied gross features depending on degree of malignancy
  • Well differentiated tend to be firm, grey-white, and poorly demarcated (may be difficult to detect, especially if involving the white matter
  • Poorly differentiated (i.e. high-grade) tend to be more readily apparent, with increased demarcation, soft to friable texture, and typically have areas of hemorrhage, necrosis, and cavitation
• Considerable brain swelling (edema of surrounding neuropil) and often fatal herniation
• May infiltrate cribriform plate (Reyes, 2023)

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• High-grade features:
  • Hemorrhage and necrosis
  • “Glomeruloid” blood vessels- adventitial and endothelial cells proliferate
  • Few cells recognizable as astrocytes
  • Pseudopalisading around serpiginous necrotic areas (perinecrotic palisades)
  • Pleomorphism, giant nuclei, multinucleated giant cells
  • Common and atypical mitotic figures

ULTRASTRUCTURAL FINDINGS:

• Cytoplasm contains bundles of 10 nm intermediate filaments and glycogen granules

ADDITIONAL DIAGNOSTIC TESTS:

• Fine needle aspirate or squash preparation: Pleomorphic plasmacytoid to histiocytic cytomorphology with eccentric nuclei, prominent nucleoli and moderate amount of eosinophilic to basophilic cytoplasm (+/- vacuolation)
• Majority of astrocytomas exhibit positive immunoreactivity for glial fibrillary acidic protein (GFAP), nestin, S-100, vimentin
  • GFAP immunoreactivity varies from sparse to abundant (GFAP is most reliable for confirmation)
• Negative cytokeratin immunoreactivity

DIFFERENTIAL DIAGNOSIS:

• Differentials of glial origin are dependent on grading scheme utilized (i.e. WHO vs. Comparative Brain Tumor Consortium); see chart below “comparative pathology”
• Many rare neoplasms of glial origin using WHO grading scheme are classified as “undefined gliomas” under Comparative Brain Tumor Consortium grading scheme
• Gross:
  • Undefined glioma: Similar features
  • Oligodendroglioma (N-N02): Usually well-demarcated; soft, red-pink to grey; gelatinous
  • Neuroblastoma: Well-demarcated, pink-grey neoplasm with areas of hemorrhage, necrosis, and calcification
  • Medulloblastoma (N-N05): Cerebellum of puppies, calves, and adult dogs
  • Primitive neuroectodermal tumor (PNET) (N-N05): Soft, grey-pink
  • Metastatic brain tumors
  • Inflammatory lesions
• Micro:
  • Low grade astrocytoma (N-N02): Lack necrosis, microvascular proliferation, and easily identifiable mitotic activity
  • Undefined glioma: >30-40% of each phenotype OR undifferentiated cellular morphology
  • Primitive neuroectodermal tumor (N-N05): Densely packed round to polygonal cells with often hyperchromatic carrot-shaped nuclei, rosettes, pseudorosettes, and palisading of neoplastic cells
• Additional neoplasms of glial cell origin described under WHO grading scheme:
  • Gliosarcoma: Biphasic neoplasm with areas of highly anaplastic glial cells with glioblastoma features (serpentine foci of necrosis with a pseduopalisading tumor cells, glomeruloid vascular proliferation) and abundant sarcomatous components; GFAP positive
  • Gliomatosis cerebri: Diffuse infiltrate of cells reminiscent of astrocytes rather than a distinct mass; infiltrates often present bilaterally but asymmetrically in the brain and may also be present in discontinuous areas in the spinal cord; normal neural structures remain intact, with only slight damage to axons and neurons; GFAP negative
  • Astroblastoma
  • Giant cell glioblastoma
  • Anaplastic oligiodendroglioma: Neoplastic oligodendroglial cells are round with clear to lightly stained cytoplasm and hyperchromatic nuclei; anaplastic variants exhibit high cellularity, glomeruloid vessel proliferation, nuclear pleomorphism, meningeal infiltration, mitoses and/or necrosis

COMPARATIVE PATHOLOGY:

• Horses: Primary brain tumors are rare.
• Cattle: Recent retrospective case series identified gliomas as the most common intracranial neoplasia in cattle, with astrocytomas the second most common tumor, after oligodendrocytomas. (Jahns, 2022)
• African Hedgehogs: Astrocytomas are one of the most common CNS neoplasms
• NHPs: rare reports of astrocytoma and glioblastoma multiforme, some associated with induction by viruses (simian virus 40 [SV40], concurrent polyomavirus and SIV infection) and radiation (macaques, baboons)
• Sheep: High grade astrocytoma reported in a sheep (Mignacca, 2025)
• Avian: Glioblastoma multiforme reported in a Budgerigar and Green-cheeked Parakeet

WHO Astrocytoma Classification Table for Non-Canine Species

Astrocytoma	WHO Grade	Histologic features	Diagnostics
Low-grade (4 variants)	I	Unencapsulated, expansile, subtly invasive, increased population of fibrous astrocytes; no mitosis 4 Variants – - Fibrillary astrocytoma: neoplastic cells have scant cytoplasm, abundant fibrillary process and filaments - Protoplasmic astrocytoma: neoplastic cells have scant cytoplasm, few short processes and filaments - Pilocytic astrocytoma: neoplastic cells are bipolar, elongated (piloid or hair-like) astrocytes and have Rosenthal fibers - Subependymal giant cell astrocytoma: originates from subependymal tissue of lateral and fourth ventricles, composed of spindloid to polygonal large eosinophilic cells arranged in short interlacing streams and irregular nests
Medium-grade	II	Denser cell population, larger and darker nuclei w/ slight variation in size & shape, no mitosis; vessel walls may be slightly thickened Variant: Gemistocytic astrocytoma: neoplastic cells have abundant acidophilic cytoplasm and eccentric, oval to round nuclei	Recognizable astrocytes show GFAP & vimentin immunoreactivity
Anaplastic	III	Nuclear atypia, mitotic figures, high proliferative index
High-grade astrocytoma or glioblastoma (formerly glioblastoma multiforme)	IV	Hemorrhage and necrosis; neoplastic cell pseudopalisade around necrotic areas; proliferation of vascular adventitial & endothelial cells forming glomeruloid blood vessels - Few cell recognizable of astrocytes - Pleomorphism (marked), giant nuclei, multinucleated giant cells are common - Increased cell density, marked nuclear atypia, high mitotic rate - Infiltrative growth pattern	Canine glioblastomas over-express: - Epidermal growth factor (EGFR) - Platelet-derived growth factor (PDGFR- α) - Insulin-like growth factor binding protein 2 (IGFB-2)
Rare variants reported in dogs includes: Astroblastoma, Giant cell Glioblastoma, Gliomatosis cerebri & Gliosarcoma - Gliomatosis cerebri: diffuse, infiltrating disease of dogs (predominately brachycephalic breeds) and humans   - Gliosarcoma: rare tumor		- Gliomatosis cerebri: diffuse infiltrates involve brain, often bilaterally but asymmetrically & discontinuous areas also in spinal cord; No tumor mass just diffuse enlargement of affected regions w/ cells insinuating among normal structures that remain intact with only slight damage to axons and neurons; composed mainly of cells reminiscent of fibrillary astrocytic cells w/ elongated, hyperchromatic nuclei and oligodendrocytes, cells of transitional character & small unclassified cells; pattern of infiltration is unexplained, but involves participation of cell adhesion molecule - Gliosarcoma: composed of highly anaplastic glial cells w/ abundant sarcomatous components.	- Gliomatosis cerebri: origin of neoplastic cells controversial, as they do not stain with glial markers such as GFAP - Gliosarcoma: Positive GFAP staining differentiate this tumor from other spindle cell, tumors, i.e., fibrosarcoma

References:

1. Agnew D. Camelidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:193.
2. Agnew D, Nofs S, Delaney MA, Rothenburger JL. Xenartha, Erinacoemorpha, Some Afrotheria, and Phloidota. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:526-7.
3. Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. Vol 1, 6th ed. Philadelphia, PA: Saunders Elsevier; 2016:398-399.
4. Fahey MA, Westmoreland SV. Nervous system disorders of nonhuman primates and research models. In: Abee CR, Mansfield K, Tardif S, et al, eds. Nonhuman Primates in Biomedical Research. Volume 2: Diseases. 2^nd ed. San Diego, CA: Academic Press;2012:757-758.
5. Howerth E, Nemeth N, Reyser-Degiorgis MP. Cervidae. In: Terio K, McAloose D, St. Leger J, ed. Pathology of Wildlife and Zoo Animals. 1^st ed. San Diego, CA: Elsevier; 2018:155.
6. Koehler J, Miller A, Miller R, et. al. A Revised Diagnostic Classification of Canine Glioma: Towards Validation of the Canine Glioma Patient as a Naturally Occurring Preclinical Model for Human Glioma. Jour Neuropathol Exp Neurol. 2018;77(11):1039-1054.
7. Labelle P. The Eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1423.
8. Levine GJ, Cook JR. Cerebrospinal fluid and central nervous system cytology. In: Valenciano AC, Cowell RL, eds. Cowell and Tyler’s Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier; 2020:224.
9. Lorenzi DD, Pintore L. Nervous system. In: Raskin RE, Meyer DJ, Boes KM, eds. Canine and Feline Cytopathology, A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023:550-553.
10. Merickel JL, Pluhar GI, et al. Prognostic histopathologic features of canine glial tumors. Vet Pathol. 2021;58(5):945-951.
11. Mignacca SA, Konold T, Gallisai E, Maestrale C, Gomez-Vitores A, Nunez A. High-grade astrocytoma in a sheep: clinical, pathology, and genetic investigations. J Vet Diagn Invest. 2025;37(3):499-503.
12. Miller AD, Porter, BF. Nervous System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:954-957.
13. Reyes VAA, Howerth EW, Blas-Machado U, et al. Glioma with cribriform plate involvement in 6 dogs. J Vet Diagn Invest. 2023;35(6):800-805.
14. Rissi DR. A review of primary central nervous system neoplasms of cats. Vet Pathol. 2023;60(3):294-307.
15. St. Leger J, Raverty S, Mena A. Cetacea. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:550.
16. Struthers JD, Schmidt RE. Nervous System. In: Schmidt RE, Struthers JD, and Phalen DN. Pathology of Pet and Aviary Birds. 3rd ed. Hoboken, NJ: John Wiley & Sons, Inc.; 2024: 396.
17. Van de Weyer Y, Ricci E, Leeming G. A case of epithelioid glioblastoma with lung metastases in a young Cane Corso dog. J Comp Pathol. 2024;215:42-46.
18. Yoshida K, Chambers JK, Nibe K, Kagawa Y, Uchida K. Immunohistochemical analyses of neural stem cell lineage markers in normal feline brains and glial tumors. Vet Pathol. 2024;61(1):46-57.

Click the slide to view.

---