JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

February 2023

N-N01

 

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

 

HISTORY: This dog developed severe convulsions.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum (2 sections): Expanding and focally infiltrating the neuropil and extending to the cut margins is a 7mm diameter, unencapsulated, poorly circumscribed, densely cellular neoplasm composed of spindle cells arranged in indistinct whorls on a loose fibrovascular stroma interspersed by numerous small caliber blood vessels lined by a single layer of reactive endothelium (reactive vasculature) and small foci of hemorrhage, fibrin, and edema. Neoplastic cells have indistinct borders, a small to moderate amount of eosinophilic, vacuolated, fibrillar cytoplasm, and an irregularly round nucleus with finely stippled chromatin and one variably distinct nucleolus. Anisocytosis and anisokaryosis are mild. Mitotic figures average 1 per 2.37 mm2. Multifocally the adjacent white matter and neuropil is mildly vacuolated (spongiosis) with mildly increased numbers of microglia (microgliosis), several foci of hemorrhage, fibrin, and edema, and perivascular infiltrates of lymphocytes, fewer plasma cells, and macrophages (perivascular cuffing).

 

MORPHOLOGIC DIAGNOSIS: Brain, cerebrum: Astrocytoma, focally infiltrative, low-grade, breed unspecified, canine.

 

Slide B: Signalment (JPC #420072): A cat

 

HISTORY: None

 

HISTOPATHOLOGIC DESCRIPTION: Spinal cord, 3 cross sections: Effacing up to 80% of each section, replacing both gray and white matter, surrounding and separating few remaining neurons, and laterally displacing the central canal, is an unencapsulated, poorly demarcated, diffusely infiltrative, densely cellular neoplasm composed of spindle 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, and an oval to elongate nucleus with finely stippled chromatin and 1-3 variably distinct nucleoli. Anisocytosis and anisokaryosis are moderate; mitoses average 1 per 2.37 mm². Within the neoplasm there are low numbers of remaining dilated myelin sheaths with swollen eosinophilic axons (spheroids) and few remaining neurons that are swollen with central chromatolysis (degenerate) or, rarely, shrunken, angular and hypereosinophilic with pyknotic or karyolytic nuclei (necrotic). The remaining adjacent compressed neuroparenchyma is mildly spongiotic with slightly increased numbers of glial cells (gliosis).

 

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

 

GENERAL DISCUSSION:  

• Astrocytoma is the most common primary intracranial tumor of dogs; comprising approximately 17% of all canine primary CNS tumors
• Diagnosis is based on the histomorphology of the predominant neuroepithelial cell type
• Common in the brachycephalic breeds, particularly the boxer, bulldog, Boston terrier, and pit bulls
• Typically dogs are between 5-11 years old
• Most common sites are the cerebral hemispheres, thalamus, hypothalamus, and midbrain
• The Comparative Brain Tumor Consortium recently published a revised diagnostic classification of canine gliomas (Koehler J Neuropathol Exp Neurol 2018)

 

TYPICAL CLINICAL FINDINGS:  

 

TYPICAL GROSS FINDINGS:  

• Considerable variation, most are poorly defined and can be felt (very firm) more than seen. May only suspect due to deviation of some architectural feature.
• Low-grade tumors are usually poorly defined, firm and white to pink
• High-grade tumors are often easier to see grossly and soft due to associated hemorrhage and necrosis +/- cavitated
• Distortion of the sulci and gyri may occur with tumor expansion

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• WHO classification system, currently in use 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)
  • Uniform tumor cells
• Anaplastic astrocytomas (medium-grade; WHO grade III)
  • Increased cellular pleomorphism
  • High mitotic rate
  • Areas of necrosis
• Glioblastoma (N-N04; high-grade; WHO grade IV)
  • Glomeruloid-like vascular proliferation
  • Serpinous tracts of necrosis lined by neoplastic cells (pseudopalisading)
  • Hemorrhage common

• Canine glioma diagnostic classification scheme recently developed and published by the Comparative Brain Tumor Consortium (Koehler Jour Neuropathol Exp Neurol 2018)

• 1. Glioma type:

• Astrocytoma if morphology of >80% of the tumor is consistent with astrocytic origin, i.e.:

• Oval to elongate nuclei (angular); open-faced chromatin pattern; naked nuclei; random, disorganized pattern; spindle cell morphology; pleomorphic cells (large nucleoli, multinucleate cells); mineralization
• Tumor cell variations:
  • Gemistocytic: Eosinophilic, abundant cytoplasm
  • Pilocytic: Elongate cells
  • Well-defined: Rare mucin microcysts
  • Fibrillary: Eosinophilic stroma 

• Oligodendroglioma if morphology of >80% of the tumor is consistent with oligodendroglial origin (see N-N02)
• Undefined glioma if morphology is consistent with neither of the above

• 2.  Level of infiltration as assessed at low magnification: 

• No infiltration: compact tumor growth or growth pattern and/or rare foci of infiltration
• Focal infiltration: Compact with focal/multifocal regions of infiltration
• Diffuse infiltration

• 3.  Tumor is assigned a grade:

• Low grade:  
  • No necrosis (other than single cell necrosis)
  • No microvascular proliferation (must differentiate from reactive vasculature) or pseudopalisading 
  • No mitotic figures
  • No overt features of malignancy 
  • Often are poorly demarcated and infiltrative
• High grade: any of the following:
  • Necrosis
  • Microvascular proliferation
  • Pseudopalisading (neoplastic cells perpendicular to necrosis)
  • Mitotic figure(s) present
  • Overt features of malignancy (nuclear pleomorphism, anisokaryosis, anisocytosis, cellular atypia)
  • Tend to be more densely cellular, tend to have visible cytoplasm

• 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 Vet Pathol 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

 

ULTRASTRUCTURAL FINDINGS:  

• Cytoplasmic glycogen granules
• 10 nm bundles of intermediate filaments

 

ADDITIONAL DIAGNOSTIC TESTS:  

• GFAP (glial fibrillary acid protein) positive, although may be patchy 
  • Astrocytomas in rats are predominantly GFAP negative (Bertrand Tox Pathol 2014)
• Variably Olig2 positive (high grade astrocytomas more likely positive)
• Vimentin positive
• S-100 positive

 

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
• Undefined glioma (oligoastrocytoma) – >30-40% of each phenotype OR undifferentiated cellular morphology
• Inflammatory lesions
• Metastatic brain tumors:  Less common than primary tumors

 

Microscopic

• Oligodendroglioma:  Artifactual perinuclear halos (“honeycomb effect”), delicate branching vasculature
• Undefined glioma:  Biphenotyopic tumor composed of 30-40% astrocytic AND 30-40% oligodendroglial morphology
• Primitive neuroectodermal tumors:  Closely packed round to polygonal cells in sheets and bands, often with Homer-Wright or Flexner-Wintersteiner rosettes 

 

COMPARATIVE PATHOLOGY:  

• Horses: Primary brain tumors are rare. One recent report of intracerebral astrocytoma in an Anglo-European gelding (Cavasin J Comp Pathol 2020)
• Cats: One report of an angiocentric astrocytoma where neoplastic cells were confined to perivascular spaces with palisading (Rissi J Vet Diagn 2019)
• 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 Vet Pathol 2022)
• 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 (Bertrand Tox Pathol 2014)
• Atlantic spotted dolphin: Case report of high grade astrocytoma (glioblastoma multiforme, N-N04)
• African Hedgehogs: Astrocytomas are one of the most common CNS neoplasms, along with gangliogliomas (Muñoz-Gutiérrez J Vet Diagn Invest 2018)
  • All were gemistocytic and within the cerebrum; no metastasis observed
  • GFAP, S100, CD34 positive
• 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)

 

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. Cavasin JP, Miller AD, and Duhamel GE. Intracerebral astrocytoma in a horse. J Comp Pathol. 2020; 177:1-4.
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. Jahns H and McElroy MC. Bovine intracranial neoplasia: a retrospective case series. Vet Pathol. 2022; 59(5):824-835.
6. Koehler JW, Miller AD, 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. J Neuropathol Exp Neurol. 2018; Vol. 77, No. 11:1039-1054.
7. 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.
8. 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: 550-552.
9. Merickel JL, Pluhar GI, et al. Prognostic histopathologic features of canine glial tumors. Vet Pathol. 2021;58(5):945-951.
10. Muñoz-Gutiérrez JF, Garner MM, Kuipel M. Primary central nervous system neoplasms in African hedgehogs. J Vet Diagn Invest. 2018; 30(5):715-720.
11. Rissi DR, McHale BJ, Armién AG. Angiocentric astrocytoma in a cat. J Vet Diagn Invest. 2019; 31(4):576-580.
12. 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. 

 

 

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