JPC SYSTEMIC PATHOLOGY
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 10 HPF. 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
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 marked; mitoses average 2 per 10 HPF. 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.
· 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 transformed
· 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 Jour Neuropathol Exp Neurol 2018)
TYPICAL CLINICAL FINDINGS:
· Mentation changes, seizures, vestibular disturbances, and vision loss,
TYPICAL GROSS FINDINGS:
· Considerable variation, most are poorly defined
· 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 multiforme (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 seen in 10 HPF
· No overt features of malignancy
· Often are poorly demarcated and infiltrative
· High grade: any of the following:
· Large areas of necrosis
· Microvascular proliferation +/- pseudopalisading
· Mitotic figure(s) present in 10 HPF
· Overt features of malignancy (nuclear pleomorphism, anisokaryosis, anisocytosis, cellular atypia)
· Tend to be more densely cellular, tend to have visible cytoplasm
· Cytoplasmic glycogen granules
· 10 nm bundles of intermediate filaments
ADDITIONAL DIAGNOSTIC TESTS:
· GFAP (glial fibrillary acid protein) positive, although may be patchy
· GFAP reactivity can be negatively impacted by increased time to fixation, increased time in fixative, and buffering of the fixative (Koehler Jour Neuropathol Exp Neurol 2018)
· Astrocytomas in rats are predominantly GFAP negative (Fraser Vet Pathol 2016)
· Variable Olig2 positive
· Vimentin positive
· S-100 positive
· AQP4 and p75NTR in one study discriminated between canine astrocytomas and oligodendrogliomas (Fraser Vet Pathol 2016)
· 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
· 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
· Also reported in cats, cattle, horses, and pigs
· 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) (Diaz-Delgado Jour Comp Pathol 2015)
· African Hedgehogs: Astrocytomas are one of the most common CNS neoplasms, along with gangliogliomas (Muñoz-Gutiérrez Jour Vet Diagn Invest 2018)
· All were gemistocytic and within the cerebrum; no metastasis observed
· GFAP, S100, CD34 positive
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. Diaz-Delgado J, Sacchini S, Suarez-Bonnet A, et al. High grade astrocytoma (glioblastoma multiforme) in an Atlantic spotted dolphin (Stenella frontalis). Jour Comp Pathol. 2015; 152(2-3):278-82.
4. 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.
5. 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: John Wiley & Sons, Inc; 2017:838-44.
6. 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.
7. 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.
8. Muñoz-Gutiérrez JF, Garner MM, Kuipel M. Primary central nervous system neoplasms in African hedgehogs. J Vet Diagn Invest. 2018; 30(5):715-720.
9. Rissi DR, McHale BJ, Armién AG. Angiocentric astrocytoma in a cat. Jour Vet Diagn Invest. 2019; 31(4):576-580.
10. Spitzbarth I, Heinrich F, Herder V, Recker T, Wohlsein P, Baumgärtner W. Canine central nervous system neoplasm phenotyping using tissue microarray technique. Vet Pathol. 2017; 54(3):369-379.