JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

February 2023

N-N03

 

Signalment (JPC #1716400): 7-year-old cat

 

HISTORY: This cat exhibited depression and anorexia of 2 weeks duration that progressed to convulsions. Sidestepping and placing responses were absent on the left side.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum, lateral ventricle: Multifocally expanding the ventricle as well as infiltrating and compressing adjacent cortical neuroparenchyma is a densely cellular, well-circumscribed, lobulated, unencapsulated neoplasm composed of polygonal cells arranged in solidly cellular areas, true rosettes (both Flexner-Wintersteiner and Homer Wright variants), and pseudorosettes on a fine fibrovascular stroma. Neoplastic cells have indistinct cell borders, a small to moderate amount of amphophilic, fibrillar to granular cytoplasm, and rare, poorly discernible, pale, luminal cilia. Nuclei are round to oval and basally oriented with dense to coarsely stippled chromatin. There is minimal anisocytosis and anisokaryosis and a mitotic rate of 1 per 2.37mm². Within the neoplasm there are multifocal to coalescing areas of coagulative necrosis characterized by loss of differential staining with retention of architecture that occasionally are admixed with foci of liquefactive necrosis characterized by replacement by eosinophilic cellular and karyorrhectic debris, fibrin, hemorrhage, and edema. Within the adjacent neuroparenchyma, there is mild lymphocytic perivascular cuffing, blood vessel endothelium is occasionally reactive, there are increased numbers of glial cells (gliosis), and rarely at the interface with the neoplasm there are moderate numbers of gitter cells.  

 

MORPHOLOGIC DIAGNOSIS: Cerebrum: Ependymoma, breed not specified, feline.

 

GENERAL DISCUSSION:  

• Extremely rare tumors derived from ependymal cells lining the ventricles and central canal of the spinal cord; can arise from the lateral, third, and fourth ventricles, mesencephalic aqueduct, or central canal
• Reported subtypes: Papillary, clear cell, myoxopapillary, tanycytic, extraventricular, and subependymomas

 

TYPICAL CLINICAL FINDINGS:  

• Neurological signs consistent with a slow-growing, space occupying lesion
• Ataxia, circling, head tilt
• Reflexes are not affected until the lesion is well advanced

 

TYPICAL GROSS FINDINGS:  

• Slow-growing, variably demarcated, expansile neoplasm that replaces and compresses the brain or spinal cord
• Gray and fleshy but may be dark from hemorrhage if they project into a ventricle
• +/- Cavitations
• May metastasize locally via cerebrospinal fluid
• Often cause secondary hydrocephalus

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Well-circumscribed, densely cellular, expansile neoplasm composed of polygonal cells arranged in sheets, pseudorosettes, and true rosettes (pseudorosettes and rosettes are an important histologic feature of these tumors; however, they are not specific to ependymomas)
  • True rosettes appear as tubular cavities lined by cells of epithelial appearance; bound together by desmosomes; in ependymomas, they have surface cilia anchoring phosphotungstic acid hematoxylin (PTAH) - positive blepharoplast, and are more common in feline ependymoma
    • Flexner-Wintersteiner rosettes are a spoke-and-wheel-shaped cell formation with an empty lumen
    • Homer Wright rosettes are a circular or spherical groupings of tumor cells around a pale, eosinophilic, central area that contains neurofibrils but lacks a lumen
  • Pseudorosettes form around blood vessels and are characterized by a perivascular nuclear free zone
• Neoplastic cells have pale, eosinophilic, fibrillar cytoplasm with indistinct cellular borders; basally located nuclei are round to oval with hyperchromatic chromatin and empty perinuclear halos; variable mitotic rate
  • Cells often contain diagnostically characteristic globular eosinophilic intracytoplasmic (pseudo)inclusions; inclusions are strongly and uniformly immunoreactive for GFAP
• Features specific to ependymomas include:  ependymal canals (linear spaces lined by ependymal cells), ciliated epithelial cells lining the rosettes, and blepharoplasts (basal ciliary bodies)
• Papillary variant: Branching papillary stroma covered by recognizable ependymal cells; spinal cord ependymomas may be more papilliferous, cells embedded in mucinous intercellular stroma
• Clear cell variant: Resemble oligodendroglioma with perinuclear halos
• Tanycytic variant: Elongated cells with fibrillar processes forming bundles and fascicles
• Malignancy characterized by increased cellular atypia and mitoses

 

ULTRASTRUCTURAL FINDINGS:

• Intercellular tight junctions and microvilli that project into a lumen or interdigitate between cells
• Cells lining cavities or papillae have desmosomes, cilia, and cytoskeletal ciliary basal bodies (blepharoplasts)
• Clear cell variant: cells filled with dense whorls of intracytoplasmic intermediate filaments

 

ADDITIONAL DIAGNOSTIC TESTS:

• Phosphotungstic acid-hematoxylin (PTAH) positive staining of basal bodies
• Immunohistochemistry: Immunoreactive for GFAP, pan-cytokeratin (multifocal within rosettes, pseudorosettes, and other neoplastic cells), +/- scant Olig2 (<1% of cells were Olig2 immunoreactive in one study, Miller Vet Pathol 2019)
  • Feline and equine ependymomas are often GFAP positive 
  • A study in feline ependymoma revealed varied Olig2 staining with >50% having moderate to strong immunoreactivity (Demeter, J Vet Diag Invest 2022)
  • Canine ependymomas are GFAP immunoreactive in perivascular nuclear-free zone
• GFAP and pancytokeratin staining does not correlate with tumor variant in feline ependymomas
• Cytology may show neoplastic cells palisading around vascular structures

 

DIFFERENTIAL DIAGNOSIS:

Grossly:

• Astrocytoma, high-grade (N-N01, N-N04) – also have hemorrhage and necrosis
• Nephroblastoma – spinal thoracolumbar tumor of young dogs; grows by expansion into spinal cord; pathognomonic WT-1 immunoreactivity 
• Neuroblastoma – have neuroblastic (Homer-Wright) rosettes not pseudorosettes,  stain with neuronal-specific cell markers
• Choroid plexus tumor (N-N06) –  No rosettes, cytokeratin and Kir7.1 positive and Olig2/GFAP negative; may cause obstructive hydrocephalus; commonly arise within fourth ventricle
• Meningioma (N-N07) – may be associated with pia mater of choroid plexus; papillary sub-type can have pseudorosettes, but the presence of characteristic meningothelial whorls and Olig2 negativity aid in diagnosis
• Germinoma (suprasellar germ cell tumor) – can invade the 3^rd ventricle and mimic ependymoma grossly

Microscopically: Tumors that may have pseudorosettes and mimic ependymoma (may require immunohistochemistry to differentiate; Miller Vet Pathol 2019):

• Medulloblastoma 
• Pituitary gland adenoma
• Oligodendroglioma
• Choroid plexus tumor
• Papillary meningioma

 

COMPARATIVE PATHOLOGY:

• Ependymomas are very rare in species other than man; have been reported in nonhuman primates, cats, dogs, rats, cattle, horses, deer, and fish; more prevalent in dogs 
• Human ependymomas stain strongly with anti-epithelial membrane antigen antibody (EMA); however information about immunoreactivity of domestic animal ependymomas to EMA is not available

 

References:  

1. 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; 2016:400-401.
2. De Lorenzi D, Mandara MT. The Central Nervous System. In: Raskin RE, Meyer DJ, eds. Canine and Feline Cytology: A Color Atlas and Interpretation Guide. 3rd ed. St. Louis, MO: Elsevier; 2016:552-553. 
3. Demeter, EA, Kent M, Miller AD. OLIG2 immunolabeling in feline ependymoma. J of Vet Diag Invest. 2022;34(5):898-901.
4. Higgins RJ, Bollen AW, Dickinson PJ, et al.   Tumors of the nervous system In: Meuten DJ, ed.  Tumors in domestic animals. 5th ed. Ames, IA: John Wiley & Sons, Inc.; 2017:849-853.
5. Levine GJ, Cook JR. Cerebrospinal Fluid and Central Nervous System Cytology. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:224. 
6. Michimae Y, Moria T, Sunagawa Y, Sawada M, Okamotoa Y, Shimada A.  Anaplastic ependymoma in the cervical spinal cord of a Maltese dog.  Jour Vet Med Sci. 2004;66(9):1155-1158.
7. Miller AD, Koehler JW, Donovan TA, et al. Canine Ependymoma: Diagnostic Criteria and Common Pitfalls. Vet Pathol. 2019;56(6):860–867.
8. Miller AD, Porter BF. Nervous system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:957.
9. Traslavina RP, et al. Clear cell ependymoma in a dog. J Comp Pathol. 2013;49:53-56.
10. Woolford L, de Lahunta A, Baiker K, Dobson E, Summers BA. Ventricular and extraventricular ependymal tumors in 18 cats. Vet Pathol. 2012; 50(2): 243-251. 

 

 

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