JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

February 2023

N-N02

 

Signalment (JPC #1525763): Adult dog; age, breed, and gender unspecified

 

HISTORY: This dog developed progressive deterioration of the CNS with sudden aggressive behavior. 

 

HISTOPATHOLOGIC DESCRIPTION: Cerebellum and brainstem: Superficially infiltrating the fourth ventricle and brainstem white matter and compressing the adjacent cerebellum is an unencapsulated, poorly demarcated, densely cellular neoplasm composed of polygonal cells arranged in solidly cellular areas on a scant fibrovascular stroma. Neoplastic cells have variably distinct cell borders, scant eosinophilic cytoplasm with clear retraction artifact (“honeycomb pattern”), and a round, hyperchromatic nucleus with an indistinct nucleolus. Anisocytosis and anisokaryosis are mild and there are less than 1 mitotic figures per 10 HPF (2.37mm²). Neoplastic cells are occasionally admixed with hemorrhage, edema, fibrin, and karyorrhectic and cellular debris (necrosis). In the brainstem at the periphery of the neoplasm are few multifocal capillary microvascular proliferations with hypertrophied endothelial cells piling up to 4-5 cell layers thick and occasional formation of glomerular-like tufts (glomeruloid microvascular proliferation).  

 

MORPHOLOGIC DIAGNOSIS: Cerebellum and brainstem: Oligodendroglioma, focally infiltrative, high-grade, breed unspecified, canine.

 

GENERAL DISCUSSION:  

• Oligodendrogliomas are the most common of the gliomas (up to 70% incidence); gliomas include oligodendrogliomas, astrocytomas, and undifferentiated gliomas 
• Derived from oligodendrocytes; these cells are located in both the white and gray matter and are responsible for myelinating axons and regulating the perineural microenvironment 
• Usually occur in the cerebrum (especially frontal, olfactory, temporal, and piriform lobes), brainstem, interventricular septum; usually in close proximity to the lateral ventricles
• Tend to extend to meningeal and ventricular surfaces; commonly disseminate via CSF to distant brain sites 
• Most common in dogs, 5-11 years old; brachycephalic breed predilection (Boston terriers, boxers, and bulldogs)

 

TYPICAL CLINICAL FINDINGS:

 

TYPICAL GROSS FINDINGS:  

• Variably-sized, well-demarcated neoplasm
• Pink-red to gray, soft, gelatinous, fluctuant, and/or translucent
• Occasional multifocal hemorrhage; central area may be cystic in larger tumors

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Densely cellular neoplasm with minimal stroma composed of neoplastic oligodendrocytes with round, central, hyperchromatic, uniform nuclei surrounded by a clear halo (“honeycomb cell pattern”) due to non-staining cytoplasm (JKP) or artifactual cytoplasm retraction (PBVD)
• +/- cells arranged in rows (often at periphery) or in pseudorosettes 
• +/- mineralization
• +/- cystic or mucinous degeneration, edema
• +/-   glomerular-like blood vessel proliferation at neoplasm margins
• Often infiltrated by Iba+ microglia/macrophages and smaller numbers of CD3+ and CD20+ lymphocytes; Mac387+ and CD163+ macrophages present in greater numbers in high grade tumors (Krane et al, Vet Pathol, 2021)
• Anaplastic variant (WHO grade III): Multifocal hemorrhage and necrosis, prominent neovascularization, nuclear atypia, neoplastic cells disseminated throughout CSF
• Leptomeningeal oligodendroliomatosis (dogs, humans; one case report in cattle – Kauer et al, Vet Pathol 2020): Diffuse subarachnoid/leptomeningeal dissemination within the brainstem and spinal cord
• Gliomatosis cerebri (dogs): a subtype of gliomas, including oligodendroglioma, with diffuse neuroparenchymal infiltration; does not distort tissue architecture; confirmed to have glial histogenesis and can be graded same as glial tumors (Rissi et al, Vet Pathol 2021)
• Oligodendroglioma with ganglioglioma-like maturation (humans, dogs): glioma with sheets of oligodendroglial cells and multifocal regions of neuronal differentiation (Cornax et al, J Comp Pathol 2019)
• Classification scheme: low or high grade based on the presence of necrosis, nuclear atypia, microvascular proliferation, pseudopalisading, or mitotic rate 
  • Mitotic rate is the only histologic feature with strong correlate to survival (Merickel et al, Vet Pathol 2021)

 

ADDITIONAL DIAGNOSTIC TESTS:  

• CSF cytology: Large cells with eccentric nuclei 4-6x RBC size, dense basophilic moderately abundant cytoplasm 
• Touch impression cytology: highly cellular; dense aggregates and loose individualized cells enmeshed in eosinophilic wispy matrix; cells are small with round-ovoid nuclei with condensed chromatin, scant to moderate amounts of wispy basophilic cytoplasm 
• Fine needle aspirate cytology: Large numbers of blood vessels surrounded by neoplastic oligodendrocytes with small amounts of eosinophilic cytoplasm and uniform round nuclei +/- lakes of basophilic mucin 
• IHC: CNPase, PDGFR-alpha, Olig2, NG2, SOX10 +/- DCX positive; GFAP typically negative (intermingling astrocytes would be positive); NeuN negative; higher Ki-67 index 
  • Exception: Olig2 is a poor marker for oligodendroglioma in cats due to positive immunoreactivity in ependymomas (Demeter el a, JVDI 2022) 
  • DCX immunolabeling more prominent at tumor margins (Elbert et al, JDVI 2022)

 

DIFFERENTIAL DIAGNOSIS:  

• Undefined glioma (oligoastrocytoma): at least 30-40% proportion of both oligodendroglia and astrocytes OR undifferentiated cellular morphology; will be IHC positive for both astrocytic and oligodendroglial markers
• Astrocytoma (N-N01): Nuclei are more elongate and angular; GFAP +/- Olig2 positive
• Primitive neuroectodermal tumor (PNET, N-N05): Closely packed round to polygonal cells in sheets and bands, often with Homer-Wright or Flexner-Wintersteiner rosettes
• Canine clear cell ependymoma (N-N03); ependymoma: Strong, uniform GFAP immunoreactivity
• Cryptococcosis (N-F02): Gelatinous appearance (especially in cats)

 

COMPARATIVE PATHOLOGY:

• Rare in cats, cattle, white-tailed deer, horses, pet birds, and multiple nonhuman primates, including SIV positive rhesus macaques
• Case report in a dog (Ros et al, J Comp Pathol 2018) with a metastatic prostatic adenocarcinoma within an anaplastic oligodendroglioma. 
• African hedgehog: One case reported (Munoz-Gutierrez et al, JDVI 2018); S100 positive, GFAP and NFP negative

 

References:

1. Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6^th ed. Philadelphia, PA: Elsevier; 2016: 400.
2. Cornax I, Pluhar GE, Clark HB, et al. Oligodendroglioma with neuronal differentiation in two boxer dogs. J Comp Pathol. 2019;172:11-16. 
3. Demeter EA, Kent M, Glass EN, et al. OLIG2 immunolabeling in feline ependymoma. J Vet Diagn Invest. 2022;34(5):898-901. 
4. Elbert JA, Rissi DR. Doublecortin immunolabeling and lack of neuronal nuclear protein immunolabeling in feline gliomas. J Vet Diagn Invest. 2022;34(4):757-760. 
5. 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;2012:757-759.
6. Howerth EW, Nemeth NM, Rsyer-Deguirgus M-P. Cervidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018: 155.
7. Jahns H, McElroy MC. Bovine intracranial neoplasia: A retrospective case series. Vet Pathol. 2022;59(5):824-835. 
8. Kauer RV, Bagatella S, Oevermann A. Diffuse leptomeningeal oligodendrogliomatosis in a cow. Vet Pathol. 2020;57(2):253-257. 
9. Kishimoto TE, Uchida K, Thongtharb A, et al. Expression of oligodendrocyte precursor cell markers in canine oligodendrogliomas. Vet Pathol. 2018;55(5):634-644. 
10. Krane GA, O’Dea CA, Malarkey DE, et al. Immunohistochemical evaluation of immune cell infiltration in canine gliomas. Vet Pathol. 2021;58(5):952-963. 
11. 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. 5^th ed. St. Louis, MO: Elsevier; 2020:224.
12. Lorenzi DD, Pintore L. Nervous system. In: Raskin RE, Meyer DJ, Boes KM, eds. Canine and Feline Cytopathology, A Color Atlas and Interpretation Guide. 4^th ed. St. Louis, MO: Elsevier; 2023: 550-552.
13. Merickel JL, Pluhar GE, Rendahl A, et al. Prognostic histopathologic features of canine glial tumors. Vet Pathol. 2021;58(5):945-951. 
14. Miller AD. Neoplasia and proliferative disorders of nonhuman primates. 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;2012:345.
15. Miller AD, Porter BF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7^th ed. St. Louis, MO: Elsevier; 2022:954-957.
16. Munoz-Gutierrez JF, Garner MM, Kiupel M. Primary central nervous system neoplasms in African hedgehogs. J Vet Diagn Invest. 2018;30(5):715-720. 
17. Rissi DR, Donovan TA, Porter BF, et al. Canine gliomatosis cerebri: Morphologic and immunohistochemical characterization is supportive of glial histogenesis. Vet Pathol. 2021;58(2):293-304. 
18. Ros C, Fernandez-Flores F, de la Fuenta C, et al. Tumor-to-tumor metastasis phenomenon: Metastatic prostatic adenocarcinoma within an anaplastic oligodendroglioma in the brain of a dog. J Comp Pathol. 2018;165;62-66. 
19. Schmidt RE, Reavill DR, Phalen DN, eds. Pathology of Pet and Aviary Birds. Ames, IA: John Wiley and Sons, Inc.; 2015:232.
20. Yoshida K, Chambers JK, Uchida K. Immunohistochemical study of neural stem cell lineage markers in canine brains, gliomas, and a glioma cell line. Vet Pathol. 2023;online ahead of print. 

 

 

 

 

 

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