JPC SYSTEMIC PATHOLOGY
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: Effacing and replacing approximately 75% of the neuropil is a poorly circumscribed, unencapsulated, infiltrative neoplasm composed of cells loosely arranged into interlacing streams or packed into dense, solidly cellular areas which blend into the surrounding neuropil. Neoplastic cells are polygonal to fusiform with variably distinct cell borders and scant to wispy eosinophilic fibrillar cytoplasm. Nuclei are oval to elongate with finely stippled chromatin and 1 to 2 nucleoli. There is moderate anisocytosis and anisokaryosis, and mitotic figures average 2 per HPF. There are multiple large serpiginous areas of liquifactive necrosis with abundant karyorrhectic and cellular debris, numerous degenerate neutrophils and erythrocytes, fewer gitter cells, fibrin, and necrotic blood vessels. Surrounding these necrotic areas are bands of pseudopalisading neoplastic cells oriented perpendicular to necrotic foci. There are numerous vascular proliferations at the periphery, which often form glomeruloid-like structures with hypertrophied (reactive) endothelim. Multifocally, neoplastic cells invade or obliterate vessel walls, and there is mild to moderate hemorrhage extending into the surrounding neuropil. There is mild gliosis at the periphery of the neoplasm.
MORPHOLOGIC DIAGNOSIS: Cerebrum: Astrocytoma, high-grade (glioblastoma multiforme), boxer, canine.
CONDITION: Astrocytoma, high grade
SYNONYMS: Glioblastoma multiforme (GBM)
· Most malignant variant of astrocytoma (high-grade), characterized by anaplastic features (nuclear and cytoplasmic pleomorphism, abundant normal and abnormal mitotic figures, multinucleate neoplastic cells), microvascular proliferation andnecrosis
· Glioblastoma is non-metastatic but highly locally invasive and diffusely disseminates into the brain parenchyma
· In dogs, there is a predilection for brachycephalic breeds, with boxers being the most represented (30%)
· Tumors overexpress EGFR, PDGFR-α and IGFBP-2
· Gliomas contain a minority of cells with stem-like properties (cancer stem cells, or CSCs) that have the ability to self-renew and sustain tumor growth
· Glioma CSCs can differentiate into cells with a neuronal, astrocytic, or oligodendroglial phenotype
· Neoplastic cells spread by subpial or perivascular extension along the white matter tracts and extends along perivascular spaces, the glial limitans externa, and subependyma
· Localized hypoxia upregulates migration-associated genes causing tumor cells to migrate away from central hypoxic center
· Increased EGFR > increased Shc-Grb2-Ras and PI3K > increased angiogenesis
· Necrosis is a central feature of high-grade malignant glioblastoma and most important prognostic indicator
· Necrosis-induced hypoxia and various angiogenic and growth factors combine to form a highly malignant state
· In response to hypoxia, small clones of tumor cells acquire characteristics that encourage active migration, such as hypoxia-inducible factor 1 alpha (HIF-1α), leaving a central region more susceptible to necrosis
· Pseudopalisading tumor cells surrounding necrotic centers are less proliferative and more prone to apoptosis
· Vascular proliferation is due to expression of αvβ3 integrin required for fibroblast growth factor 2 (FGF-2) and TNF α-induced angiogenesis; these integrins mediate vascular cell migration and regulate metalloproteinase activity and endothelial proliferation and contribute to neovascularization and invasion
· Glioblastomas also promote angiogenesis through the release of vascular endothelial growth factor (VEGF)
· VEGF increases with tumor grade, and is in highest concentration in the palisading tumor cells around areas of necrosis
· Glioblastoma is a highly angiogenic malignancy; newly formed vessels are thought to arise by sprouting of pre-existing brain capillaries
· The recent demonstration that a population of glioblastoma stem-like cells (CSCs – CD44, CD99, CD133, Oct4 +) maintains glioblastomas indicates that the progeny of these cells may not be confined to the neural lineage, as normal neural stem cells are able to differentiate into functional endothelial cells
· A variable number (range 20-90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin
TYPICAL CLINICAL FINDINGS:
· Specific nervous signs vary depending on site and size of the tumor
TYPICAL GROSS FINDINGS:
· Most commonly affects the convexities of the cerebral hemispheres, lobus piriformis, thalamus and hypothalamus
· Often well demarcated, gray to white tumor with variable amounts of necrosis and hemorrhage
· Cause considerable brain swelling and often fatal herniation
· Edema of surrounding neuropil
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Infiltrative mass of variably densely packed, highly cellular pleomorphic polygonal cells to loosely spaced fusiform cells, both of which have round-mildly oval nuclei
· “Glomeruloid” vascular proliferation of adventitial and endothelial cells – resemble vascular tufts of nephron
· Pseudopalisading of neoplastic cells around areas of necrosis
· Moderate rate of mitosis
· Scattered multinucleated cells – rare in domestic animals, and are biologically irrelevant
· Giant cell variant consists predominantly of bizarre giant cells and multinucleated cells
· Necrosis, palisading, and neovascularization are the pathognomonic features
· Cytoplasm contains bundles of 10 nm intermediate filaments
· Cytoplasmic glycogen granules
ADDITIONAL DIAGNOSTIC TESTS:
· Variable immunoreactivity for glial fibrillary acidic protein (GFAP), vimentin and cytokeratin
· Glial cells in gliosarcomas should be GFAP positive; infiltrative cells in gliomatosis cerebri are GFAP negative
· Low grade astrocytoma has only slight hypercellularity and cellular pleomorphism, with an absence of mitoses, vascular proliferation and necrosis
· Medium grade astrocytoma (anaplastic astrocytoma) also has hypercellularity, cellular pleomorphism, and mitoses, but vascular proliferation and necrosis are absent
· Rare astrocytoma/glioma variants:
· Biphasic tissue pattern displaying alternate areas of highly anaplastic glial cells and abundant sarcomatous components
· Glial component will display gliobastoma features of serpentine foci of necrosis with a pseduopalisading arrangement of surrounding radiating glial cells and glomeruloid vascular proliferation
· Gliomatosis cerebri
· Characterized by an infiltrative cell type reminiscent of astrocytes rather than the formation of a distinct tumor mass
· Infiltrates are often present bilaterally but asymmetrically in the brain; may also display discontinuous areas in the spinal cord
· Normal neural structures remain intact, with only slight damage to axons and neurons
· 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
· Mixed glioma (oligoastrocytoma): These are a mixture of neoplastic astrocytes and oligodendrocytes; anaplastic variants exhibit increased cellularity, nuclear atypia, mitoses, necrosis and vascular proliferation
· Primitive neuroectodermal tumor: Densely packed round to polygonal cells with often hyperchromatic carrot-shaped nuclei, rosettes, pseudorosettes, and palisading of neoplastic cells
· Also reported in rats, parakeets, rhesus monkeys (Macaca mulatta), baboons (Papio anubis), horses, cattle, pigs, sheep and a dolphin.
· Spontaneous astrocytomas in rats are negative for GFAP
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