History

A 7-year-old 26.6-kg (58.5-lb) neutered male mixed-breed dog was presented to a veterinary teaching hospital because of a 3-week history of altered mentation and circling to the left.

Clinical and Gross Findings

Abnormalities identified during physical examination were limited to the nervous system. The dog had obtunded mentation and compulsively walked in wide circles to the left with an otherwise normal gait. Postural reactions were abnormal in the right thoracic and right pelvic limbs. There was an inconsistent menace response in the right eye. The neuroanatomic localization of the lesion was the left side of the prosencephalon. Magnetic resonance imaging of the head revealed a well-defined, intraparenchymal, T2-weighted, hyperintense, non–contrast-enhancing mass that extended from the left side of the thalamus to the rostral portion of the medulla. There was secondary obstructive hydrocephalus, resulting in distension of the third and lateral ventricles. After a course of corticosteroid treatment, the dog's condition continued to decline and the owners elected to euthanize the animal by IV injection of euthanasia solution.

On necropsy, the brain was mildly and diffusely edematous and the lateral ventricles were moderately distended bilaterally. Serial sectioning of the brain revealed a large mass that extended from the left side of the thalamus to the rostral portion of the medulla. The mass was well circumscribed, pale, and gelatinous; it moderately compressed the third ventricle and mesencephalic aqueduct (Figure 1). There were no other important necropsy findings. Sections of the brain that contained the mass and various other tissue samples were fixed in neutral-buffered 10% formalin and processed for microscopic evaluation.

Photograph of a large mass that extended from the left side of the thalamus to the rostral portion of the medulla in a 7-year-old dog with altered mentation and circling to the left. On cut section, notice the gelatinous appearance of the expansile mass, which has caused a decrease in the luminal space of the third ventricle. The lateral ventricles are bilaterally dilated.

Citation: Journal of the American Veterinary Medical Association 258, 4; 10.2460/javma.258.4.383

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Photograph of a large mass that extended from the left side of the thalamus to the rostral portion of the medulla in a 7-year-old dog with altered mentation and circling to the left. On cut section, notice the gelatinous appearance of the expansile mass, which has caused a decrease in the luminal space of the third ventricle. The lateral ventricles are bilaterally dilated.

Citation: Journal of the American Veterinary Medical Association 258, 4; 10.2460/javma.258.4.383

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Photograph of a large mass that extended from the left side of the thalamus to the rostral portion of the medulla in a 7-year-old dog with altered mentation and circling to the left. On cut section, notice the gelatinous appearance of the expansile mass, which has caused a decrease in the luminal space of the third ventricle. The lateral ventricles are bilaterally dilated.

Citation: Journal of the American Veterinary Medical Association 258, 4; 10.2460/javma.258.4.383

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Histopathologic Findings

Serial sections of the brain and sections of major organs (heart, liver, lungs, spleen, and kidneys) were examined histologically. A moderately cellular, well-demarcated, nonencapsulated, ovoid, expansile mass was present in the brainstem; the mass extended from the left side of the midbrain to the rostral portion of the medulla, effaced 85% to 90% of the midbrain and brainstem, and crossed over the midline within the parenchyma. The cells within the mass formed sheets and had 2 morphologically distinct cell types (Figure 2). One cell type composed approximately 60% of the mass area; these cells each had a round nucleus with dense chromatin, an indistinct cell border, and scant basophilic cytoplasm. The other cell type composed approximately 40% of the mass area; these cells each had an elongated nucleus with moderate chromatin density, an indistinct cell border, and eosinophilic fibrillar cytoplasm. No mitotic figures were noted in 10 hpf (equivalent to an area of 2.34 mm²) in either cell population. The stroma was composed mainly of fibrillar processes with few vessels and abundant alcian blue stain–positive mucinous matrix. Some of the blood vessels within the mass (mainly toward the periphery) had markedly hypertrophied endothelium, forming glomeruloid capillaries (microvascular proliferation). Throughout the mass, as well as the surrounding neuroparenchyma, there was moderate vacuolation of the white matter. Scattered, infrequent gemistocytic astrocytes were identified within the mass and were also present in the surrounding neuroparenchyma. The expansile property of the mass caused a moderate reduction in the diameter of the lateral ventricle and compression of the surrounding neuroparenchyma. The immunohistochemical stain for Olig2 robustly stained the nuclei of the cells with round nuclei and scant basophilic cytoplasm (Figure 3). The immunohistochemical stain for glial fibrillary acidic protein (GFAP) highlighted the fibrillary cytoplasmic processes of the second cell type. Cytoplasmic processes were positive for vimentin and weakly positive for cytokeratin AE1/AE3. Both cell types were negative for S100.

Photomicrograph of a section of the brain mass from the dog in Figure 1. There are 2 morphologically distinct populations; one has more densely packed bipolar, spindle-shaped cells each with a small ovoid nucleus and long, wispy cytoplasmic processes (As), and the other has more loosely packed, smaller, round cells each with an indented, condensed nucleus and scant granular cytoplasm (O). H&E stain; bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 258, 4; 10.2460/javma.258.4.383

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Photomicrograph of a section of the brain mass from the dog in Figure 1. There are 2 morphologically distinct populations; one has more densely packed bipolar, spindle-shaped cells each with a small ovoid nucleus and long, wispy cytoplasmic processes (As), and the other has more loosely packed, smaller, round cells each with an indented, condensed nucleus and scant granular cytoplasm (O). H&E stain; bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 258, 4; 10.2460/javma.258.4.383

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Photomicrograph of a section of the brain mass from the dog in Figure 1. There are 2 morphologically distinct populations; one has more densely packed bipolar, spindle-shaped cells each with a small ovoid nucleus and long, wispy cytoplasmic processes (As), and the other has more loosely packed, smaller, round cells each with an indented, condensed nucleus and scant granular cytoplasm (O). H&E stain; bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 258, 4; 10.2460/javma.258.4.383

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Photomicrographs of sections of the brain mass after immunohistochemical analysis. A—With regard to analysis for glial fibrillary acidic protein, there is dense staining of cytoplasm of the bipolar spindle-shaped cells (As) with less staining in the areas of the round cells (O), consistent with an astrocytic lineage. Glial fibrillary acidic protein–specific reaction; bar = 100 μm. B—With regard to analysis for Olig2, there is robust staining of the nuclei of the round cells (O) within the mass, consistent with oligodendrocytic lineage, but not in cells in the areas of more densely packed spindle-shaped cells (As). Olig2-specific reaction; bar = 100 μm. 3,3′-diaminobenzidine chromogen with hematoxylin counterstain.

Citation: Journal of the American Veterinary Medical Association 258, 4; 10.2460/javma.258.4.383

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Photomicrographs of sections of the brain mass after immunohistochemical analysis. A—With regard to analysis for glial fibrillary acidic protein, there is dense staining of cytoplasm of the bipolar spindle-shaped cells (As) with less staining in the areas of the round cells (O), consistent with an astrocytic lineage. Glial fibrillary acidic protein–specific reaction; bar = 100 μm. B—With regard to analysis for Olig2, there is robust staining of the nuclei of the round cells (O) within the mass, consistent with oligodendrocytic lineage, but not in cells in the areas of more densely packed spindle-shaped cells (As). Olig2-specific reaction; bar = 100 μm. 3,3′-diaminobenzidine chromogen with hematoxylin counterstain.

Citation: Journal of the American Veterinary Medical Association 258, 4; 10.2460/javma.258.4.383

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Photomicrographs of sections of the brain mass after immunohistochemical analysis. A—With regard to analysis for glial fibrillary acidic protein, there is dense staining of cytoplasm of the bipolar spindle-shaped cells (As) with less staining in the areas of the round cells (O), consistent with an astrocytic lineage. Glial fibrillary acidic protein–specific reaction; bar = 100 μm. B—With regard to analysis for Olig2, there is robust staining of the nuclei of the round cells (O) within the mass, consistent with oligodendrocytic lineage, but not in cells in the areas of more densely packed spindle-shaped cells (As). Olig2-specific reaction; bar = 100 μm. 3,3′-diaminobenzidine chromogen with hematoxylin counterstain.

Citation: Journal of the American Veterinary Medical Association 258, 4; 10.2460/javma.258.4.383

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Morphologic Diagnosis and Case Summary

Morphologic diagnosis and case summary: thalamic and brainstem oligoastrocytoma (diffuse type) with secondary obstructive hydrocephalus in a dog.

Comments

Oligoastrocytomas are glial tumors composed of a mixture of neoplastic cells with the morphological qualities of a diffuse astrocytoma and an oligodendroglioma.¹ In the dog of the present report, proliferation of these 2 cell types was confirmed on the basis of their distinct histomorphologic features and immunohistochemical staining patterns. These tumors can be difficult to diagnose and classify because oligodendroglial and astrocytic cells are closely related and often have overlapping immunoreactivity patterns in poorly differentiated neoplasms.^1,2

In the case described in the present report, the robust nuclear immunopositivity for Olig2 observed in the cells with a round nucleus and scant cytoplasm was most consistent with cells of oligodendroglial origin, although other glial cells can be variably Olig2 reactive. The dual immunoreactivity for GFAP and vimentin of the cytoplasmic processes in the second cell population was more consistent with cells of astrocytic origin. Microvascular proliferation can be seen with neoplastic processes of both types of glial cells, but glomeruloid vessels (as evident in the case described in the present report) are a classic characteristic of oligodendrogliomas. To complicate matters further, astrocytes within these mixed glial masses can be nonneoplastic, having been trapped within the tumor mass or caused to react to surrounding parenchymal destruction. A cutoff value of 30% to 40% of mass area has been cited in several sources^1,2,3 for determining whether both cell populations are neoplastic, and in such instances, the diagnosis would be a mixed glioma. In the mass described in the present report, the oligodendroglial and astrocytic components each composed > 30% of the mass.

Mixed gliomas, such as oligoastrocytomas, can have 1 of 2 forms: a biphasic (compact) or intermingled (diffuse) form.¹ The biphasic form has 2 distinct neoplastic components, which are normally closely associated but not mixed together. The intermingled form has ≥ 2 admixed cell populations. The diffuse type of oligoastrocytomas is more common, accounting for 90% of oligoastrocytomas in dogs and humans,¹ and was the form of the tumor in the dog of the present report. Brachycephalic breeds are most commonly affected, and the incidence of oligoastrocytomas increases with age. The common locations of oligoastrocytomas are similar to locations of both astrocytomas and oligodendrogliomas and include the white and gray matter of the cerebral cortex, particularly the temporal and piriform lobes.¹ A previously reported case⁴ of an oligoastrocytoma in a dog had this distribution pattern, and the olfactory, frontal, and temporal lobes of the cerebral cortex were affected. For the dog of the present report, however, the tumor was localized to the midbrain and brainstem, primarily on the left side but with some extension over midline. This neuroanatomic location explained the clinical signs of inconsistent menace response and decreased postural reactions on the dog's right side.

Oligoastrocytomas have been previously, but rarely, reported in the veterinary medical literature.^{1,2,4, 5, 6} In a retrospective study⁴ of 173 primary intracranial neoplasms in dogs, 3 unclassified gliomas were identified that were described as being composed of a mixed cellular population, 1 of which had ependymoma-type cells admixed with proliferating astrocytic cells. A previously published case report⁵ describes a multifocal oligoastrocytoma with confirmatory immunohistochemical data in a male 9-month-old Cavalier King Charles Spaniel, which is atypical because most recorded masses are focal. Recently, a study² was conducted to harmonize the classification of canine gliomas. In that study,² 16 oligoastrocytomas were classified as undefined and accounted for approximately 8% of the 193 gliomas investigated. With regard to other veterinary species, 2 oligoastrocytomas (including a malignant oligoastrocytoma with abundant Ki-67 immunoreactivity and increased atypia) were reported in a retrospective study⁶ of spinal cord gliomas in cats. These 2 masses were described as having 30% to 40% oligodendroglial differentiation, as confirmed by immunohistochemical analysis for Olig2 and GFAP. Differential diagnoses considered for the mass in the case described in the present report included an astrocytoma (particularly a glioblastoma) or an oligodendroglioma, with less likely consideration of a neurocytoma or clear cell ependymoma. For the dog of the present report, the diagnosis was made on the basis of cellular morphology and the immunohistochemical staining results that confirmed that the 2 cell populations each composed > 30% of the mass.

Although there is no specific widely used grading scheme for oligoastrocytomas (in part because of their rarity), astrocytomas are commonly assigned a histologic classification and a grade (I to IV) on the basis of cell density, nuclear atypia, and mitotic count (although grade I tumors have not yet been identified in nonhuman animals).¹ Diffusely infiltrating astrocytomas are classified as diffuse (grade II), anaplastic (grade III), or glioblastoma (grade IV). Glioblastomas are the most malignant of the subtypes and are also defined by marked cellular pleomorphism, with areas of acute coagulative necrosis and surrounding palisading glial cells (not observed in the case described in the present report) and microvascular proliferation.^1,2 Immunoreactivity for both GFAP and vimentin decreases with increasing tumor grade, but GFAP is still considered the most reliable marker for diagnosis of astrocytoma.^1,2 Oligodendrogliomas are graded on a scale of I to III on the basis of the degree of hemorrhage and necrosis, nuclear atypia, and mitotic rate.^1,2 In a recent classification study⁵ of canine gliomas, undefined gliomas were graded as low or high grade on the basis of the degree of necrosis, microvascular proliferation, mitotic rate, and universal features of malignancy (nuclear pleomorphism, anisokaryosis, anisocytosis, and nuclear atypia). By use of this grading rubric, we would classify the tumor in the dog of the present report as low grade because of the lack of widespread necrosis, low mitotic rate, and lack of malignant cytologic features.

Compared with reported cases involving veterinary species, there are more reported cases of oligoastrocytomas in humans; therefore, more data have been collected regarding tumor diagnosis and grading, treatment, and prognosis in humans. As documented for humans, the MRI characteristics of oligoastrocytomas are similar to those of grade II oligodendrogliomas and diffuse astrocytomas; thus, differentiation of these tumors on the basis of results of diagnostic imaging is difficult.⁷ With MRI, the lesion appears as a homogeneously hypointense area on T1-weighted images, whereas it appears as a hyperintense area on T2-weighted images. Typically, neither edema nor hydrocephalus is associated with the tumor.⁷ Another accurate method of diagnosis is the smear technique that involves either a CT-guided stereotactic brain biopsy or a craniotomy with biopsy.⁸ This method has been a part of human medicine since the 1930s and has been used in veterinary patients since the early 2000s.⁹ In humans, oligoastrocytomas tend to be more chemotherapeutant resistant than oligodendrogliomas because of the former's astrocytic component, which is unaffected by chemotherapy.¹⁰

The case described in the present report has highlighted the benefits of performing immunohistochemical analyses on specimens of CNS tumors to better identify neoplastic components. Furthermore, such analyses contribute much-needed data regarding these rare neoplasms.