General features, classification, and subtypes

Astrocytomas form a diverse subgroup of gliomas which, in the dog, are further subdivided into two distinct morphological subgroups based on their typical infiltrative versus well‐circumscribed growth patterns. The diffusely infiltrating tumors are classified as: (1) diffuse astrocytoma, (2) anaplastic astrocytoma, (3) glioblastoma, (4) gliomatosis cerebri, whereas the well‐circumscribed tumors are: (1) subependymal giant cell astrocytoma (SEGA), (2) pilocytic astrocytoma, (3) gemistocytic astrocytoma, (4) pleomorphic xanthoastrocytoma.

Nevertheless these two subgroups of canine astrocytomas share many common features, for example MRI findings are not exclusively diagnostic, their incidence increases with age, they arise mainly within white matter of the cerebral hemispheres, and they can invade the cortex but generally not into the ventricular system.^1–4 Their overall incidence is about 15% of all primary nervous system tumors, which is only exceeded by meningiomas, the most common tumor in both dogs and cats. Certain brachycephalic breeds (e.g., boxer, bulldog, and Boston terrier) have a relatively much higher incidence of astrocytomas (about 23 times) than in any other breeds.⁴ Astrocytomas have been sporadically reported in cats, horses, cattle, and pigs, but most of the following information is based on the canine tumors.^4,5

The main criteria used for histological classification and grading (grades II–IV) of astrocytomas are increasing cell density, nuclear atypia, and mitotic count.^3,4 The most malignant astrocytoma, grade IV, commonly called a glioblastoma, additionally must exhibit at least one of two other essential diagnostic features: (a) necrosis with marked glial pseudo‐palisading and/or (b) microvascular proliferation.^2–4,6,7 Grade I tumors have a very low cell density and have not yet been recognized in animals, presumably due to their minimal clinical effect. The secondary structures of Scherer, consisting of three main morphological features of perineuronal and perivascular satellitosis, subpial spread, and invasion along the white matter tracts by neoplastic cells, are considered to reflect the upgraded migratory and invasive capability of a highly malignant clonal population of a glial tumor, of either astroglial or oligodendroglial origin (see Figure 19.10C).⁶ Astrocytomas will always express glial fibrillary acidic protein (GFAP) immunoreactivity to some degree, which decreases with increasing grades (see Figure 19.3B) and have a proliferation index (PI) up to 5, 10, and 35% in grades II, III, and IV, respectively (see Figure 19.4B).^1,7

Definition, incidence, and sites

The diffuse astrocytoma has an infiltrating pattern of growth. Fibrillary astrocytoma is the descriptive classification used for this subtype of diffuse astrocytoma grade II. These tumors represent about 30% of all astrocytomas and occur with increasing frequency with advancing age. There is no gender predilection and they occur much more frequently in some brachycephalic breeds. Although they can be located anywhere in the brain or spinal cord, their preferential site is supratentorial, in the temporal and piriform lobes and less often in the frontal lobes (Figure 19.1A–C). The anaplastic astrocytoma grade III also has about a 30% incidence within the glioma group and can only be confidently distinguished from a grade II diffuse astrocytoma by histological criteria (Figure 19.1E,F).^4,7

Glioblastomas (astrocytoma grade IV) (Figures 19.2–19.4) are the most malignant primary CNS tumor of astrocytic derivation, most likely arising from a stem cell population in a subependymal niche around the lateral ventricles. Their incidence in the dog increases with age, tumors arise mainly supratentorially in subcortical white matter in parietal and temporal lobes, and glioblastomas represent about 30% of all canine astrocytomas (Figure 19.2B).^4,7,8 It is an extremely rare tumor outside of these sites but is found in the spinal cord. They have been reported rarely in cats, horses, and cattle. No molecular genetic studies have yet been made in canine glioblastomas to distinguish, as in people, between the rapid onset of primary de novo and the much slower progress towards the secondary glioblastomas. The incidence of the latter is much lower (up to 10%) and they have a slower clinical evolution driven by progressively consistent genetic mutations from a diffuse grade II glioma. The primary and secondary glioblastomas have only been recognized to date in people: they are considered to be distinct entities that evolve through different genetic pathways, with characteristic genetic profiles, but they are similar histologically.⁷

Gliomatosis cerebri is a diffusely infiltrating glioma in at least three separate brain lobes or in the spinal cord (Figure 19.6A,B). In dogs, the original diagnosis was termed microgliosis but the human tumor is of a morphologic and molecularly and genetically defined astrocytic phenotype.⁷ In addition, human oligodendrogliomas and mixed astro‐oligodendrogliomas may have a similar morphological pattern. Gliomatosis cerebri has characteristic long, thin, slender, almost helical hyperchromatic nuclei with minimal bipolar cytoplasm. Although very rare, it occurs in middle‐aged dogs.⁹ Recently a cluster suggestive of a familial inheritance pattern has been found in young siblings of several families of bearded collie dogs (A. Oevermann, personal communication, 2013).

Infiltrative astrocytomas account for approximately 90% of all canine astrocytomas while the circumscribed astrocytic tumors form a much smaller subgroup. A subependymal giant cell astrocytoma (SEGA) has been reported once in a cat in a subependymal site of the lateral ventricle. Two pilocytic astrocytomas have been described in a larger case series of canine astroglial tumors as supratentorial tumors affecting the temporal lobe and thalamus.⁴ A third possible canine pilocytic astrocytoma has been described in the optic nerve, resembling the adult type of human pilocytic astrocytoma, termed optic chiasmatic‐hypothalamic glioma.¹⁰ Gemistocytic astrocytomas are a rare variant of well‐circumscribed astrocytomas, which in the canine are found mainly in the cerebellum and less often in the spinal cord (Figure 19.5A). They are characterized by a dominant fraction (>70%) of neoplastic cells resembling reactive gemistocytes.^4,7 A pleomorphic xanthoastrocytoma has been described as an intra‐axial well‐demarcated mass in the medulla oblongata of a 13‐week‐old mixed‐breed poodle.¹¹

Neuroimaging

With MRI, most diffuse astrocytomas are hypointense on both T1‐ and T2‐weighted images (Figure 19.1A), and tend to have minimal post‐contrast enhancement.^1,2 Anaplastic astrocytomas tend to have some T2‐weighted hyperintensity and also more pronounced post‐contrast enhancement (Figure 19.1B). Glioblastomas commonly have a post‐contrast peripheral ring or ring‐enhancing pattern with central T1‐weighted hypointense regions of necrosis on post‐contrast images (Figure 19.2A). FLAIR sequences illustrate moderate peritumoral edema, while T2*‐GRE images can detect the frequent intratumoral multifocal hemorrhages. However these findings only provide a provisional diagnosis with the histological confirmation of a specific subtype obtained from surgical or stereotactic biopsy samples.^1,3,7,11

In gliomatosis cerebri, MRI findings mimic those of low‐grade diffuse astrocytomas in the brain and spinal cord, but lesions on T1‐ and T2‐weighted images are restricted to white matter, and are widespread, uniform, and distinctly multifocal (Figure 19.6A).^7,8 Contrast enhancement is minimal to absent. The pleomorphic xanthoastrocytoma was variably hyperintense on T2‐weighted images,with some contrast enhancement on T1‐weighted, while the FLAIR sequences illustrated central hypointensity but was hyperintense peripherally.

Gross morphology

Diffuse astrocytomas on transverse sections of the CNS tend to have marked effacement of gray and white matter boundaries with solid, homogeneously white tissue with blurred margins (Figure 19.1C). Anaplastic astrocytomas can have a similar appearance.

Glioblastomas tend to be relatively large, poorly demarcated, are variegated with areas of yellowish to white necrosis, acute and chronic hemorrhage and sometimes multiple cysts with a turbid content (Figure 19.2B). Spread by local extension across the corpus callosum into the contralateral hemisphere, a characteristic feature of human glioblastomas, is rare in canine glioblastomas.³

In gliomatosis cerebri there are areas of whitish uniform enlargement of the infiltrated cerebral hemispheric white matter, in the brainstem, or in the spinal cord (Figure 19.6B).⁹

SEGA in the cat is a well‐circumscribed mass that protrudes into the lateral ventricle from a primary subependymal site as a firm white mass.

Pilocytic astrocytoma occurs as a well‐circumscribed mass in the thalamus, temporal lobe, and optic nerve.⁴

Gemistocytic astrocytomas are most common in the cerebellum and form well‐demarcated discrete, rather large, tan‐colored tumors with areas of yellowish necrosis and small clear cysts (Figure 19.5A). Grossly, the xanthoastrocytoma was a well‐demarcated central tan mass with an outer hemorrhagic border.¹¹

Definition, incidence, and sites

Oligodendrogliomas are diffusely infiltrating, well‐demarcated tumors derived from glial cells histologically resembling oligodendrocytes (Figures 19.9–19.11). Their overall incidence in dogs ranges up to 15% of all primary nervous system tumors with the well‐known higher incidence that oligodendrogliomas and other glial tumors have (at least 23 times greater) in certain brachycephalic breeds (e.g., boxers, Boston terriers, bulldogs, etc.) than in all other breeds.¹ In cats, horses, sheep, and cattle they are very rare with only sporadic reports.^2–4 The onset of neurological signs in canine oligodendrogliomas usually occurs between 5 and 11 years, without any gender bias, but their natural history is not well defined. Oligodendrogliomas arise in the white or gray matter of the cerebral hemispheres, with decreasing frequency caudally from the olfactory bulbs and frontal, temporal, and piriform lobes to the parietal and occipital areas with at least half exhibiting secondary intraventricular growth and invasion into the cortex (Figure 19.8B,C).^1,5,6 They may extensively infiltrate gray matter with effacement of the normally well‐defined gray–white junctions, both on MRI and grossly.^1,5,6 Oligodendrogliomas with predominant intraventricular growth have been described with focal neurocytic differentation and which therefore need to be excluded by their morphology and broadly immunonegative IHC (synaptophysin) from a differential diagnosis of a neurocytoma.⁷ Oligodendrogliomas rarely are found in the brainstem or spinal cord as primary sites, sometimes with metastases diffusely into the meninges and focally within the spinal canal.⁸ Diffuse canine spinal meningeal oligodendrogliomatosis without identification of a primary site has been rarely seen.⁴ Rarely oligodendrogliomas have been described as multifocal tumors,and can occur in conjunction with meningiomas and choroid plexus tumors.^1,5,8

Canine oligodendrogliomas are remarkably similar in their morphology and biological behavior to their human counterparts and thus, from a comparative neuro‐oncology viewpoint, are now recognized as the best spontaneous tumor of all species for translational molecular and innovative therapeutic studies, as are most other canine primary CNS tumors. Oligodendrogliomas are very rare in the cat in the spinal cord and brain.^3,4

Neuroimaging

Oligodendrogliomas on MRI may be globular or irregularly shaped, mildly hypointense on unenhanced T1‐weighted images but can be heterogeneously hyperintense on T2‐weighted images (Figure 19.8A).^5,6 Post‐contrast they can be variably enhancing, ranging from none to non‐uniform or with an intense peripheral ring‐enhancement (Figure 19.9A).^5,6 Focal or regional enhancement is often distributed centrally or eccentrically and may have a serpentine outline. There is no correlation of any of their imaging features with tumor grade except that enhancement has been more common in grade III than grade II tumors.^5,6 Intratumoral hemorrhages (detected with T2*‐GRE) and cyst formation may occur. Compared with almost identical MRI features of diffuse astrocytomas, infiltration of the cortex and growth into the adjacent ventricular system are much more likely with oligodendrogliomas (Figure 19.8).

Gross morphology

Oligodendrogliomas are often large, generally with a characteristic grayish‐blue, often gelatinous or mucoid, translucent matrix (Figure 19.8B). On section, they are usually discrete, well demarcated, soft, and gray to pink, may involve the cortex and expand to the gyral surface (Figure 19.8C). Intraventricular growth from local extension is common in the dog and cat. In the cat there also can be extensive local and metastatic invasion of the meninges.³ A primary canine leptomeningeal oligodendroglioma with spinal leptomeningeal oligodendrogliomatosis has been reported.^4,8 Grade III oligodendrogliomas usually have multifocal variegated areas of hemorrhage, yellowish to white areas of necrosis, and gelatinous cystic foci (Figure 19.8C). A dog with both an oligodendroglioma and a separate meningioma has been reported (see Figure 19.12).

Histological features

Oligodendrogliomas usually form dense, patternless sheets of monomorphic cells but can be arranged in long straight or curving cords or in cell clusters (Figures 19.9C and 19.10A). With a short interval (minutes) before fixation, the cells have an irregular hyperchromatic nuclei set in a lightly staining cytoplasm, each with a prominent cytoplasmic border. A perinuclear halo effect is common with delayed fixation and results in the essentially artifactual but classically described gourmet “honeycomb” cell pattern. There is a prominent distinctive capillary bed, often forming an almost lobular pattern. Marked nuclear atypia and occasional mitotic figures are compatible with a grade II oligodendroglioma. However in the human WHO grading system, foci of necrosis and/or microvascular proliferation or >6 mitotic figures/10 HPF are univariate markers necessary for a grade III (anaplastic) oligodendroglioma classification and which occurs in over 90% of all canine tumors (Figures 19.9C and 19.10B). Basophilic staining, mucinous‐like material can be commonly found interstitially and accumulating in large multifocal microcystic lakes (Figure 19.10A). Most grade III tumors have larger, more irregular, and less basophilic nuclei, a denser eosinophilic cytoplasm with scant vacuolization and prominent mitotic figures. The PI can be 2–5% and up to 20% in low‐ and high‐grade tumors, respectively (Figure 19.9F).^1,5,6

The microvascular proliferations consisting of foci of tumor‐derived paracrine secretions of VEGF and PDGF, which induce proliferation of endothelial and smooth muscle cells, respectively, are arranged in long lines or clusters, at both brain–tumor margins and intratumorally (Figure 19.10B).¹⁰ In grade III tumors, there can be dilated thin‐walled vessels containing intraluminal fibrin thrombi associated with areas of necrosis and hemorrhage. The necrotic areas may have a mild peripheral glial cell pseudo‐palisading, but this never approaches the cell density seen with glioblastomas (Figure 19.10B). There is minimal parenchymal reaction, including edema at the tumor margins, but the secondary structures of Scherer (neuronal satellitosis, perivascular and subpial accumulation of individual migrating tumor cells) can be a feature of grade III tumors (Figure 19.10C). Histologically, the edges of the tumor are generally very sharp and discrete. Foci of calcification, which are so common in human tumors, tend to be rare in both grade II and III tumors. Oligodendrogliomas may also grow by extension along or under the leptomeninges and ependymal surfaces respectively.

Associated with intraventricular growth there can be widespread intraventricular metastases, with tumor foci impinging upon the ependymal surface or invading the underlying neuropil away from the primary site. Two dogs have been described without a defined focal primary site, with a pattern of diffuse oligodendrogliomatosis in the spinal cord or in the brainstem meninges, and one with bilateral involvement of the piriform lobes.⁹ Multifocal oligodendrogliomas have been described.⁸ In the cat, there is extensive robust secondary spread within the ventricles and meninges.³ One has been described within the spinal cord.⁴

Intraoperative cytology

With suitable education and experience a provisional diagnosis of an oligodendroglioma or a mixed oligoastrocytoma can be made from intraoperative smears. Most characteristically the cells disperse readily and evenly, they are uniformly round with some minimal eccentrically located eosinophilic cytoplasm (Figure 19.9B). Compared with low‐grade tumors, smears from grade III tumors have more overt mitotic activity, marked nuclear atypia with very coarse chromatin and small multiple nucleoli and individual cell necrosis (Figure 19.9B). Foci of microvascular proliferation are classical determinants of a grade III tumor but are most reliably visualized in histologic sections. Careful analysis of cytospin preparations from CSF also has proved to be useful in clinical studies, with the recognition of exfoliated oligodendroglioma cells in both dog and cat tumors.³

Immunohistochemistry

There are still no reliable or available antibodies for cell‐specific markers for the routine confirmation of a diagnosis in FFPE oligodendrogliomas. The microvascular proliferations diagnostic of grade III tumors are composed of layers of human von Willebrand factor VIII–related antigen and CD31‐immunoreactive endothelial cells. Most of the remaining cells have cytoplasmic immunoreactivity for smooth muscle actin (SMA). Most oligodendrogliomas immunocytochemically overexpress PDGFRα (Figure 19.11).¹⁰ A transcription factor Olig2 can be immunoreactive in nuclei of most tumor cells (80–90%), but this factor is also a consistent marker for astrocytomas or mixed glial tumors (Figure 19.9D). In the spinal cord, confirmation of the diagnosis of oligodendrogliomatosis is largely based on immunoreactivity to Olig2. Canine oligodendrogliomas do not express myelin basic protein or myelin‐associated glycoprotein by immunostaining, although fresh‐frozen tumor tissue will be immunoreactive for galactocerebroside and sometimes for Sox‐10, another transcription factor. A huge number of monoclonal antibodies (mAbs) are available for labeling but most of these are unsuitable for routine diagnostic purposes as they are dependent on more sophisticated fixation methods.

Intratumorally, reactive gemistocytic astrocytes, presumably present as a result of entrapment, can be demonstrated in small numbers immunocytochemically with GFAP. Mini‐gemistocytes which have an eccentric eosinophilic cytoplasm are GFAP‐immunoreactive round cells which have no cytoplasmic processes, and are interpreted as part of the tumor cell phenotypic profile, although they are not included in any grading criteria. GFAP immunoreactivity is common around perivascular areas within the tumor (Figure 19.9E). Occasional synaptophysin (SYN) immunoreactive clusters of cells identifying neuronal differentiation, but of uncertain significance, can be demonstrated. The PI is up to 5% and 20% in well‐differentiated (grade II) and anaplastic (grade III) subtypes, respectively (Figure 19.9F).

Differential diagnosis

The main differential diagnosis that needs to be considered, particularly of a tumor with intraventricular growth and especially within the lateral or third ventricles, is the central neurocytoma (see Figures 19.8C and 19.24A,B). Neurocytomas share surprising close phenotypic patterns and cytology with those of oligodendrogliomas (vide infra), with which it has been confused in people. However, neurocytomas are strongly immunoreactive for SYN, NeuN, NSE, and other neuronal markers, but imunonegative for Olig2, and thus can be reliably differentiated from oligodendrogliomas (see Figure 19.24C,D). In the dog, a clear cell ependymoma also needs to be considered with any provisional oligodendroglial diagnosis. Clear cell ependymomas can be best separated on the basis of their strong uniform cytoplasmic GFAP immunoreactivity and confirmed ultrastructurally by their desmosomal junctions and intermediate filament content (see Figure 19.16A–C).

In the dog, oligoastrocytomas have prominent areas of oligodendroglial differentiation (see Figure 19.13C). Diffuse astrocytomas can be challenging, particularly from stereotactic‐derived biopsy tissue where there is minimal tissue. However, the nuclei of astrocytomas are more elongated and angular compared with those of oligodendroglioma (Figures 19.1F and 19.3A). Some glioblastomas may have small areas of oligodendroglioma‐like differentiation.

Definition, incidence, and sites

Oligoastrocytomas are diffusely infiltrating gliomas composed of a pleomorphic mixture of tumor cells resembling both diffuse astrocytoma and oligodendroglioma phenotypes. These forms are classified as either intermingled (diffuse) or compact (collision) tumors (Figure 19.13B). In people and dogs, up to 90% present as the diffuse type. Their higher incidence in some brachycephalic breeds parallels that of pure gliomas, and mixed gliomas likewise tend to exhibit an increasing incidence with age. Their overall incidence in dogs is up to 5% of all primary nervous system tumors. These tumors arise in the same predilection sites in the cerebral hemispheres as their individual glial cell tumor components, most commonly in the temporal and piriform lobes (Figure 19.13B). One tumor in a young dog has been described with discrete, multifocal distribution involving both cerebral hemispheres.

There is no specific grading scheme for mixed gliomas. The histological criteria used in the individual glioma components also applies (e.g., necrosis, cell density, nuclear atypia, mitotic activity, and microvascular proliferation). Transgenic mouse and stem cell studies confirm the current hypothesis that these tumors arise from one stem cell population able to differentiate into these biphasic cell lines. Very rarely in the dog we have found ependymoma‐like cells replacing the astrocytoma population; such tumors are then classified as oligo‐ependymomas. Two feline spinal cord oligoastrocytomas have been reported.¹

Neuroimaging and gross pathology

Oligoastrocytomas have very similar MRI characteristics to those of grade II oligodendrogliomas and diffuse astrocyomas (Figure 19.13A). Cystic cavitations as interpreted on MRI have been shown to correlate histologically with areas of low cell density of the fibrillary astrocytoma component. Grossly, mixed gliomas may present as a mass demarcated regionally into the gross features of both an astrocytoma and an oligodendroglioma (Figure 19.13B).

Histopathology and immunocytochemistry

Microscopically, these two cell types may appear most commonly as either equally admixed and intermingled (diffuse) or rarely (5–10%), but more easily recognized, juxtaposed into two or more (compact), separate cell clusters of each component – the so‐called collision tumors (Figure 19.13C). The diffuse type is the most diagnostically challenging type because of the ambiguous morphology of both populations. In canine oligoastrocytomas, areas of oligodendroglioma dominate, with up to 30% composed of astrocytomas.² The astrocytic component can be strongly GFAP immunoreactive.

Neoplastic astrocytes also have a distinctive phenotype with a reduced amount of cytoplasm, very thin and wavy processes, and the cells tend to be more dense compared with entrapped but scattered gemistocytic astrocytes (Figure 19.13C). Recognition of GFAP‐immunoreactive mini‐gemistocytes will increase the level of suspicion of an oligodendroglioma. However, it can be very difficult to make this diagnosis or to confirm with immunocytochemistry when confronted with less well‐differentiated cells without typical neoplastic phenotypes. Most canine grade II oligoastrocytomas have a minimal to absent mitotic rate with the PI up to 3%, compared with up to 15% in the much less common grade III tumors. The astrocytoma population can be visualized with GFAP immunoreactivity, often displaying small wavy cell processes, while Olig2 expression can only confirm that both populations are of glial cell origin. Immunocytochemically there is strong expression of PDGFRα in the oligodendroglial cell population.

Differential diagnosis

The main challenge with this tumor is establishing it as a mixed tumor and not as a relatively pure population of either an oligodendroglioma or astrocytoma. Otherwise the same differential considerations apply for each of these tumors as considered previously. As with other gliomas, too few canine and feline cases have been followed to know how they behave clinically.^1,2

Definition, sites, and incidence

Ependymomas are relatively rare tumors that originate from ependymal cells (possibly of radial glial stem cell derivation) which line the ventricular system of the brain and spinal cord (Figures 19.14–19.17).¹ Ependymomas have been sporadically reported in dogs, cats, cattle, and the horse.^2–6 Canine ependymomas occur as a slow‐growing, supra‐ or subtentorial expansile mass, mainly within either a lateral ventricle or less often in the third and fourth ventricles, and rarely within the central canal of the spinal cord.^1,2 They constitute about 3% of all primary canine CNS tumors. Their incidence increases with age and without any gender bias. In cats, a recent series (n = 18) of ependymomas has been described with a mean age of 8.5 years.⁶ Fifteen of these feline ependymomas were located intraventricularly and classified as the same histological subvariants in the human WHO scheme, while the three extraventricular tumors were designated as subependymomas or primary ependymomas.^1,6

Neuroimaging and gross morphology

Ependymomas are generally large, intraventricular, well‐demarcated masses that with MRI are hypointense on T1‐weighted, hyperintense on T2‐weighted, are discreetly circumscribed and with varying degrees of post‐contrast enhancement display a granular heterogeneous profile (Figure 19.15A). Obstructive hydrocephalus may be demonstrated rostral to the tumor site. Peritumoral edema is minimal.^5,7,8

Grossly, they are mostly well demarcated, soft, tan to red, with a smooth texture on cut surface in the dog, more granular in the cat and even more so in the papillary variant in all species (Figures 19.15B and 19.17A).^2,3,5,7 Intratumorally there can be cystic areas, necrosis, and focal hemorrhage. Although growth is usually confined within the ventricular system, ependymomas may infiltrate the adjacent neuropil or meninges. A secondary obstructive hydrocephalus may develop, depending on their location.²

Intraoperative cytology

The dichotomous epithelial and glial features of ependymomas are characteristic (Figure 19.17C). Both cellular and papillary ependymomas have a distinctive appearance due to the formation of a highly branching vasculature with firmly attached palisading tumor cells. These cells have an outer polar location of the nucleus and elongated cytoplasmic attachments radially arranged around blood vessels (Figure 19.17C).¹ Cellular variants display numerous cells packed closed around vessels (Figure 19.17C). Individual cells have long tapered to oblong unipolar cytoplasm with distinctive processes.

Histopathology

In the dog, cellular and papillary ependymomas comprise the two major histological variants, while clear cell ependymomas occur rarely.^2–5,7 Cellular ependymomas are moderately to densely cellular and well vascularized, with a characteristic key feature of nuclear‐free perivascular zones formed by tumor cell processes. These zones can appear fibrillated, are GFAP immunoreactive, and lead to the formation of characteristic perivascular pseudorosettes around a centrally placed blood vessel. These are to be distinguished from true ependymal rosettes that have an empty lumen (Figures 19.17D and 19.18C,D).⁸ Neuroblastomas can have Homer–Wright rosettes.⁸ The tumor cells are also clustered individually without any obvious orientation between these blood vessels. Cell nuclei are round to ovoid with poorly defined cytoplasmic borders between cells. Mitotic figures are rare.

In the other common variant, the papillary ependymoma has papilliform‐like fronds covered on their luminal surface by neoplastic ependymal cells, whose long refractile GFAP‐immunoreactive processes terminate on the underlying vascular stroma.² The third variant is a clear cell ependymoma which occurs mainly in the lateral ventricles of dogs. The tumor cells have round nuclei and empty perinuclear halos and well‐defined cytoplasmic borders resembling oligodendrocytes, although these cells have diagnostically characteristic globular eosinophilic intracytoplasmic inclusions which are strongly and uniformly immunoreactive for GFAP (Figure 19.16A,B).⁷

In contrast, in the cat other histological variants not yet reported in the dog are: subependymoma, tanycytic ependymoma, and primary extraventricular ependymoma.^1,2,6 All these variants exhibit characteristic perivascular pseudorosettes, although true ependymal rosettes are not common (Figure 19.17B). Feline cellular ependymomas are densely cellular, the cells have minimal cytoplasm and darkly staining basophilic nuclei, and have higher numbers of both perivascular pseudorosettes and ependymal rosettes than the canine ependymoma (Figure 19.17B,D). The ependymal lumens sometimes contain cilia whose anchoring blepharoplasts stain as dark blue dots with the phosphotungstic acid hematoxylin (PTAH) stain (Figure 19.17D). Between the ependymal rosettes and the pseudorosette formations there are solid sheets or clusters of cells without any defined pattern. No grading system has been applied to these feline tumors.⁶

An equine myxopapillary ependymoma has been described in the caudal fossa, an unusual site compared with the most common location in the conus medullaris in people.^1,3 In a calf, an ependymoblastoma was diagnosed on the basis of age, the small round cells, and numerous mitotic figures. However, this diagnosis is claimed to be neither precise nor specific and some authors want it abandoned.⁹

As a group, ependymomas are relatively benign cytologically and in dogs are generally classified as grade II. Tumors classified as anaplastic ependymoma grade III exhibit pleomorphism with nuclear atypia, frequent mitoses (>4/10 HPF at 400×), pseudo‐palisading necrosis, and microvascular proliferation.

Immunohistochemistry

Well‐differentiated ependymomas have a uniform and consistent cytoplasmic GFAP immunoreactivity. Vimentin and S100 are also expressed but to a much lesser intensity and extent, while pancytokeratin expression (Lu5, AE1AE3)is variably immunonegative and almost always Olig2 immunonegative. The PI is very low at <1%, which is consistent with their low grade and well‐differentiated morphology. Some authors have claimed that canine ependymomas are mainly GFAP immunonegative, but this has not been our experience, and may just reflect differences in methodology or an incorrect diagnosis. Positive immunoreactivity with GFAP may reflect their radial glial stem cell derivation.¹