Neoplasia of the Nervous System in Animals
Neoplasia of the nervous system has been reported in all domestic animal species. Nervous system tumors have been detected in 1%–3% of necropsies in dogs. In cats, nervous system tumors are less common and are mainly meningiomas and lymphomas. Primary nervous system tumors originate from neuroectodermal, ectodermal, and/or mesodermal cells normally present in (or associated with) the brain, spinal cord, or peripheral nerves. Secondary tumors affecting the nervous system may originate from surrounding structures such as bone and muscle or from hematogenous metastasis of a primary tumor in another organ. Tumor emboli can lodge and grow anywhere in the brain, meninges, choroid plexus, or spinal cord.
Dissemination or metastasis of CNS tumors is rare but may occur via the CSF pathways, especially if the tumors are located close to the subarachnoid space or ventricular cavities (eg, choroid plexus papilloma, ependymoma, medulloblastoma, neuroblastoma, pinealoblastoma), or via a hematogenous route such as the dural sinus, with later development of remote metastasis, most often in the lung. Tumors may also spread by direct extension to surrounding tissues, especially bone. The osseous tentorium may be used as a reference point to localize different areas of the brain within the cranial vault. Thus, tumors in the cerebral hemispheres are often referred to as supratentorial or anterior fossa tumors, while those in the brain stem or cerebellum are called infratentorial or posterior fossa tumors.
Classification of nervous system tumors in animals follows the criteria used for tumors in people and is based primarily on the characteristics of the constituent cell type, its pathologic behavior, topographic pattern, and secondary changes seen within and around the tumor (see Table: Tumors of the Nervous System in Dogs and Cats).
Tumors of the Nervous System in Dogs and Cats
Immunocytochemical studies and imaging techniques may aid classification. Primary tumors typically grow slowly, whereas secondary, highly malignant, metastatic tumors and bone tumors generally progress more rapidly. Many animal tumors have characteristics analogous to corresponding human neoplasms; however, 15%–20% of neuroectodermal tumors (especially gliomas) remain unclassified. Many of these are related topographically to the ventricular system and/or subependymal cell nests. As many as 26% of neuroectodermal brain tumors are undifferentiated, as shown by immunocytochemical staining. Although brain tumors are occasionally reported in animals <1 year old, most are found in mature and aged animals. No sex predilection for nervous system tumors has been identified.
The reported incidence of nervous system neoplasia in animals varies. However, such tumors are reported more often in dogs than in other domestic animals. In one survey, 2.83% of 6,175 dogs examined at necropsy had intracranial neoplasia. In another report, incidence of intracranial neoplasia was 14.5/100,000 dogs at risk and 3.5/100,000 cats at risk. A retrospective study of young dogs (<6 months old) indicated that the three most common sites for neoplasia (in decreasing order) were the hematopoietic system, brain, and skin. Brachycephalic breeds are at increased risk of some neuroectodermal tumors.
In dogs and cats, the brain is a more common site of primary tumors of the nervous system than the spinal cord or peripheral nerves. Meningiomas, gliomas (eg, astrocytomas, oligodendrogliomas), undifferentiated sarcomas, pituitary tumors, and ventricular tumors (eg, choroid plexus papillomas, ependymomas) are commonly reported primary brain tumors in dogs. Previously reported cases of neoplastic reticulosis, gliomatosis, microgliomatosis, malignant histiocytosis, or the malignant form of granulomatous meningoencephalomyelitis are now classified as histiocytic sarcomas or lymphomas. Other primary brain tumors (eg, malformation tumors), tumors of nerve cells (eg, neuroblastoma, ganglioneuroblastoma, and ganglioneuroma), pinealomas, craniopharyngiomas (a suprasellar ectodermal tumor that may destroy the pituitary gland), spongioblastomas (embryonal glioma), and medulloblastomas are rare.
Adult dogs of several brachycephalic breeds—Boxers, English Bulldogs, and Boston Terriers—are often cited as having the highest incidence of brain tumors among domestic animals; glial tumors, including unclassified gliomas, are the most numerous tumors in these breeds. One study of 97 dogs indicated that Golden Retrievers also have a high incidence of brain tumors (especially meningiomas).
Secondary tumors extending into the cranial vault from the nasal sinuses are relatively common in dogs. In some cases, usually those involving caudal nasal tumors, the only clinical signs are neurologic abnormalities such as behavioral changes, circling, paresis, seizures, or visual deficits. Respiratory signs such as epistaxis, nasal discharge, sneezing, dyspnea, stertor, or mouth breathing may develop after neurologic signs or may be absent. Nasal tumor types include adenocarcinoma, anaplastic chondrosarcoma, epidermoid carcinoma, esthesioneuroblastoma, neurofibrosarcoma, neuroendocrine carcinoma, and squamous cell carcinoma. Unlike nasal cavity tumors, tumors that originate in middle or inner ear structures rarely extend into the brain . Metastatic brain tumors are also commonly recognized in dogs, with hemangiosarcoma being the most common metastatic tumor type. In cats, metastases most frequently originate from mammary carcinomas and lymphosarcomas.
Astrocytomas are probably the most common neuroectodermal brain tumor in dogs. They are usually found in adult dogs, but they have been reported in dogs <6 months old. They are common in brachycephalic breeds but can be seen in any breed. Astrocytomas consist of relatively large, protoplasmic-rich cells or smaller cells with many processes. The cells tend to be arranged around blood vessels. There are several variants (eg, anaplastic, fibrillary, gemistocytic, protoplasmic, and pilocytic), most of which stain positively for glial fibrillary acidic protein (GFAP), the chemical subunit of the intracytoplasmic intermediate filaments of astrocytes. Regressive changes found histologically include necrosis, mucinoid degeneration, cyst formation, vascular proliferation (often in the form of glomeruloid nests), and multinucleated giant cells. Hemorrhage is rare.
Malignant astrocytomas display nuclear polymorphism, mitotic figures, and small cells with dense, hyperchromatic nuclei. In one study using CT, astrocytomas and oligodendrogliomas appeared similar to one another, because both tumors had ring-like, irregular enhancement and poorly defined margins. Differentiating oligodendrogliomas from malignant astrocytomas with MRI has been difficult. In some instances, however, MRI is considered superior to CT in defining diffuse leptomeningeal and low-grade cerebral astrocytomas. Astrocytomas are uncommon in cats; in one report of four cats, the tumors invaded the third and lateral ventricles.
Choroid plexus papillomas are common tumors in dogs, with reported frequency similar to that of glioblastomas (~12% of neuroglial tumors). Developmentally, the choroid plexus epithelium differentiates from the primitive medullary epithelium and is related to the ependymal cells. These tumors are reddish, papillary growths that may bleed. Histologically, they are well defined, grow by expansion, and have a granular papillary appearance. Tumor papillae consist of vascular stroma lined by one layer of cuboidal or cylindrical epithelium. Immunocytochemical studies reveal that these tumors express epithelial but not glial differentiation, based on absence of staining with GFAP. Keratin may be expressed from some of these tumors.
In both benign and malignant variants of choroid plexus papillomas, dissemination to other areas of the brain or spinal cord via the CSF pathways may occur after exfoliation. Obstructive hydrocephalus may occur. Meningeal carcinomatosis may follow spread of the tumor in the subarachnoid space. Choroid plexus tumors are seen as well-defined, hyperdense masses with marked, uniform contrast enhancement on CT scans. Marked enhancement, potentially including hemorrhage and mineralization, is also seen with MRI. Choroid plexus papillomas have no apparent predilection for brachycephalic breeds and are rare in cats.
Ependymomas originate from the epithelium lining the ventricles and central canal of the spinal cord. They are rare but have been reported most frequently in brachycephalic breeds. The gray to reddish, soft, lobular masses tend to invade the ventricular system and meninges, which may result in obstructive hydrocephalus. Metastases within the CSF system may be seen. Ependymomas of the fourth ventricle may encircle the brain stem. Both epithelial and fibrillary varieties have been described. Histologically, cells are isomorphic, with pale or transparent cytoplasm and round, chromatin-rich nuclei. Nucleus-free zones around blood vessels are characteristic. Some ependymomas appear hemorrhagic, with mucinoid degenerative changes and cyst formation. Malignant or anaplastic ependymomas have moderate degrees of pleomorphism and necrosis and may merge into glioblastoma multiforme. In one study, only one of nine ependymomas was positive for GFAP. In a CT study of brain tumors, ependymomas had no definitive distinguishing features.
Gangliocytomas are rare intracranial tumors reported in adult dogs of several breeds. Histologic findings include mature, neuronal-like cells with multiple processes, a central nucleus, and a nucleolus. Neuroblast-like immature cells may also be seen, and occasionally, newly formed myelin sheaths. They seem to be seen most often in the cerebellum. Pure gangliocytomas have no glial elements and do not express GFAP. Mineralization and extensive necrosis accompanied by edema and capillary proliferation may also develop.
Suprasellar germ cell tumors are located dorsal to the sella turcica at the base of the brain. They are often intimately associated with the pituitary gland, which may be trapped within or replaced by the germ cell tumor. They are thought to result from extensive migration of germ cells during embryogenesis. Neurologic signs may be acute in onset and may include lethargy; depression; bradycardia; dilated, nonresponsive pupils; ptosis; visual deficits; and blindness. Germ cell tumors may be large—extending from the olfactory peduncles to the pons and pyriform lobes—and may envelop other cranial nerves (eg, nerves III–VII). Histologically, the tumors usually contain a mixture of primitive germ cells, cords resembling hepatocytes, and acini and tubules of tall columnar epithelial cells. They may stain positively for fetoprotein. Affected animals are usually 3–5 years old; Doberman Pinschers may be at higher risk than other breeds. Some germ cell tumors have been misdiagnosed as pituitary tumors or craniopharyngiomas.
Glioblastoma multiforme, considered to be equated with the more malignant forms of astrocytomas, has been reported with varying frequency in dogs. In one study, the incidence was 12% of 215 neuroglial tumors. Most are large and found in the cerebrum. The tumor cells consist of medium-sized, round or fusiform cells with isomorphic nuclei. Some glioblastomas display considerable pleomorphism, with small and large mononucleated and multinucleated cells. They are locally invasive and destructive, well vascularized, and often contain necrotic zones. Glioblastomas sometimes express GFAP and are most common in brachycephalic breeds.
Hamartomas are formed by disorderly overgrowth of tissues normally present at a site. They are focal malformations resembling neoplasms and have been reported only rarely in dogs, usually as a subclinical finding.
Hematogenous metastatic brain tumors commonly originate from extracranial sites. In dogs, they often develop from carcinomas of the mammary glands, thyroid, bronchopulmonary epithelium, kidneys, chemoreceptor cells, nasal mucosa, squamous epithelium of the skin, prostate, pancreas, adrenal cortex, and salivary glands. Brain metastasis from a transmissible venereal tumor has been reported in a 5-year-old male mixed breed dog. Common sarcoma metastases in dogs include fibrosarcomas, hemangiosarcomas, lymphosarcomas, and melanoblastomas. Brain metastases may accompany intramedullary spinal cord metastasis in dogs with lymphosarcomas or hemangiosarcomas. In cats, metastases stem most often from mammary carcinomas or lymphosarcomas. Most CNS lymphomas, especially in dogs, are one part of a multicentric disease, with extensive infiltration of the choroid plexus and leptomeninges a common finding. Neoplastic angioendotheliomatosis in dogs is thought to be an angiotropic lymphoma, possibly of the B-cell line. Extraneural tumor cells sometimes localize in the meninges (eg, meningeal carcinomatosis), often in association with intestinal carcinoma or mammary adenocarcinoma.
Histiocytic sarcomas (previously named malignant histiocytosis or primary/neoplastic reticulosis) are rarely reported in dogs. Proliferation and/or infiltration of neoplastic histiocytes in the basiarachnoidal and ventricular areas (bilateral) is a characteristic feature. These cells may also infiltrate the spinal dura mater, arachnoidal space, leptomeninges, and spinal nerve roots. Histologically, the cells may have characteristic histiocytic morphology but exhibit moderate pleomorphism and numerous mitotic figures.
Intracranial intra-arachnoid cysts have been reported in dogs. These rare malformation tumors seem to develop most often in the quadrigeminal cistern. Of the six dogs in one report, three were <1 year old, four were males, and five of the six weighed <11 kg. One dog had additional developmental anomalies (abnormal corpus callosum and block vertebrae). On CT scans and MRI, the cysts were extra-axial, had sharply defined margins, contained fluid isodense to CSF, and did not show contrast enhancement.
Malformation tumors, including epidermoid and dermoid cysts and teratomas, originate from heterotopic tissue and are rare tumors in dogs. They typically lie close to embryonal lines of closure. Epidermoid and dermoid cysts result from inclusion of epithelial components of embryonal tissue at the time of closure of the neural tube. They reportedly have a predilection for young dogs (eg, 3–24 months old), although cysts have been found in older dogs. They usually involve the cerebellopontine angle, fourth ventricle, or both. Cysts within the fourth ventricle may secondarily compress the medulla oblongata and cerebellum. Some epidermoid cysts are incidental findings at necropsy.
Histologically, epidermoid cysts may have a multilocular structure; most are lined by stratified squamous epithelium and contain keratinaceous debris, desquamated epithelial cells, and occasional inflammatory cells. In contrast, dermoid cysts contain adnexal structures such as hair follicles, sebaceous glands, and sweat glands. Cysts may measure as much as 2.5 cm in diameter. Because of the tumor’s location, dogs may show signs of a pontomedullary syndrome (eg, trigeminal, facial, cerebellar, and/or vestibular dysfunction). Teratomas are well-differentiated germ cell tumors arising from several embryonic germ cell layers.
Medulloblastomas are highly malignant, uncommon neuroectodermal canine tumors that almost always develop in the cerebellum. The tumors tend to bulge into the fourth ventricle, often replacing part of the cerebellar vermis and compressing the midbrain rostrally and the brain stem ventrally. They may infiltrate the meninges, metastasize within the CSF pathways, and cause obstructive hydrocephalus. Histologically, these tumors include sheets of densely packed cells with pale cytoplasm and oval or carrot-shaped nuclei with coarse, granular chromatin. Mitotic figures are common. Regressive changes include pyknosis and karyorrhexis. Although most cases are seen in young dogs, a cerebellar medulloblastoma with multiple differentiation has been described in a 4-year-old Border Collie.
Meningioangiomatosis is a rare, benign malformation of CNS blood vessels, characterized by proliferation of the vessels and spindle-shaped, perivascular meningothelial cells in the cerebral cortex and brain stem of juvenile and adult dogs. The meningothelial cells stain positively for vimentin, which, along with the presence of mucopolysaccharides and collagen among proliferating cells, suggests a mesenchymal and fibroblastic origin.
Meningiomas are extra-axial tumors. They arise from elements of the dura within the cranial and spinal spaces and are the most commonly reported brain tumors in cats. They are also one of the most common intracranial tumors in dogs, with a reported incidence of 30%–39%. In most studies, meningiomas are seen in dogs >7 years old and in cats >9 years old, although they have been seen in young cats (<3 years old) with mucopolysaccharidosis type I and in dogs <6 months old. They are often found in dolichocephalic breeds, especially Golden Retrievers. Canine and feline meningiomas have estrogen, progesterone, and androgen receptors. These usually benign tumors tend to grow slowly under the dura mater, although direct brain invasion has been reported.
Pathologic findings include globular, irregular, lobulated, nodular, ovoid, or plaque-like masses ranging in diameter from a few millimeters to several centimeters. Meningiomas are typically discrete and often are firm, rubbery, and encapsulated. They may contain granular calcifications known as psammoma bodies. In addition, there may be focal or massive calcification of the tumor. A substantial proportion of basal and plaque-like meningiomas involve the floor of the cranial cavity, especially when located near the optic chiasm or suprasellar area. They also commonly are found over the convexities of the cerebral hemispheres, less often in the cerebellopontomedullary region, and infrequently in the retrobulbar space (arising from the optic nerve sheath). In cats, common locations include the tela choroidea of the third ventricle and the supratentorial meninges. Cats also have a higher incidence (17%) of multiple meningiomas. Hyperostosis, a thickening of bone adjacent to the meningioma, may develop, especially in cats.
Meningiomas rarely metastasize outside the brain, but may extend into paranasal regions and lungs or be seen as primary extracranial masses as a result of embryonic displacement of arachnoid cells or meningocytes. Those in extracranial locations differ from intracranial meningiomas primarily in their more aggressive behavior and anaplastic/malignant nature. Meningiomas may be distinguishable from tumors within the brain parenchyma on contrast CT scans by their appearance as broad-based, peripherally located masses. Cystic and edematous meningiomas have been detected using CT scans and MRI. When a dural tail (a linear enhancement of thickened dura mater adjacent to an extra-axial mass) is detected by MRI, a meningioma is the most likely cause.
The histologic classification of canine meningiomas includes angioblastic, fibroblastic, meningothelial or syncytial, psammomatous, and transitional. Papillary and microcystic forms may also be seen. The tumors usually consist of large meningothelial cells or fusiform cells arranged in whorls, nests, islands, or stream-like patterns. Cell boundaries are typically ill defined, and the nuclei contain little chromatin. Canine meningiomas commonly have vimentin intermediate filaments. Regressive changes may include cavernous vascular formations, hemorrhage, hyalinization of connective tissue, and deposits of fat, lipopigments, or cholesterol. Many have evidence of focal necrosis with suppuration. This is the likely cause of the reported predominance of polymorphonuclear cells in CSF in many dogs with meningioma.
A grading system in human patients has recently been adapted for dogs and may predict tumor behavior. Grade I tumors are considered benign, grade II tumors are considered atypical, and grade III tumors are considered malignant.
Most feline epitheliomas are meningotheliomatous or psammomatous, often with cholesterol deposits.
In meningeal sarcomatosis, sarcomas cause diffuse thickening of the meninges; extensive hemorrhages are common. These rare tumors tend to infiltrate nervous tissue and run along blood vessels. Cell types include lymphoid, plasmacytoid, mature plasma cells, immunoblastic cells, and multinucleate giant cells.
Oligodendrogliomas are common tumors in dogs, particularly in brachycephalic breeds. In one report, they comprised 28% of neuroectodermal tumors. These tumors consist of chromatin-rich, densely packed, round cells with perinuclear halos. Most grow by infiltration and destroy invaded tissue. Capillaries tend to proliferate within these tumors, producing glomerulus-like structures. Regressive changes are similar to those seen in astrocytomas. Necrosis and extensive calcification are uncommon. These tumors do not stain with GFAP; in one study, 3 of 11 oligodendrogliomas reacted with myelin-associated glycoprotein, while none reacted with myelin basic protein. Many canine oligodendrogliomas are mixed tumors with areas of astrocytic and, in some cases, ependymal differentiation. The MRI features are similar to those seen with high-grade (malignant) astrocytomas. Oligodendrogliomas are rare in cats.
Pituitary tumors are common in dogs, with an apparent predilection for brachycephalic breeds. They are infrequent in cats. Tumors may be functional or nonfunctional. Either type may cause hypopituitarism by mechanical or functional impairment of remaining pituitary tissue, although this effect is uncommon. Nonfunctional canine pituitary tumors are common and are usually chromophobe adenomas, although adenocarcinomas have also been reported. Functional pituitary tumors associated with the adenohypophysis are typically characterized by pituitary-dependent hyperadrenocorticism (PDH). Of the cases of pituitary Cushing disease, ≥80% are reportedly associated with a pituitary tumor.
In dogs, these tumors may stem from the pars distalis (80%) or the pars intermedia (20%), because both regions contain cells that can produce adrenocorticotropic hormone. The tumors are generally chromophobic microadenomas (<1 cm in diameter) that do not produce neurologic signs. MRI studies suggest that as many as 60% of dogs with PDH and no neurologic signs have pituitary tumors 4–12 mm in diameter.
As many as 50% of dogs with PDH and large chromophobic macroadenomas (>1 cm in diameter on MRI) may not show clinical signs related to an intracranial mass. In one study, seven of eight dogs with pituitary neoplasia that had been treated for PDH for varying periods of time (between 1 and 2 years) developed neurologic signs, including abnormal behavior (eg, head pressing, lethargy, hiding, wandering, pacing, tight circling, and trembling), seizures, and positional nystagmus.
Most pituitary tumors, especially those derived from the pars distalis, tend to grow dorsocaudally because the diaphragma sella is incomplete. Chromophobic canine tumors from the pars intermedia are smaller and less destructive. Dorsal extension of pituitary tumors may lead to compression and obliteration of the infundibulum, ventral portion of the third ventricle, hypothalamus, and thalamus and may eventually impinge on the internal capsule and optic tract. Hypothalamic or median eminence involvement may cause central diabetes insipidus (especially in middle-aged and older dogs with neurologic signs), manifesting as polyuria, polydipsia, and isosthenuria or hyposthenuria. Alteration in water balance results from interference with the synthesis of antidiuretic hormone (ADH) in the supraoptic nucleus or release of ADH into capillaries of the pars nervosa. Although pituitary tumors generally do not lead to visual impairment, acute blindness and dilated, nonresponsive pupils have been noted in seven dogs and one cat with pituitary masses that compressed the optic chiasm.
Approximately 80% of cats diagnosed with Cushing disease have PDH; tumor types include pituitary microadenomas, macroadenomas, and adenocarcinomas. Pituitary acidophil adenomas, especially the large variety, have been associated with acromegaly and nervous system signs (eg, circling, seizures) in cats, accompanied by insulin-resistant diabetes mellitus and high serum growth hormone concentrations.
Histologically, pituitary tumors include polygonal, round, and cylindrical cells arranged in close contact with blood vessels or formed into islands of cells divided by connective tissue. The cell pattern may be uniform, resembling normal pituitary tissue. Many pituitary tumors contain both chromophobic and chromophilic cells. Regressive changes include cyst formation, necrosis, and hemorrhage. MRI with contrast enhancement is extremely helpful to visualize microtumors (3–10 mm in diameter) and macrotumors (≥24 mm) in dogs with PDH, regardless of neurologic signs. MRI and CT scans of pituitary tumors reveal minimal peritumoral edema, uniform contrast enhancement, and well-defined margins; however, tumors <3 mm in diameter may not be visible. Adrenal and pituitary tumors may coexist in dogs with hyperadrenocorticism, complicating test results and making diagnosis and treatment more difficult.
Primary skeletal tumors do not typically cause neurologic signs. Multilobular osteochondroma originates in the flat bones of the skull, usually in older, medium- or large-breed dogs and appears as a firm, fixed mass. It may erode the cranium and compress, rather than infiltrate, underlying brain tissues. Radiographically, the tumor contains nodular or stippled areas of mineralization, resulting in a characteristic “popcorn ball” appearance. Microscopically, the tumor contains multiple lobules of osseous and chondroid tissue. Local recurrence is common in high-grade tumors (78%) and occurs in 30% and 47% of low- and intermediate-grade tumors, respectively. Metastasis frequently occurs (as many as 58%) but usually late in the disease course (>1 year) and also depends on grade, with rates of 75% in high-grade tumors and 60% in intermediate-grade tumors, as opposed to 30% in low-grade tumors. Vertebral osteochondroma is the spinal cord counterpart.
Vascular malformations are considered developmental lesions rather than true neoplasms and are uncommon in both dogs and cats. They may be located in the cingulate gyrus, pyriform-hippocampal area of the temporal lobe, basal ganglia, cerebellum, occipital lobe, or septum pellucidum and fornix and comprise variable combinations of arteries, veins, and capillaries. The vessels tend to be dilated, sinusoidal in shape, and accompanied by hemorrhages.
Spinal cord tumors are relatively common in cats and dogs. They are generally classified according to their relationship with the spinal cord and meninges as extradural, intradural-extramedullary, or intramedullary. Depending on tumor location, any of the four spinal cord syndromes may be anticipated (eg, cervical, cervicothoracic, thoracolumbar, or lumbosacral syndromes). Regardless of type, the mean age of most dogs with spinal tumors is ~6 years, and tumors appear to be more common in medium and large breeds. Cats with lymphosarcoma tend to be younger (mean age of ~3.5 years), possibly because of the infectious etiology (ie, feline leukemia virus) of most cases. However, age alone does not preclude a diagnosis of spinal tumor.
The clinical course for the various tumor types and locations is not clearly defined. In one study, the rate of progression was fastest with intramedullary tumors (1.7 weeks), followed by extradural tumors (3.4 weeks) and intradural-extramedullary tumors (5.7 weeks).
Extradural tumors are found outside the dura mater and cause spinal cord compression. They are the most common spinal tumors in both cats and dogs. The most frequent types of canine spinal cord tumors are primary, malignant bone tumors and tumors metastatic to bone and soft tissue. Primary bone tumors include:
Reports of secondary vertebral tumors in dogs also exist, including:
aortic body tumors
perianal gland carcinoma
Sertoli cell carcinoma
squamous cell carcinoma
transitional cell carcinoma
An extradural ganglioneuroma and its undifferentiated counterpart, ganglioneuroblastoma, have also been reported in dogs.
Primary vertebral tumors are rare in cats, with osteosarcoma being the most frequently reported. Metastatic, extradural spinal cord tumors are unusual in dogs, but extradural lymphosarcoma is the most common spinal tumor in cats. In most cases, these tumors are secondary to lymphosarcoma elsewhere in the body, although primary spinal cord lymphosarcomas have been reported sporadically in dogs. In one study in cats, extraneural involvement was not found in ~50% of the cases, and the tumors were solitary in 22 of 23 cats. A predilection for the thoracic and lumbar vertebral canal was seen, but the tumors may develop in any spinal region. Three of the tumors affected the brachial plexus cervical roots.
Spinal lymphomas in cats may extend over multiple vertebral bodies and involve more than one level of the spinal cord. Leptomeningeal spinal cord involvement is not common in cats. A tumor termed myxoma-myxosarcoma has been described in four dogs. These malignant tumors resembled soft-tissue myxomas, with polygonally shaped cells with gray, vacuolated cytoplasm that stained positive for S-100 protein antibody. The masses were extradural in three cases and intradural-extramedullary in the other.
Intradural-extramedullary tumors are found in the subarachnoid space and are estimated to account for ~35% of all spinal cord tumors. They are most commonly meningiomas or nerve sheath tumors (eg, neurofibromas, neurilemmomas, and schwannomas) that grow into the vertebral canal and compress the spinal cord. Approximately 14% of CNS meningiomas in dogs (but only 4% in cats) reportedly involve the spinal cord. Tumors may be seen in the cervical, lumbar, or thoracic cord regions. In a report of spinal cord tumors in 29 dogs, nerve sheath tumors were the second most common type after vertebral tumors. In another review of canine spinal tumors, 39 of 60 nerve sheath tumors involved the spinal cord. Nerve sheath tumors often affect the brachial plexus.
A primary intradural-extramedullary tumor with a predilection for T10–L2 spinal cord segments in young dogs, particularly retrievers and German Shepherds, has been variously diagnosed as ependymoma, medulloepithelioma, nephroblastoma, or neuroepithelioma. The origin of this tumor is uncertain, and immunocytochemical studies have not supported a neuroectodermal origin. Monoclonal antibody studies suggest it may be a nephroblastoma. Most cases are seen in dogs 5–36 months old, with males and females affected equally. Clinical signs include a thoracolumbar syndrome. CSF is usually normal, although the protein level was increased in one dog. The extramedullary masses are a tan to grayish white color and 1–3 cm long. They are generally found dorsal and lateral to the spinal cord, may entrap the spinal roots, and may be accompanied by areas of hemorrhage and severe spinal cord compression. Histologic findings include solid sheets of ovoid to fusiform cells interspersed with areas of acinar and tubular differentiation, rudimentary glomeruli, and focal squamous metaplasia.
Intramedullary tumors are the least common of the three categories of spinal cord tumors, with a reported frequency of 15%–24%. Primary glial tumors (eg, astrocytoma, choroid plexus papilloma, ependymoma, oligodendroglioma, and undifferentiated sarcoma) are the most commonly diagnosed. Intramedullary spinal cord metastasis is an uncommon complication of systemic malignancy in dogs, and neurologic signs may be the first indication of systemic malignancy. The mean age of affected dogs is ~6 years, any part of the spinal cord may be involved, and there may be accompanying brain metastasis.
Malformation tumors rarely affect the spinal cord. In one report, a 2-year-old, female Rottweiler presenting with a thoracolumbar syndrome had an intramedullary epidermoid cyst. The gray to off-white cyst was ~2 cm long, 1 cm in diameter, and extended from T13 to L2 spinal cord segments. The empty lumen was lined by simple stratified squamous epithelium or, in a few regions, by desquamating keratinized epithelium containing keratohyaline granules. The spinal cord was severely compressed. These cysts may arise from growth of primordial epithelial cells entrapped during closure of the neural tube.
Tumors of cranial and spinal nerves and nerve roots are common in dogs, cattle, and horses but are rarely seen in cats. In one report, peripheral nerve tumors accounted for ~27% of canine nervous system tumors. Differing opinions on the cell of origin have led to confusion over the terminology used to describe these tumors. Whereas schwannoma, neurilemmoma, and neurofibroma are common, interchangeable designations, the term malignant peripheral nerve sheath tumors (MPNST) is recommended because many of these tumors are malignant (based on cytologic criteria), and determining the cell of origin is usually impossible.
Mid to caudal cervical and/or rostral thoracic nerve roots, especially ventral roots, are the most common sites for MPNST. These tumors frequently involve nerves of the brachial plexus, often appearing as bulbous or fusiform thickenings of one or more nerves. They can spread to other nerves once they advance to the common brachial plexus bundle.
The tumors typically result in slow, progressive, unilateral thoracic limb lameness and muscle atrophy, often involving the infraspinatus and supraspinatus muscles. Affected animals may display a unilateral Horner syndrome, pain on leg movement, axillary pain on palpation (an axillary mass may be palpable), and may lick or chew at the foot or carpus of the affected limb. Intradural-extramedullary spinal cord compression is most common with tumors located at the spinal nerve roots, although more peripherally located tumors occasionally may invade the vertebral canal. The trigeminal is the cranial nerve most often affected by MPNST, producing signs of unilateral trigeminal nerve dysfunction (eg, unilateral atrophy of the masseter and temporalis muscles). Brain-stem compression and local vertebral erosion have been reported.
Peripheral nerves may also be affected by other tumor types (eg, giant cell sarcoma with cervical involvement, a malignant tumor of the apocrine sweat glands, and sarcoma extending into the brachial plexus have been described in dogs). Peripheral tumors of neuronal origin, such as ganglioneuromas and their more undifferentiated counterpart, ganglioneuroblastomas, are extremely rare but have caused extradural spinal cord compression in dogs. Sympathetic ganglia are thought to be the source of ganglioneuromas. Lymphosarcomas may involve cranial and spinal nerves and nerve roots in cats and dogs and may extend intracranially. Myelomonocytic neoplasia of the trigeminal nerve and ganglia, leading to a dropped mandible and symmetric atrophy of masticatory muscles, has been reported in dogs. Tumors of the ear canal (eg, ceruminous adenocarcinoma, fibrosarcoma, and squamous cell carcinoma), as well as osteosarcoma of the skull, may affect the facial nerve or one of its branches. Neurofibromas rarely involve the vestibulocochlear nerve. Cranial nerves may be compressed by meningiomas located on the floor of the cranial vault. The vagosympathetic trunk may be compressed by aortic body tumors.
Some of the clinical signs and syndromes associated with various CNS tumors have already been mentioned. Cerebral, hypothalamic/diencephalic, midbrain, cerebellar, pontomedullary, and vestibular syndromes associated with focal discrete intracranial masses might be expected, depending on tumor location. Accurate anatomic localization is possible in many cases, especially in the early stages of tumor growth. However, correlation of clinicopathologic signs with tumor location may be impossible because tumor location may be masked by secondary changes (eg, brain herniation, cerebral edema, hemorrhage, obstructive hydrocephalus, tissue necrosis, and tumor spread within the brain) that independently cause clinical signs. Partial brain herniation may result from increased intracranial pressure and/or shifts in the brain caused by the tumor. Care must be taken to maintain optimal oxygenation and avoid intracranial hypertension during diagnostic tests that involve anesthesia and CSF sampling because of the increased risk of herniation.
Several types of herniation have been described.
Cingulate gyrus herniation under the falx cerebri toward the unaffected hemisphere leads to compression of the opposite cingulate gyrus.
Occipital or temporal lobe herniation (primarily the parahippocampal gyrus) under the tentorium cerebelli (caudal transtentorial herniation) often causes dorsoventral and lateral compression of the midbrain at the rostral colliculi and partial occlusion of the mesencephalic aqueduct. Caudal displacement of the diencephalon and midbrain may also occur. Clinical signs include initial pupillary constriction, often followed by mydriasis, tetraplegia, and coma.
Rostral cerebellar vermis herniation under the tentorium cerebelli (rostral transtentorial herniation) may lead to flattening of the rostral cerebellum, marked compression and rostral displacement of the brain stem, and compression of the temporal cortex. Despite the gross pathology, clinical deficits may be absent.
Cerebellar herniation (especially the caudal lobe of the cerebellar vermis) through the foramen magnum compresses the underlying medulla oblongata and may cause malacia and hemorrhage. Apnea, hypoxia-induced coma, and tetraplegia may be seen. Concurrent foramen magnum and caudal transtentorial herniation may cause dysfunction in both the midbrain and medulla oblongata. Herniation combined with attenuation of the ventricular system, especially at the level of the mesencephalic aqueduct, can create obstructive hydrocephalus. The increased intracranial pressure may lead to ischemic necrosis of the herniated tissue.
Initially, seizures and behavioral changes may be the only abnormalities associated with tumors involving the rostral cerebrum (eg, olfactory and frontal lobes). Lesions of the frontal and prefrontal lobes may result in no clinical signs. Acute blindness may be the initial clinical sign in animals with tumors in the region of the optic chiasm (eg, pituitary tumors, paranasal sinus carcinoma, polycentric lymphosarcoma, and suprasellar germ cell tumors). Papilledema (often bilateral) is thought to result from a generalized increase in intracranial pressure. A variety of causes (eg, multiple, small metastatic masses from extracranial tumors, especially with malignant melanoma and hemangiosarcoma) may lead to multifocal clinical signs associated with CNS tumors.
Other tumors, such as carcinomas (pulmonary or mammary), tend to produce fewer, larger metastases. The cerebrum, hippocampus, and cerebellar cortex are common sites for hematogenous metastases. Extraneural tumor cells sometimes localize in the meninges (eg, meningeal carcinomatosis associated with mammary adenocarcinoma or intestinal carcinoma). Multifocal syndromes may also result from primary CNS tumors in multiple sites, extension of an original tumor to another site, or metastasis via the CSF.
Choroid plexus papillomas and ependymomas tend to obstruct cerebrospinal pathways because of their ventricular orientation, especially when they arise in the fourth ventricle. Neurologic signs associated with ventricular tumors result from the tumor location and the degree of ventricular dilation caused by obstructive hydrocephalus. Clinical signs often are insidious with either of these tumors; the clinical course generally is protracted, ranging from months to years. Extraneural immunoproliferative diseases in dogs and cats (eg, multiple myeloma and macroglobulinemia-associated lymphocytic leukemia) may also result in a range of intermittent cranial neurologic signs, including disorientation, ataxia, intention tremor of the head, visual impairment, circling, and staggering or falling. Intravascular erythrocyte aggregation impairs blood flow in the affected areas and probably leads to the transient signs.
Pituitary tumors are associated with various endocrine signs, including acromegaly, abnormal hair coat, gonadal atrophy, polydipsia, polyuria, and obesity. . Behavioral changes, circling, paresis, seizures, or visual deficits may result from extension of primary nasal cavity tumors into the cranial vault. Respiratory signs, such as dyspnea, epistaxis, nasal discharge, sneezing, stertor, or mouth breathing, may follow neurologic signs or may not occur at all.
A variety of diagnostic imaging aids, including plain-film radiography, contrast radiography (eg, myelography), and specialized radiographic techniques such as radionuclide imaging (scintigraphy), CT scans, and MRI are used to diagnose nervous system tumors. These techniques provide information (eg, axial origin, location, shape, pattern of growth, and edema) that can be important when determining prognosis, therapy, and outcome. Bone neoplasia may be observed with plain-film radiography. Intracranial tumors are better evaluated with MRI. Some indices of malignancy (eg, edema, extension of growth across the midline, poor margin definition, and tissue invasion) have been defined using MRI, and many tumor types can be presumptively diagnosed based on location, appearance, and contrast-enhancement patterns. Caution must be exercised, however, because presumptive diagnoses made after imaging are found to be incorrect in ~30% of patients after a histopathologic diagnosis is obtained.
Signs of extradural, intradural-extramedullary, and intramedullary tumors vary on myelography. Extradural lesions are located outside the dura mater, resulting in attenuation of the dural tube and spinal cord. Deflection of the contrast column away from the vertebral canal, resulting in a widened epidural space, confirms an extradural lesion. Intramedullary-extramedullary lesions develop in the subarachnoid space, where they act as wedges, displacing the dura mater toward the bony vertebral canal and the spinal cord toward the contralateral vertebral canal. Contrast material abuts the cranial and caudal margins of the tumor, resulting in a characteristic cup or golf tee appearance. In contrast, intramedullary tumors displace the spinal cord material from within, enlarging the circumference of the spinal cord and attenuating the contrast material in the subarachnoid space surrounding the tumor.
Results from one study suggest that CT is better than survey radiographs to visualize bony changes associated with extradural lesions but that myelography is better than CT to classify spinal cord lesions. In another canine study, MRI was used to determine tumor location in all dogs and bone infiltration in all but one. Localization of tumors in the intradural-extramedullary space was not always possible, however. Myelographic interpretation of intramedullary spinal cord metastasis may be difficult; intramedullary tumors must be differentiated from hemorrhage and spinal cord edema. Classically, myelograms of intramedullary masses reveal widening of the spinal cord shadow and tapering and attenuation of contrast in both lateral and ventrodorsal views.
Electrodiagnostic techniques (eg, electromyography, nerve conduction velocity determination), in conjunction with myelography and imaging techniques, can facilitate diagnosis of peripheral nerve tumors. Myelograms reportedly often are negative in animals with cervical MPNST.
Analysis of CSF may reveal moderate increases in total protein content, total white cell count, and CSF pressure. There is a low frequency of tumor cells in CSF from animals with brain or spinal cord neoplasia, but malignant cells have been reported in dogs and cats with intracranial and spinal cord (extradural and intramedullary) lymphosarcomas.
Palliative care for patients with brain tumors centers on controlling seizures, relieving intracranial pressure and inflammation, and minimizing pain. Survival times are generally short (a few days to a few months) with this approach.
The prognosis for animals with nervous system tumors is generally guarded to poor but depends on the extent of tissue damage, tumor location, surgical accessibility, and rate of tumor growth. Recent improvements in treatment have centered mainly on surgical resection, radiation therapy, and chemotherapy, based on more accurate tumor localization and identification using imaging techniques, such as CT scans and MRI. Better identification and characterization of tumors from tissue biopsies obtained via stereotactically guided biopsy devices may lead to additional improvement.
Although success rates for different tumor types and locations are not currently known, cerebral tumors (including meningiomas and ependymomas) without brainstem signs appear to have the best prognosis, especially in cats. Radiation therapy may be the most successful treatment for a range of intracranial tumors and, if surgery is performed, postoperative radiation therapy may prolong survival times. Radiation therapy is beneficial for treatment of inoperable tumors and may be better than surgery for dogs with infiltrative masses.
A retrospective study of 86 dogs with brain tumors showed that dogs treated with 60Co radiation, with or without other combinations of therapy, lived significantly longer than dogs that underwent surgery (some with 125I implants) or dogs that received symptomatic treatment. Dogs with a solitary site of involvement had a better prognosis. The transition to more conformal and stereotactic radiation approaches allows for good outcomes.
Longterm control of primary brain tumors using cytotoxic chemotherapy alone is guarded to poor. A study of 71 dogs with intracranial space-occupying masses did not show survival improvement with chloroethyl-cyclohexyl-nitrosourea (CCNU), but specific tumor types may respond differently. In one study, 40 dogs with presumptive glioma survived a median of 138 days when given CCNU. Corticosteroids alone or in conjunction with other treatments may relieve signs by reducing edema near the tumor and by causing temporary regression of lymphoid and reticulohistiocytic tumors.
The treatment of choice for meningioma in cats is surgery, because these tumors are usually removable in toto, with postoperative survival times preaching a median of ~2 years. Recurrence is possible, with reports of up to 20% and with a median disease-free interval of 9 months; however, second surgical resections are also feasible. In dogs, the ability to completely resect meningiomas is more limited, because tissue invasion is more frequent. The use of surgical aspirator devices and intraoperative ultrasound or endoscopic imaging may improve the surgeon's ability to perform complete removal.
Recent reports of dogs with tumors removed by a surgical aspirator and/or endoscopic-assisted removal yielded median survival times of >3–5 years. In earlier reports, surgical resection alone resulted in median survival times of ~200 days. Postoperative radiation therapy appears beneficial in some studies, with median survival times increasing by ~1 year over surgery alone.
Radiation therapy as a sole treatment, either in standard fractionated courses (usually throughout 3–4 weeks) or in stereotactic radiosurgery (SRS) approaches (usually one to four treatments), has also been attempted. Success rates are difficult to determine, because confirmation of tumor type is rarely performed. Addition of cytotoxic drugs (most commonly hydroxyurea or CCNU) postoperatively or at recurrence may lengthen survival time. In one report of 30 cases of canine infratentorial brain tumors treated with conformal radiation, median survival was approximately two years. Several reports of SRS have demonstrated survival of 500–660 days in dogs with presumptive meningiomas. Cats with pituitary tumors appear to respond well to SRS, with >50 cats with acromegaly surviving >1,000 days, with 95% having decreased insulin requirements and approximately 1/3 achieving diabetic remission, either temporarily or permanently. Dogs with pituitary tumors can also respond well to radiation, with median survival times ranging from 1–4 years.
Astrocytic tumors/gliomas are usually not treated surgically because of location but may be treated with radiation therapy, with reported survival times of 6–11 months. Additionally, newer drugs, such as temozoloamide, which has shown some promise in people, may have some use in the treatment of these tumors in dogs. However, in one study the addition of temozolamide did not improve survival over stereotactic radiotherapy alone.
Metastatic brain lesions are usually treated palliatively, with a combination of medical therapy, radiation, and/or chemotherapy. More invasive treatments, such as surgery, should be reserved for animals in which the primary tumor is well controlled and no other systemic metastases can be documented.
Most extradural spinal tumors are primary bone tumors, and removal often causes decreased spinal stability, pathologic fractures, or spinal subluxation. In a study of canine malignant extradural tumors, postsurgical survival times were short. A report of 20 vertebral tumors (primary or metastatic fibrosarcomas or osteosarcomas) in dogs treated with combinations of surgery, radiation, and chemotherapy supports a guarded prognosis for dogs with vertebral neoplasia. Median survival time was 135 days, with a range of 15–600 days. Survival time after surgical resection of spinal lymphoma and myxosarcoma in dogs was 560–1,080 days in another report, although some dogs received postsurgical radiotherapy and chemotherapy. SRS for vertebral osteosarcomas yielded short survival times as well, with a median of 139 days.
Methods recommended to treat spinal lymphosarcoma in cats include focal radiotherapy, surgical cytoreduction, and systemic chemotherapy, including L-asparaginase, cyclophosphamide, vincristine, and prednisone. Longterm results are poor, partly associated with a positive feline leukemia virus status in these patients.
Animals with MPNST have a generally poor prognosis, because only a small percentage of these tumors can be completely resected, and their recurrence rate is high. Metastasis, often to the lungs, is another complication. Early diagnosis of MPNST may lead to better results. Mean survival of 180 days after surgical resection was reported in one study. Many intradural-extramedullary tumors (eg, lipomas and meningiomas) can be successfully removed, with long postsurgical survival. However, intradural-extramedullary tumors that 1) involve spinal cord segments of an intumescence, 2) are ventrally located, or 3) invade adjacent neural parenchyma have a poor prognosis.
Surgical resection is rarely possible for intramedullary masses. However, there are successful reports of removal of a thoracolumbar intramedullary ependymoma and a tumor resembling a nephroblastoma (by exploratory laminectomy, followed by durotomy and myelotomy). Prognosis for dogs with intramedullary spinal cord metastasis is poor because of the frequent presence of disseminated disease, although corticosteroid therapy may lead to temporary improvement.
Peripheral nerve and nerve root tumors can be successfully resected but may necessitate removal of the affected nerve and nerve root. If atrophy of all muscle groups is extreme—as may develop with tumors involving multiple nerves of the brachial plexus—or if more than one root is involved, complete amputation of the limb may be required. Recurrence is common after resection of peripheral tumors, with average time to recurrence of 5 months in one report. Longterm survival times (18–42 months) have been reported. Even untreated, dogs with trigeminal nerve tumors can have prolonged survival times (as much as 21 months in seven dogs). In 45 cats, median survival time was 21.5 months, with a 20% local recurrence rate. SRS has not appreciably increased control or improved clinical signs in these patients.
Creation of an NCI comparative brain tumor consortium: informing the translation of new knowledge from canine to human brain tumor patients. LeBlanc AK, Mazcko C, Brown DE, Koehler JW, Miller AD, Miller CR, Bentley RT, Packer RA, Breen M, Boudreau CE, Levine JM, Simpson RM, Halsey C, Kisseberth W, Rossmeisl JH Jr, Dickinson PJ, Fan TM, Corps K, Aldape K, Puduvalli V, Pluhar GE, Gilbert MR. Neuro Oncol. 2016 Sep;18(9):1209-18. doi: 10.1093/neuonc/now051. Epub 2016 May 14