CNS NEOPLASIA Joe N.

Kornegay, DVM, PhD, ACVIM (Neurology) University of North Carolina-Chapel Hill School of Medicine Departments of Pathology and Laboratory Medicine and Neurology Chapel Hill, NC 27599-7525 Primary Objectives: 1. Know the breed and age predilection, the gross morphologic features, the typical location, and the biologic behavior of the following CNS neoplasms of dogs: a. b. c. d. Astrocytoma Oligodendroglioma Choroid plexus papilloma Meningioma

2. Know the gross morphologic features, typical location, and possible origin of equine cholesteatomas. Secondary Objectives: 1. Know potential secondary effects of intracranial neoplasms.

Primary intracranial neoplasms are fairly common in dogs but occur infrequently in other domestic animal species. Most of these tumors develop as solitary masses that grow primarily by expansion and seldom metastasize to points either within or outside the central nervous system. That these are biologic features of a benign neoplasm is ironic, in that brain tumors are among the most catastrophic of all illnesses. Nevertheless, this course of growth does account for the typically insidious onset and progression of clinical signs resulting from most intracranial neoplasms. Occasional variation from this clinical pattern also may be explained by the tumors biologic behavior. Dedifferentiation (anaplasia) of cells composing the tumor generally is associated with rapid growth, local invasiveness and an increased likelihood of metastasis. Tumors fulfilling these criteria are malignant and cause neurologic dysfunction that is both acute in onset and rapidly progressive. This table lists the intracranial neoplasms of dogs and cats. For the most part, the data were collected from canine cases. As a general rule, the cells of the tumor will look like the cell of origin astrocytoma cells look like astrocytes. Makes sense, doesnt it?

Central Nervous System Neoplasms of Dogs and Cats

Tumor Type Incidence (Dogs) Common Breed Predilection (Dogs) Brachycephalic Age Predilection Old Gross Morphologic Features Solid, gray-white, poorly demarcated Friable, red poorly demarcated, hemorrhage Papillary, gray-white to red, well demarcated Solid, gray-white, multilobulated, well demarcated Poorly demarcated Gray-white to red, well demarcated, hemorrhage, necrosis Solid, gray-white to red, poorly demarcated, hemorrhage, necrosis Soft, bulging, gray-red, well demarcated Histologic Features Location Biologic Behavior Benign

Astrocytoma

Oligodendroglioma Choroid Plexus Papilloma Meningioma

Common Common

Brachycephalic None

Old Middle age to old Old

Variable depending on cell origin: Protoplasmic, fibrillary, gemistocytic, pilocytic Small hyperchromatic nuclei, perinuclear halos Papilliform, resembles choroid plexus Variable: endotheliomatous, fibromatous

Cerebrum, thalamus

Cerebrum Cerebellopontine angle, third and fourth ventricles Cerebrum (dogs and cats), cerebellum and spinal cord (dogs) Cerebrum, brain stem Pituitary, third ventricle, thalamus Cerebrum, thalamus

Ventricular invasion Benign

Common

Dolichocephalic

Benign

Reticulosis Pituitary Adenoma

Common Common

None Brachycephalic

Middle age to old Old

Variable: granulomatous, neoplastic, microgliomatosis Adenomatous

Locally invasive Locally invasive Locally invasive Locally invasive, ventricular invasion Ventricular invasion, CSF metastasis Benign

Glioblastoma

Infrequent

Brachycephalic

Old

Cellular pleomorphism, hemorrhage, necrosis Small hyperchromatic nuclei, rosettes and pseudorosettes

Ependymoma

Infrequent

None

Middle age to old

Lateral ventricle, spinal cord

Medulloblastoma

Infrequent

None

Young to middle age

Soft, bulging, gray-red, well demarcated

Small hyperchromatic nuclei, pseudorosettes

Cerebellum

Epidermoid, dermoid cyst Metastatic

Infrequent

None

Young

Soft, caseous, graywhite, well demarcated Variable depending on primary; usually solid, well demarcated

Cyst, squamous epithelium, keratin Variable: sarcoma, carcinoma, melanoma

Common

None

Middle age to old

Cerebellopontine angle, fourth ventricle Cerebrum

Variable

Advance Slides 1 and 2

Slide 1 is a photograph of a transverse section of thalamus from a twelve-year-old Boston Terrier dog with neurologic dysfunction referable to the right forebrain of four weeks duration. The right thalamus contains a gray-white, homogeneous mass. Do you see it? Now look at your chart and see which of the tumors is most consistent with these features. Lets see - an older brachycephalic breed with a gray-white thalamic tumor. Sounds like an astrocytoma, doesnt it? Of course, youd have to have your suspicion confirmed by a pathologist, but in this case at least, youd be right. Slide 2 is a photomicrograph of a glial fibrillary acidic protein (GFAP) stain showing the characteristic positive yellow-brown stain seen with glial tumors. This was an astrocytoma.

Advance Slides 3 and 4

Slide 3 is a photograph of a series of transverse sections of brain from a nine-year-old Boston Terrier dog with cervical hyperesthesia and vague neurologic dysfunction referable to the brain-stem. We looked at a photograph of one of these sections earlier when we talked about hydrocephalus. Recall that the mesencephalic aqueduct was partially occluded, resulting in obstructive hydrocephalus. In the other sections here, you can see a portion of the tumor. Notice the red-black mass in the fourth ventricle. Think about this one and check the chart again. I think youll find that its features are compatible with an oligodendroglioma with one exception. The brain stem is not a typical site for this tumor. However, on histologic evaluation, it was an oligodendroglioma. Note in Slide 4 the characteristic fried egg appearance of oligodendroglioma tymor cells, i. e. a central round nucleus surrounded by a clear space (this space has been shown to be an artifact of processing).

Advance Slides 5 and 6

Slide 5 is a photograph of a transverse section of brain at the medulla oblongata from an eight-year-old Irish Setter dog with progressive neurologic dysfunction referable to a left central vestibular lesion of eight weeks duration. A large, pedunculated, well-demarcated mass compresses the left medulla oblongata and cerebellum. Again, have a look at the table. What do you think? Yes, this was a choroid plexus papilloma. In Slide 6, you see the characteristic microscopic appearance of an epithelial tumor, fronds of tissue containing central vessels and lined peripherally by epithelial cells mirroring the appearance of normal choroid plexus.

Advance Slide 7 This slide illustrates another characteristic site for choroids plexus papillomas. Note the tan mass within the third ventricle. Some such tumors will cause obstructive hydrocephalus (not well appreciated here).

Advance Slide 8 and 9

Slide 8 is a photograph of a transverse section of brain at the medulla-oblongata from a seven-year-old English Sheepdog with neurologic dysfunction referable to the brain stem of six months duration. A large, well-demarcated mass compresses the medulla oblongata. This one, again, is pretty straightforward. It was a meningioma. Meningiomas have various histologic patterns (meningothelial, fibroblastic, transitional, psammomatous, and angiomatous). One common feature seen here in Slide 9 is a whorling pattern of mesenchymal cells. It is not clear that pathologic definition of these types has any clinical significance.

Advance Slide 10 This slide illustrates characteristic features of the meningothelial meningioma, clusters or sheets of polygonal cells with prominent nuclei and nucleoli.

Advance Slide 11 Large cysts develop in some dogs and cats with meningiomas. An example from an affected dog is illustrated in these T1-weighted MRI images with (bottom) and without (top) gadolinium-DTPA enhancement. Note that portions of the tumor at the edge of the cyst enhance in the lower image

Advance Slides 12, 13, 14, and 15 Mechanisms to account for cystic lesions in meningiomas are poorly understood. Infarction could contribute. Note apparent necrosis of tumor cells in Slide 12, with marked congestion in Slide 13. However, others have speculated that tumor cells may become vacuolated, with gradual merging of affected cells leading to cysts. Tumor cell vacuolation is seen in Slide 14. Cells lining the cyst are evident in Slide 15.

Advance Slides 16 and 17 Meningiomas may occur within the ventricular system. Tumors arise from the tela choroidea of the third ventricle of cats relatively commonly. A case is illustrated in this gadolinium-DTPA-enhanced MRI and transverse section of brain. There is associated obstructive hydrocephalus.

Advance Slide 18 and 19

In Slide 18, the brain from a 1-year-old mixed breed dog with signs of cerebellar disease has been transected at the junction of the pons and midbrain. We are looking from rostral to caudal at the pons and cerebellum. Note that a large mass compresses the pons. The dogs young age and involvement of the cerebellum suggest that this tumor is a medulloblastoma. This was confirmed microscopically. Cells with hyperchromatic, rod (carrot) shaped nuclei that characterize this tumor type are seen in slide 19.

Advance Slides 20 and 21 Glioblastoma multiforme (GBM) is an anaplastic, primary brain neoplasm that occurs relatively commonly in humans but is rare in animals. Tumor cells may theoretically show differentiation towards any of the primary glial tumor types. As an example, there is a continuum between anaplastic astrocytomas and GBMs. Hemorrhage and necrosis are commonly seen. A GBM that had cellular differentiation that included multinuclear cells is seen in the ventral midbrain here.

Advance Slide 22

Most types of extracranial neoplasms (melanomas, hemangiosarcomas, carcinomas, etc) occasionally metastasize to the brain or spinal cord. Slide 22 is a transverse section of brain at the level of the thalamus from a 10-year-old, mixed breed dog with acute neurologic function. Multiple black foci typical of metastatic malignant melanoma are seen. Secondary brain tumors usually are associated with acute, progressive neurologic dysfunction referable to the site of metastasis. As the primary tumor often is subclinical, neurologic dysfunction may be the initial clinical sign. Nevertheless, aspiration or biopsy of unexplained dermal or abdominal masses can provide insight regarding the underlying disease process.

Advance Slides 23 and 24 Transverse sections of brain from a dog with a large mammary carcinoma that metastasized to multiple sites in the brain are shown in Slides 23 and 24. Note the large mass at the right cerebellopontine angle in Slide 23 and the smaller lesion ventral and to the right of the mesencephalic aqueduct in Slide 24.

Advance Slide 25

The brain may also be affected secondarily by tumors that arise from adjacent structures such as the skull or pituitary gland. This is a sagittal section of brain from a dog with a pituitary adenoma that has compressed and actually invaded the thalamus. What else do you see here? What about the black material? That is hemorrhage. The clinical effects of intracranial neoplasms are due primarily to compression of adjacent tissue. However, secondary effects may be equally detrimental. Brain tumors tend to disrupt the blood-brain barrier resulting in vasogenic edema, can obstruct CSF outflow resulting in increased intracranial pressure and hydrocephalus, and also may cause vessel wall necrosis and associated hemorrhage as we see here. Note that the caudal cerebellar vermis contains hemorrhage and has undergone necrosis subsequent to herniation through the foramen magnum (well discuss brain herniation in the next section).

Advance Slides 26 and 27

Slides 26 and 27 are photographs of brain from an adult horse. Notice the mass in the lateral ventricle. Its been hemisected in Slide 27. Describe it. Well, its a solid, spherical, tan to green mass with some evidence of hemorrhage. This is a cholesteatoma. Its really not a neoplasm but instead, on microscopic examination, consists largely of cholesterol clefts and associated granulomatous inflammation. They are fairly common in older horses and may represent a chronic reaction to hemorrhage. Choleastomas typically occur in the lateral ventricles and may obstruct CSF outflow leading to hydrocephalus.

Advance Slides 28 and 29

Lets transition from brain to spinal cord tumors. Slide 28 is a series of transverse spinal cord sections from a 10-year-old, mixed breed dog with progressive paraparesis On myelography, there was an intramedullary pattern in the caudal thoracic spinal cord. Note that the dorsal spinal cord is effaced by a poorly defined mass with a focus of hemorrhage. A microscopic transverse section is seen in Slide 29.

Advance Slides 30 and 31 The tumor was shown to be an ependymoma on microscopic examination. Note in Slide 30 one of the characteristic microscopic features of ependymomas - columnar cells arranged around a central lumen to form a rosette. Slide 31 illustrates a pseudorosette - columnar cells arranged around a vessel. Ependymoma and astrocytoma are the most common primary spinal cord tumors of dogs.

Advance Slide 32 Another primary spinal cord tumor of dogs has features similar to those of ependymoma. Various names have been used, with neuroepithelioma perhaps being used most commonly. This tumor tends to occur in the intradural-extramedullary space of young dogs. Studies suggest that the tumor may arise from embryonal nephroblasts.

Advance Slides 33 and 34 Slide 33 is a gadolinium-DTPA-enhanced T1-weighted MRI image from a dog with neuroepithelioma. Note that much of the spinal cord has been replaced or compressed by an enhancing lesion that is most pronounced on the right side. The lesion is seen at surgery after a durotomy has been performed in Slide 34.

Advance Slide 35 Nests of epithelial cells that characterize neuroepitheliomas are seen in the toluidine bluestained section in Slide 35. A single well-defined acinus is present towards the upper-left corner.

Advance Slide 36

This is a photograph of a series of transverse sections of spinal cord (cranial section at upper left; caudal section at lower right) from a seven-year-old Collie with progressive paraparesis. The central portion of the cord at the point of greatest spinal cord involvement has been replaced by a black, well-circumscribed mass. Any ideas as to what this one is? Its not a primary CNS tumor. What else could it be? Yes, as with the tumor affecting the brain that we saw earlier, this was a metastatic malignant melanoma. The primary tumor was a dermal malignant melanoma that metastasized to the spinal cord.

Advance Slides 37 and 38 Lymphosarcoma affects the spinal cord of numerous animal species, most notably dogs, cats, and cattle. Affected cats most commonly have multicentric lymphosarcoma, suggesting that the spinal lesion is metastatic. However, some cats have strict neurologic involvement. Spinal tumors may develop from small islands of lymphoid tissue within the epidural or subarachnoid spaces and compress or directly invade neural tissue. Tumors in cats and cattle are associated with the feline leukemia virus and the bovine leucosis virus, respectively. Most tumors in cats are located in the epidural space but some may extend to the intradural space and/or invade the nerve roots or spinal cord. These are photomicrographs of spinal cord from a cat with progressive tetraparesis. Note the densely cellular mass compressing the spinal cord in Slide 37. In Slide 38, you can see the cell type that composes most of the tumor. You probably recognize these cells as immature neoplastic lymphocytes.

Advance Slides 39 and 40

Nerve roots or peripheral nerves may be involved primarily or secondarily by neoplasms. Primary tumors include neurofibroma (-fibrosarcoma) and Schwannoma. Neurofibromas originate from connective tissue cells of the nerve sheath and Schwannomas from Schwann cells. They are distinguished histologically because the Schwannoma is encapsulated and distinct from the nerve and the neurofibroma is nonencapsulated and indistinct from the nerve. For our purposes, they will be considered together under the term nerve sheath tumor. Most nerve sheath tumors in the cervical area originate peripherally and only later extend intradurally, whereas thoracolumbar tumors usually begin intradurally. In either case, tumors may eventually involve other roots or nerves. Slides 39 and 40 show characteristic myelographic and pathologic features of an intradural-extramedullary nerve sheath tumor.

Advance Slide 41 Slide 41 shows a resected nerve sheath tumor that arose from the ventral root and extended subdurally. Note the dorsal root ganglion at the top of the resected mass.

Advance Slides 42 and 43

A nerve sheath tumor involving multiple nerves of the brachial plexus in a dog is seen at surgery in Slide 42 and after partial resection in Slide 43.

Advance Slide 44

Peripheral nerves and nerve roots also may be involved secondarily by a variety of neoplasms. Meningiomas originating at the outfolding of meninges around the nerve roots may compress or invade the root. Bony and soft tissue tumors also may secondarily compress nerve roots or peripheral nerves. In cats, lymphosarcoma sometimes involves peripheral nerves or nerve roots. This is particularly true at the brachial intumescence. A characteristic tumor that arose within the brachial plexus of a cat and extended to the subdural space (note the discoloration) is seen here.

Advance Slide 45 Another case in which nerve roots of a cat were directly invaded by lymphosarcoma is seen in Slide 45.

Advance Slide 46 Lymphosarcoma may also affect peripheral nerves. Lesions may be either primary or secondary. A cat in which the sciatic nerve was affected by a primary dermal lesion is seen here. Note the mass overlying the right hemipelvis.

Advance Slides 47 and 48 Characteristic immature lymphocytes were seen on evaluation of an aspirate.

Advance Slides 49 and 50 Involvement of the cavernous sinus by lymphosarcoma in a dog is illustrated in Slides 49 and 50. The pituitary and cranial nerves III, IV, V, and VI were affected (cavernous sinus syndrome).