Canine Cancer: Intracranial Neoplasia

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Description

There is not enough data supporting the incidence of brain tumors in dogs. But intracranial neoplasms appear to affect dogs more than any other domestic species. According to a report, 14.5 per 100,000 of the population are at a risk of contracting the disease. There is a broad spectrum of tumors that occur in the intracranial cavity of dogs. Intracranial neoplasms can be divided into primary and secondary brain tumors.

Primary brain tumors arise from the brain, spinal cord, and associated tissues -collectively known as the central nervous system (CNS). Primary brain tumors are categorized as benign (noncancerous) or malignant (cancerous). They are usually solitary, but multiple primary lesions have been reported. Primary brain tumors include meningioma, glioma, choroid plexus papilloma, pituitary adenoma or adenocarcinoma and others. Multiple meningiomas and cerebrospinal fluid (CSF, it is a clear bodily fluid in which the brain floats) metastases of medulloblastoma (it is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa) or choroid plexus carcinoma have been reported to occur in dogs. Extracranial (upper portion of the skull that protects the brain) metastases of primary brain meningiomas have been reported. They are usually slow growing because the brain is contained within the calvaria (roof of the skull). But they may have devastating effects. When the tumors grow slowly, they compress the brain gradually. The impact may not be palpable in this case, since our brain has a compensatory mechanism which helps it to adapt itself to the accentuating pressure. But when the mechanisms get exhausted, clinical signs appear.

The classification of the tumors of the central nervous system (CNS) is based on the traits of the constituent cell type, pathologic behavior, topographic pattern and secondary changes present within and surrounding the tumor. The ones that originate from the lymphoreticular cells (collective term for cells of the immune system that consist of the macrophages and the monocytes) have been categorized into reticulosis (abnormal increase in reticuloendothelial cells [cells of the immune system]) or histiocytic lymphoma. Morphologically, these are heterogeneous. They have been further classified on the basis of the infiltrativeness of reticulohistiocytic cells (B cell lymphoid tumors) around the vessels with different patterns of reticulin production (scleroprotein responsible for maintaining the structural integrity of most organs) combined with inflammatory cells of varying populations. The inflammatory sub-type is a part of the broad spectrum of granulomatous meningoencephalomyelitis (GME, it is a sporadic inflammatory disease of the central nervous system). T cell, B cell and histiocytic sarcoma fall within this category.

Glial neoplasms have been broadly classified into various categories based on their variable morphology or appearance. Since 1990s, pathologists have been trying to establish that in addition to monocytic gliomas there are neoplasms comprising a mixture of two or more neoplastic glial cell types.

Due to the anaplastic (less differentiated) nature of embryonal tumors, they have been consolidated under the single term- primitive neurorectodermal tumors (PNETs). It is believed that all embryonal tumors stem from a germinal neuroepithelial cell (sub-type of stem cells) that can differentiate along a number of neurorectodermal cell lines (start of a tissue that covers body surface. It differentiates to form the nervous system and the epidermis). They are usually malignant in nature.

Secondary brain tumors represent metastasis of a tumor to the brain from any other part of the body. The most widely seen secondary tumors of dogs include local extension of nasal adenocarcinoma, metastases from mammary, prostatic or pulmonary adenocarcinoma, metastases from hemangiosarcoma and extension of pituitary adenoma or carcinoma. These tumors have a very poor prognosis, since they have traveled through the body depositing clusters of abnormal tissues in their course. Nerve sheath lesions that originate from cranial nerves like the oculomotor nerve (controls most of the eye movements) and the trigeminal nerve (responsible for sensation in the face) may also occur in dogs. Skull lesions that affect the brain by local extension include osteosarcoma (most common type of primary malignant bone tumor), chondrosarcoma (type of bone cancer) and multilobular osteochondrosarcoma (uncommon tumor that affects the skull).

Although brain tumors can affect any breed at any age, they are most frequent in older dogs. Breeds over 5 years of age are highly predisposed. Certain breeds also have relatively higher incidence. Glial cell tumors and pituitary tumors are most common in brachycephalic (dogs with short, broad heads) breeds, while meningiomas are most frequently seen in dolicocephalic (dogs with long narrow skull) breeds. Canine breeds that probably have the highest incidence include Boxer, Golden Retriever, Doberman pinscher, Scottish terrier and Old English Sheepdog.

Types of primary brain tumors:

I. Glioma Neoplasms:

a. Astrocytomas are the most common neuroectodermal brain tumor in dogs. They are generally seen in brachycephalic breeds. The cells are usually arranged around blood vessels.
b. Oligodendrocytomas are seen frequently in brachycephalic breeds. Most grow by infiltration and destroy invaded tissue. Capillaries tend to proliferate within these tumors, producing glomerulus-like (capillary tuft) structures.
c. Oligogastrocytomas are usually rare. They have a mixed appearance of astrocytomas and oligodendrocytomas.

II. Tumors of the Ependyma and Choroid plexus:

a. Ependymoma– They develop from the epithelium lining and the central canal of the spinal cord. They are not very common, but have been reported in brachycephalec breeds. They infiltrate into the ventricular system and the meninges. It may result in obstructive hydrocephalus (abnormal accumulation of CSF in ventricles, or cavities of the brain).
b. Choroid plexus papilloma– These tumors can be either benign or malignant that tend to develop in the ventricular system and can obstruct the drainage of CSF. These small tumors are reddish, ulcerative growths. They can cause obstructive hydrocephalus. They grow by expansion, and have a granular papillary (they look like round or cone shaped protuberances) appearance.
c. Choroid plexus carcinoma– Choroid plexus carcinoma is a highly invasive malignant lesion. They are believed to arise from choroid plexus epithelium. They cause obstruction of CFS pathways and overproduction of cerebrospinal fluid leads to hydrocephalus and increased intracranial pressure.

III. Neuronal and mixed neuronal-glial neoplasms:

a. Gangliocytoma– These are rare intracranial tumors (lesions found in the upper part of the skull that protects the brain) that are mostly found in adult dogs. Histologic findings show mature, neuronal-like cells with multiple processes, a Central nucleus and a nucleolus. They are mostly seen in the cerebellum
b. Ganglioglioma– They arise from ganglion cells in the central nervous system. They are generally mixed cell tumors containing both neural ganglionic cells (cells that arise from ganglion) and neural glial cells (they provide protection and nutrition to neurons and participate in the signal transmission in the nervous system). Though they can occur anywhere in the brain or in the spinal cord they are most frequently seen in the temporal lobe of the brain.

IV. Embryonal tumors:

a. Olfactory neuroblastoma– They are highly malignant neurorectodermal tumor. They are located in the superior portion of the nasal cavity and may present with blockage or hemorrhage.
b. Neuroblastoma– It is a solid lesion that usually originates in one of the adrenal glands, but can also arise in nerve tissues in the neck, chest abdomen or pelvis.
c. Medulloblastoma– They are rare neurorectodermal tumors that usually develop in the cerebellum. They have a tendency to protrude into the fourth ventricle replacing part of the cerebellar vermis (it is a wormlike structure between the hemispheres of the cerebellum) and compressing the mid brain rostrally and brain stem ventrally. They may infiltrate the meninges, spread within the CSF pathways, and result in obstructive hydrocephalus.
d. Intradural extramedullary spinal cord tumor in young dogs– They grow within the spinal canal but outside the nerves. They are usually slow growing and benign tumors. They account for 35% of all spinal cord tumors in dogs. They grow into the vertebral canal and compress the spinal cord. They may be seen in the cervical, lumbar or thoracic cord regions. They are generally tan to grayish in color and 1-3 cm long. They occur frequently in young German Shepherds and Golden Retrievers.

V. Tumors of the Meninges:

a. Meningioma– It is the most common primary tumor in dogs. It arises in the arachnoid mater of the meninges. They arise within the cranial cavity and invade the brain. They mostly occur in doliococephalic breeds of dogs like the Golden Retriever. They are usually slow growing, but more malignant forms have also been observed.

VI. Lymphomas and various hematopoietic tumors:

a. Histiocytic sarcomas– They are malignant tumors that arise from histiocytic cells like the macrophages and the dendritic cells which form an integral part of the immune system. They are rarely reported in dogs.
b. Neoplastic reticulosis- These tumors are found more in dogs than in any other domestic species. These lesions occur most frequently in older dogs and preferably occur in the white matter of the brain as single or multi-focal masses. They appear grayish white and generally sharp bordered.

VII. Rare primary CNS tumors and tumor like lesions, hamartomas cysts:

a. Pineal tumors– They arise in the region of the pineal gland (it is a small gland located deep within the brain. It is believed to secrete melatonin, and may therefore be part of the body’s sleep-regulation apparatus). This gland is a small structure within the brain. They are extremely rare in dogs.
b. Germ cell tumors– The fertilized mammalian ovum differentiates into extraembryonic and embryonic tissues. Abnormal growth of tissues leads to the development of germ cell tumors. They are located dorsal to the sella turcica (saddle shaped depression in the sphenoid bone [bone situated at the base of the skull]). They are generally associated with the pituitary gland which may be trapped within or replaced by the germ cell tumor. They are believed to result from extensive migration of germ cells during embryogenesis (process by which embryo is developed). They usually occur in animals between 3-5 yrs of age. Doberman Pinschers are slightly predisposed.
i. Germinoma– They generally originate from a primordial germ cell (an aggregation of cells in the embryo indicating the first trace of an organ or structure that migrate to widely separated areas of the embryo during early fetal life. The midline location in the brain is not explained clearly. With treatment they have an overall favorable outcome. These tumors resemble testicular seminomas and are also called embryonal carcinomas and ovarian seminomas. They can be cancerous or non-cancerous.
ii. Teratoma– They are solid tumors containing differentiated tissue from two or three cell lines. Tissues within teratomas may arise from ectoderm (hair, sweat, sebaceous glands and nerve tissues, mesoderm (cartilage, bone, teeth, smooth and skeletal muscle).

VIII. Primary Melanoma of the CNS:

a. Chordoma– They are not reported frequently in dogs. But these are usually firm to cystic, slow growing, but locally destructive, with a high rate of recurrence following surgery. Around 30% of them have been reported to metastasize. They derive from remnants of the notochord (rod like structure in embryos from which the spinal column develops).
b. Hamartomas– They are elements formed by abnormal growth of local tissue elements. Unlike neoplasms, their growth is limited. They don’t expand further. Vascular (related to blood vessels) hamartomas are not common in animals, but several cases of congenital hamartomas have been reported in dogs. They don’t show any clinical signs in early life. A case was reported in a dog which was in fine fettle till the age of 13. Suddenly it started showing signs of seizures (epileptic feat, convulsions) and also developed personality changes. Upon histological investigation, he was diagnosed with vascular hamartoma. In addition to intracerebral hamartomas, a few cases have been reported to arise within meninges. They were called meningioangiomatosis.
c. Epidermoid cyst– It is perhaps the most frequently seen cystic lesion in dogs. It mostly occurs in the cerebellopontine angle (common site for growth of acoustic neuromas [benign tumor of the 8th cranial nerve]). They frequently occur in young dogs

VIII. Pituitary adenoma or adrenocorticism:

The pituitary gland lies beneath the forebrain (anterior part of the brain) and is connected by a stalk to an area of the brain called the hypothalamus (links the nervous system to the endocrine system through the pituitary gland). Pituitary tumors are also called adenomas. They are seen frequently in dogs and is also the primary cause of hyperadrenocorticism (Cushing’s syndrome). Usually they do not cause any severe neurological deficits and remains outside the cranial cavity. But in some cases, they expand quickly and compress the overlying brain. They are known as adenocarcinomas, or pituitary macroadenomas.

Causes

The etiology of brain tumors is not known. But factors like genetic syndrome, exposure to radiation, administration of nitrosamines, spraying of pesticides, are believed to be the probable causes. In certain cases, it is believed that trauma, head injuries induce the onset of tumors.

Symptoms

Many dogs with brain tumors show vague signs like changes in behavior. These symptoms are so negligible, that owners and vets tend to overlook them till signs of brain dysfunction are well developed. These include subtle behavior alterations, that usually develop over months and years. Like humans, dogs may also develop severe headaches, but since they cannot articulate, symptoms like decreased frequency of barking or diminished levels of activity.

The most prominent signs associated with a brain neoplasm in dog is seizures, especially if it occurs in the animal after 4 years of age. It could either be a generalized seizure or a focal seizure. Other clinical signs frequently associated with a brain tumor in dogs include circling, altered posture, gait abnormalities, ataxia (loss of the ability to coordinate muscular movement), head tilt, behavior change, depression, incontinence (inability to control excretory functions) and cervical spinal hyperesthesia (abnormal increase in sensitivity to stimuli of the senses).

If the neoplasm involves the brain stem cranial nerve, deficits are seen like weakness, sensory loss, vision problems, hearing or smell. Weakness and loss of energy usually indicate a tumor in the cerebral frontoparietal or sensory motor regions. Vision problems denote lesions in the visual pathways from the optic nerve to the occipital lobe of the cereberum. Difficulties in smelling are associated with tumors in the cribriform plate, olfactory bulb and peduncle (band of neurons that connect various parts of the brain) and pyriform (pear shaped neural structure on either side of the brain) or temporal lobes of the cereberum. Difficulties in balance or gait are due to cerebellar or vestibular (contributes to balance and sense of spatial orientation) involvement.

Increased intracranial pressure are indications of tumor expansion. The symptoms consist of lethargy, irritability, head pressing, compulsive walking, altered states of consciousness, or associated locomotor disturbances (inability to move from one place to another).

Diagnostic techniques

The diagnostic tests for dogs with clinical dysfunction include a hemogram, serum chemistry panel and urinanalysis. Survey radiographs of the thorax and abdominal ultrasound examination are also useful. The purpose of these tests is to rule out extracranial causes for symptoms of cerebral dysfunction.

Radiography

It is of practically no use when it comes to detecting primary brain tumors. Radiography can be useful if the tumors develop in the skull or nasal cavity that involve the brain by local extension. The dog is kept under anesthesia for precise positioning of the skull for radiographs.

Cerebrospinal fluid analysis

Examination of CSF is important in the diagnosis of brain tumors. Lot of care has to be taken while collecting CSF, because brain tumors are generally associated with increased ICP. Pressure alterations associated with CSF drainage may result in brain herniation (deadly side effect of increased intracranial pressure). CSF collection is done only after advanced imaging is complete and factors like presence of cerebral edema (excess accumulation of water in the intracellular or extracellular spaces of the brain) or hemorrhage have been evaluated. Hyperventilating and administration of mannitol help to decrease increased ICP before CSF collection.

Advanced Imaging

Computed tomography (CT scan) is very useful in determining the size and location of the tumor. Magnetic resonance imaging (MRI) is a recent breakthrough and is also a step ahead in charting the course of treatment. Images obtained by MRI are way advanced to those of CT in certain brain regions like the brain stem.

Biopsy

It remains the most important technique in determining the exact therapy for treatment. A recent innovation is the CT-guided stereotactic biopsy system. It is error free and the complications are minimalist.

Treatment

The main purpose of a therapy is to control secondary effects like increased ICP or cerebral edema, eliminate the tumor or reduce the size. Four methods of therapy for a brain tumor include surgery, irradiation, chemotherapy and immunotherapy.

Surgery

Neurosurgery is being frequently practiced in the management of intrcranial neoplasms in dogs. The size, location and the extent of proliferativeness of the lesion help in determining whether the vets should go for complete surgical excision. Meningiomas, which are located over the cerebral convexities or the frontal lobes of the cereberum may be eradicated by means of surgery. Surgical excision of neoplasms located in the caudal fossa (depression on the external surface of the maxilla [fusion of two bones along the fissure that form the upper jaw]) and brain stem of dogs, are associated with significant mortality and morbidity.

Besides, helping in tissue biopsy, partial removal of a brain neoplasm may eliminate signs of cerebral dysfunction and also makes the dog amenable to other kinds of therapies. In cytoreduction (decrease in number of cells) the volume of tumor available for therapy is reduced by other means of treatment like radiation therapy. However surgical biopsy or cytoreduction should be done carefully, because it may sometimes result in tumor seeding (spillage of tumor clusters and their subsequent malignant growth at an adjacent site).

Radiation therapy

This therapy has proven quite successful in the management of brain neoplasms in dogs. Irradiation can be used alone or in combination with other treatments. It can also be used in the treatment of secondary brain tumors. Pituitary macrocarcinomas, macroadenomas and skull tumors have been treated successfully with this therapy alone or as an adjunct to surgery. Radiation may also be useful in managing lymphoma. The purpose of this therapy is to eradicate the neoplasm, while minimizing damage to normal surrounding tissues. The selection of radiation dose is based on considerations like tumor type, location, and partially on tolerance of the tissues surrounding the lesion. Advanced radiation therapy techniques like intensity modulated radiation therapy and conformal avoidance like tomotherapy (radiation is delivered slice by slice) are becoming easily available in veterinary medicine.
Radiosurgery is the latest breakthrough in which numerous intersecting gamma ray beams are projected or a large number of ports or arch therapy are used with the help of a linear accelerator.

Chemotherapy

There are several factors affecting the impact of chemotherapeutic protocols. The most unique of them being the blood brain barrier (BBB). It protects the brain from circulating substances in the blood. Moreover, the heterogeneous nature of certain cells in the tumor may render them insensitive to certain agents. These cells may be sensitive at certain dosages which are toxic to the normal brain or other organs.
Intra-arterial administration (infusion of drug via injection into an artery) of drugs, high dose systemic therapy and blood brain barrier disruption are all under investigation in dogs. Several types of CNS malignancies vary in their degree of sensitiveness to cytotoxic drugs. Certain lesions like CNS lymphoma, medulloblastoma, and oligodendroglioma may be highly sensitive to chemo therapy. Future breakthroughs comprise transient osmotic blood brain barrier disruption or transient opening of the blood brain barrier with the help of bradykinin analogs (drug that helps to dilate blood vessels and reduce blood pressure). Lomustine, carmustine and temozolomide have proved successful in the treatment of gliomas by disrupting BBB.

Immunotherapy

The treatment of dogs with meningiomas using repeated intracisternal injections (infusion into the cisterna which carry golgi enzymes, to modify cargo proteins traveling through them but destined for other parts of the body) of stimulated lymphocytes (a type of white blood cells in the vertebrate immune system) have resulted in the reduction of tumor size and also in the improvement of clinical symptoms.

Gene therapy

This therapy was originally envisioned to treat genetic disorders. But it is gradually gaining importance as an alternative therapy for cancer. Neoplasms result due to damage in the DNA as a result of carcinogens or during DNA replication. The inability of the cell to correct this damage due to mutated DNA repair genes or absence of normal cell cycle may lead to abnormal growth of cells. These damaged cells are good targets for gene therapy. But in dogs there seem to be a number of complications though clinical trials are underway. Poor transfection (opening of pores in cell membranes for the uptake of genetic materials like DNA) of the tumor mass appears to be the greatest hurdle. Another one is increasing the delivery of genetic material. At present routes of administering the genetic material are being investigated.

Palliative therapy

If none of the above therapies work, then doctors take recourse to palliative therapy. If the dog experiences seizures, he will be placed on an anti-epileptic drug like phenobarbital. Brain tumors may lead to an accumulation of fluid (edema) around them. This can be treated with a corticosteroid like prednisone. In some dogs it has shown remarkable improvement within 24 hours. This response is usually short lived since the lesion itself is not being treated by this drug. But it can certainly give owners and pets some temporary relief.

Prognosis

There is not enough data to substantiate the probable outcome in dogs suffering from primary brain tumors. However, results from several studies have pointed that prognosis may be significantly improved by surgical removal, irradiation, chemotherapy, or immunotherapy either used alone or in combination. With palliative therapy, the prognosis is very poor. The median survival time has been found to be 2-4 months. Studies have also revealed that dogs treated with irradiation alone lived significantly longer than those treated with surgery or any other symptomatic treatment like palliative therapy. In one study dogs treated with surgery for olfactory meningiomas, showed a median survival of 138 days. In another study, dogs treated with surgery for intrcranial meningiomas showed a median survival of 198 days with a 1 year survival rate of 30%. Studies indicate that dogs undergoing surgical excision for cerebral meningiomas show an excellent prognosis for long-term survival. There is a probability of developing a second type of tumors in dogs treated for brain tumors.

References

Withrow and MacEwen’s Small Animal Clinical Oncology– Stephen J. Withrow, DVM, DACVIM (Oncology), Director, Animal Cancer Center Stuart Chair In Oncology, University Distinguished Professor, Colorado State University Fort Collins, Colorado; David M. Vail, DVM, DACVIM (Oncology), Professor of Oncology, Director of Clinical Research, School of Veterinary Medicine University of Wisconsin-Madison Madison, Wisconsin

Tumors in Domestic Animals– Donald J. Meuten, DVM, PhD, is a professor of pathology in the Department of Microbiology, Pathology, and Parasitology at the College of Veterinary Medicine, North Carolina State University, Raleigh

The Natural Vet’s Guide to Preventing and Treating Cancer in Dogs (New World Library, 2006)- S. Messonnier

New Choices in Natural Healing for Dogs and Cats (Rodale Press, Inc., 1999)-
A.D. Shojai

The Merck Veterinary Manual