Astrocytomas in Young Dogs

Introduction

Intracranial neoplasia is diagnosed relatively commonly in dogs, with an incidence reported to be 14.5 in 100,000.^1–5 With the increasing use of magnetic resonance imaging, the incidence may be found to be much higher.

Brain tumors are classified as primary or secondary, depending on their cell of origin.² Primary tumors originate from cells normally found within the central nervous system (CNS), including the neuroepithelium, lymphoid tissues, germ cells, and endothelial cells.² Secondary tumors consist of neoplasms that have reached the brain by hematogenous metastasis or by local invasion or extension from adjacent nonneural tissues, such as bone.²

Brain tumors, primary and secondary, occur most frequently in older dogs, with the greatest incidence in dogs >5 years of age.²³ The median age of 183 dogs with brain tumors in two studies was 9 years,⁴⁵ with 95% of the dogs being ≥5 years of age at the time of diagnosis.⁵

Glial cell tumors are the second most common cancer in children^6–9 and the most common solid neoplasm in childhood,⁶¹⁰¹¹ although glial cell tumors in young dogs have only been reported sporadically.^12–14 Other primary brain tumors reported in young dogs include medul-loblastomas,⁵ teratomas,¹⁵ epidermoid cysts,¹⁶ and rhabdoid tumors.¹⁷ Of the reported primary brain tumors in children, astrocytomas are the most common.^71018–20 This paper summarizes three cases of astrocytomas in young dogs.

Case Reports

Three young dogs were referred with various neurological signs and were ultimately found to have astrocytomas [see Table]. Case no. 1, a 2-year-old, male castrated English bulldog, was referred for disorientation, lethargy, and apparent pain. Case no. 2, a 1.4-year-old, female spayed terrier mix, was referred for apparent cervical pain and had a history of seizures beginning at 8 months of age. Case no. 3, a 4-year-old, male intact English bulldog, was referred for generalized seizures. Physical examinations revealed apparent cervical pain in two of the three dogs. Neurological examinations revealed central vestibular disease along with apparent cervical pain in case no. 1, cervical hyperesthesia in case no. 2, and a tendency to turn to the right in case no. 3. Case nos. 2 and 3 went into status epilepticus prior to diagnostics and needed to be anesthetized to control seizures. Lesion localization was in the cerebrum/thalamus in case nos. 2 and 3 and in the brain stem or cerebellum and possibly thalamus of case no. 1.

A cerebrospinal fluid (CSF) tap was performed prior to any imaging in case no. 1 due to the owner’s concerns over cost and the multifocal signs. Computed tomography (CT) was performed on case no. 2, revealing a large, cavitary, contrast-enhancing mass [Figure 1]. Magnetic resonance imaging (MRI) was performed on case no. 3, revealing a mass lesion in the region of the right piriform lobe [Figure 2]. There was a moderate mass effect with a midline shift and partial compression of the right lateral ventricle. The majority of the lesion was hypointense on T1 and hyperintense on T2-weighted images. The caudal-most aspect of the mass enhanced intensely in an irregular, almost striated pattern. The rest of the lesion was nonenhancing.

Cerebrospinal fluid (CSF) analysis was abnormal in case nos. 1 and 3, with a high protein concentration in both cases. An increased number of white blood cells was seen in case no. 1, which did not recover from anesthesia and was maintained by mechanical ventilation for 12 hours following the spinal tap. Case no. 2 did not have a CSF tap for fear of herniation due to the possibility of increased intracranial pressure as suggested by the significant mass effect seen on the CT scan.

All three dogs were euthanized due to the severity of clinical signs. Postmortem examinations and histopathology were obtained in all cases. Case no. 1 had mild hydrocephalus of both lateral ventricles. The right piriform lobe contained a 4-cm, soft, brown mass involving the caudate nucleus and thalamus. The histopathological diagnosis was a well-differentiated, atypical astrocytoma. The diagnosis in case no. 2 was a mucinous astrocytoma. Necropsy in case no. 3 revealed a soft, mucinous mass at the rostral aspect of the right piriform lobe [Figure 3], which was diagnosed as a low-grade astrocytoma.

Discussion

An astrocytoma is one type of glioma. Gliomas arise from neuroglial cell lineage of which astrocytes, oligodendrocytes, microglial cells, and ependymal cells originate.²¹ Astrocytes are derived from the neuroectoderm and are characterized by a star-like appearance and broad end feet on their processes, by which they fuse with the ependymal cells.²²²³ Their role is supportive, as they contribute to the blood-brain barrier by covering about 85% of the basal lamina of all blood vessels within the CNS in a continuous single-cell layer immediately beneath the pia mater.²² Astrocytes act as a scaffold upon which the neurons and their processes are arranged, and they are involved in guiding the growth of neurons during development.²² If neurons die within the neuraxis, the astrocytes multiply to form a glial scar.²²²³ Due to the high permeability of astrocytes to potassium, they help control the contents of the intercellular space by taking up excess potassium.²²²³ Astrocytes also take up neurotransmitters from synaptic zones and thereby help regulate synaptic activities.²³ Two types of astrocytes have been identified: protoplasmic and fibrous.²⁴ The concentrations differ with respect to the location within the brain; protoplasmic astrocytes are found in the gray matter, and the fibrous astrocytes are more common in the white matter.²⁴

Astrocytomas are one of the most common tumors in domestic animals.²⁵ Astrocytomas have been reported in dogs,²⁶ deer,²⁶ cattle,²⁶²⁷ cats,²⁶²⁸ a monkey,²⁹ an elk,³⁰ a goat,³¹ a llama,²⁵ a raccoon,³² a boar,³³ and a rat.³⁴ The highest incidence of astrocytomas in dogs has been found to be between the ages of 8 and 9 years.²⁶ It is most common in brachycephalic breeds²⁴³¹ and is most commonly a single tumor, located in the rostral and middle fossa.³¹³⁵

Tumors of the CNS represent the second most frequent malignancy in children under 15 years of age, following tumors of the lymphoid/hematopoietic system.⁷ Astrocytomas account for the majority of childhood brain tumors.^{6101118–2036–39} Approximately 700 children are diagnosed with low-grade astrocytomas each year, with an increased incidence in children 5 to 8 years of age.⁹ Common sites for these tumors in children are the cerebellum, cerebral hemispheres, thalamus, and hypothalamus; the cerebellum is the most common location.¹⁸ There is an increased ratio of males to females in childhood brain tumors.^71019203739 A similar sex predilection has not been noted with brain tumors in dogs.²⁴ Although two of three dogs in this study were male, the authors cannot make any specific conclusion about sex predominance in astrocytomas in young dogs because of the low sample size.

It seems that the incidence of childhood CNS tumors (1% worldwide and 6% in the United States) has gradually increased in recent decades.⁷ This may be due to improved diagnostic tools and higher awareness, but the fact that the increase in tumors has been predominantly in males weakens this line of reasoning.⁷ It is generally assumed that intracranial tumors presenting in the first year of life developed during intrauterine life.⁷ Exogenous or genetic factors can only have acted during the short intrauterine or postnatal period.⁷ Perinatal exposure to radiation has been associated with an astrocytoma in a 3-month-old dog;¹⁴ although in children, heritable syndromes, maternal infections, or exposure to exogenous compounds during pregnancy and ionizing radiation (i.e., gamma knife radiosurgery) causing primary CNS tumors only account for a small percentage of cases.⁷³⁸⁴⁰ Vitamins during pregnancy and childhood correlated with a decreased incidence of pediatric brain tumors.⁷

Classification of human astrocytomas is of considerable importance for prognosis and appropriate treatment.⁸ This has not yet been determined for dogs. Several different grading systems exist. In dogs, astrocytomas are usually classified as poorly or well differentiated and can be further subtyped based on the predominant cell type.⁴⁰ The Kernohan system and the World Health Organization (WHO) system have increasing grades of malignancy as determined by the invasive and proliferative features of the tumor.⁸⁴⁰ Well-differentiated canine astrocytomas correlate with Kernohan grade 1 or 2, while undifferentiated tumors correlate with Kernohan grade 3 or 4.⁸⁴⁰

Children and dogs present similar diagnostic challenge when trying to diagnose a brain tumor.⁴¹ In young children, headaches may not be prominent since the sutures are still open, which allows for considerable expansion of the skull and an ability to compensate for elevations in intracranial pressure.⁷⁴¹ Detection of discomfort is difficult in dogs and children. Much time is lost due to the adaptability of the developing nervous system, since there can be considerable tumor growth with scarce and mainly nonspecific symptoms.⁷⁴¹

Magnetic resonance imaging is the modality of choice, considering that a small percentage of intracranial tumors may not be recognized by CT⁴⁰ due to the decreased sensitivity for soft-tissue abnormalities. Though CT is faster and less expensive, the use of MRI has provided improvement in both sensitivity of detection and delineation of tumor boundaries.⁴⁰ Computed tomography and MRI findings associated with astrocytoma in dogs and humans are similar.⁴⁰ A nonenhanced CT will display an astrocytoma as a hypodense area that enhances brightly and uniformly with contrast material.³⁵ On MRI, low-grade gliomas show decreased signal but may be relatively inconspicuous compared to surrounding brain on T1 sequences.³⁵⁴⁰ On T2 sequences, there is higher signal intensity reflecting both the tumor and surrounding vasogenic edema.³⁵⁴⁰ The astrocytoma that was imaged with MRI in case no. 3 of this report showed these characteristics.³⁵⁴⁰ Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are sometimes used to differentiate low-grade gliomas from either high-grade tumors or other types of pathology.³⁵ Typically, low-grade gliomas will show hypometabolism via PET or SPECT, while high-grade gliomas are hypermetabolic.³⁵ Due to cost and availability, PET and SPECT on animals are presently limited to experimental situations.

Treatment of astrocytomas provides a challenge. Corti-costeroids are used frequently in veterinary medicine as palliative therapy, and treatment can reduce vascular permeability, exert cytotoxic effects on tumors, inhibit tumor formation, and decrease CSF production. Surgery is the mainstay of treatment, with 80% to 100% survival in children.³⁵ Sixty percent to 90% of childhood brain-tumor patients have no residual functional deficits following surgery.⁴² Surgery can be curative if resection is complete,⁴³ and postoperative radiation may not be needed.⁴³ Resection and radiation have been found to be better than radiation alone.⁴⁴ There is uncertainty in the human literature regarding the role of radiation in the treatment of astrocytoma,⁴² as 10% of childhood patients develop a secondary primary brain tumor (i.e., neurilemmoma, meningioma) within the radiation field.⁴⁵ Chemotherapy has been used in children and dogs.⁶⁴⁶ In dogs, the chemotherapeutic agent shown to be of some benefit with astrocytomas is lomustine (i.e., methyl chloroethyl cyclohexyl nitrous urea [CCNU]),⁴⁷ and in children, vincristine and CCNU have had confirmed efficacy.⁶ More recently, quinacrine (an antimutagenic agent) has been shown to improve the therapeutic effects of carmustine in rat gliomas.⁴⁸

Conclusion

Though brain tumors are a relatively common pathology among older dogs, they are seldom diagnosed in younger dogs. The three cases of this report not only illustrate that brain tumors occur in younger dogs, but tumors may also be overlooked on initial presentation. Two of the three dogs presented for apparent cervical pain; this has also been reported in several other cases with a primary intracranial lesion that manifested as cervical pain.⁴⁹ Two of the three dogs had also been presumed to have idiopathic epilepsy. Though not a common occurrence, it is ideal to offer all young dogs presenting with seizures a full medical and neurological workup.

Just as astrocytomas are a relatively common brain malignancy of children, they appear to occur at least occasionally in young dogs. Further clinical evaluation with histopathology or surgical excision will shed light on the possible utility of early diagnosis and aggressive treatment. Treatment options may include chemotherapy, surgery, radiation therapy, or a combination of the three.