TYPES OF BRAIN TUMORS



From: Withrow SJ & MacEwen EG (eds): Small Animal Clinical Oncology (3rd ed).

General Considerations

•brain tumors occur in dogs with an incidence of 0.015% overall and account for 2.8% of all tumors

•primary brain tumors are usually solitary


Meningioma

•meningioma is the most common tumor primary brain tumor in dogs (33%-49%)

•meningiomas are extra-axial and supratentorial tumors arising from the dura mater, pia mater, or subarachnoid

•meningiomas attachment to the dura or leptomeninges may be broad (= sessile), narrow (= pedunculated), or total (= meningioma en plaque)

•meningiomas occur more commonly in dolichocephalic breeds (i.e., GSD and Collies)

•median age 9 years with 95% dogs ≥ 5 years

•meningiomas are commonly located in the frontal lobe, falx cerebri, and cerebellopontine angle

•canine meningiomas are locally invasive with 27% invading the Virchow-Robin spaces

•18%-27% metastatic rate

•progesterone receptor immunoreactivity is present in > 70% tumor cells

•tumor proliferation fraction is inversely correlated with progesterone receptor immunoreactivity, suggesting that loss of progesterone receptors increases tumor proliferation fraction and malignant behaviour

•meningiomas are classified as meningoepithelial, fibroblastic, transitional, psammomatous, angioblastic, papillary, granular cell, myxoid, and anaplastic

•meningiomas can also be cystic as a result of tumor necrosis, isolation of CSF, or fluid production by the tumor


Other Brain Tumors

•other primary brain tumors include astrocytoma (13%), choroid plexus tumors (10%), pituitary tumor (10%), and oligodendroglioma (4%)

•astrocytomas occur more commonly in Boxers and Boston Terriers

•oligodendrogliomas occur more commonly in brachycephalic dogs with a male-to-female ratio of 2:1

•choroid plexus tumors are tumors of the ventricular system and commonly occur in the 4th ventricle

•multiple primary brain tumors have been reported with meningioma, and metastatic medulloblastoma and choroid plexus carcinoma

•secondary tumors affecting the brain include:

•local extension from nasal tumors (7%), pituitary tumors, and skull tumors such as OSA, CSA, and multilobular osteochondrosarcoma

•metastasis from mammary, prostatic or pulmonary ADC, and HSA

•nerve sheath tumors arising from oculomotor or trigeminal nerve have been reported in dogs



PATHOPHYSIOLOGY


Primary Brain Tumors


General Considerations

•intracranial tumors are classified as primary or secondary

•primary brain tumors arise from cells normally found in brain and meninges including neuroepithelium, lymphoid tissue, germ cells, endothelial cells, and malformed tissue


Benign versus Malignant

•cytologic classification of malignancy: anaplasia (i.e., cytoplasmic and nuclear pleomorphism), cellularity, necrosis, mitosis, and invasiveness

•biologic malignancy will cause death

•majority of cytologically malignant tumors will also be biologically malignant

•benign tumors can also be biologically malignant due to secondary effects such as increased intracranial pressure

•feline meningioma is well-defined with clear demarcation between tumor and abnormal tissue


Clinical Effects

•primary brain tumors can cause clinical signs through primary and secondary effects

•primary effects of primary brain tumors include:

•infiltration of nervous tissue

•compression of adjacent anatomic structures

•disruption of cerebral vasculature

•local necrosis

•secondary effects of primary brain tumors include:

•disturbed CSF flow resulting in hydrocephalus

•increased intracranial pressure

•cerebral edema

•brain herniation

•secondary effects are usually more diffuse or generalized and may mask location of focal intracranial lesion

•primary brain tumors are usually slow growing allowing adjacent structures to adapt to gradual increase in pressure with minimal and vague clinical signs (i.e., subtle behavioural changes)

•rapid progression of clinical signs can be caused by overwhelming of compensatory mechanisms

•rapidly growing tumors will result in an acute onset of clinical signs with no premonitory signs due to poor ability of compensatory mechanisms to adapt to rapid tumor growth


Invasion by Primary Brain Tumors

•primary brain tumors have a distinct pattern of spread due to lack of lymphatic channels

•major patterns include local invasion and CSF seeding

•primary brain tumors (i.e., astrocytoma) contain cells which are able to invade normal brain

•seeding may occur by spread along brain surface to local sites or through CSF to spinal subarachnoid space and distant sites (= drop metastases)

•hematogenous spread is possible, but extracranial metastasis is rare


Secondary Brain Tumors

•secondary brain tumors are due to either hematogenous metastasis or local invasion or extension



CLINICAL SIGNS


General Considerations

•nature and course of neurologic signs depends on location, extent and rate of growth


Premonitory Signs

•vague signs are common due to slow growth of primary brain tumors

•vague signs are often overlooked until brain dysfunction is well developed

•vague signs may be manifestation of headache (common in humans) and include decreased purring and reduced activity levels


Clinical Signs

•seizures (focal or generalized) are the most common clinical sign in cats and dogs with primary brain tumors

•seizures are commonly associated with tumors of the frontal lobe (44%), olfactory region (20%), parietal lobes (20%), and extension of nasal ADC (11%)

•other clinical signs include circling (23%), ataxia (21%), ataxia, and cervical spinal hyperesthesia


Neurologic Signs


From: Slatter DH (ed): Textbook of Small Animal Surgery (3rd ed).

•brain stem tumors cause cranial nerve deficits

•frontoparietal tumors cause seizures, behavioural changes, circling, head pressing, visual deficits, proprioceptive deficits with normal to near-normal gait, hemi-inattention syndrome (= hemi-neglect syndrome), and spinal hyperesthesia

•hemi-inattention syndrome: ignore environmental stimuli on contralateral side to tumor

•optic nerve or occipital lobe tumors result in visual deficits

•cerebromedullary, brain stem, and temporal lobe lesions can cause hearing loss

•cribriform plate, olfactory bulb and peduncle, and piriform or temporal lobe tumors cause problems with smelling

•cerebellar and vestibular tumors will cause ataxia, dysmetria, intention tremors, and menace deficits with normal vision


From: Slatter DH (ed): Textbook of Small Animal Surgery (3rd ed).


Secondary Neurologic Signs

•secondary effects of brain tumors represent either a large tumor or significant cerebral edema

•secondary neurologic signs include alterations in behaviour, circling, head pressing, compulsive walking, altered states of consciousness, and associated locomotor disturbances

•majority of animals with primary brain tumors will present for either seizures or secondary neurologic signs



DIAGNOSIS


General Considerations

•history, clinical signs, and physical and neurologic examination

•minimum data base: hematology, serum biochemistry, urinalysis, thoracic radiographs, and abdominal ultrasound to exclude extracranial causes of cerebral dysfunction


Survey Skull Radiographs

•survey skull radiographs have limited value except for skull and nasal tumors


Advanced Imaging


General Considerations

•advanced imaging techniques include ventriculography, cerebral angiography, cavernous sinus venography, cisternography, and scintigraphy

•however, these techniques have been superceded by CT and MRI as they do not provide information on the extent of tumor involvement and relationship to adjacent structures

•MRI is superior to CT in detecting many features associated with brain tumors such as edema, cyst formation, changes in vascularity, hemorrhage, and necrosis

•primary brain tumors may have characteristic CT or MRI features, but these are not pathognomonic


Magnetic Resonance Imaging Appearance

•majority of tumors are round or oval, except plaque-like tumors are always meningiomas

•majority of tumors are hyperintense and heterogenous on T2-weighted images

•majority of tumors are hypo- or isointense and heterogenous or homogenous on T1-weighted images

•majority of tumors show marked contrast enhancement

•ring enhancement is seen predominantly in gliomas, but also observed in meningiomas and pituitary tumors


Tumor Location

•extra-axial tumors include meningioma, LSA, pituitary tumor, olfactory neuroblastoma, ventricular tumors (i.e., choroid plexus tumor and ependymoma), and direct extension of nasal tumors

•meningioma accounts for 83% of extra-axial lesions

•extra-axial tumors affecting the frontal lobe can be difficult to predict based on axial location alone as 55% are meningiomas, 20 LSA, 15% nasal tumors, and 10% olfactory neuroblastomas

•however, meningiomas and LSA do not cause cribriform plate destruction, whereas both tumors extending from the nasal cavity and olfactory neuroblastomas cause cribriform plate destruction


Meningiomas

•MRI appearance of feline meningiomas include:

•extra-axial location

•ovoid to round in shape with distinct margins

•hyperintense and heterogenous on T2-weighted images

•hypo- or isointense on T1-weight images

•intense contrast enhancement

•mass effect (97%) with a broad base (49%) and dural tail sign (64%)

•other findings included lateral ventricular enlargement (64%), transtentorial herniation (42%), cerebellar herniation (21%) ± mineralization


From: Slatter DH (ed): Textbook of Small Animal Surgery (3rd ed).


From: Slatter DH (ed): Textbook of Small Animal Surgery (3rd ed).


From: Slatter DH (ed): Textbook of Small Animal Surgery (3rd ed).

Cerebrospinal Fluid Analysis

•CSF analysis will assist in excluding inflammatory causes of neurologic disease and may aid in diagnosis of primary brain tumor

•CSF collection can result in brain herniation due to shift in intracranial pressure

•CSF collection is recommended after advanced imaging

•CSF changes include increased protein content and normal to increased white cell count

•typical CSF changes observed in < 40% of dogs with primary brain tumors with 50% having non-specific changes and 10% with normal CSF

•neoplastic cells can occasionally be detected in CSF following sedimentation techniques


Biopsy


General Considerations

•biopsy is the only method to provide a definitive diagnosis prior to therapy

•biopsy is not commonly performed due to practical considerations such as cost and morbidity

•biopsy techniques include ultrasound-guided biopsy, freehand CT-guided biopsy, and CT-guided stereotactic brain biopsy

•FNA and Trucut needle biopsy correctly identify brain tumors as neoplastic in 100% dogs and correlate with histopathologic diagnosis in 50% and 90%, respectively

•diagnostic accuracy of impression smears using a variety of different staining techniques is 81%

•modified Wright stain is the most accurate stain with diagnostic accuracy of 86%

•touch preparation and smear preparation are the most accurate preparation techniques with diagnostic accuracy of 82%, however smear preparations are preferred because of fewer non-diagnostic samples


Computed Tomography-Guided Stereotactic Brain Biopsy

•transient problems such as epistaxis and exacerbation of neurologic signs

•severe complications such as uncontrollable seizures and progression of neurologic signs to coma (although these occur in dogs with large primary brain tumors)

•stereotactic system for CT-guided brain biopsy: mean placement error 3.5 mm which was not related to operator experience, body weight, or length of needle path, but was associated with lesion location (i.e., best for rostral fossa lesions, intermediate for middle fossa lesions, and worst for caudal fossa lesions)

•diagnostic tissue in 90% cases


Other Diagnostic Techniques

•lipid-associated sialoprotein in CSF is a marker used in humans which is diagnostic for presence of intracranial malignancy and can be used to assess response to therapy



TREATMENT


General Considerations

•aims of treatment for brain tumors include:

•tumor removal or cytoreduction

•control secondary effects (i.e., increased intracranial pressure and cerebral edema)

•treatment options include conservative or palliative management, surgery, radiation therapy, chemotherapy and immunotherapy

•gene therapy is promising but currently a research tool


Palliative Management

•corticosteroids can be used to reduce edema associated with brain tumors and retard tumor growth if LSA is suspected with dramatic improvement in clinical signs which can be sustained for weeks to months

•phenobarbitone and potassium bromide can be used to control seizure activity


Surgical Management

•surgical management of brain tumors is more common with advanced imaging providing accurate information on location, size, extent and invasiveness of tumor, and improved knowledge in anesthetic, surgical, and critical care

•complete excision is determined by location, size, extent, invasiveness, and tumor type

•complete excision is more likely with:

•meningiomas (especially cats)

•tumors over cerebral convexities and frontal lobes

•complete resection of canine meningiomas is difficult because they are friable, lack demarcation from normal brain tissue, and can be infiltrative

•morbidity and mortality is high for tumors of the caudal fossa and brain stem

•partial resection can provide a histologic diagnosis and decrease clinical signs associated with the tumor resulting in a better candidate for adjunctive radiation therapy

•radical cerebral cortical resection (i.e., frontal and parietotemporal lobectomy) is well tolerated in normal dogs with unilateral orbicularis oculi paralysis common and central amaurosis following parietotemporal lobectomy

•tumor seeding is possible with cytoreductive surgery

•complications: neurologic deterioration, seizures, pneumonia, and tension pneumocephalus


Radiation Therapy


General Considerations

•radiation therapy can be used either alone or in combination with other therapies such as surgery or chemotherapy

•radiation therapy is recommended for treatment of pituitary tumors, LSA, and secondary brain tumors

•aim: destroy tumor tissue while minimizing damage to normal cerebral tissue

•orthovoltage radiation therapy has been used but is not ideal due to poor penetration and limited field configuration

•external beam megavoltage radiation therapy is preferred as, with CT and MRI imaging, treatment planning is superior with resultant decrease damage to normal tissue


Protocols

•fractionated protocols of 2.7-3.0 Gy over 3-5 weeks provides good results with minimal adverse affects

•other techniques include:

•hypofractionated protocols with 5 weekly fractions for 34 Gy total dose

•super-fractionation with ≥ 2 fractions per day

•fractionated radiation therapy combined with hyperthermia or radiation sensitizers

•boron neutron capture therapy

•brachytherapy (limited success in dogs)

•CT-guided stereotactic radiosurgery with application of highly localized single fraction of radiation


Complications

•tissue tolerance for whole brain is 48 Gy but localized tissue tolerance is 54 Gy

•adverse effects are usually late and delayed and include brain necrosis

•delayed radiation effects responsible for up to 14% (12/83) mortality rate


Chemotherapy

•chemotherapy is not frequently used for primary brain tumors due to:

•blood-brain barrier

•tumor heterogeneity may result in only certain cell populations sensitive to chemotherapeutic drugs

•brain tumors may only be sensitive at doses which are toxic to normal brain and other tissues

•options include intra-arterial delivery, high-dose systemic therapy, liposome-encapsulated therapy, and blood-brain barrier disruption (i.e., osmotic disruption or transient disruption with bradykinin analogues)

•LSA, medulloblastoma, and oligodendroglioma are very chemotherapy sensitive brain tumors

•intrathecal cytosine arabinoside has been used for CNS LSA because of good blood-brain barrier penetrations

•carmustine and lomustine (CCNU) have resulted in significant reduction in tumor size and improvement in neurologic signs in dogs with glial cell tumors


Immunotherapy

•immunotherapy mobilizes cell-mediated immunity against brain tumor

•autogenous lymphocytes are cultured, stimulated and returned to tumor bed following resection or via intercisternal injection

•reduction in tumor size and improvement in clinical signs with cerebral glioma and meningioma in dogs


Gene Therapy

•gene therapy involves transfer of DNA or RNA to tumor cells to modify their genetic make-up

•gene therapy can be used to:

•introduce genes that confer tumor cell specificity to certain drugs

•express certain genes to invoke an immune response against tumor cells

•modification of tumor infiltrating lymphocytes to enhance effect against tumor

•insertion of suicide or tumor-suppressor gene into tumor cells

•block expression of oncogenes

•insertion of wild-type p53 gene into p53-deficient tumor cells

•regulation of angiogenesis by cationic DNA lipid complexed with endostatin gene in a DNA plasmid

•introduction of viruses which destroy tumor cells as part of their replicative cycle

•delivery of gene therapy: viral and non-viral vectors

•viral include retrovirus, adenovirus, adeno-associated virus, vaccinia virus, and herpes simplex virus

•non-viral include liposomes and DNA-conjugated proteins

•route of administration important in determining ability of agent to reach the tumor with intratumoral preferred as most direct route although intravascular and intracavitary routes also utilized



PROGNOSIS


General Considerations

•female sex hormone concentration correlates with growth and biologic behaviour of meningioma

•functional importance of progesterone receptors and their modulation is unknown


Untreated Primary Brain Tumors

•MST for untreated brain tumors: 56 days in dogs

•mean ST for untreated meningioma: 75 days (and 59-81 days for symptomatic treatment) in dogs

•mean ST for untreated astrocytoma: 77 days


Treated Primary Brain Tumors


General Considerations

•prognosis is improved with interventional therapy: surgery, radiation therapy, chemotherapy, or immunotherapy

•poor prognostic factors include:

•moderate to severe neurologic signs

•rapid and progressive clinical course

•increased CSF white cell count

•involvement of multiple brain regions

•primary brain tumor other than meningioma and secondary brain tumors

•low postoperative PCV and survival in cats with meningiomas


Surgery

•MST for intracranial meningioma in dogs 138-220 days

•1-year survival rate 30%-41% and 2-year survival rate 10%

•dogs have an excellent prognosis following complete excision of solitary cerebral meningioma

•prognosis for surgical removal of meningioma in cats and dogs affected by postoperative complications such as infection, cerebral edema, and hemorrhage


Radiation Therapy

•radiation therapy associated with better prognosis than surgery alone or conservative management

•MST for primary brain tumors in dogs treated with radiation therapy ± surgery is 160-360 days to 30 months

•survival time for dogs treated with orthovoltage radiation therapy affected by severity of neurologic signs:

•MST for dogs with mild neurologic signs 21 months

•MST for dogs with severe neurologic signs 13 months

•hypofractionation protocol associated with MST 43.7 weeks

•MST better for extra-axial compared to intra-axial tumors (49.7 weeks v 40.4 weeks for intra-axial masses and 21.0 weeks for pituitary tumors)

•MST better with combination of surgery and radiation therapy than radiation therapy alone for extra-axial tumors (63.4 weeks v 49.3 weeks)

•MST is significantly improved when surgery is combined with radiation therapy compared to surgery alone for treatment of intracranial meningiomas in dogs (16.5 months v 7.0 months)

•MST 30 months for incompletely resected meningiomas and radiation therapy, with 1-year progression-free survival rate of 79% and 2-year progression-free survival rate of 68%

•1- and 2-year progression free survival rate is significantly decreased by a high tumor proliferation fraction (≥ 24%):

•1-year progression free survival rate 63% v 91%

•2-year progression free survival rate 42% v 91%

•tumors with a high tumor proliferation fraction are 9.1-times more likely to recur

•tumor proliferation fraction was inversely correlated with progesterone receptor immunoreactivity, suggesting that loss of progesterone receptors increases tumor proliferation fraction and malignant behaviour

•complication: 2nd tumor outside radiation field within 2 years

•75% (22/29) succumb to progressive neurologic disease

 

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