Brain Tumors
A Patient Guide
Table of Contents
Basic information
What are brain tumors?
There are trillions of cells in the human body that make up different tissues. Normally, these cells are usually replaced by new cells when they are damaged or old. The rate of replacement is vary variable- being very high for skin cells and very low for cells in the brain. When new cells are created without the need for old and damaged ones to be replaced, a tumor forms. In the brain, tumors usually arise from the covering of the brain or the meninges called the meningioma, from the nerves called neuromas or schwannomas or from the neuron (nerve) supporting cells of the brain- the astrocytes, oligodendrocytes or the ependymal cells. Tumors arising from the meninges (meningiomas) are the most common benign tumor while those arising from the astrocytes (astrocytomas) are usually malignant in the adult.
Are all brain tumors cancerous?
In a word – no! Like everywhere else in the body, tumors are of two main types- benign tumors that are slow growing with defined margins that almost never spread to distant sites. These are usually operable and, if successfully treated, patients have a normal life span. However, when arising in critical and difficult to reach areas of the brain they do pose significant risks to life and limb. There are also malignant tumors or cancerous tumors that are faster growing, with ill-defined margins that infiltrate the brain and may spread to distant sites. Malignant tumors may arise in the brain substance as a primary malignant brain tumor or may be the result of spread to the brain from a cancer elsewhere on the body- commonly referred to as a metastatic tumor.
What are brain tumor grades?
Brain tumours are historically divided into four grades depending on the natural history of the disease. Grade one tumours are considered to be completely benign while tumours of grade 2, 3 and 4 form a continuum of increasing malignancy. All three grades (Grades 2,3 and 4) may be present in the same tumor though the treatment and the prognosis of the tumor will be determined by its highest grade. Grade one tumours comprised of slow growing cells and resemble the normal brain cells to a large degree. They are encapsulated usually considered to be ‘surgical lesions’. When removed completely there is no reduction in life expectancy. Grade two tumours are composed of relatively slow growing cells but are not encapsulated and infiltrate the adjacent normal brain. These tumor cells can be differentiated from normal brain cells by their pleomorphic appearance ( cells are varied in size, shape and the appearance of their nuclei). Invariably, all grade 2 tumors progress to those of a higher grade which has a markedly worse prognosis. Grade three tumours are formed by cells that are actively dividing (mitosis) and show little or no resemblance to the normal brain tissue. A significant proportion of these actively dividing cells invade the adjacent normal brain tissue. Grade 4 for tumours have the worst prognosis and consists of abnormal cells that divide rapidly. There are usually areas of neovascularisation (formation of new blood vessels) in and around the tumor that surround an area of central necrosis (area of dead cells) caused by tumor growth outstripping the blood supply. Grade 4 lesions are known to spread through the neural tracts or the CSF pathways and may even be found on the opposite side of the brain at presentation. Grade 4 tumors have a dismal prognosis. Though tumors of lower grades progress to higher ones, these are in the monority and usually occur in younger adults. The most common malignant tumor occurs in older adults is Glioblastoma and presents at Grade 4.
A large left temporal glioblastoma – patient presented with difficulty on speaking
Till recently, the pathological diagnosis by microscopic examination of the tumor was the only method used in diagnosis and prognostication. Treatment was more or less standardized across the spectrum for all patients with that particular disease. However, with the recent advances in diagnostics, molecular markers now play an equally important role in prognostication and treatment of tumors. For example, pathologically grade 2 gliomas may behave in a much more aggressive fashion if there is a loss of Chromosome 10, a gain of Chromosome 7 and an amplification of EGFR or the deletion of cell cycle regulators CKN2A and CKN2B. On the other hand, medulloblastomas with WNT pathway mutations have a much better prognosis than the other molecular subtypes. Such advances in treatment has meant that even tumors that are identical in pathological grade and diagnosis, outcomes may be variable- dependent on the molecular markers and the targetable mutations that are present in the tumor.
An MRI scan showing a large benign meningioma- Grade 1 tumor
Signs and Symptoms
Symptoms common to most brain tumors
Headaches
Nearly all of us get headaches that are transient. Even in people with recurring, severe headaches like migraine and cluster headaches a very small percentage ( far less than 1%) have brain tumours. In fact, less than 1 in 9000 patients who suffer from headaches will have a tumor, though every brain tumor patient will complain of headache at some point in the course of their disease. Characteristically, tumor headaches are worse in the morning, progressively increase in intensity and duration in-spite of medication, may be associated with vomiting, drowsiness, paralysis or difficulty in speaking or understanding. Patients who normally have headache will often describe brain tumour headache as ‘different’ from their usual symptoms. With nebulous presenting signs, and a very low incidence when compared to other pathologies, the diagnosis of brain tumors is often delayed.
Seizure/ Fits
A ‘fit’ or a seizure is a period of sudden abnormal electrical activity of the brain that usually results in loss of consciousness, uncontrolled movements of the arms and legs, biting of the tongue and frothing at the mouth. Sometimes it occurs without the loss of consciousness and at times it is marked only by a subtle change in behaviour or an abnormal sensation sweeping through one half of the body (sensory seizures). Seizures occur in a variety of different neurological diseases and are not limited to brain tumors. Seizures in patients with brain tumors are more common in tumors of a low pathological grade (though the finding is not invariable) and those that are close to the sensory or motor areas of the brain or the temporal lobe.
Symptoms due to increase in pressure inside the head
A rapid increase in intracranial pressure is characteristically diagnosed by the clinical triad that consists of increasing headaches, drowsiness and projectile vomiting. However, a more gradual rise in pressure may cause changes in a persons’ behaviour and seizures. While increase in intracranial pressure is invariable, the onset of symptoms is dependent on the rate of tumour growth. While tumors close to the eloquent areas of the brain will present with some other symptom, those in the silent areas ( the frontal lobe) may remain undetected till their size is big enough to cause an increase in intracranial pressure.
Symptoms caused by the dysfunction of specific parts of the brain.
Tumors of the cerebral hemispheres
These tumours occur in the cerebrum- the largest portion of the brain. Signs and symptoms vary, depending on the lobe involved. Tumors arising from the meninges or meningiomas are usually benign but may grow to be very large if present in a silent area of the brain. Tumors arising in the substance of the brain are usually malignant- glioblastoma or a grade 4 tumor arising from the glia being the most common in adults.
Frontal Lobe
Frontal lobe tumours or notorious representing late. The onset of symptoms are often insidious and are related to changes in behaviour and personality. Problem solving and lack of concentration are also commonly seen. Memory may be affected. When tumours affect the posterior part off the front lobe (the motor strip) there may be seizures or a weakness of the opposite side of the body.
Parietal Lobe
The parietal lobe deals with the sensory input from the rest of the body. Patients with parietal lobe tumours find it difficult to recognise the position of their body parts, may have left right confusion or inattention of one side of the body ( may only shave one half of the face). A decrease in higher mental ability, especially arithmetic may also be seen.
Temporal Lobe
Temporal lobe tumours may also be fairly large at presentation. The left temporal lobe is where the speech and language centre is usually located in all right handed and a percentage of left handed people. The hippocampus, a part of the temporal lobe that deals with memory, is known to cause seizures when damaged. So tumours in the temporal lobe often present with seizures or with a variety of speech and language disturbances- inability to speak or understand the spoken word or inability to repeat what is being said. In addition, thalamic tumors may involve the limbic system of which the hippocampus is a part. This causes changes in behaviour including hallucinations and abnormal reactions to the ‘fight’ or ‘flight’ response.
Occipital lobe
The occipital lobe processes the visual input. As this lobe deals with the interpretation of what is being seen, tumors of the occipital lobe will impair the ability to recognise objects. There may also be complete loss of vision or more frequently quadrant or one half of the visual field.
Optic Nerve sheath tumors
The optic nerves carry information from the eyes to the occipital lobes via the optic tract and the optic radiations. Hence tumours of the optic nerve or of the sheath that covers it leads to a loss of vision. This may be limited to one eye, one quadrant of one eye or both eyes if the tumor is located on both nerves or at the confluence of the two nerves commonly known as the chiasm. Optic nerve sheath tumours usually occur in children less than 10 years old and are overwhelmingly benign in nature with 5 year survival exceeding 75%.
Cerebello-pontine angle tumors
These tumours often present with unilateral hearing loss and are often detected when patients complain of being unable to hear conversations on their mobile phones. Very large tumours may present with difficulty in walking, double vision and at times decreased sensation to one side of the face. Facial weakness is an uncommon presentation. Meningiomas and schwannomas are the most common tumours in this location and can be either surgically removed or treated with focused radiation.
Brain stem tumors
The brainstem is a vital part of the brain that connects the cerebrum to this spinal cord. It consists of three parts – the midbrain, pons and medulla. Tumors of the midbrain are usually benign and cause difficulty in looking up. Tumors of the pons are usually seen in children and present with difficulty in walking, unsteadiness and double vision when looking to one side. Tumors of the medulla can present with weakness of the arms and legs, sensory disturbance of one side of the body or involvement of the lower cranial nerves that deal with movements of the tongue, the palette or of the muscles of the neck. Tumors of the midbrain and the medulla are usually benign, and may be removed surgically. However, tumours affecting the pons are malignant. The pontine tumors that affect children (Diffuse Intrinsic Pontine Gliomas) have a very poor outcome, with children usually surviving a few months. In these cases, surgery is not appropriate, if the radiological diagnosis is certain.
Thalamic tumors
The thalamus is the ‘central exchange’ for all the sensory tracts of the body. Thalamic tumors may cause tremors or a change in sensory perception on the opposite side of the body. Thalamic tumors present a surgical challenge as they are located in the centre of the brain. In children, encapsulated pilocytic astrocytomas do very well with surgical excision. However, malignant thalamic tumors have a very poor outcome.
Hypothalamic and Pituitary tumors
Hypothalamic tumors may present in children with morbid obesity where there is an increased appetite for food. Some present with uncontrollable fits of laughter, which is a form of epilepsy. These are difficult tumors to operate and tumors at this location are far more common in children. Tumors are usually benign in nature, but due to the effects of the tumor on the hypothalamus, management of these children with multiple endocrine and behavioural issues is often difficult.
Posterior Fossa tumors
These tumours arise from the back of the brain and affect mainly the cerebellum, the medulla, the 4th ventricle and the choroid plexus. Cerebellar tumors classically produce unsteadiness of the body even while sitting (truncal ataxia), a wide based gait, and an uncoordinated pattern of walking . A percentage of these patients will also have tremors. In children, the cerebellum is the site for the benign pilocytic tumors, which can be cured by surgical excision. Medulloblastomas also occur usually in children, are malignant tumors arising from the midline and have a variable prognosis. In adults, metastatic disease is the most common tumor of the cerebral hemispheres, though benign cysts are also commonly seen.
Tumors of the sella and anterior skull base
The pituitary gland is referred to as the ‘bandmaster of the endocrine orchestra’ lies at the base of the brain in the midline, just below the optic nerves, in the anterior skull base. Along with meningiomas it constitutes the majority of the tumours in this region. Anterior skull base meningiomas are usually large as they grow in a relatively silent area of the brain. They sometimes cause symptoms associated with the frontal lobe dysfunction or that of the pituitary gland. The pituitary gland releases hormones that control functions of endocrine glands. Functional pituitary tumors secrete hormones while non-functional tumors often hamper the production of hormones of the pituitary- resulting in a hypopituitarism. Non-functioning tumors are more common, and may grow to be big enough to press in the optic nerves and cause a decrease in vision.
Causation and risk factors
Brain tumor epidemiologists have studied risk factors to try and explain why people develop brain tumors, by observing habits, lifestyles and geographical locations of patients with different types of tumors. Many environmental studies have been performed looking at air pollution, residential power lines, agricultural and industrial waste, history of head trauma, epilepsy, consumption of processed foods, smoking and even the use of cell phones. All these factors are difficult to measure accurately leading to inconsistencies in the results in many of the published studies. Additional long term studies are required before the ‘cause and effect’ relationship can be established. Of the long list of factors that have been studied, only ionising radiation in the form of high frequency energy waves such as gamma rays or x-rays have consistently shown to increase the risks of developing a brain tumor. Adult brain tumors are often seen in those who have had radiation as a child. On the other hand, a history of allergies as an adult, eating fruits and vegetables or having a mother who has eaten fruits and vegetables during pregnancy or having had chickenpox as a child has been shown to reduce the risk of developing a brain tumor. Over the last decade, multiple large studies have been performed both in the United States and in Europe to look specifically at the use of cell phones in developing brain tumors. Studies have produced conflicting results. However no consistent association has been found between the use of cell phones and the risk of developing a malignant or a benign brain tumor. The risk of developing a brain tumor with prolonged and heavy use for more than 10 years may only be slightly increased, if at all.
Only five to 10% of all cancers are hereditary- or run within families. These are associated with very specific genetic syndromes caused by a germline mutation (a change in the genetic code that is present in every cell of the body as opposed to a mutation limited to the cancer causing cells alone that causes the cancer) and is passed on from parent to child. Some of these syndromes include neurofibromatosis type 1 that affects the NF1 gene, neurofibromatosis type affecting the NF 2 gene, Gorlin’s syndrome affecting the PTCH gene, Tuberose Sclerosis (TSC1), Li Fraumeni Syndrome (TP53 gene) and Turcots (APC gene). Germline mutations are present at birth and these tumors usually present in infancy or in early childhood and are often multiple. However, this subgroup forms a very small percentage of the total brain tumor burden.
Diagnosis
If the signs and symptoms arouse a high degree of suspicion a brain scan is performed. This may be a CT scan – which is cheaper, quicker and often easier to arrange. CT scans use conventional x-rays to build an image of the brain a slice at a time. During the scan a special contrast material may be injected into the veins to better delineate the tumor. However, as the link between X Ray radiation and cancer is established, the gold standard for brain tumour diagnosis is the MRI scan, which is completely safe even in pregnant women. MRI scans do not use X-Rays but rely on a ‘radio frequency pulse’ disturbing a magnetic field in which the patient lies. When the pulse stops, the atoms relax- giving off differing amounts of energy at different intervals of time. These signals are picked up by sensors and fed into a computer to generate a picture. Barring any contraindications, a contrast material, gadolinium, is injected into a forearm vein and that helps demarcate the tumor better. Magnetic resonance spectroscopy is often used as a natural extension to the MRI scan and measures the levels of N-Acetyl- Aspartate (NAA) and Choline- the ratio of which is altered in malignant tumors when compared to normal brain. Scans to detect cerebral blood flow or cerebral blood volume along with Dynamic MRI and CT scans may also be performed to demonstrate the vascularity of the tumor. Functional MRI scans show the relationship of the tumor to the eloquent areas of the brain- ie the cortico-spinal tract, that controls the movement of the opposite side of the body, or areas of the brain associated with language and memory. Positron emission tomography (PET) Scans are not routinely used in brain tumor diagnosis but may be used if metastatic deposit to the brain is suspected. PET scans do not produce high quality pictures of the brain anatomy and are therefore used in conjunction with CT and MRI images. Tumours in special locations may require additional tests. Cerebellopontine angle tumours often cause a loss of hearing and therefore an audiogram may be performed. An endocrine evaluation is performed for all tumours of the pituitary gland and that of the hypothalamus. Additional examination of the visual fields are also performed in pituitary tumours or in tumours anywhere along the optic pathway to formally document any loss of vision prior to surgery.
Common types of brain tumors
Gliomas in adults
Gliomas are the most common intrinsic brain tumour and occur throughout life. They are broadly classified into 4 grades of increasing malignancy and usually constitute two distinct cells of origin- the astrocytes and the oligodendroctyes. Well circumscribed grade 1 tumours are rare, and adults usually have the diffusely infiltrating tumours that ranges through grades 2-4, with tumours either being Gd 4 at presentation, or progressing to Gd 4 from the lower grades over time. Circumscribed grade 1 tumours do not transform to the more malignant higher grades. Recently, all glial tumours were classified on the basis of a mutation in the IDH (Isocitrate dehydrogenase, a gene of the Krebs Cycle, is a good prognostic indicator). Though the pathological phenotypic grade is of some value, it is being increasingly noted that the mutational profile of the tumour, especially in diffuse gliomas, determines its behaviour. Tumours in younger adults are usually less aggressive and are IDH mutant. However, the most common glioma in adults is ‘glioblastomas’- an aggressive grade 4 tumor. Glioblastomas are normally seen in the seventh and eighth decades of life and constitute more than 50% of all adult gliomas. They have a dismal prognosis, with a 5 year survival of less than 5%, with the majority succumbing to the disease within one year of diagnosis. Surgery aids in the reduction of symptoms, but makes negligible improvement in overall survival. Radiation is the mainstay of treatment, though certain subgroups of gliomas that have distinct molecular signatures may benefit from chemotherapy. Oligodendroglial tumours, by definition are IDH mutant and have been shown to have better outcomes when treated with procarbazine, cisplatin and vincristine. Astrocytic tumors with a methylated MGMT ( a tumor repair gene) gene benefit maximally from the administration of temozolomide, though astrocytic tumors without the methylation also show some benefit. In the absence of any other specific medication that works, Temozolomide is now the standard of care in astrocytic tumors and is used in the treatment of all gliomas.
Gliomas in the pediatric population
In children, gliomas are again broadly classified into high and low grade tumours, but unlike adults, the classification is not based on IDH. A significant percentage are grade 1, or circumscribed tumours are IDH(wt), though they have an excellent prognosis. These include Pilocytic astrocytomas, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytomas, choroid gliomas and astroblastoma. Pediatric low grade diffuse gliomas include several molecular subtypes- Diffuse Glioma MYB or MYB-L1 altered, angiocentric glioma, polymorphous low grade neuroepithelial tumor of the young (PLNTY) and diffuse glioma- MAPK- pathway altered but all of them have a good prognosis . Mixed glial and neuronal components are seen in glioneuronal tumors which also carry a very good outcome. These include ganglioglioma, desmoplastic infantile ganglioglioma, gangliocytoma and dysembryoplastic neuroepithelial tumors. In addition, the classical high grade tumor in the young is one that affects the brain-stem particularly the pons ( the midbrain, pons and medulla- as the nerve fibres descend from or ascend towards the cortex) and are called Diffuse Intrinsic Pontine Gliomas (DIPG). These tumors carry a characteristic mutation of the histone protein (histone is the protein in the centre of the DNA double helix, to which the DNA is bound) H3K27M and is known to have a dismal prognosis. H3K27M mutations are also seen in other tumours (ependymomas) and in midline tumors of the cerebral hemispheres. H3 G34 histone mutation also results in high grade glial tumors, but these occur in the cerebral hemispheres away from the midline. The two other types of high grade gliomas are the H3K27(wt) IDH(wt) tumours and the infant type hemispheric gliomas. Pediatric high grade gliomas, almost universally, have a very poor prognosis.
Ependymomas
Ependymomas can develop in the spinal cord or the brain. Spinal ependymomas are less common and have a better prognosis than intracranial ependymomas. Ependymomas have been classified into various histo-molecular subgroups with differing outcomes in the revised WHO classification of CNS cancers for 2021. To a large extent, the molecular subgroups are location specific. Ependymomas occurring above the tentorium (formed by two leaves of dura that separate the forebrain above from the hindbrain below) have characteristic gene fusions ZFTA and YAP1. YAP 1 mainly occurs in children and has a better prognosis. The tumours of the cerebellum do not have these characteristic fusions and are classified on the basis of ‘methylation studies’ (methylation of a gene decreases the RNA produced. If all the genes are screened for the amount of methylation, a tumor signature emerges) into posterior fossa A (PFA) and posterior fossa B (PFB). PFB tumors have a better prognosis when compared to PFA tumors. Spinal ependymomas are usually indolent and occur in adults, where myxopapillary ependymomas of the conus medullaris predominate. Recently however, a highly aggressive subgroup of spinal tumors with MYC-N amplification has been identified that has a very poor prognosis. Whether performing the initial surgery or a subsequent operation, a complete resection must be carried out because the majority of studies have demonstrated a significant impact on the extent of resection. For grade 3 or partially resected grade II tumours, conformal radiation is advised. Particularly in children, proton treatment is being used more frequently to lower the risk of neurocognitive and endocrine side effects. Cranio-spinal irradiation is used only for metastatic disease. Chemotherapy only used as a last resort is largely ineffective.
Pituitary tumors
The pituitary gland controls the function of several endocrine organs of the body- including the thyroid, adrenals, breast, ovaries and testes. The posterior part of the pituitary gland also controls sodium metabolism in the body- Na being the most common extracellular electrolyte. Anatomically, it occupies a very crucial position just below the optic nerves in the anterior skull base- large tumours press on the optic nerve or the chiasm often present with defects in the peripheral field of vision or in extreme cases- blindness. Functional pituitary tumors can result in a wide variety of symptoms that depend on the hormone produced- including diabetes mellitus (increase in blood glucose), weight gain, purple striae over the trunk -all caused by the secretion of ACTH that increases the secretion of endogenous steroids (Cushing’s Disease). Prolactin secreting tumors or prolactinomas result in decreased libido and may also present with the abnormal discharge of milk from the breasts. These may be extremely large at presentation but are treated medically with dopamine agonists- either bromocriptine or cabergoline, though cabergoline has been shown to be more effective in most cases. The excess production of Growth Hormone can lead to acromegaly in adults and gigantism in children. Acromegaly is characterised by the increase in the size of the hands and feet (noticed by an increase in the shoe and glove sizes) and a protrusion of the lower jaw- called prognathism. The first line of treatment includes the administration of Octreotide or Lanreotide- surgery reserved for patients with progressive visual failure or those who do not respond to therapy. The vast majority of pituitary tumors are benign. Small non-functioning tumors that are discovered incidentally, may be followed up at periodic intervals with an MRI scan. For all other tumors of the pituitary, apart from prolactin and growth hormone secreting tumors, surgery is the first line of treatment. The tumor is approached through the nose and the sphenoid sinus, which lies just below the gland. The use of endoscopes has further improved the surgical outcome in these patients. Radiation is reserved for tumors that are refractory to medical and surgical treatment. Fractionated radiotherapy does protect radiation exposure to the vital structures that surround the pituitary, but stereotactic radiosurgery has the benefit of a single sitting- and the pros and cons of treatment has to be tailored to each patient.
Acoustic Neuromas
These are tumors of the vestibular nerve or the nerve of balance (which is intertwined with the the cochlear nerve (the nerve of hearing) and runs adjacent to the nerve that supply most of the muscles of the face or the facial nerve) normally presents with one sided hearing loss, usually noticed while speaking on the phone. Large and very large tumors may present with other symptoms including abnormal sensation on one side of the face, double vision or even difficulty in walking. These tumors are largely sporadic but may be a part of genetic syndromes like neurofibromatosis. Surgery remains the treatment of choice in large tumors but in tumors that are less than 3 cms in diameter Stereotactic Radiosurgery (SRS)is an option. The main risk of surgery is the injury to the facial nerve during surgery results in the paralysis of one side of the face. Intraoperative facial nerve monitoring, however, has reduced the percentage of patients with post operative facial nerve paralysis dramatically.
Medulloblastomas
Medulloblastomas are the most common childhood malignant brain tumour with a peak age of diagnosis between 6-8 years, although it can occur in the first year of life. Histo-morphologically it is an embryonal tumour that arises in the cerebellum. The mainstay of treatment includes total removal of the tumour, cytotoxic chemotherapy and radiation (not in the under 3 year olds). In patients who do not have metastatic disease (detected by a lumbar puncture or an MRI of the spine), have a total resection and are more than 3 years (low risk group) old have a 5 year survival of about 75-80%, while the number dips to 70%, if any one of the factors is missing (high risk group). Genetically, medulloblastomas are divided into 4 separate subgroups. The WNT subgroup accounts for only 10% of medulloblastomas but has an excellent prognosis in patients less than 16 years old. WNT is the second group and they have been further subdivided using methylation arrays and each one of which has a different prognosis. SHH subgroup is the second subgroup and activation of the Sonic Hedgehog Pathway is the hallmark. This pathway is dominant in infants and adults and accounts for more than two-thirds of the cases. In older children and adolescents the SHH subtype is usually marked by the mutation and inactivation of the tumour suppressor TP53 and has a poor prognosis. In adults however, the mutation patterns for the SHH subtype are different and the prognosis is better. Targeted therapies in clinical trials have shown promising results in adults. Subgroup 3 is defined by MYC gene amplification and occurs in about 25% of cases and is usually seen in early infancy and childhood. This is known to have a poor outcome in general except for designated subtypes that have aneuploidy (an extra or a missing chromosome resulting in an unbalanced set). Subgroup 4 is not associated with any single somatic gene mutation but the putative driver seems to be the gene PDRM6 that is found in 17% of cases. The outcome is dependent on the risk profile and the low risk group with a chromosome 11 loss or chromosome 17 gain have an exceptionally favourable outcome, in contrast to the high risk group in which the prognosis is poor.
Meningiomas
Meningiomas are predominantly benign tumours that arise from the arachnoid cap cells of the meninges. Though predominantly benign or grade 1, a proportion of Grade 1 tumors recur. Surgery is the mainstay of treatment, radiotherapy being reserved for the minority of tumours in grade 2 and grade 3. Recently, several studies have identified gene clusters that better predict grade and recurrence rates when compared to the WHO classification. Meningiomas also occur with germline mutations with the Neurofibromatosis Type 2(NF2) gene being most commonly mutated. Other germline mutations including SMARCE1 of the SWI/SNF complex and mutations of SUFU in the Hedgehog pathway have recently been identified. Tumors that arise from germline mutations usually occur at a much younger age and are often multiple. They tend to recur more than the usual tumors and surgical options do run out at some point in the course of their disease. Targeted therapy may become an option for these patients in future.
Metastatic tumors
These are the most common intracranial tumors and seem to preferentially occur in lung, melanoma, breast, renal and colorectal cancer. The genetics of the primary tumor is different from the brain metastasis which makes treatment of the primary tumor ineffective against the brain metastasis. In addition, metastatic disease may be parenchymal- or within the substance of the brain (parenchymal) or limited to the CSF space that is bounded by the brain and the meninges. The prognosis of the brain metastasis will depend on the Graded Prognostic Assessment (GPA) that takes into account the primary tumor, patient’s age, degree of functional impairment, co-occurrence of extracranial metastasis and the number of brain metastasis, with each parameter being graded from 0 or 0.5 to 1- which translates to the outcome. A breast cancer patient with a GPA of 0 survives approximately 3 months while one with a GPA of 4 survives 2 years or more. The treatment for one large metastatic deposit or 3 metastatic deposits in the same craniotomy field would be surgery followed by stereotactic radiosurgery- though stereotactic deposit may be used for multiple tumors in the brain, irrespective of position. The whole brain radiotherapy has fallen out of favour because of the side effects, especially with regard to learning and memory which starts about 4 months after treatment. Targeted therapy is an option for a select number of mets that respond to drugs that cross the blood brain barrier. These include Erlotinib used for lung cancer mets with EGFR gene mutations or crizotinib for translocated ALK of Dabrefinib for BRAFV600E mutations. Research on immune checkpoint inhibitors is underway, though their exact role in the treatment of metastatic brain disease remains unclear.
Treatment
As with any disease there are three options for treatment :
Do nothing
This may be appropriate for tumours that rise in the frail and elderly who have brain imaging for some other reason. Meningiomas (benign tumours that arise from the covering of the brain) are most commonly detected. A repeat CT or MRI scan done at an interval is all that may be required. At the other end of the spectrum, aggressive malignant tumours with limited survival may not mandate treatment in the extremely elderly and fragile, or those who already have a number of comorbidities. In some of these cases even a biopsy is deemed to be too risky. These patients are usually best treated by palliative care.
Regular observation
In tumors or tumor like lesions where the exact nature is not certain. It also applies to lesions in inaccessible parts of the brain where treatment is associated with high degrees of mortality or morbidity in someone who remains neurologically intact. Though this used to be the practice in lower grade tumors, this is no longer the case and the indication for ‘wait and watch’ in brain tumors is constantly shrinking.
Treatment
In the large majority of tumours treatment will be required urgently to prevent further growth of the tumor, and to establish a pathological diagnosis which will help stratify treatment.
Surgery
This is more often than not this is the first step in treatment which may either involve only a biopsy or a larger resection (removal). If only a biopsy is being contemplated, this is usually done by insertion of a needle into the brain through a burr- hole (13 millimeter hole drilled in the skull). Needle biopsies are nowadays guided to the precise location within the brain tumor either by the application of a frame on the head or by frameless computer aided navigation, a procedure commonly known as stereotaxy. When removal of part or the whole tumor is contemplated, a craniotomy (procedure where part of the skull is removed for access to the brain tumor) is performed. Following the craniotomy the tumor is removed using endoscopic resection or microscopic neurosurgery. Craniotomies can also be more accurately localised by the use of intra operative image guidance systems or an intra operative MRI. Intra operative MRI is invaluable in determining the volume of residual tumor, if any, in real time, that may not have been apparent to the surgeon at the time of resection. As prognosis depends on the amount of tumor removed, radical removal of the tumor without causing any neurological deficit is the aim of every surgeon. However, radical surgery is not without its risks which may outweigh the possible benefits- especially in patients who present in poor neurological or general condition. In these cases, surgery may be performed to remove part of the tumor and reduce the intracranial pressure that may alleviate symptoms. In a few selected cases, surgery is used for the implantation of radiation implants or chemotherapeutic wafers or provide direct access for the external administration of chemotherapeutic agents.
Radiation
Following surgery, radiation is invariably recommended for all malignant brain tumors. This can be administered from an external source and uses beams of X-Rays, gamma rays, photons or protons to directly destroy the tumor cells. However, the effects of radiation are not limited to the cancer cells alone and do affect the normal healthy cells as well. Healthy cells possess the capacity to regenerate and recover quickly from the effects of radiation. As radiation continues, an increasing percentage of cancer cells die and are removed by the body’s immune system. A certain percentage of normal cells also die but regenerate with time. Currently, radiation can be administered in several forms. The most commonly used modality is the IMRT, or Intensity Modulated Radiation Therapy, which allows for changes in the strength of radiation beams in sensitive areas, while allowing maximal concentration at the tumor bed, reducing the damage to normal tissue. 3-D conformal radiation is an improvement on the IMRT technique and allows for a higher dose of radiation to be delivered to the tumor tissue. Recently newer types of radiation have also been added to the armamentarium. Stereotactic Radiosurgery or SRS allows for accuracy up to a millimetre and can use either beams of photon or proton. This type of radiation is useful for few (less than 4), small ( less than 3 cms) lesions with well-defined margins in hard to reach areas of the brain. In brachytherapy the radiation source is placed directly within the tumor cavity. A flexible collagen tile impregnated with radioactive material is placed within the brain bring tumor cavity and allows the maximum amount of radiation within the tumor cavity with relative sparing of the normal brain. Proton therapy is one of the newer additions to the radiation armamentarium- where positively charged particles or protons deliver a high level of energy to the tumor site, with little impact to the normal tissues in its path. It is probably the treatment of choice when radiating brain tumours that are near vital structures of the brain and in children where long term ill effects of radiation on normal tissue is well documented.
Chemotherapy
The use of chemotherapy in brain tumours has been long established. In a seminal study done in the mid 1980s it was shown that PCV (Procarbazine, Lomustine and Vincristine) chemotherapy improved the survival of oligodendroglial tumours. Temozolomide, is now the chemotherapeutic drug of choice in gliomas and is administered orally along with radiotherapy
Experimental therapies
The survival of certain tumours remain low in spite of standard of care treatment. Hence, several other therapies are now in various stages of clinical trials. Targeting specific pathways like EGFR, PDGFR, TP53 and RB1 are now being tried in the clinics – EGFR1vIII can be targeted by the EGFR vaccine Rindopepimut; KIT amplification or mutation can be targeted by Imatinib; BPO amplification can be targeted by Dasatinib and mTOR by the AKT inhibitor / mTOR inhibitor Voxtalisib. MDM2 and TP53 are targeted by the MDM2 inhibitor AMG232 while RB1 wild type may be targeted by CDK4/6 inhibitor Ribociclib. In addition, the use of monoclonal antibodies like Bevacizumab that binds to VEGF have also been tried for glioblastoma. However the most exciting research is in the ‘immune checkpoint’ blockade. Tumors often evade the body’s own immune system that would normally destroy cancer cells. T-cell inhibitory molecules such as anti-programmed cell death 1 (PD1) antibody have already been approved for the use in malignant melanoma and will surely find its way in the treatment of brain tumours. Several vaccines are now in clinical trials for patients with glioblastoma, with some of them showing very promising results.
What do you need to ask the doctor?
It may be difficult for doctors to talk about your brain tumor especially if the prognosis is poor- no one wants to be the harbinger of death. There often are a lot of factors that add up- a busy clinic, lack of privacy, lack of the patient interest in asking questions etc. However, none of these should ever stop you from getting all the information that you think you need.
Listed below are some of the relevant questions that I have been frequently asked before brain tumor operations.
Before surgery:
What does the scan show? What do you think it is, doctor? What is the prognosis of such a disease?
What will you do doc? Why surgery/biopsy? What are the chances of surviving such an operation without a significant neurological deterioration ? What are the risks to life? Are there any other modalities of treatment that are available now or may be needed after surgery – ie chemotherapy or radiotherapy. If inoperable, what are the other options ? What about the possibility of participating in clinical trials/ experimental therapies.
Ask how urgent is the surgery? How much notice do you need, doctor, to schedule the operation? What tests need to be done before surgery? How long will the surgery take? How many days in ICU/ how many days in hospital? When can I expect to go back home and then to work?
And finally, ask about cost. Budget? And what is covered? . Though cost will be a major factor that decides where you have treatment, it is always good to get a clear picture of what is being offered for the price.
It is your right to get a second, a third or even multiple opinions as the outcome is dependent on the surgeon and the practices/facilities at the hospital. However, your doctor sees patients with brain tumors day in and day out, and their knowledge and experience on what is feasible in your particular instance will probably outweigh any google search. So what they tell you will almost invariably be true, barring very few exceptions.
After surgery:
Ask about the specific pathological grade and prognosis and about the availability of advanced molecular testing. Ask if it is available in the hospital. If molecular testing is not available, ask where the centre sends its samples.
Coping
The diagnosis of a brain tumor can evoke a number of different emotions – denial, anger, resentment and finally acceptance. Unlike the Western nations, in India, the diagnosis is often shared with the family first and the plan of care is often discussed with them first- the spouse, the son, the daughter and people who are close to the patient. Invariably, the first reaction of the family is to ask the doctor not to tell the patient the diagnosis- assumptions are made about how the patient would cope with such news. The doctor is often asked to downplay the severity of the disease. Though this may temporarily reassure the patient, all patients at some point figure out that a brain operation, days in ICU, weeks of treatment first as an inpatient and then as an outpatient in the cancer centre is not a trivial matter and that his/her loved ones have not been entirely truthful. This often breaks the trust not only with the doctor but also with the near and dear. Patients are trapped in worries of their own, unable to discuss their feelings with anyone. As a result they become withdrawn, depressed and have miserable existence. So it is always preferable to be honest with the patient without taking away hope, gradually telling him the diagnosis and the plan of care. Though there may be an initial burst of negative emotions- anger, denial and despair it will finally lead to acceptance. While the situation may remain grim, it is important to concentrate on the positives and keep his/her spirits up with words of encouragement. Having family and friends around does help. As does praying at home, or going to a place of worship or reconnecting with one’s faith. It does seem to have a calming effect on the majority- the mind is temporarily distracted from pain and suffering.
With brain cancer, the road is long and hard- both for the patient and the family. So in addition to what can be done at home, professional services are also important. Getting a physiotherapist to help with mobility, talking to occupational therapy about changes that are needed at home may significantly improve the quality of living and provide valuable relief for the caretaker. It is also important to realise the mental toll this takes- not only for the patient but also for the primary caregiver. There will be times when the primary caregiver would be at his/her wits end and want this to end. The next moment, he/she would be wrapped in guilt for wanting her near and dear dead. These moments are common in brain tumor households- relationships and friendships are strained to their limits. In these circumstances professional help can help not only the patient but also the caregiver- a trained clinical psychologist often provides the much needed outlet. Not only is it a non-judgemental hearing, but it also provides tips and strategies for coping with the stress.
Other resources
For patient and caregiver related information you may also visit-
For clinical trial and experimental therapies