What causes brain tumours?

The short answer is that no-one knows why brain tumours occur. There are many theories, some of which are scientifically sound, others being nothing more than speculation. Here are some of those theories. Please remember that no definitive cause has been found and therefore we should not draw any firm conclusions based on non-factual information:

Genetic Arguments for this theory are mostly based on the close
association between some congenital syndromes and brain tumours. There is a condition called neurofibromatosis(NF) that is characterised by multiple soft tissue tumours. The abnormal chromosome has been localised to chromosome 22 and 17. Those with NF1 may suffer from tumours anywhere along the visual tract and those with NF2 get tumours of the vestibular nerve. Also, some people with brain tumours have an over-expression of certain growth factors (PDGF) and cancer genes (proto-oncogenes) and a depletion of tumour suppressor genes. These genes and growth factors are found in many people without cancer.

Ionising Radiation Ironically, radiation that is given in limited doses to treat patients with malignant tumours, may also cause malignant brain tumours when given in higher doses.

Electromagnetic Radiation The Scandinavians first alerted us to the adverse effects of very low frequency EMR. They showed quite conclusively that people who lived close to high tensile electrical wires were at greater risk of developing cancers, including brain tumours. To extrapolate this data to other electrical appliances may be over-reacting but it is generally accepted that one should try to limit exposure. Mobile phones emit EMR. More info.

Immunosuppression The scientific community accepts unequivocally that the immune system plays an important role in the genesis and control of any malignancy. The relative importance is disputed. Some people with brain tumours do have deficiencies in their immune system, but the majority are not immunosuppressed. Dr Teo is a strong believer in the importance of keeping the immune system primed. This can be done with exercise, a diet rich in anti-oxidants, positive thought, reduced stress and laughter.

What is the link between brain cancer and extremely low frequency electromagnetic radiation? For most scientific claims, one can find articles for and against. The jury is defnitely not “in” for the argument asscociating brain cancer with electromagnetic radiation. Here are several quotes from Bondy et al regarding the association between brain cancer and extremely low frequency electromagnetic radiation.

“Studies of residential wire codes and brain cancer in children, and of occupational EMF exposures and brain cancer in adults suggest that EMF exposure may be associated with brain cancer.” “Wertheimer and Leeper were the first to report a significant association between childhood cancers (most notably leukaemias and brain cancer) and residence near high-current configuration wiring (high-tension wires and wires emanating from local or substation transformers) in the Denver area. Children with brain cancer were 2.4 times more likely than children without brain cancer to have lived in homes with high-current-configuration wiring. In a subsequent independent study in Denver, Savitz et al. also found that children with brain cancer were twice as likely as control subjects to have lived in residences with high-current-configuration wiring. In a large study in Sweden, Tomenius reported similar results.”

Bondy et al. “Environmental Risk Factors in the Development of Brain Tumors” in The Practice of Neurosurgery Tindall et al (eds) Williams & Wilkins; Philadelphia, 1996  pp 517-528.

Savitz DA. Case-control study of childhood cancer and residential exposure to electric and magnetic fields. Albany,NY:NY State Power Lines Project, 1987; Contact    no.218217.

Savitz DA, Wachtel H, Barnes FA et al. Case-control study of childhood cancer and exposure to 60-Hz magnetic fileds. Am J Epidemiol 1988;128:21-38.

Tomenius L. 50-Hz electromagnetic environment and the incidence of childhood tumors in Stockholm County. Bioelectromagnetics 1986;7:191-207.

Wertheimer N, Leeper E. Electrical wiring configurations and childhood cancer. Am J Epidemiol 1979;109:273-284.

What is a primary brain tumour?
This is a tumour that has developed from normal brain cells such as astrocytes, ependyma and oligodendroglial cells. They are often referred to as intra-axial tumours.

What is a secondary brain tumour?
A secondary brain tumour has spread to the brain from a primary tumour elsewhere in the body. Secondary tumours (in any part of the body) are also known as metastases.

What is an intracranial tumour?
These are tumours arising from structures in and around the brain, but not the brain itself. Because they are so intimately connected to the brain, they are often (inaccurately) called brain tumours.

What are the most common kinds of brain Tumours?
The most common type of primary brain tumour is a glioma. The most common type of glioma is an astrocytoma, and unfortunately the most common type of astrocytoma is the malignant variety. All other gliomas are quite rare. The next most common brain tumour is one that has spread from elsewhere in the body. This is called a secondary or metastasis. If you include all intracranial tumours under the heading of “brain tumours”, the next most common tumour is the meningioma.

What is the most important thing for patients to know about a brain tumour?
For patients, the most important thing is not so much the name of the brain tumour, but its rate of growth or biological aggressiveness and its invasiveness. There are well documented cases of so called “benign” or low grade tumours, growing very rapidly and behaving like malignant tumours and conversely there are some tumours which look malignant under the microscope but behave like a benign tumour.

What kinds of Brainstem tumours are there?

1. Diffuse: These are unfortunately the most common type and are often malignant. Surgery is not indicated, except to treat the secondary hydrocephalus. Symptoms and signs are multiple and occur with rapid onset.
2. Focal: These can occur anywhere in the brainstem and may have a cystic component (fluid). The symptoms have often been present for years and may be very specific e.g. choking on one’s food. Most of these tumours are low grade and not malignant like the diffuse variety. Surgery, although high risk, may be curative or at the least prolong life significantly. A subset of these focal tumours are the tectal gliomas which carry a particularly good prognosis.
3. Exophytic: These are rare, comprising no more than 17% of all brainstem tumours. They arise from the brainstem but do not invade it. Instead they grow out of the brainstem into the fourth ventricle. They have symptoms that have often been present for more than a year. The prognosis is generally excellent with total surgical removal.
4. Cervicomedullary: These are also rare and may have primarily brainstem symptoms or spinal cord symptoms. Either way, the onset of problems spans over many years and many of these patients have been investigated by many physicians. More than 80% of these tumours are low grade and are therefore amenable to radical surgical resection. Once again, the risks are high but there is certainly potential for cure with complete macroscopic resection.

What is an Optic Glioma?
These are most commonly found in patients with neurofibromatosis, a rare condition characterised by multiple tumours under the skin, in the brain and in the spinal cord. The optic glioma is often very slow growing and may never cause symptoms or signs.

How are brain tumours diagnosed? Although we can make educated guesses when it comes to patients with brain tumours, definitive diagnosis depends on obtaining tissue. This can only be done through surgery. The least invasive technique is a needle biopsy performed through a small hole (“burr hole”). This is sometimes performed under local anaesthetic. The overall risk of complications occurring from a needle biopsy is less than 5%.

One important downside to the needle biopsy approach is the size of the sample of tissue, sometimes resulting in incorrect results. Secondly, there is the risk of bleeding, especially when the tumour is in an area rich in blood vessels e.g. the pineal region. Alternatively, the surgeon can choose to perform a total or subtotal excision of the tumour through a larger, more invasive, approach called a craniotomy. The risk is slightly higher but the tissue yield for diagnosis is much greater.

How does neurosurgery effect the symptoms of a brain tumour?
Palliation essentially means “making the patient feel better”. Some tumours can cause symptoms of headache and drowsiness because of their large size. This is called “mass effect”. Surgery to reduce the size of the tumour may relieve these symptoms. Also, reducing the size of the tumour or completely removing it can sometimes reverse neurological deficits such as weakness and visual disturbances. Unfortunately, the surgeon is unable to predict the “reversibility” of the deficits preoperatively, as some brain tumours invade the normal brain tissue. Alternatively other brain tumours push the normal tissue aside. A general rule is that patients who improve with preoperative steroids will likely improve with surgery.

What can be the down side of ‘successful’ brain tumour surgery?
It is important that patients (and their families) consider all the potential outcomes of surgery before deciding to go ahead.

What is adjuvant therapy?
In patients with cancer, adjuvant therapy generally refers to the use of chemotherapy and radiotherapy to kill cancer cells, especially those remaining after surgical removal of the tumour.

What effect does neurosurgery have on adjuvant therapy?
Younger patients with aggressive (high grade) gliomas have shown improved outcomes if most of the tumour cells have already been surgically removed. This benefit is not as applicable to older patients. Advocates of surgery say that there may be less chance of malignant transformation of tumour cells if there are less cells to transform. Those who are against surgery for low grade gliomas claim that there is the same chance for malignant transformation if there are 10,000 cells or 10 million cells. Furthermore, they also fear that surgery may invoke malignant transformation. It is very important that each patient is individually assessed.

Why offer surgery before radiotherapy or chemotherapy?
One of the most commonly accepted principles of oncological (cancer) surgery is a concept called cytoreduction. This means that chemotherapy and radiotherapy will have more of a chance of working when the bulk of the tumour has been reduced. There a few exceptions to this rule e.g. tumours that are very vascular (contain a lot of blood vessels) may be more amenable to surgery once their blood supply has been reduced, or tumours that spread when manipulated may be modified with pre-operative chemo or radiotherapy so that this doesn’t happen at the time of surgery.

What are the treatment options for low grade gliomas?
This is a controversial area. Certainly, in children, there is little doubt that surgery is indicated because of the chance of cure, the re-establishment of the normal flow of spinal fluid and the improvement surgery gives to the child’s symptoms. Even in adults, surgery can result in cure, although this is less common. Advocates of surgery say that there may be less chance of malignant transformation if there are less cells to transform. Those who are against surgery for low grade gliomas claim that there is as much chance for malignant transformation if there are 10,000 cells or 10 million cells. Furthermore, they also fear that surgery may invoke malignant transformation. For these reasons, it is very important that patients be assessed individually before any decision to operate can be made.

Needle Biopsy

What is a needle biopsy? Accurate diagnosis of brain tumors generally relies upon the analysis of affected brain tissue. The least invasive technique used to collect a tissue sample from the brain is a needle biopsy. It is performed through a small hole drilled into the skull (“bur hole”). This is procedure is sometimes performed under local anaesthetic. The overall risk of complications occurring from a needle biopsy is less than 5%.

What are the possible problems associated with a needle biopsy? An important downside to the needle biopsy approach is the small size of the tissue sample, sometimes resulting in an incorrect diagnosis. There is also the risk of bleeding, especially when the tumor is in an area rich in blood vessels e.g. the pineal region.

What is an alternative to a needle biopsy? A neurosurgeon may choose to perform a total or subtotal excision of the tumour through a larger, more invasive, approach called a craniotomy. The risk is slightly higher than a needle biopsy, but the tissue yield for diagnosis is much greater.

Can Neurosurgery Cure Brain Tumours? Radical macroscopic removal of low grade gliomas in children can be curative. Also, most extra-axial tumours, such as meningiomas, craniopharyngiomas and pituitary adenomas can be cured if removed totally. This cannot be said for high grade tumours in children and adults. The feasibility of curative surgery for low grade gliomas in adults remains unknown.

Is there scientific evidence for the benefit of radical resection of primary brain tumours?

Low grade Gliomas:

Laws ER Jr. Resection of low-grade gliomas. J Neurosurg. 2001 Nov;95(5):p731-2.
“Clearly, the more cells at risk, the more likely a tumor is to undergo the series of genetic events that ultimately leads to a more aggressive or malignant glioma. (Therefore), based on what we currently believe, the strategy of recommending radical resection of gliomas of the brain is probably a sound one.”

Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas:

Department of Neurological Surgery, Brain Tumor Research Center, University of California San Francisco, 505 Parnassus Ave, Room M-779, San Francisco, CA 94143-0112, USA. jsmith1enator@gmail.com
PURPOSE: The prognostic role of extent of resection (EOR) of low-grade gliomas (LGGs) is a major controversy. We designed a retrospective study to assess the influence of EOR on long-term outcomes of LGGs. PATIENTS AND METHODS: The study population (N = 216) included adults undergoing initial resection of hemispheric LGG. Region-of-interest analysis was performed to measure tumor volumes based on fluid-attenuated inversion-recovery (FLAIR) imaging. RESULTS: Median preoperative and postoperative tumor volumes and EOR were 36.6 cm(3) (range, 0.7 to 246.1 cm(3)), 3.7 cm(3) (range, 0 to 197.8 cm(3)) and 88.0% (range, 5% to 100%), respectively. There was no operative mortality. New postoperative deficits were noted in 36 patients (17%); however, all but four had complete recovery. There were 34 deaths (16%; median follow-up, 4.4 years). Progression and malignant progression were identified in 95 (44%) and 44 (20%) cases, respectively. Patients with at least 90% EOR had 5- and 8-year overall survival (OS) rates of 97% and 91%, respectively, whereas patients with less than 90% EOR had 5- and 8-year OS rates of 76% and 60%, respectively. After adjusting each measure of tumor burden for age, Karnofsky performance score (KPS), tumor location, and tumor subtype, OS was predicted by EOR (hazard ratio [HR] = 0.972; 95% CI, 0.960 to 0.983; P < .001), log preoperative tumor volume (HR = 4.442; 95% CI, 1.601 to 12.320; P = .004), and postoperative tumor volume (HR = 1.010; 95% CI, 1.001 to 1.019; P = .03), progression-free survival was predicted by log preoperative tumor volume (HR = 2.711; 95% CI, 1.590 to 4.623; P <or= .001) and postoperative tumor volume (HR = 1.007; 95% CI, 1.001 to 1.014; P = .035), and malignant progression-free survival was predicted by EOR (HR = 0.983; 95% CI, 0.972 to 0.995; P = .005) and log preoperative tumor volume (HR = 3.826; 95% CI, 1.632 to 8.969; P = .002).

CONCLUSION: Improved outcome among adult patients with hemispheric LGG is predicted by greater EOR.

Extent of surgical resection is independently associated with survival in patients with hemispheric infiltrating low-grade gliomas:

Department of Neurosurgery, The Johns Hopkins School of Medicine, and Neuro-oncology Surgical Outcomes Research Laboratory, Baltimore, Maryland 21231, USA.
OBJECTIVE: It remains unknown whether the extent of surgical resection affects survival or disease progression in patients with supratentorial low-grade gliomas. METHODS: We conducted a retrospective cohort study (n = 170) between 1996 and 2007 at a single institution to determine whether increasing extent of surgical resection was associated with improved progression-free survival (PFS) and overall survival (OS). Surgical resection of gliomas defined as gross total resection (GTR) (complete resection of the preoperative fluid-attenuated inversion recovery signal abnormality), near total resection (NTR) (<3-mm thin residual fluid-attenuated inversion recovery signal abnormality around the rim of the resection cavity only), or subtotal resection (STR) (residual nodular fluid-attenuated inversion recovery signal abnormality) based on magnetic resonance imaging performed less than 48 hours after surgery. Our main outcome measures were OS, PFS, and malignant degeneration-free survival (conversion to high-grade glioma). RESULTS: One hundred thirty-two primary and 38 revision resections were performed for low-grade astrocytomas (n = 93) or oligodendrogliomas (n = 77). GTR, NTR, and STR were achieved in 65 (38%), 39 (23%), and 66 (39%) cases, respectively. GTR versus STR was independently associated with increased OS (hazard ratio, 0.36; 95% confidence interval, 0.16-0.84; P = 0.017) and PFS (HR, 0.56; 95% confidence interval, 0.32-0.98; P = 0.043) and a trend of increased malignant degeneration-free survival (hazard ratio, 0.46; 95% confidence interval, 0.20-1.03; P = 0.060). NTR versus STR was not independently associated with improved OS, PFS, or malignant degeneration-free survival. Five-year OS after GTR, NTR, and STR was 95, 80, 70%, respectively, and 10-year OS was 76, 57, and 49%, respectively. After GTR, NTR, and STR, median time to tumor progression was 7.0, 4.0, and 3.5 years, respectively. Median time to malignant degeneration after GTR, NTR, and STR was 12.5, 5.8, and 7 years, respectively.

CONCLUSION: GTR was associated with a delay in tumor progression and malignant degeneration as well as improved OS independent of age, degree of disability, histological subtype, or revision versus primary resection. GTR should be safely attempted when not limited by eloquent cortex.

Malignant Gliomas:

Lacroix M. et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 2001 Aug;95(2):p190-8.
“Gross-total tumor resection is associated with longer survival in patients with GBM, especially when other predictive variables are favorable.”

Nitta T, Sato K. Prognostic implications of the extent of surgical resection in patients with intracranial malignant gliomas. Cancer 1995 Jun 1;75(11):p2727-31.
“The favorable prognosis of patients with malignant gliomas depends upon the total resection of these tumors.”

Chandler KL et al. Long-term survival in patients with glioblastoma multiforme. Neurosurgery 1993 May;32(5):p716-20.
“Among patients with glioblastoma multiforme, long-term survival is most likely for those who have a long disease-free interval after the initial diagnosis and receive multimodal therapy, including aggressive tumor removal.”

Why do people with brain tumours need steroids?
Steroids, in the form of dexamethasone, are extremely effective in reducing the swelling that results from the tumour. They do NOT reduce the size of the tumour itself (the only exception being primary lymphoma of the brain). Some tumours cause more swelling than others e.g. malignant gliomas and meningiomas seem to create an extraordinary amount of vasogenic oedema (swelling). Once the tumour has been removed the steroids can be stopped. The prescription of dexamethasone does not replace a deficiency in the patients own steroid production.

Can steroids be stopped “cold turkey”?
The short answer is yes but there are 3 situations where they need to be tapered slowly. If the patient has been on steroids for any length of time, usually more than 2 weeks, the body gets a little lazy and stops production of its own (intrinsic) steroids (cortisol). Of course, the body will sense the need to secrete its own cortisol eventually, but this may take a few days. The longer the patient takes extrinsic steroids, the longer it takes to return to normal cortisol production. The second situation is when there is residual tumour. Even small amounts of tumour can generate enormous degrees of swelling resulting in a worsening of symptoms such as headache when the steroids are stopped. Finally, tumours that involve the pituitary gland may destroy cortisol production, and similarly, surgery to remove tumours from the pituitary region may result in diminished ability or total inability to secrete cortisol. To determine the ability of the body to resume cortisol production requires special tests and consultation by an endocrinologist.

Why can’t a patient with a brain tumour take steroids indefinitely?
Unfortunately, steroids have many bad side effects apart from the obvious one of depressing intrinsic cortisol production. They reduce the ability of the brain to recover from an insult. This is called “plasticity”. They suppress the immune system resulting in more chance of infection. They worsen and sometimes “cause” diabetes. In high doses they can cause Cushing’s Syndrome. This is a condition that is characterised by protein wasting, fat redistribution causing a fat face and abdomen, thinning of the skin, osteoporosis, bruising, acne, psychosis etc.

Pineal cysts are benign fluid filled cysts of the pineal gland. Their etiology is unknown but is thought to be a form of degeneration of normal pineal tissue. They are a common finding in the normal population. Occasionally they grow and may cause pressure on surrounding neural structures. If they compress the underlying “aqueduct of Sylvius” they may result in hydrocephalus and subsequent raised pressure. If they compress the underlying tectal plate, they may cause problems with eye movement resulting in double vision and blurred vision. Uncommonly they may cause other symptoms related to compression of other parts of the brain in close proximity to the pineal gland. These symptoms vary tremendously from sensory disturbance to fluctuations in level of consciousness.

It has always been contentious whether pineal cysts have the potential to cause headache and symptoms of pressure without CT or MRI evidence of hydrocephalus. Those who believe they can presume that the cysts cause intermittent CSF obstruction especially with changes in posture or any activity that might result in distension of the cerebral veins (…which are in close proximity to the pineal gland). Those who don’t believe that pineal cysts can cause headache are in the majority of neurosurgeons and neurologists.

The only valid way of knowing if someone’s symptoms are related to the pineal cyst is by removing it. Unfortunately this is easier said than done. Access to the pineal region is difficult and treacherous. Very few neurosurgeons have had a lot of experience operating in this delicate area. Some surgeons have proposed an operation to bypass the aqueduct called an endoscopic third ventriculostomy (ETV). This would address the symptoms if they were due to intermittent CSF obstruction but we know from other pathologies that headache may also be due to local pressure effect which would not be helped by an ETV.

This article published in the Journal of Neurosurgery highlights the excellent results seen after resection of pineal cysts in a very select group of patients. Before surgery was contemplated the patient had to be seen by a neurologist to exclude other causes of headache, the MRI had to show partial obstruction of the aqueduct and the symptoms had to strongly suggest intermittent compression of structures around the pineal gland. The article was rejected for many years and for very good reason. Unfortunately we did not have objective evidence of success. Without this objectivity the apparent success may have been due to the placebo effect. Furthermore, the assessment of success was initially made by our team, which could have added subjective bias. It was eventually accepted because every year for the last 4 years separate and unbiased physicians have reviewed the results and all have concurred that they are authentic. Furthermore, placebo is unlikely to have a lasting and consistent effect.

The greatest fear from this publication is that neurosurgeons inexperienced in surgery for pineal lesions will offer surgery to desperate patients with devastating outcomes. Complications from surgery in this region are typically very severe. They include death, short-term memory loss, paralysis, sensory disturbance, temporary and permanent eye movement paralysis, coma etc. etc.

Any patient who believes that they have a symptomatic pineal cyst should make an appointment to see Dr Teo for a personal consultation.