Brain Tumors

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Brain Tumors

A brain tumor is a growth of abnormal cells that have formed in the brain. Some brain tumors are malignant (cancerous), while others are not (non-malignant, non-cancerous or benign). A brain tumor can form in the brain or other parts of the central nervous system (CNS), such as the spine or cranial nerves. The brain plays a central role in the control of most bodily functions, including awareness, movements, sensations, thoughts, speech, and memory. A tumor can affect the brain’s ability to work properly and adequately perform such functions.

What is the difference between malignant and non-malignant brain tumors?

Whether a tumor is malignant or not depends on how quickly the cells reproduce. If the tumor is made up of cells that multiply slowly, then it is usually non-malignant; however, if the cells multiply and spread quickly, then the tumor is malignant.

Non-malignant (benign) brain tumors are not cancerous. These types of tumors grow relatively slowly and do not tend to spread. Even though they are not cancerous, these tumors can still cause symptoms due to pressure on the brain and may need treatment. A non-malignant brain tumor can still be a serious medical condition.

Malignant brain tumors are cancerous. These types of tumors generally grow faster, and are more aggressive than non-malignant tumors. They often spread and damage other areas of the brain and spinal cord. Malignant brain tumors need to be treated as soon as possible to prolong life.

Glioblastoma is a type of very aggressive brain tumor. It is also known as glioblastoma multiforme. About 12 to 15 percent of people with brain tumors have glioblastomas.

This type of tumor grows very fast inside the brain. Its cells copy themselves quickly, and it has a lot of blood vessels to feed it. However, it rarely spreads to other parts of the body.

Brain tumors may also be classified as either primary or secondary/metastatic. Primary tumors originate in the brain, and the most common types are meningiomas and gliomas. Metastatic, or secondary brain tumors arise from outside the brain in another organ such as the breast or lung and spread to the brain. These are the most common brain tumors.

Various types of primary brain tumours exist getting their names from the type of cells involved.

Examples include:
1) Gliomas: These tumours commence in the brain or spinal cord. It includes astrocytomas, ependymoma, glioblastomas, oligoastrocytomas and oligodendrogliomas.
2) Meningiomas: A tumour arising from the membranes surrounding your brain and spinal cord (meninges) is called Meningioma.
3) Acoustic neuromas (schwannomas): Benign tumours developing on the nerves that regulate balance and hearing starting from your inner ear to your brain.
4) Pituitary adenomas: Mostly these are benign tumours which develop in the pituitary gland at the brain’s base. These tumours may affect the pituitary hormones with effects observed throughout the body.
5) Medullolastmas: Medulloblastomas are the most frequent cancerous brain tumours observed in children. It begins in the lower back portion of the brain and is likely to spread through the spinal fluid.Although these tumours occur in adults, they are less common.
6) PNETs: Primary neuroectodermal tumours (PNETs) are rare cancerous tumours starting in the brain’s embryonic (foetal) cells. They can take place anywhere in the brain.
7) Germ cell tumours: Germ cell tumours can begin during childhood where there will be formation of testicles or ovaries. But occasionally germ cell tumours progress to other body parts such as brain.
8) Craniopharyngiomas: It is a rare, non-cancerous tumour beginning near the pituitary gland (gland secreting hormones that controls many functions of the body) of the brain. The pituitary gland and other structures near the brain are affected as the Craniopharyngiomas gradually grows.

Secondary (metastatic) brain tumours.

Cancer that originates at other parts and spreads to the brain.
In rare cases, a metastatic brain tumour can be the initial sign of cancer that began somewhere else in your body. Secondary brain tumours are more frequent than primary tumours.

Any type of cancer can metastasize to the brain, but the most frequent types include:
  1) Breast cancer
  2) Colon cancer
  3) Kidney cancer 
  4) Lung cancer
  5) Melanoma

What is tumor grading?

Tumor grade has long been a way to define the aggressiveness of a tumor, particularly for malignant brain tumors such as glioma but also for non-malignant (benign) brain tumors including meningioma.

Traditionally, tumors have been classified as grade 1 to 4 based on histology (cells as viewed under a microscope) and molecular markers. Grade 1 tumors occur primarily in children and represent a type separate from grade 2-4 (seen primarily in adults). Grade 2 tumors are considered low grade, but some can be aggressive. Grade 3 and 4 tumors are defined as high grade.

What are molecular markers?

Not all brain tumors are the same. Some tumors have differences in the genetic or molecular makeup of the cells. These differences are called molecular markers, or biomarkers. Molecular markers are becoming increasingly important for brain tumor diagnosis and treatment. For example, some molecular markers help determine how aggressive a tumor may be. Others determine how responsive a tumor will be to treatment.

Some common molecular markers include the following:

  1. IDH1 and IDH2
  2. MGMT
  3. 1p/19q co-deletion
  4. BRAF
  5. EGFR
  6. TP53
  7. ATRX
  8. TERT
  9. PTEN
  10. NTRK
  11. FGFR
  12. Risk Factors for Brain Tumours

1.Genetic and hereditary risk factors

Inherited traits are carried in genes. Each individual has two copies of each gene, one from each parent. Genes often contain small changes. Sometimes these changes do not cause any problems, but sometimes these changes are more serious and can interfere with the way the gene is supposed to work.

There are a few rare, inherited genetic syndromes that are associated with brain tumors., including Neurofibromatosis 1 (NF1 gene), Neurofibromatosis 2 (NF2 gene), Turcot syndrome (APC gene), Gorlin syndrome (PTCH gene), Tuberous Sclerosis (TSC1 and TSC2 genes) and Li-Fraumeni syndrome (TP53 gene).

Although 5-10% of persons with brain tumors have a family history of a brain tumor, the vast majority of CNS tumors appear not to be a part of inherited genetic syndromes.

If multiple members of your family have been diagnosed with brain tumors, or you have concerns about starting a family, a genetic counselor may be able to help.

2.Environmental risk factors

Other than family history, the most consistently identified risk factor associated with brain tumor development is therapeutic or high-dose ionizing radiation.With regard to medical diagnostic radiation exposure, small increases in brain tumor risks have been reported. Although certain brain scans and radiation therapy used to treat brain tumors use ionizing radiation, the risk of developing a new brain tumor due to these causes is very low.

With respect to the impact of nonionizing radiation from cell phones, the association between this exposure and brain cancer has been the subject of much research.

Industrial chemicals have long been suspected as a cause of glioma due to their ability to cross the blood–brain barrier.The blood-brain barrier protects the brain from toxins and pathogens. Despite numerous chemical, environmental, and occupational exposures having been explored in epidemiological studies of glioma, results have been inconsistent for most factors.

Symptoms

Glioblastoma causes symptoms when it presses on parts of your brain. If the tumor isn’t very large, you might not have any symptoms. Which symptoms you have depends on where in your brain the tumor is located.

Symptoms can include:

  • Headaches
  • Nausea and vomiting
  • Sleepiness
  • Weakness on one side of your body memory loss
  • Problems with speech and language
  • Personality and mood changes
  • Muscle weakness
  • Double vision or blurred vision
  • Loss of appetite
  • Seizures

Diagnosis:

If symptoms suggesting brain tumour is detected by your doctor, he will give you a physical exam and inquire about your personal and family health history. You may have to undergo one or more of the following tests:

Your vision, hearing, alertness, muscle strength, coordination and reflexes are checked by your doctor. He also examines your to check for swelling caused by a tumour exerting pressure on the nerve connecting the eye & the brain.

Detailed pictures of areas inside your head is made using a big machine with a powerful magnet linked to a computer. At times a special dye (contrast material) is injected into your hand or arm’s
  blood vessel to distinguish the tissues of the brain. Abnormal areas like tumour can be shown by these pictures.

A computer linked x-ray machine takes a series of detailed pictures of your head. A contrast material may be injected into a blood vessel in your arm or hand. It is easier to see abnormal areas because of the contrast material.

By injecting dye into the bloodstream, blood vessels in the brain show up on an x-ray. If there is presence of a tumour, the x-ray may show the tumour or blood vessels feeding into the
  tumour.

A sample of cerebrospinal fluid may be removed by your doctor. Local anaesthesia is used in this procedure. The doctor makes use of a long, fine needle to remove fluid from the spinal column’s lower part. A spinal tap takes about half an hour. To prevent getting a headache you must lie flat for several hours following the procedure. The fluid is checked by a laboratory for cancer cells or other signs of problem.

Removing of tissue to check for tumour cells is called biopsy. A pathologist examines cells under a microscope to look for abnormal cells. A biopsy can detect cancer, alteration in tissue that may lead to cancer and other conditions. A biopsy is the only definite means of diagnosing a brain tumour, find out what grade it is, and plan treatment.

The surgeon can acquire tissue to check for tumour cells in 2 ways:

Excision biopsy (open surgery): The tissue sample is taken when you have surgery to remove a portion of the entire tumour.

Stereotactic biopsy: A local or general anaesthesia may be administered to you and you’ll be made to wear a rigid head frame for this procedure. The surgeon creates a small incision in the scalp and after drilling a tiny hole (a burr hole) into the skull through which CT or MRI is guided to the tumour’s location. A sample of tissue is withdrawn with the needle. In case the tumour is deep inside the brain or in a region of the brain that cannot be operated on, a needle biopsy may be used.

But, if the tumour exists in the brain stem or certain other regions, the surgeon may not be able to acquire tissue from the tumour without harming normal tissue of the brain. In such cases, MRI, CT or other imaging tests are used by doctors to acquire as much information as possible about a brain tumour.

Treatment:

Individuals suffering from brain tumour have a vast number of treatment options like surgery, radiation therapy, and chemotherapy. A lot of people receive a combination of treatments. The treatment choice mainly depends on the following:

  1. Type of brain tumour and its grade.
  2. Tumour’s location in the brain
  3. Size of tumour
  4. Your age and general health

i) Surgery
The usual first treatment for a majority of brain tumours is surgery. Prior to the commencement of surgery, general anaesthesia may be administered to you, and your scalp is shaved. You won’t probably need your head shaved entirely.

Craniotomy is a surgery to open the skull. An incision is made in your scalp and a special type of saw is used to remove a section of bone from the skull. You may be conscious when a part or all of the brain tumour is removed by the surgeon. The tumour is removed as much as possible. You may be asked to move a leg, count numbers, say the alphabet or recite a story. Your ability to follow these instructions helps the surgeon to protect the brain’s important parts. After the removal of the tumour, the opening of the skull is covered with a piece of bone or with a metal or fabric piece. The incision in the scalp is then closed by the surgeon. Sometimes, it isn’t possible to perform a surgery. But in case the tumour is in the brain stem or certain other areas, it is very complicated to remove the tumour without causing harm to normal brain tissue. Individuals who cannot have surgery may be given radiation therapy or other treatment.

ii) Radiation Therapy
Using high-energy x-rays, gamma rays, or protons brain tumour cells are killed by radiation therapy.
Following surgery comes radiation therapy. The tumour cells that may remain in the area is killed by the radiation. Sometimes, who can’t have surgery performed on them receive therapy instead.

It is used mainly for malignant tumours, but can also be used in a few non-malignant tumours (to control growth) particularly if they are small or located in critical locations of the brain.

Internal and external types of radiation therapy are used by doctors for treating brain tumours:
External radiation therapy: You’ll receive treatment in a hospital or clinic. A big machine outside the body aims radiation beams at the head. The radiation may be aimed at the tumour and brain tissue nearby or the entire brain since cancer cells may invade normal tissue around a tumour. Some people require radiation aimed at the spinal cord too.

The patient’s age, the type and the size of the tumour determines the treatment protocol. The most common radiation treatment for brain tumour is fractionated external beam therapy. Here the total dose of radiation is given to the patient over several weeks helping to protect the healthy tissue in the area of the tumour. The treatments generally last 5 days a week for several weeks, where each sitting takes around 1 hour.

Other ways of delivering external beam radiation are being studied by some treatment centres:
Intensity-modulated radiation therapy or 3dimensional conformal radiation therapy: computers are used by these type of treatment to target the brain tumour more closely in order to reduce thedamage to healthy tissue.

Proton beam radiation therapy: Instead of x-rays, the source of radiation here is protons. The proton beam is aimed at the tumour. Compared to the dose of radiation from an x-ray beam, the dose from a proton beam is less.

Stereotactic radiation therapy: Narrow beams of x-rays or gamma rays are directed at the tumor from different angles. For this procedure, you wear a rigid head frame. The therapy may be given during a single visit (stereotactic radiosurgery) or over several visits.

Internal radiation therapy (Implant radiation therapy or brachytherapy): Internal radiation is generally not used for brain tumours treatment and is under study. The radiation comes from radioactivematerial generally contained in very tiny implants known as seeds. The seeds are positioned in the inside of the brain and give off radiation for months. There is no need to remove them once the radiationis gone.

iii) Chemotherapy
Chemotherapy means making use of drugs for killing cancer cells. Many times, Chemotherapy is used for treating brain tumors. Drugs can be administered in the following ways:

By mouth or vein (intravenous): Chemotherapy can be administered during and after radiation therapy. After entering the bloodstream, the drugs travel throughout the body. They may be administeredin the hospital’s outpatient part, at the doctor’s office, or at home. Seldom, you may require to stay in the hospital.
Chemotherapy’s side effects depend chiefly on drugs which are given and the quantity of it. Common observed side effects are nausea and vomiting, appetite loss, headache, chills and fever, and weakness.
 If the levels of healthy blood cells are reduced by the drugs, you’re more prone to get infections, bruise or bleed easily, and experience tiredness and weakness. Your health care team would inspect for lowevels of blood cells. Few of the side effects can be relieved with the help of medicine.

Commonly used chemotherapy is temozolomide (Temodar), bevacizumab, polifeprosan 20 with carmustine implant, lomustine .

Targeted chemotherapy

Chemotherapy and targeted therapy are both treatments that attack cancer cells. Targeted therapy is less toxic to healthy cells than chemo. Both options are often done in conjunction with other treatments, such as radiation.

Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules (“molecular targets”) that are involved in the growth, progression, and spread of cancer. Targeted cancer therapies are sometimes called “molecularly targeted drugs,” “molecularly targeted therapies,” “precision medicines,” or similar names.

Targeted therapies differ from standard chemotherapy in several ways:

Targeted therapies act on specific molecular targets that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells.

Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells. 

Targeted therapies are often cytostatic (that is, they block tumor cell proliferation), whereas standard chemotherapy agents are cytotoxic (that is, they kill tumor cells). 

iv) Nutrition
You need to eat well in order to take good care of yourself. You require the correct amount of calories for maintaining a good weight. Also, you require sufficient protein to sustain your strength. Eating properly can go a long way in helping you feel better and have extra energy.

v) Supportive Care
Seizures (convulsions) cab be caused by brain tumours. Specific drugs can help in preventing or controlling seizures. You will receive supportive care before, during, and post-cancer treatment. It will help in improving your comfort and quality of life during treatment.

vi) Rehabilitation
Rehabilitation is a very significant part of the treatment plan. Rehabilitation goals depend on your needs and the extent to which the tumour has affected your ability to perform daily activities.
Few individuals may never regain all the abilities possessed by them before the brain tumour and its treatment. But every effort is made by your healthcare team to help you get back to regular activities without delay.
Children suffering from brain tumours may have special requirements. Many times in the hospital or at home, children have tutors.

Several types of therapists can help:

  1. Physical therapists: Paralysis may be caused by brain tumours and their treatment. Weakness and problems with balance may also be caused by them. Physical therapists assist people in regaining strength and balance.
  2. Speech therapists: Individuals having trouble speaking, expressing thoughts, or swallowing are helped by speech therapists.
  3. Occupational therapists: Occupational therapists assist people in learning to accomplish activities of daily living, like eating, using the washroom, having baths, and dressing.
  4. Physical medicine specialists: Medical doctors with special training assist individuals with brain tumours to stay very active. They can assist individuals to regain lost abilities and getting back to daily activities.

New treatments for glioblastoma are being tested in clinical trials. These treatments include:
immunotherapy — using your body’s immune system to kill cancer cells
gene therapy — fixing defective genes to treat cancer
stem cell therapy — using early cells called stem cells to treat cancer
vaccine therapy — strengthening your body’s immune system to fight off cancer
personalized medicine — also called targeted therapy
If these and other treatments are approved, they could one day improve the outlook for people with glioblastoma.

Survival rates and life expectancy
The median survival time with glioblastoma is about 12 months who get surgery, chemotherapy, and radiation treatment.

Extending life expectancy
New treatments are extending life expectancy even more. People whose tumors have a favorable genetic marker called MGMT methylation have better survival rates.

MGMT is a gene that repairs damaged cells. When chemotherapy kills glioblastoma cells, MGMT fixes them. MGMT methylation prevents this repair and ensures that more tumor cells are killed.

Natural History Of Glioma

Glioma is a common type of tumor originating in the brain. About 33 percent of all brain tumors are gliomas, which originate in the glial cells that surround and support neurons in the brain, including astrocytes, oligodendrocytes and ependymal cells. Gliomas are called intra-axial brain tumors because they grow within the substance of the brain and often mix with normal brain tissue.

Prognosis There are several other factors that help doctors determine prognosis. The prognosis in primary brain tumors depends on the type of tumor, age, functional status of the patient, the extent of surgical tumor removal, spread of metastasis and biogenetic markers. Patients with benign gliomas may survive for many years, while survival in most cases of glioblastoma multiforme is limited to a few months after diagnosis. The 5-year survival rate is 33.3%. In general, a tumor is referred to by grade. The higher the grade, the more rapidly growing the tumor is. Grade I is a separate group of tumors. It refers to a juvenile pilocytic astrocytoma (JPA). The term juvenile does not refer to the age of the patient, but rather the type of cell. This is a noncancerous, slow-growing tumor that can typically be cured with surgery and or chemotherapy. It is different from a low-grade astrocytoma or Grade II glioma, which are likely to recur. Grade IV tumor (glioblastoma, also called glioblastoma multiforme or GBM) is the most malignant tumour, has vascular proliferation and/or necrosis in addition to the factors common to grade II and III tumours. Age of patient. In adults, the age of the patient  at the time of diagnosis is one of the most significant predictors of outcome. Extent of tumor residual. Resection is surgery to remove a tumor, and residual refers to how much of the tumor remains in the body after surgery. Prognosis is most favorable when all of the tumor can be surgically removed. Tumor location. A tumor can form in any part of the brain. Some tumor locations cause greater damage than others, and some tumors are harder to treat because of their location than others. Functional neurologic status. The doctor will test how well a patient is able to function and carry out everyday activities by using a functional assessment scale, such as the Karnofsky Performance Scale (KPS). A higher score indicates a better functional status. Typically, the better someone is able to walk and care for themselves indicates a better prognosis. Metastatic spread. A tumor that starts in the brain or spinal cord, if cancerous, often spreads within the CNS only and rarely metastasizes to other parts of the body in adults. For that reason, with few exceptions, tests looking at the other organs of the body are typically not needed. A tumor that does spread to other parts of the brain or spinal cord is associated with a poorer prognosis. Biogenetic markers. Certain molecular markers found in the tumor tissue can provide information on the tumor’s response to treatment. For instance, for oligodendroglioma, the loss of part of chromosome 1 on the p part of the chromosome, and the loss of part of chromosome 19 on the q part of the chromosome (called 1p and 19q) is associated with a much better response to chemotherapy and more successful treatment. Also, in glioblastoma, the modification of a gene called MGMT appears to be associated with improved responsiveness to treatment and better prognosis, but this is being tested in clinical trials (research studies). Recurrent tumor. A recurrent tumor is one that comes back after treatment. If there is a recurrence, it may be treated by surgery and or adjuvant therapy as situation demands. But the 5-year survival rate  drops sharply after recurrence.

Natural History Of Meningioma

Understanding the natural course of meningiomas is important to provide appropriate treatment. The majority of previous studies investigated factors related to their growth, but failed to demonstrate their relationship with symptomatic progression (sympP) because of its rarity.  Satoshi NAKASU and Yoko NAKASU from Division of Neurosurgery, Kusatsu General Hospital, Kusatsu, Shiga, Japan reviewed and meta-analyzed 27 studies that investigated natural courses in asymptomatic or untreated meningiomas to find clinico-radiological factors predictive of radiological progression (radioP), growth speed, and sympP. In results of time-growth analysis, two thirds of meningiomas showed radioP defined by a volume criterion and the rate approached a plateau at 4–5 years. In growth curve analyses, about half of incidental meningiomas presented decelerating or no growth, while less than one-quarter of them grew exponentially. RadioP, growth speed [annual volume change (AVC) or relative growth rate], and sympP each had different factors related to them. Younger age, non-calcification, and high intensity on T2-weighted image were related to radioP and rapid growth speed, but not to sympP. Tumors in males and those of larger size were likely to be symptomatic in the meta-analysis. AVC (≥2.1 cm3 /year) was the strongest indicator of sympP. Apart from perifocal edema, radiological features at up-front imaging may not be useful for predicting sympP. This may be due to dynamic changes of those radiological markers in the long term. Quantified tumor size and growth speed, especially AVC, are important markers for deciding on treatment.  Meningiomas are the most frequently diagnosed primary brain tumor, especially in the elderly. Earlier autopsy studies showed an incidence of meningiomas from 1.4% to 2.3% in Sweden and the United States, respectively.1,2) These tumors are usually asymptomatic and smaller than 2 cm in diameter. It is conceivable that the widespread use of radiological examination has led to the more frequent detection of asymptomatic meningiomas in the era of extended life expectancy. A recent investigation using magnetic resonance imaging (MRI) showed a frequency of meningioma of 2.5% as an incidental finding in a population based neuroimaging study in the middle-aged and older.3) However, only a small proportion of the tumors appeared to become symptomatic.

In patients with asymptomatic meningioma, a long follow-up for years is advised and treatments are recommended if the tumor grows considerably. This approach may reduce unnecessary invasive treatments, but it may increase the risk associated with intervention due to enlarged tumors and deteriorating conditions of patients with age. Repeated radiological examinations may also place a burden on patients. Therefore, the accurate prediction of individual tumor growth with symptomatic progression (sympP) is crucial for determining the most appropriate form of clinical management, including active observation and/or surgical resection, to avoid unnecessary radiological follow-up or risky intervention about 30% of incidental meningiomas did not grow radiologically.

Factors predictive of no growth are tumor calcification, T2 low-intensity signal, and being elderly and female. Growth speed analysis is important to analyze complex growth patterns influenced by various factors. RGR and AVC represent different characteristics of tumor growth, and would not be constant Calcification is related to RGR, whereas initial size and edema are related to AVC. The prediction of neurological symptoms is more important than that of radio. Only a small proportion of meningiomas would become symptomatic, but this has been underestimated because of early treatment indicated at the time of radio in the majority of studies.

We showed that a tumor diameter >2.6 cm is a risk factor for sympP. We also revealed that AVC (≥2.1 cm3 /year) is a strong indicator of sympP, reflecting crucial factors of intracranial tumors, namely, both tumor volume and proliferative potential.

With the increase in the number of elderly people and advances in diagnostic imaging modalities, the frequency of detection of brain tumours in aged patients is increasing. It has been reported that the frequency of incidental detection of meningiomas is higher in aged patients than in non-aged patients. Because meningiomas are fundamentally benign tumours that can be surgically removed, surgical treatment is recommended for patients with symptomatic meningiomas, even in aged patients. However, surgical removal in elderly patients may be associated with significant morbidity. When considering the treatment for aged patients with asymptomatic meningiomas, it is important to know the natural clinical course of these patients. However, studies on the natural history of patients with meningiomas are rare. Furthermore, no such studies have examined aged patients. The purpose of this study was to clarify the natural history of elderly patients with asymptomatic meningiomas and to identify prognostic factors concerning the potential of tumour growth.

In elderly patients with asymptomatic meningiomas, because some tumours did grow and became symptomatic, careful clinical observation with repeated imaging studies is of primary importance.