Astrocytoma Tumors

Many different cells and neurons in the brain make up the electric circuitry that creates brain functions, and astrocytes, which provide structural support for neurons to properly work. Astrocytomas are tumors that come from astrocytes. It is the most common brain tumor in adults. 15,000 new astrocytomas are diagnosed each year in the United States. Males are affected more than females with a 1.3/1 ratio.

TUMOR GRADING AND ITS MEANING

The World Health Organization (WHO) classifies brain tumors on a scale. Astrocytomas range from grade 1 (benign) to grade 4 (malignant). This grading is based on: how abnormal the cells look, how much they grow, presence of new blood vessels in the tumor. The tumor’s genetic features will have a DNA analysis. Grade 1 tumors happen most often to children. Patients of older age are more likely to develop a higher grade tumor.

GRADE 1

Pilocytic Astrocytoma is a slow growing tumor that most often occurs in the cerebellum. This tumor does not invade other parts of the brain. When the tumor is resected completely it is considered cured.

Pleomorphic Xanthoastrocytoma happens most in the temporal lobes. This tumor is often related to seizures. The cells can have many different shapes as they are pleomorphic. The cells do not show proliferation. This can usually be cured with surgery

Subependymal Giant Cell Astrocytoma (SEGA) often occurs in younger people. It is associated with tuberous sclerosis. This tumor grows inside the ventricles (fluid-filled spaces deep in the brain) and can block the outflow of the ventricles fluid. This causes hydrocephalus. This can usually be cured with surgery.

GRADE 2

Diffuse Astrocytoma is an invasive tumor. There will be no clear separation from the rest of the brain. Surgery may not provide a cure. The tissue is slightly different from a normal brain, but cells appear abnormal under a microscope and are moderately increased in number.

GRADE 3

Anaplastic Astrocytoma is a more malignant tumor of a previously lower grade astrocytoma. This tumor is much more aggressive. It has faster growth and is more invasive. It has a greater degree of cell abnormalities, and cell proliferation, when compared to a grade 2 tumor. Surgery will not cure these tumors and radiation and chemotherapy will follow.

GRADE 4

Glioblastoma (GBM) is an aggressive, common (60%) , and malignant form of astrocytomas. It has many abnormal looking cells, proliferation, areas with dead tissue and new vessel formation. GBM can show as a malignant progression from a previously existing lower grade astrocytoma (10% of cases). GBM can also show as a grade 4 tumor (90% of cases). The first case is more common in younger patients while the second happens in older patients. This tumor is an extremely aggressive cancer that is invasive and destructive and progresses fast.  

IMPORTANT BIOLOGICAL FEATURES

Studying genetic and biological underpinnings of this disease have helped to progress understanding:

• IDH1 mutation is a fundamental feature that shows a subgroup of astrocytomas with mutation of a gene, called isocitrate dehydrogenase 1 (IDH1). This gene provides energy to the cells. The mutation will result in the production of a chemical called 2-HG. This chemical will build up inside of the normal astrocytes and change them leading to astrocytomas. This mutation characterizes almost all low grade astrocytomas
• MGMT silencing has to do with the methylguanine-DNA methyltransferase enzyme involved with DNA repair after damage has been made by chemotherapy, thus protecting the tumor from the drugs. Some astrocytomas have this enzyme turned off so they respond better to chemotherapy with TMZ.
• Immunologic escape is what the tumor has escaped the patrolling immune system. The patrolling immune system typically destroys anything that is unusual. Astrocytomas can escape this patrol by activating manu genes that turn the immune system off. Counteracting this escape could lead to therapeutic benefits.

RISK FACTORS

Astrocytomas are usually very sporadic tumors. It is not known why these tumors occur. Here are the main evidence directed towards the cause of the tumor:

• Hereditary syndromes (inherited DNA mutations)

1. Li-Fraumeni: Mutation of p53, the tumor suppressor gene. Characterized by young onset of many tumors such as breast cancer, bone cancer, leukemia, astrocytomas
2. Turcot: Mutation in tumor suppressor genes such as APC and MMR and characterized by an early onset of colon cancer or astrocytomas
3. Neurofibromatosis 1: Caused by mutations of NF1 tumor suppressor, causes early onset astrocytomas, peripheral nerve tumors, skin frecking, light brown skin patches.
4. Tuberous sclerosis: Genetic disorder that is very rare and related to mental retardation and early showing of subependymal giant cell astrocytoma (SEGA)

• Environmental

1. Ionizing radiations: exposure to ionizing radiations can be associated with a delayed onset of astrocytomas. Those who have been exposed to therapeutic radiation to the head or neck as a child are at higher risk. 20 to 30 years can pass from the exposure to radiation to astrocytoma.
2. Warfare chemicals: Exposure to Agent Orange in the Vietnam War could cause delayed onset of astrocytoma in veterans
3. Cell phones: Some people are suspicious of cell phones but there is no evidence for astrocytomas.

SYMPTOMS

Location, more so than biological characteristics, affects symptoms. Some parts of the brain can have tumors grow large in size before symptoms appear such as the forehead. Some locations in the brain have small tumors that can cause symptoms like weakness in limbs, speech or vision trouble.

Astrocytomas that are lower in grade usually become large before symptoms appear compared to higher grade astrocytomas. Lower grade tumors do not destroy the brain, cause less swelling, and displace the brain.

Common symptoms of astrocytomas:

• Persistent headaches
• Headaches that are worse in morning or awaken from sleep
• Double or blurred vision
• Trouble speaking
• Decreased cognitive abilities
• Limb weakness
• Seizures

DIAGNOSTIC IMAGING

• Conventional MRI
• Axial T1-weighted MRIs after IV gadolinium administration
• MRI Spectroscopy
• Functional MRI
• Functional MRI with bold imaging during object naming

TREATMENT

Surgery

The first step to treat astrocytomas is surgery. Surgery will procure tumor tissue to establish a diagnosis and create an opportunity to remove as much tumor as possible. Many factors can influence whether a simple biopsy or full removal will happen.

Important tools that increase efficiency and safety of surgery:

• Neuronavigation: GPS system for the brain and lets surgeons visualize in real time on the MRI localization of the brain. Increase precision and increases safety
• Awake surgery: This is often used when the tumor is located in a speech area or close to the motor cortex bilaterally. The patient is sedated so he or she can talk or complete tasks when asked. The surgeon can assess the patients functions during the surgery.
• Motor mapping during general anesthesia: The regions of the brain that control movement can be stimulated with an electrode with the patient under anesthesia. Currents will be applied to the brain cortex directly and muscle responses are noted. Positive responses are brain structures that should not be resurrected.
• Fluorescent dyes: Higher grade tumors can often absorb some dyes that are given IV to the patient before surgery. The tumor tissue is now colored by the dye while the normal bain is not colored. It creates a better image of what should or should not be removed.

ESTABLISHED ADJUVANT THERAPIES

• Steroids: To relieve symptoms because of brain swelling caused by the tumor, dexamethasone is often used. This is a quick acting and reliable drug. It does not have any action over the tumor and it can cause many side effects when used for over 2 or 3 weeks including weight gain, high blood sugar, hypertension, irritation, increased risk of infection.
• Chemotherapy with TMZ: Temozolomide (TMZ) is a drug that modifies the DNA of tumor cells. It is taken by the mouth. It will cause the DNA to break and cell death, unless DNA repair controls can override the damage. This is a commonly used treatment for astrocytomas that are grade 3 or 4. It is sometimes used for grade 2 astrocytomas. It is typically taken for five days followed by a three week rest, then the cycle repeats. The side effects include anemia and fatigue. Measuring the activity of the MGMT gene can predict how sensitive the astrocytoma will be to the TMZ.
• Radiotherapy: Radiation is a common treatment for astrocytomas for over 50 years. It is very effective for the first couple of months. Radiation will damage the DNA of the tumor cells and lead to cell death. The treatment is usually a small dose of radiation in the area of the tumor, 5 days a week for a 6 week period. This can cause hair loss and fatigue. Long term side effects include necrosis of the brain around the treated area and cognitive issues.
• Bevacizumab (Avastin): This is a drug that inhibits the tumor’s ability to gain blood vessels so it can feed itself and grow. Avastin was approved by the FDA in 2013 after being used in recurrent glioblastomas. This is very effective at decreasing the swelling caused by the tumor and can help improve symptoms. This is a potent alternative to steroids. This does not lengthen survival.
• Tumor treating electrical fields: this was approved by the FDA in 2011. It is the use of a device applied to the scalp as a helmet that can produce a low current electric field which can slow tumor growth. This can be used for recurrent glioblastomas and new blastomas. The device needs to be worn for 18 hours a day. The side effects include skin irritation.
• Antiseizure drugs: Levetiracetam (Keppra) is a widely used drug and is used for patients that have already had one seizure.

EXPERIMENTAL THERAPIES

• Targeted therapies: Most treating centers perform a genetic analysis that is very detailed of any tumor tissues that have been removed in surgery. This obtains patient-specific molecular signatures which can help determine the drug best suited for the tumor
• Immunotherapy: Astrocytomas develop and progress in a weak immune system. Antitumor vaccines, genetically modified immune cells, and drugs that stimulate the immune system are ways that are being researched to improve the immune system.
• Virus Therapy: Viruses that get injected into the patient can infect and destroy the tumor cell without hurting the rest of the brain. Herpes Simplex and poliovirus have been tested.

PROGNOSIS

These are the main factors that determine the length of survival after an astrocytoma diagnosis

• Tumor grade and histology

1. Grade 1 tumors are highly curative (96% survival) by surgery
2. Grade 2 tumors lead to an 8 year survival. IDH1 mutation can make survival longer
3. Grade 3 tumors have around 3-5 year of survival
4. Grade 4 tumors have a median survival of 15 months

• Extent of surgical resection

1. Complete microscopic resection of a grade 2-4 tumor is not possible but a total resection leads to a higher chance of survival. For GBM, if 80% of the tumor is removed there is a better chance of survival

• Using adjuvant radiotherapy and chemotherapy
• Age: Younger ages typically have a better survival rate
• Functional status: minimal systems and normal function neurologically can lead to a longer survival