Astrocytoma
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Astrocytoma is a type of cancer that can occur in the brain or spinal cord. It originates from astrocytes, and, in adult individuals, they are the most common brain tumors.
The brain is made up by many different cells, including neurons, which constitute the electric circuitry responsible for brain functions, and astrocytes, which provide the structure and support for neurons to work properly. Some astrocytomas grow very slowly and others can be aggressive cancers that grow quickly.
Types
Causes
Symptoms
Diagnosis
Complications
Prevention
Types
The World Health Organization (WHO) classifies astrocytomas, a type of brain tumor, on a scale from grade 1 (least malignant) to grade 4 (most malignant). This grading is determined by examining the tumor cells under a microscope, considering factors such as the abnormality of the cells (atypia), their rate of growth (mitosis), and the presence of newly formed blood vessels within the tumor (vascular proliferation). Additionally, the tumor’s genetic features, analyzed through DNA analysis of the tumor cells, contribute to this classification. In general, aside from grade 1 tumors, which are more common in the pediatric population, astrocytomas predominantly affect individuals over the age of 40. Notably, as age increases, the likelihood of the astrocytoma being of a higher grade also rises.
Grade 1
- Pilocytic Astrocytoma is a well circumscribed tumor and grows slowly. Most common in the cerebellum, i.e. the part of the brain located in the back of the head, just above the neck. It does not invade into the surrounding brain, thus when resected completely it is considered cured, and it does not require either chemotherapy or radiotherapy.
- Pleomorphic Xantoastrocytoma most frequently originates in the temporal lobes and is commonly associated with seizures. Its cells can have many different shapes (pleomorphic), but usually do not show evidence of proliferation. Surgery is usually curative.
- Subependymal Giant Cell Astrocytoma (SEGA) is most common in the younger population, usually in association with a familiar syndrome called tuberous sclerosis. It characteristically grows inside the ventricles, which are fluid-filled spaces deep into the brain, and can often block the normal outflow of this fluid, thus causing hydrocephalus. Surgical resection is usually curative.
Grade 2
- Diffuse Astrocytoma is an invasive tumor, so there is no clear separation from the surrounding brain, and surgery itself might not be enough for its cure (this depends on several other factors described below). The tissue appearance is only moderately different from a normal brain, but cells appear abnormal under the microscope and slightly increased in number.
Grade 3
- Anaplastic Astrocytoma is considered a more malignant evolution of a previously lower grade astrocytoma, which has acquired more aggressive features, including a higher pace of growth and more invasion into the brain. Histologically, it displays a higher degree of cellular abnormalities, and evidence of cell proliferation (mitoses), in comparison to grade 2 tumors. Surgery is never considered curative for these tumors, and needs to be followed by radiation and almost always chemotherapy.
Grade 4
- Glioblastoma (GBM) is the most malignant, aggressive and common (60%) form of astrocytomas. Histologically, it is characterized by very abnormal-appearing cells, proliferation, areas of dead tissue and formation of new vessels. GBM can present either as a malignant progression from a previously existing lower grade astrocytoma (usually in 10% of cases) or originate directly as a grade 4 tumor (90% of cases). The former scenario is most common in younger patients, while the latter is most common after age 60. Regardless of its presentation, this tumor is a highly aggressive cancer, with pronounced brain invasion and destruction and very fast progression.
Causes
Astrocytomas are, for the vast majority, sporadic tumors, meaning that they happen by chance, or at least, it is not yet known why these occur. There are only two situations with proven evidence to cause the tumor:
Hereditary syndromes (i.e. caused by inherited DNA mutations): Li-Fraumeni: due to mutation in tumor suppressor gene p53 and characterized by young onset of multiple tumors, including breast cancer, bone cancers, leukemias and astrocytomas.
Turcot: due to mutations in several tumor suppressor genes, including APC and MMR and characterized by early onset of colon cancer and astrocytomas.
Neurofibromatosis 1: due to mutation of tumor suppressor NF1, responsible for early onset of astrocytomas, peripheral nerve tumors, skin freckling and light-brown patches in the skin.
Tuberous sclerosis: is a rare genetic disorder associated with mental retardation and early onset of subependymal giant cell astrocytoma (SEGA).
Environmental: Ionizing radiations: exposure to ionizing radiations has been associated to delayed onset of astrocytomas. Individuals at particular risk are those exposed to therapeutic radiotherapy to the head and neck region during childhood (i.e. for treatment of leukemias or other brain tumors). The interval between exposure to radiation and astrocytoma onset can be as long as 20-30 years.
Warfare chemicals: There is a yet unproven suspicion that exposure to Agent Orange during the Vietnam War might be responsible for delayed onset of astrocytomas in veterans.
Cellular phones: despite some suspicions, particularly related to heavy use, there is no data supporting a causative risk for astrocytomas.
Symptoms
The clinical presentation of astrocytomas depends much more on their location within the brain, rather than their biologic characteristics. There are regions of the brain that can accommodate very large tumors before they become symptomatic (for example, the regions in the forehead), while there are other locations where even a small tumor can cause problems early on, like limb weakness or difficulty with speech or vision.
Generally, low grade astrocytomas tend to be of bigger size before they become symptomatic, as compared to more aggressive, higher grade astrocytomas. This is because lower grade tumors tend to displace the brain rather than destroying it, and also because they are associated with less brain swelling than malignant ones.
Common symptoms of astrocytomas are the following:
- Persistent headaches
- Headaches which are worse in the morning or cause awakening from sleep (a sign of increased intracranial pressure)
- Double or blurred vision
- Speech problems
- Decreased cognitive abilities
- Grasp or limb weakness
- New seizures
Diagnosis
Conventional MRI: Magnetic resonance imaging (MRI) is the most important imaging study for astrocytomas. Usually, images are acquired both before and after the administration of IV contrast. As a rule of thumb, if the tumor picks up the contrast (i.e. becomes bright on images), it is an indication of a higher grade astrocytoma.
Other imaging sequences provides clues as to tumor cellularity, brain swelling and brain infiltration.
MRI spectroscopy (MRS): It is an imaging tool, based on MRI, which provides information on the chemical composition of the tumor, and works based on the fact that certain chemicals are abundant in the normal brain (for example, NAA), while others are abundant in tumors (for example, choline). The output of this imaging modality is a diagram showing the amount of each chemical in the area of the brain under analysis: If the amount of NAA is more than choline, that suggests a normal brain. The opposite raises suspicion of a tumor. This technique can be considered as a non-invasive tissue sampling, although it is not as accurate or definitive as a standard biopsy.
Functional MRI (fMRI): fMRI is a useful technique to visualize in real time which parts of the brain become activated when the patient is asked to perform a certain task (for example talking, or moving one arm or leg). This is fundamental to define the regions of the brain which, if damaged, would cause problems to the patient. Activated brain is shown as a yellow/red signal superimposed to an otherwise standard MRI. For tumors that are localized in the proximity of critical areas (speech centers, motor cortex or visual cortex) fMRI provide an important adjunct, particularly in regards to surgical planning.
Complications
Damage to the brain or nervous system that causes problems with coordination, muscle strength, speech, or eyesight
Seizures
Problems after surgery, such as infection or bleeding, and problems with general anesthesia
Infection and bleeding from chemotherapy
Delayed growth and development
Learning problems
Problems having children in the future (infertility)
Return of the cancer
Growth of other cancers
Prevention
Developing an astrocytoma is often unpredictable, and in most cases, there’s no specific preventive action one can take as occurrences tend to be random.
For individuals with a genetic predisposition that elevates the risk of astrocytoma, regular check-ups with the healthcare team are crucial. This monitoring allows for the early detection of signs indicating the presence of an astrocytoma. Early identification significantly improves the chances of successful intervention and treatment.
Treatment of Astrocytoma
The approach to treating astrocytoma is contingent on various factors, encompassing the tumor’s location, size, and type, as well as the patient’s age and overall health. A collaborative effort among specialists is essential to formulate the most effective treatment plan, and the team may include neurologists, neurosurgeons, radiation oncologists, and medical oncologists.
The primary modalities of treatment for astrocytomas are:
1. Surgery: Surgical intervention is often employed to address the tumor.
2. Radiation Therapy: The use of radiation is a common method to target and treat astrocytomas.
3. Adjuvant Chemotherapy: Chemotherapy may be administered as an additional treatment following surgery or radiation.
4. Tumor-Treating Fields (for Glioblastomas): This innovative approach involves the use of tumor-treating fields, particularly relevant for glioblastomas.
Grade 3 and grade 4 astrocytomas always require treatments other than surgery alone, while Grade 2 astrocytomas may sometimes require adjuvant therapy.
Additionally, there might be opportunities for participation in clinical trials, providing access to cutting-edge treatments and advancements in astrocytoma care.
Surgery
Chemotherapy
Radiotherapy
Steroids
Others
Surgery
Surgery is the first step for the treatment of astrocytomas, as it provides two important benefits: First, it procures tumor tissue to establish a diagnosis. Secondly, it offers the possibility to remove as much tumor is safely possible to relieve mass effect, reduce swelling and facilitate response to adjuvant therapies, when indicated. The decision whether to perform a simple biopsy or a full resection depends on multiple factors, but particularly on the clinical and medical conditions of the patient, as well as the predicted extent of resectability of the tumor.
Important tools to maximize efficiency and safety of surgery are:
- Neuronavigation: it is, in essence, a GPS system for the brain, and allows the surgeon to visualize in real time on the MRI his/her localization within the patient’s brain. This significantly increases precision and minimizes the risk of injuring normal brain.
- Awake surgery: This technique is particularly useful to resect tumors located in speech areas, and also when close to primary motor cortex bilaterally. The patient is kept sedated but not intubated, so that he/she can speak and execute commands when asked to. In this way, the surgeon can continuously asses the patient’s functions while removing the tumor.
- Motor mapping during general anesthesia: The regions of the brain controlling movement can be also stimulated with an electrode even if the patient is asleep. A stimulator is used to apply currents directly to the brain cortex, and muscle responses are recorded. Positive responses are interpreted as brain structures that should be spared from resection.
- Fluorescent dyes: Tumors, particularly those of higher grade, have the characteristic to avidly absorb certain dyes that are given IV to the patient just before surgery. In this way, the tumor tissue becomes colored by the specific dye, while the normal brain does not. This allows a much more precise definition of what should be resected and what should be left untouched. Among the most reliable dyes are 5-ALA, which colors the tumor violet, and Fluoresceine, which colors the tumor yellow, when visualized with appropriate lenses.
Chemotherapy
Chemotherapy with TMZ (Temozolomide): TMZ is an oral medication that slightly modifies the DNA of tumor cells, causing cell death unless DNA repair mechanisms intervene. It is a well-established first-line treatment for grade 3 and 4 astrocytomas and is occasionally used for grade 2 tumors, especially when complete resection is not possible or if genetic analysis results are unfavorable. The typical regimen involves daily intake for 5 days, followed by a 3-week rest period before starting another cycle. Potential side effects include anemia and fatigue. Predicting TMZ sensitivity can be done by measuring the activity of the MGMT gene, which repairs TMZ-induced damage, neutralizing the drug’s therapeutic effect.
Radiotherapy
Radiation has been a fundamental treatment for astrocytomas for the past 50 years, proving highly effective, particularly in the initial months post-treatment. This approach damages the DNA of tumor cells, leading to their demise. Standard protocols involve small doses of radiation in the tumor area, administered five days a week for six weeks. Localized hair loss and fatigue are common short-term side effects, while long-term effects may include brain necrosis around the treated region and cognitive difficulties.
Steroids
Steroid Dexamethasone is the preferred medication for alleviating symptoms related to brain swelling associated with the tumor. While highly effective in providing quick relief, it does not have a direct impact on the tumor. Prolonged use, beyond 2-3 weeks, may lead to notable side effects such as weight gain, elevated blood sugars, hypertension, increased infection risk, and irritability.
Others
- Bevacizumab is a drug that hinders the tumor’s ability to recruit blood vessels, impeding their growth. While effective in reducing tumor-related swelling and improving symptoms, it doesn’t significantly prolong survival, setting it apart from radiation and TMZ. It serves as a potent alternative to steroids.
