An astrocytoma is a tumor that arises from the star-shaped cells (astrocytes) that form the supportive tissue of the brain. Other supportive cells of the brain include oligodendrocytes and ependymal cells. Collectively, these cells are known as glial cells and the tissue they form is known as glial tissue. Tumors that arise from the glial tissue, including astrocytomas, are collectively referred to as gliomas.
The World Health Organization (WHO) classifies astrocytomas into four grades depending on how fast they are growing and the likelihood that they will spread (infiltrate) to nearby brain tissue. Non-infiltrating astrocytomas usually grow more slowly than the infiltrating forms. Infiltrating, or diffuse astrocytomas are more common than non-infiltrating astrocytomas. They are generally more common in men and are most common in the cerebral hemispheres of adult patients. In children, they occur both in the cerebral hemispheres as well as the brain stem. Tumors from oligodendrocytes (oligodendrogliomas) are also in the category of infiltrating gliomas and can occasionally be difficult to distinguish from astrocytomas. Some infiltrating gliomas are categorized as mixed oligodendroglioma-astrocytoma (oligoastrocytoma).
Recently several markers have been identified in diffuse gliomas. Astrocytomas grades II and III often have acquired mutations in a gene called IDH1. These mutations ar acquired by the tumor and are not generally present in the normal cells of the patient. The presence of an IDH1 mutation in an astrocytoma is generally associated with an improved prognosis compared to an astrocytoma of a similar grade that does not have an IDH1 mutation. A second marker, relevant to GBM, is MGMT methylation. When present, MGMT methylation may be associated with a better response to chemotherapy (usual temozolomide) compared to GBMs without MGMT methylation.
Grading
Of numerous grading systems in use for the classification of tumors of the central nervous system, the World Health Organization (WHO) grading system is commonly used for astrocytoma. Established in 1993 in an effort to eliminate confusion regarding diagnoses, the WHO system established a four-tiered histologic grading guideline for astrocytomas that assigns a grade from 1 to 4, with 1 being the least aggressive and 4 being the most aggressive.
The WHO grading scheme is based on the appearance of certain characteristics: atypia, mitosis, endothelial proliferation, and necrosis. These features reflect the malignant potential of the tumor in terms of invasion and growth rate. Various types of astrocytomas are given these WHO grades:
| WHO grade | Astrocytomas | Description |
|---|---|---|
| I |
| Consist of slow-growing astrocytomas, benign, and associated with long-term survival. Individuals with very slow-growing tumors where complete surgical removal by stereotactic surgery is possible may experience total remission.[rx] Even if the surgeon is not able to remove the entire tumor, it may remain inactive or be successfully treated with radiation. |
| II |
| Consist of relatively slow-growing astrocytomas, usually considered benign that sometimes evolve into more malignant or higher-grade tumors. They are prevalent in younger people who often present with seizures. Median survival varies with the cell type of the tumor. Grade 2 astrocytomas are defined as invasive gliomas, meaning that the tumor cells penetrate into the surrounding normal brain, making a surgical cure more difficult. People with oligodendrogliomas (which might share common cells of origin[rx]) have better prognoses than those with mixed oligoastrocytomas, who in turn have better prognoses than patients with (pure) low-grade astrocytomas. Other factors which influence survival include age (younger the better) and performance status (ability to perform tasks of daily living). Due to the infiltrative nature of these tumors, recurrences are relatively common. Depending on the patient, radiation or chemotherapy after surgery is an option. Individuals with grade 2 astrocytoma have a 5-year survival rate of about 34% without treatment and about 70% with radiation therapy.[rx] The median survival time is 4 years.[rx] |
| III | Anaplastic astrocytoma | Consists of anaplastic astrocytomas. It is often related to seizures, neurologic deficits, headaches, or changes in mental status. The standard initial treatment is to remove as much of the tumor as possible without worsening neurologic deficits. Radiation therapy has been shown to prolong survival and is a standard component of treatment. Individuals with grade 3 astrocytoma have a median survival time of 18 months without treatment (radiation and chemotherapy).[rx] There is no proven benefit to adjuvant chemotherapy or supplementing other treatments for this kind of tumor. Although temozolomide is effective for treating recurrent anaplastic astrocytoma, its role as an adjuvant to radiation therapy has not been fully tested. |
| IV | Glioblastoma multiforme (GBM) | Consists of Glioblastoma multiforme (GBM), which is the most common and most malignant primary brain tumor. Primary GBM grows and spread to other parts of the brain quickly; they can become very large before producing symptoms, which often begin abruptly with seizures. Less than 10% form more slowly following degeneration of low-grade astrocytoma or anaplastic astrocytoma. These are called secondary GBM and are more common in younger patients (mean age 45 versus 62 years).[rx] “Surgical removal remains the mainstay of treatment, provided that unacceptable neurologic injury can be avoided. The extremely infiltrative nature of this tumor makes complete surgical removal impossible. Although radiotherapy rarely cures glioblastoma, studies show that it doubles the median survival of patients, compared to supportive care alone.”[rx] The prognosis is worst for these grade 4 gliomas. Few patients survive beyond 3 years. Individuals with grade 4 astrocytoma have a median survival time of 17[rx] weeks without treatment, 30[rx] weeks with radiation, and 37[rx] weeks with surgical removal of most of the tumor followed by radiation therapy. Long-term survival (at least five years) falls well under 3%.[rx][rx] |
According to the WHO data, the lowest grade astrocytomas (grade I) make up only 2% of recorded astrocytomas, grade II 8%, and the higher grade anaplastic astrocytomas (grade III) 20%. The highest graded astrocytoma (grade IV GBM) is the most common primary nervous system cancer and second most frequent brain tumor after brain metastasis. Despite the low incidence of astrocytomas compared to other human cancers, mortality is significant, as the higher grades (III & IV) present high mortality rates (mainly due to late detection of the neoplasm).
Symptoms
Symptoms of grade I and grade II astrocytomas are subtle because the brain can temporarily adapt to the presence of a slow-growing tumor. Symptoms of grade III and grade IV astrocytomas may be sudden and debilitating. Symptoms can result from increased pressure within the brain and may include headaches, vision changes, and nausea or vomiting. Symptoms may also occur based on the location of the tumor due to interference with normal brain function and include focal seizures, difficulty with speaking, loss of balance and weakness, paralysis, or loss of sensation of one side of the body. Fatigue and depression are common in individuals with astrocytoma.
Desmoplastic infantile astrocytoma (DIA) is a very rare grade I astrocytoma. This tumor tends to occur in the cerebral hemispheres and is usually diagnosed in children less than two years of age. Symptoms may include an increased head size, bulging soft spots (fontanelles) in the skull, eyes that focus downward, and seizures. A related tumor, desmoplastic infantile ganglioglioma, is a mixed astrocytic and neuronal tumor but is otherwise similar to DIA.
Subependymal giant cell astrocytoma occurs in the ventricles of the brain and is almost always associated with a genetic condition called tuberous sclerosis. Other rare neuroepithelial tumors include pleomorphic xanthoastrocytoma (PXA) and ganglioglioma (a mixed glial-neuronal tumor).
Causes
The cause of most astrocytomas is not known. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.
Astrocytomas occur with greater frequency with certain genetic disorders including Turcot syndrome, neurofibromatosis type-I tuberous sclerosis, Ollier’s disease, and Li-Fraumeni syndrome.
Diagnosis
The diagnosis of astrocytoma is based on a thorough clinical evaluation, characteristic physical findings, a careful patient history, and specialized tests, such as blood tests, neuroimaging techniques, and/or other diagnostic studies.
WHO Histological Grading: Diffuse Astrocytomas
- Grade II (diffuse astrocytoma): nuclear atypia alone
- Grade III (anaplastic astrocytoma): nuclear atypia + focal/dispersed anaplasia. There are prominent proliferation activity and mitoses
- Grade IV (glioblastoma): nuclear atypia, mitoses, microvascular proliferation or necrosis
WHO Histological Grading: Localized Astrocytomas
Pilocytic astrocytoma: corresponding to WHO-grade I
- Doesn’t recommend definitive grade allotment yet for pilomyxoid astrocytoma
- SEGCA (subependymal giant cell astrocytoma): Grade I
Common Types of Pilocytic Astrocytoma
- It is benign
- Has cystic consistency
- Location is mostly infratentorial
- Presents classically in childhood
- Can be resected surgically
- Variant: Pilomyxoid astrocytoma
Diffuse Astrocytoma
- Grade II
- Usually seen in adults
- May progress to glioblastoma
Anaplastic Astrocytoma
- Grade III
- Also usually seen in adults
- There is a lack of endothelial proliferation
Glioblastoma
- Commonest malignant brain tumor
- The peak age is around 65 years
- Very bad prognostication
- Variants: Giant cell glioblastoma, Gliosarcoma
Uncommon Types
Pleomorphic Xanthoastrocytoma (PXA)
- Prognosis is usually good
- Age group affected: Children & adults (young)
- Has big lipidized cells
- May mimic malignant tumor
Subependymal Giant Cell Astrocytoma(SEGCA)
- Located mostly intraventricularly
- Benign in nature
- Affects the adolescent age group
- Associated with Tuberous sclerosis
Gliomatosis Cerebri
- The old term, used for extensive & diffuse astrocytomas
- Not a distinct entity since 2016
- Radiological evidence of > 3 lobe involvement is required, bilaterally
- WHO grade III
- The division into 2 types is possible on the basis of solid component presence:
1. Type 1 GC: No IDH 1/2 mutation, diffusely growing
2. Type 2 GC: IDH 1 mutation +, a solid component present
- Genetically overlaps diffuse astrocytic gliomas, glioblastoma & oligodendrogliomas
H3 K27M Mutant Diffuse Midline Glioma
- High-grade
- Location: midline including spinal cord, brainstem & thalamus
- Adolescents & children are mostly involved
- DPIG(Diffuse pontine intrinsic glioma) is included
- New entry after the 2016 WHO classification
Poor prognosis is usually there when:
- Absence of EGFR amplification
- Presence of unmethylated MGMT promoter
- Enhancement in MRI: may/may not be present
- Histologically may range from minimum hypercellularity to full-blown glioblastoma
Gliosarcoma
- WHO considers it as a variant of glioblastoma
- It is quite rare, with only about 200 case reports
- Has Glioblastoma & sarcoma components(fibroblastic, osseous, cartilage, smooth & striated muscle, fat cells)
- Similar to glioblastomas, it is usually found in the temporal lobe
- Prognositicallly like glioblastoma
Immunohistochemistry:
- The astrocytic component is a glial fibrillary acidic protein (GFAP) positive & spindle cell negative
- Smooth muscle part (Gliomyosarcoma ) is Smooth muscle antibody (SMA) & factor VIII positive
Gliofibroma
- It is very rare
- Usually found in children
- Has fibroblastic part, which is non-malignant
History
Symptoms can be divided into two categories: general & focal. General symptoms include headache (usually early morning), nausea, vomiting, cognitive difficulties, personality changes, and gait disorders. Localizing symptoms include seizures, aphasia, or visual field defects. A visual field defect is often unnoticed by the patient and may be revealed after it leads to injury such as in automobile accidents. Seizures occur in about 90% of patients with low-grade glioma.
Physical
Always do a full neurological examination. All signs should be well elicited as they have localizing features. For example, a positive Babinski’s sign on the right side suggests a left lobe pathology. Similarly, the demarcation of sensory levels will help in localizing the spinal cord malignancy level. Cranial nerve palsies are a good sign for localizing intracranial locations. Further confirmation of the location of tumors should be done by neurological imaging.
Imaging Studies
Neuroimaging is the only test necessary to diagnose a brain tumor. MRI is the best imaging for the same. Gadolinium contrast-enhanced MR imaging should be used whenever possible. If there is any contraindication for MRI, such as joint implants or pacemakers in situ, computed tomography or CT may be done. Lower-grade gliomas aren’t contrasting enhancing, so fluid-attenuated inversion recovery (FLAIR) sequences of MRI are done. If a tumor is found, a neurosurgeon must perform a biopsy on it. This simply involves the removal of a small amount of tumor tissue, which is then sent to a neuropathologist for examination and grading. CT appearance of lowgrade astrocytomas is also generally not very definitive. They are homogeneous, not well defined, and appear as poorly defined and non-contrast enhancing lesions. In anaplastic astrocytomas, there may be some contrast enhancement. There may be a possible metastatic disease; hence whole-body imaging should also be considered to look for an alternate primary.
During CT scanning, a computer and x-rays are used to create cross-sectional images of certain tissue structures. MRI uses a magnetic field to create cross-sectional images of particular organs and bodily tissues. Examination of a sample of the tumor (biopsy) and microscopic examination of tumor cells are used to determine the tumor type and grade.
On MRI, T2 hyperintensity is seen in astrocytomas, whereas on T1, there is isointense. Tumor vascularity is very important; hence new techniques are being developed to identify it. These include ASL (arterial spin labeling) and DCE (dynamic contrast enhancement) MRI. Functional MRI is an upcoming imaging modality. It is useful pre-surgery to demarcate various areas of the brain based on functionality. Other modalities include PET scan, MRS (magnetic resonance spectroscopy), and perfusion. These may give information about metabolic action in the tumor, the blood flow characteristics, and the constitution of the tumor. Using this, it can be determined whether the lesion is progressive or necrosed after chemotherapy and radiotherapy.
Treatment
Grade I astrocytoma: Surgery is the standard treatment. Total surgical removal of accessible astrocytomas is often possible and successful. Accessible tumors are those that can be operated on without causing unacceptably severe damage to other parts of the brain. If surgery is performed, the surgeon will attempt to remove all identifiable parts of the astrocytoma when possible. When astrocytoma involves a crucial part of the brain, partial removal of the growth usually reduces pressure, relieves symptoms, and helps control seizures.
Full or partial removal of the astrocytoma is sometimes followed by radiation therapy to destroy any remaining tumor cells. With the use of CT (computed tomography) and MRI (magnetic resonance imaging), radiation sometimes may be deferred for several months or years while the patient is scanned at regular intervals. Radiation as primary therapy is occasionally used on grade I astrocytomas.
Chemotherapy may be administered after radiation in an attempt to destroy any cells that remain or may also be given during radiation treatment. Chemotherapy may be used instead of radiation in very young children to avoid damage to the developing brain. The type of chemotherapeutic drug therapy selected is determined by a neuro-oncologist who examines the grade of tumor, previous treatment, and current health status of the affected individual.
Grade I astrocytoma can sometimes progress to a higher grade so follow-up scans at regular intervals are necessary to check for re-growth.
Grade II astrocytoma: Treatment depends on the size and location of the tumor. Surgery may be used to remove accessible tumors. As with all infiltrating astrocytomas (grades II-IV), it cannot be completely removed with surgery because the tentacle-like projections of the tumor grow into the surrounding tissue. Radiation may be used if the tumor is not accessible or in addition to surgery. Grade II astrocytoma can also progress to a higher grade so follow-up is necessary to check for re-growth. A recurrent tumor may be treated with surgery, radiation, or chemotherapy.
Grade III astrocytoma: Treatment depends on the size and location of the tumor, what it looks like under the microscope and how far it has spread. The standard treatment is surgery and radiation therapy, accompanied or followed by chemotherapy. If surgery is not possible, radiation and chemotherapy may be recommended. Several different types of radiation therapy are available including conventional external beam radiation, focused radiation, stereotactic radiosurgery implanted radiation, or conformal radiation. A radiation oncologist determines the most appropriate form of radiation for a particular tumor. Chemotherapeutic agents that are commonly used to treat grade III astrocytoma include carmustine (BCNU), lomustine (CCNU), procarbazine, cisplatin, and temozolomide. Biodegradable wafers (called Gliadel Wafers) containing BCNU are sometimes inserted in the cavity that remains after a tumor is removed. Grade III astrocytoma tends to recur and treatment depends on the grade of tumor that recurs.
The Food and Drug Administration (FDA) has approved temozolomide (Temodar) for the treatment of adults with anaplastic astrocytoma that has not responded to other forms of therapy (refractory anaplastic astrocytoma). For more information, contact:
Grade IV astrocytoma: The three main forms of treatment for GBM are surgery and radiation or chemotherapy. These treatments may be used alone or in combination with one another. The initial treatment in most cases is surgical excision and removal of as much of the tumor as possible (resection). Often, only a portion of the tumor can be safely removed because malignant cells may have spread to surrounding brain tissue. Because surgery cannot completely remove a tumor, radiation therapy and chemotherapy are used following surgery to continue treatment.
The FDA has approved temozolomide (Temodar) for the treatment of adults with GBM. Temozolomide is used concurrently with radiation therapy, and also for some time after completion of radiotherapy.
WHO classification(2016) classifies diffuse astrocytomas as grades II, III, and IV. Grade I infiltrating astrocytoma is not mentioned. It is based on the following four characteristics: 1. Nuclear atypia: nuclear pleomorphism and hyperchromasia 2. Mitoses:
- Has to be unequivocal
- Ki67 proliferation index is used to separate grade II tumors from grade III
3. Microvascular proliferation:
- Glomeruloid type – commoner, prognostically lesser significance as it’s found in lower-grade gliomas (like pilocytic astrocytoma) also
- Endothelial proliferation – in the large vessel lumen. It is less common and has more association with high-grade gliomas
4. Necrosis:
- Coagulative necrosis
- Pseudopalisading necrosis
Glioma Treatment Recommendations Based on Grade
Grade I (pilocytic astrocytomas)
- Uncommon, typically noninvasive and are considered benign. Potentially curable by surgery but if surgical removal is not possible completely, radiotherapy or expectant management is used
Grade II (low-grade infiltrative astrocytomas, oligodendroglioma, mixed gliomas)
- Surgery is recommended with maximal safe resection
- Unfavorable prognostic factors: age > 40 years, dimension ≥6 cm, crossing midline, and presence of neurologic deficit before resection; 3 or more factors are high risk
- Low-risk, < 40-year patients: observation
- High-risk patients: fractionated external-beam radiotherapy (EBRT) or adjuvant chemotherapy[rx]
- The standard radiation dose for low-grade astrocytomas is 45-54 Gy, delivered in 1.8 to 2.0 Gy fractions
- Adjuvant therapy includes temozolomide 150 to 200 mg/m^2/day orally on days 1-5 of a 28-day cycle (6-8 cycles)
- Recurrences or progressive, low-grade disease (previously untreated): Temozolomide 75 mg/m^2 PO daily on days 1-21 or 150 to 200 mg/m^2 PO on days 1 to 5 of a 28-d cycle until disease progression or for a maximum of 24 cycles
- Postoperative radiation therapy is often employed for unresectable, residual, or recurrent tumor
- Chemotherapy is often used for low-grade oligodendrogliomas, particularly tumors with the 1p19q deletion, which is a marker for tumor susceptibility to chemotherapy
Grade III (anaplastic astrocytoma or oligoastrocytoma)
- Standard of care: surgical resection followed by EBRT (60 Gy in 30 to 35 fractions) and adjuvant temozolomide, 75 mg/m^2/day orally on days 1 to 42, usually 1 to 1.5 hours before radiation
- Post–radiation therapy: Continue temozolomide at higher doses of 150 to 200 mg/m^2/day PO on days 1 to 5 every 28 days or
- PCV (procarbazine, lomustine, vincristine): lomustine (CCNU) 90 to 130 mg/m^2 PO on day 1 plus procarbazine 60 to 75 mg/m^2 PO on days 8 to 21 plus vincristine 1.4 mg/m^2 IV (not to exceed 2 mg/dose) on days 8 and 29; administer every 6 weeks for up to 4 cycles with deferred radiotherapy
Grade IV (glioblastoma):
- Postradiation therapy: Continue temozolomide at higher doses of 150 to 200 mg/m^2/day PO on days 1 to 5 every 28 days[rx]
Recommendations for recurrent tumors: reoperation, carmustine wafers, and alternate chemotherapeutic regimens. Re-radiation is rarely helpful. Bevacizumab, a humanized VEGF monoclonal antibody, has activity in recurrent glioblastoma, increasing progression-free survival & reducing peritumoral edema & glucocorticoid use. Recurrent glioblastoma treatment decisions must take into consideration factors such as previous therapy, time to relapse, performance status, and quality of life. Whenever possible, patients with recurrent diseases should be enrolled in clinical trials.
How to Approach
As with the rest of the malignancies, a multimodal treatment approach is undertaken, including surgical, medical, and radiation oncology.
Low-grade astrocytomas: No clear superiority of any particular modality is known. As these low-grade tumors can be quite indolent, questions arise about the risk-benefit ratio of undertaking any intervention. A study by Ishkanian et al. demonstrated the efficacy of adjuvant radiotherapy for pilocytic astrocytoma (WHOgrade I), it prolongs PFS (progression-free survival) at 5 and 10 years as compared to observation.[rx] Overall, survivals were equal, however.
Grade 2 astrocytoma: Radiotherapy and adjuvant chemotherapy are better than only radiotherapy. A trial showed that chemotherapy with vincristine, procarbazine, and lomustine following radiotherapy leads to better 10 years of PFS (51% v/s 21%).[rx]
Anaplastic astrocytomas: multimodal therapy is incorporated, including surgery, radiation, and chemotherapy(adjuvant temozolomide). Data regarding concurrent temozolomide is lacking, although some studies showed improved survival (46% vs. 29%). IDH( Isocitrate Dehydrogenase ) mutation is also associated with improved 5-year survival (79% vs. 22%).[rx] Response to chemotherapy is better in Anaplastic astrocytomas than glioblastomas. In the event of recurrence, temozolomide shows a better response. Nitrosourea-treated recurrent tumors showed about 35% response with temozolomide. Moreover, 6month survivals were also better(46% v/s 31%).[rx] Adjuvant carmustine also shows a slight survival benefit.
Prophylactically starting antiepileptics is controversial. Those who have a complaint of seizure should be started on antiepileptics. The patient is usually started on levetiracetam, topiramate, lamotrigine, valproic acid, and lacosamide for seizures. These drugs interfere less with the hepatic microsomal enzyme system. Other drugs such as phenytoin and carbamazepine are used less frequently as they are potent enzyme inducers that can interfere with both glucocorticoid metabolism and the metabolism of chemotherapeutic agents. Corticosteroids are also used as they lead to excellent symptomatic relief due to their anti-inflammatory action. This leads to a decrease in mass effect. Dexamethasone is the glucocorticoid of choice because of its low mineralocorticoid activity. Initial doses are typically 12-16 mg/d in divided doses orally or IV ( both are equivalent). Concurrent prophylaxis for gastrointestinal ulcers should be prescribed with corticosteroid administration.
Surgical Care
Surgery provides to remove/debulk the tumor. Moreover, histological diagnosis is made possible by the tissue biopsy provided by the surgeon. Other symptom-relieving procedures include ICT (intracranial tension), reducing procedures like VP shunting, EVD insertion, etc. It has been shown that complete resection (>98% based on volumetric MRI) improves median survival compared with subtotal resection (13 vs. 8.8 mo).[rx] For low-grade gliomas, subtotal resection is also advocated (i.e., removal of tissue beyond the MRI-defined abnormalities), suggesting an increase in overall survival with this strategy.[rx]
Other Medications Summary
The venous thromboembolic disease occurs in 20% to 30% of patients with high-grade gliomas and brain metastasis; hence prophylactic anticoagulants should be used during hospitalization and in non-ambulatory patients. Those who have had deep venous thrombosis (DVT) or pulmonary embolus can receive safely therapeutic doses of anticoagulation without increasing the risk for hemorrhage into the tumor.
Antineoplastic Agent
Temozolomide (alkylating agent): Oral alkylating agent converted to MTIC at physiologic pH; 100% bioavailable; approximately 35% crosses the blood-brain barrier.
mTOR inhibitors are also proposed for the treatment of grade 1 astrocytomas.
References
