Astrocytomas are neuroepithelial tumors in the CNS arising from astrocytes, a type of star-shaped glial cell.
- Glial cells are supportive tissues within the brain and nervous system.
- Neuroepithelial tumors are those involving the brain parenchyma.
- Astrocytomas are graded, but not staged.
Classification of nervous system tumors
|Neuroepithelial tumors in the CNS|
|Sellar region tumors|
|Primary CNS lymphoma||Primary CNS lymphoma|
|Metastasis to the brain (5x more common than primary brain tumors)||Most commonly arising from:|
Classification of astrocytomas
There are several classification systems for astrocytomas, but the most widely used is the WHO grading system, which divides astrocytomas into 4 grades according to the extent of nuclear atypia, mitotic activity, cellularity, vascular proliferation, and necrosis.
- Grade I: noninvasive tumors that typically occur in children
- Pilocytic astrocytoma:
- Well-circumscribed, slow-growing, cystic tumors
- Usually arise in the cerebellum → may lead to compression of the 4th ventricle and/or ataxia
- Pleomorphic xanthoastrocytoma:
- Originates in temporal lobe
- Commonly associated with seizures
- Subependymal giant cell astrocytoma (SEGA):
- Periventricular tumors → may obstruct CSF outflow → hydrocephalus
- Associated with tuberous sclerosis
- Pilocytic astrocytoma:
- Grade II: low-grade diffuse astrocytomas
- Also known as fibrillary astrocytomas
- Invasive tumors with no clear separation from surrounding brain
- Show nuclear atypia alone
- May progress to glioblastoma
- Grade III: anaplastic astrocytomas
- Show nuclear atypia and ↑ mitotic activity and cellularity
- Lack necrosis and microvascular proliferation
- Progression to glioblastoma, typically within 2 years
- Grade IV: glioblastoma multiforme (GBM)
- Most malignant and aggressive type of astrocytoma
- Characterized by areas of necrosis or microvascular proliferation
- May progress from a lower-grade astrocytoma (10%) or originate directly as a GBM (90%)
- Dismal prognosis
- Age-standardized incidence: 4.7 per 100,000 person-years
- In the United States, 15,000 new astrocytomas are diagnosed per year.
- Race/ethnicity: no significant differences
- Sex predominance:
- No sex predominance in pilocytic astrocytoma.
- Slight male predominance in low-grade diffuse astrocytoma
- Male:female predominance of approximately 2:1 in anaplastic astrocytoma
- Grade IV astrocytomas:
- Most common malignant primary brain tumor: accounts for 23% of all primary brain tumors
- 60% of all astrocytomas are grade IV at diagnosis.
|Grade||Typical age of diagnosis (average age)||Typical length of survival|
|Grade I||Children and adolescents||> 10 years|
|Grade II||20–60 years (average, 35)||> 5 years|
|Grade III||30–60 years (average, 40)||2–5 years|
|Grade IV||50–80 years (average, 60)||Approximately 1 year|
The cause of most astrocytomas is unknown. Ultimately, genetic mutations lead to uncontrolled cell growth and tumor proliferation.
- Astrocytomas occur more frequently in the following genetic disorders:
- Li–Fraumeni syndrome (p53 germline mutations)
- Turcot syndrome (mutations in several tumor suppressor genes, including APC and MMR)
- Neurofibromatosis type 1 (NF1)
- Tuberous sclerosis
- Ionizing radiation is an established risk factor:
- Pituitary adenoma radiation therapy: 16× increased risk of astrocytoma
- Children who receive radiation for acute lymphocytic leukemia (ALL): 22× increased risk of developing a CNS malignancy in 5–10 years (including grade II, III, and IV astrocytomas)
Several genetic mutations are associated with astrocytomas.
- Mutations in isocitrate dehydrogenase 1 (IDH1 gene):
- Catalyzes the reversible oxidative decarboxylation of isocitrate → α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle
- Primary producer of nicotinamide adenine dinucleotide phosphate (NADPH) in most tissues, especially the brain
- Also involved in mitigating oxidative damage
- Mutations lead to production and buildup of a 2-hydroxyglutarate (2-HG):
- 2-HG inhibits enzymatic function of α-ketoglutarate (KG)-dependent dioxygenases, which are involved in DNA demethylation.
- ↑ 2-HG causes epigenetic dysregulation → can lead to tumor development
- Methylation (i.e., silencing) of the methylguanine methyltransferase (MGMT) promoter:
- MGMT is an enzyme involved in DNA repair (including DNA repair after chemotherapy with an alkylating agent).
- MGMT methylation at the promoter region:
- Silences expression of the gene
- May occur during tumor development → prevents repair of DNA damage
- Improves chemotherapy responsiveness and overall survival (independent of other risk factors)
- Inactivating p53 mutations (present in ⅔ of low-grade astrocytomas)
- Overexpression of platelet-derived growth factor alpha (PDGF-A)
- Certain human leukocyte antigen (HLA) types are associated with either decreased or increased risk.
- Astrocytomas usually arise in the cerebral hemispheres (i.e., parenchyma).
- Regional effects on brain parenchyma include:
- ↑ Intracranial pressure (ICP) may be due to:
- Direct mass effect
- Edema in surrounding brain tissue
- ↑ Blood volume
- ↑ CSF volume/hydrocephalus
- Disruption of normal parenchymal functions are due to:
- Competition for nutrients
- Release of metabolic end products:
- Free radicals
- Altered electrolytes
- Release and recruitment of cellular mediators (e.g., cytokines)
Neurologic signs and symptoms related to astrocytomas result from perturbations in CNS function.
Onset of symptoms
- Grades I and II: Onset is usually subtle and tumors develop slowly because of the brain’s ability to temporarily adapt to the presence of a slow-growing tumor.
- Grades III and IV: Onset is more often sudden and/or debilitating.
Symptoms are primarily dependent on the location of the tumor in the brain The symptoms are divided into 2 categories:
- General symptoms: symptoms that can occur with tumors in any location
- Headache (usually in the morning)
- Nausea and/or vomiting
- Cognitive difficulties:
- Memory problems
- Mood or personality changes
- Gait disorders
- Focal symptoms: symptoms that occur because of tumors in specific locations
- Most common symptom of astrocytomas
- Low-grade tumors are more likely to cause seizures than high-grade tumors.
- Visual field deficits
- Motor weakness
- Sensory abnormalities
Neuroimaging is the only test necessary to diagnose an astrocytoma. The gold standard is MRI, though CT is also sometimes used.
- Gold standard imaging study
- Preferably ordered with and without gadolinium enhancement
- Higher-grade astrocytomas show:
- T1 isointensity and T2 hyperintensity
- Enhancement with paramagnetic contrast agents
- Low-grade astrocytomas typically do not enhance with contrast.
- Contraindication to MRI
- Acute settings (e.g., where hemorrhage and/or stroke needs to be ruled out)
- CT of the chest/abdomen/pelvis may be warranted to look for alternative primary lesions if metastasis is suspected.
- Findings show a poorly defined parenchymal mass.
- Low-grade lesions typically do not enhance with contrast.
- EEG: may be used to evaluate and monitor seizure activity
- CSF studies: may assist in ruling out other diagnoses (e.g., CNS lymphoma, metastasis)
A biopsy is indicated for grading, and/or confirming the diagnosis after the tumor is identified on neuroimaging.
- Pilocytic astrocytoma: Rosenthal fibers: eosinophilic cytoplasmic inclusions, appearing as corkscrew-like fibers
- Low-grade diffuse astrocytoma:
- Mild to moderate increase in number of glial cell nuclei
- Nuclear pleomorphism
- Nucleus:cytoplasm ratio quite high
- Intervening feltwork of fine, glial fibrillary acidic protein (GFAP) astrocytic cell processes
- Grossly: poorly defined tumors that are gray in color
- Anaplastic astrocytoma:
- Increased cellularity and nuclear pleomorphism
- Marked mitotic activity and nuclear atypia
- High proliferative rate based on Ki67 staining
- Glioblastoma multiforme:
- Increased mitotic figures, cellularity, and nuclear pleomorphism
- Vascular and/or endothelial cell proliferation
- Areas of necrosis (grossly appear firm and white or soft and yellow)
- Tumor cells are “pseudopalisading.”
Management and Prognosis
Management by grade
Management depends on the grade, location of the tumor (i.e., how much can be safely resected), and symptoms. Management typically involves a combination of surgery, radiation, and chemotherapy.
- Grade I astrocytoma:
- Best management is controversial due to:
- Lack of strong data
- Relatively indolent nature of tumor
- Morbidity associated with the treatments
- Relatively young age of the typical patient
- Consider maximal safe surgical resection if tumor is accessible.
- Partial surgical removal when the tumor involves crucial parts of the brain
- Consider radiation therapy when the tumor is not fully resectable.
- Best management is controversial due to:
- Grade II astrocytoma:
- Surgical resection is recommended for accessible tumors:
- Not curative
- Additional therapies (i.e., radiation therapy and chemotherapy) are ultimately required in all patients.
- Radiation plus adjuvant chemotherapy (typically temozolomide)
- Follow-up to check for recurrence/progression
- Surgical resection is recommended for accessible tumors:
- Grade III and IV astrocytomas:
- Standard therapy is surgery, radiation, and chemotherapy (typically with temozolomide).
- Surgery may include:
- Symptom-relieving procedures (e.g., shunt placement to relieve hydrocephalus)
- If surgery is not possible, then radiation and chemotherapy are used.
- Other therapy to consider:
- DVT prophylaxis in nonambulatory and hospitalized patients
- Anticonvulsant therapy in patients with a history of seizures (prophylactic anticonvulsant therapy remains controversial)
- Corticosteroids (e.g., dexamethasone) may be used for their antiinflammatory properties to reduce tumor mass effect.
Factors that affect prognosis include:
- Tumor grade:
- Grade I: 96% 5-year survival rate
- Grade II: Median survival is 8 years.
- Grade III: Median survival is 2–5 years.
- Grade IV: Median survival is 15 months.
- Extent of surgical resection
- Use of adjuvant radiation therapy and/or chemotherapy
- Age: younger age at diagnosis associated with longer survival.
- Functional status (e.g., minimal symptoms and/or normal neurologic function) associated with longer survival
When a patient presents with neurologic symptoms on exam, the differential diagnosis may include vascular processes (e.g., hemorrhage, infarct), infections (e.g., abscess, viral encephalitis), and inflammatory processes (e.g., multiple sclerosis) in addition to primary brain tumors. Imaging is typically able to narrow the differential to a brain tumor.
- Oligodendroglioma: CNS tumor arising from oligodendrocytes. Oligodendroglioma most commonly develops in the cerebral hemisphere, usually in the frontal lobe. Oligodendrogliomas can present with focal neurologic deficits, seizures, and personality changes depending on its exact location. Diagnosis is made by MRI and biopsy. Management involves surgical resection, possibly accompanied by radiation and/or chemotherapy.
- Medulloblastoma: tumor that arises in the posterior fossa. Medulloblastoma is the most common malignant brain tumor in children. Patients present with symptoms of increased ICP as well as cerebellar signs that generally worsen over time. Diagnosis is suspected based on MRI findings, but histopathologic analysis at the time of surgical resection is required for diagnosis. Treatment is with a combination of surgery, radiation therapy, and chemotherapy.
- Ependymoma: subset of glial tumors that often arise in or adjacent to the ependymal lining of the ventricular system, most commonly within the posterior fossa, in contact with the 4th ventricle, or within the intramedullary spinal cord. The clinical presentation varies depending on the location of the tumor. MRI is the standard imaging technique, but histologic confirmation is required for diagnosis. Treatment involves surgical resection and adjuvant radiation or chemotherapy (based on age).
- Metastatic tumor: neoplastic cells that have spread to the brain from primary tumors elsewhere in the body. Metastatic neoplasms are the most common neoplasms in the brain. Neuroimaging often shows multiple foci of the carcinoma, suggesting nonbrain origin. Clinical presentation depends on the primary tumor and location and extent of brain metastasis. Treatment is directed at the underlying neoplasm and may involve surgical resection, radiation therapy, and chemotherapy.
- DeAngelis, L. M., Wen, P. Y. (2018). Primary and metastatic tumors of the nervous system. In Jameson J., et al. (Eds.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill. https://accessmedicine-mhmedical-com.aucmed.idm.oclc.org/content.aspx?bookid=2129§ionid=192016511
- Kapoor, M., Gupta, V. (2021). Astrocytoma. StatPearls. Retrieved May 2, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK559042/
- Recht, L., van den Bent, M., Shih, H. (2021). Treatment and prognosis of diffuse (grade II) and anaplastic (grade III) astrocytomas in adults. In Wen, P., Loeffler, J. (Ed.), UpToDate. Retrieved May 2, 2021, from https://www.uptodate.com/contents/treatment-and-prognosis-of-diffuse-grade-ii-and-anaplastic-grade-iii-astrocytomas-in-adults
- Kennedy, B. (2020). Astrocytoma. In Engelhard, H. (Ed.), Medscape. Retrieved May 2, 2021, from https://reference.medscape.com/article/283453-overview
- Kumar, V., Abbas, A. K., Aster, J. C. (2015). Robbins & Cotran Pathologic Basis of Disease. Philadelphia: Elsevier Saunders.
- National Cancer Institute. (2020). Childhood astrocytomas treatment (PDQ®)—patient version. Retrieved April 29, 2021, from https://www.cancer.gov/types/brain/patient/child-astrocytoma-treament-pdq
- National Organization of Rare Diseases. (2017). Anaplastic astrocytoma. Retrieved April 29, 2021, from https://rarediseases.org/rare-diseases/anaplastic-astrocytoma/
- National Organization of Rare Diseases. (2015). Astrocytoma. Retrieved April 29, 2021, from https://rarediseases.org/rare-diseases/astrocytoma/
- Peruzzi, P., Prabhu, V. (n.d.). Astrocytoma tumors. American Association of Neurological Surgeons. Retrieved April 29, 2021, from https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Astrocytoma-Tumors