Anaplastic astrocytoma is a rare malignant brain tumor. Astrocytomas are tumors that develop from certain star-shaped brain cells called astrocytes. Astrocytes and similar cells form tissue that surrounds and protects other nerve cells found within the brain and spinal cord. Collectively, these cells are known as glial cells and the tissue they form is known as glial tissue. Tumors that arise from glial tissue, including astrocytomas, are collectively referred to as gliomas. The symptoms of anaplastic astrocytomas vary depending upon the specific location and size of the tumor. The specific cause of this tumor is unknown.
Astrocytomas are classified according to a grading system developed by the World Health Organization (WHO). Astrocytomas come in four grades based upon how fast the cells are reproducing and the likelihood that they will spread (infiltrate) nearby tissue. Grades I or II astrocytomas are nonmalignant and may be referred to as low-grade. Grades III and IV astrocytomas are malignant and may be referred to as high-grade astrocytomas. Anaplastic astrocytomas are grade III astrocytomas. Grade IV astrocytomas are known as glioblastoma multiforme. Lower-grade astrocytomas can change into higher-grade astrocytomas over time.
Types
Common Types of astrocytoma
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 based on 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
Causes
The exact cause of anaplastic astrocytomas is unknown. 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 in certain genetic disorders including neurofibromatosis type I, Li-Fraumeni syndrome, and tuberous sclerosis. Except in these rare disorders, the vast majority of astrocytomas are not passed on to offspring with greater frequency. Researchers believe that some individuals may have a genetic predisposition to developing an astrocytoma. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors.
Diagnosis
A diagnosis of anaplastic astrocytoma is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of imaging techniques including computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Such imaging techniques may also be used to may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures.
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.
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.
Surgical removal and microscopic evaluation (biopsy) of tissue from a tumor may confirm a diagnosis.
Treatment
The therapeutic management of individuals with an anaplastic astrocytoma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, neurologists, oncology nurses, and other health care specialists.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, the extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites (which rarely occurs with astrocytomas); an individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of the case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.
The three main forms of treatment for anaplastic astrocytoma are surgery, radiation, and 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). Sometimes, only a portion of the tumor can be safely removed because malignant cells may have spread into surrounding brain tissue. Because surgery often cannot completely remove a tumor, radiation therapy and chemotherapy are usually used following surgery to continue treatment.
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
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
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.[8] 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. For seizures, the patient is usually started on levetiracetam, topiramate, lamotrigine, valproic acid, and lacosamide. 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.
Postoperative radiation to help treat known or possible residual disease is frequently used in anaplastic astrocytomas. If initial surgery is not an option due to the specific location and/or progression of the malignancy, therapy may include radiation alone. Radiation therapy preferentially destroys or injures rapidly dividing cells, primarily cancerous cells. However, some healthy cells (e.g., hair follicles, bone marrow, etc.) may also be damaged, leading to certain side effects. Thus, during such therapy, the radiation is passed through diseased tissue in carefully calculated dosages to destroy cancer cells while minimizing exposure and damage to normal cells. Radiation therapy works to destroy cancer cells by depositing energy that damages their genetic material, preventing or slowing their growth and replication.
Therapy with certain anticancer drugs (chemotherapy) may also be used to treat individuals with anaplastic astrocytoma. Only one chemotherapeutic agent has been approved for adults with anaplastic astrocytoma. No agents are approved for use in children. Most chemotherapeutic agents have demonstrated only limited effectiveness for treating individuals with anaplastic astrocytoma.
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). Temodar is manufactured by the Schering-Plough Corporation.
References
