Astrocytoma

• Bharti Rathore, M.D.

 Basic Information

Definition

Astrocytoma is a type of neuroepithelial tumor that arises from astrocytes, which are glial precursor cells. According to the current World Health Organization (WHO) classification astrocytoma is classified as below based on the histopathology:

1. •

   Grade I: Pilocytic astrocytoma

2. •

   Grade II: Diffuse astrocytoma

3. •

   Grade III: Anaplastic astrocytoma

4. •

   Grade IV: Glioblastoma

5. •

   Grades III and IV are considered high-grade astrocytomas (HGAs) or malignant.

The distinction of different grades of astrocytoma provides important clinical prognostic information.

Synonyms

1. Astroglial neoplasms

ICD-10CM CODES
C71.9	Malignant neoplasm of brain, unspecified

Epidemiology & Demographics

According to SEER registry, the incidence of primary CNS tumor is 6.4 cases per 100,000 persons per year with age-adjusted death rate of 4.4 per 100,000. According to the Central Brain Tumor Registry of the United States (CBTRUS) astrocytomas constitute about 10% of the central nervous system neoplasms.

Etiology

1. •

   No agent has been definitely implicated in the causation of CNS tumors, and risk factors can be identified only in minority of patients. Farmers and petrochemical workers have been shown to have a higher incidence of primary brain tumors. Exposure to ionizing radiation is a known risk factor for a small percentage of astrocytomas.

2. •

   Different hereditary syndromes are associated with increased risk and high frequency of astrocytoma.

   1. 1.

      Neurofibromatosis type 1 is associated with increased frequency of astrocytoma.

   2. 2.

      Li-Fraumeni syndrome (germ line mutation in one of p53 allele) is associated with increased frequency of malignant gliomas.

Gene and chromosomal alterations in astrocytoma

1. •

   Alteration in p53, a tumor suppressor encoded by the TP53 gene on chromosome 17p plays a key role in the development of at least one third of all grades of astrocytoma. In addition, in high-grade astrocytomas, p53 function may be deregulated by alteration of other genes, including amplification of MDM2 or MDM4 and 9p deletions that result in loss of the p14 product of the CDKN2A gene.

2. •

   Recently mutations of isocitrate dehydrogenase 1 gene (IDH1) have been shown to occur in a large fraction of grade II and grade III astrocytomas as well as in other gliomas. Antibodies specific to mutant form of IDH1 protein can now be used reliably for glioma diagnosis on routine tissue sections.

Physical Findings & Clinical Presentation

The presenting symptoms of astrocytoma depend, in part, on the location of the lesion and its rate of growth. Astrocytomas classically present with any one or more of the following features:

1. •

   Headache (less frequent)

2. •

   New-onset partial or generalized seizures (>50%)

3. •

   Nausea and vomiting

4. •

   Focal neurologic deficit (cranial nerve palsy, hemiplegia, ataxia)

5. •

   Change in mental status

6. •

   Papilledema (rare)

Diagnosis

A provisional diagnosis of astrocytoma is made on clinical grounds and radiographic imaging studies. Tissue pathology is needed to establish the diagnosis and to grade the astrocytoma.

Differential Diagnosis

The differential diagnosis is vast and includes any cause of headache, seizures, change in mental status, and focal neurologic deficits.

Workup

1. •

   The imaging modality of choice for most CNS tumors is contrast enhanced MRI which can demonstrate anatomy and pathological process in detail. CT scan is reserved for patients who are unable or unwilling to get MRI. Biopsy with histological confirmation is required to establish a diagnosis of astrocytoma.

2. •

   Stereotactic biopsy under CT or MRI guidance has been reserved for tumors that are deeply seated, multicentric tumors or diffuse nonfocal tumors where surgical resection is not practical. Major objectives of surgical resection are to maximally remove the tumor bulk, reduce tumor-associated mass effect and elevated intracranial pressure and provide tissue for pathological analysis. The surgical resection is carried out in a manner that minimizes the risk to neurological functioning. Surgery can also rapidly reduce the tumor bulk with potential benefits in terms of mass effect, edema, and hydrocephalus.

Laboratory Tests

There are no diagnostic or supportive blood tests for astrocytoma.

Imaging Studies

1. •

   MRI (Fig. 1) is the diagnostic imaging study of choice. MRI with contrast and magnetic resonance angiography are used to locate the margins of the tumor, distinguish vascular masses from tumors, detect LGAs not seen by CT scan, and provide clear views of the posterior fossa.

   

Treatment

Acute General Rx

1. •

   Corticosteroids (usually dexamethasone) need to be started immediately preoperatively in all primary CNS tumors unless CNS lymphoma is being suspected. Corticosteroids reduce cerebral edema and thus minimize secondary brain injury from cerebral retraction. Corticosteroids needs to be continued in the immediate postoperative period and tapered as quickly as possible. If there is increased intracranial pressure and impending herniation, patient should be started on IV mannitol, and mechanical ventilation with hyperventilation should be considered if there is depressed consciousness.

2. •

   The use of preoperative prophylactic anticonvulsants is less commonly indicated. The practice pattern in US seems to indicate its widespread use.

Stage-specific Rx

1. •

   Grade I astrocytoma are usually indolent and circumscribed tumors. Complete surgical resection, whenever feasible is curative and it is the mainstay therapy for these tumors. If complete surgical resection is not feasible due to location of tumor such as when the tumor is in optic pathway, hypothalamus, and in deep midline structures, asymptomatic patients can be observed in these cases until maximally safe resection is feasible upon progression. Unfortunately, despite aggressive near-total resection, delayed recurrence and eventual malignant transformation are common.

2. •

   In grade II astrocytoma, the extent of postoperative residual disease is an important variable for time to first relapse. The role of postoperative radiotherapy, in particular, timing is controversial. Observation with imaging is a reasonable option in patients who are young (<40) and had a gross tumor resection. In patients who have undergone subtotal resection and who are >40 years of age postoperative radiotherapy is recommended. Radiotherapy in this setting has been shown to improve progression-free survival (PFS) without improvement in overall survival.

3. •

   In Grade III anaplastic astrocytoma, surgical resection has shown to prolong survival but almost all of these tumors are characterized by postoperative residual disease. So, postoperative radiotherapy is used adjunctively. The role of adjunct chemotherapy is controversial. Most phase 3 clinical trials have demonstrated no benefit compared with radiation alone.

4. •

   In Grade IV glioblastoma, surgical resection has been shown to improve median survival. Multiple randomized trials have demonstrated survival benefit with use of chemotherapy concurrent with radiotherapy following surgery. Use of further adjunct temozolomide chemotherapy has been shown to improve the median survival in patients with glioblastoma in a randomized phase 3 clinical trial. Unfortunately, even with chemotherapy and radiation therapy, the 2-year survival in these patients is only 16%.

Treatment of recurrent disease

1. •

   For Grade 1 astrocytoma, re-resection should be considered. For patients who have tumors that are not amenable to resection, chemotherapy or radiotherapy can improve recurrence-free survival, although role of chemotherapy in adults remain controversial.

2. •

   For Grade 2 astrocytoma, radiation therapy can be considered in the relapsed setting if not given in the adjuvant setting. Data on use of chemotherapy in low-grade gliomas in adults is sparse. Although the results are encouraging, number of patients treated in these studies is small and there were a lot of methodological flaws in the studies. For recurrent Grade III anaplastic astrocytoma treated with radiation therapy in the past (Fig. 2), there is a role for chemotherapy. Nitrosoureas-based regimen and temozolomide (alkylating agent) have shown efficacy in this setting.

   

3. •

   Various targeted therapies are currently being studied in patients with recurrent glioblastoma. Irinotecan with bevacizumab or bevacizumab alone have been studied in a phase 2 trial, and a response rate of 38% and 28% respectively was reported in that study. Median survival was 8.7 months and 9.2 months respectively. The PD-1 checkpoint inhibitors are currently being evaluated and have shown promising early results in relapsed patients.

Prognosis

1. •

   Grade 1 astrocytoma has a good prognosis and is usually cured with surgical resection.

2. •

   Grade 2 astrocytoma has a median survival of about 7.5 years with treatment.

3. •

   Grade 3 anaplastic astrocytoma has a median survival of approximately 5 years. The patients with 1p and 19q co deletion have superior survival compared to patients without deletion.

4. •

   Median survival of glioblastoma is approximately 14 months.

Referral

A multidisciplinary consultation with a neurosurgeon, radiation oncologist, and neurooncologist is required to assist in the diagnostic workup and to provide immediate and follow-up treatment.

Suggested Readings

• D.R. Johnson, et al.: Medical management of high-grade astrocytoma: current and emerging therapies. Semin Oncol. 41 (4):511–522 2014 25173143

• E.T. Sayegh, et al.: Principles of surgery for malignant astrocytomas. Semin Oncol. 41 (4):523–531 2014 25173144

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