Malignant astrocytomas
| Malignant astrocytomas |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Epidemiology and Demographics
Brain tumors account for about 2% of all cancers, and are about 1/5 as common as breast or lung cancer. More than 50% of brain tumors are secondary, or metastatic from another site. Primary brain tumors originate from the brain parenchyma, meninges, cranial nerves or other intracrainial structures. In 1998, there were approximately 18,000 new cases of primary brain tumors. There is national and international data suggesting the incidence of these tumors is increasing. Gliomas, tumors of the neuroglia, arise from the oligodendrocytes, ependymal cells and the astrocytes.
Collectively astrocytomas are the most common type of primary brain tumor and account for 80%. These tumors are most frequently discovered in middle age. The approximate median survival is 94 months for Grade I-II, 12 months for Grade III and 5 months for Grade IV.
Histology/Classification
Astrocytomas are classified by the WHO into three major grades of increasing pathologic anaplasia and rapidity of clinical progression. These are:
- Grade II (Astrocytoma)
- Grade III (anaplastic astrocytoma)
- Grade IV (glioblastoma multiforme)
Astrocytomas are the most common and can be further classified into fibrillary, gemistocytic and protoplasmic based on histology. The rarer pilocytic type of astrocytoma (Grade I) occurs in younger patients and occurs more commonly in the cerebellum. This subtype generally has a benign biologic behavior.
>90% of the time theses are solitary lesions. A characteristic of gliomas is that they tend to become more anaplastic with time. This is a heterogeneous phenomenon and different areas of the same neoplasm may have differing histologic appearances.
A pattern of genetic alterations has also been noted. Low-grade astrocytomas are associated with deletion of material on Chromosomes 6 and 13. Progression to Grade III is associated with changes on Chromosome 19q and the retinoblastoma tumor suppressor gene. Finally, progression to glioblastoma multiforme (GBM) is associated with amplification of epidermal and hepatocyte growth factor receptor and alterations of Chromosome 10q and 18q.
Pathophysiology
Grade III and grade IV tumors tend to present with symptoms attributable to mass effect, increased ICP and brain infiltration. The exact presentation can be modified by the specific anatomic strictures involved. Involvement of the midbrain and brainstem is more likely to lead to ventricular obstruction and increased ICP. In keeping with the histologic behavior, glioblastoma multiforme tends to present approximately 10 years later than astrocytoma. The symptoms tend to remain static for a number of years and then patients may enter a period of rapid deterioration coinciding with progression of the tumor.
HA and seizures are the most common presenting features and are usually present for several months prior to diagnosis. As expected, the more aggressive tumors have a more fulminant course and are diagnosed sooner from symptom onset and can present with intracranial hemorrhage. Neurologic signs are often found including hemiparesis (61-83%), papilledema (32-66%), confusion (18-40%) and aphasia (25-32%).
These tumors can metastasize through the CNS axis, but rarely invade systemically.
Diagnosis
There are no typical findings on MRI that help identify grade of tumor. Noncontrast CTs may not show the tumor since they are often isodense to brain. They usually enhance with contrast but 30% of anaplastic astrocytoma and 4% of GBM lack this enhancement. Most patients have stereotactic needle biopsy immediately preceding or at the time of surgical resection. Needle biopsy may simply be performed to obtain tissue if surgery cannot be performed.
Differential Diagnosis
Nontumorous conditions that can mimic glial tumors include:
- abscess,
- vascular process
- cysticercocis
- Multiple Sclerosis
Less common tumors include
- primary CNS lymphoma
- ependymoma
- mixed oligoastrocytoma
- primitive neuroectodermal tumor
- oligodendroglioma
Treatment
Patients with seizures should be treated, but prophylactic treatment of patients solely with tumors has not been validated. Patients with brain tumors have a reported increase in adverse drug reactions, including Stevens-Johnson syndrome. It is thought that the combination of steroid therapy, radiation and phenytoin predispose to this adverse outcome.
Glucocorticoids (dexamethasone 4mg QID) can help relieve symptoms associated with increased ICP. The dose can be increased on a PRN basis. The dose is generally tapered after resection and continued at a low dose during adjunctive radiation therapy and eventually discontinued prior to chemotherapy.
Temporizing measures for unstable patients with increased ICP include intubation, hyperventilation, IV mannitol, and VP shunt placement. It should be noted that the usefulness of hyperventilation and mannitol diminishes with time, and these measures should be used as a bridge to definitive therapy.
Surgical resection is rarely curative and is used to relieve symptoms, further delineate histology and for debulking prior to radiation ± chemotherapy. It is generally performed in hose <65 years and selected elderly patients. It is not clear how much of the tumor/brain the surgeon should remove and what effect extensive resection has on mortality and/or neurologic complication.
Radiation therapy is used in symptomatic and for unresectable/partially resectable Grade I-II astrocytoma. Adjuvant radiation therapy increased survival from a median 14 to 36 weeks in high-grade astrocytoma. Radiation therapy originally consisted of whole brain irradiation because of the infiltrative nature of the high-grade tumors. Survival seemed to correlate with increasing dose of radiation administered, but was limited by the adverse sequelae of blood vessel injury, demyelination of the white matter and radiation necrosis.
Focal external beam radiation limits the field exposed and is thought to be sufficient since 80-90% of recurrences occur within 2 cm of the primary site. This technique is associated with fewer adverse events and similar recurrence rates. PET imaging has been used to help predict recurrence and to differentiate between radiation necrosis and recurrent tumor.
Development of new radiation techniques is ongoing. Brachytherapy is in use, but is limited by technical difficulty in placing the radioactive seeds and does not seem to be more effective than adjuvant chemotherapy. Stereotaxic radiosurgery’s (gamma knife) role is uncertain. Heavy particle radiation therapy (neutrons, charged helium or neon) is limited by unproven efficacy and the lack of widely available, inexpensive nuclear reactors.
Chemotherapy is not used in low-grade astrocytoma. Adjuvant chemotherapy with nitrosurea (BCNU) or procarbazine adds a modest survival benefit (18 month survival 19% versus 4%) in high-grade astrocytoma. With possibly the exception of temozolomide (TMZ), chemotherapy alone has not shown a mortality benefit, though response rates of 40% for 26 to 30 weeks have been reported for a variety of single and multiple-drug regimens. TMZ is approved for in relapsed Grade III astrocytoma only, not Grade IV.
Current work is underway looking at high dose IV chemotherapy with nitrosureas with autologous stem cell rescue and intraarterial delivery of chemotherapeutics and monoclonal antibodies ± disruption of the blood-brain barrier.
References
- Kumar Vinay Kumar, ed., Basic Pathology, 5th ed, (Philadelphia: W.B. Saunders Company, 1992), pp. 720-727.
- Fauci Anthony Fauci, ed., Harrison’s Principles of Internal Medicine. 14th ed, (New York: McGraw-Hill, 1998), pp. 2398-2401.
- Greenberg Greenberg HS. Clinical Manifestations and Diagnosis of High Grade Malignant Astrocytoma. UpToDate. 2000(8).
- Greenberg1 Greenberg HS. Management of High Grade malignant Astrocytoma-I. UpToDate. 2000(8).
- Greenberg2 Greenberg HS. Management of High Grade malignant Astrocytoma-II. UpToDate. 2000(8).
- Piscatelli Piscatelli N, Schiff D, Batchelor T. Classification of Brain Tumors. UpToDate. 2000(8).