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Biology and Treatment of Malignant Glioma

Biology and Treatment of Malignant Glioma

ABSTRACT: A large number of oncogenes have been identified as aberrant in gliomas, but only the erbB oncogene (gene encoding the epidermal growth factor receptor [EGFR]) is amplified in an appreciable number. The loss or mutation of tumor-suppressor genes located on different autosomes may be associated with progression of malignant gliomas. The p53 tumor-suppressor gene (located on chromosome 17) is frequently associated with the loss of one allele in malignant gliomas, although a large number of malignant gliomas have no p53 mutations. Some of the latter tumors have an amplified murine double minute 2 (MDM2) gene, which suppresses p53 gene activity. Genetic material from chromosome 10 may also be lost, especially in glioblastoma multiforme. In addition to the aberrant expression of EGFR, another growth factor, platelet-derived growth factor, or PDGF (ligand and/or receptors) can be overexpressed, giving cells a selective growth advantage. The blood-brain barrier is substantially altered in malignant gliomas, resulting in cerebral edema. Therapy for malignant gliomas includes surgery, radiation therapy, and chemotherapy. Surgical resection that leaves little residual tumor produces longer survival than less vigorous surgery. Radiation therapy to a dose of at least 60 Gy is required to treat malignant gliomas. Increased survival beyond that produced by standard external radiotherapy requires much larger doses; interstitial radiotherapy permits such dosing. Radiosurgery is being tested. Chemotherapy with nitrosoureas is modestly useful but appears to benefit patients with anaplastic astrocytoma more so than those with glioblastoma. [ONCOLOGY 12(2):233-246, 1998]

Primary brain tumors can occur at all ages but tend to cluster within two distinct peaks of age incidence: The peak occurs at 55 to 65 years of age in adults and from ages 3 to 12 in children. Approximately 15,000 new cases of adult central nervous system tumors are diagnosed each year,[1] and 11,000 deaths per year are attributed to these neoplasms. Although pediatric brain tumors are less numerous, with approximately 1,200 new cases each year,[2] they are now the leading cause of death from cancer in children.

Brain tumors affect the sexes differently. Glioma, the most common central nervous system tumor in adults, affects more males than females, and the reverse is true for meningiomas. Glioblastoma multiforme (GBM) is the most common glioma, followed equally by meningioma and astrocytoma. This discussion will be limited to gliomas occurring in adults.

A three-tiered classification system places well-differentiated astrocytomas at one end of the spectrum of malignancy, GBM at the other end, and anaplastic astrocytomas in the middle.[3] A newer classification system based on histology (Daumas-Duport) appears to correlate well with outcome.[4]

The World Health Organization (WHO) has used a modification of this system to define tumors according to their aggressiveness. Grade 1 gliomas are usually pilocytic astrocytomas occurring in young people; grade 2 gliomas include astrocytomas and oligodendrogliomas (mixed oligoastrocytomas); grade 3 gliomas consist of anaplastic astrocytomas and anaplastic oligodendrogliomas; and grade 4 gliomas are glioblastomas. Oligodendrogliomas have a somewhat better prognosis than astrocytomas of similar grade.

Biology of Gliomas

Gliomas are heterogeneous with regard to their cellular content. Karyotypically, the chromosomal complement of each cell type ranges from near diploid (2n) to hypotetraploid or hypertetraploid (4n) in chromosome number, and the distribution of cell types varies with each tumor.

Astrocytomas

Shapiro et al recently reviewed the cytogenetic characteristics of gliomas.[5] Of 68 astrocytomas in adults, 28 had normal karyotypes. Among those cases with abnormal karyotypes, the most common chromosomal abnormality was the loss of a single sex chromosome (X or Y), occurring in 25 cases. Chromosome 7, the only chromosome gained, was noted in eight cases.

Chromosomal breakpoints are rare in low-grade astrocytomas. The most common molecular abnormality is a mutation of the p53 tumor-suppressor gene located on chromosome 17,[6] but this mutation occurs without structural changes and with or without loss of heterozygosity (LOH).[7]

Anaplastic Astrocytomas

Anaplastic astrocytomas are thought to evolve from astrocytomas. In the review by Shapiro et al, of 127 anaplastic astrocytomas, only 10 had normal karyotypes.[5] Chromosomal gain and chromosomal loss were frequent. The most common gain was of chromosome 7, with less frequent gain of chromosomes 19 and 20. Loss of chromosomes 10, 22, and a single sex chromosome were prominent. Loss of a sex chromosome occurred as an isolated event, whereas multiple chromosomal abnormalities were the rule with gains of chromosome 7 or loss of chromosome 10.

Structural chromosomal abnormalities are not uncommon. More than 30% of anaplastic astrocytomas have mutation and/or deletion of the p53 gene.[8] The loss of p53 function, related to cell cycling through cyclin-dependent kinase (CDK), appears to account for some neoplastic behavior. When p53 is not mutated, in some cases there may be an amplification of another gene, murine double minute 2 (MDM2), which codes for a cellular protein that complexes with the p53 tumor-suppressor gene product and inhibits its function.[9]

Loss of heterozygosity for several other genes (CDK4, SAS, MTS-1) has been demonstrated in cases of anaplastic astrocytoma, but the frequency of these abnormalities is less than 5%. Analysis of more cases is needed to determine their significance.

Glioblastoma Multiforme

The incidence of GBM peaks in the mid-60s. Glioblastoma multiforme is the most malignant of the astrocytic tumors; median survival time of patients with this diagnosis is approximately 1 year (see below). This tumor is highly infiltrative, producing undifferentiated elements as a dominant feature, with high mitotic activity and necrosis. Vascular proliferation is invariably present, and the bromodeoxyuridine/Ki-67 labeling index is high.

Although genetic instability of this tumor results in complex, nonuniform genetic changes, malignant gliomas of the astrocytic series show several significant nonrandom chromosomal changes. The review cited above identified 198 cases of GBM.[5] The most frequent numerical chromosomal changes were the gain of chromosomes 7 and 20 and the loss of chromosomes 10, 22, and a single sex chromosome. The gain of chromosome 20 was more evident in GBM than in anaplastic astrocytoma. Chromosomal losses were more prevalent than gains, with added loss of whole chromosomes 9, 13, and 14.

The proportion of tumors in males with loss of a single sex chromosome is approximately the same as in anaplastic astrocytomas. Of the 58 cases with loss of the Y chromosome, it was the only abnormality in half the cases, while the remaining cases lost a Y chromosome in addition to other clonal abnormalities.

Structural chromosomal abnormalities are common in glioblastomas; the most frequent occur in chromosomal arms 9p, 9q, 1p, and 6q, in which multiple breakpoints have been identified, often producing rearrangements. Double minute chromosomes containing amplified DNA occur in 25% to 50% of reported cases. Marker chromosomes occur in 30%. Because markers may represent selective retention of specific genes, their origin is being assessed with fluorescence in situ hybridization (FISH) techniques.[10]

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