Supratentorial pilocytic astrocytomas, astrocytomas, anaplastic astrocytomas and glioblastomas are characterized by a differential expression of S100 proteins

The levels of expression of the S100A1, S100A2, S100A3, S100A4, S100A5, S100A6 and S100B proteins were immunohistochemically assayed and quantitatively determined in a series of 95 astrocytic tumors including 26 World Health Organization (WHO) grade I (pilocytic astrocytomas), 23 WHO grade II (astrocytomas), 25 WHO grade III (anaplastic astrocytomas) and 21 WHO grade IV (glioblastomas) cases. The level of the immunohistochemical expression of the S100 proteins was quantitatively determined in the solid tumor tissue (tumor mass). In addition twenty blood vessel walls and their corresponding perivascular tumor astrocytes were also immunohistochemically assayed for 10 cases chosen at random from each of the four histopathological groups. The data showed modifications in the level of S100A3 protein expression; these modifications clearly identified the pilocytic astrocytomas from WHO grade II-IV astrocytic tumors as a distinct biological group. Modifications in the level of S100A6 protein expression enabled a clear distinction to be made between low (WHO grade I and II) and high (WHO grade III and IV) grade astrocytic tumors. Very significant modifications occurred in the level of S100A1 protein expression (and, to a lesser extent, in their of the S100A4 and S100B proteins) in relation to the increasing levels of malignancy. While the S100A5 protein was significantly expressed in all the astrocytic tumors (but without any significant modifications in the levels of malignancy), the S100A2 protein was never expressed in these tumors. These data thus indicate that several S100 proteins play major biological roles in human astrocytic tumors.     

Differential expression of two fibroblast growth factor-receptor genes is associated with malignant progression in human astrocytomas

Malignant astrocytomas, which are highly invasive, vascular neoplasms, compose the majority of nervous system tumors in humans. Elevated expression of fibroblast growth factors (FGFs) in astrocytomas has implicated the FGF family of mitogens in the initiation and progression of astrocyte-derived tumors. In this study, we demonstrated that human astrocytomas undergo parallel changes in FGF-receptor (FGFR) expression during their progression from a benign to a malignant phenotype. FGFR type 2 (BEK) expression was abundant in normal white matter and in all low-grade astrocytomas but was not seen in malignant astrocytomas. Conversely, FGFR type 1 (FLG) expression was absent or barely detectable in normal white matter but was significantly elevated in malignant astrocytomas. Malignant astrocytomas also expressed an alternatively spliced form of FGFR-1 (FGFR-1 beta) containing two immunoglobulin-like disulfide loops, whereas normal human adult and fetal brains expressed a receptor form (FGFR-1 alpha) containing three immunoglobulin-like disulfide loops. Intermediate grades of astrocytic tumors exhibited a gradual loss of FGFR-2 and a shift in expression from FGFR-1 alpha to FGFR-1 beta as they progressed from benign to malignant phenotype. These results suggest that differential expression and alternative splicing of FGFRs may be critical in the malignant progression of astrocytic tumors.     

Expression of oligodendrocytic mRNAs in glial tumors: changes associated with tumor grade and extent of neoplastic infiltration

We examined the expression of glial- and neuronal-specific mRNAs within human gliomas using in situ hybridization. We found that low-grade astrocytomas contained a high number of proteolipid protein (PLP) mRNA-positive cells and that the number of PLP-stained cells decreased markedly with increasing tumor grade. Interestingly, the ratio of PLP mRNA-stained cells:myelin basic protein (MBP) mRNA-stained cells in normal white matter and low-grade astrocytoma was about 2:1 but approached 1:1 with increasing tumor grade. This parameter appeared to be a good indicator of tumor infiltration in astrocytomas, so we tested this in the analysis of other gliomas. Unlike astrocytomas, oligodendrogliomas were found consistently to contain few PLP mRNA- or MBP mRNA-expressing cells. In contrast, gemistocytic astrocytomas, typically highly invasive tumors, contained high numbers of PLP-positive cells and a ratio of PLP mRNA:MBP mRNA-stained cells of about 1.5:1, similar to low-grade astrocytomas. Nonradioactive in situ hybridization also enabled the morphological identification of specific cells. For example, gemistocytic astrocytes, which were found to be strongly vimentin mRNA positive, contained little glial fibrillary acidic protein mRNA and did not stain for PLP or MBP mRNAs. Neuronal mRNAs, such as neurofilament 68, were observed in small numbers of entrapped neurons within gliomas but were uninformative with respect to predicting tumor grade. Our results suggest that oligodendrocytes survive low-grade tumor infiltration and that glial tumor cells, unlike cell lines derived from them, do not express oligodendrocyte or neuronal mRNAs. In addition, the expression of mRNAs for the two major myelin protein genes, PLP and MBP, could be used to predict the grade and extent of tumor infiltration in astrocytomas.     

PTEN mutations in gliomas and glioneuronal tumors

Cytogenetic and loss of heterozygosity studies have suggested the presence of at least one tumor suppressor gene on chromosome 10 involved in the formation of high grade gliomas. Recently, the PTEN gene, also termed MMAC1 or TEP1, on chromosomal band 10q23 has been identified. Initial studies revealed mutations of PTEN in limited series of glioma cell lines and glioblastomas. In order to systematically evaluate the involvement of PTEN in gliomas, we have analysed the entire PTEN coding sequence by SSCP and direct sequencing in a series of 331 gliomas and glioneuronal tumors. PTEN mutations were detected in 20/142 glioblastomas, 1/7 giant cell glioblastomas, 1/2 gliosarcomas, 1/30 pilocytic astrocytomas and 2/22 oligodendrogliomas. No PTEN mutations were detected in 52 astrocytomas, 37 oligoastrocytomas, three subependymal giant cell astrocytomas, four pleomorphic xanthoastrocytomas, 15 ependymomas, 16 gangliogliomas and one dysembryoplastic neuroepithelial tumor. In addition, all tumors were examined for the presence of homozygous deletions of the PTEN gene; these were detected in 7 glioblastomas that did not have PTEN mutations. Therefore, PTEN mutations occur in approximately 20% of glioblastomas but are rare in lower grade gliomas. These findings confirm that PTEN is one of the chromosome 10 tumor suppressor genes involved in the development of glioblastomas.     

Immunohistochemical analysis of progesterone receptor and Ki-67 labeling index in astrocytic tumors

BACKGROUND: Intracranial tumors such as meningiomas express steroid hormone receptors but little is known regarding progesterone receptor (PR) in astrocytic tumors. The authors evaluated expression of PR in 86 astrocytic tumors in relation to tumor proliferative potential. METHODS: Paraffin embedded tumor sections were stained with polyclonal antiprogesterone antibody by the peroxidase-antiperoxidase method and with monoclonal MIB-1-Ki-67 antibody by avidin-biotin complex immunohistochemistry. RESULTS: Sixty-three of the 86 astrocytic tumors (73%) showed positive PR immunoreactivity. PR expression was observed in 4 of 9 pilocytic astrocytomas, 13 of 24 Grade 2 astrocytomas, 15 of 20 anaplastic astrocytomas, and 31 of 33 glioblastomas. In addition to the tumor cells, cells of microvascular endothelial proliferation and the smooth muscle of tumor vessel walls were frequently PR positive. Glioblastomas had a significantly higher percentage of PR positive cells compared with anaplastic (P < 0.0008) and low grade (P < 0.0001) astrocytomas. Patients with PR positive astrocytomas were of an older age than patients with PR negative astrocytomas (48.71 +/- 21.95 years vs. 37.09 +/- 24.69 years; P < 0.04). The mean Ki-67 labeling index (LI) was significantly higher in the high grade (3-4) astrocytomas compared with low grade (1-2) astrocytomas (P < 0.0001). PR positive astrocytic tumors had higher Ki-67 LI than PR negative tumors. PR expression was not correlated with tumor recurrence and patient survival. CONCLUSIONS: The current study suggests that PR in the astrocytic tumors correlates with histologic grade and PR may participate in the growth of these tumors and tumor angiogenesis. The measurement of PR in these tumors may indirectly represent tumor growth potential.     

Immunohistochemical analysis of metallothionein in astrocytic tumors in relation to tumor grade, proliferative potential, and survival

BACKGROUND: Metallothionein (MT) is the name for a family of predominantly intracellular protein thiol compounds involved in anticancer drug resistance. For certain tumors, MT is related to grade of tumor malignancy and prognosis. The authors evaluated the expression of MT in 114 astrocytic tumors in relation to the proliferative potential of tumors and the survival of patients. METHODS: Paraffin embedded tissue sections were stained with monoclonal anti-metallothionein and MIB-1 Ki-67 antibodies by avidin-biotin complex immunohistochemistry. RESULTS: MT expression was observed in 2 of 6 pilocytic astrocytomas, in 10 of 24 Grade 2 astrocytomas, in 16 of 25 anaplastic astrocytomas, and in 47 of 59 glioblastomas. In addition to the tumor cells, microvascular endothelial proliferation and smooth muscle of tumor vessel walls were frequently MT positive. The glioblastomas had a significantly higher percentage of MT positive cells compared with low grade (P < 0.0001) and anaplastic (P < 0.04) astrocytomas. MT expression in astrocytomas had no correlation with tumor recurrence. The mean Ki-67 labeling index (LI) was significantly higher in the high grade (3-4) compared with the low grade (1-2) astrocytomas. MT positive astrocytic tumors had statistically significantly higher mean Ki-67 LI compared with MT negative tumors, irrespective of histologic grade. Although the levels of MT and Ki-67 LI varied in individual tumors, the mean Ki-67 LI increased in parallel to the increasing MT staining grade, and this difference attained statistical significance only for glioblastoma. MT positive anaplastic astrocytoma and glioblastoma patients did not survive as long as the MT negative patients, although this difference attained statistical significance only for anaplastic astrocytoma. CONCLUSIONS: The current study suggests that MT might play a significant role in the growth of astrocytic tumors, with an acquired enhanced ability to produce MT as the malignant potential of a tumor increases.     

Resection, biopsy, and survival in malignant glial neoplasms. A retrospective study of clinical parameters, therapy, and outcome

Between July, 1984, and October, 1988, 263 patients (163 male, 100 female), aged from 4 to 83 years (mean 52 years), with malignant brain gliomas underwent surgical procedures: stereotactic biopsy in 160 and resection in 103 patients. There were 170 grade IV astrocytomas, 17 grade IV mixed oligoastrocytomas, 44 grade III astrocytomas, 22 grade III mixed oligoastrocytomas, and 10 malignant oligodendrogliomas. Overall median survival time was 30.1 weeks for grade IV gliomas, 87.7 weeks for grade III gliomas, and 171.3 weeks for malignant oligodendrogliomas. Multivariate analysis in 218 newly diagnosed cases revealed that the variables most strongly correlated with survival time were: tumor grade, patient age, seizures as a first symptom, a Karnofsky Performance Scale score of less than 70%, tumor resection, and a radiation therapy dose greater than 50 Gy. The proportions of patients receiving tumor resection versus biopsy in each of these prognosis factor groups were similar. Since most of the 22 patients with midline and brain-stem tumors were treated with biopsy alone, these were excluded. Considering 196 newly diagnosed patients with cortical and subcortical tumors, grade IV glioma patients undergoing resection of the contrast-enhancing mass (as evidenced on computerized tomography and magnetic resonance imaging) and postoperative external beam radiation therapy lived longer than those undergoing biopsy only and radiation therapy (median survival time 50.6 weeks and 33.0 weeks, respectively; Smirnov test, p = 0.0380). However, survival in patients with resected grade III gliomas was no better than in those with biopsied grade III lesions (p = 0.746). The authors conclude that, in selected grade IV gliomas, resection of the contrast-enhancing mass followed by radiation therapy is associated with longer survival times than radiation therapy after biopsy alone.     

"Ideal" length of stay after colectomy: whose ideal?

The tuberous sclerosis 2 (TSC2) gene is thought to function as a growth suppressor in sporadic and TSC-associated hamartomas and tumors. Clusters of dysplastic glial cells are a common feature of cortical tubers and subependymal nodules in tuberous sclerosis patients. In an effort to identify TSC2 gene alterations in sporadic gliomas, we detected a novel polymorphism adjacent to the 3'splice site of intron 4. We evaluated the distribution of this variant allele in a series of 244 patients with glial tumors, including 55 gangliogliomas, 31 pilocytic astrocytomas (WHO grade I), 50 astrocytomas (WHO grades II and III), and 108 glioblastomas (WHO grade IV). The allelic distribution in the general population was estimated by examining 381 healthy blood donors. This rare allele appeared in the control population and in the patients with astrocytic gliomas with a virtually identical frequency (8.14%, and 8.20%, respectively). The frequency of the rare allele in gangliogliomas, however, was significantly higher (15.5%; p = 0.024). The fact that both gangliogliomas and cortical tubers in tuberous sclerosis contain neuronal and astrocytic elements and may resemble each other histologically suggests that the TSC2 gene may be involved in the development of these tumors. The rare allele of the TSC2 gene emerges as a candidate for a predisposing factor for the formation of sporadic gangliogliomas.     

Telomerase activity in human gliomas

OBJECTIVE: Telomerase activity, which is undetectable in most mature normal tissues, has been identified in many types of human cancers, including neuroblastomas and oligodendrogliomas. These findings suggest that a novel mechanism in addition to activation of oncogenes and inactivation of tumor suppressor genes may play an important role in tumorigenesis. The goal of the present study was to assess and correlate the telomerase activity in astrocytic gliomas of different grades. METHODS: Telomere repeat amplification protocol and Southern blot hybridization with telomere-specific probes were used to detect telomerase activity and to measure terminal restriction fragment length, respectively. RESULTS: Telomerase activity was detected in 3 of 9 (33%) low-grade astrocytomas (World Health Organization Grade II), 5 of 11 (45%) anaplastic astrocytomas (World Health Organization Grade III), 36 of 41 (89%) glioblastomas multiforme (World Health Organization Grade IV), 3 of 4 (75%) oligodendrogliomas, and none of 4 normal brain specimens. CONCLUSION: We demonstrated that telomerase activity is absent in normal brain tissues while present in most glioma samples (72%). The frequency of such activity increases with malignancy. These results suggest that telomerase activity may be used as a tumor marker and that the activation of telomerase may correlate with initiation and malignant progression of astrocytic tumors.     

Chemotherapy of primary malignant brain tumors in adults

Chemotherapy of primary malignant brain tumors (PMBT) is palliative, except for germinomas. It is used as adjuvant therapy or alone at recurrence. The chemosensitivity of PMBT differs among tumors of different histological types. The role of chemotherapy in the treatment strategy will be reviewed by tumor type (malignant astrocytic gliomas, anaplastic oligodendrogliomas and mixed gliomas, anaplastic ependymomas, medulloblastomas, germinomas, primary malignant cerebral lymphoma).     

Preoperative evaluation of 54 gliomas by PET with fluorine-18-fluorodeoxyglucose and/or carbon-11-methionine

This study evaluates the usefulness of PET for the preoperative evaluation of brain gliomas and methods of quantification of PET results. METHODS: Fifty-four patients with brain gliomas were studied by PET with 18F-fluorodeoxyglucose (FDG) (n = 45) and/or 11C-methionine (MET) (n = 41) before any treatment. Results of visual analysis, calculation of glucose consumption and five tumor-to-normal brain ratios for both tracers were correlated with two histologic grading systems and with follow-up. RESULTS: Visual analysis (for FDG) and tumor-to-mean cortical uptake (T/MCU) ratio proved to be the best tools for the evaluation of PET results. Methionine was proven to be better than FDG at delineating low-grade gliomas. Tumor-to-mean cortical uptake ratios for FDG and MET were clearly correlated (r = 0.78), leading to the equation T/MCU(FDG) = 0.4 x T/MCU(MET). We showed a good correlation between FDG PET and histologic grading. MET uptake could not differentiate between low-grade and anaplastic astrocytomas but was significantly increased in glioblastomas. Low-grade oligodendrogliomas exhibited high uptake of FDG and MET, probably depending more on oligodendroglial cellular differentiation than on proliferative potential. Uptake was decreased in anaplastic oligodendrogliomas, probably due to dedifferentiation. Care must be taken with peculiar histologic subgroups, i.e., juvenile pilocytic astrocytomas and oligodendrogliomas, because of a discrepancy between high PET metabolism and low proliferative potential (good prognosis). Both tracers proved useful for the prediction of survival prognosis. Methionine proved slightly superior to FDG for predicting the histologic grade and prognosis of gliomas, despite the impossibility of differentiation between Grades II and III astrocytomas with MET. This superiority of MET could be explained by patient sampling (low number of Grade III gliomas submitted to examination with both tracers). The combination of both tracers improved the overall results compared to each tracer alone. CONCLUSION: Both tracers are useful for the prediction of the histologic grade and prognosis. The apparent superiority of MET over FDG could be due to the small number of Grade III gliomas studied with both tracers.     

Clonal analysis of gliomas

In malignant gliomas, the characteristically heterogeneous features and frequent diffuse spread within the brain have raised the question of whether malignant gliomas arise monoclonally from a single precursor cell or polyclonally from multiple transformed cells forming confluent clones. Although monoclonality has been shown in surgically resected tissues, these may not include the full spectrum of patterns seen on autopsy material. Little is known about the clonality of low-grade gliomas from which malignant gliomas may sometimes arise. We sought to investigate the clonality of low-grade and malignant gliomas by using and comparing surgical and autopsy material with a Polymerase chain reaction (PCR)-based assay for nonrandom X chromosome inactivation. For that, purpose, archival surgical and autopsy material from 15 female patients (group A) (age 4 to 73 years; median, 45) with malignant gliomas (12 glioblastomas, one gliosarcoma, one anaplastic oligoastrocytoma, one gliomatosis cerebri), surgical material only from 21 female patients (group S) (age 6 to 78 years; median, 60) with low-grade and malignant gliomas (four low-grade astrocytomas, three oligoastrocytomas, two anaplastic astrocytomas, one gemistocytic astrocytoma, four oligodendrogliomas, seven glioblastomas) were analyzed. In group A, representative areas (mean = 5/patient; median = 7) were microdissected from tissue sections and assayed by PCR amplification of a highly polymorphic microsatellite marker locus of the human androgen receptor gene (HUMARA) in the presence of alpha32P with and without predigestion with a methylation-sensitive restriction enzyme (HhaI). Products were resolved by denaturing gel electrophoresis and autoradiographed. In group S, selected tumor areas were used for the assay. Each patient's normal brain tissue was used for control. The band intensity of alleles were measured by densitometric scanning. In group A, 13 of 15 cases were informative (heterozygous). The same pattern of nonrandom X chromosome inactivation was present in all areas of solid dense and moderate tumor infiltration in eight including all components of the gliosarcoma. Two of eight also showed focal loss of heterozygosity (LOH). One of 13 presented global LOH. Two of 13 showed microsatellite instability, one of which in a patient with Turcot syndrome, the other in gliomatosis cerebri. Opposite skewing patterns were seen in distant areas of gliomatosis cerebri consistent with oligoclonal derivation. Clonality remained indeterminate in one glioblastoma and in the anaplastic oligoastrocytoma because of skewed lyonization in the normal control. In group S, 19 of 21 cases were informative. Fifteen of 19 were monoclonal (four low-grade astrocytomas, one anaplastic astrocytoma, one gemistocytic astrocytoma, two oligodendrogliomas, one oligoastrocytoma, six glioblastomas). Four of 19 were indeterminate. We conclude that (1) Low-grade and malignant gliomas are usually monoclonal tumors, and extensively infiltrating tumors must result from migration of tumor cells (2) Gliomatosis cerebri may initiate as an oligoclonal process or result from collision gliomas (3) Biphasic gliomas likely arise from a single precursor cell. (4) LOH at the HUMARA locus is probably related to partial or complete deletion of an X-chromosome, which occurs in malignant gliomas during clonal evolution.     

Classification and grading of low-grade astrocytic tumors in children

This article reviews current perspectives in the classification and grading of astrocytomas in children and calls attention to several histologically distinct groups of low-grade tumors that characteristically arise during childhood. Recognition of these tumors and the range of histological features that they may exhibit is essential for making rational assessments regarding their expected behavior and, more importantly, for guiding therapeutic intervention. For example, pleomorphic xanthoastrocytoma, which may exhibit "anaplastic" features, generally carries a relatively favorable prognosis and should not be classified with other high-grade gliomas, such as anaplastic astrocytoma and glioblastoma multiforme. Similarly, the finding of anaplastic features, such as vascular proliferation or necrosis, in pilocytic astrocytomas does not automatically portend the unfavorable prognosis that such features would imply for "diffuse" astrocytomas. Increased appreciation of the morphological diversity of astrocytomas in children should help to improve the management of children with low-grade astrocytic tumors by avoiding potentially dangerous overtreatment of otherwise indolent lesions.     

Growth factor profiles of human gliomas. Do non-tumour cells contribute to tumour growth in glioma?

BACKGROUND: Growth factors play a role in proliferation and motility of malignant glial cells, through autocrine and paracrine mechanisms. Also, proliferation of non-tumour cells, e.g., endothelial cells, is likely to be controlled by growth factors. Several growth factors with their appropriate receptors can be involved, but studies on tissue specimens evaluating this in glioma are rare. MATERIALS AND METHODS: We evaluated the potential role of Transforming growth factor-alpha (TGF-alpha) and Epidermal growth factor receptor (EGF-R), the Platelet-derived growth factor A- and B-chain (PDGF-A and PDGF-B) and its receptors (PDGFR alpha and PDGFR beta, and basic fibroblast growth factor (bFGF) in gliomas by analysing 86 of these tumours on the single cell level for the presence of immunoreactive growth factors and receptors. In a few cases double-staining experiments were done to directly visualize co-expression of factor and receptor. RESULTS: Multiple growth factors and their receptors are present in astrocytic tumours; the higher the grade, the more growth factors and the more positive cells are found. Oligodendroglial tumours and pilocytic astrocytomas showed little expression. Autocrine and paracrine mechanisms were frequently possible in the astrocytic tumours, often more than one loop could be involved. Interestingly, it was also frequently possible that non-tumour cells produced a growth factor for which the tumour cells expressed the receptor. CONCLUSIONS: Multiple growth factors appear to be involved in astrocytic tumours, with frequent autocrine and paracrine loops. Expression of these molecules seems to increase with increasing grade. The results argue for a contribution of non-tumour cells to the growth of a tumour.     

Production of tissue inhibitor of metalloproteinases-1 (TIMP-1) by human astrocytic tumors

Production of tissue inhibitor of metalloproteinases-1 (TIMP-1), a specific inhibitor of matrix metalloproteinases, was investigated in human astrocytic tumors (n = 15) and normal brain tissues (n = 3). Enzyme immunoassay indicated that TIMP-1 levels in the culture media of tumor explants were significantly higher in glioblastomas as compared with anaplastic astrocytomas, astrocytomas, and normal brain tissues. Immunohistochemistry using a monoclonal antibody against TIMP-1 demonstrated that TIMP-1 was detectable mainly in tumor cells, especially in glioblastoma. These results suggest that increased expression of TIMP-1 is associated with the malignant progression of astrocytic tumors.     

Management of malignant brain tumors

This review is made up of two parts. The first section describes techniques and methods used in the treatment of malignant brain tumors, stressing the most recent developments. The second part reviews the therapeutic modalities in malignant gliomas, where an attempt is made to consider separately glioblastomas, anaplastic astrocytomas and oligodendrogliomas, low-grade glioma, medulloblastoma, primary brain lymphoma, and brain metastases. A decision making algorithm is suggested for each tumor type.     

Treatment of peptic ulcer

AIMS: To establish whether MIB-1 and p53 staining are useful for differentiating pilocytic astrocytomas and astrocytomas from anaplastic astrocytomas and glioblastomas. This study was restricted to children and young adults under 30 years of age because of the differences in p53 mutations between paediatric and adult astrocytomas. METHODS AND RESULTS: Forty-five astrocytic tumours, including 18 pilocytic astrocytomas, 14 astrocytomas, four anaplastic astrocytomas and nine glioblastomas, from 45 children and young adults, between 1 and 29 years (mean 11 years) of age, were examined pathologically, and sections from paraffin-embedded blocks were used for MIB-1 and p53 immunostaining. The MIB-1 labelling index and the frequency and intensity of p53 staining in both the pilocytic astrocytoma and the astrocytoma group were significantly lower than in the anaplastic astrocytoma plus glioblastoma group (P < 0.001). In 11.1% (two of 18) of pilocytic astrocytomas and 42.9% (six of 14) of astrocytomas, immunoreactivity of either MIB-1 or p53 staining was of almost the same intensity as that of anaplastic astrocytomas and glioblastomas. However, in these cases, results using both MIB-1 and p53 stain differed from those for anaplastic astrocytomas and glioblastomas. CONCLUSIONS: MIB-1 and p53 co-staining is very useful for differentiating pilocytic astrocytomas and astrocytomas from anaplastic astrocytomas and glioblastomas. However, MIB-1 or p53 staining alone cannot differentiate pilocytic astrocytomas and astrocytomas from anaplastic astrocytomas and glioblastomas.     

The lack of a role for p53 in astrocytomas in pediatric patients

Mutations in the p53 gene, which codes for a cell division regulatory protein, have been identified in approximately one-third of adult astrocytomas. We evaluated 35 astrocytic tumors (17 pilocytic, 4 diffuse low grade, 12 anaplastic, and 2 glioblastoma) in pediatric patients for p53 mutations, using polymerase chain reaction-single-stranded conformation polymorphism analysis as a screening technique. Additionally, those tumors identified with homozygosity in the area of the p53 gene on chromosome 17 by Southern blotting were sequenced to look for p53 mutations. No tumors were identified with polymerase chain reaction-single-stranded conformation polymorphism analysis shifts indicative of mutations in the p53 gene. Five of 21 tumors were homozygous in the region of the p53 gene on chromosome 17; no mutations in exons 5 to 8 were found in any of these tumors. The frequency of p53 mutation in pediatric astrocytomas is significantly less than the frequency for adult tumors, regardless of tumor grade. Furthermore, the frequency of p53 mutations in high-grade astrocytomas is significantly lower in pediatric tumors than in adult tumors. These results suggest that p53 is not important in the oncogenesis of pediatric astrocytomas. Oncogenesis in pediatric astrocytomas may occur by different mechanisms than those of similar tumors in adults.