Malignant pilocytic astrocytoma in the medulla oblongata: case report

A 27-year-old woman visited our hospital with chief complaints of abducens nerve palsy and cerebellar symptoms. On computerized tomographic scanning and magnetic resonance imaging, a tumor with strong enhancement was found on the dorsal side of the medulla oblongata. A tumor was excised by suboccipital craniotomy and C1 laminectomy. Histologically, many Rosenthal fibers together with pilocytic tumor cells were found in some regions, but a very high Ki-67 labeling rate accompanied by cells with nuclei of irregular size and giant cells was observed in other regions. The tumor was diagnosed as malignant pilocytic astrocytoma originating from pilocytic astrocytoma by transformation. The biological behavior of pilocytic astrocytoma is obscure in several respects. We report our experience of a case of malignant pilocytic astrocytoma that developed in the brain stem and progressed extremely rapidly.     

Trigeminal nerve root entry zone pilocytic astrocytoma in an adult: a rare case of an extraparenchymal tumor

Extra-axial cerebellopontine angle (CPA) tumors account for approximately 10% of all brain neoplasms in adults. Vestibular schwannomas are the most common, followed by meningiomas. Gliomas in the CPA are rare and quite often are the exophytic extension of primary brain stem or cerebellar tumors. We describe a pilocytic astrocytoma of the CPA that was found to arise from the proximal portion of trigeminal nerve without any anatomic continuity with the brain stem and the cerebellum. Pre-operative MRI suggested a schwannoma. The proposed origin of this extremely rare tumor is the root entry zone of the involved nerve. The tumor was completely resected via a suboccipital retrosigmoid approach.     

The results of radiotherapy for brainstem tumors

Objective: This analysis was performed to examine the outcome of adult and pediatric patients with brainstem tumors. Methods and materials: Forty patients with brainstem glioma were evaluated retrospectively. Included were 24 females and 16 males ranging in age from 3 to 81 years (median, 29.5 years). These patients were treated with various combinations of surgery, chemotherapy, and ratiotherapy (RT). The length of follow-up in survivors ranged from 0.6 to 20 years (median: 3.2 years, mean: 6 years). Survival rates were calculated with the Kaplan Meier method and differences between survival curves were calculated using the log-rank test. Results: The overall 2 and 5-year survival rates were 44% and 34%, respectively. The median survival time was 19 months. The 5-year survival rate was 54% for patients with tumors outside the pons compared to 21% for those with tumors involving the pons (p=0.04). The 5-year survival rate was 59% for patients with exophytic tumors as compared to 23% for those with intrinsic tumors (p=0.05). Patients undergoing subtotal resection had a 5-year survival rate of 53% compared to 28% for those having only a biopsy or no surgical intervention (p=0.04). None of the other potential prognostic or treatment related factors evaluated [patient age, tumor grade, tumor histology, radiotherapy parameters (including BID fractionation, 3-D treatment planning, or the use of doses > 55 Gy), or the administration of adjuvant chemotherapy] evaluated were associated with patient survival. Conclusions: Brainstem gliomas generally occur in younger individuals. The survival rates were better for patients with exophytic tumors, those involving sites other than the pons, and tumors amenable to subtotal resection. Improvements in the outcome of patients with brainstem gliomas will require new therapeutic approaches.     

Cranial Nerve Root Entry Zone Primary Cerebellopontine Angle Gliomas: A Rare and Poorly Recognized Subset of Extraparenchymal Tumors

With the exception of patients with neurofibromatosis type II, pediatric extraparenchymal cerebellopontine angle (CPA) tumors of any sort are extremely rare. Most gliomas encountered in the CPA in either children or adults involve the CPA as exophytic extensions of primary brain stem and/or cerebellar tumors. We encountered an unusual case of a giant CPA pilocytic astrocytoma arising from the proximal trigeminal nerve, completely separate from the brain stem. A nine-year-old girl with no evidence for any neurocutaneous syndrome, presented with headaches, mild obstructive hydrocephalus, trigeminal hypesthesia and a subtle peripheral facial paresis. Pre-operative neuroimaging suggested a petroclival meningioma. The tumor was completely resected via a right pre-sigmoid, retro-labyrinthine, sub-temporal, transtentorial ('petrosal') approach, using intraoperative neurophysiological monitoring, with minimal morbidity. This appears to be the first reported case of a pediatric primary CPA glioma and the seventh reported case of primary CPA glioma, overall. It represents the second reported case of a primary CPA pilocytic astrocytoma. Given the findings in this case and the six other cases of primary CPA gliomas reported in the literature, as well as the results of histological studies of normal cranial nerves, we hypothesize that the point of origin of these rare and unusual tumors is the root entry zone of the involved cranial nerves. The differential diagnosis of primary CPA tumors should be expanded to include cranial nerve root entry zone primary CPA gliomas.     

Brain stem gliomas: a clinicopathological analysis of 23 histologically proven cases

The clinical and anatomic pathological findings in 23 patients with histologically proven brain stem glioma were reviewed. Eleven patients had malignant tumors (astrocytoma, grade III, and glioblastoma multiforme) and the remaining had low grade ones. The primary site of the tumor was the pons in 15 of 21 patients examined, followed by the medulla oblongata and midbrain. Contiguous cephalad and caudad involvement of pontine tumors was evident in 14 patients, and was more extensive in the high grade gliomas. At autopsy, the tumor spread via the CSF was observed in all patients with high grade but not low grade tumors.Open surgical posterior fossa exploration was performed on 12 patients. Volume reduction, by partial removal of the tumor and/or by cyst evacuation, was performed on seven, with good results. Nineteen patients were given radiation therapy, with temporary improvement of the clinical conditions. While none of the patients with malignant tumors survived more than 15 months after diagnosis, those with low grade tumors had a five-year actuarial survival rate of 50.0%, and three survived more than ten years after the diagnosis. Our data indicate that brain stem gliomas are not a homogeneous group of tumors as far as the clinical and pathological features are concerned. This heterogeneity shows the need to design specific treatments for these tumors.     

Brainstem gliomas--a clinicopathological study of 45 cases with p53 immunohistochemistry

BACKGROUND: Brainstem tumors represent 10% of central nervous system tumors, accounting for 30% of pediatric posterior fossa tumors. AIMS: The aim of this study was to clinicopathologically correlate 45 cases of brain stem gliomas and determine the occurrence and prognostic significance of p53 expression. MATERIALS AND METHOD: 45 cases of brain stem gliomas encountered during a 19-year period. 30 were diagnosed by surgical biopsy and 15 at autopsy. In 25 cases p53 immunohistochemistry (Avidin Biotinylated technique) was performed. The WHO brain tumor classification and Stroink's CT classification were applied. STATISTICAL ANALYSIS USED: Chi square test. RESULTS AND CONCLUSIONS: 51 % of gliomas were observed in the first decade of life. The female to male ratio was 1.04: 1. The commonest presenting features were cranial nerve palsies (33%) and cerebellar signs (29.8%). 55.55% of cases were located in the pons, 31.01% in the medulla and 13.33% in the midbrain. Diffuse astrocytomas were seen in 40 cases (5% were Grade I, 47.5%Grade II, 32.5% Grade III and 15% Grade IV) and pilocytic astrocytomas in 5 cases. Grade IV patients had 2- 3 mitoses /10 high power fields and had a poorer survival rate. Grade II astrocytomas were treated with excision and radiotherapy, while grade III and IV tumors were treated with radiotherapy and chemotherapy (CCNU). Improvement was noted in 20% of patients postoperatively. The outcome was better in patients who were treated surgically. p53 is a frequently mutated gene in brain stem astrocytomas. It was found in 50 % of glioblastoma multiforme, 28.57% of grade III astrocytoma and 12.5% of grade II astrocytoma, while grade 1 astrocytomas failed to express p53 protein. p53 positivity was more in high grade lesions, decreasing significantly in lower grade lesions.     

Pleiotrophin expression in astrocytic and oligodendroglial tumors and it’s correlation with histological diagnosis,microvascular density,cellular proliferation and overall survival

BACKGROUND: Pleiotrophin (PTN) is a secreted cytokine with several properties related with tumor development, including differentiation, angiogenesis, invasion, apoptosis and metastasis. There is evidence that PTN has also a relevant role in primary brain neoplasms and its inactivation could be important to treatment response. Astrocytic and oligodendroglial tumors are the most frequent primary brain neoplasms. Astrocytic tumors are classified as pilocytic astrocytoma (PA), diffuse astrocytoma (DA), anaplastic astrocytoma (AA) and glioblastoma (GBM). Oligodendroglial tumors are classified as oligodendroglioma (O) and anaplastic oligodendroglioma (AO). The aim of the present study was to compare PTN expression, in astrocytomas and oligodendrogliomas and its association with the histological diagnosis, microvascular density, proliferate potential and clinical outcome. METHODS: Seventy-eight central nervous system tumors were analyzed. The histological diagnosis in accordance with WHO classification was: 13PA, 18DA, 8AA, 15GBM, 16O and 8AO. Immunohistochemistry was realized with these specific antibodies: pleiotrophin, CD31 to microvascular density and Ki-67 to cell proliferation. RESULTS: PTN expression was significantly higher in GBM and AA when compared to PA and higher in GBM compared to DA. PTN expression did not differ between O and AO. Proliferate index and microvascular density were evaluated only in high grade tumors (AA, GBM and AO) divided in three groups according to PTN expression (low, intermediate and high). These results showed no statistical difference between PTN expression and index of cellular proliferation and neither to PTN expression and microvascular density. Overall survival (OS) analysis (months) showed similar results in high grade gliomas with different levels of PTN expression. CONCLUSIONS: Our results suggest that PTN expression is associated with histopathological grade of astrocytomas. Proliferation rate, microvascular density and overall survival do not seem to be associated with PTN expression.     

Advances toward an understanding of brainstem gliomas

The diagnosis of brainstem glioma was long considered a single entity. However, since the advent of magnetic resonance imaging in the late 1980s, neoplasms within this anatomic region are now recognized to include several tumors of varying behavior and natural history. More recent reports of brainstem tumors include diverse sites such as the cervicomedullary junction, pons, midbrain, or the tectum. Today, these tumors are broadly categorized as either diffuse intrinsic gliomas, most often in the pons, or the nondiffuse brainstem tumors originating at the tectum, focally in the midbrain, dorsal and exophytic to the brainstem, or within the cervicomedullary junction. Although we briefly discuss the nondiffuse tumors, we focus specifically on those diffuse brainstem tumors that regrettably still carry a bleak prognosis.     

MicroRNA profiling in pediatric pilocytic astrocytoma reveals biologically relevant targets,including PBX3, NFIB,and METAP2

Pilocytic astrocytoma (PA) is a World Health Organization grade I glioma that occurs most commonly in children and young adults. Specific genetic alterations have been described in PA, but the pathogenesis remains poorly understood. We studied microRNA (miRNA) alterations in a large cohort of patients with PA. A total of 43 PA, including 35 sporadic grade I PA, 4 neurofibromatosis-1 (NF1)–associated PA, and 4 PA with pilomyxoid features, as well as 5 nonneoplastic brain controls were examined. BRAF fusion status was assessed in most cases. RNA was examined using the Agilent Human miRNA Microarray V3 platform. Expression of miRNA subsets was validated using quantitative real-time PCR (qRT-PCR) with Taqman probes. Validation of predicted protein targets was performed on tissue microarrays with the use of immunohistochemistry. We identified a subset of miRNAs that were differentially expressed in pediatric PAs versus normal brain tissue: 13 miRNAs were underexpressed, and 20 miRNAs were overexpressed in tumors. Differences were validated by qRT-PCR in a subset, with mean fold change in tumor versus brain of -17 (miR-124), -15 (miR-129), and 19.8 (miR-21). Searching for predicted protein targets in Targetscan, we identified a number of known and putative oncogenes that were predicted targets of miRNA sets relatively underexpressed in PA. Predicted targets with increased expression at the mRNA and/or protein level in PA included PBX3, METAP2, and NFIB. A unique miRNA profile exists in PA, compared with brain tissue. These miRNAs and their targets may play a role in the pathogenesis of PA.     

Pediatric brain stem tumors: patterns of treatment failure and their implications for radiotherapy

There have been conflicting opinions regarding the correct volume to be used in radiotherapy fields for brain stem tumors of childhood. Whereas many clinicians recommend limited fields designed to cover the tumor volume with a margin, some have advocated whole brain radiotherapy. Using our clinical experience at Duke University Medical Center, we have made an attempt to determine the proper irradiation volume in this group of tumors. We have evaluated 38 patients with brain stem tumors in children less than 18 years of age. The most common presenting symptoms were headache, ataxia, and hemiparesis. Thirteen patients had a histologic diagnosis made prior to treatment or post-mortem. All had either an anaplastic astrocytoma or a glioblastoma multiforme. Tumors were located in the thalamus, hypothalamus, or midbrain in 9 patients and in the pons or medulla oblongata in the remaining 29 patients. All patients received a course of radiotherapy. The mean minimum tumor dose was 52.6 +/- 5 Gy given at 1.7 to 2.0 Gy/fraction. Twenty-three patients received radiation to a limited field and 14 received whole brain irradiation. In one patient, the field size could not be ascertained. The five year survival of the total group was 39%. The survival of patients with thalamic, hypothalamic, or midbrain tumors was 73% compared with 28% for those with tumors of the pons or medulla oblongata (p = 0.0159). Eighty-eight percent of the tumor recurrences in evaluable patients (22/25) occurred within the radiotherapy fields. Patients were stratified for tumor location and no difference was observed in survival or relapse-free survival among those individuals treated with limited irradiation fields or whole brain irradiation fields. When our results are examined in conjunction with previously published data, the bulk of existing evidence supports the use of limited fields for irradiation of brain stem tumors of childhood.     

Increased incidence rates but no space-time clustering of childhood astrocytoma in Sweden, 1973-1992: a population-based study of pediatric brain tumors

BACKGROUND: Incidence patterns, trends, and spatial and/or temporal clustering of childhood brain tumors were analyzed in the population-based national cancer registry of Sweden. METHODS: Temporal trends were analyzed by a logistic regression procedure in which the average annual percentages of change in incidence rates and the corresponding 95% confidence intervals (CIs) were calculated. Spatial and/or temporal clustering were investigated by using a geographic information system and analyzed with a modified version of the Knox test and a spatial scan statistic. RESULTS: Primary brain tumors in 1223 children ages 0-15 years were registered during 1973-1992. In 80% of cases, the tumor was classified as malignant. Conclusive histopathology was classified in 1142 cases. The age-adjusted incidence rate for all subtypes of brain tumors was 35.9 cases per million children, and for malignant brain tumors 28.6. A statistically significant increasing temporal trend was observed for the group of malignant brain tumors as a whole (P=0.0001) and the astrocytoma subgroup (P=0.0001). The annual average increases were 2.6% (95% CI=1.5-3.8) and 3.0%, respectively (95% CI=1.6-4.4). The increase in astrocytoma cases was significantly larger for girls than for boys (P=0.021) and was most striking for girls ages 6-15 years, with an annual average increase of 4.7%. Rates had not increased for the primitive neuroectodermal tumor (PNET)/medulloblastoma or ependymoma subgroups. The geographic distribution of astrocytoma cases was homogenous. No statistically significant space-time interaction or local clusters in space and/or time were found for astrocytomas only or when astrocytomas were grouped with PNETs/medulloblastomas and ependymomas. CONCLUSIONS: The results show statistically increased incidence rates of childhood astroglial tumors, predominantly for girls, in Sweden during the period 1973-1992, but no clustering in space or time.     

Subtelomeric analysis of pediatric astrocytoma: subchromosomal instability is a distinctive feature of pleomorphic xanthoastrocytoma

Astrocytic neoplasms are genetically heterogeneous; however a low frequency of genomic changes has been found in juvenile pilocytic astrocytoma (PA) in molecular studies. Concerning pleomorphic xanthoastrocytomas (PXA), recent studies have given heterogeneous results for chromosomal alterations. We studied the subtelomeric regions of 19 primary astrocytoma tumors. Results were near normality for the PA group with relative scarcity of chromosomal imbalances, except for the duplication of 3pter in 4/15 and deletion of 21qter in 5/15 of them. In contrast, a specific profile was observed in the 4 PXA tumoral samples. This involved 3pter, 14qter and 19pter duplication and 4qter, 6qter, 9qter, 13cen, 17pter, 18qter and 21qter deletion. Our results indicate that the chromosomal and genetic aberrations in PXAs differed from those typically associated with the diffusely infiltrating astrocytic and oligodendroglial gliomas. These genetic differences would likely contribute to the more favorable behavior of PXAs and may be helpful for molecular differential diagnosis of pediatric cerebral tumors.     

脑星形细胞瘤中TIP30、VEGF和CD34的表达及其相关性研究

目的探讨脑星形细胞瘤中TIP30、血管内皮生长因子（VEGF）、CD34的表达情况及其病理意义。方法采用免疫组织化学Elivision plus两步法,检测19例正常脑组织及71例星形细胞瘤组织中TIP30、VEGF及CD34的表达。结果TIP30在19例正常脑组织神经胶质细胞及神经元胞质内均呈阳性表达;71例星形细胞瘤组织中,TIP30总阳性表达率为33．80％,随星形细胞瘤分化程度的降低,TIP30的表达逐渐降低,Ⅱ、Ⅲ和Ⅳ级星形细胞瘤中TIP30阳性表达率分别为52％、34．78％和13．04％。高级别星形细胞瘤（Ⅲ级＋Ⅳ级）中TIP30的阳性表达率显著低于其在低级别星形细胞瘤（Ⅱ级）中的阳性表达率（x^2=5．71,P〈0．05）;VEGF及由CD34确定的MVD在星形细胞瘤中表达均高于正常脑组织,且随星形细胞瘤病理级别升高表达逐渐增高;星形细胞瘤中TIP30与VEGF强阳性表达呈负相关关系（r=-0．428,P〈0．05）。而TIP30与MVD无明显相关性（r=-0．065,P〉0．05）。结论TIP30在正常脑组织中阳性表达率高于其在星形细胞瘤中阳性表达率,且随星形细胞瘤病理级别升高表达显著下降;星形细胞瘤中,VEGF的表达与TIP30的表达呈明显的负相关关系。     

Hemorrhagic onset of pilocytic astrocytoma and pilomyxoid astrocytoma

The incidence of hemorrhagic onset in pilocytic astrocytoma and pilomyxoid astrocytoma, and the clinical and histological characteristics, were compared to other types of neuroepithelial tumors or nonhemorrhagic pilocytic astrocytoma by retrospective review of 445 consecutive neuroepithelial tumors treated at our institute. Hemorrhagic onset was observed in 4 of 35 (11.4%) patients with pilocytic astrocytoma and pilomyxoid astrocytoma, with higher incidence than in glioblastoma (3.9%), anaplastic oligodendroglioma (7.7%), and anaplastic ependymoma (7.1%). The hemorrhagic onset occurred in 2 patients with sporadic pilocytic astrocytoma, 1 with pilocytic astrocytoma associated with neurofibromatosis type 1, and 1 with pilomyxoid astrocytoma. There was no correlation between hemorrhagic onset and clinical features, including age, sex, tumor location, proliferative activity, or microvascular proliferation. Hemorrhagic onset of pilocytic astrocytoma and pilomyxoid astrocytoma is not as uncommon as was previously thought, so pilocytic astrocytoma or pilomyxoid astrocytoma should be considered in the differential diagnosis of patients with brain tumors manifesting as hemorrhagic onset.     

Heme oxygenase-1 expression in human gliomas and its correlation with poor prognosis in patients with astrocytoma

In human glioma tumors, heme oxygenase-1 (HO-1) has been shown to be upregulated both when compared with normal brain tissues and also during oligodendroglioma progression. The cell types that express HO-1 have been shown to be mainly macrophages/microglia and T cells. However, many other reports also demonstrated that cell lines derived from glioma tumors and astrocytes express HO-1 after the occurrence of a wide variety of cell injuries and stressors. In addition, the significance of HO-1 upregulation in glioma had not, so far, been addressed. We therefore aimed at investigating the expression and significance of HO-1 in human glial tumors. For this purpose, we performed a wide screening of HO-1 expression in gliomas by using tissue microarrays containing astrocytomas, oligodendrogliomas, mixed tumors, and normal brain tissues. We subsequently correlated protein expression with patient clinicopathological data. We found differences in HO-1 positivity rates between non-malignant brain (22 %) and gliomas (54 %, p?=?0.01). HO-1 was expressed by tumor cells and showed cytoplasmic localization, although 19 % of tumor samples also depicted nuclear staining. Importantly, a significant decrease in the overall survival time of grade II and III astrocytoma patients with HO-1 expression was observed. This result was validated at the mRNA level in a cohort of 105 samples. However, no association of HO-1 nuclear localization with patient survival was detected. In vitro experiments aimed at investigating the role of HO-1 in glioma progression showed that HO-1 modulates glioma cell proliferation, but has no effects on cellular migration. In conclusion, our results corroborate the higher frequency of HO-1 protein expression in gliomas than in normal brain, demonstrate that HO-1 is expressed by glial malignant cells, and show an association of HO-1 expression with patients’ shorter survival time.     

Inability of computed tomography appearance of recurrent malignant astrocytoma to predict survival following reoperation

Computed tomographic (CT) scans of 39 patients who underwent reoperation for recurrent malignant astrocytoma at Memorial Sloan-Kettering Cancer Center from 1980 through 1987 were reviewed and correlated with the patients' clinical course. Histologic diagnosis (anaplastic astrocytoma v glioblastoma multiforme) had a statistically significant impact on survival following reoperation (P = .038). Patients with high preoperative performance status (P = .29), total resection by postoperative CT scan (P = .15), and frontal lobe tumors (P = .17) tended to survive longer following reoperation. The size of the tumor at the time of recurrence did not correlate with survival following reoperation. Patients with a small amount of peritumoral edema at the time of recurrence tended to survive longer, but the effect was small (P = .16). Prognosis following reoperation cannot be accurately predicted on the basis of tumor appearance on CT scan.     

Les tumeurs gliales et glioneuronales de l'adulte et de l'enfant : principales altérations génétiques et classification histomoléculaire

Glial and glioneuronal tumors in children and adult demonstrate distinctive clinical, neuroradiological and molecular features depending on the pathological subtype and within a same subgroup according to the age. In children, gliomas are mainly located in the infratentorial part of the brain. They are most often benign and circumscribed but infiltrative tumors with dismal prognosis are recorded within the pons (DIGP) or the thalamus. Glioblastomas are very rare in children. In contrast, gliomas in adult mainly occur in the cerebral hemispheres and the most frequent subtype is glioblastoma. Glioneuronal tumors mainly occurred in children and young adults. In addition, although pilocytic astrocytomas, pleomorphic xanthoastrocytomas and gangliogliomas are classified into different subgroups according to the WHO 2007 classification, these tumors demonstrate similar neuroradiological findings: they are cystic with contrast enhancement of a mural nodule. Major advances have been made these last five years in the discovery of some master genes that are involved in gliomagenesis and point out differences between children and adults. In adults, infiltrative gliomas can be classified into two major subgroups depending on the existence or not of IDH mutations. IDH-dependent gliomagenesis encompasses diffuse grade II and grade III (they can also show additional molecular alterations such as TP53 mutation or 1p19q codeletion) and secondary glioblastomas. IDH-independent gliomagenesis include triple negative grade II gliomas, gliomatosis cerebri (grade III) and de novo glioblastomas. Pilocytic astrocytomas, pleomorphic xanthoastrocytomas and gangliogliomas share in common BRAF alterations. However, KIAA1549-BRAF fusion characterizes pilocytic astrocytomas whereas V600E BRAF mutation is mainly recorded in pleomorphic xanthoastrocytomas and gangliogliomas.     

Molecular biology of malignant gliomas

Gliomas are the most common primary brain tumours. In keeping with the degree of aggressiveness, gliomas are divided into four grades, with different biological behaviour. Furthermore, as different gliomas share a predominant histological appearance, the final classification includes both, histological features and degree of malignancy. For example, gliomas of astrocytic origin (astrocytomas) are classified into pilocytic astrocytoma (grade I), astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (GMB) (grade IV). Tumors derived from oligodendrocytes include grade II (oligodendrogliomas) and grade III neoplasms (oligoastrocytoma). Each subtype has a specific prognosis that dictates the clinical management. In this regard, a patient diagnosed with an oligodendroglioma totally removed has 10–15 years of potential survival. On the opposite site, patients carrying a glioblastoma multiforme usually die within the first year after the diagnosis is made (table 1). Therefore, different approaches are needed in each case. Obviously, prognosis and biological behaviour of malignant gliomas are closely related and supported by the different molecular background that possesses each type of glioma. Furthermore, the ability that allows several low-grade gliomas to progress into more aggressive tumors has allowed cancer researchers to elucidate several pathways implicated in molecular biology of these devastating tumors. In this review, we describe classical pathways involved in human malignant gliomas with special focus with recent advances, such as glioma stem-like cells and expression patterns from microarray studies. Supported by an unrestricted educational grant by Bristol-Myers Squibb.