Molecular genetic alterations in gliomatosis cerebri: What can we learn about the origin and course of the disease?

Gliomatosis cerebri (GC) is a neuroepithelial neoplasm with extensive infiltration of large parts of the brain. Recent data showing the involvement of TP53 mutation or nuclear protein accumulation in some cases have linked the astrocytic phenotype of the tumor cells to TP53 alterations frequently found in common astrocytomas. However, the frequency of these alterations is low, and other molecular genetic changes have been only rarely identified. Those found in common high-grade astrocytomas and glioblastomas are usually missing in GC. The distribution of TP53 point mutations, as well as non-coding polymorphic markers and some cytogenetic data, support a monoclonal origin in some cases, and are at least compatible with it in most cases, while no conclusive data suggesting a polyclonal origin have been reported. This raises the question of mechanisms responsible for the enhanced infiltrative potential of the tumor cells in this disease, which have not yet been identified.This review is dedicated to Prof. K. Dietzmann on the occasion of his 65th birthday     

Second primary glioblastoma

Although characterized by a highly variable phenotype and multiple genetic alterations, glioblastomas are considered monoclonal in origin. We here report on a 64-yr-old patient who developed a second glioblastoma in the left frontal lobe 10 yr after surgical resection of a glioblastoma of right frontal lobe. The first tumor contained 2 p53 mutations, in codon 213 (CGA-->TGA, Arg-->stop) and codon 306 (CGA-->TGA, Arg-->stop), further, 1 missense PTEN mutation (codon 257, TTC-->TTA, Phe-->Leu) and a silent PTEN mutation (codon 154, TTC-->TTT, Phe-->Phe). The second glioblastoma also contained multiple, but different mutations: p53 mutations in codons 158 (CGC-->CAC, Arg-->His) and 273 (CGT-->TGT, Arg-->Cys), and a PTEN mutation in codon 233 (CGA-->TGA, Arg-->Stop). Both neoplasms had a homozygous p16 deletion. The discordant pattern of mutations indicates that the second glioblastoma was not a recurrence but an independent second glioblastoma. The presence in these neoplasms of multiple mutations in tumor suppressor genes suggests the involvement of a novel disease mechanism but there was no indication of a DNA mismatch repair deficiency or of an inherited tumor syndrome.     

Molecular genetic alterations in glioblastomas with oligodendroglial component

Glioblastoma multiforme is the most malignant astrocytic glioma and usually resistant to chemotherapy. A small fraction of glioblastomas may contain areas with histological features of oligodendroglial differentiation. To determine the molecular genetic alterations in such "glioblastomas with oligodendroglial component", we investigated 13 of these tumors for genetic alterations and/or expression of the TP53, CDKN2A, PTEN, and EGFR genes. In addition, we performed microsatellite analyses for loss of heterozygosity (LOH) on chromosome arms 1p, 19q and 10q. None of tumors showed evidence for LOH on 10q. LOH on 1p was detected in 3 tumors, 1 of which additionally showed LOH on 19q. The 3 tumors with LOH on 1p showed neither TP53 mutations nor nuclear p53 accumulation. In contrast, 9 of 10 tumors without demonstrated losses on 1p showed nuclear p53 accumulation. TP53 mutations were identified in 3 of these cases. Further aberrations detected were epidermal growth factor receptor (EGFR) overexpression (3 of 13 tumors), homozygous CDKN2A deletion (2 of 11 tumors), and PTEN mutation (1 of 13 tumors). Taken together, our results indicate that "glioblastomas with oligodendroglial component" carry heterogeneous genetic alterations. LOH on 10q, PTEN mutation, and homozygous CDKN2A deletion appear to be less common in these tumors as compared to ordinary glioblastomas. Furthermore, a subset of these tumors demonstrates LOH on 1p, i.e., an alteration that has recently been linked to chemosensitivity and good prognosis in anaplastic oligodendrogliomas.     

Characterisation of molecular alterations in microdissected archival gliomas

Classification of gliomas according to their molecular characteristics may be important in future histopathological diagnosis. However, gliomas frequently display heterogeneity at the histological, biological and molecular level. In this study of archival diagnostic gliomas, precision microdissection was used to enrich samples in the most malignant cells or to investigate intratumoural histological heterogeneity. Analysis of tumour samples microdissected from the most aggressive regions, representative of the histopathological diagnosis, revealed PTEN mutations in 4/14 anaplastic astrocytomas, 4/13 glioblastomas and 1 gliosarcoma, but not in 19 low-grade gliomas. Using a novel PCR procedure and direct sequence analysis of the entire coding sequence, TP53 mutations were detected in 1/3 pilocytic astrocytomas, 3/13 astrocytomas, 4/14 anaplastic astrocytomas, 5/13 glioblastomas and 1 gliosarcoma. All but one of the tumours with TP53 mutation showed p53 immunopositivity, but 5 low-grade and 10 high-grade gliomas had p53 protein nuclear accumulation in the absence of detectable mutation. p53 status was unrelated to p21 expression. Neither PTEN nor TP53 mutations influenced the proliferative index or microvessel density of high-grade astrocytomas. Unusual findings include: TP53 mutation in a juvenile pilocytic astrocytoma; TP53 and PTEN mutations in a de novo glioblastoma, a gliosarcoma with identical mutations in gliomatous and sarcomatous components, and an infratentorial anaplastic astrocytoma with an earlier supratentorial grade II astrocytoma bearing the same TP53 mutation but not the PTEN mutation or loss of heterozygosity (LOH) of 10q23. Similarly, the transition to high-grade histology was associated with acquisition of PTEN mutations and 10q23.3 LOH in two de novo high-grade tumours with regions of low-grade histology.     

Analysis of the TP53 gene in laser-microdissected glioblastoma vasculature

Malignant transformation of human gliomas is accompanied by extensive proliferation of stromal blood vessels. Recent data suggest mesenchymal transdifferentiation of neoplastic cells in various human cancers, including colon and breast cancer as well as gliosarcoma. In this study, we have analyzed proliferating stromal blood vessels in glioblastoma multiforme for the presence of mutations in the tumor suppressor gene TP53. Using tissue arrays derived from glioblastoma specimens, cases with significant immunohistochemical p53 accumulation were selected for molecular genetic detection of TP53 mutations in exons 5 to 8. None of the tumors included in this series displayed properties of gliosarcoma. Proliferating glomeruloid stromal vessels were isolated by laser microdissection from paraffin sections. In six cases, single-strand conformation polymorphism analysis for mutations of the TP53 gene in stromal blood vessels compared with adjacent tumor cells and subsequent DNA sequencing of the resulting DNA fragments were carried out. Glioblastoma cells of these cases exhibited TP53 mutations in exons 5, 7 and 8. None of these tumors showed TP53 mutations in microdissected samples from glomeruloid vessels. The absence of TP53 mutations in vascular stromal components of glioblastoma multiforme supports the hypothesis that microvascular proliferations originate from the tumor stroma and are not derived from transdifferentiated glioblastoma cells.     

Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas

Published data on prognostic and predictive factors in patients with gliomas are largely based on clinical trials and hospital-based studies. This review summarizes data on incidence rates, survival, and genetic alterations from population-based studies of astrocytic and oligodendrogliomas that were carried out in the Canton of Zurich, Switzerland (approximately 1.16 million inhabitants). A total of 987 cases were diagnosed between 1980 and 1994 and patients were followed up at least until 1999. While survival rates for pilocytic astrocytomas were excellent (96% at 10 years), the prognosis of diffusely infiltrating gliomas was poorer, with median survival times (MST) of 5.6 years for low-grade astrocytoma WHO grade II, 1.6 years for anaplastic astrocytoma grade III, and 0.4 years for glioblastoma. For oligodendrogliomas the MSTwas 11.6 years for grade II and 3.5 years for grade III. TP53 mutations were most frequent in gemistocytic astrocytomas (88%), followed by fibrillary astrocytomas (53%) and oligoastrocytomas (44%), but infrequent (13%) in oligodendrogliomas. LOH 1p/19q typically occurred in tumors without TP53 mutations and were most frequent in oligodendrogliomas (69%), followed by oligoastrocytomas (45%), but were rare in fibrillary astrocytomas (7%) and absent in gemistocytic astrocytomas. Glioblastomas were most frequent (3.55 cases per 100,000 persons per year) adjusted to the European Standard Population, amounting to 69% of total incident cases. Observed survival rates were 42.4% at 6 months, 17.7% at one year, and 3.3% at 2 years. For all age groups, survival was inversely correlated with age, ranging from an MST of 8.8 months (<50 years) to 1.6 months (>80 years). In glioblastomas, LOH 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16INK4a deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations, and was the only alteration associated with shorter survival of glioblastoma patients. Primary (de novo) glioblastomas prevailed (95%), while secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hot-spot codons 248 and 273, while in primary glioblastomas, mutations were more evenly distributed. G:C-->A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas, suggesting that the acquisition of TP53 mutations in these glioblastoma subtypes may occur through different mechanisms.     

Genetic alterations in primary glioblastomas in Japan

ABSTRACT: Current knowledge of genetic alterations in glioblastomas is based largely on genetic analyses of tumors from mainly caucasian patients in the United States and Europe. In the present study, screening for several key genetic alterations was performed on 77 primary (de novo) glioblastomas in Japanese patients. SSCP followed by DNA sequencing revealed TP53 mutations in 16 of 73 (22%) glioblastomas and PTEN mutations in 13 of 63 (21%) cases analyzed. Polymerase chain reaction (PCR) showed EGFR amplification in 25 of 77 (32%) cases and p16 homozygous deletion in 32 of 77 (42%) cases. Quantitative microsatellite analysis revealed LOH 10q in 41 of 59 (69%) glioblastomas. The frequencies of these genetic alterations were similar to those reported for primary glioblastomas at the population level in Switzerland. As previously observed for glioblastomas in Europe, there was a positive association between EGFR amplification and p16 deletion (p=0.009), whereas there was an inverse association between TP53 mutations and p16 deletion (p=0.049) in glioblastomas in Japan. Multivariate analyses showed that radiotherapy was significantly predictive for longer survival of glioblastoma patients (p=0.002). SSCP followed by DNA sequencing of the kinase domain (exons 18-21) of the EGFR gene revealed mutations in 2 ou of 69 (3%) glioblastomas in Japan and in 4 of 81 (5%) glioblastomas in Switzerland. The allele frequencies of polymorphisms at codon 787 CAG/CAA (Gln/Gln) in glioblastomas in Japan were G/G (82.4%), G/A (10.8%), A/A (6.8%), corresponding to G 0.878 versus A 0.122, significantly different from those in glioblastomas in Switzerland: G/G (27.2%), G/A (28.4%), A/A (44.4%), corresponding to G 0.414 versus A 0.586 (p < 0.0001). These results suggest that primary glioblastomas in Japan show genetic alterations similar to those in Switzerland, suggesting a similar molecular basis in caucasians and Asians, despite different genetic backgrounds, including different status of a polymorphism in the EGFR gene.     

Detection of IDH1 mutations in gliomatosis cerebri, but only in tumors with additional solid component: evidence for molecular subtypes

The current WHO classification of brain tumors defines gliomatosis cerebri (GC) as an extensively infiltrating astrocytic glioma involving at least three cerebral lobes. The relation of GC to diffuse astrocytomas and glioblastoma is uncertain. Due to malignant biological behavior, GC is allotted to WHO grade III. Recent reports showed IDH1 mutations in astrocytic and oligodendroglial tumors WHO grades II and III and in secondary glioblastomas with a frequency of up to 90%, whereas IDH1 mutations occurred in only 5% of primary glioblastomas. Here, we examined the frequency of IDH1 mutations in 35 GC samples by direct sequencing, derived cleaved amplified polymorphic sequence analysis and immunohistochemistry. We identified IDH1 mutations in 10/24 (42%) cases, which also included a solid tumor portion (type 2 GC), but not in 11 “classical” cases without solid tumor mass (type 1 GC). TP53 mutations were revealed in two type 2 GC, but not in any type 1 GC, while combined chromosomal losses of 1p and 19q were not found at all. Our data suggest that GC consists of two histological/molecular subtypes, type 1 being clearly distinct from diffuse astrocytoma, and type 2 sharing features with diffuse astrocytoma.     

Genetically distinct astrocytic and oligodendroglial components in oligoastrocytomas

Oligoastrocytomas are glial tumours consisting of a mixture of neoplastic astrocytic and oligodendroglial cells. Genetic alterations of oligoastrocytomas include loss of heterozygosity of chromosomes 1p and/or 19q (LOH 1p/19q), typically occurring in oligodendrogliomas, and mutations of TP53, frequently occurring in astrocytomas. To investigate whether these neoplastic cell types in oligoastrocytomas have different genetic profiles, we examined the two different components of oligoastrocytomas in comparison with the histological diagnosis of the specific tumour area for LOH 1p/19q and TP53 mutations by using microdissection technique. We found a variety of lost markers for 1p and 19q, and the presence of two different TP53 mutations in the tumour samples. In the majority of cases (9/11), the oligodendroglial and astrocytic components of an individual oligoastrocytoma displayed the same genotype. We present two cases of biphasic oligoastrocytomas with aberrant findings, suggesting the coexistence of genetically and morphologically distinct tumour cell clones in these tumours. In one case, the oligodendroglial part of the tumour showed LOH19q, whereas the astrocytic part showed TP53 mutation (codon 273). In another case, we found LOH 1p/19q in the oligodendroglial component, but two retained areas on chromosome 1p in the astrocytic component of the tumour. No evidence was found for the coexistence of tumour cells with the two genotypical changes within the same morphological region of one individual tumour. The two cases of biphasic oligoastrocytomas in our sample that display a different genotype in the astrocytic and oligodendroglial part of the tumour show that different components of an oligoastrocytoma may be derived from different cell clones during neoplastic transformation.     

Molecular genetic analysis of the TP53, PTEN,CDKN2A,EGFR, CDK4 and MDM2 tumour-associated genes in supratentorial primitive neuroectodermal tumours and glioblastomas of childhood

Supratentorial primitive neuroectodermal tumours (sPNETs) are malignant central nervous system tumours of childhood which are histologically characterized by poorly differentiated neuroepithelial cells with the capacity for divergent differentiation into glial, neuronal, myogenic or melanotic lines. The histological differential diagnosis between sPNET and glioblastoma multiforme (GBM) may be difficult, particularly as GBMs can sometimes demonstrate a poorly differentiated PNET-like phenotype. To identify molecular genetic markers that may distinguish sPNET and GBM, we investigated 12 cerebral sPNETs and six GBMs from paediatric patients for genetic alterations of the TP53, PTEN, CDKN2A, EGFR, CDK4 and MDM2 genes, as well as for allelic loss on chromosome arms 10q and 17p. Mutations of the TP53 tumour suppressor gene were found in one of 12 sPNETs (8%) and two of six GBMs (33%). None of the sPNETs but two of six GBMs (33%, including one GBM with a TP53 mutation) showed allelic losses on chromosome arm 17p. PTEN mutations were detected in one of 12 sPNET (8%) and one of six GBMs (17%). None of the sPNETs and GBMs carried a homozygous deletion involving the CDKN2A tumour suppressor gene. No amplification of the EGFR, CDK4 or MDM2 proto-oncogenes was detected. Taken together, our results indicate that paediatric GBMs differ from sPNETs by a higher incidence of allelic losses on 17p and TP53 mutations. In addition, the patterns of genetic alterations in sPNETs and paediatric GBMs appear to be distinct from those in cerebellar medulloblastomas and adult GBMs, respectively.     

Systemic metastasis in glioblastoma may represent the emergence of neoplastic subclones

Glioblastomas only rarely metastasize to sites outside the central nervous system, for reasons that are poorly understood. We report the clinicopathological and molecular genetic findings in 6 patients with metastatic glioblastoma. Four patients were under the age of 32 and all but 1 patient died within 2 yr of diagnosis. The number of metastases ranged from 1 to 3. At the time of death, 3 patients had apparent tumor control at their primary site. We evaluated DNA from both primary and metastatic glioblastomas for genetic alterations commonly found in glioblastomas: TP53 mutations, CDKN2A/p16 deletions, EGFR amplification, and allelic loss of chromosomes 1p, 10q and 19q. Four of 6 cases had TP53 mutations and only single cases had EGFR amplification, CDKN2A/p16 deletions, or allelic loss of 1p, 10q and 19q; 2 cases had no detectable genetic alterations. In 2 cases, the primary and metastatic tumors had identical genotypes. Remarkably, however, 2 cases had different TP53 alterations in the primary and metastatic lesions, or among the metastatic tumors, which suggests that some metastatic deposits may represent emergence of subclones that were not necessarily dominant in the primary tumor. The present observations and a review of the recent literature demonstrate that metastatic glioblastomas tend to occur in younger adults who do not follow long clinical courses, and may be characterized by TP53 mutations and differential clonal selection.     

Genetic aberrations in gliomatosis cerebri support monoclonal tumorigenesis

Gliomatosis cerebri is a rare condition in which the brain is infiltrated by an exceptionally diffusely growing glial cell population involving at least 2 lobes, though often more extensive, sometimes even affecting infratentorial regions. The neoplastic proliferation may have a monoclonal origin, or alternatively, reflect progressive neoplastic change of an entire tissue field ("field cancerization"). The presence of an identical set of genetic aberrations throughout the lesion would point to monoclonality of the proliferation. In contrast, the finding of non-identical genetic changes in widely separated regions within the neoplasm would support the concept of field cancerization. In the present study, a unique autopsy case of gliomatosis was available to verify either one of these hypotheses. Tissue samples were randomly taken from 24 locations throughout the brain and used for genetic investigation. In all samples the histology showed an identical picture of slightly elongated astrocytic cells, typical for gliomatosis. TP53 exon 5-8 mutation analysis was performed on all samples. Genome-wide screening for chromosomal aberrations was accomplished by comparative genomic hybridization (CGH). In addition, loss of heterozygosity analysis for polymorphic markers on chromosomal regions of the 2 most frequently observed DNA deletions was carried out. The most widespread genetic aberration was mutation of exon 7 of TP53, which was detected in 20 of 24 samples. Bidirectional sequencing revealed a mutation in codon 234 (TAC234TGC), resulting in an amino acid substitution Tyr-Cys. CGH analysis revealed losses on 2q11-q31 in 13 of 24 samples and losses on 19q13-qter in 10 of 24 samples from both left and right hemispheres. Allelic imbalances for markers on 2q (2q14.3 and 2q22.1) and 19q (both 19q13.2) were demonstrated in 10 of 24 and 18 of 24 samples, respectively. Other widespread chromosomal aberrations included losses on 3q13-qter and 16q22-qter and gains on 7q22-qter. The wide distribution of a particular set of genetic aberrations in this case supports the concept of monoclonal tumor proliferation. The results point to involvement of TP53 mutation in the tumorigenesis of gliomatosis cerebri.     

Gliomatosis cerebri: molecular pathology and clinical course

Gliomatosis cerebri is a rare, diffusely growing neuroepithelial tumor characterized by extensive brain infiltration involving more than two cerebral lobes. Among 13 patients with gliomatosis cerebri (median age, 46 years), biopsies showed features of diffuse astrocytoma (n = 4), oligoastrocytoma (n = 1), anaplastic astrocytoma (n = 5), anaplastic oligoastrocytoma (n = 1), or glioblastoma (n = 2). Molecular genetic investigation showed TP53 mutations in three of seven tumors and both PTEN mutation and epidermal growth factor receptor overexpression in one tumor. Amplification of CDK4 or MDM2 or homozygous deletion of CDKN2A was not detected. Three of 10 patients receiving radiotherapy showed a partial response (one patient) or had stable disease (two patients) lasting for more than 1 year. Four of six patients treated with procarbazine, carmustine, vincristine chemotherapy demonstrated partial remission (one patient), minor response (two patients), or stable disease (one patient). Median survival time from diagnosis was 14 months (range, 4-91+ months). Infratentorial involvement was associated with shorter survival. We conclude that (1) the molecular genetic alterations in gliomatosis cerebri resemble those in diffuse astrocytomas; (2) the prognosis of gliomatosis cerebri is variable but for at least 50% of patients as poor as for glioblastoma; and (3) some patients respond to radiotherapy and/or procarbazine, carmustine, vincristine chemotherapy.     

The clinicopathological and prognostic significance of TP53 alteration in K27M mutated gliomas: an individual-participant data meta-analysis

This study aimed to investigate the impact of TP53 alteration on survival and clinicopathological features of glioma patients with H3K27M mutations. An individual-participant-data (IPD) meta-analysis was performed to investigate the impact of TP53 alteration on survival and clinicopathological features of patients with H3K27M mutations. Three hundred thirty-one individual records from 12 eligible glioma studies involving the H3K27M mutation were finally included in our meta-analysis, and a pooled hazard ratio (HR) of 1.53 (95%CI, 1.10–2.11; P?=?0.01) indicated that TP53 alterations were associated with a shorter overall survival. The pooled odds ratios (ORs) indicated that TP53 alterations were significantly associated with the age at diagnosis ≥?7 years (OR?=?1.97, 95%CI?=?1.15–3.38, P =?0.01), the status of histone H3.3 mutations (OR?=?9.15, 95%CI?=?4.18–20.06, P < 0.00001), and high WHO grade histology (III?+?IV) (OR?=?2.70, 95%CI?=?1.33–5.48, P?=?0.006). However, no association was found between TP53 alterations and gender or tumor location. This IPD meta-analysis suggests that TP53 alteration is a valuable predictor for the prognosis of patients with H3K27M mutated gliomas. TP53 alteration may be used for identifying a subset of patients who potentially benefit from targeted reactivation of TP53 activity.     

Clinicopathological Features and Molecular Analysis of Primary Glioblastomas in Moroccan Patients

Glioblastoma is the most frequent and most aggressive primary brain tumor. Primary and secondary glioblastomas develop through different genetic pathways. The aim of this study was to determinate the genetic and clinical features of primary glioblastoma in Moroccan patients. The blood and tumor samples were obtained from a group of 34 Moroccan patients affected with primary glioblastoma. The tumors were investigated for TP53, IDH1, and IDH2 mutations using PCR sequencing analysis. Clinicopathological data showed that the mean age at diagnosis of patients was 50.06 years, the sex ratio was 11 F/23 M, and the median of Karnofsky performance score was 60. About 18 % of patients were initially treated by total tumor resection, 41 % by subtotal, and 38 % by partial resection, but biopsy was performed for a single patient (3 %). Twenty-five patients (74 %) received radiotherapy. In addition, the median survival of the all patients was 13 months following diagnosis. There was a significant impact of higher Karnofsky performance score (KPS) (≥80) on overall survival, p-log-rank test?=?0.0002, whereas other parameters did not show any significant differences. The molecular analysis revealed TP53 mutations in 3/34 (8.82 %) cases; R273H, R306X, and Q136X. However, none of the analyzed samples contained the R132-IDH1 or R172-IDH2 mutations. These results showed the absence of IDH1 mutation in primary glioblastoma, confirming that this mutation is a hallmark of secondary glioblastoma. It can be used to distinguish primary from secondary glioblastomas. We found also that higher KPS was a significantly favorable factor in patients with primary glioblastoma.     

Phenotype versus genotype correlation in oligodendrogliomas and low-grade diffuse astrocytomas

Oligodendrogliomas typically show loss of heterozygosity (LOH) on chromosomes 1p and 19q, which correlates with their response to chemotherapy, whereas low-grade astrocytomas are characterized by frequent TP53 mutations and lack of sensitivity to alkylating therapeutic agents. Unequivocal histological distinction of low-grade diffuse astrocytomas from oligodendrogliomas and oligoastrocytomas is often difficult. To elucidate the relationships between morphological phenotype and genetic profile, we screened 19 oligodendrogliomas (WHO grade II) and 23 low-grade diffuse astrocytomas (WHO grade II) for TP53 mutations and LOH on 1p and 19q. In oligodendrogliomas, LOH on chromosomes 1p and/or 19q was found in 15 cases (79%) and TP53 mutation was detected in 4 cases (21%). The presence of a typical perinuclear halo in >50% of tumour cells and a chicken-wire vascular pattern were significantly associated with LOH on 1p or 19q (93% of cases). This suggests that oligodendrogliomas with classical histologic features are likely to have a better prognosis. In low-grade diffuse astrocytomas, LOH on chromosomes 1p and/or 19q was found in three cases (13%) and TP53 mutation was detected in ten cases (43%). Histologically, five low-grade astrocytomas (22%) contained small areas with oligodendroglial differentiation, but this did not correlate with the presence of TP53 mutations or LOH on 1p and 19q. In both oligodendrogliomas and astrocytomas, LOH on chromosomes 1p or 19q and TP53 mutation were mutually exclusive. Methylation of the promoter of the gene for O (6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein, which confers resistance to chemotherapy with alkylating agents, was detected in 47% of oligodendrogliomas and 48% of low-grade diffuse astrocytomas. There was no correlation with LOH on chromosomes 1p/19q, suggesting that MGMT may not be a prognostic marker for oligodendrogliomas.     

Pilocytic astrocytoma presenting as primary diffuse leptomeningeal gliomatosis: report of a unique case and review of the literature

We describe a 25-year-old male patient with primary diffuse leptomeningeal gliomatosis (PDLG) presenting with gait ataxia, positive Lhermittes sign, double vision, and right abducens nerve palsy. Spinal magnetic resonance imaging showed extended intradural, extramedullary, contrast-enhancing masses with compression of the myelon. Spinal leptomeningeal biopsy revealed a pilocytic astrocytoma WHO grade I. Despite chemotherapy with vincristin and carboplatin, the patient died 2 months after admission. A thorough autopsy showed no evidence for primary neoplasms in brain, spine and optic nerve. Sequence analysis of tumor protein 53 gene (TP53) revealed a missense mutation in exon 5, and expression of phosphatase and tensin homolog (mutated in multiple advanced cancers 1) (PTEN) protein was not detected, which may have contributed to astrocytoma development. To our knowledge, this is the first definitive case of pilocytic astrocytoma presenting as PDLG.