Cases Of Gliomatosis Cerebri Research Articles

Gliomatosis cerebri (GC) growth pattern: A single-center analysis of clinical, histological, and molecular characteristics of GC and non-GC glioblastoma.

The biological understanding of glioblastoma (GB) with gliomatosis cerebri (GC) pattern is poor due to the absence of GC-specific studies. Here, we aimed to identify molecular or clinical parameters that drive GC growth. From our methylome database of IDH (isocitrate dehydrogenase)-wildtype GB, we identified 158 non-GC and 65 GC cases. GC cases were subdivided into diffuse-infiltrative (subtype 1), multifocal (subtype 2), or tumors with 1 solid mass (subtype 3). We compared clinical, histological, and molecular parameters and conducted a reference-free tumor deconvolution of DNA methylation data based on latent methylation components (LMC). GC subtype 1 less frequently showed contrast-enhancing tumors, and more frequently lacked morphological GB criteria despite displaying GB DNA methylation profile. However, the tumor deconvolution did not deliver a specific LMC cluster for either of the GC subtypes. Employing the reference-based analysis MethylCIBERSORT, we did not identify significant differences in tumor cell composition. The majority of both GC and non-GC patients received radiochemotherapy as first-line treatment, but there was a major imbalance for resection. The entire GC cohort had significantly shorter overall survival (OS) and time to treatment failure (TTF) than the non-GC cohort. However, when filtering for cases in which only stereotactic biopsy was performed, the comparison of OS and TTF lost statistical significance. Our study offers clinically relevant information by demonstrating a similar outcome for GB with GC growth pattern in the surgically matched analysis. The limited number of cases in the GC subgroups encourages the validation of our DNA methylation analysis in larger cohorts.

Canine Gliomatosis Cerebri: Morphologic and Immunohistochemical Characterization Is Supportive of Glial Histogenesis.

Gliomatosis cerebri (GC) is a glioma subtype with diffuse neuroparenchymal infiltration without architectural distortion. GC was first used in human neuropathology and remained controversial until its elimination from the diagnostic lexicon in 2016. GC is currently defined as a diffuse growth pattern of glioma rather than a distinct entity. In this article, we characterize 24 cases of canine GC and classify these neoplasms as diffuse gliomas. Selected cases of canine GC were reviewed and immunolabeled for oligodendrocyte lineage transcription factor 2 (Olig2), glial fibrillary acidic protein (GFAP), and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase). The mean age of affected dogs was 7 years, and 9 were brachycephalic. Gross lesions (8 cases) consisted mainly of parenchymal swelling. Histologically, of the 24 cases, there was widespread infiltration of neoplastic cells with astrocytic (12 cases), oligodendroglial (8 cases), or mixed morphology (4 cases) in the brain (18 cases), spinal cord (4 cases), or both (2 cases). Secondary structures occurred across different tumor grades and were not restricted to high-grade neoplasms. Astrocytic neoplasms had moderate nuclear immunolabeling for Olig2 and robust cytoplasmic immunolabeling for GFAP. Oligodendroglial neoplasms had robust nuclear immunolabeling for Olig2, moderate or absent cytoplasmic immunolabeling for GFAP, and moderate cytoplasmic immunolabeling for CNPase. Tumors with mixed morphology had robust nuclear immunolabeling for Olig2 and variable cytoplasmic immunolabeling for GFAP and CNPase. Morphologic and immunohistochemical features confirmed a glial histogenesis for all tumors and allowed for their classification as diffuse, low- or high-grade astrocytoma; oligodendroglioma; or undefined glioma. Further research is needed to confirm or refute the hypothesis that canine GC represents an infiltrative growth pattern of canine glioma.

Gliomatosis cerebri - A rare cause of bilateral blindness

We describe a rare case of gliomatosis cerebri (GC) with bilateral blindness. A 45-year-male presented with gradual painless loss of vision both eyes (BE), with generalised tonic–clonic seizures. On examination, the patient denied light perception BE, with sluggishly reacting pupil. Fundus examination revealed papilledema and absent foveal reflex. Magnetic resonance imaging showed features of diffuse infiltrating glial tumor suggesting GC. Visual impairment can occur rarely due to optic nerve involvement, however bilateral cases has not been reported. Early recognition of GC may allow preservation of vision through focal radiotherapy to the optic nerve.

Incidence and survival of gliomatosis cerebri: a population-based cancer registration study.

Gliomatosis cerebri (GC) comprises a rare widespread infiltrating growth pattern of diffuse gliomas. We explored the incidence patterns and survival rates of GC in a population-based registration sample from the Surveillance, Epidemiology and End, Results database (1973-2012). GC cases (n = 176) were identified based on their International Classification of Diseases in Oncology (ICD-O-3) morphology code (9381). We calculated age-adjusted incidence rates (AIR) and evaluated temporal trends. Survival was assessed with Kaplan-Meier curves and Cox regression models. The annual AIR of GC was 0.1/million. We noted increasing trends in the preceding registration years (1973-2002; annually, + 7%)and a tendency of clinical/radiological approaches to substitute the gold-standard histological assessment for diagnosis. GC was diagnosed in the entire age spectrum (range 1-98years), but higher incidence rates (0.43/million) were noted among the elderly (≥ 65years). A slight male preponderance was identified (male-to-female ratio: 1.4). Median overall survival was 9months with a 5year survival rate of 18%. Increasing age, primary tumor location not restricted to the cerebral hemispheres and rural residence at diagnosis were identified as negative prognostic factors, whereas receipt of radiotherapy, surgical treatment, race and method of diagnosis were not associated with outcome. This first comprehensive overview of GC epidemiology exemplifies the rarity of the disease, provides evidence for male preponderance and increased incidence among the elderly and shows lower survival rates compared to the published single center reports. Expansion of registration to histological and molecular characteristics would allow emergence of clinical prognostic factors at the population level.

Canine spinal cord glioma

Spinal cord glioma is uncommonly reported in dogs. We describe the clinicopathologic and diagnostic features of 7 cases of canine spinal cord glioma and briefly review the veterinary literature on this topic. The median age at presentation was 7.2 y. Six females and 1 male were affected and 4 dogs were brachycephalic. The clinical course lasted from 3 d to 12 wk, and clinical signs were progressive and associated with multiple suspected neuroanatomic locations in the spinal cord. Magnetic resonance imaging of 6 cases revealed T2-weighted hyperintense lesions with variable contrast enhancement in the spinal cord. All dogs had a presumptive clinical diagnosis of intraparenchymal neoplasia or myelitis based on history, advanced imaging, and cerebrospinal fluid analysis. Euthanasia was elected in all cases because of poor outcome despite anti-inflammatory or immunosuppressive treatment or because of poor prognosis at the time of diagnosis. Tumor location during autopsy ranged from C1 to L6, with no clear predilection for a specific spinal cord segment. The diagnosis was based on histopathology and the immunohistochemistry expression of glial fibrillary acidic protein, oligodendrocyte lineage transcription factor 2, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, neuron-specific enolase, synaptophysin, and Ki-67. Diagnoses consisted of 4 cases of oligodendroglioma, 2 cases of gliomatosis cerebri, and 1 astrocytoma. This case series further defines the clinicopathologic features of canine spinal glioma and highlights the need for comprehensive immunohistochemistry in addition to routine histopathology to confirm the diagnosis of these tumors.

Gliomatosis Cerebri: A Report of Three Cases with Literature Review

Gliomatosis cerebri is a rare glioma of poor prognosis due to its diff use infiltration of the central nervous system involving three or more lobes of the brain. It has non-specifi c symptoms such as epilepsy, cognitivedisorders, headache and change in personality. Three cases of gliomatosis cerebri are reported. Extensive literature review was done. This review includes defi nition, type, clinical presentation, diagnosis [radiological and pathological], deferential diagnosis, treatment, and prognosis. In conclusion gliomatosis cerebri was initially a postmortem diagnosis. Following the advancement of the MRI, it became a radiological diagnosis that induces diff use involvement of at least three contiguous lobes of the brain with relative preservationof its general anatomical confi guration. It is manifested clinically as a very aggressive disease with poor prognosis. Imaging plays an important role in initial diagnosis, biopsy planning and follow up.

Unusual case of gliomatosis cerebri in a male patient with anaplastic astrocytoma

Unusual case of gliomatosis cerebri in a male patient with anaplastic astrocytoma

NI-63 * GLIOMATOSIS CEREBRI: DIAGNOSIS, MANAGEMENT AND OUTCOMES IN THE LARGEST SERIES FROM A SINGLE EUROPEAN INSTITUTION

BACKGROUND AND PURPOSE: Gliomatosis cerebri (GC) is a rare diffusely infiltrating primary glial neoplasm, which is defined as involving at least three lobes of the brain. There often is a striking discordance between clinical presentation and radiological findings. We reviewed the clinical presentation, radiographic appearance and outcome measures from a large single institution series of pathologically defined gliomatosis cerebri cases. METHODS: Between 1992 and 2014, 46 histologically proven cases with GC were encountered. Demographics, initial clinical presentation incl. Karnofsky index (KPS), imaging findings and treatment regimen were retrospectively reviewed and analyzed. RESULTS: Of 46 patients, only eleven were female (23.9%). Mean age at diagnosis was 50.7 years. Most frequent clinical signs were headaches, seizures and mental status changes. CT imaging revealed hypoattenuation of the involved brain parenchyma in 42 of the 46 cases (91.3%) and isodense parenchyma in 4 cases. Magnetic resonance imaging (MRI) generally showed T1-weighted hypointensity and T2-weighted hyperintensity. Frequently bilateral invasion with involvement of the anterior white commissure, the corpus callosum or both was observed. The extent of brain involvement did not demonstrate a significant correlation with overall survival (OS). Lower KPS upon presentation and higher histologic grade did predict shorter OS.

P17.66 * GLIOMATOSIS CEREBRI WITH MALIGNANT TRANSFORMATION TO A LONG-SURVIVAL GLIOBLASTOMA MULTIFORME AFTER TEN YEARS OF EVOLUTION

OBJECTIVES: We report an unusual case of gliomatosis cerebri which transformed into a high-grade glioma, both of them with a long-survival period. We emphasize in the lack of large studies about the biological and clinical behavior of these tumors, impeding the improvement of therapeutic options and our knowledge. METHODS: A 34-year-old male came to consulting room suffering an intense pain located around the right mastoid apophysis, with no neurological deficit associated. In the Magnetic Resonance Image (‘MRI’) it is shown a left frontal cortico-subcortical mass with no enhancing-image and not well-defined edges. This image was not initially related to the clinical process of the patient. The surgery was performed successfully and the pain was solved. Once the mass was diagnosed as a gliomatosis cerebri, the patient received adjuvant treatments and, after 10 years of uneventful consultations he referred headache and showed a nominal dysphasia. The ‘MRI’ and ‘SPECT’ confirmed the malignant transformation of the left frontal lesion into a high-grade glioma, without cerebroespinal fluid dissemination and/or multifocal progression. This mass was removed in 2011 guided with 5-ALA, and the post-operative period had not any complications. The patient received new cycles of chemotherapy and radiotherapy and, after 3 years of progression-free survival and 14 years of overall survival since the first diagnosis, the patient keeps a high-quality of life, with a Karnofsky Performance Status of 100. RESULTS: The first sample showed slight architectural changes in the white matter with higher cellular density and atypical cells which followed the myelinated bands. There was no endovascular proliferation and/or necrosis. It was positive for p53. The second sample showed all the criteria for glioblastoma multiforme, with predominance of gemistocytic cells. It was also positive for p53 and its MIB-1 index was over 20%. Currently, we are concluding the tests for IDH-1 and IDH-2 mutations. To our knowledge, this is the case with a longer survival period between both diagnosis. CONCLUSIONS: The gliomatosis cerebri is not a well-known entity and its biological mechanisms are unknown yet. Its survival is very changeable, from weeks to several years. Once the malignant transformation happens, the survival of these patients is meaningfully reduced. In our case, maybe because of the immunohistochemycal characteristics and/or not being a diffuse lesion, the patient is having a very long-surveillance period for both lesions, showing us that there are many concepts that we have to learn about the biological behavior of the tumors.

Neuroimaging diagnosis and therapeutic efficacy of different surgical methods of gliomatosis cerebri

To explore the neuroimaging diagnosis and therapeutic efficacy of different surgical methods of gliomatosis cerebri. 26 cases of gliomatosis cerebri at our department between September 2008 and September 2013 were retrospectively analyzed. Preoperative cranial computed tomography (CT), magnetic resonance imaging (MRI) and other multimodal imaging scans were performed. The procedures included stereotactic brain biopsy (n = 11) and large craniotomy lobotomy (n = 15). Whole brain radiotherapy and/or temozolomide therapy was performed postoperatively according to the malignancy of tumors. Follow-ups were conducted to analyze the survival differences between stereotactic brain biopsy and large craniotomy lobotomy groups. According to the different features of multimodal imaging, gliomatosis cerebri could be divided into two types: (1) type I(n = 19) showed a diffuse infiltrating lesion infringing multiple brain lobes or regions with central corpus callosum but without obvious enhancement; (2) type II (n = 7) appeared as sporadic or tuberous enhancement in addition to the features of type I. Pathological diagnosis: pilocytic astrocytoma (n = 2), diffuse astrocytoma (n = 13), oligodendroglial tumors (n = 3), oligoastrocytoma (n = 1), anaplastic astrocytoma (n = 5) and glioblastoma (n = 2). The degree of malignancy was a prognostic factor for postoperative survival in patients with gliomatosis cerebri. The mean survival time (MST) of large craniotomy lobotomy group (23 ± 7) was significantly longer than that of stereotactic brain biopsy group (13 ± 3) (P < 0.05). Gliomatosis cerebri is a primary brain glial tumor with diffuse infiltrative growth but retaining the general structure of central nervous system. Multimodal imaging studies plus pathological examination yield a definitive diagnosis. Comprehensive treatment of operation plus chemo- or radio-therapy can prolong postoperative MST.

Bilateral Telencephalic Gliomatosis Cerebri in a Dog

An 8-year-old intact male Lagotto Romagnolo was presented with forebrain signs. Neuroanatomic localization was diffuse prosencephalon. MRI revealed diffuse, bilateral, and symmetric T2 and FLAIR hyperintensities in the parieto-occipital white matter and corpus callosum. No mass effect or contrast enhancement was noted. Analysis of cerebrospinal fluid revealed normal protein content and mild mononuclear pleocytosis. Atypical cells were not identified. 15 days later because of the worsening of clinical condition the patient was euthanized upon owner’s request. Neuropathological investigations were consistent with gliomatosis cerebri (GC). Such an unusual imaging pattern appeared similar to some cases of human GC and to a previous reported case in a dog, suggesting a possible repeatable imaging findings for this rare brain neoplasm. GC should be included in the MRI differentials for diffuse bilateral white matter signal changes and specific MRI findings described in this report may help in reaching a presumptive diagnosis of this tumor.

Primary gliomatosis cerebri involving gray matter in pediatrics: a distinct entity? A multicenter study of 14 cases

Gliomatosis cerebri (GC) is a rare neoplasm including a variety of tumors, with extremely variable evolution and heterogeneity of prognosis. It may appear either de novo or after a focal glioma, involve predominantly the white or the gray matter, and concern either pediatric or adult patients. We focused on primary GC involving exclusively gray matter in a pediatric population in order better to define the presentation and outcome of this disease. We reviewed the databases of seven Departments of Pediatric Oncology to identify pediatric cases of GC between 1990 and 2007. Patients were included if they demonstrated a diffuse infiltrative process involving gray matter in magnetic resonance imaging (MRI) and histological tissue analyses, confirming a proliferative glial disorder. Fourteen patients with a median age of 8 years were identified. Epilepsy was the main presenting symptom. Brain MRI showed a lesion of the temporal and insular cerebral cortex associated with tumoral infiltration of the thalami and the basal ganglia. Histological examination confirmed the diagnosis of high-grade glioma. Prognosis was always very gloomy in the short term, with a median survival of less than a year. This rare entity, whose prognosis is appalling whatever the treatment proposed, should be clearly identified within the heterogeneous group of GC in the same way as diffuse intrinsic pontine gliomas have been identified among brain stem tumors. Systematic biopsies appear essential to permit the molecular studies which will assist in guiding the choice of future targeted treatments.

Gliomatosis cerebri in a patient with Ollier disease

Gliomatosis cerebri (GC) is an uncommon brain tumour defined as a diffuse neoplastic glial cell infiltration of the brain, involving more than two cerebral lobes and, occasionally, the infratentorial structures or the spinal cord. GC of the oligodendroglial phenotype is extremely rare, especially in the paediatric setting. We describe an unusual case of oligodendroglial GC diagnosed in a 16-year-old boy with Ollier disease. To our knowledge this is the first case of GC reported in a child with Ollier disease.

Oligodendroglial Gliomatosis cerebri in a Poodle

Gliomatosis cerebri (GC) is a rare, diffusely infiltrating, glial cell tumour of neuroepithelial origin. This report describes a case of oligodendroglial GC in a 6-year-old male Poodle with central nervous system symptoms. Computed tomography revealed anomalous parenchyma density and ventricular asymmetry. Cerebrospinal fluid showed elevated protein (30 mg dL(-1)) and nucleated cell count (20 µL(-1)). Presumptive diagnosis of necrotizing meningoencephalitis was made. Because of rapid deterioration of the general condition of the animal, the dog was euthanized. Histologically there was an infiltration of round or ovoid neoplastic cells in the white matter of the left cerebral hemisphere and in leptomeninges. Immunohistochemistry showed that 80% of the neoplastic cells expressed Olig2 and some 50% expressed glial fibrilary acidic protein. On the basis of clinical, histological and immunohistochemical features, a diagnosis of oligodendoglial GC was done. This case represents the first report of a case of oligodendroglial GC in the canid.

Gliomatosis cerebri: clinicopathologic study of 33 cases and comparison of mass forming and diffuse types

Gliomatosis cerebri (GC) is defined as a diffuse neoplastic glial cell infiltration of the brain with the preservation of anatomical architecture and the sparing of neurons and can be classified into Type 1 (diffuse) and Type 2 (mass forming) GCs macroscopically. There is little information on subtypes of GC. The aim of this study was to evaluate the clinicopathologic findings of GCs and to compare the clinicopathologic findings between Type 1 and Type 2 GCs. A total of 33 cases of GC were obtained from pathology file of Samsung Medical Center. The diagnosis was based on magnetic resonance imaging findings and histological confirmation for all patients. Fifteen cases were classified into Type 1 and 18 were Type 2 based on the MR images. Clinical information included patients' age, sex, tumor extent, treatment modality and survival. Pathologic features included the amount of rod cells and cytologic anaplasia such as multinucleated tumor giant cells, endothelial cell proliferation, or mitosis. Immunohistochemical study was performed for GFAP, O1, Gal-C, Ki-67, and p53. Clinicopathologic comparison between subtypes and statistical analysis were performed. Median age at diagnosis was older (56 years) in Type 1 than in Type 2 (44 years). Male to female ratio was about 1.54:1. Mean survival time was shorter (21 months) in Type 2 than in Type 1 GCs (24 months) (p = 0.0447). Histologically, 33 cases of GC were classified into two histologic grades (low and high grade) by cytologic anaplasia. High-grade GC was more common in Type 2 than Type 1 (p = 0.027). Immunohistochemical results demonstrated that the infiltrating tumor cells were undifferentiated cells with astrocytic or oligodendroglial differentiation. Ki-67 labeling index was correlated with subtypes (p = 0.0096). Pathologic features were not correlated with survival. Type 1 and 2 GCs are somewhat different in clinical presentation and pathologic features. The age group, survival time, histologic grade, and Ki-67 labeling index were significantly correlated with subtypes ofGCs. Type 2 GC was correlated with poor survival but histologic grade was not.

Array-based comparative genomic hybridization and immunohistochemical studies in gliomatosis cerebri

Gliomatosis cerebri (GC) are extensively infiltrative glial tumors classified as astrocytic tumors in the current World Health Organization (WHO) classification scheme. In investigating the tumorigenesis of GC, we reviewed 28 cases of GC immunohistochemically and carried out array-based comparative genomic hybridization (CGH) in ten of those cases. In histological and immunohistochemical review, 18 cases (64%) were of astrocytic lineage, three (11%) were of oligodendroglial lineage, and seven (25%) were of uncommitted lineage. In the array-based CGH, 52 clones were frequently lost on 6p, 9p, and 9q in more than six cases, and six clones were frequently gained on 1p, 6q, 10q, and 21q in more than three cases. Some gained or lost genetic loci differed significantly between the histologically high-grade and low-grade GC (P < 0.05), but unsupervised hierarchical clustering failed to produce evidence of any clinical significance. These altered genetic foci are not known to be involved in the development of conventional glial tumors, including astrocytic tumors. In conclusion, despite the dominant astrocytic differentiation of GC histologically, novel genomic aberrations found in our GC cases were different from those of astrocytic tumors.

Gliomatosis Cerebri: A pediatric case series and review of the literature

9056 Background: Gliomatosis Cerebri (GC) is a rare and universally fatal glial neoplasm of the central nervous system. Although over 160 cases have been reported in the medical literature, the largest pediatric case series published to date includes only three patients. We describe the largest cohort to date of children with GC and explore relationships between potential prognostic factors, treatment, and survival. Methods: Imaging, pathologic, and outcome information were reviewed for this case series of thirteen patients diagnosed with GC and treated at the Children’s Hospital of Philadelphia (CHOP) between 1982 and 2005. All patients had GC confirmed by biopsy. Twelve patients were treated with cranial irradiation; eight of these received adjuvant chemotherapy as well. A single patient under one year of age was treated with chemotherapy alone. A review of the literature identified 51 reported cases of GC in the pediatric population. Results: The progression free survival (PFS) in the CHOP cohort was 13% (range: 1.5–22.5 months) and the overall survival rate (OS) was 64% (range: 6.5–27 months) at 2 years. Time to progression was significantly prolonged for those with no evidence of tumor enhancement on initial imaging (p = .03). OS was significantly shorter for patients who presented in the first decade of life (p = .04). When survival data from patients reported in the literature are combined with the CHOP cohort, treatment significantly prolonged OS (p = .003). Conclusions: Outcome in pediatric patients with GC is extremely poor, however treatment prolongs OS. Age less that 10 years and enhancement on MRI at diagnosis may be risk factors for shorter survival. No significant financial relationships to disclose.

Gliomatosis Cerebri and Pituitary Adenoma: Case Report and Literature Review

The diagnosis of Gliomatosis cerebri (GC) is known to be difficult and is still a matter of debate. We describe an in vivo case of GC associated with a pituitary tumor. A 47-year-old woman presented with short-term memory loss. A MRI revealed the presence of a pituitary enhancing tumor and a diffuse lesion involving the brain. A left pterional craniotomy with partial temporal lobectomy and removal of the pituitary lesion were performed in order to obtain diagnosis. The histological analyses showed a pituitary non-functioning tumor and a GC consisting of neoplastic oligodendrocytes and astrocytes. Both lesions showed nuclear immunoreactivity for progesterone receptors (PGr) and estrogen receptors (EGr). This result could suggest there is a common receptor substrate in these tumors. In this case hormones could constitute a common step in tumorigenesis of both lesions.

Assessment of tumor cell invasion factors in gliomatosis cerebri

Gliomatosis cerebri (GC) is a rare brain tumor characterized by widespread infiltration of large parts of the brain and sometimes even the spinal cord. To determine the cause of this extraordinary degree of brain invasion, we studied immunoexpression of factors associated with brain infiltration in low-grade and high-grade tumor samples from nine GC cases. We further determined the allelic status of the fibroblastic growth factor receptor 4 (FGFR4) gene at position 388 (arginine [Arg(388)] or glycine [Gly(388)]) in eighteen GC patients, because the presence of at least one Arg(388) allele has been suggested to favor tumor cell motility compared to tumor cells homozygeous for the Gly(388) allele. Immunohistochemical analyses showed that tumor samples from three GC cases expressed Tenascin-C, whereas six cases had CD44 - immunopositive tumor samples. Expression of MMP-9 was not observed in any of the nine GC patients. FGFR4 genotyping revealed the presence of the Arg(388) in 72% of the eighteen GC cases, a frequency similar to the one found in 21 common astrocytomas (71%). In tumor-free control DNA, the Arg(388) phenotype was present in 60%. These data indicate that CD44 expression might be related to the tumor infiltration in GC, and that patients suffering from GC or other common astrocytomas do not have a significantly increased frequency of the tumor cell motility-favoring Arg(388) FGFR4 allele.

Alterations of cell cycle regulators in gliomatosis cerebri

Gliomatosis cerebri (GC) is regarded as a rare glial neoplasm of unknown origin, and a detailed analysis of molecular alterations underlying this disease has started only recently. However, because GC characteristically affects large parts of the brain and spinal cord, the distribution of genetic alterations may be highly variable between different tumor areas. Additionally, tumor areas with varying degrees of differentiation may be present, raising the possibility to model the genetic events associated with astrocytoma progression. Here we analyzed various tumor regions with features of low-grade and high-grade astrocytomas from 9 autopsy-proven GC cases for the immunoexpression of the cell cycle-controlling proteins mdm2, p21, p27/kip1, p16, and Rb. The samples were also screened for EGFR expression, and for amplification of the EGFR and MDM2 genes. Furthermore, allelic losses of the CDKN2A gene and of a PTEN flanking region of chromosome 10 were determined. We detected tumor regions with immunoexpression of p21 only rarely in our series, without association to the tumor grade. No MDM2 gene amplification was detected. In contrast, three cases demonstrated maintained Rb expression. The expression of p27(kip1) showed a clear reduction with increasing astrocytoma malignancy in 7 cases. Allelic loss of the CDKN2A gene occurred in 5 patients but was not related to the tumor grading, nor to the intensity of p16 immunoexpression. No homozygous CDKN2Adeletions were detected. EGFR amplification was also absent in our series, but one case demonstrated EGFR expression only in the high-grade tumor area. Allelic losses on chromosome 10 were found in one out of six informative cases. However, marked differences in the immunoexpression, as well as in the distribution of genetic aberrations were seen between different tumor samples within a given case. The distribution of the alterations suggests that these molecular genetic changes represent secondary events, which may develop within tumor clones derived from a common founder tumor clone characterized by extraordinary spreading through the brain. Moreover, the detected aberrations in gliomatosis cerebri can reflect the tumor progression associated with secondary malignant astrocytoma formation even within a single case.