Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.

Clinical relevance of molecular subgrouping of gliomatosis cerebri per 2016 WHO classification: a clinicopathological study of 89 cases.

The extremely invasive phenotypes and genotypes related to progression of gliomatosis cerebri (GC) remain unclear although GC has been removed as an independent entity from the 2016 WHO classification. Hence, categorization of GC under the current WHO molecular classification is essential, and the molecular subgroups that might contribute to GC progression should be compared with the histopathological differences between initial and new lesions identified during follow-up. Analyses of IDH1/2 and TERTp mutations and 1p/19q co-deletion, and immunohistochemistry of IDH1-R132H, ATRX, p53 and galectin-3 were performed. Anaplastic astrocytoma, IDH-wildtype (AA-IDHwt) was the common molecular subgroup (52.8%), followed by diffuse astrocytoma, IDH-wildtype (DA-IDHwt) and AA, IDH-mutant (AA-IDHmt) (each 16.9%), DA-IDHmt (7.9%), glioblastoma (GBM)-IDHwt (3.3%) and GBM-IDHmt (2.2%). Approximately 92% of the AA-IDHwt lesions progressed to histologically confirmed GBM in the newly enhanced lesions harboring the TERTp mutation and expressing galectin-3. Similar to primary GBMs, GC-related GBMs that progressed from the IDHwt subgroups showed microvascular proliferation, palisading necrosis or thrombotic occlusion, implying that a subset of IDHwt subgroups may evolve to overt GBM. Molecular subgrouping did not provide the perfect prediction for the survival of GC patients. The AA-IDHwt group showed worse overall and progression-free survival (PFS) than the AA-IDHmt group. Biopsy plus radiotherapy, chemotherapy and temozolomide treatment for DA-IDHwt, and resection plus radiotherapy and temozolomide treatment for AA-IDHwt prolonged PFS. In conclusions, majority of GC was of the AA-IDHwt subgroup, which progressed to GBM. Molecular subgroups may assist in the selection of treatment modalities, because "GC pattern" still remains as a special growth of gliomas in WHO 2016 classification without established treatment guideline.

Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors.

BACKGROUND: The use of next-generation sequencing for fusion identification is being increasingly applied and aids our understanding of tumor biology. Some fusions are responsive to approved targeted agents, while others have future potential for therapeutic targeting. Although some pediatric central nervous system tumors may be cured with surgery alone, many require adjuvant therapy associated with acute and long-term toxicities. Identification of targetable fusions can shift the treatment paradigm toward earlier integration of molecularly targeted agents. METHODS: Patients diagnosed with glial, glioneuronal, and ependymal tumors between 2002 and 2019 were retrospectively reviewed for fusion testing. Testing was done primarily using the ArcherDx FusionPlex Solid Tumor panel, which assesses fusions in 53 genes. In contrast to many previously published series chronicling fusions in pediatric patients, we compared histological features and the tumor classification subtype with the specific fusion identified. RESULTS: We report 24 cases of glial, glioneuronal, or ependymal tumors from pediatric patients with identified fusions. With the exception of BRAF:KIAA1549 and pilocytic/pilomyxoid astrocytoma morphology, and possibly QKI-MYB and angiocentric glioma, there was not a strong correlation between histological features/tumor subtype and the specific fusion. We report the unusual fusions of PPP1CB-ALK, CIC-LEUTX, FGFR2-KIAA159, and MN1-CXXC5 and detail their morphological features. CONCLUSIONS: Fusion testing proved to be informative in a high percentage of cases. A large majority of fusion events in pediatric glial, glioneuronal, and ependymal tumors can be identified by relatively small gene panels.

Astroblastoma - a rare and challenging tumor: a case report and review of the literature.

BACKGROUND: Astroblastoma is a controversial and an extremely rare central nervous system neoplasm. Although its histogenesis has been clarified recently, controversies exist regarding its cellular origin and validity as a distinct entity. Because of its extreme rarity and because its common features are shared with other glial neoplasms, this tumor is prone to misdiagnosis and remains challenging not only in terms of diagnosis and classification but also in the subsequent management. This case report describes a new case of astroblastoma. It discusses clinical, radiologic, pathological, and therapeutic features and differential diagnosis of this rare neoplasm, with a review of the recent literature. CASE PRESENTATION: We report the case of an 8-year-old Moroccan girl who presented with a 1-year history of epileptic seizure, headache, and decreased visual acuity. Cranial magnetic resonance imaging revealed a right occipito-temporal mass. A tumor resection was performed and histological examination combined with immunohistochemical study confirmed the diagnosis of low-grade astroblastoma. CONCLUSIONS: Astroblastoma is a very rare primary brain tumor. Its diagnosis is often challenging because of the astroblastic aspects that can be found in astrocytic tumors, in ependymomas, and in non-neuroepithelial tumors. Considerable confusion surrounds its histogenesis and classification. The low incidence rate makes it difficult to conduct studies to examine tumor characteristics.

Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities.

Astroblastoma is a rare and controversial glioma with variable clinical behavior. The diagnosis currently rests on histologic findings of a circumscribed glioma with astroblastomatous pseudorosettes and vascular hyalinization. Immunohistochemical studies have suggested different oncogenic drivers, such as BRAF p.V600E, but very few cases have been studied using genome-wide methodologies. Recent genomic profiling identified a subset of CNS embryonal tumors with astroblastoma-like morphology that harbored MN1 gene fusions, termed "CNS high-grade neuroepithelial tumors with MN1 alteration" (CNS-HGNET-MN1). To further characterize the genetic alterations that drive astroblastomas, we performed targeted next-generation sequencing (NGS) of 500 cancer-associated genes in a series of eight cases. We correlated these findings with break-apart fluorescence in situ hybridization (FISH) analysis of the MN1 locus and genome-wide DNA methylation profiling. Four cases showed MN1 alteration by FISH, including two pediatric cases that lacked other pathogenic alterations, and two adult cases that harbored other cancer-associated gene mutations or copy number alterations (eg, CDKN2A/B homozygous deletion, TP53, ATM and TERT promoter mutations). Three of these cases grouped with the CNS-HGNET-MN1 entity by methylation profiling. Two of four MN1 intact cases by FISH showed genetic features of either anaplastic pleomorphic xanthoastrocytoma (BRAF p.V600E mutation, CDKN2A/B homozygous deletion and TERT promoter mutation) or IDH-wildtype glioblastoma (trisomy 7, monosomy 10, CDK4 amplification and TP53, NRAS and TERT promoter mutations) and these cases had an aggressive clinical course. Two clinically indolent cases remained unclassifiable despite multimodal molecular analysis. We conclude that astroblastoma histology is not specific for any entity including CNS-HGNET-MN1, and that additional genetic characterization should be considered for astroblastomas, as a number of these tumors likely contain a methylation profile or genetic alterations that suggest classification as other tumor entities. Our heterogeneous molecular findings help to explain the clinical unpredictability of astroblastoma.

New classification of epilepsy-related neoplasms: The clinical perspective.

Neoplastic CNS lesions are a common cause of focal epilepsy refractory to anticonvulsant treatment, i.e. long-term epilepsy-associated tumors (LEATs). Epileptogenic tumors encompass a variety of intriguing lesions, e.g. dysembryoplastic neuroepithelial tumors or gangliogliomas, which differ from more common CNS neoplasms in their clinical context as well as on histopathology. Long-term epilepsy-associated tumor classification is a rapidly evolving issue in surgical neuropathology, with new entities still being elucidated. One major issue to be resolved is the inconsistent tissue criteria applied to LEAT accounting for high diagnostic variability between individual centers and studies, a problem recently leading to a proposal for a new histopathological classification by Blümcke et al. in Acta Neuropathol. 2014; 128: 39-54. While a new approach to tissue diagnosis is appreciated and needed, histomorphological criteria alone will not suffice and we here approach the situation of encountering a neoplastic lesion in an epilepsy patient from a clinical perspective. Clinical scenarios to be supported by an advanced LEAT classification will be illustrated and discussed.

Low-grade epilepsy-associated neuroepithelial tumours - the 2016 WHO classification.

Rapid developments in molecular genetic technology and research have swiftly advanced our understanding of neuro-oncology. As a consequence, the WHO invited their expert panels to revise the current classification system of brain tumours and to introduce, for the first time, a molecular genetic approach for selected tumour entities, thus setting a new gold standard in histopathology. The revised 5th edition of the 'blue book' was released in May 2016 and will have a major impact in stratifying diagnosis and treatment. However, low-grade neuroepithelial tumours that present with early-onset focal epilepsy and are mostly seen in children and young adults (previously designated as long-term epilepsy-associated neuroepithelial tumours, LEAT) lack such innovative clinicopathological and molecular genetic tools. The Neuropathology Task Force of the International League against Epilepsy will critically discuss this issue, and will offer perspectives on how to decipher and validate clinically meaningful LEAT entities using the current WHO approach that integrates clinicopathological and genetic classification systems.

Gliomatosis cerebri in children shares molecular characteristics with other pediatric gliomas.

Gliomatosis cerebri (GC), a rare and deadly CNS neoplasm characterized by involvement of at least three cerebral lobes, predominantly affects adults. While a few small series have reported its occurrence in children, little is known about the molecular characteristics of pediatric GC. We reviewed clinical, radiological, and histological features of pediatric patients with primary GC treated at our institution over 15 years. Targeted sequencing of mutational hotspots in H3F3A, IDH1/2, and BRAF, and genome-wide analysis of DNA methylation and copy number abnormalities was performed in available tumors. Thirty-two patients [23 (72 %) with type 1 and 9 (28 %) with type 2 GC] were identified. Median age at diagnosis was 10.2 years (range 1.5-19.1). A median of 4 cerebral lobes (range 3-8) was affected at diagnosis. In addition, symmetrical bithalamic involvement was observed in 9 (28 %) patients. Twenty-two patients (69 %) had an anaplastic astrocytoma. Despite aggressive therapy, only two patients younger than 3 years at diagnosis are long-term survivors. Clustering analysis of methylation array data from 18 cases classified tumors as IDH (n = 3, 17 %), G34 (n = 4, 22 %), mesenchymal (n = 3, 17 %), and RTK I 'PDGFRA' (n = 8, 44 %). No tumors were classified as K27 subgroup. PDGFRA was the most commonly amplified oncogene in 4 of 22 tumors (18 %). H3F3A p.G34 occurred in all cases classified as G34. Two of 3 cases in the IDH subgroup had IDH1 p.R132H. No H3F3A p.K27 M, IDH2 p.R172, or BRAF p.V600E mutations were observed. There was a trend towards improved survival in the IDH subgroup (P = 0.056). Patients with bithalamic involvement had worse outcomes (P = 0.019). Despite some overlap, the molecular features of pediatric GC are distinct from its adult counterpart. Like in adults, the similarity of genetic and epigenetic characteristics with other infiltrative high-grade gliomas suggests that pediatric GC does not represent a distinct molecular entity.

Gliomatosis cerebri: no evidence for a separate brain tumor entity.

Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients. Results were compared with those obtained for 105 patients with various types of conventional, i.e., non-GC gliomas including diffuse astrocytic gliomas, oligodendrogliomas and glioblastomas. In addition, we assessed the prognostic role of methylation profiles and recurrent DNA copy number aberrations in GC patients. Our data reveal that the methylation profiles in 23 of the 25 GC tumors corresponded to either IDH mutant astrocytoma (n = 6), IDH mutant and 1p/19q codeleted oligodendroglioma (n = 5), or IDH wild-type glioblastoma including various molecular subgroups, i.e., H3F3A-G34 mutant (n = 1), receptor tyrosine kinase 1 (RTK1, n = 4), receptor tyrosine kinase 2 (classic) (RTK2, n = 2) or mesenchymal (n = 5) glioblastoma groups. Two tumors showed methylation profiles of normal brain tissue due to low tumor cell content. While histological grading (WHO grade IV vs. WHO grade II and III) was not prognostic, the molecular classification as classic/RTK2 or mesenchymal glioblastoma was associated with worse overall survival. Multivariate Cox regression analysis revealed MGMT promoter methylation as a positive prognostic factor. Taken together, DNA-based large-scale molecular profiling indicates that GC comprises a genetically and epigenetically heterogeneous group of diffuse gliomas that carry DNA methylation and copy number profiles closely matching the common molecularly defined glioma entities. These data support the removal of GC as a distinct glioma entity in the upcoming revision of the WHO classification.

Astroblastoma: report of two cases with unexpected clinical behavior and review of the literature.

Astroblastoma is a rare, mostly supratentorial glial tumor, occurring predominantly in children and young adults with female preponderance. Due to the rarity, with only about 230 reported cases, treatment strategies are still to be discussed. We describe two more cases to add to the clinical experiences with this tumor entity. In both of these cases, the clinical behavior did not follow the expectations based on histopathological classification. Case 1: A sixteen-year old female presented with a six month history of intermittent headaches, nausea and dizziness. MRI scans revealed a left parietooccipital mass lesion with bubbly contrast enhancement and marked peritumoral edema. After gross total tumor resection the histology gave the diagnosis of low grade astroblastoma. Fifteen months later, the patient was operated on a local recurrence and received postoperative radiotherapy, with the histology still being that of low grade astroblastoma. Two years later, a meningeally based tumor nodule frontal of the former tumor bed was removed, now diagnosed as high grade astroblastoma. Eighteen months later, a fourth operation with excision of two more meningeally based tumor nodules of high-grade astroblastoma followed. Chemotherapy was suggested, but the patient decided against it. The last MRI follow-up 14 months after last operation showed no further recurrence so far. Case 2: A 24-year old female presented with a four week history of vomiting and headaches with focal seizures affecting her left arm. CT and MRI scans revealed a superficial partly cystic right temporal mass lesion with few edema and macrocalcifications and adjacent bone atrophy. Despite dural invasion, total tumor resection could be performed. MRI scans six months later showed no recurrence. The patient refused further MRI controls but did not show any clinical signs or symptoms suggesting tumor recurrence four years after the operation. In order to find more predictive tools that might help to determine the individual clinical course and treatment, we performed a review of the literature, analyzing 29 cases with detailed data on clinical history, MRI/CT characteristics, histopathological subtyping, treatment details and a follow-up of at least 12 months. We found, that low-grade astroblastoma with marked peritumoral edema has a tendency to early recurrence and suggest that it should be treated by combined surgery and radiotherapy. In high-grade astroblastoma with well defined tumor borders and few peritumoral edema, the prognosis may be better than expected for a high-grade glioma, if GTR is possible.

Well-differentiated pediatric glial neoplasms with features of oligodendroglioma, angiocentric glioma and dysembryoplastic neuroepithelial tumors: a morphological diagnostic challenge.

OBJECTIVE: Oligodendrogliomas are rare in the pediatric population, and most oligodendroglioma-like tumors in this age group may belong to other entities. In addition, accurate diagnosis and grading of such lesions using criteria developed for adult oligodendrogliomas prove difficult, and often controversial. MATERIAL AND METHOD: During a study of tumors previously diagnosed as pediatric oligodendroglioma, we identified four tumors displayed features of that resembled oligodendroglioma, angiocentric glioma and dysembryoplastic neuroepithelial tumor but could not be classified as either one of these entities. Ther clinical, histological and immunohistochemical features of these cases were investigated in this study. RESULTS: Two male (both 9 years old) and two female (ages 4 years and 20 months) patients presented with new onset of seizures. All patients were treated surgically, and two required reoperation. Histologically, the tumors were well-differentiated glial neoplasms with focal angiocentric pattern, delicate vascularity, diffuse growth, infiltrative margins, cortical nodules, focal myxoid areas, and leptomeningeal extension. Immunohistochemical studies showed diffuse nuclear positivity with Olig-2 and GFAP antibodies, whereas staining with neuronal markers, EMA, p53, and IDH1 were negative. Fluorescent in-situ hybridization analysis demonstrated intact 1p/19q in all tumors, and there was no ultrastructural evidence of ependymal differentiation. All patients were alive with disease with a mean follow-up of 112 months. CONCLUSION: These four cases illustrate the morphological diversity of well-differentiated, oligodendroglioma-like glial neoplasms and the uncertainty in their classification among pediatric tumors.

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

BACKGROUND AND PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Grade classification of neuroepithelial tumors using high-resolution magic-angle spinning proton nuclear magnetic resonance spectroscopy and pattern recognition.

Clinical data have shown that survival rates vary considerably among brain tumor patients, according to the type and grade of the tumor. Metabolite profiles of intact tumor tissues measured with high-resolution magic-angle spinning proton nuclear magnetic resonance spectroscopy (HRMAS (1)H NMRS) can provide important information on tumor biology and metabolism. These metabolic fingerprints can then be used for tumor classification and grading, with great potential value for tumor diagnosis. We studied the metabolic characteristics of 30 neuroepithelial tumor biopsies, including two astrocytomas (grade I), 12 astrocytomas (grade II), eight anaplastic astrocytomas (grade III), three glioblastomas (grade IV) and five medulloblastomas (grade IV) from 30 patients using HRMAS (1)H NMRS. The results were correlated with pathological features using multivariate data analysis, including principal component analysis (PCA). There were significant differences in the levels of N-acetyl-aspartate (NAA), creatine, myo-inositol, glycine and lactate between tumors of different grades (P<0.05). There were also significant differences in the ratios of NAA/creatine, lactate/creatine, myo-inositol/creatine, glycine/creatine, scyllo-inositol/creatine and alanine/creatine (P<0.05). A soft independent modeling of class analogy model produced a predictive accuracy of 87% for high-grade (grade III-IV) brain tumors with a sensitivity of 87% and a specificity of 93%. HRMAS (1)H NMR spectroscopy in conjunction with pattern recognition thus provides a potentially useful tool for the rapid and accurate classification of human brain tumor grades.

Immunohistochemical characterization of canine neuroepithelial tumors.

The expression of cell differentiation and proliferation markers of canine neuroepithelial tumors was examined immunohistochemically to identify the histogenesis of these tumors. Astrocytomas (n = 4) consisted of cells positive for glial fibrillary acidic protein (GFAP) and nestin and a few cells positive for doublecortin (DCX). Immunoreactive cells for receptor tyrosine kinases (epidermal growth factor receptor and c-erbB2) and their downstream molecules (phospho-extracellular signal-regulated kinase 1/2 and phospho-Akt) were often detected in astrocytomas, especially in medium- and high-grade tumors. Gliomatosis cerebri (n = 3) consisted of cells positive for ionized calcium-binding adaptor molecule 1 and GFAP, including a minor population of cells positive for nestin, DCX, and beta III tubulin, suggesting their glial differentiation. In choroid plexus tumors (n = 4), most tumor cells were positive for cytokeratins AE1/AE3 and 18, and few were positive for GFAP. The majority of cells of oligodendrogliomas (n = 5) were DCX positive, but the tumors also contained minor populations of cells positive for GFAP, nestin, or beta III tubulin. Primitive neuroectodermal tumors (PNETs; n = 2) consisted of heterogeneous cell populations, and the tumor cells were positive for nestin, beta III tubulin, and DCX, suggesting glial and neuronal differentiation. The major population of neuroblastoma cells (n = 3) were positive for beta III tubulin and DCX, suggesting single neuronal differentiation. As for antiapoptotic cell death molecules, most tumor cells in the choroid plexus tumors, PNETs, and neuroblastomas were intensely positive for Bcl-2 and Bcl-xL, whereas those in gliomatosis cerebri were almost negative. In astrocytomas, Bcl-xL-positive cells predominated over Bcl-2-positive cells, but the opposite was observed in oligodendrogliomas. The immunohistochemical results were analyzed by hierarchical clustering, and the constructed dendrogram clearly indicated a novel position of oligodendrogliomas: the primitive glial and neuronal differentiation.

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

OBJECTIVE: 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. MATERIAL: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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: growing evidence for diffuse gliomas with wide invasion.

Recent evidence suggests that there are no features that sufficiently distinguish gliomatosis cerebri (GC) from diffuse gliomas. They show the same age and sex distribution, clinical signs, prognostic factors and harbor similar genetic abnormalities. Furthermore, GC can progress secondarily to a higher grade of malignancy. The 2007 WHO classification itemizes GC among astrocytic tumors. Nevertheless, an oligodendroglial differentiation can be observed in up to 40%. These data implicate that treatment guidelines might follow those for diffuse gliomas in general. However, the large extension usually limits surgery to biopsies. The role of whole brain radiotherapy is unclear because no impact on survival could be demonstrated. At least some patients might benefit from chemotherapy (temozolomide).

Evaluation of molecular genetic alterations associated with tumor progression in a case of gliomatosis cerebri.

Gliomatosis cerebri (GC) is a rare tumor characterized by widespread infiltration of the brain and spinal cord. Although GC usually demonstrates histomorphological features of a low-grade tumor, the formation of secondary highly malignant tumor regions may occur. In order to reveal molecular genetic changes associated with tumor progression in GC, we analyzed factors known to be associated with malignant progression in common astocytomas in an unusual GC case of an 18-year-old patient suffering from this disease for almost 7 years. We detected allelic losses in the Rb gene and in exon 4 of the TP53 gene in a tumor region corresponding to a glioblastoma multiforme. EGFR or MDM2 gene amplifications were absent, and no PTEN mutation or allelic loss on chromosome 10 could be detected. Moreover, compared to tumor-free brain tissue of this patient, tumor regions showed increased EGFR expression. These findings show that malignant progression in GC might be associated with the acquisition of molecular genetic changes also found in low-grade astrocytomas with progression to secondary glioblastoma. These data support the notion that GC can be regarded as a subtype of a common astrocytoma.

Chromosomal abnormalities subdivide neuroepithelial tumors into clinically relevant groups.

Gliomas are the most common primary brain tumor, and are histopathologically classified according to their cell type and the degree of malignancy. However, sometimes diagnosis can be controversial,and tumors of the same entity possibly have a wide range of survival. Genetic analysis of these tumors is considered to have great importance in terms that it can provide clinically relevant classification of the tumors and compensate for the limitation of the histological classification. Previous studies using comparative genomic hybridization (CGH) demonstrated that copy number aberrations(CNAs) were frequently recognized in these tumors, and revealed that a gain on chromosomal arm 7q was the most common CNA in diffuse astrocytomas, whereas a small population of the tumor showed losses on 1p/19q which characterizes oligodendrogliomas with good responsiveness to chemotherapeutic regime using procarbazine, nitrosourea and vincristine. High grade (malignant) gliomas(i.e. anaplastic astrocytomas, anaplastic oligodendrogliomas and glioblastomas) have been reported to have a gain on 7p and losses on 9p and 10q. In case of ependymomas, frequent chromosomal aberrations in intracranial tumors were a gain on 1q and losses on 6q, and, on the other hand, a gain on chromosome 7 was recognized almost exclusively in spinal cord tumors. These data suggest that intracranial and spinal cord ependymomas are different genetic diseases and comprise different subgroups within one histological entity. In conclusion, genetic analysis of gliomas may help to classify these tumors and provide leads concerning their initiation and progression. The relationship of these aberrations to patient outcome needs to be addressed.

Nestin expression in neuroepithelial tumors.

Nestin is a marker of early stages of neurocytogenesis. It has been studied in 50 neuroepithelial tumors, mostly gliomas of different malignancy grades, by immunohistochemistry, immunofluorescence, immunoblotting, and confocal microscopy and compared with GFAP and Vimentin. As an early marker of differentiation, Nestin is almost not expressed in diffuse astrocytomas, variably expressed in anaplastic astrocytomas and strongly and irregularly expressed in glioblastomas. Negative in oligodendrogliomas, it stains ependymomas and shows a gradient of expression in pilocytic astrocytomas. In glioblastomas, Nestin distribution does not completely correspond to that of GFAP and Vimentin with which its expression varies in tumor cells in a complementary way, as confirmed by confocal microscopy. Tumor cells can thus either derive from or differentiate toward the neurocytogenetic stages. Hypothetically, they could be put in relation with radial glia where during embriogenesis the three antigens are successively expressed. Completely negative cells of invasive or recurrent glioblastomas may represent malignant selected clones after accumulation of mutations or early stem cells not expressing antigens.