Astrocytomas In Children Research Articles

Molecular genetic analysis of thirty-five diffuse high-grade astrocytomas in children < 3 years of age defines a distinct infant HGG entity

Molecular genetic analysis of thirty-five diffuse high-grade astrocytomas in children < 3 years of age defines a distinct infant HGG entity

Radiation or Chemotherapy rather than Observation may be a Better Modality after Subtotal Resection for Pilocytic Astrocytoma in Children

Radiation or Chemotherapy rather than Observation may be a Better Modality after Subtotal Resection for Pilocytic Astrocytoma in Children Se Yong Jung, M.D., Song Lee Jin, M.D., Seung Min Hahn, M.D., Hyo Sun Kim, M.D., Dong Seok Kim, M.D., Ph.D., Chang-ok Seo, M.D., Ph.D., Chuhl Joo Lyu, M.D., Ph.D. and Jung Woo Han, M.D. Division of Pediatric Hemato-Oncology, Department of Pediatrics, Department of Neurosurgery, Department of Radiation Oncology, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Korea

Anorexia: an early sign of fourth ventricle astrocytoma in children.

Paediatric low-grade astrocytomas of the fourth ventricle are rare tumours, generally revealed by hydrocephalus. However, some patients present with a history of severe anorexia. It might be a harbinger, which if recognized, could lead to earlier diagnosis. We decided to examine our database in order to evaluate the incidence and signification of anorexia in this context. Retrospective monocentric study of cases of low-grade astrocytomas of the fourth ventricle operated between 1991 and 2012 in our paediatric neurosurgery department. We particularly observed the clinical presentation and long-term clinical, oncological and radiological evolution. Non-parametrical tests were used (Mann-Whitney, Fisher). We reviewed 34 cases, 31 pilocytic astrocytomas and 3 diffuse astrocytomas, 16 boys and 18 girls, (M/F ratio 0.89). Mean age at diagnosis was 8 years old. Seven presented with notable anorexia, the average BMI in this group was ≤2 standard deviation (SD); with clinical signs evolving for 11.5 months. Twenty-seven children had no anorexia; average BMI in this group was +1 SD, with clinical evolution for 6 months on an average of p < 0.05. We found no significant difference regarding hydrocephalus or tumour location. In all children with anorexia, body mass index improved markedly in the postoperative follow-up, which lasted, on average, for 6 years. Anorexia with stunted body weight curve is a non-exceptional presentation in children with low-grade astrocytomas of the fourth ventricle. Unexplained or atypical anorexia with negative etiologic assessment should prompt cerebral imaging. Clinical improvement after surgical resection, could suggest a possible interaction between tumour tissue and appetite-suppressing peptide secretion.

Surgical and clinical aspects of cerebellar pilomyxoid-spectrum astrocytomas in children

Cerebellar pilomyxoid astrocytomas (PMAs) and intermediate pilomyxoid astrocytomas (IPAs) are collectively called "pilomyxoid-spectrum astrocytomas (PMSAs)." Cerebellar PMSAs are thought to behave more aggressively than pilocytic astrocytomas (PAs). Our objective is to compare PMSAs to PAs in terms of surgical and clinical profiles. This retrospective study included 66 cases (35 males and 31 females) with cerebellar astrocytomas treated between July 2007 and December 2012 at Children's Cancer Hospital Egypt (CCHE 57357) with a mean age of 7 (±1.5) years. Cases were divided into three subgroups as follows: 44 PAs, 10 IPAs, and 12 PMAs. Comparison between all groups was focusing on brain stem invasion, intrinsic necrotic cavitation, extent of resection, recurrence, leptomeningeal dissemination (LD), metastases, need for CSF diversion, and cerebellar mutism (CM). Cerebellar PMAs and IPAs separately and collectively had higher incidence of brain stem invasion, intrinsic necrotic cavitation, tumor recurrence, and LD when compared to PAs (P < 0.001). Gross total resection was 13.6 % in PMSAs versus 90.9 % in PAs (P < 0.001). PMAs had a higher incidence of tumor recurrence than IPAs (66.7 versus 20 %, P < 0.001). Incidence of recurrence in PAs was 9.1 % in partially resected cases. Mean interval to recurrence was 9 (±1.5) months in PMSAs and 42 (±2) months in PAs. Cerebellar PMSAs express an aggressive clinical behavior and impose more operative challenges than PAs. These tumors may represent a clinical spectrum-at its benign end lies PA, while PMA lies at the aggressive end, with IPA lying just behind. Such concepts could be used to guide management in the future.

Prominent EMA ‘dots’ in tumour‐induced Bergmann gliosis

To describe an unusual pattern of epithelial membrane antigen (EMA) immunoreactivity in highly proliferative human Bergmann glia. An immunohistochemical study was performed of postmortem cerebellar tissue from 18 adult patients with cerebellar damage of various aetiologies and 15 biopsies of diverse adult and paediatric cerebellar tumours. We observed marked proliferation of Bergmann glia with unusual prominent dot-like cytoplasmic EMA immunoreactivity in a case with extensive leptomeningeal sarcomatosis. Similar staining was not observed in association with other types of cerebellar pathology, except for other neoplastic conditions, such as leptomeningeal carcinomatosis, adult medulloblastoma, and pilocytic astrocytoma in children. At an ultrastructural level, the index case showed prominent endoplasmic reticulum with some intermediate filaments and lipofuscin granules, but no structures related to cilia or microvilli were observed. We consider that prominent EMA dots in Bergmann glia might represent excessive activation induced by an overlying leptomeningeal tumour that stimulates the expression of early developmental antigens. This observation suggests modulation of the glial phenotype when exposed to a neoplastic microenvironment that, in turn, might influence the regenerative potential of Bergmann glia.

Arrested growth and spontaneous tumor regression of partially resected low-grade cerebellar astrocytomas in children

PurposeThe prognosis of children with low-grade cerebellar astrocytoma who have partial resection of tumor is largely unpredictable. The purpose of this study was to review the long-term outcome of such patients.MethodsThe medical charts, imaging findings, operative notes, histopathological reports, and survival times of 12 patients with cerebellar astrocytoma were reviewed.ResultsFive patients had total resection and seven had partial resection. Nine patients had grade I histology and three patients had grade II. Follow-up duration ranged from 3 to 25 years. Among the seven patients with residual tumor, five had tumor progression, one had arrested tumor growth, and one had spontaneous tumor regression. Five patients with partial resection received radiotherapy and three had malignant transformation of tumor during follow-up. Six patients, including five who had partial resection, underwent a second operation. One patient with partial resection died of pneumonia 23 years after surgery.ConclusionsPatients with complete tumor resection had a better prognosis than patients with partial resection. For patients with partial resection, we recommend a “wait and see” policy with surveillance using MRI. The phenomenon of arrested tumor growth and spontaneous tumor regression in patients with cerebellar astrocytoma who have subtotal resection warrants further study.

Neurosurgical treatment of low-grade cerebellar astrocytoma in children and adolescents: a single consecutive institutional series of 100 patients

The objective of this study was to delineate the long-term results of surgical treatment of pediatric low-grade cerebellar astrocytoma. One hundred consecutive children and adolescents (0-19 years old) who underwent primary tumor resection for a low-grade cerebellar astrocytoma during the years 1980-2011 were included in this retrospective study on surgical morbidity, mortality rate, academic achievement, and/or work participation. Gross motor function and activities of daily living were scored according to the Barthel Index. Of the 100 patients, 61 children were in the 1st decade, and 39 were 10-19 years old. The male/female ratio was 1.13:1 (53 males, 47 females). No patients were lost to follow-up. There were no deaths in this series and all 100 patients are currently alive. In 29 patients, the follow-up duration was less than 10 years, in 37 it was between 10 and 19 years, and in 34 it was between 20 and 31 years. The Barthel Index was 100 (normal) in 97 patients, 90 in 2 patients, and 40 in the last patient. A total of 113 tumor resections were performed. Two patients underwent further tumor resection due to MRI-confirmed residual tumor demonstrated on the immediate postoperative MR image (obtained the day after the initial procedure). Furthermore, 9 children underwent repeat tumor resection after MRI-confirmed progressive tumor recurrence up to 10 years after the initial operation. Two of these patients also underwent a third resection, without subsequent radiation therapy, and have experienced 8 and 12 years of tumor-free follow-up thereafter, respectively. A total of 15% of the patients required treatment for persistent hydrocephalus. Low-grade cerebellar astrocytoma is a surgical disease, in need of long-term follow-up, but with excellent long-term results. Nine percent of the children in this study underwent repeated surgery due to progressive tumor recurrence, and 15% were treated for persistent hydrocephalus.

Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations

Gliomas are the most common primary brain tumors in children and adults. We recently identified frequent alterations in chromatin remodelling pathways including recurrent mutations in H3F3A and mutations in ATRX (α-thalassemia/mental-retardation-syndrome-X-linked) in pediatric and young adult glioblastoma (GBM, WHO grade IV astrocytoma). H3F3A mutations were specific to pediatric high-grade gliomas and identified in only 3.4 % of adult GBM. Using sequencing and/or immunohistochemical analyses, we investigated ATRX alterations (mutation/loss of expression) and their association with TP53 and IDH1 or IDH2 mutations in 140 adult WHO grade II, III and IV gliomas, 17 pediatric WHO grade II and III astrocytomas and 34 pilocytic astrocytomas. In adults, ATRX aberrations were detected in 33 % of grade II and 46 % of grade III gliomas, as well as in 80 % of secondary and 7 % of primary GBMs. They were absent in the 17 grade II and III astrocytomas in children, and the 34 pilocytic astrocytomas. ATRX alterations closely overlapped with mutations in IDH1/2 (p < 0.0001) and TP53 (p < 0.0001) in samples across all WHO grades. They were prevalent in astrocytomas and oligoastrocytomas, but were absent in oligodendrogliomas (p < 0.0001). No significant association of ATRX mutation/loss of expression and alternative lengthening of telomeres was identified in our cohort. In summary, our data show that ATRX alterations are frequent in adult diffuse gliomas and are specific to astrocytic tumors carrying IDH1/2 and TP53 mutations. Combined alteration of these genes may contribute to drive the neoplastic growth in a major subset of diffuse astrocytomas in adults.

Role of proton magnetic resonance spectroscopy in diagnosis of pilocytic astrocytoma in children

BackgroundPilocytic astrocytomas are the second overall most common pediatric brain tumor. Magnetic resonance (MR) imaging is widely used in the diagnosis and follow up of pediatric patients with pilocytic astrocytomas because of its ability to provide anatomical detail. However conventional MR imaging does not provide information about tissue biochemistry. Aim of the workTo study the role of proton magnetic resonance spectroscopy in diagnosis of pilocytic astrocytoma in children. Subjects and methodsThis study included seven pediatric patients with histopathologically proven pilocytic astrocytoma. All patients were subjected to full history taking and thorough clinical examination. Magnetic resonance (MR) imaging was performed at 1.5Tesla MR system using a standard head coil. Imaging included conventional MRI and proton magnetic resonance spectroscopy. Proton magnetic resonance spectroscopy was done using either single or multi-voxel technique. Surgical biopsy was then performed to all patients and correlation with histopathological data was done. ResultsOut of the seven patients included in this study, six were females and one was male with mean age of 9.5years, the tumor was located in five of them in the posterior fossa, located in right thalamo-peduncular region in one patient and located in the hypothalamic–chiasmatic region in one patient.MR spectroscopic study showed the same findings in all the lesions including high Cho/NAA and Cho/Cr ratios (3.53±1.5) and (7.21±4.2), respectively, relative low concentration of creatine with increased NAA/Cr ratio (2.32±1.1). Lactate doublet was detected in all cases while no lipid peaks were detected. ConclusionBased on the findings in this study we suggest that pilocytic astrocytoma has a specific spectroscopic metabolic profile which could be diagnostic for this type of tumor.

Infantile Cerebellar Pilocytic Astrocytoma with Autism Spectrum Disorder

The etiology of autism remains unclear, but relationships to cerebellar factors have been reported. We report 2 cases of infantile cerebellar pilocytic astrocytoma in children with autism spectrum disorder. Cerebellar tumors may be related to the pathogenesis of autism.

A single centre audit into the outcome of transsphenoidal surgery in the treatment of acromegaly

A single centre audit into the outcome of transsphenoidal surgery in the treatment of acromegaly

Chiasmatic pilocytic astrocytoma in childhood with leptomeningeal dissemination at recurrence: A case report and review of literature

Pilocytic astrocytoma is a benign variety of gliomas, which rarely spreads along the neuraxis. Leptomeningeal dissemination of pilocytic astrocytoma in children, either at the time of initial presentation or at recurrence, is a rare event. We report a case of chiasmatic pilocytic astrocytoma in a 4-year-old child with leptomeningeal dissemination at recurrence. A review of the literature is done regarding dissemination patterns, clinical picture, treatment, and outcome of pilocytic astrocytoma with leptomeningeal dissemination.

Sensitive Determination of BRAF Copy Number in Clinical Samples by Pyrosequencing

Pilocytic astrocytoma is the most frequently occurring brain tumor during childhood. It is classified as grade I by the World Health Organization and may rarely evolve into higher-grade tumors. Frequent genetic abnormalities documented in astrocytomas in children are gains on chromosomal arm 7q. Duplications at 7q34 lead to a fusion between genes KIAA1549 and BRAF resulting in constitutive activation of the BRAF kinase. The BRAF gene is located on chromosome 7q34 and a pseudogene has been identified on chromosome Xq13. We have developed a simple and sensitive pyrosequencing method for the determination of the BRAF copy number in clinical samples. The approach is based on the simultaneous amplification of a DNA fragment contained in exon 11 of BRAF and the respective pseudogene that is used as an internal control. Three different bases in the PCR product allow precise sequence assessment of products originating from the BRAF gene and the respective pseudogene and a calculation of gene copy numbers. After the calibration of the assay on 78 control DNA samples, 42 clinical PA samples were analyzed for variation in copy numbers by pyrosequencing and for fusion gene expression by reverse transcription-polymerase chain reaction. The results obtained from tumor DNA by the developed assay and the established reverse transcription-polymerase chain reaction assays show a high concordance. In summary, we have established a pyrosequencing-based assay allowing precise detection of BRAF copy numbers in DNA extracted from clinical samples.

‘MR spectroscopy differentiation between high and low grade astrocytomas: A comparison between paediatric and adult tumours’

Objective To investigate whether pathologically similar astrocytomas in adults and children may also show metabolic similarities in proton magnetic resonance spectroscopy ( 1H-MRS) and whether the MRS data could help to differentiate between low and high grade gliomas for the different groups. Material and methods Twelve children (5 WHO II astrocytomas, 7 WHO III astrocytomas) and 37 adults (21 WHO II astrocytomas, 16 WHO III astrocytomas) were included in this study. MR spectroscopic data were evaluated retrospectively using normalized measures of total choline (tCho), N-acetyl-aspartate (NAA) and total creatine (tCr). These metabolites were used to differentiate between WHO II and WHO III astrocytomas in children and adults. Histopathological grading was performed using WHO criteria. 1H-MRS was carried out prior to the commencement of any treatment. Signal intensities of tCho, NAA and tCr were normalized to their values in contralateral brain tissue. The resulting concentration ratios were then used to calculate the change in the intratumoural ratio of NAA to tCho. A Mann–Whitney U-Test was performed to evaluate differences within the respective groups. Results In both groups, loss of NAA and increase of tCho were more pronounced in WHO III than in WHO II astrocytoma. The best discriminator to differentiate between low and high grade gliomas was found to be the ratio of NAA/tCho ( p < 0.01). Conclusion The normalized metabolite signal intensities ratio NAA to tCho is the most accurate in differentiating between low and high grade astrocytomas in both children and adults.

MAPK pathway activation through BRAF gene fusion in pilocytic astrocytomas; a novel oncogenic fusion gene with diagnostic, prognostic, and therapeutic potential

Recently, a new mechanism for activation of B-RAF was identified resulting from a tandem duplication, generating a fusion protein with constitutive BRAF activity and thereby activating the MAPK pathway. Different fusion variants involving BRAF and KIAA1549 were demonstrated, present in 80% of pilocytic astrocytomas in children. As the KIAA1549-BRAF fusion gene is detected at a much lower frequency in diffuse low-grade astrocytomas and survival was much longer than expected in the patients with a 'non-pilocytic' astrocytoma carrying the fusion gene, identification of this fusion gene can be of diagnostic and prognostic value. In the near future, interference with the (fusion gene causing) activation of the MAPK signalling cascade may open new therapeutic avenues for children with pilocytic astrocytomas, as a first line of defence against tumour growth or in situations where the tumour has become refractory to other therapeutic modalities.

Proton magnetic resonance spectroscopic imaging in pediatric low-grade gliomas

Our purpose was to investigate whether in vivo proton magnetic resonance spectroscopic imaging, using normalized concentrations of total choline (tCho) and total creatine (tCr), can differentiate between WHO grade I pilocytic astrocytoma (PA) and diffuse, fibrillary WHO grade II astrocytoma (DA) in children. Data from 16 children with astrocytomas (11 children with PA and 5 children with DA) were evaluated retrospectively. MRS was performed before treatment in all patients with histologically proven low-grade astrocytomas. Metabolite concentrations of tCho and tCr were normalized to the respective concentration in contralateral brain tissue. The Mann-Whitney U test was performed to evaluate differences between these two groups. Normalized tCho did not show any statistically significant difference between the two groups. There was a strong trend (P = 0.07) toward higher values of normalized tCr in the DA group. For 3 of 5 children with DA, lactate was detectable, but only 1 of 11 children with PA showed lactate. We concluded that choline as a single parameter is not reliable in the differential diagnosis of low-grade astrocytomas in children. Our results suggest that tCr concentrations combined with lactate will be helpful in the differential diagnosis of PA and DA in children.

Radiation Therapy for Pilocytic Astrocytomas of Childhood

Though radiation therapy is generally considered the most effective treatment for unresectable pilocytic astrocytomas in children, there are few data to support this claim. To examine the efficacy of radiation therapy for pediatric pilocytic astrocytomas, we retrospectively reviewed the experience at our institution. Thirty-five patients 18 years old or younger with unresectable tumors and without evidence of neurofibromatosis have been treated since 1982. Patients were treated with local radiation fields to a median dose of 54 Gy. Six patients were treated with radiosurgery to a median dose of 15.5 Gy. Five patients were treated with initial chemotherapy and irradiated after progression. All patients were alive after a median follow-up of 5.0 years. However, progression-free survival was 68.7%. None of 11 infratentorial tumors progressed compared with 6 of 20 supratentorial tumors. A trend toward improved progression-free survival was seen with radiosurgery (80%) compared with external beam alone (66%), but this difference did not reach statistical significance. Eight of the 9 patients progressing after therapy did so within the irradiated volume. Although the survival of these children is excellent, almost one third of patients have progressive disease after definitive radiotherapy. Improvements in tumor control are needed in this patient population, and the optimal therapy has not been fully defined. Prospective trials comparing initial chemotherapy to radiation therapy are warranted.

Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas

Malignant astrocytomas are a deadly solid tumor in children. Limited understanding of their underlying genetic basis has contributed to modest progress in developing more effective therapies. In an effort to identify such alterations, we performed a genome-wide search for DNA copy number aberrations (CNA) in a panel of 33 tumors encompassing grade 1 through grade 4 tumors. Genomic amplifications of 10-fold or greater were restricted to grade 3 and 4 astrocytomas and included the MDM4 (1q32), PDGFRA (4q12), MET (7q21), CMYC (8q24), PVT1 (8q24), WNT5B (12p13), and IGF1R (15q26) genes. Homozygous deletions of CDKN2A (9p21), PTEN (10q26), and TP53 (17p3.1) were evident among grade 2 to 4 tumors. BRAF gene rearrangements that were indicated in three tumors prompted the discovery of KIAA1549-BRAF fusion transcripts expressed in 10 of 10 grade 1 astrocytomas and in none of the grade 2 to 4 tumors. In contrast, an oncogenic missense BRAF mutation (BRAF(V600E)) was detected in 7 of 31 grade 2 to 4 tumors but in none of the grade 1 tumors. BRAF(V600E) mutation seems to define a subset of malignant astrocytomas in children, in which there is frequent concomitant homozygous deletion of CDKN2A (five of seven cases). Taken together, these findings highlight BRAF as a frequent mutation target in pediatric astrocytomas, with distinct types of BRAF alteration occurring in grade 1 versus grade 2 to 4 tumors.

Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma

Independent studies have previously demonstrated that both the HIPK2 and BRAF genes are amplified and rearranged, respectively, in pilocytic astrocytomas (PAs). The purpose of this study was to further investigate the frequency of BRAF and HIPK2 alterations in PAs, the concordance of these events, and their relationship to clinical phenotype. We performed extensive characterization by array-based copy number assessment (aCGH), HIPK2 copy number analysis, and BRAF rearrangement and mutation analysis in a set of 79 PAs, including 9 tumors from patients with neurofibromatosis type 1 (NF1). We identified 1 of 3 previously identified BRAF rearrangements in 42/70 sporadic PAs. An additional 2 tumors with no rearrangement also exhibited BRAF mutation, including a novel 3-base insertion. As predicted from the genomic organization at this locus, 22/36 tumors with BRAF rearrangement also exhibited corresponding HIPK2 amplification. However, 14/36 tumors with BRAF rearrangement had no detectable HIPK2 gene amplification and 6/20 tumors demonstrated HIPK2 amplification without apparent BRAF rearrangement or mutation. Only 12/70 PAs lacked detectable BRAF or HIPK2 alterations. Importantly, none of the 9 PA tumors from NF1 patients exhibited BRAF rearrangement or mutation. BRAF rearrangement represents the most common genetic alteration in sporadic, but not neurofibromatosis type 1-associated, pilocytic astrocytomas (PAs). These findings implicate BRAF in the pathogenesis of these common low-grade astrocytomas in children, and suggest that PAs arise either from NF1 inactivation or BRAF gain of function.

Transcallosal-interforniceal approach treatment of hypothalamic astrocytoma in children

To explore the clinical features, diagnosis and efficiency of transcallosal-interforniceal approach treatment of hypothalamic astrocytoma in children. A total of 42 pediatric cases of hypothalamic astrocytoma were operated by transcallosal-interforniceal approach. All cases received post-operative radiotherapy and follow-up visits. The clinical and imaging data were analyzed retrospectively. High ICP and hypothalamic lesions were the main clinical manifestations. All patients suffering from hydrocephalus were operated by transcallosal-interforniceal approach. Seventeen cases received subtotal resection and 25 in great part. None died from operation. All cases received post-operative radiotherapy. Twenty-nine cases were followed up for 1 to 7 years. Among which, 25 led a normal life and 4 stayed in a fair condition. Hypothalamic astrocytoma in children have some characteristic in clinical manifestations and neuroradiological examinations. Transcallosal-interforniceal approach is an effective method of treating hypothalamic astrocytoma in children. Total removal is not imperative. And radiotherapy should be performed.