Pilocytic Astrocytoma WHO Research Articles

METB-11. HOW METHYLATION PROFILING HELPS IN DIAGNOSING AND TREATING PEDIATRIC BRAIN TUMORS IN INDONESIA

Abstract BACKGROUNDS Pediatric brain tumors (PBT) exhibit extensive heterogeneity, impacting treatment outcomes. While traditionally classified based on histopathological features, recent WHO classifications have integrated DNA methylation array profiling amongst other molecular characteristics, which improves diagnostic accuracy and thus treatment decisions. However, access to this technology is limited in low- and middle-income countries (LMICs) like Indonesia. As part of the MNP Outreach Consortium, we aimed to introduce methylation profiling in Indonesia to aid in diagnosing and stratifying PBT patients. METHODS In 2023, we conducted a case series involving seven challenging PBT cases from Cipto Mangunkusumo National General Hospital, re-assessing them with methylation profiling. RESULTS Through collaboration with the Institute of Neuropathology Heidelberg and the DKFZ, our centre adopted a discerning approach to re-evaluate histopathological samples from complex cases. This endeavour yielded notable results, reaffirming four initial diagnoses and altering three others Amongst the findings, one case initially diagnosed as anaplastic ependymoma, CNS WHO grade 3, was reclassified as a supratentorial ependymoma with YAP1 fusion gene, based on methylation class. Noteworthy within this latter group, one case initially categorized as low-grade pilocytic astrocytoma was reclassified as high-grade diffuse midline glioma, H3 K27 altered. Moreover identifying the copy number plot could indicate a KIAA1549::BRAF fusion to reclassify a case from diffuse pediatric glioma WHO grade 2 to pilocytic astrocytoma WHO grade 1. The recurrent pigmented neuroectodermal tumor of infancy (MNTI) was reclassified as Medulloblastoma, non-WNT/non-SHH, group 3 subtype II on methylation profiling, highlighting molecular similarities and potential treatment insights. These findings offer insights into genetic mechanisms and guide treatment strategies. CONCLUSION Accurate diagnosis, facilitated by advanced molecular profiling, enhances prognostication and enables personalized treatment plans, even in LMICs. This underscores the importance of expanding access to advanced diagnostic technologies in resource-limited settings.

68Ga-NOTA-Aca-BBN(7-14) PET imaging of GRPR in children with optic pathway glioma.

Optic pathway glioma (OPG) is a rare neoplasm that arises predominantly during childhood. Its location in a sensitive region involving the optic pathways, onset in young patients and controversial therapy choice make the management of OPG a challenge in paediatric neuro-oncology. In this study we assessed gastrin-releasing peptide receptor (GRPR)-targeted positron emission tomography (PET) imaging in children with OPG, and the application of a PET/MRI imaging-guided surgery navigation platform. Eight children (five boys, mean age 8.81years, range 5-14years) with suspicion of optic pathway glioma on MRI were recruited. Written informed consent was obtained from all patients and legal guardians. Brain PET/CT or PET/MRI acquisitions were performed 30min after intravenous injection of 1.85MBq/kg body weight of 68Ga-NOTA-Aca-BBN(7-14). Four patients also underwent 18F-FDG brain PET/CT for comparison. All patients underwent surgical resection within 1week. All 11 lesions (100%) in the eight patients showed prominent 68Ga-NOTA-Aca-BBN(7-14) uptake with excellent contrast in relation to surrounding normal brain tissue. Tumour-to-background ratios (SUVmax and SUVmean) were significantly higher for 68Ga-NOTA-Aca-BBN(7-14) than for 18F-FDG (28.4 ± 5.59 vs. 0.47 ± 0.11 and 18.3 ± 4.99 vs. 0.35 ± 0.07, respectively). Fusion images for tumour delineation were obtained in all patients using the PET/MRI navigation platform. All lesions were pathologically confirmed as OPGs with positive GRPR expression, and 75% were pilocytic astrocytoma WHO grade I and 25% were diffuse astrocytoma WHO grade II. There was a positive correlation between the SUV of 68Ga-NOTA-Aca-BBN(7-14) and the expression level of GRPR (r2 = 0.56, P < 0.01, for SUVmax; r2 = 0.47, P < 0.05, for SUVmean). This prospective study showed the feasibility of 68Ga-NOTA-Aca-BBN(7-14) PET in children with OPG for tumour detection and localization. 68Ga-NOTA-Aca-BBN(7-14) PET/MRI may be helpful for assisting surgery planning in OPG patients with severe symptoms, GRPR-targeted PET has the potential to provide imaging guidance for further GRPR-targeted therapy in patients with OPG.

Orbital tumor associated with a microphthalmic eye and colobomatous cleft: Pilocytic astrocytoma (glioma) or massive retinal gliosis

A 11-year-old boy with congenital microphthalmos of the right eye presented with gradual protrusion of his ocular prosthesis. MRI showed an orbital mass adjacent to the microphthalmic eye. After removal of the eye and the orbital soft tissue mass a gliotic mass, resembling a pilocytic astrocytoma WHO grade 1 (glioma) was diagnosed. Through a colobomatous cleft in the eye the tumour spread in the orbit. There were no clinical signs of neurofibromatosis 1. This case showed a very rare association between a microphthalmic and colobomatous eye and pilocytic astrocytoma, grade 1. However a far advanced and infiltrative massive retinal gliosis cannot be definitively excluded as differential diagnosis.

Children &lt;1 year show an inferior outcome when treated according to the traditional LGG treatment strategy: A report from the german multicenter trial HIT-LGG 1996 for children with low grade glioma (LGG)

Children diagnosed with LGG at an age <1 year are reported to have an impaired prognosis in comparison to older patients. Analysis of this subgroup could reveal the necessity to develop risk-adapted treatment approaches. Children <1 year at diagnosis (n = 66, median age 7.3 months, 33 female, none NFI) from the HIT-LGG 1996 cohort were analyzed for risk factors for EFS, PFS and OS. Several children suffered from diencephalic syndrome (DS, n = 22) and primary dissemination (DLGG, n = 9), 50 had a supratentorial midline (SML) location. Extent of resection was complete/subtotal in 12, partial in 15, biopsy in 27. Tumors were pilocytic astrocytoma WHO grade I (n = 33), other WHO grade I (n = 14), pilomyxoid astrocytomas WHO grade II (n = 3), and neuroepithelial tumors WHO grade II (n = 4). One-year EFS was 34.8%. SML-localisation, minor extent of surgery, pilocytic astrocytoma, DLGG and DS were unfavorable predictive factors. No additional non-surgical therapy was applied in 24, 36 were treated with VCR/carboplatin chemotherapy, 6 with radiotherapy (5/6 brachytherapy). Ten-year-PFS-rate following non-surgical therapy was 16.7%; DS and DLGG were unfavorable factors. Ten-year-OS-rate was 72.8%, lower for children <6 months at diagnosis, with DS, or with DLGG. At last follow up in August 2011, vision in 31 living children was often severely impaired. Children <1 year at diagnosis have a conspicuously impaired survival with current treatment approaches. Age <6 months, diencephalic syndrome and dissemination constitute risk factors for even lower PFS and OS. Treatment adaptations are needed to improve outcome and molecular genetics may explain tumor aggressiveness.

Surgery of highly eloquent gliomas primarily assessed as non-resectable: risks and benefits in a cohort study

BackgroundToday, the treatment of choice for high- and low-grade gliomas requires primarily surgical resection to achieve the best survival and quality of life. Nevertheless, many gliomas within highly eloquent cortical regions, e.g., insula, rolandic, and left perisylvian cortex, still do not undergo surgery because of the impending risk of surgery-related deficits at some centers. However, pre and intraoperative brain mapping, intraoperative neuromonitoring (IOM), and awake surgery increase safety, which allows resection of most of these tumors with a considerably low rate of postoperatively new deficits.MethodsBetween 2006 and 2012, we resected 47 out of 51 supratentorial gliomas (92%), which were primarily evaluated to be non-resectable during previous presentation at another neurosurgical department. Out of these, 25 were glioblastomas WHO grade IV (53%), 14 were anaplastic astrocytomas WHO grade III (30%), 7 were diffuse astrocytomas WHO grade II (15%), and one was a pilocytic astrocytoma WHO grade I (2%). All data, including pre and intraoperative brain mapping and monitoring (IOM) by motor evoked potentials (MEPs) were reviewed and related to the postoperative outcome.ResultsAwake surgery was performed in 8 cases (17%). IOM was required in 38 cases (81%) and was stable in 18 cases (47%), whereas MEPs changed the surgical strategy in 10 cases (26%). Thereby, gross total resection was achieved in 35 cases (74%). Postoperatively, 17 of 47 patients (36%) had a new motor or language deficit, which remained permanent in 8.5% (4 patients). Progression-free follow-up was 11.3 months (range: 2 weeks – 64.5 months) and median survival was 14.8 months (range: 4 weeks – 20.5 months). Median Karnofsky Performance Scale was 85 before and 80 after surgery).ConclusionsIn specialized centers, most highly eloquent gliomas are eligible for surgical resection with an acceptable rate of surgery-related deficits; therefore, they should be referred to specialized centers.

Abstract 64: Fine mapping and in silico analysis of the 8q24.21 region for glioma identifies a low-frequency risk variant insight into etiological basis of glioma.

Abstract Glioma comprises ∼40% of all primary brain tumors and most are associated with a poor prognosis irrespective of clinical care, with the most common type of glioma, glioblastoma (GBM), having a median overall survival of only ˜15 months. A number of glioma subtypes defined in part by malignancy grade (e.g., pilocytic astrocytomas WHO grade 1, diffuse “low-grade” gliomas WHO grade 2, anaplastic gliomas WHO grade 3, and GBM WHO grade 4) can be distinguished. Accumulating data indicate that these subtypes have different molecular genetic profiles possibly resulting from different etiologic pathways, which might be shared by different tumor subtypes or be type specific. We have previously demonstrated using a genome-wide association study (GWAS) strategy that genetic variation at 5p15.33, 8q24.21, 9p21.3, 11q23.3 and 20q13.33 influences the risk of glioma. We have sought to fine-map the location of the functional basis of the 8q24.21 association using data from four different non-overlapping GWASs of glioma, comprising a total of 4,147 glioma cases and 7,435 controls. To improve marker density across the 800kb region of association, we imputed genotypes using data from the 1000 Genomes Project and Hapmap3 data sets and high-density (80×) sequencing data generated on 250 CEU individuals. This combination of high-density genotyping and imputation allowed a wide and deep examination of SNPs with minor allele frequency (MAF) &amp;gt; 0.01 in this region. Coupled with these studies we performed a bioinformatic analysis of the most strongly associated variant to provide insight into the functional basis for the association. The region contained a number of single nucleotide polymorphisms (SNPs) showing a clearly stronger association signal than the original tagSNP rs4295627, notably the low frequency SNP rs55705857 (MAF=0.05 in the European population) which was sufficient to capture the 8q24.21 association (P= 2.24 x10-38). This 8q24 association is primarily for low-grade glioma, stronger for 1p/19q deletion oligodendroglioma and is associated with IDH mutation glioma. Functional annotation showed rs55705857 maps to a highly-evolutionarily conserved sequence predicted to impact on OCT1 binding. Glioma incidence varies between countries and is much lower in individuals of African/Asian descent than European. It is possible that these differences reflect differences in genetic predisposition. In this regard it intriguing that the rs55705857 is monomorphic in Asians, and has a MAF 30 times lower in Africans compared to Europeans. Citation Format: Victor Enciso-mora, Yanhong Liu, Fay Hosking, Richard Houlston, Melissa Bondy. Fine mapping and in silico analysis of the 8q24.21 region for glioma identifies a low-frequency risk variant insight into etiological basis of glioma. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 64.

Abstract LB-514: Contribution of ADAM17 to Kit ligand ectodomain shedding in high-grade gliomas

Abstract Background Malignant anaplastic astrocytoma and glioblastoma are considered to derive from astrocytic precursor cells. They display high vascularization, aggressive growth and invasion into the surrounding brain tissue, and respond poorly to conventional treatments. A disintegrin and metalloproteinases (ADAMs) are membrane-associated metalloproteinases with a complex multi-domain structure. Kit ligand (Kitl), also referred to as stem cell factor (SCF) is synthesized as a membrane-anchored precursor that can be processed to produce the soluble growth factor. As a ligand for Kit receptor tyrosine kinase, Kitl plays important roles in activation of various signalling pathways leading to cell proliferation, differentiation, migration and survival. Previous data has shown that ADAM17 affects Kitl shedding. Hypoxia-induced ADAM17 has been reported to contribute to glioma cell invasion whereas Kitl expression has been demonstrated in glioma cell lines but its function remains unclear. As invasive behaviour is a hallmark of high-grade gliomas, the main aim of our recent study is to investigate the functional role and contribution of ADAM17 to ectodomain shedding of Kitl in these tumors. Methods Quantitative RT-PCR analyses for ADAM17 and Kitl were performed using 36 adult glioma tumor samples including 9 pilocytic astrocytomas WHO grade I (PA I), 9 diffuse astrocytomas WHO grade II (DA II), 9 anaplastic astrocytomas WHO grade III (AA III) and 9 glioblastoma multiforme WHO grade IV (GBM) as well as three (LN-229, LN-308 and U87-MG) glioma cell lines. ADAM17 endogenous expression in glioma cell lines was knocked-down using ADAM17-specific short hairpin RNA (shRNA). The phenotype of the stable transfectants was analyzed by proliferation and migration assays. Immunoblotting and ELISA were performed to detect the Kitl ectodomain released in the cell supernatants. Results We found that ADAM17 and KITLG are overexpressed in high-grade gliomas when compared with low-grade gliomas and normal brain tissue and the higher mRNA levels correlated with the tumor grade. Knock-down of ADAM17 by shRNA significantly reduced glioma cell migration. Moreover shedding of Kitl from control cells (scrambled transfected cells) can be stimulated by addition of phorbol 12-myristate 13-acetate (PMA) together with Ionomycin for 1 hour. In contrast, the PMA/Ionomycin-stimulated Kitl shedding was completely prevented in ADAM17-knock-down cells indicating that ADAM17 is an important PMA/Ionomycin -responsive Kitl sheddase in glioma cells. These results provided evidence for an involvement of ADAM17 in PMA/Ionomycin stimulation of Kitl shedding in glioma cells. Conclusion Our results suggest that ADAM17 in high-grade gliomas effects Kitl ectodomain shedding and may substantially contribute to glioma cell migration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-514. doi:1538-7445.AM2012-LB-514

OLIG2 is differentially expressed in pediatric astrocytic and in ependymal neoplasms

The bHLH transcription factor, OLIG2, is universally expressed in adult human gliomas and, as a major factor in the development of oligodendrocytes, is expressed at the highest levels in low-grade oligodendroglial tumors. In addition, it is functionally required for the formation of high-grade astrocytomas in a genetically relevant murine model. The pediatric gliomas have genomic profiles that are different from the corresponding adult tumors and accordingly, the expression of OLIG2 in non-oligodendroglial pediatric gliomas is not well documented within specific tumor types. In the current study, the pattern of OLIG2 expression in a spectrum of 90 non-oligodendroglial pediatric gliomas varied from very low levels in the ependymomas (cellular and tanycytic) to high levels in pilocytic astrocytoma, and in the diffuse-type astrocytic tumors (WHO grades II–IV). With dual-labeling, glioblastoma had the highest percentage of OLIG2 expressing cells that were also Ki-67 positive (mean = 16.3%) whereas pilocytic astrocytoma WHO grade I and astrocytoma WHO grade II had the lowest (0.9 and 1%, respectively); most of the Ki-67 positive cells in the diffuse-type astrocytomas (WHO grade II–III) were also OLIG2 positive (92–94%). In contrast to the various types of pediatric astrocytic tumors, all ependymomas WHO grade II, regardless of site of origin, showed at most minimal OLIG2 expression, suggesting that OLIG2 function in pediatric gliomas is cell lineage dependent.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-010-0509-x) contains supplementary material, which is available to authorized users.

Natural history and management of low-grade glioma in NF-1 children

Pediatric neurofibromatosis type 1 (NF-1) patients are prone to developing low-grade glioma (LGG). The HIT-LGG study 1996 aimed to observe the natural history of pediatric LGG and to postpone irradiation in younger children by using carboplatinum and vincristine in case non-surgical treatment was required. A total of 109 of 1,044 (10.4%) protocol patients had a genetic NF-1 trait [57 female patients; median age 5.1years (range 1-15.4years)]. Eighty-three patients (76%) suffered from an optic pathway tumor. Neuroimaging only allowed diagnosis in 67 patients. Histology revealed pilocytic astrocytoma WHO grade I in 38 of 42 biopsied patients. Sixty-five (60%) patients received non-surgical treatment, either chemotherapy (n=55) or irradiation (n=10). The overall survival rate of 96% after a median observation time of 5.25years contrasts with an event free survival rate (EFS) of 0.24 at 5years. Progressive LGG were observed even in children older than 11years. Chiasmatic/postchiasmatic localization was a univariate risk factor for progressive disease. In the chemotherapy group, we observed a 5-year progression-free survival (PFS) rate of 0.73. Similarly, the PFS rate in the irradiation group was 0.78. Multivariate analysis revealed surgical intervention and localization within the optic pathway as factors that increased the risk of tumor progression. In this large prospective multinational study, LGG in NF-1 patients did progress in 75% of patients. Chemotherapy yielded acceptable PFS. The biological factors determining progression remain poorly understood.

Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma

Separation of pilocytic astrocytoma from diffuse astrocytomas frequently poses problems mostly related to small sample size. Precise classification and grading are essential due to different therapeutic strategies prompted by diagnoses of pilocytic astrocytoma WHO grade I, diffuse astrocytomas WHO grade II or anaplastic astrocytoma WHO grade III. Recently, genomic aberrations with a high specificity for distinct glioma entities have been described. Pilocytic astrocytomas carry a duplication at chromosome band 7q34 containing a BRAF-KIAA1549 gene fusion in the majority of cases. IDH1 mutations are observed very frequently in adult astrocytomas and IDH2 mutations have been reported in some astrocytomas. We examined a series of 120 astrocytomas including 70 pilocytic astrocytomas WHO grade I and 50 diffuse astrocytomas WHO grade II for both, BRAF-KIAA1549 fusion with a newly developed FISH assay and mutations in IDH1 and IDH2 by direct sequencing. Pilocytic astrocytomas contained the BRAF fusion in 49 cases (70%) but neither IDH1 nor IDH2 mutations. Astrocytomas WHO grade II exhibited IDH1 mutations in 38 cases (76%) but neither IDH2 mutations nor BRAF fusions. Thus, combined molecular analysis of BRAF and IDH1 is a sensitive and highly specific approach to separate pilocytic astrocytoma from diffuse astrocytoma.

Occurrence of a Spinal Anaplastic Pilocytic Astrocytoma and a Supratentorial PNET in an Adolescent

A 15-year-old girl was diagnosed with a spinal anaplastic pilocytic astrocytoma. The histologic features were similar to pilocytic astrocytoma WHO grade I, but with an increased mitotic rate, high nuclear pleomorphism, microvascular proliferation, and necrosis. The tumor was subtotally resected and treated with chemotherapy and irradiation. Four years after diagnosis no local progression was seen. At the age of 17, the patient developed a supratentorial primitive neuroectodermal tumor. We report the first case of a primary anaplastic pilocytic astrocytoma and primary primitive neuroectodermal tumor occurring in the same patient.

Juvenile pilocytic astrocytomas do not undergo spontaneous malignant transformation: grounds for designation as hamartomas

Aim:To determine whether juvenile pilocytic astrocytomas WHO grade I have the potential for spontaneous malignant transformation.Methods:A literature search was performed, cross-referencing juvenile pilocytic astrocytoma, pilocytic astrocytoma, astrocytoma grade I, optic...

Expression pattern of the water channel aquaporin‐4 in human gliomas is associated with blood–brain barrier disturbance but not with patient survival

Aquaporin-4 (AQP4), the most prominent CNS water channel, is restricted to the glia limitans and astrocytic endfeet. We previously showed the loss of spatial AQP4 expression in glioblastomas and a redistribution across the cell surface. However, opposing AQP4 functions have been described: protective in vasogenic but detrimental in cytotoxic brain edema. Thus, specific AQP4 induction to prevent or reduce vasogenic edema is suggested. To elucidate the AQP4 role in brain tumors, we investigated 189 WHO grade I-IV gliomas by immunohistochemistry and the prognostic significance for patients' survival. In gliomas, a remarkable de novo AQP4 redistribution was observed in comparison with normal CNS tissue. Surprisingly, the highest membraneous staining levels were seen in pilocytic astrocytomas WHO grade I and grade IV glioblastomas, both significantly higher than in WHO grade II astrocytomas. AQP4 up-regulation was associated with brain edema formation; however, no association between survival and WHO grade-dependent AQP4 expression was seen. Hence, AQP4 redistribution may go along with other tumor properties, such as vascular proliferation and resulting blood-brain barrier disturbance, features usually prominent in pilocytic astrocytomas WHO I and glioblastomas WHO grade IV. In summary, our findings question the protective role of AQP4 in vasogenic brain edema. Although AQP4 was associated with brain edema formation, one has to question the suitability of AQP4 induction as a promising approach in vasogenic brain edema prevention and treatment. In addition, our results provide unexpectedly high AQP4 levels in pilocytic astrocytomas and present AQP4 as tumor progression marker in WHO grade II-IV astrocytomas.

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

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

Shared Allelic Losses on Chromosomes 1p and 19q Suggest a Common Origin of Oligodendroglioma and Oligoastrocytoma

Loss of heterozygosity (LOH) in specific chromosomal regions, which are likely to harbor tumor suppressor genes, has been associated with human gliomas. In this study we have analyzed astrocytic and oligodendroglial tumors for LOH on chromosomes 1 and 19. By microsatellite analysis LOH was found on chromosome arm 1p in 6/15 oligodendrogliomas WHO grade II and III, 12/25 oligoastrocytomas WHO grade II and III, 6/79 glioblastomas WHO grade IV, 5/44 astrocytomas WHO grade II and III and 0/23 pilocytic astrocytomas WHO grade I. The high incidence of LOH on chromosome arm 1p in oligodendrogliomas and oligoastrocytomas indicates that a putative tumor suppressor gene in this region is involved in the formation of gliomas with oligodendroglial features. Furthermore, the frequent involvement of chromosome arm 1p in oligodendrogliomas and oligoastrocytomas, but not in astrocytomas, suggests that genetically oligoastrocytoma is more similar to oligodendroglioma than to astrocytoma. In order to support this hypothesis, oligodendroglial and astrocytic areas in three mixed oligoastrocytomas were examined differentially for LOH 1p and for LOH 19q, the second genetic region believed to be affected in these tumors. All three tumors had LOH of 1p and LOH of 19q in both areas of oligodendroglial and of astrocytic differentiation. These findings show that the astrocytic and oligodendroglial portions of oligoastrocytoma share molecular genetic features and probably are of monoclonal origin.