Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile.
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ABSTRACT: Background
The term Gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features have not been established yet.Methods
We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization.Results
Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-years survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n=49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wildtype (n=31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n=19), pedHGG_A/B (n=6), and pedHGG_MYCN (n=5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wildtype subgroup, recurrent alterations in EGFR (n=10) and BCOR (n=9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wildtype subgroup TP53 alterations had a significant negative effect on OS.Conclusion
Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).
SUBMITTER: Nussbaumer G
PROVIDER: S-EPMC11376460 | biostudies-literature | 2024 May
REPOSITORIES: biostudies-literature
Publications
Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile.
Nussbaumer Gunther G Benesch Martin M Grabovska Yura Y Mackay Alan A Castel David D Grill Jacques J Alonso Marta M MM Antonelli Manila M Bailey Simon S Baugh Joshua N JN Biassoni Veronica V Blattner-Johnson Mirjam M Broniscer Alberto A Carai Andrea A Colafati Giovanna Stefania GS Colditz Niclas N Corbacioglu Selim S Crampsie Shauna S Entz-Werle Natacha N Eyrich Matthias M Friker Lea L LL Frühwald Michael C MC Garrè Maria Luisa ML Gerber Nicolas U NU Giangaspero Felice F Gil-da-Costa Maria J MJ Graf Norbert N Hargrave Darren D Hauser Peter P Herrlinger Ulrich U Hoffmann Marion M Hulleman Esther E Izquierdo Elisa E Jacobs Sandra S Karremann Michael M Kattamis Antonis A Kebudi Rejin R Kortmann Rolf-Dieter RD Kwiecien Robert R Massimino Maura M Mastronuzzi Angela A Miele Evelina E Morana Giovanni G Noack Claudia M CM Pentikainen Virve V Perwein Thomas T Pfister Stefan M SM Pietsch Torsten T Roka Kleoniki K Rossi Sabrina S Rutkowski Stefan S Schiavello Elisabetta E Seidel Clemens C Štěrba Jaroslav J Sturm Dominik D Sumerauer David D Tacke Anna A Temelso Sara S Valentini Chiara C van Vuurden Dannis D Varlet Pascale P Veldhuijzen van Zanten Sophie E M SEM Vinci Maria M von Bueren André O AO Warmuth-Metz Monika M Wesseling Pieter P Wiese Maria M Wolff Johannes E A JEA Zamecnik Josef J Morales La Madrid Andrés A Bison Brigitte B Gielen Gerrit H GH Jones David T W DTW Jones Chris C Kramm Christof M CM
Neuro-oncology 20240901 9
<h4>Background</h4>The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established.<h4>Methods</h4>We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization.<h4>Results</h4>Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-year survival rate of 28%. Hist ...[more]
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Project description: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.
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Project description:Although gliomatosis cerebri (GC) has been removed as an independent tumor type from the WHO classification, its extensive infiltrative pattern may harbor a unique biological behavior. However, the clinical implication of GC in the context of the 2021 WHO classification is yet to be unveiled. This study investigated the incidence, clinicopathologic and imaging correlations, and prognostic implications of GC in adult-type diffuse glioma patients. Retrospective chart and imaging review of 1,211 adult-type diffuse glioma patients from a single institution between 2005 and 2021 was performed. Among 1,211 adult-type diffuse glioma patients, there were 99 (8.2%) patients with GC. The proportion of molecular types significantly differed between patients with and without GC (P = 0.017); IDH-wildtype glioblastoma was more common (77.8% vs. 66.5%), while IDH-mutant astrocytoma (16.2% vs. 16.9%) and oligodendroglioma (6.1% vs. 16.5%) were less common in patients with GC than in those without GC. The presence of contrast enhancement, necrosis, cystic change, hemorrhage, and GC type 2 were independent risk factors for predicting IDH mutation status in GC patients. GC remained as an independent prognostic factor (HR = 1.25, P = 0.031) in IDH-wildtype glioblastoma patients on multivariable analysis, along with clinical, molecular, and surgical factors. Overall, our data suggests that although no longer included as a distinct pathological entity in the WHO classification, recognition of GC may be crucial considering its clinical significance. There is a relatively high incidence of GC in adult-type diffuse gliomas, with different proportion according to molecular types between patients with and without GC. Imaging may preoperatively predict the molecular type in GC patients and may assist clinical decision-making. The prognostic role of GC promotes its recognition in clinical settings.
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Project description:Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4-17) with a median overall survival of 16.0 months (range 10.9-28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases.
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Project description:In modern clinical neuro-oncology the pathological diagnoses are very challenging creating significant clinical confusion and affecting therapeutic decisions and prognostic estimation. We investigated whether gene expression profiling, coupled with class prediction methodology, could be used to predict prognosis of gliomatosis cerebri in a more consistent manner then standard pathology. We report the results of a molecular study in fifty-nine cases of gliomatosis cerebri, correlating these results with prognosis. TP53 and PTEN gene sequences were analyzed and microarray expression profiling were also performed. At the 24 month follow-up, 17 patients were alive, while 42 patients were died. We identified a 23 gene signature able to predict patient prognosis with microarray gene expression profiling. With the aim to produce a prognostication tool useful in clinical investigation we studied the expression of this 23 gene signature by RT-qPCR. Real time expression values relative to these 23 gene features were used to built a prediction method able to distinguish patients with good prognosis (more likely responsive to therapy) from patients with a bad prognosis (more likely irresponsive to therapy). These results demonstrated not only strong association of gene expression patterns with the survival of the patients but also a robust reproducibility of these gene expression– based predictors.
2009-06-17 | GSE11822 | GEO
Project description:Gliomatosis cerebri (GC) is a rare, extensively infiltrating glioma involving multiple contiguous lobes of the brain. This lethal disease affects all age groups, and the majority of patients have a poor outcome despite aggressive treatment. Despite its initial recognition in 1938, GC remains a controversial entity with little consensus in its definition, histology, or treatment. The majority of GC tumors are astrocytic, although mixed phenotypes have been identified. Treatment of GC is challenging as surgery is generally not an option due to the extensive areas of brain involved, the benefit of radiation therapy is unclear, and no chemotherapy has proven efficacy. Due to the rarity of the disease and its heterogeneity, both at histopathological and molecular levels, it is difficult to conduct clinical trials tailored for this diagnosis. This review summarizes our current knowledge, examines clinical studies focusing on the treatment of GC, highlights ongoing challenges, and discusses the recent molecular insights into adult and pediatric GC. We conclude that, although no longer recognized as a distinct pathological entity, GC represents a unique disease phenotype. Given the histologic and molecular overlap with other diffuse gliomas, the research emphasis should be on investigating its unique invasive biology.
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Project description:Gliomatosis cerebri (GC) is an aggressive glioma characterized by an invasive growth pattern and a dismal prognosis. The low incidence and non-specific symptoms at presentation pose unique challenges for early diagnosis and disease-specific research. There is no standard of care for the treatment of patients with a GC phenotype. Understanding the biology of this entity is a critical step in determining effective treatments. Toward this end, the Second International GC Group convened at National Institutes of Health, Bethesda on June 22nd-23rd 2017. This paper summarizes the main conclusions and recommendations for research priorities to fight this fatal condition.
| S-EPMC6301002 | biostudies-literature
Project description:In modern clinical neuro-oncology the pathological diagnoses are very challenging creating significant clinical confusion and affecting therapeutic decisions and prognostic estimation. We investigated whether gene expression profiling, coupled with class prediction methodology, could be used to predict prognosis of gliomatosis cerebri in a more consistent manner then standard pathology. We report the results of a molecular study in fifty-nine cases of gliomatosis cerebri, correlating these results with prognosis. TP53 and PTEN gene sequences were analyzed and microarray expression profiling were also performed. At the 24 month follow-up, 17 patients were alive, while 42 patients were died. We identified a 23 gene signature able to predict patient prognosis with microarray gene expression profiling. With the aim to produce a prognostication tool useful in clinical investigation we studied the expression of this 23 gene signature by RT-qPCR. Real time expression values relative to these 23 gene features were used to built a prediction method able to distinguish patients with good prognosis (more likely responsive to therapy) from patients with a bad prognosis (more likely irresponsive to therapy). These results demonstrated not only strong association of gene expression patterns with the survival of the patients but also a robust reproducibility of these gene expressionâ?? based predictors. We have analyzed 59 gliomatosis cerebri bioptic tissue comparing them with normal brain tissue derived by non-tumor surrounding tissue or commercial brain tissue. We alternatively labeled test sample and reference with Cy3 and Cy5 so to avoid a systematic bias due to label efficiency. Since the aim of the work was to find a correlation between prognosis and expression profile we considered each sample of a one prognosis group like a replicate of that group. Median survival data allowed us to distinguish 59 gliomatosis cerebri patients in two group: bad prognosis group, counting 42 patients, with a median survival of 14.58 months and good prognosis group with a median survival of 41.20 months. Moreover TP53 and PTEN mutation analysis was performed on this patients. Kaplan-Meier survival curve with log-rank test showed like each prognosis group can be furthermore divided in 2 groups where bad prognosis group patients bringing a mutation in one of the two gene analized or both genes showed the wrong survival. Microarray expression profile follwed by average linkage clustering analysis based on Pearson correlation coefficients was applied to all tissues on the basis of similarity in the expression pattern over all genes. As expected, it yielded two major clusters, one representing the good prognosis group and the other the bad prognosis one. Interesting these cluster are identical to cluster based on survival. Tumour classification based upon WHO 2007.
2010-05-18 | E-GEOD-11822 | biostudies-arrayexpress
Project description:Cerebral gliomatosis (GC) is a rare diffuse infiltrative growth pattern of glioma with nonspecific clinical manifestations like visual impairment that may involve bilateral temporal lobes. Herpes simplex encephalitis (HSE) and limbic encephalitis (LE) can also lead to temporal lobe involvement. Differentiating these entities is necessary for patients with misleading presentations and imaging findings. To the best of our knowledge, this is the third case of GC presenting with blindness. The patient was a 35 years-old male in a drug rehabilitation center for heroin addiction. He presented with a headache, a single episode of seizure, and a 2-month history of bilateral decrease in visual acuity, which had acutely worsened. Magnetic resonance imaging (MRI) and computed tomography (CT) showed bilateral temporal lobe involvement. Ophthalmological studies showed bilateral papilledema, absence of visual evoked potential, and thickening of the retinal nerve fiber layer. Due to this clinical presentation, normal laboratory data, and suspicious MRI findings, further investigation with magnetic resonance spectroscopy (MRS) was performed. Results showed a greatly increased ratio of choline to creatinine(Cr) or N-acetyl aspartate (NAA), suggesting a neoplastic nature of the disease. Subsequently, the patient was referred for a brain tissue biopsy with a suspicion of malignancy. The pathology results revealed adult-type diffuse glioma with isocitrate dehydrogenase (IDH) mutation. Bilateral blindness, as well as bilateral temporal lobe involvement, each has many different causes. However, as demonstrated in this study, adult-type diffuse glioma must be considered a rare cause of concomitant bilateral temporal lobe involvement and blindness.
| S-EPMC10300258 | biostudies-literature