Gliomatosis Cerebri Patients Research Articles

Revisiting gliomatosis cerebri in adult-type diffuse gliomas: a comprehensive imaging, genomic and clinical analysis

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.

Revisiting prognostic factors of gliomatosis cerebri in adult-type diffuse gliomas.

There is lack of comprehensive analysis evaluating the impact of clinical, molecular, imaging, and surgical data on survival of patients with gliomatosis cerebri (GC). This study aimed to investigate prognostic factors of GC in adult-type diffuse glioma patients. Retrospective chart and imaging review was performed in 99 GC patients from adult-type diffuse glioma (among 1,211 patients; 6 oligodendroglioma, 16 IDH-mutant astrocytoma, and 77 IDH-wildtype glioblastoma) from a single institution between 2005 and 2021. Predictors of overall survival (OS) of entire patients and IDH-wildtype glioblastoma patients were determined. The median OS was 16.7months (95% confidence interval [CI] 14.2-22.2) in entire patients and 14.3months (95% CI 12.2-61.9) in IDH-wildtype glioblastoma patients. In entire patients, KPS (hazard ratio [HR] = 0.98, P = 0.004), no 1p/19q codeletion (HR = 10.75, P = 0.019), MGMTp methylation (HR = 0.54, P = 0.028), and hemorrhage (HR = 3.45, P = 0.001) were independent prognostic factors on multivariable analysis. In IDH-wildtype glioblastoma patients, KPS (HR = 2.24, P = 0.075) was the only independent prognostic factor on multivariable analysis. In subgroup of IDH-wildtype glioblastoma with CE tumors, total resection of CE tumor did not remain as a significant prognostic factor (HR = 1.13, P = 0.685). The prognosis of GC patients is determined by its underlying molecular type and patient performance status. Compared with diffuse glioma without GC, aggressive surgery of CE tumor in GC patients does not improve survival.

NIMG-67. REVISITING GLIOMATOSIS CEREBRI IN ADULT-TYPE DIFFUSE GLIOMAS: A COMPREHENSIVE ANALYSIS OF MANIFESTATION AND RISK FACTORS IN THE 2021 WHO CLASSIFICATION

Abstract BACKGROUND To investigate the incidence, clinicopathologic and imaging correlations and prognostic implications of gliomatosis cerebri (GC) pattern in adult-type diffuse glioma patients reflecting the 2021 WHO classification. METHODS Retrospective chart and imaging review was performed in 1,211 adult-type diffuse glioma patients at a single institution between 2005 and 2021. Clinicopathologic and imaging features were compared amongst adult-type diffuse glioma patients with and without GC based on the 2021 WHO classification. Clinical and imaging risk factors for predicting IDH mutation status within GC patients were investigated. Survival analysis was performed in entire patients and in subgroup of IDH-wildtype glioblastoma patients to evaluate whether GC is an independent prognostic factor. RESULTS Total 99 patients (8.9% of entire patients) showed GC. The distribution of tumor type was significantly different in patients with GC compared with those without GC (P = 0.017); IDH-wildtype glioblastoma being most common (77.8% vs. 68.9%), followed by IDH-mutant astrocytoma (16.2% vs 16.9%), and being less common in oligodendroglioma (6.1% vs 16.5%). 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=1.55, P=0.031) in IDH-wildtype glioblastoma patients on multivariable analyses. CONCLUSIONS The incidence of GC is 8.9% in adult-type diffuse gliomas, with IDH-wildtype glioblastoma showing significantly higher risk of GC. Preoperative imaging features may predict IDH mutation status in GC patients. GC is an independent prognostic factor in IDH-wildtype glioblastoma, and promote recognition of this pattern in clinical settings.

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

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

Gliomatosis Cerebri Growth Pattern: Association of Differential First-Line Treatment with Overall Survival in WHO Grade II and III Gliomas

Introduction: Gliomatosis cerebri (GC) is defined by diffuse, widespread glial tumor growth affecting three or more cerebral lobes. Previous studies in gliomas found no distinct histological or molecular GC subtype, yet the presence of GC is associated with worse median overall survival (OS). Here, we explored whether differing therapeutic strategies in first-line treatment could account for this. Methods: From our University Cancer Center database, 47 patients with histological diagnosis of WHO grade II or III glioma and GC imaging pattern were identified. GC criteria were confirmed by independent review. Patients with WHO grade II or III glioma with non-GC pattern served as control cohort (n = 343). Results: Within the GC patient cohort, lower WHO grade, mutated isocitrate dehydrogenase 1 (IDH1) status, and absence of contrast enhancement were associated with better OS. Compared to the control cohort, patients with GC had significantly shorter OS independent of histological diagnosis or IDH1 mutation status. Patients with GC preferentially received chemotherapy alone (62 vs. 18%), and less frequently radiochemotherapy (21 vs. 27%). OS was significantly shorter in the GC cohort compared to the non-GC cohort both for chemotherapy (3.9 vs. 7.6 years, p = 0.0085) and for combined radiochemotherapy (1.1 vs. 8.4 years, p < 0.0001). However, when only patients who received biopsy plus chemotherapy were analyzed, the differences lost statistical significance (3.5 vs. 6.6 years, p = 0.196). Conclusion: We found major differences in the selection of first-line therapies of GC versus non-GC patients. Our results suggest that these differences may partly account for the worse prognosis of GC patients.

Predictive factors for overall survival in surgical cases of gliomatosis cerebri from the National Cancer Database

Gliomatosis Cerebri (GC) is a rare, aggressive, diffusely infiltrating cerebral tumor. Prognostic indicators and management strategies are currently poorly characterized. The National Cancer Database was queried for patients with histologically confirmed GC between 2004 and 2016. Demographic, tumor, and treatment characteristics were collected, including the Charlson/Deyo score, a comorbidity index adapted from the Charleston Comorbidity Index. Allowable values for the Charlson/Deyo score are 0 (no recorded comorbidities), 1, 2, and 3+ (most severe). Factors associated with overall survival were identified via bivariate log-rank tests and multivariate stepwise Cox proportional hazards models. The query returned 108 GC patients. The median age was 60.0 years, males were predominantly affected (63%), and most patients were white (86%). While 12% of cases achieved near/gross total resection and 27% of cases achieved partial resection, most surgeries were for biopsy (61%). Treatments included radiation therapy in 64% and chemotherapy in 63% of patients. The median overall survival was 15.1 (95% confidence interval [CI] = 11.1–24.8) months. On bivariate analysis, chemotherapy improved overall survival (p = 0.01) while radiation therapy (p = 0.07) and extent of resection (p = 0.48) did not. On multivariate analysis, older patients (hazard ratio [HR] = 1.07, CI = 1.03–1.11, p < 0.01) and Charlson/Deyo scores of ≥1 versus 0 (HR = 3.47, CI = 1.40–8.60, p < 0.01) had significantly increased mortality risk following surgery. In particular, the Charlson/Deyo score is a novel prognostic factor for GC that may guide clinical and surgical decision-making for this rare, rapidly fatal tumor. Further prospective studies are warranted to clarify the effects of chemotherapy versus radiation as treatment modalities for GC.

P14.96 Gliomatosis cerebri imaging pattern: a treatment-independent marker for worse overall survival in WHO grade II and III gliomas

Abstract BACKGROUND The term gliomatosis cerebri (GC) refers to glial brain tumors with widespread tumor expansion affecting three or more cerebral lobes. Formerly considered a distinct tumor entity, recent studies found no difference in the mutational profile of glial tumors with GC growth pattern compared to non-GC gliomas. Thus, in the new WHO classification of brain tumors, GC is no longer included as a separate diagnosis. While the presence of gliomas with GC growth pattern is associated with worse overall survival (OS), the underlying factors remain to be identified. Here, we asked whether differing therapeutic strategies in first line treatment could account for the worse outcome of patients with GC growth pattern and grade II and III histology. MATERIAL AND METHODS From the patient data bank of the University Cancer Center (UCT) Frankfurt, 47 patients with histological diagnosis of WHO grade II or III glioma, and with record of GC imaging pattern were identified. GC tumor expansion was confirmed by review of MRI scans prior to treatment initiation. Patients with WHO grade II or III glioma without GC growth pattern served as control cohort (n=379). IDH mutational status was available for 75% of GC tumors (IDH R132H mutated 32%; non-mutated 43%) and 69% of non-GC tumors (IDH R132H mutated 57%; non-mutated 12%). RESULTS Within the GC patient cohort, patients with tumors without contrast enhancement, lower WHO grade and mutated IDH status showed better OS. Compared to the control cohort, patients with GC had significantly shorter OS. This was independent of histological diagnosis or IDH mutation status. Patients with GC more frequently underwent radiochemotherapy (17% vs. 9% in the non-GC cohort), and drastically more often received chemotherapy alone (51% vs. 5%). We then analyzed OS in GC and non-GC patients that had received the same first line treatments. For radiochemotherapy in GC versus non-GC patients, OS was 1.1 years vs. 12.7 years (p =0.0075, log-rank test). For upfront chemotherapy alone, OS was significantly shorter in the GC cohort than in the non-GC cohort (3,6 years vs. undefined, p =0.0016, log-rank test). CONCLUSION Differences in first-line treatment cannot account for the worse prognosis of patients with GC imaging pattern. Further studies are needed to pinpoint biological or clinical factors that might influence responsiveness to therapy and prognosis of GC tumors.

Gliomatosis Cerebri Among Children and Adolescents: An Individual-Patient Data Meta-analysis of 182 Patients.

Gliomatosis cerebri is a rare but fatal widespread infiltrating central nervous system tumor. We aimed to describe diagnostic and prognostic features of gliomatosis cerebri among children and adolescents. We conducted a systematic literature review for published case reports and case series on patients with histologically confirmed gliomatosis cerebri and extracted data on an individual patient level for those aged 0-18 years. Multivariable Cox proportional hazard models were fit for overall survival. Following screening of 274 published studies, 182 gliomatosis cerebri patients (63% males) aged 0-18 years with individual-level data available were identified. The most common presenting symptoms were seizures (52%), focal motor deficits (36%), and headache (30%). Imaging showed bilateral hemisphere involvement in 60%, infratentorial infiltration in 39%, and a focal contrast-enhanced mass (type II gliomatosis cerebri) in 27% of cases. Anaplastic astrocytoma was the most common histologic subtype of pediatric gliomatosis cerebri, whereas MGMT promoter methylation, IDH1 mutations, and codeletion of 1p/19q were less common molecular aberrations, as compared to adult gliomatosis cerebri. In the multivariable analyses, age at diagnosis >4 years, extended central nervous system infiltration, coordination abnormalities, and cognitive decline were predictors of worse outcome. Conversely, IDH1 mutations were associated with prolonged overall survival. Chemotherapy and extended surgical resection were associated with improved outcome, whereas radiotherapy was not associated with overall survival and was inferior to chemotherapy alone. Gliomatosis cerebri among children and adolescents presents distinct histopathologic and molecular features compared to adults. However, similar associations of chemotherapy, and, when feasible, extended surgical resection, with favorable outcomes were noted among the 2 age groups.

Clinical, neuroimaging and histopathological features of gliomatosis cerebri: a systematic review based on synthesis of published individual patient data.

Gliomatosis cerebri (GC) is a rare fatal widespread infiltrating CNS tumor. As consistent disease features have not been established, the tumor comprises a diagnostic challenge. We conducted a systematic literature search for published case reports and case series on patients with histologically confirmed GC. Clinical, diagnostic, neuroimaging, histopathological, and molecular data on individual or summary patient level were extracted and analyzed. A total of 274 studies were identified, including 866 patients with individual-level data and 782 patients with summary data (58.9% males, mean age 43.6years). Seizures (49.8%) were the most common presenting symptom followed by headache (35.9%), cognitive decline (32.2%), and focal motor deficits (32%). Imaging studies showed bilateral hemisphere involvement in 65%, infratentorial infiltration in 29.9% and a focal contrast-enhanced mass (type II GC) in 31.1% of cases. MRI (extensive hyperintensities in T2/FLAIR sequences) and MR spectroscopy (elevated choline, creatinine, and myoinositol levels; decreased NAA levels) showed highly consistent findings across GC patients. Low-grade and anaplastic astrocytoma were the most prevalent diagnostic categories, albeit features of any histology (astrocytic, oligodendroglial, oligoastrocytic) and grade (II-IV) were also reported. Among molecular aberrations, IDH1 mutation and MGMT promoter methylation were the most commonly reported. Increasing time elapsed from symptom onset to diagnosis comprised the only independent determinant of the extent of CNS infiltration. A distinct clinical, neuroimaging, histopathological, or molecular GC phenotype is not supported by current evidence. MRI and MR spectroscopy are important tools for the diagnosis of the tumor before confirmation with biopsy.

IDH mutations define a subset of gliomatosis cerebri patients with improved outcome (P1.160)

IDH mutations define a subset of gliomatosis cerebri patients with improved outcome (P1.160)

ACTR-36. GLIOMATOSIS CEREBRI; CLINICAL COURSE AND TREATMENT OUTCOMES IN SINGLE INSTITUTION

Gliomatosis cerebri (GC) reported by Nevin in 1938 is a mysterious and rare primary brain tumor. GC is defined as a diffuse infiltration of neoplastic glial cell at least three lobes in the World Health Organization (WHO) classification and can be categorized with two patterns. Type1 is typical infiltration and has no tumor mass, type2 has tumor mass spreading to CNS involvement. Prognosis of GC is dismal and there is no standard therapeutic regimen for them. Here, we report clinical course in gliomatosis patients at Tokyo Women’s Medical University in Japan. Fourteen GC patients at Tokyo Women’s Medical University were diagnosed by operation or stereotactic biopsy and treated between October 2003 and April 2015. Using retrospective chart review, we analyzed patient demographics, clinical outcome and duration of therapy were estimated using the Kaplan-Meier estimate. GC patients were 10 males and 4 females. The median age was 50 years (range 18–73). Median Overall Survival (mOS),median Progression Free Survival(mPFS) was 30.5 months, 12.5 months and poor OS(grade II, III, IV:38.5,30,8months; P<0.001)and PFS (18.5,17,5months; P<0.001) was related with higher grade. Among Radiation Therapy group(RT),ChemoTherapy group (CT) and Radiation Chemo Therapy group(CRT), CT was related with better prognosis (OS CT, RT, CRT:43, 34, 17months; P<0.05),PFS (24, 12, 8months; P=0.053). Higher histologic grade was associated with poor prognosis. Although radiation therapy was effective in most reported literatures, radiation alone was not effective. Chemotherapy suggested it was possible to be better prognosis.

EPIG-09GENETIC AND EPIGENETIC TUMOR EVOLUTION IN GLIOMATOSIS CEREBRI

Gliomatosis cerebri (GC) is a rare and aggressive cancer (fewer than 100 cases diagnosed in the United States each year). GC is an extensively infiltrating high-grade glial tumor to at least three lobes in the brain (median length of survival is 9.5 months). Accumulating evidence suggests that epigenetic dysregulation may play an important role in tumor progression, and epigenetic modulators have begun to show promise as therapeutic options in other pediatric and adult malignancies. However, the evolution of GC tumor genetics and epigenetic dynamics have not been well studied. Here we describe the GC somatic mutation spectrum of 12 patients and an intra-tumor evolution pattern between lower and higher grade areas in three patients. We performed exome-capture sequencing, and reduced representation bisulfite sequencing to examine the genetic and epigenetic dynamics for the GC samples. Recurrent mutations were found in genes related to Cell cycle, p53 signaling, Wnt signaling, and MAPK signaling pathways. Furthermore, we found increased epigenetic heterogeneity in tumor samples with enhancement compared to the normal brain samples, which suggests that epigenetic dynamics permits a superior evolutionary trajectory leading to GC progression. These findings may help explain tumor evolution and target mechanism for therapeutic diversification. By understanding the driver events, one may eventually provide more accurate diagnosis of the disease and define clinical targets for improvement of the treatment and survival rate of GC patients.

RTRB-13REVIEW OF GLIOMATOSIS CEREBRI IN SINGLE INSTITUTION

OBJECTIVE: Gliomatosis cerebri (GC) is a diffusely infiltrating glial neoplasm of the brain. Radiotherapy for GC can be associated with improved survival, but the optimal therapy for GC is unclear. The aim of this study is to investigate the clinical result of GC after radiotherapy with/without chemotherapy and evaluate the recurrence pattern on focal radiation and whole brain radiation. PATIENTS AND METHODS: Between October 2006 and May 2015, 17 GC patients were diagnosed by MRI and biopsy. All patients received focal radiation to the tumor or whole brain radiation. Retrospectively, we reviewed 14 patients who were surveyed. RESULTS: Four patients received focal radiation and 10 patients received whole brain radiation. Mean progression free survival and overall survival in focal radiation group and whole brain radiation group were 17.3 and 16.8 months, respectively (p = 0.95). The recurrence without apparent anatomical relation to primary lesion had developed in 2 patients of focal radiation group and 3 patients of whole brain radiation group (p= 0.73). CONCLUSION: In the clinical outcomes of GC, there were no significant differences between focal radiation and whole brain radiation. Efficacy of chemotherapy is unclear in our series.

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.

Gliomatosis cerebri having a poor performance status without recurrence after radiotherapy: A single institutional experience

ObjectiveRadiotherapy (RT) has been advocated for gliomatosis cerebri (GC) to delay tumor progression. However, patients with GC may experience poor performance status without recurrence after RT. Herein, we reviewed the responses of patients with GC treated with RT. Materials and methodsSeventeen patients with diffuse radiologic infiltration of more than two cerebral lobes and diagnosed as having grade II (N=12) or III (N=5) glioma were treated with a mean radiation dose of 51.8Gy (range, 42–59.4Gy). The mean radiation volume to a mean marginal dose of 42.8Gy (range, 36–45Gy) was 693.4cc (range, 316.5–1279.6cc), which was 45.3% of the mean whole brain volume. We reviewed the clinical prognostic factors related to progression-free survival (PFS) and overall survival (OS) in all patients and described characteristics of patients with poor performance (Eastern Cooperative Oncology Group performance scale 3–4) without recurrence. ResultsIn all patients, the median PFS was 12.3 months, and oligodendroglial pathology (p=0.002) and non-enhanced tumor (p=0.002) were associated with an improved PFS. The median OS was 39.3 months, and young age and adjuvant chemotherapy were associated with improved OS (p=0.022 and 0.002, respectively). Based on multivariate analysis, adjuvant chemotherapy was significantly associated with a longer OS (p=0.012; hazard ratio=0.099; 95% CI, 0.016–0.596). Five patients (29.4%) showed poor performance without recurrence. The median age of these 5 patients was 65 years (range, 60–75 years). The mean radiation volume to a mean marginal dose of 41Gy (range, 36–45Gy) was 539.9cc (range, 255.5–983.1cc). The pathologic diagnosis was grade II glioma in 2 patients and grade III in 3 patients. The median OS was 10.0 months (range, 8.2–45.9 months). ConclusionsSome GC patients, especially the elderly, might have a poor performance status without recurrence after RT of a larger radiation field.

Gliomatosis cerebri: clinical characteristics, management, and outcomes

Gliomatosis cerebri is a rare diffusely infiltrating primary neoplastic glial process of the brain. Our objective is to review clinical presentation, management, and outcome in a large single institution series of gliomatosis cerebri patients. 54 consecutive gliomatosis cerebri cases presenting to Mayo Clinic Rochester between 1991 and 2008 were retrospectively reviewed. Inclusion criteria included involvement of at least three cerebral lobes, lack of a single discrete mass and pathological confirmation of diffuse glioma. Median overall survival (OS) was 18.5 months. Age, gender, presenting symptoms, and contrast enhancement did not correlate significantly with survival, though there was a trend toward decreased overall survival in patients above the median age of 46 years. Karnofsky performance score <70 was associated with poor OS (median 9.5 vs. 20.5 months, p = 0.02). Higher histologic grade was associated with poor progression-free survival (PFS; median for WHO grades II, III, and IV: 21.5, 6.5, and 4 months; p = 0.03) and OS (median 34, 15.5, and 8.5 months; p < 0.05). Radiation therapy was strongly associated with better prognosis (PFS 16.5 vs. 4.5 months, p < 0.01; OS 27.5 vs. 6.5, p < 0.01), but chemotherapy was not. Gliomatosis cerebri patients have a poor prognosis. Lower KPS upon presentation and higher histologic grade predict decreased survival. Surgery's role is limited beyond biopsy for diagnostic purposes. Radiotherapy appears beneficial, although selection bias could be present in this retrospective study. Chemotherapy's value is not as clear but this must be interpreted with caution given variable treatment regimens in this series.

Clinical, Histopathologic, and Magnetic Resonance Imaging (MRI) Findings in Gliomatosis Cerebri (P03.139)

Objective: To characterize clinical, histopathologic, and radiologic features in 32 patients with gliomatosis cerebri (GC). Background GC is a rare primary tumor of the central nervous system, characterized by diffuse neoplastic glial cell infiltration of more than two cerebral lobes and relative preservation of the surrounding brain architecture. Although primarily astrocytic in origin, cases with oligodendroglial and mixed oligoastrocytic features have been described. Radiologically, GC is defined by no or minimal contrast enhancement on magnetic resonance imaging (MRI). Design/Methods: We identified 32 subjects from the neuroradiology and neuro-oncology database at the Massachusetts General Hospital who met the diagnostic criteria of GC. Clinical, histopathologic, and imaging characteristics were assessed. Results: Most common clinical symptoms at presentation were seizures (63%), cognitive dysfunction (28%) and headaches (16%). Tumors were classified as WHO grade II and WHO grade III with equal distribution, and most commonly were diagnosed as astrocytomas (n=20), oligodendrogliomas (n=4), and mixed oligoastrocytomas (n=3). Forty-four percent had bihemispheric T2/FLAIR hyperintensity on MRI, with frequent involvement of the temporal (n=31) and frontal (n=25) lobes as well as the subventricular zone (n=24). Treatment involved surgery (n=13), radiation (n=15), chemotherapy (n=26), and combined chemo-radiation (n=10). Median overall survival (OS) for all patients was 32 months from the time of radiologic diagnosis (ranging from 20 days to 231 months). Median time to progression after the first (TTP1), and second (TTP2) treatment regimen were 15 and 9 months, respectively. Conclusions: Patients with GC present with heterogeneous clinical, pathologic, and imaging findings. Some patients demonstrate prolonged overall survival of more than 10 years suggesting subpopulations of GC patients with significantly better prognosis. Further detailed characterization of molecular and histopathological features of GC and advanced neuroimaging techniques may help to identify distinct subgroups of GC and guide further treatment decisions. Supported by: The American Brain Tumor Association and the American Academy of Neurology Foundation. Disclosure: Dr. Ly has nothing to disclose. Dr. Pine has nothing to disclose. Dr. Stemmer-Rachamimov has nothing to disclose. Dr. Hochberg has nothing to disclose. Dr. Dietrich has nothing to disclose.

Mutated IDH1 Is a Favorable Prognostic Factor for Type 2 Gliomatosis Cerebri

The prognostic significance of IDH1 mutations has been demonstrated in gliomas. It is unclear whether IDH1 mutation is also a prognostic factor in gliomatosis cerebri (GC). Primary GCs can be grouped into type 1 GCs, which have the classical diffuse growth pattern without mass formation, and type 2 GCs, which form neoplastic masses in addition to classic diffuse lesions. In this study, the prognostic relevance of IDH1/2 mutations in 74 GCs (43 type 1 and 31 type 2) was evaluated. We detected 33 (44.6%) IDH1 mutations, including R132H and R132S, by bidirectional Sanger sequencing. No mutations were detected in IDH2. The percentage of 2-year overall survival for wild-type IDH1 patients was 46 vs. 72% for patients with IDH1-mutated tumors. Mutations of IDH1 were strongly correlated with both increased overall survival (OS) and progression-free survival (PFS) in patients with type 2 GCs, and IDH1 mutations were also an independent prognostic factor predicting increased OS and PFS in type 2 GC patients in multivariate analysis. However, IDH1 mutations did not correlate with survival outcomes in patients with type 1 GCs. Finally, the subgroup of GC, which has IDH1 wild-type and additional solid component showed the worst prognosis.

Genetic markers predictive of chemosensitivity and outcome in gliomatosis cerebri

Up-front temozolomide (TMZ) has been recently proposed as a treatment for gliomatosis cerebri (GC), but no predictive or prognostic markers have been identified so far. Because 1p19q codeletion and methylguanine methyl transferase promoter (MGMTP) methylation have been correlated with chemosensitivity of gliomas, their value was investigated in a cohort of patients with GC treated with TMZ. A cohort of 25 GC patients who were treated with TMZ was investigated for 1p19q codeletion and O6-methylguanine DNA. Patients with a 1p/19q codeletion had a higher response rate (88% [8/9] vs 25% [4/16], p = 0.002), higher progression-free survival (24.5 vs 13.7 months, p = 0.017), and higher overall survival (66.8 vs 15.2 months, p = 0.011) than patients without 1p/19q codeletion. Fourteen of 19 evaluable tumors for MGMTP status were methylated. MGMTP methylation was associated with 1p/19q codeletion (p = 0.045). Patients with unmethylated MGMTP tended to have a shorter progression-free survival and a higher rate of progressive disease. Response rate to temozolomide and prognosis seem tightly correlated to 1p19q loss. The impact of methylguanine methyl transferase promoter methylation status on gliomatosis cerebri is still unsettled in this population.

Assessment of tumor cell invasion factors in gliomatosis cerebri

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