Intramedullary gangliogliomas: histopathologic and molecular features of 25 cases

Gangliogliomas are uncommon glioneuronal tumors, which usually arise in the cerebral hemispheres and occasionally in the brain stem. Gangliogliomas occurring in the spinal cord are extremely rare. In this study, we analyzed the clinical, histopathologic, and molecular features of 25 spinal gangliogliomas. The cases included in our series affected mostly children and young adults (15 males and 10 females; mean age, 20 years; median age, 14 years; age range, 1-72 years) and were predominantly localized in the cervical and thoracic spine. From the clinical point of view (detailed follow-up available for 9 pediatric cases; mean follow-up: 2 years 10 months; range, 3 months to 5 years 10 months), most patients showed stable disease after subtotal resection. Radiotherapy was rarely used as adjuvant treatment. Histologically, gangliogliomas (WHO grade I) (21 cases) showed features largely similar to their supratentorial counterparts. Anaplastic gangliogliomas (World Health Organization grade III) (4 cases) showed features of anaplasia (including high cellularity and increased mitotic and proliferation activity). From a molecular point of view, only 2 tumors (2/19, 11%) harbored a BRAFV600E mutation. In conclusion, although spinal gangliogliomas display histologic and clinical features similar to their supratentorial counterparts, they show a relatively low frequency of BRAFV600E mutations, alteration otherwise common in hemispheric and brain stem gangliogliomas

Natural History of Pediatric Low-Grade Glioma Disease – First Multi-State Model Analysis

Background: Pediatric low-grade glioma [PLGG] is often a chronic progressive disease requiring multiple treatments, i.e. surgery, chemotherapy and irradiation. The multi-state model [MSM] allows an extended analysis of disease-states, that patients may undergo, incorporating competing risks over the course of time. Purpose: We studied disease-state-probabilities of the German SIOP-LGG 2004 cohort from the initial state "diagnosis" to the final state "death". Transient "disease-states" incorporated successive surgical and non-surgical treatments. We evaluated clinical risk factors for highly progressive disease requiring multiple interventions and death. Results: We identified 22 states within 1587 patients (median follow-up 6.3 years). For robust statistical calculation, we reduced the model to 7 states and eventually to three levels of disease-progressiveness: non, low and highly progressive. Five years after diagnosis state-probabilities were: 0.11 no therapy, 0.49 one and 0.11 two or more surgeries only, 0.19 one and 0.06 two or more non-surgical interventions with or without prior surgery. At this time point higher probability for highly progressive disease was found in infants (0.30), supratentorial-midline location (0.17) and diffuse astrocytoma WHO-grade II (0.12). Neurofibromatosis type-1 patients were most likely not to be treated (0.36) or to have received only non-surgical therapy (0.45). Two years after diagnosis 3-year predictions for highly progressive disease and death increased with the number of interventions patients underwent in the first 2 years after diagnosis. Conclusion: In this first MSM analysis we delineated a refined description of PLGG disease course over time, identifying three levels of progressiveness. Growth behavior in the first two years predicted future progressiveness and death

LGG-11. Analysis of neurosurgical complications in pediatric supratentorial midline low-grade glioma – results from the German LGG [Abstract]

OBJECTIVE: Around 80% of all pediatric low-grade glioma (LGG) patients undergo at least one tumor surgery. Interventions in the supratentorial midline (SML) are particularly challenging due to the proximity of eloquent areas, yet associated complications are scarcely reported. We investigated the frequency of neurosurgical complications and related impairments and aimed at identifying risk factors for their appearance related to patient characteristics or the procedure. PATIENTS AND METHOD: Records were retrospectively analyzed from 321 patients with SML-LGG from the successive multicenter German LGG studies, who underwent neurosurgery at 63 hospitals between May 12th,1998 and June 27th, 2020. RESULTS: 543 operations (235 resections, 168 biopsies, 140 non-tumor interventions) were performed on 321 patients (54% male, median age 9 years, 11% NF1 positive, 43% visual pathway glioma). Surgical mortality rate was 0,93% (n=3). Applying the Drake classification postoperative surgical morbidity was observed in 259 cases (47,7%), medical morbidity in 103 cases (19%). 30-day persistence rate of newly developed neurological deficits was 44,8% (65/165 cases); neuroendocrine impairment affected 57 patients (17,8%), visual deterioration 34 (10,6%). Complications/impairments following resections were associated with patient age below 3 years at operation, tumor volume above 80 cm(3), presence of hydrocephalus prior to surgery, complete resection, intervention in centers with fewer reported resections and surgery performed between 1998-2006 by univariate analysis. In contrast, the neurosurgical approach, tumor location, NF1 status as well as previous antineoplastic treatment were not associated with the frequency of complications. Regarding biopsies, open biopsies showed significantly more surgery-associated complications/impairments compared with stereotactic procedures. CONCLUSIONS: Neurosurgery-associated complications and impairments were frequent in pediatric patients with supratentorial midline LGG undergoing open surgery in the German LGG-studies. We identified six patient- and institution-associated factors that may increase the risk for surgical complications. Skills at the treating center and extent of resection should be considered appropriately prior to intervention

Neurosurgical morbidity in pediatric supratentorial midline low‐grade glioma: results from the German LGG studies

Surgical resection is a mainstay of treatment for pediatric low-grade glioma (LGG) within all current therapy algorithms, yet associated morbidity is scarcely reported. As supratentorial midline (SML) interventions are particularly challenging, we investigated the frequency of neurosurgical complications/new impairments aiming to identify their risk factors. Records were retrospectively analyzed from 318 patients with SML-LGG from successive German multicenter LGG studies, undergoing surgery between May 1998 and June 2020. Exactly 537 operations (230 resections, 167 biopsies, 140 nontumor procedures) were performed in 318 patients (54% male, median age: 7.6 years at diagnosis, 9.5 years at operation, 11% NF1, 42.5% optic pathway glioma). Surgical mortality rate was 0.93%. Applying the Drake classification, postoperative surgical morbidity was observed following 254/537 (47.3%) and medical morbidity following 97/537 (18.1%) patients with a 40.1% 30-day persistence rate for newly developed neurological deficits (65/162). Neuroendocrine impairment affected 53/318 patients (16.7%), visual deterioration 34/318 (10.7%). Postsurgical morbidity was associated with patient age <3 years at operation, tumor volume ≥80 cm3, presence of hydrocephalus, complete resection, surgery in centers with less than median reported tumor-related procedures and during the earlier study period between 1998 and 2006, while the neurosurgical approach, tumor location, NF1 status or previous nonsurgical treatment were not. Neurosurgery-associated morbidity was frequent in pediatric patients with SML-LGG undergoing surgery in the German LGG-studies. We identified patient- and institution-associated factors that may increase the risk for complications. We advocate that local multidisciplinary teams consider the planned extent of resection and surgical skills

QOL-04. Histology, treatment, and extent of pretreatment hydrocephalus are major determents of neurocognitive outcome for survivors of pediatric posterior fossa tumors - report from the German HIT-studies [Abstract]

BACKGROUND: Cognitive impairments following pediatric brain tumors are generally attributed to tumor site, surgical intervention, complications as well as to nonsurgical treatment. We investigated impairments for patients with medulloblastoma (MB), ependymoma (EP) and low-grade glioma (LGG) of the cerebellum treated within the German pediatric brain tumor network to compare and rank major determents. PATIENTS+METHODS: Following protocol treatment, 245 patients with MB (n=106), EP (n=32), and cerebellar LGG (n=107, surgery only) were examined 2 + 5 years after diagnosis using the German “Neuropsychological-Basic-Diagnostic” (NBD) tool based on the Cattell-Horn-Carroll model for intelligence. Within this retrospective study, multiple linear regression models were applied. RESULTS: The MB+EP vs. LGG-cohort differed slightly in median age at diagnosis (8.7/6.1 years) and location (cerebellar hemispheres: 8%MB+EP/49.5%LGG), while sex-ratio, grade of resection, extent of pre-operative hydrocephalus were comparable. With smaller median tumor-volume in the MB+EP vs. LGG-cohort (34.1/44.1cm3), ranges broadly overlapped. Median scores of age-appropriate tests were in the lower normal range for all patients for fluid and crystallized intelligence, selective attention, visual-spatial processing (VSP) and verbal short-term memory (median=93-103), but distinctly below for processing speed (PS), and psychomotor speed abilities (PMS) (median=65-84). Higher doses of craniospinal irradiation (>23.4Gy/23.4Gy) resulted in lower scores for most domains for MB-patients compared to LGG-patients (e.g., PS-estimate: >23.4Gy:-27.71, p=0.026/23.4Gy:-9.93, p=0.286). EP-patients (surgery+54Gy local radiation) scored better than LGG-patients except for PS (estimate:-15.65, p=0.111). Impairments were accentuated with higher degrees of hydrocephalus (estimate:-7.64, p=0.103) in patients with incomplete resection (estimate:12.23, p=0.006) for PMS both hands. CONCLUSION: Following age-adapted comprehensive treatment, survivors of a cerebellar tumor show significant impairments of PMS abilities in our trials. Our data suggest that slow growing LGG impair neurocognitive development more than local radiotherapy for ependymoma, while craniospinal irradiation compromises VSP and PS in MB. Initial symptomatic intracranial pressure remains a strong predictor for general neuropsychological impairment

Neurological manifestations in children and adolescents with neurofibromatosis type-1-implications for management and surveillance [Abstract]

INTRODUCTION: We aimed to (1) characterize the spectrum of clinical phenotypes of NF1 in a random pediatric population, (2) correlate genotype with phenotypic expression for those with a genetic diagnosis, and (3) explore radiological features of NF1 in the central nervous system (CNS) by radiomics analyses to predict clinical course. METHODS: We performed a database search in the hospital information system of the University Children′s Hospital between January 2017 and December 2020 for patients with NF1 and evaluated the clinical phenotype by retrospective chart review. RESULTS: 75 children/adolescents were identified with suspicion/clinical diagnosis of NF1 (median age 10.0 years (range, 1.1-22.6); 35 female), confirmatory revised “diagnostic criteria” were met in 57 patients at the last follow-up. Per number of documented items, major signs were detected as 73/75 café-au-lait macules, 31/63 freckling, 38/71 neurofibromas (thereof 21 plexiform neurofibromas), 18/43 optic pathway glioma, 5/66 Lisch nodules, and two patients with sphenoid dysplasia. Genetic analysis (31/75) identified pathogenic NF1 variants in 27 patients. In 20/66 cases a parent met diagnostic criteria. Cognitive symptoms included developmental delay (28/68), learning deficits (12/48), attention-deficit hyperactivity disorder (3/53), and behavior anomalies (7/63). Classical unidentified bright objects were seen in 29/43, other intracranial tumors in 7/43, and cerebrovascular abnormalities in 5/43. Analysis of imaging features of the CNS in these patients will involve lesion segmentation and radiomics features. Symptomatic/progressive low-grade glioma necessitated neurosurgical resection (4/25) and/or chemotherapy (12/25). In 10/25 neuropsychological functions were assessed by the German neuropsychological basic diagnostic instrument. Until June 30th, 2021, one patient died of progressive plexiform neurofibroma. CONCLUSIONS: A wide range of neurological manifestations, including neuropsychological deficits, should raise the suspicion of NF1 in an unselected pediatric population. We expect imaging features of the CNS to better predict the clinical course and enhance decision-making

ATRT-02. Neuropsychological function in infant atypical teratoid/rhabdoid tumor versus low-grade glioma survivors reflects tumor malignancy and multimodal treatment [Abstract]

BACKGROUND: Therapy of infants with brain tumors predisposes these patients to increased risks for cognitive sequelae, especially following radiotherapy. Neuropsychological outcome gains importance for those 40-60% of patients with an atypical teratoid/rhabdoid tumor (ATRT) who survive beyond 2 years. Still, reports on cognitive late-effects in children with ATRT are scarce compared to other pediatric brain tumor groups. We analyzed neuropsychological outcome for long-term ATRT-survivors registered in EU-RHAB and infant low-grade glioma (LGG) survivors from the SIOP-LGG 2004-study and LGG-registry. PATIENTS+METHODS: Age at diagnosis of both cohorts was 0-36 months. ATRT-patients (n=13) treated with up to 54Gy radiotherapy (median age 22 months (±7.1)) were evaluated with the “ATRT-Neuropsychology” tool based on SIOPE-BTG QoS-Group recommendations at median 6.8 years (±2.8) after diagnosis. LGG-patients (n=15) treated without radiotherapy (4/15 with chemotherapy) were analyzed with the German “Neuropsychological-Basic-Diagnostic” tool 5.2 years (±0.6) post-diagnosis. RESULTS: The ATRT- vs. LGG-cohorts were comparable for median age at diagnosis, sex-ratio and tumor-localization, though they differed slightly in median age at assessment (9.5/7.2 years (±2.5/1.1)). Results of age-appropriate tests showed increased impairments for ATRT-patients in fluid intelligence (FI) (p=.006, d=1.214) and in visual-spatial processing (VSP) (p<.001, d=2.233) compared to LGG-patients. The median for neuropsychological test results of ATRT-patients spanned from considerably below the normal to the lower normal range (median=65-90), while results of LGG-patients were mostly in the lower normal range (median=83-103). Results for psychomotor speed abilities (PMS) were distinctly below the norm for both patient groups (p=.002-.007). CONCLUSION: Infant ATRT- and LGG-patients develop significant impairments in PMS abilities following multimodal treatment. Long-term survivors of ATRT suffer from additional FI and VSP deficits. Our data suggest that high malignancy requiring multimodal treatment determines the inferior cognitive outcome for the ATRT-cohort. Long-term neuropsychological monitoring (and treatment options) should be implemented as standard of care in ATRT- and LGG-trials

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology