Corrigendum: Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists?

[This corrects the article DOI: 10.3389/fnmol.2024.1268038.].

Spliced FKBP51s predicts unfavorable prognosis of glioblastoma patients.

The primary treatment for glioblastoma (GBM) is removing the tumor mass as defined by magnetic resonance imaging (MRI). However, MRI has limited diagnostic and predictive value. Tumor-associated macrophages (TAMs) are abundant in GBM microenvironment (TME) and are found in peripheral blood (PB). FKBP51 expression, with its canonical and spliced isoforms, is constitutive in immune cells and aberrant in GBM. Spliced FKBP51s supports M2-polarization. To find an immunological signature that combined with MRI could advance in diagnosis, we immunophenotyped the macrophages of TME and PB from 37 GBM patients using FKBP51s and classical M1-M2 markers. We also determined the tumor levels of FKBP51s, PD-L1, and HLA-DR. Tumors expressing FKBP51s showed an increase in various M2 phenotypes and Tregs in PB, indicating immunosuppression. Tumors expressing FKBP51s also activated STAT3 and were associated with reduced survival. Correlative studies with MRI and tumor/macrophages co-cultures allowed to interpret TAMs. Tumor volume correlated with M1 infiltration of TME. Co-cultures with spheroids produced M1 polarization, suggesting that M1 macrophages may infiltrate alongside cancer stem-cells. Co-cultures of adherent cells developed the M2 phenotype CD163/FKBP51s expressing pSTAT6, a transcription factor enabling migration and invasion. In patients with recurrences, increased counts of CD163/FKBP51s monocyte/macrophages in PB correlated with callosal infiltration and was accompanied by a concomitant decrease in TME-infiltrating M1 macrophages. PB PD-L1/FKBP51s connoted necrotic tumors. In conclusion, FKBP51s identifies a GBM subtype that significantly impairs the immune system. Moreover, FKBP51s marks PB macrophages associated with MRI features of glioma malignancy that can aid in patient monitoring.

Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists?

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, established new approaches to both CNS tumor nomenclature and grading, emphasizing the importance of integrated diagnoses and layered reports. This edition increased the role of molecular diagnostics in CNS tumor classification while still relying on other established approaches such as histology and immunohistochemistry. Moreover, it introduced new tumor types and subtypes based on novel diagnostic technologies such as DNA methylome profiling. Over the past decade, molecular techniques identified numerous key genetic alterations in CSN tumors, with important implications regarding the understanding of pathogenesis but also for prognosis and the development and application of effective molecularly targeted therapies. This review summarizes the major changes in the 2021 fifth edition classification of pediatric CNS tumors, highlighting for each entity the molecular alterations and other information that are relevant for diagnostic, prognostic, or therapeutic purposes and that patients' and oncologists' need from a pathology report.

Intensive training programme for ultrasound-guided minimally invasive synovial tissue biopsy on knees and wrists in different phases of inflammation.

OBJECTIVES: To develop an intensive training programme for ultrasound (US)-guided synovial tissue (ST) biopsy on knees and wrists in inflammatory arthritis and to assess the learning curve, patient tolerability, sample quality and trainees' expectations. METHODS: Active or remission rheumatoid arthritis patients were enrolled. Nine trainees joined the 4-month programme in a centre experienced in performing US-guided ST biopsies consisting of four sequential phases: (1) observation, (2) performance of guided step-by-step phases, (3) execution of the whole procedure on paired joints (knees or wrists) of the same patient in parallel with the trainer and (4) performance of the procedure autonomously. Sample representativity was assessed by histology, and procedure-related adverse events were recorded. Before and after the programme, trainees' expectations and perceptions were collected. RESULTS: 328 ST biopsy procedures were included. The rate of trainees' informative samples was: (1) comparable to the trainers in active and remission knees, but lower in active wrists (70% for trainees vs 100% for trainers, p=0.06) in phase 3; (2) excellent on active knees and wrists (91.9% and 90.9% respectively) but lower (77.6%, p=0.0089) on remission knees in phase 4. Procedures performed by trainees did not affect patient tolerability. Trainees' expectations about procedure-related invasiveness and pain infliction decreased while the difficulty of procedure execution on active wrists and remission knees remained perceived as moderately difficult. CONCLUSIONS: This intensive training programme develops advanced skills in the performance of US-guided ST biopsy on knees and wrists, yielding high-quality specimens available for basic and translational studies on inflammatory joint diseases.

Trouillas's Grading and Post-Surgical Tumor Residue Assessment in Pituitary Adenomas: The Importance of the Multidisciplinary Approach.

BACKGROUND: We aim to assess the role of a multidisciplinary approach in pituitary adenomas (PitNETs) classification, evaluate criteria concordance, and compare intraoperative assessments with post-operative MRIs for tumor remnants. METHODS: Clinical, radiological, histological, and intra- and post-operative data of the treated PitNETs were extracted from prospectively created records. PitNETs were graded according to Trouillas, and the evaluation of the tumor remnants was recorded. RESULTS: Of 362 PitNETs, 306 underwent surgery, with Trouillas grading assigned to 296. Eight-nine radiologically non-invasive PitNETs progressed to grades 1b (27), 2a (42), or 2b (20) due to proliferative or surgical invasiveness criteria. Twenty-six radiologically invasive tumors were graded 2b due to proliferative criteria. Surgical resection details and post-surgical MRI findings revealed that residual tumors were more common in grades 2a and 2b. During surgery, small tumor remnants were documented in 14 patients which were not visible on post-surgical MRI. Post-surgical MRIs identified remnants in 19 PitNETs not seen during surgery, located in lateral recesses of the sella (4), retrosellar (2), or suprasellar regions (7), along the medial wall of the cavernous sinus (6). CONCLUSIONS: The Pituitary Board allows for the correct grading of PitNETs to be obtained and an accurate identification of high-risk patients who should undergo closer surveillance due to tumor remnants.

Giant Congenital Hemangioma of the Skull: Prenatal Diagnosis and Multimodal Endovascular and Surgical Management.

Introduction: calvarial capillary hemangiomas are vascular tumors rarely seen in newborns. Differential diagnosis may be not straightforward on imaging studies and the management depends on patient and lesion characteristics. Case report: we present the case of a large congenital intracranial extra-axial lesion detected by routine prenatal US screening, a giant calvarial congenital hemangioma, treated with a multimodal strategy. Neonatal MR showed a hemorrhagic solid lesion, causing compression of brain tissue. Conservative treatment was attempted, but a one-month follow-up MR showed growth of the lesion with increased mass effect. Pre-operative endovascular embolization and surgical resection were performed. The pathology was consistent with intraosseous capillary hemangioma. The post-operative course was uneventful. At the 8-month follow-up, the patient had no clinical deficits and MR showed complete resection of the lesion. At the 13-month follow-up, the patient was asymptomatic, showing normal neurological examination and psychophysical development. Conclusions: although wait-and-see policy is feasible for small and asymptomatic lesions, radical resection is indicated when the mass is large, thus causing severe mass effect on the brain. Hypervascularization of the tumor may be responsible for hemorrhagic complications and severe anemia. On these grounds, endovascular treatment is feasible and effective to reduce hemorrhagic complications.

The Multibiomarker Acro-TIME Score Predicts fg-SRLs Response: Preliminary Results of a Retrospective Acromegaly Cohort.

CONTEXT: The prompt control of acromegaly is a primary treatment aim for reducing related disease morbidity and mortality. First-generation somatostatin receptor ligands (fg-SRLs) are the cornerstone of medical therapies. A non-negligible number of patients do not respond to this treatment. Several predictors of fg-SRL response were identified, but a comprehensive prognostic model is lacking. OBJECTIVE: We aimed to design a prognostic model based on clinical and biochemical parameters, and pathological features, including data on immune tumor microenvironment. METHODS: A retrospective, monocenter, cohort study was performed on 67 medically naïve patients with acromegaly. Fifteen clinical, pathological, and radiological features were collected and analyzed as independent risk factors of fg-SRLs response, using univariable and multivariable logistic regression analyses. A stepwise selection method was applied to identify the final regression model. A nomogram was then obtained. RESULTS: Thirty-seven patients were fg-SRLs responders. An increased risk to poor response to fg-SRLs were observed in somatotropinomas with absent/cytoplasmatic SSTR2 expression (OR 5.493 95% CI 1.19-25.16, P = .028), with low CD68+/CD8+ ratio (OR 1.162, 95% CI 1.01-1.33, P = .032). Radical surgical resection was associated with a low risk of poor fg-SRLs response (OR 0.106, 95% CI 0.025-0.447 P = .002). The nomogram obtained from the stepwise regression model was based on the CD68+/CD8+ ratio, SSTR2 score, and the persistence of postsurgery residual tumor and was able to predict the response to fg-SRLs with good accuracy (area under the curve 0.85). CONCLUSION: Although our predictive model should be validated in prospective studies, our data suggest that this nomogram may represent an easy to use tool for predicting the fg-SRL outcome early.

Pediatric craniopharyngiomas: magnetic resonance imaging assessment for hypothalamus-pituitary axis dysfunction and outcome prediction.

BACKGROUND: In adamantinomatous craniopharyngiomas, tumor topographical categories, cystic component volume, and magnetic resonance signal intensity may impact prognosis. OBJECTIVE: To identify magnetic resonance imaging (MRI) variables associated with pituitary-hypothalamic axis dysfunction and predictive of outcome in children with cystic adamantinomatous craniopharyngiomas. MATERIALS AND METHODS: We evaluated 40 preoperative MRIs of adamantinomatous craniopharyngiomas to classify tumor topography, volume, and signal intensity of the cystic components and peritumoral edema. Volumes and normalized signal intensity minimum values were extracted from coronal T2-weighted images (nT2min). Radiological variables were compared to pituitary-hypothalamic axis dysfunction-related clinical data and surgical outcomes. RESULTS: Adamantinomatous craniopharyngiomas were categorized into five topographic classes (12 patients, sellar-suprasellar; seven patients, pseudo-intraventricular; six patients, strict intraventricular; 14 patients, secondary intraventricular; one patient, not strict intraventricular). All cases exhibited a predominant (30 patients, 80%) or total (10 patients, 20%) cystic tumor component and displayed low nT2min percentage values compared to cerebrospinal fluid (42.3% [interquartile range 28.4-54.6%]). Significant associations between tumor topographic classes and pituitary dysfunction (P<0.001), and between peritumoral edema and hypothalamic dysfunction (P<0.001) were found. Considering extent of surgical removal and tumor relapse, volume of the cystic tumor component displayed a positive correlation (P=0.002; r=0.48; P=0.02; r=0.36), while nT2min intensity values exhibited a negative correlation (P=0.01; r= - 0.40; P=0.028; r= - 0.34). CONCLUSION: Severe hypothalamic-pituitary axis dysfunction is associated with tumors along the pituitary stalk and peritumoral edema. Tumor invasion of the third ventricle, tight adherence to the hypothalamus, larger volumes, and lower nT2min intensity of the tumor cystic component are independent predictors of extent of adamantinomatous craniopharyngioma excision and recurrence.

PATZ1-Rearranged Tumors of the Central Nervous System: Characterization of a Pediatric Series of Seven Cases.

PATZ1-rearranged sarcomas are well-recognized tumors as part of the family of round cell sarcoma with EWSR1-non-ETS fusions. Whether PATZ1-rearranged central nervous system (CNS) tumors are a distinct tumor type is debatable. We thoroughly characterized a pediatric series of PATZ1-rearranged CNS tumors by chromosome microarray analysis (CMA), DNA methylation analysis, gene expression profiling and, when frozen tissue is available, optical genome mapping (OGM). The series consisted of 7 cases (M:F=1.3:1, 1-17 years, median 12). On MRI, the tumors were supratentorial in close relation to the lateral ventricles (intraventricular or iuxtaventricular), preferentially located in the occipital lobe. Two major histologic groups were identified: one (4 cases) with an overall glial appearance, indicated as "neuroepithelial" (NET) by analogy with the corresponding methylation class (MC); the other (3 cases) with a predominant spindle cell sarcoma morphology, indicated as "sarcomatous" (SM). A single distinct methylation cluster encompassing both groups was identified by multidimensional scaling analysis. Despite the epigenetic homogeneity, unsupervised clustering analysis of gene expression profiles revealed 2 distinct transcriptional subgroups correlating with the histologic phenotypes. Interestingly, genes implicated in epithelial-mesenchymal transition and extracellular matrix composition were enriched in the subgroup associated to the SM phenotype. The combined use of CMA and OGM enabled the identification of chromosome 22 chromothripsis in all cases suitable for the analyses, explaining the physical association of PATZ1 to EWSR1 or MN1. Six patients are currently disease-free (median follow-up 30 months, range 12-92). One patient of the SM group developed spinal metastases at 26 months from diagnosis and is currently receiving multimodal therapy (42 months). Our data suggest that PATZ1-CNS tumors are defined by chromosome 22 chromothripsis as causative of PATZ1 fusion, show peculiar MRI features (eg, relation to lateral ventricles, supratentorial frequently posterior site), and, although epigenetically homogenous, encompass 2 distinct histologic and transcriptional subgroups.

Case Report: Remarkable breakthrough: successful treatment of a rare intracranial mesenchymal, FET::CREB fusion-positive tumor treated with patient-tailored multimodal therapy.

Background: Intracranial mesenchymal tumors are a rare type of neoplasm (0.3% of all soft tissue tumors) characterized by a fusion of a FET family gene (usually EWSR1, rarely FUS) to CREB family genes (CREB1, ATF1, and CREM) with a slow-growing and favorable prognosis. Mesenchymal tumors are most frequently localized in the subcutaneous tissue (typically in the limbs and hands) of young adults and have rarely been diagnosed in the central nervous system. Surgery is the gold standard treatment; adjuvant radiation therapy and chemotherapy with sarcoma-based regimens have been used in rare cases when complete surgical excision was not recommended. In terms of prognosis, these tumors show a tendency for local relapse. The longest patient outcomes reported in the literature are five years. Case description: This case describes a 27-year-old woman with unconventional extracranial metastatic sites of myxoid intracranial mesenchymal tumor FET::CREB fusion-positive and high expression of PD-1 (40%) and PD-L1 (30%). Based on clinical, molecular, and histological characteristics, she underwent various local and systemic therapies, including surgery, proton beam therapy, the use of immune checkpoint inhibitors, and chemotherapy. These treatments led to a complete remission of the disease after eight years from tumor diagnosis. Conclusions: Our case sheds light on the importance of precision medicine and tailored therapy to explore new treatment opportunities for rare or unknown tumor entities.

Spinal Epidural Atypical Meningioma: Case Report and Review of the Literature.

Spinal atypical meningiomas are rare, and those whose main extension is in the epidural space are anecdotal. Here, we report a case of a young woman presenting with sensory disturbances and a radiological diagnosis of a dorsal epidural sleeve-like mass. The surgical resection of the lesion allowed the decompression of the spinal cord and led to the histopathological diagnosis of atypical meningioma. At the 3-month follow-up, her neurological recovery was complete. Because of the gross total removal of the lesion, adjuvant radiotherapy was not performed: At the 2-year follow-up, no recurrence of disease was detected. A comprehensive literature review was performed, and just two more case reports on epidural atypical meningiomas were found in the English literature. Through this case report and literature review, we described a rare manifestation of spinal meningioma that entered into a differential diagnosis for extradural spinal lesions, such as secondary malignancies.

Aggressive PitNETs and Potential Target Therapies: A Systematic Review of Molecular and Genetic Pathways.

Recently, advances in molecular biology and bioinformatics have allowed a more thorough understanding of tumorigenesis in aggressive PitNETs (pituitary neuroendocrine tumors) through the identification of specific essential genes, crucial molecular pathways, regulators, and effects of the tumoral microenvironment. Target therapies have been developed to cure oncology patients refractory to traditional treatments, introducing the concept of precision medicine. Preliminary data on PitNETs are derived from preclinical studies conducted on cell cultures, animal models, and a few case reports or small case series. This study comprehensively reviews the principal pathways involved in aggressive PitNETs, describing the potential target therapies. A search was conducted on Pubmed, Scopus, and Web of Science for English papers published between 1 January 2004, and 15 June 2023. 254 were selected, and the topics related to aggressive PitNETs were recorded and discussed in detail: epigenetic aspects, membrane proteins and receptors, metalloprotease, molecular pathways, PPRK, and the immune microenvironment. A comprehensive comprehension of the molecular mechanisms linked to PitNETs' aggressiveness and invasiveness is crucial. Despite promising preliminary findings, additional research and clinical trials are necessary to confirm the indications and effectiveness of target therapies for PitNETs.

Treatment of Clival Chordomas: A 20-Year Experience and Systematic Literature Review.

Clival chordomas are rare but aggressive skull base tumors that pose significant treatment challenges and portend dismal prognosis. The aim of this study was to highlight the advantages and limitations of available treatments, to furnish prognostic indicators, and to shed light on novel therapeutic strategies. We conducted a retrospective study of clival chordomas that were surgically treated at our institution from 2003 to 2022; for comparison purposes, we provided a systematic review of published surgical series and, finally, we reviewed the most recent advancements in molecular research. A total of 42 patients underwent 85 surgeries; median follow-up was 15.8 years, overall survival rate was 49.9% at 10 years; meanwhile, progression-free survival was 26.6% at 10 years. A significantly improved survival was observed in younger patients (<50 years), in tumors with Ki67 ≤ 5% and when adjuvant radiotherapy was performed. To conclude, clival chordomas are aggressive tumors in which surgery and radiotherapy play a fundamental role while molecular targeted drugs still have an ancillary position. Recognizing risk factors for recurrence and performing a molecular characterization of more aggressive lesions may be the key to future effective treatment.

MRI and Trouillas' grading system of pituitary tumors: the usefulness of T2 signal intensity volumetric values.

PURPOSE: To classify pituitary macroadenomas according to the Trouillas' grading system; to compare this grading system with T2 values of volumetric signal intensity to determine T2 values able to predict the final grade. METHODS: A total of 106 patients with macroadenomas were grouped according to the grading system score combining proliferation and invasiveness criteria of Trouillas' classification. Normalized volumetric signal intensity values were extracted from coronal T2-weighted images (nT2mean, nT2Max, nT2min) and were compared with the final grading score system. RESULTS: Thirty-three patients were in grade 1a (non-invasive, non-proliferative tumors), 17 patients in grade 1b (non-invasive, proliferative tumors), 36 patients in grade 2a (invasive, non-proliferative tumors), and 20 patients in grade 2b (invasive, proliferative tumors). No patient was in grade 3 (metastatic tumors). nT2Max and nT2min were the best quantitative values to discriminate invasive from non-invasive grades; in invasive grades, nT2Max intensity values were higher, and nT2min intensity values were lower than in non-invasive grades. Receiver operating characteristic analysis of nT2 values showed that nT2min values had a better diagnostic performance than nT2Max values because they allowed differentiating with a moderate accuracy invasive tumors (2a or 2b grades) from both non-invasive proliferative tumors (1b) and non-invasive-non proliferative tumors (1a) (2a vs 1b: AUCnT2min = 0.78, 2b vs 1b: AUCnT2min = 0.72, 2a vs 1a: AUCnT2min = 0.72, 2b vs 1a AUCnT2min = 0.69). CONCLUSION: Volumetric nT2Max and nT2min values of MRI might be practical and non-invasive markers for assessing tumor invasiveness although nT2 min signal intensity values have more effects in discriminating tumor's invasive behavior.

Magnetic resonance imaging-derived parameters to predict response to regorafenib in recurrent glioblastoma.

PURPOSE: Regorafenib is a multikinase inhibitor, approved as a preferred regimen for recurrent glioblastoma (rGB). Although its effects on prolonging survival could seem modest, it is still unclear whether a subset of patients, potentially identifiable by imaging biomarkers, might experience a more substantial positive effect. Our aim was to evaluate the potential value of magnetic resonance imaging-derived parameters as non-invasive biomarkers to predict response to regorafenib in patients with rGB. METHODS: 20 patients with rGB underwent conventional and advanced MRI at diagnosis (before surgery), at recurrence and at first follow-up (3 months) during regorafenib. Maximum relative cerebral blood volume (rCBVmax) value, intra-tumoral susceptibility signals (ITSS), apparent diffusion coefficient (ADC) values, and contrast-enhancing tumor volumes were tested for correlation with response to treatment, progression-free survival (PFS), and overall survival (OS). Response at first follow-up was assessed according to Response Assessment in Neuro-Oncology (RANO) criteria. RESULTS: 8/20 patients showed stable disease at first follow-up. rCBVmax values of the primary glioblastoma (before surgery) significantly correlated to treatment response; specifically, patients with stable disease displayed higher rCBVmax compared to progressive disease (p = 0.04, 2-group t test). Moreover, patients with stable disease showed longer PFS (p = 0.02, 2-group t test) and OS (p = 0.04, 2-group t test). ITSS, ADC values, and contrast-enhancing tumor volumes showed no correlation with treatment response, PFS nor OS. CONCLUSION: Our results suggest that rCBVmax of the glioblastoma at diagnosis could serve as a non-invasive biomarker of treatment response to regorafenib in patients with rGB.

Multidisciplinary management of difficult/aggressive growth-hormone pituitary neuro-endocrine tumors.

Growth Hormone-secreting adenomas exhibits variable biological behavior and heterogeneous natural history, ranging from small adenomas and mild disease, to invasive and aggressive neoplasms with more severe clinical picture. Patients not cured or controlled after neurosurgical and first-generation somatostatin receptor ligands (SRL) therapy could require multiple surgical, medical and/or radiation treatments to achieve disease control. To date, no clinical, laboratory, histopathological, or neuroradiological markers are able to define the aggressiveness or predict the disease prognosis in patients with acromegaly. Therefore, the management of these patients requires careful evaluation of laboratory assessments, diagnostic criteria, neuroradiology examinations, and neurosurgical approaches to choose an effective and patient-tailored medical therapy. A multidisciplinary approach is particularly useful in difficult/aggressive acromegaly to schedule multimodal treatment, which includes radiation therapy, chemotherapy with temozolomide and other, recent emerging treatments. Herein, we describe the role of the different members of the multidisciplinary team according to our personal experience; a flow-chart for the therapeutic approach of difficult/aggressive acromegaly patients is proposed.

CD68+ and CD8+ immune cells are associated with the growth pattern of somatotroph tumors and response to first generation somatostatin analogs.

Somatotropinomas are pituitary tumors with a heterogenous clinical behavior. The tumor microenvironment regulates the interaction between tumor cells and the host immune system, potentially modulating tumor behavior. Here, we aimed to investigate the tumor immune infiltration in a cohort of medically naïve acromegaly patients. A retrospective, monocenter study was designed to analyze the presence of CD3+, CD20+, CD138+, CD4+, CD8+, CD68+ immune cells in samples of somatotropinomas and their prognostic significance on tumor behavior and response to first generation somatostatin analogs (fg-SSA). Thirty-six patients (23 females) were included in the study. Macroadenomas were identified in 23 cases: 12 with cavernous sinus invasion. The number of CD8+ lymphocytes positively correlated with CD4+ lymphocytes (p = .05, r:0.245) and with CD68+ macrophages (p = .01, r = 0.291). The CD8+/CD4+ ratio inversely correlated with CD68+/CD8+ ratio (p < .001, r = -0.626). CD68+ macrophages positively correlated with tumor size (maximum diameter p = .003, r = 0.574; volume p = .009, r = 0.566) and were more numerous in somatotropinomas with Ki-67 > 3% (median 65/HPF, IQR:15), compared to cases with Ki67 < 3% (median 50/HPF, IQR:22, p < .001). CD8+ and CD138+ lymphocytes were more numerous in cases responsive to fg-SSA (respectively median 18/HPF IQR:18 and median 8/HPF IQR: 6.5) as compared to fg-SSA nonresponsive cases (median 14.5/HPF IQR:40 p = .03; median 3.5/HPF IQR: 14 p = .03). CD8+ lymphocytes act as single predictor of response to fg-SSA, independently from age, GH and IGF-I levels, tumor dimension and invasion. Our results support that lymphocytes and macrophages generate an immune network in somatotropinomas and the characteristic of the immune infiltrate may predict treatment outcome.

Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology.

The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.