Hjernetegn.dk-The Danish Central Nervous System Tumor Awareness Initiative Digital Decision Support Tool: Design and Implementation Report.

BACKGROUND: Childhood tumors in the central nervous system (CNS) have longer diagnostic delays than other pediatric tumors. Vague presenting symptoms pose a challenge in the diagnostic process; it has been indicated that patients and parents may be hesitant to seek help, and health care professionals (HCPs) may lack awareness and knowledge about clinical presentation. To raise awareness among HCPs, the Danish CNS tumor awareness initiative hjernetegn.dk was launched. OBJECTIVE: This study aims to present the learnings from designing and implementing a decision support tool for HCPs to reduce diagnostic delay in childhood CNS tumors. The aims also include decisions regarding strategies for dissemination and use of social media, and an evaluation of the digital impact 6 months after launch. METHODS: The phases of developing and implementing the tool include participatory co-creation workshops, designing the website and digital platforms, and implementing a press and media strategy. The digital impact of hjernetegn.dk was evaluated through website analytics and social media engagement. IMPLEMENTATION (RESULTS): hjernetegn.dk was launched in August 2023. The results after 6 months exceeded key performance indicators. The analysis showed a high number of website visitors and engagement, with a plateau reached 3 months after the initial launch. The LinkedIn campaign and Google Search strategy also generated a high number of impressions and clicks. CONCLUSIONS: The findings suggest that the initiative has been successfully integrated, raising awareness and providing a valuable tool for HCPs in diagnosing childhood CNS tumors. The study highlights the importance of interdisciplinary collaboration, co-creation, and ongoing community management, as well as broad dissemination strategies when introducing a digital support tool.

Regional Variability in Survival for Patients Diagnosed with Selected Central Nervous System Tumours in Canada.

Canada's decentralized healthcare system may lead to regional disparities in survival among Canadians diagnosed with central nervous system (CNS) tumours. We identified 50,670 patients diagnosed with a first-ever primary CNS tumour between 2008 and 2017 with follow-up until 31 December 2017. We selected the four highest incidence histologies and used proportional hazard regression to estimate hazard ratios (HRs) for five regions (British Columbia, Prairie Provinces, Ontario, Atlantic Provinces and the Territories), adjusting for sex, tumour behaviour and patient age. Ontario had the best survival profile for all histologies investigated. The Atlantic Provinces had the highest HR for glioblastoma (HR = 1.26, 95% CI: 1.18-1.35) and malignant glioma not otherwise specified (NOS) (Overall: HR = 1.87, 95% CI:1.43-2.43; Pediatric population: HR = 2.86, 95% CI: 1.28-6.39). For meningioma, the Territories had the highest HR (HR = 2.44, 95% CI: 1.09-5.45) followed by the Prairie Provinces (HR = 1.52, 95% CI: 1.38-1.67). For malignant unclassified tumours, the highest HRs were in British Columbia (HR = 1.45, 95% CI: 1.22-1.71) and the Atlantic Provinces (HR = 1.40, 95% CI: 1.13-1.74). There are regional differences in the survival of CNS patients at the population level for all four specific histological types of CNS tumours investigated. Factors contributing to these observed regional survival differences are unknown and warrant further investigation.

The Spectrum of Central Nervous System Tumors at a Tertiary Care Center Primarily Serving a Rural Population.

Background Central nervous system (CNS) tumors cause significant mortality and morbidity in all age groups. There was no data about the histological spectrum of all CNS tumors in the tertiary care center serving primarily the rural population of Uttar Pradesh. Aims and objectives The present study aimed to describe the histopathological spectrum of all CNS tumors reported in a rural tertiary care center at Saifai, Uttar Pradesh. It also aimed to provide an overview of the descriptive epidemiology of CNS tumors. Material and methods This was a retrospective, cross-sectional study. The study duration was three years. A total of 115 cases of CNS tumors were studied during that period. Cases were classified according to their histological types, and results were analyzed. Results The most common histological group was neuroepithelial tumors, with 53 cases (46.08%). This group had 36 cases of astrocytic tumors (31.3%), three cases of oligodendroglial tumors (2.6%), five cases of oligoastrocytic tumors (4.34%), five cases of ependymal tumors (4.34%), and four cases of embryonal tumors (3.47%). The second most common tumor was meningeal tumors, with 32 cases (27.82%). The male/female ratio (M/F) ratio was 0.7. Females were found to be more affected by almost all histologic categories. Most meningiomas (89.6%) were of World Health Organization (WHO) grade I (26 cases out of 29). Astrocytic tumors showed WHO grade I, II, III, and IV tumors in two cases (5.5%), twelve cases (33.3%), four cases (11.1%), and eighteen cases (50%), respectively. In the younger age group (0-20 years), ependymoma and medulloblastoma were most common, followed by pilocytic astrocytoma and schwannoma. Conclusion In this region, neuroepithelial tumors were seen more commonly than meningioma. Females were found to be more affected by CNS tumors. This study has provided relevant data, which can be used for research and better patient management. Further studies with the incorporation of advanced radiological investigation and immunohistochemistry have been recommended.

Utility of combining OLIG2 and SOX10 IHC expression in CNS tumours: promising biomarkers for subtyping paediatric- and adult-type gliomas.

AIMS: The SOX10 transcription factor is important for the maturation of oligodendrocytes involved in central nervous system (CNS) myelination. Currently, very little information exists about its expression and potential use in CNS tumour diagnoses. The aim of our study was to characterize the expression of SOX10 in a large cohort of CNS tumours and to evaluate its potential use as a biomarker. METHODS: We performed immunohistochemistry (IHC) for SOX10 and OLIG2 in a series of 683 cases of adult- and paediatric-type CNS tumours from different subtypes. The nuclear immunostaining results for SOX10 and OLIG2 were scored as positive (≥10% positive tumour cells) or negative. RESULTS: OLIG2 and SOX10 were positive in diffuse midline gliomas (DMG), H3-mutant, and EZHIP-overexpressed. However, in all DMG, EGFR-mutant, SOX10 was constantly negative. In diffuse paediatric-type high-grade gliomas (HGG), all RTK1 cases were positive for both OLIG2 and SOX10. RTK2 cases were all negative for both OLIG2 and SOX10. MYCN cases variably expressed OLIG2 and were all immunonegative for SOX10. In glioblastoma, IDH-wildtype, OLIG2 was mostly positive, but SOX10 was variably expressed, depending on the epigenetic subtype. All circumscribed astrocytic gliomas were positive for both OLIG2 and SOX10 except pleomorphic xanthoastrocytomas, astroblastomas, MN1-altered, and subependymal giant cell astrocytomas. SOX10 was negative in ependymomas, meningiomas, pinealoblastomas, choroid plexus tumours, intracranial Ewing sarcomas, and embryonal tumours except neuroblastoma, FOXR2-activated. CONCLUSION: To conclude, SOX10 can be incorporated into the IHC panel routinely used by neuropathologists in the diagnostic algorithm of embryonal tumours and for the subtyping of paediatric and adult-type HGG.

Feasibility and antitumour activity of the FGFR inhibitor erdafitnib in three paediatric CNS tumour patients.

Alterations of the fibroblast growth factor (FGF) signalling pathway are increasingly recognized as frequent oncogenic drivers of paediatric brain tumours. We report on three patients treated with the selective FGFR1-4 inhibitor erdafitinib. Two patients were diagnosed with a posterior fossa ependymoma group A (PFA EPN) and one with a low-grade glioma (LGG), harbouring FGFR3/FGFR1 overexpression and an FGFR1 internal tandem duplication (ITD), respectively. While both EPN patients did not respond to erdafitinib treatment, the FGFR1-ITD-harbouring tumour showed a significant decrease in tumour volume and contrast enhancement throughout treatment. The tumour remained stable 6 months after treatment discontinuation.

The effectiveness and safety of proton beam radiation therapy in children and young adults with Central Nervous System (CNS) tumours: a systematic review.

BACKGROUND: Central nervous system (CNS) tumours account for around 25% of childhood neoplasms. With multi-modal therapy, 5-year survival is at around 75% in the UK. Conventional photon radiotherapy has made significant contributions to survival, but can be associated with long-term side effects. Proton beam radiotherapy (PBT) reduces the volume of irradiated tissue outside the tumour target volume which may potentially reduce toxicity. Our aim was to assess the effectiveness and safety of PBT and make recommendations for future research for this evolving treatment. METHODS: A systematic review assessing the effects of PBT for treating CNS tumours in children/young adults was undertaken using methods recommended by Cochrane and reported using PRISMA guidelines. Any study design was included where clinical and toxicity outcomes were reported. Searches were to May 2021, with a narrative synthesis employed. RESULTS: Thirty-one case series studies involving 1731 patients from 10 PBT centres were included. Eleven studies involved children with medulloblastoma / primitive neuroectodermal tumours (n = 712), five ependymoma (n = 398), four atypical teratoid/rhabdoid tumour (n = 72), six craniopharyngioma (n = 272), three low-grade gliomas (n = 233), one germ cell tumours (n = 22) and one pineoblastoma (n = 22). Clinical outcomes were the most frequently reported with overall survival values ranging from 100 to 28% depending on the tumour type. Endocrine outcomes were the most frequently reported toxicity outcomes with quality of life the least reported. CONCLUSIONS: This review highlights areas of uncertainty in this research area. A well-defined, well-funded research agenda is needed to best maximise the potential of PBT. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-CRD42016036802.

CSF cytology of common primary CNS neoplasms categorized by CNS WHO 2021.

OBJECTIVE: The detection of neoplastic cells in cerebral spinal fluid (CSF) is pivotal for the management of patients with central nervous system (CNS) tumours. This article delves into the CSF cytological characteristics of common CNS neoplasms, aligning with the 2021 World Health Organization (WHO) classification of CNS tumours. METHODS: A retrospective review of CSF specimens positive for primary CNS neoplasms was performed at three tertiary medical centres. Only cases that had histopathologic confirmation and/or molecular workup were included. RESULTS: Common primary CNS neoplasms seen in CSF cytology specimens include medulloblastoma, (non-WNT/non-SHH as well as SHH-activated and TP53 mutant), pineoblastoma, atypical teratoid/rhabdoid tumour (AT/RT), IDH-wildtype glioblastoma, and primary diffuse large B-cell lymphoma of the CNS. Ependymomas and germinomas can also have CSF involvement but are less common. Although the typical histologic architecture of these tumours may not be preserved in the CSF, unique cytomorphologic features such as nuclear moulding, nuclear pleomorphism, rhabdoid cells, prominent nucleoli and rosette formation can still be appreciated. CONCLUSION: Adopting the updated terminology and correlating cytologic observations with molecular findings will streamline the diagnostic process, reducing the complexities and ambiguities pathologists often encounter when analysing CSF specimens for potential primary CNS neoplasms.

Unveiling The Neuropathology Tumour Landscape: 10-Year Statistical Analysis With Global Comparison - Single Centre Experience.

Introduction: Central nervous system (CNS) tumours represent a significant public health issue worldwide, and their incidence and distribution vary across different populations. Although studies on CNS tumours have been conducted in various countries, there is a lack of information regarding their patterns in Macedonia. Therefore, this study is aimed at investigating the distribution, histopathological types and subtypes and demographic features of CNS tumours in our country. Materials and Methods: A cross sectional study was conducted using the electronic database of the Institute of Pathology - Medical Faculty, University "Ss. Cyril and Methodius" in Skopje which contains data from 3286 received and analysed surgical specimens, mainly from the University Clinic of Neurosurgery in Skopje, and a smaller number of surgical specimens from the University Surgical Centre "St. Naum Ohridski" in Skopje between 2012 and 2022. The collected and analysed data includes patient age, sex and histopathological types and subtypes of the tumours. Results: The majority of CNS tumours were diagnosed in adults aged between 50-70, with a male to female ratio of 1.5:1. The most common location of the tumours was the cerebrum, followed by the pituitary gland and cerebellum. The most frequent histological groups were gliomas, with glioblastoma as the most common diagnosis, followed by meningiomas. Conclusion: Following a detailed and thorough review of the CNS tumours in our study, we can conclude that the R. of Macedonia follows global statistics and trends regarding brain tumours.

Childhood and Adolescent Central Nervous System Tumours in Spain: Incidence and Survival over 20 Years: A Historical Baseline for Current Assessment.

BACKGROUND: Central nervous system (CNS) neoplasms are highly frequent solid tumours in children and adolescents. While some studies have shown a rise in their incidence in Europe, others have not. Survival remains limited. We addressed two questions about these tumours in Spain: (1) Is incidence increasing? and (2) Has survival improved? METHODS: This population-based study included 1635 children and 328 adolescents from 11 population-based cancer registries with International Classification of Childhood Cancer Group III tumours, incident in 1983-2007. Age-specific and age-standardised (world population) incidence rates (ASRws) were calculated. Incidence time trends were characterised using annual percent change (APC) obtained with Joinpoint. Cases from 1991 to 2005 (1171) were included in Kaplan-Meier survival analyses, and the results were evaluated with log-rank and log-rank for trend tests. Children's survival was age-standardised using: (1) the age distribution of cases and the corresponding trends assessed with Joinpoint; and (2) European weights for comparison with Europe. RESULTS: ASRw 1983-2007: children: 32.7 cases/106; adolescents: 23.5 cases/106. The overall incidence of all tumours increased across 1983-2007 in children and adolescents. Considering change points, the APCs were: (1) children: 1983-1993, 4.3%^ (1.1; 7.7); 1993-2007, -0.2% (-1.9; 1.6); (2) adolescents: 1983-2004: 2.9%^ (0.9; 4.9); 2004-2007: -7.7% (-40; 41.9). For malignant tumours, the trends were not significant. 5-year survival was 65% (1991-2005), with no significant trends (except for non-malignant tumours). CONCLUSIONS: CNS tumour incidence in Spain was found to be similar to that in Europe. Rises in incidence may be mostly attributable to changes in the registration of non-malignant tumours. The overall malignant CNS tumour trend was compatible with reports for Southern Europe. Survival was lower than in Europe, without improvement over time. We provide a baseline for assessing current paediatric oncology achievements and incidence in respect of childhood and adolescent CNS tumours.

Transcriptional immunogenomic analysis reveals distinct immunological clusters in paediatric nervous system tumours.

BACKGROUND: Cancer immunotherapies including immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapy have shown variable response rates in paediatric patients highlighting the need to establish robust biomarkers for patient selection. While the tumour microenvironment in adults has been widely studied to delineate determinants of immune response, the immune composition of paediatric solid tumours remains relatively uncharacterized calling for investigations to identify potential immune biomarkers. METHODS: To inform immunotherapy approaches in paediatric cancers with embryonal origin, we performed an immunogenomic analysis of RNA-seq data from 925 treatment-naïve paediatric nervous system tumours (pedNST) spanning 12 cancer types from three publicly available data sets. RESULTS: Within pedNST, we uncovered four broad immune clusters: Paediatric Inflamed (10%), Myeloid Predominant (30%), Immune Neutral (43%) and Immune Desert (17%). We validated these clusters using immunohistochemistry, methylation immune inference and segmentation analysis of tissue images. We report shared biology of these immune clusters within and across cancer types, and characterization of specific immune cell frequencies as well as T- and B-cell repertoires. We found no associations between immune infiltration levels and tumour mutational burden, although molecular cancer entities were enriched within specific immune clusters. CONCLUSIONS: Given the heterogeneity of immune infiltration within pedNST, our findings suggest personalized immunogenomic profiling is needed to guide selection of immunotherapeutic strategies.

TERTmonitor-qPCR Detection of TERTp Mutations in Glioma.

Telomerase promoter (TERTp) mutations are frequently observed in various types of tumours and commonly characterised by two specific hotspots located at positions -124 and -146 upstream of the start codon. They enhance TERTp activity, resulting in increased TERT expression. In central nervous system (CNS) tumours, they are integrated as biomarkers, aiding in the diagnosis and with a role in prognosis, where, in some settings, they are associated with aggressive behaviour. In this study, we evaluated the performance of TERTmonitor for TERTp genotyping in a series of 185 gliomas in comparison to the traditional method, Sanger sequencing. Against the gold-standard Sanger method, TERTmonitor performed with a 97.8% accuracy. Inaccuracy was mainly due to the over-detection of variants in negative cases (by Sanger) and the presence of variants that can modify the chemistry of the probe detection. The distribution of the mutations was comparable to other series, with the -124 being the most represented (38.92% for Sanger and TERTmonitor) and more prevalent in the higher-grade tumours, gliosarcoma (50.00%) and glioblastoma (52.6%). The non-matched cases are debatable, as we may be dealing with the reduced sensitivity of Sanger in detecting rare alleles, which strengthens the use of the TERTmonitor. With this study, we present a reliable and rapid potential tool for TERTp genotyping in gliomas.

Cytological features of chordoid glioma: A case report with summary of prior published cases.

Chordoid glioma is an uncommon low-grade glioma and is a CNS WHO grade 2 tumour in the current WHO 2021 classification. Predominantly it is seen in the third ventricle and in young adults. Although the histological features of chordoid glioma are well documented, there is sparse literature describing its cytological features. Here we describe the squash cytological features of a case of chordoid glioma along with summary of prior published cases. The smears tend to be quite cellular, the cells show mild pleomorphism, anisonucleosis, and absent mitotic activity. The background shows a distinctive bluish myxoid stroma. It can be mistaken for high grade glioma on squash cytology.

Re-irradiation in Paediatric Tumours of the Central Nervous System: National Guidelines from the Swedish Workgroup of Paediatric Radiotherapy.

There is a lack of clinical protocols for re-irradiation in paediatric central nervous system (CNS) tumours. To fill this void, the Swedish Workgroup of Paediatric Radiotherapy (SBRTG) compiled national guidelines on re-irradiation in paediatric CNS tumours (diffuse intrinsic pontine glioma, ependymoma, germinoma and medulloblastoma). These have been in clinical practice since 2019 in all paediatric radiotherapy centres in Sweden. Since the implementation, the guidelines have been complemented with a yearly review on clinical outcome and toxicities in all paediatric patients treated according to the guidelines. This article presents the Swedish national guidelines on re-irradiation in paediatric CNS tumours.

Clinico-pathological and epigenetic heterogeneity of diffuse gliomas with FGFR3::TACC3 fusion.

BACKGROUND: Gliomas with FGFR3::TACC3 fusion mainly occur in adults, display pathological features of glioblastomas (GB) and are usually classified as glioblastoma, IDH-wildtype. However, cases demonstrating pathological features of low-grade glioma (LGG) lead to difficulties in classification and clinical management. We report a series of 8 GB and 14 LGG with FGFR3:TACC3 fusion in order to better characterize them. METHODS: Centralized pathological examination, search for TERT promoter mutation and DNA-methylation profiling were performed in all cases. Search for prognostic factors was done by the Kaplan-Meir method. RESULTS: TERT promoter mutation was recorded in all GB and 6/14 LGG. Among the 7 cases with a methylation score > 0.9 in the classifier (v12.5), 2 were classified as glioblastoma, 4 as ganglioglioma (GG) and 1 as dysembryoplastic neuroepithelial tumor (DNET). t-SNE analysis showed that the 22 cases clustered into three groups: one included 12 cases close to glioblastoma, IDH-wildtype methylation class (MC), 5 cases each clustered with GG or DNET MC but none with PLNTY MC. Unsupervised clustering analysis revealed four groups, two of them being clearly distinct: 5 cases shared age (< 40), pathological features of LGG, lack of TERT promoter mutation, FGFR3(Exon 17)::TACC3(Exon 10) fusion type and LGG MC. In contrast, 4 cases shared age (> 40), pathological features of glioblastoma, and were TERT-mutated. Relevant factors associated with a better prognosis were age < 40 and lack of TERT promoter mutation. CONCLUSION: Among gliomas with FGFR3::TACC3 fusion, age, TERT promoter mutation, pathological features, DNA-methylation profiling and fusion subtype are of interest to determine patients' risk.

Liquid biopsy for children with central nervous system tumours: Clinical integration and technical considerations.

Circulating cell-free DNA (cfDNA) analysis has the potential to revolutionise the care of patients with cancer and is already moving towards standard of care in some adult malignancies. Evidence for the utility of cfDNA analysis in paediatric cancer patients is also accumulating. In this review we discuss the limitations of blood-based assays in patients with brain tumours and describe the evidence supporting cerebrospinal fluid (CSF) cfDNA analysis. We make recommendations for CSF cfDNA processing to aid the standardisation and technical validation of future assays. We discuss the considerations for interpretation of cfDNA analysis and highlight promising future directions. Overall, cfDNA profiling shows great potential as an adjunct to the analysis of biopsy tissue in paediatric cancer patients, with the potential to provide a genetic molecular profile of the tumour when tissue biopsy is not feasible. However, to fully realise the potential of cfDNA analysis for children with brain tumours larger prospective studies incorporating serial CSF sampling are required.

Comparison of Frozen Section and Squash Cytology as Intra-Operative Diagnostic Tool in Pediatric CNS Tumors.

Background: Pediatric central nervous system (CNS) tumors have a different histological spectrum as compared to adults with the infantile group having even more varied and distinct histological profiles. Intra-operative diagnosis is especially important as it guides the neurosurgeon to tailor an approach which is best suited for a particular case. The aim of the study was to evaluate the diagnostic accuracy, sensitivity, specificity, positive predictive value, negative predictive value of frozen section (FS) and squash cytology and to find out the degree of correlation (kappa value) between the two procedures. Materials and Methods: A prospective study was conducted on 55 pediatric patients with clinicoradiologically diagnosed CNS lesions for a period of 2.5 years. Intra-operative squash smears and FS were made and stained with hematoxylin and eosin stain. Diagnosis made subsequently on paraffin embedded sections was taken as the gold standard. Results: Although the specificity (90%) and positive predictive value (96%) were comparable between the two procedures, sensitivity (91.4%) and negative predictive value (75%) of FS was more as compared to squash cytology. Both the diagnostic modalities showed substantial agreement (k = 0.728). Conclusion: Even though the histological spectrum of pediatric CNS tumors is more varied than adults, FS gives a reasonable intra-operative diagnosis and better results when compared to squash alone.

The Diagnostic Value of Pan-Trk Expression to Detect Neurotrophic Tyrosine Receptor Kinase (NTRK) Gene Fusion in CNS Tumours: A Study Using Next-Generation Sequencing Platform.

Background: Neurotrophic tyrosine receptor kinase (NTRK) fusion has been detected in rare types of CNS tumours, which can promote tumorigenesis. The efficacy of Trk inhibitor became a significant therapeutic interest. Our aim was to investigate whether Pan-Trk immunohistochemistry (IHC) is a reliable and efficient marker for detecting NTRK-fusion in different brain tumours. Methods: This study included 23 patients diagnosed with different types of CNS tumours. Testing for Pan-Trk IHC with monoclonal Ab (EPR17341) has been performed on all FFPE tissues. Parallelly, NTRK-rearrangements were tested using both DNA and RNA-based next-generation sequencing (NGS) assay using TruSight Onco500 platform. Results: The cohort included eight pilocytic astrocytomas, one oligodendroglioma, six IDHwildtype glioblastomas, four IDHmutant grade four astrocytomas, and one sample of each (astroblastoma, central neurocytoma, medulloblastoma, and liponeurocytoma). The mean age was 35 years; seven cases were in the paediatric age group, and 16 were adult. Pan-Trk expression was detected in 11 (47.8%) tumours, and 12 (52.1%) tumours showed no Pan-Trk expression. Nine Cases (82%) with different Pan-Trk expressions did not reveal NTRK-rearrangement. The other two positively expressed cases (liponeurocytoma and glioblastoma) were found to have NTRK2-fusions (SLC O 5A1-NTRK2, AGBL4-NTRK2, BEND5-NTRK2). All the 12 cases (100%) with no Pan-Trk expression have shown no NTRK-fusions. There was no statistically significant association between Pan-Trk expression and NTRK-fusion (p = 0.217). The detection of NTRK- fusions using NGS had high specificity over NTRK-fusion detection by using Pan-Trk IHC. Conclusion: Pan-Trk IHC is not a suitable tissue-efficient biomarker to screen for NTRK-fusions in CNS tumours, however RNA-based NGS sequencing should be used as an alternative method.

Rosette-forming glioneuronal tumours are midline, FGFR1-mutated tumours.

AIM: Rosette-forming glioneuronal tumour (RGNT) is a rare central nervous system (CNS) World Health Organization (WHO) grade 1 brain neoplasm. According to the WHO 2021, essential diagnostic criteria are a 'biphasic histomorphology with neurocytic and a glial component, and uniform neurocytes forming rosettes and/or perivascular pseudorosettes associated with synaptophysin expression' and/or DNA methylation profile of RGNT whereas 'FGFR1 mutation with co-occurring PIK3CA and/or NF1 mutation' are desirable criteria. MATERIAL AND METHODS: We report a series of 46 cases fulfilling the essential pathological diagnostic criteria for RGNT. FGFR1 and PIK3CA hotspot mutations were searched for by multiplexed digital PCR in all cases, whereas DNA methylation profiling and/or PIK3R1 and NF1 alterations were analysed in a subset of cases. RESULTS: Three groups were observed. The first one included 21 intracranial midline tumours demonstrating FGFR1 mutation associated with PIK3CA or PIK3R1 (n = 19) or NF1 (n = 1) or PIK3CA and NF1 (n = 1) mutation. By DNA methylation profiling, eight cases were classified as RGNT (they demonstrated FGFR1 and PIK3CA or PIK3R1 mutations). Group 2 comprised 11 cases associated with one single FGFR1 mutation. Group 3 included six cases classified as low-grade glioma (LGG) other than RGNT (one-sixth showed FGFR1 mutation and one a FGFR1 and NF1 mutation) and eight cases without FGFR1 mutation. Groups 2 and 3 were enriched in lateral and spinal cases. CONCLUSIONS: We suggest adding FGFR1 mutation and intracranial midline location as essential diagnostic criteria. When DNA methylation profiling is not available, a RGNT diagnosis remains certain in cases demonstrating characteristic pathological features and FGFR1 mutation associated with either PIK3CA or PIK3R1 mutation.

The epidemiology series of brain-related disorders in Mongolia: nationwide registry-based epidemiological study on CNS tumours in Mongolia, 2015-2019.

No epidemiological study on central nervous system tumours is available for Mongolia. The aim of this study was to determine the incidence, mortality and survival of people diagnosed with central nervous system tumours in Mongolia. It reports cancer data for the entire population (3.3 million) during the period between 2015 and 2019. Data was obtained from the National Cancer Registry of Mongolia. Diagnosis of tumours was established according to the diagnostic criteria of the International Classification of Diseases-10 (ICD-10). Incidence and mortality rates were calculated as mean annual numbers per 100,000 population. Age-standardized incidence and age-standardized mortality rates were calculated from age-specific rates by weighting directly from the World Standard Population. The three-year survival from 2015 through 2017 was calculated between treatment types by the Kaplan-Meier survival analysis. It found 515 (adults: 83 %; children: 17%) newly diagnosed central nervous system tumour cases over the five year period. The national age-standardized incidence of central nervous system tumours for the entire population was 3.7 per 100,000. The rate was higher for males than females (4.2 versus 3.4 per 100,000, respectively). Only 23% of the diagnosed cases were confirmed histologically. The most common tumour was glioma (57.6% of histologically verified tumours). In children (age 0-19 years) the age-specified incidence rate of tumours was 1.4 per 100,000. Geographically, the age-standardized incidences of the Eastern region were higher than the country average rates for both genders. During the period, 381 deaths were registered with an age-standardized mortality rate of 3.0 per 100,000 population. Furthermore, the overall three-year survival rate was 40.6% (out of 283 patients, 115 survived). The five-year prevalence of tumours was 183 and the mean per 100,000 population was 5.5. In conclusion, the data from the National Cancer Registry indicate that the incidence and survival rates of central nervous system tumours in Mongolia are relatively low. The most common location of central nervous system tumours was the brain. Glioma was the most common tumour among histologically confirmed cases. Despite the limitations, data from this study should provide information for national health policy and health care assessment. To improve the diagnosis, prognosis and treatment of central nervous system tumours, expansion of the cancer registry through collecting data on non-malignant tumours, increasing the rate of histological verification, conducting studies on cancer epidemiology and the introduction of advanced treatment technologies for central nervous system tumours are recommended.

Low-grade epilepsy-associated neuroepithelial tumours with a prominent oligodendroglioma-like component: The diagnostic challenges.

AIMS: We searched for recurrent pathological features and molecular alterations in a retrospective series of 72 low-grade epilepsy-associated neuroepithelial tumours (LEATs) with a prominent oligodendroglioma-like component, in order to classify them according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumours. METHODS: Centralised pathological examination was performed as well as targeted molecular analysis of v-Raf murine sarcoma viral oncogene homologue B (BRAF) and fibroblast growth factor receptor 1 (FGFR1) by multiplexed digital polymerase chain reaction (mdPCR). DNA methylation profiling was performed in cases with sufficient DNA. In cases with no genetic alteration by mdPCR and sufficient material, RNA sequencing was done. RESULTS: We first reclassified our cohort into three groups: ganglioglioma (GG, n = 14), dysembryoplastic neuroepithelial tumours (DNTs, n = 19) and glioneuronal tumours/paediatric-type low-grade glioma (LGG) not otherwise specified (GNT/PLGG NOS, n = 39). mdPCR found an alteration in 38/72 cases. Subsequent RNA sequencing revealed a fusion transcript involving BRAF, FGFR1/2/3 or neurotrophic tyrosine kinase receptor type 2 [NTRK2] in 9/25 cases. DNA methylation profiling found 12/46 cases with a calibrated score ≥0.9. Unsupervised hierarchical clustering revealed two clusters: Cluster 1 was enriched with cases classified as DNT at histology, belonging to the LGG-DNT methylation class (MC), with haematopoietic progenitor cell antigen (CD34) negativity and FGRF1 alterations; Cluster 2 was enriched with cases classified at histology as GG, belonging to the LGG-GG MC MC, with BRAF V600E mutation and CD34 positivity. The tumours reclassified as GNT/PLGG NOS were equally distributed across both clusters. Interestingly, all polymorphous low-grade neuroepithelial tumour of the young belonged to Cluster 2, whereas diffuse LGG mitogen-activated protein kinase (MAPK) pathway-altered were equally distributed among the two clusters. This led us to build an algorithm to classify LEATs with a prominent oligodendroglioma-like component. CONCLUSIONS: Integrated histomolecular diagnosis of LEATs with a prominent oligodendroglioma-like component remains challenging. Because these tumours can be split into two major clusters of biological significance, the clinicopathological relevance of the four types recognised by the WHO CNS5 within this spectrum of tumours is questionable.