Pleomorphic Xanthoastrocytoma Research Articles

Case report: complete long-lasting response to multimodal third line treatment with neurosurgical resection, carmustine wafer implantation and dabrafenib plus trametinib in a BRAFV600E mutated high-grade glioma

Dabrafenib plus trametinib is a promising new therapy for patients affected by BRAFV600E-mutant glioma, with high overall response and manageable toxicity. We described a complete and long-lasting response in a case of recurrent anaplastic pleomorphic xanthoastrocytoma CNS WHO-grade 3 BRAFV600E mutated. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients treated with the combined target therapy as third-line treatment. The emergence of optimized sequencing strategies and targeted agents, including multimodal and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG improving patient outcomes.

Unusual location of pleomorphic xanthoastrocytoma: a case report

BackgroundPleomorphic xanthoastrocytoma is a rare astrocytic tumor often diagnosed at a young age. Typically, they appear as supratentorial cortical tumors, frequently involving the temporal lobe with few reported rare locations. The prognosis is favorable following surgical excision; however, recurrence, dissemination, and anaplastic transformation occurred in some cases.Case presentationA 50-year-old female presented with convulsions and an altered consciousness. Imaging showed a periventricular mixed solid and cystic lesion. Histopathological examination revealed features of pleomorphic xanthoastrocytoma WHO grade 2 without necrosis or mitotic activity.ConclusionsThis report highlights the classic imaging findings of pleomorphic xanthoastrocytoma but in an atypical periventricular location. Although rare, pleomorphic xanthoastrocytoma should be considered in the differential diagnosis of mixed solid and cystic periventricular lesions.

Ganglioglioma with anaplastic/high-grade transformation: Histopathologic, molecular, and epigenetic characterization of 3 cases.

Ganglioglioma (GG) with anaplasia (anaplastic ganglioglioma) is a rare and controversial diagnosis. When present, anaplasia involves the glial component of the tumor, either at presentation or at recurrence. To date, most published cases lack molecular characterization. We describe the histologic and molecular features of 3 patients presenting with BRAF p. V600E-mutant GG (CNS WHO grade 1) with high-grade glial transformation at recurrence. The tumors occurred in pediatric patients (age 9-16 years) with time to recurrence from 20 months to 7 years. At presentation, each tumor was low-grade, with a BRAFV600E-positive ganglion cell component and a glial component resembling pleomorphic xanthoastrocytoma (PXA) or fibrillary astrocytoma. At recurrence, tumors resembled anaplastic PXA or high-grade astrocytomas without neuronal differentiation. CDKN2A homozygous deletion (HD) was absent in all primary tumors. At recurrence, 2 cases acquired CDKN2A HD; the third case showed loss of p16 and MTAP immunoexpression, but no CDKN2A/B HD or mutation was identified. By DNA methylation profiling, all primary and recurrent tumors either grouped or definitely matched to different methylation classes. Our findings indicate that malignant progression of the glial component can occur in GG and suggest that CDKN2A/B inactivation plays a significant role in this process.

BRAF V600E in a preclinical model of pleomorphic Xanthoastrocytoma: Analysis of the tumor microenvironment and immune cell infiltration dynamics in vivo

Low-grade glioma is the most common brain tumor affecting pediatric patients (pLGG) and BRAF mutations constitute the most frequent genetic alterations. Within the spectrum of pLGGs, approximately 70-80% of pediatric patients diagnosed with transforming Pleomorphic Xanthoastrocytoma (PXA) harbor the BRAF V600E mutation. However, the impact of glioma BRAF V600E cells regulation of tumor-infiltrating immune cells and their contribution to tumor progression remains unclear. Moreover, the efficacy of BRAF inhibitors in treating pLGGs is limited compared to their impact on BRAF-mutated melanoma. Here we report a novel immunocompetent RCAS-BRAF V600E murine glioma model. Pathological assessment indicates this model appears to be consistent with diffuse gliomas and morphological features of PXA. Our investigations revealed distinct immune cells signatures associated with increased trafficking and activation within the tumor microenvironment (TME). Intriguingly, immune system activation within the TME also generated a pronounced inflammatory response associated with dysfunctional CD8+ T cells, increased presence of immunosuppressive myeloid cells and regulatory T cells (Tregs). Further, our data suggests tumor-induced inflammatory processes such as cytokine storm. These findings suggest a complex interplay between tumor progression and the robust inflammatory response within the TME in preclinical BRAF V600E LGGs, which may significantly influence animal survival.

Abstract 5137: BRAF mutations in primary central nervous system tumors

Abstract Background: BRAF alterations are present in a variety of primary central nervous system (CNS) tumors from 3% in glioblastomas to 60% in pleomorphic xanthoastrocytomas. BRAF V600E mutation is the most common BRAF alteration found in tumors and has been successfully targeted by combining BRAF/MEK inhibitors in different tumor types, including gliomas. We aimed to describe the clinical and genomic features of primary CNS tumors harboring BRAF alterations and real-world data on BRAF-targeted therapy including our experience sequencing BRAF-directed therapies (BDI) in gliomas. Methods: Single-center retrospective analysis of patients with diagnosis of primary CNS tumors with NGS testing. Clinical, histological and molecular characteristics were analyzed. Results: 44 patients with BRAF mutant primary CNS tumors were included, 28 (64%) were male. 24 (55%) had histology consistent with high-grade glioma (HGG), 14 (32%) low grade glioma (LGG), 4 (9%) low grade neuroepithelial tumors and 2 (4%) others. Missense mutations were found in 77%, followed by amplifications (9%), fusions (9%) and in/del alterations (5%). V600E was the most common mutation (63%), followed by class 2 (16%) and 3 (7%) mutations and amplifications (9%). Co-occurring mutations were found in CDKN2A/B (22), TERT (20) and MTAP (12), median TMB was 2 mut/mb and only 2 patients had high TMB. 4 patients had commuted IDH1 (3 R132H), non-concurring with a V600E mutation. For patients with HGG, median age at diagnosis was 47 years and 16 (66%) were male. Lesions were more frequent in left hemisphere (70%) and temporal lobe (54%). V600E was found in 50% of cases, KIAA1549-BRAF fusion was found in 1 case. Median follow-up was 40 months (95% CI 11-68) and median overall survival (OS) was 22 months (3.4-40) for the whole population, and 56 (4-109) months for patients treated with BDI (n=4). All 4 patients had an OS >30 months. In the LGG cohort, median age at diagnosis was 34 years (IQR 24-46), 8 (57%) were male. 50% of the lesions were in the left side and 21% of the tumors were in the posterior fossa. 78% had a V600E mutation, with no statistical difference with HGG cohort (p=.082). Median follow up was 11 months, median OS was not reached. For 5 patients treated at recurrence with BDI, median PFS was 15 months (3-27).5 patients were treated with plixorafenib (PLX8394) on clinical trial achieving disease control (PR +SD) in 4 cases. Upon progression, 4 were rechallenged with dabrafenib + trametinib and 1 with another BDI. 4 patients had a partial response with duration of response >6 months in 3 cases. Conclusion: BRAF mutant CNS tumors are a heterogeneous disease. Longer survival was observed in the small group of HGG patients treated with BDI compared to SoC (56 months vs 22months). BDI rechallenge showed durable responses in heavily pretreated patients. Further molecular characterization of these patients is ongoing. The best therapeutical sequencing strategy for BDI remains uncertain. Citation Format: Juan B. Blaquier, Fulvio D'Angelo, Dalissa Tejera, Ruham A. Nasany, Gaurav Saigal, Antonio Iavarone, Macarena I. de la Fuente. BRAF mutations in primary central nervous system tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5137.

Exploring prognostic factors and treatment strategies for long-term survival in pleomorphic xanthoastrocytoma patients

Pleomorphic xanthoastrocytomas (PXA) are rare, accounting for < 1% of all astrocytomas. Literature on the clinical course and treatment outcomes of PXAs is limited. The study aimed to determine prognosis and treatment strategies for PXAs. Patients who had PXAs surgery between 2000–2021 were retrospectively analyzed for demographics and radiological characteristics. Initial and salvage treatment outcomes were recorded. Overall, 40 and 9 patients had grade 2 and 3 PXAs; their 5-year progression-free survival (PFS) rates were 75.8% and 37.0%, respectively (p = 0.003). Univariate analysis revealed that strong T1 enhancement (p = 0.036), infiltrative tumor margins (p < 0.001), peritumoral edema (p = 0.003), WHO grade (p = 0.005), and gross total resection (p = 0.005) affected the PFS. Multivariate analysis revealed that the WHO grade (p = 0.010) and infiltrative tumor margins (p = 0.008) influenced the PFS. The WHO grade (p = 0.027) and infiltrative tumor margins (p = 0.027) also affected the overall survival (OS). Subgroup analysis for grade 2 PXAs revealed no significant associations between adjuvant radiation therapy and the PFS and OS. This study highlighted the heterogeneous nature of PXAs and its impact on patient prognosis. Infiltrative tumor margins emerged as a key prognostic factor. Our findings have emphasized the prognostic relevance of radiological features and the need for larger studies on comprehensive management.

Clinical and molecular study of radiation-induced gliomas

In this study, we provide a comprehensive clinical and molecular biological characterization of radiation-induced gliomas (RIG), including a risk assessment for developing gliomas. A cohort of 12 patients who developed RIG 9.5 years (3–31 years) after previous cranial radiotherapy for brain tumors or T-cell acute lymphoblastic leukemia was established. The derived risk of RIG development based on our consecutive cohort of 371 irradiated patients was 1.6% at 10 years and 3.02% at 15 years. Patients with RIG glioma had a dismal prognosis with a median survival of 7.3 months. We described radiology features that might indicate the suspicion of RIG rather than the primary tumor recurrence. Typical molecular features identified by molecular biology examination included the absence of Histon3 mutation, methylation profile of pedHGG-RTK1 and the presence of recurrent PDGFRA amplification and CDKN2A/B deletion. Of the two long-term surviving patients, one had gliomatosis cerebri, and the other had pleomorphic xanthoastrocytoma with BRAF V600E mutation. In summary, our experience highlights the need for tissue diagnostics to allow detailed molecular biological characterization of the tumor, differentiation of the secondary tumor from the recurrence of the primary disease and potentially finding a therapeutic target.

Non-canonical ETV6:NTRK3 fusion detected in a pleomorphic xanthoastrocytoma

Non-canonical ETV6:NTRK3 fusion detected in a pleomorphic xanthoastrocytoma

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

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. 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. 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. 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.

Analysis of Histomorphologic/Molecular Association and Immune Checkpoint Regulators in Epithelioid Glioblastoma and Pleomorphic Xanthoastrocytoma: Are These Tumors Potential Candidates for Immune Checkpoint Blockade?

Accurate diagnosis of Epithelioid glioblastoma (eGB) and pleomorphic xanthoastrocytoma (PXA) is sometimes challenging owing to overlapping histologic and genetic features. There are limited reports on the immune profile of these tumors. In this study, we assessed 21 PXA [15 PXA Grade 2 (PXAG2); 6 PXA Grade 3 (PXAG3)] and 14 eGB for their histopathological and molecular association. Further, their immune profile was compared with GB, IDH1 wild-type (wt) (n-18). Morphologically, PXAG2 mostly differed from eGB; however, it was occasionally difficult to differentiate PXAG3 from eGB due to their epithelioid pattern and less obvious degenerative features. PXAG2 showed predominantly diffuse, whereas variable positivity for epithelial and glial markers was seen in PXAG3 and eGB. All cases showed retained nuclear ATRX and INI-1 . H3K27M or IDH1 mutation was seen in none. P53 mutation was more common in eGB, followed by PXAG3, and least common in PXAG2. BRAF V600E mutation was observed in 66.67% PXAG2, 33.33% PXAG3, and 50% eGB, with 100% concordance between immunohistochemistry (IHC) and sequencing. Thirty-six percent eGB, 33% PXAG3, and 61% PXAG2 harbored CDKN2A homozygous deletion. EGFR amplification was observed in 14% eGB and 66% of GB, IDH wt. PDL1 and CTLA-4 expression was higher in eGB (71.4% and 57.1%), PXAG3 (66.6% and100%), and PXAG2 (60% & 66.7%) as compared with GB, IDH wt (38.8% and 16.7%). Tumor-infiltrating lymphocytes were also observed in a majority of eGB and PXA (90% to 100%) in contrast to GB, IDH wt (66%). This analysis highlights the homogenous molecular and immune profile of eGB and PXA, suggesting the possibility that histologically and molecularly, these two entities represent 2 ends of a continuous spectrum with PXAG3 lying in between. Higher upregulation of PDL1, CTLA-4, and increased tumor infiltrating lymphocytes in these tumors as compared with GB, IDH wt suggests potential candidature for immunotherapy.

Common symptoms can uncover a rare tumor: A case report of pleomorphic xanthoastrocytoma

Transient visual disturbances (VD), such as flashing lights and scotomas, can occur in relatively benign ocular and neurologic diseases, such as migraine with aura. However, VD can also be a manifestation of visually threatening eye conditions and life-threatening neurologic conditions. The case of a 44-year-old woman is presented to highlight the importance of comprehensive ocular and neurologic examination in the diagnosis and management of patients with VD.

10006-PEDT-1 PEDIATRIC LOWER GRADE GLIOMA SURGERY IN THE ERA OF GENOMIC MEDICINE

Abstract INTRODUCTION In the new WHO Brain Tumor Classification of 2021, pediatric-type gliomas are classified separately from adult-type tumors. Additionally, with the advancement of cancer genomics, treatment options have expanded. Here we consider surgery for pediatric low-grade gliomas. METHODS We retrospectively analyzed 41 cases of low-grade gliomas or glioneuronal tumors in patients under 18 years of age who underwent surgery at our institute from 2002 to March 2023. We discussed surgical strategies based on molecular classification. RESULTS Among the cases, there were 34 gliomas and 7 glioneuronal tumors. According to the new WHO classification, they corresponded to 1) Adult-type diffuse gliomas, 2) Pediatric-type diffuse low-grade gliomas, 3) Circumscribed astrocytic tumors, or 4) Glioneuronal and neuronal tumors. Cases without molecular diagnosis were also considered in light of the new WHO classification. DISCUSSION Among molecularly diagnosed astrocytomas involving the cerebral hemisphere, brain stem, spinal cord, there were no cases of 1), and 2) 3) were the main cases. It is important in surgical selection to note that these cases generally have a more favorable prognosis compared to the adult type and have usefulness in diagnosing MAPK pathway abnormalities leading to the selection of molecularly targeted drugs. 3) includes pilocytic astrocytoma, subependymal giant cell astrocytoma, and pleomorphic xanthoastrocytoma. Among these, in the treatment of pilocytic astrocytomas located in the optic pathway and hypothalamus, biopsy becomes necessary for molecular diagnosis and the selection of appropriate therapeutic agents. Conversely, for unilateral optic nerve gliomas, options other than resection may be considered. 4) is primarily associated with epilepsy-related tumors. Surgical resection holds the promise of controlling epilepsy in these cases. However, various genetic abnormalities have been identified, which could prove useful in diagnosis and treatment. CONCLUSION Based on the new WHO classification, a reevaluation of treatment strategies for pediatric brain tumors is necessary.

CLEAR CELL TUMORS OF CNS: HISTOMORPHOLOGIC APPROACH TO DIAGNOSIS

Introduction:Tumors of the central nervous system (CNS) that may assume a clear cell appearance are diverse in nature. Primary conditions in this category include oligodendroglioma, hemangioblastoma, clear cell meningioma, pleomorphic xanthoastrocytoma, and lipid-rich glioblastoma, chordoma, central neurocytoma.They can be correctly identified by giving attention to clinical presentation, location, radiographic findings, and histomorphological features, immunohistochemistry analysis wherever necessary.The literature was reviewed with emphasis on incidence, morphology and precise histopathological assessment of clear cells tumors of CNS. Method: This study was prospective observational study of 33 Cases received from August 2020 to December 2022 for clear cell tumors of CNS. This prospective study was carried out in Department of Pathology of a tertiary care teaching hospital. The ethical permission has been obtained from Institutional Ethics Committee for conducting the study. Result:Total 33 Central nervous system clear cell tumors were observed out of which 6 were benign and 27 were malignant cases. They can be correctly identified by giving attention to clinical presentation, location, radiographic findings, and histomorphological features in most of the instances. Two cases of metastasis identified in which immunohistochemistry in addition to morphological examination was performed to arrive at final diagnosis. Conclusion:Clearing of cytoplasm or clear cell changes are seen in various entities of different locations due to diverse reasons. So whenever clear cell is encountered, algorithmic approach is required to further proceed. In most of the instances morphologic features directs us to reach at diagnosis along with clinical and radiological findings.

Pediatric Pleomorphic Xanthoastrocytoma with Neoplastic Meningitis: A Case Report with Cytopathological Evidence with Literature Review

AbstractPleomorphic xanthoastrocytoma (PXA) was regarded as grade II tumor and considered to be associated with favorable outcome. The World Health Organization Central Nervous System 5 (WHO CNS5) has classified PXA under circumscribed astrocytic gliomas and graded 2 or 3 depending on histology. Cerebrospinal fluid (CSF) and leptomeningeal spread are observed rarely in these tumors. The present case report describes a PXA, grade 3 tumor in a young male with neoplastic meningitis. This 17-year-old male child presented with history of seizure, signs of raised intracranial pressure, and meningeal irritation. Well-defined, T2 heterogeneously hyperintense lesion (5.5*4.8 cm) was seen in right frontal lobe with mild heterogenous contrast enhancement and adjacent pachy-meningeal enhancement. Right frontal craniotomy and near total excision were done. Postoperative hydrocephalus was treated with CSF diversion. Histopathology showed epithelioid and rhabdoid morphology with significant cellular pleomorphism and atypical mitosis consistent with the PXA, grade 3. The CSF cytology showed numerous tumor cells with marked nuclear and cytoplasmic pleomorphism. PXA is a rare malignancy of children and young adults, commonly seen in the temporal lobes. BRAF point mutations of V600E type are most common in PXA, grade 2. Meningeal dissemination is uncommon in PXA and its presence marks poor outcome. PXA, grade 2 tumors could be followed with serial imaging following gross total resection. PXA, grade 3 tumors are managed with maximal-safe resection, radiotherapy, and/ or chemotherapy. PXA, grade 3 with CSF spread tends to have rapid decline in the clinical course and it is advisable to get routine baseline and follow-up craniospinal screening and needs aggressive management.

Diagnostic Insights into Pediatric Pleomorphic Xanthoastrocytoma through DNA Methylation Class and Pathological Diagnosis Analysis.

This study adopts an innovative approach to utilize the DNA methylation class (MC) by prioritizing the understanding of discrepancies over traditional direct comparisons with the pathological diagnosis (PD). The aim is to clarify the morphological criteria for pleomorphic xanthoastrocytoma (PXA). Using the Children's Brain Tumor Network online database, PXA-diagnosed cases were sourced. MCs and CDKN2A/B statuses were ascertained using the Heidelberg methylation brain tumor classifier v12.5 (v12.8 for selected cases). Three distinct groups emerged: Group 1 confirmed PXA through both PD and MC (7 cases); Group 2 identified PXA via PD alone (7 cases); and Group 3 diagnosed PXA using MC (5 cases). Key insights from the study include the frequent local infiltration of PXA into gray matter structures, mirroring infiltrative astrocytoma. The MC for PXA stands out for its sensitivity. Cases with a PXA morphological diagnosis diverging from the DNA class warrant attention to newer differential diagnoses such as high-grade astrocytoma with piloid features, pilocytic astrocytoma NF1-associated, and NET-PATZ1. Tumors with a MC indicative of PXA but lacking its typical features may, if high-grade, behave as grade 4 gliomas. In contrast, their low-grade counterparts could belong to the PXA morphological continuum. Further research is pivotal for cementing these findings.

PATH-53. ANAPLASTIC PLEOMORPHIC XANTHROASTROCYTOMA WITH BEND5-NTRK2 FUSION IN A YOUNG ADULT WITH A HISTORY OF CRANIAL RADIATION FOR CHILDHOOD RHABDOMYOSARCOMA

Abstract INTRODUCTION: Pleomorphic xanthoastrocytoma (PXA) is a rare subset of circumscribed astrocytic glioma. While PXA typically has a favorable prognosis, anaplastic (WHO Grade III) PXA (aPXA) has a poorer prognosis. Molecular analysis of PXA often reveals BRAF mutations or CDKN2A/B homozygous deletions. NTRK fusions have been identified in a few cases of pediatric gliomas including PXA. BEND-5 gene alterations have been rarely reported in CNS tumors such as glioblastoma but have not been previously reported in PXA. Case Presentation The patient is a 24-year-old female with history of nasopharyngeal embryonal rhabdomyosarcoma treated with chemotherapy and radiation at age 3. She was tested for Li-Fraumeni Syndrome and was reportedly negative. One year ago, she presented with visual changes and was found to have an occipital aPXA. She underwent a gross total resection but declined further treatment with radiation. Next-generation sequencing (NGS) identified a BEND5-NTRK2 fusion, and she began treatment with Larotrectinib. Serial MRI scans have shown no evidence of disease recurrence. Discussion Pediatric patients are at increased risk for glioma after radiation which is age- and dose/volume-dependent. Radiation-induced gliomas are typically higher grade, present in atypical sites, and have a poor prognosis. Development of PXA following radiation is rare but has been reported. Our patient was diagnosed with aPXA almost 20 years after initial treatment for rhabdomyosarcoma. Her aPXA exhibited a BEND5-NTRK2 fusion and lacked classical BRAF alterations and CDKN2A/B deletions that are present in de novo cases. A Neuro-Onc Panel did not identify her fusion or include testing for BEND5 alterations. However, an expanded RNA Exome Fusion Panel NGS identified a unique fusion, which opened her up to targeted treatment with an NTRK inhibitor. Our patient is now 1 year from resection without disease progression on larotrectinib. This case highlights the importance of expanded NGS testing, particularly in rare tumors.

TMIC-83. THE MOLECULAR AND SPATIAL ARCHITECTURE OF AN IMMUNE-RICH GLIOMA SUBTYPE

Abstract Diffuse glioma exhibit an immunosuppressive microenvironment, yet glioma subsets driven by RAF-alterations exhibit an increased immune signature. In pleomorphic xanthoastrocytoma (PXA), we identified CXCL14 as an important factor promoting a cytotoxic T cell response. The molecular and spatial relationships within this tumor type, however, are unknown. To address this, we use single nucleus RNA sequencing (snRNAseq), spatial transcriptomics, and spatial molecular imaging to construct a high-resolution molecular landscape of PXA. SnRNAseq was performed on 36,781 cells from 10 tumors, including initial and recurrent pairs, spatial transcriptomes were performed on a total of 91 FOVs comprised of 17 PXAs, and spatial molecular imaging (SMI) of 1,000 RNA probes at subcellular resolution was performed on 48,518 cells from 6 tumors, including two PXA, two pilocytic astrocytoma, and two ganglioglioma. For snRNAseq, neoplastic cells were separated from non-malignant cells based on analysis of inferred copy number alterations. CellChat was used to infer cell-cell communication. For spatial transcriptomics, data from 200-300µm FOVs were normalized and divided into CD3-high versus CD3-low groups. For SMI, cells with fewer than 20 transcripts were eliminated, data were normalized using simple total counts, cells were segmented using the Nanostring pipeline, and semi-supervised clustering was performed. Dual CXCL14 RNAscope and Iba1/CD3 immunostaining confirmed spatial relationships within the tumor. In PXA with high-CD3, differential gene expression analysis demonstrated broad immune-enrichment and identified upregulation of several ligand-receptor pairs. Integrating these data with snRNAseq and cell-cell communication analysis inferred paracrine interactions between tumor cells and T cells. One such factor, CXCL14, was expressed widely by tumor cells but spatial analysis revealed cohesive clusters of CXCL14-high expressing tumor cells. In anaplastic (CNS WHO grade 3) tumors, however, both CXCL14 expression and microglia decreased. These high-resolution molecular analyses of PXA identify dynamic tumor-immune crosstalk regulating the immune microenvironment.

DISP-09. HISTOPATHOLOGIC AND MOLECULAR PROFILE OF GLIOMAS: A 9-YEAR RETROSPECTIVE STUDY OF CASES DIAGNOSED IN LAGOS NIGERIA

Abstract BACKGROUND The diagnosis and management of patients with brain tumors currently uses WHO defined morphologic and molecular features. However, neuro-oncology practice in low resource settings relies on histomorphology. This study aims to reclassify glioma cases diagnosed in the Department of Anatomic and Molecular Pathology Lagos University Teaching Hospital using the 2021 WHO classification. METHODS Fifty-six cases of glioma diagnosed between 2013 to 2021 were evaluated. Morphologic diagnosis was reassessed. Five-micron sections were obtained for immunohistochemistry (IHC), and genetic testing (DNA and RNA); after manual macrodissection for tumor enrichment using 10μm sections. IHC for IDH1-R132H, ATRX, BRAFV600E, P53,Ki67, and H3K27M and OncoScan chromosomal microarray analysis were performed. NGS mutation/fusion analysis and EPIC methylation array profiling are in progress. RESULTS Of 56 cases evaluated, median age was 22 years (range=1-60 years); 71% were males. The initial morphologic diagnosis include 21 pilocytic astrocytoma, 11 glioblastoma, 9 ependymoma, 7 diffuse astrocytoma, 3 anaplastic astrocytoma, 2 high-grade gliomas, 1 oligodendroglioma, 1 diffuse midline glioma, and 1 pleomorphic xanthoastrocytoma (PXA). Histomorphologic re-evaluation revealed discordant diagnosis in 29% (16/56) of cases. Of the 56 cases, 73% (41/56) had usable DNA yield and 38% (21/56) had DNA yield of ≥ 750ng. Chromosomal microarray analysis was completed for 50% (28/56) cases. The revised 2021 WHO diagnosis were: 5 glioblastoma, IDH-wildtype, 5 pilocytic astrocytoma, 4 glioma NEC, 3 posterior fossa ependymoma, group B, 3 PXAs, 3 astrocytoma, IDH-mutant, 2 pediatric low-grade glioma, 2 supratentorial ependymoma, ZFTA fusion-positive, 1 posterior fossa ependymoma, group A. In 71% (20/28) of cases, diagnosis was revised using the 2021 WHO criteria. CONCLUSION Most cases had usable DNA yield. Overall, hsitologic re-evaluation and molecular testing based on the 2021 WHO classification guidelines refined the diagnosis in 48% (27/56) of cases.

SURG-13. PEDIATRIC PRIMARY CENTRAL NERVOUS SYSTEM NEOPLASMS: RELATIVE UTILITY OF OPEN, MULTI-STAGE CRANIAL SURGERY

Abstract OBJECTIVE Staged surgery for skull base lesions has been utilized to facilitate maximal safe resection and optimize outcomes in pediatric patients. Despite its extensive applications, there is a paucity of information regarding open multi-stage resection of intrinsic, intra-axial neoplasms. We reviewed the literature in order to shed light on relevant considerations including the timing between surgeries, indications for staged approaches, and clinical outcomes following staged resection of pediatric intra-axial neoplasms. METHODS We conducted a literature search using PubMed, Web of Science, and Cochrane databases according to PRISMA recommendations. RESULTS Of 115 results, 7 articles were included for final analysis and consisted of 17 pediatric patients, including 6 (35%) male, 5 (29%) female, and 6 (35%) unspecified sex patients. Age ranged from 18 months to 17 years (mean 9 years). Tumor pathologies consisted of 5 (29%) astrocytomas, 2 (12%) ependymomas, 2 (12%) teratoid rhabdoid tumors, 2 (12%) oligodendromas, 1 (6%) glioma, 1 (6%) dysembryoplastic neuroepithelial tumor, 1 (6%) meningioangiomatosis, 1 (6%) pleomorphic xanthoastrocytoma, 1 (6%) ganglioglioma, and 1 (6%) germ cell tumor. Primary sites of the tumor included 4 (24%) temporal lobe, 3 (18%) thalamic, 3 (18%) thalamopeduncular, 3 (18%) frontal lobe, 2 (12%) posterior fossa, 1 (6%) cerebral hemisphere, and 1 (6%) frontoparietal lobe. Three studies reported complications, which included subtle hemiparesis, hydrocephalus, cranial nerve (CN) VI and VII palsies, truncal ataxia, and cerebellar mutism. Timing between surgeries varied from 5 days to several weeks CONCLUSION Indications for performing multi-stage resections included large tumor volume requiring multiple long stages of debulking, significant tumor vascularity, multicompartmental lesions, and planned staging due to presence of large tumors requiring resection around eloquent speech and motor cortical and white matter tract lesions that enabled use of awake functional mapping after a primary debulking performed in proximity to less eloquent regions.

EPID-24. CAPTURING EVOLVING DEFINITIONS OF 12 SELECT RARE CNS TUMORS: A TIMELY REPORT FROM CBTRUS AND NCI-CONNECT

Abstract BACKGROUND Incidence, prevalence, and survival are population-based cancer statistics that describe cancer burden. The National Cancer Institute’s Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) specializes in research of 12 rare CNS tumor types to improve approaches to care and treatment. These tumors include atypical teratoid/rhabdoid tumors, brainstem and midline glioma, choroid plexus tumors, ependymoma, high grade meningioma, gliomatosis cerebri, medulloblastoma, oligodendroglioma/anaplastic oligodendroglioma, pineal region tumors, pleomorphic xanthoastrocytoma, CNS embryonal tumors, not elsewhere classified (NEC)/not otherwise specified (NOS), and primary CNS sarcoma. This study aimed to update incidence, prevalence, and survival statistics for these tumors. METHODS The Central Brain Tumor Registry of the United States (CBTRUS) database, a combined dataset of CDC’s National Program of Cancer Registries (NPCR) and NCI’s Surveillance, Epidemiology and End RESULTS (SEER) data, was used to calculate average annual age-adjusted incidence rates (AAAIR) per 100,000 population overall and by sex, race-ethnicity, and age (2008-2019). NPCR data were used to calculate relative survival (RS) estimates (2008-2018). Prevalence on December 31, 2019 was estimated using annual age-specific incidence and survival from CBTRUS and SEER, respectively. RESULTS AAAIR was 1.51 per 100,000 for these tumors combined, with highest incidence in ependymomas (AAAIR=0.41/100,000). Most tumor types were more common in males, adults (ages 40+ years) or children ages &amp;lt; 15 years, and non-Hispanic White individuals. Ependymomas were most prevalent (19,339 cases) followed by oligodendrogliomas (15,070 cases). RS for all subtypes combined at 1-, 5-, and 10-years was 86.6%, 71.9%, and 65.3%, respectively. Ependymomas had the highest RS (5-years=90.6%) and primary CNS sarcomas had the lowest RS (5-years=7.7%). CONCLUSIONS Incidence, prevalence, and survival patterns for these 12 selected rare cancer subtypes varied significantly by type. Population-based data are critical to guiding effective design of and accrual expectations for clinical trials in rare cancers.