Anaplastic Ganglioglioma Research Articles

Clinicopathological characteristics of gangliogliomas with anaplastic morphology

Objective: To investigate the clinical, radiological, and pathological features of anaplastic gangliogliomas (AGGs) and to determine whether these tumors represent a distinct entity. Methods: Consecutive 667 cases of ganglioglioma (GG) diagnosed at the Xuanwu Hospital, Capital Medical University, Beijing, China between January 2015 and July 2023 were screened. Among these cases, 9 pathologically confirmed AGG cases were identified. Their clinical, radiological, treatment, and outcome data were analyzed retrospectively. Most of the tumor samples were subject to next-generation sequencing, while a subset of them were subject to DNA methylation profiling. Results: Among the 9 patients, there were five males and four females, with a median age of 8 years. Epileptic seizures (5/9) were the most frequently presented symptom. Radiological examinations showed three types of radiological manifestations: four cases showed abnormal MRI signals with no significant mass effects and mild enhancement; two cases demonstrated a mixed solid-cystic density lesion with peritumoral edema, which showed significant heterogeneous enhancement and obvious mass effects, and one case displayed cystic cavity formation with nodules on MRI, which showed evident enhancements. All cases exhibited mutations that were predicted to activate the MAP kinase signaling pathway, including seven with BRAF p.V600E mutation and two with NF1 mutation. Five AGGs with mutations involving the MAP kinase signaling pathway also had concurrent mutations, including three with CDKN2A homozygous deletion, one with a TERT promoter mutation, one with a H3F3A mutation, and one with a PTEN mutation. Conclusions: AGG exhibits a distinct spectrum of pathology, genetic mutations and clinical behaviors, differing from GG. Given these characteristics suggest that AGG may be a distinct tumor type, further expansion of the case series is needed. Therefore, a comprehensive integration of clinical, histological, and molecular analyses is required to correctly diagnose AGG. It will also help guide treatments and prognostication.

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.

Ganglioglioma cells potentiate neuronal network synchronicity and elicit burst discharges via released factors

Gangliogliomas (GGs) represent the most frequent glioneuronal tumor entity associated with chronic recurrent seizures; rare anaplastic GGs variants retain the glioneuronal character. So far, key mechanisms triggering chronic hyperexcitability in the peritumoral area are unresolved. Based on a recent mouse model for anaplastic GG (BRAFV600E, mTOR activation and Trp53KO) we here assessed the influence of GG-secreted factors on non-neoplastic cells in-vitro. We generated conditioned medium (CM) from primary GG cell cultures to developing primary cortical neurons cultured on multielectrode-arrays and assessed their electrical activity in comparison to neurons incubated with naïve and neuronal CMs. Our results showed that the GG CM, while not affecting the mean firing rates of networks, strongly accelerated the formation of functional networks as indicated increased synchrony of firing and burst activity. Washing out the GG CM did not reverse these effects indicating an irreversible effect on the neuronal network. Mass spectrometry analysis of GG CM detected several enriched proteins associated with neurogenesis as well as gliogenesis, including Gap43, App, Apoe, S100a8, Tnc and Sod1. Concomitantly, immunocytochemical analysis of the neuronal cultures exposed to GG CM revealed abundant astrocytes suggesting that the GG-secreted factors induce astroglial proliferation. Pharmacological inhibition of astrocyte proliferation only partially reversed the accelerated network maturation in neuronal cultures exposed to GG CM indicating that the GG CM exerts a direct effect on the neuronal component. Taken together, we demonstrate that GG-derived paracrine signaling alone is sufficient to induce accelerated neuronal network development accompanied by astrocytic proliferation. Perspectively, a deeper understanding of factors involved may serve as the basis for future therapeutic approaches.

CTNI-60. PRELIMINARY RESULTS OF BINIMETINIB AND ENCORAFENIB IN ADULTS WITH RECURRENT BRAF V600E-MUTATED HIGH-GRADE GLIOMA

Abstract BACKGROUND Although < 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are being identified more frequently as genetic testing increases in gliomas. Given the treatment-refractory nature HGG, RAF-targeted therapy is of special interest. The combination of encorafenib (BRAF inhibitor) with binimetinib (MEK inhibitor) was evaluated in adults with recurrent BRAFV600-mutated HGG. METHODS In this phase 2, open-label, Adult Brain Tumor Consortium trial(NCT03973918) encorafenib (450mg daily) and binimetinib (45mg twice daily) were administered continuously until disease progression, unacceptable toxicity, or death. Eligible patients had a histologically-confirmed HGG with BRAF-V600E mutation identified by PCR or next generation sequencing, and had progressed after radiation and any number of prior medical therapies. The primary endpoint was radiographic response rate by RANO criteria. Plasma was collected at baseline, on-study, and at progression for correlatives. RESULTS Five patients enrolled between January 2020 and November 2021. All patients had at least one prior recurrence (range 1-4) and received radiation one or more times. Median age was 27 years(range 22-77). Histopathologic diagnosis was glioblastoma(n = 2), anaplastic PXA(aPXA; n = 2), and anaplastic ganglioglioma(aGG; n = 1). Patients received treatment for 2-28months; currently 2/5 patients remain on treatment (8 and 30 months). Radiographic response rate was 60%(3/5): CR in two (glioblastoma, treated 10months; glioblastoma, 8months treatment ongoing), PR in one (aPXA, 28months treatment ongoing), SD in one (aGG, treated 3months), and PD in one (aPXA, treated 2months). Likely attributable adverse events (CTCAE grade ≥ 3) included cilioretinal artery occlusion (came off study) and asymptomatic elevated CPK. Analysis of paired plasma samples and correlation with response is ongoing. CONCLUSIONS Encorafenib and binimetinib demonstrate promising tumor responses in patients with recurrent BRAFV600E-mutated HGG with sustained responses in all GBM and 50% of aPXA in this small series, warranting careful consideration in this rare tumor subgroup. This Phase 2 study has closed due to enrollment issues

Anaplastic ganglioglioma-A diagnosis comprising several distinct tumour types.

Anaplastic ganglioglioma is a rare tumour, and diagnosis has been based on histological criteria. The 5th edition of the World Health Organization Classification of Tumours of the Central Nervous System (CNS WHO) does not list anaplastic ganglioglioma as a distinct diagnosis due to lack of molecular data in previous publications. We retrospectively compiled a cohort of 54 histologically diagnosed anaplastic gangliogliomas to explore whether the molecular profiles of these tumours represent a separate type or resolve into other entities. Samples were subjected to histological review, desoxyribonucleic acid (DNA) methylation profiling and next-generation sequencing. Morphological and molecular data were summarised to an integrated diagnosis. The majority of tumours designated asanaplastic gangliogliomas resolved into other CNS WHO diagnoses, most commonly pleomorphic xanthoastrocytoma (16/54), glioblastoma, isocitrate dehydrogenase protein (IDH) wild type and diffuse paediatric-type high-grade glioma, H3 wild type and IDH wild type (11 and 2/54), followed by low-grade glial or glioneuronal tumours including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumour and diffuse leptomeningeal glioneuronal tumour (5/54), IDH mutant astrocytoma (4/54) and others (6/54). A subset of tumours (10/54) was not assignable to a CNS WHO diagnosis, and common molecular profiles pointing to a separate entity were not evident. In summary, we show that tumours histologically diagnosed as anaplastic ganglioglioma comprise a wide spectrum of CNS WHO tumour types with different prognostic and therapeutic implications. We therefore suggest assigning this designation with caution and recommend comprehensive molecular workup.

HGG-34. Upfront Molecular Targeted Therapy for the Treatment of BRAF-mutant Pediatric High-Grade Glioma

Abstract BACKGROUND: The prognosis for pediatric high-grade glioma (pHGG) is poor despite aggressive multi-modal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. METHODS: We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. RESULTS: Nineteen patients were identified, with a median age of 10.7 years (range: 1.8–20.3). Histologic diagnoses included HGG (n=6), glioblastoma (n=3), anaplastic ganglioglioma (n=4), diffuse midline glioma (n=3), high-grade neuroepithelial tumor (n=1), anaplastic astrocytoma (n=1), and anaplastic astroblastoma (n=1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4–5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range,0.3–6.5), three-year progression-free (PFS) and overall survival (OS) for the cohort were 65% and 82%, respectively, and superior to a historical control cohort treated with conventional therapies. CONCLUSIONS: Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes observed compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children’s Oncology Group ACNS1723 clinical trial.

HGG-39. Integrative analyses of BRAFp.v600e mutated gliomas: from epigenetic to metabolic characteristics

BRAF p.v600e mutation is encountered in brain tumors, mostly low grade pediatric diffuse gliomas (LGG) and epileptogenic glioneuronal tumors such as gangliogliomas (GG) or pleomorphic xanthoastrocytomas (PXA). Less frequently this mutation is present in high grade glial or glioneuronal tumors such as pleomorphic xanthoastrocytomas with anaplasia, anaplastic ganglioglioma, anaplastic diffuse astrocytomas or glioblastomas. Recently, few publications were highlighting differently the impact of BRAF mutation and CDKN2A deletion, as independent prognostic factors linked to a worst outcome in low grade forms. We studied retrospectively a monocentric cohort of 17 LGGs (14 GG and 3 pilocytic astrocytomas) and 7 BRAF pv600e HGG. The patients were aged below 20 years. We focused on extended tumors’ biology assessment (MethylEpic 850K, Next-Generation sequencing, RNA sequencing and metabolomics), as well as tumor immune microenvironment by immunohistochemistry. Among the LGGs, only one had a CDKN2A deletion and one a gain on chromosome 5. All except two LGGs had a complete surgical resection. Four of them were treated by chemotherapies but underwent relapses. All HGGs had a surgical resection followed by a first line chemotherapy (mainly Stupp protocol) and radiotherapy. Five patients relapsed rapidly, benefiting from targeted therapy with vemurafenib and/or biotherapy associating dabrafenib plus trametinib. Among those HGGs, we had both subgroups: “de novo” tumors and patients with a history of LGG tumors. Both were responding well to targeted treatments. The biology uncovers in all HGGs a loss of CDKN2A gene and/or protein. Additionally to this gene abnormality, specific transcriptomic expressions were associated to therapeutic response and immune microenvironment. Epigenetic modulation was linked to specific metabolic switches when BRAF p.v600e gliomas were getting higher grade features (e.g., glutaminolysis, serinolysis and phospholipidic metabolism). Those characteristics seem to be able to predict in LGG p.v600e potential evolution.

Uncommon Glioneuronal Tumors: A Radiologic and Pathologic Synopsis.

Glioneuronal tumors are characterized exclusively by neurocytic elements (neuronal tumors) or a combination of neuronal and glial features (mixed neuronal-glial tumors). Most of these tumors occur in young patients and are related to epilepsy. While ganglioglioma, dysembryoplastic neuroepithelial tumor, and desmoplastic infantile tumor are common glioneuronal tumors, anaplastic ganglioglioma, papillary glioneuronal tumor, rosette-forming glioneuronal tumor, gangliocytoma, and central neurocytoma are less frequent. Advances in immunohistochemical and molecular diagnostics have improved the characterization of these tumors and favored the description of variants and new subtypes, some not yet classified by the World Health Organization. Not infrequently, the histologic findings of biopsies of glioneuronal tumors simulate low-grade glial neoplasms; however, some imaging findings favor the correct diagnosis, making neuroimaging essential for proper management. Therefore, the aim of this review was to present key imaging, histopathology, immunohistochemistry, and molecular findings of glioneuronal tumors and their variants.

Upfront molecular targeted therapy for the treatment of BRAF-mutant pediatric high-grade glioma.

The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. Nineteen patients were identified, with a median age of 11.7 years (range, 2.3-21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4-5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3-6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children's Oncology Group ACNS1723 clinical trial.

Anaplastic ganglioglioma in pregnancy a cause of cerebral edema and maternal death

Abstract Objectives The true incidence of anaplastic ganglioglioma during pregnancy is extremely rare, very few cases have been reported in the literature. Case presentation This is a report of a case of anaplastic ganglioglioma diagnosed in pregnancy. The patient is a 23-year-old primigravida who presented at 19 weeks of gestation headache and a convulsive episode. Her workup revealed a rare cerebral tumor that progressed to a neurological decline and died during the postpartum period. Conclusions Anaplastic ganglioglioma is an aggressive counterpart of Glial tumors; in pregnancy they are rare and symptoms are nonspecific. The outcome for the mother in this case fatal and a protocol for these cases has not yet been reported.

Practical aspects regarding the histopathological grading and anaplastic transformation of gangliogliomas – a literature review

Ganglioglioma represents a benign central nervous tumor, occurring predominantly in the pediatric population and affecting the temporal lobe. It is also renowned for its epileptogenic potential. However, to date, there are numerous uncertain features about this tumor, especially about its grading system. In the former World Health Organization (WHO) Classification of central nervous tumors system, gangliogliomas could have been attributed one out of three grades: grade I (benign), grade II (atypical), and grade III (anaplastic). The new classification systems have renounced to atypical ganglioglioma nomenclature, due to the lack of histopathological criteria for this entity. Another controversial aspect of grade I ganglioglioma is its potential to transform into a malignant tumor, namely, most frequently an anaplastic ganglioglioma. Based on our knowledge, there are no literature reviews to date focusing on anaplastic transformation potential. The present paper encompasses all anaplastic transformation of gangliogliomas and has analyzed the time frame between the two events, the age of the patients and its relationship to the complete or subtotal resection and administration of radiotherapy. Thirty-three cases of malignant transformation of ganglioglioma have been reported so far in the literature, with 54.54% of them undergoing progression to anaplastic ganglioglioma and 21.21% to anaplastic ganglioglioma. Median age was 26 years, and the cases were evenly distributed between the two genres. Only 27.27% of all evaluated cases had been administrated adjuvant radiotherapy, and only 44% of the latter have had an incomplete tumoral resection.

Upfront BRAF/MEK inhibitors for treatment of high-grade glioma: A case report and review of the literature.

High-grade gliomas (HGG) with BRAFV600E mutation represent a unique subset of central nervous system tumors. Targeted therapies including BRAF and MEK inhibitors are now being explored as possible new treatment options. We report an 18-year-old female with a grade 3 pleomorphic xanthoastrocytoma treated upfront with dabrafenib and trametinib. We also conducted a systematic literature review of patients with HGG and BRAFV600E mutations treated with BRAF inhibitors. Despite local recurrences resected surgically, the patient has been on dabrafenib and trametinib for more than 54 months. Thirty-two patients with HGG and BRAFV600E mutations treated with BRAF inhibitors were retrieved through our systematic review of the literature. Only 1 young patient with an anaplastic ganglioglioma was treated upfront with a BRAF inhibitor with a curative intent. Best response reported with radiation therapy and systemic therapy was a stable disease (SD) for 18 patients (56.3%) and progressive disease (PD) for 9 patients (28.1%). Responses to treatment regimens that included BRAF inhibitors were reported in 31 patients and included 4 complete responses (12.9%), 23 partial responses (74.2%), 2 SDs (6.5%), and 2 PDs (6.5%). Our patient had durable disease control with dabrafenib and trametinib. Given favorable responses reported in patients with HGG treated with BRAF inhibitors, we believe that upfront targeted therapy is a possible treatment approach that should be studied in the context of a clinical trial.

Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review.

BackgroundDetailed prevalence estimates of BRAFV600 mutations and BRAF inhibitor (BRAFi) treatment responses in V600-mutant glioma will inform trial development.MethodsOur systematic review analyzed overall prevalence of BRAFV600 mutations in glioma and BRAFi treatment response.ResultsBased on 13 682 patients in 182 publications, the prevalence of BRAFV600 in epithelioid glioblastoma (eGBM) was 69% [95% CI: 45–89%]; pleomorphic xanthoastrocytoma (PXA): 56% [48–64%] anaplastic pleomorphic xanthoastrocytoma (aPXA): 38% [23–54%], ganglioglioma (GG): 40% [33–46%], and anaplastic ganglioglioma (aGG): 46% [18–76%]. Prevalence in astroblastoma was 24% [8–43%], desmoplastic infantile astrocytoma (DIA): 16% [0–57%], subependymal giant cell astrocytoma (SEGA): 8% [0–37%], dysembryoplastic neuroepithelial tumor (DNET): 3% [0–11%], diffuse astrocytoma (DA): 3% [0–9%], and pilocytic astrocytoma (PA): 3% [2–5%]. We reviewed 394 V600-mutant gliomas treated with BRAFi from 130 publications. One hundred and twenty-nine pediatric low-grade gliomas showed 4 (3.1%) complete response (CR); 53 (41.1%) partial response (PR); 64 (49.6%) stable disease (SD) and 8 (6.2%) progressive disease (PD). 25 pediatric high-grade gliomas showed CR; PR; SD; PD in 4 (16.0%); 10 (40.0%), 4 (16.0%); and 7 (28.0%) respectively. Thirty-nine adult low-grade gliomas showed CR; PR; SD; PD of 4 (10.3%); 17 (43.6%); 16 (41.0%) and 2 (5.1%) respectively. Ninety-seven adult high-grade gliomas showed CR; PR; SD; PD of 6 (6.2%); 31 (32.0%); 27 (27.8%); and 33 (34.0%) respectively.Conclusions BRAFV600 prevalence is highest in eGBM, PXA, aPXA, GG, aGG, and lower in astroblastoma, DIA, SEGA, DNET, DA, and PA. Our data provide the rationale for adjuvant clinical trials of BRAFi in V600-mutant glioma.

Prevalence of BRAF V600 in primary gliomas: a systematic review

Abstract Aims Glioma is a fatal disease that causes significant years of life lost to an individual. Mutations in the driver gene BRAF, such as the V600 alteration, may contribute to gliomagenesis in adults and children through abnormal signaling causing uncontrolled cell proliferation. The use of BRAF-inhibitor drugs including Vemurafenib and Dabrafenib have shown a favorable response in 48% and 50% of melanoma patients with BRAF V600 mutations respectively. BRAF inhibitors and MEK inhibitors have shown efficacy in certain paediatric gliomas in the recurrent setting. Despite the potential benefit of BRAF inhibitors, the prevalence of BRAF V600 within primary gliomas is not fully discovered. Some studies identify the prevalence to be over 50%, while others find the prevalence to be around 1%. We performed a comprehensive systematic review to determine the prevalence of BRAF V600 within the adult and paediatric glioma population in different diagnostic groups. Method A systematic literature search was performed using Ovid MEDLINE and Embase from genesis to the 22nd October 2020. Studies were not restricted by language. Studies were eligible if patients were histologically diagnosed according to WHO guidelines as a primary glioma evaluating the prevalence of BRAF V600 and included ≥ 10 primary glioma patients. The review protocol was registered in PROSPERO (CRD42019127704). Search results were managed using Endnote. Two independent reviewers assessed the eligibility of the publications using Rayyan, conflicts were evaluated by a third reviewer. Included articles were extracted by one reviewer and confirmed by a second reviewer. Risk of bias assessments were conducted using Hoy et al’s risk of bias tool. Results were synthesized using “metaprop” in R. The meta-analysis was carried out in R which produced forest plots. Results Our cohort included 182 studies with a total of 13669 adult and paediatric glioma patients classified diagnostically according to WHO guidelines. Among 48 glioma entities, BRAF V600 was identified most commonly in epithelioid glioblastoma with a prevalence of 69% (95% confidence interval (CI): 45-89%), followed by pleomorphic xanthoastrocytoma with a prevalence of 56% (95% CI: 48-64%), anaplastic pleomorphic xanthoastrocytoma with a prevalence of 38% (95% CI: 23-54%), ganglioglioma with a prevalence of 40% (95% CI: 33-46%), and anaplastic ganglioglioma with a prevalence of 46% (95% CI: 18-76%). Other glioma entities were found to have a prevalence of BRAF V600, these include astroblastoma (24%), desmoplastic infantile astrocytoma (16%), subependymal giant cell astrocytoma (8%), dysembryoplastic neuroepithelial tumour (3%), diffuse astrocytoma (3%), and pilocytic astrocytoma (3%). Conclusion To our knowledge, this is the largest systematic review examining the prevalence of BRAF V600 in adult and paediatric glioma classified according to diagnostic WHO criteria. However, there were some limitations in this review. The sample sizes of some studies were very small, and the method of mutational analysis for BRAF V600 varied between papers. We found BRAF V600 in a significant prevalence of epithelioid glioblastoma, pleomorphic xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, ganglioglioma, and anaplastic ganglioglioma. Of interest, BRAF V600 mutation was found in a lower prevalence of astroblastoma, desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma, dysembryoplastic neuroepithelial tumour, diffuse astrocytoma, and pilocytic astrocytoma. Consideration of assessment of BRAF V600 mutation may enable further treatment options with BRAF and/or MEK inhibitors in these particular diagnostic entities.

Anaplastic gangliogliomas of the spinal cord: a scoping review of the literature.

Gangliogliomas (GGs) are rare, usually low-grade tumors that account for 1-2% of all central nervous system (CNS) neoplasms. Spinal GGs are exceedingly rare (1% of all spinal tumors) and the presentation of anaplastic features in them is even rarer. According to the last World Health Organization (WHO) classification of CNS neoplasms, anaplastic GG (AGG) is classified as a malignant neoplasm (grade III). We performed a scoping review of the literature to elucidate the epidemiology, clinical features, histopathology, treatment, and outcome of primary spinal AGGs, which, to the best of our knowledge, is the first such review. Relevant studies were identified by a search of the MEDLINE and SCOPUS databases, using the following combination of search strings: (anaplastic ganglioglioma or malignant ganglioglioma or high grade ganglioglioma) AND (spine or spinal or spinal cord). We included studies related to primary or recurrent AGGs and malignant transformation of low-grade GGs. The search produced 15 eligible studies, plus two studies from the references, all of which were case reports of patients with spinal AGGs (17 studies with 22 patients). The mean age of the patients was 21.4years and the sex ratio was 1:1, with male predominance. Motor impairment was the most common presentation, followed by sensory impairment, gait problems, urinary disturbances, and back pain. The thoracic spine was the most frequently involved area (14/22) followed by the cervical (6/22) and lumbar (5/22) spine. In terms of histology, the anaplastic features were usually predominant in the glial element, resembling high-grade astrocytomas, while the neuronal element was composed of the so-called dysplastic ganglion (neuronal) synaptophysin-positive cells, without mitotic figures. Complete surgical resection of the tumor without neurological compromise, plus adjuvant chemotherapy and radiotherapy, was the treatment protocol implemented in the two patients with the best outcome. Primary spinal AGG is an exceedingly rare entity, with only 22 cases being retrieved after an extensive literature search. They appear to affect children and young adults and tend to manifest aggressive behavior. Most studies report that only the glial component of AGGs presents high-grade malignant features, with low mitotic activity in the neuronal component. We therefore suggest that, pending novel targeted therapy, AGGs should be treated as high-grade gliomas, with an aggressive treatment protocol consisting of maximal safe resection and adjuvant chemotherapy and radiotherapy.

HGG-37. UPFRONT TARGETED THERAPY FOR THE TREATMENT OF BRAFV600E-MUTANT PEDIATRIC HIGH-GRADE GLIOMA – A MULTI-INSTITUTIONAL EXPERIENCE

IntroductionSustained responses to molecular targeted therapy with BRAF with or without MEK inhibitors have been reported in patients with recurrent BRAFV600E-mutant pediatric high-grade gliomas (pHGG). The role of upfront targeted therapy in this population, however, has not yet been established. MethodsWe performed a retrospective, multi-institutional record review of patients with BRAFV600E-mutant pHGGs, treated with off-label BRAF and/or MEK inhibitors as part of their initial adjuvant therapy. ResultsSeventeen patients were identified (median age at diagnosis, 8.8 years, range 1.8–20.2). Histologic diagnoses included HGG/glioblastoma (n=10), anaplastic ganglioglioma (n=3), high-grade neuroepithelial tumor (n=2), diffuse midline glioma (n=1) and anaplastic astroblastoma (n=1). Ten patients underwent biopsy (n=8) or subtotal resection (n=2), while near-total or complete resection was accomplished in seven. Concomitant genetic alterations including CDKN2A/B loss, H3K27M and TERT promotor mutations were found in eight tumors. Thirteen patients received focal radiation therapy (RT) and one received craniospinal irradiation prior to targeted therapy. Adjuvant targeted therapy was initiated shortly after diagnosis or completion of RT. Five patients received BRAF-inhibitor monotherapy (dabrafenib or vemurafenib). Twelve patients received combination therapy with the addition of a MEK inhibitor (trametinib). For patients with measurable disease, best responses per COG criteria were CR (n=3), PR (n=7), SD (n=3) and PD (n=1). With median follow-up of 29 months (range 8–78), two-year PFS and OS for the cohort were 74.7% and 81.1%, respectively. Ten (59%) patients remain free of disease recurrence or progression. Grade 3 or higher toxicities were reported in four patients (neutropenia, skin toxicity/photosensitivity, fatigue and weight loss), leading to therapy discontinuation in two. ConclusionsUpfront targeted therapy for patients with BRAFV600E mutant pHGG appears tolerable and effective, with a durable disease control rate that is superior to historical data. This promising paradigm is currently being evaluated prospectively in the COG ACNS1723 clinical trial.

A novel histopathological grading system for ganglioglioma.

Gangliogliomas are central nervous system tumors located in the temporal lobe of young patients, frequently associated with epilepsy. In this paper, we propose a grading system based solely on histopathological criteria. We reevaluated all cases of ganglioglioma, atypical ganglioglioma, and anaplastic ganglioglioma diagnosed between 2011 and 2020 in the Pathology Department of the Emergency Clinical Hospital Bagdasar-Arseni, based on the type of glial mitoses, the number of neuronal and glial mitoses, presence of necrosis, microvascular proliferation, eosinophilic granular bodies, hypercellularity, presence and disposition of inflammatory infiltrate and atypical pleomorphism. Based on the proposed grading system, a score of 0–4 corresponded to a benign ganglioglioma, 5–9 to an atypical ganglioglioma, and 10–18 to an anaplastic ganglioglioma. The survival rates were 90% for benign ganglioglioma, 71.43% for atypical ganglioglioma, and 62.54% for anaplastic ganglioglioma. One case of benign ganglioglioma underwent a malignant transformation into anaplastic ganglioglioma, and recurrences were noticed in 28.57% of atypical ganglioglioma cases and 30.7% of all anaplastic gangliogliomas. The presence of rare glial mitoses and hypercellularity was correlated with mortality in cases of atypical ganglioglioma. We believe this histopathological scoring system could be used as a three-tier system to identify atypical ganglioglioma cases that are bound to have an aggressive course of evolution and require close follow-up. The other option would be to convert it to a two-tier grading system that can separate low-grade gangliogliomas from high-grade ones. The latter category can encompass both atypical and anaplastic ganglioglioma due to the high mortality of both entities.

Novel Perspectives Regarding CD34 Immunoexpression Patterns in Gangliogliomas.

Gangliogliomas are extremely rare central nervous tumors composed of an admixture of glial and neuroepithelial elements. Gangliogliomas mainly affect the temporal lobe and occur in the pediatric population. There are several controversies in the scientific literature regarding these tumors, which debuted with the exclusion of grade II gangliogliomas in the 2006 edition of the current World Health Organization (WHO) classification. The upcoming edition due in the last months of 2021 is not expected to include changes regarding the current classification of glio-neuronal tumors. This vision has led to a number of articles that have pushed for the reintroduction of this category. However, these articles support the reintroduction of this degree in terms of prognosis and evolution, without providing clear criteria for the inclusion of certain gangliogliomas in this category. On the other hand, there are uncertainties about the relationship of gangliogliomas with focal cortical dysplasia. The coexistence of the two entities, as well as their succession are occasionally encountered in practice and have led to numerous studies that have tried to clarify the relationship between them. The most common and most accessible element in routine practice is the immunoreactivity for CD34. Both entities express this marker, and dual lesions express the highest percentage of immunoreactivity for CD34. In this article, we study the expression of CD34 on a series of cases including both grade I gangliogliomas and anaplastic gangliogliomas diagnosed between 2011 and 2020 in a Neuropathology Unit in Bucharest Romania.

HGG-47. DECREASED GROWTH VELOCITY WITH LONG TERM USE OF BRAFV600e AND MEK INHIBITION IN A PATIENT WITH ANAPLASTIC GANGLIOGLIOMA

PURPOSETo describe decreased growth velocity with long term use of BRAFV600e and MEK inhibition in a patient with anaplastic ganglioglioma.RESULTS4-year-old patient was found to have a 6 x 4.6 x 5 cm mass in the hypothalamus. Pathology consistent with anaplastic ganglioglioma and chromosomal microarray revealed a BRAFV600e mutation. Patient started on dabrafenib and trametinib and tumor decreased 85% after 3 months. She is stable without significant toxicities 39 months on therapy, and is now 8 years old. Patient had been growing at the 25% for weight and 12% for height but is now 65% for weight and 0.5% for height. It is difficult to tease out the relationship between the tumor, the location of the tumor, and the BRAF and MEK inhibitors and their effect on growth. Discussions with the family and endocrinology are ongoing but being <1% for height will lead to decrease in quality of life.CONCLUSIONSFurther follow-up study is needed to determine if this is truly a long-term toxicity, or if this may just be a direct result of the location of the tumor. Would supplementation with growth hormone in this patient lead to losing control of a high grade tumor, or would it simply replace a hormone that is not produced?

HGG-31. UNIQUE BIOLOGICAL CHARACTERISTICS OF RADIATION-INDUCED GLIOMAS

Radiation-induced gliomas (RIGs) are the most common secondary solid tumours with very unfavourable prognosis. We aimed to describe different clinical and molecular biological characteristic of RIGs from primary gliomas. We reviewed clinical data of ten patients with RIGs. In patients with available samples, we used the whole genome methylation array and performed targeted sequencing for specific mutations. Between 2000–2018, we diagnosed RIG in 10 patients (M/F 2/8) aged 5–12 years at primary diagnosis of different solid tumours and acute leukaemia. These patients developed RIG with a median 9.5 years (ranging 3–31) after primary diagnosis. Eight patients died within 1 year after diagnosis of RIG and 2 patients are still alive more than 4 years from this diagnosis. According to Heidelberg DNA methylation-based classification, most RIGs belong to the IDH-wild type glioblastoma subclass midline which biologically corresponds to diffuse midline glioma (DMG). However, compared to primary DMGs they do not carry the characteristic H3K27M mutation. One patient developed anaplastic ganglioglioma with BRAF-V600E mutation and methylation profile identical to pleomorphic xanthoastrocytoma (alive for 4 years after diagnosis of RIG). In half of the patients from the group DMGs IDH wild type, examined by methylation array, PDGFRA amplification was found. Our data shows that most RIGs are midline IDH-wild type glioblastomas with poor prognosis that are biologically different from primary DMGs. PDGFRA amplifications are potentially targetable by kinase inhibitors in order to order to prognosis of these patients.