Rosette-forming Glioneuronal Tumor Research Articles

P.073 Spontaneous fluctuation of contrast enhancement in adult pilocytic astrocytoma and other low-grade brain tumors

Background: Pilocytic astrocytoma and other circumscribed low-grade brain tumors can exhibit spontaneous enhancement changes despite stable size and clinical status. We aimed to describe this phenomenon in adults. Methods: We performed a retrospective review of our MRI database (2011-2021) to identify cases with enhancement changes in otherwise stable tumors. We searched for reports containing: “pilocytic”, “pilomyxoid”, “RGNT”, “rosette”, “glioneuronal”, “DNET”, and “dysembryoplastic”. Exclusion criteria included WHO grade 3/4 tumors, patients <19 years, equivocal diagnostic findings, and no serial MRIs. We reviewed 238 patients. Results: We identified 12 adult patients with the desired phenomenon: 6 pilocytic astrocytoma, 1 pilomyxoid astrocytoma, 2 rosette-forming glioneuronal tumor, 1 unverified low-grade glioma, and 2 cases without biopsy. Seven were untreated, while five were residual or recurrent tumors. Six showed a pattern of new/increasing and subsequent decreasing/disappearing enhancement over 1-4 years. One exhibited spontaneous regression of enhancement over 1 year. Five showed repeating cycles of increasing and decreasing enhancement over longer monitoring periods of 7-15 years, with mean duration of increasing enhancement prior to decline of 21.4 months (SD 5.9). Conclusions: Spontaneous contrast enhancement fluctuation in adult pilocytic astrocytoma and other circumscribed low-grade brain tumors can occur, and on its own should not be misconstrued as evidence of tumor progression/regression.

Clinicopathological analysis of rosette-forming glioneuronal tumors

BackgroundThis study aimed to investigate the clinicopathological characteristics, diagnostic indicators, and critical factors for the differential diagnosis of rosette-forming glioneuronal tumor (RGNT).Patients and methodsThis retrospective study included six surgically treated RGNT cases. We analyzed and summarized their clinical manifestations, radiological features, histological morphology, immunophenotype, and molecular genetic changes, supplemented with a literature review.ResultsThe patients comprised four males and two females with a mean age of 35 years. The tumors were located in the cerebellum (two cases); the fourth ventricle, quadrigeminal cistern, and third ventricle (one case each); and the fourth ventricle and brainstem (one case). Clinical manifestations included headaches in four cases, left eyelid ptosis in one case, and one asymptomatic case only identified during physical examination. Microscopically, the tumor cells were uniform in size and were marked by rosette-like or pseudorosette-like structures around the neuropil and blood vessels. Immunohistochemistry revealed biphasic patterns. The central neuropil components of the rosette-like structures around the neuropil and the pseudorosette structures of the perivascular regions expressed Syn, while the cells surrounding the rosettes expressed Olig2 and not GFAP. GFAP and S-100 were expressed in the glial components but not in the rosette or pseudorosette regions. The Ki-67 proliferation index was typically low. Molecular genetic analysis showed that the main molecular changes involved FGFR1 mutation accompanied by PIK3R1 mutation. None of the patients received chemoradiotherapy postoperatively. Follow-up durations varied between 4 and 23 months with no recorded recurrence or metastasis.ConclusionRGNT is a comparatively rare mixed glioneuronal tumor that occurs in the midline structures. Its morphology shows certain overlaps with other low-grade neuroepithelial tumors. Identifying the rosettes around the neuropil is critical for morphological diagnosis, and the molecular identification of FGFR1 mutations accompanied by PIK3R1 mutations can facilitate diagnosis.

H3 K27M mutation in rosette-forming glioneuronal tumors: a potential diagnostic pitfall.

According to the fifth edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS), diffuse midline glioma H3 K27-altered is a grade 4 infiltrative glioma that arises from midline anatomical structures and is characterized by the loss of H3 K27me3 and co-occurring H3 K27M mutation or EZHIP overexpression. However, the H3 K27M mutation has also been observed in circumscribed gliomas and glioneuronal tumors arising in midline anatomical structures, which may result in diagnostic pitfalls.Rosette-forming glioneuronal tumor (RGNT) is a CNS WHO grade 1 neoplasm that histologically features neurocytic and glial components and originates in midline anatomical structures.This study aimed to assess whether RGNTs, similar to other midline tumors, may exhibit immunohistochemical loss of H3 K27me3 and harbor the H3 K27M mutation.All seven analyzed RGNTs displayed immunohistochemical loss of H3 K27me3 in all tumor cells or H3 K27me3 mosaic immunostaining. In one case, H3 K27me3 loss was associated with the H3 K27M mutation, whereas the other six cases did not exhibit any H3 mutations or EZHIP overexpression. During a follow-up period of 23 months, the H3 K27M-mutant case remained unchanged in size despite partial resection, indicating that the H3 mutation may not confer higher biological aggressiveness to RGNT.The immunohistochemical loss of H3 K27me3 co-occurring with the H3 K27M mutation may result in the potential misdiagnosis of RGNT, especially in cases of small biopsy specimens consisting of only the glial component.

Diffusely invasive supratentorial rosette-forming glioneuronal tumor: illustrative case.

Rosette-forming glioneuronal tumors (RGNTs) are rare tumors composed of mixed glial and neurocytic components. Most lesions are confined to the posterior fossa, especially in the region of the fourth ventricle, in young adults. In few instances, diffuse involvement of the supratentorial region is identified, thereby creating significant challenges in diagnosis, surgical intervention, and prognostication. The authors present a 23-year-old female with chronic headaches, papilledema, and hydrocephalus who underwent radiographic evaluation revealing obstructive hydrocephalus and diffuse supratentorial enhancing and nonenhancing cystic and nodular lesions. The patient underwent a right frontal craniotomy and septostomy. An exophytic nonenhancing right frontal horn lesion was resected, and an enhancing third-ventricular lesion was biopsied. Final pathology of both of the lesions sampled was consistent with RGNT. Next-generation sequencing demonstrated tumor alterations in the FGFR-1 and PIK3CA genes. Targeted therapy with the FGFR inhibitor erdafitinib demonstrated a partial remission. Diffuse supratentorial spread of RGNT is an extremely rare presentation of an already uncommon pathology. In some cases, gross-total resection may not be feasible. Goals of surgery include acquiring tissue for diagnosis, maximizing safe resection, and treating any associated hydrocephalus. FGFR inhibitors may be of benefit in cases of disease progression.

Incidentally exploring natural course of a rare entity: representative case for rosette-forming glioneuronal tumors.

Rosette-forming glioneuronal tumors (RGNT) are extremely rare mostly benign tumors of the central nervous system, which are often studied for its histological aspects despite relatively small numbers of clinical especially radiological knowledge.Despite the increasing number of publications on different localizations and treatment protocols, the morphologic and temporal development process of this rare tumor entity is not clear. We were able to coincidentally observe the entire course of the tumor growth of a RGNT on subsequent MRI examinations in a typical case with mild clinical symptoms and no other neurological illnesses, thus possible clinical complications were prevented.

Endoscopic resection of thalamic lesions via supracerebellar infratentorial approach: a case series and technical note.

The deep location of the thalamus and the complex neural circuits in the surrounding area make surgery extremely challenging. Feasibility and advisability of using a supracerebellar infratentorial approach (SCITA) for endoscopic resection of thalamic lesions remains to be further evaluated. Fifteen patients who underwent endoscopic resection of thalamic via SCITA from 2014 to 2021 were retrospectively collected. We analyzed preoperative tumor-related variables and surgical procedures in detail, as well as postoperative outcomes. Lesions mainly located in the posterior and/or medial part of the thalamus, and some of them expanded downward, or backward. The mean size of them was 30 × 24mm. Five of the nine patients with preoperative hydrocephalus underwent cerebrospinal fluid shunts to relieve increased intracranial pressure. Among the 15 patients, 4 were glioblastoma, 3 were pilocytic astrocytoma, and the rest included 1 case of anaplastic astrocytoma, melanoma, polymorphous low-grade neuroepithelial tumor of the young, rosette-forming glioneuronal tumor, inflammatory lesion, diffuse midline glioma, and cavernous hemangioma. The majority of patients (10/15) achieved gross total resection, which has become more pronounced since paramedian SCITA was used in place of the midline approach in 2020 (6/8). Three patients had unresolved or new onset of clinical symptoms after surgery, resulting in a decreased KPS score at discharge. Neuro-endoscopic techniques can ameliorate many of the shortcomings of the SCITA. With the accumulation of experience and technological progress, more deficiencies of this approach may be improved, enabling safe and effective resection of posterior and/or medial part thalamic lesions.

Treatment of Pineal Region Rosette-Forming Glioneuronal Tumors (RGNT).

Simple SummaryThe WHO classification of tumors of the central nervous system described for the first time the extremely rare entity of rosette-forming glioneuronal tumors (RGNT, CNS WHO grade 1) in 2007. Due to the rarity of this entity in the pineal region, no specific therapy guidelines currently exist. With our large cohort of patients treated at a single center (from August 2018–June 2021) and with the already described cases in the literature, we would like to highlight possible therapy and follow-up concepts. After the main symptoms of headache or generalized epileptic seizure, cystic lesions adjacent to the pineal gland and the third ventricle were diagnosed in imaging. None of the patients underwent additional chemotherapy or radiotherapy after gross total (GTR)/subtotal resection or endoscopic biopsy. In cases where surgical resection seems feasible with a reasonable surgical risk, we advocate GTR. Long-term MRI follow-up is essential to detect a slow tumor progression.Background: Rosette-forming glioneuronal tumor (RGNT) is an extremely rare entity described for the first time in the WHO classification of tumors of the central nervous system in 2007. Predominantly, single case reports of RGNT in the pineal region have been published, and specific therapy concepts are pending. Methods: The study group comprised all patients with the RGNT (CNS WHO grade 1) in the pineal region that underwent microsurgical tumor removal in our center (August 2018–June 2021). Surgical strategy, histological findings, and clinical outcome are presented, and the results are evaluated and compared to published case reports. Results: Four male patients aged under 50 years (range between 20 and 48 years) and one female patient, 51 years old, were included in this study. Chronic headaches and generalized epileptic seizures were the main symptoms. Supra-cerebellar infratentorial gross total tumor resection (GTR) was performed in two cases, two patients underwent subtotal tumor resection, and an endoscopic biopsy was performed in case five. Conclusion: In cases where surgical resection seems feasible with a reasonable surgical risk, we advocate GTR. Regular and long-term MRI follow-up is essential to detect a slow tumor progression. The role of additional chemotherapy or radiotherapy remains unclear.

Redefining germline predisposition in children with molecularly characterized ependymoma: a population-based 20-year cohort

Ependymoma is the second most common malignant brain tumor in children. The etiology is largely unknown and germline DNA sequencing studies focusing on childhood ependymoma are limited. We therefore performed germline whole-genome sequencing on a population-based cohort of children diagnosed with ependymoma in Denmark over the past 20 years (n = 43). Single nucleotide and structural germline variants in 457 cancer related genes and 2986 highly evolutionarily constrained genes were assessed in 37 children with normal tissue available for sequencing. Molecular ependymoma classification was performed using DNA methylation profiling for 39 children with available tumor tissue. Pathogenic germline variants in known cancer predisposition genes were detected in 11% (4/37; NF2, LZTR1, NF1 & TP53). However, DNA methylation profiling resulted in revision of the histopathological ependymoma diagnosis to non-ependymoma tumor types in 8% (3/39). This included the two children with pathogenic germline variants in TP53 and NF1 whose tumors were reclassified to a diffuse midline glioma and a rosette-forming glioneuronal tumor, respectively. Consequently, 50% (2/4) of children with pathogenic germline variants in fact had other tumor types. A meta-analysis combining our findings with pediatric pan-cancer germline sequencing studies showed an overall frequency of pathogenic germline variants of 3.4% (7/207) in children with ependymoma. In summary, less than 4% of childhood ependymoma is explained by genetic predisposition, virtually restricted to pathogenic variants in NF2 and NF1. For children with other cancer predisposition syndromes, diagnostic reconsideration is recommended for ependymomas without molecular classification. Additionally, LZTR1 is suggested as a novel putative ependymoma predisposition gene.

Immune Microenvironment and Lineage Tracing Help to Decipher Rosette-Forming Glioneuronal Tumors: A Multi-Omics Analysis.

Rosette-forming glioneuronal tumors (RGNT) are rare low-grade primary central nervous system (CNS) tumors. The methylation class (MC) RGNT (MC-RGNT) delineates RGNT from other neurocytic CNS tumors with similar histological features. We performed a comprehensive molecular analysis including whole-exome sequencing, RNAseq, and methylome on 9 tumors with similar histology, focusing on the immune microenvironment and cell of origin of RGNT. Three RGNT in this cohort were plotted within the MC-RGNT and characterized by FGFR1 mutation plus PIK3CA or NF1 mutations. RNAseq analysis, validated by immunohistochemistry, identified 2 transcriptomic groups with distinct immune microenvironments. The "cold" group was distinguishable by a low immune infiltration and included the 3 MC-RGNT and 1 MC-pilocytic astrocytoma; the "hot" group included other tumors with a rich immune infiltration. Gene set enrichment analysis showed that the "cold" group had upregulated NOTCH pathway and mainly oligodendrocyte precursor cell and neuronal phenotypes, while the "hot" group exhibited predominantly astrocytic and neural stem cell phenotypes. In silico deconvolution identified the cerebellar granule cell lineage as a putative cell of origin of RGNT. Our study identified distinct tumor biology and immune microenvironments as key features relevant to the pathogenesis and management of RGNT.

Molecular analyses of rosette-forming glioneuronal tumor of the midbrain tegmentum: A report of two cases and a review of the FGFR1 status in unusual tumor locations

Background: Rosette-forming glioneuronal tumor (RGNT) is a rare tumor that arises primarily in the posterior fossa, with molecular features of FGFR1 mutation. A previous study reported that brainstem RGNT accounts for only 2.7% cases; therefore, midbrain RGNT is infrequent.Case Description: The authors encountered two cases of RGNT located in the midbrain tegmentum (Case 1: 23-year-old woman and Case 2: 18-year-old boy), both exhibiting similar cystic components with gadolinium-enhanced cyst walls on preoperative magnetic resonance imaging, surgically resected through the occipital transtentorial approach. Histological findings in both cases comprised two characteristic architectures of neurocytic and glial components, typical of RGNT. Molecular assessment revealed no FGFR1 mutation in the initial specimen, but revealed FGFR1 K656E mutation in the recurrent specimen in Case 1 and showed no FGFR1 mutation but showed TERT C228T mutation in Case 2. Neither case revealed IDH1/2, BRAF, H3F3A K27, H3F3A G34, or HIST1H3B K27 mutations. DNA methylation-based classification (molecularneuropathology.org) categorized both cases as RGNT, whose calibrated scores were 0.99 and 0.47 in Cases 1 and 2, respectively.Conclusion: Midbrain tegmentum RGNTs exhibited typical histological features but varied FGFR1 statuses with TERT mutation. RGNT in rare locations may carry different molecular alterations than those in other common locations, such as the posterior fossa.

Rosette-Forming Glioneuronal Tumor at Septum Pellucidum: Insights Gained from a Common Tumor at Rare Location

AbstractThe rosette-forming glioneuronal tumor (RGNT) is an uncommon entity and carries a special character because of its mixed glial and neuronal composition in the histomorphological appearance. These lesions have a benign character and carry a good outcome if undergoes gross total resection. Over the past 15 years, there have been a significant change in their nomenclature depending upon the location to histological composition. Herein, we report an interesting case of a 26-year-old lady who was diagnosed to have the lesion at the septum pellucidum with significant symptoms in the form of headache and seizure episodes. A gross total resection was achieved and she made an uneventful recovery. We discuss the literature on the incidence, location, and histological characteristics of the RGNT in various age groups.

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.

Frequent FGFR1 hotspot alterations in driver-unknown low-grade glioma and mixed neuronal-glial tumors

PurposeLow-grade gliomas (LGG) and mixed neuronal-glial tumors (MNGT) show frequent MAPK pathway alterations. Oncogenic fibroblast growth factor receptor 1 (FGFR1) tyrosinase kinase domain has been reported in brain tumors of various histologies. We sought to determine the frequency of FGFR1 hotspot mutations N546 and K656 in driver-unknown LGG/MNGT and examined FGFR1 immunohistochemistry as a potential tool to detect those alterations.MethodsWe analyzed 476 LGG/MNGT tumors for KIAA-1549-BRAF fusion, IDH1/2, TERT promotor, NF1, H3F3A and the remaining cases for FGFR1 mutation frequency and correlated FGFR1 immunohistochemistry in 106 cases.Results368 of 476 LGG/MNGT tumors contained non-FGFR1 alterations. We identified 9 FGFR1 p.N546K and 4 FGFR1 p.K656E mutations among the 108 remaining driver-unknown samples. Five tumors were classified as dysembryoplastic neuroepithelial tumor (DNT), 4 as pilocytic astrocytoma (PA) and 3 as rosette-forming glioneuronal tumor (RGNT). FGFR1 mutations were associated with oligodendroglia-like cells, but not with age or tumor location. FGFR1 immunohistochemical expression was observed in 92 cases. FGFR1 immunoreactivity score was higher in PA and DNT compared to diffuse astrocytoma, but no correlation between FGFR1 mutation in tumors and FGFR1 expression level was observed.ConclusionFGFR1 hotspot mutations are the fifth most prevailing alteration in LGG/MNGT. Performing FGFR1 sequencing analysis in driver-unknown low-grade brain tumors could yield up to 12% FGFR1 N546/K656 mutant cases.

26. Co-occurrence of rosette-forming glioneuronal tumors with Noonan Syndrome

At our pediatric hospital, we employ comprehensive molecular profiling to aid in diagnosis, prognostication, treatment, and evaluation of germline cancer predisposition in individuals with rare and refractory cancers. Here, we describe two patients with rosette-forming glioneuronal tumors (RGNT) (WHO grade I) who underwent paired tumor-comparator exome sequencing, as well as RNA-sequencing and DNA methylation analysis of the disease-involved tissue.

LGG-06. COMPREHENSIVE GENOMIC CHARACTERIZATION AND INTEGRATED CLINICAL ANALYSIS OF LOW-GRADE GLIOMAS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1

BackgroundLow-grade gliomas (LGGs) arising in children with neurofibromatosis type 1 (NF1) are usually not biopsied. To identify secondary genetic alterations or molecular features that may contribute to pathogenesis and correlate with clinical behavior, we initiated a comprehensive molecular and clinical analysis of pediatric NF1-LGGs. MethodsNF1-LGGs were analysed by whole-genome sequencing (31), targeted gene panel sequencing (9), RNAseq transcriptomal profiling (33) and genome-wide DNA methylation analysis (67). Clinical annotation was available for 48 subjects. ResultsMost LGGs harbored bi-allelic NF1 inactivation as the sole genetic abnormality, but 11% had additional alterations (FGFR1 mutation, n=3; PIK3CA mutation, n=2; homozygous 9p21 deletion, n=2; MYB:QKI fusion, n=1; SETD2 mutation, n=1; EGFR amplification, n=1). FGFR1 mutation conferred additional growth advantage in multiple complementary murine Nf1 models. 88% of NF1-LGGs resembled sporadic pilocytic astrocytoma (PA) by methylation, higher than that based on histology. Non-PA methylation patterns included low-grade glial/glioneuronal tumors, rosette-forming glioneuronal tumors, MYB/MYBL1-altered glioma, and high-grade astrocytoma with piloid features (2 tumors histologically diagnosed as LGG). In total, 18% of samples were classified as non-PA and/or harbored an additional non-NF1 mutation. Non-PA methylation class tumors were more likely to harbor an additional non-NF1 mutation (p=0.005). 7.7% of optic pathway hypothalamic gliomas (OPHGs) had other mutations or were not classified by methylation as PA, compared with 20.6% of NF1-LGGs arising elsewhere. There was no difference based on age for the presence of an additional non-NF1 mutation or non-PA methylation class. ConclusionsGiven the overall low occurrence of non-NF1 mutations or non-PA methylation class tumors in this series, routine clinical biopsy of typically-appearing NF1-LGG may not be indicated, particularly for children with OPHG. Biopsy should be considered for non-OPHG tumors refractory to conventional treatment. As additional agents are developed and treatment strategies evolve, the rationale for biopsy of NF1-LGG may become stronger.

RARE-37. NOONAN SYNDROME AND GLIONEURONAL TUMORS: A CENTRAL NERVOUS SYSTEM CANCER PREDISPOSITION ASSOCIATION?

BACKGROUNDNoonan syndrome (NS) is associated with germline Ras signaling pathway mutations, RAS overactivation and increased tumorigenesis risk. Rosette-forming glioneuronal tumors (RFGT) are rare indolent tumors. We report the molecular profiling of two patients with NS and RFGT. PATIENT 1: A 22-year-old male with NS was diagnosed with RFGT after partial tumor resection followed by focal irradiation. He was enrolled on a comprehensive genomic profiling study involving paired tumor-normal whole exome sequencing and RNA sequencing of the disease-involved tissue, revealing a germline PTPN11 alteration (p.Gly60Ala) consistent with NS, and a somatic deletion (p.Ile442_Thr454del) in PIK3R1 and a somatic variant (p.Lys656Glu) in FGFR1 with concomitant increased expression of PIK3R1 and FGFR1 by RNA-sequencing. The patient remains without tumor progression now nine months since irradiation. PATIENT 2: A 19-year-old male with persistent headaches, underwent a brain MRI demonstrated multiple abnormal signals in the pineal region and midbrain. He had a stereotactic biopsy revealing RFGT. He was enrolled on the genomic study revealing a germline PTPN11 alteration (p.Asn308Asp) resulting in a new diagnosis of NS. Several family members were subsequently identified with clinical features of NS, including his mother and two siblings, enabling appropriate counseling. Two somatic variants were found in trans in PIK3R1 (p.Thr454_Phe456del and p.Glu451_Asn453delinsAsp), and a somatic variant (p.Val695Met) in FGFR1, with resultant overexpression of PIK3R1. The patient is monitored with surveillance imaging.CONCLUSIONWe report the molecular profiling of two patients with NS and RFGT; strongly suggesting their connection to RASopathies through the overactivation of the MAPK and PI3K/AKT/mTOR signaling pathways.

LGG-47. SYSTEMIC THERAPY OF ROSETTE-FORMING GLIONEURONAL TUMOR OF THE FOURTH VENTRICLE INAN ADOLESCENT

An 11 y.o. female presented to a GI specialist with complaints of morning vomiting and periumbilical abdominal pain for several months. Had progressing symptoms with GI work-up for ~1 year. She developed diplopia and worsening headaches. Imaging revealed a T2/FLAIR hyperintense mass in the 4th ventricle with heterogeneous enhancement and obstructive hydrocephalus. Three T2 bright, non-enhancing, subcentimeter masses identified in the right cerebellum. Due to poor differentiation between tumor and normal tissue at brainstem, only partial resection (PR) was feasible. Pathology initially called pilocytic astrocytoma (PA). All symptoms resolved after PR. Slow progression in the tumor and “satellite” lesions noted over two years. Second opinion and molecular typing reclassified the tumor as rosette-forming glioneuronal tumor (RFGNT) with a mutation in PIK3CA. Therapy started with vinblastine and carboplatin with stable disease x 7 months, discontinued due to allergic reaction to carboplatin. Initiated therapy with everolimus, an mTOR inhibitor. The tumor’s characteristics on imaging changed with initial growth and increase in peripheral enhancement in one satellite and the primary tumor. Nevertheless, we persevered. When comparing pre-treatment MRI to most recent 7 months later, there has been an overall decrease in volume of expansile heterogenous tumor along the margins of the fourth ventricle. The degree of peripheral enhancement associated with the mass has increased. RFGNT is a rare tumor included in WHO classification since 2007. Ellezam et al identified recurrent PIK3CA mutations. To our knowledge, this is the only report of treatment targeting the mutation. We report a radiographic response despite initial growth.

PATH-22. COMPREHENSIVE ANALYSIS OF DIVERSE LOW-GRADE NEUROEPITHELIAL TUMORS WITH FGFR1 ALTERATIONS REVEALS A DISTINCT MOLECULAR SIGNATURE OF ROSETTE-FORMING GLIONEURONAL TUMOR

Abstract The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma (PA), dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined, nor are the histopathologic features of pilocytic astrocytomas with FGFR1 alterations versus those harboring the more common BRAF mutations or fusions. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and PA are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis refines the classification and histopathologic spectrum of LGNET with FGFR1 alterations.

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.

Endoscopic assisted craniotomy for resection of fourth ventricular lesions and confirmation of aqueductal patency via a suboccipital median aperture approach

Adequate exposure to fourth ventricular (4V) lesions located adjacent to the cerebral aqueduct and superior medullary velum often mandates extensive telovelar dissection. We assessed the utility of endoscopic assistance via a median aperture approach during suboccipital resection of 4V lesions. We retrospectively reviewed a series of nine patients who underwent suboccipital resection of a 4V lesion via an endoscopic-assisted median aperture approach from 2011 to 2018. Our series included the following pathology: ependymoma (2), rosette-forming glioneuronal tumors (2), pilocytic astrocytoma (1), metastatic melanoma (1), epidermoid cyst (1), organized hematoma (1), and neurocysticercosis (1). Preoperative symptoms included headache (n = 8, 88.9%), nausea (n = 5, 55.6%), vomiting, dizziness, and gait disturbance (n = 4 each, 44.5%). In four cases, the endoscope was used for the majority of the resection or to resect additional tumor located rostrally in the 4V following maximal microscopic resection. In five patients, it was used to confirm extent of resection and patency of the cerebral aqueduct. Gross total resection was achieved in five patients (55.6%). No postoperative complications were attributed to use of the endoscope for additional resection. No patients required immediate CSF diversion, and one patient underwent ventriculoperitoneal (VP) shunt insertion over one year after initial biopsy/fenestration due to tumor progression. Our series is the first to demonstrate the utility of angled endoscopic assistance via a median aperture approach during microsurgical approaches for a variety of 4V lesions. Confirmation of patency of the cerebral aqueduct may help avoid requirements for CSF diversion.