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

Introduction: Low-grade epilepsy-associated neuroepithelial tumors (LEATs) create a diagnostic challenge in daily practice and intraoperative pathological consultation (IC) in particular. Squash smears are extremely useful in IC for accurate diagnosis; however, the knowledge on cytopathologic features of LEATs is based on individual case reports. Here, we discuss the 3 most common and well-established entities of LEATs: ganglioglioma (GG), dysembryoplastic neuroepithelial tumor (DNT), and papillary glioneuronal tumor (PGNT). Methods: Thirty patients who underwent surgery for GG, DNT, and PGNT between 2001 and 2021 were collected. Squash smears prepared during intraoperative consultation were reviewed by 1 cytopathologist and an experienced neuropathologist. Results: Among the 30 tumors, 16 (53.3%) were GG, 11 (36.6%) DNT, and 3 (10%) PGNT. Cytomorphologically, all of the 3 tumor types share 2 common features such as dual cell population and vasculocentric pattern. GG smears were characteristically composed of dysplastic ganglion cells and piloid-like astrocytes on a complex architectural background of thin- to thick-walled vessels. DNT, on the other hand, showed oligodendroglial-like cells in a myxoid thin fibrillary background associated with a delicate capillary network. Common cytological features of PGNT were hyperchromatic cells with narrow cytoplasm surrounding hyalinized vessels forming a pseudopapillary pattern and bland cells with neuroendocrine nuclei dispersed in a neuropil background. Conclusion: A higher diagnostic accuracy can be obtained when squash smears are applied with frozen sections. However, it is important to integrate clinical and radiologic features of the patient as well as to know the cytopathologic features of the LEAT spectrum in the context of differential diagnosis to prevent misinterpretation in the IC.

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LGG-26. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) IN CHILDREN: DIFFERENT CLINICAL PRESENTATIONS AND OUTCOMES

Neuro-Oncology ◽

10.1093/neuonc/noaa222.408 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii371-iii371

Author(s):

Andge Valiakhmetova ◽

Ludmila Papusha ◽

Ludmila Yasko ◽

Alexander Druy ◽

Alexander Karachunsky ◽

...

Keyword(s):

Mapk Pathway ◽

Braf Inhibitor ◽

Complete Response ◽

Mek Inhibitor ◽

Braf V600e ◽

Glioneuronal Tumor ◽

Low Grade ◽

Conventional Chemotherapy ◽

Diffuse Leptomeningeal Glioneuronal Tumor ◽

Braf Fusion

Abstract Diffuse leptomeningeal glioneuronal tumor (DLGNT) is an extremely rare disease, newly recognized in the 2016 WHO classification of tumors of the CNS. Most DLGNTs are low-grade neuroepithelial tumors with variable elements of neuronal/neurocytic and glial differentiation, have diffuse leptomeningeal enhancement on MRI, and typically harbor KIAA1549-BRAF fusions. Other alterations, such as the BRAF V600E substitution, are less common. Here, we present three cases of DLGNT with different presentations and outcomes. The first patient is a 2yr-old male with KIAA1549-BRAF fusion, and was treated with Carbo/VCR chemotherapy after a biopsy, with resultant ongoing stable disease for 3.5 years. The second patient, an 8yr-old male had the BRAF V600E point mutation and was treated with conventional chemotherapy (VCR/carboplatin). On progression, he received the BRAF inhibitor vemurafenib, achieving a complete response which last 14 month. The third patient, a 27 month old male, harbored a KIAA1549-BRAF fusion and was treated at diagnosis with the MEK inhibitor trametinib. The tumor has been radiographically stable in the context of clinical improvement for 21 months since the treatment initiation, ongoing 24 month. In summary, we present further evidence of MAPK pathway alterations in children with DLGNT. We describe a range of molecular presentations and clinical outcomes, including one patient treated with conventional chemotherapy with further stabilization of disease during 3.5 years and two patients who were successfully treated with targeted therapy.

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Risk stratification in pediatric low-grade glioma and glioneuronal tumor treated with radiation therapy: an integrated clinicopathologic and molecular analysis

Neuro-Oncology ◽

10.1093/neuonc/noaa031 ◽

2020 ◽

Vol 22 (8) ◽

pp. 1203-1213 ◽

Cited By ~ 5

Author(s):

Sahaja Acharya ◽

Jo-Fen Liu ◽

Ruth G Tatevossian ◽

Jason Chiang ◽

Ibrahim Qaddoumi ◽

...

Keyword(s):

Overall Survival ◽

Radiation Therapy ◽

High Risk ◽

Risk Stratification ◽

Risk Groups ◽

Low Risk ◽

Glioneuronal Tumor ◽

Low Grade ◽

Diffuse Astrocytoma ◽

Prognostic Features

Abstract Background Management of unresectable pediatric low-grade glioma and glioneuronal tumor (LGG/LGGNT) is controversial. There are no validated prognostic features to guide use of radiation therapy (RT). Our study aimed to identify negative prognostic features in patients treated with RT using clinicopathologic and molecular data and validate these findings in an external dataset. Methods Children with non-metastatic, biopsy-proven unresectable LGG/LGGNT treated with RT at a single institution between 1997 and 2017 were identified. Recursive partitioning analysis (RPA) was used to stratify patients into low- and high-risk prognostic groups based on overall survival (OS). CNS9702 data were used for validation. Results One hundred and fifty patients met inclusion criteria. Median follow-up was 11.4 years. RPA yielded low- and high-risk groups with 10-year OS of 95.6% versus 76.4% (95% CI: 88.7%–98.4% vs 59.3%–87.1%, P = 0.003), respectively. These risk groups were validated using CNS9702 dataset (n = 48) (4-year OS: low-risk vs high-risk: 100% vs 64%, P < 0.001). High-risk tumors included diffuse astrocytoma or location within thalamus/midbrain. Low-risk tumors included pilocytic astrocytoma/ganglioglioma located outside of the thalamus/midbrain. In the subgroup with known BRAF status (n = 49), risk stratification remained prognostic independently of BRAF alteration (V600E or fusion). Within the high-risk group, delayed RT, defined as RT after at least one line of chemotherapy, was associated with a further decrement in overall survival (P = 0.021). Conclusion A high-risk subgroup of patients, defined by diffuse astrocytoma histology or midbrain/thalamus tumor location, have suboptimal long-term survival and might benefit from timely use of RT. These results require validation.

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PATH-65. MOLECULAR SIGNATURE OF FAT1 RELATED MOLECULES IN GLIOMAS IN THE CONTEXT OF THE WHO 2016 CLASSIFICATION

Neuro-Oncology ◽

10.1093/neuonc/noz175.660 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi158-vi158

Author(s):

Kunzang Chosdol ◽

Manvi Arora ◽

Nargis Malik ◽

Prerana Jha ◽

Jyotsna Singh ◽

...

Keyword(s):

Molecular Markers ◽

In Silico Analysis ◽

Molecular Signature ◽

World Health ◽

Low Grade ◽

Who Grade ◽

Inflammatory Microenvironment ◽

Molecular Features

Abstract Glioblastoma (GBM, WHO grade-IV) being the most malignant and aggressive form of glioma remains a major clinical challenge, with an overall 5-year survival rate of only 9.8%. Till recently, glioma diagnosis and grading were solely dependent on the phenotypic and histological features. However, with the advancement in the understanding of the molecular biology of glioma several molecules have been identified. The importance of these molecular/genotypic features of the tumor became evident by the inclusion of these molecular features by World Health Organization (WHO) in 2016 in glioma sub-grouping. Our lab is focused on studying the role of FAT1 gene (human ortholog of Drosophila tumor suppressor gene, fat) in glioma biology and aggressiveness. We observed FAT1 gene to have an oncogenic role in glioma where it has been found to upregulate migration/invasion, inflammatory microenvironment of the tumors, HIF1α expression/activity in the tumor-cells under severe hypoxia and in regulating EMT/stemness properties of GBM-cells under hypoxia. Here, we have characterized the molecular relationship between FAT1 related molecules and known- molecular markers of glioma with the hope of identifying glioma subgroup with a molecular signature of clinical significance by (i) analyzing the expression correlation of FAT1 and FAT1 regulated pro-inflammatroy molecules like COX2, IL1b and IL6 with the known- molecular markers of glioma like p53, IDH1, MGMT, EGFR, TERT in low-grade (grade-II) and high-grade (grade-III/IV) gliomas (n=50) by real-time PCR, sequencing, immunohistochemistry and in-silico analysis of TCGA-GBM-data (ii) Analyzed the regulatory role of FAT1 on the above known markers by siRNA mediated knockdown of FAT1 in in-vitro cell-culture system and (iii) further analyzed the identified molecular signature for their correlation with the patients prognosis/survival in the follow up patients. We observed a novel molecular signature with significant correlation with patients’ clinical outcome. Therapeutic targetting of FAT1 may benefit patients with high FAT1 expressing tumors.

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BRAFv600e mutated gliomas: From biology to radiology and treatments.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e13552 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e13552-e13552

Author(s):

Benoit Lhermitte ◽

Eric Guerin ◽

Agathe Chammas ◽

Izzie Jacques Namer ◽

Guillaume Gauchotte ◽

...

Keyword(s):

Surgical Resection ◽

De Novo ◽

Mapk Signaling ◽

Braf V600e ◽

Glioneuronal Tumor ◽

Low Grade ◽

Diffuse Glioma ◽

Metabolomic Profile ◽

Cdkn2a Deletion ◽

The Impact

e13552 Background: BRAF V600E mutation is encountered in brain tumor, mostly low grade pediatric diffuse glioma (LGG) and epileptogenic glioneuronal tumor 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. Methods: We studied retrospectively a monocentric cohort of 12 LGGs and 9 HGG with BRAFv600e positivity. The patients were aged from 1 to 47 years. Most of the LGG were under 25 years and only 3 patients with HGGs had less than 18 years old. We focused on extended biology assessment by Next generation sequencing of the tumors and their relapses, tumor metabolomics analyses, radiology comprising MRI, PET-scanning and spectroscopy and correlate them to tumor’s evolution and its treatment. Results: Among the LGGs, we had 9 GG and 3 pilocytic astrocytomas and only one had a CDKN2A deletion and one a gain on chromosome 5. 6 had a complete surgical resection, 2 had a minimal residue and 4 had chemotherapeutic treatment after partial surgery and underwent relapses. All HGGs had a surgical resection followed by chemotherapy (mainly Stupp protocol) and radiotherapy. 5 relapsed rapidly, benefit from targeted therapy with vemurafenib and are still in long term remission. In this HGG group, we had two subgroups: 4 patients with “de novo” tumors and 5 patients with a past history of LGG tumors in the same brain region. Both were responding well to targeted treatments and all had an additional CDKN2A deletion. Specific radiological and spectroscopic signs were linked to those two groups and seem to be associated to a specific metabolomic profile in each group. Currently, we are going further in the correlation between MAPK signaling pathway and metabolomic profile to be able to predict in LGG their potential evolution. Conclusions: BRAF mutated gliomas seem to have specific radiological and metabolomic correlations associated to their biology

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Spinal cord glioneuronal tumor with neuropil-like islands with 1p/19q deletion in an adult with low-grade cerebral oligodendroglioma

Journal of Neuro-Oncology ◽

10.1007/s11060-011-0760-9 ◽

2011 ◽

Vol 107 (2) ◽

pp. 421-426 ◽

Cited By ~ 7

Author(s):

Tyler J. Fraum ◽

Stephanie Barak ◽

Svetlana Pack ◽

Russell R. Lonser ◽

Howard A. Fine ◽

...

Keyword(s):

Spinal Cord ◽

Glioneuronal Tumor ◽

Low Grade

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Relationship among clinical, pathological and bio-molecular features in low-grade epilepsy-associated neuroepithelial tumors

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2017.06.022 ◽

2017 ◽

Vol 44 ◽

pp. 158-163 ◽

Cited By ~ 3

Author(s):

Gianfranco Vornetti ◽

Gianluca Marucci ◽

Corrado Zenesini ◽

Dario de Biase ◽

Roberto Michelucci ◽

...

Keyword(s):

Low Grade ◽

Neuroepithelial Tumors ◽

Molecular Features

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Unusual high-grade features in pediatric diffuse leptomeningeal glioneuronal tumor: comparison with a typical low-grade example

Human Pathology ◽

10.1016/j.humpath.2017.06.004 ◽

2017 ◽

Vol 70 ◽

pp. 105-112 ◽

Cited By ~ 13

Author(s):

Katherine E. Schwetye ◽

Akash P. Kansagra ◽

James McEachern ◽

Robert E. Schmidt ◽

Karen Gauvain ◽

...

Keyword(s):

Glioneuronal Tumor ◽

Low Grade ◽

High Grade ◽

Diffuse Leptomeningeal Glioneuronal Tumor

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Factors associated with seizure and cognitive outcomes after epilepsy surgery for low-grade epilepsy-associated neuroepithelial tumors in children

Clinical and Experimental Pediatrics ◽

10.3345/kjp.2019.01151 ◽

2020 ◽

Vol 63 (5) ◽

pp. 171-177

Author(s):

Ara Ko ◽

Joon Soo Lee

Keyword(s):

Epilepsy Surgery ◽

Focal Epilepsy ◽

Cognitive Outcomes ◽

Optimal Time ◽

Seizure Freedom ◽

Low Grade ◽

Neuroepithelial Tumors ◽

Factors Associated ◽

Younger Age ◽

Poor Cognitive Function

Low-grade epilepsy-associated neuroepithelial tumors (LEATs) are responsible for drug-resistant chronic focal epilepsy, and are the second-most common reason for epilepsy surgery in children. LEATs are extremely responsive to surgical treatment, and therefore epilepsy surgery should be considered as a treatment option for LEATs. However, the optimal time for surgery remains controversial, and surgeries are often delayed. In this review, we reviewed published article on the factors associated with seizure and cognitive outcomes after epilepsy surgery for LEATs in children to help clinicians in their decision whether to pursue epilepsy surgery for LEATs. The achievement of gross total resection may be the most important prognostic factor for seizure freedom. A shorter duration of epilepsy, a younger age at surgery, and extended resection of temporal lobe tumors have also been suggested as favorable prognostic factors in terms of seizure control. Poor cognitive function in children with LEATs is associated with a longer duration of epilepsy and a younger age at seizure onset.

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Diffusion Tensor Imaging Tractography for Fornix Identification in Intraventricular Tumor Surgery: A Case Series

Neurosurgery Open ◽

10.1093/neuopn/okaa005 ◽

2020 ◽

Vol 1 (3) ◽

Author(s):

Camille K Milton ◽

Ali H Palejwala ◽

Kyle P O'Connor ◽

Tressie M McCoy ◽

Andrew K Conner ◽

...

Keyword(s):

Diffusion Tensor Imaging ◽

Diffusion Tensor ◽

Case Series ◽

Glioneuronal Tumor ◽

Low Grade ◽

Case Examples ◽

Mixed Germ Cell Tumor ◽

Operative Memory ◽

Renal Cell Carcinoma Metastasis ◽

Dti Tractography

ABSTRACT BACKGROUND The proximity of intraventricular or periventricular tumors to critical white matter structures, such as the fornix, poses an operative challenge. In order to avoid significant neurological morbidity, deliberate selection of surgical approach is necessary when planning resection of tumors in this region. We report our initial experience with fornix modeling as an adjunct to standard navigational techniques across multiple pathologies. OBJECTIVE To report the feasibility of using diffusion tensor imaging (DTI) fornix modeling as an adjunct to standard navigational techniques for surgical treatment of intraventricular and periventricular tumors involving the fornix. METHODS Between July 2018 and August 2019, DTI tractography was performed on 12 patients with intraventricular or periventricular tumors involving the fornix. DTI fornix modeling was performed and included as part of the intraoperative navigation in all cases. RESULTS The patient group was composed of 6 males and 6 females. The fornix model was delineated in all cases using DTI tractography as described. The mean patient age was 45.7 yr. The 2 most-common tumor pathologies represented in our patient cohort included meningioma and cranipharyngioma, both found in 2 patients. A glioneuronal tumor, low-grade glioma, ependymoma, subependymoma, mixed germ-cell tumor, pituitary adenoma, and renal cell carcinoma metastasis were found in 1 patient each. Case examples of fornix modeling that may be incorporated into standard neuronavigation are presented. No patient experienced new or worsening post-operative memory deficits. CONCLUSION DTI tractography for fornix identification is a useful adjunct to standard navigational techniques employed in surgical resection of forniceal involving tumors.

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