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

Abstract Background Diffuse leptomeningeal glioneuronal tumor (DLGNT) has been recently described in the literature. The complete neuroimaging spectrum and histopathological characteristics of this entity are yet to be elucidated. In an endemic region, diffuse leptomeningeal enhancement on neuroimaging with associated communicating hydrocephalus is usually suggestive of infective meningitis and the patients are started on empirical anti-microbial therapy. However, it is important to consider other differential diagnosis of leptomeningeal enhancement in such cases, particularly if the clinical condition does not improve on anti-microbial therapy. An early diagnosis of a neoplastic etiology may be of particular importance as the treatment regimens vary considerably depending on the underlying disease condition. Case presentation In this case report, we describe a case of DLGNT with high-grade histopathological features which was initially managed as tubercular meningitis based on the initial neuroimaging findings. Due to worsening of the clinical course and subsequent imaging findings at follow-up, a diagnosis of DLGNT was considered and subsequently proven to be DLGNT with features of anaplasia on histopathological examination of leptomeningeal biopsy specimen. Conclusion This case highlights the importance of recognizing certain subtle finding on MRI which may help in an early diagnosis of DLGNT which is crucial for appropriate treatment.

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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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HGG-06. REMARKABLE RESPONSE TO BRAF INHIBITOR IN AN INFANT WITH DISSEMINATED DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT)

Neuro-Oncology ◽

10.1093/neuonc/noaa222.297 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii345-iii345

Author(s):

Le Le Aung

Keyword(s):

Braf Inhibitor ◽

Braf V600e ◽

Proliferation Index ◽

Glioneuronal Tumor ◽

Low Grade ◽

Braf Inhibitors ◽

Visual Contact ◽

Ki 67 ◽

Low Grade Gliomas ◽

Diffuse Leptomeningeal Glioneuronal Tumor

Abstract INTRODUCTION Diffuse Leptomeningeal Glioneuronal Tumor (DLGNT) are rare CNS tumors and in infants, they can be lethal. There are several anecdotal reports in infants with low grade gliomas (LGG) with treated with BRAF inhibitors. METHODS A six-month old baby girl presented with a 2-week history of absent visual contact and vomiting. Imaging revealed a large 4.7 X 4.2 X 2.8 cm suprasellar charismatic region mass and multiple small extra-axial plaques in spinal canal. The child developed significant ascites post VP shunt requiring shunt externalization, extensive protein infusion support and hospitalization for six weeks. Immunohisto-chemical staining revealed Olig-2 and S-100, GFAP and synaptophysin positive. EMA showed patchy cytroplasmic reactivity in stromal cells and CD99 showed diffuse reactivity in stromal and lesional cells. INI-1, IDH-1, and CD117 were negative. Ki-67 proliferation index was 8–10%. PCR for BRAF V600E/E2/D was detected and KIAA1549-BRAF fusion as negative. This was confirmed by Genome Wide Next Generation Sequencing. While waiting for GNS testing results, the baby received one dose of Vinblastine. However, within seven days of initiating Debrafenib, significant clinical and radiological responses were observed. CONCLUSION The baby continues safely on Debrafenib with continued dramatic radiological response. This suggest that there may be a role in early initiation of targeted therapy such as BRAF inhibitors rather than giving standard chemotherapy such as Vinblastine or Carboplatin-Vincristine in extremely ill infants with low grade gliomas.

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RARE-07. EFFICACY AND SAFETY OF LAROTRECTINIB IN PEDIATRIC PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION-POSITIVE PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS

Neuro-Oncology ◽

10.1093/neuonc/noab090.168 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i42-i42

Author(s):

Sébastien Perreault ◽

François Doz ◽

Birgit Geoerger ◽

Karsten Nysom ◽

Ingrid Øra ◽

...

Keyword(s):

Disease Control ◽

Pediatric Patients ◽

Objective Response ◽

High Grade Glioma ◽

Disease Control Rate ◽

Cns Tumors ◽

Glioneuronal Tumor ◽

Low Grade ◽

High Grade ◽

Gene Fusions

Abstract Background NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a highly selective TRK inhibitor approved to treat patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). We report updated data on pediatric patients with TRK fusion-positive primary CNS tumors. Methods Patients aged <18 years with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed. Results By July 2020, 26 pediatric patients with TRK fusion-positive CNS tumors were treated. Tumor histologic subtypes included high-grade glioma (n=13), low-grade glioma (n=7), glioneuronal tumor (n=2), neuroepithelial tumor (n=2), CNS neuroblastoma (n=1), and small round blue cell tumor (n=1). Median age was 7.0 years (range 1.3–16.7). The ORR was 38% (95% CI 20–59%): 3 complete responses, 7 partial responses (including 2 pending confirmation), 14 stable disease, and 2 progressive disease. The ORR in patients with high-grade glioma was 38% (95% CI 14–68%). Nineteen of 21 patients (90%) with measurable disease had tumor shrinkage. The 24-week disease control rate was 77% (95% CI 56–91%). Median duration of response (DoR), PFS and overall survival (OS) were not reached. The 12-month rates for DoR, PFS and OS were 75%, 65%, and 86%, respectively. Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events were reported for 15 patients (58%) and were Grade 3–4 in 3 patients (12%), with no discontinuations related to larotrectinib. Conclusions In pediatric patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated durable responses, high disease control rate, and good tolerability. These results support testing for NTRK gene fusions in pediatric patients with CNS tumors.

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Anaplastic Glioneuronal Tumor With KIAA1549/BRAF Fusion

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqz120.000 ◽

2019 ◽

Vol 152 (Supplement_1) ◽

pp. S102-S102

Author(s):

Zhenggang Xiong ◽

Prithvi Narayan

Keyword(s):

Neoplastic Cell ◽

Glioneuronal Tumor ◽

Low Grade ◽

High Grade ◽

Left Frontal Lobe ◽

Ki 67 ◽

Blurry Vision ◽

Immunohistochemical Assessment ◽

Braf Fusion ◽

Glioneuronal Tumors

Abstract Introduction Glioneuronal tumors are usually low grade and have a favorable prognosis. The anaplastic glioneuronal tumor with KIAA1549/BRAF fusion has not yet been documented. This article reports a pediatric case of glioneuronal tumor with anaplasia and KIAA1549/BRAF fusion to illuminate the importance of KIAA1549/BRAF fusion in the tumorigenesis and clinical management of high-grade glioneuronal tumors. Case Presentation A 10-year-old boy presented with 1 year of headache and 3 months of blurry vision and proptosis. Ophthalmologic evaluation revealed bilateral papilledema. Magnetic resonance imaging showed a large mixed cystic and solid mass in the left frontal lobe of cerebrum. Histologic analysis demonstrated a glioneuronal tumor with papillary/pseudopapillary growth pattern, focal necrosis, microcalcification, and brisk mitotic activity with a high Ki-67 labeling index of focally up to 20%. Immunohistochemical assessment identified a mixed glial and neuronal neoplastic cell population. Molecular studies revealed a KIAA1549/BRAF fusion. Conclusion KIAA1549/BRAF fusion may play an important role in the oncogenesis of high-grade glioneuronal tumors. In view of the fact that effective, targeted therapies for the tumors with KIAA1549/BRAF fusion are clinically available, detection of KIAA1549/BRAF fusion for glioneuronal tumors, particularly high-grade glioneuronal tumors, is helpful.

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RARE-48. CHARACTERISTICS AND OUTCOME OF DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT): A SINGLE INSTITUTION EXPERIENCE

Neuro-Oncology ◽

10.1093/neuonc/noaa222.758 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii452-iii452

Author(s):

Emily Owens Pickle ◽

Ana Aguilar-Bonilla ◽

Amy Smith

Keyword(s):

Mapk Pathway ◽

Clinical History ◽

Mek Inhibitor ◽

Glioneuronal Tumor ◽

Unknown Etiology ◽

Leptomeningeal Disease ◽

Low Grade ◽

Diffuse Leptomeningeal Glioneuronal Tumor ◽

Braf Fusion ◽

Chemotherapy Patients

Abstract Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare with an unknown etiology and unestablished incidence. Most frequently reported genetic alteration is KIAA1549-BRAF fusion. We present four DLGNT cases diagnosed between 2005–2018. Patient 1 is a female who presented with a 2-year history of back pain subsequently diagnosed with pilocytic astrocytoma. Re-imaging 3 months post-resection revealed a low grade glioneuronal tumor with BRAF duplication. Patient 2 is a female who presented with recurrent vomiting, dizziness, and hydrocephalus. The patient underwent biopsy which was consistent with oligodendrogliomatosis; no genetic analysis was done. Patient 3 is a male who presented with worsening headaches and intermittent vomiting. Approximately 5 months after resection, imaging showed leptomeningeal disease and further testing revealed KIAA1549-BRAF fusion and 1p deletion. Patient 4 is a male who presented with hydrocephalus. Imaging showed disseminated leptomeningeal enhancement without a dominant mass lesion; biopsy and clinical history confirmed the diagnosis. All four patients received chemotherapy, Patients 1 and 3 underwent radiation therapy, and Patient 3 received a MEK-inhibitor to which he had a great response. However, the patient was non-compliant and had PD which continued despite re-starting therapy. Patients 1, 2, and 3 have died of progressive disease; survival was Patient 1, 276 days, Patient 2, approximately 7 years and 8 months, and Patient 3, 2 years and 11 months. Patient 4 remains alive with disease 4.5 years from diagnosis. There is much to be learned about this rare, poorly understood disease but hope for improvement through therapeutic targeting of the MAPK pathway.

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RARE-23. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR: A CASE SERIES

Neuro-Oncology ◽

10.1093/neuonc/noab090.184 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i45-i45

Author(s):

Ashley Aaroe ◽

Alexander Ou ◽

Susan McGovern ◽

Arnold Paulino ◽

Jason Johnson ◽

...

Keyword(s):

Obstructive Hydrocephalus ◽

Prognostic Significance ◽

Case Series ◽

Biological Behavior ◽

Glioneuronal Tumor ◽

Low Grade ◽

Mri Findings ◽

Molecular Features ◽

Diffuse Leptomeningeal Glioneuronal Tumor

Abstract Introduction Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare diagnosis first incorporated into the WHO Classification of Tumors of the Central Nervous System in 2016. Though historically considered indolent, emerging evidence suggests that the biological behavior of these tumors may be further classified by molecular features of prognostic significance. Methods A retrospective review was conducted in accordance with IRB approval of patients with the histologic diagnosis of DLGNT. Demographic, clinical, and molecular data where abstracted from the medical record when available. Results 10 patients were identified (M = 8, F = 2). Median age at diagnosis was 6 years (range 0.3–21 years), and the most common symptoms at diagnosis were related to obstructive hydrocephalus, for which 3 patients required CSF diversion. MRI findings included diffuse leptomeningeal thickening, nodularity, or coating of the subarachnoid or ependymal surfaces. Histologically, these tumors expressed variable features of neuronal and/or glial differentiation. Four patients (40%) were treated with radiation therapy (all craniospinal), which was upfront for 2 patients. Chemotherapy regimens used included temozolomide, carboplatin and vincristine and vinblastine. NTRK or BRAF-targeted therapy were used upon progression. At follow-up, 6/10 had stable disease (4/6 of whom were on second line therapy), 1 had partial response, 1 passed away from sepsis and 2 were lost to follow-up. The median progression-free survival for the four patients who developed disease progression was 26 months (range 12–34 months). Next generation sequencing of the tumor tissue performed using a high-multiplex PCR-based NGS panel detected BRAF-KIAA1549 (4 patients) and NTRK (1 patient) fusions. Conclusions DLGNT are rare tumors with scarce data about imaging characteristic and standard of care treatment. Our case series reinforces current literature that although these tumors appear low-grade, they can be clinically aggressive. Further study is needed regarding molecular diagnosis and profiling treatment strategies.

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The Rare Phenomenon of Loss of INI1 Expression at Recurrence/Progression of Primary Central Nervous System Tumors: Report of 3 Cases

International Journal of Surgical Pathology ◽

10.1177/1066896919883942 ◽

2019 ◽

Vol 28 (3) ◽

pp. 341-347 ◽

Cited By ~ 2

Author(s):

Akash Pramod Sali ◽

Vishal Chaubey ◽

Duhita Kodare ◽

Ayushi Sahay ◽

Sridhar Epari

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Protein Expression ◽

Complete Loss ◽

Glioneuronal Tumor ◽

Low Grade ◽

High Grade ◽

Immunohistochemical Expression ◽

Not Otherwise Specified ◽

Expression Loss

It is extremely rare for loss of immunohistochemical expression of INI1 to occur primarily at recurrence/progression with retained expression at the primary/initial presentation of central nervous system (CNS) tumor. In this article, we present 3 such cases showing loss of INI1 expression primarily at recurrence. All patients were males, aged 7 years (case 1), 11 years (case 2), and 35 years (case 3), diagnosed with low-grade glial/glioneuronal tumor, not otherwise specified (case 1), craniopharyngioma (case 2), and glioblastoma (case 3); all showed retained INI1 protein expression. Case 1 at 12 months recurrence showed a high-grade tumor with relative undifferentiated morphology, case 2 after 104 months showed a sarcomatous progression, and case 3 recurred after 4 months with the presence of relative undifferentiated round cells. All these recurrences showed loss of INI1 expression. Loss of SMARCB1/INI1 gene function resulting in complete loss of INI1 protein expression is not a well-accepted genetic mechanism for transformation/progression as this series emphasizes.

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Case Report: Unusual High-Grade Diffuse Leptomeningeal Glioneuronal Tumor Mimicking Tuberculous Meningitis in a Child From an Endemic Region

Frontiers in Pediatrics ◽

10.3389/fped.2021.767614 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yong Guang Teh ◽

Nornazirah Azizan ◽

Nur Atifah Mohd Naim ◽

Chiak Yot Ng ◽

Ke Juin Wong ◽

...

Keyword(s):

Mr Spectroscopy ◽

Who Classification ◽

World Health ◽

Glioneuronal Tumor ◽

High Grade ◽

Endemic Region ◽

Case Presentation ◽

Diffuse Leptomeningeal Glioneuronal Tumor ◽

Health Organization

Background: Diffuse leptomeningeal glioneuronal tumor (DL-GNT) is a new entity described in the 2016 World Health Organization (WHO) classification of brain tumors. While DL-GNT is predominantly an indolent tumor that affects young boys, high-grade DL-GNT is unusual and seldom reported in children.Case Presentation: In this report, we describe the challenges and pitfalls associated with diagnosing this high-grade variant in a tuberculosis-endemic region. We highlight the importance of identifying non-typical imaging findings, i.e., non-enhancing cystic lesions with high T2 signal along the leptomeningeal surface, that may expedite the diagnosis of this condition. Histopathologic correlations with MR spectroscopy findings are also discussed.Conclusion: We provide the first clinical imaging report of utilizing MR spectroscopy to distinguish DL-GNT from tuberculosis with histopathologic correlation.

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Klinische Wertigkeit der Positronen-Emissions-Tomographie (PET) bei onkologischen Fragestellungen: Ergebnisse einer interdisziplinären Konsensuskonferenz

Nuklearmedizin ◽

10.1055/s-0038-1629694 ◽

1996 ◽

Vol 35 (02) ◽

pp. 42-52 ◽

Cited By ~ 22

Author(s):

R. Bares ◽

U. Bull ◽

A. Guhlmann ◽

E. Moser ◽

M. F. Wannenmacher ◽

...

Keyword(s):

Low Grade ◽

High Grade ◽

Klinische Anwendung ◽

Wissenschaftliche Studien

Zusammenfassung Ziel: Es ist das Ziel der vorliegenden Arbeit, an Hand bisher publizierter Studienergebnisse eine Beurteilung des klinischen Stellenwertes von PET in der Onkologie zu erarbeiten. Methoden: Im Rahmen einer interdisziplinären Konferenz mit namhaften Experten wurde eine Wertung des gegenwärtigen Stands von PET in der Onkologie an Hand der in der Literatur dokumentierten Studienergebnisse erarbeitet. Angestrebt wurde eine differenzierte Bewertung von PET für die klinische Anwendung in fünf Klassen (1a, 1b, 2a, 2b, 3) von »angemessen« (1a), »akzeptabel« (1b), »hilfreich« (2a), »noch keine Bewertung möglich« (2b), »ohne Nutzen« (3). Ergebnisse: Für den klinischen Einsatz in der Onkologie ist 2-F18-Fluorodeoxyglukose (FDG) das Radiopharmakon der Wahl. PET ist klinisch in der Patientenversorgung zur Rezidivdiagnostik von high-grade Gliomen (FDG), low-grade Gliomen (C-11 Methionin oder F-18 Tyrosin), für die Dignitätsdiagnostik des peripheren Lungenrundherdes bei Risikopatienten sowie für die Diagnostik des Pankreaskarzioms indiziert (Indikation 1a). PET kann in der Patientenversorgung bei folgenden Indikationen (1b) eingesetzt werden: »low-grade« Gliome, Suche nach unbekanntem Primärtumor bei Kopf-Hals-Tumoren, Rezidivdiagnostik des nicht kleinzelligen Bronchialkarzinoms sowie des Rektumkarzinoms, Lymphknotenstaging beim nicht kleinzelligen Bronchial-Karzinom, Pan-kreas-Karzinom, muskelinvasiven Blasen-Karzinom und Hoden-Karzinom. Staging bei M. Hodgkin (Stad. I/II versus III), frühe Therapiekontrolle bei Resttumor und Rezidivdiagnostik bei M. Hodgkin und hochmalignen Non-Hodgkin-Lymphomen, Lymphknoten-Staging und Fern-metastasensuche beim malignen Melanom (Breslow >1,5 mm), Lymphknoten- und Fernmetastasen-Nachweis beim Schilddrüsen-Karzinommit erhöhtem hTg und nicht radiojodspeichernden Metastasen. Zahlreiche weitere Indikationen zeichnen sich bereits jetzt ab, sind jedoch noch weniger gut durch wissenschaftliche Studien belegt. Für die meisten Indikationen außerhalb wissenschaftlicher Studien ist eine individuelle Kosten-Nutzen-Betrachtung durch den verantwortlichen Arzt geboten. Schlußfolgerungen: Die metabolische Bildgebung von PET besitzt für eine Vielzahl onkologischer Fragestellungen prinzipielle Vorteile gegenüber der anatomisch-morphologisch orientierten Schnittbilddiagnostik. Für die klinische Indikationsstellung ist allerdings eine differenzierte Betrachtung der spezifischen Leistungsfähigkeit von PET geboten.

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