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Glioneuronal tumours in childhood: Clinical picture, long-term outcome and possible new treatments
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Barnneurologi/Barnonkologi, Neuropediatrics/Paediatric oncology)
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Glioneuronal tumours are a subgroup of low-grade tumours of the central nervous system (CNS), often causing epilepsy. Overall survival is excellent, but data regarding long-term seizure outcome and late effects are scarce.

Aims: The overall aim was to gather data about pre- and postsurgical factors of importance and long-term outcomes to improve standards of care. Another aim was to explore the expression of somatostatin receptor (SSTR) subtypes and mTOR pathway markers.

Methods: This thesis, based on four population-based studies with both retrospective and cross-sectional parts, was performed through a long-term follow-up of a Swedish cohort of children with glioneuronal tumours in the Uppsala-Örebro health region. Patients were identified from the National Brain Tumour Registry and the National Epilepsy Surgery Registry. Various methods were used: reviews of hospital medical records, patient interviews, health-related quality of life (HRQoL) assessments with generic (Short Form 36version2) and disease specific (Quality of Life in Epilepsy-31) questionnaires, neuropsychological evaluations with Wechsler Intelligence Scale for Children-IV or Wechsler Adult Intelligence Test-IV and Reys Complex Figure Test and evaluation for possible depression with Hospital Anxiety Depression Scale. Immunohistochemical analyses for SSTR subtypes 1, 2a, 3 and 5 and mTOR pathway components ezrin-radixin-moesin and pS6 were performed on tumour specimens.

Results: Glioneuronal tumours seem to be more frequent than previously reported, accounting for 13.5% of all childhood CNS tumours. They often cause medically refractory epilepsy resulting in cognitive impairment. Neurosurgery was often delayed; mean time from symptom debut to lesionectomy was 4.6 years. Long-term seizure freedom was achieved in 84% of patients who had a gross total resection (GTR) and is important for long-term cognitive restitution, HRQoL, educational and vocational outcomes. SSTR2a and SSTR3 expression was a frequent finding in glioneuronal tumours. Signs of mTOR pathway activation were abundant in ganglioglioma.

Conclusions: A safe GTR should be striven for and considered a first-line treatment. Long-term clinical follow-up should be offered to all patients and for those with an inoperable tumour/tumour remnant causing tumour growth and/or medically refractory epilepsy, somatostatin analogues and/or mTOR inhibitors might represent a therapeutic alternative worth exploring further.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 66
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1530
Keywords [en]
Glioneuronal tumour, ganglioglioma, dysembryoplastic neuroepithelial tumour, childhood, cognition, psychosocial, HRQoL, outcome, mTOR pathway, somatostatin receptor
National Category
Pediatrics
Research subject
Pediatrics
Identifiers
URN: urn:nbn:se:uu:diva-371907ISBN: 978-91-513-0549-3 (print)OAI: oai:DiVA.org:uu-371907DiVA, id: diva2:1275520
Public defence
2019-03-01, Rosénsalen, Akademiska Barnsjukhuset, ingång 95/96 nbv., Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2019-02-06 Created: 2019-01-07 Last updated: 2019-02-18
List of papers
1. Clinical characteristics and late effects in CNS tumours of childhood: Do not forget long term follow-up of the low grade tumours
Open this publication in new window or tab >>Clinical characteristics and late effects in CNS tumours of childhood: Do not forget long term follow-up of the low grade tumours
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2016 (English)In: European journal of paediatric neurology, ISSN 1090-3798, E-ISSN 1532-2130, Vol. 20, no 4, p. 580-587Article in journal (Refereed) Published
Abstract [en]

Aim: To investigate clinical characteristics and late effects of CNS tumours in childhood with a special focus on low-grade tumours, especially low-grade astrocytoma and glib neuronal tumours. Methods: A retrospective population based study was performed at Uppsala University Children's Hospital, a tertiary referral centre for children with CNS tumours. Patients were identified from the National Brain Tumour Registry and the National Epilepsy Surgery Registry. Hospital medical records were analysed for patients with a follow up of >= 5 years after diagnosis. A re-evaluation of the neuro-pathological diagnosis was performed. Results: A total of 193 patients (age 0-17.99 years) during a twelve-year period (1995-2006) were included; 149 survived >= 5 years. Three larger subgroups could be identified: astrocytic, embryonal and glioneuronal tumours. A supratentorial location was found in 52%. Medical late effects were mainly neurological and endocrinological, affecting 81% and 26% of surviving patients. Cognitive late effects were a frequent finding in the whole group but also in low-grade astrocytoma and glioneuronal tumours (53% and 67%). Thirty per cent had some kind of pedagogic support in school. Conclusion: Late effects are common in long-term survivors of CNS tumours in childhood. Low-grade astrocytoma and glioneuronal tumours are no exception, and the findings support the need for long-term follow up.

Keywords
Childhood, CNS-tumour, Cognitive, Late effects, Low grade
National Category
Neurology Pediatrics Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-300544 (URN)10.1016/j.ejpn.2016.04.009 (DOI)000379106700014 ()27157245 (PubMedID)
Available from: 2016-08-10 Created: 2016-08-09 Last updated: 2020-08-28Bibliographically approved
2. Glioneuronal tumors in childhood - Before and after surgery. A long-term follow-up study
Open this publication in new window or tab >>Glioneuronal tumors in childhood - Before and after surgery. A long-term follow-up study
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2017 (English)In: Epilepsy & Behavior, ISSN 1525-5050, E-ISSN 1525-5069, Vol. 72, p. 82-88Article in journal (Refereed) Published
Abstract [en]

Aim: To give a detailed description of the long-term outcome of a cohort of children with glioneuronal tumors regarding pre-and postsurgical factors, including "dual" and "double" pathology, seizure freedom, and psychosocial outcome.

Methods: During a fifteen-year period (1995-2009), all patients (age 0-17.99 years) with a glioneuronal brain tumor diagnosed and treated at Uppsala University Children's Hospital were identified from the National Brain Tumor Registry and the National Epilepsy Surgery Registry. Hospital medical records were reviewed and neuroradiological and neuropathological findings were re-evaluated. A cross-sectional long-term follow-up prospective evaluation, including an interview, neurologic examination, and electroencephalogram, was accomplished in patients accepting participants in the study.

Results: A total of 25 out of 28 (89%) eligible patientswere included. The M: F ratiowas 1.5: 1. Mean follow-up time after surgery was 12.1 years (range 5.0-19.3). Twenty patients were adults (N18 years) at follow-up. Seizure freedomwas achieved in 64%. Gross total resection (GTR) was the only preoperative factor significantly correlating to seizure freedom (p= 0.027). Thirty-eight percent were at some time postoperatively admitted for a psychiatric evaluation. There was a trend towards both higher educational level and employment status in adults who became seizure free.

Conclusion: Long-termoutcome is good regarding seizure freedom if GTR can be achieved, but late seizure recurrence can occur. "Dual" and "double" pathology is uncommon and does not influence seizure outcome. Obtaining seizure freedomseems to be important for psychosocial outcome, but there is a risk for psychiatric comorbidities and long-term follow-up by a multi-professional team is advisable.

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2017
Keywords
Glioneuronal tumor, Childhood, "Dual" pathology, "Double" pathology, Seizure outcome, Psychosocial outcome
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-333399 (URN)10.1016/j.yebeh.2017.02.012 (DOI)000406321300015 ()28575773 (PubMedID)
Available from: 2017-11-16 Created: 2017-11-16 Last updated: 2019-01-07Bibliographically approved
3. Cognition, health-related quality of life, and mood in children and young adults diagnosed with a glioneuronal tumor in childhood
Open this publication in new window or tab >>Cognition, health-related quality of life, and mood in children and young adults diagnosed with a glioneuronal tumor in childhood
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2018 (English)In: Epilepsy & Behavior, ISSN 1525-5050, E-ISSN 1525-5069, Vol. 83, p. 59-66Article in journal (Refereed) Published
Abstract [en]

Aims: The aim of this study was to investigate long-term cognitive outcome, health-related quality of life (HRQoL), and psychiatric symptoms in children and young adults diagnosed with a glioneuronal tumor in childhood.

Methods: Twenty-eight children and adolescents (0-17.99 years) with a minimum postoperative follow-up time of five years were eligible for the study; four persons declined participation. A cross-sectional long-term follow-up evaluation was performed using the following study measures: Wechsler Intelligence Scale for Children (WISC-IV) or Wechsler Adult Intelligence Scale (WAIS-IV), Reys Complex Figure Test (RCFT), Short Form 36 version 2 (SF-36v2), Short Form 10 (SF-10), Quality of Life in Epilepsy 31 (QOLIE-31), Hospital Anxiety Depression Scale (HADS) or Beck Youth Inventory Scales (BYI), and Rosenberg Self-Esteem Scale. Historical WISC-III and RCFT data were used to compare cognitive longitudinal data.

Results: Mean follow-up time after surgery was 12.1 years. Sixty-three percent (15/24) were seizure-free. Despite a successive postoperative gain in cognitive function, a significant reduction relative to norms was seen in the seizure-free group with respect to perceptual reasoning index (PRI), working memory index (WMI), and full-scale intelligence quotient (FSIQ). Seizure freedom resulted in acceptable HRQoL. Thirty-two percent and 16% exceeded the threshold level of possible anxiety and depression, respectively, despite seizure freedom.

Conclusion: Although lower than in corresponding reference groups, cognitive outcome and HRQoL are good provided that seizure freedom or at least a low seizure severity can be achieved. There is a risk of elevated levels of psychiatric symptoms. Long-term clinical follow-up is advisable.

Keywords
Glioneuronal brain tumors, Cognition, Quality of life, Mood, Long-term outcome
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-357694 (URN)10.1016/j.yebeh.2018.03.026 (DOI)000434400600009 ()29654937 (PubMedID)
Available from: 2018-08-22 Created: 2018-08-22 Last updated: 2019-01-07Bibliographically approved
4. Somatostatin receptor expression and mTOR pathway activation in glioneuronal tumours of childhood
Open this publication in new window or tab >>Somatostatin receptor expression and mTOR pathway activation in glioneuronal tumours of childhood
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2020 (English)In: Seizure, ISSN 1059-1311, E-ISSN 1532-2688, Vol. 76, p. 123-130Article in journal (Refereed) Published
Abstract [en]

Purpose: To investigate the expression of somatostatin receptors (SSTRs) and markers of mTOR pathway in paediatric glioneuronal tumours and correlate these findings with tumour type, BRAFV600E mutational status and clinical characteristics such as tumour location, seizure frequency and duration, and age.

Method: 37 children and adolescents with a neuropathological diagnosis of glioneuronal tumour were identified over a 22-year period. Immunohistochemical analyses for SSTRs type 1, 2A, 3, 5 and ezrin-radixin-moesin (ERM) and phosphorylated S6 (pS6), which are indicators of mTOR pathway activation, were performed in tumour specimens from 33 patients and evaluated using the immunoreactive score (IRS). The IRS were compared to tumour type, BRAFV600E status and clinical characteristics.

Results: Ganglioglioma (GG) was the most frequently encountered subgroup (n = 27), followed by dysembryoplastic neuroepithelial tumour (DNET; n=4). GGs expressed SSTR2A and SSTR3 to a high extent, 56 % and 44 % respectively. Expression of SSTR2A was also found in DNETs. Signs of mTOR pathway activation were abundant in GGs, but only present in one DNET. No correlations with BRAFV600E presence or clinical characteristics were found.

Conclusions: Expression of SSTRs and activation of mTOR pathway in paediatric glioneuronal tumour suggest that somatostatin analogues and mTOR inhibitors may have potential therapeutic implications in a subset of inoperable childhood glioneuronal tumours causing medically refractory epilepsy and/or tumour growth. Further clinical studies are warranted to validate these findings.

National Category
Pediatrics Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-371905 (URN)10.1016/j.seizure.2020.01.011 (DOI)000528189000020 ()32062323 (PubMedID)
Available from: 2019-01-03 Created: 2019-01-03 Last updated: 2021-01-13Bibliographically approved

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