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Frontiers in Pediatrics 2023Optic pathway and hypothalamic glioma (OPHG) are low-grade brain tumors that arise from any part of the visual pathways frequently involving the hypothalamus. The tumors... (Review)
Review
Optic pathway and hypothalamic glioma (OPHG) are low-grade brain tumors that arise from any part of the visual pathways frequently involving the hypothalamus. The tumors grow slowly and present with features driven by their precise anatomical site, their age at presentation and the stage of growth and development of the host neural and orbital bony tissues. Up to 50% of optic pathway glioma arise in association with Neurofibromatosis type 1 (NF1), which affects 1 in 3,000 births and is a cancer predisposition syndrome. As low-grade tumors, they almost never transform to malignant glioma yet they can threaten life when they present under two years of age. The main risks are to threaten vision loss by progressive tumor damage to optic pathways; furthermore, invasion of the hypothalamus can lead to diencephalic syndrome in infancy and hypopituitarism later in life. Progressive cognitive and behavioural dysfunction can occur, as part of NF1 syndromic features and in sporadic cases where large bulky tumors compress adjacent structures and disrupt neuro-hypothalamic pathways. Persistently progressive tumors require repeated treatments to attempt to control vision loss, other focal brain injury or endocrine dysfunction. In contrast tumors presenting later in childhood can be seen to spontaneously arrest in growth and subsequently progress after periods of stability. These patterns are influenced by NF status as well as stages of growth and development of host tissues. The past two decades has seen an expansion in our understanding and knowledge of the clinical and scientific features of these tumors, their modes of presentation, the need for careful visual and endocrine assessment. This influences the decision-making surrounding clinical management with surgery, radiotherapy, chemotherapy and most recently, the potential benefit of molecularly targeted drug therapy. This article, based upon the authors' clinical and research experience and the published literature will highlight advances in approach to diagnosis, the established role of vision loss as justification of treatments and the emerging evidence of endocrine and neurological consequences that need to be incorporated into judgements for case selection for therapy or observation. Consideration is given to the current state of biological evidence justifying current trials of new therapies, the genetic studies of the NF1 gene and the potential for new approaches to OPHG detection and treatment. The outstanding health system priorities from the perspective of children, their parents and health system commissioners or insurers are discussed.
PubMed: 37033188
DOI: 10.3389/fped.2023.1038937 -
Neuro-oncology Nov 2013We wanted to determine the sensitivity and specificity of serial changes in visual acuity and visual evoked potentials (VEPs) to detect radiological progression of tumor...
BACKGROUND
We wanted to determine the sensitivity and specificity of serial changes in visual acuity and visual evoked potentials (VEPs) to detect radiological progression of tumor volume in children with optic pathway gliomas.
METHODS
From a retrospective review of a cohort of 69 patients, 54 patients met inclusion criteria (31 with primary chemotherapy, 4 with primary radiotherapy, and 19 with stable tumor volume and no treatment). Age at presentation ranged from 0.3 to 13 years. Patients were serially followed by MRI, age-corrected visual acuity in log minimum angle of resolution (logMAR), and pattern VEP. Longitudinal data averaged 7.9 years (range 0.5-16 y). Visual assessments were aligned with MRI data within 6-month intervals. Tumor progression was defined by 25% or greater increase in volume.
RESULTS
Visual acuity in the better eye had poor sensitivity and specificity for detecting tumor volume progression (0.5 and 0.5, respectively). Visual acuity in the worse eye showed worse sensitivity and specificity because false positives (visual decline without tumor progression) were more frequent than true positives (visual decline with tumor progression). VEPs showed slightly better sensitivity and specificity (0.69 and 0.58, respectively). In patients with stable tumors, visual acuity fluctuated ±0.55 logMAR (SD = 0.15) between examinations. VEP amplitude fluctuated -0.74 to 0.48 log units (SD = 0.19) between examinations.
CONCLUSIONS
Serial changes in visual function do not reliably detect tumor progression. Conversely, tumor progression does not reliably indicate decreased visual function. Objective visual function and serial MRIs are complementary in management of optic pathway gliomas.
Topics: Brain; Disease Progression; Evoked Potentials, Visual; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neurofibromatosis 1; Optic Nerve Glioma; Radiography; Visual Acuity
PubMed: 24101736
DOI: 10.1093/neuonc/not120 -
Brain Tumor Research and Treatment Apr 2022Optic pathway glioma (OPG) is a rare tumor located in optic nerve, optic tract, or optic chiasm. Treatment options for OPG include surgery, radiation therapy (RT), and... (Review)
Review
Optic pathway glioma (OPG) is a rare tumor located in optic nerve, optic tract, or optic chiasm. Treatment options for OPG include surgery, radiation therapy (RT), and chemotherapy. Although RT may provide favorable long-term outcomes in manner of either adjuvant or salvage aim, chemotherapy-first approach is increasingly performed due to possible late effects of RT. Proton beam RT may allow normal tissue sparing of radiation exposure compared to conventional X-ray treatment. Therefore, proton beam RT is expected to reduce complications from RT. This review discusses the recent updates on oncologic outcomes of OPG, late toxicities following RT, and compares the outcomes between X-ray treatment and proton beam RT.
PubMed: 35545828
DOI: 10.14791/btrt.2022.0003 -
Acta Neuropathologica Communications Feb 2024Tissue injury and tumorigenesis share many cellular and molecular features, including immune cell (T cells, monocytes) infiltration and inflammatory factor (cytokines,...
Tissue injury and tumorigenesis share many cellular and molecular features, including immune cell (T cells, monocytes) infiltration and inflammatory factor (cytokines, chemokines) elaboration. Their common pathobiology raises the intriguing possibility that brain injury could create a tissue microenvironment permissive for tumor formation. Leveraging several murine models of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome and two experimental methods of brain injury, we demonstrate that both optic nerve crush and diffuse traumatic brain injury induce optic glioma (OPG) formation in mice harboring Nf1-deficient preneoplastic progenitors. We further elucidate the underlying molecular and cellular mechanisms, whereby glutamate released from damaged neurons stimulates IL-1β release by oligodendrocytes to induce microglia expression of Ccl5, a growth factor critical for Nf1-OPG formation. Interruption of this cellular circuit using glutamate receptor, IL-1β or Ccl5 inhibitors abrogates injury-induced glioma progression, thus establishing a causative relationship between injury and tumorigenesis.
Topics: Mice; Animals; Optic Nerve Glioma; Neurofibromatosis 1; Microglia; Brain Injuries; Neurons; Carcinogenesis; Tumor Microenvironment
PubMed: 38308315
DOI: 10.1186/s40478-024-01735-w -
CNS Oncology Mar 2013Optic pathway gliomas account for 3-5% of all pediatric CNS tumors and represent the most common intrinsic optic nerve tumors. These tumors occur preferentially during... (Review)
Review
Optic pathway gliomas account for 3-5% of all pediatric CNS tumors and represent the most common intrinsic optic nerve tumors. These tumors occur preferentially during the first decade of life and are particularly frequent in children with neurofibromatosis type 1. Although optic pathway gliomas are low-grade tumors, their behavior can be aggressive, and their management is often challenging. Their management includes observation, surgery, chemotherapy and radiation. The role of each modality is discussed as well as current and future developments in treatment, in particular targeted therapies that are currently being investigated.
Topics: Humans; Neurofibromatosis 1; Optic Nerve Glioma; Optic Nerve Neoplasms; Vision Disorders
PubMed: 25057976
DOI: 10.2217/cns.12.47 -
Cancers Feb 2023This is a retrospective study conducted on patients with OPG, aged less than 19 years, treated with bevacizumab as a single agent, since 2010 at IHOPe (Institute of...
This is a retrospective study conducted on patients with OPG, aged less than 19 years, treated with bevacizumab as a single agent, since 2010 at IHOPe (Institute of Pediatric Hematology and Oncology). Efficacy of the treatment was evaluated on the tumor response rate on MRI with a centralized review basing upon RAPNO criteria and with visual assessment basing upon a 0.2 log change in the logMAR scale. Thirty-one patients with OPG have been included. From a radiological point of view, best anytime responses were: 1 major response, 6 partial responses, 7 minor responses and 14 stable diseases; achieving disease control in 28 (96%) out of 29 patients. Ophthalmological response was evaluated in 25 patients and disease control was achieved in 22 (88%) out of 25, with 14 steady states and 8 significant improvements. Among patients treated with chemotherapy after the bevacizumab course, nine relapsed and have been retreated with objective responses. Bevacizumab used as single agent seems effective in children and adolescents with OPG. Our work paves the way for a phase II study in which bevacizumab alone could be used as frontline therapy.
PubMed: 36831379
DOI: 10.3390/cancers15041036 -
Journal of Neuroscience Research Jan 2019Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 gene. The NF1-encoded protein (neurofibromin) is an inhibitor of... (Review)
Review
Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 gene. The NF1-encoded protein (neurofibromin) is an inhibitor of the oncoprotein RAS and controls cell growth and survival. Individuals with NF1 are prone to developing low-grade tumors of the optic nerves, chiasm, tracts, and radiations, termed optic pathway gliomas (OPGs), which can cause vision loss. A paucity of surgical tumor specimens and of patient-derived xenografts for investigative studies has limited our understanding of human NF1-associated OPG (NF1-OPG). However, mice genetically engineered to harbor Nf1 gene mutations develop optic gliomas that share many features of their human counterparts. These genetically engineered mouse (GEM) strains have provided important insights into the cellular and molecular determinants that underlie mouse Nf1 optic glioma development, maintenance, and associated vision loss, with relevance by extension to human NF1-OPG disease. Herein, we review our current understanding of NF1-OPG pathobiology and describe the mechanisms responsible for tumor initiation, growth, and associated vision loss in Nf1 GEM models. We also discuss how Nf1 GEM and other preclinical models can be deployed to identify and evaluate molecularly targeted therapies for OPG, particularly as they pertain to future strategies aimed at preventing or improving tumor-associated vision loss in children with NF1.
Topics: Animals; Disease Models, Animal; Genes, Neurofibromatosis 1; Humans; Mice; Neurofibromatosis 1; Optic Nerve Glioma
PubMed: 29704429
DOI: 10.1002/jnr.24250 -
Neuro-oncology Apr 2021Brain tumors are the most common solid tumors of childhood, but little is understood about the factors that influence their development. Pediatric low-grade gliomas in...
BACKGROUND
Brain tumors are the most common solid tumors of childhood, but little is understood about the factors that influence their development. Pediatric low-grade gliomas in particular display unique temporal and spatial localization associated with different genetic mutations (eg, BRAF genomic alterations, mutations in the neurofibromatosis type 1 [NF1] gene) for reasons that remain unclear. NF1 low-grade gliomas typically arise in the optic pathway of young children as optic pathway gliomas (OPGs), likely from a cell of origin that resides within the third ventricular zone (TVZ). However, the factors that contribute to their distinct temporal patterning and penetrance have not been adequately explored.
METHODS
TVZ neuroglial progenitor cells (NPCs) were analyzed over the course of mouse brain development. Progenitors isolated by fluorescence-activated cell sorting (FACS) were assessed for functional and molecular differences. The impact of different germline Nf1 mutations on TVZ NPC properties was analyzed using genetically engineered mice.
RESULTS
We identify 3 individual factors that could each contribute to Nf1 optic glioma temporal patterning and penetrance. First, there are 3 functionally and molecularly distinct populations of mouse TVZ NPCs, one of which ("M" cells) exhibits the highest clonogenic incidence, proliferation, and abundance during embryogenesis. Second, TVZ NPC proliferation dramatically decreases after birth. Third, germline Nf1 mutations differentially increase TVZ NPC proliferation during embryogenesis.
CONCLUSIONS
The unique temporal patterning and penetrance of Nf1 optic glioma reflects the combined effects of TVZ NPC population composition, time-dependent changes in progenitor proliferation, and the differential impact of the germline Nf1 mutation on TVZ NPC expansion.
Topics: Animals; Brain Neoplasms; Child; Child, Preschool; Humans; Mice; Mutation; Neurofibromatosis 1; Optic Nerve Glioma; Penetrance
PubMed: 33080011
DOI: 10.1093/neuonc/noaa237 -
BMC Endocrine Disorders Dec 2015Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder with an extremely variable phenotype. In childhood NF1 can be associated with optic glioma... (Review)
Review
BACKGROUND
Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder with an extremely variable phenotype. In childhood NF1 can be associated with optic glioma and central precocious puberty; the latter is more common when the optic chiasm is affected. The mutational spectrum of the NF1 gene is wide and complex; R681X is a rare severe mutation of the NF1 gene known to cause truncation of neurofibromin, with only ten reported cases in the literature so far.
CASE PRESENTATION
We describe a girl with NF1 associated with early central precocious puberty appearing at 2.5 years of age and optic glioma affecting the optic chiasm as seen on magnetic resonance imaging (MRI). Genetic analysis confirmed the presence of R681X. Therapy with a gonadotropin-releasing hormone agonist was instituted with good response to therapy. The lesions on MRI were stable and no significant vision impairment was present during the 6 years of follow-up.
CONCLUSION
Of the ten reported cases of NF1 due to R681X, one has presented with optic glioma and none with precocious puberty. Thus, to our knowledge, this is the first reported case of this mutation presenting with precocious puberty. We believe that this is a contribution to the few reports on the phenotype of this mutation and to the future elucidation of genotype-phenotype correlations of this disease.
Topics: Arginine; Child, Preschool; Female; Gonadotropin-Releasing Hormone; Humans; Magnetic Resonance Imaging; Mutation; Neurofibromatosis 1; Neurofibromin 1; Optic Nerve Glioma; Puberty, Precocious; Treatment Outcome; Triptorelin Pamoate
PubMed: 26666878
DOI: 10.1186/s12902-015-0076-4 -
Brain Pathology (Zurich, Switzerland) Apr 1997Neurofibromatosis (NF) 1 and 2 are multisystem disorders associated with a variety of neoplastic and non-neoplastic manifestations that typically progress in severity... (Review)
Review
Neurofibromatosis (NF) 1 and 2 are multisystem disorders associated with a variety of neoplastic and non-neoplastic manifestations that typically progress in severity during the lifetime of the affected patient. The importance of appropriately diagnosing these disorders stems from the fact that the natural history of an associated neoplasm, such as a peripheral nerve tumor or an optic glioma, may be significantly different depending on whether or not the lesion arises in a person with NF. In addition, the indications for therapeutic intervention, hierarchy of treatment options and long-term management goals may differ substantially for patients with NF-related versus sporadic tumors. Finally, recognition of the diagnosis comprises an essential step for providing appropriate multidisciplinary evaluation and counseling to affected patients and their families. This article addresses the principal manifestations of these disorders and provides a contemporary review of the diagnostic and therapeutic issues that arise in children with NF1 and NF2.
Topics: Humans; Magnetic Resonance Imaging; Nervous System Diseases; Neurofibromatosis 1; Neurofibromatosis 2
PubMed: 9161732
DOI: 10.1111/j.1750-3639.1997.tb01067.x