Pediatric low-grade gliomas: How modern biology reshapes the clinical field

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Abstract

Low-grade gliomas represent the most frequent brain tumors arising during childhood. They are characterized by a broad and heterogeneous group of tumors that are currently classified by the WHO according to their morphological appearance. Here we review the clinical features of these tumors, current therapeutic strategies and the recent discovery of genomic alterations characteristic to these tumors. We further explore how these recent biological findings stand to transform the treatment for these tumors and impact the diagnostic criteria for pediatric low-grade gliomas.

Introduction

Low-grade gliomas (LGGs) are the most common brain tumor of childhood accounting for 35% of all pediatric central nervous system tumors [1], [2]. Pediatric LGGs (PLGGs), classified as World Health Organization (WHO) grade I or II [3] represent a heterogeneous group of tumors. PLGGs are classified according to the cellular aspect of the most important constitutive cell type, including astrocytic, oligodendroglial, mixed oligoastrocytic, neuronal, or mixed glioneuronal morphology (Table 1). Although this classification aims to encompass every tumor, a significant number of tumors do not meet the typical criteria for WHO categories or have overlapping histology for multiple categories. In clinical practice, these tumors are often given non-categorical diagnoses with varied and confusing terminology. As such the category of ‘low grade glioma, non-otherwise specified’ (LGG-NOS) has been formally utilized by several groups including ours as a clinical and research diagnosis for these histologically difficult to classify tumors.

Despite having a similar histological appearance to adult LGG, PLGGs have a distinct and more favorable course and should be considered a different disease entity. Indeed, the majority of children diagnosed with PLGGs are long-term survivors well into adulthood (Bandopadhayay et al., in press, Pediatric Blood and Cancer 2014), imploring treatment strategies that minimize long-term morbidities [4], [5]. Therefore, it is crucial to understand the biology of PLGGs to allow the development of targeted therapies with less toxicity.

The explosion of novel technologies and multi-platform integrative genomics in recent years has yielded new insights into the oncogenesis of PLGGs. These findings not only bring a paradigm shift to the traditional histological classification of PLGGs but also reveal new therapeutic targets.

In this review, we highlight the biologic complexity of PLGGs, present current diagnostic and management dilemmas, and propose the natural evolution and augmentation of microscopic histological diagnoses with modern genomic profiles. Increased understanding of the molecular identity of these tumors will help drive the development of target-driven therapies.

Section snippets

Histopathologic classification

The WHO classifies low-grade gliomas according to their morphological features [3]. Tumors that do not meet the typical criteria of any single category are commonly labeled LGG-NOS for ‘not-otherwise specified’, which comprise more than a third of all PLGGs [6]. This sometimes results from small biopsy samples that lack sufficient material on which to assign a WHO grade, and at other times, as a result of pathologic features that do not fit any one category. PLGGs typically have a low

Epidemiology

Brain tumors represent the most common solid tumor of childhood, of which PLGGs are the most frequent [35]. The annual incidence of PLGGs is 2.1 per 100,000 persons in the United States [36], [37], accounting for 1600 new diagnosis each year. The relative incidence of each LGG histological subtype varies with age, with clear differences in distribution between pediatric and adult LGGs (Fig. 1). PAs most frequently develop during childhood and are extremely rare in adults. They represent the

Genetic predisposition syndromes

Initial insight into the molecular characteristics of PLGGs was derived from the subset of non-sporadic tumors associated with genetic syndromes. Among these, the most frequent association is with NF1, also known as von Recklinghausen disease. PAs and DAs are the most common subtypes associated with NF1 [53] and most commonly involve the optic pathway and hypothalamus [54], [55], [56]. NF1 is characterized by a germline mutation of neurofibromin 1 (NF1), located on chromosome 17q, which results

Clinical presentation

The clinical presentation of PLGGs is dictated by their location. Tumors in the posterior fossa typically present with acute signs and symptoms of elevated intracranial pressure secondary to obstructive hydrocephalus, as well as cerebellar signs [62], whereas LGGs of the optic pathway impair vision. PLGGs affecting the cerebral cortex typically present with focal neurological manifestations such as seizures or behavioral changes. Seizures are particularly associated with temporal, frontal, or

Natural history

The natural history of pediatric LGGs is distinct from that of adult LGGs. On the whole, PLGGs exhibit slow rates of growth. Thus, the majority of children are diagnosed at least six months after symptom onset [84]. PLGGs have been reported to spontaneously regress, especially in patients with NF1 [85], [86], [87], [88], [89], who have been reported to have superior outcomes compared to sporadic cases [90], [91], [92]. Tumors that can be completely resected often require no further therapy

Treatment strategies

Given the excellent overall survival for the majority of PLGG patients, the treatment goal is to achieve tumor control while minimizing long-term tumor and treatment related morbidity [104]. Most patients require only surveillance after surgery. If progression, recurrence and/or symptoms occur, then treatment modalities including surgery, chemotherapy (including biologic therapy), or less frequently, radiation therapy are indicated.

Surgical resection remains the cornerstone of PLGG management.

General genomic features

Recent advances in high-throughput genetic sequencing and gene expression profiling have shed important insights into the genomic alterations of PLGGs [173]. Table 4 summarizes the major mutations and chromosomal rearrangements that have been described in different cohorts of PLGGs. One important limitation to these studies is the lack of sufficient tumor tissue from rarer subtypes of PLGGs such as tectal gliomas, thalamic and optic pathway tumors.

A striking finding of PLGGs is the low number

Conclusions

Low-grade gliomas, the most common brain tumor of childhood, encompass a heterogeneous group of WHO grade I and II tumors. Although they are associated with excellent overall survival rates, children can suffer morbidity from both the tumor and therapy. The striking predominance of the RAS/RAF/MAPK pathway alteration in PLGG tumorigenesis may help redefine traditional histopathological classifications and also represents exciting new avenues for the development of novel targeted therapies. Many

Funding sources

Pediatric Low-Grade Astrocytoma Foundation (GB, PB, RB, LR, RAS, CS and MWK), Stop&Shop Pediatric Brain Tumor Program (PB and MWK), Andrysiak Fund for LGG (MWK), Nuovo-Soldati Foundation (GB), Philippe Foundation (GB), Friends of DFCI (GB and PB),Team Jack Foundation (PB, CS and MWK), the Mill Foundation for Kids (MWK), the Sontag Foundation (RB), Gray Matters Foundation (RB), NIH PO1CA142536 (RAS), NIH PO1NS047572 (CS), INCA grant PHRC 2008 (JG), L’Etoile de Martin (JG).

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