Review Improving outcomes for neurofibromatosis 1–associated brain tumors Expert Rev. Anticancer Ther. Early online, 1–9 (2015) Nicole M Brossier1 and Children and adults with neurofibromatosis type 1 (NF1) are predisposed to developing CNS David H Gutmann*2 tumors, including optic pathway gliomas (OPGs), brainstem gliomas (BSGs) and high-grade gliomas. Although current first-line treatments for low-grade gliomas (OPGs and BSGs) may 1Department of Pediatrics, St. Louis Children’s Hospital, St. Louis, MO, USA prevent further tumor growth, they rarely result in restoration of the associated visual or 2Department of Neurology, Washington neurological deficits. The availability of accurate small-animal models of NF1-associated brain University School of Medicine, tumors has established tractable experimental platforms for the discovery and evaluation of Box 8111, 660 South Euclid Avenue, promising therapeutic agents. On the basis of these preclinical studies, biologically targeted St. Louis, MO, USA *Author for correspondence: agents are now being evaluated in children with NF1-associated low-grade brain tumors. Tel.: +1 314 362 7379 Collectively, these models have also begun to reveal potential neuroprotective and risk Fax: +1 314 362 2388 assessment strategies for this brain tumor-prone population. [email protected] KEYWORDS: brainstem glioma . cyclic AMP . genetically-engineered mice . microglia . mTOR . neurofibromatosis type 1 . optic pathway glioma . preclinical . RAS Neurofibromatosis type 1 (NF1) is a common will exhibit axillary or inguinal freckling by tumor predisposition syndrome, affecting late childhood. Lisch nodules are observed in 1:2500 individuals worldwide. Although half of virtually all adults with NF1. Also included in For personal use only. children diagnosed with NF1 have an affected the NF1 diagnostic criteria are two characteris- parent with NF1, nearly 50% of all cases of tic nervous system tumors (optic pathway glio- NF1 arise in children without a family history mas [OPGs] in the CNS and neurofibromas of NF1, presumably as a result of de novo muta- in the peripheral nervous system). In addition, tion of the NF1 tumor suppressor gene. distinctive bony abnormalities (tibial dysplasia Although NF1 transmission occurs in an auto- with or without pseudarthrosis and sphenoid somal dominant fashion with complete pene- wing dysplasia) and a positive family history of trance, the clinical manifestations of this NF1 are used to make the diagnosis of NF1. disorder can be quite variable, even among fam- Although not included as NF1 diagnostic cri- ilies with the same germline NF1 mutation [1]. teria, collectively over 60% of children with This variable expressivity makes it challenging NF1 also have learning, attention and behav- to predict the clinical course and specific disease ioral delays. As such, these individuals fre- manifestations in a child with NF1. quently struggle in the classroom setting and The diagnosis of NF1 is established using often require additional educational resources. clinical criteria originally formulated by the Less commonly, children and adults with Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by St. Jude Children's Research Hospital on 02/10/15 National Institutes of Health Consensus NF1 may present with vascular abnormalities, Development Conference in 1987 [2]. Using including moya-moya disease and renal artery these criteria, children or adults harboring two stenosis [3]. or more of seven diagnostic features are given Most individuals with NF1 will manifest the diagnosis of NF1. Three of these seven neurofibromas (benign peripheral nerve sheath features – cafe-au-lait macules, skinfold freck- tumors) by adolescence or early adulthood. ling, and Lisch nodules (iris hamartomas) – Approximately one-third of young children will are pigmentary abnormalities. Although nearly have a more extensive type of neurofibroma, all children with NF1 will have more than five termed a plexiform neurofibroma. These cafe-au-lait macules by 2 years of age, most tumors can be associated with significant informahealthcare.com 10.1586/14737140.2015.1009043 Ó 2015 Informa UK Ltd ISSN 1473-7140 1 Review Brossier & Gutmann A B C D Figure 1. Anatomic localization of NF1-OPGs. (A) 6-year-old girl with an asymptomatic right optic nerve glioma; (B) 6-year-old girl with asymptomatic bilateral optic nerve gliomas; (C) 10-year-old boy with a symptomatic bilateral optic nerve/chiasm glioma and (D) 6-year-old girl with a symptomatic optic radiation glioma. Arrows denote the tumors. NF1: Neurofibromatosis type 1; OPG: Optic pathway gliomas. morbidity, including bone erosion, airway compression and in the context of NF1 tend to occur in younger children and impingement on local structures. Moreover, individuals with generally follow a more indolent course than their non-NF1 NF1 carry a 10% lifetime risk of developing a malignant periph- counterparts [5,6]. Despite their slow growth rate, however, low- eral nerve sheath tumor, a highly metastatic cancer that exhibits a grade CNS tumors in individuals with NF1 can cause vision poor response to currently available chemotherapeutic and radio- loss, precocious puberty and other neurologic deficits [7]. High- therapy regimens. Individuals with NF1 are also prone to the grade gliomas (HGGs: anaplastic astrocytomas and glioblasto- development of other cancers, including rhabdomyosarcoma, mas) occur less frequently than low-grade gliomas (LGGs) in juvenile myelomonocytic leukemia, pheochromocytomas and individuals with NF1, but their incidence is increased at least gastrointestinal stromal tumors. 10-fold relative to the general population [8–10]. Similarly, non- Although OPGs are the most common brain tumor arising gliomatous CNS tumors, such as meningioma, ependymoma in people with NF1, affected individuals are similarly predis- and medulloblastoma, are usually not encountered in people posed to develop other CNS tumors, including brainstem glio- with NF1. For personal use only. mas (BSGs) and, far less commonly, malignant gliomas (glioblastoma). These tumors can result in significant morbidity Optic pathway gliomas and mortality depending on their location and clinical progres- OPGs are the most common CNS tumor seen in individuals sion. Moreover, children with NF1 frequently manifest with NF1. OPGs account for approximately 3–5% of all pedi- T2-hyperintense abnormalities (previously referred to as atric brain tumors, but as many as 70% of these arise in chil- unidentified bright objects or UBOs) within the optic pathway, dren with NF1 [11]. In the context of NF1, gliomas can arise in brainstem, cerebellum and basal ganglia. Although these radio- any region along the optic pathway, ranging from the retro- logical findings are of unclear clinical significance, their appear- orbital optic nerve to the optic radiations (FIGURE 1). Although ance in regions where gliomas also develop may raise the not routinely biopsied or surgically removed, the vast majority suspicion for a brain tumor. These T2 hyperintensities have no of the tumors for which pathology is available have been iden- associated mass effect and lack contrast enhancement, and tified as WHO grade I gliomas (pilocytic astrocytomas [PAs]). importantly, decrease in size and number over time [4]. These low-grade glial neoplasms rarely, if ever, transform into Although current therapies for NF1-associated CNS tumors higher grade malignancies (e.g., glioblastoma). Instead, clinical may halt further tumor growth, they often fail to reverse the progression of these tumors is related to decline in visual func- associated visual or neurological deficits. For this reason, there tion or radiologic evidence of continued tumor growth. Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by St. Jude Children's Research Hospital on 02/10/15 has been significant interest in the identification and evaluation Despite a shared pathologic classification, NF1-OPGs are of new therapeutic strategies that inhibit tumor progression and distinct from their sporadic counterparts. First, the histologic improve neurological outcomes. In this review, we describe the architecture of PAs in the setting of NF1 appears to result current clinical management of NF1-associated gliomas and from circumferential growth of transformed astrocytes within discuss promising experimental therapeutic options and their the perineurial space to create a fusiform enlargement of the potential impact on the future management of children with affected nerve segment. In contrast, sporadic OPGs typically these brain tumors. demonstrate an intraneural pattern of growth with obliteration of the subarachnoid space due to fusion of the pia to the arach- CNS tumors in NF1 noid and dura mater [12]. Second, bilateral optic nerve involve- Although histologically similar to their sporadic counterparts, ment occurs almost exclusively in children with NF1, whereas NF1-associated gliomas have several distinct features. Gliomas chiasmatic and post-chiasmal tumors are more commonly doi: 10.1586/14737140.2015.1009043 Expert Rev. Anticancer Ther. Improving outcomes for NF1-associated brain tumors Review observed in sporadic OPG cases [13]. Third, progressive disease Only one-third of children with initially symptomatic is more commonly observed in sporadic OPGs, whereas NF1-OPGs will demonstrate clinical or radiographic progression NF1-associated tumors typically exhibit a more indolent clini- after the diagnosis of their tumor.