A multi-institutional study of brainstem gliomas in children with neurofibromatosis type 1 Jasia Mahdi, MD ABSTRACT Amish C. Shah, MD, Objective: To define the clinical and radiologic features of brainstem gliomas (BSGs) in children PhD with neurofibromatosis type 1 (NF1). Aimee Sato, MD Methods: We performed a retrospective cross-sectional study of 133 children with NF1 and con- Stephanie M. Morris, MD current BSGs cared for at 4 NF1 referral centers. BSG was determined using radiographic crite- Robert C. McKinstry, ria. Age at diagnosis, tumor location and appearance, clinical symptoms, treatment, and presence MD, PhD of a concurrent optic pathway glioma were assessed. Robert Listernick, MD Roger J. Packer, MD Results: The average age at BSG diagnosis was 7.2 years, and tumors occurred most often in the Michael J. Fisher, MD midbrain and medulla (66%). The majority of children with NF1-BSGs were asymptomatic (54%) David H. Gutmann, MD, and were not treated (88%). Only 9 of the 72 asymptomatic children received treatment because PhD of progressive tumor enlargement. In contrast, 61 children presented with clinical signs/symptoms attributable to their BSG; these individuals were older and more often had focal lesions. Thirty-one patients underwent treatment for their tumor, and 14 received CSF diversion only. Progression-free Correspondence to survival was ;3 years shorter for children receiving tumor-directed therapy relative to those who Dr. Gutmann: had either no treatment or CSF diversion only. Overall survival was 85% for the tumor-directed [email protected] therapy group, whereas no deaths were reported in the untreated or CSF diversion groups. Conclusions: Unlike children with sporadically occurring BSGs, most children with NF1-BSGs were asymptomatic, and few individuals died from complications of their tumor. Those requiring tumor-directed treatment tended to be older children with focal lesions, and had clinically more aggressive disease relative to those who were not treated or underwent CSF diversion only. Neurology® 2017;88:1584–1589 GLOSSARY BSG 5 brainstem glioma; CHOP 5 The Children’s Hospital of Philadelphia; CNMC 5 Children’s National Medical Center; DIPG 5 diffuse intrinsic brainstem glioma; LCH 5 Ann & Robert H. Lurie Children’s Hospital of Chicago (Northwestern University); NF1 5 neurofibromatosis type 1; OPG 5 optic pathway glioma; OS 5 overall survival; PA 5 pilocytic astrocy- toma; PFS 5 progression-free survival; WUSM 5 Washington University School of Medicine; WHO 5 World Health Organization. Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome in which affected children and adults develop benign and malignant nervous system tumors.1 WHO grade I gliomas (pilocytic astrocytomas [PAs]), including those involving the optic pathway and brain- stem, predominate in children with NF1. Optic pathway gliomas (OPGs), the most frequently encountered of these low-grade gliomas, are seen in 15%–20% of children with NF1. These tumors typically come to medical attention in young preschool children (mean age, 4.5 years) who present with reduced visual acuity or precocious puberty, or who are incidentally discovered on screening neuroimaging.2,3 While OPGs represent 66%–75% of all CNS tumors in children with NF1,4 the second most common brain tumor is the brainstem glioma (BSG), representing approximately 18% of NF1- associated brain neoplasms.4,5 Unlike NF1-OPG, NF1-BSGs tend to arise at a slightly older age Supplemental data at Neurology.org From the Departments of Neurology (J.M., S.M.M., D.H.G.) and Radiology (R.C.M.), Washington University School of Medicine, St. Louis, MO; Division of Oncology (A.C.S., M.J.F.), Children’s Hospital of Philadelphia, PA; Center for Neuroscience of Behavioral Medicine (A.S., R.J. P.), Children’s National Medical Center, Washington, DC; Division of Academic General Pediatrics (R.L.), Feinberg School of Medicine, Northwestern University, Ann & Robert H. Lurie Children’s Hospital of Chicago, IL; and Department of Pediatrics (M.J.F.), The Perelman School of Medicine at The University of Pennsylvania, Philadelphia. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 1584 © 2017 American Academy of Neurology ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. (mean age, 7 years).5 However, much less is Table 1 Patient demographics known about their presentation and ensuing clinical course, with only 3 clinical series Characteristics Values reported, each with fewer than 30 partici- Age, y, mean 6 SD 7.18 6 4.38 5–7 pants. Our limited understanding of these Female, n (%) 59 (44.4) brain tumors in the context of NF1 is prob- Symptomatic at diagnosis, n (%) 61 (45.9) lematic given the dramatic contrast in clinical Presence of concurrent OPG, n (%) 70 (52.6) outcomes when compared to sporadically Positive family history, n (%) 45 (33.8)a occurring brainstem gliomas, such as the dif- Length of follow-up, y, average 6 SD 7.5 6 4.50 4,5,8 fuse intrinsic brainstem glioma (DIPG), an Alive at last follow-up, n (%) 123 (92.5) aggressive pediatric brain tumor with frequent Abbreviation: OPG 5 optic pathway glioma. recurrence and poor overall survival (OS) a Four participants did not have a documented family rates. history. To comprehensively characterize the pre- NF1 (yes/no), and progression-free survival (PFS). The collected sentation and symptomatology of BSGs aris- data were de-identified and stored within a password-protected ing in the context of NF1, we assembled the spreadsheet on a secure laptop and were only accessed by study largest series of children and young adults with team members at WUSM. these low-grade brain tumors, representing the Statistical analysis. Data were analyzed using IBM (Armonk, collective experience of 4 tertiary care referral NY) SPSS, version 23. Categorical variables were reported as fre- centers with longstanding NF clinical quencies and proportions, and compared using logistic regression methods. Continuously distributed traits adhering to conven- programs. tional normality assumptions were reported as mean and SD, and compared using analysis of variance methods. PFS was esti- METHODS Study population. A retrospective analysis of mated using the Kaplan-Meier method and a log-rank test was the electronic medical records of 133 participants who were fol- used to compare survival curves. Statistical significance was lowed at 1 of 4 institutions was conducted over a 15-year defined as a p value of ,0.05. period (2000–2015). Participating sites included St. Louis ’ Children s Hospital (Washington University School of Medicine RESULTS A total of 133 individuals were included ’ [WUSM]), The Children s Hospital of Philadelphia (CHOP), in the study (59 from CHOP, 35 from WUSM, 22 Children’s National Medical Center (CNMC), and Ann & Robert H. Lurie Children’s Hospital of Chicago (Northwestern fromLCH,and17fromCNMC),withatotalof59 University [LCH]). female and 74 male participants. The mean age at diagnosis of a BSG was 7.18 6 4.38 years (age range Standard protocol approvals, registrations, and patient 0.6–23years;table1).Therewasanormalandcon- consents. This study was approved by the institutional review boards at WUSM, CHOP, CNMC, and LCH. All participants tinuous distribution for the age at initial diagnosis included in the study had a diagnosis of NF1 based on NIH Con- (figure 1). No statistically significant differences in sensus Development criteria9 and were identified as having mean age at diagnosis based on the region of brain- a brainstem glioma based on the following radiographic criteria: stem involvement were observed, and the location of (1) a T2-hyperintense lesion with an associated T1 hypointensity BSG did not appear to differ by sex (p 5 0.58). relative to gray matter, (2) a T2-hyperintense lesion with mass While some BSGs crossed anatomic boundaries effect with or without an associated T1 hypointensity relative to 5 gray matter, or (3) an enhancing lesion with or without mass and occurred in the midbrain and pons (n 5; effect on MRI. Participants were excluded from the study when 3.8%), midbrain and medulla (n 5 3; 2.2%), pons (1) a diagnosis of NF1 could not be established, (2) there was an and medulla (n 5 14; 10.5%), and entire brainstem ill-defined T2 hyperintensity lacking either T1 hypointensity or (n 5 4; 3.0%), the majority of tumors were localized gadolinium enhancement and not exhibiting mass effect or to only one anatomical segment (n 5 107; 80.5%). architectural distortion, likely representing a non-neoplastic T2 When confined to a single segment, tumors were hyperintensity (unidentified bright object) commonly observed 5 in children with NF1,10,11 or (3) there was incomplete clinical statistically less likely to occur in the pons (n 5 information available in the electronic medical record. The 19; 14.2%) compared to the midbrain (n 48; average length of follow-up was 7.5 years. 36.1%) or medulla (n 5 40; 30.1%, p 5 0.002) (figure 2). Record review and data collection. Data analyzed included age at diagnosis, patient sex (male/female), location of tumor Asymptomatic children with NF1-BSG. Seventy-two of (midbrain, pons, medulla, midbrain and pons, midbrain and the 133 children (54%) with NF1-BSGs were medulla, pons and medulla, or entire brainstem), focal or diffuse asymptomatic at the time of BSG diagnosis. The mass on MRI (defined as discrete mass vs an infiltrative mass 5 without a defined border; figure e-1 at Neurology.org), clinical majority of asymptomatic individuals (n 63; 88%) symptoms, treatment (chemotherapy, radiation, or surgery), the did not receive tumor-directed therapy; however, 9 presence of a concurrent optic glioma (on MRI), family history of children (12.5%) without clinical symptoms Neurology 88 April 18, 2017 1585 ª 2017 American Academy of Neurology.