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Non-optic glioma in adults and children with neurofibromatosis 1 Sellmer, Laura; Farschtschi, Said; Marangoni, Marco; Heran, Manraj K S; Birch, Patricia; Wenzel, Ralph; Friedman, Jan M; Mautner, Victor-Felix Feb 15, 2017

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RESEARCH Open AccessNon-optic glioma in adults and childrenwith neurofibromatosis 1Laura Sellmer1*, Said Farschtschi2, Marco Marangoni3, Manraj K. S. Heran3, Patricia Birch1, Ralph Wenzel4,Jan M. Friedman1 and Victor-Felix Mautner2AbstractBackground: Non-optic gliomas occur in 5% of children with NF1, but little is known about these tumours inadults. We aimed to investigate progression, spontaneous regression and the natural history of non-optic gliomasin adults and compare these findings to the results found in children.Results: One thousand seven hundred twenty-two brain MRI scans of 562 unselected individuals with NF1 werecollected at the NF outpatient department of the University Hospital Hamburg-Eppendorf between 2003 and 2015.The number of scans per patient ranged from one to 12; patients were followed for a median of 3.7 years. Weidentified 24 patients (4.3%) with non-optic gliomas. Median age at first scan with glioma was 21.2 years, muchhigher than in previous publications. Only seven of the 24 non-optic glioma patients were symptomatic. Five of 24patients had multiple non-optic gliomas. Four individuals developed a new tumour, and 4 cases showedprogression. The risk of new tumour development was 0.19% (95% confidence interval 0.06% to 0.52%) per patientyear of follow-up for patients over 10 years. The rate of progressing non-optic gliomas per patient year of follow-upin the first 5 years after tumour diagnosis was 4.7% (95% confidence interval 1.5% to 12%).Conclusions: Non-optic gliomas are twice as common in an unselected cohort of NF1 patients as previouslyreported. This is likely due to increased frequency of diagnosis of asymptomatic tumours when routine MRIs areperformed and a higher prevalence in older individuals.Keywords: Neurofibromatosis 1, Cohort study, Glioma, Adults, Children, ProspectiveBackgroundNeurofibromatosis 1 (NF1) is an autosomal dominantdisorder with an estimated incidence of 1 in 3000 livebirths [1]. It is caused by mutations in the NF1 gene, asuppressor of the RAS kinase pathway. As a result of theNF1 protein’s ubiquitous expression and important rolein cellular regulation, patients with mutations in theNF1 gene develop e.g., neurofibromas and other neo-plasms and pigmentary abnormalities of the skin [2].Gliomas outside of the optic pathways are one of themost common causes of death in NF1 patients [3, 4].Non-optic gliomas in NF1 patients are usually located inthe brainstem or cerebellum and are almost exclusivelyreported in children, although non-optic gliomas areknown to occur in adults with NF1 as well [5]. Approxi-mately 5% of children with NF1 develop a non-optic gli-oma, a prevalence more than 100 times greater than inthe general population [6]. Non-optic gliomas in NF1patients are usually low-grade astrocytomas and oftenhave a more benign course than in people without NF1[7–9]. Their natural history is only incompletely under-stood [10]. The occurrence of non-optic gliomas hasbeen found to be associated with the presence of opticgliomas in children with NF1 in some studies [11, 12].MRI is commonly used to evaluate intracranial tu-mours in clinical as well as research settings [13]. MRIprovides information on the presence, location, and sizeof the tumour and is a crucial tool in routine clinicalcare of gliomas in individuals with or without NF1.In this study, we investigated the natural history,progression, and regression of non-optic gliomas in anunselected cohort of adults and children with NF1.* Correspondence: lsellmer@cfri.ca1Department of Medical Genetics, University of British Columbia, Vancouver,CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Sellmer et al. Orphanet Journal of Rare Diseases  (2017) 12:34 DOI 10.1186/s13023-017-0588-2MethodsPatientsBetween 2003 and 2015, all patients with NF1 diagnosedaccording to standard clinical criteria seen in the NFoutpatient department of the University HospitalHamburg–Eppendorf were offered brain MRIs [14]. Be-cause patients were not selected for imaging on the basisof clinical symptoms, they are representative of the NF1population seen in the clinic.The ethical committees of the Medical Chamber inHamburg and the Research Ethics Board of the Univer-sity of British Columbia approved the study. Writtenconsent was obtained from all study participants beforestudy begin. All data were de-identified before analysis.MRI imagingLesions that were hyperintense in T2 without mass effectand enhancement were identified as unidentified brightobjects (UBO). In order to distinguish gliomas fromUBOs, we used the following criteria: location and sizeof a lesion, the presence of mass effect, the lesion beinghyperintense in T2 and hypointense in T1, and evolutionover time.Based on the 1722 German clinical MRI reports, a listof patients was generated who had been diagnosed withnon-optic gliomas. All brain MRIs from these patientswere re-evaluated by two neuroradiologists in Canada(M.M. and M.K.S.H.), and the presence of non-opticgliomas in each individual patient was established byconsensus using the criteria described above.In NF1 patients without anomalies on head MRI,follow-up imaging was performed in 2-year intervals. Inpatients with asymptomatic non-optic gliomas, imagingwas repeated after 1 year. In patients with clinically orradiologically progressive non-optic gliomas, re-imagingwas performed at 6-month intervals. Treatment deci-sions were based on location and severity of symptomsin symptomatic patients, and based on location and rateof tumour growth in asymptomatic patients. Surgical re-section was the treatment of choice if it could be donesafely; if the tumour was unresectable, chemotherapywas offered.Tumour volume was calculated by using a box model.New appearance of a glioma was defined when an indi-vidual had a tumour on at least one MRI in an area thatwas well imaged but no tumour was seen in at least oneprevious scan. Progression of a non-optic glioma was de-fined as an increase in volume of at least 30% per year.Descriptive statistical analysisPatients were divided into 10-year age groups and onlycounted once per age group. Patients who were scannedin more than one decade of life were counted once ineach age group in which a scan was performed. Patientswith more than one glioma present were counted onlyonce per age group. Ninety-five percent confidenceintervals of the percentages were calculated as ± 1.96standard deviations of a Poisson distribution.Tumour volume in younger patients was compared tothat in older patients with a Mann–Whitney U test.Ninety-five percent confidence intervals for rates of newlyappearing tumours and progressing tumours were calcu-lated using Wilson’s method with continuity correction.Results were considered to be significant if p ≤ 0.05.ResultsDemographicsA total of 562 patients with NF1, 264 males and 298 fe-males (1.0:1.1 ratio), were included in this study (seeFigs. 1a and 2). One thousand seven hundred twenty-twoMRI scans were performed, with a median of two scansper person (range, 1 to 12 scans) and a median follow-uptime of 3.7 years (range, 0 to 13.0 years). At the time ofthe MRI scan, their ages ranged from 0.4 to 72.8 years.During the study period, 51 patients were lost tofollow-up and 24 died of reasons unrelated to non-opticgliomas, equaling a dropout rate of 13.3%.Number of patients with non-optic glioma by age groupA diagnosis of non-optic glioma was made on clinicalreading of the brain MRI images in 27 NF1 patients. In24 of these cases, the study neuroradiologists (M.M. andM.K.S.H.) were able to confirm the definite presence ofa non-optic glioma using the study criteria.Thus, a total of 24 (4.3%) of the 562 NF1 patients werediagnosed with non-optic glioma. The prevalence ofindividuals diagnosed with non-optic glioma per 10-yearage group is shown in Fig. 1b. Follow-up of the 24 non-optic glioma patients ranged between 0 years and11.8 years, with a median of 5.0 years of follow-up and acombined total of 134 years of follow-up.Clinical description of gliomasAn overview of all non-optic glioma cases is provided inTable 1. There were a total of 32 gliomas in 24 patients.Nineteen patients had one glioma, two patients had twonon-optic gliomas, and three patients had three non-optic gliomas. Only seven of the 24 non-optic tumourpatients were symptomatic. Individual tumour volumesranged from 0.04 cm3 to 98.4 cm3, with a median volumeof 1.6 cm3.Twenty-five of 32 tumours enhanced after administra-tion of gadolinium. Eight tumours showed avid enhance-ment, four tumours showed diffuse enhancement, andenhancement was patchy or peripheral in 13 tumours.Enhancement increased in three tumours and decreasedin another three tumours. These changes were notSellmer et al. Orphanet Journal of Rare Diseases  (2017) 12:34 Page 2 of 8associated with alterations in clinical status or otherradiological features.Nine patients received treatment for their gliomas(Table 1): eight patients underwent surgery and onepatient received vincristine and carboplatin following abiopsy. None of these nine patients had recurrence or fur-ther growth of their non-optic gliomas after treatment.Histology was available on nine tumours. Eight tu-mours were pilocytic astrocytomas (PAs) (WHO Grade1) and one was a dysembryoplastic neuroepithelialtumour (DNET). DNETs are of glioneuronal origin andare classified as WHO Grade 1. There were no higher-grade tumours.Three patients with non-optic gliomas had concurrentoptic gliomas (Patients 9, 11 and 19 in Table 1). Therewas no significant association between the presence ofnon-optic gliomas and optic gliomas (χ2 = 0.31, p = 0.57).Newly diagnosed non-optic gliomasThere were four individuals with newly-appearing gliomas(see Fig. 2) (Patients 9c, 11, 12b, and 19 in Table 1). Sinceglioma prevalence is stable in patients over 10 years, wedetermined the rate of new tumours appearing during2111 years of follow-up of patients age 10 and older. Fournew tumours appeared, resulting in a rate of 0.19% (95%confidence interval 0.06% to 0.52%) of new non-optic gli-oma development per patient year of follow-up. Therewere no newly-appearing non-optic gliomas in the266 years of follow-up of children younger than 10 years.Progressing gliomasWe identified glioma progression in four individuals(Fig. 3) (Patients 10, 19, 23, and 24b in Table 1). The rateof progressing non-optic gliomas per patient year offollow-up in the first 5 years after tumour diagnosis wasFig. 1 Demographics and percentage of NF1 patients affected by non-optic glioma per age group. a Number of male and female NF1 patientsper age group. Each person is counted once per age group, regardless of number of scans in that age group. Individuals may appear in morethan one age group if scanned in more than one age range. b The overall prevalence of non-optic glioma appears stable in adulthood. Eachperson is counted once per age group, regardless of number of scans in that age group. Individuals may appear in more than one age group ifscanned in more than one age range. Error bars are 1.96 standard deviations of a Poisson distributionSellmer et al. Orphanet Journal of Rare Diseases  (2017) 12:34 Page 3 of 84.7% (95% confidence interval 1.5% to 12%). No progres-sion events were observed in the 48.1 patient years offollow-up that were more than 5 years after diagnosis.Tumours in four of 21 non-optic glioma patients pro-gressed (three patients did not have follow-up aftertumour diagnosis).Regressing gliomasThere were no spontaneously regressing gliomas in ourstudy.Correlation of presence non-optic gliomas with presenceof UBOsA study by Griffiths et al. suggested that gliomas mightarise from unidentified bright objects (UBOs) in childrenwith NF1 [15]. We focused on the 4 patients withnewly-appearing tumours (Patients 9, 11, 12, and 19 inTable 1) and assessed if they had UBOs in the locationwhere the glioma later appeared.None of the four non-optic glioma patients withnewly-appearing gliomas had UBOs at the location oftheir tumour before it appeared.DiscussionThis study comprises the world’s largest collection ofunselected brain MRIs of NF1 patients reported to date.Twenty-four (4.3%) of 562 patients were diagnosed withnon-optic gliomas. This overall prevalence is 1.5× to 3×higher than in previously published prospective studies(Table 2) [11, 16–21].This difference can be explained in part by the factthat the majority of non-optic glioma patients areasymptomatic (seven of our 24 glioma patients weresymptomatic) and could only be detected by offeringMRIs to all NF1 patients, as was done in our study.The median age at first scan in this study is 21.2 years –much higher than the usual age at diagnosis of non-opticgliomas in NF1 patients (Table 2).Fig. 2 Newly-appearing glioma in the left cerebral peduncle in Patient 19. a There is no visible glioma on the patient’s first scan. b 4 years later,an enhancing glioma has appeared in the left cerebral peduncle measuring 0.5 cm3. c 5 years after the initial glioma-free scan, the glioma hasincreased to a volume of 0.8 cm3. d 7 years after the initial scan, the glioma measured 1.3 cm3. All images shown are FLAIR sequences. Thepatient remained asymptomatic during follow-up and also has an optic glioma (not visible in these images)Sellmer et al. Orphanet Journal of Rare Diseases  (2017) 12:34 Page 4 of 8Since our study uses age at first scan with glioma and notage at glioma diagnosis to infer prevalence, cases in youngerage groups might be underrepresented. Additionally, themajority of adult NF1 patients with gliomas are asymptom-atic and some symptoms of brain tumours are alsocommon in NF1 patients without brain tumours (e.g.,Table 1 Clinical features of non-optic gliomas in NF1 patientsPatient number Sex Age at first scan withglioma (in years)Symptoms Histology Location Status Treatment1 M 20.9 Headache PA Grade 1 Frontal Decreased size Surgery2 F 41.6 No Temporal Decreased size Chemotherapy(breast cancer)3 F 48.6 No Brainstem Stable4 F 50.8 No Temporal No follow up5 F 23.4 Seizures Brainstem Stable6 F 10.0 Seizures, headache Cerebellum Stable7 M 31.3 No Brainstem Stable8 M 13.1 No Frontal Stable9ab M 44.6 Ataxia Cerebellum Stable9bb M 44.6 Ataxia Cerebellum Stable9cab M 50.5 Ataxia PA Grade 1 Cerebellum Increased, thendecreased sizeSurgery10 M 6.5 No PA Grade 1 Brainstem Increased size &enhancementChemotherapy,biopsy11ab F 34.9 No Brainstem No follow up12a F 16.4 No PA Grade 1 Corpus Callosum Increased enhancement Incompleteresection beforestudy begin12ba F 25.3 No Brainstem Stable13 F 38.5 No Cerebellum Stable14 M 17.2 Seizures, headache PA Grade 1 Cerebellum Stable Surgery15 M 21.3 No PA Grade 1 Corpus Callosum Decreased size &enhancementSurgery16 M 42.5 No Temporal Stable17 M 42.7 Seizures DNET Cerebellum Stable Incompleteresection beforestudy begin18a F 14.8 No PA Grade 1 Corpus Callosum No follow up Surgery18b F 14.8 No Thalamus No follow up19ab F 18.3 No Brainstem Increased in size20 F 16.0 No Internal capsule Decreased enhancement21 F 39.8 No Cerebellum Stable22a F 10.9 No Cerebellum Decreased enhancement22b F 10.9 No Cerebellum Increased, thendecreased in size22c F 10.9 No Cerebellum Stable23 M 17.4 No Brainstem Increased size &enhancement24a M 18.1 Double vision, nystagmus PA Grade 1 Brainstem Decreased size Surgery24b M 18.1 Double vision, nystagmus Corpus Callosum Increased size24c M 18.1 Double vision, nystagmus Cerebellum StableAbbreviations: PA pilocytic astrocytoma, M male, F female, DNET dysembryoplastic neuroepithelial tumouradenotes patients with newly-appearing tumoursbdenotes patients with concurrent optic gliomasSellmer et al. Orphanet Journal of Rare Diseases  (2017) 12:34 Page 5 of 8headache). Even though it is known that NF1 patients havea lifelong elevated risk for tumour development, brainMRIs are not currently recommended for tumour surveil-lance in NF1 patients of any age as part of regular clinicalcare [7, 22].The largest group of adult NF1 patients with non-optic gliomas was described by Gutmann et al. [5] Onlythree of 15 tumours for which histology was availablewere Grade 1, compared to nine of nine in our study.This may be explained by Gutmann et al. only reportingsymptomatic tumours, which are more likely to be high-grade than asymptomatic tumours. Other authorsreported three adult cases, two of which were asymp-tomatic [23].Intracranial gliomas in NF1 patients are usually associ-ated with a better outcome than those diagnosed in thenon-NF1 setting [24, 25]. Most of the tumours biopsiedin this study were PAs – the most common histologicaltype of intracranial tumour [26]. The 5-year survival rateof NF1 patients with PA was estimated to be 85% [25].However, this was calculated for patients who underwentsurgery for their gliomas, so the true 5-year survival rateis likely much higher than 85%. In further support ofthis, none of our brain tumour patients with or withoutbiopsy-proven PA died during a cumulative 134 patientyears of follow-up.While malignant transformation of low-grade non-optic gliomas has been described in NF1 patients [27, 28],this appears to be infrequent [29]. We did not see anycases of malignant transformation in this study.The majority of non-optic gliomas in children withNF1 reported in the literature have been located in theposterior fossa [9, 30]. We observed the same thing inour study. We also found that the majority of non-opticgliomas in adults with NF1 were located in the posteriorfossa. Previous reports suggested that these tumoursusually occur in other locations in adults [5], but previ-ous studies of non-optic gliomas in adults with NF1 havebeen small and focused on symptomatic patients. Mostof the patients in our study were asymptomatic.There were five patients with multiple non-optic gli-omas. These lesions could either be multiple primarytumours, or multifocal gliomas. Gliomas in NF1 patientswere shown to be multifocal [25]; however, it is impos-sible to distinguish between multifocal and multipleprimary tumours without performing molecular ana-lyses. The chance of having 1 non-optic glioma accord-ing to our results is 4.3%; therefore we expected to findone individual with two primary non-optic gliomas and0 individuals with three primary non-optic gliomas bychance in a series of this size. We found two patientswith two gliomas and three patients with three gliomaseach. Even though these numbers are small, they supportthe possibility that a patient is more likely to developadditional non-optic tumours if he or she has alreadydeveloped one. There is a correlation between the occur-rence of optic and non-optic gliomas in people with NF1[11]; however, a correlation between the development ofnon-optic gliomas has not previously been suggested.There are case reports of NF1 patients with more thanone non-optic glioma, and all of these patients wereFig. 3 Progressing glioma in Patient 9. a First scan with glioma presentin the left cerebral peduncle and left thalamus on FLAIR sequence. bAnother scan performed 2 years after the previous one (again FLAIRsequence). The glioma has drastically increased in size and was treatedwith chemotherapy 1 month after this image was takenSellmer et al. Orphanet Journal of Rare Diseases  (2017) 12:34 Page 6 of 8symptomatic [31]. Only two of the five patients in ourstudy showed symptoms, so NF1 patients can have mul-tiple brain tumours and remain asymptomatic. A publi-cation assessing prognostic factors for NF1 patients withbrain tumours found that having multiple tumours isnot a risk factor for death [32]; however, it did notdistinguish between optic and non-optic tumours.Tumours in adults with NF1 are said to be higher-gradeand carry a worse prognosis than those in children withNF1 [32, 33]; however, we did not find any higher-gradetumours in adults. This difference probably reflects thefact that adults were only included in previous studies ifthey had aggressive tumours, whereas our study includedindividuals independent of the presence of symptoms.In order to compare tumour volumes of younger andolder non-optic glioma patients, we separated the cohortinto two groups, using the median age at diagnosis(21.2 years) as cut-off. Tumours in patients diagnosedbefore 21.2 years had a significantly greater volume thanthose in patients diagnosed later (Mann–Whitney U test,p = 0.02). This is counterintuitive if most tumours inadults arose in childhood or adolescence and tumoursonly grow in young patients. However, a similar observa-tion has been made for plexiform neurofibromas inpeople with NF1 – the most rapid growth occurs duringchildhood but the tumour volume is inversely correlatedwith age [34]. In addition to having larger tumours,seven of the nine individuals requiring treatment of theirnon-optic tumour were diagnosed before 21.2 years ofage. One possible explanation for the differences intumour volume between children and adults is that largetumours in childhood require treatment or have fatalconsequences, thus only leaving patients with small in-dolent tumours to be identified later.One of the limitations of our study is that patients re-ferred to the NF clinic are probably not representative ofthe NF1 patient population as a whole. Patients withmilder manifestations may be less likely to be referredthan those more severely affected. In addition, patientswith e.g., brain tumours are more likely to get follow-upscans than tumour-free patients. Another limitation is thateven though all parents were offered brain MRIs for theirchildren, parents of asymptomatic children might be morelikely to refuse MRI, which requires sedation, than parentsof symptomatic children. Therefore, this study is probablybiased towards patients with a more severe phenotype. Itis important to note that there were patients seen in theNF outpatient department who had higher-grade tumoursbut were not included in this study.There is currently no recommended head MRI screen-ing protocol for patients with NF1, whether or not theyhave non-optic gliomas. We screen NF1 patients withoutnon-optic gliomas every 2 years, patients with asymp-tomatic gliomas every 12 months, and patients withsymptomatic gliomas every 6 months. A much largerlongitudinal cohort study would be necessary to deter-mine if this is the optimal approach.Non-optic gliomas may occur in children as well asadults with NF1, and these tumours should be consid-ered as a possible cause of neurological symptoms thatdevelop in NF1 patients of any age.ConclusionWe determined the rate of appearance, progression andspontaneous regression in an unbiased NF1 cohort. Thisis the largest prospective study of unselected brain MRIsever published and also the first study to compare gliomafrequency and natural history in an unselected cohort withan age range this wide. Our data should be consideredwhen counselling adults with NF1 who have a glioma.AcknowledgementsNot applicable.FundingThis study was funded by a grant from the BundesverbandNeurofibromatose e.V. (grant number: 2016).Table 2 Published prospective and retrospective studies assessing the prevalence of non-optic gliomas in NF1Authors Study type Cohort size Age range ofcohorts (in years)Median age atdiagnosisNumber of tumourpatientsRates of tumours How were tumourpatients identified?Cnossen et al. [16] P 150 0–18 Unknown 4 2.70% SymptomaticpatientsZöller et al. [17] P 70 20–81 Unknown 1 1.43% Cross-referencingwith cancer registryFriedman and Birch [11] R 684 0–73 <6 years 25 3.65% MRI/CT*McGaughran et al. [18] R 523 0–74 Unknown 12 2.29% Symptomatic patientsMenor et al. [19] R 72 0.8–14 Unknown 8 11% MRI*Seminog and Goldacre [20] R 6739 0–80+ Unknown 322 4.78% Hospital recordsVaran et al. [21] R 473 0–33 8 years 11 2.32% Symptomatic patients*denotes studies for which convenience MRI/CT images were usedSellmer et al. Orphanet Journal of Rare Diseases  (2017) 12:34 Page 7 of 8Availability of data and materialsThe dataset supporting the conclusions of this article is included in fullwithin the article.Authors’ contributionsJMF and VFM contributed to the study planning. VFM, SF and RW wereinvolved in image collection and provided clinical patient care. LS, MM,MKSH, PB, JMF and VFM were responsible for data analysis and datavisualization. LS, SF, JMF and VFM were involved in writing and reviewingthe manuscript. All authors read and approved the final manuscript.Competing interestsThe authors declare that they have no competing interests.Consent for publicationNot applicable.Ethics approval and consent to participateThe ethical committees of the Medical Chamber in Hamburg and theResearch Ethics Board of the University of British Columbia approved thestudy. Written consent was obtained from all study participants before studybegin. All data were de-identified before analysis.Author details1Department of Medical Genetics, University of British Columbia, Vancouver,Canada. 2Department of Neurology, University Hospital Hamburg-Eppendorf,Hamburg, Germany. 3Diagnostic and Therapeutic Neuroradiology, Universityof British Columbia, Vancouver, Canada. 4Department of Radiology, MRIInstitute Altona, Hamburg, Germany.Received: 7 December 2016 Accepted: 7 February 2017References1. Lammert M, Friedman JM, Kluwe L, Mautner V-F. 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