www.elsevier.es/cancerologia
CASE
REPORT
Arteriovenous
malformation
masking
associated
anaplastic
ganglioglioma
in
an
adolescent
Gustavo
Adolfo
Carvajal-Barrios
a,∗,
Jimena
Ortiz
b,
Natalia
González
c,
José
Arias
d,
Fernando
Velandia
e,
Pilar
Guerrero
f,
Eugenia
Espinosa
gaPhysician,pediatricsresident,UniversidadelBosque,BogotáD.C,Colombia
bNeuroradiologist,professoradhonorem,UniversidadMilitarNuevaGranada(UMNG)-HospitalMilitarCentral(HMC),BogotáD.
C,Colombia
cPediatrichematologist/oncologist,HMC-HMC,BogotáD.C,Colombia
dPathologist,HMC.ProfessoradhonoremUMNG-HMC,BogotáD.C,Colombia
eNeuropathologist,Seniorprofessor,NeuroscienceGroup,UniversidaddelRosario,BogotáD.C,Colombia
fPediatricneurologist,associateprofessorofpediatricneurology,UMNG-HMC,BogotáD.C,Colombia
gPediatricneurologist,tenuredprofesorinpediatricneurologyUMNG-HMC,Coordinatorofgraduatestudiesinpediatric
neurologyUMNG-HMC,BogotáD.C,Colombia
Received11January2018;accepted26March2018 Availableonline22May2018
KEYWORDS
Braintumour; Child; Intracranial hypertension; Ganglioglioma; Headache
Abstract GradeIIIanaplasticgangliogliomaisanaggressive,rare,andradiosensitivecentral
nervoussystem(CNS)tumour.Itismorecommoninmales,witharatioof1.3to1. Itspeak incidenceisinthethirddecadeoflife.Only10 caseswere recordedinchildren in Colom-biafrom2000to2014,withafataloutcomeinspiteofradiationtherapy.Thisisacaseofan adolescent,whobeganhavingheadaches,withwarningsignsrelatedtoanarteriovenous malfor-mationhinderingthediagnosisofthisraretumour.Thispresentedinitsaggressive,multi-focus form.Knowledgeofclinicalmanifestationsofspace-occupyingintracraniallesionsfacilitates theassessmentandtreatmentofaffectedchildren.
© 2018 Instituto Nacional de Cancerolog´ıa. Published by Elsevier Espa˜na, S.L.U. All rights reserved.
∗Correspondingauthor.
E-mailaddress:[email protected](G.A.Carvajal-Barrios). https://doi.org/10.1016/j.rccan.2018.03.002
PALABRASCLAVE
Tumorcerebral; Ni˜no;
Hipertensión endocraneana; Ganglioglioma; Cefalea
Malformaciónarteriovenosaasociadaenmascaraungangliogliomaanaplásico multifocalenunadolescente
Resumen ElgangliogliomaanaplásicogradoIIIesuntumordelsistemanerviosocentral(SNC)
agresivo,infrecuenteyradiosensible.Afectamásahombresenunarelación1,3a1.Supico deincidenciaseencuentraenlaterceradécadadelavida.Existensolo10casosregistrados enni˜nosenColombiadesdeel2000al2014,condesenlacefatalapesardelaradioterapia.Se presentauncasodeunadolescentequedebutóconcefaleaconsignosdealarmaasociadoauna malformaciónarteriovenosaquedificultóeldiagnósticodeesterarotumor,cuyapresentación fuelamásagresiva:laformamulticéntrica.Elconocerlasmanifestacionesclínicasdelesiones intracranealesocupantesdeespaciofacilitalaevaluaciónytratamientoalosni˜nosafectados. © 2018Instituto Nacional de Cancerolog´ıa.Publicado por Elsevier Espa˜na, S.L.U.Todos los derechosreservados.
Introduction
TheincidenceofCNStumorsisvariable,1andestimatedto
be35casespermillioninchildrenundertheageof15.They arethesecondgroupof pediatricmalignanttumors, mak-ing up 20-25% of all tumors;1,2 60-70% are of glialorigin,
andin most of them thereis nometastasis.2 Usually, the
supratentorial tumors are seen more in children younger than two years, and in late adolescence.2 There is an
associationwithneurofibromatosistypeI,tuberous sclero-sis,and Von Hippel-Lindau,Li-Fraumeni, Turcot,Cowden, retinoblastoma(Rb),rhabdoidtumorandGorlinsyndromes,2
aswellaswithexposuretoionizingradiation, immunosup-pression,andinfection.2Gangliogliomas(GGs)makeup0.4%
ofallintracranialtumorsinchildren,1---3theyarerare,and
theybelongtothegroupofneuronalandmixed neuronal-glialtumors.3 Theypredominantly affectmales,in aratio
of 1.3 to 1.4 In Colombia, the Instituto Nacionalde
Can-cerología[NationalCancerInstitute](INC)recorded10cases between2000and2014inchildrenundertheageof18.5
Clinical
case
A14year oldadolescentmalewithnormal neurodevelop-ment, who in 2009 began to present oppressive bilateral occipitalheadaches:intensity7/10, self-limited,andwith impairedvisualacuity.Heconsultedin2014duetoa bilat-eral global, throbbing headache with a 10/10 intensity. Magnetic resonance imaging (MRI) of the brain showed a leftthalamic arteriovenousmalformation(AVM)with mul-tipleflowvoidsforminganest, associatedwithavascular drainagestructure,withoutsignsofruptureormasseffect. He wasreferred to Hospital Militar Central (HMC) where angiography showed a Spetzler-Martin grade III AVM, and expectantmanagementwaschosen(figure1).
In2015,hepresentedanticipatoryemesiswithfood,as wellashematemesisandprogressiveoppressiveright pari-etalheadachewitha 10/10intensity,projectile vomiting, dysarthria, drowsiness, weakness, paresthesias, and left legmonoparesiaassociatedwithintracerebralhemorrhage seen oncomputerizedaxialtomography (CT);hereceived phenytoin and was referred to HMC. On admission, he
Figure1 Digitalsubtractionangiographydemonstrates
clas-sicarteriovenousmalformationintheleftthalamicregionwith drainagetotheinternalcerebralvein,Spetzler-MartinIIIb.
was normotensive, Tanner 2, without apparent growth alterations.AbrainMRIshowedanacuterightfrontalbasal hemorrhage, perilesional edema, midline shift, and left posteriortemporalcorticallesionswhichfollowedvascular territory, without an ischemic appearance (figure 2). His angiographic diagnosis was, therefore, cerebrovascular accident(CVA),withapossibletumorlesion.
Figure2 Brain MRIaxial cuts: a. T2,b. T1and c.T1+MC. Right frontal parasagittalcortical-subcorticalintra-axial massof intermediatesignalintensity,withabloodcomponent,nothighlightedbythecontrastmedia.Positivesignsofcompressionwith markedadjacentvasogenicedema,andasubfalcineherniatotheleft.Showsalesionintheleftthalamicregionwithmultipleflow voidsforminganest,associatedwithavasculardrainagestructurerelatedtoanAVM,withoutsignsofruptureormasseffect.
Figure3 AandB.Neoplasiawithcompactgrowthandextensiontothesubarachnoidspace.Twocomponentscanbeseen:the
neuronalcomponentwithdysmorphicneurons,pleomorphicnuclei(somewithaprominentnucleolus),andlossoftheNisslbodies; andthemixedglialcomponentwithneoplasticastrocytesandsomemitoses.C.Reactiveglialfibrillaryacidicprotein.D.Focally reactivep53.E.Ganglioncellswithfinegranularmarkings.F.Ki6715%lowerintheneuronalcomponent.
hypodensityofthewhitematter,diminishedbreadthofthe cisterns,whitematteredema,midlineshifttotheleftand obliterationofthefrontalhorn oftheipsilateralventricle withthickeningoftheveinofGalenandthestraightsinus, duetoleftthalamicmalformation.Duetohematemesis,a syncopal episode, right hemiparesia, peribuccal cyanosis, upward gaze deviation with progression to total paresia, andgeneralizedhypertonia,hewasreadmittedtoHMC.The head CTshowed a right frontal hypodense lesion without mass effect or signs of intracranial hypertension (IH). An interdisciplinarymedicalteamconcludedthatabiopsywas
needed, it showedhard, violet brain tissue,confirming a malignantCNSneoplasmwithsmall,anaplastictumorcells. Immunohistochemistry revealed grade III ganglioglioma, withpoorexpressionoftheP53oncogene,anda12% Ki67 cellproliferationindex(figure3).
Figure4 SagittalT1+MCbrainMRIshowsasellarmasswith suprasellarextension,lobulated,withasolidandcystic compo-nent,whichisintenselyhighlightedbythecontrastmedia.This lesionwasnotseeninpreviousstudies.
a month later. An extrainstitutional opinion requested by the parents was reported as: ¨Grade III anaplastic gan-glioma,accordingtotheWHOclassificatio¨n.Hewasassessed usingtheWISCIV+pediatricWeschlerintelligencequotient test, with a score of 58, related tothe cognitive deficit secondarytofrontalinvolvement.Hebeganantineoplastic treatment with torpid progress and intermittent memory loss, leading toreadmission to HMC. He had macroscopic hematuria, for which etiologies other than nephrotoxic-ity secondary to the antineoplastic treatment were ruled out. His condition worsened, with dyslalia, lateral pul-sion, widened stance, decreased left-sided strength, and progressivebackpainwithpainfulthoracicandlumbar par-avertebralpoints.Spinalcolumnmetastaseswereruledout byMRI.Hepresentedeuvolemichyponatremiawithelevated natriuresis, and progressed from hyponatremia to hyper-natremia secondary to neuroendocrine impairment, with supra-andsellar metastasticinvolvementof the hypophi-sis(figure4).Therewasnopubertalorneurodevelopmental changeonphysicalexam.
Heprogressedtosomnolence,leftdivergentstrabismus, dysarthria,hemiparesia,inability towalk,and respiratory failure,andwastransferredtothePICU.Hepresentedfever, leukopeniaand lymphopenia,withnomicroorganisms iso-lated in blood. Herequired hemodynamic and respiratory supportforthreeweeks,afterwhichhewasabletochange froman invasiveventilatory systemtoa non-invasive sys-tem,andwastransferred tothepediatric neurologyfloor, wherehedied14monthsafterthetumordiagnosis.
Discussion
Unexplained headaches in pediatrics are a warning sign, especially when they are associated with a progressive increaseinfrequencyorintensity,increasedintensitywith Valsalvamaneuvers,projectilevomiting,altered conscious-ness, dysarthria, diplopia, weakness, ataxia, dysmetria,
dysdiadochokinesia,strabismus,papilledema,focalization, and IH. In these cases, space occupying lesions must be ruledoutthroughneuroimaging,withtumorsbeingthemain differentialdiagnosis.6---10 This wasseen inthis case study
patient,who beganwith progressive, oppressive bilateral occipitalheadaches,alteredvisualacuity, projectile vom-iting, dysarthria, somnolence, weakness, convulsions and paresthesias related to the AVM. However, neuroimaging shouldberationalizedinchildren withheadaches,asit is reportedtobefrequentlyusedinpatientswithmigraines, chronic headaches or headaches without red flags.11 The
headMRI findingsreporteda greater impactononelobe. Ingeneral,solidspreferthetemporallobe(>70%),asinthis casestudy,althoughtheyhavebeendescribedinthefrontal, parietal,cerebellar,hypophyseal,pinealgland,brainstem, spinal cordand intraventricular regions.2,12---24 There have
beenreports ofcystic, hemorrhagicandsolid components which make tumor resection difficult because of edema, signs of IH and neuroendocrine involvement, which were observed in the reported case due to the presence of hypophyseallesions.Nocasesof GGwithangiographically documentedAVM in children werefound inthe literature review.Thiswasaninterestingfinding,sincetheAVMbleed maskedthepresentation andclinical diagnosisofthecase study,duetoitsbehaviorasaspace-occupyinglesion.
Gangliogliomahas arapid-growthneuronal,ganglionic, andglialclonalontogenesis,describedbyKoelscheetal.,25
with a V600E point mutation in the BRAF 1 gene, non-specific for GG, but whose presence is associated with a lowerrecurrence-freesurvival.Thismutationstimulatesthe cascade of the MAPK (Mitogen-Activated Protein Kinases) kinase-dependentproteinfamily,whichstimulatesthe mito-sis, differentiation, and resistance to apoptosis of cell groups which then become neoplasms by duplication of 7q34,with fusion of KIAA1549-BRAF,26 having a poor
sur-vivalprognosis. This wasnot studied in our patient since the necessary tissue was not available, as it was used fortheextrainstitutionalopinion.Anotherhistopathological characteristicisincreasedvascularendothelialproliferation manifestedbyintracranialbleeds,whichweredescribedin thiscase study.These have apoor prognosis,withloss of CD34,p53mutation,expressionoftheglialfibrillaryacidic protein(GFAP),synaptophysin,neurofilament,neuron spe-cificenolase,CD56, variablyexpressedchromogranin,and Ki67>5%,asinthedescribedcase,withKi67>12%.2---3
Withregard totreatment, thereis no chemotherapeu-ticprotocol, but the preliminary report of a phase three studystatedthattherewasnodifferenceinsurvivalinthe combination of temozolamide and radiation therapy plus bevacizumab.23 However,inthecasebeingreported,a14
monthsurvivalwasachievedwithacombination of temo-zolamideandradiationtherapy,similartothatreportedby ZanelloMetal.between2000and2015.27
Theprognosticfactorwhichimprovessurvivalisunifocal disease,which does notapply in thiscase, since multifo-cal disease was documented.4,23---29 Multifocal disease has
ahigh recurrenceratecomparedwithlow-grade GGs;30,31
it is difficult to control due to its multifocal extension, whichmakescompletesurgicalresectiondifficult.30---34Also,
radiationtherapy,becauseitdoesnotimprovethesurvival rate, and may cause CN II and VIII neuropathy, involve-ment of the lens and retina, neuroendocrine impairment and the appearance of new neoplasms.2,28,29 Unexplained
headachesinpediatricsareawarningsign.Iftheyare asso-ciated with an increase in the frequency or intensity of theheadaches,anincreasedintensitywithValsalva maneu-vers,projectilevomiting,alteredconsciousness,dysarthria, diplopia, weakness, ataxia, dysmetria, dysdiadochokine-sia, strabismus,papilledema, focalizationand IH(arterial hypertension,bradycardia,andalteredbreathingpatterns), space-occupyinglesionsmustberuledoutbyneuroimaging, withtumorsbeing themain differentialdiagnosis. Gangli-ogliomas,whicharetumors,haveverypoorsurvivalrates, which may be associated with intracranial bleeding and refractory epilepsy, and topographical neurologic impair-ment.
Funding
sources
ThisworkwascarriedoutinthePediatricNeurology Depart-mentoftheCentralMilitaryHospital.
Conflict
of
interests
Theauthorsdeclarenoconflictofinterests.
Acknowledgements
Dr.JavierMu˜nozNarváez,PediatricOncologist,Clínicadel Country, for his review and opinion of the report. To Dr. RodrigoCastroRebolledo,Physiatrist,forhishelpindrafting andbibliographicsearching.
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