Cervical paragangliomas: experience of 114 cases in 14 years.

www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

ORIGINAL

ARTICLE

Cervical

paragangliomas:

experience

of

114

cases

in

14

years

夽

Halil

Basel

_,

_Nazim

_Bozan

a_{LokmanHekimUniversityFacultyofMedicine,DepartmentofCardiovascularSurgery,Ankara,Turkey} b_{YuzuncuYilUniversityFacultyofMedicine,DepartmentofOtorhinolaryngology,Van,Turkey}

Received15January2018;accepted1May2018

KEYWORDS Angiographic embolization; Carotidbifurcation; Cervical paragangliomas; Shamblin classification Abstract

Introductionandobjective:Toreportasinglecenterexperiencewithcarotidbody paragan-glioma cases that were treated by the same surgeon in a city with high prevalence of paragangliomasduetohighaltitude.

Methods:Weretrospectivelyinvestigatedthedemographic,clinicopathologicaland radiologi-caldataof104patientsdiagnosedwithcervicalparagangliomasbetween2003and2017.The patientswereclassifiedaccordingtotheShamblinclassification.

Results:In this study atotal of104 patients (33male and71 female, witha meanage of 54.6±13years)diagnosedwithcervicalparagangliomaslocatedoncarotidbifurcationbetween 2003and2017wereincluded.Amongthosepatients,10presentedwithbilateraltumorsandin total,114paragangliomasweremanagedinthisperiod.Themeandiameterofthetumorswas 5.12±1.45cm.Malignanttumorwasdeterminedinonlyone(0.9%)patient.Allpatientswere operated.In12patientswiththetumordiameterlargerthan5cm,preoperativecoil emboliza-tionwasachieved.In14patients,preoperativeangiographicembolizationwasemployedand in4patientsintraoperativesclerosingagentinjectionswereperformed.Facialparalysiswas observedin2patientsanddysphagiawaspresentin1patient,Hornersyndromewasseenin 1patientandhoarsenesswasreportedin7patientsafteroperation. Allthosecomplications improvedduringfollow-up.Mortalitywasnotreportedinanycases.

Conclusion: Surgery is the definitive treatment for patients with cervical paragangliomas. Although, itmay bedifficultinpatients withthe advancedShamblintypes,inexperienced hands,complicationratesareverylow.

© 2018 Publishedby Elsevier Editora Ltda. onbehalf of Associação Brasileira de Otorrino-laringologiaeCirurgiaCérvico-Facial.ThisisanopenaccessarticleundertheCCBYlicense (http://creativecommons.org/licenses/by/4.0/).

夽 _{Pleasecitethisarticleas:BaselH,BozanN.Cervicalparagangliomas:experienceof114casesin14years.BrazJOtorhinolaryngol.2018.} https://doi.org/10.1016/j.bjorl.2018.05.001

∗_{Correspondingauthor.}

E-mail:hbasel@mynet.com(H.Basel).

PeerReviewundertheresponsibilityofAssociac¸ãoBrasileirade OtorrinolaringologiaeCirurgiaCérvico-Facial.

https://doi.org/10.1016/j.bjorl.2018.05.001

1808-8694/©2018PublishedbyElsevierEditoraLtda.onbehalfofAssociaçãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial. ThisisanopenaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

Embolizac¸ão angiográfica;

Bifurcac¸ãocarotídea; Paragangliomas cervicais; Classificac¸ãode Shamblin

Resumo

Introduc¸ãoeobjetivo: Relatarumexperimentoemúnicocentrodecasosdeparagangliomado corpocarotídeoqueforamtratadospelomesmocirurgiãoemumacidadecomaltaprevalência deparagangliomasdevidoàaltaaltitude.

Método: Foraminvestigadosretrospectivamente,osdadosdemográficos,clinico-patológicose radiológicosde104pacientescomdiagnósticodeparagangliomascervicaisentre2003e2017. Ospacientesforamclassificadosdeacordocomaclassificac¸ãodeShamblin.

Resultados: Nesteestudo,foramincluídos104pacientes(33homense71mulheres,commédia deidadede54,6±13anos)comdiagnósticodeparagangliomacervicallocalizadonabifurcac¸ão carotídeaentre2003e2017.Entreessespacientes,10tinhamtumoresbilateraise,nototal, 114paragangliomasforamtratadosnesseperíodo.Odiâmetromédiodostumoresfoide5,12± 1,45cm.Umtumormalignofoideterminadoemapenasum(0,9%)paciente.Todosospacientes foramoperados.Em12pacientescomdiâmetrodotumormaiorque5cm,foipossívelrealizar embolizac¸ãopré-operatóriacommolas;em14pacientes,foirealizadaembolizac¸ãoangiográfica eem4pacientes,injec¸ões deagentesesclerosantes.Apósotratamentocirúrgico, paralisia facialfoiobservadoem2pacientes,disfagiaem1paciente,síndromedeHornerem1paciente erouquidãoem7pacientes.Todasessascomplicac¸õesmelhoraramduranteoacompanhamento. Nãofoirelatadamortalidadeemnenhumcaso.

Conclusão:Acirurgia éotratamentodefinitivoempacientescomparagangliomas cervicais. Emborapossaserdifícilempacientescomostiposavanc¸adosdeShamblin,emmãos experi-entes,astaxasdecomplicac¸õessãomuitobaixas.

©2018Publicado porElsevier EditoraLtda. emnome daAssociaçãoBrasileira de Otorrino-laringologiaeCirurgiaCérvico-Facial. Esteéumartigo OpenAccess sobalicençadeCC BY (http://creativecommons.org/licenses/by/4.0/).

Introduction

Paragangliomas are rare, highly vascular neuro-endocrine

tumors originating from neural crest cells that can be

located anywhere from skullbase to the sacrum.1 _About

one-thirdofparagangliomasarehereditary;afewofthem

accompanying familial tumors suchas multiple endocrine

neoplasiaType2(MEN2),vonHippel-Lindau(vHL)diseaseor

neurofibromatosistype.2_{Metastasis,definedasthespread}

of tumor tothe sites where chromaffintissue is normally

absent,suchaslymphnodes,liver,bone,andlungshasbeen

reportedinless than5% ofcarotidbodyparagangliomas.3

Duetothe slowprogressionof thedisease, malignancyis

notalwaysassociatedwithapoorshort-termprognosis.

About2/3ofparagangliomasarelocatedintheadrenal

gland and remaining extra-adrenal tumors were reported

inthe abdomen, thorax,andrarely inthe head andneck

region.4 _{Head and neck paragangliomas generally grow}

slowlyandmayremainsilentforyears.5_{Themostcommon}

head and neck paragangliomas arecarotid body tumors.6

About70---80%ofheadandneckparagangliomasare

asymp-tomaticanddependingonthelocation,theymaymanifest

differentfindingsandsymptoms, suchaspainlesscervical

mass, cranial nerve paralysis, dysphagia and hoarseness,

pulsatiletinnitusandhearingloss,ordifficultiesinspeech,

swallowing, and airway function.7 _{Carotid tumors grow}

slowly. Although they are benign in general, they cause

symptoms due to compression on neighboring vascular or

neuralstructures.Forthatreason,theirsurgicalexploration

isrequired.Ifsurgicallycompleteexplorationisnotpossible

duetothefactorsassociatedwiththepatientortumor

local-ization,radiotherapyshouldbeconsidered.Althoughcarotid

tumorsareradiosensitive,totalresolutionwithradiotherapy

israre.Ingeneral,withradiotherapy,tumorstabilizationor

partialregressionisthegoal.8

Inthisstudy,wewillreport asinglecenterexperience

of114 cervicalparagangliomacasesin 14yearsthatwere

treatedbythesamesurgeoninacitywithhighprevalence

ofparagangliomasduetohighaltitude.

Materials

and

methods

We retrospectively investigated the demographic,

clinic-pathologicalandradiologicaldataof104patientsdiagnosed

with and operated for cervical paragangliomas between

2003 and 2017 in Van Trainingand Research Hospital and

Van Lokman Hekim Private Hospital. Postoperative results

andoperativecomplicationswerealsorecorded.

Thepatients wereclassified according totheShamblin

classification.9 _{Only patients operated for cervical}

para-gangliomas were included in the study. In preoperative

imagingofthecases,coloredDopplerultrasoundand

mag-netic resonanceimagingwere performed.In patientswho

hadembolization,carotidangiographywasalsoperformed.

In all patients with a tumor larger than 5cm and with

high vascularity, preoperative angiographic embolization

was performed (Fig. 1). The patients were operated the

day after angiographicembolization ifit wasrequired. In

patientswithlargeamountsofbleedingduringoperations,

intraoperative coils were inserted. In all patients with a

tumor largerthan5cm, divisionof internal carotidartery

was performed and end-to-endanastomosis wasachieved

afterremoval(Figs.2and3).InpatientswithShamblinIII

tumors,ifrequired,thearterywasexcisedandaPTFEgraft

orsaphenousgraftinter-positioned.Ifagraftwasrequired

Figure1 (A)Angiographybeforecoilembolization.(B)Angiographyaftercoilembolization.

Figure2 (A)Intraoperativecoilembolization.(B)ShamblinTypeIIIpatient---Carotidinvasion.(C)Divisionofexternalcarotid artery.(D)Re-anastomosisofdivisionofexternalcarotidartery.

Figure3 Macroscopicappearanceofthetumor.

wasstartedfor6months.Inpatients withapositive

fam-ily history, annual controls were performed with Doppler

ultrasoundandmagneticresonanceimaging.

Statisticalanalysis

The datawere analyzedusing SPSS21. Descriptive

statis-ticswereperformed.Numericalvariableswereexpressedas

mean±standard deviation,andcategoricalvariableswere

analyzedasfrequencyandpercentage.p<0.05was

consid-eredstatisticallysignificant.

Results

In this study,a total of 104 patients diagnosed with

cer-vical paragangliomas located on the carotid bifurcation,

treated between 2003 and 2017, were included. Among

thosepatients, 10 presented with bilateral tumors and a

totalof114 paragangliomasweremanaged inthis period.

Themeanfollow-upperiodwas54±30months(range:1---96

months).Amongthosepatients,33weremaleand71were

femalewitha meanage of 54.6±13years (range:18---83

years).Themeanageofmaleswas56.4±12yearsandthe

meanageoffemaleswas53.1±13years;therewasnotany

statisticallysignificantdifferencebetweengenders

regard-ingthemeanageatthediagnosis(p>0.05).In10(3male,

7female)ofthepatients,paragangliomaswerebilateral.In

bothgenders, inabout 9---10% ofthe patients,thetumors

werebilateral.Familyhistorywaspresentin2(2/10)ofthe

patientswithbilateraltumors.

Thedimensionsofthetumorsrangedbetween1.3cmand

10.6cmwithameandiameterof5.12±1.45cm.Malignant

In15(19.9%)patients,therewasafamilyhistoryfor

para-gangliomas.Inallpatients,themainfindingwasamassin

thecervicalregion.Thepatientsweregroupedaccordingto

theShamblinclassificationandregardingthisclassification;

15(13.2%)wereShamblinTypeI,66(57.9%)wereShamblin

TypeII,and33(28.9%)wereShamblinTypeIII.

Surgicalmethodsappliedtothepatientsaresummarized

inTable 1. In12 patients withthetumor diameter larger

than5cm,preoperativecoilembolizationwasachieved.In

14patients,preoperativeangiographicembolizationandin4

patientsintraoperativesclerosingagentinjectionswere

per-formed.In30patients,divisionoftheexternalcarotidartery

wasperformedanditwasre-anastomosedaftertheremoval

ofthemass.In4patientswithShamblinIIItumors,internal

andexternalcarotidarterieswereexcisedandrepairedwith

PTFEandsaphenousveingraft.

Thecomplicationsafteroperationswerealsorecorded.

Facialparalysiswasapparentin2(1.9%)patients,

dyspha-giaoccurredin1(0.9%)patient,Horner’ssyndromewasseen

in1(0.9%)patientandhoarsenesswasreportedin7(6.7%)

patients:thosewerenotpersistentinanyofthecases.All

those complications improved during follow-up. Mortality

wasnotreportedinanycases.

Discussion

Inthisstudy,wereportedthegeneralcharacteristicsof104

patientswithcervicalparagangliomaslocatedonthecarotid

bifurcation.Tothebestofourknowledge,thisisoneofthe

largest seriesin the literature reportingthe outcomes of

cervicalparagangliomas.

Femaletomaleratiowas2.15inthisstudy.Afemale

pre-dominancewasalsoreportedpreviouslyinsomestudies.10

However,inaretrospectivestudyon10patients,Darouassi

etal.11 _{reporteda malepredominance withasex-ratioof}

2.33.Aslowgrowing,painlessmasswasthemostcommon

clinical presentation in our study asreported before.11---13

Luna-Ortizetal.14 _{alsoreportedtheir20yearsexperience}

on69 carotid body tumorsand determined that 96.9% of

thepatientswerefemaleandthemostcommon

presenta-tionwasalsoapainlessneckmassdeterminedin78.7%of

Table1 Surgicalmethodsappliedtothepatients. Surgicalmethod Numberof

patients(%) Surgicalresection 66 Surgicalresection andexternal carotidartery division 30 Surgicalresection andPTFEgraft interposition 2 Surgicalresection andsaphena graft interposition 2 Coilembolization andsurgical resection 14

mayalsobethemaincomplaintsatdiagnosis.

In preoperative diagnosis, imaging is crucial since the differential diagnosis includes thyroid nodules, lym-phadenopathy and brachial cysts. Fine-needle aspiration biopsyisnotemployedsinceithasahighcomplicationrisk due to the hyper-vascularization of the tumor and more-overthecytologicalevaluationcannotdifferentiatebenign from malignant lesions. In this study, all patients were diagnosedwiththeimagingtechniquesandfine-needle aspi-rationbiopsywasnotperformedinanypatients.

Theincidenceoffamilialcarotidbifurcationtumorswas reportedas 20% inprevious studies.15,16 _{In this study,the}

ratiooffamilialcaseswas19.9%,whichwascompatiblewith

theliterature.

Mediounietal.17 _{analyzedthegeneralcharacteristicsof}

131benignparagangliomasandcomparedthemto11

malig-nantparagangliomascases.Theyreportedthat;thebenign

paragangliomasweremostlyobservedinwomenwithamean

ageof 45yearsat timeof diagnosis.In thatstudy

tympa-nojugular sites were the most common sites followed by

carotidandvagal sites. Onthe otherhand, themalignant

tumorsweremainlyobservedinyoungerpatientsandthey

werepredominantlycarotidtumors.Inourstudy,therewas

onlyonemalignantparagangliomainafemalepatient

diag-nosedat theage of65 years.Inthis case,the tumorwas

unilateral.

With the development of safe embolization protocols,

surgical resection has become the preferred treatment

option in cervical paragangliomas.15 _{However, due to}

its localization near large vascular structures and

cra-nial nerves, the surgical treatment is challenging. The

surgery shouldbeasconservative aspossible tominimize

the complications.In that aspect,preoperative

emboliza-tion was mainly advised in large and hyper-vascularized

tumors.16 _Jianuetal.18 _{reportedthe treatment outcomes}

of 7 patients (5 women, 2 men with a meanage of 54.7

years)diagnosedwithcervicalparagangliomas,whowereall

operatedwithoutanypreoperativeembolization.Theydid

not observeany perioperativecomplications in 6 patients

butin1case,atransientipsilateralvagusnervedeficitwas

reported. There wasno sign of recurrences in 3 years of

follow-upinthatstudy.Chanetal.19_{analyzedthetreatment}

outcomesofpatientswithheadandneckparagangliomasin

a nationwidesurveyand reportedthat 91% ofcases were

treatedwithsurgeryalone,andembolizationalonewas

per-formed in 4% of cases. Postoperative complications were

more common in patients undergoing both embolization

and surgerytogether; while acutemedical complications,

including acute renal failure and pneumonia, were more

likelyreportedinpatientsundergoingembolizationonly.In

ourstudy,although we didnot comparethe patientswho

were treated withor without endovascularinterventions;

wedidnotobserveanassociation.Itshouldalsobekeptin

mindthat, ingeneral embolization isrequired in patients

withlargetumorsanditisnotsurprisingthatlargertumors

wereassociatedwithhighercomplicationrates.

Inaretrospectivestudy,Lamblinetal.20 _evaluatedthe

treatment outcomes in 54 carotid body tumor resections

in 49 patients and reported that early (in 1 month after

surgery) complications occurred in 31 cases, including 30

cases of cranial nerve deficit (56%). They also reported

that; 8 patients (17%) showed no cranial nerve deficit

recovery, even after 18 months of follow-up. Dorobisz

etal.21_{analyzedthemedicaldataof47patientswhowere}

diagnosed with and operated for carotid paragangliomas

the tumor was performed, including 11 cases (22%) that

additionally required vascular suturing, and 5 (10%) that

required reconstruction of the internal carotid artery.

Regardingthepostoperativecomplications,3patients(6%)

werere-operatedbecauseofsymptomsofcerebralstroke,

hypoglossalnervepalsywasdeterminedin3cases(6%),and

facial nervepalsy in 2 patients (4%), while postoperative

hematomasinthewoundwasobservedin6patients(12%).

Weobservedfacialparalysisin2(1.9%)patients,dysphagia

in1 (0.9%)patient,Horner’s syndromein1 (0.9%)patient

andhoarsenessin7(6.7%)patients;allthosecomplications

werereversibleinfollow-up.

In this study, in 10 patients, the tumors were

bilat-eral. In bilateral paragangliomas, some risk factors such

asgeneticpredisposition, priornecksurgery or

radiother-apy were defined.22 _{Family history was present in 2 of}

10 patients withbilateral cervical paragangliomas.

Fortu-nately,withthedevelopmentof moreaccuratediagnostic

methods, paragangliomas are diagnosedat earlierstages.

Inourstudy,28.9% ofparagangliomaswereShamblinType

IIIandtherewerenotanyShamblinTypeIVcases.Withan

advancedstage,complicationrisksincludingnerveinjuries

alsoincrease.Inourstudyin7patientsreversible

hoarse-nesswasdeterminedthatwasduetothevagalorhypoglossal

nerveinjury.

Recently,about20---30%ofheadandneckparagangliomas

weredeterminedtobegeneticandassociatedwithgermline

mutations.23 _{Inespeciallymulticentericor recurrentcases}

geneticmutationsshouldbesuspected.However,because

oftheexpense,wedonotroutinelyperformgenetictests

indailypractice.

Conclusion

Inconclusion,surgeryisthedefinitivetreatmentinpatients

withcervicalparagangliomas.Although,itmaybedifficultin

patientswiththeadvancedShamblintypes,inexperienced

hands,complicationratesareverylow.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

References

1.Mendenhall WM, Amdur RJ, Vaysberg M, Mendenhall CM, Werning JW. Head and neck paragangliomas. Head Neck. 2011;33:1530---4.

2.Gimenez-RoqueploAP,DahiaPL,RobledoM.Anupdateonthe geneticsofparaganglioma,pheochromocytoma,andassociated hereditarysyndromes.HormMetabRes.2012;44:328---33. 3.Suárez C,Rodrigo JP, Mendenhall WM, Hamoir M, Silver CE,

GrégoireV,et al.Carotidbodyparagangliomas:a systematic studyonmanagementwithsurgeryandradiotherapy.EurArch Otorhinolaryngol.2014;271:23---34.

4.BurnichonN,CascónA,SchiaviF,MoralesNP,Comino-Méndez I,AbermilN,etal.MAXmutationscausehereditaryand spo-radicpheochromocytomaandparaganglioma.ClinCancerRes. 2012;18:2828---37.

5.JansenJC,vandenBergR,KuiperA,vanderMeyAG, Zwinder-manAH,CornelisseCJ.Headandneckparagangliomasgenerally

grow slowly and may remain silent for years. Estimationof growth rate in patients withhead and neck paragangliomas influencesthetreatmentproposal.Cancer.2000;88:2811---6. 6.Jianu DC,Muresanu DF, PetricaM.Diagnosis ofcarotid body

paragangliomasbyvariousimagingtechniques.RomJNeurol. 2014;7:161---6.

7.Corssmit EP, Romijn JA. Clinical management of paragan-gliomas.EurJEndocrinol.2014;171:231---43.

8.GilboP,Morris CG,AmdurRJ,Werning JW,DziegielewskiPT, KirwanJ,etal.Radiotherapyforbenignheadandneck para-gangliomas:a45-yearexperience.Cancer.2014;120:3738---43. 9.ShamblinWR,ReMineWH,Sheps SG,HarrisonEG Jr.Carotid

body tumor (chemodectoma): clinicopathologic analysis of ninetycases.AmJSurg.1971;122:732---9.

10.Gad A, SayedA, Elwan H, FouadFM, Kamal EldinH, Khairy H, et al.Carotid bodytumors: areview of25years experi-enceindiagnosisandmanagementof56tumors.AnnVascDis. 2014;7:292---9.

11.DarouassiY,AlaouiM,MlihaTouatiM,AlMaghraouiO,En-Nouali A, Bouaity B, et al. Carotid bodytumors: a caseseries and reviewoftheliterature.AnnVascSurg.2017;43:265---70. 12.LeeJH,BarichF,KarnellLH.Nationalcancerdatabasereport

on malignant paragangliomas of head and neck. Cancer. 2002;94:730---7.

13.FerranteAM,BoscarinoG,CreaMA,MinelliF,SniderF.Cervical paragangliomas:singlecentreexperiencewith44cases.Acta OtorhinolaryngolItal.2015;35:88---92.

14.Luna-Ortiz K, Rascon-Ortiz M, Villavicencio-Valencia V, Granados-Garcia M, Herrera-Gomez A. Carotid body tumors: reviewofa20-yearexperience.OralOncol.2005;41:56---61. 15.Ma D, Liu M, Yang H. Diagnosis and surgical treatment of

carotidbodytumor:areportof18cases.JCardiovascDisRes. 2010;1:122---4.

16.QinRF,ShiLF,LiuYP.Diagnosisandsurgicaltreatmentofcarotid bodytumors:25years’experienceinChina.IntJOralMaxillofac Surg.2009;38:713---8.

17.MediouniA,AmmariS,WassefM,Gimenez-RoqueploAP,Laredo JD, Duet M, et al. Malignant head/neck paragangliomas. Comparativestudy.EurAnnOtorhinolaryngolHead NeckDis. 2014;131:159---66.

18.Jianu DC,Jianu SN,MotocAG,DanTF, PoenaruM,T˘abanS, etal.Anevaluationonmultidisciplinarymanagementofcarotid bodyparagangliomas:areportofsevencases.RomJMorphol Embryol.2016;57:853---9.

19.ChanJY,LiRJ,GourinCG.Short-termoutcomesandcostofcare oftreatmentofheadandneckparagangliomas.Laryngoscope. 2013;123:1645---51.

20.LamblinE,AtallahI,ReytE,SchmerberS,MagneJL,Righini CA.Neurovascularcomplicationsfollowingcarotidbody para-gangliomaresection.EurAnnOtorhinolaryngolHeadNeckDis. 2016;133:319---24.

21.Dorobisz K,Dorobisz T,TemporaleH, Zato´nskiT, KubackaM, ChabowskiM,etal.Diagnosticandtherapeuticdifficultiesin carotidbodyparagangliomas,basedonclinicalexperienceand areviewoftheliterature.AdvClinExpMed.2016;25:1173---7. 22.MooreMG,NettervilleJL,MendenhallWM,IsaacsonB,

Nussen-baum B. Head and neck paragangliomas: an update on evaluation and management. Otolaryngol Head Neck Surg. 2016;154:597---605.

23.Kim ES, Kim SY, Mo EY, Jang DK, Moon SD, Han JH. Novel germline SDHDmutationina patientwithrecurrentfamilial carotidbodytumorandconcomitantpheochromocytoma.Head Neck.2014;36:131---5.