Malignant head/neck paragangliomas. Comparative Study

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EuropeanAnnalsofOtorhinolaryngology,HeadandNeckdiseases(2014)131,159—166

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ORIGINAL

ARTICLE

Malignant

head/neck

paragangliomas.

Comparative

Study

A. Mediouni

a

,

S. Ammari

a

,

M. Wassef

b,f

,

A.-P.

Gimenez-Roqueplo

c

,

J.-D.

Laredo

d,f

,

M. Duet

a,f

,

P. Tran

Ba

Huy

g

,

N. Oker

e,f,∗

a_Service_de_médecine_nucléaire,_hôpital_{Lariboisière}_(Assistance_{Publique—Hôpitaux}_de_Paris),_2,_rue

Ambroise-Paré,75010Paris,France

b_Service_de_cytologie_et_d’anatomie_{pathologique,}_hôpital_{Lariboisière}_(Assistance_{Publique—Hôpitaux}_de

Paris),2,rueAmbroise-Paré,75010Paris,France

c_Service_de_génétique,_hôpital_européen_{Georges-Pompidou}_(Assistance_{Publique—Hôpitaux}_de_Paris),_20,

rueLeblanc,75015Paris,France

d_Service_de_radiologie,_hôpital_{Lariboisière}_(Assistance_{Publique—Hôpitaux}_de_Paris),_2,_rue

e_Service_{d’otorhinolaryngologie,}_hôpital_{Lariboisière}_(Assistance_{Publique—Hôpitaux}_de_Paris),_2,_rue

f_Université_{Paris-Diderot}_Paris-7,₇₅₂₀₅_Paris_cedex_13,_France g_2,_rue_{Saint-Petersbourg,}₇₅₀₀₈_Paris,_France

KEYWORDS

Malignantheadand neckparaganglioma; Metastases; SDHxmutation; Octreoscan; 18_FDG-PET Summary

Background: The objectiveofthisstudy wastoreport11 casesofmalignantheadandneck paragangliomaandtocomparetheirepidemiological,clinical,andgeneticcharacteristics,their naturalhistoryandtheirtreatmentwiththoseofaseriesof131benignparagangliomas. Patientsandmethods: Retrospectiveanalysisof142patientswithheadandneckparaganglioma managedbetween2001and2008.Ageatthetimeofdiagnosis,gender,primarytumoursite, presenceofothernon-head/neckparagangliomasand/ormetastasesdiagnosedbyimaging(CT, MRI,Octreoscanor18_F-FDG_PET),_histology,_urinary_{catecholamine}_and_metanephrine_levels,

familyhistory,andgenetictestresultswererecorded.

Results: Thisseriescomprised131benignheadandneckparagangliomas,mostlyobservedin womenwithameanageatdiagnosisof45yearsandapredominanceoftympanojugularsites (followedbycarotidandvagalsites)with5%ofsecretingtumoursand20%ofmultifocaltumours. Elevenpatients(7.7%)witha1:1sex ratiopresentedcriteriaofmalignancy.Thesepatients, withalowermeanage(38years),predominantlypresentedcarotidlesionswithahigherrate ofsecretingandmultifocaltumours,27%and46%respectively.Themainsitesofmetastases wereboneandlymphnodes.Notympanicparagangliomaswereobserved.

∗_{Corresponding}_author._Service_{d’otorhinolaryngologie,}_hôpital_{Lariboisière}_(Assistance_{Publique—Hôpitaux}_de_Paris),_2,_rue_{Ambroise-Paré,}

75010Paris,France.

E-mailaddress:[email protected](N.Oker).

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Conclusions: Malignantparagangliomasaremainlyobservedinyoungpatientswithmultifocal tumours,particularlycarotidtumours,andarepredominantlyrelatedtosubunitSDH-B muta-tion.Thework-upinthesehigh-riskpatientsmustincludewholebodyscintigraphyandspine MRI.Malignancyisnotnecessarilyassociatedwithapoorshort-termprognosisduetotheslow courseofthedisease.

Introduction

The WorldHealthOrganisation[1] deﬁnesparagangliomas (PG) asneuroendocrine tumoursarisingfrom paraganglia, collectionsofneuralcrest-derivedparaganglionic neuroec-todermalcellspresentthroughoutthebody.

However, malignant paragangliomas are rare and no consensus has been reached concerning the histological criteria of malignancy, although multiple mitotic figures, nuclearpolymorphismandcapsulareffractionmayindicate thepresenceofmalignancy.According toLack [2],twoof thefollowingthreecriteriaarerequired toconfirm malig-nancy:centralnecrosis,vascularandlymphaticinvasionand mitotic abnormalities. There is a general consensus that malignancyischaracterisedbythepresenceofmetastases, i.e.paraganglionictissueinorgansotherthanparaganglia. Thisdefinitioncantherefore beusedtodistinguish malig-nanttumoursfrommultifocaltumoursarisinginparaganglia

[3].

Limiteddata areavailable in theliterature concerning malignantheadandneckparagangliomasandtheirnatural historyispoorlydeﬁned.However,itisgenerallyaccepted that6%to24%ofnon-adrenalparagangliaaremalignant[4]. Recentprogressinmoleculargeneticssince2000[5]hasalso revealedthatSDHxgenemutationisinvolvedinhereditary paragangliaandthatmalignantformsareoftenassociated withmutationoftheBsubunit[6].

Thisstudyreports11casesofmalignantheadandneck PGandcomparestheirepidemiological,clinicalandgenetic characteristics,naturalhistoryandtreatmentwiththoseof aseriesof131benignPGmanagedoverthesameperiodin ourinstitution.

Patients

and

methods

This retrospective studyconcerned allpatients consulting foraprimarydiagnosisorreferredforheadandneckPGin ouruniversityhospitalbetween2001and2008.

Age at the time of diagnosis, gender, primary tumour site,presenceof othernon-head/neck PGsand/or metas-tasesdiagnosedbyimaging,includingCT,MRIorfunctional whole body imaging (somatostatin scintigraphy, 18_FDG _or 123_I-MIBG _PET), _sometimes _conﬁrmed _by _histology, _urinary

metanephrinelevels,familyhistory,andgenetictestresults wererecorded.PatientswerefolloweduntilSeptember2012 oruntildeath.

Results

This series comprised 142 patients, including 11 (7.7%) patientspresentingcriteriaofmalignancy.

PatientswithbenignPG(group1)

This group comprised 131 patients (87 females; M:F sex ratio: 1:1.98). The main characteristics of these patients areshowninTable1.

Mean age at diagnosis of the primary head and neck PGwas45.3years (range:15—76). Onehundredand thir-teen(86.3%)patientspresentedanisolatedheadandneck lesion and 18 (13.7%) patients presented multiple lesions (synchronous lesions). Isolated lesions involved tympanic (n=32),tympanojugular(n=37),vagal(n=18),andcarotid (n=26)sites.Sixpatients(4.6%)hadsecretingtumours.

Another head and neck paraganglioma (metachronous lesions) was observed during follow-up in 8 of the 113 patients with a single primary tumour and 1 para-aortic PG was detected by 111_{In-pentetreotide} _{scintigraphy.} _The

globalmultifocalrate(includingheadandneckand thoraco-abdominopelvicPG)wastherefore20.6%ingroup1.

The mean interval between diagnosis of the primary lesionandrecurrenceaftersurgery(n=13)ordiagnosis of anewPG(n=9)was9.9years(range:4—20)and13years (range:2—39),respectively.

Genetictesting(when availableand whenaccepted by the patient) was performed in 43 patients: 24 patients (55.8%)presentedamutationoftheDsubunitofthe succi-natedehydrogenasecomplex(SDH-D)and4(9.3%)presented amutationof theSDH-Bsubunit; 15patients (34.9%) pre-sentednomutation.

PatientswithmalignantPG(group2)

Paraganglionicdisease

This group consisted of 11 patients (6 females; male to femaleratio: 1:1.2).The main patientcharacteristics are summarized inTable1. Meanageat thetimeofdiagnosis was 37.8 years (range: 17—65). At the time of diagno-sis, paragangliomas were isolated in 9 cases (82%) and multiple in two cases. Isolated tumours involved carotid (n=5),vagal(n=2),tympanojugular(n=1)andnasalcavity (n=1)sites. The twocases ofmultiple PGwere tympano-jugular and carotid. No pure tympanic site was observed in this series. Three patients (27.3%) presented secreting tumours.

Among the 9 patients with an isolated lesion, metachronous PG were diagnosed during follow-up in 3 cases.Inthesethreepatients,someofthesemetachronous tumoursweresituatedin regionsotherthan theheadand neck:thoracic (n=1),retroperitoneal(n=1),thoracic and retroperitoneal(n=1).Theoverallmultifocalrate (includ-ing multiple head and neck and thoraco-abdominopelvic PGs)was45.5%.

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Malignanthead/neckparagangliomas.ComparativeStudy 161

Table1 Characteristicsofthetwogroups.

Group1(n=131) Group2 (n=11) Atthetimeofdiagnosis

Numberofwomen(%) 87(66) 6(55)

Numberofsecretingtumours(%) 6(4.6) 3(27.3)

Ageatdiagnosisoftheﬁrstheadandneckparaganglioma (meanage(range)inyears)

45.3(15—76) 37.8(17—65) Siteofparaganglioma Tympanic(%) 32(24.4) 0 Tympanojugular(%) 37(28.2) 1(9) Vagalnerve(%) 18(13.7) 2(18) Carotidbulb(%) 26(19.8) 5(55.6)

Other(%) 0 1nasalcavity(9)

Multiple(%) 18(13.7) 2(18)

Follow-up

Numberofpatientswithmetachronouslesions(%) 8(6) 4(36) NumberofPGinregionsotherthantheheadandneck(%) 1(0.8) 3(27) IntervalbetweenprimaryPGandrecurrence(mean(range)

inyears)

9.9(4—20) 4.5(1.5—7)

Intervalbetweenprimarytumourandsecondtumour(mean (range)inyears)

13(2—39) 5.5(2—15)

Numberofpatientswithmultifocaltumours(headandneck PGandPGinotherregions)(%)

26(19.8) 5(45.5) Genetictesting SDH-Dmutation(%) 24(55.8) 2(18) SDH-Bmutation(%) 4(9.3) 5(50) Nomutation(%) 15(34.9) 3(27) Notperformed(%) 88(67) 1(9)

The mean interval between diagnosis of the primary lesionandrecurrenceaftersurgery(n=4)ordiagnosisofa secondPG(n=4)was4.5years(range:1.5—7)and5.5years (range:2—15),respectively.

Genetictestingwasperformedin10patients:2patients presentedamutationoftheDsubunit(SDH-D),5patients presentedamutationoftheBsubunit(SDH-B)and3patients hadnomutation.

Metastases

Metastases were present at the time of diagnosis of the primary lesion in 3 patients and were diagnosed during follow-up in another 8 patients, witha mean metastasis-freeintervalof8years(1—25).Thesemetastasesinvolved bone(n=7),cervicallymphnodes(n=7),liver(n=2),lung (n=1),andthyroid(n=1)(Table2).

Bone metastases were symptomatic in four cases and detected bysystematic imaging inthreecases. They pre-dominantlyinvolvedthespine,butalsotheiliacbone,ribs, sternumorcalvarium.

MRI demonstrated two types of lesions: nodular and expanding. Nodular lesions presented a speciﬁc radiolog-ical appearance, as we have previously described [7], consisting of a central low-intensity signal surrounded by a single fat-like halo or a double halo with a fat-density inner circle and an outer circle suggestive of oedema(Fig.1a,b).Insomepatients,theselesions coex-isted with expanding lesions characterized by cortical

destruction and soft tissue involvement, especially bone marrow.

111_{In-pentetreotide} _(Octreoscan) _scintigraphy _revealed

onlysomeofthesebonelesions(Table2).123_{Iodine-labelled}

metaiodobenzylguanidine(123_I-MIBG)_scintigraphy_was

per-formed in 4 patients and revealed only slight contrast enhancementof the spine in one patient. 18_FDG-PET _was

performedintwopatientsandwasnegativeinonecaseand stronglypositiveintheothercase.

Cervical lymph node metastases were detected in 7 cases,eitheronneckpalpationorbyimagingshowingamass situatedinazoneclearlydistinctfromthecarotidbulbor subdigastricregion.

Twopatients hadnodularliver metastasesandanother patient had lung metastases. One patient had a thy-roidmetastasis, incorrectlydiagnosed aspapillarythyroid tumourandtreatedbysurgeryand131_Iodine_therapy._Three

yearslater,thispatientdevelopedvertebralmetastasesand retrospective analysis of the thyroid operative specimen establishedthecorrectdiagnosis.

Follow-up

Meanfollow-upwas4.25years(range:1—10.5years).One foreignpatientdiedinhiscountryoforigin56monthsafter managementinourinstitution,apparentlyfrommetastatic cachexia.Twopatientswerelosttofollow-up,oneafter1 monthandtheotherafter5years.

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A.

Mediouni

et

al.

Table2 Characteristicsofmetastasesin11casesofmalignantparaganglioma.

Patient SDHmutation Site Modeof

discovery

111_{In-pentetreotide}

scintigraphy (Octreoscan)

18_FDG-PET 123_I-MIBG _Spine_MRI _Follow-up

(months)

1 B Bone,lymph

nodes

Imaging Ribs,sternum Notdone Metastasesnot

visualized

Multiplelesionsof cervical,thoracic andlumbarspine

96

2 B Bone Dorsalpain Multiplelesionsof

cervical,thoracicand lumbarspine,sacrum, occipitalbone

Notdone Metastasesnot visualized

Dead(56)

3 Nomutation Bone Weaknessof

lower

limbs+pyramidal syndrome

L3+rightclavicle Notdone Metastasesnot visualized

303

4 D Bone Imaging Metastasesnotvisualized Metastasesnot

visualized

Notdone Multiplelesionsof cervical,thoracic andlumbarspine

348

5 B Lymphnode

bone

Lowbackpain Palpation

Metastasesnotvisualized Metastasesnot visualized

Notdone Lesionsoflumbar spine Lostto follow-upat1 month 6 Nomutation Bone Liver Thyroid Bonepain Imaging Palpation

Vertebralcolumn,ribs, pelvis,liver Vertebrae, sternum, sacrum,pelvis, ribs Lesionof thoracicspine Multiplelesionsof cervical,thoracic andlumbarspine

247

7 B Lymphnodes Palpation Metastasesnotvisualized Notdone Notdone Metastasesnot

visualized

250

8 Nottested Lymphnodes Palpation Metastasesnotvisualized Notdone Notdone Metastasesnot visualized Lostto follow-upat 144months 9 B Lymphnodes Bone Liver Palpation Imaging

Thoracicspine+liver Notdone Notdone Notdone 21

10 Nomutation Lymphnodes Palpation Metastasesnotvisualized Notdone Notdone Metastasesnot visualized 14 11 D Lymphnodes Lung Palpation Imaging

Metastasesnotvisualized Notdone Notdone Metastasesnot visualized

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Figure1 MRIofthelumbarspine,sagittalsection,T1-(a)and gadolinium-enhancedT1-weighted(b)sequences:presenceof nodularbonemetastaseswithadoublehalo.

Onepatient(patient3)requiredsurgicalcurettageofa lumbarvertebraduetoprogressivelowerlimbparaparesis. In ﬁve patients (patients 2, 4, 5, 6 and 9), MRI after 4 years did not reveal any new lesions or any change in the size of the metastases. However,detailed analysisof signalintensityonT1-andT2-weightedsequencesshowed decreasedoedemaoftheouterhalooftwovertebrallesions intwopatients.

The lastpatient(patient1)wasoperatedfor leftvagal PG in 2001 and, two years later presented a very large lefttemporallesionwithintracranialextensionand multi-plemetastasesofthecervicothoracicvertebrae,calvarium andonerib.Radiotherapyatadoseof45Gywasdelivered tothetemporallesionbutbonemetastasesdidnotrequire anytreatment,astheyremainedasymptomatic.Afteralong periodof apparent stabilization, the patientconsulted in November2012 following theappearance oftwoleft cer-vicalmasses.CTandscintigraphyconfirmedthemetastatic natureofthesemasses,butalsorevealedmarked progres-sionoftheC6andC7lesions(thatinitiallyhadanosteolytic appearance)associatedwithepiduritis(Fig.2).The riskof short-termspinalcordlesionsjustifiedradiotherapyofthe vertebrallesion.Cervicallymphnodedissectionconfirmed thepresenceof metastases.Thiscase illustratesthe rela-tivelyslowrateofprogressionofmetastaticdisease.

The7patientswithlymphnodemetastasesweretreated byneckdissectionconcomitantwithsurgicaltreatmentof thetympanojugularorcarotidtumourin6cases(patients5, 7,8,9,10and11),whiletheseventhpatientcorresponded topatient1describedabove.Twoofthese6patientswere

lost to follow-up, one at 1 month, and the other at 5 years.Threepatients havenotdevelopedanylocal recur-renceandarecurrently alivewithnosignsof progression oftheirparaganglioma.The lastpatient(patient10),who initially presented a vagal PG with cervical lymph node metastasestreatedbysurgeryandexternalbeam radiothe-rapy,developedmultipleboneandlivermetastasesduring thefollowingyearandiscurrentlyinpalliativecare.

Of the twocases of liver metastases diagnosed at the time of diagnosis of the primary tumour (patient 6 and 9), one alsopresented lung metastasis and died after 56 months.Theotherpatientisalivewithnoapparentsignsof progression.

Discussion

Thisretrospective,comparativestudyofoneofthelargest seriespublishedtodatedeﬁnescertainaspectsofthe nat-uralhistoryofmalignantheadandneckparaganglioma.

Inlinewiththeliterature,patientswithbenignheadand neck PG were predominantly females (66%) and tumours were predominantly located in tympanojugular sites (fol-lowedby vagal andcarotid sites),with amean ageof 45 yearsat thetimeofdiagnosis, withlowrates ofsecreting andmultifocaltumours:5%and20%,respectively.

Incontrast,patients withmalignanthead andneck PG (7.7% of the population of this series, i.e. a comparable ratetothatreportedintheliterature[8])didnotpresent anygenderpredominance, mainlypresentedcarotidsites, hadayoungermeanageatthetimeofdiagnosis(38years), andpresentedhighratesofsecreting(27%)andmultifocal tumours(46%). These characteristics appeartoconstitute riskfactorsformalignancy.

No purelytympanic lesion wasobserved in this series. These forms are classically not multifocal, occur in the absenceofafamilyhistoryandtreatmentisbasedon sur-gicalresection,whichisusuallystraightforward.Thisseries conﬁrmsthatpuretympaniclesionsareneveraccompanied bymetastases[9]andthereforedonotrequiregenetic test-ingorstagingassessment.

Metastaticspreadmay behaematogenousor lymphatic andmainly involvebone and lymph nodes[4,7,10]. Liver andlung metastasesareobservedmorerarely.Metastases maybeeithersynchronous,atthetimeofdiagnosisofPG,or metachronous,inwhichcasetheyappeartobeassociated withabetterprognosis[11].

Bone metastases may remain asymptomatic or may present clinically in the form of neurological deﬁcits or pain,or radiologically according totwo modalities: oste-olyticand expandingor nodularsurrounded bya singleor doublefat-densityandwater-densityhalo.Reductionofthe water-density zone and increase of the fat-density zone wereobservedduringfollow-up, suggestingpossible spon-taneous involution. The results of our seriesindicate the generally slow rate of progression of PG. However, two patients developed signs of extension tothe spinal cord, requiringsurgeryinonecaseandradiotherapyintheother case.

Lymph node metastases are usually detected by neck palpation or by X-rays or scintigraphy. Tumours situated too inferiorly or too anteriorly to correspond to carotid

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Figure2 a:neckMRI,gadolinium-enhancedT1-weightedsequence,axialsection:twoleftcervicallymphnodemetastases;b: spineMRI,T2-weightedsequence,sagittal section: spinal cordcompression overC7;c: octreoscan,coronalsection: increased uptakeinalymphnode:d,e:octreoscan,axialandcoronalsections:increaseduptakeofC7vertebra.

orvagaltumoursmustbeconsideredtobepossiblelymph nodemetastases.Theyaresometimesdiscoveredonsurgical explorationandareconﬁrmedbyhistologicalexamination. Theyappeartobeassociatedwitharelatively favourable prognosis,aslymphnoderecurrencesappeartoberare.

Functional imaging does not appear to be a reliable modality for the detection of bone metastases. Although functionalimagingcandetectprimaryPGoftheheadand neckorothersiteswithsensitivitycloseto100%[12],111

In-pentetreotidescintigraphyfailedtovisualizeallmetastases inthepresentseries.Thispoorperformancehasalsobeen reportedbyTimmersetal.[13],whodescribedpooruptake of123/131_I-MIBG_[14] _by_non-adrenal_PG.123_I-MIBG_revealed

bonemetastasisinonlyoneofthefourcasesofourseries. PET-CThasbeenproposedintheliteratureforthe assess-ment of phaeochromocytomas and PG. 18_F-FDG _is _more

reliable for the detection of PG than their metastases

[13,15].18_F-DOPA_has_a_high_sensitivity_for_the_detection_of

benignheadandneckPG[16],butalowsensitivityforthe detectionofmetastases,particularlyinsubjectswithSDH-B

mutation.Thelowperformanceofthesespeciﬁcagentscan beexplainedbylossofdifferentiationofmetastasesrelated toSDH-Bmutation.

A recent study demonstrated that plasma levels of a metabolite of dopamine, methoxytyramine, higher than 0.2nmol/L constituted a useful biomarker to detect the presenceofmetastases[17].

InfamilialformsofbenignheadandneckPG,amutation oftheDsubunitoftheSDHgeneisidentifiedin50%to94% ofcases,whileamutationoftheBsubunitisidentifiedin 10%to20%ofcases[18,19].Insporadicforms,aSDHgene mutation,mainlyinvolvingtheDsubunit,isreportedin11% to29%ofcases[18].However,SDH-Bmutationsaremainly reportedin malignant headand neck PG[6,8,18,20].The resultsofthepresentseriesconfirmthesepublishedresults, withapredominanceofSDH-Dmutation(56%)inthebenign PGgroupandSDH-Bmutation(5ofthe10patientstested, i.e.50%)inthemalignantPGgroup.However,twopatients ofthemalignantPGgrouppresentedaSDH-Dmutation,as previouslyreportedbyotherauthors[21,22].Nomutation

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wasidentiﬁedinthe remaining3patients. Notethat four patientsofthebenignPGgrouppresentedSDH-Bmutation withnosignsmalignancyduringfollow-up.

Demonstration of an SDH-Bgenemutation ina patient withheadandneckPGthereforeappearstoconstitutethe mostrelevantriskfactorformalignancy,justifying radiologi-calwork-up,especiallywhentheotherriskfactorsdescribed abovearealsopresent:youngsubject,multiplesites, par-ticularlycarotid,possiblysecreting,withafamilyhistoryof PG.

The free interval between diagnosis of the primary tumour and metastases can be long and therefore justi-ﬁeslong-term follow-up, especiallyfor high-risk patients. Althoughthe5-yearoverallsurvivalreportedinthe litera-tureforphaeochromocytomasandmalignantPGrangesfrom 40%to74%[5,7,9],theindividualprognosisisunpredictable. Inourstudy,allpatientsofthemalignantPGgroup(group 2)werealiveatlastfollow-up(withafollow-upofupto29 years),exceptforonepatient(with SDH-Bmutation). Ina seriesof5patients,Havekesetal.[14]describedthecase of a patient whodied after a follow-up of 32 years: this woman with SDH-D mutation developed multiple cervical lymphnodeandbonemetastases.

Surgery is theoretically the only curative treatment for metastases of malignant PG. However, the treatment optionsformetastasesdepend ontheirsiteandtheir ope-rability.Surgeryisclearlyindicatedinthecaseofisolated or multiple lymph node metastases, in the neck, chest or abdomen, especiallyas surgeryalso allowshistological conﬁrmationofmalignancy.Similarly,isolatedliver metas-tases can be treated by resection, sometimes allowing long-termsurvival.

However,two-thirdsofmetastasesinvolveboneandare usuallyvertebraland thereforeunresectable. Acombined medicalandsurgicalapproachisindicated inthesecases: analgesicsandanti-inﬂammatorydrugstocontrolpainand nervecompression,butalsobisphosphonatesandlocalized radiotherapyorsometimesembolizationandradiofrequency ablation[23,24].Surgicaldecompressionfollowedby verte-broplastycanbeproposedinthepresenceofsignsofspinal cordcompression.

Anotherattractivetreatmentoptionismetabolic radio-therapy based on the property of paraganglionic cells to express somatostatinreceptors ontheir cell surface.This modalityusesa markerlabelled withahighly radioactive agent such as131_I-MIBG _or 90_Ytrium- _or 111_{Indium-labelled}

octreotide.However,inpractice,thistypeoftreatmentis limitedbythefactthatalmostone-halfofPGmetastasesdo nottakeupthetracerandone-thirdofpotentialcandidates forthistherapyfailtorespond[25].Thistreatmentisalso veryexpensiveandtheresultsofmetabolicradiotherapyfor metastasesof tympanojugularPGhave notbeen reported todate. Theonlypublishedstudiesconcernmetastasesof phaeochromocytomas[7,25—27].

Randomized trials of chemotherapy are methodologi-callydifﬁculttoperform,buttheadditionofchemotherapy appearedtoprovideimprovementofsymptomsand short-termremissionsinsomestudiesbasedonsmallsamplesizes

[26,27].

Targeted molecular therapy remains a promising approach, basedonthe principleofthemolecular effects of SDH-B gene mutations, resulting in activation (or

deregulation) of genes targeted by hypoxia-induced fac-tors.Targetedmoleculartherapies arethereforedesigned to inhibit these genes. Sunitinib, an oral multi-target tyrosinekinasereceptorinhibitorwithanti-angiogenicand antitumouractivity,hasbeen recentlyusedin somecases withpromisingresults[28].

Conclusion

Thisretrospectivestudyindicatesthefollowingconclusions:

• malignantparagangliomas areobservedmorefrequently among young patients with multifocal and secreting tumours,particularly,incarotidsites;

• malignantheadandneckparagangliomasaremainly asso-ciatedwithmutationoftheBsubunitoftheSDHgene,but amutationoftheDsubunitissometimesobserved;

• stagingof high-risk patients must include spine MRI, as Octreoscanfailstodetectallmetastases;

• puretympanicformsarenevermalignantanddonot jus-tifygenetictestingorstaging;

• metastases generally present a low rate of progression andarecompatiblewithoftenprolongedsurvival;

• treatmentofmetastasesmustbeadaptedtosymptoms.

Disclosure

of

interest

Theauthorsdeclarethattheyhavenoconﬂictsofinterest concerningthisarticle.

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