Available
online
at
ScienceDirect
www.sciencedirect.com
Review
Mucosal
melanoma
of
the
nasal
cavity
and
paranasal
sinuses
L.
Gilain
∗,
A.
Houette
,
A.
Montalban
,
T.
Mom
,
N.
Saroul
ServiceORLetChirurgieCervico-Faciale,CHU,Universitéd’Auvergne,58,rueMontalembert,63000Clermont-Ferrand,France
a
r
t
i
c
l
e
i
n
f
o
Keywords: Mucosalmelanoma Nasalcavity Paranasalsinuses Nasalobstruction Epistaxisa
b
s
t
r
a
c
t
Mucosalmelanomaofthenasalcavityandparanasalsinusesisararedisease,butitsincidenceappears tobeincreasing.Themeanageatdiagnosisisbetween65and70years.Unilateralnasalobstruction andepistaxisarethemostcommonpresentingcomplaints.Melanomaarisesintheseptumorlateral wallofthenasalcavityinthegreatmajorityofcases.Thehistologicaldiagnosisisbasedonspecific immunohistochemicallabellingandisusuallyestablishedatanadvancedstageofdisease:stageT3or T4tumoursaccordingtothe7theditionoftheAmericanJointCommitteeonCancer(AJCC)classification oftumours.First-linetreatmentconsistsofsurgery.Theplaceofintranasalendoscopicsurgeryremains controversialduetothedifficultyofcontrollingsurgicalmarginsandshouldbereservedforexperienced teams.Adjuvantradiotherapyisusuallyperformedduetoitsefficacyonlocalandregionaldiseasecontrol. Five-yearoverallsurvivalofmucosalmelanomaofthenasalcavityandparanasalsinusesinthemost recentseriesdoesnotexceed40%.Localrecurrenceisobservedinabout50%ofcasesandmetastatic diseaseiscommon.Thequalityofinitialtumourresectionwithnegativesurgicalmarginsisthemost importantprognosticfactorfortumoursconfinedtothenasalcavity.Hopesforimprovementofsurvival arebasedonearlydiagnosis,progressinradiotherapytechniquesandcellandgenetherapythatare currentlyunderevaluation.
©2014ElsevierMassonSAS.Allrightsreserved.
1. Introduction
Primarymucosalmelanomaofthenasalcavityandparanasal sinusesisararetumour[1,2].Positivediagnosisofthistumouris madedifficultbythenon-specificpresentingcomplaints[3,4].This tumourhasapoorprognosisduetoitsaggressivenatureandthe frequentlydelayeddiagnosis.Itmainlyoccursintheelderlyand thepresenceofcomorbiditiescanlimit theextentof treatment
[4].Treatmentoptionsessentiallyconsistofradicalsurgery and radiotherapy,whilechemotherapyisreservedforadvancedforms. Despiteabetterknowledgeofthistumour,the5-yearoverall sur-vivalremainspooranddoesnotexceed40%inanyofthepublished studies[5–8].
2. Pathogenesisandepidemiology 2.1. Pathogenesis
Melanocytesaredendriticcellsarisingintheneuraltubeand locatedatthedermo-epidermaljunctionofallmucousmembranes.
∗ Correspondingauthor.
E-mailaddress:lgilain@chu-clermontferrand.fr(L.Gilain).
Thepresenceofmelanocytesinthemucosaofthenasalcavityand paranasalsinuseshasbeenknownfor alongtime.Melanocytes are detectedunder normal conditions in about21% of individ-uals[3].Mucosalmelanomaisaneuroectodermaltumourarising fromthesemelanocytes[3,9].Ahigherdensityofmelanocytesin themucosaofthenasalcavityandparanasalsinusescomparedto othersitescouldexplaintherelativefrequencyofprimarymucosal melanomasinthissite[5].Noriskfactorhasbeenclearly identi-fiedtoexplainthedevelopmentofthesetumours.Incontrastwith melanomaoftheskin,inwhichsunexposureisknowntobethe majorriskfactor,theriskfactorsformucosalmelanomashavenot beenidentified.NolinkhasbeendemonstratedbetweenHuman PapillomaVirus(HPV)orHerpesvirusintheaetiopathogenesisof mucosalmelanoma[3].Exposuretoformaldehydehasbeen sus-pectedbutnotconfirmedinseveralstudies[3,10].Smokingmay constituteapredisposingfactoressentiallyformucosalmelanoma oftheoralcavity[3,11].Severalgeneticstudieshavedemonstrated genemutationsaffectingthetyrosinekinasereceptor[3,12].Some authorshavesuspectedtheroleofheredityandenvironmentinthe pathogenesisofmucosalmelanomainordertoexplainthe differ-entprevalenceratesofthesetumoursbetweenCaucasian(1%of melanomas)andAsianpopulations(7.5%ofmelanomas)[1,5].
CasiraghiandLefèvreconsideredthatmucosalmelanomasof thenasalcavityandparanasalsinuseswerehistologicallyrelated tothegroupofmalignantroundcelltumours[13].Theysuggested http://dx.doi.org/10.1016/j.anorl.2013.11.004
a morphologicalcontinuumof thesetumoursbetweenthe two extremesoflife,withsarcomasinchildrenandyoungadultsand mucosalmelanomaintheelderly[13].
2.2. Epidemiology
Primarymucosalmelanomaofthenasalcavityandparanasal sinuses is a rare tumour, representing between 0.7 and 1% of allmelanomasinCaucasian populationsandbetween4and 8% ofmalignant tumoursofthenasalcavityand paranasalsinuses
[3,14].Theincidenceofmucosalmelanomaappearstobe
increas-ing,especiallyinthenasalcavityandparanasalsinuses[2,15].This increasingincidenceappearstobesignificantinwomen[2,14,15]. Despitethisincrease,theprevalencecurrentlyremainsidentical inthetwosexes[4].Thepatient’sageatthetimeofdiagnosisis between60and80yearswithameanagebetween65and70years
[5,16].Primarymucosalmelanomacanariseinvarious
anatomi-calsites,butitpredominantly(55%ofcases)involvestheheadand neck[5],inwhichthenasalcavityandparanasalsinusesisthemost frequentsite,representing70%ofcases(50%inthenasalcavity,20% intheparanasalsinuses)followedbytheoralcavityinabout17% ofcases[2].
3. Diagnosisandassessment 3.1. Clinicalfeatures
Themostcommonpresenting complaintsare nasal obstruc-tionandepistaxis.Nasalobstructionisunilateral,permanentand progressive,eitherisolated orassociated withothersymptoms. Epistaxiscanbeabundantorminimalwiththepresenceofstreaks ofbloodwhenblowingthenose[4,17].Someauthorshavereported epistaxistobethemostcommonpresentingcomplaint[6].These non-specific symptoms are often considered to be responsible for the long interval between first symptoms and diagnosis of melanoma.Thisisparticularlytruewhenthetumourarisesinthe paranasalsinuses[7].Othersymptomsincluderhinorrhoeawhich canbepurulentinthecaseofsuperinfection,painandlacrimation inthecaseofinvasionoftheinferiormeatusandlacrimalduct.More advancedtumoursmaypresentintheformofmalarswelling,nasal deformityorexophthalmos.
3.2. Clinicalexamination
Unilateralsymptomsmustbeconsideredtobesuspiciousand justify thorough fibroscopic or endoscopic investigation of the nasalcavity.Intranasalexaminationdefinestheappearanceofthe tumour (sessile, nodular,polypoid or granulating), its size and implantation.Itmaybeslate-coloured,reddish,crimson,brownish orblack,whichishighlysuggestiveofthediagnosis.Thetumour surfacecanbehomogeneousorheterogeneous,withafriable con-sistencyandthetumourmaybecoveredbyagreyishexudate.An ulceratedappearanceisfrequentlyobserved[3,13].One-thirdof melanomasare achromic[4]. Theexact originofthetumour is sometimesdifficulttodetermineandthetumourisoftenalready extensiveatthetimeofdiagnosiswithameandiameterranging between2 and3cm [14].Tumoursof thenasalcavity predom-inantly involve the septum and lateral wall, while tumours of theparanasalsinusespredominantlyinvolvethemaxillarysinus followed by the ethmoid, frontal and sphenoidal sinuses [4,5]. Thecranialnervesmustbesystematicallyexaminedlookingfor oculomotordisordersandsensorylossoftheface.Complete clini-calstagingassessmentmustincludepalpationofregionallymph nodes. At the time of diagnosis of the primary tumour, cervi-callymphnodemetastasesaredetectedin10to20%ofpatients
[1,13,17]and haematogenous metastases are detectedin 6% of
Fig.1. Infiltrationofthemucosaofthenasalcavitybymelanoma.Thearrow indi-catesthecellularproliferationinvadingthemucosaunderneathanintactsurface epithelium.
patients(lungs,brain,bone,liver)[13].Acompletedermatological andophthalmologicalexaminationmustbeperformedtodetecta possibleprimarytumourinordertoconfirmtheprimaryor sec-ondary natureof thetumour of thenasalcavity and paranasal sinuses.
3.3. Histology
Thediagnosisisbasedonhistologicalexaminationoftumour biopsies. Histological examination is difficult due to marked cytologicalandarchitecturalpolymorphism[4].Thepresenceof intracytoplasmicmelaninpigmentcanbedetectedbytheaffinity forFontanastain[13,17](Figs.1and2).Severalparametersare evaluatedonhistologicalexamination: morphologyand cellular architecture,pigmentation,presenceofulceration,percentageof necrosis,numberofmitoses,inflammationandbone,perineural, lymphaticandvascularinvasion.Confirmationofthediagnosisis basedonimmunohistochemistryusingapanelofmarkers:protein S100andmelanocyticmarkers(HMB45,Melan-A,tyrosinase,MITF)
[13].Epithelialcellmarkersarenegativebutseveralaberrantcases havebeenreported[13].
3.4. Imaging
Animagingassessmentcomprisingcomputedtomography(CT) ofthefacial bonesand magneticresonanceimaging(MRI)isan
Fig.2. BrownintracytoplasmiclabellingoftumourcellswithHMB45.Thearrow indicatesazoneofintenselabellingintheformofsmallgrains.
Fig.3. MRI,T1-weightedsequence,coronalsection,showingatumour(define whetheritisahigh-orintermediate-signalintensityandaddarrows)ofthenasal cavityandahomogeneouslow-intensityrightmaxillarysinus.
essentialpartofthelocalstagingofthetumour.Computed tomo-graphyofthefacialbonesandskullbaseisperformedwithaxialand coronalsections,withcontiguous1mmthick(spiralacquisition)or amaximumof3mmthickslicesanddualwindowsettings(bone andsoft tissues).Intravenous iodinated contrastagentinjection allowsenhancementofthetumourwithrespecttosurrounding tissues.Three-dimensional(3D)reconstructionisparticularly use-fulwhenfacial reconstructionisplanned.Theusualappearance isthat ofan aggressiveosteolytictumour.Brain andfacial MRI providesthree-dimensionalsectionsandusuallycomprisesthree sequences:T1,T1post-gadoliniumandT2.Malignantmelanomais characterizedbyheterogeneouscontrastenhancement.According tosomeauthors,aspontaneoushigh-intensitysignalonT1with alow-intensitysignalonT2wouldbecharacteristicofmelanoma. Thisunusualappearance,sometimesobservedwithothertypesof tumours(angiosarcoma,cylindromaandaesthesioneuroblastoma) appearstoberelatedtothehighmelanincontentand/orbleeding insidethetumour[18,19].T2-weightedMRIcandistinguishtumour invasionfromparanasalsinusfluidretention.Finally,MRIis essen-tialtodefinetheanatomicalrelationsofthetumourwiththeorbit andskullbaseandtodetectanybrainmetastases(Figs.3and4). Dis-tantstagingisbasedonchest,abdomenandpelvisCTandpositron
Fig.4.MRI,T1-weightedwithgadoliniumadministrationsequence,axialsection. Heterogeneouscontrastenhancementofthetumour.
Table1
AmericanJointCommitteeoncancerstagingmucosalmelanomaoftheheadand neck,7thedition.
Primarytumor(T)
T3 Mucosaldisease
T4a Moderatelyadvanceddisease;tumorinvolvingdeepsoft tissue,cartilage,bone,oroverlyingskin
T4b Veryadvanceddisease;tumorinvolvingbrain,dura,skull base,lowercranialnerves(IX,X,XI,XII),masticatorspace, carotidartery,prevertebralspace,ormediastinal structures
Regionallymphnodes(N)
NX Regionallymphnodescannotbeassessed N0 Noregionallymphnodemetastases N1 Regionallymphnodemetastasespresent (M)
M0 Nodistantmetastasis M1 Distantmetastasispresent Staging
StageIII T3,N0,M0 StageIVA T4a,N0,M0
T3–T4a,N1,M0 StageIVB T4B,anyN,M0 StageIVC AnyT,anyN,M1
emissiontomography(PET).Thisstagingassessment lookingfor metastasescanbedecisiveinthechoiceoftreatmentandtoassess thevalueofcertaincosmeticallyandfunctionallydestructiveforms ofradicalsurgery(orbitalexenteration).
3.5. Classification
The clinical and imaging assessment allows staging of the melanomainordertoproposeadaptedtreatmentand toassess theprognosis.Ballantyne’sclassificationistheoldestclassification, butdoesnottaketumoursize,tumourhistologyandlocal exten-sionintoaccount[20],asstageIisdefinedastumourconfinedtothe originalsite,stageIIisdefinedastumourwithregionallymphnode metastasesandstageIIIisdefinedastumourwithdistant metas-tases.Useofthisoldclassificationallowscomparisonofvarious series[1],butitisnowpreferabletorefertotheclassification estab-lishedbytheAmericanJointCommitteeonCancer(AJCC)[21,22]. The7theditionoftheAJCCclassificationdoesnotcomprisestage T1andT2inviewofthesystematicallyaggressivenatureofthese melanomas.TheproposedclassificationcomprisingstageT3andT4 tumoursismoreconsistentwiththelocalextensionandthepoor prognosisofthisdisease(Table1).
4. Treatment 4.1. Surgicaltreatment
Ageneralconsensushasbeenreachedtoconsidersurgeryas first-linetreatment[1,5,23].Theindicationforsurgerymusttake intoaccountthepatient’squality oflife,duetothepoorglobal prognosisofthesetumours.Thetreatmentdecisionisgenerally takenbyanoncologymultidisciplinaryconsultationbasedonthe stagingassessment.Surgeryisindicatedasfirst-linetreatmentand inthecase oflocalrecurrence.Thechoicebetweenanexternal or an intranasal incisiondepends on thetumour size and site. Thechoiceof intranasalendoscopicsurgery remains controver-sialduetothedifficultyofcontrollingsurgicalmarginsandshould bereservedforexperiencedteams[16].Itisindicatedforstrictly intranasaltumoursandunderconditionsoftumourresectionthat areabletoachievethesamecancercontrolresultsasviaan exter-nalapproach.Craniofacialresectionisthereferencetechniquefor tumourssituatedincontactwithorinvadingtheskullbase[16].The tumourmustbewidelyresectedwith1.5to2cmnegativesurgical
margins[17].Marginsareconsideredtobenegativewhentheyare greaterthanorequalto5mmondefinitivehistological examina-tionoftheoperativespecimen.Systematiclymphnodedissection isnotpartofconventionalsurgicalmanagementandisonly per-formedinthepresenceofclinicallyorradiologicallypathological lymphnodes[1].Thesentinellymphnodebiopsytechnique,used incutaneousmelanoma,iscurrentlyunderevaluationinmucosal melanoma.
4.2. Radiotherapy
Mucosal melanomas are generally considered to be poorly radiosensitive. Melanomas are composed of cells with a high post-irradiationregenerativecapacity.Radiotherapyisclassically indicated in the presence of positive surgical margins, local recurrence, locally advanced tumour, or sometimes for pallia-tivepurposesorwhenthepatientrefusessurgery.Themajority of authors consider that adjuvant radiotherapy increases local andregionalcontrolwithoutincreasingsurvivalindependentlyof tumourstage[8,24–27].Theredoesnotappeartobeanysignificant survivaldifferencebetweenpatientstreatedbysurgeryaloneand patientstreatedbysurgeryandadjuvantradiotherapy[3,28]. How-ever,thefindingsofthesestudiesarecontroversial,asotherteams havedemonstratedtheefficacyofsurgeryandadjuvant radiothe-rapyonsurvival[1].
In particular, the development of new radiotherapy tech-niques,suchasintensity-modulatedradiationtherapy(IMRT)has improved the results obtained with conventional radiotherapy especiallyonlocalandregionalcontrolwithgoodlocalsafetyand lowmorbidity[29–31].Asaresultofthisprogress,radiotherapy isincreasinglyproposedsystematicallyaspartoftheinitialphase oftreatmentasanadjuvanttosurgerywhetherornotthesurgical marginsareinvaded[29,31].
4.3. Chemotherapy
Chemotherapyisclassicallyindicatedforpalliativetreatment orinmetastatic patients[7].However,someauthorshave pro-posedmultimodalfirst-linetreatmentcomprisingchemotherapy and/orimmunotherapyforthemanagementoflocallyaggressive forms[28,32].A recentstudyhighlightedthevalue ofselective intraarterialchemotherapy [33]. Immunotherapy by interleukin 2 or interferon alpha (IFN␣) either alone or in combination withchemotherapyandvaccinationiscurrentlyunderevaluation
[34,35].Inmetastaticdiseaseorunresectableformsofcutaneous
melanoma,thechemotherapystrategyisdesignedaccordingtothe presenceorabsenceofV600mutation[31,36].Vemurafenib,aBRAF proteinkinaseinhibitor,isthereforereservedforthetreatmentof advancedmelanomaassociatedwithBRAFV600mutation[31,37]. Trialsofvemurafenibandipilimumabcombinationtherapyare cur-rentlyunderwayinpatientswithBRAFmutation.Intheabsence ofBRAFV600mutation,treatmentoftheseadvanced, treatment-refractoryforms isbasedontheuseofipilimumabeitheralone orincombinationwithstandardchemotherapy(dacarbazine).The transpositionoftheserecentdatatothemanagementofstage4 mucosalmelanomaofthenasalcavityandparanasalsinusesmust beconsideredin the light ofprogress of oncogeneticsin these mucosalforms.
However,theadverseeffects ofthesetreatmentsrepresenta considerablelimitingfactorforthemanagementofpatientswith mucosalmelanomaofthenasalcavityandparanasalsinuses,who aregenerallyelderlywithcomorbiditiescontraindicatinganyform ofchemotherapyorimmunotherapy.
5. Survivalandprognosis
The5-yearoverallsurvivalofmucosalmelanomaofthenasal cavityand paranasalsinusesinthemostrecentseriesdoesnot exceed40%(20%–40%)[5–8]andmeansurvivaldoesnotexceed 28months(17–28months)[4,27].Localrecurrencesoccurinabout 50%ofcases[3,27].Thishighrecurrencerateappearstobedueto themultifocalnatureofthelesions,submucosallymphaticspread andthehighrateofvascularinvasion.Localrecurrencesarealso relatedtoinadequatefirst-linesurgicalresection.Localrecurrences arepredictiveofthepresenceofdistantmetastases[3,27].Themost commonmetastaticsitesarelungs,liver,boneand,morerarely, brainandadrenalglands. Metastasesarefoundinabout50%of cases,sometimesduringthecourseofthedisease[27],whilelymph nodemetastasesarefoundin20to40%ofcases[13,27].
Prognosticfactorshavebeenextensivelystudiedinthe litera-turebymeansofmultivariateanalyses.Thequalityoftheinitial tumour resection with negative resection margins is the most importantprognosticcriterionfortumoursconfinedtothenasal cavity[6,17].
Anadvancedageatthetimeofdiagnosisisafactorofpoor prog-nosis.Theunfavourableagelimithasbeenestimatedtobe70years accordingtosomeauthors[38]and60yearsaccordingtoothers
[1,3],whileagelessthan50yearsappearstobeassociatedwitha
betterprognosis[3].Tumoursizegreaterthan3–4cmisconsidered tobeafactorofpoorprognosis[13,38].Anisolatedseptaltumour isassociatedwithgoodprognosis[6]incontrastwithtumoursof theparanasalsinusesthathaveaverypoorprognosis.
Ballantyne’sstageIhasabetterprognosis[1].Ahighmitotic index and a pseudopapillary and sarcomatoid architecture on histologicalexaminationarefactorsofpoorprognosis[4,13,39]. Someauthorsconsiderthepresenceofmelaninandthelevelof pigmentationtobefactorsofpoorprognosis[4],whileachromic melanomasareusuallyconsideredtobeassociatedwithapoorer prognosis[40].
6. Conclusion
Earlydiagnosisofmucosalmelanomaofthenasalcavityisan essentialprognosticfactor.Thepresenceofunilateralsymptoms, suchasepistaxisornasalobstruction,inapatientovertheageof 60yearsmustbeconsideredtobesuspicious.Thediagnosisisbased onhistologicalandimmunohistochemicalexaminationofabiopsy. First-linetreatmentisbasedonwidesurgicalresection,possibly completedbyadjuvantradiotherapy.Aninitialcompleteresection withhealthymarginsisadecisivefactorforsurvival.Theoverall prognosisofthesetumoursisverypoor.Hopesforimprovementof survivalarebasedonprogressinradiotherapytechniquesandcell andgenetherapythatarecurrentlyunderevaluation.
Disclosureofinterest
Theauthorsdeclarethattheyhavenoconflictsofinterest con-cerningthisarticle.
References
[1]ChanRC,ChanJYW,WeiWI.Mucosalmelanomaoftheheadandneck:32-year experienceinatertiaryreferralhospital.Laryngoscope2012;122:2749–53.
[2]MarcusDM,MarcusRP,PrabhuRS,etal.Risingincidenceofmucosalmelanoma oftheheadandneckintheUnitedStates.JSkinCancer2012[ArticleID231693, 6p.].
[3]MihajlovicM,MihajlovicS,JovanovicP,etal.Primarymucosalmelanomas:a comprehensivereview.IntJClinExpPathol2012;5:739–53.
[4]Saint-BlancardP,KossowskiM.Mélanomesdesmuqueusesnasosinusiennes. PresseMed2006;35:1660–3.
[5]PatrickRJ,FenskeNA,MessinaJL.Primarymucosalmelanoma.JAmAcad Der-matol2007;56:828–34.
[6]MorenoMA,RobertsDB,KupfermanME.Mucosalmelanomaofthenoseand paranasalsinuses,acontemporaryexperiencefromtheM.D.AndersonCancer Center.Cancer2010;116:2215–23.
[7]RothTN,GenglerC,HuberGF,etal.Outcomeofsinonasalmelanoma:clinical experienceandreviewoftheliterature.HeadNeck2010;32:1385–92.
[8]BenlyazidA,ThariatJ,TemamS,etal.Postoperativeradiotherapyinheadand neckmucosalmelanoma:aGETTECstudy.ArchOtolaryngolHeadNeckSurg 2010;136:1219–25.
[9]CoveH.Melanosis,melanocytichyperplasia,andprimarymalignantmelanoma ofthenasalcavity.Cancer1979;44:1424–33.
[10]HolstromM,LundVJ.Sinonasaltractandnasopharyngealmelanomas:a clin-icopathologicstudyof115caseswithaproposedstagingsystem.AmJSurg Pathol2003;27:594–611.
[11]AxellT,HedinCA.Epidemiologicstudyofexcessiveoralmelaninpigmentation withspecialreferencetotheinfluenceoftobaccohabits.ScandJDentalRes 1982;90:434–42.
[12]CurtinJA,BusamK,PinkelD,etal.SomaticactivationofKITindistinctsubtypes ofmelanoma.JClinOncol2006;24:4340–6.
[13]CasiraghiO,LefèvreM.Tumeursmalignesindifférenciéesàcellulesrondesdes cavitésnaso-sinusiennesetdunasopharynx.AnnPathol2009;29:296–312.
[14]KuijpensJLP,LouwmanMWJ,PetersR,etal.TrendsinsinonasalcancerinThe Netherlands:moresquamouscellcancer,lessadenocarcinoma.A population-basedstudy1973–2009.EurJCancer2012;48:2369–74.
[15]Jangard M,Hansson J, Ragrarsson-OldingB. Primarysinonasal malignant melanoma:anationwidestudyoftheSwedishpopulation,1960–2000. Rhi-nology2013;51:22–30.
[16]CliftonN,HarrisonL,BradleyPJ,etal.Malignantmelanomaofnasalcavityand paranasalsinuses:reportof24patientsandliteraturereview.JLaryngolOtol 2011;125:479–85.
[17]LietinB,MontalbanA,Louvrier,etal.Melanomesmuqueuxnaso-sinusiens.À proposde10cas.EurAnnOtorhinolaryngolHeadNeckDis2010;127:70–6.
[18]Lynch SC, Lee AG, Graham SM, et al. Primary melanoma of the sphe-noidsinuspresentingwithathirdcranialnervepalsy.JNeuroophthalmol 2005;25:289–92.
[19]KimSS,HanMH,KimJE,etal.Malignantmelanomaofthesinonasal cav-ity:explanationofmagneticresonancesignalintensitieswithhistopathologic characteristics.AmJOtolaryngol2000;21:366–78.
[20]BallantyneAJ.Malignantmelanomaoftheskinoftheheadandneck.Ananalysis of405cases.AmJSurg1970;120:425–31.
[21]EdgeSB,ComptonCC.TheAmericanJointCommitteeonCancer:the7thedition oftheAJCCCancerStagingManualandthefutureofTNM.AnnSurgOncol 2010;17:1471–4.
[22]VandehendeC,LeroyX,ChevalierD,etal.Sinonasalmucosalmelanoma: ret-rospectivesurvivalstudyof25patients.JLaryngolOtol2012;126:147–51.
[23]WagnerM,MorrisCG,WerningJW,etal.Mucosalmelanomaoftheheadand neck.AmJClinOncol2008;31:43–8.
[24]ShigaK,OgawaT,KobayashiT,etal.Malignantmelanomaoftheheadand neck:amulti-institutionalretrospectiveanalysisofcasesinnorthernJapan. HeadNeck2012;34:1537–41.
[25]TemamS,MamelleG,MarandasP,etal.Postoperativeradiotherapyforprimary mucosalmelanomaoftheheadandneck.Cancer2005;103:313–9.
[26]KrengliM,Jereczek-FossaBA,KaandersJHAM,etal.Whatistheroleof radio-therapyinthetreatmentofmucosalmelanomaoftheheadandneck?CritRev OncolHematol2008;65:121–8.
[27]BacharG,LohKS,O’sullivanB,etal.Mucosalmelanomasoftheheadandneck: thePrincessMargaretHospitalexperience.HeadNeck2008;30:1325–31.
[28]GoreMR,ZanationAM.Survivalinsinonasalmelanomas:ameta-analysis.J NeurolSurgBSkullBase2012;73:157–62.
[29]DufloS,MonestierS,ZanaretM.Melanomesmalinscervicofaciaux.In:EMC Oto-rhino-laryngologie.Paris:ElsevierMassonSAS;2008[20-950-E-10].
[30]WuAJ,GomezJ,ZhungJE,etal.Radiotherapyaftersurgicalresectionforhead andneckmucosalmelanoma.AmJClinOncol2010;33:281–5.
[31]KhanMK,KhanN,AlmasanA,etal.Futureofradiationtherapyformalignant melanomainaneraofnewer,moreeffectivebiologicalagents.OncolTargets Ther2011;4:137–48.
[32]IvesNJ,StoweRL,LoriganP,etal.Chemotherapycomparedwith biochemother-apyforthetreatmentofmetastaticmelanoma:ameta-analysisof18trials involving2,621patients.JClinOncol2007;25:5426–34.
[33]ShojakuH,TakakuraH,Tachino,etal.Responsetointra-arterialcisplatin andconcurrentradiotherapyinapatientwithprimarymucosalmalignant melanomaofthenasalcavity.HeadNeck2013;35:131–7.
[34]WeberJ.Overcomingimmunologictolerancetomelanoma:targetingCTLA-4 withIpilimumab(MDX-010).Oncologist2008;13(Suppl.4):16–25.
[35]Nistico P, Capone I, Palermo B, et al. Chemotherapy enhances vaccine-inducedantitumorimmunityinmelanomapatients.IntJCancer2009;124: 130–9.
[36]FecherLA,CummingsSD,KeefeMJ,etal.Towardamolecularclassificationof melanoma.JClinOncol2007;25:1606–20.
[37]FlahertyKT,PuzanovI,KimKB,etal.Inhibitionofmutated,activatedBRAFin metastaticmelanoma.NEnglJMed2010;363:809–19.
[38]JethanamestD,VilaPM,SikoraAG,etal.Predictorsofsurvivalinmucosal melanomaoftheheadandneck.AnnSurgOncol2011;18:2748–56.
[39]PrasadML,PatelSG,HuvosAG,etal.Primarymucosalmelanomaofthehead andneck:aproposalformicrostaginglocalized,stageI(lymphnode-negative) tumors.Cancer2004;100:1657–64.
[40]ThompsonLD,WienekeJA,MiettinenM.Sinonasaltractandnasopharyngeal melanomas:aclinicopathologicstudyof115caseswithaproposedstaging system.AmJSurgPathol2003;27:594–611.