Braz. j. . vol.81 número3

www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

REVIEW

ARTICLE

Clinicopathological

characteristics

and

perineural

invasion

in

adenoid

cystic

carcinoma:

a

systematic

review

夽

,

夽夽

Afonso

Nóbrega

Dantas

_,

_Everton

_Freitas

_de

_Morais

_,

Rômulo

Augusto

de

Paiva

Macedo

_,

_João

_Maria

_de

_Lima

_Tinôco

,

Maria

de

Lourdes

Silva

de

Arruda

Morais

a_{UniversidadePotiguar(UnP),Natal,RN,Brazil}

b_{UniversidadedoEstadodoRioGrandedoNorte(UERN),Natal,RN,Brazil} c_{LigaNorte-RiogradensecontraoCâncer,Natal,RN,Brazil}

d_{UniversidadeFederaldoRioGrandedoNorte(UFRN),Natal,RN,Brazil}

Received15June2014;accepted22July2014 Availableonline30March2015

KEYWORDS

Salivarygland neoplasms; Salivaryglands; Mouthneoplasms

Abstract

Introduction:Adenoid cystic carcinoma is the most frequent malignant tumor of the sub-mandibularglandandtheminorsalivaryglands.Itisamalignantneoplasmthat,despiteits slowgrowth,showsanunfavorableprognosis.

Objectives: The aimofthis study was toperform asystematic reviewof theliterature on Adenoidcysticcarcinomaintheheadandneckregionanditsclinicopathologicalcharacteristics, withemphasisontheperineuralinvasioncapacityofthetumor.

Methods:A systematicsearchofarticlespublishedbetween January2000andJanuary 2014 wasperformedinthePubMed/MEDLINE,SciELO,ScienceDirect,andScopusdatabases. Results:Ninearticleswereselectedforthissystematicreview.Thesedemonstratedthatthe femalegenderwasmoreoftenaffectedandthatmalignanttumorsshowedahighrateofdistant metastasis,recurrence,andalowsurvivalrate.Thepresenceofperineuralinvasionrangedfrom 29.4%to62.5%andwasassociatedwithlocaltumorrecurrence.

Conclusion: Adenoidcysticcarcinomaiscommonlycharacterizedbythepresenceofpain,high rateofrecurrence,metastasis,andalowsurvivalrate.Reportingstudieswithpatient follow-upisofutmostimportanceforabetterclinical-pathologicalunderstandingandtoimprovethe prognosisofthispathology.

© 2015Associac¸ãoBrasileira de Otorrinolaringologiae CirurgiaCérvico-Facial. Publishedby ElsevierEditoraLtda.Allrightsreserved.

夽 _{Pleasecitethisarticleas:DantasAN,deMoraisEF,MacedoRA,TinôcoJM,MoraisML.Clinicopathologicalcharacteristicsandperineural}

invasioninadenoidcysticcarcinoma:asystematicreview.BrazJOtorhinolaryngol.2015;81:329---35.

夽夽_{Institution:UniversidadePotiguar(UnP),Natal,RN,Brazil.}

∗_{Correspondingauthor.}

E-mail:joao-tinoco@hotmail.com(J.M.d.L.Tinôco).

http://dx.doi.org/10.1016/j.bjorl.2014.07.016

PALAVRAS-CHAVE

Neoplasiasdas glândulassalivares; Glândulassalivares; Neoplasiasbucais

Característicasclinicopatológicaseinvasãoperineuraldocarcinomaadenoidecístico

Resumo

Introduc¸ão:Ocarcinomaadenoidecístico(CAC)éotumormalignomaisfrequentedaglândula Submandibularedasglândulassalivaresmenores.Sendoumaneoplasiamaligna,apesardeter crescimentolento,apresentaumprognósticodesfavorável.

Objetivos: Oobjetivodestetrabalhofoirealizarumarevisãosistemáticadeliteraturasobre ocarcinoma adenóidecístico naregião decabec¸a epescoc¸o e suascaracterísticas clínico-patológicascomênfasenacapacidadedeinfiltrac¸ãoperineuraldotumor.

Método: Umabuscasistemáticadeartigospublicadosentrejaneirode2000ajaneirode2014 foiexecutadanasbasesdedadosPubMed/MEDLINE,SciELO,ScienceDirecteScopus.

Resultados: Noveartigosforamselecionadospararealizac¸ãodarevisãosistemática.Nestes,o sexofemininofoiomaisafetadoeotumormalignoapresentouumaaltataxademetástase adistância,recidivaebaixataxadesobrevida.Apresenc¸adeinvasãoperineuralvariouentre 29,4%a62,5%efoirelacionadaàrecidivalocaldotumor.

Conclusão:OCACé comumentecaracterizado pela presenc¸a dedor, altataxade recidiva, metástase ebaixa sobrevida. A realizac¸ãode estudos comacompanhamento dospacientes édeextrema importânciapara umamelhoravaliac¸ão clinico-patológicavisandomelhoraro prognósticodadoenc¸a.

©2015Associac¸ãoBrasileira deOtorrinolaringologiaeCirurgiaCérvico-Facial.Publicadopor ElsevierEditoraLtda.Todososdireitosreservados.

Introduction

Salivaryglandneoplasmsareunusualandaccountforonly about2---6.5%oftumorsoftheheadandneckregion.1_The frequency of different types of malignant tumors varies according to the site of origin. However, adenoid cystic carcinoma (ACC) appears to be the most common malig-nanttumorofthesubmandibularsalivaryandminorsalivary glands.2

TheACCisamalignantneoplasmthat,inspiteofitsslow growth,hasapoorprognosisduetoaggressivetumor inva-sionandahighrateofrecurrence.3_{Thisneoplasmwasfirst} describedbyBillrothin1856.4

It candevelop in several anatomicalsites, suchasthe majorandminorsalivaryglands,lacrimalglands,andupper aerodigestive tract glands.5 _{In the buccal-maxillofacial} region,it accountsforapproximately22%ofneoplasms of major and minor salivary glands, with the minor salivary glandsof the hard palate representing the main affected site.2

ACCismoreprevalentinmiddle-agedadultsand accord-ing to many studies, it is more frequent in the female gender.5,6_{Distantmetastasisiscommon;thelungisthemost} commonlyaffectedsite.7

Itmaypresentclinicallyasahardenedlump,andpainis animportantandcommonfindingintheinitialcourseofthe disease.Anulceratedlesioncanbeseenonthepalate,with bonedestructionidentifiedradiographically.8

Histopathologically,ACCcanmanifestasdifferenttypes, withthreemain recognizedpatterns9_{: the cribriformand} tubularpatterns, which are lessaggressive, and thesolid pattern,whichshowscellpleomorphismandmitotic activ-ity,aswellasnecroticfociinthecentralregionofneoplastic cellislands.5,6

Perineuralinvasionisacommonhistologicalfinding,and isconsideredapossibleroutefortumorcelldissemination.5 Perineuralinvolvementoccursin approximately22---46% of casesofACC,whetheratmacro-ormicroscopiclevel.5

Surgeryisthetreatmentof choiceforACCandmaybe followedbyradiationtherapyand,inrarecases, chemother-apy. The frequency of local recurrence for ACC is high, requiringadditionalsurgicalresections.Severalstudieshave evaluated this development as a negative one, with the tumorcausingthepatient’sdeath.9

Dentalsurgeonsneedtodetect anychangesintheoral mucosaof theirpatients.Earlydiagnosis ofACCresults in betterqualityoflifeandhighersurvivalrate.Theobjective ofthisstudywastoperformasystematicreviewof litera-tureonACCoftheheadandneckregionanditsclinicaland pathological features, withemphasis on tumor perineural invasioncapacity.

Methods

Table1 Resultsobtainedbytheselectedstudies. Study Numberofpatients/

gender/age

Locationofprimary tumor

Metastasis Treatment Disease

recurrence DeAngelis etal. (Aus-tralia, 2011)3

24(7M/17F),mean ageof58years (range30---81 years).

Thepalatewasthemost oftenaffectedsite, representing37.5%of cases.

4.1%had metastasesto thecervical lymphnodes and4.1%,to thecervical spine.

Surgerywasperformedin 91.6%patients;87.5%ofcases wereassociatedwith

radiotherapy.Neckdissection wasperformedin20.8%of cases.

25%ofthe patientshad recurrence. ChenAM etal. (USA, 2006)7

140(81M/59F), meanageof57 years(range11---91 years).

Parotid(14%); submandibular(18%); sublingual(7%);lacrimal gland(2%);minor salivaryglands(24%); oropharynx(9%); hypopharynx(4%); paranasalsinuses(20%); trachea(3%).

25%ofpatients haddistant metastases.

Allpatientsweretreatedwith definitivesurgery.

16.4%had recurrence.

Minetal. (China, 2012)9

616(302M/314F), meanageof51.6 years(range11---89 years).

Parotidgland(11%); submandibulargland (13%);sublingualgland (7.5%);hard/softpalate (26.9%);maxillarysinus (9.7%);tongueventral surface(2.8%);tongue dorsalsurface(8.4%); mouthfloor(9.6%);oral mucosa(5%);others (6%).

10.06%ofcases hadmetastases tocervical lymphnodes.

Surgicaltreatmentfollowed bypostoperativeradiotherapy wasthemainoption.

Not reported.

Luksietal. (Croatia, 2013)10

26(12M/14F), meanageof58 (range34---88) years.

Palate(62%);mouth floor(15%);alveolar mucosa(12%);upperlip (8%);jugalmucosa(4%).

46.1%had distant metastases.

Surgicaltreatmentfollowed bypostoperativeradiotherapy wasthemainoption.

26.9%had recurrence. Tincani etal. (Brazil, 2006)11

21(7M/14F),aged 26---72years.

Parotid(19%); submandibulargland (33.3%);palate(47.6%).

33.3%had regional metastasesand 22.2%had distant metastasis.

Surgerywasthemain treatmentwithadjuvant radiationtherapyinmany cases,whereasresectionof thestructurewasnecessaryin othercases. 38.09%had recurrence. Bianchi etal. (Italy, 2008)12

67(28M/39F), meanageof54.5 years(range28---84 years).

Palate(71.6%);lips(3%); alveolarmucosa(1.5); jugalmucosa(4.5%); retromolarregion(4.5%); tongue(4.5%);mouth floor(9%);others(1.5%).

29.8%of patientshad distant metastases.

Allpatientsweretreatedwith surgeryastheprimary modality.Dissectionwas performedin9%ofpatients, andoverhalf(59.7%)were treatedwithadjuvant radiationtherapy.

29.8%of patientshad recurrence.

Perezetal. (Brazil, 2005)13

129(71M/58F), meanageof51.5 years(range10---96 years).

Palate(22.5%);tongue (7.7%);jugalmucosa (3.9%);mouthfloor (3.9%);upperlip(3.1%); lowerlip(0.8%);parotid (19.4%);submandibular (15.5%);sublingual (2.3%);others(20.9%).

10.07%had regional metastasesand 8.5%had distant metastasis.

Patientsweretreatedwith localresectionassociated withpostoperative radiotherapy(42.7%),local resectionalone(30.2%),or radiotherapyalone(10.1%). Othertherapeuticmodalities includedradiotherapyand chemotherapy(3.9%),local resectionandchemotherapy (2.3%),andchemotherapy alone(1.5%).9.3%ofpatients receivedonlysupportivecare.

Table1(Continued)

Study Numberofpatients/ gender/age

Locationofprimary tumor

Metastasis Treatment Disease

recurrence

Khanetal. (USA, 2001)14

68(30M/38F), meanageat diagnosisof52 years.

Themostaffectedsites weretheoropharynx (23.5%),parotid (22.05%),submandibular gland(16.17%).

10.2%had pulmonary metastasisand 5.8%hadlymph node

metastasis.

Theprimarytreatmentwas surgery.8.8%ofpatients underwentradiation,7.3%of patientswerepoorsurgical candidatesdueto

comorbidities,andwere treatedwithcurativeintent, while1.4%ofpatientswere treatedwithpalliativecare.

42.6%had recurrence.

Sungetal. (Korea, 2003)15

94(44M/50F),age of44.5years(range 20---78years).

Themostaffectedsites weretheminorsalivary glands(69.1%)andthe majorsalivaryglands (30.8%).

26.5%of patientshad distant metastasesand 3.1%had regional metastasis.

Incasesofpatientswith distantmetastases,10.6% weretreatedwithsurgery, 8.5%withradiotherapy,and 29.7%withboth.Inpatients withoutdistantmetastasis, 6.3%weretreatedwith surgery,7.4%with

radiotherapy,and37.2%with both.

18.08%had recurrence.

M,male;F,female.

Theinclusioncriteriawere:studiespublishedinEnglish, Portuguese, or Spanish; cross-sectional and longitudinal studiesaimedatevaluatingACCoftheheadandneckregion anditsperineuralinvasioncapacity;articlespublishedfrom Januaryof2000onward.Theexclusioncriteriawere:review articles,populationthatdidnotmatchtheresearch stan-dards,clinicalcases,andarticlespublishedbeforetheyear 2000orinadifferentlanguagefromthoseselectedforthis systematicreview.

Thefirststepinstudyselectionwasanalysisoftitlesand abstracts.Subsequently,allstudieswhosetitlesorabstracts were considered relevant were obtained and analyzed in full;finally,thearticlesanalyzedandselectedbythe eval-uators after a consensus meeting were included in the systematizationofdata.

Results

Among the initiallyselected studies, 29 showedpotential tobeincludedinthesystematicreview;however,afterfull analysisofthestudiesanddiscussionoftheircontentsbythe evaluators,theyagreedthatonlyninearticlesmetall inclu-sioncriteria.3,7,9---15_{Amongtheselectedstudies,threewere} carriedout in developing countries9,11,13 _{and six in} devel-opedones.3,7,10,12,14,15_{Articlemethodsandresultsareshown} inTables1and2.

Regarding the study profiles, sample size ranged from 2111_to6169_{patients,withthetotalsamplesizebeing1185} patientswithamean age>50 years.The selectedstudies werepublishedbetweentheyears2001and2013.Allofthe selectedstudieswereretrospective.

Theobjectivesoftheselectedstudieswere:toperform theanalysisoftheclinicalandpathologicalcharacteristics ofACC,analyzingvariablessuchasgender,3,7,9---15_age,3,7,9---15

metastasis,3,7,9---15 _recurrence,3,7,10---15 _{perineural invasion} capacity,3,7,9---15_{survivalrates,}3,7,9---15_{andtreatment.}3,7,9---15

Among thestudies selected for thissystematic review, sevenshoweddifferencebetweengenders,withthefemale gendermoresusceptibletoACC.3,9---12,14,15_{Onlytwostudies} showedahighernumberofcasesinmales.7,13

Thepalatewasthemostoftenaffectedsiteinthe major-ityoftheselectedstudies,3,9---13 _{reaching71.6%ofcasesin} thestudybyBianchietal.12_{InthestudybyKhanetal.,}14_the most oftenaffected sitewastheoropharynx, followed by theparotidandsubmandibularglands.Amongtheselected studies,allassessedthepresenceofmetastasis(Table1).

Thepresenceofperineuralinvasionwasaconstantinthe selectedstudies.IntheretrospectiveanalysisbyMinetal.,9 328patientshadperineuralinvasion,with40patients show-ingpositiveproximalmetastasisand288negative.Fifteen caseswererecordedinthestudybyDeAngelisetal.3_and13 casesinthestudybyLuksiéetal.10_Tincanietal.11_reported ninecasesofperineural invasion,whereasBianchietal.12 reported39cases.TheretrospectivestudybyPerezetal.13 reported the presence of 58 cases, whereas Chen etal.7 reported82cases.Khanetal.14_{reportedthepresenceof20} casesofperineuralinvasion,whileSungetal.15_reported29 patients,12withpositivedistantmetastasesand17 nega-tive.InthestudyperformedbyLukisietal.,10_therewasno significant associationbetweenthepresenceof perineural invasion andprimarytumor size, presence of proximalor distantmetastasis,orinvasionofmargins;however,itwas associatedwithlocaltumorextent.

Table2 Tumorcharacteristicsandperineuralinvasion.

Study Sizeofprimary

tumor

Histopathological pattern

Perineuralinvasion Factorsrelatedtoperineural invasion

DeAngelisetal. (Australia, 2011)3

Notmentioned. Solid(37.5%); tubularor cribriform(54,1%); nonspecific pattern(8.3%).

62.5%ofpatients hadperineural invasion.

Thepresenceofperineural invasioncanresultinahigh rateofrecurrence.

Chenetal. (USA,2006)7

Notmentioned. Notmentioned. 58.5%ofpatients hadperineural invasion.

Localrecurrencewasmore frequentinpatientswith perineuralinvasion. Minetal.

(China, 2012)9

75.3%ofthe patientshad primarytumor <3cmand24.6% hadtumor>3cm

Solid(38.63%); tubularor cribriform (61.36%).

52.2%ofpatients hadperineural invasion.

Thepresenceofperineural invasioncanresultinahigh rateofrecurrence.

Luksietal. (Croatia, 2013)10

Notmentioned. Notmentioned. 50%ofpatients hadperineural invasion.

Therewasnosignificant associationbetweenperineural invasionandtheprimarytumor sizeorpresenceofdistant metastases,buttherewasan associationwiththelocal tumorextent.

Tincanietal. (Brazil, 2006)11

Notmentioned. Cribriform (38.08%);tubular (38,08%);solid (23.8%).

42.8%ofpatients hadperineural invasion.

Thepresenceofperineural invasioniscloselyassociated withlocaltumorrecurrence.

Bianchietal. (Italy, 2008)12

Tumorsizevaried between1cmand 9cm.

Solid(46.2%); cribriform(46.2%); tubular(14.9%).

58.2%ofpatients hadperineural invasion.

Thepresenceofperineural invasionwasnotassociated withthepresenceof

metastasisorthesurvivalrate ofthestudypatients. Perezetal.

(Brazil, 2005)13

Minorgland tumorshadan averagesizeof 4.1cm,sublingual of3.8cm,and parotidof3.6cm.

Cribriform (54.2%);tubular (25.2%);solid (20.6%).

44.9%ofpatients hadperineural invasion.

Thepresenceofperineural invasionwasnotassociated withanegativeprognosis.

Khanetal. (USA,2001)14

Notmentioned. 51.4%ofpatients hadpredominantly solidtumor.

29.4%ofpatients hadperineural invasion.

Sinonasaltumorsaremore likelytoshowperineural invasionaswellastumorsof minorsalivaryglands.The presenceofpositivemargin wasalsoassociatedwith perineuralinvasion. Sungetal.

(Korea, 2003)15

Notmentioned. Cribriform (32.9%);tubular (20,2%);solid (11.7%).

30.8%ofpatients hadperineural invasion.

Perineuralinvasionwasnot associatedwiththepresence ofdistantmetastases.

totalof71patients(55%)withrecurrence.Minetal.9_does not mention the presence of recurrence. Overall survival rateswerevariablebetweenstudies.Inthestudyby DeAn-gelis etal.,3 _{overall survival rates at 5, 10,and 20 years} were,respectively,92%,72%,and54%.InthestudybyMin etal.,9_{thesurvivalratewascorrelatedwiththeoccurrence} ofmetastases,withanoverallfive-yearsurvivalinpatients withlymphnode metastasis of 48%,and in thosewithout lymphnodemetastasis,77%.InthestudybyLuksietal.,10

survivalrateswere62%atfiveyears,53%at10years,and 27%at15years.

Discussion

tumors were more frequently found among the female population,3,10---15 _{whereastwo studies showed the tumors} weremorefrequent in themalegender.7,9_{In spite ofthe} divergence,thescientificliteraturedemonstratesagreater susceptibilityinwomen.16

InthestudybyPerezetal.,13_{themostcommonclinical} signsandsymptomswerethepresenceofnodular enlarge-ment(92.1%), pain(59.8%),paresthesia (12.6%)andnasal congestion(11.8%).IntheanalysisbyBianchietal.,12 pri-marytumorsizevariedbetween1cmand9cm.Studieshave shownthattumors>3cmmayhaveahighmetastaticrate, apartfromotherfactorssuchasgender,age,andperineural invasion.17,18

Among the studies that evaluated histopathological types,the most frequent wasthe cribriformpattern, fol-lowedbytubularandsolidpatterns.3,9,11,13,15_Inthestudyby Khanetal.,14 _{therewasa predominanceof thesolid} pat-tern,whereasinthestudybyBianchietal.,12 _thenumber ofaffectedcasesshowingthecribriformandsolidpatterns weresimilar.

Thepalatewasthemostoftenaffectedsiteinthe major-ityofthe selectedstudies,which isconsistent withother studies.1,2,4 _{Only the study by Khan etal.}14 _{mentions the} oropharynxas the most often affected site. A study per-formed in 2007 shows that tumor location in the minor salivary glands may favor tumor recurrence and a worse prognosis.18

Allselectedstudiesanalyzedthepresenceofmetastases inpatients withACC. Inthestudy bySung etal.,15 _which assessedthe predictive factors and the impactof distant metastases in ACC in a total of 94 patients, 25 had dis-tantmetastases,whilethreehadregionalmetastasis.Other studies have shown similarresults, where the most com-monsites ofmetastasis werethelungs(80%),bone(15%), andliverandothersites(5%);thesemetastasesmayappear even20yearsafterprimarytumor resection,representing themajorcauseoftreatmentfailure.19,20_{However,among} theselectedstudies,thereweresimilaritiesbetweencases ofdistantandregionalmetastasis.11,13

RecurrenceisfrequentamongpatientswithACC.3,7,10---15 Tumor location in the minor salivary glands favors recur-renceandappearstobeassociatedwiththemoreadvanced casesandworseprognosis.18_{InthestudybyKhanetal.,}14₂₉ patientshadlocalrecurrenceandtheauthorassociatedthe presenceofperineural invasionwithincreasedrecurrence rates, as well as a higher incidence of positive margins, which is consistent with the other selected studies.3,7,9,11 Astudy conductedin1997found adecreasein recurrence ratesovertheyearsduetotheeffectsofradiotherapyuse, butwithnosignificantimpactondistantmetastasisrates.17 Pain and discomfort complaints are not unusual and are often attributed to tumor invasive behavior. Tumor cells tend to invade and disseminate peripherally to the nervefascicles. Perineuralinvasionis a common histolog-icalfinding, andis considered a possible route for tumor cell dissemination.5,18 _{In the study by Khan et al.,}14 per-ineuralinvasionwasassociatedwithhigherrecurrencerate andpositivesurgicalmargins;however,thestudybyPerez etal.13 _{did not show similar results. None of the studies} associatedthepresenceofperineuralinvasiontometastasis orsurvivalrate;however,studieshaveshownthatpatients withperineuralinvasionrequireradiotherapy.21,22

Themostcommonlyusedtreatmentmodalitywas surgi-cal,whetheror notfollowedbyradiotherapy.Inthestudy by deDeAngelisetal.,3 _{neckdissectionwasperformed in} five cases, whereasfor Khan et al.,14 _{this treatment was} used only in cases that showed some clinical or imaging signthatjustifieditsuse,consideringthelowrateofnodal metastaticinvolvement.Perezetal.13 _{alsoreportedcases} treatedwithassociatedchemotherapy;however,the impor-tanceofadjuvantchemotherapyaftersurgeryhasnotbeen systematicallyexplored.23

Thesurvivalratevariedamongthe selectedstudies. In thestudy byDeAngelis etal.,3_{overall survivalrates were} 92%atfiveyears,72%at10years,and54%in20years.In thestudybyLuksicetal.,14 _{survivalrateswere62%atfive} years,53%at10years,and27%at15years.ForMinetal.,9 lifeexpectancywasdirectlyassociatedwiththeoccurrence ofmetastasesandtheoverallfive-yearsurvivalofpatients withlymphnodemetastasiswas48%,whereasitwas77%in patientswithoutmetastasis.Perezetal.13 _{mentionedthat} the solidpattern hasa lowersurvival rate;the impactof the solidtumorsonsurvivalcan beexplained,inpart, by theirgreatermetastaticpotential.DeAngelisetal.3 demon-stratedthatpatientsurvivalratedecreasesconsiderablyin serieswithafollow-uplastingmorethan15years.

Conclusion

ACCisamalignantneoplasmofglandulartissuethathasa higherincidenceinfemalesandiscommonlycharacterized bythepresenceofpain,highrateofrecurrence, metasta-sis,andpoorsurvival.The presenceofperineuralinvasion wasnotassociatedwithmetastasisorsurvivalrate,butwas associatedwiththepresenceoflocalrecurrenceandmargin involvement,inadditiontoinfluencingappropriatepatient treatment.Studieswithlong-termfollow-upofpatientsto evaluate the clinical aspects of the tumor are extremely importantforbetterunderstandingofACC,aswellas bet-terclinical-pathologicalevaluation inordertoimproveits prognosis.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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