Clinicopathologic factors associated with recurrence in parotid carcinoma

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www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

ORIGINAL

ARTICLE

Clinicopathologic

factors

associated

with

recurrence

in

parotid

carcinoma

夽

Dong

Hoon

Lee

a_,b

_,

_Tae

_Mi

_Yoon

a_,b

_,

_Joon

_Kyoo

_Lee

a_,b_,_∗

_,

_Sang

_Chul

_Lim

a_,b

a_Chonnam_National_University,_Medical_School,_Department_of_{Otolaryngology-Head}_and_Neck_Surgery,_Hwasun,_South_Korea b_Chonnam_National_University,_Hwasun_Hospital,_Hwasun,_South_Korea

Received12January2017;accepted1August2017

Availableonline25August2017

KEYWORDS Parotidgland; Parotidcancer; Recurrence; Surgicalprocedures; Radiotherapy Abstract

Introduction:Parotidcarcinomashavevaryinghistologicaltypesanddiversebiologicbehaviors.

Establishinganadequatetreatmentplanandpredictingrecurrenceisimportant.

Objective: Toanalyzetheriskfactorsassociatedwithrecurrenceinour5yearexperiencewith

30casesofprimaryparotidcarcinomaundergoingsurgeryatasingleinstitute.

Methods:FromJanuary2009toDecember2013,30patientswithsurgicaltreatmentofparotid

carcinomawereidentiﬁedbasedontheirmedicalrecords.

Results:The30patientswerecomprisedof17malesand13females.Among11patientswithT4

tumors,sevenpatientshadrecurrence.Amongsevenpatientswithcervicalnodalmetastasis,

all patientexceptonehadrecurrence.Clinicallylate stages(stageIIIandIV)showedmore

commonrecurrencethanearlystage(stageIandII)lesions.Lymphovascularinvasionwasseen

in5patients,andallpatientshadrecurrence.Among11patientswithextracapsularspread,7

patientshadrecurrence.In17patientswithhighgradecarcinomas,tenpatientshadrecurrence.

In13patientswithlowgradecarcinomas,nopatientsexperiencedrecurrence.

Conclusion: T-andN-stage,clinicalstage,lymphovascularinvasion,extracapsularspread,and

histopathologicgradecorrelatesigniﬁcantlywithrecurrenceinparotidcarcinoma.

by Elsevier Editora Ltda. This is an open access article under the CC BY license (http://

creativecommons.org/licenses/by/4.0/).

夽 _Please_cite_this_article_as:_Lee_DH,_Yoon_TM,_Lee_JK,_Lim_SC._{Clinicopathologic}_factors_associated_with_recurrence_in_parotid_carcinoma.

BrazJOtorhinolaryngol.2018;84:691---6.

∗_{Corresponding}_author.

E-mail:joonkyoo@jnu.ac.kr(J.K.Lee).

PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.

https://doi.org/10.1016/j.bjorl.2017.08.003

1808-8694/©2017AssociaçãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

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PALAVRAS-CHAVE Glândulaparótida; Câncerdeparótida; Recorrência; Procedimentos cirúrgicos; Radioterapia

Fatoresclínico-patológicosassociadosàrecorrênciadecarcinomadeparótida

Resumo

Introduc¸ão:Os carcinomasdaparótida têm diferentes tiposhistológicos ecomportamentos

biológicosdiversos.Oestabelecimentodeumplanodetratamentoadequadoeaprevisãode

recorrênciasãomuitoimportantes.

Objetivo:Analisarosfatoresderiscoassociadosàrecorrênciaemnossaexperiênciadecinco

anos com 30 casos de carcinoma parotídeo primário submetidos a cirurgia em uma única

instituic¸ão.

Método: Dejaneirode2009adezembrode2013,30pacientescomtratamentocirúrgicode

carcinomaparotídeoforamidentiﬁcadoscombasenosprontuários.

Resultados: Entreos30 pacientes, 17 eram homens e13, mulheres.Dos11 pacientescom

tumoresT4,seteapresentaramrecorrência.Entresetepacientescommetástaseemlinfonodo

cervical,todos,excetoum,apresentaramrecorrência.Lesõesemestágiosclínicostardios(IIIe

IV)apresentaramrecorrênciamaiscomumentedoqueasdosestágiosiniciais(IeII).Ainvasão

linfovascularfoiobservadaemcincopacientesetodososcincoapresentaramrecorrência.Entre

11pacientescomdisseminac¸ãoextracapsular,seteapresentaramrecorrência.Dos17pacientes

comcarcinomasdealtograu,dezapresentaramrecorrência.Em13pacientescomcarcinomas

debaixograu,nenhumapresentourecorrência.

Conclusão:EstágiosTeN,estágioclínico,invasãolinfovascular,disseminac¸ãoextracapsulare

grauhistopatológicocorrelacionam-sedemaneirasigniﬁcantecomrecorrênciadocarcinoma

deparótida.

por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http://

creativecommons.org/licenses/by/4.0/).

Introduction

Parotid carcinoma is an uncommon malignancy and con-stitutes 1%---3% of all head and neck cancers.1---5 _Parotid

carcinomashavevaryinghistologicaltypesanddiverse bio-logicbehaviors.1---5_Treatment_of_parotid_carcinoma_remains

challengingbecauseofitsrelativerarity,unpredictable bio-logicalbehavior,andriskofrecurrence.1,2,5,6

Therefore,establishinganadequatetreatmentplanand predictingrecurrenceis important.5 _In_general, _surgery_is

the treatment of choice for all parotid tumors and post-operative radiotherapy (RT) is applied as supplementary treatment.2,4---6 _However, _there _have _been _few _published

reportsaboutpredictingrecurrence.5 _The_{identiﬁcation}_of

factors associated with recurrence is of paramount rele-vancefortreatmentofparotidcarcinomas.

Theaimofthisstudywastoanalyzeriskfactors associ-atedwithrecurrenceinour5yearexperiencewith30cases ofprimaryparotidcarcinomaundergoingsurgeryatasingle institute.

Methods

AfterobtainingapprovalfromtheInstitutionalReviewBoard ofour Hospital(CNUHH-2016-134), aretrospective review was performed to evaluate patients with surgical treat-ment of parotid carcinoma at the hospital’s Department of Otolaryngology-Head and Neck Surgery from January 2009toDecember2013.Thirtypatientswithsurgical treat-mentof parotidcarcinomawere identiﬁedbasedontheir medicalrecords.Clinicopathologicdataofparotid carcino-maswerereviewedincludingage,sex,symptoms,duration of symptoms, lymph node status, ﬁne-needle aspiration

cytology(FNAC),overallstage,histopathologicresults, sur-gicalproceduresandcomplications.The2010versionofthe TNM staging system of the AmericanJoint Committee on Cancerwasusedforclinicalstaging.7

All patients had computed tomography (CT) scanning performed before surgery to assess the extent of the lesionsandtoaidintreatmentplanning.Positronemission tomography-CT(PET-CT)wasperformed forthosepatients withmalignancy by FNAC.Allpatients except two under-wentFNAC.

The type and extent of surgery performed depended onthepre-operativediagnosis,primarysite,andsurgeon’s clinical judgment.Allpatientsunderwent macroscopically complete oncologic resection. Superficial parotidectomy was performed if a small carcinoma was located in the superficiallobe.Totalparotidectomywasperformedifthe carcinoma was in the deep lobe or in a tumor diagnosed as malignant by FNAC. Radical parotidectomy, involving removalofallparotidtissueaswellassacrificeofthefacial nerve,wasperformedifthefacialnervewasinvadedby car-cinomaorifpreoperativefacialnervefunctionwasimpaired inthepresence ofmalignantdisease.Neckdissectionwas performed if enlarged neck lymph nodes were found by preoperativeevaluation,suchasFNACandradiologic exam-ination.

Postoperativemanagement, suchasRT andconcurrent chemoradiotherapy(CCRT),weredependentontumorstage andhistologicalgrade.Postoperativeradiationtherapyhad been performed for patients with lymph node metasta-sis, high grade carcinoma, positive surgical margin, and high clinical stage. Drainage was performed and main-tained by aspiration. Allcases of parotidcarcinoma were conﬁrmedhistopathologically.Thecomplicationof postop-erativefacialpalsywasevaluatedbyHouseBrackmangrade.

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Intraoperative facialnervemonitoring wastypicallyused. The overallsurvival periodwasdeterminedfromthedate ofsurgerytothedateofdeathorthedateofthelastvisit. SPSS version 20.0 software was used to conduct sta-tistical analyses. Fisher’s exact test was used to analyze the association between recurrence/surgical margin and clinicopathological parameters.Survival rates were calcu-latedusingtheKaplan---Meiermethodwiththelog-ranktest. Multivariate analysis to survival was conducted using Cox proportional hazards regression model. Statistical signiﬁ-cancewasdeﬁnedasap-value<0.05.

Results

Thisgroupof30patientsincluded17(56.7%)malesand13 (43.3%)females.Theageofthepatientsrangedbetween23 and83yearswithameanof62.6±14.1years.Allpatients except2(28/30,93.3%)presentedwithaslowlyenlarging masswithintheparotidgland.Theremainingtwopatients wereincidentallydiagnosedbyPET-CT.Ofthe30lesions,13 parotidcarcinomas(43.3%)werelocatedintherightparotid glandand17parotidcarcinomas(56.7%)intheleftparotid gland.Themajorityofthelesionswereasymptomatic.The duration of symptoms ranged from 1---120 months with a meanof12.2±22.7months.

Thirteen patients (43.3%) were classiﬁed ashaving T1 tumors,5patients(16.7%)hadT2tumors,1patient(3.3%) hadT3tumors,and11patients(36.7%)hadT4tumors.Seven cases(23.3%)hadlymphnodemetastasis, andnopatients haddistantmetastasis.Theclinicalstagingshowedthat12 patients(40.0%)wereclassiﬁedasstageI,4patients(13.3%) as stage II, 1 patient (3.3%) as stage III, and 13 patients (43.3%)asstageIV.

The most common surgical procedure was superﬁcial parotidectomy(n=13,43.3%).Followedbytotal parotidec-tomy (n=12, 40.0%) and radical parotidectomy (n=5, 16.7%).Neckdissectionwasperformedin15patients(50%). Eleven patients had salivary ductal carcinoma, fol-lowed by mucoepidermoid carcinoma (n=7), squamous cellcarcinoma(n=3),carcinomaexpleomorphicadenoma (n=2), acinic cell carcinoma (n=2), adenoid cystic car-cinoma (n=2), epithelial-myoepithelial carcinoma (n=1), lymphoepithelial carcinoma(n=1), andpolymorphouslow gradeadenocarcinoma(n=1).Fourteenpatientsunderwent postoperativeRT.Sevenpatients underwentpostoperative CCRT.

Among 28 patients who underwent FNAC, 15 patients werediagnosedwithparotidcarcinoma,buttheremaining 13patientswerefailedinpreoperativediagnosis.FNAChad a diagnostic sensitivity of 53.6%, diagnostic speciﬁcity of 0%, positive-predictive value of 100%, negative-predictive value of 0% and accuracy of 53.6% for diagnosing benign parotid tumors. No speciﬁc complications were observed afterFNAC.

In histopathologic results, surgical marginswere nega-tivein16(53.3%),positivein4(13.3%),andclose(<5mm) in 10patients (33.3%) (Table1). Perineuralinvasion, lym-phovascularinvasion,andextracapsularspreadwereseenin 7,5,and11patients,respectively.Histopathologicgrading revealedthat13patients(43.3%)wereclassiﬁedashaving low gradecarcinoma, nopatientshad intermediategrade

Table1 Summary ofclinicopathologicfactorsassociated

withsurgicalmargin.

Factors Surgicalmargin p-value

Negative (n=16) Closeorpositive (n=14) Tstage 0.257 T1,T2,T3 12 7 T4 4 7 Nstage 0.675 N0 13 10 N1,N2 3 4 Stage 0.141 I,II 11 5 III,IV 5 9 Lymphovascularinvasion 0.157 Negative 15 10 Positive 1 4 Extracapsularspread 0.007 Negative 14 5 Positive 2 9 Histologicgrade 0.484 Lowgrade 8 5 Highgrade 8 9 Recurrence 0.122 No 13 7 Yes 3 7

Table2 Summary ofclinicopathologicfactorsassociated

withrecurrence.

Factors Recurrence p-value

Yes(n=10) No(n=20) Tstage 0.042 T1,T2,T3 3 16 T4 7 4 Nstage 0.001 N0 4 19 N1,N2 6 1 Stage 0.004 I,II 1 15 III,IV 9 5 Lymphovascularinvasion 0.019 Negative 5 20 Positive 5 0 Extracapsularspread 0.042 Negative 3 16 Positive 7 4 Chemoradiation 0.013 Yes 10 11 No 0 9 Histologicgrade 0.003 Lowgrade 0 13 Highgrade 10 7

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Negative ECS Group

Positive ECS Group

Negative Margin Group

close or Positive Margin Group

High Grade Cancer Group Positive LVI Group Negative LVI Group

Stage II,IV Group Stage I,I Group T4 Group

No Group

N1,N2 Group T1,T2,T3, Group

Low Grade Cancer Group 1.0 0.8 0.4 0.6 0.6 0.2 0.0 1.0 0.8 0.4 0.6 0.2 0.0 1.0 0.8 0.4 0.6 0.2 0.0 1.0 0.8 0.4 0.6 0.2 0.0 1.0 0.8 0.4 0.6 0.2 0.0 1.0 0.8 0.4 0.6 0.2 0.0 1.0 0.8 0.4 0.2 0.0 0 12 24 38 48 60 0 12 24 38 48 60 0 12 24 38 48 60 0 12 24 38 48 60 0 12 24 38 48 60 0 12 24 38 48 60 0 12 24 38 48 60 Overall Survival Overall Survival Overall Survival Overall Survival Overall Survival O verall Survival O verall Survival Months Months Months Months Months Months Months

A

B

C

D

E

G

F

Figure1 Comparisonofsurvivalaccordingtoclinicopathologicfactors.(A)T-stage(p=0.097);(B)N-stage(p=0.001);(C)clinical stage(p=0.011),(D)lymphovascularinvasion(p=0.002);(E)extracapsularspread(p=0.078);(F)histopathologicgrade(p=0.049); (G)surgicalmargin(p=0.313).

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Table3 Coxmultivariateregressionoftheassociationwith survival.

Covariate p-value Hazard

ratio 95%Conﬁdence interval Lower Upper Age 0.784 0.988 0.903 1.080 Tstage 0.626 0.495 0.029 8.362 Nstage 0.045 9.462 1.052 85.093 Extracapsular spread 0.367 4.334 0.179 105.162 Surgicalmargin 0.973 0.971 0.175 5.377

Table4 Logisticregressionoftheassociationwithsurvival.

Covariate p-value Exp(B) 95%Conﬁdence

interval Lower Upper Age 0.576 1.042 0.902 1.203 Tstage 0.675 1.949 0.087 43.888 Nstage 0.050 24.597 0.993 609.112 Extracapsular spread 0.470 4.722 0.070 318.258

carcinoma, and 17 patients (56.7%) hadhigh grade carci-noma.

Nine(30.0%)patientshadfacialnervepalsy.Fourofthese patientspresentedwithspontaneousimprovementwithin3 monthsofsurgery.Theremaining5patientshadcomplete facialnervepalsy(HouseBrackmanGradeVI),becauseinall patientsthefacialnervewasdeliberatelysacriﬁceddueto itsinvolvementwiththemalignanttumor.

Ten patients(33.3%) experiencedrecurrence(Table 2). Sitesofrecurrencewerelocalin6patientsanddistantin7 patients.Threepatientshadbothlocalanddistant metas-tases.The sites ofdistantmetastasis werelung and liver. Amongsurvivingpatients,onepatientwasalivewith recur-rentcarcinomaintheabsenceofanyothertreatmentatthe lastfollow-up.

The mean follow period after surgery was 56.7±16.0 monthswitharangeof29---86months.The2,3and5year overallsurvivalratewere80%,71%,and71%,respectively. AccordingtoKaplan---Meiermethod,N-stage,clinicalstage, lymphovascular invasion,histopathologic grade correlated signiﬁcantlywithsurvivalinparotidcarcinoma (Fig.1). In theCoxmultivariate regressionanalysis,onlyN-stage was associatedwithsurvivalinthisstudy(Tables3and4). There-fore,N-stagewasthemostsigniﬁcantfactorinpatientswith parotidcarcinoma.

Discussion

Previous studies have suggested several clinical and his-tological factors associated with recurrence of parotid carcinoma, such as TNM staging system, clinical stage, perineural or lymphovascular invasion, extracapsu-lar spread, positive surgical margin, and histological grade.1,4,5,8---12 _In _this_study,_T- _and_N-stage, _clinical _stage,

lymphovascularinvasion,extracapsularspread, histopatho-logic grade were found to be factors associated with recurrence(Table2).

Among11patientswithT4tumors,sevenpatients expe-rienced recurrence. Among 19 patients with T1, T2, and T3 tumors, only 3 patients had recurrence. T4 tumors experienced more recurrence than other T stage tumors (p<0.05). Among 7 patients with cervical nodal metas-tasis (N1, N2), all patients except one had recurrence. Therewasasigniﬁcant differencebetweencervical nodal metastasisandrecurrenceofparotidcarcinoma(p<0.05). In clinical staging, late stages (stage III and IV) showed morerecurrencemorefrequentlythanearly stages(stage I and II) lesions (p<0.05). In this study, T4 tumors, cer-vicallymphnode metastasis, andhigh clinical stagewere prognostic factors related to the recurrence of parotid carcinoma.

Inthisstudy,extracapsularspreadwasfoundtobefactors associatedwithsurgicalmargin(Table1).Inthe histopatho-logic results, lymphovascular invasion were seen in 5 patients,andallpatientshadrecurrence.Among11patients withextracapsularspread,sevenpatientshadrecurrence. Among 19 patients without extracapsular spread, only 3 patientshadrecurrence.In17patientswithhighgrade car-cinomas,10 patients had recurrence.In 13 patients with lowgradecarcinomas,nopatientsexperiencedrecurrence. Inthisstudy,thepresenceoflymphovascular invasionand extracapsular spread, as well as high grade carcinomas wereprognosticfactorsrelatedtotherecurrenceofparotid carcinoma.In particular, all5 patientswith lymphovascu-lar invasion had distant metastasis. Among 5 patients, 2 patientshadbothlocalanddistantmetastases.Inaddition, therewasnorecurrenceoflowgradeparotidcarcinomain thisstudy(Tables3and4).

Parotid carcinoma usually requires a combination of treatment modalities.1,6---13 _Surgical _resection _followed _by

RT or CCRT improves loco-regional control and overall survival.3,6,13 _Our _indications _of _{postoperative} _RT _include

positiveorclosemargins,highgradecarcinomas,perineural orlymphovascularinvasion,andcervicallymphnode metas-tasis.Ofourpatientswithlowgradecarcinomas(n=13),4 patientshadbeenwellwithoutrecurrentcombined modal-ity treatment with surgery followed by postoperative RT becauseof close surgical margins. In high grade carcino-mas(n=17),tenpatientshadsurgeryandpostoperativeRT, and7patientsunderwentsurgeryandpostoperativeCCRT. Simultaneousneck dissection is recommended when neck metastasis is clinically detected or when a histologically high grade malignancy, high stage, facial palsy or extra-parotidinvasionarediagnosed.4_In_our_sample,_radical_neck

dissectionwasperformed in seven cases ofparotid carci-nomas withcervical lymphnode metastasis, and elective neckdissectionwasperformedineightN0parotidcarcinoma patients.

In this study, signiﬁcant factors associated with recur-rence were T- and N-stage, clinical stage, lymphovas-cular invasion, extracapsular spread, and histopathologic grade. Whereas, extracapsular spread was found to be factors associated with surgical margin. However, the limiting factors of this study are the small sample size and retrospective review. Further studies involving molecular markers are necessary to provide a better

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understandingofthebiologicalmechanismsofparotid car-cinomarecurrence.

Conclusion

T- and N-stage, clinical stage, lymphovascular invasion, extracapsularspread, and histopathologicgrade correlate signiﬁcantlywithrecurrenceinparotidcarcinoma. Among them,N-stagewasthemostsigniﬁcantfactorinthisstudy. High risk patients require aggressive initial surgery with postoperativeRTandregularlong-termfollow-up.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

Acknowledgements

This study wassupported by a grant (HCRI 15004-1) from CNUHHInstituteforBiomedicalScience.Theauthorswould liketothankDr.KweonSS(ChonnamNationalUniversity)for thestatisticalevaluation.

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