Can radical surgical treatment of the vulva be justified in the absence of a conclusive diagnosis of squamous cell carcinoma on biopsy? A retrospective 10-year cohort study

Full

length

article

Can

radical

surgical

treatment

of

the

vulva

be

justi

fied

in

the

absence

of

a

conclusive

diagnosis

of

squamous

cell

carcinoma

on

biopsy?

A

retrospective

10-year

cohort

study

Lysanne

W.

Jonker

*

,

Shatavisha

Dasgupta

,

Patricia

C.

Ewing-Graham

,

Helena

C.

van

Doorn

a

DepartmentofGynecologicOncology,ErasmusMCCancerInstitute,Rotterdam,theNetherlands

b

DepartmentofPathology,ErasmusMC,UniversityMedicalCentreRotterdam,theNetherlands

ARTICLE INFO

Articlehistory:

Received20December2019

Receivedinrevisedform9March2020 Accepted15March2020

Availableonlinexxx

Keywords: Vulva

Vulvarneoplasms Squamouscellcarcinoma Gynecologicsurgicalprocedures Vulvectomy

ABSTRACT

Objectives: The extent of surgical treatment for vulvar lesions is predominantly guided by the

histopathologicdiagnosisrenderedonthepre-operativebiopsy.Forpremalignantlesions,localexcisions

are performed, whereas forvulvar squamous cellcarcinoma (VSCC), moreradical procedures are

mandatory.However,evenintheabsenceofaconclusivediagnosisofVSCConbiopsy,thesurgeonmay

optforaradicalexcisionongroundsofstrongclinicalsuspicion,withaviewtoavoidingrepeatsurgeries.

Westudiedaretrospective,10-yearcohortofpatientswhounderwentvulvarexcisions,intheabsenceof

aconclusivebiopsydiagnosisofVSCC.WeaimedtoidentifythefactorspredictiveofVSCCinthese

patients,andassesstheirtreatment.

Study design:All patientswho underwentvulvar excision(2005–2016) atErasmus MC,without a

definitivediagnosisofVSCConthepreoperativebiopsywereincluded.Logisticregressionanalysiswas

performed toidentify the factors predictiveof a final diagnosis of VSCC. Surgical treatmentwas

categorized as definitive, incomplete,or over-treatment, based on histopathology of the excision

specimenandprevioussurgicalhistory.

Results:In57%(64/113)ofallincludedpatients,thefinaldiagnosiswasVSCC.Higherpatientage(p=

0.03),andsuspicionofVSCConpre-operativebiopsy(p<0.001)wereassociatedwithafinaldiagnosisof

VSCConunivariateanalysis.SuspicionofVSCConbiopsywastheonlysignificantpredictor(p<0.001)on

multivariableanalysis.ForpatientswithasuspicionofVSCConbiopsy,radicaltreatmentwasmore

frequentlyperformed(p<0.001),whichresultedinover-treatmentinonly1case.Wherethesurgeon

hadperformedalimitedexcisiondespiteasuspicionofVSCConbiopsy,highpatientage,co-morbidities,

locationofthetumorclosetotheanus,andhistoryofpreviousvulvarsurgerieswerefactorswhich

influencedthedecision.Thetreatmentadministeredwasdefinitivefor72%.,i.e.additionalsurgeries

werenotrequired;25%receivedincompletetreatmentandneededadditionalsurgeries,and3%received

over-treatment.

Conclusion:SuspicionofVSCConbiopsyisstronglypredictiveofafinaldiagnosisofcarcinoma.Inour

cohort,radicaltreatmentperformedonpatientswithclinicalandhistopathologicalsuspicionofVSCC

resultedinminimalover-treatment,andhelpedavoidsecondsurgeries.

©2020ElsevierB.V.Allrightsreserved.

Introduction

Vulvarlesionsclinicallysuspectedtobevulvarsquamouscell carcinoma(VSCC),oritsprecursor,vulvarintraepithelialneoplasia (VIN),arebiopsiedbythesurgeon,andthesubsequent manage-mentofthepatientisguidedbythehistopathologicdiagnosison thebiopsy. For VIN,patientsreceivetopical treatment,ablative therapy,orlimitedlocalexcision[1–5].ForVSCC,moreextensive excisionsareperformed,ifnecessaryincombinationwithgroin *Correspondingauthorat:DepartmentofRadiationOncology,AmsterdamUMC,

Vrije Universiteit Amsterdam, de Boelelaan 1117, 1081HV, Amsterdam, the Netherlands.

E-mailaddresses:l.jonker1@amsterdamumc.nl(L.W. Jonker), s.dasgupta@erasmusmc.nl(S.Dasgupta),p.ewing@erasmusmc.nl (P.C. Ewing-Graham),h.vandoorn@erasmusmc.nl(H.C. vanDoorn).

1

Theseauthorscontributedequallytothearticle,andsharefirstauthorship. https://doi.org/10.1016/j.ejogrb.2020.03.027

0301-2115/©2020ElsevierB.V.Allrightsreserved.

ContentslistsavailableatScienceDirect

European

Journal

of

Obstetrics

&

Gynecology

and

Reproductive

Biology

treatment, i.e. sentinel lymph node (SLN) procedure, or groin lymphnodedissection(LND)[6,7].

Thediagnosis of VSCCmay howeverbe missedonthe pre-operative biopsy in 8–22% of cases [8–11].This is often due to samplingerror,orinsomecases,duetoimproperorientationor sectioning of the biopsy specimen, which hinder adequate histopathologic assessment. When VSCC is not conclusively diagnosedonthepre-operativebiopsy,buttheclinicalsuspicion is sufficiently high,the surgeon mayopt toperform a radical excision,withorwithoutgroin treatment.Quiteofteninthese cases, VSCC is diagnosed in the excision specimen, and the surgeon manages tospare thepatient a repeat surgery in the anatomically complex vulvar region. However, if the excision specimendoes notshow VSCC,it impliesthat thepatient was over-treated.Forthesecases,aninsightintothespecificfeatures that may predict the presence of VSCC could improve clinical decision-making.

Thisexploratorystudywasthereforeconductedonacohortof patientswho underwentsurgicaltreatmentof thevulva,in the absenceofaconclusivediagnosisofVSCConpre-operativebiopsy. The aims were to identify the factors that might predict the presenceofVSCC,andtoassessthesurgicaltreatmentsperformed. Materialsandmethods

Thisretrospective,single-center,cohort-studywasconducted atErasmusMCCancerInstitute,whichisatertiaryreferralcenter forgynecologicmalignancies. Approvalof theMedicalResearch EthicsCommitteewasobtained(MEC2017-134).

Patientpopulation

Allpatientswhounderwentvulvarsurgicalexcisionsbetween January1, 2005, and January 1, 2016were identified from the records of the Department of Gynecologic Oncology. Of these, patientswhodidnothaveaconclusivediagnosisofVSCContheir pre-operative biopsy(ies) were included. All patient data were anonymized.

Ifthepatientunderwentvulvarbiopsyfollowedbyanexcision morethanonce,onlythefirstepisodewasanalyzed.Patientswith vulvarmalignanciesotherthanconventionalVSCC,e.g.verrucous carcinoma, basal cell carcinoma, adenocarcinoma, sarcoma, or melanoma,wereexcluded.

Dataretrieval

Clinicaldatasuchasage,diameterandfocalityofthelesionas noted during clinical examination, history of previous vulvar lesions, treatment details of previous, current, and subsequent episodes, and follow-up, were collected from patient records. Remarksonthetreatmentrationale,whereavailable, werealso recorded.

Pathologydata were extractedfrom thereports of the pre-operativebiopsyandthepost-operativeexcisionspecimens.For VIN,thehistopathologictype,i.e.differentiatedVIN(dVIN),orhigh grade squamous intraepithelial lesion (HSIL) was recorded. For VSCC,tumorsize,depthofinvasion,focality,differentiationgrade, andpresenceofperineuralorlymphovascularspaceinvasionwere recorded.StatusofSLNorLNDspecimenswasnotedaspositiveor negativeformetastasis.Slidesfromallexternalreferralcaseshad been reviewed by the departmental pathologists before the surgicalprocedure.Allcaseswheretheslideswerestillavailable inthedepartmentalarchivewerereviewedbytwopathologists (SDGandPEG)forthepurposeofthisstudy.PEGisanexperienced gynecologicpathologist.

Categorizationofsurgicaltreatments

Thesurgicalprocedureswerecategorizedas: Localtreatment

Widelocalexcision(WLE),orradicalvulvectomy(RV). Theaimwastoexcisewithamarginof5mmforVIN,and10 mmforVSCC,butthiswasnotalwaysachievable.

Grointreatment

SLNprocedure,orfullgroinLND. Radicaltreatment

Treatmentofbothvulvaandgroin(s),i.e.WLEorRV,withgroin treatment.

Foreachpatient,thetreatmentwascategorizedasdefinitive, incomplete, or over-treatment, based on the histopathologic diagnosisofthepost-operativespecimen,andtakingintoaccount theprevioushistoryofvulvarsurgery,aselaboratedbelow. Definitivetreatment

The surgical procedure was deemed sufficient, and no additionalprocedureswererequired,e.g.WLEforVIN,orradical treatment for primary VSCC. For recurrent VSCC, where groin treatment had been conducted previously, WLE withadequate marginswasconsidereddefinitive.

Incompletetreatment

Thesurgicalprocedurewasdeemedinsufficient,andadditional procedureswererequired,e.g.whereWLEhadbeenperformed, andVSCCstageT1bwasdiagnosedinthepost-operativeexcision specimen;thismeantasubsequentSLNprocedurewasneeded. Over-treatment

Thesurgicaltreatmentwasdeemedtobeinexcessofwhatwas necessary,e.g.whereradicaltreatmenthadbeenperformed,and thepost-operativeexcisionspecimendidnotshowVSCC. Statisticalanalyses

Data were analyzed using SPSS Statistics 25 (IBM Corp., Armonk, NY, USA). Descriptive statistic was used for patient characteristics.Independentsample’st-testwasusedfor continu-ousdata,and Chi-squared(χ2

)test forcategoricaldata.Logistic regressionanalysiswas performedtostudytheeffectofseveral variablesonthefinaldiagnosisofVSCC,whichwasconsideredasa dichotomousoutcome(presentorabsent).Subgroupanalysis of patients withor withouta suspicionof VSCC onpre-operative biopsy was also conducted. Two-sided p-value < 0.05 was consideredsignificant.

Results

Of1245patientswhounderwentvulvarexcisions,113metthe inclusioncriteria.

Characteristicsofallincludedpatients

Thepatientshadameanageof65.3years(range24–91years). Themedianlesionaldiameterwas21.5mm,andthelesionwas unifocalin77%(87/113)ofpatients[Table1].

SuspicionofVSCCwaspresentonthepre-operativebiopsyin 49%(55/113)ofpatients[Table1].Localtreatmentwasperformed for 75 % (85/113), and radical treatment for 25 % (28/113) of patients.Thefinaldiagnosisonpost-operativehistopathologywas VSCCfor57%(64/113),dVINfor13%(15/113),HSILfor29%(33/

113),andlichenoidchangesfor1%(1/113)ofpatients.Pathology detailsoftheVSCCsarepresentedinTable2.

Thesurgicalprocedureperformedwasdefinitivefor72%(81/ 113),incompletefor25%(28/113),andover-treatmentfor3%(4/ 113)ofpatients.Thedistributionofpatientsbasedontheir pre-operative biopsies, and subsequent treatment is illustrated in

Fig.1.

ComparisonofpatientswithafinaldiagnosisofVSCC(n=64),and withoutafinaldiagnosisofVSCC(n=49)

Onunivariateanalysis,meanagewassignificantlyhigher(p= 0.03), and suspicion of VSCC on the pre-operative biopsy was significantlymorefrequent(p<0.001)forpatientswithVSCC.No otherstatisticallysignificant differencewas found[Table 1]. On multivariableanalysis,onlysuspicionofVSCCinthepre-operative

biopsyremainedasignificantpredictorofafinaldiagnosisofVSCC (p<0.001)[SupplementaryTableS1].

FortypatientswithVSCChadreceivedlocaltreatment,anda secondsurgerywasrequiredfor25ofthesepatients.Twenty-four patientswithVSCChad received radicaltreatment, and second surgerywasrequiredfor3ofthesepatients[Fig.1].Thus,56%(36/ 64)ofpatientswithVSCChadreceiveddefinitivetreatment,and44 %(28/64)hadreceivedincompletetreatment.Additionalsurgeries performedforVSCCpatientswithincompletetreatmentincluded localtreatment (WLE) in 6 cases,radicaltreatmentin 11 cases (WLEwithSLNprocedurein8cases,andWLEwithLNDin3cases), andgrointreatmentin11cases(SLNprocedurein8casesandLND in3cases)[Fig.1].

Forty-fivepatientswithoutVSCChadreceivedlocaltreatment, which was the definitive treatment, and 4 had received radical treatment(WLEwithSLNprocedure),whichwasanover-treatment Table1

Patientcharacteristics.

All(n=113) WithVSCC(n=64) WithoutVSCC(n=49) p-value* I.Age(inyears)

Mean(95%ConfidenceInterval) 65.3(62.3–68) 67.9(64.8–71.2) 61.2(57.1–66.4) 0.03

Range 24–91 32–88 24–91

Numberofpatients(percentage) II.Historyofvulvarlesions

None 65(58) 39(61) 26(53) 0.60

Lichenoidlesions 9(8) 6(9) 3(6)

VIN 17(15) 9(14) 8(16)

VSCC 22(19) 10(16) 12(25)

III.Previousgrointreatment 19(17) 9(14) 10(20) 0.37

IV.Previousradiotherapy 6(5) 5(7) 1(2) 0.18

V.Preoperativeclinicalexamination A.Diameterofthelesions

Median(Range)inmm 21.5(3–70) 25(3–65) 20(3–70) 0.75 <20mm 41(36) 25(39) 16(33) 20mm 71(63) 38(59) 33(67) 0.51 Unknown 1(1) 1(2) 0(0) B.Focality Unifocal 87(77) 49(77) 38(78) 1.00 Multifocal 26(23) 15(23) 11(22)

VI.Preoperativehistopathology <0.001

NosuspicionofVSCC 58(51) 19(30) 39(80)

SuspicionofVSCC 55(49) 45(70) 10(20)

VII.Surgicalprocedure <0.001

A.Localtreatment

WLE 85(75) 40(63) 45(92)

B.Radicaltreatment

WLE+SLNprocedure 19(17) 15(23) 4(8)

WLE+LND 9(8) 9(14) 0(0)

VIII.Treatmentcategorization <0.01

Definitive 81(72) 36(56) 45(92)

Incompletetreatment 28(25) 28(44) 0(0)

Over-treatment 4(3) 0(0) 4(8)

IX.Additionaltreatment 0.0001

None 82(73) 33(52) 49(100)

Localtreatment(WLE) 6(5) 6(9) 0(0)

Radicaltreatment(WLE+grointreatment) 11(10) 11(17) 0(0)

Grointreatmentonly 11(10) 11(17) 0(0)

Radiotherapy 3(2) 3(5) 0(0)

X.Followup Medianfollow-upduration:24months

Noevidenceofdisease 90(80) 48(75) 42(86) Death Relatedtodisease 3(2) 3(5) 0(0) Unrelatedtodisease 4(3) 3(5) 1(2) Recurrenceofdisease VIN 7(7) 3(5) 4(8) VSCC 3(2) 2(3) 1(2)

Underpalliativecare 5(5) 5(7) 0(0)

Nofollowup 1(1) 0(0) 1(2)

VIN:vulvarintraepithelialneoplasia,VSCC:vulvarsquamouscellcarcinoma,WLE:widelocalexcision,SLN:sentinellymphnode,LND:lymphnodedissection.

*

[Fig.1].For3ofthesepatients,the_finaldiagnosisonpost-operative histopathologywasVIN,andfor1patient,thiswaslichenoidchanges. Thus,treatmentadministeredwasdefinitivefor92%(45/49),and over-treatmentfor8%(4/49)ofpatientswithoutVSCC.

ComparisonofpatientswithasuspicionofVSCC(n=55),andwithout asuspicionofVSCC(n=58)inpre-operativebiopsy

SuspicionofVSCCwaspresentinthepre-operativebiopsyin 49 %(55/113) of all included patients. Radical treatment had beenperformedfor40%(22/55)ofpatientswithasuspicionof VSCC,comparedto10%(6/58)ofpatientswithoutasuspicionof VSCC(p<0.001)[Table3].Radicaltreatmentonpatientswitha suspicion of VSCC resulted in over-treatment in only 1 case [Fig.1].

ThefinaldiagnosiswasVSCCin82%(45/55)ofpatientswitha suspicion,comparedto33%(19/58)ofpatientswithoutasuspicion ofVSCConbiopsy(p<0.001).SuspicionofVSCChadapositive predictivevalue(PPV)of82%,sensitivityof70%,andspecificityof 80%forafinaldiagnosisofVSCC.

Treatmentrationale

Treatmentrationalewasnotclearlydocumentedforeverycase, hence statistical analyses could not beperformed. Information couldberetrievedforthepatientswithasuspicionofVSCC(n=55) onbiopsy.

Radicaltreatmentwasadministeredto22patients;WLEwith SLNprocedurefor14patients,andWLEwithLNDfor8patients. Radical treatmentwas chosenonthegroundsofstrong clinical suspicion,basedontheclinicalfeatures.Thisresultedindefinitive treatmentof19patients,incompletetreatmentof2patients,and over-treatmentof1patient.

Table2

PathologydetailsofVSCCcases(n=64).

Tumorcharacteristics Numberofpatients (percentage) I.Depthofinvasion <1mm 8(13) >1mm 49(77) Unknown 7(10) II.Focality Unifocal 54(84) Multifocal 10(16)

III.Differentiationgrade

Well 25(39)

Moderate 33(52)

Poor 6(9)

IV.Perineuralinvasion

Present 3(5)

Absent 61(95)

V.Lymphovascularspaceinvasion

Present 2(3)

Suspicion 7(11)

Absent 55(86)

VI.Pathologyofthegroinlymphnode(n= 24)

Positive 5(21)

Negative 19(79)

Fig.1.Distributionofpatientsaccordingtotheirpre-operativebiopsyfindings,andtreatmentsreceived(VIN:vulvarintraepithelialneoplasia,VSCC:vulvarsquamouscell carcinoma,boxesinredindicatethecaseswheretherewasanover-treatment)(Forinterpretationofthereferencestocolourinthisfigurelegend,thereaderisreferredtothe webversionofthisarticle).

Localtreatment(WLE)hadbeenperformedfor33patients.For7 patientstheVSCCwasrecurrent;apreviousSLNhadbeen performed for1patient,andLNDfor2patients.Otherfactorsthatin_fluencedthe choiceto abstain fromgrointreatmentwere co-morbidity,high patientage,lowclinicalsuspicionofVSCC,andsuspicionofonly super_ficialVSCC,oraverrucouscarcinoma.For3patients,WLEwas chosen because of the proximity of the tumor to the anus, to minimizetheriskof sphincterinjury. Thisresultedindefinitive treatmentof20patients,andincompletetreatmentof13patients.

Discussion

VSCCwasdiagnosedintheexcisionspecimenin57%ofpatients whounderwent vulvarexcisions intheabsenceofa conclusive diagnosisofcarcinomaonpre-operativebiopsy.Afinaldiagnosisof

VSCCappearedtobesignificantlyassociatedwithhigherage(p= 0.03),andsuspicionofVSCConpre-operativebiopsy(p<0.001), on univariate analysis. However, on multivariable analysis, suspicion ofVSCC remainedtheonly significant predictor(p < 0.001).

ForpatientswithasuspicionofVSCConbiopsy(n=55),radical treatmenthadbeenperformedmorefrequently,incomparisonto patientswithoutasuspicionofVSCC(40%vs.10%;p<0.001). DespitethelackofaconclusivediagnosisofVSCC,suspicionofthe pathologist probably enabled the surgeon to perform radical treatmentmorefrequentlyinthesepatients.Wheretherewasboth clinical and histopathologicsuspicion of VSCC(n =22), radical treatment(WLEwithSLNprocedure)resultedinover-treatmentin only 1 case [Fig.1]. For this patient, the final histopathology showedscartissuewithlichenoidchanges;thiscasemayhavehad asmallfocusofinvasion,whichwasremovedatbiopsy.Wherethe Table3

CharacteristicsofpatientswithandwithoutasuspicionofVSCConpre-operativebiopsy.

Characteristics SuspicionofVSCC(n=55) NosuspicionofVSCC(n=58) p-value* I.Age(inyears)

Mean(95%ConfidenceInterval) 67.9(64.3–71.5) 62.8(58.7–66.9) 0.06

Range 41–91 24–88

Numberofpatients(percentage)

II.Historyofvulvarlesions 0.27

None 36(65) 29(50)

Lichenoidlesions 5(9) 4(7)

VIN 6(11) 11(19)

VSCC 8(15) 14(24)

III.Preoperativeclinicalexamination A.Diameterofthelesions

Median(Range)inmm 30(3–65) 20(3–70) 0.16 <20mm 20(36) 21(36) 0.62 20mm 35(64) 36(62) Unknown 0(0) 1(2) B.Focality Unifocal 43(78) 44(76) 0.86 Multifocal 12(22) 14(24)

IV.Surgicalprocedure A.Localtreatment WLE 33(60) 52(90) B.Radicaltreatment <0.001 WLE+SLNprocedure 14(25) 5(8) WLE+LND 8(15) 1(2) V.Post-operativehistopathology <0.001 Lichenoidchanges 1(2) 0(0) VIN 9(16) 39(67) VSCC 45(82) 19(33)

VI.Treatmentcategorization 0.55

Definitive 39(71) 42(73)

Incompletetreatment 15(27) 13(23)

Over-treatment 1(2) 3(4)

VII.Additionaltreatment 0.34

None 37(66) 45(78)

Localtreatment(WLE) 4(7) 2(3)

Radicaltreatment(WLE+grointreatment)

WLE+SLN 3(5) 5(8)

WLE+LND 2(4) 1(2)

Grointreatmentonly

SLN 3(6) 5(9) LND 3(6) 0(0) Radiotherapy 3(6) 0(0) VIII.Followup 0.58 Noevidenceofdisease 43(78) 47(81) Death Relatedtodisease 2(4) 1(2) Unrelatedtodisease 1(2) 3(4) Recurrenceofdisease VIN 3(5) 4(7) VSCC 2(4) 1(2)

Underpalliativecare 4(7) 1(2)

Nofollowup 0(0) 1(2)

VIN:vulvarintraepithelialneoplasia,VSCC:vulvarsquamouscellcarcinoma,WLE:widelocalexcision,SLN:sentinellymphnode,LND:lymphnodedissection.

surgeonhadperformedalimitedexcisiondespiteasuspicionof VSCConbiopsy(n=33),highpatientage,co-morbidities,location of thetumor close totheanus, and history of previous vulvar surgerieswerefactorswhichinfluencedthedecision.

In contrast to previous reports,no significant association of lesionalsizeorfocalitywithafinaldiagnosisofVSCCwasfound.Preti etal.identifiedanassociationoflargersized,andmultifocalVIN lesionswithoccultSCConunivariateanalysisintheirstudy[12].On multivariableanalysishowever,theydiscoveredtumorsizetobethe confounder [12]. Raised lesions havealso been associated with occult invasivecarcinoma[8,9].Misseddiagnosesofcarcinomahavebeen reportedtobemorefrequentforperineal,clitoral,andlabiallesions [8,9,12].Similaranalysescouldnotbeperformedforourcohortas detailedmacroscopicdescriptions,ortheexactanatomicallocations ofthetumorwerenotavailableforalllesions.

For30%ofpatientswithVSCCinour cohort,there wasnosuspicion ofcarcinomaonpre-operativebiopsy.Unsuspectedinvasionisknown tobepresentin3.2–22%ofbiopsiesfromhighgradeVIN[8,10,13]. Thesefigureshowever,maybebiased,asbiopsiesaremorecommonly performedforclinicallysuspiciouslesions,andconservative/topical treatmentmodalitiesareotherwisefrequentlyadministeredforHSIL. Theseresultsmayalsobeinfluencedbythenumberofbiopsiestaken. Toavoidmissingsmallinvasivefoci,thoroughsamplingofVINisof undeniableimportance.

Onhistopathologyreview,thediagnosesdidnotchangeforany case. For biopsies reported as suspicious for VSCC, complex anastomosingepithelialarchitecture,accompaniedbyin flamma-toryinfiltratewasoftenobserved(resultsnotpresented).Inafew cases,anoverwhelmingVINlesionmaskedunderlyingsmallnests of invasion, which were not sampled in the biopsy. Accurate judgmentofinvasioncanbehinderedbytangentialsectioningof the biopsy specimen, or in biopsies from the central part of carcinoma,withoutadjacent‘normal’epithelium, orunderlying stroma.Evenlyspacednestswithroundedor bulbouscontours, withoutdesmoplasticstromalreactionaremorelikelytobethe resultoftangentialsectioning[14,15].Trueinvasion,incontrast,is characterized by single cells, or nests of keratinocytes, with irregular or angulated contours, invading from the basilar epidermisorfromelongatedreteridges,occasionallyaccompanied bydesmoplasticstromalreaction,edema,orinflammation[14,15]. Toassessitsadequacy,thesurgicaltreatmentadministeredwas categorizedasdefinitive,incomplete,andover-treatment. Seven-ty-two percent (81/113) of patients had received definitive treatment;thefinaldiagnosiswasVINfor56%,andVSCCfor44 %.Twenty-fivepercent(28/113)ofpatientshadreceived incom-pletetreatment;theirfinaldiagnosiswasVSCC.Forthesepatients, additionallocaltreatmentwasneededin6cases,radicaltreatment in11cases,andonlygrointreatmentin11cases[Fig.1].Therewas anover-treatmentof4patients(3%);thefinaldiagnosiswasVIN for3patients,andlichenoidchangesfor1patient.

Our _findings re_flect the fact that in daily clinical practice, treatmentdecisionsarenot basedentirelyonthepre-operative histopathology, but on the surgeon’s practical experience and judgmentaswell.Asurgeon_’ssuspicionforVSCC,needlesstosay, isnotatangibleparameter,andwefoundthatitwasnotalways welldocumented.Asaresult,thisfactorcouldnotbeusedforthe analysis.Nevertheless,throughthisstudy,weaimedtoenhance ourunderstandingofclinicalpracticeforpatientswhereofficial guidelines are not directly applicable.Management of patients withouta conclusivediagnosisofcarcinomaonbiopsyis nota well-studiedarea,andavailableliteratureisverylimited.Thehigh PPV(82%)ofsuspicionofVSCConpre-operativebiopsy,andthe fact that the majority (72 %) of patients received definitive treatment,reflectstheexpertiseofboththepathologistandthe clinician,anddemonstratesthebenefitsofareferralgynecologic oncologyservice.However,duetotheretrospectivenatureofthe

study,someclinicaldatacouldnotbeaccessed,andbeinga single-center study, our results may not be generalizable; these are potentiallimitations.

Conclusion

Suspicion of VSCC on pre-operative histopathology is a significantpredictorofa final diagnosisofVSCC.In ourcohort, radicaltreatmentperformedonpatientswithstrongclinicaland histopathologicsuspicionofVSCChelpedavoidsecondsurgeries and ledto minimalover-treatment. In-depth,well-documented clinical notes on treatment rationale, and protocol deviation (whereapplicable),alongwithstudyingsimilarmulti-institutional cohortscouldcontributetothedevelopmentofimproved clinico-pathologicalgorithmsforpatientmanagement.

Contributors

L.W.Jonker:studydesign,datacollection,manuscriptwriting. S. Dasgupta: statistical analysis, histopathology review, manu-scriptwriting.L.W.JonkerandS.Dasguptaaresharedfirstauthors. P.C.Ewing-Graham:histopathologyreview,scientificinput,data discussion, manuscript editing. H.C. van Doorn: study design, scientific input, data discussion, manuscript editing, study supervision.

Funding

Noexternalfundingreceived. Patientconsentforpublication

Notrequired. Ethicsapproval

The study was approved by the by the Medical Research Ethics Committee of Erasmus MC Cancer Institute (MEC 2017-134).

Dataavailabilitystatement

Dataareavailableforsharinginasecuremanner,forresearch and educational purposes, obeying our hospital policies upon reasonable request. Requests can be addressed to Dr. H.C.van Doorn(h.vandoorn@erasmusmc.nl).

DeclarationofCompetingInterest

Theauthorshavenoconflictsofinteresttodeclare Acknowledgement

Noexternalfundingwasreceived. AppendixA.Supplementarydata

Supplementarymaterialrelated to this articlecan befound,inthe onlineversion,atdoi:https://doi.org/10.1016/j.ejogrb.2020.03.027. References

[1]DellingerTH,HakimAA,LeeSJ,WakabayashiMT,MorganRJ,HanES.Surgical managementofvulvarcancer.JNatlComprCancNetw2017;15:121–8,doi: http://dx.doi.org/10.6004/jnccn.2017.0009.

[2]LawrieTA,NordinA,ChakrabartiM,BryantA,KaushikS,PepasL.Medicaland surgicalinterventionsforthetreatmentofusual-typevulvalintraepithelial neoplasia.CochraneDatabaseSystRev2016;1,doi:http://dx.doi.org/10.1002/ 14651858.CD011837.pub2CD011837.

[3]TostiG,IacoboneAD,PretiEP,etal.Theroleofphotodynamictherapyinthe treatmentofvulvarintraepithelialneoplasia.Biomedicines2018,doi:http:// dx.doi.org/10.3390/biomedicines6010013pii:E13.

[4]deWitteCJ,vandeSandeAJ,vanBeekhuizenHJ,KoenemanMM,KruseAJ, Gerestein CG. Imiquimod in cervical, vaginal and vulvar intraepithelial neoplasia:areview.GynecolOncol2015;139:377–84,doi:http://dx.doi.org/ 10.1016/j.ygyno.2015.08.018.

[5]Oncoline: Dutch National Guidelines. https://www.oncoline.nl/vin. Last accessedMar,2020.

[6]RoyalCollegeofObstetriciansandGynecologists:GuidelinesfortheDiagnosis andManagementofVulvalCarcinoma.https://www.rcog.org.uk/globalassets/ documents/guidelines/vulvalcancerguideline.pdf.LastaccessedMar,2020. [7]Oncoline: Dutch National Guidelines.

https://www.oncoline.nl/vulvacarci-noom.LastaccessedMar,2020.

[8]HusseinzadehN,RecintoC.Frequencyofinvasivecancerinsurgicallyexcised vulvar lesions with intraepithelial neoplasia (VIN 3). Gynecol Oncol 1999;73:119–20,doi:http://dx.doi.org/10.1006/gyno.1998.5327.

[9]ChafeW,RichardsA,MorganL,WilkinsonE.Unrecognizedinvasivecarcinoma invulvarintraepithelialneoplasia(VIN).GynecolOncol1988;31:154–60,doi: http://dx.doi.org/10.1016/0090-8258(88)90284-3.

[10]Modesitt SC, Waters AB, Walton L, Fowler Jr. WC, Van Le L. Vulvar intraepithelialneoplasiaIII:occultcancerandtheimpactofmarginstatus onrecurrence.ObstetGynecol1998;92:962–6,doi:http://dx.doi.org/10.1016/ s0029-7844(98)00350-0.

[11]PolterauerS,DresslerAC,GrimmC,etal.Accuracyofpreoperativevulva biopsyandtheoutcomeofsurgeryinvulvarintraepithelialneoplasia2and3. Int J Gynecol Pathol 2009;6:559–62, doi:http://dx.doi.org/10.1097/ PGP.0b013e3181a934d4.

[12]PretiM,BucchiL,GhiringhelloB,etal.Riskfactorsforunrecognizedinvasive carcinomainpatientswithvulvarhighgradesquamousintraepitheliallesion atvulvoscopy-directedbiopsy.JGynecolOncol2017;28:e27,doi:http://dx.doi. org/10.3802/jgo.2017.28.e27.

[13]vanSetersM,vanBeurdenM,deCraenAJ.Istheassumednaturalhistoryof vulvarintraepithelialneoplasiaIIIbasedonenoughevidence?Asystematic reviewof3322publishedpatients.GynecolOncol2005;97:645–51,doi:http:// dx.doi.org/10.1016/j.ygyno.2005.02.012.

[14]delPinoM,Rodriguez-CarunchioL,OrdiJ.Pathwaysofvulvarintraepithelial neoplasiaandsquamouscellcarcinoma.Histopathology2013;62:161–75,doi: http://dx.doi.org/10.1111/his.12034.

[15]YangEJ,KongCS,LongacreTA. Vulvarandanal intraepithelialneoplasia: terminology,diagnosis,andancillarystudies.AdvAnatPathol2017;3:136–50, doi:http://dx.doi.org/10.1097/PAP.0000000000000149.