OfficialreprintfromUpToDate

www.uptodate.com2017UpToDate

Cervicalandvaginalcytology:Interpretationofresults(Paptestreport)

Authors: ChristopherPCrum,MD,WarnerKHuh,MD
SectionEditor: BarbaraGoff,MD
DeputyEditor: SandyJFalk,MD,FACOG

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2017.|Thistopiclastupdated:May31,2016.

INTRODUCTIONCervicalcytologybecamethestandardscreeningtestforcervicalcancerandpremalignant
cervicallesionswiththeintroductionofthePapanicolaou(Pap)smearin1941[1].Liquidbased,thinlayer
preparationofcervicalcytologyspecimenswasasubsequentmodificationintechnique.Terminologyforreporting
cervicalcytologywasstandardizedbytheBethesdaSystemin1988[2].Thissystemhasbeenrevisedseveral
times,andthecurrentsystemwasdevelopedin2014(table1)[36].Humanpapillomavirus(HPV)testinghasnow
beenincorporatedintocervicalcancerscreening.(See"Screeningforcervicalcancer"and"Cervicalcancer
screeningtests:Techniquesforcervicalcytologyandhumanpapillomavirustesting".)

Thecervicalcytologyreportispresentedinastandardformat.Interpretationofcervicalcytologyresultswillbe
reviewedhere.Cervicalcancerscreeningstrategiesandtechniques,aswellasthefollowupofabnormalcytology
resultsandtreatmentofcervicalintraepithelialneoplasia(CIN),arereviewedseparately:

(See"Screeningforcervicalcancer".)

(See"Cervicalcancerscreeningtests:Techniquesforcervicalcytologyandhumanpapillomavirustesting".)

(See"Cervicalcytology:Evaluationofatypicalsquamouscells(ASCUSandASCH)".)

(See"Cervicalcytology:Evaluationoflowgradesquamousintraepitheliallesions(LSIL)".)

(See"Cervicalcytology:Evaluationofhighgradesquamousintraepitheliallesions(HSIL)".)

(See"Cervicalcytology:Evaluationofatypicalandmalignantglandularcells".)

(See"Cervicalintraepithelialneoplasia:Managementoflowgradeandhighgradelesions".)

ROLEOFCERVICALCYTOLOGYCervicalcytologycanbeusedincombinationwithtestingforhighriskhuman
papillomavirus(HPV)forcervicalcancerscreening.Theresultsofcervicalcytologycannotbeusedtomakea
definitivediagnosisorinitiatetreatment,withtheexceptionofhighgradesquamousintraepitheliallesion(HSIL).
Rather,thetestfunctionssolelytoscreenforcellularabnormalitiesthatareassociatedwithanincreasedriskforthe
developmentofcervicalcancer.Theresultsareusedtoguidefurtherevaluation,suchascolposcopyand/orcervical
biopsy.Treatmentdecisionsarethenmadebasedupondiagnosticresultsfromhistologicexamination,usuallyfrom
colposcopicallydirectedbiopsies.(See"Cervicalintraepithelialneoplasia:Managementoflowgradeandhighgrade
lesions".)

TERMINOLOGYFORSQUAMOUSCELLABNORMALITIESTherehavebeenfrequentmodificationsinthe
nomenclatureusedforclassifyingcytologicandhistologiccervicalchangesassociatedwithhumanpapillomavirus
(HPV)infectionandprecancerouslesions.Themajorshiftsinterminologyapplytosquamouscellabnormalities.The
currentclassificationsystemintheUnitedStatesforcervicalcytologywasintroducedwiththeBethesda1988
System[3].Thissystemhasbeenupdatedseveraltimes,asBethesda1991,Bethesda2001,andBethesda2014[4
7].Thecorrespondingtermsacrossthecurrentandpreviousterminologysystemsforsquamouscellabnormalities
areshownhere(figure1).

Squamouscervicalcytologicabnormalities(thosedetectedwithPaptests)arereportedusingthetermcervical
squamousintraepitheliallesions(CSIL).Specifying"cervical"differentiatestheselesionsfromanalsquamous
intraepitheliallesions,whichusesimilarterminology.(See"Analsquamousintraepitheliallesions:Diagnosis,
screening,prevention,andtreatment".)

CSILisstratifiedintotwocategories:

Lowgradesquamousintraepitheliallesion(LSIL)

Highgradesquamousintraepitheliallesion(HSIL)

TheshiftinterminologytoLSILandHSILwasmadeintheBethesda1988systeminrecognitionofthediffering
clinicalcourseofthesetwolevelsofcellularchange.LSIL,especiallyinyoungwomen,isgenerallyatransientHPV
infection,whereasHSILismorelikelytobeassociatedwithpersistentHPVinfectionandahigherriskofprogression
tocervicalcancer[4,8].

Cytologicabnormalitiesmustbefurtherevaluatedwithcolposcopyandbiopsy.ThefindingofLSILversusHSILon
cytologydoesnotconstituteadiagnosisofahistologicabnormalitysuchasLSIL(condyloma/cervicalintraepithelial
lesion[CIN]1)orHSIL(CIN2/CIN3).Cytologicfindingsmaybeassociatedwithasubsequenthistologicfindingthat
iseithermoreorlesssevere.

In2012,theLowerAnogenitalSquamousTerminology(LAST)projectoftheCollegeofAmericanPathologyandthe
AmericanSocietyforColposcopyandCervicalPathologypublishedchangesintheterminologyusedtodescribe
HPVassociatedsquamouslesionsoftheanogenitaltract(figure1)[9,10].Currentterminologyforhistologic
squamouscellabnormalitiesisdiscussedseparately.(See"Cervicalintraepithelialneoplasia:Terminology,
incidence,pathogenesis,andprevention",sectionon'Terminology'.)

Currentterminologyforglandularcellfindingsisdescribedinasectionbelow.(See'Glandularcellabnormalities'
below.)

ChangesintheBethesda2014guidelinesTheBethesda2014guidelinesforthereportingofcervicalcytology
specimensincludethefollowingchangesfromBethesda2001[46]:

LSILcervicalcytologicspecimensthatcontainafewcellsthataresuspiciousforbutnotdiagnosticofHSILare
reportedasatypicalsquamouscells,cannotexcludeahighgradesquamousintraepitheliallesion(ASCH).
Therewaspreviouslynorecommendationregardinghowtoreportthese.(See'ASCHincludesLSILwithsome
HSILcells'below.)

Benignappearingendometrialcellsarereportedonlyinwomen45years.ThisisachangefromBethesda
2001,whichusedanagethresholdof40years.(See'Benignappearingendometrialcellsinwomen45years'
below.)

OVERVIEWOFTHECERVICALCYTOLOGYREPORTThecervicalcytologyreportconsistsof(table1and
table2):

AdescriptionofspecimentypeandtestrequestedCervicalorvaginalsample,conventionalPapsmear,liquid
basedcytology,and/orreflexhumanpapillomavirus(HPV)test.

Adescriptionofspecimenadequacy.

Ageneralcategorization(optional)Negative,epithelialcellabnormality,orother.
 Aninterpretation/resultEitherthespecimenisnegativeforintraepitheliallesionsandmalignancy(although
organismsorreactivechangesmaybepresent)orthereisanepithelialcellabnormalityasdefinedbythe
Bethesda2014classification,orthereisanotherfinding.Thislattercategorymayindicatesomeincreasedrisk,
asanexample:endometrialcellsinawoman45yearsofage[5,6].

Adescriptionofanyancillarytestingorautomatedreviewthatwasperformed(eg,HPV,AutoPap).

Educationalnotesandsuggestionsbythepathologist(optional).

SPECIMENADEQUACYSatisfactorycervicalcytologyisdefinedbythenumberofsquamouscellsinthesample.

SatisfactoryforevaluationCriteriafor"satisfactoryforevaluation"are:

SquamouscellularityConventionalPapsmearsmusthaveatleast8000to12,000wellvisualizedsquamous
cellsliquidbasedpreparationsmusthaveaminimumof5000wellvisualizedsquamouscells.

Labeledspecimen.

Cellularitymaybediminishedinwomenwhohavebeentreatedwithpelvicradiation.Thisinformationshouldbe
includedinthecytologyrequisition,andthereportingofresultswilldependontheclinicalcontextandtheabilityof
thelaboratorytoevaluatethespecimen[11].

Cervicalcytologyspecimensthataredesignated"satisfactoryforevaluation"may,inaddition,bedescribedusing
whatarereferredtoas"qualityindicators."Qualityindicatorsincludescantcellularity,partiallyobscuringbloodor
inflammation,poorfixation,thicklysmearedslides,andabsenceofendocervicalortransformationzone(EC/TZ)
component[12].

Absentendocervicalcell/transformationzonecomponentTheclinicalsignificanceforcervicalcancer
screeningoftheabsenceoftheEC/TZcomponentinacervicalcytologyspecimeniscontroversial.Itappearsthat
womenwiththisfindingarenotatanincreasedriskofcervicalneoplasia.However,theabsenceofthiscomponent
inasampleraisesconcernforamisseddiagnosisofcervicalneoplasia,particularlyglandularabnormalitiesofthe
endocervix.

MostexpertsagreewiththeAmericanSocietyforColposcopyandCervicalPathologyguidelines,whichadvisethat
womenwithcervicalcytologythatisnegativeforanintraepitheliallesionormalignancybuthasanabsentor
insufficientEC/TZcomponentbemanagedasfollows(algorithm1)[13]:

Womenage30yearsshouldbemanagedaccordingtohighriskhumanpapillomavirus(HPV)testresults:

HPVpositiveTherearetwooptionsforfurtherevaluation:genotypingforHPVtypes16and18orHPV
andcytologycotestinginoneyear.Resultsshouldbemanagedasappropriate.(See'HPVpositive'below
and"Cervicalcytology:Evaluationofatypicalsquamouscells(ASCUSandASCH)"and"Cervical
cytology:Evaluationoflowgradesquamousintraepitheliallesions(LSIL)"and"Cervicalcytology:
Evaluationofhighgradesquamousintraepitheliallesions(HSIL)".)

HPVnegativeThepatientmayresumeroutinescreening.

HPVunknownTherearetwooptionsforfurtherevaluation.ThepreferredoptionisHPVtesting.
Alternatively,cytologymayberepeatedinthreeyears.

Womenages21to29yearsmayreturntoroutinescreening.

Thesquamocolumnarjunctionofthecervix(junctionofsquamousandglandularcells,generallyattheexternal
cervicalos)andtheTZaretheareasatgreatestriskforneoplasia(picture1)[14].TheTZisanareaofsquamous
metaplasiathatliesbetweenthesquamocolumnarjunctionandtherestofthesquamousepithelium[15].Itlies
adjacenttotheTZ,whichcontainssquamousmetaplasia[15].ThemetaplasticcellsaretheTZcomponentandthe
presenceofthesecellsortheendocervicalcells(EC)impliesthattheregionatgreatestempiricriskwassampled.
Approximately10to20percentofcytologyspecimenslackanEC/TZcomponent.Thisfindingismostcommonin
adolescentsandpostmenopausalwomen[16,17].

Theroleofthetransformationzoneinthepathogenesisofcervicalneoplasiaisdiscussedseparately.(See"Cervical
intraepithelialneoplasia:Terminology,incidence,pathogenesis,andprevention",sectionon'Cervicaltransformation
zone'.)

AnotationismadeinthecervicalcytologyreportregardingthepresenceorabsenceofanEC/TZcomponent,but
thesecellsarenotrequiredforacervicalcytologytesttobeclassifiedassatisfactoryaccordingtoBethesda2001
and2014criteria[46].ThecriterionforanEC/TZcomponentisatleast10wellpreservedendocervicalor
squamousmetaplasticcellsclustersofcellsarenotrequiredastheywereinBethesdaguidelinespriorto2001.

TheclinicalsignificanceforcervicalcancerscreeningoftheabsenceoftheEC/TZcomponentinacervicalcytology
specimeniscontroversial[11,16,1821].Inspecimensthatlackendocervicalcells,cytologicevaluationyieldsalower
rateofcellularabnormalities[16,18,20].Thiswasbestillustratedinaprospectivestudyofover4000womenin
whomcervicalcytologyspecimenswithoutanEC/TZcomponentwerefoundtohaveasignificantlylowerrateof
epithelialabnormalitiesthanspecimenswithanEC/TZcomponent(11versus18percent)[16].

Sincecytologicabnormalitiesaretheindicationforfurtherevaluationwithcolposcopyandcervicalbiopsy,thisraises
thequestionofwhetherahistologicdiagnosisofcervicalintraepithelialneoplasia(CIN)orcervicalcancerwillbe
missedinwomeninwhomaPaptestlacksanEC/TZcomponent.However,thereappearstobenoincreaseinthe
developmentofhighgradeCINorcancerinthesewomen[16,2123].

WhencervicalcytologyisrepeatedinwomenwhohavehadaPaptestwithoutanEC/TZcomponent,datasuggest
thatthereisnoincreaseincellularabnormalitiescomparedwithotherwomen[16,24].Thiswasillustratedinthe
prospectivestudyof4000womendescribedinaprecedingparagraph[16].Repeatcytologyperformedaftera
medianof60days(range13to991days)showednosignificantdifferenceintherateofepithelialabnormalitiesin
womenwithoutorwithanEC/TZcomponentontheinitialspecimen.

Inaddition,longitudinalstudies(sixmonthstoeightyearsoffollowup)of40,000to60,000womenwithaPaptest
thatwasreportedasnegativeforepithelialabnormalitiesbutlackedanEC/TZcomponentfoundnoincreasein
histologicdiagnosesofhighgradeCINorcervicalcancercomparedwithwomenwithanEC/TZcomponent(inone
study,forhighgradeCIN,0.6to2.6versus2.9per1000yearsoffollowup[21]intheotherstudy,forhighgrade
CIN,6.2versus6.1per1000yearsoffollowupandforcervicalcancer,0.53versus0.54per1000yearsoffollowup
[23]).

Ontheotherhand,theproportionofendocervicaladenocarcinomaamongallcervicalcarcinomasisincreasing.
Sincethesecancersmostcommonlyariseintheglandularcellsoftheendocervix,itisplausiblethatthedetectionof
suchcancersmaybereducedinspecimensthatlackanEC/TZcomponent[25].However,glandularabnormalities
arelesscommonthansquamousabnormalities,andtherearefewdatatosupportorrefutethisconcern[21,26].

TheadventoftestingforoncogenicHPV(table3)hasnotclarifiedthisissue.Apotentiallyclinicallyimportantgroup
iswomenwithcytologythatisnegative,butlacksanEC/TZcomponent,andapositiveHPVtest.Itisunknown
whetherabnormalendocervicalcellshavebeenmissedinthesewomen[11].WomenwithanegativePaptestand
positiveHPVhaveanincreasedriskofsubsequentcervicalneoplasiahowever,studiesofthisissuedonotreport
therateofPapswithoutanEC/TZcomponent[27].(See"Screeningforcervicalcancer".)

ForwomenwithaninadequateEC/TZcomponentandanegativeHPVtest,anotherissueiswhetherthelackof
thesecellsdecreasesthesensitivityoftheHPVtest.Tworetrospectiveseriesfromthesameinstitutionofover
26,000negativecervicalcytologyspecimensthatweretestedforhighriskHPVfoundnosignificantdifferenceinthe
prevalenceofHPVinspecimenswithoutorwithanEC/TZcomponent(2.5versus2.2percent)[17,28].
 PartiallyobscuringbloodorinflammationAspecimenisconsidered"partiallyobscured"when50to75
percentoftheepithelialcellscannotbevisualized[4].Specimensinwhichmorethan75percentofthecellsare
obscuredaredesignatedunsatisfactory.(See'Unsatisfactoryforevaluation'below.)

Womenwithpartiallyobscuringbloodorinflammationshouldhavearepeattestinsixmonthsiftheyareatan
increasedriskforcervicalcanceroriftheyhavepriorincompletetesting.Thisincludeswomenwhosetestsare
otherwisesatisfactory.Thecriteriaforrepeatingcervicalcytologyinsixmonthsare[29]:

Aprevioussquamousabnormality(atypicalsquamouscellsofundeterminedsignificanceorworse)without
threesubsequentnegativecervicalcytologyresults(withatleastonesamplewithanEC/TZcomponent).Thisis
basedonayearlyscreeningprotocolandhasnotbeenupdatedforprotocolsthatincludescreeningeverythree
tofiveyears.

ApreviousPapwithanunexplainedglandularabnormality(eg,atypicalglandularcellswithnofindingofCINor
adenocarcinomainsituonfurtherevaluation).

ApositivehighriskHPVtestwithin12months.

Cliniciansinabilitytoclearlyvisualizethecervixorsampletheendocervicalcanal.

Immunosuppression.

Similarobscuringfactor(bloodorinflammation)inconsecutivecervicalcytologyresults.

Insufficientpreviousscreening.Thishasnotbeendefinedinthecurrentscreeningguidelines.Inourpractice,
wedefineinsufficientscreeningas:(1)forwomenages21to29yearswithnocervicalcytologyformorethan
threeyearspriortothecurrentcytologyspecimen,and(2)forwomenage30yearswithnocytologyformore
thanthreeyearsornocytologyandHPVcotestingformorethanfiveyearspriortothecurrentscreeningtest.

Forpregnantpatientswithpartiallyobscuringbloodorinflammation,itispreferredtorepeatthecervicalcytology
postpartum.

Forwomenwhodonotmeetthecriterialistedabove,routinescreeningshouldbecontinuedbaseduponthe
recommendedtestingintervals(table4).

UnsatisfactoryforevaluationAnunsatisfactorycervicalcytologyspecimenisconsideredunreliableforthe
evaluationofepithelialabnormalities.Whetherwomenwithanunsatisfactorycervicalcytologyaremorelikelyto
haveintraepitheliallesionsorcanceronfollowupthanwomenwithsatisfactorytestsiscontroversial[3032].Scant
cellularitymayresultinafalsenegativeHPVtest[13].

Cervicalcytologyisreportedasunsatisfactoryforevaluationinapproximately1percentofcases[33,34].Cervical
cytologytestsaredesignated"unsatisfactoryforevaluation"foroneofthreereasons[4]:

Scantcellularity
Obscuringinflammationorblood
Unlabeledorotherwiseunabletobeprocessedbythelaboratory

Thereasonforfindingaspecimenisunsatisfactoryisnotedinthereport.Themostcommonreasonisscant
cellularity.Thecriteriaforcellularityandobscuringinflammationorbloodarenotedintheprecedingsections(see
'Satisfactoryforevaluation'aboveand'Partiallyobscuringbloodorinflammation'above).Specimensthatwerenot
processedbythelaboratorybecausetheywereunlabeledorthevialorslidebrokearedistinguishedfrom
specimensdeterminedtobeunsatisfactoryafterprocessing.

MostexpertsagreewiththeAmericanSocietyforColposcopyandCervicalPathologyguidelines,whichrecommend
thatifHPVcotestingwasperformedattimeofthePaptest,theHPVresultscanbeusedtotriagethemanagement
ofwomen30yearswithunsatisfactorycytology(algorithm2)[13].

TheresultsofhighriskHPVtestingaremanagedasfollows:

HPVpositive(age30years)WomenwithunsatisfactorycytologyandpositiveHPVtestingmaybemanaged
inoneoftwoways:

Repeatcytologyaftertwotofourmonths.

Alternatively,colposcopymaybeperformed.

HPVnegative(age30years)Repeatcytologyaftertwotofourmonths.

IfHPVtestingwasnotperformed(patientsofanyage),thencytologyisrepeatedaftertwotofourmonths.The
followupresultsarethenmanagedasfollows:

Negativecytology

ForwomenwhoareHPVpositive,HPVandcytologycotestingshouldberepeatedinoneyear.

ForwomenwhoareHPVnegativeorunknown,thepatientmayresumeroutinescreening.

AbnormalcytologyTheresultshouldbemanagedasappropriate.(See"Cervicalcytology:Evaluationof
atypicalsquamouscells(ASCUSandASCH)"and"Cervicalcytology:Evaluationoflowgradesquamous
intraepitheliallesions(LSIL)"and"Cervicalcytology:Evaluationofhighgradesquamousintraepitheliallesions
(HSIL)".)

UnsatisfactorycytologyColposcopyshouldbeperformed.

RepeatingthePaptestwithinashortinterval,evenasshortas15to30days,doesnotappeartoaffectsensitivity
fordetectionofcervicalneoplasia.(See"Cervicalcancerscreeningtests:Techniquesforcervicalcytologyand
humanpapillomavirustesting",sectionon'IntervalbetweenPaptests'.)

Ifthecellsareobscuredbyinflammationandaspecificinfectionisidentified,treatmentshouldbegivenbefore
repeatingthePaptest.Therefore,inwomenwithrepeatedlyunsatisfactorycytologyspecimensaswellasthosewith
symptoms(eg,postcoitalbleeding,pelvicpain)orphysicalexaminationfindingssuggestiveofcervicalcancer(eg,
visiblecervicallesion),additionalclinicalevaluationwithcolposcopyand/orbiopsiesisappropriate.(See"Invasive
cervicalcancer:Epidemiology,riskfactors,clinicalmanifestations,anddiagnosis",sectionon'Clinical
manifestations'.)

WomenwithanunsatisfactoryPaptestinwhomthetestwasnotindicatedwithinanappropriatescreeningprotocol
donotneedtorepeatthetest.(See"Screeningforcervicalcancer".)

GENERALCATEGORIZATIONThisisanoptionalsectioninwhichspecimensarenotedas"negativefor
intraepitheliallesionormalignancy,""epithelialcellabnormality,"or"other"[4].Specimensdesignatedas"other"
includethosethatcontainnomorphologicabnormalities,butthefindingsmayindicatesomeincreasedcancerrisk
(eg,endometrialcells).

INTERPRETATION/RESULTThespecimenisreportedaseither"negativeforintraepitheliallesionsor
malignancy,"oranepithelialcellabnormalityisspecified.Reportingofnonneoplasticfindings(eg,infectionor
inflammation)isoptionalandisreportedundertheheading"other"[4].

NegativeforintraepitheliallesionormalignancyThesearespecimensinwhichnoepithelialabnormalityis
identified.
IntraepithelialcellabnormalitiesTheseareintraepithelialabnormalitiesassociatedwithhumanpapillomavirus
(HPV)infectionandcervicalprecancerorcancer(nuclearenlargementandgranulation,thepresenceofkoilocytes,
anincreasednucleocytoplasmicratio,andfrequentmitoses)asdefinedbytheBethesda2001and2014
classifications[46].

Epithelialcellabnormalitiesareclassifiedassquamousorglandular(table1).Theterm"atypicalepithelialcells"may
beusedforcaseswhereasquamousversusglandularorigincannotbedetermined.

Thecategoriesofepithelialcellabnormalitiesarediscussedbelow.Theincidenceofeachtypeofabnormalityis
showninthetable(table5).Followupfortheseabnormalitiescanbefoundinthetopicreviewslistedwitheach
category.

Squamouscellabnormalities

Atypicalsquamouscells(ASC)arecategorizedaseitherofundeterminedsignificance(ASCUS)orcannot
excludeahighgradesquamousintraepitheliallesion(ASCH).TheASCHcategoryincludesfindingsthatare
equivocal,butlikelyconsistofamixtureoftruehighgradesquamousintraepitheliallesionsandotherfindings
thatmimicsuchlesions.Approximately5to10percentofASCresultsaredesignatedASCH[3537].(See
"Cervicalcytology:Evaluationofatypicalsquamouscells(ASCUSandASCH)".)

Lowgradeintraepitheliallesion(LSIL).TheLSILcategoryincludeschangesconsistentwithHPVinfectionanda
possiblehistologicfindingofcervicalintraepithelialneoplasia(CIN)1.(See"Cervicalcytology:Evaluationoflow
gradesquamousintraepitheliallesions(LSIL)".)
Highgradeintraepitheliallesion(HSIL).HSILincludeschangesconsistentwithHPVinfectionandapossible
histologicfindingofCIN2or3thecervicalcytologyreportshouldindicateiftherearefeaturessuspiciousfor
invasivedisease.(See"Cervicalcytology:Evaluationofhighgradesquamousintraepitheliallesions(HSIL)".)

Squamouscellcarcinoma.(See"Invasivecervicalcancer:Epidemiology,riskfactors,clinicalmanifestations,
anddiagnosis".)

ASCHincludesLSILwithsomeHSILcellsLSILcervicalcytologicspecimensoccasionallycontainafew
cellsthataresuspiciousforbutnotdiagnosticofHSIL.Retrospectivestudieshavefoundthatthesewomenhavea
significantlyhigherlikelihoodofahighgradelesiononbiopsythanotherwomenwithLSIL(approximately30versus
15percent)[38,39].Previously,thesewerereportedonthecytologyreportasLSILwithanotationthatsomecells
suggestedHSIL,andsomereportsincludedtheterm"LSILH."Thecurrentrecommendationistoclassifythesmear
asLSILandaddanadditionalinterpretationof"atypicalsquamouscells(ASC)cannotruleoutHSIL.Itisbestto
classifythesecytologyspecimensasASCHinordertoalignthediagnosiswithanappropriatemanagement
guideline[5,6].

GlandularcellabnormalitiesGlandularabnormalitiesoncytologyarereportedintheBethesda2014
classificationasfollows[5,6]:

Atypicalglandularcells(AGC).Endocervical,endometrial,ornototherwisespecifiedisnoted.Uponfurther
evaluation,eitherhighgradesquamousorglandularabnormalitiesarefoundin10to39percentofwomenwith
afindingofAGConcytology[40].Thisreplacesthepreviousterm"atypicalglandularcellsofundetermined
significance."

Atypicalglandularcells,favorneoplastic.Endocervicalornototherwisespecifiedisnoted.Thisdesignationis
forspecimensthatshowfeaturessuggestiveofbutnotsufficientforaninterpretationofadenocarcinoma.

Endocervicaladenocarcinomainsitu(AIS).

Adenocarcinoma.
Thefollowupofglandularcervicalabnormalitiesisdiscussedseparately.(See"Cervicalcytology:Evaluationof
atypicalandmalignantglandularcells".)

Whenglandularcellabnormalitiesarepresent,itshouldbenotedwhethertherearechangesfavoringneoplasia.

OtherFindingsthatarenonneoplasticorarerelatedtocancersotherthancervicalcancerarenotedas"other."
Thepresenceofendometrialcellsinawoman40yearsofageshouldbenoted.Specimensmayhaveadditional
findingsthatshouldbedescribed,suchasinfectiousorganismsorcellularchangesassociatedwithinfection,
reactivecellularchanges,atrophy,orglandularcellsafterhysterectomy.

Benignappearingendometrialcellsinwomen45yearsBenignappearingendometrialcellsonacervical
cytologyspecimenarereportedonlyinwomen45yearsoldandrequireevaluationinpostmenopausalwomenin
premenopausalwomen,evaluationisneededonlyinwomenwithabnormaluterinebleedingorriskfactorsfor
endometrialcarcinoma.

Afindingofbenignappearingexfoliatedendometrialglandularcellsinacervicalcytologyspecimen(BEC)doesnot
includeatypicalendometrialcells,whicharereportedasatypicalendometrialcells,endometrial.(See'Glandularcell
abnormalities'above.)

TheBethesda2014guidelinesadvisethatthepresenceofBECbereportedinthecytologyreportonlyinwomen
45yearsofage[5,6].ThisisachangefromthepriorBethesda2001recommendation,whichsettheageat40
years[4].

ThechangeinagewasmadetoimprovetheeffectivenessofafindingofBECasapredictorofendometrial
hyperplasiaorcarcinoma.TheevaluationofafindingofBECshouldbeguidedbymenopausalstatusandabnormal
uterinebleedingsymptoms.However,theBethesdaguidelinesuseanagecriterionbecauseitcanbedifficultto
determinemenopausalstatus.Womenforwhommenopausalstatusisuncertainshouldbeevaluatedasiftheyare
postmenopausal.

Theagecriterionwassetat40yearsintheBethesda2001systemtocaptureasmanypostmenopausalwomenas
possiblehowever,thiswasnotfoundtohaveahighpositivepredictivevalueforendometrialneoplasia[5,6,41].
Thus,inanefforttoincreasethepositivepredictivevalueofbenignendometrialcellsforpossibleneoplasia,the
Bethesda2014guidelinesrecommendedincreasingtheageatwhichendometrialinvestigationisindicatedto45
years.(See"Clinicalmanifestationsanddiagnosisofmenopause",sectionon'Diagnosis'.)

BECarenotedinupto12percentofPapcervicalcytologytestsperformedoveroneyear,morecommonlyin
premenopausalthanpostmenopausalwomen[42].TheprevalenceofBECinwomenwhoareolderthan40years
and/orpostmenopausalis0.4percentofspecimens[43].Theprevalenceissignificantlyhigherinliquidbasedthan
conventionalcytology(0.9versus0.3percent)liquidbasedcytologyismorecommonlyusedincurrentpracticein
mosthighresourcecountries.

ThepresenceofBECmayreflectphysiologicshedding(especiallyinthefirsthalfofthemenstrualcycle)orshedding
inresponsetoapathologicprocess.LargeliteraturereviewsofBECinwomenoverage40havereportedthat7to
16percentofcervicalcytologyspecimenswiththisfindingwereassociatedwithendometrialhyperplasiaor
carcinomauponfurtherevaluation[42,43].

BethesdaguidelinesadvisethatBECshouldbereportedregardlessofthelastmenstrualperioddate.The
prevalenceofafindingofBECvarieswiththemenstrualcycle.Combinedresultsfromtwolargestudiesshowedthat
benignappearingendometrialcellsaremorelikelytobeidentifiedoncervicovaginalcytologytestsinthefirst10to
12daysofthemenstrualcycle(prevalence,21to24percent)thanintheremainderofthecycle(prevalence,2
percent)[44,45].

TheincreasedriskofendometrialneoplasiainpostmenopausalwomenwithBECwasillustratedinaretrospective
studyof400PaptestswithBECinwomen40yearsthatincluded161postmenopausalwomen[46].Amongthese
women,therateofendometrialcarcinomaanditsprecursorswashigherinwomenwithBECthanotherwomen.
Thisincludedbothwomenwithpostmenopausalbleeding(BEC:16.4versus10.9percent)aswellaswithout
postmenopausalbleeding(7.6versus0percent).

Abnormaluterinebleedingisthemainsymptomofendometrialneoplasiaandwarrantsfurtherevaluation.Itappears
thatforwomenwithabnormaluterinebleeding,thepresenceofBECdoesnotaddmuchclinicalinformation
regardingrisk[4753].Manyofthedataregardingthisissuewerecompiledwithathresholdof40yearsbasedon
theBethesda2001guidelines,andoutcomesarenotgenerallyreportedaccordingtomenopausalstatus.Asan
example,aretrospectivecohortstudyof186women40years(median48years,menopausalstatuswasnot
assessed)withabnormaluterinebleedingfoundthatwomenwithversuswithoutBEConcervicalcytologyhadno
significantdifferenceintherateofatypicalendometrialhyperplasia(1.6versus1.0percent)orendometrial
carcinoma(2.2verus2.3percent)[54].Inaddition,inaliteraturereviewthatincluded22studies,amongwomenwith
significantpathology,79percentalsohadabnormalbleeding[43].

Giventheavailableevidence,forasymptomaticpatientswithBEConacervicalcytologyspecimen:

Forpostmenopausalwomen,werecommendanevaluationforendometrialhyperplasiaorcarcinoma.

Forpremenopausalwomen,wesuggestanevaluationforendometrialhyperplasiaorcarcinomaonlyifthe
patientisatincreasedriskforendometrialcarcinoma(eg,priorendometrialhyperplasia,tamoxifenuse,chronic
anovulation,obesity,diabetes)(table6).(See"Endometrialcarcinoma:Epidemiologyandriskfactors",section
on'Riskfactors'.)

Ifsymptomsofendometrialcarcinomaarepresent(ie,abnormaluterinebleedinginpremenopausalpatientsor
postmenopausalbleeding),thepatientshouldundergoevaluationforendometrialhyperplasiaorcarcinoma
regardlessofmenopausalstatus(table7).(See"Approachtoabnormaluterinebleedinginnonpregnant
reproductiveagewomen"and"Postmenopausaluterinebleeding".)

TheserecommendationsareconsistentwithAmericanSocietyforColposcopyandCervicalPathology(ASCCP)
2012guidelines[13].

OthertypesofmalignancyThepresenceofanyothertypesofmalignantcellsshouldbedescribed.Asan
example,thecervicalcytologytestmayoccasionallyidentifymalignantcellsfromthefallopiantube,ovary,peritoneal
cavity,vulva,orvagina.Thisshouldbekeptinmind,especiallyinwomenwithpersistentAGCthatremains
unexplainedaftercervicalandendometrialevaluation.Inthesecases,referraltoagynecologiconcologistis
recommended.

InfectiousorganismsThepresenceofinfectiondoesnotprecludefurtherevaluationofanepithelialcell
abnormality.Whenaninfectiousorganismisidentifiedorsuggested,thepatientshouldbecontactedtodetermineif
sheissymptomatic.Antibiotictherapyisindicatedforanysymptomaticinfection[55].(See"Approachtowomenwith
symptomsofvaginitis".)

TrichomonasAsymptomatictrichomonasinfectionshouldbetreatedifthediagnosisisreasonablycertain.
LiquidbasedcervicalcytologyfordiagnosisoftrichomoniasisismoreaccuratethanconventionalPapsmears.
Thesensitivity,specificity,andpositiveandnegativepredictivevaluesofliquidbasedcervicalcytologytestsfor
trichomonasinfectionare61,99,96,and91percent,respectively[56].ConventionalPapsmearshaveahigh
falsepositiveratefortrichomonads.Therefore,thediagnosisshouldbeconfirmedbywetprepinasymptomatic
women.However,ifthewetprepisnegative,thencultureisindicatedbecauseofthelowsensitivityofwetprep
forthisorganism.(See"Trichomoniasis".)

BacterialvaginosisCervicalcytologyisnotareliablediagnosticmethodforbacterialvaginosis(BV),and
womenwithacytologicreportofBVneedconfirmationwithclinicaltestingbeforetreatment.Further,clinical
diagnosisofBVisnotassociatedwithCIN[57].However,acytologicreportofBVoccurs10timesmore
 commonlyinwomenwithversuswithoutHSIL[58].Theclinicalsignificanceofthisfindingisunknown.(See
"Bacterialvaginosis:Clinicalmanifestationsanddiagnosis",sectionon'Diagnosis'.)

HerpessimplexHerpessimplexmayproducecharacteristiccytopathologicchanges(multinucleatedgiant
cells).(See"Epidemiology,clinicalmanifestations,anddiagnosisofgenitalherpessimplexvirusinfection".)

ActinomycesActinomycesmaybeidentifiedoncervicalcytologytests,typicallyinwomenwhohavean
intrauterinedevice.(See"Intrauterinecontraception:Managementofsideeffectsandcomplications",sectionon
'Actinomycesandrelatedorganisms'.)

ChlamydiaChlamydiainfectioncannotbereliablydiagnosedbycervicalcytologytests[59].

Othernonneoplasticfindings

Reactivechanges/inflammationMostpatientswithonlyreactivechangesduetoinflammationwillnot
haveanorganismidentifiedontheircervicalcytologytest.Thecervicalcytologysamplingdoesnotneedtobe
repeatedunlessthepatientisHIVpositive(orhasahistoryofimmunosuppression),inwhichcaseitshouldbe
repeatedinfourtosixmonths.(See"ScreeningforcervicalcancerinHIVinfectedwomenandadolescents".)

ParabasalcellsParabasalcellsaremostlikelytobeseenpriortomenarcheorfollowingmenopause,
whentheepitheliumisnotfullyglycogenated.Theycarrynosignificanceotherthanbeingoccasionallyconfusedwith
dysplasticcellsduetotheirimmatureappearance.

HyperkeratosisHyperkeratosisorparakeratosisonanotherwisenegativecervicalcytologytestisnota
markerforsignificantCIN[55,60]andmayberelatedtoinfectionortraumawithinflammation,suchasfromuseofa
diaphragm.Wedonotperformcolposcopybasedonthisfinding.Werepeatthecervicalcytologytestin6to12
months,dependinguponwhetherthepatientisatincreasedriskforCIN,suchasimmunocompromisedorageless
than30.Ifhyperkeratosispersists,treatmentwithtopicalestrogenmayresolvethefinding,butnotreatmentis
necessary.(See"Cervicalcytology:Evaluationofatypicalsquamouscells(ASCUSandASCH)".)

FOLLOWUPOFCYTOLOGICRESULTS

NormalcytologyFollowupofpatientswithanormalresultoncervicalcytologyisdiscussedseparately.(See
"Screeningforcervicalcancer".)

HPVpositiveWomenwithnegativecytologyandpositivehighriskhumanpapillomavirus(HPV)testinghave
anincreasedriskofcervicalprecancerorcancerthanwomenwithnegativeHPVtesting.HighriskHPVtesting
referstotestingforapanelofhighriskHPVtypestheresultsarereportedaspositiveornegativeandnoindividual
typeisidentified(table8).GenotypingforHPV16and18testssolelyforthesetwosubtypes.

AstudyofapproximatelyonemillioncervicalcytologyspecimensinwomenintheKaiserPermanenteMedical
Program,alargehealthcarepracticeintheUnitedStates,evaluatedthefiveyearriskofcervicalneoplasiainwomen
ages30to64[61,62].Theriskswereasfollows:

Negativecytologyalone(regardlessofHPVresults)Cervicalintraepithelialneoplasiagrade2ormoresevere
(CIN2+)(0.68percent),CIN3+(0.26percent),cervicalcancer(0.025percent)

Cytologynegative,HPVnegativeCIN2+(0.27percent),CIN3+(0.08percent),cervicalcancer(0.011
percent)

Cytologynegative,HPVpositiveCIN2+(10percent),CIN3+(4.5percent),cervicalcancer(0.34percent)

MostexpertsandsocietiesagreewiththeAmericanSocietyforColposcopyandCervicalPathologyguidelines,
whichadvisethatpatientswithnormalcytologyandpositivehighriskHPVtestingbeevaluatedinoneoftwoways
(algorithm3)[13,63]:
 CytologyandHPVcotestingat12months

Alternatively,genotypingforHPV16and18(thetypesthatareassociatedwiththehighestriskofcervical
cancer):

PositiveforHPV16or18Colposcopyshouldbeperformed.Inourpractice,wealsodoanendocervical
curettageinthesepatientsbecausenormalcytologywithpersistentHPVinfectioncanbeassociatedwith
endocervical/glandularabnormalities,whicharelessreliablydetectedbycolposcopyalone[64].

NegativeforHPV16or18RepeatcytologyandHPVcotestinginoneyear.

Ifcotestingorcolposcopyresultsarepositive,thepatientshouldbemanagedasappropriate.(See"Cervical
intraepithelialneoplasia:Managementoflowgradeandhighgradelesions"and"Cervicalcytology:Evaluationof
atypicalsquamouscells(ASCUSandASCH)"and"Cervicalcytology:Evaluationoflowgradesquamous
intraepitheliallesions(LSIL)"and"Cervicalcytology:Evaluationofhighgradesquamousintraepitheliallesions
(HSIL)".)

SomepatientswithnormalcytologywillhavepersistenthighriskHPVpositivetestingwithnoHPV16/18genotyping
ornegativeHPV16/18genotyping.ThisisnotaclinicalscenariothatisincludedintheAmericanSocietyfor
ColposcopyandCervicalPathology(ASCCP)guidelinesandtherearenolongitudinaldataregardinghowtofurther
evaluatethesepatients.WomenwithpersistentHPVinfectionareatahigherriskofcervicalneoplasiathanthose
withtransientinfection[62,65].Inourpractice,forthesewomen,weperformHPV16/18genotypingifithasnotyet
beenperformed,andthenperformcolposcopyifpositive,asadvisedbytheASCCPguidelines.Ifthepatienthas
hadtworesultsthatarecytologynegative,highriskHPVpositive,andHPV16/18genotypingnegative,weperform
colposcopy.

PersistentHPVinfectionisdiscussedindetailseparately.(See"Cervicalcytology:Evaluationofatypicalsquamous
cells(ASCUSandASCH)",sectionon'PersistentHPVpositiveASCUS'.)

AbnormalcytologyPatientswithsignificantcytologicalabnormalitiesneedfurtherevaluation,whichmayinclude
repeatcytology,HPVtesting,orcolposcopy.Evaluationoftheresultsofcervicalcytologyisdiscussedindetail
separately.(See"Cervicalcytology:Evaluationofatypicalsquamouscells(ASCUSandASCH)"and"Cervical
cytology:Evaluationoflowgradesquamousintraepitheliallesions(LSIL)"and"Cervicalcytology:Evaluationofhigh
gradesquamousintraepitheliallesions(HSIL)".)

VAGINALCYTOLOGY

RiskofmalignancyFollowingtotalhysterectomy(removaloftheuterusandcervix),vaginalcytologyisnot
requiredformostwomen,particularlythosewithdocumentedbenigncervicalfindingsinthehysterectomyspecimen.
Vaginalcancerisrare(<1per100,000women)andvaginalcytologyshouldbeperformedonlyinwomenwhoareat
increasedrisk.(See"Screeningforcervicalcancer",sectionon'Priorhysterectomy'.)

Theriskofvaginalintraepithelialneoplasia(VAIN)orvaginalcancerisextremelylowinwomenwhohaveundergone
totalhysterectomyforbenigndisease(excludingthosewithcervicalintraepithelialneoplasia[CIN]2,3).Thelargest
studyofthisissueincluded5682womenwithapriorhysterectomyforbenigngynecologicdisease[66].Ofthe9610
cytologysamples,104(1.1percent)wereabnormal,including0.5percentatypicalsquamouscellsofundetermined
significance(ASCUS),0.5percentlowgradesquamousepitheliallesion(LSIL),0.1percenthighgradesquamous
epitheliallesion(HSIL),and0.02percentsquamouscellcarcinoma.Biopsyshowednocasesofvaginalcancerand
onlysixcasesofLSIL/VaIN1orHSIL/VaIN2.

IndicationsBasedonthelowriskofvaginalcancer,screeningguidelinesintheUnitedStatesfromtheUS
PreventiveServicesTaskForce(USPSTF),theAmericanCancerSociety(ACS),andtheAmericanCollegeof
ObstetriciansandGynecologists(ACOG)concurthatwomenwhohaveundergonetotalhysterectomyandwhodo
nothaveahistoryofanalorgynecologiccancerorCIN2,3doNOTneedposthysterectomyvaginalcytology.(See
"Cervicalintraepithelialneoplasia:Treatmentandfollowup",sectionon'Posthysterectomy'and"Screeningfor
cervicalcancer",sectionon'Priorhysterectomy'.)

Humanpapillomavirus(HPV)istheetiologicagentofmostvaginalcancers,aswellasotheranogenital
malignancies.WomenwhoareimmunosuppressedhavedecreasedratesofclearanceofHPVinfection.Inaddition,
womenexposedtodiethylstilbestrol(DES)inuteroareatriskofdevelopingvaginalclearcelladenocarcinoma.
Thus,vaginalcytologyforvaginalcancerscreeningisadvisableforwomenwhohaveundergonetotalhysterectomy
whohavethefollowingcharacteristics:

CIN2,3orcervicaladenocarcinomainsitupriortoordiagnosedatthetimeoftotalhysterectomy.TheACOG
recommendsongoingscreeningofthesewomenforatleast20yearsaftertreatmentofCIN2,3[67].(See
"Cervicalintraepithelialneoplasia:Treatmentandfollowup",sectionon'Posthysterectomy'.)

Priorvaginalcancer(see"Vaginalcancer",sectionon'Posttreatmentsurveillance')

Priorcervical,vulvar,oranalcancer(see"Invasivecervicalcancer:Patternsofrecurrenceandposttreatment
surveillance",sectionon'Surveillancestrategies'and"Clinicalfeatures,staging,andtreatmentofanalcancer",
sectionon'Posttreatmentsurveillance')

InuteroexposuretoDES(see"Outcomeandfollowupofdiethylstilbestrol(DES)exposedindividuals",section
on'Clearcelladenocarcinoma')

Immunosuppression(eg,humanimmunodeficiencyinfection,historyofsolidorganorhematopoieticcell
transplant)(see"Screeningforcervicalcancer",sectionon'Immunocompromisedwomen')

ManagementofresultsIfvaginalcytologyisperformed,thefindingsarereportedinthesamemanneras
cervicalcytology.Thesampleshouldbelabeledasavaginalsamplebecausepathologyevaluationcannottypically
differentiatebetweenvaginalandsquamouscervicalcells.Ifendocervicalcolumnarorbenignglandularcellsare
present,thisismentionedinthepathologyreport.

Benignglandularcellsareseeninlessthan2percentofvaginalcytologyspecimensfollowinghysterectomy[68].
Theyarepresumedtobetheconsequenceofeithercolumnarmetaplasiaorreactivephenomena.Theydonot
requirefurtherevaluation.

ForwomenwhoundergovaginalcytologyforahistoryofCIN2,3orcervicaladenocarcinomainsitu,theAmerican
SocietyforColposcopyandCervicalPathology(ASCCP)hasproposedthefollowingevaluationforabnormalvaginal
cytologyresults(algorithm4)[69]:

HSILoratypicalsquamouscellscannotruleouthighgradelesion(ASCH)oratypicalglandularcells(AGC)
Performvaginalcolposcopy

ASCUSorLSIL

IfHPVgenotypingisnotavailable:

HPVpositive(ifHPVgenotypingisnotavailable),HPVnegative,orHPVnotperformedIn12
months,repeatcytologyorperformcotestingwithcytologyandHPVtesting

IfHPVgenotypingisavailable:

HPV16/18positiveVaginalcolposcopy

HPV16/18negativeIn12and24months,repeatcytologyorperformcotestingwithcytologyand
HPVtesting.

Negativeforintraepitheliallesionormalignancy(NILM)
 IfHPVgenotypingisnotavailable:

HPVpositive,HPVnegative,orHPVnotperformedIn12months,repeatcytologyorperform
cotestingwithcytologyandHPVtesting.

IfHPVgenotypingisavailable:

HPV16/18positiveorHPV16/18negativeIn12and24months,repeatcytologyorperform
cotestingwithcytologyandHPVtesting.Intheabsenceofcytologicabnormalities,colposcopyisnot
recommendedbytheASCCP.

ForNILM,ASCUS,LSIL,whenfollowupcytologyorcotestingareperformed,resultsshouldbemanagedas:

NILMcombinedwithHPVnegativeReturntoappropriatescreeningorstopscreening.Itisimportantto
notethatscreeningisNOTindicatedformostwomenaftertotalhysterectomy.(See'Indications'above.)

ASCUSorHPVpositivePerformvaginalcolposcopy

Forwomenwhohaveundergonetotalhysterectomy,donothavehistoryofgynecologicneoplasia,whoare
screenedwithvaginalcytology(despiteguidelinesagainstthispractice),andfoundtohaveanabnormality,followup
oftheabnormalitywillbedictatedbymultiplefactors.Theriskofvaginalneoplasiaisverylow,butfollowupshould
bedeterminedbaseduponseverityofthecytologicfindingsandclinicalestimationofriskofvaginalcancer[69].

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and
"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyondthe
Basicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe
10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewith
somemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
"patientinfo"andthekeyword(s)ofinterest.)

BeyondtheBasicstopic(see"Patienteducation:Cervicalcancerscreening(BeyondtheBasics)")

SUMMARYANDRECOMMENDATIONS

Cervicalcytology(Paptest)isastandardpartofcervicalcancerscreening.Cervicalcytologymaydetect
squamousorglandularabnormalities.(See'Introduction'above.)

Themanagementofapatientwhosecytologyisnegativeforanintraepitheliallesionbuthasno
endocervical/transformationzonecomponentcanbebasedontheresultsofhighriskhumanpapillomavirus
(HPV)testing(see'Absentendocervicalcell/transformationzonecomponent'above):

Womenages30years:

HPVpositiveTherearetwooptions:genotypingforHPVtypes16and18orHPVandcytologyco
testinginoneyear.
HPVnegativeThepatientmayresumeroutinescreening.
HPVstatusunknownTherearetwooptions:HPVtesting(preferred)orcytologymayberepeatedin
threeyears.

Womenages21to29yearsmayreturntoroutinescreening.
 Theevaluationofunsatisfactorycytology(typicallyduetoscantcellularityinthespecimen)isbasedupon
HPVtesting(see'Unsatisfactoryforevaluation'above):

Womenages30years:

HPVpositiveCytologyshouldberepeatedintwotofourmonthsorcolposcopymaybeperformed.
HPVnegativeCytologyshouldberepeatedintwotofourmonths.

IfHPVtestinghasnotbeenperformed(aspercervicalcancerscreeningguidelinesinwomenages21to29
(table4)),cytologyshouldberepeatedintwotofourmonths.

Squamousorglandularabnormalitiesrequirefurtherassessmenttoexcludecanceroraprecancerouslesion.
(See'Intraepithelialcellabnormalities'above.)

IntheBethesda2014guidelines,lowgradesquamousintraepitheliallesion(LSIL)cervicalcytologicspecimens
thatcontainafewcellsthataresuspiciousforbutnotdiagnosticofhighgradesquamousintraepitheliallesion
(HSIL)arereportedasASCH.(See'ASCHincludesLSILwithsomeHSILcells'above.)

IntheBethesda2014guidelines,benignappearingendometrialcellsarereportedonlyinwomen45years.
ThisisachangefromBethesda2001,whichusedanagethresholdof40years.Forpatientswhoare45
yearsandhaveacervicalcytologytestshowingbenignappearingendometrialcellsandwhohaveno
symptomsofabnormaluterinebleedingorpostmenopausalbleeding(see'Benignappearingendometrialcells
inwomen45years'above):

Forpostmenopausalwomen,werecommendanevaluationforendometrialhyperplasiaorcarcinoma.

Forpremenopausalwomen,wesuggestanevaluationforendometrialhyperplasiaorcarcinomaonlyif
thepatientisatincreasedriskforendometrialcarcinoma(eg,priorendometrialhyperplasia,tamoxifenuse,
chronicanovulation,obesity,diabetes)(table6).

Ifsymptomsofendometrialcarcinomaarepresent(ie,abnormaluterinebleedinginpremenopausalpatientsor
postmenopausalbleeding),thepatientshouldundergoevaluationforendometrialhyperplasiaorcarcinoma
regardlessofmenopausalstatus(table7).

PatientswithnormalcytologyandpositiveHPVtestingmaybefurtherevaluatedeitherwithcytologyandHPV
cotestingat12monthsorwithgenotypingforHPV16and18,thetypesthatareassociatedwiththehighest
riskofcervicalcancer(algorithm3).(See'HPVpositive'above.)

Forasymptomaticorsymptomaticwomenwithtrichomonasinfectiondetectedoncervicalcytology,wesuggest
treatment(Grade2C).Thesensitivityandspecificityofliquidbasedcervicalcytologytestsfortrichomonas
infectionare61and99percent,respectively.(See'Infectiousorganisms'above.)

Followingtotalhysterectomy,vaginalcytologyisnotrequiredformostwomen,particularlythosewith
documentedbenigncervicalfindingsinthehysterectomyspecimen.Ifvaginalcytologyisindicatedand
abnormalitiesarefound,theindicationsforfurtherevaluationwithvaginalcolposcopyarethesameasfor
abnormalcervicalcytologyfindings.(See'Vaginalcytology'above.)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

REFERENCES

1.PapanicolaouGN,TrautHF.Thediagnosticvalueofvaginalsmearsincarcinomaoftheuterus.AmJObstet
Gynecol194142:193.
 2.The1988BethesdaSystemforreportingcervical/vaginalcytologicaldiagnoses.NationalCancerInstitute
Workshop.JAMA1989262:931.
3.BroderS.FromtheNationalInstitutesofHealth.JAMA1992267:1892.
4.SolomonD,DaveyD,KurmanR,etal.The2001BethesdaSystem:terminologyforreportingresultsofcervical
cytology.JAMA2002287:2114.
5.NayarR,WilburDC.ThePaptestandBethesda2014.CancerCytopathol2015123:271.
6.NayarR,WilburDC.ThePapTestandBethesda2014:"Thereportsofmydemisehavebeengreatly
exaggerated.(afteraquotationfromMarkTwain)".JLowGenitTractDis201519:175.
7.KurmanR,SolomonD.TheBethesdaSystemforReportingCervical/VaginalCytologicDiagnoses,SpringerVe
rlag,NewYork,NY1994.
8.HoGY,BiermanR,BeardsleyL,etal.Naturalhistoryofcervicovaginalpapillomavirusinfectioninyoung
women.NEnglJMed1998338:423.
9.WaxmanAG,ChelmowD,DarraghTM,etal.Revisedterminologyforcervicalhistopathologyandits
implicationsformanagementofhighgradesquamousintraepitheliallesionsofthecervix.ObstetGynecol
2012120:1465.
10.DarraghTM,ColganTJ,ThomasCoxJ,etal.TheLowerAnogenitalSquamousTerminologyStandardization
projectforHPVassociatedlesions:backgroundandconsensusrecommendationsfromtheCollegeof
AmericanPathologistsandtheAmericanSocietyforColposcopyandCervicalPathology.IntJGynecolPathol
201332:76.
11.DaveyDD,CoxJT,AustinRM,etal.Cervicalcytologyspecimenadequacy:patientmanagementguidelines
andoptimizingspecimencollection.JLowGenitTractDis200812:71.
12.JosteN.Overviewofthecytologylaboratory:specimenprocessingthroughdiagnosis.ObstetGynecolClin
NorthAm200835:549.
13.MassadLS,EinsteinMH,HuhWK,etal.2012updatedconsensusguidelinesforthemanagementofabnormal
cervicalcancerscreeningtestsandcancerprecursors.JLowGenitTractDis201317:S1.
14.HerfsM,YamamotoY,LauryA,etal.Adiscretepopulationofsquamocolumnarjunctioncellsimplicatedinthe
pathogenesisofcervicalcancer.ProcNatlAcadSciUSA2012109:10516.
15.SchiffmanM,CastlePE,JeronimoJ,etal.Humanpapillomavirusandcervicalcancer.Lancet2007370:890.
16.BaerA,KiviatNB,KulasingamS,etal.LiquidbasedPapanicolaousmearswithoutatransformationzone
component:shouldcliniciansworry?ObstetGynecol200299:1053.
17.ZhaoC,AustinRM.AdjunctivehighriskhumanpapillomavirusDNAtestingisausefuloptionfordiseaserisk
assessmentinpatientswithnegativePapanicolaoutestswithoutanendocervical/transformationzonesample.
Cancer2008114:242.
18.VooijsPG,EliasA,vanderGraafY,VelingS.Relationshipbetweenthediagnosisofepithelialabnormalities
andthecompositionofcervicalsmears.ActaCytol198529:323.
19.KivlahanC,IngramE.Papanicolaousmearswithoutendocervicalcells.Aretheyinadequate?ActaCytol1986
30:258.
20.MartinHirschP,LilfordR,JarvisG,KitchenerHC.Efficacyofcervicalsmearcollectiondevices:asystematic
reviewandmetaanalysis.Lancet1999354:1763.
21.MitchellHS.Longitudinalanalysisofhistologichighgradediseaseafternegativecervicalcytologyaccordingto
endocervicalstatus.Cancer200193:237.
22.MitchellH,MedleyG.Longitudinalstudyofwomenwithnegativecervicalsmearsaccordingtoendocervical
status.Lancet1991337:265.
23.BosAB,vanBallegooijenM,vandenAkkervanMarleME,etal.Endocervicalstatusisnotpredictiveofthe
incidenceofcervicalcancerintheyearsafternegativesmears.AmJClinPathol2001115:851.
24.TackenMA,BraspenningJC,MulderJ,etal.Losstofollowupofcervicalsmearswithoutendocervical
columnarcellsisnotdisturbing.EurJGynaecolOncol200627:42.
25.SmithHO,TiffanyMF,QuallsCR,KeyCR.Therisingincidenceofadenocarcinomarelativetosquamouscell
carcinomaoftheuterinecervixintheUnitedStatesa24yearpopulationbasedstudy.GynecolOncol2000
78:97.
26.MitchellH,HockingJ,SavilleM.Cervicalcytologyscreeninghistoryofwomendiagnosedwithadenocarcinoma
insituofthecervix:acasecontrolstudy.ActaCytol200448:595.
27.CastlePE,WacholderS,ShermanME,etal.Absoluteriskofasubsequentabnormalpapamongoncogenic
humanpapillomavirusDNApositive,cytologicallynegativewomen.Cancer200295:2145.
28.BansalM,AustinRM,ZhaoC.HighriskHPVDNAdetectedinlessthan2%ofover25,000cytologynegative
imagedliquidbasedPaptestsamplesfromwomen30andolder.GynecolOncol2009115:257.
29.DaveyDD,AustinRM,BirdsongG,etal.ASCCPPatientManagementGuidelines:PapTestSpecimen
AdequacyandQualityIndicators.JLowGenitTractDis20026:195.
30.HockYL,RamaiahS,WallES,etal.Outcomeofwomenwithinadequatecervicalsmearsfollowedupforfive
years.JClinPathol200356:592.
31.RansdellJS,DaveyDD,ZaleskiS.ClinicopathologiccorrelationoftheunsatisfactoryPapanicolaousmear.
Cancer199781:139.
32.AdamsAL,GidleyJ,RobersonJ,etal.Clinicalsignificanceofunsatisfactoryconventionalpapsmearsowingto
inadequatesquamouscellularitydefinedbytheBethesda2001criterion.AmJClinPathol2005123:738.
33.MoriartyAT,ClaytonAC,ZaleskiS,etal.Unsatisfactoryreportingrates:2006practicesofparticipantsinthe
collegeofamericanpathologistsinterlaboratorycomparisonprogramingynecologiccytology.ArchPatholLab
Med2009133:1912.
34.HodaRS,LoukerisK,AbdulKarimFW.Gynecologiccytologyonconventionalandliquidbasedpreparations:a
comprehensivereviewofsimilaritiesanddifferences.DiagnCytopathol201341:257.
35.ShermanME,SolomonD,SchiffmanM,ASCUSLSILTriageStudyGroup.QualificationofASCUS.A
comparisonofequivocalLSILandequivocalHSILcervicalcytologyintheASCUSLSILTriageStudy.AmJClin
Pathol2001116:386.
36.QuddusMR,SungCJ,SteinhoffMM,etal.Atypicalsquamousmetaplasticcells:reproducibility,outcome,and
diagnosticfeaturesonThinPrepPaptest.Cancer200193:16.
37.ShermanME,TabbaraSO,ScottDR,etal."ASCUS,ruleoutHSIL":cytologicfeatures,histologiccorrelates,
andhumanpapillomavirusdetection.ModPathol199912:335.
38.NasserSM,CibasES,CrumCP,FaquinWC.ThesignificanceofthePapanicolaousmeardiagnosisoflow
gradesquamousintraepitheliallesioncannotexcludehighgradesquamousintraepitheliallesion.Cancer2003
99:272.
39.AlsharifM,KjeldahlK,CurranC,etal.Clinicalsignificanceofthediagnosisoflowgradesquamous
intraepitheliallesion,cannotexcludehighgradesquamousintraepitheliallesion.Cancer2009117:92.
40.JonesBA,NovisDA.Cervicalbiopsycytologycorrelation.ACollegeofAmericanPathologistsQProbesstudy
of22439correlationsin348laboratories.ArchPatholLabMed1996120:523.
41.ThrallM,KjeldahlK,SavikK,etal.Rateofendometrialadenocarcinomainwomenscreenedbeforeandafter
implementationoftheBethesda2001reportingsystem.ActaCytol200852:1.
42.FadareO,GhofraniM,ChachoMS,ParkashV.Thesignificanceofbenignendometrialcellsincervicovaginal
smears.AdvAnatPathol200512:274.
43.CanfellK,KangYJ,ClementsM,etal.Normalendometrialcellsincervicalcytology:systematicreviewof
prevalenceandrelationtosignificantendometrialpathology.JMedScreen200815:188.
44.VooijsGP,vanderGraafY,VooijsMA.Thepresenceofendometrialcellsincervicalsmearsinrelationtothe
dayofthemenstrualcycleandthemethodofcontraception.ActaCytol198731:427.
45.LIUW,BARROWMJ,SPITLERMF,KOCHISAF.NORMALEXFOLIATIONOFENDOMETRIALCELLSIN
PREMENOPAUSALWOMEN.ActaCytol19637:211.
46.AslanDL,CrapanzanoJP,HarshanM,etal.TheBethesdaSystem2001recommendationforreportingof
benignappearingendometrialcellsinPaptestsofwomenage40yearsandolderleadstounwarranted
surveillancewhenfollowedwithoutclinicalqualifiers.GynecolOncol2007107:86.
47.BeanSM,ConnollyK,RobersonJ,etal.Incidenceandclinicalsignificanceofmorphologicallybenign
appearingendometrialcellsinpatientsage40yearsorolder:theimpactofthe2001BethesdaSystem.Cancer
2006108:39.
48.GreenspanDL,CardilloM,DaveyDD,etal.Endometrialcellsincervicalcytology:reviewofcytological
featuresandclinicalassessment.JLowGenitTractDis200610:111.
49.ThrallMJ,KjeldahlKS,SavikK,etal.Significanceofbenignendometrialcellsinpapanicolaoutestsfrom
womenaged>or=40years.Cancer2005105:207.
50.SimsirA,CarterW,ElgertP,CangiarellaJ.Reportingendometrialcellsinwomen40yearsandolder:
assessingtheclinicalusefulnessofBethesda2001.AmJClinPathol2005123:571.
51.AshfaqR,SharmaS,DulleyT,etal.Clinicalrelevanceofbenignendometrialcellsinpostmenopausalwomen.
DiagnCytopathol200125:235.
52.ChangA,SandweissL,BoseS.Cytologicallybenignendometrialcellsinthepapanicolaousmearsof
postmenopausalwomen.GynecolOncol200180:37.
53.BealHN,StoneJ,BeckmannMJ,McAseyME.Endometrialcellsidentifiedincervicalcytologyinwomen>or=
40yearsofage:criteriaforappropriateendometrialevaluation.AmJObstetGynecol2007196:568.e1.
54.MoatamedNA,LeLT,LevinMR,etal.InPapanicolaousmears,benignappearingendometrialcellsbearno
significanceinpredictinguterineendometrialadenocarcinomas.DiagnCytopathol201341:335.
55.ZahnCM,AskewAW,HallKL,BarthWHJr.Thesignificanceofhyperkeratosis/parakeratosisonotherwise
normalPapanicolaousmears.AmJObstetGynecol2002187:997.
56.LaraTorreE,PinkertonJS.Accuracyofdetectionoftrichomonasvaginalisorganismsonaliquidbased
papanicolaousmear.AmJObstetGynecol2003188:354.
57.PetersN,VanLeeuwenAM,PietersWJ,etal.Bacterialvaginosisisnotimportantintheetiologyofcervical
neoplasia:asurveyonwomenwithdyskaryoticsmears.SexTransmDis199522:296.
58.KlompJM,BoonME,VanHaaftenM,HeintzAP.CytologicallydiagnosedGardnerellavaginalisinfectionand
cervical(pre)neoplasiaasestablishedinpopulationbasedcervicalscreening.AmJObstetGynecol2008
199:480.e1.
59.PanditAA,KlhilnaniPH,PowarHS,etal.ValueofPapanicolaousmearindetectionofChlamydiatrachomatis
infection.DiagnCytopathol19939:164.
60.CecchiniS,IossaA,CiattoS,etal.ColposcopicsurveyofPapanicolaoutestnegativecaseswith
hyperkeratosisorparakeratosis.ObstetGynecol199076:857.
61.KatkiHA,SchiffmanM,CastlePE,etal.BenchmarkingCIN3+riskasthebasisforincorporatingHPVandPap
cotestingintocervicalscreeningandmanagementguidelines.JLowGenitTractDis201317:S28.
62.KatkiHA,SchiffmanM,CastlePE,etal.FiveyearrisksofCIN3+andcervicalcanceramongwomenwhotest
PapnegativebutareHPVpositive.JLowGenitTractDis201317:S56.
 63.CommitteeonPracticeBulletinsGynecology.PracticeBulletinNo.168:CervicalCancerScreeningand
Prevention.ObstetGynecol2016128:e111.
64.CoxJT,CastlePE,BehrensCM,etal.Comparisonofcervicalcancerscreeningstrategiesincorporating
differentcombinationsofcytology,HPVtesting,andgenotypingforHPV16/18:resultsfromtheATHENAHPV
study.AmJObstetGynecol2013208:184.e1.
65.KjrSK,FrederiksenK,MunkC,IftnerT.Longtermabsoluteriskofcervicalintraepithelialneoplasiagrade3
orworsefollowinghumanpapillomavirusinfection:roleofpersistence.JNatlCancerInst2010102:1478.
66.PearceKF,HaefnerHK,SarwarSF,NolanTE.CytopathologicalfindingsonvaginalPapanicolaousmearsafter
hysterectomyforbenigngynecologicdisease.NEnglJMed1996335:1559.
67.CommitteeonPracticeBulletinsGynecology.ACOGPracticeBulletinNumber131:Screeningforcervical
cancer.ObstetGynecol2012120:1222.
68.TambouretR,PitmanMB,BellDA.Benignglandularcellsinposthysterectomyvaginalsmears.ActaCytol
199842:1403.
69.KhanMJ,MassadLS,KinneyW,etal.Acommonclinicaldilemma:Managementofabnormalvaginalcytology
andhumanpapillomavirustestresults.GynecolOncol2016141:364.

Topic3205Version29.0
GRAPHICS

Bethesdaclassificationofcervicalcytology

Specimentype
Conventionalsmear,liquidbased,orothertechnique

Specimenadequacy
Satisfactoryforevaluation(descriptionincludesqualityindicators,includingendocervical/transformationzonecomponent
andobscuringbloodorinflammation)

Unsatisfactorydueto...(specifyreason)

Generalcategorization(optional)
Negativeforintraepitheliallesionormalignancy

Epithelialcellabnormality(specifysquamousorglandular)

Other:seeinterpretation/result(eg,endometrialcellsinwomanage40)

Automatedreview
Ifexaminedbyadevice,specifydeviceandresult

Ancillarytesting
Describemethodandresult(eg,moleculartesting)

Interpretation/result
Negativeforintraepitheliallesionormalignancy(whenthereisabsenceofneoplasiathisshouldbestated
specifically,regardlessofotherfindings)

Inadditiondescribe,ifpresent:
Infection(Trichomonasvaginalis,Candidaspp,shiftinfloraconsistentwithbacterialvaginosis,Actinomycesspp,cellularchanges)

Othernonneoplasticfindings,suchas,butnotlimitedto:
Reactivecellularchangesassociatedwithinflammation/cellularrepair,radiation,oranintrauterinecontraceptivedevice
Glandularcellsposthysterectomy
Atrophy

Other

Endometrialcells(inawomanage40)andspecifywhethernegativeforsquamousintraepitheliallesion

Epithelialcellabnormalities

Squamouscell

Atypicalsquamouscells(ASC)
ofundeterminedsignificance(ASCUS)
cannotexcludehighgradesquamousintraepitheliallesion(HSILASCH)

Lowgradesquamousintraepitheliallesion(LSIL)cellularchangesconsistentwithHPV,milddysplasia,CIN1

HSILmoderate/severedysplasia,CIN2,CIN3,CIS
indicateiftherearefeaturessuspiciousforinvasion(ifinvasionsuspected)

Squamouscellcarcinoma

Glandularcell

Atypical
Endocervicalcells
Endometrialcells
Nototherwisespecified

Atypical,favorneoplastic
Endocervicalcells
Nototherwisespecified
 Endocervicaladenocarcinomainsitu(AIS)

Adenocarcinoma

Othermalignantneoplasms(specify)

Educationalnotesandsuggestions
Suggestionsshouldbeconciseandconsistentwithclinicalfollowupguidelinespublishedbyprofessionalorganizations

HPV:humanpapillomavirus.

SolomonD,DaveyD,KurmanR,etal.The2001Bethesdasystem:terminologyforreportingresultsofcervicalcytology.JAMA
2002287:2114.

Graphic71416Version6.0
Terminologyandhistologyofcervicalintraepithelialneoplasia

Terminologyregardingcytologicandhistologicprecancerouschangesoftheuterinecervix.The
correspondingterminologyfromthepreviousclassificationsystemsisshown.Imagesofthehistologic
correlatesforeachcategoryarealsoshown.

LAST:loweranogenitalsquamousterminologyLSIL:lowgradesquamousintraepitheliallesionsHSIL:highgrade
squamousintraepitheliallesionsCIN:cervicalintraepithelialneoplasia.
*CIN2thatisp16positiveisclassifiedasHSIL.CIN2thatisp16negativeisclassifiedasLSIL.

References:
1.DarraghTM,ColganTJ,ThomasCoxJ,etal.TheLowerAnogenitalSquamousTerminologyStandardization
projectforHPVassociatedlesions:backgroundandconsensusrecommendationsfromtheCollegeof
AmericanPathologistsandtheAmericanSocietyforColposcopyandCervicalPathology.IntJGynecolPathol
201332:76.
2.SolomonD,DaveyD,KurmanR,etal.The2001BethesdaSystem:terminologyforreportingresultsof
cervicalcytology.JAMA2002287:2114.

Graphic60116Version7.0
Bethesda2014classificationsystemforcervicalcytology

Specimentype
Indicateconventionalsmear(Papsmear),liquidbasedpreparation(Paptest)versusother

Specimenadequacy

Satisfactoryforevaluation(describepresenceorabsenceofendocervical/transformationzonecomponentandany
otherqualityindicators,eg,partiallyobscuringblood,inflammation,etc)
Unsatisfactoryforevaluation(specifyreason)
Specimenrejected/notprocessed(specifyreason)
Specimenprocessedandexamined,butunsatisfactoryforevaluationofepithelialabnormalitybecauseof(specify
reason)

Generalcategorization(optional)

Negativeforintraepitheliallesionormalignancy
Other:see"Interpretation/results"(eg,endometrialcellsinawomanolderthan45years)
Epithelialcellabnormality:see"Interpretation/results"(specify"squamous"or"glandular,"asappropriate)

Interpretation/results
Negativeforintraepitheliallesionormalignancy

(Whenthereisnocellularevidenceofneoplasia,statethisinthe"Generalcategorization"aboveand/orinthe
"Interpretation/results"sectionofthereportwhetherthereareorganismsorothernonneoplasticfindings)

Nonneoplasticfindings(optionaltoreport)

Nonneoplasticcellularvariations:
Squamousmetaplasia
Keratoticchanges
Tubalmetaplasia
Atrophy
Pregnancyassociatedchanges
Reactivecellularchangesassociatedwith:
Inflammation(includestypicalrepair)
Lymphocytic(follicular)cervicitis
Radiation
Intrauterinecontraceptivedevice(IUD)
Glandularcellsstatusposthysterectomy

Organisms

Trichomonasvaginalis
FungalorganismsmorphologicallyconsistentwithCandidaspp.
Shiftinflorasuggestiveofbacterialvaginosis
BacteriamorphologicallyconsistentwithActinomycesspp.
Cellularchangesconsistentwithherpessimplexvirus
Cellularchangesconsistentwithcytomegalovirus

Other

Endometrialcells(inawomanolderthan45years)
(alsospecifyif"negativeforsquamousintraepitheliallesion")

Epithelialcellabnormalities

Squamouscell
Atypicalsquamouscells
Ofundeterminedsignificance(ASCUS)
CannotexcludeHSIL(ASCH)
Lowgradesquamousintraepitheliallesion(LSIL)
(encompassing:HPV/milddysplasia/CIN1)
 Highgradesquamousintraepitheliallesion(HSIL)
(encompassing:moderateandseveredysplasia,CISCIN2andCIN3)
Withfeaturessuspiciousforinvasion(ifinvasionissuspected)
Squamouscellcarcinoma
Glandularcell
Atypical
Endocervicalcells(NOSorspecifyincomments)
Endometrialcells(NOSorspecifyincomments)
Glandularcells(NOSorspecifyincomments)
Atypical
Endocervicalcells,favorneoplastic
Glandularcells,favorneoplastic
Endocervicaladenocarcinomainsitu
Adenocarcinoma
Endocervical
Endometrial
Extrauterine
Nototherwisespecified(NOS)

Othermalignantneoplasms(specify)

Adjunctivetesting
Provideabriefdescriptionofthetestmethod(s)andreporttheresultsothatitiseasilyunderstoodbytheclinician

Computerassistedinterpretationofcervicalcytology
Ifcaseexaminedbyanautomateddevice,specifythedeviceandresult

Educationalnotesandcommentsappendedtocytologyreports(optional)
Suggestionsshouldbeconciseandconsistentwithclinicalfollowupguidelinespublishedbyprofessionalorganizations
(referencestorelevantpublicationsmaybeincluded)

From:NayarR,WilburDC.ThePapTestandBethesda2014:"Thereportsofmydemisehavebeengreatlyexaggerated.(aftera
quotationfromMarkTwain)".JLowGenitTractDis201519:175.DOI:10.1097/LGT.0000000000000115.Reproducedwith
permissionfromLippincottWilliams&Wilkins.Copyright2015AmericanSocietyforColposcopyandCervicalPathology,The
InternationalSocietyfortheStudyofVulvovaginalDisease,andTheInternationalFederationofCervicalPathologyand
Colposcopy.Unauthorizedreproductionofthismaterialisprohibited.

Graphic102346Version1.0
CytologyNILMbutEC/TZAbsent/Insufficient

Reprintedfrom:TheJournalofLowerGenitalTractDiseaseVolume17,Number5,withthepermissionofASCCPAmericanSociety
forColposcopyandCervicalPathology2013.NocopiesofthealgorithmsmaybemadewithoutthepriorconsentofASCCP.

Graphic89353Version4.0
Cervicaltransformationzoneatcolposcopy

Acervicaltransformationzonewithmaturemetaplasiaandactiveimmaturemetaplasia.

ReproducedwithpermissionfromKennethHatch,MD,UniversityofArizona,DepartmentofObstetricsandGynecology.Copyright
2016.

Graphic105122Version1.0
Riskofcervicalcancerwithhumanpapillomavirus

Highrisk(oncogenicorcancerassociated)types
Commontypes:16,18,31,33,35,39,45,51,52,56,58,59,68,69,82

Lowrisk(nononcogenic)types
Commontypes:6,11,40,42,43,44,54,61,72,81

Datafrom:CentersforDiseaseControlandPrevention.NationalCancerInstituteFactsheet.Humanpapillomavirusandcancer:
Questionsandanswers.Availableat:www.cancer.gov/cancertopics/factsheet/Risk/HPV(AccessedonJune11,2012).

Graphic76394Version3.0
CervicalcancerscreeningrecommendationsfromUnitedStatesprofessional
organizations*

Recommendedscreening Post
Ageto Ageto testandfrequency hysterectomy HPV
Organization
initiate discontinue forbenign vaccination
Age21to29 Age30 disease

ACS/ASCCP/ASCP 21 65 Paptestevery Cotesting(pap Notindicated Same

(2012) threeyears testandHPV recommendations
(preferred) testing)everyfive asunvaccinated
years(preferred) women

Paptestevery
threeyears

ASCCP/SGO 21 N/A Canconsider Canconsider N/A N/A

(2015interim primaryHPV primaryHPV
guidelines) testingevery testingevery
threeyearsfor threeyears
womenage25

USPSTF(2012) 21 65 Paptestevery Paptestevery Notindicated Same

threeyears threeyears recommendations
asunvaccinated
Alternative:Co
women
testing(paptest
andHPV
testing)everyfive
years

ACOG(2016) 21 65 Paptestevery Cotesting(pap Notindicated** Same

threeyears testand recommendations
HPVtesting)every asunvaccinated
fiveyears women
(preferred)

Canconsider Paptestevery
primaryHPV threeyears
testingevery
Canconsider
threeyearsfor
primaryHPV
womenage25
testingevery
threeyearsfor
womenage25

ACP(2015) 21 65 Paptestevery Paptestevery Notindicated N/A

threeyears threeyears

Alternative:Co
testing(paptest
andHPV
testing)everyfive
years

HPV:humanpapillomavirusACS:AmericanCancerSocietyASCCP:AmericanSocietyforColposcopyandCervicalPathology
ASCP:AmericanSocietyforClinicalPathologySGO:SocietyofGynecologicOncologyUSPSTF:UnitedStatesPreventiveServices
TaskForceACOG:AmericanCollegeofObstetriciansandGynecologistsACP:AmericanCollegeofPhysiciansDES:
diethylstilbestrolHIV:humanimmunodeficiencyvirusCIN:cervicalintraepithelialneoplasia.
*Theseguidelinesareintendedforthegeneralpopulationandarenotintendedforwomenwhohaveahistoryofcervicalcancer,
highgradecervicalprecancers,DESinuteroexposure,orwhoareimmunocompromised,aswithHIVinfection.
Regardlessoftheageofsexualinitiationorotherriskfactors.
Forwomenwithevidenceofadequatenegativepriorscreening(threeconsecutivenegativecytologyresultsortwoconsecutive
negativecotestswiththeprevious10years,withthemostrecenttestwithintheprevious5years)andnohistoryofCIN2or
greaterwithinthelast20years.Screeningshouldnotberesumedforanyreason,evenifawomanhasanewsexualpartner.
ForwomenwhohavehadabenignhysterectomywithremovalofthecervixwhodonothaveahistoryofCIN2,CIN3inthe
past20years,orahistoryofcervicalcancerever.Evidenceofadequatenegativepriorscreeningnotrequired.
Forwomenwithevidenceofadequatenegativepriorscreening,specifiedasthreeconsecutivenegativecytologyresultsortwo
consecutivenegativecotestswithintheprevious10years,withthemostrecenttestwithintheprevious5years.
Forwomenwhowanttolengthenthescreeninginterval.
ForwomenwhohavehadabenignhysterectomywithremovalofthecervixwhodonothaveahistoryofCIN2orhigher.
ForwomenwithnohistoryofCIN2orhigherwithevidenceofprioradequatescreening(threeormorenegativecytologytest
resultsinarowortwoconsecutivenegativecotestsinthepast10years,withthemostrecentwithinthepast5years).
**ForwomenwhohavehadabenignhysterectomywithremovalofthecervixwhodonothaveahistoryofCIN2,CIN3,or
cervicalcancer.Womeninwhomanegativehistorycannotbedocumentedshouldcontinuetobescreened.

1.SaslowD,SolomonD,LawsonHW,etal.AmericanCancerSociety,AmericanSocietyforColposcopyandCervical
Pathology,andAmericanSocietyforClinicalPathologyscreeningguidelinesforthepreventionandearlydetectionof
cervicalcancer.CACancerJClin201262:147.
2.MoyerVA.Screeningforcervicalcancer:UnitedStatesPreventiveServicesTaskForcerecommendationstatement.Ann
InternMed2012156:880.
3.Cervicalcytologyscreening.ACOGPracticeBulletinNo.157.AmericanCollegeofObstetriciansandGynecologists.Obstet
Gynecol2016127:e1
4.HuhWK,AultKA,ChelmowD,etal.Useofprimaryhighriskhumanpapillomavirustestingforcervicalcancerscreening:
Interimclinicalguidance.GynecolOncol2015136:178.http://dx.doi.org/10.1016/j.ygyno.2014.12.022
5.SawayaGF,KulasingamS,DenbergTD,etal.CervicalCancerScreeninginAverageRiskWomen:BestPracticeAdvice
FromtheClinicalGuidelinesCommitteeoftheAmericanCollegeofPhysicians.AnnInternMed2015162:851.

Graphic82951Version15.0
UnsatisfactoryCytology

Reprintedfrom:TheJournalofLowerGenitalTractDiseaseVolume17,Number5,withthepermissionofASCCPAmericanSociety
forColposcopyandCervicalPathology2013.NocopiesofthealgorithmsmaybemadewithoutthepriorconsentofASCCP.

Graphic89352Version4.0
Relativeincidenceofcervicalcytologyresults

Cytology Incidence(percent)

Negative 96

Atypicalsquamouscellsofundeterminedsignificance(ASCUS) 2.8

Lowgradesquamousintraepitheliallesion(LSIL) 0.97

Highgradesquamousintraepitheliallesion(HSIL) 0.21

Atypicalglandularcells(AGC) 0.21

Atypicalsquamouscells:cannotexcludehighgradesquamousintraepithelial 0.17
lesion(ASCH)

Squamouscellcervicalcarcinoma 4.5per100,000

Datafrom:KatkiHA,SchiffmanM,CastlePE,etal.BenchmarkingCIN3+RiskastheBasisforIncorporatingHPVandPap
CotestingintoCervicalScreeningandManagementGuidelines.JLowGenitTractDis201317:S28.

Graphic89228Version1.0
Riskfactorsforendometrialcancer

Relativerisk(RR)
Riskfactor
(otherstatisticsarenotedwhenused)

Increasingage 1.4%endometrialcancerprevalenceinwomen50to70
yearsold

Unopposedestrogentherapy 2to10

Tamoxifentherapy 2

Earlymenarche NA

Latemenopause(afterage55) 2

Nulliparity 2

Polycysticovarysyndrome(chronicanovulation) 3

Obesity FortypeIendometrialcancer:OR1.5for
overweight(BMI25.0to<30kg/m 2),2.5forclass
1obesity(30.0to<35kg/m 2),4.5forclass2
obesity(35.0to39.9kg/m 2),and7.1forclass3
obesity(40.0kg/m 2).
FortypeII:OR1.2foroverweight(BMI25.0to
<30kg/m 2),1.7forclass1obesity(30.0to<35
kg/m 2),2.2forclass2obesity(35.0to39.9
kg/m 2),and3.1forclass3obesity(40.0
kg/m 2).

Diabetesmellitus 2

Estrogensecretingtumor NA

Lynchsyndrome(hereditarynonpolyposiscolorectalcancer) 22to50%lifetimerisk

Cowdensyndrome 13to19%lifetimerisk

Familyhistoryofendometrial,ovarian,breast,orcolon NA
cancer

BMI:bodymassindexOR:oddsratioNA:RRnotavailable.

Datafrom:
SmithRA,vonEschenbachAC,WenderR,etal.AmericanCancerSocietyguidelinesfortheearlydetectionofcancer:
Updateofearlydetectionguidelinesforprostate,colorectal,andendometrialcancers.CACancerJClin200151:38.
SetiawanVW,YangHP,PikeMC,etal.TypeIandIIendometrialcancers:havetheydifferentriskfactors?JClinOncol
201331:2607.

Graphic62089Version13.0
Womenwhoshouldundergoevaluationforendometrialhyperplasiaorendometrial
cancer

Abnormaluterinebleeding

PostmenopausalwomenAnyuterinebleeding,regardlessofvolume(includingspottingorstaining).Pelvicultrasound
toevaluateendometrialthicknessisanalternativetoendometrialsamplinginappropriatelyselectedwomen.A
thickenedendometriumshouldbefurtherevaluatedwithendometrialsampling.

Age45yearstomenopauseInanywoman,bleedingthatisfrequent(intervalbetweentheonsetofbleeding
episodesis<21days),heavy,orprolonged(>5days).Inwomenwhoareovulatory,thisincludesintermenstrual
bleeding.

Youngerthan45yearsAnyabnormaluterinebleedinginobesewomen(BMI30).Innonobesewomen,abnormal
uterinebleedingthatispersistentandoccursinthesettingofoneofthefollowing:chronicovulatorydysfunction,other
exposuretoestrogenunopposedbyprogesterone,failedmedicalmanagementofthebleeding,orwomenathighrisk
ofendometrialcancer(eg,Lynchsyndrome,Cowdensyndrome).

Inaddition,endometrialneoplasiashouldbesuspectedinpremenopausalwomenwhoareanovulatoryandhave
prolongedperiodsofamenorrhea(sixormoremonths).

Cervicalcytologyresults

PresenceofAGCendometrial.

PresenceofAGCallsubcategoriesotherthanendometrialIf35yearsofageORatriskforendometrialcancer(risk
factorsorsymptoms).

Presenceofbenignappearingendometrialcellsinwomen40yearsofagewhoalsohaveabnormaluterinebleeding
orriskfactorsforendometrialcancer.

Otherindications

Monitoringofwomenwithendometrialpathology(eg,endometrialhyperplasia).

Screeninginwomenathighriskofendometrialcancer(eg,Lynchsyndrome).

Theserecommendationsarebasedonanaverageageofmenopauseof51years.Evaluationofwomenwhoundergo
menopauseearliershouldbeindividualizedbasedupongynecologichistoryandriskofendometrialneoplasia.

BMI:bodymassindexAGC:atypicalglandularcells.

Graphic58600Version11.0
Humanpapillomavirus(HPV)tests

NumberofHPV
Test HPVtypesidentified Results*
identified

HybridCapture2 13 16,18,31,33,35,39,45,51,52, Pooledresult

56,58,59,68(not66)

CervistaHPVHRtest 14 16,18,31,33,35,39,45,51,52, Pooledresult

56,58,59,66,68

cobasHPVtest 14 16,18 Specificfor16/18

31,33,35,39,45,51,52,56,58, Pooledresultforother12subtypes
59,66,68

AptimamRNAtest 14 16,18,31,33,35,39,45,51,52, Pooledresult

56,58,59,66,68

FDA:USFoodandDrugAdministrationHPV:humanpapillomavirus.
*Pooledresult:PositiveresultforanyoftheHPVtypes,notspecificforanyonetype.
TheCervista16/18specificallydetectsHPV16and18.ItisFDAapprovedforuseinwomen30yearsasafollowuptoa
positiveCervistaHPVHRtestorinwomenanyagewithborderlinecytologyresults.
FDAapprovedforusealoneasprimaryscreeninginwomen25yearsandolder.
TheAptimaHPV1618/45specificallydetectsHPV16,18,and/or45.ItisFDAapprovedforuseinwomen30yearsasa
followuptoapositiveAptimamRNAtestorinwomen21yearsasafollowuptoaborderlinecytologyresult.

Graphic98313Version3.0
ManagementofWomenAge30,whoareCytologyNegative,butHPVPositive

Reprintedfrom:TheJournalofLowerGenitalTractDiseaseVolume17,Number5,withthepermissionofASCCPAmericanSociety
forColposcopyandCervicalPathology2013.NocopiesofthealgorithmsmaybemadewithoutthepriorconsentofASCCP.

Graphic89354Version5.0
Followupofresultsofvaginalcytology

ASCUS:atypicalsquamouscellsofundeterminedsignificanceLSIL:lowgrade
squamousintraepitheliallesionNILM:negativeforintraepitheliallesionor
malignancyHPV:humanpapillomavirusHSIL:highgradesquamousintraepithelial
lesionASCH:atypicalsquamouscellscannotruleouthighgradeAGC:atypical
glandularcellshrHPV:highriskHPV(HPVtypesthatarehighriskforcausing
cervicalcancer).
*IfHPVgenotypingisavailable,recommendimmediatecolposcopyforASCUS/LSIL
withHPV16/18positiveandrepeattestingin1yearforthosewithNILM
cytology/HPV16/18positiveorHPV16/18negative.
Cotesting=cervicalcytology+hrHPVtesting.Giventhehighnegativepredictive
valueofhrHPVtesting,only1cotestisneeded.Ifcytologyaloneisrepeated,repeat
cytologyeveryyearshouldbeperformedatleasttwice.Ifcotestnegativeonceor
cytologynegativetwice,thenscreeningcanstop.
Cessationofscreeningifposthysterectomyforbenigndisease,OR
ContinueroutinesurveillanceifposttreatmentforcervicalHSILorcervicalcancer.

From:KhanMJ,MassadLS,KinneyW,etal.Acommonclinicaldilemma:
Managementofabnormalvaginalcytologyandhumanpapillomavirustestresults.J
LowGenitTractDis201620:119.DOI:10.1097/LGT.0000000000000185.Copyright
2016AmericanSocietyforColposcopyandCervicalPathology.Reproducedwith
permissionfromLippincottWilliams&Wilkins.Unauthorizedreproductionofthis
materialisprohibited.

Graphic108325Version1.0
Contributor Disclosures
Christopher P Crum, MD Nothing to disclose Warner K Huh, MD Consultant/Advisory Boards: Merck [Cervical
cytology (HPV vaccines)]; Intuitive Surgical (Robotic Surgery); LICOR (uorescence imaging); InCellDx (cervical
cancer screening). Barbara Go, MD Consultant/Advisory Boards: Roche Diagnostics [Biomarkers for ovarian
cancer (HE4)]. Employment (Spouse): Lilly [General oncology (Gemcitabine, pemetrexed)] - No relevant conict on
topics. Sandy J Falk, MD, FACOG Nothing to disclose

Contributor disclosures are reviewed for conicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be provided
to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate
standards of evidence.

Conict of interest policy