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Invasivecervicalcancer:Epidemiology,riskfactors,clinicalmanifestations,anddiagnosis
OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate

Invasivecervicalcancer:Epidemiology,riskfactors,clinicalmanifestations,anddiagnosis
Author
MichaelFrumovitz,MD,MPH

SectionEditors
BarbaraGoff,MD
DonSDizon,MD,FACP

DeputyEditor
SandyJFalk,MD,FACOG

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jul2016.|Thistopiclastupdated:Jun03,2015.
INTRODUCTIONCanceroftheuterinecervixisthethirdmostcommongynecologiccancerdiagnosisandcauseof
deathamonggynecologiccancersintheUnitedStates[1].Cervicalcancerhaslowerincidenceandmortalityratesthan
uterinecorpusandovariancancer,aswellasmanyothercancersites.Theserankingsaresimilartoglobalestimatesfor
otherdevelopedcountries[2].Unfortunately,incountriesthatdonothaveaccesstocervicalcancerscreeningand
preventionprograms,cervicalcancerremainsthesecondmostcommontypeofcancer(17.8per100,000women)and
causeofcancerdeaths(9.8per100,000)amongalltypesofcancerinwomen.
Humanpapillomavirus(HPV)iscentraltothedevelopmentofcervicalneoplasiaandcanbedetectedin99.7percentof
cervicalcancers[3].Themostcommonhistologictypesofcervicalcanceraresquamouscell(69percentofcervical
cancers)andadenocarcinoma(25percent)[4].
Theepidemiology,riskfactors,clinicalmanifestations,anddiagnosisofinvasivecervicalcancerwillbereviewedhere.
Screeningandprevention,staging,andthemanagementofcervicalcancerandpreinvasivediseasearediscussed
separately.(See"Screeningforcervicalcancer"and"Invasivecervicalcancer:Stagingandevaluationoflymphnodes"
and"Managementofearlystagecervicalcancer"and"Managementoflocallyadvancedcervicalcancer"and"Cervical
intraepithelialneoplasia:Managementoflowgradeandhighgradelesions".)
EPIDEMIOLOGYANDRISKFACTORS
IncidenceandmortalityGlobally,cervicalcanceraccountedforanestimated528,000newcancercasesworldwide
andfor266,000deathsin2012[5].
Globalincidenceandmortalityratesdependuponthepresenceofscreeningprogramsforcervicalprecancerandcancer
andofhumanpapillomavirus(HPV)vaccination,whicharemostlikelytobeavailableindevelopedcountries.Duetothese
interventions,therehasbeena75percentdecreaseintheincidenceandmortalityofcervicalcanceroverthepast50
yearsindevelopedcountries[6,7].
Eightyfourpercentofcervicalcancercaseswerefromlessdevelopedregions[2].Inwomenindevelopingcountries,
cervicalcancerwasthesecondmostcommontypeofcancer(15.7per100,000women)andthethirdmostcommon
causeofcancermortality(8.3per100,000).OnthecontinentofAfricaandinCentralAmerica,cervicalcanceristhe
leadingcauseofcancerrelatedmortalityamongwomen[8].
Indevelopedcountriesin2012,cervicalcancerwastheeleventhmostcommontypeofcancerinwomen(9.9per100,000
women)andtheninthmostcommoncauseofcancermortality(3.3per100,000)[2].(See"Screeningforcervicalcancer"
and"Screeningforcervicalcancerinresourcelimitedsettings"and"Recommendationsfortheuseofhuman
papillomavirusvaccines".)
IntheUnitedStates,almost13,000newcasesofinvasivecervicalcancerandapproximately4100cancerrelateddeaths
occureachyear[1].Cervicalcanceristhethirdmostcommoncancerdiagnosisandcauseofdeathamonggynecologic
cancersintheUnitedStates,withlowerincidenceandmortalityratesthanuterinecorpusorovariancancer.Cervical
cancerestimatesarehigherforcertainracialandethnicgroups:white(incidence:7.1/100,000andmortality:2.0/100,000),
nonHispanicblack(10.2/100,000and4.2/100,000),Hispanic/Latino(10.5/100,000and2.8/100,000),Asian/PacificIslander
(6.4/100,000and1.8/100,000),andAmericanIndian/AlaskaNative(9.7/100,000and3.4/100,000)[1].
IntheeraofHPVvaccination,mostexpertsexpectadecreaseintheincidenceofcervicalcancerinwomenwhoreceive
thevaccine.Bysomeestimates,ifvaccineratesof70percentworldwideareachieved,wewouldexpecttoseea
decreaseof344,520newcasesofcervicalcancerannuallyandavoid178,182cervicalcancerrelateddeaths[9].
However,duetothelatencyperiodof10to15yearsbetweenHPVexposureandcervicalcancerdevelopment,thereare
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notlikelytobesignificantdecreasesincervicaldysplasiaorcancerformanyyearsaftertheimplementationofvaccination
programs.Surprisingly,incountriessuchasAustraliathathaveachievedvaccinationrates>70percent,therehasalready
beena38percentreductioninhighgradedysplasia[10].Evenincountrieswithlowervaccinationrates,suchasthe
UnitedStates,forexample,therehasbeenadecreaseintheincidenceofhighgradecervicaldysplasia.Asanexample,
inConnecticutbetween2008and2011,thevaccinationrateincreasedfrom45to61percent.Duringthatsametime
period,therewasadecreaseinhighgradecervicaldysplasiaof18percent[11].Ashighgradedysplasiaisanecessary
precursorforsquamous,adenocarcinoma,andadenosquamouscarcinomasofthecervix,thissharpdecreaseinhigh
gradecervicaldysplasiashouldtranslateintodecreasedincidenceofcervicalcancerinthenextdecade.
AgedistributionWorldwidein2012,thecumulativerisksofdevelopingcervicalcancerandofcervicalcancer
mortalitybyage74yearswere:developedcountries(0.9percentincidence/0.3percentmortality)anddevelopingcountries
(1.6percent/0.9percent)[2].
ThelifetimeriskofdevelopingcervicalcancerforUnitedStateswomen,baseduponnationaldatafrom2000to2004,was
0.76percent[4].ThemeanageatdiagnosisofcervicalcancerintheUnitedStatesfrom2000to2004was48years.Only
5.7percentofcaseswerediagnosedinwomenage85yearsorolder.From2000to2004,theUnitedStatesageadjusted
incidenceofcervicalcanceringirlsunderage20was0.1per100,000,risingto1.5per100,000inwomenage20to24
years,andthenrangingfrom11.0to15.8per100,000forwomenage30toover85years.
RiskfactorsThetwomajorhistologictypesofcervicalcancer,adenocarcinomaandsquamouscellcarcinoma,andthe
preinvasivediseasethatcorrespondswiththesehistologiessharemanyofthesameriskfactors[1222].Mostofthese
areassociatedwithanincreasedriskofacquiringorhavingappropriatecompromisedimmuneresponsetoinfectionwith
HPV,theetiologicagentofmostcervicalcancers.Theseinclude:
EarlyonsetofsexualactivityComparedwithageatfirstintercourseof21yearsorolder,theriskisapproximately
1.5foldfor18to20yearsandtwofoldforyoungerthan18years[12]
MultiplesexualpartnersComparedwithonepartner,theriskisapproximatelytwofoldwithtwopartnersand
threefoldwithsixormorepartners[12]
Ahighrisksexualpartner(eg,apartnerwithmultiplesexualpartnersorknownHPVinfection)
Historyofsexuallytransmittedinfections(eg,Chlamydiatrachomatis,genitalherpes)
Historyofvulvarorvaginalsquamousintraepithelialneoplasiaorcancer(HPVinfectionisalsotheetiologyofmost
casesoftheseconditions)
Immunosuppression(eg,humanimmunodeficiencyvirusinfection)
Cervicalcancerislesscommoninsexualpartnersofcircumcisedmales[13].(See"Neonatalcircumcision:Risksand
benefits",sectionon'Cervicalcancerinpartners'.)
Earlyageatfirstbirth(youngerthan20yearsold)andincreasingparity(3ormorefulltermbirths)arealsoassociatedwith
anincreasedriskofcervicalcancerthesearealsolikelyduetoexposuretoHPVthroughsexualintercourse[12].
Lowsocioeconomicstatusisassociatedwithanincreasedriskofcervicalcancer.From1988to1992intheUnited
States,cervicalcancerincidencewashigherinwomenwholivedincommunitieswithhigherpovertylevels(20percent
ormoreofthepopulationbelowthepovertylevel:19.2casesper100,000womenversus<10percentbelowpovertylevel:
8.8per100,000)[23].Womeninhighcomparedwithlowpovertycountieshada71percenthigherrateofcervicalcancer
mortality.
IntheUnitedStates,cervicalcancerincidenceandmortalityishigherinnonwhitethaninwhitewomen,asnotedabove
[24].(See'Incidenceandmortality'above.)
Oralcontraceptiveusehasbeenreportedtobeassociatedwithanincreasedriskofcervicalcancer.Acollaborative
analysisofdatafrom24epidemiologicalstudiesfoundthatamongcurrentusersoforalcontraceptives,theriskofinvasive
cervicalcancerincreasedwithincreasingdurationofuse(5years'useversusneveruse:relativerisk[RR]1.90,95%CI
1.692.13).Theriskdeclinedafteruseceased,andby10ormoreyears,hadreturnedtothatofneverusers[21].Inthe
samestudy,useoforalcontraceptivesfor10yearsfromage20to30yearswasestimatedtoincreasethecumulative
incidenceofinvasivecervicalcancerbyage50from7.3to8.3per1000indevelopingcountriesandfrom3.8to4.5per
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1000indevelopedcountries.Whilesomestudiessuggestthatadenocarcinomaappearstohaveastrongerassociation
withoralcontraceptivesthandoessquamouscellcancer[25],othersfoundasimilarriskincreasewithincreasingduration
oforalcontraceptivesforbothadenoandsquamouscellcarcinomas[26].(See"Risksandsideeffectsassociatedwith
estrogenprogestincontraceptives",sectionon'Cervicalcancer'.)
Incontrasttosquamouscellcancerofthecervix,cigarettesmokingisnotassociatedwithasignificantlyincreasedriskof
adenocarcinomaofthecervixcomparedwithnonsmokers(squamouscellcarcinoma:RR1.50,95%CI1.351.66
adenocarcinoma:RR0.86,95%CI0.701.05)[12,18].
GeneticsThereisnowellestablishedmodelofageneticbasisforcervicalcancer.Populationstudieshaveshownan
increasedincidenceofcervicalcancerwithinfamilies.Inthepast,suchfamilialclusteringhadbeenattributedtoshared
environmentalexposuresandriskfactors.However,subsequentdatacomparingfullandhalfsiblingshaveconcludedthat
heritableriskfactorsfaroutweighthesharedenvironmentalcomponents.Asanexample,aSwedishstudyofover9000
siblingsorhalfsiblingswithcervicalcancerorprecancerattributed64percentofcasestogeneticsandonly36percentto
environmentalexposures[27].
InvestigationsareongoingtoidentifygeneticalterationsthatmaymakewomenlesslikelytoclearpersistentHPV
infectionsandmoresusceptibletothedevelopmentofcervicalcancer.Findingstodateincludeanassociationofcervical
cancerwithalargevarietyofpolymorphismsinawidevarietyofgenes,includingthosethatregulateimmunityand
susceptibility[28],cytokineproduction[29,30],angiogenesis[29],tumorsuppressorpathways[31,32],andsignal
transducerandactivatoroftranscription(STAT)pathways[33].
PATHOGENESISHumanpapillomavirus(HPV)iscentraltothedevelopmentofcervicalneoplasiaandcanbedetected
in99.7percentofcervicalcancers[3].ThevirologyandmolecularpathogenesisofHPVassociatedmalignanciesare
discussedindetailseparately.(See"Virologyofhumanpapillomavirusinfectionsandthelinktocancer".)
Therearefourmajorstepsincervicalcancerdevelopment[34]:
OncogenicHPVinfectionofthemetaplasticepitheliumatthecervicaltransformationzone(thejunctionbetweenthe
squamousepitheliumoftheectocervixandtheglandularepitheliumoftheendocervicalcanal)
PersistenceoftheHPVinfection
Progressionofacloneofepithelialcellsfrompersistentviralinfectiontoprecancer
Developmentofcarcinomaandinvasionthroughthebasementmembrane
GenitaltractHPVinfectionisextremelycommonbutresultsincervicalcancerinonlyasmallproportionofinfected
women.Ithasbeenestimatedthat75to80percentofsexuallyactiveadultswillacquiregenitaltractHPVbeforetheage
of50[35,36].ThediseaseburdenofgenitalHPVinfectionincludesconditionsotherthancervicalcancer,including
anogenitalwarts,andcancerofthevulva,vagina,anus,andpenis[37,38].(See"Virologyofhumanpapillomavirus
infectionsandthelinktocancer"and"Cervicalintraepithelialneoplasia:Terminology,incidence,pathogenesis,and
prevention",sectionon'Roleofhumanpapillomavirus'.)
Amongthemorethan40genitalmucosalHPVtypesidentified,approximately15areknowntobeoncogenic(table1).
SubtypesHPV16and18arefoundinover70percentofallcervicalcancers.
HPVplaysaroleprimarilyinthetwomostcommonhistologictypesofcervicalcancer:squamouscell(69percentof
cervicalcancers)andadenocarcinoma(25percent)(see'Histopathology'below).TheHPVsubtypesassociatedwith
squamouscanceraredifferentfromthoseassociatedwithadenocarcinoma.Inaninternationalstudyofover30,000
cervicalcancers,thedistributionofHPVsubtypeswas[39]:
SquamouscellcarcinomaHPV16(59percentofcases),18(13percent),58(5percent),33(5percent),45(4
percent)
AdenocarcinomaHPV16(36percent),18(37percent),45(5percent),31(2percent),33(2percent)
MostHPVinfectionsaretransient,andthevirusaloneisnotsufficienttocausecervicalneoplasia.WhenHPVinfection
persists,thetimefrominitialinfectiontodevelopmentofhighgradecervicalintraepithelialneoplasiaand,finally,invasive
cancertakesanaverageof15years,althoughmorerapidcourseshavebeenreported[40].
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Herpessimplexvirus2infectionasacofactorincervicalcancerpathogenesishasbeenreportedinsome,butnotall
studies[4144].Furtherinvestigationofthisissueisneeded.
HISTOPATHOLOGYThehistopathologictypesofcervicalcancerarelistedinthetable(table2)[45].IntheUnited
Statesfrom2001to2004,thedistributionofhistologictypeswas[4]:
Squamouscellcarcinoma69percent
Adenocarcinoma(includingadenosquamous)25percent
Otherhistologies6percent
Theincidenceofinvasivecervicaladenocarcinomaanditsvariantshasincreaseddramaticallyoverthepastfewdecades,
particularlyinyoungerwomen[46,47].Severalcausativefactorshavebeenproposedtoexplainthistrend,including
increasedprevalenceofspecificHPV16and18variantsthatareassociatedmorewithadenocarcinomathanwith
squamouscellcarcinomaaswellasexposuretoestrogens,bothendogenous(eg,obesity)andexogenous(eg,hormonal
contraception,postmenopausalestrogentherapy).
Adenosquamoustumorsexhibitbothglandularandsquamousdifferentiation.Theymaybeassociatedwithapoorer
outcomethansquamouscellcancersoradenocarcinomas[4850].
Neuroendocrineorsmallcellcarcinomascanoriginateinthecervixinwomen,butareinfrequent[51].Rhabdomyosarcoma
ofthecervixisrareittypicallyoccursinadolescentsandyoungwomen[52,53].Primarycervicallymphomaandcervical
sarcomaarealsorare[5456].(See"Rhabdomyosarcomainchildhoodandadolescence:Clinicalpresentation,diagnostic
evaluation,andstaging"and"Smallcellneuroendocrinecarcinomaofthecervix",sectionon'Introduction'and"Invasive
cervicaladenocarcinoma".)
ROUTESOFSPREADCervicalcancercanspreadbydirectextensionorbylymphaticorhematogenous
dissemination.Directextensionmayinvolvetheuterinecorpus,vagina,parametria,peritonealcavity,bladder,orrectum.
Ovarianinvolvementbydirectextensionofcervicalcancerisrareovarianmetastasesoccurinapproximately0.5percent
ofsquamouscellcarcinomasand1.7percentofadenocarcinomas[57].Themostcommonsitesforhematogenousspread
arethelungs,liver,andbonethebowel,adrenalglands,spleen,andbrainarelessfrequentsites.
Historically,obturatorlymphnodeswerethoughttobethemostfrequentsiteofnodalmetastasesinwomenwithcervical
cancer[58].Itwasalsothoughtthatlymphaticspreadadvancedinanorderlyfashionfromthelymphnodesonthepelvic
sidewalltothecommoniliac,andthentheparaaorticgroup(figure1).However,subsequentstudies,includingthose
utilizingthesentinellymphnodemappingtechnique,emphasizethatanyofthepelviclymphnodegroups,andeven
paraaorticlymphnodes,maycontainthefirstdraininglymphnodeandmaybethefirstsiteofnodalmetastasis[59,60].
Thiswasillustratedinalargeretrospectivestudy(n=619)thatevaluatedwomenwithcervicalcancerwhohadsolitary
(oneortwo)positivelymphnodesdiscoveredviaradicalhysterectomyandcompletelymphadenectomy[61].The
distributionofsitesofnodalmetastasiswere:externaliliac(43percent),obturator(26percent),parametrial(21percent),
commoniliac(7percent),presacral(1percent),andparaaortic(1percent).
Sentinelnodebiopsyincervicalcancerisdiscussedindetailseparately.
Theriskofpelviclymphnodemetastasisincreaseswithincreasingdepthofinvasion,accordingtotheInternational
FederationofGynecologyandObstetrics(FIGO)stagingsystem(table3)(see"Invasivecervicalcancer:Stagingand
evaluationoflymphnodes")[6266]:
StageIA10.6percent
StageIA27percent
Theriskofparaaorticnodalinvolvementincreasesasthelocaldiseaseextentincreases:

StageIB8percent
StageIIA12percent
StageIIB29percent
StageIIIA17percent
StageIIIB27percent
StageIVA47percent

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CLINICALMANIFESTATIONSEarlycervicalcancerisfrequentlyasymptomatic,underscoringtheimportanceof
screening.Themostcommonsymptomsatpresentationare[67]:
Irregularorheavyvaginalbleeding
Postcoitalbleeding
Somewomenpresentwithavaginaldischargethatmaybewatery,mucoid,orpurulentandmalodorous.Thisisa
nonspecificfindingandmaybemistakenforvaginitisorcervicitis.
Advanceddiseasemaypresentwithpelvicorlowerbackpain,whichmayradiatealongtheposteriorsideofthelower
extremities.Bowelorurinarysymptoms,suchaspressurerelatedcomplaints,hematuria,hematochezia,orvaginal
passageofurineorstool,areuncommonandsuggestadvanceddisease.
Inasymptomaticwomen,cervicalcancermaybediscoveredasaresultofcervicalcancerscreeningorincidentally,ifa
visiblelesionisdiscovereduponpelvicexamination.(See"Screeningforcervicalcancer"and'Physicalexamination'
below.)
DIAGNOSISThediagnosisofcervicalcancerismadebaseduponhistologicevaluationofacervicalbiopsy.
PhysicalexaminationApelvicexaminationshouldbeperformedinanywomanwithsymptomssuggestiveofcervical
cancer.Visualizationofthecervixuponspeculumexaminationmayrevealanormalappearanceoravisiblecervical
lesionlargetumorsmayappeartoreplacethecervixentirely.Anylesionthatisraised,friable,orhastheappearanceof
condylomashouldbebiopsied,regardlessofpreviousbenigncervicalcytologyresults[68].Theonlyvisiblelesionsthatdo
notrequirebiopsyareNabothiancysts,andonlywhenthisdiagnosisisconfirmedbyanexperiencedexaminer.(See
"Congenitalcervicalanomaliesandbenigncervicallesions",sectionon'Nabothiancysts'.)
Cervicalcancerusuallyoriginatesatthetransformationzone(thejunctionbetweenthesquamousepitheliumofthe
ectocervixandtheglandularepitheliumoftheendocervicalcanal).Thelesionmaymanifestassuperficialulceration,
exophytictumorintheexocervix,orinfiltrationoftheendocervix.Endophytictumorscanresultinanenlarged,indurated
cervixwhosesurfaceissmooth,referredtoasa"barrelshapedcervix."Amongcervicaladenocarcinomas,approximately
onehalfareexophytic,othersdiffuselyenlargeorulceratethecervix,andabout15percenthavenovisiblelesionbecause
thecarcinomaiswithintheendocervicalcanal.
Athoroughpelvicexaminationincludingrectovaginalexaminationwithassessmentoftumorsizeandvaginalor
parametrialinvolvementisrequiredforstagingcervicalcancer.Thisisdiscussedindetailseparately.(See"Invasive
cervicalcancer:Stagingandevaluationoflymphnodes",sectionon'Stagingprocedure'.)
Othersuspiciousphysicalexaminationfindingsarepalpablegroinorsupraclavicularlymphnodes.
CervicalcytologyCervicalcytologyistheprincipalmethodforcervicalcancerscreening.Cytologyshouldalsobe
performedforwomenwithsuspectedcervicalcancer.
Cervicalcancerscreening,techniquesforcervicalcytologytesting,andinterpretationofresultsarediscussedindetail
separately.(See"Screeningforcervicalcancer"and"Cervicalcancerscreeningtests:Techniquesforcervicalcytology
andhumanpapillomavirustesting"and"Cervicalandvaginalcytology:Interpretationofresults(Paptestreport)".)
Humanpapillomavirus(HPV)testingisusedincombinationwithcervicalcytologyforcervicalcancerscreeningandhelps
todeterminewhichwomenwithabnormalcytologyresultsrequirefurtherevaluation.However,itdoesnotplayarolein
thediagnosisofmalignancyinwomenwithsymptomsoravisiblelesionsuggestiveofcervicalcancer.(See"Screening
forcervicalcancer",sectionon'Cotesting(PaptestandHPVtesting)'.)
CervicalbiopsyandcolposcopyCervicalbiopsymaybeperformedaspartofaninitialevaluationoralongwithafull
stagingprocedure,dependingonthelevelofsuspicionofmalignancyandthepatient'saccesstohealthcare.The
approachtocervicalbiopsydiffersdependinguponthepatient'spresentationandfindingsonpelvicexamination:
Inwomenwithagrosslyvisiblelesion,asuspecteddiagnosisofcancermustbeconfirmedbyabiopsyofthelesion.
Weprefertotakethebiopsyfromtheareaofthelesionthatlooksmostsuspiciouswithcaretoavoidgrossly
necroticareas,astheseareoftennondiagnostic.Anycervixthatisunusuallyfirmorexpandedshouldbesampled
bypunchbiopsyandendocervicalcurettage,evenifthecervicalcytologytestdoesnotshowevidenceofneoplasia.
Biopsyinwomenwithgrosslesionsmayresultinsignificantbleedingandevenhemorrhage,andpractitionersshould
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beadequatelypreparedwithhemostaticagentssuchMonselsolutionandtheabilitytopackthevaginashould
bleedingbesignificant.
Womenwithoutavisiblelesion(eg,symptomatic,abnormalcervicalcytology)shouldundergocolposcopywith
directedbiopsy.
Symptomaticwomenwithoutavisiblelesionandthosewhohaveonlyabnormalcervicalcytologyshouldundergo
colposcopywithdirectedbiopsy.Anadequatecolposcopyrequiresthattheentiresquamocolumnarjunctionandall
lesionsbecompletelyvisualizedandthatbiopsiesofthelesionsexplaintheabnormalcytology.Womeninsettingsin
whichcolposcopyisnotavailablemayundergodirectedbiopsywiththeaidofvisualinspectionmethods.(See
"Colposcopy"and"Screeningforcervicalcancerinresourcelimitedsettings",sectionon'Visualinspection
methods'.)
Cervicalconizationisnecessaryifmalignancyissuspectedbutisnotfoundwithdirectedcervicalbiopsies(eg,
somewomenwithhighgradecervicalintraepithelialneoplasia,inadequatecolposcopy,andinwomenwithan
endocervicalcurettagethatispositiveformoderatetoseveredysplasia).Conizationisalsorequiredinthesettingof
microinvasivecancertodeterminewhetherconservativeorradicalsurgeryisrequiredfortreatment.
Techniquesforcolposcopyandcervicalbiopsyandthestagingevaluationforcervicalcancerarediscussedindetail
separately.(See"Colposcopy"and"Invasivecervicalcancer:Stagingandevaluationoflymphnodes".)
OtherdiagnosticmodalitiesImagingstudiesarenottypicallypartofcervicalcancerdiagnosis,althoughsomeare
usedforstagingandevaluationofwomenwithknownmalignancy.(See"Invasivecervicalcancer:Stagingandevaluation
oflymphnodes",sectionon'Stagingprocedure'and"Invasivecervicalcancer:Stagingandevaluationoflymphnodes",
sectionon'Furtherevaluation'.)
DifferentialdiagnosisThedifferentialdiagnosisofcervicalcancerincludesotherconditionsthatresultinirregularor
heavyvaginalbleeding,vaginaldischarge,oravisiblecervicallesion.
Genitaltractbleedingandvaginaldischargemaybecausedbyavarietyofconditions.Postcoitalbleeding,whichisthe
mostspecificpresentationofcervicalcancer,mayalsoresultfromcervicitis.Evaluationofwomenwiththeseconditions
isdiscussedindetailseparately.(See"Approachtoabnormaluterinebleedinginnonpregnantreproductiveagewomen"
and"Postmenopausaluterinebleeding"and"Approachtowomenwithsymptomsofvaginitis".)
BenigntumorlikelesionsthatmaymimiccervicalcancerincludeNabothiancysts,mesonephriccysts,cervicalectropion,
ulcersassociatedwithsexuallytransmittedinfections,reactiveglandularchangesfrominflammation,andendometriosis.
(See"Congenitalcervicalanomaliesandbenigncervicallesions".)
SCREENINGANDPREVENTIONTherateofcervicalcancerhasdeclinedsignificantlyinsettingsinwhichcervical
cancerscreeningisemployed.Inaddition,humanpapillomavirus(HPV)vaccinationhadbeenintroducedtoreducethe
incidenceofcervicalneoplasia.(See"Screeningforcervicalcancer"and"Recommendationsfortheuseofhuman
papillomavirusvaccines".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and"Beyond
theBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereadinglevel,and
theyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestfor
patientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducation
piecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevel
andarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicsto
yourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon"patientinfo"andthe
keyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Cervicalcancer(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Cervicalcancertreatmentearlystagecancer(Beyondthe
Basics)"and"Patientinformation:Fertilitypreservationinwomenwithearlystagecervicalcancer(Beyondthe
Basics)")
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SUMMARYANDRECOMMENDATIONS
Canceroftheuterinecervixisthethirdmostcommoncancerdiagnosisandcauseofdeathamonggynecologic
cancersintheUnitedStates.Incountriesthatdonothaveaccesstocervicalcancerscreeningandprevention
programs,cervicalcancerremainsthesecondmostcommontypeofcancerandcauseofcancerdeathsamongall
typesofcancerinwomen.(See'Incidenceandmortality'above.)
ThelifetimeriskofdevelopingcervicalcancerforUnitedStateswomenis0.76percent.Themeanageatdiagnosis
ofcervicalcancerintheUnitedStatesis48yearsold.(See'Agedistribution'above.)
Humanpapillomavirus(HPV)iscentraltothedevelopmentofcervicalneoplasiaandcanbedetectedin99.7percent
ofcervicalcancers.SubtypesHPV16and18arefoundinover70percentofallcervicalcancers.(See
'Pathogenesis'above.)
Riskfactorsforcervicalcanceraremostlyassociatedwithanincreasedriskofacquiringorhavingacompromised
immuneresponsetoHPVinfectiontheseinclude:earlyonsetofsexualactivity,multiplesexualpartners,ahighrisk
sexualpartner,historyofsexuallytransmittedinfections,historyofvulvarorvaginalsquamousintraepithelial
neoplasiaorcancer,andimmunosuppression.Oralcontraceptiveuseappearstobeassociatedwithanincreased
riskofcervicalcancer.Cigarettesmokingappearstobeassociatedwithanincreasedriskofsquamouscellcancer,
butnotadenocarcinoma.(See'Riskfactors'above.)
Themostcommonhistologictypesofcervicalcanceraresquamouscell(69percentofcervicalcancers)and
adenocarcinoma(25percent).Thehistopathologictypesofcervicalcancerarelistedinthetable(table2).(See
'Histopathology'above.)
Earlycervicalcancerisfrequentlyasymptomatic,emphasizingtheimportanceofscreening.Themostcommon
symptomsatpresentationare:abnormalvaginalbleeding(includingpostcoitalbleeding)andvaginaldischarge.A
lesionmayormaynotbevisibleorpalpableonphysicalexamination.(See'Clinicalmanifestations'aboveand
'Physicalexamination'above.).
Thediagnosisofcervicalcancerisestablishedbybiopsy.Symptomaticwomenwithoutavisiblelesionandthose
whohaveonlyabnormalcervicalcytologyshouldundergocolposcopywithdirectedbiopsyand,ifnecessary,
diagnosticconization.(See'Diagnosis'above.).
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic3179Version18.0

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GRAPHICS
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.Human
papillomavirusandcancer:Questionsandanswers.Availableat:
www.cancer.gov/cancertopics/factsheet/Risk/HPV(AccessedonJune11,2012).
Graphic76394Version3.0

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Histopathologyofcervicalcancer
A.Squamouscellcarcinoma
Largecell,keratinizingsquamouscellcarcinoma
Largecell,nonkeratinizingsquamouscellcarcinoma
Verrucouscarcinoma
Papillarysquamousandtransitionalcellcarcinoma
Lymphoepitheliomalikecarcinoma

B.Adenocarcinoma
Mucinous,endocervicalvariant
Mucinous,intestinaltype,signetringvariant
Mucinous,adenomamalignum(minimaldeviationvariant)
Mucinous,villoglandularadenocarcinoma(welldifferentiated)
Endometriodtype
Clearcelltype
Papillaryseroustype
Mesonephrictype

C.Adenosquamouscarcinoma
D.Adenoidcysticcarcinoma
E.Neuroendocrine(carcinoid,smallcell,largecell)
F.Undifferentiatedcarcinoma
G.Mixedepithelialandmesenchymaltumors
Adaptedfromdatain:NganHYS,etal.IntJGynecolObstet200070:207.
Graphic65824Version5.0

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Femalepelvicandparaaorticlymphnodes

Thepelvicandparaaorticlymphnodesandtheirrelationshiptothe
femalepelvicorgansandthemajorretroperitonealbloodvessels.
Reproducedwithpermissionfrom:BerekJS,HackerNF.PracticalGynecologic
Oncology,FourthEdition.Philadelphia:LippincottWilliams&Wilkins,2005.
Copyright2005LippincottWilliams&Wilkins.
Graphic54775Version2.0

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Stagingcervicalcancer(TNMandInternationalFederationofGynecology
andObstetrics[FIGO])
Primarytumor(T)
TNM
categories

FIGO
stages

TX

Primarytumorcannotbeassessed

T0

Noevidenceofprimarytumor

Tis*

Carcinomainsitu(preinvasivecarcinoma)

T1

Cervicalcarcinomaconfinedtouterus(extensiontocorpusshouldbedisregarded)

IA

Invasivecarcinomadiagnosedonlybymicroscopy.Stromalinvasionwithamaximum
depthof5.0mmmeasuredfromthebaseoftheepitheliumandahorizontalspreadof
7.0mmorless.Vascularspaceinvolvement,venousorlymphatic,doesnotaffect
classification.

T1a1

IA1

Measuredstromalinvasion3.0mmorlessindepthand7.0mmorlessinhorizontal
spread

T1a2

IA2

Measuredstromalinvasionmorethan3.0mmandnotmorethan5.0mmindepthwitha
horizontalspread7.0mmorless

IB

ClinicallyvisiblelesionconfinedtothecervixormicroscopiclesiongreaterthanT1a/IA2

T1b1

IB1

Clinicallyvisiblelesion4.0cmorlessingreatestdimension

T1b2

IB2

Clinicallyvisiblelesionmorethan4.0cmingreatestdimension

II

Cervicalcarcinomainvadesbeyonduterusbutnottopelvicwallortolowerthirdof
vagina

IIA

Tumorwithoutparametrialinvasionorinvolvementoftheloweronethirdofthe
vagina [1,2]

T2a1

IIA1

Clinicallyvisiblelesion4.0cmorlessingreatestdimensionwithinvolvementoflessthan
theuppertwothirdsofthevagina

T2a2

IIA2

Clinicallyvisiblelesionmorethan4.0cmingreatestdimensionwithinvolvementofless
thantheuppertwothirdsofthevagina

IIB

Tumorwithparametrialinvasion

III

Tumorextendstopelvicwalland/orinvolveslowerthirdofvagina,and/orcauses
hydronephrosisornonfunctioningkidney

T3a

IIIA

Tumorinvolveslowerthirdofvagina,noextensiontopelvicwall

T3b

IIIB

Tumorextendstopelvicwalland/orcauseshydronephrosisornonfunctioningkidney

IVA

Tumorinvadesmucosaofbladderorrectum,and/orextendsbeyondtruepelvis
(bullousedemaisnotsufficienttoclassifyatumorasT4)

T1a

T1b

T2
T2a

T2b

T3

T4

Definition

Regionallymphnodes(N)
TNM
categories

FIGO
stages

NX

Regionallymphnodescannotbeassessed

N0

Noregionallymphnodemetastasis

N1

Regionallymphnodemetastasis

Definition

Distantmetastasis(M)
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TNM
categories

FIGO
stages

M0

Nodistantmetastasis

M1

IVB

Distantmetastasis(includingperitonealspread,involvementofsupraclavicular,
mediastinal,orparaaorticlymphnodes,lung,liver,orbone)

Definition

Anatomicstage/prognosticgroups
Stage0*

Tis

N0

M0

StageI

T1

N0

M0

StageIA

T1a

N0

M0

StageIA1

T1a1

N0

M0

StageIA2

T1a2

N0

M0

StageIB

T1b

N0

M0

StageIB1

T1b1

N0

M0

StageIB2

T1b2

N0

M0

StageII

T2

N0

M0

StageIIA

T2a

N0

M0

StageIIA1

T2a1

N0

M0

StageIIA2

T2a2

N0

M0

StageIIB

T2b

N0

M0

StageIII

T3

N0

M0

StageIIIA

T3a

N0

M0

StageIIIB

T3b

AnyN

M0

T13

N1

M0

StageIVA

T4

AnyN

M0

StageIVB

AnyT

AnyN

M1

NOTE:cTNMistheclinicalclassification,pTNMisthepathologicclassification.
*FIGOnolongerincludesStage0(Tis).
AllmacroscopicallyvisiblelesionsevenwithsuperficialinvasionareT1b/IB.
References:
1.PecorelliS.RevisedFIGOstagingforcarcinomaofthecervix.IntJGynecolObstet2009105:107.
2.PecorelliS.RevisedFIGOstagingforcarcinomaofthevulva,cervix,andendometrium.IntJGynecol
Obstet2009105:103.
UsedwiththepermissionoftheAmericanJointCommitteeonCancer(AJCC),Chicago,Illinois.Theoriginal
sourceforthismaterialistheAJCCCancerStagingManual,SeventhEdition(2010)publishedbySpringerNew
York,Inc.
Graphic79282Version20.0

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ContributorDisclosures
MichaelFrumovitz,MD,MPHConsultant/AdvisoryBoards:Novadaq[Surgicalimagingtechnology(PinPointsystemfor
detectionofsentinelnodes)].BarbaraGoff,MDConsultant/AdvisoryBoards:RocheDiagnostics[Biomarkersforovarian
cancer(HE4)].Employment(Spouse):Lilly[Generaloncology(Gemcitabine,pemetrexed)].DonSDizon,MD,FACP
Consultant/AdvisoryBoards:Pfizer[Chemotherapy(Biosimilars)].SandyJFalk,MD,FACOGNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedby
vettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.
AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
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