Documente Academic
Documente Profesional
Documente Cultură
LouiseFarrell
PerthWesternAustralia
Aimforthispresentation
KnowledgeofwhatisHPVtesting
CurrentuseofHPVtestinginAustraliansetting
Use&limitationsofHPVtesting
CurrentuseofHPVtestinginothercountries
PossibleroleforHPVtestinginfuture
HPVtypes
Therearemorethan40typesofHPVthataffect
thefemalegenitaltract
Ofthese15havebeenidentifiedincervical
cancers 16,18,45,31,33,52,58,35,59,56,51,
39,68,73,82
Theseviruseshavebeencalledhighriskor
oncogenic
Oftheoncogenicstrains,2strainsareparticularly
important 16&18astheyaccountfor>70%of
allcancers
Schematicrepresentationof
HPVgenome
HPVinfection
Isalsoassociatedwithcancersinothersites
Anus
90%
Penis
40%
Vulvar
40%
Oropharynx
12%
3%
Mouth
Parkin,DM.IntJCancer2006;118:30303044
HPVinfection
Upto80%ofpopulationhaveoneorother
strainatsomepointintheirlife13
ThehighestprevalenceofHPVcarriageoccurs
inyoungwomen
Usuallycarriageistransient
Itispersistenceofthiscommonvirusthat
causescervicalprecancersandcancersto
develop
1.Baseman&Koutsky,JClinVirology2005;32S:S1624; 2.Brownetal,J
InfectDis2005;191:18292;3.Hoetal,NEJM1998;338(7):4238.
HPVAgePrevalence
35
30
25
20
HPV Prevalence %
15
10
5
0
<25
25-29
30-34
35-39
40-44
45-50
RelationshipofAgetoHPVPrevalenceandIncidenceofCervicalCancer
25
20
18
20
16
14
15
12
10
10
HPV
CvCx Cases/100,000
Cervical Cancer
4
2
0
15-19
20-24
25-29 30-34
55-59 60-64
>65
Age (years)
Sources: NCI SEER Data, 1990-94;
TheCornerstoneofpreventingcervical
cancerbydetectingprecursors
12
Squamous
Adenocarcinoma
Adenosquamous
Other
10
8
6
4
2
20
05
20
04
20
03
20
02
20
01
20
00
19
99
19
98
19
97
19
96
19
95
19
94
19
93
19
92
0
19
91
14
Note:Ratesareexpressedper100,000women,agestandardisedto Australian2001population
Source:CervicalScreeninginAustralia20062007.AIHW,Canberra
Currentcervicalscreeningstrategy
AUSTRALIA
Normal
Ifwomanis30+yrs,
&nonegcytolin
prev23yrs,option
ofimmediatecolpor
repeatsmearin6mo
Conventional
Cytology
LSILor
?LSIL
Repeatcytology12
months
Normal
Repeat12
months
HSIL
?HSIL
Abnormal
Normalor
LSIL
Colposcopy
&Biopsy
HSIL
Normal
Returnin2years
forrepeatPap
smear.Continue
untilage70
Treatment
Surrogatemarkersoncytology
HPVTesting
Viruscantbeculturedinvivo.
Noserologicalorproteintestavailablein
routinepracticeeventhoughserologywas
usedforVaccinetrials(howeverpoor
sensitivity&reliability)
Currentlyuseddetectionassaysrelyon
detectionofviralnucleicacids(DNA,RNA)
Principle:hybridisationwithcomplementarysequences
Principlesmostcommonlyused
(hr)HPVDNAdetectionassays
Hybridisationfollowedbysignalamplification
Hybrid capture2:RNAprobecocktail(HC2;Qiagen)
Invadertechnology:ThirdwaveinvaderHPVtest(Cervista)
Insituhybridisation(ISH)
UsedforyearsforresearchintoHPV.(VentanaInformthe
onlycommerciallyavailable&recommendedforhistological
materialonly)
BroadspectrumPCR
DNAamplificationwithconsensusprimersormultiplex
format(SomelabshaveinhousePCRs;Abbott Realtime
HPVtest,AmplicorHPV&LinearArrayHPVGenotyping)
HC2/Digene
MainHPVtestsinAustralia
Digene usedinALTStrial,lackofinternalcontrolforinput
DNA&crossreactivitywithlowrisktypes.Willnotidentify
specificHPVtypes
InhousePCR.Mostsensitivetechnique&allowstestingon
sampleswithfewercells.Contaminationanissue.Cando
typedistinction.Noexternalvalidation.
Cervista(Hologic)FDAapproved(invadertechnology).
Internalcontrol.CandistinguishHPV16&18fromother
highrisktypes
AbbottRealtimeHPVtest(PCR).Mostaccuratetype
specificmeasureofviralload
RocheCobas4800HPVtest Athenatrial.Internalcontrol
&canidentifyHPV16&18infections
HPVtestinginAustralia
UnderthecurrentNH&MRCguidelinestheonly
indicationforHPVtestingisastestofcure forwomen
whohavepreviouslyundergonetreatmentforahigh
gradeabnormalityofthecervix.
AwomantreatedforHSILrequiresacolposcopy&
cervicalcytologyat46monthsaftertreatment.Cervical
cytology&highriskHPVDNAtestingat12monthsafter
treatment&thenevery12monthsuntilthewomanhas
testednegativeforbothtestsontwoconsecutive
occasions.
Womenwhoareundergoingannualcytologyforapast
historyoftreatmentforHSILarealsoeligiblefora
MedicarerebateforHPVtestsothattheymayreturnto
tothe2yearlyprogramifthetestsarenegative
RationaleforHPVtestingafter
treatment
InAustraliaapprox15,000womentreatedeach
yearforHSIL
PriortonewNH&MRCrecommendations,these
womenwererequiredtohaveannualcytology
forremainderoftheirlife
HSILonlyarisesinrelationtopersistenceofHPV
infection
IfHPVcarriagehascleared,thentheriskof
furtherabnormalityissameasnormalpopulation
returntoroutinescreeningprogram
HPVDNApersistenceaftertreatment
Approx20%ofwomenwillstillhaveHPVDNA
at12monthsfollowingtreatment
Overthenext12monthsapprox1/3will
becomenegative
Onlyabout15%womentreatedforHSILwill
havepersistentHPVcarriage
Notallthesewomenwillgetrecurrenceof
HSIL
HPVtestingversusPapsmear
HPVtestingmoresensitivebutatcostofless
specificity
Specificityimprovesinwomen>30yrs
CostofHPVtestinghigherthancytology
HPVtestingcapableofautomation.Results
reproducible
At5yearsanegHPVtesthaslowerincidenceof
CIN3+(0.25%)thannegPapsmear(0.83%).
EffectofnegHPVlaststwiceaslongasnegPap
smear longerscreeningintervals
NTCC study
HPV63%moresensitivethancytology
SpecificityHPV93.3%inwomen>35yrsversus
97.1%forcytology
TherelativePPVvaluebetweenHPVtesting&
cytolwas0.67
ARBYN META-ANALYSIS
RepeatingHPVtestinginASCUSsmearsrather
thanrepeatingcytologymoresensitive&more
specificthanrepeatingcytology
HPVtestidentifyinghighriskHPVtype
TheJournaloftheNationalCancerInstitute2005TheElevated10YearRiskofCervicalPrecancerandCancerinWomenWith
HumanPapillomavirus(HPV)Type16or18andthePossibleUtilityofTypeSpecificHPVTestinginClinicalPractice,
demonstratedthatHPV16and18 screeningmayidentifywomenatgreatestriskforcervicalcancer(CIN3)1.
ImprovingHPVspecificity
Measuringviralload
Genotyping
TestingRNAofE6&E7.Levelsincreasewith
lesionseverity
OverexpressionofP16.InNTCCifreferred
onlywomenwithoverexpressionofP16
therewasnoincreaseinreferralfor
Colposcopy,butstillgaveanimproved
sensitivityof1.53overcytology
HPVvaccinationprogram
IntroducedinAustraliain2006
Gov.fundedprogramforfreevaccinationof
schoolgirls&youngwomenageupto26yrsof
quadrivalentvaccinecovering6,11,16&18
Programforyoungwomenotherthanthe
ongoinggroupof1213yrsfinishedin2009
Bothquadrivalent&bivalent(16,18)vaccine
availabletoothergroupscoveredbythe
licenceonprivatescript
HPVvaccinationera
RapiddropofHSILcytologyexpected&this
shouldhappenfromthisyear
Performanceofcytologyinpredictivevalue
expectedtodecline
Alreadydifficulttorecruitcytologists
?Newapproachrequired
Highgradeabnormalities
~80%ofwomenwithhighgradeabnormalitiesare<40
yearsold1
AIHW,2009.
EffectofHPVvaccinationoncytology
screeningprogram
CurrentlytheaveragesensitivityPapsmearfor
detectinghighgradeabnormalitiesisapprox53%(30
70%)withapprox97%specificity1
Thereisevidencetoshowthatinlowprevalence
populationsthesensitivityofPapsmearreduces.2 HPV
vaccinationwillbereducetheprevalenceofcytol
abnormalities
ThusitmaybeexpectedthatthesensitivityofPap
smearwillfurtherdecline
Attractionforcytologyasacareerdeclining
1. Cuzick et al Int J Cancer 2006;119: 1095-105
2000;9(9):945-51
THREAT
?Screeningin
thefuture
HPVTest
Negativ
e
Routine
screening
Repeat5
years
Positive
Cytology
Negative
Negative
RepeatHPV
test
Positive
Positive
Negativ
eorLSIL
Colposcopy
&Biopsy
Positive
Treatment
Liquidbasedcytology
Reducesunsatisfactoryrate
NotmoreeffectiveinAustraliansetting
Commonestmodalityofcytologyinrestof
world
Primebenefit allowsreflexHPVtesting&
othermarkersthatmaybedeveloped
InsteadofHPVDNAdetectionalonequestfor
markersofpersistenceorHPVintegration
RenewalProcessinCervicalScreening
AgeofCommencement
Screeninginterval
Liquidbasedcytology
HPVtesting
HPVtesting
WhatisHPVtesting
CurrentuseofHPVtestinginAustraliansetting
Use&limitationsofHPVtesting
CurrentuseofHPVtestinginothercountries
PossibleroleforHPVtestinginfuture
CASE PRESENTATION
USINGTRANSPONDERS
Wheredoyounormallyreside?
12%
No
n
m
et
ro
12%
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h
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Br
is
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ba
rt
12%
ba
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12%
ou
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e
12%
M
el
b
Sydney
Melbourne
Brisbane
Hobart
Darwin
Perth
Darwin
Nonmetro
Other
Sy
dn
ey
1.
2.
3.
4.
5.
6.
7.
8.
9.
Whatbestdescribesyou
12%
12%
12%
12%
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th
er
12%
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ur
se
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ra
ct
i si
ng
m
P
et
ra
...
ct
i si
ng
ru
r..
.
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P
tra
in
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ee
ai
ne
eo
Se
th
xu
er
al
h
ea
F a
lth
m
..
ily
.
P
la
nn
in
...
PractisingmetroGP
PractisingruralGP
GPtrainee
Traineeother
SexualhealthPhysician
FamilyPlanningDoctor
Nurse
Other
1.
2.
3.
4.
5.
6.
7.
8.
Scenario1
22y.o.WomanwithPapsmearLSILcytology
12monthsagohasanotherPapsmear
showingLSIL
Management?
Management?
0 of 30
re
20%
U
ns
u
te
st
R
ef
er
fo
rC
ol
...
H
PV
R
ep
ea
tP
a
p
sm
...
20%
O
th
er
1. RepeatPapsmear12
months
2. HPVtest
3. ReferforColposcopy
4. Other
5. Unsure
Case13
ManagementofbiopsyprovenCIN2
1. Treatmentwithlaserablation
2. Treatmentwithwireloop
excision
3. ConservativeManagement
withreviewin6months
4. Conservativemanagement
withreviewin12months
5. Other
0 of 30
er
O
th
e
m
...
tiv
...
tiv
C
on
se
rv
a
e
M
...
ith
w
C
on
se
rv
a
re
at
m
en
t
re
at
m
en
tw
ith
...
Rateofandrisksforregressionofcervicalintraepithelial
neoplasia2inadolescentsandyoungwomen.
MoscickiAB,MaY,WibbelsmanC,DarraghTM,PowersA,Farhat
S,ShiboskiS. ObstetGynecol. 2010Dec;116(6):137380
OBJECTIVE:
Todescribethenaturalhistoryofcervicalintraepithelialneoplasia(CIN)2inaprospectivestudyofadolescents
andyoungwomen,andtoexaminethebehavioralandbiologicfactorsassociatedwithregressionand
progression.
METHODS:
Adolescentsandwomenaged13to24yearswho werereferredforabnormalcytologyandwerefoundtohave
CIN2onhistologywereevaluatedat4monthintervals.Risksforregressionweredefinedasthreeconsecutive
negativecytologyandhistologyvisits,andprogressiontoCIN3 wasestimatedusingCoxproportionalhazards
regressionmodels.
RESULTS:
Ninetyfivepatientswithameanageof20.4years(2.3)wereenteredintotheanalysis.Thirtyeightpercent
resolvedbyyear1,63%resolvedbyyear2,and68%resolvedbyyear3.Multivariableanalysisfoundthatrecent
Neisseriagonorrhoeaeinfection(hazardratio25.27;95%confidenceinterval[CI]3.11205.42)and
medroxyprogesteroneacetateuse(permonth)(hazardratio1.02;95%CI1.0031.04)wereassociatedwith
regression.Factorsassociatedwithnonregressionincludedcombinedhormonalcontraceptionuse(permonth)
(hazardratio0.85;95%CI0.750.97)andpersistenceofhumanpapillomavirus(HPV)ofanytype(hazardratio
0.40;95%CI0.220.72).Fifteenpercentofpatientsshowedprogressionbyyear3. HPV16/18persistence(hazard
ratio25.27;95%CI2.65241.2;P=.005)andHPV16/18statusatlastvisit(hazardratio7.25;95%CI1.0749.36;
P<.05)wereassociatedwithprogressionBecauseofthesmallsamplesize,othercovariateswerenotexamined.
CONCLUSION:
ThehighregressionrateofCIN2supportsclinicalobservation
ofthislesioninadolescentsandyoungwomen.
TimetoclearanceofCIN2
.
TimetoprogressionofCIN2toCIN3
TimetoclearanceofCIN2byHPV
16/18status
Obstetricoutcomesafterconservativetreatmentforintraepithelialorearlyinvasivecervical
lesions:systematicreviewandmetaanalysis.
KyrgiouM,KoliopoulosG,MartinHirschP,ArbynM,PrendivilleW,ParaskevaidisE.
Lancet. 2006Feb11;367(9509):48998.
LaserTreatmentfollowup
SeenGynaecologistat6monthsforcolposcopy
&cytology
Colposcopy inconclusiveasTZisendocervical.
PappossibleLSIL
ReferrredbacktoGPforcytology&hrHPVtest
Whatisyouropinion?
1. Idontfeelcomfortablewith
havingtomanageanywomen
postRxforHSIL
2. Whenthe1st PapafterRxis
abnormaltheSpecialistshould
continuefollowup
3. Ifeelcomfortableinadvising
womenwhomayhaveafurther
abnormalityafterRx
4. Noneofabove
I
do
n
tf
ee
lc
.. .
W
he
n
th
e
1s
tP
...
I
fe
el
co
m
fo
rt
...
N
on
e
of
ab
ov
e
0 of 30
ResultsofPap
PapsmearPossibleHSIL
Digenepositive
Whatnextforthisyoungwoman
0 of 30
ae
co
l
e
Gy
n
O
th
er
og
...
e.
..
sh
Th
dv
ise
Y
ou
a
dv
ise
a
Y
ou
a
re
pe
at
P
...
r..
.
G
P
to
1. GPtorepeatPap&hrHPV
test
2. YouadvisearepeatRxwith
laser
3. Youadviseshewillrequire
anexcisionalRx
4. TheGynaecologistmay
electtomanage
conservatively
5. Other
Whatnow?
1. Coldknifecone
biopsy
2. LaserConebiopsy
3. LLETZ
4. Expectant
management
5. Other
0 of 30
er
O
th
an
tm
an
a
...
Z
ET
pe
ct
LL
Ex
o.
..
eb
i
se
rC
on
La
C
ol
d
k
ni
fe
co
n.
..
Thankyou
Ihopethishashelpedinunderstandingthe
currentmanagementofapatientwith
recurringCIN2
Alsogivenyouanawarenessimplicationsfor
pregnancyoftreatment
Doyouthinktheobjectivesofthe
presentationhavebeenmet?
0 of 30
25%
25%
U
ns
ur
e
25%
P
ar
tly
25%
N
o
Yes
No
Partly
Unsure
Y
es
1.
2.
3.
4.
Thank You
QUESTIONS???