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epithelium contains glycogen, and stains mahogany brown after application of iodine
solution.Normalcolumnarepitheliumandimmaturesquamousmetaplasticorneoplastic
epithelium do not contain glycogen, are not stained by iodine solution, and appear
mustardyellow.Iodinesolutionapplicationisnotuniformlyperformedbutisinvaluable
in the assessment of the vaginal mucosa. It will assist in determining if there is any
vaginalextensionoftheTZandifseparatevaginallesionsarepresent.
DelineatingtheMarginsoftheLesion
Afterthesourceofabnormalcellsinacervicalsmearhas beenlocated, theperipheral and
distalmarginsofthelesionshouldbedetermined.
DistalMargin
Thedistalorperipheralmarginofthelesionisusuallyreadilyidentified.Theuppervagina
should be assessed to avoid missing extension of CIN or isolated vaginal intraepithelial
neoplasia(VAIN)lesions.Whencytologypredictsasquamousabnormalityandthereis
nocolposcopicallyvisiblecervicallesion,carefulcolposcopicexaminationofthevagina
withaceticacidandLugolIodineshouldbeperformedtoexcludeVAIN.
ProximalMargin
Delineation of the proximal or upper margin of the lesion requires the colposcopic
visualization of the new squamocolumnar junction. Failure accurately to delineate the
position of the new squamocolumnar junction represents one of the most common
colposcopictriageerrors.Anendocervicalspeculummaybehelpfuliftheproximalmarginis
withinthecanal.
EndocervicalCurettage
Endocervicalcurettageisperformedtoexcludeanoccultcancerinthecanal(152).Cervical
AIS and invasive adenocarcinoma may be associated with squamous CIN lesions and
endocervicalcurettagemayprovideasafeguardagainstmissingsuchlesions.
Routine performance of endocervical curettage is controversial. ECC has a high
sensitivityinthediagnosisofendocervicalprecancerouslesionsandcancer(153)butthereis
a lack of evidence to support routine use in colposcopy practice. When the entire new
squamocolumnar junction can be visualized, it is reasonable to omit endocervical
curettage. Anegative endocervical curettage from a patient with an abnormal high-grade
cytologyandanunsatisfactorycolposcopydoesnotexcludeoccultendocervicalcancer,and
excisionalcone biopsy remains mandatory. When specifically indicated, collection of an
endocervicalsample using acytobrushmaybe a moresensitive sampling devicethan
endocervical curettage for endocervical squamous and glandular disease (154–157).
Specificitymaybedecreased.
ColposcopicallyDirectedCervicalBiopsy
Cervicalbiopsiesshouldbedirectedtothemostsignificantlesions.Multi-quadrantlesions
may require multiple biopsies. With larger lesions, the most severe abnormality will be
morecentrallyplacedconsistentwiththe“molecularswitch”modelforprogressiontohighgradedisease.Takingmorethanonebiopsywilldetectmorehigh-gradedisease.Themost
reliable method of ensuring the accuracy of targeted biopsies is to grade lesions by
deriving a colposcopic score. Cervical biopsies should be taken with the aid of the
colposcope. The colposcopic grading score of the lesions and the biopsy sites should be
recorded.Anyareasuspiciousforoccultinvasionmustbecarefullysampled.
DocumentationofColposcopicFindings
Thecolposcopicfindingsshouldbedocumented.Itisusefultokeepanannotateddiagramof
the cervix and vagina. Photo-documentation using digitally captured images can be
extremely valuable. A system for recording patient information, laboratory results,
management plan, and tracking log should be established and maintained to ensure
appropriatepatientcareandfollow-up.Moderncomputerizedsystemsprovideformany
oftheseneeds.
TheAbnormalTransformationZone
IftheTZisdeviatedalonganeoplasticpathway,epithelialandvascularalterationsproduce
thecharacteristicmorphologicappearancesoftheabnormalTZ(158).Thecolposcopicsigns
oftheabnormalTZaredescribedaboveinTable8.6.
Squamous metaplasia, repair and regeneration, inflammation, and infection may all
produceabnormalcolposcopicTZfindings, suchas acetowhiteepitheliumandabnormal
vessels.Significantchangesinthehormonalmilieusuchasaccompanypregnancy,oral
contraceptive pill use, estrogen withdrawal, and estrogen replacement can produce
abnormal colposcopic signs in the absence of cervical disease. Atypical vessels,
consideredoneofthecolposcopichallmarksofinvasivecancer,canoccurinassociationwith
benign conditions, including immature metaplasia, nabothian follicles, inflammation,
radiationtreatment,andgranulationtissue.
ColposcopicGradingSystems
Thebasisofcolposcopicdecisionmakingistheprocessofcytologic–colposcopic–histologic
correlation, with each component affording certain safeguards. There are four basic
colposcopic diagnoses: (i) normal, (ii) low-grade disease (HPV infection/CIN 1), (iii)
high-gradedisease (CIN 2or3), and (iv)invasivecancer. Colposcopic grading systems
have been developed to provide an objective, accurate, reproducible, and clinically
meaningful prediction of the severity of CIN lesions based on discriminatory analysis of
specificcolposcopicsigns(124,159,160).
Routine determination of a colposcopic diagnosis has permitted quality-control
measures to be implemented in colposcopy (150,161). In colposcopic quality-control
programs, the colposcopist is required to achieve at least an 80% accuracy rate in
colposcopic–histologiccorrelationorreceiveremedialtraining.
The Reid Colposcopic Index represents the most reproducible and clinically valid
meansofstandardizingtheevaluationofcervicallesions(Table8.8).InarecentASCCP
survey,36%ofhigh-volumecolposcopistsusedtheReidIndextogenerateanddocumentthe
colposcopicimpression(150).Anothercolposcopicindex,theSwedeIndex(160),basedon,
but modifying the Reid Index, has also been demonstrated to produce a high level of
colposcopic–histologiccorrelation(162,163)(Table8.9).
ReidColposcopicIndex
TheReidColposcopicIndexusesfourcolposcopicfeaturesofpremalignantcervicallesions
to achieve predictive accuracy (Table 8.8). The colposcopic index permits accurate
differentiation of low-grade from high-grade disease. It is not designed to differentiate
premalignantfrommalignantcervicalneoplasia.Thefourcolposcopiccriteriausedare(i)
themarginofthelesion;(ii)thecolorofthe acetowhitening;(iii) thetypeofvascular
pattern,and(iv)theiodinestainingreaction.
The four colposcopic signs are scored individually and sequentially. The value of these
colposcopicsignsismaximizedbycombiningthemintoaweightedscoringsystem.Scores
of0,1,or2areassignedforeachcriterion.Thefourscoresareadded,andthetotalscoreis
reportedasaratio,thedenominatorofwhichisconstantat8.Scoresof0to2arepredictive
oflow-gradelesions (HPVinfection/CIN1; Fig. 8.11).Scores of 6 to 8 usually denote
high-gradelesions (CIN 2 to 3; Fig. 8.12). Scores of 3 to 5 represent an area of overlap
betweenlow-andhigh-gradelesions.Theoverallpredictiveaccuracyoftheindexexceeds
90% after a short training period. The colposcopic index permits a significantly more
accurate colposcopic–histologic agreement than can be achieved by less systematic
approaches.
Table8.8ScoringSystemforDevelopingtheReidColposcopicIndex
Score
ColposcopicSign ZeroPoints OnePoint TwoPoints
Margin Exophyticcondylomas;areas
showingamicropapillary
contour
Lesionswithdistinctedges
Feathered,scallopededges
Lesionswithanangular,
jaggedshape
“Satellite”areasand
acetowhiteningdistaltothe
originalsquamocolumnar
junction
Lesionswitharegular
(circularor
semicircular)shape,
showingsmooth,
straightedges
Rolled,peelingedges
Anyinternaldemarcation
betweenareasof
differingcolposcopic
appearance
Color Shiny,snow-whitecolor
Areasoffaint
(semitransparent)whitening
Intermediateshade
(shiny,butgray-white)
Dullreflectancewith
oyster-whitecolor
Vessels Fine-calibervessels,poorly
formedpatterns
Nosurfacevessels Definite,coarse
punctationormosaic
Iodine Anylesionstainingmahogany
brown;mustard-yellow
stainingbyaminorlesion
(bythefirstthreecriteria)
Partialiodinestaining
(mottledpattern)
Mustard-yellowstaining
ofasignificantlesion
(anacetowhitearea
scoring3ormore
pointsbythefirstthree
criteria)
AdaptedfromReidR,ScalziP.Genitalwartsandcervicalcancer.VII.Animprovedcolposcopicindexfor
differentiatingbenignpapillomaviralinfectionsfromhigh-gradecervicalintraepithelialneoplasia.AmJObstet
Gynecol1985;153:611–618.Copyright©1985Elsevier.Withpermission.
Table8.9ScoringSystemforDevelopingtheSwedeColposcopicIndex
SwedeScore 0 1 2
Acetouptake Zeroortransparent Shady,milky
Neithertransparent
noropaque
Distinct
Opaque
White
Margins/surface Diffuse Sharpbutirregular,
jagged,
geographic
satellites
Sharp,evendifferenceinsurfacelevel,
includescuffing
Vessels Fine,regular Absent CoarseorAtypical
Lesionsize <5cm 5–15cm
or
Twoquadrants
>15cm
or
Threetofourquadrantsorundefined
endocervically
Iodinestaining Brown Faintlyorpatchy
yellow
Distinctyellow
Totalscore
FromStranderB,Ellström-AnderssonA,FranzénS,etal.Theperformanceofanewscoringsystemfor
colposcopyindetectinghigh-gradedysplasiaintheuterinecervix.ActaObstetGynecolScand2005;84:1013–
1017.AdaptedbypermissionofJohnWiley&Sons,Inc.
SwedeColposcopicIndex
The Swede Colposcopic Index (developed by Strander et al. from Sweden) (160) is
largelyderivedfromtheReidIndex,althoughthedescriptivetermsforcolorafterapplication
of acetic acid, margins of the lesion, and appearance after application of iodine are less
accurate. This scoring system adds lesion size as a further independent variable
predictiveofdiseaseseverity(Table8.9).TheimplicationoftheSwedeIndexisthatlarge
low-grade lesions may harbor foci of evolving high-grade disease and that size of a lowgrade lesion may be a predictor of risk of undetected high-grade disease. This will be
determinedby thelocation of thelesion. Largelow-grade lesionsoutside theTZor within
alreadymaturesquamousmetaplasiawillrarelybehighgrade.
Figure 8.11 Colposcopy of low-grade cervical lesions showing acetowhite epithelium
withfineabnormalvascularpattern.
Figure 8.12 Colposcopy of high-grade cervical lesion showing dense acetowhite
epitheliumandcoarseabnormalvascularpattern.
A large low-grade lesion within a large, immature TZ is very difficult to interpret
colposcopicallyandmultiplebiopsieswillfrequentlydetectfocalareasofevolvinghighgradedisease.Thisisacommonsourceofthediscrepancybetweencolposcopicprediction
andultimatediseaseseverity.AccurateuseoftheReidIndexwilloftenpredictthisevolving
severity—thevesselpatternscorewilloftenbehighgradereflectingthelocationofthelesion
withinimmature metaplasiaand nonstainingwithiodine willalso be scoredas highgrade.
Theadditionofsizeoflesionasanindependentpredictorofdiseaseseverityislikelyto
beofvalue.Thesuggestionbytheauthorsthatcolposcopicscoringcouldbeusedtoavoid
biopsyforlowscoringlesionsshouldbeinterpretedwithcaution.
ColposcopicWarningSignsofInvasiveCancer
Although most invasive cancers are clinically apparent and do not require colposcopy for
identification,early invasivelesionsmay beclinically occult. Exclusionof invasivecancer
demands both a high index of suspicion and knowledge of warning signs. Colposcopic
warningsignsareshowninTable8.10.
Otherwarningsignsforinvasivecancerinclude:
1. Anycytologicevidenceofpossiblesquamouscarcinoma,adenocarcinoma,orAISor
recurrenthigh-gradecytologicfindingsinapatientpreviouslytreatedforCIN3.
2. AnyhistologicevidenceofinvasivecancerorCIN2or3inatangentiallysectioned
punchbiopsyinwhichthebasementmembranecannotbeadequatelydefined.
3. High-grade cytologic abnormality in a postmenopausal or previously irradiated
woman.
Table8.10ColposcopicWarningSignsofInvasiveCancer
1. Yellow,degenerate,friableepitheliumparticularlywithcontactbleeding
2. Irregularsurfacecontour,particularlywhenoccurringinahigh-gradecolposcopicabnormality(RCIscore
>6points)
3. Surfaceulcerationortrue“erosion,”particularlywhenoccurringinahigh-gradecolposcopicabnormality
(RCIscore>6points)
4. Atypicalbloodvessels(coarse,varicose,bizarresubepithelialvesselswithirregularcaliberand
nondichotomousbranchingorlong,unbranchedcourse)
5. Extremelycoarseabnormalvascularpatterns(i.e.,mosaicismandpunctation),especiallywithwideand
irregularintercapillarydistancesandumbilication
6. Large,complex,high-gradelesions(RCIscore>6points)occupyingthreeorfourcervicalquadrants
7. High-gradecolposcopiclesionsextendingintocervicalcanaleither>5mmorbeyondcolposcopicview
RCI,ReidColposcopicIndex.
HumanPapillomavirusesandCervicalNeoplasia
Extensive molecular biologic and epidemiologic research has confirmed certain HPV
types to be carcinogenic in humans (13,73,74,77,164–171). The four major steps in the
developmentofcervicalcancer are (i) infection of the metaplastic epithelium of the TZ
withoneormorecarcinogenicHPVtypes;(ii)viralpersistencerather thanclearance; (iii)
progression of persistently infected epithelium to cervical precancer (CIN 3) (potentially
reflecting the host immune response and/or exposure to the confirmed cofactors for HPV
progression which include multiparity, age at first full-term pregnancy, use of oral
contraceptivesandcurrenttobaccoexposure)(55,172–175);and(iv)invasion.
TaxonomyandBiology
Papillomaviruses are small, nonenveloped, double-stranded DNA viruses encased in a 72sided icosahedral protein capsid. The HPV genome consists of circular, double-stranded
DNAof approximately7,900nucleotidebasepairs.Papillomavirusesareadivergentgroup
of evolutionarily related viruses with similar biologic characteristics but enormous
differencesinspeciesspecificity,siteofpredilectionandoncogenicpotential(176,177).
Morethan 100 types of HPVhave been fully sequenced. HPVtypes are divided into
phylogenetictrees,basedontheirDNAsequenceandproteinhomologies.Thisassistsin
understandingHPVclassification and behavior(178). The oncogenic HPV types infect
the epithelium of the anogenital and oral tracts and are generally acquired through sexual
contact.
Genetic sequencing has defined clades of viruses, which produce similar pathology (102).
Virusesofcladesalpha-7andalpha-9aremostcommonlyassociatedwithanogenitalcancers
andHPV16inparticular(analpha-9species)appearstobea“uniquelypowerfulhuman
carcinogen”(106),which is implicated in approximately50% ofcervical cancers and
themajorityofHPV-relatedcancersatotheranogenitalandoropharyngealsites.
TheHPV genome isusuallymaintained as a stableviralepisome, independent of thehost
cellgenome,inthenucleusofinfectedcells(Fig.8.13).Itcodesforonlyeightgenes(179).
Insomehigh-gradeCINlesions,andmorefrequentlyincervicalcancer,HPVgenomesare
covalentlybondedorintegratedintothehostchromosomes(180–185).Thisintegrationevent
involves the E1 and E2 genes, with important consequences for regulation of viral gene
expression(186). Thelategenes, L1and L2, the sequencesofwhich are highly conserved
amongallpapillomaviruses,encodethecommoncapsidproteins.Theseviralproteinsreflect
late viral gene expression and are exclusively present in well-differentiated keratinocytes
(187).Bothproteinsplayanimportantroleinmediatingefficientvirusinfectivity.
Figure8.13 TheHPVgenomeanditsexpressionwithintheepithelium.TheHPVgenome
consistsof approximately 8,000 base pairs of single-stranded, circular DNA.HPV genes are
designatedasEorLaccording to their expressioninearlyorlatedifferentiationstageofthe
epithelium:E1,E2, E5,E6,andE7areexpressedearlyinthedifferentiation,E4isexpressed
throughout, and L1 and L2 are expressed during the final stages of differentiation. The viral
genomeismaintainedatthebasallayeroftheepithelium,whereHPVinfectionisestablished.
Earlyproteinsareexpressedatlowlevelsforgenomemaintenance(raisingthepossibilityofa
latentstate)andcellproliferation.Asthe basal epithelial cells differentiate,thevirallifecycle
enters successive stages of genome amplification, virus assembly and virus release, with a
concomitantshiftinexpression patterns fromearlygenestolategenes,including L1andL2,
whichassembleintoviralcapsid.(ReproducedwithpermissionfromSchiffmanM,CastlePE,
Jeronimo J, et al. Human papillomavirus and cervical cancer.Lancet 2007;370(9590):890–
907.Copyright©2007Elsevier.Withpermission.)
TheproteinsencodedbytheE6andE7genesofhigh-riskHPVtypes,particularlyHPV16
(cladealpha-9)andHPV18(cladealpha-7),aredirectlyinvolvedincellulartransformation
inthepresenceofanactiveoncogene(188).E6andE7aretheprimaryHPVoncoproteins
with numerous cellular targets (189,190). Both E6 and E7 proteins can immortalize
primary keratinocytes from cervical epithelium and influence transcription from viral and
cellular promoters (191). The activity of these viral oncoproteins results in genomic
instability,leading to themalignant phenotype.E6proteinsofhigh-risk HPVtypesbind
the tumor suppressor protein p53 (192,193). This induces ubiquitination and
degradationofp53,removingthep53-dependentcontrolofthehostcellcycle(194–196).
The role of E6 as an antiapoptotic protein is of key significance in the development of
cervicalcancer.
E6increasestelomeraseactivityinkeratinocytesthroughincreasedtranscriptionofthe
telomerasecatalyticsubunitgene(hTERT)viainductionofc-myc(197,198).Telomerase
activityisusuallyabsentinsomaticcells,leadingtoshorteningoftelomereswithsuccessive
cell divisions and to eventual cell senescence. E6 mediation of telomerase activity may
predispose to long-term infection and the development of cancer. E6 and E7 viral
oncogeneshavebeenshowntoantagonizeBRCA-mediatedinhibitionofthehTERTpromoter