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(199).
TheE7geneproductisanuclearphosphoproteinthatassociateswiththeproductofthe
retinoblastomagene(pRb),whichisatumorsuppressorgeneimportantinthenegative
controlofcellgrowth(200–202).E7istheprimarytransformingprotein.Degradationof
p53 by E6 and the functional inactivation of pRb by E7 represent the main mechanisms
wherebyexpression of HPV E6andE7 oncoproteins subverts the functionofthe negative
regulatorsofthecellcycle(203–205).Deregulatedexpressionoftheviraloncogenesisa
predisposingfactortothedevelopmentofHPV-associatedcancers.
TheproductsoftheE2geneareinvolvedintranscriptionalregulationoftheHPVgenome.
TheprocessofHPVintegrationintothecellulargenome,whichoccursinsomehigh-grade
CINlesionsandmostinvasivecervicalcancers,disruptsthe E2gene (206).This resultsin
increasedlevelsofE6andE7expression,correlatingwithincreasedimmortalizationactivity
(206–209).
Aberrantexpressionofhigh-riskviraloncogenescanpredisposetothedevelopmentof
cervical cancer, but their expression alone is not sufficient (179). HPV-mediated
oncogenesis requires accumulation of additional genetic mutations over time. A schematic
model of HPV-driven carcinogenesis is demonstrated in Figure 8.14. The peak age for
development of invasive cervical cancer often occurs in women aged 35 to 40 years and
older (depending on the screening processes, if any, in place). Because CIN 3 is screen
detected,itsmedianageisoftenunder30years(dependingonthescreeningprocessesin
place). This suggests a long precancerous state, which allows the accumulation of
secondarygeneticmutations.Thesemutationscanoccur randomlybut mayalso reflectthe
influenceofcofactorssuchastobaccocarcinogensandexogenousandendogenoushormonal
influences(74).
HumanPapillomavirusType–SpecificDiseasePattern
Over100HPVtypeshavebeenidentified,butupto15anogenitaltypesmaybereferredto
as“oncogenic”;theseincludeHPV16,themostfrequentlyinvolved,HPVs18,45,31,33,
35,52,and58,whicharethenextmostcommonlyidentifiedincancer,andafurther7types
with lower level and less certain contributions (HPVs 51, 56, 39, 59, 68, 73, and 66)
(178,210)(Fig.8.15).
Low-riskHPVtypes,particularlyHPVs6and11(cladealpha-10),areassociatedwith
condylomataacuminataofthe genital tract in both sexes. HPVs 6 and 11 are detected
alone in low-grade cervical lesions (exophytic condylomata acuminata, subclinical HPV
infection, CIN 1 and some CIN 2 lesions). These viruses are unable to integrate into the
humangenome.TheE6andE7proteinsof“low-risk”HPVtypesonlyweaklybindp53and
pRb,andthusdonotimmortalizekeratinocytesinvitro.
Humanpapillomavirus16istheHPVtypeuniversallydetectedwithgreatestfrequency
in HPV-related invasive cancers. HPV 16 is associated with 50% of cervical squamous
cancers and a large proportion of adenocarcinomas (211–214). It is present in a high
proportionofhigh-gradecervical,vaginal,vulvar,perianalandpenilepreinvasivelesions.
HPV18isthesecondmostcommon(20–25%)HPVtypeininvasivecervicalcancerand
is associated with the development of a substantial proportion of cervical
adenocarcinomas. Organized cytologic screening programs have not been as effective
against adenocarcinomas, rates of which have remained stable in some settings, while
squamous cancers have declined (215). Prospects are good, however, that a transition to
primaryHPV-basedscreening,nowoccurringinmanyhigh-incomecountries,mayresultin
moreeffectivepreventionofadenocarcinoma(216).
HumanPapillomavirusandCervicalCancer:CausalAssociation
Intheprevaccinationera,mostsexuallyactivewomenwereexposedtoHPVinfection
(217)butmostclearedaspecificHPVtypewithin2years(218,219).Humoralandcellular
immune responses to natural infection with genital HPVtypesare inconsistently detected,
possibly because the virus is nonlytic to infected cells and does not spread systemically.
Secondary peaks of HPV infection in some (but not all) populations of older and
postmenopausalwomen have suggested thepossibilityof reactivationofalatent viral
reservoircaused by senescence of cell-mediated immunity, although this could also be
explainedbysexualbehavior(ofwomenorpartners).
Ithasbeenestimatedthatthemedianageawomanacquiresa“causal”HPVinfection(i.e.,
aninfectionthateventuallyleadstoinvasivecervicalcancer)isaround21yearsofage(34).
The longer a specific HPV type persists in the epithelium, the lower the probability of
clearancewithinadefinedperiod,and thegreaterthe riskofprecancer development(219).
HPV type is the strongest factor affecting risk of viral persistence (73). A number of
longitudinal studies have documented the long-term risk of cervical precancer and cancer
according to HPV type at baseline (51,52,81,220,221). Women exposed to HPV 16 are
consistentlydocumentedtobeatelevatedrisk.Oneofthelongestreportedfollow-upperiods
hasbeenfor theKaiserPermanentecohortintheUnitedStates,wherethe16-yearriskof
developingCIN3+inwomenagedunder30yearswas14.6% (95%CI: 10.0–20.9)for
womenwithHPV16atbaseline;7.0%(4.2–11.4),forwomenwithotheroncogenicHPV
types,and1.8%(1.2–2.5)forwomenwithnoHPVinfection.Forwomenover30years,
the risks were 8.5% (95% CI: 4.1–17.2) for HPV 16, 3.1% (1.6–6.1) for other oncogenic
types,and0.7%(0.5–0.9)forHPV-negativewomen(51).
Figure 8.14 Schematic model of HPV-driven carcinogenesis. A: A multistep molecular
mechanismofhost-viralinteraction.Theinitialoutcomeofcarcinogenesisismodulatedbyboth
viral (high-risk vs. low-risk HPV types, HPV integration) and host factors (inflammatory
response,oxidativestress).InflammatoryresponseuponinitialinfectionsuchasIFNresponse
plays role in reducing episomal HPV resulting clearance of infection. Integration of HPV is
(initiatedwithDNAdamage).TheIFN-inducedlossofepisomalHPVanddownregulationofE2
leadstotheselectionofcellswithintegratedHPVgenomesexpressinghigherlevelsofE6and
E7.Oncethe earlygenesE6andE7 are expressed,TLR9downregulatedand IFNresponse
impaired, resulting a conducive milieu for immune evasion and persistent infection.
Upregulation of E6/E7 increases genetic instability and chromosomal rearrangements that
increasetheriskofintegration.OverexpressionofE6/E7leadstoderegulationofthecellcycle
viap53and Rbdegradation,deregulationof oncogenes,andmiRNAsexpression.Epigenetic
and genetic modification in viral and host genome leads to the deregulation of E6 and E7
oncogenes, and host tumor suppressor genes that lead to carcinogenesis. Oxidative
modification of TFs also leads to altered gene expression and carcinogenesis. (Part A from
Senapati R, Senapati NN, Dwibedi B. Molecular mechanisms of HPV mediated neoplastic
progression. Infect Agent Cancer. 2016;11:59. http://creativecommons.org/licenses/by/4.0/.
Copyright©2016TheAuthors;andPartBfromdelMarDiaz-GonzalezS,DeasJ,Benitez-
BoijseauneauO,etal. UtilityofmicroRNAs and siRNAs in cervicalcarcinogenesis.Biomed
Res Int. 2015;2015:374924. https://creativecommons.org/licenses/by/3.0/. Copyright © 2015
SacnitedelMarDíaz-Gonzálezetal.)
Figure 8.14 (Continued) B: Schematic model of the interaction between microRNAs and
factorsinvolvedinmalignanttransformationcausedbyHPVE6andE7expressionincervical
cancercell.E6disruptstheexpressionofmiR-23b,miR-218,andmiR-34aviap53degradation
andtheirexpressionistransactivatedbythebindingofp53toconsensussitesinthepromoter
regions,affectingtheexpressionofcellcycleregulators,suchasE2,cyclinD1,CDK4,CDK6,
E2F1,E2F3,E2F5,Bcl-2,SIRT1,p18,uPA,andLAMBD3.IntheoverexpressionofmiR-15/16
clusterbyE7,E2F1transactivatesthec-Mybexpressionandrepressesthec-Mycexpression,
and then the microRNA cluster regulation is controlled by binding of c-Myc or c-Myb to
promoterregionofmicroRNAcluster.TheincreasedexpressionofmiR-15a/miR-16-1induces
theinhibitionofcellproliferation,survival,andinvasion.ThedownregulationofmiR-203byE7
is mediated by MAPK/PKC pathway. (Reproduced from Wang X, Huang X, Zhang Y.
Involvement of human papillomaviruses in cervical cancer. Front Microbiol 2018;9:2896.
Published2018Nov28.doi:10.3389/fmicb.2018.02896.)
High viral loads do not generally imply an increased risk of progression, except for
HPV16(222,223).Recentlyacquiredlow-gradecervicallesionscontainsomeofthehighest
viralloads, analogous to condylomataacuminata,and frequently regress(224).In general
terms,viralloadmeasurementisnotclinicallyuseful(13).
The median time from HPV infection to CIN 3 is short, often within 5 years (225),
although CIN 3 is screen detected and so screening recommendations and processes will
stronglyinfluence estimatesofthis timing.Infectionoften occursinthe late teensor early
20saftertheinitiation ofsexualactivity(in unvaccinatedpopulations)andthediagnosisof
CIN3peaksat25to30years(212,225)or20to24yearsinsomepopulations(215).CIN3
hasbeendiagnosedwithin2yearsofcoitarche,andCIN 2–3hasbeendocumentedto
rapidly develop within several months of an incident HPV infection (226,227). The
biologic significance and risk of invasion associated with these early CIN 3 lesions is
uncertain, but cytologic screening in women under 25 years is of limited effectiveness
(228), and the International Agency for Research on Cancer (IARC) recommends starting
screeningat25years (7). The transit time from CIN 3 to invasive cancer is variable, but
long-termfollow-upfromanunethicalexperimentinwomenmanagedonlybypunchor
wedgebiopsyhassuggestedthatabout30%ofcasesofCIN3willprogresstoinvasive
cancer over 30 years (76). The major steps in the development of cervical cancer are
summarizedinFigure8.16.
Figure 8.15 Attribution of carcinogenic HPV types to cervical disease categories.
ExpandedfromtheworkofWentzensenetal.Thetypeattributionisbasedonthehierarchical
attributionmodel forcarcinogenicgenotypespresentinmultipleinfections.HPVgenotypingis
based on concurrent cytologic specimens, not on tissue specimens. (Reprinted from
Schiffman M, Wentzensen N. Human Papillomavirus infection and the multistage
carcinogenesis of cervical cancer. Cancer Epidemiol Biomarkers Prev 2013;22(4):553–556,
withpermissionfromAACR.)
CofactorsintheProgressionofCervicalHumanPapillomavirusInfection
TheestablishedcofactorsinprogressionofHPVinfectiontoinvasivecanceraretheuseof
tobacco, multiparity, age at first full-term pregnancy and use of oral contraceptives
(172–175). Host genetic factors influencing HPV infection control exist but are not well
understood,and do not playarole in current managementofCIN. There is adocumented
human leucocyte antigen (HLA) association, likely reflecting the importance of T-cell
responsesincontrolofHPVinfectionandcervicalcancerprecursors(229).
TobaccoUse
Cigarettesmokinghasbeendemonstratedtobeariskfactorforsquamouscervicaland
vulvar carcinoma (172,230–235). An increased risk of developing an HSIL has been
demonstrated among high-risk HPV-positive women who smoke. It is uncertain whether
smokingactsviaanimmunosuppressingorgenotoxicpathway.Thedetectionofhighlevels
of genotoxic breakdown products of cigarette smoke—including nicotine, cotinine,
hydrocarbons, and tars—in cervical secretions of smokers and the demonstration of
mutagenicactivityoftheseproductsincervicalcells,similartothatobservedinlungcells,
pointtoanimportantroleforthesecompoundsincervicalcarcinogenesis.
CigarettesmokinginfluencesepithelialimmunitybydecreasingthenumbersofantigenpresentingLangerhanscellsinthegenitalepithelium(236,237).Cervical HPVinfection
and CIN are associated with diminished numbers of intraepithelial Langerhans cells. Such
local immunologic depletion could favor viral persistence, contributing to malignant
transformation.Cigarette smoke concentrateshavebeen demonstrated invitrototransform
HPV-16–immortalized endocervical cells (232). However, though squamous cervical
cancerandadenocarcinomasharehormonalriskfactors(increasingparity,youngerage
atfirstfull-termpregnancyandincreasingdurationofhormonalcontraceptiveuse),smoking
doesnotappeartobeariskfactorforadenocarcinoma(175).
SexHormonalInfluences
Condylomataacuminatamay increase rapidly in size andnumberin pregnancy.This
could suggest that maternal estrogen status is permissive for HPV replication, although it
mayreflecttheimmunosuppressiveeffectofpregnancy.IncreaseddetectionofHPVDNAin
cervicalcytologicsamplesinpregnancy,includingdetectionofoncogenicHPVtypesinup
to 27% of pregnant women (in unvaccinated/prevaccination populations), suggests
hormonallyinducedactiveviralreplication(238,239).
A pooled analysisof worldwide data hasfoundthat the relativeriskof invasive cervical
cancerforfirstfull-termpregnancyunder17yearscomparedwith25yearsorolderis
1.77(95%CI:1.42–2.23).Independentlyofageatfirstfull-termpregnancy,parityhasalso
beenshowntobeasignificantfactorinthedevelopmentofcervicalcancer.Therelativerisk
is 1.76 (95% CI: 1.53–2.02) for women having seven or more full-term pregnancies
comparedwithoneortwo(173).
TheInternationalCollaborationofEpidemiologicStudiesofCervicalCancerhaspooledthe
worldwidedataandidentifiedanincreaseintherelativeriskofcervicalcancerincurrent
usersoforalcontraceptives,whichdeclinesafteruseceases.Usefor10yearsbetweenthe
agesof20and30wasestimatedtoincreasethecumulativeincidencebyage50from7.3to
8.3 per 1,000 women in less developed countries, and from 3.8 to 4.5 in more developed
countries(174).
Figure8.16Majorsteps in the development of cervical cancer.IncidentHPV infection is
best measured by molecular tests. Most HPV infections show no concurrent cytologic
abnormality. Approximately 30% of infections produce concurrent cytopathology, usually
nonclassical (equivocal) changes. Most HPV infections clear within 2 years. Ten percent
persistfor2yearsandarehighlylinkedtodevelopmentofprecancer.(Topimagereproduced
withpermissionfromSchiffmanM,CastlePE,JeronimoJ,etal.Humanpapillomavirusand
cervical cancer.Lancet 2007;370(9590):890–907; Bottom image reproduced with permission
from Schiffman M, Wentzensen N. Human Papillomavirus infection and the multistage
carcinogenesisofcervicalcancer.CancerEpidemiolBiomarkersPrev2013;22(4):553–560.)
ExogenousandEndogenousImmunosuppression
Iatrogenicinductionofimmunosuppressioninrenaltransplantrecipientsincreasesthe
rate of CIN to 16 times that of the general community (240). The risk of CIN and
cervicalcancer isincreasedin humanimmunodeficiencyvirus (HIV)–infected women
and failure rates of treatment for preinvasive lesions are increased (241–247). Systemic
immunesuppressionfromdiseasessuchasHodgkindisease,leukemiaandcollagenvascular
diseasesareassociatedwithanincreasedincidenceofHPV-associateddisease(244,248).
HumanPapillomavirusVaccines
TheHPVvaccineisamajorscientificandpublichealthadvanceinthepreventionofHPVrelatedcancer(249,256).HPVprophylacticvaccines,designedtopreventHPVinfection,
are based on virus-like particle (VLP) technology developed through the pioneering
research of Zhou and Fraser in Brisbane, Australia, by Schiller and Lowy at the National
Institutes of Health USA and by others (249,257,258). These DNA-free VLPs are empty
capsidsandcontainnooncogenicorinfectiousmaterials.Virus-likeparticlesresemblethe
virus immunologically and induce HPV type–specific antibodies on administration
(259,260).TheimmunogenicityofHPVinvolvespresentationofthemajorcapsidproteinL1
totheimmunesystem.L1VLPvaccinesinducestrong,cell-mediatedandhumoralimmune
responses(261–264).
Since 2006–2007, when vaccines first became available and licensed by regulatory
agenciesinmanysettings,prophylacticvaccinationagainstHPVinyoungfemaleshas
been introduced in the majority of developed countries. The introduction of this
interventionhasbeensupportedbyevaluationsofitscost-effectiveness,eveninthecontext
ofcervicalscreening(251).Initially,twofirst-generationvaccinesweremadeavailable—
the quadrivalent vaccine Gardasil (Merck, USA) and the bivalent vaccine Cervarix
(GSK,Belgium).TheseprotectagainstHPV16/18,togetherresponsibleforabout70%
ofinvasivecervicalcancers(265).HPV(predominantlyHPV16)hasalsobeenidentifiedin
varyingfractionsofvulvar,vaginal,anal,penile,andoropharyngealcancers(266)and thus
the vaccines also have the potential to prevent a proportion of these cancers. The
quadrivalentvaccinealsoprotectsagainstHPVtypes6and11,whicharefoundtobe
associatedwithapproximately90%ofanogenitalwarts.
Subsequently, a second-generation nonavalent vaccine Gardasil9 (Merck, USA) has
becomeavailable.ThisvaccineincludesprotectionagainstHPVtypes16,18,31,33,45,
52, and 58, as well as types 6 and 11,thus protecting against approximately 90% of
invasivecervical cancers infullyimmunizedwomen (i.e., females whowerevaccinated
beforeexposuretoanyoftheincludedHPVtypes)(267–269).HPVvaccinationhasbeen
shown to be effective in preventing persistent infection and high-grade precancerous
cervicalintraepithelialneoplasia(CIN2+)infemalesnaïvetoHPVvaccinetypes (252)
andat preventingpersistent infection,externalgenital lesionsand anal intraepithelial
neoplasiainmales(253,254).Manyhigh-incomecountries havenowtransitioned tousing
thenextgenerationnonavalentvaccine,althoughthebivalentvaccinehasalsobeenshownto
achieve “broad-spectrum” protection via cross-protection against non–vaccine-included
types.AkeyexperienceinScotland demonstratedhighoverall efficacyofaprogram using
the bivalent vaccine against infections and high-grade cervical precancerous lesions
(270,271).
BecausethenumberofHPV-relatedcancersarelowerinmalesandheterosexualmales
benefittosomeextentfromfemalevaccinationviaherdimmunity,inclusionofyoung
males in vaccination programs is generally associated with a lower return on
investment,especiallyifcoverageinfemalesisover50%,becausethisincreasestheherdimmunity–inducedprotectiontomales(251,255,256).Malesreceivemostoftheirpotential
benefitfrom first-generationvaccinesbecause mostHPV-relatedcancers inmalesare
caused by HPV 16. This should be taken into account when considering the incremental
benefits and cost-effectiveness of second-generation vaccines in countries considering
vaccinatingboysaswellasgirls(272).
VaccineEfficacy
Clinical trials have demonstrated that HPV vaccines are effective and safe
(252,259–262,269,273,274). For ethical and scientific reasons, surrogate end points in
efficacytrials have consisted ofpreventionof HPV acquisition andofpersistent infection,
development of high-grade precancerous lesions (CIN 2+), and development of genital
neoplasia and genital warts (as opposed to development of cervical cancer). Studies have
beenlargelyundertakenamongsexuallyactivewomen16to25yearsofage,althoughsome
studies have been extended to include women up to 45 years. Immunogenicity-bridging
studies have been carried out in young females and males aged 10 to 15 years, where
antibodylevelsproducedaresubstantiallyhigherthanin16-to23-year-olds.Forpopulation
effectiveness and for cost-effectiveness reasons, vaccination of women aged over 26
yearshasnotbeenroutinelyrecommendedwithinvaccinationprograms,althoughinthe
UnitedStates,theCentreforDiseaseControl’sAdvisoryCommitteeforImmunizationPrices
(ACIP)reviseditsguidancein2019torecognizethatsomeindividuals mightbenefit from
vaccinationaged27to45years.ACIPrecommendedsharedclinicaldecisionmakingabout
HPVvaccinationinthisagegroup.Inthefuture,novel“screen-and-vaccinate”strategies
might be possible in settings where a transition to primary HPV-based screening is
takingplace,becausewomennegativeforaparticularHPVtypecouldpotentiallybeoffered
vaccination after screening. The cost-effectiveness of these new options requires detailed
consideration.
Instrictper-protocol analyses, where only women naïve to the HPV types of interest
wereconsidered, both the bivalent andquadrivalent vaccines have demonstrated 98–
100% efficacy in preventing high-grade cervical lesions among young sexually active
women where the disease endpoints were associated with the vaccine-included types
(249,250,252,259,273–280).Forthenonavalentvaccine,noninferiorityofprotectionagainst
thequadrivalent-vaccinewasdemonstrated,andthevaccinewasshowntoprotectagainstthe
HPVtypes31,33,45,52,and58whichwereincludedinthenewvaccine(269).
In trial analyses which have included less strenuously defined criteria, such as including
women with known infection or with disease associated with vaccine types prior to
vaccination,vaccine efficacyhasbeenreduced. Forexample, thequadrivalent vaccinewas
showntobe 44% effective inpreventingCIN2–3 associated with HPVtypes16 or 18 in
womenaged15to26years(252).
Notherapeuticeffecthasbeendemonstratedinwomenwithvaccine-typeexistingHPV
infectionorHPV-relateddisease,withlesionsregressingorprogressingatsimilarratesin
vaccinatedandplaceborecipients(281).Follow-upstudiesofwomenhavedemonstrated
sustainedefficacyforatleast10years.Thevaccineinducespeakantibodylevelsmany
times higher than those seen with natural HPV infection (249). Antibody levels fall
significantly in the first 2 years after immunization but remain above those stimulated by
naturalinfection(282).Amodelingstudyhassuggestedthatantibodylevelswillremain
abovethoseassociatedwithnaturalinfectionfor12yearsormore(283).Immunologic
memoryisretained,andasingleboosterdosegiven60monthspostcompletionoftheHPV
vaccination protocol has been shown to produce a strong anamnestic increase in antibody
titers, not seen in nonimmune subjects, with continued sustained efficacy typical of many
vaccines(282).
Inyounger vaccinees(<15years), 2-dose schedules arenow supported forallvaccine
types, with 3-dose vaccination still required for older adolescents and adults. Ongoing
research into the potential viability of 1-dose regimes in preadolescents and young
adolescentsisunderway.Thisisapotentialmechanismbywhichtheviabilityoflarge-scale
high-coveragevaccinationinitiativescouldbeincreased,notablyinlow-andmiddle-income
countries (284–288). Reduced dose schedules reduce the cost of HPV vaccination, so
increase its cost-effectiveness, which is also of considerable importance in low resource
settings.Amajorongoing trialinCosta Rica,run by theU.S. NationalCancer Institute,is
expectedtoprovideimportantnewinformationontheeffectivenessof1-doseschedules.
VaccineSafety
By 2017, over 170 million doses of HPV vaccine had been given. A2017 review of the
worldwide experience by the WHO’s Global Advisory Committee on Vaccine Safety
(GACVS) concluded, “Early on, the Committee was presented signals related to
anaphylaxis and syncope. The risk of anaphylaxis has been characterized as
approximately1.7 cases per million doses, and syncope was established as a common
anxietyorstress-relatedreactiontotheinjection.Nootheradversereactionshavebeen
identified and GACVS considers HPV vaccines to be extremely safe” (289,290).
Althoughvaccinationinpregnancyisnotrecommended,HPVvaccinationdoesnotappearto